Therapeutic compounds
The invention provides compounds having the general formula I: and pharmaceutically acceptable salts thereof, wherein the variables R 1 , R 2 , R 3 , R 4 , subscript m and n, have the meaning as described herein, and compositions containing such compounds and methods for using such compounds and compositions.
1. A method of treating mitochondrial disease in an animal comprising administering to the animal an effective amount of compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl, and wherein the C 1-20 alkyl, C 2-20 alkenyl and C 2-20 alkynyl are optionally substituted with one or more groups independently selected from —F, —Cl, —Br, —I, —OR a , —SR a , —NR a R b , oxo, —NO 2 and —CN;
R 2 is C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl, and wherein the C 1-20 alkyl, C 2-20 alkenyl and C 2-20 alkynyl are optionally substituted with one or more groups independently selected from —F, —Cl, —Br, —I, —OR a , —SR a , —NR a R b , oxo, —NO 2 and —CN; or
R 1 and R 2 taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with one or more groups independently selected from C 1-4 alkyl, C 1-4 haloalkyl, —F, —Cl, —Br, —I, —OR a , —SR a , —NR a R b , oxo, —NO 2 and —CN;
each R 3 is independently selected from the group consisting of —F, —Cl, —Br, —I, —OH, —OR a , —SR a , —NR a R b , —CN, C 1-4 alkyl, C 2-4 alkenyl and C 2-4 alkynyl, and wherein the C 1-4 alkyl, C 2-4 alkenyl and C 2-4 alkynyl are optionally substituted with one or more groups independently selected from —F, —Cl, —Br, —I, —OR a , —SR a , —NR a R b , oxo, —NO 2 and —CN;
each R 4 is independently selected from the group consisting of —F, —Cl, —Br, —I, —OR a , —SR a , —NR a R b , —NO 2 , —CN, C 1-4 alkyl, C 2-4 alkenyl and C 2-4 alkynyl, and wherein the C 1-4 alkyl, C 2-4 alkenyl and C 2-4 alkynyl are optionally substituted with one or more groups independently selected from —F, —Cl, —Br, —I, —OR a , —SR a , —NR a R b , oxo, —NO 2 and —CN;
each R a is independently hydrogen or C 1-4 alkyl;
each R b is independently hydrogen or C 1-4 alkyl;
the subscript m is 0, 1, 2 or 3; and
the subscript n is 0, 1, 2, or 3.
2. The method of claim 1 , wherein the compound or salt is a compound of formula Ia:
or a pharmaceutically acceptable salt thereof.
3. The method of claim 2 , wherein R 1 is C 12-20 alkyl, C 12-20 alkenyl or C 12-20 alkynyl, and wherein the C 12-20 alkyl, C 12-20 alkenyl and C 12-20 alkynyl are optionally substituted with one or more groups independently selected from —F, —Cl, —Br, —I, —OR a , —SR a , —NR a R b , oxo, —NO 2 and
—CN;
each R a is independently hydrogen or C 1-4 alkyl; and
each R b is independently hydrogen or C 1-4 alkyl.
4. The method of claim 1 wherein the compound or salt is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
5. The method of claim 1 , wherein the compound or salt is a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is C 12-20 alkyl, C 12-20 alkenyl or C 12-20 alkynyl, and wherein the C 12-20 alkyl, C 12-20 alkenyl and C 12-20 alkynyl are optionally substituted with one or more groups independently selected from —F, —Cl, —Br, —I, —OR a , —SR a , —NR a R b , oxo, —NO 2 and —CN;
R 2 is methyl each R 3 is independently selected from the group consisting of —F, —Cl, —Br, —I, —OH, —OR a , —SR a , —NR a R b , —CN, C 1-4 alkyl, C 2-4 alkenyl and C 2-4 alkynyl, and wherein the C 1-4 alkyl, C 2-4 alkenyl and C 2-4 alkynyl are optionally substituted with one or more groups independently selected from —F, —Cl, —Br, —I, —OR a , —SR a , —NR a R b , oxo, —NO 2 and —CN;
each R 4 is independently selected from the group consisting of —F, —Cl, —Br, —I, —OR a , —SR a , —NR a R b , —NO 2 , —CN, C 1-4 alkyl, C 2-4 alkenyl and C 2-4 alkynyl, and wherein the C 1-4 alkyl, C 2-4 alkenyl and C 2-4 alkynyl are optionally substituted with one or more groups independently selected from —F, —Cl, —Br, —I, —OR a , —SR a , —NR a R b , oxo, —NO 2 and —CN;
each R a is independently hydrogen or C 1-4 alkyl;
each R b is independently hydrogen or C 1-4 alkyl;
the subscript m is 0, 1, 2 or 3; and
the subscript n is 0, 1, 2, or 3.
6. The method of claim 5 , wherein the compound or salt is a compound of formula Ia:
or a pharmaceutically acceptable salt thereof.
7. The method of claim 1 , wherein R 1 is n-pentadecyl.
8. The method of claim 1 , wherein the compound or salt is selected from the group consisting of:
and
pharmaceutically acceptable salts thereof.
9. The method of claim 2 , wherein R 1 is C 1-20 alkyl.
10. The method of claim 2 , wherein R 2 is C 1-20 alkyl.
11. The method of claim 2 , wherein R 2 is C 1 alkyl.
12. The method of claim 2 , wherein R 1 is C 1-20 alkyl; R 2 is C 1 alkyl.
13. The method of claim 2 , wherein, R 1 is n-butyl, n-decyl or n-pentadecyl.
14. The method of claim 2 , wherein, R 2 is methyl, n-butyl, n-decyl or n-pentadecyl.
15. The method of claim 2 , wherein, R 1 is n-decyl; and R 2 is methyl.