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CN115461052B - Pharmaceutical use of complexes of ARB metabolites with NEP inhibitors for the prevention and/or treatment of kidney disease - Google Patents

Pharmaceutical use of complexes of ARB metabolites with NEP inhibitors for the prevention and/or treatment of kidney disease Download PDF

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CN115461052B
CN115461052B CN202180030740.8A CN202180030740A CN115461052B CN 115461052 B CN115461052 B CN 115461052B CN 202180030740 A CN202180030740 A CN 202180030740A CN 115461052 B CN115461052 B CN 115461052B
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complex
kidney disease
arb
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CN115461052A (en
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孙晶超
肖瑛
景小龙
王汝欢
胡雪峰
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Shenzhen Salubris Pharmaceuticals Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
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    • 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
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

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Abstract

Use of a complex of an ARB metabolite and a NEP inhibitor for the manufacture of a medicament for the prevention and/or treatment of kidney disease.

Description

Pharmaceutical use of complexes of ARB metabolites with NEP inhibitors for the prevention and/or treatment of kidney disease
Technical Field
The invention belongs to the technical field of medicine application, and relates to application of a complex of an ARB metabolite and an NEP inhibitor in preparing medicines for preventing and/or treating kidney diseases.
Background
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:
chronic kidney disease (chronic kidney disease, CKD) has the characteristics of high prevalence, low awareness, poor prognosis, high medical cost, and the like, and is a disease that is serious harm to human health following cardiovascular and cerebrovascular diseases, diabetes, and malignant tumors. In recent years, the prevalence of CKD is rising year by year, the prevalence of the general population is up to 14.3%, and the prevalence of CKD for people over 18 years old is 10.8% as shown by the research of cross-sectional epidemiology in China. Along with the aging of the population of China, the increasing incidence of diabetes, hypertension and other diseases, the incidence of CKD is also continuously rising.
It is known that it is important to find a targeted drug with good therapeutic effect against kidney disease.
Disclosure of Invention
In view of the technical problems of the prior art, the present invention provides the use of complexes (alternatively referred to as "supramolecular complexes") of ARB metabolites with NEP inhibitors for the preparation of a medicament for the prevention and/or treatment of kidney disease, the structural units of said complexes being as follows:
(aEXP3174·bAHU377)·xCa·nA。
as a preferred embodiment of the present invention, the kidney disease includes chronic kidney disease, and further includes chronic kidney disease complicated with hypertension, chronic kidney disease complicated with heart failure, and the like.
As a preferred embodiment of the invention, the kidney disease comprises CKD patients classified as A1, A2 and A3.
As a preferred technical scheme of the invention, the compound can effectively inhibit the rise of urinary albumin and/or urinary albumin/urinary creatinine ratio and/or urinary creatinine and blood creatinine of CKD patients.
Specifically, the chronic kidney disease refers to the guidelines for screening diagnosis and prevention and treatment of chronic kidney disease, volume 37, stage 1 in month 1 in 2017, journal of Chinese practical medicine, expert group of early discovery and standardization of diagnosis and treatment and demonstration of chronic kidney disease in Shanghai.
As a preferred embodiment of the present invention, the medicament is intended to be applied to a patient suffering from the kidney disease; according to the experimental results and the calculation of the amount of prodrug used in the present invention, the single dose form of the drug means that the complex contains between 60mg and 1000mg based on the total mass of (aEXP 3174. BAHU 377), including but not limited to 60mg, 70mg, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, 490mg, 500mg, 510mg, 520mg 530mg, 540mg, 550mg, 560mg, 570mg, 580mg, 590mg, 600mg, 610mg, 620mg, 630mg, 640mg, 650mg, 660mg, 670mg, 680mg, 690mg, 700mg, 710mg, 720mg, 730mg, 740mg, 750mg, 760mg, 770mg, 780mg, 790mg, 800mg, 810mg, 820mg, 830mg, 840mg, 850mg, 860mg, 870mg, 880mg, 890mg, 900mg, 910mg, 920mg, 930mg, 940mg, 950mg, 960mg, 970mg, 980mg, 990mg, 1000mg.
