WO2022052456A1 - 含酯基芳香丙酰胺类化合物及其代谢产物在制备治疗心衰药物中的应用 - Google Patents

含酯基芳香丙酰胺类化合物及其代谢产物在制备治疗心衰药物中的应用 Download PDF

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WO2022052456A1
WO2022052456A1 PCT/CN2021/085271 CN2021085271W WO2022052456A1 WO 2022052456 A1 WO2022052456 A1 WO 2022052456A1 CN 2021085271 W CN2021085271 W CN 2021085271W WO 2022052456 A1 WO2022052456 A1 WO 2022052456A1
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heart failure
rats
group
preparation
containing aromatic
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French (fr)
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朱新法
朱然
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Changchun Genescience Pharmaceutical Co Ltd
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Changchun Genescience Pharmaceutical Co Ltd
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Priority to CN202180062768.XA priority Critical patent/CN116406265B/zh
Priority to US18/245,270 priority patent/US20230390275A1/en
Priority to EP21865519.9A priority patent/EP4212158B1/en
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • 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

Definitions

  • the invention belongs to the technical field of medicine, and in particular relates to the application of an ester group-containing aromatic propionamide compound and its metabolite in the preparation of a medicine for treating heart failure.
  • Heart failure refers to the failure of the systolic and/or diastolic function of the heart to fully discharge the venous blood back to the heart, resulting in blood stasis in the venous system and insufficient blood perfusion in the arterial system, resulting in cardiac circulatory disorder syndrome.
  • This disorder symptoms cluster manifested as pulmonary congestion, vena cava congestion.
  • the occurrence of heart failure is generally due to the apoptosis of cardiomyocytes after myocardial infarction, resulting in the progressive loss of effective contractile function units-cardiomyocytes, the enhancement of the compensatory function of viable cardiomyocytes, the adaptive hypertrophy of cardiomyocytes, and the extracellularity of cardiomyocytes.
  • stroma and reactive interstitial fibrosis with reduced left ventricular wall thickness.
  • the increase in cardiomyocyte apoptosis further reduces the number of cardiomyocytes and reduces the overall contractility of the myocardium.
  • apoptotic cardiomyocytes after myocardial infarction will release a large number of factors to promote the production of collagen to repair the injured tissue.
  • the repair effect extends to the area surrounding the infarcted area.
  • the increase of fibrosis reduces the compliance of the left ventricle, and the myocardial contractility cannot exert its proper ejection effect, thus forming a vicious circle, resulting in decompensation of myocardial function, and ultimately leading to heart failure.
  • the purpose of the present invention is to provide an application of an ester group-containing aryl propionamide compound and its metabolite in the preparation of a medicine for treating heart failure.
  • ester-containing aromatic propionamide compounds in the preparation of medicaments for treating heart failure.
  • ester group-containing aromatic propionamide compound is C 25 H 17 F 3 N 4 O 4 .
  • the dosage of the ester group-containing aramid compound is 2 mg/kg-5 mg/kg in the preparation of a medicine for treating heart failure.
  • the dosage of the ester group-containing aramid compound in the preparation of a medicine for treating heart failure is 3 mg/kg.
  • ester group-containing aryl propionamide compound can improve the ejection fraction, the short-axis shortening rate and the reduction of cardiac output of the chronic heart failure rat, and increase the LVSP of the heart failure rat. It can play a very positive role in the application of preparing medicine for treating heart failure.
  • Figure 1 Bar graph of changes in body weight gain in rats with different compounds of the present invention.
  • Figure 2 Bar graph of cardiac weight index in rats for different compounds of the present invention.
  • Figure 3 Histogram of the weight index of different compounds of the present invention on rat brain-heart.
  • Figure 4 Bar graph of the effect of different compounds of the present invention on LVEF in rats with heart failure.
  • Figure 5 Bar graph of the effect of different compounds of the present invention on FS in rats with heart failure.
  • Figure 6 Bar graph of the effect of different compounds of the present invention on SV in rats with heart failure.
