Phenyl-dihydropyridine derivatives as aldosterone synthase inhibitors

Abstract

The invention provides novel compounds having the general formula (I) ##STR00001##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, A.sup.1 and n are as described herein, compositions including the compounds and methods of using the compounds.

Claims

1. A Compound of formula (I) ##STR00050## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are independently selected from H, halogen, cyano, nitro, alkyl, haloalkyl, cycloalkyl, alkoxy, haloalkoxy and cycloalkoxy; R.sup.6 is H, alkyl, haloalkyl, cycloalkyl, substituted aryl or substituted heteroaryl, wherein substituted aryl or substituted heteroaryl are substituted with R.sup.18, R.sup.19 and R.sup.20; R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11 and R.sup.12 are independently selected from H, halogen, alkyl and haloalkyl; A.sup.1 is (CR.sup.14R.sup.15).sub.pC(O)NR.sup.16R.sup.17 or (CR.sup.14R.sup.15).sub.pC(O)OR.sup.17; R.sup.14 and R.sup.15 are independently selected from H, alkyl, haloalkyl, cycloalkyl and halocycloalkyl; R.sup.16 is H, alkyl, haloalkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl or haloalkoxyalkyl; R.sup.17 is H, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkoxyalkyl, substituted aryl or substituted heteroaryl, wherein substituted aryl and substituted heteroaryl are substituted with R.sup.21, R.sup.22 and R.sup.23; or R.sup.16 and R.sup.17 together with the nitrogen to which they are attached form a substituted heterocycloalkyl or a substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R.sup.21, R.sup.22 and R.sup.23; R.sup.18, R.sup.19, R.sup.20, R.sup.21, R.sup.22 and R.sup.23 are independently selected from H, halogen, alkyl, haloalkyl, cycloalkyl, alkoxy and haloalkoxy; n is zero, 1 or 2; p is zero, 1 or 2; and pharmaceutically acceptable salts thereof.

2. The compound of claim 1, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are independently selected from H, halogen and haloalkyl.

3. The compound of claim 1, wherein R.sup.1 and R.sup.2 are independently selected from H and halogen.

4. The compound of claim 1, wherein R.sup.3 is haloalkyl.

5. The compound of claim 1, wherein R.sup.4 and R.sup.5 are H.

6. The compound of claim 1, wherein n is zero and R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are H.

7. The compound of claim 1, wherein R.sup.12 is H, alkyl or substituted aryl, wherein substituted aryl is substituted with R.sup.18, R.sup.19 and R.sup.20.

8. The compound of claim 1, wherein R.sup.18, R.sup.19 and R.sup.20 are H.

9. The compound of claim 1, wherein A.sup.1 is (CR.sup.14R.sup.15).sub.pC(O)NR.sup.16R.sup.17.

10. The compound of claim 1, wherein R.sup.16 is H.

11. The compound of claim 1, wherein R.sup.17 is H, alkyl, alkoxyalkyl or substituted heteroaryl, wherein substituted heteroaryl is substituted with R.sup.21, R.sup.22 and R.sup.23 or R.sup.16 and R.sup.17 together with the nitrogen to which they are attached form a substituted heterocycloalkyl, wherein substituted heterocycloalkyl is substituted with R.sup.21, R.sup.22 and R.sup.23.

12. The compound of claim 1, wherein R.sup.17 is H, alkyl, alkoxyalkyl or substituted heteroaryl, wherein substituted heteroaryl is substituted with R.sup.21, R.sup.22 and R.sup.23.

