BICYCL0 [2.2.2^ OCTANE DERIVATIVES AS CHOLESTOCYSTOKININ INHIBITORS

. This invention relates to bicyclo [2.2.2] octane derivatives, and

' more particularly to bicyclo [2.2.2] octane derivatives which bind

'. ^~ 5 to cholecystokinin and/or gastrin receptors . The invention also

* -_- relates to methods for preparing such bicyclo[2.2.2]octane derivatives and to cαrrpounds which are useful as intermediates in such methods.

10 Gastrin and the CCK's are structurally-related neuropeptides which exist in gastrointestinal tissue and in the CNS (see Mutt V., Gastrointestinal Hormones, Glass G.B.J., ed., Raven Press, N.Y., p 169 and Nisson G., ibid, p. 127) .

15 Gastrin is one of the three primary stimulants of gastric acid secretion. Several forms of gastrin are found including 34-, 17-, and 14-amino acid species with the minimum active fragment being the C-terminal tetrapeptide (TrpMetAspPhe-NH;) which is reported in the literature to have full pharmacological activity (see Tracey

20 H.J. and Gregory R.A., Nature (London), 1964, 204, 935). Much effort has been devoted to the synthesis of analogues of this tetrapeptide (and the N-protected derivative Boc-TrpMetAspPhe-NH ₂ ) in an attempt to elucidate the relationship between structure and activity.

25

Natural cholecystokinin is a 33 amino acid peptide (CCK-33), the C-terminal 5 amino acids of which are identical to those of gastrin. Also found naturally is the C-terminal octapeptide (CCK- 8) of CCK-33.

30

The cholecystokinins are reported to be important in the regulation of appetite. They stimulate intestinal motility, gall bladder contraction, pancreatic enzyme secretion, and are known to have a trophic action on the pancreas. They also inhibit gastric emptying 35 and have various effects in the CNS.

Compounds which bind to cholecystokinin and/or gastrin receptors are important because of their potential pharmaceutical use as

antagonists of the natural peptides .

A number of gastrin antagonists have been proposed for various therapeutic applications, including the prevention of gastrin- related disorders, gastrointestinal ulcers, Zollinger-Ellison syndrome, antral G Cell hyperplasia and other conditions in which lowered gastrin activity is desirable. The hormone has also been shown to have a trophic action on cells in the stomach and so an antagonist may be expected to be useful in the treatment of cancers, particularly in the stomach.

Possible therapeutic uses for cholecystokinin antagonists include the control of appetite disorders such as anorexia nervosa, and the treatment of pancreatic inflammation, biliary tract disease and various psychiatric disorders. Other possible uses are in the potentiation of opiate (e.g. morphine) analgesia, and in the treatment of cancers, especially of the pancreas. Moreover, ligands for cholecystokinin receptors in the brain (so-called CCKg receptors) have been claimed to possess anxiolytic activity.

According to the present invention, there are provided compounds for use in therapy (and particularly for use as gastrin and/or CCK antagonists) , such compounds being of the formula

wherein

W is a carbonyl, sulphonyl or sulphinyl group, and X is a carbonyl, sulphonyl or sulphinyl group or -C(0)-CH ₂ - (in which the carbonyl group is bonded to Y) , provided that at least one of and X contains carbonyl,

Y is R ₇ -0- or R,-N(R - (wherein R- is H or C to C ₁₅ hydrocarbyl, up to two carbon atoms of the hydrocarbyl

moiety optionally being replaced by a nitrogen, oxygen or sulphur atom provided that Y does not contain a -O-O- group, and Rg is H, to C ₃ alkyl, carboxymethyl or i esterified carboxymethyl) ,

5

* Z is selected from

i) -O-R, wherein R, is H, C. to C ₅ alkyl, phenyl, substituted 10 phenyl, benzyl or substituted benzyl;

ii)

- ?N — H

^' 15 wherein Q is H, to C ₅ hydrocarbyl, or -R ₁₀ -U, wherein R ₁₀ is a bond or C _: to C- ₃ alkylene and U is aryl, substituted aryl , heterocyclic, or substituted heterocyclic ,

20

wherein a is 0 or 1 and b is from 0 to 3,

R _π is H or methyl,

25

R ₁₂ is H or methyl; or R _: . is CH_= and Q' is absent; or R _n and R ₁₂ are linked to form a 3- to 7-meπibered ring,

R ₁₃ is a bond or to Cr hydrocarbylene,

30

G is a bond, -CHOH- or -C(O)-

Q' is as recited above for Q or

-R ₁₀ -(C(O) ) _d -L-(C(0) ) _e -R_ ₃ (wherein R, and R ₁₀ are as defined above, L is 0, S or -N(R ₁₄ )- in which R ₁₄ is as defined above for R ₈ , and d and e are 0 or 1, provided that d+e<2) ; or Q' and R ₁₂ , together with the carbon atom to which they are attached, form ^' a 3- to

7-merribered ring,

Q is as defined above; or Q and R ₁₂ together form a group of the formula -(CH ₂ ) _f -V-(CH ₂ ) _g - wherein V is -S-, -S(O)-, -S(0) ₂ -, -CH,-, -CHOH- or -C(0)-, f is from 0 to 2 and g is from 0 to 3; or, when Q' is -R ₁₀ -U and U is an aromatic group, Q may additionally represent a methylene link to U, which link is σrfcfaσ to the R _]0 link to U,

T is H, cyano, C _j to C ₄ alkyl, -CH ₂ 0H _f carboxy, esterified carboxy or amidated carboxy; or

wherein A and B are independently a bond or _x to C ₃ alkylene, provided that A and B together provide from 2 to 4 carbon atoms in the ring, R, and R ₁₀ are as defined above, and R _: c is as defined above for Rg

or Z is absent and W is H,

Ri is H, methyl, halo, carboxy, esterified carboxy, amidated carboxy, carboxymethyl, esterified carboxymethyl or amidated carboxymethyl,

R ₂ is selected from the groups recited above for R,; or, when Z is absent and is H, R_ nay additionally

represent -C(0)-Z' wherein Z' is selected from the groups recited above for Z; or R _α and R ₂ together form a second bond between the carbon atoms to which they are attached,

R ₃ and R, (or each R ₃ and j group, when m or n is 2 or more) are independently selected from halo, amino, nitro, cyano, sulphamoyl, to C ₃ alkyl, C to C ₃ alkoxy, carboxy, esterified carboxy and amidated carboxy

Rς and Rg are independently selected from H and the groups recited above for R ₃

m is from 0 to 4, provided that is not more than 2 unless R is exclusively halo,

n is from 0 to 4, provided that n -is not more than 2 ^■ unless R ₄ is exclusively halo,

or pharmaceutically acceptable salts thereof.

Compounds according to the above definition are believed to be novel per se, provided that

if one (but only one) of R, and R. is methyl, m and n are not both 0, .

Z is not ethoxy when Y is ethoxy,

Z and Y are not trans to each other when Z is Rg-O- and Y is R ₇ -0- , and

if Z is absent and R, and R ₂ are both H, Y is not R ₇ -0-.

The term "hydrocarbyl", as used herein, refers to monovalent groups consisting of carbon and hydrogen. Hydrocarbyl groups thus include alkyl, alkenyl, and alkynyl groups (in both straight and branched chain forms) , cycloalkyl (including polycycloalkyl) , cycloalkenyl, and aryl groups, and combinations of the foregoing, such as

alkylaryl, alkenylaryl, alkynylaryl, cycloalkylaryl, and cycloalkeπylaryl groups,

A "carbocyclic" group, as the term is used herein, comprises one or more closed chains or rings, which consist entirely of carbon atoms. Included in such groups are alicyclic groups (such as cyclαpropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl) , groups containing both alkyl and cycloalkyl moieties (such as methyl adamantyl) , and aromatic groups (such as phenyl, naphthyl, indaπyl, fluoreπyl, (l,2,3,4)-tetrahydronaphthyl, indenyl and isoindeπyl) .

The term "aryl" is used herein to refer to aromatic carbocyclic groups, including those mentioned above.

A "heterocyclic" group comprises one or more closed chains or rings which have at least one atom other than carbon in the closed chain or ring. Exaiηples include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolidiπyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetral^drofuraπyl, \p_rcanyl, pyronyl, pyridyl, pyrazinyl, pyridaziπyl, piperidyl, piperazinyl, morpholinyl, thionaphthyl, benzofuranyl, isobenzofuryl, indolyl, - oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, isoindazolyl, benzopyraπyl, coumarinyl, isocoumarinyl, quinolyl, isoquinolyl, naphthridiπyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl,

-guinoxadinyl, chrαmeπyl, chromanyl, isochromanyl and carboliπyl.

The term "halogen", as used herein, refers to any of fluorine, chlorine, bromine and iodine. Most usually, however, halogen substituents in the compounds of the invention are chlorine or fluorine substituents.

Preferably, m and n are both 0. However, when m and n are not both 0, R ₃ and R are preferably selected from halo, amino, nitro, cyano, sulphamoyl, to C ₃ alkyl and C, to G, alkoxy. As mentioned above, when m or n is 2 or more, each R-. and R ₄ group is independent of the others. For exaπple, the compounds of the

invention may include two different R ₃ groups.

Particularly preferred groups for R__ and R* are hydrogen and the v ^« i ggrroouuppss just recited for R ₃ , and especially hydrogen, methyl and fluoro.

V

When reference is made herein to a "substituted" aromatic group, the substituents will generally be from 1 to 3 in number (and more usually 1 or 2 in number) , and selected from the groups recited 10 above for R ₃ .

An "esterified" carboxy group, as the term is used herein, is preferably of the form -CCOR _lfc , wherein R _ϊo is C- _; to C ₅ alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, or one of 15 the following:

Most commonly, R ₁₆ is C, to C ₅ alkyl, benzyl or substituted benzyl, and particularly C, to C ₅ alkyl. Similarly, an "amidated" carboxy group is preferably of the form -CONR ₁₇ R ₁₈ wherein R ₁₇ and R ₁₈ are 20 independently H, C_ to C ₅ alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl.

In the case of the group T, preferred amidated carboxy groups take the form -CONR ₁₇ R ₁₈ (wherein R ₁₇ and R._ are as defined above) or

25 — — N-tCH ) _v — C C J

II I I II

0 R ₁₇ R _{2 0} 0

wherein R ₁₇ is as defined above, R _J and R_,. are independently H or methyl, or R ₁₉ and R ₂₀ (together with the carbon atom to which they are attached) form a 3- to 7-membered carbocyclic group, J is -OH,

-0-R ₁₆ or -NHR ₁₈ , wherein R ₁₆ and R ₁₈ are as defined above, and x is 0 to 3.

When R _π and R ₁₂ are linked to form a ring, such ring will generally be saturated, and usually also carbocyclic. Similarly, when Q' and R ₁₂ are linked to form a ring, this will also usually be saturated and carbocyclic.

Exenplary carbocyclic and heterocyclic groups which may form the group U include:

wherein R ₂₁ is as defined above for R-., and h is from 0 to 3, and

wherein P is H or -COOR ₂₂ , in which R ₂₂ is as defined above for R ₁₇ .

Z is preferably -NH ₂ , -O-Ro or

wherein i is from 0 to 4, j is from 0 to 3, R ₂₃ and R ₂₄ are independently H or methyl, or R ₂₃ and R ₄ together form a group of the formula -(CH,) _k -V'-CH ₂ - (wherein V is -CH,-, -CHOH- or -C(O)-, and k is 0 to 2) . Most commonly, i is 0 or 1 and j is 0 to 2.

When W is sulphinyl, Y is preferably R--NH-.

Preferably, , is C ₆ to C ₈ straight or branched chain alkyl, or R _2£ -(CH ₂ ) _P -, wherein R ₂₅ is selected from phenyl, 1-naphthyl, 2-

naphthyl, indolyl, norbornyl, adamantyl or cyclohexyl, and p is from 0 to 3.

Pharmaceutically acceptable salts of the acidic compounds of the invention include salts with alkali metals and alkaline earth metals, such as sodium, potassium, calcium and magnesium, and salts with organic bases. Suitable organic bases include amines such as N-methyl-D-glucamine.

Pharmaceutically acceptable salts of the basic coπpounds of the invention include salts derived from organic or inorganic acids. Suitable acids include hydrochloric acid, phosphoric acid, oxalic acid, maleic acid, succinic acid and citric acid.

The coitpounds of the invention exist in various enantiomeric and diastereomeric forms as a result of the asymmetric carbon atoms to which W and X are attached. It will be understood that the invention cαπprehends the different enantio ers and diastereomers in isolation from each other, as well as mixtures of enantiomers and diastereomers. Also, the structural formulae herein show.the groups W and X arranged cis to each other, but it will be appreciated that the invention includes the corresponding trans isomers.

Compounds according to the present invention in which W is a carbonyl group, X is carbonyl or sulphonyl, and Z is OH may conveniently be made by the process depicted in Reaction Scheme A.

Reaction Scheme A

In this scheme, anthracene or an anthracene derivative (1) is reactedwith the acid anhydride (2) in a Diels-Alder reaction. .The reactants are conveniently refluxed together in a suitable solvent such as toluene to form the adduct (3) . In some cases, it may be appropriate to conduct the reaction at elevated pressure and/or in the presence of a Lewis acid catalyst. The adduct (3) is then reacted with a-compound of the formula YH (ie. either an alcohol or an ^' amine) to form the acid cαrrpound (4) . If YH is an amine, the reaction is suitably carried out in a solvent such as THF in .the presence of a catalytic amovint of DMAP. If YH is an alcohol, the reaction may be conducted in pyridine at elevated temperature.

The invention therefore also provides a method of making compounds wherein W is carbonyl and X is carbonyl or sulphonyl, said method including the step of reacting a coπpound of the formula

with a compound of formula YH.

The equivalent trans adducts can be prepared using a suitably differentiated fumaric acid (eg the mono- methyl mono benzyl diester) , which, after addition to anthracene or an anthracene derivative (1) , allows independent elaboration of the two sidechains.

10

Coitpounds in which Z is other than OH may of course be made from the acid compound (4) by conventional esterification or amidation reactions. Suitable amidation methods are described in detail in "The Peptides, Vol. 1", Gross and Meinenhofer, Eds., Academic

15 Press, N.Y., 1979. These include the carbodiimide method (using, for example, 1,3-dicyclohexylcarbodiimide [DCC] or l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride [EDCI] ,. and optionally an additive such as 1-hydroxybenzotriazole [HOBT] to prevent racemization) , the azide method, the mixed anhydride

20 method, the symmetrical anhydride method, the acid chloride method, the use of bis (2-oxo-3-oxazolidinyl) phosphinic chloride [BOP-C1] , the use of PyBOP, the use of the isopropenylsuccinimido carbonate method and the active ester method (using, for example, N-hydroxysuccinimide esters, 4-nitrophenyl esters or

25 2,4,5-trichlorophenol esters).

The coupling reactions are generally conducted under an inert atmosphere, such as an atmosphere of nitrogen or argon. Suitable solvents for the reactants include methylene chloride,

30 tetrahydrofuran [THF] , dimethoxyethane [DME] and dimethylfonrBmide

[DMF] .

A procedure analogous to that shown in reaction scheme A may also

be used as the basis for preparing the compounds of the invention in which W is sulphonyl and Y is R ₇ -0-, as depicted in reaction scheme B below:

Reaction Scheme B

In this case, the Diels-Alder adduct (6) is opened with an alcohol such as benzyl alcohol (represented as QOH) , so that product (7) is the corresponding sulphonyl ester. The free carboxylic acid group of this sulphonyl ester may then be esterified by conventional methods, followed by hydrogenolysis of the product (8)

to yield the desired sulphonic acid carboxylic ester (9) .

The compounds of the invention in which W is sulphonyl and Y is R ₇ -NH- may be prepared by analogous means, in which cσπpound (7) is amidated (rather than esterified) prior to hydrogenolysis. Alternatively, a process such as is depicted in reaction scheme C may be employed:

Reaction Scheme C

In this scheme, anthracene or an anthracene derivative (1) is reacted with the N-protected compound ( 10 ) in a Diels-Alder reaction analogous to that of the first step in reaction scheme A.

The deprotected product Diels-Alder adduct (11) is then reacted with a cσπpound of the formula R ₇ -Hal (wherein Hal represents a halogen atom) to form compound (12) . The N-containing ring may then be openedusing an alkoxide (eg. sodiummethoxide inmethanol) to produce the target compound (13) .

The invention therefore also provides a method of making compounds wherein W is sulphonyl and Y is R ₇ -NH-, said method comprising the step of reacting a coπpound of the formula

with a coπpound of the formula R,-Hal, and then reacting the product with an alkoxide.

Compounds of the invention wherein W or X is a sulphinyl group may conveniently be prepared by the route shown in reaction scheme D:

Reaction Scheme D

Reaction scheme D is analogous to reaction scheme C, except that the sulphinyl analogue of coπpound (10) is used in the Diels-Alder

reaction, to yield the sulphinyl analogue of adduct (12) . This can then be opened both ways to give on the one hand the sulphinamide acid alkyl ester (17) , and on the other the sulphinic acid amide

(18) . The free sulphinamide acid can of course be obtained from the alkyl ester (12) by conventional methods.

Accordingly, the invention also provides a method of making coitpounds wherein W or X is sulphinyl, said method comprising the step of reacting a compound of the formula:

with a compound of the formula R ₇ -Hal, and then reacting the product with an alkoxide.

While reaction schemes C and D above lead, to the free sulphonic or sulphinic acid coπpounds, it will, be appreciated that the corresponding ester or amide derivatives can be prepared from the free acid coπpounds by conventional methods. Most usually, coupling of the sulphonic or sulphinic acid coπpounds will be via the corresponding sulphonic or sulphinic acid chlorides.

Pharmaceutically acceptable salts of the acidic or basic compounds of the invention can of course be made _~y conventional procedures, such as by reacting the free base or acid with at least a stoichiometric amount of the desired salt-forming acid or base.

The coπpounds of the invention can be administered by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical administration.

For oral administration, the compounds of the invention will generally be provided in the form of tablets or capsules or as an

aqueous solution or suspension.

Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.

Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.

For intramuscular, intraperitoneal, subcutaneous and intravenous use, the coπpounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl- pyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.

The invention is now further illustrated by means of the following examples.

Example 1 Preparation of (±) -cis-8-(3-phenylpropylaminocarbonyl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane-7-carboxylic acid

a. 2,3,5,6-dibenzobicyclo[2.2.2]octane-7,8-dicarboxylic acid

anhydride

Anthracene (8.9 g, 0.05 mol) and maleic anhydride (4.9 g, 0.05 mol) were refluxed for 3h in toluene (200 ml) . Upon cooling, the title coπpound was obtained as white crystals which were isolated by filtration (10.2g 74%).

b. (±)-cis-8-(3-phenylpropylaminocarbonyl)-2,3,5,6-dibenzo- bicyclo[2.2.2]octane-7-carboxylic acid

2,3,5,6-dibenzobicyclo[2.2.2]octane-7,8-dicarboxylic acidanhydride

(107 mg, 0.39 mmol) and 1-phenyl-3-propylamine (55 mg, 0.4 mmol) were dissolved in dry THF (5 ml) and DMAP {2 mg) was introduced.

The mixture was stirred at room temperature overnight during which time a thick white precipitate formed. The solid was filtered off, washed with THF and dried to give the title coπpound (100 mg 62%) , πp 190-1°, found: C, 78.82; H, 5.99; N, 3.40. C ₂₇ H ₂₅ N0 ₃ requires C, 78.81; H, 6.12; N, 3.38%

Example 2 Preparation of (±)-cis-8-(2-(3-indolyl)ethylamino- carbonyl)-2,3,5,6-dibenzobicyclo[2.2.2]octane-7-carboxylic _. acid

The cαπpound was prepared essentially as in example 1 except that tryptamine was vised instead of l-phenyl-3-propylamine in step b. Yield 84%, m.p. 137-8°, found: C, 74.13; H, 6.12; N, 5.73. C ₂₈ H ₂₄ N ₂ 0 ₃ . 0.7 H ₂ 0. 0.6 THF requires C, 74.16; H, 6.18; N, 5.69%

Example 3 Preparation of (±)-cis-8-(phenylmethylaminocarbonyl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane-7-carboxylic acid

The cαtpound was prepared essentially as in exairple 1 except that benzylamine was used instead of 1-phenyl-3-propylamine in step b. Yield 27%, m.p. 194-5°, found: C, 77.35; H, 5.97; N, 3.36. C ₂₅ H ₂₁ N0 ₃ . 0.5 THF requires C, 77.30; H, 6.18; N, 3.34%

Exaπple 4 Preparation of (±)-cis-8-(l-naphthylmetl^laminocarbonyl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane-7-carboxylic acid

The compound was prepared essentially as in exaπple 1 except that 1-naphthylιrethylamine was used instead of 1-phenyl-3-propylamine in step b. Yield 35%, m.p. 135-7°, found: C, 78.37; H, 6.07; N, 2.98. C ₂₉ H ₂₃ N0 ₃ . 1.0 THF requires C, 78.39; H, 6.18; N, 2.77%

Example 5 Preparation of (±)-cis-8-{2-naphthylmetbylaιninocarbonyl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane-7-carboxylic acid

The compound was prepared essentially as in exaπple 1 except that 2-naphthylmethylamine was used instead of 1-phenyl-3-propylamine in step b. Yield 35%, m.p. 247-8°, found: C, 80.46; H, 5.03; N, 3.32. C ₂₉ H ₂₃ N0 ₃ requires C, 80.46; H, 5.03; N, 3.23%

Example 6 Preparation of (±) -cis-8-(2-norbornylmethylamino- carbonyl)-2,3,5,6-dibenzobicyclo[2.2.2]octane-7-carboxylic acid

The coπpound was prepared essentially as in exaπple 1 except that 2-norborτr^lmethylamine was used instead of 1-phenyl-3-propylamine in step b. Yield 24%, m.p. 127-9°, found: C, 74.93; H, 7.07; N, 3.76. C ₂₆ H ₂₇ N0 ₃ . 0.75 H ₂ 0 requires C, 75.24; H, 6.92; N, 3.38%

Example 7 Preparation of (±) -cis-8-(hexylaminocarbonyl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane-7-carboxylic acid

The compound was prepared essentially as in exaπple 1 except that hexylamine (2eq) was used instead of 1-phenyl-3-propylamine in step b. and the product was precipitated with 2M HCl and then filtered and washed with water. Yield 91%, m.p. 174-6°, found: C, 76.52; H, 7.24; N, 3.98. C ₂₄ H ₂₇ N0 ₃ requires C, 76.36; H, 7.21; N, 3.71%

Example 8 Preparation of (±) -cis-8- (octylaminocarbonyl)-

2,3,5,6-dibenzobicyclo[2.2.2]octane-7-carboxylic acid

The cσπpound was prepared essentially as in exaπple 7 except that octylamine was used instead of hexylamine. Yield 89%, m.p.116-8°, found: C, 76.83; H, 7.70; N, 3.58. C _2c H ₃₁ N0 ₃ requires C, 77.01; H, 7.71; N, 3.45%

Exaπ ^p le 9 Preparation of (±)-cis-8-(cyclohexylmettylaminocarbonyl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane-7-carboxylic acid

The coπpound was prepared essentially as in exaπple 7 except that cyclohexylmethylamine was used instead of hexylamine. Yield 93%, m.p. 185-7°, found: C, 76.88; H, 7.09; N, 3.69. C ₂₅ H ₂₇ N0 ₃ requires C, 77.09; H, 6.99,- N, 3.60%

Exam ^p le 10 Preparation of (±)-cis-8-(3,3-dimethylbutylamino- carbonyl)-2,3,5,6-dibenzobicyclo[2.2.2]octane-7-carboxylic acid

The coπpound was prepared essentially as in exaπple 7 except that 3,3-dimethylbutylamine was used instead of hexylamine. Yield 25%, m.p. 128-30°, found: C, 75.56; H, 7.22; N, 3.92. C ₂₄ H ₂₇ N0 ₃ .0.2 H ₂ 0 requires C, 75.64; H, 7.25; N, 3.68%

Example 11 Preparation of (±)-cis-8-(1-adamantylaminocarbonyl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane-7-carboxylic acid

2,3,5,6-dibenzobicyclo[2.2.2]octane-7,8-dicarbox lic acidanhydride (prepared in example 1 step a) (276 mg, 1.0 mmol) was dissolved in THF (5 ml) and 1-adamantamine ( 215 mg, 1.4 i ole) was added followed by triethylamine (0.16 ml) . The solution was heated at a gentle reflux for 1.5 h and the clear solution on cooling was poured onto 2M HCl (20 ml) . The resulting gummy solid was extracted with dichloromethane (10 ml) and the organic layer was dried, filtered and evaporated. The residue was taken up in methanol (5 ml) and diluted with water (5 ml) to precipitate a white solid.

This was filtered off and dried. The product (230 mg, 54%) , m.p. 234-5°, found: C, 76.14 ; H, 6.72 ; N, 3 .10. C ₂₈ H ₂₉ NO ₃ .0.75 H ₂ 0 requires C, 76.25; H, 6.97 ; N, 3 .17%

Example 12 Preparation of (±)-cis-8-(2-(1-adamantyl)ethylamino- carboπyl)-2,3,5,6-dibenzobicyclo[2.2.2]octane-7-carboxylic acid

The compound was prepared essentially as in exaπple 11 except that 1-adamantylethylamine was used instead of 1-adamantylamine. Yield 26%, m.p. 138-40°, found: C, 77.31; H, 7.21; N, 2.70. C ₃₀ H ₃₃ NO ₃ .0.6 H ₂ 0 requires C, 77.26; H, 7.39? N, 3.00%

Example 13 Preparation of (±)-cis-8-(-1-adamantylmethyloxy- carbonyl)-2,3,5,6-dibenzobicyclo[2.2.2]octane-7-carboxylic acid

2,3,5,6-dibenzobicyclo[2.2.2]octane-7,8-dicarboxylic acid anhydride (prepared in exaπple 1 step a) (276 mg, 1.0 πmol) and 1-adamantanemethanol (166 mg, 1.0 mmol) were heated together in pyridine (2 ml) at 100° for 4 h. After cooling the solution was poured onto 2M HCl and extracted with dichloromethane (20 ml) . The solution was dried filtered and evaporated to leave a white residue which was further purified by column chromatography (silica . dichloromethaneXethyl acetate\methanol 9:1:0.5 as eluent) . The product was further triturated with hexane to leave the title coπpound (110 mg, 25%), m.p. 165°, found: C, 77.14; H, 6.88. C ₂₉ H ₃₀ O ₄ .0.5 H ₂ 0 requires C, 77.13; H, 6.91%

Example 14 Preparation of (±)-cis-8-(l-adamantylmetbylamino- carbonyl)-2,3,5, 6-dibenzobicyclo[2.2.2]octane-7-carboxylic acid

2,3,5,6-dibenzobicyclo[2.2.2]octane-7,8-dicarbox lic acid anhydride (prepared in exaπple 1 step a) (276 g, 1.0 i iol)' and 1-adamantanemethylamine (182 mg, 1.1 mmol) were dissolved in dry THF (5 ml)' and refluxed for lh. A thick white precipitate was formed and this was isolated by filtration and washed with THF to

leave the title coπpound (320 mg, 72%) , m.p. 237-9° , found: C 78.76; H, 7.18; N, 3 .33. C ₂₉ H ₃₁ N0 ₃ requires C, 78.88; H, 7.08; N, 3.17% The coπpound was further characterised as the

N-methyl-D-glucamine salt found: C, 63.48; H, 7.61; N, 3.79. C ₃₆ H ₄₈ N ₂ 0 ₈ . 2.5H ₂ 0 requires C, 63.42 ; H, 7.83 ; N, 4.11%

Example 15 Preparation of (±) -cis-7- (metho^carboπylmetbylamino- carbonyl) -8- (1-adamantylmethylaminocarbonyl) -2 , 3 , 5, 6-dibenzo- bicyclo [2.2.2] octane .

(±)-cis-8-(1-adamantylmetbylaminocarbonyl)-2,3,5,6-diben zobicyclo- [2.2.2]octane-7-carboxylic acid prepared as in example 14 (441 g, 1.0 mmol) was dissolved in warm DMF (5 ml) and then the solution was cooled to 0°. N-bydroxysuccinimide (115 mg, 1.0 mmol) was added followed by DCCI (206 mg, 1.0 mmol) . The reaction was allowed to warm to roam temperature and stirred overnight. The white precipitate was removed by filtration. Triethylamine (0.2 ml) was added to the filtrate followed by glycine methyl ester hydrochloride (125 mg, 1 mmol) and the reaction mixture was stirred for a further 24h. The reaction mixture was poured onto a mixture of 2M HCl and ice. The white precipitate was isolated by filtration and washed well with water and dried. The solid was taken up in ethyl acetate (20 ml) and filtered through celite. ^' The residue on evaporation was trituratedwithmethanol leaving a white• crystalline solid (125 mg, 24%)., m.p. 209-11°, found: C74.16; H, 7.14; N, 5.53 C ₃₂ H ₃₆ N ₂ 0 ₄ requires C, 74.19; H, 7.12; N, 5.40%

Example 16 Preparation of (±) -cis-7-(carboxymetbylamino- carbonyl) -8-(1-adamantylmethylaminocarbonyl) -2,3, 5, 6-dibenzo- bicyclo[2.2.2]octane

a. (±) -cis-7- (benzyloxycarbonylmethylaminocarbonyl) - 8- (1-adamantylmethylaminocarbonyl) -2,3,5, 6-dibenzobicyclo- [2.2.2]octane

(±) -Cis-8- (1-adamantylmethylaminocarbonyl) -2,3, 5, 6-dibenzo- bicyclo[2.2.2]octane-7-carboxylic acid (prepared as in exaπple 14)

(440 mg, 1 m ole) and PyBOP (520 mg, 1 mmole) were taken up in dry dichloromethane (15 ml) and Hunigs base (0.52 ml, 3 mmole) was added. The reaction mixture was stirred under an atmosphere of dry argon for lh. glycine benzyl ester 4-toluenesulphonic acid salt (340 mg, 1 mmole) was added and the mixture stirred overnight. The organic layer was washed with 5% potassium hydrogensulphate (15 ml) , sodium hydrogencarbonate (15 ml) and saturated brine (15 ml) . It was then dried, filtered and evaporated to leave the crude title compound which was further purified by column chroπatograpby on silica using 80% ethyl acetate and 20% hexane as eluent. The title compound (510 mg, 87%) was isolated as a white solid, m.p. 130-3° ^'

b. (±) -cis-7- (carboxymethylaminocarbonyl) -8- (1-adamantyl- methylaminocarboπyl)-2,3,5,6-dibenzobicyclo[2.2.2]octane

The product of step a (350 mg, 0.59 mmole) was dissolved in methanol (20 ml) and 10% palladium on charcoal (100 mg) was added.

The mixture was stirred under an atmosphere of hydrogen for 3h.

The product was filtered through celite and on evaporation yielded the title coπpound ( 0.30 g, 100%) . The product was characterised and tested as the N-metbyl-D-glucamine salt, m.p. 110-2°, found:

C, 63.42; H, 7.55; N, 5.66. C ₃₈ H ₅₁ NA. 1.5 H _: 0 requires C, 63.42;

H, 7.68; N, 5.66%.

Example 17 Preparation ofmethyl (±) -cis-8-(1-adamantylmethylamino- ^• carbonyl) -2,3,5, 6-dibenzobicyclo[2.2.2]octane-7-carboxylate

2,3,5,6-dibenzobicyclo[2.2.2]octane-7,8-dicarboxylicacid anhydride (prepared as in exaπple 1 step a) (2.76 g, 6.0 mmol), methanol (0.41 ml) and DMAP (20 mg) were stirred in pyridine (5 ml) . The solution was stirred and refluxed for 4h, poured onto 2M HCl (50 ml) and extracted with dichloromethane. The organic layer was washed with mor 2M HCl and then water. The solution was dried filtered and evaporated to yield the crude monoester (1.7 g) . This material (308 mg, limiol) and 1-adamantanemethylamine (181 mg, 1.0 mmol) were dissolved in dry dichloromethane (10 ml) and diisopropylethylamine (0.35 ml) was added followed by PyBOP (520

mg, 1 mmol) . The solution was stirred at room temperature for 72h. It was then evaporated and the residue taken up in ethyl acetate andwashed successively with 5% aqueous potassiumbydrogensulphate (3x40 ml) , saturated aqueous sodium hydrogencarbonate (40 ml) and brine (40 ml) . The organic layerwas dried, filtered and evaporated to leave a foam that was purified by column chrαmatograpby (silica eluent 90% dichloromethane and 10% ethyl acetate) . Further purification was achieved by recrystallisation from methanol. Yield 200 mg, 44%, m.p. 227-30°, found: C,79.06; H, 7.54; N, 2.94. C ₃₀ H ₃₃ NO ₃ requires C, 79.09; H, 7.30; N, 3.07%

Example 18 Preparation of (±)-cis-8-(2-naphtbyl_πethylamino- carboπyl)-2,3,5,6-dibenzobicyclo[2.2.2]octane-7-sulphonic acid

a. Diels-Alder adduct of anthracene and. 3-oxo-2,3-dihydro- isothiazolone

N-t-butyl-3-oxo-2,3-dihydroisothiazolone ( prepared as in Helv.Chim. Acta., 1989, 72, 1416) (200 mg, l.limcl) and anthracene

(178 mg, Immol) were suspended in dry toluene - (2 ml) and a catalytic amovint of anhydrous aluminium chloride was added.. The reaction mixture was stirred and refluxed overnight. On cooling a white solid separated which was filtered and washed successively with toluene and pentane and air dried. The solid was then taken up in ethyl acetate and washed with dilute HCl and brine and

• finally dried and evaporated to leave a white solid (185 mg, 62%)

b. Alk lation of the Diels-Alder adduct

The product from step a (312 mg, 1 mmol) , anhydrous potassium carbonate (138 mg, 1 mmol) and 2-bromometbylnaphthalene (225 mg, 1 mmol) were dissolved in dry EMF (3 ml) and stirred and heated to 100° for 4h. After cooling the solution was poured onto cold water (30 ml) and the resulting white solid filtered off and dried in an oven. The solid was triturated with hexane/toluene/ethanol 9:9:2 and the solid was recrystallised from ethanol (178 mg, 39%) , m.p. 184-5°

c. 8-(2-naphthylmethylaminocarbonyl) -2,3,5, 6-dibenzobicyclo- [2.2.2]octane-7-sulphonic acid

Sodium (16 mg, 0.7 mmol) was dissolved in methanol (5 ml) and the product from step b was added (225 mg, 0.5 i ol) . The reaction was stirred and refluxed for lh. The reaction mixture was cooled and acidified with concentrated HCl. The reaction mixture was then evaporated and the residue partitioned between water and ethyl acetate. The organic layer was dried and evaporated. The product was recrystallised from chloroform. Yield 152 mg, 32%, m.p. 245-7° found: C, 68.74; H, 4.88; N, 2.83. C_ ₆ H.-.N0 ₄ S. 1.0 H ₂ 0 requires C, 68.97; H, 5.16; N, 2.87%

Example 19 Preparation of (±)-cis-8- (phenylmethylaminocarbonyl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane-7-sulphonic acid

This was prepared essentially as in exaitple 18 using benzyl bromide in step b instead of 2-bromomethylnaphthalene m.p. 245-7° .found: C, 68.764; H, 4.81; N, 3.19. C ₂₄ H ₂₁ NO.S requires C/ 68.72; H, 5.05; N, 3.34%

Example 20 Preparation of (±)-cis-8- (2-naphthylmethylamino- sulphonyl)-2,3,5,6-dibenzobicyclo[2.2.2]octane-7-carboxylic acid

a. Diels-Alder adduct of anthracene and β-sulphoacrylic anhydride

β-sulphoacrylic anhydride (prepared as in J.A.C.S. 1962, 84, 653) (184 mg, 1.0 mmol) and anthracene (178 rng, lmmol) were suspended in dry toluene (6 ml) and refluxed under an atmosphere of dry nitrogen for 3h. The reaction mixture was decanted from a small amount of tarry residue and cooled in ice. White crystals that separated were filtered off and washed with a little hexane and dried. Yield 163 mg, 52%

b. (±)-cis-8-(2-naphthylmeth laminosulphonyl) -2,3,5, 6-dibenzo-

bicyclo[2.2.2]octane-7-carboxylic acid

Ihe Adduct from step a (207 mg, 0.66 mmole) and 2-naphthylmethylamine (209 mg, 1.33 mmol) were dissolved in dry THF (5 ml) and EMAP (5 mg) was added. The solution was stirred at room temperature overnight and evaporated to dryness. The residue was taken up in methanol and water and stirred with Aπiberlite IR-120(plus) resin, filtered and evaporated. he residue was triturated with ether, to yield the title compound 215 g, 68% m.p. 212-15 found: C, 69.78; H, 4.98; N, 2.98. C ₂₈ H ₂₃ N0 ₄ S. 0.7 H ₂ 0 requires C, 69.75; H, 5.10; N, _. 2.91%

Example 21 Preparation of (±)-cis-8-(2-(3-indolyl)ethylamino- sulphonyl)-2,3,5,6-dibenzobicyclo[2.2.2]octane-7-carbθ3Qrli c acid

This was prepared essentially as in exaπple 20 but using tryptamine instead of 2-naphthylmethylamine in step b, m.p. >220° found: C, 68.87; H, 5.17; N, 6.07. C ₂₇ H ₂₄ N0 ₄ S requires C, 68.63; H, 5.12; N, 5.92%

Example 22 Preparation of (±)-cis-8-(l-adamantylmethylamino- sulphonyl)-2,3,5,6-dibenzobicyclo[2.2.2]octane-7-carboxylic acid

This was prepared essentially as in exaπple 21 but using 1-adamantylmetbylamine instead of 2-naphthylmethylamine in step b, m.p. 135-40° found: C, 69.90; H, 6.49; N, 2.68. C ₂₈ H ₃₁ N0 ₄ S. 0.2H ₂ O requires C, 69.89; H, 6.58; N, 2.91%

Example 23 Preparation of cis-7- (1-R-carboxy-ethylaminocarboπyl) - 8- (1-adamantylmethylaminocarbonyl ) -2 , 3 , 5 , 6-dibenzobicyclo- [2.2.2] octane (mixture of diastereomers)

(±) -cis-8- (l-adamantylmethylaminoc ^" arbonyl) -2 , 3 , 5 , 6-dibenzo- bicyclo [2.2.2]octane-7-carboxylic acid (prepared as in exaπple 14) (440 mg, 1 mmole) was dissolved by warming in dry EMF (10 ml) . Isopropeπylsuccinimido carbonate (200 mg, 1 mmole) was then added

at room temperature. A catalytic amount of EMAP was added and the reagents stirred for 4h. Triethylamine (0.168 ml, 1.2 mmole) was added followed by D-alanine (100 mg, 1.1 πmole) and the reaction left to stir at room temperature for 60h. The reaction mixture was poured onto 2N HCl and the white precipitate so formed was isolated by filtration. The solid was further purified by column chromatography (silica, dichloromethane to 90% dichloromethane and 10% methanol) to leave the title compound (50 mg) . The compound was characterised and tested as the N-metbyl-D-glucamine salt m.p 128-30°, found: C, 61.98; H, 7.42; N, 5.85. C^N . 2.4H ₂ 0 requires C, 62.32; H, 7.75; N, 5.59%

Example 24 Preparation of cis-(±) -7-(2-methoxycarbonyl- ethylaminocarbonyl) -8- (1-adamantylmethylaminocarbonyl) - 2,3,5,6-dibenzobicyclo[2.2.2]octane

This was prepared essentially as in exaπple 23 using beta-alanine methyl ester instead of D-alanine, m.p. 207°, found: C, 74.98; H, 7.46; N, 5.27. C ₃₃ H ₃₈ N ₂ 0 ₄ requires C, 75.26; H, 7.27; N, 5.32%.

