Tricyclic lactam derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors

Abstract

Compounds of the formula (I) useful as 11-Beta Hydroxysteroid Dehydrogenase Inhibitors ##STR00001##

Claims

1. A compound having the formula ##STR00069## the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein X represents C; Y represents C; L represents a methyl or a direct bond; Z.sup.1 represents a direct bond, C.sub.1-2alkyl- or a divalent radical of formula CH.sub.2CH (a) or CH (b); Z.sup.2 represents a direct bond, C.sub.1-2alkyl- or a divalent radical of formula CH.sub.2CH (a) or CH (b); R.sup.1 represents hydrogen, halo, cyano, amino, phenyl, hydroxy, C.sub.1-4alkyloxycarbonyl, O(CO)C.sub.1-4alkyl, hydroxycarbonyl, NR.sup.3R.sup.4 or C.sub.1-4alkyl wherein said C.sub.1-4alkyl or O(CO)C.sub.1-4alkyl are optionally substituted with one or more substituents selected from halo, hydroxycarbonyl, phenyl, C.sub.1-4alkyloxy or NR.sup.5R.sup.6 or R.sup.1 represents C.sub.1-4alkyloxy- optionally substituted with one or more substituents selected from halo, hydroxycarbonyl, phenyl, C.sub.1-4alkyloxy or NR.sup.7R.sup.8; R.sup.2 represents hydrogen, halo, C.sub.1-4alkyl or C.sub.1-4alkyloxy-; R.sup.3 and R.sup.4 each independently represent hydrogen, C.sub.1-4alkyl or C.sub.1-4alkylcarbonyl-; R.sup.5 and R.sup.6 each independently represent hydrogen, C.sub.1-4alkyl or C.sub.1-4alkylcarbonyl-; R.sup.7 and R.sup.8 each independently represent hydrogen, C.sub.1-4alkyl or C.sub.1-4alkylcarbonyl-; A represents a monocyclic heterocycle selected from the group consisting of thiophenyl, furanyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrridinyl, pyridazinyl, pyrimidinyl and piperazinyl.

2. A compound according to claim 1 wherein; X represents C; Y represents C; L represents a methyl or a direct bond; Z.sup.1 represents a direct bond, C.sub.1-2alkyl- or a divalent radical of formula CH.sub.2CH (a) or CH (b); Z.sup.2 represents a direct bond, C.sub.1-2alkyl- or a divalent radical of formula CH.sub.2CH (a) or CH (b); R.sup.1 represents hydrogen, halo, cyano, amino, phenyl, hydroxy, C.sub.1-4alkyloxycarbonyl, hydroxycarbonyl, NR.sup.3R.sup.4 or C.sub.1-4alkyl optionally substituted with one or more substituents selected from hydroxycarbonyl, phenyl, C.sub.1-4alkyloxy or NR.sup.5R.sup.6 or R.sup.1 represents C.sub.1-4alkyloxy- optionally substituted with one or more substituents selected from hydroxycarbonyl, phenyl, C.sub.1-4alkyloxy or NR.sup.7R.sup.8; R.sup.2 represents hydrogen, halo, C.sub.1-4alkyl or C.sub.1-4alkyloxy-; R.sup.3 and R.sup.4 each independently represent hydrogen, C.sub.1-4alkyl or C.sub.1-4alkylcarbonyl-; R.sup.5 and R.sup.6 each independently represent hydrogen, C.sub.1-4alkyl or C.sub.1-4alkylcarbonyl-; R.sup.7 and R.sup.8 each independently represent hydrogen, C.sub.1-4alkyl or C.sub.1-4alkylcarbonyl-; A represents a monocyclic heterocycle selected from the group consisting of thiophenyl, furanyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrridinyl, pyridazinyl, pyrimidinyl and piperazinyl.

3. A compound according to claim 1 wherein; L represents methyl or a direct bond; R.sup.1 represents hydrogen, halo or hydroxy; R.sup.2 represents hydrogen, halo or C.sub.1-4alkyloxy-; A represents a monocyclic heterocycle selected from the group consisting of pyridinyl and thiophenyl.

4. A compound according to claim 1 wherein; A represents pyridinyl and wherein L represents a direct bond; and/or R.sup.1 represents halo, cyano, amino, phenyl, hydroxy, C.sub.1-4alkyloxycarbonyl-, hydroxycarbonyl, NR.sup.3R.sup.4 or C.sub.1-4alkyl substituted with one or more substituents selected from hydroxycarbonyl, phenyl, C.sub.1-4alkyloxy or NR.sup.5R.sup.6.

5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, an effective 11-HSD1 inhibitory amount of a compound as described in claim 1.

6. A process of preparing a pharmaceutical composition as defined in claim 5, characterized in that, a pharmaceutically acceptable carrier is intimately mixed with an effective 11-HSD1 inhibitory amount of a compound as described in claim 1.

7. A compound of formula ##STR00070## the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein X represents C; Y represents C; L represents a methyl or a direct bond; Z.sup.1 represents a direct bond, C.sub.1-2alkyl- or a divalent radical of formula CH.sub.2CH (a) or CH (b); Z.sup.2 represents a direct bond, C.sub.1-2alkyl- or a divalent radical of formula CH.sub.2CH (a) or CH (b); R.sup.1 represents hydrogen, halo, cyano, amino, phenyl, hydroxy, C.sub.1-4alkyloxycarbonyl, O(CO)C.sub.1-4alkyl, hydroxycarbonyl, NR.sup.3R.sup.4 or C.sub.1-4alkyl wherein said C.sub.1-4alkyl or O(CO)C.sub.1-4alkyl are optionally substituted with one or more substituents selected from halo, hydroxycarbonyl, phenyl, C.sub.1-4alkyloxy or NR.sup.5R.sup.6 or R.sup.1 represents C.sub.1-4alkyloxy- optionally substituted with one or more substituents selected from halo, hydroxycarbonyl, phenyl, C.sub.1-4alkyloxy or NR.sup.7R.sup.8; R.sup.2 represents hydrogen, halo, C.sub.1-4alkyl or C.sub.1-4alkyloxy-; R.sup.3 and R.sup.4 each independently represent hydrogen, C.sub.1-4alkyl or C.sub.1-4alkylcarbonyl-; R.sup.5 and R.sup.6 each independently represent hydrogen, C.sub.1-4alkyl or C.sub.1-4alkylcarbonyl-; R.sup.7 and R.sup.8 each independently represent hydrogen, C.sub.1-4alkyl or C.sub.1-4alkylcarbonyl-; A represents a monocyclic heterocycle selected from the group consisting of thiophenyl, furanyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrridinyl, pyridazinyl, pyrimidinyl and piperazinyl.

8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound as described in claim 7.

