WO2022037512A1 - 血管紧张素ii受体拮抗剂代谢产物与nep抑制剂的复合物的心衰应用 - Google Patents

血管紧张素ii受体拮抗剂代谢产物与nep抑制剂的复合物的心衰应用 Download PDF

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WO2022037512A1
WO2022037512A1 PCT/CN2021/112668 CN2021112668W WO2022037512A1 WO 2022037512 A1 WO2022037512 A1 WO 2022037512A1 CN 2021112668 W CN2021112668 W CN 2021112668W WO 2022037512 A1 WO2022037512 A1 WO 2022037512A1
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heart failure
ahu377
exp3174
complex
application according
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PCT/CN2021/112668
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English (en)
French (fr)
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孙晶超
景小龙
肖瑛
谢恒�
陈涛
陆银锁
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深圳信立泰药业股份有限公司
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Priority to CN202180030807.8A priority Critical patent/CN115443272B/zh
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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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • 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 pharmaceutical applications, and relates to the application of a complex of angiotensin II receptor antagonist metabolites and NEP inhibitors in heart failure, in particular to the preparation of the complex for heart failure with median ejection fraction. drug use.
  • Heart failure is a severe manifestation or late stage of various heart diseases, with high mortality and rehospitalization rates.
  • the prevalence of heart failure in developed countries is 1.5% to 2.0%, and the prevalence of people aged ⁇ 70 years is ⁇ 10%.
  • An epidemiological survey in 2003 showed that the prevalence of heart failure among adults aged 35 to 74 in my country was 0.9%.
  • my country's population is aging, and the incidence of chronic diseases such as coronary heart disease, hypertension, diabetes, and obesity is on the rise.
  • the improvement of medical level has prolonged the survival period of patients with heart disease, resulting in a continuous increase in the prevalence of heart failure in my country.
  • WO2007056546A1 discloses a sodium salt complex of Valsartan-Sacubitril (LCZ696) and its preparation method, which was approved for listing in China in 2017, trade name: Nuoxinto for heart failure. Its molecular structural units are as follows:
  • WO2017125031A1 discloses a series of complexes composed of angiotensin receptor antagonist metabolites (EXP3174) and NEP inhibitors (Sacubitril), which show a certain effect on heart failure HFpEF with preserved ejection fraction.
  • EXP3174 angiotensin receptor antagonist metabolites
  • Sacubitril NEP inhibitors
  • the present invention provides a complex (or called "supramolecular complex") of angiotensin II receptor antagonist metabolites and NEP inhibitors in preparation for the treatment of heart failure
  • a complex or called "supramolecular complex” of angiotensin II receptor antagonist metabolites and NEP inhibitors in preparation for the treatment of heart failure
  • the heart failure refers to the heart failure of the median ejection fraction
  • the structural unit of the complex is as follows:
  • a:b 1:0.25 ⁇ 4;
  • x is a value between 0.5 ⁇ 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.
  • the heart failure with median ejection fraction refers to HFmrEF as defined in Table 1 of the "Chinese Heart Failure Diagnosis and Treatment Guidelines" 2018 - Classification and Diagnostic Criteria for Heart Failure.
  • the drug refers to being applied to patients with heart failure with the median ejection fraction;
  • the single-dose form of AHU is meant to contain between about 60 mg and 500 mg of the complex based on the total mass of (aEXP3174.bAHU377), including but not limited to 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg , 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg , 390mg, 400mg, 410mg, 420mg, 430mg, 440mg, 450mg,
  • the single-dose form of the medicine contains 60, 120, 180, 240, 300, 360, 420, 480 mg of the compound.
  • a single dosage form refers to a daily dosage form administered to a patient containing 60 mg/day to 500 mg/day of the complex, including but not limited to once a day, 1 day 2 times, 3 times a day, 4 times a day, etc.
  • the dose refers to the initial dose or maintenance dose for drug application, and in the application of hypertension, the initial dose is usually lower than the maintenance dose.
  • the dosage is for refractory hypertensive patients with special conditions, and the dosage may be appropriately increased.
  • the calculation method includes calculating according to the daily dosage of the prodrug, EXP3174 is the metabolite of allisartan medoxomil, the generic name of the listed drug: Allisartan medoxomil, English name: Allisartan Isoproxil Tablets, trade name: Xinlitan , the dosage is 240mg per day.
