CN101361736A - Compound of losartan or pharmaceutical salt thereof and calcium channel blockers or pharmaceutical salt thereof - Google Patents
Compound of losartan or pharmaceutical salt thereof and calcium channel blockers or pharmaceutical salt thereof Download PDFInfo
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Abstract
The invention relates to a Valsartan compound or medicinal salt thereof and calcium channel blocker or a formula of the medicinal salt and belongs to the field of medicine technology. The invention comprises the following components according to parts by weight: ((2-n-propyl-4-methyl-1H-benzoglioxaline)-6-methanamide-1-base)methyl biphenyl tetrazole and carboxylic acid compounds and the salts thereof, which all account for 5-200 and 0.5-60 of calcium ion blocker, with the preferential proposal being ((2-n-propyl-4-methyl-1H-benzoglioxaline)-6-methanamide-1-base)methyl biphenyl tetrazole and carboxylic acid compounds and the salts thereof, which all account for 20-100, and 1-30 of calcium ion blocker; the administration form can be one of oral, sucking, subcutaneous, hypoglossis, iutramuscular, intravenous, transdermal, local and rectal administration forms. By the research on a medicine I resisting hypertension and calcium channel blocker or the medicinal salt, the invention provides a new medicine compound preparation used for curing hypertension with small dosage, obvious antihypertensive effect and little adverse reaction.
Description
Technical field
The present invention relates to the compound recipe of the smooth compound or pharmaceutically acceptable salt thereof of a kind of sand and calcium channel blocker or officinal salt, belong to medical technical field.
Background technology
Hypertension is modal cardiovascular disease, and its complication is to cause one of human main causes of death.It is the great public problem of submiing in the global range.China is in the period of social economy's high speed development, along with the transition of society, adds the aggravation of aged tendency of population, and huge change has taken place for people's living standard and way of act, and hypertensive prevalence also presents swift and violent ascendant trend.According to according to World Health Organization (WHO) prediction, the cardiovascular diseases will be in the Asia, the certain areas in Latin America, the Middle East and Africa are popular on a large scale.China accounts for 58% of total cause of the death to the year two thousand twenty noninfectious and will rise to 79%, and wherein the cardiovascular diseases accounts for the first place.After 20 years, the cardiovascular diseases will be popular in developing country, wherein mainly be apoplexy and coronary heart disease.Height generally speaking, the hypertensive prevalence of China increases fast.The hypertension number of estimating among China adult is 1.6 hundred million now, annual newly-increased hyperpietic more than 600 ten thousand, and other has 1,500,000 people to die from the apoplexy that is caused by hypertension.Hypertension has become great public health problem that needs to be resolved hurrily of China, and it is extremely urgent with the treatment present situation to improve hypertension prevention.
The long-term bright hypertension drug of taking is to the heart, brain, and target organs such as kidney can produce grievous injury, even having influence on each organ of body, medical evidence shows, low dose of drug combination, can improve curative effect, reduce untoward reaction, the compensation response that is taken place when preventing single therapy.And the different depressor of synergy mechanism often can strengthen therapeutic effect, take into account patient's pathogenetic different links simultaneously, make multiple and deposit disease to obtain Optimal Control, the 26S Proteasome Structure and Function of target organ is played certain protective role, can reduce the incidence rate of cardiovascular event; Because the dosage of constituent parts medicine reduces greatly, its side effect also reduces thereupon.Therefore it is feasible advocating drug combination treatment cardiovascular disease.
Angiotensin ii receptor antagonist (ARB) is one of at present the most frequently used hypertension first-line treatment medicine.ARB is by selective exclusion angiotensin receptor 1 (AT
1), block Angiotensin II (Ang II) vasoconstrictive, rising blood pressure, promoted effects such as aldosterone secretion, water-sodium retention, sympathetic activation, produce and the similar pharmacotoxicological effect of angiotensin converting enzyme inhibitor (ACEI).On the other hand, because the synthetic feedback of Ang II increases, Ang II level raises in blood and the tissue, acts on AT
2, produce effects such as expanding blood vessel, cell proliferation, adjusting apoptosis.The Fournier meta-analysis showed in 2007, and the medicine of rising Ang II has the effect that blood pressure lowering reduces the apoplexy risk outward, and the medicine of reduction Ang II can weaken the protective effect of blood pressure lowering to apoplexy.The summary that William in 2007 etc. deliver also points out, protective effect is better than reducing the medicine of Ang II to the medicine of rising Ang II to apoplexy.And ARB is as at RAS system antihypertensive agent, show strong affinity, high selectivity, oral effectively, advantages such as long half time, better tolerance, effect directly, side effect is little.ARB effect clinically comprises: resisting hypertension, heart failure resistance, antithrombotic form, protect the heart, brain, kidney and blood vessel, also have the effect of reversing left ventricular hypertrophy in addition.Up-to-date result of study shows also have the effect that suppresses tumor growth factor TGF-β.ARB is controlling blood pressure effectively, reduces with hypertension patient's apoplexy risks such as diabetes, atrial fibrillation, left ventricular hypertrophy, carotid artery intima sclerosis, recommends ARB to prevent a line medication of apoplexy as the hyperpietic.ARB is effectively blood pressure lowering not only, also has the outer benefit of blood pressure lowering simultaneously.Delay carotid artery intima middle level thickness: carotid artery sclerosis progress is directly related with apoplexy.In a word, follow the card evidence and confirm, ARB is as hypertension one line medication, effectively reducing and controlling blood pressure, reversing LVH, prevents and treats aspect diabetes and the prevention atrial fibrillation effect certainly, in the generation of prevention apoplexy and the originating party face is significant again.Remarkable in the ARB antihypertensive effect, especially to unique curative effect of cardiovascular disease, ARB has become one of specified depressor of the WHO of World Health Organization (WHO).The analysis of LIEF research subgroup confirms that losartan can make the progress of carotid artery intima middle level thickness delay 7.9%.Improve insulin resistant: ARB has peculiar advantage aspect the carbohydrate metabolism disturbance improving.[(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-Methanamide-1-yl] methyl biphenyl tetrazolium and carboxylic acid compound are that the present invention is that lead compound is carried out structural modification and transformation with the losartan that has gone on the market, the chemical compound of design synthetic chemistry novel structure.Experimental result confirms that his antihypertensive effect is better than the sartans that has gone on the market, and toxicity is minimum, is a kind of new promising angiotensin ii receptor antagonist.With other mechanism of action different pharmaceutical drug combination treatment hypertension, cardiovascular and cerebrovascular diseases such as hyperlipidemia, more safe and effective, the utmost point has market value.
