CN106214680B - A kind of compound of angiotensin receptor antagonist and Levosimendan and application thereof - Google Patents
A kind of compound of angiotensin receptor antagonist and Levosimendan and application thereof Download PDFInfo
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- CN106214680B CN106214680B CN201610620682.5A CN201610620682A CN106214680B CN 106214680 B CN106214680 B CN 106214680B CN 201610620682 A CN201610620682 A CN 201610620682A CN 106214680 B CN106214680 B CN 106214680B
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Abstract
The present invention provides a kind of compound of angiotensin receptor antagonist and Levosimendan and application thereof, the compound is made of angiotensin receptor antagonist and Levosimendan, it can directly be mixed, or it is indirectly connected with by hydrogen bond, it is more stable that the cocrystallization sodium hydrate property to be formed is connected by hydrogen bond, and pharmacokinetic property significantly improves；Although angiotensin receptor antagonist and Levosimendan mechanism of action are different, the compound that both form has unexpected synergistic effect, has positive application prospect in anti-heart failure, antihypertensive therapy field.
Description
Technical field
The invention belongs to treat the drug field of disease of cardiovascular system, more particularly to a kind of angiotensin receptor antagonist
Compound of agent and Levosimendan and application thereof.
Background technology
Heart failure (abbreviation heart failure) is a kind of complicated clinical symptom group, is various cardiopathic severe stages, it is sent out
Sick rate is high, and 5 annual survival rates and malignant tumour are similar.The incidence of heart failure will continue to increase at no distant date, as 21 century
Most important cardiovascular disorder.
According to foreign statistic, the illness rate that population centers decline is about 1.5%~2.0%, over-65s up to 6%~10%,
And in past 40 years, death caused by heart failure adds 6 times.Heart failure be due to the initial myocardial damage of any reason (such as
Myocardial infarction, cardiomyopathy, haemodynamics overload, inflammation etc.), cause the change of cardiac structure and function, finally result in
Ventricular pump blood and (or) full hypofunction.Main performance is expiratory dyspnea, powerless and fluid retention.Heart failure is a kind of progressive
Lesion, once starting, even if without new cardiac damage, clinic is also at the stabilization sub stage, still can itself continue to develop.Heart failure
It is divided into acute heart failure and chronic heart failure.
Acute heart failure (acute heart failure) is clinically most commonly seen with acute left ventricular failure, and acute right ventricular failure is then less
See.The myocardial contractive power that acute left ventricular failure refers to the left heart function caused by abnormal of acute attack or exacerbation substantially reduces, heart is born
Lotus is aggravated, and is caused acute cardiac output rapid drawdown, pressure of pulmonary circulation to raise suddenly, peripheral resistance increase, is caused pulmonary circulation to be filled
Blood and there is acute pulmonary venous pleonaemia, pulmonary edema simultaneously can be with the clinical syndrome of histoorgan hypoperfusion and cardiogenic shock.It is acute
Right heart failure refers to that some reasons make that myocardium of right ventricle convergent force drastically declines or the front and rear load of right ventricle aggravates suddenly, so that
The clinical syndrome for causing right cardiac output drastically to lower.Acute heart failure can onset or on the basis of original chronic heart failure suddenly
Acute exacerbation, it is most of to show as shrinkage heart failure, diastolic heart failure can also be shown as；Premorbid most patients are associated with device
Matter angiocardiopathy.For the acute heart failure occurred on the basis of chronic heart failure, the stable disease after treatment, should not be known as again
Acute heart failure.The normal threat to life of acute heart failure, it is necessary to emergency rescue and treatment.
According to《Acute heart failure diagnose and treat guide》, positive inotropic medicament (including but not limited to phosphodiesterase
Inhibitor, Levosimendan, catecholamines, digitalis etc..Preferable phosphodiesterase inhibitors include but not limited to ammonia power
Agriculture, milrinone, Olprinone etc.；Preferable catecholamines includes but not limited to dopamine, dobutamine；Preferable ocean ground
Yellow class includes but not limited to digoxin, cedilanid, strophanthin K etc.) it is suitable for the earth's core cardiac output syndrome, such as with symptom
Property low blood pressure or CO reduce with circulation extravasated blood patient, the symptom caused by tissue Low perfusion can be alleviated, ensure important organ
Supply of blood flow.Blood pressure is relatively low and blood vessel dilatation medicine and diuretics are not tolerated or react bad patient is particularly effective.To urgency
Property heart failure drug therapy, phosphodiesterase inhibitors (II b classes, C grades) first choice milrinone, first dose of 25-50ug/kg intravenous injection
(being more than 10min), after with 0.25-0.50ug ug/kg.min intravenous drips.Common adverse reactions have low blood pressure and arrhythmia cordis.
According to《Be grown up diagnosing patients with heart failure and treatment more new guidance-ACC/AHA》, when patient is mainly shown as that Low output is comprehensive
Simulator sickness or when there is congested and Low output amount at the same time, it is contemplated that use vein positive inotropic medicament (such as dopamine, dobutamine
And milrinone).These medicines contribute to alleviation severe shrinkage cardiac insufficiency and dilated cardiomyopathy bad by irrigating
Caused symptom, and protect end-organ function.
The treatment of chronic heart failure (CHF) there has been the transformation highly paid attention to since the 1990s：From short-term
Haemodynamics/pharmaceutical practice switchs to long-term, prosthetic strategy, it is therefore an objective to changes the biological property of failure heart.
The therapeutic purpose of heart failure is not only to improve symptom, improve the quality of living, it is often more important that for the mechanism of myocardial remodelling, is prevented
With delay the development of myocardial remodelling, so as to reduce the death rate and admission rate of heart failure.
Levosimendan is calcium sensitizer, is worked by varying the transmission of calcium combining information；Its directly with flesh calcium egg
It is combined in vain, the steric configuration of cardiac muscle fibre albumen is stabilized necessary to making the myocardial contraction of calcium ion induction, so that
Myocardial contractive power increase, and heart rate, myocardial oxygen consumption are without significant change；Levosimendan has the vasodilative effect of strength, by swashing
The potassium channel of atriphos (ATP) sensitivity living distends the blood vessels, and mainly expands peripheral vein, reduces cardiac preload,
It is favourable to treatment heart failure；When heavy dose uses Levosimendan, there is certain di-phosphate ester enzyme inhibition, the heart can be made
CAMP concentration increases in myocyte, plays extra positive inotropic action.
High blood pressure is most common disease of cardiovascular system, is that one kind is increased as main feature with arterial pressure continuation
Progressive " cardiovascular syndrome ", most of hypertension pathogenies are unknown, are essential hypertension, patient constitute about 95% with
On；Secondary hypertension is mostly to have after in the hypertension of kidney, endocrine or the nervous system disease, common antihypertensive：Blood
Angiotensin receptor antagonist, calcium ion antagonist etc..
Angiotensin receptor antagonist include but not limited to Valsartan, Losartan, Irb, Telmisartan, according to general
Luo Shatan, Candesartan, Olmesartan, husky Puli's sand smooth (saprisartan), Tasosartan, Elisartan etc..Such medicine
With the obvious effect of reducing blood pressure, while anti-heart failure is also used in recent years.Wherein Valsartan is most widely used.
But the treatment for heart failure and hypertension at present, clinically alleviating the heart without specific medicament, most of medicine
There is inevitable toxic side effect while the symptom that declines and hypertension.And the treatment of single medicine is easy to be resistant to
Property, in order to more effectively treat heart failure and hypertension, the prior art have developed some compounds, such as CN1816533 is disclosed
The medicinal composition for including Valsartan, it contains Valsartan and inotropic agent, the medicinal composition be mainly used for treat the heart
Decline, but Valsartan disclosed in the prior art and inotropic agent do not have the effect of anti-hypertension, and Valsartan and positivity
The crystalline structure that the compound of muscular strength medicine composition does not determine, causes the compound property that Valsartan and inotropic agent form not
Stablize.
The content of the invention
In order to solve the above technical problem, the present invention provides a kind of angiotensin receptor antagonist and Levosimendan
Compound, the compound are mainly made of angiotensin receptor antagonist and Levosimendan, which has anti-height at the same time
The effect of blood pressure and anti-heart failure.
The present invention provides a kind of compound of angiotensin receptor antagonist and Levosimendan, which includes blood vessel
Angiotensin receptor antagonist and Levosimendan, the molar ratio of the angiotensin receptor antagonist and inotropic agent is 1:1-
2, the angiotensin receptor antagonist is selected from Valsartan, Losartan, Irb, Irbesartan, Telmisartan, Yi Puluo
Sha Tan, Candesartan, Olmesartan, husky Puli's sand are smooth, Tasosartan or Elisartan.
Further to improve, angiotensin receptor antagonist is Valsartan.
Further to improve, the compound further includes fenofibrate, the angiotensin receptor antagonist, Zuo Ximeng
Denier and the molar ratio of fenofibrate are 1:1:0.3.
The present invention is not only right by the compound being made of angiotensin receptor antagonist, Levosimendan and fenofibrate
Heart failure and hypertension have significant therapeutic effect, while also have the effect of fine to hyperlipemia.
Further to improve, angiotensin receptor antagonist is connected with Levosimendan by Hydrogenbond.
Further to improve, above-mentioned compound is cocrystallization salt hydrate, and the cocrystallization salt hydrate general formula is (figured silk fabrics is husky
Smooth-hydrogen bond-Levosimendan) ﹒ 0.5Na ﹒ 1.5H2O, the cocrystallization salt hydrate with the X-ray diffraction that 2 θ are represented 4.9 °,
There is characteristic peak at 5.7 °, 7.6 °, 8.9 °, 11.6 °, 13.1 °, 14.8 °, 20.9 °, 22.7 °, 28.4 ° and 35.9 °.
Another aspect of the present invention provides the preparation method of cocrystallization salt hydrate, and this method comprises the following steps：
S1：The Levosimendan solutions for being 0.05mol/mL with mixed liquor configuration concentration, wherein mixed liquor are matched somebody with somebody by following component
Put and form：1mL sodium-chloride water solutions, 2.5-3mL tetrahydrofurans, the concentration of sodium-chloride water solution is 0.03mol/mL；
S2：It is 5 with volume ratio:2 ethanol and the Valsartan solution that the solvent configuration concentration of hexamethylene is 0.05mol/mL,
The step S1 Levosimendan solutions configured are added drop-wise in Valsartan solution, are stirred when being added dropwise, the speed of dropwise addition is 20-30
Drop/min, drop finish, continue to stir, and 24h are stood under ice bath, crystallization, spontaneously dries, to obtain the final product.