  • Figure 7 Bar graph of the effect of different compounds of the present invention on CO in rats with heart failure.
  • Figure 8 Bar graph of the effect of different compounds of the present invention on ESV in rats with heart failure.
  • Figure 9 Bar graph of the effect of different compounds of the present invention on EDV in rats with heart failure.
  • Figure 10 Bar graph of the effect of different compounds of the present invention on LVPWTs in rats with heart failure.
  • Figure 11 Bar graph of the effect of different compounds of the present invention on LV mass in rats with heart failure.
  • Figure 12 Bar graph of the effect of different compounds of the present invention on heart rate in rats with heart failure.
  • Figure 13 Bar graph of the effect of different compounds of the present invention on arterial blood pressure SBP in rats with heart failure.
  • Figure 14 Bar graph of the effect of different compounds of the present invention on the arterial blood pressure DBP in rats with heart failure.
  • Figure 15 Bar graph of the effect of different compounds of the present invention on arterial blood pressure MBP in rats with heart failure.
  • Figure 16 Bar graph of the effect of different compounds of the present invention on heart failure rats and LVSP.
  • the invention discloses the application of an ester group-containing aryl propionamide compound in the preparation of a medicine for treating heart failure.
  • the following specific experiments are used to confirm the application of the invention.
  • the EG017 mentioned in the text is C 25 H 17 F 3 N 4 O 4 , and the preparation method and structural formula of the EG017 refer to the content described in the patent document with the patent number of CN201410033958.0.
  • the columns are arranged in the order of Sham, Model, and EG017 groups from left to right.
  • Powerlab 8/35 signal acquisition system model: 8/35, manufacturer: ADinstrunents.
  • Constant temperature magnetic stirrer model: 85-2, manufacturer: Shanghai Sile Instrument Co., Ltd.
  • Micro vortex mixer model: XW-80A, manufacturer: Shanghai Huxi Analytical Instrument Co., Ltd.
  • the tested compounds used in the experiments of the present invention are as follows:
  • test compound Production batch supplier Storage conditions EG017 Q18-078 Yaoyuan Medicinal Chemistry (Shanghai) Co., Ltd. Airtight, store at room temperature
  • Pentobarbital sodium injection manufacturer: AlfaMedic Ltd, batch number: 1709296-02, physical state: pink liquid, 0.2g/ml, expiration date: September 2020, storage conditions: sealed at room temperature.
  • Gentamicin sulfate injection manufacturer: Huazhong Pharmaceutical Co., Ltd., batch number: 20180622 Storage conditions: dark at room temperature.
  • EG017 Configuration: Weigh an appropriate amount of the sample, add 0.5% CMCNa of the recipe, prepare 1mg/kg, 3mg/kg, 10mg/kg, stir with a stirrer until dissolved.
  • Dosing scheme 1 week after animal modeling, sham-operated/myocardial infarction rats were divided into groups, and they were orally administered once a day for 28 consecutive days, and the administration volume was 10 ml/kg.
  • SD rat Sprague Dawley rat
  • SCXK Beijing 2019-0006, laboratory animal certificate number: 1100112011006510.
  • the animals used in the following experiments are all SD rats. After the animals arrive at the facility of Shanghai WuXi AppTec New Drug Development Co., Ltd., they are kept in the animal breeding room with strictly controlled environmental conditions, and the temperature in the breeding room is maintained at 20-24 °C , the humidity is maintained at 30 to 70%. The temperature and humidity in the breeding room were monitored in real time by a thermo-hygrometer, and the temperature and humidity were recorded twice a day (once in the morning and once in the afternoon). The lighting in the animal breeding room is controlled by an electronic timed light-on system, with the lights on for 12 hours a day and off for 12 hours (on at 6:00AM and off at 18:00PM). Animals were fed ad libitum feed and guaranteed free drinking water.
