Compositions and methods for the treatment of cancer

• US 20030114504A1
• Filed: 08/27/2002
• Published: 06/19/2003
• Est. Priority Date: 08/31/2001
• Status: Abandoned Application

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Webster, Kevin R., Kimball, Spencer David
• Application Number:
  US10/228,544
• Publication Number:
  US 20030114504A1
• Time in Patent Office: Days
• US Class Current: 514/369
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/425 Thiazoles
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/555 containing heavy metals, e.g. hemin, hematin, melarsoprol
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 33/24 Heavy metals; Compounds thereof
• CPC Class Codes: A61K 33/243 Platinum; Compounds thereof
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The compounds of the invention are protein kinase inhibitors and are useful in the treatment of proliferative diseases. Compositions and methods are provided for the synergistic treatment of proliferative disorders.

Claims

1. A method for the treatment of proliferative diseases, including cancer, which comprises administering to a mammalian specie in need thereof a therapeutically effective amount of (1) at least one anti-proliferative agent(s) and (2) a compound of Formula I:

2. The method according to claim 1, wherein the Formula I compound is

3. The method according to claim 2, wherein the Formula I compound is N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide or a pharmaceutically acceptable salt thereof.

4. The method according to claim 3 wherein said pharmaceutically acceptable salt is a tartrate salt.

5. The method according to claim 1 wherein the antiproliferative agent is administered prior to administration of the Formula I compound.

6. The method according to claim 1 wherein the antiproliferative agent is administered following administration of the Formula I compound.

7. The method according to claim 1 wherein the antiproliferative agent is administered simultaneously with the Formula 1 compound.

8. The method according to claim 1 for the treatment of cancerous solid tumors.

9. The method according to claim 1 for the treatment of refractory tumors.

10. The method according to claim 1 wherein the anti-proliferative agent is selected from the group consisting of a microtubule-stabilizing agent, a microtubule-disruptor agent, an alkylating agent, an anti-metabolite, epidophyllotoxin, an antineoplastic enzyme, a topoisomerase inhibitor, procarbazine, mitoxantrone, radiation and a platinum coordination complex.

11. The method according to claim 1 wherein the anti-proliferative agent is selected from the group consisting of an anthracycline drug, a vinca drug, a mitomycin, a bleomycin, a cytotoxic nucleoside, a taxane, an epothilone, discodermolide, a pteridine drug, a diynene, an aromatase inhibitor and a podophyllotoxin.

12. The method according to claim 1, wherein said method comprises the administration of a compound of Formula I and the anti-proliferative agent is Compound 2.

13. The method according to claim 2, wherein the antiproliferative agent is Compound 2.

14. The method according to claim 3, wherein the antiproliferative agent is Compound 2.

15. The method according to claim 1, wherein said method comprises the administration of a compound of Formula I and the anti-proliferative agent is Cisplatin.

16. The method according to claim 2, wherein the antiproliferative agent is Cisplatin.

17. The method according to claim 3, wherein the antiproliferative agent is Cisplatin.

18. The method according to claim 1, wherein said method comprises the administration of a compound of Formula I and the anti-proliferative agent is Carboplatin.

19. The method according to claim 2, wherein the antiproliferative agent is Carboplatin.

20. The method according to claim 3, wherein the antiproliferative agent is Carboplatin.

21. The method according to claim 1, wherein said method comprises the administration of a compound of Formula I and the anti-proliferative agent is Gemcitabine.

22. The method according to claim 2, wherein the antiproliferative agent is Gemcitabine.

23. The method according to claim 3, wherein the antiproliferative agent is Gemcitabine.

24. The method according to claim 10, wherein said compound of Formula I is selected from the group consisting of:

N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide;

(±

)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-3-piperidinecarboxamide;

(±

)-1-(2,3-dihydroxypropyl)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide;

N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-1-(1-methylethyl)-4-piperidinecarboxamide;

1-cyclopropyl-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide;

N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-1-(2-hydroxyethyl)-4-piperidinecarboxamide;

(R)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-3-piperidinecarboxamide;

(S)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-3-piperidinecarboxamide;

cis-4-amino-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]cyclohexylcarboxamide; and

trans-4-amino-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]cyclohexylcarboxamide; and

pharmaceutically acceptable salts thereof.

25. The method according to claim 11, wherein said compound of Formula I is selected from the group consisting of N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide;

(±

)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-3-piperidinecarboxamide;

(±

)-1-(2,3-dihydroxypropyl)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide;

N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-1-(1-methylethyl)-4-piperidinecarboxamide;

1-cyclopropyl-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide;

N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-1-(2-hydroxyethyl)-4-piperidinecarboxamide;

(R)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-3-piperidinecarboxamide;

(S)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-3-piperidinecarboxamide;

cis-4-amino-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]cyclohexylcarboxamide; and

trans-4-amino-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]cyclohexylcarboxamide; and

pharmaceutically acceptable salts thereof.

26. A pharmaceutical composition for the treatment of cancer which comprises at least one anti-proliferative agent and a compound of Formula I as described in claim 1, and a pharmaceutically acceptable carrier.

27. A pharmaceutical composition for the treatment of cancer which comprises at least one anti-proliferative agent and a compound of Formula I as described in claim 2, and a pharmaceutically acceptable carrier.

28. A pharmaceutical composition for the treatment of cancer which comprises at least one anti-proliferative agent and a compound of Formula I as described in claim 3, and a pharmaceutically acceptable carrier.

29. The pharmaceutical composition according to claim 26 for the synergistic treatment of cancerous solid tumors.

30. The pharmaceutical composition according to claim 27 for the synergistic treatment of cancerous solid tumors.

31. The pharmaceutical composition according to claim 28 for the synergistic treatment of cancerous solid tumors.

32. The pharmaceutical composition according to claim 26 for the treatment of refractory tumors.

33. The pharmaceutical composition according to claim 27 for the treatment of refractory tumors.

34. The pharmaceutical composition according to claim 28 for the treatment of refractory tumors.

35. The pharmaceutical composition according to claim 26 wherein the antiproliferative agent is one or more agent selected from the group consisting of a microtubule-stabilizing agent, a microtubule-disruptor agent, an alkylating agent, an anti-metabolite, epidophyllotoxin, an antineoplastic enzyme, a topoisomerase inhibitor, procarbazine, mitoxantrone, a platinum coordination complex, an anthracycline drug, a vinca drug, a mitomycin, a bleomycin, a cytotoxic nucleoside, a taxane, compound 2, an epothilone, discodermolide, a pteridine drug, a diynene, an aromatase inhibitor and a podophyllotoxin.

36. The pharmaceutical composition according to claim 27 wherein the antiproliferative agent is one or more agent selected from the group consisting of a microtubule-stabilizing agent, a microtubule-disruptor agent, an alkylating agent, an anti-metabolite, epidophyllotoxin, an antineoplastic enzyme, a topoisomerase inhibitor, procarbazine, mitoxantrone, a platinum coordination complex, an anthracycline drug, a vinca drug, a mitomycin, a bleomycin, a cytotoxic nucleoside, a taxane, compound 2, an epothilone, discodermolide, a pteridine drug, a diynene, an aromatase inhibitor and a podophyllotoxin.

37. The pharmaceutical composition according to claim 28 wherein the antiproliferative agent is one or more agent selected from the group consisting of a microtubule-stabilizing agent, a microtubule-disruptor agent, an alkylating agent, an anti-metabolite, epidophyllotoxin, an antineoplastic enzyme, a topoisomerase inhibitor, procarbazine, mitoxantrone, a platinum coordination complex, an anthracycline drug, a vinca drug, a mitomycin, a bleomycin, a cytotoxic nucleoside, a taxane, compound 2, an epothilone, discodermolide, a pteridine drug, a diynene, an aromatase inhibitor and a podophyllotoxin.

38. The pharmaceutical composition according to claim 26 wherein the compound of Formula I is selected from the group consisting of N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide;

(±

)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-3-piperidinecarboxamide;

(±

)-1-(2,3-dihydroxypropyl)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide;

N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-1-(1-methylethyl)-4-piperidinecarboxamide;

1-cyclopropyl-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide;

N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-1-(2-hydroxyethyl)-4-piperidinecarboxamide;

(R)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-3-piperidinecarboxamide;

(S)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-3-piperidinecarboxamide;

cis-4-amino-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]cyclohexylcarboxamide; and

trans-4-amino-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]cyclohexylcarboxamide; and

pharmaceutically acceptable salts thereof.

39. The pharmaceutical composition according to claim 26 wherein the pharmaceutically acceptable salt is selected from the group consisting of the tartrate salt, hydrochloride salt, the methanesulfonic acid salt and the trifluoroacetic acid salt.

40. The pharmaceutical composition according to claim 27 wherein the pharmaceutically acceptable salt is selected from the group consisting of the tartrate salt, hydrochloride salt, the methanesulfonic acid salt and the trifluoroacetic acid salt.

41. The pharmaceutical composition according to claim 28 wherein the pharmaceutically acceptable salt is selected from the group consisting of the tartrate salt, hydrochloride salt, the methanesulfonic acid salt and the trifluoroacetic acid salt.

42. The pharmaceutical composition according to claim 26 wherein the Formula I compound is N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide or a pharmaceutically acceptable salt thereof and the anti-proliferative agent is Compound 2.

43. The pharmaceutical composition according to claim 26 wherein the antiproliferative agent is Cisplatin and the Formula I compound is N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide or a pharmaceutically acceptable salt thereof.

44. The pharmaceutical composition according to claim 26 wherein the antiproliferative agent is gemcitabine and the compound of Formula I is N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide or a pharmaceutically acceptable salt thereof.

45. The pharmaceutical composition according to claim 37 wherein said composition comprises Compound 1 and Carboplatin.

46. The pharmaceutical composition according to claim 37 wherein said composition comprises Compound 1 and Doxorubicin.