AHU-377alpha-phenethylamine salt polycrystalline type and preparation method and application thereof

Abstract

The invention discloses AHU-377alpha-phenethylamine salt polycrystalline type and a preparation method and application thereof and particularly discloses the AHU-377alpha-phenethylamine salt polycrystalline type. An X-radial powder diffraction pattern comprises peaks located at the diffraction angles 2 theta, namely 20.58 + / -0.2 degrees, 24.28 + / -0.2 degrees, 8.38 + / - 0.2 degrees and 23.20 + / -0.2 degrees or peaks located at the diffraction angles 2 theta, namely 23.28+ / -0.2 degrees, 18.9+ / -0.2 degrees, 13.7+ / -0.2 degrees and 14.72+ / -0.2 degrees. The AHU-377 is prepared into the phenethylamine salt to change the physicochemical properties of the AHU-377, such as crystallinity, solubleness and hygroscopicity. The AHU-377alpha-phenethylamine salt polycrystalline type and the preparation method and application thereof are mature in process and high in operability, the obtained product is high in quality, homogeneous and stable, chemical stability is achieved, storage is facilitated, and wide application prospect is achieved.

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to a NEP inhibitor AHU-377α-phenethylamine salt crystal form and a preparation method and application thereof. Background technique [0002] Neutral endopeptidase (EC 3.4.24.11; neprilysin; neprilysin; NEP) is a zinc-containing metalloprotease that cleaves various peptide substrates at the amino terminus of aromatic amino acids. Substrates for this enzyme include, but are not limited to, atrial natriuretic peptide (ANF, also known as ANP), brain natriuretic peptide (BNP), met and leu enkephalins, bradykinin, neurokinin A and substance P. [0003] ANF ​​is a family of vasodilatory, diuretic and antihypertensive peptides, and one form, ANF99-126, is a circulating peptide hormone released by the heart during cardiac dilation. The function of ANF is to maintain salt and water homeostasis and to regulate blood pressure. ANF ​​is rapidly inactivated in circulation by at le...

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Problems solved by technology

[0006] U.S. Patent US5217996 Example 1 reports that its 2-methyl usually exists in the form of a pair of diastereomers (R- or S-configuration), AHU-377 and 2S-methyl diastereomers The ratio of AHU-377 is about 80:20. In the actual production and preparation process, AHU-377 usually appears as oil, which is not conducive to its separation and purification, subsequent formulation development and storage

AHU-377 crude product is esterified with tert-butanol and hydrolyzed with sodium hydroxide, and the aggregation state of AHU-377 sodium salt obtained after dichloromethane / n-hexane recrystallization is unknown, and the inventors found that AHU-377 sodium salt after in-depth research The hygroscopicity is quite large, the substance is unstable and not conducive to storage. Therefore, AHU-377, as an active ingredient of a drug, has great problems in product quality, substance stability, storage or weighing, etc., and its sodium salt has not solved the above problems , although patents US5217996 and WO2007056546 both disclose that AHU-377 can also be prepared into various salt compounds, such as alkali metal salts, alkaline earth metal salts, amine salts, alkylamine salts, hydroxyalkylamine salts, etc., but mainly It is inferred from the chemical structure of AHU-377 that contains a carboxyl group that various salt compounds other than sodium salt have not been actually obtained, which cannot solve the problem of poor product quality, unstable substances, and difficulty in storage and weighing of AHU-377. And other issues

In addition, the application of this drug is for patients with hypertension and heart failure-like cardiovascular diseases, and sodium intake will also increase cardiovascular burden, so it is very necessary to replace sodium salts with salts that do not contain sodium ions, or Other types of salts that are not harmful or beneficial to cardiovascular

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