  • the animals were anesthetized by intraperitoneal injection of pentobarbital sodium injection (60mpk), and atropine (0.5mpk) was injected intraperitoneally to expel phlegm, and then the trachea was connected to a ventilator to assist breathing; between the third and fourth ribs
  • the chest was opened and opened with a chest expander; the pericardium was torn, the left anterior descending coronary artery was ligated with 5-0 silk thread, the ribs and skin were sutured, and a thermal blanket was placed for recovery after surgery.
  • the sham operation group (Sham group) also performed the same operation, except that silk ligation was not performed.
  • the rats were anesthetized with isoflurane, and the left ventricular function of the model rats was examined by the Vevo small animal ultrasound imaging system. The model was successful if the LVFE% decreased by 30%.
  • A. Echocardiography (one day after the last dose): The animals were anesthetized with isoflurane (1.5%-5% v/v in oxygen), and left ventricular ejection fraction (LVEF), short-axis shortening rate (FS) were detected ), left ventricular end-systolic volume (ESV), left ventricular end-diastolic volume (EDV), stroke output (SV), cardiac output (CO), left ventricular mass (LV mass), left ventricular posterior wall end-systolic thickness (LVPWTs) and left ventricular posterior wall end-diastolic thickness (LVPWTd).
  • ESV left ventricular end-systolic volume
  • EDV left ventricular end-diastolic volume
  • SV stroke output
  • CO cardiac output
  • LV mass left ventricular posterior wall end-systolic thickness
  • LVPWTd left ventricular posterior wall end-diastolic thickness
  • Organ weight index heart weight/100g body weight
  • heart-brain specific gravity heart weight/brain weight
  • Myocardium staining The myocardium was stained with Sirius red to observe the level of myocardial fibrosis.
  • the hearts were dissected and washed with normal saline, and weighed after absorbing water, and the heart weight index was calculated according to the body weight.
  • the brain-heart weight ratio was calculated after the brain was weighed. It can be seen from Figure 2- Figure 3 and Table 1 that compared with the Sham group, the heart weight index and the brain-heart weight ratio of the Model group were significantly increased, and the heart weight of the rats in the test group was significantly increased. The index and brain-heart weight ratio were not significantly different from the Model group (P>0.05)
  • LVEF left ventricular ejection fraction
  • FS short-axis shortening rate
  • CO cardiac Changes in output
  • SV output per stroke
  • Left ventricular myocardial infarction in rats after myocardial infarction leads to a decrease in left ventricular systolic function, manifested as a decrease in ventricular systolic pressure and a decrease in the rate of increase/decrease of intraventricular pressure ( ⁇ dp/dt max).
  • Intraventricular pressure is shown in Figure 16 and Table 6.
  • LVSP left ventricular systolic blood pressure
  • EG017 significantly alleviated the reduction of LVSP caused by heart failure, and the difference was statistically significant (P ⁇ 0.05).
  • the +dp/dt max of the Model group was 5164 ⁇ 352mmHg/s, and the -dp/dt max was -3789 ⁇ 220mmHg/s, which were significantly lower than the 6210 ⁇ 429mmHg/s, 5091 ⁇ 456mmHg of the Sham group. /s, the difference was statistically significant (P ⁇ 0.05, P ⁇ 0.01).
  • Name/Code Sodium Carboxymethyl Cellulose/CMC-Na; Appearance: White or slightly yellow fibrous powder;
  • Preparation method of the test suspension Weigh a certain amount of EG017 according to the following table, place it in a mortar, add a small amount of 0.5% CMC-Na to fully grind, transfer it to a container, wash the mortar 4 times, and transfer the washing liquid To the container, and add 0.5% CMC-Na to dilute to the required volume, and prepare the test suspension of the required concentration. The samples were agitated with a magnetic stirrer at 1200 rpm for at least 15 min prior to analytical sampling and administration.
  • Beagle dogs Thirty-two Beagle dogs were used in the experiment and randomly divided into 4 groups, with 8 dogs in each group, half male and half male. They were set as the intravenous injection group (1mg/kg) and the kinetics of intragastric administration of low (1mg/kg), medium ( 3mg/kg) and high (10mg/kg) dose groups, blood samples were collected at the corresponding time points after administration, EDTA-K2 anticoagulation, and the animals in the middle dose group were administered by intragastric administration for 7 consecutive days after sample collection was completed. Blood samples were collected at corresponding time points. The concentrations of EG017 and the main metabolite EG-2 in plasma were detected by LC-MS/MS, and the pharmacokinetic parameters were calculated by WinNonlin 6.4 software.