Description

EXPERIMENTAL PART

(1) In the procedures described hereinafter the following abbreviations were used: THF, which stands for tetrahydrofuran; DIPE stands for diisopropylether; EtOAc stands for ethyl acetate; DMF stands for N,N-dimethylformamide, BMS stands for trihydro[thiobis[methane]]boron [13292-87-0].

(2) Extrelut is a product of Merck KgaA (Darmstadt, Germany) and is a short column comprising diatomaceous earth. Supelco is a prepacked silicagel liquid chromatography column.

(3) For some chemicals the chemical formula was used, e.g. CH.sub.2Cl.sub.2 for dichloromethane CH.sub.3OH for methanol, HCl for hydrochloric acid, KOH for potassium hydroxide, NaOH for sodium hydroxide, Na.sub.2CO.sub.3 for sodium carbonate, NaHCO.sub.3 for sodium hydrogen carbonate, MgSO.sub.4 for magnesium sulfate, N.sub.2 for nitrogen gas, CF.sub.3COOH for trifluoroacetic acid.

A. Preparation of the Intermediates

Example A1

Preparation of

(4) ##STR00012##

Intermediate 1

(5) Thionyl chloride (0.5 ml) was added to a solution of bicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid [14381-41-0] (0.001 mol) in dichloromethane. The reaction mixture was refluxed for 1 hour. Then stirred overnight at room temperature. The solvents were co-evaporated 2 times with benzene to obtain bicyclo[4.2.0]octa-1,3,5-triene-7-carbonyl chloride [1473-47-8] which was dissolved in DIPE. The obtained solution was added dropwise to a cooled mixture (0 C.) of N-allyl-2-adamantanamine [24161-63-5] and sodium carbonate in DIPE. The reaction mixture was stirred for 30 minutes on ice and then for 2 hours at room temperature. The mixture was poured out into water and extracted with dichloromethane. The organic layer was filtered through Extrelut and the filtrate was evaporated. The residue was purified by flash column chromatography on TRIKONEX FlashTube (eluent: CH.sub.2Cl.sub.2/EtOAc 90/10). The product fractions were collected and the solvents were evaporated, yielding 0.13 g of intermediate 1.

Example A2

a) Preparation of

(6) ##STR00013##

Intermediate 2

(7) A mixture of 3-phenyl-2-propenoic acid [140-10-3] (0.01 mol) and thionyl chloride (30 ml) was refluxed for 2 hours. The solvent was co-evaporated with methylbenzene. The residue was dissolved in DIPE (20 ml) and the resulting solution was added dropwise to a mixture of N-allyl-2-adamantanamine [24161-63-5] (0.01 mol) and sodium carbonate (2 g) in DIPE (50 ml) on ice. The reaction mixture was stirred overnight, poured out into dichloromethane and washed with water. The organic layer was separated, dried (MgSO.sub.4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH.sub.2Cl.sub.2). The product fractions were collected and the solvent was evaporated. The residue was triturated under DIPE and the desired product was collected, yielding 1.68 g (56%) of intermediate 2.

Example A3

a) Preparation of

(8) ##STR00014##

Intermediate 3

(9) A solution of bicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid [14381-41-0] (0.0033 mol) in dichloromethane (25 ml) and N,N-diethylethanamine (5 ml) was stirred and 1-hydroxy-1H-benzotriazole (0.0035 mol) was added. Then N-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine, monohydrochloride (0.0035 mol) was added and the mixture was stirred for 10 minutes. Tricyclo[3.3.1.13,7]decan-2-amine, hydrochloride (1:1) [10523-68-9] (0.0035 mol) was added and the reaction mixture was stirred for 2 days. The mixture was washed with a 15% citric acid solution and with a sodium carbonate solution. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was triturated with DIPE and the desired product was collected, yielding 0.6 g of intermediate 3.

b) Preparation of

(10) ##STR00015##

Intermediate 4

(11) Lithium Aluminum hydride (0.0042 mol) was stirred in diethyl ether (10 ml) (on ice) and Aluminum chloride (0.0042 mol) was added, the mixture was stirred for 15 minutes and intermediate 3 (0.0021 mol) was added portionwise. The reaction mixture was stirred at room temperature for 2 hours and then quenched with a diluted HCl solution. A diluted KOH solution was added until pH 10 and the resulting mixture was extracted with dichloromethane. The organic layer was separated and dried, then filtered through Extrelut and the filtrate was evaporated, yielding 0.489 g of intermediate 4.

c) Preparation of

(12) ##STR00016##

Intermediate 5

(13) A mixture of intermediate 4 (0.0018 mol) and sodium carbonate (0.3 g) in dichloromethane (10 ml) was stirred on ice. 2-Propenoyl chloride [814-68-6] (0.002 mol) was added dropwise and the reaction mixture was stirred overnight at room temperature. The mixture was washed with water (4 ml) and filtered through Extrelut and the filtrate was evaporated, yielding 0.497 g of intermediate 5.

Example A4

a) Preparation of

(14) ##STR00017##

Intermediate 6

(15) 1-Hydroxy-1H-benzotriazole (0.02 mol) was added to a mixture of N-[(1,1-dimethylethoxy)carbonyl]-D-phenylalanine [18942-49-9] (0.0075 mol) and N,N-diethylethanamine (5 ml) in dichloromethane (100 ml). After 5 minutes stirring N-(ethylcarbonimidoyl)-N,N-dimethyl-, 1,3-propanediamine, monohydrochloride [25952-53-8] (0.02 mol) was added. After stirring for 10 minutes, tricyclo[3.3.1.13,7]decan-2-amine, hydrochloride [10523-68-9] (0.015 mol) was added and the reaction mixture was stirred overnight at room temperature. The mixture was poured out into water and extracted with dichloromethane. The organic layer was dried, filtered and the solvent was evaporated, yielding 2.5 g of intermediate 6.

b) Preparation of

(16) ##STR00018##

Intermediate 7

(17) A mixture of intermediate 6 (0.0075 mol) in dichloromethane (50 ml) and trifluoroacetic acid (10 ml) was stirred overnight and the solvents were evaporated. The residue was dissolved in dichloromethane and washed with a sodium carbonate solution. The organic layer was dried, filtered and the solvent was evaporated. The residue was triturated with DIPE and the desired product was collected, yielding 1.4 g of intermediate 7.

c) Preparation of

(18) ##STR00019##

Intermediate 8

(19) A mixture of intermediate 7 (0.0046 mol), 1H-benzotriazole [95-14-7] (0.0092 mol), paraformaldehyde (0.0138 mol) and 4-methylbenzenesulfonic acid [104-15-4] (0.18 g) in benzene (60 ml) was refluxed over a Dean-Starck setting for 3 hours. Then stirred overnight at room temperature. The solvent was evaporated, toluene (60 ml) was added and the mixture was refluxed over a Dean-Starck setting for next 2 hours. The mixture was cooled and washed with a NaOH-solution (2M). The organic layer was dried over MgSO.sub.4, filtered and the solvent was evaporated, yielding 2.3 g of intermediate 8.

