USES OF ANGIOTENSIN II RECEPTOR ANTAGONIST METABOLITE COMPLEX AND NEP INHIBITOR IN THE TREATMENT OF HEART FAILURE

Abstract

The uses of a complex of an angiotensin II receptor antagonist metabolite and a NEP inhibitor for heart failure relate specifically to the uses of the complex in the preparation of a drug for use in heart failure with reduced ejection fraction (HFrEF).

Description

The invention belongs to the technical field of medicinal use and relates to new uses of a complex of an angiotensin II receptor antagonist metabolite and a NEP inhibitor for heart failure, specifically to the uses of the complex in the preparation of a medicament for its use. Use in heart failure with reduced ejection fraction. BACKGROUND Heart failure is a severe manifestation or late stage of various heart diseases, with high rates of death and rehospitalization. In developed countries, the prevalence of heart failure is 1.5% to 2.0% and >10% in population groups older than 70 years. An epidemiological survey conducted in 2003 showed that the prevalence of heart failure was 0.9% among adults aged 35 to 74 years in China. With the aging population in China, the incidence of chronic diseases such as heart disease, hypertension, diabetes and obesity is increasing. Improved medical techniques have prolonged the survival period of heart disease patients, leading to a continuous increase in the prevalence of heart failure in China. A survey of 10,714 patients hospitalized with heart failure in China showed that the mortality rates of patients with heart failure were 15.4%, 12.3%, and 6.2% during hospitalization in 1980, 1990, and 2000, respectively, and that the main causes Deaths were left ventricular failure (59%), arrhythmia (13%), and sudden cardiac death (13%). The China-HF study showed that the mortality rate was 4.1% in hospitalized patients with heart failure. A valsartan-sacubitril sodium salt complex (LCZ696) and its preparation method are described in WO2007056546A1. In 2017, it was approved for marketing in China under the trade name Entrcsto® for heart failure. Its molecular structure units are the following: Qnfrenn / zznz / E / YiAi I Qnfrrnn / zznz / E / YiAi Furthermore, WO2017125031A1 describes a series of complexes of an angiotensin receptor antagonist metabolyl (EXP3174) and a NEP inhibitor (sacubitril) that have certain effects on heart failure with preserved ejection fraction (HFpEF) and have the structural units following molecular: It can be seen that it is essential to find a targeted drug that has a good therapeutic effect for heart failure with reduced ejection fraction. DESCRIPTION OF THE INVENTION In view of the technical problems existing in the state of the art, the invention provides uses of a complex of an angiotensin II receptor antagonist metabolite and a NEP inhibitor (or a supramolecular complex) in the preparation of a medicament for use in heart failure with reduced ejection fraction. The complex has the following structural units: (a EXP3174-bAHU377)-x Ca-nA Specifically, heart failure with reduced ejection fraction refers to HFrEF as defined in Table 1 of Chinese Guidelines for the Diagnosis and Treatment of Heart Failure 2018: classification and diagnostic criteria of heart failure. As a preferred technical solution of the invention, the medicament is used in patients suffering from heart failure with reduced ejection fraction. As inferred from the experimental results of the invention and the dose of prodrug used, a single dose form of the drug contains 60 mg to 500 mg of the complex calculated by the total mass of (aEXP3174 · bAHU377), which includes, among others , 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg and 500 mg. As a more preferred technical solution of the invention, a single dose form of the medicament contains 60, 120, 180, 240, 300, 360, 420 and 480 mg of the complex. In one embodiment, a single dose form refers to the daily dosage form. A content of 60 mg / d to 500 mg / d of the complex is administered to patients, and dosing frequencies include, but are not limited to, once a day, twice a day, 3 times a day, 4 times a day, etc. . The dose refers to the initial dose or maintenance dose of the use of the drug. In use for hypertension, the initial dose is usually less than the maintenance dose. The dose can be appropriately increased in patients with resistant hypertension under special conditions. Specifically, the calculation method includes calculating according to the daily dose of pro drug. EXP3174 is the body's metabolite of allisartan isoproxil which has been on the market under the generic name Allisartan Isoproxil Tablets and the trade name Xinlitan, and is administered at 240 mg per day. Allisartan isoproxil has the molecular formula C27H29CIN6O5 