However, these agents also have undesirable side effects such as skin atrophy which limit the duration of therapy. In addition, topical application of a drug is difficult for many patients where the affected area may be very large.

Phospholipase A2 (PLA2) is the common name for phosphatide 2- acylhydrolase which catalyzes the hydrolysis of the sn-2-acyl ester bond of phosphoglycerides and results in production of lysophospholipids and free fatty acids. When the fatty acid is arachidonic acid, further action by cyclooxygenase and 5-lipoxygenase enzymes results in eicosanoid production, which is implicated in inflammation, and leukotrienes which are linked to asthma. Lysophophospholipid metabolism results in production of platelet activating factor and both lysophospholipids and platelet activating factor also play a role in inflammation.

PLEA, enzymes exist as secreted forms (MW - 12,000-15,000) and cytosolic forms (MW - 85,000). The cytosolic or cPLA2 enzymes appear to play a key role in the pathway leading to the formation of platelet activating factor and the eicosanoids.

Inappropriate activation of the cytosolic PLA2 enzymes, therefore, can result in a variety of chronic and acute conditions including asthma, cerebral ischemia (Clemens et al, Stroke 1996, 27, 527-535), Alzheimer's Disease (Stephenson et al, Neurobiology of Stroke, 1996, 3, 51-63 and see also U.S. Patent 5,478,857), rheumatoid arthritis, neutrophil and platelet activation (Huang et al, Mediators of Inflammation, 1994, 3, 307-308), chronic skin inflammation and damage to the skin resulting from exposure to ultraviolet light (Gresham et al., American Tournal of Physiology. 1996, 270; Cell Physiology 39:C1037-C1050) and macrophage activation (Balsinde et al, Tournal of Biological Chemistry 1996, 271, 6758- 6765).

Selective inhibitors of the cPLA2 enzymes may, therefore, be of use in controlling a wide variety of inflammatory diseases. The literature describes a significant number of compounds said to be phospholipase A2 inhibitors, but few selective inhibitors for the cPLA2 enzymes are available. The present inventors had as their goal the synthesis of novel compounds which would be selective and potent inhibitors of the cPLA2 enzymes. As used herein, the term "selective inhibitors of the cPLA2 enzymes" means that the inhibitors inhibit the cPLA2 enzymes with a potency 20-fold or greater than they inhibit the lower molecular weight synovial PLA2 enzymes.

Biochemistry 32: 5935-5940, 1993, discloses a trifluoromethyl ketone analog of arachidonic acid having the formula

as a selective inhibitor of cPLA2.

Bioorganic Med. Chem. Lett. 5: 519-522, 1995, discloses selective cPLA2 inhibitors of the formula

where R is either H or OH.

Japanese published patent application JP09268153A (Derwent No.

97-554679/51) discloses cPLA2 inhibitors of the formula RCOCF3 where RCO is an acyl residue of an n-3 series highly unsaturated fatty acid. The compounds are said to be useful as antiinflammatory or antiallergic drugs.

Published PCT Application WO 98/25893 discloses arylsulfonamide compounds of the general formula wherein

A represents a C4-Cl0 alkyl group, an aryl group, an arylalkyl group, radicals selected from the group consisting of -CH=CH-B, -O-B,-S-B, and -NH-B, or radicals of formula -CH2 -X, wherein B represents a non-aromatic C3-C8 carbocycle, a C3-C8 alkyl group, a heterocycle or an arylalkyl group, each of which is optionally substituted with one or more members independently selected from the group consisting of a halogen atom, a Cl-C4 alkyl group, a Cl-C4 alkoxy group, cyano, nitro, a heterocycle, an aryl group and an aryloxy group, and X is a member selected from the group consisting of a halogen atom, -S-aryl,-S-heterocycle, and PO3R2 wherein each R is independently selected from the group consisting of a hydrogen atom and Cl-C3 alkyl; Rl and R2 each independently represent a hydrogen atom, a lower alkyl group, or a group represented by the formula: (CH2)qA' wherein q is an integer of 2 to 4, and A' is a member selected from the group consisting of a hydroxyl group, a group represented by the formula: wherein R5 and R6 each independently represent a hydrogen atom, a lower alkyl group, or a group represented by the formula:

wherein R7 represents a hydrogen atom, a lower alkyl group, or a group represented by the formula: wherein s is an integer of 2 to 5; or Rl and R2 each independently represent an unsubstituted cycloalkyl group, or a cycloalkyl substituted with a lower alkyl or halogen or condensed with an aromatic ring, a bicycloalkyl, or tricycloalkyl, said bicycloalkyl or tricycloalkyl being an aliphatic saturated hydrocarbon group made of two or three rings, respectively, with at least two carbon atoms being common to each ring, or an azabicycloalkyl group which is a bicycloalkyl group as described above in which one carbon atom is replaced by a nitrogen atom or a group represented by the formula: wherein g and h are each an integer of 1 to 4, and B' stands for a lower alkyl group, an arylalkyl group, an arylalkyl group substituted by lower alkyl; halogen or a lower alkoxy group, or a pyridylalkyl group, or a pyridylalkyl group substituted with a lower alkyl group, a halogen or a lower alkoxy group; or

Rl and R2 may be combined together to form a 6- or 7-membered ring which may contain a nitrogen or oxygen atom in addition to the nitrogen atom to which Rl and R2 are bonded, and said 6- or 7-membered ring may be substituted with a lower alkyl, arylalkyl, cycloalkylalkyl or heteroarylalkyl group; R3 represents a hydrogen atom, a lower alkyl group, or a C3-C8 cycloalkyl group; R4 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom; n is an integer of 1 to 4, provided that when n is 2, the two R4 groups may form a cyclohexenyl or phenyl ring together with two adjacent carbon atoms constituting the benzene ring; and any pharmacologically acceptable salts thereof as inhibitors of phospholipase A2 activity, particularly cPLA2.

Drugs 1998, Vol. 1, No. 1, pp. 49-50 discloses cPLA2 inhibitors of the type

U.S. Patent 5,453,443 discloses a series of biaryl ketones which are reported to inhibit PLA2 enzymes, but it is not indicated whether these compounds are selective for the cytosolic enzymes or even whether they inhibit the cytosolic enzymes. These compounds have the generic formula wherein: Rl is selected from (a) hydrogen, (b) - C1-6alkyl, and (c) - 6alkyl-phenyl; or wherein Rl and R5 are joined such that together with the carbon atoms to which they are attached there is formed a saturated or unsaturated carbon ring of 3, 4, 5, 6, 7 or 8 atoms; R2 and R3 are each independently selected from

(a) hydrogen, (b) - C1-6alkyl, and (c) - C1-6alkyl-phenyl, or wherein two R2 or two R3 are joined such that together with the carbon atoms to which they are attached there is formed a saturated or unsaturated carbon ring of 3, 4, 5, 6, 7 or 8 atoms; R5 is as defined above or is selected from (a) hydrogen (b) -C16alkyl, (c) - C1-6alkyl-phenylC1-6alkyl, (d) -OH, (e) -O - C1-6alkyl, or (f) - C1-6alkyl-phenylC1-6alkyl; R6 is selected from (a) hydrogen

(b) - 6alkyl (c) - C1-6alkyl-phenyl, wherein the phenyl is optionally substituted with C1-2alkyl; (d) - OH , (e) -O-C1-6alkyl, or (f) -O-C1 C1-6alkyl-phenyl, wherein the phenyl is optionally substituted with Cl 2alkyl; or wherein two R6 are joined to form O= or are joined together such that together with the carbon atom to which they are attached there is formed a saturated or unsaturated carbon ring of 3, 4, 5, 6, 7 or 8 atoms; R8, R9 and R14 are each independently selected from (a) H, (b) - 6alkyl (c) halo (d) - CN (e) -OH

(f) - OC1-6alkyl, (g) - OC1-6alkyl-phenyl, (h) - SR11 (i) S(O)R11, or (j) S(O)2R11; R10, Rl5, R16 and R17 are each independently selected from (a) hydrogen, (b) -Cl 6 alkyl, and (c) -C1-6 alkyl-phenyl; R11 is selected from (a) -C1-6 alkyl, (b) -C2-6 alkenyl, (c) -CF3, (d) -phenyl(R12)2, or

(e) -C2-6 alkenyl-phenyl(R12)2, R12 is (a) hydrogen, (b) -C1-6 alkyl, (c) Cl, F, I or Br; R13 is perfluoroC1-6alkyl; A and B are each independently (a) covalent bond, (b) o, (c) S, (d) S(O), or (e) S(O)2; Q is selected from (a) - CH(OH)R13,

(b) -COR13, (c) - COR16, or (d) - C1-4alkylCOCOOR17; X1 is selected from (a) -O-, (b) -S-, (c) - S(O)-, (d) - S(O)2-; Z is (a) H, or (b) - phenyl-(R14)3, m is 0, 1, 2, 3, or 4; n is 2, 3, 4, 5, 6 or 7; and r and s are each independently 0, 1, 2, 3, 4, 5, 6, 7 or 8.

SUMMARY OF THE INVENTION The present invention is directed to selective cytosolic PLA2 inhibitor compounds of the formula wherein W is CH=CH, CH=N, O or S; R1 is (Cl-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C 1-C6)alkoxy, (C1-C6)alkylthio, halo, hydroxy, cyano, in which R2 and R3 are each independently hydrogen or (C1-C6)alkyl, -COO-(C1-C6)alkyl, CF3, (C1-C6)alkylphenyl, phenyl or phenyl substituted by one or more, preferably 1-3, of (C1-C6)alkyl, -COO-(C1-C6)alkyl, in which R2 and R3 are as defined above, halo, hydroxy, -O-(C1-C6)alkyl, -S-(Cl-C6)alkyl or (C2-C6)alkenyl; p is 0, 1 or 2; A is V-(RC) -; R' is a straight or branched chain alkyl group; n is 0 or an integer of from 1 to 6;

R" and Rb when taken together form an oxo (=0) group, or R" and Rb are each independently hydrogen or OH; V is O, -S-, -SO-, -SO2, -CONH or NHCO when n is an integer of from 1 to 6 or V is (C2-C6) alkenyl or a bond when n is 0 or an integer of from 1 to 6; D is -(CH2)m or a bond linking the ring to Y; m is an integer of from 1 to 6; Y is -O-, -S-, -SO-, -SO2; or a bond; R4 is as defined below for R7; Z is: in which B is: - SO2- or a bond; XisSorO; q is an integer from 1 to 6;

R9 is hydrogen or (C1-C6)alkyl; R10 is hydrogen, CN, NO2, OH, -C-(C1-C6)alkyl, (C1-C6) alkyl, phenyl or (C1-C6)alkylphenyl; R5 and R6 are each independently hydrogen or (C1-C18) alkyl; R7 and R8 are each independently; (a) hydrogen; (b) (C1-C18)alkyl; (c) (C1-C18)alkyl substituted by one or more of (1) phenyl; (2) phenyl substituted by 1-5 fluoro, 1-3 (for each of the following phenyl substituents) halo (other than fluoro), 1-3 (C1-C6)alkoxy, 1-3(C1-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6)alkylthio, amino, 1-3 (C1-C6) alkylamino, di(C1-C6)alkylamino, -CO2H, -COO- (C1-C6)alkyl, -SO3H, -SO2NHR15 in which R15 is hydrogen or (C1-C6)alkyl, or 3 <BR> in which R2 and R3 are as defined above;

(3) heterocyclic selected from oxadiazolyl, isoxazolyl, oxazolyl, furyl and thiazolyl; (4) heterocyclic substituted by one or more of, preferably 1-3, phenyl, phenyl substituted by 1-3 (for each of the following halo, (Cl-C6)alkoxy, (C,-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Cl-C6) alkylthio, amino, (Cl-C6) alkylamino, di(C1-C6) alkylamino, CO2H, -COO-(Cl-C6) alkyl, -SO3H, SO2NHR15 in which R15 is hydrogen or (C1-C6) alkyl, or in which R2 and R3 are as defined above, (Cl-C6) alkyl or (C1-C6) alkyl substituted by one or more, preferably 1-3, phenyl or heterocyclic groups, said phenyl or heterocyclic group being unsubstituted or substituted by 1-3 (for each of the following) halo, 1-3 (C1-C6) alkoxy, 1-3 (C1-C6) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Cl-C6) alkylthio, amino, 1-3 (C1-C6) alkylamino, di(C1-C6) alkylamino, COOH, -COO- (C1-C6) alkyl, -SO3H, -SO2NHR15 in which R'5 is hydrogen or (C1-C6) alkyl, or in which R2 and R3 are each independently hydrogen or (C1-C6) alkyl, the heterocyclic radical being selected from imidazolyl, oxadiazolyl, isoxazolyl, pyrrolyl, pyrazolyl, oxazolyl, furyl, thianyl or thiazolyl; (5) carboxy or -COO-(C1-C6) alkyl;

(6) hydroxy, halo, -O-(Cl-C6) alkyl or -S-(Cl-C6) alkyl, with the proviso that the OH, ethers or thioethers cannot be on the carbon bearing the heteroatoms; (7) cyano; (8) halo, trifluoromethyl or trifluoroacetyl; (9) CH2 L-R16 in which L is or -O-SiR16R18R19 or a bond in which R16 and R17 are each independently (C1-Cls)alkyl or (C2-C18)alkenyl or (C1-Cls)alkyl or (C2-C18)alkenyl substituted by one or more, preferably 1-3, phenyl or heterocyclic radicals, said phenyl or heterocyclic radicals being unsubstituted or substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3 (C1-C6)alkoxy, 1-3(C1-C6)alkyl, nitro, cyano, hydroxy, 1-3 trifluoromethyl, 1-3 (C 1-C6)alkylthio, amino, 1-3(C 1-C6)alkylamino, 1-3 di(C1-C6)alkylamino, CO2H, 1-3 -COO(C1-C6)alkyl, or -SO2NHR9 in which R9 is hydrogen or (C1-C6)alkyl and R2 and R3 are as defined above;

in which Bl is - SO2 -, -PO(OR9)2 or a bond; providing that when Bl is -PO(OR9)2, then R7 becomes R9, and when Bl is or -SO2-, then R7 cannot be hydrogen; X, q, R5, R6, R7, R8, R9 and Rl° are as defined in (a); in which q, R5 and R6 are as defined above; R18, R19and R11 are as defined above for R7 and R8 except that they may not be hydrogen, or R18 and R19 taken together with the nitrogen to which they are attached represent a 4, 5- or 6-membered heterocyclic ring and Y, R7 and R11 are as defined above, or R18, R19 and R11 taken together with the nitrogen to which they are attached represent pyridinium, said pyridinium group being unsubstituted or substituted by (C1-C12)alkyl, (C1-C12)alkoxy, amino, (C1-C12)alkylamino, di

(C1-C12)alkylamino, O O R2 II - C -o -(C1-C6)alkyl, -S-(C1-C12)alkyl, -C-N- R3 in which R2 and R3 are as defined above, phenyl or phenyl (C1-C10)alkyl; d) in which R13 is (C1-C18)alkyl or (C1-Cl8)alkyl substituted by carboxy, alkyl, in which R2 and R3 are as defined above, hydroxy, -O-(Cl-C6) alkyl, -O-(Cl-C6) alkyl or -S-(Cl-C6) alkyl substituted by 1 or 2 phenyl or substituted phenyl groups, the substituents for the substituted phenyl groups being 1-5 fluoro or 1-3 (for each of the following phenyl substituents) halo (other than fluoro), (Cl-C6) alkoxy, (C,-C6) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Cl-C6) alkylthio, amino, (Cl-C6) alkylamino, di(C1-C6) alkylamino, CO2H, COO-(C1-C6) alkyl, SO3H, OR SO2NHRis in which R15 is hydrogen or (C1-C6) alkyl or - c- N- R3 in which R2 and R3 are as defined above; r is 0 or an integer of from 1 to 3; R7 is as defined above; M is -(CH2-)mT where T is in which R2is as defined above, 502 or a bond when MR7 is on nitrogen and providing that when T is or -SO- or -SO2-, then R7 cannot be hydrogen, and T

or a bond when MR7 is on a carbon atom of the heterocyclic ring; R14 is hydrogen or (C1-C6)alkyl; m is 0 or an integer of 1-6; wherein Q is -O-, -S-, -SO- or -SO2-, and q, R5, R6 and R7 are as defined above, providing that when Q is -SO- or -SO2-, R7 cannot be hydrogen; f) R7 wherein R7 is defined above, providing that when Y is -SO- or -SO2-, R7 cannot be hydrogen; and R18 and R'9 are phenyl or phenyl substituted by 1-3 halo, (Cl-C6) alkoxy, (Cl-C6) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Cl-C6) alkylthio, amino, (C1-C6) alkylamino, di(C1-C6) alkylamino, CO2H, -COO-(C1-C6) alkyl, -SO3H, SO2NHR15 in which R15 is hydrogen or (C1-C6) alkyl, or in which R2 and R3 are as defined above; or pharmaceutically acceptable salts, solvates or pro drugs thereof.

Also provided by this invention are methods for inhibiting cytosolic PLA2 in a mammal in need thereof which comprises administering to said mammal a therapeutically effective amount of a

compound of formula I and methods for using the compounds of formula I to treat various diseases characterized by inappropriate activation of the cytosolic PLA2 enzymes such as asthma, allergic rhinitis, cerebral ischemia, Alzheimer's Disease, rheumatoid arthritis, acute pancreatitis, inflammatory bowel disease, psoriasis, gout, neutrophil and platelet activation, chronic skin inflammation, shock, trauma-induced inflammation such as spinal cord injury, damage to the skin resulting from UV light or burns and macrophage activation. In further aspects, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier and processes for preparing the compounds of formula I.

DETAILED DESCRIPTION The object of this invention was to discover a selective cPLA2 inhibitor which is active, both topically and orally, in treating inflammary disease of the skin and other tissues as well as other chronic and acute conditions which have been linked to inappropriate activation of the cPLA2 enzymes. Preferably such compound would also be devoid of undesirable lipid-perturbing activities associated with skin irritation.

The above-mentioned objectives have been met by the compounds of formula I described above.

In the present application the numbers in the subscript after the symbol "C" define the number of carbon atoms a particular group can contain. For example, Cl l8alkyl refers to straight and branched chain alkyl

groups with 1 to 18 carbon atoms. Similarly, C2-Cl8 alkenyl refers to a straight or branched unsaturated hydrocarbon group containing from 2 to 18 carbon atoms and at least one carbon-carbon double bond. Likewise, C2-Cl8 alkynyl refers to a straight or branched unsaturated hydrocarbon group containing from 2 to 18 carbon atoms and at least one carbon-carbon triple bond.

The term "halogen" or "halo" as used herein refers to fluorine, chlorine, bromine or iodine.

Aryl as used herein refers to a C6 monocyclic aromatic ring system or a C9 or C10 bicyclic carbocyclic ring system having one or two aromatic rings such as phenyl or naphthyl. Unless otherwise indicated, substituted aryl" refers to aryl groups substituted with one or more (preferably from 1 to 3) substituents independently selected from (C1-C6)alkyl, haloalkyl, (C1-C6)alkoxy, (C1-C6)alkoxy-carbonyl, (C1-C6)alkanoyl, hydroxy, halo, mercapto, nitro, amino, cyano, (C1-C6)alkylamino, di(C<-C6)alkylamino, carboxy, aryl, aryl (C1-C6)alkyl, aryl (C1-C6)alkoxy, heterocyclic, heterocyclic (C1-C6)alkyl and the like.

The term "heterocyclic" as used herein refers to a 4-, 5- or 6- membered ring containing one, two or three heteroatoms selected from N, 0 and S. The 5-membered ring has 0-2 double bonds and the 6- membered ring has 0-3 double bonds. The nitrogen heteroatoms can be optionally quaternized or N-oxidized. The sulfur heteroatoms can be optionally S-oxidized. The term "heterocyclic" also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring. Heterocyclics

include: pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolidinyl, pyridyl, piperidyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzofuranyl, furyl, dihydrofuranyl, tetrahydrofuranyl, pyranyl, dihydropyranyl, dioxolanyl, thienyl, benzothienyl and diaxanyl.

Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention is meant to include such possible diastereomers as well as their racemic and resolved, enantiomerically pure forms, and pharmaceutically acceptable salts thereof.

As mentioned above the invention also includes pharmaceutically acceptable salts of the compounds of formula I. A compound of the invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups. Accordingly, a compound may react with any of a number of inorganic bases, and organic and inorganic acids, to form a pharmaceutically acceptable salt.

The term "pharmaceutically acceptable salt" as used herein refers to salts of the compounds of formula I which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an inorganic base.

Such salts are known as acid addition and base addition salts.

Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p- toluenesulfonic, methanesulfonic acid, oxalic acid, p- bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propionate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylene-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, y-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1 - sulfonate, napthalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic acid.

Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. Suitable organic bases include trialkylamines such as

triethylamine, procaine, dibenzylamine, N-benzyl- P-phenethylamine, 1- ephenamine, N,N'-dibenzylethylene-diamine, dehydroabietylamine, N- ethylpiperidine, benzylamine, dicyclohexylamine, or the like pharmaceutically acceptable amines. The potassium and sodium salt forms are particularly preferred.

It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.

The present invention also includes solvated forms of the compounds of formula I, particularly hydrates, in which the trifluoromethyl ketone group exists as a mixture of ketonic I and hydrated forms II and are each independently interconvertible and pharmacologically active.

The present invention also includes prodrug forms of the compounds of formula I or II above such as trifluoromethylketone enol ester derivatives, enol phosphate derivatives, cyclic or acylic unsubstituted or substituted O,O-ketals, O,S-ketals, O,N-ketals or S,N- ketals such as cyclic cysteamyl derivatives, cyclic glycolates, thioglycolates, glyoxylates or oxalates, and the like. It also includes

trifluoromethylalcohols obtained by chemical reduction of trifluoromethylketones. Such forms are physiologically hydrolyzable groups which are converted in vivo to a pharmacologically active compound of formula I or II, or a crystalline form of such compounds, see scheme below. P-y-z w (R1)p- W 3CRA-C/CF3 CF3 x<X R= alkyl x= o,s or x=o,s substituted alkyl X = NH, O, S Iorll \ (R1)p gD-Y-Z ,CF3 ttACo 3 /Cs X ASo gD-Y-Z Ho PH (R')p- rH X=O,S3r%kP X=OS TH X=O,S X1- NH, 0,5 X1 - NH, 0,5 R= alkylor substituted alkyl

Preferred compounds of formula I are those where the substituent is linked to the phenyl ring at the para or meta position, most preferably at the para position.

Preferred embodiments of the compounds of general formula I include (a) compounds of formula I wherein W is CH=CH, D is a bond linking Y to the ring and Y is -O-; (b) compounds of (a) immediately above wherein R' is benzyl, A is V-(CH2)n-, V is (C2-C6) alkenyl or a bond, p is 0, 1 or 2, and n is 0 or an integer of from 1 to 6; and (c) compounds of (b) immediately above wherein A is -(CH2)n, n n is 0 or an integer of from 1 to 6, and the group -(CH2)nCOCF3 is in the meta or para position of the phenyl ring.

Another preferred embodiment comprises a compound of the formula wherein Rl is benzyl; p is 0, 1 or 2; A is V-(CH2)n-; V is (C2-C6) alkenyl or a bond; n is 0 or an integer of from 1 to 6; Ra and Rb are as defined above and Z is

in which B is or a bond; X is S or O; q is an integer of from 1 to 6; R9 is hydrogen or (Cl-C6) alkyl; Rl° is hydrogen, CN, NO2, OH, -O-(C1-C6) alkyl, (Cl-C6) alkyl, phenyl or (Cl-C6) alkylphenyl; R5 and R6 are each independently hydrogen or (Cl-C6) alkyl; and R7 and R8 are each independently a) hydrogen; b) (C,-C,8) alkyl; c) (C,-C,8) alkyl substituted by one or more of, preferably 1-3, (1) phenyl; (2) phenyl substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3 (C1-C6) alkoxy, 1-3 (C1-C6) alkyl, nitro, cyano, hydroxy,

trifluoromethyl, (C,-C6) alkylthio, amino, 1-3 (C,-C6) alkylamino, di(C1-C6) alkylamino, -CO2H, -C OO-(C1-C6) alkyl; -SO3H, - SO2NHRl5 in which R15 is hydrogen or (C1-C6) alkyl, or in which R2 and R3 are each independently hydrogen or (C1-C6) alkyl; (3) heterocyclic selected from oxadiazolyl, isoxazolyl, oxazolyl, furyl and thiazolyl; (4) heterocyclic substituted by one or more of, preferably 1-3, phenyl, phenyl substituted by 1-3 halo, (C1-C6)alkoxy, (C1-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Cl-C6) alkylthio, amino, (Cl-C6) alkylamino, di(C1-C6) alkylamino, CO2H, -COO-(Cl-C6) alkyl, -SO3H, SO2NHR15 in which R15 is hydrogen or (C1-C6) alkyl, or in which R2 and R3 are as defined above, (Cl-C6) alkyl or (C1-C6) alkyl substituted by one or more, preferably 1-3, phenyl or heterocyclic groups, said phenyl or heterocyclic group being unsubstituted or substituted by 1-3 halo, 1-3 (C1-C6) alkoxy, 1-3 (C1-C6) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6) alkylthio, amino, 1-3 (C1-C6) alkylamino, di(C1-C6) alkylamino, COOH, -COO-(Cl-C6) alkyl, -SO3H, -SO2NHRls in which R15 is hydrogen or (C1-C6) alkyl, or in which R2 and R3 are each independently hydrogen or (C1-C6) alkyl, the heterocyclic radical being selected from imidazolyl, oxadiazolyl, isoxazolyl, pyrrolyl, pyrazolyl, oxazolyl, furyl, thianyl or thiazolyl; (5) carboxy or -COO-(Cl-C6) alkyl; (6) hydroxy, halo, -O-(Cl-C6) alkyl or -S(Cl-C6) alkyl, with the proviso that the OH, ethers or thioethers cannot be on the carbon bearing the heteroatoms;

(7) cyano; (8) halogen, trifluoromethyl or trifluoroacetyl; or (9) CH2 L-R16 in which L is or -o-siRl6Rl8Rl9 or a bond in which R16 and R17 are each independently (C1-Cl8)alkyl or (C2-C18)alkenyl or (C1-Cl8)alkyl or (C2-C18)alkenyl substituted by one or more, preferably 1-3, phenyl or heterocyclic radicals, said phenyl or heterocyclic radicals being unsubstituted or substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3 (C1-C6)alkoxy, 1-3(C1-C6)alkyl, nitro, cyano, hydroxy, 1-3 trifluoromethyl, 1-3 (C1-C6)alkylthio, amino, 1-3 (C1-C6)alkylamino,1-3 di(C1-C6)alkylamino, CO2H, 1-3 O R2 -COO(C1-C6)alkyl, -C-N- R3 or -SO2NHR9 in which R9 is hydrogen or (C1-C6)alkyl and R2 and R3 are as defined above; and R18 and R19 are phenyl or phenyl substituted by 1-3 halo, (Cl-C6) alkoxy, (Cl-C6) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Cl-C6) alkylthio, amino, (Cl-C6) alkylamino, di(C1-C6) alkylamino, CO2H, -COO- (C1-C6) alkyl, -SO3H, SO2NHR15 in which R15 is hydrogen or (C1-C6) alkyl, or in which R2 and R3 are as defined above; or pharmaceutically acceptable salts, solvates or prodrugs thereof.

in which Bl is - SO2-, -PO(OR9)2 or a bond; providing that when Bl is -PO(OR9)2, then R7 becomes R9, and when Bl is or -SO2-, then R7 cannot be hydrogen; and X, q, R5, R6, R7, R8, R9 and Rl° are as defined above in (a); in which R13 is (C1-Cl8)alkyl or (C1-Cl8)alkyl substituted by carboxy, 91 O R2 - C- 0- (C1-C12) alkyl, - c- N- R3 in which R2 and R3 are as defined above, hydroxy, -O-(C1-C6) alkyl, -O-(C1-C6) alkyl or -S-(C1-C6) alkyl substituted by 1 or 2 phenyl or substituted phenyl groups, the substituents for the substituted phenyl groups being 1-5 fluoro or 1-3 halo (other than fluoro), (C1-C6) alkoxy, (C1-C6) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6) alkylthio, amino, (C1-C6) alkylamino, di(C1-C6) alkylamino, CO2H, COO- (C1-C6) alkyl, SO3H, SO2NHR15 in which R15 is hydrogen or (C1-C6) alkyl or in which R2 and R3 are as defined above;

r is 0 or an integer of from 1 to 3; R7 is as defined above; M is -(CH2-)mT where T is in which R2is as defined above, 502 or a bond when MR7 is on nitrogen and providing that when T is or -SO- or -SO2-, then R7 cannot be hydrogen, and T or a bond when MR7 is on a carbon atom of the heterocyclic ring; R14 is hydrogen or (C1-C6)alkyl; m is 0 or an integer of 1-6; wherein Q is -O-, -S-, -SO-, or -SO2- and q, R5, R6 and R7 are as defined above, providing that when Q is -SO- or SO2-, R7 cannot be hydrogen; or (e) R7 where R7 is as defined above, providing that when Y is -SO- or -SO2-, R7 cannot be hydrogen; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

Another preferred embodiment comprises a compound of the formula wherein n is 0 or an integer of from 1 to 6, the substituent -(CH2)nCOCF3 is in the meta or para position of the phenyl ring and Z is in which B is or a bond; X is S or O; q is an integer of from 1 to 6; and R5, R6, R7 and R8 are as defined above; or a pharmaceutically acceptable salt, hydrate or pro drug thereof.

