Aza-bicycles which modulate the inhibition of cell adhesion

• US 6,608,084 B1
• Filed: 10/17/2001
• Issued: 08/19/2003
• Est. Priority Date: 08/26/1998
• Status: Expired due to Term

• Current Assignee: Aventis Recherche Developpment
• Original Assignee: Aventis Recherche Developpment, Aventis Pharma Ltd. (Sanofi )
• Inventors: Filoche, Bruno Jacques Christophe, McCarthy, Clive, Harris, Neil Victor, Commercon, Alain, Bourzat, Jean-Dominique
• Primary Examiner(s): McKane, Joseph K.
• Assistant Examiner(s): SMALL, ANDREA D SOUZA
• Application Number:
  US09/856,106
• Time in Patent Office: 671 Days
• Field of Search: 514/311, 514/314, 514/443, 546/164, 548/492, 548/493
• US Class Current: 514/311
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 209/12 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 215/08 with acylated ring nitrogen atom
• CPC Class Codes: C07D 215/14 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links

Abstract

The invention is directed to physiologically active compounds of formula (I) wherein R¹ represents R³—Z³—, R³—L²—R⁴—Z³—, R³—L³—Ar¹—L⁴—Z³— or R³—L³—Ar¹—L²—R⁴—Z³—; R² represents hydrogen, halogen, lower alkyl or lower alkoxy; A¹ represents a straight chain C_1-3alkylene linkage optionally substituted by one or more groups chosen from alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, imino, oxo, thioxo, or alkyl substituted by —ZR⁶, —NY¹Y², —CO₂R⁶ or —C(═O)—NY¹Y²; L¹ represents a direct bond; an alkenylene, alkylene, alkynylene, cycloalkenylene, cycloalkylene, heteroaryldiyl, heterocycloalkylene or arylene linkage each optionally substituted by (a) an acidic functional group, cyano, oxo, —S(O)_mR⁹, R³, —C(═O)—R³, —C(═O)—OR³, —N(R⁸)—C(═O)R⁹, —N(R⁸)—SO₂—R⁹, —NY⁴Y⁵ or —[C(═O)—N(R¹⁰)—C(R⁵)(R¹¹)]_p—C(═O)—NY⁴Y⁵, or by (b) alkyl substituted by an acidic functional group, or S(O)_mR⁹, —C(═O)—NY⁴Y⁵ or —NY⁴Y⁵; a —[C(═O)—N(R¹⁰)—C(R⁵)(R¹¹)]_p— linkage; a —Z²—R¹²— linkage; a —C(═O)—CH₂—C(═O)— linkage; a —R¹²—Z²—R¹²— linkage; a —C(R⁴)(R¹³)—[C(═O)—N(R¹⁰)—C(R⁵)(R¹¹)]_p— linkage; or a —L⁵—L⁶—L⁷— linkage; Z¹ is C(R⁷)(R^7a), C(═O) or CH(OH); Y is carboxy or an acid bioisostere; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates of such compounds and their N-oxides and prodrugs. Such compounds have valuable pharmaceutical properties, in particular the ability to regulate the interaction of VCAM-1 and fibronectin with the integrin VLA-4 (α4β1).

Claims

1. A compound of general formula (I):

wherein;

R¹ represents R³—

L³—

Ar¹—

L⁴—

Z³—

;

R² represents hydrogen, halogen, C_1-4alkyl or C_1-4alkoxy;

R³ represents alkyl, alkenyl allynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocycloalkyl or heterocycloalylalkyl;

R⁵ represents hydrogen or C_1-4alkyl;

R⁷ and R^7a are each independently hydrogen or C_1-4alkyl;

R⁸ represents hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;

R⁹ represents alkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, or alkyl substituted by aryl, carboxy, cycloalkyl, heteroaryl, heterocycloallyl, —

S(O)_mR³, —

C(═

O)—

NY⁴Y⁵ or —

NY⁴Y⁵;

R¹⁰ represents hydrogen, R³ or alkyl substituted with alkoxy, cycloalkyl, hydroxy, mercapto, alkylthio or —

NY⁴Y⁵;

R¹⁴ represents alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, hetetoarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;

A¹ represents a methylene or ethylene linkage;

Ar¹ represents arylene;

L¹ represents;

an allylene linkage optionally substituted by (a) carboxy, hydroxy, mercapto, R³, —