Calcium ion blocker (CCB) blood pressure lowering effectively, stable, his basic role is to suppress stream in the Ca2+ of extracellular, promptly lax vascular smooth muscle cell, vasodilator and blood pressure lowering.Its hypotensive effect is relevant with dosage, does not reduce cardiac output, does not cause postural hypotension and water-sodium retention, can obviously reduce the generation of apoplexy, is the most frequently used, and a most basic line depressor is applicable to senile systolic hypertension.Long lasting CCB has the organ protection beyond the blood pressure lowering, promptly reverses carotid artery intima-middle level and thickens (IMT), alleviates calcification coronarius, reduces the patient with angina pectoris admission rate.Long lasting CCB can reduce the albuminuria of diabetics and improve renal function, reduce the middle emphasis of cardiovascular and cerebrovascular disease and the incidence rate of whole last terminal point incident, most results of study show that CCB is being better than beta-blocker and diuretic class hypertension agents aspect the reduction stroke incidence.CCB can effectively prevent angina pectoris, bring high blood pressure down.Enter the calcium ionic current of muscle cell by blocking-up, calcium channel blocker can play vasodilatory effect, thereby the oxygen that can improve cardiac muscle supplies, CCB is as a kind of resisting hypertension medication, vascular smooth muscle there is stronger selection, the vascular smooth muscle that can directly relax, the expansion peripheral blood vessel reduces the effect of peripheral blood vessel drag overall.
The hypertension therapeutic alliance because of its superiority (collaborative or synergistic effect, the metabolism improving effect, perhaps the two and deposit) widely accepted.Low dosage use in conjunction variety classes antihypertensive drug helps reducing the dose dependent that single medicine may exist, and every kind of composition is all with low dose applications during the two drug combination.Even dosage is used for the effective dose of blood pressure lowering separately less than every kind of composition, drug combination still keeps hypotensive effect.Experimental data proof AT1 antagonist and CCB reduce intracellular calcium and promote vasodilation by machine-processed complementation, and endothelial dysfunction is reversed.
I compounds of the present invention or its officinal salt and the medication of calcium ion blocker meet the Therapeutic Principle of drug combination.At first, [(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-Methanamide-1-yl] methyl biphenyl tetrazolium and carboxylic acid compound are sartans, act on the effect of the end eventually link in epinephrine-angiotensin booster system, the direct effect of blocking-up Angiotensin II (AngII) also is reduced in the tension force that has sympathetic nervous system in the blood pressure regulating process; The calcium ion blocker then acts on the target organ-blood vessel wall tension force of various neuro humor factors in the blood pressure regulating process.Carry out complementation from pharmacotoxicological effect mechanism, strengthen its hypotensive effect.Moreover drug combination can reduce the relative consumption of each medicine, reduces the untoward reaction of medicine, improves patient's drug compliance, thereby improves patient's quality of life; In addition, this two classes medicine is better to the hypertension induced effect of chronic kidney hypofunction institute, can delay the deterioration of nephropathy disease after share, and plays the effect of protection kidney, and especially the patient to renal hypertension or companion's diabetes renal function injury has positive therapeutic.U.S.'s hypertension clinical research proves: the hypertension therapeutic alliance is widely accepted because of its superiority (collaborative or synergistic effect, metabolism improving or the two are also deposited).Drug combination often can reduce dose and reach antihypertensive effect; The more independent a kind of depressor expense of therapeutic alliance drug cost is lower, and the blood pressure reaching standard time is shorter.One piece of article wherein
[1]In when demonstration single medicine and drug combination are treated rational clinical experiment, point out: the employing single therapy, antihypertensive drugs may be controlled half patient's blood pressure.The use in conjunction of different mechanisms antihypertensive drugs can significantly increase the ratio of controlling of blood pressure to normal patient.When the while administration, half is just much of that for the antihypertensive drugs of low dosage.
Summary of the invention
It is good to the purpose of this invention is to provide a kind of antihypertensive effect, the composite antihypertensive preparation that untoward reaction is few.The problem that will solve of another object of the present invention is studied the antihypertensive drug A of novel structure and calcium channel blocker or officinal salt, provide a kind of consumption few, antihypertensive effect is remarkable, and untoward reaction is used for the treatment of hypertensive medicine new compound preparation less.The molecular formula of antihypertensive drug A is:
R in the formula
1=phenethylamine base, N methyl piperazine, R
2=tetrazol group, tetrazolium sodium salt, tetrazolium potassium salt, calcium salt, hydroxy-acid group, carboxylic acid sodium salt, potassium salt, calcium salt etc.
