CN115461052A - Pharmaceutical use of a complex of an ARB metabolite and a NEP inhibitor for the prevention and/or treatment of renal disease - Google Patents

Pharmaceutical use of a complex of an ARB metabolite and a NEP inhibitor for the prevention and/or treatment of renal disease Download PDF

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CN115461052A
CN115461052A CN202180030740.8A CN202180030740A CN115461052A CN 115461052 A CN115461052 A CN 115461052A CN 202180030740 A CN202180030740 A CN 202180030740A CN 115461052 A CN115461052 A CN 115461052A
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ahu377
exp3174
complex
pharmaceutical use
use according
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CN115461052B (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
    • 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
    • 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

Abstract

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

Description

Pharmaceutical use of a complex of an ARB metabolite and a NEP inhibitor for the prevention and/or treatment of renal disease Technical Field
The invention belongs to the technical field of medicine application, and relates to application of a compound of an ARB metabolite and a NEP inhibitor in preparation of a medicine for preventing and/or treating nephropathy.
Background
WO2007056546A1 discloses a sodium salt complex (LCZ 696) of Valsartan (Valsartan) -sackurtz (secubitril) and a preparation method thereof, which were sold in china in 2017 under the trade name:
Figure PCTCN2021132617-APPB-000001
can be used for treating heart failure. The molecular structural unit is as follows:
Figure PCTCN2021132617-APPB-000002
in addition, WO2017125031A1 discloses a series of complexes of angiotensin receptor antagonist metabolites (EXP 3174) and NEP inhibitors (securitil) and shows certain effects on heart failure HFpEF with preserved ejection fraction, the molecular structural units of which are as follows:
Figure PCTCN2021132617-APPB-000003
chronic Kidney Disease (CKD) is a disease seriously harming human health following cardiovascular and cerebrovascular diseases, diabetes and malignant tumors, and has the characteristics of high prevalence rate, low awareness rate, poor prognosis, high medical cost and the like. In recent years, the prevalence rate of CKD is increased year by year, the prevalence rate of general population in the world is up to 14.3%, and cross section epidemiological research in China shows that the prevalence rate of CKD of people over 18 years old is 10.8%. With the aging population of China and the increasing incidence of diseases such as diabetes, hypertension and the like, the incidence of CKD also rises continuously.
It is known that finding a targeted drug with good therapeutic effect against renal disease is crucial.
Disclosure of Invention
In view of the technical problems of the prior art, the present invention provides the use of a complex (alternatively referred to as "supramolecular complex") of an ARB metabolite and a NEP inhibitor, the building blocks of which are as follows, for the preparation of a medicament for the prevention and/or treatment of renal disease:
(aEXP3174·bAHU377)·xCa·nA。
as a preferable technical scheme of the invention, the nephropathy comprises chronic kidney diseases, and further comprises chronic kidney diseases with hypertension, chronic kidney diseases with heart failure and the like.
As a preferred embodiment of the present invention, the renal disease comprises CKD patients classified as A1, A2 and A3.
As a preferred technical scheme, the compound can effectively inhibit urinary albumin and/or urinary albumin/urinary creatinine ratio and/or increase of urinary creatinine and blood creatinine of CKD patients.
Specifically, the chronic kidney diseases are referred to "guidelines for screening, diagnosing, and preventing chronic kidney diseases", vol.37, no.1, month 1, 2017, journal of chinese practical medicine, and shanghai early discovery of chronic kidney diseases and standardized diagnosis and demonstration project expert group.
As a preferred technical scheme of the invention, the medicament is applied to patients suffering from the nephropathy; according to the experimental results and the amount of prodrug used, the single dose form of the drug means that the drug contains the compound between 60mg and 1000mg in terms of 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 dosage form of the medicament comprises 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, and the patient is administered a dose containing from 60 mg/day to 1000 mg/day of the complex, including, but not limited to, 1 time a day, 1, 2 times a day, 3 times a day, 4 times a day, etc.
The medicine is a solid preparation suitable for oral administration, preferably oral tablets or capsules, and the total amount of the medicine 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 the preparation method thereof are incorporated in the present invention.
As a more preferred embodiment of the present invention, the value of a.
In a more preferred embodiment of the present invention, the structural units of the complex are as follows:
(EXP3174·AHU377)·xCa·nH 2 O
or
Figure PCTCN2021132617-APPB-000004
Wherein x is a number between 0.5 and 2; n is a number between 0 and 3.
In a more preferred embodiment of the present invention, x is selected from 0.5,1, 1.5 and 2.
As a more preferable technical scheme of the invention, the structural unit of the compound is as follows:
(EXP3174·AHU377)·1.5Ca·nH 2 O
or
(EXP3174·AHU377)·2Ca·nH 2 O
Wherein n is any value between 1 and 3.
In a more preferred embodiment of the present invention, n is selected from 0.5,1, 1.5, 2, 2.5 and 3.
