WO2022111493A1 - Arb代谢产物与nep抑制剂的复合物预防和/或治疗肾病的药物用途 - Google Patents

Arb代谢产物与nep抑制剂的复合物预防和/或治疗肾病的药物用途 Download PDF

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WO2022111493A1
WO2022111493A1 PCT/CN2021/132617 CN2021132617W WO2022111493A1 WO 2022111493 A1 WO2022111493 A1 WO 2022111493A1 CN 2021132617 W CN2021132617 W CN 2021132617W WO 2022111493 A1 WO2022111493 A1 WO 2022111493A1
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ahu377
exp3174
complex
pharmaceutical use
use according
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PCT/CN2021/132617
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English (en)
French (fr)
Inventor
孙晶超
肖瑛
景小龙
王汝欢
胡雪峰
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深圳信立泰药业股份有限公司
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Priority to CN202180030740.8A priority Critical patent/CN115461052B/zh
Publication of WO2022111493A1 publication Critical patent/WO2022111493A1/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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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 use of a compound of an ARB metabolite and an NEP inhibitor in preparing a medicine for preventing and/or treating kidney disease.
  • 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: 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 have a certain effect on heart failure HFpEF with preserved ejection fraction.
  • EXP3174 angiotensin receptor antagonist metabolites
  • Sacubitril NEP inhibitors
  • Chronic kidney disease has the characteristics of high prevalence, low awareness, poor prognosis and high medical costs. It is another disease that seriously endangers human health after cardiovascular and cerebrovascular diseases, diabetes and malignant tumors. In recent years, the prevalence of CKD has increased year by year, and the prevalence of the global general population has reached 14.3%. A cross-sectional epidemiological study in my country shows that the prevalence of CKD in people over 18 years old is 10.8%. With the aging of the population in my country, the incidence of diseases such as diabetes and hypertension is increasing year by year, and the incidence of CKD is also showing a rising trend.
  • the present invention provides the use of a complex of an ARB metabolite and a NEP inhibitor (or referred to as a "supramolecular complex") in the preparation of a medicament for preventing and/or treating nephropathy,
  • the structural units of the complex are as follows:
  • the kidney disease includes chronic kidney disease, and further includes chronic kidney disease combined with hypertension, chronic kidney disease combined with heart failure, and the like.
  • the renal disease includes CKD patients with A1, A2 and A3 grades.
  • the complex of the present invention can effectively inhibit the increase of urinary albumin, and/or urinary albumin/urine creatinine ratio, and/or urinary creatinine and serum creatinine of CKD patients.
  • Chronic kidney disease please refer to "Chronic Kidney Disease Screening, Diagnosis and Prevention Guidelines", Vol. 37, No. 1, January 2017, Chinese Journal of Practical Internal Medicine, expert in Shanghai Early Detection and Standardized Diagnosis and Treatment and Demonstration Project of Chronic Kidney Disease Group.
  • the drug refers to being applied to patients suffering from the renal disease; according to the experimental results of the present invention and the application amount of the prodrug, the single-dose form of the drug refers to taking
  • the total mass of (aEXP3174.bAHU377) contains approximately between 60 mg and 1000 mg of the complex, including but not limited to 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 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
  • the single-dose form of the drug contains 60, 120, 180, 240, 300, 360, 420, 480, 540, 600, 660, 720, 780, 840, 900, 960 mg of the complex.
  • a single dosage form refers to a daily dosage form administered to a patient containing 60 mg/day to 1000 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 drug is a solid preparation suitable for oral administration, preferably a tablet or capsule for oral administration, and the total amount of the drug may be 60 mg to 1000 mg in multiple tablets and multiple capsules.
  • 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, including:
  • the present invention provides a series of supramolecular complexes (complexes) with dual effects of allisartan medoxomil metabolite (EXP3174) and neprilysin inhibitor (AHU377) for preventing and/or treating nephropathy.
  • EXP3174 allisartan medoxomil metabolite
  • AHU377 neprilysin inhibitor
  • the compound of the present invention has a better effect, which fully shows that the use of the compound has obvious advantages over the use of 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-necked 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 (named compound A). Repeat the test to obtain sufficient experimental doses for efficacy.
  • EXP3174 Batch number: 20190501Z, Huizhou Xinlitai Pharmaceutical Co., Ltd.;
  • Sacubitril calcium salt batch number: DYF20003, Huizhou Xinlitai Pharmaceutical Co., Ltd.;
  • LCZ696 Batch number: DYF19005, Huizhou Xinlitai Pharmaceutical Co., Ltd.;
  • Creatinine determination kit (sarcosine oxidase method): batch number: 141120017, Shenzhen Mindray Biomedical Electronics Co., Ltd.;
  • Albumin determination kit (bromocresol chloride method): batch number: 148320004, Shenzhen Mindray Biomedical Electronics Co., Ltd.;
  • the laboratory animal quality certificate number is No.110011201106160342, provided by Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.
  • the laboratory animal production license number is SCXK (Beijing) 2016-0006. It was raised in the SPF-level experimental animal center of Shenzhen Xinlitai Pharmaceutical Co., Ltd., and the experimental animal use license number is SYXK (Guangdong) 2019-0142, and it was raised in the SPF-level experimental animal center.
  • the rats were randomly divided into two groups, one group was the sham operation group (6 rats), and the other group was the operation group that underwent 5/6 nephrectomy (72 rats).
  • the rats in the operation group were anesthetized by intraperitoneal injection of 1.5% sodium pentobarbital (30 mg/kg), and the rats were fixed in the prone position on the rat board, skin preparation, routine disinfection, wearing sterile gloves, and laying sterile gauze.
  • a longitudinal incision was made about 0.5 cm below the left costal spine point and about 1 cm on the left side of the spine, about 1 cm long, and incised into the abdomen layer by layer.
  • the surviving animals resumed feeding for 3 weeks and were divided into groups.
  • Each rat was numbered and weighed, blood was collected with heparin anticoagulation, and plasma creatinine was detected.
  • SPSS software was used to perform block random grouping according to the level of plasma creatinine, and the groups were divided into model group , EXP3174 group (35mg/kg), Sacubitril group (33mg/kg), LCZ696 low dose group (34mg/kg), LCZ696 high dose group (68mg/kg), S086 low dose group (34mg/kg), S086 high-dose group (68mg/kg), 5-6 animals in each group.
  • the groups were given intragastric administration on the next day, and the administration volume was 10 mL/kg, once a day, for 4 consecutive weeks.
  • the sham operation group and the model group were given 0.5% CMC-Na vehicle every day, and the administration volume was 10 mL/kg.
  • blood was collected from the tail vein and urine was collected from the metabolic cage for 24 hours.
  • Plasma creatinine, urinary albumin and urinary creatinine concentrations were detected in the 4th week after administration, and the 24-h urinary albumin and urinary albumin/urine creatinine ratio were calculated.
  • the experimental data are expressed as the mean ⁇ standard deviation, and the statistics use SPSS 24.0 software, and the statistics are carried out according to the following methods: First, the normal distribution (Shapiro-Wilk test) and the homogeneity of variance (Levene's test) analysis are carried out, if the data conforms to normality distribution (P>0.05) and homogeneity of variance (P>0.05), then perform the SNK test in the one-way analysis of variance test (ANOVA), if the analysis result P ⁇ 0.05, it is significant; if the data does not conform to the normal distribution ( P ⁇ 0.05) or heterogeneity of variance (P ⁇ 0.05), the two independent sample test in the nonparametric test was selected, and if the analysis result P ⁇ 0.05, it was significant.
  • ANOVA analysis of variance test
  • the compound of the present invention has a significantly better effect on the index 24h urine albumin, urine albumin/urine creatinine ratio in the CKD model than the equimolar dose of LCZ696;
  • the molar doses of EXP3174 and AHU377 also have better effects when administered alone, which fully shows that the complex has obvious advantages.
  • the effect of the complex of the present invention on the index serum creatinine in the CKD model is significantly better than that of LCZ696 at an equimolar dose; at the same time, the complex of the present invention is also more effective than the equimolar doses of EXP3174 and AHU377 administered alone.
  • the good effect fully shows that the compound has obvious advantages.

Abstract

ARB代谢产物与NEP抑制剂的复合物在制备用于预防和/或治疗肾病的药物用途。

Description

ARB代谢产物与NEP抑制剂的复合物预防和/或治疗肾病的药物用途 技术领域
本发明属于药物应用技术领域，涉及ARB代谢产物与NEP抑制剂的复合物在制备用于预防和/或治疗肾病的药物用途。
背景技术
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：
Figure PCTCN2021132617-appb-000001
用于心力衰竭。其分子结构单元如下：
Figure PCTCN2021132617-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 PCTCN2021132617-appb-000003
慢性肾脏病(chronic kidney disease，CKD)具有患病率高、知晓率低、预后差和医疗费用高等特点，是继心脑血管疾病、糖尿病和恶性肿瘤之后，又一严重危害人类健康的疾病。近年来CKD患病率逐年上升，全球一般人群患病率已高达14.3％，我国横断面流行病学研究显示，18岁以上人群CKD患病率为10.8％。随着我国人口老龄化、糖尿病和高血压等疾病的发病率逐年增高，CKD发病率也呈现不断上升之势。
可知，寻找一种针对肾病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ARB代谢产物与NEP抑制剂的复合物(或者称之为“超分子络合物”)在制备用于预防和/或治疗肾病的药物用途，所述复合物的结构单元如下：
(aEXP3174·bAHU377)·xCa·nA。
作为本发明的一种优选技术方案，所述肾病包括慢性肾脏病，进一步包括慢性肾脏病合并高血压，慢性肾脏病合并心衰等。
作为本发明的一种优选技术方案，所述肾病包括A1、A2和A3分级的CKD患者。
作为本发明的一种优选技术方案，本发明复合物可以有效抑制CKD患者的尿白蛋白、和/或尿白蛋白\尿肌酐比值，和/或尿肌酐、血肌酐的升高。
具体地，所述慢性肾脏病参见《慢性肾脏病筛查诊断及防治指南》，2017年1月第37卷第1期，中国实用内科杂志，上海慢性肾脏病早发现及规范化诊治与示范项目专家组。
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肾病的患者；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1000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、510mg、520mg、530mg、540mg、550mg、560mg、570mg、580mg、590mg、600mg、610mg、620mg、630mg、640mg、650mg、660mg、670mg、680mg、690mg、700mg、710mg、720mg、730mg、740mg、750mg、760mg、770mg、780mg、790mg、800mg、810mg、820mg、830mg、840mg、850mg、860mg、870mg、880mg、890mg、900mg、910mg、920mg、930mg、940mg、950mg、960mg、970mg、980mg、990mg、1000mg。
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、540、600、660、720、780、840、900、960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1000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60毫克至1000毫克。
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 PCTCN2021132617-appb-000004
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包括：
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)用于预防和/或治疗肾病的药物用途，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。
具体实施方式
下面结合实施例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 PCTCN2021132617-appb-000005
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 PCTCN2021132617-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 1.6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(命名为化合物A)。重复试验，以获得足够的药效实验用量。
实施例4
4.1试剂、供试品及仪器信息
羧甲基纤维素钠：批号：B1707016，上海阿拉丁生化科技股份有限公司；
EXP3174：批号：20190501Z，惠州信立泰药业有限公司；
沙库巴曲钙盐：批号：DYF20003，惠州信立泰药业有限公司；
LCZ696：批号：DYF19005，惠州信立泰药业有限公司；
S086：批号：SWV20001，惠州信立泰药业有限公司；
肌酐测定试剂盒(肌氨酸氧化酶法)：批号：141120017，深圳迈瑞生物医疗电子股份有限公司；
白蛋白测定试剂盒(溴甲酚氯法)：批号：148320004，深圳迈瑞生物医疗电子股份有限公司；
全自动生化分析仪：BS-240VET型号，深圳迈瑞生物医疗电子股份有限公司。
4.2实验动物
健康SPF级雄性SD大鼠80只，体重180～220g，实验动物质量合格证号为No.110011201106160342，由北京维通利华实验动物科技有限公司提供，实验动物生产许可证号为SCXK(京)2016-0006。在深圳信立泰药业股份有限公司SPF级实验动物中心饲养，实验动物使用许可证号为SYXK(粤)2019-0142,于SPF级实验动物中心饲养。
4.3大鼠5/6肾切除CKD模型制备及分组
适应性饲养1周后，大鼠随机分为两组，一组作为假手术组(6只)，另外一组作为手术组进行5/6肾切除(72只)。手术组大鼠采用1.5％戊巴比妥钠(30mg/kg)腹腔内注射麻醉，将大鼠俯卧位固定于鼠板，备皮，常规消毒，戴无菌手套，铺无菌纱布，在大鼠背部，左侧肋脊点下约0.5cm、脊柱左侧约1cm作纵向切口，约1cm长，逐层切开进腹，见肾脏位于脊柱旁，充分暴露肾脏，剥离肾包膜,将肾的两端各切除1/3,明胶海绵压迫切面止血,逐层缝合切口，青霉素钠肌肉注射抗感染，每天观察、常规护理。1周后再以相同手术方式切除右肾。两次手术共切除5/6肾脏。假手术组只分离脂肪囊，不切除肾组织。
第二次术后存活动物恢复饲养3周进行分组，各只大鼠编号称重、肝素抗凝采血，检测血浆肌酐，用SPSS软件根据血浆肌酐水平进行区组随机分组，组别分为模型组、EXP3174组(35mg/kg)、沙库巴曲组(33mg/kg)、LCZ696低剂量组(34mg/kg)、LCZ696高剂量组(68mg/kg)、S086低剂量组(34mg/kg)、S086高剂量组(68mg/kg)，每组5～6只。分组次日开始灌胃给药，给药体积为10mL/kg，每天1次，连续给药4周。假手术组、模型组每日给予0.5％CMC-Na溶媒，给药体积为10mL/kg。分别于实验第4周，尾静脉采集血液及代谢笼收集24h尿液。
4.4检测指标和方法
给药后第4周检测血浆肌酐、尿白蛋白及尿肌酐浓度，并计算24h尿白蛋白量及尿白蛋白/尿肌酐比值。
4.5统计方法
实验数据均以平均值±标准差表示，统计采用SPSS24.0软件，并按照以下方法统计：首先进行正态分布(Shapiro-Wilk检验)和方差齐性(Levene’s检验)分析，如果数据符合正态分布(P>0.05)及方差齐性(P>0.05)，则进行单因素方差分析检验(ANOVA)中SNK检验，如果分析结果P<0.05，则具有显著性；如果数据不符合正态分布(P<0.05)或方差不齐(P<0.05)，则选用非参数检验中两独立样本检验，如果分析结果P<0.05，则具有显著性。
4.6实验结果
Figure PCTCN2021132617-appb-000007
备注：与假手术组比， #P<0.05；与模型组比， *P<0.05；与等摩尔LCZ696比， $P<0.05， $$P<0.01；与等摩尔EXP3174比， &&P<0.01；与等摩尔AHU377比， ^^P<0.01。
Figure PCTCN2021132617-appb-000008
备注：与假手术组比， #P<0.05；与模型组比， *P<0.05；与等摩尔LCZ696比， $P<0.05， $$P<0.01；与等摩尔EXP3174比， &&P<0.01；与等摩尔AHU377比， ^^P<0.01。
Figure PCTCN2021132617-appb-000009
备注：与假手术组比， ##P<0.01；与模型组比， **P<0.01；与等摩尔AHU377比， ^P<0.05。
从上述结果可见，本发明复合物在CKD模型的在指标24h尿白蛋白、尿白蛋白\尿肌酐比值效果比等摩尔剂量的LCZ696具有明显更好的效果；同时，本发明复合物相对于等摩尔剂量的EXP3174、AHU377单独给药也有更好的效果，充分说明复合物具有明显的优势。
并且，本发明复合物在CKD模型的在指标血肌酐的效果比等摩尔剂量下的LCZ696具有明显更好的效果；同时，本发明复合物相对于等摩尔剂量的EXP3174、AHU377单独给药也有更好的效果，充分说明复合物具有明显的优势。
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 (11)

