Phenyl-dihydropyridine derivatives as inhibitors of aldosterone synthase

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) ##STR00039## wherein R.sup.1, R.sup.2 R.sup.4 and R.sup.5 are independently selected from H, halogen, cyano, nitro, alkyl, haloalkyl, cycloalkyl, alkoxy, haloalkoxy and cycloalkoxy; R.sup.3 is haloalkyl; R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.11 are independently selected from H, halogen, alkyl and haloalkyl; R.sup.12 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; A.sup.1 is (CR.sup.14R.sup.15).sub.pNR.sup.16R.sup.17, (CR.sup.14R.sup.15).sub.pOR.sup.17, (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.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.4 and R.sup.5 are H.

5. 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.

6. 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.

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

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

9. The compound of claim 1, wherein A.sup.1 is (CR.sup.14R.sup.15).sub.pOR.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. A compound selected from 4-(3-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-amine; 4-(3-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-ol; 4-(3-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-5-ol; 4-(3-fluoro-4-(trifluoromethyl)phenyl)-5-phenyl-6,7-dihydro-5H-cyclopenta[c]pyridin-5-ol; 4-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-ol; 4-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-5-ol; 4-(2-fluoro-4-(trifluoromethyl)phenyl)-5-isopropyl-6,7-dihydro-5H-cyclopenta[c]pyridin-5-ol; 4-(2-fluoro-4-(trifluoromethyl)phenyl)-5-phenyl-6,7-dihydro-5H-cyclopenta[c]pyridin-5-ol; (+)-4-(2-fluoro-4-(trifluoromethyl)phenyl)-5-phenyl-6,7-dihydro-5H-cyclopenta[c]pyridin-5-ol; (+4-(2-fluoro-4-(trifluoromethyl)phenyl)-5-phenyl-6,7-dihydro-5H-cyclopenta[c]pyridin-5-ol; (R)-4-(2-fluoro-4-(trifluoromethyl)phenyl)-5-phenyl-6,7-dihydro-5H-cyclopenta[c]pyridin-5-ol; (S)-4-(2-fluoro-4-(trifluoromethyl)phenyl)-5-phenyl-6,7-dihydro-5H-cyclopenta[c]pyridin-5-ol; ethyl 2-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)acetate; 2-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)-N-methylacetamide; N-(cyclopropylmethyl)-2-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)acetamide; 2-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)-N-propylacetamide; 2-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)-1-(piperidin-1-yl)ethanone; 2-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)-1-morpholinoethanone; 2-[4-(3-Fluoro-4-trifluoromethyl-phenyl)-6,7-dihydro-5H-[2]pyrindin-5-yl]-N-isoxazol-3-yl-acetamide; 2-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)-N-(1H-pyrazol-3-yl)acetamide; 2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)-1-(pyrrolidin-1-yl)ethanone; N-ethyl-2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)-N-methylacetamide; 2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)-N-isopropyl-N-methylacetamide; N-cyclopropyl-2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)-N-methylacetamide; N-cyclopropyl-N-ethyl-2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)acetamide; 2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)-1-((S)-2-methylpyrrolidin-1-yl)ethanone; 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); ##STR00040## 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 of claim 1 and a therapeutically inert carrier.

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

Description

EXAMPLES

Intermediate A-1

4-[3-Fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydrocyclopenta[c]pyridin-5-one

(1) ##STR00007##

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

(2) ##STR00008##

(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]4-[3-Fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridine

(4) ##STR00009##

(5) A solution of 5-[3-fluoro-4-(trifluoromethyl)phenyl]oxazole (0.50 g, 2.16 mmol), cyclopentene (2.95 g, 43.3 mmol) and trifluoroacetic acid (0.49 g, 4.33 mmol) in o-dichlorobenzene (12 mL) was heated under microwave irradiation to 220 C. for 6 h. To the reaction mixture was added triethylamine (5 mL) and the solvent mixture removed under reduced pressure. Purification by MPLC (70 g SiO.sub.2, Telos-cartridge) eluting with a 0 to 50% EtOAc-n-heptane gradient provided the title compound (0.27 g, 44%) as a slightly brown solid. MS: 282.5 (M+H).sup.+.

