Compounds and methods for preventing, treating and/or protecting against sensory hair cell death
Disclosed herein are compounds, and pharmaceutical compositions that include such compounds, for preventing, treating, and/or protecting against sensory hair cell death. Methods of using the compounds, alone or in combination with other therapeutic agents, are also disclosed.
1. A compound having the structure of Formula (Ia):
wherein:
R 1 is C 6 -C 10 aryl or C 3 -C 9 heteroaryl, wherein C 6 -C 10 aryl and C 3 -C 9 heteroaryl are optionally substituted with one or more R 4 ;
R 2 is H, C 1 -C 4 alkyl, or C 2 -C 4 alkenyl;
R 3 is C 2 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 4 haloalkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 2 -C 7 heterocycloalkyl, optionally substituted C 6 -C 10 aryl, —OR 6 , —NR 5 R 6 , —C(O)R 7 , —CO 2 R 6 , —C(O)NR 5 R 6 , —N(R 5 )C(O)R 7 , —N(R 5 )CO 2 R 7 , —NHS(O) 2 R 7 , —S(O) 2 NR 5 R 6 ,
or
R 2 and R 3 together form an optionally substituted C 2 -C 7 heterocycloalkyl ring;
each R 4 is independently selected from F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OR 9 , —OCF 3 , —NR 8 R 9 , —C(O)R 10 , —CO 2 R 9 , —C(O)NR 8 R 9 , —N(R 8 )C(O)R 10 , —N(R 8 )CO 2 R 10 , —NHS(O) 2 R 10 , —S(O) 2 NR 8 R 9 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 7 heterocycloalkyl, C 6 -C 10 aryl, and C 3 -C 9 heteroaryl;
R 5 is H or C 1 -C 6 alkyl;
R 6 is H, C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 2 -C 7 heterocycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 3 -C 9 heteroaryl, optionally substituted C 1 -C 6 alkylC 6 -C 10 aryl, or optionally substituted C 1 -C 6 alkylC 3 -C 9 heteroaryl;
R 7 is C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 2 -C 7 heterocycloalkyl, optionally substituted C 6 -C 10 aryl, C 3 -C 9 heteroaryl, optionally substituted C 1 -C 6 alkylC 6 -C 10 aryl, or optionally substituted C 1 -C 6 alkylC 3 -C 9 heteroaryl;
R 8 is H or C 1 -C 6 alkyl;
R 9 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 7 heterocycloalkyl, C 6 -C 10 aryl, C 3 -C 9 heteroaryl, C 1 -C 6 alkylC 6 -C 10 aryl, or C 1 -C 6 alkylC 3 -C 9 heteroaryl;
R 10 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 7 heterocycloalkyl, C 6 -C 10 aryl, C 3 -C 9 heteroaryl, C 1 -C 6 alkylC 6 -C 10 aryl, or C 1 -C 6 alkylC 3 -C 9 heteroaryl;
R 11 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 2 -C 7 heterocycloalkyl, C 6 -C 10 aryl, C 3 -C 9 heteroaryl, C 1 -C 6 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 alkylC 6 -C 10 aryl, or C 1 -C 6 alkylC 3 -C 9 heteroaryl;
R 12 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 2 -C 7 heterocycloalkyl, C 6 -C 10 aryl, C 3 -C 9 heteroaryl, C 1 -C 6 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 alkylC 6 -C 10 aryl, or C 1 -C 6 alkylC 3 -C 9 heteroaryl;
or R 11 and R 12 together with the nitrogen to which they are attached form an optionally substituted C 2 -C 7 heterocycloalkyl ring;
R 13 , R 14 , R 15 , and R 16 are each independently H or C 1 -C 4 alkyl; and
n is an integer selected from 0-4;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, pharmaceutically acceptable salt hydrate, or pharmaceutically acceptable prodrug thereof.
2. The compound of claim 1 wherein R 1 is C 6 -C 10 aryl.
3. The compound of claim 2 wherein R 1 is phenyl.
4. The compound of claim 3 wherein R 1 is substituted with one or more R 4 , wherein each R 4 is independently selected from F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OR 9 , —OCF 3 , —NR 8 R 9 , —C(O)R 10 , —CO 2 R 9 , C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl.
5. The compound of claim 4 wherein R 1 is substituted with one R 4 , wherein R 4 is selected from F, Cl, Br, I, —CN, —CF 3 , —OR 9 , —OCF 3 , —C(O)R 10 , —CO 2 R 9 , and C 1 -C 6 alkyl.
6. The compound of claim 4 wherein R 1 is 4-fluorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-bromophenyl, 4-iodophenyl, 3-cyanophenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-phenoxyphenyl, or 4-benzoylphenyl.
7. The compound of claim 6 wherein R 1 is 4-chlorophenyl.
8. The compound of claim 7 wherein R 11 and R 12 are each H.
9. The compound of claim 8 wherein R 13 , R 14 , R 15 and R 16 are each H.
10. The compound of claim 9 wherein R 2 is H.
11. The compound of claim 9 wherein R 2 is methyl.
12. The compound of claim 10 wherein R 3 is C 2 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 7 heterocycloalkyl, —OR 6 , —CO 2 R 6 , —C(O)NR 5 R 6 , —N(H)C(O)R 7 , —N(H)CO 2 R 7 ,
13. The compound of claim 12 wherein R 6 is H, C 1 -C 6 alkyl, or C 1 -C 6 alkylC 6 -C 10 aryl, and R 7 is C 1 -C 6 alkyl, C 6 -C 10 aryl, C 1 -C 6 alkylC 6 -C 10 aryl, or C 1 -C 6 alkylC 3 -C 9 heteroaryl.
14. The compound of claim 9 wherein R 2 and R 3 together form an optionally substituted C 2 -C 7 heterocycloalkyl ring.
15. The compound of claim 14 wherein R 2 and R 3 together form an optionally substituted oxetane, pyrrolidine, piperidine, or tetrahydropyran ring.
16. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, pharmaceutically acceptable salt hydrate, or pharmaceutically acceptable prodrug thereof, and a pharmaceutically acceptable excipient.
17. The pharmaceutical composition of claim 16 further comprising an aminoglycoside antibiotic.
18. A method for preventing, treating, and/or protecting against sensory hair cell death in an individual comprising administering to the individual a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, pharmaceutically acceptable salt hydrate, or pharmaceutically acceptable prodrug thereof.
19. The method of claim 18 wherein the sensory hair cell death is associated with exposure to an ototoxic agent.
20. The method of claim 19 wherein the ototoxic agent is an aminoglycoside antibiotic.