N-substituted piperidine amide 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 good pharmacokinetic properties, good bioavailability, and good safety effects

Active Publication Date: 2020-03-31
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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  • N-substituted piperidine amide derivative and application thereof
  • N-substituted piperidine amide derivative and application thereof
  • N-substituted piperidine amide derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0201] Example 1 Synthesis of 4-amino-5-chloro-N-(1-(3-fluorobenzyl)piperidin-4-yl)-2,3-dihydrobenzofuran-7-carboxamide

[0202]

[0203] Step 1) Synthesis of tert-butyl (1-(3-fluorobenzyl)piperidin-4-yl)carbamate

[0204] Weigh tert-butyl piperidin-4-yl carbamate (1.00g, 4.99mmol), dichloromethane (10mL), triethylamine (1.00g, 9.98mmol) and 1-(bromomethyl)-3-fluoro Benzene (1.13g, 5.99mmol) was placed in a 100mL single-neck flask, dichloromethane (10mL) was added, and the reaction was carried out at room temperature for 12 hours. The reaction solution was directly concentrated, and the residue was subjected to column chromatography (petroleum ether / ethyl acetate (v / v)= 5 / 1) The title compound was isolated as a white solid (1.09 g, 71%).

[0205] MS(ESI,pos.ion)m / z:309.25[M+H] + .

[0206] 1 H NMR(400MHz, CDCl 3 )δ(ppm) 7.32–7.27(m,1H),7.11–7.05(m,2H), 6.96(td,J=8.3,1.7Hz,1H), 4.49(s,1H), 3.50(s,3H) , 2.81 (d, J = 11.6 Hz, 2H), 2.13 (t, J = 10.6 Hz, 2H), 1.97-1.86 (m, 3H), 1.48 (s,...

Embodiment 2

[0215] Example 2 Synthesis of 4-amino-5-chloro-N-(1-(4-fluorobenzyl)piperidin-4-yl)-2,3-dihydrobenzofuran-7-carboxamide

[0216]

[0217] Step 1) Synthesis of tert-butyl (1-(4-fluorobenzyl)piperidin-4-yl)carbamate

[0218] Weigh tert-butyl piperidin-4-yl carbamate (1.00g, 4.99mmol), dichloromethane (10mL), triethylamine (1.00g, 9.98mmol) and 1-(bromomethyl)-4-fluoro Benzene (1.13g, 5.99mmol), add dichloromethane (10mL) to a 100mL single-necked flask, react at room temperature for 12h, directly concentrate the reaction solution, and subject the residue to column chromatography (petroleum ether / ethyl acetate (v / v) = 5 / 1) The title compound was isolated as a white solid (1.35 g, 88%).

[0219] MS(ESI,pos.ion)m / z:309.20[M+H] + .

[0220] Step 2) Synthesis of 1-(4-fluorobenzyl)piperidin-4-amine

[0221] Add dichloromethane (5mL) to a 50mL single-necked flask containing tert-butyl (1-(4-fluorobenzyl)piperidin-4-yl)carbamate (0.80g, 2.6mmol), then add hydrochloric acid and acetic acid Eth...

Embodiment 3

[0228] Example 3 4-Amino-5-chloro-N-(1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-2,3-dihydrobenzofuran Synthesis of -7-formamide

[0229]

[0230] Step 1) Synthesis of tert-butyl (1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)carbamate

[0231] Sequentially combine tert-butyl N-(4-piperidinyl) carbamate (1.00g, 4.99mmol), 4-(bromomethyl)tetrahydropyran (1.16g, 6.48mmol) and potassium carbonate (5.52g, 39.9 mmol) was added to a 100mL single-neck flask, acetonitrile (20mL) was added, the reaction was heated to 90°C for 24 hours, the reaction was stopped, cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was separated and purified by column chromatography (petroleum ether / ethyl acetate Ester (v / v) = 2 / 1) gave the title compound as a white solid (0.68 g, 46%).

[0232] MS(ESI,pos.ion)m / z:299.30[M+H] + .

[0233] Step 2) Synthesis of 1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-amine hydrochloride

[0234] Weigh (1-((tetrah...

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Abstract

The invention discloses an N-substituted piperidine amide derivative and application thereof and particularly relates to a series of novel N-substituted piperidine amide derivatives and medicine compositions comprising same. The compounds can be used as a 5-HT4 receptor stimulant. The invention further relates to method for preparing the compounds and medicine compositions, and applications thereof in preparing medicines for treating diseases related to 5-HT4 receptor activity, especially medicines for treating irritable bowel syndrome-constipation (IBS-C).

Description

Technical field [0001] The present invention belongs to the field of pharmaceutical technology, and specifically relates to novel N-substituted piperidinamide derivatives and pharmaceutical compositions containing these compounds, as well as methods and uses thereof. In particular, the novel N-substituted piperidinamide derivatives of the present invention can be used as 5-HT 4 Receptor agonist, used to prevent, treat or alleviate 5-HT 4 Receptor activity-related diseases, especially constipation-type irritable bowel syndrome (IBS-C). Background technique [0002] Irritable Bowel Syndrome (Irritable Bowel Syndrome, IBS), also known as irritable bowel syndrome, is a group of persistent or intermittent attacks, with abdominal pain, bloating, bowel habits and / or changes in stool characteristics as clinical manifestations, but lack of stomach Intestinal dysfunction disease with abnormal intestinal structure and biochemistry. Rome III classifies it as a type of functional bowel disea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12C07D405/14A61K31/4525A61K31/453A61P1/00A61P3/10A61P1/10
CPCC07D405/12C07D405/14A61P1/00A61P3/10A61P1/10
Inventor 金传飞陈康智许腾飞
Owner SUNSHINE LAKE PHARM CO LTD
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