(6) Alternatively, this reaction step has also been conducted under flow conditions:

(7) The reaction was performed on a custom-made flow system consisting of a Dionex P580 pump and a HP 6890 Series Gas Chromatography oven used as a heating source. The GC oven was equipped with a stainless steel coil reactor (53 mL volume) made from Supelco stainless steel tube (ID=2.1 mm). After heating to 230 C. using toluene as a system solvent, a mixture of cyclopentene (1.77 g, 26.0 mmol) and trifluoroacetic acid (0.30 g, 2.60 mmol) in toluene (1.0 mL), a mixture of 5-[3-fluoro-4-(trifluoromethyl)phenyl]oxazole (0.30 g, 1.30 mmol), cyclopentene (1.77 g, 26.0 mmol) and trifluoroacetic acid (0.30 g, 2.60 mmol) in toluene (1.0 mL) and finally a mixture of cyclopentene (1.77 g, 26.0 mmol) and trifluoroacetic acid (0.30 g, 2.60 mmol) in toluene (1.0 mL) were injected onto the stainless steel coil reactor in sequential order. The system was run at a flow rate of 0.35 mL/min equaling to a nominal residence time of t.sub.R=150 min and an effective residence time of t.sub.R,eff=120 min taking the 25% volume expansion of toluene at 230 C. into account (R. E. Martin et al., Eur. J. Org. Chem. 2012, 47-52). A 750 psi back-pressure regulator with a protection guard (filled with sand/glass wool) was used at the exit of the reactor to maintain system pressure. The reaction mixture was collected in a round bottom flask, triethylamine (5 mL) was added and the solvent mixture removed under reduced pressure. Purification by MPLC (50 g SiO.sub.2, Telos-cartridge) eluting with a 0 to 50% EtOAc-n-heptane gradient provided the title compound (0.18 g, 50%) as a slightly brown solid. MS: 282.5 (M+H).sup.+.

[C]4-[3-Fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydrocyclopenta[c]pyridin-5-one

Intermediate A-1

(8) ##STR00010##

(9) To a solution of 4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridine (76.0 mg, 0.27 mmol) and dirhodium(II, III) tetrakis caprolactamate (1.8 mg, 0.0027 mmol; synthesis described in M. P. Doyle et al., J. Am. Chem. Soc. 1993, 115, 958-964) in DCM (0.5 mL) was added sodium bicarbonate (22.7 mg, 0.27 mmol) and tert-butyl hydroperoxide (0.25 mL, 1.35 mmol). The reaction mixture was stirred at room temperature for 48 h. During this time period additional equivalents of tert-butyl hydroperoxide (1.25 mL, 6.75 mmol) were added in small portions. The solvent was removed under reduced pressure and the crude reaction mixture purified by MPLC (20 g SiO.sub.2, Telos-cartridge) eluting with a 0 to 50% EtOAc-n-heptane gradient to provide 4-[3-fluoro-4-(trifluoromethyl)phenyl]-5,6-dihydrocyclopenta[c]pyridin-7-one [15.5 mg, 19%; MS: 296.1 (M+H).sup.+] and the title compound [17.4 mg, 22%; MS: 296.4 (M+H).sup.+] both as slightly yellow solids.

Intermediate A-2

4-[2-Fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydrocyclopenta[c]pyridin-5-one

(10) ##STR00011##

[A]4-[2-Fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridine

(11) ##STR00012##

(12) In analogy to the procedure described for the preparation of 4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridine (intermediate A-1, step B, flow approach), replacing 5-[3-fluoro-4-(trifluoromethyl)phenyl]oxazole with 5-[2-fluoro-4-(trifluoromethyl)phenyl]oxazole (CAS[1146694-91-8]). The flow process was run at 250 C. with an effective residence time of t.sub.R,eff=120 min. The title compound was obtained as a light brown solid (54%). MS: 282.1 (M+H).sup.+.

[B]4-[2-Fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydrocyclopenta[c]pyridin-5-one

Intermediate A-2

(13) ##STR00013##

(14) In analogy to the procedure described for the preparation of 4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydrocyclopenta[c]pyridin-5-one (intermediate A-1) and 4-[3-fluoro-4-(trifluoromethyl)phenyl]-5,6-dihydrocyclopenta[c]pyridin-7-one (intermediate A-2), replacing 4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridine with 4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridine. The title compound [20%; MS: 296.1 (M+H).sup.+] and 4-[2-fluoro-4-(trifluoromethyl)phenyl]-5,6-dihydrocyclopenta[c]pyridin-7-one [30%; MS: 296.1 (M+H).sup.+] were obtained as off-white solids.

