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Benzamide compound and application thereof

A compound and hydrate technology, applied in the field of medicinal chemistry, can solve problems such as adverse side effects, inapplicability to patients, and unsuitability for long-term medication

Pending Publication Date: 2022-04-12
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

[0007] 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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  • Benzamide compound and application thereof
  • Benzamide compound and application thereof
  • Benzamide compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0274] Embodiment 1: the preparation of target compound I-1

[0275] 2-fluoro-3-(5-methylthiazol-2-yl)-5-(((R)-tetrahydrofuran-3-yl)oxy)-N-((R)-1-(2-(tri Fluoromethyl) pyrimidin-5-yl) ethyl) benzamide (target compound I-1)

[0276]

[0277] The synthetic route of target compound 1-1 is as follows:

[0278]

[0279] The first step: the synthesis of 3-bromo-2-fluoro-5-iodobenzoic acid

[0280]

[0281] 3-Bromo-2-fluorobenzoic acid (10g, 45.7mmol) was dissolved in concentrated sulfuric acid (40mL), NIS (10.27g, 45.7mmol) was added in batches at 0°C, and stirred at room temperature for three hours. Quenched with ice water (200mL), filtered, and the filter cake was washed five times with water (200mL) and dried in vacuo to obtain 3-bromo-2-fluoro-5-iodobenzoic acid as a white solid (10.9g, yield 69.2%) .

[0282] The second step: the synthesis of 3-bromo-2-fluoro-5-hydroxybenzoic acid

[0283]

[0284] Add cuprous oxide (0.656g, 4.74mmol) to a solution of 3-bromo-2...

Embodiment 2

[0308] Embodiment 2: the preparation of target compound 1-2

[0309] 2-fluoro-5-(5-methylthiazol-2-yl)-3-(((R)-tetrahydrofuran-3-yl)oxy)-N-((R)-1-(2-(tri Fluoromethyl) pyrimidin-5-yl) ethyl) benzamide (target compound I-2)

[0310]

[0311] The synthetic route of target compound 1-2 is as follows:

[0312]

[0313] The first step: the synthesis of 5-bromo-2-fluoro-3-iodobenzonitrile

[0314]

[0315] At room temperature, 2,2,6,6-tetramethylpiperidine (8.86mL, 52.5mmol) was dissolved in THF (100mL), and n-butyllithium (21.00mL, 52.5mmol, 2.5M n-hexane solution), the dropping time is more than 30min, and the reaction is stirred at -10°C for 1h, then cooled to -70°C, diethylzinc (58.0mL, 58.0mmol, 1M n-hexane solution) is added, Slowly raise the temperature to 0°C, keep the temperature and stir the reaction for 2h. Then cool to -70°C, add a solution of 5-bromo-2-fluorobenzonitrile (10g, 50.0mmol) in THF (50mL), and react at -70°C for 0.5h , and then warmed up to -30°C,...

Embodiment 3

[0322] Embodiment 3: the preparation of target compound 1-3

[0323] 4-fluoro-3-(5-methylthiazol-2-yl)-5-(((R)-tetrahydrofuran-3-yl)oxy)-N-((R)-1-(2-(tri Fluoromethyl) pyrimidin-5-yl) ethyl) benzamide (target compound I-3)

[0324]

[0325] The synthetic route of target compound 1-3 is as follows:

[0326]

[0327] The synthetic method refers to Example 1.

[0328] 1 H NMR (400MHz, CDCl 3 )δ8.91(d,2H),8.15(dd,1H),7.62-7.59(m,1H),7.55-7.46(m,1H),6.88(d,1H),5.39-5.29(m,1H) , 5.09-5.04 (m, 1H), 4.08-4.00 (m, 3H), 3.93 (td, 1H), 2.57 (d, 3H), 2.32-2.16 (m, 2H), 1.72 (d, 3H).

[0329] LC-MS, M / Z:497.2[M+H] + .

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Abstract

The invention provides a novel compound capable of effectively antagonizing P2X3 receptor, which is a compound as shown in formula I, tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof, preparation methods of the novel compound and the tautomers, the stereoisomers, the hydrates, the solvates and the pharmaceutically acceptable salts or the prodrugs thereof, and application of the novel compound in preparation of drugs

Description

technical field [0001] The present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to benzamide compounds. More specifically, the present invention relates to a benzamide compound, a preparation method thereof, and an application thereof in preparing medicines. Background technique [0002] P2X receptors are non-selective ATP-gated ion channel receptors, that is, purinergic receptors, which can bind extracellular ATP, which is mainly derived 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, the regulation of vascular tension, the regulation of nociception, especially chronic pain, and the contraction of the vas deferens during ejaculation , contraction of the bladder during urination, aggregation of platelets, activation of macropha...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/14A61K31/506A61K31/5377A61P13/00A61P13/08A61P15/00A61P13/02A61P13/10A61P11/00A61P11/06A61P11/14A61P29/00A61P25/00A61P25/04A61P25/02A61P25/06
CPCA61K31/506A61P11/00C07D417/14C07D417/12C07D493/08A61K31/5377A61P29/00A61P13/00A61P11/14
Inventor 张学军臧杨李学强杨成兵王永刚张博李杨刘礼飞杨俊李莉娥
Owner WUHAN HUMANWELL INNOVATIVE DRUG RES & DEV CENT LTD CO
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