13. The compound of claim 1, wherein R.sup.21, R.sup.22 and R.sup.23 are independently selected from H and alkyl.

14. The compound of claim 1, wherein R.sup.14 and R.sup.15 are H.

15. The compound of claim 1, wherein p is zero or 1.

16. The compound of claim 1, selected from Ethyl 2-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)acetate; 2-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-N-methylacetamide; N-Ethyl-2-[4-(3-fluoro-4-trifluoromethyl-phenyl)-6,7-dihydro-5H-[2]pyrindin-7-yl]-acetamide; 2-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-N-propylacetamide; N-Cyclopropyl-2-[4-(3-fluoro-4-trifluoromethyl-phenyl)-6,7-dihydro-5H-[2]pyrindin-7-yl]-acetamide; N-(cyclopropylmethyl)-2-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)acetamide; 2-[4-(3-Fluoro-4-trifluoromethyl-phenyl)-6,7-dihydro-5#H!-[2]pyrindin-7-yl]-#N!-(2-methoxy-ethyl)-acetamide; 2-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-1-(piperidin-1-yl)ethanone; 2-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-1-morpholinoethanone; 2-[4-(3-Fluoro-4-trifluoromethyl-phenyl)-6,7-dihydro-5#H!-[2]pyrindin-7-yl]-#N!-isoxazol-3-yl-acetamide; 2-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-N-(1H-pyrazol-3-yl)acetamide; 2-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-N-(1-methyl-1H-pyrazol-4-yl)acetamide; 2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-N,N-dimethylacetamide; N-ethyl-2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-N-methylacetamide; 2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-N-isopropyl-N-methylacetamide; N-cyclopropyl-2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-N-methylacetamide; N-cyclopropyl-N-ethyl-2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)acetamide; 1-(azetidin-1-yl)-2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-6, 7-dihydro-5H-cyclopenta[c]pyridin-7-yl)ethanone; 2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-1-(3-(hydroxymethyl)azetidin-1-yl)ethanone; 2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-1-(3-methoxyazetidin-1-yl)ethanone; 2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-1-(pyrrolidin-1-yl)ethanone; 2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-1-((S)-2-methylpyrrolidin-1-yl)ethanone; Ethyl 2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)acetate; 2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)ethanol; 2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)-N-methylacetamide; 2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)-N,N-dimethylacetamide; (S)-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydroisoquinolin-8-yl]-N,N-dimethylacetamide; (R)-2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)-N,N-dimethylacetamide; N-ethyl-2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)acetamide; N-cyclopropyl-2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)acetamide; N-(cyclopropylmethyl)-2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)acetamide; 2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)-N-(2-methoxyethyl)acetamide; and pharmaceutically acceptable salts thereof.

17. A process to prepare a compound of claim 1, comprising the reaction of a compound of formula (II) in the presence of a compound of formula (III); ##STR00051## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.14, R.sup.15, R.sup.16, R.sup.17, n and p are as defined herein, R.sup.24 is alkyl and A.sup.1 is (CR.sup.14R.sup.15)C(O)NR.sup.16R.sup.17.

18. A pharmaceutical composition comprising a compound according to claim 1 and a therapeutically inert carrier.

19. A method for the treatment of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing syndrome, which method comprises administering to a subject in need thereof an effective amount of a compound of claim 1.

Description

EXAMPLES

Intermediate A-1

(rac)-2-[4-[3-Fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]acetic acid and (rac)-2-[4-[3-Fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl]acetic acid

(1) ##STR00009##

[A]5-[3-Fluoro-4-(trifluoromethyl)phenyl]oxazole

(2) ##STR00010##

(3) A solution of 3-fluoro-4-(trifluoromethyl)benzaldehyde (1.40 g, 7.07 mmol) and p-toluenesulfonylmethyl isocyanide (1.53 g, 7.68 mmol; TosMIC) in MeOH (100 mL) was treated with potassium carbonate (1.97 g, 14.14 mmol) and the suspension heated to reflux for 14 h. After being cooled to room temperature, the solvent was removed under reduced pressure and the crude product triturated with water at 0 C. (225 mL). The slightly orange precipitate was collected by filtration and dried under vacuum (4.46 g, 92%). MS: 232.0 (M+H).sup.+.

[B] (rac)-2-[4-[3-Fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]acetic acid and (rac)-2-[4-[3-Fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl]acetic acid [Intermediate A-1]

(4) ##STR00011##

(5) A solution of 5-[3-fluoro-4-(trifluoromethyl)phenyl]oxazole (0.30 g, 1.30 mmol), 2-cyclopent-2-en-1-ylacetic acid (1.64 g, 13.0 mmol; CAS[13668-61-6]) and trifluoroacetic acid (0.30 g, 2.60 mmol) was heated neat under microwave irradiation to 180 C. for 17 h. After purification by MPLC (70 g SiO.sub.2, Telos-cartridge) eluting with a 0 to 100% EtOAc-n-heptane gradient the title compounds were obtained as slightly brown oil (36%; approximate 1:1 mixture). MS: 340.2 (M+H).sup.+ (rac)-(2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl]acetic acid) and MS: 340.2 (M+H).sup.+ (rac)-(2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]acetic acid). The subsequent reactions were conducted without further separation of the two regioisomers.

