WO2020238885A1 - 血管紧张素ii受体拮抗剂代谢产物与nep抑制剂的复合物的治疗方法 - Google Patents

血管紧张素ii受体拮抗剂代谢产物与nep抑制剂的复合物的治疗方法 Download PDF

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WO2020238885A1
WO2020238885A1 PCT/CN2020/092264 CN2020092264W WO2020238885A1 WO 2020238885 A1 WO2020238885 A1 WO 2020238885A1 CN 2020092264 W CN2020092264 W CN 2020092264W WO 2020238885 A1 WO2020238885 A1 WO 2020238885A1
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exp3174
ahu377
complex
treatment method
present
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PCT/CN2020/092264
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French (fr)
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孙晶超
杨思娆
李磊
杨月
沈雪歌
林威
何世英
陈绩
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深圳信立泰药业股份有限公司
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Priority to US17/615,013 priority Critical patent/US20220226285A1/en
Publication of WO2020238885A1 publication Critical patent/WO2020238885A1/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
    • A61K31/33—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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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 present invention belongs to the technical field of drug application, and relates to a treatment method of a complex of an angiotensin II receptor antagonist metabolite and a NEP inhibitor, and specifically relates to administering a suitable dose of the complex to a patient, and more specifically, to the The compound is used in the treatment of hypertension or chronic heart failure.
  • Hypertension is a clinical syndrome characterized by increased systemic arterial pressure, and is the most common cardiovascular disease. Most hypertension has a slow onset and lacks special clinical manifestations, leading to a delay in diagnosis. It is only discovered when blood pressure is measured or when complications such as heart, brain, and kidney occur. There is a close causal relationship between long-term hypertension and the risk of cardiovascular and cerebrovascular diseases.
  • hypertension is not effectively controlled and treated, it can cause coronary atherosclerosis, coronary heart disease, angina pectoris, and serious complications such as hypertensive heart disease and heart failure.
  • long-term high blood pressure can cause damage to the kidneys, brain, cardiovascular and other organs.
  • Heart failure is a serious manifestation or late stage of various heart diseases. It is an important part of the prevention and treatment of chronic cardiovascular diseases in the world. The mortality rate and rehospitalization rate remain high. Epidemiological data in Europe and the United States show that the prevalence of adult heart failure is 1.5% to 2.0%, and with the increase of age, the prevalence of heart failure also increases, and the prevalence of people ⁇ 70 years old is ⁇ 10%. The 2003 Chinese epidemiological survey showed that the prevalence of heart failure among adults aged 35 to 74 in my country was 0.9%. "China Cardiovascular Disease Report 2016" pointed out that the prevalence of cardiovascular disease in my country is on the rise, and the mortality rate of cardiovascular disease ranks first, higher than that of tumors and other diseases.
  • WO2007056546A1 discloses a Valsartan (Sacubitril, AHU377) sodium salt complex (LCZ696) and a preparation method thereof, which was approved for marketing in China in 2017, and the trade name is: Used for heart failure. Its molecular structure units are as follows:
  • WO2017125031A1 discloses a series of complexes of angiotensin receptor antagonist metabolites (EXP3174) and NEP inhibitors (Sacubitril), and exhibits certain effects on heart failure HFpEF with retention of ejection fraction. Its molecular structural units are as follows :
  • EXP3174 the major active metabolite of losartan, Cardio Vasc Drug ReV, 1997, Volume 15, No 2,122–136, doi: 10.1111/j.1527-3466.1997.tb00327.x. reported that in a mouse model of renal hypertension, It is difficult to achieve the corresponding effectiveness of Losartan through oral administration of EXP3174, and the low bioavailability limits the clinical application of EXP3174.
  • the present invention provides a treatment method for a complex of an angiotensin II receptor antagonist metabolite and a NEP inhibitor (or called a "supramolecular complex").
  • the treatment method for hypertension or heart failure includes administering a complex of an angiotensin II receptor antagonist metabolite and NEP inhibitor 60-500 mg per day to the patient, 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 0-3.
  • the present invention includes administering the compound containing 60, 120, 180, 240, 300, 360, 420 or 480 mg to the patient every day.
  • the complex is administered to the patient once, twice or three times a day.
  • the method for treating hypertension includes administering the compound containing 120, 240, or 480 mg to the patient daily, and administering to the patient once, twice or 3 times a day; the heart failure
  • the method of treatment includes administering the complex containing 60, 120, 240 or 480 mg to the patient daily, and administering to the patient once, twice or 3 times a day.
  • the drug is a solid preparation suitable for oral administration, preferably oral tablets or capsules, which can be multiple tablets and multiple capsules, and the total amount of the drug is 60 mg and 500 mg.
  • the hypertension is selected from essential hypertension, salt-sensitive hypertension, etc.
  • the heart failure is selected from heart failure with preserved ejection fraction and heart failure with reduced ejection fraction. Decay and so on.
  • the drug is applied to patients suffering from heart failure with reduced ejection fraction.
