Substituted benzamide derivative and application thereof

A technology of drugs and compounds, applied in the field of constipation-type irritable bowel syndrome, can solve problems such as poor clinical treatment effect, and achieve the effects of good pharmacokinetic properties, good brain/plasma ratio, and stable properties

Active Publication Date: 2020-04-03
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007]Although drug substances that regulate the activity of 5-HT4 receptors have been widely used, the current clinical treatment effect of IBS is still not good. Few 5-HT4 receptor agonist compounds are in clinical use

Method used

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  • Substituted benzamide derivative and application thereof
  • Substituted benzamide derivative and application thereof
  • Substituted benzamide derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0188] Example 1 4-amino-5-chloro-N-(1-(3-((5-fluoropyrimidin-2-yl)oxy)propyl)piperidin-4-yl)-2-methoxybenzene Synthesis of formamide

[0189]

[0190] Step 1) Synthesis of (1-(3-hydroxypropyl) piperidin-4-yl) tert-butyl carbamate

[0191] In a 100mL single-necked bottle, add tert-butyl N-(4-piperidinyl)carbamate (2g, 9.99mmol), 3-bromopropan-1-ol (2.08g, 14.98mmol), potassium carbonate (2.78g, 19.97mmol) and acetonitrile (30mL), placed at 80°C for 12 hours to stop the reaction, the reaction solution was directly concentrated, and the residue was separated by column chromatography (dichloromethane / methanol (v / v)=20 / 1) to obtain the title Compound was a white solid (1.5 g, 59%). MS(ESI,pos.ion)m / z:259.25[M+H] + ;

[0192] 1 H NMR (400MHz, CDCl 3 )δ(ppm)4.45(s,1H),3.79–3.73(m,2H),3.45(dd,J=6.9,5.3Hz,1H),2.95(s,2H),2.61–2.53(m,2H) ,2.05(t,J=9.7Hz,2H),1.92(d,J=11.9Hz,2H),1.68(dt,J=10.8,5.4Hz,2H),1.41(s,9H),1.26(d, J=15.8Hz, 2H).

[0193] Step 2) Synthesis of (1-(3-...

Embodiment 2

[0205] Example 2 Synthesis of 2-(3-(4-amino-5-chloro-2-methoxybenzamido)piperidin-1-yl)propoxy)pyrimidine-4-carboxylic acid

[0206]

[0207] Step 1) of 2-(3-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)propoxy)pyrimidine-4-carboxylic acid methyl ester synthesis

[0208] Weigh (1-(3-hydroxypropyl) piperidin-4-yl) tert-butyl carbamate (300mg, 1.16mmol) in a 50mL single-necked bottle, add anhydrous tetrahydrofuran (6mL) and sodium hydride (55mg, 1.39mmol ), stirred for 30 minutes, and then a solution of methyl 2-chloropyrimidine-4-carboxylate (260 mg, 1.51 mmol) dissolved in anhydrous tetrahydrofuran (4 mL) was added dropwise to the reaction flask, and stirred at room temperature for 10 hours. The reaction was stopped, the reaction solution was directly concentrated, and the residue was separated by column chromatography (petroleum ether / ethyl acetate (v / v)=1 / 1) to obtain the title compound as a white solid (160 mg, 35%).

[0209] MS(ESI,pos.ion)m / z:395.20[M+H] + ;

...

Embodiment 3

[0223] Example 3 Synthesis of 4-amino-5-chloro-N-(1-(3-(cyclopentyloxy)propyl)piperidin-4-yl)-2-methoxybenzamide

[0224]

[0225] Step 1) Synthesis of (1-(3-(cyclopentyloxy) propyl) piperidin-4-yl) tert-butyl carbamate

[0226] Weigh (1-(3-hydroxypropyl) piperidin-4-yl) tert-butyl carbamate (1.00g, 3.87mmol) in a 100mL single-necked bottle, add dichloromethane (20mL), add silver carbonate (3.2 g, 11.7mmol) and silver perchlorate (250mg, 1.21mmol), add iodocyclopentane (2.37g, 12mmol) dropwise, and react in the dark at room temperature under nitrogen protection for 7 hours. The reaction was terminated, filtered with suction, and the filtrate was concentrated. The residue was separated and purified by column chromatography (dichloromethane / methanol (v / v)=20 / 1) to obtain the title compound as a white solid (989 mg, 78%).

[0227] MS(ESI,pos.ion)m / z:327.35[M+H] + .

[0228] 1 H NMR (400MHz, CDCl 3 )δ(ppm)3.99–3.79(m,1H),3.47(t,J=6.0Hz,2H),3.32(s,2H),3.18(s,2H),2.88–2.64...

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PUM

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Abstract

The invention discloses a substituted benzamide derivative and application thereof and particularly relates to a novel substituted benzamide derivative and a pharmaceutical composition containing thecompound, and the substituted benzamide derivative can be used as a 5-HT4 receptor agonist. The invention also relates to a method for preparing the compound and the pharmaceutical composition, and the application of the compound and the pharmaceutical composition in the preparation of drugs for treating diseases related to the activity of a 5-HT4 receptor, especially constipation type irritable bowel syndrome (IBS-C).

Description

technical field [0001] The present invention belongs to the technical field of medicines, and specifically relates to novel substituted benzamide derivatives and pharmaceutical compositions containing these compounds, as well as their application methods and purposes. In particular, the novel substituted benzamide derivatives described in the present invention can be used as 5-HT 4 Receptor agonists, for the prevention, treatment or alleviation of 5-HT 4 Diseases associated with receptor activity, especially irritable bowel syndrome with constipation (IBS-C). Background technique [0002] Irritable bowel syndrome (Irritable Bowel Syndrome, IBS), also known as irritable bowel syndrome, is a group of continuous or intermittent attacks, with abdominal pain, bloating, changes in bowel habits and / or stool characteristics as clinical manifestations, and lack of stomach Intestinal dysfunction diseases with abnormal intestinal structure and biochemistry. Rome III listed it as a c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D417/12C07D211/58A61K31/506A61K31/4427A61K31/44A61P3/10A61P1/04A61P1/00A61P1/10
CPCC07D401/12C07D417/12C07D211/58A61P3/10A61P1/04A61P1/00A61P1/10
Inventor 金传飞许腾飞
Owner SUNSHINE LAKE PHARM CO LTD
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