Intermediate A-2

(rac)-2-[4-[2-Fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]acetic acid and (rac)-2-[4-[2-Fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl]acetic acid

(6) ##STR00012##

(7) In analogy to the procedure described for the preparation of (rac)-2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]acetic acid and (rac)-2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl]acetic acid (intermediate A-1, step B), replacing 5-[3-fluoro-4-(trifluoromethyl)phenyl]oxazole with 5-[2-fluoro-4-(trifluoromethyl)phenyl]oxazole (CAS[1146694-91-8]). The reaction was conducted neat and heated under microwave irradiation to 200 C. for 10 h. After purification by MPLC (70 g SiO.sub.2, Telos-cartridge) eluting with a 0 to 100% EtOAc-n-heptane gradient the title compounds were obtained as slightly brown oil (34%; approximate 1:1 mixture). MS: 340.5 (M+H).sup.+ (rac)-(2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl]acetic acid) and MS: 340.5 (M+H).sup.+ (rac)-(2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]acetic acid). The subsequent reactions were conducted without further separation of the two regioisomers.

Intermediate A-3

Ethyl (2E)-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-isoquinolin-8-ylidene]acetate and Ethyl (2Z)-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-isoquinolin-8-ylidene]acetate

(8) ##STR00013##

[A] Ethyl 5-bromo-4-methylnicotinate

(9) ##STR00014##

(10) To a stirred light brown suspension of 5-bromo-4-methylnicotinic acid (10.00 g, 46.3 mmol) and ethanol (2.35 g, 2.97 mL, 50.9 mmol) in DCM (231 mL) at 0 C. under Ar was added EDCI (10.9 g, 55.5 mmol) and DMAP (566 mg, 4.63 mmol), stirring was continued over night and the reaction mixture was allowed to warm up to rt. The reaction mixture was poured on aq. 10% KH.sub.2PO.sub.4 solution followed by extraction with EtOAc (3). The organic phases were washed once with aq. 10% KH.sub.2PO.sub.4, aq. sat. NaHCO.sub.3 and with aq. sat. NaCl solution. The combined organic phases were dried (Na.sub.2SO.sub.4), filtered and evaporated to afford the title compound as brown solid (9.49 g, 84%). MS: 244.0 (M+H).sup.+.

[B] (rac)-Methyl 4-bromo-8-oxo-5,6,7,8-tetrahydroisoquinoline-7-carboxylate

(11) ##STR00015##

(12) Ethyl 5-bromo-4-methylnicotinate (7.04 g, 28.8 mmol) in THF (28.8 mL) was added over a period of 20 min to a solution of LDA (31.7 mmol) [generated from N,N-diisopropylamine (4.52 mL, 31.7 mmol) and n-butyllithium (19.8 mL, 31.7 mmol; 1.6 M solution in hexane) in THF (144 mL)] at 78 C. The resulting dark red solution was stirred for 20 min, then methyl acrylate (6.5 mL, 72.1 mmol) in THF (28.8 mL) was added over 15 min. The reaction was stirred an additional 1.5 h, then aq. 10% AcOH (57.8 mL, 101 mmol) was added (pH 4-5) and the reaction was allowed to warm to rt. After evaporation, the residue was partitioned between aq. sat. NaHCO.sub.3 and EtOAc and extracted with EtOAc (3). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated to afford the title compound as brown solid (7.80 g, 95% in 70% purity with 30% starting material). MS: 280.0 (M+H).sup.+.

[C] 4-Bromo-6,7-dihydroisoquinolin-8(5H)-one

(13) ##STR00016##

(14) The crude (rac)-methyl 4-bromo-8-oxo-5,6,7,8-tetrahydroisoquinoline-7-carboxylate (7.79 g, 27.4 mmol) was dissolved (small amount of not dissolved material) in aq. 6 M HCl (84.1 mL, 505 mmol) and heated at reflux for 2.5 h (dark brown solution, no more starting material visible on TLC). The acidic solution was concentrated in vacuo, suspended in water (ca. 25 mL), cooled in ice, and basified with 6.0 M KOH. The aqueous solution was washed with Et.sub.2O (2) and DCM (3), the combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated to afford after evaporation under reduced pressure the title compound as brown solid (4.30 g, 69%). MS: 226.0 (M+H).sup.+.