Example A5

a) Preparation of

(20) ##STR00020##

Intermediate 9

(21) 1-Hydroxy-1H-benzotriazole (0.0012 mol) and N-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine, monohydrochloride [25952-53-8] (0.0012 mol) were added to a mixture of (3R)-3,4-dihydro-2,3(1H)-isoquinolinedicarboxylic acid, 2-(1,1-dimethylethyl) ester [115962-35-1] (0.001 mol) in DMF (10 ml) and N,N-diethylethanamine (0.2 ml). The mixture was stirred for 20 minutes at room temperature. Tricyclo[3.3.1.13,7]decan-2-amine, hydrochloride [10523-68-9] (0.0012 mol) was added and the reaction mixture was stirred overnight. The mixture was poured out into water and stirred for 10 minutes, then the resulting precipitate was filtered off and dissolved in dichloromethane. The obtained solution was washed with water, dried over MgSO.sub.4, filtered and the solvent was evaporated, yielding 0.38 g of intermediate 9.

b) Preparation of

(22) ##STR00021##

Intermediate 10

(23) A mixture of intermediate 9 (0.00087 mol) in toluene (10 ml) was stirred on ice (under N.sub.2). BMS (0.001 mol) was added dropwise, then the reaction mixture was stirred on ice for 30 minutes. The mixture was refluxed overnight. The mixture was cooled and washed with a Na.sub.2CO.sub.3-solution. The organic solvent was evaporated. The residue was dissolved in CH.sub.2Cl.sub.2/CF.sub.3COOH (20%) and stirred for 20 hours at room temperature. The solvents were evaporated. The residue was dissolved in CH.sub.2Cl.sub.2, and washed with a Na.sub.2CO.sub.3 solution. The organic layer was concentrated and the residue was purified over Supelco column filled by silica gel (eluent: CH.sub.2Cl.sub.2/CH.sub.3OH gradient). The product fractions were collected and the solvents were evaporated, yielding 0.120 g of intermediate 10.

Example A6

a) Preparation of

(24) ##STR00022##

Intermediate 11

(25) To a stirred solution of 1-isoquinolinecarboxylic acid (0.0056 mol) and N,N-diethylethanamine (0.7 g) in DMF (50 ml) were added 1-hydroxy-1H-benzotriazole (0.0067 mol) and N-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine, monohydrochloride [25952-53-8] (0.0067 mol). The mixture was stirred for 20 minutes at room temperature. Tricyclo[3.3.1.13,7]decan-2-amine, hydrochloride [10523-68-9] (0.0067 mol) was added and the reaction mixture was stirred overnight. The mixture was poured out into water, stirred for 10 minutes and extracted with dichloromethane. The organic layer was separated, dried over MgSO.sub.4, filtered and the solvent was evaporated. The residue was dissolved in 2-propanol and converted into the hydrochloric acid salt (1:1) with HCl/2-propanol. The desired product was filtered, yielding 1.2 g of intermediate 11.

b) Preparation of

(26) ##STR00023##

Intermediate 12

(27) A solution of intermediate 11 (0.0035 mol) in HCl, 2-propanol (1 ml) and methanol (50 ml) was hydrogenated overnight with platinum on activated carbon (0.5 g) as a catalyst. After uptake of hydrogen (2 equiv.), the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in dichloromethane and washed with a Na.sub.2CO.sub.3-solution. The organic layer was separated, dried (MgSO.sub.4), filtered and the solvent was evaporated. The residue was purified on Supelco column filled by silica gel (eluent: CH.sub.2Cl.sub.2/CH.sub.3OH 99/1). Two product fractions were collected and the solvent was evaporated, yielding 0.370 g of intermediate 12.

c) Preparation of

(28) ##STR00024##

Intermediate 13

(29) A solution of intermediate 12 (0.0012 mol) in toluene (10 ml) was stirred on ice (N.sub.2). BMS (0.002 mol) was added dropwise, then the reaction mixture was stirred on ice for 30 minutes and stirred overnight at 100 C. The mixture was washed with a NaHCO.sub.3 solution and extracted with CH.sub.2Cl.sub.2. The organic layer was separated, dried (MgSO.sub.4), filtered and the solvent was evaporated, yielding 0.29 g of residue. The residue was triturated with DIPE and the precipitate was filtered. The filtrate was evaporated, yielding 0.22 g of intermediate 13.

Example A7

a) Preparation of

(30) ##STR00025##

Intermediate 14

(31) A mixture of 7-bromo-3,4-dihydro-1,2(1H)-isoquinolinedicarboxylic acid, 2-ethyl ester [135335-12-5] (0.006 mol) and N,N-diethylethanamine (5 ml) in DMF (40 ml) was stirred and 1-hydroxy-1H-benzotriazole (0.0067 mol) was added. Then N-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine, monohydrochloride [25952-53-8] (0.0067 mol) was added and the mixture was stirred for 20 minutes. Tricyclo[3.3.1.13,7]decan-2-amine, hydrochloride [10523-68-9] (0.0067 mol) was added and the reaction mixture was stirred overnight at room temperature. The mixture was poured out into water, stirred for 10 minutes. The resulting precipitate was filtered, dissolved in CH.sub.2Cl.sub.2, dried over MgSO.sub.4, filtered and the solvent was evaporated. The residue was triturated with DIPE and the desired product was collected, yielding 1.6 g of intermediate 14.

b) Preparation of

(32) ##STR00026##

Intermediate 15

(33) A solution of intermediate 14 (0.0034 mol) in a HBr/CH.sub.3COOH mixture (50 ml) was stirred at room temperature for 1 week. The mixture was poured out into water and stirred for 15 minutes. The precipitate was filtered and dissolved in CH.sub.2Cl.sub.2. The solution was washed with a NaHCO.sub.3-solution, dried (MgSO.sub.4), filtered and the solvent was evaporated. The residue was triturated under DIPE and the desired fraction was collected (yielding 0.7 g). This fraction was dissolved in diluted HCl and the resulting solution was washed with CH.sub.2Cl.sub.2. The aqueous layer was alkalised with a Na.sub.2CO.sub.3 solution and extracted with CH.sub.2Cl.sub.2. The organic layer was separated, dried (MgSO.sub.4), filtered and the solvent was evaporated, yielding 0.35 g of intermediate 15.

c) Preparation of

(34) ##STR00027##

Intermediate 16

(35) A mixture of intermediate 15 (0.00089 mol) in toluene (50 ml) and THF (20 ml) was stirred under N.sub.2 until complete dissolution and then the solution was stirred under N.sub.2 on ice. BMS (0.002 mol) was added dropwise and the reaction mixture was stirred for 30 minutes under N.sub.2 on ice. The mixture was further stirred overnight at 100 C. and was then cooled. IN HCl (50 ml) was added. The mixture was stirred and refluxed for 2 hours. The resulting mixture was cooled, neutralised with a Na.sub.2CO.sub.3 solution and extracted with CH.sub.2Cl.sub.2. The organic layer was separated, dried (MgSO.sub.4), filtered and the solvent was evaporated, yielding 0.3 g of intermediate 16.