^' Example 25 Preparation of cis-7-(1-S-methoxycarbonyl-ethylamino¬ carbonyl) -8-(1-adamantylmethylaminocarbonyl) -2, 3, 5, 6-dibenzo- bicyclo[2.2.2]octane (mixture of diastereomers)

(±) -cis-8- (1-adamantylmethylaminocarbonyl) -2,3,5, 6-dibenzo- bicyclof2.2.2]octane-7-carboxylic acid (prepared as in exaπple 14) (440 mg, 1 mmole) and PyBOP (520 mg, 1 mmole) were taken up in dry dichloromethane (15 ml) and Hunigs base (0.52 ml, 3 mmole) was added. The reaction mixture was stirred under an atmosphere of dry argon for lh. L-alanine methyl ester hydrochloride (140 mg, 1 mmole) was added and the mixture stirred overnight. The organic layer was washed with 5% potassium hydrogensulphate (15 ml) , sodium hydrogencarbonate (15 ml) and saturated brine (15 ml) . It was then dried, filtered and evaporated to leave the crude title cαπpound which was further purified by column chromatography on silica using 80% ethyl acetate and 20% hexane as eluent. The title compound

(300 mg, 57%) was isolated as a white solid, m.p. 107°, found: C, 75.33 ; H, 7.25; N, 5.16. C ₃₃ H ₃₈ N ₂ 0 ₄ requires C, 75.26; H, 7.27; N, 5.32%

Example 26 Preparation of cis-7-(1-S-methoxycarbonyl-ethylamino- carbonyl)-8-(1-adamantylmethylaminocarbonyl) -2,3,5, 6-dibenzo- bicyclo[2.2.2]octane (diastereomer A)

The cαπpound of exaπple 25 was separated into its coπponent diastereomers by preparative HPLC using a silica phase column and 50% ethyl acetate and 50% hexane as eluant. The title coπpound diastereomer A had a retention time of 18.4 minutes and was isolated as a white powder, m.p.95-100°, [α] ^D = -10.5° (c= 1.66 in methanol), found: C, 75.32; H, 7.14; N, 5.33. C ₃₃ H ₃₈ N ₂ 0 ₄ requires C, 75.26; H, 7.27; N, 5.32%

Example 27 Preparation of cis-7-(1-S-methoxycarbonyl-ethylamino- carbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5, 6-dibenzo- bicyclo[2.2.2]octane (diastereomer B)

The compound of this exaπple was the second diastereomer isolated by the HPLC technique described in exairple 26. The title cαπpound diastereomer B had a retention time of 21.7 minutes and was isolated as a white powder, m.p:75-85°, [α] ^r = +3.8° (c= 1.57 in methanol), found: C, 73.41; H, 7.37; N, 5.20. C ₃₃ H ₃₈ N ₂ 0 ₄ . 0.73 H ₂ 0 requires C, 73.42; H, 7.37; N, 5.20%

Example 28 Preparation of cis-7-(l-R-metho_xycarbonyl-etbylamino- carbonyl) -8-(1-adamantylmethylaminocarbonyl) -2,3, 5,6-dibenzo- bicyclo[2.2.2]octane (mixture of diastereomers)

The reaction was performed essentially as in exaπple 25 but using D-alanine methyl ester hydrochloride instead of the L-isomer. The title compound (300 mg, 57%) was isolated as a white solid, m.p. 113-5°, found: C, 74.41; H, 7.42; N, 5.14. C ₃₃ H ₃₈ N ₂ 0 ₄ .0.33 H ₂ 0

requires C, 74.41; H, 7.32; N, 5.26%

Example 29 Preparation of cis-(±) -7- (2-benzyloxycarbonyl-etbyl- aminocarbonyl) -8- (1-adamantylmethylaminocarbonyl) -2,3,5,6- dibenzobicyclo[2.2.2]octane

The reaction was performed essentially as in exaπple 25 but using the benzyl ester of beta alanine instead of L-alanine methyl ester hydrochloride. Yield 70%, m.p. 77-8°, found: C, 76.67; H, 7.04; N, 4.52. C ₃₉ H ₄₂ N ₂ O ₄ .0.43 H ₂ 0 requires C, 76.73; H, 7.08; N, 4.59%

Example 30 Preparation of cis- (±) -7- (2-carboxy-ethylamino- carbonyl) -8- (1-adamantylmethylaminocarbonyl) -2,3,5, 6-dibenzo- bicyclo[2.2.2]octahe

The product of exaπple 29 (370 mg, 0.6 mmole) was dissolved in ethanol (20 ml) and 10% palladium on charcoal (100 mg) was added. The mixture was stirred under an atmosphere of hydrogen overnight. The product was filtered through celite and on evaporation yielded the title coπpound, 56%. The product was characterised and tested as the N-methyl-D-glucamine salt, m.p. 75-8°, found: C, 62.54; H, - 7.94; N, 5.31.- C ₃₉ H ₅₃ N ₃ 0 ₉ . 2.44 H _: .0 requires C, 62.31; H, 7.76; N, 5.59%.

Example 31 Preparation of cis-7- ( 1-S-aιr nocarbonyl-ethylamino- carbonyl) -8- (1-adamantylmethylaminocarbonyl ) -2 , 3 , 5 , 6-dibenzo- bicyclo [2.2.2] octane (mixture of diastereomers )

The reaction was performed essentially as in example 25 but using L-alaninamide hydrochloride instead of the L-alanine methyl ester hydrochloride. Yield 81%, m.p. 175-185°, [α] ^p = -6.5° (c=l in methanol), found: C, 73.13; H, 7.53; N, 7.95. C ₃₂ H ₃₇ N ₃ 0 ₃ . 0.76 H ₂ 0 requires C, 73.16; H, 7.39; N, 8.00%

Example 32 Preparation of cis-7- (1-s- (hydroxymethyl)-ethyl-

aminocarbonyl ) -8- (1-adamantylmethylaminocarbonyl ) -2 , 3 , 5 , 6- dibenzobicyclo [2.2.2] octane (mixture of diastereomers)

The reaction was performed essentially as in exaπple 25 but using L-alaninol instead of the L-alanine methyl ester hydrochloride. Yield 76%, m.p. 115-120°, [α] ^D = -4.0° (c=l in methanol) , found: C 73.09; H, 7.82; N, 5.32. C ₃₂ H ₃₈ N ₂ 0 ₂ . 1.5 H ₂ 0 requires C, 73.14; H, 7.86; N, 5.33%

Example 33 Preparation of cis-7-(1-S-benzyloxycarbonyl-etl^ - aminocarbonyl) -8- (1-adamantylmethylaminocarbonyl) -2,3,5,6- dibenzobicyclo[2.2.2]octane (diastereomer A)

The reaction was performed essentially as in exaπple 25 but using the L-alanine benzyl ester of instead of L-alanine methyl ester hydrochloride. Overall yield 62%, The two diastereomers were separated by column chromatography (silica eluant 93% dichloromethane and 7% ethyl acetate) . The less polar isomer has been designated diastereomer A, the title coπpound, Retention time HPLC silica 50% hexane and 50% ethyl acetate 7.9 min, m.p. 92-4°, [α] ^D = -5.0° (c=l in chloroform), found: C, 75.49; H, 7.12; N, 4.40. C ₃₉ H ₄₂ N ₂ O ₄ .1.0 H ₂ 0 requires C, 75.39; H, 7.15; N, 4.51%

Example 34 Preparation of cis-7-(1-S-benzyloxycarbonyl-etbyl- aminocarbonyl) -8- (1-adamantylmethylaminocarbonyl) -2,3, 5, 6- dibenzobicyclo[2.2.2]octane (diastereomer B)

Ihe more polar isomer from the chromatographic separation outlined in exaπple 33 was designated diastereomer B, Retention time HPLC silica 50% hexane and 50% ethyl acetate 10.9 min, m.p. 90-5°, [α] ^D = -1.0° (c=l in chloroform), found: C, 77.66; H, 7.24; N, 4.41. C ₃₉ H ₄₂ N ₂ 0 ₄ requires C, 77.71; H, 7.02; N, 4.65%

Example 35 Preparation of cis-7-(1-S-carboxyethyl- a inocarbonyl) -8- (1-adamantylmethylaminocarbonyl) -2,3,5,6-

dibenzobicyclo[2.2.2]octane (diastereomer A)

The cαπpound was prepared essentially as described in exaπple 30 but using the product of example 33 instead of cis- (±) -7- (2-benzyloxycarbonyl-ethylaminocarbonyl ) -8- (1- adamantylmethylaminocarbonyl ) -2 , 3 , 5 , 6-dibenzobicyclo [2.2.2] octane

(the product of exaπple 29) as the substrate. Yield 87%, [α] =

-16.0° (c=l in methanol) . The compound was further characterised and tested as the N-methyl-D-glucamine salt, m.p. 100-105°, found: C, 60.66; H, 7.82; N, 5.74. C ₃₉ H ₅₃ N ₃ 0c 3.4 H ₂ 0 requires C, 60.93;

H, 7.84; N, 5.47%.

Example 36 Preparation of cis-7- (1-S-carboxye ^' thyl- aminocarbonyl) -8- (1-adamantylmethylaminocarbonyl) -2,3,5,6- dibenzobicyclo[2.2.2]octane (diastereomer B)

The cαπpound was prepared essentially as described in exaπple 30 but using the product of exaπple 34 instead of cis- (±) -7- (2-benzyloxycarbonyl-ethylaminocarbonyl) -8- (1- adamantylmethylaminocarbonyl ) -2 , 3 , 5 , 6 -dibenzobicyclo [2.2.2] octane (the product of exaπple 29) as the substrate. Yield 99%, [α] ^D = +3.5° (c=l in methanol). The coπpound was further characterised and tested as the N-methyl-D-glucamine salt, m.p. 105-110°, found: C, 61.89; H, 7.67; N, 5.72. • 2.6 H_.0 requires C, 62.03; H, 7.77; N, 5.57%.

Example 37 Preparation of endo-cis-(±)-8-(l-adamantyl- methylaminocarbonyl) -2 , 3-benzo-5, 6- (2 , 5-dimethoxybenzo) - bicyclo[2.2.2]octane-7-carboxylic acid

a. Diels-Alder adduct of 1,4-dimethoxyanthracene

Maleic anhydride (0.21 g, 2.18 mmole) and 1,4-dimethoxyanthracene (0.52 g, 2.18 πmole) were dissolved in toluene (5 ml) and heated to reflux for 4h under an atmosphere of argon. The solvent was evaporated and the residue washed with dichloromethane affording

a white powder which was recrystallised from acetone to yield the exo adduct (140 mg) , used in the preparation of exaπple 38. Ihe endo adduct was obtained as a white solid on addition of hexane to the dichloromethane solution, which was filtered and dried (143 mg) .

b. endo-cis- (±) -8- (1-adamantylmethylaminocarbonyl) - 2 , 3-benzo-5 , 6- (2 , 5-dimethαxybenzo) bicyclo [2.2.2] octane-7-carbαxylic acid

The endo adduct (from step a) (132 mg, 0.39 mmole) was dissolved in THF (3 ml) and 1-adamantylmethylamine (70 mg, 0.39 ππole) was added. The reaction was stirred at room temperature under an atmosphere of argon for 15 min. The solution was evaporated and taken up in dichloromethane and precipitated with hexane. Ihe solution was filtered and dried, dissolved in warm ether and decanted from insoluble material. Addition of hexane, cooling and filtration gave the title coπpound (93 mg, 48%) . The cαπpound was characterised and tested as the N-methyl-D-glucamine salt, m.p. 99-103°, found: C, 61.63; H, 7.73; N, 3.92. C ₃₈ H ₅₂ N ₂ O ₁₀ . 2.3 H ₂ 0 requires C, 61.76; H, 7.73; N, 3.79%.

Example 38 Preparation of exo-cis-(±)-8-(l-adamantylmethyl- aminocarbonyl) -2 , 3-benzo-5 , 6- (2 , 5-dimethoxybenzo) bicyclo- [2.2.2 ]octane-7 -carboxylic acid

The coπpound was prepared essentially as in exaπple 37 step b but using the exo anhydride from exaπple 37, step a, rather than the endo isomer. Yield 88%. The ^' coπpound was characterised and tested as the N-methyl-D-glucamine salt, m.p. 109-112°, found: C, 63.07; H, 7.70; N, 3.71. C ₃₈ H _S2 N ₂ O ₁₀ . 1.5 H _: 0 requires C, 63.04; H, 7.66; N, 3.87%. ^'

Example 39 Preparation of cis-(±) -8-(2-adamantylmethyl~ aminocarbonyl) -2,3-benzo-5, 6- (2 , 5-dimethoxybenzo)bicyclo- [2.2.2]octane-7-carboxylic acid

The compound was prepared essentially as in exaπple 1 step b using 2-adamantylmethylamine instead of l-phenyl-3-propylamine. Yield 85%. The coπpound was characterised and tested as the

N-methyl-D-glucamine salt, found: C, 67.73; H, 7.81; N, 4.41. C ₃₆ H ₄₈ N ₂ 0 ₈ requires C, 67.90; H, 7.60; N, 4.40%.

Example 40 Preparation of cis-7- ( 1-S-dimethylamino- carbonyl -ethylaminocarbonyl) -8- (1-adamantylmethylaιιάno-carboπyl) - 2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The reaction was performed essentially as in exaπple 25 but using L-alanine-N, N-dimethylamide trifluoroacetate instead of the L-alanine methyl ester hydrochloride. Yield 79%, m.p. 130-5°, [α] ^D = -14° (c=l in methanol) found: C, 72.58; H, 7.86; N, 7.35. C ₃₄ H ₄₁ N ₃ 0 ₃ . 1.3 H ₂ 0 requires C, 72.49; H, 7.81; N, 7.46%

Example 41 Preparation of cis-7- (1-S-πethoxycarbonyl- ethylaminocarbonyl) -8- (cyclohexylmethylaminocarbonyl) -2,3, 5,'6-di benzobicyclo[2.2.2]octane (mixture of diastereomers)

The reaction was performed essentially as in example 25 but using

(±) -cis-8- (1 -cyclohexylmethylaminocarbonyl ) -2 , 3 , 5 , 6- dibenzobicyclo [2.2.2] octane-7-carboxylic acid (prepared in exaπple

.9) instead of (±) -cis-8- (1-adamantylmethylaminocarbonyl) -

^■ 2,3,5,6-dibenzobicyclo[2.2.2]octane-7-carboxlic acid. Yield 59%, m.p. 80-2°, found: C, 73.10; H, 7.31; N, 5.78. C ₂₉ H ₃₄ N ₂ 0 ₄ requires

C, 73.39; H, 7.22; N, 5.90%

Example 42 Preparation of cis-7-[methoxycarbonylmethyl- (N-methyl) -aminocarbonyl] -8-(1-adamantylmethylaminocarbonyl) - 2,3,5,6-dibenzobicyclo[2.2.2]octane

The reaction was performed essentially as in example 25 but using the methyl ester of sarcosine hydrochloride instead of the L-alanine methyl ester hydrochloride. Yield 74%, m.p. 185-7°,

found: C, 75.47 ; H, 7.33 ; N, 5.22. C ₃₃ H ₃₈ N ₂ 0 ₄ requires C, 75.26; H, 7.27; N, 5.32%

Example 43 Preparation of cis-7- [ ethoxycarbonylmethyl- (N-methyl) -aminocarbonyl] -8- (1-adamantylmethylaminocarbonyl) - 2,3, 5, 6-dibenzobicyclo [2.2.2] octane

The reaction was performed essentially as in exaπple 25 but using the ethyl ester of sarcosine hydrochloride instead of the L-alanine methyl ester hydrochloride. Yield 57%, found: C, 75.40; H, 7.51,- N, 5.03. C ₃₄ H ₄₀ N ₂ O ₄ requires C, 75.53 ; H, 7.46; N, 5.18%

Example 44 Preparation of (±) -trans-8- (l-adamantylmethyl- aminocarbonyl ) -2 , 3 , 5 , 6-dibenzobicyclo [2 .2.2] octane-7 -carboxylic acid

a . (±) -trans-8-ethoxycarbonyl-2 , 3 , 5 , 6-dibenzobicyclo- [2.2.2 ] octane-7 -carboxylic acid

Anthracene (5 g, 28 mmol) and fumaric acid monoethyl ester (4.04 g, 28 πmol) were dissolved in dioxan (50 ml) and the solution heated at reflux for 3d. The reaction mixture was evaporated and the solid obtained recrystallised from hot toluene and dried (5.06 g, 56%) .

b . (±) -trans-ethyl- 8- ( 1-adamantylmethylaminocarbonyl) - 2,3 ,5, 6-dibenzobicyclo [2.2.2] octane-7 -carboxy late

The product of step a (0.2 g, 0.62 mmol) was stirred in anhydrous benzene (25 ml) and thionyl chloride (0.27 ml, 3.1 mπol) was added. The mixture was stirred at room teπperature for 2h. The solution was evaporated in vacuo to leave a gum. This was taken up in dry dichloromethane (25 ml) and 1-adamantylmethylamine (0.103 g, 0.62 πmol) was added followed by triethylamine (0.095 0ml, 0.68 πnol) and the mixture stirred at room teπperature for lh. The dichloromethane solution was washed successively with 2M

hydrochloric acid, water and saturated brine and dried, filtered and evaporated to afford a colourless solid (0.28 g, 96%) .

c. (±) -trans-8- ( 1-adamantylmethylaminocarbonyl ) - 2,3,5,6-dibenzobicyclo[2.2.2]octane-7-carboxylic acid

The product of step b (0.28 g, 0.6 mmol) was dissolved in ethanol (20 ml) and sodium hydroxide (48 mg, 1.2 mmole) was added. The reaction mixture was heated to reflux for 2 min whereupon it was diluted with 2N hydrochloric acid, cooled to room temperature and filtered. The precipitated solid was washed successively with water, ethanol (2 ml), ether (10 ml) and dried (165 mg, 63%). The compound was characterised and tested as the. N-methyl-D-glucamine salt, found: C, 67.73; H, 7.62; N, 4.22. C ₃₆ H ₄₈ N ₂ 0 ₈ requires C, 67.90; H, 7.60; N, 4.40%.

Example 3 Preparation of methyl cis-(±)-8-(l-adamantyl- methyloxycarbonyl) -2,3,5, 6-dibenzobicyclo [2.2.2] octane- 7-carboxylate

cis- (±) -8- (1-adamantylmethyloxycarbonyl) -2,3,5, 6-dibenzo- bicyclo[2.2.2]octane-7-carboxylic acid prepared as in exaπple 13

(115 mg, _. 0.26 mmol) was dissolved in ether (10 ml) and a solution of diazαmethane in ether was .added dropwise until a yellow colour persisted in solution. After 20 min at room teπperature the reaction was quenched by dropwise addition of acetic acid. ^' The reaction mixture was diluted with ether and washed sequentially with 5% sodium hydrogencarbonate solution and brine. The organic layer was dried, filtered and evaporated to give a colourless glass. Trituration with hexane then gave the desired product as a white solid (65 mg, 55%), m.p. 186-7°, found: C, 78.86; H, 7.06. C ₃₀ H ₃₂ O ₄ requires C 78.92; H, 7.06%

Example 46 Preparation of cis-7- (2-R-benzyloxycarbonyl- pyrrolidinocarbonyl) -8- (1-adamantylmethylaminocarbonyl) - 2, 3, 5, 6 -dibenzobicyclo [2.2.2] octane (mixture of diastereomers)

(±) -cis-8-(1-adamantylmethylaminocarbonyl) -2,3, 5,6-dibenzo- bicyclo[2.2.2]octane-7-carboxylic acid (prepared as in exaπple 14) (440 mg, 1 mmole) and PyBOP (520 mg, 1 mole) were taken up in dry dichloromethane (15 ml) and Hunigs base (0.52 ml, 3 mmole) was added. The reaction mixture was stirred under an atmosphere of dry argon for lh. D-Proline benzyl ester hydrochloride (266 mg, 1.1 mmole) was added and the mixture stirred overnight. Ihe organic layerwas washedwith 5% potassiumbydrogensulphate (15 ml) , sodium hydrogencarbonate (15 ml) and saturated brine (15 ml) . It was then dried, filtered and evaporated to leave the crude title cαπpound whichwas further purifiedby column chromatography on silica using a gradient elution starting with 50% ethyl acetate and 50% hexane going up to 80% ethyl acetate and 20% hexane. The title coπpound (580 mg, 92%) was isolated, m.p. 89-90°, found: C, 78.14; H, 7.13; N, 4.41. C ₄₁ H ₄₄ N ₂ 0 ₄ requires C, 78.31; H, 7.05; N, 4.45%

Example 47 Preparation of cis-7-(2-S-benzyloxycarbonyl- pyrrolidinocarbonyl) -8- (1-adamantylmethylaminocarbonyl) - 2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

This coπpound was prepared essentially as in exaπple 46 using L-proline benzyl ester hydrochloride instead of D-proline benzyl ester hydrochloride. m.p. 91-2°, found: C, 77.03; H, 7.12; N, 4.22. C ₄₁ H ₄₄ N ₂ 0 ₄ . 0.6 H ₂ 0 requires C, 76.99; H, 7.12; N, 4.38%

Example 48 Preparation of cis-7-(2-R-carboxy-pyrrolidinocarboryl)- 8- (1-adamantylmethylaminocarbonyl) -2,3,5, 6-dibenzo- bicyclo[2.2.2]octane (mixture of diastereomers)

The product of exaπple 46 ( 520 mg, 0.83 mmol) was dissolved in ethanol (20 ml) and 10% palladium on charcoal (100 mg) was added. The reaction mixture was stirred overnight under an atmosphere of hydrogen and then filtered through celite and evaporated to yield the title compound (380 mg, 86%) . The coπpound was characterised and tested as the N-methyl-D-glucamine salt m.p. 124-7°, found: C,

64.58; H, 7.92; N, 5.38. C^H^N . 1.71 H ₂ 0 requires C, 64.40; H, 7.70; N, 5.45%

Example 49 Preparation of cis-7-(2-S-carboxy-pyrrolidino¬ carbonyl) -8-(1-adamantylmethylaminocarbonyl) -2,3,5, 6-dibenzo- bicyclo[2.2.2]octane (mixture of diastereomers)

This cαπpound was prepared essentially as in example 48 but using the product of example 47 as substrate rather than the product of exaπple 46. Yield 60% The coπpound was characterised and tested as the N-methyl-D-glucamine salt m.p. 98-101°, found: C, 61.12; H, 8.11; N, 5.08. C ₄₁ H ₅₅ N ₃ 0 ₉ . 3.88 H _: 0 requires C, 61.26; H, 7.87; N, 5.23%

Example 50 Preparation of cis-7-(2-methoxycarbonyl-pyrrolidino¬ carbonyl) -8-(1-adamantylmethylaminocarbonyl) -2, 3, 5, 6-dibenzo- bicyclo[2.2.2]octane (mixture of diastereomers)

The coπpound of exaπple 46 (320 mg, 0.59 mmol) was dissolved in dioxan (10 ml) and a solution of diazomethane in ether was added

^■ dropwise until the colour persisted. After stirring for lh at room temperature acetic acid was added to quench the reaction and the solution was evaporated and taken up in ethyl acetate. The product was then washed with saturated sodium hydrogencarbonate solution and saturated brine. The organic phase was dried filtered and evaporated and the title coπpound purified on silica using 50% ethyl acetate and 50% hexane as eluent. Yield (120 mg, 37%), m.p. 112-5°, found: C, 75.86; H, 7.43; N, 4.96. C-, ₅ H ₄₀ N ₂ O ₄ requires C, 75.86; H, 7.29; N, 5.07%

Example 51 Preparation of cis-7-(2-S-methoxycarbonyl- pyrrolidinocarbonyl) -8- (1-adamantylmethylaminocarbonyl) - 2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

This cαπpound was prepared essentially as in exaπple 50 using the

cαπpound of exaπple 47 as substrate instead of the coπpound of exaπple 46. Yield 43%, m.p. 104-6°, found: C, 74.55; H, 7.43; N, 4.88. C ₃₅ H ₄₀ N ₂ O ₄ . 0.6 H ₂ 0 requires C, 74.57; H, 7.37; N, 4.97%

Example 52 Preparation of (±)-cis-7-(3-indolylethyl- aminocarbonyl) -8- (1-adamantylmethylaminocarbonyl) -2,3,5,6- dibenzobicyclo[2.2.2]octane

(±) -cis-8-(1-adamantylmethylaminocarbonyl) -2,3, 5, 6-dibenzo- bicyclo[2.2.2]octane-7-carboxylic acid (prepared as in exaπple 14)

(440 mg, 1 mmole) and PyBOP (520 mg, 1 mmole) were taken up in dry dichloromethane (15 ml) and Hunigs base (0.52 ml, 3 mole) was added. The reactionmixture was stirred under an atmosphere of dry argon for lh. Tryptamine hydrochloride (197 mg, 1 mmole) was added and the mixture stirred overnight. The organic layer was washed with 5% potassium hydrogensulphate (15 ml) , sodium hydrogencarbonate (15 ml) and saturated brine (15 ml) . It was then dried, filtered and evaporated to leave the crude title coπpound whichwas further purifiedby column chromatography on silica using 15% ethyl acetate and 85% dichloromethane as eluent. The title cαπpound (432 mg, 74%) was isolated as a white solid, m.p. 130-40°, found: C, 75.92; H, 6.98; N, 7.19. C _; .,H ₄₁ NA requires C, 76.26; H, 7.28; N, 6.84%

Example 53 Preparation of cis-7-[R-2-(3-indolyl)-1-methoxy- carboryl-ethyla inocarbonyl]-8-(1-adamantylmethylaminocarboπyl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

This cαπpound was prepared essentially as in exaπple 52 using D-tryptophan methyl ester hydrochloride instead of tryptamine hydrochloride. Yield 78%, m.p. 135-40° ; found: C, 75.64; H, 6.81; N, 6.09. C ₄₁ H ₄₃ N ₃ 0 ₄ . 0.65 H ₂ 0 requires C, 75.35 ; H, 6.83 ; N, 6.43%

Example 54 Preparation of cis-7- [2-S- (3-indolyl) -l-metho_>^- carboryl-ethylaminocarbonyl] -8- (1-adamantylmethylaminocarbonyl) -

2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

This compound was prepared essentially as in example 52 using L-tryptophan methyl ester hydrochloride instead of tryptamine hydrochloride. Yield 80%, m.p. 135-42°, found: C, 76.55; H, 6.95; N, 6.77. C ₄₁ H ₄₃ N ₃ 0 ₄ requires C, 76.63; H, 6.75; N, _. 6.55%

Example 55 Preparation of cis-7- [2-R-(3-indolyl) -1-carboxy- ethylaminocarbonyl] -8- (1-adamantylmethylaminocarbonyl) - 2,3,5,6-dibenzobicyclo[2.2.2]octane (diastereomer 1)

a. cis-7- [2-R- (3-indolyl) -1-benzyloxycarbonyl-ethylamino- carbonyl] -8-(l-adamantylmethylaminocarbonyl) -2,3,5, 6-dibenzo- bicyclo [2.2.2] octane and separation of diastereomers

The mixture of diastereomers was prepared essentially as in exaπple 52 using D-tryptophan benzyl ester trifluoroacetate salt instead of tryptamine hydrochloride. The diastereomers were separated by column chromatography (silica 15% ethyl acetate and 85% dichloromethane) to give a 35% yield of each component.

b. cis-7- [2-R- (3-indolyl) -1-carboxy-ethylaminocarbonyl] - 8- (1-adamantylmethylaminocarbonyl) -2,3,5, 6-dibenzobicyclo- [2.2.2] octane (diastereomer 1) .

Diastereomer 1 (from step a) (0.23 g, 0.32 mmol) was dissolved in methanol (10 ml) and a catalytic amount of 10% palladium on charcoal was added. The mixure was stirred under an atmosphere of hydrogen overnight, filtered and evaporated to leave the title coπpound (0.21 g, 100%) . The coπpound was characterised and tested as the N-methyl-D-glucamine salt, m.p. 130-5°, [α] ^D = -18.5° (c=l in methanol), found: C, 67.17; H, 7.36; N, 6.49. C ₄₇ H ₅₈ N ₄ 0 ₉ . H ₂ 0 requires C, 67.09; H, 7.19; N, 6.65%

Example 56 Preparation of cis-7- [2-R- (3-indolyl) -1-carboxy- ethylaminocarbonyl] -8- (1-adamantylmethylaminocarbonyl) -

2,3,5,6-dibenzobicyclo[2.2.2]octane (diastereomer 2)

The coπpound was prepared essentially as in exaπple 4 but using diastereomer 2 (isolated in exaπple 4 step a) instead of diastereomer 1 in step b. Yield 90% The compound was further characterised and tested as the N-methyl-D-glucamine salt, m.p. 140-5°, [α] ^D = -22.0° (c=l in methanol) , found: C, 67.16; H, 7.18; N, 6.68. C ₄₇ Hs ₈ N ₄ 0 ₉ . H ₂ 0 requires C, 67.09; H, 7.19; N, 6.65%

Example 57 Preparation of cis-7-[2-S-(3-indolyl)-l-carboxy- ethylaminocarbonyl] -8- (1-adamantylmethylaminocarbonyl) - 2, 3, 5, 6 -dibenzobicyclo [2.2.2] octane (diastereomer 1)

This was prepared essentially as in exaπple 55 but using L-tryptophan benzyl ester trifluoracetate instead of the D-isomer in step a. Separation of diastereomers was achieved at the benzyl ester stage as indicated in exaπple 55 step a. and diastereomer 1 used in step b. was again the isomer with the higher R _f . Overall yield 22% based on starting racemic carboxylic acid.

The cαπpound was further characterised and tested as the N-methyl-D-glucamine salt, m.p. 119-24°, [α] ^r '= -5.7° (c=0.7 in methanol), found: C, 65.07; H, 7.25; N, 6.44. C ₄₇ H ₅₈ N ₄ 0 ₉ requires C, 65.03; H, 7.32; N, 6.45%

Example 58 Preparation of cis-7- [2-S-(3-indolyl) -1-carboxy- ethylaminocarbonyl] -8- (1-adamantylmethylaminocarbonyl) - 2,3,5,6-dibenzobicyclo[2.2.2]octane Diastereomer 2

The compound was prepared essentially as in example 55 but using diastereomer 2 (isolated in example 57 step a) instead of diastereomer 1 in step b. Overall yield 26% based on starting racemic carboxylic acid. The cαπpound was characterised and tested as the N-methyl-D-glucamine salt, m.p. 133-8°, [α] ^D = +7.6° (c=0.66 in methanol), found: C, 64.42; H, 7.17; N, 6.41. C ₄₇ H ₅₈ N ₄ 0 ₉ .3H ₂ 0 requires C, 64.37; H, 7.35; N, 6.39%

Exaπple 59 Preparation of cis-(±)-7-(2-Furaιylmethylaminocarbonyl)- 8- ( 1-adamantylmethylaminocarbonyl) -2 , 3 , 5 , 6 - dibenzobicyclo[2.2.2]octane

The reaction was performed essentially as in Exaπple 25 but using furfurylamine instead of L-alanine methyl ester hydrochloride. Yield 65%, m.p. 300°, found: C, 78.15; H, 6.99; N, 5.42. C ₃₄ H ₃₆ N ₂ 0 ₃ requires C, 78.43; H, 6.97; N, 5.38%

Example 60 Preparation of cis-(±) -7-[2-(5-methyloxycarbonyl)- furanylaminocarbonyl]-8-(1-adamantylmethylaminocarbonyl)-2,3 ,5,6- dibenzobicyclo[2.2.2]octane

The reaction was performed essentially as in Exaπple 25 but using 5-methoxycarbonyl-2-aminofuran instead of L-alanine methyl ester hydrochloride. Yield 65%, m.p. 225°, found: C, 74.31; H. 6.54; N, 4.91. C ₃₅ H ₃₆ N ₂ 0 ₅ requires C, 74.45; H, 6.43; N, 4.96%

Example 61 Preparation of cis-7- (l-S-benzyloxycarbonyl-2- methylpropylaminocarbonyl) -8- (1-adamantylmethylaminocarbonyl)- 2,3,5, 6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The reaction was performed essentially as in exaπple 46 but using the p-toluenesulphonate salt of the benzyl ester of L-valine instead of D-proline benzyl ester hydrochloride. m.p 85-87°. Found: C, 77.99; H, 7.52; N, 4.17. C ₄ ,H _4t N;0 ₄ • 0.1H ₂ O requires C, 77.86; H, 7.36; N, 4.42%

Example 62 Preparation of cis-7- (l-S-carboxy-2-metbyl- propylaminocarbonyl)-8-(1-adamantylmethylaminocarboryl)-2,3, 5,6- dibenzobicyclo-[2.2.2]octane (mixture of diastereomers)

The reaction was performed essentially as in exaπple 48 but using

the product of exaπple 61 as substrate instead of the product of exaπple 46. The compound was characterised and tested as the N- methyl-D-glucamine salt m.p 105-8°. Found: C, 64.00; H, 8.06; N, 5.37. C ₄₁ Hs ₇ NA- 1.8H ₂ 0 requires C, 64.09; H, 7.95; N, 5.46%

Example 63 Preparation of cis-7-(l-S-_methoxycarbonyl-2-methyl- propylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3, 5,6- dibenzobicyclo-[2.2.2]octane (mixture of diastereomers)

cis-7- (l-S-carboxy-2-methylpropylaminocarbonyl) -8- (1- ada antylmethylaminocarboiyl) -2,3,5,6-dibenzobicyclo-[2.2.2]octane (mixture of diastereomers) (150 mg) prepared as in exaπple 62 was dissolved in ethyl acetate (5ml) and a solution of diazαmethane in diethyl ether was added until a yellow colour persisted in solution. After stirring the rection mixture at room teπperature for 10 min, glacial acetic acid was added and the organic layer was washedwith saturated sodiumhydrogencarbonate solution, dried over magnesium sulphate, filtered and evaporated. Yield 130 mg, 85%, m.p. 103-5°. Found: C, 75.51; H, 7.67; N, 5.06. C ₃₅ H ₄₂ N ₂ 0 ₄ requires C, 75.78; H, 7.63; N, 5.05%

Example 64 Preparation of cis-7-(l-S-2-dicarboxyethyl- aminocarbonyl) -8- (1-adamantylmethylaminocarbonyl) -2,3,5,6- dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

a. cis-7-(l-S-2-dibenzyloxycarbonylethylaminocarbonyl)-8-(1- adaπantylmethylaminocarboryl)-2,3,5,6-dibenzobicyclo-[2.2.2 ]octane (mixture of diastereomers)

The reaction was performed essentially as in exaπple 46 but using the dibenzyl ester of L-aspartic acid instead of D-proline benzyl ester hydrochloride. The product was used directly in step b.

b . cis -7 - ( l-S -2 -dicarboxyethylaminocarbonyl ) - 8 - ( 1 - adaπantylmethylaminocarboπyl ) -2 , 3 , 5 , 6-dibenzobicyclo- [2.2.2] octane (mixture of diastereomers)

The reaction was performed essentially as in exaπple 48 but using the product of step a. as substrate instead of the product of exaπple 46. he cαπpound was characterised and tested as the mono- N-methyl-D-glucamine salt, m.p 115-7°. Found: C, 62.84; H, 7.03; N, 5.35. C _IO H _{M J} O _Π . 0.62H ₂ O requires C, 62.54; H, 7.03; N, 5.61%

Example 65 Preparation of 7-(l-S-carboxy-2-pheryl-ethyl- aminocarbonyl) -8- (1-adamantylmethylaminocarbonyl) -2,3,5,6- dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The reaction was performed essentially as in exaπple 64 but using the benzyl ester of phenylalanine in step a. instead of the dibenzyl ester of aspartic acid. The coπpound was characterised and tested as the N-methyl-D-glucamine salt, m.p 101-3°. Found: C, 66.13; H, 7.64; N, 5.05. C _4S H ₅₇ NA- l.-9H ₂ 0 requires C, 66.06; H, 7.49; N, 5.14%