[D] Ethyl (2E)-2-(4-bromo-6,7-dihydro-5H-isoquinolin-8-ylidene)acetate and Ethyl (2Z)-2-(4-bromo-6,7-dihydro-5H-isoquinolin-8-ylidene)acetate

(15) ##STR00017##

(16) To a solution of sodium bis(trimethylsilyl)amide (33.2 mL, 33.2 mmol; 1.0 M solution in THF) in THF (80 mL) was added slowly ethyl 2-(diethoxyphosphoryl)acetate (9.92 g, 8.78 mL, 44.2 mmol; CAS[867-13-0]) at 50 C. and after completed addition the reaction mixture stirred at 0 C. After 1 h, 4-bromo-6,7-dihydro-5H-isoquinolin-8-one (2.5 g, 11.1 mmol) was added and stirring continued under heating to reflux for 4 h. The reaction mixture was quenched by addition of a sat. aq. solution of ammonium chloride (50 mL) and the aqueous phase extracted with ethyl acetate (350 mL). The combined organic phases were dried over MgSO.sub.4 and concentrated under reduced pressure. Purification by MPLC (70 g SiO.sub.2, Telos-cartridge) eluting with a 0 to 5% EtOAc-n-heptane gradient provided the two title compounds as slightly yellow oil (2.1 g, 65%; approximate ratio (E)/(Z)=4:6). MS: 296.0 (M+H).sup.+. The subsequent reaction was conducted without further separation of the two configurational isomers.

[E] Ethyl (2E)-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-isoquinolin-8-ylidene]acetate and Ethyl (2Z)-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-isoquinolin-8-ylidene]acetate

(17) ##STR00018##

(18) To a solution of ethyl (2E)-2-(4-bromo-6,7-dihydro-5H-isoquinolin-8-ylidene)acetate and ethyl (2Z)-2-(4-bromo-6,7-dihydro-5H-isoquinolin-8-ylidene)acetate (0.70 g, 2.36 mmol), 2-fluoro-4-(trifluoromethyl)phenylboronic acid (0.59 g, 2.84 mmol) and sodium carbonate (0.28 g, 2.60 mmol) in a mixture of ethanol (13.5 mL) and water (2.5 mL) was added tetrakis(triphenyl-phosphine)palladium(0) (0.28 g, 0.24 mmol) under Ar. The reaction mixture was heated under microwave irradiation to 85 C. for 6 h. A sat. aq. solution of sodium chloride (50 mL) was added and the aqueous phase extracted with ethyl acetate (350 mL). The combined organic phases were dried over MgSO.sub.4 and concentrated under reduced pressure. Purification by MPLC (70 g SiO.sub.2, Telos-cartridge) eluting with a 0 to 10% EtOAc-n-heptane gradient provided the two title compounds as white solid (0.38 g, 42%). MS: 380.1 (M+H).sup.+. The subsequent reaction was conducted without further separation of the two configurational isomers.

Example 1

(rac)-Ethyl 2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]acetate

(19) ##STR00019##

(20) A solution of 2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]acetic acid and 2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl]acetic acid one (intermediate A-1) (67.9 mg, 0.20 mmol) and N,N-diisopropylethylamine (0.17 mL, 1.0 mmol) in DMF (0.4 mL) and ethanol (0.4 mL) under Ar was treated with HATU (98.9 mg, 0.26 mmol) at rt for 2 h. Evaporation of the solvent mixture and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water provided the title compound as light brown solid (11.0 mg, 15%). MS: 368.1 (M+H).sup.+.

