Compounds and methods for preventing or treating sensory hair cell death

Patent metadata

Field	Value
Publication number	US-2016229869-A1
Application number	US-201615017472-A
Country	US
Kind code	A1
Filing date	Feb 5, 2016
Priority date	Feb 6, 2015
Publication date	Aug 11, 2016
Grant date	—

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

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

wherein:
Z is a single bond, double bond, —CH 2 —, or —O—;
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;
R 3 and 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 aryl ring, or an optionally substituted 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, 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;
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; and
R 13 and 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 11 and R 12 are each H.

3 . The compound of claim 2 wherein R 3 and R 5 are each H.

4 . The compound of claim 3 wherein Z is a single bond.

5 . The compound of claim 4 wherein R 13 and R 14 are each H.

6 . The compound of claim 4 wherein R 13 and R 14 are each —CH 3 .

7 . The compound of claim 5 wherein R 1 is aryl optionally substituted with one or more R 4 .

8 . The compound of claim 7 wherein R 1 is phenyl optionally substituted with one or more R 4 .

9 . The compound of claim 8 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.

10 . The compound of claim 9 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.

11 . The compound of claim 10 wherein R 1 is 4-chlorophenyl.

12 . The compound of claim 11 wherein R 2 is H.

13 . The compound of claim 11 wherein R 2 is C 1 -C 6 alkyl.

14 . The compound of claim 13 wherein R 2 is —CH 3 .

15 . The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, pharmaceutically acceptable salt hydrate, or pharmaceutically acceptable prodrug thereof.

16 . The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, pharmaceutically acceptable salt hydrate, or pharmaceutically acceptable prodrug thereof.

17 . The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, pharmaceutically acceptable salt hydrate, or pharmaceutically acceptable prodrug thereof.

18 . 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.

19 . The pharmaceutical composition of claim 18 further comprising an aminoglycoside antibiotic.

20 . A method for preventing or treating 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.

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

• A61P27/00

  Drugs for disorders of the senses · CPC title

• C07D495/18 Primary

  Bridged systems · 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

• A61K31/46

  8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine · CPC title

• A61K33/243

  Platinum; Compounds thereof · CPC title