  • the molecular formula of allisartan medoxomil is C 27 H 29 ClN 6 O 5 and the molecular weight is 553.0; the molecular formula of EXP3174 is C 22 H 21 ClN 6 O 2 , and the molecular weight is about 436.9; the molecular formula of AHU377 is C 24 H 29 NO 5 , the molecular weight is about 411.5, and the daily dosage of the compound should be equivalent to the daily dosage of allisartan medoxomil. Therefore, the single-dose form of the aforementioned compound is calculated.
  • the effective dose in humans is 100 mg/day, and the dose range is 100 mg/day to 500 mg/day.
  • the drug is a solid preparation suitable for oral administration, preferably a tablet or capsule for oral administration, and may be the compound in which the total amount of the drug in multiple tablets and multiple capsules is between 100 mg and 500 mg.
  • the complex of the drug can be obtained by methods known in the prior art, wherein the complex disclosed in WO2017125031A1 and the preparation method thereof are incorporated into the present invention.
  • the value of a:b is selected from 1:0.25, 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5 , 1:4.
  • the structural unit of the composite is as follows:
  • x is selected from 0.5, 1, 1.5, and 2.
  • the structural unit of the composite is as follows:
  • n is any value between 1 and 3.
  • n is selected from 0.5, 1, 1.5, 2, 2.5, and 3.
  • the compound is selected from:
  • the supramolecular complex (complex) of the present invention is distinguished from a mixture obtained by simple physical mixing of two active ingredients.
  • the XRD patterns of the obtained supramolecular complexes (complexes) are significantly different from those of EXP3174 and AHU377 calcium salts, and their solubility in various solvents (such as water, ethanol, ethanol-water, etc.) is also significantly different. , there are obvious differences in other physical and chemical properties such as hygroscopicity, melting point, infrared spectrum and so on.
  • the present invention has the following advantages and beneficial effects:
  • the present invention provides a series of supramolecular complexes (complexes) with dual effects of allisartan medoxomil metabolite (EXP3174) and enkephalinase inhibitor (AHU377) for heart failure with median ejection fraction Compared with the use of LCZ696, it has a significantly better effect at the same dose;
  • the compound of the present invention has a better effect, which fully shows that the use of the compound has obvious advantages over the physical combination of drugs.
  • X-ray powder diffraction was detected by Empyrean X-ray diffractometer equipment. Detection conditions: Cu target K ⁇ ray, voltage 40KV, current 40mA, emission slit 1/32°, anti-scatter slit 1/16°, anti-scattering slit
  • the scattering slit is 7.5mm, the 2 ⁇ range is 3°-60°, the step size is 0.02°, and the dwell time of each step is 40s.
  • Differential scanning calorimetry spectrum was detected by DSC204F1 differential scanning calorimeter equipment of NETZSCH company in Germany, detection conditions: atmosphere: N 2 , 20mL/min; scanning program: from room temperature to 250°C at 10°C/min, record heating curve.
  • Moisture content was detected by TG209 thermogravimetric analyzer equipment from NETZSCH Company in Germany, detection conditions: atmosphere: N 2 , 20 mL/min; scanning program: room temperature -700 °C, heating rate: 10 °C/min.
  • the EXP3174 used in the examples was made by the company, with a purity of 98.3%.
  • the AHU377 calcium salt used in the examples was made by the company, with a purity of 99.4%.
  • AHU377 free acid 2.36g, EXP3174 2g and 40mL acetone obtained according to the method in Example 1 were added to a 250mL there-neck flask, and dissolved; Stir at °C for 6 h, add 40 mL of acetone, and react for 8 h. Under nitrogen protection, it is filtered through a Buchner funnel, and the solid is rinsed with acetone to obtain a white solid, which is dried under vacuum for 8 h at 50 ° C to obtain 3.1 g of solid (EXP3174 ⁇ AHU377 ) 3- ⁇ 1.5Ca 2+ ⁇ 2H 2 O. Repeat the test to obtain sufficient experimental doses for efficacy.
  • Animals were adaptively housed upon arrival at the facility, and randomized after echocardiography and electrocardiography before starting the trial.
  • the animals were anesthetized by intramuscular injection of Shutai (5 mg/kg), the trachea of the anesthetized dog was connected to a ventilator, and the dog was fixed in a supine position.
  • the chest was opened between the third and fourth ribs, the left anterior descending coronary artery was ligated to close the chest cavity, and the skin was sutured.
  • the animals were given the therapeutic drugs by gavage, once a day, for 4 consecutive weeks. During the experiment, the animals' living conditions were observed daily, and abnormal conditions were recorded. After 4 weeks of dosing, echocardiography was performed.
  • the protective gauze was removed, and the thoracic cavity was sutured with No. 7 sutures through the fourth and fifth ribs; the lungs were recruited using manual compression.
  • the tissue and skin are sutured layer by layer.
  • the animals were kept warm after the operation, and the normal saline was supplemented appropriately; the blood oxygen saturation, heart rate, electrocardiogram, body temperature and respiratory changes were closely observed; the gas anesthesia machine was turned off, and the tracheal intubation was removed after the animals fully recovered spontaneous breathing.
  • postoperatively, intramuscular injection of dophine (meloxicam, 0.67 mg/kg) was given to relieve pain, and intramuscular injection of ampicillin sodium 20 mg/kg was given to fight infection.
  • the important manifestation of chronic heart failure is the decrease of left ventricular systolic function, which is the main clinical endpoint of chronic heart failure.
  • the echocardiography showed that the left ventricular ejection fraction (LVEF) of the model group was significantly reduced to 46.84% after modeling. Compared with the sham operation group, P ⁇ 0.001, it could better simulate the chronic clinical ejection fraction in humans.
  • Heart failure As can be seen from Table 2, the end point LVEF of dogs in the compound, LCZ696 and physical mixing groups were 59.88%, 57.01% and 55.75, respectively, which were significantly higher than those in the model group (P ⁇ 0.001, P ⁇ 0.001, P ⁇ 0.001 ). At the same time, 100mpk compound of the present invention increased the median ejection fraction significantly better than the LCZ696 group of equal mass dose and the physical mixing group of equal molar dose (P ⁇ 0.05, P ⁇ 0.01).
  • the dual-action supramolecular complex (complex) provided by the present invention is used for the medicinal purposes of heart failure with median ejection fraction, and has a significantly better effect than using LCZ696 100mpk under the same dose;
  • the compound of the present invention Compared with the physical mixture of EXP3174+AHU377, the compound of the present invention has a better effect, which fully shows that the use of the compound has obvious advantages over the physical combination of drugs.
  • Animals were adaptively housed upon arrival at the facility, and randomized after echocardiography and electrocardiography before starting the trial.
  • the animals were anesthetized by intramuscular injection of Shutai (5 mg/kg), the trachea of the anesthetized dog was connected to a ventilator, and the dog was fixed in a supine position.
  • the chest was opened between the third and fourth ribs, the left anterior descending coronary artery was ligated to close the chest cavity, and the skin was sutured.
  • the animals were given the therapeutic drugs by gavage, once a day, for 2 consecutive weeks. During the experiment, the animals' living conditions were observed daily, and abnormal conditions were recorded. Echocardiography was performed 14 days after dosing.
  • the protective gauze was removed, and the thoracic cavity was sutured with No. 7 sutures through the fourth and fifth ribs; the lungs were recruited using manual compression.
  • the tissue and skin are sutured layer by layer.
  • the animals were kept warm after the operation, and the normal saline was supplemented appropriately; the blood oxygen saturation, heart rate, electrocardiogram, body temperature and respiratory changes were closely observed; the gas anesthesia machine was turned off, and the tracheal intubation was removed after the animals fully recovered spontaneous breathing.
  • postoperatively, intramuscular injection of dophine (meloxicam, 0.67 mg/kg) was given to relieve pain, and intramuscular injection of ampicillin sodium 20 mg/kg was given to fight infection.
  • the important manifestation of chronic heart failure is the decrease of left ventricular systolic function, which is the main clinical endpoint of chronic heart failure.
  • the echocardiography showed that the left ventricular ejection fraction (LVEF) of the model group was significantly reduced after modeling but was still greater than 50%. Compared with the sham operation group, P ⁇ 0.001, which could better simulate the preserved ejection fraction in humans. chronic heart failure.