As a more preferred embodiment of the invention, the single dose form of the medicament contains 60, 120, 180, 240, 300, 360, 420, 480, 540, 600, 660, 720, 780, 840, 900, 960mg 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 1000 mg/day of the complex, including but not limited to 1 day 1,1 day 2,1 day 3,1 day 4, etc.
The medicament is a solid preparation suitable for oral administration, preferably an oral tablet or capsule, and the total amount of the medicament in a plurality of tablets and a plurality of capsules is 60mg to 1000mg.
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 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.
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 medicinal uses of supermolecule complex (compound) with double functions of an alisartan ester metabolite (EXP 3174) and an enkephalinase inhibitor (AHU 377) for preventing and/or treating kidney diseases, and the supermolecule complex has obviously better effect than LCZ696 at the same dosage;
2. 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.
Detailed Description
The present invention will be described in further detail with reference to examples, 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 (designated compound A). The test was repeated to obtain a sufficient amount of the drug effect test.
Example 4
4.1 reagents, test samples and instrument information
Sodium carboxymethyl cellulose: lot number: b1707016, shanghai aladine Biochemical technologies Co., ltd;
EXP3174: lot number: 20190501Z, huizi Xinritai pharmaceutical Co Ltd;
sha Kuba Qu Gaiyan: lot number: DYF20003, huizi pharmaceutical Co., ltd;
LCZ696: lot number: DYF19005, huizitai pharmaceutical Co., ltd;
compound a: lot number: SWV20001, huizitai pharmaceutical Co., ltd;
creatinine assay kit (sarcosine oxidase method): lot number: 141120017 Shenzhen Michael biomedical electronic Co., ltd;
albumin assay kit (bromocresol chloride method): lot number: 148320004 Shenzhen Michael biomedical electronic Co., ltd;
full-automatic biochemical analyzer: BS-240VET model, shenzhen Mairui biomedical electronics Co., ltd.
4.2 laboratory animals
80 healthy SPF-class male SD rats with weight of 180-220 g and quality qualification number of experimental animals of No.110011201106160342 are provided by Beijing vitamin Tonglihua experimental animal science and technology Co., ltd, and the production license number of experimental animals is SCXK 2016-0006. The test animals were kept at SPF-class laboratory animal center of Shenzhen Xinritai pharmaceutical Co., ltd. With license number SYXK 2019-0142, and were kept at SPF-class laboratory animal center.
4.3 preparation and grouping of rat 5/6 nephrectomy CKD model
After 1 week of adaptive feeding, rats were randomly divided into two groups, one group being sham operated (6) and the other group being operated to perform 5/6 nephrectomy (72). The rats in the operation group are anesthetized by 1.5% pentobarbital sodium (30 mg/kg) intraperitoneal injection, the prone position of the rats is fixed on a rat plate, skin preparation, conventional sterilization, sterile glove wearing, sterile gauze laying, longitudinal incision about 0.5cm below the dorsal aspect of the rib at the left side and about 1cm at the left side of the spine, incision about 1cm long, abdominal incision layer by layer, kidney positioning beside the spine, kidney full exposure, kidney capsule stripping, 1/3 resection of the two ends of the kidney respectively, hemostasis by gelatin sponge compression section, incision layer by layer suture, penicillin sodium intramuscular injection anti-infection, daily observation and conventional nursing. After 1 week, the right kidney was excised in the same surgical manner. Two surgeries cut 5/6 kidney altogether. The sham group only separated fat sacs, without resecting kidney tissue.
The animals surviving the second operation were recovered and raised for 3 weeks and were grouped, each rat was weighed, heparin was anticoagulated and blood was collected, plasma creatinine was detected, and group random grouping was performed according to the plasma creatinine level using SPSS software, and the groups were divided into model group, EXP3174 group (35 mg/kg), sha Kuba Qu Zu (33 mg/kg), LCZ696 low dose group (34 mg/kg), LCZ696 high dose group (68 mg/kg), compound A low dose group (34 mg/kg), compound A high dose group (68 mg/kg), 5 to 6 each group. The administration by gastric lavage was started on the next day of the group, the administration volume was 10mL/kg, 1 time a day, and the administration was continued for 4 weeks. The sham operation group and the model group were given 0.5% CMC-Na vehicle daily in a volume of 10mL/kg. Blood was collected from the tail vein and 24h urine was collected from the metabolic cage at week 4 of the experiment, respectively.
