CN115443272A - Heart failure application of compound of angiotensin II receptor antagonist metabolite and NEP inhibitor - Google Patents
Heart failure application of compound of angiotensin II receptor antagonist metabolite and NEP inhibitor Download PDFInfo
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- CN115443272A CN115443272A CN202180030807.8A CN202180030807A CN115443272A CN 115443272 A CN115443272 A CN 115443272A CN 202180030807 A CN202180030807 A CN 202180030807A CN 115443272 A CN115443272 A CN 115443272A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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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
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- 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
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- 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
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- 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
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- 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
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- Chemical Kinetics & Catalysis (AREA)
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- Heart & Thoracic Surgery (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- General Chemical & Material Sciences (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract
The application of the compound of angiotensin II receptor antagonist metabolite and NEP inhibitor in preparing heart failure (HFmrEF) for intermediate value of ejection fraction is disclosed.
Description
The invention belongs to the technical field of medicine application, and relates to a heart failure application of a compound of an angiotensin II receptor antagonist metabolite and a NEP inhibitor, in particular to a use of the compound in preparing a medicine for heart failure with an intermediate value of an ejection fraction.
Heart failure is a severe manifestation or late stage of various heart diseases, with high mortality and readmission rates. The prevalence rate of heart failure in developed countries is 1.5-2.0%, and the prevalence rate of people aged more than or equal to 70 years old is more than or equal to 10%. Epidemiological survey in 2003 shows that the heart failure prevalence rate of adults 35-74 years old in China is 0.9%. The aging of the population of China is aggravated, the incidence of chronic diseases such as coronary heart disease, hypertension, diabetes, obesity and the like is on the rise, and the improvement of the medical level prolongs the life cycle of heart disease patients, so that the heart failure morbidity of China is on the continuous rise. The domestic 10714 inpatient heart failure patients were investigated to show that: 1980. the fatality rates during hospitalization of heart failure patients in 1990 and 2000 were 15.4%, 12.3% and 6.2%, respectively, with the main causes of death being left heart failure (59%), arrhythmia (13%) and sudden cardiac death (13%). The China-HF study showed that the mortality rate of hospitalized heart failure patients was 4.1%.
WO2007056546A1 discloses a sodium salt complex (LCZ 696) of Valsartan (Valsartan) -savonil (Sacubitril) and a preparation method thereof, which was approved and marketed in china in 2017 under the trade name: nuoxin pill
Can be used for treating heart failure. The molecular structural unit is as follows:
in addition, WO2017125031A1 discloses a series of complexes of angiotensin receptor antagonist metabolites (EXP 3174) and NEP inhibitors (secubitril) and showing certain effects on heart failure HFpEF with preserved ejection fraction, the molecular structural units of which are as follows:
it is known that it is important to find a targeted drug with good therapeutic effect on heart failure with median ejection fraction.
Disclosure of Invention
In view of the technical problems of the prior art, the present invention provides the use of a complex (alternatively referred to as "supramolecular complex") of a metabolite of an angiotensin II receptor antagonist and a NEP inhibitor for the preparation of a medicament for the treatment of heart failure, i.e. heart failure with an intermediate value of the ejection fraction, the structural units of said complex being as follows:
(aEXP3174·bAHU377)·xCa·nA
the structural formulas of EXP3174 and AHU377 are respectively as follows:
a: b = 1; x is a number between 0.5 and 3; a refers to water, methanol, ethanol, 2-propanol, acetone, ethyl acetate, methyl-tert-butyl ether, acetonitrile, toluene, dichloromethane; n is a number between 0 and 3.
Specifically, the heart failure of the mean ejection fraction refers to HFmrEF defined in chinese guidelines for diagnosis and treatment of heart failure 2018-classification and diagnosis criteria for heart failure table 1.
