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N-But-3-Enyl norbuprenophine and its use as analgesic

A compound and composition technology, applied in the field of N-but-3-enyl norbuprenorphine and its use as an analgesic, can solve the problems of unknown pharmacological effects and the like

Inactive Publication Date: 2004-06-23
EURO-CELTIQUE SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

kappa 2 Receptor subtypes are identified based on binding studies, but pharmacological effects of this receptor are currently unknown

Method used

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  • N-But-3-Enyl norbuprenophine and its use as analgesic
  • N-But-3-Enyl norbuprenophine and its use as analgesic
  • N-But-3-Enyl norbuprenophine and its use as analgesic

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] Example 1 : Synthesis of N-but-3-enyl norbuprenorphine

[0082] To α-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy-α-methyl, (αS, 5α, 7α )-6,14-vinylidenemorphinan-7-methanol (norbuprenorphine) (0.2 g, 0.47 mmol; obtained from Tasmanian Alkaloids (Tasmania)) in 2 ml Bicarbonate (0.146 g, 1.74 mmol) and 4-bromo-1-butene (0.064 g, 0.47 mmol) were added to the suspension in DMF. The reaction mixture was stirred at 95°C for 16 hours. The cooled reaction mixture was concentrated to dryness under reduced pressure, and the residue was added to 10 ml of dichloromethane and washed with 3×10 ml of water. The resulting organic layer was dried (sodium sulfate) and concentrated under reduced pressure to yield a beige oil which crystallized on standing. This material was purified by flash chromatography on silica gel (2% methanol / dichloromethane) to afford 0.1 g of the desired product as a white crystalline solid. FAB high resolution mass spectrum m / z 468.3091...

Embodiment 2

[0083] Example 2 : Receptor Binding Studies

[0084] δ 2Binding test: The source of the receptor is a human recombinant cell line. The radioligands used in the study were [ 3 H]-naltrindole. Binding reaction in the presence of 5mM MgCl 2 50mM Tris-HCl (PH=7.4) at 25°C for 60 minutes. Binding reactions were terminated by rapid vacuum filtration on glass fiber filters. The radioactivity captured on the filter was measured and compared to the control value.

[0085] κ binding test: the source of the receptor is human recombinant cell line. The radioligand used in the study is [ 3 H]-Cypromorphine. Binding reaction in the presence of 10mM MgCl 2 and 1 mM EDTA in 50 mM Tris-HCl (pH=7.4) at 25° C. for 60 minutes. Binding reactions were terminated by rapid vacuum filtration on glass fiber filters. The radioactivity captured on the filter was measured and compared to the control value.

[0086] μ binding test: the source of the receptor is human recombinant cell line. T...

Embodiment 3

[0091] Example 3 : Binding and functional characterization of N-(3'-butenyl)-norbuprenorphine to opioid receptors; activity at mu, delta, kappa and ORL-1 receptors

[0092] The purpose of this in vitro pharmacology study was to evaluate the binding and functional properties of buprenorphine and its analog N-(3'-butenyl)-norbuprenorphine. Compared with buprenorphine, butenylbuprenorphine derivatives have the same high affinity for μ receptors and reduced affinity for kappa, delta and ORL-1 receptors. The potency ranking formed by the functional characteristics of N-(3-butenyl)-norbuprenorphine is μ>κ δ>ORL-1. This compound is a partial agonist at all four opioid receptors, with the highest potency at the delta receptor.

[0093] A. Binding to opioid μ receptors

[0094] In a final volume of 500gl binding buffer (10mM MgCl 2 , 1mM EDTA, 5% DMSO, 50mM Trizma base, pH7.4) using 0.2nM [ 3 H]-hydramorph (PerkinElmer, Boston, MA; 50.0 Ci / mmol) was radioligated with 20 μg of a...

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PUM

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Abstract

The present invention provides compound having the structure and pharmaceutically acceptable salts or derivatives thereof, as well as compositions including such compounds. The invention also provides methods of (1) preventing pain, (2) treating pain, (3) inducing sedation, (4) treating opiate addiction, (5) treating opiate withdrawal (abstinence syndrome) and / or (6) treating cough in a patient in need thereof by administering a compound or composition of the invention.

Description

[0001] cross-referenced related applications [0002] This application claims priority to US Provisional Patent Application Serial No. 60 / 272,819, filed March 2, 2001, the entire contents of which are hereby incorporated by reference. field of invention [0003] The present invention relates to a compound having significant selectivity for opioid mu receptors over opioid delta, kappa and ORL-1 receptors, compositions and unit dosage forms of said compounds and the use of such compounds, compositions and unit dosages method of form. Background of the invention [0004] The opioid system regulates several physiological processes including analgesia, stress response, immune response, respiratory and neuroendocrine function (Herz, "Opioids", 1993, vol. 1, Springer-Verlag, Berlin). Pharmacological and molecular cloning studies have identified four opioid receptor types (μ, δ, κ, and ORL-1) that mediate the various functions described above (Miotto et al., "The pharmacology of op...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/08A61K9/10A61K9/14A61K9/19A61K9/20A61K9/48A61K31/485A61P11/14A61P25/04A61P39/00A61P43/00C07D489/12
CPCC07D489/12A61P11/14A61P25/04A61P39/00A61P43/00
Inventor B·E·赖登伯格D-D·盖尔V·J·斯里尼瓦桑
Owner EURO-CELTIQUE SA
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