  • the heart failure with reduced ejection fraction refers to "Chinese Guidelines for Diagnosis and Treatment of Heart Failure" 2018-HFrEF as defined in Table 1 for classification and diagnostic criteria of heart failure.
  • the single-dose form of the drug refers to the total mass of (aEXP3174 ⁇ bAHU377) containing approximately 60 mg and 500 mg of the complex, including But not limited to 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, 470
  • the single-dose form of the drug contains 120, 180, 240, 300, 360, 420, 480 mg of the complex.
  • the single-dose form refers to the daily dosage form, and the compound containing 100 mg/day to 500 mg/day is administered to the patient, and the number of administrations includes but is not limited to once a day, 1 day 2 times, 3 times a day, 4 times a day, etc.
  • the drug is applied to patients suffering from the salt-sensitive hypertension; according to the experimental results of the present invention and the application amount of the prodrug, the single dose of the drug
  • the form refers to the total mass of (aEXP3174 ⁇ bAHU377) containing approximately 60 mg and 500 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, 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, 440
  • the single-dose form of the drug contains 240, 300, 360, 420, 480 mg of the complex.
  • the single-dose form refers to the daily dosage form, which is administered to the patient with the compound containing 200 mg/day to 500 mg/day, and the number of administrations includes but is not limited to 1 day Once, twice a day, 3 times a day, 4 times a day, etc.
  • 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 and the molecular weight is about 411.5. Therefore, unless otherwise stated, the dosage of the complex of the present invention is based on the anhydrous free acid C 46 H 50 ClN 7 O 7 .
  • the complex of the drug can be obtained by a method known in the prior art, wherein the complex disclosed in WO2017125031A1 and the preparation method thereof are introduced 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 units of the composite are as follows:
  • x is selected from 0.5, 1, 1.5, and 2.
  • the structural units of the composite are 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. EXP3174 and AHU377 in the complex molecule and pharmaceutically acceptable calcium cations are combined to obtain supramolecular complexes (complexes) through non-covalent bonds, which are well known to those of ordinary skill in the art. Including but not limited to hydrogen bonds, coordination bonds, ionic bonds, etc., the XRD spectrum of the obtained supramolecular complex (complex) is obviously different from the XRD spectrum of EXP3174 and AHU377 calcium salt. , Ethanol, ethanol-water, etc.). There are also obvious differences in the solubility properties, and there are obvious differences in other physical and chemical properties such as hygroscopicity, melting point, infrared spectrum, etc.
  • the present invention has the following advantages and beneficial effects:
  • the exposure of EXP3174 in the human body shall not be lower than the total active ingredient exposure in the human body after oral administration of 100 mg of losartan, and the exposure of LBQ657 in the human body shall not be lower than that after oral administration of LCZ696 200 mg.
  • the compound of the present invention increases the renin activity concentration in a significant dose-dependent manner, which is significantly improved compared to placebo; and, compared with placebo, the compound of the present invention can significantly reduce NT-proBNP (The level of brain natriuretic peptide) suggests its inhibitory effect on NEP enzyme, which proves that the complex of the present invention shows the effect of lowering blood pressure and anti-heart failure in the human body.
  • X-ray powder diffraction is detected by an Empyrean X-ray diffractometer.
  • the detection conditions Cu target K ⁇ rays, voltage 40KV, current 40mA, emission slit 1/32°, anti-scatter slit 1/16°, anti-scattering Scattering slit 7.5mm, 2 ⁇ range: 3°-60°, step length 0.02°, residence time per step 40s.
  • Differential scanning calorimetry spectra were tested with DSC204F1 differential scanning calorimeter equipment from NETZSCH, Germany. Test conditions: atmosphere: N 2 , 20mL/min; scanning program: heating from room temperature at 10°C/min to 250°C, record Heating curve.
  • the moisture content is detected by the TG209 thermogravimetric analyzer equipment from NETZSCH, Germany, and the detection conditions are: 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%.
  • the pharmaceutical composition of the compound of the present invention is formed by mixing the compound of Example 3 with a suitable carrier, and then compressing the tablets by a powder direct compression process and then coating, wherein the composition of each tablet is as follows:
  • Production process the aforementioned raw and auxiliary materials except for the coating material and purified water are mixed and directly compressed. After the coating material and the purified water are mixed, the tablets obtained by coating the mixed powder and directly compressed to obtain a coated tablet.
  • Example 6 Using the pharmaceutical composition of Example 5 to conduct a clinical phase I trial
  • the composite tablet of the present invention has completed single-center, randomized, double-blind, placebo-controlled multi-dose, single-time, multiple-dose tolerance, and pharmacokinetic phase I clinical trials in healthy subjects.
  • the impact test while collecting urine and fecal samples in the first cycle of the food impact test for recovery rate and drug metabolism transformation studies; to evaluate the resistance of the composite tablet of the present invention in single and multiple administrations in healthy subjects
  • the results of the Phase I clinical test of the composite tablet of the present invention show that the composite tablet of the present invention has good pharmacokinetic properties within a single dose of 60-1080 mg and multiple doses of 180-720 mg, and has good tolerance.
