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N-formamido pyrazoline derivative serving as P2X3 receptor antagonist and application thereof

A technology of carboxamidopyrazolines and derivatives, which is applied in the field of medicine and can solve the problems of insufficient patient compliance and the like

Inactive Publication Date: 2020-11-06
HANGZHOU WESTAN PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, the development of antagonists with P2X3 subtype receptor selectivity could address the lack of patient compliance during the treatment of such chronic diseases

Method used

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  • N-formamido pyrazoline derivative serving as P2X3 receptor antagonist and application thereof
  • N-formamido pyrazoline derivative serving as P2X3 receptor antagonist and application thereof
  • N-formamido pyrazoline derivative serving as P2X3 receptor antagonist and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0059] One, the preparation method of main intermediate

[0060] 1. Preparation of intermediate N-formyl chloride pyrazoline derivative (A)

[0061] 1). Synthesis of 4-(N-methylacetamido)-3-(4-methylphenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl chloride (A-1)

[0062]

[0063] Step 1. Synthesis of N-methyl-N-(2-oxo-2-(4-methylphenyl)ethyl)acetamide (A-1a)

[0064] 30% Methanol solution (7.29 g, 70.41 mmol) was added into acetonitrile (20 mL), N 2 Under protection, lower the temperature to -15°C to -10°C, slowly add dropwise a solution of 4-methyl-α-bromoacetophenone (5g, 23.47mmol) in acetonitrile (40mL), and keep at -15°C after the addition is complete Stir at ~-10°C for 20 min. The temperature of the reaction solution was raised to -5°C to 0°C, ice water (60mL) was added dropwise, stirred for 5min, ethyl acetate (30mL) was added, stirred for 5min, the layers were allowed to stand, and the aqueous phase was extracted with ethyl acetate (20mL×2 ), combined the organic phas...

preparation Embodiment 1

[0130] Preparation Example 1. (S)-4-(3-oxomorpholin-4-yl)-3-(4-methylphenyl)-N-((R)-1-(6-(trifluoro Synthesis of methyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (Compound 1)

[0131]

[0132] Synthetic steps: compound A-2 (1.05g, 3.26mmol), compound B-9 (0.62g, 3.26mmol) are added in methylene chloride (10mL), then add N,N-diisopropylethylamine ( DIPEA, 1.26g, 9.75mmol), stirred overnight at room temperature, added 0.5N hydrochloric acid (10mL) and stirred for 10min. Stand to separate the layers, separate the organic phase, extract the aqueous phase with dichloromethane (10mL×3), combine the organic phases, and wash with anhydrous Na 2 SO 4 Drying, filtration, the filtrate was concentrated to dryness under reduced pressure, and the residue was separated by silica gel column chromatography (PE:EA=3:1~1:3, v / v) to obtain the title compound 1 with a yield of 32% and its R , R-epimer 1a, yield 29%.

[0133] The structures of the title compound 1 and its epi...

preparation Embodiment 2

[0139] Preparation Example 2. (S)-4-(4-methyl-2-oxopiperazin-1-yl)-3-(4-methylphenyl)-N-((R)-1-( Synthesis of 4-chlorophenyl)ethyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (compound 2)

[0140]

[0141] Synthesis steps: Compound B-2 (500mg, 2.63mmol) was added in dichloromethane (5mL), cooled to 0°C, N 2 Add triphosgene (370mg, 1.25mmol) under protection, Et 3 N (660mg, 6.55mmol), raised to room temperature and stirred for 1h. The reaction solution was poured into water, extracted with dichloromethane (10mL×2), and the organic phase was washed with anhydrous Na 2 SO 4 Dry, filter, and recover the solvent under reduced pressure to obtain crude isocyanate, which is directly used in the next reaction without further purification.

[0142]Compound 1-(3-(4-methylphenyl)-4,5-dihydro-1H-pyrazol-4-yl)-4-methylpiperazin-2-one (500mg, 1.80mmol), Crude isocyanate (410mg, 2.27mmol), K 2 CO 3 Added to acetone (10mL), N 2 Protected, stirred at room temperature for 2h, TLC showed th...

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PUM

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Abstract

The invention discloses an N-formamido pyrazoline derivative, a compound represented by a general formula (I) or an enantiomer, a diastereoisomer, an epimer, a racemate or pharmaceutically acceptablesalt thereof. The compound is an antagonist of a ligand gated non-selective cationic channel receptor subtype P2X3, and can be used for treating or preventing various diseases mediated by a P2X3 receptor.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to an N-formamidopyrazoline derivative as a ligand-gated non-selective cation channel receptor subtype P2X3 inhibitor, and its preparation and treatment of diseases mediated by P2X3 application in medicine. Background technique [0002] P2X3 is a ligand-gated non-selective cation channel receptor subtype, which belongs to the ionotropic P2X receptor in the purinergic receptor P2 class, and was first cloned in mammals in 1995 (Chen C et al., Nature , 1995, 428; Lewis, C et al., Nature, 1995, 432), so far, there are 7 subtypes of P2X receptors (P2X1~P2X7) that have been cloned in mammals. Each P2X receptor molecule consists of intracellular N-terminal and C-terminal and two transmembrane domains. Although there are differences in subtypes and species of P2X receptors, there is no significant difference in the basic structure of P2X receptors. They are all trimers composed of three homologous o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14C07D403/04C07D403/12C07D231/06C07D413/04C07D405/14C07D401/12C07D401/14C07D403/14A61P11/00A61P11/06A61P11/14A61P29/00A61P25/06A61P25/04A61P17/00A61P17/04A61K31/4439A61K31/5377A61K31/4245A61K31/506A61K31/501A61K31/497A61K31/444A61K31/496A61K31/4178A61K31/4155A61K31/422A61K31/415
CPCC07D413/14C07D403/04C07D403/12C07D231/06C07D413/04C07D405/14C07D401/12C07D401/14C07D403/14A61P11/00A61P11/06A61P11/14A61P29/00A61P25/06A61P25/04A61P17/00A61P17/04A61K31/415A61K31/5377A61K45/06A61K31/496A61K31/506A61K31/422A61K31/4166A61K31/4439A61K31/501A61K31/4245
Inventor 程云锋朱心强
Owner HANGZHOU WESTAN PHARM TECH CO LTD
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