WO2021143898A1 - Arb代谢产物与nep抑制剂的复合物新晶型及其制备方法 - Google Patents

Arb代谢产物与nep抑制剂的复合物新晶型及其制备方法 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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French (fr)
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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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    • 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

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  • 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.

Abstract

提供ARB代谢产物与NEP抑制剂的复合物新晶型及其制备方法。

Description

ARB代谢产物与NEP抑制剂的复合物新晶型及其制备方法 技术领域
本发明属于药物化学多晶型技术领域，特别涉及ARB代谢产物与NEP抑制剂的复合物新晶型及其制备方法。
背景技术
阿利沙坦酯(CAS：947331-05-7)，化学名：2-丁基-4-氯-1-[2’-(1H-四唑-5-基)-1,1’-联苯基-甲基]-咪唑-5-羧酸,1-[(异丙氧基)-羰氧基]-甲酯，商品名：信立坦，是一种新型的血管紧张素II受体(AT1)拮抗剂，简称ARB，中国专利CN200610023991.0中首次公开了其结构式，并披露了其在制备高血压药物中的应用。与同类型其他降压产品(如氯沙坦)相比，阿利沙坦酯具有毒性小、降压效果优等特点。
ARB阿利沙坦酯在体内通过水解代谢得到EXP3174进而发挥治疗作用。但是EXP3174单独成药使用生物利用度较低，治疗效果不佳，主要源于其分子结构极性大，难以通过扩散等被动吸收形式穿过细胞膜，必须经过结构改造才能改善其被动吸收。但现有技术报道了多种通过化学修饰、制剂给药优化等方法均不能有效提高EXP3174的生物利用度。
Figure PCTCN2021072414-appb-000001
脑啡肽酶(NEP)是一种中性内肽酶，能够降解包括利钠肽、缓激肽在内的多种内源性血管活性肽，也能降低肾上腺髓质素水平，脑啡肽酶抑制剂(NEPi)则能够提高这些物质的水平，以对抗血管收缩、钠潴留及神经内分泌***过度激活。
脑啡肽酶抑制剂(NEPi)例如AHU377(Sacubitril，CAS：149709-62-6)，化学式为：C 24H 29NO 5，其结构如下：
Figure PCTCN2021072414-appb-000002
专利WO2007056546公开了一种缬沙坦-沙库匹曲(Sacubitril)的钠盐复合物(LCZ696)及其制备方法。
专利WO2017/125031公开了一系列由血管紧张素受体拮抗剂代谢产物与NEP抑制剂的复合物，其特征在于，所述复合物的结构单元如下：(aEXP3174·bAHU377)·xCa·nA其中a:b＝1:0.25～4；x为0.5～3之间的数值；A指代水、甲醇、乙醇、2-丙醇、丙酮、乙酸乙酯、甲基-叔-丁基醚、乙腈、甲苯、二氯甲烷；n为0～3之间的数值。
寻找一种更适宜制药使用的晶型，对于所述(aEXP3174·bAHU377)·xCa·nA复合物的应用具有非常重要的价值。
发明内容
本发明首先提供了一种ARB代谢产物与NEP抑制剂的复合物新晶型。
具体的，所述ARB的代谢产物为EXP3174，化学式为：C 22H 21ClN 6O 2，其结构如下：
