WO2024027779A1 - ARNi化合物新晶型及其制备方法与应用 - Google Patents

ARNi化合物新晶型及其制备方法与应用 Download PDF

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WO2024027779A1
WO2024027779A1 PCT/CN2023/110874 CN2023110874W WO2024027779A1 WO 2024027779 A1 WO2024027779 A1 WO 2024027779A1 CN 2023110874 W CN2023110874 W CN 2023110874W WO 2024027779 A1 WO2024027779 A1 WO 2024027779A1
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crystal form
compound
arni
new crystal
new
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PCT/CN2023/110874
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French (fr)
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颜杰
许文杰
李松
谭端明
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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

Definitions

  • the invention belongs to the technical field of medicinal chemistry polymorphism, and particularly relates to a new crystal form of ARNi compound and its preparation method and application.
  • 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: Xinlitan, is a new type of angiotensin II receptor (AT1 ) antagonist, referred to as ARB, its structural formula was disclosed for the first time 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), allisartan medoxomil has the characteristics of less toxicity and excellent antihypertensive effect.
  • EXP3174 ARB allisartan medoxomil is hydrolyzed and metabolized in the body to obtain EXP3174, which then exerts its therapeutic effect.
  • EXP3174 has low bioavailability and poor therapeutic effect when used as a single drug. This is mainly due to the polarity of its molecular structure, which makes it difficult to cross the cell membrane through passive absorption such as diffusion. It must undergo structural modification to improve its passive absorption.
  • various methods such as chemical modification and formulation optimization can not effectively improve the bioavailability of EXP3174.
  • Neprilysin is a neutral endopeptidase that can degrade a variety of endogenous vasoactive peptides including natriuretic peptides and bradykinin. It can also reduce the levels 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.
  • Neprilysin 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 compound of valsartan-sacubitril (LCZ696) and its preparation method.
  • Patent WO2021143898 discloses a new crystal form of (aEXP3174 ⁇ bAHU377) ⁇ xCa ⁇ nA, but the physical and chemical properties still need to be improved.
  • the present invention first provides a new crystal form of ARNi compounds.
  • ARNi is a compound composed of ARB and NEPi, wherein the metabolite of ARB is EXP3174, the chemical formula is: C 22 H 21 ClN 6 O 2 , and its structure is as follows:
  • NEPi neprilysin inhibitor
  • the structural units of the supramolecular complex are as follows:
  • the specific structure is as follows: a new crystal form of ARNi compound.
  • the structure of the compound is as follows:
  • the water content is 2.8%-5.7%, and the preferred water content is 3.8%-5.7%.
  • n 1.5, 2, 2.5, 3, 3.5 or 4.
  • the new crystal form ⁇ of this compound has an X-ray powder diffraction spectrum in 2 ⁇ of 4.42°, 5.15°, 6.48°, 8.58°, 9.68°, 10.68°, 11.14°, 12.77°, 15.71°, 16.79°, 19.07°, 20.04°, 20.69°, 24.60°, 26.30°, 28.84°, 29.61° have higher absorption Strong diffraction peak, acceptable error range ⁇ 0.2°.
  • the X-ray powder diffraction spectrum of the new crystal form ⁇ of the compound is as shown in Figure 1, 4 or 6.
  • the differential thermal analysis spectrum of the new crystal form ⁇ of the compound has an endothermic peak at 241.1.4 ⁇ 5°C, and the differential thermal analysis spectrum is as shown in Figure 2 or 5.
  • the new crystal form eta of the compound has an X-ray powder diffraction spectrum in 2 ⁇ of 4.09°, 5.02°, 6.43°, 8.41°, 12.27°, 13.08°, 14.82°, There are strong absorption diffraction peaks at 16.11°, 16.98°, 18.42°, 19.18°, 21.98°, 22.53°, 23.85°, 26.14°, 28.23°, and 29.46°, and the acceptable error range is ⁇ 0.2°.