Example 66 Preparation of (±)-cis-7-(1-methoxycarboπyl-l-methyl- ethylaminocarbonyl) -8-(1-adamantylmethylaminocarbonyl)-2,3,5,6- dibenzobicyclo[2.2.2]octane

The reaction was performed essentially as in exaπple 46 but using the trifluoromethylacetate salt of the methyl ester of aminoisobutyric acid instead of D-proline ^' benzyl ester hydrochloride. m.p 120-2°. Found: C, 75.51; H, 7.43; N, 4.90. C ₃₄ H ₄₀ N ₂ O ₄ requires C, 75.53; H, 7.46; N, 5.18%

Example 67 Preparation of (±) -cis-7- (1-carboxy-l-methyl- ethylaminocarbonyl) -8-(1-adamantylmethylaminocarbonyl) -2,3,5,6- dibenzobicyclo[2.2.2]octane

The reaction was performed essentially as in exaπple 64 but using the benzyl ester of aminoisobutyric acid in step a. instead of the dibenzyl ester of aspartic acid. The coπpound was characterised and tested as the N-methyl-D-glucamine salt, m.p 115-25°. Found:

C, 64.71; H, 7.74; N, 5.92. requires C, 64.93; H, 7.76; N, 5.68%

Example 68 Preparation of cis-7-(2-R-carboxy-4-R-hydroxy- pyrrolidinocarbonyl)-8-(1-adamantylmetbylaminocarboπyl)-2,3 ,5,6- dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The reaction was performed essentially as in exaπple 64 but using the benzyl ester of cis hydroxy-D-proline in step a. instead of the dibenzyl ester of aspartic acid. The cαπpound was characterised and tested as the N-methyl-D-glucamine salt, m.p 118-21°. Found: C, 58.59; H, 7.48; N, 5.10. C _4] H ₅₅ N ^ 4.8 π l H ₂ 0 requires C, 58.89; H, 7.78; N, 5.02%

Example 69 Preparation .of cis-7-(2-R-carboxy-4-R-hydroxy- pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3, 5,6- dibenzobicyclo[2.2.2]octane (diastereomer 1)

Ihe cis-7-(2-R-ben2ylo^carboryl-4-R-hydro^-pyrrolidino-carboryl) - 8 - ( 1 - adamantylmethy1 amino _. carbonyl) -2 , 3 , 5, 6- dibenzobicyclo[2.2.2]octane mixture of diastereomers prepared as referenced in exaπple 68 was separated into its two diastereomeric coπponents by repeated recrystallisation from ethyl acetate. The insoluble isomer was designated diastereomer 1. The soluble material isolated by evaporation was designated diastereomer 2. Diastereomer 1 was converted to the title coπpound essentially as in exaπple 48 using it as substrate instead of the product of exaπple 46. Ihe compound was characterised and tested as the N- methyl-D-glucamine salt, m.p 112-4°. Found: C, 60.81; H, 7.86; N, 4.96. C _4I H ₅₅ N ₃ O ₁₀ . 4.4 mol H ₂ 0 requires C, 60.70; H, 7.68; N, 5.18%

Example 70 Preparation of cis-7-(2-R-carboxy-4-R-hydroxy- pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3, 5,6- dibenzobicyclo[2.2.2]octane (diastereomer 2)

Diastereomer 2 prepared as described in example 69 was converted to the title coπpound essentially as in exaπple 48 using it as substrate instead of the product of exaπple 46. Ihe coπpound was characterised and tested as the N-methyl-D-glucamine salt, m.p 132- 35°. Found: C, 63.69; H, 7.51; N, 5.04. ^H^NAc- 1.5 mol H ₂ 0 requires C, 63.40; H, 7.52; N, 5.41%

Example 71 Preparation of cis-7-(2-R-methoxycarbonyl-4-R-hydroxy- pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl) -2,3,5,6- dibenzobicyclo[2.2.2]octane (diastereomer 1)

The cαπpound was prepared essentially as in.exaπple 63 but using the product of exaπple 69 as substrate instead of cis-7-(1-S- carboxy-2-methylpropylaminocarbonyl) -8- (1-adamantylmethyl¬ aminocarbonyl)-2,3,5, 6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers), m.p 133-35°. Found: C, 72.81; H, 7.21; N, 4.88. C ₃₅ H ₄₀ N ₂ O ₅ . 0.5 mol H ₂ 0 requires C, 72.81; H, 7.15; N, 4.85%

Example 72 Preparation of cis-7-(2-R-methoxycarbonyl-4-R-hydroxy- pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3, 5,6- dibenzobicyclo[2.2.2]octane (diastereomer 2)

The coπpound was prepared essentially as in exaπple 63 but using the product of exaπple 70 as substrate instead of cis-7-(1-S- carboxyl-2-methylpropylaminocarbonyl) -8-(1-adamantylmethylamino¬ carbonyl) -2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers), m.p 133-35°. Found: C, 70.28; H, 7.14; N, 4.81. C ₃₅ H ₄₀ N ₂ O ₅ . 1.5 mol H ₂ 0 requires C, 70.42; H, 7.28; N, 4.69%

Example 73 Preparation of (±) -cis-7-(3-(±)-carboxy- piperidinocarbony1) -8-(1-adamantylmethylaminocarbonyl) -2,3,5,6- dibenzobicyclo[2.2.2]octane

The reaction was performed essentially as in exaπple 46 but using the trifluoromethylacetate salt of the benzyl ester of racemic

nipecotic acid instead of D-proline benzyl ester hydrochloride. The coπpound was characterised and tested as the N-methyl-D- glucamine salt. Found: C, 65.54; H, 8.12; N, 5.23. C ₄₂ H ₅₇ N ₃ 0 ₉ - !•* H ₂ 0 requires C, 65.24; H, 7.80; N, 5.43%

Example 74 Preparation of (±)-cis-7-(3-(±)-methoxycarbonyl- piperidinocarboπyl)-8-(1-adamantylmethylaminocarbonyl) -2,3,5,6- dibenzobicyclo[2.2.2]octane

The coπpound was prepared essentially as in exaπple 63 but using the product of exaπple 73 as substrate instead of cis-7-(1-S- carbx_>xy-2-methylpropylaminocarbonyl) -8-(l-adamantylmethylamino- carbonyl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers). Found: C, 74.24; H, 7.30; N, 4.65. C ₃₆ H ₄₂ N ₂ 0 ₄ . 0.8 H ₂ 0 requires C, 74.40; H, 7.56; N, 4.82%

Exaπple 75 Preparation of cis-7-(1-S-cyanoethylaminocarboryl)-8-(1- adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo[2.2.2]o ctane ^' (mixture of diastereomers)

The cαπpound of exaπple 31 (0.33 g, 0.59 mπpl) was dissolved in pyridine (5 ml) and cooled to .0° under an atmosphere of dry argon. Tosyl chloride (0.13 g, 0.70 mmol) was added and the reaction allowed to warm to room teπperature and was then stirred overnight. The solvent was removed by evaporation and the residue partitioned between ethyl acetate and water. The organic phase was washed successively with 1M hydrochloric acid and saturated sodium hydrogen carbonate solution, dried, filtered and evaporated to leave the crude product. This material was purified by column chromatography {silica, 90% dichloromethane and 10% ethyl acetate) to leave the title cαπpound (150 mg) , m.p. 125-8°. Found: C, 76.30; H, 7.23; N, 8.21. C ₃₂ H ₃₅ NA- 0.6 H_0 requires C, 76.19; H, 7.23; N, 8.32%

Exam ^p le 76 Preparation of cis-7-(1-S-methylcarbonyl-

ethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5 ,6- dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The compound of exaπple 75 (0.25 g, 0.5 πtnol) was dissolved in THF (3 ml) and cooled to 0° under an atmosphere of dry argon. Methyl magnesium bromide solution (1.4M in THF 1.4 ml, 2.0 mmol) was added. The solution was stirred at 0° for lh. 2M hydrochloric acid

(2ml) was added followed by saturated aππonium cliloride solution.

(20 ml) . The product was extracted with ethyl acetate (2 x 20 ml) , dried, filtered and evaporated (0.25 ml). The crude product was purified by column chromatography (silica 90% dichloromethane and 10% ethyl acetate) to leave the title coπpound (130 mg) , m.p. 105- 10°. Found: C, 76.61; H, 7.40; N, 5.25. C33H38N203. 0.4 H20 requires C, 76.54; H, 7.5.5; N, 5.41%

Example 77 Preparation of cis-7-(1-S-propyloxycarbonyl- ethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5 ,6- dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The reaction was performed essentially as in exaπple 46 but using the trifluoromethylacetate.salt of the propyl ester of L-alanine (prepared from alklation of the caesium salt of BOC-L-alanine with propyl bromide followed by treatment with trifluoroacetic acid) instead of D-proline benzyl ester hydrochloride. m.p 90-3°. Found: C 75.33; H, 7.74; N, 4.81. C ₃₅ H ₄₂ NA- 0.25 H.0 requires C, 75.33; H, 7.66; N, 5.01%

Example 78 Preparation of cis-7- (2-R-carboxy-pyrrolidinocarbonyl)- 8- ( 1-adamantylmethylaminocarbonyl ) -2 , 3 , 5 , 6 - dibenzobicyclo[2.2.2]octane (diastereomer 1)

The compound of exaπple 48 was separated into its constituent diastereomers by reverse phase HPLC (silica C8 column 60% acetonitrile, 40% water and 0.1% acetic acid modifier) . Ihe first coπpound eluted was designated diastereomer 1, the title coπpound. The cαπpound was characterised and tested as the N-methyl-D-

glucamine salt. Found: C, 64.23; H, 7.86; N, 5.38. C ₄₁ Hs ₅ NAo- I- ⁸ H ₂ 0 requires C, 64.22; H, 7.71; N, 5.48%

Example 79 Preparation of cis-7- ( 2 -R-carl_κ>_xy -pyrrolidinocarbonyl) - 8- (1-adamantylme thyl amino carbonyl ) -2 , 3 , 5, 6- dibenzobicyclo[2.2.2]octane (diastereomer 2)

The second coπpound eluted during the HPLC separation referred to in exaπple 78 was designated diastereomer 2. The compound was characterised and tested as the N-methyl-D-glucamine salt. Found: C, 64.23; H, 7.86; N, 5.38. C ₄₁ H ₅₅ N ₃ O ₁₀ . 1.8 H,0 requires C, 64.22; H, 7.71; N, 5.48%

Example 80 Preparation of cis-7-(2-S-metho^carboryl- pyrrolidinocarbonyl)-8-(l-adaπantylmethylaminocarbonyl)-2,3 ,5,6- dibenzobicyclo[2.2.2]octane (diastereomer 1)

Ihe coπpound of exaπple 51 was separated into its constituent diastereomers by repeated recrystallisation from 80% ethyl acetate and 20% hexane. Ihe crystals isolated were designated diastereomer 1, the title compound, m.p. 256°. Found: C, 76.01; H, 7.31; N, 4.98. C ₃₅ H ₄₀ N ₂ 0 ₄ requires C 76.06; H, 7.29; N, 5.07%

Example 81 Preparation of cis-7-(2-S-methoxycarbonyl- pyrrolidinocarbonyl) -8- (1 -adamantylmethylaminocarbonyl) -2,3,5,6- dibenzobicyclo[2.2.2]octane (diastereomer 2)

The mother liquors from the recrystallisation described in exaπple 80 were concentrated to yield the other pure isomer designated diastereomer 2, m.p. 94-6°. Found: C, 74.88; H, 7.31; N, 5.03. C ₃₅ H ₄₀ N ₂ O ₄ . 0.5 H,0 requires C, 74.91; H, 7.35; N, 4.99%

Exaπple 82 Preparation of cis-7-(l-S-carboxy-2-bydroxyetbyl- aminocarbonyl) -8- (1-adamantylmethylaminocarbonyl) -2,3,5,6-

dibenzobicyclo[2.2.2]octane (diastereomer 1)

Step a. cis-7-(l-S-Benzyloxycarbonyl-2-hydrαxyethylaminocarbonyl)- 8- (1-adamantylmethylaminocarbonyl) -2 , 3 , 5 , 6 - dibenzobicyclo[2.2.2]octane (diastereomer 1 and 2)

The reaction was performed essentially as in example 46 but using L-serine benzyl ester hydrochloride instead of D-proline benzyl ester hydrochloride. The cαπpound was separated into its cαπponent diastereomers by column chromatography (silica 25% ethyl acetate and 75% dichloromethane) . The less polar material was designated diastereomer 1 and the more polar diastereomer 2.

Step b. cis-7-(l-S-carboxy-2-hydroxyethylaminocarboryl)-8-(l- adamantylmethylaminocarbonyl) -2,3,5, 6-dibenzobicyclo[2.2.2]octane (diastereomer 1)

The reaction was performed essentially as in exaπple 48 but using the diastereomer 1 from step a. above as substrate instead of the product of exaπple 46. The compound was characterised and tested ^• as the N-methyl-D-glucamine salt, m.p 102-5° found: C, 61.24; H, 7.78; N, 5.22. C ₃₀ Hς ₃ NAo- 2.4 H _: ,0 requires C, 61.08; H, 7.59; N, 5.48%

Example 83 Preparation of cis-7-(l-S-carboxy-2-hydrσxy- ethylaminocarbony1) -8-(1-adamantylmethylaminocarbonyl) -2,3,5,6- dibenzobicyclo[2.2.2]octane (diastereomer 2)

The reaction was performed essentially as in exaπple 48 but using the diastereomer 2 from exaπple 82 step a. as substrate instead of the product of exaπple 46. The coπpound was characterised and tested and tested as the N-methyl-D-glucamine salt, m.p 107-10° found: C, 61.27; H, 7.69; N, 5.29. C.JL-.NA _. ... 2.3 H ₂ 0 requires C, 61.19; H, 7.59; N, 5.49%

Example 84 Preparation of cis-7-(l-S-methoxycarbonyl-2-

hydroxyethylaminocarbonyl ) -8- (1 -adamantylmethylaminocarbonyl) - 2,3,5,6-dibenzobicyclo[2.2.2]octane (diastereomer 1)

Step a. cis-7- (l-S-πetho_3ycarbonyl-2-_hydroxyetl^lam__i_nocarboπyl) -8- (1-adamantylmethylaminocarbonyl ) -2 , 3 , 5 , 6 - dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

Ihe reaction was performed essentially as in exaπple 46 but using L-serine methyl ester hydrochloride instead of D-proline benzyl ester hydrochloride.

Step b . cis-7- (1-S -methoxy carbon l -2 -hydroxyethylaminocarbonyl ) -8- (1-adamantylmethylaminocarbonyl) -2,3,5, 6-dibenzobicyclo- [2.2.2] octane (diastereomer 1)

The cαπpound prepared in step a. was separated into its component diastereomers by column, chromatography (silica 30% ethyl acetate and 70% dichloromethane) . The less polar material was designated diastereomer 1, the title coπpound, m.p 115-20° found: C, 68.94; H, 6.95; N, 4.91. C ₃₃ H ₃₈ N ₂ 0 ₅ . 1.6 H ₂ 0 requires C, 69.26; H, 7.27; N, 4.90%

Example 85 Preparation of cis-7-(l-S-methoxycarbonyl-2- hydroxyethylaminocarbonyl) -8-(1-adamantylmethylaminocarbonyl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane (diastereomer 2)

Ihe compound of this exaπple was the more polar diastereomer • isolated from the column chromatography described in exaπple 84 step b, m.p 100-10° found: C, 56.92; H, 6.03; N, 3.49. C ₃₃ H ₃₈ N ₂ 0 ₅ . 2.4 DCM requires C, 56.91; H, 5.78; N, 3.75%

Example 86 Preparation of (±) - cis-7-(1-methoxycarboπyl-l- ethyleneaminocarboryl)-8-(1-adamantylmethyla inocarbonyl)-2,3,5,6- dibenzobicyclo[2.2.2]octane

The product of exaπple 64 step a. (270 mg, 0.5 nmol) was dissolved

in THF (2 ml) and N,N-carboπyldiimidazole (80 mg, 0.5 mmol) was added followed by triethylamine (0.07 ml) . The solution was stirred at roam teπperature ovemight under an atmosphere of dry argon. Ihe solvent was evaporated and the crude material purified by column chromatography (silica 10% ethyl acetate and 90% dichloromethane) to give the title coπpound as a solid (50 mg) , m.p 98-108° found: C, 73.59; H, 7.05; N, 5.06. C ₃₃ H ₃₆ N ₂ 0 ₄ . 0.8 H ₂ 0 requires C, 73.55; H, 7.03; N, 5.20%

Example 87 Preparation of cis-7-(1-S-methoxycarbony1-2- carboxyethylaminocarbonyl) -8- (1-adamantylmethylaminocarbonyl) - 2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The reaction was performed essentially as in exaπple 64 but using the alpha methyl beta benzyl diester of aspartic acid in step a. instead of the dibenzyl ester. The coπpound was characterised and tested as the N-methyl-D-glucamine salt, m.p 103-5° found: C, 56.56; H, 7.70; N, 4.71. 5.9 H ₂ 0 requires C, 56.48; H, 7.72; N, 4.82%

Example 88 Preparation of cis-7- (2-R-carboxypiperidinocarboryl) -8- ( 1- adamantylmethylaminocarbonyl ) -2,3,5,6-dibenzo- bicyclo [2.2.2] octane (mixture of diastereomers)

^' The reaction was performed essentially as in exaπple 64 but using the benzyl ester of D-pipecolinic acid in step a. instead of the dibenzyl ester of aspartic acid. The coπpound was characterised and tested as the N-methyl-D-glucamine salt. Found: C, 65.13; H, 8.07; N, 5.64. C ₄₂ Hs ₇ N ₃ 0 ₉ . 1.5 H ₂ 0 requires C, 65.10; H, 7.81; N, 5.42%

Example 89 Preparation of cis-7- (2-R-methoxycarbonylpiperidino- carbonyl) -8- (1-adamantylmethylaminocarbonyl) -2,3,5,6- dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The cσπpound was prepared essentially as in exaπple 63 but using the product of exaπple 88 as substrate instead of cis-7-(1-S- carboxy-2-methylpropylaminocarbonyl) -8-(1-adamantylmethyl- aminocarboryl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers). Found: C, 70.00; H, 7.18; N, 4.70. C ₃₆ H ₄₂ N ₂ 0 ₄ . 0.5 CHC1 ₃ requires C, 70.04; H, 6.78; N, 4.40%

Example 90 Preparation of cis-7-(2-S-methαxycarboιyl-4-S-hydro_ι^'- pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3, 5,6- dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The reaction was performed essentially as in exaπple 46 but using the trifluoroacetate salt of the methyl ester of cis-bydroxy-L- proline instead of D-proline benzyl ester hydrochloride. Found: C, 76.36; H, 7.24; N, 4.38. C ₃₅ H ₄₀ NA.. 0.9 toluene requires C, 76.25; H, 7.31; N, 4.26%

Example 91 Preparation of cis-7-(2-S-methoxycarbonyl-4-R-hydroxy- pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3, 5,6- dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The reaction was performed essentially as in exaπple 46 but using the trifluoroacetate salt of the methyl ester of trans-hydroxy-L- proline instead of D-proline benzyl ester hydrochloride. Found: C, 75.16; H, 7.32; N, 4.19. C ₃₅ H ₄₀ NA.. 0.6 toluene requires C, 75.45; H, 7.24; N, ^' 4.49% .

Example 92 Preparation of cis-7- ( l-S-methθ3ycarboπyl-2- benzylsulphenylethylaminocarbonyl) -8- (1 -adamantylmethylamino¬ carbonyl ) -2 , 3 , 5 , 6-dibenzobicyclo [2.2.2] octane ( diastereomer 1 )

Step a. cis-7- (l-S-methoxycarboπyl-2-benzylsulphenylethyl- aminocarbonyl ) -8- (1-adamantylmethylaminocarbonyl ) -2 , 3 , 5 , 6- dibenzobicyclo [2.2.2] octane (mixture of diastereomers)

Ihe reaction was performed essentially as in example 46 but using the benzylthioether of L-cysteine methyl ester hydrochloride instead of D-proline benzyl ester hydrochloride.

Step b. cis-7-(l-S-methoxycarboryl-2-benzylsulphenylethyl- aminocarbonyl) -8- (1-adamantylmethylaminocarbonyl) -2,3,5,6- dibenzobicyclo[2.2.2]octane (diastereomer 1)

The cαπpound prepared in step a. was separated into its coπponent diastereomers by column chromatography (silica 15% ethyl acetate and 85% dichloromethane). The more polar material(R _f 0.4) was designated diastereomer 1, the title coπpound, m.p. 80-1° found: C, 72.93; H, 6.88; N, 4.08. C ₄₀ H ₄₄ N ₂ O ₄ S. 0.5 H ₂ 0 requires C, 73.04; H, 6.89; N, 4.25%

Example 93 Preparation of cis-7-(l-S-methoxycarboπyl-2- benzylsulphenylethylaminocarbonyl) -8-(1-adamantylmethylamino¬ carbonyl)^,3,5,6-dibenzobicyclo[2.2.2]octane (diastereomer 2)

The less polar material isolated by the chromatography (R _£ 0.6) described in exaπple 92 step b. was designated as diastereomer 2, m.p. 85° found: C, 74.03; H, 7.01; N, 4.38. C ₄₀ H ₄₄ N ₂ O ₄ S requires C, 74.04; H, 6.64; N, 4.32%

Example 94 Preparation of cis-7- (1-S-carboxyethyl-(N-methyl)- aminocarbonyl) -8- (1-adamantylmethylaminocarbonyl) -2,3,5,6- dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The reaction was performed essentially as in exaπple 64 but using the trifluoroacetate salt of the benzyl ester of N-metbyl-L-alanine in step a. instead of the dibenzyl ester of aspartic acid. The cαπpound was characterised and tested as the N-methyl-D-glucamine salt, m.p. 100-10° found: C, 64.12; H, 7.89; N, 5.71. C ₄₀ H ₄₅ N ₃ O ₉ - 1.5 H ₂ 0 requires C, 64.21; H, 7.80; N, 5.62%

Exaπple 95 Preparation of cis-7-(l-R-carboxyethyl-(N-methyl)- aminocarbonyl ) -8- (1-adamantylmethylaminocarbonyl) -2,3,5,6- dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The reaction was performed essentially as in exaπple 64 but using the trifluoroacetate salt of the benzyl ester of N-methyl-D-alanine in step a. instead of the dibenzyl ester of aspartic acid. The cαπpound was characterised and tested as the N-methyl-D-glucamine salt, m.p. 105-15° found: C, 62.06; H, 7.81; N, 5.55. C ₄₀ Hs ₅ NA- 2.8 H ₂ 0 requires C, 62.18; H, 7.91; N, 5.44%

Example 96 Preparation of cis-7- (1-S-methoxycarboπylethyl- (N- etiyl) -aminocarbonyl) -8- (1 -adamantylmethylaminocarboryl) -2,3,5,6- dibenzobicyclo [2.2.2] octane (mixture of diastereomers)

The reaction was performed essentially as in exaπple 63 but using the product of exaπple 94 as substrate instead of cis-7- (1-S- carboxy-2-methylpropylaminocarboryl) -8- (l-adamantylmethylamino- carbonyl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers), m.p. 96-8° found: C, 75.55; H, 7.68; N, 5.10. C ₃₄ H ₄₀ N ₂ O ₄ requires C, 75.53; H, 7.46; N, 5.18%

Exaπple 97 Preparation of cis-7- (l-R-methoxycarbonylethyl-(N- methyl ) -aminocarbonyl ) -S- ( 1-adamantylmethy la inocarboπy 1 ) -2 , 3 , 5 , 6- dibenzobicyclo [2.2.2 ] octane (mixture of diastereomers)

he reaction was performed essentially as in exaπple 63 but using the product of exaπple 95 as substrate instead of cis-7- (1-S- carboxy-2-methylpropylaminocarbonyl) -8- ( 1-adamantylmethylamino- carbonyl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers), m.p. 95-105° found: C, 75.49; H, 7.53; N, 5.24. C ₃₄ H ₄₀ N ₂ O ₄ requires C, 75.53; H, 7.46; N, 5.18%

Exaπple 98 Preparation of (±) -cis-7- (pyrrolidinocarbonyl) -8- (1- adaπantylmethylaminocarboryl) -2,3,5, 6-dibenzobicyclo [2.2.2] octane

Ihe reaction was performed essentially as in exaπple 64 but using pyrrolidine in step a. instead of the dibenzyl ester of aspartic acid, m.p. 205-7° found: C, 80.15; H, 7.77; N, 5.78. C ₃₃ H _{38 2} θ ₂ requires C, 80.12; H, 7.74; N, 5.66%

Example 99 Preparation of (±)-cis-7-(methylaminocarbonyl)-8-(l- adaπantylmethylaminocarboiyl)-2,3,5,6-dibenzobicyclo[2.2.2] octane

Ihe compound of exaπple 14 (440 mg, 1 mmol) was dissolved in dichloromethane (15 ml) and diisopropylethylamine (0.52 ml) and PyBOP (520 mg) were added. The solution was stirred for 5-10 min until a clear solution was obtained. Dry methylamine gas was bubbled through the solution for 5 min until this was saturated. Ihe solution was stirred for lh and then evaporated. The residue was taken up in ethyl acetate and washed successively with 5% aqueous potassium hydrogensulphate solution (2 x 20 ml) saturated sodium hydrogencarbonate solution (20 ml) , brine (20 ml) , dried, filtered and evaporated to leave a crude product whichwas purified by column chromatography (silica 70% dichloromethane and 30% ethyl acetate) . The title cαπpound was a white solid (240 mg) , m.p. 192- 3° found: C, 79.15; H, 7.72; N, 5.91. C ₃₀ H ₃₄ NA requires C, 79.26; H, 7.53; N, 6.16%

Example 100 Preparation of (±)-cis-7-(dimethylaminocarboπyl)-8-(1- adaπantylmethylaminocarbory1)-2,3,5,6-dibenzobicyclo[2.2.2] octane

The cαπpound was prepared essentially as in example 99 but using dimethylamine instead of methylamine, m.p. 253-5° found: C, 78.86; H, 7.78; N, 5.67. C ₃₁ H ₃₆ N ₂ 0 ₂ requires C, 78.69; H, 7.8 N, 5.92%

Example 101 Preparation of (±)-cis-7-(ethylaminocarbonyl)-8-(1- adamantylmethylaminocarboryl)-2,3,5,6-dibenzobicyclo[2.2.2]o ctane

The cαπpound was prepared essentially as in exaπple 99 but using ethylamine instead of methylamine, m.p. 200-1° found: C, 79.82; H,

7.67; N, 5.94. C ₃₁ H _{36 2} θ ₂ requires C, 79.45; H, 7.74 N, 5.98%

Example 102 Preparation of (±) -cis-7- (1 -methyl ethylaminocarbonyl) - 8- (1-adamantylmethylaminocarbonyl) -2 , 3 , 5 , 6 - dibenzobicyclo [2.2.2] octane

Ihe cαrrpound was prepared essentially as in exaπple 99 but using isσpropylamine instead of methylamine, m.p.122-4° found: C, 74.80; H, 7.21; N, 5.38. C ₃₂ H ₃₈ NA. 0.4 DCM. 0.1 ethyl acetate requires C, 74.94; H, 7.56 N, 5.33%

Exaπple 103 Preparation of (±) -cis-7 -aminocarbonyl-8-(l- adairantylmethylaminocarboryl ) -2 , 3 , 5 , 6-dibenzobicyclo [2.2.2] octane

The compound was prepared essentially as in exaπple 99 but using aπmonia instead of methylamine, m.p. 238-40° found: C, 78.78; H, 7.45; N, 6.41. C ₂₉ H ₃₂ N ₂ 0 ₂ requires C, 79.06; H, 7.32 N, 6.36%

Example 104 Preparation of (±) -cis-7- (2-benzyloxycarbonyl- ethylaminocarbonyl) -8- (1-adamantylmethylaminocarbonyl) -1-cyano- 2, 3, 5, 6 -dibenzobicyclo [2.2.2] Octane (regioisomer 1)

The mixture of regioisomers was prepared essentially as in exaπple 29 but using (±) -cis-8- (1-adamanty lmethylaminocarbonyl) -1-cyano- 2,3,5,6-dibenzobicyclo[2.2.2]octane-7-carboxylic acid instead of (±) -cis-8- (1-adamantylmethylaminocarbonyl) -2,3,5,6- dibenzobicyclo [2.2.2 ]octane-7 -carboxylic acid. This in turn was made by reaction of 1-adamantanemethylamine with l-cyano-2, 3,5,6- dibenzobicyclo [2.2.2] octane-7 , 8 -dicarboxylic acid anhydride essentially as in exaπple 14. Ihe anhydride was prepared by reaction of maleic anhydride with 9-cyanoanthracene in refluxing toluene. Ihe regioisomers were separated by preparative HPLC (silica, ethyl acetate 15% and dichloromethane 85%) . The less polar regioisomer was designated regioisomer 1, the title coπpound, m.p. 205-8° found: C, 76.55; H, 6.61; N, 6.68. C ₄₀ H ₄₁ N ₃ O ₄ requires C,

76.53 ; H, 6.58 ; N, 6.69%

Example 105 Preparation of (±)-cis-7-(2-benzyloxycarboπyl- ethylaminocarbonyl) -8-(1-adamantylmethylaminocarbonyl) -1-cyano- 2,3,5,6-dibenzobicyclo[2.2.2]octane (regioisomer 2)

The more polar regioisomer from the HPLC separation described in exaπple 104 was designated regioisomer 2, the title coπpound, m.p. 104-7° found: C, 76.48; H, 6.65; N, 6.59. C ₄₀ H ₄₁ N ₃ O ₄ requires C, 76.53; H, 6.58; N, 6.69%

Exaπple 106 Preparation of cis-7-(l-s-methoxycarbonylethyl- aminocarbonyl) -8- (neopentylaminocarbonyl) -2 , 3 , 5, 6-dibenzo- bicyclo[2.2.2]octane (mixture of diastereomers)

a. (±) -8- (neopentylaminocarbonyl) -2,3,5, 6-dibenzobicyclo- [2.2.2]octane-7-carboxylic acid

Ihe material was prepared essentially as in exaπple 14 but using neopentylamine hydrochloride as substrate instead of 1-adamantyl- a ine.

b. cis-7-(1-S-methoxycarbonylethylaminocarbonyl)-8-(neopentyl¬ aminocarbonyl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The material was prepared essentially as in exaπple 25 but using the cαπpound prepared in step a. above instead of (±)-cis-8-(1- adamantyl ethylaminocarboryl)-2,3,5, 6-dibenzobicyclo[2.2.2]octane- 7-carboxylic acid as substrate, found: C, 72.14; H, 7.32; N, 6.29. C ₂₇ H ₃₂ N ₂ 0 ₄ requires C, 72.30; H, 7.19; N, 6.25%

Exaπple 107 Preparation of cis-7- ( 2 -R-carbox -pyrrolidinocarbonyl ) - 8- (neopentylaminocarbonyl ) -2 , 3 , 5 , 6 -dibenzobicyclo [2 .2 .2 ] octane (mixture of diastereomers)

a. cis-7- (2-R-benzyloxycarbonylpyrrolidinocarbonyl) -8- (neopentylaminocarbonyl) -2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers) Ihe cαπpound was prepared essentially as in exaπple 46 but using the product of exaπple 106 step a. as substrate instead of (±)-cis-8-(1-adamantylmethylaminocarboryl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane-7-carboxylic acid.

b. cis-7- (2-R-carboxypyrrolidinocarbonyl) -8-(neopentyl¬ aminocarbonyl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

he reaction was performed essentially as in exaπple 48 but using the product of exaπple 107 step a. as substrate instead of the product of exaπple 46. Ihe coπpound was characterised and tested as the N-methyl-D-glucamine salt, m.p. 105-15° found: C, 57.98; H, 7.89; N, 6.07. C ₃₅ H ₄₉ N ₃ 0 ₉ . 4.0 H ₂ 0 requires C, 57.75; H, 7.89; N, 5.77%

Exaπple 108 Preparation of 7-(l-adamantylmethylaminocarboπyl)- 2,3,5,6-dibenzobicyclo[2.2.2]oct-7,8-ene

a. 7-carboxy-2,3,5,6-dibenzobicyclo[2.2.2]oct-7,8-ene

7-(methoxycarbonyl) -2,3,5, 6-dibenzobicyclo[2.2.2]oct-7, 8-ene (prepared as in J.C.S. Perkin I, 1984, 779) (0.5 g, 1.9 ππol) was dissolved in ethanol (20 ml) and sodium hydroxide (0.5 g) was added along with water (2 ml) . The solution was stirred and refluxed for 1.5 h. The hot solution was poured onto 2M HCl (50 ml) . Ihe white precipitate formed was filtered off, washed with water and dried at 50° in vacuo. This coπpound was used without further purification.

b. 7-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo- [2.2.2]oct-7,8-ene

The acid prepared in step a. above (248 mg, 1 mmol) was dissolved in dry dichloromethane (10 ml) and diisopropylamine (0.52 g, 3

πmol) and PyBOP (0.52 g, 1 πmol) were added. After stirring at room teπperature for 5 min, 1-adamantylmetbylamine (180 mg) was added.

After stirring for a further 30 min whereupon the reaction mixture was evaporated. Ihe residue was taken up in ethyl acetate and washed successively with 5% aqueous potassium hydrogensulphate solution (2 x 20 ml) , saturated sodium hydrogencarbonate solution

(20 ml) , brine (20 ml) , dried, filtered and evaporated to leave a crude product which was recrystallised from toluene. The white solid was dried in vacuo, m.p. 254-5° found: C, 81.28; H, 7.81; N, 3.40. C ₂₈ H ₂₉ NO. H ₂ 0 requires C, 81.32; H, 7.50; N, 3.39%

Example 109 Preparation of (±)-7-(1-adamantylmethylaminocarbonyl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane

a. (±)-2,3,5,6-dibenzobicyclo[2.2.2]octane-7-carboxylic acid

7-(methoxycarbonyl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (prepared as in US patent 5,055,468) (20 g, 80 πmol) was dissolved in methanol (220 ml) and potassium hydroxide (40 g) was added along with water (40 ml) . Ihe solution was stirred and.refluxed for 4h. The solution was cooled, filtered through charcoal and treated with concentrated HCl. Ihe buff precipitate formed was filtered off, washed with water and recrystallised from hot benzene. This coπpound was used without further purification.

. (± 7- (1-adamantylmethylaminocarbonyl) -2 , 3 , 5, 6- dibenzobicyclo[2.2.2]octane

(±)-2,3,5,6-dibenzobicyclo[2.2.2]octane-7-carboxylic acid (prepared in step a. above) (1.0 g) was heated with thionyl chloride (5 ml) and EMF (2 drops) at reflux for 30 rnin. On cooling and evaporation the pale yellow acid chloride was isolated.

