Nuclear receptor binding agents
The present invention relates to a novel class of nuclear receptor binding agents (NRBAs). The NRBAs are applicable for use in the prevention and/or treatment of a variety of diseases and conditions including prevention and treatment of cancers such as prostate and breast cancer, osteoporosis, hormone-related diseases, inflammatory diseases, oxidative stress related disorders such as Parkinson's and stroke, neurological disorders, ophthalamic disorders, cardiovascular disease, and obesity.
1. A nuclear receptor binding agent (NRBA) represented by the structure of Formula VI:
wherein
R 1 , R 2 and R 11 are independently selected from hydrogen, COOH, —C(═NH)—OH, CHNOH, CH═CHCO 2 H, CH═CHCO 2 R, —CH═CH 2 , halogen, hydroxyl, alkoxy, cyano, nitro, CF 3 , NH 2 , 4-methoxyphenyl, 4-hydroxyphenyl, SH, COR, COOR, OCOR, alkenyl, OSO 2 CF 3 , OSO 2 CH 3 , NHR, NHCOR, N(R) 2 , sulfonamide, SO 2 R, alkyl, haloalkyl, or protected hydroxyl;
R 9 is hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, or CF 3 ;
R 10 is hydrogen, C(═NH)—OH, CHNOH, CH═CHCO 2 H, CH═CHCO 2 R, —CH═CH 2 , halogen, hydroxyl, alkoxy, cyano, nitro, CF 3 , NH 2 , 4-methoxyphenyl, 4-hydroxyphenyl, SH, COR, COOR, OCOR, alkenyl, OSO 2 CF 3 , OSO 2 CH 3 , NHR, NHCOR, N(R) 2 , sulfonamide, SO 2 R, alkyl, haloalkyl, aryl, phenyl, or protected hydroxyl;
R 3 , R 6 , R 7 and R 8 are independently selected from hydrogen, aldehyde, C(═NH)—OH, CHNOH, CH═CHCO 2 H, CH═CHCO 2 R, —CH═CH 2 , halogen, hydroxyl, alkoxy, cyano, nitro, CF 3 , NH 2 , 4-methoxyphenyl, 4-hydroxyphenyl, SH, COR, COOR, OCOR, alkenyl, OSO 2 CF 3 , OSO 2 CH 3 , NHR, NHCOR, N(R) 2 , sulfonamide, SO 2 R, alkyl, haloalkyl, or protected hydroxyl;
R′ is hydrogen, Alk or COR;
R″ is hydrogen, Alk or COR;
R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, benzyl, -Ph-CF 3 , -Ph-CH 2 F, -Ph-CHF 2 , -Ph-CF 2 CF 3 , halogen, alkenyl, CN or NO 2 ; and
Alk is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, or cyclic alkyl of 3-8 carbons.
2. A composition comprising the NRBA of claim 1 and a suitable carrier or diluent.
3. A nuclear receptor binding agent (NRBA), wherein said nuclear receptor binding agent is 4-bromo-6,8-dihydroxy-2-(4-hydroxyphenyl)isoquinolin-1(2H)-one.
4. A composition comprising the NRBA of claim 3 and a suitable carrier or diluent.
5. A nuclear receptor binding agent (NRBA), or its pharmaceutically acceptable salt, pharmaceutical product or any combination thereof, wherein said nuclear receptor binding agent is 4-chloro-6,8-dihydroxy-2-(4-hydroxyphenyl)isoquinolin-1(2H)-one.
6. A composition comprising the NRBA of claim 5 and a suitable carrier or diluent.
7. A nuclear receptor binding agent (NRBA), or its pharmaceutically acceptable salt, pharmaceutical product or any combination thereof, wherein said nuclear receptor binding agent is 4-bromo-6,8-dihydroxy-2-(3-fluoro-4-hydroxyphenyl)isoquinolin-1(2H)-one.
8. A composition comprising the NRBA of claim 7 and a suitable carrier or diluent.
9. The nuclear receptor binding agent (NRBA) of claim 1 , wherein said NRBA is a pharmaceutically acceptable salt.
10. The nuclear receptor binding agent (NRBA) of claim 1 , wherein said NRBA is an isomer.
11. The nuclear receptor binding agent (NRBA) of claim 3 , wherein said NRBA is a pharmaceutically acceptable salt.
12. A nuclear receptor binding agent (NRBA), wherein said nuclear receptor binding agent is 6,8-dihydroxy-2-(4-hydroxyphenyl)-1-oxo-1,2-dihydroisoquinolin-4-carbonitrile.
13. The nuclear receptor binding agent (NRBA) of claim 12 , wherein said NRBA is a pharmaceutically acceptable salt.