Sigma 2 receptor ligands and therapeutic uses therefor

US7612085B2 · kind B2 · utility

Assignee

• Washington University · US

Inventors

• Robert H. Mach · Eureka, US
• Zhude Tu · Frontenac, US
• Wenhua Chu · Chesterfield, US
• Suwanna VANGVERAVONG · Chesterfield, US
• Richard Hotchkiss · Chesterfield, US
• William G. Hawkins · Webster, US
• Rebecca Aft · Chesterfield, US

Key dates

• Filing date: Jul 11, 2007
• Grant date: Nov 3, 2009
• Expiry date: Jul 28, 2027

Classification

• Technology area (CPC C): Chemistry; Metallurgy
• CPC primary: C07D451/02
• WIPO field: Organic fine chemistry
• WIPO sector: Chemistry

Abstract

A series of N-substituted 9-azabicyclo[3.3.1]nonan-3α-yl phenylcarbamate analogs are disclosed, as well as methods of their preparation. Their affinities for sigma (σ1 and σ2) receptors are described. Two new compounds, N-(9-(4-aminobutyl)-9-azabicyclo[3.3.1]nonan-3α-yl)-N′-(2-methoxy-5-methylphenyl)carbamate and N-(9-(6-aminohexyl)-9-azabicyclo[3.3.1]nonan-3α-yl)-N′-(2-methoxy-5-methylphenyl)carbamate, are shown to have a high affinity and selectivity for σ2 versus σ1 receptors. Among the disclosed compounds are biotinylated and fluorescent analogs. These compounds can serve as probes to the σ2 receptor. In addition, some disclosed compounds can induce apoptotic cell death by both caspase-dependent and caspase-independent mechanisms, and are effective for treatment of tumors. The compounds can be used as chemotherapeutics or chemosensitizers in the treatment of a wide variety of solid tumors.