Benzoate derivatives of taxol

Abstract

This invention relates to a compound of formula I ##STR1## or a pharmaceutically acceptable salt thereof, in which R 2 is a radical of the formula ##STR2## in which R a and R b are independently hydrogen or C 1-6 alkyl, said C 1-6 alkyl being optionally substituted with hydroxy, phosphono, phosphonooxy, carboxy or di(C 1-6 alkyl) amino; or NR a R b together represents a radical of the formula ##STR3## in which y is one to three, and R a is as defined above; R p and R r are independently same or different C 1-6 alkyl; R 1 is hydrogen or a radical Z of the formula ##STR4## in which Q is --(CH 2 ) f --, optionally substituted with one to six same or different C 1-6 alkyl or C 3-6 cycloalkyl, or a carbon atom of said --(CH 2 ) f -- radical may also be a part of C 3-6 cycloalkylidene; R 3 and R 4 are independently hydrogen or C 1-6 alkyl, or R 3 and R 4 taken together with the carbon atom to which they are attached form C 3-6 cycloalkylidene; R 5 is --OC(═O)R, --OP═O(OH) 2 or --CH 2 OP═O(OH) 2 , in which R is C 1-6 alkyl; R 6 , R 7 , R 8 and R 9 are independently halogen, C 1-6 alkyl, C 1-6 alkoxy or hydrogen, but when R 5 is --OC(═O)R, one of R 6 , R 7 , R 8 or R 9 is --OP═O(OH) 2 ; f is 2 to 6; n is O, and m is 1 or 0 when R 5 is --CH 2 OP═O(OH) 2 ; and n is 1 or 0, and m is 1 when R 5 is --OC(═O)R or --OP═O(OH) 2 . Also provided by this invention are pharmaceutical formulations and a method for treating mammalian tumors with a compound of formula I.

What is claimed: 
     
       1. A compound of formula I ##STR63## or a pharmaceutically acceptable salt thereof, in which R 2  is a radical of the formula ##STR64##  in which R a  and R b  are independently hydrogen or C 1-6  alkyl, said C 1-6  alkyl being optionally substituted with hydroxy, phosphono, phosphonooxy, carboxy or di(C 1-6  alkyl)amino; or NR a  R b  together represents a radical of the formula ##STR65## in which y is one to three, and R a  is as defined above; R p  and R r  are independently same or different C 1-6  alkyl; R 1  is hydrogen or a radical Z of the formula ##STR66## in which Q is --(CH 2 ) f  --, optionally substituted with one to six same or different C 1-6  alkyl or C 3-6  cycloalkyl, or a carbon atom of said --(CH 2 ) f  -- radical may also be a part of C 3-6  cycloalkylidene;   R 3  and R 4  are independently hydrogen or C 1-6  alkyl, or R 3  and R 4  taken together with the carbon atom to which they are attached form C 3-6  cycloalkylidene;   R 5  is --OC(═O)R, --OP═O(OH) 2  or --CH 2  OP═O(OH) 2 , in which R is C 1-6  alkyl;   R 6 , R 7 , R 8  and R 9  are independently halogen, C 1-6  alkyl, C 1-6  alkoxy or hydrogen, but when R 5  is --OC(═O)R, one of R 6 , R 7 , R 8  or R 9  is --OP═O(OH) 2  ; f is 2 to 6;   n is O, and m is 1 or 0 when R 5  is --CH 2  OP═O(OH) 2  ; and n is 1 or 0, and m is 1 when R 5  is --OC(═O)R or --OP═O(OH) 2 .   
     
     
       2. A compound as claimed in claim 1 in which R 1  is hydrogen; R a  and R b  are same or different C 1-6  alkyl, said C 1-6  alkyl being optionally substituted with hydroxy, phosphonooxy or di (C 1-6  alkyl) amino, with the proviso that hydroxy or di(C 1-6  alkyl)amino is not attached to a carbon atom adjacent to nitrogen; or NR a  R b  together represents a radical of the formula ##STR67## 
     
     
       3. The compound of claim 2 that is 2'-[4-(diethylaminomethyl)benzoate]taxol. 
     
     
       4. The compound of claim 2 that is 2'-[4(morpholinomethyl)benzoate]taxol. 
     
     
       5. The compouud of claim 2 that is 2'-[4-[1-(piperidinyl)methyl]benzoate]taxol. 
     
     
       6. The compound of claim 2 that is 2'-[4-[[(diethanolamino)methyl]benzoate]taxol. 
     
     
       7. The compound of claim 2 that is 2'-[4-[(4-methyl-1-piperazinyl)methyl]benzoate]taxol. 
     
     
       8. The compound of claim 2 that is 2'-[4-[[4-(2-hydroxyethyl)-1-piperazinyl]methyl]benzoate]taxol. 
     
     
       9. The compound of claim 2 that is 2'-[4-[[4-(2-hydroxyethyl)-1-piperidinyl]methyl]benzoate]taxol. 
     
     
       10. The compound of claim 2 that is 2'-[4-[[2-S-(hydroxymethyl)-1-pyrrolidinyl]methyl]benzoate]taxol. 
     
     
       11. The compound of claim 2 that is 2'-[4- [(N,N,N'-trimethylethylenediamino)methyl]benzoate]taxol. 
     
     
       12. The compound of claim 2 that is 2'-[4-[(N,N,N'-trimethyl-1,3-propanediamino)methyl]benzoate]taxol. 
     
     
       13. The compound of claim 2 that is 2'-[4-(dimethylamino)benzoate]taxol. 
     
     
       14. The compound of claim 2 that is 2'-[4-[[4-[2-(phosphonooxy)ethyl]-1-piperazinyl]methyl]benzoate]taxol. 
     
     
       15. The compound of claim 2 that is 2'-[4-[[[bis(2-phosphonooxy)ethyl]amino]methyl]benzoate]taxol. 
     
     
       16. A pharmaceutical formulation which comprises as an active ingredient a compound as claimed in any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, associated with one or more pharmaceutically acceptable carriers, excipients or diluents therefor. 
     
     
       17. A method for treating mammalian tumors which comprises administering to a mammal a tumor sensitive amount of a compound as claimed in any one of claims 1 to 15.