Compounds that enhance Atoh1 expression

摘要

This invention generally provides compounds, pharmaceutical compositions, and methods for their use, which include methods that result in increased expression in an Atoh1 gene (e.g., Hath1) in a biological cell. More specifically, the invention relates to the treatment of diseases and/or disorders that would benefit from increased Atoh1 expression, e.g., a hearing impairment or imbalance disorder associated with a loss of auditory hair cells, or a disorder associated with abnormal cellular proliferation.

主权项

1. A sterile pharmaceutical composition comprising a compound of the following formula and a pharmaceutically acceptable carrier suitable for local administration into the ear: wherein: R43 is C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally substituted with from 1-5 Rm; R44 is: (i) C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally substituted with from 1-5 Rm; or (ii) —Z4—(C1-C6 alkyl), wherein: Z4 is a bond or NH; and the C1-C6 alkyl is substituted with one of the following: (a) heterocyclyl including 5-6 atoms, which is optionally substituted with from 1-3 substituents independently selected from oxo and C1-C6 alkyl; or (b) phenoxy, which is optionally substituted with from 1-5 Rm; and Rm at each occurrence is, independently: (i) halo; NH2; NH(C1-C3 alkyl); N(C1-C3 alkyl)2; hydroxy; C1-C6 alkoxy or C1-C6 haloalkoxy; nitro; or cyano; or (ii) C1-C6 alkyl or C1-C6 haloalkyl; or a pharmaceutically acceptable salt thereof.