Estrogen receptor ligands and methods of use thereof
The present invention relates to methods of treating androgen deprivation therapy (ADT) induced hot flashes and severe hot flashes in a subject.
1. A method of treating androgen deprivation therapy (ADT) induced hot flashes in a subject comprising administering a therapeutically effective amount of a compound of formula I, or its optical isomer or pharmaceutical acceptable salt, or any combination thereof:
wherein
Y is C(O) or CH 2 ;
R 1 , R 2 are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF 3 , N(R) 2 , sulfonamide, SO 2 R, alkyl, haloalkyl, aryl, O-Alk-NR 5 R 6 or O-Alk-heterocycle in which the heterocycle is a 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic;
R 3 , R 4 are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF 3 , NHCOR, N(R) 2 , sulfonamide, SO 2 R, alkyl, haloalkyl, aryl or protected hydroxyl;
R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl, CN, NO 2 , or OH;
R 5 and R 6 are independently hydrogen, phenyl, an alkyl group of 1 to 6 carbon atoms, a 3 to 7 membered cycloalkyl, a 3 to 7 membered heterocycle, a 5 to 7 membered aryl; or R 5 and R 6 form a 3 to 7 membered ring with the nitrogen atom;
j and k are independently 1-4;
Alk is linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, or cyclic alkyl of 3-8 carbons.
2. The method of claim 1 , wherein said compound of formula I is selected from:
3. The method of claims 1 , wherein said subject is human.
4. The method of claim 3 , wherein said human subject is male.
5. The method of claims 1 , wherein said subject has prostate cancer.
6. The method of claim 5 , wherein said prostate cancer is advanced prostate cancer.
7. A method of reducing the incidence of, suppressing, or inhibiting androgen deprivation therapy (ADT) induced hot flashes in a subject comprising administering a therapeutically effective amount of a compound of formula I, or its optical isomer or pharmaceutical acceptable salt, or any combination thereof:
wherein
Y is C(O) or CH 2 ;
R 1 , R 2 are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF 3 , N(R) 2 , sulfonamide, SO 2 R, alkyl, haloalkyl, aryl, O-Alk-NR 5 R 6 or O-Alk-heterocycle in which the heterocycle is a 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic;
R 3 , R 4 are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF 3 , NHCOR, N(R) 2 , sulfonamide, SO 2 R, alkyl, haloalkyl, aryl or protected hydroxyl;
R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl, CN, NO 2 , or OH;
R 5 and R 6 are independently hydrogen, phenyl, an alkyl group of 1 to 6 carbon atoms, a 3 to 7 membered cycloalkyl, a 3 to 7 membered heterocycle, a 5 to 7 membered aryl; or R 5 and R 6 form a 3 to 7 membered ring with the nitrogen atom;
j and k are independently 1-4;
Alk is linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, or cyclic alkyl of 3-8 carbons.
8. The method of claim 7 , wherein said compound of formula I is selected from:
9. The method of claims 7 , wherein said subject is human.
10. The method of claim 9 , wherein said human subject is male.
11. The method of claims 7 , wherein said subject has prostate cancer.
12. The method of claim 11 , wherein said prostate cancer is advanced prostate cancer.
13. A method of treating androgen deprivation therapy (ADT) induced severe hot flashes in a subject comprising administering a therapeutically effective amount of a compound of formula I, or its optical isomer or pharmaceutical acceptable salt, or any combination thereof:
wherein
Y is C(O) or CH 2 ;
R 1 , R 2 are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF 3 , N(R) 2 , sulfonamide, SO 2 R, alkyl, haloalkyl, aryl, O-Alk-NR 5 R 6 or O-Alk-heterocycle in which the heterocycle is a 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic;
R 3 , R 4 are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF 3 , NHCOR, N(R) 2 , sulfonamide, SO 2 R, alkyl, haloalkyl, aryl or protected hydroxyl;
R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl, CN, NO 2 , or OH;
R 5 and R 6 are independently hydrogen, phenyl, an alkyl group of 1 to 6 carbon atoms, a 3 to 7 membered cycloalkyl, a 3 to 7 membered heterocycle, a 5 to 7 membered aryl; or R 5 and R 6 form a 3 to 7 membered ring with the nitrogen atom;
j and k are independently 1-4;
Alk is linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, or cyclic alkyl of 3-8 carbons.
14. The method of claim 13 , wherein said compound of formula I is selected from:
15. The method of claims 13 , wherein said subject is human.
16. The method of claim 15 , wherein said human subject is male.
17. The method of claims 13 , wherein said subject has prostate cancer.
18. The method of claim 17 , wherein said prostate cancer is advanced prostate cancer.
19. A method of reducing the incidence of, suppressing, or inhibiting androgen deprivation therapy (ADT) induced severe hot flashes in a subject comprising administering a therapeutically effective amount of a compound of formula I, or its optical isomer or pharmaceutical acceptable salt, or any combination thereof:
wherein
Y is C(O) or CH 2 ;
R 1 , R 2 are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF 3 , N(R) 2 , sulfonamide, SO 2 R, alkyl, haloalkyl, aryl, O-Alk-NR 5 R 6 or O-Alk-heterocycle in which the heterocycle is a 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic;
R 3 , R 4 are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF 3 , NHCOR, N(R) 2 , sulfonamide, SO 2 R, alkyl, haloalkyl, aryl or protected hydroxyl;
R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl, CN, NO 2 , or OH;
R 5 and R 6 are independently hydrogen, phenyl, an alkyl group of 1 to 6 carbon atoms, a 3 to 7 membered cycloalkyl, a 3 to 7 membered heterocycle, a 5 to 7 membered aryl; or R 5 and R 6 form a 3 to 7 membered ring with the nitrogen atom;
j and k are independently 1-4;
Alk is linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, or cyclic alkyl of 3-8 carbons.
20. The method of claim 19 , wherein said compound of formula I is selected from:
21. The method of claims 19 , wherein said subject is human.
22. The method of claim 21 , wherein said human subject is male.
23. The method of claims 19 , wherein said subject has prostate cancer.
24. The method of claim 23 , wherein said prostate cancer is advanced prostate cancer.