COMBINATION THERAPY EMPLOYING ILEAL BILE ACID TRANSPORT INHIBITING BENZOTHIEPINES AND HMG Co-A REDUCTASE INHIBITORS

This application claims the benefit of priority of U.S. provisional application Serial No. 60/040,660, filed March 11, 1997. This application is also a continuation- in-part application of U.S. Serial No. 08/831,284, filed March 31, 1997, which is a continuation application of U.S. Serial No. 08/517,051, filed August 21, 1995, which is a continuation-in-part application of U.S. Serial No.

08/305,526 filed September 12, 1994; and is a continuation-in-part application of U.S. Serial No.

08/816,065, filed March 11, 1997, which claims priority from U.S. provisional application Serial No. 60/013,119, filed March 11, 1996.

BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to novel benzothiepines, derivatives and analogs thereof, in combination with HMG Co-A reductase inhibitors, pharmaceutical compositions containing them, and use of these compositions in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions such as is associated with atherosclerosis or hypercholesterolemia, in mammals.

Description of Related Art It is well-settled that hyperlipidemic conditions associated with elevated concentrations of total cholesterol and low-density lipoprotein cholesterol are major risk factors for coronary heart disease and particularly atherosclerosis. Interfering with the circulation of bile acids within the lumen of the intestinal tract is found to reduce the levels of serum cholesterol in a causal relationship. Epidemiological data has accumulated which indicates such reduction leads to an improvement in the disease state of

atherosclerosis. Stedronsky, in "Interaction of bile acids and cholesterol with nonsystemic agents having hypocholesterolemic properties," Biochimica et Biohvsica Acta, 1210 (1994) 255-287 discusses the biochemistry, physiology and known active agents surrounding bile acids and cholesterol.

Pathophysiologic alterations are shown to be consistent with interruption of the enterohepatic circulation of bile acids in humans by Heubi, J.E., et al. See "Primary Bile Acid Malabsorption: Defective in Vitro Ileal Active Bile Acid Transport", Gastroenteroloov, 1982:83:804-11.

In fact, cholestyramine binds the bile acids in the intestinal tract, thereby interfering with their normal enterohepatic circulation (Reihnr, E. et al, in "Regulation of hepatic cholesterol metabolism in humans: stimulatory effects of cholestyramine on HMG- CoA reductase activity and low density lipoprotein receptor expression in-gallstone patients", Journal of Livid Research, Volume 31, 1990, 2219-2226 and Suckling el al, "Cholesterol Lowering and bile acid excretion in the hamster with cholestyramine treatment", Atherosclerosis, 89(1991) 183-190). This results in an increase in liver bile acid synthesis by the liver using cholesterol as well as an upregulation of the liver LDL receptors which enhances clearance of cholesterol and decreases serum LDL cholesterol levels.

In another approach to the reduction of recirculation of bile acids, the ileal bile acid transport system is a putative pharmaceutical target for the treatment of hypercholesterolemia based on an interruption of the enterohepatic circulation with specific transport inhibitors (Kramer, et al, "Intestinal Bile Acid Absorption" The Journal of Bioloaical Chemistry, Vol. 268, No. 24, Issue of August 25, pp. 18035-18046, 1993).

In a series of patent applications, eg Canadian Patent Application Nos. 2,025,294; 2,078,588; 2,085,782; and 2,085,830; and EP Application Nos. 0 379 161; 0 549 967; 0 559 064; and 0 563 731, Hoechst Aktiengesellschaft discloses polymers of various naturally occurring constituents of the enterohepatic circulation system and their derivatives, including bile acid, which inhibit the physiological bile acid transport with the goal of reducing the LDL cholesterol level sufficiently to be effective as pharmaceuticals and; in particular for use as hypocholesterolemic agents.

In vitro bile acid transportinhibition is disclosed to show hypolipidemic activity in The Wellcome Foundation Limited disclosure of the world patent application number WO 93/16055 for "Hypolipidemic Benzothiazepine Compounds" Selected benzothiepines are disclosed in world patent application number W093/321146 for numerous uses including fatty acid metabolism and coronary vascular diseases.

Other selected benzothiepines are known for use as hypolipaemic and hypocholesterolaemic agents, especially for the treatment or prevention of atherosclerosis as disclosed by application Nos. EP 508425, FR 2661676, and WO 92/18462, each of which is limited by an amide bonded to the carbon adjacent the phenyl ring of the fused bicyclo benzothiepine ring.

The above references show continuing efforts to find safe, effective agents for the prophylaxis and treatment of hyperlipidemic diseases and their usefulness as hypocholesterolemic agents.

Additionally selected benzothiepines are disclosed for use in various disease states not within the present invention utility. These are EP 568 898A as abstracted by Derwent Abstract No. 93-351589; WO 89/1477/A as abstracted in Derwent Abstract No. 89-

370688; U.S. 3,520,891 abstracted in Derwent 50701R-B; US 3,287,370, US 3,389,144; US 3,694,446 abstracted in Derwent Abstr. No. 65860T-B and WO 92/18462.

HMG Co-A reductase inhibitors have been used as cholesterol-lowering agents. This class of compounds inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG Co- A) reductase. This enzyme catalyzes the conversion of HMG Co-A to mevalonate, which is an early and rate- limiting step in the biosynthesis of cholesterol.

Benzothiazepine anti-hyperlipidemic agents are disclosed in WO 94/18183, WO 94/18184, WO 96/05188, WO 96/16051, AU-A-30209/92, AU-A-61946/94, AU-A-61948/94, and AU-A- 61949/94.

The present invention furthers such efforts by providing novel pharmaceutical compositions and methods for the treatment of hyperlipidemic conditions.

SUMMARY OF THE INVENTION Accordingly, among its various apects, the present invention provides compounds of formula (I): wherein: q is an integer from 1 to 4; n is an integer from 0 to 2; R1 and R2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl,

dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N+R9R10RWA-, SR9, S+R9R10A-, P+R9R10R1A-, S(O)R9, SO2R9, SO3R9, C02R9, CN, halogen, oxo, and CONR9R10, wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl . optionally have one or more carbons replaced by 0, NR9, N+R9R10A-, S, SO, SO2, S+R9A-, P+R9R10A-, or phenylene. wherein R9, R10, and Rw are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, heteroaryl, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; or R1 and R2 taken together with the carbon to which they are attached form C1-C10 cycloalkylidene; R3 and R4 are independently selected from the <BR> <BR> <BR> group consisting of H, alkyl, alkenyl, alkynyl,<BR> heteroaryl,<BR> <BR> <BR> <BR> <BR> acyloxy, aryl, heterocycle, OR9, NR9R10, SR9, S(O)R9, SO2R9, and SO3R9, wherein R9 adn R10 are as defined above; or R3 and R4 together form =0, =N0R11, S, =NNR11R12, =NR9, or = CR11R12, wherein R11 and R12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heteroaryl,<BR> <BR> <BR> heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR9, NR9R10, SR9, S(O)R9, SO2R9, SO3R9. C02R9, CN, halogen, oxo, and CONR9R10,

wherein R9 and R10 are as defined above, provided that both R3 and R4 cannot be OH, NH2 and SH, or R1l and R12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; R5 and R6 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, quaternary heterocycle, quaternary @@@@@@@@@ SR9 S(O)R9 SOR9 and SO@R9 heteroaryl, SR ,S(O)R , @@2@ , and @@3@@ wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocycle, quaternary heterocycele, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR13, NR13R14, SR13, S(O)R13, SO2R13, SO3R13, NR13OR143, NR13NR14R15, NO2, CO2R13, CN, OM, S020M, 502NR13R14, C(O)NR13R14, C(O)OM, COR13, P(O)R13R14, P+R13R14R15A-, P(OR13)OR14, S+R13R14A-, and N+R9R11R12A-, wherein: A is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can be further substituted with one or more substituent groups selected from the group consisting of OR7, NR7R8, SR7, S(O)R7, SO2R7, SO3R7, CO2R7, CN, oxo, CONR7R8, N+R7R8R9A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary

heterocycle, quaternary heteroaryl, P(O)R7R8, P+R7R8R9A-, and P(O) (OR7) OR8, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl,heterocycle and heteroaryl can optionally have one or more carbons replaced by 0, NR7, N+R7R8A-, S, SO, SO2, S+R7A-, PR7, P(O)R7, P+R7R8A-, or phenylene, and R13, R14, and R15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heteroaryl, heterocycle, and polyalkyl optionally have one or more carbons replaced by 0, NR9, N+R9R10A-, S, SO, S02, S+R9A, PR9, P+R9R10A-, P(O)R', phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R13, R14, and R15 are optionally substituted with one or more groups selected from the group consisting of sulfoal, quaternary heterocycle, quaternary heteroaryl, OR9 NR9R1O, N+R9R11R12A-, SR9, S(O)R9, S02R9, SO3R9, oxo, C02R9, CN, halogen, CONR9R10, SO2OM, SO2NR9R10, PO(OR16)OR17, P+R9R10R11A-, S+R9R10A-, and C(O)CM, wherein R16 and R17 are independently selected from the substituents constituting R9 and M; or R14 and R15, together with the nitrogen atom to which they are attached, form a cyclic ring; R7 and R8 are independently selected from the group consisting of hydrogen and alkyl; and one or more RX are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen,

haloalkyl, cycloalkyl, heterocycle, heteroarylp polyether, quaternary heterocycle, quaternary heteroaryl, OR13, NR13R14, SR13, S(O)R13, S(O)2R13, SO3R13, S+R13R14A-, NR13OR14, NR13NR14R15, NO2, CO2R13, CN, OM, SO2OM, SO2NR13R14, NR14C(O)R13, C(O)NR13R14, NR14C(O)R13, C(O)OM, COR13, OR18, S(O)nNR18, NR13R18, NR18OR14, N+R9R11R12A-, P+R9R11R12A-, amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, polyalkyl, heterocycle, acyloxy, arylalkyl, heloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR9, NR9R10, N+R9R11R12A-, SR9, S(O)R9, SO2R9, SO3R9, oxo, CO2R9, CN, halogen, CONR9R10, SO2OM, SO2NR9R10, PO(OR16)OR17, P+R9R11R12A-, S+R9R10A-, or C(O)OM, and wherein R18 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl\ quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group consisting of OR9 NR9R10, N+R9R11R12A-, SR9, S(O)R9, SO2R9, SO3R9, oxo, CO2R9, CN, halogen, CONR9R10, SO3R9, SO2OM, SO2NR9R10, PO(OR16)OR17, and C(O)OM, wherein in RX, one or more carbons are optionally replaced by O, NR13, N+R13R14A-, S, SO, SO2, S+R13A-, PR13, p(O)R13 P+R13 R14A-, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl,

wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by 0, NR9, N+R9R10A-, <BR> <BR> <BR> <BR> S, SO, SO2, S+R9A-, PR9, P+R9R10A-, or P(O)R9;<BR> heteroaryl,<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S(O)R13, SO2R13, SO3R13, NR13OR14, NR14NR14R15, NO2, CO2R14, CN, OM, SO2OM, SO2NR13R14, C(O)NR13R14, C(O)OM, COR13, P(O)R13R14, P+R13R14R15A-, P(OR13)OR14, S+R13R14A-, and N+R9R11R12A-, provided that both R5 and R6 cannot be hydrogen, OH, or SH, and when R5 is OH, R1, R2, R3, R4, R7 and R8 cannot be all hydrogen; provided that when R5 or R6 is phenyl, only one of R1 or R is H; provided that when q = 1 and Rx is styryl, anilido, or anilinocarbonyl, only one of R5 or R6 is alkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

Preferably, R5 and R6 can independently be selected from the group consisting of H, aryl, heteroaryl, heterocycle, quaternary heterocycle, and quaternary heteroaryl, wherein said aryl, heterocycle, heteroaryl, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of <BR> <BR> <BR> <BR> alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,<BR> heterparyl,<BR> <BR> <BR> <BR> <BR> <BR> haloalkyl, cycloalkyl, heterocycle, arylalkyl, helogen, oxo, OR13, NR13R14, SR13, S(O)R13, SO2R13, SO3R13,

NR13OR14, NR13NR14R15, N02, C02R13, CN, OM, S020M, SO2NR13R14, C(O)NR13R14, C(O)OM, COR13, P(O)R13R14, P+R13R14R15A-, P(OR13)OR14, S+R13R14A-, and N+R9R11R12A-, wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can optionally have one or more carbons replaced by 0, NR7, N+R7R8A-, S, SO, SO2, S+R7A-, PR7, P(O)R7 P+R7R8A-, or phenylene, wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can be further substituted with one or more substituent groups selected from the group consisting of OR7, NR7R8, SR7, S(O)R7, SO2R7, SO3R7,CO2R7, CN, oxo, <BR> <BR> <BR> <BR> <BR> <BR> CONR7R8, N+R7R8R9A-, alkyl, alkenyl, alkynyl, aryl,<BR> <BR> hereroaryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R7R8, P+R7R8R9A-, and P(O) (OR7) OR9.

More preferably, R5 or R6 has the formula: -Ar-(RY)t wherein: t is an integer from 0 to 5; Ar is selected from the group consisting of phenyl, thiophenyl, pyridyl, piperazinyl, piperonyl, pyrrolyl, naphthyl, furanyl, anthracenyl, quinolinyl, isoquinolinyl, quinoxalinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrimidinyl, thiazolyl, triazolyl, isothiazolyl, indolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, and benzoisothiazolyl; and one or more RY are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl,

cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroary OR9, SR9, S(O)R9, SO2R9, and SO3R9, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkvl. heterocycle, and heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S(O)R13, SO2R13, SO3R13, NR13OR14, NR13NR14R15, NO2, CO2R13, CN, OM, S020M, S02NR13R14, C(O)NR13R14, C(O)OM, COR13, P(O)R13R14, P+R13R14R15A-, P(OR13)OR14, S+R13R14A-, and N+R9R11R12A-, wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, heloalkyl, cycloalkyl, heterocycle, and heteroaryl can be further substituted with one or more substituent quoups selected from the group consisting of OR7, NR7R8, SR7, S(O)R7, SO2R7, SO3R7, CO2R7, CN, oxo, CONR7R8, N+R7R@R@A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quateroary heterocycle, quaternary heteroaryl, P(O)R7R8, P+R7R8R9A-, and P(O) (OR7) OR8, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, and heteroaryl can optionally have one or more carbons replaced by 0, NR7, N+R7R8A-, S, SO, SO2, S+R7A-, PR7, P(O)R7, P+R7R8A-, or phenylene.

Most preferably, R5 or R6 has the formula (II) :

The invention is further directed to a compound selected from among: R20 - R19 - R21 (Formula DI) and wherein Rl' is selected from the group consisting of alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can optionally have one or more carbon atoms replaced by 0, NR7, N+R7R8, S, SO, S02, S +R7R8,

PR7, P +P7R8, phenylene, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, or aryl, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl1 haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S(O)R13, SO2R13, SO3R13, NR13OR14, NR13NR14R15, NO2, CO2R13, CN, OM, SO2OM, SO2NR13R14, C9O)NR13R14, C(O)OM, COR13, P(O)R13R14, P+R13R14R15A-, P(OR13)OR14, S+R13414A-, and N+R9R11R12A-, wherein R19 further comprises functional linkages by which Rl' is bonded to 420, R'1, or R22 in the compounds of Formulae DII and DIII, and R23 in the compounds of Formula DIII. Each of R2o, R21, or R422 and R" comprises a benzothiepine moiety as described above that is therapeutically effective in inhibiting ileal bile acid transport.

The invention is also directed to a compound selected from among Formula DI, Formula DII and Formula DIII in which each of R", R31, R22 and R" comprises a benzothiepine moiety corresponding to the Formula: (Formula DIV) or:

(Formula DIVA) wherein R1, R2, R3, R4, R5, R6, R7, R8, Rx, q, and n are as defined in Formula I as described above, and R'5 is either a covalent bond or arylene.

In compounds of Formula DIV, it is particularly preferred that each of R20, R21, and R22 in Formulae DII and DIII, and R in Formula DIII, be bonded at its 7- or 8-position to R29. In compounds of Formula DIVA, it is particularly preferred that R55 comprise a phenylene moiety bonded at a m- or p-carbon thereof to Rl9.

Examples of Formula DI include:

and In any of the dimeric or multimeric structures discussed immediately above, benzothiepine compounds of the present invention can be used alone or in various combinations.

In any of the compounds of the present invention, Rl and R2 can be ethyl/butyl or butyl/butyl.

Other compounds useful in the present invention as ileal bile acid transport inhibitors are shown in Appendix A.

In another aspect, the present invention provides a pharmaceutical composition for the prophylaxis or treatment of a disease or condition for which a bile acid transport inhibitor is indicated, such as a hyperlipidemic condition, for example, atherosclerosis.

Such compositions comprise any of the compounds disclosed above, alone or in combination, in an amount effective to reduce bile acid levels in the blood, or to reduce transport thereof across digestive system membranes, and a pharmaceutically acceptable carrier, excipient, or diluent.

In a further aspect, the present invention also provides a method of treating a disease or condition in mammals, including humans, for which a bile acid transport inhibitor is indicated, comprising administering to a patient in need thereof a compound of the present invention in an effective amount in unit dosage form or in divided doses.

In yet a further aspect, the present invention also provides processes for the preparation of compounds of the present invention.

In yet another aspect, the present invention provides a combination therapy comprising the use of a first amount of an ileal bile acid transport inhibitor and a second amount of a HMG Co-A reductase inhibitor useful to treat hyperlipidemic disorders, wherein said first and second amounts together comprise an anti- hyperlipidemic condition effective amount of said compounds.

HMG Co-A reductase inhibitor compounds useful in the present invention are shown in Appendix B.

Further scope of the applicability of the present invention will become apparent from the detailed description provided below. However, it should be

understood that the following detailed dscription and examples, while indicating preferred embodiments of the invention, are given by way of illustration only since various changes and modifications within the spirit and scope of the invention will beomce apparent to those skilled in the art from this detailed description.

DETAILED DESCRIPTION OF THE INVENTION The following detailed description is provided to aid those skilled in the art in practicing the present invention. Even so, this detailed description should not be construed to unduly limit the present invention as modifications and variations in the emobodiments discussed herein can be made by those of ordinary skill in the art without departing from the spirit or scope of the present inventive discovery.

The contents of each of the references cited herein, including the contents of the references cited within these primary references, are herein incorporated by reference in their entirety.

Definitions In order to aid the reader in understanding the following detailed description, the following definitions are provided: "Alkyl", "alkenyl," and "alkynyl" unless otherwise noted are each straight chain or branched chain hydrocarbons of from one to twenty carbons for alkyl or two to twenty carbons for alkenyl and alkynyl in the present invention and therefore mean, for example, methyl, ethyl, propyl, butyl, pentyl or hexyl and ethenyl, propenyl, butenyl, pentenyl, or hexenyl and ethynyl, propynyl, butynyl, pentynyl, or hexynyl respectively and isomers thereof.

"Aryl" means a fully unsaturated mono- or multi- ring carbocyle, including, but not limited to,

substituted or unsubstituted phenyl, naphthyl, or anthracenyl.

"Heterocycle" means a saturated or unsaturated mono- or multi-ring carbocycle wherein one or more carbon atoms can be replaced by N, S, P, or 0. This includes, for example, the following structures: wherein Z, Z', Z or Z"' is C, S, P, O, or N, with the proviso that one of Z, Z', Zn or zn &num is other than carbon, but is not 0 or S when attached to another Z atom by a double bond or when attached to another 0 or S atom. Furthermore, the optional substituents are understood to be attached to Z, Z', zn or Zn, only when each is C.

The term "heteroaryln means a fully unsaturated heterocycle.

In either "heterocyclen or "heteroaryl, " the point of attachment to the molecule of interest can be at the heteroatom or elsewhere within the ring.

The term "quaternary heterocycle" means a heterocycle in which one or more of the heteroatoms, for example, 0, N, S, or P, has such a number of bonds that it is positively charged. The point of attachment of the quaternary heterocycle to the molecule of interest can be at a heteroatom or elsewhere.

The term "quaternary heteroaryln means a heteroaryl in which one or more of the heteroatoms, for example, 0, N, S, or P, has such a number of bonds that it is positively charged. The point of attachment of the quaternary heteryaryl to the molecule of interest can be at a heteroatom or elsewhere.

The term "halogen" means a fluoro, chloro, bromo or iodo group.

The term "haloalkyl" means alkyl substituted with one or more halogens.

The term "cycloalkyl" means a mono- or multi- ringed carbocycle wherein each ring contains three to ten carbon atoms, and wherein any ring can contain one or more double or triple bonds.

The term "diyl" means a diradical moiety wherein said moiety has two points of attachment to molecules of interest.

The term "oxo means a doubly bonded oxygen.

The term "polyalkyl" means a branched or straight hydrocarbon chain having a molecular weight up to about 20,000, more preferably up to about 10,000, most preferably up to about 5,000.

The term "polyether" means a polyalkyl wherein one or more carbons are replaced by oxygen, wherein the polyether has a molecular weight up to about 20,000, more preferably up to about 10,000, most preferably up to about 5,000.

The term "polyalkoxy" means a polymer of alkylene oxides, wherein the polyalkoxy has a molecular weight up to about 20,000, more preferably up to about 10,000, most preferably up to about 5,000.

The term "cycloaklylidenen means a mono- or multi- ringed carbocycle wherein a carbon within the ring structure is doubly bonded to an atom which is not within the ring structures.

The term "carbohydrate" means a mono-, di-, tri-, or polysaccharide wherein the polysaccharide can have a molecular weight of up to about 20,000, for example, hydroxypropyl-methylcellulose or chitosan.

The term "peptide" means polyamino acid containing up to about 100 amino acid units.

The term "polypeptide" means polyamino acid containing from about 100 amino acid units to about

1000 amino acid units, more preferably from about 100 amino acid units to about 750 amino acid untis, most preferably from about 100 amino acid units to about 500 amino acid units.

The term "alkylammoniumalkyl" means a NH2 group or a mono-, di- or tri-substituted amino group, any of which is bonded to an alkyl wherein said alkyl is bonded to the molecule of interest.

The term "triazolyl" includes all positional isomers. In all other heterocycles and heteroaryls which contain more than one ring heteroatom and for which isomers are possible, such isomers are included in the definition of said heterocycles and heteroaryls.

The term "sulfoalkyl means an alkyl group to which a sulfonate group is bonded, wherein said alkyl is bonded to the molecule of interest.

The term "active compounds means a compound of the present invention which inhibits transport of bile acids.

When used in combination, for example "alkylaryl" or "arylalkyl," the individual terms listed above have the meaning indicated above.

The term "a bile acid transport inhibitor" means a compound capable of inhibiting absorption of bile acids from the intestine into the circulatory system of a mammal, such as a human. This includes increasing the fecal excretion of bile acids, as well as reducing the blood plasma or serum concentrations of cholesterol and cholesterol ester, and more specifically, reducing LDL and VLDL cholesterol. Conditions or diseases which benefit from the prophylaxis or treatment by bile acid transport'inhibition include, for example, a hyperlipidemic condition such as atherosclerosis.

The phrase "combination therapy refers to the administration of an ileal bile acid transport inhibitor and a HMG Co-A reductase inhibitor to treat a hyperlipidemic condition, for example atherosclerosis

and hypercholesterolemia. Such administration encompasses co-administration of these inhibitors in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each inhibitor agent. In addition, such administration also encompasses use of each type of inhibitor in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the hyperlipidemic condition.

The phrase "theraputically effective" is intended to qualify the combined amount of inhibitors in the combination therapy. This combined amount will achieve the goal of reducing or eliminating the hyperlipidemic condition.

Compounds The compounds of the present invention can have at least two asymmetrical carbon atoms, and therefore include racemates and stereoisomers, such as diastereomers and enantiomers, in both pure form and in admixture. Such stereoisomers can be prepared using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present invention.

Isomers may include geometric isomers, for example cis isomers or trans isomers across a double bond. All such isomers are contemplated among the compounds of the present invention.

The compounds of the present invention also include tautomers.

The compounds of the present invention as discussed below include their salts, solvates and prodrugs.

Compound Syntheses

The starting materials for use in the preparation of the compounds of the invention are known or can be prepared by conventional methods known to a skilled person or in an analogous manner to processes described in the art.

Generally, the compounds of the present invention can be prepared by the procedures described below.

For example, as shown in Scheme I, reaction of aldehyde II with formaldehyde and sodium hydroxide yields the hydroxyaldehyde III which is converted to mesylate IV with methanesulfonyl chloride and triethylamine similar to the procedure described in Chem. Ber. 98, 728-734 (1965). Reaction of mesylate IV with thiophenol V, prepared by the procedure described in WO 93/16055, in the presence of triethylamine yields keto-aldehyde VI which can be cyclized with the reagent, prepared from zinc and titanium trichloride in refluxing ethylene glycol dimethyl ether (DME), to give a mixture of 2,3-dihydrobenzothiepine VII and two racemic steroisomers of benzothiepin-(5H)-4-one VIII when R1 and R2 are nonequivalent. Oxidation of VII with 3 equivalents of m-chloro-perbenzoic acid (MCPBA) gives isomeric sulfone-epoxides IX which upon hydrogenation with palladium on carbon as the catalyst yield a mixture of four racemic stereoisomers of 4-hydroxy- 2,3,4,5-tetrahydrobenzothiepine-1,1-dioxides X and two racemic stereoisomers of 2,3,4,5-tetrahydro- benzothiepine-l,1-dioxides XI when R' and R2 are nonequivalent.

Optically active compounds of the present invention can be prepared by, using optically active starting material III or by resolution of compounds X with optical resolution agents well known in the art as described in J.

Org. Chem., 39, 3904 (1974), ibid., 42, 2781 (1977), and ibid., 44, 4891 (1979).

Scheme 1 PATENT HCOH.NOH RIR MICVet )N R R1 R20 ---F Fr s-R H g C7 R1 R1 C R H i s3" a, a R1 S. R2 1StR2 n n L? e8 ? eP i ir, SORIR 12 ½i$;lSO1;lR: C' R2 Alternatively, keto-aldehyde VI where R2 is H can be prepared by reaction of thiophenol V with a 2- substituted acrolein.

PAEJT 8H o C 4 0 51S S H ¼;Rs (wx vi Benzothiepin-(5H)-4-one VIII can be oxidized with MCPBA to give the benzothiepin-(5H)-4-one-ll-dioxide XII which can be reduced with sodium borohydride to give four racemic stereoisomers of X. The two stereoisomers of X, Xa and Xb, having the OH group and Rs on the opposite sides of the benzothiepine ring can be converted to the other two isomers of X, Xc and Xd, having the OH group and R5 on the same side of the benzothiepine ring by reaction in methylene chloride with 40-50% sodium hydroxide in the presence of a phase transfer catalyst (PTC). The transformation can also be carried out with potassium t-butoxide in THF.

2MCPBA~ PvENT 80 ff VI I ? f R2 NaOH. 202 tClaI R2 Ra OH or k ----------f 80R1 80 <, R, < ql'I R2 Ra OH OH Ra n Xn R ," , R2w Et, R P)S XI Y p 1 X .biXb OCIX: ed.Xd The compounds of the present invention where R5 is OR, NRR' or S(O)R and R4 is hydroxy can be prepared by reaction of epoxide IX where R5 is H with thiol, alcohol, or amine in the presence of a base.

R7 R2 R1 R2 ( R") HOR, or HNRR1 or HS(O),R base R7 R8 S Ro R2 (R') OH R5 Rs = OR, NRRl, S(O)aR Another route to Xc and Xd of the present invention is shown in Scheme 2. Compound VI is oxidized to compound XIII with two equivalent of m-chloroperbenzoic acid.

Hydrogenolysis of compound XIII with palladium on carbon yields compound XIV which can be cyclized with either potassium t-butoxide or sodium hydroxide under phase transfer conditions to a mixture of Xc and Xd.

Separation of Xc and Xd can be accomplished by either HPLC or fractional crystallization.

The thiophenols XVIII and V used in the present invention can also be prepared according to the Scheme 3. Alkylation of phenol XV with an arylmethyl chloride in a nonpolar solvent according to the procedure in J.

Chem. Soc., 2431-2432 (1958) gives the ortho substituted phenol XVI. The phenol XVI can be converted to the thiophenol XVIII via the thiocarbamate XVII by the procedure described in J. Org. Chem., 31, 3980 (1966). The phenol XVI is first reacted with dimethyl thiocarbamoyl chloride and triethylamine to give thiocarbamate XVII which is thermally rearranged at 200-300 OC, and the rearranged product is hydrolyzed with sodium hydroxide to yield the thiophenol XVIII.

Similarly, Thiophenol V can also be prepared from 2- acylphenol XIX via the intermediate thiocarbamate XX.

1<BR> a 2 1 I > RtRg gI R; H f I H < H J I I xr (x)$aVR r rR) (RXe xy vr wr KOrBu a .',&flI +fl'IIIR 1 (<)4 5 OH OH

Scheme 3 PATENT OH ½' 8 oA NX 1 1. A OH t 2. NOH 8H {½)a f" 2 1)Ra 1)Ra XYI XMII 8 on kt , t C R #x Ra R0 V Scheme 4 shows another route to benzothiepine-l,l- dioxides Xc and Xd starting from the thiophenol XVIII.

Compound XVIII can be reacted with mesylate IV to give the sulfide-aldehyde XXI. Oxidation of XXI with two equivalents of MCPBA yields the sulfone-aldehyde XIV which can be cyclized with potassium t-butoxide to a mixture of Xc and Xd. Cyclyzation of sulfide-aldehyde with potassium t-butoxide also gives a mixture of benzothiepine XXIIc and XXIId.

Scheme 4 PATENT aH RI Ra e7 RI H ¼MRlRIH nbC FuzzJ so, i) Ra C Ra Ra t R $ X H xvg ~ (RK $ C R2 ?' KDIBU RI RI so RI P7 R2 + I =Ra"" It: Ra OH Ra"'OH xD TCIRa <1 11II1 Rt Ra Examples of amine- and hydroxylamine-containing compounds of the present invention can be prepared as shown in Scheme 5 and Scheme 6. 2-Chloro-5- nitrobenzophenone is reduced with triethylsilane and trifluoromethane sulfonic acid to 2-chloro-5- nitrodiphenylmethane 32. Reaction of 32 with lithium sulfide followed by reacting the resulting sulfide with mesylate IV gives sulfide-aldehyde XXIII. Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone- aldehyde XXIV which can be reduced by hydrogenation to the hydroxylamine XXV. Protecting the hydroxylamine XXV with di-t-butyldicarbonate gives the N,O-di-(t-

butoxycarbonyl)hydroxylamino derivative XXVI.

Cyclization of XXVI with potassium t-butoxide and removal of the t-butoxycarbonyl protecting group gives a mixture of hydroxylamino derivatives XXVIIc and XXVIId. The primary amine XXXIIIc and XXXIIId derivatives can also be prepared by further hydrogenation of XXIV or XXVIIc and XXVIId.

Scheme 5 SR 6046 t 2 N02 2 ;02n R3 }e2Rr N N I-dtrcEacnne ,S R2 I 02 Y'PdlC nm ¼ oTh N(B0C)O(BOC) ,ocvz pOCa== thrtrmddc NH6HxXV HOHN I' H etc HOHN £ OH Pt: HOHN OH Ph Ptc.ioo 5D.C i 50 c m + Ph OH Ph OH H2O Ph = In Scheme 6, reduction of the sulfone-aldehyde XXV with hydrogen followed by reductive alkylation of the resulting amino derivative with hydrogen and an aldehyde catalyzed by palladium on carbon in the same reaction vessel yields the substituted amine derivative

Scheme 6 0 'ton, HrNCR o C,ti oo W X IC, X»l cH goal It ng XXVIII. Cyclization of XXVIII with potassium t-butoxide yields a mixture of substituted amino derivatives of this invention XXIXc and XXIXd.

Scheme 7 describes one of the methods of introducing a substituent to the aryl ring at the 5- position-of benzothiepine. Iodination of 5-phenyl derivative XXX with iodine catalyzed by mercuric triflate gives the iodo derivative XXXI, which upon palladium-catalyzed carbonylation in an alcohol yields the carboxylate XXXII. Hydrolysis of the carboxylate

Scheme 7 o RI RI a t 12 25 C OK OH zooa )oOC co'R7OH \ / looc RI "ill Ra OK 0 RI ~ l and derivatization of the resulting acid to acid derivatives are well known in the art.

Abbreviations used in the foregoing description have the following meanings: THF---tetrahydrofuran

PTC---phase transfer catalyst Aliquart 336---methyltricaprylylammonium chloride MCPBA---m-chloroperbenzoic acid Celite--- a brand of diatomaceous earth filtering aid DMF---dimethylformamide DME----ethylene glycol dimethyl ether BOC---t-butoxycarbonyl group R' and R2 can be selected from among substituted and unsubstituted C1 to C10 alkyl wherein the substituent(s) can be selected from among alkylcarbonyl, alkoxy, hydroxy, and nitrogen-containing heterocycles joined to the Cl to C10 alkyl through an ether linkage. Substituents at the 3-carbon can include ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, -CH2C(=O)CzH5, -CH2OC2H5, and -CH2O- (4- picoline). Ethyl, n-propyl, n-butyl, and isobutyl are preferred. In certain particularly preferred compounds of the present invention, substituents Rl and R2 are identical, for example n-butyl/n-butyl, so that the compound is achiral at the 3-carbon. Eliminating optical isomerism at the 3-carbon simplifies the selection, synthesis, separation, and quality control of the compound used as an ileal bile acid transport inhibitor. In both compounds having a chiral 3-carbon and those having an achiral 3-carbon, substituents (RX) on the benzo- ring can include hydrogen, aryl, alkyl, hydroxy, halo, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkyl, haloalkoxy, (N)-hydroxy- carbonylalkyl amine, haloalkylthio, haloalkylsulfinyl, haloalkylsufonyl, amino, N-alkylamino, N,N- dialkylamino, (N)-alkoxycarbamoyl, (N)- aryloxycarbamoyl, (N) -aralkyloxycarbamoyl, trialkyl- ammonium (especially with a halide counterion), (N)- amido, (N) -alkylamido, -N-alkylamido, -N,N-

dialkylamido, (N)-haloalkylamido, (N)-sulfonamido, (N)- alkylsulfonamido, (N)-haloalkylsulfonamido, carboxyalkylamino, trialkyl-ammonium salt, (N)-carbamic acid, alkyl or benzyl ester, N-acylamine, hydroxylamine, haloacylamine, carbohydrate, thiophene a trialkyl ammonium salt having a carboxylic acid or hydroxy substituent on one or more of the alkyl substituents, an alkylene bridge having a quaternary ammonium salt substituted thereon, -[O(CH2)w]X-X where x is 2 to 12, w is 2 or 3 and X is a halo or a quaternary ammonium salt, and (N)-nitrogen containing heterocycle wherein the nitrogen of said heterocycle is optionally quaternized. Among the preferred species which may constitute Rx are methyl, ethyl, isopropyl, t-butyl, hydroxy, methoxy, ethoxy, isopropoxy, methylthio, iodo, bromo, fluoro, methylsulfinyl, methylsulfonyl, ethylthio, amino, hydroxylamine, N-methylamino, N,N- dimethylamino, N, N-diethylamino, (N) -benzyloxycarbamoyl, trimethylammonium, A-, -NHC(=O)CH3, -NHC(=O)C5H,l, -NHC(=O)C6H,3, carboxyethylamino, (N)-morpholinyl, (N)-azetidinyl, (N) -N-methylazetidinium A-, (N) -pyrrolidinyl, pyrrolyl, (N) -N-methylpyridinium A, (N) -N-methylmorpholinium A-, and N-N'-methylpiperazinyl, (N)-bromomethylamido, (N)- N-hexylamino, thiophene, -N (CH,)2CO2H I-, -NCH3CH2CO2H, - (N) -N' -dimethylpiperazinium I, (N)-t- butyloxycarbamoyl, (N)-methylsulfonamido, (N)N' - methylpyrrolidinium, and -(OCH2CH2),I, where A- is a pharmaceutically acceptable anion. The benzo ring can be mono-substituted at the 6, 7 or 8 position, or disubstituted at the 7- and -8 positions. Also included are the 6,7,8-trialkoxy compounds, for example the 6,7,8-trimethoxy compounds. A variety of other substituents can be advantageously present on the 6, 7, 8, and/or 9- positions of the benzo ring, including, for example, guanidinyl, cycloalkyl, carbohydrate (e.g., a 5 or 6 carbon monosaccharide), peptide, and quaternary ammonium salts linked to the ring via poly(oxyalkylene) linkages, e.g., -(OCH2CH2)x-NR+R13R14R15A-, where x is 2 to 10. Exemplary compounds are those set forth below in Table 1.

TABLE 1 Alternative compounds #3 (Family F101.xxx.yyy) * Prefix Cpd# R1=R2 R5 (Rx)q (FFF.xxx. vvv).

F101.001 01 n-propyl Ph- 7-methyl 02 n-propyl Ph- 7-ethyl 03 n-propyl Ph- 7-iso-propyl 04 n-propyl Ph- 7-terz-butyl 05 n-propyl Ph- 7-OH 06 n-propyl Ph- 7-OCH3 07 n-propyl Ph- 7-O(iso-propyl) 08 n-propyl Ph- 7-SCH3 09 n-propyl Ph- 7-SOCH3 10 n-propyl Ph- -So2c:-:3 * General Notes In the description of the substituents (n)" indicates that a nitrogen bearing substituent is bonded to the ring structure via the nitrogen atom.

Similarly, 2-thiophene indicates a bond in the 2 position of the thiophene ring. A similar convention is used for other heterocyclic substituents.

Abbreviations and Definitions NH-CBZ is defined as -NHC(=O)OCH2Ph 11 n-propyl Ph- 7-SCH2CH3 12 n-propyl Ph- 7-NH2 13 n-propyl Ph- 7-NHOH 14 n-propyl Ph- 7-NHCH3 15 n-propyl Ph- 7-N(CH3)2 16 n-propyl Ph- 7-N+(cH3)3, I- 17 n-propyl Ph- 7-NHC(=O)CH3 18 n-propyl Ph- 7-N(CH2CH3)2 19 n-propyl Ph- 7-NMeCH2CO2H 20 n-propyl Ph- 7-N+(Me)2CHCO2H, I- 21 n-propyl Ph- 7-(N)-morpholine 22 n-propyl Ph- 7- (N) -azetidine 23 n-propyl Ph- 7-(N)-N-methylazetidinium, I- 24 n-propyl Ph- 7- (N) -pyrrolidine 25 n-propyl Ph- 7-(N)-N-methyl-pyrrolidinium, I.

26 n-propyl Ph- 7-(N)-N-methyl-morpholinium, I 27 n-propyl Ph- 7-(N)-N'-methylpiperazine 28 propyl Ph- 7-(N)-N'-dimethylpiperazinium, I- 29 n-propyl Ph- 7-NE-C3Z 30 n-propyl Ph- 7-NHC(O)C5H11 31 n-propyl Ph- 7-NHC(O)CH2Br 32 n-propy. Ph- 7-NH-C(NH)NH2 33 n-propyl Ph- 7-(2)-th ophene 34 n-propyl Ph- 8-methyl 35 n-propyl Ph- 8-ethyl 36 n-propyl Ph- 8-iso-propyl 37 n-propyl Ph- 8-tert-butyl 38 n-propyl Ph- 8-OH 39 propyl Ph- 8-OCH3 40 n-propyl Ph- 8-O(iso-propyl) 41 n-propyl Ph- 8-SCH3 42 n-propyl Ph- 8-SOCH3 43 n-propyl Ph- 8-SO2CH3 44 n-propyl Ph- 8-SCH2CH3 45 n-propyl Ph- 8-NH2 46 n-propyl Ph- 8-NHOH 47 n-propyl Ph- 8-NHCH3 48 propyl Ph- 8-N(CH3)2 49 n-propyl Ph- 8-N+(CH3)3, I- 50 n-propyl Ph- 8-NHC(=O)CH3 51 n-propyl Ph- 8-N(CH2CH3)2 52 n-propyl Ph- 8-NMeCH2C02H 53 n-propyl Ph- 8-N+(Me)2CH2CO2H,PATENT 54 n-propyl Ph- 8-(N)-morpholine 55 n-propyl Ph- 8-(N)-a:etidine 56 n-propyl Ph- 8-(N)-N-methylazetidinium, I- 57 n-propyl Ph- 8- (N) -pyrrolidine 58 n-propyl Ph- 8-(N)-N-methyl-pyrrolidinium, I- 59 n-propyl Ph- 8-(N)-N-methyl-morpholinium, I- 60 n-propyl Ph- 8-(N)-N'-methylpiperazine 61 n-propyl Ph- 8-(N)-N'-dimethylpiperazinium, I- 62 n-propyl Ph- 8-NH-CBZ 63 n-propyl Ph- 8-NHC(O)C5H11 64 n-propyl Ph- 8-NYHC(O)CH2Br 65 n-propyl Ph- 8-NH-C(NH)NH2 6G n-propyl Ph- 8-(2)-thiophene 67 n-propyl Ph- 9-methyl 68 n-propyl Ph- 9-ethyl 69 n-propyl Ph- 9-ito-propyl 70 n-propyl Ph- 9-tert-butyl 71 n-propyl Ph- 72 n-propyl Ph- 9-OCH3 73 n-propyl Ph- 9-O(iso-propyl) 74 n-propyl Ph- 9-SCH3 75 n-propyl Ph- 9-SOCH3 76 n-propyl Ph- 9-s02CR3 77 n-propyl Ph- 9-SCH2CH3 78 n-propyl Ph- 9-NH2 79 n-propyl Ph- 9-NHOH 80 n-propyl Ph- 9-NHCH3 81 n-propyl Ph- 9-N(CX3)2 82 n-propyl Ph- 9-N+(CH3)3, I- 83 n-propyl Ph- 9-NRC(-O)CH3 84 n-propyl Ph- 9-N(CH2CH3)2 85 n-propyl Ph- 9-NMeCH2C02H 86 n-propyl Ph- 9-N+(Me)2CH2CO2H, z- 87 n-propyl Ph- 9-(N)-morpholine 88 n-propyl Ph- 9-(N)-azetidine 89 n-propyl Ph- 9-(N)-N-methylazetidinium, I- 90 n-propyl Ph- 9-(N)-pyrrolidine 91 n-propyl Ph- 9-(N)-N-methyl-pyrrolidinium, I- 92 n-propyl Ph- 9-(N)-N-nethyl-morpholintum, I- 93 n-propyl Ph- 9-(N)-N'-methylpiperazine 93 n-propyl Ph- 9-(N) -N'-dimethylpipeIazinium, I- 95 n-propyl Ph- 9-NH-CBZ 96 n-propyl Ph- 9-NHC(O)C5H11 97 n-propyl Ph- 9-NHC(O)CH2Br 98 n-propyl Ph- 9-NH-C(NH)NH2 99 n-propyl Ph- 9-(2)-thiophene 100 n-propyl Ph- 7-OCH3, 8-OCH3 101 n-propyl Ph- 7-SCH3, 8-OCH3 102 n-propyl Ph- 7-SCH3, 8-SCH3 103 n-propyl Ph- 6-OCH3, 7-OCH3, 8-OCH3 Prefix Cpd# R1=R2 R5 (Rx)q (FFF.xxx. yyy) F101.002 01 n-butyl Ph- 7-methyl 02 n-butyl Ph- 7-ethyl 03 n-butyl Ph- 7-iso-propyl 04 n-butyl Ph- 7-tert-butyl 05 n-butyl Ph- 7-OH 06 n-butyl Ph- 7-OCH3 07 n-butyl Ph- 7-O(iso-propyl) 08 n-butyl Ph- 09 n-butyl Ph- 7-SOCH3 10 n-butyl Ph- 7-SO2CH3 11 n-butyl Ph- 7-SCH2CH3 12 n-butyl Ph- 7-NH2 13 n-butyl Ph- 7-NHOH 14 n-butyl Ph- 7-NHCH3 15 n-butyl Ph- 7-N(CH3)2 16 n-butyl Ph- 7-N+(CH3)3, I 17 n-butyl Ph- 7-NHC(=O)CH3 18 n-butyl Ph- 7-N(CH2CH3)2 19 n-butyl Ph- 7-NMeCH2CO2H 2O n-butyl Ph- 7-N+(Me)2CH2CO2,H, I- 21 n-butyl Ph- 7-(N)-morpholine 22 n-butyl Ph- 7-(N)-azetidine 23 n-butyl Ph- 7-(N)-N-methylazetidinium, I 24 n-butyl Ph- 7-(N)-pyrrolidine 25 n-butyl Ph- 7-(N)-N-methyl-pyrrolidinium, I- 26 n-butyl Ph- 7-(N)-N-methyl-morpholinium, 1- 27 n-butyl Ph- 7-(N)-N'-methylpiperazine 28 n-butyl Ph- 7-(N)-N' -dimethypipeIarinium, I- 29 n-butyl Ph- 7-NH-CBZ 30 n-butyl Ph- 7-NHC(O)C5H11 31 n-butyl Ph- 7-NHC(O)CH2Br 32 n-butyl Ph- 7-NH-C(NH)NH2 33 n-butyl Ph- 7-(2)-thiophene 34 n-butyl Ph- 8methyl 35 n-butyl Ph- 8-ethyl 36 n-butyl Ph- 8-iso-propyl 37 n-butyl Ph- 8-tert-butyl 38 n-butyl Ph- 8-OH 39 n-butyl Ph- 8-OCH3 40 n-butyl Ph- 8-O(iso-propyl) 41 n-butyl Ph- 8-SCH3 42 n-butyl Ph- 8-SOCH3 43 n-butyl Ph- 8-S02CR3 44 n-butyl Ph- 8-SCH2CH3 45 n-butyl Ph- 8-NH2 46 n-butyl Ph- 8-NHOH 47 n-butyl Ph- 8-NHCH3 48 n-butyl Ph- 8-N(CH3)2 49 n-butyl Ph- 8-N+(CH3)3, I- 50 n-butyl Ph- 8-NHC(=C)CH3 51 n-butyl Ph- 8-N(CH2CH3)2 52 n-butyl Ph- 8-NMeCH2CO2H 53 n-butyl Ph- 8-N+(Me)2CH2CO2H, I 54 n-butyl Ph- 8-(N)-morpholine 55 n-butyl Ph- 8-(N)-azetidine 56 n-butyl Ph- 8-(N)-N-methylazetidinium, I- 57 n-butyl Ph- 8-(N)-pyrroidine 58 n-butyl Ph- 8-(N)-N-methyl-pyrrolidinium, I 59 n-butyl Ph- 8-(N)-N-methyl-morpholinium, I 60 n-butyl Ph- 8-(N)-N'-methylpiperazine 61 n-butyl Ph- 8-(N)-N'-dimethylpiperazinium, Z 62 n-butyl Ph- 8-NH-CBZ 63 n-butyl Ph- 8-NHC(O)C5H11 64 n-butyl Ph- 8-NHC(O)CH2Br 65 n-butyl Ph- 8-NH-C(NH)NH2 66 n-butyl Ph- 8-(2)-thiophene 67 n-butyl Ph- 9-methyl 68 n-butyl Ph- 9-ethyl 69 n-butyl Ph- 9-iso-propyl 70 n-butyl Ph- 9-tert-butyl 71 n-butyl Ph- 9-OH 72 n-butyl Ph- 9-OCH3 73 n-butyl Ph- 9-O(iso-propyl) 74 n-butyl Ph- 9-SCH3 75 n-butyl Ph- 9-SOCH3 76 n-butyl Ph- 9-SO2CH3 77 n-butyl Ph- 9-SCH2CH3 78 n-butyl Ph- 9-NH2 79 n-butyl Ph- 9-NHOH 80 n-butyl Ph- 9-NHCH3 81 n-butyl Ph- 9-N(CH3)2 82 n-butyl Ph- 9-N+(CH3)3, I 83 n-butyl Ph- 9-NHC(=O~CH3 84 n-butyl Ph- 9-N(CH2CH3)2 85 n-butyl Ph- 9-NMeCH2CO2H 86 n-butyl Ph- 9-N+(Me)2CH2CO2H, Z 87 n-butyl Ph- 9-(N)-morpholine 88 n-butyl Ph- 9-(N)-azetidine 89 n-butyl Ph- 9-(N)-N-methylazetidinium, Z 90 n-butyl Ph- 9- (N) -pyrrolidine 91 n-butyl Ph- 9-(N)-N-methyl-pyrrolidinium, I- 92 n-butyl Ph- 9-(N)-N-methyl-morpholinium, I- 93 n-butyl Ph- 9-(N)-N'-methylpiperazine 93 n-butyl Ph- 9-(N)-N'-dimethhylpiperazazinium, I- 95 n-butyl Ph- 9-NH-C3Z 96 n-butyl Ph- 9-NHC(O)C5H11 97 n-butyl Ph- 9-NHC(O)CH2Br 98 n-butyl Ph- 9-NH-C(NH)NH2 99 n-butyl Ph- 9-(2)-thiophene 100 n-butyl Ph- 7-OCR3, 8-OCH3 101 n-butyl Ph- 7-SCH3, 8-OCR3 102 n-butyl Ph- 7-SCH3, 8-SCH3 103 n-butyl Ph- 6-OCH3, 7-OCH3, 8-OCH3 Prefix Cpd# R1=R2 R5 (Rx)q (FFF.xxx. yyy) F101.003 01 n-pentyl Ph- 7-methyl 02 n-pentyl Ph- 7-ethyl 03 n-pentyl Ph- 7-iso-propyl 04 n-pentyl Ph- 7-tert-butyl 05 n-pentyl Ph- 7-OH 06 n-pentyl Ph- 7-OCH3 07 n-pentyl Ph- 7-O(iso-propyl) 08 n-pentyl Ph- 7-SCH3 09 n-pentyl Ph- 7-SOCH3 10 n-pentyl Ph- 7-SO2CH3 11 n-pentyl Ph- 7-SCH2CH3 12 n-pentyl Ph- 7-NH2 13 n-pentyl Ph- 7-NHOH 14 n-pentyl Ph- 7-NHCR3 15 n-pentyl Ph- 7-N(CH3)2 1 n-pentyl Ph- 7-N+(CH3)3, I- 17 n-pentyl Ph- 7-NHC(=O)CH3 18 n-pentyl Ph- 7-N(CH2CH3)2 19 n-pentyl Ph- 7-NMeCH2CO2H 20 n-pentyl Ph- 7-N+(Me)2CR2CO2R, I 21 n-pentyl Ph- 7-(N)-morpholine 22 n-pentyl Ph- 7-(N)-azetidine 23 n-pentyl Ph- 7-(N) -N-nethylazetidiniur;rl I- 24 n-pentyl Ph- 7- (N) -pyrrolidine 25 n-pentyl Ph- 7-(N)-N-methyl-pyrrolidinium, I- 26 n-pentyl Ph- 7-(N)-N-methyl-morpholinium, Z- 27 n-pentyl Ph- 7-(N)-N'-methylpiperazine 28 n-pentyl Ph- 7-(N)-N'-dimethylpiperaziniun, I- I- 29 n-pentyl Ph- 7-NH-CBZ 30 n-pentyl Ph- 7-NHC(O)C5H11 31 n-pentyl Ph- 7-NHC(O)CH2Br 32 n-pentyl Ph- 7-NH-C(NH)NH2 33 n-pentyl Ph- 7-(2)-thiophene 34 n-pentyl Ph- 8-methyl 35 n-pentyl Ph- 8-ethyl 36 n-pentyl Ph- 8-iso-propyl 37 n-pentyl Ph- 8-tert-butyl 38 n-pentyl Ph- 8-OH 39 n-pentyl Ph- 8-OCH3 40 n-pentyl Ph- 8-O(iso-propyl) 41 n-pentyl Ph- 8-SCR3 42 n-pentyl Ph- 8-SOCR3 43 n-pentyl Ph- 8-SO2CH3 44 n-pentyl Ph- 8-SCH2CR3 45 n-pentyl Ph- 8-NH2 46 n-pentyl Ph- 8-NHOH 47 n-pentyl Ph- 8-NHCH3 48 n-pentyl Ph- 8-N(CH3)2 49 n-pentyl Ph- 8-N+(CH3)3, 1 50 n-pentyl Ph- 8-NHC(=O)CH3 51 n-pentyl Ph- 8-N(CH2CH3)2 52 n-pentyl Ph- 8-NMeCH2CO2H 53 n-pentyl Ph- 8-N+(Me)2CH2CO2H, I- 54 n-pentyl Ph- 8-(N)-morpholine 55 n-pentyl Ph- 8-(N)-azetidine 56 n-pentyl Ph- 8-(N)-N-methylazetidinium, I- 57 n-pentyl Ph- 8-(N)-pyrrolidine 58 n-pentyl Ph- 8-(N)-N-methyl-pyrrolidinium, I- 59 n-pentyl Ph- 8-(N)-N-methyl-morpholinium, I- 60 n-pentyl Ph- 8-(N)-N'-methylpiperazine 61 n-pentyl Ph- 8-(N)-N'-dimethylpiperazinium, I- 62 n-pentyl Ph- 8-NH-CBZ 63 n-pentyl Ph- 8-NHC(O)C5H11 64 n-pentyl Ph- 8-NHC(O)CH2Br 65. n-pentyl Ph- 8-NH-C(NH)NR2 66 n-pentyl Ph- 8-(2)-thiophene 67 n-pentyl Ph- 9-ethyl 68 n-pentyl Ph- 9-ethyl 69 n-pentyl Ph- 9-ito-propyl 70 n-pentyl Ph- 9-tert-butyl 71 n-pentyl Ph- 9-OH 72 n-pentyl Ph- 9-OCH3 73 n-pentyl Ph- 9-O(iso-propyl) 74 n-pentyl Ph- 9-SCH3 75 n-pentyl Ph- 9-SOCH3 76 n-pentyl Ph- 9-SO2CH3 77 n-pentyl Ph- 9-SCH2CH3 78 n-pentyl Ph- 9-NH2 79 n-pentyl Ph- 9-NHOH 80 n-pentyl Ph- 9-NHCH3 81 n-pentyl Ph- 9-N(CH3)2 82 n-pentyl Ph- 9-N+(CH3)3, I 83 n-pentyl Ph- 9-NHC(=O)CH3 84 n-pentyl Ph- -N(CH2CH3)2 85 n-pentyl Ph- 9-NMeCH2CO2H 86 n-pentyl Ph- 9-N+(Me)2CH2CO2H, I 87 n-pentyl Ph- 9-(N)-morpholine 88 n-pentyl Ph- 9-(N)-azetidine 89 n-pentyl Ph- 9-(N)-N-methylazetidinium, z 90 n-pentyl Ph- 9-(N)-pyrrolidine 91 n-pentyl Ph- 9-(N)-N-methyl-pyrrolidinium, I- 92 n-pentyl Ph- 9-(N)-N-methyl-morpholinium, I 93 n-pentyl Ph- 9-(N)-N'-methylpiperazine 93 n-pentyl Ph- 9-(N)-N'-dimethylpiperazinium, I- 95 n-pentyl Ph- 9-NH-CBZ 96 n-pentyl Ph- 9-NHC(O)C5H11 97 n-pentyl Ph- 9-NHC(O)CH2Br 98 n-pentyl Ph- 9-NH-C(NH)NH2 99 n-pentyl Ph- 9-(2)-thiophene 100 n-pentyl Ph- 7-OCH3, 8-OCH3 101 n-pentyl Ph- 7-SCH3, 8-OCH3 102 n-pentyl Ph- 7-SCH3, 8-SCH3 103 n-entvl Ph- 6-OCH3, 7-OCR3, 8-OCH3 Prefix Cpd# R1=R2 R5 (Rx)q (FFF.xxx. yyy) F101.004 01 n-hexyl Ph- 7-methyl 02 n-hexyl Ph- 7-ethyl 03 n-hexyl Ph- 7-iso-propyl 04 n-hexyl Ph- 7-tert-butyl 05 n-hexyl Ph- 7-OH 06 n-hexyl Ph- 7-OCH3 07 n-hexyl Ph- 7-O-(iso-propyl).

08 n-hexyl Ph- 7-SCH3 09 n-hexyl Ph- 7-SOCH3 10 n-hexyl Ph- 7-SO2CH3 11 n-hexyl Ph- 7-SCH2CH3 12 n-hexyl Ph- 7-NH2 13 n-hexyl Ph- 7-NHOH 14 n-hexyl Ph- 7-NHCH3 15 n-hexyl Ph- 7-N(CH3)2 16 n-hexyl Ph- 7-N+(CH3)3, 1 17 n-hexyl Ph- 7-NHC(=O)CH3 18 n-hexyl Ph- 7-N(CH2CH3)2 19 n-hexyl Ph- 7-NMeCH2CO2H 20 n-hexyl Ph- 7-N+(Me)2CH2CO2H, I- 21 n-hexyl Ph- 7-(N)-morpholine 22 n-hexyl Ph- 7-(N)-azetidine 23 n-hexyl Ph- 7-(N)-N-methylazetidinium, I- 24 n-hexyl Ph- 7-(N)-pyrrolidine 25 n-hexyl Ph- 7-(N)-N-methyl-pyrrolidinium, I- 26 n-hexyl Ph- 7-(N)-N-methyl-morpholinium, I- 27 n-hexyl Ph- 7-(N)-N'-methylpiperazine 28 n-hexyl Ph- 7-(N)-N'-dimethylpiperazinium, I- 29 n-hexyl Ph- 7-NH-CBZ 30 n-hexyl Ph- 7-NHC(O)C5H11 31 n-hexyl Ph- 7-NHC(O)CH2Br 32 n-hexyl Ph- 7-NY-C(NH)NH2 33 n-hexyl Ph- 7-(2)-thiophene 34 n-hexyl Ph- 8-methyl 35 n-hexyl Ph- 8-ethyl 36 n-hexyl Ph- 8-iso-propyl 37 n-hexyl Ph- 8-tert-butyl 38 n-hexyl Ph- 8-OH 39 n-hexyl Ph- 8-OCH3 40 n-hexyl Ph- 8-O(iso-propyl) 41 n-hexyl Ph- 8-SCH3 .42 n-hexyl Ph- 8-SOCH3 43 n-hexyl Ph- 8-SO2CH3 44 n-hexyl Ph- 8-SCH2CH3 45 n-hexyl Ph- 8-NR2 46 n-hexyl Ph- 8-NHOH 47 n-hexyl Ph- 8-NRCR3 48 n-hexyl Ph- 8-N(CH3)2 49 n-hexyl Ph- 8-N+(CH3)3, I 50 n-hexyl Ph- 8-NHC(=O)CH3 51 n-hexyl Ph- 8-N(CH2CH3)2 52 n-hexyl Ph- 8-NMeCH2CO2H 53 n-hexyl Ph- 8-N+(Me)2CH2CO2H, I- 54 n-hexyl Ph- 8-(N)-morpholine 55 n-hexyl Ph- 8- (N) -azetidine 56 n-hexyl Ph- 8-(N)-N-methylazetidinium, I- 57 n-hexyl Ph- 8-(N)-pyrrolidine 58 n-hexyl Ph- 8-(N)-N-methyl-pyrroidinium, I- 59 n-hexyl Ph- 8-(N)-N-methyl-morpholinium, I- 60 n-hexyl Ph- 8-(N)-N'-methylpiperazine 61 n-hexyl Ph- 8-(N)-N'-dimethylpiperazinium, I- 62 n-hexyl Ph- 8-NH-C3Z 63 n-hexyl Ph- 8-NHC(O)C5H11 64 n-hexyl Ph- 8-NHC(O)CH2Br 65 n-hexyl Ph- 8-NH-C(NH)NH2 66 n-hexyl Ph- 8-(2)-thiophene 67 n-hexyl Ph- 9-methyl 68 n-hexyl Ph- 9-ethyl 69 n-hexyl Ph- 9-ito-propyl 70 n-hexyl Ph- 9-tert-butyl 71 n-hexyl Ph- 9-OH 72 n-hexyl Ph- 9-CCH3 73 n-hexyl Ph- 9-O(iso-propyl) 74 n-hexyl Ph- 9-SCH3 75 ' n-hexyl Ph- 9-SOCH3 76 n-hexyl Ph- 9-SO2CH3 77 n-hexyl Ph- 9-SCH2CH3 78 n-hexyl Ph- 9-NH2 79 n-hexyl Ph- 9-NHOH 80 n-hexyl Ph- 9-NHCH3 81 n-hexyl Ph- 9-N(CH3)2 82 n-hexyl Ph- 9-N+(CH3)3, I- 83 n-hexyl Ph- 9-NHC(=O)CH3 84 n-hexyl Ph- 9-N(CH2CH3)2, 85 n-hexyl Ph- 9-NMeCH2CO2H 86 n-hexyl Ph- 9-N+(Me)2CH2CO2H, I- 87 n-hexyl Ph- 9-(N)-morpholine 88 n-hexyl Ph- 9-(N)-azetidine 89 n-hexyl Ph- 9-(N)-N-methylazetidinium, I- 90 n-hexyl Ph- 9-(N)-pyrrolidine 91 n-hexyl Ph- 9-(N)-N-methyl-pyrrolidinium I- 92 n-hexyl Ph- 9-(N)--N-methyl-morpholinium, I- 93 n-hexyl Ph- 9-(N)-N'-methylpiperazine 93 n-hexyl Ph- 9-(N)-N'-dimethylpiperazinium, I- 95 n-hexyl Ph- 9-NH-CBZ 96 n-hexyl Ph- -NHC(O)C5H11 97 n-hexyl Ph- 9-NHC(O)CH2Br 98 n-hexyl Ph- 9-NH-C(NH)NH2 99 n-hexyl Ph- 9-(2)-thiophene 100 n-hexyl Ph- 7-OCR3, 8-OCH3 101 n-hexyl Ph- 7-SCR3, 8-OCH3 102 n-hexyl Ph- 7-SCH3, 8-SCH3 103 n-hexvl Ph- 6-OCH3, 7-CCR3, 8-OCH3 Prefix Cpd# R1=R2 (FFF.xxx. yyy) F101.005 Ol io-propyl Ph- 7-methyl 02 iso-propyl Ph- 7-ethyl 03 iso-propyl Ph- 7-iso-propyl 04 iso-propyl Ph- 7-tert-butyl 05 iso-propyl Ph- 7-OH 06 iso-propyl Ph- 7-OCH3 07 iso-propyl Ph- 7-O(iso-propyl) 08 iso-propyl Ph- 7-SCH3 09 iso-propyl Ph- 7-SOCH3 10 iso-propyl Ph- 7-SO2CH3 11 iso-propyl Ph- 7-SCH2CH3 12 iso-propyl Ph- 7-NH2 13 iso-propyl Ph- 7-NHOH 14 iso-propyl Ph- 7-NHCH3 15 iso-propyl Ph- 7-N(CH3)2 16 iso-propyl Ph- 7-N+(CH3)3, I- 17 iso-propyl Ph- 7-NHC(=O)CH3 18 iso-propyl Ph- 7-N(CH2CH3)2 19 iso-propyl Ph- 7-NMeCH2CO2H 20 iso-propyl Ph- 7-N+(Me)2CH2C02H, z 21 iso-propyl Ph- 7-(N)-morpholine 22 iso-propyl Ph- 7-(N)-azetidine 23 iso-propyl Ph- 7-(N)-N-methylazetidinium, I- 24 iso-propyl Ph- 7- (N) -pyrrolidine 25 iso-propyl Ph- 7-(N)-N-methyl-pyrrolidinium, I- 26 iso-propyl Ph- 7-(N)-N-methyl-morpholinium, I- 27 iso-propyl Ph- 7-(N)-N'-methylpiperazine 28 iso-propyl Ph- 7-(N)-N'-dimethylpiperazinium, I- 29 iso-propyl Ph- 7-NH-CBZ 30 iso-propyl Ph- 7-NHC(O)C5H11 31 iso-propyl Ph- 7-NHC(O)CH2Br 32 iso-propyl Ph- 7-NY-C(NH)NH2 33 iso-propyl Ph- 7-(2)-thiophene 34 iso-propyl Ph- 8-methyl 35 iso-propyl Ph- 8-ethyl 36 iso-propyl Ph- 8-iso-propyl 37 iso-propyl Ph- 8-tert-butyl 38 iso-propyl Ph- 8-OH 39 iso-propyl Ph- 8-OCH3 40 iso-propyl Ph- 8-O(iso-propyl) 41 iso-propyl Ph- 8-SCH3 42 iso-propyl Ph- 8-SOCH3 43 iso-propyl Ph- 8-SO2CH3 44 iso-propyl Ph- 8-SCH2CH3 45 iso-propyl Ph- 8-NH2 46 iso-propyl Ph- 8-NHOH 47 iso-propyl Ph- 8-NHCH3 48 iso-propyl Ph- 8-N(CR3)2 49 iso-propyl Ph- 8-N+(CH3)3, I 50 iso-propyl Ph- 8-NHC(-O)CH3 51 iso-propyl Ph- 8-N(CH2CH3)2 52 iso-propyl Ph- 8-NMeCH2C02H 53 iso-propyl Ph- 8-N+(M.e)2CH2C02H I- 54 iso-propyl Ph- 8-(N)-morpholine 55 iso-propyl Ph- 8-(N)-azetidine 56 iso-propyl Ph- 8-(N)-N-methylazetidinium, I 57 iso-propyl Ph- 8-(N)-pyrrolidine 58 iso-propyl Ph- 8-(N)-N-methyl-pyrrolidinium, I- 59 iso-propyl Ph- 8-(N)-N-methyl-morpholinium, I- 60 iso-propyl Ph- 8- (N) -N' -methylpiperazine 61 iso-propyl Ph- 8-(N)-N'-dimethylpiperazinium, I- 62 iso-propyl Ph- 8-NH-CBZ 63 iso-propyl Ph- 8-NHC(O)C5H11 64 iso-propyl Ph- 8-NHC(O)CH2Br 65 iso-propyl Ph- 8-NH-C(NH)NH2 66 iso-propyl Ph- 8-(2)-thiophene 67 iso-propyl Ph- 9-methyl 68 iso-propyl Ph- 9-ethyl 69 iso-propyl Ph- 9-iso-propyl 70 iso-propyl Ph- 9-ter-butyl 71 iso-propyl Ph- 9-OH 72 iso-propyl Ph- 9-OCH3 73 iso-propyl Ph- 9-O(iso-propyl) 74 iso-propyl Ph- 9-SCH3 75 iso-propyl Ph- 9-SOCH3 76 iso-propyl Ph- 9-SO2CH3 77 iso-propyl Ph- 9-SCH2CH3 78 iso-propyl Ph- 9-NH2 79 iso-propyl Ph- 9-NHOH 80 iso-propyl Ph- 9-NHCH3 81 iso-propyl Ph- 9-N(CH3)2 82 iso-propyl Ph- 9-N+(CH3)3, I 83 iso-propyl Ph- 9-NHC(=O)CH3 84 iso-propyl Ph- 9-N(CH2CH3)2 85 iso-propyl Ph- 9-NMeCH2C02H 86 iso-propyl Ph- 9-N+(Me)2CH2CO2H, I- 87 iso-propyl Ph- 9-(N)-morpholine 88 iso-propyl Ph- 9-(N)-azetidine 89 iso-propyl Ph- 9-(N)-N-methylazetidinium, I- 90 iso-propyl Ph- 9-(N)-pyrroldine 91 iso-propyl Ph- 9-(N)-N-methyl-pyrrolidiniumf I- 92 iso-propyl Ph- 9-(N)-N-methyl-morpholinium, 1 93 iso-propyl Ph- 9-(N)-N'-methylpiperazine 93 iso-propyl Ph- 9-(N)-N'-dimethylp PATENT inium, I- 95 iso-propyl Ph- 9-NH-CBZ 96 iso-propyl Ph- 9-NHC(O)C5H11 97 iso-propyl Ph- 9-NYC(O)CH2Br 98 iso-propyl Ph- 9-NH-C(NH)NH2 99 iso-propyl Ph- 9-(2)-thiophene 100 iso-propyl Ph- 7-OCH3, 8-OCH3 101 iso-propyl Ph- 7-SCH3, 8-OCH3 102 iso-propyl Ph- 7-SCH3, 8-SCH3 103 iso-propyl Ph- 6-OCH3, 7-OCH3, 8-OCH3 Prefix Cpd# R1=R2 R5 (Rx)q (FFF.xxx. yyy) F101.006 01 iso-butyl Ph- 7-methyl 02 iso-butyl Ph- 7-ethyl 03 isobutyl Ph- 7-iso-propyl 04 iso-butyl Ph- 7-tert-butyl 05 iso-butyl Ph- 7-OH -6 iso-butyl Ph- 7-OCH3 07 iso-butyl Ph- 7-O(iso-propyl) 08 iso-butyl Ph- 7-SCH3 09 iso-butyl Ph- 7-SOCH3 1- iso-butyl Ph- 7-SO2CH3 11 iso-butyl Ph- 7-SCH2CH3 12 iso-butyl Ph- 7-NH2 13 iso-butyl Ph- 7-NHOH 14 iso-butyl Ph- 7-NHCH3 15 iso-butyl Ph- 7-N(CH3)2 16 iso-butyl Ph- 7-N+(CH3)3, I- 17 iso-butyl Ph- 7-NHC(=O)CH3 18 iso-butyl Ph- 7-N(CH2CH3)2 19 iso-butyl Ph- 7-NMeCH2CO2H 20 iso-butyl Ph- 7-N+(Me)2CH2CO2H, I 21 iso-butyl Ph- 7-(N)-morpholine 22 iso-butyl Ph- 7-(N)-azetidine 23 iso-butyl Ph- 7-(N) -N-nethylazetidinium, I- 24 iso-butyl Ph- 7-(N)-pyrrolidine 25 iso-butyl Ph- 7-(N)-N-methyl-pyrrolidinium, I- 26 iso-butyl Ph- 7-(N)-N-methyl-morpholinium, I- 27 iso-butyl Ph- 7-(N)-N'-methylpiperazine 28 iso-butyl Ph- 7- (N) -N' -dimethylpiperazinium, 1- 29 iso-butyl Ph- 7-NH-CBZ 30 isobutyl Ph- 7-NHC(O)C5H11 31 iso-butyl Ph- 7-NHC(O)CH2Br 32 iso-butyl Ph- 7-NH-C(NH)NH2 33 iso-butyl Ph- 7-t2)-thiophene 34 iso-butyl Ph- 8-methyl 35 iso-butyl Ph- 8-ethyl 36 iso-butyl Ph- 8-iso-propyl 37 iso-butyl Ph- 8-tert-butyl 38 iso-butyl Ph- 8-OH 39 iso-butyl Ph- 8-OCH3 40 iso-butyl Ph- 8-O(iso-propyl) 41 iso-butyl Ph- 8-SCH3 42 iso-butyl Ph- 8-SOCH3 43 iso-butyl Ph- 8-S02CH3 44 iso-butyl Ph- 8-SCH2CH3 45 iso-butyl Ph- 8-NH2 46 iso-butyl Ph- 8-NHOH 47 iso-butyl Ph- 8-NHCH3 48 iso-butyl Ph- 8-N(CR3)2 49 iso-butyl Ph- 8-N+(CH3)3, I- 50 iso-butyl Ph- 8-NF.C(-O)CH3 51 iso-butyl Pb- 8-N(CH2CH3)2 52 iso-butyl Ph- 8-NMeCH2CO2H 53 iso-butyl Ph- 8-N+(Me)2CH2CO2H, I- 54 iso-butyl Ph- 8-(N)-morpholine 55 ito-butyl Ph- 8-(N)-azetidine 56 iso-butyl Ph- 8-(N)-N-methylazetidinium I- 57 iso-butyl Ph- 8- (N) -pyrrolidine 58 iso-butyl Ph- 8-(N)-N-methyl-pyrrolidinium, I 59 iso-butyl Ph- 8-(N)-N-methyl-morpholinium, z 60 iso-butyl Ph- 8-(N)-N'-methylpiperazine 61 iso-butyl Ph- 8-(N)-N'-dimethylpiperazinium, I 62 iso-butyl Ph- 8-NH-CBZ 63 iso-butyl Ph- 8-NHC(O)C5H11 64 iso-butyl Ph- 8-NYC(O)CH2Br 65 iso-butyl Ph- 8-NH-C(NH)NH2 66 iso-butyl Ph- 8-(2)-thiophene 67 iso-butyl Ph- 9-methyl 68 iso-butyl Ph- 9-ethyl 69 isobutyl Ph- 9-iso-propyl 70 iso-butyl Ph- 9-tert-butyl 71 iso-butyl Ph- 9-OH 72 iso-butyl Ph- 9-OCH3 73 iso-butyl Ph- 9-o(iso-propyl) 74 iso-butyl Ph- 9-SCH3 75 iso-butyl Ph- 9-SOCH3 76 iso-butyl Ph- -SO2CH3 77 iso-butyl Ph- 9-SCH2CH3 78 iso-butyl Ph- 9-NH2 79 iso-butyl Ph- 9-NHOH iso-butyl Ph- 9-NHCH3 81 iso-butyl Ph- 9-N(CH3)2 82 iso-butyl Ph- 9-N+(CH3)3, Z 83 iso-butyl Ph- 9-NHC(=O)CH3 84 iso-butyl Ph- 9-N(CH2CH3)2 85 iso-butyl Ph- 9-NMeCH2CO2H 86 iso-butyl Ph- 9-N+(Me)2CH2CO2H, I 87 iso-butyl Ph- 9-(N)-morpholine 88 iso-butyl Ph- 9-(N)-azetidine 89 iso-butyl Ph- 9-(N)-N-methylazetidinium, 1- 90 iso-butyl Ph- 9-(N)-pyrrolidine 91 iso-butyl Ph- 9-(N)-N-methyl-pyrrolidinium, I- 92 iso-butyl Ph- 9-(N)-N-methyl-morpholinium, I- 93 iso-butyl Ph- 9-(N)-N'-methylpiperazine 93 iso-butyl Ph- 9-(N)-N'-dimethylpiperazinium, I- 95 iso-butyl Ph- 9-NH-CBZ 96 ito-butyl Ph- 9-NHC(O)C5H11 97 iso-butyl Ph- 9-NHC(O)CH2Br 98 iso-butyl Ph- 9-NH-C(NH)NH2 99 iso-butyl Ph- 9-(2)-thiophene 100 iso-butyl Ph- 7-OCR3, 8-CCR3 101 iso-butyl Ph- 7-SCR3, 8-OCH3 102 iso-butyl Ph- 7-SCR3, 8-SCH3 103 iso-butvl Ph- 6-OCH3, 7-OCH3, 8-OCH3 Prefix Cpd# R1=R2 R5 @ (FFF.xxx yyy) F101.007 01 iso-pentyl Ph- 7-methyl 02 iso-pentyl Ph- 7-ethyl 03 iso-pentyl Ph- 7-iso-propyl 04 iso-pentyl Ph- 7-tert-butyl 05 iso-pentyl Ph- 7-OH 06 iso-pentyl Ph- 7-OCH3 07 iso-pentyl Ph- 7-O(iso-propyl) 08 iso-pentyl Ph- 7-SCH3 09 iso-pentyl Ph- 7-SOCH3 10 iso-pentyl Ph- 7-S02CH3 11 iso-pentyl Ph- 7-scH2cH3 12 iso-pentyl Ph- 7-NH2 13 iso-pentyl Ph- 7-NHOH 14 iso-pentyl Ph- 7-NHCH3 15 iso-pentyl Ph- 7-N(CH3)2 16 iso-pentyl Ph- $7-N+(CH3)3, I- 17 iso-pentyl Ph- 7-NHC(=O)CH3 18 iso-pentyl Ph- 7-N(CH2CH3)2 19 iso-pentyl Ph- 7-NMeCH2CO2H 20 iso-pentyl Ph- 7-N+(Me)2CR2C02H, I- 21 iso-pentyl Ph- 7-(N)-mo:pholine 22 iso-pentyl Ph- 7- (N) -azetidine 23 iso-pentyl Ph- 7-(N)-N-methylazetidinium, I- 24 iso-pentyl Ph- 7-(N)-pyrrolidine 25 iso-pentyl Ph- 7-(N)-N-methyl-pyrrolidinium, I- 26 iso-pentyl Ph- 7-(N)-N-methyl-morpholinium, I- 27 iso-pentyl Ph- 7- (N)-N'-methylpiperazine 28 iso-pentyl Ph- 7-(N)-N'-dimethylpiperazinium, T 29 iso-pentyl Ph- 7-Nn-C3Z 30 iso-pentyl Ph- 7-NHC(O)C5H11 31 iso-pentyl Ph- 7-NHC(O)CH2Br 32 iso-pentyl Ph- 7-NH-C(NH)NH2 33 iso-pentyl Ph- 7-(2)-thiophene 34 iso-pentyl Ph- 8-methyl 35 iso-pentyl Ph- 8-ethyl 36 iso-pentyl Ph- 8-iso-propyl 37 iso-pentyl Ph- 8-ter;-butyl 38 iso-pentyl Ph- 8-OH 39 iso-pentyl Ph- 8-OCH3 40 iso-pentyl Ph- 8-OXiso-propyl) 41 iso-pentyl Ph- 8-SCH3 42 iso-pentyl Ph- 8-SOCH3 43 iso-pentyl Ph- 8-S02CH3 44 iso-pentyl Ph- 8-SCH2CH3 45 iso-pentyl Ph- 8-NH2 46 iso-pentyl Ph- 8-NHOH 47 iso-pentyl Ph- 8-NHCH3 48 iso-pentyl Ph- 8-N(CH3)2 49 iso-pentyl Ph- 8-N+(CH3)3, I 50 iso-pentyl Ph- 8-NHC(=O)CH3 51 iso-pentyl Ph- 8-N(CH2CH3)2 52 iso-pentyl Ph- 8-NM#CH2CO2H 53 iso-pentyl Ph- 8-N+(Me)2CH2CO2H, I 54 iso-pentyl Ph- 8-(N)-morpholine 55 iso-pentyl Ph- 8-(N)-azetidine 56 iso-pentyl Ph- 8-(N)-N-methylazetidinium, I- 57 iso-pentyl Ph- 8-(N)-pyrrolidine 58 iso--entyl Ph- 8-(N)-N-methyl-pyrrolidinium, I 59 iso-pentyl Ph- 8-(N)-N-methyl-morpholinium, I- 60 iso-pentyl Ph- 8-(N)-N'-methylpiperazine 61 iso-pentyl Ph- 8-(N)-N'-dimethylpiperazinium, z 62 iso-pentyl Ph- 8-NH-C3Z 63 iso-pentyl Ph- 8-NHC(O)C5H11 64 iso-pentyl Ph- 8-NHC(O)CH2Br 65 iso-pentyl Ph- 8-NH-C(NH)NH2 66 iso-pentyl Ph- 8-(2)-thiophene 67 iso-pentyl Ph- 9-methyl 68 iso-pentyl Ph- 9-ethyl 69 iso-pentyl Ph- 9-iso-propyl 70 iso-pentyl Ph- 9-tert-butyl 71 iso-pentyl Ph- 9-OH 72 iso-pentyl Ph- 9-OCR3 73 iso-pentyl Ph- 9-O(iso-pro?yl) 74 iso-pentyl Ph- 9-SCH3 75 iso-pentyl Ph- 9-SOCH3 76 iso-pentyl Ph- 9-SO2CH3 77 iso-pentyl Ph- 9-SCH2CH3 78 iso-pentyl Ph- 9-NH2 79 iso-pentyl Ph- 9-NHOH 80 iso-pentyl Ph- 9-NHCH3 81 iso-pentyl Ph- 9-N(CH3)2 82 iso-pentyl Ph- 9-N+(CH3)3, I- 83 iso-pentyl Ph- -NHC(=O)CH3 84 iso-pentyl Ph- 9-N(CH2CH3)2 85 iso-pentyl Ph- 9-NMeCH2CO2H 86 iso-pentyl Ph- 9-N* (Me) 2CH2C02H, I- 87 iso-pentyl Ph- 9- (N) -morpholine 88 iso-pentyl Ph- 9-(N)-azetidine 89 iso-pentyl Ph- 9-(N)-N-methylazetidinium, I- 90 iso-pentyl Ph- 9-(N)-pyrrolidine 91 iso-pentyl Ph- 9-(N)-N-methyl-pyrrolidinium, I- 92 iso-pentyl Ph- 9-(N)-N-methyl-morpholinium, I- 93 iso-pentyl Ph- 9-(N)-N'-methylpip@@@@@@he 93 iso-pentyl Ph- 9-(N)-N'-dimethylpiperazinium, I- 95 iso-pentyl Ph- 9-NH-CBZ 96 iso-pentyl Ph- 9-NHC(O)C5H11 97 iso-pentyl Ph- 9-NHC(O)CH2Br 98 iso-pentyl Ph- 9-NH-C(NH)NH2 99 iso-pentyl Ph- 9-(2)-thiophene 100 iso-pentyl Ph- 7-OCH3, 8-OCH3 101 iso-pentyl Ph- 7-SCH3, 8-OCH3 102 iso-pentyl Ph- 7-SCH3, 8-SCH3 1-3 iso-pentyl Ph- 6-OCH3, 7-OCH3, 8-OCH3 Prefix Cpd# R1=R2 R5 (Rx)q (FFF.xxx. yyy) F101.008 01 CH2C(=O)C2H5 Ph- 7-methyl 02 CH2C(=O)C2H5 Ph- 7-ethyl 03 CH2C(=O)C2H5 Ph- 7-iso-propyl 04 CH2C(=O)C2H5 Ph- 7-ter-butyl 05 CH2C(=O)C2H5 Ph- 7-OH.

