CN115443272B - Heart failure application of complex of angiotensin II receptor antagonist metabolite and NEP inhibitor - Google Patents

Heart failure application of complex of angiotensin II receptor antagonist metabolite and NEP inhibitor Download PDF

Info

Publication number
CN115443272B
CN115443272B CN202180030807.8A CN202180030807A CN115443272B CN 115443272 B CN115443272 B CN 115443272B CN 202180030807 A CN202180030807 A CN 202180030807A CN 115443272 B CN115443272 B CN 115443272B
Authority
CN
China
Prior art keywords
heart failure
complex
angiotensin
receptor antagonist
ejection fraction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202180030807.8A
Other languages
Chinese (zh)
Other versions
CN115443272A (en
Inventor
孙晶超
景小龙
肖瑛
谢恒�
陈涛
陆银锁
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenzhen Salubris Pharmaceuticals Co Ltd
Original Assignee
Shenzhen Salubris Pharmaceuticals Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shenzhen Salubris Pharmaceuticals Co Ltd filed Critical Shenzhen Salubris Pharmaceuticals Co Ltd
Publication of CN115443272A publication Critical patent/CN115443272A/en
Application granted granted Critical
Publication of CN115443272B publication Critical patent/CN115443272B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Emergency Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The use of complexes of angiotensin II receptor antagonist metabolites with NEP inhibitors for heart failure is disclosed, in particular to the use of said complexes for the preparation of heart failure (HFmrEF) for intermediate ejection fraction values.

