IP Library Granted Patent US 7,220,760
Granted Patent B2
US 7,220,760 · App. 10/688,566 · Granted May 22, 2007

Quinoline derivatives as CRTH2 antagonists

Assignee: Pfizer Inc.
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Quick Facts
Patent No.
US 7,220,760
App. No.
10/688,566
Granted
May 22, 2007
Kind
B2
Abstract

The invetion relates to compounds of formula (I) wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in the description, their use as medicament, pharmaceutical compositions containing them and processes for their preparation.

Claims (302)

1. A compound of formula (I):

wherein

R 1 is H, (C 1 –C 4 )alkyl, (C 2 –C 4 )alkenyl, (C 2 –C 4 )alkynyl or (CH 2 ) m —R 1 , in which

R′ 1 is selected from aromatic heterocycle, phenyl and (C 3 –C 6 )cycloalkyl wherein the phenyl, the heterocycle and the cycloalkyl groups are unsubstituted or substituted by one to three groups independently selected from

Q 1 , and

(C 1 –C 4 )alkyl optionally substituted with one to three groups which are the same or different and which are selected from Q 1 ,

wherein Q 1 is selected from halogen, NO 2 , CN, SO 2 CH 3 , SO 2 NR 0 R 10 , OR 9 , COOR 9 , C(═O)NR 9 R 10 , NR 9 R 10 , NR 9 SO 2 R 10 , NR 9 C(═O)R 10 and C(═O)R 9 wherein R 9 and R 10 are the same or different and are selected from H and (C 1 –C 4 )alkyl;

m is an integer selected from 0, 1 and 2;

R 2 is (C 1 –C 4 )alkyl, wherein the alkyl group is substituted with one to three substituents independently selected from halogen, OR 9 , NR 9 R 10 , COOR 9 , C(═O)NR 9 R 10 , NHSO 2 R 9 and C(═O) (C 1 –C 4 )alkyl;

R 3 is (C 3 –C 6 )cycloalkyl or -A- R′ 3 , wherein

A is a bond, (C 1 –C 3 )alkylene or (C 2 –C 3 )alkenylene;

R′ 3 is (C 6 –C 12 )aryl or a 5- to 10-membered heterocycle, optionally aromatic, wherein the aryl and the heterocycle groups are unsubstituted or substituted by one to three substituents independently selected from

(C 6 –C 12 )aryl,

2,2,2-trifluoro-N-phenyl-N-[1,2,3,4-tetrahydro-1-(3-methoxybenzoyl)-2-methyl-4-quinolinyl]-acetamide,

N-(1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-N-(3-methoxyphenyl)-acetamide,

N-(1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-N-(4-methylphenyl)-acetamide,

N-[1-(4-chloro-3-nitrobenzoyl)-1,2,3,4-tetrahydro-2-methyl-4-quinotinyl]-Nphenyl-acetamide,

N-phenyl-N-[1,2,3,4-tetrahydro-2-methyl-1-(3-nitrobenzoyl)-4-quinolinyl]-acetamide,

N-phenyl-N-1,2,3,4-tetrahydro-1-3-(4-methoxyphenyl)-1-oxo-2-propenyl]-2-methyl-4-quinolinyl]-acetamide,

N-[1-(3-chlorobenzoyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenylacetamide,

N-[1-(3-fluorobenzoyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinyt]-N-phenylacetamide,

N-[1-[4-(1,1-dimethylethyl)benzoyl]-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl-acetamide,

N-phenyl-N-[1,2,3,4-tetrahydro-2-methyl-1-(1-oxo-3-phenyl-2-propenyl)-4-quinolinyl]-acetamide,

N-phenyl-N-[1>2,3,4-tetrahydro-2-methyl-1-(2-thienylcarbonyl)-4-quinolinyl]-acetamide,

N-phenyl-N-[1,2,3,4-tetrahydro-1-(4-methoxybenzoyl)-2-methyl-4-quinolinyl]-acetamide,

N-[1-(3,5-dinitrobenzoyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenylacetamide,

N-phenyl-N-[1,2,3,4-tetrahydro-2-methyl-1 -(4-nitrobenzoyl)-4-quinolinyl]-acetamide,

N-phenyl-N-[1,2,3I4-tetrahydro-1-(2-iodobenzoyl)-2-methyl-4-quinolinyl]-acetamide,

N-phenyl-N-[1,2,3,4-tetrahydro-1-(3-methoxybenzoyl)-2-methyl-4-quinolinyl]-acetamide,

N-(1benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-N-phenyl-pentanamide,

N-(1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-N-phenyl-butan amide,

N-(1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-N-phenyl-propanarnide,

1-benzoyl-1,2,3,4-tetrahydro-4-(N-phenylacetamido)-quinaldine,

N-[(1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-2-methyl-N-phenyl propanamide;

N-[1-(4-bromobenzoyl)-1,2,3,4-tetrahydro-2,6-dimethyl-4-quinolinyl]-acetamide;

N-(1-benzoyl-1,2,3,4-tenahydro-2,6-dimethyl-4-quinoUnyl)-acetamide; and

N-(1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-acetamide.