  • the present invention still has multiple embodiments, and all technical solutions formed by using equivalent transformations or equivalent transformations fall within the protection scope of the present invention.

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Abstract

一种含酯基芳香丙酰胺类化合物及其代谢产物在制备治疗心衰药物中的应用，所述含酯基芳香丙酰胺类化合物为C25H17F3N4O4。含酯基芳香丙酰胺类化合物可以改善慢性心衰大鼠的射血分数、短轴缩短率和心输出量的降低，提高心衰大鼠的LVSP。

Description

含酯基芳香丙酰胺类化合物及其代谢产物在制备治疗心衰药物中的应用 技术领域
本发明属于医药技术领域，尤其涉及一种含酯基芳香丙酰胺类化合物及其代谢产物在制备治疗心衰药物中的应用。
背景技术
心力衰竭简称心衰，是指由于心脏的收缩功能和(或)舒张功能发生障碍，不能将静脉回心血量充分排出心脏，导致静脉系统血液淤积，动脉系统血液灌注不足，从而引起心脏循环障碍症候群，此种障碍症候群集中表现为肺淤血、腔静脉淤血。心力衰竭的发生一般是由于心肌梗死后，随着心肌细胞的凋亡，从而导致有效收缩功能单位-心肌细胞进行性丧失，存活心肌细胞的代偿性功能增强，心肌细胞适应性肥大，细胞外基质的沉积和反应性间质纤维化，左心室壁厚度降低。随着肥厚程度的进展，心肌细胞凋亡的增加使心肌细胞数量进一步减少，心肌整体收缩力下降。同时，心肌梗死后凋亡的心肌细胞会释放大量的因子促进胶原的生成来对受伤的组织进行修复，过度表达的胶原沉积进一步表现为心肌纤维化，导致心脏收缩和舒张功能异常，同时这种修复作用会扩展到梗死区周围的区域。纤维化的增加又使左室的顺应性下降，心肌收缩力不能发挥其应有的射血效应，于是形成恶性循环，致使心肌功能失代偿，最终导致心力衰竭。
发明内容
鉴于现有技术存在上述缺陷，本发明的目的在于提供一种含酯基芳香丙酰胺类化合物及其代谢产物在制备治疗心衰药物中的应用。
本发明的目的，将通过以下技术方案得以实现：
含酯基芳香丙酰胺类化合物在制备治疗心衰药物中的应用。
优选地，所述含酯基芳香丙酰胺类化合物为C 25H 17F 3N 4O 4。
优选地，所述含酯基芳香丙酰胺类化合物在制备治疗心衰药物中剂量为2mg/kg-5mg/kg。
优选地，所述含酯基芳香丙酰胺类化合物在制备治疗心衰药物中剂量为3mg/kg。
本发明突出效果为：含酯基芳香丙酰胺类化合物可以改善慢性心衰大鼠的射血分数、短轴缩短率和心输出量的降低，提高心衰大鼠的LVSP。可以在制备治疗心衰药物的应用中有很积极的作用。
以下便结合实施例附图，对本发明的具体实施方式作进一步的详述，以使本发明技术方案更易于理解、掌握。
附图说明
图1：本发明中不同化合物对大鼠的体重增长变化柱状图。
图2：本发明中不同化合物对大鼠的心脏重量指数的柱状图。
图3：本发明中不同化合物对大鼠的脑心的重量指数的柱状图。
图4：本发明中不同化合物对心衰大鼠LVEF的影响柱状图。
图5：本发明中不同化合物对心衰大鼠FS的影响柱状图。
图6：本发明中不同化合物对心衰大鼠SV的影响柱状图。
图7：本发明中不同化合物对心衰大鼠CO的影响柱状图。
图8：本发明中不同化合物对心衰大鼠ESV的影响柱状图。
图9：本发明中不同化合物对心衰大鼠EDV的影响柱状图。
图10：本发明中不同化合物对心衰大鼠LVPWTs的影响柱状图。
图11：本发明中不同化合物对心衰大鼠LV mass的影响柱状图。