  • the X-ray powder diffraction spectrum of the compound is as shown in Figure 7 or 8.
  • the supramolecular complex (compound) of the present invention is distinguished from a mixture obtained by simple physical mixing of two active ingredients.
  • the second object of the present invention is to provide the use of the supramolecular complex (compound) of the present invention for preparing drugs for treating 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, etc., as well as other damage to the kidneys, brain, cardiovascular and other organs caused by long-term hypertension.
  • the present invention further provides a pharmaceutical composition, which contains the aforementioned new crystal form of the ARNi compound and one or more pharmaceutically acceptable carriers, wherein the new crystal form of the compound is in the pharmaceutical composition.
  • the mass percentage is 0.1 ⁇ 99.9%.
  • the states of solid substances can be divided into two categories: crystalline (or crystal) and amorphous (or amorphous, vitreous, etc.).
  • Molecules, atoms or ions in crystalline substances are arranged in a periodic and orderly manner in three-dimensional space. Its smallest repeating unit is called a unit cell, which consists of three axis lengths a, b, c, and three clamps.
  • a parallelepiped defined by the angles ⁇ , ⁇ , and ⁇ (unit cell parameters).
  • Single crystal X-ray diffraction is currently the most mature analytical method for detecting three-dimensional structural information of crystalline compounds. It can independently complete the structural analysis of crystalline compounds, the composition of eutectics/solvates/hydrates/salts, and Proportional analysis. However, this method has extremely high requirements on the quality and size of the crystal. Generally, the shortest direction of the crystal must be at least larger than 10 microns before it is possible to obtain usable data with a laboratory-level single crystal X-ray diffractometer.
  • MicroED Micro Electron Diffraction
  • the supramolecular complex (compound) of the present invention has excellent crystallinity and other aspects, and is more suitable for production and treatment applications.
  • the pharmaceutical carrier includes, but is not limited to, a mixture of one or more of fillers, disintegrants, binders, lubricants, surfactants, etc. in any proportion.
  • the medicines include but are not limited to capsules, powders, granules, tablets, injections, etc.
  • the supramolecular complex (compound) of the present invention has good crystallinity and other aspects, and is suitable for pharmaceutical preparation and use.
  • the X-ray powder diffraction (XRD) spectrum was detected using a PANalytical Empyrean X-ray diffractometer. Detection conditions: Cu-K ⁇ 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° (2 ⁇ ), the step size is 0.0262606°, and the dwell time of each step is 33.915s.
  • DSC was detected using DSC 200F3 differential scanning calorimeter from NETZSCH, Germany: experimental atmosphere, N 2 , 20 ml/min. Scanning procedure: heating from room temperature to 250°C at 10k/min, using an aluminum sample pan.
  • TG was detected using TG 209F3 thermogravimetric analyzer from NETZSCH, Germany: experimental atmosphere, N2, 20ml/min. Scanning procedure: from room temperature to a specific temperature at 10k/min, using an Al 2 O 3 sample pan.
  • MicroED Electron diffraction was collected using a JEM-2100Plus transmission electron microscope produced by JEOL, using an accelerating voltage of 200kV and equipped with a MerelinEM high-speed direct electron camera. MicroED collected the data and used XDS to restore the diffraction data. In order to improve the completeness, 15 sets of data were used for merge processing, SHELXT was used to analyze the initial structure, and SHELXL and OLEX 2 were used to assist in refinement.
  • Preparation method Repeat the test of Example 1, weigh 10g crystal form ⁇ sample, add 40ml methylene chloride while stirring, stir at room temperature for 1 day, take a small amount of sample to dry and measure XRD to confirm whether the crystallization is complete. If the crystallization is not complete, then Continue stirring until the measured XRD shows that the crystal form is crystal form ⁇ , then filter under nitrogen protection. Then it was vacuum dried at 35°C for 2 days to obtain a white solid of crystal form ⁇ . The moisture content was 3.9% as measured by Karl Fischer.