As a preferred technical scheme of the invention, the medicament is applied to a patient suffering from heart failure with the intermediate value of the ejection fraction; according to the experimental results and the calculation of the amount of prodrug used, the single dosage form of the drug refers to a drug containing between 60mg and 500mg of the compound based on the total mass of (aEXP 3174. BAHU 377), 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, 470mg, 480mg, 490mg, 500mg.
As a more preferred embodiment of the invention, the single dosage form of the medicament comprises 60, 120, 180, 240, 300, 360, 420, 480mg of the complex.
In one embodiment, a single dosage form refers to a daily dosage form, and the patient is administered a dose containing from 60 mg/day to 500 mg/day of the complex, including, but not limited to, 1 time a day, 1, 2 times a day, 3 times a day, 4 times a day, etc. The dosage refers to the initial dosage or maintenance dosage of the drug application, and in the application of hypertension, the initial dosage is generally lower than the maintenance dosage. The dosage is aimed at the patients with difficult hypertension in special cases, and the dosage can be properly increased.
Specifically, the calculation method comprises that EXP3174 is an in vivo metabolite of the allisartan isoproxil calculated according to the daily dose of the prodrug, and the general name of the marketed drug is as follows: allisartan isoproxil tablets, english name: allisartan Isoproxil Tablets, trade name: xinritan is used at a dosage of 240mg per day.
Wherein the molecular formula of the allisartan isoproxil is C 27 H 29 ClN 6 O 5 Molecular weight 553.0; and EXP3174 has the formula C 22 H 21 ClN 6 O 2 A molecular weight of about 436.9; AHU377 has a molecular formula of C 24 H 29 NO 5 The molecular weight is about 411.5, and the daily amount of the complex should be equivalent to the daily amount of the allisartan isoproxil used, so that the single dose form of the complex described above is estimated.
The effective dose of the human body is presumed to be 100 mg/day and the dose application range is 100 mg/day-500 mg/day according to the canine heart failure model data of the intermediate ejection fraction value.
The medicament is a solid preparation suitable for oral administration, preferably an oral tablet or capsule, and can be the compound with the total amount of the medicaments of a plurality of tablets and a plurality of capsules being between 100mg and 500mg.
Said complexes of said drugs can be obtained by methods known in the art, wherein the complexes disclosed in WO2017125031A1 and the preparation method thereof are incorporated in the present invention.
As a more preferred embodiment of the present invention, the value of a.
In a more preferred embodiment of the present invention, the structural units of the complex are as follows:
(EXP3174·AHU377)·xCa·nH 2 O
or alternatively
Wherein x is a number between 0.5 and 2; n is a number between 0 and 3.
In a more preferred embodiment of the present invention, x is selected from 0.5,1, 1.5 and 2.
In a more preferred embodiment of the present invention, the structural units of the complex are as follows:
(EXP3174·AHU377)·1.5Ca·nH 2 O
or alternatively
(EXP3174·AHU377)·2Ca·nH 2 O
Wherein n is any number between 1 and 3.
In a more preferred embodiment of the present invention, n is selected from 0.5,1, 1.5, 2, 2.5 and 3.
As a more preferred embodiment of the present invention, the complex is selected from the group consisting of:
(EXP3174·AHU377)·1.5Ca·1H 2 O；
(EXP3174·AHU377)·1.5Ca·1.5H 2 O；
(EXP3174·AHU377)·1.5Ca·2H 2 O；
(EXP3174·AHU377)·1.5Ca·2.5H 2 O；
(EXP3174·AHU377)·1.5Ca·3H 2 O；
(EXP3174·AHU377)·2Ca·1H 2 O；
(EXP3174·AHU377)·2Ca·1.5H 2 O；
(EXP3174·AHU377)·2Ca·2H 2 O；
(EXP3174·AHU377)·2Ca·2.5H 2 O；
(EXP3174·AHU377)·2Ca·3H 2 O。
it will be understood by those skilled in the art that in the unit cell of the supramolecular complex (complex) the metabolite of alisartan ester (EXP 3174), AHU377, calcium ion (Ca) 2+ ) And solvent molecules will fill in it in the form of several building blocks.