N(R⁸)—

C(═

O)—

R⁹, —

N(R⁸)—

C(═

O)—

OR⁹, —

N(R⁸)—

SO₂—

R⁹ or —

NY⁴Y⁵, or by (b) alkyl substituted by carboxy, hydroxy, mercapto, S(O)_mR⁹, —

C(═

O)—

NY⁴Y⁵ or —

NY⁴Y⁵;

L³ represents an —

NR⁵—

C(═

Z)—

NR⁵—

linkage;

L⁴ represents an alkylene chain;

Y¹ and Y² are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl;

or the group —

NY¹Y² may form a cyclic amine;

Y⁴ and Y⁵ are independently hydrogen, alkenyl, alkyl, alkynyl, aryl, cycloalkenyl, cycloalkyl, heteroaryl, heterocycloalkyl, or alkyl substituted by alkoxy, aryl, cyano, cycloalkyl, heteroaryl, heterocycloalkyl, hydroxy, oxo, —

NY¹Y², or one or more —

CO² R⁸ or —

C(═

O)—

NY¹Y² groups;

or the group —

NY⁴Y⁵ may form a 5- to 7-membered cyclic amine which (i) may be optionally substituted with one or more substituents selected from alkoxy, carboxamido, carboxy, hydroxy, oxo, or a 5-, 6- or 7-membered cyclic acetal derivative thereof, or R¹⁰;

(ii) may also contain a after heteroatom selected from O, S, SO₂, or NY⁶; and

(iii) may also be fused to additional aryl, heteroaryl, heterocycloalkyl or cycloalkyl rings to form a bicyclic or tricyclic ring system;

Y⁶ represents hydrogen, alkyl, aryl, arylalkyl, —

C(═

O)—

R¹⁴, —

C(═

O)OR¹⁴ or SO₂R¹⁴;

Z is an oxygen or sulphur atom;

Z¹ is C(R⁷)(R^7a);

Z³ is C(═

O) or OC(═

O);

m is an integer 1 or 2; and

Y is carboxy;

and their ester prodrugs; and

phamaceutically acceptable salts and solvates of such compounds and their ester prodrugs.

2. A compound according to claim 1 in which R¹ represents a group R³—

L³—

Ar¹—

L⁴—

Z³—

in which Z³ is C(═

O), L⁴ is a straight or branched C_1-6alkylene chain, Ar¹ is optionally substituted phenylene, L³ is an —

NH—

C(═

O)—

NH—

linkage and R³ is optionally substituted aryl.

3. A compound according to claim 2 in which L⁴ is methylene, Ar¹ is optionally substituted p-phenylene and R³ is optionally substituted phenyl.

4. A compound according to claim 3 in which Ar¹ is p-phenylene or p-phenylene substituted in the 3-position by halo, C_1-4alkyl, C_1-4alkoxy, C_1-4alkylthio, C_1-4alkylsulphinyl or C_1-4alkylsulphonyl and R³ is phenyl substituted in the 2-position by C_1-4alkyl.

5. A compound according to claim 1 in which R² is hydrogen.

6. A compound according to claim 1 in which A¹ is methylene.

7. A compound according to claim 1 in which A¹ is ethylene.

8. A compound according to claim 1 in which Z¹ is CH₂.

9. A compound according to claim 1 in which L¹ is ethylene or propylene, each optionally substituted by C_1-4alkyl, aryl, heteroaryl, —

N(R⁸)—

C(═

O)—

R⁹, —

N(R⁸)—

C(═

O)—

OR⁹, —

N(R⁸)—

SO₂—

R⁹ or —

NY⁴Y⁵;

or alkyl substituted by carboxy, —

ZH, —

ZR³, —

C(═

O)—

NY⁴Y⁵ or —

NY⁴Y⁵, wherein R³, R⁸, R⁹, Y⁴, Y⁵ and Z are as defined in claim 1.

10. A compound according to claim 1 in which L¹ is a group

where R⁵ is hydrogen or C_1-4alkyl and R¹⁵ is hydrogen or C_1-4alkyl, or where R⁵ is hydrogen and R¹⁵ is aryl, heteroaryl, — N(R⁸)—

C(═

O)—

R⁹, —

N(R⁸)—

C(═

O)—

OR⁹, —

N(R⁸)—

SO₂—

R⁹ or —

NY⁴Y⁵;

or alkyl substituted by carboxy, —

ZH, —

ZR³, —

C(═

O)—

NY⁴Y⁵ or —

NY⁴Y⁵, wherein R³, R⁸, R⁹, Y⁴, Y⁵ and Z are as defined in claim 1.