  • sacubitril and EXP3174 combine into calcium salt compound crystals at a molar ratio of 1:1.
  • a unit cell contains 4 sacubitril molecules, 4 EXP3174 molecules, 6 calcium ions, and 8 water molecules.
  • Eight water molecules all form hydrates with calcium ions, of which two calcium ions form ionized hydrates with two water molecules respectively, and the remaining four calcium ions form ionized hydrates with one water molecule respectively, that is (EXP3174 ⁇ AHU377 ) ⁇ 1.5Ca ⁇ 2H 2 O.
  • Preparation method Repeat the test of Example 1, weigh 5g crystal form ⁇ sample, add 20ml methylene chloride while stirring, then raise the temperature to 50°C, keep stirring for 1 day, take a small amount of the suspension and blow it dry with nitrogen. If it cannot be blown dry immediately, If a translucent solid is obtained, continue stirring until the suspension can be dried immediately to obtain a white powdery solid. Filter under nitrogen protection, and then vacuum dry at 45°C for 1 day to obtain a crystalline white solid. Karl Fischer determines the water content. 3.9%.
  • Preparation method Repeat the test of Example 1, weigh 30g crystal form ⁇ sample, add 150 ml methylene chloride, stir at room temperature for 1 day, filter under nitrogen protection, and then vacuum dry at 40°C for 2 days to obtain crystal form ⁇ white solid, Karl Fischer measurement Moisture content 3.9%.
  • the water content was 3.9% as determined by Karl Fischer and calculated as (EXP3174 ⁇ AHU377) ⁇ 1.5Ca ⁇ 2H 2 O).
  • the water content was 3.9% as determined by Karl Fischer and calculated as (EXP3174 ⁇ AHU377) ⁇ 1.5Ca ⁇ 2H 2 O).
  • Preparation of the mobile phase Weigh 2.72g of potassium dihydrogen phosphate, weigh it accurately, add 2000mL of ultrapure water to dissolve, adjust the pH to 2.80 with phosphoric acid, filter, measure 1860mL of the above solution and mix it with 1140mL of acetonitrile, and degas by ultrasonic, that is have to.
  • the new crystal form of the compound of the present invention has good crystallinity, stability and solubility, and it can be predicted that the series of supramolecular complexes (compounds) of the present invention may have better pharmaceutical properties.
  • Beagle male, 10-13kg, purchased from Yizheng Anlimao Biotechnology Co., Ltd.
  • Test substance Fill the capsule directly with the raw material drug
  • the experiment was conducted using a cross-dosing method with 6 beagle dogs. Each beagle was given a capsule containing the raw material drug. Each capsule contained 240 mg (calculated as anhydrous free acid C 46 H 50 ClN 7 O 7 ). Crystal form ⁇ and crystal form ⁇ , after oral administration to beagle dogs, collect 1000 ⁇ L of venous blood at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h in anticoagulant tubes containing EDTA-K2, centrifuge at 12000 rpm for 2 min, and collect plasma. Store frozen at -80°C until testing.
  • test sample Precisely weigh a certain amount of the test sample and dissolve it in DMSO to 2 mg/mL as a stock solution. Accurately draw an appropriate amount of compound stock solution and add acetonitrile to dilute it to prepare a standard series of solutions. Accurately draw 10 ⁇ L of each of the above standard series solutions, add 90 ⁇ L of blank plasma, vortex and mix, and prepare plasma samples equivalent to plasma concentrations of 1, 3, 5, 10, 30, 100, 300, 1000, and 3000ng/mL. Analyze two samples at one concentration to establish a standard curve.
  • LC-MS detection conditions are as follows:
  • Chromatographic column YMC Triart C18, 50*3.0mm, 2.1 ⁇ m.
  • WinNonlin 6.1 software was used to calculate the pharmacokinetic parameters using the non-compartmental model method. The results are shown in the table below.