Another aspect of the present invention provides a kind of capsule, which includes compound of the present invention and auxiliary material, its
The ratio of weight and number of middle compound and auxiliary material is 1:2-4, the auxiliary material include parts by weight be 2-4.8 parts hydroxypropul starch,
The dioctylis sulfosuccinas natricus of 5-10 parts of hexadecyl metrhacrylate and 1.5-3 part.
The present invention is pungent by adding hydroxypropul starch, hexadecyl metrhacrylate and sodium sulfo-succinate two in capsule
The mixture of fat, on the one hand as filler, on the other hand improves the stability of capsule, and can also promote compound
Absorb.
Further to improve, auxiliary material further includes the sodium taurocholate that parts by weight are 0.5-1 parts, 1-3 parts of polydimethylsiloxanes
Alkane and 0.2-0.5 parts of microcrystalline cellulose.
By adding the mixture of sodium taurocholate, dimethyl silicone polymer and microcrystalline cellulose in capsule, glue is improved
The disintegration time limited of wafer so that capsule can be all disintegrated in 10min.
Further to improve, the capsule further includes capsule shells, and the compound and auxiliary material are filled in capsule shells,
The capsule shells are mainly prepared by the component of following parts by weight：Parts by weight are 5-10 parts of two myristoyl phosphatidyl second
Hydramine, 1-3 part diglycidyl ether and 2-6 parts of Gan You behenic acid esters.
The capsule shells of the present invention are prepared via a method which to obtain：The water that parts by weight are 5-10 parts is heated to 75
DEG C, lower addition Gan You behenic acid esters are stirred, continues to stir, adds two myristoyl phosphatidyl-ethanolamines and 2-glycidyl
Ether, stirs evenly, vacuum outgas, and capsule shells are made.
The present invention is using by the preparation of two myristoyl phosphatidyl-ethanolamines, diglycidyl ether and Gan You behenic acids ester
Capsule shells can significantly improve the stability of compound and auxiliary material in capsule, so as to further improve the stability of whole capsule.
Another aspect of the present invention provides the purposes of the compound, it is being prepared for treating heart failure, hypertension and high blood
Application in the medicine of fat.
The beneficial effects of the present invention are the present invention provides answering for a kind of angiotensin receptor antagonist and Levosimendan
Compound and application thereof, the compound can be used for treatment hypertension and heart failure；The compound of the present invention is short of money by angiotensin receptor
Anti-agent and Levosimendan composition, it can directly be mixed, or be indirectly connected with by hydrogen bond, and the common knot to be formed is connected by hydrogen bond
Brilliant sodium hydrate property is more stable, and pharmacokinetic property significantly improves；Although angiotensin receptor antagonist and a left side
Simendan mechanism of action is different, but the compound that both form has unexpected synergistic effect, in anti-heart failure, anti-height
The therapy field of blood pressure has positive application prospect.
Brief description of the drawings
Fig. 1 is the x-ray diffraction pattern of cocrystallization salt hydrate；
Fig. 2 is the average Drug-time curve figure that 4 groups of rats take compound.
Specific embodiment mode
The compound of a kind of 1 angiotensin receptor antagonist of embodiment and Levosimendan
The compound includes the Valsartan of 1mol and the Levosimendan of 1mol.
The compound of a kind of 2 angiotensin receptor antagonist of embodiment and Levosimendan
The compound includes the Olmesartan of 1mol and the Levosimendan of 1mol.
The compound of a kind of 3 angiotensin receptor antagonist of embodiment and Levosimendan
The compound includes the Telmisartan of 1mol and the Levosimendan of 2mol.
The compound of a kind of 4 angiotensin receptor antagonist of embodiment and Levosimendan
The compound includes the Irb of 1mol and the Levosimendan of 1mol.
The compound of a kind of 5 angiotensin receptor antagonist of embodiment and Levosimendan
The compound includes the Eprosartan of 1mol and the Levosimendan of 2mol.
The compound of a kind of 6 angiotensin receptor antagonist of embodiment and Levosimendan
The compound includes the Tasosartan of 1mol and the Levosimendan of 1mol.
The compound of a kind of 7 angiotensin receptor antagonist of embodiment and Levosimendan
The compound includes Valsartan, the Levosimendan and 0.3mol fenofibrates of 1mol of 1mol.
