WO2021143898A1 - Nouvelle forme cristalline de complexe de métabolite d'arb et d'inhibiteur de nep et son procédé de préparation - Google Patents

Nouvelle forme cristalline de complexe de métabolite d'arb et d'inhibiteur de nep et son procédé de préparation Download PDF

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WO2021143898A1
WO2021143898A1 PCT/CN2021/072414 CN2021072414W WO2021143898A1 WO 2021143898 A1 WO2021143898 A1 WO 2021143898A1 CN 2021072414 W CN2021072414 W CN 2021072414W WO 2021143898 A1 WO2021143898 A1 WO 2021143898A1
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complex
arb
ahu377
exp3174
crystal form
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PCT/CN2021/072414
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English (en)
Chinese (zh)
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许文杰
李松
程冲
孙晶超
华怀杰
颜杰
陈涛
周世强
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深圳信立泰药业股份有限公司
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Priority to CN202180008769.6A priority Critical patent/CN114945564B/zh
Publication of WO2021143898A1 publication Critical patent/WO2021143898A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention belongs to the technical field of medicinal chemistry polymorphs, and particularly relates to a new crystal form of a complex of ARB metabolites and NEP inhibitors and a preparation method thereof.
  • Allisartan medoxomil (CAS: 947331-05-7), chemical name: 2-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl -Methyl]-imidazole-5-carboxylic acid, 1-[(isopropoxy)-carbonyloxy]-methyl ester, trade name: Xin Litan, is a new type of angiotensin II receptor (AT1 ) Antagonist, abbreviated as ARB, its structural formula is disclosed for the first time in Chinese patent CN200610023991.0, and its application in the preparation of hypertension drugs is disclosed. Compared with other antihypertensive products of the same type (such as Losartan), Allisartan medoxomil has the characteristics of low toxicity and superior antihypertensive effect.
  • ARB allisartan medoxomil is hydrolyzed and metabolized in the body to get EXP3174 to play a therapeutic role.
  • the bioavailability of EXP3174 as a single medicine is low, and the treatment effect is not good. It is mainly due to the high polarity of its molecular structure, which is difficult to pass through the cell membrane through passive absorption such as diffusion. It must be structurally modified to improve its passive absorption.
  • various methods such as chemical modification and formulation administration optimization cannot effectively improve the bioavailability of EXP3174.
  • Enkephalinase is a neutral endopeptidase that can degrade a variety of endogenous vasoactive peptides including natriuretic peptide and bradykinin, and can also reduce the level of adrenomedullin and enkephalin Enzyme inhibitors (NEPi) can increase the levels of these substances to combat vasoconstriction, sodium retention and excessive activation of the neuroendocrine system.
  • Enkephalinase inhibitors such as AHU377 (Sacubitril, CAS: 149709-62-6), the chemical formula is: C 24 H 29 NO 5 , and its structure is as follows:
  • Patent WO2007056546 discloses a sodium salt complex (LCZ696) of valsartan-sacubitril (Sacubitril) and a preparation method thereof.
  • the present invention first provides a new crystal form of a complex of ARB metabolites and NEP inhibitors.
  • the metabolite of the ARB is EXP3174, the chemical formula is: C 22 H 21 ClN 6 O 2 , and its structure is as follows:
  • the enkephalinase inhibitor is AHU377 (Sacubitril, CAS: 149709-62-6), the chemical formula is: C 24 H 29 NO 5 , and its structure is as follows:
  • the structural units of the supramolecular complex are as follows:
  • x is a value between 0.5 and 2; n is further any value between 0 and 3. Specifically, such as 0, 0.5, 1, 1.5, 2, 2.5, 3, etc.
  • n is a value between 0 and 3.
  • the supramolecular complex (complex) of the present invention is different from a mixture obtained by simple physical mixing of two active ingredients.
  • the X-ray powder diffraction (XRD) spectrum of the supramolecular complex (complex) has a diffraction peak with strong absorption at 4.7° 2 ⁇ ,
  • the acceptable error range is ⁇ 0.2°.
  • peaks with strong absorption intensity it is less affected by factors such as product characteristics, testing equipment, testing conditions, etc., so the probability of recurrence is very high.
  • peaks with weaker absorption intensity may not have high reproducibility. The inventors are reviewing the same batch/different batches. Repeated testing of samples also found that this phenomenon also exists for this supramolecular complex (complex), which is named crystal form ⁇ .
  • the X-ray powder diffraction (XRD) spectrum of the supramolecular complex (complex) is shown in FIG. 1.
  • the molar ratio of EXP3174 to AHU377 in the supramolecular complex (complex) can be obtained directly/indirectly by the content analysis method.
  • the high performance liquid method HPLC
  • the molar ratio is 1:1.
  • the differential scanning calorimetry (DSC) of the supramolecular complex (complex) has a melting and decomposition peak at 241.38 ⁇ 5°C. Because the supramolecular complex (complex) contains crystal water, it is known in the art The skilled person can understand that under different detection conditions, such as heating rate, etc., as well as different sample properties, such as sample particle size state, etc., certain peaks in the DSC spectrum (such as the endothermic peak of water loss) may have large fluctuations. For example, there is a relatively large displacement difference in the position of the water loss endothermic peak of the spectrum obtained at different heating rates.
  • DSC differential scanning calorimetry
