THERAPEUTIC USES OF BICYCLIC LIGANDS OF SIGMA 2 RECEPTOR

• US 20100048614A1
• Filed: 08/19/2009
• Published: 02/25/2010
• Est. Priority Date: 07/11/2006
• Status: Active Grant

• Current Assignee: Washington University In St Louis
• Original Assignee: Washington University In St Louis
• Inventors: Hawkins, William, Aft, Rebecca, Tu, Zhude, Mach, Robert H., Hotchkiss, Richard
• Granted Patent: US 8,168,650 B2
• Time in Patent Office: Days
• US Class Current: 514/304
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 451/02 containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
• CPC Class Codes: C07D 451/14 containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof

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.

Claims

1. A method of inducing apoptosis in a tumor cell, the method comprising contacting the cell with at least one σ

2 receptor ligand or a salt thereof, wherein the at least one σ

2 receptor ligand is selected from the group consisting of

wherein n is an integer from 1 to about 20.

2. A method of inducing apoptosis in accordance with claim 1, wherein n=6.

3. A method for treating a cancer, the method comprising administering to a subject in need of cancer therapy a therapeutically effective amount of a σ

2 receptor ligand or a salt thereof, wherein the ligand is selected from the group consisting of

wherein n is an integer from 1 to about 20.

4. A method for treating a cancer in accordance with claim 3, wherein n=6.

5. A method for treating a cancer in accordance with claim 3, further comprising administering a chemotherapeutic agent.

6. A method for treating a cancer in accordance with claim 5, wherein the chemotherapeutic agent is selected from the group consisting of doxorubicin, colchicine, adriamycin, vinblastine, digoxin, saquinivir, cisplatin and paclitaxel.

7. A method for treating a cancer in accordance with claim 3, wherein the σ

2 receptor ligand or a salt thereof is comprised by a pharmaceutical composition.