  • the new crystal form ⁇ of the present invention exhibits excellent PK effect.

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Abstract

提供ARNi化合物新晶型及其制备方法与应用。

Description

ARNi化合物新晶型及其制备方法与应用 技术领域
本发明属于药物化学多晶型技术领域，特别涉及ARNi化合物新晶型及其制备方法与应用。
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。
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系统过度激活。
脑啡肽酶抑制剂(NEPi)例如AHU377(Sacubitril，CAS：149709-62-6)，化学式为：C24H29NO5，其结构如下：
专利WO2007056546公开了一种缬沙坦-沙库匹曲(Sacubitril)的钠盐化合物(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抑制剂的化合物，其特征在于，所述化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。
专利WO2021143898公开了(aEXP3174·bAHU377)·xCa·nA新晶型，但理化性质仍需要改进。
寻找一种更适宜制药使用的晶型，对于所述(aEXP3174·bAHU377)·xCa·nA化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ARNi化合物的新晶型。
具体的，ARNi为ARB与NEPi组成的化合物，其中，所述ARB的代谢产物为EXP3174，化学式为：C22H21ClN6O2，其结构如下：
所述脑啡肽酶抑制剂(NEPi)为AHU377(Sacubitril，CAS：149709-62-6)，化学式为：C24H29NO5，其结构如下：
具体的，所述超分子络合物(化合物)的结构单元如下：
(EXP3174·AHU377)·1.5Ca·nH2O；
具体结构如下：一种ARNi化合物新晶型，所述化合物的结构如下：
其中，含水量2.8％—5.7％，优选含水量3.8％—5.7％。
作为优选技术方案，n＝1.5，2，2.5，3，3.5或4。
作为本发明的一种优选技术方案，为该化合物新晶型ξ，其X-射线粉末衍射谱图在2θ为4.42°、5.15°、6.48°、8.58°、9.68°、10.68°、11.14°、12.77°、15.71°、16.79°、19.07°、20.04°、20.69°、24.60°、26.30°、28.84°、29.61°处具有吸收较 强的衍射峰，可接受的误差范围±0.2°。
作为本发明的一种优选技术方案，该化合物新晶型ξ的X-射线粉末衍射谱图如图1、4或6所示。
作为本发明的一个优选方案，所述化合物新晶型ξ的差热分析图谱在241.1.4±5℃有吸热峰值，所述差热分析图谱如图2或5所示。
作为本发明的一种优选技术方案，为该化合物新晶型η，其X-射线粉末衍射谱图在2θ为4.09°、5.02°、6.43°、8.41°、12.27°、13.08°、14.82°、16.11°、16.98°、18.42°、19.18°、21.98°、22.53°、23.85°、26.14°、28.23°、29.46°处具有吸收较强的衍射峰，可接受的误差范围±0.2°。
作为本发明的一种优选技术方案，该化合物的X-射线粉末衍射谱图如图7或8所示。
本领域的技术人员可以理解，在超分子络合物(化合物)的单位晶胞中，所述阿利沙坦酯代谢产物(EXP3174)、AHU377、钙离子(Ca2+)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(化合物)区别于两种活性成分通过简单的物理混合得到的混合物。