  • thermogravimetric analysis spectrum (TG) of the supramolecular complex (complex) shows that the water content of the supramolecular complex (complex) is 1.89%.
  • the atomic absorption spectrum of the supramolecular complex (complex) shows that the calcium content of the supramolecular complex (complex) is 6.36%.
  • the structural unit of the supramolecular complex is: (EXP3174 ⁇ AHU377) 3- ⁇ 1.5Ca 2+ ⁇ 1H 2 O.
  • Another object of the present invention is to provide a method for preparing the series of supramolecular complex (complex) crystal form ⁇ of the present invention, which comprises the following steps:
  • the composite is obtained by the prior art, and further heated from room temperature to 195°C at a temperature increase rate of 10°C/min, and then cooled to room temperature to obtain the crystal form ⁇ of the composite.
  • the X-ray powder diffraction (XRD) spectrum of the supramolecular complex (complex) has absorption at 2 ⁇ of 3.6, 5.1, and 5.7° Strong diffraction peaks, the acceptable error range is ⁇ 0.2°. For peaks with strong absorption intensity, it is less affected by product characteristics, testing equipment, testing conditions and other factors, so the probability of recurrence is very high.
  • the technology in this field Personnel can also understand that for some specific compounds, affected by product characteristics, testing equipment, testing conditions and other factors, peaks with weaker absorption intensity may not have high reproducibility.
  • the inventor is correcting Repeated testing of the same batch/different batch of samples also found that this phenomenon also exists for the supramolecular complex (complex), which is named crystal form ⁇ .
  • X-ray powder diffraction (XRD) spectrum has strong absorption diffraction peaks at 10.3, 14.0, 15.7, and 17.2°, and the acceptable error range is ⁇ 0.2°.
  • the X-ray powder diffraction (XRD) spectrum of the supramolecular complex (complex) is shown in FIG. 4.
  • the molar ratio of EXP3174 to AHU377 in the supramolecular complex (complex) can be obtained directly/indirectly by the content analysis method.
  • the high performance liquid method HPLC
  • the molar ratio is 1:1.
  • the differential scanning calorimetry (DSC) of the supramolecular complex (complex) has a melting and decomposition peak at 242.85 ⁇ 5°C. Because the supramolecular complex (complex) contains crystal water, it is known in the art The skilled person can understand that under different detection conditions, such as heating rate, etc., as well as different sample properties, such as sample particle size state, etc., certain peaks in the DSC spectrum (such as the endothermic peak of water loss) may have large fluctuations. For example, there is a relatively large displacement difference in the position of the water loss endothermic peak of the spectrum obtained at different heating rates.
  • DSC differential scanning calorimetry
  • thermogravimetric analysis spectrum (TG) of the supramolecular complex (complex) shows that the water content of the supramolecular complex (complex) is 4.11%.
  • the atomic absorption spectrum of the supramolecular complex (complex) shows that the calcium content of the supramolecular complex (complex) is 6.42%.
  • the structural unit of the supramolecular complex is: (EXP3174 ⁇ AHU377) 3- ⁇ 1.5Ca 2+ ⁇ 2H 2 O.
  • Another object of the present invention is to provide a method for preparing the series of supramolecular complex (complex) crystal form ⁇ of the present invention, which comprises the following steps:
  • the complex is obtained by the prior art, and the complex is obtained by the prior art, suspended and stirred in n-butyl acetate: NMP N-methyl-2-pyrrolidone (volume ratio 20:1), and the solvent is removed to obtain the complex crystal Type ⁇ .
  • the third object of the present invention is to provide a use of the supramolecular complex (complex) of the present invention for the preparation of drugs for the treatment of a series of cardiovascular diseases and other complications including hypertension, heart failure, etc. .
  • 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 pectoris , Pulmonary hypertension, renal vascular hypertension, and other damages to the kidney, brain, cardiovascular and other organs caused by long-term hypertension.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising the aforementioned new crystal form of the complex of the ARB metabolite and the NEP inhibitor, and one or more pharmaceutically acceptable carriers, wherein the complex
  • the mass percentage of the new crystal form in the pharmaceutical composition is 0.1-99.9%.
  • the supramolecular complex (complex) of the present invention has advantages in solubility, stability, bulk density, etc., and further corresponds to better clinical treatment effects and druggability, and is more suitable for production and Application of treatment.
  • the drug carrier includes, but is not limited to, one or two or more of fillers, disintegrants, binders, lubricants, surfactants, etc., mixed in any ratio to obtain a mixture.
  • the medicine includes but is not limited to capsules, powders, granules, tablets, injections and the like.
  • the supramolecular complex (complex) of the present invention has advantages in solubility, fluidity, stability, etc., and is suitable for pharmaceutical preparation and use.
  • the X-ray powder diffraction (XRD) spectrum was detected by the Empyrean X-ray diffractometer, and the detection conditions: Cu-K ⁇ radiation, wavelength Divergence slit 1/8°, X-ray tube voltage 45kV, X-ray tube current 40mA, scanning range 2-40°(2 ⁇ ), step size 0.0262606°, scanning speed 0.169423°/s.
  • XRD X-ray powder diffraction
  • the DSC spectrum was detected by scanning calorimeter Q2000 (TA instrument in the United States), and the detection conditions: the heating rate was 10°C/min, and the temperature was raised from room temperature to a specific temperature.
