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...

Examples

Embodiment 1

[0068] Weigh 20mg (0.049mmol) of AHU-377 free acid (oil) into a 5.0mL glass bottle, add 1.0mL isopropyl acetate, stir to dissolve, add 5.9mg (0.049mmol) (R)-(+)- α-Phenylethylamine, continue to stir and react for 48 hours, collect the AHU-377(R)-(+)-α-Phenylethylamine salt crystal form obtained by collecting the reaction product, and its powder X-ray diffraction pattern is as follows figure 1 As shown, melting point: 126.6°C (onset point) as figure 2 shown.

Embodiment 2

[0070] Weigh 20mg (0.049mmol) of AHU-377 free acid (oil) into a 5.0mL glass bottle, add 0.4mL of isopropanol, stir to dissolve, add 6.5mg (0.053mmol) of (R)-(+)-α -Phenylethylamine, continue to stir and react for 48 hours, collect the AHU-377 (R)-(+)-alpha-phenethylamine crystal form obtained by the reaction product, its powder X-ray diffraction pattern is basically the same as figure 1 unanimous.

Embodiment 3

[0072] Weigh 20mg (0.049mmol) of AHU-377 free acid (oil) into a 5.0mL glass bottle, add 0.2mL methyl tert-butyl ether, heat to 50°C and stir to dissolve, add 5.9mg (0.049mmol) (R )-(+)-α-phenylethylamine, lower the temperature to room temperature (20-25°C) and continue stirring for 48 hours, and collect the AHU-377(R)-(+)-α-phenylethylamine salt crystals obtained from the reaction product type, its powder X-ray diffraction pattern is basically the same as figure 1 unanimous.

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...

Examples

Embodiment 1

[0068] Weigh 20mg (0.049mmol) of AHU-377 free acid (oil) into a 5.0mL glass bottle, add 1.0mL isopropyl acetate, stir to dissolve, add 5.9mg (0.049mmol) (R)-(+)- α-Phenylethylamine, continue to stir and react for 48 hours, collect the AHU-377(R)-(+)-α-Phenylethylamine salt crystal form obtained by collecting the reaction product, and its powder X-ray diffraction pattern is as follows figure 1 As shown, melting point: 126.6°C (onset point) as figure 2 shown.

Embodiment 2

[0070] Weigh 20mg (0.049mmol) of AHU-377 free acid (oil) into a 5.0mL glass bottle, add 0.4mL of isopropanol, stir to dissolve, add 6.5mg (0.053mmol) of (R)-(+)-α -Phenylethylamine, continue to stir and react for 48 hours, collect the AHU-377 (R)-(+)-alpha-phenethylamine crystal form obtained by the reaction product, its powder X-ray diffraction pattern is basically the same as figure 1 unanimous.

Embodiment 3

[0072] Weigh 20mg (0.049mmol) of AHU-377 free acid (oil) into a 5.0mL glass bottle, add 0.2mL methyl tert-butyl ether, heat to 50°C and stir to dissolve, add 5.9mg (0.049mmol) (R )-(+)-α-phenylethylamine, lower the temperature to room temperature (20-25°C) and continue stirring for 48 hours, and collect the AHU-377(R)-(+)-α-phenylethylamine salt crystals obtained from the reaction product type, its powder X-ray diffraction pattern is basically the same as figure 1 unanimous.

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