Another preferred embodiment comprises a compound of the formula in which Rl is benzyl; p is 0, 1 or 2; n is 0 or an integer of from 1 to 6; the substituent -(CH2)nCOCF3 is in the meta or para position of the phenyl ring; and Z is

in which Bl is or a bond; q is an integer of from 1 to 6; X is S or O; and R5, R6, R7, R8, R9 and Rl° are as defined above; or a pharmaceutically acceptable salt, solvate or prodrug thereof. Within this embodiment, it is preferred that the substituent -(CH2)nCOCF3 is in the para position of the phenyl ring, R5 and R6 are both hydrogen, q is 1, 2 or 3, n is 2 or 3, B1 is or-SO2-, and R7 and R8 are each independently hydrogen or (C1-C18) alkyl. Especially preferred are compounds where q is 1, n is 2 and Bl is Another preferred embodiment comprises a compound of the formula

wherein n is 0 or an integer of from 1 to 6; the substituent -(CH2)nCOCF3 is in the meta or para position of the phenyl ring; and Z is in which R'3, r, M and R7 are as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

Another preferred embodiment comprises a compound of the formula in which n is 0 or an integer of from 1 to 6, the substituent -(CH2)nCOCF3 is in the meta or para position of the phenyl ring; and Z is

wherein q is an integer of from 1 to 6; R5 and R6 are each independently hydrogen or (C1-Cl8)alkyl; and Q and R7 are as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

Another preferred embodiment comprises a compound of the formula in which n is 0 or an integer of from 1 to 6; the substituent -(CH2)nCOCF3 is in the meta or para position of the phenyl ring; and Z is (a) hydrogen; (b) (C1-C18)alkyl; (c) (C1-C18)alkyl substituted by one or more, preferably 1-3, of (1) phenyl; (2) phenyl substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3 (C 1-C6)alkoxy, 1-3(C 1-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6)alkylthio, amino, 1-3 (C,-C6) alkylamino, di(C1-C6)alkylamino, -CO2H, -COO-

(C1-C6)alkyl, -SO3H, -SO2NHR15 in which R15 is hydrogen or (C1-C6)alkyl, or in which R2 and R3 are each independently hydrogen or (C,-C6) alkyl; (3) heterocyclic selected from oxadiazolyl, isoxazolyl, oxazolyl, furyl and thiazolyl; (4) heterocyclic substituted by one or more, preferably 1-3, of phenyl, phenyl substituted by 1-3 halo, (C1-C6)alkoxy, (C,-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C,-C6) alkylthio, amino, (C,-C6) alkylamino, di(C,-C6) alkylamino, CO2H, -COO-(C1-C6) alkyl, -SO3H, SO2NHRl5 in which Rl5 is hydrogen or (Cl-C6) alkyl, or in which R2 and R3 are as defined above, (Cl-C6) alkyl or (C1-C6) alkyl substituted by one or more, preferably 1-3, phenyl or heterocyclic groups, said phenyl or heterocyclic group being unsubstituted or substituted by 1-3 halo, 1-3 (C1-C6) alkoxy, 1-3 (C1-C6) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Cl-C6) alkylthio, amino, 1-3 (C1-C6) alkylamino, di(C1-C6) alkylamino, COOH, -COO-(Cl-C6) alkyl, -SO3H, -SO2NHR15 in which Rl5 is hydrogen or (C1-C6) alkyl, in which R2 and R3 are each independently hydrogen or (C,-C6) alkyl, the heterocyclic radical being selected from imidazolyl, oxadiazolyl, isoxazolyl, pyrrolyl, pyrazolyl, oxazolyl, furyl, thianyl or thiazolyl; (5) carboxy or-COO-(C,-C6) alkyl;

(6) hydroxy, halo, -O-(C,-C6) alkyl or -S-(Cl-C6) alkyl, with the proviso that the OH, ethers or thioethers cannot be on the carbon bearing the heteroatoms; (7) cyano; (8) halogen, trifluoromethyl or trifluoroacetyl; (9) CH2 L-R16 in which L is or -O-SiR16Rl8Rl9 or a bond in which R16 and R17 are each independently (C1-Cl8)alkyl or (C2-C 1 8)alkenyl or (C1-C18)alkyl or (C2-C18)alkenyl substituted by one or more, preferably 1-3, phenyl or heterocyclic radicals, said phenyl or heterocyclic radicals being unsubstituted or substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3 (C1-C6)alkoxy, 1-3(C1-C6)alkyl, nitro, cyano, hydroxy, 1-3 trifluoromethyl, 1-3 (C1-C6)alkylthio, amino, 1-3(C1-C6)alkylamino, 1-3 di(C1-C6)alkylamino, CO2H, 1-3 -COO(C1-C6)alkyl, -SO2NHR9 in which R9 is hydrogen or (C1-C6)alkyl and R2 and R3 are as defined above; and R18 and R'9 are phenyl or phenyl substituted by 1-3 halo, (Cl-C6) alkoxy, (Cl-C6) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C,-C6) alkylthio, amino, (C,-C6) alkylamino, di(C,-C6) alkylamino, CO2H, -COO-(C,-C6) alkyl, -SO3H, SO2NHR'5 in which R15 is o R2 hydrogen or (C,-C6) alkyl, or - c- N- R3 in which R2 and R3 are as defined above; or pharmaceutically acceptable salts, solvates or prodrugs thereof.

Another preferred embodiment comprises a compound of the formula in which n is 0, 1 or 2; or a pharmaceutically acceptable salt or prodrug thereof.

Preferred embodiments comprise a compound selected from those of the following

wherein (a) R25 is -(CH2)3CH3; (b) R25 is -(CH2)3CO2C2H5; (c) R25 is -(CH2)3CONHC2Hs; (d) R25 is -COCF3; (e) R25 is -COC6Hs; and (f) R25 is -PO(OC2Hs)2; or a pharmaceutically acceptable salt thereof.

Still other preferred embodiments comprise a compound of the formula wherein (a) R20 is -CO(CH2)10CH3; (b) R20 is -COCH(p-chlorophenyl)2; and

(c) R20 is -5O2(CH2)11CH3; or a pharmaceutically acceptable salt thereof.

Still other preferred embodiments comprise a compound selected from those of the following wherein (a) X11 and XIII are Cl; (b) XII and XIII are F; (c) XII and XIII are OCH3; and (c) XII is Cl and XIII is OCH3; or a pharmaceutically acceptable salt thereof.

Another preferred embodiment comprises a compound of the formula

wherein (a) n is 1 and R21 is OCH3; (b) n is 1 and R21 is Cl; (c) n is 2 and R21 is OCH3; and (d) n is 1-4 and R21 is OCH3 or Cl; or a pharmaceutically acceptable salt thereof.

Another preferred embodiment comprises a compound of the formula wherein (a) R22 is hydrogen and R23 is Cl; or (b) R22 is -CO2CH3 and R23 is -OCH3; or a pharmaceutically acceptable salt thereof.

Another preferred embodiment comprises a compound of the formula wherein R24 is Cl or-OCH3; or a pharmaceutically acceptable salt thereof.

Another preferred embodiment comprises a compound of the formula

wherein (a) R26 and R27are both CH3 or (C1-C6)alkyl-CF3; (b) R26 and R27are both Cl, F or Br; (c) R26 and R27are both OCH3 or SCH3; (d) R26 is Cl and R27 is OCH3; or (e) R26 and R27are both -COO-(Cl-C6)alkyl; or a pharmaceutically acceptable salt thereof.

Still other preferred embodiments comprise a compound selected from those of the following wherein (a) n is 0; (b) n = 1; and (c) n = 2; or a pharmaceutically acceptable salt thereof.

Still other preferred embodiments comprise a compound selected from those of the formula wherein (a) n = 0; (b) n = 1; and (c) n = 2; or a pharmaceutically acceptable salt thereof.

Some specific preferred embodiments of the present invention are:

R25 = (CH2)3CH3 R20 = CO(CH2)10CH3 R25 = (CH2)3CO2Et R20 = COCH(PhpCl)2 R25 = (CH2)3CONHEt R20 = SO2(CH2)11CH3 R25 = COCF3 R25 = COC6H5 R25 = PO(OEt)2 X" and X"' are CI n = 1, R21 = OCH3 XII and XIII are F n = 1 R21 = Cl XII and XIII are OCH3 n = 2, R21 = OCH3 X" is CI and X"' is OCH 3 n = 1-4, R21 = OCH3, CI R22 = H, , R23 = Cl R24 = CI R22 = CO2CH3, R23 = OMe R24 = OCH3 and

wherein (a) R26 and R27 are both CH3 or -(C,-C6)alkyl-CF3; (b) R26 and R27 are both Cl, F or Br; (c) R26 and R27 are both OCH3 or SCH3; (d) R26 is Cl and R27 is OCH3; or (e) R26 and R27 are both -COO-(Cl-C6)alkyl.

Especially preferred embodiments of the present invention include: The compounds of the present invention can be prepared by various methods which are known in the art. Illustrative methods of preparation are provided in the reaction schemes which follow and in the Examples.

Scheme 1 R R oH H°(CH2)n Ns PPh3-DIAD OCH Hn)n ;5, R PPh3-DIAD O(CH2) 4 (CH2),C02Me x1½½ R or (CH2)mCO2Me (CH2)mCO2Me R (cH2)mco2Me X(CH2)n potassium 3b R R O(CH2)nNs R O(CH2)nNs R XX , XX P O(CH2)n p ethanol (CH2)mCO2H dichloromethane (CH2)mCOCF3 2) TFAA-Pyridine 6 21 2) TFAA-Pyridine Scheme 2 OH O Br ~~~~ BrCH2CH2Br x P1 NH2 x BrCH2CH2Br ~ x~ K2C03 ~ K2C03 Nal isopropanol I 7 (CH2)nP2 \HOzK R PPh3-DIAD tetrahydrofuran\ H (GH2)nR2 P (CH2)(n.1)CHO o/\/ Y R' NaBH3CN methanol x or Ewg x or R2(CH2)nl 9 or Ewg I 9 10 ( ICH2)nR2 ( ICH2)nR2 OH O~ K R' o/\/ Y 1) H2,PdIC CF3 , ethyl acetate A Pd(OAc)2 Ap 2) Dess-Martin (BU)4NCI | Periodinane dimethylformamide j dichloromethane HO CF3 OW CF3 11 12

Scheme 3 Scheme 4 OMe 1)(COCl)2 OMe dichloromethane 2) TFAA-Pyridine- CO2H 0 CF3 17 BBr3 OH HC(OMe)3 OH dichloromethane Hz nitromethane ;3 Q methanol O CF3 MeO CF3 OMe 18 19 O~ o~NHR ~~~~~~ RNH2 5 isopropanol 1 NleO of MeO MeO 3 MeO CF3 20 21 OHC(CH2)(n.l )R' (CH2)nR1 (CH2)nR2 NaBH3CN O~ N O~N*R N methanol or I 1) Reaction on P1 RX 9 2) Reaction or R1 TFA or EWG AeO/t CF3 MeO 22

Scheme 5 H P1 o~Ns R O~Ns R P1 1 isopropanol MeO YeOO CF3 MeO CF3 21 24 R1 O ~ Ns R TFA ° CF3 25

Scheme 6 OH ROH o,R PPhDlAD W tetrahydrofuran, W or < RX <] MOO MoO MoO CF3 MoO CF3 Ia o,R 0 TFA N ° CF3 7 Scheme 7 R OH 0 CO2tBu Q + HO > PPH3-DIAD 143 CO2tBU benzene CHO CHO 28 29 R R °~ CO2tBu 1) H2/Pd/BaSO4 COBu ethyl acetate gA CF3COCH3 N N Piperidine-AcOH T 2) Dess-Martin tetrahydrofuran t Periodinane C 0 CF3 CF3 31 32 R R I tetrahydrofuran TFA ~ water-sodium acetate f or N N R2S 02CI dichloromethane triethyl amine CF3 CF3 33a 33b Scheme 8 H OH N 0 I I CF3COCH3 N Piperidine-AcOH CHO tetrahydrofuran o CF3 8 BrCH2CO2tBu BrCH 2COztBuacetone acetone \ potassium carbonate potassium carbonate S (or R2COCI) OCH2CO2tBu 0CH2CO2tBu / 2 Fo CF3COCH3 N or N Piperidine-AcOH CHO tetrahydrofuran CF3 CF3 36 36 36b (from 34) W0 CO2H --"NCONRR1 36 TFA I EEDQ 3 dichloro- EEDO N methane tR tetrahydrofuran o CF3 CF3 Z ,0 CONRRt H;EPd/BaSO ethyl acetate N Dess-Martin Periodinane dlchloromethane CF3

Scheme 8 (cont.) CO2tBu 0> H2, Pd/BaSO4 9" ° ethyl acetate N Doss-Martin Periodinane L dichloromethane O '' CF3 CF3 40 ~~ NPp1 o CO2H 1)(COCI)2 0 TFA Iatl dichloromethane dichloromethane N 2) RR1NH tetrahydrofuran water/sodium acetate 0 CF3 CF3 41 Scheme 9 RSH + BrCH2CH20H < RSCH2CH20H DMF potassium carbonate 43 OH C + HOCHCHPSR g v PPh3-DIAD < 43 benzene OMe 0 °;\OMe °;OMe 42 44 Osp .SR 1)(COCl)2 KOH dichioromethane I water <t/ 2) TFAA-Pyridine N ethanol dichloromethane OH CF3 45 46 mCPBA/ | NalO4 / I methanol 99 O ~SR O~SR NI NI CF3 CF3 47 48 R = C1-C18 alkyl = (C1-C6) alkyl X(C1-C6) mono or bis aryl or mono or bis heterocycles X = N-R1O, S, SO, SO2

Method of Preparation Preparation of compounds of formula I may be accomplished via one or more of the synthetic schemes which are described below.

Scheme 1 Scheme I shows a method of preparing compounds of general structure 6. Reaction of a phenol 2 bearing a protected carboxylate group with an alcohol 3, triphenylphosphine and diethyl azodicarboxylate or diisopropyl azodicarboxylate under Mitsunobu conditions (0. Mitsunobu, Synthesis, 1, 1981) in a solvent such as tetrahydrofuran or benzene gave the ether 4. Alternatively, the phenol 2 can be alkylated with a substituted alkyl halide (RX) and a base such as potassium carbonate in a solvent such as acetonitrile or dimethylformamide to give the ether 4. The ester group of 4 is then saponified to the acid 5 by treatment with a base such as sodium hydroxide or potassium hydroxide in a solvent such as aqueous ethanol followed by neutralization with a diluted acid. The acid 5 is then treated with oxalyl chloride or thionyl chloride in a solvent such as dichloromethane to give an intermediate acid chloride. The acid chloride is then treated with trifluoroacetic anhydride and a base such as pyridine following conditions similar to those used by S.Z. Zard (Tetrahedron 51, 2573-2584, 1995) to give the trifluoromethyl ketone 6.

Scheme 2 Scheme 2 describes a method of preparing compounds of structure 12. Reaction of an iodo-substituted phenol 7 with a dibromo alkane of structure Br(CH2)nBr in the presence of a base such as potassium carbonate gives 8. The bromide 8 is then displaced with a mono or disubstituted amine in the presence of sodium iodide in a solvent such as isopropanol to give 9 or 10. Alternatively, compound 10 can also be obtained under Mitsunobu conditions as described in Scheme 1. Tertiary amines 10 are also obtained by reaction of 9 with various aldehydes RCHO by reaction with a reducing agent such as sodium cyanoborohydride in a solvent such as methanol. Similar tertiary amines 10 are also prepared by

reaction of 9 with an iodo compound R(CH2)nI in the presence of a base such as potassium carbonate in a solvent such as isopropanol.

Reaction of secondary amine 9 with a Michael-type acceptor CH2=CH2-EWG such as ethyl acrylate or acrylonitrile in a solvent such as ethanol also yields substituted amines 10. Reaction of iodophenol 10 with 4,4,4-trifluorobut-1-en-3-ol (J.A. Pegolotti and W.G. Young, J. Am. Chem.

Soc., 1961, X, 3251), under Heck-type conditions (T. Jeffery, J. Chem. Soc.

Chem. Commun., 1287, 1984) in the presence of a palladium catalyst such as palladium (II) acetate in a solvent such as N,N-dimethylformamide gives the allylic alcohol 11. Hydrogenation of this allylic alcohol in the presence of a catalyst such as palladium on activated carbon in a solvent such as ethyl acetate gave an intermediate alcohol which was oxidized to the ketone 12 with the Dess-Martin periodinane (D.B. Dess and J.C.

Martin, J. Org. Chem., 1983, , 4155) in a solvent such as dichloromethane.

Scheme 3 Scheme 3 describes a method of preparing quaternary structures of type 14 and 15. The tertiary amine 13 is alkylated with an alkyl iodide such as methyl iodide or ethyl iodoacetate in a solvent such as isopropanol to give the quaternary amine 14. In the case where one of the R groups contains an ester group, saponification with a base such as potassium hydroxide in a solvent such as aqueous ethanol gives the zwitterionic species 15.

Scheme 4 Scheme 4 shows a method of preparing various trifluoromethyl ketones 23 from intermediates in which the trifluoromethyl ketone is protected as a ketal group. Starting from the acid Al which is commercially available, the trifluoromethyl ketone 17 is prepared using the method described in Scheme 1. The methyl ether 17 is then cleaved with boron tribromide in a solvent such as dichloromethane to give the phenol Th. The ketone group is then protected as a ketal 19 by reaction with an orthoester such as trimethyl orthoformate catalyzed by an acid

such as trifluoromethanesulfonic acid and in solvents such as nitromethane and methanol. The phenol 19 is then treated as described for 7 in Scheme 2 to give AQ 21 and 22. The protected trifluoromethyl ketone in 22 allows various modifications on R1 such as reduction of an ester group with lithium aluminum hydride or diisobutyl aluminum hydride. The ketal group is then cleaved with an acid such as trifluoroacetic acid to give 23.

Scheme 5 Scheme 5 describes preparation of tertiary amines by alkylation of intermediate 21 obtained in Scheme 4 by reaction with an alkyl iodide such as iodopropane in a solvent such as isopropanol and in the presence of a hindered base such as N,N-diisopropylethylamine. The ketal 24 is then cleaved as described in Scheme 4 to give the trifluoromethyl ketone 25.

Scheme 6 Scheme 6 describes preparation of a variety of trifluoromethyl ketones 27 starting from the phenol 19 obtained in Scheme 4. Reaction of 19 with various alcohols of structure ROH under the Mitsunobu conditions described in Scheme 1 gave 26. Deprotection of the ketal group as described in Scheme 4 gives 27 possessing a variety of ether substituents.

Scheme 7 Scheme Z shows a synthetic route to acylated or sulfonylated amines 33. Reaction of 4-hydroxybenzaldehyde with a t-butoxycarbonyl- protected amino-alcohol such as 29 under Mitsunobu conditions similar to those described in Scheme 1 gives the aldehyde 30. Aldol condensation of 30 with 1,1,1-trifluoroacetone catalyzed by piperidine and acetic acid using conditions similar to those used by R.S.H. Liu (Tetrahedron Lett., X, 2873, 1985) gave the enone 31. The enone 31 was then hydrogenated in the presence of a catalyst such as palladium on barium sulfate and treated with Dess-Martin periodinane as described in Scheme 2 to re-oxidize the

partially reduced carbonyl group to give 32. The t-butoxycarbonyl- protected amino derivative 32 is then treated with an acid such as trifluoroacetic acid in a solvent such as dichloromethane to give an intermediate amine as a trifluoroacetate salt. This amine is then acylated with various acyl chlorides such as palmitoyl chloride under Schotten- Baumann conditions in a mixture of solvents such as tetrahydrofuran and saturated aqueous sodium acetate to give amide 33. Alternatively, the amine trifluoroacetate salt can be treated with an alkylsulfonyl chloride such as 1-heptanesulfonyl chloride or an alkyl isothiocyanate such as N- decyl isothiocyanate in presence of a base such as triethylamine and in a solvent such as dichloromethane to give a sulfonamide or a thiourea respectively.

Scheme 8 Scheme 8 describes a method of preparing amides of structure 39 which are regioisomers of structures described in Scheme 7. 4- Hydroxybenzaldehyde was treated with 1,1,1-trifluoroacetone as described in Scheme 7 and alkylated with a bromoester such as t-butyl bromoacetate in the presence of a base such as potassium carbonate and in a solvent such as acetone to give 36. Alternatively 36 can be obtained via the same sequence of steps but in inverse order. The phenol 34 can also be acylated with various acid chlorides such as a palmitoyl chloride to give ester derivatives such as 36b. The t-butyl protecting group of 36 is then cleaved with an acid such as trifluoroacetic acid in dichloromethane to give the acid 37. This acid is then reacted with primary and secondary amines such as dodecylamine in the presence of a condensing agent such as N- ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline (EEDQ) to give the amide 38. Reduction and oxidation of the enone as described in Scheme 2 gave the amide 39. Alternatively, the enone 36 can be reduced first to 40 and then cleaved as above to the acid 41. The acid 41 is then treated with oxalyl chloride in dichloromethane to give an intermediate acid chloride.

Reaction of this acid chloride with primary and secondary amines such as p-chlorobenzhydrylamine hydrochloride in a mixture of tetrahydrofuran and saturated aqueous sodium acetate also gives amides of structure 39.

Scheme 9 Scheme 9 describes a method for making compounds of structure X, 47 and 48 which contain a sulfur atom. Reaction of an alcohol 43 which contains a sulfur atom, usually obtained by reaction of a thiol with a halogen-substituted alcohol, with phenol 42 under Mitsunobu conditions as described in Scheme 1 gives the ether 44. Preparation of the trifluoromethylketone 46 is then achieved via the two-step sequence also described in Scheme 1. Oxidation of 46 with a peracid such as m- chloroperbenzoic acid gives the sulfone 47. Oxidation of 46 with sodium periodate in a mixture of methanol and water affords the sulfoxide 48.

Biological Activitv Assay for determining activity as cPLA2 inhibitors: 3H-arachidonate-labeled U937 membranes were prepared from U937 cells grown in RPMI 1640 medium containing L-glutamine supplemented with 10% fetal calf serum and 50 ,ug/ml gentamycin in a 5% CO2 incubator at 370C. Sixteen hours prior to harvesting the cells, 3H- arachidonate (100 Ci/mmol) was added to the cell culture (1x106 cells/ml, 0.5 ,uCi/ml). After washing the cells with HBSS (Hank's Balanced Salts) containing 1 mg/ml HSA (Human Serum Albumin), the cells were lysed by nitrogen cavitation and the homogenate was centrifuged at 2,000x g for 10 minutes. The supernatant was further centrifuged at 50,000x g for 30 minutes after which the pellet was resuspended in water and autoclaved at 1200C for 15 minutes to inactivate any residual phospholipase A2 activity. This suspension was then recentrifuged at 50,000x g for 30 minutes and the pellet resuspended in distilled water.

Assays of cPLA2 activity using these 3H-arachidonate-labeled U937 membranes as substrate typically employ human recombinant cPLA2 (see

Burke et al., Biochemistry 34: 15165-15174, 1995) and membrane substrate (22 ,um phospholipid) in 20 mm HEPES [N-(2-hydroxyethyl)piperazine-Nl- (2-ethanesulfonic acid)] buffer, pH 8, containing 6 mm CaCl2, 0.9 mg/ml albumin and 4 m glycerol. Enzyme assays are allowed to proceed for 3 hours at 37CC before removing the non-hydrolyzed membranes. The hydrolyzed, radiolabeled fatty acid is then measured by liquid scintillation counting of the aqueous phase.

The effects of inhibitor are calculated as percent inhibition of 3H- arachidonate formation, after correcting for nonenzymatic hydrolysis, as compared to a control lacking inhibitor according to the following formula: percent inhibition = ((Control DPM - Inhibitor DPM)/Control DPM) x 100% Various concentrations of an inhibitor were tested, and the percent inhibition at each concentration was plotted as log concentration (abscissa) versus percent inhibition (ordinate) to determine the IC50 values.

In this assay the compounds of Examples 1-274 below exhibited cPLA2 IC50 values in the range of from about 1 to 50 Clam.

Since the compounds of the present invention are selective inhibitors of cytosolic phospholipase A2, they are of value in the treatment of a wide variety of clinical conditions.

Inflammatory disorders which may be treated by inhibition of cytosolic cPLA include such conditions as arthritis, psoriasis, asthma, inflammatory bowel disease, gout, trauma-induced inflammation such as spinal cord injury, Alzheimer's Disease, cerebral ischemia, chronic skin inflammation, shock, damage to skin resulting from exposure to ultraviolet light or burns, allergic rhinitis, acute pancreatitis, and the like.

The compounds of formula I are usually administered in the form of pharmaceutical compositions. They can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. The compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound defined by formula I and a pharmaceutically acceptable carrier.

In making the compositions employed in the present invention the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semisolid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.

The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

The active compound is effective over a wide dosage range. For example, dosages per day normally fall within the range of about 0.5 to about 30 mg/kg of body weight. In the treatment of adult humans, the range of about 1 to about 15 mg/kg/day, in single or divided dose, is especially preferred. However, it will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaller doses for administration throughout the day.

SPECIFIC EXAMPLES The following examples further illustrate the preparation of the compounds of formula I. The examples are illustrative only and are not intended to limit the scope of the invention in any way. The following abbreviations have the indicated meanings: AcOH acetic acid EWG electron-withdrawing groups DIAD diisopropyl azodicarboxylate TFAA trifluoroacetic anhydride r.t. room temperature THF tetrahydrofuran TFA trifluoroacetic acid EEDQ N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroxyquinoline DMF N,N-dimethylformamide DEAD diethyl azodicarboxylate CPBA m-chloroperbenzoic acid Me CH3 Ph phenyl tBu tert-butyl Scheme 1 R R OH HO(CH2)n Ns R PPh3-DIAD O(CH2)n;J- X- tetrahydrofuran X- or XWN\ (cH2)mco2Me R (CH2)mCO2Me X(CH2)n potassium 4 p carbonate 4 3b R R °(cH2)nNs R O(CH2),N, R KOH 1) (COCI)2 4 ethanol (CH2)mCO2H dichloromethane (CH2)mCOCF3 5 2) TFAA-Pyridine 6

Example 1 4-[4-[2-(N-Dodecyl-N-methylamino)ethoxy)phenyl]1,1,1-trifluo ro-2- butanone N-Methyl-N-Dodecylethanolamine A solution of iodododecane (18.1 g, 61.09 mmol) and 2- (methylamino)ethanol (23.0 g, 0.3 mol) in isopropanol (75 ml) was heated under reflux for 3 h. The cooled mixture was diluted with ether (500 ml), washed with water, brine and dried (magnesium sulfate). Evaporation of the solvent under reduced pressure and distillation of the residue under vacuum gave 14.5 g (97%) of N-methyl-N-dodecylethanolamine as a clear oil: b.p. 100-111°C/0.3 torr (bulb to bulb distillation, air bath temperature).

IR (NaCl, film) umax (cm ) 3400 (OH).

1H NMR 400 MHz (CDCl3) d (ppm): 0.89 (3H, t, J=5.36 Hz, CH3), 1.1-1.5 (20H, br m, (CH2)10)I 2.24 (3H, s, NCH3), 2.39 (2H, t, J=7.4 Hz, NCH2), 2.52 (2H, t, J=5.35 Hz, OCHvCHvN), 3.58 (2H, t, J=5.35 Hz, OCH2CH2N).

3-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]phenyl]-propanoic acid methyl ester A solution of methyl 3-(4-hydroxyphenyl)propionate (10.0 g, 55. 5 mmol), N-methyl-N-dodecylethanolamine (13.5 g, 55.5 mmol) and triphenylphosphine (16.0 g, 61.0 mmol) in dry tetrahydrofuran (200 ml) was treated at 22°C with diisopropyl azodicarboxylate (12.3 g, 61.0 mmol) added dropwise over 50 min. After 3 h at 220C, the reaction mixture was evaporated under reduced pressure and the residue was triturated with hexane. The solid formed was filtered, washed with hexane and the combined filtrate was chromatographed on silica gel using a gradient of ethyl acetate in hexane (20% - 60%) as eluent. Distillation under vacuum then gave 18.0 g (75%) of 3-{4-[2-(N-dodecyl-N- methylamino)ethoxy]phenyll propanoic acid, methyl ester as a clear oil: b.p. 180-183"C/0.02 torr (bulb to bulb distillation, air bath temperature).

1H NMR 400 MHz (CDCl3) d (ppm): 0.89 (3H, t, J=6.8 Hz, CH3), 1.2-1.6 (20H, m, CH2)10)I 2.33 (3H, s, NCH3), 2.43 (2H, t, J=7.6 Hz, NCH2), 2.60 (2H, t, J=7.77 Hz, CH2-2), 2.78 (2H, t, J=6.06 Hz, OCHvCH2N), 2.89 (2H, t, J=7.77 Hz, CH2-3), 3.67 (3H, s, OCH3), 4.04 (2H, t, J=6.06 Hz, OH~2CH2N), 6.84 (2H, d, J=8.55 Hz, aromatic), 7.11 (2H, d, J=8.55 Hz, aromatic).

The hydrochloride salt was obtained by treating the amine with anhydrous hydrochloric acid (1M) in ether.

Anal. Calcd. for C25H43NO3.HCl: C 67.92, H 10.03, N 3.17.

Found: C 67.74, H 9.46, N 3.25.

3-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]phenyl]-propanoic acid. hvdrochloride salt.

A solution of 3-[4-[2-(N-dodecyl-N-methylamino)ethoxy]phenyl]propanoic acid methyl ester (2.30 g, 5.69 mmol) in ethanol (25 ml) was treated with potassium hydroxide (0.64 g, 11.4 mmol) and water (5 ml) and stirred at 220C for 2 h. The reaction mixture was then acidified to pH 4 with 1M hydrochloric acid and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure to give a white solid. Recrystallization from ethyl acetate gave 2.20 g (89%) of 3-[4-[2-(N-dodecyl-N- methylamino)ethoxy]phenyl]propanoic acid as white crystals.

IR (KBr) umax (cm 1) 1725 (C=O of carboxylate).

