Claims for Patent: RE35524

Summary for Patent: RE35524

Title:	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.
Inventor(s):	Mark G. Saulnier, Peter D. Senter, John F. Kadow
Assignee:	Bristol Myers Squibb Co
Application Number:	US08/229,659
Patent Claims:	1. A compound having the formula ##STR10## wherein R6 is H and R1 is selected from the group consisting of (C1-10)alkyl; (C2-10)alkenyl; (C5-6)cycloalkyl; 2-furyl; 2-thienyl; (C6-10)aryl; (C7-14)aralkyl; and (C8-14)aralkenyl wherein each of the aromatic rings may be unsubstituted or substituted with one or more groups selected from halo, (C1-8)alkyl, (C1-8)alkoxy, hydroxy, nitro, and amino; or R1 and R6 are each (C1-8)alkyl; or R1 and R6 and the carbon to which they are attached join to form a (C5-6)cycloalkyl group;X is oxygen or sulfur; R7 R8 are independently selected from the group consisting of H, (C1-5)alkyl, halo-substituted (C1-5)alkyl, cyano-substituted (C1-5)alkyl, (C3-6)cycloalkyl, (C6-10)aryl, (C7-14)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 R1, R6 and X are as defined in claim 1; or a pharmaceutically acceptable salt thereof. 3. The compound of claim 1 wherein R6 is H and R1 is methyl or 2-thienyl. 4. The compound of claim 2 wherein R6 is H and R1 is methyl or 2-thienyl. 5. The compound of claim 2 wherein R6 is H and R1 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 R7 and R8 are the same and are selected from the group consisting of (C1-5)alkyl; halo-substituted (C1-5)alkyl; cyano-substituted (C1-5)alkyl; (C6-10)aryl; and (C7-14)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 R6 is H and R1 is methyl or 2-thienyl. 13. The compound of claim 12 wherein R1 is methyl. 14. The compound of claim 13 wherein X is oxygen. 15. The compound of claim 14 wherein R7 and R8 are each phenyl. 16. The compound of claim 14 wherein R7 and R8 are each 2,2,2-trichloroethyl. 17. The compound having the formula ##STR14## wherein R1, R6 and X are as defined in claim 1; Y is Cl, OH, or NR4 R5 ; R2, R3, R4, and R5 are each independently selected from the group consisting of H, (C1-5)alkyl, (C2-5)alkenyl, (C3-6)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 R2, R3, and the nitrogen to which they are attached together represent a 3 to 6 membered ring; or R4, R5, 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 R1 is methyl, R6 is H, and R2 and R3 are each 2-chloroethyl, Y is not NR4 R5 where R4 is H and R5 is either 3-hydroxypropyl or ##STR15## 18. The compound of claim 17 wherein R6 is H: R1 is methyl or 2-thienyl; Y is Cl or NR4 R5 ; X is oxygen or sulfur, and R2, R3, R4 and R5 are independently selected from the group consisting of H, (C1-5) alkyl, halo substituted (C1-5) alkyl, hydroxy substituted (C1-5) alkyl, and nitropyridyl disulfide substituted (C1-5) alkyl. 19. The compound of claim 18 wherein X is oxygen. 20. The compound of claim 19 wherein R1 is methyl. 21. The compound of claim 20 wherein R2 and R3 are each 2-chloroethyl; and Y is Cl. 22. The compound of claim 20 wherein Y is NR4 R5. 23. The compound of claim 22 wherein R2, R3, R4, and R5 are each ethyl. .[.24. The compound of claim 22 wherein R2 and R3 are each 2-chloroethyl; R4 is H; and R5 is 3-hydroxypropyl..]..[.25. The compound of claim 22 wherein R2 and R3 are each 2-chloroethyl; R4 is H; and R5 is .].26. An intermediate having the formula ##STR16## wherein R1, R6, and X are as defined in claim 1. 27. The compound of claim 26 wherein R6 is H; R1 methyl; and X is oxygen. 28. The compound of claim 26 wherein R6 is H; R1 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 R1, R6, 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 R1, R6, and X are as defined in claim 1, in acetonitrile or (C2-5)CN and in the presence of a trialkylamine to form a compound of formula X ##STR19## and (b) removing the phosphate protecting group.