Intermediate A-3

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

(15) ##STR00014##

(16) In analogy to the procedure described for the preparation of 4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridine (intermediate A-1, step B, batch approach), replacing cyclopentene with 2-cyclopent-2-en-1-ylacetic acid (CAS[13668-61-6]). The reaction was conducted neat and heated 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.+ (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.+ (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-4

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

(17) ##STR00015##

(18) In analogy to the procedure described for the preparation of 4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridine (intermediate A-1, step B, batch approach), replacing cyclopentene with 2-cyclopent-2-en-1-ylacetic acid (CAS[13668-61-6]). 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.+ (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.+ (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.

Example 1

(rac)-4-(3-Fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-amine

(19) ##STR00016##

(20) A solution of ammonium acetate (1.57 g, 20.4 mmol) in MeOH (7 mL) was treated with 4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydrocyclopenta[c]pyridin-5-one (intermediate A-1) (0.20 g, 0.68 mmol) and the reaction mixture stirred at room temperature for 1 h. Sodium cyanoborohydride (0.15 g, 2.39 mmol) was added and stirring continued at room temperature. After 15 min, the reaction mixture was heated to reflux for 90 min. The solvent was removed under reduced pressure, a sat. aq. solution of ammonium chloride (2 mL) and a 1 M solution of HCl (2 mL) were added and the aq. phase washed with DCM (35 mL). To the aq. phase was added a 1 M solution of NaOH (4 mL) and extracted with DCM (35 mL). The combined organic phases were dried over MgSO.sub.4 and concentrated under reduced pressure. The title compound was isolated as light brown solid (74 mg, 37%). MS: 297.4 (M+H).sup.+.

Example 2

(rac)-4-(3-Fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-ol

(21) ##STR00017##

(22) A solution of 4-(3-fluoro-4-trifluoromethyl-phenyl)-6,7-dihydro-[2]pyrindin-5-one (intermediate A-1) (15.9 mg, 0.054 mmol) in methanol (1 mL) was treated at 0 C. with sodium borohydride (2.0 mg, 0.954 mmol). After 10 min, the reaction mixture was quenched by addition of acetic acid (0.43 mL) and the crude reaction mixture concentrated under reduced pressure. A sat. aq. solution of sodium bicarbonate (5 mL) was added and the aq. phase extracted with EtOAc (310 mL). The combined organic phases were dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. Purification by MPLC eluting with a gradient of DCM-isopropanol provided the title compound as off-white solid (14 mg, 88%). MS: 298.1 (M+H).sup.+.

Example 3

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

(23) ##STR00018##

(24) A solution of 4-(3-fluoro-4-trifluoromethyl-phenyl)-6,7-dihydro-[2]pyrindin-5-one (intermediate A-1) (25 mg, 0.085 mmol) and lithium chloride (10.9 mg, 0.25 mmol) in diethyl ether (3 mL) under argon was treated with methyllithium (0.063 mL, 0.10 mmol; 1.6 M solution in diethyl ether) and the reaction mixture stirred at 0 C. After 1 h stirring was continued at room temperature for 3 h. The reaction mixture was quenched by addition of a sat. aq. solution of ammonium chloride (10 mL) and the aq. phase extracted with EtOAc (310 mL). The combined organic phases were dried over MgSO.sub.4 and concentrated under reduced pressure. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water provided the title compound as off-white solid (12 mg, 46%). MS: 312.1 (M+H).sup.+.

