Crf Receptor Antagonists and Methods
CRF receptor antagonists are disclosed which have utility in the treatment of a variety of disorders, including the treatment of disorders manifesting hypersecretion of CRF in a warm-blooded animals, such as stroke. 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 3 , Y, 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:
“---” represents the second bond of an optional double bond;
R 1 is hydrogen, alkyl, substituted alkyl, —NH 2 , or halogen;
R 2 is —NR 7 R 8 or —OR 10 ;
R 3 is null, hydrogen, or alkyl;
Y is ═(CR 4 )— or —(C═O)—;
R 4 is hydrogen, alkyl, substituted alkyl, thioalkyl, alkylsulfinyl, or alkylsulfonyl;
Ar is phenyl, phenyl optionally substituted with 1 or 2 R 5 , pyridyl, or pyridyl optionally substituted with 1 or 2 R 5 ;
R 5 at each occurrence is alkyl, substituted alkyl, alkoxy, substituted alkoxy, cyano, halogen, alkylsulfinyl, or alkylsulfonyl;
Het is heteroaryl optionally substituted with 1 or 2 R 6 ;
R 6 at each occurrence is alkyl, substituted alkyl, alkoxy, substituted alkoxy, cyano, halogen, —C(O)OR 11 , or hydroxy;
R 7 is hydrogen, alkyl, substituted alkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, alkoxyalkyl, substituted alkoxyalkyl, aryl, substituted aryl, aryloxyalkyl, substituted aryloxyalkyl, arylalkyl, or substituted arylalkyl;
R 8 is alkyl, substituted alkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, alkoxyalkyl, substituted alkoxyalkyl, aryl, substituted aryl, aryloxyalkyl, substituted aryloxyalkyl, arylalkyl, or substituted arylalkyl; or
R 7 and R 8 , together with the nitrogen atom to which they are attached, form a heterocycle which is optionally substituted by 1, 2, or 3 R 9 ;
R 9 at each occurrence is hydroxy, alkylsulfonyl, alkylsulfinyl, —CH 2 —OC(O)R 13 , —C(O)OR 11 , —C(O)NR 11 R 12 , alkyl, substituted alkyl, alkoxy, substituted alkoxy, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, alkoxyalkyl, or substituted alkoxyalkyl;
R 10 is alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, aryloxyalkyl, or substituted aryloxyalkyl;
R 11 , and R 12 are the same or different and independently hydrogen, alkyl, substituted alkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, alkoxyalkyl, substituted alkoxyalkyl, aryl, substituted aryl, aryloxyalkyl, substituted aryloxyalkyl, arylalkyl, or substituted arylalkyl; and
R 13 is alkyl, substituted alkyl, heterocycle, substituted heterocycle, alkoxy, substituted alkoxy.
2 . The compound of claim 1 wherein R 1 is hydrogen, alkyl, or substituted alkyl.
3 . The compound of claim 1 wherein R 2 is —NR 7 R 8 .
4 . The compound of claim 3 wherein R 7 and R 8 together with the nitrogen atom to which they are attached form a heterocycle substituted by 1 R 9 .
5 . The compound of claim 4 where R 9 is hydroxy, alkylsulfonyl, alkylsulfinyl, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, alkoxyalkyl, or substituted alkoxyalkyl.
6 . The compound of claim 1 wherein R 3 is null.
7 . The compound of claim 6 wherein Y is ═(CR 4 )—.
8 . The compound of claim 7 wherein R 4 is hydrogen, alkyl, or substituted alkyl.
9 . The compound of claim 1 wherein R 3 is hydrogen or alkyl.
10 . The compound of claim 9 wherein Y is —(C═O)—.
11 . The compound of claim 1 wherein Ar is substituted by 1 R 5 .
12 . The compound of claim 11 wherein R 5 is alkyl, substituted alkyl, alkoxy, substituted alkoxy, cyano, or halogen.
13 . The compound of claim 1 wherein Het is substituted by 1 R 6 .
14 . The compound of claim 13 wherein R 6 is alkyl, substituted alkyl, alkoxy, substituted alkoxy, cyano, or halogen.
15 . The compound of claim 1 wherein R 2 is —OR 10 .
16 . The compound of claim 3 wherein Y is ═(CR 4 )—.
17 . The compound of claim 16 wherein R 5 is alkyl, substituted alkyl, alkoxy, or substituted alkoxy.
18 . The compound of claim 17 wherein R 8 is alkyl, substituted alkyl, heteroarylalkyl, substituted heteroarylalkyl, alkoxyalkyl, substituted alkoxyalkyl, aryloxyalkyl, substituted aryloxyalkyl, arylalkyl, or substituted arylalkyl.
19 . The compound of claim 18 wherein R 7 is hydrogen, alkyl, substituted alkyl, or alkoxyalkyl.
20 . A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or diluent.
21 . A method for treating a disorder manifesting hypersecretion of CRF in a mammal comprising administering to the animal an effective amount of the pharmaceutical composition of claim 20 .
22 . The method of claim 21 wherein the disorder is stroke.
23 . The method of claim 21 wherein the disorder is depression.
24 . The method of claim 21 wherein the disorder is obsessive-compulsive disorder.
25 . The method of claim 21 wherein the disorder is irritable bowel syndrome.