Description

Heart failure application of complex of angiotensin II receptor antagonist metabolite and NEP inhibitor
Technical Field
The invention belongs to the technical field of medicine application, relates to heart failure application of a complex of an angiotensin II receptor antagonist metabolite and an NEP inhibitor, and in particular relates to application of the complex in preparing medicines for heart failure with intermediate ejection fraction values.
Background
Heart failure is a severe manifestation or advanced stage of various heart diseases, with mortality and readmission rates remaining high. The prevalence of heart failure in developed countries is 1.5% -2.0%, and the prevalence of people aged 70% or more is 10% or more. Epidemiological investigation in 2003 shows that the heart failure prevalence rate of 35-74 year old adults 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 in an ascending trend, and the life cycle of heart disease patients is prolonged due to the improvement of medical level, so that the prevalence of heart failure of China is in a continuous ascending trend. Investigation of 10714 hospitalized heart failure patients at home showed that: 1980. the mortality rates during hospitalization of heart failure patients in 1990 and 2000 were 15.4%, 12.3% and 6.2%, respectively, and the main causes of death were left heart failure (59%), arrhythmia (13%) and sudden cardiac death (13%). China-HF study showed that the death rate of hospitalized heart failure patients was 4.1%.
WO2007056546A1 discloses a sodium salt complex (LCZ 696) of Valsartan (Valsartan) -Sha Kupi koji (sacubiril) and a process for its preparation, commercially available in 2017 in china under the trade name:is used for treating heart failure. The molecular structural unit is as follows:
in addition, WO2017125031A1 discloses a series of complexes consisting of an angiotensin receptor antagonist metabolite (EXP 3174) and a NEP inhibitor (sacubiril) and exhibiting a certain effect 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 intermediate ejection fraction.
Disclosure of Invention
In view of the technical problems existing in the prior art, the present invention provides the use of a complex of an angiotensin II receptor antagonist metabolite and a NEP inhibitor (alternatively referred to as a "supramolecular complex") for the manufacture of a medicament for the treatment of heart failure, which is heart failure with an intermediate value of ejection fraction, the structural units of the complex being as follows:
(aEXP3174·bAHU377)·xCa·nA
wherein, EXP3174 and AHU377 have the following structural formulas:
a: b=1:0.25 to 4; 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 intermediate value of the ejection fraction refers to HFmrEF defined in classification and diagnosis criteria table 1 of China heart failure diagnosis and treatment guideline 2018-heart failure.
As a preferred embodiment of the present 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 application amount of the prodrug of the present invention, the single dosage form of the drug means that the compound contains between 60mg and 500mg, 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, based on the total mass of (aEXP 3174. BAHU 377).
As a more preferred embodiment of the present invention, the single dosage form of the drug contains 60, 120, 180, 240, 300, 360, 420, 480mg of the complex.
In one embodiment, a single dosage form refers to a daily dosage form that is administered to a patient containing 60 mg/day to 500 mg/day of the complex, including but not limited to 1 day 1,1 day 2,1 day 3,1 day 4, etc. The dose refers to the initial or maintenance dose for pharmaceutical applications, typically lower than the maintenance dose in applications of hypertension. The dosage is suitable for patients with refractory hypertension in special cases, and the dosage can be increased.
Specifically, the calculation method comprises the steps of calculating according to the daily dosage of a prodrug, wherein EXP3174 is an in-vivo metabolite of alisartan, and the general name of the marketed drug is as follows: alisartan cilexetil tablet, english name: allisartan Isoproxil Tablets, trade name: the dosage of the sulbactam is 240mg per day.
Wherein the molecular formula of the alisartan ester is C 27 H 29 ClN 6 O 5 Molecular weight is 553.0; and EXP3174 has the formula C 22 H 21 ClN 6 O 2 A molecular weight of about 436.9; AHU377 has molecular formula C 24 H 29 NO 5 The molecular weight was about 411.5, and the daily amount of the complex was equivalent to that of the alisartan ester, so that the single dose form of the complex was estimated.
The heart failure model data of dogs with intermediate ejection fraction is used for estimating the effective dose of a human body to be 100 mg/day, and the dosage application range is 100 mg/day to 500 mg/day.
The medicament is a solid preparation suitable for oral administration, preferably an oral tablet or capsule, and can be a plurality of tablets and a plurality of capsules, wherein the total amount of the medicament is between 100mg and 500mg of the compound.
Said complexes of said drugs can be obtained by methods known in the art, wherein the complexes disclosed in WO2017125031A1 and methods for their preparation are incorporated into the present invention.
As a more preferred embodiment of the invention, the value of a:b is selected from the group consisting of 1: 0.25,1:0.5, 1:1, 1:1.5, 1:2, 1: 2.5,1:3, 1: 3.5,1:4.
As 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.
As a more preferred embodiment of the present invention, x is selected from 0.5,1, 1.5, 2.
As 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.
As a more preferable embodiment of the present invention, n is selected from 0.5,1, 1.5, 2, 2.5, 3.
As a more preferred embodiment of the present invention, the complex is selected from:
(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。