11. A compound according to claim 10 in which L¹ is a group

where R¹⁵ represents hydrogen, C_1-4alkyl, aryl, heteroaryl, —

N(R⁸)—

C(═

O)—

R⁹, —

N(R⁸)—

C(═

O)—

OR⁹, —

N(R⁸)—

SO₂—

R⁹ or —

NY⁴Y⁵, or alkyl substituted by carboxy, —

OH, —

OR³ or —

C(═

O)—

NY⁴Y⁵, wherein R³, R⁸, R⁹, Y⁴ and Y⁵ are as defined in claim 1.

12. A compound according to claim 10 in which L¹ is a group

where R¹⁵ represents hydrogen, C_1-4alkyl, aryl, heteroaryl, —

N(R⁸)—

C(═

O)—

R⁹, —

N(R⁸)—

C(═

O)—

OR⁹, —

N(R⁸)—

SO₂—

R⁹ or —

NY⁴Y⁵, or alkyl substituted by carboxy, —

OH, —

OR³ or —

C(═

O)—

NY⁴Y⁵, wherein R³, R⁸, R⁹, Y⁴ and Y⁵ are as defined in claim 1.

13. A compound according to claim 1 in which L¹ is a group

where R⁵ is hydrogen or C_1-4alkyl and R^15a represents C_1-4alkyl, or where R⁵ is hydrogen and R^15a represents aryl, heteroaryl, —

N(R⁸)—

C(═

O)—

R⁹, —

N(R⁸)—

C(═

O)—

OR⁹, —

N(R⁸)—

SO₂—

R⁹ or —

NY⁴Y⁵, or alkyl substituted by carboxy, —

ZH, —

ZR³, —

C(═

O)—

NY⁴Y⁵ or —

NY⁴Y⁵, wherein R³, R⁵, R⁸, R⁹, Y⁴, Y⁵ and Z are as defined in claim 1.

14. A compound according to claim 13 in which L¹ is a group

where R^15a represents, —

N(R⁸)—

C(═

O)—

R⁹ or —

N(R⁸)—

SO₂—

R⁹, wherein R⁸ and R⁹ are as defined in claim 1.

15. A compound according to claim 13 which L¹ is a group

where R^15a represents —

N(R⁸)—

C(═

O)—

R⁹ or —

N(R⁸)—

SO₂—

R⁹, wherein R⁸ and R⁹ are as defined in claim 1.

16. A compound according to claim 1 having the formula (Ia):

in which R², R³, A¹, Ar¹, L¹, L⁴, Y and Z¹ are as defined in claim 1, and their ester prodrugs; and

pharmaceutically acceptable salts and solvates of such compounds and their ester prodrugs.

17. A compound according to claim 16 in which R³ is phenyl substituted in the 2-position by C_1-4alkyl.

18. A compound according to claim 16 in which Ar¹ is p-phenylene or p-phenylene substituted in the 3-position by halo, C_1-4alkyl, C_1-4alkoxy, C_1-4alkylthio, C_1-4alkylsulphinyl or C_1-4alkylsulphonyl.

19. A compound according to claim 16 in which L⁴ is a straight or branched C_1-4alkylene chain.

20. A compound according to claim 19 in which L⁴ is methylene.

21. A compound according to claim 16 in which A¹ is methylene.

22. A compound according to claim 16 in which A¹ is ethylene.

23. A compound according to claim 16 in which Z¹ is CH₂.

24. A compound according to claim 16 which R² is hydrogen.

25. A compound of formula (Ia) according to claim 16 in which R² is hydrogen, R³ is a 2-substituted phenyl, A¹ is methylene or ethylene, Ar¹ is optionally substituted m- or p-phenylene or optionally substituted p-pyridinediyl L¹ is a

where R¹⁵ represents hydrogen, C_1-4alkyl, aryl, heteroaryl, —

N(R⁸)—

C(═

O)—

R⁹, —

N(R⁸)—

C(═

O)—

OR⁹, —

N(R⁸)—

SO₂—

R⁹ or —

NY⁴Y⁵, or alkyl substituted by carboxy, —

OH, —

OR³, —

C(═

O)—

NY⁴Y⁵, L⁴ represents a straight or branched C_1-6alkylene chain and Z¹ represents CH₂; and

their ester prodrugs; and

pharmaceutically acceptable salts and solvates of such compounds and their ester prodrugs.

