Pyrrolopyrimidine derivatives as NR2B NMDA receptor antagonists

Abstract

Disclosed are chemical entities of formula I: [INSERT CHEMICAL FORMULA HERE] wherein X, Y, Z, R1, R3, R4, R5 and R6 are defined herein, as NR2B subtype selective receptor antagonists. Also disclosed are pharmaceutical compositions comprising a chemical entity of formula I, and methods of treating various diseases and disorders associated with NR2B antagonism, e.g., diseases and disorders of the CNS, such as depression, by administering a chemical entity of formula I.

Description

Background technique [0001] Nonselective NMDA receptor antagonists were originally developed for stroke and head trauma, and have shown clinical efficacy in the treatment of depression in recent years. The nonselective NMDA receptor antagonist ketamine has been shown to have rapid onset and efficacy in depression resistant to standard monoamine reuptake inhibitor therapy (Mathews and Zarat Zarate), 2013, J. Clin. Psychiatry 74:516-158). However, nonselective NMDA receptor antagonists, such as ketamine, have various undesirable pharmacological activities that limit their application in humans. Specifically, dissociative or psychotropic side effects are particularly prominent for non-selective NMDA receptor antagonists. In recent years, NR2B subtype-selective NMDA receptor antagonists have shown potential in numerous clinical indications. Specifically, NR2B antagonists have also demonstrated antidepressant activity in early clinical trials (Ibrahim et al., 2012, J. Clin. Psyc...

AI Technical Summary

Problems solved by technology

The present invention specifically addresses the need for improved NR2B receptor antagonists in one or more of aspects such as pharmacokinetic properties, oral activity, cardiovascular safety, and in vitro and in vivo therapeutic safety index measures

Images