  • the RAAS system and NEP enzyme of healthy subjects have a certain effect, and have a certain effect on reducing diastolic and systolic blood pressure. details as follows:
  • the test results show that the compound tablet of the present invention is well tolerated within a single dose of 60-1080 mg and multiple doses of 180-720 mg, and all dose groups are tolerated. There were no adverse events of grade III or above or serious adverse events, and no adverse events that caused the subjects to withdraw. All adverse events were grade I or II, which was transient, and the result was a complete recovery without sequelae.
  • a single administration of 480 mg of the compound tablet of the present invention in the state of fasting or eating a high-fat meal has no adverse events and has good safety.
  • the analysis is based on the PK parameter set (PKPS), and the non-compartmental model PK parameter analysis is performed using Phoenix WinNonlin8.1 software, and the pharmacokinetic parameters of sacubitril, LBQ657 and EXP3174 of each subject are calculated, and examples of each parameter are calculated at the same time. Number, mean, standard deviation, coefficient of variation, median, minimum, maximum, and geometric mean. If the subject’s AUC Extra% >20%, AUC 0- ⁇ , t 1/2 , AUC Extra% , ⁇ z, V z /F, CL/F, AUC 0- ⁇ ,ss , t 1/2,ss , Vz/F ,ss , MRT 0- ⁇ ,ss do not perform descriptive statistical analysis.
  • PK parameters of multiple administration test 1) PK parameters of the first administration: T max , C max , t 1/2 , AUC 0-72 , AUC 0- ⁇ ; 2) PK parameters of the last administration: T max,ss , C max,ss , C min,ss , C av,ss , t 1/2,ss , ⁇ z , AUC 0-72,ss , AUC 0- ⁇ ,ss , AUC 0- ⁇ , V z /F ,ss , CL/F , ss , MRT 0- ⁇ ,ss , AUC Extra% , R a( AUC ) , R a( C max) , volatility index, volatility range.
  • Losartan (trade name: ) After entering the body, it can be oxidized to the active metabolite EXP3174 by the metabolic enzymes CYP3A4 and CYP2C9.
  • the literature reports that the latter binds to the AT1 receptor more firmly, and the dissociation constant is about 5 times that of the former prototype drug. Both of them exert pharmacological effects in the body. .
  • the compound of the present invention is a compound of EXP3174 and sacubitril. After entering the human body, only EXP3174 exerts ARB-like pharmacological effects. Therefore, the exposure of EXP3174 in the human body after oral administration of the compound of the present invention is compared with the total human body after oral administration of losartan.
  • the exposure of the active ingredient is known: 60 mg of the compound of the present invention is not less than 50 mg of Losartan; 180 mg of the compound of the present invention is not less than 80 mg of Losartan; 360 mg of the compound of the present invention is not less than 150 mg of Losartan; and 540 mg of the compound of the present invention Significantly higher than Losartan 200mg and not less than Losartan 300mg.
  • the compound of the present invention is a compound of EXP3174 and sacubitril. After entering the human body, sacubitril is metabolized to LBQ657 (the active metabolite of the prodrug sacubitril). Then, the compound of the present invention is compared after oral administration.
  • the exposure of LBQ657 in human body and the exposure of LBQ657 after oral administration of LCZ696 show that: 60 mg of the compound of the present invention is not less than LCZ696 50 mg; 180 mg of the compound of the present invention is significantly higher than LCZ696 100 mg; 360 mg of the compound of the present invention is significantly higher than LCZ696 200 mg; this The 540mg of the invention complex is significantly higher than LCZ696 400mg.
  • the clinical doses of LCZ696 are 100 mg, 200 mg, and 400 mg, and the planned market doses of the complex of the present invention are 240 mg and 480 mg. Based on the above data, it can be estimated that the exposure of LBQ657 in the human body after oral administration of 240 mg of the compound of the present invention is not lower than the exposure of LBQ657 in the human body after oral administration of 200 mg of LCZ696; the exposure of LBQ657 in the human body after oral administration of 480 mg of the compound of the present invention is not lower than that of people after oral administration of LCZ696 400 mg LBQ657 exposure in the body.
  • the exposure of EXP3174 in the human body is not less than the exposure of total active ingredients in the human body after oral administration of 100 mg of losartan, and the exposure of LBQ657 in the human body
  • the amount of exposure to LBQ657 in the human body after oral administration of LCZ696 200 mg; the exposure of EXP3174 in the human body after oral administration of 480 mg of the compound of the present invention is not less than the total active ingredient exposure in the human body after oral administration of Losartan 200 mg, and the exposure of LBQ657 in the human body is not Lower than the human body exposure to LBQ657 after oral administration of LCZ696 400mg.
  • the treatment method for obtaining the hypertension includes administering the compound containing 120, 240, or 480 mg to the patient every day, once, twice or 3 times a day; the treatment method for heart failure includes daily The compound containing 60, 120, 240, or 480 mg is administered to the patient once, twice or 3 times a day.