those skilled in the art will appreciate that in the unit cell of the supramolecular complex (complex), the alisartan ester metabolite (EXP 3174), AHU377, calcium ion (Ca 2+ ) And solvent molecules will be filled therein in the form of several structural units.
The supramolecular complexes (complexes) according to the invention are distinguished from mixtures of two active ingredients obtained by simple physical mixing. The XRD spectra of the obtained supermolecular complex (compound) are obviously different from those of EXP3174 and AHU377 calcium salt, the solubility of the supermolecular complex (compound) in various solvents (such as water, ethanol-water and the like) is obviously different, and other physicochemical properties such as hygroscopicity, melting point, infrared spectra 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 drug uses of supermolecule complex (compound) with double functions of an alisartan ester metabolite (EXP 3174) and an enkephalinase inhibitor (AHU 377) for heart failure with an intermediate value of ejection fraction, and the supermolecule complex has obviously better effect than LCZ696 at the same dosage;
2. the effect of the compound in the canine model with the intermediate value of the ejection fraction is better than that in the canine model with the retained ejection fraction, so that the pharmaceutical composition has specific selectivity for heart failure with the intermediate value of the ejection fraction, which is difficult to predict according to the prior art.
3. The better effect of the complexes of the invention relative to the EXP3174+AHU377 physical mixture, fully demonstrates the significant advantages of the use of the complexes over the use of a physical combination of drugs.
Drawings
FIG. 1 is a table of classification and diagnosis criteria for heart failure, china guidelines for diagnosis and treatment of heart failure, 2018.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but embodiments of the invention are not limited thereto.
In the following examples:
x-ray powder diffraction was detected using a sharp (Empyrean) X-ray diffractometer apparatus, detection conditions: cu target K alpha rays, voltage 40KV, current 40mA, emission slit 1/32 DEG, anti-scattering slit 1/16 DEG, anti-scattering slit 7.5mm,2 theta range: 3-60 deg., step size of 0.02 deg., dwell time of 40s per step.
Differential scanning calorimeter spectra were measured using a DSC204F1 differential scanning calorimeter apparatus from NETZSCH, germany, under the following conditions: atmosphere: n (N) 2 20mL/min; scanning procedure: the temperature was raised from room temperature to 250℃at 10℃per minute, and the temperature rise curve was recorded.
The moisture content was measured using a TG209 thermogravimetric analyzer device from NETZSCH, germany, under the following conditions: atmosphere: n (N) 2 20mL/min; scanning procedure: room temperature-700 ℃, temperature rising rate: 10 ℃/min.
EXP3174 used in the examples was prepared by the company with a purity of 98.3%.
The AHU377 calcium salt used in the examples was made by the company and had a purity of 99.4%.
Example 1
Preparation of AHU377 free acid:
2.1g AHU377 calcium salt, 40mL isopropyl acetate were added to a 250mL single-necked flask, and 4.5mL stirring solution of 2mol/L hydrochloric acid was added at room temperature. Separating, collecting an organic layer, and washing the organic layer twice by using 20mL of water; decompression desolventizing at 35 deg.c to obtain AHU377 free acid.
Example 2
Preparation of the composite: (prepared according to example 2 of patent WO2017125031A 1)
AHU377 free acid 2.36g, EXP3174 g and 40mL acetone obtained in accordance with example 1 were added to a 250mL three-necked flask at room temperature and cleared; adding 1.3 equivalent 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 by a Buchner funnel under the protection of nitrogen, leaching the solid by acetone to obtain white solid, vacuum drying at 35 ℃ for 8h, and drying to obtain 3.5g of solid (EXP 3174. AHU 377) 3- ·1.5Ca 2+ ·2.5H 2 O, 99% purity by HPLC. The test was repeated to obtain a sufficient amount of the drug effect test.
Example 3
Preparation of the composite: (prepared according to example 3 of patent WO2017125031A 1)
AHU377 free acid 2.36g, EXP3174 g and 40mL acetone obtained in accordance with example 1 were added to a 250mL three-necked flask at room temperature and cleared; 1.6 equivalent of calcium hydroxide solid and 0.6mL of water relative to AHU377 are added at room temperature, stirring is carried out for 6 hours at 35 ℃, 40mL of acetone is added, the mixture is reacted for 8 hours again, suction filtration is carried out on the solid through a Buchner funnel under the protection of nitrogen, the solid is leached by acetone, white solid is obtained, vacuum drying is carried out for 8 hours at 50 ℃, and 3.1g of solid (EXP 3174. AHU 377) is obtained after drying 3- ·1.5Ca 2+ ·2H 2 O. The test was repeated to obtain a sufficient amount of the drug effect test.
Example 4
Drug effect research-ejection fraction intermediate value of compound in canine chronic heart failure model
4.1 method:
animals were fed adaptively after reaching the facility, randomly grouped after echocardiographic and electrocardiographic examination, and the trial was restarted. On the day of the operation, the animals are anesthetized by intramuscular injection of sultai (5 mg/kg), the anesthetic dog is connected with a respirator through a trachea, the upper position is fixed, the chest is opened between the third rib and the fourth rib, the left anterior descending branch of the coronary artery is ligated to close the chest, and the skin is sutured. After 3 days of post-operative recovery, the animals were given therapeutic drugs by gavage once a day for 4 weeks. During the experiment, the living state of the animals is observed daily, and the abnormal condition is recorded. Echocardiography was performed 4 weeks after dosing.
4.2, molding:
the day before surgery, animals will fasted overnight. On the day of surgery, intramuscular injection of animal muscle sultai (dose: 5 mg/kg) induces anesthesia; simultaneously, the atropine sulfate injection (dosage: 0.5 mg/dog) is intramuscular injected. The animals were anesthetized and shaved with left chest hair; rapidly performing tracheal intubation, switching on a respirator to provide artificial respiration and providing 1.5% isoflurane gas to maintain an anesthetic state, and simultaneously monitoring blood oxygen saturation, heart rate, electrocardiogram, body temperature, respiratory rate and the like by using a monitor. After the skin of the forelimb was sterilized with 70% alcohol, the head vein was found, and a vein cannula was made and a vein administration route was left. Sterilizing and sterilizing the left chest skin with iodophor and 70% alcohol; laying a sterile surgical hole towel; skin is incised along the fourth and fifth intercostals by using a sterile scalpel, subcutaneous tissue and muscle layers are incised layer by using an electrotome after hemostasis, and hemostasis is performed in time. Carefully open the chest membrane to expose the lung tissue, avoiding damaging the lung tissue; the surgical field was gradually enlarged to 20-25cm along the lower edge of the fourth rib, and the surgical window was enlarged using a chest expander. The lung tissue was removed and protected using sterile gauze saturated with warm saline. The left atrial appendage was removed with sterile gauze soaked with warm saline, carefully exposed between the left ventricle and left atrium and left anterior descending coronary artery was free using blunt right forceps, passed through the artery with a number 4 wire, and protected from pulling the artery during the free and threading process. Ligating left anterior descending branch of coronary artery with silk thread, and closely observing blood oxygen saturation, heart rate, electrocardiogram, body temperature and breath of animal during ligature; if the animal is suffering from abnormal conditions such as ventricular fibrillation, the operation is immediately stopped and lidocaine injection therapy (10 mg/kg) is rapidly administered through the head vein. After no hemorrhage in the chest cavity is determined, taking out the protective gauze, and suturing the chest cavity through the fourth and fifth ribs by using a No. 7 suture; the manual pressing method is used for repeating Zhang Fei. The tissue and skin are sutured layer by layer. Keeping the animal warm after operation, and properly supplementing physiological saline; closely observing blood oxygen saturation, heart rate, electrocardiogram, body temperature and respiratory variation; the gas anesthesia machine is closed until the animal completely resumes spontaneous breathing and then the tracheal cannula is pulled out. Postoperative intramuscular injection of buprenorphine (meloxicam, 0.67 mg/kg) to relieve pain and intramuscular injection of ampicillin sodium 20mg/kg to combat infection.
4.3 grouping and administration:
each canine was subjected to echocardiography and electrocardiographic monitoring before grouping, and was randomly divided into 5 groups (5-6 animals per group) according to ejection fraction, and after 3d after animal molding, each group of dogs was given the corresponding drug by gavage once daily for 4 weeks. All procedures were performed in 6 batches of 4-5 animals per batch and 0-1 per group. Each group of conditions is shown in table 1 below:
all doses administered were calculated as anhydrous free acid.
4.4 results of the study:
an important manifestation of chronic heart failure is the reduced function of left ventricular contractions, which is the clinically significant endpoint of detection of chronic heart failure. The ultrasonic cardiography examination shows that the Left Ventricular Ejection Fraction (LVEF) of the model group dog is obviously reduced to 46.84% after the model is made, and compared with a false operation group, P is less than 0.001, so that the model group dog can better simulate the chronic heart failure of the clinical ejection fraction intermediate value of a human body. As can be seen from Table 2, the end point LVEF of the inventive complex, LCZ696 and physical blend group dogs was 59.88%, 57.01% and 55.75, respectively, which were significantly higher than the model group (P < 0.001 ). At the same time, 100mpk of the compound of the invention has an intermediate value of raised ejection fraction which is significantly better than that of the LCZ696 group with equal mass dose and the physical mixed group with equal mole dose (P is less than 0.05 and P is less than 0.01).
Effect of the compounds of table 2 on heart failure canine endpoint left ventricular ejection fraction (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 mix group.
Note that: the compound obtained in example 3 was used as a complex 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 at equivalent doses than using LCZ696 100mpk for pharmaceutical use of heart failure with intermediate ejection fraction values;
the better effect of the complexes of the invention relative to the EXP3174+AHU377 physical mixture, fully demonstrates the significant advantages of the use of the complexes over the use of a physical combination of drugs.
Example 5
Drug efficacy study-ejection fraction retention of compound in canine chronic heart failure model
5.1 method:
animals were fed adaptively after reaching the facility, randomly grouped after echocardiographic and electrocardiographic examination, and the trial was restarted. On the day of the operation, the animals are anesthetized by intramuscular injection of sultai (5 mg/kg), the anesthetic dog is connected with a respirator through a trachea, the upper position is fixed, the chest is opened between the third rib and the fourth rib, the left anterior descending branch of the coronary artery is ligated to close the chest, and the skin is sutured. After 3 days of post-operative recovery, the animals were given therapeutic drugs by gavage once a day for 2 weeks. During the experiment, the living state of the animals is observed daily, and the abnormal condition is recorded. Echocardiography was performed 14 days after administration.
