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 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 CH 2 ;
or pharmaceutically acceptable salts thereof.
2. The compound according to claim 1 , wherein:
R x is CN; or
pharmaceutically acceptable salts thereof.
3. The compound according to claim 1 , wherein:
R y is CF 3 or Cl; or
pharmaceutically acceptable salts thereof.
4. The compound according to claim 1 , wherein:
R z is H, CH 3 , CF 3 or Cl; or
pharmaceutically acceptable salts thereof.
5. The compound according to claim 1 , wherein:
P 1 is hydrogen or (C═O)—C 1-6 alkyl; or
pharmaceutically acceptable salts thereof.
6. The compound according to claim 1 , wherein:
P 1 is hydrogen.
7. The 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.
8. The 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.
9. The compound according to claim 1 wherein:
R a is CH 3 and R b is hydrogen; or
a pharmaceutically acceptable salt thereof.
10. The compound according to claim 1 wherein:
R a and R b are each hydrogen; or
a pharmaceutically acceptable salt thereof.
11. The compound according to claim 1 wherein the exocyclic stereochemical center is as shown in structure la below:
or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 1 wherein the exocyclic stereochemical center is as shown in structure Ib below
or a pharmaceutically acceptable salt thereof.
13. A compound selected from the group consisting of
4-((R)-2-oxo-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile,
4-((R)-2-oxo-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile,
3-methyl-4-((R)-2-oxo-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile,
3-methyl-4-((S)-2-oxo-5-((S)-2,2,2-trifluoro-1 -hydroxyethyl)pyrrolidin-1 -yl)-2-(trifluoromethyl)benzonitrile,
and pharmaceutically acceptable salt of any of the foregoing.
14. A compound selected from the following:
4-((R)-2-oxo-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile,
3-methyl-4-((R)-2-oxo-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile,
or a pharmaceutically acceptable salt of any of the foregoing.
15. A pharmaceutical composition comprising a compound according to claim 1 and at least one pharmaceutically acceptable excipient.
16. 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.
17. 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.
18. A method of treating sarcopenia, frailty, multiple sclerosis, osteoporosis, muscular dystrophy, low body weight, anorexia nervosa, AIDs wasting, chronic fatigue syndrome, short stature, low testosterone levels, diminished libido, benign prostate hypertrophy, infertility, erectile dysfunction, male hormone replacement therapy, myalgia, metabolic syndrome, dwarfism, lethargy, osteopenia, osteoarthritis, connective tissue disease or disorders, injury, burns, wounds, bone fracture, cachexia, and cancer cachexia, in a mammal in need thereof, comprising the administration to said mammal of an effective amount of a compound, or a pharmaceutically acceptable salt thereof, according to claim 1 .
19. A compound selected from the following:
(R)-1-(3,4-dichlorophenyl)-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-2-one,
(R)-1-(3,4-dichlorophenyl)-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-2-one,
or a pharmaceutically acceptable salt of any of the foregoing.