06 CH2C(=O)C2H5 Ph- 7-OCH3 07 CH2C(=O)C2H5 Ph- 7-O(iso-propyl) 08 CH2C(=O)C2H5 Ph- 7-SCR3 09 CH2C(=O)C2H5 Ph- 7-SOCR3 10 CH2C(=O)C2H5 Ph- 7-s02cY3 11 CH2C(=O)C2H5 Ph- 7-SCH2CH3 12 CH2C(=O)C2H5 Ph- 7-NH2 13 CH2C(=O)C2H5 Ph- 7-NHOH 14 CH2C(=O)C2H5 Ph- 7-NHCH3 15 CH2C(=O)C2H5 Ph- 7-N(CH3)2 16 CH2C(-O)C2H3 Ph- 7-N+(CH3)3, I- 17 CH2C(=O)C2H5 Ph- 7-NHC(=O)CH3 18 CX2C(-O)C2H5 Ph- 7-N(CH2CH3)2 19 CH2C(=O)C2H5 Ph- 7-NMeCH2CO2R 20 CH2C(=O)C2H5 Ph- 7-N+(Me)2CH2C02H, I- 21 CH2C(=O)C2H5 Ph- 7-(N)-morpholine 22 CH2C(-O)C2H5 Ph- 7- (N) -azetidine 23 CH2C(=O)C2H5 Ph- 7-(N)-N-methylazetidinium, I- 24 CH2C(=O)C2H5 Ph- 7-(N)-pyrrolidine 25 CH2C(=O)C2H5 Ph- 7-(N)-N-methyl-pyrrolidinium, I- 26 CH2C(=O)C2H5 Ph- 7-(N)-N-methyl-morpholinium, I- 27 CH2C(-0)C2H5 Ph- 7- (N) -N'-methylpipera:ine 28 CH2C(=O)C2H5 Ph- 7-(N)-N'-dimethylpiperazinium, I- 29 CH2C(=O)C2H5 Ph- 7-NH-C3Z 30 CH2C(=O)C2H5 Ph- 7-NHC(O)C5H11 31 CH2C(=O)C2H5 Ph- 7-NHC(O)CH2Br 32 CH2C(=O)C2H5 Ph- 7-NH-C(NH)NH2 33 CH2C(=O)C2H5 Ph- 7-(2)-thiophene 34 CH2C(-O)C2Hs Ph- 8-methyl 35 CH2C(=O)C2H5 Ph- 8-ethyl 36 CH2C(=O)C2H5 Ph- 8-iso-propyl~ 37 CH2C(=O)C2H5 Ph- 8-tert-butyl 38 CH2C(-O)C2H5 Ph- 8-OH 39 CH2C(=O)C2H5 Ph- 8-OCH3 40 CH2C(=O)C2H5 Ph- 8-O(iso-propyl) 41 CH2C(=O)C2H5 Ph- 8-SCH3 42 CH2C(=O)C2H5 Ph- 8-SOCH3 43 CH2C(=O)C2H5 Ph- 8-SO2CH3 44 CH2C(=O)C2H5 Ph- 8-SOCH2CH3 45 CH2C(=O)C2H5 Ph- 8-NH2 46 CH2C(=O)C2H5 Ph- 8-NHOH 47 CH2C(=O)C2H5 Ph- 8-NHCH3 48 CH2C(=O)C2H5 Ph- 8-N(CH3)2 49 CH2C(=O)C2H5 Ph- 8-N+(CH3)3, I- 50 CH2C(=O)C2H5 Ph- 8-NHC(=O)CH3 51 CH2C(=O)C2H5 Ph- 8-N(CH2CH3)2 52 CH2C(=O)C2H5 Ph- 8-NMeCH2CO2H 53 CH2C(-O)C2H5 Ph- 8-N+(Me)2CH2CO2H, T 54 CH2C(=O)C2H5 Ph- 8-(N)-norpholine 55 CH2C(=O)C2H5 Ph- 8-(N)-a:etidine 56 CH2C(=O)C2H5 Ph- 8-(N)-N-ethylazetidinium, I- 57 CH2C(=O)C2H5 Ph- 8- (N) -pyrrolidine 58 CH2C(=O)C2H5 Ph- 8-(N)-N-methyl-pyrrolidinium, I- 59 CH2C(=O)C2H5 Ph- 8-(N)-N-methyl-morpholinium, I- 60 CH2C(=O)C2H5 Ph- 8-(N)-N'-methylpiperazine 61 CH2C(=O)C2H5 Ph- 8-(N)-N'-dimethylpiperazinium, I- 62 CH2C(=O)C2H5 Ph- 8-NH-CBZ 63 CH2C{-O)C2Hs Ph- 8-NHC(O)C5H11 64 CH2C(-O)C2H5 Ph- 8-NHC(O)CH2Br 65 CH2C(=O)C2H5 Ph- 8-NH-C(NH)NH2 66 CH2C(=O)C2H5 Ph- 8-(2)-thiophene 67 CH2C(=O)C2H5 Ph- 9-methyl 68 CH2C(=O)C2H5 Ph- 9-ethyl 69 CR2C(-O)C2Hs Ph- 9-iso-propyl 70 CH2C(-a)C2Hs Ph- 9-tert-butyl 71 CH2C(=O)C2H5 Ph- 9-OH 72 CH2C(=O)C2H5 Ph- 9-OCH3 73 CH2C(=O)C2H5 Ph- 9-O(iso-propyl) 74 CH2C(-O)C2H; Ph- 9-SCH3 75 CH2C(=O)C2H5 Ph- 9-SOCH3 76 CH2C(=O)C2H5 Ph- 9-SO2CH3 77 CH2C(-o)C2H5 Ph- 9-SCR2CH3 78 CH2C(=O)C2H5 Ph- 9-NH2 79 CH2C(=O)C2H5 Ph- 9-NHOH 80 CH2C(=O)C2H5 Ph- 9-NHCH3 81 CH2C(=O)C2H5 Ph- 9-N(CH3)2 82 CH2Ct-O)C2Hs Ph- 9-N+(CH3)3, I 83 . CH2C(-O)C2R5 Ph- 9-NHC(=O)CH3 84 CH2C(-O)C2H5 Ph- 9-N(CH2CH3)2 85 CH2C(=O)C2H5 Ph- 9-NMeCH2CO2H 86 CH2C(=O)C2H5 Ph- 9-N+(ME)2CH2CO2H, I- 87 CH2C(=O)C2H5 Ph- 9- (N) -morpholine 88 CH2C(=O)C2H5 Ph- 9-(N)-azetidine 89 CH2C(=O)C2H5 Ph- 9-(N)-N-methylazetidinium, I- 90 CH2C(=O)C2H5 Ph- 9-(N)-pyrrolidine 91 CH2C(=O)C2H5 Ph- 9-(N)-N-methyl-pyrrolidinium, I- 92 CH2C(=O)C2H5 Ph- 9-(N)-N-methyl-morpholinium, I- 93 CH2C(=O)C2H5 Ph- 9-(N)-N'-methylpiperazine 93 CH2C(=O)C2H5 Ph- 9-(N)-N'-dimethylpiperazinium, I- 95 CH2C(=O)C2H5 Ph- 9-NH-CBZ 96 CH2C(=O)C2H5 Ph- 9-NHC(O)C5H11 97 CH2C(=O)C2H5 Ph- 9-NHC(O)CH2Br 98 CHzC(-O)C2H5 Ph- 9-NH-C(NH)NH2 99 CH2C(=O)C2Hs Ph- 9-(2)-thiophene 100 CH2C(-O)C2H5 Ph- 7-OCH3, 8-CCH3 101 CH2C(=O)C2Hs Ph- 7-SCH3, 8-OCH3 102 CH2C(=O)C2H5 Ph- 7-SCH3, 8-SCH3 103 CH2C(=O)C2H5 Ph- 6-OCH3, 7-OCH3, 8-OCH3 Prefix Cpd# R1=R2 R5 (Rx)q (FFF.xxx. yyy) F101.009 01 CH20C2H5 Ph- 7-methyl 02 CH20C2g5 Ph- 7-ethyl 03 CH20C2H5 Ph- 7-iso-propyl 04 CH2OC2H5 Ph- 7-tert-butyl 05 CH2OC2H5 Ph- 7-OH 06 CH2OC2H5 Ph- 7-OCH3 07 CH20C2Hs Ph- 7-O(iso-propyl) 08 CH20C2H5 Ph- 7-SCH3 09 CH2OC2Hs Ph- 7-SOCH3 10 CH20C2H5 Ph- 7-SO2CH3 11 CH20C2H5 Ph- 7-SCH2CH3 12 CH2OC2H5 Ph- 7-NH2 13 CH20C2H5 Ph- 7-NHOH 14 CH20C2H5 Ph- 7-NHCH3 15 CH20C2H5 Ph- 7-N(CH3)2 16 CH20C2R5 Ph- 7-N+(CH3)3, I- 17. CH2OC2H5 Ph- 7-NHC(=C)CH3 18 CH20C2H5 Ph- 7-N(CH2CH3)2 19 CH20C2H5 Ph- 7-NMeCH2C02H 20 CH2OC2H5 Ph- 7-N+(Me)2CH2CO2H, I- 21 CH2OC2H5 Ph- 7-(N)-morpholine 22 CH2OC2H5 Ph- 7-(N)-azetidine 23 CH2OC2H5 Ph- 7-(N)-N-methylazetidinium, I- 24 CH2OC2H5 Ph- 7-(N)-pyrrolidine 25 CH2OC2H5 Ph- 7-(N)-N-methyl-pyrrolidinium, I- 26 CH2OC2H5 Ph- 7-(N)-N-methyl-morphoinium, I- 27 CH2OC2H5 Ph- 7-(N)-N'-methylpiperazine 28 CH2OC2H5 Ph- 7-(N)-N'-dimethylpperazinium, I- 29 CH2OC2H5 Ph- 7-NH-CBZ 30 CX20C2R5 Ph- 7-NHC(O)C5H11 31 CH2OC2HS Ph- 7-NHC(O)CH2Br 32 CH2OC2H5 Ph- 7-NH-C(NH)NH2 33 CH20C2H, Ph- 7-(2)-thiophene 34 CH2OC2H5 Ph- 8-methyl 35 CH2OC2H5 Ph- 8-ethyl 36 CH20C2H5 Ph- 8-iso-propyl 37 CH2OC2H5 Ph- 8-tert-butyl 38 CH20C2H5 Ph- 8-OH 39 CH2OC2H5 Ph- 8-OCH3 40 CH20C2R5 Ph- 8-O(iso-propyl) 41 CH20C2R5 Ph- 8-SCH3 42 CH20C2H5 Ph- 8-SOCH3 43 CH2OC2R5 Ph- 8-SO2CH3 44 CH20C2H5 Ph- 8-SCH2CH3 45 CH2OC2H5 Ph- 8-NH2 46 CH20C2H5 Ph- 8-NHOH 47 CH2Oc2Hs Ph- 8-NHCH3 48 CH20C2HS Ph- 8-N(CH3)2 49 CH2OC2H5 Ph- 8-N+(CH3)3, I 50 CH2OC2H5 Ph- 8-NHC(=O)CH3 51 CH20C2HS Ph- 8-N(CH2CH3)2 52 CH20C2HS Ph- 8-NMeCH2CO2H 53 CH2OC2H5 Ph- 8-N+(Me)2CR2C02H, I- 54 CH2Oc2Hs Ph- 8-(N)-morpholine 55 CH2OC2H5 Ph- 8-(N)-azetidine 56 CH2OC2H5 Ph- 8-(N)-N-methylazetidinium, I- 57 CH20C2H5 Ph- 8-(N)-pyrrolidine 58 CH2OC2H5 Ph- 8-(N)-N-Methyl-Pyrrolidinium, I- 59 CH2OC2H5 Ph- 8-(N)-N-Methyl-morpholinium, I- 60 - CH20C2H5 Ph- 8-(N)-N'-methylpiperazine 61 CH20C2H5 Ph- 8-(N)-N'-dimethylpiperazinium, I- 62 CH20C2H5 Ph- 8-NH-CBZ 63 CH2OC2H5 Ph- 8-NHC(O)C5H11 64 CH2OC2H5 Ph- 8-NHC(O)CH2Br 65 CH2OC2H5 Ph- 8-NH-C(NH)NH2 66 CH2OC2H5 Ph- 8-(2)-thiophene 67 CH2OC2H5 Ph- 9-methyl 68 CH2OC2H5 Ph- 9-ethyl 69 CH2OC2H5 Ph- 9-iso-propyl 70 CH2OC2H5 Ph- 9-tert-butyl 71 CH20C2H5 Ph- 9-OH 72 CH2OC2H5 Ph- 9-OCH3 73 CH2OC2H5 Ph- 9-O(iso-propyl) 74 CH2OC2H5 Ph- 9-SCH3 75 CH2OC2Hs Ph- 9-SOCH3 76 CH20C2H5 Ph- 9-SO2CH3 77 CH2OC2H5 Ph- 9-SCH2CR3 78 CH20C2H5 Ph- 9-NH2 79 CH2OC2H5 Ph- 9-NHOH 80 CH2OC2H5 Ph- 9-NHCH3 81 CH2OC2H5 Ph- 9-N(CH3)2 82 CH2OC2H5 Ph- 9-N+(CH3)3, I 83 CH20C2H5 Ph- 9-NHC(=O)CH3 84 CH2OC2H5 Ph- 9-N(CH2CH3)2 85 CH20C2H5 Ph- 9-NMeCH2CO2H 86 CH2OC2H5 Ph- 9-N+(Me)2CH2CO2H, I- 87 CH20C2H5 Ph- 9-(N)-morpholine 88 CH20C2H5 Ph- 9-(N)-azetidine 89 CH2OC2H5 Ph- 9-(N)-N-methylazetidinium, I- 90 CH2OC2H5 Ph- 9-(N)-pyrrolidine 91 CH2OC2H5 Ph- 9-(N)-N-methyl-pyrrolidinium, I- 92 CH20C2H5 Ph- 9-(N)-N-mdethyl-morpholinium, I- 93 CH2OC2H5 Ph- 9-(N)-N'-methylpiperazine 93 CH2OC2H5 Ph- 9-(N) -N'-dimethylpiperazinium, I- 95 CH2OC2H5 Ph- 9-NH-CBZ 96 CH2OC2H5 Ph- 9-NHC(O)C5H11 97 CH20C2Hs Ph- 9-NHC(O)CH2Br 98 CH2OC2H5 Ph- 9-NH-C(NH)NH2 99 CH2OC2H5 Ph- 9-(2)-thiophene 100 CH2OC2H5 Ph- 7-OCH3, 8-OCH3 101 CH20C2H5 Ph- 7-SCR3, 8-OCH3 102 CH2OC2H5 Ph- 7-SCH3, 8-SCH3 103 CH2OC2H5 Ph- 6-OCR3, 7-OCH3, 8-OCR3 Prefix Cpd« R1=R2 R5 (RX)@ @@@@@@ @@@@ @@@@@ @@ @@@@ (FFF.xxx. vvv) F101.010 01 CH2CH(OH)C2H5 Ph- 7-methyl 02 CH2CH(OH)C2H5 Ph- 7-ethyl 03 CH2CH(OH)C2H5 Ph- 7-iso-propyl 04 CH2CH(OH)C2H5 Ph- 7-tert-butyl 05 CH2CH(OH)C2H5 Ph- 7-OH 06 CH2CH(OH)C2H5 Ph- 7-OCH3 07 CH2CH(OH)C2H5 Ph- 7-o(ito-propyl) 08 CH2CH(OH)C2H5 Ph- 7-SCH3 09 CH2CH(OH)C2H5 Ph- 7-SOCH3 10 CH2CH(OH)C2H5 Ph- 7-SO2CH3 11 CH2CH(OH)C2H5 Ph- 7-SCH2CH3 12 CH2CH(OH)C2H5 Ph- 7-NH2 13 CH2CH(OH)C2H5 Ph- 7-NHOH 14 CH2CH(OH)C2H5 Ph- 7-NHCH3 15 CH2CH(OH)C2H5 Ph- 7-N(CH3)2 16 CH2CH(OH)C2H5 Ph- 7-N+(CH3)3, I- 17 CH2CH(OH)C2Hs Ph- 7-NHC(=O)CH3 18 CH2C8(OH)C2H5 Ph- 7-N(CH2CH3)2 19 CH2CH(OH)C2H5 Ph- 7-NMeCH2CO2H 20 CH2CH(OH)C2H5 Ph- 7-N+ (Me) 2CH2C02R, I- 21 CH2CH(OH)C2H5 Ph- 7-(N)-morpholine 22 CH2CH(OH)C2H5 Ph- 7-(N)-azetidine 23 CH2CH(OH)C2H5 Ph- 7-(N)-N-methylazetidinium, I-<BR> PATENT<BR> <BR> 24 CH2CH(OH)C2H5 Ph- 7-(N)-pyrrolidine 25 CH2CH(OH)C2H5 Ph- 7-(N)-N-methyl-pyrrolidinium, I- 26 CH2CH(OH)C2H5 Ph- 7-(N)-N-methyl-morpholinium, I- 27 CH2CH(OH)C2H5 Ph- 7-(N)-N'-methylpiperazine 28 CH2CH(OH)C2H5 Ph- 7-(N)-N'-dimethylpiperazinium, I- 29 CH2CH(OH)C2Hs Ph- 7-NH-CBZ 30 CH2CH(OH)C2H5 Ph- 7-NHC(O)C5H11 31 CH2CH(OH)C2H5 Ph- 7-NHC(O)CH2Br 32 CH2CH(OH)C2H5 Ph- 7-NH-C(NH)NH2 33 CH2CH(OH)C2H5 Ph- 7-(2)-thiophene 34 CH2CH(OH)C2H5 Ph- 8-methyl 35 - CH2CH(OH)C2H5 Ph- 8-ethyl 36 CH2CH(OH)C2H5 Ph- 8-iso-propyl 37 CH2CH(OH)C2H5 Ph- 8-tert-butyl 38 CH2CH(OH)C2H5 Ph- 8-OH 39 CH2CH(OH)C2H5 Ph- 8-OCH3 40 CH2CH(OH)C2H5 Ph- 8-O(iso-propyl) 41 CH2CH(OH)C2H; Ph- 8-sch3 42 CH2CH(OH)C2H5 Ph- 8-SOC3 43 CH2CH(OH)C2H5 Ph- 8-SO2CH3 44 CH2CH(OH)C2H5 Ph- 8-SCH2CH3 45 CH2CH(OH)C2H5 Ph- 8-NH2 46 CH2CH(OH)C2H5 Ph- 8-NHOH 47 CH2CH(OH)C2H5 Ph- 8-NHCR3 48 CH2CH(OH)C2H5 Ph- 8-N(CH3)2 49 CH2CH(OH)C2H5 Ph- 8-N+(CH3)3, I- 50 CH2CH(OH)C2H5 Ph- 8-NHC(=O)CH3 51 CH2CH(OH)C2H5 Ph- 8-N(CH2CH3)2 52 CH2CH(OH)C2H5 Ph- 8-NMeCH2CO2H 53 CH2CH(OH)C2H5 Ph- 8-N+(Me)2CH2CO2H, I- 54 CH2CH(OH)C2H5 Ph- 8-(N)-morpholine 55 CH2CH(OH)C2H5 Ph- 8-(N)-azetidine 56 CH2CH(OH)C2H5 Ph- 8-(N)-N-methylazetidinium, I- 57 CH2CH(OH)C2H5 Ph- 8-(N)-pyrrolidine 58 CH2CH(OH)C2H5 Ph- 8-(N)-N-methyl-pyrrolidinium, I- 59 CH2CH(OH)C2H5 Ph- 8-(N)-N-methyl-morpholinium, I- 60 CH2CR (OH) C2H5 Ph- 8- (N) -N' methylpiperazine 61 CH2CH(OH)C2H5 Ph- 8-(N)-N'-dimethylpiperazinium, I- 62 CH2CH(OH)C2H5 Ph- 8-NH-CBZ 63 CH2CH(OH)C2H5 Ph- 8-NHC(O)C5H11 64 CH2CH(OH)C2H5 Ph- 8-NHC(O)CH2Br 65 CH2CH(OH)C2H5 Ph- 8-NH-C(NH)NH2 66 CH2CH(OH)C2H5 Ph- 8-(2)-thiophene 67 CH2CH(OH)C2H5 Ph- 9-methyl 68 cH2cH(oH)c2Hs Ph- 9-ethyl 69 CH2CH(OH)C2H5 Ph- 5-iso-propyl 70 CH2CH(OH)C2H5 Ph- 5-tert-butyl 71 CH2CH(OH)C2H5 Ph- 9-OH 72 CH2CH(OH)C2H5 Ph- 9-OCH3 73 CH2CH(OH)C2H5 Ph- 9-0 (iso-propyl) 74 CH2CH(OH)C2H5 Ph- 9-SCH3 75 CH2CH(OH)C2H5 Ph- 9-SOCH3 76 CH2CH(OH)C2H5 Ph- 9-SO2CH3 77 CH2CH(OH)C2H5 Ph- 9-SCH2CH3 78 CH2CH(OH)C2H5 Ph- 9-NH2 79 CH2CH(OH)C2H5 Ph- 9-NHOH 80 CH2CH(OH)C2H5 Ph- 9-NHCH3 81 CH2CH(OH)C2H5 Ph- 9-N(CH3)2 82 CH2CH(OH)C2H5 Ph- 9-N+(CH3)3, I- 83 CH2CH(OH)C2H5 Ph- 9-NHC(=O)CH3 84 CH2CH(OH)C2H5 Ph- 9-N(CH2CH3)2 85 CH2CH(OH)C2H5 Ph- 9-NMeCH2CO2H 86 CH2CH(OH)C2H5 Ph- 9-N+(Me)2CH2CO2H, I- 87 CH2CH(OH)C2H5 Ph- 9-(N)-morpholine 88 CH2CH(OH)C2H5 Ph- 9-(N)-azetidine 89 CH2CH(OH)C2H5 Ph- 9-(N)-N-methylazetidinium, I- 90 CH2CH(OH)C2H5 Ph- 9-(N)-pyzrolidine 91 CH2CH(OH)C2H5 Ph- 9-(N)-N-methyl-pyrrolidinium, I- 92 CH2CH(OH)C2H5 Ph- 9-(N)-N-methyl-morpholinium, I- 93 CH2CH(OH)C2H5 Ph- 9-(N)-N'-methylpiperazine 93 CH2CH(OH)C2H5 Ph- 9-(N)-N'-dimethylpiperazinium, I- 95 CH2CH(OH)C2H5 Ph- 9-NH-CBZ 96 CH2CH(OH)C2H5 Ph- 9-NHC(O)C5H11 97 CH2CH(OH)C2H5 Ph- 9-NHC(O)CH2Br 98 CH2CH(OH)C2H5 Ph- 9-NH-C(NH)NH2 99 CH2CH(OH)C2H5 Ph- 9-(2)-thiophene 100 CR2CH(OH)C2H5 Ph- 7-OCH3, 8-CCH3 101 CH2CH(OH)C2H5 Ph- 7-SCH3, 8-OCH3 102 CH2CHtOH)C2H5 Ph- 7-SCH3, 8-SCH3 103 CH2CH(OH)C2H5 Ph- 6-OCH3, 7-OCH3, 8-OCH3 Prefix CpdZ R1=R2 R5 F101.011 01 CH20-(4-picoline) Ph- 7-methyl 02 CH20-(4-picoline) Ph- 7-ethyl 03 CH20-(4-picoline) Ph- 7-iso-propyl 04 CH2O-(4-picoline) Ph- 7-tert-butyl 05 CH2O-(4-picoline) Ph- 7-OH 06 CH20-(4-picoline) Ph- 7-OCH3 07 CH2O-(4-picoline) Ph- 7-O(iso-propyl) 08 CH20-(4-picoline) Ph- 7-SCH3 09 CH20-(4-picoline) Ph- 7-SOCH3 10 CH2O-(4-picoline) Ph- 7-SO2CH3 11 CH2O-(4-picoline) Ph- 7-sCH2CH3 12 CH20-(4-picoline) Ph- 7-NH2 13 CH20-(4-picoline) Ph- 7-NHOH 14 CH2O-(4-picoline) Ph- 7-NHCH3 15 CH2O-(4-picoline) Ph- 7-N(CH3)2 16 CH2O-(4-picoline) Ph- 7-N+(CH3)3, I 17 CH2O-(4-picoline) Ph- 7-NHC(=O)CH3 18 CH2O-(4-picoline) Ph- 7-N(CH2CH3)2 19 CH2O-(4-picoline) Pb- 7-NMeCH2C02H 20 CR2O-(4-picoline) Ph- 7-N+(Me)2CH2CO2H, I- 21 CH20-(4-picoline) Ph- 7-(N)-morpholine 22 CH2O-(4-picoline) Ph- 7- (N) -azetidine 23 CH20-(4-picoline) Ph- 7- (N) N-metbylazetidinium, I- 24 CR20- (4-picoline) Ph- 7-(N)-pyrrolidine 25 CH20-(4-picoline) Ph- 7-(N)-N-methyl-pyrrolidinium, I- 26 CR2O- (4-picoline) Ph- 7-(N)-N-methyl-morpholinium, I- 27 CH2O-(4-picoline) Ph- 7-(N)-N'-methylpiperazine 28 CH20- (4-picoline) Ph- 7-(N)-N'-dimethylpiperazinium, I- 29 CH20-(4-picoline) Ph- 7-NH-CBZ 30 CH20-(4-picoline) Ph- 7-NHC(O)C5H11 31 CH20-(4-picoline) Ph- 7-NHC(O)CH2Br 32 CH20-(4-picoline) Ph- 7-NH-C(NH)NH2 33 CH2O-(4-picoline) Ph- 7-(2)-thiophene 34 CH20-(4-picoline) Ph- 8-methyl 35 CR2O-(4-picoline) Ph- 8-ethyl 36 CH20-(4-picoline) Ph- 8-iso-propyl 37 CH2O-(4-picoline) Ph- 8-tert-butyl 38 CH2O-(4-picoline) Ph- 8-OH 39 CH20-(4-picoline) Ph- 8-OCH3 40 CH2O-(4-picoline) Ph- 8-O(iso-propyl) 41 CH20-(4-picoline) Ph- 8-SCH3 42 CH2O-(4-picoline) Ph- 8-SOCH3 43 CH20-(4-picoline) Ph- 8-S02CH3 44 CR2O-(4-piooline) Ph- 8-SCH2CH3 45 CH2O-(4-picoline) Ph- 8-NH2 46 CH20-(4-picoline) Ph- 8-NHOH 47 CH2O-(4-picoline) Ph- 8-NHCH3 48 CH2O-(4-picoline) Ph- 8-N(CH3)2 49 CH2O-(4-picoline) Ph- 8-N+(CH3)3, 1 50 CR2O-(4-picoline) Ph- I8-NHC(=O)CH3 51 CH20-(4-picoline) Ph- 8-N(CH2CH3)2 52 . CH20-(4-picoline) Ph- 8-NMeCH2CO2H 53 CH20-(4-picoline) Ph- 8-N+(Me)2CH2CO2H, I- 54 CH2O-(4-picoline) Ph- 8- (N) -morpholine 55 CH2O-(4-picoline) Ph- 8- (N) -azetidine 56 CH2O-(4-picoline) Ph- 8-(N)-N-methylazetidinium, I- 57 CH2O-(4-picoline) Ph- 8-(N)-pyzzolidine 58 CH2O-(4-picoline) Ph- 8-(N)-N-methyl-pyrrolidinoium, I- 59 CH2O-(4-picoline) Ph- 8-(N)-N-methyl-morpholinium, I- 60 CR2O-(4-picoline) Ph- 8-(N)-N'-methylpiperazine 61 CH2O-(4-picoline) Ph- 8-(N)-N'-dimethylpiperazinium, I- 62 CP.20-(4-picoline) Ph- 8-NH-CBZ 63 CH2O-(4-picoline) Ph- 8-NHC(O)C5H11 64 CH2O-(4-picoline) Ph- 8-NHC(O)CH2Br 65 CH2O-(4-picoline) Ph- 8-NH-C(NH)NH2 66 CH2O-(4-picoline) Ph- 8-(2)-thiophene 67 CH20-(4-picoline) Ph- 9-methyl 68 CH20-(4-picoline) Ph- 9-ethyl 69 CH20-(4-picoline) Ph- 9-iso-propyl 70 CH2O- (4-picoline) Ph- 9-tert-butyl 71 CR20-(4-picoline) Ph- 9-OH 72 CR2O-(4-picoline) Ph- 9-OCH3 73 CH2O- (4-picoline) Ph- 9-O(iso-pzopyl) 74 CH20-(4-picoline) Ph- 9-SCH3 75 CH20-(4-picoline) Ph- 9-SOCH3 76 CH20-(4-picoline) Ph- 9-SO2CH3 77 CH2O-(4-picoline) Ph- 9-SCH2CH3 78 CH2O-(4-picoline) Ph- 9-NH2 79 CH2O-(4-picoline) Ph- 9-NHOH 80 CH2O-(4-picoline) Ph- 9-NHCR3 81 CH20-(4-picoline) Ph- 9-N(CH3)2 82 CH2O-(4-picoline) Ph- 9-N+(CH3)3, I 83 CH2O-(4-picoline) Ph- 9-NHC(-O)CH3 84 CH20-(4-picoline) Ph- 9-N(CH2CH3)2 85 CH2O-(4-picoline) Ph- 9-NMeCH2C02H 86 CH20-(4-picoline) Ph- 9-N+(Me)2CH2CO2H, I 87 CH2O-(4-picoline) Ph- 9-(N)morpholine 88 CH2O-(4-picoline) Ph- 9-(N)-azetidine 89 CH2O-(4-picoline) Ph- 9-(N)-N-methylazetidinium, I- 90 CH2O-(4-picoline) Ph- 9-(N)-pyrrolidine 91 CH2O-(4-picoline) Ph- 9-(N)-N-methyl-pyrrolidinium, I- 92 CH2O-(4-picoline) Ph- 9-(N)-N-methyl-morpholinium, I- 93 CH2O-(4-picoline) Ph- 9-(N)-N'-methylpiperazine 93 CH2O-(4-picoline) Ph- 9-(N)-N'-dimethylpiperazinium, I- 95 CH2O-(4-picoline) Ph- 9-NH-CBZ 96 CH20-(4-picoline) Ph- 9-NHC(O)C5H11 97 CH20-(4-picoline) Ph- 9-NHC(O)CH2Br 98 CH2O-(4-picoline) Ph- 9-NH-C(NH)NH2 99 CH2O-(4-picoline) Ph- 9-(2)-thiophene 100 CH2O-(4-picoline) Ph- 7-OCH3, 8-OCH3 101 CH2O-(4-picoline) Ph- 7-SCH3, 8-OCR3 102 CH2O-(4-picoline) Ph- 7-SCH3, 8-SCH3 103 CH2O-(4-picoline) Ph- 6-OCH3, 7-OCH3, 8-OCH3 Additional Structures of the Present Invention - l SX Y:I\\ rrrrrrrrt at the 7- OsitiOn 102 et n.but I . z 7tnzith Iatnrnoniuin i()(ii e 103 n.but I h I OH H I: I H 7 Inineth Limrntinjurn iodide 104 eth I n-but I OH H hLll I H 7-dineth Iflfl)ino 105 eth I n-but I OH H 'I1'n I H 7-meth,ie.uI(nanido etI' I n-but I 0 hei I 7-(2'-I'niiuicet;iiiidu) 107 n-but I etli I OH 4-(dtc lox ) I'w I H I 7-,inino 108 eth I n-bu I OH H hei I H 7.(I'x lainido) 109 eth I n-but I OH H 4.(dec I£'x ) ,It I H 7-amino 1)0 etI' I n-but I 0 Ie:' -acetainido a n-butI etI' 9 r r T 2 T r ' ~ r ~ r r r I r r r r :r: r ~ O O D O O O D O O O !> Bc > S>=, >»c S Y :s c c > ,«~ >>v :F 112 eihyi i.butyl OH H O\8 H 7.alniIL) H2N 11i34 :CIbu)ti Lui : oO{iI lH eth I OH H 4-rnt:tIcx I' I H 7-(O.ben, Icarbamalo) I 1G eth I n-but I OH H I-rntI'ox Iei' I H 7-(O-bn?. Icarbimito) 117 n-but 1 tth I OH I'i I 7-(O-benz Ica rkiinato) I IB cli' I i-but I OH I-I )I,fl I H 7.(O-bcnz Icarbamato) 119 cII I n-but I OH H )IL1 I H 7-(O-tcrt-bui Icarbamalo) 120 n-but I eth I OH H lLE' I H 7-(O-bcn. Icarbaiiiato) 121 clI' I n-btLt I 0 H Icn I 7-amino 122 n.but I eth I OH H Icn I at t)c S- osition > p t °, vOT CI1CPQ I clI' I OH H 4-(Iuoru I'cn I H 7-amino 12B etli I n-but I OH H 4-fluoro I'cn I H 7-(O-bcnz Icarbamato) 129 eth I n-but I 0 44luoro hcn I 7-amino 131 ethyl n.butyi OH H 4-fIucnpI'w'yI H {;Y I 0 g Fo lo E k 133 eth I n.but I 0 H hen I H 8-(hex lox ) 134 ethyl n.butyl 0 H phenyl H at the 8- osition f et y I, at the S- osition 13 eth n-bu I1ei I 8-I' drox r n.butyi etII r r r " E ~ ~ r ~ nt the 7 rr = 1 S'- ut eth 1 hen I 8-acetox I n. utyl ;s ! ~ ffi D ffi CE ffi G C; D ~ ~ hen 3-in-tI't'x )lLn I I 7-n'th Imerca to 144 et I n-but I OH H 4-Iu£r )Iefl I II 7.(N-a?.etidifl I) r eth I n-but I OH II 3-mth£'x r I H 7-'netIox 23 CI . n-btityl H ~ H 3imt-thtxy- . ~ D Or r O tO O jI Or Or Or r t t , { y X i > cS } c =, An . > > > > k F F F k F 264 eth I n-but H -Irifluorinietli I lien I lien I 7-metliox 265 ethyl n.butyl H 0 H 3-trifluoro- 7-ineilitixy methyl. hen I 266 eth I n.but I OH H 3-li drox lieu I H 7-h drox 267 cliii n.but I OH H 3-li drox lien I H 7-metliox 268 etli I n-but I OH H 4-fluoni lien I H 7-methox 2 9 ethyl n utyl 0 II 4- luoro- 7-inetlioxy hen I 270 eth I n-but I OH H 4-fluoni lieii I H 7.Ii drnx 2 1 eth I n.but I OH H 3-nietliiix lie'i I H 7-brorno 2 ethyl ii.butyl O H 'h 3-metlioxy. 7-broino lien I 273 ethyl n.butyl H 0 H 4-fluoro- 7-fluoro lien I 274 eth I n.but I OH H 4-fl'sirti lien I H 7-fluoro 27 et iyl n uty 0 3-inetlioxy. 7-fluoro lien I 276 etli I n-but I OH H 3-inetlitix lieii H 7-fluoro 277 3~yrrZrrf5tr H 3-fluiirii le'i I H 7-inetliox = ci T T ut T 2-fluort' Iitii I 7-nietliox 2 9 Ct I n- Lit I OH 3-jIuor' 'liiii I 7-'neiliix 2fl() etli I i-but I OH I-I 2-flii£'ri 'liLil I H 7-nietliox 281 etli I n-but I OH H 4-flisoro lien I H 7.rnetli Imerca to 28 etli n- ut I 0 t-(luorii lien I 7-met Ii I 283 ethyl n- utyl 0 I 4-fluoro- 7-methyl lien I 284 etli I n- ut I OH H 4-fluoni lien I H 7-(4'-mor linlino) 28 x 28 cli I eth I I liLli I 1 -(0-benz Icar imato) 287 etli I etli I OH H )IiCii I H 7-ainini' 288 metli I metli I 0 H heii I H 7-aiiiioo 289 n-but I n-but I OH H lieii I H 7-aniinii 2C n-but I n-but I 0 liei' I 7-amino 291 n-but I n-but I 0 H )lieii I H 7-(O-ben. Icarbimato) 292 n-but I n-but I OH H 4-flunro lien I H 7-anino 293 n-but I. n-but I 0 II lien I H 7-benz amino 94 nut I n- ut I 0 lien I - imelli lamino 295 ethyl n-butyl 0 H oI H 7-amino O = O O O r O O = r o I O : = e o T T D O O O D # O O Sx > >~ b >~ x ~ X ~~ > Xb, ~ b > cS >~ W- W F t H M ethyl n.butyl OH H H 7-amino O¼N (CH3)3 1000 etltyl n.lautyl OH H . Imetliylamino 1 1 et y n. uty $i½0¼yN+(CH2CH)3 . methy amino 1002 ethyl n- utyl OH H ½½Di 7.dimeiliylamino 1003 ethyl n- uty (½0$mN+5 -diiiiethy amino l +0 ethyl li-butyl OH H Q CFOo+#¼N$1 ; H 10 n. uty n- utyl .dimetliylamino ~ Or o Or . ~ n s x D b e } 1 F F 1006 n.butyl n-butyl OH H I H 7.dimetl'yImino Dr- 1007 n.butyl n-butyl OH H H 7.dirnetliy amino I- + 0N(CH2CH3)3 1 n- uty n- uty .dimetliy amino I- N I 0ThN1Gi 1009 n. uty n.butyl OH H ONN1 q 7-d imethylamino 1012 n.butyl n.butyl OH H 1-IiyJrnxyplienyl 7-dimethy amino; r: '------ LIty Ii. tity 0 F I- 7.JiiiietIiyIaii'i'ii Io + I- II(0H3)3 3 1014 n.btityl n-butyl : H 1.iiietIi'xypIienyI e 7.Jimetliyla'nino; 9-IflCtI'L'Xy 1 15 n.butyl n-LNtyI 0 H F H 7.dinietliylamino Dr- iO&2\+ 10)6 n-butyl i- utyl 0 H 7-d Irnethylarnlno I 0+ CO2H 1017 n.butyl n- utyl OH H I- 7-dhiiet tylarnlno I I 1019 n- uty n.butyl 0 OF(/CHk4OYcH2)\4 N 7-d ilnethylamino ii ( 2 -''J » =, X » x . >v 11121 n-butyl n-butyl 0 H H 7.dirnethylamirio 102 n-buty n-butyl OH H H 7.d metliylarnino 0 W zSotl X < 4 =l o o 1024 n uty Ii ty 7.dimcthylamino 1 n. uty n- utyl 0 ½ii$F 7. rnctliy amino Si = =: = >,7r- .= 1 X 1 1029 ii.butyl n-butyI 0 H 7-dimetliylamino °e o o c s b 4 s s zero OMN 5 n.butyl r utyl r F 7.diinelliylamino |g \ /O H2)4 N(CH2CH3)3 + 1 3 n- tity n- uty - -dimet 'y am no Cpp)2 zion + J! DN 10 n.butyl a.butyl 0 H .dimetliylamino Dr- 1034 n-butyl n.butyl 0 H -d i'nethyIainin Or D a } 8 3 n OX 1035 n-butyl n.btityl OH H H 7-dirnethylamino O#3N$+ II 1(n n.butyl n-butyl 0 H oN'%$+0CHII, 7-d imethylamino 1037 nut I n-but I 0 H 4-h dtiix )liLn I 7-dimeti' lamino I n- uty n- uty 0 - niet ,y amino N+(0H3)3 1039 n-but I n-but I OH H )heIi I H 7.dimeth Ianiino 1040 n.butyl n-butyl 0 H FYCH2)\4 (,CH2 H 7-dimethylnmino 0 0 " TIE + = T O ~ O 104) n-bulyl n-butyl OH H H 7.dii'iIliyla'nino : o : o o . o c c c c c , c ½) o;½ N (C6Hi)3 1043 n.butyl n-butyl OH H [½)½ H 7.dimetliylamino 1044 n.butyl n-buIyl OH H F H 7.dimetliylamino Cr,Co2 0, 1045 n.butyl n-butyl OH H ¼½;0F CpCO2 H 7-dimethylamino (OH2)8 + d; 1046 n-but I n-but I OH H 3-amino hei I H 7-dimeth lamino 1047 n.butyl n.butyl 0 o 7-dimethy amino N(CH2CH2 > W 0t 0, O o4 i.buIyI a-bUIyI 0 1 H H 7-dinictliylaniino 9 d 3 9 1049 n-butyl n.butyl OH 1F lIr- ¼ii 7-dimethylamino loso n.buty) n.butyl == ------------ I. oYN#ii +u- 0 sg3 1 f > ~ r r r r ~ 5 Or D ~ ~ E E 3 lU53 n-butyl .butyl OH H ci?,C02 H 7.diinetliylamino £CH2k3 10 4 n- utyl Ii- uly 0 7. imethylamino 7- imet iylamlno i S iPt ~ a e E ; 2 nuty cS uty g ~ cu t^ I b r r r r Dr Or D r r { { @ fa tE 1058 ii-buiyl ii.butyl OH H 7-LIi"ititltyla'iiinu io7N+Ni)¼ 105 n.butyl n- tityl 0 1FIlrDI -d i:nt:tl'ylamino 106 etli - n-bu - 3-fItor'i-4-0metIioxlien' 7-meth lainino 106) n.butyl n.buty OH H 7.metliylarnino I rlr s 3 1062 n.buty L uty '¼0)yN+/N%s methylamino 1e > F 4 t 1w= 3H 10(4 i. utyl li-butyl OH H D H 7.nietl'ylamiiio 10£ n- uty n. utyl . imetliy Imino I N+((CH2Cll2O)2CH3)3 l0££ n.l'utyl n-butyl OH H H 7.diinetIyIainino 10 Ii- iltyl n- uty 0 pheiiy 7-d imetliylamino; -dimetl' lamino X J < 14 1 llC F @D D b D X 1070 i'.bt'Iyi i'.butyl 0 H F I 7.Jimt:thyIniinu 1071 n.butyl n.buty 0 H H 7-dimetbylamino I Th+5 OThNJ I i i I uty IT T F X jA ~340 n- uty n. uty F Dr - imet y amino 4"T Thy o7% N (OH 3)2 'i-buIyI n-biI I OH H 3-hyIr'ymL-iI' )II' I H 7-J i'ieihyIaminc' > = i a> > @ > R s v E a ~ a 1078 etli I i-but I H H 1-I rox )Ii'i I 7-dimetli iinino 1079 ethyl ii.butyl OH H 7-dimeihylimino 0 O Q Ii P N- 1¼ r 10 n- utyl n-buIyI 0 H H -dimethylamino , 108) n.butyl n-buiyl 0 H 7-d imethylimino i F > >s b ->W b : I # nc ? 1083 i.butyI ii- utyl OH H dimet iylamino o o o o o o o o C C .4 E .C n- uty a uty a imet ; amino D » ~ » ~ ~ ~ ~ t ?i'ii t ?iV .j .f 9 .I.E.E uer 1086 ----------------- I r r -- n.butyl n- utyl I H L 2 Ir r . t uty n- uty t 1 imet iy amino 1088 eth I n-but I OH H 3,4-meth lenediox lien I 7-diinetli amino 108 cth I n-but I OH H 4-methox hen I H 7-dimetli lamino 10 n.butyl n.butyl 0 - -z I oN$ Q r I r I r I r T T I r I r r r T o o o o o o o o X D e b b > > x :,> Is?- ° ne nC ~ @ "? nc sE i % æ Si. utyl n.butyl OH H -,lii'i'tl'ylai'ii'io !093 n-buty n- utyl 0 oN/)¼+00 H 7-dimethylamino i i SX on o<tow 4 4 e 4 Os Or o 1095 ii-butyl n-butyl OH H H 7.dinietliylainino 'ii n uty s5 uty s imet iylamino n n J cnn cn ~ . ~ ~ i 14 N 1> T X r etli I #\om# +oao31 1099 n-but I OH H 4-methox lien I H 7-dimeth Inmino Xt 1101 n.butyl n-butyl OH H N1 H 7.dimetliylamino 0 9, 1102 n-but I n-but I OH H 3-c'irb'x metli I hen I H 7-dimeth lamino 1103 n.butyl n-butyi 0 H H 7-dimethylamino o¼;+N+N(cHa)i 1104 ii-butyl n.butyi OH H H 7-d imethytamino yD I A; L S É n-bull n-but E OH E S. c rwi E E 1e n-but X X ut . n v X X X 1107 n- utyl n. uly flr -d imethylamino ------------------ H I H rid I ------- ------ 1109 n.butyl n.butyl OH H ¼½;0F ?-d imethylamino 1110 n-butyl n- utyl H H H 7-dimethylamino 1 11 O ~ ~ = T r r = = r r Or Or Dr O 3 o o- - 8 1113 n- utyl n. utyl H F 1111311 0¼ 1114 n-but I n- ut 0 3-met iL)X iwi I -metli amino 1115 n-but .1 n-but I OH H 4-fIuoct hen I H 7-dimetli lamino 1)16 etli I n-but OH H 3-toll H 7-dimeth lamino ;i117 ethyl n-butyl OH H H 7-dimeihylam no I 0+N(OH2) 11)8 eth I n-but I 0 H 3-fluon-'l-I Jnmx hen I 7-dimetli lamino 111 n-buty n- utyl -dimet ylamino 1 11 n- uty n- uty I- - imet y amino I o7%o) 1121 n.butyl n.butyl 0 H 0M½1 -dimethylamino 1122 n.butyl ii.butyl OH H tIr H ?-diinethylamino 0N F 2 o o o o o o : o o o o o o 1123 n-but S n-but c OH .S lien I 7-dimetli lamino 1124 n-bui I n-but c E OH é c é E E E 99 n-but n 9 e e ~ e ~ C ethyl n-butyl -- C ~ ~ 5 Tt bf tS E EEEE E EEEE EE a aa aa r rrrr rIrrr rr I r n-but I n-but I OH H 3-fluon'-4-h r Iieii I H 7-dimetli amino 112t) n-but I n-but 0 4-flutr Iieii I 9-dimetli anilno 1130 n-but n-but 0 1-1 3-cIihmri-I-flutir hii I -dinieth lainino 1131 etli I n-but I OH H 4-inetliox I'eii I H 7-dimetli lamino v n.butyl ii.butyl OH H H 7-dimethylamino 1134 ethyl n.butyl OH H ~ ~ ~ ~ ~ ~ ~ ~ r T . T r T T T ~ . r r T r lOr ° ° Or Or Or Or T O O D Or > N > w rs > > ro ~ en n X 113 n-bui I n-ba' c)l H 3,,l-jimLIhiix 'hatis I 7-diiiictI lamino 1)36 n.butyl n.bulyl 0 H H 7.dimetliyianiino 3 113 n ut I n-bull 0 H 4-flu'irss hen I ' 9-(,2'-dieth Ih draxino) 1138 n. utyl n.buty 0 7<1 imethylamino $'yYi 1139 n- ut I n-but 0 3,4-JIflusr' Ii"ii 1 7- isnel i Iamiiio --S X fi 1140 n-but I si-but r H rrrrsrrrrT . r = T ' ~ r T T 1141 n.bui I n-but I OH 4-tIusrsi lien I H 7-etli Irnetli lamino - isobutyl ~ ~ 0 ,,, ~ ,,,,,,,,, I oc2c3t 114 ii. uty n- uly - Lioro- - - met iy amiiio =\ lien I 1144 n-but I n-but I 0 5- i cross I H 7-dimeth lamino 14 n- ut ii- ut 4-mdhix lesi 9- imet amino 1146 n.butyl n.butyl 0 II H 7-d imetliylsmhio u, 0 'Z t N(0H3)3 + 1147 Ii- tit I n-but I OH H 3-mL-thLiX ilILli I H 7-dielI' lainino 111 n- ut li-but 0 4-fIuro lien I - inieth Isul "nium, luoside sa I 119 n- LII I ii-bui I OH H 'I-fI'igir )IlLIi I H 7-elI' amino 1150 n-but D i-but I rr H 3-miIiox TLI 1 H 7-etli Imetli amino H 7-dimeth larnino 1156 n- ul I n-but I OH H 4-tluur' lieii I 7-metli linerca to 115 n.bulyl ii-btiiyl OH H 4.fIurpliiiyl 7-fluoro; 9-dimetli lamino 1158 n- LII I n-but I OH H 'I- ritliii I, Ii dr&it-tilt'rij' .att 7-methox Ii ' n-but I eih I 0 liL'I1 I 7-dimelli lainino 1 1( n-bui I li-but I OH I-i 4-fILI("(i hcn I I 7-ditli lainin'i 1161 u-but I n-but I OH I-I 3,5-jichItrt-4-ii'thx htii I H 7<ii'neth lamino 11(2 n-but I n-bull OH H lici I 7-dimetli laniino 1163 n-but I i-but 0 3-((liIiiCIh Iamiiiti) )htIi I 7-melliox 1164 n-but I n.but 1 OH H 4- ridiii I . 7-metliox 1165 n-but I li-but OH H 3-fluoro-4-metliox lieii I 7-trimetli lammonium iodide 116 n-but I n-but I OH H 3-li dmx hen I 7.trimetli lammonlum iodide 1167 ji-butyl n- uty 0 7-dimethy amino i - n-but i n-but t OH H 4-Il Jr'mx )Ileii j i T]0 1169 n-btit I li-bIll I OH H )IiLli I H 8-d T;T laminli 1170 li-bIll I u-but I 0 I 3-liiLlhiX ilILli I I 7-etli I ri limbo T n-but T u-but I OH H 4-(Irifloortil'tI Isijlttisi Itix = r I H 7-dimetli Inminti 1172 u-but I u-but I OH H 'I- rittli I H 7-liiL'IIi()x 1173 li-but I lI-bill I OI Ii 4-fIit'rt )IILII I It 7-tIli I ro Iaiiino 1 174 CIII I ii-bul I 0 I 3-iii-Iht'x )IIt'Ii I - hen I 1175 eli I n-biLl I OH H 3-iiit'tliix iliLli I H 7-meIli I:ulfon I 1176 n-but I n-bill I OH H 4-fluorti Ii&ii I H 'J-fluoro 1177 u-but I n-but I OH H 3-nit-thox lieu I H 7-but Imetli Ianiiiio 1178 u-but I u-but I H 3-(lrltluoroliit'IIi I.uIfoii lox ) lien I H -dimetli amino 1179 n-but "x I n-but I OH Ii lien I H 8-metliox 1180 n-bui I n-bul I OH H ilieli I H -trimeth lamninniuni iodide 1181 Ii- III I Il-but I OH H 4-fluort llli I H 7-but linetli Iarnllio 1182 n- ut I n-but I 0 4-(dimelli lamino) lien I 7-niel iox I 1S3 n-but I n-but I 0 H 3-nieth'x Iieii I H 7-fluoro 1184 li-bulyl li-bulyl OH H 'I.fluortipIieiyI II 7-tIuuri; L L 118 ii- ut Ii- ut I 4-flutirti hen I -fluoro 1186 n.buty n-butyl p iCilyI -fluoro; 9-fluort' 1 1S7 n-but I li-but I OH 1 4-(Iu.iro ilien I II 7-melli I 1188 n-but I o-bul I OH H 4-metlitix Ileli I H 7-trimetli Iamniiinitm iodide | S 2 12 ; X r ; L 2 > > i " S z > i i 1i 1d i 1194 n.butyi ii-butyl OH H H 7-dimCtiiylamino ft S - lI-but - n-but - OH H 4-i1Iiux Icn - H 7-(4.metIi I i elizin-1- I) 1196 n-butyl n.butyl 0 '½; H 7-methoxy N(OH3 r n.butyl thyI r = r I 7.(N.rnetl'y > I X n-but n ;'-but J t H lien I 7-dimetli lamino Ol n- uty A 5 D / e- t = r :b b bS ~ n ~ e 1202 n.butyl si-butyl OH H 7-inetlioxy I N(0H3)3 1203 n-but I u-but I OH H 5- ii traxin I ?-(4-tcrt-but I lien I) 1204 n-but I n-but I OH 4-iIutro Ien I 7-metliox 120 n-butyl ii-buty yitom;i . imeilIy am no ~ ~~~ ~ ~ ~. ~ ~ ~ ~~ ~~ ~ -siz ~ ~ 1207 n-but I n-but I OH H 3, -dichioro hen I 7-dimetli lamino 1 08 n-bui I n- ut I I 4-mt.tIx Ien I 7-dimetli lamino 1209 n-but I n-but I aceto H Iie,i I H 7-dimetli I hen I 1210 n-but I n-but 1 OH H 2-(dimeih lamino) lien I H 7-dimetli lamino 1211 ethyl n-bulyl H H H 7-dimethylamino IO T r n- ul I n-but I OH H 4-methix ICli É H I htiiintm) V o r 4 < ;s r n-butyl ethyl H ~ OH T I 7.dimetliylamino I lien I 1 14 n-but I eth 0 len I 7-( -metli I orinamido) 1 O n- tit E n-but O OH T 4-meth(lx heny r 9-ineth Imerca to D nX = b b > Ss D»C > > > ~ nx SSW 1 >,~ ^ > AZ Yo 3 Y r æ E æ O 12 I(' ottIl I n-but I OH H 5- ) L.fl)n I H 7-bruniu 121 :i-but I n-but I OH H 4-carbix heii I H 7-diinctli lamino 1218 n-btit 'I n-bull OH H 4-'n'thix IIeii I H I 9-meth kuifon I 121* ii.butyl ii.butyl 0 7-dimethylamino iF W 4 h r n-but I n-but I OH r 3-mttliux lien I I 122 1'- uly n-butyl 0 plleiiyl 8-bn'mo; ,,, lamino 1224 li-bLil I li-but I CII H 3-nitni )llL-li I H 7-fluoro 1225 n-but I etli I OH H 3-liiLlII I IILII I H 7-dimeth lainino 1226 eth I n-but I 0 5- i ,'n'n I 7-bromo 1227 n-but I n-but I OH H 4-fluow lien I H 7-(tcrt-but lamino 1228 n.butyl n.butyl OH H 2-pyrnilyl H 8-bromo; 7-dimetli lamino 1229 n- ut X n-but o 3-cIIIoru-I-II Jwx lien I 7-dimeth lainino 12 n.buty n-butyl 0 plienyl 9. imethylamino; 7-fluoro i BQ " - t0 ie H H =I; N r r I r r T (OH3) r D ° ° r Or Or O T D T O O O T r a: oi X 5b > > ~ ~ > Se ~ E n E ~ I l li.butyi li-butyl -- II - - + 001 3 c E E o Q n.buty n.buty 0 7.dimctliy amino c c EC C C ~ ~ E X E E E E E E 12 n-but n-but 0 I-( roni'im"th I) hen I -dimetli amino - n-butyl n-butyl ----- - -- '-- -- + TTT o Nr(ctl)a 12 n- uty n-buty )i½0F; - imet iylnmilio 12 n- uty n-buty ¼½i0Fnr -dimetliy amino 2 1240 n-but I n-but I 0 H 4-inetliox -3-metI I lien I 7-dimetli lamino 12 1 n- ut n-bu 3.(dimeth laininometli I) hen I -dimeth lamino S n.butyl n-butyl ,' H 0F01 8 imetliyiamilio 4 12 3 n- uty n.buty 0 + -dimetliy amino I p/\ ~ r r r r r . r r r i 1: D O Or O D OZ ° . l s ~ > ~ b S.D z D g ç ~, ffi i >, 3 x i 1! > 1- 1 11 31313 L 1244 n-but I n-but I OH H 3-itItix )iill I H 7-(1-metIi lii drazido) 1245 ii-butyl n-butyl OH H '½; H 7diliiCthyIamino ô o o o o o o o o o o N(0113)3 124 n-but e ut e 3-(bromometh a a x a 1 É C: n.butyl OH H H dimethylamino h h OH 1248 ----------- - ~ ~ ~ ~ ~ ~ OH 1249 - n.butyl n-butyl r H 2rT f r IO 1250 n- ut n-but I 0 3-(dimeth lamino) hen I 7-dimetli lamino 1251 n-but I n-but I OH H 1-na lith I H 7-dimetli lamino 1252 lX fr ,,/+t r r r r r r r r I r I = I r I r r r r o o o o o o o o o o o ~ n = s b > > > > > X > X X > > X > c c c c s c c : c c . z > wN ON wN ON s - S S m 2 n uty ii. lity N+ I- 7.dimetliylaniino (OH3)3 n- ut n- ut 0 -liiirO lien - imeth amino 5 n.butyl ~~~ X pIiiiyl S-bwm£m; Eo lamino 1258 n-but n-but I OH H 4-fluow lleii I H 9.(tert.but lamino) et I n- ut 0 I ien 7- imetli lamino r et s ut r r rox v. n X 2 X X 1261 n-but n-butyl 0 7.dimetliylamino 126 > r I r r r = r = = = 1263 n-but I n-but I 0 5- i eroii I H 7-bromo 1264 n-but I n-but I 0 H 4-Iluoro hen I H 7-iso ro lamino t/ e q xi L Fop n- uty n- uty 0 + -dinict iy amino 0CH3 126 n1'ut etli I 0 1 cion I ox , meth I ester 1268 L-UI) n.buty 0 OH2OH3)i --H- 7-dimethylamino S r r r r Dr r r r r I I I r I I Os O r r Or r Or Or Or oS O O O 3 > 2 2 ~+ 7^2= ~ 2 2= ~3s > t iux >]: 2 ~ 2 b 2 2> x . 1 ~ t;i e S a ~ ~ 5 S M1 + 5 1270 si-butyl ii.butyl OH H mD;0F Br H 7.diietllylaiiiino VT é n-butyl n-butyl c c c c oc 'E E X a E ~ = 1272 n.butyl n-butyl OH H CO2 H 7-dimethylamino I I 1273 n.butyl n-butyl OH H 7-dimethylamino I. c, +1 ou (0H2)80H3 It' 1274 < n.butyl + H %y10Fy;;w01 7-dimethylamino 2 ;e 2 L imet C amino N F R N r R g ~ 12 ' .i.butyl nutyI OH H 7-d imethytarnino I- (CHH(CII)a I IE I É 17 3 X o o o 12 n. uty n- uty %½0F;1 OO2H imet y amino --1278 X utyl n.butyl n H -dimethy amino I. (0H2)4OH3 1 +1 I 112? n. utyl n-butyl 0 7.dimct lylamino 1282 etIl 1 n-but , OH H 3-fltiort'-4-metliox IlLil jH 7-trimetli laminonium iodide r n-but r n-but r r r r 11 4-li 'Irtmx 'iitthyI htii r l rTTI 1284 n-but I 'i-but I OH II 'I-(lt'ir )litli I H *-ttli lamino r. 85 u-but g etli 5 f LS Or O r D r ie k a 23 Z mN N » um 1286 n.butyl ii-butyl OH %%1F cPjC() .diinetliylaiiiino o N+((C)3CH3)3 12 7 n-but cili I 0 4-li dwx Iieii I -dimeth lamino 12M n-butyl n.bulyl S ar H 7-dimcthylamiio 128 n- uty n- uty E E imethylammo TI a hh h p: 1290 li-butyl n- utyl 0 HO 7 ----------- OWN z + I I 129 n-butyl n-butyl 0 H F 7-dimethylamino a I 0;(OaH5)l r r r r r r D D D sr T O W- <y t n-butyl ii. utyl OH I i p<W b uty n- uty X ? Imet iy aniliio OThN + 1295 - - n.buty n- utyl 0 mDi;O¼j0 7. Imethylamino 12% n- utyl n-butyl 0 H c, 7.dimetliylamino I o 129 n-butyl >X 0 ¼oY H 7-dimethylamino =; n- uty (½o;:½,N(Cli - lnietliy amilit) o D o o o D nD s $ S D b tu l > i f 1 W n.buiy n. tity 0 p S1 - imet iy amino 1OTh:+(OII2OHi)2 n- ut cli s 0 en - Imat i amino 13 1 n-btit I n-but 0 3-mctIi'x lieu I rimelli ammon urn lo a 1 nuI n- ut 0 3-li lox Iicii 1 9- diox 1 n- uty n.buty 0 - imethy am no 1307 n.buty n- uty 0 I 4-methoxy. 9. 4'.morpliolino hen I at y n- uty F - met yam no O 0 S 0 1309 n-but I n-but I 0 I 4-iiitIit'x Iit:ii I lI-(Iuow 1 et I n- ut iLIi I -amin'i 1 11 n- ut CII 0 IIli I -(i drox amino 1312 n-but I cili I OH )IICli I H 8-hex Ix 1313 n-but I etli I OH I ilL-il I II h'-etIiix 314 etli I u-but 0 hell I 7.(II drux tainino r ci I r tity r leli iex t r i r D O D O D O Or D O ' O O D D b = 2 2 2 i 2 », ~ 2 .> I FF FF j i 1316 n-but I eth I 0 1 hell I fl-h dnix 1317 n.butyl ethyl OH I plleliyl H I Thtt+(CH at tlic 8- osition 1318 eli 0 n- ut L ; lien I -dimeti lamino 131 et i n- ut 0 3-metliox lieu 7-fluoro 13 0 et I n- u 0 lien I -amino 8 n.butyl ethyl r: phenyl H ~ ~ ~ ~~~~ ~~ I ~~~ ~ ~ N H I lot S D D D D Or D O O wn ~ fq > ~ S3 n eq 1 26 Ii- utyl li-butyl OH H 7.dimetliy amino I OH N(OH2OH3)3 4iS W iou 3 '8 Z? <03'8- 1332 it-buty n.butyl OH H 7-Jirnethyloiiiino n- uty n- uty - imet iy amino N(0H20H3)3 13I ii-butyl n-butyl H 7-dimetliylamino I 0 0M;N In- Lity Ii- uty . iiietliy amino 1n- uty n- uty - met 'y amino I 0NV Ni /L v < 1337 ii.'butyl II ulyl Ott ll H 7.dimetIiylamiio (H3O)N 1338 n-but I n-but I OH H 4-Int:tll('x lien I H 7-(4-meth I i erazin I) 1339 Ii- utyl n- uty 0 0 =6Mass I O(OH3)3 6/ ------- I 0 - t)1i I -met ' r li-but I = ~ I acetox H 3-iiittItx 'IlL-li I H 7-dilietli lamino 1342 n-but I n-bt I OH H 5 ) L-wfl I H 7-(4.fIuoro lien I) 1343 etlI I li-bLIt OH H )hii I H 7-amiiio 1344 n-but I n-but I 0 3-fluow-4-mt-tliox lien I 7-dimetli lamino 1345 eth I n-but I OH H lien I H 7-tnmeth lamnionium iodide )34 ethyl n.butyl OH H pIiCliyI H at tlie S- osition 1 4 n- ut I n-but 3-floro-4-metIiox liei I -dimetli larnino 1348 isobut I 6obut I OH H lien I H 7-dimetli larnino 1349 etli I n-but 1 OH H lieli I H 7-dimt:th lamino s c= 13 O, 1 % n-butyl f.18 ;½6/I#{o;y Biq o c P I L LIITZTI ITITTT D O D O u D ' O O O ~ r ° ° O & ~ @ ~ : 2 > n ~ : ~ > x e ~ 7 rs O v ro rs r 7 ~ o 1352 lI-butyl ii, utyl OH I I flr -d imutliylamino 13 n.butyl ii- utyl 0 (OHOH2OH3CH2t#¼ - -dimetltylamino -- ---- + p N(OH2OH3)3 1354 n- utyl n- utyl 0 H I 7-diniethy amino - e | 0 / ~ r ~ r r I D r ~ rD ii i 355 n.buiyl 1i.butyl OH H 7-dilnethylamino I 0+P(OHaCH3)3 1 9 n.butyl n- uty OH H (¼ 7-dimet ylamlno 2 1 n- uty n- uty - met y amino . C t tS r r r I Dr r Dr 1362 Ii- Lityl n.butyl OI Ii 7.lIiinetIylainino I ()Th;Ny;OH 1 uty n- uty H p X , S i r T t : C r r r r r . .. r r r r r O D O O D 2 2 U 0 ~ s :l36 ii.butyl ,n.butyl 7.11 iiiietlly amino 8 c c o 3 I Z C e 4 -4 < rs s m ~ 1371 n.butyl li-bulyl OH H H 7-dimethylamino 13fl n-butyl n.butyl OH H H 7.dinietliy amino I- C oTh3NNWe I 1374 n-butyl n-buty H 1375 n-butyl n-butyl H H o o;½ H 7-dimetliylamino r r r r r Or Dr Or rD 1376 ii-butyl n-butyl OH H I H 7-dimethylamino M¼YlNffi 1377 n-butyl OH X H )1 I. + 0/¼;(0H20H3)i 1378 n-butyl n.butyl OH H H 7.dimetliylamino N(0H20H3)3 i n.buty fl. %t- e N(OH2OH)3 1380 n.butyl n-butyl OH H 0, H 7-dimetliylamino 1381 n.butyl n.butyl OH H FN+(OH2OH3 H r Or Or Or O c =: @> nS nc > X : nc @> > f t a N 8 » 1382 ii-butyi i-butyI OH H I H 7.diletliylainino iA¼+1N 138 n- uty I'. uty 0 I - imet iy amino FYi 1354 n.butyl n-butyl OH H I ii H 7.dlmetliylamino F 1385 n.butyl n-butyl OH H H 7-dimethylamino 1386 n.butyl n.butyl OH H H 7.dimetliyliniino 0N(OH2OH3)3 2 /2 ilJ) v T r r r r D O O O cn n ro n 1387 n- utyl n.butyl OH H I 7.d ilnetllylamino F 0N(cII2OH)3 388 n- uty n- uty I inet iylam no #iOYI+\ffi 1 91 n. utyl n-butyl 0 1 7.dimetliy anilno Dr O rO rO . R | R O . > 1392 n-butyl ii-bcityl OH H 7.dilnetlylaniiio I- K OgN¼ ED n.butyl n-butyl OH H ?.dinietliylamino 4 n-butyl n-buty Q H a r r r r r . D Or Or i ffi i D ~ S s b nC 9 S 139 li-butyl n-butyl OH (½N -dimetliylamino C S i- X . E E E x uty n- uty ½. c -dimet E amino I n- uly n- uty I NQj+;; - imet ly anilno 1400 n. utyl n.butyl OH H 7-dimethylamino F + X -- ( Zl 4 1 n- uty n- uty I - imet 'y amIno f r I r r r Or Z; 1102 ii.butyl n.butyl OH H I H 7-dililet iylamino 1403 n.butyl n-butyl OH H H 7-dimet ylamino sly ND 1401 n.butyl n-butyl OH H H 7.dinietliylamiiio $lMyy 1405 n.butyl n.buty 0 H 7-d imetIyIaznino 1,109 n- utyl n-butyl H 7-dimthyl.mino 0¼ N(CCHs 14)0 n- utyl | OH H H 7.diiiietliylamino + -P 1. 1412 fl. uty il-buty OH H 7-d iiiietliylaliijno K 4 ii. uly n- uty I. - met iy alnilic N T Xl 0t3 9 zrS - C 14)7 li-butyl li-butyl OH '½1N H 7-dimethylalitino l n. uty n- uty 7 1 -dimet iylatnino + ½\HoH p: HO 4)9 n-butyl n.butyl 0 7.dimcthylamlno F I 0 o U. I Or Dr 1421 n.butyl n-butyl 0 H 7.dimetliylamino 1422 ii- utyl ti-butyl OH H lO\iO 7.diliietliylamino + N(OH2OH3)3 1423 n- utyl n.butyl OH H 7-d iinetliylamino 1424 n.butyl n-butyl OH H 7.dimctliylamino # I . .0 ~ zr | °> f l ~zl ~ rl l 4 n.butyl n-butyl 4' H tz 7.d We<ozl D o = ~ ~ N 3 S n 1426 si-butyl n.biyI 0 II [½ 1- + 7-d imetliy amiiio N(0112CH3)3 14 7 n.buty n- utyl 0 7-dlmetliylamino OH OH 0 4 n- uty n- uty - lmet iy am no nr- N(C0H5)3 4 n- uty Il- uty - imet ylamino Dr 1131 ii. utyl .b(styI OH H 7.diinetliylainino N(CH2CH3)3 1X --bn-utyl n-butyl i I 7-dimethylamino i i 5 i 1433 n- utyl n-butyl 011 H I I 7-dimethylamino i n-butyl li-butyl OH S LS X #\OFN%j\0)i 7.dimctliyliinino I r r r 5 ~ Or . r X t x 1436 n-butyi ii.bbtyl OH H )¼I1 7.d Imethylamiio 143? n-butyl n.butyl OH H H 7.dimethylamino j Br S 14 9 n-buty n-butyl 0 I 7-diinet iylamino N(0H20H3)3 W cSi S 1441 ri-butyl n.butyl 0 H +H H 7.diinetliylamino X < o 5 - ~ 3 3 3 . )442 n-butyl n-butyl 0 7-d imethylamino 1445 n.butyl n-butyl OH H H 7-dimethylamino L b I S03 1449 n-butyi :i.butyi OH H H ?-dlrnethyiarnino 1- I 3 14 n-bu I fl-bLit I OH H Ii&n I H 7-dirneth Iarnjno 145) n.butyl n-butyi OH H H 7-dimethylamino :t PEG = 3400 molecular weight polyethylene glycol polymer chain PEG = 3400 molecular weight polyethylene glycol polymer chain PEG = 3400 molecular weight polyethylene glycol polymer chain C22 H25 N 03 S 387.543 C22 H25 N 03 S 387.543 C22 H28 03 S 372.525 C21 H24 03 S 356.486 C22 H28 0 S 340.53 C22 H28 0 S 343.53 C22 H28 04 S 388.528 C22 H32 03 5 . C22 H28 03 S 749.089 C22 H28 02 S 36.525 C28H41 H 03 S 471.704 C22 H27 I 03 S<BR> 458.425 C24 H00 05 S 430.563 C22 H25 N 04 S 403.543 C22 H25 N 04 S 403.543 C28 H41 N 03 S 471.704 C28 H40 04 S 472.685 C24 H30 05 S 430.565 C36 H43 N 06 S 617.807 C23 H30 04 S 402.555 C22 H29 04 S 388.528 C24 H32 04 S 416.582 C22 H28 03 S 372.523 C22 H28 03 S 372.523 C23 H30 04 S 402.555 C22 H28 04 S . C22 H28 03 S 761.056 2 C22 H28 03 S2 404.535 C22 H26 12 03 S 524.322 C21 H24 03 S 356, 486 C23 H30 04 S 402.555 C23 H30 04 S 402.555 C18 H20 03 S 316.421 C18 H20 03 S 316.421 C22 H28 02 S 356, 523 C18 H20 02 S 300.422 C22 H28 03 S 372.523

