CN108619138B - Compound of angiotensin receptor antagonist and enkephalinase inhibitor and application thereof - Google Patents
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Abstract
The invention provides a compound of an angiotensin receptor antagonist and an enkephalinase inhibitor and application thereof, the compound consists of the angiotensin receptor antagonist and the enkephalinase inhibitor, the angiotensin receptor antagonist and the enkephalinase inhibitor can be directly mixed or indirectly connected through hydrogen bonds, the property of a sodium cocrystal hydrate formed by the hydrogen bond connection is more stable, and the pharmacokinetic property is obviously provided; although the action mechanisms of the angiotensin receptor antagonist and the enkephalinase inhibitor are different, the compound formed by the angiotensin receptor antagonist and the enkephalinase inhibitor has unexpected synergistic effect and has positive application prospect in the treatment field of heart failure resistance and hypertension resistance.
Description
The application is a divisional application of Chinese patent application with the application number of 201610627302.0, the application date of 2016, 08 and 01, and the title of the invention is "a compound of angiotensin receptor antagonist and enkephalinase inhibitor and the application thereof".
Technical Field
The invention belongs to the field of medicaments for treating cardiovascular system diseases, and particularly relates to a compound of an angiotensin receptor antagonist and an enkephalinase inhibitor and application thereof.
Background
Heart failure (heart failure for short) is a complex group of clinical symptoms, is a severe stage of various heart diseases, has high morbidity, and has a survival rate of 5 years similar to that of malignant tumors. The incidence of heart failure will continue to increase in the near future, becoming the most important cardiovascular disorder in the 21 st century.
According to foreign statistics, the prevalence rate of heart failure in the population is about 1.5E-2.0E, and can reach 6% -10% above 65 years old, and death caused by heart failure is increased by 6 times in the last 40 years. Heart failure is the initial damage to the heart muscle (e.g., myocardial infarction, cardiomyopathy, hemodynamic overload, inflammation, etc.) from any cause, resulting in structural and functional changes in the heart muscle, ultimately resulting in poor ventricular pumping and/or filling function. The main manifestations are dyspnea, weakness and fluid retention. Heart failure is a progressive disorder that once initiated, even without new myocardial damage, is clinically in a stable stage and can develop itself continuously. Heart failure is classified into acute heart failure and chronic heart failure.
Acute heart failure (acute heart failure) is clinically the most common of acute left heart failure and less common of acute right heart failure. Acute left heart failure refers to the clinical syndrome of acute pulmonary congestion, pulmonary edema, tissue organ perfusion insufficiency and cardiogenic shock caused by acute attack or aggravated left heart dysfunction, such as marked reduction of myocardial contractility, aggravated heart load, acute cardiac output drop, sudden increase of pulmonary circulation pressure, and increased peripheral circulation resistance. Acute right heart failure refers to the clinical syndrome of sudden decrease of myocardial contractility in the right ventricle or sudden increase of the front and rear loads in the right ventricle caused by some reasons, thereby causing a sudden decrease of right cardiac output. Acute heart failure can suddenly become sick or be aggravated acutely on the basis of the original chronic heart failure, and most of the acute heart failure can be manifested as systolic heart failure or diastolic heart failure; most patients before onset have an organic cardiovascular disease. For acute heart failure occurring on the basis of chronic heart failure, the condition is stable after treatment, and the acute heart failure is not called again. Acute heart failure often endangers life and must be rescued and treated urgently.
The treatment of Chronic Heart Failure (CHF) has changed very significantly since the 90 s of the 20 th century: moving from short-term hemodynamic/pharmacological measures to long-term, reparative strategies, the aim is to alter the biological properties of the failing heart. The treatment target of heart failure is not only symptom improvement and life quality improvement, but also prevention and delay of the development of myocardial remodeling aiming at the mechanism of myocardial remodeling, thereby reducing the death rate and hospitalization rate of heart failure.
Neprilysin inhibitors, also known as neutral endopeptidase inhibitors, are zinc-containing metalloproteases that cleave peptide substrates on the amino terminus of various hydrophobic residues. Substrates for this enzyme include, but are not limited to, Atrial Natriuretic Peptide (ANP), Brain Natriuretic Peptide (BNP), methionine enkephalin and leucine enkephalin, bradykinin, neurokinin A, endothelin-1, and substance P. It has been disclosed that enkephalinase inhibitors have the effect of enhancing hypotension, diuresis, natriuresis and plasma ANF response in experimental animals. And the prior art also discloses that enkephalinase inhibitors also have anti-heart failure efficacy. Commonly used enkephalinase inhibitors include candesartan, racecadotril, dexcadotril, seofulfin, caratoxaphen, pentobarbital sodium, Phe-Leu dipeptide sulfhydryl derivatives, and the like.
Hypertension is the most common disease of cardiovascular system, and is a progressive cardiovascular syndrome with continuous increase of arterial blood pressure as the main characteristic, most of the hypertension causes are unknown, and is primary hypertension, and the patients account for more than 95 percent of the hypertension; secondary hypertension is mostly hypertension secondary to renal, endocrine or nervous system diseases, and commonly used antihypertensive drugs include: angiotensin receptor antagonists, calcium ion antagonists, and the like.
Angiotensin receptor antagonists include, but are not limited to valsartan, losartan, irbesartan, telmisartan, eprosartan, candesartan, olmesartan, sapprisartan (saprisartan), tasosartan, elisartan, and the like. The medicine has obvious effect of lowering blood pressure and is also used for resisting heart failure in recent years.
However, no specific medicine is clinically available for treating heart failure and hypertension at present, and most medicines have inevitable toxic and side effects while relieving heart failure symptoms and hypertension. And single drug order is easily tolerated, in order to more effectively treat heart failure and hypertension, the prior art has developed complexes, such as a pharmaceutical combination of an angiotensin receptor antagonist and a NEP inhibitor as disclosed in CN101098689, which comprises valsartan and ethyl (2R,4S) -5-biphenyl-4-yl-5- (3-carboxy-propionylamino) -2-methyl-pentanoate (shakubata), marketed in the us, europe in 2015 for the treatment of chronic heart failure; however, the prior art does not disclose a complex consisting of an angiotensin receptor antagonist and candesartan, and also does not disclose whether the complex has efficacy against heart failure and hypertension, and in addition, the complex consisting of the angiotensin receptor antagonist and candesartan has no definite crystal structure, resulting in unstable properties and low bioavailability of the complex.