B. Preparation of the Compounds

Example B1

Preparation of

(36) ##STR00028##

Compound 1

(37) A mixture of intermediate 1 (0.00093 mol) in anhydrous methylbenzene (10 ml) was stirred for 6 hours at 190 C. and then stirred overnight at room temperature. The solvent was evaporated and the residue was purified by column chromatography over silica gel (eluent: CH.sub.2Cl.sub.2). The product fractions were collected and the solvent was evaporated, yielding 0.19 g (63%) of compound 1.

Example B2

Preparation of

(38) ##STR00029##

Compound 2

(39) A mixture of intermediate 2 (0.00031 mol) and 4-methoxyphenol (catalytic quantity) in methylbenzene (10 ml) was stirred for one hour at 220 C. The solvent was evaporated. The residue was purified (2) by flash column chromatography on TRIKONEX FlashTube (eluent: CH.sub.2Cl.sub.2/EtOAc 90/10). The product fractions were collected to give 0.008 g of compound 2.

Example B3

Preparation of

(40) ##STR00030##

Compound 3

(41) A solution of intermediate 5 (0.0015 mol) in methylbenzene (15 ml) was stirred in pressure vessel at 190 C. for 6 hours. Then the reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was purified on Supelco column filled with silica gel (eluent: CH.sub.2Cl.sub.2). Fractions were collected and the solvent was evaporated, yielding 0.1 g of compound 3.

Example B4

Preparation of

(42) ##STR00031##

Compound 4

(43) Intermediate 8 (0.006 mol) in dichloromethane (250 ml) was stirred and aluminum chloride (0.018 mol) was added. The reaction mixture was refluxed for 3 hours. The mixture was cooled and washed with KOH (1M). The organic layer was washed, dried, filtered and the solvent was evaporated, yielding 0.7 g of residue. A part (0.3 g) of the residue was purified over silica gel (eluent: CH.sub.2Cl.sub.2/EtOAc 90/10). The product fractions were collected and the solvent was evaporated, yielding 0.133 g of compound 4.

Example B5

Preparation of

(44) ##STR00032##

Compound 5

(45) A solution of intermediate 10 (0.00040 mol) in tetrahydrofuran (10 ml) was stirred and 1,1-carbonylbis-1H-imidazole [530-62-1] (0.00045 mol) was added. The mixture was refluxed overnight. After cooling, water (2 ml) was added. The mixture was extracted with dichloromethane and the organic layer was filtered through Extrelut. The obtained residue was purified by column chromatography over silica gel (Supelco) (eluent: CH.sub.2Cl.sub.2). The product fractions were collected and the solvent was evaporated, yielding 0.063 g of compound 5.

Example B6

Preparation of

(46) ##STR00033##

Compound 6

(47) 1,1-Carbonylbis-1H-imidazole [530-62-1] (0.00185 mol) was added to a stirred solution of intermediate 13 (0.00048 mol) in tetrahydrofuran (15 ml). The reaction mixture was stirred for 48 hours at 60 C. and cooled. Water (4 ml) was added. The mixture was stirred for 10 minutes and extracted with dichloromethane (10 ml). The organic layer was separated, dried (MgSO.sub.4), filtered and the solvent was evaporated. The residue (0.337 g) was purified 2 times on Supelco column filled by silica gel (eluent: CH.sub.2Cl.sub.2). The product fractions were collected and the solvent was evaporated, yielding 0.051 g of compound 6.

Example B7

Preparation of

(48) ##STR00034##

Compound 7

(49) A mixture of intermediate 16 (0.0008 mol) in tetrahydrofuran (5 ml) was stirred and 1,1-carbonylbis-1H-imidazole (0.5 g) was added. The reaction mixture was stirred overnight at room temperature and the solvent was evaporated. The residue was purified by column chromatography (Supelco) over silica gel (eluent: CH.sub.2Cl.sub.2/EtOAc 90/10). The product fractions were collected and the solvents were evaporated, yielding 0.068 g of compound 7.

(50) Table F-1 lists the compounds that were prepared according to one of the above Examples.

(51) TABLE-US-00001 TABLE F-1 Co. No. 1 Ex. B1. Co. No. 2 Ex. B2. Co. No. 3 Ex. B3. Co. No. 8 Ex. B3. Co. No. 4 Ex. B4. 0 Co. No. 9 Ex. B2. Co. No. 10 Ex. B2. Co. No. 5 Ex. B5. Co. No. 11 Ex. B5. Co. No. 12 Ex. B4. Co. No. 6 Ex. B6. Co. No. 13 Ex. B6. Co. No. 14 Ex. B6. Co. No. 15 Ex. B3. Co. No. 16 Ex. B3. 0 Co. No. 17 Ex. B3. Co. No. 18 Ex. B2. Co. No. 19 Ex. B3. Co. No. 20 Ex. B3. Co. No. 7 Ex. B7. Co. No. 21 Ex. B2. Co. No. 22 Ex. B2. Co. No. 23 Ex. B7. Co. No. 24 Ex. B6. Co. No. 25 Ex. B6. 0 Co. No. 26 Ex. B2. Co. No. 27 Ex. B2. Co. No. 28 Ex. B2. Co. No. 29 Ex. B2. Co. No. 30 Ex. B2. Co. No. 31 Ex. B3. Co. No. 32 Ex. B3. Co. No. 33 Ex. B3. Co. No. 34 Ex. B2.

(52) Table F-2 provides the .sup.1H NMR and .sup.13C NMR chemical shifts data for the compounds of the present invention using CDCl.sub.3 as a solvent.