2. A compound of formula (Ia) or formula (Ib), or a racemic mixture of formula (Ia) and (Ib):

R 1 is H, (C 1 –C 4 )alkyl, (C 2 –C 4 )alkenyl, (C 2 –C 4 )alkynyl or (CH 2 ) m -R 1 , in which R 1 is elected from aromatic heterocycle, phenyl and (C 3 –C 6 )cycloalkyl

wherein the phenyl, the heterocycle and the cycloalkyl groups are unsubstituted or substituted by one to three groups independently selected from

Q 1 , and

(C 1 –C 4 )alkyl optionally substituted with one to three groups which are the same or different and which are selected from Q 1 ,

wherein Q 1 is selected from halogen, NO 2 , CN, SO 2 CH 3 , SO 2 , NR 9 R 10 , COOR 9 , C(═O)NR 9 R 10 , NR 9 R 10 , NR 9 SO 2 R 10 , NR 9 C(═O)R 10 and C(═O)R 9 wherein R 9 and R 10 are the same or different and are selected from H and (C 1 –C 4 )alkyl;

m is an integer selected from 0, 1 and 2;

R 2 is (C 1 –C 4 )alkyl, wherein the alkyl group is substituted with one to three substituents independently selected from halogen, OR 9 , NR 9 R 10 , COOR 9 , C(═O)NR 9 R 10 , NHSO 2 R 9 and C(═O) (C 1 –C 4 )alkyl;

R 3 is (C 3 –C 6 )cycloalkyl or —A—R 3 , wherein

A is a bond, (C 1 –C 3 )alkylene or (C 2 –C 3 )alkenylene;

R 3 is (C 6 –C 12 )aryl or a 5 to 10-membered heterocycle, optionally aromatic, wherein the aryl and the heterocycle groups are unsubstituted or substituted by one to three substituents independently selected from

(C 6 –C 12 )aryl,

an aromatic heterocyle,

Q 2 , and

(C 1 –C 4 )alkyl optionally substituted with one to three groups which are the same or different and which are selected from Q 2 ,

wherein Q 2 is selected from halogen, NO 2 , CN, SO 2 Ch 3 , SO 2 NR 9 R 10 , OR 9 , SR 9 , OCH 2 CF 3 , COOR 9 , C(═O)NR 9 R 10 , NR 9 R 10 , NR 9 SO 2 R 10 , NR 9 C(═O)R 10 and C(═O)R 9 ;

R 4 is 1 (C 1 –C 4 )-alkyl;

R 5 , R 6 , R 7 and R 8 are the same or different and are selected from

H, Q 3 , and

R 4 is 1(C 1 –C 4 )-alkyl;

R 5 , R 6 , R 7 and R 8 are the same or different and are selected from

H, Q 3 , and

(C 1 –C 4 )alkyl optionally substituted with one to three groups which are the same or different and which are selected from Q 3 ,

wherein Q 3 is selected from halogen, NO 2 , CN, SO 2 CH 3 , SO 2 NR 9 R 10 , OR 9 , SR 9 , COOR 9 , C(═O))NR 9 R 10 , NR 9 R 10 , NR 9 SO 2 R 10 , NR 9 C(═O)R 10 and C(═O)R 9 ;

an N-oxide thereof or a pharmaceutically acceptable salt of the compound or N-oxide; with the proviso that the following compounds are excluded:

N-[(2R,4S)-1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-2-methyl-Nphenyl propanamide;

N-[(2R,4S)-1-benzoyl-1,2,3yl-1,2,3)4-tetrahydro-2-methyl-4-quinolinyl]-2,2-dimethyl-Nphenyl-propanamide;

N-[(2R,4S)-1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl butanamide;

N-[(2R,4S)-1-benzoyl-1,2,3,4-tetrahydrp-2-methyl-4-quinolinyl]-N-phenyl acetamide;

N-[(2R,4S)-1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenylpentanamide; and

N-[(2R,4S)-1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-acetamide.

