WO2020238884A1 - 血管紧张素ii受体拮抗剂代谢产物与nep抑制剂的复合物的新用途 - Google Patents

血管紧张素ii受体拮抗剂代谢产物与nep抑制剂的复合物的新用途 Download PDF

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WO2020238884A1
WO2020238884A1 PCT/CN2020/092256 CN2020092256W WO2020238884A1 WO 2020238884 A1 WO2020238884 A1 WO 2020238884A1 CN 2020092256 W CN2020092256 W CN 2020092256W WO 2020238884 A1 WO2020238884 A1 WO 2020238884A1
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complex
exp3174
ahu377
spectrum
use according
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French (fr)
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孙晶超
景小龙
肖瑛
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深圳信立泰药业股份有限公司
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Priority to CN202080008628.XA priority Critical patent/CN113286789B/zh
Priority to CN202210127199.9A priority patent/CN114452287B/zh
Publication of WO2020238884A1 publication Critical patent/WO2020238884A1/zh

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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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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

Definitions

  • the invention belongs to the technical field of drug application, and relates to a new use of a complex of an angiotensin II receptor antagonist metabolite and a NEP inhibitor, in particular to the use of the complex in the preparation of drugs for salt-sensitive hypertension.
  • Hypertension is a clinical syndrome characterized by increased systemic arterial pressure, and is the most common cardiovascular disease. Moreover, the incidence of hypertension is on the rise. According to statistics, there are approximately 290 million people with cardiovascular disease in China ("China Cardiovascular Disease Report 2013"). High blood pressure if the lack of effective control and treatment, can lead to coronary artery disease, appears coronary heart disease, angina, high blood pressure may also cause cardiac ⁇ heart disease, heart failure and other serious complications. In addition, long-term high blood pressure can cause damage to the kidneys, brain, cardiovascular and other organs.
  • hypertension and systemic arteriolar spasm are the direct consequence of increased peripheral vascular resistance, arterial spasm and genetic/mental stimulation, stress, renal ischemia, adrenal cortex action and sodium
  • SHR Spontaneously Hypertensive Rats
  • DPA Deoxycorticosterone Acetate
  • sodium salt can significantly increase the risk of hypertension and the risk of hypertension, and moderately reducing sodium intake can effectively lower blood pressure.
  • Excessive sodium intake and (or) insufficient potassium intake, as well as a low ratio of potassium to sodium intake are important risk factors for the onset of hypertension in my country.
  • 75.8% of the sodium in the diet of Chinese residents comes from the salt used in home cooking, followed by sodium salt in high-salt condiments and processed foods. Therefore, excessive sodium intake is an important cause of hypertension in my country.
  • WO2007056546A1 discloses a Valsartan-Sacubitril sodium salt complex (LCZ696) and a preparation method thereof. It was approved for marketing in China in 2017, and its trade name is Nocinto It is used for adult patients with chronic heart failure (NYHA II-IV, LVEF ⁇ 40%) with reduced ejection fraction to reduce the risk of cardiovascular death and heart failure hospitalization. Its molecular structure units are as follows:
  • WO2017125031A1 discloses a series of complexes composed of an angiotensin receptor antagonist metabolite (EXP3174) and NEP inhibitor (Sacubitril). Compared with LCZ696, the complex has solubility, hygroscopicity, stability, etc. It has advantages and excellent heart failure effect; and has its unique application advantages compared with EXP3174 and Sacubitril used alone or in combination. Its molecular structure units are as follows:
  • the present invention provides a complex of angiotensin II receptor antagonist metabolites and NEP inhibitors (or “supramolecular complexes”) in preparation for use in salt-sensitive For medical use of hypertension, the structural units of the complex are as follows:
  • the drug is applied to patients suffering from the salt-sensitive hypertension; according to the experimental results of the present invention and the application amount of the prodrug, the single dose of the drug
  • the 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, 140 mg, 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, 440
  • 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, 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.
  • it includes administering to the patient 60, 120, 180, 240, 300, 360, 420, or 480 mg of the complex daily.
  • the complex is administered to the patient once, twice or three times a day. More preferably, it includes administering the complex containing 120, 240, or 480 mg to the patient daily, and administering to the patient once, twice or 3 times a day.
  • ⁇ the calculated according to the estimation method comprises daily dosage prodrug, metabolite EXP3174 in vivo Alicante medoxomil, marketed drugs common name: Alicante medoxomil tablets, English name: Allisartan Isoproxil Tablets, trade name: Li letter Tan, 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.
  • 23mg/kg is the effective dose of the compound in the hypertension animal model, converted according to the rat-human body surface area (human body weight is calculated according to 60kg), 23mg/kg rat
  • the administration dose is approximately equivalent to the human administration dose of 223 mg. Therefore, it is estimated that the effective human dose is 200 mg/day, and the dosage range is 200 mg/day to 500 mg/day, that is, the expected maximum dose is about 2.5 times the effective dose.
  • the initial dose is recommended to be slightly lower than the effective dose, usually a fraction of the effective dose, such as 60mg, 120mg, 180mg, etc.
  • the pharmaceutical solid preparation suitable for oral administration preferably as tablets or capsules, the total amount of the drug may be a plurality of sheets and a plurality of capsules is 6 ⁇ 0 mg and 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 distinguished 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.
  • a specific supramolecular complex (complex) of the present invention the X-ray powder diffraction (XRD ⁇ ) spectrum of the supramolecular complex (complex) is 4.35°, 5.15°, 5.90°, 2 ⁇ There are diffraction peaks with strong absorption at 12.80° and 15.85°, and the acceptable error range is ⁇ 0.2°. For peaks with strong absorption intensity, it is less affected by product characteristics, testing equipment, testing conditions and other factors, so it recurs The probability is very high, and those skilled in the art can also understand that for some specific compounds, affected by factors such as product characteristics, detection equipment, detection conditions, etc., peaks with weaker absorption intensity may not have higher potential.