(53) TABLE-US-00002 TABLE F-2 melting point Co. No. NMR data ( C.) 1 1H-NMR, CDCl.sub.3; 1.48-1.98 (m, 16H, 14H-adamantane, 2HCH2); 2.75 (m, 3H, CH.sub.2, CH); 3.45(dd, 1H, H.sup.ANCH.sub.2); 3.62 (d, CH); 3.80 (dd, 1H, H.sup.BNCH.sub.2); 3.96 (s, 1HCH); 7.07 (d, 1H-aromatic); 7.15 and 7.25 (2xt, 2H-aromatic) 13C-NMR, CDCl3: 26.17; 27.82; 32.68; 33.00; 37.70; 37.99; 38.14; 51.12 (8xCH2); 27.12; 27.54; 30.96; 31.09; 31.56; 45.01; 58.83(7xCH); 126.01; 126.34; 128.19; 130.68 (4xCH-aromatic); 131.89; 136.50(C-ipso-aromatic); 174.39 CO. 2 1H-NMR, CDCl.sub.3; 1.53-1.95 (m, 14H-adamantane); 2.28 (dd, H.sup.ACH.sub.2); 2.45(m, 1H, CH); 2.55(dd, H.sup.BCH.sub.2); 2.65-2.79 (m, CHCO, H.sup.ACH.sub.2); 2.93 (dd, H.sup.ANCH.sub.2); 3.00 (m, H.sup.BCH.sub.2); 3.40 (dd, H.sup.BNCH.sub.2); 3.77(s, 1H, CH); 6.95-7.15 (m, 4H-aromatic) 3 1H-NMR, CDCl.sub.3; 1.61-2.12 (m, 14H-adamantane, H.sup.ACH.sub.2); 2.20-2.43(m, CHCO and H.sup.BCH.sub.2); 2.80-3.12 (m, CH, CH.sub.2); 3.55 (dd, H.sup.ANCH.sub.2); 4.07 (s, CH); 4.18 (dd, H.sup.BNCH.sub.2); 7.02-7.22 (m, 4H- aromatic) 13C-NMR, CDCl3: 22.22; 28.78; 32.76; 32.91; 37.68; 37.91; 38.20; 49.24 (8xCH2); 27.21; 27.54; 31.05; 31.27; 42.30; 45.42; 58.45(7xCH); 124.04; 125.58; 126.78; 129.16 (4xCH-aromatic); 136.98; 137.26 (C-ipso-aromatic); 176.01 CO. 8 1H-NMR, CDCl.sub.3; 1.55-2.25 (m, 14H-adamantane, CH.sub.2); 2.70- (t, 2H, CH.sub.2); 2.77 (m, 1H, CHCO); 3.51 (dd, H.sup.ANCH.sub.2); 3.57 (m, CH); 4.01 (s, CH); 4.12 (dd, H.sup.BNCH.sub.2); 7.08-7.18 (m, 4H- aromatic) 4 1H-NMR, CDCl.sub.3; 1.59-2.30 (m, 14H-adamantane); 2.95-3.12 (m, 2H, CH.sub.2); 3.30 (m, 1H, CHCO); 3.69 (d, H.sup.ANCH.sub.2); 3.96(d, H.sup.BCH.sub.2); 3.99(s, CH); 4.28 (dd, H.sup.ACH.sub.2); 4.63 (d, H.sup.BCH.sub.2); 7.08-7.22(m, 4H-aromatic) 9 mixture 10 1H-NMR, CDCl.sub.3; 1.65-2.32 (m, 14H-adamantane, 2x CH); 2.68-2.73 (m, 2H, 2x H.sup.ACH.sub.2); 2.95 (dd, H.sup.BCH.sub.2); 3.17 (dd, H.sup.BCH.sub.2); 3.35 (dd, H.sup.ANCH.sub.2); 3.78(s, 3H, CH.sub.3); 3.80-3.92 (m, H.sup.BNCH.sub.2); 4.06(s, 1H, CH); 6.72 and 7.05 (2x m, 3H-aromatic) 5 1H-NMR, CDCl.sub.3; 1.58-2.04(m, 12H-adamantane); 2.35 and 2.46 (2x brs, 2x 1H-adamantane); 2.76-2.93(m, 2H, CH.sub.2); 3.31 (dd, 1H, H.sup.ACH.sub.2); 3.66 (s, 1H, CH); 3.67-3.75 (m, 2H, CH, H.sup.BCH.sub.2); 4.22 and 4.86 (2x d, H.sup.A and H.sup.BCH.sub.2); 7.09-7.23 (m, 4H-aromatic) 11 1H-NMR, CDCl.sub.3; 1.58-2.05(m, 12H-adamantane); 2.45 and 2.55 (2x brs, 2x 1H-adamantane); 2.76-2.93(m, 2H, CH.sub.2); 3.33 (dd, 1H, H.sup.ACH.sub.2); 3.66 (s, 1H, CH); 3.67-3.75 (m, 2H, CH, H.sup.BCH.sub.2); 4.22 and 4.86 (2x d, H.sup.A and H.sup.BCH.sub.2); 7.09-7.23 (m, 4H-aromatic) 12 1H-NMR, CDCl.sub.3; 1.61-2.25 (m, 14H-adamantane); 2.96-3.11 (2xdd, 2H, CH.sub.2); 3.30 (m, 1H, CHCO); 3.79 (d, H.sup.ACH.sub.2); 3.96(d, H.sup.BCH.sub.2); 3.99(s, CH); 4.28 (dd, H.sup.ACH.sub.2); 4.64 (d, H.sup.BCH.sub.2); 7.08-7.22(m, 4H-aromatic) 6 1H-NMR, CDCl.sub.3; 158-1.95(m, 12H-adamantane); 2.22 and 2.50 (2x brs, 2x 1H-adamantane); 2.64(m, 1H, H.sup.ACH.sub.2); 2.96-3.11 (m, 2H, H.sup.BCH.sub.2 and H.sup.ACH.sub.2); 3.42 (dd, 1H, H.sup.ACH.sub.2); 3.62 (s, 1H, CH); 4.04 (dd, 1H, H.sup.BCH.sub.2); 4.12 (m, 1H, H.sup.BCH.sub.2); 4.65 (t, 1H, CH); 7.07-7.25(m, 4H-aromatic) 13 1H-NMR, CDCl.sub.3; 1.61-2.12(m, 14H, 12H-adamantane, CH.sub.2); 2.15 and 2.53 (2x brs, 2x 1H-adamantane); 2.85(dd, 