Crf Receptor Antagonists and Methods Relating Thereto
CRF receptor antagonists are disclosed which have utility in the treatment of a variety of disorders in mammals, including the treatment of disorders, such as stroke, manifesting hypersecretion of CRF. The CRF receptor antagonists of this invention have the following structure: including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 5 , Ar, and Het are as defined herein. Compositions containing a CRF receptor antagonist in combination with a pharmaceutically acceptable carrier are also disclosed, as well as methods for use of the same.
1 . A compound having the following structure:
or a pharmaceutically acceptable salt, ester, solvate, stereoisomer or prodrug thereof,
wherein:
R 1 and R 2 are the same or different and independently are hydrogen, alkyl, or substituted alkyl;
Ar is phenyl, phenyl substituted by 1 or 2 R 3 , pyridyl or pyridyl substituted by 1 or 2 R 3 ;
R 3 at each occurrence is independently alkyl, substituted alkyl, alkoxy, substituted alkoxy, cyano, halogen, alkylsulfinyl, or alkylsulfonyl;
Het is heterocycle or heterocycle substituted with 1 or 2 R 4 ;
R 4 at each occurrence is independently alkyl, substituted alkyl, alkoxy, substituted alkoxy, halogen, cyano or oxo; and
R 5 and R 6 are the same or different and independently are hydrogen, alkyl or substituted alkyl.
2 . A compound according to claim 1 , wherein R 1 is alkyl.
3 . A compound according to claim 1 , wherein R 2 is alkyl or substituted alkyl.
4 . A compound according to claim 1 , wherein Ar is phenyl substituted by 1 R 3 .
5 . A compound according to claim 4 , wherein R 3 is alkyl, substituted alkyl, alkoxy, cyano or halogen.
6 . A compound according to claim 4 , wherein R 3 is halogen.
7 . A compound according to claim 1 , wherein Het is heterocycle substituted with 1 R 4 .
8 . A compound according to claim 7 , wherein R 4 is alkyl, substituted alkyl, or alkoxy.
9 . A compound according to claim 7 , wherein R 4 is oxo.
10 . A compound according to claim 3 , wherein R 5 at each occurrence is hydrogen.
11 . A compound according to claim 10 , wherein Ar is phenyl, pyridyl or phenyl substituted by one R 3 , wherein R 3 is halogen.
12 . A compound according to claim 11 , wherein Ar is phenyl substituted by one R 3 , and wherein R 3 is chloro.
13 . A compound according to claim 12 , wherein Het is heterocycle.
14 . A compound according to claim 13 , wherein Het is pyrazole.
15 . A compound according to claim 12 , wherein Het is heterocycle substituted by one or two R 4 .
16 . A compound according to claim 15 , wherein Het is dimethylisoxazole.
17 . A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.
18 . A method for treating a disorder manifesting hypersecretion of CRF in a mammal comprising administering to the mammal a pharmaceutically effective amount of the pharmaceutical composition of claim 17 .
19 . A method according to claim 18 , wherein the disorder is an affective disorder, an axiety-related disorder, a feeding disorder, a stress-induced immunosuppressive disorder, an inflammatory disorder or a substance abuse or withdrawal disorder.
20 . A method according to claim 18 , wherein the disorder is irritable bowel syndrome.
21 . A method according to claim 18 , wherein the disorder is depression.
22 . A method according to claim 18 , wherein the disorder is anxiety.
23 . A method according to claim 18 , wherein the disorder is obsessive-compulsive disorder.
24 . A method according to claim 18 , wherein the disorder is stroke.