In further compounds of the present invention, R' and R6 are independently selected from among hydrogen and ring-carbon substituted or unsubstituted aryl, thiophene, pyridine, pyrrole, thiazole, imidazole, pyrazole, pyrimidine, morpholine, N-alkylpyridinium, N- alkyl-piperazinium, N-alkylmorpholinium, or furan in which the substituent(s) are selected from among halo, hydroxyl, trihaloalkyl, alkoxy, amino, N-alkylamino, N,N-dialkylamino, quaternary ammonium salts, a Cl to C alkylene bridge having a quaternary ammonium salt substituted thereon, alkoxycarbonyl, aryloxycarbonyl, alkylcarbonyloxy and arylcarbonyloxy, (0,0)- dioxyalkylene, -[O(CH2)w]xX where x is 2 to 12, w is 2 or 3 and X comprises halo or a quaternary ammonium salt, thiophene, pyridine, pyrrole, thiazole, imidazole, pyrazole, or furan. The aryl group of Ri or Rb is preferably phenyl, phenylene, or benzene triyl, i.e., may be unsubstituted, mono-substituted, or di- substituted. Among the species which may constitute the substituents on the aryl ring of R' or R6 are fluoro, chloro, bromo, methoxy, ethoxy, isopropoxy, trimethylammonium (preferably with an iodide or chloride counterion), methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, propanoyl, (N)-hexyldimethylammonium, hexylenetrimethylammonium, tri(oxyethylene)iodide, and tetra(oxyethylene)trimethylammonium iodide, each substituted at the p-position, the m-position, or both of the aryl ring. Other substituents that can be present on a phenylene, benzene triyl or other aromatic ring include 3,4-dioxymethylene (5-membered ring) and 3,4-dioxyethylene (6- membered ring). Among compounds which have been or can be demonstrated to have desirable ileal bile acid transport inhibiting properties are those in which R5 or Rb is selected from phenyl, p-fluorophenyl, m-fluorophenyl, p- hydroxyphenyl, m-hydroxyphenyl, p-methoxyphenyl, m- methoxyphenyl, p-N,N-dimethylaminophenyl, m-N,N-

dimethylaminophenyl, I- p-(CH3)3-N@-phenyl, I@ m-(CH2)3-N@- phenyl, I@ m-(CH3)3-N-CH2CH2-(OCH2CH2)3-O-phenyl. I@ p- (CH3)3-N-CH3CH2-(OCH2CH2)2-O-phenyl, I- m-(N,N-dimethyl- piperazinium)-(N')-CH2-(OCH2CH2)2-O-phenyl, 3-methoxy-4- fluorophenyl, thienyl-2-yl, 5-cholorothienyl-2-yl, 3,4-difluorophenyl, I- p-(N,N-dimethylpiperazinium)- (N')-CH2-(OCH2CH2)2-O-phenyl, 3-fluoro-4-methoxyphenyl, - 4-pyridinyl. 2-pyridinyl,- 3-pyridinyl, N-methyl-4- pyridinium, I N-emthyl-3-pyridinium, 3,4- dioxymethylenephenyl, 3,4-dioxyethylenephenyl, and p- methoxyzarbonylphenyl. Preferred compounds include 3- ethyl-3-butyl and 3-butyl-3-butyl compounds having each of the above preferred ' substituents in combination with the R- substituents shown in Table 1. It is particularly praferred that one but not both of R' and R' is hydrogen.

It is especially preferred that R4 and R' be hydrogen, that R3 and R' not be hydrogen. and that R3 and R' be oriented in the same direction relative to the plane of the molecule, i.e., both in oa or both in -configuration. It is further preferred that, where R' is butyl and R' is ethyl, then ' has the same orientation relative to the plane of the molecule as and R'.

Set forth in Table 1A are lists of species of R1/R2, R3/R4 and Ra.

Table 1A : Alternative R groups R1, R2 R3, R4 R5 (Rz) #<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> ethyl HO- Ph- 7-methyl<BR> <BR> n-propyl H- p-F-Ph- 7-ethyl<BR> <BR> <BR> <BR> n-butyl m-F-Ph- 7-iso-propyl<BR> <BR> <BR> n-pentyl p-CH3O-Ph- 7-tert-butyl<BR> <BR> n-hexyl 7-OH iso-propyl m-CH3O-Ph- 7-OCH3 iso-butyl p-(CH3)N-Ph- 7-O(iso-propyl)<BR> iso-pentyl m-(CH3)2N-Ph- 7-SCH3<BR> CH2C(=O)C2H5 I-, p-(CH3)3-N@-Ph- 7-SOCH3<BR> <BR> <BR> <BR> CH2CC2H5 I-, m-(CH3)3-N@-Ph- 7-SO2CH3<BR> CH2CH(OH)C2H5 I-, p-(CH3)3-N@-CH2CH2- 7-SCH2CH3<BR> CH2O-(4-picoline) (CCH2H2)2-O-Ph- 7-NH2<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> I-, m-(CH3)3-N@-CH2CH2- 7-NHOH<BR> (CCH2CH2)2-O-Ph- 7-NHCH3<BR> <BR> <BR> I-, p-(N,N- 7-N(CH3)2<BR> dimethylpiperazine)- 7-N@(CH3)3, I- (N')-CH1-(CCH2CH2)2-O- 7-NHC(=O)CH3 Ph- 7-N(CH2CH3)2 I-, m-(N,N- 7-NMeCH2CO2H deimethylpiperazine)- 7-N@(Me)2CH2CO2@, I- (N')-CH2-(CCH2CH2)2-O- 7-(N)-morpholine Ph- 7-(N)-azetidine m-F, p-CH3O-Ph- 7-(N)-N-methylazetidinium, I- 3,4,dioxymethylene-Ph 7-(N)-pyrrolidine m-CH3O-, p-F-Ph- 7-(N)-N-methyl-pyzzolidinium, I- 4-pyridine 7-(N)-N-methyl-morpholinium, I- N-methyl-4-pyridinium, I- 7-(N)-N'-methylpiperazine 3-pyridine 7-(N)-N-dimethylpiperazionium, I- <BR> <BR> N-methyl-3-pyridinium, I- 7-NH-CEZ<BR> 2-pyridine 7-NHC(=O)C5H11<BR> p-CH3O2C-Ph- 7-NHC(=O)CH2Br thienyl-2-yl 7-NH-C(NH)NH2 5-Cl=thienyl-2-yl 7-(2)-thiophene 3,4-difluoro m-F, P-CH3O-Ph continued next page ...

8-methyl 8-ethyl 8-iso-propyl 8-tert-butyl 8-OH 8-OCH3 8-O(iso-propyl) 8-SCH3 8-SCCH3 8-SO2CH3 8-SCH2CH3 8-NH2 8-NEOH 8-NECH3 8-N(CH3)2 8-N+(CH3)3, I- 8-NEC(=O)CH3 8-N(CH3CH3)2 8-NMeCH2CO2H 8-N+(Me)2CH2CO2H, I- 8-(N)-morpholine 8-(N)-azatidine 8-(N)-N-methylazetidinium, I- 8-(N)-pyzzolidine 8-(N)-N-methyl-pyrrolidinium, I- 8-(N)-N-methyl-morpholinium, I- 8-(N)-N'-methylpiperazine 8-(N)-N'-dimethylpiperazinium, I- 8-NE-CBZ 8-NHC(O)C5H11 8-NHC(O)CH2Br 8-NH-C(NH)NH2 8-(2)-thiophene continued next page...

9-methyl 9-ethyl 9-iso-propyl 9-tert-butyl 9-OH 9-OCH3 9-O(iso-propyl) 9-SCH3 9-SOCH3 9-SO2CH3 9-SCH2CH3 9-NH2 9-NHOH 9-NHCH3 9-N(CH3)2 9-N+(CH3)3, I- 9-NHC(=O)CH3 9-N(CH2CH3)2 9-NMeCH2CO2H 9-N+(Me)2CH2CO2H, I- 9-(N)-morpholine 9-(N)-azetidine 9-(N)-N-methylazetidinium, I- 9-(N)-pyzzolidine 9-(N)-N-methyl-pyrrolidinium, I- 9-(N)-N-methyl-morpholinium, I- 9-(N)-N'-methylpiperazine 9-(N)-N'-dimethylpiperazinium, I- 9-NH-CBZ 9-NHC(O)C3H11 9-NHC(O)CH2Br 9-NH-C(NH)NH2 9-(2)-chiophene 7-CCH3, 8-CCH3 7-SCH3, 8-CCH3 7-SCH3, 8-SCH3 6-OCH3, 7-CCH3, 8-OCH3

Further preferred compounds of the present invention comprise a core structure having two or more pharmaceutically active benzothiepine structures as described above, covalently bonded to the core moiety via functional linkages. Such active benzothiepine structures preferably comprise: (Formula DIV) or: (Formula DIVA) where R1, R2, R3, R4, R6, R5, R6, R7, R8, X, q and n are as defined above, and R55 is either a covalent bond or arylene.

The core moiety can comprise alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, and peptide, polypeptide, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, and peptide polypeptide, can optionally have one or more carbon replaced by NR7, N+R7R8, S, SO, S02 S+R7R8, PR7, P+R7R8, phenylene, heterocycle, quatarnary heterocycle, quaternary heteroaryl, or aryl, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S(O)R13.

SO2R13, SO3R13, NR13OR14, NR13NR14R15, NO2, CO2R13, CN, OM, SO2OM, SO2NR13R14, C(O)NR13R14, C(O)OM, COR13, P(O)R13R14, P+R13R14R15A-, P(OR13)OR14, S+R13R14A-, and N+R9R11R12A-; wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR7, NR7R8, SR7, S(O)R7, SO2R7, SO3R7, CO2R7, CN, oxo, CONR7R8, N+R7R8R9A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary

heterocycle, quaternary heteroaryl, P(O)R7R8, P+R7R8A-, and P(O) (OR7)OR8, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by 0, NR7, N+R7R8A-, S, SO, S02, S+R7A-, PR7, P(O)R7, P+-R7R8A-, or phenylene.

Exemplary core moieties include:

wherein: R:S is selected from the group consisting of C and N, and R2' and R27 are independently selected from the group consisting of: wherein R:a, R", R30 and R31 are independently selected from alkyl, alkenyl, alkylaryl, aryl, arylalkyl, cycloalkyl, heterocycle, and heterocycloalkyl, At is a pharmaceutically acceptable anion, and k = 1 to 10.

In compounds of Formula DIV, R20, R21, R22 in Formulae DII and DIII, and R23 in Formula DIII can be bonded at any of their 6-, 7-, 8-, or 9- positions to R1,. In compounds of Formula DIVA, it is preferred that R55 comprises a phenylene moiety bonded at a m- or p- position thereof to Rl'.

In another embodiment, a core moiety backbone, Rl', as discussed herein in Formulas DII and DIII can be multiply substituted with more than four pendant active benzothiepine units, i.e., R20, R21, R22, and R23 as discussed above, through multiple functional groups within the core moiety backbone. The core moiety backbone unit, R19, can comprise a single core moiety unit, multimers thereof, and multimeric mixtures of the different core moiety units discussed herein, i.e., alone or in combination. The number of individual core moiety backbone units can range from about one to about 100, preferably about one to about 80, more preferably about one to about 50, and even more preferably about one to about 25. The number of points of attachment of similar or different pendant active benzothiepine units within a single core moiety backbone unit can be in the range from about one to about 100, preferably about one to about 80, more preferably about one to about 50, and even more preferably about one to about 25. Such points of attachment can include bonds to C, S, O, N, or P within any of the groups encompassed by the definition of Rl'.

The more preferred benzothiepine moieties comprising R20, R2l R22 and/or R23 conform to the preferred structures as outlined above for Formula I.

The 3-carbon on each benzothiepine moiety can be achiral, and the substituents R1, R2, R3, R', R5 and RX

can be selected from the preferred groups and combinations of substituents as discussed above. The core structures can comprise, for example, poly( oxyalkylene) or oligo(oxyalkylene), especially poly- or oligo(oxyethylene) or poly- or oligo(oxypropylene).

Dosages, Formulations, and Routes of Administration The ileal bile acid transport inhibitor compounds of the present invention can be administered for the prophylaxis and treatment of hyperlipidemic diseases or conditions by any means, preferably oral, that produce contact of these compounds with their site of action in the body, for example in the ileum of a mammal, e.g., a human.

For the prophylaxis or treatment of the conditions referred to above, the compounds of the present invention can be used as the compound per se.

Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compound. Such salts must clearly have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids. The chloride salt is

particularly preferred for medical purposes. Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, and alkaline earth salts such as magnesium and calcium salts.

The anions of the definition of A- in the present invention are, of course, also required to be pharmaceutically acceptable and are also selected from the above list.

The compounds of the present invention can be presented with an acceptable carrier in the form of a pharmaceutical composition. The carrier must, of course, be acceptable in the sense of being compatible with the other ingredients of the composition and must not be deleterious to the recipient. The carrier can be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from 0.05% to 95% by weight of the active compound.

Other pharmacologically active substances can also be present, including other compounds of the present invention. The pharmaceutical compositions of the invention can be prepared by any of the well known techniques of pharmacy, consisting essentially of admixing the components.

These compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic compounds or as a combination of therapeutic compounds.

The amount of compound which is required to achieve the desired biological effect will, of course, depend on a number of factors such as the specific compound chosen, the use for which it is intended, the

mode of administration, and the clinical condition of the recipient.

In general, a daily dose can be in the range of from about 0.3 to about 100 mg/kg bodyweight/day, preferably from about 1 mg to about 50 mg/kg bodyweight/day, more preferably from about 3 to about 10 mg/kg bodyweight/day. This total daily dose can be administered to the patient in a single dose, or in proportionate multiple subdoses. Subdoses can be administered 2 to 6 times per day. Doses can be in sustained release form effective to obtain desired results.

Orally administrable unit dose formulations, such as tablets or capsules, can contain, for example, from about 0.1 to about 100 mg of benzothiepine compound, preferably about 1 to about 75 mg of compound, more preferably from about 10 to about 50 mg of compound.

In the case of pharmaceutically acceptable salts, the weights indicated above refer to the weight of the benzothiepine ion derived from the salt.

Oral delivery of an ileal bile acid transport inhibitor of the present invention can include formulations, as are well known in the art, to provide prolonged or sustained delivery of the drug to the gastrointestinal tract by any number of mechanisms.

These include, but are not limited to, pH sensitive release from the dosage form based on the changing pH of the small intestine, slow erosion of a tablet or capsule, retention in the stomach based on the physical properties of the formulation, bioadhesion of the dosage form to the mucosal lining of the intestinal tract, or enzymatic release of the active drug from the dosage form. The intended effect is to extend the time

period over which the active drug molecule is delivered to the site of action (the ileum) by manipulation of the dosage form. Thus, enteric-coated and enteric- coated controlled release formulations are within the scope of the present invention. Suitable enteric coatings include cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methacrylic acid methyl ester.

When administered intravenously, the dose can, for example, be in the range of from about 0.1 mg/kg body weight to about 1.0 mg/kg body weight, preferably from about 0.25 mg/kg body weight to about 0.75 mg/kg body weight, more preferably from about 0.4 mg/kg body weight to about 0.6 mg/kg body weight. This dose can be conveniently administered as an infusion of from about 10 ng/kg body weight to about 100 ng/kg body weight per minute. Infusion fluids suitable for this purpose can contain, for example, from about 0.1 ng to about 10 mg, preferably from about 1 ng to about 10 mg per milliliter. Unit doses can contain, for example, from about 1 mg to about 10 g of the compound of the present invention. Thus, ampoules for injection can contain, for example, from about 1 mg to about 100 mg.

Pharmaceutical compositions according to the present invention include those suitable for oral, rectal, topical, buccal (e.g., sublingual), and parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular compound

which is being used. In most cases, the preferred route of administration is oral.

Pharmaceutical compositions suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water- in-oi emulsion. As indicated, such compositions can be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound(s) and the carrier (which can constitute one or more accessory ingredients). In general, the compositions are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet can be prepared by compressing or molding a powder or granules of the compound, optionally with one or more assessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). Molded tablets can be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid diluent.

Pharmaceutical compositions suitable for buccal (sub-lingual) administration include lozenges comprising a compound of the present invention in a flavored base, usually sucrose, and acacia or tragacanth, and pastilles comprising the compound in an

inert base such as gelatin and glycerin or sucrose and acacia.

Pharmaceutical compositions suitable for parenteral administration conveniently comprise sterile aqueous preparations of a compound of the present invention. These preparations are preferably administered intravenously, although administration can also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations can conveniently be prepared by admixing the compound with water and rendering the resulting solution sterile and isotonic with the blood.

Injectable compositions according to the invention will generally contain from 0.1 to 5% w/w of a compound disclosed herein.

Pharmaceutical compositions suitable for rectal administration are preferably presented as unit-dose suppositories. These can be prepared by admixing a compound of the present invention with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.

Pharmaceutical compositions suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which can be used include vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound is generally present at a concentration of from 0.1 to 15% w/w of the composition, for example, from 0.5 to 2%.

Transdermal administration is also possible.

Pharmaceutical compositions suitable for transdermal administration can be presented as discrete patches

adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain a compound of the present invention in an optionally buffered, aqueous solution, dissolved and/or dispersed in an adhesive, or dispersed in a polymer. A suitable concentration of the active compound is about 18 to 35%, preferably about 3% to 15%. As one particular possibility, the compound can be delivered from the patch by electrotransport or iontophoresis, for example, as described in Pharmaceutical Research, 3(6), 318 (1986).

In any case, the amount of active ingredient that can be combined with carrier materials to produce a single dosage form to be administered will vary depending upon the host treated and the particular mode of administration.

The solid dosage forms for oral administration including capsules. tablets, pills, powders, and granules noted above comprise one or more compounds of the present invention admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.

Such compositions may also comprise adjuvants, such as

wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or setting agents and suspending agents.

The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

Pharmaceutically acceptable carriers encompass all the foregoing and the like.

In combination therapy, administration of the ileal bile acid transport inhibitor and HMG Co-A reductase inhibitor may take place sequentially in separate formulations, or may be accomplished by simultaneous administration in a single formulation or separate formulations. Administration may be accomplished by oral route, or by intravenous, intramuscular, or subcutaneous injections. The formulation may be in the form of a bolus, or in the form of aaqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more pharmaceutically-acceptable

carriers or diluents, or a binder such as gelatin or hydroxypropylmethyl cellulose, together with one or more of a lubricant, preservative, surface active or dispersing agent.

For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension, or liquid. Capsules, tablets, etc., can be prepared by conventional methods well known in the art. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient or ingredients. Examples of dosage units are tablets or capsules. These may with advantage contain one or more ileal bile acid transport inhibitors in an amount described above. In the case of HMG Co-A reductase inhibitors, the dose range may be from about 0.01 mg to about 500 mg or any other dose, dependent upon the specific inhibitor, as is known in the art.

The active ingredients may also be administered by injection as a composition wherein, for example, saline, dextrose, or water may be used as a suitable carrier. A suitable daily dose of each active inhibitor is one that achieves the same blood serum level as produced by oral administration as described above - The active inhibitors may further be administered by any dual combination of oral/oral, oral/parenteral, or parenteral/parenteral route.

Pharmaceutical compositions for use in the treatment methods of the present invention may be administered in oral form or by intravenous administration. Oral administration of the combination therapy is preferred. Dosing for oral administration

may be with a regimen calling for single daily dose, or for a single dose every other day, or for multiple, spaced doses throughout the day. The inhibitors which make up the combination therapy may be administered simultaneously, either in a combined dosage form or in separate dosage forms intended for substantially simultaneous oral administration. The inhibitors which make up the combination therapy may also be administered sequentially, with either inhibitor being administered by a regimen calling for two-step ingestion. Thus, a regimen may call for sequential administration of the inhibitors with spaced-apart ingestion of the separate, active agents. The time period between the multiple ingestion steps may range from a few minutes to several hours, depending upon the properties of each inhibitor such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the inhibitor, as well as depending upon the age and condition of the patient. The inhibitors of the combined therapy whether administered simultaneously, substantially simultaneously, or sequentially, may involve a regimen calling for administration of one inhibitor by oral route and the other inhibitor by intravenous route. Whether the inhibitors of the combined therapy are administered by oral or intravenous route, separately or together, each such inhibitor will be contained in a suitable pharmaceutical formulation of pharmaceutically- acceptable excipients, diluents or other formulations components. Examples of suitable pharmaceutically- acceptable formulations containing the inhibitors for oral administration are given above.

Treatment Regimen The dosage regimen to prevent, give relief from, or ameliorate a disease condition having hyperlipemia as an element of the disease, e.g., atherosclerosis, or to protect against or treat further high cholesterol plasma or blood levels with the compounds and/or compositions of the present invention is selected in accordance with a variety of factors. These include the type, age, weight, sex, diet, and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetics and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized, and whether the compound is administered as part of a drug combination. Thus, the dosage regimen actually employed may vary widely and therefore deviate from the preferred dosage regimen set forth above.

Initial treatment of a patient suffering from a hyperlipidemic condition can begin with the dosages indicated above. Treatment should generally be continued as necessary over a period of several weeks to several months or years until the hyperlipidemic disease condition has been controlled or eliminated.

Patients undergoing treatment with the compounds or compositions disclosed herein can be routinely monitored by, for example, measuring serum LDL and total cholesterol levels by any of the methods well known in the art, to determine the effectiveness of the combination therapy. Continuous analysis of such data permits modification of the treatment regimen during

therapy so that optimal effective amounts of each type of inhibitor are administered at any point in time, and so that the duration of treatment can be determined as well. In this way, the treatment regimen/dosing schedule can be rationally modified over the course of therapy so that the lowest amount of ileal bile acid transport inhibitor and HMG Co-A reductase inhibitor which together exhibit satisfactory effectiveness is administered, and so that administration is continued only so long as is necessary to successfully treat the hyperlipidemic condition.

A potential advantage of the combination therapy disclosed herein may be reduction of the amount of ileal bile acid transport inhibitor, HMG Co-A reductase inhibitor, or both, effective in treating hyperlipidemic conditions such as atherosclerosis and hypercholesterolemia.

The following non-limiting examples serve to illustrate various aspects of the present invention.

EXAMPLES OF SYNTHETIC PROCEDURES 0 PreDaration z< Preraration 1 2-Ethyl-2-(mesyloxymethyl)hexanal (1) To a cold (10 OC) solution of 12.6 g (0.11 mole) of methanesulfonyl chloride and 10.3 g (0.13 mole) of triethylamine was added dropwise 15.8 g of 2-ethyl-2- (hydroxymethyl)hexanal, prepared according to the procedure described in Chem. Ber. 98, 728-734 (1965), while maintaining the reaction temperature below 30 OC.

The reaction mixture was stirred at room temperature for 18 h, quenched with dilute HC1 and extracted with methlyene chloride. The methylene chloride extract was dried over MgSO, and concentrated in vacuo to give 24.4 g of brown oil.

Pretaration 2 <BR> <BR> <BR> 2-((2-Benzoylphenylthio)methyl)-2-ethylhexan;al A mixture of 31 g (0.144 mol) of 2- mercaptobenzophenone, prepared according to the procedure described in WO 93/16055, 24.4 g (0.1 mole) of 2-ethyl-2-(mesyloxymethyl)-hexanal (1), 14.8 g (0.146 mole) of triethylamine, and 80 mL of 2- methoxyethyl ether was held at reflux for 24 h. The reaction mixture was poured into 3N HC1 and extracted

with 300 mL of methylene chloride. The methylene chloride layer was washed with 300 mL of 10% NaOH, dried over MgSO, and concentrated in vacuo to remove 2- methoxyethyl ether. The residue was purified by HPLC (10% EtOAc-hexane) to give 20.5 g (58%) of 2 as an oil.

Example 1 3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepine (3), <BR> <BR> <BR> cis-3-Butyl-3-ethyl-5-phenyl-2, 3-dihydrobenzothiepin- (SH)4-one (4a) and trans-3-Butyl-3-ethyl-5-phenyl-2,3- dihydro-benzothiepin- (5H)4-one (4b) A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g 4ev, (0.047 mole) of TiCl, and 80 mL of anhydrous ethylene glycol dimethyl ether (DME) was held at reflux for 2 h.

The reaction mixture was cooled to 5 OC. To the reaction mixture was added dropwise a solution of 3.54 g (0.01 mole) of 2 in 30 mL of DME in 40 min. The reaction mixture was stirred at room temperature for 16 h and then was held at reflux for 2 h and cooled before being poured into brine. The organic was extract into methylene chloride. The methylene chloride extract was dried over MgSO, and concentrated in vacuo. The residue was purified by HPLC (hexane) to give 1.7 g (43%) of 3 as an oil in the first fraction. The second fraction was discarded and the third fraction was further purified by HPLC (hexane) to give 0.07 g (2%) of 4a in the earlier fraction and 0.1 g (3%) of 4b in the later fraction.

Example 2 <BR> <BR> <BR> <BR> cis-3-Butyl-3-ethyl-5-phenyl-2, 3-dihydrobenzothiepin- (5H)-4-one-1,1-dioxide (5a) and trans-3-Butyl-3-ethyl-5- <BR> <BR> phenyl-2,3-diBydro-benzothiepin-(5X)4-one-1,1-dioxide (5b) To a solution of 1.2 g (3.5 mmole) of 50-60% MCPBA in 20 mL of methylene chloride was added 0.59 g (1.75

mmole) of a mixture of 4a and 4b in 10 mL of methylene chloride. The reaction mixture was stirred for 20 h. An additional 1.2 g (1.75 mmole) of 50-60% MAPBA was added and the reaction mixture was stirred for an additional 3 h then was triturated with 50 mL of 10% NaOH. The insoluble solid was filtered. The methylene chloride layer of the filtrate was washed with brine, dried over MgSO4, and concentrated in vacuo. The residual syrup was purified by HPLC (5% EtOAc-hexane) to give 0.2 g (30%)of 5a as an oil in the first fraction and 0.17 g (26%) of 5b as an oil in the second fraction.

Example 3 (3a,4a,5b) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5- tetrahydrobenzothiepine-1,1-dioxide (6a), (3a,4b,5a) 3- Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydro- benzothiepine-1,1-dioxide (6b), (3a,4a,5a) 3-Butyl-3- ethyl-4-hydroxy-5-phenyl-2,3,4,5- tetrahydrobenzothiepine-1,1-dioxide (6c), and (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5- tetrahydrobenzothiepine-1,1-dioxide (6d) A. Reduction of 5a and 5b with Sodium Borohydride To a solution of 0.22 g (0.59 mmole) of 5b in 10 mL of ethanol was added 0.24 g (6.4 mmole) of sodium borohydride. The reaction mixture was stirred at room temperature for 18 h and concentrated in vacuo to remove ethanol. The residue was triturated with water and extracted with methylene chloride. The methylene chloride extract was dried over MgSO, and concentrated in vacuo to give 0.2 g of syrup. In a separate experiment, 0.45 g of 5a was treated with 0.44 g of sodium borohydride in 10 mL of ethanol and was worked up as described above to give 0.5 g of syrup which was identical to the 0.2 g of syrup obtained above. These two materials were combined and purified by HPLC using 10% EtOAc-hexane as eluant. The first fraction was 0.18 g (27%) of 6a as a syrup. The second fraction was 0.2 g

(30%) of 6b also as a syrup. The column was then eluted with 20% EtOAc-hexane to give 0.077 g (11%) of Ec in the third fraction as a solid. Recrystallization from hexane gave a solid, mp 179-181 OC. Finally, the column was eluted with 30% EtOAc-hexane to give 0.08 g (12%) of 6d in the fourth fraction as a solid.

Recrystallization from hexane gave a solid, mp 160-161 OC.

B. Conversion of 6a to Ec and 6d with NaOH and PTC To a solution of 0.29 g (0.78 mmole) of 6a in 10 mL CH2C12 , was added 9 g of 40% NaOH. The reaction mixture was stirred for 0.5 h at room temperature and was added one drop of Aliquat-336 (methyltricaprylylammonium chloride) phase transfer catalyst (PTC). The mixture was stirred for 0.5 h at room temperature before being treated with 25 mL of ice-crystals then was extracted with CH2C12 (3x10 ml), dried over MgSO,and concentrated in vacuo to recover 0.17 g of a colorless film. The components of this mixture were separated using an HPLC and eluted with EtOAc-hexane to give 12.8 mg (4%) of 2- (2-benzylphenylsulfonylmethyl)-2-ethylhexenal in the first fraction, 30.9 mg (11%) of Ec in the second fraction and 90.0 mg (31%) of 6d in the third fraction.

Oxidation of 6a to 5b To a solution of 0.20 g (0.52 mmole) of 6a in 5 mL of CH2C12 was added 0.23 g (1.0 mmole) of pyridinium chlorochromate. The reaction mixture was stirred for 2 h then was treated with additional 0.23 g of pyridinium chlorochromate and stirred overnight. The dark reaction mixture was poured into a ceramic filterfrit containing silica gel and was eluted with CH2Cl2. The filtrate was concentrated in vacuo to recover 167 mg (87%) of 5b as a colorless oil.

Example 4 3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepine-1,1- dioxide (7) To a solution of 5.13 g (15.9 mmole) of 3 in 50 mL of CH,Cl2was added 10 g (31.9 mmole)of 50-60% MCPBA (m- chloroperoxybenzoic acid) portionwise causing a mild reflux and formation of a white solid. The reaction mixture was allowed to stir overnight under N2 and was triturated with 25 mL of water followed by 50 mL of 10% NaOH solution. The organic was extracted into CH2Cl2 (4x20 mL). The CH2Cl2 extract was dried over MgSO, and evaporated to dryness to recover 4.9 g (87%) of an opaque viscous oil.

Example 5 (1aa,2b,8ba) 2-Butyl-2-ethyl-8b-phenyl-1a,2,3,8b- tetrahydro-benzothiepino[4,5-b] oxirene-4,4-dioxide (8a) (laa,2a,8ba) 2-Butyl-2-ethyl-8b-phenyl-la,2,3,8b- tetrahydro-benzothiepino (4,5-b) oxirene-4, 4-dioxide To 1.3 g (4.03 mole) of z in 25 mL of CHCl3 was added portionwise 5 g (14.1 mmole) of 50-60 % MCPBA causing a mild exotherm. The reaction mixture was stirred under N2 overnight and was then held at reflux for 3 h. The insoluble white slurry was filtered. The filtrate was extracted with 10% potassium carbonate (3x50 mL), once with brine, dried over MgSO4, and concentrated in vacuo to give 1.37 g of a light yellow oil. Purification by HPLC gave 0.65 g of crystalline product. This product is a mixture of two isomers. Trituration of this crystalline product in hexane recovered 141.7 mg (10%) of a white crystalline product. This isomer was characterized by NMR and mass spectra to be the (laa,2b,8ba) isomer 8a. The hexane filtrate was concentrated in vacuo to give 206 mg of white film which is a mixture of 30% 8a and 70% 8b by 1H NMR.

Example 6 cis-3-Butyl-3-ethyl-5-phenyl-2,3,4,5-tetrahydro- benzothiepine-1,1-dioxide (9a), trans-3-Butyl-3-ethyl- 5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (9b), and 3-Butyl-3-ethyl-4-hydroxy-5-cyclohexylidine- 2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (10) A mixture of 0.15 g (0.4 mmole) of a 3:7 mixture of 8a and 8b was dissolved in 15 ml MeOH in a 3 oz.

Fisher/Porter vessel, then was added 0.1 g of 10% Pd/C catalyst. This mixture was hydrogenated at 70 psi H2 for 5 h and filtered. The filtrate was evaporated to dryness in vacuo to recover 0.117 g of a colorless oil.

This material was purified by HPLC eluting with EtOAc- hexane. The first fraction was 4.2 mg (3%) of 9b. The second fraction, 5.0 mg (4%), was a 50/50 mixture of 9a and 9b. The third fraction was 8.8 mg (6%) of 6a . The fourth fraction was 25.5 mg (18%) of 6b. The fifth fraction was 9.6 mg (7%) of a mixture of 6b and a product believed to be 3-butyl-3-ethyl-4,5-dihydroxy-5- phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide based on mass spectrum. The sixth fraction was 7.5 mg (5%) of a mixture of 6d and one of the isomers of 10, 10a.

Example 7 In another experiment, a product (3.7 g) from epoxidation of 3 with excess MCPBA in refluxing CHCl3 under air was hydrogenated in 100 mL of methanol using 1 g of 10% Pd/C catalyst and 70 psi hydrogen. The product was purified by HPLC to give 0.9 g (25%) of 9b, 0.45 g (13%) of 9a, 0.27 g (7%) of 6a, 0.51 g (14%) of 6b, 0.02 g (1%) of 6c, 0.06 g (2%) of one isomer of 10, 10a and 0.03 g (1%) of another isomer of 10, 10b.

Example 8 2-((2-Benzoylphenylthio)methyl)butyraldehyde (11) To an ice bath cooled solution of 9.76 g (0.116 mole of 2-ethylacrolein in 40 mL of dry THF was added 24.6 g (0.116 mole) of 2-mercaptobenzophenone in 40 mL of THF followed by 13 g (0.128 mole) of triethylamine. The reaction mixture was stirred at room temperature for 3 days , diluted with ether, and was washed successively with dilute HCl, brine, and 1 M potassium carbonate.

The ether layer was dried over MgSO, and concentrated in vacuo. The residue was purified by HPLC (10% EtOAc- hexane) to give 22 g (64%) of 11 in the second fraction. An attempt to further purifiy this material by kugelrohr distillation at 0.5 torr (160-190 OC) gave a fraction (12.2 g) which contained starting material indicating a reversed reaction during distillation.

This material was dissolved in ether (100 mL) and was washed with 50 mL of 1 M potassium carbonate three times to give 6.0 g of a syrup which was purified by HPLC (10% EtOAc-hexane) to give 5.6 g of pure 11.

Example 9 3-Ethyl-5-phenyl-2, 3-dihydrobenzothiepine (12) To a mixture of 2.61 g (0.04 mole) of zinc dust and 60 mL of DME was added 7.5 g (0.048 mole) of TiC1,. The reaction mixture was held at reflux for 2 h. A solution of 2.98 g (0.01 mole) of 11 was added dropwise in 1 h.

The reaction mixture was held at reflux for 18 h, cooled and poured into water. The organic was extracted into ether. The ether layer was washed with brine and filtered through Celite. The filtrate was dried over MgSO, and concentrated. The residual oil (2.5 g) was purified by HPLC to give 2.06 g (77%) of 12 as an oil in the second fraction.

Example 10 (laa,2a,8ba) 2-Ethyl-8b-phenyl-la,2,3,8b-tetrahydro- benzothiepino-t4,5-bZoxirene-4,4-dioxide (13) To a solution of 1.5 g (5.64 mmole) of 12 in 25 ml of CHCl3 was added 6.8 g (19.4 mmole) of 50-60% MCPB portionwise causing an exothem and formation of a white solid. The mixture was stirred at room temperature overnight diluted with 100 ml methylene chloride and washed successively with 10% K2CO, (4x50 ml), water (twice with 25 ml) and brine. The organic layer was then dried over MgSO, and evaporated to dryness to recover 1.47 g of an off white solid. 1H NMR indicated that only one isomer is present. This solid was slurried in 200 ml of warm Et2O and filtered to give 0.82 g (46%) of 13 as a white solid, mp 185-186.5 OC, Example 11 (3a,4b,5a)- 3-Ethyl-4-hydroxy-5-phenyl-2,3,4,5- tetrahydro-benzothiepine-1,1-dioxide (14a), (3a,4b,5b) 3-Ethyl-4-hydroxy-5-phenyl-2,3,4,5- tetrahydrobenzothiepine-1, 1-dioxide (14b), and cis-3- Ethyl-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1- dioxide (15) A mixture ot 0.5 g (1.6 mole) of 13, 50 ml of acetic acid and 0.5 g of 10% Pd/C catalyst was hydrogenated with 70 psi hydrogen for 4 h. The crude. reaction slurry was filtered and the filtrate was stirred with 150 ml of a saturated NaHCO, solution followed by 89 g of NaHCO, powder portionwise to neutralize the rest of acetic acid. The mixture was extracted with methylene chloride (4x25 ml), then the organic layer was dried over MgSO, and concentrated in vacuo to give 0.44 g (87%) of a voluminous white solid which was purified by HPLC (EtOAc-Hexane) to give 26.8 mg (6%) of 15 in the first fraction, 272 mg (54%) of 14a as a solid, mp 142-

143.5 OC, in the second fraction, and 35 mg (7%) of impure 14b in the third fraction.

Example 12 2-Ethyl-2-((2-Hydroxymethylphenyl)thiomethyl)hexenal A mixture of 5.0 g (0.036 mole) of 2-mercaptobenzyl alcohol, 6.4 g (0.032 mole) of 1, 3.6 g (0.036 mole) of triethylamine and 25 mL of 2-methoxyethyl ether was held at reflux for 7 h. Additional 1.1 g of mercaptobenzyl alcohol and 0.72 g of triethylamine was added to the reaction mixture and the mixture was held at reflux for additional 16 h. The reaction mixture was cooled and poured into 6N HCl and extracted with methylene chloride. The methylene chloride extract was washed twice with 10% NaOH, dried over MgSO, and concentrated in vacuo to give 9.6 g of residual.

Purification by HPLC (20% EtOAc-hexane) gave 3.7 g (41%)of 16 as an oil.

ExamDle 13 2-Ethyl- 2 - ( ( 2 - formylphenyl)thiomethyl)hexenal (17) A mixture of 3.7 g of 16, 5.6 g (0.026 mole) of pyridinium chlorochromate, 2 g of Celite and 30 mL of methylene chloride was stirred for 18 h and filtered through a bed of silica gel. The silica gel was eluted with methylene chloride. The combined methylene chloride eluant was purified by HPLC (20% ETOAc-hexane) to give 2.4 g (66%) of an oil.

Example 14 3-Butyl-3-ethyl-2,3-dihydrobenzothiepine (18) A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047 mole) of TiCl3, and 50 mL of DME was held at

reflux for 2 h and cooled to room temperature. To this mixture was added 2.4 g (8.6 mmole) of 17 in 20 mL of DME in 10 min. The reaction mixture was stirred at room temperature for 2 h and held at reflux for 1 h then was let standing at room temperature over weekend. The reaction mixture was poured into dilute HCl and was stirred with methylene chloride. The methylene chloride-water mixture was filtered through Celite. The methylene chloride layer was washed with brine, dried over MgSQ, and concentrated in vacuo to give 3.0 g of a residue. Purification by HPLC gave 0.41 g (20%) of 18 as an oil in the early fraction.

Example 15 (laa,2a,8ba ) 2-Butyl-2-ethyl-la,2,3,8b-tetrahydro- benzothiepinot4,5-b] oxirene-4,4-dioxide (19a) and (laa,2b,8ba) 2-Butyl-2-ethyl-8b-phenyl-la,2,3,8b- tetrahydro-benzothiepino (4,5-b) oxirene-4, 4-dioxide To a solution of 0.4 g of 0.4 g (1.6 mmole) of 18 in 30 mL of methylene chloride was added 2.2 g (3.2 mmole) of 50-60% MCPBA. The reaction mixture was stirred for 2 h and concentrated in vacuo. The residue was dissolved in 30 mL of CHCl, and was held at reflux for 18 h under N2.

The reaction mixture was stirred with 100 mL of 10% NaOH and 5 g of sodium sulfite. The methylene chloride layer was washed with brine, dried over MgSO, and concentrated in vacuo. The residue was purified by HPLC (20% EtOAc-hexane) to give a third fraction which was further purified by HPLC (10% EtOAc-hexane) to give 0.12 g of syrup in the first fraction.

Recrystallization from hexane gave 0.08 g (17%) of 19a, mp 89.5-105.5 °C. The mother liquor from the first fraction was combined with the second fraction and was further purified by HPLC to give additional 19a in the first fraction and 60 mg of 19b in the second fraction.

Crystallization from hexane gave 56 mg of a white solid.

Example 16 <BR> <BR> <BR> 3-Butyl-3-ethyl-4, S-dihydroxy-5-phenyl-2, 3,4, 5- tetrahydro-benzothiepine-1, 1-dioxide (20) This product was isolated along with 6b from hydrogenation of a mixture of 8a and 8b.

Example 17 3-Butyl-3-ethyl-4-hydroxy-5-phenylthio-2, 3,4,5- tetrahydro-benzothiepine-1, 1-dioxide (21) C A mixture of 25 mg (0.085 mmole) of 19b, 0.27 g (2.7 mmole) of thiophenol, 0.37 g (2.7 mmole) of potassium carbonate, and 4 mL of DMF was stirred at room temperature under N2 for 19 h. The reaction mixture was poured into water and extracted with methylene chloride. The methylene chloride layer was washed successively with 10% NaOH and brine, dried over MgSO4, and concentrated in vacuo to give 0.19 g of semisolid which contain substantial amounts of diphenyl disulfide. This material was purified by HPLC (5% EtOAc-hexane) to remove diphenyl disulfide in the first fraction. The column was then eluted with 20% EtOAc- hexane to give 17 mg of a first fraction, 4 mg of a second fraction and 11 mg of a third fraction which were three different isomers of 21, i.e. 21a, 21b, and 21c, respectively, by 1H NMR and mass spectra.

Example 18 Alternative Synthesis of Ec and 6d A. Preparation from 2- ( (2-Benzoylphenylthio)methyl) -2- ethylhexanal (2) Step 1. 2-((2-Benzoylphenylsulfonyl)methyl)-2- ethylhexanal (44)

To a solution of 9.0 g (0.025 mole) of compound 2 in 100 ml of methylene chloride was added 14.6 g (0.025 mol) of 50-60% MCPBA portionwise. The reaction mixture was stirred at room temperature for 64 h then was stirred with 200 ml of 1 M potassium carbonate and filtered through Celite. The methylene chloride layer was washed twice with 300 ml of l M potassium carbonate, once with 10% sodium hydroxide and once with brine. The insoluble solid formed during washing was removed by filtration through Celite. The methylene chloride solution was dried and concentrated in vacuo to give 9.2 g (95%)of semisolid. A portion (2.6 g) of this solid was purified by HPLC(10% ethyl acetate- hexane) to give 1.9 g of crystals, mp 135-136 OC Step 2. 2-((2-BenzylphenylsuIfonyl)metyl)-2- 2- ( (2-Benzylphenylsulfonyl)methyl ethylhexanal (45) LEt t C 1+ A solution of 50 g (0.13 mole) of crude 44 in 250 ml of methylene chloride was divided in two portions and charged to two Fisher-Porter bottles. To each bottle was charged 125 ml of methanol and 5 g of 10% Pd/C. The bottles were pressurized with 70 psi of hydrogen and the reaction mixture was stirred at room temperature for 7 h before being charged with an additional 5 g of 10% Pd/C. The reaction mixture was again hydrogenated with 70 psi of hydrogen for 7 h. This procedure was repeated one more time but only 1 g of Pd/C was charged to the reaction mixture. The combined reaction mixture was filtered and concentrated in vacuo to give 46.8 g of 45 as brown oil.

Step 3. (3a, 4a, Sa) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl- 2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (6c), and <BR> <BR> <BR> (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5- tetrahydrobenzothiepine-1, 1-dioxide (6d)

To a solution of 27.3 g (73.4 mmole) of 45 in 300 ml of anhydrous THF cooled to 2 OC with an ice bath was added 9.7 g (73.4 mmole) of 95% potassium t-butoxide. The reaction mixture was stirred for 20 min, quenched with 300 ml of 10% HC1 and extracted with methylene chloride. The methylene chloride layer was dried over magnesium sulfate and concentrated in vacuo to give 24.7 g of yellow oil. Purification by HPLC (ethyl acetate-hexane) yielded 9.4 g of recovered 45 in the first fraction, 5.5 g (20%) of 6c in the second fraction and 6.5 g (24%) of 6d in the third fraction.

B. Preparation from 2-hydroxydiphenylmethane Step 1. 2-mercaptodiphenylmethane (46) To a 500 ml flask was charged 16 g (0.33 mol) of 60% sodium hydride oil dispersion. The sodium hydride was washed twice with 50 ml of hexane. To the reaction flask was charged 100 ml of DMF. To this mixture was added a solution of 55.2 g (0.3 mol) of 2- hydroxydiphenylmethane in 200 ml of DMF in 1 h while temperature was maintained below 30 OC by an ice-water bath. After complete addition of the reagent, the mixture was stirred at room temperature for 30 min then cooled with an ice bath. To the reaction mixture was added 49.4 g (0.4 mole) of dimethyl thiocarbamoyl chloride at once. The ice bath was removed and the reaction mixture was stirred at room temperature for 18 h before being poured into 300 ml of water. The organic was extracted into 500 ml of toluene. The toluene layer was washed successively with 10% sodium hydroxide and brine and was concentrated in vacuo to give 78.6 g of a yellow oil which was 95% pure dimethyl O-2-benzylphenyl thiocarbamate. This oil was heated at 280-300 OC in a kugelrohhr pot under house vacuum for 30 min. The residue was kugelrohr distilled at 1 torr (180-280 OC).

The distillate (56.3 g) was crystallized from methanol to give 37.3 g (46%) of the rearranged product dimethyl

S-2-benzylphenyl thiocarbamate as a yellow solid. A mixture of 57 g (0.21 mole) of this yellow solid, 30 g of potassium hydroxide and 150 ml of methanol was stirred overnight then was concentrated in vacuo. The residue was diluted with 200 ml of water and extracted with ether. The aqueous layer was made acidic with concentrate HCl, The oily suspension was extracted into ether. The ether extract was dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from hexane to give 37.1 g (88%) of 2- mercaptodiphenylmethane as a yellow solid.

Step 2. 2-((2-senzylphenylthio)methyl)-2-ethylhexanal A mixture of 60 g (03 mole) of yellow solid from step 1, 70 g (0.3 mole) of compound 1 from preparation 1, 32.4 g (0.32 mole) of triethylamine, 120 ml of 2- methoxyethyl ether was held at reflux for 6 hr and concentrated in vacuo. The residue was triturated with 500 ml of water and 30 ml of concentrate HC1. The organic was extracted into 400 ml of ether. The ether layer was washed successively with brine, 10% sodium hydroxide and brine and was dried over magnesium sulfate and concentrated in vacuo. The residue (98.3 g) was purified by HPLC with 2-5% ethyl acetate-hexane as eluent to give 2-((2-benzylphenylthio)methyl)-2- ethylhexanal 47 as a yellow syrup.

Step 3. 2-((2-Benzylphenylsulfonyl)methyl)-2- ethylhexanal (45) To a solution of 72.8 g (0.21 mole) of yellow syrup from step 2 in 1 liter of methylene chloride cooled to 10 OC was added 132 g of 50-60% MCPBA in 40 min. The reaction mixture was stirred for 2 h. An additional 13 g of 50-60% MCPBA was added to the reaction mixture.

The reaction mixture was stirred for 2 h and filtered

through Celite. The methylene chloride solution was washed twice with 1 liter of 1 M potassium carbonate then with 1 liter of brine. The methylene chloride layer was dried over magnesium sulfate and concentrated to 76 g of 2-((2-benzylphenylsulfonyl)methyl)-2- ethylhexanal 45 as a syrup.

Step 4. (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl- 2, 3,4,5-tetrahydrobenzothiepine-1, 1-dioxide (6c), and (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,S- tetrahydrobenzothiepine-1, 1-dioxide (6d) Reaction of 45 with potassium t-butoxide according to the procedure in step 3 of procedure A gave pure 6c and 6d after HPLC.

Example 19 (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5- <BR> <BR> <BR> phenyl-2, 3,4, 5-tetrahydrobenzotbiepine-1, 1-dioxide (25) and (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-B-methoxy-5- phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (26) Step 1. Preparation of 2-((2-benzoyl-4-methoxy phenylthio)methyl)-2-ethylhexanal (22) 2-Hydroxy-4-methoxybenzophenone was converted to the dimethyl O-2-benzoyphenyl thiocarbamate by methods previously described in example 18. The product can be isolated by recrystallization from ethanol. Using this improved isolation procedure no chromatography was needed. The thermal rearrangement was performed by reacting the thiocarbamate( 5 g) in diphenyl ether at 260 °C as previously described. The improved isolation procedure which avoided a chromatography step was described below.

The crude pyrolysis product was then heated at 65 °C in 100 ml of methanol and 100 ml of THF in the presence of 3.5 g of KOH for 4 h. After removing THF and methanol

by rotary evaporation the solution was extracted with 5 % NaOH and ether. The base layer was acidified and extracted with ether to obtain a 2.9 g of crude thiophenol product. The product was further purified by titrating the desired mercaptan into base with limited KOH. After acidification and extraction with ether pure 2-mercapto-4-methoxybenzophenone (2.3 g) was isolated.

2-mercapto-4-methoxybenzophenone can readily be converted to the 2-((2-benzoyl-4- methoxyphenylthio)methyl)-2-ethylhexanal (22) by reaction with 2-ethyl-2-(mesyloxymethyl)hexanal (1) as previously described.

Step 2. 2-((2-Benzoyl-5-methoxyphenylsulfonyl)methyl)- 2-ethylhexanal (23) Substrate 22 was readily oxidized to 2-((2-benzoyl-5- methoxyphenyl-sulfonyl)methyl)-2-ethylhexanal (23) as described in example 18. Step 3. 2-((2-benzyl-5-methoxyphenylsulfonyl)methyl)-2- ethylhexanal (24) Sulfone 23 was then reduced to 2-((2-benzyl-5- methoxyphenyl-sulfonyl)methyl)-2-ethylhexanal (24) as described in example 18. Step 4. (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-8-methoxy- 5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (25) and (3a,4a,Sa) 3-Butyl-3-ethyl-4-hydroxy-8- methOxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1- dioxide (26) A 3-neck flask equipped with a powder addition cH funnel,thermocouple and nitrogen bubbler was charged with 19.8 g (0.05 mole) of sulfone 24 in 100 ml dry THF. The reaction was cooled to -1.6 °C internal

temperature by means of ice/salt bath. Slowly add 5.61 g (0.05 mole) of potassium t-butoxide by means of the powder addition funnel. The resulting light yellow solution was maintained at -1.6 OC. After 30 min reaction 400 ml of cold ether was added and this solution was extracted with cold 10 % HC1. The acid layer was extracted with 300 ml of methylene chloride.

The organic layers were combined and dried over magnesium sulfate and after filtration stripped to dryness to obtain 19.9 g of product. lH nmr and glpc indicated a 96% conversion to a 50/50 mixture of 25 and 26. The only other observable compound was 4% starting sulfone 24.

The product was then dissolved in 250 ml of 90/10 hexane/ethyl acetate by warming to 50 OC. The solution was allowed to cool to room temperature and in this way pure 26 can be isolated. The crystallization can be enhanced by addition of a seed crystal of 26. After 2 crystallizations the mother liquor which was now 85.4% 25 and has a dry weight of 8.7 g. This material was dissolved in 100 ml of 90/10 hexane/ethyl acetate and 10 ml of pure ethyl acetate at 40 C. Pure 25 can be isolated by seeding this solution with a seed crystal of 25 after storing it overnight at 0 C.

Example 20 (3a,4a,5a) 3-Butyl-3-ethyl-4, 8-dihydroxy-5-phenyl- 2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (27) In a 25 ml round bottomed flask, 1 g of 26( 2.5 mmoles) and 10 ml methylene chloride were cooled to - 78 OC with stirring. Next 0.7 ml of boron tribromide(7.5 mmole) was added via syringe. The reaction was allowed to slowly warm to room temperature and stirred for 6 h.

The reaction was then diluted with 50 ml methylene chloride and washed with saturated NaCl and then water. The organic layer was dried over magnesium

sulfate. The product (0.88g) 27 was characterized by NMR and mass spectra.

ExamPle 21 General Alkylation of phenol 27 A 25 ml flask was charged with 0.15 g of 27(0.38 mmole), 5 ml anhydrous DMF, 54 mg of potassium carbonate(0.38 mmole) and 140 mg ethyl iodide (0.9 mmole). The reaction was stirred at room temperature overnight.The reaction was diluted with 50 ml ethyl ether and washed with water (25 ml) then 5% NaOH (20 ml) and then sat. NaCl. After stripping off the solvent the ethoxylated product 28 was obtained in high yield.

The product was characterized by NMR and mass spectra.

This same procedure was used to prepare products listed in table 1 from the corresponding iodides or bromides.

For higher boiling alkyl iodides and bromides only one equivalent of the alkyl halide was used.

Table 1 Compound No. R 27 H 26 Me 28 Et 29 hexyl 30 Ac 31 (CH2)6-N-pthalimide Example 22 <BR> <BR> <BR> (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-7-hydroxyamino-5- phenyl-2,3,4,5-tetrahydrobenzothiepine-1, 1-dioxide (37) and (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-7- <BR> <BR> <BR> hydroxyamino-5-phenyl-2, 314, 5-tetrahydrobenzothiepine- 1, 1-dioxide (38) Step 1. Preparation of 2-chloro-5-nitrodiphenylmethane Procedure adapted from reference :Synthesis -Stuttgart 9 770-772 (1986) Olah G. Et al Under nitrogen, a 3 neck flask was charged with 45 g (0.172 mole ) of 2-chloro-5-nitrobenzophenone in 345 ml methylene chloride and the solution was cooled to ice/water temperature. By means of an additional funnel, 150 g( 0.172 mole) of trifluoromethane sulfonic acid in 345 ml methylene chloride was added slowly.

Next 30 g of triethylsilane (0.172 mole) in 345 ml methylene chloride was added dropwise to the chilled solution. Both addition steps( trifluoromethane sulfonic acid and triethylsilane)were repeated. After the additions were completed the reaction was allowed to slowly warm up to room temperature and stirred for 12 h under nitrogen. The reaction.mixture was then poured into a chilled stirred solution of 1600 ml of saturated sodium bicarbonate. Gas evolution occurred.

Poured into a 4 liter separatory funnel and separated layers. The methylene chloride layer was isolated and

combined with two 500 ml methylene chloride extractions of the aqueous layer. The methylene chloride solution was dried over magnesium sulfate and concentrated in vacuo. The residue was recrystallized from hexane to give 39 g product. Structure 32 was confirmed by mass spectra and proton and carbon NMR. ct 0 Step 2. Preparation of 2-((2-benzyl-4- OLS nitrophenylthio) methyl) -2-ethylhexanal (33 The 2-chloro-5-nitrodiphenylmethane product 32 (40 g, 0.156 mole) from above was placed in a 2 liter 2 neck flask with water condenser. Next 150 ml DMSO and 7.18 g (0.156 mole) of lithium sulfide was added and the solution was stirred at 75 OC for 12 h. The reaction was cooled to room temperature and then 51.7 g of mesylate IV was added in 90 ml DMSO. The reaction mixture was heated to 80 OC under nitrogen. After 12 h monitored by TLC and added more mysylate if necessary.

Continued the reaction until the reaction was completed. Next the reaction mixture was slowly poured into a 1900 ml of 5% acetic aqueous solution with stirring, extracted with 4 X 700 ml of ether, and dried over MgSO4. After removal of ether, 82.7 g of product was isolated. The material can be further purified by silica gel chromatography using 95% hexane and 5 % ethyl acetate. If pure mysylate was used in this step there was no need for further purification. The product 33 was characterized by mass spectra and NMR.

Step 3. Oxidation of the nitro product 33 to the sulfone 2-((2-benzyl-4-nitrophenylsulfonyl)methyl)-2- ethylhexanal (34) The procedure used to oxidize the sulfide 33 to the sulfone 34 has been previously described.

Step 4. Reduction of 34 to 2-((2-benzyl-4- hydroxya:ninophenylsulfonyl)methyl) -2-ethyihexanal (35) A 15 g sample of 34 was dissolved in 230 ml of ethanol and placed in a 500 ml rb flask under nitrogen. Next 1.5 g of 10 wt.% Pd/C was added and hydrogen gas was bubbled through the solution at room temperature until the nitro substrate 34 was consumed. The reaction could be readily monitored by silica gel TLC using 80/20 hexane/EtOAc. Product 35 was isolated by filtering off the Pd/C and then stripping off the EtOH solvent. The product was characterized by NMR and mass spectra.

Step 5. Preparation of the 2-((2-benzyl-4-N,O-di-(t- butoxy-carbonyl)hydroxyaminophenylsulfonyl)methyl)-2-5o G ethylhexanal (36). sco ('-'cO A 13.35 g sample of 35 (0.0344 mole) in 40 ml of dry THF was stirred in a 250 ml round bottomed flask. Next added 7.52 g (0.0344 mole) of di-t-butyl dicarbonate in 7 ml THF. Heated at 60 OC overnight. Striped off THF and redissolved in methylene chloride. Extracted with 1 % HCl; and then 5% sodium bicarbonate.

The product was further purified by column chromatography using 90/10 hexane/ethyl acetate and then 70/30 hexane/ethyl acetate. The product 36 was obtained (4.12 g) which appeared to be mainly the di- (t-butoxycarbonyl) derivatives by proton NMR. C 5° Inc (\3E Step 6. (3a, 4a, 5a) 3-Butyl-3-ethyl-4-hydroxy-7- hydroxyamino-5 -phenyl-2,3,4, S-tetrahydroben:othjepine- 1,1-dioxide (37) and (3a,4b,5b) 3-Butyl-3-ethyl-4- hydroxy-7-hydroxyamino-S-phenyl-2,3,4, S- so tetrahydrobenzothiepine-1,1-dioxide (38)ton t (3c,) A 250ml 3-neck round bottomed flask was charged with 4 - g of 36 (6.8 mmoles), and 100 ml of anhydrous THF and cooled to -78 OC under a nitrogen atmosphere. Slowly add 2.29 g potassium tert-butoxide(20.4 mmoles) with

stirring and maintaining a -78 0C reaction temperature.

After 1 Ii at -78 0C the addition of base was completed and the temperature was brought to -10 0C by means of a ice/salt bath. After 3 h at -10 °C, only trace 36 remained by TLC. Next add 35 ml of deionized water to the reaction mixture at -10 0C and stirred for 5 min.

Striped off most of the THF and added to separatory funnel and extracted with ether until all of the organic was removed from the water phase. The combined ether phases were washed with saturated NaCl and then dried over sodium sulfate. The only products by TLC and NMR were the two BOC protected isomers of 37 and 38.

The isomers were separated by silica gel chromatography using 85% hexane and 15 % ethyl acetate; BOC-37 (0.71 g) and BOC- 38 (0.78 g).

Next the BOC protecting group was removed by reacting 0.87 g of BOC-38 (1.78 mmoles) with 8.7 ml of 4 M HCl (34.8 mmoles)in dioxane for 30 min. Next added 4.74 g of sodium acetate (34.8 mmoles) to the reaction mixture and 16.5 ml ether and stirred until clear. After transferring to a separatory funnel extracted with ether and water and then dried the ether layer with sodium sulfate. After removing the ether, 0.665 g of 38 was isolated. Isomer 37 could be obtained in a similar procedure.

Example 23 (3a,4a,5a) 3-Butyl-3-ethyl-7-(n-hexylamino)-4-hydroxy- 5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1,-dioxide (40) and (3a,4b,Sb) 3-Butyl-3-ethyl-7-(n-hexylamino)-4- hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1- dioxide (41) Step 1. 2-((2-Benzyl-4-(n- hexylamino)phenylsulfonyl)methyl)-2-ethylhexanal (39) In a Fischer porter bottle weighed out 0.5 g of 34 (1.2 moles) and dissolved in 3.8 ml of ethanol under

nitrogen. Next added 0.1 g of Pd/C and 3.8 ml of hexanal. Seal and pressure to 50 psi of hydrogen gas.

Stirred for 48 h. After filtering off the catalyst and removing the solvent by rotary evaporation 39 was isolated by column chromatography (0.16 g) using 90/10 hexane ethyl acetate and gradually increasing the mobile phase to 70/30 hexane/ethyl acetate. The product was characterized by NMR and mass spectra.

Step 2. (3a, 4a, Sa) 3-Butyl-3-ethyl-7- (n-hexylamino) -4- <BR> <BR> <BR> hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1- dioxide (40) and (3a,4b,5b) 3-Butyl-3-ethyl-7-(n- hexylamino)-4-hydroxy-5-phenyl-2,3,4,5- tetrahydrobenzothiepine-l, 1-dioxide (41) A 2-neck, 25 ml round bottomed flask with stir bar was charged with 0.158 g 39 (0.335 =ole) and 5 ml anhydrous THF under nitrogen. Cool to -10 OC by means of a salt/water bath. Slowly add 0.113 g of potassium tert butoxide (0.335 mmole). After 15 min at -10 OC all of the starting material was consumed by TLC and only the two isomers 40 and 41 were observed. Next added 5 ml of chilled 10% HC1 and stirred at -10 OC for 5 min.

Transferred to a separatory funnel and extract with ether. Dried over sodium sulfate. Proton NMR of the dried product (0.143 g) indicated only the presence of the two isomers 40 and 41. The two isomers were separated by silica gel chromatography using 90/10 hexane ethyl acetate and gradually increasing the mobile phase to 70/30 hexane/ethyl acetate. 40 ( 53.2 mg); 41(58.9 mg).

Example 24 Quaternization of amine substrates 40 and 41 Amine products such as 40 and 41 can be readily alkylated to quaternary salts by reaction with alkyl halides. For example 40 in DMF with 5 equivalents of

methyl iodide in the presence of 2,6 dimethyl lutidine produces the dixnethylhexylamino quaternary salt.

Example 25 (3a,4b,Sb) 3-Butyl-3-ethyl-4-hadroxy-5- (4-iodophenyl) - 2,3,4,5-tetrahydrobenzothiepine-1,l-dioxide (42) In a 25 ml round bottomed flask 0.5 g (1.3 mmole) of 6d 0.67 g of mercuric triflate were dissolved in 20 ml of dry methylene chloride with stirring. Next 0.34 g of 'Iodine was added and the solution was stirred at room temperature for 30 h. The reaction was then diluted with 50 ml methylene chloride and washed with 10 ml of 1 M sodium thiosulfate; 10 ml of saturated KI ; and dried over sodium sulfate. See Tetrahedron, Vol.50, No. 17, pp 5139-5146 (1994) Bachki, F. Et al.Mass spectrum indicated a mixture of 6d , mono iodide 42 and a diiodide adduct. The mixture was separated by column chromatography and 42 was characterized bt NMR and mass spectra.