and the molecular weight of 553.0; EXP3174 has the molecular formula C22H21CIN6O2 and the molecular weight of approximately 436.9; AHU377 has the molecular formula C24H29NO5 and the molecular weight of approximately 411.5. The daily dose of the complex should be equivalent to that of allisartan isoproxil. Therefore, the single dose form of the above complex is obtained by calculation. Based on data from the canine heart failure model with decreased ejection fraction, the effective dose is inferred to be 100 mg / d in humans with a dose range of 60 mg / d to 500 mg / d. The drug is a solid preparation for oral administration, preferably an oral tablet or capsule, which can be administered in multiple tablets and multiple capsules with a total dose of 60 mg to 500 mg. The drug complex can be obtained by a method known in the state of the art, where the complex and its preparation method described in WO2017125031 Al se 3 Qnfrenn / zznz / E / YiAi incorporate the invention. As a more preferred technical solution of the 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 and 1:4. As a more preferred technical solution of the invention, the complex has the following structural units: (EXP3174-AHU377) x CanH2O or Qnfrrnn / zznz / E / YiAi where x is a value between 0.5 and 2, and n is a value between 0 and 3. As a more preferred technical solution of the invention, x is selected from 0.5, 1, 1.5 and 2. As a more preferred technical solution of the invention, the complex has the following structural units: (EXP3174«AHU377) · 1.5Ca«nH2O or (EXP3174«AHU377) · 2Ca-nH2O where n is any value between 1 and 3. As a more preferred technical solution of the invention, n is selected from 0.5, 1, 1.5, 2, 2.5 and 3. As a more preferred technical solution of the invention, the complex is selected from the following: (ΕΧΡ3174 AHU377) 1.5Ca 1H2O: (EXP3174 • AHU377) · 1 5Ca · 1.5H2O ( EXP3 1 74 • AHU377) • 1 5Ca · 2H2O: ( EXP3 1 74 • AHU377) • 1.5Ca · 2 5H2O ( EXP3 1 74 • AHU377) • 1 5Ca · 3H2O : (EXP3 174 • AHU377) • 2Ca · 1H2O; (EXP3174 • AHU377) • 2Ca · 1.5H2O; (EXP3 174 • AHU377) • 2Ca · 2H2O; (EXP3174 • AHU377) • 2Ca · 2.5H1O; ( EXP3 1 74 • AHU377) • 2Ca · 3H2O. Qnfrenn / zznz / E / YiAi Those skilled in the art can understand that in the unit cell of a supramolecular complex, the metabolite allisartan isoproxil (EXP3174), AHU377, calcium ion (Ca2+) and solvent molecules will be filled therein in the form of a plurality of structural units. The supramolecular complex of the invention is different from a mixture obtained by simple physical mixing of two active ingredients. The XRD spectrum of the obtained supramolecular complex is clearly different from that of EXP3174 and the calcium salt of AHU377, and its solubility is also significantly different in various solvents (such as water, ethanol, ethanol-water, etc.). There are also significant differences in other physical and chemical properties such as hygroscopicity, melting point, infrared spectrum, etc. Compared to the state of the art, the invention has the following advantages and beneficial effects: 1. The invention provides uses of a series of supramolecular complexes with double effects of the metabolite allisartan isoproxil (EXP3174) and the enkephalinase inhibitor (AHU377) in heart failure with reduced ejection fraction, which have a significantly better effect than LCZ696 at the same dose; 2. The complex of the invention in a canine model with reduced ejection fraction has a better effect than that in a canine model with preserved ejection fraction. It can be seen that the pharmaceutical composition of the invention has a specific selectivity for heart failure with reduced ejection fraction, which is difficult to predict based on the state of the art. 3. The complex of the invention has a better effect than the physical mixture of EXP3174+AHU377, which fully demonstrates that the use of the complex has significant advantages over the use of a physical combination of drugs. DESCRIPTION OF THE DRAWINGS Figure 1 Chinese Guidelines for the Diagnosis and Treatment of Heart Failure 2018: classification table and diagnostic criteria for heart failure. SPECIFIC MODALITIES The invention will now be described in more detail with reference to examples and drawings, but embodiments of the invention are not limited thereto. In the following examples: An Empyrean X-ray diffractometer was used for X-ray powder diffraction detection. Detection conditions: Cu targeting Ka beam, voltage 40 KV, current 40 mA, emission slit 1 / 32°, anti-scattering slit 1 / 16°, anti-scattering slit 7.5 mm, 2Θ range 3° at 60°, step length 0.02°, and dwell time per step 40 s. Differential scanning calorimeter DSC204F1 from NETZSCH, Germany was used to detect differential scanning