  • the inventor also found that this phenomenon also exists for the supramolecular complex (complex) in repeated testing of the same batch/different batch of samples.
  • the X-ray powder diffraction (XRD) spectrum of the supramolecular complex (complex) also has highly reproducible diffraction peaks at 2 ⁇ of 9.00°, 10.15°, and 15.02°, with acceptable errors The range is ⁇ 0.2°; more specifically, in one detection, the X-ray powder diffraction spectrum of the supramolecular complex (complex) has the following peaks:
  • the X-ray powder diffraction (XRD) spectrum of the supramolecular complex (complex) is shown in FIG. 1.
  • the molar ratio of EXP3174 to AHU377 in the supramolecular complex (complex) can be obtained directly/indirectly by the content analysis method.
  • the high performance liquid method HPLC
  • HPLC high performance liquid method
  • the differential scanning calorimetry (DSC) of the supramolecular complex (complex) has two water loss endothermic peaks at 94.4 ⁇ 10°C and 164.1 ⁇ 10°C, because the supramolecular complex (complex) ) Contains crystalline water, so those skilled in the art can understand that under different detection conditions, such as heating rate, etc., and different sample properties, such as sample particle size, certain peaks in the DSC spectrum (such as water loss absorption Heat peak) may have large fluctuations. For example, the position of the water loss endothermic peak of the spectrum obtained at different heating rates has a relatively large displacement difference, and the spectrum also has an endothermic peak at 244.6 ⁇ 5°C. More specifically, the differential scanning calorimetry (DSC) of the supramolecular complex (complex) is shown in FIG. 2.
  • the Raman spectrum of the supramolecular complex (complex) at the wavelength (cm -1 ) is 3061 (m), 2935 (m, width), 1613 (st), 1521 (m), 1482 (w), 1286(m), 995(w), 816(w, wide), and 408(w) have diffraction peaks.
  • the infrared spectrum (cm -1 ) of the supramolecular complex (complex) is in the important bands of 3383 (st, width), 1709 (m), 1634 (m), 1577 (st), 1549 (st), 1459 ( st), 1407(st), 1262(m), 1173(w), 762(m), 698(w), etc. have diffraction peaks.
  • thermogravimetric spectrum (TG) of the supramolecular complex (complex) shows that the water content of the supramolecular complex (complex) is 5.0%, and the supramolecular is measured by Karl Fischer method The water content of the complex (composite) is 4.9%. More specifically, the thermogravimetric analysis spectrum (TG) of the supramolecular complex (complex) is shown in FIG. 3.
  • the atomic absorption spectrum of the supramolecular complex (complex) shows that the calcium content of the supramolecular complex (complex) is 6.46%.
  • the structural unit of the supramolecular complex is: (EXP3174 ⁇ AHU377) 3- ⁇ 1.5Ca 2+ ⁇ 2.5H 2 O.
  • X-ray powder diffraction (XRD) spectrum of the supramolecular complex (complex) is similar to the aforementioned supramolecular complex (complex) X-ray powder diffraction (XRD) spectra are similar.
  • XRD X-ray powder diffraction
  • the X-ray powder diffraction (XRD) spectrum of the supramolecular complex (complex) is shown in FIG. 4.
  • the molar ratio of EXP3174 to AHU377 in the supramolecular complex (complex) can be obtained directly/indirectly by the content analysis method.
  • the high performance liquid method HPLC
  • the molar ratio is 1:1.
  • the molar ratio of EXP3174 to AHU377 in the supramolecular complex (complex) can be obtained directly/indirectly by the content analysis method.
  • the high performance liquid method HPLC
  • the molar ratio is 1:1.
  • DSC differential scanning calorimetry
  • the differential scanning calorimetry (DSC) of the supramolecular complex (complex) is the same as the differential scanning calorimetry (DSC) of the previous supramolecular complex
  • the difference is objective, and the differential scanning calorimetry (DSC) of the supramolecular complex (complex) is shown in Figure 5.
  • thermogravimetric spectrum (TG) of the supramolecular complex (complex) For the detection of the water content in the supramolecular complex (complex), methods commonly used in the art can be used, such as Karl Fischer method and/or thermogravimetric analysis. Specifically, after many repetitions, it was found that the difference between the thermogravimetric spectrum (TG) of the supramolecular complex (complex) and the thermogravimetric spectrum (TG) of the previous supramolecular complex is also objective. More specifically, the spectrum shows that the water content of the supramolecular complex (complex) is 3.97%, and the water content of the supramolecular complex (complex) measured by Karl Fischer method is 3.83%. More specifically, the thermogravimetric spectrum (TG) of the supramolecular complex (complex) is shown in FIG. 6.
  • the atomic absorption spectrum of the supramolecular complex (complex) shows that the calcium content of the supramolecular complex (complex) is 6.50%.
  • the measured values of the elemental analysis of the supramolecular complex are: C: 58.51%; H: 5.41%; N: 10.25%.
  • the structural unit of the complex is: (EXP3174 ⁇ AHU377) 3- ⁇ 1.5Ca 2+ ⁇ 2H 2 O.
  • 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 salt-sensitive hypertension.
  • EXP3174 allisartan medoxomil metabolite
  • AHU377 enkephalinase inhibitor
  • the compound of the present invention has obvious advantages over EXP3174, AHU377 substances and their combined use, as detailed in WO2017125031A1. Among them, according to the currently known clinical trial reports, AHU377 is difficult to be used as a clinical drug alone. The compound of the invention does not need to be reconfirmed in the new application of the present invention for its specific pharmacodynamic advantages over EXP3174, AHU377 alone and substance combination.