1H NMR 400 MHz (CDCl3) d (ppm) : 0.89 (3H, t, J=6.8 Hz, -CH3), 1.2-1.4 (18H, br m, (CH2)9), 1.87 (2H, m, NCHCH2), 2.61 (2H, t, J=7.5 Hz, CH2-2), 2.87 (3H, s, NCH3), 2.88 (2H, t, J=7.5 Hz, CH2-3), 3.11 (2H, br t, NCH2(CH2), 3.44 (2H, br t, OCH2CH2N), 4.41 (2H, br t, O H2CH2N) 6.81 (2.11, d, J=8.58 Hz, aromatic), 8.56 (2H, d, J=8.58 Hz, aromatic).

Anal. Calcd. for C24H41NO.HCl: C 67.34, H 9.89, N 3.27.

Found: C 67.08, H 9.82, N 3.18.

4-14- [2-(N-Dodecyl-N-methylamino)ethoxy] phenyl] 1.1.1 -trifluoro-2- butanone A solution of 3- [4- [2-(N-dodecyl-N-methylamino)ethoxyjphenyl]propanoic acid hydrochloride salt (3.30 g, 7.71 mmol) in dry dichloromethane (35 ml) was treated with oxalyl chloride (1.61 g, 12.7 mmol) and a small drop of N,N- dimethylformamide. After 1 h at 220C, the solvent and excess reagent were evaporated under reduced pressure and the residue was dissolved in dry dichloromethane (35 ml). This solution was then added to a solution of trifluoroacetic anhydride (5.31 g, 24.2 mmol) in dry dichloromethane (30 ml) cooled to OOC and treated dropwise with pyridine (1.4 ml, 17.3 mmol). After stirring for 30 min at OOC and another 1.5 h at 220C, the reaction mixture was cooled again to OOC and treated dropwise with water (13 ml). After 30 min at 0°C and another 30 min at 220C, the reaction mixture was adjusted to pH 8-9 with solid sodium bicarbonate and diluted with dichloromethane (200 ml).

The organic phase was then washed with brine and dried (magnesium sulfate). The solvent was evaporated under reduced pressure and the residual oil was chromatographed on silica gel. Elution with a gradient of ethyl acetate in hexane gave an oil which was distilled under vacuum to give 2.45 g (71%) of 4-[4-[2-(N-dodecyl-N-methylamino)ethoxy]phenyl]1,1,1- trifluoro-2-butanone as a clear oil: b.p. 1600C/0.02 torr (bulb to bulb distillation, air bath temperature).

IR (NaCl, film) umax (cm : 1760 (C=O).

1H NMR 400 MHz (CDCl3) d (ppm) : 0.89 (3H, t, J=6.8 Hz, -CH3), 1.1-1.6 (20H, m, (CH2)10)I 2.32 (3H, s, NCH3), 2.44 (2H, t, J=7.6 Hz, NCH2), 2.79 (2H, t, J=6.0 Hz, OCH2CH2N), 2.94 and 3.0 (2 x 2H, 2m, CH2-3 and 4), 4.06 (2H, t, J=6.0 Hz, OCH2CH2N), 6.86 (2H, d, J=8.6 Hz, aromatic), 7.10 (2H, d, J=8.6 Hz, aromatic).

Anal. Calcd. for C25H40F3NO2.0.6 H2O: C 68.08, H 9.09, N 3.16.

Found: C 68.08, H 9.19, N 3.11.

The hydrochloride salt was obtained by treating the amine with anhydrous hydrochloric acid (1M) in ether.

Anal. Calcd. for C25H40F3NO2.HCl. 1.1 H2O: C 60.07, H 8.71, N 2.80.

Found: C 59.99, H 8.62, N 2.98.

Example 2 4-[4-[3-(N-Dodecyl-N-methylamino)propoxy]phenyl]-1,1,1-trifl uoro-2- butanone 3-(N-dodecyl-N-methylamino)propanol A solution of 3-(methylamino)propanol (5.71 g, 64.0 mmol, S. Koepke, R.

Kupper, and C.J. Michejda, J. Org. Chem., X, 2718, 1979)), and iodododecane (7.58 g, 25.6 mmol) was reacted as described in example 1 to give 6.33 g (96%) of the title material as an oil, b.p. 100-105°C/0.04 torr.

3-[4-[3-(N-dodecyl-N-methylamino)propoxy]phenyl]propanoic acid, methyl ester.

Methyl 3-(4-hydroxyphenyl)propanoate (1.0 g, 5.5 mmol) and 3-(N- dodecyl-N-methylamino)propanol (1.43 g, 5.5 mmol) were reacted as described in example 1 to give 1.57 g (43%) of title material as an oil.

Anal. Calcd. for C26H45NO3: C 74.42, H 10.81, N 3.34.

Found: C 74.02, H 10.54, N 3.49.

3-[4-[3-(N-Dodecyl-N-methylamino)propoxy]phenyl]propanoic acid, hydrochloride 3-[4-[3-(N-dodecyl-N-methylamino)propoxy]phenyl]propanoic acid, methyl ester (1.53 g, mmol) was reacted as described in example 1 to give 1.20 g (74%) of the starting material as an amorphous solid.

Anal. Calcd. for C26H45NO3: C 74.42, H 10.81, N 3.34.

Found: C 74.02, H 10.54, N 3.49.

4-[4-[3-(N-Dodecyl-N-methylamino)propoxy]phenyl]1,1,1-tri fluoro-2- butanone 3-[4-[3-(N-dodecyl-N-methylamino)propoxy]phenyl]propanoic acid, hydrochloride (0.45 g, 1.11 mmol) was reacted as described in example 1 to give 0.185 g (36%) of the title material as an oil, b.p. 140-160"C/0.04 torr (bulb to bulb distillation, air bath temperature).

Anal. Calcd. for C26H42F3NO2.0.2H2O: C 67.71, H 9.27, N 3.04.

Found: C 67.75, H 9.35, N 2.90.

The hydrochloride was obtained as a syrup.

Example 3 4-[4-14-(N-Dodecyl-N-methylamino)butoxyiphenylil,1 1-trifluoro-2- butanone Methyl 3-[4-(4-bromobutoxy)phenyl]propanoate A mixture of methyl 3-(4-hydroxyphenyl) propionate (1.19 g, 6.6 mmol), 1,4-dibromobutane (10 g, 46.3 mmol) and powdered anhydrous potassium carbonate (2.3 g) was maintained at 800C and stirred vigorously for 24 h.

Alter cooling, the solid was filtered and washed with a mixture of hexane and ethyl acetate (4:1). The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel. Elution with a gradient of ethyl acetate (0-3%) in toluene gave 1.80 g (86%) of the title material as an oil.

Anal. Calcd. for C14H19BrO3: C 53.25, H 6.08.

Found: C 53.24, H 5.74.

3-[4-t4-(N-Dodecvl-N-methylamino)butoxv]phenyl]-propanoic acid. methyl ester A mixture of methyl 3-(4-bromobutoxy)phenyl]propanoate (1.46 g, 4.63 mmol), N-methyldodecylamine (2.31 g, 11.6 mmol) and sodium iodide (50 mg) in acetonitrile (17 ml) was heated at 750C for 3 h. The reaction mixture was then cooled, diluted with dichloromethane, washed with saturated sodium bicarbonate, brine and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure and the residue was chromatographed on silica gel. Elution with

a gradient of methanol (0 - 5%) in ether gave 1.69 g (85%) of the title material as an oil.

Anal. Calcd. for C27H47NO3: C 79.48, H 10.92, N 3.23.

Found: C 74.62, H 10.58, N 3.25.

3-[4-[4-(N-Dodecyl-N-methylamino)butoxy@phenyl]-propanoic acid, hydrochloride 3-[4-[4-N-dodecyl-N-methylamino)butoxy]phenyl]propanoic acid, methyl ester (0.800 g, 1.84 mmol) was saponified as described in example 1 to give 0.778 g (93%) of the title material as white crystals after crystallization from ethyl acetate; m.p. 109 - 111°C.

Anal. Calcd. for C26H45NO3.HCl: C 68.47, H 10.17, N 3.07.

Found: C 68.49, H 9.92, N 3.07.

4-[4-[4-(N-Dodecyl-N-methylamino)butoxy@phenyl]-1,1,1-tri fluoro-2- butanone 3-[4-[4-(N-dodecyl-N-methylamino)butoxy]phenyl]-propanoic acid, hydrochloride (0.740 g, 1.76 mmol) was reacted as described in example 1 to give 0.420 g (51%) of the title material as an oil: b.p. 150 - 1800C/0.025 torr (bulb to bulb distillation, air bath temperature).

Anal. Calcd. for C27H44F3NO2: C 68.76, H 9.40.

Found: C 68.52, H 9.38.

The hydrochloride was obtained as a syrup.

Anal. Calcd. for C27H44F3NO2.HCl.0.5 H2O: C 62.71, H 8.97, N 2.71.

Found: C 62.69, H 8.71, N 2.76.

Example 4 [2-[2-(N-Dodecyl-N-methylamino)ethoxy]phenyl]-2,2,2-trifluor oethanone 2-Trifluoroacetylphenol (Matsumoto, S.; Kobayashi, H. and Ueno, K.

Bull.Chem. Soc. Jpn. 1969, 42, 960) (490mg, 2.57mmol) and 2-[N-dodecyl-N- methylamino] ethanol (627mg, 2.58mmol) were reacted by the general procedure as described in example 1 and afforded the title compound (654mg, 61%) as a pale yellow oil.

Analysis for C23H36F3NO2 0.3H2O calcd. C 65.63%, H 8.76%, N 3.33%; Found: C 65.44%, H 8.74%, N 3.48%.

Treatment of the above free amine with anhydrous hydrogen chloride (1.0 M in ether) gave the hydrochloride salt as a white waxy solid.

Analysis for C23H36F3NO2 HCl 0.5H2O calcd. C 59.92%, H 8.31%, N 3.04%; Found: C 59.67%, H 8.49%, N 3.16%.

Example 5 4-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]-2-methoxyphenyl]-1, 1,1- trifluoro-2-butanone 7- r [2-(N-Dodecyl-N-methylamino)ethoxy] -2H-1 -benzopyran-2-one 7-Hydroxycoumarin (6.0g, 37.0mmol) and 2- [N-dodecyl-N-methylamino] ethanol (9.0g, 37.0mmol) were reacted by the general procedure as described in example 1 and afforded the title compound (6.7g, 47%) as a white solid.

Analysis for C24H37NO3 calcd C 74.38%, H 9.62%, N 3.61%; Found: 74.35%, H 9.45%, N 3.66%.

7-[2-(N-Dodecyl-N-methylamino)ethoxy]-3,4-dihydro-2H-1-be nzopyran-2- one 7-[2-(N-Dodecyl-N-methylamino)ethoxy]-2H-1-benzopyran-2-one (5.62g, 14.5mmol) in ethyl acetate was hydrogenated over palladium on activated carbon uder 30 psi and afforded the title compound (4.7g, 84%) as a white solid.

Treatment of the above free amine with anhydrous hydrogen chloride (1.0 M in ether) gave the hydrochloride salt as a white solid.

Analysis for C24H39N O3 HCl 0.7H20 calcd. C 65.72%, H 9.51%, N 3.19%; Found: C 65.76% H 9.35% N 3.26%.

3-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]-2-hydroxyphenyl] propanoic acid, methyl ester A solution of 7-[2-(N-Dodecyl-N-methylamino)ethoxy] -3,4-dihydro-2H-1- benzopyran-2-one (2.0g, 5.13mmol) in methanol (30ml) was stirred at 220C for 0.5h. The solvent was then removed in vacuo at 400C to afford the title compound (2.14g, 100%) as a white solid.

3-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]-2-methoxyphenyl] propanoic acid, methyl ester 3-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]-2-hydroxyphenyl]pro panoic acid, methyl ester (500mg, 1.18mmol) and methanol (0.096ml, 2.37mmol) were reacted under Mitsunobu conditions as described in example 1 and afforded the title compound (471mg, 81%) as a pale yellow oil.

3-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]-2-methoxyphenyl] propanoic acid. hvdrochloride 3-[4- [2-(N-Dodecyl-N-methylamino)ethoxy]-2-methoxyphenyl]propanoi c acid, methyl ester (468mg, 1.07mmol) was saponified as described in the preparation of 3-[4-[2-(N-dodecyl-N- methylamino)ethoxy]phenyl]propanoic acid, hydrochloride and afforded the title compound (280mg, 62%) as a white solid.

Analysis for C25H43NO4 calcd. C 64.60%, H 9.46%, N 3.01%; Found: C 64.69%, H 9.52%, N 3.22%.

4-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]-2-methoxyphenyl] -1,1,1- trifluoro-2-butanone 3-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]-2-methoxyphenyl]pro panoic acid, hydrochloride (274mg, 0.598mmol) was reacted by the general

procedure as described in the preparation of 4-[4-[2-(N-dodecyl-N- methylamino)- ethoxy]phenyl]-1,1,1-trifluoro-2-butanone and afforded the title compound (165mg, 58%) as a pale yellow oil (b.p. 138- 1400C /0.015mmHg).

Treatment of the above free amine with anhydrous hydrogen chloride (1.0 M in ether) gave the hydrochloride salt as a off-white sticky solid.

Analysis for C26H42F3NO3 HCl 0.7H2O calcd. C 58.80%, H 8.76%, N 2.74%; Found: C 58.89%, H 8.53%, N 2.64%.

Example 6 7-[2-(N-Dodecyl-N-methylamino)ethoxy]-3,4-dihydro-2-(trifluo romethyl)- 2H-1-benzopvran-2-ol A mixture of 4-[4-[2-(N-dodecyl-N-methylamino)ethoxy]-2- methoxyphenyl]-1,1,1-trifluoro-2-butanone (157mg, 0.33mmol) and hydrobromic acid (47%, 3ml) was refluxed for 3.5h. After cooling to r.t., the mixture was diluted with water, extracted with dichloromethane. The organic layer was washed with sat. sodium bicarbonate, brine, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (ethyl acetate/acetone 3 : 1) to afford the title compound (60mg, 40%) as a clear oil.

Treatment of the above free amine with anhydrous hydrogen chloride (1.0 M in ether) gave the hydrochloride salt as a off-white sticky solid.

Analysis for C2sH40F3NO3 HCl 0.3H2O calcd. C 59.88%, H 8.36%, N 2.79%; Found: C 59.84%, H 8.29%, N 2.79%.

Example 7 4-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]-2-vinylphenyl]-1,1, 1-trifluoro- 2-butanone 3- [4- [2-(N-Dodecyl-N-meffiylamino)ethoxyl-2- {frifluoromethanesulfonyloxyl phenyll propanoic acid, methyl ester

To a solution of 3-[4-[2-(N-dodecyl-N-methylamino)ethoxy]-2 hydroxyphenyl]propanoic acid, methyl ester (2.53g, 6.0mmol) and dry pyridine (1.94ml, 24.0mmol) in dichloromethane (30ml) at OOC was added dropwise trifluoromethanesulfonic anhydride (2.lml, 12.0mmol). After- stirring for 20h at 220C, the mixture was diluted with ethyl acetate (120ml), washed with water (3x50ml), brine (50ml), dried over magnesium sulfate and concentrated in vacuo. The residue was placed at 0°C and triturated with diethyl ether. The formed solid (trifluoromethanesulfonic acid salt of the title compound) was dissolved in dichloromethane, washed with sat. sodium bicarbonate, brine and dried over magnesium sulfate. The solvent was removed in vacuo to afford the title compound (2.15g, 69%) as a brown oil which solidified upon standing.

3-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]-2-vinylphenyl]pr opanoic acid, methyl ester To a solution of 3-[4-[2-(N-dodecyl-N-methylamino)ethoxyj-2- [trifluoromethanesulfonyloxy]- phenyl]propanoic acid, methyl ester (250mg, 0.48mmol) in 1,4-dioxane (2.5ml) were added tributylvinyltin (1.2ml, 4.0mmol), lithium chloride (123mg, 1.44mmol), tetrakis(triphenylphosphine)-palladium(0) (1 Omg) and 2,6-di-tert-butyl-4- methylphenol (lOmg). The resulting mixture was then stirred at 1000C for 5h. After cooling to r.t., the mixture was diluted with diethyl ether, washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (diethyl ether/acetone 100 : 0 to 80 : 20) to afford the title compound (170mg, 80%) as a yellow oil.

3-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]-2-vinylphenyl]pr opanoic acid, hvdrochloride 3-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]-2-vinylphenyl]propa noic acid, methyl ester (178mg, 0.412mmol) was saponified as described in the preparation of 3-[4-[2-(N-dodecyl-N- methylamino)ethoxy]phenyl]propanoic acid, hydrochloride and afforded the title compound (175mg, 93%) as a clear oil.

4-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]-2-vinylphenyl]-1 ,1,1-trifluoro- 2-butanone 3-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]-2-vinylphenyl]propa noic acid, hydrochloride (830mg, 1.83mmol) was reacted by the general procedure as described in the preparation of 4- [4- [2- (N-dodecyl-N-methylamino)- ethoxy]phenyl]- 1,1, 1-trifluoro-2-butanone. The residue was chromatographed on silica gel (ethyl acetate) to afforded the title compound (0.46g, 54%) as a pale purple oil.

Analysis for C27H42F3NO2 0.5H2O calcd. C 67.75%, H 9.06%, N 2.93%; Found: C 67.85%, H 8.92%, N 2.90%.

Treatment of the above free amine with anhydrous hydrogen chloride (1.0 M in ether) gave the hydrochloride salt as a pale green sticky solid.

Analysis for C27H42F3NO2 HCl 1.3H2O calcd. C 61.24%, H 8.68%, N 2.65%; Found: C 61.07%, H 8.42%, N 2.63%.

Example 8 8-[2-(N-Dodecyl-N-methylamino)ethoxy]-3-hydroxy-1-(hydroxyme thyl)-3- (trifluoromethyl)-1 3g4,5-tetrahydro-2-benzoxepin A solution of 4-methylmorpholine N-oxide (31mg, 0.23mmol) and osmium tetroxide (lmg, 0.004mmol) in acetone (lml) and water (2.5ml) was treated with 4- [4-[2-(N-dodecyl-N-methylamino)ethoxy]-2 vinylphenyl]-1,1,1-trifluoro-2-butanone (100mg, 0.2lmmol) dissolved in tert-butanol (lml). After stirring at 220C for 16h, the mixture was treated with aqueous sodium bisulfite (20%, 5ml) and extracted with diethyl ether. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (diethyl ether/acetone 80 : 20 to 50 :50) to afford the title compound (40mg, 39%) as a clear oil.

Treatment of the above free amine with anhydrous hydrogen chloride (1.0 M in ether) gave the hydrochloride salt as an off-white solid.

Analysis for C27H44F3NO4'HCl'0.7H2O calcd. C 58.67%, H 8.46%, N 2.53%; Found: C 58.67%, H 8.18%, N 2.45%.

Example 9 4-[4-[2-(N-[Bis-(4-chlorophenyl)methyl]N-methylamino)ethoxy] phenyl]- 1,1,1-trifluoro-2-butanone.

2- [N- [Bis-4-chlorophenyl)methyllN-methylaminolethanol A solution of 4,4'-dichlorobenzhydryl chloride (5.20 g, 19.1 mmol) and 2- (methylamino)ethanol (9.0 g, 0.106 mol) in acetonitrile (100 ml) was treated with powdered anhydrous potassium carbonate (10 g) and the resulting mixture was heated under reflux for 4 h. The cooled mixture was filtered and the filtrate was concentrated in vacuo. The residual oil was diluted with ethyl acetate, washed with water and brine and then dried over anhydrous magnesium sulfate. Evaporation of the solvent in vacuo followed by chromatography on silica gel (elution toluene-ethyl acetate 9:1) gave 4.29 g (79%) of the title material as a white solid: mp 49- 50"C.

Anal. Calcd. for Cl6Hl7Cl2NO: C 61.95, H 5.52, N 4.52.

Found: C 61.58, H 5.43, N 4.61.

3-[4-[2-[N-[Bis-(4-chlorophenyl)methyl]-N-methylamino]eth oxy]phenyl]- propanoic acid methyl ester.

A solution of methyl 3-[4-hydroxyphenyl)propanoate (0.594 g, 3.3 mmol) and 2-[N-[bis-(4-chlorophenyl)methyl]-N-methylamino]ethanol and triphenylphosphine (0.952 g, 3.63 mmol) in tetrahydrofuran (12 ml) was treated dropwise at 220C with diisopropyl azodicarboxylate (0.734 g, 3.63 mmol). After 3 h, the solvent was evaporated in vacuo and the residue was chromatographed on silica gel (elution hexane-ethyl acetate 83:17) to give 1.12 g (72%) of the title material as an oil.

Anal. Calcd. for C26H27Cl2NO3. 0.4 H2O: C 65.11, H 5.84, N 2.92.

Found: C 65.34, H 5.89, N 3.08.

3- [4-[2-[N-[Bis-(4-chlorophenyl)methyllmethyl]-N- methylamino] ethoxy]phenyl]p ropanoic acid.

A solution of 3-[4-[2-(bis-(4-chlorophenyl)methyl]-N- methylamino]ethoxy]phenyl]-propanoic acid methyl ester (0.80 g, 1.7 mmol) in ethanol (7 ml) was treated with potassium hydroxide (0.2 g, 3.5 mmol) in water (2.4 ml) and the resulting mixture was stirred at 45CC for 2 h. The cooled mixture was adjusted to pH 4 with HCl 1N and concentrated in vacuo. The residue was partitioned between dichloromethane and water and the aqueous phase was extracted a second time with dichloromethane. The combined organic phases were dried over anhydrous magnesium sulfate and evaporated to give 0.746 g (95%) of the title material as an amorphous solid.

Anal. Calcd. for C25H25Cl2NO3.0.1 C7H8: C 66.01, H 5.56, N 3.00.

Found: C 66.21, H 5.91, N 3.01.

4-[4-[2-[N-[Bis-(4-chlorophenyl)methyl]-N-methylamino]eth oxy]phenyl]- 1,1 ,1-trifluoro-2-butanone.

A solution of 3-[4-[2- [N-[Bis-(4-chlorophenyl)methyl]-N- methylamino]ethoxy]phenyl]-propanoic acid (0.592 g, 1.29 mmol) in dichloromethane (10 ml) was treated at 220C with oxalyl chloride (0.25 g, 1.97 mmol) and the resulting mixture was stirred for 1.5 h. The solvent was evaported in vacuo and the crude acid chloride was diluted with toluene (20 ml) and cooled to OOC. Then trifluoroacetic anhydride (0.81 g, 3.87 mmol) was added followed by pyridine (0.22 g, 2.8 mmol) added dropwise over 10 min. The resulting mixture was then stirred at 220C for 2.5 h. The mixture was then cooled to OOC and treated dropwise with water (1 ml) and stirred for 15 min. The reaction mixture was then diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine, and dried (magnesium sulfate). Evaporation of the solvent in vacuo and chromatography of the residue on silica gel (elution toluene ethyl acetate, 92:8) gave 0.465 g (70%) of title material as an oil.

Anal. Calcd. for C26H24Cl2F3NO2: C 61.19, H 4.74, N 2.74.

Found: C 61.17, H 4.60, N 2.96.

The hydrochloride salt was obtained as an amorphous solid.

Anal. Calcd. for C26H24Cl2F3NO2.HCl: C 57.11, H 4.61, N 2.56.

Found: C 57.09, H 4.97, N 2.38.

Example 10 4-[4-[2-[N-[3-Bis-(4-chlorophenyl)propyl]N-methylamino]ethox y]phenyl]- 1,1,1-trifluoro-2-butanone.

3-Bis-(4-chlorophenvl!propanoic acid. ethyl ester.

Ethyl bromoacetate (3.0 g, 18.0 mmol) was added dropwise to a boiling solution of zinc powder (1.7 g, 26.0 at g) and iodine (30.0 mg) in dichloromethane (5 ml) to form the Reformatsky reagent (K. Bott, Tetrahedron Lett., 1984, 35, 555-556). The mixture was then cooled to OOC and treated dropwise with a solution of 4,4'-dichlorobenzhydryl chloride (5.11 g, 15.8 mmol) in dichloromethane (10 ml) and the resulting mixture was stirred at 22"C for 3 h. The reaction mixture was then diluted with ether, washed with 10% sulfuric acid, brine and dried (magnesium sulfate). Evaporation of the solvent in vacuo gave an oil which was chromatographed on silica gel to give 2.99 g (59%) of the title material as an oil: bp 110-115°C/0.1 torr.

Anal. Calcd. for C17H16Cl202: C 63.17, H 4.99.

Found: C 62.94, H 4.90.

3-Bis-(4-chlorophenyl)propanoic acid.

A solution of 3-Bis-(4-chlorophenyl)propanoic acid, ethyl ester (2.80 g, 8.66 mmol) in ethanol (40 ml) was treated with potassium hydroxide (1.0 g, 15.2 mmol) in water (10 ml) and the resulting mixture was heated at 600C for 1 h. The cooled mixture was concentrated in vacuo, water and dichloromethane were added and the aqueous phase was adjusted to pH3 with 2N hydrochloric acid. The aqueous phase was extracted two times with dichloromethane and the combined organic extracts were dried (magnesium sulfate). Evaporation of the solvent gave 2.40 g (94%) of the title material as a white solid: mp 188-189"C.

N-(2-Hydroxyethyl!-N-methvl-3-bis-(4-chlorophen,vl!propan amide.

A solution of 3-Bis-(4-chlorophenyl)propanoic acid (2.33 g, 7.89 mmol) in dry dichloromethane (75 ml) was treated at 220C with oxalyl chloride (2.18 g, 17.2 mmol) and a small drop of N,N-dimethyl formamide. After lh, the solvent and excess reagent were evaporated in vacuo. The residual oil was diluted with dry tetrahydrofuran (10 ml) and added dropwise to a vigorously stirred solution of 2-(methylamino) ethanol (0.75 g, 10.0 mmol) in tetrahydrofuran (15 ml) and water (15 ml) containing sodium bicarbonate (1 g). After 2 h at 220C, the mixture was diluted with ethyl acetate, washed with brine and dried (magnesium sulfate). Evaporation of the solvent under vacuum and chromatography of the residue on silica gel (elution dichloromethane-methanol 95:5) gave 2.63 g (93%) of the title material as an oil.

2- [N- [3-Bis-(4-chlorophenyl)propyl] -N-methylamino] ethanol, A solution of N-(2-hydroxyethyl)-N-methyl-3-bis-(4- chlorophenyl)propanamide (2.63 g, 7.47 mmol) in dry tetrahydrofuran (35 ml) was treated with solid lithium aluminum hydride (0.66 g, 17.4 mmol) added in small portion over 10 min. The resulting mixture was then heated at 600C for 2.5 h. The cooled solution was then quenched by successive addition of water (1 ml), 10% sodium hydroxide (1 ml) and water (2 ml). The solid formed was filtered and the filtrate was dried (magnesium sulfate) and concentrated in vacuo. The residual oil was chromatographed on silica gel (elution ethyl acetate and methanol 0-20%) to give 1.72 g (68%) of the title material as an oil.

Anal. Calcd. for C18H21Cl2NO: C 63.91, H 6.26, N 4.14.

Found: C 63.95, H 6.13, N 3.81.

3- [4- [2- [N- [3-Bis-(4-chlorophenyl)propyl]-N-methylamino]ethoxyjphenyl]- propanoic acid. methyl ester.

A solution of methyl 3-(4-hydroxyphenyl)propanoate (0.80 g, 4.44 mmol), 2-[N- [3-bis-(4-chlorophenyl)propyl]-N-methylamino]ethanol (1.62 g, 4.79 mmol) and triphenyl-phosphine (1.51 g, 5.76 mmol) in dry benzene (20 ml) was treated dropwise at 220C with diethyl azodicarboxylate (1.00 g, 5.77 mmol). After 3h at 220C, the reaction mixture was diluted in the ethyl acetate, washed with saturated sodium bicarbonate, brine and dried (magnesium sulfate).

Evaporation of the solvent under vacuo and chromatography of the residue on silica gel (elution toluene-ethyl acetate 0-15%) gave 0.893 g (40%) of the title material as an oil.

Anal. Calcd. for C28H31Cl2NO3.0.2 H2O: C 66.72, H 6.28, N 2.78.

Found: C 66.60, H 6.31, N 2.92.

3- [4- [2- [N-[3-Bis-(4-chlorophenyl)propyl]-N-methylamino]ethoxylpheny ll propanoic acid, hydrochloride salt, A solution of 3-[4-[2- [N-[3-Bis-(4-chlorophenyl)propyl]-N- methylamino]ethoxy]phenyl]-propanoic acid, methyl ester (0.801 g, 1.60 mmol) in ethanol (16 ml) was treated with potassium hydroxide (0.25 g, 3.8 mmol) in water (4 ml) and the resulting mixture was heated at 60CC for 1 h. After cooling, the reaction mixture was concentrated in vacuo and the residue was diluted with water and dichloromethane. The aqueous phase was adjusted to pH 4 with 2N hydrochloric acid and extracted two times with dichloromethane. The combined organic extracts were dried (magnesium sulfate) and evaported in vacuo to give 0.700 g (90%) of the title material as a white foam.

Anal. Calcd. for C27H29Cl2NO3.0.7 HCl: C 63.34, H 5.85, N 2.74.

Found: C 63.13, H 5.88, N 2.73.

4-[4-[2-[N-[3-Bis-(4-chlorophenyl)propyl]-N-methylamino]e thoxy]phenyl]- 1 ,1-trifluoro-2-butanone.

A solution of 3-[4-[2-[N-[3-Bis-(4-chlorophenyl)propyl]-N- methylamino]ethoxy]phenyl] propanoic acid, hydrochloride salt (0.660 g, 1.36 mmol) in dry dichloromethane (30 ml) was treated with oxalyl chloride (0.45 g, 3.5 mmol) and a trace of N,N-dimethylformamide. After 1 h at 25"C, the solvent and excess reagents were evaporated in vacuo.

The residual oil was dissolved in dry toluene (30 ml), cooled to OOC and then treated with trifluoroacetic anhydride (0.6 ml, 4.25 mmol) followed by pyridine 0.3 ml, 3.71 mmol) added dropwise over 10 min. The resulting mixture was then stirred at 220C for 2.5 h. After cooling again to 0°C, water (5 ml) was added dropwise and the mixture was stirred at 220C for 30 min. The reaction mixture was then diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent under vacuum and chromatography of the residue on silica gel (elution gradient of toluene-ethyl acetate 1:1 to ethyl acetate) gave 0.307 g (42%) of the title material as an oil.

Anal. Calcd. for C28H28Cl2F3NO2.0.5 H2O: C 61.43, H 5.34, N 2.56.

Found: C 61.46, H 5.13, N 2.60.

The hydrochloride salt was obtained as a white foam.

Anal. Calcd. for C28H28Cl2F3NO2.HCl. H2O: C 56.72, H 5.27, N 2.36.

Found: C 56.95, H 4.97, N 2.23.

The following compounds may be prepared by the general procedure of Scheme 1.

SCHEME 1 TABLE A Example No. Position n Analysis C25H40F3N02. HC1.1.3 H20 11 meta 2 Calcd: C 59.64, H 8.73, N 2.78 Found: C 59.57, H 8.99, N 2.68 C25H40F3N02. HC1.0.4 H20 12 ortho 2 Calcd: C 61.32, H 8.65, N 2.87 Found: C 61.63, H 8.73, N 2.88 C26H42F3N02. HC1.0.7 H20 13 para 3 Calcd: C 61.53, H 8.83, N 2.76 Found: C 61.63, H 8.72, N 2.84 C24H38F3NO2. HCl.1.5 H2O 14 meta 1 Calcd: C 58.47, H 8.59, N 2.84 Found: C 58.43, 8.29, 3.12 C26H42F3NO2. 0.4 H2O 15 para 3 Calcd: C 67.18, H 9.28, 3.01 Found: C 67.27, H 9.30, N 2.89 C24H38F3NO2. HCl.0.4 H2O 16 para 1 Calcd: C 60.91, H 8.48, N 2.96 Found: C 60.94, H 8.88, N 3.21 SCHEME 1 TABLE B | Example ] No. R Analysis C19H28F3NO2. HC1.1.2 H20 17 (CH2)5CH3 Calcd: C 54.66, H 7.58, N 3.35 Found: C 54.64, H 7.42, N 3.47 C21H32F3No2. HC1.0.7 H20 (C113)7CH3 Calcd: C 57.78, H 7.94, N 3.21 Found: C 57.73, H 7.84, N 3.22 C31H52F3NO2. HC1.0.7 H2O (CH2)17CH3 Calcd: C 65.57, H 9.48, N 2.47 19 Found: C 65.58, H 9.85, N 2.78 C28H42F3NO2. HC1.0.3 H2O Calcd: C 68.48, H 9.57, N 2.85 20 Hz Found: C 68.51, H 9.36, N 2.86 C22H26F3NO2. 0.3 H20 21 (CH2)3C6H5 Calcd: C 68.85, H 6.68, N 3.54 Found: C 66.73, H 6.51, N 3.61 C26H34F3N03 HCI. H20 (cm2)3 -'O(CH2)3CH3 Calcd: C 60.05, H 7.17, N 2.69 Found: C 59.88, H 7.06, N 2.83 TABLE B (cont'd.) Example sample No. R Analysis Analpsis 23 3 C26H26F3N02. HC1.0.5 H20 23 0 Calcd: C 64.13, H 5.80, N 2.88 Found: C 64.25, H 5.75, N 2.93 F 24 n C26H24F5NO2. HC1.0.25 H2O Calcd: C 60.24, H 4.96, N 2.70 0 Found: C 60.24, H 5.01, N 2.78 F LOCHS 25 Hz C28H30F3N04. He1.0.5 H20 Calcd: C 61.48, H 5.90, N 2.56 1 Calcd: C 61.58, H 5.93, N 2.57 OcH3 C OCH3 C28H30F3No4.HCl-H2o 26 CaI£d: C 60.48, H 5.98, N 2.52 v OCH3 Found: C 60.91, H 5.46, N 2.68 Scheme 1, Table B (continued) Exp. # R Analgsis CI S C27H27CIF3NO3-HCl-05 H20 27 1) Calcd: C 58.81, H 5.30, N 2.54 OCH3 OCH3 Found: C 58.42, H 4.94, N 2.66 Cl 28 OCH3 C28H28C12F3N04.HCI.O.4 H20 Calcd: C 54.76, H 4.89, N 2.28 OCH3 , OCH3 Found: C 54.81, H 4.87, N 2.40 CI Cl 6 OCH3 C28H29ClF3N04.HCI 2 9 < Calcd: C 58.75, H 5.28, N 2.45 OCH3 Found: C 58.42, H 5.39, N 2.37 Cl 30 f OCH3 C27H26C12F3N03.HCI.O.4 H20 Calcd: C 55.52, H 4.80, N 2.40 Found: C 55.47, H 4.92, N 2.45 Cl 31 () C27H28F3NO2.1.2 H2O CHP Calcd: C 63.13, H 6.16, N 2.73 Found: C 62.90, H 5.50, N 2.58 32 2 C27H26C12F3N02.O.5 H20 - Calcd: C 56.76, H 4.94, N 2.45 1$ Found: C 56.40, H 4.99, N 2.48 Cl OCH3 33 4 C2gH32F3NO4- HCI .H2O 33 - CH2 Calcd: C 61.10, H 6.19, N 2.46 (! q Found: C 61.17, H 5.88, N 2.27 \OCH3 O C28H30F3N02.HCl-H20 3 4 CH2CH2 % Calcd: C 65.30, H 6.26, N 2.72 Found: C 65.30, H 6.36, N 3.10 OCH3 0.7 C30H34F3NOq.HCI. H2O 35 5 CH2CH2 < Calcd: C 62.27, H 6.34, N 2.42 Found: C 62.28, H 6.23, N 2.41 OCH3 Q C29H32F3N02.HCI . H2O 36 - CH2CH2CH2 - Calcd: C 64.74, H 6.56, N 2.60 Found: C 64.80, H 6.54, N 2.63 CI d C29H30C12F3NO2.HCI . H20 37 7 CH2CH2CH2 4 Calcd: C 57.39, H 5.48, N 2.31 1$ -C Found: C 57.07, H 5.45, N 2.30 CI OCH3 4 C31H36F3N04-HCl H20 38 - CH2CH2CH2 Hz Calcd: C 62.25, H 6.57 Found: C 61.89, H 6.37 OCH3 O C30H34F3NO2 HCI .1.25. H20 39 - CH2CH2CH2CH2 X Calcd: C 64.74, H 6.79, N 2.52 Found: C 64.78, H 6.83, N 2.56 --CH2CH2CH2CH2 0.6 . 0.6 . H2O >+ Calcd: 1CI C 58.71, H 5.62, N 2.28 4 0 CH2CH2CH2CH2 H Found: C 58.62, H 5.39, N 2.29 CI Cl C28H28CI2F3NO3.HCI 0.8. H2O 41 CHCHO Calcd: C 55.56, H 5.10, N 2.31 > Found: C 55.62, H 5.21, N 1.95 wCI Cl X C28H26C12F3N02.HCI 1120 4 2 CH2 Calcd: C 56.92, H 4.95, N 2.37 Found: C 56.51, H 4.63, N 2.35 Cl Cl 1.5 C30H30Cl2F3No2.HCI . 1.5 H2O 43 CHCH2 i$ C 57.38, H 5.46, N 2.23 2 '$cl Found: C 57.57, H 5.36, N 2.23 tCI C26H24F3NO2.HCI. 1.5 H2O 44 8 Calcd: C 62.09, H 5.61, N 2.78 Found: C 62.08, H 5.69, N 2.82

SCHEME 1 TABLE C Example No.11 No. l | Analysis C31H44F3N02. HCI. 1.2 H20 45 CH2Ph Calcd: C 64.44, H 8.27, N 2.42 Found: C 64.53, H 8.27, N 2.37 C28H46F3NO2, HC1. 1.5 H2O 46 (CH2)3CH3 Calcd: C 61.24, H 9.18, N 2.55 Found: C 61.34, H 9.14, N 2.60 CH3 C30H46F3N302. HCI. H20 47 Calcd: C 59.25, H 8.12, N 6.91 (CH2)3 ,N Calcd: C 59.25, H 8.12, N Found: C 59.51, H 7.59, N 6.90

Scheme 2 OH O~ Br X-S BrCH2CH2Br , X A R1 NH2 Nal N 9 K2C03 S Nal isopropanol isopropanol 7 (CH2)nR2 8 HOp1 PPh3-DlAD tetrahydrofu H (CH2)nR2 o~ p1 P (CH2)(nl)CHO ohk p1 NaBH3CN methanol ~~ x or -"Ewg x < or P2(CH2)nl I or < Ewg 9 R2CH2),1 10 (9H2)nR2 (9H2)nR2 OH 0Npi o/\/ Y 1) H2,Pd"C aCF3 A ethyl acetate, xa X Pd(OAc)2 Hz, 2) Dess-Martin N (BU)4NCl 0 Periodinane dimethylformamide at dichloromethane HO CF3 0 CF3 11 12

Example 48 4-[N-Dodecyl-N-[2-[4-(3-oxo-4,4,4-trifluorobut-1- yl)phenoxylethyllaminolbutanoic acid, ethyl ester Method I 1-[2-Bromoethoxy]-4-iodobenzene A mixture of 4-iodophenol (15.0g, 68.2mmol) and 1,2-dibromoethane (50ml, 580mmol) and potassium carbonate (14.0g, 0.1mol) was stirred and refluxed for 22h. After cooling to r.t., the mixture was filtered, washed with ethyl acetate and concentrated in vacuo. The residue was chromatographed on silica gel (Hexane/ethyl acetate 40:1 to 20: 1) to afford the title compound (18.7g, 84%) as a white solid.

N-2- [4-Iodophenoxylethyldodecylamine A mixture of dodecylamine (30g, 162mmol), diisopropylethylamine (22ml, 128mmol), sodium iodide (1.3g, 8.5mmol), 1-[2-bromoethoxy]-4- iodobenzene (13.9g, 42.5mmol) and isopropanol (250ml) was stirred and refluxed for 24h. After cooling to r.t., the mixture was filtered, washed with dichloromethane and concentrated in vacuo . The residue was chromatographed on silica gel (dichloromethane/methanol 50: 1 to 20 1) to afford the title compound (15g, 82%) as a white solid.

Analysis for its hydriodide salt C20H34NIOHI calcd. C 42.95%, H 6.31%, N 2.50%; Found: C 42.73%, H 6.16%, N 2.50%.

4-[N-dodecyl-N-2-[4-iodophenoxy]ethylamino]butanoic acid, ethyl ester To a mixture of N-2-[4-iodophenoxy]ethyldodecylamine ( 4.0g, 9.3mmol) and sodium cyanoborohydride (1.45g, 23mmol) in methanol (80ml) was added dropwise a solution of ethyl 4-oxobutyrate (Fournet, G.; Balme, G.; Barieux, J.J. and Gore, J.Tetrahedron, 1988, 44, 5821) (2.4g, 18mmol) in methanol (20ml) over a period of 10min. The resulting mixture was stirred at 220C for 24h, and then diluted with ethyl acetate (600ml), washed with brine (3x250ml). The aqueous phase was extracted with ethyl

acetate (150ml), and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (Hexane/ethyl acetate 8 : 1 to 6 : 1) to afford the title compound (4.5g, 89%) as a colorless oil.

Analysis for C26H44N I03-0.3H20, calcd. C 56.68%, H 8.16%, N 2.54%; Found: C 56.4% H 7.77%, N 2.63%.

4- TN-dodecvl-N-2- [4-(E)- 13-hvdroxv4 .4 AA-trifluorobut-1-en-1 - yl]phenoxy]ethylamino]butanoci acid, ethyl ester To a solution of 4-[N-dodecyl-N-2-[4-iodophenoxy]ethylamino]butanoic acid, ethyl ester (4.5g, 8.3mmol) and 4,4,4-trifluorobut-1-en-3-ol (Pegolotti, J.A. and Young, W.G. J. Amer. Chem. Soc., 1961, 83, 3251) (complex with 1 tetrahydrofuran, 3.3g, 16.6mmol) in N, N-dimethylformamide (17ml) were added sodium bicarbonate (1.75g, 20.8mmol), tetrabutyl ammonium chloride hydrate (2.5g, 8.32mmol) and palladium (II) acetate (56mg, 0.25mmol). The resulting mixture was stirred at 500C for 24h, and then diluted with ethyl acetate (300ml), washed with brine (100ml), sat. aq. sodium thiosulfate (2x100ml), brine (2x100ml), dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (Hexane/ethyl acetate 4: 1 to 2: 1) to afford the title compound (3.5g, 78%) as a colorless oil and 0.3g (6.6%) of 4-[N- Dodecyl-N-[2-[4-(4,4,4-trifluoro-3-oxo-but-1- yl)phenoxy] ethyl] amino]butanoic acid, ethyl ester.

Analysis for C30H48F3N 04 calcd. C 66.27%, H 8.90%, N 2.58%; Found: C 65.92%, H 8.73%, N 2.59% 4-[N-Dodecyl-N-2-[4-[3-hydroxy-4,4,4- trifluorobutyl]phenoxy]ethylamino]butanoic acid, ethyl ester A mixture of 4-[N-dodecyl-N-2-[4-(E)-[3-hydroxy-4,4,4-trifluorobut-1-en-1 - yl]phenoxy] ethylamino] butanoic acid, ethyl ester (3.5g, 6 .46mmol), palladium on activated carbon (10%, 0.6g) and ethyl acetate (250ml) was hydrogenated under 30psi for 6h. After filtration, the solvent was removed in vacuo to give the title compound (3.3g, 94%) as a colorless oil.

4-[N-Dodecyl-N-[2-[4-(3-oxo-4,4,4-trifluorobut-1- yl)phenoxy]ethyl]amino]butanoic acid. ethyl ester A suspension of 1,1, 1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane, 1.7g, 4.0mmol) in dichloromethane (20ml) was treated with 4-[N-dodecyl-N-2- [4- [4,4,4-trifluoro-3- hydroxybutyl]phenoxy]ethylamino]butanoic acid, ethyl ester (430mg, 0.79mmol) dissolved in dichloromethane (5ml). The mixture was stirred at 220C for 4h, poured into a saturated aqueous sodium bicarbonate and sodium thiosulfate (100ml) and extracted with ethyl acetate (2x100ml). The combined oganic layers were washed with sat. sodium bicarbonate (2x60ml), brine (60ml), dried over sodium sulfate and concentrated in vacuo . The residue was chromatographed on silica gel (hexane/ethyl acetate 2:1 to 1.5:1) to afford the title compound (333mg, 77%) as a colorless oil.

Analysis for C30H48F3N 04 1.1H20 calcd. C 63.94%, H 8.98%, N 2.49%; Found: C 63.55% H 8.55% N 2.61%.

Treatment of the above free amine with anhydrous hydrogen chloride (1.0 M in ether) gave the hydrochloride salt as a pale yellow syrup.

Example 49 3-[N-Dodecyl-N-[2-[4-(3-oxo-4,4,4-trifluorobut-1- yl)phenoxylethyllaminolpropanoic acid, ethyl ester 3-[N-Dodecyl-N-[2-[4-iodophenoxy]ethyl]amino]propanoic acid. ethyl ester A mixture of N-2-[4-iodophenoxy]ethyldodecylamine (1.0g, 2.3mmol), ethyl acrylate (1.2g, 12mmol) and ethanol (3ml) was stirred and refluxed for 6h, and then concentrated in vacuo . The residue was chromatographed on silica gel (hexane/ethyl acetate 8:1) to afford the title compound (1.05g, 86%) as a colorless oil.

Analysis for C25H42IN 03 calcd. C 56.49%, H 7.97%, N 2.64%; Found: C 56.79% H 8.10% N 2.59%.

3-[N-Dodecyl-N-2-[4-(E)-[3-hydroxy-4,4,4-trifluorobut-1-e n-1- vllDbenoxvlethvlaminolDroDanoic acid. ethyl ester [N-Dodecyl-N-[2-[4-iodophenoxy]ethyl]amino]propanoic acid, ethyl ester (0.95g, 1.79mmol) and 4,4,4-trifluorobut-1-en-3-ol (complex with 0.7 THF, 0.95g, 5.4mmol) were reacted by the general procedure as described in the preparation of 4-[N-dodecyl-N-2-[4-(E)-[3-hydroxy-4,4,4-trifluorobut-1-en-1 - yl]phenoxy]ethylamino]butanoic acid, ethyl ester (Example 48 ) and afforded the title compound (0.633g, 76%) as a colorless oil.

3-[N-Dodecyl-N-2-[4-[3-hydroxy-4,4,4- trifluorobutyl]phenoxy]ethylamino]propanoic acid. ethyl ester [N-dodecyl-N-2-[4-(E)-[3-hydroxy-4,4,4-trifluorobut-1-en-1- yl]phenoxy]ethylamino]propanoic acid, ethyl ester (620mg, 1.17mmol) was hydrogenated as described in the preparation of 4-[N-dodecyl-N-2-[4-[3- hydroxy-4,4,4-trifluorobutyl]phenoxy]ethylamino]butanoic acid, ethyl ester (Example 48) and afforded the title compound (573mg, 92%) as a clear oil.

Analysis for C2gH4gF3N O4 calcd. C 65.51%, H 9.10%, N 2.63%; Found: C 65.83% H 9.41% N 2.50%.

3-TN-Dodecvl-N- r2- [4-(3-oxo-4 .4 A-trifluorobut-l - yl)phenoxy]ethyl]amino]propanoic acid, ethy ester 3-[N-Dodecyl-N-2-[4-[3-hydroxy-4,4,4- trifluorobutyl]phenoxy]ethylamino]propanoic acid, ethyl ester (320mg, 0.60mmol) was oxidized as described in the preparation of 4-[N-dodecyl-N- [2-[4-(3-oxo-4,4,4-trifluorobut-1-yl)phenoxy]ethyl]amino]but anoic acid, ethyl ester (Example 48 ) and afforded the title compound (216mg, 68%) as a pale yellow oil.

Analysis for C2gH46F3N O4 0.8H20calcd. C 64.02%, H 8.82%, N 2.57%; Found: C 63.94% H 8.85% N 2.59%.

Treatment of the above free amine with anhydrous hydrogen chloride (1.0 M in ether) gave the hydrochloride salt as a pale yellow syrup.

Analysis for C2gH46F3N O4 HC1 1.5H20 calcd. C 58.72%, H 8.50%, N 2.36%; Found: C 58.45% H 8.22% N 2.55%.

Example 50

(2S, 4S)-l-N-Dodecy14-[4-(3-hydroxvZ 4 4-trifluorobut-1- yl)phenoxy]pyrrolidine-2-carboxylic acid, methyl ester trans-4-Hydroxv-L-proline methyl ester, hydrochloride To a freshly prepared sat. solution of hydrogen chloride in methanol (100ml) was added trans-4-hydroxy-L-proline (10.0g, 76.26mmol). The resulting mixture was stirred at 220C for 24h, concentrated in vacuo and triturated with acetone at OOC. Filtration afforded the title compound (12.8g, 92%) as a white solid.

(2S 4R)-1-N-Dodecyl-4-hydroxypyrrolidine-2-carboxylic acid, methyl ester A solution of trans-4-hydroxy-L-proline, methyl ester, hydrochloride (4.0g, 22.02mmol) and l-iodododecane (3.04g, 44.04mmol) in methanol (30ml) was treated with potassium carbonate. The mixture was stirred and refluxed for 7h, cooled to r.t., diluted with ethyl acetate (700ml), washed with water (400ml), brine (200ml), dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (petroleum ether/ethyl acetate 60 : 40 to 40 : 60) to afford the title compound (3.72g, 54%) as a white solid.

(25, 45)-1-N-Dodecyl-4-C4-iodophenoxy)pyrrolidine-2-carboxylic acid, methyl ester (2S, 4R)-l-N-Dodecyl-4-hydroxypyrrolidine-2-carboxylic acid, methyl ester (1.75g, 7.94mmol) and 4-iodophenol (2.26g, 7.22mmol) were reacted under Mitsunobu conditions as described in the preparation of 3-[4-[2-(N- Dodecyl-N-methylamino)ethoxy]phenyl]propanoic acid, methyl ester. The residue was chromatographed on silica gel (hexane/ethyl acetate 15: 1 to 10:1) to afford the title compound (3.23g, 79%) as a white solid. [a]D= - 30.80 (c 1.0, CHC13) Analysis for C24H38INO3 calcd. C 55.92%, H 7.43%, N 2.72%; Found: C 55.87%, H 7.48%, N 2.68%.

(2S, 4S)-1-N-Dodecyl-4-[4-(E)-[3-hydroxy-4,4,4-trifluorobut-1-en- 1- yl]phenoxy]pyrrolidine-2-carboxylic acid, methyl ester (2S, 4S)-1 -N-Dodecyl-4-(4-iodophenoxy)pyrrolidine-2-carboxylic acid, methyl ester (800mg, 1.55mmol) and 4,4,4-trifluorobut-1-en-3-ol (complex with 1 tetrahydrofuran, 620mg, 3.lmmol) were reacted by the general procedure as described in the preparation of 4-[N-dodecyl-N-2-[4-(E)-[3- hydroxy-4,4,4-trifluorobut-1-en-1-yl]phenoxy]ethylamino]buta noic acid, ethyl ester and afforded the title compound (575mg, 72%) as a colorless oil [[a]D= -28.7° (c 0.8, CHC13)] and (2S, 4S)-l-N-dodecyl-4-[4-(3-oxo-4,4,4- trifluorobut-l-yl)phenoxy]pyrrolidine-2-carboxylic acid, methyl ester (68mg, 9%) as a pale yellow oil.

Analysis for C28H42F3N O4 0.3H20 calcd. C 64.79%, H 8.27%, N 2.70%; Found: C 64.74% H 8.23% N 2.87%.

(2S. 4S)-l-N-DodecvlQ- 14- [3-hvdroxv-4.4 A-trifluoro-1- butyl]phenoxy]pyrrolidine-2-carboxylic acid. methyl ester (2S, 4S)-1-N-Dodecyl-4-[4-(E)-[3-hydroxy-4,4,4-trifluorobut-1-en- 1- yl]phenoxy]pyrrolidine-2-carboxylic acid, methyl ester (552mg., 1.07mmol) was hydrogenated as described in the preparation of 4-[N-dodecyl-N-2-[4- [3-hydroxy-4,4,4-trifluorobutyl]phenoxy] ethylamino]- butanoic acid, ethyl ester and afforded the title compound (546mg, 99%) as a clear oil. [a]D= - 89.00 (c 0.4, CHC13) Analysis for C2gH44F3N O4 calcd. C 65.22%, H 8.60%, N 2.72%; Found: C 65.13% H 8.59% N 2.68%.

Example 51 (2S, 4S)-l-N-Dodecyl-4-[4-(3-oxo-4,4 4-trifluorobut-1- yl)phenoxy]pyrrolidine-2-carboxylic acid, methyl ester (2S, 4S)-1-N-Dodecyl-4-[4-[3-hydroxy-4,4,4- trifluorobutyl] phenoxy]pyrrolidine-2-carboxylic acid, methyl esterl425mg, 0.825mmol) was oxidized as described in the preparation of 4-[N-dodecyl- N-[2-[4-(3-oxo-4,4,4-trifluorobut-1-yl)phenoxy]ethyl]amino]b utanoic acid,

ethyl ester and afforded the title compound (272mg, 64%) as a pale yellow oil.

Analysis for C28H42F3N 04 0.4H20 calcd. C 64.57%, H 8.28%, N 2.69%; Found: C 64.61% H 8.08% N 2.76%.

Treatment of the above free amine with anhydrous hydrogen chloride (1.0 M in ether) gave the hydrochloride salt as a pale yellow foam. [a]D= -9.20 (c 0.74, CHC13) C28H43F3N O4#HCl#1.2H2O calcd. C 58.82%, H 8.00%, N 2.45%; Found: C 58.79% H 7.85% N 2.41%.

Example 52 (2S, 4S)-1-Dodecyl-4-[4-(3-oxo-4,4,4-trifluorobut-1-yl)phenoxy]py rrolidine- 2-propanoic acid, methyl ester (2S. 4S!-l-N-Dodecyl-4-(4-iodophenoxy!pvrrolidine-2-methanol To a solution of (2S, 4S)-l-N-dodecyl-4-(4-iodophenoxy)pyrrolidine-2- carboxylic acid, methyl ester (2.09g, 4.06mmol) in tetrahydrofuran (20ml) at -780C was added dropwise diisobutylaluminum hydride (1.OM in hexane, 15.0ml, 15.0mmol). After stirring at this temperature for Smin. and at OOC for 2.5h, the reaction was quenched with water at 0°C. After stirring at r.t. for lOmin., the mixture was diluted with ethyl acetate (250ml), washed with 2N sodium hydroxide (3x100ml), 35% sodium and potassium tartrate (2x100ml), brine (100ml), dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (hexane/ethyl acetate 3: 1 to 2: 1) to afford the title compound (1.65g, 79%) as a colorless oil. [a]D= -18.5° (c 0.92, CHC13).

Analysis for C23H38F3IN02 calcd. C 56.67%, H 7.86%, N 2.87%; Found: C 56.65% H 7.39% N 2.95%.

(2S, 4S)-1-N-Dodecyl-4-(4-iodophenoxy)pyrrolidine-2-propenoic acid, methyl ester To a solution of oxalyl chloride (1.lml, 12.lmmol) in dichloromethane (17ml) at -600C was added dropwise dimethylsufoxide (1.7ml, 24.2mmol).

After stirring for Smin., a solution of (2S, 4S)-1-N-dodecyl-4-(4-

iodophenoxy)- pyrrolidine-2-methanol (1.18g, 2.42mmol) in dichloromethane (6ml) was then added dropwise. The resulting mixture was stirred, and the temperature allowed to rise gradually to -200C over a period of 2h. The reaction was quenched with sat. ammonium chloride, diluted with dichloromethane , washed three times with sat. ammonium chloride, brine and dried over sodium sulfate . The solvent was removed in vacuo to afford the corresponding aldehyde which was directly used in the next step.

The above material was dissolved in dichloromethane (20ml) and treated with methyl (triphenyl-phosphoranylidene) acetate (1.44g, 4.3mmol). The mixture was stirred at 220C for 22h and concentrated in vacuo. The residue was chromatographed on silica gel (hexane/ethyl acetate 15 :1 to 10 : 1) to afford E-- (2 S, 4S)-1-N-Dodecyl-4-(4-iodophenoxy)pyrrolidine-2- propenoic acid , methyl ester (934mg, 61%) as a white solid [m.p. 60-610C, [a]D= -42.2° (c 0.96, CDC13)] and Z- (2 S, 4S)-l-N-dodecyl-4-(4- iodophenoxy)pyrrolidine-2-propenoic acid, methyl ester (149mg, 9%) as a clear oil. [a]D= -79.3° (c 1.24, CHC13).

Analysis for E-isomer C26H40INo3 calcd. C 57.67%, H 7.45%, N 2.59%; Found: C 57.41% H 7.50% N 2.64%.

(2S 4S!-l-N-Dodecyl-4-[4-(E!-[3-hydroxv-44.4-trifluorobut-1-en-1 - yl]phenoxy]pyrrolidine-2-propenoic acid, methyl ester (2S, 4S)-1 -N-Dodecyl-4-(4-io dophenoxy)pyrro lidine-2-p rop enoic acid, methyl ester (677mg, 1 .24mmol) and 4,4,4-trifluorobut-1 -en-3-ol (complex with 1 tetrahydrofuran, 1.23g, 6.2mmol) were reacted by the general procedure as described in the preparation of 4-[N-dodecyl-N-2-[4-(E)-{3- hydroxy-4,4,4-trifluorobut-1-en-1-yl]phenoxy]ethylamino]buta noic acid, ethyl ester and afforded the title compound (250mg, 37%) as a colorless oil.

Analysis for C30H44F3N 04-0.2H20 calcd. C 66.32%, H 8.24%, N 2.58%; Found: C 66.14% H 8.03% N 2.55%.

(2S, 4S)-1-N-Dodecyl-4-[4-[3-hydroxy-4,4,4-trifluoro-1- butyl]phenoxy]pyrrolidine-2-propanoic acid, methyl ester (2S, 4S)-1-N-Dodecyl-4-[4-(E)-[3-hydroxy-4,4,4-trifluoro-1-en-1- yl]phenoxy]pyrrolidine-2-propenoic acid, methyl ester (260mg., 0.482mmol) was hydrogenated as described in the preparation of 4- [N- dodecyl-N-2-[4- [3-hydroxy-4,4,4-trifluorobutyl]phenoxy] ethylamino]- butanoic acid, ethyl ester and afforded the title compound (185mg, 71%) as a colorless oil. [a]D= -35.3° (c 0.85, CHC13) Analysis for C30H48F3N 04 0.1H20 calcd. C 66.05%, H 8.91%, N 2.57%; Found: C 65.89% H 8.68% N 2.51%.

(2S. 4S)-1-N-Dodecyl-4-[4-(3-oxo-4 A A-trifluorobut-1 - yl)phenoxy]pyrrolidine-2-propanoic acid, methyl ester (2S, 4S)-1-N-Dodecyl-4-[4-[3-hydroxy-4,4,4- trifluorobutyl]phenoxy]pyrrolidine-2-propanoic acid, methyl ester (150mg, 0.276mmol) was oxidized as described in the preparation of 4-[N-dodecyl- N-[2-[4-(3-oxo-4,4,4-trifluorobut-1-yl)phenoxy]ethyl]amino]b utanoic acid, ethyl ester and afforded the title compound (70mg, 47%) as a pale yellow oil. [a]D= -35.70 (c 0.84, CDC13) Treatment of the above free amine with anhydrous hydrogen chloride (1.0 M in ether) gave the hydrochloride salt as a pale yellow foam.