Figure PCTCN2021072414-appb-000003
所述脑啡肽酶抑制剂(NEPi)为AHU377(Sacubitril，CAS：149709-62-6)，化学式为：C 24H 29NO 5，其结构如下：
Figure PCTCN2021072414-appb-000004
具体的，所述超分子络合物(复合物)的结构单元如下：
(EXP3174·AHU377)·XCa·nH 2O；
具体结构如下：
Figure PCTCN2021072414-appb-000005
其中x为0.5～2之间的数值；n进一步为0～3之间的任意数值。具体如0、0.5、1、1.5、2、2.5、3等。
进一步地，所述复合物的结构式如下：
Figure PCTCN2021072414-appb-000006
或者
Figure PCTCN2021072414-appb-000007
其中n为0～3之间的数值。
进一步地，所述复合物的结构单元如下：
(EXP3174·AHU377)·1.5Ca·1H 2O；
(EXP3174·AHU377)·1.5Ca·1.5H 2O；
(EXP3174·AHU377)·1.5Ca·2H 2O；
(EXP3174·AHU377)·1.5Ca·2.5H 2O；
(EXP3174·AHU377)·1.5Ca·3H 2O；
(EXP3174·AHU377)·2Ca·1H 2O
(EXP3174·AHU377)·2Ca·1.5H 2O；
(EXP3174·AHU377)·2Ca·2H 2O；
(EXP3174·AHU377)·2Ca·2.5H 2O；
(EXP3174·AHU377)·2Ca·3H 2O。
本领域的技术人员可以理解，在超分子络合物(复合物)的单位晶胞中，所述阿利沙坦酯代谢产物(EXP3174)、AHU377、钙离子(Ca 2+)和溶剂分子会以数个结构单元的形式填充于其中。
本发明所述超分子络合物(复合物)区别于两种活性成分通过简单的物理混合得到的混合物。
本发明的一个具体的超分子络合物(复合物)，该超分子络合物(复合物)的X-射线粉末衍射(XRD)谱图在2θ为4.7°处具有吸收较强的衍射峰，可接受的误差范围±0.2°，对于吸收强度强的峰，其受产品特性、检测仪器、检测条件等因素的影响较小，因此重复出现概率非常大，本领域的技术人员也可以理解，对于某些具体的化合物，受产品特性、检测仪器、检测条件等因素的影响，对于吸收强度较弱的峰，则可能不具有较高的可重现性，发明人在对同批/ 不同批样品的重复检测中也发现，对于该超分子络合物(复合物)也存在该现象，命名为晶型β。
该超分子络合物(复合物)的X-射线粉末衍射(XRD)谱图如图1所示。
采用含量分析法可直接/间接得知超分子络合物(复合物)中EXP3174与AHU377的摩尔比，比如采用高效液相法(HPLC)可以测得超分子络合物(复合物)中EXP3174与AHU377(游离酸)的质量/含量进一步换算即可得知其摩尔比为1:1。
该超分子络合物(复合物)的差示扫描量热谱图(DSC)在241.38±5℃有熔融分解峰，由于该超分子络合物(复合物)含有结晶水，因此本领域的技术人员可以理解在不同的检测条件，诸如升温速率等，以及不同的样品性状，诸如样品粒径状态等，DSC谱图中的某些峰(诸如失水吸热峰)可能出现较大波动，比如不同升温速率下所得谱图的失水吸热峰位置出现相对较大位移区别
更具体的，该超分子络合物(复合物)的差示扫描量热谱图(DSC)如图2所示。
对于该超分子络合物(复合物)中含水量的检测可采用本领域常用的方法，如卡尔费休法和/或热重分析法。具体的，该超分子络合物(复合物)的热重分析谱图(TG)显示该超分子络合物(复合物)的含水量为1.89％。
该超分子络合物(复合物)的原子吸收谱图显示该超分子络合物(复合物)的钙含量为6.36％。
综合以上信息判断，该超分子络合物(复合物)的结构单元为：(EXP3174·AHU377) 3-·1.5Ca 2+·1H 2O。