4.4 detection indicators and methods
Plasma creatinine, urinary albumin and urinary creatinine concentrations were measured at week 4 post-administration and the 24h urinary albumin amount and urinary albumin/urinary creatinine ratio were calculated.
4.5 statistical methods
Experimental data are all expressed as mean ± standard deviation, statistics using SPSS24.0 software, and are counted as follows: firstly, normal distribution (shape-Wilk test) and variance alignment (level's test) analysis are carried out, if the data accords with the normal distribution (P > 0.05) and the variance alignment (P > 0.05), SNK test in single factor analysis of variance (ANOVA) is carried out, and if the analysis result P <0.05 is significant; if the data does not accord with normal distribution (P < 0.05) or variance is uneven (P < 0.05), two independent sample tests in non-parameter test are selected, and if the analysis result P <0.05, the data has significance.
4.6 experimental results
Remarks: in contrast to the sham-operated group, # P<0.05; compared with the model group, the method has the advantages of high accuracy, * P<0.05; in comparison to an equimolar LCZ696, $ P<0.05， $$ P<0.01; compared with the equimolar EXP3174, && P<0.01; in comparison to an equimolar AHU377, ^^ P<0.01。
remarks: in contrast to the sham-operated group, # P<0.05; compared with the model group, the method has the advantages of high accuracy, * P<0.05; in comparison to an equimolar LCZ696, $ P<0.05， $$ P<0.01; compared with the equimolar EXP3174, && P<0.01; in comparison to an equimolar AHU377, ^^ P<0.01。
remarks: in contrast to the sham-operated group, ## P<0.01; compared with the model group, the method has the advantages of high accuracy, ** P<0.01; in comparison to an equimolar AHU377, ^ P<0.05。
from the results, the compound has obviously better effect than that of LCZ696 with equimolar dosage in the CKD model in the indexes of 24h urinary albumin, urinary albumin/urinary creatinine ratio; meanwhile, the compound of the invention has better effect compared with the single administration of the EXP3174 and AHU377 with equimolar dosages, which fully shows that the compound has obvious advantages.
Moreover, the effect of the compound in CKD model in index of blood creatinine is obviously better than that of LCZ696 in equimolar dosage; meanwhile, the compound of the invention has better effect compared with the single administration of the EXP3174 and AHU377 with equimolar dosages, which fully shows that the compound has obvious advantages.
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 ARB metabolite with a NEP inhibitor in the manufacture of a medicament for the prevention and/or treatment of chronic kidney disease, the ARB metabolite being EXP3174 and the NEP inhibitor being AHU377, the complex exhibiting a significant reduction of plasma creatinine, urinary albumin and urinary creatinine, the structure of the complex being as follows:
  2. 2. use of a complex of an ARB metabolite and a NEP inhibitor according to claim 1 in the manufacture of a medicament for the prevention and/or treatment of kidney disease, characterized in that: the single dosage form of the drug is based on the total mass of (EXP 3174 AHU 377),
    ，
    containing between 60mg and 1000mg of said complex.
  3. 3. Use of a complex of an ARB metabolite and a NEP inhibitor according to claim 1 in the manufacture of a medicament for the prevention and/or treatment of kidney disease, characterized in that: the single dosage form of the drug is based on the total mass of (EXP 3174 AHU 377),
    ，
    containing 60, 120, 180, 240, 300, 360, 420, 480, 540, 600, 660, 720, 780, 840, 900 or 960 milligrams of said complex.
  4. 4. Use of a complex of an ARB metabolite and a NEP inhibitor according to claim 1 in the manufacture of a medicament for the prevention and/or treatment of kidney disease, characterized in that: the medicament is a solid formulation suitable for oral administration.
  5. 5. Use of a complex of an ARB metabolite and a NEP inhibitor according to claim 4 in the manufacture of a medicament for the prevention and/or treatment of kidney disease, characterized in that: the oral solid preparation is selected from oral tablet or capsule.
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