Vanilloid analogues containing resiniferatoxin pharmacophores as potent vannilloid receptor agonists and analgesics, compositions and uses thereof

A group and drug technology, applied in the field of vanilla analogs, can solve the problems of low efficiency, complex structure, difficult synthesis and acquisition, etc.

Inactive Publication Date: 2002-03-27
AMOREPACIFIC CORP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Although a variety of vanilla agonists based on CAP and RTX structures have been reported as potential analgesics (for example, USP 5,021,450 discloses homovanillyl diterpene derivatives such as 12-deoxyphorbol, 13-phenyl acetate , 20-homovanillyl and michitoxin 20-homovanillyl as RTX mimics), these CAP-like analogs are limited by their inherent low potency and narrow therapeutic index
On the other hand, RTX is limited by available natural resources and is difficult to obtain synthetically due to the complexity of its structure

Method used

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  • Vanilloid analogues containing resiniferatoxin pharmacophores as potent vannilloid receptor agonists and analgesics, compositions and uses thereof
  • Vanilloid analogues containing resiniferatoxin pharmacophores as potent vannilloid receptor agonists and analgesics, compositions and uses thereof
  • Vanilloid analogues containing resiniferatoxin pharmacophores as potent vannilloid receptor agonists and analgesics, compositions and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] A cold solution of diethyl malonate (6.4 g, 40 mmol) in DMF (20 mL) at 0 °C was treated stepwise with sodium hydride (60%, 1.92 g, 48 mmol) and stirred at room temperature for 40 min. The reaction mixture was treated with the corresponding substituted benzyl chloride (48 mmol) and stirred overnight at room temperature. The reaction mixture was diluted with water and extracted several times with EtOAc. Combine the organic layers, wash with water and brine, wash with MgSO 4 Dry and concentrate in vacuo. Flash column chromatography of the residue on silica gel with EtOAc / hexane (1:10) as eluent afforded 1. Example 1: Diethyl 3,4-dimethylbenzylmalonate (1b)

[0079] 70% yield, colorless oil; 1 H NMR (CDCl 3 )δ6.9-7.05 (m, 3H), 4.14 (m, 4H, 2×CO 2 CH 2 ), 3.61(t, 1H, CH), 3.25(d, 1H, CH 2 Ar), 3.14(d, 1H, CH 2 Ar), 2.2-2.25(m, 6H, 2×CH 3 ), 1.21(m, 6H, 2×CO 2 CH 2 CH 3 ) Example 2: Diethyl 4-chlorobenzylmalonate (1c)

[0080] 74% yield, colorless oil; 1 H NMR ...

Embodiment 4

[0083] 98% yield, white solid, mp=67°C; 1 H NMR (CDCl 3 ) δ7.15-7.30 (m, 5H, phenyl), 3.74 (dd, 2H, CH 2 OH), 3.62 (dd, 2H, CH 2 OH), 2.9-3.0 (bs, 2H, OH), 2.58 (d, 2H, CH 2 Ph), 2.03 (m, 1H, CH). Example 5: 2-(3,4-Dimethylbenzyl)-1,3-propanediol (2b)

Embodiment 5

[0084] 92% yield, colorless oil; 1 H NMR (CDCl 3 ) δ6.88-7.06 (m, 3H, phenyl), 3.6-3.8 (m, 4H, 2×CH 2 OH), 2.5-2.7 (bs, 2H, OH), 2.60 (d, 1H, CH 2 Ph), 2.52(d, 1H, CH 2 Ph), 2.2-2.28(m, 6H, 2×CH 3 ), 2.02 (m, 1H, CH). Example 6: 2-(4-chlorobenzyl)-1,3-propanediol (2c)

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PUM

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Abstract

The present invention is related to new vanilloid analogues containing resiniferatoxin pharmacophores, pharmaceutical compositions comprising such analogues, and their uses as vanilloid receptor agonists and potent analgesics. The present invention provides a pharmaceutical composition for treating acute, chronic, inflammatory or neuropathic pains or for treating bladder hypersensitivity.

Description

[0001] Vanilla analogues of pharmacophores, compositions and applications thereof technical field [0002] The present invention relates to vanilloid analogues containing resiniferatoxin pharmacophore, pharmaceutical compositions containing these analogues, and the use of these analogues as vanilloid receptor agonists and effective analgesics method. Background technique [0003] Capsaicin (CAP), having the structure shown below, stimulates and then desensitizes sensory afferent C-fibres. This induced desensitization can be used in arthritis, asthma, allergic reactions including rhinitis, fever, pain, bladder hypersensitivity, etc. [0004] Furthermore, the vanilloid receptor (VR) (or capsaicin receptor) is the specific neuronal membrane recognition site for CAP and related excitatory compounds. It is almost exclusively expressed by primary sensory neurons involved in nociception and neuroinflammation. This receptor functions as a cation-selective ion channel, preferably ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C235/34C07C335/12
CPCC07C235/34C07C335/12A61P13/02A61P13/10A61P25/04A61P29/00A61P43/00
Inventor 李智雨吴禹泽朴永镐徐永钜朴亨根金煕斗
Owner AMOREPACIFIC CORP
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