5.2, molding:
the day before surgery, animals will fasted overnight. On the day of surgery, intramuscular injection of animal muscle sultai (dose: 5 mg/kg) induces anesthesia; simultaneously, the atropine sulfate injection (dosage: 0.5 mg/dog) is intramuscular injected. The animals were anesthetized and shaved with left chest hair; rapidly performing tracheal intubation, switching on a respirator to provide artificial respiration and providing 1.5% isoflurane gas to maintain an anesthetic state, and simultaneously monitoring blood oxygen saturation, heart rate, electrocardiogram, body temperature, respiratory rate and the like by using a monitor. After the skin of the forelimb was sterilized with 70% alcohol, the head vein was found, and a vein cannula was made and a vein administration route was left. Sterilizing and sterilizing the left chest skin with iodophor and 70% alcohol; laying a sterile surgical hole towel; skin is incised along the fourth and fifth intercostals by using a sterile scalpel, subcutaneous tissue and muscle layers are incised layer by using an electrotome after hemostasis, and hemostasis is performed in time. Carefully open the chest membrane to expose the lung tissue, avoiding damaging the lung tissue; the surgical field was gradually enlarged to 20-25cm along the lower edge of the fourth rib, and the surgical window was enlarged using a chest expander. The lung tissue was removed and protected using sterile gauze saturated with warm saline. The left atrial appendage was removed with sterile gauze soaked with warm saline, carefully exposed between the left ventricle and left atrium and left anterior descending coronary artery was free using blunt right forceps, passed through the artery with a number 4 wire, and protected from pulling the artery during the free and threading process. Ligating left anterior descending branch of coronary artery with silk thread, and closely observing blood oxygen saturation, heart rate, electrocardiogram, body temperature and breath of animal during ligature; if the animal is suffering from abnormal conditions such as ventricular fibrillation, the operation is immediately stopped and lidocaine injection therapy (10 mg/kg) is rapidly administered through the head vein. After no hemorrhage in the chest cavity is determined, taking out the protective gauze, and suturing the chest cavity through the fourth and fifth ribs by using a No. 7 suture; the manual pressing method is used for repeating Zhang Fei. The tissue and skin are sutured layer by layer. Keeping the animal warm after operation, and properly supplementing physiological saline; closely observing blood oxygen saturation, heart rate, electrocardiogram, body temperature and respiratory variation; the gas anesthesia machine is closed until the animal completely resumes spontaneous breathing and then the tracheal cannula is pulled out. Postoperative intramuscular injection of buprenorphine (meloxicam, 0.67 mg/kg) to relieve pain and intramuscular injection of ampicillin sodium 20mg/kg to combat infection.
5.3 grouping and administration:
each canine was subjected to echocardiography and electrocardiographic monitoring before grouping, and was randomly divided into 5 groups (5-6 animals per group) according to ejection fraction, and after 3d after animal molding, each group of dogs was given the corresponding drug by gavage once daily for 2 weeks. All procedures were performed in 6 batches of 4-5 animals per batch and 0-1 per group. Each group of conditions is shown in table 3 below:
note that: all doses were given as anhydrous free acid, and the compound obtained in example 3 was used as the complex according to the invention.
5.4 experimental results:
an important manifestation of chronic heart failure is the reduced function of left ventricular contractions, which is the clinically significant endpoint of detection of chronic heart failure. The ultrasonic cardiography examination shows that the Left Ventricular Ejection Fraction (LVEF) of the model group dog is obviously reduced but still greater than 50% after molding, and compared with a false operation group, the model group dog has P less than 0.001 and can better simulate the chronic heart failure of the clinical ejection fraction retention of a human body. As can be seen from table 4, the end point LVEF for dogs in LCZ696 group was 57.98% significantly higher than that in model group (P < 0.001). The compound and the physical mixture group can raise LVEF, and have statistical significance (P is less than 0.05) compared with a model group. Meanwhile, the compound of the invention with 100mpk has equivalent drug effect compared with the equimolar dose group of LCZ696 on LVEF, and is obviously superior to a physical mixed group. The experimental results are shown in table 4:
effect of the compounds of table 4 on heart failure canine endpoint left ventricular ejection fraction (mean±sd)
Wherein, model LVEF is 51.80 percent and is more than or equal to 50 percent, which indicates the ejection fractionReservation ofThe molding was successful, as shown in FIG. 1.
# # P < 0.001, compared to Sham group; * P < 0.05, P < 0.01, P < 0.001, compared to Model group; @ p < 0.05, compared with the physical mixture group
Note that: the compound obtained in example 3 was used as a complex of the present invention.
From the above results, it can be seen that the effect of the inventive complex in the intermediate ejection fraction canine model is superior to that in the intermediate ejection fraction canine model, and thus it can be seen that the inventive pharmaceutical composition has specific selectivity against heart failure in the intermediate ejection fraction, which is difficult to predict according to the prior art.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims (5)