3. A compound of formula (Ic) or formula (Id), or is a racemic mixture of formula (Ic) and (Id):

R 1 is H, (C 1 –C 4 )alkyl, (C 2 –C 4 )alkenyl, (C 2 –C 4 )alkynyl or (CH 2 ) m —R′ 1 , in which

R′ 1 is selected from aromatic heterocycle, phenyl and (C 3 –C 6 )cycloalkyl

wherein the phenyl, the heterocycle and the cycloalkyl groups are unsubstituted or substituted by one to three groups independently selected from

Q 1 , and

(C 1 –C 4 )alkyl optionally substituted with one to three groups which are the same or different and which are selected from Q 1

wherein Q 1 is selected from halogen, NO 2 , CN, SO 2 CH 3 , SO 2 NR 9 R 10 , OR 9 , COOR 9 , C(═O)NR 9 R 10 , NR 9 R 10 , NR 9 SO 2 R 10 , NR 9 C(═O)R 10 and C(═O)R 9 wherein R 9 and R 10 are the same or different and are selected from H and (C 1 –C 4 )alkyl;

m is an integer selected from 0, 1 and 2;

R 2 is (C 1 –C 4 )alkyl, wherein the alkyl group is substituted with one to three substituents independently selected from halogen, OR 9 , NR 9 R 10 , COOR 9 , C(═O)NR 9 R 10 , NHSO 2 R 9 and C(═O)(C 1 –C 4 )alkyl;

R 3 is (C 3 –C 6 )cycloalkyl or -A-R′ 3 , wherein

A is a bond, (C 1 –C 3 )alkylene or (C 2 –C 3 )alkenylene;

R′ 3 is (C 6 –C 12 )aryl or a 5- to 10-membered heterocycle, optionally aromatic, wherein the aryl and the heterocycle groups are unsubstituted or substituted by one to three substituents independently selected from

(C 6 –C 12 )aryl,

an aromatic heterocyle,

Q 2 , and

(C 1 –C 4 )alkyl optionally substituted with one to three groups which are the same or different and which are selected from Q 2 ,

wherein Q 2 is selected from halogen, NO 2 , CN, SO 2 CH 3 , SO 2 NR 9 R 10 , OR 9 , SR 9 , OCH 2 CF 3 , COOR 9 , C(═O)NR 9 R 10 , NR 9 R 10 , NR 9 SO 2 R 10 , NR 9 C(═O)R 10 and C(═O)R 9 ;

R 4 is 1( 1 –C 4 )-alkyl;

R 5 , R 6 , R 7 and R 8 are the same or different and are selected from

H, Q 3 , and

(C 1 –C 4 )alkyl optionally substituted with one to three groups which are the same or different and which are selected from Q 3 ,

wherein Q 3 is selected from halogen, NO 2 , CN, SO 2 CH 3 , SO 2 NR 9 R 10 , OR 9 , SR 9 , COOR 9 , C(═O)NR 9 R 10 , NR 9 R 10 , NR 9 SO 2 R 10 , NR 9 C(═O)R 10 and C(═O)R 9 ;

an N-oxide thereof or a pharmaceutically acceptable salt of the compound or N-oxide.

4. A compound according to claim 1 wherein R 1 is H, (C 1 –C 4 )alkyl, (C 2 –C 4 )alkenyl, (C 2 –C 4 )alkynyl or (CH 2 ) m —R′ 1 , wherein

R′ 1 is selected from phenyl and (C 3 –C 6 )cycloalkyl wherein the phenyl and the cycloalkyl groups are unsubstituted or substituted by one to three groups selected from

Q 1 , and

(C 1 –C 4 )alkyl optionally substituted with one to three groups which are the same or different and which are selected from Q 1 ,

wherein Q 1 is selected from halogen, NO 2 , CN, SO 2 CH 3 , SO 2 NR 9 R 10 , OR 9 , COOR 9 , C(═O)NR 9 R 10 , NR 9 R 10 , NR 9 SO 2 R 10 , NR 9 C(═O)R 10 and C(═O)R 9 .

5. A compound according to claim 2 wherein R 1 is H, (C 1 –C 4 )alkyl, (C 2 –C 4 )alkenyl, (C 2 –C 4 )alkynyl or (CH 2 ) m —R′ 1 , wherein

R′ 1 is selected from phenyl and (C 3 –C 6 )cycloalkyl wherein the phenyl and the cycloalkyl groups are unsubstituted or substituted by one to three groups selected from

Q 1 , and

(C 1 –C 4 )alkyl optionally substituted with one to three groups which are the same or different and which are selected from Q 1 ,

wherein Q 1 is selected from halogen, NO 2 , CN, SO 2 CH 3 , SO 2 NR 9 R 10 , OR 9 , COOR 9 , C(═O)NR 9 R 10 , NR 9 R 10 , NR 9 SO 2 R 10 , NR 9 C(═O)R 10 and C(═O)R 9 .