Disclosure of Invention
In order to solve the technical problems, the invention provides a compound of an angiotensin receptor antagonist and an enkephalinase inhibitor, which mainly comprises the angiotensin receptor antagonist and candesartan cilexetil, and has the effects of treating heart failure, hypertension, hyperlipidemia, analgesia and diarrhea.
The invention provides a compound of an angiotensin receptor antagonist and an enkephalinase inhibitor, which comprises the angiotensin receptor antagonist and the enkephalinase inhibitor, wherein the molar ratio of the angiotensin receptor antagonist to the enkephalinase inhibitor is 1-2:1-2, and the angiotensin receptor antagonist is selected from valsartan, losartan, irbesartan, telmisartan, eprosartan, candesartan, olmesartan, saprepitasartan, tasosartan or elisartan; the enkephalinase inhibitor is candesartan, racecadotril, dextrocadotril, seofulfen, Kalatorfin, pentobarbital sodium or Phe-Leu dipeptide sulfhydryl derivative.
In a further improvement, the angiotensin receptor antagonist is valsartan or irbesartan, and the enkephalinase inhibitor is candesartan, dextrocadotril or seoxafen.
In a further improvement, the compound further comprises atorvastatin, and the molar ratio of the angiotensin receptor antagonist to the enkephalinase inhibitor to the atorvastatin is 1:1: 0.5.
The compound consisting of the angiotensin receptor antagonist, the enkephalinase inhibitor and the atorvastatin not only has obvious treatment effect on heart failure and hypertension, but also has good curative effect on hyperlipidemia.
In a further improvement, the angiotensin receptor antagonist and the enkephalinase inhibitor are linked by hydrogen bonding.
In a further improvement, the compound is a co-crystal hydrate, and the general formula of the co-crystal hydrate is (valsartan-hydrogen bond-candesartan) ∙ 2.5.5H2O, the co-crystalline hydrate has characteristic peaks at 3.8 °, 5.4 °, 9.7 °, 12.6 °, 14.1 °, 16.6 °, 18.4 °, 23.1 °, 26.9 ° and 31.4 ° by X-ray diffraction expressed in 2 θ.
In a further improvement, the cocrystallization unit is formed by hydrogen bonding of 2mol of valsartan and 2mol of dextrocadotril, and the space group of the cocrystallization unit is an orthorhombic system, wherein a is 34.2, b is 15.6, c is 17.8, and α is β is γ is 90 °.
In another aspect, the present invention provides a method for preparing a co-crystalline hydrate, the method comprising the steps of:
t1: taking 1mol of valsartan, adding 20-35mL of mixed solvent of ethyl acetate and tetrahydrofuran with the volume ratio of 7.5:1, heating to 50-55 ℃, and stirring to completely dissolve the valsartan to prepare a valsartan solution;
t2: and (3) adding 1mol of candesartan cilexetil into 10-15mL of 5% ethanol aqueous solution, heating to 40 ℃, stirring to completely dissolve the candesartan cilexetil, dropwise adding the valsartan solution prepared in the step T1, cooling to room temperature after dropwise adding, standing for 24h under ice bath, crystallizing, and naturally drying to obtain the candesartan cilexetil crystal.
In another aspect, the present invention provides a method for preparing a co-crystallization unit, the method comprising the steps of:
s1: adding dextro-cadotril into water, heating to 45 ℃ to completely dissolve the dextro-cadotril to prepare a dextro-cadotril water solution, wherein the concentration of the dextro-cadotril is 0.05 mol/mL;
s2: preparing a valsartan solution with the concentration of 0.05mol/mL by using a solvent of ethanol and cyclohexane in a volume ratio of 5: 2;
s3: and (4) dropwise adding the valsartan solution obtained in the step (S2) into the dextrocadotril solution obtained in the step (S1), uniformly stirring, standing for 24 hours at the temperature of 5-10 ℃, crystallizing, and naturally drying to obtain the valsartan drug.
The invention also provides a capsule, which comprises the compound and an auxiliary material, wherein the weight part ratio of the compound to the auxiliary material is 1:2-4, and the auxiliary material comprises 2-4.8 parts by weight of ethyl succinate, 5-10 parts by weight of xylitol anhydride glyceryl monostearate and 1.5-3 parts by weight of sodium octaalkyl fumarate.
The mixture of the ethyl succinate, the xylitol anhydride glycerin monostearate and the sodium sulfosuccinate dioctyl ester is added into the capsule, so that the stability of the capsule can be improved, and the absorption of the compound can be promoted.
In a further improvement, the auxiliary materials also comprise 0.5 to 1 part of sodium alginate, 1 to 3 parts of calcium glycerophosphate and 0.2 to 0.5 part of modified starch by weight.
By adding the mixture of sodium alginate, calcium glycerophosphate and modified starch into the capsule, the disintegration time of the capsule is improved, so that the capsule can be completely disintegrated within 10 min.
In a further improvement, the capsule further comprises a capsule shell, the compound and the auxiliary materials are filled in the capsule shell, and the capsule shell is mainly prepared from the following components in parts by weight: 5-10 parts of dimyristoyl phosphatidylethanolamine, 1-3 parts of diglycidyl ether and 2-6 parts of glycerol behenate.
The capsule shell is prepared by the following method: heating 5-10 parts by weight of water to 75 ℃, adding glycerol behenate while stirring, continuing stirring, adding dimyristoyl phosphatidylethanolamine and diglycidyl ether, stirring uniformly, and vacuum degassing to obtain the capsule shell.
The capsule shell prepared from dimyristoyl phosphatidylethanolamine, diglycidyl ether and glycerol behenate can obviously improve the stability of the compound and the auxiliary materials in the capsule, thereby further improving the stability of the whole capsule.
The invention also provides the application of the compound in preparing medicines for treating heart failure, hypertension and hyperlipidemia.
The invention has the beneficial effects that the invention provides a compound of angiotensin receptor antagonist and enkephalinase inhibitor and the application thereof, the compound can be used for treating hypertension, heart failure, hyperlipemia, analgesia and diarrhea; the compound consists of angiotensin receptor antagonist and candesartan cilexetil, which can be directly mixed or indirectly connected through hydrogen bonds, wherein the property of the sodium co-crystal hydrate formed by hydrogen bond connection is more stable, and the pharmacokinetic property is obviously provided; although the action mechanisms of the angiotensin receptor antagonist and the enkephalinase inhibitor are different, the compound formed by the angiotensin receptor antagonist and the enkephalinase inhibitor has unexpected synergistic effect and has positive application prospect in the treatment field of heart failure resistance and hypertension resistance.
The complex of angiotensin receptor antagonist and enkephalinase inhibitor achieves a higher therapeutic effect than that achieved with either angiotensin receptor antagonist or enkephalinase inhibitor alone and presents a lower angioedema than that observed with angiopeptidase inhibitor alone. An additional benefit is that the incidence of side effects can be reduced by using the complexes of the invention to reduce the dosage administered by individual species.
Drawings
FIG. 1 is an X-ray diffraction pattern of a co-crystalline hydrate;
FIG. 2 is a molecular perspective view of X-ray diffraction of a co-crystallization unit;
FIG. 3 is a graph showing the mean time of administration of the compound to rats in experiment 1 and experiment 3;
FIG. 4 is a graph showing the mean time of administration of the compound to rats in experiment 2 and experiment 4;
FIG. 5 is a bar graph of the analgesic activity of the complexes of the invention measured by hot plate pain;
1 is a control group, 2 is an indometacin group, 3 is an administration 1 group, 4 is an administration 2 group, and 5 is an administration 3 group;
FIG. 6 is a bar graph of the analgesic activity of the complexes of the invention measured in torsos;
1 is a control group, 2 is an indomethacin group, 3 is an administration 1 group, 4 is an administration 2 group, and 5 is an administration 3 group.
Detailed description of the preferred embodiments
EXAMPLE 1A Complex of an angiotensin receptor antagonist and an enkephalinase inhibitor
The complex comprises 1mol of valsartan and 1mol of candesartan.
EXAMPLE 2A Complex of an angiotensin receptor antagonist and an enkephalinase inhibitor
The complex comprises 1mol of irbesartan and 1mol of candesartan.
EXAMPLE 3A Complex of an angiotensin receptor antagonist and an enkephalinase inhibitor
The compound comprises 1mol of telmisartan and 1mol of candesartan.
EXAMPLE 4A Complex of an angiotensin receptor antagonist and an enkephalinase inhibitor
The compound comprises 1mol of olmesartan and 1mol of candesartan.
EXAMPLE 5A Complex of an angiotensin receptor antagonist and an enkephalinase inhibitor
The compound comprises 1mol of valsartan and 1mol of racecadotril.
EXAMPLE 6A Complex of an angiotensin receptor antagonist and an enkephalinase inhibitor
The compound comprises 1mol of telmisartan and 1mol of dextrocadotril.
EXAMPLE 7A combination of an angiotensin receptor antagonist and an enkephalinase inhibitor
The compound comprises 1mol of irbesartan and 1mol of dextrocadotril.
EXAMPLE 8A combination of an angiotensin receptor antagonist and an enkephalinase inhibitor
The complex comprises 1mol of valsartan and 1mol of seoxafen.
EXAMPLE 9A Complex of an angiotensin receptor antagonist and an enkephalinase inhibitor
The compound comprises 1mol of telmisartan and 1mol of seoofene.
EXAMPLE 10A combination of an angiotensin receptor antagonist and an enkephalinase inhibitor
The compound comprises 1mol of candesartan and 1mol of seoxafen.
EXAMPLE 11A combination of an angiotensin receptor antagonist and an enkephalinase inhibitor
The complex comprises 1mol of irritartan and 2mol of pentobarbital.
EXAMPLE 12A combination of an angiotensin receptor antagonist and an enkephalinase inhibitor
The compound comprises 1mol of tasosartan and 1mol of caratolene.
EXAMPLE 13A combination of an angiotensin receptor antagonist and an enkephalinase inhibitor
The compound comprises 1mol of valsartan, 1mol of candesartan and 0.5mol of atorvastatin.
EXAMPLE 14A combination of an angiotensin receptor antagonist and an enkephalinase inhibitor
The compound is a co-crystal hydrate, and the general formula of the co-crystal hydrate is (valsartan-hydrogen bond-candesartan) ∙ 2.5.5H2O, the co-crystalline hydrate has characteristic peaks at 3.8 °, 5.4 °, 9.7 °, 12.6 °, 14.1 °, 16.6 °, 18.4 °, 23.1 °, 26.9 ° and 31.4 ° by X-ray diffraction expressed in 2 θ, as shown in fig. 1, and the relative intensities of the above characteristic peaks are as follows:
EXAMPLE 15A combination of an angiotensin receptor antagonist and an enkephalinase inhibitor
The compound is a co-crystal hydrate, and the general formula of the co-crystal hydrate is (valsartan-hydrogen bond-candesartan) ∙ 2.5.5H2O, the co-crystalline hydrate has characteristic peaks at 3.8 °, 5.4 °, 9.7 °, 12.6 °, 14.1 °, 16.6 °, 18.4 °, 23.1 °, 26.9 ° and 31.4 ° by X-ray diffraction expressed in 2 θ;
the preparation method of the compound comprises the following steps:
t1: taking 1mol of valsartan, adding 20-35mL of mixed solvent of ethyl acetate and tetrahydrofuran with the volume ratio of 7.5:1, heating to 50-55 ℃, and stirring to completely dissolve the valsartan to prepare a valsartan solution;
t2: and (3) adding 1mol of candesartan cilexetil into 10-15mL of 5% ethanol aqueous solution, heating to 40 ℃, stirring to completely dissolve the candesartan cilexetil, dropwise adding the valsartan solution prepared in the step T1, cooling to room temperature after dropwise adding, standing for 24h under ice bath, crystallizing, and naturally drying to obtain the candesartan cilexetil crystal.
EXAMPLE 16A combination of an angiotensin receptor antagonist and an enkephalinase inhibitor
The complex is a cocrystallization unit formed by hydrogen bonding of 2mol of valsartan and 2mol of dextrocadotril, and as shown in fig. 2, the space group of the cocrystallization unit is orthorhombic, a is 34.2, b is 15.6, c is 17.8, and α is β and γ is 90 °.
EXAMPLE 17A combination of an angiotensin receptor antagonist and an enkephalinase inhibitor
The compound is a cocrystallization unit, wherein the cocrystallization unit is formed by 2mol of valsartan and 2mol of dextrocadotril through hydrogen bonding, the space group of the cocrystallization unit is an orthorhombic system, and a is 34.2, b is 15.6, c is 17.8, α is β and gamma is 90 degrees;
the preparation method of the compound comprises the following steps:
s1: adding dextro-cadotril into water, heating to 45 ℃ to completely dissolve the dextro-cadotril to prepare a dextro-cadotril water solution, wherein the concentration of the dextro-cadotril is 0.05 mol/mL;
s2: preparing a valsartan solution with the concentration of 0.05mol/mL by using a solvent of ethanol and cyclohexane in a volume ratio of 5: 2;
s3: and (4) dropwise adding the valsartan solution obtained in the step (S2) into the dextrocadotril solution obtained in the step (S1), uniformly stirring, standing for 24 hours at the temperature of 5-10 ℃, crystallizing, and naturally drying to obtain the valsartan drug.
EXAMPLE 18 capsules
The dosage of each component of the capsule is as follows:
prepared according to the conventional method.
EXAMPLE 19 capsules
The dosage of each component of the capsule is as follows:
the capsule is prepared according to a conventional method.
EXAMPLE 20 capsules
The dosage of each component of the capsule is as follows:
the capsule is prepared by conventional method.
EXAMPLE 21 capsules
The dosage of each component of the capsule is as follows:
the capsule is prepared by conventional method.
EXAMPLE 22 Capsule
The dosage of each component of the capsule is as follows:
the capsule is prepared by conventional method.
EXAMPLE 23 capsules
The dosage of each component of the capsule is as follows:
the capsule is prepared by conventional method.
Control example 1 Capsule
The dosage of each component of the capsule is as follows:
example 1 Complex 10g
Xylitol anhydride glycerin monostearate 12g
Sodium octaalkylfumarate 3.6g
Prepared according to the conventional method.
The dosage of each component of the capsule is as follows:
prepared according to the conventional method.
Stability test
The composites of example 1, example 5, example 14 and example 16 were placed at 40 ℃ and 75% or higher Relative Humidity (RH), respectively, and the appearance, valsartan content (labeled amount) and water content of the composites were observed, and the results of the measurements were recorded on days 0, 15 and 30 of the measurements, respectively, as shown in table 1.
Table 1 stability results for each example
As can be seen from table 1, the composites provided in examples 1 and 5 of the present invention absorb moisture easily and the content of valsartan is significantly reduced after being placed under high temperature and high humidity conditions for a while, but the moisture content and the content of valsartan are not significantly changed after the composites provided in examples 14 and 16 of the present invention are stored for a long time, and from the appearance, spots appear on the surface of the composite of example 1 of the present invention, while the appearances of the composites of examples 14 and 16 are not changed; the stable properties of the co-crystallized hydrate and the co-crystallized unit provided by the invention are shown.
The stability of the composites provided in examples 14 and 16 was examined for acoustic factors under high temperature (60 ± 2 ℃), intensity irradiation (4500Lx ± 500Lx), and high humidity (92.5%, RH) as indices of appearance, valsartan content, and water content of the composites, as shown in table 2.
TABLE 2 stability results for various influencing factors of the examples
It can be seen from table 2 that the co-crystallization unit provided by the present invention has stable properties under high temperature, high humidity and strong light irradiation.
Pharmacokinetic experiments
The complexes of example 1, example 5, example 14 and example 16 were subjected to pharmacokinetic testing by LC/MS as follows:
4 rats having a weight of 200g, which are labeled as experiment 1 group, experiment 2 group, experiment 3 group and experiment 4 group, respectively, were selected as experimental animals, and each group was fasted for 1 day, and then rats of the experiment 1-4 groups were gavaged with the complex of example 1, example 5, example 14 and example 16, respectively, and the administration dose of each group was 1 mg.
Each group was administered with 2mL of blood taken from hind limb vein at 0, 5min, 15min, 30min, 45min, 1h, 2h, 3h, 4h, 6h, 8h, 10h and 12h, placed in a centrifuge tube coated with heparin, immediately centrifuged for 5min at 15000rmp, upper plasma was aspirated, plasma sample 100. mu.L was collected precisely, placed in a test tube, 100. mu.L of internal standard solution (3ng/mL of felbinac solution) was added, 400. mu.L of acetonitrile, 10. mu.L of formic acid solution was added, vortex mixed for 1min, centrifuged for 10min (15000rmp), vortex mixed, 20. mu.L was taken for LC/MS/MS analysis, and rats of experiment 1 and experiment 3 groups were given the mean drug timing curves of the complexes, as shown in FIG. 3, and rats of experiment 2 and experiment 4 groups were given the mean drug timing curves of the complexes, as shown in FIG. 4.
As can be seen from fig. 3 and 4, the Cmax of the complex provided in example 14 is 2.68 times that of example 1, the Cmax of the complex provided in example 16 is 2.84 times that of example, and the AUC of the complex provided in example 14 and example 16 is more than 2 times that of example 1 and example 5, respectively, which results in that the bioavailability of the complex provided in examples 14 and 16 of the present invention is higher than that of example 1 and example 5.
Heart failure resistance test
Therapeutic effect of complex on canine acute heart failure
1. Material
Animals-healthy adult dogs weighing 12.5-13.5 kg, sodium pentobarbital (Sigma, import split, specification: 25 g); instrument us BIC16 lead physiological recorder (manufactured by BIC corporation); electromagnetic flowmeter (MFV-3200 type): manufactured by japan photonics corporation.
2. Experimental methods and results
Dogs were randomly divided into NS groups (equal volume solvent), administered 1-8 groups, valsartan groups, and candesartan groups, and administered 1-8 groups corresponding to intragastric administration of 1.0mg/kg of examples 1-5, example 8, example 13, and example 13, respectivelyThe compound of example 14, valsartan and candesartan groups were gavaged with 1.0mg/kg valsartan and candesartan, respectively, 6 per group. After fasting for 12 hours, pentobarbital sodium 40mg/kg was intravenously administered for anesthesia, endotracheal intubation, artificial respiration, and Aortic Pressure (AP) and electrocardiogram were monitored. Left thoracotomy, catheterization from apex of heart to left ventricular pressure and rate of change of pressure (+ -dp/dt)max). The myocardial contractility was measured by implanting a Waltan-Brodie strain arch into the anterior wall of the left ventricle. The ascending aorta blood flow is measured with an electromagnetic flow meter. The flow of ascending aorta is used as Cardiac Output (CO), and Cardiac Index (CI), Stroke Index (SI), work per Stroke (SW) and left heart work (LVW) are calculated. Various parameter records and a BIC physiological recorder. After half an hour of operation, all parameters are stable. Pentobarbital sodium (0.5 mL/kg. min) was infused from the femoral vein at constant rate, +/-dp/dtmaxA drop to about 1000mHg/s is the primary indicator for acute heart failure. After the acute heart failure model is stabilized, corresponding medicines are given to duodenum of each group of animals. And (4) performing T test between groups and performing statistical treatment.
TABLE 3 Effect of the groups of complexes on acute Heart failure Canine dP/dt (n ═ 6)
Comparison with NS group, pa<0.01，pb<0.05, p in comparison with valsartand<0.01，pe<0.05，pc> 0.05, p compared to group 1 administeredf<0.01，pg<0.05。
TABLE 4 Effect of the combinations on Heart work in dogs with acute Heart failure (n ═ 6)
Comparison with NS group, pA<0.01，pB<0.05, p compared to the valsartan groupD<0.01，pE<0.05，pC> 0.05, p compared to group 1 administeredF<0.01，pH<0.05。
TABLE 5 Effect of the combinations on cardiac output in Heart failure dogs (n ═ 6)
Compared with before administration, pM<0.01，pN<0.05, comparison with NS group, pM<0.01，pN<0.05, p compared to the valsartan groupK<0.01，pX<0.05，pW> 0.05, p compared to group 1 administeredZ<0.01，pY<0.05。
As can be seen from tables 1-5, compared with NS group, the angiotensin receptor antagonist and enkephalinase inhibitor compound provided by the invention can improve dP/dt, work per stroke, work per left heart, stroke output index and heart output index of heart failure dogs; compared with the valsartan group or the candesartan group, the compound of the angiotensin receptor antagonist and the enkephalinase inhibitor has better enhancing effect on dP/dt, work per stroke, work of the left heart, stroke volume index and heart volume index of heart failure dogs than that of a single product of valsartan or candesartan; the compound consisting of valsartan or irbesartan and candesartan, the compound consisting of valsartan, candesartan and atorvastatin and the cocrystal hydrate have better enhancement effects on dP/dt, work per stroke, left heart work, stroke output index and cardiac output index of heart failure dogs than other angiotensin receptor antagonists and enkephalinase inhibitors, and the compound consisting of irbesartan and candesartan or valsartan, candesartan and atorvastatin and the cocrystal hydrate have better enhancement effects on dP/dt, work per stroke, left heart work, stroke output index and cardiac output index of heart failure dogs than the compound consisting of valsartan and candesartan.
And (4) conclusion: therefore, the compound provided by the invention can be used for preparing a medicament for treating or preventing acute heart failure, and the curative effect is better than that of the existing compound.
Effect of (II) Complex on Chronic Heart failure rats
Experimental methods and results
130 rats, male and female halves, 10 rats as normal control groups, 120 rats were intraperitoneally injected with doxorubicin hydrochloride at 2mg/kg 1 time per week for 6 weeks, and at 5 weeks, the rats were randomly divided into 1-8 groups for administration, valsartan groups and candesartan groups, and administration of 1-8 groups corresponded to intragastric administration of 2.5mg/kg of the compound according to examples 1-5, 8, 13 and 14, respectively, and valsartan groups and candesartan groups were intragastric administration of 2.5mg/kg of valsartan and candesartan, 10 rats each for 21 days. 20% urethane 1.1g/kg abdominal cavity injection anesthesia, surgery stripping trachea and intubation, simultaneously dissociating right side artery, inserting self-made ventricular intubation (diameter 1mm, full of 1% heparin) through the trachea, tracing blood pressure curve; inserting again, making it pass through left side artery valve and enter left ventricle, tracing indoor pressure curve, automatically analyzing and processing Left Ventricular Systolic Pressure (LVSP), and maximum rising rate of ventricular pressure (+ dp/dt)max) Maximum rate of decrease (-dp/dt) of intraventricular pressuremax) And the measured myocardial maximum contraction velocity (Vpm). Another 10 rats were used as normal control groups without doxorubicin hydrochloride, and statistical treatment was performed as described above for group T test.
TABLE 6 Effect of the combinations on Heart function in rats with chronic heart failure (n ═ 10)
Comparison with NS group, pR<0.01，pT<0.05, p compared to the valsartan groupP<0.01，pS<0.05，pU> 0.05, p compared to group 1 administeredV<0.01，pJ<0.05。
As can be seen from Table 6, the complexes of angiotensin receptor antagonist and enkephalinase inhibitor provided by the present invention can increase LVSP, + dp/dt of heart failure rats caused by doxorubicin hydrochloride compared with NS groupmax，-dp/dtmaxAnd a reduction in Vpm (P compared to NS group)<0.05); the compound of the angiotensin receptor antagonist and the enkephalinase inhibitor provided by the invention can treat heart failure rat LVSP, + dp/dtmax，-dp/dtmaxThe raising effect of Vpm is obviously better than that of valsartan or candesartan; the invention provides a compound consisting of valsartan or irbesartan and candesartan, a compound consisting of valsartan, an enkephalinase inhibitor and atorvastatin and a co-crystal hydrate of LVSP, + dp/dt of a heart failure ratmax，-dp/dtmaxThe Vpm raising effect is obviously better than the compound of other angiotensin receptor antagonists and enkephalinase inhibitors, and the compound consisting of irbesartan and candesartan or valsartan, enkephalinase inhibitors and atorvastatin and the co-crystal hydrate thereof have LVSP, + dp/dt of heart failure ratsmax，-dp/dtmaxAnd Vpm increase effect is obviously better than that of a compound consisting of valsartan and an enkephalinase inhibitor.
And (4) conclusion: the compound provided by the invention has the effect of treating heart failure, can be used for preparing a medicine for treating or preventing chronic heart failure, and has better curative effect than the known compound.
Antihypertensive test
1. Hypertension animal model:
modeling was performed according to conventional methods.
4-week-old clean-grade SHR male rats with the average body weight of 109.2 +/-0.8 g are modeled into a hypertension model group, and the same-week-old clean-grade WKY male rats are used as a normal control group, and the average body weight is 109.4 +/-1.9 g. After the conventional diet and adaptive feeding for one week, the hypertension model groups are randomly divided into a model group, a normal control group, 1-8 administration groups and a valsartan group, wherein the 1-8 administration groups are respectively corresponding to intragastric administration of 1.0mg/kg of the compound of examples 1-5, the compound of example 8, the compound of example 13 and the compound of example 14, the valsartan group and the candesartan group are respectively administered intragastric administration of 1.0mg/kg of valsartan and candesartan, and each group of mice is administered according to 6.3 times of the dosage of a human body. The experimental group, the valsartan group and the positive control group are separately gavaged at 1mg/d at the beginning of the 6 th week, and the normal control group and the model group are given with PBS with the same volume for 10 weeks. Animals were sacrificed at 18 weeks of age.
2. The blood pressure of the rats was measured at week 18 using tail pressure method. During measurement, rats were fixed in rat bags, kept at a constant temperature, receptors were placed at the roots of rat tails, blood pulsation at the tails of rats was manually monitored, and systolic pressure and diastolic pressure of each group of rats were calculated, and the results are shown in table 7.
TABLE 7 therapeutic Effect of the combinations of the groups on hypertension
Compared with before administration, pI＜0.01，pO<0.05, comparison with model group, pO<0.05，pI<0.01, p in comparison with the valsartan groupI<0.05，pL> 0.05, p compared to group 1 administeredL<0.05。
As can be seen from Table 7, the complexes of angiotensin receptor antagonist and enkephalinase inhibitor provided by the invention can reduce the diastolic pressure and the systolic pressure of hypertensive rats; the angiotensin receptor antagonist and enkephalinase inhibitor compound provided by the invention has a blood pressure reducing effect on hypertensive rats which is obviously better than that of valsartan; the blood pressure reducing effect of the compound consisting of valsartan or irbesartan and candesartan, the compound consisting of valsartan, candesartan and atorvastatin and the co-crystal hydrate on hypertensive rats is obviously better than that of the compound of other angiotensin receptor antagonists and enkephalinase inhibitors.
And (4) conclusion: the compound provided by the invention has the effect of treating hypertension, and can be used for preparing a medicine for treating or preventing hypertension.
Experiments on hyperlipemia
1. Experimental Material
1.1 drugs and reagents
Total cholesterol (Tc), Triacylglycerol (TG), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C), superoxide dismutase (SOD) and Malondialdehyde (MDA) test kit (Nanjing institute of bioengineering); sodium cholate (Beijing chemical company, lot number 69022680); propylthiouracil (Torre pharmaceutical Co., Ltd., Suzhou, lot number: 20070712); the rest reagents are all analytically pure.
1.2 Instrument 7150 model full-automatic Biochemical Analyzer (Hitachi, Japan).
1.3 Experimental animals
The SPF SD rats comprise 45 animals, each half of the animals is male and female, and the weight of the rats is 160-190 g, and the animals are provided by the Guangdong province medical experimental animal center.
2. Experimental methods
2.1 replication of the model
55 SD rats were randomly assigned 8 blank controls and 47 remaining controls were used for model replication.
Preparing high fat emulsion (10% of cholesterol, 20% of lard, 2% of sodium cholate, 1% of propylthiouracil, 20% of sorbitol methyl ester and 20% of propylene glycol) by referring to the existing method, administering the high fat emulsion in a dose of 10mL & kg, administering physiological saline to a blank control group for 1 time every day for 20 days, cutting the tail, taking blood, measuring the serum TC value, successfully duplicating the model by taking the TC value which is obviously higher than that of the blank control group, and selecting 40 rats as the hyperlipidemia model.
2.2 grouping and administration
Except for the blank control (isotonic normal saline) group, 40 hyperlipemia model rats were randomly divided into 5 groups according to body weight and sex, namely, the model group (isotonic normal saline) and the administration 1 group (6 g. kg. is administered)-1The complex of example 1), administration 2 groups (3 mg. kg administration)-1The complex of example 13), administration 3 groups (administration of 6 mg. kg)-1The complex of example 13), 4 groups (6 mg. kg administration)-1Atorvastatin), continuously administered 1 time per day for 20 days.
2.3 determination of index
Blood is collected from the orbit, serum is separated, and the contents of TC, TG and LDL-C, HDL-C are measured by an oxidase method.
2.4 statistical methods
Statistical analysis was performed using the sps13.0 statistical software package. The multiple-group comparison adopts a one-factor analysis of variance method, and the two-group comparison adopts £ test. P <0.05 indicates significant differences.
3. Results of the experiment
The results of the groups on the blood lipids of the rat with the hyperlipidemia model are shown in Table 8.
TABLE 8 therapeutic effect of the compounds of each group on hyperlipidemia
As can be seen from Table 8, p is compared with the model groupm<0.05，pn<0.01, compared with group 4 administered, pq<0.01，pk<0.05，pm<0.05。
Therefore, the compound of the angiotensin receptor antagonist and the enkephalinase inhibitor has a certain blood fat reducing effect; the lipid-lowering effect of the compound consisting of the angiotensin receptor antagonist, the enkephalinase inhibitor and the atorvastatin on hyperlipidemic rats is obviously better than that of other compounds of the angiotensin receptor antagonist and the enkephalinase inhibitor, and is obviously better than that of the atorvastatin.
And (4) conclusion: the compound provided by the invention has the function of treating hyperlipidemia, and can be used for preparing a medicament for treating or preventing hyperlipidemia.
Anti-diarrhea test
Experimental animals: is a clean male Kunming white mouse with the weight of 20 +/-2 g and is purchased from the center of laboratory animals of Kunming medical college. Two days before experiment, healthy and active animals are selected for experiment.
The experimental example is a model of mouse diarrhea caused by virus, the modeling method refers to the prior art, 10 values are reserved as blank control, and the rest are injected with rotavirus to cause the mouse diarrhea.
Grouping and administration: taking male Kunming mice, and randomly grouping the mice according to the body weight, wherein each group contains 10 mice;
(1) blank control group: gavage 0.1mL/10g normal saline;
(2) diarrhea model control group: gavage 0.15mL/10 g/time, 2 times daily, normal saline;
(3) group 1 of administration: gavage 200mg/kg of the compound of example 5;
(4) administration 2 groups: gavage 200mg/kg of the compound of example 6;
(5) administration 3 groups: gavage 200mg/kg of the compound of example 7;
(6) administration of 4 groups: gavage 200mg/kg of the compound of example 16;
on the third day after the modeling of the rats above, rats in each group were administered the corresponding drug 1 time a day for 13 consecutive days. During the administration, the mice were observed for changes in feces and signs at any time, and the body weights of the mice were measured before daily administration. The mice are fasted for 12h before the experiment, the groups are administrated for 1 time again on the 16 th day, the mice are gavaged with 0.1mL/10g of 5% carbon powder suspension for 1.5 h after the administration, the mice are killed after cervical vertebra removal, the abdominal cavity is opened, mesentery is carefully separated, an intestinal canal with the upper end from the pylorus, the lower end to the ileocecal part is cut, the intestinal canal is flatly paved on a glass plate without traction, and the total length of the small intestine and the propelling distance of the carbon powder are measured by a metric ruler. The carbon powder advancing rate was calculated by the following formula, and the experimental results of each group are shown in Table 9.
Carbon powder propulsion rate (%) -, carbon powder propulsion distance in intestine/total small intestine length × 100%
TABLE 9 therapeutic Effect of the combinations on diarrhea
Comparison with diarrhea model control group, pG<0.01，pA<0.05, p compared to group 1 administrationQ<0.05。
As a result: after the mice are modeled, the mice of the model group and each administration group begin to soften stool and diarrhea after 4 hours on the modeling day, and spleen deficiency symptoms such as anorexia, hypoactivity, slow movement, erect hair and arch dorsum, hair color loss and the like appear on the 4 th day. The normal control group showed no such phenomenon. The mice of each administration group are obviously better than the mice of the model group in hair color and mental state when the compound of the invention starts to be infused in each administration group on the 3 rd day after the model is made.
The compound provided by the invention is continuously administrated for 16 days, and compared with a normal control group, the gastrointestinal propulsion movement of mice can be obviously slowed down (P is less than 0.01). The result indicates that the compound provided by the invention has obvious antagonistic action on the acceleration of gastrointestinal motility, so that the gastrointestinal motility function tends to be normal, and the inhibition effect of the valsartan and the dextrocadotril on the acceleration of the gastrointestinal propulsion motility of mice is obviously better than that of other compounds.
And (4) conclusion: the compound provided by the invention has the effect of treating diarrhea and can be used for preparing a medicament for treating or preventing diarrhea.
Analgesia experiment
(I) Hot plate pain method for testing analgesic activity of compound
The hot plate pain test employs the procedures of conventional procedures to measure the analgesic activity of the complexes of examples 8, 9 and 10.
The pain threshold of each mouse is measured before administration, and the mice are qualified if the average value does not exceed 30s, and the skipping phenomenon is avoided. 50 female mice meeting the above conditions were selected and divided into a normal saline group (normal saline administration), an indomethacin group (indomethacin administration), and 1-3 groups (corresponding to the administration of the complexes of examples 8-10), 10 mice per group, wherein the normal saline group was a control group and the indomethacin group was a positive control group.
The test was fasted for 12 hours before the test, and the test was started 1 hour after the administration, and was completed after 4 hours after the administration, and every 1 hour thereafter. The metal plate is placed in a water bath kettle which is adjusted to 55 +/-0.5 ℃ in advance, heat stimulation is carried out after heating, the time(s) from the time when the mouse is put into the hot plate to the time when the mouse licks feet is recorded by a stopwatch is taken as the pain threshold value of the mouse, if the pain threshold value exceeds 60s, the test is stopped, and the calculation is carried out according to 60 s.
The pain threshold increase percentage was × 100% as mean pain threshold (mean pain threshold after drug administration-mean pain threshold for control group)/mean pain threshold for control group ×%, and the results are shown in fig. 5.
As shown in fig. 5, the percentage increase in pain threshold of indomethacin as a positive control drug was 237%, and the percentage increase in pain threshold of the complexes provided in examples 8, 9 and 10 were 700%, 400% and 415%.
Experiments show that the compound provided by the invention has an inhibition effect on pain reaction caused by a hot plate, can prolong the latency period of a phenomenon that a mouse licks hindpaw, and shows that the compound has central analgesic activity, and the inhibition effect of the compound consisting of valsartan and seofulfin on the pain reaction is obviously higher than that of other compounds.
(II) determination of analgesic Activity of Complex by writhing method
In this example, the analgesic activity of the complexes of examples 8, 9 and 10 was measured by the writhing method using a conventional procedure.
The pain threshold of each mouse is measured before administration, and the mice are qualified if the average value does not exceed 30s, and the skipping phenomenon is avoided. 50 female mice meeting the above conditions were selected and divided into a normal saline group (normal saline administration), an indomethacin group (indomethacin administration), and 1-3 groups (corresponding to the administration of the complexes of examples 8-10), 10 mice per group, wherein the normal saline group was a control group and the indomethacin group was a positive control group.
The mice were fasted for 12 hours before the experiment, and were injected with 0.6% acetic acid, 0.2 ml/mouse, for a number of writhing times within 20min, i.e., after 1 hour of administration. One time the abdomen and hind limbs of the mice were elongated by the stimulus is defined as one writhing response. The results of the experiment are reflected by the percentage inhibition.
The percent inhibition was × 100% percent (mean number of twists in saline group-mean number of twists in administered group)/mean number of twists in saline group, and the results are shown in fig. 6.
As shown in fig. 6, the compound and the positive drug indomethacin provided by the invention both significantly inhibit writhing reaction caused by acetic acid, so that the writhing frequency of mice is reduced, the compound provided by the invention can significantly reduce the writhing frequency of mice compared with indomethacin, and the reduction effect of the compound consisting of valsartan and seofuran on the writhing frequency of mice is significantly better than that of other compounds, which indicates that the compound provided by the invention has peripheral analgesic activity.
And (4) conclusion: the compound provided by the invention has an analgesic effect and can be used for preparing analgesic drugs.
Stability test of capsules
1. Accelerated test
The capsules of example 18, comparative example 1 and comparative example 2 were all placed at 40 ℃ ± 2 ℃ under a relative humidity of 75% ± 5% for 6 months, and were sampled once at the end of 1 month, 2 months, 3 months and 6 months during the experiment, and the properties, color, odor, main component content (indicated amount%) and moisture of the capsules were detected, and as a result, it was found that all the indicators of example 18 were not significantly changed; the capsules of comparative examples 1 and 2 had a significantly darker color, significantly reduced labeled amount of the main ingredient, and increased water content.
2. Long term experiment
Taking the capsules of the example 18, the comparative example 1 and the comparative example 2, placing the capsules at 25 ℃ +/-2 ℃ under the condition that the relative humidity is 60% +/-10% for 12 months, respectively sampling once at the end of 0 month, 3 months, 6 months, 9 months and 12 months during the experiment period, and detecting the properties, the color, the main component content (marked amount%) and the moisture of the capsules, wherein the results show that all indexes of the example 8 have no obvious change; the capsules of comparative examples 1 and 2 had a significantly darker color, a significantly reduced content of the main ingredient, and an increased moisture content.
It can be seen from accelerated and long-term experiments that the mixture of ethyl succinate, glyceryl monostearate xylitol anhydride and sodium octaalkyl fumarate and a special capsule shell can obviously improve the stability of the capsule, and the stability of the capsule is reduced due to the lack of one component or the change of one component.
Determination of disintegration time Effect
1. Different disintegrants consisting of sodium alginate, calcium glycerophosphate and modified starch were selected, and the remaining ingredients were the same as in example 21; the disintegration time limit of the capsules was measured according to the regulations in the Chinese pharmacopoeia, and the results are shown in Table 10;
TABLE 10 Effect of different disintegrants on disintegration time of capsules
As can be seen from the table, the disintegration time limit of the capsule can be obviously improved only by adopting the mixture of the sodium alginate, the calcium glycerophosphate and the modified starch in special parts by weight.
Claims (6)
1. A complex of an angiotensin receptor antagonist and an enkephalinase inhibitor for the treatment of diarrhea, wherein the complex comprises an angiotensin receptor antagonist and an enkephalinase inhibitor, the angiotensin receptor antagonist is valsartan, the enkephalinase inhibitor is dexcadotril, the complex is a co-crystallizing unit formed by hydrogen bonding of 2mol of valsartan and 2mol of dexcadotril, the spatial group of the co-crystallizing unit is orthorhombic, a is 34.2, b is 15.6, c is 17.8, α is β is γ is 90 °.
2. A method of preparing the composite of claim 1, comprising the steps of:
s1: adding dextro-cadotril into water, heating to 45 ℃ to completely dissolve the dextro-cadotril to prepare a dextro-cadotril water solution, wherein the concentration of the dextro-cadotril is 0.05 mol/mL;
s2: preparing a valsartan solution with the concentration of 0.05mol/mL by using a solvent of ethanol and cyclohexane in a volume ratio of 5: 2;
s3: and (4) dropwise adding the valsartan solution obtained in the step (S2) into the dextrocadotril solution obtained in the step (S1), uniformly stirring, standing for 24 hours at the temperature of 5-10 ℃, crystallizing, and naturally drying to obtain the valsartan drug.
3. A capsule comprising the compound of claim 1, wherein the capsule further comprises an auxiliary material, and the weight ratio of the compound to the auxiliary material is 1: 2-4.
4. The capsule according to claim 3, wherein the auxiliary materials comprise, by weight, 2-4.8 parts of ethyl succinate, 5-10 parts of xylitol anhydride glyceryl monostearate and 1.5-3 parts of sodium octaalkyl fumarate.
5. The capsule according to claim 4, wherein the auxiliary materials further comprise 0.5-1 part by weight of sodium alginate, 1-3 parts by weight of calcium glycerophosphate and 0.2-0.5 part by weight of modified starch.
6. Use of a complex according to claim 1 in the manufacture of a medicament for the treatment of diarrhea.
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Address after: 410000 No. 1, Hongfeng Road, Xingsha industrial base, Changsha Economic and Technological Development Zone, Hunan Province Patentee after: Cylon Pharmaceutical Group Co.,Ltd. (Changsha) pharmaceutical R & D Center Address before: 410005 No. 1318, Kaiyuan East Road, Xingsha industrial base, Changsha Economic and Technological Development Zone, Hunan Province Patentee before: Zhuhai Sailong Pharmaceutical Co.,Ltd. (Changsha) Pharmaceutical R&D Center |