  • the analysis was performed based on the pharmacodynamic analysis data set (PDPS), and the analysis was performed using SAS9.4 statistical analysis software.
  • the percentage (%) of the change between GM (Geometric Mean) of each dose group and GM of the placebo group (%) (GM of each dose group-GM of the placebo group)/GM of the placebo group ⁇ 100%.
  • Blood pressure and pulse make a statistical description of the changes from the baseline at each time point of Day 10, calculate the number of cases, mean, standard deviation, median, minimum, maximum, quartiles Q1 and Q3 and list them.
  • Indicators include: renin activity and N-terminal B-type natriuretic peptide precursor (NT-proBNP). Only collected in multiple dosing trials.
  • NT-proBNP was lower than the baseline within the range of 180 ⁇ 540mg for multiple administrations.
  • Fig. 2 indicates that the composite tablet of the present invention has positive effects on healthy subjects’ NEP enzymes. A certain inhibitory effect.
  • the clinically effective dose is estimated to be 60 mg to 480 mg.
  • Example 7 This trial is a randomized, double-blind, placebo and positive drug parallel controlled, multi-center phase II clinical study
  • Olmesartan medoxomil tablets as a positive control drug to initially compare the efficacy differences between tablets composed of the compound prescription of Example 5 of different doses and Olmesartan medoxomil tablets.
  • Subjects who have passed the screening first enter the 2-week wash-in period; after the 2-week wash-out period, those who meet the selection criteria enter the 2-week lead-in period; after the lead-in period, if the subject still meets the selection criteria, enter 8
  • the subjects were randomly allocated to the 120 mg composite tablet of the present invention group, the 240 mg composite tablet of the present invention group, the 480 mg composite tablet of the present invention group, and the positive control at a ratio of 2:2:2:2:1 Group (olmesartan medoxomil tablets 20mg) and placebo group.
  • Effective rate of blood pressure reduction at the 8th weekend the proportion of the number of effective blood pressure reduction subjects in each group to the total number of subjects in each group.
  • Treatment-effective cases refer to patients whose blood pressure reaches normal (systolic blood pressure/diastolic blood pressure ⁇ 140/90mmHg) or systolic blood pressure lower than baseline by more than 20mmHg and/or diastolic blood pressure lower than baseline by more than 10mmHg;
  • the rate of reaching the blood pressure standard the proportion of the number of subjects in each group that reached the treatment standard to the total number of subjects in each group.
  • Treated cases refer to the blood pressure reaching normal (systolic blood pressure/diastolic blood pressure ⁇ 140/90mmHg);