As a more preferred embodiment of the present invention, the complex is selected from the group consisting of:
(EXP3174·AHU377)·1.5Ca·1H 2 O；
(EXP3174·AHU377)·1.5Ca·1.5H 2 O；
(EXP3174·AHU377)·1.5Ca·2H 2 O；
(EXP3174·AHU377)·1.5Ca·2.5H 2 O；
(EXP3174·AHU377)·1.5Ca·3H 2 O；
(EXP3174·AHU377)·2Ca·1H 2 O；
(EXP3174·AHU377)·2Ca·1.5H 2 O；
(EXP3174·AHU377)·2Ca·2H 2 O；
(EXP3174·AHU377)·2Ca·2.5H 2 O；
(EXP3174·AHU377)·2Ca·3H 2 O。
it will be understood by those skilled in the art that in the unit cell of the supramolecular complex (complex), the alisartan medoxomil metabolite (EXP 3174), AHU377, calcium ion (Ca) 2+ ) And solvent molecules will fill in it in the form of several building blocks.
The supramolecular complexes (complexes) according to the invention are distinguished from mixtures of two active ingredients obtained by simple physical mixing. The XRD spectrum of the obtained supramolecular complex is obviously different from those of EXP3174 and AHU377 calcium salt, and the solubility in each solvent (such as water, ethanol-water, etc.) is also obviously different, and other physicochemical properties such as hygroscopicity, melting point, infrared spectrum, etc. are also obviously different.
Compared with the prior art, the invention has the following advantages and beneficial effects that:
1. the invention provides a series of medicinal uses of supramolecular complex (compound) with double functions of alisartan medoxomil metabolite (EXP 3174) and enkephalinase inhibitor (AHU 377) for preventing and/or treating nephropathy, wherein the supramolecular complex (compound) has obviously better effect compared with LCZ696 under the same dosage;
2. compared with the physical mixture of EXP3174 and AHU377, the compound of the invention has better effect, which fully shows that the use of the compound has obvious advantages compared with the use of the pharmaceutical physical combination.
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the invention are not limited thereto.
The following examples:
the X-ray powder diffraction is detected by adopting an X-ray diffractometer with a sharp shadow (Empyrean), and the detection conditions are as follows: cu target Kalpha ray, voltage 40KV, current 40mA, emission slit 1/32 degrees, anti-scattering slit 1/16 degrees, anti-scattering slit 7.5mm,2 theta range: 3-60 degrees, step length 0.02 degrees and residence time of 40s in each step.
DifferentialThe scanning calorimetry spectrogram is detected by adopting a DSC204F1 differential scanning calorimeter device of Germany NETZSCH company, and the detection conditions are as follows: atmosphere: n is a radical of 2 20mL/min; and (3) scanning procedure: the temperature was raised from room temperature to 250 ℃ at 10 ℃/min and the temperature rise curve was recorded.
The moisture content is detected by adopting a TG209 thermogravimetric analyzer device of Germany NETZSCH company, and the detection conditions are as follows: atmosphere: n is a radical of 2 20mL/min; and (3) scanning procedure: room temperature-700 ℃, heating rate: 10 ℃/min.
The EXP3174 used in the examples was prepared by the company having a purity of 98.3%.
The calcium salt of AHU377 used in the examples was made by the company as 99.4% pure.
Example 1
Preparation of AHU377 free acid:
2.1g of AHU377 calcium salt, 40mL of isopropyl acetate was added to a 250mL single-neck flask, and 4.5mL of 2mol/L hydrochloric acid was added to the flask at room temperature and dissolved by stirring. 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 complex: (prepared according to example 2 of patent WO2017125031A 1)
Figure PCTCN2021132617-APPB-000005
Adding 2.36g of AHU377 free acid obtained according to the method of example 1, 2g of EXP3174 and 40mL of acetone into a 250mL three-neck bottle at room temperature, and dissolving; adding 1.3 equivalents of calcium hydroxide solid and 1mL of water relative to AHU377 at room temperature, stirring at room temperature for 10h, adding 40mL of acetone, reacting for 8h, filtering with a Buchner funnel under nitrogen protection, leaching the solid with acetone to obtain white solid, vacuum drying at 35 deg.C for 8h, and oven drying to obtain solid 3.5g (EXP 3174. AHU 377) 3- ·1.5Ca 2+ ·2.5H 2 And O, the purity is 99 percent by HPLC detection. The test was repeated to obtain sufficient dose for the pharmacodynamic test.
Example 3
Preparation of the complex: (prepared according to example 3 of patent WO2017125031A 1)
Figure PCTCN2021132617-APPB-000006
2.36g of AHU377 free acid obtained according to the method of example 1, 2g of EXP3174 and 40mL of acetone are added into a 250mL three-neck flask at room temperature and dissolved to be clear; adding 1.6 equivalents of calcium hydroxide solid and 0.6mL of water relative to AHU377 at room temperature, stirring for 6h at 35 ℃, adding 40mL of acetone, reacting for 8h, filtering by a Buchner funnel under the protection of nitrogen, leaching the solid by acetone to obtain a white solid, drying for 8h in vacuum at 50 ℃, and drying to obtain 3.1g of solid (EXP 3174. AHU 377) 3- ·1.5Ca 2+ ·2H 2 O (designated Compound A). The test was repeated to obtain sufficient dose for the pharmacodynamic test.
Example 4
4.1 reagent, test article and Instrument information
Sodium carboxymethylcellulose: batch number: b1707016, shanghai Aladdin Biotechnology, inc.;
EXP3174: batch number: 20190501Z, huizhou xinlite pharmaceutical ltd;
calcium salt of Shakuba kojic: batch number: DYF20003, huizhou believitai pharmaceuticals ltd;
LCZ696: batch number: DYF19005, huizhou believitai pharmaceuticals, ltd;
s086: batch number: SWV20001, huizhou Xin Li Tai pharmaceuticals Co., ltd;
creatinine assay kit (sarcosine oxidase method): batch number: 141120017, shenzhen meirui biomedical electronics, incorporated;
albumin assay kit (bromocresol chloride method): batch number: 148320004, shenzhen mairui biomedical electronics incorporated, inc.;
