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 compound having the following structure (I):
or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
i) R 1 is —P(═O)(OH) 2 , and R 2 and R 3 are each H;
ii) R 2 is —P(═O)(OH) 2 , and R 1 and R 3 are each H; or
iii) R 3 is —P(═O)(OH) 2 , and R 1 and R 2 are each H.
2. The compound of claim 1 , having the following structure (I′):
3. The compound of claim 1 , having the following structure (IA):
4. The compound of claim 3 , having the following structure (IA′):
5. The compound of claim 1 , having the following structure (IB):
6. The compound of claim 5 , having the following structure (IB′):
7. The compound of claim 1 , having the following structure (IC):
8. The compound of claim 7 , having the following structure (IC′):
9. A pharmaceutically acceptable salt of a compound according to claim 1 .
10. The pharmaceutically acceptable salt of claim 9 , wherein the pharmaceutically acceptable salt is a base addition salt.
11. The pharmaceutically acceptable salt of claim 10 , wherein the pharmaceutically acceptable salt is a sodium salt.
12. The pharmaceutically acceptable salt of claim 9 , wherein the pharmaceutically acceptable salt is an acid addition salt.
13. The pharmaceutically acceptable salt of claim 12 , wherein the pharmaceutically acceptable salt is a hydrochloride salt.