  • Figure 7 The effect of the compound of the present invention on the area under the curve of mean arterial pressure in DSS rats administered 28 days;
  • Figure 8 The effect of the compound of the present invention on the area under the curve of mean arterial pressure in SHR rats administered for 14 days.
  • 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 was made by the company, with a purity of 99.4%.
  • the X-ray powder diffraction (XRD) spectrum has strong absorption diffraction peaks at 2 ⁇ of 4.35°, 5.15°, 5.90°, 12.80°, and 15.85°, and the acceptable error range is ⁇ 0.2°.
  • the X-ray powder diffraction (XRD) spectrum of the supramolecular complex (complex) also has highly reproducible diffraction peaks at 2 ⁇ of 9.00°, 10.15°, and 15.02°, with acceptable errors The range is ⁇ 0.2°; more specifically, the X-ray powder diffraction spectrum shown in Figure 1 has the following peaks:
  • the Raman spectra of the obtained products are at wavelengths (cm -1 ) 3061 (m), 2935 (m, width), 1613 (st), 1521 (m), 1482 (w), 1286 (m), 995 (w) , 816 (w, width), 408 (w) have diffraction peaks.
  • the infrared spectrum (cm -1 ) of the resulting product is in the important bands of 3383 (st, width), 1709 (m), 1634 (m), 1577 (st), 1549 (st), 1459 (st), 1407 (st), There are diffraction peaks at 1262(m), 1173(w), 762(m), and 698(w).
  • Elemental analysis measured value: C: 57.81%; H: 5.48%; N: 10.36%.
  • Theoretical value (by (EXP3174 ⁇ AHU377) 3- ⁇ 1.5Ca 2+ ⁇ 2.5H 2 O): C: 58.08%; H: 5.47%; N: 10.31%.
  • the TG spectrum of the obtained product is shown in Figure 3, and the water content of the obtained product measured by thermogravimetric analysis (TG) is 5.0%.
  • the water content of the product obtained by Karl Fischer method was 4.9%.
  • the calcium content of the obtained product measured by atomic absorption method is 6.46%.
  • Elemental analysis measured value: C: 58.51%; H: 5.41%; N: 10.25%.
  • Theoretical value (by (EXP3174 ⁇ AHU377)3- ⁇ 1.5Ca2+ ⁇ 2H2O): C: 58.68%; H: 5.46%; N: 10.41%.
  • the TG spectrum of the obtained product is shown in Figure 6, and the water content of the obtained product measured by thermogravimetric analysis (TG) is 3.97%.
  • the water content of the product obtained by Karl Fischer method was 3.83%.
  • the calcium content of the obtained product measured by atomic absorption method was 6.50%.
  • the XRD spectrum of the obtained product tends to be consistent with the XRD spectrum of the product obtained in Example 2 (as shown in Figure 4).
  • the XRD spectrum of the supramolecular compound (complex) is 4.40°, 5.19° in 2 ⁇ , There is a strong absorption diffraction peak at 5.96°, and the acceptable error range is ⁇ 0.2°.
  • the XRD spectrum of the supramolecular compound (complex) also has repetitive diffraction peaks at 2 ⁇ of 15.82° and 26.34°, with an acceptable error range of ⁇ 0.2°; more specifically, shown in Figure 4.
  • the XRD spectrum is shown in Table 2 below:
  • the animals were surgically implanted with hypertension implants on the day of the experiment (Day 1). After 3 days of postoperative care, the animals were given 8% high-salt feed for modeling. On the 8th day of the modeling, the animals’ 24-hour basal blood pressure and heart rate were monitored through the DSI telemetry system, and they were randomly divided into 8 groups according to the basal blood pressure, with 0.3% low-salt feed The rearing group was used as the sham operation sham control group, and there were 9 experimental groups.
  • the prodrug of EXP3174 usually has an initial and maintenance dose of 240 mg once a day, 23 mpk (mg per kg) is preferred for experiments in rats.
  • the area under the mean arterial pressure curve (AUC 0-28day ) of 28 days of administration in each group was calculated.
  • the model Vehicle group had a significant increase in AUC 0-28day (P ⁇ 0.001).
  • Vehicle compared with the model group, LCZ696 group, EXP3174 group, Sha Kuba music group, the composite 23mpk group AUC 0 ⁇ 28day present invention were significantly reduced, wherein the AUC 0 ⁇ 28day group LCZ696 inhibition rate of 12.7%, EXP3174 group 14.5%, 8.3% in the sacubartra group, and 14.9% in the -23mpk group of the present invention.
  • the details are shown in Figure 7.
  • the average arterial pressure inhibition rate and AUC 0-28day inhibition rate of the complex of the present invention are significantly better than the only clinically confirmed drug LCZ696 at present.
  • the 14-day inhibition rate is increased by about 29%, and the 28-day inhibition rate is about increased. It is about 16%, and the dosage of the present invention is 23mg/kg, while the dosage of LCZ696 is 68mg/kg, this effect is difficult to predict.
  • the compound -23mpk group of the present invention uses the compound obtained in Example 3. Since the antihypertensive effect has basically entered a "platform" state at 14 days, only the effect of 14 days was measured.
  • the area under the mean arterial pressure curve (AUC 0-14day ) was calculated for each group after 14 days of administration.
  • the model Vehicle group had a significant increase in AUC 0-14day (P ⁇ 0.001).
  • Vehicle compared with the model group, LCZ696 group, EXP3174 group, complexes of the invention 23mpk AUC 0 ⁇ 14day group were significantly decreased, wherein the AUC 0 ⁇ 14day group LCZ696 inhibition rate of 12.4%, EXP3174 group was 11.7%, the composite of the present invention It was 8.6% in the -23mpk group.
  • the details are shown in Figure 8.
  • the average arterial pressure inhibition rate and AUC 0-28day inhibition rate of the compound of the present invention are not superior to the currently only clinically confirmed drug LCZ696 in the SHR spontaneous rat hypertension model. It can be seen that the present invention
  • the pharmaceutical composition has specific selectivity for salt-sensitive hypertension, and is expected to be used as a therapeutic drug for this indication. This effect is difficult to predict.

