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TRPV3 small molecule allosteric inhibitor and preparation method thereof

A technology of allosteric inhibitors and small molecules, which is applied in the field of compounds and their preparation, can solve the problems of slow development, large effective dose, and few structural types, and achieve the effect of increasing structural types and promoting development

Active Publication Date: 2021-03-12
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, most of the original TRPV3 inhibitors are natural products, and the effective dose is large, which may cause serious side effects
Subsequently, three companies, Glenmark, Hydra Biosciences and Abbvie, began to develop TRPV3 small molecule inhibitors, but the existing TRPV3 inhibitors still have problems such as few structural types and slow development

Method used

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  • TRPV3 small molecule allosteric inhibitor and preparation method thereof
  • TRPV3 small molecule allosteric inhibitor and preparation method thereof
  • TRPV3 small molecule allosteric inhibitor and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Synthesis of 2,6-dimethoxy-N-(4-(4-(trifluoromethyl)phenyl)oxazol-2-yl)benzamide:

[0050]

[0051] Step 1: Simultaneously add 2,6-dimethoxybenzoic acid (1.76mmol, 2.0eq.) and excess thionyl chloride, reflux at 85°C for 1-2h, and monitor the reaction by thin-layer chromatography until the raw material disappears. The excess thionyl chloride was evaporated under reduced pressure to obtain a solid.

[0052] Step two:

[0053] Method 1: Put IB 1 (0.88mmol, 1.0eq.) was dissolved in THF, and TEA (2.64mmol, 3.0eq.) was added. The solid obtained in Step 1 (1.76mmol, 2.0eq.) was dissolved in THF under the condition of ice bath and added dropwise to the mixture. After reacting for 1h, the temperature was raised to 75°C and refluxed overnight. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature, and an appropriate amount of saturated NaHCO was slowly added thereto. 3 The solution was quenched and extracte...

Embodiment 2

[0056] Synthesis of 2,3-dimethoxy-N-(4-(4-(trifluoromethyl)phenyl)oxazol-2-yl)benzamide:

[0057]

[0058] The synthetic method of reference compound (I-1), white solid, the yield is 80%. 1 H NMR (400MHz, DMSO-d 6 )δ8.07(s,1H),7.90(s,2H),7.78(dd,J=49.2,8.2Hz,2H),7.53–7.39(m,1H),7.29(t,J=8.1Hz,1H ),6.84(s,1H),3.87(d,J=21.6Hz,6H).HRMS(ESI):calcd.for C 19 h 15 f 3 N 2 o 4 (M+H) + 393.1057; found 393.1046.

Embodiment 3

[0060] Synthesis of 2,4-dimethoxy-N-(4-(4-(trifluoromethyl)phenyl)oxazol-2-yl)benzamide:

[0061]

[0062] Referring to the synthetic method of compound (I-1), method 1 in step 2 was adopted, and the yield was 26% as a pale yellow solid. Method 2 in step 2 can be used, and the yield will be improved. 1 H NMR (400MHz, DMSO-d 6 )δ10.83(s,1H),8.64(s,1H),7.98(d,J=8.1Hz,2H),7.81(d,J=8.2Hz,2H),7.76(d,J=8.6Hz, 1H),6.72–6.67(m,2H),3.90(d,J=30.6Hz,6H).HRMS(ESI):calcd.for C 19 h 15 f 3 N 2 o 4 (M+H) + 393.1057; found 393.1048.

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Abstract

The present invention discloses a TRPV3 small molecule allosteric inhibitor and a preparation method thereof. The small molecule inhibitor comprises compounds represented by a general formula (I) anda general formula (II) shown in the specification or pharmaceutically acceptable salts thereof, wherein X is selected from N or C, Y is selected from (CH2) or (CO); R2 is selected from hydrogen and halogen; R4 is selected from C1-C8 alkyl groups, C3-C8 cycloalkyl groups, a naphthalene ring, an adamantyl group, morpholine, 4-(methylsulfonyl) piperazine and 4-(trifluoromethyl)pyridine-2-amine; and R1 and R3 are respectively and independently selected from hydrogen, deuterium, halogen, hydroxyl, sulfydryl, cyano, nitro, C1-C8 alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, C3-C8 naphthenic bases, C3-C8 cycloalkenyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C10 aryl, C3-C10 heteroaryl and C4-C8 heterocyclic radical.

Description

technical field [0001] The invention relates to a compound and a preparation method thereof, in particular to a TRPV3 small molecule allosteric inhibitor and a preparation method thereof. Background technique [0002] Transient receptor potential (TRP) channels, as a family of non-selective cation channels, were first discovered in Drosophila photoreceptor cells by Cosen et al. in 1969. Mammalian TRP channels have a total of 28 members, which are divided into 7 subgroups according to amino acid sequence homology: TRPC (Canonical), TRPV (Vanilloid), TRPM (Melastatin), TRPP (Polycystin), TRPA (Ankyrin), TRPML (Mucolipin ) and TRPN (NOMPC-like). These channels are activated through a variety of mechanisms and participate in nearly all sensory modalities. [0003] The vanilloid family of transient receptor potentials (TRPV) consists of six ion channels: TRPV1-TRPV6. where TRPV1 / 2 / 3 / 4 is for Ca 2+ A temperature-sensitive channel with suitable permeability, TRPV5 / 6 is for Ca ...

Claims

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Application Information

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IPC IPC(8): C07D263/48C07D413/12A61K31/421A61K31/4439A61K31/5377A61K31/496
CPCC07D263/48C07D413/12
Inventor 杨鹏于烨张芳林义雨陈玮娇王格非
Owner CHINA PHARM UNIV
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