C30H46F3N O4#HCl#1.1H2O calcd. C 60.26%, H 8.29%, N 2.34%; Found: C 60.29% H 8.10% N 2.34%.

The following compounds may be prepared by the general procedure of Scheme 2.

SCHEME 2 TABLE A Exp. Exp # Ib31 R1 1l R2 11 1(2~11 Analysis 2 . l l l l , C28H44F3NO4. HC1.1.5 H20 53 1 CQE: H Calcd: C 58.07, H 8.35, N 2.42 Found: C 57.95, H 8.29, N 2.45 C31H50F3NO4. HC1.1.5 H20 54 4 C02Et H Calcd: C 59.94, H 8.76, N 2.25 Found: C 59.80, H 8.46, N 2.17 C2gH44F3N04. 0.7 HCl 55 3 CO2H H Calcd: C 62.14, H 8.33, N 2.59 Found: C 62.25, H 8.36, N 2.58 C2gH46F3N04. HCl 56 4 CO2H H Calcd: C 61.52, H 8.37, N 2.47 Found: C 61.91, H 8.28, N 2.51 o C33H54F3N04. HCl .0.7 H20 57 4 o - c - C(CH3)3 H Calcd: C 62.43, H 8.95, N 2.21 Found: C 62.48, H 9.10, N 2.14 C25H3gF4N02. HCl .1.6 H20 58 1 H 2-F Calcd: C 56.99, H 8.26, N 2.66 Found: C 57.00, H 8.14, N 2.65 C32H46F3NO2. HCl .0.7 H2O 59 1 H 3-CH2Ph Calcd: C 65.95, H 8.37, N 2.40 Found: C 65.93, H 8.41, N 2.20

Scheme 3

Example 60 N,N-Dimethyl-N-r2-r4-83-oxo4,4,4-trifluorobut-1-yl)-phenoxyl ethyll dodecyl- ammonium iodide A solution of 4-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]phenyl]-1,1,1- trifluoro-2-butanone (250mg, 0.56mmol) in isopropanol (6ml) and methyl iodide (2ml) was heated to reflux for 0.5h. After cooling to r.t., the mixture was evaporated in vacuo and the last traces of isopropanol co-evaporated with dichloromethane to afford the title compound (327mg, 100%) as a yellow waxy solid.

Analysis for C26H43F3IN02 0.7H20 calcd. C 52.21%, H 7.48%, N 2.34%; Found: C 52.21%, H 7.43%, N 2.40%.

Example 61 N,N-Dimethyl-N-[2-[3-(3-oxo-4,4,4-trifluorobut-1-yl)-phenoxy ]ethyl] dodecyl- ammonium. iodide 4-[3-[2-(N-Dodecyl-N-methylamino)ethoxy]phenyl]-1,1,1-triflu oro-2- butanone (300mg, 0.68mmol) was reacted by the general procedure as described in the preparation of N,N-dimethyl-N-[2-[4-(3-oxo4,4,4- trifluorobut-l-yl)-phenoxy]ethyl] dodecyl- ammonium, iodide and afforded the title compound (397mg, 100%) as a yellow syrup.

Analysis for C26H43F3IN02 1H20 calcd. C 51.74%, H 7.52%, N 2.32%; Found: C 51.90%, H 7.58%, N 2.32%.

Example 62 N,N-Dimethyl-N-[2-[2-(3-oxo-4,4,4-trifluorobut-1-yl)-phenoxy ]ethyl] dodecyl- ammonium, iodide 4-[2-[2-(N-Dodecyl-N-methylamino)ethoxy]phenyl]-1,1,1-triflu oro-2- butanone (417mg, 0.94mmol) was reacted by the general procedure as described in the preparation of N,N-dimethyl-N-[2-[4-(3-oxo4,4,4- trifluorobut-l-yl)-phenoxy]ethyl] dodecyl- ammonium, iodide and afforded the title compound (550mg, 100%) as a yellow syrup.

Analysis for C26H43F3IN02 0.5H20 calcd. C 52.53%, H 7.46%, N 2.36%; Found: C 52.46%, H 7.42%, N 2.42%.

Example 63 N,N-Dimethyl-N-[2-[2-(trifluoroacetyl)phenoxylethyll dodecylammonium iodide [2-[2-(N,N-Dimethylamino)ethoxy]phenyl]-2,2,2-trifluoroethan one A mixture of 2-trifluoroacetyiphenol (380mg, 2.0mmol), 2-[N, N- dimethylamino]ethyl chloride, hydrochloride (432mg, 6.0mmol) potassium carbonate (1.38g, lOmmol) and toluene (5ml) was refluxed for 3.5h. After cooling to r.t., the mixture was treated with water and ether.

The organic layer was washed twice with brine, dried over sodium sulfate and concentrated in vacuo . The residue was chromatographed on silica gel (acetone/ether 1 : 1 to 1 : O) to give the title compound (375mg, 72%) as a white solid.

N,N-Dimethyl-N-[2-[2-(trifluoroacetyl)phenoxy]ethyl] dodecylammonium iodide A mixture of [2-[2-(N,N-Dimethylamino)ethoxy]phenyl]-2,2,2 trifluoroethanone (416mg, 1.59mmol), l-iodododecane (1.42g, 4.8mmol) and isopropanol (20ml) was refluxed for 24h. After cooling to r.t., the solvent was removed in vacuo. The residue was chromatographed on silica gel [dicloromethane/methanol/ammonium hydroxide (28%) 90 : 10 : 1 to 85: 15: 1] to give a pale yellow solid. Recrystallization from acetone/ether (1 : 3) afforded the title compound (512mg, 58%) as fine needles.

Analysis for C24H39F3IN02 calcd. C 51.71%, H 7.05%, N 2.51%; Found: C 51.83%, H 7.07%, N 2.51%.

Example 64 N,N-Dimethyl-N-[2-[2-(trifluoroacetyl)phenoxylethyll octadecylammonium, iodide [2- [2- (N ,N-Dimethylamino)ethoxy]p henyl]-2,2,2-trifluoroethanone (400mg, 1.Smmol) and l-iodooctadecane (1.8g, 4.8mmol) were reacted by the general procedure as described in the preparation of N,N-dimethyl-N- [2-[2-(trifluoroacetyl)phenoxy]ethyl] dodecylammonium, iodide.

Recrystallization from Acetone/ether (1 : 2) afforded the title compound (500mg, 52%) as fine needles.

Analysis for C30H5lF3INO2 calcd. C 56.16%, H 8.01%, N 2.18%; Found: C 56.06%, H 7.90%, N 2.13%.

Example 65 N ,N-Dimethyl-N.[2-[4-(trifluoroacetyl)phenoxyiethyll octadecylammonium, iodide N,N-Dimethyl-2-(4-bromophenoxy!ethylamine A mixture of 4-bromophenol (5.0g, 28.9mmol), 2-(N, N- dimethylamino)ethyl chloride, hydrochloride (6.24g, 43.4mmol), sodium iodide (600mg, 4mmol), cesium carbonate (28g, 86.7mmol) and methyl ethyl ketone (120ml) was heated to reflux for 4h. After cooling to r.t., the mixture was filtered and washed with acetone. The combined filtrates were concentrated in vacuo, and the residue was chromatographed on silica gel (dichloromethane/methanol 95 : 5 to 90: 10) to give a pale yellow liquid. Bulb-to-bulb distillation (80-840C /0 .05mmHg) afforded the title compound (5.19g, 74%) as a colorless liquid.

[4- [2- (N N-Dimethylamino!ethoxy]phenyl]-2,2 2-trifluoroethanone To a solution of N,N-dimethyl-2-(4-bromophenoxy)ethylamine (1.0g, 4.lmmol) in tetrahydrofuran (lOml) at -780C was added dropwise n- butyllithium (1.5M in hexane, 2.7ml, 4.lmmol). The mixture was stirred at this temperature for 15min. and then transferred via a cannula into a

pre-cooled solution of ethyl trifluoroacetate (0.64g, 4.5mmol) in ether (8ml) at -780C. The resulting mixture was stirred and the temperature allowed to rise gradually to r.t. over a period of 1.5h. The reaction mixture was then quenched with water (5ml) and diluted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo . Bulb-to-bulb distillation (82-840C /O.OlmmHg) afforded the title compound (423mg, 39%) as a pale yellow oil. Analysis for C12Hl4F3No2 0.3H20 calcd. C 54.05%, H 5.52%, N 5.25%; Found: C 54.12%, H 5.39%, N 5.28%.

N.N-Dimethyl-N-[2- F4-(trifluoroacetyl)phenoxylethyl] octadecvlammonium. iodide [4-[2-(N,N-Dimethylamino)ethoxy]phenyl]-2,2,2-trifluoroethan one (343mg, 1.3lmmol) and l-iodooctadecane (1.16g, 53.93mmol) were reacted by the general procedures as described in the preparation of N,N- dimethyl-N-[2-[2-(trifluoroacetyl)phenoxy]ethyl] dodecylammonium, iodide. The residue was chromatographed on silica gel [dichloromethane/methanol/ammonium hydroxide (28%) 98 : 2 : 0.5 to 90 : 10: 1] to give the title compound (722mg, 86%) as a white solid.

Analysis for C30H5lF3INO2 calcd. C 56.16%, H 8.01%, N 2.18%; Found: C 56.33%, H 7.79%, N 2.09%.

Example 66 N,N-Dimethyl-N-[2-r3-(trifluoroacetyl)phenoxvlethyll octadecylammonium iodide N,N-Dimethyl-2-(3-bromophenoxy)ethylamine 3-Bromophenol (5.0g, 28.9mmol) and 2-(N, N-dimethylamino)ethyl chloride, hydrochloride (6.24g, 43.3mmol) were reacted by the general procedures as described in the preparation of N,N-dimethyl-2-(4- bromophenoxy)ethylamine. The residue was chromatographed on silica gel (dichloromethane/methanol 100 : 0 to 90 : 10) to give the title compound (5.2g, 74%) as a pale yellow liquid.

[3-[2-(N,N-Dimethylamino)ethoxy]phenyl]-2,2,2-trifluoroet hanone N,N-Dimethyl-2-(3-bromophenoxy)ethylamine (2.87g, 11.7mmol) and ethyl trifluoroacetate (2.5g, 17.6mmol) were reacted by the general procedure as described in the preparation of [4-[2-(N,N- dimethylamino)ethoxy]phenyl]-2,2,2-trifluoroethanone. The residue was distilled under reduced pressure to afford the title compound (1.34g, 44%) as a pale yellow liquid. Analytically pure sample was obtained by a second distillation under reduced pressure. Analysis for Cl2Hl4F3NO2 O-8H2o calcd. C 52.29%, H 5.70%, N 5.08%; Found: C 52.61%, H 5.53%, N 4.96%.

N,N-Dimethyl-N-[2-[3-(Trifluoroacetyl)phenoxy]ethyl] octadecylammonium. iodide [3-[2-(N,N-Dimethylamino)ethoxy]phenyl]-2,2,2-trifluoroethan one (438mg, 1.67mmol) and l-iodooctadecane (1.9g, 5.0mmol) were reacted by the general procedure as described in the preparation of N,N-dimethyl-N- [2-[2-(trifluoroacetyl)phenoxy]ethyl] dodecylammonium, iodide.

Recrystallization from acetone/ether (1 : 2) afforded the title compound (530mg, 50%) as fine needles.

Analysis for C30H51F3INO20.2H2O calcd. C 55.84%, H 8.03%, N 2.17%; Found: C 55.79%, H 7.98%, N 2.10%.

Example 67 N-[(Ethoxycarbonyl)methyl]-N-[2-[4-(3-oxo-4,4,4-trifluorobut -1- yl)phenoxylethyll-N-(methyl)- dodecylammonium iodide A solution of 4-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]phenyl]-1,1,1- trifluoro-2-butanone (620mg, 1.4mmol) and ethyl iodoacetate (0.5ml, 4.2mmol) in ethanol (20ml) was heated to reflux for 3h. After cooling to r.t., the mixture was concentrated in vacuo. The residue was chromatographed on silica gel [dichloromethane/methanol/ ammonium hydroxide (28%) 95 : 5 : 0.5 to 90: 10:1] to give a colorless syrup. This material was dissolved in aqueous tetrahydrofuran (90%), evaporated in vacuo and co-evaporated with acetonitrile to afford the title compound (855mg, 93%) as a colorless syrup.

Example 68 <BR> <BR> <BR> <BR> <BR> <BR> <BR> N-(Carboxymethyl)-N-[2-r4-13-oxo-4,4,4-trifluorobut-1-yl)phe noxylethyll- N-(methyl)dodecyl ammonium, hydroxide. inner salt A solution of N- [(ethoxycarbonyl)methyl]-N- [2- [4-(3-oxo-4,4,4-trifluorobut- l-yl)phenoxy]ethyl]-N-(methyl)- dodecylammonium, iodide (617mg, 0.938mmol) in ethanol (95%, 20ml) was treated with potassium hydroxide (63mg, 1.12mmol). The mixture was stirred at 220C for 3h, and then concentrated in vacuo. The residue was chromatographed on silica gel [dichloromethane/methanol/ ammonium hydroxide (28%) 90 : 10: 1 to 85 : 15 : 1] to give a white solid. Recrystallization from ethanol-water (1 : 1) afforded the title compound (300mg, 64%) as fine needles.

Analysis for C27H42F3N04 H20 calcd. C 62.41%, H 8.54%, N 2.70%; Found: C 62.30%, H 8.70%, N 2.56%.

Example 69 N N-Dimethyl-N-[2-r2-benzyl-4-(3-oxo-4 4 4-trifluorobut-1- yl)phenoxylethyll dodecyl- ammonium. iodide 4-[3-Benzyl-4-[2-(N-dodecyl-N-methylamino)ethoxy]phenyl]-lBl ,l- trifluoro-2-butanone (180mg, 0.338mmol) was reacted by the general procedure as described in the preparation of N,N-dimethyl-N-[2-[4-(3-oxo- 4,4,4-trifluorobut-1-yl)-phenoxy]ethyl] dodecyl- ammonium, iodide and afforded the title compound (228mg, 100%) as a yellow syrup.

Analysis for C33H49F3IN021.1H20 calcd. C 56.99%, H 7.42%, N 2.01%; Found: C 56.98%, H 7.25%, N 2.07%.

Example 70 N-[(Ethoxycarbonyl)methyl]-N-[2-[2-benzyl-4-(3-oxo-4,4,4-tri fluorobut-1- yl)phenoxvlethyll-N-(methyl)- dodeevlammonium iodide 4-[3-Benzyl-4-[2-(N-dodecyl-N-methylamino)ethoxy]phenyl]-1,1 ,1- trifluoro-2-butanone (340mg, 0.638mmol) was reacted by the general procedure as described in the preparation of N-[(ethoxycarbonyl)methyl]-

N-[2-[4-(3-oxo-4,4,4-trifluorobut-1-yl)phenoxy]ethyl]-N-(met hyl)- dodecylammonium, iodide and afforded the title compound (455mg, 93%) as a yellow waxy solid.

Analysis for C36H53F3IN04 calcd. C 57.83%, H 7.14%, N 1.87%; Found: C 57.83%, H 7.56%, N 1.78%.

Example 71 N-(Carboxymethyl)-N-[2-[2-benzyl-4-(3-oxo-4x4,4-trifluorobut -1- yl)phenoxylethyll-N-(methyl)dodecyl ammonium. hydroxide, inner salt N-[(Ethoxycarbonyl)methyl]-N-[2-[2-benzyl-4-(3-oxo-4,4,4-tri fluorobut-1- yl)phenoxy] ethyl]-N-(methyl)- dodecylammonium, iodide (330mg, 0.442mmol) was saponified as described in the preparation of N- (carboxymethyl)-N-[2-[4-(3-oxo-4,4,4-trifluorobut-1-yl)pheno xy]ethyl]-N- (methyl)dodecyl ammonium, hydroxide, inner salt, and afforded the title compound (182mg, 70%) as a white foam.

Analysis for C34H48F3NO4#H2O calcd. C 66.19%, H 8.30%, N 2.27%; Found: C 66.21%, H 8.15%, N 2.29%.

Example 72 N-[(Ethoxycarbonyl)methyl]-N-[2-[2-benzyl-4- (trifluoroacetyl)phenoxy]ethyl]-N-(methyl)- dodecylammonium, iodide [3-Benzyl-4- [2-(N-dodecyl-N-methylamino)ethoxy]phenyl] -2,2,2- trifluoroethanone (2.81g, 5.56mmol) was reacted by the general procedure as described in the preparation of N- [(ethoxycarbonyl)methyl]-N- [2- [4-(3- oxo-4,4,4-trifluorobut-1-yl)phenoxy]ethyl]-N-(methyl)- dodecylammonium, iodide and afforded the title compound (2.lg, 52%) as a yellow solid.

Analysis for C34H48F3IN04 calcd. C 56.75%, H 6.86%, N 1.95%; Found: C 57.14%, H 6.94%, N 2.05%.

Example 73 N-(Carboxymethyl)-N-[2-[2-benzyl-4-(trifluoroacetyl)phenoxy] ethyl]-N- (methyl)dodecyl ammonium, hydroxide inner salt N-[(Ethoxycarbonyl)methyl]-N-[2-[2-benzyl-4- (trifluoroacetyl)phenoxy]ethyl]-N-(methyl)- dodecylammonium, iodide (500mg, 0.69mmol) was saponified as described in the preparation of N- <BR> <BR> <BR> (carboxymethyl)-N-[2-[4-(3-oxo-4,4,4-trifluorobut-1-yl)pheno xy]ethyl]-N- (methyl)dodecyl ammonium, hydroxide, inner salt, and afforded the title compound (259mg, 65%) as an off-white solid.

Analysis for C32H44F3N04 0.7H20 calcd. C 66.69%, H 7.94%, N 2.43%; Found: C 66.63%, H 8.00%, N 2.42%.

Scheme 4 OMe 1) (cOClk OMe dichloromethane I 2) 2) TFAA-Pyridino CO2H 0 CF3 16 21 BBr3 OH HC(OMe)3 OH dichloromethane 1 nitromethane N I methanol Q 1 o CF3 Me CF3 OMe 18 Al 0~ o~NHR Wi PNH2 I isopropanol MeO CF3 MeO CF3 21 OHC(CH2)(n1)R' (CH2)nRr (CH2)nR2 NaBH3CN O~ N methanol or [@ 1) Reaction on R1 Q 2)TFA N or EWG MeO 3 ° CF3 Mec 23 23 22

Example 74 4-[N-Dodecyl-N-r2-[4-(3-oxo-4,4,4-trifluorobut-1- yl)phenoxylethyllaminolbutanoic acid, ethyl ester Method II 4-F4-Methoxyphenyll-1 1 ,1-trifluoro--2-butanone To a solution of 3-[4-methoxyphenyl]propionic acid (40.0g, 0.222mol) in dichloromethane (300ml) at 220C was added slowly oxalyl chloride (29ml, 0.333mol). After stirring for 2.5h, the solvent and excess reagent were removed in vacuo . The residue was dissolved in dichloromethane (300ml), and was then added to a solution of trifluoroacetic anhydride (294ml, 0.666mol) in dichloromethane (300ml) at OOC (ice bath). Pyridine (36ml, 0.444mol) was then added dropwise at 0°C, and the reaction mixture was stirred for 0.5h at which time the cooling bath was removed.

After stirring at 220C for 3h, the reaction was cooled again to 0°C and quenched with distilled water (100ml). The mixture was stirred at 220C for lh, neutralized with solid sodium bicarbonate, diluted with dichloromethane (1L), washed with sat. aq. sodium bicarbonate (300ml), brine (300ml), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by bulb-to-bulb distilation (96-980C, 0.2mmHg) to afford the title compound (43.5g, 84%) as a yellow liquid.

Analysis for CllHllF302 calcd. C 56.90%, H 4.78%; Found: C 56.61% H 4.98%.

4-[4-Hydroxyphenyl]-1 1 1-trifluoro-2-butanone To a solution of 1,1,1-trifluoro-4-[4-methoxyphenyl]-2-butanone (43.5g, 0.187mol) in dichloromethane (500ml) at -780C (dry ice-acetone) was added dropwise boron tribromide (53ml, 0.561mol). The mixture was then stirred at OOC (ice bath) for 3h, and cautiously quenched by dropwise addition of ice-water (200ml) over a period of lh. The aqueous phase was saturated with solid sodium chloride, extracted with dichloromethane (500ml) followed by diethyl ether (500ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated in

vacuo. The residue was purified by bulb-to-bulb distilation (96-1000C, 0.2mmHg) to afford the title compound (34.4g, 84%) as a yellow liquid which solidified upon standing.

Analysis for C10H9F3O2 0.5H20 calcd. C 52.87%, H 4.44%; Found: C 52.93% H 4.53%.

4-(3 .3-Dimethoxv-4 4A-trifluorobut-1-yl)phenol) To a solution of 1,1,1-trifluoro-4-[4-hydroxyphenyl]-2-butanone (40.4g, 0.185mol) in nitromethane (300ml) were added methanol (40ml), trimethyl orthoformate (100ml) and trifluoromethanesulfonic acid (lml).

The resulting mixture was heated to 750C for 20h, then cooled to r.t. and poured into sat. sodium bicarbonate (700ml). After stirring for lOmin., the mixture was extracted with ethyl acetate (2x2L). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (dichloromethane/methanol 98 : 2 to 97: 3) to afford the title compound (21.5g, 44%) as a yellow oil and 1,1,1-trifluoro-4[4-hydroxyphenyl]-2- butanone (23g, 57%). Analytically pure sample (20.2g, 41%) of 4-(4,4,4- trifluoro-3,3-dimethoxybut-1-yl)phenol was obtained by bulb-to-bulb distilation (98-1020C, 0.02mmHg).

[2-[4-(3,3-Dimethoxy-4,4,4-trifluorobut-1-yl)phenoxy]ethyl] bromide A mixture of 4-(3,3-dimethoxy-4,4,4-trifluorobut-1-yl)phenol (1.64g, 6.2mmol), potassium carbonate (1.3g, 9.3mmol) and 1,2-dibromoethane (5ml, 58mmol) was stirred and heated under reflux (1300C) for 26h. After cooling to room temperature, the mixture was filtered and washed with ethyl actate. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate 20 : 1 to 4: 1) to give the title compound (2.0g, 85%) as a colorless liquid.

Analysis for C14Hl8BrF3o3 calcd. C 45.30%, H 4.89%; Found: C 45.57% H 4.72%.

N-[2-[4-(3,3-Dimethoxy-4,4,4-trifluorobut-1- yDphenoxyjethyl] dodecanamine A mixture of 4-[4-(2-bromoethoxy)phenyl]-1,1,1-trifluoro-2-butanone, dimethyl ketal (5.0g, 13.5mmol), dodecylamine (12.5g 67.4mmol), disopropylethylamine (7.0ml, 40.4mmol), NaI (2.0g, 13.5mmol) and isopropanol(lOOml) was stirred and heated under reflux for 16h. After cooling to room temperature, the mixture was concentrated in vacuo, diluted with ethyl acetate (300ml), washed with brine (lOOml), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (dichloromethane/methanol 98 : 2 to 96 : 4) to afford the title compound (5.3g, 83%) as a colorless syrup.

Treatment of the above free amine with anhydrous hydrogen chloride (1.0 M in ether) gave the hydrochloride salt as a white solid.

Analysis for C26H44F3N 03 HC1 calcd. C 60.98%, H 8.86%, N 2.74%; Found: C 60.73% H 8.56% N 2.73%.

4-[N-Dodecyl-N-[2-[4-(3,3-Dimethoxy-4,4,4-trifluorobut-1- yl)phenoxylethyllaminojbutanoic acid, ethyl ester A solution of N-[2-[4-(3,3-dimethoxy-4,4,4-trifluorobut-1-yl)phenoxy]- ethyl]dodecanamine (2.0g, 4.2mmol) in methanol (50ml) was treated with sodium cyanoborohydride (0.55g, 8.4mmol) and ethyl 4-oxobutyrate (1.04g, 8.4mmol). The resulting mixture was stirred at 220C for 16h, diluted with diethyl ether (350ml), washed with water (200ml), brine (200ml), dried over magnesium sulfate and concentrated in vacuo . The residue was chromatographed on silica gel (hexane/AcOEt 9: 1 to 6:1) to afford the title compound (1.8g, 73%) as a liquid.

Analysis for C32H54F3N 05 0.3H20 calcd. C 64.58%, H 9.25%, N 2.35%; Found: C 64.54% H 9.02% N 2.39%.

4-[N-Dodecyl-N-[2-[4-(3-oxo-4,4,4-trifluorobut-1- yl)phenoxy]ethyl]amino]butanoic acid, ethyl ester A solution of 4-[N-Dodecyl-N-[2-[4-(3,3-dimethoxy-4,4,4-trifluorobut-1- yl)phenoxy]ethyl]amino]- butanoic acid, ethyl ester (315mg, 0.53mmol) in trifluoroacetic acid (5ml) was heated to 700C for 2h, and then concentrated in vacuo . The residue was diluted with ethyl acetate (100ml), washed with sat. sodium bicarbonate (30ml), brine (30ml), dried over magnesium sulfate and concentrated in vacuo . The residue was chromatographed on silica gel (Hexane/ethyl acetate 2: 1 to 1.5: 1) to afford the title compound (224mg, 77%) as a colorless oil.

The following compounds may be prepared by the general procedure of Scheme 4.

SCHEME 4 Table Example No. n R Analysis C24H38F3NO4. H2O.0.3 CO2 75 0 H Calcd: C 63.34, H 8.75, N 3.04 Found: C 63.66, H 8.36, N 3.19 C28H46F3NO2. HCl.0.6 H2O 76 1 CH(CH3)2 Calcd: C 63.10, H 9.12, N 2.63 Found: C 62.92, H 9.18, N 2.68 C29H48F3NO2. HCl .0.6 H20 77 1 C(CH3)3 Calcd: C 63.68, H 9.25, N 2.56 Found: C 63.51, H 8.91, N 2.61 C31H51F3N2O3. HCl .1.8 H2O 78 4 CONHEt Calcd: C 59.51, H 8.96, N 4.48 Found: C 59.48, H 8.70, N 4.50 C30H49F3N2O3. HCl .1.1 H2O 79 3 CONHEt Calcd: C 60.15, H 8.78, N 4.68 Found: C 60.15, H 8.54, N 4.63 C29H48F3NO3. HCl .0.6 H2O 80 5 OH Calcd: C 61.87, H 8.99, N 2.49 Found: C 61.81, H 8.58, N 2.66 C2gH46F3N03. HC1.0.5 H20 81 4 OH Calcd: C 61.47, H 8.84, N 2.56 Found: C 61.44, H 8.91, N 2.67 C28H46F3NO3. HCl.1.2H2O 82 3 OCH3 Calcd: C 60.08, H 8.90, N 2.50 Found: C 60.08, H 8.46, N 2.77 C27H41F3N203. HC1.0.8 H20 83 2 CN Called: C 60.79, H 8.24, N 5.25 Found: C 60.75, H 8.16, N 5.23 Scheme 5

H R M oN\R p O P t R I %3 N N isopropanol MeO 3 MeO CF3 21 24 l TFA N CF3 25

Example 84 4-[4-r2-(N-Dodecyl-N-propylaminolethoxylphenyll-l,l,l-triflu oro-2- butanone N-Propyl-N-[2-[4-(3,3-dimethoxy-4,4,4-trifluorobut-1- yl)phenoxyl ethyll dodecylamine A solution of N-[2-[4-(3,3-dimethoxy-4,4,4-trifluorobut-1- yl)phenoxy]ethyl] dodecylamine (500mg, 1.05mmol), diisopropyl ethylamine (0.35ml, 2.lmmol) and l-iodopropane (0.26ml, 2.66mmol) in isopropanol was heated to reflux for 21 h. After cooling to r.t., the mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated in vacuo , and the residue was chromatographed on silica gel (dichloromethane/methanol 98 : 2 to 95 : 5) to afford the title compound (0.526g, 73%) as a colorless oil.

4-14- [2-(N-Dodecyl-N-propylamino]ethoxy]phenyl]-1 1,1 -trifluoro-2- butanone N-Propyl-N-[2-[4-(4,4,4-trifluoro-3,3-dimethoxybut-1- yl)phenoxy]ethyl]dodecylamine (300mg, 0.58mmol) was treated with trifluoroacetic acid as described in the preparation of 4-[N-dodecyl-N-[2-[4- (4,4,4-trifluoro-3-oxobut-1-yl)phenoxy]ethyl]amino]butanoic acid, ethyl ester and afforded the title compound (169mg, 62%) as a pale yellow oil.

Analysis for C27H44F3NO2#0.9H2O calcd. C 66.47%, H 9.46%, N 2.87%; Found: C 66.39%, H 9.10%, N 2.87%.

Treatment of the above free amine with anhydrous hydrogen chloride (1.0 M in ether) gave the hydrochloride salt as a pale yellow syrup.

Analysis for C27H44F3N02 HC1 1.2H20 calcd. C 61.22%, H 9.02%, N 2.64%; Found: C 61.38%, H 8.61%, N 2.75%.

Example 85 4-[4-[2-(N-Dodecyl-N-hexylamino]ethoxy]phenyl]-1,1,1-trifluo ro-2- butanone N-Hexyl-N-[2-[4-(3,3-dimethoxy-4,4,4-trifluorobut-1- yl)phenoxyi ethyl] dodecylamine N-[2-[4-(3,3-Dimethoxy-4,4,4-trifluorobut-1- yl)phenoxy]ethyl]dodecylamine (500mg, 1.05mmol) and l-iodohexane (0.186ml, 1.26mmol) were reacted as described in the preparation of N- propyl-N-[2-[4-(3,3-dimethoxy-4,4,4-trifluorobut-1- yl)phenoxy]ethyl]dodecylamine and afforded the title compound (390mg, g, 67%) as a liquid.