The CCB compounds mainly comprises dihydropyridine compounds (DHP) and non-DHP compounds, for example diltiazem and little handkerchief rice CCB that draws.Be applicable in the combinations thereof preferably nifedipine (Nifedipine) of CCB, felodipine (Felodipine), amlodipine (Amlodipine), Levamlodipine (Levamlodipine), lacidipine (Lacidipine), nimodipine (Nimodipine), nitrendipine (Nitredipine), nicardipine (Nicardipine), nisoldipine (Nisodipine), nilvadipine (Nivadipine), niludipine (Ninudipine), isradipine (Isradipine), lercanidipine (Lercanidipine), barnidipine (Barnidipine), or a kind of DHP representative in the Manidipine calcium ion antagonists such as (Manidipine), and preferably from Buddhist osmanthus piperazine, prenylamine, diltiazem, Mi Baila ground, Gallopamil, fendiline, Mi Baila ground, anipamil, tiapamil, non-DHP representative such as verapamil and pharmaceutical salts thereof.But the preferred thing of representative of DHP class medicine is amlodipine or its medication salt, especially its benzene sulfonate.Particularly preferred non-DHP class representative is little La Pami or its officinal salt, especially its hydrochlorate.The chemical compound that is combined can be used as the pharmaceutical salts form and exists.Corresponding C CB compounds preferred salt is amlodipine benzenesulphonate, diltiazem hydrochloride, HK-137, Buddhist osmanthus piperazine dihydrochloride, hydrochloric acid Gallopamil, Mi Baila ground dihydrochloride, Licardipine Hydrochloride and verapamil hydrochloride.
Composite antihypertensive preparation of the present invention, according to parts by weight, form by following component:
[(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-Methanamide-1-yl] methyl biphenyl tetrazolium and sour acid compounds and its esters
5～200
Calcium ion blocker 0.5～60
Above-mentioned compound preparation, its preferably scope be:
[(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-Methanamide-1-yl] methyl biphenyl tetrazolium and carboxylic acid compound and its esters
20～100
Calcium ion blocker 1～30
Above-mentioned [(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-Methanamide-1-yl] methyl biphenyl tetrazolium and carboxylic acid compound and its esters are [(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-Methanamide-1-yl] methyl biphenyl tetrazolium; The tetrazolium sodium salt, tetrazolium potassium salt, calcium salt, slaines such as magnesium.When pharmaceutically acceptable salt or solvate are as drug use, should be mixed with pharmaceutical composition separately or with another active component.
The preferred substance of the representative of above-mentioned DHP class medicine be amlodipine (Amlodipine) but or a kind of mixture in its medication salt, especially its benzene sulfonate, Levamlodipine (Levamlodipine), lacidipine, felodipine or the barnidipine.Above-mentioned the best is an amlodipine.
Above-mentioned non-DHP representative is Buddhist osmanthus piperazine, prenylamine, diltiazem, Mi Baila ground, Gallopamil, fendiline, Mi Baila ground, anipamil, tiapamil, verapamil and pharmaceutical salts thereof.Particularly preferred non-DHP class representative is verapamil or its officinal salt, especially one of its hydrochlorate.
Corresponding C CB compounds preferred salt is one of amlodipine benzenesulphonate, diltiazem hydrochloride, HK-137, Buddhist osmanthus piperazine dihydrochloride, hydrochloric acid Gallopamil, Mi Baila ground dihydrochloride, Licardipine Hydrochloride and verapamil hydrochloride.
Wherein felodipine or its officinal salt and compd A and its esters and weight proportion be 1:2～1:1000.
Wherein amlodipine, Levamlodipine or its officinal salt or its officinal salt and compd A and its esters and weight proportion be 1:1～1:2000.
Wherein lacidipine or its officinal salt or its officinal salt and antihypertensive drug A and its esters and weight proportion be 1:2～1:1100.
Wherein nimodipine or its officinal salt or its acceptable salts and antihypertensive drug A and its esters and weight proportion be 1:1～1:1100.
Wherein nitrendipine, nicardipine, nisoldipine, nilvadipine, niludipine, isradipine, lercanidipine, barnidipine or Manidipine or its officinal salt or its officinal salt and antihypertensive drug A and its esters and weight proportion be 1:5～1:1200.
In oral, suction of the present invention, subcutaneous, Sublingual, intramuscular, vein, transdermal, part or the rectally composition of medicine, active component combines separately or with another kind of active component, with standard drug vehicle group resulting mixture, can give and the animal or human by the unit form of medication again.Concrete form of medication comprises: various dosage forms such as tablet, capsule, pill, granule, powder and oral liquid or suspension, the river mouth, Sublingual contains administration, aerosol, topical type, implant, transdermal, subcutaneous, intramuscular, vein, intranasal or ophthalmic and rectally type.When preparing the drug regimen of tablet or capsule form, add the drug excipient mixture in micronized active component, this mixture can be made up of lubricants such as fluidizer such as disintegrating agent, silicon dioxide, Talcums such as diluent such as lactose, mannitol, microcrystalline Cellulose, starch or dicalcium phosphate, polyvinylpyrrolidone, crosslinked carboxy methylcellulose sodium and magnesium stearate, hard ester acid, ester acyl fumaric acid sodium etc. is formed firmly.
Beneficial effect: [(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-yl] of the present invention Methanamide-1-yl] methyl biphenyl tetrazolium and carboxylic acid compound be that a class has Angiotensin II AT1 receptor and suppresses active chemical compound, have effectively and bring high blood pressure down, side effect is little, safe and reliable characteristics.The present invention is in conjunction with the physiological characteristics and the mechanism of drug action of essential hypertension, finds [(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-yl] Methanamide-1-yl] combination of methyl biphenyl tetrazolium and carboxylic acid compound and calcium ion blocker is the hypertensive prescription of a kind of effective treatment.Preparation of the present invention is applicable to eurypalynous hypertensive patient, be applicable to treatment high blood pressure disease (constitutional, the kidney blood vessel, diabetes, isolated systole or other secondary hypertensions), can also effectively treat and prevent heart failure, left ventricular dysfunction, hypertrophy or diabetic cardiomyopathy, arrhythmia, atrial fibrillation, atherosclerosis, angina pectoris, diabetes diseases such as (non-insulin-dependent diabetes mellitus).In addition to treatment and prophylaxis of aldosterone increase disease, renal failure disease and diabetic nephropathy, glomerulonephritis, glomerular sclerosis, urine protein disease and renal hypertension, diabetic retinopathy, symptoms such as ischemic migraine and apoplexy.Uniting use and not only can producing synergy of AT1 antagonist or its officinal salt and a kind of CCB or its officinal salt found in experiment, can also obtain other effects intentionally: prolong curative effect, range of application is more extensive: anti-hypertrophy, antithrombotic forms and antiatherogenic characteristic.