  • ABPM 24h ambulatory blood pressure monitoring

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Abstract

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抑制剂的复合物的治疗方法，具体涉及该药物的使用剂量。

Description

血管紧张素II受体拮抗剂代谢产物与NEP抑制剂的复合物的治疗方法 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抑制剂的复合物的治疗方法，具体涉及给予患者适宜剂量的所述复合物，更为具体地，涉及所述复合物用于高血压或者慢性心力衰竭的治疗方法。
背景技术
高血压是以体循环动脉压增高为主要表现的临床综合征，是最常见的心血管疾病。高血压大多数起病缓慢，缺乏特殊临床表现，导致诊断延迟，仅在测量血压时或发生心、脑、肾等并发症时才被发现。长期的高血压与心脑血管病发病和死亡风险之间存在密切的因果关系。
据统计，目前全世界有超过十亿人高血压未得到控制，预计到2030年会增加到15亿。在我国，2012～2015年中国高血压调查(CHS)调查结果显示：中国≥18岁成人高血压患病率为27.9％(加权率为23.2％)，知晓率、治疗率和控制率分别为51.6％，45.8％和16.8％，治疗控制率为37.5％。高血压的发病率呈不断上升的趋势，据统计，我国心血管病患者约为2.9亿人(《中国心血管病报告2013》)。高血压如果得不到有效的控制和治疗，可以引起冠状动脉硬化，出现冠心病、心绞痛，还可能造成高血压性心脏病、心力衰竭等严重并发症。另外，长期高血压可导致肾、脑、心血管等器官损伤。
心衰是各种心脏疾病的严重表现或晚期阶段，是全球慢性心血管疾病防治的重要内容，死亡率和再住院率居高不下。欧美流行病学数据显示，成人心衰患病率为1.5％～2.0％，并且随着年龄增加，心力衰竭的患病率也随之增加，≥70岁人群患病率≥10％。2003年中国流行病学调查显示，我国35～74岁成人心衰患病率为0.9％。《中国心血管病报告2016》提出我国心血管病患病率处于持续上升阶段，心血管病死亡率居首位，高于肿瘤和其他疾病。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)-沙库巴曲(Sacubitril，AHU377)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 PCTCN2020092264-appb-000001
用于心力衰竭。其分子结构单元如下：
Figure PCTCN2020092264-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 PCTCN2020092264-appb-000003
文献EXP3174：the major active metabolite of losartan,Cardio Vasc Drug ReV,1997, Volume 15,No 2,122–136,doi：10.1111/j.1527-3466.1997.tb00327.x.报道，在肾高血压小鼠模型中，通过口服给予EXP3174难以达到氯沙坦相应的有效性，低生物利用度限制了EXP3174的临床应用。
然而，寻找一种适宜的所述复合物用于高血压或者心衰的治疗方法至关重要。
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”)的治疗方法，具体地，高血压或者心衰的治疗方法，包括每天给予患者60～500mg的血管紧张素II受体拮抗剂代谢产物与NEP抑制剂的复合物，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。
作为本发明的一种优选技术方案，包括每天给予患者含有60、120、180、240、300、360、420或者480毫克的所述复合物。
作为本发明的一种优选技术方案，所述每天给予患者1次、2次或者3次所述复合物。
作为本发明的一种优选技术方案，所述高血压的治疗方法包括每天给予患者含有120、240或者480毫克的所述复合物，每天给予患者1次、2次或者3次；所述心衰的治疗方法包括每天给予患者含有60、120、240或者480毫克的所述复合物，每天给予患者1次、2次或者3次。
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毫克和500毫克。
作为本发明的一种优选技术方案，所述高血压选自原发性高血压，盐敏感性高血压等，所述心衰选自射血分数保留的心衰，以及射血分数降低的心衰等。
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降低的心衰的患者所述射血分数降低的心衰是指《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HFrEF。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100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。
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盐敏感型高血压的患者；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240、300、360、420、480毫克的所述复合物。作为本发明的一种更为优选技术方案，单剂量形式是指日剂量形式，给予患者含有200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。
其中，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。所以，无另有说明的情况下，本发明复合物的剂量以无水游离酸C 46H 50ClN 7O 7计。
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 PCTCN2020092264-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。所述复合物分子中EXP3174和AHU377和药学上可接受的钙阳离子，通过非共价键结合得到超分子络合物(复合物)，所述非共价键为本领域普通技术人员所熟知，包含但不限于氢键、配位键、离子键等等，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、根据PK结果进行推算，口服本发明复合物240mg后，人体内EXP3174暴露量不低于口服氯沙坦100mg后人体内总活性成分暴露量，人体内LBQ657暴露量不低于口服LCZ696200mg后人体内LBQ657暴露量；口服本发明复合物480mg后，人体内EXP3174暴露量不低于口服氯沙坦200mg后人体内总活性成分暴露量，人体内LBQ657暴露量不低于口服LCZ696 400mg后人体内LBQ657暴露量。
2、从药效上统计发现，本发明复合物增加肾素活性浓度具显著剂量依赖性，相比安慰剂有明显的提高；并且，本发明复合物相比安慰剂能显著降低NT-proBNP(脑钠肽)水平，提示其对于NEP酶抑制效应，证明本发明复合物在人体内显示出降血压和抗心衰的效果。
3、在现有技术已知直接口服EXP3174具有低生物利用度的情况下，本发明的复合物作为单一分子解决了这样的技术问题，实现EXP3174有效利用。
附图说明
图1，肾素活性Day 10平均浓度-时间曲线(PDPS，N＝48)示意图。
图2，NT-proBNP指标Day 10平均浓度-时间曲线(PDPS，N＝48)示意图。
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 PCTCN2020092264-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 PCTCN2020092264-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。重复试验，以获得足够的药效实验用量。
实施例4
参照实施例2和3的制备方法，分别制备得到以下复合物：
(EXP3174·AHU377)·1.5Ca·1H 2O；
(EXP3174·AHU377)·1.5Ca·1.5H 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。
实施例5
本发明复合物的药物组合物，采用实施例3的复合物与适合的载体混合，采用粉末直压工艺压片后包衣而成，其中，每片的组成如下：
Figure PCTCN2020092264-appb-000007
生产工艺：除包衣材料和纯化水外的前述原辅料进行混粉直压，所述包衣材料和纯化水混合后，包衣混粉直压得到的片剂，得到包衣片。
实施例6采用实施例5的药物组合物进行临床I期试验
本发明复合物片已完成在健康受试者中单中心、随机、双盲、安慰剂对照的多剂量、单次、多次给药的耐受性、药代动力学Ⅰ期临床试验。单次给药设置60mg、180mg、360mg、540mg、720mg、960mg、1080mg，共7个剂量组；多次给药设置180mg、360mg、540mg、720mg，共4个剂量组；在480mg剂量组开展食物影响试验，同时在食物影响试验第一周期采集尿样和粪样，用于回收率和药物代谢转化研究；以评价本发明复合物片在健康受试者中单次、多次给药的耐受性、药代动力学、药物代谢转化及回收率以及食物对其药代动力学的影响，并初步评价药效学。
本发明复合物片I期临床试验结果表明，本发明复合物片单次给药60～1080mg，多次给药180～720mg剂量范围内具有良好的药代动力学特性，耐受性良好，对健康受试者RAAS系统及NEP酶有一定作用，且有一定的降舒张压和收缩压作用。具体如下：
6.1I期临床耐受性和安全性结果
试验结果显示本发明复合物片单次给药60～1080mg，多次给药180～720mg剂量范围内耐受性良好，各剂量组均耐受。未发生III级及以上不良事件或严重不良事件，无导致受试者退出的不良事件，所有不良事件均为I级或II级，为一过性，转归为完全恢复无后遗症。在空腹或进食高脂餐状态下单次给药480mg本发明复合物片，未发生不良事件，具有良好的安全性。
6.2I期临床药代动力学
药代动力学分析方法：
基于PK参数集(PKPS)进行分析，采用Phoenix WinNonlin8.1软件进行非房室模型PK参数分析，计算各受试者的沙库巴曲、LBQ657和EXP3174的药代参数，同时计算各参数的例数、均值、标准差、变异系数、中位数、最小值、最大值以及几何均值。若受试者的AUC Extra％＞20％，AUC 0-∞、t 1/2、AUC Extra％、λz、V z/F、CL/F、AUC 0-∞,ss、t 1/2,ss、Vz/F ,ss、MRT 0-∞,ss不进行描述性统计分析。
单次给药试验和食物影响试验PK参数：T max、C max、t 1/2、λ z、AUC 0-72、AUC 0-∞、V z/F、CL/F、AUC Extra％。
多次给药试验PK参数：1)首次给药PK参数：T max、C max、t 1/2、AUC 0-72、AUC 0-∞；2)末次给药PK参数：T max,ss、C max,ss、C min,ss、C av,ss、t 1/2,ss、λ z、AUC 0-72,ss、AUC 0-∞,ss、AUC 0-τ、V z/F ,ss、CL/F ,ss、MRT 0-∞,ss、AUC Extra％、R a(AUC )、R a(C max)、波动指数、波动幅度。
采用幂函数模型对单次给药中PK参数(C max、AUC 0-t和AUC 0-∞)，多次给药首次给药后PK参数(C max、AUC 0-t和AUC 0-∞)以及多次给药末次给药后PK参数(C max，ss、AUC 0-t,ss和AUC 0-∞,ss)和剂量间的关系进行探讨，计算β值及其90％置信区间。同时绘制PK参数与剂量间的比例化剂量反应关系图。
6.2.3数据统计：
1)EXP3174暴露量比对
本发明复合物片I期临床药代动力学中体内EXP3174的暴露量数据如下表1和表2：
表1本发明复合物单次给药(SAD)后体内EXP3174的暴露量数据(PKPS)
Figure PCTCN2020092264-appb-000008
*此处AUC取值为算术均值。
表2本发明复合物多次给药(MAD)后体内EXP3174的稳态下暴露量数据(PKPS)
Figure PCTCN2020092264-appb-000009
*此处AUC取值为算术均值。
氯沙坦(商品名：
Figure PCTCN2020092264-appb-000010
)进入体内后可通过代谢酶CYP3A4和CYP2C9氧化为活性代谢产物EXP3174，文献报道后者与AT1受体结合更牢固，解离常数约为前者原型药物的5倍，二者在体内共同发挥药理作用。
(参见“2012年艾力沙坦酯片(CXHS10000101－102)审评概述，
http://www.cde.org.cn/reviewDe.do？method＝showFAQ&id＝2。”)。
临床数据显示，健康受试者单次口服氯沙坦后，EXP3174在人体内暴露量(AUC)约是原型药物的4倍。
(参见“
Figure PCTCN2020092264-appb-000011
label.Reference ID：4334171，
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020386s062lbl.pdf。”)。
Tamaki等研究表明EXP3174同氯沙坦摩尔质量相近(从化学结构上分析，二者分子量仅相差14)，且EXP3174体外活性远优于氯沙坦。
(参见文献：“Tamaki T,Nishiyama A,Kimura S,et al.EXP3174：The Major Active Metabolite of Losartan[J].cardiovascular therapeutics,1997,15(2)：122-136.”)。
在不考虑二者疗效差异的前提下，可假设氯沙坦总活性成分体内疗效同EXP3174相似，则口服氯沙坦后总活性成分暴露量约为氯沙坦原型与EXP3174二者暴露量之和(总活性成分＝氯沙坦+EXP3174)。计算氯沙坦总活性成分暴露量如下表3所示：
表3氯沙坦单次给药(SAD)后体内氯沙坦和EXP3174的暴露量数据 $
Figure PCTCN2020092264-appb-000012
*此处AUC取值为算术均值。 **总活性成分＝氯沙坦+EXP3174，#n＝14， $数据来源：Lorsartan FDA报告，1995.04.04。
已知本发明复合物为EXP3174与沙库巴曲的复合物，进入人体后仅EXP3174发挥ARB类药理作用，于是对比口服本发明复合物后人体内EXP3174暴露量与口服氯沙坦后人体内总活性成分暴露量可知：本发明复合物60mg不低于氯沙坦50mg；本发明复合物180mg不低于氯沙坦80mg；本发明复合物360mg不低于氯沙坦150mg；本发明复合物540mg明显高于氯沙坦200mg且不低于氯沙坦300mg。
氯沙坦临床常用剂量为50mg、100mg，本发明复合物拟上市剂量为240mg、480mg。结合上述数据可推算，口服本发明复合物240mg后人体内EXP3174暴露量不低于口服氯沙坦100mg后人体内总活性成分暴露量；口服本发明复合物480mg后人体内EXP3174暴露量不低于口服氯沙坦200mg后人体内总活性成分暴露量。
2)LBQ657暴露量比对
本发明复合物片I期临床药代动力学中体内LBQ657(Cas#149709-44-4)的暴露量数据如下表4和表5：
表4本发明复合物单次给药(SAD)后体内LBQ657的暴露量数据(PKPS)
Figure PCTCN2020092264-appb-000013
*此处AUC取值为算术均值。
表5本发明复合物多次给药(MAD)后体内LBQ657的稳态下暴露量数据(PKPS)
Figure PCTCN2020092264-appb-000014
*此处AUC取值为算术均值。
沙库巴曲缬沙坦钠片(LCZ696片，商品名：
Figure PCTCN2020092264-appb-000015
)在健康受试者体内被快速吸收并产生LBQ657(AHU377经酶裂解得到)和缬沙坦的全身暴露
(参见“
Figure PCTCN2020092264-appb-000016
label.Reference ID：4499982，
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/207620s013lbl.pdf”)。单次给药后，中国健康人体内LBQ657的全身暴露量见表6。
表6沙库巴曲缬沙坦钠片单次给药(SAD)后体内LBQ657的暴露量数据(PKPS)
Figure PCTCN2020092264-appb-000017
数据来源：参见文献“Han Y,et al.Pharmacokinetics,Safety and Tolerability of Sacubitril/Valsartan(LCZ696)After Single-Dose Administration in Healthy Chinese Subjects[J].European Journal of Drug Metabolism&Pharmacokinetics,2017,42(1)：109-116.DOI：10.1007/s13318-016-0328-3”。
*此处AUC取值为算术均值。
已知本发明复合物为EXP3174与沙库巴曲的复合物，进入人体后沙库巴曲经酶代谢为LBQ657(前药沙库巴曲的活性代谢产物)，于是对比口服本发明复合物后人体内LBQ657暴露量与口服LCZ696后人体内LBQ657暴露量可知：本发明复合物60mg不低于LCZ696 50mg；本发明复合物180mg明显高于LCZ696 100mg；本发明复合物360mg明显高于LCZ696 200mg；本发明复合物540mg明显高于LCZ696 400mg。
LCZ696临床用剂量为100mg、200mg、400mg，本发明复合物拟上市剂量为240mg、480mg。结合上述数据可推算，口服本发明复合物240mg后人体内LBQ657暴露量不低于口服LCZ696200mg后人体内LBQ657暴露量；口服本发明复合物480mg后人体内LBQ657暴露量不低于口服LCZ696 400mg后人体内LBQ657暴露量。
3)小结
根据单次给药和多次给药的PK结果进行推算，口服本发明复合物240mg后，人体内EXP3174暴露量不低于口服氯沙坦100mg后人体内总活性成分暴露量，人体内LBQ657暴露量不低于口服LCZ696 200mg后人体内LBQ657暴露量；口服本发明复合物480mg后，人体内EXP3174暴露量不低于口服氯沙坦200mg后人体内总活性成分暴露量，人体内LBQ657暴露量不低于口服LCZ696 400mg后人体内LBQ657暴露量。
综上，优选得到所述高血压的治疗方法包括每天给予患者含有120、240或者480毫克的所述复合物，每天给予患者1次、2次或者3次；所述心衰的治疗方法包括每天给予患者含有60、120、240或者480毫克的所述复合物，每天给予患者1次、2次或者3次。
6.3I期临床药效学
I期临床药效学分析方法
基于药效动力学分析数据集(PDPS)进行分析，采用SAS9.4统计分析软件进行分析。
肾素活性、NT-proBNP指标分析如下：
1)对Day7、Day10每个时间点与基线变化的百分比进行统计描述，计算百分比的例数、均值、标准差、中位数、最小值、最大值、四分位数Q1和Q3。
2)计算基线、Day7及Day10每个时间点各剂量组几何均值与安慰剂组几何均值变化的百分比。