  • the TG spectrum was detected by the thermogravimetric analyzer Q500 (TA instrument in the United States), and the detection conditions: heating rate 10°C/min, heating from room temperature to specific temperature.
  • the Raman spectroscopy uses Renishaw’s inVia Raman microscope, equipped with a near-infrared diode laser source and a Rencam charge-coupled device (CCD) silicon detector. Place the sample on a microscope slide, focus observation and single-point inspection under a 50-fold objective lens.
  • the detection conditions are as follows: detection wavelength 785nm, detection range 200cm-1-1800cm-1, laser intensity 50%, exposure time 1s. Data acquisition and analysis software wire4.3.
  • AHU377 free acid 2g of EXP3174 and 40mL of acetone into a 250mL three-necked flask, and dissolve it; add 1.6 equivalents of calcium hydroxide solid and 0.6mL of water to AHU377 at room temperature, stir at 35°C for 6h, and add 40mL Acetone was reacted for another 8 hours, filtered through a Buchner funnel under nitrogen protection, and the solid was rinsed with acetone to obtain a white solid. The solid was dried under vacuum for 8 hours at 50°C and dried to obtain 3.1 g of solid. The molar ratio of AHU377 is 1:1.
  • Example 1 The product of Example 1 was heated to 195°C at a temperature increase rate of 10°C/min, and then cooled to room temperature to obtain the complex crystal form ⁇ .
  • the X-ray powder diffraction spectrum of the composite has a strong absorption diffraction peak at 2 ⁇ of 4.7°, and the acceptable error range is ⁇ 0.2°. More specifically, the X-ray powder diffraction spectrum of the composite is shown in Fig. 1.
  • the differential scanning calorimetry spectrum of the composite has a melting decomposition peak at 241.38 ⁇ 5°C. More specifically, the differential scanning calorimetry chart of the composite is shown in FIG. 2.
  • thermogravimetric analysis spectrum (TG) of the supramolecular complex (complex) shows that the water content of the supramolecular complex (complex) is 1.89%. More specifically, their TG measurement spectra are shown in Figure 3, respectively.
  • the complex is a monohydrate structural unit: (EXP3174 ⁇ AHU377) 3- ⁇ 1.5Ca 2+ ⁇ 1H 2 O, and the structural formula is as follows:
  • Example 1 The product of Example 1 (27.85 mg) was suspended and stirred in a total volume of 0.63 mL of n-butyl acetate:N-methyl-2-pyrrolidone (volume ratio 20:1), and the solvent was removed to obtain the complex crystal form ⁇ .
  • the X-ray powder diffraction spectrum of the composite has strong absorption peaks at 2 ⁇ of 3.6, 5.1, and 5.7°, and the acceptable error range is ⁇ 0.2°; the X-ray powder diffraction spectrum of the composite is further There are diffraction peaks with strong absorption at 10.3, 14.0, 15.7, and 17.2°, and the acceptable error range is ⁇ 0.2°; more specifically, the X-ray powder diffraction spectrum of the composite is shown in Figure 4.
  • the differential scanning calorimetry spectrum of the composite has a melting decomposition peak at 242.85 ⁇ 5°C; more specifically, the differential scanning calorimetry (DSC) of the composite is shown in FIG. 5.
  • thermogravimetric analysis spectrum (TG) of the supramolecular complex (complex) shows that the water content of the supramolecular complex (complex) is 4.11%. More specifically, its TG and Raman spectra are shown in Figures 6 and 7, respectively.
  • the complex is a dihydrate
  • the structural unit is: (EXP3174 ⁇ AHU377) 3- ⁇ 1.5Ca 2+ ⁇ 2H 2 O
  • the structural formula is as follows:
  • Example 3 of WO2017/125031 at room temperature, add 2.36g of AHU377 free acid, EXP31742g and 40mL of acetone into a 250mL three-necked flask, and dissolve it; add 1.6 equivalents of calcium hydroxide solid and 0.6mL of water to AHU377 at room temperature, 35 Stir at °C for 6h, add 40mL of acetone, and react for 8h. Under nitrogen protection, filter through Buchner funnel. The solid is rinsed with acetone to obtain a white solid. Vacuum oven at 50°C for 8h, and dry to obtain 3.1g of solid to obtain a compound. For the crystal form ⁇ , the molar ratio of EXP3174 to AHU377 in the obtained product is 1:1 through content test calculation.
  • Example 3 The composite was prepared using the method disclosed in Example 3 of Patent WO2017/125031 (Comparative Example 1), and the samples obtained in Example 3 were tested for hygroscopicity under the conditions of RH 75% and RH 85% (naked samples). The results obtained are as follows:
  • the supramolecular complex (complex) of the present invention exhibits an unexpectedly good hygroscopicity (low) advantage under RH 75% and RH 85%, which is represented by the super molecular complex obtained in Example 3. Even if the molecular complex (complex) is exposed to a RH 75% storage environment, the mass increase of ⁇ 1.00% for 5 days, and the mass increase of ⁇ 1.10% when exposed to a RH 85% storage environment is significantly better than the comparative example. 1 The product obtained.
  • Example 3 of Patent WO2017/125031 Comparative Example 1
  • Example 3 of Patent WO2017/125031 Comparative Example 1
  • the results obtained are as follows:
  • Example 3 of Patent WO2017/125031 Comparative Example 1
  • Example 2 and Example 3 of the present invention were at 40°C and 75% RH.
  • the supramolecular complex (complex) of the present invention has high stability and meets the requirements of clinical pharmacy.
  • the hygroscopicity (lower) of the new crystal form of the composite of the present invention has greater advantages than similar products disclosed in the prior art, and the powder properties (fluidity, bulk density, etc.) also have advantages, especially solubility Obviously better, it can be predicted that the series of supramolecular complexes (complexes) of the present invention may have better pharmacological properties.

