ARNi compound amorphous form and preparation method and application thereof

Abstract

The invention belongs to the technical field of pharmaceutical chemistry polymorphic forms, and particularly relates to an ARNi compound amorphous form and a preparation method and application thereof, and an X-ray powder diffraction pattern of the ARNi compound has no sharp diffraction peak. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of polymorphic forms of pharmaceutical chemistry, and particularly relates to an amorphous ARNi compound and a preparation method and application thereof. Background Art

[0002] Alisartan medoxomil (CAS: 947331-05-7), chemical name: 2-butyl-4-chloro-1-[2'-(1H-tetrazolyl-5-yl)-1,1'-biphenyl-methyl]-imidazole-5-carboxylic acid, 1-[(isopropoxy)-carbonyloxy]-methyl ester, trade name: Xinlitan, is a new type of angiotensin II receptor (AT1) antagonist, referred to as ARB. Its structural formula was first disclosed in Chinese patent CN200610023991.0, and its application in the preparation of hypertension drugs was disclosed. Compared with other antihypertensive products of the same type (such as losartan), Alisartan medoxomil has the characteristics of low toxicity and excellent antihypertensive effect.

[0003] ARB Alisartan medoxomil is hydrolyzed and metabolized in vivo to obtain EXP3174, which then exerts a therapeutic effect. However, the bioavailability of EXP3174 alone is low and the therapeutic effect is poor, mainly because its molecular structure is highly polar and difficult to pass through the cell membrane through passive absorption such as diffusion. It must undergo structural modification to improve its passive absorption. However, the prior art reports that various methods such as chemical modification and formulation administration optimization cannot effectively improve the bioavailability of EXP3174.

[0004]

[0005] Neprilysin (NEP) is a neutral endopeptidase that can degrade a variety of endogenous vasoactive peptides including natriuretic peptides and bradykinin, and can also reduce the level of adrenomedullin. Neprilysin inhibitors (NEPi) can increase the levels of these substances to counteract vasoconstriction, sodium retention and overactivation of the neuroendocrine system.

[0006] Neprilysin inhibitors (NEPi) such as AHU377 (Sacubitril, CAS: 149709-62-6), the chemical formula is: C 24 H 29 NO5, its structure is as follows:

[0007]

[0008] Patent WO2007056546 discloses a sodium salt compound of valsartan-sacubitril (LCZ696) and a preparation method thereof.

[0009] Patent WO2017 / 125031 discloses a series of compounds composed of angiotensin receptor antagonist metabolites and NEP inhibitors, characterized in that the structural units of the compounds are as follows: (aEXP3174·bAHU377)·xCa·nA, wherein 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, dichloromethane; n is a value between 0 and 3.

[0010] Patent WO2021143898 discloses the (aEXP3174·bAHU377)·xCa·nA crystal form, but the physical and chemical properties still need to be improved. Summary of the invention

[0011] The present invention first provides an amorphous ARNi compound.

[0012] Specifically, ARNi is a compound composed of ARB and NEPi, wherein the metabolite of ARB is EXP3174, and the chemical formula is: C 22 H 21 ClN6O2, its structure is as follows:

[0013]

[0014] The neprilysin inhibitor (NEPi) is AHU377 (Sacubitril, CAS: 149709-62-6), and its chemical formula is: 24 H 29 NO5, its structure is as follows:

[0015]

[0016] Specifically, the present invention is implemented by the following technical scheme, providing an amorphous ARNi compound (compound B), the structure of which is as follows:

[0017]

[0018] Among them, its X-ray powder diffraction spectrum has no sharp diffraction peaks.

[0019] As a preferred technical solution of the present invention, the infrared spectrum of the compound is 1708.86, 1639.99, 1556.65, 1521.01cm -1 There is an endothermic peak, with an error of ±5cm -1 .

[0020] As a preferred technical solution of the present invention, the infrared spectrum of the compound is as follows Figure 2 shown.

[0021] As a preferred technical solution of the present invention, the X-ray powder diffraction spectrum of the compound is as follows Figure 3 shown.