The acid chloride (267 mg, 1.0 mmol) was dissolved in dry dichloromethane (5 ml) and and added with stirring to a solution of 1-adamantane ethylamine (182 mg, 1.1 mmol) and triethylamine (0.3 ml) . After 30 min the solution was washf ".uccessively with

2M HCl and brine, dried, filtered and evaporated to leave a solid whichwas recrystallised from toluene (253 mg) , m.p.220-1° found: C, 84.88; H, 7.81; N, 3.39. C ₂₈ H ₃₁ NO requires C, 84.81; H, 7.63; N, 3.39%

Example 110 Preparation of (±)-7-(1-adamantylmethox carbonyl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane

Thematerial was prepared essentially as in exaπple 109 except that 1-adamantanemethanol was used instead of 1-adamantanemethylamine in step b, m.p. 152-3° found: C, 84.42; H, 7.65. C ₂₈ H ₃₀ O ₂ requires C, 84.38; H, 7.59%

Exaπple 111 Preparation of cis-7- (1-S-methoxycarborylethyl- aminocarbonyl ) -8 - ( 1 -adamantylmethoxycarbonyl ) -2 , 3 , 5 , 6- dibenzobicyclo [2.2.2] octane (mixture of diastereomers)

The material was prepared essentially as in exaπple 25 but using the coπpound prepared in exaπple 13 instead of (±) -cis-8- (1- adamantylmethylaminocarboryl ) -2 , 3 , 5 , 6 -dibenzobicyclo [2.2.2] octane- 7-carboxylic acid as substrate, m.p. 75-7° found: C, 74.27 ; H, 7.36; N, 2.80. C ₃₃ H ₃₇ N0 ₅ . 0.06 rrol DCM requires C, 74.53 ; H, 7.02; . N, 2.62%

Exaπple 112 Preparation of cis-7- ( 1-R-methoxycarboπy lethyl- amino carbonyl ) -8 - ( 1 -adamantylmethoxycarbonyl ) -2 , 3 , 5 , 6- dibenzobicyclo [2.2.2] octane • (mixture of diastereomers )

The material was prepared essentially as in exaπple 111 but using D-alanine methyl ester hydrochloride instead of L-alanine methyl ester hydrochloride as substrate, m.p . 85-7° found: C, 74.38 ; H, 7.29 ; N, 2.75. C ₃₃ H ₃₇ N0 ₅ . 0.05 mol DCM requires C, 74.63 ; H, 7.03 ; N, 2.63%

Example 113 Preparation of (±)-cis-7-(2-benzyloxycarborylethyl¬ aminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-1,4-dimeth yl- 2,3,5,6-dibenzobicyclo[2.2.2]octane

The cαπpound was prepared essentially as in exaπple 29 but using (±)-cis-8-(1-adamantylmethylaminocarboπyl)-1,4-dimethyl-2, 3,5,6- dibenzobicyclo[2.2.2]octane-7-carboxylic acid instead of (±)-cis-8- (1-adamantylmethylaminocarbonyl) -2,3,5, 6-dibenzobicyclo- [2.2.2]octane-7-carboxylic acid. This in turn was made by reaction of 1-adamantanemethylamine with 1,4-dimeth l-2,3, 5, 6- dibenzobicyclo[2.2.2]octane-7,8-dicarboxylic acid anhydride essentially as in exaπple 14. The anhydride was prepared by reaction of maleic anhydride with 9,10-dimethylanthracene in refluxing toluene, m.p. 170-3° found: C, 77.89; H, 7.49; N, 4.49. C ₄₁ H ₄₆ N ₂ 0 ₄ requires C, 78.06; H, 7.49; N, 4.44%

Exaπple 114 Preparation of (±)-cis-7-(1-S-methoxycarboπylethyl- aminocarboryl)-8-(l-adaπantylmethylaminocarbonyl)-l-nitro-2 ,3,5,6- dibenzobicyclo[2.2.2]octane (diastereomer 1)

Ihe cαπpound was prepared essentially as in exaπple 25 but using

(±)-cis-8-(1-adamantylmethylaminocarboryl)-l-nitro-2,3,5 ,6-dibenzo- bicyclot2.2.2]octane-7-carboxylic acid instead of (±)-cis-8-(1- adamantylmethylaminocarboryl)-2,3,5,6-dibenzo-bieyclo[2.2.2] octane-

7-carboxylic acid . This in turn was made by reaction of 1- adamantane ethylamine with l-nitro-2,3,5,6-dibenzobicyclo-

[2.2.2]octane-7,8-dicarboxylic acid anhydride essentially as in exaπple 14. The anhydride was prepared by reaction of maleic anhydride with 9-nitroanthracene in refluxing toluene. The final mixture of diastereomers was separated into three coπponents by HPLC (silica gradient elution of 5% ethyl acetate and 95% dichloromethane to 15% ethyl acetate and 85% dichloromethane) . The least polar fraction was designated diastereomer 1. Found: C, 68.99; H, 6.78; N, 7.24. C ₃₃ H ₃₇ N ₂ 0 ₆ requires C, 69.33; H, 6.52; N, 7.35%

Example 115 Preparation of (±)-cis-7-(1-S-methoxycarbonylethyl- aminocarboryl)-8-(1-adamantylmethylaminocarboryl)-l-nitro-2, 3,5,6- dibenzobicyclo[2.2.2]octane (diastereomer 2)

Ihe second least polar fraction from the HPLC separation described in exaπple 114 was designated diastereomer 2. Found: c, 69.43; H, 6.69; N, 7.37. C ₃₃ H ₃₇ N ₃ 0 ₆ requires C, 69.33; H, 6.52; N, 7.35%

Exaπple 116 Preparation of (±)-cis-7-(1-S-methoxycarboπylethyl- aminocarboπyl)-8-(1-adamantylmethylaminocarbonyl)-l-nitro-2 ,3,5,6- dibenzobicyclo[2.2.2]octane (diastereomer 3)

Ihe most polar fraction from the HPLC separation described in exaπple 114 was designated diastereomer 3, found: C, 69.21; H, 6.80; N, 7.22. C ₃₃ H _i7 NA requires C, 69.33; H, 6.52; N, 7.35%

Example 117 Preparation of cis-7-(l-S-methoxycarbonyl-2-(3- indolyl)ethylaminocarbonyl)-8-(neopentylaminocarbonyl)-2,3,5 ,6- dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

Ihe cαπpound was prepared essentially as ^' in exaπple 54 but using the product of exaπple 106 step a. as substrate instead of (±)-cis- 8- (1-adamantylmethylaminocarbonyl) -2 , 3 , 5, 6 - dibenzobicyclo[2.2,2]octane-7-carboxylic acid. Found: C, 73.81; H, 6.49; N, 7.23. C ₃₅ H ₃₇ N ₃ 0 ₄ . 0.25 H ₂ 0 requires C, 73.98; H, 6.65; N, 7.39%

Example 118 Preparation of cis-7-(l-S-carboxy-2-(3- indolyl)ethylaminocarbonyl)-8-(neopentylaminocarbonyl)-2,3,5 ,6- dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The compound was prepared essentially as in exaπple 107 but using the benzyl ester of L-tryptophan as substrate in step a. as substrate instead of the benzyl ester of D-proline. Ihe coπpound

was characterised and tested as the N-πvethyl-D-glucamine salt Found: C, 65.91; H, 7.01; N, 7.31. C^H^N requires C, 66.11; H, 7.04; N, 7.52% ,

Example 119 Preparation of cis-7-(2-R-(carboxymethylamino- carboryl)pyrrolidinocarbonyl)-8-(1-adaπantylmethylaminocarb oryl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The reaction was performed essentially as in exaπple 64 but using the benzyl ester of D-prolylglycine in step a. instead of the dibenzyl ester of aspartic acid. The coπpound was characterised and tested as the N-methyl-D-glucamine salt. Found: C 61.52; H, 7.52; N, 6.81. C^N o- 2.6 H ₂ 0 requires C, 61.65; H, 7.60; N, 6.69%

Example 120 Preparation of cis-7-(2-R-(carboxymethylamino- carboryDpyrrolidinocarboiyl)-8-(1-adamantylmethylaminocarbor yl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane (diastereomer 1)

Ihe benzyl ester intermediate isolated after exaπple 119 step a. was separated into its constituent diastereomers by recrystallisation from ethyl acetate. The mother liquors on concentration gave a benzyl ester which on hydrogenolysis gave the diastereomer of this exaπple. The coπpound was characterised and tested as the N-methyl-D-glucamine salt. Found: C, 65.12; H, 7.40; N, 6.95. C ₄₃ H ₅₈ NAo requires C, 65.30; H, 7.39; N, 7.08%

Exaπple 121 Preparation of cis-7-(2-R-(carboxymethylamino- carboryl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbo nyl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane (diastereomer 2)

The crystalline material from the recrystallisation described in exaπple 120 on hydrogenolysis gave the diastereomer of this exaπple. The cαπpound was characterised and tested as the N- methyl-D-glucamine salt. Found: C, 61.54; H, 7.75; N, 6.34.

C ₄₃ I^ ₈ N ₄ O _I0 . 2.9 H ₂ 0 requires C, 61.29; H, 7.62 ; N, 6.64%

Example 122 Preparation of cis-7- (2-R- (carbσxyethylamino- carbonyl ) pyrrolidinocarbonyl ) -8- ( 1-adamantylmethylaminocarboryl ) - 2,3, 5, 6-dibenzobicyclo [2.2.2] octane (mixture of diastereomers)

The reaction was performed essentially as in exaπple 64 but using the benzyl ester of D-prolyl-beta-alanine in step a. instead of the dibenzyl ester of aspartic acid. The compound was characterised and tested as the N-methyl-D-glucamine salt. Found: C, 63 .14; H, 7.78; N, 6.60. C ₄₄ H ₆₀ NAo- - 9 H ₂ 0 requires C, 63 .02 ; H, 7.66; N, 6.68%

Exaπple 123 Preparation of cis-7-(2-R-(methoxycarborylmethy1- aminocarbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylamino ¬ carbonyl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

Ihe coπpound was prepared essentially as in exaπple 63 but using the cαπpound of exaπple 119 as substrate instead of the coπpound of example 62. Found: C 69.77; H, 7.08; N, 6.58. C ₃₇ H ₄₃ N ₃ 0 ₅ . 1.4 H ₂ 0 requires C, 69.97; H, 7.27; N, 6.62%

Example 124 Preparation of cis-7-(2-R-(methoxycarborylethyl- aminocarbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylamino ¬ carbonyl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The coπpound was prepared essentially as in exaπple 63 but using the cαπpound of exaπple 122 as substrate instead of the coπpound of exaπple 62. Found: C, 71.15; H, 7.40; N, 6.56. C ₃₈ H ₄₅ N ₃ 0 ₅ . H ₂ 0 requires C, 71.13; H, 7.38; N, 6.54%

Exaπple 125 Preparation of cis-7-(l-S-(carboxyethylamino-

carbonyl)ethylaminocarbonyl)-8-(1-adamantylmethylaminocarbor yl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The reaction was performed essentially as in exaπple 64 but using the benzyl ester of L-alanyl-beta-alanine in step a. instead of the dibenzyl ester of aspartic acid. The ccπpound was characterised and tested as the N-methyl-D-glucamine salt. Found: C, 60.56; H, 7.74; N, 6.53. C ₄₂ H _5β N ₄ 0 ₁ o. 3.1 H ₂ 0 requires C, 60.40; H, 7.75; N, 6.71%

Exaπple 126 Preparation of cis-7-(l-S-(methoxycarborylethyl- aminocarbonyl)ethylaminocarbonyl) -8- (1-adamantylmethylamino¬ carbonyl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The coπpound was prepared essentially as in exaπple 63 but using the cαπpound of exaπple 125 as substrate instead of the coπpound of example 62. Found: C, 69.51; H, 7.39; N, 6.49. C ₃₆ H ₄₃ N ₃ 0 ₅ - - ⁴ H ₂ 0 requires C, 69.35; H, 7.41; N, 6.73%

Exaπple 127 Preparation of cis-7-(l-S-(methylaminocarboryl)- ethylaminocarboryl) -8-(1-adamantylmethylaminocarbonyl) -2,3,5,6- dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The coπpovind was prepared essentially as in exaπple 25 but using the trifluoroacetate salt of N-methyl-L-alaninamide instead of L- alanine methyl ester hydrochloride. Found: C, 72.12; H, 7.37; N, 7.50. C ₃₃ H ₃₉ N ₃ 0 ₃ . 1.2 H ₂ 0 requires C, 72.37; H, 7.63; N, 7.67% ^"

Example 128 Preparation of cis-7-(1-S-(methoxycarbonyl)- ethylaπiinocarbonyl) -8-(1-RS-(1-adamantyl) ethylaminocarbonyl) - 2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers A)

a. 8- (1-(1-adamantyl)ethylaminocarbonyl) -2,3,5, 6-dibenzo- bicyclo[2.2.2]octane-7-carboxylic acid (mixture of diastereomers)

This compound was prepared essentially as in example 14 but using l-R≤-(l-adamantyl)ethylamine (prepared as described in EP 178668) as substrate instead of 1-adamantanemethylamine.

b. cis-7-(1-S-(methoxycarbonyl)ethylaminocarbonyl)-8-(1-RS-(1- adamantyl)ethylaminocarbonyl)-2,3,5, 6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers A)

This was prepared essentially as in exaπple 25 but using the product of step a. instead of the product of exaπple 14. The mixture of four coπpounds thus produced was separated into two pairs by use of preparative MPLC (silica 35% ethyl acetate and 65% hexane) . The least polar pair were designated as the product of this exaπple. found: C, 74.26; H, 7.60; N, 4.86. C ₃₄ H ₄₀ N ₂ O ₄ . 0.5 H ₂ 0 requires C, 74.29; H, 7.52; N, 5.10%

Example 129 Preparation of cis-7-(1-S-(πvsthoxycarboryl)- ethylaminocarbonyl) -8-(1-RS-(1-adamantyl) ethylaminocarbonyl) - 2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers B)

The most polar pair of coπpounds isolated after the MPLC procedure described in exaπple 128 were designated mixture B, the compounds of this exaπple. Found: C, 74.01; H, 7.69; N, 4.90. C ₃₄ H ₄₀ N ₂ O ₄ . 0.5 H ₂ 0 requires C, 74.29; H, 7.52; N, 5.10%

Example 130 Preparation of cis-7-(1-S-(ethylcarboryl)- ethylaminocarbonyl) -8-(1-adamantylmethylaminocarbonyl) -2,3,5,6- dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The coπpound of example 75 (0.37 g, 0.74 πmol) was dissolved in THF under an atmosphere of argon and cooled to 0°. A 1M solution of ethyl magnesium bromide in THF (3 ml) was added and the solution stirred for a further 2h before being allowed to warm to room temperature for overnight stirring. The reaction was quenched with 2M hydrochloric acid and after evaporation the the product was dissolved in ethyl acetate and washed succesiveiy with saturated

aqueous sodium hydrogencarbonate and with brine. Ihe organic layer was dried, filtered and evaporated to leave the crude product which was purified by column chromatography (silica 90% dichloromethane and 10% ethyl acetate). Yield 0.19 g, 50%, m.p 105-8°. Found: C, 77.87; H, 7.61; N, 5.22. CsAol^Qs requires C, 77.83; H, 7.68; N, 5.34%

Exaπple 131 Preparation of (±)-7-(methαxycarbonylmethyl)-cis-7- carboxy-8- (1-adamantylmethylaminocarbonyl) -2,3,5, 6-dibenzo- bicyclo[2.2.2]octane

a. Diels-Alder adduct of the methyl ester of aconitic anhydride and anthracene

Ihe methyl ester of aconitic anhydride (10.2 g, 60 i ol) was dissolved in dry dichlorόmenthane (200 ml) and anthracene (7.12 g, 40 mmol) was added followed by anhydrous aluminium chloride (9.0 g, 60 mmol) . The solution was stirred at room teπperature overnight and then poured onto a mixture of ice and hydrochloric acid. The organic layer was separated and dried, filtered and evaporated to leave an orange oil which was recrystallised from toluene after treatment with activated charcoal. The product, a buff .solid, ^' as dried in air (9.01 g) and used in the next step.

b. (±) -7- (methoxycarbonylmethyl) -cis-7-carboxy-8- (1- adamantylmethylaminocarboryl)-2,3,5,6-dibenzobicyclo[2.2.2]o ctane

The material was prepared essentially as in exaπple 14 but using the material prepared in step a. above instead of (±)-2,3,5,6- dibenzobicyclo[2.2.2]octane-7,8-dicarboxylic anhydride. The cαπpound was characterised and tested as the N-methyl-D-glucamine salt found: C, 65.72; H, 7.61; N, 3.83. C ₃₉ H ₅₂ NAo requires C, 66.08; H, 7.39; N, 3.95%

Exaπple 132 Preparation of cis-7-(1-S-(methoxycarbonyl)- ethylaminocarbonyl)-8-(2-adamantylmethylaminocarbonyl)-2,3,5 ,6-

dibenzobicyclo [2.2.2] octane (mixture of diastereomers)

Ihe compound was prepared essentially as in exaπple 25 but using the cαπpound of exaπple 39 instead of 8- (l-adamantylmethyl- aminocarbonyl ) -2 , 3 , 5 , 6-dibenzobicyclo [2.2.2 ] octane-7 -carboxylic acid as substrate, m.p. 105-110° . Found: C, 74.13 ; H, 7.17; N, 4.85. C ₃₃ H ₃₈ N ₂ 0 ₄ .0.5 H ₂ 0 requires C. 73.99; H, 7.33 ; N, 5.23%

Exaπple 133 Preparation of cis-7- (2-R-carboxypyrrolidinocarboryl) - 8- (2-adamantylmethylaminocarbonyl) -2 , 3 , 5 , 6-dibenzobicyclo- [2.2.2] octane (mixture of diastereomers)

The benzyl ester of the coπpound was prepared essentially as in exaπple 46 but using the coπpovind of exaπple 39 instead of 8- (l- adamantylmethylaminocarboryl ) -2 , 3 , 5 , 6-dibenzobicyclo [2.2.2] octane- 7-carboxylic acid as substrate. The hydrogenolysis was performed as described in exaπple 48. m.p. 105-110° . The coπpound was further characterised and tested as its N-methyl-D-glucamine salt found: C, 64.86; H, 7 .79 ; N, 5.19. C ₄₁ H ₅₅ NA C.6 H ₂ 0 requires C, 64.56; H, 7.69; N, 5.51%

Exaπple 134 Preparation of 8-(l-adamantylmethylaminocarboryl) - 2, 3 , 5, 6-dibenzobicyclo [2.2.2] oct-7-ene-7-carboxylic acid

a. dimethyl-2 , 3 , 5 , 6, -dibenzobicyclo [2 .2 .2 . ] oct-7-ene-7 , 8- dicarbosylate

The Diels-Alder reaction between anthracene (lOg, 0.06 mol) and dimethyl acetylenedicarboxylate (8.3 ml, 0.07 mol) was performed essentially as in step a. of exaπple 1 with the exeption that the reactants were refluxed for 24 hours .

b. 2 , 3 , 5, 6, -dibenzobicyclo [2.2 .2. ] oct-7-ene-7 , 8-dicarboxylic acid

To a solution of potassium hydroxide (1.05 g, 18.8 mmol) in water (30 ml) was added the solution of the product of step a. (2.0 g,

6.2 mmol) -in dioxan (10 ml). The reaction mixture was heated to reflux for 20 mins, cooled to room teπperature and diluted with 2N hydrochloric acid. The precipitated solidwas filtered, washedwith water and dried (1.42 g, 78%) .

c.2,3,5,6,-dibenzobicyclo[2.2.2.]oct-7-ene-7,8-dicarboxyl ic acid anhydride

A mixture of the product of step b (1.4 g, 4.8 mmol and acetic anhydride (36 ml) was heated at reflux for 45 mins. The solvent was evaporated and the residue was triturated with diethyl ether to afford white solid (0.73 g, 55%).

d. 8- (1-adamantylmethylaminocarbonyl) -2, 3 , 5, 6-dibenzo- bicyclo[2.2.2]oct-7-ene-7-carboxylic acid

This was performed essentially as in exaπple 14 using the product of step c above as substrate instead of 2,3,5,6-dibenzo- bicyclo[2.2.2]oct-7,8-dicarboxylic anhydride. The compound was characterised and tested as the N-methyl-D-glucamine salt. Found: C, 67.79; H, 7.51; N, 4.33. C ₃₆ H ₄₆ N ₂ Q ₈ requires C, 68.12; H, 7.30; N, 4.41%

Example 135 Preparation of cis-7-(1-S-methoxycarbonyl-ethylamino- carbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5, 6-dibenzo- bicyclo[2.2.2]oct-7-ene

This was performed essentially as in exaπple 25 using the product of exaπple 134 as substrate instead of (±)-cis-8-(1- adamantylmethylaminocarboryl)-2,3,5,6-dibenzobicyclo[2.2.2]o ct-7- carboxylic acid found: C, 75.45; H, 6.79; N, 5.26. C ₃₃ H ₃₆ N ₂ 0 ₄ requires C, 75.55; H, 6.92; N, 5.34%

Example 136 Preparation of cis-7-(2-R-(carbojymethylamino- carboryl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbo ryl)- 2,3,5,6-dibenzobicyclo[2.2.2]oct-7-ene

This was performed essentially as in exaπple 119 using the product of exaπple 134 as substrate instead of 8- (l-adamantylmethylamino- carboryl ) -2 , 3 , 5 , -dibenzobicyclo [2 .2.2] oct -7 -carboxylic acid . Ihe compound was tested as the N-methyl-D-glucamine salt.

Exaπple 137 Preparation of cis-7- (2-R-carboxy-pyrrolidinocarboryl) - 8- (1-adamantylmethylaminocarboryl) -1, 4-dif luoro-2 , 3 , 5, 6-dibenzo- bicyclo[2.2.2]octane (mixture of diastereomers)

a. Diels alder reaction

This was performed essentially as in step a. of exaπple 1 using 9,10-difluoroanthracene (prepared as in J.Org.Chem., 1989, 54, 1018) as substrate instead of anthracene.

b. (±)-cis-8-(l-adaπantylmethylaminocarboryl)-1,4-difluoro-2, 3,5,6- dibenzobicyclo[2.2.2]octane-7-carboxylic acid

This was performed essentially as in exaπple 14 using the product of step a. above as substrate instead of 2,3,5,6-dibenzo- bicyclo[2.2.2]oct-7,8-dicarboxylic anhydride

c. cis-7-(2-R-benzyloxycarbonylpyrrolidinocarbonyl) -8- (1- adamantylmethylaminocarbonyl) -1,4-difluoro-2,3,5, 6-dibenzo- bicyclo[2.2.2]octane (mixture of diastereomers)

This was performed essentially as in example 46 using the product of step b above as substrate instead of (±)-cis-8-(1- adamantylmethylaminocarboryl) -2 ,3,5,6-dibenzobicyclo[2.2.2]oct-7- carboxylic acid

d. cis-7-(2-R-carboxy-pyrrolidinocarbonyl)-8-(1-adamantylmethyl ¬ aminocarbonyl)-1,4-difluoro-2,3,5,6-dibenzobicyclo[2.2.2]oct ane (mixture of diastereomers)

This was performed essentially as in exaitple 48 using the product of step c above as substrate instead of the product of exaπple 46.

Ihe coπpound was characterised and tested as the N-methyl-D- glucamine salt. Found: C, 57.48; H, 7.43; N, 5.28. C^H^NA- 4.5H ₂ 0 requires C, 57.82; H, 7.35; N, 4.93%

Example 138 Preparation of cis-7- (2-R-carboxy-4-R-hydrojy- pyrrolidinocarbonyl) -8- (2-adaπantylaminocarboπyl) -2,3,5, 6-dibenzo- biyclo[2.2.2]octane (mixture of diastereomers)

a. (±) -cis-8- (2-adamantylaminocarbonyl) -2,3,5, 6-dibenzo- bicyclo [2.2.2 ]octane-7 -carboxylic acid

This was prepared essentially as in exaπple 11 using 2-adamantamine as substrate instead of 1-adamantamine .

b. cis-7-(2-R-benzylQxycarboιyl-4-R-hydrojy-pyrrolidinocarbory i)-8- ' (2-adamantylaminocarbonyl ) -2 , 3 , 5 , 6 -dibenzobicyclo [2.2.2] octane (mixture of diastereomers)

This was performed essentially as in exaπple 46 using the product of step a. above as substrate instead of cis-8- (1-adamanty lmethyl- aminocarboryl) -2,3,5, 6 -dibenzobicyclo [2.2.2] oct -7 -carboxylic acid ^'

c. 7- ( 2 -R-carboxy-4-R-hydroxy -pyrrolidinocarbonyl) -8- (2- adamantylaminocarbonyl) -2,3,5, 6 -dibenzobicyclo [2.2.2] octane (mixture of diastereomers)

This was performed essentially as in exaπple 48 using the product of step b above as substrate instead of the product of exaπple 46. Ihe coπpound was characterised and tested as the N-methyl-D- glucamine salt. Found: C, 60.86; H, 7.40; N, 5.31. C ₄₀ H ₅₃ NA ₀ . 2.9H ₂ 0 requires C, 60.97; H, 7.52; N, 5.33%

Exaπple 139 Preparation of cis-7- (2-S-carboxypiperidinocarboryl)-8- ( 1- adamantylmethylaminocarbonyl ) -2 , 3 , 5 , 6-dibenzo- bicyclo[2.2.2]octane (mixture of diastereomers)

The reaction was performed essentially as in exaπple 64 but using

the benzyl ester of L-pipecolinic acid in step a. instead of the dibenzyl ester of aspartic acid. Ihe cαπpound was further characterised and tested as the N-methyl-D-glucamine salt . Found: C, 64.39 ; H, 7.97 ; N, 5.28. C ₄₂ Hs ₇ NA . 2 .0H ₂ O requires C, 64.35; H, 7.84; N, 5.36%

Example 140 Preparation of cis-7- (4-carbαxypiperidinocarboryl) -8- ( 1 -adamantylmethylaminocarbonyl ) - 2 , 3 , 5 , 6 -dibenzo - bicyclo [2.2.2] octane (mixture of diastereomers)

The reaction was performed essentially as in exaπple 64 but using the benzyl ester of 4-carboxypiperidine in step a. instead of the dibenzyl ester of aspartic acid. The coπpound was further characterised and tested as the N-methyl-D-glucamine salt. Found: C, 64.29; H, 8.05; N, 5.14. C ₄ H ₅₇ N ₃ 0 _o . 2. OHO requires C, 64.35; H, 7.84; N, 5.36%

Exaπple 141 Preparation of cis-7- (2-S- (carboxymethyl) - pyrrolidinocarbonyl) -8- (1-adamantylmethylaminocarboryl) -2 , 3, 5, 6- dibenzobicyclo [2.2.2] octane (mixture of diastereomers)

Ihe reaction was performed essentially as in exaπple 64 but using the benzyl ester of 2-S-carboxymethylpyrrolidine (prepared as in WO 92/00295) in step a . instead of the dibenzyl ester of aspartic acid, [α] ^D = -22.0° (c= 1.0 in methanol) . The coπpound was further characterised and tested as the N-methyl-D-glucamine salt . Found: C, 61.76; H, 7.89 ; N, 5.31. C ₄₂ Hs ₇ - 3.7H _; 0 requires C, 61.91; H, 7.97; N, 5.16%

Example 142 Preparation of cis-7- (2-R- (carboxymethyl) - pyrrolidinocarbonyl ) -8- (1 -adamantylmethylaminocarbonyl) -2 , 3 , 5, 6- dibenzobicyclo [2.2.2] octane (mixture of diastereomers)

The reaction was performed essentially as in exaπple 64 but using the benzyl ester of 2 -R-carboxymethylpyrrolidine (prepared as in

WD 92/00295) in step a. instead of the dibenzyl ester of aspartic acid, [α] ^D = +18.0° (c= 1.0 in methanol) . The cαnpound was further characterised and tested as the N-metbyl-D-glucamine salt. Found: C 59.01; H, 8.12; N, 5.49. C^H^NA- 5.9H ₂ 0 requires C, 59.07; H, 8.12; N, 4.92%

Exaπple 143 Preparation of cis-7-(2-S-(methoxycarboryl- methyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbony l)- 2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The coπpovind was prepared essentially as in exaπple 63 using the product of exaπple 141 as substrate instead of cis-7-(1-S-carboxyl- 2-methylpropylaminocarbonyl)-8-(1-adamantylmeth laminocarboryl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane, [α] ^D = -21.0° (c=2.0 inCHC13) . Found: C, 75.80; H, 7.49; N, 4.62. C _3b H ₄₂ N ₂ 0 ₄ . 0.3 H ₂ 0 requires C, 75.62; H, 7.50; N, 4.90%

Exaπple 144 Preparation of cis-7-(2-R-(methoxycarbonyl- methyl) yrrolidinocarbonyl) -8- (1-adamantylmethylaminocarbonyl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The cαπpound was prepared essentially as in exaπple 63 using the product of exaπple 142 as substrate instead of cis-7-(1-S-carboxy1- 2-methylpropylaminocarbonyl)-8-(1-adamantylmethylaminocarbor yl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane, [α] ^p = +18.0° (c=2.0 in CHC1 ₃ ) . Found: C, 76.48; H, 7.46; N, 5.05. C ₃₆ H ₄₂ N ₂ 0 ₄ requires C, 76.30; H, 7.47; N, 4.94%

Example 145 .Preparation of cis-7- (2R- (lS-carboxyethylamino- carboryl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbo ryl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane (diastereomer 1)

The compound was prepared essentially as in exaπple 64 but using the benzyl ester of D-prolyl-L-alanine in step a. instead of the dibenzyl ester of aspartic acid. The diastereomers were separated

at the benzyl ester stage by column chromatography (silica 60% dichloromethane and 40% ethyl acetate) . The cαπpound with the higher _f was converted to the title coπpovind by hydrogenation. The cαπpound was tested as the N-methyl-D-glucamine salt.

Exaπple 146 Preparation of cis-7-(2R-(lS-carbαxyethylamino- carbonylmetbyl) yrrolidinocarbonyl) -8-(1-adamantylmethylamino¬ carboryl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (diastereomer 2)

The coπpound was prepared essentially as in exaπple 145 but using the compound with lower R _f after diastereomer separation in the final hydrogenation step. The compound was tested as the N-rnethyl- D-glucamine salt..

Exaπple 147 Preparation of cis-7-(2R-(IR-carboxyethylamino- carboryl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbo ryl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane .(diastereomer 1)

The coπpound was prepared essentially as in exaπple 64 but using the benzyl ester of D-prolyl-D-alanine in step a. instead of the dibenzyl ester of aspartic acid. Ihe diastereomers were separated at the benzyl ester stage by column chromatography (silica 60% dichloromethane and 40% ethyl acetate) . The coπpovind with the higher R _f was converted to the title cαπpound by hydrogenation. The compound was further characterised and tested as the N-methyl- D-glucamine salt. Found: C 59.62; H, 8.06; N, 6.23. 4.7H ₂ 0 requires C, 59.45; H, 7.86; N, 6.30%

Exaπple 148 -Preparation of cis-7-(2R-(lR-carboxyethylamino- carboryl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbo ryl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane (diastereomer 2) The coπpovind was prepared essentially as in exarple 147 but using the compound with lower R _f after diastereomer separation in the final hydrogenation step. The coπpound was tested as the N-methyl- D-glucamine salt.

Exaπple 149 Preparation of cis-7-(2R-carboxy-4-S-bydroxy- pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarboryl)-2,3, 5,6- dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The cαπpound was prepared essentially as in exaπple 64 but using the benzyl ester of trans hydrαxy-D-proline in step a. instead of the dibenzyl ester of aspartic acid. The compound was further characterised and tested as the N-methyl-D-glucamine salt. Found: C, 65.63; H, 7.48; N, 5.38. C ₄₁ H ₅₅ N ₃ O ₁₀ requires C, 65.67; H, 7.39; N, 5.38%

Example 150 Preparation of cis-7-(3-carboxy-pyrrolidinocarbonyl)- 8- (1-adamantylmethylaminocarbonyl ) -2 , 3 , 5 , 6-dibenzo¬ bicyclo[2.2.2]octane (mixture of diastereomers)

The compound was prepared essentially as in exaπple 64 but using the benzyl ester of 3-carboxypyrrolidine (prepared as in WD 92/00295) in step a. instead of the dibenzyl ester of aspartic acid. The cαπpound was further characterised and-tested as the N- methyl-D-glucamine salt.. ^' Found: C, 65.33; H, 7.67; N, 5.48. C ₄₁ H ₅₅ N ₃ 0 ₉ . 1.4 H ₂ 0 requires C, 65.27; H, 7.65; N, 5.57%

Example 151 Preparation of cis-7-(3-methoxycarbonyl- pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarboryl)-2,3, 5,6- dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The cαπpound was prepared essentially as in exaπple 63 using the product of exaπple 150 as substrate instead of cis-7-(1-S-carboxyl- 2-methylpropylaminocarbonyl)-8-(1-adamantylmethylaminocarbon yl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane. Found: C, 75.83; H, 7.41; N, 5.08. C ₃₅ H ₄₀ N ₂ O ₄ requires C 76.06; H, 7.29; N, 5.07%

Exaπple 152 Preparation of cis-7- (3- (+) -ethoxycarbonyl - piperidinocarboryl) -8- (1-adamantylmethylaminocarbonyl) -2 , 3 , 5 , 6-

dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The cαπpound was prepared essentially as in exarrple 64 but using (+)ethyl nipecotate (prepared as described in J. Neuroche ., 1976, 2_ , 1029) in step a. instead of the dibenzyl ester of aspartic acid to give the title cαrpound directly without the need for subsequent deprotection. Found: C, 76.69; H, 7.64; N, 4.81. C^H^ requires C, 76.52; H, 7.63; N, 4.82%

Example 153 Preparation of cis-7-(3-(-)-ethoxycarboryl- piperidinocarboryl)-8-(1-adamantylmethylaminocarbonyl) -2,3,5,6- dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The cαπpound was prepared essentially as in exaπple 64 but using (-)ethyl nipecotate in step a. instead of the dibenzyl ester of aspartic acid to give the title cαπpound directly without the need for subsequent deprotection. Found: C, 76.29; H, 7.61; N, 4.68. C ₃₇ H ₄ _,N ₂ 0 ₄ requires C, 76.52; H, 7.63; N, 4.82%

Exaπple 154 Preparation of cis-7-(3-(+)-methoxycarbonyl- piperidinocarboryl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5 ,6- dibenzobicyclo[2.2.2]octane (diastereomer 1)

a. cis-7-(3-(+)-carboxy-piperidinocarboryl)-8-(1-adamantylmethy l¬ aminocarboryl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (separated diastereomers)

The cαπpound was prepared essentially as in exaπple 64 but using (+)benzyl nipecotate (prepared by standard means from (+) ethyl nipecotate) in step a. instead of the dibenzyl ester of aspartic acid to give the carboxylic acid as a mixture of diastereomers. The two diastereomers were separated by chromatography (silica 90% dichloromethane and 10% ethyl acetate) .

b. cis-7-(3-(+) -methoxycarbonyl-piperidinocarbonyl)-8-(l- adamantylmethylaminocarboryl)-2,3,5,6-dibenzobicyclo[2.2.2]o ctane

diastereomer 1

The compound was prepared essentially as in exaπple 63 using the less polar (higher R _f material) isolated in step a. above as substrate instead of cis-7-(l-S-carboxyl-2-methylpropylamino- carbonyl) -8-(1-adamantylmethylaminocarbonyl) -2,3,5, 6-dibenzo¬ bicyclo[2.2.2]octane.

Exaπple 155 Preparation of cis-7-(3-(+)-methoxycarbonyl- piperidinocarboryl) -8-(1-adamantylmethylaminocarbonyl) -2,3,5,6- dibenzobicyclo[2.2.2]octane (diastereomer 2)

Ihe coπpound was prepared essentially as in exaπple 63 using the more polar (lower R _f material) isolated in step a. of exaπple 154 as substrate instead of cis-7-(1-S-carboxyl-2-methylpropylamino¬ carbonyl) -8-(1-adamantylmethylaminocarbonyl) -2,3, 5, 6-dibenzo- bicyclo[2.2.2]octane.

Exaπple 156 Preparation of cis-7-(3-(-)-methoxycarbonyl- piperidinocarboryl) -8-(1-adamantylmethylaminocarbonyl) -2,3,5,6- dibenzobicyclo[2.2.2]octane (diastereomer 1)

The compound was prepared essentially as in exaπple 154 but _. using (-) benzyl nipecotate as substrate in step a. rather than (+) benzyl nipecotate. As. in that exaπple the less polar material was converted to the title coπpovind in step b.

Example 157 Preparation of ^' cis-7- (3- (-) -methoxycarbonyl - piperidinocarboryl) -8- (1 -adamantylmethylaminocarbonyl) -2 , 3 , 5 , 6- dibenzobicyclo [2.2.2] octane (diastereomer 2 )

The coπpound was prepared essentially as in exaπple 63 using the more polar (lower R _f material) isolated in step a . of exaπple 156 as substrate instead of cis-7- (l-S-carboxyl-2-metbylpropylamino- carbonyl) -8- ( 1 -adamantylmethylaminocarbonyl ) -2 , 3 , 5 , 6-dibenzo-

bicyclo[2.2.2]octane.

Example 158 Preparation of cis-7-(2R-(lmethyl-l-carboxy- cyclcprc_pylaπ nocarhoryl) rrol -8-(1-adamantylmethyl- aminocarboryl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (diastereomer 1)

Ihe cαπpound was prepared essentially as in exaπple 64 but using the benzyl ester of D-prolyl-cyclopropylalanine (prepared by standard means) in step a. instead of the dibenzyl ester of aspartic acid. The diastereomers were separated at thebenzyl ester stage by column chromatography (silica 60% dichloromethane and 40% ethyl acetate) . The cαπpound with the higher R _f was converted to the title coπpound by hydrogenation, [α] ^D = +10.0° (c= 1.0 in methanol) . The compound was further characterised and tested as the N-methyl-D-glucamine salt. Found: C, 58.54; H, 7.44; N, 6.03. CisHβoN o 5.6H ₂ 0 requires C 58.92; H, 7.81; N, 6.11%

Exaπple 159 Preparation of cis-7-(2R-(lmethyl-1-carboxy- cyclcρropylaminocarboτyl)Fy_rrolidinocarboryl)-8-(1-adaman tylmethyl¬ aminocarboryl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (diastereomer ^■ 2)

The coπpovind was prepared essentially as in exaπple 158 but using the compound with lower R _f after diastereomer separation in the final hydrogenation step. Ihe coπpound was tested as the N-methyl- D-glucamine salt.

Example 160 Preparation of cis-7-(2-R-carboxypyrrolidinocarboryl)- 8-(1-adamantylmethylaminocarboryl)-2,3-(2-fluorobenzo)-5,6-b enzo- bicyclo[2.2.2]octane (mixture of isomers 1)

a. 2,3-(2-fluorobenzo) -5,6-benzobicyclo[2.2.2]octane-7,8- dicarboxylic anhydride

This was performed essentially as described in exaπple 1 step a. except that 2-fluoroanthracene was used as reactant instead of anthracene.

b. 8-(1-adamantylmethylaminocarboryl)-2,3-(2-fluorobenzo) -5,6- benzobicyclo[2.2.2]octane-7-carboxylic acid.

The reaction was performed essentially as described in exaπple 14 but using the cαπpound described in step a. above rather than 2,3,5,6-dibenzobicyclo[2.2.2]octane-7,8-dicarboxylic anhydride.

c. cis-7- (2-R-benzyloxycarbonylpyrrolidinocarbonyl) -8- (1- adamantylmethylaminocarbonyl) -2,3- (2-fluorobenzo) -5, 6-benzo- bicyclo[2.2.2]octane.

