Heterocyclic compound and application thereof

A technology of heterocyclic compounds and heteroatoms, applied in the field of heterocyclic compounds, can solve the problems of single structure of TRPC5 inhibitors, and achieve good clinical pharmacokinetic properties, good metabolic stability, and good inhibitory activity

Active Publication Date: 2022-01-04
WUHAN LL SCI & TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The technical problem to be solved by the present invention is that the structure of the existing TRPC5 inhibitors is relatively single. Therefore, the present invention provides a heterocyclic compound and its application

Method used

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  • Heterocyclic compound and application thereof
  • Heterocyclic compound and application thereof
  • Heterocyclic compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0486] Example 1 Compound 4-chloro-5-(3-(2-(trifluoromethyl)benzyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl ) Preparation of pyridazin-3 (2H) ketone (L001)

[0487]

[0488] 1.1 Preparation of compound 5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-tert-butyl carboxylate (L001-1)

[0489] 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (700mg, 5.68mmol) and K 2 CO 3 (1.57g, 11.37mmol) add in the one-necked bottle, add H 2 O (8mL) and THF (8mL), after the complete dissolution, add dropwise (Boc) 2 O, react overnight at room temperature after the addition is complete. TLC (DCM / MeOH=10 / 1) showed that the reaction was complete. NaCl was added to the reaction solution to make it saturated, extracted with EA, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain compound L001-1 (1.2 g) as a brown solid.

[0490] 1.2 Preparation of compound 3-bromo-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-tert-butyl carboxylate (L001-2)

[0491] Add tert-butyl 5,6-dihy...

Embodiment 2

[0500] Example 2 Compound 5-(2-bromo-3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7 (8H)-yl)-4-chloropyridazin-3(2H)-one (L002) preparation process

[0501]

[0502]

[0503] 2.1 Preparation of compound imidazo[1,2-a]pyrazine-3-carbaldehyde (L002-1)

[0504]Aminopyrazine (10.0 g, 0.11 mol) was dissolved in absolute ethanol (100 mL), 2-bromomalondialdehyde (15.8 g, 0.11 mmol) was added, and the mixture was stirred at 90° C. for 2 h. After the reaction, cool to room temperature, spin the solvent to obtain a black viscous object, add 30mL of hydrogen chloride in 1,4-dioxane solution (4mmol / L), stir at 25°C for 12h, after the reaction, add 50mL of water, Use sodium carbonate solution to adjust the pH value to about 8, extract with ethyl acetate (50mL*4), wash the organic phase with saturated brine (30mL*2), dry with anhydrous sodium sulfate, spin dry the solvent, and reconstitute with ethyl acetate After three crystallizations, 3.5 g of a yellow...

Embodiment 3

[0523] Example 3 Compound 7-(5-chloro-6-carbonyl-1,6-dihydropyridazin-4-yl)-3-(4-fluoro-2-(trifluoromethyl)benzyl)-N Preparation of -methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide (L003)

[0524]

[0525] 3.1 Compound 3-(4-fluoro-2-(trifluoromethyl)benzyl)-2-iodo-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate Preparation of tert-butyl acid ester (L003-1)

[0526] 3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester ( L002-6, 0.50 g, 1.25 mmol) was dissolved in dichloroethane (6 mL), and N-iodosuccinimide (0.42 g, 1.87 mmol) was added. Under the protection of nitrogen, the reaction solution was stirred at 90° C. for 1 hour. After the reaction, cool to room temperature, add sodium thiosulfate aqueous solution (10mL) and stir for five minutes, extract with dichloromethane (10mL*3), dry over anhydrous sodium sulfate, filter, and the crude product after the filtrate is concentrated is subjected to ...

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Abstract

The invention discloses a heterocyclic compound and application thereof. The invention specifically discloses a heterocyclic compound as shown in a formula I, and a tautomer or pharmaceutically acceptable salt thereof. The compound has better inhibitory activity on TRPC5, has better metabolic stability in liver microsome, and has better clinical pharmacokinetic properties.

Description

technical field [0001] The present invention relates to a heterocyclic compound and its application. Background technique [0002] A variety of ion channel proteins exist to regulate the flow of ions through cell membranes. Proper expression and function of ion channel proteins are important for the maintenance of cellular function as well as intracellular communication. Many diseases are due to dysregulation of membrane potential or abnormal calcium handling. Given the central importance of ion channels in the regulation of membrane potential and ion flow in cells, the identification of agents that promote or inhibit specific ion channels is of great interest as research tools and as possible therapeutic agents. [0003] TRPC (Transient Receptor Potential Canonical) is one of the most important subfamilies in the TRP superfamily, including TRPC1-7, among which TRPC2 is a pseudogene and does not express in humans. According to amino acid sequence homology and structural c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/501A61K31/551A61P25/18A61P25/00A61P13/12A61P25/22A61P25/24A61P25/20A61P25/28A61P25/14A61P25/08A61P21/00A61P25/16A61P35/00A61P25/04A61P9/10A61P3/10
CPCC07D487/04A61P25/18A61P25/00A61P13/12A61P25/22A61P25/24A61P25/20A61P25/28A61P25/14A61P25/08A61P21/00A61P25/16A61P35/00A61P25/04A61P9/10A61P3/10A61K31/501A61K31/551A61P1/16
Inventor 李金平郭晓丹周锋娄军柳力陈晓亚张轶涵陈永凯王朝东
Owner WUHAN LL SCI & TECH DEV
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