本发明的第二个目的在于提供一种本发明所述超分子络合物(化合物)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ARNi化合物新晶型，和一种以上药学上可接受的载体，其中，所述化合物新晶型在药物组合物中的质量百分数为0.1～99.9％。
固体物质的状态可分为晶态(或称晶体)和非晶态(或称无定型态、玻璃体等)两大类。晶态物质(晶体)中的分子、原子或离子在三维空间呈周期性有序排列，其最小的重复单元称做晶胞，为一个由三个轴长a、b、c，和三个夹角α、β、γ(晶胞参数)定义的平行六面体。
单晶X射线衍射法是目前针对检测晶态化合物三维立体结构信息最成熟的分析方法，它可独立完成对晶体化合物的结构分析、共晶/溶剂合物/水合物/成盐的成分组成及比例分析。然而此法对晶体的质量与尺寸大小要求极高，一般需要晶体最短的方向至少大于10微米，才有可能在实验室级单晶X射线衍射仪得到可用的数据。
电子与物质的相互作用是X射线的几百万倍，使得电子可以用于研究比X射线衍射所需尺寸小得多的微米、纳米级的晶体。通过连续倾转晶体收集不同方向的电子衍射数据，经过数据还原后即可得到类似单晶的电子衍射数据。目前已成功解析大量的有机、无机晶体，从结构较简单的有机小分子、无机晶体，到结构十分复杂的沸石分子筛、金属有机框架材料(Metal Organic Framework,MOF)、共价有机框架材料(covalent organic framework,COF)，结合冷冻电镜技术还可以成功解析蛋白质晶体结构。然而在数据收集过程中，电子会将能量传递给材料并缓慢加热样品，从而破坏材料中的分子间相互作用或是化学键导致结晶性下降，这种情况称之为辐照损伤。对于电子束敏感样品，在数据收集过程中需要特殊方法来保护，如冷冻条件、高速相机等，最大限度的降低电子对材料的破坏，从而得到高质量的电子衍射数据。其中，MicroED(Micro Electron Diffraction，微晶电子衍射)为一种新的结构解析方法。
与现有技术产品相比，本发明超分子络合物(化合物)在结晶性等方面具有，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。
本发明所述超分子络合物(化合物)在结晶性等方面具有，适合药用制备使用。
附图说明
图1实施例2所得化合物晶型ξ的XRD谱图
图2实施例2所得化合物晶型ξ的DSC谱图
图3实施例2所得化合物晶型ξ的样品分子的晶体结构图(球棍图)
图4实施例3所得化合物晶型ξ的XRD谱图
图5实施例3所得化合物晶型ξ的DSC谱图
图6实施例4所得化合物晶型ξ的XRD谱图
图7实施例5所得化合物晶型η的XRD谱图
图8实施例6所得化合物晶型η的XRD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，波长发散狭缝1/4°，X射线光管电压45kV，X射线光管电流40mA，扫描范围3-40°(2θ)，步长0.0262606°，每步停留时间33.915s。
DSC采用德国耐驰的DSC 200F3差示扫描量热仪检测：实验气氛，N2，20ml/min。扫描程序：从室温以10k/min升温至250℃，使用铝质样品盘。
TG采用德国耐驰的TG 209F3热重分析仪检测：实验气氛，N2，20ml/min。扫描程序：从室温以10k/min升温至特定温度，使用Al2O3样品盘。
MicroED：电子衍射的收集使用日本电子公司生产的JEM-2100Plus透射电子显微镜，使用加速电压200kV，配备有MerelinEM高速直接电子相机。MicroED收集数据，使用XDS进行衍射数据还原，为了提高完整度，使用15套数据进行合并处理，以SHELXT解析初始结构，以SHELXL以及OLEX 2辅助精修。
实施例1
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，烘干得到晶型α固体3.1g(重复该试验或等比放大，得到足够量的原料用于后续试验)，通过含量测试计算可知所得产品中EXP3174与AHU377游离酸的摩尔比为1:1。