Example 2

(rac)-2-[4-[3-Fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N-methyl-acetamide

(21) ##STR00020##

(22) A solution of 2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]acetic acid and 2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl]acetic acid one (intermediate A-1) (50 mg, 0.15 mmol) and N,N-diisopropylethylamine (0.13 mL, 0.74 mmol) in DMF (0.4 mL) under Ar was treated with HATU (72.9 mg, 0.19 mmol). To this solution was added methylamine (0.22 mL, 0.44 mmol; 2.0 M solution in THF) and the reaction mixture stirred at rt for 16 h. Evaporation of the solvent mixture and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water provided the title compound as light brown solid (9.9 mg, 38%). MS: 353.1 (M+H).sup.+.

Example 3

(rac)-2-[4-[3-Fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N-ethyl-acetamide

(23) ##STR00021##

(24) In analogy to the procedure described for the preparation of (rac)-2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N-methyl-acetamide (example 2), replacing methylamine with ethylamine (2.0 M solution in MeOH). Evaporation of the solvent mixture and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water provided the title compound as a white solid (8.1 mg, 15%). MS: 366 (M).sup.+.

Example 4

(rac)-2-[4-[3-Fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N-propyl-acetamide

(25) ##STR00022##

(26) In analogy to the procedure described for the preparation of (rac)-2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N-methyl-acetamide (example 2), replacing methylamine with propylamine. Evaporation of the solvent mixture and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water provided the title compound as light brown solid (7.4 mg, 13%). MS: 381.6 (M+H).sup.+.

Example 5

(rac)-N-Cyclopropyl-2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]acetamide

(27) ##STR00023##

(28) In analogy to the procedure described for the preparation of (rac)-2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N-methyl-acetamide (example 2), replacing methylamine with cyclopropylamine. Evaporation of the solvent mixture and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water provided the title compound as light brown solid (5.9 mg, 21%). MS: 379.1 (M+H).sup.+.

Example 6

(rac)-N-(Cyclopropylmethyl)-2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]acetamide

(29) ##STR00024##

(30) In analogy to the procedure described for the preparation of (rac)-2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N-methyl-acetamide (example 2), replacing methylamine with cyclopropylmethylamine. Evaporation of the solvent mixture and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water provided the title compound as light brown solid (10.0 mg, 34%). MS: 393.2 (M+H).sup.+.

Example 7

(rac)-2-[4-[3-Fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N-(2-methoxyethyl)acetamide

(31) ##STR00025##

(32) In analogy to the procedure described for the preparation of (rac)-2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N-methyl-acetamide (example 2), replacing methylamine with 2-methoxyethanamine. Evaporation of the solvent mixture and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water provided the title compound as light brown solid (7.4 mg, 25%). MS: 397.2 (M+H).sup.+.

Example 8

(rac)-2-[4-[3-Fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-1-(1-piperidyl)ethanone

(33) ##STR00026##

(34) In analogy to the procedure described for the preparation of (rac)-2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N-methyl-acetamide (example 2), replacing methylamine with piperidine. Evaporation of the solvent mixture and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water provided the title compound as light brown solid (2.7 mg, 9%). MS: 407.6 (M+H).sup.+.

Example 9

(rac)-2-[4-[3-Fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-1-morpholino-ethanone

(35) ##STR00027##

(36) In analogy to the procedure described for the preparation of (rac)-2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N-methyl-acetamide (example 2), replacing methylamine with morpholine. Evaporation of the solvent mixture and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water provided the title compound as light brown solid (5.1 mg, 17%). MS: 409.6 (M+H).sup.+.

Example 10

(rac)-2-[4-[3-Fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N-isoxazol-3-yl-acetamide

(37) ##STR00028##

(38) In analogy to the procedure described for the preparation of (rac)-2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N-methyl-acetamide (example 2), replacing methylamine with isoxazol-3-amine. Evaporation of the solvent mixture and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water provided the title compound as light brown solid (5.8 mg, 19%). MS: 406.1 (M+H).sup.+.

Example 11

(rac)-2-[4-[3-Fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N-(1H-pyrazol-3-yl)acetamide

(39) ##STR00029##

(40) In analogy to the procedure described for the preparation of (rac)-2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N-methyl-acetamide (example 2), replacing methylamine with 1H-pyrazol-3-amine. Evaporation of the solvent mixture and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water provided the title compound as light brown solid (10.6 mg, 35%). MS: 405.1 (M+H).sup.+.