ExamPle 26 (3a,4b,5b) 3-Butyl-5-(4-carbomethoxyphenyl)-3-ethyl-4- hydroxy-2,3,4, 5-tetrahydrobenzothiepine-1, 1-dioxide (43) A 0.1 g sample of 42 ( 0.212 mmole), 2.5 ml dry methanol, 38 ul triethylamine (0.275 mmole) , 0.3 ml toluene and 37 mg of palladium chloride (0.21 mmole) was charged to a glass lined mini reactor at 300 psi carbon monoxide. The reaction was heated at 100 OC overnight. The catalyst was filtered and a high yield of product was isolated.

The product was characterized by NMR and mass spectra.

Note the ester functionalized product 43 can be converted to the free acid by hydrolysis.

Example 27 (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5- phenyl-2, 3,4, 5-tetrahydrobenzothiepine-1, 1-dioxide (48), and (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-7- methOxy-5-phenyl-2, 3, 4, 5-tetrahydrobenzothiepine-l, 1- dioxide (49) Step 1. 2-Mercapto-5-methoxybenzophenone (50) Reaction of 66.2 g of 4-methoxythiophenol with 360 ml of 2.5 N n-butyllithium, 105 g of tetramethylethylenediamine and 66.7 g of benzonitrile in 600 ml cyclohexane according to the procedure in WO 93/16055 gave 73.2 g of brown oil which was kugelrohr distilled to remove 4-methoxythiophenol and gave 43.86 g of crude 50 in the pot residue.

Step 2. 2-((2-Benzoyl-4-methoxyphenylthio)methyl)-2- ethylhexanal (51) Reaction of 10 g (0.04 mole) of crude 50 with 4.8 g (0.02 mole)of mesylate 1 and 3.2 ml (0.23 mole) of triethylamine in 50 ml of diglyme according to the procedure for the preparation of 2 gave 10.5 g of crude product which was purified by HPLC (5% ethyl acetate- hexane) to give 1.7 g (22%) of 51.

Step 3. 2-((2-Benzoyl-4-methoxyphenylsulfonyl)methyl)- 2-ethyl-hexanal (52) A solution of 1.2 g (3.1 mmoles) of 51 in 25 ml of methylene chloride was reacted with 2.0 g (6.2 mmoles) of 50-60% MCPBA according to the procedure of step 2 of procedure A in example 18 gave 1.16 g (90%) of 52 as a yellow oil.

Step 4. 2- ( (2-Benzyl-4-methoxyphenylsulfonyl)methyl) - 2-ethylhexanal (53)

Hydrogenation of 1.1 g of 52 according to the procedure of step 3 of procedure A of example 18 gave 53 as a yellow oil (1.1 g).

Step 5. (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy- 5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,l-dioxide (48), and (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-7- methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1- dioxide A solution of 1.1 g of 53, 0.36 g orpotassium t- butoxide and 25 ml of anhydrous THF was held at reflux for 2 h and worked up as in step 4 of procedure A of example 18 to give 1.07 g of a crude product which was purified by HPLC to give 40 mg (4%) of 48 as crystals, mp 153-154 °C and 90 mg (8%) of 49 as solid, mp 136-140 OC.

Example 28 5-Phenyl-2,3,-dihydrospirobenzothiepine-3,1'-cyclohexane (57) Step 1. 1-(HYdroxymethyl)-cyclohexanecarboxaldehyde (54) To a cold (O C mixture of 100 g (0.891 mole) of cyclohexanecarboxaldehyde, 76.5 g of 37% of formaldehyde in 225 ml of methanol was added dropwise 90 ml of 1 N Sodium hydroxide in 1 h. The reaction mixture was stirred at room temperature over 48 then was evaporated to remove methanol. The reaction mixture was diluted with water and extracted with methylene chloride. The organic layer was washed with water, brine, and dried over sodium sulfate and concentrated under vacuum to give 75 g (59.7%) of thick oil. Proton NMR and mass spectra were consistent with the product.

Step 2. 1- (mesyloxymethyl) cyclohexanecarboxaldehyde (55)

To a cold (0 C'mixture of alcohol 54 (75 g, 0.54 mole) and 65.29 g (0.57 mole) of methanesulfonyl chloride in 80 ml of methylene chloride was added a solution of pyridine (47.96 g, 0.57 mole) in 40 ml of methylene chloride. The reaction mixture was stirred at room temperature for 18 h then quenched with water, acidified with conc. HCl and extracted with methylene chloride. The organic layer was washed with water, brine, and dried over sodium sulfate and concentrated under vacuum to give 91.63 g (77.8%) of thick oil.

Proton NMR and mass spectra were consistent with the product.

Step 3. 1-((2- Benzoylphenylthio) methyl) cyclohexanecarboxaldehyde (56) A mixture of 69 g (0.303 mole) of 2- mercaptobenzophenone, 82 g (0.303 mole) of mesylate 55, 32 g of triethylamine, and 150 ml of diglyme was stirred and held at reflux for 24 h. The mixture was cooled, poured into dil. HC1 and extracted with methylene chloride. The organic layer was washed with 10% NaOH, water, brine, and dried over sodium sulfate and concentrated under vacuum to remove excess diglyme.

This was purified by silica gel flush column (5% EtOAc: Hexane) and gave 18.6 g (75.9%) of yellow oil. Proton NMR and mass spectra were consistent with the product.

Step 4. S-Phenyl-2,3-dihydrospirobenzothiepine-3,1'- cyclohexane (57) To a mixture of 6.19 g of zinc dust and 100 ml of dry DME was added TiC1,(16.8 g, 0.108 mole) . The reaction mixture was heated to reflux for 2 h. A solution of compound 56 (8.3 g, 0.023 mole) in 50 ml of DME was added dropwise to the reaction mixture in 1 h and the mixture was held at reflux for 18 h. The mixture was

cooled, poured into water and extracted with ether. The organic layer was washed with water, brine, and dried over sodium sulfate, filtered through celite and concentrated under vacuum. The residue was purified by HPLC (10% EtOAc: Hexane) to give 4.6 g (64%) of white solid, mp 90-91 C. Proton and carbon NMR and mass spectra were consistent with the product.

Example 29 8b-Phenyl-la,2,3,8b-tetrahydrospiro(benzothiepinot4,5- bZoxirene-2,1'-cyclohexane)-4,4-dioxide (58) To a solution of 57 (4.6 g, 15 mmole) in 50 ml chloroform under nitrogen was added 55% MCPBA (16.5 g, 52.6 mmole) portionwise with spatula. The reaction was held at reflux for 18 h and washed with 10% NaOH(3X), water, brine, and dried over sodium sulfate and concentrated under vacuum to give 5 g of crude product.

This was recrystallized from Hexane/EtOAc to give 4.31 g (81%) of yellow solid, mp 154-155 C. Proton and carbon NMR and mass spectra were consistent with the product.

Example 30 trans-4-Hydroxy-5-phenyl-2,3,4,5-tetrahydro spiro(benzothiepine-3, 1'-cyclohexane) -1,1-dioxide (59) A mixture of 0.5 g (1.4 mmoles) of 58 , 20 ml of ethanol,10 ml of methylene chloride and 0.4 g of 10% Pd/C catalyst was hydrogenated with 70 psi hydrogen for 3 h at room temperature. The crude reaction slurry was filtered through Celite and evaporated to dryness. The residue was purified by HPLC (10% EtOAc-Hexane, 25% EtOAc-Hexane). The first fraction was 300 mg (60%) as a white solid, mp 99-100 C. Proton NMR showed this was a trans isomer. The second fraction gave 200 mg of solid which was impure cis isomer.

Example 31 cis-4-Hydroxy-S-phenyl-2,3,4, 5-tetrahydro spiro(benzothiepine-3,1'-cyclohexane)-1,l-dioxide (60) To a solution of 0.2 g (0.56 mmole) of 59 in 20 ml of CH2Cl2, was added 8 g of 50% NaOH and one drop of Aliquat-336 (methyltricaprylylammonium chloride) phase transfer catalyst. The reaction mixture was stirred for 10 h at room temperature. Twenty g of ice was added to the mixture and the mixture was extracted with CH2C12 (3x10 ml) washed with water, brine and dried over MgSO, and concentrated in vacuo to recover 0.15 g of crude product. This was recrystallized from Hexane/EtOAc to give 125 mg of white crystal, mp 209-210 C . Proton and carbon NMR and mass spectra were consistent with the product.

Example 32 (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,S- tetrahydrobenzothiepine (61), and (3a,4b,Sb) 3-Butyl-3- ethyl-4-hydroxy-5-phenyl-2, 3,4,5- tetrahydrobenzothiepine (62) To a solution of 0.5 g (1.47 mmole) of compound 47 in 5 ml of anhydrous THF was added 0.17 g (1.47 mmole) of 95% potassium t-butoxide. The reaction mixture was stirred at room temperature for 18 h and quenched with 10 ml of 10% HC1. The organic was extracted into methylene chloride. The methylene chloride extract was dried over magnesium sulfate and concentrated in vacuo.

The residue was purified by HPLC (2% EtOAc-hexane) to give 47 mg of 61 in the second fraction and 38 mg of 62 in the third fraction. Proton NE and mass spectra were consistent with the assigned structures.

Example 33

(3a,4a,5a) 3-Butyl-3ethyl-4-hydroxy-7-amino-5-phenyl- 2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (63) and (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-7-amino-5-phenyl- 2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(64) An autoclave was charged with 200 mg of 37 in 40 cc ethanol and .02 g 10 % Pd/C. After purging with nitrogen the crave was charged with 100 psi hydrogen and heated to 55 C. The reaction was monitored by TLC and mass spec and allowed to proceed until all of 37 was consumed. After the reaction was complete the catalyst was filtered and the solvent was removed in vacuo and the only observable product was amine 63.

This same procedure was used to produce 64 from 38.

Example 34 (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-(3O- methOxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1- dioxide (65), and (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy- 7-methoxy-5-(3'-methoxyphenyl)-2,3,4,5- tetrahydrobenzothiepine-l,l-dioxide (66).

Alkylation of e-methoxyphenol with 3-methoxybenzyl chloride according to the procedure described in J.

Chem. Soc, 2431 (1958) gave 4-methoxy-2-(3'- methoxybenzyl)phenol in 35% yield. This material was converted to compound 65, mp 138.5-141.5 OC, and compound 66, mp 115.5-117.5 OC, by the procedure similar to that in Example 18 method B.

ExamDle 35 (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-.5-(3 I- (trifluoromethyl)phenyl)-2,3,4,5- tetrahydrobenzothiepine-1,1-dioxide, (67), and.

(3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-(3' (trifluoromethyl)phenyl)-2,3,4,5- tetrahydrobenzothiepine-1,1-dioxide (68).

Alkylation of 4-methoxyphenol with 3- (trifluoromethyl)benzyl chloride according to the procedure described in J. Chem. Soc. 2431 (1958) gave 4-methoxy-2-(3'-(trifluoromethyl)benzyl)phenol. This material was converted to compound 67, mp 226.5-228 OC, and compound 68, mp 188-1900C, byu the procedure similar to that in Example 18 method B.

Example 3 f (3a,4a,5a) 3-ButytY3-ethyl-5-(4-.fluorophenyl)-4- hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1- dioxide (69), and (3a,4b,5b) 3-Butyl-3-ethyl-5-(4'- fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5- tetrahydrobenzothiepine-l,l-dioxide (70).

Alkylation of 4-methoxyphenol with 4-fluorobenzyl chloride according to the procedure described in J.

Chem. Soc, 2431 (1958) gave 4-methoxy-2-(4'- fluorobenzyl)phenol. This material was converted to compound 69 and compound 70 by the procedure similar to that in Example 18 method B . Xb B .Jg >>B. C0 or sl I3c Example 37 o0fi6-1 (3a,4a,5a) 3-Butyl-3-ethyl-5-(3'-fluorophenyl)-4- hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1- dioxide (71), and (3a,4b,5b) 3-Butyl-3-ethyl-5-(3'- fluorophenyl) -4-hydroxy-7-methoxy-2, 3,4,5- tetrahydrobenzothiepine-1,l-dioxide (72).

Alkylation of 4-methoxyphenol with 3-fluorobenzyl chloride according to the procedure described in J.

Chem. Soc, 2431 (1958) gave 4-methoxy-2-(31- fluorobenzyl)phenol. This material was converted to compound 71 and compound 72 by the procedure similar to that in Example 18 method B.

Example 38

(3a,4a,5a) 3-Butyl-3-ethyl-5-(2'-fluorophenyl)-4- hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1- dioxide (73), and (3a,4b,Sb) 3-Butyl-3-ethyl-5-(2'- fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5- tetrahydrobenzothiepine-1, 1-dioxide (74).

Alkylation of 4-methoxyphenol with 2-fluorobenzyl chloride according to the procedure described in J.

Chem. Soc, 2431 (1958) gave 4-methoxy-2-(2'- fluorobenzyl)phenol. This material was converted to compound 73 and compound 74 bv the procedure similar to that in Example 18 method B. that Example 39 Mecs 15) Gov oC (3a, 4a, 5a) 3-Butyl-7-bromo-3-ethyl-4-hydroxy-5-(3'- ~ <BR> <BR> <BR> <BR> <BR> <BR> methOxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1- dioxide (75), and (3a,4b,5b) 3-Butyl-7-bromo-3-ethyl-4- hydroxy-5-(3'-methoxyphenyl)-2,3,4,5- tetrahydrobenzothiepine-1,1-dioxide (76).

Alkylation of 4-bromophenol with 3-methoxybenzyl chloride according to the procedure described in J.

Chem. Soc, 2431 (1958) gave 4-bromo-2-(3'- methoxybenzyl)phenol. This material was converted to compound 75, mp 97-101.5 OC, and compound 76, mp 102- 106 OC. bv the procedure similar to that in Example 18 method B. (oY'o F F"> F l&t F Example 40 F C17) ' F (3a, 4a, Sa) 3-Butyl-3-ethyl-7-fluoro-S-(4'~F fluorophenyl) -4-hydroxy-2, 3,4,5- tetrahydrobenzothiepine-l,l-dioxide (77), and (3a,4b,Sb)- 3-Butyl-3-ethyl-7-fluoro-5-(4'- fluorophenyl)-4-hydroxy-2,3,4,5- tetrahydrobenzothiepine-l,l-dioxide (78).

Alkylation of 4-f luorophenol with 4-fluorobenzyl chloride according to the procedure described in J.

Chem. Soc, 2431 (1958) gave 4-fluoro-2-(4'- fluorobenzyl)phenol. This material was converted to compound 77, mp 228-230 OC, and compound 78, mp 134.5- 179 Oc. bv the procedure similar to that in Example 18 method B.

Example 41 (3a,4a,5a) 3-Butyl-3-ethyl-7-fluoro-4-hydroxy-5-(3'- methOxyphenyl)-2,3,4,S-tetrahydrobenzothiepine-l,1- dioxide (79), and (3a,4b,Sb) 3-Butyl-3-ethyl-7-fluoro- 40hydroxy-5-(3'-methoxyphenyl)-2,3,4,5- tetrahydrobenzothiepine-l,1-dioxide (80).

Alkylation of 4-fluorophenol with 3-methoxybenzyl chloride according to the procedure described in J.

Chem. Soc, 2431 (1958) gave 4-fluoro-2-(3'- methoxybenzyl)phenol. This material was converted to compound 79, as a solid and compound 80, mp 153-155 OC, by the procedure similar to that in Example 18 method B.

Example 42 (3a,4b,Sb) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4- <BR> <BR> <BR> hydroxy-7-methylthio-2,3,4,S-tetrahydrobenzothiepine- 1,1-dioxide (81).

A mixture of 0.68 (1.66 mmol) of compound 77, 0.2 g (5 mmol) of sodium methanethiolate and 15 ml of anhydrous DMF was stirred at room temperature for 16 days. The reaction mixture was dilute with ether and washed with water and brine and dried over M0SO4- The ether solution was concentrated in vacuo. The residue was purified by HPLC (20% ethyl acetate in hexanes). The first fraction was impure (3a,4a,5a) 3-butyl-3-ethyl-4- hydroxy-7-methylthio-5- (4 '-fluorophenyl) -2,3,4,5- tetrahydrobenzothiepine-1,1-dioxide. The second fraction was compound 81, mp 185-186.5 °C.

Example 43 (3a,4b,5b) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4- hydroxy-7- (1-pyrrolidinyl) -2,3,4,5- tetrahydrobenzothiepine-l,1-dioxide (82).

A mixture of 0.53 g (1.30 mmol) of compound 78 and 5 ml of pyrrolidine was held at reflux for 1 h. The reaction mixture was diluted with ether and washed with water and brine and dried over MgSO The ether solution was concentrated in vacuo. The residue was crystallized from ether-hexanes to aive compound 82, mP 174.5-177 OC.

Example 44 (3a,4b,5b) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4- ') hydroxy- 7 - ( 1 -morpho linyl ) -2,3,4,5- tetrahydrobenzothiepine-l, 1-dioxide (83) - G ( s 33 A mixture of 0.4 g (0.98 mmol) of compound 78 and 5.0 g (56 mmol) of morpholine was held at reflux for 2 h and concentrated in vacuo. The residue was diluted with ether (30 ml) and washed with water and brine and dried over M,SQ. The ether solution was concentrated in vacuo. The residue was recrystallized from ether- hexanes to give compound 83, mp 176.5-187.5 OC.

Example 45 (3a,4a,5a) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4- hydroxy-7-methyl-2,3,4,5-tetrahydrobenzothiepine-1,1- dioxide (84), and (3a,4b,5b) 3-Butyl-3-ethyl-5-(4'- fluorophenyl)-4-hydroxy-7-methyl-2;3,4,5- tetrahydrobenzothiepine-l,l-dioxide (85).

Alkylation of 4-methylphenol with 4-fluorobenzyi' chloride according to the procedure described in J.

Chem. Soc, 2431 (1958) gave 4-methyl-2-(41- fluorobenzyl)phenol). This material was converted to

compound 84 and compound 85 by the procedure similar to that in Example 18 method B. 0 that in 3 -- Example 46 9 " c6) oN 46 C (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-5-(4'- hydroxyphenyl) -7-methoxy-2,3,4,5- tetrahydrobenzothiepine-l,l-dioxide (86), and (3a,4b,5b) 3-Butyl-3-ethyl-4,7-dihydroxy-5-(4'- hydroxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1- dioxide (87).

To a solution of 0.52 (1.2 mmol) of compound 66 in 20 ml of methylene chloride was added 1.7 g (6.78 mmol) of born tribromide. The reaction mixture was cooled to - 78 °C and was stirred for 4 min. An additional 0.3 ml of boron tribromide was added to the reaction mixture and the reaction mixture was stirred at -78 °C for 1 h and quenced with 2 N HCl. The organic was extracted into ether. The ether layer was washed with brine, dried over MgSO" and concentrated in vacuo. The residue (0.48 g) was purified by HPLC (30% ethyl acetate in hexanes). The first fraction was 0.11 g of compound 86 as a white solid, mp 171.5-173 OC. The second fraction was crystallized from chloroform to give 0.04 g of compound 87 as a white solid, mp 264 °C (dec).

Example 47 (3a,4b,5b) 3-Butyl-3-ethyl-4,7-dihydroxy-5-(4'- fluorophenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1- dioxide (88).

Reaction of compound 70 with excess boron tribromide at room temperature and worked up as in Example 46 gave compound 88 after an HPLC purification.

Example 48

(3a,4b,5b) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4- hydroxy-7- (1-azetidinyl) -2,3,4,5- tetrahydrobenzothiepine-1,1-dioxide (89).

A mixture of 0.20 g (0.49 mmol) of compound 78, and 2.0 g (35 mmol) of aztidine was held at reflux for 3 h and concentrated in vacuo. The residue was diluted with ether (30 ml) and washed with water and brine and dried over MgSO4. The ether solution was concentrated on a steam bath. The separated crystals were filtered to aive 0.136 a of 89 as Drisms. mD 196.5-199.5 OC.

Example 49 (3a,4a,5a) 3-Butyl-3-ethyl-5-(3'-methoxyphenyl)-4- hydroxy-7-methylthio-2,3,4,5-tetrahydrobenzothiepine- 1,1-dioxide (90). (3a,4b,5b) 3-Butyl-3-ethyl-5-(3'- methoxyphenyl)-4-hydroxy-7-methylthio-2,3,4,5- tetrahydrobenzothiepine-l,l-dioxide (91).

A mixture of 0.4 g (0.95 mmol) of compound 79, 0.08 g (1.14 mmol) of sodium methanethiolate and 15 ml of anhydrous DMF was stirred at 60 °C for 2 h. An additional 1.4 mmol of sodium methanethiolate was added to the reaction mixture and the mixture was stirred at 60 °C for an additional 2 h. The reaction mixture was triturated with 100 ml of water and extracted methylene chloride. The methylene chloride water mixture was filtered through Celite and the methylene chloride layer was dried over MgSO and concentrated in vacuo.

The first fraction (0.1 g) was compound 90, mp 117-121 OC. The second fraction (0.16 g) was compound 91, mp 68-76 OC.

Example 50 Preparation of polyethyleneglycol functionalized benzothiepine A.

136 A 50 ml rb flash under a nitrogen atmosphere was charged with 0.54 g of M-Tres-5000 (Polyethyieneglycol

Tresylate [methoxy-PEG-Tres,MW 5000] purchased from Shearwater Polymers Inc., 2130 Memorial Parkway, SW, Huntsville, Alabama 35801), 0.055 g Compound No. 136, 0.326 C.CO, and 2cc anhydrous acetonitrile. The reaction was stirred at 30 C for 5 days and then the solution was filtered to remove salts. Next, the acetonitrile was removed under vacuum and the product was dissolved in THF and then precipitated by addition of hexane. The polymer precipitate was isolate by filtration from the solvent mixture (THF/hexane). This precipitation procedure was continued until no Compound No. 136 was detected in the precipitated product (by TLC SiO2). Next, the polymer precipitate was dissolved in water and filtered and the water soluble polymer was dialyzed for 48 hours through a cellulose dialysis tube (spectrum 7 ,45 mmx O.5 ft, cutoff 1,000 MW). The polymer solution was then removed from the dialysis tube and lyophilized until dried. The NMR was consistent with the desired product A and gel permeation chromatography indicated the presence of a 4500 MW polymer and also verified that no free Compound No. 136 was present. This material was active in the IBAT in vitro cell assay.

Example 51 Preparation of Compound 140 OoS "1OOH "' 0 h NH2 o-polyethyleneglycol-o 2 No. 140 A 2-necked 50 ml round bottom Flask was charged with 0.42g of Tres-3400 (Polyethyleneglycol Tresylate [Tres- PEG-Tres,MW 3400] purchased from Shearwater Polymers Inc., 2130 Memorial Parkway, SW, Huntsville, Alabama 35801), 0.1 potassium carbonate, 0.100g of Compound No.

111 and 5 ml anhydrous DMF. Stir for 6 days at 27 OC.

TLC indicated the disappearance of the starting Compound No. 111. The solution was transferred to a separatory funnel and diluted with 50 cc methylene chloride and then extracted with water. The organic layer was evaporated to dryness by means of a rotary

evaporator. Dry wgt. 0.4875 g. Next, the polymer was dissolved in water and then dialyzed for 48 hours at 40 °C through a cellulose dialysis tube (spectrum 7 ,45mm x 0.5 ft, cutoff 1,000 MW). The polymer solution was then removed from the dialysis tube and lyophilized until dried 0.341 g). NMR was consistent with the desired product B.

Example 52 A 10 ce vial was charged with 0.21 g of Compound No.

136 (0.Smmoles), 0.17g (1.3 mmoles)potassium carbonate, 0.6g (1.5 mmoles) of 1,2-bis-(2-iodoethoxy)-ethane and 10 cc DMF. The reaction was stirred for 4 days at room temperature and then worked up by washing with ether/water. The ether layer was stripped to dryness and the desired product Compound No. 134 was isolated on a silica gel column using 80/20 bexane ethyl acetate.

Example 53 Example 54

A two necked 25 ml round bottom Flask was charged with 0.5g (1.24mmoles) of 69462, 13 mls of anhydrous DMF, 0.055g of 60% NaH dispersion and 0.230g (0.62 mmoles) of 1,2-Bis [2-iodoethoxylethane] at 10 OC under nitogen. Next, the reaction was slowly heated to 40 OC. After 14 hours all of the Compound No. 113 was consumed and the reaction was cooled to room temperature and extracted with ether/water. The ether layer was evaporated to dryness and then chromatographed on Silicage (80/20 ethyl acetate/hexane). Isolated Compound No. 112 (0.28 g) was characterized by NMR and mass spec.

Example 55

In a 50 ml round bottom Flask, add 0.7g (1.8 moles) of Compound No. 136, 0.621g of potassium carbonate, 6 ml DMF, and 0.33g of 1,2-Bis [2-iodoethoxylethane]. Stir at 40 OC under nitrogen for 12 hours. The workup and isolation was the same procedure for Compound No. 112.

Examples 56 and 57 (Compound Nos. 131 and 137) The compositions of these compounds are shown in Table 3.

The same procedure as for Example 55 except appropriate benzothiepine was used.

ExamDle 58 (Compound No. 139) The composition of this compound is shown in Table 3.

Same procedure as for Example 55 with appropriate benzothiepine 1,6 diiodohexane was used instead of 1,2- Bis [2-iodoethoxylethane].

Example 59 (ComDound No. 101) 101 This compound is prepared by condensing the 7-NH2 benzothiepine with the 1,12-dodecane dicarboxylic acid or acid halide.

Example 60 (Compound No. 104) 2-Chloro-4-nitrobenzophenone is reduced with triethylsilane and trifluoromethane sulfonic acid to 2- chloro-4-nitrodiphenylmethane 32. Reaction of 32 with lithium sulfide followed by reacting the resulting sulfide with mesylate IV gives sulfide-aldehyde XXIII.

Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIV (see Scheme 5). Reduction of the sulfone-aldehyde XXV formaldehyde and 100 psi hydrogen and 55 C for 12 hours catalyzed by palladium on carbon in the same reaction vessel yields the substituted dimethylamine derivative XXVIII. Cyclization of XXVII with potassium t-butoxide yields a mixture of substituted amino derivatives of this invention Compound No. 104.

Scheme 6 Example 61 A 1 oz. Fisner-porter bottle was charged with 0.14 g (0.34 mmoles) of 70112, 0.97 gms (.6.8 mmoles) of methyl iodide, and 7 ml of anhydrous acetonitrile. Heat to 50 OC for 4 days. The quat. Salt Compound No. 192 was isolated by concentrating to 1 cc acetonitrile and then precipitating with diethyl ether.

Example 62 A 0.1 g (0.159 mmoles) sample of Compound No. 134 was dissolved in 15 ml of anhydrous acetonitrile in a Fischer-porter bottle and then trimethylamine was bubbled through the solution for 5 minutes at O °C and then capped and warmed to room temperature. The reaction was stirred overnight and the desired product was isolated by removing solvent by rotary evaporation.

Example 63 ( Compound No. 295)

Sodium Hydride 60% (11 mg, 0.27 mmoles) in 1 cc of acetonitrile at 0 °C was reacted with 0.248 mmoles (.10 g) of Compound No. 54 in 2.5cc of acetonitrile at 0 OC.

Next, 0.(980g 2.48 mmoles) of 1,2-Bis [2- iodoethoxylethane]. After warming to room temperature, stir for 14 hours. The product was isolated by column chromatography.

Example 64 (Compound No. 286) Following a procedure similar to the one described in Example 86, infra (see Compound No. 118), the title compound was prepared and purified as a colorless solid; mp 180-181 OC; 1H NMR (CHCl3) 8 0.85 (t, J = 6 Hz, 3H~, 0.92 (t, J = 6 Hz, 3H), 1.24-1.42 (m, 2H), 1.46-1.56 (m, 1H), 1.64-1.80 (m, 1H), 2.24-2.38 (m, 1H), 3.15 (AB, JAB = 15 Hz, Av = 42 Hz, 2H), 4.20 (d, J

= 8 Hz, 1H), 5.13 (s, 2H), 5.53 (s, 1H), 6.46 (s, 1H), 6.6S (s, 1H), 7.29-7.51 (m, 10H), 7.74 (d, J = 8 Hz, 1H), 8.06 (d, J = 8 Hz, 1H). FABMS m/z 494 (M+H), HRMS calcd for (M+H) 494.2001, found 494.1993. Anal. Calcd. for C28H31NO5S: C, 68.13; H, 6.33; N, 2.84. Found: C, 68.19; H, 6.56; N, 2.74.

Example 65 (Compound No. 287) Following a procedure similar to the one described in Example 89, infra (see Compound No. 121), the title compound was prepared and purified as a colorless solid: mp 245-246 OC, 1H NMR (CDC1,) 8 0.84 (t, J = 6 Hz, 3H), 0.92 (t, J = 6 Hz, 3H), 1.28, (d, J = 8 Hz, 1H), 1.32-1.42 (m, 1H), 1.48-1.60 (m, 1H), 1.64-1.80 (m, 1H), 2.20-2.36 (m, 1H), 3.09 (AB, JAB = 15 Hz, Av = 42 Hz, 2H), 3.97 (bs, 2H), 4.15 (d, J = 8 Hz, 1H), 5.49 (s, 1H), 5.95 (s, 1H), 6.54 (d, J = 7 Hz, 1H), 7.29- 7.53 (m, 5H), 7.88 (d, J = 8 Hz, 1H); ESMS 366 (M+Li).

Anal. Calcd. for C20H2^NO3S: C, 66.82; H, 7.01; N, 3.90.

Found: C, 66.54; H, 7.20; N, 3.69.

Example 66 (Comround No. 288)

Following a procedure similar to the one described in Example 89, infra (see Compound No. 121), the title compound was prepared and purified by silica gel chromatography to give the desired product as a colorless solid: mp 185-186°C; 1H NMR (CDC1,) 61.12 (s, 3H), 1.49 (s, 3H), 3.00 (d, J = 15 Hz, 1H), 3.28 (d, J = 15 Hz, 1H), 4.00 (s, 1H), 5.30 (s, 1H), 5.51 (s, 1H), 5.97 (s, 1H), 6.56 (dd, J = 2.1, 8.4 Hz, 1H), 7.31-7.52 (m, 5H), 7.89 (d, J = 8.4 Hz, 1H). MS (FAB+) (M+H) m/z '332.

Example 67 (Comnound No. 289) Following a procedure similar to the one described in Example 89 (see Compound No. 121), the title compound was prepared and purified by silica gel chromatography to give the desired product as a white solid: mp 205-206 °C; 1H NMR (CDC1,) 6 0.80-0.95 (m, 6H), 1.10-1.70 (m, 7H), 2.15 (m, 1H), 3.02 (d, J = 15.3 Hz, 2H), 3.15 (d, J = 15.1 Hz, 2H), 3.96 (s, br, 2H), 4.14 (d, J:= 7.8 Hz, 1H), 5.51 (s, 1H), 5.94 (d, J = 2.2, 1H), 6.54 (dd, J = 8.5, 2.2 Hz, 1H), 7.28-7.50 (m, 6H), 7.87 (d, J = 8.5 Hz, 1H). MS (FAB): m/z 388 (M+H).

Example 68 (Compound No. 290)

Following a procedure similar to the one described in Example 89, infra (see Compound No. 121), the title compound was prepared and purified as a colorless solid: mp = 96-98 OC, 1H NMR (CDCl1) # 0.92 (t, J = 7 Hz, 6H), 1.03-1.70 (m, llH), 2.21 (t, J = 8 Hz, 1H), 3.09 (AB, JAB =- 18 Hz, Av = 38 Hz, 2H), 3.96 (bs, 2H), 4.14 (d, J = 7 Hz, 1H), 5.51 (s, 1H), 5.94 (s, 1H), 6.56 (d, J = 9 Hz, 1H), 7.41-7.53 (m, 6H), 7.87 (d, J = 8 Hz, 1H); FABMS m/z 416 (M+H).

Example 69 Following a procedure similar to the one described in Example 86, infra (see Compound No. 118), the title compound was prepared and purified as a colorless solid: 1H NMR (CDC1,) 6 0.91 (t, J = 7 Hz, 6H), 1.02- 1.52 (m, 11H), 1.60-1.70 (m, 1H), 2.23 (t, J = 8 Hz,

1H), 3.12 (AB, JAB = 18 Hz, Av = 36 Hz, 2H), 4.18 (d, J = 7 Hz, 1H), 5.13 (s, 2H), 5.53 (s, 1H), 6.43 (s, 1H), 6.65 (s, 1H), 7.29-7.52 (m, 10H), 7.74 (d, J = 9 Hz, 1H), 8.03 (d, J = 8 Hz, lH); ESMS m/z 556 (M+Li).

Example 70 (Compound No. 292) Following a procedure similar to the one descried in Example 89, infra (see Compound No. 121), the title compound was prepared and purified as a colorless solid: mp = 111-112.5°C, 1H NMR (CDC1,) 3 0.90 (t, J = 8 Hz, 6H), 1.03-1.50 (m, 10H), 1.55-1.70 (m, 2H), 2.18 (t, J = 12 Hz, 2H), 3.07 (AB, JAB = 15 Hz, Av = 45 Hz, 2H), 4.09 (bs, 2H), 5.49 (s, 1H), 5.91 (s, 1H), 6.55 (d, J = 9 Hz, 1H), 7.10 (t, J = 7 Hz, 2H), 7.46 (t, J = 6 Hz, 2H), 7.87 (d, J = 9 Hz, 1H).

Example 71 (Comnound No. 293) During the preparation of Compound No. 290 from Compound No. 291 using BBr3, the title compound was

isolated: lH NMR (CDCl3) 6 0.85 (t, J = 6 Hz, 6H), 0.98- 1.60 (m, 10H), 1.50-1.66 (m, 2H), 2.16 (t, J = 8 Hz, 1H), 3.04 (AB, JAB = 15 Hz, Av = 41 Hz, 2H), 4.08 (s, 1H), 4.12 (s, 1H), 5.44 (s, 1H), 5.84 (s, 1H), 6.42 (d, J = 9 Hz, 1H), 7.12 (d, J = 8 Hz, 2H), 7.16-7.26 (m, 10H), 7.83 (d, J = 8 Hz, 1H); ESMS m/z 512 (M+Li).

Example 72 (Compound No. 294) Following a procedure similar to the one described in Example 60 (Compound No. 104), the title compound was prepared and purified as a colorless solid: lH NMR (CDC1,) 6 0.90 (t, J = 6 Hz, 6H), 1.05-1.54 (m, 9H), 1.60-1.70 (m, 1H), 2.24 (t, J = 8 Hz, 1H), 2.80 (s, 6H), 3.05 (AB, J, = 15 Hz, Av = 42 Hz, 2H), 4.05-4.18 (m, 2H), 5.53 (s, 1H), 5.93 (s, 1H), 6.94 (d, J = 9 Hz, 1H), 7.27-7.42 (m, 4H), 7.45 (d, J = 8 Hz, 2H), 7.87 (d, J = 9 Hz, lH) ; ESMS m/z 444 (M+H).

Structures of the compounds of Examples 33 to 72 are shown in Tables 3 and 3A.

Examples 73-79, 87. 88 and 91-102 Using in each instance a method generally described in those of Examples 1 to 72 appropriate to the substituents to be introduced, compounds were prepared having the structures set forth in Table 3.

The starting materials illustrated in the reaction schemes shown above were varied in accordance with principles of organic synthesis well known to the art to introduce the indicated substituents in the 4- and 5- positions (R3, R4, R5, R6) and in the indicated position on the benzo ring (RX).

Structures of the the compounds produced in Examples 73-102 are set forth in Tables 3 and 3A.

Examples 80-84 Preparation of 115, 116, 111, 113 Preparation of 4-chloro-3-[4-methoxy- phenylmethyl]-nitrobenzene.

In a 500 ml 2-necked rb flask weigh out 68.3 gms phosphorus pentachloride (0.328 mole 1.1 eq). Add 50 mls chlorobenzene. Slowly add 60 gms 2-chloro-5- nitrobenzoic acid (0.298 mole). Stir at room temp overnight under N2 then heat 1 hr at SOC.

Remove chlorobenzene by high vacuum. Wash residue with hexane. Dry wt=55.5 gms.

In the same rb flask, dissolve acid chloride (55.5 g 0.25 mole) from above with 100 mls anisole (about 3.4 eq). Chill solution with ice bath while purging with N2. Slowly add 40.3g aluminum chloride (1.2 eq 0.3 mole). Stir under N, for 24 hrs.

After 24 hrs, the solution was poured into 300 mls 1N HC1 soln. (cold). Stir this for 15 min. Extract several times with diethyl ether. Extract organic layer once with 2% aqueous NaOH then twice with water.

Dry organic layer with MgSO4, dry on vac line. Solid is washed well with ether and then ethanol before drying. Wt=34.57g (mixture of meta, ortho and para).

Elemental theory found C 57.65 57.45 H 3.46 5.51 N 4.8 4.8 Cl 12.15 12.16

With the next step of the reduction of the ketone with trifluoromethane sulfonic aid and triethyl silane, crystallization with ethyl acetate/hexane affords pure <BR> <BR> <BR> <BR> <BR> 4-chloro-3- [4-methoxy-phenylmethyl] -nitrobenzene. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> 4-Chloro-3- [4-methoxy-phenylmethyl) -nitrobenzene was then reacted as specified in the synthesis of 117 and 118 from 2-chloro-4-nitrophenylmethane. From these procedures 115 and 116 can be synthesized. Compounds 111 and 113 can be synthesized from the procedure used to prepare compound 121.

Compound 114 can be prepared by reaction of 116 with ethyl mercaptan and aluminum trichloride.

Examples 85 and 86 Preparation of 117 and 118 2-Chloro-4-nitrobenzophenone is reduced with triethylsilane and trifluoromethane sulfonic acid to 2- chloro-4-nitrodiphenylmethane 32. Reaction of 32 with lithium sulfide followed by reacting the resulting sulfide with mesylate IV gives sulfide-aldehyde XXIII.

Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIII. Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIV (see Scheme 5).

The sulfone-aldehyde (31.8 g) was dissolved in ethanol/toluene and placed in a parr reactor with 100 ml toluene and 100 ml of ethanol and 3.2 g of 10% Pd/C and heated to 55 C and 100 psi of hydrogen gas for 14 hours. The reaction was then filtered to remove the catalyst. The amine product (.076 moles, 29.5 g) from this reaction was then reacted with benzyl chloroformate (27.4g) in toluene in the presence of 35 g of potassium carbonate and stirred at room

temperature overnight. After work up by extraction with water, the CBZ protected amine product was further purified by precipitation from toluene/hexane.

The CBZ protected amine product was then reacted with 3 equivalents of potassium t-butoxide in THF at O C to yield compounds 117 and 118 which were separated by silica gel column chromatography.

Examples 89 and 90 Preparation of 121 or 122 Compound 118 (.013 moles, 6.79g) is dissolved in 135 ml of dry chloroform and cooled to -78 C, next 1.85 ml of boron tribromide (4.9 g) was added and the reaction is allowed to warm to room temperature.

Reaction is complete after 1.5 hours. The reaction is quenched by addition of 10% potassium carbonate at 0 C and extract with ether. Removal of ether yields compound 121. A similar procedure can be used to produce 122 from 117.

Examples 93-96 Compounds 126, 127, 128 and 129 as set forth in Table 3 were prepared substantially in the manner described above for compounds 115, 116, 111 and 113, respectively, except that fluorobenzene was used as a starting material in place of anisole.

TABLE 3 Specific compounds (#102-111,113-130,132- 134,136,138,142-144,262-296) Ex. Cp@ R1 R2 R3 R4 R5 R6 (Rz) q 61 102 Et- n-Bu- HO- H- Ph- H- I-, 7- (CH3)3N+- 73 103 n-Bu- Et- HO- H- Ph- H- I-, 7- (CH3)3N+- 60 104 Et- n-Bu- HO- H- Ph- H- 7-(CH3)2N- 74 105 Et- n-Bu- HO- H- Ph- H- 7- CH3SO2NH- 75 106 Et- n-Bu- HO- H- Ph- H- 7-Br-CH2- CONH- 76 107 n-Bu- Et- HO- H- p-n-C10H21- H- 7-NH2- -O-Ph- 77 108 Et- n-Bu- HO- H- Ph- H- 7- C5H11CONH- 78 109 Et- n-Bu- HO- H- p-n-C10H21- H- 7-NH2- -O-Ph- 79 110 Et- n-Bu- HO- H- Ph- H- 7-CH3CONE- 80 111 n-Bu- Et- HO- H- p-BO-Ph- H- 81 113 Et- n-Bu- HO- H- p-EO-Ph- H- 7-NH2- 82 114 Et- n-Bu- HO- H p-CH3O-Ph- H- 7-NH2- 83 115 n-Bu- Et- HO- H- p-CH3O-Ph- H- 7-NH-CBZ 84 116 Et- n-Bu- HO- H- p-CH3O-Ph- H- 7-NH-CBZ 85 117 n-Bu- Et- HO- H- Ph- H- 7-NH-CBZ 86 118 Et- n-Bu- HO- H- Ph- H- 7-NH-CBZ 87 119 Et- n-Bu- HO- H- Ph- H- 7-NHC02-t- Bu 88 120 n-Bu- Et- HO- H- Ph- H- 7-NHC02-t- Bu 89 121 Et- n-Bu- HO- H- Ph- H- 7-NH2- 90 122 n-Bu- Et- Ho- H- Ph- H- 7-NH2- 91 123 Et- n-Bu- HO- H- Ph- H- 7-n-C6H13- NH- 92 124 n-Bu- Et- HO- H- Ph- H- 7-n-C6H13- NH- 62 125 Et- n-Bu- HO- H- Ph- H- I-, 8- (CH3)3 N+ ( CH2CH2O) 3- 93 126 n-Bu- Et- HO- H- p-F-Ph- H- 7-NH-CBZ 94 126 n-Bu- Et- HO- H- p-F-Ph- H- 7-NH2- 95 128 Et- n-Bu- HO- H- p-F-Ph- H- 7-NH-CBZ 96 129 Et- n-Bu- HO- H- p-F-Ph- H- 7-NH2- 97 130 Et- n-Bu- HO- e- Ph- H- I-, 8- (CH3) 3N+ C6H12O- 98 132 Et- n-Bu- HO- H- Ph- H- 8-phthal- imidyl- C6H12O- 99 133 Et- n-Bu- HO- H- Ph- H- 8-n-C10H21- 52 134 Et- n-Bu- HO- H- Ph- H- 8- I- (C2H4O) 3- 100 136 Et- n-Bu- HO- H- Ph- H- 8- HO- 101 138 n-Bu- Et- HO- H- Ph- H- 8- CH3CO2- 49 90 Et- n-Bu- H- HO- H- m-CH3O-Ph- 7-CH3S- 49 91 Et- n-Bu- HO- H- m-CH3O-Ph- H- 7-CH3S- 48 89 Et- n-Bu- HO- H- p-F-Ph- H- 7- (N)- azetidine 34 66 Et- n-Bu- HO- H- m-CH3O-Ph- H- 7-CH3O- 34 65 Et- n-Bu- H- HO- H- m-CH3O-Ph- 7-CH3O- 35 68 Et- n-Bu- HO- H- m-CF3-Ph- H- 7-CH3O- 35 67 Et- n-Bu- H- HO- H- m-CF3-Ph- 7-CH3O- 46 87 Et- n-Bu- HO- H- m-HO-Ph- H- 7-HO- 46 86 Et- n-Bu- HO- H- m-HO-Ph- H- 7-CH3O- 36 70 Et- n-Bu- HO- H- p-F-Ph- H- 7-CH3O- 36 69 Et- n-Bu- H- HO- H- p-F-Ph- 7-CH3O- 47 88 Et- n-Bu- HO- H- p-F-Ph- H- 7-HO- 39 76 Et- n-Bu- HO- H- m-CH3O-Ph- H- 7-Br- 39 75 Et- n-Bu- H- HO- H- m-CH3O-Ph- 7-Br- 40 77 Et- n-Bu- H- HO- H- p-F-Ph- 7-F- 40 78 Et- n-Bu- HO- H- p-F-Ph- H- 7-F- 41 79 Et- n-Bu- H- HO- H- m-CH3O-Ph- 7-F- 41 80 Et- n-Bu- HO- H- m-CH3O-Ph- H- 7-F- 37 72 Et- n-Bu- HO- H- m-F-Ph- H- 70-CH3O- 38 73 Et- n-Bu- H- HO- H- o-F-Ph- 7-CH3O- 37 71 Et- n-Bu- H- HO- H- m-F-Ph- 7-CE30- 38 74 Et- n-Bu- HO- H- o-F-Ph- H- 7-CH30- 42 81 Et- n-Bu- HO- H- p-F-Ph- H- 7-CH3S- 45 85 Et- n-Bu- HO- H- p-F-Ph- H- 7-CH3- 45 84 Et- n-Bu- H- HO- H- p-F-Ph- 7-CH3- 44 83 . Et- n-Bu- HO- H- p-F-Ph- H- 7-(N)- morpholine 43 82 Et- n-Bu- HO- H- p-F-Ph- H- 7-(N)- pyrroli- dine 64 286 Et- Et- HO- H- Ph- H- 7-NH-CBZ 65 287 Et- Et- HO- H- Ph- H- 7-NH2- 66 288 CH3- CH3- HO- H- Ph- H- 7-NH2- 67 289 n- n- HO- H- Ph- H- 7-NH2- C3H7- C3H7- 68 290 n-Bu- n-Bu- HO- H- Ph- H- 7-NH2- 69 291 n-Bu- n-Bu- HO- H- Ph- H- 7-NH-CBZ 70 292 n-Bu- n-Bu- HO- H- p-F-Ph- H- 7-NH2- 71 293 n-Bu- n-Bu- HO- H- Ph- H- 7-PhCE2N- 72 294 n-Bu- n-Bu- HO- H- Ph- H- 7-(CH3)2N- 63 295 Et- n-Bu- HO- H- p-I- H- 7-NH2- (C2H4O)3- Ph- 102 296 Et- n-Bu- HO- H- I-, p- H- 7-NE2- (CH3)3N+(C2 H4O)3-Ph- TABLE 3A Bridged Benzothiephenes (#101, 112, 131, 135, 137, 139-141) 0 O S4II Sko X- so NH2 -polyethyleneglycol- NH2 3400 MW polyethyleneglycol bridge CPD g140 (vex. 51)

Examples 104-231 Using in each instance a method generally described in those of Examples 1 to 72 appropriate to the substituents to be introduced, including where necessary other common synthesis expedients well known to the art, compounds are prepared having the structures set forth in Table 4. The starting materials illustrated in the reaction schemes shown above are varied in accordance with principles of organic synthesis well known to the art in order to introduce the indicated substituents in the 4- and 5- positions (R3, R', R5, R6) and in the indicated position on the benzo ring (RX).

TABLE 4 Alternative compounds #1 (#302-312, 314-430) Cpd# R5 (Rx) q 302 p-F-Ph- 7-(1-aziridine) 303 p-F-Ph- 7-EtS- 304 p-F-Ph- 7-CH3S (O)- 305 p-F-Ph- 7-CH3S (O)2- 306 p-F-Ph- 7-PhS- 307 p-F-Ph- 7-CH3S- 9-CH3S- 308 p-F-Ph- 7-CE3O- 9-CH3O- 309 p-F-Ph- 7-Et- 310 p-F-Ph- 7-iDr- 311 p-F-Ph- 7-t-Bu- 312 p-F-Ph- 7-(1-pyrazole)- 314 m-CH3O-Ph 7-(1-azetidine) 315 m-CH3O-Ph- 7-(1-aziridine) 316 m-CH3O-Ph- 7-EtS- 317 m-CH3O-Ph- 7-CH3S (O)- 318 m-CH3O-Ph- 7-CH3S (O) 2- 319 m-CH30-Ph- 7-PhS- 320 m-CH3O-Ph 7-CH3S- 9-CH3S- 321 m-CH3O-Ph 7-CH3O- 9-CH3O- 322 m-CH3O-Ph 7-Et- 323 m-CH3O-Ph 7-iPr- 324 m-CH3O-Ph 7-t-Bu- 325 p-F-Ph- 6-CH3O- 7-CH3O- 8-CH3O- 326 p-F-Ph- 7-(1-azetidine) 9-CH3- 327 p-F-Ph- 7-EtS- 9-CH3- 328 p-F-Ph- 7-CH3S (O)- 9-CH3- 329 p-F-Ph- 7-CH3S (O)2- 9-CH3- 330 p-F-Ph- 7-PhS- 9-CH3- 331 p-F-Ph- 7-CH3S- 9-CH3- 332 p-F-Ph- 7-CH3O- 9-CH3- 333 p-F-Ph- 7-CH3- 9-CH3- 334 p-F-Ph- 7-CH3O- 9-CH3O- 335 p-F-Ph- 7-(1-pyrrole) 336 p-F-Ph- 7-(N)-N'-methylpiperazine 337 p-F-Ph- Ph- 338 p-F-Ph- 7-CH3C (CH2)- 339 p-F-Ph- 7-cyclpropyl 340 p-F-Ph- 7- (CH3)2NH - 341 p-F-Ph- 7-(N)-azetidine 9-CH3S- 342 p-F-Ph- 7-(N-pyrrolidine) 9-CH3S- 343 p-F-Ph- 7-(CH3)2N- 9-CH3S- 344 m-CH3O-Ph- 7-(1-pyrazole) 345 m-CH3O-Ph- 7-(N)-N'-methylpipera 346 m-CH3O-Ph- Ph- 347 m-CH3O-Ph- 7-CH3C (=CH2)- 348 m-CH3O-Ph- 7-cyclopropyl 349 m-CH30-Ph- 7-(CH3)2NH - 350 m-CH3O-Ph- 7-(N)-azetidine 9-CH3S- 351 m-CH3O-Ph- 7-(N-pyrrolidine)- 9-CH3S- 352 m-CH3O-Ph- 7-(CH3)2N- 9-CH3S- 353 m-CH3O-Ph- 6-CH3O- 7-CH3O- 8-CH3O- 354 m-CH3O-Ph- 7-(1-azetidine) 9-CH3- 355 m-CH3O-Ph- 7-EtS- 9-CH3- 356 m-CH3O-Ph- 7-CH3S(O)- 9-CH3- 357 m-CH3O-Ph- 7-CH3S(O)2- 9-CH3- 358 m-CH3O-Ph- 7-PhS- 9-CH3- 359 m-CH3O-Ph- 7-CH3S- 9-CH3- 360 m-CH3O-Ph- 7-CH3O- 9-CH3- 361 m-CH3O-Ph- 7-CH3- 9-CH3- 362 m-CH3O-Ph- 7-CH3O- 9-CH3O- 363 thien-2-yl 7-(1-aziridine) 364 thien-2-yl 7-EtS- 365 thien-2-yl 7-CH3S (O)- 366 thien-2-yl 7-CH3S (O)2- 367 thien-2-yl 7-PhS- 368 thien-2-yl 7-CH3S- 9-CH3S- 369 thien-2-yl 7-CH3O- 9-CH3O- 370 thien-2-yl 7-Et- 371 thien-2-yl 7-iPr- 372 thien-2-yl 7-t-Bu- 373 thien-2-yl 7-(1-pyrrole)- 374 thien-2-yl 7-CH3O- 375 thien-2-yl 7-CH3S- 376 thien-2-yl 7-(l-azetidine) 377 thien-2-yl 7-Me- 378 5-Cl-thien-2-yl 7- (l-azetidine) 379 5-Cl-thien-2-yl 7-(l-aziridine) 380 5-Cl-thien-2-yl 7-EtS- 381 5-Cl-thien-2-yl 7-CH3S(O)- 382 5-Cl-thien-2-yl 7-CH3S (O)2- 383 5-Cl-thien-2-yl 7-PhS- 384 5-Cl-thien-2-yl 7-CH3S- 9-CH3S- 385 5-Cl-thien-2-yl 7-CH3O- 9-CH3O- 386 S-Cl-thien-2-yl 7-St- 387 5-Cl-thien-2-yl 7-iPr- 388 5-Cl-thien-2-y' 7-t-8u- 389 5-Cl-thien-2-yl 7-CH3O- 390 5-Cl-thien-2-yl 7-CH3S- 391 5-Cl-thien-2-yl 7-Me 392 thien-2-yl 7-(1-AZETIDINE) 9-CH3- 393 thien-2-yl 7-EtS- 9-CH3- 394 thien-2-yl 7-CH3S (O)- 9-CH3- 395 thien-2-yl 7-CH3S (O)2- 9-CH3- 396 thien-2-yl 7-PhS- 9-CH3- 397 thien-2-yl 7-CH3S- 9-CE3- 398 thien-2-yl 7-CH3O- 9-CH3- 399 thien-2-yl 7-CH3- 9-CH3- 400 thien-2-yl 7-CH3O- 9-CH3O- 401 thien-2-yl 7-(l-pyrazrole) 402 thien-2-yl 7-(N)-N'-methylpiperazine 403 thien-2-yl Ph- 404 thien-2-yl 7-CH3C (=CH2)- 405 thien-2-yl 7-cyclpropyl 406 thien-2-yl 7-(CH3)2NH - 407 thien-2-yl 7-(N)-azetidine 9-CH3S- 408 thien-2-yl 7-(N-pyrrolidine) 9-CH3S- 409 thien-2-yl 7-(CH3)2N- 9-CH3S- 411 5-Cl-thien-2-yl 7-(1-pyrazrole) 412 5-Cl-thien-2-yl 7-(N)-N'-methylpiperazine 413 5-Cl-thien-2-yl Ph- 414 5-Cl-thien-2-yl 7-CH3C (=CH2)- 415 5-Cl-thien-2-yl 7-cyclopropyl 416 5-Cl-thien-2-yl 7- (CH3)2NH - 417 5-Cl-thien-2-yl 7- (N)-azetidine 9-CH3S- 418 5-Cl-thien-2-yl 7- (N-pyrrolidine) - 9-CH3S- 419 5-Cl-thien-2-yl 7- (CH3)2N- 9-CH3S- 420 5-Cl-thien-2-yl 7- (l-azetidine) 9-CH3- 421 5-Cl-thien-2-yl 7-EtS- 9-CH3- 422 5-Cl-thien-2-yl 7-CH3S (O)- 9-CH3- 423 5-Cl-thien-2-yl 7-CH3S (O) 2 9-CH3- 424 5-Cl-thien-2-yl 7-PhS- 9-CH3- 425 5-Cl-thien-2-yl 7-CH3S- 9-CH3- 426 5-Cl-thien-2-yl 7-CH3O- 9-CH3- 427 5-Cl-thien-2-yl 7-CH3- 9-CH3- 428 5-Cl-thien-2-yl 7-CH3O- 9-CH3O- 429 thien-2-yl 6-CH3O- 7-CH3O- 8-CH3O- 430 5-Cl-thien-2-yl 6-CH3O- 7-CH3O- 8 -CH3O-

Examples 232-1394 Using in each instance a method generally described in those of Examples 1 to 72 appropriate to the substituents to be introduced, including where necessary other common synthesis expedients well known to the art, compounds are prepared having the structures set forth in Table 1. The starting materials illustrated in the reaction schemes shown above are varied in accordance with principles of organic synthesis well known to the art in order to introduce the indicated substituents in the 4- and 5- positions (R', R, R5, R') and in the indicated position on the benzo ring (RX).

Example 1395 Dibutyl 4-fluorobenzene dialdehyde SteD 1: Preparation of dibutyl 4-fluoro benzene dialdehyde To a stirred solution of 17.5 g (123 mmol) of 2,5- difluorobenzaldehyde (Aldrich) in 615 mL of DMSO at ambient temperature was added 6.2 g (135 mmol) of lithium sulfide (Aldrich). The dark red solution was stirred at 75 C for 1.5 hours, or until the starting material was completely consumed, and then 34 g (135 mmol) of dibutyl mesylate aldehyde was added at about 50 C. The reaction mixture was stirred at 75 C for three hours or until the reaction was completed. The cooled solution was poured into water and extracted with ethyl acetate. The combined extracts were washed with water several times, dried (MgSO,) and

concentrated in vacuo. Silica gel chromatographic purification of the crude product gave 23.6 g (59%) of fluorobenzene dialdehyde as a yellow oil: 1H NMR (CDCl3) d 0.87 (t, J = 7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.5-1.78 (m, 4H), 3.09 (s, 2H), 7.2-7.35 (m, 1H), 7.5- 7.6 (m, 2H), 9.43 (s, 1H), 10.50 (d, J = 2.62 Hz, 1H).

Step 2: Preparation of dibutyl 4-fluorobenzyl alcohol To a solution of 22.6 g (69.8 mmol) of the dialdehyde obtained from Step 1 in 650 mL of THF at -60 C was added 69.8 mL (69.8 mmol) of DIBAL (1M in THF) via a syringe. The reaction mixture was stirred at -40 C for 20 hours. To the cooled solution at -40 C was added sufficient amount of ethyl acetae to quench the excess of DIBAL, followed by 3 N HC1. The mixture was extracted with ethyl acetate, washed with water, dried (MgSO,), and concentrated in vacua. Silica gel chromatographic purification of the crude product gave 13.5 g (58%) of recovered starting material, and 8.1 g (36%) of the desired fluorobenzyl alcohol as a colorless oil: 1H NMR, (CDC13) d 0.88 (t, J = 7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.5-1.72 (m, 4H), 1.94 (br s, 1H), 3.03 (s, 2H), 4.79 (s, 2H), 6.96 (dt, J = 8.46, 3.02 Hz, 1H), 7.20 (dd, J = 9.47, 2.82 Hz, 1H), 7.42 (dd, J = 8.67, 5.64, 1H), 9.40 (s, 1H).

Step 3: Preparation of dibutyl 4-fluorobenzyl bromide To a solution of 8.1 g (25 mmol) of benzyl alcohol obtained from Step 2 in 100 mL of DMF at -40 C was added 47 g (50 mmol) of bromotriphenyphosphonium bromide (Aldrich). The resulting solution was stirred cold for 30 min, then was allowed to warm to 0 C. To the mixture was added 10% solution of sodium sulfite and ethyl acetate. The extract was washed a few times with water, dried (MgSO4), and concentrated in'vacuo.

The mixture was stirred in small amount of ethyl acetate/hexane mixture (1:4 ratio) and filtered through a pad of silica gel, eluting with same solvent mixture.

The combined filtrate was concentrated in vacuo to give 9.5 g (98%) of the desired product as a colorless oil: 1H NMR (CDC13) d 0.88 (t, J = .7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.55-1.78 (m, 4H), 3.11 (s, 2H), 4.67 (s, 2H), 7.02 (dt, J = 8.46, 3.02 Hz, 1H), 7.15 (dd, J = 9.47, 2.82 Hz, 1H), 7.46 (dd, J = 8.67, 5.64, 1H), 9.45 (s, 1H).

Stews 4: Preparation of sulfonyl 4-fluorobenzyl bromide To a solution of 8.5 g (25 mmol) of sulfide obtained from Step 3 in 200 mL of CH2C12 at O °C was added 15.9 g (60 mmol) of mCPBA (64% peracid). The resulting solution was stirred cold for 10 min, then was allowed to stirred ambient temperature for 5 hours. To the mixture was added 10% solution of sodium sulfite and ethyl acetate. The extract was washed several times with saturated Na2CO3, dried (MgSO,), and concentrated in vacuo to give 10.2 g (98%) of the desired product as a colorless oil: 1H NMR (CDCl3) d 0.91 (t, J = 7.05 Hz, 6H), 1.03-1.4 (m, 8H), 1.65-1.82 (m, 2H), 1.90-2.05 (m, 2H), 3.54 (s, 2H), 5.01 (s, 2H), 7.04-7.23 (m, 1H), 7.30 (dd, J = 8.87, 2.42 Hz, 1H), 8.03 (dd, J = 8.86, 5.64, 1H), 9.49 (s, 1H).

Example 1396 Generic Scheme X RX aF 1. Li2S, DMSO, heat 1-,,,-S%1R2 F HO CHO 2. mesylate aldehyde, heat CHO 0 CHO 1. BuLi, PMETA 40 OC, ThF 2. DMF DIBAL, THF RX-- PMETA: ,NN~ Ns -40 OC V RXa)f R2 z BrPh3PBr, .400C R2 OHO R2 RX-- CHO HO Br mCPBA orS)R1 Rs B(OR, heat 95OHC Pd(Ph3P)4. Na2C°3 R sOHC Br EtOH, toluene or DME 5R or R5 SnR3, heat Pd(Ph3P)4, solvent base; e.g. KOtBu R = H, or short alkyl (C1-C6) 0. Xo .QI:l1 RX nRR12 OH RS Generic Scheme X: The nucleophilic substitution of an appropriately substituted 2-fluorobenzaldehyde with

lithium sulfide or other nucleophilic sulfide anion in polar solvent (such as DMF, DMA, DMSO, etc), followed by the addition of dialkyl mesylate aldehyde (X), provided a dialkyl benzene dialdehyde Y. DIBAL reduction of the dialdehyde at low temperature yielded benzyl alcohol monoaldehyde Z. Conversion of benzyl alcohol to benzyl bromide, followed by oxidation of sulfide to sulfone yielded the key intermediate W.

Pretaration of N-trotvlsulfonic acid To a solution of 51 mg (111 um) Compound X in ethanol (400 pl) was added 1,3 propane sultone (19.5 ul, 222 µm). The reaction was stirred in a sealed vial at 55 °C for 25 hr. Sample was concentrated under a nitrogen stream and purified by reversed phase chromatography using acetonitrile/water as eluent (30-45%) and afforded the desired material as an off-white solid (28.4 mg, 44%): 1H NMR (CDCL,) d 0.82-0.96 (m, 6H), 1.11-1.52 (m of m, 10H), 1.58-1.72 (m, 1H), 2.08-2.21 (m, 1H), 2.36-2.50 (m, 2H), 2.93 (s, 6H), 3.02-3.22 (m of m, SH), 3.58-3.76 (m, 2H), 4.15 (s, 1H), 5.51 (s, 1H), 6.45-6.58 (m, 1H), 6.92-7.02 (m, 1H), 7.35-7.41 (m, 1H), 7.41-7.51 (m, 2H), 8.08 (d, J = 8.1 Hz, 1H), 8.12-8.25 (m, 1H); MS ES- M-H m/z 579.

Example 1397 The 7-fluoro, 9-fluoro and 7,9-difluoro analogs of benzothiepine compounds of this invention can be reacted with sulfur and nitrogen nucleophiles to give the corresponding sulfur and nitrogen substituted analogs. The following example demonstrates the synthesis of these analogs.

3,3-Dibutyl-5a-(4'-fluorophenyl)-4a-hydroxy-7- methylthio-2, 3, 4, 5-tetrahydrobenzothiepine-1, 1-dioxide.

A mixture of 0.4 g Of 3,3-dibutyl-7-fluoro-5a-(4'- fluorophenyl)-4a-hydroxy-2,3,4,5- tetrahydrobenzothiepine-l,l-dioxide, prepared by previously described method, 0.12 g of sodium methanethiolate and 20 ml of DMF was stirred at 50 C for 3 days. An additional 0.1 g of sodium methanethiolate was added to the reaction mixture and the mixture was stirred for additional 20 h at 50 C then was concentrated in vacuo. The residue was triturated with water and extracte wiith ether. The ether extract was dried over MgS04 and concentrated in vacuo to 0.44 g of an oil. Purification by HPLC (10% EtOAc in hexane) gave 0.26 g of needles, mp 164-165.5 %C.

3,3-Dibutyl-9-dimethylamino-7-fluoro-5a-(4'- fluorophenyl)-4a-hydroxy-2,3,4,5- tetrahydrobenzothiepine-l,l-dioxide and 7,9- Bis(dimethylamino)-3,3-dibutyl-5a-(4'-fluorophenyl)-4a- hydroxy-2, 3,4, S-tetrahydrobenzothiepine-1, 1-dioxide.

A solution of 0.105 g of 3,3-dibutyl-7,9-difluoro- 5a-(4'-fluorophenyl)-4a-hydroxy-2,3,4,5- tetrahydrobenzothiepine-l,l-dioxide, prepared by the method described previously, in 20 ml of 2 N dimethylamine in TEF was heated at 160 C in a sealed Parr reactor overnight. The reaction mixture was cooled and concentrated in vacuo. The residue was triturated with 25 ml of water and extracted with ether. The ether extract was dried over MgS04 and concentrated in vacuo.

The resdue was purified by HPLC (10% EtOAc in hexane) to give 35 mg of an earlier fraction which was identified as 3,3-dibutyl-9-dimethylamino-7-fluoro-5a- (4' -fluorophenyl) -4a-hydroxy-2,3,4,5- tetrahydrobenzothiepine-l,l-dioxide, MS (CI) m/e 480 (M+ +1), and 29 mg of a later fraction which was identified as 7,9-bis(dimethylamino)-3,3-dibutyl-5a- (4'-fluorophenyl)-4a-hydroxy-2, 3, 4, 5- tetrahydrobenzothiepine-l,l-dioxide, MS (CI) m/e 505 (M+ +1) The compounds of this invention can also be synthesized using cyclic sulfate (A, below) as the reagent as shown in the following scheme. The following example describes a procedure for using the cyclic sulfate as the reagent. R2 2 R R2 r( RuC13, Al OH OH n O 0. S S II 0 0 0 A (RX))¼iSH l.NaH, diglyme HO/ 4RX)q HO R2 ~~~~~~~~~~ 2. (RY)p O O S o// o 3. H2S°4 R1 MCPBA (RX)q 0 H R2 ()q ) R2 (RY)p (RY)p o /wo KOtBu S i R2 (RX)q OH (RY)p Dibutyl cyclic sulfite:

A solution of 2,2-dibutyl-1,3-propandiol (103g, 0.548 mol) and triethylamine (221g, 2.19 mol) in anhydrous methylene chloride (500 ml) and was stirred at 0 degrees C under nitrogen. To the mixture, thionyl chloride (97.8 g, 0.82 mol) was added dropwise and within 5 min the solution turned yellow and then turned black when the addition was completed within half an hour. The reaction mixture was stirred for 3 hrs. GC showed that there was no starting material left. The mixture was washed with ice water twice then with brine twice. The organic phase was dried over magnesium sulfate and concentrated under vacuum to give the cyclic sulfite 128 g (100%) as a black oil. Mass spectrum (MS) was consistent with the product.

To a solution of the above compound (127.5g , 0.54 mol) in 600 ml acetonitrile and 500 ml of water cooled in an ice bath under nitrogen was added ruthenium(III) chloride (1 g) and sodium periodate (233 g, 1.08 mol) The reaction was stirred overnight and the color of the solution turned black. GC showed that there wasno starting material left. The mixture was extracted with 300 ml of ether and the ether extract was washed three .times with brine. The organic phase was dried over magnesium sulfate and passed through celite. The filtrate was concentrated under vacuum and gave the cyclic sulfate 133 g (97.8%) as an oil. Proton, carbon NMR and MS were consistent with the product. <BR> <BR> <P> 2- [(2- (4' -Fluoroben:yl) -4- <BR> <BR> <BR> <BR> methylphenylthio)methyl) -2-butylhexanol:

Sodium hydride (60% oil dispersion), 0.27 g (6.68 mole), was washed with hexane and the hexane wash was decanted. To the washed sodium hydride was added 20 ml of 2-methoxyethyl ether (diglyme) and the mixture was cooled in an ice bath. A solution of 1.55 g (6.68 mmole) of 2- (4'-fluorobenzyl)-4-methylbenzenethiol in 10 ml of 2-methoxyethyl ether was added dropwise to the reaction mixture in 15 min. A mixture of 2.17 g (8.68 mmole) of the dibutyl cyclic sulfate in 10 ml of 2- methoxyethyl ether was added once and stirred for 30 min at O C then at room temperature for 1 hr under nitrogen. GC showed that there was no thiol left. The solvent was evaporated and triturated wth water then was extracted with ether twice. The water layer was separated, treated with 20 ml of 10% NaOH then was boiled for 30 min and cooled, acidified with 6N HC1 and boiled for 10 min. The reaction mixture was cooled and extracted with ether. The organic layer was washed successively with water and brine, dried over magnesium -sulfate and concentrated under vacuum to give 2. 47 g 92.5%) of an oil. Proton NMR , 13C NMR and MS were consistent with the product. <BR> <BR> <P> 2- [(2- (4' -Fluorobenzyl) -4- <BR> <BR> <BR> <BR> <BR> <BR> :nethylphenylthio ) methyli -2-butylhexanal:

To a solution of the above product (2 g , 4.9 mmol) in 40 ml methylene chloride cooled in an ice bath under nitrogen was added pyridinium chlorochromate (2.18 g, 9.9 mmol) at once. The reaction was stirred with 3 hrs and filtered through a bed of silica gel.

The filtrate was concentrated under vacuum to give 1.39 g (70%) of an oil. Proton, carbon NMR and MS were consistent with the product. <BR> <BR> <BR> <P> 2- ((2- (4'-Fluorobenzyl) -4- <BR> <BR> methylphenylsulfonyl ) methyl) -2-butylhexanal To a solution of the above product (0.44 g ,1.1 mmole) in 20 ml methylene chloride solution cooled in an ice bath under nitrogen was added 70% m- chloroperbenzoic acid (0.54 g, 2.2 mmol) at once. The reaction mixture was stirred for 18 hrs and filtered.

The filtrate was washed successively with 10% NaOH (3X), water and brine, dried over magnesium sulfate and concentrated under vacum to give 0.42 g (90%) of an oil. Proton, carbon NMR and MS were consistent with the product. <BR> <BR> <P> 3,3-Dibutyl-7-methyl-5a-(4'-fluorophenyl)-4a- <BR> <BR> <BR> <BR> <BR> hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,l-dioxide: A mixture of 0.37 g (0.85 mmol) of the above product in 30 ml of anhydrous TEF was stirred at O %C.

Then potassium t-butoxide (102 mg, 0.85 mmol) was added. After 3 hrs, TLC showed that there was a product and some starting material left. The crude reaction mixture was acidified with 10% HC1 and extracted with ether. The ether extract was washed successively with water and brine, dried with MgS04 and concentrated under vacuum. The residue was purified by HPLC (10% EtOAc-Hexane). The first fraction was 0.1 g of starting material as an oil and the second fraction was a white solid, 0.27 g (75%). Proton NMR and carbon NMR were consistent withthe desired product. Mass spectrum (CI) also confirmed the product, m/e 433 (M+ 1).

Example 1398 Step 1 In an inert atmosphere, weigh out 68.3 gms phosphorus pentachloride (0.328mole Aldrich 15,777-5) into a 2-necked 500ml round bottom flask. Fit flask with a N2 inlet adapter and suba seal. Remove from inert atmosphere and begin N, purge. Add 50mls anhydrous chlorobenzene (Aldrich 28,451-3) to the PC1, via syringe and begin stirring with magnetic stir bar.

Weigh out 60 gms 2-chloro-5-nitrobenzoic acid (0.298 mole Aldrich 12,511-3). Slowly add to the chlorobenzene solution while under N2 purge. Stir at room temperature overnight. After stirring at room temperature for -20hrs,.place in oil bath and heat at 50C for lhr. Remove chlorobenzene by high vacuum. Wash residue with anhydrous hexane. Dry acid chloride wt=61.95gms. Store in inert and dry atmosphere.

In inert atmosphere, dissolve acid chloride with 105mls anhydrous anisole (0.97 mole Aldrich 29, 629-5).

Palace solution in a 2-necked 500ml round-bottom flask.

Weigh out 45.lgms aluminum chloride (0.34 moles Aldrich 29,471-3) and place in a solid addition funnel.

