Selective 11-beta-hydroxysteroid dehydrogenase type 1 inhibitors

Abstract

The present invention relates to novel selective 11-beta-hydroxysteroid dehydrogenase type 1 (11-HSD1) inhibitors and the use thereof to prevent age-induced skin structure and function defects.

Claims

1. A cosmetic composition comprising: (i) a compound of formula (I): ##STR00028## wherein X is CH or N, Y is CHR.sup.8 or O, n is 0, 1 or 2, R.sup.1, R.sup.2 and R.sup.3 are independently of each other selected from the group consisting of H, OH, a halogen atom, a carbamoyl group and C.sub.1-C.sub.6alkyl group, and R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are independently of each other H or a C.sub.1-C.sub.6alkyl group, and (ii) a cosmetically acceptable carrier.

2. The cosmetic composition according to claim 1, wherein the compound of formula (I) is present in an amount within a range of about 0.00001 to 0.5 wt.-%, based on total weight of the cosmetic composition.

3. The cosmetic composition according to claim 1, wherein the compound of formula (I) is a compound of formula (Ia): ##STR00029## wherein X is CH or N, Y is CHR.sup.8 or O, n is 1 or 2, R.sup.1, R.sup.2 and R.sup.3 are independently of each other selected from the group consisting of H, OH, a halogen atom, a carbamoyl group and a C.sub.1-C.sub.6alkyl group, and R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are independently of each other H or a C.sub.1-C.sub.6alkyl group, with the proviso that if (i) n is 1 and Y is CHR.sup.8, then at least one of R.sup.4, R.sup.5 or R.sup.8 is a C.sub.1-6alkyl group; or (ii) n is 2, Y is CHR.sup.8, X is CH and R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are H, then R.sup.2 is not F; or (iii) n is 1 and Y is O, then R.sup.2 and at least one of R.sup.4 or R.sup.5 are a C.sub.1-C.sub.6alkyl group.

4. The cosmetic composition according to claim 1, wherein the compound of formula (I) contains only one residue selected from the group consisting of OH, a halogen atom and a carbamoyl group.

5. The cosmetic composition according to claim 1, wherein the C.sub.1-C.sub.6alkyl group is an unbranched C.sub.1-C.sub.3alkyl group.

6. The cosmetic composition according to claim 1, wherein the halogen atom is F or Cl.

7. The cosmetic composition according to claim 1, wherein the compound of formula (I) is a compound of formula (II): ##STR00030## wherein X is CH or N, R.sup.1, R.sup.2 and R.sup.3 are independently of each other selected from the group consisting of H, OH, a halogen atom, a carbamoyl group and a C.sub.1-C.sub.6alkyl group, and R.sup.4, R.sup.5 and R.sup.8 are independently of each other H or a C.sub.1-C.sub.6alkyl group, with the proviso that at least one of R.sup.4, R.sup.5 and R.sup.8 is a C.sub.1-6alkyl group.

8. The cosmetic composition according claim 7, wherein the compound of formula (II) is a compound selected from the group consisting of (4-methylpiperidin-1-yl) (3-(6-methylpyridin-3-yl)phenyl)methanone (II-a), (4-hydroxy-[1,1-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone (II-b), (4-fluoro-[1,1-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone (III-c), (3-fluoro-4-methyl-[1,1-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone (III-d), (2-chloro-[1,1-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone (II-e), (4-methyl-[1,1-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone (II-f), (4-chloro-[1,1-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone (II-g), (3,3-dimethylpiperidin-1-yl)(3-fluoro-4-methyl-[1,1-biphenyl]-3-yl)methanone (II-h), 3-(4-methylpiperidine-1-carbonyl)-[1,1-biphenyl]-4-carboxamide (II-i), (3-hydroxy-[1,1-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone (II-j), and 3-(4-methylpiperidine-1-carbonyl)-[1,1-biphenyl]-3-carboxamide (II-k).

9. The cosmetic composition according to claim 1, wherein the compound of formula (I) is a compound of formula (III): ##STR00031## wherein R.sup.1 and R.sup.3 are independently of each other selected from the group consisting of H, OH, a halogen atom and a C.sub.1-C.sub.6alkyl group, R.sup.2 is a C.sub.1-C.sub.6alkyl group, and R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are independently of each H or a C.sub.1-C.sub.6alkyl group, with the proviso that at least one of R.sup.4 or R.sup.5 are a C.sub.1-C.sub.6alkyl group.

10. The cosmetic composition according claim 9, wherein the compound of formula (III) is a compound selected from the group consisting of (2,2-dimethylmorpholino) (3-fluoro-4-methyl-[1,1-biphenyl]-3-yl)methanone (III-a), (2,6-dimethylmorpholino) (3-fluoro-4-methyl-[1,1-biphenyl]-3-yl)methanone (III-b) and (2,6-dimethylmorpholino) (4-methyl-[1,1-biphenyl]-3-yl)methanone (III-c).

11. The cosmetic composition according to claim 1, wherein the compound of formula (I) is a compound of formula (IV): ##STR00032## wherein X is CH or N, and R.sup.1, R.sup.2 and R.sup.3 are independently of each other selected from the group consisting of H, OH, a halogen atom and a C.sub.1-C.sub.6alkyl group, with the proviso that if X is CH and R.sup.1 and R.sup.3 are H, then R.sup.2 is not a F atom.

12. The cosmetic composition or the compound according claim 11, wherein the compound of formula (IV) is a compound selected from the group consisting of azepan-1-yl(3-fluoro-4-methyl-[1,1-biphenyl]-3-yl)methanone (IV-a), azepan-1-yl(4-chloro-[1,1-biphenyl]-3-yl)methanone (IV-b), azepan-1-yl(4-methyl-[1,1-biphenyl]-3-yl)methanone (IV-c), azepan-1-yl(4-hydroxy-[1,1-biphenyl]-3-yl)methanone (IV-d), azepan-1-yl(3-(6-methylpyridin-3-yl)phenyl)methanone (IV-e), [1,1-biphenyl]-3-yl(azepan-1-yl)methanone (IV-f), and azepan-1-yl(3,4-dimethyl-[1,1-biphenyl]-3-yl)methanone (IV-g).

13. The cosmetic composition according to claim 1, wherein n is 1 or 2.

14. The cosmetic composition according to claim 2, wherein the compound of formula (I) is present in an amount with a range of 0.0001 to 0.25 wt.-%, based on the total weight of the cosmetic composition.

15. The cosmetic composition according to claim 2, wherein the compound of formula (I) is present in an amount with a range of 0.0001 to 0.1 wt.-%, based on the total weight of the cosmetic composition.

16. The cosmetic composition according to claim 5, wherein the C.sub.1-C.sub.6alkyl group is a C.sub.1-C.sub.2alkyl group.

17. The cosmetic composition according to claim 5, wherein the C.sub.1-C.sub.6alkyl group is a methyl group.

18. A method to smoothen wrinkles and fine lines and/or to decrease volume and depth of wrinkles and fine lines, wherein the method comprises the step of applying to an area of skin affected by wrinkles and fine lines an effective amount of the cosmetic composition according to claim 1.

19. The method according to claim 18, wherein the cosmetic composition is applied to the area of skin in an amount of between 0.1 to 3 mg/cm.sup.2 of skin.

20. A method for the treatment of (photo)age-induced skin structure and function defects which comprises applying to an area of skin affected by (photo)age-induced skin structure and function defects an effective amount of the cosmetic composition according to claim 1.

21. The method according to claim 4, wherein the cosmetic composition is applied to the area of skin in an amount of between 0.1 to 3 mg/cm.sup.2 of skin.