3)计算Day7、Day10每个时间点各剂量组几何均值与安慰剂组几何均值的比值，及其95％的置信区间。
4)计算Day7、Day10每个时间点的几何均值与基线几何均值的比值，及其95％的置信区间。
5)计算肾素活性指标Day7及Day10给药后的T max值。
6)计算NT-proBNP指标Day7及Day10给药后的T min值。
7)按照计划采样时间点绘制Day7及Day10的平均浓度-时间曲线图。
与基线变化的百分比(％)＝(具体访视的数值–基线值)/基线值×100％。
各剂量组GM(Geometric Mean,几何均数)与安慰剂组GM变化的百分比(％)＝(各剂量组的GM–安慰剂组GM)/安慰剂组GM×100％。
血压和脉搏：对Day10各个时间点相对基线的变化进行统计描述，计算例数、均值、标准差、中位数、最小值、最大值、四分位数Q1和Q3并列表总结。
指标包括：肾素活性和N端B型利钠肽前体(NT-proBNP)。仅在多次给药试验中采集。
试验结果如下：
肾素活性
在180，360，540mg剂量组，给药后均较基线明显升高，约4h达最大效应。结果：多次给药180～540mg剂量范围内，本发明复合物片在Day10给药后各时间点肾素活性几何均值均较基线明显升高，肾素活性结果如图1，提示本发明复合物片对于健康受试者RAAS系统有一定的抑制作用。
NT-proBNP
在180，360，540mg剂量组，给药后均较基线降低，约4h达最大效应。结果：多次给药180～540mg剂量范围内，NT-proBNP几何均值均较基线有所降低，NT-proBNP结果具体如图2所示，提示本发明复合物片对于健康受试者NEP酶有一定的抑制作用。
综合多次给药药效研究数据，结合PK研究结果及氯沙坦和LCZ696的临床起效剂量，预计临床药效剂量为60mg～480mg。
实施例7本试验是一项随机、双盲、安慰剂和阳性药平行对照、多中心II期临床研究
主要目的：以安慰剂为对照，探索不同剂量的实施例5复合物处方组成的片剂治疗轻、中度原发性高血压的有效性和安全性，为III期临床试验提供依据；
次要目的：以奥美沙坦酯片为阳性对照药，初步比较不同剂量实施例5复合物处方组成的片剂与奥美沙坦酯片的疗效差异。
计划入组216例，18周岁≤年龄≤75周岁，无靶器官并发症的轻、中度原发性高血压患者。
经筛选合格的受试者首先进入2周清洗期；2周清洗期结束后，符合入选标准的受试者进入2周导入期；导入期结束后，若受试者仍符合入选标准，进入8周双盲治疗期，受试者按2：2：2：2：1的比例随机分配至本发明复合物片120mg组、本发明复合物片240mg组、本发明复合物片480mg组、阳性对照组(奥美沙坦酯片20mg)及安慰剂组。
主要疗效评价指标：第8周末平均坐位收缩压(msSBP)较基线的变化
次要疗效评价指标：
1)第8周末平均坐位舒张压(msDBP)较基线的变化；
2)第8周末平均动脉压(MAP)较基线的变化；
3)第8周末降压有效率：各组降压有效受试者例数占各组受试者总例数的比例。治疗有效病例是指血压达到正常(收缩压/舒张压＜140/90mmHg)或收缩压较基线降低＞20mmHg和/或舒张压较基线降低＞10mmHg的患者；
4)第8周末降压达标率：各组治疗达标的受试者例数占各组受试者总例数的比例。治疗达标病例是指血压达到正常(收缩压/舒张压＜140/90mmHg)；
5)24h动态血压监测(ABPM)：第8周末收缩压和舒张压谷峰比(T/P)；第8周末24h平均收缩压和舒张压较基线的变化；第8周末白天(6：00am～22：00pm)、夜间(22：00pm～次日6：00am)平均收缩压和舒张压较基线的变化。
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. 高血压或者心衰的治疗方法，其特征在于：包括每天给予患者60～500mg的血管紧张素II受体拮抗剂代谢产物与NEP抑制剂的复合物，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所述的治疗方法，其特征在于：每天给予患者60mg、70、80、90、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的所述复合物；优选包括每天给予患者含有60、120、180、240、300、360、420或者480毫克的所述复合物。
  3. 根据权利要求1所述的治疗方法，其特征在于：所述每天给予患者1次、2次或者3次所述复合物。
  4. 根据权利要求1所述的治疗方法，其特征在于：所述高血压的治疗方法包括每次给予患者含有120、240或者480毫克的所述复合物，每天给予患者1次、2次或者3次；所述心衰的治疗方法包括每次给予患者含有60、120、240或者480毫克的所述复合物，每天给予患者1次、2次或者3次。
  5. 根据权利要求1所述的治疗方法，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治疗方法，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1-5任一项权利要求所述的治疗方法，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 PCTCN2020092264-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1-5任一项权利要求所述的治疗方法，其特征在于：x选自0.5、1、1.5、2。
  9. 根据权利要求1-5任一项权利要求所述的治疗方法，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1-5任一项权利要求所述的治疗方法，其特征在于：n选自0.5、1、1.5、2、2.5、3。
  11. 根据权利要求1-5任一项权利要求所述的治疗方法，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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CN104826115A (zh) * 2015-04-19 2015-08-12 浙江巨泰药业有限公司 一种抗心衰药物组合物及其制备方法
WO2017125031A1 (zh) * 2016-01-20 2017-07-27 深圳信立泰药业股份有限公司 血管紧张素ii受体拮抗剂代谢产物与nep抑制剂的复合物及其制备方法

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