The supramolecular complex (complex) of the present invention is distinguished from a mixture of two active ingredients obtained by simple physical mixing. The XRD spectrum of the obtained supramolecular complex (compound) is obviously different from the XRD spectrum of EXP3174 and AHU377 calcium salt, the solubility of the supramolecular complex (compound) in various solvents (such as water, ethanol-water and the like) is also obviously different, and other physicochemical properties such as hygroscopicity, a melting point, an infrared spectrum and the like are obviously different.
Compared with the prior art, the invention has the following advantages and beneficial effects:
1. the invention provides a series of pharmaceutical uses of supramolecular complex (compound) with dual functions of alisartan medoxomil metabolite (EXP 3174) and enkephalinase inhibitor (AHU 377) for heart failure with intermediate ejection fraction, and the supramolecular complex has obviously better effect compared with LCZ696 under the same dosage;
2. the effect of the compound in the intermediate value of the ejection fraction in the canine model is better than that in the intermediate value of the ejection fraction retention canine model, so that the pharmaceutical composition has specific selectivity on the heart failure of the intermediate value of the ejection fraction, and is difficult to predict according to the prior art.
3. Compared with the physical mixture of EXP3174 and AHU377, the compound of the invention has better effect, which fully shows that the use of the compound has obvious advantages compared with the use of the pharmaceutical physical combination.
FIG. 1, chinese guidelines for diagnosis and treatment of heart failure 2018, a Classification and diagnostic criteria Table for heart failure.
The present invention will be described in further detail with reference to examples and drawings, but the embodiments of the invention are not limited thereto.
In the following examples:
the X-ray powder diffraction is detected by adopting an X-ray diffractometer with sharp shadow (Empyrean), and the detection conditions are as follows: cu target Kalpha ray, voltage 40KV, current 40mA, emission slit 1/32 degrees, anti-scattering slit 1/16 degrees, anti-scattering slit 7.5mm,2 theta range: 3-60 degrees, step length 0.02 degrees and residence time of 40s in each step.
The DSC204F1 differential scanning calorimeter of the Germany NETZSCH company is adopted as a spectrogramEquipment detection, detection conditions: atmosphere: n is a radical of hydrogen 2 20mL/min; and (3) scanning procedure: the temperature was raised from room temperature to 250 ℃ at 10 ℃/min and the temperature rise profile was recorded.
The moisture content is detected by adopting a TG209 thermogravimetric analyzer device of Germany NETZSCH company, and the detection conditions are as follows: atmosphere: n is a radical of hydrogen 2 20mL/min; and (3) scanning procedure: room temperature-700 ℃, heating rate: 10 ℃/min.
The EXP3174 used in the examples was made by the company, with a purity of 98.3%.
The calcium salt of AHU377 used in the examples was made by the company as pure as 99.4%.
Example 1
Preparation of AHU377 free acid:
2.1g of AHU377 calcium salt, 40mL of isopropyl acetate, was added to a 250mL one-neck flask, and 4.5mL of 2mol/L hydrochloric acid was added thereto at room temperature and the mixture was stirred to dissolve. Separating, collecting an organic layer, and washing the organic layer twice by using 20mL of water; decompression desolventizing at 35 ℃ to obtain AHU377 free acid.
Example 2
Preparation of the complex: (prepared according to example 2 of patent WO2017125031A 1)
Adding 2.36g of AHU377 free acid obtained according to the method of example 1, 2g of EXP3174 and 40mL of acetone into a 250mL three-neck bottle at room temperature, and dissolving; adding 1.3 equivalents of calcium hydroxide solid and 1mL of water relative to AHU377 at room temperature, stirring at room temperature for 10h, adding 40mL of acetone, reacting for 8h, filtering with a Buchner funnel under nitrogen protection, leaching the solid with acetone to obtain white solid, vacuum drying at 35 deg.C for 8h, and oven drying to obtain solid 3.5g (EXP 3174. AHU 377) 3- ·1.5Ca 2+ ·2.5H 2 And O, the purity is 99 percent by HPLC detection. The test is repeated to obtain sufficient dose for pharmacodynamic experiments.
