WO2021052441A1 - 血管紧张素ii受体拮抗剂代谢产物与nep抑制剂的复合物治疗心衰的用途 - Google Patents
血管紧张素ii受体拮抗剂代谢产物与nep抑制剂的复合物治疗心衰的用途 Download PDFInfo
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- WO2021052441A1 WO2021052441A1 PCT/CN2020/116023 CN2020116023W WO2021052441A1 WO 2021052441 A1 WO2021052441 A1 WO 2021052441A1 CN 2020116023 W CN2020116023 W CN 2020116023W WO 2021052441 A1 WO2021052441 A1 WO 2021052441A1
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- ahu377
- exp3174
- complex
- heart failure
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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
-
- 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
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- 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
- 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
- A61K31/4164—1,3-Diazoles
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Definitions
- the present invention belongs to the technical field of drug application, and relates to a new heart failure application of a complex of an angiotensin II receptor antagonist metabolite and a NEP inhibitor, and specifically relates to the preparation of the complex for use in heart failure with reduced ejection fraction Drug use.
- Heart failure is a serious manifestation or late stage of various heart diseases, and the mortality and rehospitalization rate remain high.
- the prevalence of heart failure in developed countries is 1.5% to 2.0%, and the prevalence of people ⁇ 70 years old is ⁇ 10%.
- An epidemiological survey in 2003 showed that the prevalence of heart failure among adults aged 35 to 74 in my country was 0.9%.
- the aging of the population in my country is increasing, and the incidence of chronic diseases such as coronary heart disease, hypertension, diabetes, and obesity is on the rise.
- the improvement of medical standards has prolonged the survival time of patients with heart diseases, leading to a continuous increase in the prevalence of heart failure in my country.
- WO2007056546A1 discloses a Valsartan-Sacubitril sodium salt complex (LCZ696) and a preparation method thereof, which was approved for marketing in China in 2017, and the trade name is: Used for heart failure. Its molecular structure units are as follows:
- WO2017125031A1 discloses a series of complexes of angiotensin receptor antagonist metabolites (EXP3174) and NEP inhibitors (Sacubitril), and exhibits certain effects on heart failure HFpEF with retention of ejection fraction. Its molecular structural units are as follows :
- the present invention provides a complex of angiotensin II receptor antagonist metabolites and NEP inhibitors (or “supramolecular complexes”) used in the preparation of ejection fractions.
- angiotensin II receptor antagonist metabolites and NEP inhibitors or “supramolecular complexes” used in the preparation of ejection fractions.
- the structural units of the complex are as follows:
- the heart failure with reduced ejection fraction refers to HFrEF as defined in Table 1 of "Chinese Heart Failure Diagnosis and Treatment Guidelines" 2018-Heart Failure Classification and Diagnostic Criteria.
- the drug is applied to patients suffering from heart failure with reduced ejection fraction; according to the experimental results of the present invention and the application amount of the prodrug, the drug Single-dose form refers to the total mass of (aEXP3174 ⁇ bAHU377) containing approximately 60 mg and 500 mg of the complex, including but not limited to 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 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,
- the single-dose form of the drug contains 60, 120, 180, 240, 300, 360, 420, 480 mg of the complex.
- the single-dose form refers to the daily dosage form, which is administered to the patient with the compound containing 60 mg/day to 500 mg/day, and the number of administrations includes but is not limited to once a day, 1 day 2 times, 3 times a day, 4 times a day, etc.
- the dose refers to the initial dose or maintenance dose of the drug application. In the application of hypertension, the initial dose is usually lower than the maintenance dose. The dosage is aimed at patients with refractory hypertension in special circumstances, and the dosage may be appropriately increased.
- the calculation method includes calculating according to the daily dosage of the prodrug, EXP3174 is the metabolite of allisartan medoxomil, the generic name of the marketed drug: Allisartan Isoproxil Tablets, the English name: Allisartan Isoproxil Tablets, the trade name: Xin Litan , The dosage is 240mg per day.
