Alvocidib prodrugs having increased bioavailability
Compounds having the following structure (I): or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein one of R 1 , R 2 or R 3 is —P(═O)(OH) 2 , and the other two of R 1 , R 2 and R 3 are each H, are provided. Pharmaceutical compositions comprising the compounds, and methods for use of the compounds for treating diseases associated with overexpression of a cyclin-dependent kinase (CDK) are also provided.
1. A method for preparing a compound of structure (I):
or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
one of R 1 , R 2 or R 3 is —P(═O)(OH) 2 , and the other two of R 1 , R 2 and R 3 are each H,
the method comprising adding a phosphate group to one of three free hydroxyls of alvocidib, or a salt or solvate thereof.
2. The method of claim 1 , wherein the compound has the following structure (I′):
3. The method of claim 1 , wherein the compound has the following structure (IA):
4. The method of claim 3 , wherein the compound has the following structure (IA′):
5. The method of claim 1 , wherein the compound has the following structure (IB):
6. The method of claim 5 , wherein the compound has the following structure (IB′):
7. The method of claim 1 , wherein the compound has the following structure (IC):
8. The method of claim 7 , wherein the compound has the following structure (IC′):
9. The method of claim 1 , further comprising treating the compound of structure (I) with an inorganic or organic base or acid to convert the compound of structure (I) to a pharmaceutically acceptable salt of the compound of structure (I).
10. The method of claim 1 , further comprising converting a salt of the compound of structure (I) to its free base or acid form.