Abstract

一种属于药物应用技术领域、涉及血管紧张素II受体拮抗剂代谢产物与NEP抑制剂的复合物的新用途，具体涉及所述复合物在制备用于盐敏感型高血压的药物用途。

Description

血管紧张素II受体拮抗剂代谢产物与NEP抑制剂的复合物的新用途 技术领域
本发明属于药物应用技术领域，涉及血管紧张素II受体拮抗剂代谢产物与NEP抑制剂的复合物的新用途，具体涉及所述复合物在制备用于盐敏感型高血压的药物用途。
背景技术
高血压是以体循环动脉压增高为主要表现的临床综合征，是最常见的心血管疾病。并且，高血压的发病率呈不断上升的趋势，据统计，我国心血管病患者约为2.9亿人(《中国心血管病报告2013》)。高血压如果得不到有效的控制和治疗，可以引起冠状动脉硬化，出现冠心病、心绞痛，还可能造成高血压性心 ●脏病、心力衰竭等严重并发症。另外，长期高血压可导致肾、脑、心血管等器官损伤。
由于高血压的病因及发病机制多样，血压的控制不力往往会影响到机体多个器官的结构和功能，高血压患者也会同时伴有其他器官的疾病或病变，如心脑血管疾病、高血脂症等等。在治疗方面，联合使用机制不同的降压药有利于更好的控制血压，更重要的是，不同降压机制药物的联合使用可能具有协同作用，有利于降低药物使用量，进而达到降低药物副反应的目的。
已知的高血压病作用机制研究发现：高血压与全身小动脉痉挛引起血管外周阻力增加的直接后果，小动脉的痉挛与遗传/精神刺激、应激、肾脏缺血、肾上腺皮质的作用及钠的作用等诸多因素有关，目前动物高血压模型的复制多以不同角度模拟高血压这些易患因素而形成。具体的动物模型包括：自发性高血压大鼠(SHR)、神经原型、肾外包扎型和醋酸脱氧皮质酮(DOCA)盐型高血压大鼠、肾血管型高血压狗、盐敏感性和盐抵抗性高血压大鼠等。
根据《中国高血压防治指南(2018年修订版)》，钠盐可显著升高血压以及高血压的发病风险，适度减少钠盐摄入可有效降低血压。钠盐摄入过多和(或)钾摄入不足，以及“钾钠摄入比值”较低是我国高血压发病的重要危险因素。我国居民的膳食中75.8％的钠来自于家庭烹饪用盐，其次为高盐调味品和加工食品中的钠盐。所以，钠盐摄入过多是我国高血压疾病的重要诱因。然而，目前未有较为明确的针对性药物。
WO2007056546A1公开了一种缬沙坦(Valsartan)-沙库匹曲(Sacubitril)的钠盐复合物(LCZ696)及其制备方法，于2017年在中国获批上市，商品名：诺欣妥
Figure PCTCN2020092256-appb-000001
，用于射血分数降低的慢性心力衰竭(NYHA Ⅱ-Ⅳ级，LVEF≤40％)成人患者，降低心血管死亡和心力衰竭住院的风险。其分子结构单元如下：
Figure PCTCN2020092256-appb-000002
近期的 ●研究Hypertension，2017，69(1)：32-41报道，LCZ696在盐敏感亚洲人群中具有控制血压的效果。
另外，现有技术WO2017125031A1公开了一系列由血管紧张素受体拮抗剂代谢产物(EXP3174)与NEP抑制剂(Sacubitril)的复合物，该复合物相对于LCZ696在溶解性、吸 湿性、稳定性等方面具有优势，且具有优异的心衰效果；并且相对于EXP3174与Sacubitril单独或者联合使用具有其独特的应用优势。其分子结构单元如下：
Figure PCTCN2020092256-appb-000003
可知，寻找一种针对钠盐摄入过多而引起的高血压具有好的治疗效果的针对性药物至关重要。
发明内容
鉴于现有技术存在的技术问题，本发明提供了血管紧张素II受体拮抗剂代谢产物与NEP抑制剂的复合物(或者称之为“超分子络合物”)在制备用于盐敏感型高血压的药物用途，所述复合物的结构单元如下：
(aEXP3174·bAHU377)·xCa·nA。
作为本发明的一种优选技术方案，所述药物是指应用于患有所述盐敏感型高血压的患者；根据本发明的实验结果及前体药物的应用量推算，所述药物的单剂量形式是指以(aEXP3174·bAHU377)的总质量计约含有60毫克和500毫克之间的所述复合物，包括但不限于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。
作为本发明的一种更为优选技术方案，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。
在一种实施方案中，单剂量形式是指日剂量形式，给予患者含有60毫克/天至500毫克/天的所述复合物，所述给药次数包括但不限于1天1次，1天2次，1天3次，1天4次等。所述剂量是指药物应用的起始剂量或者维持剂量，在高血压的应用中，通常起始剂量低于维持剂量。所述剂量针对特殊情况的难治高血压患者，可能适当提高使用剂量。
在一种优选实施方案中，包括每天给予患者含有60、120、180、240、300、360、420或者480毫克的所述复合物。每天给予患者1次、2次或者3次所述复合物。更优选包括每天给予患者含有120、240或者480毫克的所述复合物，每天给予患者1次、2次或者3次。
具体的， ●所述推算方法包括按照前体药物日用量计算，EXP3174为阿利沙坦酯的体内代谢物，已上市药物通用名称：阿利沙坦酯片，英文名称：Allisartan Isoproxil Tablets，商品名称：信立坦，使用剂量为每天240mg。
其中，阿利沙坦酯的分子式为C 27H 29ClN 6O 5，分子量为553.0；而EXP3174的分子式为C 22H 21ClN 6O 2，分子量约为436.9；AHU377的分子式为C 24H 29NO 5，分子量约为411.5，复合物的日用量应相当于使用阿利沙坦酯的日用量，所以，推算得到前述的复合物的单剂量形式。
由SHR及DSS大鼠高血压模型数据可知，23mg/kg为该复合物在高血压动物模型上的 起效剂量，根据大鼠-人体表面积折算(人体重按照60kg计)，23mg/kg大鼠给药剂量约相当于人体给药剂量223mg，因此，推测人体起效剂量在200mg/天，剂量使用范围在200mg/天～500mg/天，即预期最高剂量约为起效剂量的2.5倍。