4-[4-[2-(N-Dodecyl-N-hexylamino]ethoxy]phenyl]-1,1,1-trif luoro-2- butanone N-Hexyl-N-[2-[4-(3,3-dimethoxy-4,4,4-trifluorobut-1- yl)phenoxy]ethyl]dodecylamine (353mg, 0.63mmol) was treated with trifluoroacetic acid as described in the preparation of 4-[N-dodecyl-N-[2-[4- (4,4,4-trifluoro-3-oxobut-1-yl)phenoxy]ethyl]amino]butanoic acid, ethyl ester . The residue was chromatographed on silica gel (dichloromethane/methanol 98 : 2 to 94 : 6) to afford the title compound (253mg, 78%) as a pale yellow oil.

Analysis for C30H50F3NO2 calcd. C 70.14%, H 9.81%, N 2.73%; Found: C 69.79%, H 9.82%, N 2.76%.

Treatment of the above free amine with anhydrous hydrogen chloride (1.0 M in ether) gave the hydrochloride salt as a pale yellow syrup.

Analysis for C30H50F3NO2'HCl'0.7H2O calcd. C 64.02%, H 9.39%, N 2.49%; Found: C 64.09%, H 9.05%, N 2.61%.

Scheme 6 OH PPh3-DIAD ROH R PPh3-DlAD tetrahydrofuran N N or t RX Iz MeO 3 MeO CF3 MoO CF3 19 26 p 0" TFA h CF3 27

Example 86 4-r4-r2-(N-dodecyl-N-ethylaminolethoxylphenyll-l,l,l-trifluo ro-2- butanone 2-[N-Dodecyl-N-ethylaminolethanol 2-[Dodecylamino]ethanol (2.0g, 8.73 mmol) ,l-iodoethane (1.63g, 10.48 mmol) and N,N-diisopropylethylamine ( 2.51g,17.5 mmol) in isopropanol ( 25 ml )were heated under reflux for 4 h. The solvent was then evaporated in vacuo and the residue was diluted with ethyl acetate washed with aqueous sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent followed by chromatography on silica gel (ethyl acetate/methanol 90 : 10 to 80 : 20) afforded the title compound (1.65g, 73%) as a white solid. <BR> <BR> <BR> <BR> <BR> <P>N-Ethyl-N-[2- 4-(3 ,3-dimethoxy-4 .4 A-trifluoro-but-1- <BR> <BR> <BR> <BR> yl)phenoxylethyljdodecylamine 2-[N-Dodecyl-N-ethylamino]ethanol (250mg, 0.96mmol) and 4-(3,3- dimethoxy-4,4,4-trifluorobut-1-yl)phenol (230mg, 0.87mmol) were reacted under Mitsunobu conditions as described in the preparation of 3-[4-[2-(N- dodecyl-N-methylamino)ethoxy]phenyl]propanoic acid, methyl ester. The usual work-up followed by chromatography on silica gel (Hexane/ethyl acetate 95 : 5 to 80 : 20) afforded the title compound (200mg, 46%) as a colorless oil.

4-F4-[2-(N-dodecyl-N-ethylaminol ethoxylphenyli-1 11 -trifluoro-2- butanone N-Ethyl-N-[2-[4-(3,3-dimethoxy-4,4,4-trifluorobut-1- yl)phenoxy]ethyl]dodecylamine (123mg, 0.244mmol) was treated with trifluoroacetic acid as described in the preparation of 4-[N-dodecyl-N-[2-[4- (4,4,4-trifluoro-3-oxobut-1-yl)phenoxy]ethyl]amino]butanoic acid, ethyl ester and afforded the title compound (60mg, 54%) as a pale yellow oil.

Treatment of the above free amine with anhydrous hydrogen chloride (1.0 M in ether) gave the hydrochloride salt as a pale yellow syrup.

Analysis for C26H42F3NO2#HCl#0.6H2O calcd. C 60.45%, H 8.64%, N 2.69%; Found: C 60.19%, H 8.27%, N 3.08%.

The following compounds may be prepared by the general procedure of Scheme 6.

SCHEME 6 Tables Er ll Analysis 1l "'II R Analysis C24H38F3NO2. HCl. 1.4 H2O Calcd: C N(CH2)s 3 C C 58.68, H 8.58, N 2.85 CH,CH,N, (cH,),cH, Found: C 58.81, H 8.45, N 2.91 88 CH CH N/( 2h 3 Called: C 62.68, H 9.18, N 2.61 hCH3 Found: C 62.52, H 9.25, N 2.69 C26H26F3NO2. HCl. 0.8 H2O 89 cH2C6H5 Calcd: C 63.43, H 5.86, N 2.84 CH2CH2N\ CH2C6Hs Found: C 63.39, H 5.95, N 2.88 yI C26H24Cl2F3NO2. HCI. 0.7 H2O 90 cH2cH2Ns Calcd: C 55.82, H 4.76, N 2.50 Found: C 55.81, H 4.90, N 2.52 \CI 91 cH2cH2N3 cH24 Calcd: C 61.05, H 6.58, N 2.97 Found: C 61.17, H 6.54, N 3.05 C25H38F3N03. HCI. 0.7 H2O 92 CH2CH2.N3 O(CH2)7CH3 Calcd: C 59.27, H 8.04, N 2.76 Found: C 59.26, H 8.18, N 2.98 93 CH3 C29H32F3NO3. HCI. 0.9 H2O 93 cH2cH2N-(cH2)3° CHO Calcd: C 63.07, H 6.35, N 2.54 Found: C 62.95, H 6.40, N 2.67 9H3 C26H34F3NO3. HCI. H2O (CH)O Calcd: C 60.05, H 7.17, N 2.69 CH2CH2 (CH2)3 C 60.03, H 7.26, N 2.79 C25H32F3N03. HCI. 0.6 H20 9H3 Calcd: C 60.20, H 6.91, N 2.81 CH2CH2(CH2)3oo Found: C 60.11, H 7.11, N 2.89 C22H33F302 96 (CH2)11CH3 Calcd: C 68.37, H 8.61 Found: C 68.09, H 8.42 C25H29F302.H20 97 (CH2)14CH3 Calcd: C 69.48, H 9.19 Found: C 69.37, H 9.29 C24H37F303 98 CH2CH2O(CH2)l lCH3 Calcd: C 66.95, H 8.66 Found: C 66.76, H 8.47 C22H20F604. 0.5 H20 99 CH2}2 (dimer) Calcd: C 56.06, H 4.49 Found: C 56.11, H 4.45 C17HlSF302- 100 cH24 Calcd: C 66.23, H 4.90 Found: C 66.25, H 4.99 Cl2H12BrF3O2 101 CH2CH2Br Calcd: C 44.33, H 3.72 Found: C 44.71, H 3.80 SCHEME 6 - Table (continued) Exp. # R Analysis C20H16F3N02.HCI. 0.8 H2O 102 Calcd: 0-8 58.56, H 4.57, N H2O CH2 / Calcd: C S8.56, H 4.57, N 3.41 Found: C 58.31, H 4.19, N 3.45 C26H39F303.0.3 H20 103 C(CH2h4cHs C26H39F3O3.O.3 8.64 Calcd: C 67.60, H 8.64 Found: C 67.55, H 8.45 104 Q C26H19Cl2F3N2O2 N- N Calcd: C 60.13, H 3.69, N 5.39 CH2 Found: C 60.37, H 3.71, N 5.39 CI Cl Q C29H26C12F3N302.HCI. 1.1 1120 105 CH3 N-N Calcd: C 55.05, H 4.65, N 6.64 CH2CH2N < Found: C 54.96, H 4.61, N 6.62 Cl (CH2)3CH3 106 CH2CH2N Cl C29H3OC12F3NO2.HCI.0.7 H2O Calcd: C 57.91, H 5.43, N 2.33 Found: C 57.98, H 5.42, N 2.12 CI 107 Calcd: C 62.82, H OCH3 C31H36F3N04-HC1-0-7 H2O Calcd: C 62.82, H 6.53, N 2.36 Found: C 62.87, H 6.33, N 2.08 OCH3 (CH2hCH3 | C30H32Cl2F3NO2-HCl- 0-6 H2O 108 CH2CH2 < CH2 Calcd: C 58.71, H 5.62, N 2.28 Found: C 58.64, H 5.51, N 2.33 Cl H2)3C OCH3 CH2)3CH13 OCH3 C32H38F3N04. HCl .H20 109 CH2CH2 CH2 Calcd: C 62.79, H 6.75, N 2.29 Found: C 62.81, H 6.82, N 2.15 OCH3 9 9 C28H28F3NO2.HCI. 0.3 H2O 1 1 0 15 Calcd: C 66.02, H 5.86, N 2.75 Found: C 65.93, H 5.98, N 2.74 CI C 28H26C12F3N02.HCI H20 111 - C alcd: C 56.84, H 4.77, N 2.36 XNa Calcd: C 56.84, H 4.77, N 2.36 9 Found: C 56.76, H 4.88, N 2.42 CI OCH3 C30H32F3NO4.HCI. 0.9 H20 112 9, Calcd: C 62.10, H 6.05, N 2.41 Found: C 62.11, H 6.33, N 2.48 OCH3 OCH3 CO2 Sd C32H34F3NO6.HCI .2.5 H2O 1 1 3 J4 N< Calcd: C 57.61, H 6.04, N 2.10 Found: C 57.56, H 5.44, N 2.11 OCH3 OCH3 CHO C32H36F3NO5-HCl . 1.5 H2O 114 CHIk Calcd: C 60.52, H 6.35, N 2.21 Found: C 60.49, H 6.34, N 2.17 OCH3 OCH3 d C30H32F3NO4.HCI. 0.7 H2O 115 { N>> Calcd: C 62.49, H 6.01, N 2.43 > Found: C 62.36, H 6.00, N 2.36 OCH3 N1 C29H30F3N02.HCl 2 H20 1 1 6 Said: Calcd: C 62.87, H 6.37, N 2.53 Found: C 62.89, H 6.02, N 2.62 Cl 29H28CI2F3N02.HCI 1.6 H20 117 CC -C alcd: C 56.57, H 5.27, N 2.27 Found: C 56.2, H 4.86, N 2.25 Cl

OCH3 C31H34F3N04.HC1 0.9 H20 118 8 < Calcd: C 62.65, H 6.24, N 2.36 Found: Found: C 62.58, H 6.15, N 2.42 OCH3

Scheme 7 R OH O CO2tBu i) + HO\E(R CO2tBu benzene CHO CHO 28 29 R R °~ CO2tBu I)HdPdIBaS04 CO2tBu ethyl I ethyl acetate I I N N Piperidine-AcOH 2) Dess-Martin tetrahydrofuran 9 Periodinane dichloromethane CF3 CF3 31 R R RlCOCI o~ coRt O~ SO2R2 tetrahydrofuran TFA ~ water-sodium acetate or Or N1 Or N 2so dichloromethane triethyl amine ° CF3 ° CF3 Xa 33b

Example 119 N-r2-[4-(4,4,4-trifluoro-3-oxo-1-butyl)phenoxylethyll-N-meth yl dodecanamide N-[2-(4-formylphenoxy)ethyl]-N-methylcarbamic acid, l,l-dimethylethyl ester A solution of N-(2-hydroxyethyl)-N-methylcarbamic acid, 1,1- dimethylethyl ester (7.05 g, 40.2 mmol; W.S. Saari and all, J. Med. Chem.

X, 97 (1990)), 4-hydroxybenzaldehyde (3.75 g, 30.7 mmol) and triphenylphosphine (10.57 g, 40.3 mmol) in dry benzene (120 ml) was cooled to 150C and treated with diisopropyl azodicarboxylate (8.15 g, 40.3 mmol) in dry benzene (20 ml) added dropwise over 20 min. After 16 h at 22"C, and chromatography on silica gel (elution toluene-ethyl acetate 9:1- 8:2) gave 4.40 g (52%) of the title material as white cubes: mp 62-65"C (ether-hexane).

Anal. Calcd. for C15H21N04: C 64.50, H 7.58, N 5.01.

Found: C 64.25, H 7.59, N 5.00. <BR> <BR> <BR> <BR> <BR> <BR> <P>E-N-[2-[4-(4-trifluoro-3-oxo-1-butenyl)phenoxylethy ll-N-methylcarbamic acid, l l-dimethylethyl ester A solution of N-[2-(4-formylphenoxy)ethyl]-N-methylcarbamic acid, 1,1- dimethylethyl ester (3.72 g, 13.3 mmol) in dry tetrahydrofuran (65 ml) was cooled to 10°C and treated with acetic acid (1.4 ml) and piperidine (1.4 ml).

Then l,l,l-trifluoroacetone (7 ml) in dry tetrahydrofuran was added dropwise over 10 min. After 2 h and 4 h at 200C, two other successive portions of l,l,l-trifluoromethylacetone (2 x 7 ml) were also added. After another 2 h at 220C, the reaction mixture was diluted with ethyl acetate (300 ml) washed with water, saturated ammonium chloride, saturated sodium bicarbonate and brine. The organic phase was then dried, concentrated and chromatographed on silica gel. Elution with a gradient of ethyl acetate in hexane (0 - 20%) gave 3.05 g (61%) of the title material as yellow crystals: mp 76-77"C (hexane).

Anal. Calcd. for C18H22N04F3: C 57.90, H 5.94, N 3.75.

Found: C 57.82, H 5.92, N 3.72.

N- [2-14- (4-trifluow-3-oxo4-butyl)phenoxyiethyli-N-methylcarbamic acid, l l-dimethylethyl ester A solution of (E)-N-[2-[4-(4-trifluoro-3-oxo-1-butenyl)phenoxy] ethyl]-N- methylcarbamic acid, l,l-dimethylethyl ester (1.10 g, 2.95 mmol) in ethyl acetate (80 ml) was hydrogenated at atmospheric pressure over 5% palladium on barium sulfate (0.20 g) for 1 hour. The catalyst was then filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (60 ml) and then treated at 22"C with Dess-Martin periodinane reagent (2.50 g, 5.90 mmol). After 1 hour, the reaction mixture was diluted with ethyl acetate, washed with 10% aqueous sodium thiosulfate and saturated sodium bicarbonate. After drying, the organic phase was concentrated and chromatographed on silica gel. Elution with a gradient of ethyl acetate (0 - 10%) in toluene gave 0.880 g (79%) of the title material as an amorphous solid. By 'H NMR this product is a mixture of ketone and hydrated ketone.

Anal. Calcd. for C18H24N04F3. 0.7 H20: C 55.72, H 6.60, N 3.61.

Found: C 55.80, H 6.52, N 3.52. <BR> <BR> <BR> <BR> <BR> <BR> <P>N-[2-[4-(4-trifluoro-3-oXo-1-butyl)phenoxylethyll-N -methyldodecanamide A solution of N-[2-[4-(4-trifluoro-3-oxo-1-butyl)phenoxy]ethyl]-N- methylcarbamic acid, l,l-dimethylethyl ester (0.200 g, 0.53 mmol) in dichloromethane (10 ml) was treated with trifluoroacetic acid (1 ml) and stirred at 220C for 1 h. The solvent was evaporated in vacuo and the residue was co-evaporated with toluene three times. The product was then dissolved in tetrahydrofuran (10 ml) treated with 40% sodium acetate in water (10 ml) and while stirred vigorously treated with lauroyl chloride (0.116 g, 0.53 g mmol) added dropwise over 2 min. After 1 hour at 220C, the reaction mixture was diluted with ethyl acetate (150 ml), washed with water, saturated sodium bicarbonate and brine. After drying (magnesium sulfate) the solvent was evaporated in vacuo and the residue was chromatographed on silica gel. Elution with a gradient of ethyl acetate (0 - 30%) in toluene gave 0.181 g (74%) of the title material as a waxy solid. By 'H NMR, this product is a mixture of ketone and hydrated ketone.

Anal. Calcd. for C25H38F3N03. H20: C 63.14, H 8.48, N 2.95.

Found: C 63.26, H 8.03, N 2.87.

The following compounds may be prepared by the general procedure of Scheme 7.

SCHEME 7 lr R1 I[ RI ]I Analysis II Exp. II # II C24H36F3N03 0.2 H20 120 H o. u Calcd: C 64.47, H 8.21, N 3.13 o d O\\ C27H24C12F3N03. H20 121 CH3 cr Calcd: C 58.28, H 4.71, N 2.52 Found: C 58.43, H 4.38, N 2.64 cl C26H40F3NO3. 1.7 H2O 122 (CH2)11CH3 COCH3 Calcd: C 62.18, H 8.71, N 2.79 Found: C 61.95, H 8.51, N 2.83 C29H46F3N04 123 (CH2)11CH3 C02tBu Calcd: C 64.66, H 8.79, N 2.60 Found: C 64.81, H 8.79, N 2.70 C 17H22F3No4 124 H C02tBu Calcd: C 56.51, H 6.14, N 3.88 Found: C 56.35, H 6.19, N 3.84 C19H28F3NO4S.O.2 H2O 125 H SO2(CH2)6CH3 Calcd: C 53.43, H 6.70, N 3.28, S 7.51 Found: C 53.43, H 6.72, N 3.28, S 7.50 C24H38F3NO4S 126 H SO2(CH2)11CH3 Calcd: C 58.40, H 7.76, N 2.84, S 6.50 Found: C 58.29, H 7.77, N 2.84, S 6.40 C25H40F3NO4S 127 CH3 SO2(CH2)11CH3 Calcd: C 59.15, H 7.94, N 2.76, S 6.32 Found: C 59.02, H 7.70, N 2.79, S 6.25 C23H35F3N2O2S 128 H CSNH(CH2)9CH3 Calcd: C 59.98, H 7.66, N 6.08, S 6.96 Found: C 59.80, H 7.70, N 6.05, S 7.06

SCHEME 7 (continued) Exp. # R1 R2 Analysis C26H37F6NO3. 0.4 H2O 129 (CH2)11CH3 COCF3 Calcd: C 58.61, H 7.15, N 2.63 Found: C 58.48, H 6.98, N 2.73 C31H42F3NO3.0.4 H2O 130 (CH2)11CH3 COC6H5 Calcd: C 68.84, H 7.98, N 2.59 Found: C 68.61, H 8.05, N 2.59 C30H46F3NO5. 0.4 H2O 131 (CH2)llCH3 COCH2CH2CO2Et Calcd: C 63.79, H 8.35, N 2.48 Found: C 63.5, H 8.38, N 2.49 C28H47F3NO5P. 0.4 H20 132 (CH2)11CH3 PO(OEt)2 Calcd: C 58.71, H 8.41, N 2.45 Found: C 58.43, H 8.59, N 2.52 Scheme 8 OH NH ~~~~~~ CF3COCH3 N Piperidine-AcOH CHO tetrahydrofuran CF3 28 14 BrCH2CO2tBu BrCH 2CO2tBu acetone acetone potassium carbonate potassium carbonate (or R2COCI) CH2C O2tBu R2 OCH2CO2tBu R2° ,vl CF3COCH3 N or Q Piperidine-AcOH CHO tetrahydrofuran CF3 CF3 35 36 36b (from 34) 9/\ COpH CONRR1 TFA ~ g PR1NH dichloro- N EEDO N methane 9 tetrahydrofuran CF3 CF3 31 I38 ,0 CONRR1 H2,PdIBaSO4 ethyl acetate N Dess-Martin Periodinane dichloromethane CF3 CO2tBu 0tOtBu H2, Pd/BaSO4 A I ethyl acetate I Dess-Martin Periodinane : dichloromethane O CF3 CF3 36 40 O CO2H 1 °> 1)(COCl)2 0 TFA 1 dichloromethane 4 dichloromethane N 2) PP1 NH N tetrahydrofuran water/sodium acetate 0 CF3 Q/'\CF3 41

Example 133 <BR> <BR> <BR> <BR> <BR> <BR> <BR> N-Dodecyl-4-(4,4,4-trifluoro-3-oxo-1-butyl)phenoxyacetamide <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> (E)-1 trifluoro-4-(4-hydroxyphenyl!-3-buten-2-one A solution of 4-hydroxybenzaldehyde (5.0 g, 40.9 mmol) in tetrahydrofuran (165 ml) was treated with acetic acid (3.5 ml) and piperidine (3.5 ml). Then l,l,l-trifluoroacetone (8 ml) was added dropwise. After 2 h at 220C, another portion of l,l,l-trifluoroacetone (8 ml) was added and the mixture was stirred for another 3 h. The reaction mixture was then diluted with ethyl acetate, washed with water, saturated ammonium chloride, saturated sodium bicarbonate, and brine.

The organic phase was dried (magnesium sulfate), concentrated under reduced pressure and chromatographed on silica gel. Elution with a gradient of ethyl acetate (0 - 5%) in toluene gave 4.16 g (47%) of title material as yellow needles after crystallization from ether-hexane: mp 106- 107"C.

Anal. Calcd. for C10H7F302: C 55.57, H 3.26.

Found: C 55.30, H 3.27.

(E)-4-(4,4 .4-trifluoro-3-oxo-1-butenyl)phenoxyacetic acid, 1. l-dimethylethyl ester A solution of (E)-l,l,l-trifluoro-4-(4-hydroxyphenyl) 3-buten-2-one (0.105 g, 0.49 mmol) in acetone (6 ml) was treated with powdered potassium carbonate (0.3 g) and tert-butyl bromoacetate (0.20 g, 1.02 mmol) and stirred at 22"C for 3 h. The reaction mixture was then diluted with toluene, washed with brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was chromatographed on silica gel (elution toluene-ethyl acetate 2%) and gave 0.150 g (94%) of the title material as yellow needles: mp 112-113"C.

Anal. Calcd. for C16H17F304: C 58.18, H 5.19.

Found: C 58.12, H 5.18.

(E)-4-(4.4A-trifluoro-3-oxo-1-butenyl)phenoxyacetic acid A solution of (E)-4-(4,4,4-trifluoro-3-oxo- 1 -butenyl)phenoxyacetic acid, 1,1- dimethylethyl ester (1.578 g, 4.77 mmol) in dichloromethane (90 ml) was treated with trifluoroacetic acid (10 ml) and stirred at 220C for 4 h. The solvent and excess reagent were evaporated under reduced pressure and the last traces of trifluoroacetic acid were co-evaporated with toluene.

Crystallization of the residue from ethyl acetate-hexane gave 1.29 g (98%) of the title material as white cubes: mp 156-156.5"C.

Anal. Calcd. for C12H9F304: C 52.57, H 3.31.

Found: C 52.66, H 3.29.

(E)-N-dodecyl-4-(4.4A-trifluoro-3-oxo-1 -butenyl)phenoxyacetamide A solution of (E)-4-(4,4,4-trifluoro-3-oxo-1-butenyl)phenoxyacetic acid (0.810 g, 2.95 mmol) in tetrahydrofuran (20 ml) was treated with EEDQ (0.767 g, 3.10 mmol) and dodecylamine (0.575 g, 3.10 mmol). After 2 h at 22"C, the reaction mixture was diluted with ethyl acetate, washed with water, 0.1N hydrochloric acid, saturated sodium bicarbonate, brine and dried. Evaporation of the solvent under reduced pressure gave a solid which was chromatographed on silica gel. Elution with a mixture of toluene and ethyl acetate (8:12) gave 0.750 g (58%) of the title material as white needles after recrystallization from ethyl acetate-hexane: mp 78.5- 79"C.

Anal. Calcd. for C24H34F3N03: C 65.29, H 7.76, N 3.17.

Found: C 65.30, H 7.73, N 3.13.

N-dodecvl-4-(4.4.4-trifluoro-3-oxo-1 -butyl)phenoxyacetamide (E)-N-dodecyl-4-(4,4,4-trifluoro-3-oxo-1-butenyl)phenoxyacet amide (0.530 g, 1.20 mmol) was hydrogenated and re-oxidized as described in example 119 to give 0.490 g (92%) of the title material as an amorphous solid.

Anal. Calcd. for C24H36F3N03H20: C 62.45, H 8.30, N 3.03.

Found: C 62.54, H 8.19, N 3.18.

Example 134 N-[Bis-(4-chlorophenyl)methyl]-4-(4,4,4-trifluoro-3-oxo-1-bu tyl)- phenoxyacetamide 4-(4.4A-trifluoro-3-oxo-1-butyl)-phenoxyacetacetic acid. l l-dimethvlethvl ester E-(4,4,4-trifluoro-3-oxo-1 -butenyl)-phenoxyacetacetic acid, 1,1- dimethylethyl ester (1.95 g, 5.90 mmol) was hydrogenated and re-oxidized as described in example 133 to give 1.93 g (98%) of the title material as a wax.

Anal. Calcd. for C16H19F304: C 55.43, H 5.99.

Found: C 55.32, H 5.90.

4-(4.4.4-trifluoro-3-oxo-1-butyl)phenoxyacetic acid 4-(4,4,4-trifluoro-3-oxo-1 -butyl)phenoxyacetic acid l,l-dimethylethyl ester (0.450 g, 1.35 mmol) was treated with trifluoroacetic acid as described in example (133) to give 0.373 g (100%) of the material as a white solid. <BR> <BR> <BR> <BR> <BR> <BR> <P>N-[Bis-(4-chlorophenvl!methvl]-4-(4.4 4-trifluoro-3-oxo-1- <BR> <BR> <BR> <BR> <BR> <BR> butyl)phenoxyacetamide A solution of 4-(4,4,4-trifluoro-3-oxo-1-butyl)phenoxyacetic acid (0.374 g, 1.35 mmol) in dichloromethane (10 ml) was treated with oxalyl chloride (0.17 ml, 2.03 mmol) and a trace of N,N-dimethylformamide. After 30 min at 220C, the solvent and excess reagent were evaporated under reduced pressure and the residual oil obtained was dissolved in anhydrous tetrahydrofuran (10 ml). This solution was then added dropwise to a vigorously stirred solution of p-chlorobenzhydrylamine hydrochloride (0.39 g, 1.35 mmol) in a mixture of tetrahydrofuran (10 ml) and 40% aqueous sodium acetate (10 ml). After 30 min at 220C, the reaction mixture was diluted with ethyl acetate, washed with water, brine and dried. Evaporation of the solvent under reduced pressure gave a solid which was chromatographed on silica gel. Elution with a mixture of toluene and ethyl acetate (8:2) gave 0.603 g (87%) of the title product as white crystals: mp 145-146"C.

Anal. Calcd. for C25H20C1F3N03: C 58.84, H 3.85, N 2.74, C1 13.89, F 11.17.

Found: C 58.73, H 4.07, N 2.82, C1 13.60, F 10.46.

Scheme 9 CH3(CH2)nSH + BrCH2CH20H » (CH3)(CH2)nSGH2CH20H DMF potassium carbonate OH O~ S(CH2)nCH3 hl + HOCH2CH2S(CH2)nCH3 , h 9 HOCH2CH2S(CH2)nCH3 PPh3-DlAD N 43 benzene O;oMe OMe 42 44 ~ S(CH2)nCH3 O~ S(CH2)nCH3 1 1) (COCI)2 KOH 43 dichloromethane water N water ethanol Hz 2) TFAA-Pyridine dichloromethane OH ° CF3 45 46 mCPBA | NalO4 dichloromethane | methanol 0 O/C:SiCH2),CH3 FIZZ S(CH2)nCH3 NI NI ° CF3 ° CF3 47 48

Example 135 4-[4-[2-(Dodecylthio)ethoxyphenyl]-1,1,1-trifluoro-2-butanon e 2-(Dodecylthio! Ethanol HOCH2CH2Br + HS(CH2)11CH3 HOCH2CH2S(CH2)11 CH3 A mixture of 2-bromoethanol (6.08 g, 48.7 mmol), dodecanethiol (9.86 g, 48.7 mmol) and potassium carbonate (11 g) in dry N,N- dimethylformamide (100 ml) was stirred at 220C for 10 h. The reaction mixture was then diluted with toluene (400 ml) washed with water and dried (magnesium sulfate). The solvent was evaporated under reduced pressure and the residue was filtered through a silica gel pad (toluene - ethyl acetate 95:5) and distilled under vacuum to give 9.18 g (77%) of 2- (dodecylthio)ethanol as a clear oil which solidified on standing: b.p. 100- 105"C/0,01 torr (bulb to bulb distillation, air bath temperature); m.p. 31- 32°C.

IR (NaCl, film) may (cm 1): 3380 (OH).

H NMR 400 MHz (CDC13) d (ppm) : 0.89 (3H, t, J=6.8 Hz, CH3), 1.2-1.7 (20H, m, (CH2)10), 2.16 (1H, br t, OH), 2.52 (2H, t, J=7.4 H, SCH2), 2.74 (2H, t, J=6.0 Hz, OCHtCHvS), 3.7 (2H, q, J=6.0 Hz, Oli2CH2S.

Anal. Calcd. for C14H300S: C 68.23, H 12.27, N 13.01.

Found: C 68.06, H 12.29, N 12.95.

3-[4-[2-(Dodecylthio)ethoxy]phenyl]propanoic acid methyl ester A solution of methyl 3-[4-hydroxyphenyl)propionate (2.46 g, 13.6 mmol), 2-(dodecylthio)ethanol (3.40 g, 13.7 mmol) and triphenylphosphine (3.60 g, 13.8 mmol) in dry benzene (50 m8) was treated at 220C with diethyl azodicarboxylate (2.43 g, 13.9 mmol) added dropwise over 10 min. After 3 h at 22°C, the reaction mixture was diluted with ethyl acetate, washed with water, brine and dried (magnesium sulfate). Evaporation under reduced pressure gave an oil which was triturated with hexane to precipitate the triphenylphosphine oxide and the hydrazine side products.

The filtrate was chromatographed on silica gel using a gradient of ethyl acetate (0-5%) in hexane as eluent to give 4.70 g(84%) of 3-[4-[2- (dodecylthio)ethoxy]phenyl]propanoic acid methyl ester as a white solid.

