Method for decreasing opioid metabolism

Abstract

8-Substituted-2,6-methano-3-benzazocines of general streucture I in which A is —CH2—OH, —CH2NH2, —NHSO2CH3, and Y is O, S or NOH are useful as analgesics, anti-diarrheal agents, anticonvulsants, antitussives and anti-addiction medications. 8-Carboxamides, thiocarboxamides, hydroxyamidines and formamides are preferred.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of copending U.S. application Ser. No. 10 / 987,527, filed Nov. 12, 2004, which was a continuation of U.S. application Ser. No. 10 / 409,803, filed Apr. 9, 2003, now U.S. Pat. No. 6,887,998, which was a divisional of Ser. No. 10 / 305,287, filed Nov. 26, 2002, now U.S. Pat. No. 6,784,187. U.S. Ser. No. 10 / 305,287 was a continuation-in-part of PCT International application PCT / USO1 / 45581, filed Oct. 31, 2001, and published under PCT Article 21(2) in English on May 10, 2002, as WO 02 / 36573. PCT US01 / 45581 claimed benefit from U.S. provisional application 60 / 244,438, filed Oct. 31, 2000. The entire contents of each of the prior applications are incorporated herein by reference.STATEMENT AS TO RIGHTS UNDER FEDERALLY-SPONSORED RESEARCH [0002] This invention was made with Government support under Contract No. RO1 DA12180, awarded by the National Institutes of Health. Accordingly, the U.S. Government has certain ri...

AI Technical Summary

Benefits of technology

The modified compounds exhibit increased oral bioavailability and prolonged action, making them effective analgesics, anti-diarrheal agents, anticonvulsants, and treatments for various conditions including drug addiction, pain, and gastrointestinal disorders, with potential anti-retroviral and anti-inflammatory properties.

Problems solved by technology

Many opioid receptor-interactive compounds including those used for producing analgesia (e.g., morphine) and those used for treating drug addiction (e.g., naltrexone and cyclazocine) in humans have limited utility due to poor oral bioavailability and a very rapid clearance rate from the body.

Furthermore, the 8-(or 3-)OH group is prone to sulfonation and glucuronidation (Phase II metabolism), both of which facilitate rapid excretion of the active compounds, leading to disadvantageously short half-lives for the active compounds.

Unfortunately, the uniform experience in the art of the past seventy years has been that removal or replacement of the 8-(or 3-)OH group has lead to pharmacologically inactive compounds.