calorimetry spectra. Detection conditions: atmosphere: N2, 20 ml / min; Sweep procedure: Record the heating curve by increasing the temperature from room temperature at 10°C / min to 250°C. TG209 thermogravimetric analyzer from NETZSCH, Germany was used to detect moisture content. Detection conditions: atmosphere: N2, 20 ml / min; Sweeping procedure: room temperature 700°C, heating rate: 10°C / min. The EXP3174 used in the examples was manufactured in-house by the company, with a purity of 98.3%. The AHU377 calcium salt used in the examples was manufactured in-house by the company, with a purity of 99.4%. Example 1 Preparation of AHU377 free acid: To a 250 ml one-neck flask, 2.1 g of calcium salt of AHU377 and 40 ml of isopropyl acetate were added, and then 4.5 ml of 2 mol / 1 hydrochloric acid were added at room temperature and stirred. for its dissolution. The liquids were separated to collect the organic layer which was passed twice through 20 ml of water; after precipitating under reduced pressure at 35 °C, it provided AHU377 free acid. Example 2 Preparation of the complex: (prepared according to Example 2 of patent WO2017125031A1) Qnfrenn / zznz / E / YiAi Qnfrrnn / zznz / E / YiAi At room temperature, 2.36 g of AHU377 free acid, 2 g of EXP3174 and 40 ml of acetone obtained according to the method of Example 1 were added to a 250 ml three-necked flask and dissolved; 1.3 equivalents of calcium hydroxide solid were added to AHU377 and 1 ml of water at room temperature, stirred at room temperature for 10 h and 40 ml more of acetone were added to react for another 8 hours. Under nitrogen protection, it was filtered using a Buchner funnel. The solid was passed through acetone to give a white solid which was dried under vacuum at 35 °C for 8 h and dried to give 3.5 g of solid (EXP3174 · AHU377)3' · 1.5Ca2+ · 2.5H2O, with a purity of 99 % determined by HPLC. The test was repeated to obtain sufficient doses for pharmacodynamic experiments. Example 3 Preparation of the complex: (prepared according to Example 3 of patent WO2017125031A1) Qnfrenn / zznz / E / YiAi At room temperature, 2.36 g of AHU377 free acid, 2 g of EXP3174 and 40 ml of acetone obtained according to the method of Example 1 were added to a 250 ml three-necked flask and dissolved; 1.6 equivalents of calcium hydroxide solid were added to AHU377 and 0.6 ml of water at room temperature, stirred for 6 h at 35 °C and 40 ml more acetone were added to react for another 8 hours. Under nitrogen protection, it was filtered using a Buchner funnel. The solid was passed through acetone to give a white solid which was dried in vacuo at 50 °C for 8 h and dried to give 3.1 g of solid (EXP3174· AHU377)3' · 1.5Ca2+· 2H2O. The test was repeated to obtain sufficient doses for pharmacodynamic experiments. Example 4 A Pharmacodynamic Study on the Complex in the Canine Model of Chronic Heart Failure, Reduced Ejection Fraction 4.1 Methods: Once the animals arrived at the facility, they were subjected to adaptive feeding and were randomly assigned after echocardiography and ECG, and then the experiment was started. On the day of the operation, the animals were anesthetized by intramuscular injection of Zoletil (5 mg / kg). The trachea of ​​the anesthetized dogs was connected to the ventilator, and then they were fixed in the supine position, the chest was opened between the third and fourth ribs, the left anterior descending coronary artery was ligated to close the thoracic cavity, and then sutured. the skin. After the animals recovered for 3 days postoperatively, they were administered drugs by gavage once a day for four consecutive weeks. During the experiment, the animals' living conditions were observed every day and abnormal conditions were recorded. After 42 days of administration, echocardiography was performed. 4.2 Modeling: The day before the operation, the animals were fasted overnight. On the day of operation, animals were injected intramuscularly with Zoletil (dose: 5 mg / kg) to induce anesthesia, and they were also given intramuscular injection of atropine sulfate (dose: 0.5 mg / dog). . After the animals were anesthetized, the hair on the left hemithorax was shaved. Tracheal intubation was quickly performed to connect them to the ventilator to provide artificial respiration and provide 1.5% isoflurane gas to maintain the anesthesia state, and a monitor was also used to monitor blood oxygen saturation, heart rate, electrocardiogram, body temperature and respiratory rate, etc. After disinfecting the skin of the forelimbs with 70% alcohol, the cephalic veins were found for intravenous intubation and remained intravenously as administration access. Iodophor and 70% alcohol were used to sterilize the skin of the left hemithorax as an aseptic treatment. A