Sri International

Japan Tobacco Inc.

Other

Leland Stanford Junior University

Pharmaco Development Partners

John A Lawson

Gilda H Loew

Joseph I DeGraw

Howard L Johnson

Masato Tanabe

Dennis Mitsugu Yasuda

Itsuo Uchida

Joseph I De Graw

Donald A Berkowitz

Anjali Pandey

A method is provided for treating a drug-dependent individual so as to effect withdrawal from a drug of abuse, e.g., an opiate such as heroin or oxycodone, a stimulant such as cocaine, or alcohol. The method involves substitution therapy wherein a substantially nonaddicting normorphine or norcodeine derivative is substituted for the drug of abuse. The active agent has the structure of formula (I) wherein: R is H, alkyl, or acyl; X is CH(OR') or C&#x2550;O, wherein R&#x2032; is H or acyl; &#x3b1; is an optional double bond, with the proviso that when &#x3b1; is present, then X is necessarily CH(OH), or an acid addition salt thereof, wherein preferred such agents are in a stereoisomerically pure form that corresponds to that of N-[(1R)-1-cyclopropylethyl]-normorphine (1) which melts at approximately 188&#xb0; C.-189&#xb0; C.

Treatment of chemical dependency with substantially nonaddicting normorphine and norcodeine derivatives

Analgesic compositions containing stereoisomerically pure normorphine and norcodeine derivatives or pharmaceutically acceptable acid addition salts thereof are described. Methods of administering the novel compositions to achieve analgesia are described as well.

Orally active nonaddicting analgesics

Compounds of the formula I ##STR1## are disclosed. In this formula, R is a member selected from the group consisting of --CR.sub.1 R.sub.2 R.sub.3, hydroxy, an alkoxy group having 1 to 4 carbon atoms and --NR.sub.4 R.sub.5, in which at most one of R.sub.1, R.sub.2 and R.sub.3 is hydrogen and the remainder are each independently selected from the group consisting of an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, an alkynyl group having 2 to 4 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a cycloalkylalkyl having 4 to 9 carbon atoms and a 3 to 6 membered cyclic ether; R.sub.4 and R.sub.5 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms; R.sub.6 and R.sub.7 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms; and R.sub.8 is hydrogen, an alkyl group having 1 to 4 carbon atoms, hydroxy, an alkoxy group having 1 to 4 carbon atoms or halogen. Salts of these compounds are also disclosed. Also disclosed are pharmaceutical compositions of these compounds with a pharmaceutically acceptable carrier, the use of these materials as N-methyl-D-aspartate receptor antagonists, processes for preparing these compounds and salts, and methods to treat cerebral diseases by administering an effective amount of these compounds, salts or compositions.

Benzomorphans useful as NMDA receptor antagonists

Compounds of formula I ##STR1## wherein X is ##STR2## or .dbd.N--O--, in which R.sub.4 is hydrogen or halogen, R.sub.1, R.sub.2, and R.sub.3 independently represent hydrogen or a C.sub.1-4 alkyl group, and n has a value of zero to four are disclosed. Also disclosed are pharmaceutically acceptable salts of these compounds, pharmaceutical compositions of these compounds or salts with a pharmaceutically acceptable carrier, the use of these materials as N-methyl-D-aspartate receptor antagonists, processes for preparing these compounds and salts, and methods to treat cerebral diseases by administering an effective amount of these compounds, salts or compositions.

2-piperidinecarboxylic acid derivatives useful as NMDA receptor

Stereoisomerically pure forms of normorphine analogs which have superior analgesic and nonaddicting qualities are described. In addition, a method of separating diastereomeric forms of N-sec-alkyl-substituted analogs utilizes the hydrocarbyl(1-8C) diesters of the normorphine derivatives. A new method for preparing the N-methylalkylmethyl derivatives of normorphine and norcodeine and their conventional analogs is also disclosed. This method employs the corresponding methyl alkyl ketones and a reducing agent.

Novel N-sec-alkyl derivatives of norcodeine and normorphine wherein the sec-alkyl group contains either four or five carbon atoms. Specifically included are those derivatives of norcodeine and normorphine wherein the sec-alkyl group is 2-butyl, 3-pentyl, .alpha.-methylallyl and .alpha.-methylcyclopropylmethyl. The normorphine derivatives having strong agonist potency combined with strong antagonist qualities and indicated low addiction potential. The norcodeine analogs are useful as intermediates in preparing the corresponding normorphine compounds.

N-Sec-alkyl analogs of norcodeine and normorphine and analgesic

Novel N-sec-alkyl derivatives of norcodeine and normorphine wherein the sec-alkyl group contains either four or five carbon atoms. Specifically included are those derivatives of norcodeine and normorphine wherein the sec-alkyl group is 2-butyl, 3-pentyl, .alpha.-methylallyl and .alpha.-methylcyclopropylmethyl. The normorphine derivatives have strong agonist potency combined with strong antagonist qualities and indicated low addiction potential. The norcodeine analogs are useful as intermediates in preparing the corresponding normorphine compounds.

Growing community of inventors

Fremont, CA, United States of America

John A Lawson