This experimenter can enoughly confirm above-mentioned described symptom zoopery.
The specific embodiment:
High heavy hypertensive observation of curative effect in embodiment 1 Compound I and the amlodipine therapeutic alliance
1. materials and methods
One, object of study
1.1 case is selected: outpatient service and the 18-70 that is in hospital the year untreated or used the light of antihypertensive drugs, in, height blood pressure patient is totally 90 examples, male's 35 examples wherein, women's 35 examples, Body Mass Index 30, SiDBP is 95-109mnHg (1mmHg=0.133kPa) behind the clothes placebo, seat systolic pressure 180Hg.Exclusion standard: secondary hypertension, the cardiovascular and cerebrovascular disease history of attack is arranged, the arrhythmia that need heal with medicine is to ingredient allergy, drug dependence or alcoholic, gestation and age of sucking, type 2 diabetes mellitus, low, hyperkalemia symptom, dysthyroid, serious liver, renal insufficiency.
Two research methoies
2.1 test method: selected patient divides two groups, all stops using 2 weeks of antihypertensive drugs before two groups of patients test, change take placebo (make with excipient with test in used medicine I and amlodipine shape, size, medicine that color is identical).(1) low-low dosage drug combination group: the Compound I group gives I capsule (self-control), every 40mg; The amlodipine group gives amlodipine sheet (production of Dalian pfizer inc), every 2.5mg, all 1 decoction being taken at a draught every day (8PM).(2): high dose group 1: amlodipine 10mg; (3) high dose group: Compound I: 160mg. (3) positive controls: losartan (Hangzhou MSD Corp.) 100mg.1 blood pressure of per 2 week records in the therapeutic process, total 12 weeks of the course of treatment.Treatment before and after look blood glucose, blood fat, creatinine, glutamate pyruvate transaminase, potassium, sodium and electrocardiogram.
2.2 observation index: clinic blood pressure: measure patient's seat right upper extremity blood pressure 1 time every half an hour after taking 2 all placebo when Drug therapy begins, continuous measurement 3 times is got its meansigma methods as the preceding basic blood pressure of treatment; Per 1～2 week is measured 1 blood pressure during the treatment.24 weeks measured patient's seat right upper extremity blood pressure every other day 1 time by standard method of measurement in treatment, its meansigma methods is treatment back blood pressure; (2) ambulatory blood pressure monitoring (ABPM): respectively the patient is carried out 24 hours ABPM in the placebo importing end of term and the Drug therapy end of term, instrument is that the U.S. produces the non-invasive ambulatory blood pressure monitoring instrument of 90207 types.Be divided into 6:00～22:00 on daytime, in night 22.00～6.00 two stage, per 30 minutes of daytime measured 1 time, and per 45 minutes of night measured 1 time.
2.3 efficacy of antihypertensive treatment is judged: the hypertension efficacy assessment standard with reference to the unified regulation of Ministry of Public Health carries out efficacy evaluation.(1): produce effects: diastolic pressure descends〉10mmHg, and reduce to normal or more than the decline 20mmHg; (2) effective: diastolic pressure decline 10-19mmHg, or decline＜10mmHg, but reached normal; (3) invalid: as not reach above-mentioned standard.
2.4 statistical procedures measurement data: so that (x ± s) expression adopts the t check, and effective percentage carries out statistical disposition with the chi-square criterion method, and P＜0.05 difference has significance.
Three. the result
3.1 efficacy analysis: (1) treatment 12 all blood pressure: after treating for 12 weeks, 2 groups of patient's seat DBP, SBP obviously descend, and difference has the statistical significance (P＜0.001) (as table 1.) of highly significant.The average seat DBP fall that is amlodipine 2.5mg/ Compound I 40mg is than losartan group bigger (20mmHg:9mmHg), and difference has significant statistical significance (P＜0.05).2 groups of patient's seat SBP also have remarkable decline, come can with average seat SBP fall be higher than losartan group (22mmHg:10mmHg), difference has significant statistical significance (P＜0.05).The average seat DBP of coupling, SBP descend and are significantly higher than amlodipine list medication group or the single medication group of Compound I, the statistical significance of significant difference (P＜0.05).(2) antihypertensive effect relatively: amlodipine 2.5mg/ Compound I 40mg group patient is 85.9% at the total effective rate of treatment 12 week back blood pressure lowering, be significantly higher than losartan (65.7%), the amlodipine list is single with group (75.5%) (P＜0.05) with group (62.9%) and Compound I.
3.2 toleration and safety: through follow-up observation: the cardiovascular and cerebrovascular vessel incident does not all take place in the patient.Losartan group 1 example is coughed, and two lower limb Mild edema appear in amlodipine group 2 examples, and 1 example withdraws from test (being not counted in observation of curative effect), and surplus all finishing smoothly treated in 12 weeks; The drug combination group is not found tangible untoward reaction.
