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Isolated hydroxy and N-oxide metabolites and derivatives of O-desmethylvenlafaxine and methods of treatment

A technology for metabolites and derivatives, applied in the field of isolated O-desmethylvenlafaxine hydroxyl and N-oxide metabolites and derivatives and therapeutics

Inactive Publication Date: 2009-09-09
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thus, while some information is known on the metabolites of venlafaxine, see Howell, S.R. et al., " 14 Metabolic Disposition of C-venlafaxine in mice, rats, dogs, macaques and humans 14 C-Venlafaxine in Mouse, Rat, Dog, Rhesus Monkey and Man)", Xenobiotica 23(4):349-359 (1993), but the prior art lacks a complete understanding of all metabolites and their activities

Method used

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  • Isolated hydroxy and N-oxide metabolites and derivatives of O-desmethylvenlafaxine and methods of treatment
  • Isolated hydroxy and N-oxide metabolites and derivatives of O-desmethylvenlafaxine and methods of treatment
  • Isolated hydroxy and N-oxide metabolites and derivatives of O-desmethylvenlafaxine and methods of treatment

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Experimental program
Comparison scheme
Effect test

Embodiment 5

[0061] C. Synthesis

[0062] 1. Synthesis of Free Base Compounds

[0063] The compounds of the present invention can be prepared by those skilled in the art using the methods described below, as well as synthetic methods known in the art of organic synthesis, or modifications of these methods. In general, see Comprehensive Organic Synthesis, "Selectivity, Strategy & Efficiency in Modern Organic Chemistry", edited by I. Fleming, Pergamon Press, New York (1991); Comprehensive Organic Chemistry, "The Synthesis and Reactions of Organic Compounds", edited by J.F. Stoddard, Pergamon Press, New York (1979). Suitable methods include, but are not limited to, those listed below.

[0064] figure 2 A method of synthesizing the 2-hydroxy DV compound of the present invention is provided. In the first step of this synthesis, 4-(demethylcarbamoylmethyl)phenol is protected with a benzyl group. The bromobenzyl protecting group is very suitable for use in the methods of synthesizing the com...

Embodiment 1

[0112] Example 1. In Sprague Dawley rats after oral administration alone [ 14 C] Metabolism of DVS

[0113] Following individual oral gavages to male and female rats as described below, in urine, feces, and plasma, [ 14 C] Six hydroxyl DV compounds and N-oxide DV compounds, among others, were detected in the metabolic profile of DVS.

[0114] Radioactively labeled [ 14 C] DVS (Lot #CFQ13003, [Cyclohexyl-1- 14 C] DVS) was provided by Amersham Biosciences (Buckinghamshire, UK). Unlabeled DVS (lot RB1636; free base 65.2%) was obtained from Wyeth Research, Rouses Point, NY. The average molecular weight of DVS is 381.5, and O-desmethylvenlafaxine accounts for 69.0% by weight. As determined by HPLC with radioactive detection, [ 14 C] The specific activity of DVS (crude drug) is 144 μCi / mg (209 μCi / mg for the free base), and the radiation purity of the free base is 99.3%.

[0115]Water used to prepare solutions for oral administration was obtained from EM Science (Gibbstown, N...

Embodiment 2

[0178] [ 14 Metabolism of C]O-desmethylvenlafaxine

[0179] Following oral gavage alone in male beagle dogs, [ 14 C] (2 or 3)-hydroxy DV compounds, hydroxy DV glucuronides, N-oxide DV compounds, among others, and benzyl hydroxy compounds were detected in the metabolic profile of DVS.

[0180] Materials and methods

[0181] Radiolabeled [ 14 C] DVS (Lot #CFQ13003, [Cyclohexyl-1- 14 C] DVS) was provided by Amersham Biosciences (Buckinghamshire, UK). Unlabeled DVS (lot RB1636; free base 65.2%) was from Wyeth Research, Rouses Point, NY. The average molecular weight of DVS is 381.5, of which the free base O-desmethylvenlafaxine accounts for 69.0% by weight. Measured by HPLC using radioactive detection method, [ 14 C] The specific activity of DVS (crude drug) is 144 μCi / mg (209 μCi / mg for the free base), and the radiation purity of the free base is 99.3%.

[0182] Water used to prepare solutions for oral administration was obtained from EM Science (Gibbstow, NJ). Methylcell...

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Abstract

The present invention provides novel isolated compounds characterized as metabolites or derivatives of desmethylvenlafaxine including hydroxy-DV metabolites, hydroxy-DV-glucuronide metabolites, N-oxide-DV metabolites, and benzyl-hydroxy-DV metabolites. The invention includes pharmaceutical compositions comprising any of the metabolites or derivatives of the invention in combination with a pharmaceutically acceptable carrier or excipient. The invention also includes a method of treating at least one central nervous system disorder in a mammal comprising providing to a mammal in need thereof an effective amount of the compounds of the invention.

Description

Background technique [0001] This application claims priority to US Provisional Patent Application No. 60 / 854,063, filed October 25, 2006, which is incorporated by reference in its entirety. [0002] Venlafaxine, chemically known as 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol, has been shown to be a potent monoamine neurotransmitter Inhibitor of mass uptake, a mechanism implicated in clinical antidepressant activity. Due to its novel structure, venlafaxine has an unrelated mechanism of action to other available antidepressants such as the tricyclic antidepressants desipramine, nostriptyline , protriptyline, imipramine, amitriptyline (amitryptyline), trimipramine, and doxepin. [0003] The mechanism of action of venlafaxine is believed to be related to potent inhibition of the uptake of the monoamine neurotransmitters serotonin and norepinephrine. Venlafaxine also inhibits dopamine reuptake to a lesser extent but has no inhibitory activity on monoamine oxidase....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C215/64C07C291/02C07C305/20C07C305/24A61K31/135A61K31/351A61K31/095
CPCC07C215/64C07C291/04C07C2101/14C07C2601/14A61P13/00A61P25/00A61P25/04A61P25/08A61P25/16A61P25/22A61P25/24A61P25/28A61P25/34
Inventor M·J·霍夫曼W·德迈欧J·王J·W·乌尔里希
Owner WYETH LLC
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