Phosphonooxymethyl ethers of taxane derivatives

• US 5,646,176 A
• Filed: 05/19/1995
• Issued: 07/08/1997
• Est. Priority Date: 12/24/1992
• Status: Expired due to Term

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Kadow, John F., Wittman, Mark D., Wright, John J., Wong, Henry, Li, Wen-Sen, Vyas, Dolatrai, Thottathil, John K., Golik, Jerzy, Kaplan, Murray A., Perrone, Robert K.
• Primary Examiner(s): Trinh, Ba K.
• Application Number:
  US08/445,360
• Time in Patent Office: 781 Days
• Field of Search: 514/444, 514/449, 514/471, 549/60, 549/214, 549/220, 549/472, 549/473, 549/510, 549/511
• US Class Current: 514/444
• CPC Class Codes: C07D 305/14 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 407/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896
• CPC Class Codes: C07F 9/65512 condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/65586 at least one of the hetero rings does not contain nitrogen as ring hetero atom
• CPC Class Codes: H01L 21/4839 Assembly of a flat lead with an insulating support, e.g. for TAB

Abstract

The present invention concerns antitumor compounds. More particularly, the invention provides novel taxane derivatives, pharmaceutical compositions thereof, and their use as antitumor agents.

Claims

1. A compound having the formula ##STR113## wherein R¹ is hydroxy, --OCH₂ (OCH₂)_m OP(O)(OH)₂, --OC(O)R^x or --OC(O)OR^x ;

R^2'"'"' is hydrogen, and R² is hydrogen, hydroxy, --OCH₂ (OCH₂)_m OP(O)(OH)₂, --OC(O)R^x or --OC(O)OR^x ;

R³ is hydrogen, hydroxy, C_1-6 alkyloxy, --OC(O)R^x, --OCH₂ (OCH₂)_m OP(O)(OH)₂ or --OC(O)OR^x ;

one of R⁶ or R⁷ is hydrogen and the other is hydroxy, C_1-6 alkanoyloxy, or --OCH₂ (OCH₂)_m OP(O)(OH₂);

or R⁶ and R⁷ together form an oxo group;

with the proviso that at least one of R¹, R², R³, R⁶ or R⁷ is --OCH₂ (OCH₂)_m OP(O)(OH)₂ ;

m is zero or an integer one to six inclusive;

R⁴ and R⁵ are independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, or --Z--R⁶ ;

Z is a direct bond, C_1-6 alkyl or C_2-6 alkenyl;

R⁶ is aryl, substituted aryl, C_3-6 cycloalkyl, or heteroaryl;

p is 0 or 1; and

R^x is C_1-6 alkyl optionally substituted with one to six same or different halogen atoms, C_3-6 cycloalkyl, C_2-6 alkenyl or hydroxy;

or R^x is a radical of the formula ##STR114## wherein D is a bond or C_1-6 alkyl; and

R^a, R^b and R^c are independently hydrogen, amino, C_1-6 alkylamino, di-C_1-6 alkylamino, halogen, C_1-6 alkyl, or C_1-6 alkoxy.

2. A compound of claim 1 wherein R^2'"'"' is hydrogen, and R² is --OCH₂ OP(O)(OH)₂ ;

or a pharmaceutically acceptable salt thereof.

3. A compound of claim 2 wherein R¹ is hydroxy, --OC(O)R^x or --OC(O)OR^x.

4. A compound of claim 3 wherein R^x is C_1-6 alkyl.

5. A compound of claim 3 wherein R³ is hydrogen, hydroxy or acetoxy.

6. A compound of claim 3 wherein R⁴ (O)_p is phenyl or t-butoxy.

7. A compound of claim 3 wherein R⁵ is phenyl, 2-furyl or 2-thienyl.

8. A compound of claim 1 which is 2'"'"'-O-(ethoxycarbonyl)-7-O-(phosphonooxymethyl)paclitaxel, or a pharmaceutically acceptable salt thereof.

