Heterocyclic derivative inhibitor as well as preparation method and application thereof

A technology of heterocyclyl and heterocyclylalkyl, which is applied in the field of heterocyclic derivative inhibitors and their preparation, and can solve problems such as loss of taste

Pending Publication Date: 2021-02-26
SHANGHAI HANSOH BIOMEDICAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Taste effects, including altered taste and partial loss of taste, were infrequent and mostly mild in nature at all dose levels, with no patients reporting complete loss of taste

Method used

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  • Heterocyclic derivative inhibitor as well as preparation method and application thereof
  • Heterocyclic derivative inhibitor as well as preparation method and application thereof
  • Heterocyclic derivative inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0190] 4-(1-(2-((5-chloropyridin-2-yl)amino)-2-oxoethyl)-5-methyl-1H-benzo[d]imidazol-2-yl)-3 -Fluoro-N-methylbenzamide

[0191]

[0192] The first step: the preparation of 2-bromo-N-(5-fluoropyridin-2-yl)acetamide

[0193]

[0194] To a solution of (1 g, 7.78 mmol) 5-fluoro-pyridin-2-ylamine and 0.3 mL of pyridine in 20 mL of toluene was added dropwise (1.9 g, 7.92 mmol) bromoacetyl bromide dissolved in 5 mL of toluene under ice cooling . After 2 hours, a white solid was precipitated, and the precipitate was separated by filtration and recrystallized from toluene to obtain Example 1-1 (1.8 g, yield: 70%) as a white solid.

[0195] MS m / z(ESI):249.23[M+H] + .

[0196] 1 H NMR (400MHz, MeOD) δ8.29(d, J=2.7Hz, 1H), 8.12(d, J=8.9Hz, 1H), 7.80(dd, J=8.9, 2.7Hz, 1H), 4.04(s ,2H).

[0197] The second step: the preparation of 4-(bromomethyl)-3-fluorobenzoic acid

[0198]

[0199] 3-Fluoro-4-methyl-benzoic acid (7 g, 45.4 mmol) and NBS (8.08 g, 45.4 mmol) were dissolv...

Embodiment 2

[0214] (S)-6-(3-((4-acetylmorpholin-2-yl)methyl)-7-methylimidazol[1,2-a]pyridin-2-yl)-5,7-difluoro -2-Methyl-3,4-dihydroisoquinolin-1(2H)-one

[0215]

[0216] Step 1: Preparation of 5,7-difluoro-2-methyl-3,4-dihydroisoquinolin-1(2H)-one

[0217]

[0218] Example 2-1 (800mg, 5mmol) was dissolved in acetonitrile (10ml), and 1-chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octane bis(tetrafluoroboron Acid acid) (3.54g, 10mmol), the mixture was heated at 80°C to reflux overnight. The reaction solution was cooled to room temperature, concentrated and purified by silica gel column to obtain Example 2-2 (460 mg, 47% yield).

[0219] MS m / z(ESI):198.0[M+H] + ;

[0220] The second step: the preparation of 5,7-difluoro-2-methyl-1-oxo-1,2,3,4-tetrahydroquinoline-6-carbaldehyde

[0221]

[0222] To a solution of Example 2-2 (460 mg, 2.33 mmol) in 2-methyltetrahydrofuran (6 mL) was added TMEDA (595 mg, 5.13 mmol) at room temperature. The resulting solution was cooled to -78°C...

Embodiment 3

[0229] (S)-6-(3-((4-acetylmorpholin-2-yl)methyl)-7-methylimidazol[1,2-a]pyridin-2-yl)-5,7-difluoro -2-Methylisoquinolin-1(2H)-one

[0230]

[0231] Referring to Example 2 for the synthesis method of Example 3, 2-methylisoquinolin-1(2H)-one was used instead of Example 1-1 to obtain Example 3 (23 mg, 10% yield).

[0232] MS m / z(ESI):467.1[M+H] + .

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PUM

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Abstract

The invention relates to a heterocyclic derivative inhibitor as well as a preparation method and an application thereof. In particular, the present invention relates to a compound represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and a use thereof as a P2X3 inhibitor in the treatment of P2X3 receptor dysfunction diseases, especially in the treatment of neurogenic diseases.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a heterocyclic derivative inhibitor and its preparation method and application. Background technique [0002] P2X receptors (P2X receptors) or P2X purinoreceptors (P2X purinoreceptor) is a family of cation-permeable ATP ligand-gated ion channels that can bind to extracellular ATP. P2X receptors have seven subunits and exist in the form of homotrimers or heterotrimers. They are mainly expressed in nerve terminals (pre-synaptic and post-synaptic) of the nervous system and regulate synaptic transmission. The P2X3 receptor is one of the members of the P2X family. It is a key sensory receptor for sensing upper airway stimuli and triggering cough reflexes. It is believed to play a key role in the sensitization of specific sensory nerves, participate in pain and cough, and In bone cancer pain perception, blocking P2X3 suppresses cough signaling. [0003] Cough is a defensive ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D471/04C07D487/04C07D471/14C07D498/04C07D473/18C07D519/00C07D513/14A61K31/4439A61K31/5377A61K31/519A61K31/444A61K31/522A61K31/4545A61P35/00A61P11/14A61P15/00A61P13/00A61P11/00A61P13/10A61P25/02A61P25/04
CPCC07D401/12C07D471/04C07D487/04C07D471/14C07D498/04C07D473/18C07D519/00C07D513/14A61P35/00A61P11/14A61P15/00A61P13/00A61P11/00A61P13/10A61P25/02A61P25/04Y02P20/55
Inventor 肖华玲蔡加强
Owner SHANGHAI HANSOH BIOMEDICAL
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