- the molecular formula of allisartan medoxomil is C 27 H 29 ClN 6 O 5 and the molecular weight is 553.0; the molecular formula of EXP3174 is C 22 H 21 ClN 6 O 2 and the molecular weight is about 436.9; the molecular formula of AHU377 is C 24 H 29 NO 5 , The molecular weight is about 411.5, and the daily dosage of the complex should be equivalent to the daily dosage of allisartan medoxomil. Therefore, the single-dose form of the aforementioned complex is calculated.
- the effective dose in humans is 100 mg/day, and the dosage range is 60 mg/day to 500 mg/day.
- the drug is a solid preparation suitable for oral administration, preferably oral tablets or capsules, which can be multiple tablets and multiple capsules with a total drug content of 60 mg to 500 mg.
- the complex of the drug can be obtained by a method known in the prior art, wherein the complex disclosed in WO2017125031A1 and the preparation method thereof are introduced into the present invention.
- the value of a:b is selected from 1:0.25, 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5 , 1:4.
- the structural units of the composite are as follows:
- x is selected from 0.5, 1, 1.5, and 2.
- the structural units of the composite are as follows:
- n is any value between 1 and 3.
- n is selected from 0.5, 1, 1.5, 2, 2.5, and 3.
- the compound is selected from:
- the supramolecular complex (complex) of the present invention is different from a mixture obtained by simple physical mixing of two active ingredients.
- the XRD spectrum of the obtained supramolecular complex (complex) is obviously different from that of EXP3174 and AHU377 calcium salt, and its solubility in various solvents (such as water, ethanol, ethanol-water, etc.) is also significantly different , There are obvious differences in other physical and chemical properties such as hygroscopicity, melting point, infrared spectrum, etc.
- the present invention has the following advantages and beneficial effects:
- the present invention provides a series of supramolecular complexes (complexes) with dual effects of allisartan medoxomil metabolite (EXP3174) and enkephalinase inhibitor (AHU377) for heart failure with reduced ejection fraction For drug use, it has a significantly better effect than using LCZ696 at the same dose;
- the effect of the compound of the present invention in a dog model with reduced ejection fraction is better than that in a dog model with ejection fraction retention. It can be seen that the pharmaceutical composition of the present invention has specific selectivity for heart failure with reduced ejection fraction. It is difficult to predict based on the existing technology.
- the compound of the present invention has a better effect than the physical mixture of EXP3174+AHU377, which fully shows that the use of the compound has obvious advantages over the use of a physical combination of drugs.
- X-ray powder diffraction is detected by an Empyrean X-ray diffractometer.
- the detection conditions Cu target K ⁇ rays, voltage 40KV, current 40mA, emission slit 1/32°, anti-scatter slit 1/16°, anti-scattering Scattering slit 7.5mm, 2 ⁇ range: 3°-60°, step length 0.02°, residence time per step 40s.
- Differential scanning calorimetry spectra were tested with DSC204F1 differential scanning calorimeter equipment from NETZSCH, Germany. Test conditions: atmosphere: N 2 , 20mL/min; scanning program: heating from room temperature at 10°C/min to 250°C, record Heating curve.
- the moisture content is detected by the TG209 thermogravimetric analyzer equipment from NETZSCH, Germany, and the detection conditions are: atmosphere: N 2 , 20 mL/min; scanning program: room temperature-700°C, heating rate: 10°C/min.
- the EXP3174 used in the examples was made by the company, with a purity of 98.3%.
- the AHU377 calcium salt used in the examples is self-made by the company, with a purity of 99.4%.
- each dog was subjected to echocardiography and ECG monitoring. According to the ejection fraction, the dogs were randomly divided into 5 groups (4-6 animals in each group). The corresponding drugs were given to the stomach once a day for 6 weeks. All operations were divided into 6 batches for experiment, each batch of 4-5 animals, each group of 0-1 animals. The situation of each group is as follows in Table 1:
- Model LVEF was 35.82%, ⁇ 40%, indicating a reduced ejection fraction successful model, see Figure 1.
- the compound of the present invention uses the compound obtained in Example 3.
