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Phosphate ester-containing piperazine derivative and preparation method as well as application thereof

An unsaturated compound technology, applied in the field of medicine, can solve the problems such as insufficient activity and side effects of benzoazepine compounds, and achieve obvious effect of receptor antagonism

Inactive Publication Date: 2012-08-08
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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  • Phosphate ester-containing piperazine derivative and preparation method as well as application thereof
  • Phosphate ester-containing piperazine derivative and preparation method as well as application thereof
  • Phosphate ester-containing piperazine derivative and preparation method as well as application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052]

[0053] Dissolve II-1 (20g, 232mmol) in 40ml of pyridine. At this time, pyridine serves as the reaction solvent and acid-binding agent at the same time. Stir at -5°C, add III-1 (26.2g, 232mmol) drop by drop, and keep the temperature for reaction 3h. TLC detection showed that the reaction was complete (developing solvent ethyl acetate:petroleum ether=1:1). The reaction solution was poured into 80ml of water, and a white solid was precipitated. After filtering, the filter cake was washed with water (50ml×3) and dried to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 30.6 g of white solid. The purity is 99.0% (HPLC normalization method), and the yield is 81.0%. EI-MS: 163.1.

Embodiment 2

[0055]

[0056] II-2 (20 g, 200 mmol) was dissolved in CH 2 Cl 2 (50ml), add triethylamine (40g, 400mmol) as an acid-binding agent, stir at 20°C, add III-1 (22.6g, 200mmol) dropwise, and keep the temperature for 2h. TLC detection showed that the reaction was complete (developing solvent ethyl acetate:petroleum ether=1:1). The reaction solution was washed with water (50ml×3), the organic layer was separated, dried over anhydrous sodium sulfate, and left to stand overnight. After filtration, the filtrate was evaporated to dryness to obtain a light yellow solid crude product. The crude product was purified by silica gel column chromatography to obtain 30.0 g of white solid. The purity is 98.0% (HPLC normalization method), and the yield is 85.2%. EI-MS: 177.1.

Embodiment 3

[0058]

[0059] Dissolve II-3 (20g, 200mmol) in 200ml tetrahydrofuran, add potassium carbonate (55.2g, 400mmol) as an acid-binding agent, stir at 60°C, add III-2 (28.2g, 200mmol) dropwise, and keep Temperature reaction 1h. TLC detection showed that the reaction was complete (developing solvent ethyl acetate:petroleum ether=1:1). The reaction solution was poured into 400ml of water, stirred thoroughly to dissolve potassium carbonate, and a yellow solid was precipitated. After filtering, the filter cake was washed with water (100ml×3) and dried to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 31.2 g of white solid. The purity is 96.9% (HPLC normalization method), and the yield is 76.1%. EI-MS: 205.1.

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Abstract

The invention relates to a phosphate ester-containing piperazine derivative and a preparation method as well as application thereof, in particular to one type of phosphate ester-containing piperazine derivatives with a structure shown by a formula I and a preparation method thereof, a medicinal composition with the phosphate ester-containing piperazine derivative with the structure shown by the formula I as an active ingredient and application thereof to preventing or treating diseases related to arginine vasopressin V1a receptors, arginine vasopressin V1b receptors, arginine vasopressin V2 receptors, a sympathetic nervous system or a renin-angiotensin-aldosterone system.

Description

technical field [0001] The invention belongs to the technical field of medicine, more specifically, relates to a class of piperazine derivatives containing phosphoric acid ester and its preparation method and application. 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 c...

Claims

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Application Information

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IPC IPC(8): C07F9/6509A61K31/675A61P1/16A61P5/10A61P5/38A61P9/00A61P9/04A61P9/12A61P15/00A61P15/06
Inventor 刘登科穆帅刘颖祁浩飞解晓帅刘昌孝
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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