The reaction was performed essentially as in exaπple 46 but using the compound prepared in step b above, rather than (±)cis-8-(1- adanantylmethylaminocarboryl)-2,3,5,6-dibenzobicyclo[2.2.2]o ctane- 7-carboxylic acid.

d. cis-7-(2-R-carboxypyrrolidinocarbonyl) -8-(1-adamantylmethyl¬ aminocarboryl)-2,3-(2-fluorobenzo) -5, 6-benzobicyclo[2.2.2]octane (mixture of isomers 1)

The reaction was performed essentially as in exaπple 48 but using the compound prepared in step c above, rather than cis-7-(2-R- benzyloxycarboπylpyrrolidinocarbonyl) -8-(1-adamantylmethylamino¬ carbonyl)-2,3,5, 6-dibenzobicyclo[2.2.2]octane. The material which by this stage was a mixture of eight coπpounds was separated by HPLC (C8 column 60% acetonitrile, 40% water and 0.1% acetic acid) into three components. The material with a retention time of 15 min was designated the compound of this exaπple. Ihe cαπpound was further characterised and tested as the N-methyl-D-glucamine salt found: C, 65.22; H, 7.38; N, 5.42. C ₄₁ Hc ₄ FN ₃ 0, requires C, 65.49; H, 7.24; N, 5.59%

Example 161 Preparation of cis-7- (2-R-carboxypyrrolidinocarboryl) -

8-(1-adamantylmethylaminocarboπyl)-2,3-(2-fluorobenzo)-5,6- benzo- bic clot2.2.2]octane (mixture of isα ers 2)

Ihe mixture from exaπple 160 step dwith a retention time of 16 min was designated the cαπpound of this exaπple. The cαπpound was further characterised and tested as the N-methyl-D-glucamine salt found: C, 64.99; H, 7.29; N, 5.59. C ₄₁ Hs ₄ FNA requires C, 65.49; H, 7.24; N, 5.59%

Example 162 Preparation of cis-7-(2-R-carboxypyrrolidinocarboryl)- _. 8-(1-adamantylmethylaminocarboryl)-2,3-(2-fluorobenzo)-5,6-b enzo- bicyclo[2.2.2]octane (mixture of isomers 3)

The mixture from exaπple 160 step d with a retention time of 22 min was designated the compound of this exaπple. The cαπpound was further characterised and tested as the N-methyl-D-glucamine salt found: C, 65.29; H, 7.42; N, 5.65. C ₄₁ H ₅₄ FNA requires C, 65.49; H, 7.24; N, 5.59%

Exaπple 163 Preparation of cis-7-(2R-(1-carboxy-l-methyl- ethylaminocarboryl)pyrrolidinocarbonyl)-8-(1-adamantylπethy lamino- carboryl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (diastereomer 1)

The compound was prepared essentially as in exaπple 64 but using the benzyl ester of D-prolyl-alpha-aminobutyric acid in step a. instead of the dibenzyl ester of aspartic acid. The diastereomers were separated at the benzyl ester stage by recrystallisation from ethyl acetate and column chromatography (silica 50% hexane and 50% ethyl acetate) . The compound with the lower R _f was converted to the title compound by hydrogenation. Ihe coπpound was further characterised and tested as the N-methyl-D-glucamine salt. Found: C, 65.91; H, 7.65; N, 6.60. C ₄₅ H _b: N ₄ 0 _lc requires C, 65.99; H, 7.63; N, 6.84%

Exaπple 164 Preparation of cis-7-(2R-(l-carboxy-l-methyl-

ethylaminocarboryl)pyrrolidinocarbonyl)-8-(l-adaπentylmethy lamino- carboryl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (diastereomer 2)

The compound was prepared essentially as in exaπple 147 but using the cαπpound with higher R _f after diastereomer separation in the final hydrogenation step. The cαπpound was tested as the N-methyl- D-glucamine salt.

Exaπple 165 Preparation of cis-7-(2-R-carboxypyrrolidinocarboryl)- 8- (1-adamantylmethylaminocarbonyl) -8-fluoro-2,3,5, 6-dibenzo- bicyclo[2.2.2]octane (mixture of diastereomers)

The compound was prepared essentially as described in exaπple 160 but performing the reaction in step a. with anthracene and 2- fluorα aleic anhydride (prepared as in J.Am.Chem.Soc. , 1959, ,81, 2678) instead of the reagents stated. No attempt was made at separation of the diastereomers at any stage. The compound "was further characterised and tested as the N-methyl-D-glucamine salt found: C, 65.59; H, 7.18; N, 5.61. C ₄₁ H _M FN ₃ 0 ₉ requires C, 65.49; H, 7.24; N, 5.59%

Example 166 Preparation of cis-7-(-N-(carboxymethyl)-N- (methoxycarborylmethyl)aminocarbonyl) -8-(1-adamantylmethylamino¬ carbonyl)-2,3,5,6-dibenzobicyclo[2.2.2]octane

The reaction was performed essentially as in exaπple 25 but using methyl N-(carboxymethyl)glycine (prepared as in Tetrahedron, 1984, j40, 1151) as substrate instead of L-alanine methyl ester. The compound was further characterised and tested as the N-methyl-D- glucamine salt found: C, 64.21; H, 7.25; N, 5.22. C ₄₁ H ₅ N ₃ O _n requires C, 64.30; H, 7.24; N, 5.49%

Exaπple 167 Preparation of cis-7- ( -N- (4- (2 -oxo-N- (carboxy¬ methyl ) pyrrol idine) ) aminocarbonyl ) -8- ( 1 -adamantylmethylamino¬ carbonyl) -2 , 3 , 5, 6-dibenzobicyclo [ 2.2.2 ] octane (diastereomers 1 and

2)

The reaction was performed essentially as in exaπple 64 but using the benzyl ester of N-carboxymethyl-2-oxo-4-aminopyrrolidine (prepared as in Peptide Research 1991, .4, 171) in step a. instead of the dibenzyl ester of aspartic acid. The cαπpound was separated at the end of step a. into two pairs of diastereoisαmers by column chromatography the higher R _f coπponents being hydrogenated at step b to give the title coπpounds of this exaπple. The cαπpound was further characterised and tested as the N-methyl-D-glucamine salt. Found: C, 57.23; H, 7.41; N, 6.13. C ₄₂ H ₅₆ NAo 5.5H ₂ 0 requires C, 57.54; H, 7.71; N, 6.39%

Example 168 Preparation of cis-7-(-N-(4-(2-oxo-N-(carboxy¬ methyl)pyrrolidine) )aminocarbonyl) -8- (1-adamantylmethylamino¬ carboryl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (diastereomers 3 and 4)

The reaction was performed essentially as in exaπple 167 except that the lower R _f components were used in the hydrogenation step b. The cαπpound was further characterised and tested as the N- metbyl-D-glucamine salt. Found: C, 56.07; H, 7.39; N, 6.56. C ₄₂ H ₅₆ N ₄ O ₁₀ 6.5H ₂ 0 requires C, 56.46; H, 7.78; N, 6.27%

Exaπple 169 Preparation of cis-7- (-N- (4- (2-oxo-N- (methoxy- carborylmethyl) pyrrolidine) ) aminocarbonyl) -8- (1 -adamantylmethyl¬ aminocarbonyl) -2 , 3 , 5, 6-dibenzobicyclo [2 .2 .2] octane (diastereomers 1 and 2)

The cσirpound was prepared essentially as in exanple 63 using the coπpound of exanple 167 as substrate instead of cis-7- (1-S- carboxyl-2-metbylpropylaminocarbonyl) -8- (l-adamantylmethylamino- carboryl) -2 , 3 , 5, 6-dibenzobicyclo [2 .2 .2] octane. Found: C, 66.83 ; H, 7.21; N, 6.15. C ₃₆ H ₄₁ N ₃ 0 ₅ - 1.7CH ₃ OH and 0 .4 CH ₂ C1 ₂ requires C, 66.89 ; H, 7.21; N, 6.15%

Example 170 Preparation of cis-7-(-N-(4-(2-oxo-N-(methoxy- carbonylmethyl) yrrolidine) )aminocarbonyl)-8-(1-adamantylmetbyl- aminocarboryl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (diastereomers 3 and 4)

The cαπpound was prepared essentially as in exaπple 63 using the compound of exaπple 168 as substrate instead of cis-7-(1-S- carboxyl-2-me hylpropylaminocarboιyl) -8-(1-adamantylmethylamino¬ carboryl)-2,3,5,6-dibenzobicyclo[2.2.2]octane. Found: C, 64.05; H, 6.71; N, 5.82. C ₃₆ H ₄₁ NA- 1.0CH ₃ OH and 1.0 CH ₂ C1 ₂ requires C, 64.04; H, 6.65; N, 5.90%

Exaπple 171 Preparation of cis-7-(IS-(carbojymethylaminocarboryl) - 2-pherylethylaminocarbonyl) -8-(1-adamantylmethylaminocarbonyl) - 2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The reaction was performed essentially as in exaπple 64 but using the benzyl ester of L-phenylalanylglycine in step a. instead of the dibenzyl ester of aspartic acid. The cαπpound was further characterised and tested as the N-methyl-D-glucamine salt. Found: C, 64.11; H, 7.62; N, 6.35. C ₄₇ H _< ,o Ao. 2.3H _; 0 requires C, 63.95; H, ^■ 7.38; N, 6.35%

Example 172 Preparation of cis-7- (is- (lR-carboxyethylamino- carboryl) -2 -phery lethylaminocarbonyl) -8- ( 1 -adamantylmethylamino¬ carbonyl) -2 ,3 , 5, 6-dibenzobicyclo [2 .2.2] octane (mixture of diastereomers)

The reaction was performed essentially as in exaπple 64 but using the benzyl ester of L-phenylalanyl -D-alanine in step a. instead of the dibenzyl ester of aspartic acid. The coπpound was tested as the mono-N-methyl-D-glucamine salt .

Exaπple 173 Preparation of cis-7- (IR- (carboxymetbylaminocarboryl) - 2 -pheny lethylaminocarbonyl) -8- (1 -adamantylmethylaminocarbonyl) -

2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

Ihe reaction was performed essentially as in exaπple 64 but using the ben^l ester of D-pherylalanylglycine in step a. instead of the dibenzyl ester of aspartic acid. Ihe compound was further characterised and tested as the mono-N-methyl-D-glucamine salt. Found: C, 62.18; H, 7.48; N, 5.74. C ₄₇ H ₆₀ N^O ₁₀ . 4.0H ₂ O requires C, 61.86; H, 7.51; N, 6.14%

Exa ole 174 Preparation of cis-7-(IS-(carboxymethylaminocarboryl)- 2-(3-indolyl)pherylethylaminocarboryl)-8-(1-adamantylmethyla mino- carbonyl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The reaction was performed essentially as in exaπple 64 but using the benzyl ester of L-tryptopharylglycine in step a. instead of the diben∑yl ester of aspartic acid. Ihe compound was further characterised and tested as the rrono-N-methyl-D-glucamine salt. Found: C, 58.88; H, 7.07; N, 6.62. 3.2H ₂ 0 and 1.0 CH ₂ C1 ₂ requires C, 58.73; H, 6.84; N, 6.85%

Example 175 Preparation of cis-7-(2R-(l-S-carboxy-2-carboxy- ethylamdiocarbαryl)pyrrolidinocarbonyl)-8-(1-adaπantylmeth ylamino- carboryl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (diastereomer 1)

Ihe compound was prepared essentially as in exaπple 64 but using the dibenzyl ester of D-prolyl-L-aspartic acid in step a. instead of the dibenzyl ester of aspartic acid. Ihe diastereomers were separated at the benzyl ester stage by column chromatography

(silica 60% dichloromethane and 40% ethyl acetate) . The compound with the higher R _f was converted to. the title coπpound by hydrogenation. Found: C, 64.46; H, 6.97; N, 5.30. C ₃₈ H ₄₃ NA- 3.0 H ₂ 0 requires C, 64.48; H, 6.97; N, 5.63% ^l E NMR

Exaπ ^p le 176 Preparation of cis-7-(2R-(l-S-carboxy-2-

carboxyethylaminocarbonyl ) pyrrolidinocarbonyl) -8- (1- adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo[2.2.2]o ctane (diastereomer 2)

The compound was prepared essentially as in exanple 175 but using the cαπpound with lower R _f after diastereomer separation in the final hydrogenation step. Found: C, 69.21; H, 6.73; N, 5.93. 0.5 H ₂ 0 requires C, 68.86; H, 6.69; N, 6.34%

Exaπple 177 Preparation of (±)-cis-8-(6-undecylaminocarboryl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane-7-carboxylic acid

The compound was prepared essentially as in exaπple 14 but using 6-undecylamine as substrate instead of 1-adamantylmethylamine. The compound was further characterised and tested as the N-methyl-D- glucamine salt. Found: C, 65.38; H, 8.53; N, 5.33. C ₃₆ Hs ₄ N ₂ 0 ₈ - 1.0H ₂ O requires C, 65.43; H, 8.54; N, 4.23%

Exam ^p le 178 Preparation of cis-7-(-N-(3S-(2-oxo-N-(carboxy¬ methyl)pyrrolidine) )aminocarbonyl) -8- (1-adamantylmethylamino¬ carboryl)-2,3,5,6-dibenzobicyclo[2.2.2]octane

The reaction was performed essentially as in exaπple 64 but using the benzyl ester of N-carboxymethyl-2-oxo-3S-aminopyrrolidine (prepared as in J. Org. Chem. 1982, .47, 105) in step a. instead of the dibenzyl ester of aspartic acid. The conpound was tested as the N-methyl-D-glucamine salt.

Example 179 Preparation of cis -7- (-N- (3R- ( 2 -oxo-N- ( carboxy¬ methyl) pyrrol idine) ) aminocarbonyl ) -8- ( 1 -adamantylmethylamino¬ carboryl ) -2 , 3 , 5 , 6 -dibenzobicyclo [2.2.2 ] octane

The reaction was performed essentially as in exaπple 64 but using the benzyl ester of N-carboxymethyl-2-oxo-3R-aminopyrrolidine (prepared as in J. Org. Chem. 1982 , J7 , 105) in step a . instead of

the dibenzyl ester of aspartic acid. The cαπpound was tested as the N-methyl-D-glucamine salt.

Example 180 Preparationof cis-7-(2R-(carboxymethyla inocarbonyl)- 2S-methyl-pyrrolidinocarboryl)-8-(1-adamantylmethylaminocarb oryl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane

The cαπpound was prepared essentially as in exaπple 64 but using the benzyl ester of α-methyl-D-prolyl-glycine (prepared as in J. Am. Chem. Soc, 1983, 205, 5390) in step a. instead of the dibenzyl ester of aspartic acid. The cαπpound was tested as the N-methyl-D- glucamine salt.

Exaπple 181 Preparation of cis-7-(2R-(aminocarboryImethylamino- carboryl)-pyrrolidinocarbonyl)-8-(l-adamantylmethylaminocarb onyl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane

The compound was prepared essentially as in exaπple 64 but using D-prolyl-glycinamide in step a. instead of the dibenzyl ester of aspartic acid to give the title coπpound directly. Obviously there was no need for a hydrogenation step. Found: C, 67.41; H, 7.01; N, 8.54. C ₃₆ H ₄₂ N ₄ 0 ₄ . 2.4H ₂ 0 requires C, 67.79; H, 7.39; N, 8.78%

Example 182 Preparation of cis-7-(lR-(aminocarboryImethylamino- carbonyl) -phenethylaminocarbonyl) -8-(1-adamantylmethylamino¬ carboryl)-2,3,5,6-dibenzobicyclo[2.2.2]octane

The compound was prepared essentially as in exaπple 64 but using D-phenylalaryl-glycinamide in step a. instead of the dibenzyl ester of aspartic acid to give the title coπpound directly. Obviously there was no need for a hydrogenation step. Found: C, 71.76; H, 7.01; N, 8.09. C ₄₀ H ₄₄ N ₄ O ₄ . 1.5H,0 requires C, 71.51; H, 7.05; N, 8.33%

Example 183 Preparation of cis-7-(2R-(carboxymethylaminocarboryl) - 4R-hydro^-pyrrolidinocarboryl)-8-(1-adamantylmethylaminocarb oryl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane

The coitpound was prepared essentially as in exaπple 64 but using the benzyl ester of cis-4-hydroxy-D-prolylglycine in step a. instead of the dibenzyl ester of aspartic acid. The coπpovind was further characterised and tested as the N-methyl-D-glucamine salt. Found: C, 56.39; H, 7.65; N, 7.96. C ₄₃ H ₅₈ N ₄ 0 _π . 6.2H ₂ 0 and 1.6 CH ₃ CN requires C, 56.37; H, 7.70; N, 7.97%

Exaπple 184 Preparation of cis-7- (2S- (lS-carboxyethylamino- carbonylmethyl)pyrrolidinocarbonyl) -8-(l-adamantylmethylamino- carbonyl) -2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

a. cis-7- (2S- (lS-benzyloxycarbonylethylaminocarbonylmethyl) - pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarboryl)-2,3, 5,6- dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The compound of exanple 141 (250 mg, 0.45 mmol) was dissolved in dichloromethane (30 ml) and L-alanine benzyl ester p- toluenesulphonate salt (160 mg, 0.45 mmol) was added followed by PyBOP (235 mg, 0.45 mmol) and Hunigs base (240 ml, 1.35 mttpl) . Ihe mixture was stirred at room teπperature for 42 h and then washed with 5% potassium hydrogensulphate solution (15 ml) , sodium hydrogencarbonate solution (15 ml) and saturated brine (15 ml) . The solution was then dried and the product purified by chromatography (silica and ethyl acetate) to yield a colourless solid.

b. cis-7-(2S-(lS-carboxyethylaminocarbonylmethyl) -pyrrolidino¬ carbonyl) -8-(1-adamantylmethylaminocarbonyl) -2,3,5, 6-dibenzo- bicyclo[2.2.2]octane (mixture of diastereomers)

The reaction was performed essentially as in exaπple 48 but using the product of step a. as substrate instead of the product of exanple 46. The coπpound was tested as the N-methyl-D-glucamine

salt.

Example 185 Preparation of cis-7- (2S- ( IR-carboxyetbylamino- carbonylmethyl) pyrrolidinocarbonyl) -8- (1-adamantylmethylamino- carbonyl) -2, 3 , 5, 6-dibenzobicyclo [2.2.2] octane (mixture of diastereomers )

The reaction was performed essentially as in exaπple 184 but using D-alanine benzyl ester p-toluenesulphonate salt in step a. rather than L-alanine benzyl ester p-toluenesulphonate salt . The coπpovind was further characterised and tested as the N-methyl-D-glucamine salt. Found: C, 59.20; H, 7.64; N, 6.11. C ₄₅ .H _e2 N ₄ O _n - 4.9H ₂ 0 requires C, 59.54; H, 7.98 ; N, 6.17%

Exaπple 186 Preparation of cis-7- (2S- (IR-carboxyethylamino- carbonylmethyl) pyrrolidinocarbonyl) -8- (1 -adamantylmethylamino¬ carboryl) -2, 3 , 5, 6-dibenzobicyclo [2 .2 .2] octane (diastereomer 1)

a . cis-7- (2S-carboxymethylpyrrolidinocarbonyl ) -8- (1- adamantylmethylaminocarboryl ) -2 , 3 , 5 , 6-dibenzobicyclo [2.2.2] octane

(diastereomer 1)

The ccmpoimd of exanple 141 was separated into its constituent diastereomers by recrystallisation from dichloromethane. The crystals isolated were the title coπpound. In addition the other diastereomer was isolated by concentration of the mother liquors.

b. cis-7- (2S- (IR-carboxyethylaminocarbonylmethyl) pyrrolidino¬ carbonyl) -8- (1 -adamantylmethylaminocarbonyl) -2 , 3 , 5, 6-dibenzo- bicyclo [2 :2.2] octane (diastereomer 1)

This was prepared in two steps as described in exaπple 185 but using the product from step a. above rather than the ccmpoimd of exaπple 141 as the substrate in step a. The coitpound was tested as the N-methyl-D-glucamine salt .

Exanple 187 Preparation of cis-7-(2S-(lR-carboxyethylamino- carbonylmethy1)pyrrolidinocarbonyl) -8- (1-adamantylmethylamino¬ carbonyl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (diastereomer 2)

This was prepared essentially as in exaπple 185 but using the dichloromethane soluble diastereomer described in exaπple 186 step a. as substrate in step a. rather than the ccmpoimd of exanple.141. The compound was tested as the N-methyl-D-glucamine salt.

Exanple 188 Preparation.of cis-7- (2R- (methoxycarborylmethylamino- carboryl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbo ryl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane (diastereomer 1)

The cαπpound of exaπple 123 was separated into its constituent diastereomers by chromatography (silica 30% ethyl acetate and 70% dichloromethane) . The less polar material was designated the ccmpoimd of this exaπple. Found: C, 64.59; H, 6.76; N, 5.94. C ₃₇ H ₄₃ N ₃ O ₅ .0.3 EtOAc and 1.1 CHC1 ₂ requires C, 64.70; H, 6.58; N, 5.76%

Example 189 Preparation of cis-7-(2R- (methoxycarbonylmetylamino- carbonyl)pyrrolidinocarbonyl)-8-(l-adaπantylmethylaminocarb onyl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane.

The more polar material isolated in exaπple 188 was designated the ccmpoimd of this exanple. Found: C, 70.27; H, 7.70; N, 6.63. C ₃₇ H ₄₃ N ₃ 0 ₅ requires C, 69.97; H, 7.27; N, 6.62%

Example 190 Preparation of cis-7- (2R- (carboxymethyl(N-methyl)- aminocarbonyl)pyrrolidinocarbonyl) -8- (1-adamantylmethylanti.no- carbonyl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The cαπpound was prepared essentially as in exaπple 64 but using

the benzyl ester of D-prolyl-sarcosine in step a. instead of the dibenzyl ester of aspartic acid. The ccmpound was tested as the N-methyl-D-glucamine salt.

Exaπple 191 Preparation of cis-7-(-N-(3R-(.2-oxo-N-(methoxy- carborylmethyl) yrrolidine) )aminocarbonyl)-8-(1-adamantylmethyl- aminocarboryl)-2,3,5,6-dibenzobicyclo[2.2.2]octane

Ihe reaction was performed essentially as in exaπple 63 using the ccmpound of exaπple 179 as substrate instead of cis-7-(1-S- carboxyl-2-methylpropylaminocarbonyl) -8-(1-adamantylmethylamino¬ carboryl)-2,3,5,6-dibenzobicyclo[2.2.2]octane. The ccmpound was tested as the N-methyl-D-glucamine salt.

Exanple 192 Preparation of cis-7- (2-R-carboxy-pyrrolidinocarboryl) - 8- (1-adamantylmethylaminocarbonyl ) -1 , 4-dimethyl-2 , 3 , 5, 6-dibenzo- bicyclo[2.2.2]octane (diastereomer 1)

The ccmpound was prepared essentially as in exanple 137 but using 9,10-dimethylanthracene as substrate in step a. instead of 9,10- difluoroanthracene. In addition the mixture of diastereomers isolated after step c was separated into its constituent isomers using chromatography (silica 10% ethyl acetate and 90% dichloromethane) . The less polar material was taken through to the

■ title coπpound. The cαπpound was further characterised and tested as the N-methyl-D-glucamine salt found: C, 64.71; H, 7.88; N,

5.06. jHsgNA- 2.0H ₂ O requires C, 64.65; H, 7.96; N, 5.26%

Exanple 193 Preparation of cis-7- (2-R-carboxy-pyrrolidinocarboryl) - 8- (1-adamantylmethylaminocarbonyl) -1, 4 -dimethyl -2 , 3 , 5 , 6-dibenzo- bicyclo [2.2.2] octane (diastereomer 2)

Ihe more polar ccmpound described in exanple 192 was hydrogenated to give the coitpound of this exanple . The corrpound was further characterised and tested as the N-methvl-D-σlucamine salt . Found:

C, ^" 61.67; H, 7.88; N, 4.82. C ₄₃ Hs ₉ N ₃ 0 ₉ . 4.0H ₂ O requires C, 61.88; H, 8.10; N, 5.04

Exaπple 194 Preparation of cis-7-(2S-(carboxymetbylamino- carbonylmethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylamin o¬ carbonyl) -2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

Ihe reaction was performed essentially as in exaπple 184 but using the benzyl ester of glycine in step a. rather than L-alanine benzyl ester p-toluenesulphonate salt. The coπpound was further characterised and tested as the N-methyl-D-glucamine salt, HPLC; _P =16.2 mins, C8 column, CH ₃ CN 50%, H ₂ 050%, 0.1% CH ₃ CCOH.

Exaπple 195 Preparation of cis-7-(2R-(lR-(2,2-dimethyl-l,3- dioxolane-4-methoxycarbonyl) -ethylaminocarbonyl)pyrrolidino¬ carbonyl) -8-(1-adamantylmethylaminocarbonyl) -2,3,5, 6-dibenzo- bicyclo[2.2.2]octane

The coπpound of exaπple 147 (305 mg, 0.5 mmol) was dissolved in dry dichloromethane (3 ml) and solketal (66 ml, 0.5 mmol) was added. EMAP (2 mg) and DCCI (103 mg, 0.5 nttvol) were added and the reaction mixture stirred at room teπperature for lh. After filtration the solution was evaporated to leave a foam which was purified by column chromatography (silica 95% dichloromethane and 5% methanol) to leave the title coπpound (195 mg) . Found: C, 71.42; H, 7.45; N, 5.84. C ₄₃ H ₅₃ NA requires C, 71.35; H, 7.38; N, 5.81%

Exaπple 196 Preparation of cis-7-(2R-(lR-(pivalcyloxy- methoxycarbonyl) -ethylaminocarbonyl)pyrrolidinocarbonyl) -8-(1- adamantylmethylaminocarboryl) -2,3,5,6-dibenzobicyclo[2.2.2]octane

The coitpound of exanple 147 (305 mg, 0.5 mmol) was dissolved in DMF (2 ml) and pivalσyloxymethyl chloride (72 ml, 0.55 mmol) and caesium carbonate (82 mg, 0.5 mmol) was added. After gentle warming

the reaction was stirred at room teπperature for lh. The reaction mixture was poured onto brine (30 ml) and extracted with ethyl acetate (30 ml) . The organic layer was washed with brine (2 x 30 ml) dried and evaporated. The material was completely purified by passage through a silica pad eluting with a 1:1 mixture of dichloromethane and ethyl acetate to leave the title ccmpound (160 mg) . Found: C, 71.21; H, 7.48; N, 5.62. C ₄₃ Hs ₃ NA requires C, 71.35; H, 7.38; N, 5.81%

Exanple 197 Preparation of cis-7-(2R-aminocarboryl)- pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarboryl)-2,3, 5,6- dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The ccmpound was prepared essentially as in exaπple 25 but using D-prolinamide instead of the methyl ester of l-alanine.

Example 198 Preparation of cis-7-(2R-(carboxymethylamino- carbonylmethyl)pyrrolidinocarbonyl)-8-(l-adamantylmethylamin o- - carbonyl)-2,3,5,6-dibenzobicyclo[-2.2.2]octane (diastereomer ϊ)

a. cis-7-(2R-carboxymethylpyrrolidinocarboryl)-8-(1-adarriantyl - methylaminocarbonyl) -2,3,5, 6-dibenzobicyclo[2.2.2Joctane (separation of diastereomers)

The ccmpound of exaπple 142 was treated with dichloromethane. The dichloromethane insoluble material was designated diastereomer 1 and the soluble isomer designated diastereomer 2.

b. cis-7-(2R-(carboxymethylaminocarbonylmethyl)-pyrrolidino¬ carbonyl) -8-(1-adamantylmethylaminocarbonyl) -2,3,5,6-dibenzo- bicyclo[2.2.2]octane (diastereomer 1)

The coπpoundwas prepared essentially as in exaπple 194 except that the diastereomer 1 from step a. above was used as substrate instead of the coπpound of exanple 141. Ihe coπpound was tested as the N- methyl-D-glucamine salt.

Exaπple 199 Preparation of cis-7-(2R-(carboxymethylamino- carbonylmethy1)pyrrolidinocarbony1) -8-(1-adamantylmethylamino¬ carboryl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (diastereomer 2)

The compoundwas prepared essentially as in exaπple 194 except that the diastereomer 2 from exaπple 198 step a. was used as substrate instead of the compound of exaπple 141. The coπpound was tested as the N-methyl-D-glucamine salt.

Example 200 Preparation of cis-7-(2R-(lS-carboxyethylamino- carbonylmethyl)pyrrolidinocarbonyl) -8-(1-adamantylmethylamino¬ carboryl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (diastereomer 1)

The ccmpound was prepared essentially as in exanple 184 except that the diastereomer 1 from exaπple 198 step a. was used as substrate instead of the coπpound of exaπple 141. The coπpound was tested as the N-methyl-D-glucamine salt.

Exaπple 201 Preparation of cis-7-(2R-(lS-carhoxyethylamino- carbonylmety1)pyrrolidinocarbonyl) -8-(1-adamantylmethylamino¬ carbonyl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (diastereomer 2)

The ccmpound was prepared essentially as in exaπple 184 except that the diastereomer 2 from exaπple 198 step a. was used as substrate instead of the ccmpound of exaπple 141. The ccmpound was tested as the N-methyl-D-glucamine- salt.

Exaπple 202 Preparation of cis-7-(2R-(lR-carboxyethylamino- carbonylmethyl)pyrrolidinocarbonyl) -8- (1-adamantylmethylamino¬ carboryl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (diastereomer 1)

The cαπpound was prepared essentially as in exaπple 185 except that the diastereomer 1 from exanple 198 step a. was used as substrate instead of the ccmpound of exanple 141. The cαπpound was tested

as the N-methyl-D-glucamine salt.

Exanple 203 Preparation of cis-7-(2R-(lR-carboxyethylamino- carbonylmethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylamin o¬ carboryl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (diastereomer 2)

The compoundwas prepared essentially as in exaπple 185 except that the diastereomer 2 from exaπple 198 step a. was used as substrate instead of the ccmpound of exanple 141. Ihe coπpound was tested as the N-methyl-D-glucamine salt.

Exaπple 204 Preparation of cis-7-(2R-(carboxyethyl)pyrrolidino- carbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5, 6-dibenzo- bicyclo[2.2.2]octane (mixture of diastereomers)

The ccmpound was prepared essentially as in exaπple 64 but using the benzyl ester of trans-3-(2R-pyrrolidino) -but-2-enoic acid (prepared frombenzyl(triphenylphosphoranylidene)acetate andN-(t- butoxycarboryl)-D-prolinal hy Wittig reaction ) in step a. instead of the dibenzyl ester of aspartic acid. The compound was further characterised and tested as the N-methyl-D-glucamine salt. Found: C, 64.81; H, 7.94; N, 5.14. C ₄₃ H ₅₉ NA- 2.OHO requires C, 64.77; H, 7.96; N, 5.27%

Example 205 ^■ Preparation of cis-7-(2S-(methoxycarbonyl- etheryl) yrrolidinocarbonyl)-8-(1-adamantylmethylaminocarboryl)- 2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers)-

The ccmpound was prepared essentially as in exaπple 25 but using the methyl ester of trans-3-(2S-pyrrolidino) -but-2-enoic acid (prepared frommethyl(triphenylphosphoranylidene)acetate andN-(t- butojycarbonyl)-L-prolinal byWittigreaction) insteadof L-alanine methyl ester. Found: C, 76.66; H, 7.39; N, 4.73. C ₃₇ H ₄₂ N ₂ 0 ₄ requires C, 76.79; H, 7.32; N, 4.84%

Example 206 Preparation of cis-7-(2S-(methoxycarbonyl- ethyl)pyrrolidinocarbonyl) -8-(1-adamantylmethylaminocarbonyl) - 2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

This was prepared by treating the cαπpound of exaπple 205 with 10% palladium on charcoal in an atmosphere of hydrogen gas. Found: C, 76.73; H, 7.79; N, 4.91. C ₃₇ H ₄₄ N ₂ 0 ₄ requires C, 76.52; H, 7.64; N, 4.82%

Exaπple 207 Preparation of cis-7-(IS- (aπtinocarbonylmethylamino- carboryl) -2-pherylethylaminocarbonyl) -8-(1-adamantylmethylamino¬ carboryl) -2,3,5,6-dibenzobicyclo[2.2.2]octane (diastereomer 1)

The reaction was performed essentially as in exanple 25 but using L-phenylalanylglycinamide as substrate instead of L-alaniήe methyl ester. The mixture of diastereomers produced by this reaction was separated by column chromatography (silica and ethyl acetate) . The less polar material was designated the title coπpound of this exaπple. Found: C, 72.24; H, 7.02; N, 8.21. C ₄₀ H ₄₄ N ₄ O ₄ .1.2 H ₂ 0 requires C, 74.50; H, 6.87; N, 8.68% .

Exaπple 208 Preparation of cis-7-(IS-(aminocarbonylmethylamino- carbonyl) -2-phenylethylaminocarbonyl) -8- (1-adamantylmethylamino¬ carboryl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (diastereomer 2)

The more polar material isolated from the separation in exanple 207 ■ was designated the ccmpound of this exanple. Found: C, 72.12; H, 6.95; N, 8.39. C ₄₀ H ₄₄ N ₄ O ₄ .1.2 H ₂ 0 requires C, 74.50; H, 6.87; N, 8.68%

Exanple 209 Preparation of (±) -7- (1-adamantylmethylamino- carborylmethyl) -2,3,5,6-dibenzobicyclo[2.2.2]octane-7-carboxylic acid

The ccmpound was prepared essentially as in exanple 131 except that

itaconic anhydride was used as substrate instead of the methyl ester of aconitic anhydride in step a. The ccmpound was further characterised and tested as the N-methyl-D-glucamine salt, m.p. 115-120° . Found: C, 68.06; H, 7.71; N, 4.37. C^H^N requires C, 68.29; H, 7.74; N, 4.30%

Exaπple 210 Preparation of 7- (IS -methoxycarbory lethylamino¬ carbonyl) -7- (l-adaπBnty__lπet_±ylaπι_ij ocarbo_rylmethyl) -2, 3, 5, 6-dibenzo- bicyclo [2.2.2 ] octane (mixture of diastereoisomers)

The ccmpound was prepared essentially as in exanple 25 except that the ccmpound of exanple 209 was used as substrate instead of the ccmpound of exanple 14. Found: C, 75.36; H, 7.56; N, 4.99. C ₃₄ H ₄₀ N ₂ O ₄ requires C, 75.53 ; H, 7.46; N, 5.18%

Exanple 211 Preparation of 7- (2R-carboxypyrrolidinocarboιyl) -7- (1- adamantylmethylaminocarbonylmethyl ) -2 , 3 , 5 , 6-dibenzo- bicyclo [2.2.2] octane (mixture of diastereoisomers)

The ccmpound was prepared essentially as in exanple 160 except that the compound of exanple 209 was used in step c as substrate instead of the ccmpound of exanple 160 step b. The compound was further characterised and tested as the N-methyl-D-glucamine salt . Found: C, 67.24; H, 7.74; N, 5.81. C ₄₂ H ₅₇ NA requires C, 67.45; H, 7.68; N, 5.62%

Example 212 Preparation of (±) -cis-7- (2-carboxycyclopentylamino- carbonyl) -8- (1-adamantylmethylaminocarbonyl) -2, 3 , 5, 6-dibenzo- bicyclo [2.2.2] octane (mixture of diastereomers 1)

The coπpound was prepared essentially as in exaπple 64 but using the benzyl ester of cis 2-amino-cyclopentanoic acid in step a. instead of the dibenzyl ester of aspartic acid. The mixture of compounds after step a. was separated, by column chromatography

(silica 85% dichlorσmenthane 15% ethyl acetate) to give two pairs

of diastereomers. The less polar material was hydrogenated to give the ccmpound of this exaπple. The ccmpound was further characterised and tested as the N-methyl-D-glucamine salt. Found: C, 65.12; H, 7.75; N, 5.42. C^H^NA.1.5 H ₂ 0 requires C, 65.1; H, 7.80; N, 5.42%

Exaπple 213 Preparation of (±)-cis-7-(2-carboxycyclopentylanri.no- carbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5, 6-dibenzo- bicyclo[2.2.2]octane (mixture of diastereomers 2)

The cαπpound was prepared essentially as in exaπple 212 except that the more polar material after separation was hydrogenated to give the ccmpound of this exaπple. The coπpound was further characterised and tested as the N-methyl-D-glucamine salt. Found: C, 64.88; H, 7.91; N, 5.28. C ₄₂ H ₅₇ N ₃ 0 ₉ .1.7 HO requires C, 64.8; H, 7.82; N, 5.40%

Example 214 Preparation of cis-7-(2R-(lR-πethoxycarboryl- ethylaminocarboryl)pyrrolidinocarbonyl)-8-(1-adamantylπethy lamino- carboryl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (single diastereomer)

The coπpound was prepared essentially as in exaπple 63 except that the cαπpound of example 147 was used as substrate instead of cis-7- (l-S-carboxyl-2-methylpropylaminocarbonyl)-8- (1-adamantylmethyl¬ aminocarboryl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers). Found: C, 72.88; H, 7.51; N, 6.58. C ₃₈ H ₄₅ N ₃ 0 ₅ requires C, 73.17; H, 7.27; N, 6.74%

Exanple 215 Preparation of cis-7- (2S-(carboxyetryl)- pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarboryl)-2,3, 5,6- dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The cαπpound was prepared essentially as in exanple 64 but using the benzyl ester of trans-3-(2S-pyrrolidino) -but-2-enoic acid (prepared frombenzyl(triphenylphosphoranylidene)acetate andN-(t-

butoxycarboryl)-L-prolinal by Wittig reaction) in step a. instead of the dibenzyl ester of aspartic acid. Ihe ccmpound was further characterised and tested as the N-methyl-D-glucamine salt. Found: C, 66.64; H, 8.02; N, 5.60. H ₂ 0 requires C, 66.80; H, 7.85; N, 5.44%

Exaπple 216 Preparation of cis-7-(lS-carboxy-(2-naphthyl)- ethylaminocarboryl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5 ,6- dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The compound was prepared essentially as in exaπple 64 but using the benzyl ester L-3-(2-naphthyl)alanine in step a. instead of the dibenzyl ester of aspartic acid. Ihe coπpound was further characterised and tested as the N-methyl-D-glucamine salt. Found: C 70.15; H, 7.33; N, 5.05. C _4q H ₅₉ -0.3 ED requires C, 70.05; H, 7.16; N, 5.00%

Exaπple 217. Preparation of cis-7-(lS-carboxy-(1-naphthyl)- ethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5 ,6- dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

Ihe cαπpound was prepared essentially as in exaπple 64 but using the benzyl ester L-3-(l-naphthyl)alanine in step a. instead of the dibenzyl .ester of aspartic acid. The coitpound was further characterised and tested as the N-methyl-D-glucamine salt. Found: C, 69.94; H, 7.14; N, 5.23. .0.3 H ₂ 0 requires C 70.05; H, 7.16; N, 5.00%

Exanple 218 Preparation of cis-7-(lR-(IR-carboxyethyla ino- carboryl) -2-pherylethylaminocarbonyl) -8-(1-adamantylmethylamino- carbonyl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

Ihe ccmpound was prepared essentially as in exanple 64 but using the benzyl ester D-phenylalanyl-D-alanine in step a. instead of the

dibenzyl ester of aspartic acid. The compound was further characterised and tested as the N-methyl-D-glucamine salt . Found: C, 64.21 ; H, 7.63 ; N, 6.36. C ₄₈ H ₆₂ NAo .2 .3 H ₂ 0 requires C 64.28; H, 7.63 ; N, 6.36%

Example 219 Preparation of cis-7- (3-S-carboxy-l, 2 , 3 , 4- tetrahydroisoquinolinocarboryl) -8- (l-adamantylitethylaminocarboiyl) - 2 , 3 , 5, 6-dibenzobicyclo [2.2.2] octane (mixture of diastereomers)

The ccmpound was prepared essentially as in exaπple 64 but using the benzyl ester l,2,3,4-tetrahydroisoquinoline-3-S-carboxylic acid in step a. instead of the dibenzyl ester of aspartic acid. The ccmpound was further characterised and tested as the N-methyl-D- glucamine salt. Found: C, 66.75; H, 7.37; N, 5.08. C ₄₆ Hs ₇ NAo _* 1•7 . H ₂ 0 requires C, 66.80; H, 7.37; N, 5.08%

Exaπple 220 Preparation of 7-(2R-carboxypyrrolidinocarboryl)-8-(1- adamantylmethyl-N- (methyl) aminocarbonyl) -2,3,5, 6-dibenzo- bicyclo[2.2.2]octane (mixture of diastereoisomers)

a. (±)-8-(1-adamantylmethyl-N-(methyl)aminocarboryl ethyl)-2,3,5 ,6- dibenzobicyclo[2.2.2]octane-7-carboxylic acid ^■ . ^{" '} , This was prepared essentially as in exaπple 14 except that N- methyl-1-adamantanemethylamine was used as substrate instead of 1- adamantanemethylamine.

b. 7-(2R-benzyloxycarborylpyrrolidinocarboryl)-8-(l-adamantyl- methyl-N-(methyl)aminocarbonyl)-2,3,5,6-dibenzobicyclo[2.2.2 ]octane (mixture of diastereoisomers)

This was prepared essentially as in exanple 46 except that the product of step a. was used as substrate instead of the product of exaπple 14.

c. 7- (2R-carboxypyrrolidinocarbony1) -8- (1-adamantylmethy1-N-

(methyl) aminocarbonyl) -2 , 3 , 5, 6-dibenzobicyclo [2.2.2] octane (mixture of diastereoisomers)

This was prepared essentially as in exaπple 48 except that the product of step b above was used as substrate instead of the product of exaπple 46. The compound was further characterised and tested as the N-methyl-D-glucamine salt . Found: C, 63.54; H, 7.87; N, 5.32. C ₄₂ H ₅₇ N ₃ 0 ₉ .2.3 H ₂ 0 requires C, 63.91; H, 7.87 ; N, 5.32%

Exaπple 221 Preparation of 7- (2R- (carboxymethylaminocarboryl) - pyrrolidinocarboryl) -8- (1-adamantylmethyl-N- (methyl) aminocarboryl) - 2, 3 , 5, 6-dibenzobicyclo [2.2.2 ] octane (mixture of diastereoisomers)

Ihe ccmpound was prepared essentially as. in exanple 194 except that the coπpound of exaπple 220 was used as substrate instead of the ccmpound of example 141 in step a. The coitpound was tested as the N-methyl-D-glucamine salt.