- the dual-acting supramolecular complex (complex) provided by the present invention is used for the drug use of heart failure with reduced ejection fraction, and has a significantly better effect than using LCZ696 100mpk at the same dose;
- the compound of the present invention Compared with the physical mixture of EXP3174+AHU377, the compound of the present invention has a better effect, which fully shows that the use of the compound has obvious advantages over the use of a physical combination of drugs.
- each dog was subjected to echocardiography and ECG monitoring. According to the ejection fraction, the dogs were randomly divided into 5 groups (5-6 animals in each group). 3 days after the animal model, the dogs in each group were irrigated The corresponding drugs were given to the stomach once a day for 2 weeks. All operations were divided into 6 batches for experiment, each batch of 4-5 animals, each group of 0-1 animals. The situation of each group is as follows in Table 3:
- Model LVEF was 51.80%, ⁇ 50%, ejection fraction retained successful model described, referring to FIG. 1.
- the compound of the present invention uses the compound obtained in Example 3.
Abstract
Description
Claims (10)
- 血管紧张素II受体拮抗剂代谢产物与NEP抑制剂的复合物在制备用于射血分数降低的心衰的药物用途,所述复合物的结构单元如下:(aEXP3174·bAHU377)·xCa·nA其中a:b=1:0.25~4;x为0.5~3之间的数值;A指代水、甲醇、乙醇、2-丙醇、丙酮、乙酸乙酯、甲基-叔-丁基醚、乙腈、甲苯、二氯甲烷;n为0~3之间的数值。
- 根据权利要求1所述药物用途,其特征在于:所述药物的单剂量形式含有60毫克和500毫克之间的所述复合物。
- 根据权利要求1所述药物用途,其特征在于:所述药物的单剂量形式含有60、120、180、240、300、360、420、480毫克的所述复合物。
- 根据权利要求1所述药物用途,其特征在于:所述药物是适于口服的固体制剂,优选口服的片剂或胶囊。
- 根据权利要求1-4任一项权利要求所述的药物用途,其特征在于:a:b的值选自1:0.25,1:0.5,1:1,1:1.5,1:2,1:2.5,1:3,1:3.5,1:4。
- 根据权利要求1-6任一项权利要求所述的药物用途,其特征在于:x选自0.5、1、1.5、2。
- 根据权利要求1-7任一项权利要求所述的药物用途,其特征在于:所述复合物的结构单元如下:(EXP3174·AHU377)·1.5Ca·nH 2O或者(EXP3174·AHU377)·2Ca·nH 2O其中n为1~3之间的任意数值。
- 根据权利要求1-8任一项权利要求所述的药物用途,其特征在于:n选自0.5、1、1.5、2、2.5、3。
- 根据权利要求1-9任一项权利要求所述的药物用途,其特征在于,所述复合物选自:(EXP3174·AHU377)·1.5Ca·1H 2O;.(EXP3174·AHU377)·1.5Ca·1.5H 2O;(EXP3174·AHU377)·1.5Ca·2H 2O;(EXP3174·AHU377)·1.5Ca·2.5H 2O;(EXP3174·AHU377)·1.5Ca·3H 2O;(EXP3174·AHU377)·2Ca·1H 2O;(EXP3174·AHU377)·2Ca·1.5H 2O;(EXP3174·AHU377)·2Ca·2H 2O;(EXP3174·AHU377)·2Ca·2.5H 2O;(EXP3174·AHU377)·2Ca·3H 2O。
Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2020348813A AU2020348813A1 (en) | 2019-09-20 | 2020-09-18 | Uses of complex of angiotensin II receptor antagonist metabolite and NEP inhibitor in treating heart failure |
EP20866108.2A EP4032532A4 (en) | 2019-09-20 | 2020-09-18 | USES OF A COMPLEX CONSISTING OF AN ANGIOTENSIN II RECEPTOR ANTAGONIST METABOLISM AND A NEP INHIBITOR IN THE TREATMENT OF HEART FAILURE |
CA3151788A CA3151788A1 (en) | 2019-09-20 | 2020-09-18 | Uses of complex of angiotensin ii receptor antagonist metabolite and nep inhibitor in treating heart failure |
KR1020217042035A KR20220012317A (ko) | 2019-09-20 | 2020-09-18 | 안지오텐신 ii 수용체 길항제 대사물질 및 nep 억제제의 복합체의 심부전 치료에서의 용도 |