Example 3
Preparation of the complex: (prepared according to example 3 of patent WO2017125031A 1)
Adding 2.36g of AHU377 free acid obtained according to the method of example 1, 2g of EXP3174 and 40mL of acetone into a 250mL three-neck bottle at room temperature, and dissolving; adding 1.6 equivalent of calcium hydroxide solid and 0.6mL of water relative to AHU377 at room temperature, stirring for 6h at 35 ℃, adding 40mL of acetone, reacting for 8h, performing suction filtration by a Buchner funnel under the protection of nitrogen, leaching the solid by acetone to obtain white solid, drying for 8h in vacuum at 50 ℃ and drying to obtain 3.1g of solid (EXP 3174. AHU 377) 3- ·1.5Ca 2+ ·2H 2 And O. The test was repeated to obtain sufficient dose for the pharmacodynamic test.
Example 4
Pharmacodynamic study of compound in dog chronic heart failure model-ejection fraction median
4.1, method:
after the animals arrive at the facility, the animals are fed adaptively, grouped randomly after echocardiography examination and electrocardio examination, and then the test is started. On the day of operation, animals were anesthetized by intramuscular injection of Shutai (5 mg/kg), dogs were anesthetized with a tracheal tube respirator, fixed in the supine position, thoracotomy was performed between the third and fourth ribs, the left anterior descending coronary artery was ligated to close the thoracic cavity, and the skin was sutured. After 3 days of post-operative recovery of the animals, the treatment was gavaged once a day for 4 consecutive weeks. During the experiment, the living state of the animals is observed every day, and abnormal conditions are recorded. 4 weeks after administration, echocardiography was performed.
4.2, molding:
the day before surgery, animals will be fasted overnight. On the day of surgery, animals are injected intramuscularly with muscle shutita (dosage: 5 mg/kg) to induce anesthesia; and simultaneously, atropine sulfate injection (dosage: 0.5 mg/dog) is injected intramuscularly. After the animal is anesthetized, the left chest hair is shaved; the endotracheal intubation is performed rapidly, the ventilator is switched on to provide artificial respiration and 1.5% isoflurane gas to maintain the anesthetic state, while the monitor is used to monitor the blood oxygen saturation, heart rate, electrocardiogram, body temperature, respiratory rate, etc. After the forelimb skin was disinfected with 70% alcohol, the cephalic vein was found, and the vein was cannulated and the intravenous route was left. Sterilizing and disinfecting the left chest skin by using iodophor and 70% alcohol; laying a sterile operation hole towel; the skin is incised along the fourth and fifth intercostals with a sterile scalpel, the subcutaneous tissue and the muscle layer are incised layer by layer with an electrotome after hemostasis, and hemostasis is timely performed. The pleural membranes are carefully opened to expose the lung tissue, avoiding damage to the lung tissue; the operative field is gradually enlarged to 20-25cm along the lower edge of the fourth rib, and the operative window is enlarged by using a chest expander. Sterile gauze saturated with warm saline is used to push and protect lung tissue. The left atrial appendage was removed using sterile gauze soaked with warm saline, carefully exposed between the left ventricle and left atrium and the coronary artery left anterior descending was freed using blunt forceps at right angles, and the artery was threaded with a number 4 wire to avoid lifting the artery during the freeing and threading process. Ligating the left anterior descending branch of the coronary artery by using silk threads, and closely observing the blood oxygen saturation, heart rate, electrocardiogram, body temperature and respiration of an animal in the ligation process; if the animals have abnormal conditions such as ventricular fibrillation, the operation is stopped immediately and lidocaine is given quickly through the cephalic vein for injection treatment (10 mg/kg). After determining that no bleeding exists in the thoracic cavity, taking out protective gauze, and suturing the thoracic cavity through the fourth rib and the fifth rib by using a No. 7 suture; the lung was re-expanded using an artificial compression method. The tissue and skin are sutured layer by layer. Keeping the temperature of the animals after the operation, and properly supplementing normal saline; closely observing the blood oxygen saturation, the heart rate, the electrocardiogram, the body temperature and the respiratory variation; and closing the gas anesthesia machine until the trachea cannula is pulled out after the animal completely recovers the spontaneous respiration. Postoperative intramuscular injection of buprenorphine (meloxicam, 0.67 mg/kg) for analgesia, intramuscular injection of ampicillin sodium, 20mg/kg for anti-infection.