Recrystallization from methanol gives white leaflets : m.p. 48°C.

IR (KBr) µmax (cm-1) : 1729 (C=O of ester).

1H NMR 400 MHz (CDC13) d (ppm) : 0.89 (3H, t, J=6.8 Hz, CH3), 1.2-1.7 (20H, m, (CH2)10), 2.6 (4H, br t, SCH2 and CH2CO), 2.9 (4H, br t, OCH2CH2S and PhCH2), 3.68 (3H, s, OCH3), 4.11 (2H, t, J=7.03 Hz, OCH2CH2S), 6.83 (2H, d, J=8.7 Hz aromatic), 7.12 (2H, d, J=8.7 Hz, aromatic).

Anal. Calc. for C24H4003S: C 70.54, H 9.87, S 7.85.

Found: C 70.25, H 9,38, S 7.87.

3-[4-[2-(Dodecylthio)ethoxy]phenyl]propanoic acid A suspension of 2-[4-[2-(dodecylthio)ethoxy]phenyl]propanoic acid methyl ester (4.70 g, 11.5 mmol) in 80% ethanol (100 ml) was treated with a solution of potassium hydroxide (1.33 g, 20.1 mmol) in water (10 ml) and the mixture was stirred at 550C for 1 h. The solvent was then concentrated in vacuo and the residue was diluted with water (100 ml) and dichloromethane (250 ml). The solution was then adjusted to pH 2 with diluted hydrochloric acid and the aqueous phase was extracted a second time with dichloromethane. The combined organic extracts were washed with brine and dried (magnesium sulfate). Evaporation of the solvent under reduced pressure and crystallization of the residue from ethyl acetate-hexane gave 3.56 g (78%) of 3-[4-[2- (dodecylthio)ethoxy]phenyl]propanoic acid as white prisms: m.p. 68-69°C.

IR (NaCl, film) ,u (cm1): 1710 (C=O).

1H NMR 400 MHz (CDCl3) d (ppm) : 0.89 (3H, t, J=6.8 Hz, -CH3), 1.1-1.7 (20H, m, (CH2)10), 2.63 (4H, m, SCH2 and CH2CO), 2.90, (4H, m, OCH2CH2S and PhCH2), 4.12 (2H, t, J=6.99, OCH2CH2S), 6.84 (2H, d, J=8.5 Hz, aromatic), 7.13 (2H, d, J=8.5 Hz, aromatic).

Anal. calcd. for C23H38O3S. 0.1 H20: C 69.69, H 9.71, S 8.09.

Found: C 69.55, H 9.86, S 8.15.

4-[4-[2-(Dodecylthio)ethoxy]phenyl]-1,1,1-trifluoro-2-but anone A solution of 3-[4-[2-(dodecylthio)ethoxy]phenyl]propanoic acid (14.13 g, 35.8 mmol) in dichloromethane (400 ml) was treated with oxalyl chloride (6.5 ml) and a drop of N,N-dimethylformamide and the resulting mixture was stirred at 220C for 1 h. The solvent and excess reagent were evaporated under reduced pressure and the residue was dissolved in dry dichloromethane (200 ml). This solution was added to a cold (0°C) solution of trifluoroacetic anhydride (19.2 ml, 0.107 mol) in dichloromethane (200 ml). Then pyridine (6.1 ml, 75.4 mmol) was added dropwise and the resulting solution was stirred at 0°C for 30 min and then at 22°C for 2 h. Water (50 ml) was added and the mixture was stirred for another 30 min. The organic phase was then washed with brine, dried and concentrated under reduced pressure. Chromatography on silica gel (elution with a gradient of ethyl acetate 0-10% in toluene) gave 10.50 g (66%) of 4-[4-[2-(dodecylthio)ethoxy]phenyl]-1,1,1-trifluoro-2-butano ne as an amorphous solid.

IR (NaCl, film) µmax (cm1): 1758 (C=O).

1H NMR 400 MHz (CDCl3) d (ppm) : 0.89 (3H, t, J=6.8 Hz, -CH3), 1.2-1.7 (20H, m, (CH2)10), 2.62 (2H, t, J=7.46 Hz, SCH2), 2.89 (2H, t, J=6.95 Hz, OCHvCHzS), 2.9-3.1 (4H, m, CH2CH2CO), 4.12 (2H, t, J=6.95 Hz, OCH2CH2S), 6.85 (2H, d, J=8.7 Hz, aromatic), 7.11 (2H, d, J=8.7 Hz, aromatic).

Anal. Calcd. for C24H37F302S: C 64.54, H 8.35.

Found: C 64.47, H 8.32.

Example 136 4-[4-[2-(Dodecylsulfinyl)ethoxy]phenyl]-1,1,1-trifluoro-2-bu tanone A solution of 4-[4-[2-(dodecylthio)ethoxy]phenyl]-1,1,1-trifluoro-2- butanone (0.340 g, 0.76 mmol) in methanol (15 ml) was treated with a solution of sodium periodate (0.165 g, 0.77 mmol) in water (3 ml) and the resulting mixture was stirred at 22"C for 18 h. The solid formed was filtered and washed with methanol. This filtrate was then concentrated under reduced pressure and then partitioned between water and ethyl acetate. The organic phase was then dried (magnesium sulfate) and concentrated. The residue was chromatographed on silica gel (elution toluene-ethyl acetate 1:1) to give 0.335 g (90%) of 4-[4-[2- (dodecylsulfinyl)ethoxy]phenyl]-l,l,l-trifluoro-2-butanone as a white solid. By 'HNMR this product was a 6:4 mixture of trifluoromethyl ketone and hydrated trifluoromethyl ketone. The pure hydrate precipitates from ethyl acetate-hexane: m.p. 98-100"C.

IR (NaCl, film) R (cm 1): 3400 (OH), 1650.

1H NMR 400 MHz (CDCl3) d (ppm) : 0.89 (3H, t, J=6.8 Hz, -CH3), 1.3, 1.45 and 1.8 (16H, 2H and 2N, 3m, (CH2)10), 2.09 (2H, br t, J=8 Hz, CH2CH2CO), 3.7 (2H, br, OH), 4.4 (2H, m, OCH2), 6.84 (2H, d, J=8.5 Hz, aromatic), 7.15 (2H, d, J=8.5 Hz, aromatic).

Anal. Calcd. for C24H37F3S.H20: C 59.98, H 8.18, S 6.67.

Found: C 60.06, H 8.17, S 6.67.

Example 137 4-[4-[2-(Dodecylsulfonyl)ethoxy]phenyl]-1,1,1-trifluoro-2-bu tanone A solution of 4-[4-[2-(dodecylthio)ethoxy]phenyl]-1,1,1-trifluoro-2- butanone (0.394 g, 0.88 mmol) in dichloromethane (25 ml) was treated at 22°C with 85% m-chloroperbenzoic acid (0.40 g, 1.8 mmol) and the resulting mixture was stirred for 2.5 h. The reaction mixture was then washed with aqueous sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation and chromatography on silica gel (elution with a gradient of ethyl acetate 0-20% in toluene) gave 0.344 g (82%) of 4-[4-[2- <BR> <BR> <BR> (dodecylsulfonyl)ethoxy]phenyl]-1,1,1-trifluorobutanone as as an amorphous solid. By 'HNMR, this product is a -1:1 mixture of trifluoromethylketone and hydrated trifluoromethyl ketone: m.p. 55-56°C.

IR (NaCl, film) umax (cm-1) : 3400 (OH) and 1760 (C=O).

1H NMR 400 MHz (CDC13) .

Ketone form: d (ppm) : 0.89 (3H, t, J=6.8 Hz, -CH3), 1.28, 1.45 and 1.9 (16H, 2H and 2H, 3 m, (CH2)10)I 3.0 (4H, m, CH2CH2CO), 3.12 (2H, m, SOL), 3.4 (2H, t, J=5.35 Hz, OCH2CH2S), 4.41 (2H, t, J=5.35 Hz, OCH2CH2S), 6.84 (2H, d, J=8.6 Hz, aromatic), 7.15 (2H, d, J=8.6 Hz, aromatic).

Hydrate form: d (ppm) : 2.14 (2H, br t, J=8.1 Hz, CH2CH2CO), 2.87 (2H, br t, J=8.1 HJz, CH2CH2CO), 6.86 (2H, d, J=8.6 Hz, aromatic), 7.2 (2H, d, J=8.6 Hz, aromatic).

Anal. Calcd. for C24H37F304S .0.6 H20: C 58.90, H 7.87, S 6.55.

Found: C 58.86, H 7.79, S 6.63.

Example 138 4-[4-[2-[2-[Bis(4-chlorophenyl)methoxy]ethylsulfonyl]ethoxy] phenyl]-1,1,1- trifluoro-2-butanone 2-[Bis(4-chlorophenyl)methoxy]ethyl bromide.

A mixture of 4,4'-dichlorobenzhydrol (4.40 g, 0.17 mmol) and 2- bromoethanol (3.0 g, 24.0 mmol) in benzene (50 ml) was treated with sulfuric acid (0.25 ml) and the resulting mixture was heated under reflux

for 1 h. The cooled mixture was diluted with ethyl acetate (200 ml), washed with saturated sodium bicarbonate, brine and dried over magnesium sulfate. Evaporation of the solvent gave an oil which was chromatographed on silica gel using a mixture of toluene and hexane (1:1) as eluent to give the title compound as a clear oil (5.13 g, 82%).

2-[2-[Bis(4-chlorophenyl)methoxy]ethylthio]ethanol A solution of 2-[bis(4-chlorophenyl)methoxy]ethyl bromide (5.13 g, 14.2 mmol) in N,N-dimethylformamide (50 ml) was treated at 220C with powdered anhydrous potassium carbonate (3.0 g, 21.7 mmol) followed by 2-mercaptoethanol (1.25 g, 16.0 mmol). The resulting mixture was stirred at 22° for 18 h. The reaction mixture was then diluted with toluene (400 ml) washed with water, brine and dried over magnesium sulfate.

Evaporation of the solvent gave an oil which was chromatographed on silica gel (elution ethyl acetate 0-10% in toluene) to give 4.93 g (96%) of the title material as a clear oil.

Anal. Calcd. for C17Hl8Cl2o2S: C 57.15, H 5.08, S 8.97. Found: C56.99, H 4.82, S 9.05.

3-[4-[2-[2-[Bis(4-chlorophenyl)methoxy]ethylthio]ethoxy]p henyl]propionic acid methyl ester A solution of methyl 3-(4-hydroxyphenyl) propionate (1.40 g, 7.77 mmol), 2-[2-[bis(4-chlorophenyl)methoxy]ethylthio] ethanol (2.80 g, 7.80 mmol) and triphenylphosphine (2.0 g, 7.8 mmol) in dry benzene (30 ml) was treated at 220C with diethyl azodicarboxylate (1.34 g, 7.8) added dropwise over 5 min. After 18 h at 220C, the reaction mixture was diluted with ethyl acetate (200 ml) washed with saturated sodium bicarbonate and dried over magnesium sulfate. Evaporation of the solvent gave an oil which was triturated in a mixture of hexane and toluene (6:4) to crystallize the triphenylphosphine oxide and the hydrazine side products. The filtrate was chromatographed on silica gel (elution ethyl acetate 0-5% in toluene) to give 2.90 g (71%) of the title material as an oil.

Anal. Calcd. for C27H28C1204S: C 62.43, H 5.43, S 6.17. Found: C 61.89, H 5.21, S 6.11.

3-l4-[2-[2-[Bis(4-chlorophenyl)methoxy]ethylthio]ethoxy]p henyl]propionic acid A mixture of 3-[4-[2-[2-[Bis(4- chlorophenyl]methoxy]ethylthio]ethoxy]phenyl] propionic acid methyl ester (2.76 g, 5.31 mmol) and 80% aqueous ethanol (50 ml) was treated with a solution of potassium hydroxide (0.7 g, 10.6 mmol) in water (3 ml) and the resulting mixture was heated at 600C for 1 h. The solvent was then concentrated in vacuo and the residue was diluted with water (30 ml) and dichloromethane (50 ml) and acidified to pH4 with 2N hydrochloric acid. The aqueous phase was extracted a second time with dichloromethane and the combined organic extracts were washed with brine and dried (magnesium sulfate). Evaporation of the solvent under reduced pressure gave 2.63 g (98%) of the title acid as a white solid.

Anal. Calcd. for C26H26C1204S: C 61.78, H 5.18, S 6.34. Found: C 61.42, H 5.11, S 6.34.

4-[4-[2-[2-FBis(4-chlorophenyl)methoxy] ethylthio]ethoxyiphenyll-1 .1- trifluoro-2-butanone A solution of 3-[4-[2-[2-[bis(4- chlorophenyl)methoxy]ethylthio]ethoxy]phenyl]propionic acid (2.49 g, 4.93 mmol) in dry dichloromethane (25 ml) was treated at 220C with oxalyl chloride (1.5 g, 11.8 mmol) and a small drop of N,N-dimethylformamide.

After 1 h, the solvent and excess reagent were evaporated in vacuo and the residue was diluted with dry toluene (75 ml). The solution was then cooled to 0-5"C, treated with trifluoroacetic anhydride (3.12 g, 14.9 mmol) followed by pyridine (0.98 g, 12.4 mmol) added dropwise over 10 min. The reaction mixture was then allowed to warm up to 200C and stirred for another 2 h. Then water (5 ml) was added dropwise and the mixture was stirred for another 15 min. The reaction mixture was then diluted with ethyl acetate (300 ml) washed with water, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation gave an oil which was chromatographed on silica gel. Elution with a gradient of ethyl acetate (0- 4%) in toluene gave 2.35 g (85%) of the title material as an oil.

Anal. Calcd. for C27H25C12F303S.0.4 H20: C 57.43, H 4.63, S 5.68. Found: C 57.42, H 4.41, S 5.49.

4-F4-[2-[2-[Bis(4-chlorophenyl)methoxy]ethylsulfinyl]etho xy]phenyll-1 .1.1- trifluoro-2-butanone A solution of 4-[4-[2-[2-[bis(4- chlorophenyl)methoxy]ethylthio]ethoxy]phenyl]-1,1,1-trifluor o-2- butanone (0.88 g, 1.58 mmol) in methanol (40 ml) was treated at 220C with a solution of sodium periodate (0.34 g, 1.58 mmol) in water (2 ml). After 6.5 h the solid formed was filtered and the filtrate was evaporated in vacuo. The residue was diluted with ethyl acetate, washed successively with sodium bicarbonate, water and brine, dried (magnesium sulfate) and concentrated. The residue was chromatographed on silica gel (elution ethyl acetate) to give 0.691 g (76%) of the title material as an oil.

Anal. Calcd. for C27H25C12F304S. 0.6 H20: C 55.51, H 4.52, S 5.49. Found: C 55.37, H 4.31, S 5.39.

4-[4-[2-[2-[Bis(4-chlorophenyl)methoxy]ethylsulfonyl]etho xy]phenyl]-1,1,1- trifluoro-2-butanone A solution of 4-[4-[2-[2-[bis(4- chlorophenyl)methoxy]ethylthio]ethoxy]phenyl]-1,1,1-trifluor o-2- butanone (1.51 g, 2.71 mmol) in dichloromethane (50 ml) was treated at 22"C with m-chloroperbenzoic acid (0.94 g, 5.4 mmol) and the resulting mixture was stirred for 2 h. The reaction mixture was then diluted with ethyl acetate, washed with sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation and chromatography on silica gel (elution toluene-ethyl acetate 8:2) gave 1.46 g (92%) of the title material as an oil which crystallized upon standing: mp 98-100"C.

IR (NaCl, film) umax (cm 1) 1755.

1H NMR 400 MHz (CDC13) d (ppm): 2.97 (2H, m), 3.02 (2H, m), 3.45 (2H, t, J=5.6 Hz), 3.53 (2H, t, J=5.6 Hz), 3.92 (2H, t J=5.6 Hz), 4.41 (2H, m), 5.39 (1H, s), 6.92 and 7.1-7.3 (12H, aromatic). Hydrated form: 2.15 and 2.87 (2m).

Anal. Calcd. for C27H25C12F305S: C 55.02, H 4.27, S 5.44. Found: C 54.83, H 4.36, S 5.54.

The following compounds may be prepared by the general procedure of Scheme 9.

SCHEME 9 # n R Analysis C19H27F3O2S 139 0 (CH2)6CH3 Calcd: C 60.62, H 7.23, S 8.52 Found: C 60.65, H 7.06, N 8.25 C l9H27F303S 140 1 (CH2)6CH3 Calcd: C 55.59, H 7.12, S 7.81 Found: C 55.55, H 6.94, S 7.72 C19H27F3O4S 141 2 (CH2)6CH3 Calcd: C 55.87, H 6.66, S 7.85 Found: C 55.61, H 6.30, S 7.80 Scheme 9 (continued) Exp. # n R Analysis C19H27F3O5S. 0.7 H2O 142 0 (CH2CH2O)3CH3 Calcd: C 52.21, H 6.55, S 7.34 Found: C 52.20, H 6.76, S 7.37 C19H27F3O6.O.8 H20 143 1 (CH2CH2O)3CH3 Calcd: C 50.17, H 6.34, S 7.05 Found: C 50.11, H 6.25, S 7.08 C19H27F3O7S. 0.7 H2O 144 2 (CH2CH2O)3CH3 Calcd: C 48.65, H 6.10, S 6.84 Found: C 48.72, H 6.16, S 7.00 145 0 5 C25H21Cl2F302S C alcd: C 58.49, H 4.12, S 6.25 ID Found: C 58.43, H 4.06, S 6.39 Cl 146 1 d C2SH2lCI2F3O3S. 1.5 H2O Calcd: C 53.96, H 4.35, S 5.76 Found: C 53.92, H 4.08, S 5.90 Cl 147 2 d C25H21Cl2F3o4S- 0.3 H2O Calcd: C 54.52, H 3.95, S 5.82 Found: C 54.52, H 3.79, S 5.91 Cl C31H34F3NO4S. HCl .0.5 H20 148 0 CH2CH2OX Calcd: C 60.14, H 5.86, N 2.26 Found: C 59.94, H 5.96, N 2.31 t0 C27H25F3O3S 149 ½ CH2CH20--( Found: C 66.83, H 5.16 C27H25F3O5S. 1.1 H20 150 2 Calcd: 1.1 CH2CH2O Calcd: C 60.24, H 5.09 Found: C 59.96, H 4.73 C26H24CIF304S 151 O CH2CH20 04 Calcd: C 59.48, H 4.61, S 6.11 Found: C 59.21, S 4.45, S 6.16 C26H24CIF305S. 0.8 H20 152 1 CH2CH2OoOC \ / Calcd: C 56.23, H 4.65, S 5.77 Found: C 56.13, S 4.62, S 5.96 C26H24CIF306S. 0.4 H2O 1S3 2 CH2CH2OvOç \ / Calcd: C 55.35, H 4.43, S 5.68 Found: C 55.30, S 4.27, S 5.88 C20H31F306SSi. 0.2 H20 154 0 CH2CH2OSi(CH3)2tBu Calcd: C 54.57, H 7.19 Found: C 54.26, H 7.01 C30H3SF3O3S Si 155 0 CH2CH2OSi(Ph)2tBu Calcd: C 64.26, H 6.29, S 5.72 Found: C 64.01, H 6.16, S 5.58 C30H35F304SS 0.9 H20 156 1 CH2CH2OSi(Ph)2tBu Calcd: C 60.77, H 6.26, S 5.41 Found: C 60.45, H 6.45, S 5.41 C30H35F305SSi. 0.2 H20 157 2 CH2CH2OSi(Ph)2tBu Calcd: C 60.42, H 5.98 Found: C 60.34, H 5.75 CH2 , Cl C28H23CI2F3N2O4S. OA H2O 158 2 CH2-- Calcd: C 54.36, H 3.88, S 4.53 Found: C 54.03, H 3.76, S 4.69 Scheme 9B. H ,O~ S OH N S(CH2CH2OH)2 N PPh3-DEAD I Y Benzene Y o OCH3 0 OCH3 42 OAc OAc O~S S OAc 1)KOH N 1) (COCI)2 N 2) AcOH 2) TFAA-Pyridine 9 o OH 0 CF3 50 <t 51 ~ SOH o KOH N Benzhydrol p-toluenesulfonic N acid o CF3 o CF3 52 53

Example 159 4-r4-r2-r2-Hydroxyethylthiolethoxylphenyll-l,l,l-trifluoro butanone.

3-[4-[2-(2-hydroxyethylthio)ethoxy]phenyl]propanoic acid, methyl ester A solution of methyl 3-[4-hydroxyphenyl) propionate (30.0 g, 0.166 mol), 2,2'-thiodiethanol (61.0 g, 0.50 mol) and triphenylphosphine (48.0 g, 0.183 mol) in dry benzene (450 ml) was treated at 22"C with diethyl azodicarboxylate (33.2 g, 0.19 mol) added dropwise over 10 min and the resulting mixutre was stirred at 220C for 5 h. The reaction mixture was then diluted with ether (300 ml) washed with water, saturated sodium bicarbonate and brine. After drying (magnesium sulfate) the solvent was evaporated in vacuo and the residue was chromatographed on silica gel (elution toluene-ethyl acetate 85:15) to give 37.64 g (79%) of the starting material as a white solid: mp 47-48°C.

Anal. Calcd. for C14H20O4S: C 59.13, H 7.09. Found: C 58.94, H 7.04.

3-r4-[2-(2-hydroxyethylthiolethoxylphenyll propanoic acid.

A solution of 3-[4-[2-(2-hydroxyethylthio)ethoxy]phenyl] propanoic acid, methyl ester (37.64 g, 0.132 mol) in 80% aqueous ethanol (300 ml) was treated with a solution of potassium hydroxide (17.0 g, 0.257 mol) in water (25 ml) and the resulting mixture was stirred at 220C for 1 h. The solvent was then concentrated in vacuo and the residue was diluted with water (200 ml) and dichloromethane (200 ml). The aqueous phase was then adjusted to pH 2 with 6N hydrochloric acid and extracted several times with dichloromethane. The combined organic extracts were washed with brine, dried (magnesium sulfate) and evaporated to give 35.67 g (100%) of the title material as a white solid: mp 64-65"C.

Anal. Calcd. for C13H1804S: C 57.76, H 6.71. Found: C 57.74, H 6.80.

3-[4-r2-(2-acetoxyethylthiolethoxylphenyll propanoic acid.

A solution of 3-[4-[2-(2-hydroxyethylthio)ethoxy]phenyl] propanoic acid, (35.67 g, 0.13 mol) in a mixture of toluene (500 ml) and acetic acid (500 ml) was treated with p-toluenesulfonic acid (1.2 g) and then heated under reflux using a Dean-Stark apparatus for 2 h. The cooled mixture was concentrated in vacuo and the residue was diluted with ethyl acetate, washed with water and dried (magnesium sulfate). Evaporation of the solvent under vacuum gave a solid which was crystallized from hexane to give 36.13 g (88%) of title material as a white solid: mp 48-49"C.

4-r4-r2-(2-acetoxsethylthiolethoxylphenyll-1,1,1-trifluor o-2-butanone.

A solution of 3-[4-[2-(2-acetoxyethylthio)ethoxy]phenyl] propanoic acid, (36.13 g, 0.115 mol) in dichloromethane (250 ml) was treated with oxalyl chloride (24 ml) and a drop of N,N-dimethylformamide. After 1 h at 250C, the solvent and excess reagent were evaporated in vacuo. The residual oil was dissolved in toluene (250 ml) cooled to OOC and treated with trifluoroacetic anhydride (49.0 ml, 0.347 mol). Then pyridine (19.0 ml, 0.232 mol) was added dropwise over 30 min and the resulting mixture was stirred at 220C for 3 h. The solution was then cooled again to 0°C, treated dropwise with water (70 ml) and then stirred at 220C for 30 min. The solution was then diluted with ethyl acetate, washed with water, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent in vacuo gave an oil which was chromatographed on silica gel. Elution with a mixture of dichlorimethane and ethyl acetate (0 - 2%) gave 26.10 g (62%) of the title material as an oil.

4-[4-[2-(2-hydroxyethylthio]ethoxy]phenyl]-1,1,1-trifluor o-2-butanone.

A solution of 4-[4-[2-(2-acetoxyethylthio)ethoxy]phenyl]-1,1,1-trifluoro-2 - butanone (26.10 g, 71.6 mmol) in ethanol (275 ml) was treated at 220C with a solution of potassium hydroxide (6.0 g, 91.0 mmol) in water (70 ml) and the resulting mixture was stirred for 30 min. The solvent was then evaporated in vacuo and the residual oil was dissolved in ethyl acetate, washed with water, brine and dried (magnesium sulfate). Evaporation of the solvent gave 23.0 g (100%) of the title material as an oil.

Anal. Calcd. for Cl4Hl7F303S. 0.3 H20: C 51.31, H 5.41. Found: C 51.11, H 5.42.

Example 160 <BR> <BR> <BR> <BR> 4-r4-r2-r2-rBis(4-methylphenyl)methoxylethylthiolethoxylphen yll-1,1,1- trifluoro-2-butanone.

A solution of 4- [4- [2-(2-hydroxyethylthio)ethoxy]phenyl]-1,1 ,1-trifluoro-2- butanone (1.20 g, 3.72 mmol), 4,4'-dimethylbenzhydrol (0.95 g, 4.47 mmol) and p-toluenesulfonic acid (0.035 g) in toluene (20 ml) was heated under reflux for 15 min. The cooled reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent in vacuo and chromatography of the residue on silica gel (elution with a gradient of ethyl acetate 20-40% in hexane) gave 1.81 g (94%) of the title material as an oil.

Anal. Calcd. for C29H31F303S: C 67.42, H 6.05. Found: C 67.43, H 6.08.

The following compounds may be prepared by the general procedure of Scheme 9B.