[0022] As a preferred technical solution of the present invention, the differential thermal analysis spectrum of the compound has an endothermic peak at 242.9±5°C.

[0023] As a preferred technical solution of the present invention, the differential thermal analysis spectrum of the compound is as follows Figure 4 shown.

[0024] As a preferred technical solution of the present invention, the TG spectrum of the compound is as follows Figure 5 shown.

[0025] As a preferred technical solution of the present invention, the Raman spectrum of the compound is as follows Figure 6 shown.

[0026] The second object of the present invention is to provide a use of the supramolecular complex (compound) of the present invention for preparing drugs for treating a series of cardiovascular diseases including hypertension, heart failure and other complications.

[0027] 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, etc., as well as other damage to the kidneys, brain, cardiovascular and other organs caused by long-term hypertension.

[0028] Furthermore, the present invention provides a use of the compound of the present invention for preparing a drug for treating a series of cardiovascular diseases including hypertension, heart failure and other complications. Specifically, the diseases / complications treated include but are not limited to hypertension, essential hypertension, acute and chronic heart failure, congestive heart failure, heart failure with reduced ejection fraction, heart failure with intermediate ejection fraction, and heart failure with preserved ejection fraction.

[0029] The present invention further provides a pharmaceutical composition, which contains the aforementioned amorphous ARNi compound and one or more pharmaceutically acceptable carriers, wherein the mass percentage of the amorphous compound in the pharmaceutical composition is 0.1 to 99.9%.

[0030] The pharmaceutical composition can be further used in combination with more than one antihypertensive drug for hypertension or drug-resistant hypertension, for example, diuretics such as ethacrynic acid, furosemide and torsemide; angiotensin converting enzyme (ACE) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril; ACE / NEP inhibitors such as omapatrilat, sampatrilat and fasidotril; β-adrenergic receptor blockers such as acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol and timolol; positive inotropic drugs such as digoxin, butamine and milrinone; calcium channel blockers such as amlodipine, bepridil, diltiazem Felodipine, nicardipine, nimodipine, nifedipine, nisoldipine and verapamil; aldosterone receptor antagonists; and aldosterone synthase inhibitors. The most preferred combination components are diuretics (e.g. hydrochlorothiazide) and / or calcium channel blockers (e.g. amlodipine or its salts, levamlodipine or its salts).

[0031] The pharmaceutical composition can be further used in combination with one or more heart failure drugs for heart failure or drug-resistant heart failure, for example, sodium-glucose co-transporter 2 inhibitors (SGLT2i), such as dapagliflozin, empagliflozin, canagliflozin, ertogliflozin and hengagliflozin.

[0032] The beneficial effects of the present invention compared to the prior art include:

[0033] The amorphous material provided by the present invention has better in vivo absorption, smaller particle size, narrower particle size distribution range, and fast removal of solvent residues. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 Infrared spectrum of the crystal form of the compound obtained in Example 1

[0035] Figure 2 Infrared spectrum of the amorphous compound obtained in Example 2

[0036] Figure 3 Example 2 Amorphous XRD spectrum of the compound obtained

[0037] Figure 4 DSC spectrum of the amorphous compound obtained in Example 2

[0038] Figure 5 TG spectrum of the amorphous compound obtained in Example 2

[0039] Figure 6 Example 2 Amorphous solid-state NMR carbon spectrum of the compound obtained

[0040] Figure 7 SEM image of the amorphous compound obtained in Example 2 DETAILED DESCRIPTION

[0041] The present invention is further described in detail below with reference to embodiments and drawings, but the embodiments of the present invention are not limited thereto.

[0042] In the following embodiments:

[0043] X-ray powder diffraction (XRD) spectra were obtained using an Empyrean X-ray diffractometer. The detection conditions were Cu-Kα radiation, wavelength Divergence slit 1 / 4°, X-ray tube voltage 45 kV, X-ray tube current 40 mA, scanning range 3-40° (2θ), step size 0.0262606°, dwell time per step 33.915 s.

