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US RE35,524 EGranted
Epipodophyllotoxin glucoside 4'-phosphate derivatives
AssigneeBristol-Myers Squibb Company
InventorsMark G. Saulnier, Peter D. Senter, John F. Kadow
Life of this patent
Estimating the term…
Abstract
Phosphate derivatives of 4'-demethylepipodophyllotoxin glucosides are novel antitumor agents and the salts thereof offer the pharmaceutical advantage of high water solubility.
Claims25
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.
9 more elements
The compound etoposide 4'-phosphate disodium salt. ##STR12##
The compound etoposide 4'-thiophosphate disodium salt. ##STR13##
[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.
10 more elements
Dependencies are inferred from the claim text.