Description

EXPERIMENTAL PART

1. General Information

(1) Abbreviations:

(2) TABLE-US-00004 AcOEt ethyl acetate Boc.sub.2O di-tert-butyl-dicarbonate DCM dichloromethane DIEA N,N-diisopropylethylamine DMAP N,N-dimethylaminopyridine DME 1,2-dimethoxyethane EDCHCl N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride EtOH ethanol HOBt 1-hydroxybenzotriazole MeCN acetonitrile Py pyridine TBAB tetra-n-butylammonium bromide tBu tert-butyl TFA trifluoroacetic acid EDTA ethylenediaminetetraacetic acid EGTA ethylene glycol bis(2-aminoethylether) tetraacetic acid HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid NADPH nicotinamide adenine dinucleotide phosphate Tris tris(hydroxymethyl)aminomethane DMSO dimethyl sulfoxide TLC Thin Layer Chromatography tr retention time

(3) Low-resolution mass-spectra (LR-MS): measured on a Waters Acquity I-Class Ultra Performance Liquid Chromatography, equipped with an Acquity HSS T3 100 , 1.8 m 2.150 mm.sup.2 analytical column and a photodiode array (PDA) detector operating in the 200-400 nm wavelength range coupled to a Waters Single Quadrupole Detector mass spectrometer operating in positive electrospray ionization (ESI+) mode and detecting in the m/z range 100-1500. H.sub.2O+0.04% HCOOH (A phase) and MeCN+0.04% HCOOH (B phase) were used as eluents, with a flow of 0.6 mL/min.

(4) Analytical chromatograms for solubility tests: measured on a Waters Acquity Ultra Performance Liquid Chromatography (UPLC), equipped with an Acquity HSS T3 100 , 1.8 m 2.150 mm.sup.2 analytical column and a PDA detector operating in the 200-400 nm wavelength range. H.sub.2O+0.02% TFA (A phase) and MeCN+0.02% TFA (B phase) were used as eluents, with a flow of 0.5 mL/min.

(5) Preparative HPLC purifications: performed on a Waters High Performance Liquid Chromatography LC-2525 equipped with a Waters 2767 Sample Manager and a Waters FCII automated fraction collector, using a Grom Saphir 110 C18 10 m 50300 mm.sup.2 preparative column and a Waters 2487 double wavelength UV-Vis detector operating at 220 and 254 nm.

(6) H.sub.2O+0.07% TFA (A phase) and MeCN+0.07% TFA (B phase) were used as eluents, with a flow of 55 mL/min.

(7) General Synthesis Strategies

(8) Where not otherwise stated, the reported analogues were synthesized by means of one of the following four general two-step synthesis strategies; literature protocols.sup.1-3 as outlined below were applied for the Suzuki ArAr cross-coupling reactions as indicated. All air- and water-sensitive reactions, including Suzuki cross-couplings, were performed under argon. Dichloromethane for amidation reactions was dried over sodium sulfate and stored under argon. Diethyl ether was dried over phosphoric anhydride and stored under argon.

(9) MilliQ water for cross-coupling reaction was degassed by sparging with argon under vacuum for 30 minutes prior to use. The catalytic 10 mM Pd(EDTA) solution was prepared from palladium(II) chloride, ethylenediaminetetraacetic acid disodium dihydrate and sodium carbonate as described in D. N. Korolev, N. A. Bumagin, Tetrahedron Lett. 46, 5751 (2006).

LITERATURE PROTOCOLS

(10) (1) D. N. Korolev, N. A. Bumagin, Tetrahedron Lett. 46, 5751 (2006) (2) M. Venkatraj, J. Messagie, J. Joossens, A.-M. Lambeir, A. Haemers, P. Van der Veken, K. Augustyns, Bioorg. Med. Chem. 20, 1557 (2012) (3) M. J. Burk, J. R. Lee, J. P. Martinez, J. Am. Chem. Soc. 114, 10847 (1994)

(11) Strategy A

(12) Step A1: In a round-bottomed flask 3-bromobenzoic acid is dissolved in anhydrous DCM (5 mL/mmol) under stirring at room temperature, HOBt (1.11 eq) and EDC.HCl (1.10 eq) are added. After the activation is quantitative (as judged by ultra high-performance liquid chromatography analysis), the required secondary amine (1.2 eq) and DIEA (1.5 eq) are added. After 30 min the mixture is concentrated under reduced pressure, taken-up with AcOEt (40 mL/mmol 3-bromobenzoic acid), washed with 5% KHSO.sub.4 (215 mL/mmol 3-bromobenzoic acid), H.sub.2O (12 mL/mmol 3-bromobenzoic acid), 5% NaHCO.sub.3 (312 mL/mmol 3-bromobenzoic acid) and brine (12 mL/mmol 3-bromobenzoic acid), dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness under reduced pressure.

(13) Step A2.sup.2: The aryl bromide derivative obtained in step A1, the required aryl boronic acid (1.1 eq), K.sub.2CO.sub.3 (3 eq) and palladium(0) tetrakis(triphenylphosphine) (0.02 eq) are given in this order in a screw-cap reactor, a 8:8:1 toluene/EtOH/H.sub.2O mixture (8.5 mL/mmol aryl bromide) is added, the reactor is closed tightly and heated to 100 C. under stirring. After 4 h the mixture is cooled to room temperature, diluted with H.sub.2O (12 mL/mmol aryl bromide), and extracted with AcOEt (225 mL/mmol aryl bromide), the pooled organic phases are washed with 5% NaHCO.sub.3 (212 mL/mmol aryl bromide) and brine (12 mL/mmol aryl bromide), dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness under reduced pressure. If necessary, the crude product is purified by preparative HPLC.

(14) Strategy B

(15) Step B1: To a suspension of 3-carboxyphenylboronic acid in a 3:2 mixture of DCM/MeCN (anhydrous, 5 mL/mmol) HOBt (1.11 eq) and EDC.HCl (1.10 eq) are added. After complete dissolution the required secondary amine (1.2 eq) and DIEA (1.5 eq) are added. After 30 min the mixture is concentrated under reduced pressure, taken-up with AcOEt (40 mL/mmol boronic acid), washed with 2.5% KHSO.sub.4 (610 mL/mmol boronic acid), H.sub.2O (212 mL/mmol boronic acid) and brine (12 mL/mmol boronic acid), dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness under reduced pressure.

(16) If necessary, the crude product is purified by preparative HPLC.

(17) Step B2.sup.1: The required aryl bromide, the aryl boronic acid derivative obtained in step B1 (1.05 eq), Na.sub.2CO.sub.3 (2 eq) and TBAB (0.01 eq) are given in this order in a screw-cap reactor. H.sub.2O (2.0 mL/mmol aryl bromide) and 10 mM Pd(EDTA) solution (0.3 mL/mmol aryl bromide) are added, the reactor is closed tightly and heated to 100 C. under stirring. After 5 h the mixture is cooled to room temperature, diluted with AcOEt (40 mL/mmol aryl bromide), washed with 5% NaHCO.sub.3 (15 mL/mmol aryl bromide), H.sub.2O (15 mL/mmol aryl bromide), 5% KHSO.sub.4 (15 mL/mmol aryl bromide) and brine (15 mL/mmol aryl bromide), dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness under reduced pressure.

(18) If necessary, the crude product is purified by preparative HPLC.

(19) Strategy C

(20) Step C1.sup.2: 3-bromobenzoic acid, the required aryl boronic acid (1.1 eq), K.sub.2CO.sub.3 (3 eq) and palladium(0) tetrakis(triphenylphosphine) are given in a screw-cap reactor, a 8:8:1 toluene/EtOH/H.sub.2O mixture (8.5 mL/mmol 3-bromobenzoic acid) is added, the reactor is closed tightly and heated to 100 C. under stirring. After 4 h the mixture is cooled to room temperature, diluted with AcOEt (10 mL/mmol 3-bromobenzoic acid) and extracted with 5% NaHCO.sub.3 (410 mL/mmol 3-bromobenzoic acid). The pooled basic extracts are acidified to pH 3 by dropwise addition of concentrated HCl under stirring, then extracted with AcOEt (310 mL/mmol 3-bromobenzoic acid). The pooled organic extracts are washed with water (10 mL/mmol 3-bromobenzoic acid) and brine (10 mL/mmol 3-bromobenzoic acid), dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness under reduced pressure.

(21) Step C2: To a suspension of the benzoic acid derivative obtained in step C1 in anhydrous DCM (5 mL/mmol) in a round-bottomed flask HOBt (1.11 eq) and EDC.HCl (1.10 eq) are added. After complete dissolution the required secondary amine (1.2 eq) and DIEA (1.5 eq) are added. After 30 min the mixture is concentrated under reduced pressure, taken-up with AcOEt (40 mL/mmol benzoic acid), washed with 5% KHSO.sub.4 (215 mL/mmol benzoic acid), H.sub.2O (12 mL/mmol benzoic acid), 5% NaHCO.sub.3 (312 mL/mmol benzoic acid) and brine (12 mL/mmol benzoic acid), dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness under reduced pressure.