  • LVEF left ventricular ejection fraction
  • the end-point LVEF of dogs in LCZ696 group was 57.98%, which was significantly higher than that in model group (P ⁇ 0.001).
  • Both the compound of the present invention and the physical mixture group can increase LVEF, and the comparison with the model group has statistical significance (P ⁇ 0.05).
  • the 100mpk compound of the present invention has the same effect on LVEF compared with the LCZ696 equimolar dose group, and is significantly better than the physical mixing group.
  • Table 4 The experimental results are shown in Table 4:
  • Model LVEF was 51.80%, ⁇ 50%, indicating that the ejection fraction preservation model was successful, as shown in Figure 1.

Abstract

公开了血管紧张素II受体拮抗剂代谢产物与NEP抑制剂的复合物的心衰应用，具体涉及所述复合物在制备用于射血分数中间值的心衰(HFmrEF)的应用。

Description

血管紧张素II受体拮抗剂代谢产物与NEP抑制剂的复合物的心衰应用 技术领域
本发明属于药物应用技术领域，涉及血管紧张素II受体拮抗剂代谢产物与NEP抑制剂的复合物的心衰应用，具体涉及所述复合物在制备用于射血分数中间值的心衰的药物用途。
背景技术
心衰是各种心脏疾病的严重表现或晚期阶段，死亡率和再住院率居高不下。发达国家的心衰患病率为1.5％～2.0％，≥70岁人群患病率≥10％。2003年的流行病学调查显示，我国35～74岁成人心衰患病率为0.9％。我国人口老龄化加剧，冠心病、高血压、糖尿病、肥胖等慢性病的发病呈上升趋势，医疗水平的提高使心脏疾病患者生存期延长，导致我国心衰患病率呈持续升高趋势。对国内10714例住院心衰患者的调查显示：1980、1990、2000年心衰患者住院期间病死率分别为15.4％、12.3％和6.2％，主要死亡原因依次为左心衰竭(59％)、心律失常(13％)和心脏性猝死(13％)。China-HF研究显示，住院心衰患者的病死率为4.1％。
WO2007056546A1公开了一种缬沙坦(Valsartan)-沙库匹曲(Sacubitril)的钠盐复合物(LCZ696)及其制备方法，于2017年在中国获批上市，商品名：诺欣妥
Figure PCTCN2021112668-appb-000001
用于心力衰竭。其分子结构单元如下：
Figure PCTCN2021112668-appb-000002
另外，WO2017125031A1公开了一系列由血管紧张素受体拮抗剂代谢产物(EXP3174)与NEP抑制剂(Sacubitril)的复合物，且对射血分数保留的心力衰竭HFpEF表现一定效果，其分子结构单元如下：
Figure PCTCN2021112668-appb-000003
可知，寻找一种针对射血分数中间值的心衰具有好的治疗效果的针对性药物至关重要。
发明内容
鉴于现有技术存在的技术问题，本发明提供了血管紧张素II受体拮抗剂代谢产物与NEP抑制剂的复合物(或者称之为“超分子络合物”)在制备用于治疗心衰的药物中的应用，所述心衰是指射血分数中间值的心衰，所述复合物的结构单元如下：
(aEXP3174·bAHU377)·xCa·nA
其中，EXP3174和AHU377结构式分别如下：
Figure PCTCN2021112668-appb-000004
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。