Table 1 amlodipine 2.5mg/ Compound I 40mg (1), amlodipine 10mg (2), Compound I 160mg (3) treat average SiDBP of 6 weeks, systolic pressure variation with preceding the reaching of losartan 100mg (4) group patient treatment:
Compare before the treatment: annotate: with ratio before the treatment, P＜0.001; With losartan ratio, P＜0.05
Discuss: Angiotensin II (Ang II) is the important endocrine hormone of blood pressure regulation and water-electrolyte metabolism, it by with the target organ cell membrane on AT1 and AT2 receptors bind bring into play biological effect, cause vasoconstriction with the AT1 receptors bind, cell proliferation, it is Ang II 1 receptor antagonist (AT1RA) that Endothelin and catecholamine discharge Compound I, this medicine optionally with the AT1 receptors bind, the untoward reaction of blocking-up Ang II reaches hypotensive effect.Amlodipine is long-acting dihydropyridine calcium ion antagonist, by suppressing the calcium channel of calcium ion through the cell serous coat, stops calcium ion to enter the peripheral arterial smooth muscle cell, reduces peripheral vascular resistance, makes blood pressure drops.
This test is contrast with the losartan, observes curative effect and safety that the light camber blood stasis of amlodipine and telmisartan therapeutic alliance is pressed.The result shows drug combination, orally once a day all effectively bring high blood pressure down, onset time for 1.5 weeks of treatment after.The antihypertensive effect of drug combination is better obviously, apparently higher than the losartan group, compares with independent medication, also apparently higher than single with amlodipine or Compound I group.The untoward reaction of drug combination obviously reduces, and patient tolerability is good.Therefore, drug combination is treated light moderate hypertension can improve efficacy of antihypertensive treatment, reduces untoward reaction, and scheme of combination drug therapy is reasonable.
Embodiment 2 Compound I and amlodipine drug combination are to the synergistic observation treatment of spontaneous hypertensive rat
One. material and method
1. be subjected to the reagent thing
(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-yl] Methanamide-1-yl] the methyl biphenyl tetrazole compound, off-white color powder (system), content 99.8% (w/w); Amlodipine, white powder, Changzhou Pharmaceutical Co., Ltd of inferior group provides.Two medicines are prepared into suspension by 0.3%CMC, and according to the stock solution of irritating stomach concentration, refrigerator keeps in Dark Place.
2. laboratory animal
5 groups of spontaneous hypertensive rats (SHR), 8 every group, available from: Fuwai Hospital, academy of science of Chinese medicine institute Beijing zoopery section meets primary standard, body weight (250 ± 30) g; The animal quality certification: 011085.Laboratory and animal feeding room ambient temperature are 25 ℃, artificial lighting 12h/d every day.Freely drink water, feed high protein feed, renew bright tap water every day once with 20%.Measure 25 ℃ of pressure room temperatures.
3. experimental technique
Plan adopts gastric infusion with route of administration, and dosage is 1.0ml/kg, and matched group is given and isopyknic distilled water.SHR body constitution amount (250 ± 30) g.
3.1 blood pressure measuring method:
Earlier rat is placed (36 ± 1 ℃) heating in the electrothermostat before the pressure measurement, use CRB-III type rat computer blood pressure cordiotach (Shanghai Research Institute of Hypertension's production) the indirect determination rat arteria caudalis systolic pressure (SBP) and the rhythm of the heart (HR) after 10 minutes.With clear-headed rat arteria caudalis manometry, pressure measurement every day once in about two weeks, waits rat to conform and formally tests behind the blood pressure stabilization before the formal experiment.Report that meansigma methods in 24 hours of each rat and the sample that collected at interval in per 10 minutes form, mean values that blood pressure and rhythm of the heart numerical value were gathered by drug treatment in first three successive 24 hours is formed.SHR is according to blood pressure, and the body constitution amount is divided into 6 groups at random, and 8 every group, irritate distilled water respectively, medicine, volume is 1.0ml/1kg.Measure administration before and after 1,2,3,4,6,8,12,24,48 hours the systolic pressure and the rhythm of the heart are with the t check significance of mean difference before and after the administration relatively.Measure the body weight of a rat weekly, 5 water consumption draw the dosage of I and amlodipine thus, and drug solution upgraded in average per 2 days.
Every group of SHR irritates distilled water respectively, I (200mg/l; High dose), amlodipine (80mg/l; High dose), I (100mg/l) and amlodipine (540mg/l), I (100mg/l) and amlodipine (80mg/l), I (200mg/l) and amlodipine (40mg/l), I (200mg/l) and amlodipine (80mg/l).SHR is carried out eight all therapeutic alliance researchs, and recording processing is carried out in the reaction of ACU under the blood pressure curve, prove that with this therapeutic alliance is obvious than unit medicine therapeutic effect.
The result shows that I or amlodipine treatment that the combination of I and amlodipine is more independent have better significant effect.Studies show that, use I (200mg/l separately; High dose) can make blood pressure drops about 30,21mmHg, I that is used in combination (100mg/l) and amlodipine (5mg/l), I (100mg/l) and amlodipine (10mg/l), I (200mg/l) and amlodipine (5mg/l), I (200mg/l) and amlodipine (10mg/l) can make average amplitude that blood pressure descends respectively greater than 53mmHG..
Embodiment 3 Compound I and Gallopamil drug combination are observed the treatment of Diabetes with Hypertension rat
Carry out representative studies with the representative of non-DHP among I and the CCB such as the combination of Gallopamil.
I and Gallopamil have good blood pressure lowering synergism between the two, especially Diabetes with Hypertension are had excellent curative, and promptly the The combined result of use is than the algebraical sum height of the independent result of use of two compositions.
At present the Diabetes with Hypertension symptom is that of worsening of diabetes development is important factor, bring high blood pressure down can well the control of diabetes patient in urine protein and nephropathy factor.In the present line CCB hypertension therapeutic medicine; do not have evidence to show renal hypertension is had protection and therapeutical effect; and this medicine of this experiment confirm and the medication combined therapeutic effect of CCB class are obvious; preferred I and Gallopamil are in treatment diabetic SHR experiment, and survival rate improves greatly following blood pressure obviously to descend simultaneously.