Fit reaction flask with addition 'funnel and a N2 inlet adapter. Remove from inert atmosphere. Chill reaction solution with ice bath and begin N, purge. Slowly add AlCl, to chilled solution. After addition is complete, allow to warm to room temperature. Stir overnight

Quench reaction by pouring into a solution of 300 mls 1N HC1 and ice. Stir 15 min. Extract twice with ether. Combine organic layers and extract twice with 2% NaOH, then twice with deionized H2O. Dry with MgSO4, filter and rotovap to dryness. Remove anisole by high vacuum. Crystalize product from 90% ethanol 10% ethyl acetate. Dry on vacuum line. Wt=35.2gms. Yield 41%.

Obtain NMR and mass spec (m/z=292).

Step 2 Dissolve 38.10gms (0.131 moles) of the benzophenone from step 1 in 250mls anhydrous methylene chloride. Place in a 3 liter flask fitted with N2 inlet, addition funnel and stopper. Stir with magnetic stir bar. Chill solution with ice bath.

Prepare a solution of 39.32 gms trifluoromethane sulfonic acid (0.262 mole Aldrich 15,853-4) and 170 mls anhydrous methylene chloride. Place in addition funnel and add dropwise to chilled solution under N2.

Stir 5 minutes after addition is complete.

Prepare a solution of 22.85 gms triethyl silane (0.197mole Aldrich 23,019-7) and 170mls anhydrous methylene chloride. Place in addition funnel and add dropwise to chilled solution under N,. Stir 5 minutes after addition is complete.

Prepare a second solution of 39.32 gms trifluoromethane sulfonic acid and 170mls anhydrous methylene chloride. Place in addition funnel and add dropwise to chilled solution under N,. Stir 5 minutes after addition is complete.

Prepare a second solution of 22.85 gms triethyl silane and 170mls anhydrous methylene chloride. Place in addition funnel and add dropwise to chilled solution under N2. After all additions are made allow to slowly warm to room temperature overnight. Stir under N2 overnight.

Prepare 1300 mls saturated NaHCO, in a 4 liter beaker. Chill with ice bath. While stirring vigorously, slowly add reaction mixture. Stir at chilled temperature for 30 min. Pour into a separatory funnel and allow separation. Remove organic layer and extract aqueous layer 2 times with methylene chloride.

Dry organic layers with MgSO,. Crystallize from ethanol. Dry on vacuum line. Dry wt=28.8gms. Confirm by NMR and mass spec (m/z=278).

Step 3 Dissolve 10.12 gms (0.036 moles) of product 2 with 200 mls anhydrous DMSO. Place in a 500 ml round bottom flask with magnetic stir bar. Fit flask with water condenser, N2 inlet, and stopper. Add 1.84 gms Li2S (0.040 moles Aldrich 21; 324-1) . Place flask in oil bath and heat at 750C under N2 overnight then cool to room'temperature.

Weigh out 10.59 gms dibutyl mesylate (0.040 moles) - Dissolve with anhydrous DMSO and add to reaction solution. Purge well with N2, heat overnight

at 800C.

Cool to room temperature. Prepare 500 mls of 5% acetic acid in a 2 liter beaker. While stirring, slowly add reaction mixture. Stir 30 min. Extract with ether 3 times. Combine organic layers and extract with water and sat'd Nail. Dry organic layer with MgSO4, filter and rotovap to dryness. Dry oil on vacuum line. Obtain pure product by column chromatography using 95% hexane and 5% ethyl acetate as the mobile phase. Dry wt=7.8 gms. Obtain NMR and mass spec (m/z=444).

Step 4 Dissolve 9.33 gms (0.021 moles) of product 3 with 12D mls anhydrous methylene chloride. Place in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N2 inlet and stopper. Chill solution with ice bath under N2 purge. Slowly add 11.54 gms 3- chloroperbenzoic acid (0.0435 moles Fluka 25800, -65%). After addition is complete warm to room temperature and monitor reaction by TLC. Reaction goes quickly to the sulphoxide intermediate but takes 8 hrs to convert to the sulphone. Chill solution over night in freezer. Filter solid from reaction, extract filtrate with 10% K,CO,. Extract aqueous layer twice with methylene choride. Combine organic layers and dry

with MgSO,. Filter and rotovap to dryness. Obtain pure product by crystallizing from ethanol or isolating by column chromatography. Obtain NMR and mass spec (m/z=476).

Step 5 Reaction is done in a 300 ml stainless steel Parr stirred mini reactor. Place 9.68 gms (0.0204 moles) of product 4 in reactor base. Add 160 mls ethanol. For safety reasons next two compounds are added in a N2 atmosphere glove bag. In glove bag, add 15.3 mls formaldehyde (0.204 moles, Aldrich 25,254-9, about 37 wt% in water) and 1.45 gms 10% Pd/Carbon (Aldrich 20,569-9). Seal reactor before removing from glove bag. Purge reactor three times with H,. Heat to 55"C under H2. Run reaction at 200 psig H2, 55"C, and a stir rate of 250 rpm. Run overnight under these conditions.

Cool reactor and vent H2. Purge with N2. Check progress of run by TLC. Reaction is a mixture of desired product and intermediate. Filter reaction mixture over a bed of celite washing well with ether.

Rotovap and redissolve with ether. Extract with water.

Dry organic layer with MgSO4, filter and rotovap to dryness. Dry on vacuum line.

Charge reactor again with same amounts, seal reactor and run overnight under same conditions.

After second run all of the material has been converted to the desired product. Cool and vent H2 pressure.

Purge with N2. Filter over a bed of celite, washing well with ether. Rotovap to dryness. Dissolve with ether and extract with water. Dry organic layer with MgSO4, filter and rotovap to dryness. Dry on vacuum line. Obtain NMR and mass spec (m/z=474).

Step 6 Dissolve 8.97 gms (0.0189 mole) of product 5 with 135 mls anhydrous THF. Place in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N2 inlet and stopper. Chill solution with ice/salt bath under N2 purge. Slowly add 2.55 gms potassium t-butoxide (0.227 mole Aldrich 15,667-1). After addition is complete, continue to stir at -10°C monitoring by TLC.

Once reaction is complete, quench by adding 135 mls 10% HC1 stirring 10 min. Extract three times with ether. Dry organic layer with MgSQ, filter and rotovap to dryness. Crystallize from ether. Obtain NMR and mass spec (m/z=474).

Step 7

Dissolve 4.67 gms (0.01 moles) of product 6 with 100 mls anhydrous chloroform. Place in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N; inlet adapter and suba seal. Chill solution with dry ice /acetone bath under a N2 purge. Slowly add, via syringe, 2.84 mls boron tribromide (0.03 moles Aldrich 20,220-7) . Stir at cold temperature for 15 min after addition then allow to warm to room temperature.

Monitor reaction progress by TLC. Reaction is usually complete in 3 hrs.

Chill solution with ice bath. Quench with 100 mls 10% K2CO, while stirring rapidly. Stir 10 min. then transfer to sep funnel and allow separation. Remove aqueous layer. Extract organic layer once with 10% HC1, once H,O, and once with saturated NaCl solution.

Dry organic layer with MgSO4, filter and rotovap to dryness. Crystallize product from ether. Obtain NMR and mass spec (m/z=460).

Step 8

Weigh 0.38 gms NaH (9.57 mmoles Aldrich 19,923-0 60% disp. in mineral oil) in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N2 inlet and stopper. Chill NaH with ice bath and begin N2 purge.

Dissolve 4.0 gms (8.7 mmoles) of product 7 with 60 mls anhydrous DMF. Add to the cold NaH. Stir at cold temperature for 30 min. Add 1.33 gms K2CO, (9.57 mmoles Fisher P-208).

Dissolve 16.1 gms 1,2-bis-(2-iodoethoxy)ethane (43.5 mmoles Aldrich 33,343-3) with 60 mls anhydrous DMF. Add to cold reaction mixture. Warm to room temperature then heat to 400C overnight under N2.

Cleanup by diluting with ether and extracting sequentially with 5% NaOH, H20, and saturated Nazi.

Dry organic layer with MgSO4, filter and dry. Obtain pure product by column chromatography using 75% hexane 25% ethyl acetate as the mobile phase. Obtain NMR and mass spec (m/z=702).

Step 9

Dissolve 1.0 gms (1.43 mmoles) of product 8 with 10 mls anhydrous acetonitrile. Place in a 3 ounce Fischer-Porter pressure reaction vessel with magnetic stir bar. Add 2.9 gms triethyl amine (28.6 mmoles Aldrich 23,962-3) dissolved in 10 mls anhydrous acetonitrile. Purge well with N2 then close system .

Heat at 4sac. Monitor reaction by TLC. Reaction is usually complete in 48 hrs.

Perform cleanup by removing acetonitrile under vacuum. Redissolve with anhydrous chloroform and precipitate quaternary ammonium salt with ether.

Repeat several times. Dry to obtain crystalline product. Obtain NMR and mass spec (m/z=675).

Example 1399 Step 1. Preparation of 1 To a solution of 144 g of KOH (2560 mmol) in 1.1 L of DMSO was added 120 g of 2-bromobenzyl alcohol (641 mmol) slowly via addition funnel. Then was added 182 g of methyliodide (80 mL, 1282 mmol) via addition funnel.

Stirred at ambient temperature for fifteen minutes.

Poured reaction contents into 1.0 L of water and extracted three times with ethyl acetate. The organic layer was dried over MgSO, and concentrated in vacuo.

Purified by silica-gel chromatography through a 200 mL plug using hexanes (100%) as elutant yielded 103.2 g (80%) of 1 as a clear colorless liquid. 1H NMR (CDC1,) d 3.39 (s, 3H), 4.42 (s, 2H), 7.18-7.27 (m, 2H), 7.12 (d, J = 7.45, 1H), 7.50 (s, 1H).

Step 2. Preparation of 2 To a cooled (-78 C) solution of 95 g (472 mmol) of 1 in 1.5 L THF was added 240 mL of 2.5 M n-butyl lithium (576 mmol). The mixture was stirred for one hour, and then to it was added 180 g of zinc iodide (566 mmol) dissolved in 500 ml TEF. The mixture was stirred thirty minutes, allowed to warm to S C, cooled to -10 °C and to it was added 6 g of Pd(PPh,), (5.2 mmol) and 125 g 2,5-difluorobenzoyl chloride (708 mmol). The mixture was stirred at ambient temperature for 18 hoursand then cooled to 10 "C, quenched with water, partitioned between ethyl acetate and water, and washed

organic layer with 1N HCL and with 1N NaOH. The organic layer was dried over MgSO, and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500) using 5% ethyl acetate/hexanes as elutant gave 53.6 g (43 %) of 2 as an orange oil. 1H NMR (CDC1,) d 3.40 (s, 3H), 4.51 (s, 2H), 7.12-7.26 (m, 3H), 7.47 (t, J = 7.50, 1H), 7.57 (d, J = 7.45, 1H), 7.73 (d, J = 7.45, 1H), 7.80 (s, 1H).

Step 3. Preparation of 3 A solution of 53 g (202.3 mmol) of 2 and 11.2 g Li2S (242.8 mmol) in 250 mL DMF was heated to 100 °C for 18 hours. The reaction was cooled (0 °C) and 60.7 g of X (the cyclic sulfate compound of example 1397) (242.8 =ol) in 50 mL DMF was added. Stirred at ambient temperature for 18 hours then condensed in vacuo.

Added 1 L water to organic residue and extracted twice with diethyl ether. Aqueous layer acidified (pH 1) and refluxed 2 days. Cooled to ambient temperature and extracted with methylene chloride, dried organic layer over MgSO, and condensed in vacuo. Purification by silica gel chromatography (Waters Prep-500) using 10% ethyl acetate / hexanes as elutant gave 42.9 g (48 %) of 3 as a yellow oil. 1H NMR (CDC1,) d 0.86 (t, J = 7.25 Hz, 6H), 1.10 - 1.26 (m, 12H), 2.83 (s, 2H), 3.32 (s, 2H), 3.40 (s, 3H), 4.48 (s, 3H), 7.02 (dd, J = 8.26 Hz and 2.82 Hz, 1H), 7.16 (dt, J = 8.19 Hz and 2.82 Hz, 1H), 7.45 (t, J = 7.65 Hz, 1H), 7.56-7.61 (m, 2H), 7.69 (d, J = 7.85 Hz, 1H), 7.74 (s, 1H), Step 4. Preparation of 4

To a cooled (-40 "C) solution of 42.9 g (96.2 mmol) of 3 in 200 mL of methylene chloride was added 21.6 g trifluoromethane sulfonic acid (12.8 mL, 144 mmol) followed by the addition of 22.4 g triethyl silane (30.7 mL, 192.4 mmol). Stirred at -20 °C for two hours, quenched with water and warmed to ambient temperature.

Partitioned between methylene chloride and water, dried the organic layer over MgSO, and condensed Ifl vacuo. Purification by silica gel chromatography (Waters Prep-500) using 10% ethyl acetate/ hexanes as elutant gave 24.2 g (60%)of 4 as a oil. 1H NMR (CDC1,) d 0.89 (t, J = 7.05 Hz, 6H), 1.17 - 1.40 (m, 12H), 1.46 (t, J = 5.84 Hz, 1H), 2.81 (s, 2H), 3.38 (s, 3H), 3.43 (d, J = 5.23 Hz, 2H), 4.16 (s, 2H), 4.42 (s, 2H), 6.80 (d, J = 9.67 Hz, 1H), 6.90 (t, J = 8.46 Hz, 1H), 7.09 (d, J = 7.45 Hz, 1H), 7.15 - 7.21 (m, 2H), 7.25 - 7.32 (m, 2H), 7.42 (m, 1H).

Step 5. Preparation of 5 To a cooled (15-18 C) solution of 24.2 g (55.8 mmol) of 4 in 100 mL DMSO was added 31.2 g sulfur trioxide pyridine complex (195 mmol). Stirred at ambient temperature for thirty minutes. Poured into cold water and extracted three times with ethyl acetate. Washed organics with 5% HCl (300 mL) and then with brine (300 mL), dired organics over MgSO, and condensed in vacuo to give 23.1 g (96 %) of 5 as a light brown oil. 'H NMR

(CDC13) d 0.87 (t, J = 7.05 Hz, 6H), 1.01 - 1.32 (m, 8H), 1.53 - 1.65 (m, 4H), 2.98 (s, 2H), 3.38 (s, 3H), 4.15 (s, 2H), 4.43 (s, 2H), 6.81 (dd, J = 9.66 Hz and 2.82 Hz, 1H), 6.91 (t, J = 8.62 Hz, 1H), 7.07 (d, J = 7.46 Hz, 1H), 7.14 (s, 1H), 7.19 (d, J = 7.65 Hz, 1H), 7.26 - 7.32 (m, 1H), 7.42 (dd, J = 8.66 Hz and 5.64 Hz, 1H), 9.40 (s, 1H).

Step 6, Preparation of 6 To a cooled (0 °C) solution of 23.1 g (53.6 mmol) of 5 in 200 mL methylene chloride was added 28.6 g meta cholorperoxy-benzoic acid (112.6 mmol) - Stirred at ambient temperature for 24 hours. Quenched with 100 mL 10% Na2SQ, partitioned between water and methylene chloride. Dried organic layer over MgSO, and condensed in vacuo to give 24.5 g (98%) of 6 as a light yellow oil. 1H NMR (CDC13) d 0.86 - 1.29 (m, 14H), 1.58 - 1.63 (m, 2H), 1.82 - 1.91 (m, 2H), 3.13 (s, 2H), 3.39 (s, 3H), 4.44 (s, 2H), 4.50 (s, 2H), 6.93 (d, J = 9.07 Hz, 1H), 7.10 - 7.33 (m, 5H), 8.05 (s, 1H), 9.38 (s, 1H).

Step 7. Preparartion of 7 To a solution of 24.5 g (52.9 mmol) of 6 in 20 mL of THF contained in a stainless steel reaction vessel was added 100 mL of a 2.0 M solution of dimethyl amine and

20 mL of neat dimethyl amine. The vessel was sealed and heated to 110 °C for 16 hours. The reaction vessel was cooled to ambient temperature and the contents concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500) using 15 % ethyl acetate/hexanes gave 21.8 g (84 %) of 7 as a clear colorless oil. 1H NMR (CDC1,) d 0.85 (t, J = 7.25 Hz, 6H), 0.93 - 1.29 (m, 8H), 1.49 - 1.59 (m, 2H), 1.70 - 1.80 (m, 2H), 2.98 (s, 8H), 3.37 (s, 3H), 4.41 (s, 2H), 4.44 (s, 2H), 6.42 (s, 1H), 6.58 (dd, J = 9.0 Hz and 2.61 Hz, 1H), 7.13 (d, J = 7.45 Hz, 1H), 7.21 (s, 1H), 7.28 (t, J = 7.85 Hz, 1H), 7.82 (d, J = 9.06 Hz, 1H), 9.36 (s, 1H).

Step 8. Preparation of 8 A solution of 21.8 g (44.8 mmol) of 7 in 600 mL of THF was cooled to O °C. 58.2 mL of a 1 M solution of potassium t-butoxide was added slowly, maintaining the temperature at <5 °C. Stirred for 30 minutes, then quenched with 50 mL of saturated ammonium chloride.

The organic layer was partitioned between ethyl acetate and water, dried over MgSO4 and concentrated in vacuo.

Purification by recrystalization from -10% ethyl acetate/hexanes gave 15.1 g of 8 as a white solid. The mother liquor was purified by silica gel chromatography (Waters Prep-500) using 30% ethyl acetate/hexanes as the elutant to give 3.0 g of 8 as a white solid. MS (FABLi*) m/e 494.6. HRMS (EI ) calculated for M+H 487.2756. Found 487.2746.

Step 9. Preparation of 9 A solution of 2.0 g (4.1 mmol) of 8 in 20 mL of methylene chloride was cooled to -60 OC. 4.1 mL of a 1M solution of boron tribromide was added. Stirred at ambient tempersture for thirty minutes. Cooled reaction to -10 "C and quenched with 50 mL of water.

The organic layer was partitioned between methylene chloride and water, dried over MgSO, and concentrated in vacuo. Purification by recrystalization from 50% ethyl acetate/methylene chloride gave 1.95 g (89%) of 9 as a white solid. MS (FABH) m/e 537. HRMS (FAB) calculated for M 536.1834. Found 536.1822.

Step 10. Preparation of 10 A solution of 1.09 g (2.0 mmol) of 9 and 4.9 g (62 mmol) of pyridine in 30 mL of acetonitrile was stirred at ambient temperature for 18 hours. The reaction was concentrated in vacuo. Purification by recrystallization from methanol/ diethyl ether gave 1.19 g (96%) of 10 as an off white solid. MS (FAB) m/e 535.5.

Example 1398 Step 1. Preparation of 2 To a solution of 6.0 g of dibutyl 4-fluorobenzene dialdehyde of Example 1395 (14.3 mmol) in 72 ml, of toluene and 54 mL of ethanol was added 4.7 g 3- nitrobenzeneboronic acid (28.6 mmol), 0.8 g of tetrakis (triphenylphosphine) palladium(0) (0.7 mmol) and 45 mL of a 2 M solution of sodium carbonate in water. This heterogeneous mixture was refluxed for three hours, then cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was dried over MgSO, and concentrated invacuo.

Purification by silica gel chromatography (Waters Prep- 2000) using ethyl acetate/hexanes (25/75) gave 4.8 g (73%) of the title compound as a yellow solid. 1H NMR (CDC1,) d 0.88 (t, J = 7.45 Hz, 6H), 0.99-1.38 (m, 8H), 1.62-1.75 (m, 2H), 1.85-2.00 (m, 2H), 3.20 (s, 2H), 4.59 (s, 2H), 6.93 (dd, J = 10.5 and 2.4 Hz, 1H), 7.15 (dt, J = 8.4 and 2.85 Hz, 1H), 7.46-7.59 (m, 2H), 8.05- 8.16 (m, 3H), 9.40 (s, 1H).

Step 3. Preparation of 3 A solution of 4.8 g (10.4 mmol) of 2 in 500 mL THF was cooled to O °C in an ice bath. 20 mL of a 1 M solution of potassium t-butoxide was added slowly, maintaining the temperature at <5 °C. Stirring was continued for 30 minutes, then the reaction was quenched with 100 mL of saturated ammonium chloride. The mixture was partitioned between ethyl acetate and water; the organic layer was washed with brine, then dried (MgSO4) and concentrated in vacuo. Purification by silica gel chromatography through a 100 ml plug using CH2C12 as eluent yielded 4.3 g (90%) of 3 as a pale yellow foam.

1H NMR (CDCl3) d 0.93 (t, J = 7.25 Hz, 6H), 1.00-1.55 (m, 8H), 1.59-1.74 (m, 3H), 2.15-2.95 (m, 1H), 3.16 (qAB, JAB = 15.0 Hz, AV = 33.2 Hz, 2H), 4.17 (d, J = 6.0 Hz, 1H), 5.67 (s, 1H), 6.34 (dd, J=9.6 and 3.0 Hz, 1H), 7.08 (dt, J = 8.5 and 2.9 Hz, 1H), 7.64 (t, J = 8.1 Hz, 1H), 7.81 (d, J = 8.7 Hz, 1H), 8.13 (dd, J = 9.9 and 3.6 Hz, 1H), 8.23-8.30 (m, 1H), 8.44 (s, 1H).

MS(FABH+) m/e (relative intensity) 464.5 (100), 446.6 (65). HRMS calculated for M+H 464.1907. Found 464. 1905.

Step 4. Preparation of 4 To a cooled (0 °C) solution of 4.3 g (9.3 mmol) of 3 in 30 ml THF contained in a stainless steel reaction vessel was added 8.2 g dimethyl amine (182 mmol). The vessel was sealed and heated to 110 °C for 16 hours.

The reaction vessel was cooled to ambient temperature and the contents concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-2000) using an ethyl acetate/hexanes gradient (10-40% ethyl acetate) gave 4.0 g (88%) of 4 as a yellow solid. 'H NMR (CDCl3) d 0.80-0.95 (m, 6H), 0.96-1.53 (m, 8H), 1.60-1.69 (m, 3H), 2.11-2.28 (m, 1H), 2.79 (s, 6H), 3.09 (qAB, JAB = 15.0 Hz, DV= 45.6 Hz, 2H), 4.90 (d, J = 9.0 Hz, 1H), 5.65 (s, 1H), 5.75 (d, J = 2.1 Hz, 1H), 6.52 (dd, J = 9.6 and 2.7 Hz, IH), 7.59 (t, J = 8.4 Hz, 1H), 7.85 (d, J = 7.80 Hz, 1H), 7.89 (d, J = 9.0 Hz, 1H), 8.20 (dd, J = 8.4 and 1.2 Hz, 1H), 8.43 (s, 1H), MS(FABH+) m/e (relative intensity) 489.6 (100), 471.5 (25). HRMS calculated for M+H 489.2423.. Found 489.2456.

Step 5. Preparation of 5 To a suspension of 1.0 g (2.1 mmol) of 4 in 100 ml ethanol in a stainless steel Parr reactor was added 1 g 10% palladium on carbon. The reaction vessel was sealed, purged twice with H2, then charged with H2 (100 psi) and heated to 45 °C for six hours. The reaction vessel was cooled to ambient temperature and the contents filtered to remove the catalyst. The filtrate was concentrated in vacuo to give 0.9 g (96%) of 5. 1H NMR (CDCl3) d 0.80-0.98 (m, 6H), 1.00-1.52 (m, 10H), 1.52-1.69 (m, 1H), 2.15-2.29 (m, 1H), 2.83 (s, 6H), 3.07 (qAB, JAB = 15.1 Hz, DV = 44.2 Hz, 2H), 3.70 (s, 2H), 4.14 (s, 1H), 5.43 (s, 1H), 6.09 (d, J = 2.4 Hz, 1H), 6.52 (dd, J = 12.2 and 2.6 Hz, 1H), 6.65 (dd, J = 7.8 and 1.8 Hz, 1H), 6.83 (s, 1H), 6.93 (d, J = 7.50 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.89 (d, J = 8.9 Hz, 1H), MS(FABH+) m/e (relative intensity) 459.7 (100).

HRMS calculated for M+H 459.2681. Found 459.2670.

Step 6. Preparation of 6 To a solution of 914 mg (2.0 mmol) of S in 50 ml THF was added 800 mg (4.0 mmol) 5-bromovaleroyl chloride.

Next was added 4 g (39.6 mmol) TEA. The reaction was stirred 10 minutes, then partitioned between ethyl acetate and brine. The organic layer was dried (MgSO4) and concentrated in vacuo. Purification by silica gel chromatography through a 70 ml MPLC column using a gradient of ethyl acetate (20-50%) in hexane as eluent yielded 0.9 g (73%) of 6 as a pale yellow oil.

'H NMR (CDCl3) d 0.84-0.95 (m, 6H), 1.02-1.53 (m, 10H), 1.53-1.68 (m, 1H), 1.80-2.00 (m, 4H), 2.12-2.26 (m, 4H), 2.38 (t, J = 6.9 Hz, 2H), 2.80 (s, 6H), 3.07 (qAB, JAB = 15.6 Hz, DV = 40.4 Hz, 2H), 3.43 (t, J = 6.9 Hz, 2H), 4.10 (s, 1H), 5.51 (s, 1H), 5.95 (d, J = 2.4 Hz, 1H), 6.51 (dd, J = 9.3 and 2.7 Hz, 1H), 7.28 (s, 1H), 7.32-7.41 (m, 2H), 7.78 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 9.0 Hz, 1H).

Step 7. Preparation of 7 To a solution of 0.9 g (1.45 mmol) of 6 in 25 ml acetonitrile add 18 g (178 mmol) TEA. Heat at 55 °C for 16 hours. The reaction mixture was cooled two ambient temperature and concentrated in vacuo.

Purification by reverse-phase silica gel chromatography (Waters Delta Prep 3000) using an acetonitrile /water gradient containing 0.05% TFA (20-65% acetonitrile)

gave 0.8 g (73%) of 7 as a white foam. 1H NMR (CDCl3) d 0.80-0.96 (m, 6H), 0.99-1.54 (m, 19H), 1.59-1.84 (m, 3H), 2.09-2.24 (m, 1H), 2.45-2.58 (m, 2H), 2.81 (s, 6H), 3.09 (q, JAB = 15.6 Hz, DV = 18.5 Hz, 2H), 3.13- 3.31 (m, 8H), 4.16 (s, 1H), 5.44 (s, 1H), 6.08 (d, J = 1.8 Hz, 1H), 6.57 (dd, J = 9.3 and 2.7 Hz, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.34 (t, J = 8.4 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.74 (s, 1H), 7.88 (d, J = 9.0 Hz, 1H), 9.22 (s, 1H). HRMS calcd 642.4304; observed 642.4343.

Example 1400 Step 1 A 12-liter, 4-neck round-bottom flask was equipped with reflux condenser, N2 gas adaptor, mechanical stirrer, and an addition funnel. The system was purged with N2.

A slurry of sodium hydride (126.0g/4.988mol) in toluene (2.5 L) was added, and the mixture was cooled to 6 C. A solution of 4-fluorophenol (560.5g/5.000mol) in toluene (2.5 L) was added via addition funnel over a period of 2.5 h. The reaction mixture was heated to reflux (100 C) for lh. A solution of 3-methoxybenzyl chloride (783.0g/5.000mol) in toluene (750 mL) was added via addition funnel while maintaining reflux.

After 15 h. refluxing, the mixture was cooled to room temperature and poured into H20 (2.5 L). After 20 min. stirring, the layers were separated, and the organic layer was extracted with a solution of potassium hydroxide (720g) in MeOH (2.5 L). The MeOH layer was added to 20% aqueous potassium hydroxide, and the

mixture was stirred for 30 min. The mixture was then washed 5 times with toluene. The toluene washes were extracted with 20% aq. KOH. All 20% aq. KOH solutions were combined and acidified with concentrated HC1. The acidic solution was extracted three times with ethyl ether, dried (MgS04), filtered and concentrated in vacuo. The crude product was purified by Kugelrohr distillation to give a clear, colorless oil (449.Og/39% yield). b.p.: 120-130 C/SOmtorrHg. 1H NMR and MS [(M + H)+ = 2331 confirmed desired structure.

Step 2 A 12-liter, 3-neck round-bottom flask was fitted with mechanical stirrer and N2 gas adaptor. The system was purged with N2. 4-Fluoro-2-(3-methoxybenzyl)-phenol (455.5g/1.961mo1) and dimethylformamide were added.

The solution was cooled to 6 C, and sodium hydride t55.5g/2.197mol) was added slowly. After warming to room temperature, dimethylthiocarbamoyl chloride (242.4g/1.961mol) was added. After 15 h, the reaction mixture was poured into H20 (4.0 L), and extracted two times with ethyl ether. The combined organic layers were washed with H20 and saturated aqueous Nail, dried (MgSO4), filtered, and concentrated in vacuo to give the product (605.3g, 97% yield). 1H NMR and MS [(M+H)+ = 320] confirm desired structure.

Step 3 A 12-liter, round-bottom flask was equipped with N2 gas adaptor, mechanical stirrer, and reflux condenser. The system was purged with N2. 4-Fluoro-2-(3- methoxybenzyl) -phenyldimethylthiocarbamate (605.3g/1.895mol) and phenyl ether (2.0kg) were added, and the solution was heated to reflux for 2 h. The mixture was stirred for 64 h. at room temparature and then heated to reflux for 2 h. After cooling to room temperature, MeOH (2.0 L) and TEF (2.0 L) were added, and the solution was stirred for 15 h. Potassium hydroxide (425.9g/7.590mol) was added, and the mixture was heated to reflux for 4 h. After cooling to room temparature, the mixture was concentrated by rotavap, dissolved in ethyl ether (1.0 L), and extracted with H20. The aqueous extracts were combined, acidified with concentrated HC1, and extracted with ethyl ether.

The ether extracts were dried (MgSO4), filtered, and concentrated in vacuo to give an amber oil (463.0g, 98% yield). 1H NMR confirmed desired structure.

Step 4

A 5-liter, 3-neck, round-bottom flask was equipped with N2 gas adaptor and mechanical stirrer. The system was purged with N2. 4-Fluoro-2-(3-methoxybenzyl)- thiophenol (100.Og/403.2rnrnol) and 2-methoxyethyl ether (1.0 L) were added and the solution was cooled to O C.

Sodium hydride (9.68g/383.2mmol) was added slowly, and the mixture was allowed to warm to room temparature, 2,2-Dibutylpropylene sulfate (110.89g/443.6mmol) was added, and the mixture was stirred for 64 h. The reaction mixture was concentrated by rotavap and dissolved in H20. The aqueous solution was washed with ethyl ether, and concentrated H2S04 was added. The aqueous solution was heated to reflux for 30 min, cooled to room temperature, and extracted with ethyl ether The ether solution was dried (MgSO4), filtered, and conc'd in vacuo to give an amber oil (143.94g/85% yield). 1H NMR and MS [(M + H)+ = 419] confirm the desired structure.

Step 5

A 2-liter, 4-neck, round-bottom flask was equipped with N2 gas adaptor, and mechanical stirrer. The system was purged with N2. The corresponding alcohol (143.94g/343.8mmol) and CH2C12 (1.0 L) were added and cooled to O C. Pyridinium chlorochromate (140.53g/651.6mmol) was added. After 6 h., CH2C12 was added. After 20 min, the mixture was filtered through silica gel, washing with CH2C12. The filtrate was concentrated in vacuo to give a dark yellow-red oil (110.6g, 77% yield). 1H NMR and MS [(M + H)+ = 417] confirm the desired structure.

Step 6 A 2-liter, 4-neck, round-bottom flask was equipped with N2 gas adaptor and mechanical stirrer. The system was purged with N2. The corresponding sulfide

(110.6g/265.5mmol) and CH2Cl2 (1.0 L) were added. The solution was cooled to O C, and 3-chloroperbenzoic acid (158.21g/531.7mmol) was added portionwise. After 30 min, the reaction mixture was allowed to warm to room temperature After 3.5 h, the reaction mixture was cooled to O C and filtered through a fine fritted funnel. The filtrate was washed with 10% aqueous K2C03. An emulsion formed which was extracted with ethyl ether. The organic layers were combined, dried (MgSO4), filtered, and concentrated in vacuo to give the product (93.2g, 78% yield) . NXR confirmed the desired structure.

Step 7 A 2-liter, 4-neck, round-bottom flask was equipped with N2 gas adaptor mechanical stirrer, and a powder addition funnel. The system was purged with N2. The corresponding aldebyde (93.2g/208mol) and TEP (1.0 L) were added. and the mixture was cooled to O C.

Potassium ert-butoxide (23,35g/208.1mmol) was added via addition funnel. After 1h, 10% aq/ HCl (1.0 L) was added. After 1 h, the mixture was extracted three times with ethyl ether. dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by recryst. from 80/20 hexane/ethyl acetate to give a white solid (32.18 g). The mother liquor was concentrated in vacuo and zecrystelized from 95/5 toluene/ethyl acerate to give a white solid (33.60g combined yield: 71%). 1H NMR confirmed the desired product.

Step 8 A Fisher porter bottle was fitted with N2 line and magnetic stirrer. The system was purged with N2. The corresponding fluoro-compound (28.lg/62.6mmol) was added, and the vessel was sealed and cooled to -78 C.

Dimethylamine (17.lg/379mmol) was condensed via a C02/acetone bath and added to the reaction vessel. The mixture was allowed to warm to room temperature and was heated to 60 C. After 20 h, the reaction mixture was allowed to cool and was dissolved in ethyl ether. The ether solution was washed with H20, saturated aqueous NaCl, dried (MgSO4), filtered, and concentrated in vacuo to give a white solid (28.5g/96% yield). 1H NMR confirmed the desired structure.

Step 9 A 250-mL, 3-neck, round-bottom flask was equipped with N2 gas adaptor and magnetic stirrer. The system was purged with N2. The corresponding methoxy-compound (6.62g/14.Ommol) and CHCl3 (150 mL) were added. The reaction mixture was cooled to -78 C, and boron tribromide (10.50g/41.9mmol) was added. The mixture was allowed to warm to room temperature After 4 h, the reaction mixture was cooled to O C and was quenched with 10% K2C03 (100 mL). After 10 min, the layers were separated, and the aqueous layer was extracted two times with ethyl ether. The CHCl3 and ether extracts were combined, washed with saturated aqueous NaCl, dried (MgS04), filtered, and concentrated in vacuo to give the product (6.27g/98% yield) , 1H NMR confirmed the desired structure.

Step 10 In a 250 ml single neck round bottom Flask with stir bar place 2- diethylamineoethyl chloride hydochloride (fw 172.10g/mole) Aldrich D8, 720-1 (2.4 mmol,4.12g), 34 ml dry ether and 34 ml of 1N KOH(aqueous). Stir 15 minutes and then separate by ether extraction and dry over anhydrous potassium carbonate.

In a separate 2-necked 250 ml round bottom flask with stir bar add sodium hydride (60% dispersion in mineral oil, 100 mg , 2.6 mmol) and 34 ml of DMF. Cool to ice temperature. Next add phenol product(previous step) 1.1 g (2.4 mmilomoles in 5 ml DMF and the ether solution prepared above. Heat to 40C for 3 days. The product which contained no starting material by TLC was diluted with ether and extracted with 1 portion of 5% NaOH, followed by water and then brine. The ether layer was dried over magnesium sulfate and isolated by removing ether by rotary evaporation (1.3 gms).The product may be further purified by chromatography (Si02 99% ethyl acetate/1% NH40H at Sml/min.). Isolated yield: 0.78 g (mass spec , and H1 NMR)

Step 11 The product from step 10 ( 0.57gums, 1.02 millimole fw 558.83 g/mole) and 1.6 gms iodoethane (10.02 mmol) was <BR> <BR> <BR> placed in 5 ml acetonitrile in a fischer-porter bottle<BR> <BR> <BR> and heated to 45 C for 3 days. The solution was<BR> <BR> <BR> evaporated to dryness and redissolved in 5 mls of<BR> <BR> <BR> chloroform. Next ether was added to the chloroform<BR> <BR> <BR> solution and the resulting mixture was chilled. The<BR> <BR> <BR> desired product is isolated as a precipitate 0.7272 gms. Mass spec M-I = 587.9 , H NMR).

Example 1401 A 12-liter, 4-neck round-bottom flask was equipped with

reflux condenser, N2 gas adaptor, mechanical stirrer, and an addition funnel. The system was purged with N2.

A slurry of sodium hydride (126 . Og/4 . 988mol) in toluene (2.5 L) was added, and the mixture was cooled to 6 C. A solution of 4-fluorophenol (560.5g/5.OOOmol) in toluene (2.5 L) was added via addition funnel over a period of 2.5 h. The reaction mixture was heated to reflux (100 C) for lh. A solution of 3-methoxybenzyl chloride (783.Og/5.OOOmol) in toluene (750 mL) was added via addition funnel while maintaining reflux.

After 15 h. refluxing, the mixture was cooled to room temperature and poured into H20 (2.5 L). After 20 min. stirring, the layers were separated, and the organic layer was extracted with a solution of potassium hydroxide (720g) in MeOH (2.5 L). The MeOH layer was added to 20% aqueous potassium hydroxide, and the mixture was stirred for 30 min. The mixture was then washed 5 times with toluene. The toluene washes were extracted with 20% aq. KOH. All 20% aqueous KOH solutions were combined and acidified with concentrated HC1. The acidic solution was extracted three times with ethyl ether, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by Kugelrohr distillation to give a clear, colorless oil (449.0g/39% yield). b.p.: 120-130 C/S0mtorrEg.

1H NMR and MS [(M + H)+ = 233] confirmed desired structure.

Step 2

A 12-liter, 3-neck round-bottom flask was fitted with mechanical stirrer and N2 gas adaptor. The system was purged with N2. 4-Fluoro-2-(3-methoxybenzyl)- phenol (455.5g/1.961mol) and dimethylformamide were added. The solution was cooled to 6 C, and sodium hydride (55.5g/2.197mol) was added slowly. After warming to room temperature, dimethylthiocarbamoyl chloride (242.4g/1.961mol) was added. After 15 h, the reaction mixture was poured into H20 (4.0 L), and extracted two times with ethyl ether. The combined organic layers were washed with H20 and saturated aqueous NaCl, dried over MgS04, filtered, and concentrated in vacuo to give the product (605.3g, 97% yield). 1H NMR and MS [(M+H)+ = 320] confirm desired structure.

C14H130F5 fw=248.32 A 12-liter, round-bottom flask was equipped with N2 gas adaptor, mechanical stirrer, and reflux condenser. The system was purged with N2. 4-Fluoro-2- (3 -methoxybenzyl) -phenyldimethylthiocarbamate (605.3g/1.895mol) and phenyl ether (2.0kg) were added, and the solution was heated to reflux for 2 h. The mixture was stirred for 64 h. at room temperature and then heated to reflux for 2 h. After cooling to room temperature, MeOH (2.0 L) and TEF (2.0 L) were added, and the solution was stirred for 15 h. Potassium hydroxide (425.9g/7.590mol) was added, and the mixture was heated to reflux for 4 h. After cooling to room temperature, the mixture was concentrated by rotavap, dissolved in ethyl ether (1.0 L), and extracted with H20. The aqueous extracts were combined, acidified with conc. HC1, and extracted with ethyl ether. The ether extracts were dried (MgSO,), filtered, and concentrated in vacuo to give an amber oil (463.Og, 98% yield). 1H NMR confirmed desired structure.

Step 4 A 5-liter, 3-neck, round-bottom flask was equipped with N2 gas adaptor and mechanical stirrer. The system

was purged with N2. 4-Fluoro-2-(3-methoxybenzyl)- thiophenol (100 . Og/403 . 2mmol) and 2-methoxyethyl ether (1.0 L) were added and the solution was cooled to O C.

Sodium hydride (9.68g/383.2mmol) was added slowly, and the mixture was allowed to warm to room temperature 2, 2-Dibutylpropylene sulfate (110 . 89g/443 . 6mmol) was added, and the mixture was stirred for 64 h. The reaction mixture was concentrated by rotavap and dissolved in H20. The aqueous solution was washed with ethyl ether, and conc. H2S04 was added. The aqueous solution was heated to reflux for 30 min, cooled to room temperature, and extracted with ethyl ether. The ether solution was dried (MgS04), filtered, and concentrated in vacuo to give an amber oil (143.94g/85% yield). 1H NMR and MS [(M + H)+ = 419) confirm the desired structure.

Step 5 A 2-liter, 4-neck, round-bottom flask was equipped with N2 gas adaptor, and mechanical stirrer. The system was purged with N2. The corresponding alcohol (143.94 g/343.8 mmol) and CH2C12 (1.0 L) were added and cooled to O C. Pyridinium chlorochromate (140.53g/651.6mmol) was added. After 6 h., CH2C12 was

added. After 20 min, the mixture was filtered through silica gel, washing with CH2C12. The filtrate was concentrated in vacuo to give a dark yellow-red oil (110.6g, 77% yield). 1H NMR and MS [(M + H)+ = 417] confirm the desired structure.

Step 6 A 2-liter, 4-neck, round-bottom flask was equipped with N2 gas adaptor and mechanical stirrer. The system was purged with N2. The corresponding sulfide (110.6g/265.5mmol) and CH2C12 (1.0 L) were added. The solution was cooled to O C, and 3-chloroperbenzoic acid (158.21g/531.7mmol) was added portionwise. After 30 min, the reaction mixture was allowed to warm to room temperature After 3.5 h, the reaction mixture was cooled to O C and filtered through a fine fritted funnel. The filtrate was washed with 10% aqueous K2C03. An emulsion formed which was extracted with ethyl ether. The organic layers were combined, dried (MgS04), filtered, and concentrated in vacuo to give the product (93.2g, 78% yield). 1H NMR confirmed the desired structure.

Step 7 A 2-liter, 4-neck, round-bottom flask was equipped with N2 gas adaptor, mechanical stirrer, and a powder addition funnel. The system was purged with N2. The corresponding aldehyde (93.2g/208mmol) and TEF (1.0 L) were added, and the mixture was cooled to O C.

Potassium tert-butoxide (23.35g/208.lmmol) was added via addition funnel. After lh, 10% aq/ HC1 (1.0 L) was added. After 1 h, the mixture was extracted three times with ethyl ether, dried (MgS04), filtered, and concentrated in vacuo. The crude product was purified by recrystallized from 80/20 hexane/ethyl acetate to give a white solid (32.18g). The mother liquor was concentrated in vacuo and recrystallized from 95/5 toluene/ethyl acetate to give a white solid (33.60g, combined yield: 71%). 1H NMR confirmed the desired product.

Step 8 A Fisher porter bottle was fitted with N2 line and magnetic stirrer. The system was purged with N2. The corresponding fluoro-compound (28.lg/62.6mmol) was added, and the vessel was sealed and cooled to -78 C.

Dimethylamine (17.lg/379mmol) was condensed via a CO2/acetone bath and added to the reaction vessel. The mixture was allowed to warm to room temperature and was heated to 60 C. After 20 h, the reaction mixture was allowed to cool and was dissolved in ethyl ether. The ether solution was washed with H20, saturated aqueous NaCI, dried over MgSO4, filtered, and concentrated in vacuo to give a white solid (28.5g/96% yield). 1H NMR confirmed the desired structure.

Step 9 A 250-mL, 3-neck, round-bottom flask was equipped with N2 gas adaptor and magnetic stirrer. The system was purged with N2. The corresponding methoxy-compound (6.62g/14.0mmol) and CHCl3 (150 mL) were added. The reaction mixture was cooled to -78 C, and boron tribromide (10.50g/41.9mmol) was added. The mixture was allowed to warm to room temperature After 4 h, the reaction mixture was cooled to O C and was quenched with 10% K2C03 (100 mL). After 10 min, the layers were separated, and the aqueous layer was extracted two times with ethyl ether. The CHC13 and ether extracts were combined, washed with saturated aqueous NaCI, dried over MgS04, filtered, and concentrated in vacuo to give the product (6.27g/98% yield). 1H NMR confirmed the desired structure.

Step 10 In a 250 ml single neck round bottom flask with stir bar place 2- diethylamineoethyl chloride hydochloride (fw 172.10g/mole) Aldrich D8, 720-1 (2.4 millimoles, 4.12g), 34 ml dry ether and 34 ml of 1N KOH (aqueous). Stir 15 minutes and then separate by ether extraction and dry over anhydrous potassium carbonate.

In a separate 2-necked 250 ml round bottom flask with stir bar add sodium hydride (60% dispersion in mineral oil, 100 mg, (2.6 mmol) and 34 ml of DMF. Cool to ice temperature. Next add phenol product (previous step) 1.1 g (2.4 mmol in 5 ml DMF and the ether solution prepared above. Heat to 40C for 3 days. The product which contained no starting material by TLC was diluted with ether and extracted with 1 portion of 5% NaOH, followed by water and then brine. The ether layer was dried over Magnesium sulfate and isolated by removing ether by rotary evaporation (1.3 gms). The product may be further purified by chromatography (silica 99% ethyl acetate/l% NH4OH at 5m1/min..).

Isolated yield: 0.78 g (mass spec , and H1 NMR) Step 11

The product from step 10 (O.57gms, 1.02 millimole fw 558.83 g/mole) and iodoethane (1.6 gms (10.02 mmol)was place in 5 ml acetonitrile in a Fischer-Porter bottle and heated to 45 C for 3 days. The solution was evaporated to dryness and redissolved in 5 mls of chloroform. Next ether was added to the chloroform solution and the resulting mixture was chilled. The desired product is isolated as a precipitate 0.7272 gms. Mass spec M-I = 587.9, 'H NMR) .

BIOLOGICAL ASSAYS The utility of the compounds of the present invention is shown by the following assays. These assays are performed in vitro and in animal models essentially using a procedure recognized to show the utility of the present invention.

In vitro Assay of compounds that inhibit IBAT-mediated uptake of [14C]-Taurocholate (TC) in H14 Cells Baby hamster kidney cells (BHK) transfected with the cDNA of human IBAT (H14 cells) are seeded at 60,000 cells/well in 96 well Top-Count tissue culture plates for assays run within in 24 hours of seeding, 30,000

cells/well for assays run within 48 hours, and 10,000 cells/well for assays run within 72 hours.

On the day of assay, the cell monolayer is gently washed once with 100 ml assay buffer (Dulbecco's Modified Eagle's medium with 4.5 g/L glucose + 0.2% (w/v) fatty acid free bovine serum albumin- (FAF)BSA).

To each well 50 ml of a two-fold concentrate of test compound in assay buffer is added along with 50 ml of 6 mM [l'C]-taurocholate in assay buffer (final concentration of 3 mM ["C]-taurocholate). The cell culture plates are incubated 2 hours at 370 C prior to gently washing each well twice with 100 ml 4" C Dulbecco's phosphate-buffered saline (PBS) containing 0.2% (w/v) (FAF)BSA. The wells are then gently washed once with 100 ml 4 C PBS without (FAF)BSA. To each 200 ml of liquid scintillation counting fluid is added, the plates are heat sealed and shaken for 30 minutes at room temperature prior to measuring the amount of radioactivity in each well on a Packard Top-Count instrument.

In Vitro Assay of compounds that inhibit uptake of [14C]-Alanine The alanine uptake assay is performed in an identical fashion to the taurocholate assay, with the exception that labeled alanine is substituted for the labeled taurocholate.

In Vivo Assav of compounds that inhibit Rat Ileal uptake of 14CI-Taurocholate into Bile (See"Metabolism of 3a, 7b-dihydroxy-7a-methyl-5b- cholanoic acid and 3a,7b-dihydroxy-7a-methyl-5b- cholanoic acid in hamsters in Biochimica et Biophysica Acta 833 (1985) 196-202 by Une et al.) Male wistar rats (200-300 g) are anesthetized with inactin @100 mg/kg. Bile ducts are cannulated with a 10" length of PE10 tubing. The small intestine is exposed and laid out on a gauze pad. A canulae (1/8" luer lock, tapered female adapter) is inserted at 12 cm from the junction of the small intestine and the cecum.

A slit is cut at 4 cm from this same junction (utilizing a 8 cm length of ileum). 20 ml of warm Dulbecco's phosphate buffered saline, pH 6.5 (PBS) is used to flush out the intestine segment. The distal opening is cannulated with a 20 cm length of silicone tubing (0.02" I.D. x 0.037" O.D.). The proximal cannulae is hooked up to a peristaltic pump and the intestine is washed for 20 min with warm PBS at 0.25 ml/min. Temperature of the gut segment is monitored continuously. At the start of the experiment, 2.0 ml of control sample (!14C)-taurocholate (t 0.05 mi/ml with 5 mM cold taurocholate) is loaded into the gut segment with a 3 ml syringe and. bile sample collection is begun. Control sample is infused at a rate of 0.25 ml/min for 21 min. Bile samples fractions are collected every 3 minute for the first 27 minutes of the procedure. After the 21 min of sample infusion, the ileal loop is washed out with 20 ml of warm PBS (using a 30 ml syringe), and then the loop is washed out for 21 min with warm PBS at 0.25 ml/min. A second

perfusion is initiated as described above but this with test compound being administered as well (21 min administration followed by 21 min of wash out) and bile sampled every 3 min for the first 27 min. If necessary, a third perfusion is performed as above that typically contains the control sample.

Measurement of Heatic Cholesterol Concentration ( HEPATIC CHOL) Liver tissue was weighed and homogenized in chloroform:méthanol (2:1). After homogenization and centrifugation the supernatant was separated and dried under nitrogen. The residue was dissolved in isopropanol and the cholesterol content was measured enzymatically, using a combination of cholesterol oxidase and peroxidase, as described by Allain, C. A., et al. (1974) Clin. Chem. 20, 470.

Measurement of Hepatic HMG CoA-Reductase ActivitY (RMG COA) Hepatic microsomes were prepared by homogenizing liver samples in a phosphate/sucrose buffer, followed by centrifugal separation. The final pelleted material was resuspended in buffer and an aliquot was assayed for HMG CoA reductase activity by incubating for 60 minutes at 370 C in the presence of "C-HMG-CoA (Dupont- NEN). The reaction was stopped by adding 6N HC1 followed by centrifugation. An aliquot of the supernatant was separated, by thin-layer chromatography, and the spot corresponding to the enzyme product was scraped off the plate, extracted and radioactivity was determined by scintillation counting.

(Reference: Akerlund, J. and Bjorkhem, I. (1990) J.

Lipid Revs. 31, 2159).

Determination of Serum Cholesterol (SER.CHOL, HDL-CHOL, TGT and VLDL + tDL) Total serum cholesterol (SER.CHOL) was measured enzymatically using a commercial kit from Wako Fine

Chemicals (Richmond, VA); Cholesterol Cull, Catalog No.

276-64909. HDL cholesterol (HDL-CHOL) was assayed using this same kit after precipitation of VLDL and LDL with Sigma Chemical Co. HDL Cholesterol reagent, Catalog No. 352-3 (dextran sulfate method). Total serum triglycerides (blanked) (TGI) were assayed enzymatically with Sigma Chemical Co. GPO-Trinder, Catalog No. 337-B. VLDL and LDL (VLDL + LDL) cholesterol concentrations were calculated as the difference between total and HDL cholesterol.

Measurement of Hepatic Cholesterol 7-a-Hydroxylase Activity (7a-ORase ) Hepatic microsomes were prepared by homogenizing liver samples in a phosphate/sucrose buffer, followed by centrifugal separation. The final pelleted material was resuspended in buffer and an aliquot was assayed for cholesterol 7-a-hydroxylase activity by incubating for 5 minutes at 370 C in the presence of NADPH.

Following extraction into petroleum ether, the organic solvent was evaporated and the residue was dissolved in acetonitrile/ methanol. The enzymatic product was separated by injecting an aliquot of the extract onto a C18 reversed phase HPLC column and quantitating the eluted material using W detection at 240nm.

(Reference: Horton, J. D., et al. (1994) J. Clin.

Invest. 93, 2084).

Measurement of Fecal Bile Acid Concentration (FBA) Total fecal output from individually housed hamsters was collected for 24 or 48 hours, dried under a stream of nitrogen, pulverized and weighed.

Approximately 0.1 gram was weighed out and extracted into an organic solvent (butanol/water). Following separation and drying, the residue was dissolved in methanol and the amount of bile acid present was measured enzymatically using the 3a-hydroxysteroid steroid dehydrogenase reaction with bile acids to reduce NAD. (Reference: Mashige, F., et al. (1981)

Clin. Chem. 27, 1352). fHitaurocholate Uptake in Rabbit Brush Border Membrane Vesicles (BBMV) Rabbit Ileal brush border membranes were prepared from frozen ileal mucosa by the calcium precipitation method describe by Malathi et al. (Reference: (1979) Biochimica Biophysica Acta, 554, 259). The method for measuring taurocholate was essentially as described by Kramer et al. (Reference: (1992) Biochimica Biophysica Acta, 1111, 93) except the assay volume was 200 ul instead of 100 ul. Briefly, at room temperature a 190 ul solution containing 211M [3H]-taurocholate(0.75 pCi), 20 mM tris, 100 mM NaCl, 100 mM mannitol pH 7.4 was incubated for 5 sec with 10 ul of brush border membrane vesicles (60-120 pg protein) - The incubation was initiated by the addition of the BBMV while vortexing and the reaction was stopped by the addition of 5 ml of ice cold buffer (20 mM Hepes-tris, 150 mM KCl) followed immediately by filtration through a nylon filter (0.2 urn pore) and an additional 5 ml wash with stop buffer.

Acyl-CoA;cholesterol Acyl Transferase (ACAT) Hamster liver and rat intestinal microsomes were prepared from tissue as described previously (Reference: (1980) J. Biol. Chem. 255, 9098) and used as a source of ACAT enzyme. The assay consisted of a 2.0 ml incubation containing 24 pM Oleoyl-CoA (0.05 µCi) in a 50 mM sodium phosphate, 2 mM DTT ph 7.4 buffer containing 0.25 % BSA and 200 pg of microsomal protein. The assay was initiated by the addition of oleoyl-CoA. The reaction went for 5 min at 370 C and was terminated by the addition of 8.0 ml of chloroform/ methanol (2:1). To the extraction was added 125 pg of cholesterol oleate in chloroform methanol to act as a carrier and the organic and aqueous phases of the extraction were separated by centrifugation after thorough vortexing. The chloroform phase was taken to

dryness and then spotted on a silica gel 60 TLC plate and developed in hexane/ethyl ether (9:1). The amount of cholesterol ester formed was determined by measuring the amount of radioactivity incorporated into the cholesterol oleate spot on the TLC plate with a Packard instaimager.

Data from each of the noted compounds in the assays described above is as set forth in TABLES 5, 6, 7, and 8 as follows: TABLE 5 COMPOUND IC50 In vitro % % % of Control uM* Inhibition Inhibition Transport of TC in of TC of Alanine Rat Ileum @ 0.1mM # Uptake @ Uptake @ 100 uM # 100 uM # Benzothiaze 2 0 45.4 +/- 0.7 pine= 12 25 3 0 4a 3 5a 34 5b 40 0 72.9 # 5.4 @ 0.5 mM 4b 9 18 6 14b 18 14a 13 13 23 15 60 19a 0 19b 15 8a 41 Mixture of 69 8a and 8b Mixture of 6 9a and 9b 6a 5 6b 85 9a 5 0% @ 25 mM 53.7 +/- 3.9 Mixture of 13 6a and 20 Mixture of 0.8 14% @ 25 6d and 10a mM 21a 37 21c 52 21b 45 6c 2 58.5 68,8 +/- 5.7 at 0.4 mM 6d 0.6 77.7 16.1 +/- 1.1 @ 0.5 mM 30.2 +/- 0.9 @ 0.15 mM 17 10 7 50 49.3 10a 7 77.6 62.4 =/- 2.5 @ 0.2 10b 15 68.6 25 0.1 4% @ 10 mM 26.0 +/- 3.3 26 2 31% @ 25 87.9 +/- 1.5 mM 27 5 7% @ 20 mM 28 8 31% @ 20rnM 29 88 @ 50 mM 30 96 @ 50 mM 31 41 (it 50 mM 37 3 0% @ 5 mM 38 0.3 118 (it 5rnM 20.6 +/- 5.7 40 49 @ 50 mM

41 2 0% @ 20 mM 42 1.5 43 1.5 16% @ 25 mM 48 2 22% @ 20 mM 49 0.15 21% @ 200 21.2 +/- 2.7 nX 57 51 @ 50 mM 58 20 @ 50 mM 59 70 60 9 59 61 30 175 62 10 63 90 @ 6 mM 64 100 @ 6 mM * In vitro Taurocholate Cell Uptake # Unless otherwise noted = Comparative Example is Example No. 1 in WO 93/16055 TABLE 6 Compound TC-uptake TC-uptake TC-uptake ACAT ACAT (H14 Ileal (BBMV) (liver) intestine cells) Loop IC (50) EC(50) IC(50) IC(50) IC(50) COMP. 1 mM 74 mM 3 mM 20 mM 20 mM EXAMPLE 6d 0.6 mM 31 mM 1.5 mM 25 mM 20 mM * 38 0.3 mM 12 mM 2 mM 15 mM N.D. 49 0.1 mM 12 mM N.D. 6 6 mM N.D. 25 0.1 mM 20 mM 0.8 mM 8 mM 8 mM

Comparative Example is Example No. 1 in WO 93/16055 TABLE 7 EFFICACY OF COMPOUND NO. 25 IN CHOLESTEROL-FED HAMSTERS PARAMETER CONTROL 4% CHOLES- 0.2% TYRAMINE CPD. NO. 25 WEIGHT (G) (mean # SEM, *p<0.05, A-Student's t, B- Dunnett's) day 1 117 (2) 114(6) 117(5) day 14 127(3) 127(3) 132(4) LIVER WEIGHT (G) 5.4(0.3) 4.9(0.4) 5.8(0.2) SER.CHOL (mg%) 143 (7) 119 (4)*A, B 126 (2)*A, B HDL-CHOL (mg%) 89 (4) 76 (3) *A, B 76 (1) * A, B VLDL + LDL 54(7) 42(3)*A 50(3) TGI (mg%) 203 (32) 190 (15) 175 (11) HEPATIC CHOL(mg/g) 2.5(0.3) 1.9 (0.1) *A, B 1.9(0.l)*A,B HMG COA (pm/mg/min.) 15.8 (7.6) 448.8(21.6)* 312.9(37.5)*A A,B 7a-OHase (pm/mg/min.) 235.3 (25.1 24 HR. FECAL Wt (G) ) 357.2(28.3)* 291.0(6.0)*A FBA (mM/24H/100g) 2.3(0.1) A, B 2.4(0.04) 6.2(0.8) 2.7(0.1)*A, B 11.9(0.5)*A, B 12.3(1.5)*A, B

TABLE 8 EFFICACY OF COMPOUND NO. 25 IN RAT ALZET MINIPUMP MODEL PARAMETER CONTROL 20 MPL/DAY CPD. NO. 25 WEIGHT (G) (mean + SEM, *p<0.05, A-Student's t, B- Dunnett ' s) day 1 307 (4) 307 (3) day 8 330 (4) 310 (4)*A,B LIVER WEIGHT (G) 15.5 (0.6) 14.6 (0.4) SER.CHOL(mg%) 85 (3) 84 (3) HEPATIC CHOL (mg/g) 21 (0.03) 2.0 (0.03) HMG COA pm/mg/min 75.1 (6.4) 318.0 (40.7)*A, B 7a-OHase (pm/mg/min) 281.9 (13.9) 535.2 (35.7)*A, B 24 HR. FECAL WT (G) 5.8 (0.1) 5.7 (0.4) FBA (mM/24H/100g) 17.9 (0.9) 39.1 (4.5)*A,B Additional taurocholate uptake tests were conducted in the following compounds listed in Table 9.

TABLE 9 Biological Assay Data for Some Compounds of the Present Invention Compound Human TC Alanine Uptake Number IC50 Percent Inhibition (ltM) @ 'iM 101 0 @ 1.0 102 0.083 103 13 @ 0.25 104 0.0056 105 0.6 106 0.8 107 14.0 @ 0.063 108 0.3 109 2.0 @ 0.063 110 0.09 111 2.5 112 3.0 113 0.1 114 0.19 115 8.0 116 0.3 117 @ 12.0 @ 0.625 118 0.4 119 1.3 120 34.0 @ 5.0 121 0.068 122 1.07 123 1.67 124 14.0 @ 6.25 125 18.0 126 18 @ 1.25 127 0.55 128 0.7 129 0.035 131 1.28 132 5.4 @ 0.063 133 16.0 134 0.3 135 22.0 136 0.09 137 2.4 138 3.0 139 >25.0 142 0.5 143 0.03 144 0.053 262 0.07 263 0.7 264 0.2 265 2.0 266 0.5 267 0.073 268 0.029 269 0.08 270 0.12 271 0.07 272 0.7 273 1.9 274 0.18 275 5.0 @ 0.25 276 0.23 277 0.04 278 3.0 279 0.4 280 0.18 281 0.019 282 0.021 283 0.35 284 0.08 286 19.0 287 4.0 288 10.0 @ 6.25 289 0.23 290 0.054 291 0.6 292 0.046 293 1.9 294 0.013 295 1.3 296 1.6 1005 0.0004 1006 0.001 1007 0.001 1008 0.001 1009 0.001 1010 0.001 1011 0.001 1012 0.0015 1013 0.002 1014 0.002 1015 0.002 1016 0.002 1017 0.002 1018 0.002 1019 0.002 1020 0.002 1021 0.002 1022 0.002 1023 0.002 1024 0.002 1025 0.002 1026 0.002 1027 0.002 1028 0.002 1029 0.002 1030 0.002 1031 0.002 1032 0.002 1033 0.002 1034 0.002 1035 0.002 1036 0.002 1037 0.0022 1038 0.0025 1039 0.0026 1040 0.003 1041 0.003 1042 0.003 1043 0.003 1044 0.003 1045 0.003 1046 0.003 1047 0.003 1048 0.003 1049 0.003 1050 0.003 1051 0.003 1052 0.003 1053 0.003 1054 0.003 1055 0.003 1056 0.003 1057 0.003 1058 0.003 1059 0.003 1060 0.0036 1061 0.004 1062 0.004 1063 0.004 1064 0.004 1065 0.004 1066 0.004 1067 0.004 1068 0.004 1069 0.004 1070 0.004 1071 0.004 1072 0.004 1073 0.004 1074 0.004 1075 0.0043 1076 0.0045 1077 0.0045 1078 0.0045 1079 0.005 1080 0.005 1081 0.005 1082 0.005 1083 0.005 1084 0.005 1085 0.005 1086 0.005 1087 0.005 1088 0.0055 1089 0.0057 1090 0.006 1091 0.006 1092 0.006 1093 - 0.006 1094 0.006 1095 0.006 1096 0.006 1097 0.006 1098 0.006 1099 0.0063 1100 0.0068 1101 0.007 1102 0.007 1103 0.007 1104 0.007 1105 0.007 1106 0.0073 1107 0.0075 1108 0.0075 1109 0.008 1110 0.008 1111 0.008 1112 0.008 1113 0.009 1114 0.009 1115 0.0098 1116 0.0093 1117 0.01 1118 0.01 1119 0.01 1120 0.01 1121 0.01 1122 0.011 1123 0.011 1124 0.011 1125 0.012 1126 0.013 1127 0.013 1128 0.017 1129 0.018 1130 0.018 1131 0.02 1132 0.02 1133 0.02 1134 0.02 1135 0.021 1136 0.021 1137 0.021 1138 0.022 1139 0.022 1140 0.023 1141 0.023 1142 0.024 1143 0.027 1144 0.028 1145 0.029 1146 0.029 -1147 0.029 1148 0.03 1149 0.03 1150 0.03 1151 0.031 1152 0.036 1153 0.037 1154 0.037 1155 0.039 1156 0.039 1157 0.04 1158 0.06 1159 0.06 1160 0.062 1161 0.063 1162 0.063 1163 0.09 1164 0.093 1165 0.11 1166 0.11 1167 0.12 1168 0.12 1169 0.12 1170 0.13 1171 0.14 1172 0.14 1173 0.15 1174 0.15 1175 0.17 1176 0.18 1177 0.18 1178 0.19 1179 0.19 1180 0.2 1181 0.22 1182 0.25 1183 0.28 1184 0.28 1185 0.28 1186 0.3 1187 0.32 1188 035 1189 0.35 1190 0.55 1191 0.65 1192 1.0 1193 1.0 1194 1.6 1195 1.7 1196 2.0 1197 2.2 1198 2.5 1199 4.0 1200 6.1 1201 8.3 1202 40.0 1203 O @ 0.063 1204 0.05 1205 0.034 1206 0.035 1207 0.068 1208 0.042 1209 0 @ 0.063 1210 0.14 - ~~~~ 1211 0.28 1212 039 1213 1.7 1214 0.75 1215 0.19 1216 0.39 1217 0.32 1218 0.19 1219 0.34 1220 0.2 1221 0.041 1222 0.065 1223 0.28 1224 0.33 1225 0.12 1226 0.046 1227 0.25 1228 0.038 1229 0.049 1230 0.062 1231 0.075 1232 1.2 1233 0.15 1234 0.067 1235 0.045 1236 0.05 1237 0.07 1238 0.8 1239 0.035 1240 0.016 1241 0.047 1242 0.029 1243 0.63 1244 0.062 1245 0.32 1246 0.018 1247 0.017 1248 0.33 1249 10.2 1250 0.013 1251 0.62 1252 29. 1253 0.3 1254 0.85 1255 0.69 1256 0.011 1257 0.1 1258 0.12 1259 16.5 1260 0.012 1261 0.019 1262 0.03 1263 0.079 1264 0.21 1265 0.24 1266 0.2 1267 0.29 1268 0.035 1269 1270 0.02 1271 0.01 1272 0.047 1273 0.029 1274 0.028 1275 0.024 1276 0.029 1277 0.018 1278 0.017 1279 0.028 1280 0.76 1281 0.055 1 1282 0.17 ~ 1283 0.17 1284 0.011 1285 0.027 1286 0.068 1287 0.071 1288 0.013 1289 0.026 1290 0.017 1291 0.013 1292 0.025 1293 0.019 1294 0.011 1295 0.014 1296 0.063 1297 0.029 1298 0.018 1299 0.012 1300 1.0 1301 0.15 1302 - 1.4 1303 0.26 1304 0.25 1305 0.25 1306 1.2 1307 3.1 1308 0.04 1309 0.24 1310 1.16 1311 3.27 1312 5.0 1313 6.1 1314 0.26 1315 1.67 1316 3.9 1317 21.0 1319 11.0@0.25 1321 11.1 @ 5.0 1322 3.0 @ 0.0063 1323 4.0 @ 0.0063 1324 43.0 @ 0.0008 1325 1.0 @ 0.0063 1326 36.0 @ 0.0008 1327 3.0 @ 0.0063 1328 68.0 @ 0.0063 1329 2.0 @ 0.0063 1330 9.0 @ 0.0063 1331 57.0 @ 0.0008 1332 43.0 @ 0.0008 1333 0 @ 0.0063 1334 50.0 @ 0.0008 1335 @ 38.0 @ 0.0008 1336 45.0 @ 0.0008 1337 O @ 0.0063 1338 1.0 @ 0.25 1339 O @ 0.063 1340 9.0 @ 0.063 1341 1.0 @ 0.063 1342 1.0 @ 0.063 1345 13.0 @ 0.25 1347 0.0036 1351 0.44 1352 0.10 1353 0.0015 1354 0.006 1355 0.0015 1356 0.22 1357 0.023 1358 0.008 1359 0.014 1360 0.003 1361 0.004 1362 0.019 1363 0.008 1364 0.006 1365 0.008 1366 0.015 1367 0.002 1368 0.005 1369 0.005 1370 0.002 1371 0.004 1372 0.004 1373 0.008 1374 0.007 1375 0.002 1449 0.052 1450 0.039 1451 0.014

The examples herein can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

Novel compositions of the invention are further illustrated in attached Exhibits A and B.

The invention being thus described, it is apparent that the same can be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the present invention, and all such modifications and equivalents as would be obvious to one skilled in the art are intended to be included within the scope of the following claims.

Table C2: Alternative compounds #2 (Families F101-F123) Family Cpd# R1=R2 R5 F101 CHOSEN FROM Ph- CHOSEN FROM TABLE D * TABLE D F102 CHOSEN FROM p-F-Ph- CHOSEN FROM TABLE D TABLE D F103 CHOSEN FROM m-F-Ph- CHOSEN FROM TABLE D TABLE D F104 CHOSEN FROM p-CH3O-Ph- CHOSEN FROM TABLE D TABLE D F105 CHOSEN FROM m-CH3O-Ph- CHOSEN FROM TABLE D TABLE D F106 CHOSEN FROM p-(CH3)2N-Ph- CHOSEN FROM TABLE D TABLE D F107 CHOSEN FROM r,-(CH3)2N-Ph CHOSEN FROM TABLE D TABLE D F108 CHOSEN FROM I-, p-(CH3)3-N+-Ph- CHOSEN FROM TABLED TABLED F109 CHOSEN FROM I-, m-(CH3)3-N+-Ph- CHOSEN FROM TABLE D TABLE D F110 CHOSEN FROM I-, p- (CR3) 3-N+-CH2CH2- CHOSEN FROM TABLE D (OCH2CH2)2-O-Ph- TABLE D Flil CHOSEN FROM I-, m-(CH3)3-N+-CH2CH2- CHOSEN FROM TABLE D (OCH2CH2) 2-O-Ph- TABLE D F112 CHOSEN FROM I-, p-(N,N- CHOSEN FROM TABLE D dimethylpiperazine)-(N')- TABLE D CH2-(OCH2CH2)2-O-Ph- F113 CHOSEN FROM I-, m-(N,N- CHOSEN FROM TABLE D dimethylpiperazine)-(N')- TABLE D CH2-(OCH2CH2)2-O-Ph- F114 CHOSEN FROM m-F-Ph- CHOSEN FROM TABLE D p-CH3O- TABLE D F115 CHOSEN FROM 3, 4, dioxy-methylene-Ph- . CHOSEN FROM TABLE D TABLE D F116 CHOSEN FROM m-F-Ph- CHOSEN FROM TABLE D p-F-Ph- TABLE D F117 CHOSEN FROM m-CH3O- CHOSEN FROM TABLE D p-F-Ph- TABLE D F118 CHOSEN FROM 4-pyridine CHOSEN FROM TABLE D TABLE D F119 CHOSEN FROM N-methyl-4-pyridinium CHOSEN FROM TABLED TABLED F120 CHOSEN FROM 3-pyridine CHOSEN FROM TABLE D TABLE D F121 CHOSEN FROM N-methyl-3-pyridinium CHOSEN FROM TABLED TABL D F122 CHOSEN FROM 2-pyridine CHOSEN FROM TABLED TABLED F123 CHOSEN FROM p-CH3O2C-Ph- CHOSEN FROM TABLE D TABLE D Similar families can be generated where R1<>R2, such as R1 = Et and R2 = n-Bu, but (Rx)q is chosen from table C1.

Exhibit B APPENDIX A The ileal bile acid transport inhibitors used in the present invention include, for example, thosecompounds disclosed in this Appendix A.

