Compound with function of diuresis, preparation method and functions thereof

A compound and drug technology, applied in the field of medicine, can solve the problems of dosage form and route of administration, insufficient intestinal absorption, low water solubility, etc.

Inactive Publication Date: 2012-09-26
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the low water solubility of tolvaptan and insufficient intestinal absorption, the dosage form and route of administration are subject to many restrictions

Method used

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  • Compound with function of diuresis, preparation method and functions thereof
  • Compound with function of diuresis, preparation method and functions thereof
  • Compound with function of diuresis, preparation method and functions thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Preparation of Intermediate III

[0047]

[0048] Add II (50g, 260mmol), triethylamine (40g, 390mmol) and dichloromethane (350ml) to a 1000ml reaction flask, cool to 0°C in an ice bath, stir until it dissolves, and add 5-nitro-2 -Pyridine acid chloride (57.2g, 300mmol), react at room temperature for 30 minutes. TLC [developing agent: ethyl acetate-petroleum ether (1:1), the same below] After detecting that the reaction is complete, add 100 ml of a saturated solution of sodium bicarbonate to the reaction solution, stir for 10 minutes, filter, and filter the cake with dichloromethane (50ml×3)), combined the organic phases, washed with saturated brine (50ml×3), dried over anhydrous sodium sulfate, and filtered. The solvent was recovered from the filtrate under reduced pressure to obtain a crude product, which was recrystallized from absolute ethanol to obtain 55.1 g (62.4%, HPLC 95.5%) of a light yellow powder.

Embodiment 2

[0050] Preparation of Intermediate IV

[0051]

[0052] Add intermediate III (50g, 145mmol) to the 1000ml reaction flask, then add 250ml of dehydrated alcohol and 200ml of concentrated hydrochloric acid, stir for half an hour, slowly add dropwise 150ml of ethanol solution of stannous chloride (115g, 510mmol) in the mixed solution . React at 30°C for four hours. TLC [developer: ethyl acetate-petroleum ether (1:1)] detected that after the reaction was complete, distilled about 300 ml of ethanol under reduced pressure, cooled, precipitated solid, and filtered. Pour the filter cake into 500ml of water, adjust the pH to 9 with about 300ml of 20% sodium hydroxide solution, and filter to obtain a crude product. Recrystallized from absolute ethanol to obtain 31.6 g (69.2%, HPLC 96.6%) of light yellow solid powder.

Embodiment 3

[0054] Preparation of Compound I-1

[0055]

[0056] Add intermediate IV (30g, 95mmol) and pyridine (100ml) successively to a 250ml reaction flask equipped with stirring and a thermometer, stir to dissolve, and then add 1-methylindoline-5-sulfonic acid to the mixed solution dropwise. Pyridine solution of acid chloride (23g, 100mmol) was reacted at room temperature for 1 hour. After the reaction was complete as detected by TLC, it was poured into ice water, fully stirred, filtered, and the obtained solid was recrystallized through anhydrous methanol-petroleum ether (2:1) to obtain light Yellow solid powder 42.7g, (88%, HPLC 96.1%).

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Abstract

The invention belongs to the technical field of medicaments with a function of diuresis, and discloses benzazepine compound with a general formula I structure, pharmaceutically acceptable salts, an R definition and R claims. The invention further discloses a preparation method for the compound, a medicament composition which takes the compound or the pharmaceutically acceptable salts as active effective components and functions of preventing or treating illnesses related to an arginine vasopressin receptor V1a, an arginine vasopressin receptor V1b, an arginine vasopressin receptor V2, a sympathetic nervous system or a system of rennin-angiotensin-aldosterone.

Description

technical field [0001] The present invention belongs to the technical field of medicine, more specifically, relates to a class of compounds with diuretic effect and their preparation methods, pharmaceutical compositions containing them and as arginine vasopressin receptor antagonists, especially arginine vasopressin receptor antagonists. Use of a vasopressin V2 receptor antagonist. Background technique [0002] Arginine vasopressin (AVP), also known as antidiuretic hormone, vasopressin, and vasopressin, is a peptide hormone secreted by the pituitary gland through the receptor-G protein-second messenger pathway , participate in the regulation of various functions such as body fluid balance. AVP plays an important role in regulating the reabsorption of free water, 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 ef...

Claims

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Application Information

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IPC IPC(8): C07D401/12A61K31/55A61P1/16A61P3/12A61P5/10A61P5/38A61P7/10A61P9/00A61P9/04A61P9/12A61P15/00A61P15/06A61P25/24
Inventor 刘登科牛端刘颖穆帅陈旭王平保
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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