(22) Strategy D

(23) Step D1.sup.1: The required aryl bromide, 3-carboxyphenylboronic acid (1.05 eq), Na.sub.2CO.sub.3 (2 eq), TBAB (0.01 eq) are given in a screw-cap reactor. H.sub.2O (2 mL/mmol aryl bromide) and 10 mM Pd(EDTA) solution (0.3 mL/mmol aryl bromide) are added, the reactor is closed tightly and heated to 100 C. under stirring. After 5 hours the mixture is cooled to room temperature, diluted with AcOEt (10 mL/mmol aryl bromide) and extracted with 5% NaHCO.sub.3 (410 mL/mmol aryl bromide). The pooled basic extracts are acidified to pH 3 by dropwise addition of concentrated HCl under stirring, then extracted with AcOEt (310 mL/mmol aryl bromide). The pooled organic extracts are washed with H.sub.2O (10 mL/mmol aryl bromide) and brine (10 mL/mmol aryl bromide), dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness under reduced pressure.

(24) If necessary, the crude product is purified by preparative-HPLC.

(25) Step D2: To a suspension of the benzoic acid derivative obtained in step D1 in anhydrous DCM (5 mL/mmol) in a round-bottomed flask HOBt (1.11 eq) and EDC.HCl (1.10 eq) are added. After complete dissolution the required secondary amine (1.2 eq) and DIEA (1.5 eq) are added. After 30 min the mixture is concentrated under reduced pressure, taken-up with AcOEt (40 mL/mmol benzoic acid), washed with 5% KHSO.sub.4 (215 mL/mmol benzoic acid), H.sub.2O (12 mL/mmol benzoic acid), 5% NaHCO.sub.3 (312 mL/mmol benzoic acid) and brine (12 mL/mmol benzoic acid), dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness under reduced pressure.

2. Synthesized Compounds

Example 1 (4-Methylpiperidin-1-yl)(3-(6-methylpyridin-3-yl)phenyl)methanone (II-a)

(26) The derivative was prepared following general strategy D; work-up in step D1 and reaction conditions for amide formation in step D2 were modified due to the basicity of the intermediate.

(27) Step D1: The reaction was performed with the standard protocol using 178 mg 3-carboxyphenylboronic acid (1.05 mmol) and 176 mg 5-bromo-2-methylpyridine (1.0 mmol). After acidification of the basic extracts, the aqueous phase was saturated with NaCl and extracted with 1-butanol (410 mL). The pooled organic extracts were washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure, taken-up with toluene (5 mL) and evaporated to dryness under reduced pressure. 222 mg 3-(6-methylpyridin-3-yl)-benzoic acid hydrochloride were obtained (85% yield). LR-MS: m/z 214.1 ([M+H].sup.+, clc 214.09).

(28) Step D2: To a suspension of 210 mg 3-(6-methylpyridin-3-yl)-benzoic acid hydrochloride (0.81 mmol) in a 2:1 DCM/MeCN mixture (6 mL) in a round-bottomed flask 0.15 mL DIEA (0.89 mmol) were added. After 5 min 186 mg HOBt (1.37 mmol) and 264 mg EDC.HCl (1.35 mmol) were added under stirring. After 30 min 147 L 4-methylpiperidine (0.98 mmol) and 0.21 mL DIEA (1.24 mmol) were added. After 50 min the mixture was concentrated under reduced pressure, taken-up with AcOEt (45 mL), washed with 5% NaHCO.sub.3 (415 mL) and H.sub.2O (15 mL) and extracted with 5% KHSO.sub.4 (222 mL). The pooled acidic extracts were brought to pH 8 by addition of solid Na.sub.2CO.sub.3 and extracted with AcOEt (415 mL), the pooled organic extracts were washed with H.sub.2O (10 mL) and brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness under reduced pressure. 181 mg product II-a were obtained (74% yield).

(29) LR-MS: m/z 295.2 ([M+H].sup.+, clc 295.18).

Example 2 (4-Methylpiperidin-1-yl)(4-hydroxy-[1,1-biphenyl]3-yl)methanone (II-b)

(30) The derivative was prepared following general strategy D; one preliminary protection step and one final deprotection step were required and a different literature protocol.sup.2 for the cross-coupling in step D1 was applied.

(31) Protection step: To a solution of 874 mg 4-bromophenol (5.0 mmol) in 10 mL anhydrous DCM and 0.49 mL py (6.0 mmol) in a round-bottomed flask 12.3 mg DMAP (0.1 mmol) and 1.20 g Boc.sub.2O (5.3 mmol) were added. After 30 min CO.sub.2 evolution ceased, the mixture was concentrated under reduced pressure, taken-up in AcOEt (50 mL), washed with 5% KHSO.sub.4 (225 mL), H.sub.2O (18 mL), 5% Na.sub.2CO.sub.3 (225 mL) and brine (18 mL), then dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness under reduced pressure. 1.25 g 4-bromophenyl-tert-butylcarbonate were obtained (91% yield).

(32) Step 1: 276 mg 4-bromophenyl-tert-butylcarbonate (1.0 mmol), 186 mg 3-carboxyphenylboronic acid (1.05 mmol), 419 mg K.sub.2CO.sub.3 (3.0 mmol) and 23 mg palladium(0) tetrakis(triphenylphosphine) (0.02 mmol) were given in a screw-cap reactor, 8.5 mL of a 8:8:1 toluene/EtOH/H.sub.2O mixture were added, the reactor was closed tightly and heated to 100 C. under stirring. After 4 h the mixture was cooled to room temperature, diluted with AcOEt (10 mL) and extracted with 3% Na.sub.2CO.sub.3 (415 mL). The pooled basic extracts were acidified to pH 3 by dropwise addition of 6 N HCl under stirring, whereas a solid precipitated, which was filtered and washed with 6 N HCl and H.sub.2O. The crude product was dissolved in AcOEt (30 mL), washed H.sub.2O (10 mL) and brine (10 mL), then dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness under reduced pressure. 150 mg 3-(4-tert-butyloxycarbonyloxyphenyl)-benzoic acid were obtained (46% yield).

(33) Step D2: The reaction was performed using 142 mg 3-(4-tert-butyloxycarbonyloxyphenyl)-benzoic acid (0.44 mmol) and 65 L 4-methylpiperidine (0.53 mmol). 180 mg N-(3-(4-tert-butyloxycarbonyloxyphenyl)-benzoyl)-4-methylpiperidine were obtained (quantitative yield). LR-MS: m/z 396.2 ([M+H].sup.+, clc 396.22).

(34) Deprotection step: 172 mg N-(3-(4-tert-butyloxycarbonyloxyphenyl)-benzoyl)-4-methylpiperidine were dissolved under argon in 2 mL of a 4:1 DCM/95% TFA.sub.(aq) mixture in a round-bottomed flask. After stirring for 2 h at room temperature the mixture was stripped with nitrogen; the residue was taken-up in DCM and stripped with nitrogen 3 more times. The residue was taken-up with Et.sub.2O and evaporated under reduced pressure; this was repeated 2 times, until a solid was obtained. 125 mg product II-b were obtained (98% yield).

(35) LR-MS: m/z 296.2 ([M+H].sup.+, clc 296.17).

Example 3 (4-Fluoro-[1,1-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone (II-c)

(36) The derivative was prepared following general strategy D.

(37) Step D1: The reaction was performed using 178 mg 3-carboxyphenylboronic acid (1.05 mmol) and 111 L 1-bromo-4-fluorobenzene (1.0 mmol). 190 mg 3-(4-fluorophenyl)-benzoic acid were obtained (86% yield).

(38) Step D2: The reaction was performed using 180 mg 3-(4-fluorophenyl)-benzoic acid (0.83 mmol) and 123 L 4-methylpiperidine (1.00 mmol). 215 mg product II-c were obtained (85% yield).

(39) LR-MS: m/z 298.2 ([M+H].sup.+, clc 298.18).

Example 4 (3-fluoro-4-methyl-[1,1-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone (II-d)

(40) The derivative was prepared following general strategy B; a different literature protocol.sup.2 was applied for the cross-coupling in step B2.