JP2022513095A JP7316449B2 (ja) | 2019-09-20 | 2020-09-18 | 心不全治療におけるアンジオテンシンii受容体アンタゴニスト代謝産物とnep阻害剤との複合体の使用 |
US17/761,543 US20220395491A1 (en) | 2019-09-20 | 2020-09-18 | Uses of complex of angiotensin ii receptor antagonist metabolite and nep inhibitor in treating heart failure |
MX2022003408A MX2022003408A (es) | 2019-09-20 | 2020-09-18 | Usos del complejo de metabolito antagonista del receptor de angiotensina ii e inhibidor de nep en el tratamiento de la insuficiencia cardiaca. |
CN202080008624.1A CN113286585B (zh) | 2019-09-20 | 2020-09-18 | 血管紧张素ii受体拮抗剂代谢产物与nep抑制剂的复合物治疗心衰的用途 |
CN202211186846.XA CN115487175B (zh) | 2019-09-20 | 2020-09-18 | 血管紧张素ii受体拮抗剂代谢产物与nep抑制剂的复合物治疗心衰的用途 |
ZA2022/04370A ZA202204370B (en) | 2019-09-20 | 2022-04-19 | Uses of complex of angiotensin ii receptor antagonist metabolite and nep inhibitor in treating heart failure |
CONC2022/0004910A CO2022004910A2 (es) | 2019-09-20 | 2022-04-19 | Un complejo de metabolito antagonista del receptor de angiotensina ii e inhibidor de nep en el tratamiento de la insuficiencia cardíaca |
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CN201910890853 | 2019-09-20 | ||
CN201910890853.X | 2019-09-20 | ||
CN202010901984 | 2020-09-01 | ||
CN202010901984.6 | 2020-09-01 |
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US (1) | US20220395491A1 (zh) |
EP (1) | EP4032532A4 (zh) |
JP (1) | JP7316449B2 (zh) |
KR (1) | KR20220012317A (zh) |
CN (1) | CN113286585B (zh) |
AU (1) | AU2020348813A1 (zh) |
CA (1) | CA3151788A1 (zh) |
CO (1) | CO2022004910A2 (zh) |
EC (1) | ECSP22031078A (zh) |
MX (1) | MX2022003408A (zh) |
TW (1) | TWI809313B (zh) |
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CN115443272B (zh) * | 2020-08-17 | 2023-11-17 | 深圳信立泰药业股份有限公司 | 血管紧张素ii受体拮抗剂代谢产物与nep抑制剂的复合物的心衰应用 |
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- 2020-09-18 TW TW109132385A patent/TWI809313B/zh active
- 2020-09-18 EP EP20866108.2A patent/EP4032532A4/en active Pending
- 2020-09-18 JP JP2022513095A patent/JP7316449B2/ja active Active
- 2020-09-18 AU AU2020348813A patent/AU2020348813A1/en active Pending
- 2020-09-18 KR KR1020217042035A patent/KR20220012317A/ko unknown
- 2020-09-18 CN CN202080008624.1A patent/CN113286585B/zh active Active
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CA3151788A1 (en) | 2021-03-25 |
JP7316449B2 (ja) | 2023-07-27 |
CN115487175A (zh) | 2022-12-20 |
EP4032532A1 (en) | 2022-07-27 |
US20220395491A1 (en) | 2022-12-15 |
TW202114652A (zh) | 2021-04-16 |
AU2020348813A1 (en) | 2022-04-14 |
TWI809313B (zh) | 2023-07-21 |
EP4032532A4 (en) | 2023-10-04 |
CN113286585A (zh) | 2021-08-20 |
JP2022545904A (ja) | 2022-11-01 |
MX2022003408A (es) | 2022-07-12 |
CN113286585B (zh) | 2022-11-08 |
CO2022004910A2 (es) | 2022-05-31 |
ECSP22031078A (es) | 2022-08-31 |
ZA202204370B (en) | 2022-11-30 |
KR20220012317A (ko) | 2022-02-03 |
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