  1. ARB代谢产物与NEP抑制剂的复合物在制备用于预防和/或治疗肾病的药物用途，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。
  2. 根据权利要求1所述药物用途，其特征在于：所述肾病包括慢性肾脏病，进一步包括慢性肾脏病合并高血压，慢性肾脏病合并心衰。
  3. 根据权利要求1或2所述药物用途，其特征在于：所述药物的单剂量形式含有60毫克和1000毫克之间的所述复合物。
  4. 根据权利要求1或2所述药物用途，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、540、600、660、720、780、840、900、960毫克的所述复合物。
  5. 根据权利要求1或2所述药物用途，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。
  6. 根据权利要求1-5任一项权利要求所述的药物用途，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。
  7. 根据权利要求1-6任一项权利要求所述的药物用途，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 PCTCN2021132617-appb-100001
    其中x为0.5～2之间的数值；n为0～3之间的数值。
  8. 根据权利要求1-7任一项权利要求所述的药物用途，其特征在于：x选自0.5、1、1.5、2。
  9. 根据权利要求1-8任一项权利要求所述的药物用途，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。
  10. 根据权利要求1-9任一项权利要求所述的药物用途，其特征在于：n选自0.5、1、1.5、2、2.5、3。
  11. 根据权利要求1-10任一项权利要求所述的药物用途，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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