(41) Step B1: The reaction was performed using 169 mg 3-carboxyphenylboronic acid (1.0 mmol) and 148 L 4-methylpiperidine (1.2 mmol). 108 mg N-(3-boronobenzoyl)-4-methylpiperidine were obtained (42% yield).

(42) Step B2: 101 mg N-(3-boronobenzoyl)-4-methylpiperidine (0.41 mmol), 50 L 4-bromo-3-fluorotoluene (0.39 mmol), 162 mg K.sub.2CO.sub.3 (1.16 mmol) and palladium(0) tetrakis(triphenylphosphine) (7.7 mol) were given in a screw-cap reactor, 3.4 mL of a 8:8:1 mixture of toluene/EtOH/H.sub.2O were added, the reactor was closed tightly and heated to 100 C. under stirring. After 3 h the mixture was cooled to room temperature, diluted with H.sub.2O (5 mL) and extracted with AcOEt (210 mL), the pooled organic phases were washed with 5% NaHCO.sub.3 (10 mL) and brine (5 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness under reduced pressure. The crude product was purified by preparative HPLC. 89 mg of compound II-d were obtained (74% yield). LR-MS: m/z 312.3 ([M+H].sup.+, clc 312.18).

Example 5 (2-Chloro-[1,1-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone (II-e)

(43) The derivative was prepared following general strategy D.

(44) Step D1: The reaction was performed using 356 mg 3-carboxyphenylboronic acid (2.1 mmol) and 236 L 1-bromo-2-chlorobenzene (2.0 mmol). 203 mg 3-(2-chlorophenyl)-benzoic acid were obtained after preparative HPLC purification (44% yield).

(45) Step D2: The reaction was performed using 62 mg 3-(2-chlorophenyl)-benzoic acid (0.26 mmol) and 40 L 4-methylpiperidine (0.32 mmol). 68 mg product II-e were obtained (82% yield).

(46) LR-MS: m/z 314.2 ([M(.sup.35Cl)+H].sup.+, clc 314.13), 316.2 ([M(.sup.37Cl)+H].sup.+, clc 316.13).

Example 6 (4-Methyl-[1,1-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone (II-f)

(47) The derivative was prepared following general strategy D; a different literature protocol.sup.2 was applied for the cross-coupling in step D1

(48) Step D1: 186 mg 3-carboxyphenylboronic acid (1.05 mmol), 126 L 4-bromotoluene (1.0 mmol), 417 mg K.sub.2CO.sub.3 (3.0 mmol) and 23 mg palladium(0) tetrakis(triphenylphosphine) (0.02 mmol) were given in a screw-cap reactor, 8.5 mL of a 8:8:1 toluene/EtOH/H.sub.2O mixture were added, the reactor was closed tightly and heated to 100 C. under stirring. After 4 h the mixture was cooled to room temperature, diluted with AcOEt (10 mL) and extracted with 2% NaHCO.sub.3 (410 mL). The pooled basic extracts were acidified to pH 3 by dropwise addition of 6 N HCl under stirring and extracted with AcOEt (312 mL), the pooled organic extracts were washed H.sub.2O (10 mL) and brine (10 mL), then dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness under reduced pressure. The crude product was purified by preparative HPLC, yielding 128 mg 3-(4-tolyl)-benzoic acid (60% yield).

(49) Step D2: The reaction was performed using 128 mg 3-(4-tolyl)-benzoic acid (0.60 mmol) and 89 L 4-methylpiperidine (0.72 mmol). 154 mg product II-f were obtained (87% yield).

(50) LR-MS: m/z 294.3 ([M+H]+, clc 294.19).

Example 7 (4-Chloro-[1,1-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone (II-g)

(51) The derivative was prepared following general strategy D.

(52) Step D1: The reaction was performed using 178 mg 3-carboxyphenylboronic acid (1.05 mmol) and 193 mg 1-bromo-4-chlorobenzene (1.0 mmol). 94 mg 3-(4-chlorophenyl)-benzoic acid were obtained after preparative HPLC purification (39% yield).

(53) Step D2: The reaction was performed using 87 mg 3-(4-chlorophenyl)-benzoic acid (0.36 mmol) and 53 L 4-methylpiperidine (0.43 mmol). 112 mg product II-g were obtained (quantitative yield).

(54) LR-MS: m/z 314.2 ([M(.sup.35Cl)+H].sup.+, clc 314.13), 316.2 ([M(.sup.37Cl)+H].sup.+, clc 316.13).

Example 8 (3,3-Dimethylpiperidin-1-yl)(3-fluoro-4-methyl-[1,1-biphenyl]-3-yl)methanone (II-h)

(55) The derivative was prepared following general strategy D; a different protocol was applied for amide formation in step D2.

(56) Step D1: The reaction was performed using 178 mg 3-carboxyphenylboronic acid (1.05 mmol) and 129 L 4-bromo-2-fluorotoluene (1.0 mmol). 205 mg 3-(3-fluoro-4-methylphenyl)-benzoic acid were obtained (87% yield).

(57) Step D2: To a suspension of 165 mg 3-(2-fluoro-4-methylphenyl)-benzoic acid (0.68 mmol) in 6 mL of a 5:1 DCM/MeCN mixture in a round-bottomed flask 101 mg HOBt (0.74 mmol) and 144 mg EDC.HCl (0.73 mmol) were added under stirring. After 15 min 98 L 3,3-dimethylpiperidine (0.67 mmol) and 0.14 mL DIEA (0.78 mmol) were added. After 1.2 h the mixture was concentrated under reduced pressure, taken-up in AcOEt (40 mL), washed with 5% KHSO.sub.4 (218 mL), H.sub.2O (12 mL), 5% NaHCO.sub.3 (313 mL) and brine (12 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness under reduced pressure. 208 mg product 11-h were obtained (94% yield). LR-MS: m/z 326.2 ([M+H].sup.+, clc 326.19).

Example 9 3-(4-methylpiperidine-1-carbonyl)-[1,1-biphenyl]4-carboxamide (II-i)

(58) The derivative was prepared following general strategy D; the aryl bromide building block for step D1 was prepared in-house and a modified work-up was applied in step D1. Preparation of the aryl bromide building block: In a round-bottomed two-neck flask 812 mg 4-bromobenzoic acid (4.0 mmol) were suspended in 14 mL of a 6:1 DCM/MeCN mixture under argon and 600 mg HOBt (4.44 mmol) and 861 mg EDC.HCl (4.4 mmol) were added under stirring. After 10 min the mixture became clear and was cooled to 0 C. in an ice bath. In a round-bottomed flask 1.64 g NaOH (40 mmol) were added to 2.8 mL of a 28% NH.sub.4OH solution (20 mmol) and the resulting gaseous NH.sub.3 was bubbled into the reaction vessel after passing through a NaOH trap. After NH.sub.3-bubbling had ceased the mixture was concentrated under reduced pressure, taken-up in AcOEt (60 mL), washed with 5% KHSO.sub.4 (230 mL), H.sub.2O (20 mL), 5% NaHCO.sub.3 (320 mL) and brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness under reduced pressure. 636 mg 4-bromobenzamide were obtained (79% yield).

(59) Step D1: The reaction was performed using 178 mg 3-carboxyphenylboronic acid (1.05 mmol) and 202 mg 4-bromobenzamide (1.00 mmol). After 4 h at 100 C. the reaction mixture was cooled to room temperature, diluted with AcOEt (10 mL), extracted with 5% NaHCO.sub.3 (315 mL) and the pooled basic extracts were acidified to pH 3 by dropwise addition of concentrated HCl under stirring, whereas precipitation occurred. The precipitate was filtered and washed with 0.05 N HCl (20 mL) and with Et.sub.2O (10 mL). 227 mg 3-(4-aminocarbonylphenyl)-benzoic acid were obtained (93% yield).

(60) Step D2: The reaction was performed using 220 mg 3-(4-aminocarbonylphenyl)-benzoic acid (0.89 mmol) and 132 L 4-methylpiperidine (1.07 mmol). 188 mg product II-i were obtained (64% yield). LR-MS: m/z 323.2 ([M+H].sup.+, clc 323.18).