The compound of a kind of 8 angiotensin receptor antagonist of embodiment and Levosimendan
The compound is cocrystallization salt hydrate, and the cocrystallization salt hydrate general formula is (Valsartan-hydrogen bond-Zuo Ximeng
Denier) ﹒ 0.5Na ﹒ 1.5H2O, the cocrystallization salt hydrate with the X-ray diffraction that 2 θ are represented 4.9 °, 5.7 °, 7.6 °, 8.9 °,
There is characteristic peak at 11.6 °, 13.1 °, 14.8 °, 20.9 °, 22.7 °, 28.4 ° and 35.9 °, as shown in Figure 1, each characteristic peak of the above
Relative intensity is as follows：
The compound of a kind of 9 angiotensin receptor antagonist of embodiment and Levosimendan
The compound is cocrystallization salt hydrate, and the cocrystallization salt hydrate general formula is (Valsartan-hydrogen bond-Zuo Ximeng
Denier) ﹒ 0.5Na ﹒ 1.5H2O, the cocrystallization salt hydrate with the X-ray diffraction that 2 θ are represented 4.9 °, 5.7 °, 7.6 °, 8.9 °,
There is characteristic peak at 11.6 °, 13.1 °, 14.8 °, 20.9 °, 22.7 °, 28.4 ° and 35.9 °；
The preparation method of the compound is：
S1：The Levosimendan solutions for being 0.05mol/mL with mixed liquor configuration concentration, wherein mixed liquor are matched somebody with somebody by following component
Put and form：1mL sodium-chloride water solutions, 2.5mL tetrahydrofurans, the concentration of sodium-chloride water solution is 0.03mol/mL；
S2：It is 5 with volume ratio:2 ethanol and the Valsartan solution that the solvent configuration concentration of hexamethylene is 0.05mol/mL,
The step S1 Levosimendan solutions configured are added drop-wise in Valsartan solution, stirs when being added dropwise, the speed of dropwise addition drips for 20/
Min, drop finish, continue to stir, and 24h are stood under ice bath, crystallization, spontaneously dries, to obtain the final product.
10 capsule of embodiment
The dosage of each component of capsule is：
Conventionally prepare.
11 capsule of embodiment
The dosage of each component of capsule is：
Conventionally prepare.
12 capsule of embodiment
The dosage of each component of capsule is：
Conventionally prepare.
13 capsule of embodiment
The dosage of each component of capsule is：
Conventionally prepare.
14 capsule of embodiment
The dosage of each component of capsule is：
Conventionally prepare.
15 capsule of embodiment
The dosage of each component of capsule is：
Conventionally prepare.
16 capsule of embodiment
The dosage of each component of capsule is：
Compound：The compound 10g of embodiment 1
Auxiliary material：
Capsule shells：
Two myristoyl phosphatidyl-ethanolamine 5g
Diglycidyl ether 1g
Gan You behenic acid esters 2g
Wherein, compound and auxiliary material are filled in capsule shells.
Conventionally prepare.
17 capsule of embodiment
The dosage of each component of capsule is：
Compound：The compound 10g of embodiment 7
Auxiliary material：
Capsule shells：
Two myristoyl phosphatidyl-ethanolamine 10g
Diglycidyl ether 3g
Gan You behenic acid esters 6g
Wherein, compound and auxiliary material are filled in capsule shells.
Conventionally prepare.
18 capsule of embodiment
The dosage of each component of capsule is：
Compound：The compound 10g of embodiment 8
Auxiliary material：
Capsule shells：
Two myristoyl phosphatidyl-ethanolamine 7.5g
Diglycidyl ether 2g
Gan You behenic acid esters 4g
Wherein, compound and auxiliary material are filled in capsule shells.
Conventionally prepare.
The compound of a kind of 1 Valsartan of comparative example and milrinone
The compound includes the Valsartan of 1mol and the milrinone of 1mol.
1 capsule of reference examples
The dosage of each component of capsule is：
The compound 10g of embodiment 1
Hexadecyl metrhacrylate 12g
Dioctylis sulfosuccinas natricus 3.6g
Conventionally prepare.
2 capsule of reference examples
The dosage of each component of capsule is：
Conventionally prepare.
Stability experiment
The compound of embodiment 1, embodiment 8 and embodiment 9 is respectively placed in 40 DEG C, more than 75% bar of relative humidity (RH)
Under part, the moisture content of the appearance of compound, valsartan content (labelled amount) and compound is observed, 0 day, 15 days respectively at detection
Testing result was recorded with 30 days, as shown in table 1.
Each embodiment stability result of table 1
From table 1 it follows that the compound that the embodiment of the present invention 1 provides is when placing one section under conditions of hot and humid
Hou Hou, the easy moisture absorption, and the content of Valsartan significantly reduces, but the compound that the embodiment of the present invention 8 and 9 provides is for a long time
After preservation, the content of moisture and Valsartan does not have significant change, from the point of view of appearance, the compound table of the embodiment of the present invention 1
There is spot in face, and the compound appearance of embodiment 8 and 9 does not change；Show cocrystallization salt hydrate provided by the invention
Property is stablized.
The stability of the compound provided embodiment 8 and embodiment 9 carries out the investigation of influence factor, investigates condition as height
Warm (60 ± 2 DEG C), intensity illumination (4500Lx ± 500Lx), high humidity (92.5%, RH), inspection target are appearance, valsartan content
And complex aqueous rate, as shown in table 2.
Each embodiment influence factor stability result of table 2
Cocrystallization salt hydrate provided by the invention property under high temperature, high humidity and strong illumination as can be seen from Table 2
Stablize.
Pharmacokinetic studies
Pharmacokinetics test, method are carried out to the compound of embodiment 1, embodiment 8 and embodiment 9 by LC/MS/MS
It is as follows：
3 rats that weight is 200g are selected to be respectively labeled as 1 group of experiment as experimental animal, test 2 groups and experiment 3
Group, the equal fasting of each group 1 day, the rat for then testing 1-3 groups distinguish the compound of gavage embodiment 1, embodiment 8 and embodiment 9,
The dosage of each group is 1mg.