为了满足不同患者需求，特别是对于ARB类药物不耐受患者的临床用药，初始剂量建议略低于起效剂量，通常为起效剂量的几分之一，例如60mg、120mg、180mg等。
所述药物是适于口服的固体制剂，优选口服的片剂或胶囊，可以是多个片及多个胶囊的药物总量为6 ●0毫克和500毫克。
所述药物的所述复合物可以通过现有技术已知的方法获得，其中，WO2017125031A1公开的复合物及其制备方法引入本发明。
作为本发明的一种更为优选技术方案，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。
作为本发明的一种更为优选技术方案，所述复合物的结构单元如下：
(EXP3174·AHU377)·xCa·nH 2O
或者
Figure PCTCN2020092256-appb-000004
其中x为0.5～2之间的数值；n为0～3之间的数值。
作为本发明的一种更为优选技术方案，x选自0.5、1、1.5、2。
作为本发明的一种更为优选技术方案，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。
作为本发明的一种更为优选技术方案，n选自0.5、1、1.5、2、2.5、3。
作为本发明的一种更为优选技术方案，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。
本领域的技术人员可以理解，在超分子络合物(复合物)的单位晶胞中，所述阿利沙坦酯代谢产物(EXP3174)、AHU377、钙离子(Ca 2+)和溶剂分子会以数个结构单元的形式填 充于其中。
本发明所述超分子络合物(复合物)区别于两种活性成分通过简单的物理混合得到的混合物。所得超分子络合物(复合物)的XRD谱图明显区别于EXP3174和AHU377钙盐的XRD谱图，其在各溶剂(诸如水、乙醇、乙醇-水等)中的溶解性能也存在明显区别，在其他各项理化性质诸如吸湿性、熔点、红外谱图等均存在明显差异。
本发明的一个具体的超分子络合物(复合物)，该超分子络合物(复合物)的X-射线粉末衍射(XRD ●)谱图在2θ为4.35°、5.15°、5.90°、12.80°、15.85°处具有吸收较强的衍射峰，可接受的误差范围±0.2°，对于吸收强度强的峰，其受产品特性、检测仪器、检测条件等因素的影响较小，因此重复出现概率非常大，本领域的技术人员也可以理解，对于某些具体的化合物，受产品特性、检测仪器、检测条件等因素的影响，对于吸收强度较弱的峰，则可能不具有较高的可重现性，发明人在对同批/不同批样品的重复检测中也发现，对于该超分子络合物(复合物)也存在该现象。进一步的，该超分子络合物(复合物)的X-射线粉末衍射(XRD)谱图还在2θ为9.00°、10.15°、15.02°处具有重复性较强的衍射峰，可接受的误差范围±0.2°；更具体的，在一次检测中，该超分子络合物(复合物)的X-射线粉末衍射谱图具有如下峰：
编号 2θ(°，±0.2) 相对强度(％)
1 4.35 70.97
2 5.15 100.00
3 5.90 32.67
4 9.00 2.80
5 10.15 3.40
6 12.80 5.21
7 15.02 5.59
8 15.85 8.27
9 16.81 2.57
10 20.27 2.39
11 22.09 2.48
12 23.79 1.34
13 26.22 1.87
该超分子络合物(复合物)的X-射线粉末衍射(XRD)谱图如图1所示。
采用含量分析法可直接/间接得知超分子络合物(复合物)中EXP3174与AHU377的摩尔比，比如采用高效液相法(HPLC)可以测得超分子络合物(复合物)中EXP3174与AHU377(游离酸)的质量/含量进一步换算即可得知其摩尔比为1:1。
该超分子络合物(复合物)的差示扫描量热谱图(DSC)在94.4±10℃、164.1±10℃有两处失水吸热峰，由于该超分子络合物(复合物)含有结晶水，因此本领域的技术人员可以理解在不同的检测条件，诸如升温速率等，以及不同的样品性状，诸如样品粒径状态等，DSC谱图中的某些峰(诸如失水吸热峰)可能出现较大波动，比如不同升温速率下所得谱图的失水吸热峰位置出现相对较大位移区别，该谱图另在244.6±5℃处存在吸热峰。更具体的，该超分子络合物(复合物)的差示扫描量热谱图(DSC)如图2所示。
该超分子络合物(复合物)的拉曼光谱图在波长(cm -1)为3061(m)、2935(m，宽)、1613(st)、1521(m)、1482(w)、1286(m)、995(w)、816(w，宽)、、408(w)存在衍射峰，吸收波段的强度表示如下：(w)＝弱；(m)＝中；和(st)＝强。
该超分子络合物(复合物)的红外光谱(cm -1)在重要波段3383(st，宽)、1709(m)、1634(m)、1577(st)、1549(st)、1459(st)、1407(st)、1262(m)、1173(w)、762(m)、698(w)等存在衍射峰。吸收波段的强度表示如下：(w)＝弱；(m)＝中；和(st)＝强。
对于该超分子络合物(复合物)中含水量的检测可采用本领域常用的方法，如卡尔费休法和/或热重分析法。具体的，该超分子络合物(复合物)的热重分析谱图(TG)显示该超分子络合物(复合物)的含水量为5.0％，通过卡尔费休法测得该超分子络合物(复合物)的含水量为4.9％。更具体的，该超分子络合物(复合物)的热重分析谱图(TG)如图3所示。
该超分子络合物(复合物)的原子吸收谱图显示该超分子络合物(复合物)的钙含量为6.46％。
该超分子络 ●合物(复合物)的元素分析实测值为：C：57.81％；H：5.48％；N：10.36％。
综合以上信息判断，该超分子络合物(复合物)的结构单元为：(EXP3174·AHU377) 3-·1.5Ca 2+·2.5H 2O。