With 18 6 groups of SHR in age age-20 week in week (chain urine rhzomorph is handled), eight every group, survey rat body weight weekly.Preparing experiment before the administration is the same, works in coordination with experimentation after two weeks.Untreated diabetes SHR organizes in contrast.Every group of SHR irritates distilled water respectively; Untreated diabetes SHR matched group, other group diabetes SHR irritates I (30mg/Kg) (2 groups) respectively; Gallopamil (20mg/Kg) (3 groups); I (15mg/Kg) and Gallopamil (10mg/Kg) (4 groups).SHR is carried out the treatment research of 20 weeks, prove that with this therapeutic alliance is obvious than unit medicine therapeutic effect.
The result shows that I or verapamil treatment that the combination of I and Gallopamil is more independent have better significant effect.Promptly except that the survival rate of matched group for being lower than 30%, the survival rate of all the other groups is all greater than more than 40%, especially I (15mg/Kg) and Gallopamil (10mg/Kg) do not change because of dosage lowers antihypertensive effect, otherwise its antihypertensive effect and survival rate all improve greatly, and the progress step has confirmed that its therapeutic alliance is better than the treatment of single medicine.In this experiment, can also observe drug combination can reduce greatly to the organ injury of diabetic SHR.Therefore the combination of I and CCB class can be suitable for treatment diabetes and related symptoms, and the hypertension of diabetics for example improves quality of life of patient, can be used for slowing down the development process of diabetic nephropathy, reduces its albumen disease.
One object of the present invention is to provide pharmaceutical composition, be used for the treatment of following disease: constitutional, the kidney blood vessel, diabetes, isolated systole or other secondary hypertensions, heart failure, left ventricular dysfunction, hypertrophy or diabetic cardiomyopathy, arrhythmia, atrial fibrillation, atherosclerosis, angina pectoris, diabetes diseases such as (non-insulin-dependent diabetes mellitus) are effectively treated and are prevented.In addition to treatment and prophylaxis of aldosterone increase disease, renal failure disease and diabetic nephropathy, glomerulonephritis, glomerular sclerosis, urine protein disease and renal hypertension, diabetic retinopathy, symptoms such as ischemic migraine and apoplexy.Composition of medicine comprises: I or its officinal salt and CCB (B) or its officinal salt and pharmaceutically suitable carrier.
In this combination, can be independent I composition, can be the unit dosage forms administration of the combination of I and B composition.
Other purpose of the present invention is that the pharmaceutical composition of a kind of IAT1 of containing antagonist or its officinal salt and B or its officinal salt and pharmaceutically suitable carrier is being used for the treatment of or is preventing following disease to use: constitutional, the kidney blood vessel, diabetes, isolated systole or other secondary hypertensions, heart failure, left ventricular dysfunction, hypertrophy or diabetic cardiomyopathy, arrhythmia, atrial fibrillation, atherosclerosis, angina pectoris, diabetes diseases such as (non-insulin-dependent diabetes mellitus) are effectively treated and are prevented.In addition to treatment and prophylaxis of aldosterone increase disease, renal failure disease and diabetic nephropathy, glomerulonephritis, glomerular sclerosis, urine protein disease and renal hypertension, diabetic retinopathy, symptoms such as ischemic migraine and apoplexy.
Each composition of combined therapy effective dose of the present invention can be simultaneously or sequentially and with any order administration.
Corresponding active component or its medicinal acceptable salts can also or contain the chess circles crystallization with hydrate to be used with the form of solvent.
Pharmaceutical preparation of the present invention: for oral, rectum and non-rectally are in mammal; These chemical compounds can be singly with or with one or more pharmaceutically suitable carrier.
New pharmaceutical preparation contains has an appointment 5% to 100%, and preferred 15-65%'s is active.Of the present inventionly be used for enteral or parenterai administration pharmaceutical preparation is: described aforementioned pharmaceutical compositions is characterized in that described oral formulations can be made into tablet, capsule, dispersible tablet, soft capsule, chewable tablet, oral cavity disintegration tablet, drop pill etc.
Research worker is come [(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-Methanamide-1-yl] methyl biphenyl tetrazolium of the present invention and carboxylic acid compound and its esters and amlodipine preparation done by following example and is specified,
But not only for following example, [(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-Methanamide-1-yl] methyl biphenyl tetrazolium and carboxylic acids refer in particular to [(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-Methanamide-1-yl] methyl biphenyl tetrazolium and carboxylic acid compound and its esters among the embodiment.This dosage depends on the species of animal, age and individual instances and administering mode.Under normal conditions, general administration be 10mg to about 1000mg, preferred 20mg to 200mg, the I of 20mg to 80mg most preferably from about, and B is 0.5mg to 900mg, the preferred CCB of 1mg to 60mg, CCB its concrete dosage of taking temperature.Below
Embodiment 4 [(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-Methanamide-1-yl] methyl biphenyl tetrazolium and carboxylic acids tablet
Prescription:
Preparation method:
[(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-Methanamide-1-yl] methyl biphenyl tetrazolium and carboxylic acid, starch are crossed 80 mesh sieves respectively, behind the mix homogeneously, add 5% ethanol and make soft material in right amount, 20 mesh sieves are granulated, drying, 16 mesh sieve granulate add stearic acid, adopt suitable punch die compressed tablets behind the mix homogeneously, promptly.
Embodiment 5:[(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-and 6-Methanamide-1-yl] methyl biphenyl tetrazolium and carboxylic acids capsule
Prescription
[(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-Methanamide-1-yl] methyl biphenyl tetrazolium and carboxylic acid, Celluloasun Microcrystallisatum are crossed 80 mesh sieves respectively, behind the mix homogeneously, add the polyvidone aqueous solution and make soft material in right amount, 24 mesh sieves are granulated, dry, 20 mesh sieve granulate add the stearic acid of recipe quantity, in No. 1 suitable capsule shells of packing into behind the mix homogeneously promptly.