Each group is quiet in hind leg in administration 0,5min, 15min, 30min, 45min, 1h, 2h, 3h, 4h, 6h, 8h, 10h and 12h
Arteries and veins takes blood 2mL, is placed in the centrifuge tube for scribbling heparin, immediately under the conditions of 15000rmp, centrifuges 5min, draws upper plasma,
Precision takes 100 μ L of plasma sample, is placed in test tube, adds inner mark solution (the felbinac solution of 3ng/mL) 100 μ L, adds second
400 μ L of nitrile, 10 μ L formic acid solutions, vortex mixing 1min, centrifugation 10min (15000rmp), vortex mixing, takes 20 μ L to carry out LC/
MS/MS is analyzed, and measure each group rat takes the average Drug-time curve of compound, and the results are shown in Figure 2.
From figure 2 it can be seen that the Cmax for the compound that embodiment 8 and embodiment 9 provide be 2.22 times of embodiment 1 and
2.81 times, and the AUC of the compound of embodiment 8 and embodiment 9 is respectively more than 2 times of embodiment 1, and embodiment 9 carries
The Cmax and AUC of the compound of confession are bigger than embodiment 8, it follows that, the life for the compound that the embodiment of the present invention 8 and 9 provides
Thing availability is higher than embodiment 1, and the bioavilability of the compound of the offer of embodiment 9 is higher than embodiment 8.
Anti- heart failure experiment
(1) therapeutic effect of the compound to dog acute heart failure
1. material
Animal -- healthy adult dog 12.5~13.5kg of weight, yellow Jackets (Sigma, import packing, specification：25g)；
Instrument U.S. BIC16 leads physiograph (production of BIC Corp. of the U.S.)；Electromagnetic flowmeter (MFV-3200 types)：Japanese photoelectricity is public
Department's production.
2. experimental method and result
Dog is randomly divided into NS groups (waiting capacity solvent), 1-9 groups are administered, Valsartan group, Levosimendan group and control group, give
Medicine 1-9 groups correspond to the compound of gastric infusion 1.0mg/kg embodiments 1-9, Valsartan group, Levosimendan group and control group respectively
The compound of gastric infusion 1.0mg/kg Valsartans, Levosimendan and comparative example respectively, every group 6.After when fasting 12 is small, vein
Inject yellow Jackets 40mg/kg anesthesia, trachea cannula, artificial respiration, monitoring aortic pressure (AP) and electrocardiogram.Open in left side
Chest, conduit is inserted to left chamber pressure and its rate of pressure change (± dp/dt from the apex of the heartmax).Waltan-Brodie is strained into bow implantation
Left ventricle antetheca, measures myocardial contractive power.With electromagnetic flowmeter determination aorta ascendens blood flow.The heart is used as using aorta ascendens flow
Output quantity (CO), calculates cardiac index (CI), index (SI) of often fighting, work done (SW) of often fighting, left heart work done (LVW).Parameters
Record and BIC physiographs.Postoperative half an hour, parameters reach stable.From femoral vein constant speed gasing injection yellow Jackets
(0.5mL/kgmin), with ± dp/dtmaxDrop to about 1000mHg/s and form acute heart failure for leading indicator.Treat acute
After Heart Failure Model is stablized, each group animal duodenum gives relative medicine.T is examined between group, carries out statistical procedures.
Influence (n=6) of the 3 each group compound of table to acute heart-failure dog dP/dt
Compared with NS groups, pa<0.01, pb<0.05, compared with control group, pd<0.01, pe<0.05, compared with 1 group of administration,
pf<0.01, pg<0.05, pw＞ 0.05.
Influence (n=6) of the 4 each group compound of table to acute heart-failure dog cardiac work
Compared with NS groups, pA<0.01, pB<0.05, compared with control group, pD<0.01, pE<0.05, compared with 1 group of administration,
pF<0.01, pH<0.05, pG＞ 0.05.
Influence (n=6) of the 5 each group compound of table to heart failure canine cardiac output
Compared with before administration, pM<0.01, pN<0.05, compared with NS groups, pM<0.01, pN<0.05, compared with control group, pK
<0.01, pX<0.05, compared with 1 group of administration, pZ<0.01, pY<0.05, pW＞ 0.05.
From table 1, table 2 and table 3 as can be seen that compared with NS groups, angiotensin receptor antagonist provided by the invention
The dP/dt of Heart Failure Dogs, often fight work done, a left side can be improved with the compound and Valsartan of Levosimendan and the compound of milrinone
Heart work done, Stroke volume index and cardiac output index；Angiotensin receptor antagonist and Zuo Xi provided by the invention
The compound of Meng's denier is to the dP/dt of Heart Failure Dogs, work done of often fighting, left heart work done, Stroke volume index and cardiac output index
Enhancing effect significantly better than Valsartan and milrinone compound；It is provided by the invention to be made of Valsartan and Levosimendan
The dP/ of compound, the compound being made of Valsartan, Levosimendan and fenofibrate and cocrystallization salt hydrate to Heart Failure Dogs
Dt, work done of often fighting, left heart work done, Stroke volume index and cardiac output index enhancing effect significantly better than the present invention its
The compound of his angiotensin receptor antagonist and Levosimendan, and be made of Valsartan, Levosimendan and fenofibrate
Compound and cocrystallization salt hydrate to the dP/dt of Heart Failure Dogs, work done of often fighting, left heart work done, Stroke volume index and the heart
The enhancing effect of dirty output volume index is significantly better than the compound being made of Valsartan and Levosimendan.