sterile surgical gauze with holes was spread. A sterile scalpel was used to cut the skin along the fourth and fifth intercostal spaces, and after hemostasis, an electric scalpel was used to open the subcutaneous tissues layer by layer and muscle layers, and the bleeding was stopped in a timely manner. . The pleural membrane was carefully opened to expose the lung tissues, which avoided damage to the lung tissues; The surgical field of view was gradually expanded from 20 to 25 cm along the inferior border of the fourth rib, and a chest extender was used to expand the surgical margin. Sterile gauze soaked in warm normal saline was used to push and protect the lung tissues. Sterile gauze soaked in warm normal saline was used to push the left appendage to expose it between the left ventricle and left atrium, and a blunt right-angle clamp was used to separate the left anterior descending coronary artery. A silk thread no. 4 to cross the artery, and avoid Qnfrenn / zznz / E / YiAi pull on the artery during separation and threading. A silk thread was used to ligate the left anterior descending coronary artery. During ligation, the animals were closely observed for blood oxygen saturation, heart rate, electrocardiogram, body temperature, and respiratory rate. If an animal had abnormalities such as ventricular fibrillation, the operation would be stopped immediately and lidocaine injection (10 mg / kg) would be rapidly administered through the cephalic veins for treatment. After it was confirmed that there was no bleeding in the thoracic cavity, the protective gauze was removed. A suture no. 1 to pass through the fourth and fifth ribs to suture the thoracic cavity. The manual compression method was used for lung recruitment. The tissue and skin were sutured layer by layer. After the operation, the animals were kept warm and appropriately replenished with physiological saline, and blood oxygen saturation, heart rate, electrocardiogram, body temperature and respiratory changes were closely observed; The gas anesthesia machine was turned off and tracheal intubation was removed until the animals completely recovered spontaneous breathing. After the operation, they were injected intramuscularly with an analgesic (meloxicam, 0.67 mg / kg) to relieve pain, and they were injected intramuscularly with ampicillin sodium 20 mg / kg to combat infection. 4.3 Groups and administration: Before grouping, echocardiography and ECG monitoring were performed on each dog. According to the expulsion fraction, the dogs were randomly assigned into 5 groups (4-6 animals in each group). Three days after animal modeling, dogs in each group received the corresponding drugs by gavage once a day for 6 weeks. All operations were performed in 6 batches for the experiment, with 4-5 animals in each batch and 0 - 1 animal in each group. Information about each group is shown in Table 1: Qnfrenn / zznz / E / YiAi Table 1, group no. Group Number of animals Dose administered Frequency of administration Duration 1 Reference surgical group 4 orally every day 3 d after modeling for 6 weeks 2 Model 5 orally every day 3 d after modeling for 6 weeks 3 Drug positive (LCZ696 ) 6 100 mg / kg orally every day 3 d after shaping for 6 weeks 4 EXP3174 + sacubitril calcium salt physical mixture 6 EXP3174 52 mpk+ Sacubitril 48 mpk orally every day 3 d after shaping for 6 weeks 5 Complex of the invention 6 100 mg / kg orally every day 3 days after modeling for 6 weeks Note: All doses are administered based on anhydrous free acid and the compound obtained in Example 3 is used as the complex of the invention. 4.4 Experimental results: An important manifestation of chronic heart failure is the reduction of left ventricular systolic function, which is the primary endpoint for clinical detection of chronic heart failure. Echocardiography showed that left ventricular ejection fraction (LVEF) was significantly reduced (<40%) in dogs in the model group after modeling, with a P value less than 0.001 compared to the reference surgical group, which could better simulate chronic heart failure with reduced clinical ejection fraction. Table 2 showed that the criterion of Qnfrenn / zznz / E / YiAi LVEF assessment of the dogs was 46.45% in the LCZ696 group, which was significantly higher than that in the model group (P < 0.001). The LVEF could be increased by both the inventive complex and the physical mixture, which was statistically significant compared with that of the model group (P < 0.001). Furthermore, the 100 mpk (mg / kg) of the complex of the invention and the equimolar dose of LCZ696 had better effects on LVEF. The details are shown in the table below: Table 2 Effects of compounds on the endpoint of left ventricular ejection fraction in dogs with heart failure (Mean±SD) Qnfrrnn / zznz / E / YiAi Group Number LVEF (%) Reference surgical group 4 66.20 + 2.83 Model 5 35.82 ± 2.02### LCZ696, 100 mpk 6 46.45 + 3.39*** EXP3174 + physical mixture of sacubitril calcium salt 6 46.34 + 2.59*** Complex of the invention, 100 mpk 6 51.87 + L01***@$ Among them, the model LVEF is 35.82% (< 40%), indicating that the ejection fraction is reduced and the modeling is successful, as shown in Figure 1. ###P < 0.001, compared with the reference surgical group; *P < 0.05, **P < 0.01, ***P < 0.001, compared with the model group;@P < 0.05, compared with the physical mixture;$P < 0.05, compared with the surgical reference group LCZ696. Note: The compound obtained in Example 3 is used as the complex of the invention. It can be seen from the above results that the supramolecular complexes with double effects provided by the invention are used as a medicine for heart failure with reduced ejection fraction, which have a significantly better effect at the same dose than 100 mpk of LCZ696 100 mpk ; The complex of the invention has a better effect than the physical mixture of EXP3174 + AHU377, which fully demonstrates that the use of the complex has significant advantages over the use of a physical combination of drugs. Example 5 A Pharmacodynamic Study on the Complex in the Canine Model of Chronic Heart Failure, Preserved Ejection Fraction 5.1 Methods: Once the animals arrived at the facility, they were subjected to adaptive feeding and were randomly assigned after echocardiography and ECG, and then the experiment was started. On the day of the operation, the animals were anesthetized by intramuscular injection of Zoletil (5 mg / kg). The tracheas of the anesthetized dogs were connected to the ventilator, then they were fixed in the supine position, the chest was opened between the third and fourth ribs, the left anterior descending coronary artery was ligated to close the thoracic cavity, and then sutured. the skin. After the animals recovered for 3 days postoperatively, they were administered drugs by gavage once a day for two consecutive weeks. During the experiment, the animals' living conditions were observed every day and abnormal conditions were recorded. After 14 days of administration, echocardiography was performed. 5.2 Modeling: The day before the operation, the animals were fasted overnight. On the day of operation, animals were injected intramuscularly with Zoletil (dose: 5 mg / kg) to induce anesthesia, and they were also given intramuscular injection of atropine sulfate (dose: 0.5 mg / dog). . After the animals were anesthetized, the hair on the left hemithorax was shaved. Tracheal intubation was quickly performed to connect them to the ventilator to provide artificial respiration and provide 1.5% isoflurane gas to maintain the anesthesia state, and a monitor was also used to monitor blood oxygen saturation, heart rate, electrocardiogram, body temperature and respiratory rate, etc. After disinfecting the skin of the forelimbs with 70% alcohol, the cephalic veins were found for intravenous intubation and remained intravenously as administration access. Iodophor and 70% alcohol were used to sterilize the skin of the left hemithorax as an aseptic treatment. A sterile surgical gauze with holes was spread. A sterile scalpel was used to cut the skin along the fourth and fifth intercostal spaces, and after hemostasis, an electric scalpel was used to open the subcutaneous tissues layer by layer and muscle layers, and the bleeding was stopped in a timely manner. . The pleural membrane was carefully opened to expose the lung tissues, which avoided damage to the lung tissues; The surgical field of view was gradually expanded to 20–25 cm along the inferior border of the fourth rib, and an ex-thorax tensor was used to expand the surgical margin. Sterile gauze soaked in warm normal saline was used to push and Qnfrenn / zznz / E / YiAi protect lung tissues. Sterile gauze soaked in warm normal saline was used to push the left appendage to expose it between the left ventricle and left atrium, and a blunt right-angle clamp was used to separate the left anterior descending coronary artery. A silk thread no. 4 to pass through the artery, and avoid pulling on the artery during separation and threading. A silk thread was used to ligate the left anterior descending coronary artery. During ligation, the animals were closely observed for blood oxygen saturation, heart rate, electrocardiogram, body temperature, and respiratory rate. If an animal had abnormalities such as ventricular fibrillation, the operation would be stopped immediately and lidocaine injection (10 mg / kg) would be quickly administered through the cephalic veins for treatment. After it was confirmed that there was no bleeding in the