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N-substituted benzoyl phenothiazine compounds as well as preparation method and application thereof

A compound and mono-substituted technology, applied in the field of medicine, can solve the problems of insufficient activity, side effects and physicochemical properties of benzoazepines

Active Publication Date: 2014-12-24
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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  • N-substituted benzoyl phenothiazine compounds as well as preparation method and application thereof
  • N-substituted benzoyl phenothiazine compounds as well as preparation method and application thereof
  • N-substituted benzoyl phenothiazine compounds as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Preparation of IV-1:

[0059]

[0060] II-1 (100g, 500mmol) was placed in a 1000mL reaction flask, and CH was added 2 Cl 2 (500mL) stirred to dissolve it, added triethylamine (76g, 750mmol), stirred under ice-water bath, added intermediate III-1 (102g, 550mmol) in batches, kept the temperature and stirred for 1h, TLC detection showed that the reaction was complete (developed Agent ethyl acetate: petroleum ether = 1:3).

[0061] 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. The resulting product was recrystallized from ethanol to obtain 161 g of a white solid. The purity is 98.4% (HPLC normalization method), and the yield is 92.1%. ESI-MS ([M+H]+): 349....

Embodiment 2

[0063] Preparation of IV-2:

[0064]

[0065] II-1 (20g, 100mmol) was placed in a 250mL reaction flask, and CHCl was added 3 (100mL) was stirred to dissolve, added pyridine (8.7g, 110mmol), stirred and dissolved at 50°C, added intermediate III-2 (19.5g, 105mmol) in batches, kept the temperature and stirred for 5h, TLC detection showed that the reaction was complete (Developer ethyl acetate:petroleum ether=1:3).

[0066] 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 resulting crude product was purified by silica gel column chromatography to obtain 29.8 g of a white solid. The purity is 99.3% (HPLC normalization method), and the yiel...

Embodiment 3

[0068] Preparation of IV-3:

[0069]

[0070] Put II-2 (20g, 86mmol) in a 250mL reaction flask, add pyridine (60mL), stir to dissolve, cool down to -5°C, add intermediate III-3 (17.2g, 86mmol) in batches, keep stirring at the temperature After 4 hours, TLC detection showed that the reaction was complete (developing agent ethyl acetate:petroleum ether=1:3).

[0071] 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 32.2 g of a white solid. The purity is 98.0% (HPLC normalization method), and the yield is 94.8%. ESI-MS ([M+H]+): 397.0.

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Abstract

The invention relates to N-substituted benzoyl phenothiazine compounds as well as a preparation method and application thereof, and particularly relates to N-substituted benzoyl phenothiazine compounds having a structure as shown in a formula I described in the specification as well as a preparation method of the compounds, pharmaceutical compositions taking the N-substituted benzoyl phenothiazine compounds having a structure as shown in the formula I as active ingredients and use of the pharmaceutical compositions for preventing or treating diseases related to an arginine vasopressin V1a receptor, an arginine vasopressin V1b receptor, an arginine vasopressin V2 receptor, a sympathetic nervous system or a rennin-angiotensin-aldosterone system.

Description

technical field [0001] The invention belongs to the technical field of medicine, and more specifically, relates to a class of N-substituted benzoylphenothiazine compounds and a preparation method and application thereof. 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 ce...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D279/30A61K31/5415A61P9/12A61P15/00A61P5/38A61P9/04A61P1/16A61P5/00A61P3/14A61P25/24A61P25/14
CPCC07D279/30
Inventor 刘登科刘颖穆帅岳南黄阳谭初兵周植星
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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