CRF receptor antagonists and methods relating thereto
View Patent ↗CRF receptor antagonists are disclosed which may have utility in the treatment of a variety of disorders, including the treatment of disorders manifesting hypersecretion of CRF in mammals, such as stroke. The CRF receptor antagonists of this invention have the following structure: and pharmaceutically acceptable salts, esters, solvates, stereoisomers and prodrugs thereof, wherein R 1 , R 2 , n, R 5 , Ar, and Het are as defined herein. Compositions containing a CRF receptor antagonists in combination with a pharmaceutically acceptable carrier are also disclosed, as well as methods for use of the same.
1. A compound represented by the following structure:
or a pharmaceutically acceptable salt, ester, or stereoisomer thereof,
wherein:
R 1 at each occurrence is independently C 1 -C 6 alkyl;
n is 0, 1 or 2;
R 2 is C 1 -C 10 alkyl, substituted C 1 -C 10 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyclyl, substituted heterocyclyl, —OR 3 , or —NR 4a R 4b ;
R 3 is C 1 -C 10 alkyl, substituted C 1 -C 10 alkyl, arylalkyl, substituted arylalkyl, C 1 -C 10 alkoxyalkyl, substituted C 1 -C 10 alkoxyalkyl, heterocyclealkyl, or substituted heterocyclealkyl;
R 4a and R 4b are the same or different and independently hydrogen, C 1 -C 10 alkyl, substituted C 1 -C 10 alkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, C 1 -C 10 alkoxyalkyl or substituted C 1 -C 10 alkoxyalkyl, with the proviso that R 4a and R 4b cannot both be hydrogen;
R 5 is hydrogen or C 1 -C 6 alkyl;
Ar is substituted phenyl, pyridyl or substituted pyridyl; and
Het is heterocyclyl or substituted heterocyclyl.
2. A compound according to claim 1 , wherein R 1 is methyl.
3. A compound according to claim 1 , wherein n is 1.
4. A compound according to claim 1 , wherein R 2 is C 1 -C 6 alkyl.
5. A compound according to claim 1 , wherein R 2 is substituted aryl.
6. A compound according to claim 1 , wherein R 2 is substituted heteroaryl.
7. A compound according to claim 1 , wherein R 2 is —OR 3 .
8. A compound according to claim 7 , wherein R 3 is C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl or heteroarylalkyl.
9. A compound according to claim 1 , wherein R 2 is —NR 4a R 4b .
10. A compound according to claim 9 , wherein R 4a and R 4b are independently C 1 -C 6 alkyl.
11. A compound according to claim 1 , wherein R 5 is methyl.
12. A compound according to claim 1 , wherein Het is substituted heterocyclyl.
13. A compound according to claim 1 , wherein each of R 1 and R 5 is methyl.
14. A compound according to claim 13 , wherein n is 1.
15. A compound according to claim 14 , wherein Ar-Het is
wherein:
m is 1, 2, 3 or 4; and
R 6 at each occurrence is independently C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen.
16. A compound according to claim 15 , wherein R 6 is selected from the group of methyl, methoxy and trihalomethyl.
17. A compound according to claim 16 , wherein Het is pyridyl or substituted pyridyl.
18. A compound according to claim 17 , wherein Het is pyridyl.
19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a pharmaceutically effective amount of a compound represented by the following structure:
or a pharmaceutically acceptable salt, ester, or stereoisomer thereof,
wherein:
R 1 at each occurrence is independently C 1 -C 6 alkyl;
n is 0, 1 or 2;
R 2 is C 1 -C 10 alkyl, substituted C 1 -C 10 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyclyl, substituted heterocyclyl, —OR 3 , or —NR 4a R 4b ;
R 3 is C 1 -C 10 alkyl, substituted C 1 -C 10 alkyl, arylalkyl, substituted arylalkyl, C 1 -C 10 alkoxyalkyl, substituted C 1 -C 10 alkoxyalkyl, heterocyclealkyl, or substituted heterocyclealkyl;
R 4a and R 4b are the same or different and independently hydrogen, C 1 -C 10 alkyl, substituted C 1 -C 10 alkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, C 1 -C 10 alkoxyalkyl or substituted C 1 -C 10 alkoxyalkyl, with the proviso that R 4a and R 4b cannot both be hydrogen;
R 5 is hydrogen or C 1 -C 6 alkyl;
Ar is substituted phenyl, pyridyl or substituted pyridyl; and
Het is heterocyclyl or substituted heterocyclyl.
20. A composition according to claim 19 , wherein R 1 is methyl.
21. A composition according to claim 19 , wherein n is 1.
22. A composition according to claim 19 , wherein R 2 is C 1 -C 6 alkyl.
23. A composition according to claim 19 , wherein R 3 is C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl or heteroarylalkyl.
24. A composition according to claim 19 , wherein R 5 is methyl.
25. A composition according to claim 19 , wherein Het is substituted heterocycle.
26. A composition according to claim 19 , wherein each of R 1 and R 5 is methyl.
27. A composition according to claim 26 , wherein n is 1.
28. A composition according to claim 27 , wherein Ar-Het is
wherein:
m is 1, 2, 3 or 4; and
R 6 at each occurrence is independently C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen.
29. A composition according to claim 28 , wherein R 6 is selected from the group of methyl, methoxy and trihalomethyl.
30. A composition according to claim 29 , wherein Het is pyridyl or substituted pyridyl.
31. A composition according to claim 30 , wherein Het is pyridyl.
32. A method for the treatment of a disease or condition selected from the group consisting of depression, anxiety, and irritable bowel syndrome, in a human comprising administering to said human a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a pharmaceutically effective amount of a compound represented by the following structure
or a pharmaceutically acceptable salt, ester, or stereoisomer thereof
wherein:
R 1 at each occurrence is independently C 1 -C 6 alkyl;
n is 0, 1 or 2;
R 2 is C 1 -C 10 alkyl, substituted C 1 -C 10 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyclyl, substituted heterocyclyl, —OR 3 , or —NR 4a R 4b ;
R 3 is C 1 -C 10 alkyl, substituted C 1 -C 10 alkyl, arylalkyl, substituted arylalkyl, C 1 -C 10 alkoxyalkyl, substituted C 1 -C 10 alkoxyalkyl, heterocyclealkyl, or substituted heterocyclealkyl;
R 4a and R 4b are the same or different and independently hydrogen, C 1 -C 10 alkyl, substituted C 1 -C 10 alkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, C 1 -C 10 alkoxyalkyl or substituted C 1 -C 10 alkoxyalkyl, with the proviso that R 4a and R 4b cannot both be hydrogen;
R 5 is hydrogen or C 1 -C 6 alkyl;
Ar is substituted phenyl, pyridyl or substituted pyridyl; and
Het is heterocyclyl or substituted heterocyclyl.
33. A method according to claim 32 , wherein the disease or condition is depression.
34. A method according to claim 32 , wherein the disease or condition is anxiety.
35. A method according to claim 32 , wherein the disease or condition is irritable bowel syndrome.