Example 4

(rac)-4-(3-Fluoro-4-(trifluoromethyl)phenyl)-5-phenyl-6,7-dihydro-5H-cyclopenta[c]pyridin-5-ol

(25) ##STR00019##

(26) A solution of 4-(3-fluoro-4-trifluoromethyl-phenyl)-6,7-dihydro-[2]pyrindin-5-one (intermediate A-1) (25 mg, 0.085 mmol) and lithium chloride (10.9 mg, 0.25 mmol) in diethyl ether (3 mL) under argon was treated with phenyllithium (0.050 mL, 0.10 mmol; 2.0 M solution in dibutyl ether) and the reaction mixture stirred at 0 C. After 1 h, the reaction mixture was quenched by addition of a sat. aq. solution of ammonium chloride (10 mL) and the aq. phase extracted with EtOAc (310 mL). The combined organic phases were dried over MgSO.sub.4 and concentrated under reduced pressure. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water provided the title compound as light brown oil (3.3 mg, 10%). MS: 374.2 (M+H).sup.+.

Example 5

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

(27) ##STR00020##

(28) In analogy to the procedure described for the preparation of (rac)-4-(3-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-ol (example 2), replacing 4-(3-fluoro-4-trifluoromethyl-phenyl)-6,7-dihydro-[2]pyrindin-5-one (intermediate A-1) with 4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydrocyclopenta[c]pyridin-5-one (intermediate A-2). The title compound was obtained as white solid (10.6 mg, 66%). MS: 298.1 (M+H).sup.+.

Example 6

(rac)-4-[2-Fluoro-4-(trifluoromethyl)phenyl]-5-methyl-6,7-dihydrocyclopenta[c]pyridin-5-ol

(29) ##STR00021##

(30) In analogy to the procedure described for the preparation of (rac)-4-(3-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-5-ol (example 3), replacing 4-(3-fluoro-4-trifluoromethyl-phenyl)-6,7-dihydro-[2]pyrindin-5-one (intermediate A-1) with 4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydrocyclopenta[c]pyridin-5-one (intermediate A-2). Purification by preparative TLC (EtOAc-n-heptane=1:1) provided the title compound as white solid (6.1 mg, 23%). MS: 312.1 (M+H).sup.+.

Example 7

(rac)-4-[2-Fluoro-4-(trifluoromethyl)phenyl]-5-isopropyl-6,7-dihydrocyclopenta[c]pyridin-5-ol

(31) ##STR00022##

(32) A solution of isopropylmagnesium chloride (0.044 mL, 0.088 mmol; 2.0 M solution in THF) in THF (1 mL) under argon was treated with isopropylmagnesium chloride (0.044 mL, 0.088 mmol; 2.0 M solution in THF) at rt for 1 h. The reaction mixture was cooled to 0 C. and a solution of 4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydrocyclopenta[c]pyridin-5-one (intermediate A-2) (20 mg, 0.068 mmol) in THF (2 mL) was added. After 2 h, the reaction mixture was quenched by addition of a sat. aq. solution of ammonium chloride (10 mL) and the aq. phase extracted with EtOAc (310 mL). The combined organic phases were dried over MgSO.sub.4 and concentrated under reduced pressure. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water provided the title compound as off-white solid (5.0 mg, 22%). MS: 340.1 (M+H).sup.+.

Example 8

(rac)-4-[2-Fluoro-4-(trifluoromethyl)phenyl]-5-phenyl-6,7-dihydrocyclopenta[c]pyridin-5-ol

(33) ##STR00023##

(34) In analogy to the procedure described for the preparation of (rac)-4-(3-fluoro-4-(trifluoromethyl)phenyl)-5-phenyl-6,7-dihydro-5H-cyclopenta[c]pyridin-5-ol (example 4), replacing 4-(3-fluoro-4-trifluoromethyl-phenyl)-6,7-dihydro-[2]pyrindin-5-one (intermediate A-1) with 4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydrocyclopenta[c]pyridin-5-one (intermediate A-2). Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water provided the title compound as light brown solid (5.0 mg, 15%). MS: 374.1 (M+H).sup.+.

