Combination of epothilone analogs and chemotherapeutic agents for the treatment of proliferative diseases

• US 20040024032A1
• Filed: 06/12/2003
• Published: 02/05/2004
• Est. Priority Date: 06/14/2002
• Status: Active Grant

• Current Assignee: Huma Therapeutics Ltd.
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Lebwohl, David, Voi, Maurizio
• Granted Patent: US 7,008,936 B2
• Time in Patent Office: Days
• US Class Current: 514/365
• 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 31/282 Platinum compounds
• CPC Class Codes: A61K 31/33 Heterocyclic compounds
• CPC Class Codes: A61K 31/335 having oxygen as the only ring hetero atom, e.g. fungichromin
• CPC Class Codes: A61K 31/425 Thiazoles
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Abstract

Compositions and methods are disclosed which are useful of the treatment and prevention of proliferative diseases.

Claims

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

2. The method of claim 1 wherein the antiproliferative agent is administered after administration of the compound of formula I.

3. The method of claim 2 for the treatment of cancerous solid tumors.

4. The method of claim 2 for the treatment of refractory tumors.

5. The method of claim 1 wherein the anti-proliferative agent is selected from the group consisting of a microtubule affecting agent, an alkylating agent, an anti-metabolite, epidophyllotoxin, an antineoplastic enzyme, a topoisomerase inhibitor, procarbazine, mitoxantrone, inhibitors of cell cycle progression, radiation and a platinum coordination complex.

6. The method of claim 5 wherein the anti-proliferative agent is carboplatin.

7. The method of claim 1 wherein the compound of formula I is [1S-1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamenthyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione (Compound 1).

8. The method of claim 2 wherein the compound of formula I is [1S-1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione (Compound 1).

9. The method of claim 1 wherein the compound of formula I is [1S-1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione (Compound 1) and the anti-proliferative agent is carboplatin.

10. The method of claim 2 wherein the compound of formula I is [1S 1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione (Compound 1) and the anti-proliferative agent is carboplatin.

11. A method for modulating tumor growth in a human in need thereof, comprising sequential or simultaneous administration of [1S 1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione (Compound 1) and carboplatin.

12. The method of claim 11 wherein said [1S 1R*,3R*(E),7R*,10S*,11R*, 12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione (Compound 1) is administered first, followed by administration of carboplatin, and wherein this combination of Compound 1 and carboplatin is administered every three weeks for at least one treatment cycle.

13. The method of claim 12 wherein said [1S 1R*,3R*(E),7R*,10S*,11R*, 12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione (Compound 1) is administered as a 60-minute infusion, 30 minutes prior to a 30-minute infusion of carboplatin.

14. The method of claim 12 wherein the dosage of said [1S 1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione (Compound 1) is between 5 mg/m² and 60 mg/m² and the dosage of carboplatin is between 5 mg/m² and 1000 mg/m².

15. The method of claim 14 wherein the dosage of said [1S 1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione (Compound 1) is between 25 mg/m² and 50 mg/m² and the dosage of carboplatin is between 5 mg/m² and 1000 mg/m².

16. The method of claim 11 wherein said [1S 1R*, 3R*(E),7R*,10S*,11R*, 12R*, 16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione (Compound 1) is administered on day 1 and again on day 8, and carboplatin is administered on day 1, for at least one treatment cycle.

17. The method of claim 16 wherein said [1S 1R*,3R*(E),7R*,10S*,11R*, 12R*,16S*]]7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione (Compound 1) is administered as a 60-minute infusion, 30 minutes prior to a 30-minute infusion of carboplatin.

18. The method of claim 16 wherein the dosage of said [1S 1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione (Compound 1) is between 5 mg/m² and 60 mg/m² and the dosage of carboplatin is between 5 mg/m² and 1000 mg/m².

19. The method of claim 18 wherein the dosage of said [1S 1R*,3R*(E),7R*,10S *,11R*,12R*,16S *]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione (Compound 1) is between 15 and 30 mg/m² and the dosage of carboplatin is between 5 mg/m² and 1000 mg/m².