Epipodophyllotoxin glucoside 4'-phosphate derivatives

Abstract

Phosphate derivatives of 4'-demethylepipodophyllotoxin glucosides are novel antitumor agents and the salts thereof offer the pharmaceutical advantage of high water solubility.

What is claimed is: 
     
       1. A compound having the formula ##STR10## wherein R 6  is H and R 1  is selected from the group consisting of (C 1-10 )alkyl; (C 2-10 )alkenyl; (C 5-6 )cycloalkyl; 2-furyl; 2-thienyl; (C 6-10 )aryl; (C 7-14 )aralkyl; and (C 8-14 )aralkenyl wherein each of the aromatic rings may be unsubstituted or substituted with one or more groups selected from halo, (C 1-8 )alkyl, (C 1-8 )alkoxy, hydroxy, nitro, and amino; or R 1  and R 6  are each (C 1-8 )alkyl; or R 1  and R 6  and the carbon to which they are attached join to form a (C 5-6 )cycloalkyl group; X is oxygen or sulfur;   R 7  R 8  are independently selected from the group consisting of H, (C 1-5 )alkyl, halo-substituted (C 1-5 )alkyl, cyano-substituted (C 1-5 )alkyl, (C 3-6 )cycloalkyl, (C 6-10 )aryl, (C 7-14 )aralkyl, wherein the ring portion of said aryl and aralkyl groups is unsubstituted or substituted with a group selected from the group consisting of alkyl, halo, and nitro; or a pharmaceutically acceptable salt thereof.     
     
     
       2. The compound of claim 1 having the formula ##STR11## wherein R 1 , R 6  and X are as defined in claim 1; or a pharmaceutically acceptable salt thereof. 
     
     
       3. The compound of claim 1 wherein R 6  is H and R 1  is methyl or 2-thienyl. 
     
     
       4. The compound of claim 2 wherein R 6  is H and R 1  is methyl or 2-thienyl. 
     
     
       5. The compound of claim 2 wherein R 6  is H and R 1  is methyl. 
     
     
       6. The compound of claim 5 wherein X is oxygen. 
     
     
       7. The compound of claim 5 wherein X is sulfur. 
     
     
       8. The compound of claim 2 wherein the pharmaceutically acceptable salt is the sodium salt. 
     
     
       9. The compound etoposide 4'-phosphate disodium salt. ##STR12## 
     
     
       10. The compound etoposide 4'-thiophosphate disodium salt. ##STR13## 
     
     
       11. The compound of claim 1 wherein R 7  and R 8  are the same and are selected from the group consisting of (C 1-5 )alkyl; halo-substituted (C 1-5 )alkyl; cyano-substituted (C 1-5 )alkyl; (C 6-10 )aryl; and (C 7-14 )aralkyl; wherein the ring portion of said aryl and aralkyl groups is unsubstituted or substituted with a group selected from alkyl, halo, and nitro. 
     
     
       12. The compound of claim 11 wherein R 6  is H and R 1  is methyl or 2-thienyl. 
     
     
       13. The compound of claim 12 wherein R 1  is methyl. 
     
     
       14. The compound of claim 13 wherein X is oxygen. 
     
     
       15. The compound of claim 14 wherein R 7  and R 8  are each phenyl. 
     
     
       16. The compound of claim 14 wherein R 7  and R 8  are each 2,2,2-trichloroethyl. 
     
     
       17. The compound having the formula ##STR14## wherein R 1 , R 6  and X are as defined in claim 1; Y is Cl, OH, or NR 4  R 5  ; R 2 , R 3 , R 4 , and R 5  are each independently selected from the group consisting of H, (C 1-5 )alkyl, (C 2-5 )alkenyl, (C 3-6 )cycloalkyl; wherein said alkyl, alkenyl, cycloalkyl may be unsubstituted or substituted with one or more of a group selected from the group consisting of hydroxy, alkoxy, halo, mercapto, cyano, alkylthio, alkanoylamino, dialkylamino, alkylamino, and nitropyridyl disulfide, or R 2 , R 3 , and the nitrogen to which they are attached together represent a 3 to 6 membered ring; or R 4 , R 5 , and the nitrogen to which they are attached together represent a 3 to 6 membered ring; or a pharmaceutically acceptable salt thereof.Iadd., provided that when R 1  is methyl, R 6  is H, and R 2  and R 3  are each 2-chloroethyl, Y is not NR 4  R 5  where R 4  is H and R 5  is either 3-hydroxypropyl or ##STR15## 
     
     
       18. The compound of claim 17 wherein R 6  is H: R 1  is methyl or 2-thienyl; Y is Cl or NR 4  R 5  ; X is oxygen or sulfur, and R 2 , R 3 , R 4  and R 5  are independently selected from the group consisting of H, (C 1-5 ) alkyl, halo substituted (C 1-5 ) alkyl, hydroxy substituted (C 1-5 ) alkyl, and nitropyridyl disulfide substituted (C 1-5 ) alkyl. 
     
     
       19. The compound of claim 18 wherein X is oxygen. 
     
     
       20. The compound of claim 19 wherein R 1  is methyl. 
     
     
       21. The compound of claim 20 wherein R 2  and R 3  are each 2-chloroethyl; and Y is Cl. 
     
     
       22. The compound of claim 20 wherein Y is NR 4  R 5 . 
     
     
       23. The compound of claim 22 wherein R 2 , R 3 , R 4 , and R 5  are each ethyl. .[.24. The compound of claim 22 wherein R 2  and R 3  are each 2-chloroethyl; R 4  is H; and R 5  is 3-hydroxypropyl..]..[.25. The compound of claim 22 wherein R 2  and 
     
     
        R 3  are each 2-chloroethyl; R 4  is H; and R 5  is .].26. An intermediate having the formula ##STR16## 
     
     
        wherein R 1 , R 6 , and X are as defined in claim 1. 27. The compound of claim 26 wherein R 6  is H; R 1  methyl; and X is 
     
     
        oxygen. 28. The compound of claim 26 wherein R 6  is H; R 1  is 
     
     
        methyl; and X is sulfur. 29. A pharmaceutical composition which comprises an antitumor effective amount of a compound of claim 1 or claim 17, and a 
     
     
        pharmaceutically acceptable carrier. 30. A composition according to claim 
     
     
        29 wherein said compound is etoposide 4'-phosphate disodium salt. 31. A process for preparing a compound of the formula ##STR17## wherein R 1 , R 6 , and X are as defined in claim 1 or a pharmaceutically acceptable salt thereof which comprises the steps of: (a) reacting a compound of formula IX ##STR18## with a compound of the formula Hal-P(X)(O-G) 2 , wherein Hal is a halogen, G is a phosphate protecting group, and R 1 , R 6 , and X are as defined in claim 1, in acetonitrile or (C 2-5 )CN and in the presence of a trialkylamine to form a compound of formula X ##STR19## and (b) removing the phosphate protecting group.