IP Library › Granted Patent US 7,994,189

Granted Patent B2

US 7,994,189 · App. 11/912,719 · Granted Aug 9, 2011

Dihydropyridine derivatives

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Quick Facts

Patent No.: US 7,994,189
App. No.: 11/912,719
Granted: Aug 9, 2011
Kind: B2

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Abstract

The present invention relates to dihydropyridine derivatives having general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 is (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, phenyl, (1-5C)heteroaryl R 2 , R 3 are independently (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (24C)alkenyloxy, (2-4C)alkynyloxy, halogen X is SO 2 , CH 2 , C(O) or X is absent R 4 is (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl, (3-6C)cycloalkyl(1-4C)alkyl, (2-6C)heterocycloalkyl, (2-6C)heterocycloalkyl(14C)alkyl, (6-1 OC)aryl, (6-10C)aryl(1-4C)alkyl, (1-9C)heteroaryl or (1-9C)heteroaryl(14C)alkyl. The compounds are useful for the treatment of fertility disorders.

Claims (60)

1. A dihydropyridine derivative compound according to Formula I,

or a pharmaceutically acceptable salt thereof, wherein

R 1 is (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl or phenyl, (1-5C)heteroaryl, both optionally substituted with one or more substituents selected from hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (1-4C)(di)alkylamino;

R 2 , R 3 are independently (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (2-4C)alkenyloxy, (3-4C)alkynyloxy, halogen;

R 4 is (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl, (3-6C)cycloalkyl(1-4C)alkyl, (2-6C)heterocycloalkyl, (2-6C)heterocycloalkyl(1-4C)alkyl or (6-10C)aryl, (6-10C)aryl(1-4C)alkyl, (1-9C)heteroaryl, (1-9C)heteroaryl(1-4C)alkyl, the aryl or heteroaryl group optionally substituted with one or more substituents selected from hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (1-4C)(di)alkylamino, and if R 4 is phenyl, phenyl may, in addition, optionally be substituted with the substituents provided for under “aryl” and/or one or more substituents selected from (1-4C)alkylthio, (1-4C)alkylsulfonyl, R 5 -oxycarbonyl, R 5 -carbonyl or R 5 ,R 6 -aminocarbonyl;

X is SO 2 , CH 2 , C(O) or X is absent, wherein if X is CH 2 , R 4 may furthermore be R 5 -oxycarbonyl or R 5 -carbonyl;

R 5 , R 6 is independently H, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-4C)alkyl, (2-6C)heterocycloalkyl, (2-6C)heterocycloalkyl(1-4C)alkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl, (1-4C)(di)alkylaminocarbonyl(1-4C)alkyl or (6-10C)arylaminocarbonyl(1-4C)alkyl, (1-9C)heteroarylaminocarbonyl(1-4C)alkyl, (6-10C)aryl, (1-9C)heteroaryl, (6-10C)aryl(1-4C)alkyl, (1-9C)heteroaryl(1-4C)alkyl, the aryl or heteroaryl group optionally substituted with one or more substituents selected from hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (1-4C)(di)alkylamino or

R 5 , R 6 in R 5 , R 6 -aminocarbonyl may be joined in a (2-6C)heterocycloalkyl ring;

wherein (1-9C)heteroaryl is selected from the group consisting of tetrazolyl, imidazolyl, thiadiazolyl, pyridinyl, (benzo)thienyl, (benzo)furyl, (iso)quinolinyl, tetrahydro(iso)quinolinyl, coumarinyl, quinoxalinyl and indolyl;

with the proviso that the compound is not 2-methyl-5-oxo-7-phenyl-4-(3,4,5-trimethoxyphenyl)-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile.

2. The compound according to claim 1 wherein R 4 is phenyl optionally substituted with one or more substituents selected from hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (1-4C)(di)alkylamino, (1-4C)alkylthio, (1-4C)alkylsulfonyl, R 5 -oxycarbonyl, R 5 -carbonyl or R 5 ,R 6 -aminocarbonyl.

3. The compound according to claim 2 wherein the substituent of phenyl at R 4 is R 5 , R 6 -aminocarbonyl, (1-4C)alkoxy and/or halogen.

4. The compound according to claim 3 wherein R 5 , R 6 in R 5 ,R 6 -aminocarbonyl is (1-4C)(di)alkylamino.

5. The compound according to claim 3 wherein R 5 in R 5 ,R 6 -aminocarbonyl is (1-4C)alkoxycarbonyl(1-4C)alkyl and R 6 is H.

6. The compound according to claim 3 wherein R 5 in R 5 ,R 6 aminocarbonyl is (1-9C)heteroaryl(1-4C)alkyl , the aryl or heteroaryl group optionally substituted with one or more substituents selected from hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (1-4C)(di)alkylamino or (1-4C)alkoxycarbonyl(1-4C)alkyl and R 6 is H.

7. The compound according to claim 1 wherein X is CH 2 .

8. The compound according to claim 1 wherein R 1 is (1-6C)alkyl, phenyl or (1-5C)heteroaryl.

9. The compound according to claim 1 wherein R 2 , R 3 are halogen and/or (1-4C)alkoxy.

10. A pharmaceutical composition comprising the compound according to Formula I,

or a pharmaceutically acceptable salt thereof, wherein

R 2 , R 3 are independently (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (2-4C)alkenyloxy, (3-4C)alkynyloxy, halogen;

X is SO 2 , CH 2 , C(O) or X is absent, wherein if X is CH 2 , R 4 may furthermore be R 5 -oxycarbonyl or R 5 -carbonyl;

R 5 , R 6 in R 5 ,R 6 -aminocarbonyl may be joined in a (2-6C)heterocycloalkyl ring, and pharmaceutically suitable auxiliaries;

11. A method of treating hypogonadism in a patient, the method comprising administering to the patient an effective amount of the compound according to Formula I,

or a pharmaceutically acceptable salt thereof, wherein

R 2 , R 3 are independently (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (2-4C)alkenyloxy, (3-4C)alkynyloxy, halogen;

R 4 is (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl, (3-6C)cycloalkyl(1-4C)alkyl, (2-6C)heterocycloalkyl, (2-6C)heterocycloalkyl(1-4C)alkyl or (6-10C)aryl, (6-10C)aryl(1-4C)alkyl, (1-9C)heteroaryl, (1-9C)heteroaryl(1-4C)alkyl, the aryl or heteroaryl group optionally substituted with one or more substituents selected from hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (1-4C)(di)alkylamino, and if R 4 is phenyl in addition with (1-4C)alkylthio, (1-4C)alkylsulfonyl, R 5 -oxycarbonyl, R 5 -carbonyl or R 5 ,R 6 -aminocarbonyl;

X is SO 2 , CH 2 , C(O) or X is absent, wherein if X is CH 2 , R 4 may furthermore be R 5 -oxycarbonyl or R 5 -carbonyl;

R 5 , R 6 in R 5 ,R 6 -aminocarbonyl may be joined in a (2-6C)heterocycloalkyl ring,

12. A method for treating infertility in a patient by ovulation induction or by controlled hyperstimulation, wherein the infertility is associated with a fertility disorder which is responsive to FSH receptor mediated pathways, the method comprising administering to the patient an effective amount of the compound according to Formula I,

or a pharmaceutically acceptable salt thereof, wherein

R 2 , R 3 are independently (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (2-4C)alkenyloxy, (3-4C)alkynyloxy, halogen;

R 4 is (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl, (3-6C)cycloalkyl(1-4C)alkyl, (2-6C)heterocycloalkyl, (2-6C)heterocycloalkyl(1-4C)alkyl or (6-10C)aryl, (6-10C)aryl(1-4C)alkyl, (1-9C)heteroaryl, (1-9C)heteroaryl(1-4C)alkyl, the aryl or heteroaryl group optionally substituted with one or more substituents selected from hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (1-4C)(di)alkylamino, and if R 4 is phenyl in addition with (1-4C)alkylthio, (1-4C)alkylsulfonyl, R 5 -oxycarbonyl, R 5 -carbonyl or R 5 ,R 6 -aminocarbonyl;

X is SO 2 , CH 2 , C(O) or X is absent, wherein if X is CH 2 , R 4 may furthermore be R 5 -oxycarbonyl or R 5 -carbonyl;

R 5 , R 6 in R 5 ,R 6 -aminocarbonyl may be joined in a (2-6C)heterocycloalkyl ring,

13. A dihydropyridine derivative compound selected from the group consisting of

3-[2-Bromo-4-(3-cyano-2-methyl-5-oxo-7-phenyl-1,4,5,6,7,8-hexahydroquinolin-4-yl)-6-methoxyphenoxymethyl]-N-thiophen-2-ylmethylbenzamide;

Glycine, N-3-[2-bromo-4-(3-cyano-2-methyl-5-oxo-7-phenyl-1,4,5,6,7,8-hexahydroquinolin-4-y1)-6-ethoxyphenoxymethyl]benzoyl, methyl ester;

3-[2-Bromo-4-(3-cyano-7-ethyl-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinolin-4-yl)-6-ethoxyphenoxymethyl]-benzoic acid methyl ester;

3-[2-Bromo-4-(3-cyano-7-ethyl-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinolin-4-yl)-6-ethoxyphenoxymethyl]- N-tert-butylbenzamide;

3-[2-Bromo-4-(3-cyano-7-ethyl-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinolin-4-yl)-6-ethoxyphenoxymethyl]-N-cyclohexylbenzamide;

3-[2-Bromo-4-(3-cyano-7-ethyl-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinolin-4-yl)-6-ethoxyphenoxymethyl]-N-(2-morpholin-4-yl-ethyl)-benzamide;

4-[3-Bromo-4-(2-chloro-3-methoxybenzyloxy)-5-ethoxyphenyl]-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile;

Glycine, N-3-[2-bromo-4-(3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydroquinolin-4-y1)-6-ethoxyphenoxymethyl]benzoyl, methyl ester;

4-[3-Bromo-5-ethoxy-4-(3-methoxybenzyloxy)-phenyl]-7-furan-2-yl-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile;

4-[3-Bromo-5-ethoxy-4-(3-pyridinylmethoxy)phenyl]-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile trifluoroacetic acid;

4-[2-Bromo-4-(3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydroquinolin-4-yl)-6-ethoxyphenoxymethyl]-N-thiophen-2-ylmethylbenzamide;

4-[3-Bromo-5-ethoxy-4-(5-fluoro-2-propylamino-benzyloxy)-phenyl]-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile; and

4-[3-Bromo-4-(2-dipropylamino-5-fluoro-benzyloxy)-5-ethoxy-phenyl]-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile,

or a pharmaceutically acceptable salt thereof.

Assignments (4)

MERGER Recorded Mar 8, 2013

From: ORGANON BIOSCIENCES NEDERLAND B.V.

To: MERCK SHARP & DOHME B.V.

Reel/Frame 029940/0296 →

MERGER Recorded Mar 7, 2013

From: MSD OSS B.V.

To: ORGANON BIOSCIENCES NEDERLAND B.V.

Reel/Frame 029939/0001 →

MERGER Recorded Dec 1, 2011

From: N.V. ORGANON

To: MSD OSS B.V.

Reel/Frame 027307/0482 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 26, 2007

From: VAN STRATEN, NICOLE CORINE RENEE; GERRITSMA, GERRITDINA GEZIENA; VAN DER VEEN, LARS ANDERS

To: N.V. ORGANON

Reel/Frame 020154/0167 →