Example 222 Preparation of 7- (2R- (lS-carboxyethylaminocarboryl) - pyrrolidinocarboryl) -8- (1-adamantylmethyl-N- (methyl) aminocarboryl) - 2 , 3 , 5, 6-dibenzobicyclo [2.2.2] octane (mixture of diastereoisomers)

The compound was prepared essentially as in example 184 except that the compound of exaπple 220 was used as substrate instead of the ccmpound of exaπple 141 in step a. The coπpound was tested as the N-methyl-D-glucamine salt .

Exaπple 223 Preparation of 7- (2R- (lR-carboxyethylaminocarboryl) - pyrrolidinocarboryl) -8- (l-adamantylmethyl-N- (methyl) aminocarboryl) - 2, 3, 5, 6-dibenzobicyclo [2.2.2] octane (mixture of diastereoisomers )

The ccmpound was prepared essentially as in exanple 185 except that the compound of exaπple 220 was used as substrate instead of the cαπpound of exaπple 141 in step a. The coπpound was tested as the

N-methyl-D-glucamine salt .

Exaπple 224 Preparation of cis-7- (2S- ( IR- carboxyethylanri.no- carbonylmethyl ) pyrrolidinocarbonyl ) -8- ( 1-adamantylmethyl-N- (methyl ) aminocarboryl ) -2 , 3 , 5 , 6 -dibenzobicyclo [2.2.2] octane (mixture of diastereomers)

a. cis-7- (2S- (carboxymethyl) yrrolidinocarbonyl) -8- (1-adamantyl- methyl-N- (methyl ) aminocarboryl ) -2 , 3 , 5 , 6 -dibenzobicyclo [2.2.2] octane

(mixture of diastereomers)

The reaction was performed essentially as in exanple 141 except that the ccmpound of exaπple 220 step a . was used instead of the ccmpound of exaπple 14.

b . cis -7 - ( 2 S - ( IR- carboxy ethy l ami no carbonylmethyl ) - pyrrolidinocarbonyl) -8- (1 -adamantylmethyl-N- (methyl) aminocarboryl) - 2 , 3 , 5, 6 -dibenzobicyclo [2.2.2] octane (mixture of diastereomers)

The ccmpound was prepared essentially as in exaπple 185 except that the ccmpound from step a. above was used as substrate instead of the cαπpound of exaπple 141 in step a. The coπpound was tested as the N-methyl-D-glucarnine salt.

Exaπple 225 Preparation of cis-7-(2Ξ-(lS-carboxyethylamino- carbonylmethyl)pyrrolidinocarbonyl) -8- (1-adamantylmethyl-N- (methy1)aminocarboryl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The ccmpound was prepared essentially as in exanple 184 except that the ccmpound from exanple 224 step a. was used as substrate instead of the coitpound of exanple 141 in step a. The coitpound was tested as the N-methyl-D-glucamine salt.

Example 226 Preparation of cis-7- (2R- (IS-carboxyethylamino-

carbonylmethyl) pyrrolidinocarbonyl) -8- (1-adamantylmethyl-N- (methyl ) aminocarboryl ) -2 , 3 , 5 , 6-dibenzobicyclo [2.2.2] octane (mixture of diastereomers)

a . cis-7- (2R- (carboxymethyl) pyrrolidinocarbonyl ) -8 - ( 1- adamantylmethyl-N- (methyl) aminocarbonyl) -2 , 3 , 5, 6-dibenzobicyclo- [2.2.2] octane (mixture of diastereomers)

The reaction was performed essentially as in exaπple 142 except that the ccmpound of exaπple 220 step a . was used instead of the ccmpound of exanple 14.

b . cis-7- ( 2R- ( lS-carboxyethylaminocarbonylmethyl) pyrrolidino¬ carbonyl) -8- (1-adamantylmethyl-N- (methyl) aminocarboryl) -2 , 3 , 5, 6- dibenzobicyclo [2.2.2] octane (mixture of diastereomers)

The ccmpound was prepared essentially as in exanple 184 except that the compound from step a. above was used as substrate instead of the ccmpound of example 141 in step a . The ccmpound was tested as the N-methyl-D-glucamine salt .

Example 227 Preparation of cis-7- (2S- (methoxycarborylmethy lamino- carboryl) pyrrolidinocarbonyl) -8- (1 -adamantylmethylaminocarboryl) - 2 , 3, 5, 6-dibenzobicyclo [2.2.2.] octane (mixture of diastereomers)

The ccmpound was prepared essentially as in exanple 25 but using the methyl ester L-prolylglycine as substrate instead of L-alanine methyl ester. Found: C, 62.87 ; H, 7.47 ; N, 5.02. C ₃₇ H ₄₃ N ₃ 0 ₅ - 1 -1 EtOAc and 4.5 H ₂ 0 requires C, 63.12 ; H, 7.78 ; N, 5.33%

Example 228 Preparation of cis-7 - (2S- ( lR-carboxyethy lamino- carboryl) pyrrolidinocarbonyl) -8- (1 -adamantylmethylaminocarboryl) - 2 ,3 , 5, 6-dibenzobicyclo [2.2.2 ] octane (mixture of diastereomers)

Ihe ccmpoimd was prepared essentially as in exaπple 64 but using the benzyl ester L-prolyl -D-alanine in step a. instead of the

dibenzyl ester of aspartic acid. The ccmpound was further characterised and tested as the N-methyl-D-glucamine salt. Found: C, 60.11; H, 8.22; N, 6.22. C ₄ _,H ₆ oN ₄ 0 ₁₀ .4.4 H ₂ 0 requires C, 59.81; H, 7.84; N, 6.34%

Exaπple 229 Preparation of cis-7- (2R- (carboxymethylaminocarboryl) - 5-oxopyrrolidinocarbonyl) -8- (1-adamantylmethylaminocarbonyl) - 2,3,5,6-dibenzobicyclo[2.2.2]octane (diastereomer 1)

The coπpound was prepared essentially as in exanple 64 but using the benzyl ester D-pyroglutanyl-glycine in step a. instead of the dibenzyl ester of aspartic acid. The product of step a. was separated into its constituent diastereomers by chromatography ( silica 30% ethyl acetate and 70% dichloromethane) . The less polar material was hydrogenated to give the coπpound of this exaπple. The cαπpound was further characterised and tested as the N-methyl- D-glucamine salt. Found: C, 54.22; H, 7.26; N, 5.54. .8.0 H ₂ 0 requires C, 54.42; H, 7.60; N, 5.90%

Example 230 Preparation of cis-7- (2R- (carboxymethylaminocarbonyl) - 5-oxopyrrolidinocarbonyl) -8- (1-adamantylmethylaminocarbonyl) - 2,3,5,6-dibenzobicyclo[2.2.2]octane (diastereomer 2)

The cαπpound was prepared essentially as in exaπple 229 except that the more polar material isolated after the chromatography was hydrogenated to give the coitpound of this exaπple. The cαπpound was further characterised and tested as the N-methyl-D-glucamine salt. Found: C, 54.88; H, 7.20; N, 6.11. C ₄₃ H ₅₆ N ₄ O _n -8.0 H ₂ 0 requires C, 54.42; H, 7.60; N, 5.90%

Exaπple 231 Preparation of cis-7- (2R- (lR-carboxyethy la ino- carbonylmethyl) pyrrolidinocarbonyl) -8- (1-adamantylmethyl-N- (methyl) aminocarboryl) -2 , 3 , 5, 6-dibenzobicyclo [2.2.2] octane (mixture of diastereomers)

The cαπpoundwas prepared essentially as in exanple 185 except that the cαπpound from exaπple 226 step a. was used as substrate instead of the ccmpound of exaπple 141 in step a.

Exaπple 232 Preparation of cis-7-(2S-(1R-(methoxycarbonyl)- ethyla inocarbonylmethyl) -pyrrolidinocarbonyl)-8-(1-adamantyl- methylaminocarboryl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (single diastereomer)

The compound was prepared essentially as in exaπple 63 except that the compound of exaπple 186 was used as substrate instead of cis-7- (1-S-carboxyl-2-methylpropylaminocarbonyl)-8-(1-adamantylmet hyl- aminocarboryl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

Exaπple 233 Preparation of cis-7-(2R-(carboxymethylaminocarboryl)- 4-thiopyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl )- 2,3,5,6-dibenzobicyclo[2.2.2]octane

a. cis-7-(2R-(t-butoxycarboylmethylaminocarbonyl) -4~thio- pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarboryl)-2,3, 5,6- dibenzobicyclo[2.2.2]octane

This conpoundwas prepared essentially as in exaπple 25 except that 2R-(t-butαjycarborylmethylaminocarbonyl)-4-thiopyrrolidinew as used as substrate instead of L-alanine methyl ester.

b. cis-7-(2R-(carboxymethylaminocarbonyl) -4-thiopyrrolidino- carbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzo - bicyclo[2.2.2]octane

The ccmpound of step a. above was treated with trifluoroacetic acid to give the title coitpound of this exanple.

Exam ^p le 234 Preparationof cis-7-(2R-(carboxymethylaminocarboryl)-

4-oxothio-pyrrolidinocarbαryl)-8-(1-adamantylmethylaminocar boryl)- 2,3,5, 6-dibenzobicyclo[2.2.2]octane

This was prepared from the ccmpound of exaπple 233 step a. by treatment with ozone followed by treatment with trifluoroacetic acid.

Exanple 235 Preparation of cis-7-(2R-(carboxymethylaminocarboryl)- 4-dioxothio-pyrrolidinocarbonyl) -8- (1-adamantylmethylamino¬ carboryl)-2,3,5,6-dibenzobicyclo[2.2.2]octane

This was prepared from the conpound of exaπple 233 step a. by treatment with the tetrabutylammonium salt of oxone followed by treatment with trifluoroacetic acid.

Exanple 236 Preparation of cis-7-(2R-(3,5-dicarboxypherylamino- carboryl)-pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarb onyl)- 2,3,5, 6-dibenzobicyclo[2.2.2]octane (diastereomer 1)

The conpound was prepared essentially as iri exaπple 64 but using the dibenzyl ester of D-prolyl-5-aminoisophthalic acid in step a. instead of the dibenzyl ester of aspartic acid. The diastereomers were separated at the benzyl ester stage by column chromatography

(silica, 92% dichloromethane and 8% ethyl acetate) . The ccmpound with the higher R _£ was converted to the title conpound by hydrogenation. Ihe conpound was further characterised and tested

■ as the mono-N-methyl-D-glucamine salt, HPLC; Rι.=17.4 mins, C8 column, CH ₃ CN 50%, H ₂ 0 50%, 0.1% CH.COOH.

Exanple 237 Preparation of cis-7-(2R- (3,5-dicarboxyphenyl- aminocarbonyl) -pyrrolidinocarbonyl) -8- (1-adamantylmethyl- aminocarbonyl) -2,3,5,6-dibenzobicyclo[2.2.2]octane (diastereomer 2)

The conpound was prepared essentially as in exanple 237 but using

the ccmpound with lower R _f after diastereomer separation in the final hydrogenation step. Ihe ccmpound was further characterised and tested as the mono-N-methyl-D-glucamine salt, HPLC; R;.=9.4 mins, C8 column, CH ₃ CN 60%, H ₂ 040%, 0.1% CH ₃ COOH.

Exaπple 238 Preparation of cis-7-(2S-(1-R-carboxyethylamino- carbonylethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylamino ¬ carbonyl)-2,3,5,6-dibenzobicyclo[2.2.2]octane (mixture of diastereomers)

The coπpound was prepared essentially as in exaπple 185 but using the product of exaπple 215 instead of the conpound of exaπple 141. The coπpound was further characterised and tested as the N-methyl- D-glucamine salt, HPLC; Rj.=21.7.mins, C8 column, CH ₃ CN 50%, H ₂ 050%, 0.1% CH ₃ CCOH.

The following ^~ H NMR data were obtained for the coπpounds described in the Examples:

Ex.la. (d ⁶ -EMSO) δ 7.5 (2H, ) , 7.3 (2H, m), ^' 7.2 (4H, m) , 4.8 (2H, s), 3.6 (2H,s) .

Ex.lb. (d ⁶ -EMSO) 511.6 (IH, br s) , 7.9 (IH, t) , 7.4-6.9 (13H, ) , 4.5 (IH, s), 4.4 (IH, s), 3.1 (IH, d) , 2.9 (2H, m) , 2.8 (IH, d) , 2.5 (2H, t), 1.6 (2H, m) .

Ex.2 (d ⁶ -DMSO) δ 11.6 (IH, br s) , 10.8 (IH, s) , 8.0 (IH, t) , 7.6-6.8 (13H, m) , 4.5 (IH, s) , 4.3 (IH, d) , 3.3-3.0 (3H, d) , 2.2-2.4 (3H, m) .

Ex.3 (d ⁶ ~DMSO) δ 8.4 (IH, br s) , 8.4 (IH, t) , 7.4-6.8 (13H, m) , 4.4 (2H, d), 4.1 (2H, m) , 3.2 (IH, d) , 2.8 (IH, d) .

Ex.4 (d ⁶ -DMSO) δ 8.4 (IH, t) , 8.0-6.9 (15H, ) , 4.7 (IH, dd) , 4.5 (IH, dd), 4.5 and 4.3 (2H, 2xs) , 3.3 (IH, d) , 2.8 (IH, d) .

Ex.5 (d ⁶ -EMSO) δ 8.5 (IH, t) , 8.0-6.9 (15H, m) , 4.5 (2H, d) , 4.3 (2H, m), 3.2 (IH, d), 2.8 (IH, d) .

Ex.6 (d ⁶ -DMSO) δ 11.6 (IH, br s) , 7.8 (IH, m) , 7.4-6.9 (8H, ) , 4.5 (IH, s), 4.4 (IH, s) , 3.2-2.6 (4H, m) , 2.2-0.9 (11H, m) .

Ex.7 (d ⁶ -E SO) δ 11.6 (IH, br s) , 7.8 (IH, m) , 7.4-6.9 (8H, ) , 4.5 (IH, s), 4.4 (IH, s) , 3.2 (IH, dd) , 3.0-2.8 (2H, m) , 2.8 (IH, dd) 1.2 (8H, ), 0.9 (3H, t) .

Ex.8 (d ⁶ -DMSO) δ 11.6 (IH, br s) , 7.8 (IH, t) , 7.4-6.9 (8H, ) , 4.5 (IH, d), 4.4 (IH, d) , 3.1 (IH, dd) , 3.0-2.8 (2H, m) , 2.7 (IH, dd) 1.3 (12H, m), 0.9 (3H, t) .

Ex.9 (d ⁶ -EMSO) δ 11.6 (IH, -br s) , 7.8 (IH, t) , 7.4-6.9 (8H, ) , 4.5 (IH, d), 4.4 (IH, d) , 3.1 (IH, dd) , 2.8-2.6 (3H, m) , 1.8-0.7 (11H, m) .

Ex.10 (d ⁶ -DMSO) δ 12.6 (IH, br s) , 7.7 (IH, t) , 7.4-6.9 (8H, m) , 4.5 (IH, d), 4.4 (IH, d) , 3.0 (IH, dd) , 2.9 (2H, m) , 2.8 (IH, dd),

1.3 (2H, ), 0.9 (9H, s) .

Ex.11 (d ⁶ -DMSO) δ 7.3 (3H, m) , 7.2 (IH, m) , 7.1 (5H, m) , 4.5 (IH, d), 4.4 (IH, d), 3.1 (IH, dd) , 2.7 (IH, dd) , 1.9 (3H, s) , 1.8 (6H, ), 1.6 (6H, m) .

• Ex.12 (d ⁶ -DMSO) δ. 7.6 (IH, t) , 7.4-6.9 (8H, m) _. , 4.5 (IH, d) , 4.4 (IH, d), 3.0 (IH, dd), 2.. (2H, m) , 2.8 (IH, dd) , 1.9 (3H, s) , 1.6 (6H, m), 1.4 (6H, m) , 1.1 (2H, t).

Ex.13 (d ⁶ -DMSO) δ 12.2 (IH br s) , 7.4-7.0 (8H, m) , 4.6 (IH, dd) ,

3.4 (IH, d), 3.3 (IH, d) , 3.1 (IH, d) , 1.9 (3H, s) , 1.6 (6H, m) , 1.4 (6H, m).

Ex.14 (d ⁷ -DMF) δ 7.7 (IH, t) , 7.4 (3H, m) , 7.2 (3H,m) , 7.1 (2H, ), 4.7 (IH, d), 4.6 (IH, d), 3.5 (IH, dd) , 3.0 (IH, dd) , 2.9 (IH, dd), 2.7 (IH, dd), 2.0 (3H, s) , 1.7 (6H, m) , 1.5 (6H, s) .

Esc.15 (d ⁶ -EMSO) δ 7.9 (IH, t) , 7.0-7.4 (8H, m) , 6.6 (lH,t), 4.5 (2H, d), 3.8-3.5 (2H, 2xdd) , 3.6 (3H, s) , 3.2- (IH, d) , 3.0 (IH, dd), 2.5 (IH, dd), 1.9 (3H, b s) , 1.2-1.7 (12H, ) .

Ex.16a (d ⁶ EMSO) δ 8.0 (IH, m) , 7.4-7.0 (13, m) , 6.6 (IH, m) , 5.1 (2H, s), 4.4 (2H, s), 3.8 (IH, dd) , 3.6 (IH, dd),-3-.l (IH, ) , 3.0 (IH, d), 2.5 (2H, m), 1.9 (3H, s) , 1.6 (6H, q) , 1.3 (6H, d) .

Ex.l6b (d ⁶ -EMSO) δ 7.8 (IH, m) , 7.3-7.0 (8H, m) , 6.6 (IH, m) , 4.5 (2H, s), 3.7 (IH, dd), 3.4 (IH, m) , 3.1 (IH, d) , 2.9 (IH, d) , 2.5 (2H, m), 1.9 (3H, s) , 1.6 (6H, q) , 1.2 (6H, d) .

Ex.17 (CDC1 ₃ ) δ 7.6 (IH, d) , 7.1-7.4 (7H, m) , 4.9 (IH, t) , 4.6 (IH, d), 4.5 (IH, d), 3.6 (3H, s) , 3.3 (IH, dd) , 3.2 (IH, dd) , 2.9 (IH, m), 2.6 (IH, m) , 2.0 (3H, s) , 1.6 (6H, m) , 1.3 (6H, s) .

Ex.lβa (CDC1 ₃ ) δ 7.6-7.1 (8H, m) , 6.0 (IH, d) , 5.9 (IH, d) , 4.0 (IH, dd), 3.8 (IH, dd) .

Ex.l8b (CDC1 ₃ ) δ 7.8-6.9 (15H, m) , 4.9 (2H, d) , 4.6 _. (IH, d) , _. 4.4 (IH, d), 4.0 (IH, dd),3.8 (IH, dd) .

Ex.18c (d ⁶ -DMSO) δ 9.0 (IH, bs) , 7.9-7.0 (15H, m) , 5.4 (IH, s) ,

4.6 (2H, d), 4.4 (IH, ) , 4.3 (IH, ) , 3.1 (IH, m) , 2.9 (IH, m) .

Ex.19 (d ⁶ -DMSO) δ 8.9 (IH, bs) , 7.4-6.8 (13H, m) , 4.6 (2H, s) , 4.3 (IH, dd), 4.1 (IH, ,dd), 3.5 (IH, ) , 3.0 (IH, dd) , 2.8 (IH, dd) .

Ex.20a (CDC1 ₃ ) δ 7.6-7.1 (8H, ) , _. 5.0 (IH, d) , 4.9 (IH, d) , 4.2 (IH, dd), 4.1 (IH, dd)

Ex.20b (d ⁶ -EMSO) δ 8.2 (IH, bs) , 7.9-6.9 (15H, m) , 4.7 and 4.5 (2H, 2xs), 4.2 (IH, d) , 4.1 (IH, d) , 3.1 (2H, m) .

Ex.21 (d ⁶ -EMSO) δ 10.8 (IH, s) , 8.0 (IH, bs) , 7.5-6.8 (13H, m) ,

4.7 and 4.4 (2H, 2xs) , 3.2-2.9 (6H, ) ..

Ex.22 (d ⁶ -DMSO) δ 7.7 (IH, bs) , 7.4-6.9 (8H, ) , 4.7 and 4.4 (2H,

2xs), 3.1 (2H, m) , 2.7 (IH, dd) , 2.3 (IH, d) , 1.8 (3H, s) , 1.6 (6H, m) , 1.2 (6H, m) .

Ex.23 (d ^δ -DMSO) δ 8.0 (IH, t) , 7.9 (IH, m) , 7.4-7.0 (8H, m) , 4.6 5 (2H, d), 3.9 (IH, ), 3.2 (IH, m) , 3.1 (IH, ) , 2.9 (IH, m) , 2.5 (IH, m), 1.9 (3H, s), 1.6 (6H, q) , 1.4 (6H, s) , 1.2 (3H, dd) .

Ex.24 (CDC1 ₃ ) δ 7.5-7.1 (8H, m) , 6.2 (IH, t) , 5.3 (IH, t) , 4.5 (2H, s), 3.7 (3H, s) , 3.3 (2H, ) , 3.2 (2H, q) , 2.7 (2H, ddd), 2.4 10 (2H, t), 1.9 (3H, s), 1.4 (6H, q) , 1.2 (6H, s) .

Ex.25 (CDC1 ₃ ) δ 7.5-7.1 (8H, m) , 5.9 and 5.7 (IH, 2 x d) , 5.3 and

5.1 (IH, 2 x t), 4.6 (2H, ) , 4.3 (IH, ) , 3.7 (3H, s) , 3.3-3.1 (2H, dd), 2.9-2.5 (2H, m) , 1.9 (3H, s), 1.7 (6H, q) , 1.3 (6H, d) ,

15 1.2 and 0.9 (3H, d) .

Ex.26 (CDClj) δ 7.5-7.1 (8H, m) , 5.7 (IH, d ), 5.3 (IH, t) , 4.6

(2H, m), 4.3 (IH, m) , 3.7 (3H, s) , 3.2 (2H, s) , 2.8-2.6 (2H, dd) ,

1.9 (3H, s), 1.7 (6H, q) , 1.3 (6H, d) , 1.1 (3H, d) .. 20

Ex.27 (CDC1 ₃ ) δ 7.5-7.1 (8H, m) , 6.1 (IH, t ), -5.2 (IH, d) , 4.6 -

(2H, m) , 4.2 (IH, m) , 3.7 (3H, s) , 3.2 (2H, dd) , 2.8-2.5 ^' (2H, dd) ,

1.9 (3H, s), 1.6 (6H, q) , 1.3 (6H, d) , ^' 0.9 (3H, d) .

25 Ex.28 (CDClj) δ 7.5-7.1 (8H, ) , 6.1 and 5,9 (IH, 2 x d) , 5.4 and

5.2 (IH, 2 x t), 4.6 (2H, d) , 4.3 (IH, m) , 3.7 (3H, s) , 3.2 (2H, ddd), 2.9-2.5 (2H, ) , 2.0 (3H, s) , 1.7 (6H, q) , 1.3 (6H, d) , 1.2

(3H, d) .

30 Ex.29 (CDC1,) δ 7.5-7.1 (13H, m) , 5.8 (IH, t) , 5.2 (2H, s) , 5.K1H, t) 4.6 (2H, d), 3.3 (2H, q) , 3.3-3.0 (2H, q) , 2.8-2.6 (2H, ddd), 2.4 (2H, q) , 1.8 (3H, s) , 1.7 (6H, q) , 1.3 (6H, d) .

Ex.30 (CDClj) δ 7.6 (2H, d) , 7.3-7.1 (7H, ) , 4.8(1H, t) 4.6 (IH, ^• 35 d), 4.5 (IH, d) , 3.5 (IH, m) , 3.3 (IH, d) , 3.1 (2H, m) , 2.9 (IH, q) , 2.4 (3H, m), 1.9 (3H, s) , 1.6 (6H, q) , 1.2 (6H, d) .

Ex.31 (d*-DMSO) δ 7.5-6.8 (12H, m) , 4.5 (2H, ) , 4.0 (IH, m) ,

3.3-2.5 (4H, m), 1.9 (3H, s) , 1.6 (6H, m) , 1.4 and 1.3 (6H, 2 x s), 1.1 and 1.0 (3H, 2 x d) .

Ex.32 (d ⁶ -EMSO) δ 7.3 (4H, m) , 7.1 (4H, m) , 6.9-6.6 (2H, m) , 4.5 and 4.3 (IH, 2 x t) , 4.5 (2H, m) , 3.6 (IH, m) , 3.2 (IH, m) , 3.0-2.8 (3H, m), 2.5 (2H, ) , 1.9 (3H, s), 1.6 (6H, m) , 1.3 (6H, m) , 0.9 and 0.8 (3H, 2 x d) .

Ex.33 (CDC1 ₃ ) δ 7.4-7.1 (13H, m) , 5.7 (IH, d) , 5.3 (IH, t) , 5.1 (2H, s), 4.6 (IH, s) , 4.5 (IH, s) , 4.3 (IH, m) , 3.2 (2H, s) , 2.8 (IH, dd), 2.6 (IH, dd), 1.9 (3H, s) , 1.6 (6H, q) , 1.3 (6H, d) , 1.1 (3H, d).

Ex.34 (CDC1 ₃ ) δ 7.5-7.1 (13H, m) , 6.0 (IH, d) , 5.1 (3H, m) , 4.6 (2H, m), 4.4 (IH, m) , 3.3 (IH, dd) , 3.2 (IH, dd) 2.9 (IH, dd) , 2.5 . (IH, dd), 2.0 (3H, s), 1.7 (6H, q) , 1.3 (9H, m) .

Ex.35 (d ⁶ -DMSO) δ 7.5 (IH, d) , 7.4-7.2 (4H, m) , 7.0 (4H, m), 6.8 (IH, t), 4.5 (2H, s), 4.0 (IH, m) , 3.0 (2H, m) , 2.5 (2H, m) , 1.8 (3H, s), 1.6 (6H, q) , 1.2 (6H, m) , 1.1 (3H, d) .

Ex.36 (d ⁶ -EMSO) δ 7.7 (IH, d) , 7.3 ^' (2H, m) , 7.2 (2H, m) , 7.1 (2H, m), 7.0 (2H, ), 6.6 (IH, t) , 4.5 (2H-, S), 4.0 (IH, m) , 3.0 (IH, d), 2.9 (IH, d), 2.6 (2H, m) , 1.9 (3H, s) , 1.6 (6H, q) , 1.3 (6H, m), 1.1 (3H, d) .

Ex.37b (d ⁶ -EMSO) δ 7.6 (IH, t), 7.3 (2H, m) , 7.0 (4H, m) , 4.8 (IH, d), 4.6 (IH, d), 3.7 (6H, 2 x s) , 3.1 (IH, dd) , 2.7-2.4 (3H, m), 1.9 (3H, s)., 1.6 (6H, q) , 1.4 (6H, m) .

Ex.38 (d ⁶ -DMSO) δ 7.4 (IH, t) , 7.3 (2H, m) , 7.0 (2H, m) , 6.6 (2H, m), 4.8 (IH, d), 4.7 (IH, d) , 3.7 (6H, 2 x s) , 3.1 (IH, dd) , 2.7-2.4 (3H, m), 1.9 (3H, s) , 1.6 (6H, q) , 1.4 (6H, m) .

Ex.39 (d ⁶ -EMSO) δ 11.6 (IH, bs) , 7.8 (IH, t) , 7.3 (3H, m) , 7.0 (5H, m), 4.5 (IH, d), 4.4 (IH, d) , 3.1 (2H, m) , 2.9 (IH, m) , 2.7 (IH, dd), 2.0-1.4 (15H, m) .

Ex.40 (d ⁶ -DMSO) δ 7.7 and 7.5 (IH, 2 x d) , 7.4-7.0 (8H, m) , 6.8 and 6.7 (IH, 2 x t) , 4.5 (IH, ) , 4.4 (2H, s) , 3.0-2.7 (8H, m) , 2.5 (2H, m), 1.9 (3H, s), 1.6 (6H, m) , 1.3 (6H, 2 x s) , 1.1 and 1.0 (3H, 2 x d) .

Ex.41 (CDC1 ₃ ) δ 7.5-7.1 (8H, m) , 6.0 and 5.7 (IH, 2 x d) , 5.4 and 5.0 (IH, 2 x t), 4.6 (2H, m) , 4.3 (IH, m) , 3.7 (3H, s), 3.3-3.1 (2H, m), 3.0-2.6 (2H, m) , 1.6-1.4 (5H, m) , 1.2-1.1 (7H, m),0.7 (2H, m) .

Ex.42 (CDC1 ₃ ) δ 7.6 (IH, m) , 7.3-7.0 (7H, ) , 4.6 (3H, m) , 4.3 (IH, m) , 3.7 (3H, s) ^' , 3.5-3.3 (3H, ) , 3.0 and 2.8 (3H, 2 x s) , 2.8 (IH, m), 2.3 (IH, m) , 1.9 (3H, s) , 1.6 (6H, q) , 1.1 (6H, d) .

Ex.43 (CDClj) δ 7.6 (IH, m) , 7.3-7.0 (7H, ) , 4.6 (3H, m). , 4.3

(IH, m) , 4.2 (2H, m) , 3.5-3.3 (3H, ) , 3.0 and 2.8 ^' (3H, 2 x s) , 2.8

(IH, m) , 2.4 (IH, m) , 1.9 (3H, s) , 1.6 (6H, q) , 1.3 (3H, m) , 1.1 (6H, d) .

Ex.44a (d ⁶ -DMSO) δ 12.7 (IH, s) , 7.4-7.1 (8H, m) 4.8 (2H, m) , 4.0 (2H, ) 3.2 (IH, dd) , 3.15 (IH, dd) , 1.43 (3H, t) .

Ex.44b (d ⁶ -DMSO) δ 8.1 (IH, t) , 7.4-7.0 (8H, ) , 4.7 (IH, d) , 4.65 (IH, d) , 4.0 (2H, ), 3.4 (IH, dd) , 3.1 (IH, dd) , 2.9 (IH, dd) , 2.6 (IH, dd), 1.9-1.4 (15H, m) , 1.1 (3H, t) .

Ex.44c (d ⁶ -EMSO) δ 15-13 (IH, br s) , 7.5-7.0 (9H, m) , 4.8 (2H, s) , 3.2 (2H, s), 2.7 (2H, s) , 1.7-0.9 (15H, ) .

Ex.45 (CDC1 ₃ ) 7.3 (4H, m) , 7.1 (4H, m) , 4.6 (2H, m) , 3.5 (3H, s) , 3.4-3.6 (2H, m) , 3.2 (IH, 2 x s) , 2.0 (3H, br s) , 1.7 (6H, q) , 1.4 (6H, d) .

Ex.46 (CDC1 ₃ ) δ 7.6 (IH, m) , 7.3 (13H, ) , 5.4-5.0 (2H, ) , 4.9-4.4 (3H, m) , 3.7-3.1 (4H, ) , 3.0-2.2 (2H, m) , 2.2-1.8 (7H, m) , 1.6 (6H, q), 1.2 (6H, ) .

Ex.47 (CDC1,) δ 7.6 (IH, ) , 7.3 (13H, m) , 5.4-5.0 (2H, m) ,

4.9-4.4 (3H, m), 3.7-3.1 (4H, m) , 3.0-2.2 (2H, m) , 2.2-1.8 (7H, m) , 1.6 (6H, q), 1.2 (6H, m) .

Ex.48 (CDC1 ₃ ) δ 7.6 (IH, m) , 7.3 (7H, ) , 5.3 (IH, br s) , 4.7-4.2 (3H, m), 3.8-3.2 (5H, m) , 3.1 and 2.8 (IH, m) 2.3 (2H, m) , 2.0 (5H, m), 1.6 (6H, q), 1.2 (6H, m) .

Ex.49 (CDC1 ₃ ) δ 7.6 (IH, ) , 7.3 (7H, m) , 5.3 (IH, br s) , 4.7-4.2 (3H, m), 3.8-3.2 (5H, m) , ^' 3.1 and2.8 (IH, m) 2.3 (2H, ) , 2.0 (5H, m), 1.6 (6H, q), 1.2 (6H, m) .

Ex.50 (CDC1 ₃ ) δ 7.6 (IH, m) , 7.3 (7H, m) , 4.7-4.3 (4H, m) , 3.8-3.2

(7H, m), 3.0 and 2.8 (IH, m) , 2.4-1.8 (8H, m) , 1.6 (6H, q) , 1.2

(6H, m) .

Ex.51 (CDC1 ₃ ) δ 7.6 (IH, m) , 7.3 (7H, ) , 4.7-4.3 (4H, m) , 3.8-3.2

(7H, m), 3.0 and 2.8 (IH, m) , 2.4-1.8 (8H, m) , 1.6 (6H, q) , 1.2

(6H, m) .

Ex.52 (d6-EMS0) δ 10.8 (IH, s) , 7.5 (IH, d) , 7.3 (6H, m) , 7.0 (7H, m), 6.5 (IH, m), 4.5 (IH, m) , 4.4 (IH, m) , 3.1 (2H, s) , 3.0 (IH, dd), 2.9 (IH, dd), 2.7 (2H, m) , 2.5 (2H, m) , 1.8 (3H, s) , 1.6 (6H, q), 1.3 (6H, d).

Ex.53 (d6-DMSO) δ 10.9 (IH, 2 x s) , 7.9 and 7.6 (IH, 2 x d) ,

7.5-7.2 (6H, m), 7.1 (7H, m) , 6.6 (IH, ) , 4.5 (2H, m) , 4.3 (IH, m), 3.5 (3H, s), 3.0 (4H, dd) , 2.5 (2H, m) , 1.8 (3H, s) , 1.6 (6H, q), 1.2 (6H, d>.

