Azaindoles

• US 20040009983A1
• Filed: 06/24/2002
• Published: 01/15/2004
• Est. Priority Date: 12/24/1999
• Status: Active Grant

• Current Assignee: Aventis Pharma Ltd. (Sanofi )
• Original Assignee: Aventis Pharma Ltd. (Sanofi )
• Inventors: Lai, Justine Y.Q., Deprets, Stephanie D., Morley, Andrew D., Amendola, Shelley, Edlin, Christopher, Majid, Tahir N., Cox, Paul J.
• Granted Patent: US 6,770,643 B2
• Time in Patent Office: Days
• US Class Current: 514/249
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/14 Decongestants or antiallergics
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

The invention is directed to compositions containing physiologically active compounds of general formula (I):

wherein R¹ is aryl or heteroaryl; R² represents hydrogen, acyl, cyano, halo, lower alkenyl or lower alkyl optionally substituted by a substituent selected from cyano, heteroaryl, heterocycloalkyl, —Z¹R⁸, —C(═O)—NY³Y⁴, —CO₂R⁸, —NY³Y⁴, —N(R⁶)—C(═O)—R⁷, —N(R⁶)—C(═O)—NY³Y⁴, —N(R⁶)—C(═O)—OR⁷, —N(R⁶)—SO₂—R⁷, —N(R⁶)—SO₂—NY³Y⁴ and one or more halogen a toms ; R³ represents hydrogen, aryl, cyano, halo, heteroaryl, lower alkyl, —C(═O)—OR⁵ or —C(═O)—NY³Y; and X¹ represents N, CH, C-halo, C—CN, C—R⁷, C—NY³Y⁴, C—OH, C—Z²R⁷, C—C(═O)—OR⁵, C—C(═O)—NY³Y⁴, C—N(R⁸)—C(═O)—R⁷, C—SO₂—NY³Y⁴, C—N(R⁸)—SO₂—R⁷, C-alkenyl, C-alkynyl or C—NO₂; and their prodrugs, and pharmaceutically acceptable salts and solvates of such compounds and their prodrugs, as well as to novel compounds within the scope of formula (I).

Such compounds and compositions have valuable pharmaceutical properties, in particular the ability to inhibit protein kinases.

Claims

1. A pharmaceutical composition comprising an effective selective kinase inhibitory amount of a compound of general formula (I):

2. A compound of formula (I) according to claim 1, but excluding the compounds 2-phenyl-1H-pyrrolo[2,3-b]pyridine, 2-(4-bromo-phenyl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 4-(3-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-benzoic acid methyl ester, 2-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine, 2-(4-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine, 5-methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridine, 4-methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridine, 2-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine, 4-(3-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-benzoic acid, 2-(4-methoxy-phenyl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 2-(4-methyl-phenyl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 4-(3-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-benzoic acid isopropyl ester, 2-phenyl-3-methyl-1H-pyrrolo[2,3-b]pyridine, 6-phenyl-5H-pyrrolo[2,3-b]pyrazine, 6-(4-methoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine, 6-(4-chloro-phenyl)-5H-pyrrolo[2,3-b]pyrazine, 6-(2-chloro-phenyl)-5H-pyrrolo[2,3-b]pyrazine, 3-methyl-6-phenyl-5H-pyrrolo[2,3-b]pyrazine, 2-methyl-6-phenyl-5H-pyrrolo[2,3-b]pyrazine and 7-methyl-6-phenyl-5H-pyrrolo[2,3-b]pyrazine.

3. A compound according to claim 2 in which R¹ is optionally substituted heteroaryl.

4. A compound according to claim 3 in which R¹ is optionally substituted azaheteroaryl.

5. A compound according to claim 2 in which R¹ is optionally substituted indolyl, optionally substituted furanyl, optionally substituted pyridyl, optionally substituted pyrrolyl, optionally substituted pyrazolyl, optionally substituted quinolinyl, optionally substituted isoquinolinyl, optionally substituted imidazolyl, optionally substituted indazolyl, optionally substituted indolizinyl, optionally substituted tetrahydroindolizinyl or optionally substituted indazolinyl.