4.3 grouping and administration:
before grouping, each dog is subjected to echocardiography examination and electrocardio monitoring, the dogs are randomly divided into 5 groups (5-6 animals in each group) according to ejection fraction, and after 3d after animal modeling, each group of dogs are subjected to intragastric administration of corresponding drugs once a day for 4 weeks. All procedures were performed in 6 batches of 4-5 animals each, 0-1 each. The following table 1 shows the respective cases:
all doses were calculated as anhydrous free acid.
4.4 results of the study:
the important manifestation of chronic heart failure is that the contraction function of the left ventricle is reduced, and the chronic heart failure is the clinical main detection endpoint. The echocardiography examination shows that the Left Ventricular Ejection Fraction (LVEF) of the model group dog is remarkably reduced to 46.84 percent after model building, and compared with a sham operation group, P is less than 0.001, so that the model group can better simulate the chronic heart failure of the median value of the clinical ejection fraction of a human body. As can be seen from Table 2, the end points LVEF of the inventive complexes, LCZ696 and mixed physical group dogs were 59.88%, 57.01% and 55.75%, respectively, which were significantly higher than those of the model group (P <0.001, P < -0.001 and P < -0.001). At the same time, the 100mpk intermediate rise in ejection fraction of the complexes of the invention was significantly better than the equal mass dose of the LCZ696 group and the equal molar dose of the physically mixed group (P < 0.05.
TABLE 2 Effect of Compounds on endpoint left ventricular ejection fraction of Heart failure dogs (Mean SD)
###P<0.001, compared to Sham group; * P<0.001, compared to Model group; $ P<0.05, compared to LCZ696 group; @@ P<0.01, compared to the physical mixed group.
Note: the compound obtained in example 3 was used for the compound of the present invention.
From the above results, it can be seen that the dual-acting supramolecular complexes (complexes) provided by the present invention have significantly better effects for the pharmaceutical use of heart failure with intermediate ejection fraction compared to the use of LCZ696 mpk at the same dose;
compared with the physical mixture of EXP3174 and AHU377, the compound of the invention has better effect, which fully shows that the use of the compound has obvious advantages compared with the use of the pharmaceutical physical combination.
Example 5
Pharmacodynamic study of compound on canine chronic heart failure model-ejection fraction retention
5.1, method:
after the animals arrive at the facility, the animals are fed adaptively, grouped randomly after echocardiography examination and electrocardio examination, and then the test is started. On the day of operation, animals were anesthetized by intramuscular injection of Shutai (5 mg/kg), dogs were anesthetized with a tracheal tube respirator, fixed in the supine position, thoracotomy was performed between the third and fourth ribs, the left anterior descending coronary artery was ligated to close the thoracic cavity, and the skin was sutured. After 3 days of post-operative recovery of the animals, the therapeutic agents were administered by gavage once a day for 2 weeks. During the experiment, the living state of the animals is observed every day, and abnormal conditions are recorded. Echocardiography examination was performed 14 days after dosing.