1H, H.sup.ACH.sub.2); 2.95 (m, 1H, H.sup.BCH.sub.2); 3.24 (dd, H.sup.ANCH.sub.2); 3.73 (s, 1H, CH); 3.81 (dd, H.sup.BNCH.sub.2); 3.91 (m, 1H, CH); 6.91 and 7.17 (2xt, 2H-aromatic); 7.08 and 8.28 (2xd, 2H-aromatic) 14 1H-NMR, CDCl.sub.3; 1.48-1.94(m, 15H-adamantane); 2.65 (m, 2H, 2x H.sup.ACH.sub.2); 2.96 (d, 1H, H.sup.BCH.sub.2); 2.98-3.14 (m, 2H, H.sup.BCH.sub.2 and H.sup.ACH.sub.2); 3.35 (dd, 1H, H.sup.ACH.sub.2); 3.98 (dd, 1H, H.sup.BCH.sub.2); 4.12 (m, H.sup.BCH.sub.2); 4.78 (t, 1h, CH); 7.08-7.24 (m, 4H-aromatic 15 1H-NMR, CDCl.sub.3; 1.50-1.74(m, 12H-adamantane); 1.80(m, H.sup.ACH.sub.2); 1.98 (brs, 3H, H-adamantane); 2.28 (dd, 1H, CHCO); 2.82-2.92 (m, 2H, CH.sub.2); 2.89 and 3.16 (2xd, H.sup.A and H.sup.BCH.sub.2); 2.93-3.12 (m, 3H, CH and CH.sub.2); 3.58 (dd, H.sup.ANCH.sub.2); 3.83 (dd, H.sup.BCH.sub.2); 6.96 (d, 1H-aromatic); 7.12-7.21 (m, 3H-aromatic) 16 1H-NMR, CDCl.sub.3; 1.40-1.94(m, 15H-adamantane); 2.01(m, CH.sub.2); 2.65-2.76 (m, 3H, CH.sub.2, H.sup.ACH.sub.2); 2.82 (m, 1H, CHCO); 3.05 (d, H.sup.BCH.sub.2); 3.39 (dd, H.sup.ACH.sub.2); 3.58(m, 1H, CH); 3.86 (dd, H.sup.BCH.sub.2); 7.08-7.22 (m, 4H-aromatic) 17 1H-NMR, CDCl.sub.3; 1.66-1.81 (m, 6H-adamantane, H.sup.ACH.sub.2); 2.12-2.34(m, 12H, 9H-adamantane, CHCO and H.sup.BCH.sub.2); 2.88-3.08 (m, 3H, CH, CH.sub.2); 3.32 (dd, H.sup.ANCH.sub.2); 3.98 (dd, H.sup.BNCH.sub.2); 6.98 (d, 1H-aromatic); 7.11-7.20 (m, 3H-aromatic) 18 1H-NMR, CDCl.sub.3; 1.63-2.06 (m, 13H-adamantane); 2.20-2.43(m, 3H, 1H-adamantane, CH.sub.2); 2.58 and 2.74 (2x t, 2x CH); 3.07 (m, 2H, CH.sub.2); 3.36 (dd, 1H, H.sup.ACH.sub.2); 3.90 (dd, 1H, H.sup.BCH.sub.2); 4.05 (s, CH), 6.84 and 7.13 (2x d, 2H-aromatic) 19 1H-NMR, CDCl.sub.3; 1.78-1.92 (m, 1H, H.sup.ACH2); 2.32 (dt, 1H, H.sup.BCH2); 2.45 (m, 1H, CHCO); 2.94-3.16 (m, 3H, CH, CH.sub.2); 3.39 (dd, 1H, H.sup.ANCH.sub.2); 3.64 (dd, 1H, H.sup.BNCH.sub.2); 4.55 (s, 2H, CH.sub.2); 6.90 (d, 1H-aromatic); 7.07-7.36 (m, 8H-aromatic) 20 1H-NMR, CDCl.sub.3; 1.92-2.09 (m, 2H, CH2); 2.72 (m, 2H, CH2); 2.89 (m, 1H, H.sup.ACH.sub.2); 3.09 (dd, 1H, H.sup.ANCH.sub.2); 3.60 (m, 1H, CH); 3.70 (dd, 1H, H.sup.BNCH.sub.2); 4.47 (s, 2H, CH.sub.2); 7.02-7.30 (m, 4H-aromatic) 7 1H-NMR, CDCl.sub.3; 1.56-1.95(m, 11H-adamantane); 2.24 and 2.46 (2x brs, 2x 1H-adamantane); 2.59(m, 1H, H.sup.ACH.sub.2); 2.85-3.06 (m, 2H, H.sup.BCH.sub.2 and H.sup.ACH.sub.2); 3.40 (dd, 1H, H.sup.ACH.sub.2); 3.62 (s, 1H, CH); 4.04 (dd, 1H, H.sup.BCH.sub.2); 4.12 (m, 1H, H.sup.BCH.sub.2); 4.70 (t, 1H, CH); 7.00 and 7.22 (2x d, 2H-aromatic; 7.32(dd, 1H-aromatic) 21 1H-NMR, CDCl.sub.3; 1.69-2.07(m, 12H-adamantane); 2.28 and 2.43 (2x brs, 2x 1H-adamantane); 2.84(t, 1H, H.sup.ACH.sub.2); 3.06-3.20 (m, 1H, CH); 3.25-3.39 (m, H.sup.BCH.sub.2 and H.sup.ACH.sub.2); 4.18 (s, 1H, CH); 4.21 (t, 1H, H.sup.BCH.sub.2); 7.12 (d, 1H, CH); 7.19; 7.53 and 8.40 (3x dd, 3H-aromatic 22 1H-NMR, CDCl.sub.3; 1.67-2.04(m, 12H-adamantane); 2.26 and 2.43 (2x brs, 2x 1H-adamantane); 2.68 (t, 1H, H.sup.ACH.sub.2); 2.92-3.10 (m, 2H, CH, H.sup.BCH.sub.2); 3.32 (dd, 1H, H.sup.ACH.sub.2); 4.18 (m, 2H, CH, H.sup.BCH.sub.2); 7.16 (d, 1H, CH); 7.21 and 8.43 (2x d, 2H-aromatic); 8.50 (s, 1H-aromatic) 23 1H-NMR, CDCl.sub.3; 1.54-1.93(m, 11H-adamantane); 2.23 and 2.47 (2x brs, 2x 1H-adamantane); 2.82(m, 2H, CH.sub.2); 2.98-3.07 (m, 1H, H.sup.ACH.sub.2); 3.39 (dd, 1H, H.sup.ACH.sub.2); 3.61 (s, 1H, CH); 4.03 (dd, 