1. Use of a complex of an angiotensin II receptor antagonist metabolite and a NEP inhibitor for the manufacture of a medicament for the treatment of heart failure with an intermediate value of ejection fraction, the structural units of said complex being as follows:
2. the use according to claim 1, characterized in that: the single dosage form of the drug is defined as the total mass of (angiotensin II receptor antagonist metabolite EXP3174 NEP inhibitor AHU 377),
,
containing between 60mg and 500mg of said complex.
3. The use according to claim 1, characterized in that: the single dosage form of the drug is defined as the total mass of (angiotensin II receptor antagonist metabolite EXP3174 NEP inhibitor AHU 377),
,
containing 60, 120, 180, 240, 300, 360, 420 or 480 milligrams of said complex.
4. The use according to claim 1, characterized in that: the medicament is a solid preparation for oral administration.
5. The use according to claim 4, characterized in that: the oral solid preparation is an oral tablet or capsule.
CN202180030807.8A 2020-08-17 2021-08-16 Heart failure application of complex of angiotensin II receptor antagonist metabolite and NEP inhibitor Active CN115443272B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN2020108232337 2020-08-17
CN202010823233 2020-08-17
PCT/CN2021/112668 WO2022037512A1 (en) 2020-08-17 2021-08-16 Use of complex of angiotensin ii receptor antagonist metabolite and nep inhibitor in treatment of heart failure