9. The sodium salt of the compound of claim 8.

10. The triethanolamine salt of the compound of claim 8.

11. The triethylamine salt of the compound of claim 8.

12. The arginine salt of the compound of claim 8.

13. The lysine salt of the compound of claim 8.

14. The ethanolamine salt of the compound of claim 8.

15. The N-methylglucamine salt of the compound of claim 8.

16. A compound of claim 1 which is 7-O-(phosphonooxymethyl)paclitaxel, or a pharmaceutically acceptable salt thereof.

17. The sodium salt of the compound of claim 16.

18. A compound of claim 1 which is 3'"'"'-N-debenzoyl-3'"'"'-desphenyl-3'"'"'-N-(t-butyloxycarbonyl)-3'"'"'-(2-furyl)-2'"'"'-O-ethyloxycarbonyl-7-O-phosphonooxymethylpaclitaxel, or a pharmaceutically acceptable salt thereof.

19. The triethanolamine salt of the compound of claim 18.

20. A compound of claim 1 which is 3'"'"'-N-debenzoyl-3'"'"'-desphenyl-3'"'"'-N-(t-butyloxycarbonyl)-3'"'"'-(2-thienyl)-2'"'"'-O-ethyloxycarbonyl-7-O-phosphonooxymethylpaclitaxel or a pharmaceutically acceptable salt thereof.

21. The triethanolamine salt of the compound of claim 20.

22. A compound of claim 1 which is 2'"'"'-O-methoxycarbonyl-7-O-phosphonooxymethylpaclitaxel.

23. A compound of claim 1 which is 2'"'"'-O-methylcarbonyl-7-O-phosphonooxymethylpaclitaxel.

24. A compound of claim 1 which is 2'"'"'-O-n-propylcarbonyl-7-O-phosphonooxymethylpaclitaxel.

25. A compound of claim 1 wherein R¹ is --OCH₂ OP(O)(OH)₂, or a pharmaceutically acceptable salt thereof.

26. A compound of claim 25 wherein R^2'"'"' is hydrogen, R² is hydrogen, hydroxy or --OC(O)OR^x, and R^x is as defined as claim 1.

27. A compound of claim 26 wherein R³ is hydrogen, hydroxy or acetoxy.

28. A compound of claim 26 wherein R⁴ (O)_p is phenyl or t-butoxy.

29. A compound of claim 26 wherein R⁵ is phenyl.

30. A compound of claim 1 which is 2'"'"'-O-(phosphonooxymethyl)paclitaxel, or a pharmaceutically acceptable salt thereof.

31. A compound of claim 1 wherein R¹ and R² are both --OCH₂ OP(O)(OH)₂, or a pharmaceutically acceptable salt thereof.

32. A compound of claim 1 which is 2'"'"',7-O-bis(phosphonooxymethyl)paclitaxel or a pharmaceutically acceptable salt thereof.

33. The sodium salt of the compound of claim 32.

34. A compound of claim 1 wherein R¹ is --OCH₂ OCH₂ OP(O)(OH)₂, or a pharmaceutically acceptable salt thereof.

35. A compound of claim 1 which is 2'"'"'-O-phosphonooxymethoxymethyl-7-O-phosphonooxymethylpaclitaxel.

36. A compound of claim 1 which is 2'"'"'-O-phosphonooxymethoxymethylpaclitaxel, or a pharmaceutically acceptable salt thereof.

37. The triethanolamine salt of the compound of claim 36.

38. A compound of claim 1 wherein R³ is --OCH₂ OP(O)(OH)₂, or a pharmaceutically acceptable salt thereof.

39. A compound of claim 1 which is 10-desacetyl-3'"'"'-N-desbenzoyl-3'"'"'-N-(t-butyloxycarbonyl)-10-O-(phosphonooxymethyl)paclitaxel, or a pharmaceutically acceptable salt thereof.

40. The triethanolamine salt of compound of claim 39.

41. A compound of claim 1 wherein R¹ is --OCH₂ OCH₂ OCH₂ OP(O)(OH)₂.

42. A compound of claim 41 which is 2'"'"'-O-[(phosphonooxymethoxy)methoxymethyl]paclitaxel.

43. A compound of claim 41 which is 2'"'"'-O-[(phosphonooxymethoxy)methoxy]methyl-7-O-phosphonooxmethylypaclitaxel.