6. A compound according to claim 3 wherein R 1 is H, (C 1 –C 4 )alkyl, (C 2 –C 4 ) alkenyl, (C 2 –C 4 )alkynyl or (CH 2 ) m —R′ 1 , wherein

R′ 1 is selected from phenyl and (C 3 –C 6 )cycloalkyl wherein the phenyl and the cycloalkyl groups are unsubstituted or substituted by one to three groups selected from

Q 1 , and

(C 1 –C 4 )alkyl optionally substituted with one to three groups which are the same or different and which are selected from Q 1 ,

wherein Q 1 is selected from halogen, NO 2 , CN, SO 2 CH 3 , SO 2 NR 9 R 10 , OR 9 , COOR 9 , C(═O)NR 9 R 10 , NR 9 R 10 , NR 9 SO 2 R 10 , NR 9 C(═O)R 10 and C(═O)R 9 .

7. A compound according to claim 4 wherein R 1 is (CH 2 ) m —R′ 1 , wherein

R′ 1 is selected from phenyl and (C 3 –C 6 )cycloalkyl wherein the phenyl and the cycloalkyl groups are unsubstituted or substituted by 1 to 3 groups selected from OR 9 , COOR 9 and (C 1 –C 4 )alkyl optionally substituted with COOR 9 , and

m is an integer selected from 0 and 1.

8. A compound according to claim 5 wherein R 1 is (CH 2 ) m —R′ 1 , wherein

R′ 1 is selected from phenyl and (C 3 –C 6 )cycloalkyl wherein the phenyl and the cycloalkyl groups are unsubstituted or substituted by 1 to 3 groups selected from OR 9 , COOR 9 and (C 1 –C 4 )alkyl optionally substituted with COOR 9 , and

m is an integer selected from 0 and 1.

9. A compound according to claim 6 wherein R 1 is (CH 2 ) m —R′ 1 , wherein

R′ 1 is selected from phenyl and (C 3 –C 6 )cycloalkyl wherein the phenyl and the cycloalkyl groups are unsubstituted or substituted by 1 to 3 groups selected from OR 9 , COOR 9 and (C 1 –C 4 )alkyl optionally substituted with COOR 9 , and

m is an integer selected from 0 and 1.

10. A compound according to claim 1 wherein R 1 is (C 1 –C 4 )alkyl, (C 2 –C 4 )alkenyl, (C 2 –C 4 )alkynyl or (CH 2 ) m —R′ 1 , in which

R′ 1 is selected from aromatic heterocycle and (C 3 –C 6 )cycloalkyl wherein the heterocycle and the cycloalkyl groups are unsubstituted or substituted by one to three groups selected from

Q 1 , and

(C 1 –C 4 )alkyl optionally substituted with one to three groups which are the same or different and which are selected from Q 1 ,

wherein Q 1 is selected from halogen, NO 2 , CN, SO 2 CH 3 , SO 2 NR 9 R 10 , OR 9 , COOR 9 , C(═O)NR 9 R 10 , NR 9 R 10 , NR 9 SO 2 R 10 , NR 9 C(═O)R 10 and C(═O)R 9 .

11. A compound according to claim 2 wherein R 1 is (C 1 –C 4 )alkyl, (C 2 –C 4 )alkenyl, (C 2 –C 4 )alkynyl or (CH 2 ) m —R′ 1 , in which

R′ 1 is selected from aromatic heterocycle and (C 3 –C 6 )cycloalkyl wherein the heterocycle and the cycloalkyl groups are unsubstituted or substituted by one to three groups selected from

Q 1 , and

(C 1 –C 4 )alkyl optionally substituted with one to three groups which are the same or different and which are selected from Q 1 ,

wherein Q 1 is selected from halogen, NO 2 , CN, SO 2 CH 3 , SO 2 NR 9 R 10 , OR 9 , COOR 9 , C(═O)NR 9 R 10 , NR 9 R 10 , NR 9 SO 2 R 10 , NR 9 C(═O)R 10 and C(═O)R 9 .