thoracic cavity, the protective gauze was removed. A suture no. 7 to pass through the fourth and fifth ribs to suture the thoracic cavity. The manual compression method was used for lung recruitment. The tissue and skin were sutured layer by layer. After the operation, the animals were kept warm and appropriately replenished with physiological saline, and blood oxygen saturation, heart rate, electrocardiogram, body temperature and respiratory changes were closely observed; The gas anesthesia machine was turned off and tracheal intubation was removed until the animals completely recovered spontaneous breathing. After the operation, they were injected intramuscularly with an analgesic (meloxicam, 0.67 mg / kg) to relieve pain, and they were injected intramuscularly with ampicillin sodium 20 mg / kg to combat infection. 5.3 Groups and administration: Before grouping, echocardiography and ECG monitoring were performed on each dog. According to the expulsion fraction, the dogs were randomly assigned into 5 groups (5-6 animals in each group). Three days after animal modeling, dogs in each group received the corresponding drugs by gavage once a day for 2 weeks. All operations were carried out in 6 batches for the experiment, with 4-5 animals in each batch and 0-1 animal in each group. Information about each group is shown in Table 3: Qnfrenn / zznz / E / YiAi Table 3, group no. Group Number of animals Dose administered Frequency of administration Duration 1 Reference surgical group 5 orally every day 3 d after modeling for 2 weeks 2 Model 5 orally every day 3 d after modeling for 2 weeks 3 Drug positive (LCZ696 ) 6 100 mpk orally every day 3 d after modeling for 2 weeks 4 EXP3174 + sacubitril calcium salt physical mixture 6 EXP3174 52 mpk + sacubitril 48 mpk orally every day 3 d after modeling for 2 weeks 5 Complex of the invention 6 100 mpk orally every day 3 d after modeling for 2 weeks Note: All doses are administered based on anhydrous free acid and the compound obtained in Example 3 is used as the complex of the invention. 5.4 Experimental results: An important manifestation of chronic heart failure is the reduction of left ventricular systolic function, which is the primary endpoint for clinical detection of chronic heart failure. Echocardiography showed that the left ventricular ejection fraction (LVEF) was significantly reduced, but even more than 50%, in the dogs in the model group after modeling, with a P value less than 0.001 compared with the surgical group. reference, which could better simulate chronic heart failure with preserved clinical ejection fraction. Table 4 showed Qnfrenn / zznz / E / YiAi that the LVEF endpoint of the dogs was 57.98% in the LCZ696 group, which was significantly higher than that in the model group (P < 0.001). The LVEF could be increased by both the inventive complex and the physical mixture, which was statistically significant compared with that of the model group (P < 0.05). Furthermore, the 100 mg / kg of the complex of the invention and the equimolar dose of LCZ696 had better effects on LVEF and significantly better effects than those in the physical mixture group. The experimental results are shown in Table 4. Table 4 Effects of compounds on the endpoint of left ventricular ejection fraction in dogs with heart failure Qnfrenn / zznz / E / YiAi (Mean + SD) Group Number LVEF(%) Reference surgical group 4 68.15 + 1.89 Model 5 51.80 ± 0.80### LCZ696, 100 mpk 6 57.98 ± 2.64*** EXP3174 + physical salt mixture 6 55.18 + 2.96* sacubitril calcium Complex invention, 100 mpk 6 58.04 ± 1.29***@ Among them, the model LVEF is 51.80% (>50%), indicating that the ejection fraction is preserved and the modeling is successful, as shown in Figure 1. ### P < 0.001, compared with the reference surgical group; *P < 0.05, **P < 0.01, ***P < 0.001, compared with the model group; @P < 0.05, compared with the physical mixture Note: The compound obtained in Example 3 is used as the complex of the invention. The above results show that the complex of the invention in a canine model with reduced ejection fraction has a better effect than that in a canine model with preserved ejection fraction. It can be seen that the pharmaceutical composition of the invention has a specific selectivity for heart failure with reduced ejection fraction, which is difficult to predict based on the state of the art. The above-mentioned examples are preferred embodiments of the invention, but the embodiments of the invention are not limited by the above-mentioned embodiments. Any other changes, modifications, substitutions, combinations and simplifications made without departing from the spirit and principle of the invention shall be equivalent methods of substitution and shall be within the scope of the invention.