本发明的另一个具体的超分子络合物(复合物)，该超分子络合物(复合物)的X-射线粉末衍射(XRD)谱图与前述超分子络合物(复合物)的X-射线粉末衍射(XRD)谱图相近。具体的，其X-射线粉末衍射(XRD)谱图在2θ为4.40°、5.19°、5.96°处具有吸收较强的衍射峰，可接受的误差范围±0.2°；进一步的，该超分子化合物(复合物)的X-射线粉末衍射(XRD)谱 ●图还在2θ为15.82°、26.34°处具有重复性较强的衍射峰，可接受的误差范围±0.2°；更具体的，在一次检测中，所述超分子络合物(复合物)的X-射线粉末衍射谱图具有如下峰：
编号 2θ(°，±0.2) 相对强度(％)
1 4.40 77.30
2 5.19 100.00
3 5.96 19.78
4 15.82 5.11
5 26.34 3.44
该超分子络合物(复合物)的X-射线粉末衍射(XRD)谱图如图4所示。
采用含量分析法可直接/间接得知超分子络合物(复合物)中EXP3174与AHU377的摩尔比，比如采用高效液相法(HPLC)可以测得超分子络合物(复合物)中EXP3174与AHU377(游离酸)的质量/含量进一步换算即可得知其摩尔比为1:1。
采用含量分析法可直接/间接得知超分子络合物(复合物)中EXP3174与AHU377的摩尔比，比如采用高效液相法(HPLC)可以测得超分子络合物(复合物)中EXP3174与AHU377(游离酸)的质量/含量进一步换算即可得知其摩尔比为1:1。
其差示扫描量热谱图(DSC)在95.4±10℃、166.4±10℃有两处失水吸热峰，由于该超分子络合物(复合物)含有结晶水，因此本领域的技术人员可以理解在不同的检测条件，诸如升温速率等，以及不同的样品性状，诸如样品粒径状态等，DSC谱图中的某些峰(诸如失水吸热峰)可能出现较大波动，比如不同升温速率下所得谱图的失水吸热峰位置出现较大位移区别，该谱图另在242.4±5℃处存在吸热峰。更具体的，经多次重复发现，该超分子络合物(复合物)的差示扫描量热谱图(DSC)与前一个超分子络合物的差示扫描量热谱图(DSC)的差别是客观存在的，该超分子络合物(复合物)的差示扫描量热谱图(DSC)如图5所示。
对于该超分子络合物(复合物)中含水量的检测可采用本领域常用的方法，如卡尔费休法和/或热重分析法。具体的，经多次重复发现该超分子络合物(复合物)的热重分析谱图(TG)与前一个超分子络合物的热重分析谱图(TG)的差别同样是客观存在的，更具体的，谱图显示该超分子络合物(复合物)的含水量为3.97％，通过卡尔费休法测得该超分子络合物(复合物)的含水量为3.83％。更具体的，该超分子络合物(复合物)的热重分析谱图(TG)如图6所示。
该超分子络合物(复合物)的原子吸收谱图显示该超分子络合物(复合物)的钙含量为6.50％。
该超分子络合物(复合物)的元素分析实测值为：C：58.51％；H：5.41％；N：10.25％。
综合以上信息判断，该复合物的结构单元为：(EXP3174·AHU377) 3-·1.5Ca 2+·2H 2O。
本发明相对于现有技术具有如下的优点及有益效果：
1、本发明提供了一系列由阿利沙坦酯代谢产物(EXP3174)与脑啡肽酶抑制剂(AHU377)具有双重作用的超分子络合物(复合物)用于盐敏感型高血压的药物用途，其23mpk相对于使用LCZ696 68mpk具有明显更好的降压效果；
2、本发明复合物在SHR自发性高血压大鼠模型研究中的平均动脉压抑制率及AUC 0～28day抑制率并未优于目前唯一临床确认的药物LCZ696，由此可见，本发明药物组合物针对盐敏感型高血压具有特异的选 ●择性，是根据现有技术难以预计的。
3、本发明复合物相对于EXP3174、AHU377物质及组合使用具有明显的优势，详见于WO2017125031A1的记载，其中，根据现有已知的临床试验报道，AHU377难以单独作为临床药品使用，所以，本发明复合物无需在本发明新用途中再证实其相对于EXP3174、AHU377单独使用及物质组合的具体药效优势。
附图说明
图1.实 ●施例2所得复合物的XRD谱图；
图2.实施例2所得复合物的DSC谱图；
图3.实施例2所得复合物的TG谱图；
图4.实施例3所得复合物的XRD谱图；
图5.实施例3所得复合物的DSC谱图；
图6.实施例3所得复合物的TG谱图；
图7.本发明复合物对DSS大鼠给药28天平均动脉压曲线下面积的影响；
图8.本发明复合物对SHR大鼠给药14天平均动脉压曲线下面积的影响。
具体实施方式
下面结合实施例和附图对本发明作进一步详细的描述，但发明的实施方式不限于此。
以下实施例中：
X-射线粉末衍射采用锐影(Empyrean)X射线衍射仪设备检测，检测条件：Cu靶Kα射线，电压40KV，电流40mA，发射狭缝1/32°，防散射狭缝1/16°，防散射狭缝7.5mm，2θ范围：3°-60°，步长0.02°，每步停留时间40s。
差示扫描量热法谱图采用德国NETZSCH公司DSC204F1差示扫描量热仪设备检测，检测条件：气氛：N 2，20mL/min；扫描程序：从室温以10℃/min升温至250℃，记录升温曲线。
水份含量采用德国NETZSCH公司TG209热重分析仪设备检测，检测条件：气氛：N 2，20mL/min；扫描程序：室温-700℃，升温速率：10℃/min。
实施例所使用EXP3174通过公司自制，纯度98.3％。
实施例所使用AHU377钙盐通过公司自制，纯度99.4％。
实施例1
AHU377游离酸的制备：
将2.1g AHU377钙盐、40mL醋酸异丙酯加入250mL的单口瓶中，室温下加入2mol/L盐酸4.5mL搅拌溶清。分液，收集有机层，使用20mL水洗涤有机层两次；35℃下减压脱溶，得AHU377游离酸。
实施例2
复合物的制备：
Figure PCTCN2020092256-appb-000005
