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):	Saulnier; Mark G. (Middletown, CT), Senter; Peter D. (Northeast Seattle, WA), Kadow; John F. (Wallingford, CT)
Assignee:	Bristol-Myers Squibb Company (New York, NY)
Application Number:	08/229,659
Patent Claims:	1. A compound having the formula ##STR10## wherein R.sup.6 is H and R.sup.1 is selected from the group consisting of (C.sub.1-10)alkyl; (C.sub.2-10)alkenyl; (C.sub.5-6)cycloalkyl; 2-furyl; 2-thienyl; (C.sub.6-10)aryl; (C.sub.7-14)aralkyl; and (C.sub.8-14)aralkenyl wherein each of the aromatic rings may be unsubstituted or substituted with one or more groups selected from halo, (C.sub.1-8)alkyl, (C.sub.1-8)alkoxy, hydroxy, nitro, and amino; or R.sup.1 and R.sup.6 are each (C.sub.1-8)alkyl; or R.sup.1 and R.sup.6 and the carbon to which they are attached join to form a (C.sub.5-6)cycloalkyl group; X is oxygen or sulfur; R.sup.7 R.sup.8 are independently selected from the group consisting of H, (C.sub.1-5)alkyl, halo-substituted (C.sub.1-5)alkyl, cyano-substituted (C.sub.1-5)alkyl, (C.sub.3-6)cycloalkyl, (C.sub.6-10)aryl, (C.sub.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.sup.1, R.sup.6 and X are as defined in claim 1; or a pharmaceutically acceptable salt thereof. 3. The compound of claim 1 wherein R.sup.6 is H and R.sup.1 is methyl or 2-thienyl. 4. The compound of claim 2 wherein R.sup.6 is H and R.sup.1 is methyl or 2-thienyl. 5. The compound of claim 2 wherein R.sup.6 is H and R.sup.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.sup.7 and R.sup.8 are the same and are selected from the group consisting of (C.sub.1-5)alkyl; halo-substituted (C.sub.1-5)alkyl; cyano-substituted (C.sub.1-5)alkyl; (C.sub.6-10)aryl; and (C.sub.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.sup.6 is H and R.sup.1 is methyl or 2-thienyl. 13. The compound of claim 12 wherein R.sup.1 is methyl. 14. The compound of claim 13 wherein X is oxygen. 15. The compound of claim 14 wherein R.sup.7 and R.sup.8 are each phenyl. 16. The compound of claim 14 wherein R.sup.7 and R.sup.8 are each 2,2,2-trichloroethyl. 17. The compound having the formula ##STR14## wherein R.sup.1, R.sup.6 and X are as defined in claim 1; Y is Cl, OH, or NR.sup.4 R.sup.5 ; R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are each independently selected from the group consisting of H, (C.sub.1-5)alkyl, (C.sub.2-5)alkenyl, (C.sub.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.sup.2, R.sup.3, and the nitrogen to which they are attached together represent a 3 to 6 membered ring; or R.sup.4, R.sup.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.sub.1 is methyl, R.sub.6 is H, and R.sup.2 and R.sup.3 are each 2-chloroethyl, Y is not NR.sup.4 R.sup.5 where R.sup.4 is H and R.sup.5 is either 3-hydroxypropyl or ##STR15## 18. The compound of claim 17 wherein R.sup.6 is H: R.sup.1 is methyl or 2-thienyl; Y is Cl or NR.sup.4 R.sup.5 ; X is oxygen or sulfur, and R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are independently selected from the group consisting of H, (C.sub.1-5) alkyl, halo substituted (C.sub.1-5) alkyl, hydroxy substituted (C.sub.1-5) alkyl, and nitropyridyl disulfide substituted (C.sub.1-5) alkyl. 19. The compound of claim 18 wherein X is oxygen. 20. The compound of claim 19 wherein R.sup.1 is methyl. 21. The compound of claim 20 wherein R.sup.2 and R.sup.3 are each 2-chloroethyl; and Y is Cl. 22. The compound of claim 20 wherein Y is NR.sup.4 R.sup.5. 23. The compound of claim 22 wherein R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are each ethyl. .[.24. The compound of claim 22 wherein R.sup.2 and R.sup.3 are each 2-chloroethyl; R.sup.4 is H; and R.sup.5 is 3-hydroxypropyl..]..[.25. The compound of claim 22 wherein R.sup.2 and R.sup.3 are each 2-chloroethyl; R.sup.4 is H; and R.sup.5 is .].26. An intermediate having the formula ##STR16## wherein R.sup.1, R.sup.6, and X are as defined in claim 1. 27. The compound of claim 26 wherein R.sup.6 is H; R.sup.1 methyl; and X is oxygen. 28. The compound of claim 26 wherein R.sup.6 is H; R.sup.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.sup.1, R.sup.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).sub.2, wherein Hal is a halogen, G is a phosphate protecting group, and R.sub.1, R.sub.6, and X are as defined in claim 1, in acetonitrile or (C.sub.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.