5.2, molding:
the day before surgery, animals will be fasted overnight. On the day of surgery, animals are injected intramuscularly with suutai (dose: 5 mg/kg) to induce anesthesia; and simultaneously, atropine sulfate injection (dosage: 0.5 mg/dog) is injected intramuscularly. After the animal is anesthetized, the left chest hair is shaved; the endotracheal intubation is performed rapidly, the ventilator is switched on to provide artificial respiration and 1.5% isoflurane gas to maintain the anesthetic state, while the monitor is used to monitor the blood oxygen saturation, heart rate, electrocardiogram, body temperature, respiratory rate, etc. After the forelimb skin was sterilized with 70% alcohol, the cephalic vein was found, the vein was cannulated and the intravenous route was left. Sterilizing and disinfecting the skin of the left chest by using iodophor and 70% alcohol; laying a sterile operation hole towel; the skin is incised along the fourth and fifth intercostals with a sterile scalpel, the subcutaneous tissue and the muscle layer are incised layer by layer with an electrotome after hemostasis, and hemostasis is timely performed. Carefully open the pleural membranes to expose the lung tissue, avoiding damage to the lung tissue; the operative field is gradually enlarged to 20-25cm along the lower edge of the fourth rib, and the operative window is enlarged by using a chest expander. Sterile gauze saturated with warm saline is used to push and protect lung tissue. The left atrial appendage was removed using sterile gauze soaked with warm saline, carefully exposed between the left ventricle and left atrium and the coronary artery left anterior descending was freed using blunt forceps at right angles, and the artery was threaded with a number 4 wire to avoid lifting the artery during the freeing and threading process. Ligating the left anterior descending branch of the coronary artery by using silk threads, and closely observing the blood oxygen saturation, the heart rate, the electrocardiogram, the body temperature and the respiration of an animal in the ligation process; if the animals have abnormal conditions such as ventricular fibrillation, the operation is immediately stopped and lidocaine is rapidly injected and treated through the cephalic vein (10 mg/kg). After determining that no bleeding exists in the thoracic cavity, taking out protective gauze, and suturing the thoracic cavity through the fourth rib and the fifth rib by using a No. 7 suture; the lung was re-expanded using an artificial compression method. The tissue and skin are sutured layer by layer. Keeping the temperature of the animals after the operation, and properly supplementing normal saline; closely observing the blood oxygen saturation, the heart rate, the electrocardiogram, the body temperature and the respiratory variation; and closing the gas anesthesia machine until the trachea cannula is pulled out after the animal completely recovers the spontaneous respiration. Postoperative injection of buprenorphine (meloxicam, 0.67 mg/kg) into muscle can relieve pain, and injection of ampicillin sodium 20mg/kg can resist infection.
5.3 grouping and administration:
before grouping, performing echocardiography examination and electrocardio monitoring on each dog, randomly dividing the dogs into 5 groups (5-6 animals in each group) according to ejection fraction, and performing intragastric administration on each group of dogs 3d after animal modeling for 2 weeks once a day after the dogs take corresponding drugs. All procedures were performed in 6 batches of 4-5 animals each, 0-1 each. The following table 3 is shown for each group:
note: all doses administered are in terms of anhydrous free acid, and the compound obtained in example 3 is used in the complexes of the invention.
5.4 Experimental results:
the important manifestation of chronic heart failure is that the contraction function of the left ventricle is reduced, and the chronic heart failure is the clinical main detection endpoint. The echocardiography examination shows that the Left Ventricular Ejection Fraction (LVEF) of the model group dog is obviously reduced after model building but still more than 50 percent, and compared with a sham operation group, P is less than 0.001, so that the chronic heart failure reserved by the clinical ejection fraction of a human body can be well simulated. As can be seen from table 4, the LCZ696 group canine endpoint LVEF was 57.98%, significantly higher than the model group (P < 0.001). Both the compound and the physical mixed group can increase the LVEF, and have statistical significance (P is less than 0.05) compared with a model group. Meanwhile, the 100mpk compound of the invention has equivalent efficacy compared with the LVEF effect of the LCZ696 equimolar dose group and is obviously superior to the physical mixed group. The results of the experiment are shown in table 4:
TABLE 4 Effect of Compounds on Heart failure dog endpoint left ventricular ejection fraction (Mean SD)
Wherein the Model LVEF is 51.80% and is more than or equal to 50%, which indicates that the ejection fraction retention modeling is successful, and is shown in figure 1.
