Derivatives of taxol, pharmaceutical compositions thereof and methods for the preparation thereof

• US 4,960,790 A
• Filed: 03/09/1989
• Issued: 10/02/1990
• Est. Priority Date: 03/09/1989
• Status: Expired due to Fees

• Current Assignee: University of Kansas Office of Research Graduate Studies & Public Service
• Original Assignee: University of Kansas
• Inventors: Mathew, Abraham E., Stella, Valentino J.
• Primary Examiner(s): Raymond, Richard L.
• Assistant Examiner(s): RUSSELL, MARK
• Application Number:
  US07/321,152
• Time in Patent Office: 572 Days
• Field of Search: 549/510, 549/511, 514/449, 514/908, 514/320, 514/422, 548/525, 546/196
• US Class Current: 514/449
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 305/14 condensed with carbocyclic rings or ring systems

Abstract

Derivatives of taxol represented by the formula ##STR1## wherein R and R'"'"' are each H or the residue of an amino acid selected from the group consisting of alanine, leucine, isoleucine, saline, phenylalanine, proline, lysine and arginine or a group of the formula ##STR2## wherein n is an integer of 1 to 3 and R² and R³ are each hydrogen on an alkyl radical having from one to three carbon atoms or wherein R² and R³ together with the nitrogen atom to which they are attached form a saturated heterocyclic ring having four to five carbon atoms, with the proviso that at least one of R and R¹ is not hydrogen, are provided together with pharmaceutical compositions of such derivatives. The taxol derivatives have increased water solubility as compared to taxol, and have excellent antitumor activity.

Claims

1. A compound of the formula ##STR19## wherein R and R'"'"' are each H or the residue of an amino acid selected from the group consisting of alanine, leucine, isoleucine, valine, phenylalanine, proline, lysine and arginine or a group of the formula ##STR20## wherein n is an integer of 1 to 3 and R² and R³ are each hydrogen or an alkyl radical having from one to three carbon atoms or wherein R² and R³ together with the nitrogen atom to which they are attached form a saturated heterocyclic ring having four or five carbon atoms or an acid addition salt thereof, with the proviso that at least one of R and R¹ is not hydrogen, and with the second proviso that said compound is not 2'"'"'-(β

-alanyl)taxol.

2. A compound according to claim 1, wherein at least one of R and R'"'"' is a member selected from the group consisting of L-alanine, L-leucine, L-isoleucine, L-valine, L-phenylalanine, L-proline, L-lysine, and L-arginine.

3. A compound according to claim 1, wherein at least one of R and R'"'"' is a group of the formula ##STR21## wherein n is an integer of from 1 to 3 and R² and R³ are each an alkyl radical having from one to three carbon atoms.

4. A compound according to claim 1, which is 2'"'"'-(N,N-dimethylglycyl)taxol or an acid addition salt thereof.

5. A compound according to claim 1, which is 2'"'"'-(N,N-diethylaminopropionyl)taxol or an acid addition salt thereof.

6. A compound according to claim 1, which is 7-(N,N-dimethylgylcyl)taxol, or an acid addition salt thereof.

7. A compound according to claim 1, which is 2'"'"',7-di(N,N-dimethylglycyl)taxol, or an acid addition salt thereof.

8. A compound according to claim 1, which is 7-(alanyl)taxol or an acid addition salt thereof.

12. A method for treating tumors which comprises administering to a patient an effective antitumor amount of at least one compound according to claim 1.

13. A method according to claim 12, wherein said treatment comprises treating tumors selected from the group consisting of human lung tumors, melanoma, leukemia, mammary tumors and colon cancer.

14. A compound according to claim 1, which is 7-(N,N-dimethylaminopropionyl)taxol or an acid addition salt thereof.

15. A compound according to claim 1, which is 2'"'"'-(L-alanyl)taxol or an acid addition salt thereof.

16. A compound according to claim 1, which is 2'"'"'-(L-lysyl)taxol or an acid addition salt thereof.

17. A compound according to claim 1, which is 7-(L-lysyl)taxol or an acid addition salt thereof.

9. A pharmaceutical composition comprising an effective antitumor amount of at least one compound of the formula ##STR22## wherein R and R'"'"' are each H or the residue of an amino acid selected from the group consisting of alanine, leucine, isoleucine, valine, phenylalanine, proline, lysine and arginine or a group of the formula ##STR23## wherein n is an integer of 1 to 3 and R² and R³ are each hydrogen or an alkyl radical having from one to three carbon atoms or wherein R² and R³ together with the nitrogen atom to which they are attached form a saturated heterocyclic ring having four to five carbon atoms, with the proviso that at least one of R and R¹ is not hydrogen, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

10. A pharmaceutical composition according to claim 9, wherein said at least one compound is 2'"'"'-(N,N-dimethylglycyl)taxol.

11. A pharmaceutical composition according to claim 10, wherein said at least one compound is 2'"'"'-(N,N-diethylaminopropionyl)taxol.

18. A pharmaceutical composition according to claim 9, wherein said at least one compound is 7-(N,N-dimethylglycyl)-taxol.

19. A pharmaceutical composition according to claim 9, wherein said at least one compound is 2'"'"'7-di-(N,N-diethylaminopropionyl)taxol.

20. A pharmaceutical composition according to claim 9, wherein said at least one compound is 7-(N,N-diethylaminopropionyl)taxol.

21. A pharmaceutical composition according to claim 9, wherein said at least one compound is 2'"'"'-(L-alanyl)taxol.

22. A pharmaceutical composition according to claim 9, wherein said at least one compound is 7-(L-alanyl)taxol.

23. A pharmaceutical composition according to claim 9, wherein said at least one compound is 2'"'"'-(L-lysyl)taxol.

24. A pharmaceutical composition according to claim 9, wherein said at least one compound is 7-(L-lysyl)taxol.

25. A taxol derivative selected from the group consisting of

2'"'"'-(N,N-diethylaminopropionyl)taxol;

2'"'"'-(N,N-dimethylglycyl)taxol;

7-(N,N-dimethylglycyl)taxol;

2'"'"',7-di-(N,N-dimethylglycyl)taxol;

7-(N,N-diethylaminopropionyl)taxol;

2'"'"'-(L-lysyl)taxol;

7-(L-lysyl)taxol; and

acid addition salts thereof.

26. A compound according to claim 25, wherein the acid addition salt is a methanesulphonic acid salt.

27. A compound according to claim 25, wherein the acid addition salt is an HCl salt.

28. A compound according to claim 25, which 2'"'"'-(N,N-diethylaminopropionyl)taxol methanesulphonic acid salt.

29. A compound according to claim 25, which is 2'"'"'-(N,N-diethylaminopropionyl)taxol HCl salt.

30. A pharmaceutical composition comprising an effective antitumor amount of at least one compound according to claim 25, and a pharmaceutically acceptable carrier.

31. A pharmaceutical composition according to claim 30, wherein said compound is 2'"'"'-(N,N-diethylaminopropionyl)taxol methanesulphonic acid salt or 2'"'"'-(N,N-diethylaminopropionyl)taxol HCl salt.

32. A method for treating tumors which comprises administering to a patient an effective antitumor amount of at least one compound according to claim 25.

33. A method for treating tumors which comprises administering to a patient an effective antitumor amount of at least one compound according to claim 28.

34. A method for treating tumors which comprises administering to a patient an effective antitumor amount of at least one compound according to claim 29.