Conclusion：Thus show that compound provided by the invention can be used to prepare the medicine for treating or preventing acute heart failure, and
And curative effect is better than existing compound.
(2) influence of the compound to chronic heart failure rat
Experimental method and result
Rat 130, half male and half female, 10 are only used as Normal group, and 120 are injected intraperitoneally doxorubicin hydrochloride 2mg/kg,
1 times a week, totally 6 weeks, the 5th week when be randomly divided into administration 1-9 groups, Valsartan group, Levosimendan group and control group, be administered 1-9 groups
The compound of gastric infusion 2.5mg/kg embodiments 1-9, Valsartan group, Levosimendan group and control group difference gavage are corresponded to respectively
The compound of 2.5mg/kg Valsartans, Levosimendan and comparative example 1 is administered, every group 10, is administered 21 days.20% urethane
1.1g/kg intraperitoneal injection of anesthesia, peeling operation tracheae are simultaneously intubated, while the total artery in right side that dissociates, and the homemade heart is inserted into through it
Room is intubated (diameter 1mm, full of 1% heparin), traces blood pressure curve；It is further continued for being inserted into, is passed to left arterial valve and enters a left side
Ventricle, traces intraventricular pressure curve, Automatic analysis left ventricular systolic pressure (LVSP), intraventricular pressure maximum climbing speed (+dp/
dtmax), intraventricular pressure maximum falling speed (- dp/dtmax) and the data such as the myocardium maximal velocity of contraction (Vpm) of actual measurement.Separately take 10
Rat does not give doxorubicin hydrochloride as Normal group, and with above-mentioned, T is examined between group, is carried out at statistics for remaining operation
Reason.
Influence (n=10) of the 6 each group compound of table to chronic heart failure Cardiac Function in Rat
Compared with NS groups, pR<0.01, pT<0.05, compared with control group, pP<0.01, pS<0.05, compared with 1 group of administration,
pV<0.01, pJ<0.05, pU＞ 0.05.
As can be seen from Table 6, compared with NS groups, angiotensin receptor antagonist and Levosimendan provided by the invention
Compound and the compound of Valsartan and milrinone can raise the LVSP ,+dp/ of the Heart Failure Wistar Rats as caused by doxorubicin hydrochloride
dtmax,-dp/dtmaxWith the reduction of Vpm (compared with NS groups, P<0.05)；Angiotensin receptor antagonist provided by the invention
Compound with Levosimendan is to Heart Failure Wistar Rats LVSP ,+dp/dtmax,-dp/dtmaxIt is husky significantly better than figured silk fabrics with the elevating effect of Vpm
The smooth and compound of milrinone；The compound provided by the invention being made of Valsartan and Levosimendan, by Valsartan, Zuo Ximeng
The compound and cocrystallization salt hydrate of denier and fenofibrate composition are to the LVSP of Heart Failure Wistar Rats ,+dp/dtmax,-dp/dtmaxWith
The elevating effect of Vpm is significantly better than the compound of of the invention other angiotensin receptor antagonists and Levosimendan, and by
Valsartan, the compound of Levosimendan and fenofibrate composition and cocrystallization salt hydrate are to the LVSP of Heart Failure Wistar Rats ,+dp/
dtmax,-dp/dtmaxIt is significantly better than the compound being made of Valsartan and Levosimendan with Vpm elevating effects.
Conclusion：Compound provided by the invention has the function that treatment heart failure, can be chronic for preparing treatment or prevention
The medicine of heart failure, and curative effect is better than known compound.
Antihypertensive experiment
1. hypertension animal model：
Conventionally model.
The 4 week old cleaning grade SHR male rats of 109.2 ± 0.8g of average weight are modeled as hypertension model group, with same
Week old cleaning grade WKY male rats are Normal group, 109.4 ± 1.9g of average weight.Regular diet, adaptability are raised one week
Afterwards, hypertension model group is randomly divided into model group, Normal group, administration 1-9 groups, Valsartan group and control group, and 1-9 groups are administered
The compound of gastric infusion 1.0mg/kg embodiments 1-9, Valsartan group, Levosimendan group and control group difference gavage are corresponded to respectively
The compound of 1.0mg/kg Valsartans, Levosimendan and comparative example 1 is administered, every group of mouse is given according to 6.3 times of human body dosage
Medicine.Each experimental group, control group and positive controls started gavage 1mg/d, Normal group respectively in the 6th week and are given with model group
Isometric PBS, is administered 10 weeks altogether.Animal is put to death when 18 week old.
2. the 18th week uses tail platen press measurement rat blood pressure.During measurement, rat is fixed in mouse bag, keeps constant temperature, will
Receptor is placed in rat root of the tail portion, and the pulsation of manual monitoring rat tails blood flow, calculates the systolic pressure and diastolic pressure of every group of rat, tie
Fruit is shown in Table 7.