实施例2
制备方法：重复实施例1的试验，称10g晶型α样品，边搅拌边加入40ml二氯甲烷，室温搅拌1天后，取少量样品干燥后测XRD确证是否转晶完全，若未转晶完全则继续搅拌，直至测的XRD显示晶型为晶型ξ后，氮气保护下过滤， 然后35℃真空干燥2天得晶型ξ白色固体，卡尔费休测定含水量为3.9％。
该化合物的X-射线粉末衍射谱图、DSC和MicroED分别如图1-3所示。
从晶体结构分析，沙库巴曲与EXP3174按照1:1的摩尔比结合成钙盐化合物晶体。如图所示，一个晶胞内，包含4个沙库巴曲分子，4个EXP3174分子，6个钙离子，8个水分子。8个水分子均与钙离子形成水合物，其中两个钙离子分别与两个水分子形成离子化水合物，其余四个钙离子分别与一个水分子形成离子化水合物，即(EXP3174·AHU377)·1.5Ca·2H2O。
具体地：2个水分子同时与临近的羧酸氧和四氮唑的氮原子形成氢键，4个水分子与四氮唑的氮原子形成氢键，2个水分子与临近的羧酸氧形成氢键，具体结果如下表1所示。
表1样品的晶体学及精修信息

实施例3
制备方法：重复实施例1的试验，称5g晶型α样品，边搅拌边加入20ml二氯甲烷，然后升温至50℃，保温搅拌1天后取少量混悬液氮气吹干，若不能马上吹干且得到半透明状固体则继续搅拌，直至混悬液能马上吹干得到白色粉末状固体，则氮气保护下过滤，然后45℃真空干燥1天得晶型ξ白色固体，卡尔费休测定含水量3.9％。
该化合物的X-射线粉末衍射谱图、DSC分别如图4-5所示。
实施例4
制备方法：重复实施例1的试验，称30g晶型α样品，加150ml二氯甲烷，室温搅拌1天后氮气保护下过滤，然后40℃真空干燥2天得晶型ξ白色固体，卡尔费休测定含水量3.9％。
该化合物的X-射线粉末衍射谱图如图6所示。
其中，实施例2、3、4的实施例的X-射线粉末衍射峰总结如下表，误差范围±0.2°：
表2
实施例5
制备方法：重复实施例1的试验，称10g晶型α样品，加40ml乙酸丁酯和DMF的混合溶剂(体积比＝9：1)，室温搅拌1天，氮气保护下过滤，然后40℃真空干燥7天得晶型η白色固体，卡尔费休测定含水量3.9％，计算得(EXP3174·AHU377)·1.5Ca·2H2O)。
该化合物的X-射线粉末衍射谱图如图7所示。
实施例6
制备方法：重复实施例1的试验，称5g晶型α样品，加20ml乙酸丁酯和DMF的混合溶剂(体积比＝9：1)，室温搅拌1天，氮气保护下过滤，然后45℃真空干燥7天得晶型η白色固体，卡尔费休测定含水量3.9％，计算得(EXP3174·AHU377)·1.5Ca·2H2O)。
该化合物的X-射线粉末衍射谱图如图8所示。
其中，实施例5和6的实施例的X-射线粉末衍射峰总结如下表，误差范围±0.2°：
表3
实施例7溶解性研究
称取样品适量，至容量瓶中，然后加入不同pH缓冲溶液，充分混匀后在37℃水浴中恒温振摇24h，然后取出趁热过滤(PES 0.45μm滤膜)，用流动相稀释后进液相进行测试。
流动相的配置：称取磷酸二氢钾2.72g，精密称定，加超纯水2000mL溶解，用磷酸调节pH至2.80，过滤，量取上述溶液1860mL与乙腈1140mL混匀，超声脱气，即得。
表4
从上述结果可知，本发明新晶型ξ，相对于现有技术晶型α有溶解度的改善，特别是在接近中性条件(Ph＝6.8)下，有2倍左右的提高。
实施例8稳定性研究
称取样品适量，在以下条件下放置进行影响因素考察10天和30天，采用HPLC法进行杂质检测，结果如下：
表5


同等条件下，WO2021143898A1的晶型的稳定性不及本发明晶型。
综上，本发明所述化合物新晶型具有良好的结晶性、稳定性和溶解性，由此可预测本发明所述系列超分子络合物(化合物)可能具有更好的药学成药性。
实施例9化合物的比格犬药代动力学研究
(1)实验材料
比格犬：雄性，10-13kg，购于仪征安立卯生物科技有限公司。
受试物：将原料药直接填充胶囊
试剂：乙腈，甲酸，普萘洛尔(内标)均为市售可得。
仪器：AB SCIEX TripleQuad5500+三重四级杆质谱。
