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Sacubitril derivatives and medicine compositions, preparation methods and application thereof

A technology of sacubitril and sacubitril, applied in pharmaceutical composition, preparation of drugs for preventing or treating chronic heart failure and/or hypertension, sacubitril derivatives, its crystal form, preparation field, It can solve the problems of unstable crystal form and long preparation period of crystal form

Active Publication Date: 2016-06-22
SICHUAN HAISCO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the process of preparing and measuring the physical and chemical properties of the crystalline form α of the tritamine salt of Shakubi, we found that the crystalline form has disadvantages such as long preparation period and relatively unstable crystal form.

Method used

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  • Sacubitril derivatives and medicine compositions, preparation methods and application thereof
  • Sacubitril derivatives and medicine compositions, preparation methods and application thereof
  • Sacubitril derivatives and medicine compositions, preparation methods and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0364] Example 1: Preparation of Shakubiqu potassium salt and its crystal form A

[0365] Dissolve 1.4 g (24.3 mmol) of potassium hydroxide in 20 ml of absolute ethanol, and dissolve 10.0 g (24.3 mmol) of sacubi in 100 ml of absolute ethanol. Under stirring, the above-mentioned ethanol solution of potassium hydroxide was added dropwise to the ethanol solution of Shakubiqu. Concentrate under reduced pressure at 40-45°C to a foamy solid. Dissolve the concentrate in 100ml of toluene at 55-60°C, then add n-heptane dropwise, stop the dropwise addition when a precipitate precipitates and dissolves rapidly again (about 100ml of n-heptane is consumed), and cool to about 10°C. Filtrate, wash the filter cake with methyl tert-butyl ether, and dry under reduced pressure at 55-60°C to obtain the potassium salt of sacubitril.

[0366] 1 HNMR (400MHz, DMSO-d 6 ( m,2H),3.891-4.017(m,3H),7.250-7.271(d,2H),7.319-7.355(m,1H),7.428-7.466(m,2H),7.561-7.581(d,2H), 7.639-7.660(d,2H).

[0367]...

Embodiment 2

[0371] Example 2: Preparation of Shakubiqu potassium salt and its crystal form A

[0372] Dissolve 0.12 g (2.19 mmol) of potassium hydroxide in 2 ml of absolute ethanol, and dissolve 1.00 g (2.43 mmol) of sacubi in 10 ml of absolute ethanol. Under stirring, the above-mentioned ethanol solution of potassium hydroxide was added dropwise to the ethanol solution of Shakubiqu. Concentrate under reduced pressure at 40-45°C. Dissolve the concentrate in 5ml of acetone at 50-55°C, then add methyl tert-butyl ether dropwise, stop the dropwise addition when a precipitate precipitates out and dissolves rapidly again (about 20ml of methyl tert-butyl ether is consumed), Cool to about -10°C. After filtering, the filter cake was washed with methyl tert-butyl ether, and dried under reduced pressure at 40-45°C to obtain the crystal form A of the potassium salt of Shakubiqu.

Embodiment 3

[0373] Example 3: Preparation of Shakubiqu potassium salt and its crystal form A

[0374] Dissolve 0.16 g (1.94 mmol) of potassium ethoxide in 2 ml of absolute ethanol, and 1.00 g (2.43 mmol) of sacubiqu in 10 ml of absolute ethanol. Under stirring, the above-mentioned ethanol solution of potassium ethoxide was added dropwise to the ethanol solution of Sacubitra. Concentrate under reduced pressure at 40-45°C. At 55-60°C, dissolve the concentrate in a mixed solvent composed of 20ml of ethyl acetate and 35ml of methyl tert-butyl ether, and cool to about 20°C. After filtering, the filter cake was washed with methyl tert-butyl ether to obtain the crystalline form A of the potassium salt of Sacubitril.

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Abstract

The invention provides sacubitril derivatives and medicine compositions, preparation methods and application thereof and belongs to the fields of medicine compounds and preparation thereof. The sacubitril derivatives comprise sacubitril lithium salt, sacubitril kali salt, sacubitril magnesium salt, sacubitril calcium salt, sacubitril strontium salt, sacubitril zinc salt, sacubitril ferric salt, sacubitril ammonium salt, sacubitril diethylamine salt, sacubitril ethylenediamine salt, sacubitril piperazine salt, sacubitril N-(2-ethoxyl)-pyrrolidine salt, sacubitril choline salt, sacubitril cholamine salt, sacubitril diethanol amine salt, sacubitril triethanolamine salt, sacubitril tromethamine salt, sacubitril meglumine salt, sacubitril diisopropylamine salt, sacubitril tert-butylamine salt, sacubitril N, N'-bis-benzyl ethylenediamine salt, sacubitril L-lysine salt, sacubitril L-arginine salt or sacubitril L-histidine salt.

Description

technical field [0001] The present invention relates to the field of pharmaceutical compounds and their preparation, in particular to sacubitril derivatives, their crystal forms, pharmaceutical compositions, preparation methods, and their use in the preparation of drugs for the prevention or treatment of chronic heart failure and / or hypertension the use of. Background technique [0002] Heart failure (HF) is a disease with high morbidity and mortality worldwide, and also generates a lot of medical costs. The pathophysiological mechanism of HF includes increased ventricular filling pressure, increased vascular stiffness, abnormal systolic function (normal ejection fraction in some patients), etc. In heart failure, the sympathetic nerve and RAAS are overactivated, which can compensatoryly change the blood supply function of the heart in the early stage, and the long-term continuous excitement increases the oxygen consumption of the myocardium and accelerates the death of the ...

Claims

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Application Information

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IPC IPC(8): C07C233/47C07C211/05C07C211/10C07C215/08C07C211/06C07C215/12C07C211/07C07D295/027C07C215/10C07C229/26C07D233/64C07C279/14C07C231/24C07C227/42C07C277/08C07C209/86A61K31/216A61K31/4184A61K31/4178A61K31/41A61K31/4245A61P9/12A61P9/04
CPCA61K9/0053A61K9/2054A61K31/216A61K31/41A61K31/4178A61K31/4184A61K31/4245C07B2200/13C07C209/86C07C211/05C07C211/06C07C211/07C07C211/10C07C215/08C07C215/10C07C215/12C07C227/42C07C229/26C07C231/24C07C233/47C07C277/08C07C279/14C07D233/64C07D295/027A61K2300/00
Inventor 陈大峰高炳呻何永耀赵永龙陆崇玉雷有成李方群罗杰向志祥王宇惠帅唐志勇
Owner SICHUAN HAISCO PHARMA CO LTD
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