具体地，所述射血分数中间值的心衰是指《中国心力衰竭诊断和治疗指南》2018-心力衰竭的分类和诊断标准表1所定义的HFmrEF。
作为本发明的一种优选技术方案，所述药物是指应用于患有所述射血分数中间值的心衰的患者；根据本发明的实验结果及前体药物的应用量推算，所述药物的单剂量形式是指以(aEXP3174·bAHU377)的总质量计约含有60毫克和500毫克之间的所述复合物，包括但不限于60mg、70mg、80mg、90mg、100mg、110mg、120mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg、260mg、270mg、280mg、290mg、300mg、310mg、320mg、330mg、340mg、350mg、360mg、370mg、380mg、390mg、400mg、410mg、420mg、430mg、440mg、450mg、460mg、470mg、480mg、490mg、500mg。
作为本发明的一种更为优选技术方案，所述药物的单剂量形式含有60、120、180、240、300、360、420、480毫克的所述复合物。
在一种实施方案中，单剂量形式是指日剂量形式，给予患者含有60毫克/天至500毫克/天的所述复合物，所述给药次数包括但不限于1天1次，1天2次，1天3次，1天4次等。所述剂量是指药物应用的起始剂量或者维持剂量，在高血压的应用中，通常起始剂量低于维持剂量。所述剂量针对特殊情况的难治高血压患者，可能适当提高使用剂量。
具体的，所述推算方法包括按照前体药物日用量计算，EXP3174为阿利沙坦酯的体内代谢物，已上市药物通用名称：阿利沙坦酯片，英文名称：Allisartan Isoproxil Tablets，商品名称：信立坦，使用剂量为每天240mg。
其中，阿利沙坦酯的分子式为C 27H 29ClN 6O 5，分子量为553.0；而EXP3174的分子式为C 22H 21ClN 6O 2，分子量约为436.9；AHU377的分子式为C 24H 29NO 5，分子量约为411.5，复合物的日用量应相当于使用阿利沙坦酯的日用量，所以，推算得到前述的复合物的单剂量形式。
由射血分数中间值的犬心衰模型数据，推测人体起效剂量在100mg/天，剂量使用范围在100mg/天～500mg/天。
所述药物是适于口服的固体制剂，优选口服的片剂或胶囊，可以是多个片及多个胶囊的药物总量为100毫克和500毫克之间的所述复合物。
所述药物的所述复合物可以通过现有技术已知的方法获得，其中，WO2017125031A1公开的复合物及其制备方法引入本发明。
作为本发明的一种更为优选技术方案，a:b的值选自1:0.25，1:0.5，1:1，1:1.5，1:2，1:2.5，1:3，1:3.5，1:4。
作为本发明的一种更为优选技术方案，所述复合物的结构单元如下：
(EXP3174·AHU377)·xCa·nH 2O
或者
Figure PCTCN2021112668-appb-000005
其中x为0.5～2之间的数值；n为0～3之间的数值。
作为本发明的一种更为优选技术方案，x选自0.5、1、1.5、2。
作为本发明的一种更为优选技术方案，所述复合物的结构单元如下：
(EXP3174·AHU377)·1.5Ca·nH 2O
或者
(EXP3174·AHU377)·2Ca·nH 2O
其中n为1～3之间的任意数值。
作为本发明的一种更为优选技术方案，n选自0.5、1、1.5、2、2.5、3。
作为本发明的一种更为优选技术方案，所述复合物选自：
(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。所得超分子络合物(复合物)的XRD谱图明显区别于EXP3174和AHU377钙盐的XRD谱图，其在各溶剂(诸如水、乙醇、乙醇-水等)中的溶解性能也存在明显区别，在其他各项理化性质诸如吸湿性、熔点、红外谱图等均存在明显差异。
本发明相对于现有技术具有如下的优点及有益效果：
1、本发明提供了一系列由阿利沙坦酯代谢产物(EXP3174)与脑啡肽酶抑制剂(AHU377)具有双重作用的超分子络合物(复合物)用于射血分数中间值的心衰的药物用途，同等剂量下相对于使用LCZ696具有明显更好的效果；
2、本发明复合物在射血分数中间值犬模型的效果优于射血分数保留犬模型中的效果，由此可见，本发明药物组合物针对射血分数中间值的心衰具有特异的选择性，是根据现有技 术难以预计的。