Example 12

(rac)-2-[4-[3-Fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N-(1-methylpyrazol-4-yl)acetamide

(41) ##STR00030##

(42) In analogy to the procedure described for the preparation of (rac)-2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N-methyl-acetamide (example 2), replacing methylamine with 1-methylpyrazol-4-amine. Evaporation of the solvent mixture and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water provided the title compound as light brown solid (3.9 mg, 12%). MS: 419.6 (M+H).sup.+.

Example 13

(rac)-2-[4-[2-Fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N,N-dimethyl-acetamide

(43) ##STR00031##

(44) In analogy to the procedure described for the preparation of (rac)-2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N-methyl-acetamide (example 2), replacing 2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]acetic acid and 2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl]acetic acid one (intermediate A-1) with 2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]acetic acid and 2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl]acetic acid (intermediate A-2) and methylamine with dimethylamine. Evaporation of the solvent mixture and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water and preparative TLC on normal phase (DCM-MeOH=93:7) provided the title compound as light brown solid (2.5 mg, 9%). MS: 367.1 (M+H)+.

Example 14

(rac)-N-Ethyl-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N-methyl-acetamide

(45) ##STR00032##

(46) In analogy to the procedure described for the preparation of (rac)-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N,N-dimethyl-acetamide (example 13), replacing dimethylamine with N-methylethanamine. Evaporation of the solvent mixture and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water and preparative TLC on normal phase (DCM-MeOH=93:7) provided the title compound as light brown solid (2.5 mg, 9%). MS: 381.2 (M+H).sup.+.

Example 15

(rac)-2-[4-[2-Fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N-isopropyl-N-methyl-acetamide

(47) ##STR00033##

(48) In analogy to the procedure described for the preparation of (rac)-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N,N-dimethyl-acetamide (example 13), replacing dimethylamine with N-methylpropan-2-amine. Evaporation of the solvent mixture and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water and preparative TLC on normal phase (DCM-MeOH=93:7) provided the title compound as light brown solid (2.5 mg, 9%). MS: 395.2 (M+H).sup.+.

Example 16

(rac)-N-Cyclopropyl-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N-methyl-acetamide

(49) ##STR00034##

(50) In analogy to the procedure described for the preparation of (rac)-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N,N-dimethyl-acetamide (example 13), replacing dimethylamine with N-methylcyclopropanamine. Evaporation of the solvent mixture and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water and preparative TLC on normal phase (DCM-MeOH=93:7) provided the title compound as light brown solid (2.5 mg, 9%). MS: 393.2 (M+H).sup.+.

Example 17

(rac)-N-Cyclopropyl-N-ethyl-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]acetamide

(51) ##STR00035##

(52) In analogy to the procedure described for the preparation of (rac)-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N,N-dimethyl-acetamide (example 13), replacing dimethylamine with N-ethylcyclopropanamine. Evaporation of the solvent mixture and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water and preparative TLC on normal phase (DCM-MeOH=93:7) provided the title compound as light brown solid (2.5 mg, 8%). MS: 407.2 (M+H).sup.+.

Example 18

(rac)-1-(Azetidin-1-yl)-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]ethanone

(53) ##STR00036##

(54) In analogy to the procedure described for the preparation of (rac)-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N,N-dimethyl-acetamide (example 13), replacing dimethylamine with azetidine. Evaporation of the solvent mixture and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water and preparative TLC on normal phase (DCM-MeOH=93:7) provided the title compound as light brown solid (2.5 mg, 9%). MS: 379.1 (M+H).sup.+.

Example 19

(rac)-2-[4-[2-Fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-1-[3-(hydroxymethyl)azetidin-1-yl]ethanone

(55) ##STR00037##

(56) In analogy to the procedure described for the preparation of (rac)-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N,N-dimethyl-acetamide (example 13), replacing dimethylamine with azetidin-3-ylmethanol. Evaporation of the solvent mixture and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water and preparative TLC on normal phase (DCM-MeOH=93:7) provided the title compound as light brown solid (2.6 mg, 9%). MS: 409.2 (M+H).sup.+.

Example 20

(rac)-2-[4-[2-Fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-1-(3-methoxyazetidin-1-yl)ethanone

(57) ##STR00038##

(58) In analogy to the procedure described for the preparation of (rac)-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N,N-dimethyl-acetamide (example 13), replacing dimethylamine with 3-methoxyazetidine. Evaporation of the solvent mixture and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water and preparative TLC on normal phase (DCM-MeOH=93:7) provided the title compound as light brown solid (2.5 mg, 8%). MS: 409.2 (M+H).sup.+.