6. A compound according to any one of claims 3-5 in which the optionally substituents within R¹ are one or more groups selected from alkylenedioxy, alkenyl, alkenyloxy, aryl, carboxy (or an acid bioisostere), cyano, halo, hydroxy, heteroaryl, heterocycloalkyl, R⁴, —

C(═

O)—

R⁴, —

C(═

O)—

NY¹Y², —

C(═

O)—

OR⁵, —

NY¹Y² and —

OR⁴.

7. A compound according to claim 2 in which R¹ is optionally substituted aryl.

8. A compound according to claim 7 in which R¹ is phenyl substituted by one or more groups selected from alkylenedioxy, halo, R⁴, —

NY¹Y² and —

OR⁴.

9. A compound according to any one of claims 2-8 in which R² is hydrogen.

10. A compound according to any one of claims 2-8 in which R² is halo.

11. A compound according to any one of claims 2-8 in which R² is lower alkyl optionally substituted by carboxy, cyano, halo, hydroxy, tetrazolyl, or —

CONY³Y⁴.

12. A compound according to any one of claims 2-8 in which R² is lower alkenyl.

13. A compound according to any one of claims 2-12 in which R³ is hydrogen.

14. A compound according to any one of claims 2-12 in which R³ is optionally substituted aryl.

15. A compound according to any one of claims 2-12 in which R³ is optionally substituted phenyl.

16. A compound according to any one of claims 2-12 in which R³ is lower alkyl.

17. A compound according to any one of claims 2-16 in which X¹ is N.

18. A compound according to any one of claims 2-16 in which X¹ is CH.

19. A compound according to any one of claims 2-16 in which X¹ is C-lower alkoxy.

20. A compound according to any one of claims 2-16 in which X¹ is C-aryl.

21. A compound according to any one of claims 2-16 in which X¹ is C—

Cl.

22. A compound according to any one of claims 2-16 in which X¹ is C—

CN.

23. A compound of formula (Ia):

24. A compound according to claim 23 in which R² is hydrogen.

25. A compound according to claim 23 or 24 in which R³ is hydrogen, optionally substituted aryl or lower alkyl.

26. A compound according to any one of claims 23 to 25 in which X¹ is CH, C-lower alkoxy, C-aryl, C-halo, C—

CN, or N.

27. A compound according to any one of claims 23 to 26 in which R⁹ is:

(i) hydrogen;

(ii) C_1-4alkyl;

(iii) C_1-4alkyl substituted by hydroxy;

(iv) C_1-4alkyl substituted by —

N(R⁶)C(═

O)—

R⁷;

(v) C_1-4alkyl substituted by —

C(═

O)—

NY¹Y²;

or

(vi) cycloalkylalkyl substituted by hydroxy.

28. A compound according to any one of claims 23 to 27 in which R¹⁰ is:

(i) hydroxy;

(ii) —

OR⁴ in which R⁴ is alkyl;

(iii) —

OR⁴ in which R⁴ is alkyl or cycloalkylalkyl, each substituted by one or more hydroxy groups;

(iv) —

OR⁴ in which R⁴ is alkyl substituted by one or more alkoxy groups;

(v) —

OR⁴ in which R⁴ is alkyl or cycloalkyl, each substituted by one or more carboxy;

(vi) —

OR⁴ in which R⁴ is cycloalkyl substituted by —

C(═

O)—

NY¹Y²;

(vii) —

N(R⁶)—

C(═

O)—

R⁷;

(viii) —

CONY¹Y²;

(ix) carboxy

(x) alkyl substituted by carboxy;

(xi) heteroaryl;

(xii) —

C(═

O)—

R⁴ in which R⁴ is alkyl;

or

(xii) tetrazolyl or N-methyltetrazolyl;

29. A compound according to claim 28 in which R¹⁰ is attached to position 5 of the indolyl ring.

30. A compound of formula (Ib):

31. A compound according to claim 30 in which R² is hydrogen.

32. A compound according to claim 30 or 31 in which R³ is hydrogen, optionally substituted aryl or lower alkyl.

33. A compound according to any one of claims 30 to 32 in which X¹ is CH, C-lower alkoxy, C-aryl, C-halo, C—

CN, or N.