Example 9 and Example 10

(+)-4-[2-Fluoro-4-(trifluoromethyl)phenyl]-5-phenyl-6,7-dihydrocyclopenta[c]pyridin-5-ol and ()-4-[2-Fluoro-4-(trifluoromethyl)phenyl]-5-phenyl-6,7-dihydrocyclopenta[c]pyridin-5-ol

(35) ##STR00024##

(36) The title compounds were prepared by chiral separation of (rac)-4-[2-fluoro-4-(trifluoromethyl)phenyl]-5-phenyl-6,7-dihydrocyclopenta[c]pyridin-5-ol (227 mg, 0.61 mmol; example 8) on a Reprosil Chiral NR column (isopropanol-n-heptane=1:4) to give (+)-(R or S)-4-[2-fluoro-4-(trifluoromethyl)phenyl]-5-phenyl-6,7-dihydrocyclopenta[c]pyridin-5-ol [64.2 mg, 28%; MS: 374.1 (M+H).sup.+; example 9] and ()-(R or S)-4-[2-fluoro-4-(trifluoromethyl)phenyl]-5-phenyl-6,7-dihydrocyclopenta[c]pyridin-5-ol [63.0 mg, 27%; MS: 374.1 (M+H).sup.+; example 10] as off-white foams.

Example 11

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

(37) ##STR00025##

(38) A solution of (rac)-2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl]acetic acid and (rac)-2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]acetic acid one (intermediate A-3) (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 argon 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 (6.2 mg, 17%). MS: 368.1 (M+H).sup.+.

Example 12

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

(39) ##STR00026##

(40) A solution of (rac)-2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl]acetic acid and (rac)-2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]acetic acid one (intermediate A-3) (50 mg, 0.15 mmol) and N,N-diisopropylethylamine (0.13 mL, 0.74 mmol) in DMF (0.4 mL) under argon 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 (8.0 mg, 30%). MS: 353.1 (M+H).sup.+.

Example 13

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

(41) ##STR00027##

(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-5-yl]-N-methyl-acetamide (example 12), 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 yellow solid (6.0 mg, 20%). MS: 393.2 (M+H).sup.+.

Example 14

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

(43) ##STR00028##

(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-5-yl]-N-methyl-acetamide (example 12), 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 (2.0 mg, 4%). MS: 381.6 (M+H).sup.+.

Example 14

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

(45) ##STR00029##

(46) 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-5-yl]-N-methyl-acetamide (example 12), 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 (4.8 mg, 16%). MS: 407.6 (M+H).sup.+.

Example 16

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

(47) ##STR00030##

(48) 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-5-yl]-N-methyl-acetamide (example 12), 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 (4.2 mg, 14%). MS: 409.6 (M+H).sup.+.

Example 17

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

(49) ##STR00031##

(50) 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-5-yl]-N-methyl-acetamide (example 12), 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 (6.6 mg, 22%). MS: 406.1 (M+H).sup.+.

Example 18

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

(51) ##STR00032##

(52) 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-5-yl]-N-methyl-acetamide (example 12), 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 (10.4 mg, 34%). MS: 405.1 (M+H).sup.+.

Example 19

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

(53) ##STR00033##

(54) 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-5-yl]-N-methyl-acetamide (example 12), replacing (rac)-2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl]acetic acid and (rac)-2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]acetic acid one (intermediate A-3) with (rac)-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl]acetic acid and (rac)-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]acetic acid one (intermediate A-4) and methylamine 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 white solid (2.2 mg, 8%). MS: 393.2 (M+H).sup.+.

Example 20

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

(55) ##STR00034##

(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-5-yl]-1-pyrrolidin-1-yl-ethanone (example 19), replacing pyrrolidine 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 white solid (2.4 mg, 9%). MS: 381.2 (M+H).sup.+.

Example 21

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

(57) ##STR00035##

(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-5-yl]-1-pyrrolidin-1-yl-ethanone (example 19), replacing pyrrolidine 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 white solid (2.2 mg, 8%). MS: 395.2 (M+H).sup.+.

Example 22

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

(59) ##STR00036##

(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-5-yl]-1-pyrrolidin-1-yl-ethanone (example 19), replacing pyrrolidine 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 white solid (1.4 mg, 5%). MS: 393.2 (M+H).sup.+.

Example 23

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

(61) ##STR00037##

(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-5-yl]-1-pyrrolidin-1-yl-ethanone (example 19), replacing pyrrolidine 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 white solid (2.4 mg, 8%). MS: 407.2 (M+H).sup.+.

Example 24

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

(63) ##STR00038##

(64) 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-5-yl]-1-pyrrolidin-1-yl-ethanone (example 19), replacing pyrrolidine 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 white solid (2.3 mg, 7%). MS: 407.2 (M+H).sup.+.

Example A

(65) 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:

(66) 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

(67) 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:

(68) 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