Ex.54 (d ⁶ -EMSO) δ 10.9 (IH, 2 x s) , 7.9 and 7.6 (IH, 2 x d) ,

7.5-7.2 (6H, m), 7.1 (7H, m) , 6.6 (IH, m) , 4.5 (2H, m) , 4.3 (IH, m), 3.5 (3H, s), 3.0 (4H, dd) , 2.5 (2H, m) , 1.8 (3H, s) , 1.6 (6H, q), 1.2 (6H, d) .

Ex.55a (diastereomer 1, higher R.) (d ^" --DMSO) δ 10.9 (IH, s) ,

7.5-6.9 (19H, m), 6.7 (IH, ) , 4.9 (2H, ) , 4.5 (2H, m) , 4.3 (IH, ), 3.0 (4H, m) , 2.5 (2H, m) , 1.8 (3H, s) , 1.6 (6H, q) , 1.2 (6H, d).

Ex.55a (diastereomer 2, lower R _f ) (d ⁶ -DMSO) δ 10.8 (IH, s) , 7.9 (IH, d), 7.4-6.9 (18H, m) , 6.6 (IH, ) , 5.0 (2H, ) , 4.5 (IH, s) , 4.42 (IH, s), 4.38 (IH, m) , 3.1-2.9 (4H, m) , 2.5 (2H, m) , 1.8 (3H, s), 1.6 (6H, q), 1.2 (6H, d) .

Ex.55b (d ⁶ -EMSO) δ 10.9 (IH, s) , 7.5 (2H, m) , 7.4-6.9 (12H, m) , 6.6 (IH, t), 4.4 (2H, m), 4.2 (IH, s) , 3.0 (4H, m) , 2.5 (2H, m) , 1.9 (3H, s), 1.6 (6H, q) , 1.2 (6H, ) .

Ex.56 (d ⁶ -DMSO) δ 10.8 (IH, s) , 7.8 (IH, d) , 7.4-6.9 (13H, m) , 6.5

(IH, t), 4.5 (IH, s), 4.4 (IH, s) , 4.3 (IH, m) , 3.1 (IH, m) , 3.0

(IH, dd), 2.9 (2H, m) , 2.4 (2H, ) , 1.8 (3H, s) , 1.6 (6H, q) , 1.2 (6H, m) .

Ex.57 (d ⁶ -DMSO) δ 10.9 (IH, s)., 7.6 (2H, ) , 7.4-6.9 (12H, m) , 6.6 (IH, t), 4.4 (2H, m), 4.2 (IH, s) , 3.0 (4H, m) , 2.5 (2H, m) , 1.8 (3H, s), 1.6 (6H, q), 1.2 (6H, m) .

Ex.58 (CDC1 ₃ ) δ 8.1 (IH, s) ,- 7.6 (IH, d) , 7.4-6.9 (11H, m) , 6.6 (IH, m), 6.5 (IH, m) , 5.5 (IH, m) , 4.8 (IH, m) , 4.4 (IH, s) , 4.2

(IH, m), 3.2 (4H, m) , 2.7 (IH, m) , 2.3 (IH, m) , 2.0 (3H, s) , 1.6 (6H, q), 1.2 (6H, m) .

Ex.59 (d ⁶ -EMSO) δ 8.6 (lH,t) 8.1 (lH,t), 7.3-7.0 (9H,τn) , 6.4 (lH,d), 6.2 (lH,d), 4.6 (2H,dd), 4.2 (2H,m) , 3.2 (2H,d), 2.9(lH,m), 2.5 (lH,m), 1.9 (3H,s), 1.6 (6H,q), 1.4 (6H,d).

Ex.60 (CDC1 ₃ ) δ 7.7 (lH,d), 7.4 (lH,d), 7.3-7.0 (9H,m) , 4.9 (1H,S), 4.7 (lH,d), 4.6 (lH,t), 3.9 (3H,m) , 3.3 (2H,s), 2.6 (lH,q), 2.2 (lH,q), 1.7 (3H,s), 1.5(6H,q), 0.9 (6H,s).

Ex.61 (CDC1 ₃ ) δ 7.6-7.0 (13H, m) , 6.1 and 5.8 (IH 2xd) , 5.5 and 5.3 (IH, 2xt), 5.1 (2H, m) , 4.6-4.2 (3H, m) , 3.3-3.1 (2H, m) , 2.9 (IH, m), 2.6 (IH, m) , 1.9 (4H, s) , 1.6 (6H, m) , 1.3 (6H, ) , 0.8- 0.6 (6H, ) .

Ex.62 (CDClj) δ 7.5-7.1 (8H, m) , 6.9 and 6.5 (IH 2xm) , 5.5 and 5.4 (IH, 2xm) , 4.5 (2H, ) , 4.3 and 4.2 (IH, m) , 3.3 (2H, ) , 3.0-2.4

(2H, m) , 2.0 (4H, s) , 1.6 (6H, m) , 1.3 (6H, m) , 0.8 (6H, m) .

Ex.63 (CDC1 ₃ ) δ 7.5-7.2 (8H, m) , 5.9 and 5.7 (IH 2xd) , 5.3 and 5.2 (IH, m), 4.6(2H, bt) , 4.2 (IH, ) , 3.7 (3H, d) , 3.3 (2H, m) , 2.9 and 2.6 (2H, ) , 1.9 (4H, s) , 1.6 (6H, m) , 1.3 (6H, m) , 0.98-0.76 (6H, m) .

Ex.64b (d ⁶ -EMSO) δ 12.4 (IH, br s) , 7.8-6.8 (11H, m) , 4.4 (2H, m) , 4.2 (IH, m), 3.0 (2H, m) , 2.6-2.3 (4H, m) , 1.9 (3H, s) , 1.6 (6H, m), 1.3 (6H, ) .

Ex.65 (d ⁶ -EMSO) δ 12.6 (IH, br s), 7.9-6.9 (14H, m) , 6.6 and 6.5 (IH, 2xt), 4.5 (2H, m), 4.4 (IH, m) , 3.0 (2H, m) , 2.8-2.3 (4H, m) ,

1.9 (3H, s), 1.6 (6H, m) , 1.3 (6H, m) .

Ex.66 (d ⁶ -EMSO) δ 7.3-7.0 (10H, m) , 4.5 (IH, s) , 4.4 (IH, ^' s) , 3.6 (3H, s), 3.0 (2H, m), 2.7 (IH, m) , 2.5 (IH, m) , 1.9 (3H, s), 1.6 {6H, m), 1.3 (6H, m) , 1.1 (6H, 2 x s) .

Ex.67 (d ⁶ -DMSO) δ 7.4-7.0 (10H, m) , 4.5 (IH, s) , 4.4 (IH, s) , 3.1 (IH, m), 2.9 (IH, m) , 2.7 (IH, ) , 2.5 (IH, ) , 1.9 (3H, s) , 1.6 (6H, ), 1.3 (6H, m) , 1.1 (6H, 2 x s) .

Ex.68 (CDC1 ₃ ) δ 7.6 (IH, m) , 7.4-7.0 (7H, m) , 5.8 (IH, br s) , 4.9- 4.3 (5H, m), 3.7- 3.1 (4H, m) , 2.9-2.1 (4H, m) , 2.0 (3H, s) , 1.6 (6H, m), 1.3 (6H, m) .

Ex.69 (CDC1 ₃ ) δ 7.6 (IH, d),- 7.4-7.1 (8H, ) , 4.7 (IH, t) , 4.6

(IH, d), 4.5 (IH, d), 4.4 (2H, m) , 3.8 (IH, m) , 3.6 (IH, d) , 3.4 (IH, dd), 3.2 (IH, d) , 2.8 (IH, dd) , 2.4 (2H, m) , 2.2 (IH, m) , 2.0

(3H, s), 1.6 (6H, m), 1.3 (6H, m) .

Ex.70 (CDCΪ ₃ ) δ 7.6 (IH, ) , 7.4-7.0 (7H, m) , 5.8 (IH, br s) , 4.9- 4.3 (5H, ), 3.7- 3.1 (4H, m) , 2.9-2.1 (4H, m) , 2.0 (3H, s) , 1.6 (6H, m), 1.3 (6H, m) .

Ex.71 (CDCL) δ 7.6 (IH, d) , 7.4-7.1 (8H, ) , 4.7 (IH, d) , 4.6 (IH, d), 4.4 (3H, m), 3.8 (3H, s) , 3.7 (IH, ) , 3.6-3.2 (4H,m) , 2.8

(IH, dd), 2.4 (IH, dd) , 2.1 (IH, m) , 1.9 (3H, s) , 1.6 (6H, m) , 1.2 (6H, m) .

Ex.72 (CDC1 ₃ ) δ 7.6 (IH, m) , 7.4-7.0 (8H, ) , 4.8-4.4 (5H, m) , 3.9-3.1 (8H, ), 2.9-2.1 (3H, m) , 2.0 (3H, s) , 1.6 (6H,. m) , 1.3 (6H, ) .

Ex.73 (CDC1 ₃ ) δ 7.6 (IH, ) , 7.4-7.0 (8H, m) , 4.8-4.4 (4H, ) , 3.9-3.7 (3H, ), 3.3-2.6 (3H, m) , 2.5-2.1 (3H, ) , 2.0 (3H, s) , 1.6 (8H, m), 1.1 (6H, ) .

Ex.74 (CDC1 ₃ ) δ 7.6 (IH, m) , 7.4-7.0 (8H, m) , 4.8-4.2 (4H, m) , 3.9-2.1 (12H, m), 2.0 (3H, s) , 1.6 (8H, m) , 1.1 (6H, m) .

Ex.75 (CDC1 ₃ ) δ 7.5-7.1 (8H, ) , 6.2 and 6.1 (IH., 2 x d) , 5.4 and 5.3 (IH, 2 x t), 4.5 (3H, s) , 3.3-3.1 (2H, m) , 2.7 (2H, m) , 1.9 (3H, s), 1.7 (6H, m), 1.3 (9H, m) .

Ex.76 (CDC1 ₃ ) δ 7.5-7.1 (8H, m) , 6.2 and 5.9 (IH, 2 x d) , 5.4 and 5.2 (IH, 2 x t), 4.6 (2H, m) , 4.3 (IH, m) , 3.2 (2H, m) , 2.9-2.4 (2H, m), 2.1 (3H, s) , 1.9 (3H, s) , 1.7 (6H, m), _. 1.3 (9H, m) .

Ex.77 (CDC1 ₃ ) δ 7.5-7.0 (8H, m) , 6.2 and 5.8 (IH, 2 x d) , 5.4 and 5.1 (IH, 2 x t), 4.6 (2H, m) , 4.3 (IH, ) , 4.1 (2H, m) , 3.5-3.2 . (2H, m), 2.8 (IH, m) , 2.6 (IH, ) , 1.9 (3H, s) , 1.7 (8H, ) , 1.2 (9H, m), 0.9 (3H, m)

Ex.78 (CDC1 ₃ ) δ 7.6 (IH, d) , 7.4-7.1 (8H, m) , 4.6-4.2 (3H, m) , . 3.6-3.2 (5H, m), 2.8 (IH, dd) , 2.4 (2H, m) , 2.0 (5H, m) _. , 1.6 (6H, m), 1.3 (6H, ) .

Ex.79 (CDC1 ₃ ) δ 7.6-7.1 (8H, m) , 5.4 (IH, br s) , 4.86-4.4 (3H, m) , 3.7-2.8 (6H, m), 2.4 (2H, m) , 2.0 (5H, ) , 1.6 (6H, m) , 1.3 (6H, m) .

Ex.80 (CDC1 ₃ ) δ 7.6 (IH, d) , 7.4-7.1 (7H, m) , 4.6-4.3 (4H, m) , 3.8

(3H, s), 3.5 (3H, ), 3.2 (IH, dd) , 2.8 (IH, dd) , 2.4 (IH, dd) , 2.0

(7H, ), 1.6 (6H, m) , 1.2 (6H, s) .

Ex.81 (CDClj) δ 7.6-7.1 (8H, m) , 4.8-4.4 (4H, m) , 3.7 and 3.6 (3H, 2 xs), 3.5-2.9 (5H, m) , 2.4-1.8 (8H, m) , 1.6 (6H, m) , 1.2 (6H, m) .

Ex.82 (d ⁶ -EMSO) δ 7.6-6.9 (8H, m) , 4.5 (2H, m) , 4.1 (IH, m) , 3.7- 3.3 (2H, m), 3.1 (2H, m) , 2.5 (2H, m) , 1.9 (3H, s) , 1.6- (6H, m) ,

1.2 (6H, m) .

Ex.83 (d ⁶ -EMSO) δ 7.7-6.9 (8H, m) , 4.5 (2H, m) , 4.1 (IH, m) , 3.6-

3.3 (2H, m), 3.1 (2H, m) , 2.6 (2H, m) , 1.9 (3H, s) , 1.6 (6H, m) , 1.2 (6H, m) .

Ex.84 (CDC1 ₃ ) δ 7.6 (IH, d) , 7.3-7.1 (7H, m) , 6.6 (IH, d) , 5.9 (IH, t), 4.6 (IH, d), 4.4 (2H, m) , 3.8 (3H, s) , 3.7 (2H, m) , 3.6 (IH, ) 3.2 (IH, dd) , 3.0 (IH, dd) , 2.9 (IH, dd) , 2.7 (IH, dd) , 2.0 (3H, s), 1.7 (6H, m) , 1.4 (6H, m) .

Ex.85 (CDC1 ₃ ) δ 7.5-7.1 (8H, ) , 6.5 (IH, d) , 5.6 (IH, t) , 4.5 (2H, 2 xs), 4.4 (IH, ) , 3.7 (6H, m) , 3.3 (IH, dd) , 3.2 (IH, dd) , 2.9 (IH, dd), 2.5 (IH, dd) , 2.0 (3H, s) , 1.7 (6H, m) , 1.3 (6H, m) .

Ex.86 (CDC1 ₃ ) δ 7.7-7.1 (8H, m) , 6.4 (IH, s), 5.8 (IH, s) , 5.3 (IH, s), 5.0 (IH, t), 4.6 (IH, d) , 4.5 (IH, d) , 3.8 (3H, s) , 3.4 (IH, dd), 3.2 (IH, dd), 2.7 (IH, dd) , 2.5 (IH, dd), 1.9 (3H, s), 1.6 (6H, m), 1.2 (6H, s) .

Ex.87 (d ⁶ -EMSO) δ 8.0-6.9 (9H, m) , 4.9 a d 4.8 (IH, 2 x m) , 4.6- 4.3 (3H, m), 3.5-2.7 (7H, m) , 2.5-2.2 (2H, m) , 1.8 (3H, s) , 1.5 (6H, m), 1.1 (6H, m) .

Ex.88 (CDC1 ₃ ) δ 7.6 (IH, ) , 7.4-7.0 (8H, ) , 5.5-5.2 (IH, m) , 4.6-4.4 (3H, m), 3.7- 3.2 (3H, m) , 3.1-2.6 (2H, m) , 2.3 (2H, m) , 1.9 (3H, s), 1.6 (6H, m) , 1.4 (5H, m) , 1.2 (6H, m) .

Ex.89 (CDClj) δ 7.6 (IH, m) , 7.4-7.0 (7H, ) , 5.3-4.3 (4H, m) , 3.8-2.6 (8H, m) , 2.3 (2H, m) , 1.9 (3H, s) , 1.6 (6H, m) , 1.4 (5H, m) , 1.2 (6H, m) .

Ex.90 (d ⁶ -EMSO) δ 8.1-6.9 (9H, m) , 4.9-4.1 (5H, m) , 3.7-3.1 (7H,

m), 2.9-2.1 (4H, m) , 2.0 (3H, s) , 1.6 (6H, m) , 1.3 (6H, m) .

Ex.91 (d ⁶ -EMSO) δ 8.1-6.9 (9H, m) , 4.9-4.1 (5H, m) , 3.8-3.1 (7H, m), 2.9-2.1 (4H, m) , 2.0 (3H, s) , 1.6 (6H, m) , 1.1 (6H, m) .

Ex.92 (d ⁶ -EMSO) δ 7.5-7.0 (13H, m) , 6.4 (IH, d) , 5.2 (IH, t) , 4.5

(3H, m), 3.7 (3H, s) , 3.6 (2H, s) , 3.2 (2H, dd) , 2.6 (4H, ) , 2.0

(3H, s), 1.6 (6H, m), 1.2 (6H, s) .

Ex.93 (CDC1 ₃ ) δ 7.4-6.9 (13H, m) , 6.3 (IH, d) , 5.2 (IH, t) , 4.5 (3H, m), 3.6 (3H, s), 3.5 (2H, s) , 3.1 (2H, dd) , 2.6 (4H, m) , 1.9. (3H, s), 1.6 (6H, m), 1.2 (6H, s) .

Ex.94 (d ⁶ -DMSO) δ 7.3 (3H, m) , 7.1 (6H, m) , 4.9-4.5 (3H, m) , 3.3 (IH, m), 3.0 (IH, m) , 2.8-2.5 (5H, m) , 1.9 (3H, s) , 1.6 (6H, m) , 1.4 (6H, m), 1.1 (3H, m) .

Ex.95 (d ⁶ -DMSO) δ 7.3 (3H, m) , 7.1-6.9 (6H, m) , 4.9-4.5 (3H, m) , 3.3 (IH, m), 3.0 (IH, m) , 2.8-2.5 (5H, m) , 1.9 (3H, s) , 1.6 (6H, m), 1.4 (6H, m) , 1.1 (3H, m) .

Ex.96 (d ⁶ -EMSO) δ 7.4 (3H, m) , 7.1 (5H, m) , 5.0-4.4 (3H, m) , 3.6 and 3.5 (3H, 2 x s) , 3.2 (IH, m) , 3.0 (IH, m) , 2.8 and 2.7 (3H, 2 x s), 2.5 (2H, m), 1.9 (3H, s) , 1.6 (6H, m) , 1.3 (6H, m) , 1.2-0.9 (3H, m) .

Ex.97 (d ⁶ -DMSO) δ 7.4 (3H, m) , 7.1-6.9 (5H, m) , 5.0-4.3 (3H, m) , 3.6 and 3.5 (3H, 2 x s) , 3.3 (IH, m) , 3.0 (IH, ) , 2.8-2.5 (5H, m) , 1.9 (3H, s), 1.6 (6H, m) , 1.3-1.0 (9H, m) .

Ex.98 (CDC1 ₃ ) δ 7.7 (IH, d) , 7.4-7.1 (7H, ) , 4.6 (2H, m) , 4.5 (IH, t), 3.5 (IH, m), 3.4 (2H, m) , 3.3 (2H, ) , 3.1 (IH, m) , 2.7 (IH, q), 2.4 (IH, q) , 1.9 (3H, s) , 1.9-1.8 (4H, ) , 1.6.(6H, m) , 1.2 (6H, m) .

Ex.99 (d ⁶ -DMSO) δ 7.4-7.0 (9H, ) , 6.4 (IH, t) , 4.4 (2H, ) , 3.3 (IH, d), 3.1 (IH, dd), 2.9 (IH, dd) , 2.5 (IH, q) , 2.4 (3H, d) , 1.9 (3H, s), 1.6 (6H, m) , 1.2 (6H, ) .

Ex.100 (CDCl,) δ 7.7 (IH, d) , 7.4-7.1 (7H, m) , 4.6 (2H, ) , 4.4 (IH, t), 3.5 (IH, d), 3.1 (IH, dd) , 2.9 (6H, 2 x s) , 2.7 (IH, dd) , 2.5 (IH, dd), 1.9 (3H, s) , 1.6 (6H, m) , 1.2 (6H, m) .

Ex.lOl (CDCl,) δ 7.4 (2H, ) , 7.3-7.1 (6H, ) , 5.9 (IH, ) , 5.7 (IH, ), 4.5 (2H, m), 3.2 (2H, d) , 3.0 (2H, m)-, 2.6 (2H, m) , 1.9 (3H, s), 1.6 (6H, m), 1.2 (6H, m) , 0.9 (3H, t) .

Ex.102 (CDC1 ₃ ) δ 7.5-7.1 (8H, m) , 5.9 (IH, t) , 5.3 (IH, d) , 4.5 (2H, d), 3.7 (2H, m) , 3.1 (2H, s) , 2.8 (IH, ) , 2.6 (IH, m) , 1.9 (3H, s), 1.6 (6H, m), 1.2 (6H, m) , 0.8 (6H, d) .

Ex.103 (d ⁶ -EMSO) δ 7.4-7.0 (8H, ) , 6.7 (IH, ) , 6.6 (2H, m) , 4.5 (2H, d), 3.0 (IH, d), 2.9 (IH, d) , 2.6 (IH, m) , 2.5 (IH, m) , 1.9 (3H, s), 1.6 (6H, m), 1.3 (6H, ) .

Ex.104 (CDC1 ₃ ) δ 7.7 (IH, m) , 7.6 (IH, m) , 7.4 (IH, m) , 7.4-7.2 (10H, m), 6.0 (IH, t) , 5.3 (IH, t) , 5.1 (2H, s) , 4.5 (IH, d) , 3.4 (IH, ), 3.3 (2H, dt) , 3.1 (IH, dd) , 2.8 (IH, dd) , 2.7 (IH, dd) , 2.4 (2H, t), 1.9 (3H, s) , 1.6 (6H, m) , 1.3 (6H, s) .

Ex.105 (CDC1 ₃ ) δ 7.8 (IH, ) , 7.7 (IH, m) , 7.4 (IH, m) , 7.4-7.2 (10H, ), 6.3 (IH, t) , 5.2 (IH, t) , 5.1 (2H, s) , 4.6 (IH, d) , 3.4 (IH, m), 3.3 (2H, dd) , 3.2 (IH, d) , 2.8 (IH, dd) , 2.7 (IH, dd) , 2.4 (2H, t), 1.9 (3H, s) , 1.6 (6H, m) , 1.3 (6H, m) .

Ex.106 (CDC1 ₃ ) δ 7.5-7.1 (8H, m) , 6.3-6.0 (IH, 2 x d) , 5.6 and 5.3 (IH, 2 x t), 4.6 (2H, m) , 4.3 (IH, m) , 3.7 (3H, ) , 3.3 (2H, m), 2.9 (IH, m), 2.7 (IH, m) , 1.2 (3H, dd) , 0.8 (9H, d) .

Ex.107 (d ⁶ -EMSO) δ 8.0-6.9 (9H, m) , 4.5-3.9 (3H, ) , 3.5-2.6 (6H, m), 2.2-1.6 (4H, m) , 0.8 (9H, d) .

Ex.108 (CDC1 ₃ ) δ 7.4 (4H, ) , 7.0 (4H, ) , 5.7 (2H, d) , 5.2 (IH, d), 3.0 (2H, d), 2.0 (3H, s) , 1.7 (6H, q) , 1.5 (6H, s) .

Ex.109 (CDClj) δ 7.4-7.1 (8H, m) , 5.0 (IH, t) , 4.6 (IH, d) , 4.4 (IH, d), 2.8 (3H, m), 2.2 (IH, m) , 1.9 (4H, m) , 1.6 (6H, m) , 1.3

(6H, s) .

Ex.110 (CDClj) δ 7.4-7.0 (8H, m) , 4.7 (IH, d) , 4.4 (IH, t) , 3.6 (2H, dd), 3.0 (IH, m), 2.2 (IH, m) , 2.1 (IH, m) , 2.0 (3H, s) , 1.7 (6H, m), 1.5 (6H, q) .

Ex.lll (CDClj) δ 7.5-7.1 (8H, m) , 5.6 (IH, t), 4.6 (IH, s) , 4.5 (IH, dd), 4.3 (IH, m), 3.7 (3H, 2 x s) , 3.6 (IH, t) , 3.4-3.1 (3H, m), 1.9 (3H, m), 1.7 (6H, q) , 1.4 (6H, s) , 1.2 (3H, dd) .

Ex.112 (CDC1 ₃ ) δ 7.5-7.1 (8H, ) , 5.6 (IH, t) , 4.6 (IH, s) , 4.5 (IH, dd), 4.3 (IH, m) , 3.8 (3H, 2 x s) , 3.6 (IH, t) , 3.4-3.1 (3H, m), 1.9 (3H, m), 1.7 (6H, q) , 1.4 (6H, s) , 1.2 (3H, dd)

Ex.113 (d ⁶ -DMSO) δ 7.4 (5H, m) , 7.3. (4H, m) , 7.1 (4H, m) , 5.1 (2H, q), 3.1 (2H, m) , 2.8 (2H, q) , 2.4 (2H, ) , 1.8 (3H, s) , 1.6 (6H, m), 1.2 (6H, s) .

Ex.114 (d ⁶ -DMSO) δ 7.7-6.8 (10H, m) , 4.6 (IH, s) , 4.1 ^' (IH, m) , 3.6 (4H, m), 3.4 (IH, m),.2.7 (IH, q) , 2.3 (IH, ) , 1.8 (3H, s) , ^• 1.6 (6H, m), 1.3 (6H, s), 1.2 (3H, d) .

Ex.115 (d ⁶ -DMSO) δ 8.1-6.8 (10H, ) , 4.6 (IH, s) , 4.0 (IH, m) , 3.6 (4H, m) , 3.4 (IH, m) , 2.7 (IH, q) , 2.3 (IH, m) , 1.8 (3H, s) , 1.6 (6H, m), 1.3 (6H, s) , 1.2 (3H, m) .

Ex.116 (d ⁶ -DMSO) δ 8.0-6.8 (10H, m) , 4.5 (IH, s) , 4.0 (IH, . m) , 3.6 (4H, m), 3.4 (IH, m) , 2.6 (IH, q) , 2.3 (IH, ) , 1.9 (3H, s) , 1.6 (6H, ) , 1.4 (6H, s) , 1.0 (3H, d) .

Ex.117 (CDC1 ₃ ) δ 8.6 and 8.2 (IH, 2 x s) , 7.5-7.1 (13H, m) , 6.3 and 6.0 (IH, 2 x. d) , 5.4 and 5.2 (IH, 2 x t) , 4.8-4.4 (3H, m) , 3.6 (3H, s), 3.3-2.3 (6H, m) , 0.8 (9H, 2 x s) .

Ex.118 (CDC1-.) δ 8.2-6.4 (15H, m) , 5.6 and 5.4 (IH, 2 x t) , 4.8- 4.2 (3H, m) , 3.3-2.5 (6H, ) , 0.8 (9H, 2 x s) .

Ex.119 (CDCl,) δ 7.6-7.0 (10H, ) , 6.4 (IH, m) 5.0 (IH, m) , 4.6-

4.4(2H, m), 4.3-4.0 (2H, m) , 3.9-3.2 (3H, m) , 2.9-2.6 (2H, m) , 2.3 (IH, ), 2.1-1.9 (7H, m) , 1.6 (6H, m) , 1.4 and 1.2 (6H, 2 x s) .

Ex.120 (CDC1 ₃ ) δ 7.6-7.0 (10H, m) , 6.1 (IH, m) , 5.0-4.4 (3H, m) , 4.2 (2H, ), 3.9-3.2 (3H, m) , 2.9-2.6 (2H, m) , 2.1-1.9 (8H, m) , 1.6 (6H, m), 1.2 (6H, s) .

Ex.121 (CDC1 ₃ ) δ 7.6-7.0 (10H, ) , 6.1 (IH, s) , 4.8-4.4 (3H, m) , 4.2-3.3 (5H, m), 2.9 (2H, ) , 2.3 (IH, ) , 2.1-1.9 (7H, m) , 1.6 (6H, m) , 1.2 (6H, s) .

Ex.122 (CDC1 ₃ ) ^' δ 7.6-7.1 (10H, m) , 6.0 (IH, m) , 4.8-4.3 (3H, m) ,

3.8-3.2 (7H, m), 2.9 (IH, m) , 2.6 (2H, m) , 2.1-1.9 (7H, m) , 1.6

(6H, m), 1.2 (6H, s) .

Ex.123 (CDC1 ₃ ) δ 7.6-7.1 (9H, ) , 6.0 (IH, m) , 4.6-4.0 (5H, m) ,

3.9-3.2 (6H, m), 2.9-2.3 (3H, m) , 2.1-1.9 (7H, m) , 1.6 (6H, m) , 1.4 and 1.2 (6H, 2 x s) .

Ex.124 (CDC1 ₃ ) δ 7.6-7.1 (9H, m) , 5.9 (IH, ) , 4.6-4.2 (3H, m) , 3.8-3.1 (8H, m), 3.0-2.2 (5H, m) , 2.1-1.9 (7H, m) , 1.6 (6H, m), ^' 1.4 and 1.2 (6H, 2 x s) .

Ex.125 (d ⁶ -EMSO) δ 7.7-7.5 (2H, m) , 7.4-6.9 (9H, m) , 4.5 (.2H, m) , 4.0 (IH, ), 3.8-3.2 (4H, m) , 2.8-2.6 (2H, m) , 2.3 (2H, m) , 1.9 (3H, m), 1.6 (6H, m), 1.3 (6H, 2 x s) , 1.1 (3H, 2 x d) .

Ex.126 (CDC1 ₃ ) δ 7.4-6.9 (9H, m) , 5.9 (IH, m) , 5.6 (IH, m), ^' 4.5

(2H, ), 4.2 (IH, ) , 3.7 (3H, s) , 3.4 (4H, m) , 2.8 (2H, m) , 2.5 (2H, m), 2.0 (3H, s), 1.7 (6H, ) , 1.3 (6H, 2 x s) , 1.1 (3H, 2 x d).

Ex.127 (CDClj) δ 7.5-7.1 (8H, m), -6.8 (IH, m),6.1 and 5.9 (2H, m) , 4.5 (2H, ), 4.3 (IH, ) , 3.2 (2H, s) , 2.9-2.5 (5H, ) , 2.0 (3H, s), 1.6 (6H, m), 1.3 (9H, m) .

Ex.128b (CDCl,) δ 7.5-7.1 (8H, ) , 6.0 and 5.4 and 5.3 and 5.2 (2H, 4 x d), 4.6 (2H, ) , 4.3 (IH, m) , 3.7 (3H, 2 x s) , 3.5 (IH,

m), 3.2 (2H, m) , 2.0 (3H, s) , 1.6-0.9 (15H, m) , 0.8 (3H, 2 x d) .

Ex.129 (CDClj) δ 7.5-7.1 (8H, m) , 6.2 and 6.0 and 5.3 and 5.2 (2H, 4 x d), 4.6 (2H, ) , 4.4 (IH, m) , 3.7 (3H, 2 x s) , 3.5 (IH, m), 3.2 (2H, m) , 2.0 (3H, ) , 1.8-0.9 (15H, m) , 0.8 (3H, 2 x d) .

Ex.130 (CDC1 ₃ ) δ 7.5-7.1 (8H, m) , 6.2 and 6.0 (IH, 2 x d) , 5.4 and

5.2 (IH, 2 x t), 4.6 (2H, ) , 4.3 (IH, m) , 3.3-3.1 (2H, m) , 2.9-

2.3 (4H, ) , 2.0 (3H, s) , 1.6 (6H, ) ,1.3 (6H, 2 x s) , 1.1 (6H, m) .

Ex.131b (d ⁶ -DMSO) δ 7.6-6.9 (9H, m) , 4.6 (IH, s) , 4.3 (IH, s) , 3.6 (3H, s), 3.5 (IH, ), 2.9-2.5 (4H, ) , 2.0 (3H, s) , 1.6 (6H, m),1.3 (6H, s) .

Ex.132 (d ⁶ -DMSO) δ 7.9 and 7.5 (IH, 2 x d) , 7.4-6.9 (9H, m) , 4.4 (2H, m), 4.2-4.0 (IH, m) , 3.6 (3H, 2 x s) , 3.0 (4H, m) , 2.0 (3H, s), 1.6 (6H, m),1.3 (6H, 2 x s) , 1.2 (3H, m) .

Ex.133 (CDC1 ₃ ) δ 7.6-7.1 (9H, m) , 5.3 (2H, m) , 4.6-4.2 (3H, m) , 3.6-3.1 (4H, m) , 2.7 (IH, m) , 2.1-1.2 (18H, m) .

Ex.l34d (d ⁶ -DMSO) δ 13.5-12.5 (IH, br s) , 8.3 (IH, t) , 7.4-7.0

(8H, m), 5.7 (IH, s) , 5.4 (IH, s) , 2.8 (2H, m) , 1.9 (3H, s) , 1.6

(6H, m), 1.4 (6H, ) .

Ex.135 (d ⁶ -DMSO) δ 8.8 (IH, d), 8.1 (IH, t) , 7.5-7.0 (8H, m) , 5.59 (IH, s), 5.56 (IH, s) , 4.4 (IH, ) , 3.6 (3H, s) , 2.9 (2H, d) ,

1.9 (3H, s), 1.6 (6H, m) , 1.4 (6H, ) , 1.3 (3H, d) .

Ex.136 (d ⁶ -DMSO) δ 12.6 (IH, br s),8.4 (IH, t) , 8.1 (IH, t) , 7.5-6.9 (8H, m), 5.8 (IH, s) , 5.4 (IH, s) , 4.4 (IH, m) , 3.9-3.5 (2H, ) , 3.3-2.5 (4H, ) , 2.1-1.4 (13H, m) , 1.3 (6H, m) .

Ex.l37d (CDC1 ₃ ) δ 7.8 (4H, ) , 7.3 (4H, ) , 6.1 and 5.5 (IH, br s), 4.6 and 4.33 (IH, dd) , 3.9-2.3 (7H, ) , 2.0 (6H, m) , 1.7 (6H, m), 1.4 (6H, ) .

Ex.138c (CDClj) δ 7.6-7.0 (8H, m) , 5.9 and 5.0 (IH, .2xd) , 4.6-4.3

(5H, m), 3.8-3.1 (4H, m) , 2.4-1.9 (2H, m) , 1.8-1.0 (15H, ) .

Ex.139 (CDClj) δ 7.7-7.0 (8H, m) , 4.6-4.3 (3H, m) , 3.8-2.8 (7H, m), 2.3 (2H, m), 1.9-1.0 (19H, m) .

Ex.140 (CDClj) δ 7.7-7.0 (8H, ) , 4.6-4.0 (4H, m) , 3.8-2.2 (8H, m), 1.9 (4H, m), 1.6 (9H, m) , 1.0 (6H, m) .

Ex.141 (CDClj) δ 7.6-7.0 (8H, m) , 5.0-4.5 (3H, m) , 4.3 and 4.2 (IH, 2xm), 3.6-3.0 (5H, m) , 2.7 (IH, m) , 2.4 (IH, m) , 2.2 (IH, m) , 1.8 (7H, m), 1.6 (6H, m) , 1.2 (6H, ) .

Ex.142 (CDClj) δ 7.6 (IH, m) , 7.2 (7H, ) , 5.0-4.6 (3H, m) , 4.3 and 4.1 (IH, 2xm) , 3.6-3.0 (5H, m) , 2.9 (IH, m) , 2.7 (IH, m) , 2.4 (IH, m), 2.2 (IH, m) , 1.9 (6H, ) , 1.6 (6H, ) , 1.2 (6H, m) .

Ex.143 (CDClj) δ 7.6 (IH, m) , 7.2 (7H, m) , 4.6 (3H, m) , 4.4 and

4.2 (IH, 2m), 3.65 and 3.6 (3H, 2s), 3.5-3.0 (5H, m) , 2.7 (IH, m) ,

2.3 (IH, m), 2.1-1.4 (14H, m) , 1.2 (6H, m) .

Ex.144 (CDCl _j ) δ 7.6-7.1 (8H, m) , 4.8-4.5 (3H, m) , 4.4 and 4.2 (IH, 2m), 3.6 (3H, m) , 3.5-2.0 (7H, m) , 2.0-1.4 (14H, m) , 1.2 (6H, m) .

Ex.145 (CDClj) δ 7.6-6.9 (8H, m) , 5.5 (IH, m) , 4.7 (IH, t) , 4.5 (2H, m), 4.2 (IH, m) , 3.7-3.2 (5H, m) , 2.9 (IH, m) , 2.7 (IH, m) , 2.2-1.7 (7H, m), 1.5 (9H, m) , 1.2 (6H, m) .

Ex.146 (CDClj) δ 7.6-7.0 (8H, m) , 6.3 (IH, m) , 4.5 (2H, d) , 4.3 (2H. ), 3.8-3.2 (5H, m) , 2.9 (IH, m), 2.6 (IH, m) , 2.0 (7H,-m), 1.7 (6H, m), 1.4 (9H, m) .

Ex.147 (CDCl,) δ 7.6-7.0 (8H, m) , 6.1 (IH, m) , 4.8-4.2 (4H, m) , 3.6-3.2 (5H, m), 2.9 (IH, m) , 2.3 (IH, ) , 2.2-1.8 (7H, m) , 1.6 (9H, m), 1.2 (6H, m) .

Ex.148 (CDCl,) δ 7.8-7.0 (8H, ) , 4.8-4.2 (5H, m) , 3.7-3.3 (3H, m), 3.2 (IH, m), 2.7 (IH, d) , 2.6 (IH, m) , 2.4 (IH, m) , 2.2-1.2

(13H, m), 1.1 (6H, m) , 0.8 (3H, d) .

Ex.149 (d ⁶ -EMSO) δ 12.5 (IH, br s) , 7.4-6.8 (9H, m) , 5.1-4.1 (5H, m), 3.9 (IH, m), 3.7 (IH, m) , 3.3-2.9 (4H, m) , 2.5 (2H, m) , 1.9 5 (3H, s), 1.6 (6H, m), 1.3 (6H, m) .

Ex.150 (d ⁶ -EMSO) δ 7.3 (3H,m) , 7.1 (5H, m) , 6.8-6.3 (IH, ) , 4.5 (2H, s), 3.7-2.7 (7H, m) , 2.5 (2H, m) , 1.9 (5H, m) , 1.6 (6H, m) , 1.2 (6H, s) . 10

Ex.151 (CDC1 ₃ ) δ 7.7-7.1 (8H, m) , 4.6 (2H, br,s), 4.5 (IH, m) , 3.7 (3H, ), 3.65-2.0 (9H, m) ^' , 1.9 (3H, br,s), 1:6 (7H, m) , 1.3 (IH, m), 1.1 (6H, s) .

