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Pharmaceutical composition of P2X3 inhibitor and P2X4 inhibitor and application thereof

A P2X4, inhibitor technology, used in drug combinations, antipyretics, anti-inflammatory agents, etc., to achieve good curative effect

Pending Publication Date: 2021-07-09
WUHAN LL SCI & TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are some patients whose etiology cannot be identified after a comprehensive examination, which was previously called chronic idiopathic cough or chronic cough of unknown cause. This type of patients is currently the difficulty in the treatment of chronic cough

Method used

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  • Pharmaceutical composition of P2X3 inhibitor and P2X4 inhibitor and application thereof
  • Pharmaceutical composition of P2X3 inhibitor and P2X4 inhibitor and application thereof
  • Pharmaceutical composition of P2X3 inhibitor and P2X4 inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0104] Preparation Example 1 Preparation of 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2 -(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

[0105] (1) Step 1: Preparation of methyl 3-bromo-5-hydroxybenzoate (intermediate 1A)

[0106]

[0107] A solution of 3-bromo-5-hydroxybenzoic acid (5.0 g, 23.0 mmol) and acetyl chloride (4.0 g, 50.6 mmol) in methanol (50 mL) was stirred at reflux for 16 hours. TLC showed complete conversion of starting material and formation of a new spot. The reaction solution was spin-dried to obtain 4.83 g (91% yield) of the title compound as an off-white solid, which was used in the next step without further purification.

[0108] 1 H-NMR (250MHz, CDCl 3 ): δ[ppm] 7.74(t, J=1.5Hz, 1H), 7.46(dd, J=2.4, 1.3Hz, 1H), 7.25-7.16(m, 1H), 5.57(s, 1H), 3.92( s, 3H).

[0109] (2) Step 2: Preparation of 4-methylbenzenesulfonic acid (3S)-tetrahydrofuran-3-yl ester (intermediate 1B)

[0110]

[0111] A solution of (3S)-te...

preparation example 2

[0138] Preparation Example 2 Preparation of 2-(2-chlorophenyl)-N-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide

[0139] (1) Step 1: Preparation of 2-bromo-5-nitrobenzenesulfonamide (intermediate 2A)

[0140]

[0141] 2-Bromo-5-nitrobenzenesulfonyl chloride (5 g, 16.6 mmol) was dissolved in 1,4-dioxane (25 ml) and cooled to 0 °C. Aqueous ammonia (100ml, 0.50M, 50mmol) was added slowly and stirring was continued at room temperature until the reaction was complete. The solvent was removed under reduced pressure and dichloromethane was added. The organic phase was washed three times with water. The suspension was filtered (solid was product) and the organic phase was washed with brine. The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. The crude product was recrystallized from diethyl ether to give 4.4 g of product (94% yield).

[0142] LC-MS (method Y): Rt = 0.45min; MS (ESIpos): m / z = 281 [...

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Abstract

The invention discloses a pharmaceutical composition of a P2X3 inhibitor and a P2X4 inhibitor and an application of the pharmaceutical composition. The pharmaceutical composition comprises a P2X3 inhibitor and a P2X4 inhibitor, and the weight ratio of the P2X3 inhibitor to the P2X4 inhibitor is 1: (0.5-200). The P2X3 inhibitor and the P2X4 inhibitor play a synergistic role in preventing and / or treating respiratory or pain-related diseases, particularly cough, especially chronic cough, and the curative effect of combined use of the P2X3 inhibitor and the P2X4 inhibitor is better than that of single use of the P2X3 inhibitor or the P2X4 inhibitor.

Description

technical field [0001] The invention relates to a drug combination of a P2X3 inhibitor and a P2X4 inhibitor and application thereof. Background technique [0002] P2X receptors are non-selective cation channels gated by extracellular adenosine triphosphate (ATP), which are ubiquitous in excitatory and non-excitatory cells of higher organisms. In recent years, P2X receptors have attracted much attention as new drug targets, and a number of small molecule drugs targeting this receptor have entered the clinical trial stage. Among them, the discovery of highly specific drug molecules for each subtype of P2X receptors is one of the hot and difficult issues in this field. To date, a variety of P2X receptors have been discovered, including six homologous receptors (P2X1, P2X2, P2X3, P2X4, P2X5, P2X7) and three heterologous receptors (P2X2 / 3, P2X4 / 6, P2X1 / 5). [0003] Among them, P2X3 is a receptor protein expressed on sensory afferent neurons. It is involved in chronic inflamma...

Claims

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Application Information

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IPC IPC(8): A61K31/39A61K31/415A61P29/00A61P11/06A61P11/14A61P11/08A61P11/00A61P25/04
CPCA61K31/39A61K31/415A61P29/00A61P11/06A61P11/14A61P11/08A61P11/00A61P25/04A61K2300/00
Inventor 郭晓丹娄军陈永凯彭微张轶涵柳力钱丽娜陈晓亚王朝东
Owner WUHAN LL SCI & TECH DEV
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