Quinolines as cytoprotective agents
View Patent ↗Provided herein are compounds of Formula I, pharmaceutical compositions thereof, and methods of their use for treating, preventing, or ameliorating one or more symptoms of a neurological disease, neurodegenerative disorder, or diabetes.
1. A compound of Formula I:
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each as defined herein;
R 1 is (a) hydrogen or (b) C 1-3 alkyl;
R 2 is 2-thienyl, wherein R 2 is optionally substituted with one to two substituents independently selected from halo, —O—(C 1 -C 4 alkyl), C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and —N(CH 3 ) 2 ;
R 3 is CH 3 ; and
R 4 , R 5 , R 6 , R 7 , and R 8 are each independently (a) hydrogen, cyano, or halo; (b) C 1-4 alkyl, —O—(C 1 -C 4 alkyl), or —N(CH 3 ) 2 .
2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen.
3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 , R 5 , R 6 , R 7 , and R 8 are hydrogen.
4. The compound according to claim 1 selected from the group consisting of:
5. A method for treating or ameliorating one or more symptoms of diabetes in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula I:
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof;
wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each as defined herein;
R 1 is (a) hydrogen or (b) C 1-3 alkyl;
R 2 is (a) phenyl, (b) 2-thienyl, or (c) 2-furyl, wherein R 2 is optionally substituted with one to two substituents independently selected from halo, —O—(C 1 -C 4 alkyl), C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and —N(CH 3 ) 2 , with the proviso that R 2 is not —(H 5 )Ph, -(2,6-di-CH 3 )Ph, -(2,4,6-tri-CH 3 )Ph, -(2,6-di-F)Ph, -(2,6-di-iPr)Ph, or -(2,6-di-Et)Ph;
R 3 is CH 3 ; and
R 4 , R 5 , R 6 , R 7 , and R 8 are each independently (a) hydrogen, cyano, or halo; (b) C 1-4 alkyl, —O—(C 1 -C 4 alkyl), or —N(CH 3 ) 2 .
6. The method of claim 5 wherein the diabetes is type 1.
7. The method of claim 5 wherein the diabetes is type 2.
8. The method of claim 5 wherein the compound is selected from the following: