Crystalline ARB-NEPi dicationic compound and preparation method and application thereof

A dual-cation, crystalline technology, applied in organic chemical methods, active ingredients of heterocyclic compounds, drug combinations, etc., can solve problems such as increasing the risk of cardiovascular burden

Inactive Publication Date: 2016-04-20
SHANGHAI HANSOH BIOMEDICAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, the pure use of sodium salts in complexes carries the risk of increased cardiovascular burden

Method used

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  • Crystalline ARB-NEPi dicationic compound and preparation method and application thereof
  • Crystalline ARB-NEPi dicationic compound and preparation method and application thereof
  • Crystalline ARB-NEPi dicationic compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101] Weigh 500mg of AHU-377 free acid (oil) and 529mg of valsartan into a 100-mL round bottom flask, then add 50mL of acetone to dissolve, and stir at room temperature. In addition, 97 mg of sodium hydroxide and 68 mg of potassium hydroxide were weighed and dissolved in 0.4 mL of water, then added to the acetone solution of AHU377 and valsartan, and stirred overnight at room temperature. Distill about half of the acetone under reduced pressure, then add 25 mL of isopropyl acetate, continue stirring for 4 hours, distill off about half of the solvent volume again under reduced pressure, then add 25 mL of isopropyl acetate, and stir for 4 hours. Filter under the protection of nitrogen, wash the filter cake with isopropyl acetate, and dry to obtain a powdery solid. Its powder X-ray diffraction pattern (XRPD) is as figure 1 shown. See the TGA analysis chart figure 2 . The content of each component in the crystal powder is shown in the table below:

[0102]

[0103] The r...

Embodiment 2

[0108] Weigh 500mg of AHU-377 free acid (oil) and 529mg of valsartan into a 100-mL round bottom flask, then add 50mL of acetone to dissolve, and stir at room temperature. In addition, 121.5 mg of sodium hydroxide and 34 mg of potassium hydroxide were weighed and dissolved in 0.4 mL of water, then added to the acetone solution of AHU377 and valsartan, and stirred overnight at room temperature. Distill about half of the acetone under reduced pressure, then add 25 mL of isopropyl acetate, continue stirring for 4 hours, distill off about half of the solvent volume again under reduced pressure, then add 25 mL of isopropyl acetate, and stir for 4 hours. Filter under the protection of nitrogen, wash the filter cake with isopropyl acetate, and dry to obtain a powdery solid. Its powder X-ray diffraction pattern (XRPD) is as image 3 shown. See the TGA analysis chart Figure 4 . The content of each component in the crystal powder is shown in the table below:

[0109]

[0110] Th...

Embodiment 3

[0115] Weigh 500mg of AHU-377 free acid (oil) and 529mg of valsartan into a 100-mL round bottom flask, then add 50mL of acetone to dissolve, and stir at room temperature. In addition, 24.3 mg of sodium hydroxide and 170.1 mg of potassium hydroxide were weighed and dissolved in 0.4 mL of water, then added to the acetone solution of AHU377 and valsartan, and stirred overnight at room temperature. Distill about half of the acetone under reduced pressure, then add 25 mL of isopropyl acetate, continue stirring for 4 hours, distill off about a normal volume of solvent again under reduced pressure, then add 25 mL of isopropyl acetate, and stir for 4 hours. Filter under the protection of nitrogen, wash the filter cake with isopropyl acetate, and dry to obtain a powdery solid. Its powder X-ray diffraction pattern (XRPD) is as Figure 5 shown. See the TGA analysis chart Figure 6 . The content of each component in the crystal powder is shown in the table below:

[0116]

[0117]...

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PUM

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Abstract

The present invention discloses a crystalline ARB-NEPi dicationic compound and a preparation method and application thereof. In particular, the present invention relates to the crystalline ARB-NEPi dicationic compound having the formula of NEPi.Nax.Ky.ARB.ZH2O. The present invention also relates to a pharmaceutical composition containing an effective amount of the crystalline dicationic compound and application of the pharmaceutical composition in the preparation of drugs for treatment or prevention of neutral-endopeptidase-related diseases, cardiovascular diseases, hypertension, acute and chronic heart failures, congestive heart failure, left ventricular dysfunction, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular arrhythmia and ventricular arrhythmia, atrial fibrillation, atrial flutter or detrimental vascular remodeling, and the like, and the pharmaceutical composition has broad application prospects.

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to a crystalline ARB-NEPi dication complex with dual functions 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 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D257/04C07C233/47A61K31/41A61K31/216A61K45/06A61P9/00A61P9/12A61P13/12A61P3/10A61P9/04A61P9/06A61P9/10A61P25/00A61P25/06A61P25/28A61P27/06
CPCC07D257/04C07B2200/13C07C233/47
Inventor 申志祥李响张磊
Owner SHANGHAI HANSOH BIOMEDICAL
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