US 2018/0022756 A1Published application

Compounds and methods for preventing or treating sensory hair cell death

AssigneesUniversity of Washington, Fred Hutchinson Cancer Research Center, Oricula Therapeutics LLC

InventorsJulian Simon, Graham Johnson, Edwin W. Rubel, David W. Raible, Mario D. Gonzalez, Peter C. Meltzer, Weishi Miao

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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.

Claims64

Dependent claims

A compound having the structure of Formula (I):

wherein:
Z is a single bond, double bond, —CH2—, or —O—;
R1 is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted with one or more R4;
R2 is H, C1-C6alkyl, C1-C6alkyl-OR6, C1-C6alkylC3-C6cycloalkyl, C1-C6alkylC2-C7heterocycloalkyl, C1-C6alkyl-CO2R6, optionally substituted C1-C6alkylaryl, or optionally substituted C1-C6alkylheteroaryl;
R3 and R5 are each independently H, or C1-C6alkyl;
or
R3 and R5 together form an optionally substituted C3-C6cycloalkyl ring, optionally substituted C2-C7heterocycloalkyl ring, optionally substituted aryl ring, or an optionally substituted heteroaryl ring;
each R4 is independently selected from F, Cl, Br, I, —CN, —NO2, —CF3, —OR9, —OCF3, —NR8R9, —C(O)R10, —CO2R9, —C(O)NR8R9, —N(R8)C(O)R10, —N(R8)CO2R10, —NHS(O)2R10, —S(O)2NR8R9, C1-C6alkyl, C3-C6cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C7heterocycloalkyl, aryl, and heteroaryl;
R6 is H, or C1-C6alkyl;
R8 is H, or C1-C6alkyl;
R9 is H, C1-C6alkyl, C3-C6cycloalkyl, C2-C7heterocycloalkyl, aryl, heteroaryl, C1-C6alkylaryl, or C1-C6alkylheteroaryl;
R10 is C1-C6alkyl, C3-C6cycloalkyl, C2-C7heterocycloalkyl, aryl, heteroaryl, C1-C6alkylaryl, or C1-C6alkylheteroaryl;
R11 is H, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C2-C7heterocycloalkyl, aryl, heteroaryl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkylaryl, or C1-C6alkylheteroaryl;
R12 is H, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C2-C7heterocycloalkyl, aryl, heteroaryl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkylaryl, or C1-C6alkylheteroaryl;
or R11 and R12 together with the nitrogen to which they are attached form an optionally substituted C2-C7heterocycloalkyl ring;
and
R13 and R14 are each independently H, or C1-C6alkyl;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, pharmaceutically acceptable salt hydrate, or pharmaceutically acceptable prodrug thereof.

15 more elements

A compound having the structure of Formula (II):

wherein:
X− is a counterion;
Z is a single bond, double bond, —CH2—, or —O—;
R1 is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted with one or more R4;
R2a is C1-C6alkyl, —C1-C6alkyl-OR5, or —C1-C6alkylC3-C6cycloalkyl;
R2 is C1-C6alkyl, —C1-C6alkyl-OR6, —C1-C6alkylC3-C6cycloalkyl, or —C1-C6alkyl-CO2R6;
R3 and R5 are each independently H, or C1-C6alkyl;
or
R3 and R5 together form an optionally substituted C3-C6cycloalkyl ring, optionally substituted C2-C7heterocycloalkyl ring, optionally substituted aryl ring, or an optionally substituted heteroaryl ring;
each R4 is independently selected from F, Cl, Br, I, —CN, —NO2, —CF3, —OR9, —OCF3, —NR8R9, —C(O)R10, —CO2R9, —C(O)NR8R9, —N(R8)C(O)R10, —N(R8)CO2R10, —NHS(O)2R10, —S(O)2NR8R9, C1-C6alkyl, C3-C6cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C7heterocycloalkyl, aryl, and heteroaryl;
R6 is H, or C1-C6alkyl;
R8 is H, or C1-C6alkyl;
R9 is H, C1-C6alkyl, C3-C6cycloalkyl, C2-C7heterocycloalkyl, aryl, heteroaryl, —C1-C6alkylaryl, or —C1-C6alkylheteroaryl;
R10 is C1-C6alkyl, C3-C6cycloalkyl, C2-C7heterocycloalkyl, aryl, heteroaryl, —C1-C6alkylaryl, or —C1-C6alkylheteroaryl;
R11 is H, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C2-C7heterocycloalkyl, aryl, heteroaryl, —C1-C6alkylC3-C6cycloalkyl, —C1-C6alkylaryl, or —C1-C6alkylheteroaryl;
R12 is H, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C2-C7heterocycloalkyl, aryl, heteroaryl, —C1-C6alkylC3-C6cycloalkyl, —C1-C6alkylaryl, or —C1-C6alkylheteroaryl;
or R11 and R12 together with the nitrogen to which they are attached form an optionally substituted C2-C7heterocycloalkyl ring;
and
R13 and R14 are each independently H, or C1-C6alkyl;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, pharmaceutically acceptable salt hydrate, or pharmaceutically acceptable prodrug thereof.

17 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/547,438Filed 5 Feb 2016
Priority: 6 Feb 2015
Published: 25 Jan 2018
Term ends: Not estimatedThe source records don’t support an estimate.

Classification12 codes

C07D 495/18
In which the condensed system contains three hetero rings: bridged systems
A61K 31/439
Having six-membered rings with one nitrogen as the only ring hetero atom: the ring forming part of a bridged ring system, e.g. quinuclidine
A61K 31/46
Having six-membered rings with one nitrogen as the only ring hetero atom: 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
A61K 31/7036
Attached to a carbocyclic compound, e.g. phloridzin: having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin,…

Family

Application62/113,245Us provisional application · filed 6 Feb 2015
US 10,399,994 B2Related patent
US 2018/0022756 A1This patent

From the US filing history. Foreign family members aren’t listed.

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