12. A compound according to claim 3 wherein R 1 is (C 1 –C 4 )alkyl, (C 2 –C 4 )alkenyl, (C 2 –C 4 )alkynyl or (CH 2 ) m —R′ 1 , in which

R′ 1 is selected from aromatic heterocycle and (C 3 –C 6 )cycloalkyl wherein the heterocycle and the cycloalkyl groups are unsubstituted or substituted by one to three groups selected from

Q 1 , and

(C 1 –C 4 )alkyl optionally substituted with one to three groups which are the same or different and which are selected from Q 1 ,

wherein Q 1 is selected from halogen, NO 2 , CN, SO 2 CH 3 , SO 2 NR 9 R 10 , OR 9 , COOR 9 , C(═O)NR 9 R 10 , NR 9 R 10 , NR 9 SO 2 R 10 , NR 9 C(═O)R 10 and C(═O)R 9 .

13. A compound according to claim 10 wherein R 1 is a (C 3 –C 6 )cycloalkyl wherein the cycloalkyl group is unsubstituted or substituted by one to three groups selected from

Q 1 , and

(C 1 –C 4 )alkyl optionally substituted with one to three groups which are the same or different and which are selected from Q 1 ,

wherein Q 1 is selected from halogen, NO 2 , CN, SO 2 CH 3 , SO 2 NR 9 R 10 , OR 9 , COOR 9 , C(═O)NR 9 R 10 , NR 9 R 10 , NR 9 SO 2 R 10 , NR 9 C(═O)R 10 and C(═O)R 9 .

14. A compound according to claim 11 wherein R 1 is a (C 3 –C 6 )cycloalkyl wherein the cycloalkyl group is unsubstituted or substituted by one to three groups selected from

Q 1 , and

(C 1 –C 4 )alkyl optionally substituted with one to three groups which are the same or different and which are selected from Q 1 ,

wherein Q 1 is selected from halogen, NO 2 , CN, SO 2 CH 3 , SO 2 NR 9 R 10 , OR 9 , COOR 9 , C(═O)NR 9 R 10 , NR 9 R 10 , NR 9 SO 2 R 10 , NR 9 C(═O)R 10 and C(═O)R 9 .

15. A compound according to claim 12 wherein R 1 is a (C 3 –C 6 )cycloalkyl wherein the cycloalkyl group is unsubstituted or substituted by one to three groups selected from

Q 1 , and

(C 1 –C 4 )alkyl optionally substituted with one to three groups which are the same or different and which are selected from Q 1 ,

wherein Q 1 is selected from halogen, NO 2 , CN, SO 2 CH 3 , SO 2 NR 9 R 10 , OR 9 , COOR 9 , C(═O)NR 9 R 10 , NR 9 R 10 , NR 9 SO 2 R 10 , NR 9 C(═O)R 10 and C(═O)R 9 .

16. A compound according to claim 13 wherein R 1 is (C 3 –C 6 )cycloalkyl.

17. A compound according to claim 14 wherein R 1 is (C 3 –C 6 )cycloalkyl.

18. A compound according to claim 15 wherein R 1 is (C 3 –C 6 )cycloalkyl.

19. A compound according to claim 4 wherein R 1 is phenyl unsubstituted or substituted in the para position by a substituent selected from halogen, OR 9 , CH 2 COOR 9 and CH 2 COOR 9 .

20. A compound according to claim 5 wherein R 1 is phenyl unsubstituted or substituted in the para position by a substituent selected from halogen, OR 9 , CH 2 COOR 9 and CH 2 COOR 9 .

21. A compound according to claim 6 wherein R 1 is phenyl unsubstituted or substituted in the para position by a substituent selected from halogen, OR 9 , CH 2 COOR 9 and CH 2 COOR 9 .

22. A compound according to any one of claim 1 to 21 wherein R 2 is (C 1 –C 4 ) alkyl.

23. A compound according to any one of claim 1 to 21 wherein R 4 is (C 1 –C 4 ) alkyl.

24. A compound according to claim 22 wherein R 3 is selected from (C 3 –C 6 ) cycloalkyl and -A-R′ 3 , wherein

A is a bond, (C 1 –C 3 )alkylene, straight or branched, or (C 2 –C 3 )alkenylene;

R′ 3 is a 5- to 10-membered heterocycle, optionally aromatic, unsubstituted or substituted by 1 to 3 substituents selected from

(C 6 –C 12 )aryl, an heterocycle,

Q 2 , and

(C 1 –C 4 )alkyl optionally substituted with 1 to 3 groups which are the same or different and which are selected from Q 2 ,

wherein Q 2 is selected from halogen, NO 2 , CN, SO 2 CH 3 , SO 2 NR 9 R 10 , OR 9 , SR 9 , OCH 2 CF 3 , COOR 9 , C(═O)NR 9 R 10 , NR 9 R 10 , NR 9 SO 2 R 10 , NR 9 C(O)R 10 and C(═O)R 9 , with the proviso that R 3 is not selected from unsubstituted thienyl or unsubstituted furanyl.