Embodiment 6:[(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-and 6-Methanamide-1-yl] methyl biphenyl tetrazolium and carboxylic acids chewable tablet
Prescription
[(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-Methanamide-1-yl] methyl biphenyl tetrazolium and carboxylic acid, Celluloasun Microcrystallisatum, mannitol are crossed 80 mesh sieves respectively, behind the mix homogeneously, add the polyvidone aqueous solution and make soft material in right amount, 24 mesh sieves are granulated, dry, 20 mesh sieve granulate add in No. 1 suitable capsule shells of packing into behind the aspartame, grape essence, Mentholum mix homogeneously of recipe quantity promptly.
Embodiment 7 [(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-Methanamide-1-yl] methyl biphenyl tetrazolium and carboxylic acids and amlodipine tablet
Prescription
Preparation method:
With [(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-Methanamide-1-yl] methyl biphenyl tetrazolium and carboxylic acid compound, amlodipine etc. take by weighing supplementary material according to recipe quantity, cross the 60-100 mesh sieve respectively, behind the mix homogeneously, add the polyvidone aqueous solution and make soft material in right amount, 20 mesh sieve system granules, dry, granulate adds magnesium stearate, CMS-Na, micropowder silica gel is adopted suitable punch die compressed tablets, promptly behind the mix homogeneously.
Embodiment 8:[(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-and 6-Methanamide-1-yl] methyl biphenyl tetrazolium and carboxylic acid compound and amlodipine capsule
Prescription
Preparation method:
With supplementary material difference powder essence, cross the 60-100 mesh sieve, according to recipe quantity weighting raw materials mix homogeneously, make soft material with the polyvidone aqueous solution, 18 mesh sieves are granulated, and drying adds magnesium stearate, mix homogeneously, granulate, filling promptly gets product.
Embodiment 9 [(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-Methanamide-1-yl] methyl biphenyl tetrazolium and carboxylic acid and amlodipine preparation of granules
Prescription
Preparation method:
[(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-Methanamide-1-yl] methyl biphenyl tetrazolium and carboxylic acid, amlodipine, lactose, microcrystalline Cellulose, carmethose, correctives stevioside etc. are taken by weighing supplementary material according to recipe quantity, cross the 60-100 mesh sieve respectively, behind the mix homogeneously, add the polyvidone aqueous solution and make soft material in right amount, 20 mesh sieve system granules, drying, granulate, add, CMS-Na, micropowder silica gel, mix homogeneously, fill, promptly.
Embodiment 10 compound recipes [(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-Methanamide-1-yl] methyl biphenyl tetrazolium and carboxylic acid compound and the preparation of amlodipine chewable tablet
Prescription
Preparation method:
[(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-Methanamide-1-yl] methyl biphenyl tetrazolium and carboxylic acid, amlodipine, mannitol, microcrystalline Cellulose etc. are taken by weighing supplementary material according to recipe quantity, cross the 60-100 mesh sieve respectively, behind the mix homogeneously, add the polyvidone aqueous solution and make soft material in right amount, 20 mesh sieve system granules, dry, granulate adds stevioside, grape essence starch, mix homogeneously, tabletting gets final product.
Embodiment 11: compound recipe [(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-Methanamide-1-yl] methyl biphenyl tetrazolium and carboxylic acid compound and amido chloro diping dispersion tablet
Prescription: prescription
[(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-Methanamide-1-yl] methyl biphenyl tetrazolium and carboxylic acid compound, amlodipine, lactose, polyvinylpyrrolidone, dodecyl sodium sulfate are taken by weighing supplementary material according to recipe quantity, cross the 60-100 mesh sieve respectively, behind the mix homogeneously, add the polyvidone aqueous solution and make soft material in right amount, 20 mesh sieve system granules, drying, granulate, add magnesium stearate and micropowder silica gel, the mix homogeneously rear panel promptly
Embodiment 12: compound recipe [(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-Methanamide-1-yl] methyl biphenyl tetrazolium and carboxylic acid compound and amlodipine buccal tablet
Prescription:
With [(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-Methanamide-1-yl] methyl biphenyl tetrazolium and carboxylic acid compound, amlodipine, lactose, xylitol, take by weighing supplementary material according to recipe quantity, cross the 60-100 mesh sieve respectively, behind the mix homogeneously, add the polyvidone aqueous solution and make soft material in right amount, 20 mesh sieve system granules, drying, granulate, add aspartame, glucose essence, Mentholum mix homogeneously magnesium stearate and the micropowder silica gel of recipe quantity, the mix homogeneously rear panel promptly.
Embodiment 13: compound recipe [(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-Methanamide-1-yl] methyl biphenyl tetrazolium and carboxylic acid compound and amlodipine soft capsule
Prescription: prescription
With [(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-Methanamide-1-yl] methyl biphenyl tetrazolium and carboxylic acid compound, amlodipine, lactose, xylitol, take by weighing supplementary material according to recipe quantity, cross the 60-100 mesh sieve respectively, behind the mix homogeneously, add the polyvidone aqueous solution and make soft material in right amount, 20 mesh sieve system granules, drying, granulate, add aspartame, glucose essence, Mentholum mix homogeneously magnesium stearate and the micropowder silica gel of recipe quantity, the mix homogeneously rear panel promptly.
Claims (10)
1. the compound recipe of the smooth compound or pharmaceutically acceptable salt thereof of sand and calcium channel blocker or officinal salt is characterized in that: be made up of following component according to parts by weight:
[(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-Methanamide-1-yl] methyl biphenyl tetrazolium and sour acid compounds and its esters
5～200
Calcium ion blocker 0.5～60
Above-mentioned compound preparation, its preferably scope be:
[(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-Methanamide-1-yl] methyl biphenyl tetrazolium and carboxylic acid compound and its esters
20～100
Calcium ion blocker 1～30.