Example 21

(rac)-2-[4-[2-Fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-1-pyrrolidin-1-yl-ethanone

(59) ##STR00039##

(60) In analogy to the procedure described for the preparation of (rac)-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N,N-dimethyl-acetamide (example 13), replacing dimethylamine with pyrrolidine. Evaporation of the solvent mixture and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water and preparative TLC on normal phase (DCM-MeOH=93:7) provided the title compound as light brown solid (2.5 mg, 9%). MS: 393.2 (M+H).sup.+.

Example 22

(rac)-2-[4-[2-Fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-1-[(2S)-2-methylpyrrolidin-1-yl]ethanone

(61) ##STR00040##

(62) In analogy to the procedure described for the preparation of (rac)-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]-N,N-dimethyl-acetamide (example 13), replacing dimethylamine with (2S)-2-methylpyrrolidine. Evaporation of the solvent mixture and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water and preparative TLC on normal phase (DCM-MeOH=93:7) provided the title compound as light brown solid (2.5 mg, 8%). MS: 407.2 (M+H).sup.+.

Example 23

(rac)-Ethyl 2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydroisoquinolin-8-yl]acetate

(63) ##STR00041##

(64) To a solution of ethyl (2E)-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-isoquinolin-8-ylidene]acetate and ethyl (2Z)-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-isoquinolin-8-ylidene]acetate (intermediate A-3) (0.23 g, 0.60 mmol) in MeOH (10 mL) was added 10% Pd/C (0.019 g, 0.018 mmol) and the reaction mixture stirred under hydrogen (3 bar) for 15 h at rt. The reaction mixture was filtered through Dicalite, concentrated in vacuo and purified by MPLC (50 g SiO.sub.2, Telos-cartridge) eluting with a 0 to 20% EtOAc-n-heptane gradient to provide the title compound as colorless oil (0.21 g, 93%). MS: 382.1 (M+H).sup.+.

Example 24

(rac)-2-[4-[2-Fluoro-4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydroisoquinolin-8-yl]ethanol

(65) ##STR00042##

(66) To a solution of (rac)-ethyl 2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydroisoquinolin-8-yl]acetate (example 23) (20 mg, 0.052 mmol) in THF (2 mL) was added diisobutylaluminium hydride (0.11 mL, 0.11 mmol; 1.0 M in toluene) and the reaction mixture stirred 15 h at rt. The reaction mixture was quenched by addition of a solution of sodium tartrate (0.2 g) in water (1 mL) and stirring continued for 30 min. The aqueous phase was extracted with ethyl acetate (35 mL), the combined organic phases dried over MgSO.sub.4 and concentrated under reduced pressure. Purification by MPLC (10 g SiO.sub.2, Telos-cartridge) eluting with a 0 to 5% MeOH-DCM gradient provided the title compound as colorless oil (9.9 mg, 56%). MS: 340.1 (M+H).sup.+.

Example 25

(rac)-2-[4-[2-Fluoro-4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydroisoquinolin-8-yl]-N-methyl-acetamide

(67) ##STR00043##

(68) To a solution of (rac)-ethyl 2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydroisoquinolin-8-yl]acetate (example 23) (28.5 mg, 0.075 mmol) in THF (0.5 mL) was added methylamine (0.056 mL, 0.11 mmol; 2.0 M solution in THF) and trimethylaluminium (0.045 mL, 0.090 mmol; 2.0 M solution in toluene) under Ar. The reaction mixture was heated under microwave irradiation to 120 C. for 1 h. The reaction mixture was quenched by addition of a solution of sodium tartrate (0.2 g) in water (1 mL) and then stirred for 30 min. The aqueous phase was extracted with ethyl acetate (35 mL), the combined organic phases dried over MgSO.sub.4 and concentrated under reduced pressure. Purification by MPLC (20 g SiO.sub.2, Telos-cartridge) eluting with a 0 to 5% MeOH-DCM gradient provided the title compound as white solid (26.0 mg, 95%). MS: 367.2 (M+H).sup.+.