Example 10 (4-Methylpiperidin-1-yl)(3-hydroxy-[1,1-biphenyl]-3-yl)methanone (II-j)

(61) The derivative was prepared following general strategy D.

(62) Step D1: The reaction was performed using 178 mg 3-carboxyphenylboronic acid (1.05 mmol) and 112 L 3-bromophenol (1.0 mmol). 183 mg 3-(3-hydroxyphenyl)-benzoic acid were obtained (84% yield).

(63) Step D2: The reaction was performed using 188 mg 3-(3-hydroxyphenyl)-benzoic acid (0.94 mmol) and 130 L 4-methylpiperidine (1.05 mmol). 295 mg product II-j (oil) were obtained (quantitative yield, according to NMR analysis the product contained about 11% solvent).

(64) LR-MS: m/z 296.2 ([M+H].sup.+, clc 296.17).

Example 11 3-(4-Methylpiperidine-1-carbonyl)-[1,1-biphenyl]-3-carboxamide (II-k)

(65) The derivative was prepared following general strategy D; the aryl bromide building block for step D1 was prepared in-house and a modified work-up was applied in step D1. Preparation of the aryl bromide building block: In a round-bottomed two-neck flask 820 mg 3-bromobenzoic acid (4.0 mmol) were suspended in 14 mL of a 6:1 DCM/MeCN mixture under argon and 600 mg HOBt (4.44 mmol) and 861 mg EDC.HCl (4.4 mmol) were added under stirring. After 10 min the mixture became clear and was cooled to 0 C. in an ice bath. In a round-bottomed flask 1.64 g NaOH (40 mmol) were added to 2.8 mL of a 28% NH.sub.4OH solution (20 mmol) and the resulting gaseous NH.sub.3 was bubbled into the reaction vessel after passing through a NaOH trap. After NH.sub.3-bubbling had ceased, the mixture was concentrated under reduced pressure, taken-up in AcOEt (60 mL), washed with 5% KHSO.sub.4 (230 mL), H.sub.2O (20 mL), 5% NaHCO.sub.3 (320 mL) and brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness under reduced pressure. 700 mg 3-bromobenzamide were obtained (87% yield).

(66) Step D1: The reaction was performed using 178 mg 3-carboxyphenylboronic acid (1.05 mmol) and 201 mg 3-bromobenzamide (1.00 mmol). After 4 h at 100 C. the reaction mixture was cooled to room temperature, diluted with AcOEt (10 mL), extracted with 5% NaHCO.sub.3 (315 mL) and the pooled basic extracts were acidified to pH 3 by dropwise addition of concentrated HCl under stirring, whereas precipitation occurred. The precipitate was filtered and washed with 0.01 N HCl (20 mL) and with cold MeCN (5 mL). 221 mg 3-(3-aminocarbonylphenyl)-benzoic acid were obtained (90% yield).

(67) Step D2: The reaction was performed using 211 mg 3-(3-aminocarbonylyphenyl)-benzoic acid (0.87 mmol) and 128 L 4-methylpiperidine (1.04 mmol). 278 mg product II-k (dry foam) were obtained (93% yield, according to NMR analysis the product contained about 5% solvent).

(68) LR-MS: m/z 323.2 ([M+H].sup.+, clc 323.18).

Example 12 (2,2-Dimethylmorpholino)(3-fluoro-4-methyl-[1,1-biphenyl]-3-yl)methanone (III-a)

(69) The derivative was prepared according to general strategy D, a different protocol was applied for amide formation in step D2.

(70) Step D1: The reaction was performed using 533 mg 3-carboxyphenylboronic acid (3.15 mmol) and 387 L 4-bromo-2-fluorotoluene (3.0 mmol). 614 mg 3-(3-fluoro-4-methylphenyl)-benzoic acid were obtained (87% yield).

(71) Step D2: To a suspension of 178 mg 3-(3-fluoro-4-methylphenyl)-benzoic acid (0.76 mmol) in 7 mL of a 6:1 DCM/MeCN mixture in a round-bottomed flask 114 mg HOBt (0.83 mmol) and 161 mg EDC.HCl (0.83 mmol) were added and after complete dissolution 91 mg 2,2-dimethylmorpholine (0.75 mmol) were given. After stirring for 1.2 h the mixture was concentrated under reduced pressure, taken-up in AcOEt (40 mL), then washed with 5% KHSO.sub.4 (218 mL) and H.sub.2O (12 mL). The organic phase was concentrated under reduced pressure, taken-up in 4 mL of an 1:1 MeOH/H.sub.2O mixture and 42 mg LiOH*H.sub.2O (1.0 mmol) were added, then the mixture was stirred at 50 C. to hydrolyze the unreacted active ester. After 1 h the mixture was cooled to room temperature, diluted with AcOEt (30 mL), washed with 5% Na.sub.2CO.sub.3 (515 mL) and brine (15 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness under reduced pressure. 219 mg product III-a were obtained (88% yield).

(72) LR-MS: m/z 328.2 ([M+H].sup.+, clc 328.17).

Example 13 (2,6-Dimethylmorpholino)(3-fluoro-4-methyl-[1,1-biphenyl]-3-yl)methanone (III-b)

(73) The derivative was prepared according to general strategy D.

(74) Step D1: The reaction was performed using 533 mg 3-carboxyphenylboronic acid (3.15 mmol) and 387 L 4-bromo-2-fluorotoluene (3.0 mmol). 614 mg 3-(3-fluoro-4-methylphenyl)-benzoic acid were obtained (87% yield).

(75) Step D2: The reaction was performed using 183 mg 3-(3-fluoro-4-methylphenyl)-benzoic acid (0.79 mmol) and 121 L 2,6-dimethylmorpholine (0.95 mmol). 251 mg product III-b were obtained (95% yield). Due to the composition of the secondary amine used, the product was obtained as a mixture of two diastereomeric pairs of enantiomers in about 4:1 ratio.

(76) LR-MS: major diastereomer (1.59 min) m/z 328.3 ([M+H].sup.+, clc 328.17); minor diastereomer (1.62 min) m/z 328.3 ([M+H].sup.+, clc 328.17).

Example 14 2,6-Morpholino(4-methyl-[1,1-biphenyl]-3-yl)methanone (III-c)

(77) The derivative was prepared following general strategy C.

(78) Step C1: The reaction was performed using 154 mg 4-tolylboronic acid (1.05 mmol) and 205 mg 3-bromobenzoic acid (1.0 mmol). 172 mg 3-(4-tolyl)-benzoic acid were obtained (80% yield).

(79) Step C2: The reaction was performed using 171 mg 3-(4-tolyl)-benzoic acid (0.79 mmol) and 121 L 2,6-dimethylmorpholine (0.95 mmol). 216 mg product III-c were obtained (84% yield). Due to the composition of the secondary amine used, the product was obtained as a mixture of two diastereomeric pairs of enantiomers in about 4:1 ratio.

(80) LR-MS: major diastereomer (1.57 min) m/z 310.3 ([M+H].sup.+, clc 310.19); minor diastereomer (1.62 min) m/z 310.3 ([M+H].sup.+, clc 310.19).

Example 15 Azepan-1-yl-(3-fluoro-4-methyl-[1,1-biphenyl]-3-yl)methanone (IV-a)

(81) The derivative was prepared following general strategy A; a different literature protocol.sup.3 was applied for the cross-coupling in step A2.

(82) Step A1: The reaction was performed using 410 mg 3-bromobenzoic acid (2.0 mmol) and 275 uL azepane (2.4 mmol). 545 mg N-(3-bromobenzoyl)-azepane were obtained (96% yield).

(83) Step A2: 264 mg N-(3-bromobenzoyl)-azepane (0.92 mmol), 217 mg 3-fluoro-4-tolylboronic (1.36 mmol), 194 mg Na.sub.2CO.sub.3 (1.84 mmol), 10.4 mg PdCl.sub.2 (0.046 mmol), 29.5 mg tris(2-methylphenyl)-phosphine (0.092 mmol) were given in a screw-cap reactor, DME (5.5 mL) and H.sub.2O (1.0 mL) were added, the reactor was closed tightly and heated to 80 C. under stirring. After 4 h the mixture was cooled to room temperature, diluted with H.sub.2O (10 mL) and extracted with AcOEt (220 mL), the pooled organic extracts were washed with 5% NaHCO.sub.3 (210 mL) and brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness under reduced pressure. The crude product was purified by preparative-HPLC. 205 mg of the compound IV-a were obtained (71% yield).