Publications (2)

Publication Number Publication Date
CN115443272A CN115443272A (en) 2022-12-06
CN115443272B true CN115443272B (en) 2023-11-17

Family

ID=80323395

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202180030807.8A Active CN115443272B (en) 2020-08-17 2021-08-16 Heart failure application of complex of angiotensin II receptor antagonist metabolite and NEP inhibitor

Country Status (3)

Country Link
CN (1) CN115443272B (en)
TW (1) TW202228677A (en)
WO (1) WO2022037512A1 (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220395491A1 (en) * 2019-09-20 2022-12-15 Shenzhen Salubris Pharmaceuticals Co. Ltd Uses of complex of angiotensin ii receptor antagonist metabolite and nep inhibitor in treating heart failure
CN118176190A (en) * 2022-08-04 2024-06-11 深圳信立泰药业股份有限公司 ARNi novel crystal form of compound and preparation method and application thereof

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102702119A (en) * 2005-11-09 2012-10-03 诺瓦提斯公司 Pharmaceutical combinations of an angiotensin receptor antagonist and an NEP inhibitor
CN105963296A (en) * 2015-03-12 2016-09-28 深圳信立泰药业股份有限公司 A pharmaceutical composition containing allisartan isoproxil or a salt thereof or a hydrolysate thereof or a salt of the hydrolysate thereof and uses of the composition
CN106214680A (en) * 2016-07-29 2016-12-14 珠海赛隆药业股份有限公司（长沙）医药研发中心 A kind of complex of angiotensin receptor antagonist and levosimendan and application thereof
CN108473474A (en) * 2016-01-20 2018-08-31 深圳信立泰药业股份有限公司 The compound and preparation method thereof of angiotensin II receptor antagonist metabolite and nep inhibitor
CN108619138A (en) * 2016-08-01 2018-10-09 珠海赛隆药业股份有限公司（长沙）医药研发中心 The compound and application thereof of angiotensin receptor antagonist and enkephalinase inhibitor
CN109893653A (en) * 2017-12-11 2019-06-18 王慧敏 The new application of PDE9 inhibitor
WO2021093697A1 (en) * 2019-11-11 2021-05-20 深圳信立泰药业股份有限公司 Composite of angiotensin ii receptor antagonist and nep inhibitor and preparation method therefor
CN113286585A (en) * 2019-09-20 2021-08-20 深圳信立泰药业股份有限公司 Use of complexes of angiotensin II receptor antagonist metabolites and NEP inhibitors for the treatment of heart failure

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160206597A1 (en) * 2013-08-26 2016-07-21 Toni Lynne Bransford New Use

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102702119A (en) * 2005-11-09 2012-10-03 诺瓦提斯公司 Pharmaceutical combinations of an angiotensin receptor antagonist and an NEP inhibitor
CN105963296A (en) * 2015-03-12 2016-09-28 深圳信立泰药业股份有限公司 A pharmaceutical composition containing allisartan isoproxil or a salt thereof or a hydrolysate thereof or a salt of the hydrolysate thereof and uses of the composition
CN108473474A (en) * 2016-01-20 2018-08-31 深圳信立泰药业股份有限公司 The compound and preparation method thereof of angiotensin II receptor antagonist metabolite and nep inhibitor
CN106214680A (en) * 2016-07-29 2016-12-14 珠海赛隆药业股份有限公司（长沙）医药研发中心 A kind of complex of angiotensin receptor antagonist and levosimendan and application thereof
CN108619138A (en) * 2016-08-01 2018-10-09 珠海赛隆药业股份有限公司（长沙）医药研发中心 The compound and application thereof of angiotensin receptor antagonist and enkephalinase inhibitor
CN109893653A (en) * 2017-12-11 2019-06-18 王慧敏 The new application of PDE9 inhibitor
CN113286585A (en) * 2019-09-20 2021-08-20 深圳信立泰药业股份有限公司 Use of complexes of angiotensin II receptor antagonist metabolites and NEP inhibitors for the treatment of heart failure
WO2021093697A1 (en) * 2019-11-11 2021-05-20 深圳信立泰药业股份有限公司 Composite of angiotensin ii receptor antagonist and nep inhibitor and preparation method therefor

