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Diaryl substituted pyrazole derivative, preparation method and application thereof

A methyl and alkyl technology, applied in the field of new diaryl substituted pyrazole derivatives, can solve the problems of unsatisfactory affinity and low selectivity of CB1 receptors

Inactive Publication Date: 2010-05-19
SHANGHAI SUN SAIL PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, these compounds in the prior art also have disadvantages such as unsatisfactory affinity and low selectivity to CB1 receptors, so there is an urgent need in this field to develop new antagonists and / or anti-CB1 receptors with high selectivity. agonist

Method used

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  • Diaryl substituted pyrazole derivative, preparation method and application thereof
  • Diaryl substituted pyrazole derivative, preparation method and application thereof
  • Diaryl substituted pyrazole derivative, preparation method and application thereof

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preparation example Construction

[0054] In the preparation method of the present invention, each reaction is usually carried out in an inert solvent at room temperature to solvent reflux temperature (such as 0°C-80°C, preferably 0°C-50°C). The reaction time is usually 0.1-60 hours, preferably 0.5-48 hours.

[0055] In a preferred example, the compound of formula (I) of the present invention can be prepared according to the following process:

[0056] Reaction scheme I

[0057]

[0058] Step 1. Compound 1 [J.Med.Chem.2004,47,627] and compound 7 [Chem.Ber.1966,99,2885; J.Med.Chem.2004,47,627] in the presence of a base, in Compound 2 can be obtained by reacting in a suitable solvent.

[0059] The base suitable for the above reaction is an organic base and an inorganic base, and the most suitable base is triethylamine, pyridine, dimethylaminopyridine; the solvent suitable for the above reaction is acetonitrile, DMF, pyridine, methylene chloride, DMSO, tetrahydrofuran, benzene , Toluene.

[0060] The reacti...

Embodiment 1

[0126] Example 1: 3-(4-chlorophenyl)-N-(4-chlorophenylsulfonyl)-4-hydroxy-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbonyl Methyl iminothioate (2a)

[0127] Compound 1 (12.75g, 46.8mmol) and compound 7a (17.73g, 60.0mmol) were dissolved in a mixed solution of acetonitrile (200ml) and triethylamine (20ml), and the mixture was heated to reflux until compound 1 was completely reacted. Concentrate the reaction mixture to dryness, add dichloromethane, wash twice with water, dry over sodium sulfate, and concentrate the residue. %). 1 NMR (CDCl 3)δ: 2.31(s, 3H), 4.62(d, 1H, J=12.18Hz), 4.83(d, 1H, J=12.18Hz), 7.20-7.40(m, 9H), 7.66(dt, 2H, J = 6.97 Hz), 7.82 (dt, 2H, J = 6.78 Hz).

Embodiment 2

[0128] Example 2: N 1 -Methyl-N 2 -(4-chlorophenylsulfonyl)-3-(4-chlorophenyl)-4-hydroxy-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbonylamidine (3a)

[0129] Compound 2a (1.2g, 2.3mmol) was dissolved in a mixed solution of methanol (30ml) and dichloromethane (30ml), and methylamino alcohol solution (18ml) (or excess other amines) was added at room temperature. Stir until compound 2a reacts completely. The reaction mixture was concentrated to dryness, and the residue was directly subjected to column chromatography (developing solvent: petroleum ether: ethyl acetate = 5:1) to obtain compound 3a (0.6 g, 51.7%). 1 NMR (DMSO) δ: 2.95 (s, 3H), 4.13 (d, 1H, J = 12.18Hz), 4.30 (d, 1H, J = 12.18Hz), 7.27-7.57 (m, 9H), 7.65-7.68 ( m, 1H), 7.76-7.85 (m, 4H).

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Abstract

The invention relates to a novel antagonist and / or an inverse agonist of cannabinoide receptor-1 (cannabinoid receptor type 1, CB1) with a structural formula shown as a formula (I), a preparation method and an application thereof. In the structural formula, R1, R2, R3, R4, R5, R6, R7 and R8 are defined as the specification sheet. The compound of the invention can be used for treating, preventing or relieving diseases mediated by the CB1 receptor. The compound and pharmaceutically acceptable salt thereof can also be used for treating, preventing or relieving adiposity, diabetes mellitus, drug dependence, cognitive defect, nervous system diseases, diseases of gastrointestinal tract and cirrhosis.

Description

technical field [0001] The present invention relates to a novel diaryl-substituted pyrazole derivative, its preparation method and application. This type of compound can be used as a powerful cannabinoid receptor-1 (Cannabinoid receptor type 1, CB1) receptor antagonist and / or inverse agonist and has high selectivity to CB1, the compound of the present invention and its pharmacologically acceptable Salts of CB1 can be used to treat, prevent or alleviate diseases mediated by CB1 receptors, such as obesity, diabetes, drug dependence, cognitive deficits, nervous system diseases, gastrointestinal diseases, and liver cirrhosis. Background technique [0002] Obesity is a complex metabolic disease caused by multiple factors and has become a global health problem. Obesity occurs when the energy intake of the human body is greater than the energy consumed by the human body, which has extremely adverse effects on human health and maintaining a good physical and mental state. Accordin...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D231/14A61K31/415A61P25/00A61P3/00A61P1/00
Inventor 易维银陈义朗
Owner SHANGHAI SUN SAIL PHARMA SCI & TECH CO LTD
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