Example 26

(rac)-2-[4-[2-Fluoro-4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydroisoquinolin-8-yl]-N,N-dimethyl-acetamide

(69) ##STR00044##

(70) In analogy to the procedure described for the preparation of (rac)-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydroisoquinolin-8-yl]-N-methyl-acetamide (example 25), replacing methylamine with dimethylamine. Evaporation of the solvent mixture and purification by MPLC (20 g SiO.sub.2, Telos-cartridge) eluting with a 0 to 5% MeOH-DCM gradient provided the title compound as white solid (25.3 mg, 89%). MS: 381.2 (M+H).sup.+.

Example 27 and Example 28

(+)-2-[4-[2-Fluoro-4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydroisoquinolin-8-yl]-N,N-dimethyl-acetamide and (+2-[4-[2-Fluoro-4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydroisoquinolin-8-yl]-N,N-dimethyl-acetamide

(71) ##STR00045##

(72) The title compounds were prepared by chiral separation of (rac)-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydroisoquinolin-8-yl]-N,N-dimethyl-acetamide (80 mg, 0.21 mmol; example 26) on a Reprosil Chiral NR column (ethanol-n-heptane=3:7) to give (+)-(R or S)-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydroisoquinolin-8-yl]-N,N-dimethyl-acetamide [22.6 mg, 28%; MS: 381.2 (M+H).sup.+; example 27] and ()-(R or S)-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydroisoquinolin-8-yl]-N,N-dimethyl-acetamide [32.4 mg, 41%; MS: 381.2 (M+H).sup.+; example 28] as colorless oils.

Example 29

(rac)-N-Ethyl-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydroisoquinolin-8-yl]acetamide

(73) ##STR00046##

(74) In analogy to the procedure described for the preparation of (rac)-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydroisoquinolin-8-yl]-N-methyl-acetamide (example 25), replacing methylamine with ethylamine (2.0 M solution in MeOH). Evaporation of the solvent mixture and purification by MPLC (20 g SiO.sub.2, Telos-cartridge) eluting with a 0 to 5% MeOH-DCM gradient and preparative TLC on normal phase (EtOAc) provided the title compound as white solid (8.3 mg, 29%). MS: 381.2 (M+H).sup.+.

Example 30

(rac)-N-Cyclopropyl-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydroisoquinolin-8-yl]acetamide

(75) ##STR00047##

(76) In analogy to the procedure described for the preparation of (rac)-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydroisoquinolin-8-yl]-N-methyl-acetamide (example 25), replacing methylamine with cyclopropylamine. Evaporation of the solvent mixture and purification by MPLC (20 g SiO.sub.2, Telos-cartridge) eluting with a 0 to 5% MeOH-DCM gradient and preparative TLC on normal phase (EtOAc) provided the title compound as white solid (19.5 mg, 67%). MS: 437.2 (M+HCOO).sup..

Example 31

(rac)-N-(Cyclopropylmethyl)-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydroisoquinolin-8-yl]acetamide

(77) ##STR00048##

(78) In analogy to the procedure described for the preparation of (rac)-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydroisoquinolin-8-yl]-N-methyl-acetamide (example 25), replacing methylamine with cyclopropylmethylamine. Evaporation of the solvent mixture and purification by MPLC (20 g SiO.sub.2, Telos-cartridge) eluting with a 0 to 5% MeOH-DCM gradient provided the title compound as white solid (26.9 mg, 89%). MS: 407.2 (M+H).sup.+.

Example 32

(rac)-2-[4-[2-Fluoro-4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydroisoquinolin-8-yl]-N-(2-methoxyethyl)acetamide

(79) ##STR00049##

(80) In analogy to the procedure described for the preparation of (rac)-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydroisoquinolin-8-yl]-N-methyl-acetamide (example 25), replacing methylamine with 2-methoxyethanamine. Evaporation of the solvent mixture and purification by MPLC (20 g SiO.sub.2, Telos-cartridge) eluting with a 0 to 5% MeOH-DCM gradient provided the title compound as white solid (18.2 mg, 59%). MS: 411.2 (M+H).sup.+.

Example A

(81) A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:

(82) TABLE-US-00002 Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg

Example B

(83) A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition:

(84) TABLE-US-00003 Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg