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P2X3 inhibitors and uses thereof

A solvate, C3-C6 technology, applied in the field of medicinal chemistry, can solve the problems of unsuitability for long-term medication, unsuitable patients, adverse side effects, etc., and achieve excellent pharmacokinetic properties, good efficacy or druggability, and novel structure Effect

Pending Publication Date: 2022-06-07
WUHAN HUMANWELL INNOVATIVE DRUG RES & DEV CENT LTD CO +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] P2X3 antagonists show great promise. The current clinically used cough drugs gabapentin, morphine and amitriptyline or treatment with speech pathology can improve cough in many patients, but not in all patients, and gabapentin Such central drugs may have adverse side effects and are not suitable for long-term medication. There is an urgent need to develop chronic refractory cough drugs that can be used for a long time to provide doctors with medication options. Therefore, the development of P2X3 antagonists is of great clinical significance

Method used

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  • P2X3 inhibitors and uses thereof
  • P2X3 inhibitors and uses thereof
  • P2X3 inhibitors and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101] Example 1: Preparation of target compound 1

[0102] (R)-3-(5-Methylthiazol-2-yl)-5-(morpholine-4-carbonyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl yl)benzamide (target compound 1)

[0103]

[0104] The synthetic route of target compound 1 is as follows:

[0105]

[0106] The first step: Synthesis of dimethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)isophthalate (1B)

[0107]

[0108] 1,4-Dimethyl 5-bromoisophthalate (1A) (20 g, 73.2 mmol), pinacol Pd(dppf)Cl was added to the solution of dioxane (150 mL) 2 (2.68g, 3.66mmol), after replacing nitrogen three times, the reaction was carried out at 90°C for 16h. TLC showed that the reaction of the raw materials was complete, the system was cooled to room temperature and filtered, the filtrate was concentrated to dryness, and the residue was separated and purified by silica gel column to obtain the product 5-( Dimethyl 4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)isophthalate (1B) (13 g, 55.4% yield).

[...

Embodiment 2

[0130] Example 2: Preparation of target compound 2

[0131] (R)-3-(4-Methylpiperazine-1-carbonyl)-5-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidine-5) -yl)ethyl)benzamide (target compound 2)

[0132]

[0133] The synthetic route of target compound 2 is as follows:

[0134]

[0135] The synthetic method refers to Example 1.

[0136] 1 H NMR (400MHz, DMSO-d 6 )δ9.29(d,1H),9.13(s,2H),8.41(t,1H),8.00-7.95(m,2H),7.69(d,1H),5.37-5.27(m,1H),3.66 (s,2H),3.42-3.37(m,1H),3.30-3.23(m,1H),2.53(d,3H),2.38(d,4H),2.23(s,3H),1.62(d,3H) ).

[0137] LC-MS, M / Z: 519.3 [M+H] + .

Embodiment 3

[0138] Example 3: Preparation of target compound 3

[0139] (R)-3-(3-Hydroxyazetidine-1-carbonyl)-5-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidine) -5-yl)ethyl)benzamide (target compound 3)

[0140]

[0141] The synthetic route of target compound 3 is as follows:

[0142]

[0143] The synthetic method refers to Example 1.

[0144] 1 H NMR (400MHz, DMSO-d 6 )δ9.33(d,1H),9.14(s,2H),8.46(t,1H),8.19-8.15(m,2H),7.69(d,1H),5.81(d,1H),5.38-5.28 (m,1H),4.58-4.44(m,2H),4.37-4.25(m,1H),4.12-4.05(m,1H),3.88-3.80(d,1H),2.53(d,3H),1.63 (d,3H).

[0145] LC-MS, M / Z: 492.2 [M+H] + .

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Abstract

The invention provides a novel compound capable of effectively antagonizing a P2X3 receptor, which is a compound as shown in a formula I, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, a preparation method of the novel compound, and application of the novel compound in preparation of medicines.

Description

[0001] priority information [0002] This application claims the priority and rights of patent application No. 202011411777.9 filed with the State Intellectual Property Office of China on December 4, 2020, and is hereby incorporated by reference in its entirety. technical field [0003] The invention belongs to the field of medicinal chemistry, specifically, the invention relates to P2X3 inhibitors and uses thereof, more specifically, the invention relates to a benzamide compound and a preparation method thereof, and its use in the preparation of medicines. Background technique [0004] P2X receptors are non-selective ATP-gated ion channel receptors, purinergic receptors, that bind to extracellular ATP, mainly from damaged or inflamed tissues. The receptor is widely expressed in the nervous, immune, cardiovascular, skeletal, gastrointestinal, respiratory, endocrine and other systems, and is involved in the regulation of heart rhythm and contractility, regulation of vascular ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12C07D417/14C07D491/107C07D491/08A61K31/5377A61K31/496A61K31/506A61K31/5383A61P29/00A61P11/00A61P13/00A61P13/02A61P13/08A61P13/10A61P11/06A61P11/14A61P9/12
CPCC07D417/12C07D417/14C07D491/107C07D491/08A61P29/00A61P11/00A61P13/00A61P13/02A61P13/08A61P13/10A61P11/06A61P11/14A61P9/12C07B2200/07Y02P20/55
Inventor 张学军臧杨李群叶大炳陈登辉孙红娜杨俊李莉娥
Owner WUHAN HUMANWELL INNOVATIVE DRUG RES & DEV CENT LTD CO
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