###P<0.001, compared to Sham group; * P<0.05，**P<0.01，***P<0.001, compared to the Model group; @ P<0.05, compared to the physically mixed group
Note: the compound obtained in example 3 was used for the compound of the present invention.
From the above results, it can be seen that the effect of the complex of the present invention in the intermediate value of the ejection fraction canine model is superior to that in the ejection fraction retention canine model, and thus it can be seen that the pharmaceutical composition of the present invention has a specific selectivity for heart failure of the intermediate value of the ejection fraction, which is difficult to predict according to the prior art.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
- Use of a complex of a metabolite of an angiotensin II receptor antagonist and a NEP inhibitor for the manufacture of a medicament for the treatment of heart failure, said heart failure being heart failure with an intermediate injected blood fraction, said complex having the structural unit:(aEXP3174·bAHU377)·xCa·nAwherein, the structural formulas of EXP3174 and AHU377 are respectively as follows:
a: b = 1; x is a number between 0.5 and 3; a refers to water, methanol, ethanol, 2-propanol, acetone, ethyl acetate, methyl-tert-butyl ether, acetonitrile, toluene, dichloromethane; n is a number between 0 and 3. - The use of claim 1 for heart failure, wherein: a single dose form of the medicament contains between 60mg and 500mg of the complex.
- The use of claim 1 for heart failure, wherein: single dose forms of the medicament contain 60, 120, 180, 240, 300, 360, 420, 480 milligrams of the complex.
- The use of claim 1 for heart failure, wherein: the medicament is a solid formulation suitable for oral administration, preferably a tablet or capsule for oral administration.
- The use of any one of claims 1-4 for heart failure, wherein: the value of a to b is selected from 1.25,1.
- The use of any one of claims 1-5 for heart failure, wherein: the structural units of the complex are as follows:(EXP3174·AHU377)·xCa·nH 2 Oor alternatively
Wherein x is a number between 0.5 and 2; n is a number between 0 and 3. - The use of any one of claims 1-6 for heart failure, wherein: x is selected from 0.5,1, 1.5 and 2.
- The use of any one of claims 1-7 for heart failure, wherein: the structural units of the complex are as follows:(EXP3174·AHU377)·1.5Ca·nH 2 Oor alternatively(EXP3174·AHU377)·2Ca·nH 2 OWherein n is any value between 1 and 3.
- The use of heart failure as claimed in any one of claims 1 to 8, wherein: n is selected from 0.5,1, 1.5, 2, 2.5, 3.
- The use of any one of claims 1 to 9, wherein the complex is selected from the group consisting of:(EXP3174·AHU377)·1.5Ca·1H 2 O；(EXP3174·AHU377)·1.5Ca·1.5H 2 O；(EXP3174·AHU377)·1.5Ca·2H 2 O；(EXP3174·AHU377)·1.5Ca·2.5H 2 O；(EXP3174·AHU377)·1.5Ca·3H 2 O；(EXP3174·AHU377)·2Ca·1H 2 O；(EXP3174·AHU377)·2Ca·1.5H 2 O；(EXP3174·AHU377)·2Ca·2H 2 O；(EXP3174·AHU377)·2Ca·2.5H 2 O；(EXP3174·AHU377)·2Ca·3H 2 O。
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| CN115487175B (en) * | 2019-09-20 | 2024-05-14 | 深圳信立泰药业股份有限公司 | Use of complexes of metabolites of angiotensin II receptor antagonists and NEP inhibitors for the treatment of heart failure |
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| TW202228677A (en) | 2022-08-01 |
| CN115443272B (en) | 2023-11-17 |
| WO2022037512A1 (en) | 2022-02-24 |
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