图12：本发明中不同化合物对心衰大鼠心率的影响柱状图。
图13：本发明中不同化合物对心衰大鼠动脉血压SBP的影响柱状图。
图14：本发明中不同化合物对心衰大鼠动脉血压DBP的影响柱状图。
图15：本发明中不同化合物对心衰大鼠动脉血压MBP的影响柱状图。
图16：本发明中不同化合物对心衰大鼠和LVSP的影响柱状图。
具体实施方式
本发明揭示了一种含酯基芳香丙酰胺类化合物在制备治疗心衰药物中 的应用，以下采用具体实验证实本发明的应用。文中所提到的EG017为C 25H 17F 3N 4O 4，所述EG017制备方法和结构式参考专利号为CN201410033958.0的专利文件记载的内容。本发明所有附图中柱状顺序由左向右依次按照Sham、Model、和EG017组进行排列。
本发明实验所采用的仪器
小动物呼吸机，型号：V-200046；生产商：Harvard Apparatus。
Vevo小动物超声成像系统，型号：1100，生产商：Visualsonics。
Powerlab 8/35信号采集系统，型号：8/35，生产商：ADinstrunents。
动物实验跑台，型号：DB030，生产商：北京智鼠生物科技有限公司。
分析天平，型号：SQP，生产厂商：sartorius。
电子天平，型号：FA-2204，生产商：邦西仪器科技(上海)有限公司。
电子天平，型号：MP5002，生产商：常州市天之平仪器设备有限公司。
离心机，型号：5424R，生产商：Eppendorf。
恒温磁力搅拌器，型号：85-2型，生产商：上海司乐仪器有限公司。
微型漩涡混合仪，型号：XW-80A，生产商：上海沪西分析仪器有限公司。
本发明实验所采用的受试化合物如下所示：
受试化合物 生产批号 供应商 储存条件
EG017 Q18-078 药源药物化学(上海)有限公司 密闭，室温保存
试剂：
CMC Na，生产厂商：Sigma，Lot#：SLBV9664，存储条件：室温。
异氟烷，生产厂商：江苏恒丰强生物技术有限公司，批号：20191223，储存条件：室温密封。
戊巴比妥钠注射液，生产厂商：AlfaMedic Ltd，批号：1709296-02，物理状态：粉红色液体，0.2g/ml，有效期2020年09月，存储条件：室温密封。
美洛昔康注射液，生产厂商：齐鲁动物保健品有限公司，批号： 1710002，存储条件：室温密封。
硫酸庆大霉素注射液，生产厂商：华中药业股份有限公司，批号：20180622储存条件：室温避光。
生理盐水，生产厂商：辰欣药业股份有限公司，批号：18101907，存储条件：室温密封。
溶媒及化合物配制
1、溶媒(0.5％CMC Na)：配置：称取5g CMC Na，定容于1000ml的ddwater中，用搅拌器搅拌至溶解即得。
2、EG017：配置：称取样品适量，加处方量的0.5％CMCNa，配制成1mg/kg、3mg/kg、10mg/kg，用搅拌器搅拌至溶解即得。
给药方案：在动物造模1周后，将假手术/心肌梗死大鼠分组，每日口服给药一次，连续28天，给药体积为10ml/kg。
实验动物使用
Sprague Dawley rat(SD大鼠)，由维通利华实验动物技术有限公司提供，雌性，120只，许可证编号：SCXK(京)2016-0006，实验动物合格证号：1100112011006510。雌性，50只，许可证编号：SCXK(浙)2019-0001，实验动物合格证号：2003050021。
动物的饲养
以下实验中所使用的动物均为SD大鼠，动物到达上海药明康德新药开发有限公司设施后，将其饲养于严格控制环境条件的动物饲养间中，饲养间的温度维持在20～24℃，湿度维持在30～70％。通过温湿度计对饲养间的温度和湿度进行实时监控，并且每天对温度和湿度记录两次(上午和下午各1次)。动物饲养间的采光由一个电子定时开灯系统来控制，每天开灯12小时关灯12小时(6:00AM开，18:00PM关)。动物自由采食饲料，保证自由饮水。
具体实验方法
动物适应后，实验当天，动物使用戊巴比妥钠注射液(60mpk)腹腔注射麻醉，腹腔注射阿托品(0.5mpk)祛痰，然后气管接通呼吸机辅助呼吸；在第三和第四肋骨间开胸，并用扩胸器撑开；撕开心包膜，用5-0丝线结扎冠状动脉左前降支，缝合肋骨和皮肤，术后放入保温毯恢复。假手术组(Sham组)也进行相同手术操作，只是不进行丝线结扎操作。手术结束后所有动物均肌肉注射美洛昔康(1mpk)和盐酸庆大霉素注射液(8mpk)进行镇痛和抗感染。给药前1天，大鼠吸入异氟烷麻醉(1.5％-5％v/v in oxygen)后行心脏超声检查，左心室前壁无明显收缩，左心室腔变大，与正常对照组相比左心室射血分数下降30％表示结扎成功。选取模型成功的大鼠，进入之后的实验(备注：保证造模后入组动物每组7只，假手术组7只)。各组大鼠给予治疗药物每天1次，灌胃给药，连续四周。实验期间，观察动物生活状态，对异常状况进行记录；末次给药后一天进行终点指标检测和样本收集。
动物造模1周以后，使用异氟烷麻醉大鼠，Vevo小动物超声成像系统检查模型大鼠左心室功能，以LVFE％降低30％即为模型成功。
除Sham组外，根据LVEF％和体重分成9组，每组7只。各组情况如下表：
Figure PCTCN2021085271-appb-000001
终点检测指标
A.超声心动图检查(末次给药后一天)：动物使用异氟烷吸入麻醉 (1.5％-5％v/v in oxygen)，检测左室射血分数(LVEF)、短轴缩短率(FS)、左心室收缩末期容积(ESV)、左心室舒张末期容积(EDV)、每博输出量(SV)、心输出量(CO)、左心室重量(LV mass)、左心室后壁收缩末期厚度(LVPWTs)和左心室后壁舒张末期厚度(LVPWTd)。
B.血流动力学(末次给药后一天)：大鼠用戊巴比妥钠麻醉(～60mpk,ip)，仰位固定于手术台，分离颈总动脉，插入导管经Powerlab系统检测大鼠颈总动脉血压(SP/DP)，再将导管推入左心室检测左心室左心室收缩压/舒张压(LVSP/LVDP)；左心室内压最大上升/下降速率(±dp/dtmax)心率(HR)，所有程序均于麻醉后30min内检测完成。
C.脏器重量指数：心脏重量/100g体重；心脑比重：心脏重量/脑重量。
D.心肌染色：对心肌进行天狼星红染色，观察心肌纤维化水平。
数据统计
数据使用Mean±S.E.M表示，Graphpad Prism 5.0进行统计作图。使用单因素方差分析检验(by one-way ANOVA Dunntt‘s test)和t-test，P<0.05表示差异有统计学意义。
初步观察
研究表明单独给予EG017的受试组体重增长明显，终点解剖心脏可见Sham组心脏红润饱满，模型大鼠心脏左心室干瘪，梗死区呈灰白色。
化合物对心衰大鼠心脏重量指数的影响
大鼠终点数据采集，解剖取心脏使用生理盐水洗净，吸取水分后称重并将根据体重计算心脏重量指数。取脑称重后计算脑心重量比，从图2-图3和表1可以看出，与Sham组比较，Model组心脏重量指数和脑心重量比明显升高，受试组大鼠心脏重量指数和脑心重量比与Model组无显著的统计学差异(P>0.05)
表1大鼠的心脏重量指数和脑心重量比(Mean±SEM)N＝7
Figure PCTCN2021085271-appb-000002
△P<0.05vs sham,&P<0.05vs model,by t-test；#P<0.05vs sham,by one-way ANOVA Dunnett’s test.