25. A compound according to claim 23 wherein R 3 is selected from (C 3 –C 6 ) cycloalkyl and -A-R′ 3 , wherein

A is a bond, (C 1 –C 3 )alkylene, straight or branched, or (C 2 –C 3 )alkenylene;

R′ 3 is a 5- to 10-membered heterocycle, optionally aromatic, unsubstituted or substituted by 1 to 3 substituents selected from

(C 6 –C 12 )aryl, an heterocycle,

Q 2 , and

(C 1 –C 4 )alkyl optionally substituted with 1 to 3 groups which are the same or different and which are selected from Q 2 ,

wherein Q 2 is selected from halogen, NO 2 , CN, SO 2 CH 3 , SO 2 NR 9 R 10 , OR 9 , SR 9 , OCH 2 CF 3 , COOR 9 , C(═O)NR 9 R 10 , NR 9 R 10 , NR 9 SO 2 R 10 , NR 9 C(O)R 10 and C(═O)R 9 , with the proviso that R 3 is not selected from unsubstituted thienyl or unsubstituted furanyl.

26. A compound according to claim 22 wherein R 3 is selected from -A-R′ 3 , wherein

A is a bond, straight or branched (C 1 –C 3 )alkylene, or (C 2 –C 3 )alkenylene;

R′ 3 is a phenyl, unsubstituted or substituted by one to three substituents selected from

(C 6 –C 12 )aryl, n heterocycle,

Q 2 , and

(C 1 –C 4 )alkyl optionally substituted with one to three groups which are the same or different and which are selected from Q 2 ,

wherein Q 2 is selected from halogen, NO 2 , CN, SO 2 CH 3 , SO 2 NR 9 R 10 , OR 9 , SR 9 , OCH 2 CF 3 , COOR 9 , C(═O)NR 9 R 10 , NR 9 R 10 , NR 9 SO 2 R 10 , NR 9 C(O)R 10 and C(═O)R 9 .

27. A compound according to claim 23 wherein R 3 is selected from -AR′ 3 , wherein

A is a bond, straight or branched (C 1 –C 3 )alkylene, or (C 2 –C 3 )alkenylene;

R′ 3 is a phenyl, unsubstituted or substituted by one to three substituents selected from

(C 6 –C 12 )aryl, n heterocycle,

Q 2 , and

(C 1 –C 4 )alkyl optionally substituted with one to three groups which are the same or different and which are selected from Q 2 ,

wherein Q 2 is selected from halogen, NO 2 , CN, SO 2 CH 3 , SO 2 NR 9 R 10 , OR 9 , SR 9 , OCH 2 CF 3 , COOR 9 , C(═O)NR 9 R 10 , NR 9 R 10 , NR 9 SO 2 R 10 , NR 9 C(O)R 10 and C(═O)R 9 .

28. A compound according to claim 24 wherein R 5 , R 6 , R 7 and R 8 are the same or different and are selected from H, halogen and OR 9 .

29. A compound according to claim 25 wherein R 5 , R 6 , R 7 and R 8 are the same or different and are selected from H, halogen and OR 9 .

30. A compound according to claim 26 wherein R 5 , R 6 , R 7 and R 8 are the same or different and are selected from H, halogen and OR 9 .

31. A compound according to claim 27 wherein R 5 , R 6 , R 7 and R 8 are the same or different and are selected from H, halogen and OR 9 .

32. A compound selected from the group consisting of

Cis-N-[2-Methyl-1-(pyridine-4-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-(1-oxy-pyridine-4-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(4-Hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-(4-trifluoromethyl-benzoyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(4-Cyano-benzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(4-Chloro-benzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

4-[Cis-4-(Acetyl-phenyl-amino)-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl]-benzoic acid methyl ester;

4-[Cis-4-(Acetyl-phenyl-amino)-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl]-benzoic acid;

