Tyrosine kinase inhibitors

• US 20040220201A1
• Filed: 01/29/2004
• Published: 11/04/2004
• Est. Priority Date: 08/01/2001
• Status: Active Grant

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Merck & Co., Inc.
• Inventors: Bilodeau, Mark T., Manley, Peter J., Hartman, George D., Rodman, Leonard, Balitza, Adrienne
• Granted Patent: US 6,958,340 B2
• Time in Patent Office: Days
• US Class Current: 514/275
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings

Abstract

The present invention relates to compounds which inhibit, regulate and/or modulate tyrosine kinase signal transduction, compositions which contain these compounds, and methods of using them to treat tyrosine kinase-dependent diseases and conditions, such as angiogenesis, cancer, tumor growth, atherosclerosis, age related macular degeneration, diabetic retinopathy, inflammatory diseases, and the like in mammals.

Claims

1. A compound of Formula I

2. The compound according to claim 1, as illustrated by Formula I:

3. The compound, according to claim 1, as illustrated by Formula II:

11. A pharmaceutical composition which is comprised of a compound in accordance with claim 1 and a pharmaceutically acceptable carrier.

12. A method of treating or preventing cancer in a mammal in need of such treatment which is comprised of administering to said mammal a therapeutically effective amount of a compound of claim 1.

13. A method of treating cancer or preventing cancer in accordance with claim 12 wherein the cancer is selected from cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung.

14. A method of treating or preventing cancer in accordance with claim 12 wherein the cancer is selected from histiocytic lymphoma, lung adenocarcinoma, small cell lung cancers, pancreatic cancer, gioblastomas and breast carcinoma.

15. A method of treating or preventing a disease in which angiogenesis is implicated, which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1.

16. A method in accordance with claim 15 wherein the disease is an ocular disease.

17. A method of treating or preventing retinal vascularization which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of compound of claim 1.

18. A method of treating or preventing diabetic retinopathy which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of compound of claim 1.

19. A method of treating or preventing age-related macular degeneration which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1.

20. A method of treating or preventing inflammatory diseases which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1.

21. A method according to claim 20 wherein the inflammatory disease is selected from rheumatoid arthritis, psoriasis, contact dermatitis and delayed hypersensitivity reactions.

22. A method of treating or preventing a tyrosine kinase-dependent disease or condition which comprises administering a therapeutically effective amount of a compound of claim 1.

23. A pharmaceutical composition made by combining the compound of claim 1 and a pharmaceutically acceptable carrier.

24. A process for making a pharmaceutical composition which comprises combining a compound of claim 1 with a pharmaceutically acceptable carrier.

25. A method of treating or preventing bone associated pathologies selected from osteosarcoma, osteoarthritis, and rickets which comprises administering a therapeutically effective amount of a compound of claim 1.

26. The composition of claim 11 further comprising a second compound selected from:

1) an estrogen receptor modulator,

2) an androgen receptor modulator,

3) retinoid receptor modulator,

4) a cytotoxic agent,

5) an antiproliferative agent,

6) a prenyl-protein transferase inhibitor,

7) an HMG-CoA reductase inhibitor,

8) an HIV protease inhibitor,

9) a reverse transcriptase inhibitor, and

10) another angiogenesis inhibitor.

27. The composition of claim 26, wherein the second compound is another angiogenesis inhibitor selected from the group consisting of a tyrosine kinase inhibitor, an inhibitor of epidermal-derived growth factor, an inhibitor of fibroblast-derived growth factor, an inhibitor of platelet derived growth factor, an MMP inhibitor, an integrin blocker, interferon-α

, interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor, carboxyamidotriazole, combretastatin A4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1, and an antibody to VEGF.

28. The composition of claim 26, wherein the second compound is an estrogen receptor modulator selected from tamoxifen and raloxifene.

29. A method of treating cancer which comprises administering a therapeutically effective amount of a compound of claim 1 in combination with radiation therapy.

30. A method of treating or preventing cancer which comprises administering a therapeutically effective amount of a compound of claim 1 in combination with a compound selected from:

1) an estrogen receptor modulator,

2) an androgen receptor modulator,

3) retinoid receptor modulator,

4) a cytotoxic agent,

5) an antiproliferative agent,

6) a prenyl-protein transferase inhibitor,

7) an HMG-CoA reductase inhibitor,

8) an HIV protease inhibitor,

9) a reverse transcriptase inhibitor, and

10) another angiogenesis inhibitor.

31. A method of treating cancer which comprises administering a therapeutically effective amount of a compound of claim 1 in combination with radiation therapy and a compound selected from:

1) an estrogen receptor modulator,

2) an androgen receptor modulator,

3) retinoid receptor modulator,

4) a cytotoxic agent,

5) an antiproliferative agent,

6) a prenyl-protein transferase inhibitor,

7) an HMG-CoA reductase inhibitor,

8) an HV protease inhibitor,

9) a reverse transcriptase inhibitor, and

10) another angiogenesis inhibitor.

32. A method of treating or preventing cancer which comprises administering a therapeutically effective amount of a compound of claim 1 and paclitaxel or trastuzumab.

33. A method of treating or preventing cancer which comprises administering a therapeutically effective amount of a compound of claim 1 and a GPIIb/IIIa antagonist.

34. The method of claim 33 wherein the GPIIb/IIIa antagonist is tirofiban.

35. A method of reducing or preventing tissue damage following a cerebral ischemic event which comprises administering a therapeutically effective amount of a compound of claim 1.

36. A method of treating or preventing cancer which comprises administering a therapeutically effective amount of a compound of claim 1 in combination with a COX-2 inhibitor.

37. A method of treating or preventing preeclampsia which comprises administering a therapeutically effective amount of a compound of claim 1.

38. A method of inhibiting at least two tyrosine kinase receptors which comprises administering a therapeutically effective amount of a compound according to claim 1.

39. The method according to claim 38 wherein the tyrosine kinase receptors are selected from KDR, EGFR and SRC.

40. A method of treating or preventing tissue damage due to bacterial meningitis which comprises administering a therapeutically effective amount of a compound of claim 1.

4. A compound selected from

4-(2-Phenyl-1H-imidazol-1-yl)-N-pyridin-4-ylpyrimidin-2-amine;

4-(2-Phenyl-1H-imidazol-1-yl)-N-pyrimidin-4-ylpyrimidin-2-amine;

4-(2-Phenyl-1H-imidazol-1-yl)-N-pyrimidin-2-ylpyrimidin-2-amine;

4-(2-Phenyl-1H-imidazol-1-yl)-N-pyrazin-2-ylpyrimidin-2-amine;

4-(2-Phenyl-1H-imidazol-1-yl)-N-(1,3,4-thiadiazol-2-yl)pyrimidin-2-amine;

N-(5-Methyl-1,3,4-thiadiazol-2-yl)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

N-Isoxazol-3-yl-4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

N-(3-Methylisoxazol-5-yl)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

N-(4-Methyl-1,3-thiazol-2-yl)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

N-(2-Methylpyridin-4-yl)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

N-(2,6-Dimethylpyridin-4-yl)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

4-(2-Phenyl-1H-imidazol-1-yl)-N-pyridin-3-ylpyrimidin-2-amine;

N-(1-Oxidopyridin-3-yl)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

N-[3-Methoxy-5-(trifluoromethyl)phenyl]-4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

(3-Methyl-5-{[4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-yl]amino}phenyl)methanol;

N-{3-[(4-Acetylpiperazin-1-yl)methyl]-5-methylphenyl}-4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

N-(3,5-Dimethylphenyl)-4-(2-pyridin-2-yl-1H-imidazol-1-yl)pyrimidin-2-amine;

N-(3,5-Dimethylphenyl)-4-(2-pyrimidin-5-yl-1H-imidazol-1-yl)pyrimidin-2-amine;

N-(3,5-Dimethylphenyl)-4-(2-pyridin-3-yl-1H-imidazol-1-yl)pyrimidin-2-amine;

4-(2-Cyclopropyl-1H-imidazol-1-yl)-N-(3,5-dimethylphenyl)pyrimidin-2-amine;

N-(3,5-Dimethylphenyl)-4-(4-methyl-2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

1-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1H-imidazole-2-carbonitrile;

N-(3,5-Dimethylphenyl)-4-(2-methyl-1H-imidazol-1-yl)pyrimidin-2-amine;

4-(2-Amino-1H-imidazol-1-yl)-N-(3,5-dimethylphenyl)pyrimidin-2-amine;

N-(2-methylphenyl)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

N-(2-methoxyphenyl)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

N-(2-fluorophenyl)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

N-(3-chlorophenyl)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

N-(3,5-dichlorophenyl)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

N-(3-fluorophenyl)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

N-(3-methoxyphenyl)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

N-(3-methylphenyl)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

N-(3,5-dimethoxyphenyl)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

N-(4-chlorophenyl)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

N-(4-fluorophenyl)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

N-(4-methoxyphenyl)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

N-(4-methylphenyl)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

N-[3,5-bis(trifluoromethyl)phenyl]-4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

N-[3-methyl-5-(trifluoromethyl)phenyl]-4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

N-(3,5-difluorophenyl)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

4-(2-phenyl-1H-imidazol-1-yl)-N-[3-(trifluoromethyl)phenyl]pyrimidin-2-amine;

N-(3,5-dimethylphenyl)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

4-(2-Phenyl-1H-imidazol-1-yl)-N-pyridin-2-ylpyrimidin-2-amine;

N-{3-[(4-acetylpiperazin-1-yl)methyl]phenyl}-4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

4-(2-Chloro-1H-imidazol-1-yl)-N-(3,5-dimethylphenyl)pyrimidin-2-amine;

N-(3,5-Dimethylphenyl)-4-[2-(3-fluorophenyl)-1H-imidazol-1-yl]pyrimidin-2-amine;

or the pharmaceutically acceptable salts thereof.

5. The compound according to claim 4 which is

N-[3-methyl-5-(trifluoromethyl)phenyl]4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

or the pharmaceutically acceptable salts thereof.

6. The compound according to claim 4 which is

N-(3,5-dimethylphenyl)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

or the pharmaceutically acceptable salts thereof.

7. The compound according to claim 4 which is

N-(3-chlorophenyl)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

or the pharmaceutically acceptable salts thereof.

8. The compound according to claim 4 which is

N-(3,5-dimethoxyphenyl)-2-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-amine;

or the pharmaceutically acceptable salts thereof.

9. The compound according to claim 4 which is

4-(2-phenyl-1H-imidazol-1-yl)-N-[3-(trifluoromethyl)phenyl]pyrimidin-2-amine;

or the pharmaceutically acceptable salts thereof.

10. The compound according to claim 4 which is

(3-methyl-5-{[4-(2-phenyl-1H-imidazol-1-yl)pyrimidin-2-yl]amino}phenyl)methanol;

or the pharmaceutically acceptable salts thereof.