1H, H.sup.BCH.sub.2); 4.18 (dt, 1H, H.sup.BCH.sub.2); 4.72 (t, 1H, CH); 7.04 and 7.14 (m, 2H-aromatic; 7.49(d, 1H-aromatic) 24 1H-NMR, CDCl.sub.3; 1.40-2.35 (m, 13H, adamantane); 3.10 (m, 3H, 235-237 CH.sub.2, CH); 3.35 (t, 1H, H.sup.ANCH.sub.2); 3.50 (s, CH); 4.00 (t, 1H, H.sup.BNCH.sub.2); 4.10 (dd, 1HCH); 4.75 (t, 1H, CH); 7.07 (d, 1H-aromatic); 7.15 and 7.25 (2xt, 2H-aromatic) 25 1H-NMR, CDCl.sub.3; 1.52-2.30 (m, 13H, adamantane); 3.05 (m, 3H, 210-212 CH.sub.2, CH); 3.45 (t, 1H, H.sup.ANCH.sub.2); 3.45 (s, CH); 4.05 (t, 1H, H.sup.BNCH.sub.2); 4.10 (dd, 1H, H.sup.BNCH.sub.2); 4.75 (t, 1HCH); 7.09 (d, 1H- aromatic); 7.13 and 7.22 (2xt, 2H-aromatic) 26 1H-NMR, CDCl.sub.3; 1.18-1.61 (m, 10H-adamantane); 2.08 and 2.32 and 2.43 (2x brs, 3H-adamantane); 2.58 (dd, 1H, H.sup.ACH.sub.2); 2.69-3.15 (m, 5H, 2x CH, H.sup.BCH.sub.2); 3.12 (dd, H.sup.ANCH.sub.2); 3.59(s, 1H, CH); 3.72 (dd, 1H, H.sup.BNCH.sub.2); 7.14-7.21 (m, 4H-aromatic) 27 1H-NMR, CDCl.sub.3; 1.45-1.84 (m, 10H-adamantane); 2.01 and 2.26 (brs, 3H-adamnatane); 2.56 (dd, 1H, H.sup.ACH.sub.2); 2.70-3.03 (m, 5H, 2x CH, H.sup.BCH.sub.2); 3.12 (dd, H.sup.ANCH.sub.2); 3.68-3.76 (m, 2H, CH, H.sup.BNCH.sub.2); 7.12-7.19 (m, 4H-aromatic) 28 1H-NMR, CDCl.sub.3; 1.25, 1.37 (2x d, 2H-adamantane); 1.52-1.98 (m, 8H-adamantane); 2.08, 2.26, 2.35 (3x brs, 3H-adamantane); 2.80-3.15 (m, 6H, 2x CH, 2x CH2); 3.21 (dd, 1H, H.sup.ANCH.sub.2); 3.63 (s, CH); 3.78 (dd, H.sup.BNCH.sub.2); 7.12 (dd, 1H-aromatic), 7.45 and 8.46 (2x d, 2H-aromatic) 29 1H-NMR, CDCl.sub.3; 1.34, 1.44 (2x d, 2H-adamantane); 1.52-1.94 (m, 8H-adamantane); 2.10 and 2.35 (2x brs, 3H-adamantane); 2.59 (dd, 1H, H.sup.ACH.sub.2); 2.78-2.93 (m, 3H, CH, H.sup.ACH.sub.2, H.sup.BCH.sub.2); 2.96-3.08 (m, 2H, CH and H.sup.BCH.sub.2); 3.13 (dd, 1H, H.sup.ANCH.sub.2); 3.66 (s, CH); 3.78 (dd, H.sup.BNCH.sub.2); 7.12 (d, 1H-aromatic), 8.41 (m, 2H-aromatic) 30 1H-NMR, CDCl.sub.3; 1.52-1.99 (m, 11H-adamantane); 2.23 and 2.47 (2x brs, 2H-adamantane); 2.66-2.75 (m, 1H, H.sup.ACH.sub.2); 2.93-3.11 (m, 2H, CH, H.sup.BCH.sub.2); 3.28 (dd, 1H, H.sup.ANCH.sub.2); 4.07 (s, CH); 4.14 (dd, H.sup.BNCH.sub.2); 7.17 (d, 1H, CH), 7.22 and 8.44 (2x d, 2H- aromatic); 8.50 (s, 1H-aromatic) 31 1H-NMR, CDCl.sub.3; 1.50-2.02 (m, 11H-adamantane); 2.19-2.41(m, 3H, CHCO and CH.sub.2); 2.54 (brd, 2H-adamantane); 2.92-3.13 (m, 3H, CH, CH.sub.2); 3.53 (dd, H.sup.ANCH.sub.2); 3.98 (s, CH); 4.14 (dd, H.sup.BNCH.sub.2); 7.02 (d, 1H-aromatic); 7.12-7.22 (m, 3H-aromatic) 32 1H-NMR, CDCl.sub.3; 1.53-2.02 (m, 9H-adamantane); 2.10 and 2.63(2x brd, 4H-adamantine); 2.22-2.40 (m, 3H, CHCO and CH.sub.2); 2.92-3.12 (m, 3H, CH, CH.sub.2); 3.52 (dd, H.sup.ANCH.sub.2); 3.98 (s, CH); 4.10 (dd, H.sup.BNCH.sub.2); 7.02 (d, 1H-aromatic); 7.12-7.22 (m, 3H- aromatic) 33 1H-NMR, CDCl.sub.3; 1.42-2.01 (m, 10H, 9H-adamantane, H.sup.ACH.sub.2); 2.12 and 2.43(2x brs, 3H-adamantine); 2.71 (t, 2H, CH.sub.2); 2.80 (m, 1H, CHCO); 3.43-3.51 (m, 2H, and H.sup.BCH.sub.2) 3.61 (dd, H.sup.ANCH.sub.2); 3.92 (s, 1H, CH); 4.06 (dd, H.sup.BNCH.sub.2); 7.11-7.22 (m, 4H- aromatic) 34 1H-NMR, CDCl.sub.3; 1.20-2.29 (m, 13H-adamantane); 2.59 (dd, 1H, H.sup.ACH.sub.2); 2.78-2.93 (m, 3H, CH, H.sup.ACH.sub.2, H.sup.BCH.sub.2); 2.96-3.08 (m, 2H, CH and H.sup.BCH.sub.2); 3.13 (dd, 1H, H.sup.ANCH.sub.2); 3.71 (s, CH); 3.77 (dd, H.sup.BNCH.sub.2); 7.09 (d, 1H-aromatic), 8.39 (m, 2H-aromatic)