化合物对大鼠心脏功能的影响
化合物对大鼠心脏收缩功能的影响
心衰的重要表现即为左心室收缩功能降低，因此，在实验终点纵向超声心动图检查各组大鼠的心脏，分析比较左室射血分数(LVEF)、短轴缩短率(FS)、心输出量(CO)和每博输出量(SV)的变化。从图4-7和表2，可以看出，Model组大鼠心肌梗死后出现严重左室功能障碍，LVEF、FS、CO和SV分别为36.3±3.83％、18.5±2.22％、55.7±4.90ml/min和159±8.62ul，显著低于Sham组的84.8±2.83％、56.1±3.14％、77.2±5.10ml/min和187±9.46ul，统计学差异显著(P<0.001、P<0.001、P<0.05、P<0.05)。与Model组比较，EG017组对心衰大鼠LVEF和FS的降低有明显的改善作用，统计学差异显著(P<0.05)。EG017组对CO和SV的降低有明显的改善作用(P<0.05)。
表2化合物对心衰大鼠LVEF、FS、CO和SV的影响(Mean±SEM)N＝7
Figure PCTCN2021085271-appb-000003
***#<0.001vs sham,*P<0.05,**P<0.01vs Model,by one-way ANOVA Dunnett’s test；△P<0.05vs sham,&P<0.05,&&P<0.01vs Model by t-test.
化合物对大鼠左心室容量的影响
心衰形成后，由于代偿作用，左心室腔室变大，左心室后壁变薄。从图8-图9和表3可以看出，与Sham组比较，心衰大鼠心脏EDV、ESV均明显升高，有极显著的统计学差异(P<0.001)。与Model组比较，EG017组8对心衰造成的心脏的收缩容积(ESV)的升高有显著的改善作用(P<0.05)。
表3化合物对心衰大鼠收缩和舒张期左心室容积的影响(Mean±SEM)N＝7
Group dose ESV(ul) EDV(ul)
Sham Vehicle 36.0±9.05 223±16.1
Model Vehicle 294±32.6### 453±28.5###
EG017 3mpk 238±52.0 477±48.2
###P<0.001vs Sham,by one-way ANOVA Dunnett’s test；&P<0.05vs model,by t-test.
化合物对大鼠心室后壁厚度和心脏质量的影响
从图10-图11和表4可以看出，与Sham组比较，Model组大鼠LVPWTs和LVPWTd略有降低(P>0.05)，而心脏质量明显增加，具有显著的统计学差异(P<0.05)。与Model组比较，各给药组对LVPWTs、LVPWTd和LV mass的影响不明显(P>0.05)。
表4化合物对心衰大鼠左心室后壁厚和左心室质量的影响(Mean±SEM)N＝7
Figure PCTCN2021085271-appb-000004
&P<0.05vs model by t-test.
化合物对心衰大鼠血流动力学的影响
心肌梗死后大鼠左心室心肌梗死，导致其左心室收缩功能降低，表现为 心室收缩压降低，心室内压上升/下降速度(±dp/dt max)降低。
从图12-图15，和表5可以看出，各实验组心率无显著影响(P>0.05)。Model组动脉血压(SBP、DBP、MBP)与Sham比较明显降低，有显著的统计学差异(P<0.001，P<0.05，P<0.01)。与Model组比较，EG017组对心衰后大鼠的动脉血压无显著影响。
表5化合物对心衰大鼠心率和动脉血压的影响(Mean±SEM)N＝7
Figure PCTCN2021085271-appb-000005
#P<0.05,##P<0.01,###P<0.001vs sham,*P<0.05vs model，by one-way ANOVA Dunnett's test；&P<0.05vs model,by t-test.