1) The compounds of the formula (I) wherein R1 and R2 are the same or differcnt and each is optionally substituted C1-6 alkyl, C3.6 cycloalkyl, or R1 and R2 together with the carbon atom to which they are attached form an optionally substituted C3 6 spiro-cycloalkyl group; R4 is a C6 14 aryl, or a C3 13 heteroaryl group each optionally substituted with one to eight substituents which are the same or different and are each selected from halogen, hydroxy, nitro, phenyl-C 1-6 alkoxy, C1-6 alkoxy, optionally substituted C1 1-6 alkyl, S(O)nR8, S02NR8R9, C02R8, O(CH2CH2O)nR8, OS02R8, O(CH2)pS03R8, O(CH2)pNR9R10 and O(CH2)pN+R9R10R11 wherein R8 to R11 are the same or different and are independently selected from hydrogen or optionally substituted C1 -6 alkyl, and wherein p is an integer from 1-4 and n is an integer from 0-3; R5a, R5b, R5, and R5d each represent atoms or groups which are the same or different and each is hydrogen, halogen, cyano, R8-acetylide, OR8, optionally substituted C1-6 alkyl, COR8, CH(OH)R8, S(O)nR8, SO2NR8R9, P(O)(OR8)2, OCOR8, OCF3, OCN, SCN, NHCN, CH2OR8, CHO, (CH2)pCN, CONR9R10, (CH2)pCO2R8, (CH2)pNR9R10, CO2R8, NHCOCF3, NHSO2R8, OCH2OR8, OCH-CHR8, O(CH2CH2O)nR8, OSO2R8, O(CH2)pSO3R8, O(CH2)pNR9R10 and O(CH2)pN+R9R10R11 wherein R8 to R11, n, and p are as hereinbefore defined; or R5a and R5b, R5b, and R5c, or R5c and R5d together with the ring to which they are attached form a cyclic group -O(CR9R10)mO- wherein R9 and R1O are as hereinbefore defined and m is 1 or 2; R6 and R7 are the same or differed and each is hydrogen, optionally substituted C1-6 alkyl, C3-6 cycloalkyl, or R6 and R7 together with the carbon atom to which they are attached form an optionally substituted C3 6 spiro-cycloalkyl group; X is CH2, C=O, C=S, or C=NR8 wherein R8 is as hereinbefore defined; and I is an integer from 0-2; and salts, solvates or a physiologically functional derivatives thereof.

2) A compound of formula (I) according to claim I wherein R1 is methyl or ethyl; R2 is methyl, ethyl or n.butyl; R4 is phenyl; R5a and RSd are hydrogen; R5b and R5c are the same or different and are each hydrogen, methyl, methoxy, hydroxy, trifluoromethyl or halo; R6 and R7 are the same or different and are each hydrogen, methyl, ethyl or i-butyl; X is CH2 or CeO; lis2; or a salt, solvate, or physiologically functional derivative thereof.

3) A compound of formula (I) sdected from the group consisting of <BR> <BR> (#)-3-n-Butyl-3-ethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepi n-4-one;<BR> <BR> <BR> <BR> <BR> (#)-3-n-Butyl-3-ethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepi n-4-one-1,1-dioxide;<BR> <BR> <BR> <BR> (#)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzot hiazepine;<BR> <BR> <BR> <BR> <BR> (#)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzot hiazepine-1,1-dioxide;<BR> <BR> <BR> <BR> <BR> (#)-3-n-Butyl-2-isobutyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl -1,5-benzothiazepine-<BR> <BR> <BR> <BR> <BR> 1,1-dioxide; 3,3-Diethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one; 3,3-Diethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one 1,1-dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine; 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine- 1,1-dioxide; 3,3-Dimethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one; 3,3-Dimethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one-1 ,1-dioxide; 3,3-Dimethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine ; 3,3-Dimethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine -1,1-dioxide; (#)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phe nyl-1,5- benzothiazepine-1,1-dioxide; 3.3-Diethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,5-be nzothiazepine-1,1- dioxide; <BR> <BR> (#)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl- 1,5-benzothiazepine-<BR> <BR> <BR> <BR> <BR> <BR> 1,1 dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzot hiazepine-1,1-dioxide; (#)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzot hiazepin-8-ol-1,1- dioxide; 3,3-diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-8 -ol-1,1-dioxide; <BR> <BR> (#)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl- 1,5-benzothiazepin-8-<BR> <BR> <BR> <BR> <BR> <BR> ol-l,l-dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,5-benzot hiazepin-8-ol-1,1- dioxide; (#)-7-bromo-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5 -phenyl-1,5- benzothiazepine-1,1-dioxide; 7-bromo-3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1, 5-benzothiazepine- I,l-dioxide; (#)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl- I ,5-benzothiazepin-7,Sdiol- 1,1- dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-7 ,8-diol-1,1-dioxide; <BR> <BR> (#)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl- 1,5-benzothiazepine-1- monoxide; 3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzot hiazepine-1-monoxide; (#)-3-n-Butyl-3-ethyl-2,3,4,5-etrahydro-5-phenyl-1,5-benzoth iazepin-8-ol-1- monoxide; 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-8 -ol-1-monoxide; <BR> <BR> <BR> (#)-3-n-Butyl-3-ethyl-2,3-dihydro-8-methoxy-5-phenyl-1,5-ben zothiazepin-4-one;<BR> <BR> <BR> <BR> <BR> (#)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1, 5-benzothiazepine;<BR> <BR> <BR> <BR> <BR> <BR> (#)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl- 1,5-benzothiazepine-<BR> <BR> <BR> <BR> <BR> <BR> l,l-dioxide; (#)-3-n-Butyl-3-ethyl-2,3 ,4,5-tetrahydro-8-hydroxy-5-phenyl- 1 ,5-benzothiazepine- 1,1-dioxide; (#)-7-Bromo-3-n-butyl-3-ethyl-2,3-dihydro-8-methoxy-5-phenyl -1,5-benzothiazepin-<BR> <BR> <BR> <BR> <BR> 4-one; <BR> <BR> <BR> <BR> (#)-7-Bromo-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5 -phenyl-1,5- benzothiazepine 1,1-dioxide; (#)-7-Bromo-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1, 5-benzothiazepin-8- ol l,l-dioxide; (#)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-1,5-benzo thiazepin-8-ol 1,1-dioxide; (#)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phe nyl-1,5-benzothiazepine 1,1-dioxide; (#)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzot hiazepine-7,8-diol 1,1- dioxide; <BR> <BR> <BR> (#)-7-Bromo-3-n-butyl-3-ethyl-2,3-dihydro-5-phenyl-1,5-benzo thiazepin-4-one;<BR> <BR> <BR> <BR> (#)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl- 1,5-benzothiazepine 1,1-dioxide; and (#)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzot hiazepin-7-ol 1,1- dioxide.

4) A compound of formula (I) selected from: (#)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl- 1,5-benzothiazepin-8- ol l,l-dioxide; and <BR> <BR> (#)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-hydroxy-5-phenyl- 1,5-benzothiazepine-<BR> <BR> <BR> <BR> <BR> 1,1-dioxide or a salt, solvate, or physiologically functional derivative thereof.

(#)-3-n-Butyl-3-ethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepi n-4-one-1,1-dioxide;<BR> <BR> <BR> <BR> <BR> <BR> (#)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzot hiazepine; ( ' )-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl- 1 ,5-benzothiazepine- 1,1-dioxide; (#)-3-n-Butyl-3-isobutyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl - 1 ,5-benzothiazepine- 1,1- dioxide; 3,3 -Diethyl-2,3-dihydro-5-phenyl- 1 ,5-benzothiazepin-4-one; 3,3-Diethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one 1,1-dioxide; 3,3-Diethyl-2,3,4,5-tetrahydr-5-phenyl-1,5-benzothiazepine; 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl- 1,5-benzothiazepine- 1,1 dioxide; 3,3-Dimethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one; 3,3-Dimethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one-1 ,1-dioxide; 3,3-Dimethyl-2,3,4 ,5 -tetrahydro.5-phenyl. 1 ,5-benzothiazepine; 3,3-Dimethyl-2,3,4,5-tetrahydro-50phenyl-1,5-benzothiazepine -1,10dioxide; (#)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phe nyl- 1 ,5-benzothiazepine- 1,1 - dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,5-be nzothiazepine-1,1-dioxide; (#)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl- 1,5-benzothiazepine-1,1- dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzot hiazepine-1,1-dioxide; <BR> <BR> (#)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzot hiazepin-8-ol-1,1-dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-8 -ol-1,1-dioxide; (#)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl- 1, 5-benzothiazepin-8-ol- 1,1- dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,5-benzot hiazepin-8-ol-1,1-dioxide; (i)-7-bromo-3 -n-Butyl-3 ethyl-2,3 ,4,5-tetrahydro-8-methoxy-5-phenyl- 1,5- benzothiazepine-1,1-dioxide; 7-bromo-3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1, 5-benzothiazepine-1,1- dioxide; <BR> <BR> <BR> (#)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzot hiazepin-7,8-diol-1,1-dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-7 ,8-diol-1,1-dioxide; (#)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl- 1,5-benzothiazepine-1- monoxide; 3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzot hiazepine-1-monoxide; <BR> <BR> <BR> (#)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzot hiazepin-8-ol-1-monoxide; 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-8 -ol-1-monoxide; <BR> <BR> <BR> (#)3-n-Butyl-3-ethyl-2,3-dihydro-8-methoxy-5-phenyl-1,5-benz othiazepin-4-one;<BR> <BR> <BR> <BR> <BR> <BR> (#)3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1 ,5-benzothiazepine; (#)-3-n-Butyl-3- -ethyl-2,3 ,4,5-tetrahydro-8-methoxy-5-phenyl- 1 ,5-benzothiazepine- 1.1 - dioxide; (+)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-hydroxy-5-phenyl- 1 1,5 -berzothiazepine- 1,1- dioxide; <BR> <BR> <BR> (#)-7-Bromo-3-n-butyl-3-ethyl-2,3-dihydro-8-methoxy-5-phenyl -1,5-benzothiazepin-4-one;<BR> <BR> <BR> <BR> <BR> <BR> <BR> (#)-7-Bromo-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5 -phenyl-1,5- benzothiazepine l,l-dioxide; (i)-7-Bromo-3-n-butyl-3-ethyl-2,i,4,5-tetrahydro-5-phenyl- 1 ,5-benzothiazepin-8-ol 1,1- dioxide; (#)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl- 1,5-benzothiazepin-8-ol 1.1- dioxide; <BR> <BR> <BR> (#)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phe nyl-1,5-benzothiazepine 1.1- dioxide: (#)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzot hiazepine-7,8-diol 1,1-dioxide; (#)-7-Bromo-3-n-butyl-3-ethyl-2,3-dihydro-5-phenyl-1,5-benzo thiazepin-4-one; (#)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl- 1 ,5-benzothiazepine 1.1 - dioxide; and (#)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzot hiazepin-7-ol 1,1-dioxide.

Particularly preferred compounds include: (#)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl- 1,5-benzothiazepin-8-ol 1,1- dioxide; and (#)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-hydroxy-5-phenyl- 1 ,5-benzothiazepine- 1 1 - dioxide.

3,3-Diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzot hiazepin-8-yl aspartate.

(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy- 5-phenyl-1,4-benzothiazepine- 1,1-dioxide; (3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-p henyl-1,4-benzothiazepin-4- ol 1,1-dioxide; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy- 5-phenyl-1,4-benzothiazepine- 1,1-dioxide; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy- 5-phenyl-1,4-benzothiazepin- 4-ol 1,1-dioxide; (3R,5R)-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy -5-phenyl-1,4- benzothiazepine 1,1-dioxide; (3R,5R)-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy -5-phenyl-1,4- benzothiazepin-4-ol 1,1-dioxide; (3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benz othiazepine-7,8-dioll, 1- dioxide; (3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-pheny l-1,4-benzothiazepin-7-ol 1,1-dioxide; (3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-pheny l-1,4-benzothiazepin-8-ol 1,1-dioxide; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-ph enyl-1,4-benzothiazepine 1,1- dioxide; (+->Trans-3 -butyl-3 -ethyl-2,3 ,4,5-tetrahydro-5-phenyl- 1 ,4-benzothiazepin-8-ol 1,1-dioxide; (+-)-Trans-3 -butyl-3 -cthyl-2,3 ,4,5-tetrahydro-5 -phenyl- I ,4-benzothiazepine-4,8-diol; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-ph enyl-1,4-benzothiazepine-7- carbaldehyde 1,1-dioxide; (+-)-Trans-2-((3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy- 5-phenyl-1,4-benzothiazepin- 7-yl)methoxy) ethanol S,S-dioxide; (+-)-Trans-3-butyl-3-ethyl-2,3 ,4,5-tetrahydro-8-hydroxy-5-phenyl- 1 ,4-benzothiazepine-7- carbaldehyde 1,1-dioxide; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-b enzothiazepin-8-thioll, 1- dioxide; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-b enzothiazepin-8-sulfonic acid- 1,1-dioxide; (7R,9R)-7-Butyl-7-ethyl-6,7,8,9-tetrahydro-9-phenyl-1,3-diox olo(4,5-H)(1,4)- benzothiazepine 5,5-dioxide; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8,9-dimethoxy- 5-phenyl-1,4-benzothiazepine- 1,1-dioxide; (3R,5R)-3-butyl-3-ethyl-5-(4-fluorophenyl)-2,3,4,5-tetrahydr o-7,8-dimethoxy-1,4- benzothiazpin-4-ol 1,1-dioxide; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-ph enyl-1,4-benzothiazepine-7- methanol S,S-dioxide; (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-7-nitro -5-phenyl-1,4- benzothiazepine-1,1-dioxide; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-metoxy-7-(me thoxymethyl)-5-phenyl-1,4- benzothiazepine 1,1-dioxide; (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benz othiazeipin-7,8-diyl diacetate- 1,1-dioxide; (8R, 1 OR)-8-Butyl-8-ethyl-2,3,7,8,9, 1 O-hexahydro- 10-1 ,4-dioxono(2,3 -H)( 1,4)- benzothiazepine 6,6-dioxide; (3R,5R)-3-butyl-7,8-diethoxy-2,3,4,5-tetrahydro-5-phenyl-1,4 -benzothiazepine 1,1-dioxide; (+-)-Trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phe nyl-1,4-benzothiazepine-1,1- dioxide; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5 -phenyl-1,4- benzothiazepine 1,1-dioxide hydrochloride; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-b enzothiazepin-8-carbaldehyde- 1,1-dioxde; 3,3-Diethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-be nzothiazepine 1,1-dioxide; 3,3-Diethyl-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-8-methoxy- 1,4-benzothiazepine 1,1- dioxide; 3 ,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl- 1 ,4-benzothiazepine 1,1 -dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazpin-4, 8-dioll,1-dioxide; (RS)-3,3-Diethyl-2,3,4,5-tetrahydro-4-hydroxy-7,8-dimethoxy- 5-phenyl-1,4- benzothiazcpine l,l-dioxide; (+-)-Trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phe nyl-1,4-benzothiazepin-4-ol- 1,1-dioxide; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5 -phenyl-1,4-benzothiazepin-4- ol l,l-dioxide; (+-)-Trand-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8,9-trimetho xy-5-phenyl-1,4- berzothiazepin-4-ol 1,1-dioxide; (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benz othiazpin-4,7,8-triol 1,1- dioxide; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-4,7,8-trimetho xy-5-phenyl-1,4- benzothiazepine 1,1-dioxide; (+-)-Trans-3-butyl-3-ethyl-5-phenyl-2,3,4,5-tetrahydro-7,8-d imethoxy-1,4-benzothiazepin- 4-yl acetate S,S-dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8 -l 1,1-dioxide; 3,3.Diethyl-2,3 ,4, 5-tetrahydro-7-methoxy-5-phenyl- 1 .4-benzothiazepin-8-ol 1,1-dioxide; 3 ,3-Dibutyl-2,3,4,5-tetrahydro-5-phenyl- I ,4-benzothiazepin-8-ol 1,1 dioxide; (+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-ph enyl-1,4-benzothiazepin-8-yl hydrogen sulfate; (+-)-Trans-3-Butyl-3-ethyl-2,3 ,4, 5-tetrahydro- 1,1 -dioxo- 5-phenyl. 1 ,4-benzothiazepin-8-yl dihydrogen phosphate; 3,3-diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzot hiazepin-8-yl hydrogen sulfate; 3 ,3-Diethyl.2,3,4,5-tetrahydro- 1,1 -dioxo-5-phenyl- 1 ,4-benzothiazepin-8-yl- dihydrogen phosphate; (+-)-Trans-3 -Butyl-3 -ethyl-2,3 ,4, 5-tetrahydro-1,1 -dioxo-5-phenyl. 1,4- benzothiazepin-8-yl aspartate; and (22( (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-ph enyl-1,4- benzothiazepine-7-methanol S,S-dioxide, mp 122-123°C (23) (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-7-nitro -5-phenyl-1,4- benzothiazepine l,l-dioxide 0.40 hydrate, mp 122-1230 C (24) (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-7-(m ethoxymethyl)-5- phenyl-1,4-benzothiazepine 1,1-dioxide, mp 118-119°C (25) (+-)-Trans-7-bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phen yl-1,4- benzothiazepin-8-ol l,l-dioxide 0.40 hydrate, mp 137.1380 C (26) (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8,9-trimetho xy-5-phenyl-1,4- benzothiazepine 1,1-dioxide, mp 169-1700 C (27) (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benz othiazepin-7,8-diyl diacetate 1,1-dioxide, mp 79-810 C (28) (8R,10R)-8-Butyl-8-ethyl-2,3,7,8,9,10-hexahydro-10-1,4-dioxo no(2,3-H)(1,4)- berizothiazepine 6,6dioxide, mp 820 C (29) (3R,5R)-3-butyl-7,8-diethoxy-2,3,4,5-tetrahydro-5-phenyl-1,4 -benzothiazepine 1,1 dioxide 0.20 hydrate, mp 110.1110 C (30) (+-)-Trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phe nyl-1,4- benzothiazepine 1,1-dioxide, mp 45-540 C (3 1) (+-)-Trans-3-butyl-3-ethyl-2,3 ,4,5.tetrahydro.8.(methylthio).5.phenyl- 1,4- benzothiazepine 1,1-dioxide hydrochloride,mp 194-197°C (32) (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5 -phenyl-1,4- benzothiazepine l,l-dioxide hydrochloride, mp 178-1810 C (33) (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-b enzothiazepin-8- carbaldehyde 1,1-dioxide, mp 165-1700 C (34) 3,3-Diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzot hiazepin-8-yl aspartate (35) 3,3-Diethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-be nzothiazepine-1,1- dioxide, mp 163-1640 C (36) 3,3-Diethyl-5-(4-fluorophenyl)-2,3 ,4,5-tetrahydro-8-methoxy- 1 ,4-benzothiazepine- 1,1-dioxide mp 101.1030 C (37) 3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzot hiazepine-1,1- dioxide, mp 132-1330 C (38) 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-4 ,8-diol- 1,1-dioxide, mp 225-2270 C (39) (RS)-3,3-Diethyl-2,3,4,5-tetrahydro-4-hydroxy-7,8-dimethoxy- 5-phenyl-1,4- benzothiazepine 1,1-dioxide, mp 205-2060 C (40) (+-)-Trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phe nyl-1,4- benzothiazepin-4-ol 1,1-dioxide, mp 149-150°C (41) (+-)-Trans-3-butyl-3-ethyl-2,3 ,4, 5-tetrahydro-8.isopropoxy-5.phenyl. 114- benzothiazepin-4-ol 1,1-dioxide, mp 109-115°C (42) (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8,9-trimetho xy-5-phenyl-1,4- benzothiazepin-4-ol 1,1-dioxide, mp 84-96°C (43) (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benz othiazpin-4,7,8-triol- 1,1-dioxide, mp 215-2200 C (44) (+-)-Trans-3-butyl-3-etyl-2,3,4,5-tetrahydro-4,7,8-trimethox y05-phenyl-1,4- benzothiazepine 1,1-dioxide, mp 169-1870 C (45) (+-)-Trans-3-butyl-3-ethyl-5-phenyl-2,3,4,5-tetrahydro-7,8-d imethoxy-1,4- benzothiazepin-4-yl acetate S,S-dioxidc, mp 154-1560 C (46) 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8 -ol 1,1-dioxide, mp 177-1780 C (47) 3,3-Diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl- 1 ,4-benzothiazepin-8-ol 1,1- dioxide (48) 3,3-Dibutyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8 -oll 1,1-dioxide (49) (+-)-Trans-3-Butyl3-ethyl-2,3 4,5-tetrahydro- 1,1 -dioxo-5-phenyl- 1,4- benzothiazcpin-8-yl hydrogen sulfate, mp 1 96.5-2000C (50) (+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-ph enyl-1,4- benzothiazepin.8-yl dihydrogen phosphate (51) 3,3.Diethyl.2,3,4,5-tetrahydro. 1,1 -dioxc-5-phenyl- I ,4-henzothiazepin.3 -ylhydrogen sulfate (52) 3,3-Diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzot hiazepin-8- yldibydrogen phosphate (53) (+-)-Trans-3-Butyl-3-cthyl-2,3 ,4,5-tetrahydro- 1,1 -dioxo-5-phenyl- 1,4- benzothiazepin-8-y aspartate 1. The compounds of the formula (I): wherein R1 is a straight chained C1 6 alkyl group; R2 is a straight chained C1-6 alkyl group; R3 is hydrogen or a group OR1 1 in which R11 is hydrogen, optionally substituted C1 6 alkyl or a C1 6 alkylcarbonyl group; R4 is pyridyl or optionally substituted phenyl; R5, R6, R7 and R8 are the same or different and each is selected from hydrogen, halogen, cyano, R15-acetylide, OR15, optionally substituted C1 6 alkyl, COR15, CH(OH)R15, S(O)nR15, R(O)(OR15)2, OCOR15, OCF3, OCN, SCN, NHCN, CH2OR15, CHO, (CH2)pCN, CONR12R13, (CH2)pCO2R15, (CH2)pNR12R13, CO2R15, NHCOCF3, NHSO2R15, OCH2OR15, OCH=CHR15, O(CH2CH2O)nR15, O(CH2)pSO3R15. O(CH2)pNR12R13 and O(CH2)pN+R12R13R14 wherein p is an integer from 1-4, n is an integer from 0-3 and, R12, 13, R14 and R15 are independently selected from hydrogen and optionally substituted C1-6 alkyl; or R6 and R7 are linked to form a group wherein R12 and R13 are as hereinbefore defined and m is 1 or 2; and R9 and R10 are the same or different and each is hydrogen or C1 -6 alkyl; with the proviso that when R3 is hydrogen either R7 is not hydrogen or at least two of R5, R6, R7 and R8 are not hydrogen; and salts, solvates and physiologically functional derivatives thereof 2. The compounds as claimed in claim I which are of the formula (11) wherein R1 to R10 are as hereinbefore defined and R7a is selected from halogen, cyano, R15-acetyllde, OR15, optionally substituted C1 6 alkyl, COR15, CH(OHR15, S(O)nR15, P(O)(OR15)2, OCOR15, OCF3, OCN, SCN, HNCN, CH2OR15, CHO, (CH2)pCN, CONR12R13, (CH2)pCO2R15, (CH2)pNR12R13, C02R15, NHCOCF3, NHSo2R15, OCH20R15, OCH=CHR15, O(CH2CH2O)nR15, O(CH2)pSO3R15, O(CH2)pNR12R13 and O(CH2)pN+R12R13R14 wherein n, p and R12 to R15 are as hereinbefore defined; and salts, solvates or physiologically functional derivatives thereof.

3. The compounds as claimed in claim 1 which are ofthe formula (m): wherein R1-R10 are as defined in claim 1; and salts, solvates and physiologically functional derivatives thereof 4. The compounds as claimed in claim 1 which are of the formula ('V) wherein R1-R10 are as defined in claim 1; and salts, solvates and physiologically functional derivatives thereof.

5. The compounds as claimed in claim I which are of the formula (IVa) wherein Rl-R1O are as defined in claim 1; and salts, solvates and physiologically functional derivatives thereof 6. The compounds as claimed in claim 1 wherein: R1 and R2 are straight chained C1 6 alkyl; R3 is hydrogen or hydroxy; R4 is unsubstituted phenyl; R5 is hydrogen; R9 and R10 are both hydrogen; and either R7 is selected from halogen, hydroxy, C1-6 alkoxy, optionally substituted C1-6 alkyl, -S(O)nR15, -OC(O)R15, and -CH20RI S wherein R15 is hydrogen or C1.6 alkyl; and R6 and R8 are independently selected from hydrogen and those groups listed in the definition of R7; or R8 is hydrogen and R6 and R7 are linked to form a group -0-(CH2)m-0- wherein mis 1 or2; and Salts, solvates, and physiologically functional derivatives thereof 7. A compound according to any of claims 1 to 6 wherein R6 and R7 are both methoxy.

8. A compound selected from the group consisting of: (3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-p henyl-1,4- benzothiazepine 1,1-dioxide; (3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-p henyl-1,4- benzothiazepin-4-ol 1,1-dioxde; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy- 5-phenyl-1,4- benzothiazepine 1,1-dioxide; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy- 5-phenyl-1,4,- benzothiazepin-4-ol 1,1-dioxide; (3R,5R)-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy -5-phenyl-1,4- benzothiazepine 1,1-dioxide; (3R,5R)-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy -5-phenyl-1,4- benzothiazepin-4-ol 1,1-dioxide; (3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benz othiazeipine-7,8-diol 1,1-dioxide; (3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-pheny l-1,4- benzothiazepin-7-ol 1,1-dioxide; (3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-pheny l-1,4- benzothiazepin-8-ol 1,1-dioxide; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-ph enyl-1,4- benzothiazepine 1,1-dioxide; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-b enzothiazepin-8-ol 1,1-dioxide; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-b enzothiazepine-4,8- diol; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-ph enyl-1,4- benzothiazepine-7-carbaldehyde 1,1-dioxide; (+-)-Trans-2-((3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy- 5-phenyl-1,4- benzothiazepin-7-yl)methoxy) ethanol S,S-dioxide; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-hydroxy-5-ph enyl-1,4- benzothia:zepine-7-carbaldehyde 1,1-dioxide; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-b enzothiazepin-8-thiol 1,1-dioxide; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-b enzothiazepin-8- sulfonic acid 1,1-dioxide; (7R,9R)-7-Butyl-7-ethyl-6,7,8,9-tetrahydro-9-phenyl-1,3-diox olo(4,5-H)(1,4)- benzothiazepine 5,5-dioxide; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8,9-dimethoxy- 5-phenyl- 1 ,4- benzothiazepine l,l-dioxide; (3R,5R)-3-butyl-3-ethyl-5-(4-fluorophenyl)-2,3,4,5-tetrahydr o-7,8-dimethoxy-1,4- benzothiazpin-4-ol 1,1-dioxide; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-ph enyl-1,4- benzothiazepine-7-methanol S,S-dioxide; (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-7-nitro -5-phenyl-1,4- benzothiazepine 1,1 -dioxide; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-7-(m ethoxymethyl)-5- phmyl-l ,4-benzothiaztpine 1,1 -dioxide; (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benz othiazepin-7,8-diyl diacetate 1,1-dioxide; (8R,10R)-8-Butyl-8-ethyl-2,3,7,8,9,10-hexahydro-10-1,4-dioxo no(2,3-H)(1,4)- benzothiazepine 6,6-dioxide; (3 R 5R)-3 -butyl-7,8aiethoxy-2,3 ,4,5-tetrahydro-5-phenyl- 1 ,4.benzothiazepine 1,1- dioxide; (+-)-Trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phe nyl-1,4- benzothiazepine 1,1-dioxide; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5 -phenyl-1,4- benzothiazepine 1,1-dioxide hydrochloride; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl- 1 14.benzothiazepin-8- carbaldehyde 1,1-dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-be nzothiazepine 1,1- dioxide; 3,3-Diethyl-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-8-methoxy- 1,4-benzothiazepine 1,1 -dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzot hiazepine 1,1- dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazpin-4, 8-diol 1,1-dioxide; (RS)-3,3-Diethyl-2,3,4,5-tetrahydro-4-hydroxy-7,8-dimethoxy- 5-phenyl-1,4- benzothiazepine 1,1-dioxide; (+-)-Trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phe nyl-1,4- benzothiazepin-4-oll, 1,1-dioxide; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5 -phenyl-1,4- benzothiazepin-4-ol l,l-dioxide; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8,9-trimetho xy-5-phenyl-1,4- benzothiazepin-4-ol l,l-dioxide; (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benz othiazpin-4,7,8-triol 1,1-dioxide; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-4,7,8-trimetho xy-5-phenyl-1,4- benzothiazcpinc 1,1-dioxide; (+-)-Trnas-3-butyl-3 -ethyl-5-phenyl-2,3 ,4,5-tetrahydro-7,8-dimethoxy- 1,4- benzothiazepin-4-yl acetate S,S-dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8 -ol 1,1-dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzot hiazepin-8-ol 1,1- dioxide; 3,3-Dibutyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8 -ol 1,1-dioxide; (+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-ph enyl-1,4- benzothiazepin-8-yl hydrogen sulfate; (+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-ph enyl-1,4- benzothiazepin-8-yl dihydrogen phosphate; 3,3-Diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzot hiazepin-8-yl hydrogen sulfate; 3,3 -Diethyl-2,3 ,4,5-tetrahydro-1,1 -dioxo-5-phenyl- 1 ,4-benzothiazepin-8-yl dihydrogen phosphate; (+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-ph enyl-1,4- benzothiazepin-8-y1 aspartate; and 3,3-Diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzot hiazepin-8-yl aspartate.

9. (3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7, 8-dimethoxy-5-phenyl- 1,4- berizothiazepine 1,1-dioxide, or a salt, solvate, or physiologically functional derivative thereof.

Compounds ) having exceptional hypolipidaemic properties include:- (+-)-trans-3-ethyl-2,3,4,5-tetrahydro-3-((2R)-2-hydroxybutyl )-5-phenyl-1,4- benzothiazepine l,l-dioxide; (+-)-trans-1-(3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl- 1,4-benzothiazepin-3- yl-2(R)-2-butanol S,S-dioxidc; (+-)-trans-1-(3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl- 1,4-benzothiazepin-3- yl)-3-butanol S,S-dioxide; (+-)-trans-1-(3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl- 1,4-benzothiazepin-3- yl)-2(R)-2-butanol S,S-dioxide; (+-)-trans- 1 -(3-ethyl-5-(4-fluorophenyl)-2,i,4,5-tetrahydro-7-methOxy- 1,4- benzothiazepin-3-yl)-2(R)-2-butanol S,S0dioxide; (+-)-trans-1-(3-ethyl-5-(4-hydroxyphenyl)-2,3,4,5-tetrahydro -1,4-benzothiazepin-3- yl)-2(R)-2-butanol S,S-dioxide 0.5 hydrate; (+-)-Trans-3-butyl-3 -ethyl-2,3 ,4,5.tetrahydro.5.(4-hydroxyphenyl). 1,4- benzothiazepine 1,1-dioxide hydrochloride; <BR> <BR> <BR> (+.)-cis-3-ethyl-2,3 ,4,-tetrahydro-;-(4-hvdroxybutyl)-5-phenyl- 1 ,4-benzothlazepine 1,1-dioxide hydrochloride; (+-)-trans-3-ethyl-2,3,4,5-tetrahydro-3-(4-hydroxybutyl)-5-p henyl-1,4- benzothiazepine l,l-dioxide; (+-)-trans-3 -butyl-3 -ethyl-2,3 ,4 ,5-tetrahydro-7-hydroxy-S-phenyl-1 ,4- benzothiazepine 1,1 dioxide; (+-)-trans-1-(3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzot hiazepin-3-yl)-4,4,4- trifluoro-(2S)-2-butanol- S,S-dioxide; (+-)-trans-1-(3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl- 1,4-benzothiazepin-3- yl)-4,4,4-trifluoro-(2S)-2-butanol-S,S-dioxide; (+-)-trans-3-Ethyl-2,3,4,5-tetrahydro-3-(3-hydroxybutyl)-5-p henyl-1,4- benzothiazepine 1,1-dioxide; (+-)-trans-3-Ethyl-2,3,4,5-tetrahydro-3-(2R)-2-hydroxybutyl) -5-(4- hydroxyphenyl)-1,4-benzothiazepine 1,1-dioxide; (+-)-trans-1-(3-Ethyl-5-(4-fluorophenyl)-2,3,4,5-tetrahydro- 1,4- benzothiazepin-j-yl)-2(R)-2-butanol S,S-dioxide; (+-)-trans-1-(3-Ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl- 1,4 benzothiazepin-3-yl)-4,4,4-trinuoro-2(S)-2-butanol S,S-dioxide; (+-)-trans-1-(3-Ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl- 1,4- benzothiazepin-3-yl)-4,4,4-trifluoro-2(S)-butanol S,S-dioxide; (+->trans- 1 -(3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl- 1 ,4-benzothiazepin- 3-yl-2(R)-2-butanol S,S dioxide; (+-)-trans-1-(3-Ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phe nyl-1,4- benzothiazepin-3-yl)-4,4,4-trifluoro-2-butanol S,S-dioxide; (+-)-trans-1-(3-Ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phe nyl-1,4- benzothiazepin.3.yl).3,3,4,4,4.pentafluoro.2-butanol S,S-dioxide; (+-)-trans-3-((3-ethyl-2,3,4,5-tetrahydro-5-phenyl-3-(4,4,4- trifluoro-2- hydroxybutyl)-l, 4-benzothiazepin-8-yl)oxy)propanesulfonic acid 1, dioxide; (+-)-trans-3-((3-ethyl-2,3,4,5-tetrahydro-3-(2-hydroxybutyl) -5-phenyl-1,4- benzothiazepin-8-yl)oxy)ethyltrimethylammonium iodide 1, dioxide; (+-)-trans-1-(3-Ethyl-2,3,4,5-tetrahydro-7,8-diethoxy-5-phen yl-1,4- benzothiazepin-;-yl)-4,4,4-trifluoro-2-butanol S,S-dioxide; (+-)-trans-3-((3-ethyl-2,3,4,5-tetrahydro-5-phenyl-3(4,4,4-t rifluoro-2- hydroxybutyl)-1,4-benzothiazepin-8-yl)oxy)ethyltrimethylammo nium iodide 1,1-dioxide; (+-)-trans-3-((3 -ethyl-2,3 ,4,5-tetrahydro-3 -(2-hydroxybutyl)-5-phenyl- 1,4- benzothiazepin-8-yl)oxy)propanesulfonic acid 1,1-dioxide; (+-)-trans-1-(3-ethyl-2,3,4,5-tetrahydro-7,8-diethoxy-5-phen yl-1,4- benzothiazepin-3-yl)-2-butanol S,S-dioxide; (+-)-trans-1-(3-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-7, 8-dimethoxy-5- phenyl-1,4-benzothiazepin-3-yl)-4,4,4-trifluoro-2-butanol S,S-dioxide; (+-)-trans-1-(3-Ethyl-2,3,4,5-tetrahydro-7,8-dihydroxy-5-phe nyl-1,4- benzothiazepin-3-yl)-4,4,4-trifluoro-2-butanol S,S-dioxide; (+-)-trans- 1 -(3 -ethyl-2 ,3 ,4,5-tetrahydro-7,8 -d imethoxy-5-phenyl-l ,4- benzothiazepin-3-yl)-1-butanol S,S-dioxide; (+-)-trans-1-(3-Ethyl-2,3,4,5-tetrahydro-7,8-dihydroxy-5-phe nyl-1,4- benzothiazepin-3-yl)-2-butanol S,S-dioxide; (+-)-trans-1-(3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl- 1,4- benzothiazepin-j-yl)-4,4,4-trifluoro-1 -butanol S ,S-dioxide; (+-)-trans-1-(3-ethyl-2,3,4,5-tetrahydro-7,8-dihydroxy-5-phe nyl-1,4- benzothiazepin-3-yl)-2-butanone S,S-dioxide; Of the above the following compounds are most preferred:- (+-)-trans-1-(3-ethyl-5-(4-fluorophenyl)-2,3,4,5-tetrahydro- 7-methoxy-1,4- benzothiazepin-3-yl)-2(R)-2-butanol S,S-dioxide; (+-)-trans-1-(3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzot hiazepin-3-yl)-4,4,4- trifluoro-(2S)-2-butanol-S,S-dioxide; <BR> <BR> <BR> (+-)-trans- 1 -(3 -ethyl ,3 ,4,5-tetrahydro-7-methoxy-5-phenyl- 1 ,4-benzothiazepin-3- yl)-4,4,4-trifluoro-(2S)-2-butanol-S,S-dioxide; (+-)-tans-1-(3 -Ethyl-2,3 ,4,5 -tetrahydro-8 -methoxy-5-phenyl- 1 ,4- benzothiazepin-3-yl)-4,4,4-trifluoro-2(S)-butanol S,S-dioxide; (+.)-trans- 1 -(3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1 ,4-benzothiazepin- 3-yl-2(R)-2-butanol S,S dioxide; 13) (+-)-Trans-2,3,4,5-Tetrahydro-3-methyl-5-phenyl-1,4-benzothi azepine-3- methanol 1,1-dioxide, mp 79-80°C; 14) (+-)-Cis-2,3,4,5-Tetrahydro-3-methyl-5-phenyl-1,4-benzothiaz epine-3- methanol l,l-dioxide hydrochloride 0.25 hydrate mp 222-224°C; 15) (+-)-Trans-4-(3 -Butyl-3 -ethyl-2,3 ,4 ,5-tetrahydro- I ,4-benzothiazepin-5- yl)phenol hydrochloride, mp 234-23 50cC(dec.); 16) (+-)-Trans-5-(4-Benzyloxyphenyl)-3-ethyl-2,3,4,5-tetrahydro- 1,4- benzothiazepine-3-methanol, mp 138-1 430C; 17) (+-)-Trans-3-Ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothia pzepine-3- methanol l.l-dioxide, mp I34-1370C; 18) (+-)-Trans-3-Ethyl-2,3,4,5-tetrahydro-3-(3-hydroxybutyl)-5-p henyl-1,4- benzothiazepine 1,1-dioxide, mp 151-1550C; 19) (+-)-Cis-3-Ethyl-2,3,4,5-tetrahydro-3-butyl-4-hydroxy-5-(3-p yridyl)-1,4- benzothiazepine 1,1-dioxide, mp 202-2050C; 20) (+-)-cis-4-(3-Butyl-3 -ethyl -2 ,3 -tetrahydro- 1 ,4-benzothiazepin-5- yl)phenol hydrochloride, mp 236-237°C(dec.); 21) (+-)-Cis-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(4-hydroxyphen yl)-1,4- benzothiazepine 1,1-dioxide, mp 163-165°C; 22) (+-)-Cis-3-Ethyl-2,3,4,5-tetrahydro-3-(3-hydroxybutyl))-5-ph enyl-1,4- benzothiazepine 1.1-dioxide hydrochloride. mp 206-2090C; 23) (+-)-Trans-3-Ethyl-2,3,4,5-tetrahydro-3-(2(R)-2-hydroxybutyl )-5-(4- hydroxyphenyl)- I .4-benzothiazepine 1.1-dioxide, mp 197-198°C; 24) (+-)-Trans-3-Ethyl-2,3,4,5-tetrahydro-3-(2(S)-2-hydroxybutyl )-5-(4- hydroxyphenyi)-l ,4-benzothiazepine 1,1-dioxide, mp 178-1 790C; 25) (+-)-Trans-3-Ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothia zepine-3- methanol, mp 104-1060C; 26) (+-)-Cis-5-(4-Benzyloxyphenyl)-3-ethyl-2,3,4,5-tetrahydro-1, 4- benzothiazepine-3-methanol, mp 123-128°C; 27) (+-)-:Ea=- 1 -(3-Ethyl-5-(4-fluorophenyl)-2,3,4,5-tetrahydro- 1,4- benzothiazepin-3 -y1)-2(R)-2-butanol S,S-dioxide, mp 130-1 320C; 28) (+-Ins- 1 -(3-Ethyl-2,3,4,5-tetrahydro-5-phenyl- 1 ,4-benzothiazepin-3- yl)4P,4-trifluoro-2(R)-2-butanol S,S-dioxide, mp 140-1450C; 29) (+-)-Trans-1-(3-Ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzot hiazepin-3- yl)-4-fluoro-2-(RS)-2-butanol S,S-dioxide 0.50 hydrate, mp 130-147°C; 30) (+-)-Trans-1-(3 -Ethyl-2 ,3 ,4,5-tetrahydro-5-phenyl- 1 ,4-benzothiazepin-3- yl)-4,4,4-trifluoro-2(S)-2-butanol S,oxide, mp 159-161°C; 31) (+-)-Trans-1-(3-Ethyl)-2,3,4,5-tetrahydro-7-methoxy-5-phenyl -1,4- benzothiazepin-3-yl)-4,4,4-trifluoro-2-(S)-2-butanol S,S-dioxide, mp 168- 1700C; 32) (+-)-Trans-1-(3-Ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl- 1,4- benzothiazepin-3-yl)-4,4,4-trifluoro-2(S)-2-butanol S ,S-dioxide, mp 175-1 790C; 33) (+-)-Trans-(3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-pheny l-1,4- benzothiazepin-3-yl-2(R)-2-butanol S,S-dioxide, mp 156-15 70C; 34) (+-)-Trans-1-(3-Ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phe nyl-1,4- benzothiazepin-3-yl)-4,4,4-trifluoro-2-butanol S,S-dioxide; 35) (+-)-Trans- I -(3-Ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl- 1,4- benzothiazepin-3-yI)-3 ,3 ,4,4,4.pentafluoro-2.butanol S,S-dioxide; 36) (+-)-Trans-1-(3-Ethyl-2,3,4,5-tetrahydro-7.8-dimethoxy-5-phe nyl-1,4- benzothiazepin-3-yl)-3,3,4,4,4-pentafluoro-2-butanol S,S-dioxide; 37) (+-)-Trans-3-((3-ethyl-2,3,4,5-tetrahydro-5-phenyl-3-(4,4,4- trifluoro-2 hvdroxybutyl)-1.4-benzothiazepin-7-yl)oxy)propanesulfonic acid 1,1 -dioxide; 38) (+-)-Trans-3-((3-ethyl-2,3,4,5-tetrahydro-5-phenyl-3-(4,4,4- trifluoro-2 hydroxybutyl)-1,4-benzothiazepin-8-yl)oxy)propanesulfonic acid 1,1-dioxide; 39) (+-)-Trans-3-((3-ethyl-2,3,4,5-tetrahydro-3-(2-hydroxybuty)- 5-phenyl-1,4- benzothiazepin-7-yl)oxy)ethyltrimethylammonium iodide 1,1-dioxide; 40) (+-)-Trans-3-((3-ethyl-2,3,4,5-tetrahydro-3-(2-hydroxybuty)- 5-p benzothiazepin-8-yl)oxy)ethyltrimethylammonium iodide 1,1-dioxide; 41) (+-)-Trans-3-(3-Ethyl-2,3,4,5-tetrahydro-7,8-(diethoxy-5-phe nyl-1,4- benzothiazepin-3-yl)-4,4,4-trifluoro-2-butanolS,S-dioxide; 42)(+-)-Trans-3-((3-ethyl-2,3,4,5-tetrahydro-5-phenyl-3(4,4, 4-trifluoro-2- hydroxybutyl)-1,4-benzothiazepin-7-yl)oxy)ethyltrimethylammo nium iodide l,l-dioxide 43)(+-)-Trans-3-((3-ethyl-2,3,4,5-tetrahydro-5-phenyl-3(4,4, 4-trifluoro hydroxybutyl)-1,4-benzothiazepin-8-yl)oxy)ethyltrimethylammo nium iodide 1 ,1 -dioxide; 44)(+-)-Trans-3-((3-ethyl-2,3,4,5-tetrahydro-3-(2-hydroxybut yl)-5-phenyl-1,4 benzothiazepin-8-yl)oxy)propanesulfonic acid 1,1-dioxide; 45) (+-)-Trans-3-((3-ethyl-2,3,4,5-tetrahydro-3-(2-hydroxybuty)- 5-phenyl-1,4 benzothiazepin-7-yl)oxy)propanesulfonic acid 1,1-dioxide; 46) (+-)-Trans-3-(3-ethyl-2,3,4,5-tetrahydro-7,8-diethoxy-5-peny l-1,4- benzothiazepin-3-yl)-2-butanol S,S-dioxide; 47) (+-)-Trans-1-(3-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-7, 8-dimethoxy-5- Penyl-1,4-benzothiazepin-3-yl)-4,4,4-trifluoro-2-butanol S,S-dioxide; 48) (+-)-Trans-1-(3-(2,2,2,-trifluoroethyl)-2,3,4,5-tetrahydro-8 -methoxy-5- phenyl-l ,4-benzothiazepin-j -yl)-4,4P-trifluoro-2-butano S,S-dioxide; 49) (+-)-Trans-1-(3-Ethyl-2,3,4,5-tetrahydro-9-methoxy-5-phenyl- 1,4- benzothiazepin-3-y-)-4,4,4-trifluoro-2-butanol S,S-dioxide; 50) (+-)-Trans-1-(3-ethyl-2,3,4,5-tetrahydro-9-methoxy-5-phenyl- 1,4- benzothiazepin-3-yl)-2-butanol S,S-dioxide; 51) (+-)-Trans-1-(3-Ethyl-2,3,4,5-tetrahydro-7,8-dihydroxy-5-phe nyl-1,4- benzothiazepin-3-y-)-4,4,4-trifluoro-2-butanol S,S-dioxide; 52) (+-)-Trans-1-(3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl- 1,4- benzothiazepin-3-yl)-2-butanol S,S-dioxide; 53) (+-)-Trans-1-(3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phe nyl-1,4- benzothiazepin-3-yl)-1-butanol S,S-dioxide; 54) (+-)-Trans-1-(3-Ethyl-2,3,4,5-tetrahydro-7,8-dihydroxy-5-phe nyl-1,4- benzothiazepin-3-yl)-2-butanol S,S-dioxide; 55) (+-)-Trans-1-(3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl- 1,4- bcnzothiaztpin-3-yl)4,4,4-trifluoro- 1-butanol S,S-dioxide; 56) (+-)-Trans-1-(3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phe nyl-1,4- benzothiazepin-3-yl)-4,4,4-trifluoro-1-butanol S,S-dioxide; 57) (+-)-Trans-1-(3-Ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phe nyl-1,4- benzothiazepin-3-yl)-2-butanol S,S-dioxide; 1. A compound of formula (I): Wherein 1 is an integer of from 0 to 4; n is an integer of from 0 to 2; R is an atom or group selected from halogen, cyano, hydroxy, nitro, alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, aralkyl, alkaryl, -O(CH2)pS03Rl 1, -O(CH2)pNR11R12, -O(CH2)pN+R11R12R14,-COR11,-CO2R11, -CONR11R12, -CH2OR11, -NR11R12, -NHCOR11, -NHSO2R11, -SR11, -S02R1 1, -SO2NR11R12 and -S03R11 or R is a group -OCH2O- which forms a further ring attached to X wherein p is an integer of from 1 to 4, R11 R12 are independently selected from hydrogen, C1-6 alkyl and phenyl and R14 is hydrogen or C1-6 alkyl, wherein said alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, aralkyl and alkaryl groups are optionally substituted by one or more atoms or groups selected from halogen, hydroxy, nitro, nitrile, alkyl, alkoxy, -COR1 1, -C02R1 1, -SO3R11 wherein R11 is as hereinbefore defined and -NR14Rl5 wherein R14 is as hereinbefore defined and R15 is hydrogen or C1-6 alkyl R1 is hydrogen or C1 6 alkyl; R2 is an atom or--group selected from hydrogen, C1 -6 alkyl (including-cycloalkyl and cycloalkylalkyl), C14 alkoxy, pyrryl, thienyl, pyridyl, 1 ,3-benzodioxolo, phenyl and naphthyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, cyano, hydroxy, nitro, carboxyl, phenyl, phenoxy, benzyloxy, -COR1 1, -C02R1 1, -CONR1 1R12, -CH20R1 1, -NR11R12. -NHCOR11, -NHSO2R11, -SR11, -SO2R11, -S03R11 (wherein R11 and R12 are as hereinbefore defined), -OCH2)pNR11R12, -O(CH2)pN+R11R12R13 and -O(CH2) S03R11 (wherein p, R11 and R12 are as hereinbefore defined and R13 is hydrogen or C1.6 alkyl); R3 is hydrogen, hydroxy C1-6 alkyl, alkoxy or -O-C1-6 Acyl; R4 is a group independently selected from C 1-6 alkyl (including cycloalkyl and cycloalkylalkyl), C2 6 alkenyl, and C2 6 alkynyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, oxo, -OR14, -C02R14, -NR14R1 5, -SR14, -S(O)C1-6 alkyl, -SO2R14 and -S03R14 (wherein R14 and R15 are as hereinbefore defined); R5 is a group independently selected from C2 6 alkyl (including cycloalkyl and cycloalkylalkyl), C2 6 alkenyl and C2 6 alkynyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, oxo, -OR14, -CO2R14, -NR14R15, -SR14, -S(O)CI,6 alkyl, -S02R14 and -S03R14 (wherein R14 and R15 are as hereinbefore defined); or R4 and R5, together with the carbon atom to which they are attached, form a C3 7 spiro cycloalkyl group which is optionally substituted by one or more atoms or groups independently selected from halogen, -OR1 4, -C02R14, -S03R14 and -NR14R15 (wherein R14 and R15 are as hereinbefore defined); R6 and R7 are independently selected from hydrogen and C1-6 alkyl; and X is an aromatic or non-aromatic monocyclic or bicyclic ring system having from 5 to 10 carbon atoms (including the two carbon atoms forming part of the thiazepine ring) wherein optionally one or more of the carbon atoms is/are replaced by heteroatom(s) independently selected from nitrogen, oxygen and sulphur; with the proviso that at least one of R, R2, R4 and R5 is hydroxy or a group containing hydroxy; and salts solvates and physiologically functional derivatives thereof.

2. A compound as claimed in Claim I wherein: 1 is 0, 1, or 2; n is 1 or 2; and R1, R6 and R7 are all hydrogen; and R3 is hydrogen or hydroxy 3. A compound as claimed in Claim 2 which is a trans isomer wherein: (a) 1 is 0 or 1; nis 2; and R4 and R5 are groups independently selected from C1 -6 alkyl (including cycloalkyl and cycloalkylalkyl), C2 6 alkenyl and C2 6 alkynyl, wherein said alkyl, alkenyl, or alkynyl group may be substituted by one or more hydroxy groups, or R4 and R5, together with the carbon atom to which they are attached, form a C3-7 spiro cycloalkyl group which can be substituted by one or more hydroxy groups; or (b) lisOorl; nis2; R2 is a phenyl group which may be substituted by one or more atoms or groups independently selected from halogen, cyano, hydroxy, nitro, carboxyl, phenyl, phenoxy, benzyloxy, -COR11, -CO2R11, -CONR11R12, -CH2OR11, -NR11R12, -NHCOR11, -NHSO2R11, -SR11, -S02R11, -S03R11 (wherein R11 and R12 are independently selected from hydrogen, C1-6 alkyl and phenyl), -O(CH2) NR11R12, -O(CH2) NR+ 11R12R13 and -O(CH2) SO3R11 (wherein p is an intePger of from 1 to 4, Rh 1 and R12 are as hereinbefore defined-and R13 is hydrogen or C1-6 alkyl); R4 and R5 are groups independently selected from C1-6 alkyl (including cycloalkyl and cycloalkylalkyl), C2 6 alkenyl and C2 6 alkynyl, wherein said alkyl, alkenyl, or alkynyl group may be substituted by one or more hydroxy groups, or R4 and R5, together with the carbon atom to which they are attached, form a C3 7 spiro cycloalkyl group which can be substituted by one or more hydroxy groups; or (c) lisOorl: nis2; R2 is a phenyl group which may be substituted by one or more atoms or groups independently selected from halogen, cyano, hydroxy, nitro, carboxyl, phenyl, phenoxy, benzyloxy, -COR11, -CO2R11, -CONR11 R12, -CH2OR11, -NR11R12, -NHCOR11, -NHSO2R11, -SR11, -SO2R11, -SO3R11 (wherein R11 and R12 are independently selected from hydrogen, C1 6 alkyl and phenyl), - O(CH2) NR11R12, -O(CH2) NR+ 11R12R13 and -O(CH2) SO3R11 (wherein p is p p p<BR> <BR> an integer of from 1 to 4, R11 and R12 are as hereinbefore defined and R13 is hydrogen or C1.6 alkyl); R4 and R5 are groups independently selected from C1.6 alkyl (including cycloalkyl and cycloalkylalklyl), C2.6 alkenyl and C2.6 alkynyl, which groups can be substituted by one or more hydroxy groups; and X is a fused phenyl, naphthyl, pyrryl, thienyl, or pyridyl group; 4. A compound as claimed in Claim 1 which is: (+-)-trans-3-ethyl-2,3,4,5-tetrahydro-3-((2R)-2-hydroxybutyl )-5-phenyl-1,4- benzothiazepine 1,1-dioxide; (+-)-trans-l -(;-ethyl- ,3,4,5 -tetrahydro-8 -methoxy-5-phenyl-l ,4-benzothiazepin-3- yl-2(R)-2-butanol S.S-dioxide; (+-)-trans-1-(3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl- 1,4-benzothiazepin-3- yl)-3-butanol S,S-dioxide; ~~~~~~~~~~~ (+-)-trans-1-(3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl- 1,4-benzothiazepin-3- yl)-2(R)-2-butanol S,S-dioxide; (+-)-trans-1-(3-ethyl-5-(4-fluorophenyl)-2,3,4,5-tetrahydro- 7-methoxy-1,4- benzothiazepin-3-yl)-2(R)-2-butanol S,S-dioxide; (+-)-trans-1-(3-ethyl-5-(4-hydroxyphenyl)-2,3,4,5-tetrahydro -1,4-benzothiazepin-3- yl)-2(R).2.butanol S.S-dioxide 0.5 hydrate: (+-)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-(4-hydroxyph enyl)-1,4- benzothiazepine l,l-dioxide hydrochloride; (+-)-cis-3-ethyl-2,3,4,5-tetrahydro-3-(4-hydroxybutyl)-5-phe nyl-1,4- berizothiazepine 1,1-dioxide hydrochloride; (+-)-trans-3-ethyl-2,3,4,5-tetrahydro-3-(4-hydroxybutyl)-5-p henyl-1,4- benzothiazepine 1,1-dioxide; (+-)-trans-3-buty-3-ethyl-2,3,4,5-tetrahydro-7-hydroxy-5-phe nyl-1,4- benzothiazepine 1,1 dioxide; (+-)-trans-1-(3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzot hiazepin-3-yl)-4,4,4- trifluoro-(2S)-2-butanol- S,S-dioxide; (+-)-trans-1-(3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl- 1,4-benzothiazepin-3- yl)-4,4,4-trifluoro-(2S)-2-butanol-S,S-dioxide; (+-)-trans-3-Ethyl-2,3,4,5-tetrahydro-3-(3-hydroxybutyl)-5-p henyl-1,4- benzothiazepine l,l-dioxide; (+-)-trans-3-Ethyl-2,3,4,5-tetrahydro-3-(2(R)-2-hydroxybutyl )-5-(4- hydroxyphenyl)- 1 ,4-benzothiazepine 1,1-dioxide; (+-)-trans-1-(3-Ethyl-5-(4-fluorophenyl)-2,3,4,5-tetrahydro- 1,4- benzothiazepin-3-yl)-2(R)-2-butanol S,S-dioxide; (+-)-trans-1-(3-Ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl- 1,4 benzothiazepin-3-yl)-4,4,4-trifluoro-2(S)-2-butanol S,S-dioxide; (+-)-trans-1-(3-Ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl- 1,4- benzothiazepin-3-yl)-4,4,4,-trifluoro-2(S)-butanol S,S-dioxide; (+-)-trans-1-(3-ethyl-23,4,5-tetrahydro-7,8-dimethoxy-5-phen yl-1,4- benzothiazepin-3-yl-2(R)-2-butanol S,S dioxide; (+-)-trans-1-(3-Ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phe nyl-1,4- benzothiazepin-3-yl)-4,4,4-trifluoro-2-butanol S,S-dioxide; (+-)-trans-1-(3-Ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phe nyl-1,4- benzothianzepin-3-yl)-3,3,4,4,4-pentafluoro-2-butanol S,S-dioxide; (+-)- trans-3-((3-ethyl-2,3,4,5-tetrahydro-5-phenyl-3-(4,4,4-trifl uoro-2- hydroxybutyl)-1,4-benzothiazepin-8-yl)propanesulfonic acid 1,1-dioxide; (+-)-trans-3-((3 -ethyl-2,3 ,4,5-tetrahydro-3-(2-hydroxybutyl)-5-phenyl- 1,4- benzothiazepin-8-yl)oxy)ethyltrimethylammonium iodide 1,1-dioxide; (+-)-trans- 1 -(3-Ethyl-2,3 ,4,5.tetrahydro.7.8.diethoxy-5-phenyl. 1,4- benzothiazepin-;-yl)4,4,4-trifluoro-2-butanol S,S-dioxide; (+-)-trans-3-((3-ethyl-2,3,4,5-tetrahydro-5-phenyl-3(4,4,4-t rifluoro-2- hydroxybutyl)-1,4-benzothiazepin-8-yl)oxy)ethyltrimethylammo nium iodide 1,1-dioxide: (+-)-trans-3-((3-ethyl-2,3,4,5-tetrahydro-3-(2-hydroxybutyl) -5-phenyl-1,4- benzothiazepin-8-yl)oxy)propanesulfonic acid 1,1-dioxide; (+-)-trans-1-(3-ethyl-2,3,4,5-tetrahydro-7,8-diethoxy-5-phen yl-1,4 benzothiazepin-3-yl)-2-butanol S,S-dioxide; (+-)trans-1-(3-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-7,8 -dimethoxy-5- phenyl-1,4-benzothiazepin-3-yl)-4,4,4-trifluoro-2-butanol S,S-dioxide; (+-)-trans- 1 -(3-Ethyl-2,3,4,5-tetrahydro-7,8-dihydroxy-5-phenyl- 1,4- benzothiazepin-3-yl)-4,4,4-trifluoro-2-butanol S,S-dioxide; (+-)-trans-1-(3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phe nyl-1,4 benzothiazepin-3-yl)-1-butanol S,S-dioxide; (+-)-trans-1-(3-Ethyl-2,3,4,5-tetrahydro-7,8-dihydroxy-5-phe nyl-1,4- benzothiazepin-3-yl)-2-butanol S,S-dioxide; (+-)-trans-1-(3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl- 1,4- benzothiazepin-3-yl)-4,4,4-trifluoro-1-butanol S,S-dioxide; or (+-)-trans-1-(3-ethyl-2,3,4,5-tetrahydro-7,8-dihydroxy-5-phe nyl-1,4- benzothiazepin-3-yl)-2-butanone S,S-dioxide 5. A compound as claimed in claim 1 of the formula aa) wherein 1 is an integer offrom 0 to4; n is an integer of from 0 to 2; Ris an atom or group selected from halogen, cyano, hydroxy, nitro, alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, aralkyl, alkaryl, -COR1 1, -CO2R11, -CONR11R12, -CH20R11, -NR11R12, -NHCOR11, -NHS02RI 1, -SRI 1, -S02R11 and -SO3R11 wherein R1 1 and R12 are independently selected from hydrogen, Cl.6 alkyl and phenyl, wherein said alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, aralkyl and alkaryl groups are optionally substituted by one or more atoms or groups selected from halogen, hydroxy, nitro, nitrile, alkyl, alkoxy, -COR11, -C02R11, - SO3R11 wherein R11 is as hereinbefore defined and -NR14R15 wherein R14 and R15 are as hereinbefore defined; R1 is hydrogen or C1 6 alkyl; R2 is an atom or group selected from hydrogen, C1 6 alkyl (including cycloalkyl and cycloalkylalkyl), C1-4 alkoxy, pyrryl, thienyl, pyridyl, 1,3-benzodioxolo, phenyl and naphthyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, cyano, hydroxy, nitro, carboxyl, phenyl, phenoxy, benzyloxy, -COR11, -CO2R11, -CONR11R12, -CH2OR11, -NR11R12, -NHCOR11, -HNSO2R11, -SR11, -SO2R11, -SO3R11 (wherein R11 and R12 are independently selected from hydrogen, C1-6 alkyl and phenyl), -O(CH2) NR11R12, p<BR> <BR> -O(CH2)nN+R11R12R13 and -O(CH2)nSO3R11 (wherein p is an integer of from 1 to 4, R1 1p and R12 are as hereinbefore defined and R13 is hydrogen or C1 6 alkyl); R3 is selected from hydrogen, hydroxy and C1-6 alkyl; R4 is a group independently selected from C1-6 alkyl (including cycloalkyl and cycloalkylalkyl), C2 6 alkenyl and C2 6 alkynyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, -OR14, -C02R14, -NR14R15 and -S03R14 (wherein R14 and R15 are independently selected from hydrogen and C1 6 alkyl); R5 is a group independently selected from C2 6 alkyl (including cycloalkyl and cycloalkylalkyl), C2 6 alkenyl and C2 6 alkynyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, -OR14, -C02R14, -NR14R15 and -So3R14 (wherein R14 and R15 are independently selected from hydrogen and C1-6 alkyl); or R4 and R5, together with the carbon atom to which they are attached, form a C3-7 spiro cycloalkyl group which is optionally substituted by one or more atoms or groups independently selected from halogen, -OR14, -CO2R14, -S03R14 and -NR14R15 (where R14 and R15 are as hereinbefore defined; R6 and R7 are independently selected from hydrogen and C1-6 alkyl; and X is an aromatic or non-aromatic monocyclic or bicyclic ring system having from 5 to 10 carbon atoms (including the two carbon atoms forming part of the thiazepine ring) wherein optionally one or more of the carbon atoms is/are replaced by heteroatom(s) independently selected from nitrogen, oxygen and sulphur; with the proviso that at least one of R, R2, R4 and R5 is hydroxy or a group containing hydroxy; and salts, solvates and physiologically functional derivatives thereof.

6. A compound of formula (I): wherein 1 is an integer of from 0 to 4; n is an integer of from 0 to 2; R is an atom or group selected from halogen, cyano, hydroxy, nitro, alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, aralkyl, alkary!, -O(CH2)pS03RI 1, -O(CH2)pNR11R12, .O(CH2)pN+Rl 1R12R14, -COR1 1, -C02R1 1, -CONR11R12, -CH2OR11, -NR11R12, -NHCOR11, -NHSO2R11, -SR11, -S02R11 -S02NRI IR12 and -S03RI I or R is a group -OCH2O- which forms a further ring attached to X wherein p is an integer of from 1 to 4, R11 and R12 are independently selected from hydrogen, C1 6 alkyl and phenyl and R14 is hydrogen or C 1-6 alkyl, wherein said alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, aralkyl and alkaryl groups are optionally substituted by one or more atoms or groups independently selected from halogen, hydroxy, nitro. nitrile, alkyl, alkoxy, -COR1 1, -CO2R11, -SO3R11 wherein Rl I is as hereinbefore defined and -NR14R15 wherein R14 is as hereinbefore defind and RID is hydrogen or C1-6 alkyl; R1 is hydrogen or C1.6 alkyl; R2 is an atom or group selected from hydrogen, C1-6 alkyl (including cycloalkyl and cycloalkylalkyl), C1-4 alkoxy, pyrryl, thienyl, pyridyl, 1,3-benzodioxolo, phenyl and naphthyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, cyano, hydroxy, nitro, carboxyl, phenyl, phenoxy, benzyloxy, -COR11, -C02RI 1, -CONR1 1R12, -CH2OR1 I, -NR11R12, -NHCOR11, -NHSO2R11, -SR11, -SO2R11, -SO3R11 (wherein R11 and R12 are independently selected from hydrogen, C1 6 alkyl and phenyl), -O(CH2) NR11R12, -O(CH2) N+R11R12R13 and -O(CH2) S03R11 (wherein p is an integer of from 1 to 4, RP1 and R12 are as hereinbefore defined and R13 is hydrogen or C1-6 alkyl); R3 is hydrogen, hydroxy C1-6 alkyl, alkoxy or -O-C1-6 Acyl; R4 is a group independently selected from C1-6 alkyl (including cycloalkyl and cycloalkylalkyl), C2-6 alkenyl and C2 6 alkynyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, oxo, -OR14, -C02R14, -NR14R15, -SR14, -S(O)C1.6 alkyl, -SO2R14 and -S03R14 (wherein R14 and R15 are as hereinbefore defined); R5 is a group independently selected from C2 6 alkyl (including cycloalkyl and cycloalkylalkyl), C2 6 alkenyl and C2 6 alkynyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, oxo, -OR14, -C02R14, -NR14R15, -SR14,-S(O)C1-6 alkyl, -502R14 and -S03R14 (wherein R14 and R15 are as hereinbefore defined); or R4 and R5, together with the carbon atom to which they are attached, form a C3-7 spiro cycloalkyl group which is optionally substituted by one or more atoms or groups independently selected from halogen, -ORI4 -CO2R14, -S03R14 and -NR14R15 (where R14 and R15 are as hereinbefore defined; R6 and R7 are independently selected from hydrogen and C1 6 alkyl; and X is an aromatic or non-aromatic monocyclic or bicyclic ring system having from 5 to 10 carbon atoms (including the two carbon atoms forming part of the thiazepine ring)' wherein optionally one or more of the carbon atoms is/are replaced by heteroatom(s) independently selected from nitrogen, oxygen and sulphur; with the proviso that at least one of R, R2, R4 and R5 is hydroxy or a group containing hydroxy; and salts, solvates and physiologically functional derivatives thereof, for use in the prophylaxis or treatment of clinical conditions for which a bile acid uptake inhibitor in indicated.