3、本发明复合物相对于EXP3174+AHU377物理混合物更好的效果，充分说明复合物的使用相对于药物物理组合使用具有明显的优势。
附图说明
图1.《中国心力衰竭诊断和治疗指南》2018-心力衰竭的分类和诊断标准表。
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-射线粉末衍射采用锐影(Empyrean)X射线衍射仪设备检测，检测条件：Cu靶Kα射线，电压40KV，电流40mA，发射狭缝1/32°，防散射狭缝1/16°，防散射狭缝7.5mm，2θ范围：3°-60°，步长0.02°，每步停留时间40s。
差示扫描量热法谱图采用德国NETZSCH公司DSC204F1差示扫描量热仪设备检测，检测条件：气氛：N 2，20mL/min；扫描程序：从室温以10℃/min升温至250℃，记录升温曲线。
水份含量采用德国NETZSCH公司TG209热重分析仪设备检测，检测条件：气氛：N 2，20mL/min；扫描程序：室温-700℃，升温速率：10℃/min。
实施例所使用EXP3174通过公司自制，纯度98.3％。
实施例所使用AHU377钙盐通过公司自制，纯度99.4％。
实施例1
AHU377游离酸的制备：
将2.1g AHU377钙盐、40mL醋酸异丙酯加入250mL的单口瓶中，室温下加入2mol/L盐酸4.5mL搅拌溶清。分液，收集有机层，使用20mL水洗涤有机层两次；35℃下减压脱溶，得AHU377游离酸。
实施例2
复合物的制备：(按照专利WO2017125031A1的实施例2制备)
Figure PCTCN2021112668-appb-000006
室温下，将依据实施例1方法所得的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 1.3当量的氢氧化钙固体和1mL水，室温搅拌10h，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，35℃下真空烘8h，烘干得到固体3.5g(EXP3174·AHU377) 3-·1.5Ca 2+·2.5H 2O，HPLC检测纯度为99％。重复试验，以获得足够的药效实验用量。
实施例3
复合物的制备：(按照专利WO2017125031A1的实施例3制备)
Figure PCTCN2021112668-appb-000007
室温下，将依据实施例1方法所得的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(EXP3174·AHU377) 3-·1.5Ca 2+·2H 2O。重复试验，以获得足够的药效实验用量。
实施例4
复合物对犬慢性心衰模型中的药效研究-射血分数中间值
4.1方法:
动物到达设施后经适应性饲养，超声心动图检查和心电检查后随机分组，再开始试验。手术当天，肌肉注射舒泰(5mg/kg)麻醉动物，麻醉犬气管接呼吸机，仰位固定，在第三和第四肋骨间开胸，结扎冠状动脉左前降支关闭胸腔，缝合皮肤。动物术后恢复3天后，灌胃给予治疗药物，每天一次，连续4周。实验期间，每日观察动物生活状态，对异常状况进行记录。给药4周后，进行超声心动图检查。
4.2造模:
手术前一天，动物将禁食过夜。手术当天，动物肌肉舒泰(剂量：5mg/kg)肌肉注射诱导麻醉；同时肌肉注射硫酸阿托品注射液(剂量：0.5mg/犬)。动物麻醉后剃净左侧胸部毛； 迅速进行气管插管，接通呼吸机提供人工呼吸并且提供1.5％异氟烷气体维持麻醉状态，同时使用监护仪监测血氧饱和度，心率，心电图，体温及呼吸频率等。在前肢皮肤使用70％酒精消毒后，找到头静脉，做静脉插管并留置静脉给药通路。使用碘伏及70％酒精对左侧胸部皮肤进行消毒无菌处理；铺无菌手术洞巾；使用无菌手术刀沿第四与第五肋间切开皮肤，止血后使用电刀逐层切开皮下组织，肌肉层，并及时止血。小心打开胸腔膜，暴露肺组织，要避免损伤肺组织；沿第四肋骨下缘逐步扩大手术视野至20-25cm，使用扩胸器将手术窗口撑大。使用温生理盐水浸透的无菌纱布推移并保护肺组织。使用温生理盐水浸湿的无菌纱布推移左侧心耳，在左侧心室与左侧心房之间小心暴露并使用钝性直角镊游离冠状动脉左前降支，用4号丝线穿过该动脉，在游离和穿线过程中避免提拉动脉。使用丝线结扎冠状动脉左前降支，结扎过程中密切观察动物血氧饱和度，心率，心电图，体温及呼吸；如果动物出现室颤等异常情况，立即停止手术操作并通过头静脉快速给与利多卡因注射治疗(10mg/kg)。确定胸腔内无出血后，取出保护用纱布，使用7号缝合线穿过第四和第五肋骨缝合胸腔；使用人工按压方法复张肺。逐层缝合组织及皮肤。术后保持动物保温，适当补充生理盐水；密切观察血氧饱和度，心率，心电图，体温及呼吸变化；关闭气体麻醉机，直至动物完全恢复自主呼吸后拔除气管插管。术后肌肉注射痛啡(美洛昔康，0.67mg/kg)止痛，肌肉注射氨苄西林钠20mg/kg抗感染。