Therapeutic effect of the 7 each group compound of table to hypertension
Compared with before administration, pI＜ 0.01, pO＜ 0.05, compared with model group, pO<0.05, pI<0.01, with control group ratio
Compared with pI<0.05, pL＞ 0.05, compared with 1 group of administration, pL<0.05。
As can be seen from Table 7, the compound of angiotensin receptor antagonist and Levosimendan provided by the invention and
The compound of Valsartan and milrinone can reduce the diastolic pressure and systolic pressure of Hypertensive Rats；Vasotonia provided by the invention
Antihypertensive effect and Valsartan and the compound of milrinone of the compound of hormone receptor antagonists and Levosimendan to Hypertensive Rats
Quite；The compound provided by the invention being made of Valsartan and Levosimendan, by Valsartan, Levosimendan and fenofibrate group
Into compound and cocrystallization salt hydrate be significantly better than other angiotensins of the invention to the antihypertensive effects of Hypertensive Rats
The compound of receptor antagonist and Levosimendan, and the compound that is made of Valsartan, Levosimendan and fenofibrate and altogether
Crystallization salt hydrate is better than the compound being made of Valsartan and Levosimendan to the antihypertensive effect of Hypertensive Rats.
Conclusion：Compound provided by the invention has the function that to treat hypertension, can be used for preparing treatment or prevention height
The medicine of blood pressure.
The experiment of lipidemia
1. experiment material
1.1 medicines and reagent
It is T-CHOL (Tc), triacylglycerol (TG), low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C), super
Superoxide dismutase (SOD) and malonaldehyde (MDA) testing cassete (Bioengineering Research Institute is built up in Nanjing)；Sodium taurocholate (Beijing chemistry
Reagent Company, lot number：69022680)；Propylthiouracil (PTU) (Suzhou Dawnrays Pharmaceutical Co., Ltd., lot number：20070712)；Remaining examination
Agent is pure to analyze.
1.2 instrument, 7150 type automatic clinical chemistry analyzer (Hitachi, Japan).
1.3 experimental animal
SPF grades of SD rats, 45, half male and half female, 160~190g of weight, is provided by Guangdong Medical Lab Animal Center.
2. experimental method
The duplication of 2.1 models
45 SD rats are separated 8 at random and make blank control, remaining 37 duplication for being served only for model.
With reference to existing method prepare high lipoprotein emulsion (cholesterol 10%, lard 20%, sodium taurocholate 2%, propylthiouracil (PTU) 1%,
Sorbierite methyl esters 20%, propane diols 20%), it is administered with 10mLkg dosage, blank control group gives physiological saline, 1 time a day,
Continue 20 days, docking takes blood, measures its serum TC value, is significantly higher than blank control group as model copy success using TC values, therefrom
Select 32 and be only used as high blood lipid model rat.
2.2 packets and administration
Except blank control (waits and hold physiological saline) group, 32 high blood lipid model rats are randomly divided into 4 groups by weight, gender,
I.e. model group (wait and hold physiological saline), 1 group of administration (give 6gkg-1The compound of embodiment 1), administration 2 groups (give 3mg
kg-1The compound of embodiment 7) and administration 3 groups (give 6mgkg-1The compound of embodiment 7), administration 4 groups (give 6mg
kg-1Fenofibrate), successive administration, 1 time a day, continues 20d.
The measure of 2.3 indexs
Eye socket takes blood, separates serum, and the measure of TC, TG, LDL-C, HDL-C content uses enzymatic measurement.
2.4 statistical method
Statistical analysis is carried out using SPsS13.0 statistical packages.More comparison among groupss use one-way analysis of variance method,
Two comparison among groupss are examined using ￡.P<0.05 indicates significant difference.3. experimental result
Each group the results are shown in Table 8 to high blood lipid model rat fat.
Therapeutic effect of the 8 each group compound of table to hyperlipidemia
As can be seen from Table 8, compared with model group, pm<0.05, pn<0.01, compared with 4 groups of administration, pq<0.01, pk<
0.05, pm<0.05。
Thus the compound of angiotensin receptor antagonist and Levosimendan provided by the invention is drawn and with certain
Lipid-lowering effect；The compound provided by the invention being made of Valsartan, Levosimendan and fenofibrate is to hyperlipemia rat
Lipid-lowering effect be significantly better than the compound of of the invention other angiotensin receptor antagonists and Levosimendan, it is and significantly excellent
In fenofibrate.
Conclusion：Compound provided by the invention has the function that to treat hyperlipidemia, can be used for preparing treatment or prevention height
The medicine of blood fat.
Capsule stability experiment
1. Acceleration study
Example 10, embodiment 16, the capsule of reference examples 1 and reference examples 2, at 40 DEG C ± 2 DEG C of temperature, relatively
Humidity places 6 months under conditions of being 75% ± 5%, 1 month during the experiment, 2 months, 3 months, 6 the end of month it is separately sampled
Once, the character of capsule, color and luster, smell, principal component content (labelled amount %), moisture are detected, it turns out that, 10 He of embodiment
The indices of embodiment 16 have no significant change；Also, the indices of the capsule of embodiment 16 are better than embodiment 10；And
The color of the capsule of reference examples 1 and reference examples 2 substantially deepens, and the labelled amount of principal component significantly reduces, moisture increase.
2. long-term experiment
Example 10, embodiment 16, the capsule of reference examples 1 and reference examples 2, at 25 DEG C ± 2 DEG C of temperature, relatively
Humidity is placed 12 months under conditions of being 60% ± 10%, 0 month during the experiment, 3 months, 6 months, 9 months, 12 the end of month
It is separately sampled once to detect the character of capsule, color and luster, principal component content (labelled amount %), moisture, it turns out that, embodiment
10 and the indices of embodiment 16 have no significant change；Also, the indices of the capsule of embodiment 16 are better than embodiment
10；And the color of the capsule of reference examples 1 and reference examples 2 substantially deepens, the content of main component is decreased obviously, moisture increase.
As can be seen that hydroxypropul starch, hexadecyl metrhacrylate and sulfo group fourth two from Acceleration study and long-term experiment
The mixture of sour sodium dioctyl ester and special capsule shells are remarkably improved the stability of capsule, lack one of component, or become
Change one of component, the stability of capsule declines.
Disintegration time limited effect measuring
1. selection is made of different disintegrants sodium taurocholate, dimethyl silicone polymer and microcrystalline cellulose, remaining component
It is identical with embodiment 13；Regulation in Chinese Pharmacopoeia, surveys the disintegration time limited of capsule, the results are shown in Table 9；
Influence of the different disintegrants of table 9 to capsule disintegration time limited
As can be seen from the table, using sodium taurocholate, dimethyl silicone polymer and the microcrystalline cellulose of the special parts by weight of the present invention
Plain mixture is just remarkably improved the disintegration time limited of capsule.
Claims (7)
1. the compound of a kind of angiotensin receptor antagonist and Levosimendan, it is characterised in that the compound includes blood
Angiotensin receptor antagonist and Levosimendan, the molar ratio of the angiotensin receptor antagonist and Levosimendan is 1:1-
2, the angiotensin receptor antagonist is Valsartan, and the compound is cocrystallization salt hydrate, the cocrystallization brine
Compound general formula is (Valsartan-hydrogen bond-Levosimendan) ﹒ 0.5Na ﹒ 1.5H2O, the X- that the cocrystallization salt hydrate is represented with 2 θ
X ray diffraction has at 4.9 °, 5.7 °, 7.6 °, 8.9 °, 11.6 °, 13.1 °, 14.8 °, 20.9 °, 22.7 °, 28.4 ° and 35.9 °
Characteristic peak.
A kind of 2. method for preparing compound described in claim 1, it is characterised in that described method includes following steps：
S1：The Levosimendan solutions for being 0.05mol/mL with mixed liquor configuration concentration, the mixed liquor configured by following component and
Into：1mL sodium-chloride water solutions and 2.5-3mL tetrahydrofurans, the concentration of the sodium-chloride water solution is 0.03mol/mL；
S2：It is 5 with volume ratio:2 ethanol and the Valsartan solution that the solvent configuration concentration of hexamethylene is 0.05mol/mL, will walk
The Levosimendan solutions of rapid S1 configurations are added drop-wise in Valsartan solution, stirs when being added dropwise, the speed of dropwise addition be 20-30 drops/
Min, drop finish, continue to stir, and 24h are stood under ice bath, crystallization, spontaneously dries, to obtain the final product.
3. a kind of capsule, including the compound described in claim 1, it is characterised in that the capsule further includes auxiliary material, institute
The ratio of weight and number for stating compound and auxiliary material is 1:2-4.
4. capsule as claimed in claim 3, it is characterised in that the auxiliary material includes the hydroxypropyl that parts by weight are 2-4.8 parts
Base starch, 5-10 parts of hexadecyl metrhacrylate and 1.5-3 parts of dioctylis sulfosuccinas natricus.
5. capsule as claimed in claim 3, it is characterised in that the auxiliary material further includes the courage that parts by weight are 0.5-1 parts
Sour sodium, 1-3 parts of dimethyl silicone polymer and 0.2-0.5 parts of microcrystalline cellulose.
6. capsule as claimed in claim 3, it is characterised in that the capsule further includes capsule shells, the compound and auxiliary
Material is filled in capsule shells, and the capsule shells are mainly prepared by the component of following parts by weight：Parts by weight are 5-10 parts
Two myristoyl phosphatidyl-ethanolamines, 1-3 parts of diglycidyl ether and 2-6 parts of Gan You behenic acid esters.
7. the compound described in a kind of claim 1 is preparing the application in being used to treat the medicine of heart failure and hypertension.
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| CN115443272B (en) * | 2020-08-17 | 2023-11-17 | 深圳信立泰药业股份有限公司 | Heart failure application of complex of angiotensin II receptor antagonist metabolite and NEP inhibitor |
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Non-Patent Citations (2)
| Title |
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| CARDIOVASCULAR EFFECTS OF THE COMBINATION OF LEVOSIMENDAN AND VALSARTAN IN HYPERTENSIVE DAHL/RAPP RATS;A. BIALA，等;《Journal of physiology and pharmacology》;20110630;第62卷(第3期);275-285 * |
| Levosimendanaloneandincombinationwithvalsartanprevents strokeinDahlsalt-sensitiverats;Jouko Levijoki，等;《EuropeanJournal of Pharmacology》;20150129;132–140 * |
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