Substituted pyrazinones, pyridines and pyrimidines as corticotropin releasing factor ligands
View Patent ↗Compounds provided herein are novel substituted pyrazinones, pyridines and pyrimidines of Formula (I) and (II): Such compounds are particularly useful as CRF receptor ligands, and hence, in the treatment of various neurologically-related disorders such as affective disorder, anxiety and depression.
1. A compound of Formula (I-d):
or a pharmaceutically acceptable salt form thereof, wherein:
R 1 is H, F, Cl, Br, —CN, methyl, ethyl, methoxy, or C 1 -C 2 haloalkyl;
R 3 is C 1 -C 6 alkyl optionally substituted with 1 or 2 substituents independently selected at each occurrence from the group consisting of methyl, ethyl, methoxy, ethoxy, methyl-S—, ethyl-S—, cyclopropyl, cyclobutyl, and —CF 3 ;
R 4 is —H, F, Cl, Br, —CN, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C 1 -C 2 haloalkyl, or C 1 -C 2 haloalkoxy; and
R 5 is independently at each occurrence —H, F, Cl, Br, —CN, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C 1 -C 2 haloalkyl, or C 1 -C 2 haloalkoxy.
2. A compound of claim 1 of Formula (I-d):
or a pharmaceutically acceptable salt form thereof, wherein:
R 1 is H, F, Cl, Br, methyl, ethyl, —CN, or —CF 3 ;
R 3 is butyl-, pentyl-, hexyl-, heptyl-, methoxy-ethyl-, methoxy-propyl-, methoxy-butyl-, methoxy-pentyl-, methoxy-hexyl-, methylthio-ethyl-, methylthio-propyl-, methylthio-butyl-, methylthio-pentyl-, methylthio-hexyl-, 1-cyclopropyl-propyl-, 1-cyclopropyl-butyl-, 1-cyclopropyl-pentyl-, 1-cyclobutyl-propyl-, 1-cyclobutyl-butyl-, 1-cyclobutyl-pentyl, 1-cyclopropyl-1-(CF 3 )-methyl-, 1-cyclopropyl-2-(CF 3 )-ethyl-, 1-cyclopropyl-3-(CF 3 )-propyl-, 1-cyclobutyl-1-(CF 3 )-methyl-, 1-cyclobutyl-2-(CF 3 )-ethyl-, or 1-cyclobutyl-3-(CF 3 )-propyl-;
R 4 is H, methyl-, ethyl-, methoxy-, ethoxy-, isopropoxy-, n-propoxy-, F, Cl, Br, —CF 3 , —OCF 3 , —OCHF 2 , or —CN; and
R 5 is independently at each occurrence, —H, methyl, ethyl, methoxy, ethoxy, F, Cl, Br, or —CF 3 .
3. A compound of claim 1 that is:
3-(8-Bromo-6-methoxy-1,2,3,4-tetrahydroquinoline)-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone;
3-(8-Bromo-6-methoxy-1,2,3,4-tetrahydroquinoline)-5-chloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone;
3-(8-Bromo-6-methoxy-1,2,3,4-tetrahydroquinoline)-5-chloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone;
3-(8-Bromo-6-methoxy-1,2,3,4-tetrahydroquinoline)-5-chloro-1-[(1R)-2-methoxy-1-methylethyl]-2(1H)-pyrazinone;
5-Bromo-3-(8-bromo-6-methoxy-1,2,3,4-tetrahydroquinoline)-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone; or
3-(8-Bromo-6-methoxy-1,2,3,4-tetrahydroquinoline)-5-chloro-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone.
4. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
5. A method of treating a mammal afflicted with anxiety or depression which method comprises administering to the mammal a dose of the pharmaceutical composition of claim 4 .
6. The method of claim 5 wherein the mammal is afflicted with anxiety.
7. The method of claim 5 wherein the mammal is afflicted with depression.