Compounds of formula (I) having exceptional hypolipidaemic properties include:- (-)-(RR)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4,-be nzothiazepine 1,1-dioxide; (+-)-trans-3-((E)-2-butenyl)-3-ethyl-2,3,4,5-tetrahydro-5-ph enyl-1,4-benzothiazepine, 1,1- dioxide; (+-)-trans-3-ethyl-2,3,4,5-tetrahydro-3-(3-methoxypropyl)-5- phenyl-1,4-benzothiazepine 1,1-dioxide; (+-)-trans-1-(3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzot hiazepin-3-yl)-2-butanoneS,S- dioxide; (+-)-trans-1-(3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl- 1,4-benzothiazepin-3-yl)-2- butanone S,S-dioxide hydrochloride 1.1 hydrate; (+-)-trans-3-(1-butenyl)-3-ethyl-2,3,4,5-tetrahydro-5-phenyl -1,4-benzothiazepinel,1-dioxide hydrochloride 0.4 hydrate; (+-)-trans-3-(ethoxyethyl-3-ethyl-2,3 ,4,5-tetrahydro-5-phenyl- 1 ,4-benzothiazepinel ,1 - dioxide hydrochloride hemihydrate; (+-)-trans-3-(ethoxy)methyl)-3-ethyl-2,3,4,5-tetrahydro-5-ph enyl-1,4-benzothiazepine,1- dioxide hydrochloride; (+-)-trans.ethyl 3-(3-ethyl-2,3,4,5-tetrahydro-5-phenyl- 1 ,4-benzothiazepin-3-yl)propionate l,l-dioxide; (+-)-trans-(E)-4-(3-ethyl-2,3 ,4,5-tetrahydro-5-phenyl- 1 ,4-benzothiazepin-3-yl)-3-buten-2- one 1,1-dioxide; (+-)-2,3,4,5-tetrahydro-8-methoxy-5-phenylspiro(1,4-benzothi azepine-3,1-cyclohexane) l,l-dioxide; (+-)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-(4-pyridyl)- 1,4-benzothiazepine 1,1-dioxide; (+-)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-4-hydroxy-5-(4 -pyridyl)-1,4-benzothiazepine 1,1-dioxide; (+-)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-(2-theinyl)- 1,4-benzothiazepine 1,1-dioxide; (+-)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-(1H-pyrrol-1 -yl)-1,4-benzothiazepine1,1- dioxide; (+-)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenylpyrido (4,3-F)-1,4-benzothiazepine 1,1-dioxide; (+-)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5--phenyl-2H-p yrrolo(3,4-F)-1,4- benzothiazepine l.l-dioxide 0.1 hydrate; (+-)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenylthieno (2,3-F)-1,4-benzothiazepinel,1- dioxide; (+-)-trans-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-3-(4,4,4-trif luorobutyl)-1,4-benzothiazepine 1,1-dioxide; (+-)-trans-2,3,4,5-tetrahydro-3-isopropyl-3-methyl-5-phenyl- 1,4-benzothiazepine, 1,1- dioxide 0.25 H20; (+-)-trans-3-((E)-2-B utenyl)-3 -ethyl-2,3,4,5-tetrahydro-5-phenyl- 1 ,4-benzothiazepine; (+-)-Cis-2,3,4,5-Tetrahydro-3-isopropyl-3-methyl-5-phenyl-1, 4-benzothiazepine 1,1-dioxide 0.66 H20; (+-)-trans-3-(3-Ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzot hiazepin-3-yl)propanol 1,1 dioxide; (+-)-trans-3-Ethyl-5-(4-Fluorophenyl)-2,3,4,5-tetrahydro-7-m ethoxy-3-(3-methoxypropyl)- I ,4-benzothiazepine 1,1-dioxide hydrochloride; (+-)-2 ,3,4,5-Tetrahydro-7-Methoxy-5-phenylsipiro( 1 ,4-benzothiazepine-3 , 1 -cyclohexane) 1,1-dioxide; (+-)-trans- 1 .(3-Ethyl.2,3,4,5-tetrahydro-7.methoxy-5-phenyl. 1 ,4-benzothiazepin-3-yl)-2- butanone S,S-dioxide hydrochloride; (+-)- trans-3 -butyl-3 -ethyl-2,3 ,4,5 -tetrahydro-5-phenylnaphtho(; ,2-F)- 1 ,4-benzothiazepine l,l-dioxide; (+-)-trans- 1 -(3-Ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl- 1 ,4-benzothi azepin3 -yI)- 2-butanone S,S-dioxide; (+-)-trans-3-( 1 -butenyl)-3 -ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl -1,4- benzothiazepine 1,1-dioxide; (+-)-trans- 1 -(3-Ethyl-2,3 ,4,5-tetrahydro-7,8-dimethoxy-5-phenyl- 1 ,4-benzothiazepin-3-yl)- 3-butanone S,S-dioxide; (+-)-trans-1-(3-Ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl- 1,4-benzothiazepin-3-yl)-1- butanone S,S-dioxide; (+-)-trans-1-(3-Ethyl-2,3- ,4,5-tetrahydro-7,8-dimethoxy-5-phenyl- 1 ,4-benzothiazepin-3-yl)- 1 -butanone S,S-dioxide; (+-)-trans-1-(3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phe nyl-1,4-benzothiazepin-3-yl)- 4,4,4-trifluoro-1 -butanone S,S-dioxide; (+-)-trans-1-(3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phe nyl-1,4-benzothiazepin-3-yl)- 3,3,4,4,4-pentafluoro-2-butanone S,S-dioxide; (+-)-trans- l -(3 -ethyl-2,3 ,4,5-tetrahydro-7 8-dimethoxy-5-phenyl- 1 ,4-benzothiazepin-3-yl)- 4,4,4-trifluoro-2-butanone S,S-dioxide; (+-)-trans-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl -3-(4,4,4-rifluorobutyl)-1,4- benzothiazepine 1,1-dioxide; (+-)-trans-1-(3-(2,2,2-rifluoroethyl)-2,3,4,5-tetrahydro-7,8 -dimethoxy-5-phenyl-1,4- benzothiazepin-3-yl)-2-butanone S,S-dioxide; (+-)-trans-1-(3-Ethyl-2,3,4,5-tetrahydro-7,8-diethoxy-5-phen yl-1,4-benzothiazepin-3-yl)-2- butanone S,S-dioxide; (+-)-trans-3-((3-ethyl-2,3,4,5-tetrahydro-3-(2-oxobutyl)-5-p henyl-1,4-benzothiazepin-8- yl)oxy)propanesulfonic acid 1,1-dioxide; (+-)-trans-2-((3-ethyl-2,3,4,5-tetrahydro-3-(2-oxobutyl)-5-p henyl-1,4-benzothiazepin-8- yl)oxy)ethyltrimethylarnmonium iodide l,l-dioxide; (-)-(RR)-3-butyl-3ethyl-2,3,4,5.tetrahydro.5.phenyl- 1 ,4-benzothiazepine 1,1-dioxide; (+-)-trans-1-(3 -ethyl-2 ,3,4 ,5-tetrahydro-8-methoxy-5-phenyl- 1 ,4-benzothiazepin-3 -yl)-2- butanone S,S-dioxide hydrochloride 1.1 hydrate; (+-)-Cis-2,3,4,5-Tetrahydro-3-isopropyl-3-methyl-5-phenyl-1, 4-benzothiazpine 1,1-dioxide 0.66 H20; (+-)-trans- 1 -(3-Ethyl-2,3 ,4,5-tetrahydro.7,8-dimethoxy-5-phenyl. 1 ,4-benzothiazepin-3-yl)- 2-butanone S,S-dioxide; 20) (+-)-2,3,4,5-Tetrahydro-5-phenylspiro(1,4-benzothiazepine-3, 1'- cyclohexane) 1,1-dioxide, mp 177-1 790C; 21) (+-)-Trans-2,3,4,5-tetrahydro-3-isopropyl-3-methyl-5-phenyl- 1,4- benzothiazepine 1,1-dioxide 0.25 H2O, mp 130-132°C; 22) (+-)-(S)-2,3,4,5-Tetrahydro-5-phenylspiro(1,4-benzothiazepin e-3,1'- cyclohexane) 1,1-dioxide, mp 210-21 10C; 23) (-)-(R)-2,34,5-Tetrahydro-5-phenylspir(1,4-benzothiazepine-3 ,1'- cyclohexane) 1,1-dioxide, mp 210-21 10C; 24) (+-)-Trans-2,3,4,5-tetrahydro-3-isopropyl-3-methyl-5-phenyl- 1,4- benzothiazepine hydrochloride, mp 21 1-2130C; 25) (+-)-Cis-2,3,4,5-tetrahydro-3-isopropyl-3-methyl-5-phenyl-1, 4- benzothiazepine hydrochloride, mp 268-2700C; 26) (+-)-3 -s-Butyl-Zj ,4,5-tetrahydro-3-methyl-5-phenyl- 1,4- benzothiazepine hydrochloride, mp 202-2050C; 27) (+-)-4,5-Dihydro-5-phenylspiro(1,4-benzothiazepine-3-(2H),1' - cyclopentane) hydrochloride 0.25 H20, mp 224-226°C; 28) (+-)-2,3,4,5-Tetrahydro-5-phenylspiro(1,4-benzothiazepine-3, 1'- cyclohexane) hydrochloride H2O, mp 167-169°C (eff.); 29) (+-)-5-(2-Fluorphenyl)-2,3,4,5-tetrahydropspiro(1,4-benzothi azepine- 3,1'-cyclohexane) 1,1-dioxide. mp 160-161°C; 30) (+-)-Cis-3-(2,3,4,5-tetrahydro-3-methyl-5-phenyl-1,4,-benzot hiazepin-3- yl)propionic acid 1.1-dioxide 0.5 HO2, mp 132-1330C; 31) (--)-Trans-Ethyl-3-(2,3,4,5)-tetrahydro-3-methyl-5-phenyl-1, 4- benzothiazepin-3-yl)propioniate 1.1-dioxide, mp 143-1 480C; 32) (--)-Cis-Ethyl 5-(2,3,4,5-tetrahydro-3-methyl-5-phenyl-1,4- benzothiazepin-3-yl)valerate 1,1-dioxide, mp 121-1220C; 33) (--)-Trans-3-((E)-2-Butenyl)-3-ethyl-2,3,4,5-tetrahydro-5-ph enyl-1,4- benzothiazepine, mp 69-74°C; 34) (+-)-Trans-3-Ethyl-2,3,4,5-tetrahydro-3-isopropyl-5-phenyl-1 ,4- benzothiazepine 1,1-dioxide, mp 116-118°C; 35) (+-)-Cis-3-iso-Butyl-3-ethyl-2,3 ,4.5-tetrahydro-5-phenyl- 1,4- benzothiazepine dioxide, mp 91-930C; 36) (+-)-Cis-3-iso-Butyl-3-ethyl-2,3,4,5,-tetrahydro-5-phenyl-1, 4- benzothiazepine 1,1-dioxide, mp 149-151 0C; 37) (--)-Trans-3-iso-Butyl-3-ethyl-2,3 .4,5-tetrahydro-5-phenyl- I ,4- benzothiazepine l-oxide, mp 92-930C; 38) (+-)-Trans-3-iso-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1 ,4- benzothiazepinc 1,1-dioxide, mp 101-1 030C; 39) (+-)-Cis-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(3-pyridyl)-1, 4- benzothiazepine 1,@-dioxide, mp 60-610C; 40) (+-)-Cis-Ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepi ne-3- carbaldehyde l,l-dioxide, mp 162-164°C; 41) (+-)-cis-2,3,4,5-Tetrahydro-3-isopropyl-3-methyl-5-phenyl-1, 4- benzothiazepine 1,1-dioxide 0.66 H20, mp 119-1200C; 42) (+-)-Trans-3-Ethyl-2,3,4,5-tetrahydro-3-isopropyl-5-phenyl-1 ,4- benzothiazepine 1,1-dioxide, mp 121-124°C; 43) (+-)-Cis-3-Ethyl-2,3,4,5-tetrahydro-3-isopropyl-5-phenyl-1,4 - benzothiazepine 1,1-dioxide, mp 150-1520C; 44) (+-)-Cis-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-4-hydroxy-5-(3-p yridyl)-1,4- benzothiazepine 1,1-dioxide, mp 202-2050C; 45) (+-)-Trans-3-(3-Ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzot hiazepin-3- yl)propanol 1,1-dioxide mp 164-1650C; 46) (--)-Trans-3-Ethyl-5-(4-Fluorophenyl)-2,3,4,5-tetrahydro-7-m ethoxy-3- (3-methoxypropyl)-1,4-benzothiazepine 1,1-dioxide hydrochloride, mp 179-1810C; 47) (+-)-Cis-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenylpyrido(4 ,3-F)-1,4- thiazepine l.l-dioxide 0.333 H20, mp 111-1 120C; 48) (+-)-Cis-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(1H-pyrrol-1-y l)-1,4- benzothiazepine 1,1-dioxide, mp 50-520C; 49) (+-)-Cis-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-7H-pyrr olo(3,4,-F)- 1,4-thiazepine l.l-dioxide 0.125 H20, mp 75-770C; 50) (+-)-2,3,4,5-Tetrahydro-7-methoxy-5-phenylspiro(1,4-benzothi azepine- 3,1-cyclohexane) 1,1-dioxide, mp 142-143°C; 51) (+-)-Trans-1-(3-Ethyl-2,3,4,5-tetrahydro-7-Methoxy-5-phenyl- 1,4- benzothiazepin-i-yl)-2-butanone S,S-dioxide hydrochloride mp 175- 1760C; 52) (+-)- Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenylnaphtho(3,2 ,-F)- 1,4-benzothiazepine 1,1-dioxide, mp 128-131 0C; 53) (+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(2-pyridyl)- 1,4- benzothiazepine 1,1-dioxide, mp 50-530C; 54) (+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(3-pyridyl)- 1,4- benzothiazepine 1;1-doxide 0.25 hydrate, mp 153-155°C; 55) (+-)-trans-1-(3-Ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phe nyl-1,4- benzothiazepin-3-yl)-2-butanone S,S-dioxide, mp 142-1460 C; <BR> <BR> <BR> <BR> <BR> 56) (+-)-Trans-3-( 1 -butenyl)-3.ethyl.2,3 ,4,5-tetrahydro-8-methoxy.5-phenyl -1,4-benzothiazepine 1,1-dioxide 57) (+-)-Trans-3-(1-butenyl)-3-ethyl-2,3,4,5-tetrahydro-7,8-dime thoxy-5- phenyl -1,4-benzothiazepine 1,1-dioxide 58) (+-)- 1 -(3-Ethyl-2.3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4- benzothiazepin-3-yl)-3-butanone S,S-dioxide 59) (+-)-Trans-1-(3-Ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phe nyl-1,4- benzothiazepin-3-yl)-3-butanone S,S-dioxide 60) (+-)-Trans-1-(3-Ethyl-2,3,4,5-tetrahydro-8-mehtoxy-5-phenyl- 1,4- benzothiazepin-3-yl)-1-butanone S.S-dioxide 61) (+-)-Trans-1 -(3-Ethyl-2.3 .4,5-tetrahydro-7.8-dimethoxy.5.phenyl. 1.4- benzothiazepin-3-yl)-1-butanone S,S-dioxide 62) (+-)-Trans- I -(3-ethyl-2.3 .4..5-tetrahydro-8.methoxy.5.phenyl. 14- benzothiazepin-3-yl)-4,4,4-trifluoro-1-butanone S,S-dioxide 63) (+-)-Trans-1-(3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phe nyl-1,4- benzothiazepin-3-yl)-4,4,4-trifluoro-1-butanone S,S-dioxide 64) (+-)-Trans-1-(3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phe nyl-1,4- benzothiazepin-3-yl)-3,3,4,4,4-pentafluoro-2-butanone S,S-dioxide 65) (+-)-Trans-1-(3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl- 1,4- benzothiazepin-3-yl)-3,3,4,4,4-pentafluoro-2-butanone S,S-dioxide 66) (+-)-Trans-1-(3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phe nyl-1,4- benzothiazepin-3-yl)-4,4,4-trifluoro-2-butanone S,S-dioxide 67) (+-)-Trans- I -(3-ethyl-2,; ,4,5,-tetrahydro-8-methoxy-5-phenyl- 1,4- benzothiazepin-3-yl)-4,4,4-trifluoro-2-butanone S,S-dioxide 68) (+-)-Trans-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-3-( 4,4, 4-trifluorobutyl)- 1 ,4-benzothiazepine 1,1 dioxide 69) (+-)-Trans-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl -3-(4,4, 4-trifluorobuty)-1,4-benzothiazepine 1,1-dioxide 70) (+-)-Trans-1-(3-(2,2,2,-trifluoroethyl)-2,3,4,5-tetrahydro-8 -methoxy-5- phenyl-1,4- benzothiazepin-3-yl)-2-butanone S,S-dioxide 71) (+-)-Trans-1-(3-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-7, 8-dimethoxy-5- phenyl-1,4- benzothiazepin-3-yl)-2-butanone S,S-dioxide 7 2) (+ -)-Trans- 1-(3 -Ethyl-2,3 ,4,5-tetrahydro.9-methoxy.5.phenyl. 1,4- benzothiazepin-3-yl>2-butanone S,S-dioxide 73) (+-)-Trans-3-((3-ethyl-2,3,4,5-tetrahydro-3-(2-oxobutyl)-5-p henyl-1,4- benzothiazepin-7-yl)oxy)propanesulfonic acid l,l-dioxide 74) (+-)-Trans-1-(3-Ethyl-2,3,4,5-tetrahydro-7,8-diethoxy-5-phen yl-1,4- benzothiazepin-3-yl)-2-butanone S,S-dioxide 75) (+-)-Trans-1-(3-Ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-4-hyd roxy-5-phenyl- 1,4-benzothiazepin-3-yl)-2-butanone S,S-dioxide 76) (+-)-Trans-3-((3-ethyl-2,3,4,5-tetrahydro-3-(2-oxobutyl)-5-p henyl-1,4- benzothiazepin-8-yl)oxy!propanesuifonic acid l.l-dioxide 77) (+-)-Trans-2-((3-ethyl-2,3,4,5-tetrahydro-3-(2-oxobutyl)-5-p henyl-1.4- benzothiazepin-7-yl)oxy)ethyltrimethylammonium iodide 1,1-dioxide 78) (+-)-Trans-2-((3-ethyl-2,3,4,5-tetrahydro-3-(2-oxobutyl)-5-p henyl-1,4- benzothiazepin-8-yl)oxy)ethyltrimethylammonium iodide 1,1-dioxide 1, A compound of formula (I): wherein 1 is an integer of from 0 to 4; n is an integer offrom 0 to 2; R is an atom or group selected from halogen, cyano, nitro, alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, aralyl, alkary, -O(CH2)pSO3R11, -O(CH2)pNR11R12,-O(CH2)PN+R11R12R14,COR11,-CO2R11,-CONR11R12 , -CH2OR11,-NR11R12, -NHCOR11, 0NHSO2R11, -SR11, -SO2R11, -SO1NR11R12, -SO3R11, wherein p is an integer from 1 to 4, R11 and R12 are independently selected from hydrogen, C1 6 alkyl and phenyl, and R14 is hydrogen or C1 6 alkyl, or R is a group -OCHsO- which forms a fUrther ring attached to X, wherein said alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, arlakyl and ailcaryl groups are optionally substituted by one or more atoms or groups selected from halogen, nitro, nitrile, alkyl, alkoxy, -COR11, -C02R11, -SO3R11 wherein R11 is as hereinbefore defined and -NR14R15 wherein R14 is as hereinbefore defined and R15 is hydrogen or Clg alkyl; R1 is hydrogen or C1 alkyl; R2 is an atom or group selected from hydrogen. C 1-6 alkyl (including cycloalkyl and cycloalkylalkyl), C1-4 alkoxy. pyrryl, thienyl, pyridyl, 1,3-benzodioxolo, phenyl and naphthyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen. cyano. nitro, carboxyl, phenyl, phenoxy, benzyloxy, -COR11, -CO2R11. -CONR11R12, -CH2OR11, -NR11R12, -NHCOR11, -NHSO2R11, -SR11, -SO2R11, -SO3R11 (wherein R11 and R12 are as hereinbefore defined). -O(CH2)pNR11R12.-O(CH2)pN+R1 1R12R13 and -O(CH2)pSO3R11 (wherein p, R11 and R12 are as hereinbefore defined and R13 is hydrogen or C1 -6 alkyl); R3 is hydrogen, OH, C1-6 alkyl. C1 -6 alkoxy or -OC 1-6 acyl; R4 is a group independently selected from C1-6 alkyl (including cycloalkyl and cycloalkylalkyl), C2 6 alkenyl and C2-6 alkynyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, oxo, C1 4 alkoxy, -C02R14, -NR14R15, -SR14, -S(O)C1.6 alkyl, -SO2R14, -So3R14 (wherein R14 and R15 are hereinbefore defined); R5 is a group independently selected from C2-6 alkyl (including cycloalkyl and cycloalkylalkyl), C2.6 alkenyl, and C2-6 alkynyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, oxo, C1-4 alkoxy, -CO2R14, -NR14R15, -SR14, -S(O) C1-6 alkyl, -SO2R14, -SO3R14 (wherein R14 and R15 are hereinbefore defined); or R4 and R5, together with the carbon atom to which they are attached, form a C3 7 spiro cycloalkyl group which is optionally substituted by one or more atoms or groups independently selected from halogen, C1-6 alkoxy, -C02R14, -sojRI4 and -NR14RlD (where R14 and R15 are as hereinbefore defined); R6 and R7 are independently selected from hydrogen and C 1-6 alkyl; and X is an aromatic or non-aromatic monocyclic or bicyclic ring system having from 5 to 10 carbon atoms (including the two carbon atoms forming part of the thiazepine ring) wherein optionally one or more of the carbon atoms is/are replaced by heteroatom(s) independently selected from nitrogen, oxygen and sulphur; with the proviso that when 1 is an integer of from 0 to 4, R1 = R6 = R7 = H, R3 = H or OH, R2 = unsubstituted phenyl or phenyl substituted by one or more atoms or groups independently selected from halogen, nitro, phenylalkoxy, C1-4 alkoxy, C1-6 alkyl and -0(CH2)pSO3R11 wherein p and R1 1 are as hereinbefore defined, wherein said phenylalkoxy, alkoxy and alkyl groups are optionally substituted by one or more halogen atoms, and X is a fused phenyl ring, then R4 is other than a C1 6 straight alkyl group and R5 is other than a C2-5 straight alkyl group, and salts, solvates and physiologically functional derivatives thereof.

2. A compound as claimed in claim 1 which is a trans isomer wherein lisO, 1 or2; nis 1 or2; R1, R6 and R7 are all hydrogen; R3 is hydrogen or hydroxy; and X is a fused phenyl, naphthyl, pyrryl, thienyl or pyridyl, group.

3. A compound as claimed in claim 1 or claim 2 wherein 1 is 0 ro 1; nis 2; and R2 is pyrryl, thienyl, pyridyl, phenyl or naphthyl, such groups being optionally substituted by one or more atoms or groups independently selected from halogen, cyano, nitro, carboxyl, phenyl, phenoxy, benzyloxy, -COR1 1, -CO2R11, -CONR11R12, -CH2OR11, -NR11R12, -NHCOR11, -NHSO2R11, -SR11, -5O2R11, -S03Rll (wherein R11 and R12 are independently selected from hydrogen, C1 6 alkyl and phenyl), .O(CH2)pNR11R12, -O(CH2)N+R1 1R12R13 and -O(CH2)pSO3R11 (wherein p is an integer of from I to 4, R11 and R12 are as hereinbefore defined and R13 is hydrogen or C 1-6 alkyl).

4. A compound as claimed in Claim 1 which is: (-)-(RR)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-ben zothiazepine 1,1- dioxide (+-)-trans-3-((E)-2-butenyl)-3-ethyl-2,3,4,5-tetrahydro-5-ph enyl-1,4- benzothiazepine 1,1-dioxide; (+-)-trans-3-ethyl-2,3,4,5-tetrahydro-3-(3-methoxypropyl)-5- phenyl-1,4- benzothiazepine 1,1-dioxide; (+-)-trans-1-(3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzot hiazepin-3-yl)-2- butanoneS,S-dioxide; (+-)-trans-1-(3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl- 1,4,-benzothiazepin-3- yl)-2-butanone S,S-dioxide hydrochloride 1.1 hydrate; (+-)-trans-3-( 1 -butenyl)-3-ethyl-2,3 ,4,5-tetrahydrp-5-phenyl- 1 .4-benzothiazepine 1,1 - dioxide hydrochloride 0.4 hydrate; (+-)-trans-3-(ethoxyethyl)-3-ethyl-2,3,4,5-tetrahydro-5-phen yl-1,4- benzothiazepine 1,1-dioxide hydrochloride hemihydrate; (+-)-trans-3-(ethoxyethyl)-3-ethyl-2,3,4,5-tetrahydro-5-phen yl-1,4- benzothiazepine 1,1-dioxide hydrochloride; (+-)-trans-ethyl 3-(3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4,-benzothiazepin-3 - yl)propionate l,l-dioxide; (+-)-trans-(E)-4-(3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-be nzothiazepin-3-yl)-3- buten-2-one l,l-dioxide; (+-)-2,3,4,5-tetrahydro-8-methoxy-5-phenylspiro(1,4-benzothi azepine-3,1- cyclohexane) dioxide; (+-)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-(4-pyridyl-1 ,4-benzothiazepine 1,1- dioxide; (+-)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-4-hydroxy-5-(4 -pyridyl)-1,4 benzothiazepine l,l-dioxide; (+-)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-(2-thienyl)- 1,4-benzothiazepine dioxide; (+-)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-(1H-pyrrol-1 -yl)-1,4- benzothiazepine 1,1-dioxide; (+-)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenylpyrido (4,3-F)-1,4- benzothiazepine l,l-dioxide; (+-)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-2H-py rrolo(3,4-F)-1,4- benzothiazepine 1.l1-dioxide 0.1 hydrate; (+-)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenylthieno (2,3-F)-1,4- benzothiazepinel,1-dioxide; (+-)-trans-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-3-(4,4,4-trif luorobutyl)-1,4- benzothiazepine, 1,1-dioxide; (+-)-trans-2,3 ,4,5-tetrahydro-3-isopropyl-3-methyl-5-phenyl- 1 ,4-benzothiazepine l,l-dioxide 0.25 H20; (+-)-trans-3-((E)-2-Butenyl-3-ethyl-2,3,4,5-tetrahydro-5-phe nyl-1,4- benzothiazepine; (+-)-Cis-2,3 ,4,5-Tetrahydro-3-isopropyl-3-methyl-5-phenyl- 1 ,4.benzothiazepine 1,1- dioxide 0.66 H20; (+-)-trans-3-(3-Ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzot hiazepin-3-yl)propanol 1,1 dioxide; (+-)-trans-3-Ethyl-5-(4-Fluorophenyl)-2,3,4,5-tetrahydro-7-m ethoxy-3-(3- methoxypropyl)- 1 ,4-benzothiazepine 1 1-dioxide hydrochloride; (+-)-2,3,4,5-Tetrahydro-7-methoxy-5-phenylspiro(1,4-benzothi azepine-3,1- cyclohexane) 1,1-dioxide; (+-).trans- 1 -(3-Ethyl-2,3 ,4,5-tetrahydro-7-methoxy-5-phenyl- 1 ,4-benzothiazepin-3- yl)-2-butanone S,S-dioxide hydrochloride; (+-)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenylnaphth o(3,2-F)-1,4- benzothiazepine 1,1-dioxide; (+-)-trans-1-(3-Ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phe nyl-1,4- benzothiazepin-3-yl)-2-butanone S,S-dioxide; (+-)-trans-3-(1-butenyl)-3-ethyl-2,3,4,5-tetrahydro-7,8-dime thoxy-5-phenyl-1,4- benzothiazepine 1,1-dioxide; (+-)-trans- 1 -(3 -Ethyl-2,3 ,4 ,5 -tetrahydro-7,8-dimethoxy-5 -phenyl-1,4- benzothiazepin-3-yl)-3-butanone S,S-dioxide; (+1)-trans-1-(3-Ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl- 1,4-benzothiazepin-3- yl)-l-butanone S,S-dioxide; (+-)-trans-1-(3-Ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phe nyl-1,4- benzothiazepin-3-yl)-1-butanone S,S-dioxide; (+-)-trans-1-(3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phe nyl-1,4- benzothiazepin-3-yl)-4,4,4-trifluoro-1-butanone S,S-dioxide; (+-)-trans- I -(3-ethyl-2,3,4,5-tetrahydro-7.,8-dimethoxy-5-phenyl- 1,4- benzothiazepin-3-yl)-3,3,4,4,4-pentafluoro-2-butanone S,S-dioxide; (+-)-trans-1-(3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phe nyl-1,4- benzothiazepin-3-yl)-4,4,4-trifluoro-2-butanone S,S-dioxide; (+-)-trans-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl -3-(4,4,4- trifluorobutyl)-1,4-benzothiazepine 1,1-dioxide; (+-)-trans-1-(3-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-7, 8-dimethoxy-5-phenyl- 1,4- benzothiazepin-3-yl)-2-butanone S,S-dioxide; (+-)-trans- 1 -(3-Ethyl-2,3,4,5-tetrahydro-7,8-diethoxy-5-phenyl- 1 ,4-benzothiazepin- 3-yl)-2-butanone S,S-dioxide; (+-)-trans-3-((3-ethyl-2,3,4,5-tetrahydro-3-(2-oxobutyl)-5-p henyl-1,4- benzothiazepin-8-yl)oxy)propanesulfonic acid 1,1-dioxide; (+-)-trans-2-((3-ethyl-2,3,4,5-tetrahydro-3-(2-oxobutyl)-5-p henyl-1,4- benzothiazepin-8-yl)oxy)ethyltrimethylammonium iodide 1,1-dioxide; 5. A compound as claimed in claim 1 of the formula (Ia): wherein 1 is a integer of from 0 to 4; n is an integer of from 0 to 2; R is an atom or group selected from halogen, cyano, nitro, alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, aralkyl, alkaryl, -COR11, -CO2R11, -CONR1 1R12, -CH2OR11, -NR11R12, -NHCOR11, -NHSO2R11, -SR11, -SO2R11, -SO3R11 wherein R11 and R12 are independently selected from hydrogen, C1-6 alkyl and phenyl, wherein said alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, aralyl and alkaryl groups are optionally substituted by one or more atoms or groups selected from halogen, nitro, nitrile. alkyl, alkoxy, -COR11, -CO2R11, -SO3R11 wherein R11 is as hereinbefore defined and -NR14Rl5 wherein R14 and R15 are as hereinbefore defined; R1 and R3 are independently selected from hydrogen and C1-6 6 alkyl: R2 is an atom or group selected from hydrogen, C1 6 alkyl (including cycloalkyl and <BR> <BR> <BR> cycloalkylalkyl), C1 4 alkoxy, pyrryl, thienyl, pyridyl, 1,3-benzodioxolo, phenyl and naphthyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, cyano, nitro, carboxyl, phenyl, phenoxy, benzyloxy, -COR11, -CO2R11, -CONR11R12, -CH2OR11, -NR11R12, -NHCOR11, -NHSO2R11, -SR11, -SO2R11, -SO3R11 (wherein R11 and R12 are independently selected from hydrogen, C1-6 alkyl an dphenyl), -O(CH2) NR11R12, -O(CH2) N+R1 1R12R13 and -O(CH2) SO3R11 (wherein p is an integer of from 1 to 4, R1 IPand R12 are as hereinbefore defined and R13 is hydrogen or C1-6 alkyl); R4 is a group independently selected from C1-6 alkyl (including cycloalkyl and cycloalkylalkyl), C2 6 alkenyl and C2 6 alkynyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, C1-4 alkoxy, -CO2R14, -NR14R15, -So3R14 (wherein R14 and R15 are independently selected from hydrogen and C1 6 alkyl) and R16COR17 where R16 is a C1-4 alkylene group and R17 is a C14 alkyl group; R5 is a group independently selected from C2 6 alkyl (including cycloalkyl and cycloalkylalkyl), C2 6 alkenyl and C2 6 alkynyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, C1-4 alkoxy, -Co2R14, -NR14R15, -S03R14 (wherein R14 and R15 are independently selected from hydrogen and C1 6 alkyl) and -R16COR17 where R16 is a C1-4 alkylene group and R17 is'a C1 4 alkyl group; or R4 and R5, together with the carbon atom to which they are attached, form a C3 7 spiro cycloalkyl group which is optionally substituted by one or more atoms or groups independently selected from halogen, C1-6 alkoxy, -C02R14, -So3R14 and -NR14R15 (where R14 and R15 are as hereinbefore defined; R6 and R7 are independently selected from hydrogen and C1-6 alkyl; and X is an aromatic or non-aromatic monocyclic or bicyclic ring system having from 5 to 10 0 carbon atoms (including the two carbon atoms forming part of the thiazepine ring) wherein optionally one or more of the carbon atoms is/are replaced by heteroatom(s) independently selected from nitrogen, oxygen and sulphur; with the proviso that when 1 is an integer of from 0 to 4, R1 = R3 = R6 = R7 = H, R2 = unsubstituted phenyl or phenyl substituted by one or more atoms or groups independently selected from halogen, nitro, phenylalkoxy, C1-4 alkoxy, C1-6 alkyl and -O(CH2) SO3R11 wherein p and R1 1 are as hereinbefore defined, wherein said phenylalkoxy, alkoxy and allcyl groups are optionally substituted by one or more halogen atoms, and X is a fused phenyl ring, then R4 is other than a C1 6 straight alkyl group and R5 is other than a C2-5 straight alkyl group; and salts, solvates and physiologically functional derivatives thereof.

6. A compound of formula (I): wherein 1 is an integer of from 0 to 4; n is an integer of from 0 to 2; R is an atom or group selected from halogen, cyano, nitro, alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, aralkyl, alkaryl, -O(CH2)PSO3R11, -O(CH2)pNR11 R12, -O(CH2)PN+R11R12R14, -CORI 1, -C02R1 1, -CONR11R12, -CH2OR11, -NR11R12, -NHCOR11, -NHSO2R11, -SR11, -SO2R11, -S02NRI 1R12, -SO;RII wherein p is an integer of from 1 to 4, R11 and R12 are independently selected from hydrogen, C1 6 alkyl and phenyl, and R14 is hydrogen or C1-6 alkyl, or R is group -OCH2O- which forms a further ring attached to X, wherein said alkyl alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, aralkyl and alkaryl groups are optionally substituted by one or more atoms or groups selected from halogen, nitro, nitrile, alkyl, alkoxy, -COR11, -CO2R11, -S03R11 wherein R11 is as hereinbefore defined and -NR14R15 wherein R14 is as hereinbefore defined and R15 is hydrogen or C1-6 alkyl; R1 is hydrogen or C1-6 alkyl; R2 is an atom or group selected from hydrogen, C1 6 alkyl (including cycloalkyl and cycloalkylalkyl), C1-4 alkoxy, pyrryl, thienyl, pyridyl, 1,3-benzodioxolo, phenyl and naphthyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, cyano, nitro, carboxyl, phenyl, phenoxv, benzyloxy, -COR11, -CO2R11, -CONR11R12, -CH2OR11, -NR11R12, -NHCORI 1, -NHSO2R11, -SR1 1, -SO2R11 -SO3R11 (wherein R11 and R12 are as hereinbefore defined), .O(CH2)pNR1 1R12, .O(CH2)pN+Rl 1R12R13 and -O(CH2)PSO3R1 1 (wherein p, R1 I and R12 are as hereinbefore defined and R13 is hydrogen or C1 6 alkyl); R3 is hydrogen, OH, C1 6 alkyl, C1-6 alkoxy or -OC1-6 acyl; R4 is a group independently selected from C1-6 alkyl (including cycloalkyl and cycloalkylalkyl), C2 6 alkenyl and C2 6 alkynyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, oxo, C1-4 alkoxy, -CO2R14, -NR14R15, -SR14, -S(O)C1-6 alkyl, -S02R14, -S03R14 (wherein R14 and R15 are as hereinbefore described); R5 is a group independently selected from C2 6 alkyl (including cycloalkyl and cycloalkylalkyl), C2 6 alkenyl, and C2 6 alkynyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, oxo, C1 4 alkoxy, -C02R14, -NR14R15, -SRI4, -S(O)C1.6 alkyl, -So2R14 -SO3R14 (wherein R14 and R15 are as hereinbefore defined); or R4 and R5, together with the carbon atom to which they are attached, form a C3 7 spiro cycloalkyl group which is optionally substituted by one or more atoms or groups independently selected from halogen, C1 6 alkoxy, -C02R14, -So3R14 and -NR14R15 (where R14 and R15 are as hereinbefore defined; R6 and R7 are independently selected from hydrogen and C1-6 alkyl; and X is an aromatic or non-aromatic monocvclic or bicyclic ring system having from 5 to 10 carbon atoms (including the two carbon atoms forming part of the thiazepine ring) wherein optionally one or more of the carbon atoms is/are replaced by heteroatom(s) independently selected from nitrogen, oxygen and sulphur; with the proviso that when 1 is an integer of from 0 to 4, R1 = R6 = R7 = H, R3 = H or OH, R2 = unsubstituted phenyl or phenyl substituted by one or more atoms or groups independently selected from halogen, nitro, phenylalkoxy, C1-4 alkoxy, C1 6 alkyl and -O(CH2)PSO3R11 wherein p and R1 1 are as hereinbefore defined, wherein said phenylalkoxy, alkoxy and alkyl groups are optionally substituted by one or more halogen atoms, and X is a fused phenyl ring, then R4 is other than a C1-6 straight alkyl group and R5 is other than a C2.5 straight alkyl group, and salts, solvates and physiologically functional derivatives thereof for use in therapy, 4) 3-Ethyl-3-methyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiaze pine, mp 124-125°C; 5) (+)-3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazep ine 1,1- dioxide, mp 100-1020C; 6) 3-Butyl-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1,4-benzothiaze pine 1,1-dioxide, mp 103-104°C; 7) 3-Methyl-3-propyl-2,3,4,5-tetraphydro-5-phenyl-1,4-benzothia zepine 1,1- dioxide, mp 120-1210C; 8) 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine 1,1-dixodie, mp 115-116°C; 9) (+)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-be nzo- thiazepine 1,l-dioxide, mp 1010C; 10) (+)-Trans-2,3,4,5-Tetrahydro-3-methyl-5-phenyl-3-propyl-1,4- . benzothiazepine 1,1-dioxide, mp 129-1300C; 11) (-)-3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazep ine 1,1-dioxide, mp 101-103°C; 12) 3-Ethyl-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1,4-benzothiaze pine, mp 110-112°C; 13) 3-Ethyl-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1,4-benzothiaze pie hydrochloride 0.25H20, mp 162-1640C (eff.); 14) 3-Ethyl-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1,4-benzothiaze pine 1.1-dioxide, mp 128-1290C; 15) 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine hydrochloride, mp 211-2140C; 16) (+-)-2,3,4,5-Tetrahydro-3-methyl-5-phenyl-3-propyl-1,4-benzo thia- zepine, mp 101-103°C; 17) 2,3,4,5-Tetrahydro-3-methyl-5-phenyl-3-propyl-1,4-benzothiaz e- pine, mp 72-740C; 18) 3-Ethyl-2,3,4,5-tetrahydro-5-phenyl-3-propyl-1,4-benzothiaze pine hydrochloride 0.25H20, mp 205-2070C; 19) 3-Ethyl-2,3,4,5-tetrahydro-5-phenyl-3-propyl-1,4-benzothiaze pine l,l-dioxide 0.25H20, mp 115-118°C; 20) 2,3,4,5-Tetrahydro-5-phenyl-3,3-dipropyl-1,4-benzothiazepine hydrochloride, 209-2110C; 21) 3-Ethyl-2,3,4,5-tetrahydro-5-phenyl-3-propyl-1,4-benzothiaze pine l,l-dioxide hydrochloride 0.33H20, 206-2090C; 22) 2,3,4,5-Tetrahydrox-5-phenyl-3,3-propyl-1,4-benzothiazepine 1,1-dioxide, mp 104-1060C; 23) 3,3-Dibutyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine hydrochloride, mp 209-2120C; 24) 3-Butyl-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1,4-benzothiaze pine hydrochloride, mp 203-2050C; 25) 3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazep ine hydrochloride, mp 205-2070C; 26) 3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazep ine l,l-dioxide hydrochloride. mp 209-2120C; 27) 2,3,4,5-Tetrahydro-3-methyl-3-pentyl-5-phenyl-1,4-benzothiaz epine maleate, mp 182-183°C; 28) 3-Ethyl-2,3,4,5-tetrahydro-5-phenyl-3-propyl-1,4-benzothiaze pine hydrochloride, mp 198-200°C; 29) (+-)-Cis-3-Butyl-3-ethy6l-2,3,4,5-tetrahydro-7-methyl-5-phen yl- 1,4.benzothiazepine l,l-dioxide, mp 138-1400C; 30) (+-)-Cis-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phen yl- 1,4-benzothiazepine, light yellow oil; 31) (+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-ph enyl- 1,4-benzothiazepine, light yellow oil; 32) (+-)-Cis-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phen yl- 1,4-benzothiazepine l,l-dioxide, mp 113-115°C; 33) (+-)-Cis-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phen yl- 1,4-benzothiazepine 1-oxide, mp 103-105°C; 34) (+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-ph enyl- 1,4-benzothiazepine l,l-dioxide hydrochloride, mp 199-20l0C; 35) (+-)-Trans-3-Butyl-3-ethyl-5-phenyl-2,3,4,5-tetrahydro-1,4- benzothiazepine 1-oxide, mp 98-101°C; 36) (+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrhydro-5-phenyl-1,4- benzothiazepine l-oxide, mp 133-136°C; 37) (+-)-cis-7-Chloro-3-butyl-3-ethyl-2,3,4,5-tetrahvdro-5-pheny l- 1,4-benzothiazepine 0.4 toluene, light yellow oil; 38) (+-)-Trans-7-Chloro-3-butyl-3-ethyl-1,2,3,4,5-tetrahydro-5-p henyl- l,4.benzothiazepine 0.3 toluene, light yellow oil: 39) (+-)-Trans-3-Butyl-7-Chloro-3-ethyl-2,3,4,5-tetrahydro-5-phe nyl- l.4.benzothiazepine 1.1-dioxide, mp 100-1020C; 40) (+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(4-methoxyph en- yl)-1,4-benzothiazepine l,l-dioxide hydrochloride, mp 194-1960C; 41) (+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(4-tolyl)-1, 4- benzothiazepine 1,1-dioxide hydrochloride, mp 204-2060C: 42) (+-)-Cis-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(4-tolyl)-1,4- benzothiazepine 1,1-dioxide, mp 155-156C; 43) (+-)-Cis-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(4-methoxyphen yl)- 1,4.benzothiazepine, mp 75-770C; <BR> <BR> <BR> <BR> <BR> 44) (+- ) .Cis-3-Butyl-3-ethyl-2 .3,4.5- tetrahydro-5- (4-methoxyphenyl) - 1,4-benzothiazepine 1,1-dioxide, mp 109-1110C; 45) (+-)-Cis-3-Butyl-3-ethyl-5-(4-fluorophenyl)-2,3,4,5-tetrahyd ro- l,4-benzothiazepine, mp 76-780C; 46) (+-)-Trans-3-Butyl-5-(3,4-dichlorophenyl)-3-ethyl-2,3,4,5-te tra- hydro-1,4-benzothiazepine, mp 98-100°C; 47) (+-)-Trans-3-Butyl-5-(4-chlorophenyl)-3-ethyl-2,3,4,5-tetrah ydro- 1,4-benzothiazepine 1,1-dioxide hydrochloride 0.3 H2O. mp 178-180°C; 48) (+-)-Cis-3-Butyl-5-(4-chlorophenyl)-5-ethyl-2,3,4,5-tetrahyd ro- 1,4.benzothiazepine l,l-dioxide hydrochloride. mp 186-1880C; 49) Trans-3-Butyl-3-ethyl-2,3,4,5-terahydro-5-(3-nitrophenyl)-1, 4- benzothiazepine 1,1-dioxide, mp 139-142°C; 50) Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(4-nitrophenyl)-1 ,4- benzothiazepine l,l-dioxide, mp 139-142°C; 51) (+-)-Trans-5-(4-Benzyloxyphenyl)-3-butyl-3-ethyl-2,3,4,5- tetrahydro-1,4-benzothiazepine l,l-dioxide, mp 94-950C; 52) (+-)-Cis-5-(4-Benzyloxyphenyl)-3-butyl-3-ethyl-2,3,4,5-tetra - hydro-1,4-benzothiazepine 1,1-dioxide, mp 137-1380C; 53) (+-)-Trans-5-(4-Benzyloxyphenyl)-3-butyl-3-ethyl-2,3,4,5-tet ra- hydro-1,4-benzothiazepine, mp 97-98°C; 54) (+--Trans-3-[4-(3-Butyl-3-ethyl-2,3,4,5-tetrahydro-1,4-benzo - thiazepin-5-yl)phenoxylpropanesulphonic acid 1,l-dioxide, mp 2700C (dec.); 55) (+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(2-fluorophe nyl)- 1,4-benzothiazepine l.l-dioxide hydrochloride, mp 194-1960C; 56) (+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(3-fluorophe nyl)- 1,4-benzothiazepine l,l-dioxide, mp 143-1450C; 57) (+-)-Cis-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(4-pyridyl)-1, 4- benzothiazepine 1,1-dioxide, mp 121-1230C; 58) (+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(4-pyridyl)- 1,4- benzothiazepine 1,1-dioxide, mp 110-11l0C; 59) (+-)-Cis-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(4-trifluorome thyl- phenyl)-1,4-benzothiazepine l,l-dioxide, mp 64-650C; 60) (+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(3-trifluoro - methylphenyl)-1,4-benzothiazepine 1,1,-dioxide, mp 110-112°C; 61) (+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(3,4-difluor o- phenyl)-1,4-benzothiazepine 1.1-dioxide. mp 205-2150C; 62) (+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(2,4-difluor o- phenyl)-1.4-benzothiazepine 1,1-dioxide. mp 97-990C; 63) (+-)-Trans-30isopentyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1 ,4- benzothiazepine 1,1-dioxide, mp 86-87°C; and 64) (+-)-Cis-3-isopentyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4 - benzothiazepine 1,1-dioxide, mp 123-1250C.

(-)-(RR)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5- phenyl-1,4-benzothiazepine 1,1-dioxide hydrochloride 2) (+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-henyl-1,4-be nzo- thiazepine 1,1-dixoide, mp 98-1000C; 3) (-)-Trans-3-Methyl-3-propyl-2,3,4,5-terahydro-5-phenyl-1,4- benzothiazepine l.l-dioxide, mp 129-1300C; 1. A compound of formula (I) wherein 1 is an integer of from 0 to 4; m is an integer of from 0 to 5; n is an integer of from 0 to 2; R and R' are atoms or groups independently selected from halogen, nitro, phenylalkoxy, C1-4 alkoxy, C1-6 alkyl and -O(CH2) S03R" wherein p is an integer of from 1 to 4 and R" is hydrogen or C16 alkyl, wherein said phenylalkoxy, alkoxy and alkyl groups are optionally substituted by one or more halogen atoms; R4 is a C1-6 straight alkyl group; and R5 is a C 2-6 straight alkyl group; and salts, solvates and physiologically functional derivatives thereof .

2. A compound of formula (I) as claimed in Claim 1, wherein n is 2; R4 is methyl. ethyl, n-propyl. or n-butyl; and R5 is ethyl, n-propyl, or n-butyl; and salts, solvates and physiologically functional derivatives thereof.

3. A compound of formula (I) as claimed in Claim 2. which compound is in the trans configuration as herein defined, or a salt. solvate, or physiologically functional derivative thereof.

4. A compound of formula (I) as claimed in Claim 3, which compound is trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzo- thiazepine l,l-dioxide, or a salt, solvate, or physiologically functional derivative thereof.

5. The compound of formula (I) claimed in Claim 4, which compound is in the (RR)-, (SS)-, or (RP.SS)-form. or is a salt, solvate. or physiologically functional derivative of any thereof.

6. (-)-(RR)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-ben zo- thiazepine l,l-dioxide or a salt, solvate, or physiologically functional derivative thereof.

7. (-)-(RR)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-ben zo- tbiaepine 1,1-dioxide 8. (+-)- (RR.SS)-3-Butyl-3-ethyl-2 .3.4.5-tetrahydro-5-phenyl.1,4. benzothiazepine 1,l-dioxide or a salt. solvate. or phvsioloeicallv functional thereof.

9. (+-)-(RR,SS)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4 - benzothiazepine 1,l-dioxide 1. A polymeric or oligomeric bile acid, prepared by polymerization of a monomeric bile acid of the formula G-X-A (I) in which G is a free bile acid or its alkali metal salt or a bile acid having rings A, B, C, D esterified on ring D and which is bonded via its ring A, B or C, to the group x.

X is a bridge group and A is a polymerizable, ethylenically unsaturated group, or by copolymerization with a monomer containing a polymerizable, ethylenically unsatu- rated double bond, or by copolyrnerization with N-vinylpyrrolidone or its derivatives, and/or by copolymerization with ethylenically unsat- urated dicarboxylic anhydrides and ethylenically unsaturated dicarboxylic acids each having 2 to 6 carbon atoms; their esters or half esters, esters being understood as alkyl esters having 1-6 carbon atoms, cycloalkyl esters having 5 to 8 carbon atoms, benzyl esters or phenyl esters.

2. A polymer or oligomer as claimed in claim 1, wherein G is a free bile acid or its alkali metal salt or a bile acid esteritied on ring D and which is bonded via its ring A, B or C, to the group X, to which the for- mula II applies (Y)o-(Z)p (II) in which Y is adjacent to G and is -0-, -N'R'-, is (C1-C12)-alkylene or (C7-C13)-aralkylene, where individual methylene groups in the alkylene chain of the alkylene or aralkylene radical can be re- placed by one or more groups selected from -O-, -NR'-, o and p independently of one another are zero or 1, where o and p are not simultaneously zero, A is an ethylenically unsaturated group of the for- mula in which R1 is hydrogen or CH3 and R2is , -NR'- or a single bond, where the carbonyl groups are adjacent to the c-c double bond, R' and R" independently of one another are hydro gen or (C1-C6)alkyl.

3. A polymer or oligomer as claimed in claim 2, wherein G corresponds to the formula III

in which R3 to R8 independently of one another are hydrogen, OH, NH20r an OH group protected by an OH protective group and one of the radicals R3 to R6 is a bond to the group X, where this bond starts from the positions 3 (R3 or R4) or 7 (R5 or R6), and the other position 7 or 3 in each case carries an OH group or a protected OH group, B is -OH, -O-alkali metal, -O-alkaline earth metal, -O-(C1-C12)-alkyl, -O-allyl or -O-ben- zyl where alkyl is either n-alkyl or iso-alkyl and where the ester group formed is an ester which can be saponified both by acid and by base, Y is -0-, -NR'-, Z is (Cl-C12)-alkylene, (C7-C13)-aralkylene, where 1 to 3 methylene groups in the alkylene chain are replaced by the groups -O-, -NR', and o and p independently of one another are zero or I, where o and p are not simultaneously zero A is where Rl is hydrogen or CH3 and R2 is or or a single bond, in which R' and R" indepen- dently of one another are hydrogen or (Cl-C6)-alkyl.

4. The polymeric or oligomeric bile acid of claim 1, wherein said monomer containing a polmerizable, eth- ylenically unsaturated double bond is a monomer of formula IV in which R9 is hydrogen or methyl and Rio is -CN, -O-R15, hydrogen halogen -SO3H, or -O-(CH2-CH2O)nR16, in which R11 is hydrogen, (C1-C10)-alkyl, (C1-C10)-monohy- droxyalkyl or-(CH2CH2-O-)nR16, r12, R13, R15, and R16 are identical or different and are (CiCio)-alkyl, R14 is (Ci-Cit).alkyl and n is 1 to 50.

5. A polymer or oligomer as claimed in claim 1, wherein the weight-average molecular weight is up 250,000 g/mol.

6. A polymer or oligomer as claimed in c]aim 1, wherein in the case of copolymers the molar ratio of bile acid units to copolymerized monomer units is be- tween 300:1 and 1:300.

7. A polymer or oligomer as claimed in claim 1, wherein the crosslinking is carried out by means of copolymerization with ethylenically polyunsaturated monomers.

8. A polymer or oligomer as claimed in claim 7, wherein the crosslinking is carried out with ethyleni- cally polyunsaturated acrylic acid and methacrylic acid derivatives.

9. A polymer or oligomer as claimed in claim 7, wherein the crosslinking is carried out with acid amides of the formula V

in which R9 is hydrogen or methyl and D is-(CHE)m-, where m is I to 10 and E is hydrogen or OH.

10. A pharmaceutical composition comprising a com- pound of claim 1 and a pharmaceutically acceptable carrier.

11. The polymer or oligomer as claimed in claim 5, wherein the weight-average molecular weight is be- tween 2,000 and 100,000 g/mol.

12. The polymer or oligomer as claimed in claim 12, wherein the weight-average molecular weight is be. tween 3.000 and 60,000 g/mol.

13. The polymer or oligomer as claimed in claim 3, wherein B is -OH, -O-alkali metal, -OHC1-C6)- alkyl, -0-allyl or -O-benzyl.

14. The polymer or oligomer as claimed in claim 3, wherein R3 to R6 independently of one another are hydrogen, OH, NH2 or an OH group protected by an OH protective group and one of the radicals R3 to R6 is a bond to the group X, where this bond starts from the positoons 3 (R3 or R4) or 7 (R5 or R6) in the -position. and the other position 7 or 3 in each case carries an OH group or a protected OH group.

15. The polymer or oligomer as claimed in claim 2, wherein G is a free bile acid or its alkali metal salt or a bile acid estenied on ring D which is bonded via its ring A to the group X.

16. A polymer or oligomer as claimed in claim 4, wherein the monomers are compounds according to the formula IV (meth)acrylic acid, (meth)acrylic acid es- ters, acrylamide and its derivatives, carboxylic acid vinyl esters having 3-20 carbon atoms or N-vinylpyr. rolidone and its derivatives.

17. The polymeric or oligomeric bile acid of claim 4, wherein said halogen is chlorine, bromine, or iodine EXAMPLE 1 48 g (122 mmol) of 3a,7n,l 2n-trihydroxy--nor-23- cholanic add (norcholic acid), 200 ml of formic acid and 1 ml of perchioric acid (60%) are stirred at 500 C. for 1.5 hours the mixture is cooled to room temperature, 160 ml of acetic anhydride are added and the mixture is stirred for a funher IS minutes. It is poured onto 1.5 1 of water and the solid constituents are filtered off with suction and washed with 11 of water. The residue is dissolved in 700 ml of ether and washed three times with water. The organic phase is dried (MgSO4) and concentrated. Yield 52 g (89%) of Example 1.

Ms (FAB, 3-NBA/LiCl) C26H38O8(478), 485 (M+Li+) EXAMPLE 2 5 g (10.4 mmol) of Example 1 are dissolved in 20 ml of trifluoroacetic acid/5 mll of trifluoroacetic anhydride at 0° C.

840 mg (12 mmol) of sodium nitrite are added in portions in the course of one hour. The mixture is subsequently stirred at 0° C. for a further hour then at 40° C. for 2 hours. The solution is cooled to 0°C. again, neutralized with 5N NaOH and extracted with dichloromethane, The organic phase is dried (MgSO4) and concennated Chromatography of the residue over silica gel (cyclohexane/ethyl acetate=2:1) gives 3.1 g (67%) of Example 2.

MS (FAB, 3-NBA/LiCl) C26H35NO6 (445), 452 (M+Li+) EXAMPLE 3 1.5 g (3.37 mmol) of Example 2 and 5 g of KOH are dissolved in 50 ml of ethanol/water (=1:1) and the solution is heated under reflux. When the reaction has ended (moni- toring by thin layer chromatography). the ethanol is stripped off and the residue is washed with ether. The aqueous phase is acidified with 2N HCl and extracted three times with ethyl acetate. The combined organic phases are dried (MgSO4) and concentrated. 1.25 g (97%) of Example 3 are obtained.

MS (FAB, 3-NBA/LiCl) C22H36O5(380), 387 (M+Li+) EXAMPLE 4 500 mg (12.87 mrnol) of 3α,7α,12α-trihydroxy-24-nor- 23-cholanic acid and 370 mg (36 mmol) of N-methylmor. pholine are dissolved in 20 ml lof THF. 0.34 ml (36 mmol) of ethyl chloroformate is added at 10° C. After 15 minutes, a solution of 270 mg (36 mmol) of glycine in 5 ml of IN NaOH is added dropwise. The mixture is subsequently

stirred at room temperature for 18 hours. The reaction mixture is concentrated and the residue is chromatographed over silica gel (dichloromethane/methanol- 8:2). 320 mg (56%) of Example 4 are obtained.

MS (FABJ3-NBA) C25H41NO6 (451)452 (M+H+) EXAMPLE 5 340 mg (53%) of Example 5 are obtained from 500 mg (12.67 mmol) of norcholic acid and 450 mg (836 mmol) of taurine by the process described for Example 4.

MS (FAB, 3-NBA) C25H43NO7S (501), 502 (M+H+) EXAMPLE 6 10 g (25.3 ramol) of norcholic acid are dissolved in 50 ml of pyridine. 2.6 ml of methanesulfonyl chloride are added dropwise at 0° C. The reaction mixture is then stirred at room temperature for 3 hours. It is poured onto ice-water and extracted three times with ethyl acetate. The organic phase is dried (MgSO4) and concentrated. The erode product is crystallized from diisopropyl ether, filtered off with suc- ion and then dried in vacuo. 112 g (93%) of Example 6 are obtained MS (FAB, 3-NBA/LiCl) C24H40O7S (472), 485 (M+2Li+) -H+) EXAMPLE 7 38.7 g (81.9 mmol) of Example 6 and 6.9 g (106 mmol) of sodium azide are stirred in 350 ml of dimethylformamide at 130° C. for 2.5 hours. After cooling. the mixture is poured onto 1.5 1 of ice-water and extracted three times with ethyl acetate. The organic phase is dried (MgSO4) and concen- trated. The crude product is esterifled in a methanolic hydrochloric acid solution, prepared from 100 ml of metha- nol and 14 ml of acetyl chloride, at room temperature for 2 hours. For working up, the mixture is partly concentrated and the product is poured onto 11 of water and extracted three times with ethyl acetate. After drying and concentra- tion of the organic phase. the crude product is chromato- graphed over silica gel (cyclohexanelethyl acetate=6:4). 9.0 g (25%) of Example 7 are obtained MS (FAB, 3-NBA/LiCI) C24H39N3O4 (433), 440 (M+Li+) EXAMPLE 8

8.0 g (185 mmol) of Example 7 are hydrogenated with hydrogen in 220 ml of ethyl acetate in the presence of about 50 mg of 10% Pd/C. When the reaction has ended, the catalyst is filtered off and the filtrate is concentrated. Chro- matography of the residue (methanol/triethylamine= 95:5) gives 6.0 g (80%) of Example 8.

MS (FAB, 3-NBALiCl) C24H4,NO4 (407), 414 (M+Lr) EXAMPLE 9 4.3 g (8.6 mrnol) of the mesylate (cf. EP-A-O 489 423) are heated at 100 to 110° C. in 80 ml of dry DMF with 0.42 g (8.6 mmol) of sodium cyanide for 3 hours. The mixture is poured onto ice-water and extracted with ethyl acetate, and the residue from the organic phase is filtered over silica gel.

(Ethyl acetatelheptane=2:l). 890 mg (25%) of nitrile are obtained.

MS (FAB, 3-NBA/LiCl) C26H4,NO4 (431), 438 (M+Li+) EXAMPLE 10 1.5 g (3.48 mmol) of the nitrile from Example 9 are - hydrogenated in 100 ml of methanol with addition of 10 ml of concentrated ammonia solution and 1 g of 5% strength rhodium-on-AI203 under 140 bar at 50° C. for 24 hours. The catalyst is filtered off with suction, the filtrate is concentrated and the residue is purified over silica gel (CH2Cl2/MeOH/ concentrated NH3 solution=100:15:2). 1.1 g (73%) of amine (Example 10) are obtained MS (FAB, 3-NBA/LiCl) C26H45NO4 (435), 442 (M+Li+) EXAMPLE llA 270 mg of dry zinc iodide are added to 9 g (21.4 mmol) of ketone (see equation 4) under argon in 50 ml of dry dichloromethane, and 10 ml (3.5 equivalents) of trimethyl- silyl cyanide are added in portions, while cooling with ice.

After about 15 hours, the reaction has ended. The residue which rernains after concentration is purified with n-hep- tanelethyl acetate=10:1 over silica gel. 12.1 g (85%) of the product are obtained as a colorless oil which predominantly (>9:1) comprises one stereoisomer.

MS (FAB, 3-NBA/LiCI) C35H65NO5Si3 (664), 671 (M+Li+) EXAMPLE llB 2.1 ml (27.4 mmol) of tifluoroacetic acid are first added to a suspension of 1.036 g (827.4 rnmol) of sodium boro- hydride in dry THF, the mixture is stirred for 15 minutes and 12.1 g (18.2 mmol) of the nitrile from Example llA in 40 ml of dry Ilir are then added, while cooling with ice. After 24 hours at room temperature. the mixture is worked up by addition of water and ether. the organic phase is extracted by shaking with hydrogen carbonate solution and the residue is purified by chromatography with CH2Cl2/CH3OH/concen- trated NH3 solution=100:10:1.5. 7.83 g (48%) of the amine

are obtained.

MS (FAB, 3-NBA/LiCI) C32H6,NO,Si2 (596), 603 (M+L;» EXAMPLE 12A 20 g (42 mmol) of methyl ketone (cf. equation 2) are dissolved in 400 ml of methanol, 2.48 g (64 mmol) of sodium borohydride are added and the mixture is stirred at room temperature for 45 minutes. After addition of 400 ml of water, 2N HCI is carefully added until the pH reaches 3.

The mixture is concentrated, water is added again and the mixture is extracted with EA. The organic phase is dried and concentrated, and the residue is chromatographed over silica gel (cyclohexane/ethyl acetate 1:1).

Yield: 15.1 g (75%) MS (FAB, 3-NBA/LiCl) C27H42O7 (478), 485 (M+Li+) EXAMPLE 12B' 15.1 g (31.5 mol) of alcohol (Example 12A) are dissolved in 250 ml of dichloromethane/250 ml of pyridine, 4 g (35 mmol) of methanesulfonyl chloride are added at OD C. and the mixture is stirred at room temperature for 2 tours. For working up, water is added and the mixture is extracted with ethyl acetate. After drying and concentration of the ethyl acetate phase, 17.5 g of (quaternary) mesyl compound, which can be reacted without further purification, are obtained.

MS (FAB, 3-NBA/LiCI) C28H44O9S (556). 563 (M+Li» EXAMPLE 12C 18 g (32.3 mmol) of Example 12B and 80 ml of diazabi- cycloundecene are dissolved in 400 ml of DMF, The mixture is stirred at 100° C. for 16 hours. After cooling, the reaction mixture is concentrated and the residue is chromatograhed over silica gel (cyclohexanclethyl acetate=7:3). The yield is 9.6 g (64%).

MS (FAB, 3-NBA/LiCl) C27H40O6 (460), 467 (M+Li+) EXAMPLE 12D 13 g (28.2 mmol) of Example 12C are dissolved in 100 ml of dichloromethane, 10 ml of pyridine are added and the mixture is cooled to -60° C. Ozone is passed in, while stirring, until a blue coloration is obtained The mixture is then Bushed with N2 and warmed to room temperature, and

dimethyl sulfide is added. The reaction mixture is concen- trated and the residue is chromatographed over silica gel (cyclohexanelethyl acetate=7.3). 5.8 g (44%) of aldehyde are obtained.

MS (FAB, 3-NBA/LiCl) C26H38O7 (462), 469 (M+Li+) EXAMPLE 12E The aldehyde Example 12D is oxidized to the free C-20- carboxylic acid Example 12E by Jones oxidation (J. Chem.

Soc. 1953, 2548).

MS (FAB, 3-NBA/LiCl) C26H38O8 (478), 485 (M+Li+) EXAMPLE 12F 550 mg (1.15 mmol) of Example 12E are dissolved in 20 ml of ethanol, 10 ml of 2N NaOH are added and the mixture is stirred at room temperature for 24 hours. Water is added and the organic solvents are stripped off. The pH is brought to 3 to 4 with 2N HCl. Thereafter, the mixture is concen- trated completely and the residue is chromatographed over silica gel (CHCl3/MeOH=4:1). 270 mg (67%) of product are obtained.

MS (FAB, 3-NBA/LiCl) C20H32O5 (352), 359 (M+Li+) EXAMPLE 13 2 0 g (5.01 rnmol) of 3α,7α,12α-trihydroxy-24-nor-23- cholanic acid, 2.1 g (498 mmol) of methyl amino 7α,12α-dihydroxy-24-cholanate (cf. EP-A-O 417 725), 1.36 g (10 mmol) of hydroxybenzotriazole and 1.04 g (5.4 mmol) of dicyclohexylcarbodiimide are stirred in 100 ml of dry tetrahydrofuran at room temperature for 24 hours. The reaction mixture is concentrated and the residue is chro

matographed over silica gel (chloroform/methanol=85:15).

3.0 g (75%) of Example 13 are obtained.

MS (FAB, 3-NBA/LiCl) C48H79NO8 (798), 805 (M+Li+) Examples 14 to 31 of Tables 1 to 3 are obtained analo- gously to Example 13 (reactive -X-G2 derivatives are described in EP-A-O 489 423 or EP-A-O 417 725).

TABLE 1 Ho X--G2 H I ) ao'' Er -x-02 MSAB.NflAiUO) 14 s A C*HrNOg (842). HO 849 (M+Li) ~\ 0> OMe H I ) \ o9" aH TABLE 1-continued Hox-cz us (FAB. 3-MBAniQ) , H Ex. --XX-GZ HO' w ON Ex. XG2 MS AB. 3-NBALiCI) 15 A C,2h7NOlo (886). H HO V 893 (M+Li+) nu\/O Ct: '8 - OH 16 C54H9,NO9(898), HO I 1 905 (M+Li+) 0 0^ OMe 1/ 0 1 OH 17 \< GsH79NO7 (782). 789 (M+Li» < 0 OMe H ) OH H 18 or G91iNOs (812). HO l l 819 (M+Li» Ha 0A OMe ,< HNJ OH t9 ~ A C,5H97NO95i2 (972) HO T 1 979 (M+Li+) f ,< < ' OH H TABLE 2 o x-02 HO H HO " OH H Er -X-G2 MS (FAB, 3-NBARiO) 20 A C7HnNOs (784), HO 791 Oul+Li*) t} O OMe n CsHalN09 (828). OH H 21 A C9Hs,NO9 (828), HO 1 A 835 (M+Li» < O 835 (M+u) OR H 22 A ClHu5NOlo(S72),c,1H&sN010 (872). 22 Ci. I R HNz °( + OH -HN 23 83bPNOs(es4X I'D: 89i (M+U+) 1 W OMa 24 C7H,7NO7 (768). OMe + 0) OMe ~ Ulit 775 OH H TABLE 2-continued o HO II H H HO"' H H Ex. -X-02 MS (FAD. 3-NBAniCL) 25 A 1NO, (812 H?. 819 (M+U) )Me H:HH 0 OMe OH H 26 HO, (814). '8? 821 (M+U za 0^ OMe HC 821(M+Li+) OMe OH H TABLE 3 Hox--cz HO OH H Ms XL2 MS (FAB. 3NBAhia) 27 A C,5H73NO, (756), H?. 763 (M+Li+) H\ 0> OMe H 0 OMe NNw OH TABLE 3-continued - HO zXG2 H H HO"' 'OH H Ex. -X-G2 MS O'. 3-Ns3At8CI) ul 3rj G?WNO,(BOO) 28 807(M+Li3A C7HnNob(1100), OMa 8(7 (M+U) \3 OMe ZOO 29 A C9H"NO10(844 HO 1 ; s5s (M+Li+) its O OMe H H ssi (M+tt+) OH A CsHnNO7 (740), f 747(M+1l+) c Nhq OH OH H 31 C«H5NO7 (7541 HO 761 OM+Li3 6 HNJ ' OH H 3.0 g (3.76mmol) of Example 13 are dissolved in 80 ml of ethanol, 30 mol of 1N aqueous NaOH are added and the mixture is stirred at room temperature for 16 hours. For working up. 30 ml of water are added and the alcohol is stripped off completely. After acidification with IN HCl, the precipitate is filtered off with suction, washed with water and dried in vacuo. 2.5 g (85%) of Example 32 are obtained.

MS (FAB. 3-NBA/LiCI) C47H77NO8 (784), 791 (M+Li+) Examples 33 to 50 of Tables 4 to 6 are obtained analogs gously to Example 32 from the methyl esters (Tables 1-3). TABLE 4 HO wF XG2 : .#;½O:,,::0 o H HO " ON H Er --XX-02 MS (FAB. 9-NBAIIlCI) 33 C,H,,NO, (828). 835 (M+Li*) HOOH ts °) sOH , OH H j4 C,H,NOIO (872), 879 (M+Li3 HO ft) ° ) sOH OH H 35 HO 1 OH 36 #½½0.,:ooH C5311s,1(09 ~oW' ON H OH ) O OH ~ ~ ' OH 97 C H,9NO, (.79S), 805 HD 40H OH H TABLE 4-continued HO X-02 HO X--GI I HO"' H HO " OH 38 - )½½HH1, MS 0011 c.H,NO9 (FAB. 821 3-NBANQ) 38 C,,HO, (814). 821 (M+LI*) RO OH OH OH H OH TABLE 5 o Ho X--02 H H HO"' OH H HO " OH H Er --XX-GZ MS (FAB, 3-NBAhiCI) 19 CH,NOI mo,, m (M+L)) 39 %½½½H:;.ooH dv. OH H U) CIHPNO) (814)1 821 (M+L HO OH t H if 14), 821 J OH '-INo* HO H 0 OH H OH H TABLE 5-continued 0 X-02 o L XG2 NO R HO"' "al H it". -X-02 MS OH E,. XG2 Ho --XX-02 (FAB, 865 3-NBL 41 w (858), 865 S65 tiO t) O8OH HN~ °oW OH 5 NO l l t) O > OH ~ ooh H so ctt,,NO, (754)755 aid OH. 44 )½½,,::0'al aH,,'lO. (M+LI*) 45 ms C4,H,7NO, (SOO), S07 (M+li» 45 --BDOH HN H* OH TABLE 6 H HO''rlI/h H ExP XG2 MS (FAR, 3 Ni3A/UCI) OH H 46 < C,H,,NO. -X-02 MS(FA.NBMUC) HO' OH lit OH 47 CH,,NO, C186). 793 (M+IS) 'O11 HNs ow OH 48 C,,HNO,, (830), 837 (M+Li3 48 v\s O OH 49 81 OH it.,,oH: < O OH zoo OH 50 HO I 1 w\ O^OH N H) HN w ON Examples 51 to 54 from Table 7 are obtained analogously<BR> to Example 5 from the acids described above.

TABLE 7 HO X -02 H HE"' OOH H Ex. --X-G2 MS (PAD 3-NBAhiCD 51 wl C49H,2NtO3oS (891), 892 s0,1t N )H 52 HO \e c,RMN2O,,S (935) 942 HC (V SOJI H H -HN H,,it OH H 53 HO z C,3H90N20l,5 (976). 3024 (M+H» SolH H H O 1. OH H 54 Y | c,,H£2N,O,S (875). 920 N/VSOJI H Examples 55@ to 57 of Table 8 are obtained analogously to Example 4.

TABLE 8 Ho 3Ya x-cz o HO X OH Er -XGZ MS (FAB, 3-NBARjQ) 55 CpHmNO, (B41X HO l H?. cOOH H OOH H 56 z C,1H,£N2010 (855) HO 892 CM+Li*) 0 coo 892 M+U) OOH H 57 so c,,e2o1 (929). 93a (M+Il*) < 0) s NA COOH HN~OO I ' OH Examples 58 to 63 of Table 9 are obtained analogously to Example 13.

TABLE 9 (in the following formulae, the free valency of G1 is not shown). Ex. Gl MS 58 H HO 805(M+Li*) \ o d H HO"' OH H 59 C£gHO, (711). 789 < oS H ) H WHO"' 60 a CsH79NO (782L 7Sg M+Ljt) HO"' OH H 61 v C«N"NO, (798). HO } 1 805 (M+Lit) < ov HO ' OH 62 H G7H77NO (784S HO I 11 791 (M+U+) HO OH H < w HO X' OH ABLE 9-continued ~/ OMe HO E Glw'OH H H (in the following formulu.lhe fiee (FAB. or go is not houn3), Ex Gl my 01- 63 0 CeH7sNOg (7701 I mcM+Li HO 2 3 ,9 HO' H Examples 64 to 69 of Table 10 are obtained analogously to Example 32.

TABLE 10 st~OH Who : l o ,Xp Glow OH H H (lMe fse valency of go is noî sbow3 in th: foDowing Ex, Gl my ffAD, Ex. ,a G,HnNOI 084X 64 791 C47H"NOa t10 o H H 1GhH f: HO z ' OH CIBnN07CI68X- 65 .o Q7H"N07 (768N 1 775(M+U» Gh H TABLE 10-continued oH Ho MO=t.::O H H fee flee valency of Gl is flOE 1hOWn in the MS (FAB. foSe) Ex. GI- MS AH,3A)UC) 66 z «,H77NO7 (7681 HO''C rrs (M+Li') H I } HO N OH H 67 C47H"NOt (7U1 HO 8 1 791 (M+') + o H HOH HOw OH HO OH 68 C46H7,NO (770N HO 771(M+u+) : C p HO' 69 0 GJHnNOI (75 763 763 (MtLit) T H HO ' 08 H ~~~~~~ ~ - -- The sodium salts of Example 32 and all the examples of Tables 4 to 8 and 10 can be prepared. The compound is dissolved in methanol, an equimolar amount of IN aqueous NaOH is added and the mixture is then evaporated in vacuo.

1. A bile acid derivative of the formula I G1-X-G2 wherein G, is linked via the side chain on atom No. 17 with the bonding member X to atom No. 3 of G2, and G1 is a radical of the formula II in which Z is one of the following radicals or a single bond, R(1) is H, an alkyl radical having 1 to 10 carbon atoms or an alkenyl radical having 2 to 10 carbon atoms, R(2), R(3), R(4), R(5) are independently H, OH or R(2) and R(3),or R(4) and R(5) together form the oxygen of a carbonyl group, X is a single bond or a bridge member of the formula m -- in which - A is an alkylene chain, which is branched or unbranched, and which is optionally interrupted by 4, 4, or phenylene, the linkage of the phenyl ring being in the ortho-, meta- or para-position and the chain comprising 2 to 12 chain members, B is an alkylene chain which is branched or unbranched, and which is optionally interrupted by 4, S, or phenylene, the linkage of the phenyl ring being in the ortho, meta- or para-position and the chain comprising 2 to 12 chain members,

L(l), L(2) and L(3) are identical or different and are sdecd from H, an alkyl radical or slkenyl radical having up to 10 carbon atoms, a cycloalkyl radical having 3 to 8 carbon atoms, a phenyl radical, which is unsubstituted or mono- to trisubstituted by F, Cl, Br.

(C1-C4-alkyl or (C1-C4-alkoxy, or a benzyl radical, which is unsubstitoted or mono- to trisubstituted by F, Cl, Br, (C1-C4)-alkyl or (C1-C4)-alkoxy, q is 0 to 5; r is O or 1; s is O or 1; and t is O or 1, G2 is a radical of the formula IV in which Z is one of the following radicals or a single bond, with the proviso that Z may be in only one of formulas II and IV; V is -O- or when <BR> <BR> WisHor, <BR> <BR> V is -CH2- or - -CH2-CH2- when @ W is H or OH, Y is -OL, NHL, or an amino add or amino-sulfonic acid bonded via the amino group. selected from the group consisting of -NH-CH2-COOH, -NH-CH2-CH2-, SO3H, in which L is H, an alkyl radical or alkenyl radical having up to 10 carbon atoms, a cycloalkyl radical having 3 to 8 carbon atoms, a phenyl radical, which is unsubstituted or mono- to trisubstituted by F, Cl, Br, (C1-C6)-alkyl or (C1-C4)-alkoxy, or a benzyl radical, which is unsubstituted or mono- to trisubstituted by F, Cl, Br, (C1-C4)-alkyl or (C1-C4)-alkoxy, and R(6), R(7), R(8), R(9) are independently H, OH or R(6) and R(7) or R(8) and R(9) together form the oxygen of a carbonyl group.

2. The bile acid derivative of the formula I, as claimed in claim 1, wherein L is an alkenyl radical having 2 to 10 carbon atoms.

3. The bile acid derivative of formula I, as claimed in claim 1, wherein one or more of L(l), L(2) or L(3) is an alkenyl radical having 2 to 10 carbon atoms.

Description Bile acid derivatives, processes for their preparation and the use of these compounds as medicaments The invention relates to novel bile acid derivatives, processes for their preparation, pharmaceutical prepara- tions based on these compounds and the use of the bile acid derivatives as medicaments.

Bile acids have an important physiological function in lipolysis, for example as cofactors of pancreatic lipases and as natural detergents for solubilizing fats and fat- soluble vitamins. As the end product of cholesterol metabolism, they are synthesized in the liver, stored in the gall bladder and secreted from this by contraction into the small intestine, where the display their physiological action. The greatest proportion of the bile acids secreted is recovered via the enterohepatic circu- lation. They return to the liver via the mesenterial veins of the small intestine and the portal vein system.

Both active and passive transportation processes play a role in reabsorption in the intestine. Most of the bile acids is reabsorbed at the end of the small intestine, the terminal ileum, by a specific Na+-dependent trans- portation system, and returns to the liver with the mesenterial vein blood via the portal vein, to secreted by the liver cells again into the bile. The biie acids appear in the enterohepatic circulation both as free acids and in the form of glycine conjugates and taurine conjugates.

