Compounds and methods for preventing or treating sensory hair cell death

Patent metadata

Field	Value
Publication number	US-9493482-B2
Application number	US-201615017472-A
Country	US
Kind code	B2
Filing date	Feb 5, 2016
Priority date	Feb 6, 2015
Publication date	Nov 15, 2016
Grant date	Nov 15, 2016

Abstract

Disclosed herein are compounds, and pharmaceutical compositions that include such compounds, for preventing or treating hearing loss. The compounds and pharmaceutical compositions described herein prevent or treat hair cell death. In addition, the compounds and pharmaceutical compositions described herein protect against kidney damage in an individual receiving an aminoglycoside antibiotic. Methods of using the compounds, alone or in combination with other therapeutic agents, are also disclosed.

First claim

What is claimed is:

1. A compound having the structure of Formula (I):

Formula (I);
wherein:
R 1 is aryl or heteroaryl, wherein aryl and 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 alkylaryl, or optionally substituted C 1 -C 6 alkylheteroaryl;
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, aryl, and 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, aryl, heteroaryl, C 1 -C 6 alkylaryl, or C 1 -C 6 alkylheteroaryl;
R 10 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 7 heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylaryl, or C 1 -C 6 alkylheteroaryl;
R 11 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 2 -C 7 heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 alkylaryl, or C 1 -C 6 alkylheteroaryl; and
R 12 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 2 -C 7 heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 alkylaryl, or C 1 -C 6 alkylheteroaryl; 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;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein R 11 and R 12 are each H.

3. The compound of claim 2 wherein R 1 is aryl optionally substituted with one or more R 4 .

4. The compound of claim 3 wherein R 1 is phenyl optionally substituted with one or more R 4 .

5. The compound of claim 4 wherein R 1 is phenyl 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.

6. The compound of claim 5 wherein R 1 is phenyl 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.

7. The compound of claim 6 wherein R 1 is 4-chlorophenyl.

8. The compound of claim 7 wherein R 2 is H.

9. The compound of claim 7 wherein R 2 is C 1 -C 6 alkyl.

10. The compound of claim 9 wherein R 2 is —CH 3 .

11. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

13. The pharmaceutical composition of claim 12 further comprising an aminoglycoside antibiotic.

Assignees

• Univ Washington
• Hutchinson Fred Cancer Res
• Oricula Therapeutics Llc

Inventors

• Simon Julian
• Johnson Graham
• Rubel Edwin
• Raible David
• Gonzalez Mario D
• Meltzer Peter C
• Miao Weishi

Classifications

• C07D495/18 Primary

  Bridged systems · CPC title

• A61P27/00

  Drugs for disorders of the senses · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/439

  the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46) · CPC title

• A61K31/7036

  having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins · CPC title