Cis-N-[2-Methyl-1-(3-phenyl-propionyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-(5-methyl-thiophene-2-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(Benzofurazan-5-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-(2-Methyl-1-phenylacetyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-(pyrazine-2-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(6-Chloro-pyridine-3-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-(6-trifluoromethyl-pyridine-3-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(2,6-Dimethoxy-pyridine-3-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(2-Methoxy-pyridine-3-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-(2-methylsulfanyl-pyridine-3-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(2-Chloro-pyridine-3-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-(5-methyl-pyrazine-2-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(2-Chloro-6-methyl-pyridine-3-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(4-Chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-(6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-(2-propylsulfanyl-pyridine-3-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(5,6-Dichloro-pyridine-3-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(2,6-Dichloro-pyridine-3-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-(4-methyl-[1,2,3]thiadiazole-5-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-(5-methyl-isoxazole-3-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(2,5-Dimethyl-2H-pyrazole-3-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-(1-methyl-1H-pyrrole-2-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(Isoxazole-5-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-(5-methyl-isoxazole-4-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(2,4-Dimethyl-thiazole-5-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(5-Chloro-thiophene-2-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(1,5-Dimethyl-1H-pyrazole-3-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-(4-methyl-isothiazole-5-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-5-[4-(Acetyl-phenyl-amino)-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl]-thiophene-2-carboxylic acid dimethylamide;

Cis-N-[1-(4-Hydroxy-quinoline-6-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(4-tert-Butyl-thiazole-2-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(2-Ethyl-pyridine-4-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(3,6-Dichloro-pyridine-2-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(4-Chloro-2H-pyrazole-3-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-2-[4-(Acetyl-phenyl-amino)-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl]-isonicotinic acid methyl ester;

Cis-N-[2-Methyl-1-(4-[1,2,4]triazol-4-yl-benzoyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(2,6-Dimethoxy-pyridine-4-carbonyl)-2-methyl 1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(5-Ethyl-isoxazole-3-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-(2-tetrazol-1-yl-pyridine-4-carbonyl)-1,2,3>4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-(5-propyl-isoxazole-3-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(5-Isobutyl-2-methyl-2H-pyrazole-3-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(5-Bromo-furan-2-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-(6-phenyl-pyridine-3-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-(2-phenyl-pyridine-4-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-(quinoline-6-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(3,4-Dimethoxy-furan-2-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-(3-methyl-furan-2-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(2,5-Dimethyl-furan-3-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(2,4-Dimethyl-oxazole-5-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(5-Methoxymethyl-furan-2-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(5-Fluoro-pyridine-3-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-(quinoline-2-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-(6-methyl-pyridine-3-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-(quinoline-3-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-(1H-pyrazole-3-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-(2H-pyrazole-3-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(5-Isobutyl-isoxazole-3-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-(quinoline-4-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-(6-methyl-pyridine-2-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-(quinoxaline-5-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(3-Methoxy-thiophene-2-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(5-tert-Butyl-2-methyl-furan-3-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[1-(5-Ethyl-2-methyl-2H-pyrazole-3-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-([1,2,5]thiadiazole-3-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-[2-Methyl-1-(2-methyl-5-propyl-2H-pyrazole-3-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-(1-Benzoyl-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-Benzyl-acetamide;

Cis-N-Benzyl-N-[2-methyl-1-(thiophene-2-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-acetamide;

Trans-N-Benzyl-N-[2-methyl-1-(thiophene-2-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-acetamide;

Cis-N-Cyclohexyl-N-[2-methyl-1-(thiophene-2-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-acetamide;

Cis-N-(1-Benzoyl-6-methoxy-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-phenyl-acetamide;

Cis-N-(1-Benzoyl-6-hydroxy-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-phenyl-acetamide;

Cis-N-(1-Benzoyl-6-chloro-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-phenyl-acetamide;

N-(1-Benzoyl-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-prop-2-ynyl-acetamide;

Cis-N-(1-Benzoyl-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-(4-methoxy-phenyl)-acetamide;

Cis-N-(1-Benzoyl-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-(4-hydroxy-phenyl)-acetamide;

Cis-{4-[Acetyl-(1-benzoyl-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-amino]-phenyl}-acetic acid ethyl ester;

Cis-N-(1-Benzoyl-2-methyl-1,2,3,4-tetrahydroquinolin-4^yl)-N-phenyl-malonamic acid methyl ester;

Cis-N-(1-Benzoyl-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-phenyl-malonamic acid;

Cis-N-[2-Methyl-1-(pyridine-3-carbonyl)-1,2)3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide;

Cis-N-(1-Benzoyl-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-Cyclopropyl-acetamide;

Cis-N-Cyclopropyl-N-[2-methyl-1-(pyridine-3-carbonyl)-1,2,3)4-tetrahydroquinolin-4-yl]-acetamide;

(-f)-Cis-N-cyclopropyl-N-[2-methyl-1-(pyridine-3-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-acetamide;

(−)-Cis-N-cyclopropyl-N-[2-methyl-1 (pyridine-3-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-acetamide;

Cis-N-Cyclopropyl-N-[2-methyl-1-(3-methyl-isoxazole-5-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-acetamide;

Cis-N-Phenyl-N-[1-(thiophene-2-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-acetamide;

Cis-N-(1-Benzoyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-phenyl-acetamide;

Cis-N-[2-Ethyl-1-(pyridine-3-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide; and

Cis-N-Ethyl-N-[2-Methyl-1-(pyridine-3-carbonyl)-1,2,3,4-tetrahydroquinolin-yl]-acetamide.