4.3分组和给药：
分组前各犬进行超声心动图检查和心电监测，根据射血分数随机分为5组(每组5-6只动物)，动物造模后3d以后，各组犬灌胃给予相应药物，每天一次，连续给药4周。所有手术分为6批进行实验，每批4-5只动物，每组0-1只。各组情况如下表1：
Figure PCTCN2021112668-appb-000008
所有给药剂量以无水游离酸计。
4.4研究结果：
慢性心衰的重要表现即为左心室收缩功能降低，是慢性心衰的临床主要检测终点。经超声心动图检查可见模型组犬左室射血分数(LVEF)在造模后显著降低至46.84％，与假手术组相比P<0.001，能够较好模拟人体临床射血分数中间值的慢性心衰。从表2可以看出，本发明复合物、LCZ696及物理混合组组犬的终点LVEF分别为59.88％、57.01％及55.75，均显著高于模型组(P<0.001，P<0.001，P<0.001)。同时，100mpk本发明复合物升高射血分数中间值显著优于等质量剂量的LCZ696组及等摩尔剂量的物理混合组(P<0.05，P<0.01)。
表2化合物对心衰犬终点左心室射血分数的影响(Mean±SD)
Figure PCTCN2021112668-appb-000009
###P<0.001，与Sham组相比；***P<0.001，与Model组相比； $P<0.05，与LCZ696组相比； @@P<0.01，与物理混合组相比。
注：本发明复合物采用实施例3获得的化合物。
从上述结果可见，本发明提供的双重作用的超分子络合物(复合物)用于射血分数中间值的心衰的药物用途，同等剂量下相对于使用LCZ696 100mpk具有明显更好的效果；
本发明复合物相对于EXP3174+AHU377物理混合物更好的效果，充分说明复合物的使用相对于药物物理组合使用具有明显的优势。
实施例5
复合物对犬慢性心衰模型中的药效研究-射血分数保留
5.1方法：
动物到达设施后经适应性饲养，超声心动图检查和心电检查后随机分组，再开始试验。手术当天，肌肉注射舒泰(5mg/kg)麻醉动物，麻醉犬气管接呼吸机，仰位固定，在第三和第四肋骨间开胸，结扎冠状动脉左前降支关闭胸腔，缝合皮肤。动物术后恢复3天后，灌胃给予治疗药物，每天一次，连续2周。实验期间，每日观察动物生活状态，对异常状况进行记录。给药14天后，进行超声心动图检查。
5.2造模:
手术前一天，动物将禁食过夜。手术当天，动物肌肉舒泰(剂量：5mg/kg)肌肉注射诱导麻醉；同时肌肉注射硫酸阿托品注射液(剂量：0.5mg/犬)。动物麻醉后剃净左侧胸部毛；迅速进行气管插管，接通呼吸机提供人工呼吸并且提供1.5％异氟烷气体维持麻醉状态，同时使用监护仪监测血氧饱和度，心率，心电图，体温及呼吸频率等。在前肢皮肤使用70％酒精消毒后，找到头静脉，做静脉插管并留置静脉给药通路。使用碘伏及70％酒精对左侧胸部皮肤进行消毒无菌处理；铺无菌手术洞巾；使用无菌手术刀沿第四与第五肋间切开皮肤，止血后使用电刀逐层切开皮下组织，肌肉层，并及时止血。小心打开胸腔膜，暴露肺组织，要避免损伤肺组织；沿第四肋骨下缘逐步扩大手术视野至20-25cm，使用扩胸器将手术窗口撑大。使用温生理盐水浸透的无菌纱布推移并保护肺组织。使用温生理盐水浸湿的无菌纱布推移左侧心耳，在左侧心室与左侧心房之间小心暴露并使用钝性直角镊游离冠状动脉左前降支，用4号丝线穿过该动脉，在游离和穿线过程中避免提拉动脉。使用丝线结扎冠状动脉左前降支，结扎过程中密切观察动物血氧饱和度，心率，心电图，体温及呼吸；如果动物出现室颤等异常情况，立即停止手术操作并通过头静脉快速给与利多卡因注射治疗(10mg/kg)。确定胸腔内无出血后，取出保护用纱布，使用7号缝合线穿过第四和第五肋骨缝合胸腔；使用人工按压方法复张肺。逐层缝合组织及皮肤。术后保持动物保温，适当补充生理盐水；密切观察血氧饱和度，心率，心电图，体温及呼吸变化；关闭气体麻醉机，直至动物完全恢复自主呼吸后拔除气管插管。术后肌肉注射痛啡(美洛昔康，0.67mg/kg)止痛，肌肉注射氨苄西林钠20mg/kg抗感染。
5.3分组和给药：