室温下，将依据实施例1方法所得的AHU377游离酸2.36g、EXP3174 2g与40mL丙酮加入至250mL三口瓶，溶清；室温下加入相对于AHU377 1.3当量的氢氧化钙固体和1mL水，室温搅拌10h，补加40mL丙酮，再反应8h，氮气保护下经布氏漏斗抽滤，固体用丙酮淋洗，得白色固体，35℃下真空烘8h，烘干得到固体3.5g，HPLC检测纯度为99％，通过含量测试计算可知所得产品中EXP3174与AHU377的摩尔比为1:1。
所得产品的X-射线粉末衍射谱图如图1所示，DSC谱图如图2所示。
通过与EXP3174及AHU377钙的XRD谱图的比对发现，所得产品的XRD谱图存在明显的区别，综合DSC谱图及HPLC检测分析，可判断所得产品为复合物。
具体的，X-射线粉末衍射(XRD)谱图在2θ为4.35°、5.15°、5.90°、12.80°、15.85°处具有吸收较强的衍射峰，可接受的误差范围±0.2°。进一步的，该超分子络合物(复合物)的X-射线粉末衍射(XRD)谱图还在2θ为9.00°、10.15°、15.02°处具有重复性较强的衍射峰，可接受的误差范围±0.2°；更具体的，图1所示X-射线粉末衍射谱图具有如下峰：
表1.实施例2所得产品XRD谱图峰位移
Figure PCTCN2020092256-appb-000006
Figure PCTCN2020092256-appb-000007
所得产品的拉曼光谱图在波长(cm -1)3061(m)、2935(m，宽)、1613(st)、1521(m)、1482(w)、1286(m)、995(w)、816(w，宽)、408(w)存在衍射峰。
所得产品的红外光谱(cm -1)在重要波段3383(st，宽)、1709(m)、1634(m)、1577(st)、1549(st)、1459(st)、1407(st)、1262(m)、1173(w)、762(m)、698(w)等存在衍射峰。吸收波段的强度表示如下：(w)＝弱；(m)＝中；和(st)＝强。
元素分析，实测值：C：57.81％；H：5.48％；N：10.36％。理论值(按(EXP3174·AHU377) 3-·1.5Ca 2+·2.5H 2O)：C：58.08％；H：5.47％；N：10.31％。
所得产品的TG谱图如图3所示，通过热重分析法(TG)测得所得产品的含水量为5.0％。
卡尔费休法测得所得产品的含水量为4.9％。
通过原子吸法测得所得产品的钙含量为6.46％。
综合判断所述复合物结构单元为：(EXP3174·AHU377) 3-·1.5Ca 2+·2.5H 2O。
实施例3
复合物的制备：
Figure PCTCN2020092256-appb-000008
室温下，将依据实施例1方法所得的AHU377游离酸2.36g、EXP3174 2g与40mL丙酮加入至250mL三口瓶，溶清；室温下加入相对于AHU377 1.6当量的氢氧化钙固体和0.6mL水，35℃搅拌6h，补加40mL丙酮，再反应8h，氮气保护下经布氏漏斗抽滤，固体用丙酮淋洗，得白色固体，50℃下真空烘8h，烘干得到固体3.1g，通过含量测试计算可知所得产品中EXP3174与AHU377的摩尔比为1:1。
所得产品的DSC谱图如图5所示。
元素分析，实测值：C：58.51％；H：5.41％；N：10.25％。理论值(按(EXP3174·AHU377)3-·1.5Ca2+·2H2O)：C：58.68％；H：5.46％；N：10.41％。
所得产品的TG谱图如图6所示，通过热重分析法(TG)测得所得产品的含水量为3.97％。
卡尔费休法测得所得产品的含水量为3.83％。
通过原子吸法测得所得产品的钙含量为6.50％。
综合判断所得产品结构单元为为：(EXP3174·AHU377) 3-·1.5Ca 2+·2H 2O。
所得产品的XRD谱图与实施例2所得产品的XRD谱图趋于一致(如图4所示)，具体的，该超分子化合物(复合物)的XRD谱图在2θ为4.40°、5.19°、5.96°处具有吸收较强的衍射峰，可接受的误差范围±0.2°。进一步的，该超分子化合物(复合物)的XRD谱图还在2θ为15.82°、26.34°处具有重复性较强的衍射峰，可接受的误差范围±0.2°；更具体的，图4所示XRD谱图具有如下表2所示：
表2.实施例3所得产品XRD谱图峰位移
●编号 2θ(°，±0.2) 相对强度(％)
1 4.40 77.30
2 5.19 100.00
3 5.96 19.78
4 15.82 5.11
5 26.34 3.44
实施例4
复合物的制备：
室温下，将依据实施例1方法所得的AHU377游离酸2.40g、EXP3174 2g与40mL丙酮、10mL异丙醇加入至250mL三口瓶，溶清；室温下加入相对于AHU377 1.5当量的氢氧化钙固体和1mL水，40℃搅拌6h，补加40mL丙酮，再反应8h，气保护下经布氏漏斗抽滤，固体用丙酮淋洗，得白色固体，35℃下真空烘16h，烘干得到固体3.3g，HPLC检测纯度为99％，通过含量测试计算可知所得产品中EXP3174与AHU377的摩尔比为1:1。
所得产品的XRD谱图、DSC谱图、拉曼光谱图、红外光谱均与实施例2所得产品趋于一致。
综合元素分析、含水量检测、钙含量检测综合判断所述复合物结构单元为：(EXP3174·AHU377) 3-·1.5Ca 2+·2.5H 2O。
实施例5
复合物的制备：
室温下，将依据实施例1方法所得的AHU377游离酸2.4g、EXP3174 2.1g与50mL异丙醇加入至250mL三口瓶，溶清；室温下加入相对于AHU377 1.4当量的氢氧化钙固体和0.6mL水，室温搅拌过夜，补加约40mL异丙醇，再反应8h，氮气保护下经布氏漏斗抽滤，固体用丙酮淋洗，得白色固体，50℃下真空烘10h，烘干得到固体2.8g，通过含量测试计算可知所得产品中EXP3174与AHU377的摩尔比为1:1。
所得产品的XRD、DSC谱图与实施例3所得产品趋于一致。