15 Ex.152 (CDC1 ₃ ) δ 7.6 (IH, d) , -7.2 (7H, ) , 4.8-4.2 (3H, m) , 4.1 (2H, m), 3.9-2.0 (9H, m) , 1.9 (3H, s) , 1.6 (10H, m) , 1.2 (3H, m) , 1.1 (6H, s) .

Ex.153 (CDC1 ₃ ) δ 7.6 (IH, d) , 7.2 (7H, m) , 4.8-4.2 (3H, m) , 4.1 20 (2H, m), 3.9-2.0 (9H, m) , 1.9 (3H, s) , 1.6 (10H, m) , 1.2 (3H, m) , 1.1 (6H, s).

Ex.154b (CDC1 ₃ ) δ 7.7 (IH, m) , 7.2 (7H, ) , 4.8-4.2 (3H, ) , 3.8 (IH, m), 3.62 and 3.64 (3H, 2xs) , 3.6-2.0 (8H, m) , 1.9 (3H, s) , 1.6 25 (8H, _. m), 1.2 (2H, m) , 1.1 (6H, s) .

Ex.155 (CDClj) δ 7.7 (IH, m) , 7.2 (7H, ) , 4.6-4.2 (3H, m) , 3.8 (IH, m), 3.63 and 3.65 (3H, 2xs) , 3.6-2.0 (8H, ) , 1.9 (3H, s) , 1.6 - (10H, m), 1.1 (6H, s) . 30

Ex.156 (CDC1 ₃ ) δ 7.7 (IH, m) , 7.2 (7H, m) , 4.8-4.2 (3H, m) , 3.8 (IH, m), 3.63 and 3.65 (3H, 2xs) , 3.6-2.0 (8H, ) , 1.9 (3H, s) , 1.6 (8H, m), 1.3 (2H, m) , 1.1 (6H, s) .

^" 35 Ex.157 (CDC1 ₃ ) δ 7.6 (IH, d) , 7.2 (7H, m) , 4.8-4.3 (3H, m),.3.8 (IH, m), 3.63 and 3.65 (3H, 2xs) , 3.6-2.0 (8H, m) , 1.9 (3H, s) , 1.6 (10H, m), 1.1 (6H, s) .

Ex.158 (d ⁶ -EMSO) δ 8.2 (IH, s) , 7.3 (3H, m) , 7.0 (5H, ) , 6.7 (IH, t), 4.47 and 4.48 (2H, 2xs) , 3.9 (IH, m) , 3.5-2.9 (4H, ) , 2.6 (IH, m), 2.4 (IH, m) , 1.8 (4H, m) , 1.6 (9H, m) , 1.3 (8H, m) , 1.0 (2H,s).

Ex.159 (d ⁶ -ΣMSO) δ 8.3 (IH, t), 7.5 (IH, s) , 7.3 (3H, m) , 7.0 (5H, m) _r 4.50 and 4.52 (2H, 2xs) , 4.1 (IH, t) , 3.4 (2H, ) , 3.1 (IH, m), 2.9 (IH, d), 2.7 (2H, ) , 1.9 (4H, ) , 1.6 (9H, m) , 1.3 (6H, ), 1.2 (IH, m), 0.9 (IH, m) , 0.7 (2H,m) .

Ex.l60d (CDC1 ₃ ) δ 7.7 (IH, d) , 7.4-7.1 (6H, m) , 6.9 (IH, m) , 5.0 (IH, d), 4.6 (IH, s), 4.3 (IH, m) , 3.5 (3H, ) , 3.3 (IH, m) , 2.9 (IH, m), 2.5-1.4 (14H, m) , 1.2 (6H, m) .

Ex.161 (CDClj) δ 7.6 (IH, d) , 7.4-7.0 (6H, m) , 6.9 (IH, m) , 5.0 (IH, s), 4.6 (2H, ), 4.3 (IH, ) , 3.5 (3H, m) , 3.2 (2H, m) , 2.8-1.4 (13H, m), 1.2 (6H, m) .

Ex.162 (CDClj) δ 7.7 (IH, d) , 7.4-7.1 (6H, m) , 6.9 (IH, m) , 5.0 (IH, ), 4.6 (IH, m) , 4.3 (IH, m) , 3.5 (3H, ) , 3.3 (IH, m) , 2.9 (IH, m), 2.5-1.4 (14H, m) , 1.2 (6H, m) .

Ex.163 (d ⁶ -EMSO) δ 8.2 (IH, t) , 7.5 (IH, s) , 7.3 (3H, m) , 7.0 (5H, ), 4.5 (2H, d), 4.0 (IH, m) , 3.1-3.4 (2H, m) , 3.0 (IH, m) , 2.9 (IH, d), 2.8-2.6 (2H, m) , 1.9-1.3 (19H, m) , 1.08 and 1.13 (6H 2xs) .

Ex.164 (d ⁶ -EMSO) δ 7.9(1H, s) , 7.3-6.8 (8H, m) , 6.8 (IH, t) , 4.5 (2H, s), 4.0 (IH, m), 3.1-3.4 (3H, m) , 3.0 (IH, m) , 2.85 (2H, m) , 2.1 (IH, m), 2.0-1.0 (24H, m) .

Ex.165 (CDClj) δ 7.7-6.9 (8H, m) , 5.7 (IH, m) , 5.4 (IH, m) , 4.9-4.4 (2H, m), 3.8-2.4 (5H, ) , 2.2-1.2 (19H, m) .

Ex.166 (CDClj) δ 7.5 (IH, m) , 7.4-7.1 (7H, m) , 5.4 and 5.1 (IH, 2xbr,s), 4.5 (2H, m) , 4.4 (2H, m) , 4.2 (2H, m) , 3.75 and 3.72 (3H, 2xs), 3.5. (2H, m), 2.8 (IH, ) , 2.5 (IH, m) , 1.9 (3H, br, s) , 1.6 (6H, m) , 1.2 (6H, m) .

Ex.167 (d ⁶ -EMSO) δ 12.8 (IH, br s) , 7.5 (IH, d) , 7.4-6.9 (9H, m) , 4.4 (2H, s), 4.1 (IH, m) , 3.8 (2H, m) , 3.4 and 3.0 (2H, 2xdd) , 3.1 and 2.8 (2H, 2xdd) , 2.5 (2H, m) , 2.45 and 2.0 (2H, 2xdd) , 1.9 (3H, s), 1.6 (6H, m), 1.3 (6H, s) .

Ex.168 (d ⁶ -EMSO) δ 12.8 (IH, br s) , 7.7 (IH, d) , 7.4-6.9 (8H, m) , 6.8 (IH, t), 4.4 (2H, s) , 4.1 (IH, ) , 3.9 (2H, ) , 3.5 and 3.1 (2H, 2xdd), 2.9 (2H, 2xdd) , 2.6 (2H, m) , 2.4 and 1.9 (2H, 2xdd) , 1.85 (3H, s), 1.6 (6H, m) , 1.3 (6H, s) .

Ex.169 (d ⁶ -DMSO) δ 7.5 (IH, d) , 7.4-6.9 (9H, m) , 4.4 (2H, s) , 4.2-3.8 (3H, m), 3.6 ^' (3H, s) , 3.5-2.9 (4H, m) , 2.8 (IH, d) , 2.5 (2H, m), 2.0 (IH, m) , 1.9 (3H, s) , 1.6 (6H, ) ^' , 1.3 (6H, s) .

Ex.170 (d ⁶ -DMSO) δ 7.6 (IH, d) , 7.4-6.9 (8H, m) , .6.8 (IH, t) , 4.4 (2H, s), 4.0 (3H, ), 3.6 (3H, s) , 3.6-1.95 (8H, m) , 1.9 (3H, s) , 1.6 (6H, m), 1.3 (6H, s) .

Ex.171 (d ⁶ -DMSO) δ 8.1 (IH, m) , 7.9 and 7.5 (IH, 2xm) , 7.4-6.9 (14H, m), 4.6-4.2 (3H, m) , 3.8-2.4 (8H, m) , 1.9 (3H, br,s), 1.6 (6H, m), 1.3 (6H, m) .

Ex.172 (d ⁶ -DMSO) δ 8.0-6.8 (16H, m) , 4.5-4.0 (4H, m), '3.4-2.4 (6H, m), 1.8 (3H, s), 1.6 (6H, m) , 1.2 (6H, ) , 1.1 (3H, d) .

Ex.173 (d ⁶ -DMSO) δ 8.0-6.9 (16H, ) , 4.5-4.0 (3H, m) , 3.3-2.5 (8H, m), 1.8 (3H, m), 1.6 (6H, m) , 1.2 (6H, ) .

Ex.174 (d ⁶ -DMSO) δ 10.85 and 10.8 (IH, 2xs) , 8.1 (IH, m) , 7.7-6.7 (15H, m), 4.5-4.1 (3H, m) , 3;8-2.3 (8H, m) , 1.9 (3H, m) , 1.6 (6H, m), 1.2 (6H, m) .

Ex.175 (CDC1 ₃ ) δ 7.6-7.0 (8H, m) , 4.8 (2H, ) , 4.6 (2H, m) , 4.3 (IH, m) , 3.6-2.2 (9H, m) , 2.1-1.4 (13H, m) , 1.2 (6H, s) .

Ex.176 (CDC1 ₃ ) δ 7.6-6.7 (8H, ) , 4.8-4.0 (5H, m) , 3.3-2.0 (9H, ), 1.8-0.8 (19H, m) .

Ex.177 (CDClj) δ 7.1 (IH, m) , 7.0-6.6 (8H, m) , 5.6 (IH, br,s), 4.3 (IH, s), 4.1 (IH, s), 3.3 (IH, m) , 2.9 (IH, d) , 2.7 (IH, d) , 0.9 (16H, m), 0.6 (6H, t) .

Ex.178 (d ⁶ -EMSO) δ 12.8 (IH, br s) , 7.7 (IH, m) , 7.4-6.9 .(8H, m) , 6.7 and 6.6 (IH, 2xm) , 4.4 (2H, m) , 4.3-3.8 (3H, m) , 3.4-2.8 (4H, m), 2. ^' 5 (2H, ), 2.1 (IH, m) , 1.9 (3H, s) , 1.6 (7H, m) , 1.3 (6H, m) .

Ex.179 (d ⁶ -EMS0) δ 12.8 (IH, br s) , 7.7 (IH, ) , 7.5-7.0 (8H, m) , 6.7 and 6.6 (IH, 2xm) , 4.4 (2H, m) , 4.3-3.5 (3H, m) , 3.4-2.9 (4H, m), 2.5 (2H, m), 2.1 (IH, m) , 1.9 (3H, s) , 1.6 (7H, ) , 1.3 ^' (6H, m) .

Ex.180 (d ⁶ -EMSO) δ 8.3-6.9 (10H, m) , 4.5 (2H, m) , 4.0-2.5 (8H, m), 1.9 (4H, m), 1.7 (9H, m) , 1.4-1.2 (9H, m) .

Ex.181 (d ⁶ -EMSO) δ 8.3 and 8.25 (IH, 2t) , 7.7-6.9 (10H, ) , 6.6 and 6.5 (IH, 2s), ^' 4.5 (2H, m) , ^' 4.1 and 3.8 (IH, 2m), 3.6-2.4 (8H, m), 2.0-1.5 (13H, m) , 1.4 and 1.3 (6H, m) .

Ex.182 (d ⁶ -EMSO) δ 8.1-6.8 (18H, ) , 4.5-4.1 (3H, m) , 3.6-2.4 ^' (8H, ), 1.9 (3H, sm) , 1.6 (6H, m) , 1.3 (6H, m) .

Ex.183 (d ^& -EMSO) δ 12.0 (IH, br s) , 7.9 (IH, m) , 7.4 (4H, m) , 7.1-6.8 (5H, m), 4.6-4.3 (3H, m) , 3.9 (IH, ) , 3.7 (2H, m) , 3.5-2.9 (5H, m), 2.6 (2H, _. m), 1.9-1.5 (11H, ) , 1.3 (6H, m) .

Ex.l84b (d ⁶ -DMSO) δ 12.6 (IH, br s) , 8.1 and 6.3 (IH, 2xt) , 7.4-6.9 (9H, m) , 4.5 (2H, m),-4.2-3.9 (2H, m) , 3.5-2.8 (6H, m) , 2.6 (2H, m), 2.1-1.5 (13H, m) , 1.4-1.1 (9H, m) .

Ex.185 (d ⁶ -DMSO) δ 12.6 (IH, br s) , 8.0 and 6.3 (IH, 2xm) , 7.4-6.9 (9H, m), 4.5 (2H, m), 4.2-3.9 (2H, ) , 3.5-2.8 (6H, m) , 2.6 (2H, m), 2.1-1.5 (13H, m) , 1.4-1.1 (9H, m) .

Ex.186b (d ^δ -DMSO) δ 12.5 (IH, br s), 8.2 and 8.0 (IH, 2xd) , 7.4-6.9 (9H, m), 4.5 (2H, ) , 4.1 (2H, m) , 3.5-2.3 (8H, m) , 2.2-1.5

(13H, ) , 1.4-1.1 (9H, m) .

Ex.187 (d ⁶ -EMSO) δ 12.4 (IH, br s) , 8.1 (IH, d) , 7 .3 (3H, m) , 7 .1 (5H, m) , 4.5 (2H, d) , 4.1 (IH, m) , 3 .9 (IH, m) , 3 .3-2 .9 (6H, m) , 2.5 (2H, m) , 2.1-1.4 (13H, m) , 1.2 (9H, m) .

Ex.188 (CDClj) δ 9.1 and 6.0 (IH, 2xt), 7.6-7.0 (8H, m) , 4.6-4.3 (3H, m), 4.1 (IH, m), 3.8 and 3.3 (3H, 2xs) , 3.6-3.1 (6H, m) , 2.9 (IH, m), 2.7-2.2 (2H, m) , 2.0-1.6 (12H, m) , 1.4 and 1.2 (6H, 2xs) .

Ex.189 (CDClj) δ 7.6-7.0 (8H, m) , 5.9 (IH, m) , 4.5 (3H, m), 4.1 (IH, m), 3.7 (3H, s) , 3.6-3.4 (4H, ) , 3.3 (2H, s) , 2.8 (IH, m) , 2.6 (IH, m), 2.3 (IH, m) , 2.0-1.6 (12H, ) , 1.4 (6H, s) .

Ex.190 (d ⁶ -DMSO) δ 7.4-6.9 (8H, ) , 6.8 (IH, t), 4.8-4.1 (3H, m) , 3.6-2.6 (9H, m), 2.5 (2H, m) , 1.9-1.4 (13H, ) , 1.2 (6H, m) .

Ex.191 (d ⁶ -EMSO) δ 7.8 (IH, t) , 7.5-6.9 (8H, ) , 6.8 and 6.7 (IH, 2xt), 4.8-3.8 (5H, m) , 3.6 (3H, m) , 3.4-2.9 (4H, m) , 2.5 (2H, m) , 2.1 (IH, m), 1.9 (3H, br s) , 1.7-1.2 (13H, ) .

Ex.192 (CDClj) δ 7.6-7.1 (8H, m) , 5.1 and 4.7 (IH 2xm) , 4.5 and 4.3 (IH, 2xd), 3.5 (2H, m) , 3.4-2.8 (4H, m) , 2.4-1.1 (25H, m) .

Ex.193 (CDClj) δ 7.5 (IH, d) , 7.4-7.1 (7H, _, ) , 4.6 (IH, m) , 4.2 (IH, m) , 3.5 (2H, m) , 3.2 (2H, m) , 2.9 (IH, ) , 2.3 (IH, m) , 2.2-1.8 (13H, m), 1.6 (6H, m) , 1.2 (6H, ) .

Ex.194 (d ⁶ -DMSO) δ 12.5 (IH, br s) , 8.1 (IH, t) , 7.3 (3H, m) , 7.0 (5H, m), 6.3 (IH, t) , 4.5 (2H, ) , 3.9 (IH, ) , 3.7 (2H, m) , 3.4-2.9 (4H, m), 2.7-2.3 (4H, m) , 2.1 (IH, m) , 1.8 (3H, s) , 1.6 (9H, m), 1.3 (6H, s) .

Ex.195 (CDCl,) δ 7.7-7.1 (8H, ) , 6.9 and 6.0 (IH 2xt) , 4.6(3H, m), 4.4-4.0 (3H, ) , 3.8 (IH, ) , 3.5 (4H, ) , 3.2 (2H, m) , 2.8 (IH, m), 2.3 (2H, m) , 1.9 (6H, m) , 1.8-1.2 (22H, ) .

Ex.196 (CDCl,) δ 7.6 (IH, d) , 7.5-7.1 (7H, m) , 6.9 (IH, d) , 5.8

and 5.2 (2H, dd) , 4.5 (3H, m) , 4.3 (IH, m) , 3 .5 (4H, m) , 3 .2 (IH, d) , 2.9 (IH, m) , 2.5-2.1 (2H, m) , 2 .0-1.1 (30H, m) .

Ex.197 (d ⁶ -EMSO) δ 8.2 and 6.7 (lH,2xm), 7.4-6.8 (10H, ) , 4.5 (2H, m), 4.1 and 3.8 (IH, 2xm) , 3.6-2.5 (6H, m) , 1.9 (3H, ) , 1.8-1.5 (10H, m), 1.4 and 1.2 (6H, 2xs) .

Ex.l98b (d ⁶ -EMSO) δ 12.6 (IH, br s) , 8.0 (IH, t) , 7.4 (3H, m) , 7.0 (6H, m), 4.5 (2H, d) , 4.1 (IH, m) , 3.6 (2H, m) , 3.4-2.8 (4H, m) , 2.6-2.2 (4H, m) , 1.9 (3H, s) , 1.6 (10H, m) , 1.35 (6H, s) .

Ex.199 (d ⁶ -EMSO) δ 12.6 (IH, br s) , 8.1 (IH, t) , 7.3 (3H, m) , 7.0 (5H, m), 6.4 (IH, t) , 4.5 (2H, ) , 3.9 (IH, m) , 3.6 (2H, m) , - 3.4-2.9 (4H, m), 2.6-2.4 (4H, m) , 2.1 (IH, m) , 1.8 (3H, s) , 1.6 (9H, ), 1.2 (6H, s) .

Ex.200 (d ⁶ -DMSO) δ 12.6 (IH, br s) , 8.0 (IH, d) , 7.3 (3H, m) , .7.0 (6H, m), 4.5 (2H, ) , 4.0 (2H, m) , 3.4-2.8 (4H, m) , 2.6-2.1 (5H, m), 1.9 (3H, s), 1.6 (9H, m) , 1.2 (9H, m) .

Ex.201 (d ⁶ -EMSO) δ 12.6 (IH, br s) , 8.0 (IH, d) ; 7.3 (3H, m) , 7.0 (5H, m), 6.3 (IH, t) , 4.5 (2H, d) , 4.1 (IH, ) , 3.9 (IH, m) , 3.4-2.9 (4H, m), 2.6-2.4 (4H, m) , 2.0 (IH, m)., 1.9 (3H, s) , 1.6 (9H, m), -1.2 (9H, m) . ^" - -

Ex.202 (d ⁶ -EMSO) δ 12.6 (IH, br s) , 8.0 (IH, d) ; 7.3 (3H, ) , 7.0 (6H, m), 4.5 (2H, d) , 4.1 (2H, m) , 3.5-2.8 (4H, m) , 2.7-2.2 (5H, ), 1.9 (3H, s), 1.6 (9H, m) , 1.4-1.1 (9H, ) .

Ex.203 (d ⁶ -EMSO) δ 12.6 (IH, br sj , 8.1 (IH, d) , 7.3 (3H, m) , 7.0 (5H, m), 6.4 (IH, t) , 4.5 (2H, d) , 4.1 (IH, m) , 3.9 (IH, m) , 3.4-2.9 (4H, ), 2.7-2.3 (4H, ) , 2.0 (IH, m) , 1.8 (3H, s) , 1.6 (9H, m), 1.2 (9H,. m) .

Ex.204 (CDCl,) δ 7.6-7.1 (8H, m) , 5.1-4.5 (3H, m) , 4.0 (IH, m) , 3.6-2.2 (10H, m), 2.0-1.4 (13H, m) , 1.2 (6H, m) .

Ex.205 (CDC1 ₃ ) δ 7.6 (IH, m) , 7.4-7.0 (7H, m) , 6.8 (IH, m) , 5.8

(IH, dd), 4.7-4.4 (4H, ) , 3.8 and 3.75 (3H, 2xs) , 3.6-2.2 (6H, m) , 2.0-1.4 (13H, m), 1.2 (6H, m) .

Ex.206 (CDC1 ₃ ) δ 7.7-7.1 (8H, ) , 4.5 (3H, m) , 3.9 (IH, m) , 3.7 and 3.6 (3H, 2xs) , 3.5-2.1 (10H, ) , 2.0-1.5 (13H, m) , 1.2 (6H, ) .

Ex.207 (d ⁶ -E SO) δ 8.0 (IH, t) , 7.5 (IH, d) , 7.4-6.8 (16H, ) , 4.4 (2H, s), 4.1 (IH, m), 3.6-3.1 (3H, m) , 2.9 (3H. ) , 2.5 (2H, m) , 1.9 (3H, s), 1.6 (6H, m) , 1.3 (6H, s) .

Ex.208 (d ⁶ -DMSO) δ 8.0 (IH, t) , 7.8 (IH, d) , 7.5 (IH, t) , 7.4-6.9 (15H, ), 4.5 (IH, s), 4.3 (IH, m) , 4.2 (IH, s) , 3.6-3.0 (4H, m) , 2.7 (2H, m), 2.5 (2H, m) , 1.9 (3H, s) , 1.6 (6H, m) , 1.3 (6H, ) .

Ex.209 (CDC1 ₃ ) δ 7.4-7.0 (8H, m) , 5.6 (IH, t) , 4.6 (IH, s) , 4.4 (IH, s), 2.9 (3H, m), 2.3 (2H, dd) , 2.0 (3H, s) , 1.6 ^" (6H, m) , 1.3 (IH, d), 1.2 (6H, s) .

Ex.210 (CDC1 ₃ ) δ 7.2 (8H, m) , 7.1 and 6.2 (IH, 2xd) , 5.7 and 5.6 (IH, 2xt), 4.7-4.2 (3H, m) , 3.7 (3.H, s) , 3.0-2.2 (5H, m) , 2.0 (3H, s), 1.7 (7H, ), 1.43 and 1.40 (6H, 2xs) , 1.3 and 1.1 (3H, 2xd) .

Ex.211 ^' (CDC1 ₃ ) δ 7.5-7.0 (8H, m) , 5.8 and 5.6 (IH, 2xt) , 4.8-4.3 (3H, m), 3.9-3.2 (3H, ) , 3.0 (3H, ) , 2.6-1.0 (21H, m) .

Ex.212 (CDC1 ₃ ) δ 7.5 (IH, d) , 7.4-7.1 (7H, m) , 6.2 (IH, d) , 5.8 (IH, t), 4.5 (2H, d), 3.8 (IH, m) , 3.2 (2H, dd) , 2.8 (IH, m) , 2.7 (IH, m), 2.4 (IH, m) , 2.0 (3H, s) , 1.8-1.1 (18H, m) .

Ex.213 (CDC1 ₃ ) δ 7.5-7.1 (8H, ) , 6.3 (IH, d) , 5.7 (IH, t) , 4.5 (2H, d), 3.8 (IH, m), 3.2 (2H, dd) , 2.8 (IH, ) , 2.7 (IH, m) , 2.5 (IH, m), 2.0 (3H, s) , 1.8-1.1 (18H, ) .

Ex.214 (CDCl,) δ 7.6-6.8 (9H, ) , 6.0 (IH, m) , 4.8-4.2 (4H, m) , 3.8 (3H, s), 3.6-2.1 (7H, m) , 2.0-1.1 (21H, ) .

Ex.215 (CDClj) δ 7.6-7.1 (8H, m) , 5.1-4.5 (3H, m) , 4.0 (IH, m) , 3.6-2.2 (10H, m), 2.0-1.4 (13H, m) , 1.2 (6H, m) .

Ex.216 (d ⁶ -EMSO) δ 8.0-7.0 (15H, m) , 6.8-6.5 (2H, m) , 4.5-4.0 (3H, m), 3.4-3.0 (4H, m) , 2.5 (2H, m) , 1.82 and 1.78 (3H, 2xs) , 1.6 (6H, m), 1.1 and 1.2 (6H, 2xs) .

Ex.217 (d ⁶ -EMSO) δ 8.2-6.8 (16H, m) , 6.5 (IH, t) , 4.5-4.1 (3H, m), 3.4-2.2 (6H, m) , 1.8 and 1.7 (3H, 2xs) , 1.6 (6H, m) , 1.1 and 1.2 (6H, 2xs) .

Ex.218 (d ⁶ -EMSO) δ 8.0 (IH, t) , 7.7 (IH, d) , 7.4-6.7 (14H, m) , 4.5-4.0 (4H, ), 3.6-2.3 (6H, m) , 1.8 (3H, s) , 1.6 (6H, m) , 1.3-1.0

(9H, m) .

Ex.219 (d ⁶ -DMSO) δ 12.6 (IH, br s) ,. 7.4-6.9 (13H, m) , 5.0-4.0

(4H, m), 3.6-3.0 (3H, m) , 2.8-2.1 (4H, m) , 1.7 (3H, br s) , 1.6 (6H, m), 1.1 and 1.08 (6H, 2xs) .

Ex.220c (CDClj) δ 7.6-7.0 (8H, ) ^' , 4.8-4.3 (3H, m) , 3.8-2.3 _. (9H, m), 2.2-1.4 (19H, m) .

Ex.221 (CDClj) δ 7.6-7.0 (8H, m) , 6.4 (IH, m) , 4.6-4.4 (2H, m) , 4.3-4.0. (IH, m), 3.9-3.1 (9H, m) , 2.9-2.6 (2H, m) , 2.3 (IH, m) , 2.1-1.9 (6H, m) , 1.6 (6H, m) , 1.4 and 1.2 (6H, 2 x s) .

Ex.222 (CDC1 ₃ ) δ 7.6-6.9 (8H, m) , 5.5 (IH, m) , 4.5 (2H, m) -, 4.2 (IH, m), 3.7-3.1 (8H, m) , 2.9 (IH, m) , 2.7 (IH, m) , 2.2-1.7 (7H, m), 1.5 (9H, ), 1.2 (6H, m) .

Ex.223 (CDClj) δ 7.6-7.0 (8H, m) , 6.1 (IH, m) , 4.7-4.2 (3H, m) , 3.6-3.1 (8H, m), 2.9 (IH, m) , 2.3 (IH, m) , 2.2-1.8 (7H, m) , 1.6 (9H, m), 1.2 (6H, ) .

Ex.224b (d ⁶ -EMSO) δ 12.6 (IH, br s) , 7.4-6.9 (9H, m) , 4.5 (2H, m) , 4.2-3.9 (2H, ), 3.5-2.8 (9H, m) , 2.6 (2H, m) , 2.1-1.5 (13H, ) , 1.4-1.1 (9H, ) .

Ex.225 (d ⁶ -EMSO) δ 12.6 (IH, br s) , 7.4-6.9 (9H, m) , 4.5 (2H, m) , 4.2-3.9 (2H, m), 3.5-2.8 (9H, m) , 2.6 (2H, m) , 2.1-1.5 (13H, m) , 1.4-1.1 (9H, m) .

Ex.226b (d ⁶ -EMSO) δ 12.6 (IH, br s) , 8.0 (IH, d) , 7.3 (3H, ) , 7.0 (5H, m), 4.5 (2H, d) , 4.1 (IH, m) , 3.9 (IH, m) , 3.4-2.9 (7H, m) , 2.6-2.4 (4H, ), 2.0 (IH, m) , 1.9 (3H, s) , 1.6 (9H, ) , 1.2 (9H, m) .

Ex.227 (CDC1 ₃ ) δ 7.6-7.0 (9H, m) , 6.0 (IH, m) , 4.6-4.0 (5H, m) , 3.8-3.2 (6H, m), 2.9-2.2 (3H, m) , 2.0-1.2 (19H, ) .

Ex.228 (CDC1 ₃ ) δ 7.8-7.1 (9H, m) , 6.6 (IH, m) , 4.6-4.2 (4H, m) , 3.6-3.0 (4H, m), 2.9-2.0 (3H, m) , 2.0-1.2 (21H, m) .

Ex.229 (CDC1 ₃ ) δ 8.1 (IH, t) , 7.6 (IH, d) , 7.4-7.1 (7H, m) , 6.0 (IH, t), 4.8 (IH, m), 4.6 (IH, s) , 4.4 (IH, s) , 4.1 (IH,. dd) , 3.8 (IH, dd) , 3.5 (2H, m), 2.9-2.2 (6H, m) , 2.0 (3H,- s) , 1.6 (6H, m) , 1.4 (6H, s) .

Ex.230 (CDC1 ₃ ) δ 7.6-6.9 (9H, m) , 5.8 (IH, m) , 4.5 (2H, ) , 4.2-3.6 (3H, m), 3.2 (2H, m) , 2.5 (2H, m) , 2.2-1.2 (19H, m) .

Ex.231 (d ⁶ -DMSO) δ 12.6 (IH, br s) , 8.1 (IH, d) , 7.3 (3H, m) , 7.0 (5H, m), 4.5 (2H, d) , 4.1 (IH, ) , 3.9 (IH, m) , 3.4-2.9 (7H, m) , 2.7-2.3 (4H, ), 2.0 (IH, m) , 1.8 (3H, s) , 1.6 (9H, m) , 1.2 (9H, m).

Ex.232 (d ⁶ -DMSO) δ 12.5 (IH, br s) , 8.2 and 8.0 (IH, 2xd) , 7.4-6.9 (9H, m), 4.5 (2H, m) , 4.1 (2H, m) , 3.7 (3H, s) , 3.5-2.3- (8H, m) , 2.2-1.5 (13H, m), 1.4-1.1 (9H, ) .

Ex.233 (d ⁶ -DMSO) δ 12.6 (IH, br s) ^' , 8.6 and 8.4 (IH, 2xt) , 8.2 and 7.8 (IH, 2xt), 7.6 (lH,m) , 7.3 (3H, m) , 7.0 (4H, m) , 5.0 and 4.7 (IH, 2xd), 4.55 (2H, d) , 4.5-4.1 (2H, ) , 3.9-3.5 (4H, m) , 3.3-2.4 (4H, m) , 1.9 (3H, s) , 1.6 (6H, m) , 1.3 (6H, m) .

Ex.234 (d ⁶ -LMSO) δ 12.6 (IH, br s) , 8.9 and 8.3 (IH, 2xm) , 7.6

(IH, t) , 7.3 (3H, m) , 7.0 (5H, m) , 5.1 and 4.6 (IH, 2xm) , 4.5 (IH, s) , 4.4 (IH, s) , 4.3-3 .6 (6H, ) , 3 .4-2 .2 (4H, ) , 1.9 (3H, s) , 1.6-1.3 (12H, m) .

Ex.235 (d ⁶ -EMSO) δ 12.7 (IH, br s) , 9.0 (IH, m) , 8.6-8.2 (3H, m) , 7.7-6.9 (6H, m) , 4.9-3 .0 (9H, m) , 2.8-2 .2 (4H, ) , 1.9 (3H, m) , 1.6-1.3 (12H, m) .

Ex.236 (d ⁶ -EMSO) δ 9.4 (IH, s) , 8.4 (2H, s) , 8.3 (IH, t) , 8.1 (IH, s), 7.3 (3H, m), 7.1 (3H, m) , 6.9 (2H, m) , 4.6 (2H, s) , 4.3 (IH, m), 3.5 (2H, m), 3.1 and 3.0 (2H, 2xd) , 2.8 and 2.6 (2H, m) , 2.1- 1.2 (19H, m) .

Ex.237 (d ⁶ -EMSO) δ 11.7 (IH, s) , 10.2 (IH, s) , 8.44 (2H, s) , 8.4 (IH, t), 8.1 (IH, s), 7.3 (3H, m) , 7.1 (3H, m) , 6.9 (2H, m) , 4.5

(2H, s), 4.0 (IH, m), 3.5 (2H, m) , 3.1 and 3.0 (2H, 2xd) , 2.8-2.5 (2H, ), 2.0-1.1 (19H, m) .

Ex.238 (d ⁶ -DMSO) δ 8.1 and 8.0 (IH, 2xd) , 7.3 (3H, m) , 7.0 (5H, m), 7.0 and 6.3 (IH, 2xt) , 4.5 (2H, m) , 4.2-2.1 (12H, m) , 2.0-1.1 (22H, m) .

The coitpounds of the examples were tested for binding at the CCKβ receptor in mouse cortical membranes by means of a radioligand binding assay. Ihe procedure was as follows:

The whole brains from male mice (CD1 22-25g; Charles River) were removed and placed in ice-cold buffer (pH7.2 @ 21 ± 3°C) of the following composition (nM) ; 10 HEPES, 130 NaCl, 4.7 KC1, 5 MgCl ₂ , 1 EDTA and containing O^Sg.l ^"1 bacitracin. The cortex was dissected, weighed and homogenised in 40ml ice-cold buffer using a Teflon-in-glass homogeniser. Ihe homogenate was centrifuged at 39,800g for 20 min at 4°C, the supernatant discarded and the pellet resuspended by hα ogenisation in fresh buffer. Ihe homogenate was recentrifuged (39,800g; 20 min @ 4°C) and the final pellet was resuspended in HEPES buffer to give a tissue concentration of 2mg.ml ^~1 (original wet weight) .

The membranes (400ml) were incubated for 150 min at 21 ± 3°C in a final volume of 0.5ml with HEPES buffer containing [ ¹²⁵ I]-CCK8S

(0.05ml; 200pM NEN 2200Ci.mtιol ^"1 ) and competing ccmpound. Total and non-specific binding of [ ¹²⁵ I]-CCK8S were defined using 0.05ml of buffer and 0.05ml of lOπM L-365,260, respectively. The assay was terminated by rapid filtration through pre-soaked Whatman GF/B filters using a Brandell Cell harvester. The filters were washed

(3 x 3ml) with ice-cold 50τrM Tris-HCl (pH7.4 @ 4°C) and bound radioactivity determined by counting (1 min.) in a gamma-counter.

The results obtained from the CCKg assays are set out in Table 1.

TABLE 1

Exaπple K_ pKi Exanple CCK _B pK _j

TABLE 1 (continued)

Exaπple cσ pi Exanple CCi pK _t

TABLE 1 (continued)

Exaπple CCKβ piς Exanple CCKg pi

TABLE 1 (continued)

Exaπple CCK _B pKi Exaπple cα pKi

The compounds of the exanples were also tested for . gastrin antagonist activity ^' in an immature rat stomach assay. The procedure was as follows:

The oesophagus of imtBture rats (33-50 g, ca. 21 days old) was

ligated at the level of the cardiac sphincter and the duodenal sphincter was cannulated. The stcπach was excised and flushed with ca. 1 ml of unbuffered physiological saline solution. The fundus was punctured and cannulated. A further 4-5 ml of unbuffered solution was flushed through the stomach to ensure the preparation was not leaking. The stcπach was lowered into a jacketed organ bath containing 40 ml of buffered solution containing 3 10 ^" ^ 5-methylfurmethide, πaintained at 37° and gassed vigorously with 95% C^/ 5% CPz- The stomach was continuously perfused at a rate of 1 ml min ^"1 with unbuffered solution gassed with 100%. __ with the perfusate passing over an internally referenced pH-electrode fixed 12 cm above the stomach.

After 120 min of stabilisation the drugs were added directly to the serosal solution in the organ bath and after a further 60 min - cumulative pentagastrin dose-response curves were started. Changes in acid secretion were monitored and the curves analysed according to Black et.al., Br. J. Pharmacol., 1985, .86, 581.

The results obtained from the gastrin assays are set out in Table 2.

TABLE 2 (continued)

The coπpounds of the exanples were also tested in a CCK^ binding assay as follows:

The pancreatata were removed from male guinea-pigs (200-300g; Dunkin Hartley) and placed in ice-cold HEPES buffer (pH 7.2 @ 21 ± 3 ^' ) . The pancreatata were homogenised in 40 ml ice-cold HEPES buffer using a polytron (Brinkmann, PT10, setting 10).4 x 1 second.

The homogenate was centrifuged at 39,800g for 15 min at 4'. The supernatant was discarded and the pellet re-suspended using a Teflon-in-glass hαmogeniser in 20 volumes of fresh buffer and re- centrifuged as above. Ihe final pellet was re-suspended using a Teflon-in-glass hαmogeniser to a tissue concentration of 1 mg.ml ^"1 (original wet weight) , and filtered through 500 μm pore-size Nytex mesh.

The membranes (400μl; containing 0.375 μM PD134,308) are incubated for 150 minutes at 21 ± 3' in a final volume of 0.5ml with HEPES buffer containing [ ¹²⁵ I]-CCK ₈ (S) (50μl; 200pM) and competing cαπpound. Total and non-specific binding of [ ¹²⁵ I] -CCKa(S) are defined using 50μl of buffer and 50μl of lOOnM L-364,718 respectively. The assay is terminated by rapid filtration through pre-soaked Whatman GF/B filters using a Brandell Cell Harvester. The filters were washed (3 x 3ml) with ice-cold 50mM Tris HCl (pH 7.4 at 4 ^* ) and bound radioactivity is determined by counting (1 min) in a gamma counter.

The results are set out in Table 3.

TABLE 3

Exanple CCK _A pi Exaπple CCK _A pi

TABLE 3 (continued)

Exanple CCK _A pK _j Exaπple CCK _A pKi

TABLE 3 (continued)

Exaπple CCK _A pi Exanple CCK _A pK,