ARNi compound new crystal form theta and preparation method and application thereof

Abstract

The invention belongs to the technical field of pharmaceutical chemistry polymorphic forms, and particularly relates to a novel ARNi compound crystal form theta as well as a preparation method and application thereof.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry polymorph technology, and specifically relates to a new crystal form θ of ARNi compounds, its preparation method and application. Background Technology

[0002] Patent WO2017 / 125031 discloses a series of compounds consisting of angiotensin receptor antagonist metabolites and NEP inhibitors, characterized by the following structural unit: (aEXP3174·bAHU377)·xCa·nA, where a:b = 1:0.25–4; x is a value between 0.5 and 3; A refers to water, methanol, ethanol, 2-propanol, acetone, ethyl acetate, methyl tert-butyl ether, acetonitrile, toluene, and dichloromethane; and n is a value between 0 and 3. Among these, compounds of the following formula and their crystal form α are included:

[0003]

[0004] Patent CN114945564A discloses novel crystal forms β and γ of (aEXP3174·bAHU377)·xCa·nA; CN118176190A discloses novel crystal forms ξ and η of (aEXP3174·bAHU377)·xCa·nA. Finding a more suitable crystal form for pharmaceutical use is of great value for the application of the aforementioned (aEXP3174·bAHU377)·xCa·nA compound. Summary of the Invention

[0005] This invention first provides a new crystal form θ of ARNi compounds.

[0006] Specifically, ARNi is a compound composed of ARB and NEPi, wherein the metabolite of ARB is EXP3174, with the chemical formula: C 22 H 21 ClN6O2 has the following structure:

[0007]

[0008] The enkephalinase inhibitor (NEPi) is AHU377 (Sacubitril, CAS: 149709-62-6), with the chemical formula: C 24 H 29 NO5 has the following structure:

[0009]

[0010] Specifically, the structural units of the supramolecular complex (compound) are as follows:

[0011] (EXP3174·AHU377)·1.5Ca·nH2O;

[0012] The specific structure is as follows: A novel crystal form θ of an ARNi compound, the structure of which is as follows:

[0013]

[0014] Its X-ray powder diffraction pattern shows strong absorption diffraction peaks at 2θ of 4.08°, 4.68°, 5.25°, and 6.13°, with an acceptable error range of ±0.2°.

[0015] As a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the new crystal form θ of the compound is as follows: Figure 1 Or as shown in Figure 3.

[0016] As a preferred embodiment of the present invention, the differential thermal analysis (DTA) spectrum of the new crystal form θ of the compound exhibits an endothermic peak at 245.9 ± 5 °C, and the DTA spectrum is as follows: Figure 2 Or as shown in Figure 4.

[0017] Those skilled in the art will understand that, within the unit cell of the supramolecular complex (compound), the alisartan ester metabolite (EXP3174), AHU377, and calcium ions (Ca) are present. 2+ Solvent molecules and other molecules will fill it in the form of several structural units.

[0018] The supramolecular complex (compound) described in this invention is different from a mixture obtained by simply mixing two active ingredients physically.

[0019] A second objective of this invention is to provide the use of the supramolecular complex (compound) described herein for the preparation of medicaments for treating a range of cardiovascular diseases, including hypertension, heart failure, and other complications.

[0020] Specifically, the diseases / complications treated include, but are not limited to, hypertension, acute and chronic heart failure, congestive heart failure, arrhythmia, atrial fibrillation, myocardial infarction, arteriosclerosis, coronary heart disease, unstable or stable angina, pulmonary hypertension, renal vascular hypertension, and other damage to organs such as the kidneys, brain, and cardiovascular system caused by long-term hypertension.

[0021] The present invention further provides a pharmaceutical composition comprising the aforementioned novel crystal form θ of the ARNi compound and one or more pharmaceutically acceptable carriers, wherein the novel crystal form θ of the compound comprises 0.1% to 99.9% by mass in the pharmaceutical composition.

[0022] The drug carrier includes, but is not limited to, one or more of fillers, disintegrants, binders, lubricants, surfactants, etc., mixed in any proportion.

[0023] The drugs include, but are not limited to, capsules, powders, granules, tablets, and injections.

[0024] Compared with existing technology products, the supramolecular complex (compound) of the present invention is stable in a humid environment and has advantages in terms of acetone solubility, and can be used as an intermediate in the preparation of crystal form α. Attached Figure Description

[0025] Figure 1 XRD pattern of crystal form θ of the compound obtained in Example 2

[0026] Figure 2 DSC spectrum of crystal form θ of the compound obtained in Example 2

[0027] Figure 3 XRD pattern of the compound with crystal form θ obtained in Example 3

[0028] Figure 4 DSC spectrum of crystal form θ of the compound obtained in Example 3

[0029] Figure 5 XRD patterns of the transformation of the compound from crystal form θ to crystal form α Detailed Implementation

[0030] The present invention will now be described in further detail with reference to the embodiments and accompanying drawings, but the implementation of the invention is not limited thereto.