Table 9B Ex . # n R1 R2 Analysis C27H27F3O3S. H2O 161 0 H H Calcd: C 64.02, H 5.77 Found: C 63.90, H 5.50 C27H27F3O4S.0.6 H2O 162 1 H H Calcd: C 62.90, H 5.52 Found: C 62.89, H 5.57 C27H27F3O5S. 0.6 H2O 163 2 H H Calcd: C 61.03, H 5.35 Found: C 60.99, H 5.12 C29H31F3O4S. 0.6 H2O 164 1 p-CH3 p-CH3 Calcd: C 64.10, H 5.97 Found: C 64.20, H 5.88 C29H31F3O5S. 0.5 H2O 165 2 p-CH3 p-CH3 Calcd: C 62.46, H 5.78 Found: C 62.40, H 5.70 C29H31F3O3S. 0.3 H2O 166 o p-CH2CH3 H Calcd: C 66.72, H 6.10 Found: C 66.84, H 5.96 C29H31F304S. 0.5 H20 167 1 p-CH2CH3 H Called: C 64.31, H 5.96 Found: C 64.38, H 6.08 C29H31F3O5S. 0.3 H2O 168 2 p-CH2CH3 H Calcd: C 62.87, H 5.75 Found: C 62.88, H 5.73 C31H35F3O3S. 0.4 H2O 169 o p-tBu H Calcd: C 67.47, H 6.54 Found: C 67.51, H 6.41 C31H35F3O4S. 0.5 H2O 170 1 p-tBu H Calcd: C 65.36, H 6.37 Found: C 65.37, H 6.29 C31H35F3O5S. 0.4 H2O 171 2 p-tBu H Calcd: C 63.77, H 6.18 Found: C 63.84, H 5.81 C27H26ClF3O3S 172 O p-CI H Calcd: C 62.01, H 5.01 Found: C 62.40, H 4.80 C27H26C1F305S 173 2 p-Cl H Calcd: C 58.43, H 4.72 Found: C 58.14, H 4.71 C27H26ClF3O3S 174 0 m-Cl H Calcd: C 62.01, H 5.01 Found: C 61.97, H 5.04 C27H26ClF3O4S.0.5H2O 175 1 m-Cl H Calcd: C 59.18, H 4.97 Found: C 59.15, H 4.80 C27H26ClF3O5S.0.5H2O 176 2 m-Cl H Calcd: C 57.50, H 4.63 Found: C 57.51, H 4.65 C27H25Cl2F3O3S.0.2H2O m-Cl 177 0 H Calcd: C 57.80, H 4.56 p-Cl Found: C 57.93, H 4.59 C27H25Cl2F3O4S.0.5H2O m-Cl 178 2 H Calcd: C 54.19, H 4.38 p-Cl Found: C 54.20, H 4.35 C27H25Cl2F3O4S. H2O 179 2 m-Cl m-Cl Calcd: C 53.38, H 4.48 Found: C 53.15, H 4.14 C27H25F5O3S 180 0 p-F p-F Calcd: C 61.82,H 4.80,S 6.11 Found: C 61.90, H 4.66, S6.07 C27H25F5O4S 181 1 p-F p-F Calcd: C 57.59, H 4.92, S 5.69 Found: C 57.55, H 4.66, S 5.83 C27H25F5O5S. 0.25 H2O 182 2 p-F p-F Calcd: C 57.80, H 4.58, S 5.71 Found: C57.66, H 4.34, S 5.83 C27H25Br2F3O3S 183 0 p-Br p-Br Calcd: C 50.17, H 3.90, S 4.96 Found: C49.97, H 3.88, S 5.06 C27H25Br2F3O4S. 1.2 H2O 184 1 p-Br p-Br Calcd: C 47.41, H 4.04, S 4.69 Found: C47.22, H 3.77, S 4.74 C27H25Br2F3O5S. H2O 185 2 p-Br p-Br Calcd: C 46.57, H 3.91, S 4.60 Found: C46.71, H 3.87, S 4.71 C27H17F13O5S. 0.7 H2O 186 2 penta-F penta-F Calcd: C 45.48, H 2.60 Found: C 45.53, H 2.49 C33H30ClF3O3S 187 0 p-Cl p-Ph Calcd: C 66.16, H 5.05 Found: C 66.08, H 4.81 C33H30ClF3O4S. 0.6 H2O 188 1 p-Cl p-Ph Calcd: C 63.32, H 5.02 Found: C 63.08, H 4.75 C33H30ClF3O5S. 0.8 H2O 189 2 p-Cl p-Ph Calcd: C 61.40, H 4.93 Found: C 61.27, H 4.46 C27H25F3N207S- 0.8 H2O 190 0 m-NO2 m-NO2 Calcd: C54.69, H4.52, N 4.72, S 5.41 Found: C 54.57, H 4.36, N N 4.76, S 5.36 C27H25F3N208S-H20 191 1 m-NO2 m-NO2 Calcd: C 52.94, H 4.44, N 4.57, S 5.23 Found: C 52.97, H 4.22, N 4.59, S 5.38 C27H25F3N209S- 0.5 H20 192 2 m-NO2 m-NO2 Calcd: C 52.34, H 4.23, N 4.52, S 5.18 Found: C 52.29, H 4.02, N N 4.47, S 5.39 p-Cl C27H25ClF3NO5S 193 0 m-NO2 H Calcd: C57.09, H 4.44, N 2.47 Found: C57.12, H 4.47, N 2.73 p-Cl C27H25ClF3NO7S. 0.3 H2O 194 2 m-NO2 H Calcd: C53.37, H 4.26, N 2.31 Found: C53.56, H 4.26, N 2.47 p-Cl p-Cl C27H23Cl2F3N207S- 0.3 H2O 195 0 m-NO2 m-NO2 Calcd: C 49.67, H 3.64, N N 4.29, S 4.91 Found: C 49.40, H 3.47, N 4.59, S 4.81 p-Cl p-Cl C27H23Cl2F3N2O8S. 0.3 H2O 196 1 m-NO2 m-NO2 Calcd: C 48.49, H 3.56, N 4.19, S 4.79 Found: C 48.52, H 3.73, N 4.15, S 4.85 p-CI p-CI C27H23C12F3N209S 197 2 m-NO2 m-N02 Calcd: C 47.73, H 3.41, N 4.12, S 4.72 Found: C 47.57 H 3.31, N N 4.14, S 4.76 C29H31F3O5S. 0.5 H2O 198 0 m-OCH3 m-OCH3 Calcd: C 62.46, H 5.78 Found: C 62.51, H 5.79 C29H31F3O6S. 0.9 H2O 199 1 m-OCH3 m-OCH3 Calcd: C 59.97, H 5.69 Found: C 59.98, H 5.53 C29H31F3O7S. 0.2 H2O 200 2 m-OCH3 m-OCH3 Calcd: C 59.62, H 5.42 Found: C 59.55, H 5.47 C29H31F3O5S. 0.1 H2O 201 0 p-OCH3 p-OCH3 Calcd: C 63.28, H 5.71 Found: C 62.90, H 5.60 C29H31F3O6S. 0.6 H2O 202 1 p-0CH3 p-OCH3 Calcd: C 60.53, H 5.64, S 5.57 Found: C60.41, H 5.54, S 5.62 C29H31F3O7S. 0.7 H2O 203 2 p.OCH3 p-OCH3 Calcd: C 58.72, H 5.51, S 5.40 Found: C 58.5, H 5.48, S 5.47 C33H35F305S 204 0 p-O Allyl p-O Allyl Calcd: C 65.98, H 5.87, S 5.34 Found: C65.89, H 5.93, S 5.36 C33H35F3O6S. 0.6 H2O 205 1 p-OAllyl p-O Allyl Calcd: C 63.17, H 5.81, S 5.11 Found: C63.10, H 5.69, S 5.14 C33H35F3O7S. 0.4 H2O 206 2 p-O Allyl p-O Allyl Calcd: C 61.94, H 5.64, S 5.01 Found: C61.89, H 5.53, S 5.05 C28H29F3O4S. 0.3 H2O 207 0 p-OCH3 H Calcd: C 64.18, H 5.69 Found: C 64.14, H 5.82 C28H29F3O5S. 0.6 H2O 208 1 p-0CH3 H Calcd: C 61.66, H 5.58 Found: C 61.86, H 5.51 C28H29F3O6S. 0.6 H2O 209 2 p-OCH3 H Calcd: C 59.91, H 5.42 Found: C 59.90, H 5.20 C28H26F6O3S 210 0 m-CF3 H Calcd: C 60.43, H 4.71 Found: C 60.43, H 4.54 C28H26F6O4S. 0.7 H2O 211 1 m-CF3 H Calcd: C 57.47, H 4.72 Found: C 57.29, H 4.46 C28H26F6O5S. 0.5 H2O 212 2 m-CF3 H Calcd: C 56.28, H 4.55 Found: C 56.28, H 4.53 C28H26F603S 213 o p-CF3 H Calcd: C 60.43, H 4.71 Found: C 60.45, H 4.78 C28H26F6O4S. 0.5 H2O 214 1 p-CF3 H Calcd: C 57.83, H 4.68 Found: C 57.82, H 4.57 C28H26F6O5S. 0.2 H2O 215 2 p-CF3 H Calcd: C 56.79, H 4.49 Found: C 56.83, H 4.44 C29H25F9O5S. 0.2 H2O 216 2 p-CF3 p-CF3 Calcd: C 52.76, H 3.86 Found: C 52.63, H 3.87 C29H25F9O5S 217 2 m-CF3 m-CF3 Calcd: C 53.05, H 3.84 Found: C 52.96, H 3.79 C29H25F9O5S. 0.4 H2O 218 2 m-CF3 | p-CF3 Calcd: C 52.48, H 3.92 Found: C 52.43, H 3.90 C28H28CIF304S 219 0 p-OCH3 p-Cl Calcd: C 60.81, H 5.10 Found: C 60.67, H 5.07 C28H28ClF3O5S. 0.7 H2O 220 1 p-OCH3 p-Cl Calcd: C 57.82, H 5.09 Found: C 57.82, H 5.05 C28H28C1F306S. 0.4 H2O 221 2 p-OCH3 p-CI Calcd: C 56.79, H 4.90 Found: C 56.77, H 4.81 C28H28F4O4S 222 0 p-OCH3 p-F Calcd: C 62.68, H 5.26 Found: C 62.61, H 5.30 C28H28F4O5S. 0.4 H2O 223 1 p-OCH3 p-F Calcd: C 60.08, H 5.19 Found: C 60.05, H 5.24 C28H28F4O6S. 0.3 H2O 224 2 p.OCH3 p-F Calcd: C 58.59, H 5.02 Found: C 58.50, H 5.10 m-Cl C28H28ClF3O4S 225 0 o-OCH3 H Calcd: C 60.81, H 5.10 Found: C 60.70, H 5.20 m-Cl C28H28ClF3O5S. 0.3 H2O 226 1 o-OCH3 H Calcd: C 58.55, H 5.02 Found: C 58.53, H 4.72 C28H28ClF3O6S. 0.4 H2O m-Cl 227 2 o-OCH3 H Calcd: C 56.79, H 4.990 Found: C 56.73, H 4.95 C28H28C1F303S2 228 0 p-Cl p-SCH3 Calcd: C 59.09, H 4.96 Found: C 59.06, H 5.00 C28H28C1F304S2. 0.8 H2O 229 1 p-Cl p-SCH3 Calcd: C 56.10, H 4.98 Found: C 56.10, H 4.79 C28H28ClF3O5S2. 0.2 H2O 230 2 p-Cl p-SCH3 Calcd: C 55.62, H 4.73 Found: C 55.59, H 4.66 C28H28ClF3O5S2. H2O 231 1 p-Cl p-SOCH3 Calcd: C 54.32 H 4.88 Found: C 54.31, H 5.06 C28H28ClF3O6S2. H2O 232 2 p-Cl p-SOCH3 Calcd: C 52.95, H 4.76 Found: C 53.05, H 4.68 C28H28ClF3O7S2. 0.4 H2O 233 2 p-Cl p-SO2CH3 Calcd: C 52.52, H 4.53 Found: C 52.53, H 4.55 C29H31F3O5S3. 0.4 H2O 234 2 p-SCH3 p-SCH3 Calcd: C 56.18, H 5.17 Found: C 56.11, H 5.06 C29H32F3NO5S2. 0.3 H2O 235 0 p-SO2N(CH3)2 H Calcd: C 57.95, H 5.47, N 2.33, S 10.69 Found: C 58.10, H 5.41, N 2.49, S 10.29 C29H32F3NO7S2. H2O 236 2 p-SO2N(CH3)2 H Calcd: C 53.94, H 5.31, N 2.17, S 9.93 Found: C 54.04, H 5.13, N N 2.25, S 9.44 C29H29F3O5S. 0.7 H2O 237 0 p-CO2CH3 H Calcd: C 62.29, H 5.48 Found: C 62.15, H 5.07 C29H29F3O6S. 2 H2O 238 1 p-CO2CH3 H Calcd: C 58.19, H 5.56 Found: C 57.77, H 5.03 C29H29F3O7S. 0.3 H2O 239 2 p-CO2CH3 H Calcd: C 59.64, H 5.11 Found: C 59.66, H 4.87 C29H29F3O5S. 0.6 H2O 240 0 m-CO2CH3 H Calcd: C 62.49, H 5.46 Found: C 62.39, H 5.25 C29H29F3O6S. 1.3 H2O 241 1 m-CO2CH3 H Calcd: C 59.44, H 5.44 Found: C 59.17, H 5.14 C29H29F3O7S. H2O 242 2 m-CO2CH3 H Calcd: C 58.38, H 5.24 Found: C 58.03, H 4.87 C28H27F3O7S. 1.9 H2O 243 2 m-CO2H H Calcd: C 56.16, H 5.18 Found: C 56.31, H 4.63

Example 244 Scheme 9C C C 1) t) BuLl cox ,CI Nal 2) 2) ICH2CH2CH2CI 2-Butanone CI ci c c CX /1 HSCH2CH20H so OH DMF Potassium carbonate CI Potassium carbonate Cl I 57 I It N I CI I CI PPh3-OEAD N 1 KOH g o OCH3 OH 58 N bop N N 1) (COClk, ~ 14 Ci P)TFAA mCPBA- Pyridine 1; 2)TFAA N mCPBA CF3 ° CF3 60

4-[4-[2-[4-Bis(4-methylphenyl)butylsulfonyl]ethoxy]phenyl-1, 1,1-trifluoro- 2-butanone.

1-Chloro-4,4-di-(4-chlorophenyl)butane A solution of 4,41-dichlorodiphenylmethane (4.37 g, 18.4 mmol) (Blackwell, J. et all, J. Chem. Soc., 1961, 1405) in dry tetrahydrofuran (50 ml) was treated at OOC with butyllithium (12.1 ml of 1.6 M, 19.36 mmol) added dropwise over 15 min. After 15 min, the red solution was then added dropwise to a cold (-78"C) solution of l-chloro-3-iodopropane (15.0 g, 73.4 mmol) in dry tetrahydrofuran (120 ml). After 20 min at -78°C, the reaction mixture was quenched by the addition of saturated ammonium chloride (100 ml) and diluted with toluene. The organic phase was washed with brine and dried. The oil obtained after evaporation of the solvent was purified on silica gel (elution hexane- toluene 85:15) and distilled under vacuum to give 2.54 g (44%) of the title material as a clear oil: bp 110-1300C/1.5 torr (air bath temperature). l-Iodo-4 .4-di-(4-chlorophenyl)butane A solution of methyl l-chloro-4,4-di-(4-chlorophenyl)butane (1.77 g, 5.64 mmol) in 2-butanone (20 ml) was treated with sodium iodide (1.5 g) and heated under reflux for 18 h. The solid formed was filtered, the filtrate was evaporated and purified on silica gel (elution hexane-toluene 96:5) to give 2.13 g (93%) of the title material as a clear oil.

2- [4-Bis-(4-chlorophenyl)butylthiol ethanol A solution of 1-iodo-4,4-di-(4-chlorophenyl)butane (3.22 g, 7.96 mmol) in N,N-dimethyl formamide (45 ml) was treated at 220C with powdered anhydrous potassium carbonate (2.2 g) followed by 2-mercaptoethanol (0.71 g, 9.20 mmol) and the resulting mixture was stirred at 220C for 18 h.

The reaction mixture was then diluted with toluene (400 ml) washed with water and brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (elution toluene-ethyl acetate 8:2) to give 2.58 g (92%) of the title material as a clear oil.

Anal. Calcd. for C18H20Cl2O5: C 60.84, H 5.67, S 9.02. Found: C 61.12, H 5.75, 5 9.28.

3-[4- [2-[4-Bis-(4-chlorophenyl)butylffiio] ethoxy]phenyl]propionic acid. methyl ester A solution of methyl 3-(4-hydroxyphenyl)propionate (1.22 g, 6.77 mmol), 2-[4-bis-(4-chlorophenyl)butylthio]ethanol (2.58 g, 7.26 mmol) and triphenylphosphine (1.95 g, 7.43 mmol) in dry benzene (30 ml) was treated at 22"C with diethyl azodicarboxylate (1.29 g, 7.41 mmol) added drowise over 10 min. After 3 h at 220C, the solvent was evaporated and the residue was chromatographed on silica gel (elution hexane ethyl acetate, 84:16) to give 3.17 g (91%) of the title material as a clear oil.

Anal. Calcd. for C28H30C1203S: C 64.99, H 5.84, S 6.20. Found: C 65.01, H 5.86, S 6.38.

3-[4-[2-[4-Bis-(4-chlorophenyl)butylthio]ethoxy]phenyl]pr opionic acid.

A suspension of 3-[4-[2-[4-bis-(4- chlorophenyl)butylthio]ethoxy]phenyl]propionic acid, methyl ester (3.09 g, 5.98 mmol) in ethanol (25 ml) was treated with a solution of potassium hydroxide (0.8 g, 14.3 mmol) in water (9.5 ml) and the resulting mixture was maintained at 35"C for 2 h. The pH of the solution was then adjusted to 4.0 with 1N hydrochloric acid and the mixture was extracted with dichloromethane. The organic extract was dried (magnesium sulfate) and evaporated to give a white solid. Recrystallization from cyclohexane gave 2.93 g (97%) of the title material as a white solid: mp 89-92"C.

4-[4-[2-[4-Bis-(4-chlorophenyl)butylthio]ethoxy]phenyl]-1 ,1,1-trifluoro-2- butanone.

A solution of 3-[4-[2-[4-bis-(4- chlorophenyl)butylthio]ethoxy]phenyl]propionic acid (2.85 g, 5.66 mmol) in dichloromethane (25 ml) was treated with oxalyl chloride (1.65 g, 13.0 mmol) and a small drop of N,N-dimethylformamide. After 1 h at 220C, the solvent and excess reagent were evaporated in vacuo and the residual acid chloride was dissolved in dry toluene (85 ml). The solution was then cooled to 0°C and treated with trifluoroacetic anhydride (3.57 g, 17.0 mmol) in dry toluene (15 ml) added dropwise over 10 min. After 3.5 h at 22"C, the mixture was cooled again to OOC and treated dropwise with water (5 ml) and stirred for 15 min. The reaction mixture was then diluted with toluene (200 ml), washed with saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with a mixture of hexane and ethyl acetate (75:25) gave 2.62 g (83%) of the title material as an oil.

Anal. Calcd. for C28H27Cl2F3O2S: C 60.54, H 4.90, S 5.77. Found: C 60.43, H 4.85, S 5.88.

4-[4-[2-[4-Bis-(4-chlorophenyl)butylsulfinyl]ethoxy]pheny l]-1,1,1-trifluoro- 2-butanone.

A solution of 4-[4- [2-[4-bis-(4-chlorophenyl)butylthio] ethoxy]phenyl]-1 ,1,1- trifluoro-2-butanone (0.741 g, 1.33 mmol) in methanol (35 ml) was treated with a solution of sodium periodate (0.32 g, 1.5 mmol) in water (1.5 ml) and the resulting mixture was stirred at 220C for 18 h. The solid formed was filtered and the filtrate was evaporated in vacuo. The residue was diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent in vacuo gave an oil which was chromatographed on silica gel. Elution with a gradient of ethyl acetate in dichloromethane (40 - 90%) gave 0.654 g (86%) of the title material as a white solid: mp 31-35"C.

Anal. Calcd. for C28H27C12F303S. 0.4 H20: C 58.12, H 4.84, S 5.54. Found: C 58.05, H 4.97, S 5.73.

4-[4-[2-[4-Bis-(4-chlorophenyl)butvlsulfonyl]ethoXv]pheny l]-1 1.1 -trifluoro- 2-butanone.

A solution of 4-[4-[2-[4-bis-(4-chlorophenyl)butylthio]ethoxy]phenyl]-1,1, 1- trifluoro-2-butanone (0.583 g, 1.05 mmol) in dichloromethane (25 ml) was treated at 220C with m-chloroperbenzoic acid (0.592 g, 3.43 mmol) and the resulting mixture was stirred for 2 h. The reaction mixture was then diluted with ethyl acetate, washed with sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent in vacuo and chromatography of the residue on silica gel (elution ethyl acetate-hexane 1:1) gave 0.533 g (70%) of the title material as a clear oil.

Anal. Calcd. for C2gH27Cl2F304S. 0.4 H20: C 56.55, H 4.71 S 5.39. Found: C 56.43, H 4.61, S 5.46.

The following compounds may be prepared by the general procedure shown above.

Table 10 Exp. # X Analysis C25H21Cl2F3O3 245 CH2CH2O Calcd: C 60.38, H 4.26 Found: C 60.28, H 4.18 C28H27Cl2F3O3 246 CH2CH2CH2CH2CH2O Calcd: C 62.35, H 5.05 Found: C 62.19, H 5.12 C28H27Cl2F3O3S 247 CH2CH2CH2SCH2CH2O Calcd: C 58.85, H 4.76, S 5.61 Found: C58.98, H 4.76, S 5.34 C28H27Cl2F3O4S. 1.5 H2O 248 CH2CH2CH2S(O)CH2CH2O Calcd: C54.73, H 4.92, N 5.22 Found: C54.90, H 4.68, N 5.45 C28H27CI2F3O5S. 0.4 H2O 249 CH2CH2CH2S(O2)CH2CH2O Calcd: C55.07, H 4.59, N 5.25 Found: C 55.0, H 4.44, N 5.46 C28H27Cl2F303S- 0.3 H2O 250 CH2CH2SCH2CH2CH2O Calcd: C58.30, H 4.82, N 5.56 Found: C58.31, H 4.52, N 5.11 C28H27C12F304S. 0.8 H2O 251 CH2CH2S(O)CH2CH2CH2O Calcd: C55.87, H 4.79, N 5.33 Found: C55.96, H 5.08, N 4.93 C28H27C12F3O5S. 0.4 H2O 252 CH2CH2S(O2)CH2CH2CH2O Calcd: C55.07, H 4.59, N 5.25 Found: C55.07, H 4.10, N 4.78 C29H27Cl2F3O2S CH2CH2SCH2.CH=CH-CH2 253 Calcd: C61.38, H 4.80, N 5.65 (E) Found: C61.34, H 4.83, N 5.33 C29H27Cl2F3O3S. 0.7 H2O CH2CH2S(O)CH2.CH=CH-CH2 254 Calcd: C58.43, H 4.80, N 5.38 (E) Found: C 58.28, H 4.91, N 5.2 C29H27Cl2F3O4S CH2CH2S(O2)CH2.CH=CH-CH2 255 Calcd: C58.10, H 4.54, N 5.35 (E) Found: C57.79, H 4.39, N 5.17

Table 11 Exp. # X Analysis C25H19Cl2F3O2 256 CH2 Calcd: C 62.65, H 4.00 Found: C 62.58, H 3.95 C28H25Cl2F3O2S. 0.7 H2O 257 CH2CH2SCH2CH2 Calcd: C 59.41, H 4.70, S 5.66 Found: C59.30, H 4.40, S 5.67 C28H25Cl2F3O3S. 0.6 H2O 258 CH2CH2S(O)CH2CH2 Calcd: C 57.96, H 4.55, S 5.53 Found: C58.29, H 4.53, S 5.13 C28H25Cl2F3O4S. 0.5 H2O 259 CH2CH2S(O2)CH2CH2 Calcd: C 56.57, H 4.41, S 5.39 Found: C56.82, H 4.38, S 4.93

Example 260 <BR> <BR> <BR> <BR> (Z)-4-[4-[2-(Dodecylsulfonyl) ethoxy]phenyl]-1,1,1-trifluoro-2-acetoxy-2- butene.

A solution of 4-[4-[2-(dodecylsulfonyl)ethoxy]phenyl]-1,1, 1 -trifluoro-2- butanone (1.10 g, 2.30 mmol) in dichloromethane (15 ml) was cooled to - 25"C and treated with triethylamine (0.5 ml) and 4- dimethylaminopyridine (0.560 g, 4.58 mmol). Then acetic anhydride (0.65 ml, 6.9 mmol) was added and the resulting mixture was stirred at -250C for 2.5 h. The solution was then diluted with ethyl acetate, washed with saturated sodium bicarbonate, dried (magnesium sulfate) and evaporated in vacuo. The residue was chromatographed on silica gel (elution toluene-ethyl acetate, 9:1) to give 0.94 g (78%) of a solid which was recrystallized from hexane to give white crystals: mp 48-49"C.

Anal. Calcd. for C26H39F305S: C 59.98, H 7.55, S 6.16. Found: C 59.95, H 7.51, S 6.38.

Example 261 <BR> <BR> <BR> <BR> 4-r4-[2-rBis(4-chlorophenyl)methoxylethylsulfonyllethoxylphe nyll-1,1,1- trifluoro-2-butanol.

A solution of 4-[4-[2-[bis(4- chlorophenyl)methoxy]ethylsulfonyl]ethoxy]phenyl]-1,1,1-trif luoro-2- butanone (0.77 g, 1.30 mmol) in tetrahydrofuran (45 ml) and water (5 ml) was treated with sodium borohydride (0.10 g, 2.6 mmol) and the resulting mixture was stirred at 220C for 1 h. The reaction mixture was then diluted with ethyl acetate, washed successively with water and brine and then dried (magnesium sulfate). Evaporation of the solvent under reduced pressure gave an oil which was chromatographed on silica gel. Elution with a mixture of toluene and ethyl acetate (8:2) gave the title material as a white solid: mp 75-76"C.

Anal. Calcd. for C27H27C12F305S: C 54.83, H 4.60, S 5.42. Found: C 54.84, H 4.39, S 5.07.

Example 262 (Z)-4-[4-[2-[Bis-(4-chlorophenyl)methoxy)ethylsulfonyl)ethox y]phenyl]- 1,1,1-trifluoro-2-acetoxy-2-butene.

Reaction of 4- [4-[2- [bis (4-chlorophenyl)methoxy] ethylsulfonyl]ethoxy]phenyl]-l,l,l-trifluoro-2-butanone with acetic anhydride as described in example 260 gave the title material as an oil (85%).

Anal. Calcd. for C2gH27Cl2F306S. 0.5 H20: C 54.38, H 4.41, S 5.01. Found: C 54.38, H 4.26, S 4.86.

Example 263 (Z)-4-[4-[2-(Dodecylsulfonyl)ethoxy]phenyl]-1,1,1-trifluoro- 2-propionyloxy- 2-butene.

Reaction of 4-[4-[2-(dodecylsulfonyl)ethoxy]phenyl]-1,1,1-trifluoro-2- butanone (0.87 g, 1.82 mmol) with propionic anhydride using the procedure described above gave 0.866 g (89%) of the title material as a white solid: mp 60-63"C.

Anal. Calcd. for C27H41F305S: C 60.65, H 7.73, S 6.00. Found: C 60.51, H 7.83, S 6.01.

Example 264 4-[4-[2-(Dodecylsulfonyl)ethoxy]phenyl]-1,1,1-trifluoro-2-bu tanone, glycolic acid-ketal ester.

A solution of 4-[4-[2-(dodecylsulfonyl)ethoxy]phenyl]-1,1,1-trifluoro-2- butanone (0.80 g) in toluene (40 ml) was treated with glycolic acid (0.16 g) and p-toluene sulfonic acid (0.10 g) and the resulting mixture was heated

under reflux for 6 h. Additional quantities of glycolic acid (5 x 0.16 g) and p-toluenesulfonic acid (5 x 0.06 g) were added periodically after every hour of heating. The cooled reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure and chromatography of the residue on silica gel (elution toluene-ethyl acetate 8:2) gave 0.187 g (21%) of the title material as a white solid: mp 69- 71"C.

Anal. Calcd. for C26H39F306S: C 58.19, H 7.33, S 5.97. Found: C 58.11, H 7.35, 5 6.09.

Example 265 4-r4-r2-(Dodecylsulfonyl)ethoxylphenyll-l,l,l-trifluorobutan one, thiazolidine derivative with 2-aminoethanethiol.

A solution of 4-[4-[2-(dodecylsulfonyl)ethoxy]phenyl]-1,1,1- trifluorobutanone (0.60 g, 1.25 mmol) in dry toluene (50 ml) was heated under reflux and then treated with 2-aminoethanethiol (3 x 0.20 g) added in three portions over 12 h. The reaction mixture was then washed with brine and dried over magnesium sulfate. Evaporation of the solvent in

vacuo and chromatography of the residue on silica gel (elution toluene- ethyl acetate 85:15) gave 0.603 g (89%) of the title thiazolidine as a syrup.

Anal. Calcd. for C26H42F3NO3S2: C 58.07, H 7.87, N 2.60, S 11.93. Found: C 57.93, H 8.09, N 2.52, S 11.46.

Example 266 (Z)-4-[4-[2-(Dodecylsulfonyl)ethoxy]phenyl]-1,1,1-trifluoro- 2- diethylphosphoryloxy-2-butene.

A solution of 4-[4-[2-(dodecylsulfonyl)ethoxy]phenyl]-1,1,1- trifluorobutanone (1.50 g, 3.13 mmol) in dry dichloromethane (40 ml) was cooled to OOC and treated with triethylamine (0.87 ml) and 4- dimethylaminopyridine (0.77 g) then diethyl phosphorochloridate (1.35 ml) was added dropwise and the resulting mixture was stirred at OOC for 2 h. The reaction mixture was then diluted with ethyl acetate, washed with sodium bicarbonate, brine and dried (magnesium sulfate). After evaporation of the solvent under reduced pressure, the residue was chromatographed on silica gel (elution toluene-ethyl acetate, 8:2) to give 1.539 (80%) of the title enol phosphate as white crystals (hexane) : mp 33°C.

Anal. Calcd. for C28H46F3O7PS: C 54.71, H 7.54, S 5.22. Found: C 54.82, H 7.64, 5 5.39.

Example 267 Q)-4-r4-r2-(Dodecylsulfonyl)ethoxylphenyll-l,l,l-trifluoro-2 - ethylphosphoryloxy-2-butene sodium salt and (Z)-4-[4-[2-(Dodecylsulfonyl)ethoxy]phenyl]-1,1,1-trifluoro- 2- phosphoryloxy-2-butene, disodium salt.

A solution of (Z)-4-[4-[2-(dodecylsulfonyl)ethoxy]phenyl]-1,1,1-trifluoro- 2- diethylphosphoryloxy-2-butene (0.778 g, 1.27 mmol) in acetonitrile (20 ml) was treated with chlorotrimethylsilane (1.0 ml) and potassium iodide (0.63 g) and the resulting mixture was heated under reflux for 5 h. The cooled mixture was then treated with sodium bicarbonate (1 g) and water (5 ml) and stirred for 30 min. The solid was then removed by filtration and the filtrate was concentrated in vacuo. The residue was then purified on silica gel using a mixture of ethyl acetate, methanol and water (7:3:0 to 65:35:5) as eluent.

The first fractions gave the ethyl-phosphoryloxy sodium salt (0.210 g, 27%) as a white solid.

Anal. Calcd. for C26H4lF3o7PSNa. 0.3 H20: C 50.86, H 6.83, S 5.22. Found: C 50.81, H 6.98, S 5.32.

The tail fractions gave the phosphoryloxy disodium salt (0.259 g, 34%) as a white solid.

Anal. Calcd. for C24H36F3O7PSNa2. 0.3 H20: C 43.90, H 6.45, S 4.88. Found: C 43.97, H 6.08, S 5.08.

The following prodrugs may be prepared by the general procedure described above.

Table: Pro-drugs (1) Exp. No. R Analysis OAc C27H42F3NO3.HCI. 0.5 H2O 268 CH2> of Calcd: C 61.06, H 8.35, N 2.64 Found: C 60.76, H 7.83, N 2.70 C30H48F3N03.HCI. 0.5 H20 269 O C + Calcd: C 62.87, H 8.79, N 2.44 CH2> CF3 Found: C 62.91, H 8.98, N 2.52 CF3 CH2CH2 CF3 C27H42F3NO4.HCl 270 O5<o Calcd: C 60.27, H 8.05, N 2.60 Found: C 60.15, H 7.52, N 2.62 Table: Pro-drugs (2) EXP. # STRUCTURE ANALYSIS 91 271 C 54.38, C29H27Cl2F3O6S.HCl. 0.5 H20 5 Calcd: C 54.38, H 4.41, N 5.01 Found: C 54.38, H 4.26, N 4.86 AcO CF3 CI °e ° ~t o\/ SV 272 $ Cl Calcd: C 51.32, H 4.72, N 4.42 0 \ Calcd: C 51.32, H 4.72, N 4.42 EtO - 1CF3 Found: P 51.39, H 4.54, N CF3 OEt 91 Q C32H36C12F3O7P5. 0.8 H2O 273 Calcd: c 52.08, H 0.8 1120 WiJJ Cl Calcd: C 52.08, H 5.14 '91 EtO - F3P ~ CF3 OEt CI 0. .0 C28H26C12F30?PSNa2 274 Cl Calcd for (M - 2Na + H)- = 665 CI Found: 665 NaO-P-O CF3 ONa