本发明的另一目的在于提供一种本发明所述系列超分子络合物(复合物)晶型β的制备方法，包含如下步骤：
通过现有技术获得复合物，进一步地以10℃/min的升温速率由室温加热至195℃，然后冷却至室温，得复合物晶型β。
通过大量的实验研究发现，当升温超过250℃，产物熔融分解，不再呈晶型状，当升温低于100℃，保持现有技术的晶型，不转化为晶型β。
本发明的另一个具体的超分子络合物(复合物)，该超分子络合物(复合物)的X-射线粉末衍射(XRD)谱图在2θ为3.6、5.1、5.7°处具有吸收较强的衍射峰，可接受的误差范围±0.2°，对于吸收强度强的峰，其受产品特性、检测仪 器、检测条件等因素的影响较小，因此重复出现概率非常大，本领域的技术人员也可以理解，对于某些具体的化合物，受产品特性、检测仪器、检测条件等因素的影响，对于吸收强度较弱的峰，则可能不具有较高的可重现性，发明人在对同批/不同批样品的重复检测中也发现，对于该超分子络合物(复合物)也存在该现象，命名为晶型γ。
进一步地，所述X-射线粉末衍射(XRD)谱图在10.3、14.0、15.7、17.2°处具有吸收较强的衍射峰，可接受的误差范围±0.2°。
该超分子络合物(复合物)的X-射线粉末衍射(XRD)谱图如图4所示。
采用含量分析法可直接/间接得知超分子络合物(复合物)中EXP3174与AHU377的摩尔比，比如采用高效液相法(HPLC)可以测得超分子络合物(复合物)中EXP3174与AHU377(游离酸)的质量/含量进一步换算即可得知其摩尔比为1:1。
该超分子络合物(复合物)的差示扫描量热谱图(DSC)在242.85±5℃有熔融分解峰，由于该超分子络合物(复合物)含有结晶水，因此本领域的技术人员可以理解在不同的检测条件，诸如升温速率等，以及不同的样品性状，诸如样品粒径状态等，DSC谱图中的某些峰(诸如失水吸热峰)可能出现较大波动，比如不同升温速率下所得谱图的失水吸热峰位置出现相对较大位移区别
更具体的，该超分子络合物(复合物)的差示扫描量热谱图(DSC)如图5所示。
对于该超分子络合物(复合物)中含水量的检测可采用本领域常用的方法，如卡尔费休法和/或热重分析法。具体的，该超分子络合物(复合物)的热重分析谱图(TG)显示该超分子络合物(复合物)的含水量为4.11％。
该超分子络合物(复合物)的原子吸收谱图显示该超分子络合物(复合物)的钙含量为6.42％。
综合以上信息判断，该超分子络合物(复合物)的结构单元为：(EXP3174·AHU377) 3-·1.5Ca 2+·2H 2O。
本发明的另一目的在于提供一种本发明所述系列超分子络合物(复合物)晶型γ的制备方法，包含如下步骤：
通过现有技术获得复合物，通过现有技术获得复合物，在乙酸正丁酯：NMP N-甲基-2-吡咯烷酮(体积比20：1)中混悬搅拌，去除溶剂，得复合物晶型γ。
通过大量的实验研究发现，采用多种近似的溶剂，乃至其他比例，保持现有技术的晶型，不转化为晶型γ。
本发明的第三个目的在于提供一种本发明所述超分子络合物(复合物)用于制备治疗包括高血压、心力衰竭等一系列心血管疾病及其他并发症的药物的药物的用途。
具体的，所述治疗的疾病/并发症包含但不限于高血压、急慢性心衰、充血性心衰、心律失常、房颤、心肌梗塞、动脉硬化症、冠心病、不稳定或稳定型心绞痛、肺高血压、肾血管高血压等以及长期高血压所导致的肾、脑、心血管等器官的其他损伤。
本发明进一步提供了一种药物组合物，所述药物组合物含有前述的ARB代谢产物与NEP抑制剂的复合物新晶型，和一种以上药学上可接受的载体，其中，所述复合物新晶型在药物组合物中的质量百分数为0.1～99.9％。
与现有技术产品相比，本发明超分子络合物(复合物)在溶解性、稳定性、堆密度等方面具有优势，进一步对应更优的临床治疗效果及成药性，更适用于生产和治疗的应用。
所述药物载体包含但不限于填充剂、崩解剂、粘合剂、润滑剂、表面活性剂等中的一种或两种以上以任意比例混合所得混合物。
