Mono- and di-phosphates of 3-(3-fluoro-4-hydroxy-phenyl)-7-hydroxy-naphthalene-1-carbonitrile
Compounds of formula II wherein each R 1 and R 2 is independently selected from H and —P(O)(R 3 )(R 4 ), provided that at least one of R 1 and R 2 is —P(O)(R 3 )(R 4 ); each R 3 and R 4 is independently selected from the group consisting of H, —OH, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy; or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions comprising a compound of formula II, and methods of administering such compounds and compositions.
1. A compound of formula II
wherein each R 1 , and R 2 is independently selected from H and —P(O)(R 3 )(R 4 ), provided that at least one of R 1 and R 2 is —P(O)(R 3 )(R 4 );
each R 3 , and R 4 is independently selected from the group consisting of H, —OH, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein each of R 1 and R 2 is —P(O)(R 3 )(R 4 ).
3. The compound of claim 1 , wherein each R 3 and R 4 is —OH.
4. The compound of claim 1 , wherein R 3 and R 4 are independently C 1 -C 6 alkyl or C 1 -C 6 alkoxy.
5. The compound of claim 4 , wherein each R 3 and R 4 are the same.
6. A pharmaceutical composition comprising a compound of formula II
wherein each R 1 , and R 2 is independently selected from H and —P(O)(R 3 )(R 4 ), provided that at least one of R 1 and R 2 is —P(O)(R 3 )(R 4 );
each R 3 , and R 4 is independently selected from the group consisting of H, —OH, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy;
or a pharmaceutically acceptable salt thereof; and
a pharmaceutically acceptable carrier or excipient.
7. The composition of claim 6 , wherein each of R 1 and R 2 is —P(O)(R 3 )(R 4 ).
8. The composition of claim 6 , wherein each R 3 and R 4 is —OH.
9. The composition of claim 6 , wherein R 3 and R 4 are independently C 1 -C 6 alkyl or C 1 -C 6 alkoxy.
10. The composition of claim 9 , wherein each R 3 and R 4 are the same.
11. A method of administering a compound of formula I
comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound of formula II
wherein each R 1 , and R 2 is independently selected from H and —P(O)(R 3 )(R 4 ), provided that at least one of R 1 and R 2 is —P(O)(R 3 )(R 4 );
each R 3 , and R 4 is independently selected from the group consisting of H, —OH, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy;
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 11 , wherein each of R 1 and R 2 is —P(O)(R 3 )(R 4 ).
13. The compound of claim 11 , wherein each R 3 and R 4 is —OH.
14. The compound of claim 11 , wherein R 3 and R 4 are independently C 1 -C 6 alkyl or C 1 -C 6 alkoxy.
15. The compound of claim 14 , wherein each R 3 and R 4 are the same.
16. A method for preparing compounds of formula II, comprising:
dissolving a compound of formula 1
and tetrazole in an organic solvent or mixture of solvents;
adding a diisopropyl-phosphoramidite;
adding 30% hydrogen peroxide;
reducing excess hydrogen peroxide;
extracting the reaction mixture to produce an intermediate;
reacting said intermediate with ethyl acetetate and HCl to obtain the desired product.
17. The method of claim 16 , wherein said diisopropyl-phosphoramidite is di-tert-butyl diisopropyl-phosphoramidite.
18. The method of claim 16 , wherein said organic solvent or mixture of solvents is a mixture of tetrahydrofuran and methylene chloride.
19. The method of claim 18 , wherein said mixture is a 1:1 mixture of tetrahydrofuran and methylene chloride.
20. A method of making compounds of formula I wherein R 1 and R 2 are both PO(OH) 2 , comprising:
dissolving a compound of formula 1 and pyridine in an organic solvent;
adding resultant solution to cold (0° C.) phosphorous oxychloride.
21. The method of claim 20 , wherein said organic solvent is dichloromethane.
22. A method of preparing a monophosphate compound of formula I, comprising:
dissolving diphosphate compound 3
in water;
adding alkaline phosphatase enzyme gradually.
23. A method for treating sepsis in a patient in need thereof, comprising administering a pharmaceutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
24. A method for treating rheumatoid arthritis in a patient in need thereof, comprising administering a pharmaceutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
25. A method for treating endometriosis in a patient in need thereof, comprising administering a pharmaceutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
26. A method for treating fibroids in a patient in need thereof, comprising administering a pharmaceutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.