Novel benzamide derivatives and process for the preparation thereof

A kind of technology of methoxybenzamide and methoxybenzamide group, applied in the field of benzamide derivatives and preparation thereof, and can solve problems such as safety restrictions

Inactive Publication Date: 2010-02-03
DONG A PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, 5-HT 4 Safety of agonists with gastrointestinal prokinetic activity is questioned due to undesired cardiac effects (QT interval prolongation, tachycardia, and torsades de pointes) and drug side effects due to hepatic cytochrome P450 metabolism restricted

Method used

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  • Novel benzamide derivatives and process for the preparation thereof
  • Novel benzamide derivatives and process for the preparation thereof
  • Novel benzamide derivatives and process for the preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0156] Example 1: Preparation of 4-[(cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl Ethyl]piperidine-1-carboxylate

[0157] Step 1: Preparation of ethyl 4-(hydroxymethyl)piperidine-1-carboxylate

[0158] 15 g of 4-piperidinemethanol were dissolved in dichloromethane, and the solution was cooled to 0°C. Next, add 38.4 mL of triethylamine (Et 3 N) followed by the slow addition of 13.7 mL of ethyl chloroformate. The reaction mixture was warmed to room temperature, stirred for 3 hours, then extracted with dichloromethane. The extracted organic layer was dissolved in anhydrous magnesium sulfate (MgSO 4 ), concentrated under reduced pressure, and purified by column chromatography to afford 12 g (49%) of the title compound.

[0159] 1 H NMR (CDCl 3 ): δ4.23-4.08(m, 4H), 3.49(d, J=6.0Hz, 2H), 2.80-2.68(m, 2H), 1.76-1.60(m, 3H), 1.24(t, J=7.2Hz , 3H), 1.20-1.08(m, 2H)

[0160] Step 2: Preparation of ethyl 4-(bromomethyl)piperidine-1-carboxylat...

Embodiment 2

[0167] Example 2: Preparation of 4-[((3S, 4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methanol Ethyl]piperidine-1-carboxylate

[0168] Similar to Example 1, from 485 mg of 4-piperidinemethanol, 0.4 mL of ethyl chloroformate and 400 mg of 4-amino-5-chloro-2-methoxy-N-((3S, 4R)-3- Methoxypiperidin-4-yl)benzamide yielded 208 mg of the title compound (hereinafter referred to as "(+)-norcisapride").

[0169] [α] 25 D =+11.5 (c=0.5, MeOH)

Embodiment 3

[0170] Example 3: Preparation of 4-[2-(cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)ethyl Ethyl]piperidine-1-carboxylate

[0171] Similar to Example 1, 157 mg of the title compound were prepared from 591 mg of 4-piperidineethanol, 0.73 mL of ethyl chloroformate, and 300 mg of cis-norcisapride.

[0172] 1 H NMR (CDCl 3 ): δ8.16(d, J=8.4Hz, 1H), 8.01(s, 1H), 6.25(s, 1H), 4.49(bs, 2H), 4.15-3.96(m, 4H), 3.80(s, 3H), 3.37(bs, 4H), 3.04-2.96(m, 1H), 2.75-2.61(m, 3H), 2.41-2.24(m, 3H), 2.16-2.00(m, 2H), 1.85-1.71( m, 2H), 1.65-1.56(m, 2H), 1.48-1.33(m, 3H), 1.19(t, J=6.8Hz, 3H), 1.15-1.00(m, 2H)

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Abstract

The present invention provides a novel benzamide derivative represented by formula 1 and an isomer, a pharmaceutically acceptable salt or hydrate thereof, and a composition for activating a 5-HT4 receptor comprising the same, as an active ingredient. Benzamide derivatives of the present invention has superior affinity for 5-HT4 receptors, capability to reduce the gastric evacuation time, capability to alleviate ventricular tachycardia, ventricular fibrillation, torsades de pointes and QT prolongation, and low toxicity. Therefore, benzamide derivatives of the present invention are therapeutically effective for digestive system diseases.

Description

technical field [0001] The present invention relates to new benzamide derivatives represented by formula 1 and their isomers, pharmaceutically acceptable salts or hydrates, and also to activating 5-HT containing the derivatives as active ingredients 4 The composition of the receptor. [0002] Background technique [0003] It is generally known that 5-HT 4 Receptor agonists are useful in the treatment of diseases such as gastroesophageal reflux disease, gastrointestinal diseases, gastric motility disorders, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, postoperative ileus, gastric Paresis, dyspepsia, esophagitis, gastroesophageal disease, motion sickness, central nervous system disease, Alzheimer's disease, cognitive impairment, vomiting, migraine, neurological disease, pain, cardiovascular disease, heart Various diseases such as failure, arrhythmia, diabetes and respiratory arrest syndrome are effective in treatment (see: Tips,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/62C07D401/06C07D401/12C07D417/12A61K31/165A61K31/445A61P1/00A61P1/06
CPCC07D405/06C07D401/12C07D211/58C07D401/06C07D417/12C07D413/06A61P1/00A61P1/04A61P1/06A61P1/08A61P1/10A61P1/12A61P1/14A61P11/00A61P25/00A61P25/04A61P25/06A61P25/28A61P3/10A61P43/00A61P9/00A61P9/04A61P9/06C07D211/62A61K31/165A61K31/445
Inventor 刘武姬李在杰任元彬崔成鹤金恩玎朴正祥崔善镐孙兑炅成铉贞金慈映孙铸姬
Owner DONG A PHARMA
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