所述药物包含但不限于胶囊剂、散剂、颗粒剂、片剂、注射剂等。
本领域技术人员完全能够通过溶解性等相关实验证明本发明所述超分子络合物(复合物)在溶解性、流动性、稳定性等方面具有优势，适合药用制备使用。
附图说明
图1实施例2所得复合物晶型β的XRD谱图
图2实施例2所得复合物晶型β的DSC谱图
图3对比实施例1所得晶型α和实施例2所得复合物晶型β的TG对比谱图
图4对比实施例1所得晶型α和实施例3所得复合物晶型γ的XRD对比谱图
图5对比实施例1所得晶型α和实施例3所得复合物晶型γ的DSC对比谱图
图6实施例3所得复合物晶型γ的TG谱图
图7对比实施例1所得晶型α和实施例3所得复合物晶型γ的拉曼对比谱图
具体实施方式
下面结合实施例和附图对本发明作进一步详细的描述，但发明的实施方式不限于此。
以下实施例中：
X-射线粉末衍射(XRD)谱图采用帕纳科锐影(Empyrean)X-射线衍射仪检测得到，检测条件：Cu-Kα辐射，波长
Figure PCTCN2021072414-appb-000008
发散狭缝1/8°，X射线光管电压45kV，X射线光管电流40mA，扫描范围2-40°(2θ)，步长0.0262606°，扫描速度0.169423°/s。
DSC谱图采用扫描量热仪Q2000(美国TA仪器)检测得到，检测条件：升温速率为10℃/min，从室温升温至特定温度。
TG谱图采用热重分析仪Q500(美国TA仪器)检测获得，检测条件：升温速率10℃/min，从室温加热至特定温度。
拉曼谱图应用雷尼绍inVia拉曼显微光谱仪，配置近红外二极管激光源和Rencam电荷耦合器件(CCD)硅检测器。将样品置显微镜载玻片上，于50倍物镜下聚焦观察并单点检测。检测条件如下：检测波长785nm，检测范围200cm-1-1800cm-1，激光强度50％，曝光时间1s。数据采集分析软件wire4.3。
实施例1
Figure PCTCN2021072414-appb-000009
室温下，将AHU377游离酸2.36g、EXP3174 2g与40mL丙酮加入至250mL三口瓶，溶清；室温下加入相对于AHU377 1.6当量的氢氧化钙固体和0.6mL水，35℃搅拌6h，补加40mL丙酮，再反应8h，氮气保护下经布氏漏斗抽滤，固体用丙酮淋洗，得白色固体，50℃下真空烘8h，烘干得到固体3.1g，通过含量测试计算可知所得产品中EXP3174与AHU377的摩尔比为1:1。
实施例2
将实施例1的产物以10℃/min的升温速率加热至195℃，然后冷却至室温，得复合物晶型β。
该复合物的X-射线粉末衍射谱图在2θ为4.7°处具有吸收较强的衍射峰，可接受的误差范围±0.2°。更为具体地，该复合物的X-射线粉末衍射谱图如图 1所示。
该复合物的差示扫描量热谱图在241.38±5℃有熔融分解峰。更为具体地，该复合物的差示扫描量热谱图如图2所示。
该超分子络合物(复合物)的热重分析谱图(TG)显示该超分子络合物(复合物)的含水量为1.89％。更为具体地，其TG测定谱图分别如图3所示。
通过化学分子计算，所述复合物为1水合物结构单元为：(EXP3174·AHU377) 3-·1.5Ca 2+·1H 2O，结构式如下：
Figure PCTCN2021072414-appb-000010
实施例3
将实施例1的产物(27.85mg)在乙酸正丁酯：N-甲基-2-吡咯烷酮(体积比20：1)总体积0.63mL中混悬搅拌，去除溶剂，得复合物晶型γ。
该复合物的X-射线粉末衍射谱图在2θ为3.6、5.1、5.7°处具有吸收较强的衍射峰，可接受的误差范围±0.2°；该复合物的X-射线粉末衍射谱图进一步在10.3、14.0、15.7、17.2°处具有吸收较强的衍射峰，可接受的误差范围±0.2°；更为具体地，该复合物的X-射线粉末衍射谱图如图4所示。
该复合物的差示扫描量热谱图在242.85±5℃有熔融分解峰；更为具体地，该复合物的差示扫描量热谱图(DSC)如图5所示。