full-automatic biochemical analyzer: BS-240VET model, shenzhen Merry biomedical electronics, inc.
4.2 Experimental animals
80 healthy SPF male SD rats with weight of 180-220 g and quality certification number of experimental animals of No.110011201106160342 are provided by Beijing Wintonlifa experimental animal science and technology Limited, and the production license number of the experimental animals is SCXK (Beijing) 2016-0006. The animal is bred in the SPF level experimental animal center of Shenzhen Xin Li Tai pharmaceutical industry, the number of the approved license is SYXK (Guangdong) 2019-0142, and the animal is bred in the SPF level experimental animal center.
4.3 rat 5/6 nephrectomy CKD model preparation and grouping
After 1 week of acclimatization, the rats were randomly divided into two groups, one group was a sham-operated group (6), and the other group was subjected to 5/6 nephrectomy (72) as an operated group. The rats in the operation group are anesthetized by intraperitoneal injection of 1.5% sodium pentobarbital (30 mg/kg), the prone position of the rat is fixed on a rat board, the rat board is prepared, the rat board is disinfected conventionally, sterile gloves are worn, sterile gauze is laid, a longitudinal incision is made on the back of the rat, about 0.5cm below the left side rib point and about 1cm on the left side of the spine, the rat board is about 1cm long, the rat board is cut into the abdomen layer by layer, the kidney is located beside the spine, the kidney is fully exposed, the kidney envelope is peeled off, 1/3 of the two ends of the kidney are respectively cut off, the section is pressed by gelatin sponge to stop bleeding, the incision is sewed layer by layer, penicillin sodium intramuscular injection is used for resisting infection, and daily observation and routine nursing are carried out. The right kidney was resected 1 week later in the same surgical manner. The 5/6 kidney was excised by two operations. Only the fat sac was isolated in the sham group, and no kidney tissue was excised.
The surviving animals after the second operation are recovered and raised for 3 weeks for grouping, each rat is numbered and weighed, heparin anticoagulated and blood-collected, plasma creatinine is detected, SPSS software is used for carrying out block random grouping according to the plasma creatinine level, and the groups are divided into a model group, an EXP3174 group (35 mg/kg), a Shakuba kojiu group (33 mg/kg), an LCZ696 low dose group (34 mg/kg), an LCZ696 high dose group (68 mg/kg), an S086 low dose group (34 mg/kg) and an S086 high dose group (68 mg/kg), and each group comprises 5-6 animals. The administration by gavage is started on the following days, the administration volume is 10mL/kg, 1 time per day, and the administration is continued for 4 weeks. The sham-operated group and the model group were administered 0.5% of the CMC-Na vehicle per day in a volume of 10mL/kg. Blood was collected from the tail vein and urine was collected in a metabolic cage for 24h at week 4 of the experiment, respectively.
4.4 detection indices and methods
Plasma creatinine, urinary albumin and urinary creatinine concentrations were measured at 4 weeks post-dose, and urinary albumin amount and urinary albumin/urinary creatinine ratio were calculated for 24 h.
4.5 statistical methods
The experimental data are all expressed as mean ± standard deviation, and the statistics are performed by using SPSS24.0 software according to the following method: firstly, analyzing normal distribution (Shapiro-Wilk test) and variance homogeneity (Leven's test), if the data accords with the normal distribution (P > 0.05) and the variance homogeneity (P > 0.05), carrying out SNK test in one-way variance analysis test (ANOVA), and if the analysis result P <0.05, having significance; if the data do not conform to normal distribution (P < 0.05) or variance is not uniform (P < 0.05), two independent sample tests in nonparametric tests are selected, and if the analysis result P <0.05, the significance is obtained.
4.6 results of the experiment
Figure PCTCN2021132617-APPB-000007
Remarking: compared with the group of the pseudo-operation, # P<0.05; in comparison to the model set, * P<0.05; compared with the equimolar LCZ696, $ P<0.05， $$ P<0.01; in comparison with an equimolar EXP3174 ratio, && P<0.01; compared with an equimolar AHU377 ratio, ^^ P<0.01。
Figure PCTCN2021132617-APPB-000008
remarking: compared with the group of the false operation, # P<0.05; in comparison to the model set, * P<0.05; compared with the equimolar LCZ696, $ P<0.05， $$ P<0.01; in comparison with an equimolar EXP3174 ratio, && P<0.01; compared with an equimolar AHU377 ratio, ^^ P<0.01。
Figure PCTCN2021132617-APPB-000009
remarking: compared with the group of the false operation, ## P<0.01; in comparison to the model set, ** P<0.01; compared with an equimolar AHU377 ratio, ^ P<0.05。
from the results, the effect of the compound in the CKD model at the index of 24h urine albumin, urine albumin \ urine creatinine ratio is obviously better than that of LCZ696 with equal molar dose; meanwhile, compared with the single administration of EXP3174 and AHU377 with equimolar dose, the compound of the invention has better effect, and fully shows that the compound has obvious advantages.
In addition, the effect of the compound of the invention on the CKD model is obviously better than that of LCZ696 under the condition of equimolar dose; meanwhile, compared with the single administration of EXP3174 and AHU377 with equimolar dose, the compound of the invention has better effect, and the obvious advantages of the compound are fully demonstrated.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims (11)