(84) LR-MS: m/z 312.3 ([M+H].sup.+, clc 312.18).

Example 16 Azepan-1-yl(4-chloro-[1,1-biphenyl]-3-yl)methanone (IV-b)

(85) The derivative was prepared following general strategy A.

(86) Step A1: The reaction was performed using 410 mg 3-bromobenzoic acid (2.0 mmol) and 275 L azepane (2.4 mmol). 545 mg N-(3-bromobenzoyl)-azepane were obtained (96% yield).

(87) Step A2: The reaction was performed using 259 mg N-(3-bromobenzoyl)-azepane (0.90 mmol) and 156 mg 4-chlorophenylboronic acid (0.99 mmol). 237 mg compound IV-b were obtained after preparative HPLC purification (83% yield).

(88) LR-MS: m/z 314.2 ([M(.sup.35Cl)+H].sup.+, clc 314.13), 316.2 ([M(.sup.37Cl)+H].sup.+, clc 316.13).

Example 17 Azepan-1-yl(4-methyl-[1,1-biphenyl]-3-yl)methanone (IV-c)

(89) The derivative was prepared according to general strategy D; a different protocol was applied for amide formation in step D2.

(90) Step D1: The reaction was performed using 178 mg 3-carboxyphenylboronic acid (1.05 mmol) and 126 L 4-bromotoluene (1.0 mmol). 186 mg 3-(4-tolyl)-benzoic acid were obtained (87% yield).

(91) Step D2: 185 mg 3-(4-tolyl)-benzoic acid (0.87 mmol) were suspended in anhydrous DCM (5 mL) in a round-bottomed flask and 0.64 mL SOCl.sub.2 (8.7 mmol) were added. After 25 min a clear solution was obtained, which was stripped with argon. The residue was taken-up in anhydrous Et.sub.2O and stripped with argon 4 times, then evaporated to dryness under reduced pressure. The residue was taken-up in anhydrous DCM (5 mL) and 200 L azepane (1.80 mmol) were given. After 20 min the mixture was concentrated under reduced pressure, taken-up with AcOEt (40 mL), washed with 5% KHSO.sub.4 (215 mL), H.sub.2O (10 mL), 5% NaHCO.sub.3 (215 mL) and brine (10 mL), then dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness under reduced pressure. 250 mg product IV-c were obtained (97% yield).

(92) LR-MS: rniz 294.3 ([M+H].sup.+, clc 294.19).

Example 18 Azepan-1-yl(4-hydroxy-[1,1-biphenyl]-3-yl)methanone (IV-d)

(93) The derivative was prepared following general strategy B; a slightly modified work-up was applied in step 82.

(94) Step B1: The reaction was performed using 1.016 g 3-carboxyphenylboronic acid (6.0 mmol) and 0.82 mL diazepane (7.2 mmol), 1.179 g N-(3-boronobenzoyl)-azepane were obtained after preparative HPLC purication (79% yield).

(95) Step B2: The reaction was performed using 262 mg N-(3-boronobenzoyl)-azepane (1.05 mmol) and 175 mg 4-bromophenol (1.0 mmol). After taking-up in MeOH the crude product obtained by the usual extractive work-up 80 mg pure product IV-d (26% yield) precipitated from the mixture and were collected by filtration. Additional 99 mg product IV-d (33% yield) were obtained after preparative HPLC purification of the concentrated mother liquors (total yield 59%).

(96) LR-MS: m/z 296.2 ([M+H].sup.+, clc 296.17).

Example 19: Azepan-1-yl(3-(6-methylpyridin-3-yl)-phenyl)methanone (IV-e)

(97) The derivative was prepared following general strategy B.

(98) Step B1: The reaction was performed using 1.016 g 3-carboxyphenylboronic acid (6.0 mmol) and 0.82 mL diazepane (7.2 mmol). 1.179 g N-(3-boronobenzoyl)-azepane were obtained after preparative HPLC purication (79% yield).

(99) Step B2: The reaction was performed using 262 mg N-(3-boronobenzoyl)-azepane (1.05 mmol) and 175 mg 5-bromo-2-methylpyridine (1.0 mmol). 150 mg product IV-e were obtained after preparative HPLC purification (50% yield).

(100) LR-MS: m/z 295.2 ([M+H].sup.+, clc 295.18).

Example 20 [1,1-Biphenyl]-3-yl(azepan-1-yl)methanone (IV-f)

(101) The derivative was prepared following general strategy B.

(102) Step B1: The reaction was performed using 1.016 g 3-carboxyphenylboronic acid (6.0 mmol) and 0.82 mL azepane (7.2 mmol). 1.179 g N-(3-boronobenzoyl)-azepane were obtained after preparative HPLC purication (79% yield).

(103) Step B2: The reaction was performed using 262 mg N-(3-boronobenzoyl)-azepane (1.05 mmol) and 106 L bromobenzene (1.0 mmol). 250 mg product IV-f were obtained (86% yield).

(104) LR-MS: m/z 280.2 ([M+H].sup.+, clc 280.17).

Example 21 Azepan-1-yl(3,4-dimethyl[1,1-biphenyl]3-yl)methanone (IV-g)

(105) The derivative was prepared following general strategy B.

(106) Step B1: The reaction was performed using 1.016 g 3-carboxyphenylboronic acid (6.0 mmol) and 0.82 mL azepane (7.2 mmol). 1.179 g N-(3-boronobenzoyl)-azepane were obtained after preparative HPLC purication (79% yield).

(107) Step B2: The reaction was performed using 262 mg N-(3-boronobenzoyl)-azepane (1.05 mmol) and 136 L 4-bromo-o-xylene (1.0 mmol). 192 mg product IV-g were obtained after preparative HPLC purification (63% yield).

(108) LR-MS: m/z 308.3 ([M+H].sup.+, clc 308.20).

Example 22 11-beta-hydroxysteroid Dehydrogenase Type 1 Inhibition Activity

(109) A: Cell Assay

(110) Preparation of Cell Lysates:

(111) Stably transfected human embryonic kidney (HEK-293) cells expressing 11-HSD1 and hexose-6-phosphate dehydrogenase (the so called HHH7 clone) were cultivated for 48 h in Dulbecco's modified Eagle medium (DMEM) containing 4.5 g/L glucose, 10% fetal bovine serum, 100 U/mL penicillin, 0.1 mg/mL streptomycin, 1MEM nonessential amino acids, and 10 mM HEPES buffer, pH 7.4. The cells were then washed with phosphate-buffered saline, and centrifuged for 4 min at 150g. After removal of the supernatants, cell pellets were snap frozen on dry ice and stored at 80 C. until further use.

(112) Activity Assay in Cell Lysates:

(113) Cell lysates were incubated for 10 min at 37 C. in TS2 buffer (100 mM NaCl, 1 mM EGTA, 1 mM EDTA, 1 mM MgCl.sub.2, 250 mM sucrose, 20 mM Tris-HCl, pH 7.4) in a final volume of 22.2 L containing either solvent (0.1% DMSO) or the inhibitor at the respective concentration as indicated in Table 4 (see below). Enzyme activities were measured using the following conditions: 192 nM unlabeled cortisone, 8 nM radiolabeled cortisone, 450 M NADPH.

(114) Reactions were stopped after 10 min by adding an excess of unlabeled cortisone and cortisol (1:1, 2 mM, in methanol). The steroids were separated by TLC, using methanol-chloroform (1:9) as solvent, followed by scintillation counting and calculation of substrate concentration. Data were collected from four independent measurements (standard deviation<10%).