该超分子络合物(复合物)的热重分析谱图(TG)显示该超分子络合物(复合物)的含水量为4.11％。更为具体地，其TG及拉曼测定谱图分别如图6和7所示。
通过化学分子计算，所述复合物为2水合物，结构单元为：(EXP3174·AHU377) 3-·1.5Ca 2+·2H 2O，结构式如下：
Figure PCTCN2021072414-appb-000011
对比实施例1
参照WO2017/125031实施例3，室温下，将AHU377游离酸2.36g、EXP31742g与40mL丙酮加入至250mL三口瓶，溶清；室温下加入相对于AHU377 1.6当量的氢氧化钙固体和0.6mL水，35℃搅拌6h，补加40mL丙酮，再反应8h，氮气保护下经布氏漏斗抽滤，固体用丙酮淋洗，得白色固体，50℃下真空烘8h，烘干得到固体3.1g，得复合物晶型α，通过含量测试计算可知所得产品中EXP3174与AHU377的摩尔比为1:1。
实施例4
吸湿性
采用专利WO2017/125031实施例3(对比实施例1)公开的方法制备复合物，与前述实施例3所得样品一起分别测试在RH 75％和RH 85％条件下的吸湿性(裸样)并对所得结果如下表：
表1吸湿性对比数据
Figure PCTCN2021072414-appb-000012
**含水增量
从上表可看出本发明所述超分子络合物(复合物)在RH 75％和RH 85％下表现为超乎预料的好的吸湿性(低)优势，表现为实施例3所得超分子络合物(复合物)即便是暴露在RH 75％储存环境下5天质量增量<1.00％，暴露在RH 85％储存环境下5天质量增量<1.10％，明显优于对比实施例1获得的产物。
流动性
采用专利WO2017/125031实施例3(对比实施例1)公开的方法制备复合物，以及本发明前述实施例2与实施例3所得样品粉碎相近的粒径分布范围内，所得结果如下表：
表2.流动性对比数据
Figure PCTCN2021072414-appb-000013
从以上数据可以看出，本发明所述超分子络合物(复合物)的流动性适中，且无明显静电现象，粉体堆密度性质明显优于对比实施例1。
实施例5
加速稳定性试验
采用专利WO2017/125031实施例3(对比实施例1)公开的方法制备复合物，与本发明实施例2和实施例3所得超分子络合物(复合物)在40℃，75％RH条件下保存6个月以检测其在加速条件下(带包装)的储存稳定性，结果如下表：
表3.加速稳定性数据
Figure PCTCN2021072414-appb-000014
可知，本发明所述超分子络合物(复合物)具有较高的稳定性，符合临床制药要求。
实施例6
溶解性试验
采用专利WO2017/125031 3(对比实施例1)公开的方法制备复合物，与实施例2和实施例3在水溶剂参照药典标准进行溶解实验，结果如下表：
表4.溶解性试验数据
Figure PCTCN2021072414-appb-000015
综上，本发明所述复合物新晶型的吸湿性能(低)较现有技术公开的同类产品具有较大优势，且粉体性质(流动性、堆密度等)亦存在优势，特别是溶解度明显更优，由此可预测本发明所述系列超分子络合物(复合物)可能具有更好的药学成药性。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (15)

  1. ARB代谢产物与NEP抑制剂的复合物新晶型，其特征在于，所述复合物的结构单元如下(EXP3174·AHU377)·XCa·nH 2O；
    具体结构如下：
    Figure PCTCN2021072414-appb-100001
    其中x为0.5～2之间的数值；n为0～3之间的数值，该复合物的X-射线粉末衍射谱图在2θ为4.7°处具有吸收较强的衍射峰，可接受的误差范围±0.2°。
  2. 根据权利要求1所述的ARB代谢产物与NEP抑制剂的复合物新晶型，其特征在于，该复合物的X-射线粉末衍射谱图如图1所示。