[0044] DSC was performed using a German NETZSCH DSC 214 differential scanning calorimeter: experimental atmosphere, N2, 40 ml / min. Scanning procedure: heating from room temperature to 250°C at 10°C / min, using an aluminum sample pan.

[0045] TG was tested using a TG 209F1 thermogravimetric analyzer from NETZSCH, Germany: experimental atmosphere, air, 20 ml / min. Scanning procedure: heating from room temperature to 700°C at 10°C / min, using a platinum sample pan.

[0046] Attenuated total reflection infrared (ATR-IR): Thermo Scientific Nicolet iS5 FTIR Fourier transform infrared spectrometer, number of scans, 32; collection length: 51.21s; laser frequency: 15798.00cm -1 ;

[0047] Solid-state carbon NMR spectrum: Instrument: superconducting pulsed Fourier transform NMR spectrometer, Bruker AVANCENEO600; Conditions: probe, 1.9 mm HX, pulse sequence, CP, rotation speed 25 kHz.

[0048] Scanning electron microscope: Quanta-400 thermal field emission scanning electron microscope

[0049] Example 1

[0050]

[0051] At room temperature, 2.36 g of AHU377 free acid, 42 g of EXP317 and 40 mL of acetone were added to a 250 mL three-necked flask and dissolved; 1.6 equivalents of calcium hydroxide solid and 0.6 mL of water were added relative to AHU377 at room temperature, stirred at 35°C for 6 h, 40 mL of acetone was added, and the mixture was reacted for another 8 h. The mixture was filtered through a Buchner funnel under nitrogen protection, and the solid was rinsed with acetone to obtain a white solid. The solid was vacuum dried at 50°C for 8 h and dried to obtain 3.1 g of compound A crystalline form α solid (the experiment was repeated to obtain a sufficient amount of raw materials for subsequent experiments). The molar ratio of EXP3174 to AHU377 in the obtained product was 1:1 as calculated by content test.

[0052] Example 2 Amorphous Sample Preparation

[0053] Preparation method: Repeat the steps of Example 1, add 8 to 10 times ethanol to 700 g of the α crystal in Example 1, heat to about 50°C, stir and dissolve; filter and set aside; spray drying: inlet temperature 100°C, outlet temperature 60°C, flow rate 8.2-14.4 mL / min, nozzle pressure 0.1 MPa, blowing pressure 4 to 7 cubic meters / minute, to obtain an amorphous product compound B, the composition is as follows:

[0054]

[0055] The infrared spectrum, XRD spectrum, DSC spectrum, TG spectrum, solid-state NMR spectrum and scanning electron microscope spectrum of the amorphous product are shown as follows: Figure 2-7 shown.

[0056] Example 3 Pharmacokinetic Study of Compound in Beagle Dogs

[0057] (1) Experimental Materials

[0058] Beagle dogs: male, 8-10 kg, purchased from Beijing Mas Biotechnology Co., Ltd.

[0059] Test substance: The invisible API obtained in Example 2 was directly filled into capsules

[0060] Reagents: acetonitrile, formic acid, and propranolol (internal standard) are all commercially available.

[0061] Instrument: AB SCIEX TripleQuad5500+ triple quadrupole mass spectrometer.

[0062] (2) Experimental methods

[0063] Five beagle dogs were used for the experiment. Each beagle dog was given a capsule containing the raw material drug. Each capsule contained 240 mg (in the form of anhydrous free acid C 46 H 50ClN7O7) amorphous samples, beagle dogs after oral administration, venous blood 1000μL in anticoagulant tube containing EDTA-K2 was collected at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h, centrifuged at 12000rpm for 2min, plasma was frozen at -80℃ for testing. Accurately weigh a certain amount of test sample and dissolve it in DMSO to 2mg / mL as a stock solution. Accurately draw an appropriate amount of compound stock solution, add acetonitrile to dilute to prepare a standard series of solutions. Accurately draw 10μL of each of the above standard series solutions, add 90μL of blank plasma, vortex mix, and prepare plasma samples equivalent to plasma concentrations of 1, 3, 5, 10, 30, 100, 300, 1000, 3000ng / mL. Double sample analysis was performed for each concentration to establish a standard curve. Take 30 μL of plasma, add 200 μL of acetonitrile solution of internal standard propranolol (50 ng / mL), vortex mix, add 100 μL of purified water, vortex mix again, centrifuge at 4000 rpm for 5 min, and take the supernatant for LC-MS analysis. LC-MS detection conditions are as follows:

[0064] Chromatographic column: YMC Triart C18, 50*3.0mm, 2.1μm.

[0065] Mobile phase: water (0.1% formic acid)-acetonitrile with gradient elution as shown in the table below.

[0066] Table 6

[0067] Time (min) Water (containing 0.1% formic acid) Acetonitrile 0 80％ 20％ 0.6 80％ 20％ 1.2 15％ 85％ 2.6 15％ 85％ 2.61 80％ 20％ 3.2 80％ 20％

[0068] (3) Data processing

[0069] AHU377 and EXP3174 in the composition of compound A, as well as the metabolite LBQ657 of AHU377 were used as analytes, and the results are as follows:

[0070]

[0071] In vivo studies found that the amorphous form showed better in vivo exposure.

[0072] Example 4

[0073] Particle size test, the results are as follows:

[0074] Particle size D10 / μm D50 / μm D90 / μm Compound B Amorphous 7.80 13.90 27.00

[0075] From the above results, it can be seen that the amorphous D50 and D90 have smaller particle sizes than the crystalline forms α, ζ and , and the particle size distribution range (span = (D90-D10) / D50) is narrower, which is more conducive to drug preparation.

[0076] Example 5

[0077] After crystallization, the crystalline solid needs to be quickly filtered and the solvent residue needs to be removed. How to quickly filter and remove the solvent is crucial for industrialization. The present invention unexpectedly found that the amorphous form is easier to filter and remove the solvent than the crystalline form α and the crystalline form ζ. The results are as follows:

[0078]

[0079] Note: The qualified solvent residues refer to ICH Q3C.

[0080] In summary, the amorphous material provided by the present invention has better in vivo absorption, smaller particle size, narrower particle size distribution range, and fast removal of solvent residues.

[0081] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. The ARNi compound is amorphous, characterized in that: The structure of the compound is as follows: Among them, its X-ray powder diffraction spectrum has no sharp diffraction peaks.

2. The ARNi compound according to claim 1 is amorphous, characterized in that The infrared spectrum of the compound is 1708.86, 1639.99, 1556.65, 1521.01 cm -1 There is an endothermic peak, with an error of ±5cm -1 .

3. The ARNi compound according to claim 1 is amorphous, characterized in that The infrared spectrum of the compound is shown in FIG2 .

4. The ARNi compound according to claim 1 or 2 is amorphous, characterized in that The X-ray powder diffraction spectrum of the compound is shown in FIG3 .

5. The ARNi compound according to claim 1 or 2 is amorphous, characterized in that The differential scanning calorimetry analysis spectrum of the compound has an endothermic peak at 242.9±5°C.

6. The ARNi compound according to claim 1 or 2 is amorphous, characterized in that The differential scanning calorimetry analysis spectrum of the compound is shown in FIG4 .

7. The ARNi compound according to claim 1 or 2 is amorphous, characterized in that The thermogravimetric spectrum of the compound is shown in FIG5 .

8. The ARNi compound according to claim 1 or 2 is amorphous, characterized in that The solid-state NMR carbon spectrum of the compound is shown in FIG6 ; and / or the scanning electron microscope image of the compound is shown in FIG7 .

9. Use of the amorphous ARNi compound as described in any one of claims 1 to 8 for preparing a drug for treating heart failure or hypertension.

10. A pharmaceutical composition, characterized in that The pharmaceutical composition contains the amorphous ARNi compound as described in any one of claims 1-8, and one or more pharmaceutically acceptable carriers.

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