Selective androgen receptor modulators
View Patent ↗This invention provides compounds of formula I, pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable excipient, methods of modulating the androgen receptor, methods of treating diseases beneficially treated by an androgen receptor modulator (e.g., sarcopenia, prostate cancer, contraception, type 2 diabetes related disorders or diseases, anemia, depression, and renal disease) and processes for making compounds and intermediates useful in the preparation of same.
1. A compound according to formula I:
wherein R x is CN, Cl, Br, or NO 2 ;
R y is CH 3 , CF 3 , or halogen;
R z is hydrogen or optionally C 1-3 alkyl, C 2-3 alkenyl, C 1-3 hydroxyalkyl, C 1-3 haloalkyl, NO 2 , NH 2 , OMe, halogen or OH;
P 1 is hydrogen or a metabolically labile group;
R a and R b are each independently selected from hydrogen or C 1 -C 3 alkyl; and
X is O;
or pharmaceutically acceptable salts thereof.
2. A compound according to claim 1 , wherein:
R x is CN; or
pharmaceutically acceptable salts thereof.
3. A compound according to claim 1 , wherein:
R y is CF 3 or Cl; or
pharmaceutically acceptable salts thereof.
4. A compound according to claim 1 , wherein:
R z is H, CH 3 , CF 3 or Cl; or
pharmaceutically acceptable salts thereof.
5. A compound according to claim 1 , wherein:
R x is CN;
R y is CF 3 or Cl;
R z is H or CH 3 ; or
pharmaceutically acceptable salts thereof.
6. A compound according to claim 1 , wherein:
P 1 is hydrogen or (C═O)—C 1-6 alkyl; or
pharmaceutically acceptable salts thereof.
7. A compound according to claim 1 , wherein:
P 1 is hydrogen.
8. A compound according to claim 1 , wherein:
R a and R b are each independently selected from hydrogen and CH 3 ; or
pharmaceutically acceptable salts thereof.
9. A compound according to claim 1 , wherein:
R a is CH 3 and R b is hydrogen; or
R a and R b are each hydrogen; or
pharmaceutically acceptable salts thereof.
10. A compound according to claim 1 wherein:
R a is CH 3 and R b is hydrogen; or
a pharmaceutically acceptable salt thereof.
11. A compound according to claim 1 wherein:
R a and R b are each hydrogen; or
a pharmaceutically acceptable salt thereof.
12. A compound according to claim 1 wherein the exocyclic stereochemical center is as shown in structure Ia below:
or a pharmaceutically acceptable salt thereof.
13. A compound according to claim 1 wherein the exocyclic stereo chemical center is as shown in structure Ib below
or a pharmaceutically acceptable salt thereof.
14. A compound selected from the following:
4-((R)-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;
4-((R)-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;
2-chloro-4-((S)-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl) benzonitrile;
2-chloro-4-((S)-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl) benzonitrile;
2-chloro-3-methyl-4-((R)-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxy ethyl)oxazolidin-3-yl)benzonitrile;
2-chloro-3-methyl-4-((R)-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxy ethyl)oxazolidin-3-yl)benzonitrile;
3-methyl-4-((R)-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoro methyl)benzonitrile;
3-methyl-4-((R)-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxy ethyl)oxazolidin-3-yl)-2-(trifluoro methyl)benzonitrile;
2-chloro-3-methyl-4-((4S,5R)-5-methyl-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxy ethyl)oxazolidin-3-yl)benzonitrile;
2-chloro-3-methyl-4-((4S,5R)-5-methyl-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;
2-chloro-3-methyl-4-((4S,5S)-5-methyl-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;
2-chloro-3-methyl-4-((4S,5S)-5-methyl-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;
4-((4S,5S)-5-methyl-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;
4-((4S,5S)-5-methyl-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;
2-chloro-4-((4S,5S)-5-methyl-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;
2-chloro-4-((4S,5S)-5-methyl-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;
3-methyl-4-((4S,5S)-5-methyl-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;
3-methyl-4-((4S,5S)-5-methyl-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;
or a pharmaceutically acceptable salt of any of the foregoing.
15. A compound selected from the following:
4-((R)-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl) benzonitrile;
2-chloro-4-((S)-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl) benzonitrile;
2-chloro-3-methyl-4-((R)-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxy ethyl)oxazolidin-3-yl)benzonitrile;
3-methyl-4-((R)-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoro methyl) benzonitrile;
2-chloro-3-methyl-4-((4S, 5S)-5-methyl-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;
4-((4S,5S)-5-methyl-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;
4-((4S,5S)-5-methyl-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;
2-chloro-4-((4S,5S)-5-methyl-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile; and
2-chloro-4-((4S,5S)-5-methyl-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile or a pharmaceutically acceptable salt of any of the foregoing.
16. A pharmaceutical composition comprising a compound according to claim 1 , and at least one pharmaceutically acceptable excipient.
17. A method of modulating an androgen receptor in a cell, comprising the administration of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
18. A method of identifying a compound capable of modulating an androgen receptor comprising contacting a cell expressing an androgen receptor with a compound according to claim 1 , and monitoring the effect of the compound on the cell.