  3. 根据权利要求1或2所述的ARB代谢产物与NEP抑制剂的复合物新晶型，其特征在于，该复合物的差示扫描量热谱图在241.38±5℃有熔融分解峰。
  4. 根据权利要求1或2所述的ARB代谢产物与NEP抑制剂的复合物新晶型，其特征在于，该复合物的差示扫描量热谱图如图2所示。
  5. ARB代谢产物与NEP抑制剂的复合物新晶型，其特征在于，所述复合物的结构单元如下(EXP3174·AHU377)·XCa·nH 2O；
    具体结构如下：
    Figure PCTCN2021072414-appb-100002
    其中x为0.5～2之间的数值；n为0～3之间的数值，该复合物的X-射线粉末衍射谱图在2θ为3.6、5.1、5.7°处具有吸收较强的衍射峰，可接受的误差范围 ±0.2°。
  6. 根据权利要求5所述的ARB代谢产物与NEP抑制剂的复合物新晶型，其特征在于，该复合物的X-射线粉末衍射谱图进一步在10.3、14.0、15.7、17.2°处具有吸收较强的衍射峰，可接受的误差范围±0.2°。
  7. 根据权利要求5或6所述的ARB代谢产物与NEP抑制剂的复合物新晶型，其特征在于，该复合物的X-射线粉末衍射谱图如图4所示。
  8. 根据权利要求5-7任一权利要求所述的ARB代谢产物与NEP抑制剂的复合物新晶型，其特征在于，该复合物的差示扫描量热谱图在242.85±5℃有熔融分解峰。
  9. 根据权利要求5-7任一权利要求所述的ARB代谢产物与NEP抑制剂的复合物新晶型，其特征在于，该复合物的差示扫描量热谱图(DSC)如图5所示。
  10. 根据权利要求1或5所述的ARB代谢产物与NEP抑制剂的复合物新晶型，其特征在于，所述复合物的结构式如下：
    Figure PCTCN2021072414-appb-100003
    或者
    Figure PCTCN2021072414-appb-100004
    其中n为0～3之间的数值。
  11. 根据权利要求1或5所述的ARB代谢产物与NEP抑制剂的复合物新晶型，其特征在于，所述复合物的结构单元如下：
    (EXP3174·AHU377)·1.5Ca·1H 2O；
    (EXP3174·AHU377)·1.5Ca·1.5H 2O；
    (EXP3174·AHU377)·1.5Ca·2H 2O；
    (EXP3174·AHU377)·1.5Ca·2.5H 2O；
    (EXP3174·AHU377)·1.5Ca·3H 2O；
    (EXP3174·AHU377)·2Ca·1H 2O；
    (EXP3174·AHU377)·2Ca·1.5H 2O；
    (EXP3174·AHU377)·2Ca·2H 2O；
    (EXP3174·AHU377)·2Ca·2.5H 2O；
    (EXP3174·AHU377)·2Ca·3H 2O。
  12. 一种制备如权利要求1-4任意一项所述的ARB代谢产物与NEP抑制剂的复合物新晶型的方法，包括如下步骤：制备前述结构单元的复合物，进一步地以10℃/min的升温速率由室温加热至195℃，然后冷却至室温，得所述复合物新晶型。
  13. 一种制备如权利要求5-9任意一项所述的ARB代谢产物与NEP抑制剂的复合物新晶型的方法，包括如下步骤：制备前述结构单元的复合物，在乙酸正丁酯：N-甲基-2-吡咯烷酮(体积比20：1)中混悬搅拌，去除溶剂，得所述复合物新晶型。
  14. 一种如权利要求1-11任意一项所述的ARB代谢产物与NEP抑制剂的复合物新晶型用于制备治疗心力衰竭或高血压的药物的用途。
  15. 一种药物组合物，其特征在于，所述药物组合物含有如权利要求1-11任意一项所述的ARB代谢产物与NEP抑制剂的复合物新晶型，和一种以上药学上可接受的载体，其中，所述复合物新晶型在药物组合物中的质量百分数为0.1～99.9％。
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