  1. 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, said complex having the structural elements:
    (aEXP3174·bAHU377)·xCa·nA
    wherein a: b = 1; x is a number between 0.5 and 3; a refers to water, methanol, ethanol, 2-propanol, acetone, ethyl acetate, methyl-tert-butyl ether, acetonitrile, toluene, dichloromethane; n is a number between 0 and 3.
  2. The pharmaceutical use according to claim 1, wherein: the nephropathy comprises chronic kidney disease, and further comprises chronic kidney disease combined with hypertension and chronic kidney disease combined with heart failure.
  3. The pharmaceutical use according to claim 1 or 2, wherein: a single dose form of the medicament contains between 60mg and 1000mg of the complex.
  4. The pharmaceutical use according to claim 1 or 2, wherein: single dose forms of the medicament contain 60, 120, 180, 240, 300, 360, 420, 480, 540, 600, 660, 720, 780, 840, 900, 960 milligrams of the complex.
  5. The pharmaceutical use according to claim 1 or 2, wherein: the medicament is a solid formulation suitable for oral administration, preferably a tablet or capsule for oral administration.
  6. The pharmaceutical use according to any one of claims 1 to 5, wherein: the value of a to b is selected from 1.25,1.
  7. The pharmaceutical use according to any one of claims 1 to 6, wherein: the structural units of the complex are as follows:
    (EXP3174·AHU377)·xCa·nH 2 O
    or alternatively
    Figure PCTCN2021132617-APPB-100001
    Wherein x is a number between 0.5 and 2; n is a number between 0 and 3.
  8. The pharmaceutical use according to any one of claims 1 to 7, wherein: x is selected from 0.5,1, 1.5 and 2.
  9. The pharmaceutical use according to any one of claims 1 to 8, wherein: 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 value between 1 and 3.
  10. The pharmaceutical use according to any one of claims 1 to 9, wherein: n is selected from 0.5,1, 1.5, 2, 2.5, 3.
  11. The pharmaceutical use according to any one of claims 1 to 10, wherein the complex is selected from the group consisting of:
    (EXP3174·AHU377)·1.5Ca·1H 2 O；
    (EXP3174·AHU377)·1.5Ca·1.5H 2 O；
    (EXP3174·AHU377)·1.5Ca·2H 2 O；
    (EXP3174·AHU377)·1.5Ca·2.5H 2 O；
    (EXP3174·AHU377)·1.5Ca·3H 2 O；
    (EXP3174·AHU377)·2Ca·1H 2 O；
    (EXP3174·AHU377)·2Ca·1.5H 2 O；
    (EXP3174·AHU377)·2Ca·2H 2 O；
    (EXP3174·AHU377)·2Ca·2.5H 2 O；
    (EXP3174·AHU377)·2Ca·3H 2 O。
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