综合元素分析、含水量检测、钙含量等检测综合判断所述复合物结构单元为：(EXP3174·AHU377) 3-·1.5Ca 2+·2H 2O。
实施例6
复合物对盐敏感性大鼠(DSS)血压影响
方法：动物于实验当天(Day1)手术植入高血压植入子。术后护理3天，给予动物8％高盐饲料造模，造模第8天，通过DSI遥测系统监测动物24小时基础血压和心率，并根据基础血压随机分为8组，0.3％低盐饲料饲养组作为假手术sham对照组，实验共9组。造模第9天，按照分组和给药方案开始给药，每天给药1次，连续给药28天，测定给药第1、14、28天24小时平均动脉压(MAP)和以及给药28天血压曲线下面积AUC 0～28day抑制率。实验结果如表3所示：
由于所述EXP3174的前体药物阿利沙坦酯通常起始和维持剂量为每天一次240mg，在大鼠中优选23mpk(mg per kg)进行实验。计算方法包括：按照人标准体重60kg计，每公斤的应用剂量约为4mg/kg，而应用于大鼠时，大鼠剂量/人的剂量＝大鼠比表面积/人比表面积＝0.1525/0.02471＝6.17。
表3.本发明复合物对DSS大鼠24h平均动脉压(MAP)的影响(平均值±标准误)
Figure PCTCN2020092256-appb-000009
注：本发明复合物-23mpk组采用实施例3获得的化合物
对各组给药28天的24h平均动脉压曲线下面积(AUC 0～28day)进行统计，模型Vehicle组与假手术sham组相比，AUC 0～28day显著升高(P<0.001)。与模型Vehicle组比，LCZ696组、EXP3174组、沙库巴曲组、本发明复合物23mpk组AUC 0～28day均有明显的降低，其中LCZ696组AUC 0～28day抑制率为12.7％，EXP3174组为14.5％，沙库巴曲组为8.3％，本发明复合物-23mpk组为14.9％。具体如图7所示。
从上述结果可见，本发明复合物的平均动脉压抑制率及AUC 0～28day抑制率明显优于目前唯一临床确认的药物LCZ696，14天抑制率约提高了约29％，28天抑制率约提高了约16％，并且本发明使用剂量为23mg/kg，而LCZ696使用剂量为68mg/kg，此效果是难以预计的。
实施例7 复合物对自发性高血压大鼠(SHR)血压影响
方法：动物于实验当天(Day1)手术植入高血压植入子。术后恢复7-10天后，SHR大鼠根据基础血压随机分为5组，WKY大鼠作为假手术sham对照组，实验共6组。在Day10连续监测24小时基础血压和心率。Day 11按照分组和给药方案开始给药，每天给药1次，连续给药14天，观察给药第14天24小时平均动脉压(MAP)，以及给药14天血压曲线下面积AUC 0～14day抑制率。实验结果如表4所示：
表4.对SHR大鼠24h平均动脉压(MAP)的影响(平均值±标准误)
Figure PCTCN2020092256-appb-000010
注：本发明复合物-23mpk组采用实施例3获得的化合物，由于14天时降压效果已基本进入“平台”状态，故只测定了14天的效果。
对各组给药14天的24h平均动脉压曲线下面积(AUC 0～14day)进行统计，模型Vehicle组与假手术sham组相比，AUC 0～14day显著升高(P<0.001)。与模型Vehicle组比，LCZ696组、EXP3174组、本发明复合物23mpk组AUC 0～14day均有明显的降低，其中LCZ696组AUC 0～14day抑制率为12.4％，EXP3174组为11.7％，本发明复合物-23mpk组为8.6％。具体如图8所示。
从上述结果可见，本发明复合物的平均动脉压抑制率及AUC 0～28day抑制率在SHR自发性大鼠高血压模型上并未优于目前唯一临床确认的药物LCZ696，由此可见，本发明药物组合物针对盐敏感型高血压具有特异的选择性，预期可用于该适应症的针对治疗药物，此效果是难以预计的。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (10)

  1. 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盐敏感型高血压的药物用途，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。
  2. 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。
  3. 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。
  4. 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。
  5. 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。
  6. 根据权利要求1-5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)·xCa·nH 2O
    或者
    Figure PCTCN2020092256-appb-100001
    其中x为0.5～2之间的数值；n为0～3之间的数值。
  7. 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。
  8. 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。
  9. 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。
  10. 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。
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