Claims

1. The use of a complex of an angiotensin II receptor antagonist metabolite and a NEP inhibitor in the preparation of a medicament for use in heart failure with reduced ejection fraction, wherein the complex has the following structural units: (aEXP3174· bAHU377)· x Ca· nA where a:b = 1 : 0.25 - 4; x is a value between 0.5 and 3; A refers to water, methanol, ethanol, 2-propanol, acetone, ethyl acetate, methyl ethyl butyl ether, acetonylryl, toluene and dichloromethane; and n is a value between 0 and 3.

2. The use of the drug according to claim 1, characterized in that a single-dose form of the drug contains from 60 mg to 500 mg of the complex.

3. The use of the drug according to claim 1, characterized in that a single-dose form of the drug contains 60, 120, 180, 240, 300, 360, 420 and 480 mg of the complex.

4. The use of the drug according to claim 1, characterized in that the drug is a solid preparation for oral administration, preferably an oral tablet or capsule.

5. The use of the drug according to any one of claims 1 to 4, characterized in that 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 and 1:

4. Qnfrrnn / zznz / E / YiAi 6. The use of the drug according to any one of claims 1 to 5, characterized in that the complex has the following structural units: (EXP3174 AHU377) x Ca nH2O or where x is a value between 0.5 and 2; yn is a value between 0 and 3. Qnfrenn / zznz / E / YiAi 7. The use of the drug according to any one of claims 1 to 6, characterized in that x is selected from 0.5, 1, 1.5 and 2.

8. The use of the drug according to any one of claims 1 to 7, characterized in that the complex has the following structural units: (EXP3174»AHU377) · 1.5Ca«nH2O or (EXP3174*AHU377) · 2Ca«nH2O where n is any value between 1 and 3.

9. The use of the drug according to any one of claims 1 to 8, characterized in that n is selected from 0.5, 1, 1.5, 2, 2.5 and 3.

10. The use of the drug according to any one of claims 1 to 9, characterized in that the complex is selected from: (EXP3174 · AHU377) · 1 5Ca · 1H2O; (EXP3174 · AHU377) · 1 5Ca · 1 5H2O (EXP3174 · AHU377) · 1 5Ca · 2H2O; (EXP3174 · AHU377) · 1 5Ca · 2 5H2O (EXP3174 · AHU377 ) · 1 5Ca · 3H2O; (EXP3174 AHU377) 2Ca 1H2O: (EXP3174 AHU377) 2Ca 1.5H2O; (EXP3174 AHU377) 2Ca 2H2O: (EXP3174 AHU377) 2Ca 2.5H2O; (EXP3174 AHU377) 2Ca 3H2Oo