2. according to the smooth compound or pharmaceutically acceptable salt thereof of a kind of sand of claim 1 and the compound recipe of calcium channel blocker or officinal salt, it is characterized in that: above-mentioned [(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-Methanamide-1-yl] methyl biphenyl tetrazolium and carboxylic acid compound and its esters are [(2-n-propyl group-4-methyl isophthalic acid H-benzimidazole)-6-Methanamide-1-yl] methyl biphenyl tetrazolium; The tetrazolium sodium salt, tetrazolium potassium salt, one of calcium salt or magnesium;
But the preferred substance of the representative of above-mentioned DHP class medicine is a kind of in amlodipine or its medication salt, especially its benzene sulfonate, Levamlodipine (Levamlodipine), lacidipine, felodipine or the barnidipine;
Above-mentioned non-DHP representative is Buddhist osmanthus piperazine, prenylamine, diltiazem, Mi Baila ground, Gallopamil, fendiline, Mi Baila ground, anipamil, tiapamil, verapamil and pharmaceutical salts thereof; Particularly preferred non-DHP class representative is verapamil or its officinal salt, especially one of its hydrochlorate; Corresponding C CB compounds preferred salt is one of amlodipine benzenesulphonate, diltiazem hydrochloride, HK-137, Buddhist osmanthus piperazine dihydrochloride, hydrochloric acid Gallopamil, Mi Baila ground dihydrochloride, Licardipine Hydrochloride or verapamil hydrochloride.
3. according to the smooth compound or pharmaceutically acceptable salt thereof of a kind of sand of claim 1 and the compound recipe of calcium channel blocker or officinal salt, it is characterized in that: administering mode has one of oral, suction, subcutaneous, Sublingual, intramuscular, vein, transdermal, part or rectum.
4. according to the smooth compound or pharmaceutically acceptable salt thereof of a kind of sand of claim 3 and the compound recipe of calcium channel blocker or officinal salt, it is characterized in that: concrete form of medication comprises: one of tablet, capsule, pill, granule, powder and oral liquid or suspension.
5. according to the smooth compound or pharmaceutically acceptable salt thereof of a kind of sand of claim 4 and the compound recipe of calcium channel blocker or officinal salt, it is characterized in that: when preparing the drug regimen of tablet or capsule form, add the drug excipient mixture in micronized active component, the adjuvant of this mixture comprises diluent, disintegrating agent, lubricant and fluidizer; Wherein, diluent comprises one of lactose, mannitol, microcrystalline Cellulose, starch or dicalcium phosphate; Disintegrating agent comprises polyvinylpyrrolidone or crosslinked carboxy methylcellulose sodium; Fluidizer comprises silicon dioxide or Talcum; Lubricant comprises one of magnesium stearate, hard ester acid or hard ester acyl fumaric acid sodium.
6. according to the smooth compound or pharmaceutically acceptable salt thereof of a kind of sand of claim 2 and the compound recipe of calcium channel blocker or officinal salt, it is characterized in that: wherein felodipine or its officinal salt and compd A and its esters and weight proportion be 1:2～1:1000.
7. according to the smooth compound or pharmaceutically acceptable salt thereof of a kind of sand of claim 2 and the compound recipe of calcium channel blocker or officinal salt, it is characterized in that: wherein amlodipine, Levamlodipine or its officinal salt or its officinal salt and compd A and its esters and weight proportion be 1:1～1:2000.
8. according to the smooth compound or pharmaceutically acceptable salt thereof of a kind of sand of claim 2 and the compound recipe of calcium channel blocker or officinal salt, it is characterized in that: wherein lacidipine or its officinal salt or its officinal salt and compd A and its esters and weight proportion be 1:2～1:1100.
9. according to the smooth compound or pharmaceutically acceptable salt thereof of a kind of sand of claim 2 and the compound recipe of calcium channel blocker or officinal salt, it is characterized in that: wherein nimodipine or its officinal salt or its acceptable salts and compd A and its esters and weight proportion be 1:1～1:1100.
10. according to the smooth compound or pharmaceutically acceptable salt thereof of a kind of sand of claim 2 and the compound recipe of calcium channel blocker or officinal salt, it is characterized in that: wherein nitrendipine, nicardipine, nisoldipine, nilvadipine, niludipine, isradipine, lercanidipine, barnidipine or Manidipine or its officinal salt or its officinal salt and compd A and its esters and weight proportion be 1:5～1:1200.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008101677998A CN101361736A (en) | 2008-10-08 | 2008-10-08 | Compound of losartan or pharmaceutical salt thereof and calcium channel blockers or pharmaceutical salt thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008101677998A CN101361736A (en) | 2008-10-08 | 2008-10-08 | Compound of losartan or pharmaceutical salt thereof and calcium channel blockers or pharmaceutical salt thereof |
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| Publication Number | Publication Date |
|---|---|
| CN101361736A true CN101361736A (en) | 2009-02-11 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2008101677998A Pending CN101361736A (en) | 2008-10-08 | 2008-10-08 | Compound of losartan or pharmaceutical salt thereof and calcium channel blockers or pharmaceutical salt thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107837240A (en) * | 2017-12-12 | 2018-03-27 | 临沂齐泽医药技术有限公司 | A kind of CV-4093 tablet for treating hypertension and preparation method thereof |
-
2008
- 2008-10-08 CN CNA2008101677998A patent/CN101361736A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107837240A (en) * | 2017-12-12 | 2018-03-27 | 临沂齐泽医药技术有限公司 | A kind of CV-4093 tablet for treating hypertension and preparation method thereof |
| CN107837240B (en) * | 2017-12-12 | 2020-07-07 | 佛山德芮可制药有限公司 | Manidipine hydrochloride tablet for treating hypertension and preparation method thereof |
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Open date: 20090211 |