[0031] In the following embodiments:

[0032] X-ray powder diffraction (XRD) patterns were obtained using an Empyrean X-ray diffractometer under the following conditions: Cu-Kα radiation, wavelength... The divergence slit is 1 / 4°, the X-ray tube voltage is 45kV, the X-ray tube current is 40mA, the scanning range is 3-40° (2θ), the step size is 0.0262606°, and the dwell time per step is 30s.

[0033] DSC was performed using a Netzsch DSC 200F3 differential scanning calorimeter: experimental atmosphere, N2, 20 ml / min. Scanning program: temperature increased from room temperature to 260 °C at 10 °C / min, using an aluminum sample pan.

[0034] Example 1

[0035]

[0036] At room temperature, 2.36 g of AHU377 free acid, 2 g of EXP3174, and 40 mL of acetone were added to a 250 mL three-necked flask and dissolved. At room temperature, 1.6 equivalents of calcium hydroxide solid relative to AHU377 and 0.6 mL of water were added, and the mixture was stirred at 35 °C for 6 h. 40 mL of acetone was added, and the reaction was continued for another 8 h. The mixture was filtered through a Buchner funnel under nitrogen protection. The solid was washed with acetone to obtain a white solid, which was dried under vacuum at 50 °C for 8 h to obtain 3.1 g of crystalline α solid. (This experiment was repeated or scaled up to obtain a sufficient amount of raw material for subsequent experiments.) The molar ratio of EXP3174 to AHU377 free acid in the obtained product was 1:1, as determined by content analysis.

[0037] Example 2: Preparation of crystal form θ:

[0038] Repeat the experiment of Example 1. Weigh 1g of sample and stir in 2ml of DMSO solution for about 45min. After filtration through a 0.22um filter membrane, take 1ml of the sample DMSO solution and slowly add 25-70ml of mixed solvent (acetonitrile: methyl acetate: volume ratio 4:1) while shaking to mix. After the addition is complete, filter and evaporate in a glass bottle at 25℃±2℃ to obtain a crystalline solid. HPLC results: purity 99.98%, molar ratio 1:1, water 4.35% (calculated n=2).

[0039] The X-ray powder diffraction pattern and DSC of the compound are as follows: Figure 1 , 2 As shown.

[0040] Example 3: Preparation of crystal form θ:

[0041] Repeat the experiment of Example 1. Weigh 1g of sample and stir in 2ml of DMSO solution for about 45min. After filtration through a 0.22um filter membrane, take 1ml of the sample DMSO solution and then place it in 25-70ml of mixed solvent (acetonitrile:ethyl acetate: volume ratio 4:1) for diffusion. After 3 days, a crystalline solid was obtained. HPLC results: purity 99.91%, molar ratio 1:1, water content 4.05% (calculated n=2).

[0042] The X-ray powder diffraction pattern and DSC of the compound are as follows: Figure 3 , 4 As shown.

[0043] The X-ray powder diffraction peaks of Examples 2 and 3 are summarized in the table below, with an error range of ±0.2°:

[0044] Table 1

[0045]

[0046] Example 4 Stability Study

[0047] (1) Crystal form θ of Example 2 was placed under different humidity levels for different times, and the crystal transformation was observed. The results are as follows:

[0048] sample condition result 1 Place for 1 hour under 75% RH conditions Crystal form θ 2 After being placed at 75% RH for 1 hour, then at 95% RH for 1 hour. Crystal form θ

[0049] The results showed that crystal form θ is stable in a humid environment.

[0050] (2) Crystallization in acetone: Add about 127 mg of crystal form θ to 0.5 ml of acetone and stir at room temperature. After stirring, the solid dissolves. Continue stirring to slowly precipitate the solid until it becomes too thick to stir. Stir for about 4 hours. Purge the solid with nitrogen until dry and measure XRD.

[0051] The results showed that crystal form θ transformed into crystal form α after stirring in acetone (crystal form θ had better solubility in acetone than the original crystal form, and its calcium content was consistent with the original crystal form), such as Figure 5 As shown.

[0052] Therefore, this crystal form is more easily dissolved in formulation processes using acetone as a solvent, and it can be used as an intermediate in the preparation of crystal form α.

[0053] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A novel crystal form θ of ARNi compound, characterized in that, The structure of the compound is as follows: Its X-ray powder diffraction pattern shows strong absorption diffraction peaks at 2θ of 4.08°, 4.68°, 5.25°, and 6.13°, with an acceptable error range of ±0.2°.

2. The new crystal form θ of the ARNi compound according to claim 1, characterized in that, The X-ray powder diffraction pattern of the crystal form θ of the compound is shown in Figure 1 or 3.

3. The new crystal form θ of the ARNi compound according to claim 1 or 2, characterized in that, The differential thermal analysis spectrum of the crystal form θ of the compound showed an endothermic peak at 245.9±5℃.

4. The new crystal form θ of the ARNi compound according to claim 3, characterized in that, The differential thermal analysis spectrum of the crystal form θ of the compound is shown in Figure 2 or 4.

5. Use of a novel crystal form θ of the ARNi compound as described in any one of claims 1-4 for the preparation of a medicament for treating heart failure or hypertension.

6. A pharmaceutical composition, characterized in that, The pharmaceutical composition contains the novel crystal form θ of the ARNi compound as described in any one of claims 1-4, and one or more pharmaceutically acceptable carriers.

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