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Abstract

Une nouvelle forme cristalline de complexe de métabolite d'ARB et d'inhibiteur de NEP et son procédé de préparation.
PCT/CN2021/072414 2020-01-19 2021-01-18 Nouvelle forme cristalline de complexe de métabolite d'arb et d'inhibiteur de nep et son procédé de préparation WO2021143898A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024027779A1 (fr) * 2022-08-04 2024-02-08 深圳信立泰药业股份有限公司 Nouvelle forme cristalline de composé arni, son procédé de préparation et son utilisation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101098689A (zh) * 2005-11-09 2008-01-02 诺瓦提斯公司 血管紧张素受体拮抗剂和nep抑制剂的药物组合产品
WO2017125031A1 (fr) * 2016-01-20 2017-07-27 深圳信立泰药业股份有限公司 Métabolite antagoniste du récepteur de l'angiotensine ii et composite inhibiteur de la nep, et procédé de préparation associé

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113286789B (zh) * 2019-05-30 2022-03-11 深圳信立泰药业股份有限公司 血管紧张素ii受体拮抗剂代谢产物与nep抑制剂的复合物的新用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101098689A (zh) * 2005-11-09 2008-01-02 诺瓦提斯公司 血管紧张素受体拮抗剂和nep抑制剂的药物组合产品
WO2017125031A1 (fr) * 2016-01-20 2017-07-27 深圳信立泰药业股份有限公司 Métabolite antagoniste du récepteur de l'angiotensine ii et composite inhibiteur de la nep, et procédé de préparation associé

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024027779A1 (fr) * 2022-08-04 2024-02-08 深圳信立泰药业股份有限公司 Nouvelle forme cristalline de composé arni, son procédé de préparation et son utilisation

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