33. A pharmaceutical composition comprising a compound of formula (I):

wherein

R 1 is H, (C 1 –C 4 )alkyl, (C 2 –C 4 )alkenyl, (C 2 –C 4 )alkynyl or (CH 2 ) m —R′ 1 , in which

R′ 1 is selected from aromatic heterocycle, phenyl and (C 3 –C 6 )cycloalkyl wherein the phenyl, the heterocycle and the cycloalkyl groups are unsubstituted or substituted by one to three groups independently selected from

Q 1 , and

(C 1 –C 4 )alkyl optionally substituted with one to three groups which are the same or different and which are selected from Q 1 ,

wherein Q 1 is selected from halogen, NO 2 , CN, SO 2 CH 3 , SO 2 NR 9 R 10 , OR 9 , COOR 9 , C(═O)NR 9 R 10 , NR 9 R 10 , NR 9 SO 2 R 10 , NR 9 C(═O)R 10 and C(═O)R 9 wherein R 9 , R 10 , are the same or different and are selected from H and (C 1 –C 4 )alkyl;

m is an integer selected from 0, 1 and 2;

R 2 is (C 1 –C 4 )alkyl, wherein the alkyl group is substituted with one to three substituents independently selected from halogen, OR 9 , NR 9 R 10 , COOR 9 , C(═O)NR 9 R 10 , NHSO 2 R 9 and C(═O)(C 1 –C 4 )alkyl;

R 3 is (C 3 –C 6 )cycloalkyl or -A-R′ 3 , wherein

A is a bond, (C 1 –C 3 )alkylene or (C 2 –C 3 )alkenylene;

R′ 3 is (C 6 –C 12 )aryl or a 5- to 10-membered heterocycle, optionally aromatic, wherein the aryl and the heterocycle groups are unsubstituted or substituted by one to three substituents independently selected from

(C 6 –C 12 )aryl,

an aromatic heterocyle,

Q 2 , and

(C 1 –C 4 )alkyl optionally substituted with one to three groups which are the same or different and which are selected from Q 2 ,

wherein Q 2 is selected from halogen, NO 2 , CN, SO 2 CH 3 , SO 2 NR 9 R 10 , OR 9 , SR 9 , OCH 2 CF 3 , COOR 9 , C(═O)NR 9 R 10 , NR 9 R 10 , NR 9 SO 2 R 10 , NR 9 C(═O)R 10 and C(═O)R 9 ;

R 4 is H or (C 1 –C 4 )-alkyl;

R 5 , R 6 , R 7 and R 8 are the same or different and are selected from

H, Q 3 , and

(C 1 –C 4 )alkyl optionally substituted with one to three groups which are the same or different and which are selected from Q 3 ,

wherein Q 3 is selected from halogen, NO 2 , CN, SO 2 CH 3 , SO 2 NR 9 R 10 , OR 9 , SR 9 , OCH 2 CF 3 COOR 9 , C(═O)NR 9 R 10 , NR 9 R 10 , NR 9 SO 2 R 10 , NR 9 C(═O)R 10 and C(═O)R 9 ;

an optical isomer thereof, an N-oxide thereof or a pharmaceutically acceptable salt of the compound, optical isomer or N-oxide together with a pharmaceutically acceptable carrier, excipient, diluent or delivery system.

Assignments (2)
CONSENT Recorded Jan 12, 2004
From: PFIZER INC.
To: WARNER-LAMBERT COMPANY LLC
Reel/Frame 014872/0405 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 12, 2004
From: AWAD, MOHAMED MOHAMED ALI; BAZIN, MARC JACQUES; FERU, FREDERIC; GOLDSTEIN, STEVEN WAYNE; KUHN, CYRILLE FRANCOIS
To: WARNER-LAMBERT COMPANY LLC
Reel/Frame 015003/0785 →
Priority Claims (1)
EP 02292606 · Oct 21, 2002 · regional
Continuity (2)
Provisional Application 6043489600 · Dec 19, 2002
Related Publication 20040132772A1 · Jul 8, 2004