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Details for Patent: 4,904,768

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Details for Patent: 4,904,768

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. (Seattle, WA), Kadow; John F. (Meriden, CT)
Assignee: Bristol-Myers Company (New York, NY)
Filing Date:May 27, 1988
Application Number:07/199,731
Claims:1. A compound having the formula ##STR10## wherein R.sup.6 is H and R.sup.1 is selected from the group consistng 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 and 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. A 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.

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 ##STR15##

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 is 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.
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