分组前各犬进行超声心动图检查和心电监测，根据射血分数随机分为5组(每组5-6只动物)，动物造模后3d以后，各组犬灌胃给予相应药物，每天一次，连续给药2周。所有手术分为6批进行实验，每批4-5只动物，每组0-1只。各组情况如下表3：
Figure PCTCN2021112668-appb-000010
注：所有给药剂量以无水游离酸计，本发明复合物采用实施例3获得的化合物。
5.4实验结果：
慢性心衰的重要表现即为左心室收缩功能降低，是慢性心衰的临床主要检测终点。经超声心动图检查可见模型组犬左室射血分数(LVEF)在造模后显著降低但仍大于50％，与假手术组相比P<0.001，能够较好模拟人体临床射血分数保留的慢性心衰。从表4可以看出，LCZ696组犬终点LVEF为57.98％，显著高于模型组(P<0.001)。本发明复合物及物理混合组均能够升高LVEF，与模型组比较均具有统计学意义(P<0.05)。同时，100mpk本发明复合物与LCZ696等摩尔剂量组对LVEF影响相比药效相当，并显著优于物理混合组。实验结果如表4所示：
表4化合物对心衰犬终点左心室射血分数的影响(Mean±SD)
Figure PCTCN2021112668-appb-000011
其中，Model LVEF为51.80％，≥50％，说明射血分数保留造模成功，参见图1所示。
###P<0.001，与Sham组相比；*P<0.05，**P<0.01，***P<0.001，与Model组相比； @P<0.05，与物理混合组相比
注：本发明复合物采用实施例3获得的化合物。
从上述结果可见，本发明复合物在射血分数中间值犬模型的效果优于射血分数保留犬模型 中的效果，由此可见，本发明药物组合物针对射血分数中间值的心衰具有特异的选择性，是根据现有技术难以预计的。
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. 血管紧张素II受体拮抗剂代谢产物与NEP抑制剂的复合物在制备用于治疗心衰的药物中的应用，所述心衰是指射血分数中间值的心衰，所述复合物的结构单元如下：
    (aEXP3174·bAHU377)·xCa·nA
    其中，EXP3174和AHU377结构式分别如下：
    Figure PCTCN2021112668-appb-100001
    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。
  2. 根据权利要求1所述的心衰应用，其特征在于：所述药物的单剂量形式含有60毫克和500毫克之间的所述复合物。
  3. 根据权利要求1所述的心衰应用，其特征在于：所述药物的单剂量形式含有60、120、180、240、300、360、420、480毫克的所述复合物。
  4. 根据权利要求1所述的心衰应用，其特征在于：所述药物是适于口服的固体制剂，优选口服的片剂或胶囊。
  5. 根据权利要求1-4任一项权利要求所述的心衰应用，其特征在于：a:b的值选自1:0.25，1:0.5，1:1，1:1.5，1:2，1:2.5，1:3，1:3.5，1:4。
  6. 根据权利要求1-5任一项权利要求所述的心衰应用，其特征在于：所述复合物的结构单元如下：
    (EXP3174·AHU377)·xCa·nH 2O
    或者
    Figure PCTCN2021112668-appb-100002
    其中x为0.5～2之间的数值；n为0～3之间的数值。
  7. 根据权利要求1-6任一项权利要求所述的心衰应用，其特征在于：x选自0.5、1、1.5、2。
  8. 根据权利要求1-7任一项权利要求所述的心衰应用，其特征在于：所述复合物的结构单元如下：
    (EXP3174·AHU377)·1.5Ca·nH 2O
    或者
    (EXP3174·AHU377)·2Ca·nH 2O
    其中n为1～3之间的任意数值。
  9. 根据权利要求1-8任一项权利要求所述的心衰应用，其特征在于：n选自0.5、1、1.5、2、2.5、3。
  10. 根据权利要求1-9任一项权利要求所述的心衰应用，其特征在于，所述复合物选自：
    (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。
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