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Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist

A compound and pharmaceutical technology, applied in the field of pharmaceutical compositions containing these compounds, can solve problems such as nerve function damage and nerve cell death

Active Publication Date: 2009-09-02
AMOREPACIFIC CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, primary cultures of afferent sensory neurons were treated with TRPV1 agonist capsaicin, etc., resulting in impairment of nerve function and death of nerve cells

Method used

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  • Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist
  • Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist
  • Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0912] Example 1: 3-(6-tert-butyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonylamino-benzyl)-acrylamide

[0913]

[0914] Step 1: Synthesis of 3-(6-tert-butyl-pyridin-3-yl)-acrylic acid

[0915] To a solution of 6-tert-butyl-pyridine-3-carbaldehyde (1.34 g, 8.75 mmol) in toluene prepared according to a known method was added methyl (triphenylphosphino)acetate (2.93 g) to give The mixture was heated at 90°C for 3 hours. The reaction mixture was diluted with EtOAc, then washed with water and brine. Several layers were dried over anhydrous MgSO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex / EtOAc=4 / 1) to give the ester product (1.56 g, 81%). The resulting ester was dissolved in 1,4-dioxane, treated with water and KOH, stirred, then heated at reflux for 18 hours. The reaction mixture was cooled to room temperature, diluted with water, and washed with ether. The aqueous phase was acidified with 1N HCl, followed by CH...

Embodiment 2

[0921] Example 2: 3-(6-tert-butyl-pyridin-3-yl)-N-(3-chloro-4-methanesulfonylamino-benzyl)-acrylamide

[0922]

[0923] N-(4-Aminomethyl-2-chloro-phenyl)-methanesulfonamide, HCl salt (100mg, 0.35mmol) and 3-(6-tert-butyl-pyridin-3-yl)-acrylic acid (70mg) The reaction afforded 3-(6-tert-butyl-pyridin-3-yl)-N-(3-chloro-4-methanesulfonylamino-benzyl after column chromatography purification (Hex / EtOAc=1 / 2) )-acrylamide (110 mg, 74%).

[0924] 1 H NMR (300MHz, CDCl 3 ): δ 8.66 (d, 1H, J = 2.1Hz), 7.74 (dd, 1H, J = 2.1 and 8.1Hz), 7.64 (d, 1H, J = 15.6Hz), 7.57 (d, 1H, J = 8.7 Hz), 7.41(d, 1H, J=2.1Hz), 7.36(d, 1H, J=8.1Hz), 7.24(dd, 1H, J=2.1 and 8.7Hz), 6.82(s, 1H), 6.48( d, 1H, J=15.6Hz), 6.42(t, 1H), 4.53(d, 2H, J=6.0Hz), 3.00(s, 3H), 1.37(s, 9H)

[0925] ESI[M+H] + : 422.2.

Embodiment 3

[0926] Example 3: 3-(6-tert-butyl-pyridin-3-yl)-N-(3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-acrylamide

[0927]

[0928] N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (70mg, 0.25mmol) and 3-(6-tert-butyl-pyridin-3-yl) - reaction of acrylic acid (52 mg) to give 3-(6-tert-butyl-pyridin-3-yl)-N-(3-ethynyl-5-fluoro after purification by column chromatography (Hex / EtOAc=1 / 2) - 4-Methanesulfonylamino-benzyl)-acrylamide (63 mg, 64%).

[0929] 1 H NMR (300MHz CDCl 3 ): δ 8.71 (d, 1H, J = 2.4Hz), 7.76 (dd, 1H, J = 2.4 and 8.4Hz), 7.63 (d, 1H, J = 16.0Hz), 7.39 (d, 1H, J = 8.4 Hz), 7.28(s, 1H), 7.16(dd, 1H, J=2.1 and 11.0Hz), 6.64(s, 1H), 6.52(d, 1H, J=16.0Hz), 6.47(t, 1H), 4.51(d, 2H, J=6.0Hz), 3.45(s, 1H), 3.24(s, 3H), 1.38(s, 9H)

[0930] ESI[M+H] + : 430.1.

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Abstract

This present invention relates to novel compounds, isomer thereof or pharmaceutically acceptable salts thereof as vanilloid receptor (Vanilloid Receptor 1; VR1; TRPV1 )antagonist; and a pharmaceuticalcomposition containing the same. The present invention provides a pharmaceutical composition for preventing or treating a disease such as pain, migraine, arthralgia, neuralgia, neuropathies, nerve injury, skin disorder, urinary bladder hypersensitiveness, irritable bowel syndrome, fecal urgency, a respiratory disorder, irritation of skin, eye or mucous membrane, stomach-duodenal ulcer, inflammatory diseases, ear disease, heart disease and so on.

Description

technical field [0001] The present invention relates to novel compounds as TRPV1 antagonists, isomers or pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising these compounds. Background technique [0002] Described vanillic acid receptor-1 (VR1, or transient receptor potential vanillic acid-1, TRPV1) is a kind of excitant component in capsicum---capsaicin (8-methyl-N-vanillyl-6-nonyl Enamide) receptors. The molecular cloning of TRPV1 was reported in 1997 (Caterina et al., 1997, Nature, 389, pp816-824), which belongs to the TRP channel family of non-selective cation channels. TRPV1 is activated or sensitized by stimuli such as capsaicin, resinotoxin, heat, acid, anandamide, lipid metabolites, etc., and thus plays a key role in mammals as a molecular integrator of noxious stimuli Sex (Tominaga et al., 1998, Neuron, 21 pp531-543; Hwang et al., 2000, PNAS, 97, pp6155-6160). TRPV1 is primarily expressed in primary afferent sensory neurons, but ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D419/08C07D411/04C07D413/04
CPCC07D213/56C07D213/64C07D213/61C07D213/65A61P25/00A61P29/00
Inventor 金善映金镇官李玘和禹柄英申松锡牟周炫金星日郑然守林庆珉崔镇圭河骏龙高现珠朴永镐徐永钜金熙斗朴亨根吴禹泽
Owner AMOREPACIFIC CORP
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