26. A compound of formula (Ia) according to claim 16 in which R² is hydrogen, R³ is a 2-substituted phenyl, A¹ is methylene or ethylene, Ar¹ is optionally substituted m- or p-phenylene, L¹ is a

group where R^15a represents —

N(R⁸)—

C(═

O)—

R⁹ or —

N(R⁸)—

SO₂—

R⁹, L⁴ represents a straight or branched C_1-6alkylene chain and Z¹ represents CH₂; and

their ester prodrugs; and

pharmaceutically acceptable salts and solvates of such compounds and their ester prodrugs.

27. A compound according to claim 26 in which L¹ is a group

28. A compound according to claim 27 in which R^15a represents —

N(R⁸)—

C(═

O)—

R⁹ where R⁸ is hydrogen or C_1-4alkyl and R⁹ is C_1-4alkyl, aryl, heteroaryl, alkyl substituted by alkoxy, alkyl substituted by carboxy or alkyl substituted by —

NY⁴Y⁵.

29. A compound according to claim 27 in which R^15a represents —

N(R⁸)—

C(═

O)—

R⁹ where R⁸ is hydrogen or C_1-4alkyl and R⁹ is selected from 2-chlorophenyl, 5-chloro-2-cyanophenyl, 2-chloro-6-methylphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl, 4-fluoro-2-trifluoromethyl, 2-methyl-4-nitrophenyl, 2-methyl-5-nitrophenyl, 2-nitrophenyl, 3-nitrophenyl and 2-phenoxyphenyl.

30. A compound according to claim 27 in which R^15a represents —

N(R⁸)—

C(═

O)—

R⁹ where R⁸ is hydrogen or C_1-4alkyl and R⁹ is selected from quinolin-4-yl, isoquinolin-2-yl, 2,4-pyridin-3-yl, 2,6-dimethyl-4-trifluoromethylpyridin-3-yl, 4-trifluoromethylpyridin3-yl, 2-phenyl-4-methyl-1,2,3-triazol-5-yl, 3,5-dimethylisoxazol4-yl, 2,7-dimethylpyrazolo-[1,5-a]pyrimidin-6-yl, 2-isopropyl-4-methylthiazol-5-yl and 4-trifluoromethylpyrimidin-5-yl.

31. A compound according to claim 1 selected from:

3-(1-{[3-methoxy-4-(3-[2-methylphenyl]-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-propionic acid;

3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-butyric acid;

3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolinyl-6-yl)-butyric acid;

3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-pentanedioic acid;

3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-pentanedioic acid;

4-[2-carboxy-1-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-ethylcarbamoyl]-butyric acid;

N-[2-carboxy-1-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-ethyl]-succinamic acid;

3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-3-[(5-methylisoxazole-3-carbonyl)-amino]-propionic acid;

3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-3-phenyl-propionic acid;

3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-pentanoic acid;

and their ester prodrugs; and

pharmaceutically acceptable salts and solvates of such compounds and their ester prodrugs.

32. A pharmaceutical composition comprising an effective amount of a compound according to claim 1, or an ester prodrug thereof;

or a pharmaceutically acceptable salt or solvate of such a compound or an ester prodrug thereof, in association with a pharmaceutically acceptable carrier or excipient.

33. A method for the treatment of a human or non-human animal patient suffering from, or subject to, a condition which can be ameliorated by the administration of an inhibitor of α

4β

1 mediated cell adhesion comprising administering to said patient an effective amount of a compound according to claim 1, or an ester prodrug thereof, or a pharmaceutically acceptable salt or solvate of such a compound or an ester prodrug thereof.

34. A method according to claim 33 wherein said condition is an inflammatory disease.

35. A method according to claim 33 wherein said condition is asthma.

36. A method for the treatment of a human or non-human animal patient suffering from, or subject to, a condition which can be ameliorated by the administration of an inhibitor of α

4β

1 mediated cell adhesion comprising administering to said patient an effective amount of a composition according to claim 32.

37. A method according to claim 36 wherein said condition is an inflammatory disease.

38. A method according to claim 36 wherein said condition is asthma.