Non-a}: sorbakle, insolubl v basic, crosslinked polymers have been used for many years or binding bile acids and utilized therapeutically on the basis of these proper- ties. Bile acid derivatives described in Patent Application EP-A-O 489 423 have a high affinity for the

intestinal bile acid transportation system and therefore allow specific inhibition of the enterohepatic circuTation. All diseases in which inhibition of bile acid resorption in the intestine, in particular in the small intestine, seems desirable are regarded as the therapeutic object. For example, the biligenic diarrhea following ileum resection or increased blood cholesterol levels are treated in this manner. In the case of increased blood cholesterol level, a reduction in this level' can be achieved by intervention in the enterohepatic circulation. The corresponding new synthesis of bile acids from cholesterol in the liver is caused by lowering the bile acid pool in the enterohepatic circulation. The LDL-cholesterol in the blood circulation is resorted to in order to meet the cholesterol requirement in the liver, the hepatic LDL receptors increasingly being used. The acceleration of LDL metabolism which has thus occurred takes effect by reducing the atherogenic cholesterol content in the blood.

The object was to discover novel medicaments which are capable of reducing the atherogenic cholesterol content in the blood or of influencing the enterohepatic circul- ation in respect of increased excretion of bile acid and consequent reduction in the cholesterol level.

This object is achieved by the bile acid derivatives according to the invention.

EP-A-O 489 423 relates to dimeric bile acid derivatives of the formula G1-X-G2 in which G1 and G2 are linked in positions 3, 7 or 12 or by the side chain via the linker X. Bile acid derivatives in which G1 is bonded to X via positions 7 or 12 and G2 is bonded to X via positions 3, 7 or 12 or the side chain

are not described in the examples of the European Patent Application cited.

The invention therefore relates to bile acid derivatives of the formula 1 G1 - X - G2 I in which G1 is a radical of the formula II in which Y has the following meaning: OKa, in which Ka is an alkali metal, alkaline earth metal or quaternary ammonium ion, -OL, -NHL, -NL2, an amino acid or aminosulfonic acid bonded via the amino group, such as, for example and (C1-C4)-alkyl esters, alkali metal and alkaline earth metal salts and quaternary ammonium salts thereof, and in which L is H, an alkyl or alkenyl radical having up to 10 carbon atoms, which is branched or unbranched, a cycloalkyl radical having 3 to 8 carbon atoms or a phenyl or benzyl radical, which are unsubstituted or mono- to trisubstituted by F, C1, Br, (C,-C)-alkyl

or (C1-C4)-alkoxy, R' is H, an alkyl or alkenyl radical having up to 10 carbon atoms, which is branched or unbranched, a cycloalkyl radical having 3 to 8 carbon atoms, a benzyl radical, a biphenylmethyl or a triphenyl- methyl radical, in which the nuclei are unsubstituted or mono- to trisubstituted by F, C1, Br, (C1-C4)-alkyl or (C1-C4)-alkoxy, or a radical in which L has the abovementioned meaning, R2 to Rs, R2 and R3 or R' and R5 in each case together being the oxygen of a carbonyl group, or indi- vidually and in each case independently of one another being in which T has the meaning of L or is a free valency for bonding the group X, and--in-which in total only one free valency starts from G1 for bonding the group X, X is a single bond or a group of the formula III in which

A and B are alkylene chains, which are branched or unbrdnched, it being possible for the chains to be optionally interrupted by -O- or -S-, L1, L' and L3 are identical or different and have the meaning of L and q is zero to 5, r is zero or 1, s is zero or 1 and t is zero or 1 and G2 is a radical of the formula IV in which Z is a free valency to the group X or has the meaning given under Y, R' is a free valency to the group X or has the meaning given under R' and R7 to R10 have the meaning given under R2 to R5, and in which in total only one free valency starts from G2 to the group X.

The compounds according to the invention have a high affinity for the specific bile acid transportation system of the small intestine and inhibit bile acid absorption in a concentration-dependent and competitlive mannerI The compounds according to the invention furthermore are not themselves absorbed and thus do not enter the blood circulation. The enterohepatic circulation can be inter- rupted very specifically and efficiently by application of this principle of action.

By using the compounds according to the invention, it is possible to reduce the amount of bile acids in the

enterohepatic circulation such that a reduction of the cholesterol level in the serum occurs. Avitaminoses are just as unlikely during their use as effects on the absorption of other medicaments or an adverse effect on the intestinal flora. Furthermore, the side-effects known of polymers (constipation, steratorrhea) are not found, i.e. lipolysis is not adversely influenced. Because of the high affinity for the specific bile acid transport- ation system of the small intestine, low daily doses are sufficient, so that acceptance of such medicaments by the doctor and patient will be very high.

Particularly preferred compounds of the formula I are those in which G1 is a radical of the formula II in which Y OH, O-(C1-C4)-Alkyl, -NHCH2COOH, - R1- is H, benzyl, biphenylmethyl, formyl or acetyl, R2 to Rs, R2 and R) or R4 and Rs in each case together being the oxygen of a carbonyl group, or indi- vidually and in each case independently of one another being in which T is H, a branched or unbranched, (C,-C,)-alkyl radical or

a free valency to bridge group X, and in which a total of one free valency starts from G1 for bonding the group X, X is a bond, -N-, H -CH2CH2NH- -CH2CH2CH2NH where n is 2 or 3, m is 1 to 4 and o is 2 or 3, and G2 is a radical of the formula IV in which Z is a free valency to- group X or has the- meaning given above under Y, is is a free valency to group X or has the meaning given above under R1 and R' to R10 have the meaning given above under R7 to R5, and in which only one free valency starts from G2 to the group X.

The invention furthermore relates to a process for the preparation of compounds of the formula I, which

comprises a) in the case where X is a single bond, reacting suitable forms of G1 and G2 with one another by processes which are known in principle, or b) in the case where X is a bridge group, reacting a) reactive forms of Gl-X with G2 or ) ) reactive forms of G2-X with G1 by processes which are known in principle, or c) preparing compounds of the formula 1 (Gl-X-G2) from Gl-Xl and X2-G2 by processes which are known or, where they are not known, by the processes described below in more detail, X being formed from X1 and X2 by formation of a covalent bcrd, in particular within a condensation or substitution reaction. a) X is a single bond The bile acids G1 are employed either in the free form or in protected form. After linking with G2, which is likewise present in a free or protected form, the protective groups are split off, if appropriate, and the C-24 carboxyl function is converted into a derivative, if appropriate. Suit- able protective groups for the alcohol groups are expediently fornyl, acetyl, tetrahydropyranyl or t-b-atyldimethylsilyl. Various alkyl or benzyl esters, and also, for example, orthoesters, are suitable protective groups for the C-24 carboxyl group.

For example, bile acid preferentially redots at position 3, but also at position 7, with activated forms of carboxylic acids, such as acid chlorides or mixed anhydrides, with addition of bases, such as trialkylamine or pyridine, but also NaOH, at room temperature in suitable solvents, such as tetra- hydrofuran, methylene chloride or ethyl acetate, but also dimethylformamide (DMF) or dimethoxyethane (DME).

The various isomers can be separated, for example by chromatography. The reaction can be carried out selectively by using suitable protective groups.

The corresponding amino-bile acids can be converted into corresponding amides analogously. Here also, the reaction can be carried out either with protec- ted or with free bile acids.

Other compounds according to the invention can be linked analogously by known standard processes. b) X is a bridge group The processes specified under a) are also used to carry out the linking of G1-X with G2 or G1 with X-G2. Here also, the bile acid portion is expediently employed either in protected or in unprotected form.

A preferred preparation process comprises reacting reactive forms of G1 with reactive forms of X-G2. If appropriate, the linking reaction is followed by splitting-off of protective groups and conversion of C-24 carboxyl into derivatives.

The preparation of reactive bile acid units G1-X and X-G2 is shown in the following equation.

R = H, formyl or acetyl, R' = H or OH, R" = formyl or acetyl

R = H, formyl or acetyl, R' - H or OH, n s 2 or 3 Compounds of the type V in which the 3-position is protected are reacted with allyl bromide/Hünig base or triethylamine. If the compound V has one OB group, the alkylation is unambiguous; if two free OH groups are present, monoalkylation takes place at positions 7 and 12 in approximately equal proportions and only traces of the dialkylated product are formed. The protective group in the 3-position can either be split off with sodium methylate or retained for further reactions. The

monoalkylated compounds VI and VII can be split with ozone or with OsO,/NaIO, to give the aldehydes VIII and IX. The 7-and 12-hydroxyethyl compounds X and XI are readily accessible from these by simple reduction, for example with Nabs4. The corresponding 7- and 12-hydroxy- propyl derivatives XII and XIII can be synthesized from the allyl compounds VI and VII by hydroboration. The aminoalkyl derivatives XIV and XV can be prepared from the hydroxyalkyl compounds of the type X to XIII by a reaction sequence which is known in principle (mesylation of the primary OH group with methanesulfonyl chloride/ pyridine, azide exchange with NaN3 in dimethylformamide, reduction of the azide function with hydrogen under catalytic conditions). Further reaction of the amino functions of these compounds with succinic anhydride gives bile acid units of the type XVI and XVII. Suitable bile acid units furthermore are described in EP-A- o 489 423.

The invention furthermore relates to the use of the compounds according to the invention for the preparation of a medicine. For this, the compounds of the formula I are dissolved or suspended in pharmacologically accept- able organic solvents, such as mono- or polyhydric alcohols, such as, for example, ethanol or glycerol, or in triacetin, oils, such as, for example, sunflower oil or cod-liver oil, ethers, such as, for example, diethyl- ene glycol dimethyl ether, or also polyethers, such as, for example, polyethylene glycol, or also in the presence of other pharmacologically acceptable polymeric carriers, such as, for example, polyvinylpyrrolidone, or other pharmaceutically acceptable additives, such as starch, cyclodextrin or polysaccharides. The compounds according to the invention furthermore can be administered in combination with other medicaments.

The compounds of the formula I are administered in various dosage forms, preferably orally in the form of tablets, capsules or liquids. The daily dose varies in

the range from 3 mg to 5000 mg, but preferably in the dose range from 10 to 1000 mg, depending on the body weight and constitution of the patient.

On the basis of their pharmacological properties, the compounds are particularly suitable as hypolipidemic agents.

The invention therefore also relates to medicaments based on the compounds of the formula (I) and to the use of the compounds as medicaments, in particular for lowering the cholesterol level.

The compounds according to the invention were tested biologically by determination of the inhibition of [3H]- taurocholate uptake in brush border membrane vesicles of the ileum in rabbits. The inhibition test was carried out as follows: 1. Preparation of brush border membrane vesicles from the ileum of rabbits The brush border membrane vesicles from the intestinal cells of the small intestine were prepared by the so-called Mg2+ precipitation method. Male New Zealand rabbits (2 to 2.5 kg body weight) were sacrificed by intravenous injection of 0.5 ml of an aqueous solution of 2.5 mg of tetracaine HCl, 100 T 61R and 25 mg of mebezonium iodide. The small intestine was removed and flushed with ice-cold physiological saline solution. The terminal 7/10 of the small intestine (measured in the oral-rectal direction, i.e. the terminal ileum which contains the active Na'-dependent bile acid transport- ation system) was used for preparation of the brush border membrane vesicles. The intestines were frozen in plastic bags under nitrogen at -800C. To prepare the membrane vesicles, the frozen intestines were thawed at 300C in a water-bath. The mucosa was scraped off and suspended in 60 ml of ice-cold 12 mM Tris/HC1 buffer (pH

7.1)/300 mM mannitol, 5 mM EGTA/10 mg/l of phenylmethyl- sulfonyl fluoride/l mg/l of trypsin inhibitor from soybeans (32 U/mg)/0.5 mg/l of trypsin inhibitor from bovine lung (193 U/mg)/5 mg/l of bacitracin. After dilution to 300 ml with ice-cold distilled water, the mixture was homogenized with an Ultraturrax (18-rod, IKA Werk Staufen, FRG) for 3 minutes at 75% of the maximum output, while cooling with ice. After addition of 3 ml of 1M MgCi2 solution (final concentration 10 mM), the mixture was left to stand at O*C for exactly 1 minute. By addition of Mg'', the cell membranes aggregate and pre- cipitate with the exception of the brush border membranes. After centrifugation at 3000 x g (5000 rpm, SS-34 rotor) for 15 minutes, the precipitate is discarded and the supernatant, which contains the brush border membranes, is centrifuged at 267000 x g (15000 rpm, SS-34 rotor) for 30 minutes. The supernatant was discarded and the precipitate was rehomogenized in 60 ml of 12 mM Tris/HCl buffer (pH 7.1)/60 mM mannitol, 5 mM EGTA using a Potter Elvejhem homogenizer (Braun, Melsungen, 900 rpm, 10 strokes). After addition of 0.1 ml of 1 M MgCl2 solution and an incubation time of 15 minutes at OOC, the mixture was centrifuged again at 3000 x g for 15 minutes.

The supernatant was then centrifuged again at 46000 x g (15000 rpm, SS-34 rotor) for 30 minutes. The precipitate was taken up in 30 ml of 10 mM Tris/Hepes buffer (pH 7.4)/300 mM mannitol and resuspended homogeneously by' 20 strokes in a Potter Elvejhem homogenizer at 1000 rpm.

After centrifugation at 48000 x g (20000 rpm, SS-34 rotor) for 30 minutes, the precipitate was taken up in 0.5 to 2 ml of Tris/Hepes buffer (pH 7.4)/280 mM mannitol (final concentration 20 mg/ml) and resuspended with the aid of a tuberculin syringe with a 27 gauge needle. The vesicles were either used for transportation studies immediately after preparation or stored in 4 mg portions in liquid nitrogen at -1960C.

2. Inhibition of Na+-dependent uptake of [3H)-tauro- cholate in the brush border membrane vesicles of the

ileum The uptake of substrates in the brush border membrane vesicles described above was determined by means of the so-called membrane filtration technique. 10 pl of the vesicle suspension (100 µg of protein) were pipetted as drops onto the wall of a polystyrene incubation tube (11 x 70 mm) which contained the incubation medium with the corresponding ligands (90 p1 ) . The incubation medium contained 0.75 µl - 0.75 pci [3H(G))-taurocholate (specific activity: 2.1 Ci/mmol)/0.5 µl of 10 mM tauro- cholate/8.75 p1 of sodium transportation buffer (10 mM Tris/Hepes (pH 7.4)/100 mM mannitol/100 mM NaCl) (Na-T-P) or 8.75 pl of potassium transportation buffer (10 mM Tris/Hepes (pH 7.4)/100 mM mannitol/100 mM KCl) (K-T-P) and 80 p1 of the inhibitor solution in question as a solution in Na-T buffer or K-T buffer, depending on the experiment. The incubation medium was filtered through a polyvinylidene fluoride membrane filter (SYHV LO 4NS, 0.45 pm, 4 mm #, Millipore, Eschborn, FRG). The transpor- tion measurement was started by mixing the vesicles with the incubation medium. The concentration of taurocholate in the incubation batch was 50 pM. After the desired incubation time (usually 1 minute), the transportation was stopped by addition of 1 ml of ice-cold stopping solution (10 mM Tris/Hepes (pH 7.4)/150 mM KC1).

The mixture formed was immediately filtered off with suction over a membrane filter of cellulose nitrate (ME 25, 0.45 pm, 25-mm-diameter, Schleicher & Schuell, Dassell, FRG) under a vacuum of 25 to 35 mbar. The filter was rinsed with 5 ml of ice-cold stopping solution.

To measure the uptake of radioactively labeled tauro- cholate, the membrane filter was dissolved with 4 ml of the scintillator Quickszint 361 (Zinssr Analytik GmbB, Frankfurt, FRG) and the radioactivity was measured by liquid scintillation measurement in a TriCarb 2500 measuring instrument (Canberra Packard GmbH, Frankfurt,

FRG). After calibration of the instrument with the aid of standard samples and after correction for any chemi- Iminescence present, the values measured were obtained as dpm (decompositions per minute).

The control values were determined in each case in Na-T-P and K-T-P. The difference between the uptake in Na-T-P and K-T-P gave the Na+-dependent transportation content.

The concentration of inhibitor at which the Na+-dependent transportation content was inhibited by 50% - based on the control - was designated the IC,O Na+.

The pharmacological data include a test series in which the interaction of the compounds according to the inven- tion with the intestinal bile acid transportation system in the terminal small intestine was investigated. The results are summarized in Table 11.

Examples 1 and 2 150 g (0.32 mol) of methyl 3-acetyl-cholate, 500 ml of dimethylformamide, 125 ml of N-ethyl-diisopropylamine and 70 ml of allyl bromide are heated under reflux for 16 hours. New allyl bromide (25 ml) is added every 2 hours.

The reaction solution is evaporated on a rotary evapora- tor. The residue is partitioned between water/methylene chloride and the organic phase is separated off and dried with magnesium sulfate. After column chromatography (ethyl acetate/cyclohexane 1:2, silica0 gel 70-200 pom), the product fractions are evaporated on a rotary evaporator.

Yield = 92.2 g of 7-/12-allyl mixture.

C30H48O6 (504), MS 511 (M + Li+) The mixture was separated by fractional crystallization with n-heptane.

Example 3 50 g (0.1 mol) of Example 1, 250 ml of diethyl ether and 250 ml of water are initially introduced into the reac- tion vessel, while stirring vigorously. 503 mg (0.002 mol) of osmium tetroxide are added. The mixture is stirred at room temperature for 15 minutes. 53 g (0.25 mol) of sodium periodate are added in portions over the course of 1 hour, and the mixture is subsequently stirred for 8 hours, while stirring vigorously. The ether phase is separated off, dried with magnesium sulfate and evaporated on a rotary evaporator.

Yield: 47 g of crude C2gE4607 (506), MS 513 (M + Li+) Example 3 is further reacted without additional purifica- tion.

Example 4 4.2 g (0.11 mol) of sodium borohydride are added in portions to 47 g (0.093 mol)@ of Example 3 and 250 ml of

methanol at OOC. After 2 hours at OOC, the reaction solution is poured onto saturated ammonium chloride solution, the mixture is extracted 3 times with ethyl acetate and the combined organic phases are dried with magnesium sulfate and evaporated on a rotary evaporator.

After column chromatography (ethyl acetate/cyclohexane 1.5:1, silica gel 35 - 70 pm), the product fractions are evaporated on a rotary evaporator and the residue is crystallized with diisopropyl ether. Yield: 25 g of C29134,O, (508), MS 515 (M + Li+) Example 5 10 g (0.02 mol) of Example 1 and 250 ml of tetrahydro- furan were initially introduced into a reaction vessel at room temperature, and 40 ml (0.04 mol) of borane-tetra- hydrofuran complex (1 molar) were added dropwise at room temperature. The mixture was subsequently stirred at room temperature for 2 hours, and 25 ml of water, 25 ml of 2 N sodium hydroxide solution and 25 ml of 35% strength hydrogen peroxide solution were added dropwise in succession. The mixture was subsequently stirred at room temperature for a further 15 minutes. The reaction solution was poured onto water, the mixture was extracted 3 times with diethyl ether and the combined organic phases were dried with magnesium sulfate and evaporated on a rotary evaporator.

Yield: 8.5 g of C30HsoOz (522), MS 529, (M + Li+) Example 5 was further reacted without additional purifi- cation.

Example 6 10 g (0.02 mol) of Example 4 and 100 ml of pyridine are initially introduced into a reaction vessel at OOC.

1.7 ml (0.022 mol) of methanesulfonyl chloride are added dropwise at OOC and the mixture is subsequently stirred at OOC for a further JO minutes and at room temperature for 2 hours. The reaction solution is poured onto water, the mixture is extracted 3 times with ethyl acetate, and the combined organic phases are dried with magnesium sulfate and evaporated on a rotary evaporator. The residue is dissolved in 100 ml of dimethylformamide, 1.4 g (0.022 mol) of sodium azide are added and the mixture is stirred at 800C for 2 hours. The reaction solution is poured onto water and the mixture is worked up as described above. The residue is dissolved in 100 ml of methanol1 100 mg of palladium-on-charcoal (10%) are added and hydrogenation is carried out under normal pressure for 2 hours. The catalyst is filtered off and the filtrate is evaporated on a rotary evaporator. After column chromatography (ethyl acetate/ MeOH/Et3N 10:1:1, silica gel 70-200 pm), Example 6 is obtained.

Yield = 7.3 g of C"H,sNOs (507), MS 514- (M + Li+) Example 7

98.6 mg (0.001 mol) of succinic anhydride are added to 500 mg ("0.001 mol) of amino compound, 20 ml of tetra- hydrofuran and 4 ml of triethylamine at room temperature.

The mixture is subsequently stirred at room temperature for 1 hour. The reaction solution is poured onto 25% strength sodium dihydrogen phosphate solution, the mixture is extracted 3 times with ethyl acetate and the organic phase is dried with magnesium sulfate and evaporated on a rotary evaporator.

Yield: 580 mg of C33H,3NO, (607), MS 614 (M + Li+) Example 7 was further reacted without additional purifi- cation.

Examples 8 to 12 were prepared analogously to Examples 3 to 7.

Examples 8-12 Example R11 MS 8 -CH,CHO 513 (M + Li+) 9 -CH2CH2OH 515 (M + Li+) 10 -CH2CH2CH2OH 529 (M + Li+) 11 -CH2CH2NH2 514 (M + Li+) 12 -CH,CH,NHCOCH2CH2COOH 614 (M + Li+)

Example 13 H-? - 0/ ou. -6 w - H + cholic acid f^w Hz NH2 M H OH 300 mg (0.73 mmol) of cholic acid, 330 mg (0.78 mmol) of methyl 7 -amino-3a, 12a-dihydroxy-5-cholanate (Redel, Bull. Soc. Chim. Fr., page 877, 1949), 240 mg (0.97 mmol) of EEDQ and 0.25 ml of diisopropylethylamine are stirred in 20 ml of DMF at 900C for 4 hours. After cooling, the reaction mixture is concentrated and the residue is chromatographed over silica gel (CH2Cl2/MeOH 8.2). C49H91NO8 (812) 819 (M + Li+). The two bile acid derivatives can also be linked with triethylamine in methylene chloride or with dicyclohexylcarbodiimide, hydroxybenzotriazole or triethylamine in tetrahydrofuran.

The compounds of Table 1 were prepared analogously to Example 13.

Table 1

Example R12 R13 R14 MS (FAB, 3-NBA/Licl) 14 α-OH H -OH C49H81NO7 (796) 803 (M + Li+) 15 -OH H -OH C49H81NO7 (796) 803 (M + Li+) 16 H H -OCHO C50H81NO7 (808.5) 809.S (M+H+) The examples of Table 2 were obtained analogously to Example 13 from Examples 7 and 8.

Table 2 Example X3 R15 MS (FAB, 3-NBA/LiCl) 17 -NH- H $C53H87NO10 (898) 905 (M + Li+) 18 -NH- diphenylmethyl C66H97NO10 (0164) 1071 (M = Li+) 19 -NHCO(CH2)2CONH(CH2)NB- H C6H99N2O12 (1054) 1061 (M + LI+) 20 -NHC(202)2CNH(CH2)3NH- diphenylmethyl C73H109N3O12 (1220) 1227 (M + Li+)

The examples of Tables 3 and 4 were likewise obtained analogously to Example 13.

Table 3 - I 1 Example R'6 MS (FAB, 3-NEA/LiC1) 21 V C"E,ooN,O" (1097) 1104 (M+L+) AeD"" ) 22 0 H,,N,O,, (1055) 1104 (N+t+) 22 | zo < | C,oH9eN03 (1055) 1104 (M+L+) HO '1 H -Nv%0

Table 4 - - - Example R17 MS (FAB, 3-NSA/LiCl) 23 ol C53H87N°zo (898) 905 (M+L+) Hb l HO" Ho''E H1H c/'o H 24 o H o C,,B,,,rJ,0,,(1097) 1104 (M+L+) MNO L0U( N W 1 o

Example 26 250 mg (0.31 mmol) of Example 13 are dissolved in 20 ml of ethanol, 2 ml of 1N NaOH solution are added and the mixture is stirred at room temperature for 16 hours. For working up, the mixture is concentrated, the residue is dissolved in H,O, the pH is brought to 1-2 with 2N HCl and the mixture is concentrated again. The residue is chromatographed over silica gel (CHCl3/MeOH 8:2). 220 mg of free acid are obtained (90%).

MS (FAB, 3-NBAJLiCl) C48H79NO@ (798) 805 (M + Li+) The examples of Tables 5 to 8 are obtained analogously to Example 26.

Table 5

Example R12 R13 MS 27 α-OH H C48H79NO7 (782) 789 (M+Li+) 28 -OH H C48H79NO7 (782) 789 (M+Li+) 29 H H C48H79NO7 (766) 773 (M+Li+) Table 6 Example x3 R15 MS 30 -NH- H C50H85NO10 (860) 867 (M + Li+) 31 -NH= diphenylmethyl C63H95NO10 (1026) 1033 (M + Li+) 32 -NHCO(CH2)2CONH(CH2)3NH H C57H97N3O12 (1016) 1023 (M + Li+) 33 -NHCO(CH2)2CONH(CH2)3NH- diphenylmethyl C70H107N3O12 (1182) 1189 (M + Li+) Table 7 I I Example Rl' MS 34 0 C"H,2N201,(985) 992 (M+Li') HO 35 M° OH CssH9sN20lz ( 985 ) 992 (M+Li+) 1H N- 1 Z O H

Table 8 1 I 1 Example Rl7 MS (FAB, 3-NBA/LiC1) 36 C50H23N0, (842) 849 (M+Li+) HO fii H ' U j. H 37 0 wN~ O or C,,B,,NIO,, "H"N,O" (985) 992 (N+Li') 0 0 H Hz HO"' H 38 0 side C"H"N,0,2 (985) 992 (M+Li+) oWPomX o w The following glycine con3ugates and taurine conjugates were obtained analogously to synthesis processes which have already been described (EP 489 423).

Table 9 Example R12 R13 MS (FAB, 3-NBA/LiCl 39 α-OH α-OH C50H84N2O10S (905) 918 (M + 2Li+-B+) 40 α-OH H C50H84N2O9S (889) 890 (M + H+) 41 -OH H C50H84N2O9S (889) 912 (M + Na+) 42 H H C50H84N2O6S (872.5) 895.5 (M + Na+) Table 10 Example X3 R15 MS 43 -NH- H C52H90N2O12S (967) 974 (M + Li+) 44 -NH- diphenylmethyl C65H100N2O12 (1133) 1140 (M + Li+) 45 -NHCO(CH2)2CONH(CH2)3NH- H C55H102N4O14B (1123) 1130 (M + Li+) 46 -NHCO(CH2)2CNH(CH2)2NH- diphenylmethyl C72H102N4O14S (1989) 1296 (M + Li+)

Example 47 MS (FAB, 3-NBA/LiCl) C60H101N3O14S (1092) 1099 (M + Li+) Example 48 MS (FAB, 3-NBA/LiCl) C72H110N4O13 (1239) 1246 (M + Li+) Table 11 shows measurement values for the inhibition of the uptake of [3H]-taurocholate in brush border membrane vesicles from the ileum of rabbits. The quotients of the IC50 and IC50 Na values of the reference substance tauro- chenodeoxycholate (TCDC) and of the particular test substance are stated.

Table 11 Compound IC50-TCDC]µmol] IC50n@-TCDC[µmol] form Example IC50-substance[µmol] IC50Na-substance [µmol] 20 0.00 0.12 26 0.00 0.29 270.64 0.44 28 0.54 0.43 29 0.23 0.17 30 0.93 0.85 32 1.00 0.80 39 0.92 1.05 40 0.54 0.52 43 1.18 0.96 47 0.35 0.26 48 0.75 0.71

1. A bile acid derivative of the formula I G1 - X - G2 I in which G1 is a radical of the formula II in which Y has the following meaning: OKa, in which Ka is an alkali metal, alkaline earth metal or quaternary ammonium ion, -OL, -NHL, -NL2, an amino acid or aminosulfonic acid bonded via the amino group, such as, for example and (C1-C,)-alkyl esters, alkali metal and alkaline earth metal salts and quaternary ammonium salts thereof, and in which L is H, an alkyl or alkenyl radical having up to 10 carbon atoms, which is branched or unbranched, a cycloalkyl radical having 3 to 8 carbon atoms or a phenyl or benzyl radical, which are unsubsti- tuted or mono- to trisubstituted by F, C1, Br, (C1-C4)-alkyl or (C1-C4)-alkoxy is is H, an alkyl or alkenyl radical having up to 10 carbon atoms, which is branched or unbranched, a cycloalkyl radical having 3 to 8 carbon atoms, a

benzyl radical, a biphenylmethyl or a triphenyl- methyl radical, in which the nuclei are unsubstituted or mono-to trisubstituted by F, C1, Br, (Cl-C,)-alkyl or (C1-C4)-alkoxy, or a radical in which L has the abovementioned meaning, R2 to R5, R' and R3 or R' and R5 in each case together being the oxygen of a carbonyl group, or indi- vidually and in each case independently of one another being in which T has the meaning of L or is a free valency for bonding the group X, and in which in total only one free valency starts from G1 for bonding the group X, X is a single bond or a group of the formula III in which A and B are alkylene chains, which are branched or unbranched, it being possible for the chains to be optionally interrupted by -O- or -S-, L', L2 and L3 are identical or different and

have the meaning of L and q is zero to 5, r is zero or 1, 8 i8 zero or 1 and t is zero or 1 and G2 is a radical of the formula IV in which Z is a free valency to the group X or has the meaning given under Y, R' is a free valency to the group X or has the meaning given under R1 and Rz to R10 have the meaning given under R' to R5, and in which in total only one free valency starts from G2 to the group X.

2. A bile acid derivative of the formula I as claimed in claim 1, in which G1 is a radical of the formula II

in which y is OH, O-(C1-C4)-Alkyl, -NHCH2COOH, R' is H, benzyl, biphenylmethyl, formyl or acetyl, R2 to R5, R2 and R3 or R' and R5 in each case together being the oxygen of a carbonyl group, or individually and in each case independently of one another being in which T is H, a branched or unbranched (C1-C4)-lkyl radical or a free valency to bridge group X, and in which a total of one free valency starts from G1 for bonding the group X, X is a bond, -N-, H <BR> <BR> <BR> -CH2CH2NH- <BR> <BR> <BR> <BR> <BR> <BR> <BR> -CH2CH2CH2NH- where n is 2 or 3, m is 1 to 4 and o is 2 or 3, and G2 is a radical of the formula IV

in which Z is a free valency to group X or has the meaning given above under Y, R' i8 a free valency to group X or has the meaning given above under R1 and R7 to R10 have the meaning given above under R' to R5, and in which only one free valency starts from G2 to the group X.

3. Process for the preparation of a bile acid deriva- tive of the formula I as claimed in claim 1, which comprises a) in the case where X is a single bond, reacting suitable forms of G1 and G2 with one another by processes which are known in principle, or b) in the case where X is a bridge group, reacting a) reactive forms of G1-X with G2 or p ) reactive forms of G2-X with G1 by processes which are known in principle, or c) preparing compounds of the formula I (G1-X-G2) from G1-X1 and X2-G2 by processes which are known or, where they are not known, by the processes described below in more detail, X being formed from X1 and X2 by formation of a covalent bond, in particular within a condensa- tion or substitution reaction.

4. A medicament comprising a bile acid derivative as claimed in claim 1.

5. A hypolipidemic agent comprising a bile acid MONOMERIC BILE ACID DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND THE USE OF THESE COMPOUNDS AS MEDICAMENTS Bile acids are synthesized in the liver from cholesterol in scvcral enzymatic steps. They are stored in the gall bladder, from which they are secreted with the bile into the small intcstinc. Thcy fulfill imporant physiological functions there during the digestion process, for example as cofactors or pancrcatic lipases and as natural detergents for absorption of fats and fat-solublc vitamins. The greatest proportion of bilc acids rcturns to the liver from the small intestine via the ponal vein blood by active and passive transponation pro- cesses.

Polymers which bind bile acids have been employed as therapeutics for a relatively long time. They are used for diseases where inhibition of the absorption of bile acid is desirablc. In cases of an increased blood cholesterol level, increased synthesis of bile acids from cholesterol can be induced in the liver by redudng the amount of bile acids in the cntcrohcpatic circulation. This leads to an increased LDL cholesterol uptake from the blood into the liver and an accelerated LDL catabolism. The effect achieved is a reduc- tion in the atherogenic LDL cholesterol in the blood.

The polymers used as medicaments for this purpose, for example cholestyramine or colestipol, must be administered in very high daily doses of 12 to 30 g. In addition to the high dosage, the taste and smell make acceptance by patient and doctor more difficult The polymers mentioned display sideeffects because their sclectivity is too low and their binding of vitamins is too high, and because of interactions with drugs adminis- tered at the same time. Furthermore they can modify the composition of bile acid in the bile. These properties mani- fest themselves in various gatrointestinal disturbances (for example constipation, steatorthea), avitaminoses and an increased risk of cholelithiasis.

Surprisingly, novel monomeric bile acid derivatives have now been found which can interrupt the enterohepatic circulation of bile acids and do not have the disadvantages mentioned.

The invention therefore relates to monomeric bile acid derivatives of the formula I z-x-cs 1. in which GS is a bile add radical having an add function in the side chain or a salt thereof, X is a covalent bond or a bridge group of the formula (CH2)n, where n=1 to 10, in which the alkylene chain can contain 1 to 3 oxygen atoms, NH or

groups, and in which GS is bonded via X as desired, and Z is HO-. O(-O-, HO-O2-CH=CH-CH,-. where R is in each case c8-C7 alkyl, or H2-N-(CH2)6-, where the alkyl moiety is optionally substituted by a C00H group, where A is in each case OH or NH(C,-C10)alkyl.

Preferred compounds of the formula 1 are those in which GS is linked to X in the 3-position. linking taking place in the a- or -position.

An acid function is understood as meaning, in particular, the COOH group or the sulfonic acid group.

Alkyl radicals are straight-chain or branched.

The compounds of the formula (I) according to the invention have a high affinity for the specific bile acid transportation system of the small intestine and inhibit bile acid absorption in a concentration-dependent and competi- tive manner.

By competitive inhibition, intervention in the enterohe- patic circulation can be considerably more selective. Avita- .minoses are not to be expected, and a qualitative change in the bile acid composition in the bile is just as unlikely. A controlled reduction in the serum cholesterol level can be achieved with compounds according to the invention, with- out the known side effects being observed. Because of their high affinity for the bile acid transportation system, very much lowcr daily doses than with the commercially avail- able polymers are sufficient; this also Icads to a high acceptance by patient and doctor; The compounds have valuable pharmacological proper- ties and are therefore particularly suitable as hypolipidemic agents.

The invention thus also relates to medicaments based on the compounds of the formula n) and to the use of the compounds as medicaments, in particular for reducing the cholesterol level, The compounds according to the invention were tested biologically by determination of the inhibition of [3H] taurocholate uptake in the brush border membrane vesicles

from the ileum of rabbits. The inhibition test was carried out as follows: 1. Preparation of brush border membrane vesicles from the ileum of rabbits Brush border membrane vesicles were prepared from the intestinal cells of the small intestine by the so-called Mg2 precipitation method. Male New Zealand rabbits (2 to 25 kg body weight) were sacrifice by intravenous injection of 0.5 ml of an aqueous solution of 2.5 mg of tetracaine HCI, 100 T 61R @ and 25 mg of mcbczonium iodide. The small intestine was removed and rinsed with ice-cold physiological saline solution. The terminal 7/10 of the small inlestine (measured in the oral-rectal direction. i.e. the terminal ileum, which contains the active Na -dependent bile acid transportation system) was used for preparation of the brush border mem- brtane vesicle. The intestines were frozen in plastic bags under nitrogen at -80" C. For preparation of the membrane vesicles, the frozen intestines were thawed at 300 C. in a water bath. The mucosa was scraped off and suspended in 60 ml of ice-cold 12 mM Tris/HCl buffer (pH 7.1)t300 mM mannitol, 5 mM EGTA/IO mgll of phenylmethylsulfonyl fluoroiel mg/l of trypsin inhibitor from soybeans (32 U/mg)/O.S mg/l of uypsin inhibitor from bovine lung (193 Ulmg)/5 mgll of bacitractin. After dilution to 300 ml with ice-cold distilled water, the mixture was homogenized with an Ultraturrax (18-rod, IKA Werk Staufen, FRG) for 3 minutes at 75 of the maximum output, while cooling with ice. After addition of 3 ml of 1M MgC12 solution (final concentration 10 mM), the mixture was left to stand at 0° C. for exactly 1 minute. The cell membranes aggregate by addition of Mg2+ and precipitate, with the exception of the brush border membranes. After centrifugation at 3000x g (5000 rpm, SS-34 rotor) for 15 minutes, the precipitate was discarded, and the supcmatant, which contained thc brush bordcr membrancs, was ccntrifugcd at 267000x g (15000 rpm, SS-34 rotor) for 30 minutcs. The supematant was discarded and the prccipiuite was rchomogcnized in 60 ml of 12 mM Tris/HCl buffer (pH 7.1)/60 mM mannitol, 5 mM EGTA using a Potter Elvejhem homogenizer (Braun, Mel- sungcn, 900 rpm, 10 storkes). After addition of 0.1 ml of 1 M MgCl2 solution and an incubation time of 15 minutes at 0" C., thc mixture was centrifuged again at 3000x g for 15 minutcs. Thc supernatant was then centrifuged again at 46000x g (15000 rpm, SS-34 rotor) for 30 minutes. The precipitate was taken up in 30 ml of 10 mM Tris/Hepes buffer (pH 7.4)1300 mM mannitol and resuspended homo- geneously by 20 strokes in a Potter Elvejhem homogenizer at 1000 rpm. After centrifugation at 48000x g (20000 rpm, SS-34 rotor) for 30 minutes, the precipitate was taken up in 0.5 to 2 ml of Tris/Hepes buffer (pH 7.4)/280 mM mannitol (final conccntration 20 mg/ml) and resupended with the aid of a tuberculin syringe with a 27 gauge needle. The vesicles were either used immediately for transportation studies after preparation, or stored at -196° C. in portions of 4 mg in liquid niuogen.

2. Inhibition of Na+-dependent [3H]-taurocholate uptake in the brush border membrane vesicles of the leum The uptake of substrates into the brush border membrane vesicles described above was determined by means of the so-called membrane filtration technique. 10 µl of the vesicle suspension (100 pg of protein) were pipetted as drops onto the wall of a polystyrene incubation tube (11 x70 mm) which contained the incubation medium with the corresponding ligands (90 lii). The incubation medium contained 0.75 µ=0.75 µCi of [3H](G)]-taurocholate (specific activity: 2.1 Ci/mmol)/0.5 pi of 10 mM taurocholate18.75 µl of sodium transportation buffer (10 mM TrislHepes (pH 7A)I100 mM mannitol/100 mM NaCI) Na-T-P) or 8.75 ul of potas- sium transportation buffer (10 mM TrislHepes (pH 7.4)1100 mM mannitol/100 mM KCI) (K-T-P) and 80 ul of the inhibitor solution in question, dissolved in Na-T buffer or K-T buffer, depcnding on the experiment The incubation medium was filtered through a polyvinylidene fluoride membrane filter (SYHV LO 4NS, 0.45 llm, 4 mm #. Milli- pore, Eschborn. FRG). The transportation measurement was started by mixing the vesicles with the incubation medium.

The concentration of taurocholate in the incubation batch was 50 gM. After the desired incubation time (usually 1 minute), the transportation was stopped by addition of 1 ml of ice-cold stopping solution (10 mM Trislllepes (pH 7.4)/ 150 mmM KCl).

The mixture formed was immediately filtered off with suction over a membrane filter of cellulose nitrate (ME 25, 0.45 µm, 25 mm diameter, Schleicher & Schuell, Dassell, FRG) under a vacuum of 25 to 35 mbar. The filter was rinsed with 5 ml of ice cold stopping solution.

To measure the uptake of the radioactively labeled tau- rocholate, the membrane filter was dissolved with 4 ml of the scintillator Quickszint 361 (Zinsser Analytik GmbH, Frankfurt, FRG) and the radioactivity was measured by liquid scintillation measurement in a TriCarb 2500 measur- ing instrument (Canberra Packard GmbH, Frankfurt, FRG). <BR> <P>After calibration of the instrument with the aid of standard samples and after correction for any chemitumincscence

present the values measured were obtained as dpm (decom- positions per minute).

The control values were in each case determined in Na-T-P and K-T-P. The difference between the uptake in Na-T-P and K-T-P was the Na+-dependent trans- portion content The concentration of inhibitor at which the Na+-dependent transportation content was inhibited by 50%-based on the control-was designated as the IC50Na+.

The table shows the measurement values of the inhibition of the 13H]-taurocholate uptake in brush border membrane vesicles from the ileum of rabbits. The quotients of the IC, and ICsoN values of the taurochenodesoxycholate CCDC) investigated as the standard in each vesicle preparation and the particular substance are stated.

Subsuance IC50(TCDC) IC50N/@ (TCDC) from Example: IC50 (Substance) IC50N/s(Substance) 3 0.4 0.35 4 0.77 0.69 18 0.47 0.42 21 0.34 0.33 33 033 035 35 1.0 1.02 36 0.19 0.20 38 0.49 0.41 40 0.52 0.50 43 0.78 0.37 The invention furthermore relates to the use of the com- pounds according to the invention for tbe preparation of a medicine.

For this, the compounds of the formula I are dissolved or suspended in pharmacologically acceptable organic sol- vents, such as mono- or polyhydric alcohols, such as, for example, ethanol or glycerol, or in triacetin, oils, for example sunflower oil or cod-liver oli. ethers. such as. for example, methylene glycol dimethyl ether, or also poly- ethers, for example polyethylene glycol, or also in the presence of other pharmacologically acceptable polymeric carriers, such as, for example, polyvinylpyrrolidone, or other pharmaceutically acceptable additives, such as starch, cyclo- dextrin or polysaccharides. The compounds according to the invention furthermore can be administered in combination with other medicaments.

The compounds of the formula I are administered in various dosage forms, preferably orally in the form of tablets, capsules or liquids. The daily dose varies in the range from 3 mg to 5000 mg, but preferably in the dose range of 10 to 1000 mg, depending on the body weight and constitution of the patient The particular monoisotopic molecular weights calculated are stated in the following examples.

Unless stated otherwise, mass spectra were recorded by the FAB technique with addition of LiCI and 3-nitrobenzal- dehyde[3-NBA].

Starting compounds which have the bile acid structure have already been described in some cases (cf., for example, EP-A-O 417 725, EP-A-O 489 423 and EP-A-O 548 793.

Rl is defined in Example 6.

EXAMPLE 1 I g (1.96 mmol) of the methyl ester a is dissolved in 15 m of tetrahydrofuran (THF) or 1,4-dioxane and the solution i stirred intensively with 10 ml of 2N NaOH overnight a room temperature. It is then diluted with a large quantity of water and acidified with half-concenuated hydrochloric acid, while cooling with ice. Precipitation is brought t@ completion by subsequent stirring for I hour, while cooling with ice, and the precipitate formed is filtered off wit'c suction and rinsed with cold water. Recrystallization from ethanol/water and drying in vacuo give 940 mg (96%) of Example 1.

C29H50O6494) MS: 501 (M+Li+).

The following Examples 2 to 7 are prepared analogously to "Example 1" from the corresponding bile acid esters: Example as "Example 1" Empirical No. where n = formula MW MS <BR> <BR> 2 6 C30H52O6 508 515 (M + Li+)<BR> 3 8 C22H56O6 536 543 (M + Li+)<BR> <BR> 4 9 C33H58O6 550 557 (M + Li+)<BR> 5 10 C34H60O6 564 571 (M + Li+) EXAMPLE 6 EXAMPLE 7

EXAMPLE 8 100 mg (0.2 mmol) of the methyl ester are dissolved in 10 ml of dioxide and the solution is stirred with 3 ml of half-concentrated sodium hydroxide solution at room tem- pcraturc for 6 hours. The mixture is diluted with water and acidified with half-concenuated hydrochloric acid to give, after filtration with suction and washing, the acid "Example 8" (50 mg, 51%).

C29H47NO5(489) MS: 496 (M+Li+) The followin substance examples were prepared as for "Example 8": EXAMPLE 9 EXAMPLE 10 EXAMPLE 11

EXAMPLE 12 EXAMPLE 13 EXAMPLE 14 EXAMPLE 15 EXAMPLE 16 continued 0.84 ml of triethylamine is added to 3.14 g (6 mmol) of the primary alcohol a (n =6) in 100 ml of dry methylene chloride and the mixture is cooled to -10° C. 0.4 mi (6 mmol) of chlorosulfonic acid in 20 ml of dry methylene chloride is added to the solution at this temperature. After I hour at OD C. and 1 hour at room temperature, water is added, the organic phase is separatcd off, the aqueous phase is extracted several times with ethyl acetate and the combined organic phases arc dried and concentrated. The residue is purified by chromatography (SiO2, ethyl acctate/methanol=3:1). 1.45 g (40%) of "Example 16" are obtained.

C3,H5409S (602) MS: 61 (M-H++Li++Na-) 615 (M-H+ 2Li+) EXAMPLE 17 Compound hom Example 16 0.5 g (0.83 mmol) of "Example 16" is stirred in 20 ml of dioxane with 7 ml of half-concentrated sodium hydroxide solution at room temperature for 6 hours. The mixture is then acidified with half-concentrated hydrochloric acid, while cooling, and is concentrated in vacua. The residue is purified by column filtration (SiO2. ethyl acetate/methanol=3:1). 254 mg (52%) of "Example 17" are obtained.

C3H2:C9S (610) MS=6l7 (M+Li+) 601 (M-Na++2Li+) EXAMPLE 18 15 ml of phosphoric acid diphenyl ester chloride are added. dropwise to a solution of 2.6 g (5.12 mmol) of "Example 2" in 20 mi of pyridine at o to 5D C. and the mixture is subsequently stirred at room temperature for 2 hours. It is poured onto 200 ml of ice-water, about 15 ml of concen- trated sulfuric acid are added, while stirring and cooling, and the mixture is extracted several times with ethyl acetate. The organic phase is dried and concentrated and the residue is purified by chromatography (SiO2, CH2C12CH3CH= 10:1).

1.78 g (47%) of "Example 18" arc obtained.

C42H",09P (740) MS: 747 (M+Li+~

EXAMPLE 19 I g (1.35 mmol) of "Example 18" is hydrogenated in 50 ml of glacial acetic acid with a spatula-tip of platinum-on- charcoal in a shaking vessel. When the reaction has ended (about 4 hours), the catalyst is filtered off with suction and the filtrate is concentrated. The residue is purified by column filtration (SiO2, ethyl acetate/CH3OH=2:1). 270 mg (34%) of "Example 19" arc obtained.

C30H53O9P (588) MS: 601 (M-H +2Li+) 595 (M+Li EXAMPLE 20 2.24 g (4 mmol) of amine h and 324 mg (4 mmol) of potassium cyanate are suspended in 60 ml of water and the suspension is heated to boiling point. A solution is formed, from which a solid precipitates after a shon time. The mixture is stirred at boiling point for 30 minutes and cooled, about 40 ml of water are added and the mixture is acidified with dilute hydrochloric acid. It is extracted several times with ethyl acetate, the organic phase is dried and concen- trated in vacuo and the residue is purified by chromatogra- phy (SiO2, EtOAc/CH3OH=10:1). 520 mg (23%) of "Example 20" are obtained.

C32H36N2O6 (564 ) MS: 571 (M+Ltn EXAMPLE 21 450 mg (O.mmol) of "Example 20" are stirred in 10 ml of dioxane with 5 ml of half-concentrated sodium hydroxide solution at room temperature for 6 hours. When the reaction has ended, the mixture is diluted with water, acidified with hydrochloric acid and subsequently stirred in an ice-bath for 1 hour. The precipitate is filtered off with suction and rinsed with water to give, after drying in vacuo, 430 mg (97%) of "Example 21".

C3lH5.N206 (550) MS: 557 (M+Li+) EXAMPLE 22 raphy (SiO2, CH2Cl2/CH3OH=10: 1). 1.2 g (43%) of 2 mmol of phenyl isocyanate in 5 ml of methylene chloride are added to 1.04 g (2 mmol) of amine b (Example 20) in 50 ml of dry methylene chloride and 28 ml of triethylamine at 0° C. The mixture is subsequently stirred at room tempera. lure for 6 hours and worked up as described under "Example 16", the aqueous phase being acidified. After column filtra- tion (CH2ClCH3OH=10:1), 6540 mg (51%) of "Example 22" are obtained.

C38H60N2O6 (640) MS: 647 (M+Li+) EXAMPLE 23 C3,H,8N206 MS: 633 (M+Li') EXAMPLE 24

"Example 24" are obtained.

C34H62INO5(691)MS (FAB, 3-NBA): 564-(M-I#) EXAMPLE 25 <BR> <BR> <BR> (H3C3)3)#-(CH2)6-R'<BR> <BR> CI# Compound Example 25 is prepared from Example 24 analo- gously to "Example 21". The crude product is purified by medium pressure chromatography over RP-8 silica gel (CH3OH/H2O=7:3).

C33H60CINO5(585)MS(FAB, 3-NBA): 550 (M-Cl#) EXAMPLE 26 2.08 g (4 mmol) of amine b. 10 ml of trissobutylamine and 5 ml of indomethane are heated at boiling point in 50 ml of acetonitrile for 2 hours. All the volatile constituents are removed in vacuo and the residue is purified by chromatog-

1.04 g (2 mmol) of amino b and 276 mg (2 mmol) of pyrazolc c are hcated under reflux in 40 ml of dry acetoni- trile for 10 hours. Aftcr cooling and addition of ether, a prccipitatc is formed, and is filtered off with suction and rinsed with dry ether. After drying, 450 mg of "Example 26" are obtained C32H28BrN3O5 (643) MS: 570 (M-HBr+Li+) 564 (M-Bre) EXAMPLE 27 is prepared analogously to "Example 21".

C3,H,oCIN30, (585) MS: 556 9M-HCl+Li+) 550 (M-Cle) EXAMPLE 28

EXAMPLE 29 is prepared analogously to "Example 21". The aqueous phase is decanted off from the oily crude product after acidification, and the residue is extracted by stirring with ethyl acetate and then filtered off with suction and dried.

C44H82CiNO5 (740) MS: 711 (M-HCl+Li+) 705 (M-Cl#) EXAMPLE 30 1.0 g (1.9 mmol) of amine b, 265 mg of NaBH3CN and 610 mg of heptanal are stirred in 10 ml of dry methanol at room temperature for 48 hours. The mixture is concentrated in vacuo, the residue is partitioned between ethyl acetate and

saturated bicarbonate solution and the residue of the organic phase is purified by chromatography. In addition to a small amount of monoheptylamino derivative. 650 mg (49%) of "Example 28" are obtained.

C4,H83NO, (718) MS: 725 (M+Li+)

is prepared analogously to "Example 28" and "Example 29" by reduce amination of anthracene-9-carbaldehyde with methyl 3α-(aminoethyl)-7α, 12α-dihydroxy-24-cholanate (d) and subsequent alkaline hydrolysis.

C14H35NO4 (625) MS: 632 (M+Li+) EXAMPLE 31 is prepared ana]ogously to "Example 30" using cyclodode- canonc as the carbonyl component C,8H,,7NO4 (602) MS: 609 (M+Li+) EXAMPLE 32

0.38 g (2 mmol) of naphthoyl chloride in 5 ml of CH2CI2 is added to 0.9 g (2 mmol) of amine d and 0.6 ml of triethy. lamine in 20 ml of dry CH2Cl2, while cooling with ice. The mixture is subsequently stirred at 0° C. for 1 hour and left to stand overnight. Water is added, and the mixture is acidified and extracted several times with CH2CI2. The residuc from the organic phase is purified by chromatogra- phy (SiO2, EtOAc/cyclohexane=3:1). 1 g (83%) of "Example 32" is obtained.

C38H53NO5 (603) MS: 610 (M+Li+) EXAMPLE 33

is prepared analogously to "Example 21".

C3,H3sNO5 (589 ) MS: 596 (M+Li+)

EXAMPLE 34 is prepared analogously to "Example 32" and "Example 33" using anthiacome-90earbonyl chloride.

C@@H33NO5 (639) MS: 645 (M+Li+) EXAMPLE 35 is prepared analogously to "Example 34" using p-toluene- snlfonyl chlorids and smise b.

C37H39No7S(66) MS: 668 (M+Li@) EXAMPLE 36 is prepared analogously to "Example 35". The methyl ester obusincd as an intemediate produat is methylasted in dim- othylformanide, after depretonmaion by soditm hydride, with iodomsthane at room tamperaure. The produr is then uibjected to alkaine bydrolyts malogodudy to "Example 35".

C36H33NO7S(675) MS: 688 (M-H-+2Li+) 682 (M+Li-)

EXAMPLE 37 is prepared analogously to "Example 34" using o-phihalic anhydrie and s@@@e b.

C38H37NO@(655)MS: 688(M-H-+2Li+)662 M+Li-) EXAMPLE 38 is propared analogously to "Example 32" /Example 33" using arrioue b.

C41H39NO6(661) MS: 668(M+Li-) EXAMPLE 39 426 mg (1 mmol) of urcthanc and 782 mg (15 mmol) of aminc b arc healed under reflux in 50 ml of dioxane for 4 hours. Thc mixture is then concentrated and the residue is purified by chromatograpy (SiO2, CH2Cl2/CH3OH=10:1).

540 g (59%) of "Example 39" are obtain C48H70CIN3O10S(915) MS: 922 (M+Li+) EXAMPLE 40

is prcparcd analogously to "Example 21".

C47H68CIN3O10S (901) MS (electrospray): 902 (M+H+) EXAMPLE 41

750 mg (3.6 mmol) of dicyclohexylcaibodiimide are added to a solution of 1.56 g (3 mmol) of amine b, 576 mg (3 mmol) of China acid and 490 mg (83.6 mmol) of hydroxy. benzotriazole in 100 ml of THE The mixture is stirred at room temperature for 40 hours. The urea formed is filtered off, the solution is concentrated and the residue is taken up in ethyl acetate. The solution is washed with saturated NaHCO3 solution, 2N citric acid. saturated NaHCO3 solu- tion and water. The residue from the organic phase is purified by chromatography (SiO2, ethyl acetateICH3OH= 5:1). 1.2 g (58%) of "Example 41" are obtained.

C38H65NO10 (695) MS: 702 (M+Li+) EXAMPLE 42 is prepared analogously to "Example 21".

C37H63NOzo (681) MS (FAB, 3-NBA): 682 (M+H+)

EXAMPLE 43 is prepared analogously to "Example 41"/"Example 4Z' using gluconic acij C36H63NO11(685) MS: 714 (M-H++Li++Na+) EXAMPLE 44 1.04 g (4 mmdl) of aid chloride e, 2.1 g (4 mmol) of amine b and a spatula-tip of 4-dimethylaminopyridinc art stirred in 40 ml of dry pyridine at room temperature for 6 hours. After standing ovemight at room temperature, the mixture is conccntrated in vacuo. "Example 44" is isolated after puri- fication by chromatogrphy (SiO2, CH2Cl2/CH3OH=20:1).

C43HagNO9 (743) MS: 750 (M+Li+) EXAMPLE 45 is prepared analogously to "Example 21".

C42H6?NO9 (729) MS: 742 (M-H++2Li» 736 (M+Li+) EXAMPLE 46

EXAMPLE 47 is prepared analogously to "Example 21".

C42H69NO10(727)MS: 760 (M-H++2Li+) 74 ((M+Li+) 2.6 g (5 mmol) of amine bin CH2CI2 are added to 1.3 g (5 mmol) of acid chloride e and 0.8 ml of triethylamine in 50 ml of dry CH2Cl2, while cooling with ice, and the mixture is stirred at 0° C. for 1 hour. An excess of methanol is then added, the mixture is allowed to come to room temperatare, water is added and the mixture is acidified with dilute hydrochloric acid. The aqueous phase is extracted several times by shaking with CH2CI2. After purification of the residue from the organic phase by chromatography (SiO2, CH2Cl2/CH3OH=10:1). "Example 46' is obtained, C44H73NO10 (775) MS: 783 (M+Li+)

EXAMPLE 48 3.14 g (6 mmol) of alcohol a (n=6) are heated at lOOC C. with 3 ml of cthyldiisopropylamihe and 1.5 g of diphenylmethyl bromide in 50 ml of DMF for 8 hours. After aqueous working up and purification by chromatography (SiO2, CHzClz/CH3OH=10:1). "Example 48" is obtained.

C44H64O6 (688) MS: 695 (M+Li+) EXAMPLE 49 is prepared analogously to "Example 21".

C43H62O6 (674) MS: 681 (M+Li» The following compounds are prepared analogously to Example 1 from the corresponding bile acid esters by alkaline ester hydrolysis: EXAMPLE 50

C28H46O6 MW: 478 MS: 485 (M+Li+)

EXAMPLE 51 C28H46O5 MW: 462 MS: 469 (M+Li+) hour, and the precipitate formed is filtered off with suction.

15 After drying, 154 mg of "Example 54" are obtained.

EXAMPLE 52 C48H82N2O9 (831) MS: 838 (M+Li» C30H53NO44 MW: 491 MS: 498 (M+H+) EXAMPLE 53

EXAMPLE 55 is prepared from Example 44 and n-hexylamine analogously to Example 41 with a reaction time of 25 hours.

C,9H82N2O8 (827) MS: 834 (M+Li+) EXAMPLE 54 170 mg of "Example 53" are dissolved in 5 ml of dioxane, 1.5 ml of half-concentrated sodium hydroxide and 25 ml of water are added, and the mixulre is stirred at room tempera- ture for 12 hours.

A suspended solid is filtered off and the filtrate is acidified with dilute hydrochloric acid, stirring is continued for 1

Prepared analogously to "Example 53" and "Example 54" from fluoresceine and amine b.

C50H63NO9 ( (821) MS: 828 (M+Li+) EXAMPLE 56 Prepared analogously to "Example 55" from pivalic acid and amine b.

C35H61NO6 (591) MS: 598 (M+Li+) EXAMPLE 57 is prcparcd analogously to "Example 55" from 2-ethylhex- anoic acid and amine b.

C38H67NO6 (633) MS: 640 (M+Li+) EXAMPLE 58 is prepared analogously to "Example 5S; from clofibric acid and amine b.

C40H62CINO7 (703) MS: 710 (M+Li+) EXAMPLE 59 is prepared analogously to "Example 55" from gemfibrcil and amine b.

C45H73NO7 (740) MS: 747 (M+Li+) EXAMPLE 60

Prepared from 522 mg of amine b and 94.1 mg of di-n-propylmainic acid in ThF in the presence of DCCt HOBT. Isolated after 54 h. The yield is 69%.

C40H69N8 (690) MS: 697 (M+Li+)

EXAMPLE 61 250 mg of "Example 60" are hydrolyzed in dioxane using 2N NaOH. Aftcr aqueous work-up and purification by column chromatography (EtOActCH3OH 10:1), 160 mg of compound 61 are obtained C39H67NO8 (676) MS: 677 (M+1) We claim: 1. A monomeric bile add derivative of the formula IA wherein R is H, CH3 or M and M is a metal capable of forming a salt, X is a bridge group of the formula (CH2)n, where n=l to 3, in which 1 to 3 (CH2)-groups can be replaced by NH or groups, or a bridge group of the formula (CH2),, where n=4 to 10, in which 1 to 3 (CH2)-groups can be replaced by oxygen atoms, NH or groups with the proviso that no neighboring (CH2). groups are replaced by oxygen atoms and in which GS is bonded via X as desired: and Z is

-continued where R is in each case C1-C7 a alkyl, or H2-N-(CH2)o: where the alkyl moiety is optionally substituted by a COOH group, -continued

continued where A is in each case OH or NH (C1-C10) alkyl.

2. A bile acid derivative of the formula I as claimed in claim 1, in which GS is linked to X in the 3-position, linking taking place in the a- or position.

3. A medicament comprising a bile acid derivative as claimed in claim 1.

4. A hypolipidemic agent comprising a bile add deriva- tive as claimed in claim 1.

APPENDIX B HMG CoA Reductase Inhibitors COMPOUNDS CAS NUMBERS REFERENCE and for SPECIFIC and COMPOUND CLASSES REPRESENTATIVE COMPOUNDS Benfluorex 23602-78-0 $ES 474498 fluvastatin 93957-54-1 EP 244364 Lovastatin 75330-75-5 EP 22478 Pravastarin 81093-37-0 DE 3122499 Simvastation 79902-63-9 EP 33538 Atorvastatin 134523-00-5 EP 409281 Cerivastatin 145599-86-86 JP 08073432 Bervasatin and related benzopyrans 132017-01-7 EP 380392 BMS 180431 12929-03-4 Sit, Parke, Motoc, Han, Balasubra- manian, Cart, Brown, Harte, Thompson, and Wright, J.Med. Chen (1990), 33(11), 2982-99.

NK-104 141750-63-2 Takano, Kamikubo, Sugihara, Suzuki Ogaswara, Techedron:Assymetry (1993), 4(2), 201-4 (Carboxydihydroxyheptenyl)sulfonylpyrro 148966-78-2, 139993-445, 139993- EP464845 les including S-4522 456-6, 139993-46-7. 139993-47-8.

139993-48-9, 139993-49-0, 139993- 50-3, 139993-51-4, 19993-52-5, 139993-53-6, 139993-54-7. 139993- 55-8, 139993-56-9, 139993-57-0, 139993-58-1 139993-59-2, 139993- 60-5, 139993-61-6, 139993-62-7, 139993-63-8, 139993-649, 139993- 65-0, 139993-66-1, 139993-67-2, 139993-63-8, 139993-69-4, 139993- 70-7, 139993-71-8, 139993-72-9, 19993-73-0, 139993-74-1, 139993- 75-2, 139993-763, 139993-774, 139993-78-5, 139993-79-6, 139993- 80-9, 140110-63-0, 140128-98-9.

140128-99-0, 140157-62-6 Boron Analogs of di-and tripetides 12894-01-1, 125894-02-2, 125894- Sood Sood, Spielvogel, Hall, Dur. J.

03-3, 125894-04-4, 125894-05-5. Med chem. (1990), 25(4), 301-8.

125894-08-8, 125894-09-9, 125914- 96-7 Zaragozic acids 157058-13-4, 157058-14-5, 157058- GB 2270312 15-6, 157058-16-7, 157058-17-8.

15705818-9, 157058-190 Seco-oxysterol analogs including 157555-28-7, 157555-29-8 Larsen, Spilman, Yagi, Dith, Hart, and U-88156 Hess, J. med. Chem. (1994), 37 (15).

2313-51.

Pyridopyrimidines including acitemate 64405-40-9, 101197-99-3 Hermecz, Meszaros, Vasvari-Debreczy, Horvath, Virag, and Sipos, Hung.

Arzheim-Forsch (1919), 29(12), 1833-5 BMY22566 129829-03-4 Sit, Parker, Motoc, Han, Balasubrar- manian, Cart, Brown, Harte, Thompson, and Wright, J.Med. Chem.

(1990), 33(11), 2982-99.

Colestolone 50673-97-7 Raulstion, Mishaw, Parish and Schroepfer, Biochem. Biophys. Res.

Comun. (1976). 71(4), 984-9.

CP-83101 130746-82-6, 130778-27-7 Wint and McCarthy, J. Labelled Compd. Radiopharm. (1988). 25 (11).

1289-97.

Dalvastatin 132100-55-1 Kurnar, Windisch, Trivedi and Golebiowski, J. Chromatogr., A (1994), 678(2), 259-63.

Dihydromevinolin 775 17-294 Fralck and Yang, Tetrahedron Lett.

(1984), 25(33), 3563-66.

DMP-565 Ko. Trazskos, Chen, Hausaer, Brosz, and Serivastava, Abstr. Papers Am.

Chem. Soc. (207th National Meeting.

Part 1, MEDI 10, 1994) Pyridyl and Pyrimidinylethenyldesmethyl- 122254-45-9 Beck, Kesseler, Baader, Bartmann, mevalonates including glenvastin Berginann, Granzer, Jendralla, Von Kerekjano, Krause, et al, J. Mcd Chem. (1990), 33(1), 52-60.

GR95030 157243-22-6 US 5316765 Isoxazolopyridylmevalonates, carboxylic 130581-42-9, 130581-43-0, 130581- EP 369323 acics and esters 44-1. 130581-45-2, 130581-46-3, 130581-47-4, 130581-48-5, 130581- 49-6, 130581-50-9, 130581-51-0.

130581-52-1, 130619-07-7, 130619- 08-8, 130619-09-9 Lactones of 6-phenyoxy-3,5-dihydroxy 127502-48-1, 136006-66-1, 136034- Jenderella, Granzer, von Kerekjarto, hexanoic acids 04-3 Karuse, Schacht, Baader, Barmann, Back, Bergmann, et al., J. Med Chem.

L 659699 29066-42-0 Chiang, Yang, Heck, Chabala, and Chang, J. Org. Chem. (1989), 54(24).

5708-12.

L 669262 130468-11-0 Stokker, J. Org. Chem. (1994), 59(20).

3983-6.

Mevastatin 73573-88-3 JP 56051992 Pannorin 137023-81-5 Ogawa, hasumi, Sakai, Murakawa and Endo, J. Antibito (1991), 44(7). 762-7 Rawsonol 12511-69-6 Carte, Troupe, Chan, Westley and Faulkner, Phytochemistry (1989).

28(11), 2917-19 RP 61969 126059-69-6 EP 326386 Bile acid derived HMG CoA reductase kramer, Wess, Enhsen, Bock, Falk, hihibitors including Na S-2467 and Hoffmann, Neckermann, Gantz, Schoulz, S-2468 (1994), 1227 (3), 137-54.

SC 32361 76752-41-5 US 4230626 SC 45355 125793-76-2 EP 329124 Phosphorus containing HMG COA 133983-25-2 US 5274155 reductase inhibitors including SQ 33600 6-Aryloxymethyl-4-hydroxyterahydro 135054-71-6, 136215-82-2, 136215- EP 418648 pyran-2-ones, carboxlic acids and stalts 83-3, 136215-84-4, 136215-85-5, 136315-18-9, 136315-19-9, 136315- 20-3, 136315-21-4, 136316-20-6 Atorvastatin calcium (CI 981) 134523-03-8 aumann, Butler, Deering, Mennen, Millar, Nanninga, Palmer and Roth, Tetrahedron Lett (1992), 33(17).

2284@ Fenofibrate 49562-28-9 DE 2250327 Benzafibrate 41859-67-0 DE 2149070 Etofibrate 31637-97-5 US 3723446 Mevinolin analogs EP 245003 'Pyr=o= derivatives US 4937259 1,2,4-Triazolidine-3,5-diones 16044-43-2 WO 9000897 Isoazolidine-3,5-diones 124756-24-7 EP 321090 CS-514 81181-70-6 DE 3122499 1,10-bis(carboxymethylthio)decane 328727-49-9 dE 2038835 a-, -, and y-alkylaniinophenone analogs Huang and Hall, Eur. J. bled. Chem. including N-phenylpiperazinopropio- (1996), 31(4),281-90. phenoce 3-Amino-1-(2,3,4-mononitro-, mono-, or Huang and Hall, Arch. Pharm. (1996). dihalopenyl)propan-1-ones including 3- 329(7), 339-346 morpholino- or piperidino-1-(3- nitrophenyl)propan-1-one Substituted isoxazolo pyridinones 64769-68-2 US 4049813 Biphenyl derivatives JP 07089898 4-[1-(Substituted phenyl)-2-oxo- Watanabe, Ogawa, Ohno, Yano, pyrrolidin-4-yl]methoxybenzoic adds Yam2da and Shirasaka, Eur. J. bled Chem. (1994). 29(9). 675-86.

Dihydroxy(tetrahydroindazolyl, US 5134155 tetrahydrocyclopentapyrazolyl, or hexahydropcycloheptapyrazole)heptencate derivatives benf luorex Servier fluvastatin Sandoz lovastatin ere & Co pravastatin Sankyo simvastatin Merck & Co atorvastatin Warner-Lambert cerivastatin Bayer bervastatin Merck KGaA BMS-180431 Bristol-Myers Squibb NK-104 Nissan Chemical s-4522 Shionogi Boron Analogs Boron Biologicals HMG-CoA Reductase Inhibitors Eritish Biotech & Japan Tobacco HMG-CoA Reductase Inhibitors Merck & Co U-88156 Pharmacia & Upjohn A-1233 Kitasato University acitemate Mitsubishi Chemical BAY-w-9533 Eayer BB-476 British Biotech BMS-180436 Eristol-Myers Squibb BMY-22566 colestonone American Home Porducts CP-83101 Pfizer dalvastatin Rhone-Poulenc Rorer dihydromevinolin Merck & Co DMP-565 DuPont Merck genvastatin Hoechst Marion Roussel GR-95030 Glaxo elocme HMG-CoA Reductase Inhibitors Bristol-Myers Squibb HMG-CoA Reductase Inhibitors Ono HMG-CoA Reductase Inhibitors, Chiral Chiroscience HMG-CoA Reductase Inhibitors, isoxazolo- Nissan Chemical pyridine HMG-CoA Reductase Inhibitors, seco-oxysterol Pharmacia & Upjohn HMG-CoA Reductase Inhibitors, thiophene Sandoz HMG-CoA Reductase Inhibitors, 6-phenoxy- Hoechst Marion Roussel 3, 5-dihydoxyhexanoic acids hypolipaemics, Warner-Lambert Warner-Lambert L-659699 Merck & Co L-669262 Merck & Co mevastatin Sankyo N- ((1-methylpropyl) carbonyl)- Sandoz 8-(2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran- 2-yl)ethyl)-perhydro-isoquinoline N-(1-cxododecyl)-4alpha, 10-dimethyl-8- Hocehst Marion Roussel aza-trans-decal-3beta-ol P-882222 Nissan Chemical pannorin Tokyo Noko University rawsonol Smithkline Beecham RP 61969 Rhone-Poulenc Rorer S-2468 Hoechst Marion Roussel S-853,,,58A Hoechst Marion Roussel (s)-4-((2-(4-(4-fluorophenyl)-5-methyl- Bistol-Myers Squibb 2-(2-methylethyl)-6-phenyl-3-pyridinyl) ethyl)hydroxyphosphinyl)- 2-hydroxybutanoic acid, disodium salt SC-32561 Monsanto sc-45355 Non-industrial source SDZ-265859 Sandoz SQ-33600 Bristol-Myers Squibb (4R-(4alpha, @beta(E)))-6-(2-(5-(4- Warner Lambert fluorophenyl)-3-(1-methyl-ethyl)-1- (2-pyridinyH-pyrazol-4-yl)ethenyl) tetrahydro-4-hydroxy-2H-pyran-2-one 5-beta-amino-ethylthiopentanic Boehringer Mannheim acid derivatives 6-maino-2-mercapto-5-methylpyrimidin North Carolina University -4-c2rboxylic acid 6-phenoxymethyl- & 6-phenylethylen- Hoechst Marion Roussel (4-hydroxy-terahydropyran-2-one) analogues atorvastatin (4R)-(4alpha, 6beta(E))))-6-(2-(5-(4-fluorophenyl)-3- (l-methyl-ethyl)-1-(2-pyridinyU-pyrazol-4-yl)ethenyl) tetrahydro-4-hydroxy-2H-pyran-2-one