Bisamide compounds and preparation method and use thereof

A compound and low-level technology, applied in the field of medicine, can solve the problems of insufficient physicochemical properties of benzoazepines, side effects, etc., and achieve the effect of obvious antagonism

Inactive Publication Date: 2014-10-15
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] As drugs for the treatment of the above-mentioned diseases, benzazepine compounds still have certain deficiencies in terms of activity, side effects and physicochemical properties.

Method used

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  • Bisamide compounds and preparation method and use thereof
  • Bisamide compounds and preparation method and use thereof
  • Bisamide compounds and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055]

[0056] II-1 (100g, 322mmol) was placed in a 2000mL reaction flask, and CH was added 2 Cl 2 (1000mL) was stirred to make it dissolve, added triethylamine (50g, 490mmol), stirred at room temperature, added intermediate III-1 (59.8g, 322mmol) in batches, kept the temperature and stirred for 8h, TLC detection showed that the reaction ended ( Developing agent ethyl acetate:petroleum ether=1:3).

[0057] The reaction solution was poured into 500ml of cold water, fully shaken to separate the layers, and the organic layer was separated and washed three times in succession. The organic layer was dried over anhydrous sodium sulfate and left overnight. After filtration, the solvent was evaporated to dryness under reduced pressure to obtain a light yellow solid crude product. The obtained crude product was recrystallized from ethanol to obtain 140.2 g of light yellow solid. The purity is 98.9% (HPLC normalization method), and the yield is 94.7%. ESI-MS: 460.1.

Embodiment 2

[0059]

[0060] II-1 (20g, 64mmol) was placed in a 250mL reaction flask, and CHCl was added 3 (100mL) stirred to dissolve, added pyridine (7.8g, 98mmol), stirred at 50°C, added intermediate III-2 (12.5g, 67mmol) in batches, kept the temperature and stirred for 5h, TLC detection showed that the reaction was complete (developed Agent ethyl acetate: petroleum ether = 1:3).

[0061] The reaction solution was poured into 100ml of cold water, fully shaken to separate the layers, and the organic layer was separated and washed three times in succession. The organic layer was dried over anhydrous sodium sulfate and allowed to stand overnight. After filtration, the solvent was evaporated to dryness under reduced pressure to obtain a light yellow solid crude product. The obtained crude product was purified by silica gel column chromatography to obtain 23.7 g of a white solid. The purity is 99.9% (HPLC normalization method), and the yield is 80.6%. ESI-MS: 460.1.

Embodiment 3

[0063]

[0064] Put II-2 (20g, 72mmol) in a 250mL reaction flask, add pyridine (60mL), stir to dissolve, stir at -5°C, add intermediate III-3 (15.2g, 76mmol) in batches, keep stirring at the temperature After 24 hours, TLC detection showed that the reaction was complete (developing agent ethyl acetate:petroleum ether=1:3).

[0065] The reaction solution was poured into 300ml of cold water, stirred, and solids were precipitated. After filtering, the filter cake was washed with water and dried to obtain a yellow crude product. The crude product was recrystallized from ethanol to obtain 29.5 g of white solid. The purity is 98.3% (HPLC normalization method), and the yield is 93.1%. ESI-MS: 440.2.

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Abstract

The invention relates to a compound with two amido bonds and a preparation method and use thereof, and particularly relates to the compound with the two amido bonds and a structure shown as the formula I, A pharmaceutically acceptable salt, a preparation method thereof, a pharmaceutical composition using the compound with the two amido bonds and the structure shown as the formula I and the pharmaceutically acceptable salt as active ingredients, and the use of the pharmaceutical composition in prevention or treatment of arginine vasopressin V1a receptor, arginine vasopressin V1b receptor, arginine vasopressin V2 receptor, sympathetic nervous system or renin-angiotensin-aldosterone system related diseases.

Description

technical field [0001] The invention belongs to the technical field of medicine, more specifically, relates to a class of bisamide compounds, a preparation method thereof and an application in the field of medicine. Background technique [0002] Arginine vasopressin (AVP), also known as antidiuretic hormone and vasopressin, is a peptide hormone secreted by the pituitary gland. It regulates body fluids through the receptor-G protein-second messenger pathway. Balance and other functions. AVP plays an important role in regulating the reabsorption of free water in the human body, the isotonic concentration of body fluids, blood volume, blood pressure, cell contraction, cell proliferation, and secretion of adrenal cortex hormones. [0003] Arginine vasopressin exerts various physiological effects by binding to vasopressin receptors. Vasopressin receptors can be divided into three subtypes, V1a, V1b and V2. V1a receptors are distributed in vascular smooth muscle, muscle cells a...

Claims

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Application Information

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IPC IPC(8): C07D401/04A61K31/454A61P9/12A61P15/00A61P15/06A61P25/24A61P25/00A61P1/16A61P9/04A61P7/02
CPCC07D401/04
Inventor 刘登科穆帅刘颖岳南牛端刘昌孝
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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