34. A compound according to any one of claims 30 to 33 in which R⁹ is hydrogen or C_1-4alkyl.

35. A compound according to any one of claims 30 to 34 in which p is zero.

36. A compound of formula (Ic):

37. A compound according to claim 36 in which R² is hydrogen.

38. A compound according to claim 36 or 37 in which R³ is hydrogen, optionally substituted aryl or lower alkyl.

39. A compound according to any one of claims 36 to 38 in which X¹ is CH, C-lower alkoxy, C-aryl, C-halo, C—

CN, or N.

40. A compound according to any one of claims 36 to 39 in which R⁹ is hydrogen or C_1-4alkyl.

41. A compound according to any one of claims 36 to 40 in which p is 1.

42. A compound according to any one of claims 36 to 41 in which R¹⁰ represents aryl.

43. A compound according to claim 42 in which R¹⁰ is attached at position 4 of the pyrrole ring.

44. A compound of formula (Id):

45. A compound according to claim 44 in which R² is hydrogen, lower alkyl, lower alkyl substituted by —

CONY³Y⁴, lower alkyl substituted by carboxy, lower alkyl substituted by tetrazolyl or lower alkyl substituted by hydroxy.

46. A compound according to claims 44 or 45 in which R³ is hydrogen, optionally substituted aryl or lower alkyl.

47. A compound according to any one of claims 44 to 46 in which X¹ is CH, C-lower alkoxy, C-aryl, C-halo, C—

CN, or N.

48. A compound according to claims any one of claims 44 to 47 in which p is 1.

49. A compound according to any one of claims 44 to 48 in which R¹⁰ is alkyl.

50. A compound according to claim 49 in which R¹⁰ is attached at position 4 of the phenyl ring.

51. A compound according to claim 2 selected from the group consisting of:

6-(5-methoxy-1-methyl-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazine;

1-[1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-5-yloxy]-cyclobutanecarboxylic acid amide;

2-(5-methoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile;

{1-[1-methyl-3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-1H-indol-5-yloxy]-cyclobutyl}-methanol;

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

52. A compound according to claim 2 or a corresponding prodrug, or a pharmaceutically acceptable salt or solvate of such a compound or a prodrug thereof, for use in therapy.

53. A compound according to claim 2 or a corresponding prodrug, or a pharmaceutically acceptable salt or solvate of such a compound or a prodrug thereof, for use in the treatment of a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of the catalytic activity of Syk kinase.

54. A composition according to claim 1 for use in the treatment of a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of the catalytic activity of Syk kinase.

55. A composition according to claim 1 for use in the treatment of inflammatory diseases.

56. A composition according to claim 1 for use in the treatment of asthma.

57. A composition according to claim 1 for use in the treatment of psoriasis.

58. A composition according to claim 1 for use in the treatment of joint inflammation.

59. A composition according to claim 1 for use in the treatment of inflammatory bowel disease.

60. Use of a compound according to claim 2 or a corresponding prodrug, or a pharmaceutically acceptable salt or solvate of such a compound or a prodrug thereof, in the manufacture of a medicament for the treatment of a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of the catalytic activity of Syk kinase.

61. Use of a compound according to claim 2 or a corresponding prodrug, or a pharmaceutically acceptable salt or solvate of such a compound or a prodrug thereof, in the manufacture of a medicament for the treatment of asthma.

62. Use of a compound according to claim 2 or a corresponding prodrug, or a pharmaceutically acceptable salt or solvate of such a compound or a prodrug thereof, in the manufacture of a medicament for the treatment of psoriasis.

63. Use of a compound according to claim 2 or a corresponding prodrug, or a pharmaceutically acceptable salt or solvate of such a compound or a prodrug thereof, in the manufacture of a medicament for the treatment of joint inflammation.

64. Use of a compound according to claim 2 or a corresponding prodrug, or a pharmaceutically acceptable salt or solvate of such a compound or a prodrug thereof, in the manufacture of a medicament for the treatment of inflammatory bowel disease.

65. A method for the treatment of a human or non-human animal patient suffering from, or subject to, conditions which can be ameliorated by the administration to said patient of an inhibitor of Syk kinase—

comprising administering to said patient an effective amount of a compound according to claim 2 or a corresponding prodrug, or a pharmaceutically acceptable salt or solvate of such a compound or a prodrug thereof.

66. A compound substantially as hereinbefore described with references to the Examples.