Semi-synthetic taxanes with antitumor and antiangiogenetic activities

Abstract

Seco-baccatin III derivatives of formula: wherein R, R 1 -R 4 , R 1 R′, R 11 R″, and R 111 R′″ are disclosed herein; pharmaceutical compositions comprising seco-baccatin III derivative; and methods for treating cancer, arthritis, and inhibiting angiogenesis in an animal comprising administrating to a patient in need thereof a therapeutically effective amount of a seco-baccatin III derivative are disclosed.

1. A compound of formula: 
                 
 wherein R and R 1  are each independently hydrogen, a C 1 -C 18  acyl group, an aroyl group which may be substituted or unsubstituted, or —CONR 6 R 7 ;  
 R 2  is hydrogen or R 2  forms a carbonate or thiocarbonate  with R 3 ;  
 R 3  is hydrogen,  hydrogen or —OH, or R 3  forms a carbonate or thiocarbonate  with R 2 ;  
 R 4  is a benzoyl group which is unsubstituted or substituted at the meta position or a hetaroyl group;  
 R 6  and R 7  are a C 1 -C 4  alkyl group, a benzyl group, or a phenyl group;  
 R 1 R′ is hydrogen or a C 1 -C 4  alkyl group;  
 R 11 R″ is a C 1 -C 4  alkyl group, a C 2 -C 6  alkenyl group, an aryl group, or a hetaryl group; and  
 R 111 R′″ is a C 1 -C 4  alkyl group, a C 1 -C 18  acyl group, an aryl group, or a tert-butoxy group, with the proviso that both R and R 1  cannot be hydrogen.  
 
     
     
       2. The compound of  claim 1 , wherein both R and R 1  are a C 1 -C 18  acyl group, an aroyl group which may be substituted or unsubstituted, or —CONR 6 R 7 ;
 R 2  is hydrogen;  
 R 3  is hydrogen;  
 R 4  is benzoyl;  
 R 1 R′ is hydrogen or methyl;  
 R 11 R″ is a C 1 -C 4  alkyl group or a C 2 -C 6  alkenyl group; and  
 R 111 R′″ is a tert-butoxy group.  
 
     
     
       3. The compound of  claim 2 , wherein R and R 1  are acetyl or 3,4,5-trimethoxybenzoyl. 
     
     
       4. The compound of  claim 2 , wherein R 11   R″ is isobutyl or isobutenyl. 
     
     
       5. The compound of  claim 1 , wherein R and R 1  are acetyl or 3,4,5-trimethoxybenzoyl and R 11   R″ is isobutyl or isobutenyl. 
     
     
       6. The compound of  claim 1 , wherein R is hydrogen;
 R 1  is a C 1 -C 18  acyl group, an aroyl group which may be substituted or unsubstituted, or —CONR 6 R 7 ;  
 R 2  and R 3  are hydrogen;  
 R 4  is benzoyl;  
 R 1 R′ is hydrogen or methyl;  
 R 11 R″ is a C 1 -C 4  alkyl group, a C 2 -C 6  alkenyl group; and  
 R 111 R′″ is a tert-butoxy group.  
 
     
     
       7. The compound of  claim 1 , selected from the group consisting of
 13-[(2R, 3S)-3-iso-butyl-2-hydroxy-3-tert-butoxycarbonylamino-propanoyl]-C-seco-10-dehyrdo-10-deacetyl-7,9-bis-acetyl-baccatine III 
   13 - [ (   2 R,  3 S )-   3   - iso - butyl -   2   - hydroxy -   3   - tert - butoxycarbonylamino - propanoyl] - C - seco -   10   - dehydro -   10   - deacetyl -   7 , 9   - bis - acetyl - baccatine III ;  
 13-[(2R, 3S)-3-phenyl-2-hydroxy-3-tert-butoxycarbonylamino-propanoyl]-C-seco-10-dehyrdo-10-deacetyl-7,9-bis-acetyl-baccatine III 
   13 - [ (   2 R,  3 S )-   3   - phenyl -   2   - hydroxy -   3   - tert - butoxycarbonylamino - propanoyl] - C - seco -   10   - dehydro -   10   - deacetyl -   7 , 9   - bis - acetyl - baccatine III ;  
 13-[(2R, 3S)-3-phenyl-2-hydroxy-3-tert-butoxycarbonylamino-propanoyl]-C-seco-10-dehyrdo-10-deacetyl-7,9-bis-trimethoxybenzoyl-baccatine III 
   13 - [ (   2 R,  3 S )-   3   - phenyl -   2   - hydroxy -   3   - tert - butoxycarbonylamino - propanoyl] - C - seco -   10   - dehydro -   10   - deacetyl -   7 , 9   - bis - trimethoxybenzoyl - baccatine III ;  
 13-[(2R, 3S)-3-phenyl-2-hydroxy-3-tert-butoxycarbonylamino-propanoyl]-C-seco-10-dehyrdo-10-deacetyl-7,9-bis-acetyl-baccatine III 1,14-carbonate 
   13 - [ (   2 R,  3 S )-   3   - phenyl -   2   - hydroxy -   3   - tert - butoxycarbonylamino - propanoyl] - C - seco -   10   - dehydro -   10   - deacetyl -   7 , 9   - bis - acetyl - baccatine III  1 , 14   - carbonate .  
 
     
     
       8. A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       9. A pharmaceutical composition comprising the compound of  claim 2  and a pharmaceutically acceptable carrier. 
     
     
       10. A pharmaceutical composition comprising the compound of  claim 3  and a pharmaceutically acceptable carrier. 
     
     
       11. A pharmaceutical composition comprising the compound of  claim 4  and a pharmaceutically acceptable carrier. 
     
     
       12. A pharmaceutical composition comprising the compound of  claim 5  and a pharmaceutically acceptable carrier. 
     
     
       13. A pharmaceutical composition comprising the compound of  claim 6  and a pharmaceutically acceptable carrier. 
     
     
       14. A pharmaceutical composition comprising the compound of  claim 7  and a pharmaceutically acceptable carrier. 
     
     
       15. A method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of the compound of  claim 1 . 
     
     
       16. The method of  claim 15 , wherein the compound is administered to the patient intravenously in an amount of up to 600 mg/m 2 . 
     
     
       17. The method of  claim 15 , wherein the compound is administered to the patient orally in an amount of up to 1000 mg/m 2 . 
     
     
       18. A method of treating rheumatoid arthritis comprising administering to a patient in need thereof a therapeutically effective amount of the compound of  claim 1 . 
     
     
       19. The method of  claim 18 , wherein the compound is administered to the patient in an amount of up to 50 mg/m 2 . 
     
     
       20. A method of inhibiting angiogenesis comprising administering to a patient in need there of a therapeutically effective amount of the compound of  claim 1 .