化合物对心室压及心室压变化率的影响
心室内压如图16和表6所示，与Sham组比较，Model组大鼠的左心室收缩压(LVSP)降低比较明显，有显著的统计学差异(P<0.01)。与Model组比较，EG017对心衰造成的LVSP降低有较明显的缓解作用，统计学差异显著(P<0.05)。
与Sham组比较，Model组大鼠的+dp/dt max为5164±352mmHg/s、-dp/dt max为-3789±220mmHg/s，显著低于Sham组的6210±429mmHg/s、5091±456mmHg/s，统计学差异显著(P<0.05，P<0.01)。
表6化合物对心衰大鼠左心室血压的影响(Mean±SEM)N＝7
Figure PCTCN2021085271-appb-000006
##P<0.01,###P<0.001vs sham,*P<0.05vs model,by one-way ANOVA  Dunnett's test；&P<0.05,&&P<0.01vs model,by t-test.
以下实施例用以证明EG017的代谢产物在制备治疗心衰药物中应用具有积极推动作用。
2.1.供试品和溶媒
2.1.1.供试品
名称：EG017；物理状态：类白色粉末；
主要成分：(S)-1-((4-氰基-3-(三氟甲基)苯基)氨基)-3-(4-氰基苯氧基)-2-甲基-1-氧代丙-2-基烟酸酯；含量：99.3％；
2.1.2.溶媒
2.1.2.1.CMC-Na
名称/代号：羧甲基纤维素钠/CMC-Na；性状：白色或微黄色纤维状粉末；
2.1.2.2.DMA
名称/代号：N,N-二甲基乙酰胺/DMA
性状：无色或近似无色澄清液体；
2.1.2.3.solutol
名称/代号：15-羟基硬脂酸聚乙二醇酯/solutol；性状：在室温下是微黄浆糊状，在约30℃时变成液体状。溶解于水或乙醇形成澄清的溶液；
保存条件：2～8℃；
2.1.2.4.氯化钠注射液
名称：氯化钠注射液；
批号：1804172726；性状：无色透明液体；
供试品配制
供试品混悬液
取一定量的CMC-Na(允许称量误差±1％)，加入纯水溶解，配制成0.5％CMC-Na。供试品混悬液的配制方法：按下表称取一定量EG017，置于研钵中，加入少量0.5％CMC-Na充分研磨，转移至容器中，再洗涤研钵4次，洗涤液转移至容器，并加0.5％CMC-Na稀释至所需体积，配制成所需浓度的供试品混悬液。分析取样及给药前用磁力搅拌器以1200rpm的转速搅拌至少15min。
实验采用32只Beagle犬，随机分为4组，每组8只，雌雄各半，分别设为静脉注射组(1mg/kg)和灌胃给药的动力学低(1mg/kg)、中(3mg/kg)、高(10mg/kg)剂量组，给药后分别在相应时间点采集血样，EDTA-K2抗凝，中剂量组动物完成样本采集后用于连续7天灌胃给药并在相应时间点采集血样。LC-MS/MS法检测血浆中EG017和主要代谢物EG-2的浓度，并用WinNonlin 6.4软件进行药代动力学参数计算。
本发明尚有多种实施方式，凡采用等同变换或者等效变换而形成的所有技术方案，均落在本发明的保护范围之内。

Claims (6)

  1. 含酯基芳香丙酰胺类化合物在制备治疗心衰药物中的应用。
  2. 如权利要求1所述的应用，其特征在于：所述含酯基芳香丙酰胺类化合物为C 25H 17F 3N 4O 4。
  3. 如权利要求2所述的应用，其特征在于：所述含酯基芳香丙酰胺类化合物在制备治疗心衰药物中剂量为1mg/kg-10mg/kg。
  4. 如权利要求3所述的应用，其特征在于：所述含酯基芳香丙酰胺类化合物在制备治疗心衰药物中剂量为3mg/kg。
  5. 含酯基芳香丙酰胺类化合物的代谢产物在制备治疗心衰药物中的应用。
  6. 如权利要求5所述的应用，其特征在于：所述代谢产物为EG-2。
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