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 (III):
wherein:
X is a single bond, double bond, —CH 2 —, or —O—;
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 6 alkyl, C 1 -C 6 alkyl-OR 6 , C 1 -C 6 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 alkylC 2 -C 7 heterocycloalkyl, C 1 -C 6 alkyl-CO 2 R 6 , optionally substituted C 1 -C 6 alkylC 6 -C 10 aryl, or optionally substituted C 1 -C 6 alkylC 3 -C 9 heteroaryl;
R 3 are R 5 are each independently H, or C 1 -C 6 alkyl; or
R 3 and R 5 together form an optionally substituted C 3 -C 6 cycloalkyl ring, optionally substituted C 2 -C 7 heterocycloalkyl ring, optionally substituted C 6 -C 10 aryl ring, or an optionally substituted C 3 -C 9 heteroaryl 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 6 is H, or C 1 -C 6 alkyl;
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; and
R 13 are R 14 are each independently H, or C 1 -C 6 alkyl;
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 phenyl optionally substituted with one or more R 4 .
3. The compound of claim 2 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.
4. The compound of claim 3 wherein R 11 and R 12 are each H.
5. The compound of claim 4 wherein R 3 and R 5 are each H.
6. The compound of claim 5 wherein R 13 and R 14 are each CH 3 .
7. The compound of claim 5 wherein R 13 and R 14 are each H.
8. The compound of claim 7 wherein X is a single bond.
9. The compound of claim 8 wherein R 1 is 4-chlorophenyl.
10. The compound of claim 9 wherein R 2 is H.
11. The compound of claim 9 wherein R 2 is C 1 -C 6 alkyl.
12. The compound of claim 11 wherein R 2 is CH 3 .
13. The compound of claim 9 wherein R 2 is C 1 -C 6 alkylC 3 -C 6 cycloalkyl.
14. The compound of claim 13 wherein R 2 is —CH 2 C 3 -C 6 cycloalkyl.
15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , and a pharmaceutically acceptable excipient.
16. The pharmaceutical composition of claim 15 further comprising an aminoglycoside antibiotic.
17. 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 .
18. The method of claim 17 wherein the sensory hair cell death is associated with exposure to an ototoxic agent.
19. The method of claim 18 wherein the ototoxic agent is an aminoglycoside antibiotic.
20. A compound having the structure of Formula (I):
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
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;
n is an integer selected from 0-4;
p is an integer selected from 0-3; and
q is an integer selected from 0-3;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, pharmaceutically acceptable salt hydrate, or pharmaceutically acceptable prodrug thereof.