(115) TABLE-US-00005 TABLE 4 Results of the enzyme assay 11-HSD1 Remaining activity [% of control] # Compound 1 M 100 nM 1 (4-methylpiperidin-1-yl)(3-(6-methylpyridin-3-yl)phenyl)methanone (II-a) 5 36 2 (4-hydroxy-[1,1-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone (II-b) 5 38 3 (4-fluoro-[1,1-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone (II-c) 4 43 4 (3-fluoro-4-methyl-[1,1-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone (II-d) 1 45 5 (2-chloro-[1,1-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone (II-e) 4 49 6 (4-methyl-[1,1-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone (II-f) 2 52 7 (4-chloro-[1,1-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone (II-g) 3 58 8 (3,3-dimethylpiperidin-1-yl)(3-fluoro-4-methyl-[1,1-biphenyl]-3-yl)methanone (II-h) 3 60 9 3-(4-methylpiperidine-1-carbonyl)-[1,1-biphenyl]-4-carboxamide (II-i) 19 65 10 (3-hydroxy-[1,1-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone (II-j) 8 70 11 3-(4-methylpiperidine-1-carbonyl)-[1,1-biphenyl]-3-carboxamide (II-k) 34 89 12 (2,2-dimethylmorpholino) (3-fluoro-4-methyl-[1,1-biphenyl]-3-yl)methanone (III-a) 1 14 13 (2,6-dimethylmorpholino) (3-fluoro-4-methyl-[1,1-biphenyl]-3-yl)methanone (III-b) 4 44 14 (2,6-dimethylmorpholino) (4-methyl-[1,1-biphenyl]-3-yl)methanone (III-c) 3 60 15 azepan-1-yl(3-fluoro-4-methyl-[1,1-biphenyl]-3-yl)methanone (IV-a) 1 19 16 azepan-1-yl(4-chloro-[1,1-biphenyl]-3-yl)methanone (IV-b) 2 50 17 azepan-1-yl(4-methyl-[1,1-biphenyl]-3-yl)methanone (IV-c) nd 17 18 azepan-1-yl(4-hydroxy-[1,1-biphenyl]-3-yl)methanone (IV-d) nd 28 19 azepan-1-yl(3-(6-methylpyridin-3-yl)phenyl)methanone (IV-e) nd 31 20 [1,1-biphenyl]-3-yl(azepan-1-yl)methanone (IV-f) nd 21 21 azepan-1-yl(3,4-dimethyl-[1,1-biphenyl]-3-yl)methanone (IV-g) nd 69

(116) B: Human Keratinocytes Assay

(117) Cell Culture: Primary human skin keratinocytes obtained from CelINTec advanced Cell Systems were maintained in CnT-PR medium at 37 C. in a humidified 5% CO.sub.2-air atmosphere. Cells were subcultured before reaching confluence.

(118) Assessment of 11-HSD1 activity: Human primary keratinocytes were pre-cultured in complete culture media (CnT-PR, CelINTec) to 90% of confluence. Subsequently cells were washed twice with PBS-buffer to remove remaining corticosteroids and media were exchanged to custom made hydrocortisone-free media. Cells were then treated with 1000 nM cortisone in combination with different concentrations of inhibitors as indicated in Table A. 48 hrs later cell culture supernatant was collected and cortisol levels were assessed with the Cortisol Parameter Assay Kit (R&D Systems) following the instructions of the protocol and using a Multiskan Ascent plate reader (Labsystems).

(119) Calculation: % remaining 11-HSD1 activity=(cortisol-level with inhibitor/cortisol-level without inhibitor)*100%

(120) TABLE-US-00006 TABLE A Results Concentration remaining 11-HSD1 activity Compound [nM] [%] Control 0.00 100 (II-h) 0.04 74 0.10 45 0.32 24 1.00 10 (III-a) 0.32 70 1.00 55 3.16 37 10.00 11 31.62 3 100.00 0 (II-e) 1.00 85 3.16 70 10.00 50 31.62 21 100.00 4 (IV-a) 1.00 74 3.16 45 10.00 22 31.62 8 100.00 2 (IV-c) 1.00 70 3.16 42 10.00 23 31.62 9 100.00 3 (IV-f) 1.00 83 3.16 73 10.00 52 31.62 28 100.00 10

(121) C: Ex Vivo Assays

(122) 1. Total Dermal Collagen after Cortisone and Cortisone/Inhibitor Treatment

(123) Human skin from abdominal plastic surgery was used. The skin samples were cut in pieces of 83 mm (thickness) and cultured up to day 6 in an air-liquid interface in a perforated ring of stainless steel in contact with a culture medium (modified Williams' E medium), while renewing the culture medium on day 3. Six skin specimens were used for each test sample. Each test sample (4 l) was applied topically on top of each piece after cleaning of the surface with a cotton pad, which was subsequently covered with a 6 mm delivery membrane, this procedure was repeated daily. After 6 days skin sections were stained with Picrosirius Red histochemical staining, that dyes collagen fibers in purple-red. The papillary dermis was selected for the analysis. The different colors of the pictures were separated by using a deconvolution matrix. After deconvolution only pink-reddish images are used. Within these images the evaluation of dermal collagen was performed by estimating both color intensity and distribution with IMAGE J (NIH) analysis software. Two slides of each skin sample were processed by image acquisition and related analysis (i.e. 12 images for each treatment).

(124) TABLE-US-00007 TABLE B Results of the comparison treatments versus cortisone 0.1 l at day 6 Test sample Increase conc. Dermal versus cortisone # compound (in DMSO) collagen* (#2) 1 none (untreated) 0 M 100% 2 cortisone 0.1 M 77% 3 (IV-a) 10 M 96% +25% 4 100 M 97% +26% 5 200 M 86% +12% 6 (IV-e) 10 M 103% +34% 7 100 M 101% +31% 8 200 M 96% +25% 9 (IV-f) 10 M 103% +34% 10 100 M 103% +34% 11 200 M 93% +21% 12 (II-a) 10 M 94% +22% 13 100 M 108% +40% 14 200 M 114% +48% *Score of the dermal collagen of the untreated sample (#1) was set to 100% Positive control for collagen inhibition (23% vs. untreated (#1))

(125) As can be retrieved from the results outlined in Table B, the 11-HSD1 inhibitors according to the present invention counteracted cortisone activity by restoring or even enhancing total collagen in the papillary dermis.

(126) 2. Total Dermal Collagen III After UV-Irradiation

(127) Human skin from abdominal plastic surgery classified as Intermediate (ITA angle=42) was used. The skin samples were cut in pieces of approx. 83 mm (0thickness) and cultured up to day 6 in an air-liquid interface in a perforated ring of stainless steel in contact with a culture medium (modified Williams' E medium, while renewing the culture medium on day 3. Six skin specimens were used for each test sample. Each test sample (4 l) was topically applied on top of each piece after gentle cleaning of the surface with a cotton pad, which was subsequently covered with a 6 mm delivery membrane, this procedure was repeated daily. The samples were irradiated daily with 80% of the Biological effective dose for daylight (i.e. 6 J/cm.sup.2) using an adopted BIO-SUN system (Vilber Lourmat). At day 6 twelve skin sections were immunostained with mouse monoclonal anti-collagen III antibody (Sigma cat #c7805). The papillary dermis was selected for the analysis. The evaluation was performed by estimating both color intensity and distribution with IMAGE J (NIH) analysis software. Two slides of each skin sample have been processed by image acquisition and related analysis (i.e. 12 images for each treatment).

(128) TABLE-US-00008 TABLE C Dermal Collagen III at day 6 Increase Test sample Dermal versus UV Conc. collagen treatment # compound (in DMSO) UV III* (#2) 1 none 0 M N 100% 2 none 0 M Y 80% 3 (IV-a) 10 M Y 90% +13% 4 100 M Y 97% +21% 5 (II-a) 10 M Y 84% +5% 6 100 M Y 114% +43% 7 (IV-f) 10 M Y 85% +6% 8 100 M Y 106% +33% *Score of the dermal collagen III of the non UV treated sample (#1) was set to 100% Positive control for UV-damage (20% vs. untreated (#1))

(129) As can be retrieved from the results outlined in Table C, the 11-HSD1 inhibitors according to the present invention counteracted UV damage by restoring or even enhancing dermal collagen III in the papillary dermis.

Example 23 Solubility Test

(130) The solubility of selected compounds was tested in the cosmetic oils Cetiol B (INCI name: dibutyl adipate from BASF Personal Care), DUB DIS (INCI name: diisopropyl sebacate from Stearinerie Dubois) and Finsolv EB ((INCI name: ethylhexyl benzoate from Innospec Performance Chemicals).

(131) Preparation of Calibration Curves

(132) Samples of about 1 mg of the compounds to be tested were exactly weighted and dissolved in 90% MeCN.sub.(aq) to provide 0.1% (1000 ppm) w/v stock solutions. Aliquots of the stock solutions were diluted with 90% MeCN.sub.(aq) to provide 10, 100 and 250 ppm diluted solutions, which were tested by UPLC. The integrals of the analogue peaks detected at 216 nm proved to be directly proportional to the sample concentration in the calibration range and were used for the preparation of calibration curves.

(133) Determination of the Solubility from Saturated Mixtures

(134) For each compound to be tested about 20 mg material were weighted in three microcentrifuge tubes and to each tube about 150 mg of one cosmetic oil were added, as reported in Table 5 below.

(135) TABLE-US-00009 TABLE 5 Amount of compound and cosmetic oil used in the preparation of the saturated mixtures.sup.a Compound in Cetiol B in DUB DIS in Finsolv EB IIa 21.12 mg in 148.82 mg 20.44 mg in 146.09 mg 21.15 mg in 156.54 mg IIk 19.85 mg in 151.04 mg 20.13 mg in 146.86 mg 19.80 mg in 152.55 mg IIIb 23.77 mg in 149.78 mg 19.18 mg in 148.30 mg 20.54 mg in 153.06 mg IVc 21.26 mg in152.14 mg 21.02 mg in 146.80 mg 20.18 mg in 156.81 mg IVf 20.28 mg in 150.28 mg 19.66 mg in 146.40 mg 19.74 mg in 152.51 mg .sup.aThe first number refers to amount of compound, the second to the amount of cosmetic oil.

(136) After mixing on a Vortex mixer for 5 min, the respective samples were mixed on a waving platform shaker (20 cycles/min) for 7 days at room temperature (22 C.). After that time, the tubes were centrifuged for 5 min at 12000 rpm, 10 L samples of the supernatant were diluted to 1.00 mL with MeOH, 100 L of these solutions were diluted to 1.00 mL with 90% MeCN.sub.(aq) and subsequently analyzed by UPLC. The compound concentration in each solution was calculated using the respective calibration curve. From the compound concentration in the diluted solutions the concentrations of the respective parent mixtures was calculated accordingly. The results are outlined in Table 6 below.

(137) TABLE-US-00010 TABLE 6 Solubility in cosmetic oils Compound Cetiol B DUB DIS Finsolv EB IIa.sup.a 13.2%.sup.b 10.6%.sup.b 10.2%.sup.b IIk 3.0% 2.4% 3.4% IIIb 10.0% 4.3% 2.6% IVc 3.3% 2.6% 4.0% IVf 10.6%.sup.b 10.2%.sup.b 10.3%.sup.b .sup.aMixture of two diastereomers (4:1). .sup.bMixture not saturated, therefore solubility might be even higher.

(138) Determination of the Solubility of IIe and IIh

(139) Precisely weighted amounts of the respective compounds (see Tables 7 and 8) were weighted into 2 mL clear glass vials to which 0.50-0.60 mL of either Cetiol B or DUB DIS was then added. After preliminary mixing on a Vortex mixer for 1 min, the probes were mixed on a waving platform shaker for 3 days at room temperature. After that time, solutions were added with further precisely weighted amounts of the same compound, whereas suspensions were added with small amounts of the same cosmetic oil. This procedure was repeated until suspensions became clear or solutions became saturated. In case the difference between the concentration of the most concentrated clear solution and of the most diluted suspension was larger than 7%, one further intermediate concentration value was tested.

(140) TABLE-US-00011 TABLE 7 Solubility ranges obtained in Cetiol B Most diluted Most Com- saturated concentrated Solubility in pound Amount solution clear solution Cetiol B (S.sub.CB) IIe 100 mg 0.90 mL 0.92 mL 10.8% < S.sub.CB < 11.2% IIh 263 mg 0.54 mL 0.55 mL 47.2% < S.sub.CB < 49.2%

(141) TABLE-US-00012 TABLE 8 Solubility ranges obtained in in DUB DIS Most diluted Most Com- saturated concentrated Solubility in pound Amount solution clear solution DUB DIS (S.sub.DD) IIe 42 mg 0.50 mL 0.52 mL 8.2% < S.sub.DD < 8.5% IIh 201 mg 0.52 mL 0.54 mL 37.0% < S.sub.DD < 38.9%

(142) As can be retrieved from table 7 and 8, the compound according to the present invention exhibit a high solubility in the cosmetic oils Cetiol B and Dub Dis.

Example 24 Cosmetic Composition

(143) Table 9 outlines exemplary O/W emulsions, wherein one compound selected from the group of II(a-k) [Table 1], III(a-c) [Table 2], and IV(a-g) [Table 3] is incorporated in the indicated amount.

(144) TABLE-US-00013 TABLE 9 Exemplary O/W emulsion O/W Emulsions 1 2 3 4 5 6 7 8 Glyceryl Stearate 2.5 2 1.2 1 1 1 PEG-40 Stearate 1 PEG-100 Stearate 2.5 1 Ceteareth-20 1 Glyceryl Stearate Citrate 0.5 Potassium Cetyl Phosphate 3 1.5 Stearic Acid 2.5 3 Cetearyl Alcohol 4 2 2 Stearyl Alcohol 2 1 Cetyl Alcohol 1 1 0.5 Acrylates/C.sub.10-30 Alkyl Acrylate 0.2 0.2 0.4 0.2 Crosspolymer Carbomer 0.1 0.2 Xanthan Gum 0.3 0.3 C.sub.12-15Alkyl Benzoate 5 2 5 5 10 5 Petrolatum 5 3 Butylene Glycol Dicaprylate/Dicaprate 4 2 9 9 Hydrogenated Polydecene 3 2 2 Caprylic/Capric Triglyceride 1 3 5 5 5 Cyclomethicone 5 2 10 Methylpropanediol 2 3 3 Glycerine 4 7 3 4 3 5 3 Glyceryl Glucoside 3.5 3 1 1 2 2 Alcohol denat. 1 3 0.5 10 4 8 4 Butylene Glycol 3 Ascorbylglucoside 0.5 1.0 1.5 0.1 Ubiquinone (Coenzyme 10) 0.1 0.05 0.01 Hyaluronic acid 0.2 Bisabolol 0.5 0.2 Isotridecylsalicylate 1 3 5 2 3 5 Compound selected from the group of 0.001 0.25 0.0001 0.05 0.1 0.0003 0.03 0.002 II(a-k), II(a-c), and IV(a-g) Dibutyl Adipate 1.5 3 Diisopropyl sebacate 1 1 2 3 Ethylhexyl Benzoate 0.75 1.5 1 Titanium Dioxide (PARSOL TX) 0.5 2 Methylene Bis-Benzotriazolyl 0.5 4 6 2 Tetramethylbutylphenol Ethylhexyl methoxycinnamate 2 Phenylbenzimidazole Sulfonic Acid 2 2 2 Butyl Methoxydibenzoylmethane 1 2 2 3 3 3 Methylbenzylidene Camphor 2 3 Octocrylene 5 2 10 Polysilicone-15 2 3 Ethylhexyl Salicylate 5 Homosalate 4 2 Bis-Ethylhexyloxyphenol 1.5 2 Methoxyphenyltriazine Silica 1 2.5 0.5 Silica & Methicone 4 1 2.5 Methyl Methacrylate Crosspolymer 1 2 Disodium EDTA 0.1 0.5 Fragrance, Preservatives q.s. Sodium Hydroxide q.s. Water Ad 100

Example 25 Microbiological Challenge Test

(145) 500 mg [1,1-Biphenyl]-3-yl(azepan-1-yl)methanone (IV-f) was added separately to either 250 g ZEMEA (INCI: Propanediol), 250 mg Myritol (INCI: Caprylic/Capric Triglyceride), or 250 g Cetiol OE (INCI: Dicaprylyl Ether). Afterwards the respective mixtures were stirred at room temperature with magnetic stirrer until dissolved. The solutions were then tested according to European Pharmacopoeia 8.0, method 5.1.3. EFFICACY OF ANTIMICROBIAL PRESERVATION, table 2 and additionally with Escherichia coli.

(146) Result: only the solution in ZEMEA fulfilled all of the requirements of the Pharm. Eu. 8, Ear preparations, nasal preparations, preparations for cutaneous application and preparation for inhalation, Criteria A and B.