C. Pharmacological Examples

Example C1

Enzymatic Assays to Test the Effect of Compounds on 11b-Hydroxysteroid Dehydrogenase Type 1 and Type 2

(54) The effects of compounds on 11b-HSD1 dependent conversion of cortisone into cortisol (reductase activity) was studied in a reaction mixture containing 30 mM Tris-HCl buffer pH 7.2, 180 M NADPH, 1 mM EDTA, 2 M cortisone, 1 l drug and/or solvent and 11 g recombinant protein in a final volume of 100 l.

(55) The effect on the 11b-HSD1-dehydrogenase activity (conversion of cortisol into cortisone) was measured in a reaction mixture containing 0.1M sodium phosphate buffer pH 9.0, 300 M NADP, 25 M cortisol, 1 l drug and/or solvent and 3.5 g recombinant protein in a final volume of 100 l.

(56) The effects on the 11b-HSD2 dependent dehydrogenase activity was studied in a reaction mixture containing 0.1M sodium phosphate buffer pH 7.5, 300 M NAD, 100 nM cortisol (of which 2 nM is 3H-radio labelled), 1 l drug and/or solvent and 2.5 g recombinant protein in a final volume of 100 l.

(57) All incubations were performed for 45 min at 37 C in a water bath. The reaction was stopped by adding 100 l acetonitrile containing 20 g corticosterone as internal standard. After centrifugation, the product formation was analysed in the supernatant by HPLC on a Hypersyl BDS-C18 column using 0.05 mM ammonium acetate/methanol (50/50) as solvent. In all of the aforementioned assays, the drugs to be tested were taken from a stock solution and tested at a final concentration ranging from 10.sup.5M to 3.Math.10.sup.9M. From the thus obtained dose response curves, the pIC50 value was calculated and scored as follows; Score 1=pIC50 value <5, Score 2=pIC50 value in the range of 5 to 6, Score 3=pIC50 value >6. Some of the thus obtained results are summarized in the table below. (in this table NT stands for Not Tested).

Example C2

Cellular Assays to Test the Effect of Compounds on 11b-Hydroxysteroid Dehydrogenase Type 1 and Type 2

(58) The effects on 11b-HSD1 activity was measured in differentiated 3T3-L1 cells and rat hepatocytes.

(59) Mouse fibroblast 3T3-L1 cells (ATCC-CL-173) were seeded at a density of 16500 cells/ml in 12 well plates and grown for 7 days in DMEM medium (supplemented with 10% heat inactivated foetal calf serum, 2 mM glutamine and 25 mg gentamycin) at 37 C. in a humidified 5% CO.sub.2 atmosphere. Medium was refreshed twice a week. Fibroblasts were differentiated into adipocytes at 37 C. in a 5% CO.sub.2 humidified atmosphere in growth medium containing 2 g/ml insulin, 55 g/ml IBMX and 39.2 g/ml dexamethasone.

(60) Primary hepatocytes from male rats were seeded on normal Falcon 12 well plates at a density of 250000 cells/well and incubated for 16 hours at 37 C. in a 5% CO.sub.2 humidified atmosphere in DMEM-HAM's F12 medium containing 5% Nu-serum, 100 U/ml penicillin, 100 g/ml streptomycin, 0.25 g/ml amphotericin B, 50 g/ml gentamycin sulfate, 5 g/ml insulin and 392 ng/ml dexamethasone. Following a 4 hour pre-incubation with test compound, 0.5 Ci .sup.3H-cortisone or dehydrocorticosterone, was added to the 3T3-L1 cultures. One hour later, the medium was extracted on Extrelut.sup.3-columns with 15 ml diethyl ether and the extract was analysed by HPLC as described above. The effects of JNJ-compounds on rat hepatocyte HSD1 activity was measured after an incubation period of 90 minutes with 0.5 Ci.sup.3H-dehydrocorticosterone. Corticosterone formation was analysed by HPLC.

(61) The effects on 11b-HSD2 activity was studied in HepG2 and LCC-PK1-cells HepG2-cells (ATCC HB-8065) were seeded in 12 well plates at a density of 100,000 cells/ml and grown at 37 C. in a humidified 5% CO.sub.2 atmosphere in MEM-Rega-3 medium supplemented with 10% heat inactivated foetal calf serum, 2 mM L-glutamine and sodium bicarbonate). Medium was refreshed twice a week.

(62) Pig kidney cells (LCC-PK1, ATCC CRL-1392) were seeded at a density of 150,000 cells/ml in 12 well plates and grown at 37 C. in a humidified 5% CO.sub.2 atmosphere in Medium 199 supplemented with Earls modified salt solution, 100 U/ml penicillin, 100 g/ml streptomycin and 10% foetal calf serum. Medium was refreshed twice a week. Twenty four hours prior to the onset of the experiment, medium was changed by medium containing 10% charcoal stripped foetal calf serum.

(63) Following a 4 hour pre-incubation with test compound, 0.5 Ci .sup.3H-cortisol or corticosterone, was added to the cultures. One hour later, the medium was extracted on Extrelut.sup.3-columns with 15 ml diethyl ether and the extract was analysed by HPLC as described above.

(64) As for the enzymatic assays, the compounds to be tested were taken from a stock solution and tested at a final concentration ranging from 10.sup.5M to 3.Math.10.sup.9M. From the thus obtained dose response curves, the pIC50 value was calculated and scored as follows; Score 1=pIC50 value <5, Score 2=pIC50 value in the range of 5 to 6, Score 3=pIC50 value >6. Some of the thus obtained results are summarized in the table below. (in this table NT stands for Not Tested).

(65) TABLE-US-00003 [C2] HSD1 [C1] hHSD1 [C2] HSD2 Compound cellular 3T3-L1 reductase cellular HepG2 Number Score Score Score 1 2 2 NT 2 3 3 2 3 3 3 3 8 3 2 2 4 3 1 1 9 3 2 2 10 3 3 1 5 3 2 2 11 3 NT NT 12 2 NT NT 6 3 3 3 13 1 1 1 14 3 3 2 15 3 3 2 16 3 3 2 17 3 3 3 18 3 3 2 19 3 1 NT 20 3 2 NT 7 3 3 NT 21 3 1 NT 22 3 2 NT 23 3 3 3 24 3 3 3 25 3 2 NT 26 2 2 1 27 3 3 2 28 1 1 1 29 1 1 1 30 2 1 1 31 3 3 3 32 3 3 3 33 3 3 3 34 2 2 NT

D. Composition Examples

(66) The following formulations exemplify typical pharmaceutical compositions suitable for systemic or topical administration to animal and human subjects in accordance with the present invention.

(67) Active ingredient (A.I.) as used throughout these examples relates to a compound of formula (I) or a pharmaceutically acceptable addition salt thereof.

Example D1

Film-Coated Tablets

Preparation of Tablet Core

(68) A mixture of A.I. (100 g), lactose (570 g) and starch (200 g) was mixed well and thereafter humidified with a solution of sodium dodecyl sulfate (5 g) and polyvinyl-pyrrolidone (10 g) in about 200 ml of water. The wet powder mixture was sieved, dried and sieved again. Then there was added microcrystalline cellulose (100 g) and hydrogenated vegetable oil (15 g). The whole was mixed well and compressed into tablets, giving 10.000 tablets, each comprising 10 mg of the active ingredient.

(69) Coating

(70) To a solution of methyl cellulose (10 g) in denaturated ethanol (75 ml) there was added a solution of ethyl cellulose (5 g) in CH.sub.2Cl.sub.2 (150 ml). Then there were added CH.sub.2Cl.sub.2 (75 ml) and 1,2,3-propanetriol (2.5 ml). Polyethylene glycol (10 g) was molten and dissolved in dichloromethane (75 ml). The latter solution was added to the former and then there were added magnesium octadecanoate (2.5 g), polyvinyl-pyrrolidone (5 g) and concentrated color suspension (30 ml) and the whole was homogenated. The tablet cores were coated with the thus obtained mixture in a coating apparatus.