(2)实验方法
采用6只比格犬交叉给药方式进行实验，每只比格犬给予一粒含有原料药的胶囊，每粒胶囊中分别含有240mg(以无水游离酸C46H50ClN7O7计)的晶型α 和晶型ξ，比格犬口服给药后，于15min、30min、1h、2h、4h、6h、8h、24h采集静脉血1000μL于含有EDTA-K2的抗凝管中，12000rpm离心2min，取血浆-80℃冻存待测。精密称取一定量供试品用DMSO溶解至2mg/mL，作为储备液。准确吸取适量的化合物储备液，加入乙腈稀释制成标准系列溶液。准确吸取上述标准系列溶液各10μL，加入空白血浆90μL，涡旋混匀，配制成相当于血浆浓度为1、3、5、10、30、100、300、1000、3000ng/mL的血浆样品，每一浓度进行双样本分析，建立标准曲线。取30μL血浆，加入内标普萘洛尔(50ng/mL)的乙腈溶液200μL，涡旋混匀后，加入100μL纯化水，再次涡旋混匀，4000rpm离心5min，取上清LC-MS分析。LC-MS检测条件如下：
色谱柱：YMC Triart C18，50*3.0mm，2.1μm。
流动相：水(0.1％甲酸)-乙腈按下表进行梯度洗脱如下表。
表6
(3)数据处理
LC-MS检测血药浓度后，采用WinNonlin 6.1软件，非房室模型法计算药动学参数，结果见下表。
表7

本发明的新晶型ξ表现出优异的PK效果。
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 (10)

  1. ARNi化合物新晶型，其特征在于，所述化合物的结构如下：
    其中，含水量2.8％—5.7％。
  2. 根据权利要求1所述的ARNi化合物新晶型，其特征在于，n＝1.5，2，2.5，3，3.5或4。
  3. 根据权利要求1所述的ARNi化合物新晶型，其特征在于，n＝2，所述晶型为该化合物的晶型ξ，其X-射线粉末衍射谱图在2θ为4.42°、5.15°、6.48°、8.58°、9.68°、10.68°、11.14°、12.77°、15.71°、16.79°、19.07°、20.04°、20.69°、24.60°、26.30°、28.84°、29.61°处具有吸收较强的衍射峰，可接受的误差范围±0.2°。
  4. 根据权利要求3所述的ARNi化合物新晶型，其特征在于，所述化合物的晶型ξ的X-射线粉末衍射谱图如图1、4或6所示。
  5. 根据权利要求3或4所述的ARNi化合物新晶型，其特征在于，所述化合物的晶型ξ的差热分析图谱在241.1.4±5℃有吸热峰值。
  6. 根据权利要求3或4所述的ARNi化合物新晶型，其特征在于，所述化合物的晶型ξ的差热分析图谱如图2或5所示。
  7. 根据权利要求1所述的ARNi化合物新晶型，其特征在于，n＝2，所述晶型为该化合物的晶型η，其X-射线粉末衍射谱图在2θ为4.09°、5.02°、6.43°、8.41°、12.27°、13.08°、14.82°、16.11°、16.98°、18.42°、19.18°、21.98°、22.53°、23.85°、26.14°、28.23°、29.46°处具有吸收较强的衍射峰，可接受的误差范围±0.2°。
  8. 根据权利要求7所述的ARNi化合物新晶型，其特征在于，所述化合物的晶型η的X-射线粉末衍射谱图如图7或8所示。
  9. 一种如权利要求1-8任意一项所述的ARNi化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。
  10. 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1-8任 意一项所述的ARNi化合物新晶型，和一种以上药学上可接受的载体，其中，所述化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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