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
Pharmacodynamic and pharmacokinetic effects of S086, a novel angiotensin receptor neprilysin inhibitor;Jingchao Sun，et al;Biomedicine & Pharmacotherapy;第129卷(第01期);第1-15页 *
慢性心力衰竭治疗新进展――LCZ696;谭漪扬，等;心血管病学进展;第12卷(第01期);第158-165页 *
沙库巴曲缬沙坦钠片对射血分数中间值心力衰竭患者疗效及预后的影响分析;王国坤;海峡药学;第31卷(第11期);第176页"摘要"，第177页"3 讨论" *
血管紧张素受体脑啡肽酶抑制剂在心力衰竭治疗中的研究进展及展望;李小荣，等;中国循环杂志;第11卷(第02期);第12-16页 *
血管紧张素受体脑啡肽酶抑制剂――沙库巴曲缬沙坦治疗心力衰竭的研究进展;王晓雪，等;实用心脑肺血管病杂志;第15卷(第01期);第236-241页 *

Also Published As

Publication number Publication date
CN115443272A (en) 2022-12-06
TW202228677A (en) 2022-08-01
WO2022037512A1 (en) 2022-02-24

Similar Documents

Publication Publication Date Title
CN115443272B (en) Heart failure application of complex of angiotensin II receptor antagonist metabolite and NEP inhibitor
CN115487175B (en) Use of complexes of metabolites of angiotensin II receptor antagonists and NEP inhibitors for the treatment of heart failure
CN101658524B (en) Compound anesthetic for dogs
Akata et al. Hemidiaphragmatic paralysis following subclavian vein catheterization
WO2022233310A1 (en) Salvianolic acid a salt hydrate, preparation method therefor, and use thereof
CN115461052B (en) Pharmaceutical use of complexes of ARB metabolites with NEP inhibitors for the prevention and/or treatment of kidney disease
RU2820827C1 (en) Versions of using complex of angiotensin ii receptor antagonist metabolite and nep inhibitor in treating heart failure
Kulkarni et al. A new flexible laryngeal mask airway introducer
Elsberg EXPERIENCES IN THORACIC SURGERY UNDER ANÆSTHESIA BY THE INTRATRACHEAL INSUFLATION OF AIR AND ETHER
CN110693882A (en) Sublingual pharmaceutical composition
AU2021100444A4 (en) A compound anesthetic and its preparation method and application in animal model of myocardial infarction
Šidlauskaitė et al. Comparison of two different sedation protocols for laringoscopy procedure in 17 dogs
Lichtenberger et al. Exotic companion mammal emergency techniques
Ko et al. Anesthesia and analgesia in ferrets
Shivaraj et al. Airway Obstruction due to Mucus Plug in Patients with Organophosphorus Poisoning–Atropine the Culprit? A Case Series
Bailie et al. Traumatic perforation of the lower oesophagus
US20120225817A1 (en) Therapeutic agent for gastrointestinal disease
WO2020003107A1 (en) Low dose oral pharmaceutical composition of pirfenidone or salt thereof
CN114075260A (en) Use of compound P57 or its analogs for hypothermia and neuroprotection
RU2340367C1 (en) Method of treatment of intestinal insufficiency in postoperative period
Patch The Toxic Action of Arsphenamine and Neoarsphenamine
CN108904501A (en) A kind of compound is treating or preventing the purposes in altitude sickness
JP2007528878A (en) Novel 2- (α-n-pentanonyl) benzoate and production method and use thereof
JPS60346B2 (en) S-(3-methyl-2-butenyl)cysteine and its production method
CN106983755A (en) A kind of pharmaceutical composition with treatment skin injury effect and its preparation technology and application

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant