CN101822837A - Medicine composition containing allisartan isoproxil salts - Google Patents

Medicine composition containing allisartan isoproxil salts Download PDF

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CN101822837A
CN101822837A CN201010301112A CN201010301112A CN101822837A CN 101822837 A CN101822837 A CN 101822837A CN 201010301112 A CN201010301112 A CN 201010301112A CN 201010301112 A CN201010301112 A CN 201010301112A CN 101822837 A CN101822837 A CN 101822837A
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disease
pharmaceutically acceptable
acceptable salt
inhibitor
salt
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王丽燕
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract

The invention relates to a medicine composition containing pharmaceutically acceptable salts containing allisartan isoproxil, at least one cardiovascular and cerebrovascular medicine and pharmaceutically acceptable vectors. The composition is used for preventing, slowing the progress of or treating the following diseases or symptoms of: hypertension, hypertension complications, diabetes, diabetes complications, dyslipidemia, ischemic diseases, coronary heart disease, angina, cardiac arrhythmia, stroke, arteriosclerosis, cerebral infarction, cerebral vascular diseases, cardiovascular diseases, coronary artery diseases, ventricular dysfunction, endothelial dysfunction, heart insufficiency, glaucoma and cataract, reducing the incidence and/or the mortality of cardiovascular and cerebrovascular diseases, decreasing the side effects, and also improving the medication compliance of patients.

Description

The pharmaceutical composition that comprises Ai Lishatan ester salt
Technical field
The present invention relates to a kind of pharmaceutical composition, it comprises pharmaceutically acceptable salt and at least a cardiovascular and cerebrovascular medicine or its pharmaceutically acceptable salt and the pharmaceutically acceptable carrier of Ai Lishatan ester, belongs to medical technical field.
Background technology
The World Health Organization (WHO) studies show that: the whole world has 1,500 ten thousand people to die from cardiovascular and cerebrovascular disease every year approximately, at majority state, cardiovascular and cerebrovascular disease is first cause of death of male more than 45 years old, is women's second cause of death, is having a strong impact on human life expectancy and life quality.The trend that cardiovascular and cerebrovascular disease obviously presents rejuvenation, becomes younger, according to the statistics of WHO to global various diseases death, the cardiovascular and cerebrovascular disease death toll accounts for 28.8% of total death toll.There is 2,600,000 people every year in China because of cardiovascular and cerebrovascular disease death, the cerebrovascular disease therapy expense holds pride of place always in inpatient's wholesale consumer center, and wherein the ratio that accounts for coronary heart disease, acute myocardial infarction, cerebral hemorrhage, hypertension, these five kinds of diseases of cerebral infarction again is the highest.If can treat cardiovascular and cerebrovascular disease in early days, effectively, just can improve patient's quality of life, reduce disability rate and mortality rate, therefore develop effectively, safe drugs are exactly crucial.
Ai Lishatan ester of the present invention; English name is Allisartan/Isoproxil; chemical name is 2-butyl-4 chloro-1-[2 '-(1H-tetrazolium-5-yl) 1; 1 '-xenyl-methyl] imidazole-5-carboxylic acid; the 1-[(isopropoxy) carbonyl acyl group] methoxyl group ester or 1-[(isopropoxy) carbonyl oxygen base] methyl ester, its structural formula is shown in the 21st page of chemical compound 8 among the Chinese patent Granted publication CN100506818C (application number CN200680000397.8).The pharmaceutically acceptable salt of described Ai Lishatan ester is selected from the alkali metal salt or the alkali salt of Ai Lishatan ester, further is selected from a kind of in potassium salt, sodium salt or the calcium salt of Ai Lishatan ester.Patent documentation CN200710093852.X, PCT/CN2006001914, CN200680000397.8, CN200610023991.0, CN200710094021.4, CN200610119184.9, PCT/CN2006003301 disclosed those, be incorporated herein by reference in its entirety.
The pharmaceutically acceptable salt of Ai Lishatan ester is an Angiotensin II (AT) receptor antagonist, the AT1 receptor there are the affinity of height and special selectivity, comprehensive antagonism AT1 body in body circulation and local organization, to the affinity of AT1 receptor than strong about 2000 times of AT2 receptor, selectivity also is higher than like product, but antagonism activates the arteries contraction that the back is produced by AT1, sympathetic activation and pressure receptor sensitivity increase, physiological effecies such as increased blood pressure, bring high blood pressure down, weaken myocardial cell and shrink, and the water sodium storage that retardance kidney AT1 activation back produces is stayed; Also can reverse by the cardiac muscle of AT1 mediation and the hypertrophy and the plumpness of arterial blood tube wall smooth muscle, delay the process of myocardial hypertrophy and kidney interstitial fibrosis, reduce the sickness rate and the case fatality rate of heart failure.Therefore, it is mainly used in the treatment cardiovascular and cerebrovascular disease, and wherein said cardiovascular and cerebrovascular disease is selected from hypertension, left ventricular hypertrophy, apoplexy, renal cortex atrophy, aorta and thickens (patent documentation 1).In addition, the pharmaceutically acceptable salt of Ai Lishatan ester also show have the blood fat reducing effect, to the undesired increase of heart, liver and kidney weight, to the inhibitory action and the diuresis (patent documentation 2) of renal function disease and renal artery inflammation.Compare with other Ang II receptor antagonists, the pharmaceutically acceptable salt of Ai Lishatan ester have metabolic pathway more economical, use is safer, toxicity is lower, the advantage that transformation efficiency is higher.
The pharmaceutically acceptable salt of Ai Lishatan ester and at least a cardiovascular and cerebrovascular medicine use in conjunction, can obtain beyond thought therapeutic effect, produce collaborative, add up or complementary action, be used for prevention, delay of progression or treat following disease or disease: hypertension, hypertensive patients disease, diabetes, diabetic complication, dyslipidemia, ischemic diseases, coronary heart disease, angina pectoris, congestive heart failure, arrhythmia, apoplexy, atherosclerosis, cerebral infarction, cerebrovascular disease, cardiovascular disease, coronary artery disease, ventricular dysfunction, pulmonary vascular disease, renal vascular, nephropathy, the visceral vessel disease, the vascular flow occlusive disease, inflammatory diseases, autoimmune disease, the immunologic function disease, pulmonary disease, the antioxidant disease, sexual dysfunction, cognitive dysfunction, endothelial function disturbance, cardiac insufficiency, glaucoma, vascular dementia, edema, thrombosis, hypothyroidism, peripheral vascular disease, diseases of eye, ear, nose and throat section disease, aneurysm, renin secreting tumor, cataract, post-stroke depression, depression after cerebral infarction, the hypertensive cerebral hemorrhage aftertreatment, vertebral-basilar artery insufficiency, polycystic ovary syndrome, vascular compliance is impaired, schistosomicide or cancer.
The pharmaceutically acceptable salt of Ai Lishatan ester and cardiovascular and cerebrovascular medicine drug combination, its benefit is: the drug effect of different mechanism of action can add up, work in coordination with or be complementary, and the reverse adjusting of passivation is compensatory, improves curative effect of medication; Minimizing increases drug safety because of the excessive adverse effect that causes of single medicine consumption; Take into account multiple risk factor and relevant disease that the patient exists, favourable individualized treatment; Improve patient's quality of life, improve patient's compliance; Can work in coordination with the protection of reinforcement to organ.
Be surprisingly found out that: pharmaceutical composition of the present invention is used the bigger therapeutic effect of each generation in these medicines more separately.It is bigger effect that the acting duration prolongation also can be considered as.Other benefits are: can use each medicine of low dosage more to make up to reduce dosage according to the present invention, for example required dosage is not only littler usually but also frequency of administration is littler, perhaps can be used for reducing the side effect incidence rate.Regardless of the basic cause of disease of disease, using of pharmaceutical composition can cause being had significantly by the treatment patient of bigger percent to reply promptly bigger respondent's ratio result.This meets the patient's that treats hope and requirement.
Pharmaceutical composition of the present invention or medicine box administering drug combinations are preferably every day 1 time or 2 times every day 1～4 time, and the patient takes medicine very conveniently like this, has improved the compliance that the patient takes medicine, and improves patient's quality of life.
Patent documentation 1: Chinese patent CN200710093852.X
Patent documentation 2: Chinese patent CN93116714.0
Summary of the invention
For convenience, before explanation the present invention, be collected in some terms that use among claims, description and the embodiment at this.Should partly read these definition and understanding as skilled in the art to understand according to the disclosure.Unless otherwise defined, all technology and scientific terminology have identical implication with those of ordinary skills' common sense as used herein.
Term " medicine ", " chemical compound ", " active matter ", " active substance " and " activating agent " can use interchangeably, and refer to a kind of material such as chemical compound or complex, described material is when using with effective dose, health had measurable useful physiological effect, as the treatment effect in the treatment of disease or obstacle; Further, when using these terms, or when specific active matter passes through title or kind specific recognition, should be understood that and describedly enumerate expection and comprise active matter itself, with and pharmaceutically acceptable pharmacological activity derivant, or with the chemical compound of its significant correlation, include but not limited to mixture, different crystal forms or armorphous, solvate, hydrate, oxide, fragment and the radiosiotope of any ratio of salt or ester, pharmaceutically acceptable salt or ester, prodrug, active metabolite, various isomer or these isomers.
Term " pharmaceutically acceptable salt " refers to can be according to normally used nontoxic salt or ester in the pharmaceutical industries of method preparation well known in the art.On the one hand, based on inorganic acid salts such as the halogen acid salt of the preferred hydrofluoride of the salt of basic group, hydrochlorate, hydrobromate, hydriodate and so on, nitrate, perchlorate, sulfate, phosphate; Acylates such as the aromatic sulfonic acid salt of the lower alkane sulfonate of mesylate, fluoroform sulphonate, esilate and so on, benzene sulfonate, tosilate and so on, maleate, acetate, malate, fumarate, hemifumarate, succinate, citrate, succinate, Ascorbate, tartrate, acetate, trifluoroacetate, lactate, malonate, tosilate, oxalates; And the amino acid salts of glycinate, lysinate, arginine salt, ornithine salt, glutamate, Glu, aspartate and so on; On the other hand, based on alkali salt, the aluminum salt of the alkali metal salt of the salt particular certain cancers of acidic-group, potassium salt, lithium salts and so on, calcium salt, magnesium salt and so on, slaines such as iron salt; The inorganic salt of ammonium salt and so on, t-octanylamine salt, dibenzyl amine salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucosamine salt, guanidinesalt, diethyl amine salt, triethylamine salt, hexanamine salt, N, the amine salt such as organic salt of N '-dibenzyl ethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-1-phenylethylamine salt, piperazine salt, tetramethyl ammonium, three (methylol) aminomethane salt and so on; And the amino acid salts of glycinate, lysinate, arginine salt, ornithine salt, glutamate, Glu, aspartate and so on.Should be understood that described nontoxic salt or ester comprise pharmaceutically acceptable pharmacological activity derivant, or with the chemical compound of its significant correlation, include but not limited to mixture, different crystal forms or armorphous, solvate, hydrate, oxide, fragment and the radiosiotope of any ratio of salt or ester, pharmaceutically acceptable salt or ester, prodrug, active metabolite, various isomer or these isomers.
Term " pharmaceutically acceptable carrier " is art-recognized, and refer to participate in to deliver or transport any theme composition or its component pharmaceutically acceptable material, component or carrier from the part of an organ or health to the part of another organ or health, as liquid or solid filler, diluent, excipient, solvent or encapsulating material.With theme composition and the compatible meaning of component thereof on, every kind of carrier must be acceptable and be harmless to the patient.Some examples that can be used as the material of pharmaceutically acceptable excipient comprise: (1) saccharide, as lactose, dextrose plus saccharose; (2) starch based is as corn starch and potato starch; (3) cellulose and derivant thereof are as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) pulverous Tragacanth; (5) Fructus Hordei Germinatus; (6) gelatin; (7) Talcum; (8) excipient is as cupu oil and suppository wax; (9) oils is as Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, safflower oil, Oleum sesami, olive oil, Semen Maydis oil and soybean oil; (10) glycols is as propylene glycol; (11) polyalcohols is as glycerol, Sorbitol, mannitol and Polyethylene Glycol; (12) esters is as ethyl oleate and ethyl laurate; (13) agar; (14) buffer agent class is as magnesium hydroxide and aluminium hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline solution; (18) fluid used of intravenous includes but not limited to Ringer's mixture, contains the water of 5% glucose and manages saline half a lifetime; (19) ethanol; (20) phosphate buffer; (21) used nontoxic compatible material in the other drug preparation.
Term " patient " refers to animal, preferred mammal, and optimum is chosen, and comprises masculinity and femininity.
(1), the present invention relates to a kind of novel medicament compositions, it is characterized in that it comprises pharmaceutically acceptable salt and a certain amount of at least a cardiovascular and cerebrovascular medicine or its pharmaceutically acceptable salt and the pharmaceutically acceptable carrier of a certain amount of Ai Lishatan ester.
Ai Lishatan ester of the present invention; English name is Allisartan/Isoproxil; chemical name is 2-butyl-4 chloro-1-[2 '-(1H-tetrazolium-5-yl) 1; 1 '-xenyl methyl] imidazole-5-carboxylic acid; the 1-[(isopropoxy) carbonyl acyl group] methoxyl group ester or 1-[(isopropoxy) carbonyl oxygen base] methyl ester, its structural formula is shown in the 21st page of chemical compound 8 among the Chinese patent Granted publication CN100506818C (application number CN200680000397.8).Patent documentation CN200710093852.X, PCT/CN2006001914, CN200680000397.8, CN200610023991.0, CN200710094021.4, CN200610119184.9, PCT/CN2006003301 disclosed those, be incorporated herein by reference in its entirety.
(2) in another preference,, it is characterized in that the pharmaceutically acceptable salt of described Ai Lishatan ester is the inorganic salt or the organic salt of Ai Lishatan ester as (1) described pharmaceutical composition; Preferentially be selected from alkali metal salt, alkali salt, slaine, ammonium salt, amine salt or the amino acid salts of Ai Lishatan ester; Be selected from the alkali metal salt or the alkali salt of Ai Lishatan ester especially.
The alkali metal salt of wherein said Ai Lishatan ester is selected from sodium salt, potassium salt or the lithium salts of Ai Lishatan ester;
The alkali salt of wherein said Ai Lishatan ester is selected from calcium salt, magnesium salt, strontium salt or the barium salt of Ai Lishatan ester;
The slaine of wherein said Ai Lishatan ester is selected from aluminum salt, iron salt, vanadic salts, mantoquita or the chromic salts of Ai Lishatan ester;
The amine salt of wherein said Ai Lishatan ester is selected from t-octanylamine salt, dibenzyl amine salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucosamine salt, guanidinesalt, diethyl amine salt, triethylamine salt, hexanamine salt, the N of Ai Lishatan ester, N '-dibenzyl ethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-1-phenylethylamine salt, piperazine salt, tetramethyl ammonium or three (methylol) aminomethane salt;
The amino acid salts of wherein said Ai Lishatan ester is selected from glycinate, lysinate, arginine salt, ornithine salt, glutamate, Glu or the aspartate of Ai Lishatan ester.
(3), in another preference,, it is characterized in that the pharmaceutically acceptable salt of described Ai Lishatan ester is a kind of in potassium salt, sodium salt or the calcium salt of Ai Lishatan ester as (1), (2) described pharmaceutical composition.
The potassium salt of described Ai Lishatan ester, chemical name is 2-butyl-4-chloro-1-[2 '-(1H-tetrazolium-5-yl) 1,1 ' xenyl methyl] imidazole-5-carboxylic acid, the 1-[(isopropoxy) carbonyl oxygen base] potassium salt of methyl ester, chemical structural formula is shown in the chemical compound two among the 14th page of embodiment 1 of Chinese patent publication number CN101596189A (application number CN200810043449.0);
The sodium salt of described Ai Lishatan ester, chemical name is 2-butyl-4-chloro-1-[2 '-(1H-tetrazolium-5-yl) 1,1 ' xenyl methyl] imidazole-5-carboxylic acid, the 1-[(isopropoxy) carbonyl oxygen base] sodium salt of methyl ester, chemical structural formula is shown in the chemical compound three among the 15th page of embodiment 2 of Chinese patent publication number CN101596189A (application number CN200810043449.0);
The calcium salt of described Ai Lishatan ester, chemical name is-2-butyl-4-chloro-1-[2 '-(1H-tetrazolium-5-yl) 1,1 ' xenyl methyl] imidazole-5-carboxylic acid, the 1-[(isopropoxy) carbonyl oxygen base] calcium salt of methyl ester, chemical structural formula is shown in the chemical compound four among the 15th page of embodiment 3 of Chinese patent publication number CN101596189A (application number CN200810043449.0).Patent documentation CN200810043449.0 disclosed those, be incorporated herein by reference in its entirety.
(4), in another preference, as (1) to (3) described pharmaceutical composition, it is characterized in that described cardiovascular and cerebrovascular medicine is selected from least a following active matter: calcium channel blocker, angiotensin converting enzyme inhibitor, B-adrenergic receptor blocker, alpha-adrenergic receptor blocker, diuretic, renin inhibitor, neutral endopeptidase inhibitor, Na +/ Ca 2+The exchange transporter inhibitors, angiotensin ii receptor antagonist (ARB), antihypertensive, dipeptidyl peptidase/IV inhibitor, antidiabetic drug, the HMG-CoA reductase inhibitor, antihyperlipidemic, 2-adrenergic agonist components, anti-anginal drug, anti-arrhythmic, antiplatelet drug, anticoagulant, anti-inflammatory agent, the CETP inhibitor, cox 2 inhibitor, direct thrombin inhibitor, inotropic agent, vasodilation, vasopressor, the crosslinked blocker of AGE, sinuatrial node If electric current blocker, prostacyclin, the PDE inhibitor, or its pharmaceutically acceptable salt or ester.
(5), in another preference, as (1) to (4) described pharmaceutical composition, it is characterized in that:
Described calcium channel blocker (CCB) is selected from: Levamlodipine, amlodipine, lacidipine, cilnidipine, lercanidipine, nisoldipine, nicardipine, azelnidipine, nitrendipine, felodipine, nifedipine, nimodipine, benidipine, aranidipine, isradipine, pranidipine, nilvadipine, Manidipine, efonidipine, niguldipine, dexniguldipine, niludipine, barnidipine, 1-tert-butyl-4,4-diphenylpiperidine., clevidipine, cronidipine, darodipine, elgodipine, elnadipine, flordipine, furnidipine, iganidipine, lemildipine, mesudipine, olradipine, oxodipine, palonidipine, prodipine, riodipine, Sagandipine, sornidipine, teludipine, vatanidipine, diltiazem, clentiazem, iprotiazem, nictiazem, siratiazem, verapamil, anipamil, dagapamil, devapamil, dexverapamil, emopamil, falipamil, gallopamil, levemopamil, nexopamil, ronipamil, tiapamil, or its pharmaceutically acceptable salt; Certainly preferred especially: Levamlodipine, amlodipine, lacidipine, lercanidipine, nicardipine, cilnidipine, nitrendipine, nimodipine, felodipine, nifedipine, nisoldipine, benidipine, diltiazem, verapamil or its pharmaceutically acceptable salt; Certainly preferred especially: Levamlodipine, amlodipine, lacidipine, lercanidipine, nicardipine, cilnidipine, nitrendipine, nimodipine, felodipine, nifedipine, nisoldipine, benidipine, diltiazem, verapamil or its pharmaceutically acceptable salt.
Described angiotensin converting enzyme inhibitor (ACEI) is selected from: perindopril, ramipril, fosinopril, lisinopril, quinapril, enalapril, imidapril, trandolapril, benazepril, cilazapril, captopril, delapril, zofenopril, moexipril, alacepril, ceronapril, idrapril, indolapril, libenzapril, moveltipril, orbutopril, pentopril, pivopril, rentiapril, spirapril, temocapril, utibapril, zabicipril, enalaprilat, ramiprilat, fosinoprilat, perindoprilat, trandolaprilat, benazeprilat, cilazaprilat, imidaprilat, quinaprilat, moexiprilat, spiraprilat, temocaprilat, the utibaprilat, zabiciprilat, zofenoprilat, or its pharmaceutically acceptable salt; Certainly preferred especially: perindopril, ramipril, fosinopril, lisinopril, quinapril, enalapril, imidapril, trandolapril, delapril, benazepril, zofenopril, enalaprilat or its pharmaceutically acceptable salt.
Described Beta-3 adrenergic receptor blocker comprises Beta-3 adrenergic receptor blocker and α, the Beta-3 adrenergic receptor blocker is selected from: metoprolol, bisoprolol, Propranolol, dexpropranolol, levobetaxolol, betaxolol, esmolol, atenolol, oxprenolol, pindolol, celiprolol, timolol, the dextrorotation timolol, carteolol, levobunolol, acebutolol, adaprolol, adimolol, afurolol, alprenolol, ancarolol, arnolol, befunolol, bevantolol, bometolol, bopindolol, bornaprolol, bucindolol, bucumolol, bufetolol, bunitrolol, bunolol, bupranolol, butocrolol, butofilolol, carazolol, carpindolol, cetamolol, cicloprolol, cinamolol, cloranolol, diacetolol, draquinolol, ecastolol, epanolol, ericolol, esatenolol, exaprolol, falintolol, flestolol, flusoxolol, idropranolol, indenolol, indopanolol, iprocrolol, different Luo Er, Landiolol, levomoprolol, mepindolol, metipranolol, moprolol, nadolol, nadoxolol, nafetolol, nebivolol, pacrinolol, pafenolol, pamotolol, pamotolol, pargolol, penbutolol, penirolol, pirepolol, practolol, primidolol, procinolol, ridazolol, ronactolol, soquinolol, spirendolol, stanozolol, talinolol, tazolol, teoprolol, tertatolol, tienoxolol, tilisolol, tiprenolol, tolamolol, toliprolol, trigevolol, xibenolol, xipranolol, hedroxalol, metrizoranolol, sotalolnadolol, arotinolol, sotalol, dexsotalol, labetalol, acetaminosalol, amosulalol, bendacalol, brefonalol, bufuralol, dilevalol, medroxalol, metalol, nifenalol, pronetalol, sulfinalol, carvedilol, dioxadilol, dramedilol, flavodilol, mindodilol, nipradilol, oberadilol, parodilol, Prizidilol, tribendilol, or its pharmaceutically acceptable salt; Certainly preferred especially: metoprolol, bisoprolol, Propranolol, dexpropranolol, levobetaxolol, betaxolol, esmolol, atenolol, oxprenolol, pindolol, celiprolol, arotinolol, sotalol, dexsotalol, labetalol, carvedilol or its pharmaceutically acceptable salt; Certainly preferred especially: metoprolol, bisoprolol, Propranolol, dexpropranolol, levobetaxolol, betaxolol, esmolol, atenolol, oxprenolol, pindolol, celiprolol, arotinolol, sotalol, dexsotalol, labetalol, carvedilol or its pharmaceutically acceptable salt.
Described alpha receptor blocking agent is selected from: terazosin, alfuzosin, doxazosin, prazosin, bunazosin, neldazosin, quinazosin, tiodazosin, trimazosin, minoxidil, urapidil, naftopidil, trapidil, nicorandil, Alprostadil, buflomedil, fasudil, mibefradil, suloctidil, aviptadil, belfosdil, bepridil, biclodil, bumepidil, carprazidil, cetiedil, cinepaxadil, dopropidil, ecipramidil, eliprodil, fenetradil, fenoxedil, floredil, flosatidil, fostedil, fronepidil, ifenprodil, ipramidil, levosemotiadil, manozodil, mefenidil, mepramidil, metrifudil, nanometer Buddhist nun ground that, nesapidil, perfomedil, phenobutiodil, pinacidil, piribedil, pirozadil, pitenodil, pretiadil, razinodil, semotiadil, sinitrodil, stevaladil, tipropidil, tixadil, Qu Suoluo ground, viquidil, phentolamine, phenoxybenzamine, or its pharmaceutically acceptable salt; Certainly preferred especially: terazosin, alfuzosin, doxazosin, prazosin, minoxidil, urapidil, naftopidil, trapidil, nicorandil, Alprostadil, buflomedil, fasudil or its pharmaceutically acceptable salt.
Described diuretic is selected from: hydrochlorothiazide, methyclothiazide, hydroflumethiazide, the trifluoro thiazine, cyclopenthiazide, althiazide, bemetizide, butizide, carmetizide, epitizide, hydrobentizide, mebutizide, paraflutizide, penflutizide, sumetizide, chlortalidone, teclothiazide, polythiazide, benzthiazide, cyclothiazide, epithiazide, ethiazide, furosemide, torasemide, galosemide, sulosemide, azosemide, eplerenone, spironolactone, bromchlorenone, canrenone, dicirenone, drospirenone, menatetrenone, mespirenone, spirorenone, teprenone, ubidecarenone, indapamide, alipamide, besulpamide, chlorpropamide, clopamide, cropropamide, tripamide, xipamide, Zidapamide, etacrynic acid, brocrinat, sulicrinat, triamterene, methazolamide, acetazolamide, ethoxzolamide, disulfamide, mefruside, the Mei Tuola parent, cicletanine, piretanide, cloth is played his Buddhist nun, bumetanide, or its pharmaceutically acceptable salt; Certainly preferred especially: hydrochlorothiazide, chlortalidone, indapamide, methyclothiazide, triamterene, spironolactone, furosemide, amiloride, torasemide, eplerenone, bumetanide or its pharmaceutically acceptable salt.
Described renin inhibitor, comprise peptide class and non-peptide class, preferably certainly: aliskiren, terlakiren, ditekiren, zankiren, enalkiren, (racemization)-(1R*, 5S*)-7-{4-[3-(2-chloro-3,6-two fluorophenoxies) propyl group] phenyl }-3-oxa--9-azabicyclo [3.3.1] ninth of the ten Heavenly Stems-6-alkene-6-carboxylic acid cyclopropyl-(3-methoxyl group-2-methyl-benzyl) amide, (racemization)-(1R*, 5S*)-and 7-{4-[3-(2-chloro-3,6-two fluorophenoxies) propyl group] phenyl }-3,3-dioxy base-3 λ 6-sulfo--9-azabicyclo [3.3.1] ninth of the ten Heavenly Stems-6-alkene-6-carboxylic acid cyclopropyl (2, the 3-dichloro benzyl) amide, (racemization)-(1R*, 3R*, 5S*)-and 7-{4-[3-(2-chloro-3,6-two fluorophenoxies) propyl group] phenyl }-3-oxygen base-3 λ 4-sulfo--9-azabicyclo [3.3.1] ninth of the ten Heavenly Stems-6-alkene-6-carboxylic acid cyclopropyl-(3-methoxyl group-2-methyl-benzyl) amide, (racemization)-(1R*, 3R*, 5S*)-and 7-{4-[3-(2-chloro-3,6-two fluorophenoxies) propyl group] phenyl }-3-oxygen base-3 λ 4-sulfo--9-azabicyclo [3.3.1] ninth of the ten Heavenly Stems-6-alkene-6-carboxylic acid cyclopropyl (2-methoxyl group-3-picoline-4-ylmethyl) amide, (racemization)-(1R*, 5S*)-7-{4-[3-(2-chloro-3,6-two fluorophenoxies) propyl group] phenyl }-3-oxa--9-azabicyclo [3.3.1] ninth of the ten Heavenly Stems-6-alkene-6-carboxylic acid cyclopropyl-[2-(3-hydroxyl propoxyl group)-3-picoline-4-ylmethyl] amide, (racemization)-(1R*, 5S*)-7-{4-[3-(2-chloro-3,6-two fluorophenoxies) propyl group] phenyl }-3,3-dioxy base-3 λ 6-thio-aza dicyclo [3.3.1] ninth of the ten Heavenly Stems-6-alkene-6-carboxylic acid cyclopropyl-[2-(3-hydroxyl propoxyl group)-3-picoline-4-ylmethyl] amide, RO66-1132, RO66-1168 or its pharmaceutically acceptable salt; More preferably be selected from: aliskiren, terlakiren, ditekiren, zankiren, enalkiren or its pharmaceutically acceptable salt; Certainly preferred especially: aliskiren or its pharmaceutically acceptable salt; Further certainly preferred: half fumaric acid aliskiren.Chinese patent CN200480011637.5, CN200580008590.1, CN200680022627.0, CN200680039056.1, CN02819046.7, CN200580026162.1, CN00811394.7 and CN200680009338.7 disclosed those, be incorporated herein by reference in its entirety.
Described neutral endopeptidase (NEP) inhibitor is selected from: candoxatril, candoxatrilat, ecadotril, phosphoramidone, (.+-.)-Thiorphan and enantiomer thereof, retro-Thiorphan, SCH34526, SCH42495, N-(3-carboxyl-1-oxopropyl)-(4S)-to the phenyl methyl)-4-amino-2R-methylbutanoic acid ethyl ester via, N-(3-carboxyl-1-oxopropyl)-(4S)-right-phenyl methyl-4-amino-2R-methylbutanoic acid, N-[N-[1 (S)-carboxyl-3-phenyl propyl]-(S)-the phenyl alanyl]-(S)-isoerine, N-[N-[((1S) ethyl carboxyl-2-phenyl)]-(S) phenyl alanyl]-beta Alanine, N-[2 (S)-mercapto methyl-3-(2-aminomethyl phenyl)-propiono] methionine, (suitable-4-[[[1-[2-carboxyl-3-(2-methoxy ethoxy) propyl group]-cyclopenta] carbonyl] amino]-naphthenic acid), SQ28603, SQ29072, or its pharmaceutically acceptable salt; More preferably be selected from: candoxatril, ecadotril, candoxatrilat or its pharmaceutically acceptable salt.Chinese patent CN03802268.0, CN200580020770.1, U.S. Pat 4610816, US4929641, US5127996, European patent EP 00342850 disclosed those, be incorporated herein by reference in its entirety.
Described Na +/ Ca 2+Exchange transport protein (NCX) inhibitor can be treated hypertension and myocardial infarction effectively, it comprises three kinds: the NCX1 inhibitor, NCX2 inhibitor and NCX3 inhibitor, isothiourea derivatives for example, the phenoxybenzamine derivant, phenoxypyridine derivative, or its pharmaceutically acceptable salt, preferably from the NCX1 inhibitor, or its pharmaceutically acceptable salt, more preferably be selected from the phenoxybenzamine derivant, phenoxypyridine derivative, or its pharmaceutically acceptable salt, further preferentially be selected from 2-[4-[(2, the 5-difluorophenyl) methoxyl group] phenoxy group]-the 5-phenetidine, the disclosed SEA0064 of Chinese patent CN03803728.9, or its pharmaceutically acceptable salt.Chinese patent CN03803728.9, international monopoly Wo98/43943, Wo99/20598, Japanese kokai publication hei 10-26546, spy open flat 10-218844, spy open flat 11-49752, spy open flat 11-92454 disclosed those, be incorporated herein by reference in its entirety.
Described ARB is selected from: telmisartan, losartan, irbesartan, Candesartan, valsartan, Olmesartan, Eprosartan, Ai Lishatan, Abitesartan, Elisartan, Embusartan, Forasartan, milfasartan, Pomisaratan, Pratosartan, Ripisartan, saprisartan, Tasosartan, zolasartan or its pharmaceutically acceptable salt; Certainly preferred especially: telmisartan, losartan, irbesartan, Candesartan, valsartan, Olmesartan, Eprosartan or its pharmaceutically acceptable salt; Certainly preferred especially: telmisartan, losartan, irbesartan, Candesartan, valsartan, Olmesartan, Eprosartan or its pharmaceutically acceptable salt.
Described antihypertensive is selected from: the endogenous endothelin producing system inhibitor, the chemical compound that serves a dual purpose that suppresses neutral endopeptidase and endogenous endothelin producing system, dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor, Endothelin (ET) receptor antagonist, the medicament that suppresses connective tissue production factor (CTGT), treble angiotensin converting enzyme/endothelin-converting enzyme inhibitor/neutral endopeptidase (ACE/ECE/NEP) inhibitor, vasopressin antagonists, urotensin I I receptor antagonist, the angiotensin vaccine, or its pharmaceutically acceptable salt.
Wherein said endogenous endothelin producing system inhibitor, comprise endothelin-converting enzyme (ECE) inhibitor, human soluble endopeptidase (hSEP) inhibitor and inhibition endothelin-converting enzyme (ECE) and both chemical compounds that serves a dual purpose of human soluble endopeptidase (hSEP), FR901533 (Zhu Chenggang for example, Dou Kefei. application and the progress of Endothelin in the coronary heart disease diagnosis and treatment. Chinese molecular cardiology magazine, in October, 2005,5 (5), 744-748), Phosphoramidon (Yan Xiaowei, Wolfgang/Kiowski.BQ123 and Phosphoramidon reach the vasoactive effect of use in conjunction to heart failure patient separately. preclinical medicine and clinical, 2001,21 (2), 154157), FR901533, PD-069185, CGS-26303, CGS-34043, CGS-35066, CGS-30084, SM-19712, Ro0677447, or its pharmaceutically acceptable salt; More preferably be selected from: Phosphoramidon or its pharmaceutically acceptable salt.Chinese patent CN200580020770.1 disclosed those, be incorporated herein by reference in its entirety.
The chemical compound that serves a dual purpose of wherein said inhibition neutral endopeptidase and endogenous endothelin producing system, comprise the chemical compound that serves a dual purpose that suppresses neutral endopeptidase and human soluble endopeptidase (hSEP), dual endothelin-converting enzyme inhibitor/neutral skin chain restriction endonuclease (ECE/NEP) inhibitor and inhibition neutral endopeptidase, the chemical compound that serves a dual purpose of endothelin-converting enzyme inhibitor ECE and human soluble endopeptidase (hSEP), Dagiutril (2-[1-(1-carboxymethyl-2-oxo-2 for example, 3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-3-base carbamoyl)-cyclopentyl-methyl]-4-phenylbutyric acid second vinegar), 2-[1-(1-carboxymethyl-2-oxo-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-3-base carbamoyl)-cyclopentyl-methyl]-4-naphthalene-1-base-butanoic acid second vinegar, 2-[1-(1-carboxymethyl-2-oxo-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-3-base carbamoyl)-cyclopentyl-methyl]-4-phenyl-butanoic acid, 2-[1-(1-carboxymethyl-2-oxo-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-3-base carbamoyl)-cyclopentyl-methyl]-4-naphthalene-1-base-butanoic acid, or its pharmaceutically acceptable salt; More preferably be selected from: Daglutril or its pharmaceutically acceptable salt.Chinese patent CN200580020770.1 disclosed those, be incorporated herein by reference in its entirety.
Wherein said dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor is selected from that omapatrilat, fasidotril, fasidotril draw, Z13752A, MDL-100240, sampatrilat, gemopatrilat (Leibo, Zhong Yuhui. the research and development present situation of vasopeptidase inhibitors system medicine. world's medicine information, in June, 2002, the 3rd the 3rd phase of volume, 1618) or its pharmaceutically acceptable salt; More preferably be selected from: omapatrilat, fasidotril, fasidotril draw or its pharmaceutically acceptable salt.Chinese patent CN00811394.7 disclosed those, be incorporated herein by reference in its entirety.
Wherein said Endothelin (ET) receptor antagonist is selected from: bosentan, ambrisentan, sitaxentan, enrasentan, atrasentan, reach Lu Shengtan, tezosentan, BMS193884 or its pharmaceutically acceptable salt; Further preferentially be selected from bosentan, ambrisentan, sitaxentan or its pharmaceutically acceptable salt.Chinese patent CN200480027660.3, CN200480011637.5, CN02819046.7, CN200580008590.1, CN200810169057.9 disclosed those, be incorporated herein by reference in its entirety.
The medicament of wherein said inhibition connective tissue production factor (CTGT) is selected from polypeptide, polynucleotide or micromolecule, comprises the polynucleotide of the activated protein kinase of serine/threonine mitogen, cyclin dependent kinase, glycogen synthase kinase, small interference ribonucleic acid, micro ribonucleic acid, ribozyme and antisense sequences and antisense constructs or its pharmaceutically acceptable salt that targeting is expressed in CTGF; More preferably be selected from and the bonded antibody of CTGT, antisense molecule, siRNA or micromolecular compound or its pharmaceutically acceptable salt; Further preferentially be selected from human monoclonal antibodies or its pharmaceutically acceptable salt at CTGT; Further preferentially be selected from CLN-1 or its pharmaceutically acceptable salt described among the international publication WO2004/108764.Chinese patent CN200680044730.5 disclosed those, be incorporated herein by reference in its entirety.
Wherein said treble angiotensin converting enzyme/endothelin-converting enzyme inhibitor/neutral endopeptidase (ACE/ECE/NEP) inhibitor be selected from CGS-26582, SA-6817, SCH-54470 (Leibo, Zhong Yuhui. the research and development present situation of vasopeptidase inhibitors system medicine. world's medicine information, in June, 2002, the 3rd the 3rd phase of volume, 16-18) or its pharmaceutically acceptable salt.
Described DPP IV (DPP/IV) inhibitor is selected from: (s)-1-{2-(5-cyanopyridine-2 base) amino } ethyl-glycyl-2-Cyanopyrolidine, (s)-1-((3-hydroxyl-1-adamantyl) amino) acetyl group 2-cyano group-pyrrolidine, aminoacid 2-pyrrolidine amide, borate proline, the isoleucine Thiazolidine, vildagliptin, sitagliptin, Sha Gelieting, Rui Gelieting, Bei Gelieting, denagliptin, sulphostin, beispiele, NVP-DDP-728, P93/01, P32/98, TS-021, T-6666, PT-100, or its pharmaceutically acceptable salt; More preferably be selected from: vildagliptin, sitagliptin, Sha Gelieting, Rui Gelieting, Bei Gelieting, denagliptin, sulphostin or its pharmaceutically acceptable salt; Has the blood sugar lowering effect.Wherein said DPP/IV inhibitor also has the effect of bringing high blood pressure down, and is selected from: the glutamine Thiazolidine that aminoacid Thiazolidine, side chain are modified; Further be selected from: L-threo form isoleucyl-pyrrolidine, the other isoleucyl-thiazolidine of L-, L-threo form isoleucyl-thiazolidine, the other isoleucyl-pyrrolidine of L-, L-glutaminate acyl Thiazolidine, L-glutaminate acyl pyrrolidine, L-glutamic acid Thiazolidine, L-glutamy pyrrolidine, alanyl pyrrolidine, N-valyl prolyl-O-benzoyl azanol or its pharmaceutically acceptable salt; More preferably be selected from: L-threo form isoleucyl-pyrrolidine, the other isoleucyl-thiazolidine of L-or its pharmaceutically acceptable salt; Described DPP IV inhibitor also comprises DPP/IV sample activity inhibitor, also have the effect of bringing high blood pressure down, be selected from: the acid dipeptidase of the α-connection of fibroblast activation protein alpha, DPP IV β, two peptidyl amino peptidase sample albumen, N-second phthaleinization, rest cell prolidase, two skin base peptidase II, suction lure element, DPP IV associated protein (DPP8), dipeptidyl peptidase 9 (DPP9), DPRP1, DPRP2, DPRP3, KIAA1492 or its pharmaceutically acceptable salt.Chinese patent CN200380105260.5, CN200580028653.X, CN02802674.8, CN01806315.2, CN200580034381.4, CN200680020499.6, CN200780027567.6, CN03805803.0 disclosed those, be incorporated herein by reference in its entirety.
Described antidiabetic drug is selected from: insulin sensitizer, insulin secretion stimulators, Alpha-glucosidase inhibitor, acetylcholinesteraseinhibitors inhibitors, alpha-amylase inhibitor, the FBPase inhibitor, Na dependent glucose transport vehicle (SGLT) 1 inhibitor optionally, suppress the active material of farnesol X receptor (FXR), the ap2 inhibitor, hydroxamic acid derivatives, glucagon receptor antagonist, insulin, insulin derivates or analog, 4-ketobutyric acid (Wo98/07681 describes as patent), calcium dobesilate, aldose reductase inhibitor, the AGE inhibitor, or its pharmaceutically acceptable salt.
Wherein said insulin sensitizer is selected from: peroxisome proliferation-activated receptors (PPAR) agonist, biguanides, phosphorylated tyrosine phosphatase (PTPase) inhibitor, stearoyl-CoA dehydrogenase-1 (SCD-1) inhibitor, diacylglycerol acyltransferase (DGAT) inhibitor, diabetes aluminiferous chemical compound or its pharmaceutically acceptable salt.
PPAR agonist described here is the ANOMALOUS VARIATIONS of blood sugar control effectively not only, can also reduce in the blood that glycerol is three cruel, free fatty and low density lipoprotein, LDL content, while high density lipoprotein increasing concentration, reach the effect of the ANOMALOUS VARIATIONS of blood sugar control, blood fat, it is selected from: PPAR gamma agonist, PPAR alfa agonists, PPAR α/γ dual agonists, PPAR delta agonists, optionally PPAR gamma modulators or its pharmaceutically acceptable salt.
PPAR gamma agonist described here is selected from: thiazolidinediones medicine (also claiming the glitazone medicine), non-glitazone PPAR gamma agonist or its pharmaceutically acceptable salt; Be preferably glitazone medicine or its pharmaceutically acceptable salt.Described glitazone medicine is selected from: pioglitazone, rosiglitazone, troglitazone, ciglitazone, englitazone, darglitazone, balaglitazone, Li Gelie ketone, Rui Gelie ketone, Yi Gelie ketone, netoglitazone, reglixane, isaglitazone, DRF2189, BM-13.1246, AY-31637, YM268, AD-5075, DN-108, T-174, KRP297, (2-(2 for 5-{[4-, 3-indoline-1-yl) phenyl ethyoxyl)] methyl } thiazolidine-2, the 4-diketone, 5-[3-(4-chlorphenyl)-2-propynyl]-the 5-benzenesulfonyl) thiazolidine-2, the 4-diketone, 5-[3-(4-chlorphenyl)-2-propynyl]-5-(4 fluorobenzene sulfonyl)-thiazolidine-2, the 4-diketone, or its pharmaceutically acceptable salt; More preferably be selected from: pioglitazone, rosiglitazone, troglitazone, ciglitazone, englitazone, darglitazone, darglitazone, balaglitazone, Li Gelie ketone, Rui Gelie ketone, Yi Gelie ketone, netoglitazone or its pharmaceutically acceptable salt; Especially preferably from pioglitazone hydrochloride, rosiglitazone, rosiglitazone maleate, Tartraric rosiglitazone, Luogelie ketone hydrochloride, methanesulfonic acid rosiglitazone, hydrobromic acid rosiglitazone, aminoacid rosiglitazone, phosphoric acid rosiglitazone, Rosiglitazone sodium, rosiglitazone potassium.Patent documentation CN200780002881.9, CN97181434.1, CN200680013844.3, CN200680027183.X, CN 200680026876.7, CN02824406.0, CN200480018359.6, CN01806315.2, CN200480008391.6, CN200480020764.1, CN200480032105.X, CN200580004882.8, CN200580034381.4, CN200710027579.0, CN200780027567.6, CN03805803.0, CN99813380.9, CN00818412.7, CN200780027567.6 disclosed those, be incorporated herein by reference in its entirety.Described non-glitazone PPAR gamma agonist is selected from N-(2-benzoyl phenyl)-L-tyrosine analog, for example, and GI-262570 and JTT501 or its pharmaceutically acceptable salt.
PPAR alfa agonists described here is selected from Bezalip Tablets analog derivative or its pharmaceutically acceptable salt; Described Bezalip Tablets analog derivative is selected from: fenofibrate, bezafibrate, etofibrate, clinofibrate, ciprofibrate, clofibrate, chlorine Bei Te, gemfibrozil, simfibrate, Ronifibrate, binifibrate or its pharmaceutically acceptable salt; Be preferably fenofibrate, bezafibrate, etofibrate, clinofibrate, ciprofibrate or its pharmaceutically acceptable salt especially.Chinese patent CN02804219.0, CN200810169057.9, CN200380105260.5, CN200610051370.3, CN99816149.7, CN200580028653.X, international monopoly Wo98/43081 disclosed those, the disclosed phenylpropionic acid chemical compound of Wo00/75103, U.S. Pat 6028109 disclosed fluorine phenyl compounds, be incorporated herein by reference in its entirety.
PPAR α/γ dual agonists described here is selected from: Mo Geta azoles, Luo Lige prick, according to lattice Liezong, Fa Gelietazha, tesaglitazar, metagliddasen, naveglitazar, GW1929, DRF2725, AZ242, KRP297, NC-2100 or its pharmaceutically acceptable salt; Be preferably especially Mo Geta azoles, Luo Lige prick, according to lattice Liezong, Fa Gelietazha or its pharmaceutically acceptable salt.Chinese patent CN02804219.0, CN200580028653.X, CN200810169057.9, CN02821152.9, CN200580034381.4, CN200780027567.6, CN03805803.0 disclosed those, be incorporated herein by reference in its entirety.
PPAR delta agonists described here is selected from thiazole, oxazole derivatives or its pharmaceutically acceptable salt.Chinese patent CN02804219.0 disclosed those, be incorporated herein by reference in its entirety.
Wherein said biguanides is selected from metformin, phenformin, metformin, buformin, phenformin or its pharmaceutically acceptable salt; Be preferably metformin hydrochloride.Patent documentation CN02821152.9, CN99815382.6, CN200580028653.X, CN200610078888.6, CN200580047981.4 disclosed those, be incorporated herein by reference in its entirety.
Wherein said PTPase inhibitor is selected from: vanadic acid sodium, Protein Tyrosine Phosphatases-1B (PTP-1B) inhibitor, vanadium complex BMOV, BEOV or its pharmaceutically acceptable salt.In addition, be used for PTPase inhibitor of the present invention and comprise but be not limited to CN200780027567.6, CN200680022627.0, the defined chemical compound of CN200580028653.X, be incorporated herein by reference in its entirety.
Wherein said stearoyl-CoA dehydrogenase-1 inhibitor is selected from: 1-amyl group-3-{6-[4-(2-trifluoromethyl benzoyl) piperazine-1-yl] pyridazine-3-yl } urea; 1-benzyl 3-{6-[4-(2-trifluoromethyl benzoyl) piperazine-1-yl] pyridazine-3-yl } urea; 1-(4-fluorophenyl)-3-{6-[4-(2-trifluoromethyl benzoyl) piperazine-1-yl] pyridazine-3-yl } urea; 1-(2-fluorophenyl)-3-{6-[4-(2-trifluoromethyl benzoyl) piperazine-1-yl] pyridazine-3-yl } urea; 1-[1-(4-fluorophenyl) ethyl]-3-{6-[4-(2-trifluoromethyl benzoyl) piperazine-1-yl] pyridazine-3 base } urea; 1-[3-(4-fluorophenyl) propyl group]-3-{6-[4-(2-trifluoromethyl benzoyl) piperazine-1-yl] pyridazine-3-yl } urea; 1-phenethyl-3-{6-[4-(2-trifluoromethyl benzoyl) piperazine-1-yl] pyridazine-3-yl } urea; or its pharmaceutically acceptable salt.Patent documentation CN200680022627.0 disclosed those, be incorporated by reference in its entirety.
Wherein said diacylglycerol acyltransferase inhibitors is selected from: diacylglycerol acyltransferase 1 (DGAT1) inhibitor, diacylglycerol acyltransferase 2 (DGAT2) inhibitor or its pharmaceutically acceptable salt.Be used for DGAT inhibitor of the present invention and comprise but be not limited to WO2005044250, WO2005013907, WO2004094618, WO2004047755, the defined chemical compound of CN200680022627.0, be incorporated herein by reference in its entirety.
Wherein said diabetes aluminiferous chemical compound is selected from vanudium complex or its pharmaceutically acceptable salt of the bidentate monobasic chelating agen that physiology can tolerate, and described intercalating agent is Alpha-hydroxy pyrone or Alpha-hydroxy pyridone.Patent documentation CN200910002801.0, CN03806655.6 disclosed those, be incorporated herein by reference in its entirety.
Wherein said insulin secretion stimulators is selected from: sulfonylureas, meglitinides medicine, glucokinase (GK) activator, glucagon or its pharmaceutically acceptable salt.
Wherein said sulfonylureas is selected from: tolbutamide, chlorpropamide, tolazamide, acetohexamide, glibenclamide, glipizide, gliclazide, glimepiride, gliquidone, glibornuride, glisoxepide, glibenclamide, Glisentide, glisolamide, glybuzole, glyclopyramide, 1-butyl-3-metanilic acid urea, carbutamide, glybuthiazole, glyhexamide, 2-benzenesulfonamido-5-(.beta.-methoxyethoxy)pyrimidine, Azepinamide, Phenbutamide, toluene hexamethylene urea, glipentide, or its pharmaceutically acceptable salt; Be preferably gliclazide, glibenclamide, glimepiride, glipizide, gliquidone or its pharmaceutically acceptable salt especially.Patent documentation CN97181434.1, CN99816149.7, CN200610051370.3, CN200380105260.5, CN200810169057.9, CN02804219.0, CN02804219.0, CN02821152.9, CN200580028653.X, CN97181434.1, CN200480023230.4 disclosed those, be incorporated herein by reference in its entirety.
Wherein said meglitinides medicine is selected from: Nateglinide, repaglinide, Mitiglinide, KAD1229, BTS67582 or its pharmaceutically acceptable salt; Mitiglinide or its pharmaceutically acceptable salt are preferably Mitiglinide Calcium.Patent documentation CN200580028653.X, CN200910002801.0, CN200610051370.3, CN200410088900, CN03808436.8, CN03805803.0, CN01821217.4, CN01821299.9, CN03821921.2, CN200480005672.6, CN200580014509.0 disclosed those, be incorporated herein by reference in its entirety.
Wherein said GK activator is selected from: amino 6-[(3-isobutoxy-5-isopropoxy benzoyl)] nicotinic acid (GKA1), 5-(3-isopropoxy-5-[2-(3-thienyl) ethyoxyl] and benzoyl } amino)-1; 3,4-thiadiazoles-2-formic acid (GKA2), 2-(s)-cyclohexyl-1-(R)-(4 mesyl phenyl) cyclopropane-carboxylic acid thiazol-2-yl amide, RO-28-1675 or its pharmaceutically acceptable salt.Patent documentation CN200680022627.0, CN200580028653.X disclosed those, be incorporated herein by reference in its entirety.
Wherein said glucagon is selected from: GLP-l (peptide-1), GLP-l analog or analogies, GLP-l receptor stimulating agent (for example exenatide, liraglutide, CJC-1131, LY-307161, GLP1, GLP-1) and those disclosed or its pharmaceutically acceptable salt in WO00/42026 and WO00/59887.Chinese patent CN200580028653.X, CN200910002801.0 disclosed those, be incorporated herein by reference in its entirety.
Wherein said Alpha-glucosidase inhibitor is selected from: acarbose, voglibose, miglitol, kind of alpha glycosidase inhibitor, emiglitate or its pharmaceutically acceptable salt; More preferably be selected from: acarbose, voglibose or its pharmaceutically acceptable salt.Chinese patent CN200780002881.9, Japan Patent the 1611546th communique, Japan Patent the 2502551st communique, Japan Patent the 1442470th communique, US4062950, US4701559, US4639436 disclosed those, be incorporated herein by reference in its entirety.
Wherein said acetylcholinesteraseinhibitors inhibitors is selected from: (5R, 9R, 11E)-5-amino-11-ethidine 5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring suffering is (b) pyridine-2 (1H) ketone (huperzine A) also, (±)-2-[(1-benzyl-4-piperidyl) methyl]-5,6-dimethoxy-1-Indanone, 3-[1-(benzyl)-4-piperidyl]-1-(2,3,4,5-tetrahydrochysene-1H-1-benzazepine-8-yl)-1-acetone, (s)-and N-ethyl-N-methyl-3-[(1-dimethylamino) ethyl] carbanilate, 1,2,3,3a, 8,8a-six hydrogen-1,3a, 8-trimethyl pyrrolo-[2,3-b] indole-5-phenol methyl carbamate, 9-amino-1,2,3, the 4-tetrahydro acridine, 11-methyl-3-methoxyl group-4a, 5,9,10,11,12-six hydrogen-6H-benzofuran [3a, 2-ef] [2] benzo-aza-6-alcohol, O, O-dimethyl-(2,2,2-three chloro-1-hydroxyethyls) phosphate ester, the tetra isopropyl pyrophosphoramide, Fasciculin-I, Fasciculin-II, or its pharmaceutically acceptable salt; Certainly preferred especially: huperzine A, (±)-2-[(1-benzyl-4-piperidyl) methyl]-5,6-dimethoxy-1-Indanone or its pharmaceutically acceptable salt.Chinese patent CN200510027127.3 disclosed those, be incorporated herein by reference in its entirety.
Wherein said alpha-amylase inhibitor is selected from: (2R, 3R, 4R)-4-hydroxyl-2-hydroxymethyl pyrrolidine-3-base-4-O-(6-deoxidation-α-D-glucopyranosyl)-α-D-pyranglucoside, (2R, 3R, 4R)-4-hydroxyl-2-hydroxymethyl pyrrolidine-3-base-4-O-(6-deoxidation-β-D-glucopyranosyl)-α-D-pyranglucoside or its pharmaceutically acceptable salt; Preferentially be selected from halogen acid salt; Most preferably from hydrochlorate.Chinese patent CN200780002881.9, Japanese kokai publication hei 2004-250446 communique disclosed those, be incorporated herein by reference in its entirety.
Wherein said FBPase inhibitor is the disclosed FBPase inhibitor of Chinese patent CN200580047981.4.Among the present invention, " FBPase inhibitor " is so long as suppress the active medicine of FBPase and get final product, be not particularly limited, for example have international disclose put down in writing in the WO01/47935 pamphlet have the phosphoramidate skeleton as the phosphoramidate chemical compound of prodrug moiety, international WO00/14095 pamphlet, the Journal/of/Medicinal/Chemistry of disclosing, 45 rolled up the 3865-3877 page or leaf 2002 years and Bioorganic/﹠amp; / Medicinal/Chemistry/Letters, the chemical compound of 11 volume 17-21 page or leaf calendar year 2001 records, be preferably the phosphoramidate chemical compound, be preferably 2-amino-5-isobutyl group-4-{2-[5-N especially, N '-two ((S)-1-ethoxy carbonyl) ethyl) phosphine acylamino] furyl } thiazole or its pharmaceutically acceptable salt.Chinese patent CN200580047981.4 disclosed those, be incorporated herein by reference in its entirety.
Wherein said optionally Na dependent glucose transport vehicle (SGLT) 1 inhibitor, basically be to the SGLT1 inhibitor of glucose transport carrier (GLUT) 2 and/or GLUT5 unrestraint effect, be preferably phlorhizin (being degraded into phloretin) or its pharmaceutically acceptable salt especially.Chinese patent CN200380109504.7 disclosed those, be incorporated herein by reference in its entirety.
The active material of wherein said inhibition farnesol X receptor (FXR) is selected from antagonist or its pharmaceutically acceptable salt of pharmaceutically useful anion exchange resin, farnesol X receptor.Wherein said pharmaceutically useful anion exchange resin is hereinafter described those; The antagonist of wherein said farnesol X receptor is selected from: ileum brush border sodium salt dependency bile acid transport body/ileal bile acid transfer body (ASBT/IBAT), Na+/taurocholic acid cotransport body polypeptide (NTCP), ileal bile acid conjugated protein (IBABP) or its pharmaceutically acceptable salt are preferably ASBT/IBAT, NTCP or its pharmaceutically acceptable salt especially.Chinese patent CN200580035300.2 disclosed those, be incorporated herein by reference in its entirety.
Wherein said ap2 inhibitor is selected from: oxazole or similar ring, pyrimidine derivatives or pyridazinone derivative or its pharmaceutically acceptable salt; Preferably certainly: the benzoyl of replacement or xenyl-2-oxazole-alkane acid derivative oxazole derivant, 2-sulfydryl-4,5-diphenyl-oxazole S-derivant, the phenyl heterocycles oxazole derivatives, diaryl oxazole derivatives, 4, the phenoxy alkane acid derivative that 5-diphenyl-oxazole derivant oxazole carboxylic acid derivates Ben Ji Evil Zuo oxazole derivatives or 2-(4, the 5-diaryl)-2-oxazolyl replaces, 2-Bian Yang oxazole derivatives, dihydro (alkane sulfydryl) (naphthyl methyl) Yang oxazole derivatives Liu Niao oxazole derivant, α replaces De oxazole alkylthio or alkyl ether derivative, pyridazinone acetic acids, the Benzoylbenzene or the xenyl alkane acid derivative that replace, or its pharmaceutically acceptable salt; More preferably be selected from benzoyl or xenyl-2-oxazole alkane acid derivative or its pharmaceutically acceptable salt of replacement; Be selected from preferred those or its pharmaceutically acceptable salt of the 15th of Chinese patent CN99811096.5 claims institute especially.Patent documentation CN99811096.5, CN00805831.8 disclosed those, be incorporated herein by reference in its entirety.
Wherein said hydroxamic acid derivatives is selected from O-(3-piperidino-2-hydroxyl-1-propyl group) nicotinoyl amidoxim or its pharmaceutically acceptable salt.Chinese patent CN200610051370.3 disclosed those, be incorporated herein by reference in its entirety.
Wherein said glucagon receptor antagonist is selected from and is particularly related to the chemical compound described in the Wo98/04528, BAY27-9955 particularly, and Bioorg/Med.Chem.Lett/1992,2, those chemical compounds described in the 915-918, CP-99 particularly, 711, J.Med.Chem.1998,41, those chemical compounds described in the 5150-5157, particularly NNC92-1687, J.Biol/Chom.1999,274; Those chemical compounds described in 86945697.Chinese patent CN200580028653.X, CN03805803.0 disclosed those, be incorporated herein by reference in its entirety.
Wherein said aldose reductase inhibitor is selected from: epalrestat, tolrestat, zenarestat, zopolrestat, fidarestat, Pa Nasita, sorbinil, alrestatin, minalrestat, ranirestat, CT-112 or its pharmaceutically acceptable salt.Chinese patent CN200780027567.6 disclosed those, be incorporated herein by reference in its entirety.
Wherein said AGE inhibitor is selected from: aminoguanidine (pimagedine), pyratoxanthine, N-phenacyl thiazole drone bromide, ALT946, EXO-226, ALT-711, pyridorin, pyridoxamine or its pharmaceutically acceptable salt.Chinese patent CN200780027567.6 disclosed those, be incorporated herein by reference in its entirety.
Described HMG-CoA reductase inhibitor is selected from: atorvastatin, Rosuvastatin, simvastatin, Pitavastatin, fluvastatin, pravastatin, lovastatin, bervastatin, crilvastatin, dalvastatin, lattice logical sequence cut down his spit of fland, mevastatin, for cutting down his spit of fland or its pharmaceutically acceptable salt; Certainly preferred especially: atorvastatin, Rosuvastatin, simvastatin, Pitavastatin, fluvastatin, pravastatin, lovastatin or its pharmaceutically acceptable salt.Patent documentation CN200810169057.9, CN200610051370.3, CN200480017955.2, CN03823984.1 disclosed those, be incorporated herein by reference in its entirety.
Described antihyperlipidemic is selected from: acyl coenzyme A: cholesterol acyltransferase (ACAT) inhibitor; bile acid chelating agent; the nicotinic acid analog derivative; cholesterol absorption inhibitor; the Squalene synthetic inhibitor; cyclooxygenase inhibitors of squalene; the microsomal triglyceride transport inhibitors; intramolecularly has the beta-lactam cholesterol absorption inhibitor of C-glucosides; the low density lipoprotein receptor activator; water-soluble fiber; the ileal bile acid transfer inhibitor; cholesterol alienation excretion promoter; omega-3 fatty acid; bile acids medicine; the bile acid cell reabsorption inhibitor; or its pharmaceutically acceptable salt.
Wherein said ACAT inhibitor is selected from: ACAT-1 selective depressant, ACAT-2 selective depressant and ACAT-1 and ACAT-2 double inhibitor; Further certainly preferred: avasimibe, Yi Lumaibu, lecimibide, 2,6-two (1-Methylethyl) phenylester, (N-(2 for CI-277082, the 4-difluorophenyl)-N-[[4-(2, the 2-dimethyl propyl) phenyl] methyl]-N-heptyl urea), N-(1-octyl group-5-carboxymethyl-4,6-dimethyl indoline-7-yl)-2,2-dimethyl propylene amide, N-(1-amyl group-4,6-dimethyl indoline-7-yl)-2,2-dimethyl propylene amide, HL-004, KY505, SMP797, FR-129169, F-1394, F-12511, T-2591, FCE-28654, K-10085, HL-004, NTE-122, FR-186054, or its pharmaceutically acceptable salt; Be preferably avasimibe, lecimibide or its pharmaceutically acceptable salt especially.Chinese patent CN200680039056.1, CN02804219.0, CN200580028653.X, CN02821364.5, CN200810169057.9 disclosed those, be incorporated herein by reference in its entirety.
Wherein said bile acid chelating agent is selected from insoluble anion exchange resin, pharmaceutically useful anion exchange resin or its pharmaceutically acceptable salt; Wherein pharmaceutically useful anion exchange resin preferably from: colestyramine, colestipol, examine come rice, polyallylamine polymers, polidexide, colesevelem or its pharmaceutically acceptable salt; Be preferably colestyramine, colestipol especially, examine rice to get or its pharmaceutically acceptable salt.Chinese patent CN200580035300.2, CN02804219.0, CN200810169057.9, CN200610051370.3, CN200680039056.1 disclosed those, be incorporated herein by reference in its entirety.
Wherein said nicotinic acid analog derivative is selected from that nicotinic acid (nicotinic acid), acipimox, niceritrol, Buddhist nun restrain the More, the Buddhist nun restrains chlorine ester, nicofuranose, nicotinyl alcohol or its pharmaceutically acceptable salt; Be preferably nicotinic acid, acipimox or its pharmaceutically acceptable salt especially.Chinese patent CN200610051370.3 disclosed those, be incorporated herein by reference in its entirety.
Wherein said cholesterol absorption inhibitor is selected from azetidin ketone (for example according to Ezetimibe), sterol glycoside (for example tiqueside), vegetable esters, cupreol, stigmasterol or its pharmaceutically acceptable salt; Be preferably especially according to Ezetimibe, tiqueside or its pharmaceutically acceptable salt.Chinese patent CN200810169057.9, CN200680039056.1, CN02804219.0 disclosed those, be incorporated herein by reference in its entirety.
Wherein said Squalene synthetic inhibitor is selected from squalestatin 1 or its pharmaceutically acceptable salt.Patent documentation CN02804219.0, CN200480017955.2, CN200810169057.9, CN200680039056.1, CN01806315.2 disclosed those, be incorporated herein by reference in its entirety.
Wherein said cyclooxygenase inhibitors of squalene is selected from (E)-N-ethyl-N-(6,6-dimethyl-2-heptyne-4-alkynyl)-3-[3,3 '-dithio benzene-5-ylmethoxy] benzene methanamine or its pharmaceutically acceptable salt.Chinese patent CN02804219.0, CN200480017955.2, CN200810169057.9 disclosed those, be incorporated herein by reference in its entirety.
Wherein said microsomal triglyceride transhipment (MTP) inhibitor is selected from implitapide (Bayer), LAB687, CP346086 or its pharmaceutically acceptable salt; Be preferably implitapide or its pharmaceutically acceptable salt especially.Chinese patent CN01806315.2, CN200680039056.1, CN200810169057.9 disclosed those, be incorporated herein by reference in its entirety.
The beta-lactam cholesterol absorption inhibitor that wherein said intramolecularly has the C-glucosides is selected from the described chemical compound 1～chemical compound 58 of Chinese patent CN200480017955.2 or its pharmaceutically acceptable salt; Be preferably chemical compound 37, chemical compound 56 or its pharmaceutically acceptable salt.Chinese patent CN200480017955.2 disclosed those, be incorporated herein by reference in its entirety.
Wherein said low density lipoprotein receptor activator is selected from: imidazolidinyl pyrimidine derivatives or its pharmaceutically acceptable salt, for example HOE-402 or its pharmaceutically acceptable salt.Chinese patent CN02804219.0 disclosed those, be incorporated herein by reference in its entirety.
Wherein said water-soluble fiber is selected from Psyllium, guar gum, Herba bromi japonici, pectin or its pharmaceutically acceptable salt.Chinese patent CN02804219.0 disclosed those, be incorporated herein by reference in its entirety.
Wherein said ileal bile acid transfer inhibitor is selected from benzimidazole thiophanate heterocycle heptantriene chemical compound or its pharmaceutically acceptable salt, for example Wo00/38727 disclosed 2,3,4,5-benzimidazole thiophanate heterocycle heptantriene 1,1-dioxide or its pharmaceutically acceptable salt.Chinese patent CN02804219.0, CN200580028653.X disclosed those, be incorporated herein by reference in its entirety.
Wherein said cholesterol alienation excretion promoter is selected from probacol or its pharmaceutically acceptable salt.Chinese patent CN200480043437.8 disclosed those, be incorporated herein by reference in its entirety.
Wherein said omega-3 fatty acid is selected from fish oil, 20 carbon penetenoic acids (EPA), 22 carbon hexenoic acid (DHA) or its pharmaceutically acceptable salts.Chinese patent CN02804219.0 disclosed those, be incorporated herein by reference in its entirety.
Wherein said bile acids medicine is selected from ursodeoxycholic acid, chenodeoxycholic acid, deoxycholic acid, cholic acid, cholate, bile extractum, Fel Ursi, Calculus Bovis or its pharmaceutically acceptable salt.Chinese patent CN03823984.1 disclosed those, be incorporated herein by reference in its entirety.
Wherein said bile acid cell reabsorption inhibitor is selected from BARI1453, SC435, PHA384640, S8921 or its pharmaceutically acceptable salt.Chinese patent CN200680039056.1 disclosed those, be incorporated herein by reference in its entirety.
Described 2-adrenergic agonist components (α and Beta-3 adrenergic agonist) is selected from adrafinil, Adrenalone, husky butylamine amine, amidefrine, apraclonidine, bitolterol, cloth is bent throat, carbuterol, clenbuterol, clonidine, atmosphere third that woods, cyclopentamine, denopamine, detomidine, dimetofrine, dipivefrine, dopexamine, ephedrine, epinephrine, etafedrine, ethylnorephinephrine, fenoterol, fenoxazoline, formoterol, guanabenz, guanfacine, methoxamedrine, 2-amino-4-methylhexane, methoxiphenadrin, the midodrine, modafinil, moxonidine, salmaterol, xamoterol, or its pharmaceutically acceptable salt.
Described anti-anginal drug is selected from amlodipine, betaxolol, bevantolol, butoprozine, carvedilol, cineqazat maleate ethyl cinepazate, metoprolol, molsidomine, monatepil, nitrate esters medicine (glyceryl trinitrate (GTN, nitroglycerin and Nitro-Bid), isosorbide mononitrate, sorbide nitrate, amyl nitrate, the Buddhist nun restrains the ground that), Soquad-5-Mononitrate, amyl nitrite, primidolol, the Reynolds lacquer, verapamil, or its pharmaceutically acceptable salt.
Described anti-arrhythmic is selected from acebutolol, acecainide, the arabinose gland is general, ajmaline, alprenolol, amiodarone, gram hat beautiful jade, aprindine, atenolol, azimilide, fourth benzyl eyeball is felt at ease, betadrenol, butidrine, butobendine, capobenic acid, carazolol, carteolol, cibenzoline, disopyramide, dofetilide, encainide, esmolol, flecainide, ibutilide, indecainide, indenolol, lignocaine, lorajmine, lorcainide, meobentine, mexiletine, moracizine, nifenazone, oxprenolol, penbutolol, pentisomide, pilsicainide, practolol, procainamide, Propafenone, Propranolol, pyrinoline, quinidine, sematilide, sotalol, talinolol, tilisolol, tocainide, verapamil, viquidil, xibenolol, or its pharmaceutically acceptable salt.
Described antiplatelet drug is selected from clopidogrel, ozagrel, anagrelide, dipyridamole, abciximab, Ticlopidine or its pharmaceutically acceptable salt.
Described anticoagulant is selected from anagrelide, aminocaproic acid, sulfinpyrazone, warfarin, Fragmin, heparin, Enoxaparin, anisindione, persantin, Bo Liwei, Pei Da, ticlid see ticlopidine, Trental, warfarin, anagrelide, bivalirudin, reaches heparin, danaparoid, dazoxiben, efegatran, ifetroban, booth are pricked heparin, trifenagrel, Low molecular heparin or its pharmaceutically acceptable salt.
Described anti-inflammatory agent is selected from alclofenac, alclometasone, algestone acetonide, amcinafal, amcinafide, amfenac sodium, Amiprilose, Antril (Synergen), anirolac, anitrazafen, azapropazone, balsalazide disodium, bendazac, benzene Lip river sweet smell, benzydamine, bromelain, broperamole, budesonide, carprofen, cicloprofen, cinnopentazone, cliprofen, chlorine times Mi Song, clobetasone butyrate, cloticasone, Cormetasone, cortodoxone, deflazacort, desonide, desoximetasone, dexamethasone, diclofenac potassium, diflorasone, diflumidone sodium, diflunisal, difluoro ripple Buddhist nun ester, diftalone, drocinonide, endrysone, enlimomab, enolicam sodium, epirizole, fluticasone, or its pharmaceutically acceptable salt.
Described synthesizing epoxy synthase-2 (COX-2) inhibitor be selected from rofecoxib, celecoxib, valdecoxib, parecoxib, nabumetone and, etodolac, etoricoxib, silymarin or its pharmaceutically acceptable salt.Patent documentation CN200380106231.0 disclosed those, be incorporated herein by reference in its entirety.
Described direct thrombin inhibitor is selected from hirudin, hirugen, Hylarana guentheri peptide, Argatroban, PPACK, thrombin is fit or its pharmaceutically acceptable salt.
The inhibitor of described cholesterol ester transfer protein (CETP) is selected from Torcetrapib (torcetrapib) or its pharmaceutically acceptable salt.Patent documentation CN03815575.3, CN03815558.3, CN02804219.0, CN99816149.7, CN200580028653.X, CN200810169057.9, CN200680039056.1, CN200810169057.9 disclosed those, be incorporated herein by reference in its entirety.
Described inotropic agent is selected from theophylline, acetyldigitoxin, 2-amino-4-picoline, amrinone, benfurodil, bucladesine, Camphotamide, convallatoxin, alvonal, denopamine, deslanoside, lanatoside, Folium Digitalis Purpureae, Digitoxin, digoxin, dobutamine, docarpamine, dopamine, dopexamine, enoximone, erythrophleine, fenalcomine, gitalin, loprinone, milrinone, vesnarinone, oxyfedrine, pimobendan, prenalterol, Proscillaridin, theobromine, xamoterol, or its pharmaceutically acceptable salt.
Described vasodilation is selected from bencyclan, cinnarizine, citicoline, cyclandelate, ciclonicate, DIEDI, vinpocetine, fasudil, fenoxedil, flunarizine, ibudilast, ifenprodil, sorbide nitrate, isosorbide 5-mono-nitrate, lomerizine, cigarette amine second vinegar, nicergoline, nimodipine, tinofedrine, viquidil, floredil, trapidil, cinepazide, trimetazidine, cetiedil, kallidin, visnadine, iloprost, or its pharmaceutically acceptable salt.
Described vasopressor is selected from methylsulfuric acid amezinium, angiotensinamide, dimetofrine, dopamine, etifelmine, etilefrine, gepefrine, metaradrine, methoxamedrine, midodrine, norepinephrine, pholedrine, synephrine or its pharmaceutically acceptable salt.
The crosslinked blocker of described AGE is selected from Alagebrium or its pharmaceutically acceptable salt.
Described sinuatrial node If electric current blocker is selected from selectivity and specificity sinuatrial node If electric current blocker, is preferably Ivabradine or its pharmaceutically acceptable salt; The more preferably hydrochlorate of Ivabradine, hydrogen Australia hydrochlorate, sulfate, phosphate, acetate, trifluoroacetate, lactate, pyruvate, malonate, succinate, glutarate, fumarate, tartrate, maleate, citrate, Ascorbate, oxalates, mesylate, benzene sulfonate or camphorate; Be preferably hydrochloric acid Ivabradine especially.CN200910150417.5, CN200810111115.2, CN200910013935.2, CN200510051779.0, CN200510054209.7, CN200510054216.7, CN200510051768.2, CN200610058074.6, CN200610058076.5, CN200610058077.X, CN200610058078.4, CN200610132229.6, CN200610132230.9, CN200610064317.7, CN200610064318.1, CN200710039418.3, CN200710044290.X, CN200810009566.5 disclosed those, be incorporated herein by reference in its entirety.
Described prostacyclin is selected from: iloprost, Beraprost, cicletanine or its pharmaceutically acceptable salt; Patent documentation CN200480027660.3 disclosed those, be incorporated herein by reference in its entirety.
Described phosphodiesterase (PDE) inhibitor is selected from: sldenafil, Vardenafil, tadalafil, Bei Minafei, Da Shengtafei, enoximone, milrinone, amrinone, 5-(3-chloro-benzyl)-3-isopropyl-1,6-dihydro-pyrazolo (4,3-d) pyrimidin-7-ones, 5-(3-ethoxy benzyl)-3-isopropyl-1,6-dihydro-pyrazolo (4,3-d) pyrimidin-7-ones, 5-cyclohexyl methyl-3-isopropyl-1,6-dihydro-pyrazolo (4,3-d) pyrimidin-7-ones, 3-isopropyl-5-(3-phenoxy benzyl)-1,6-dihydro-pyrazolo (4,3-d) pyrimidin-7-ones, 3-isopropyl-5-(2-trifluoromethyl benzyl)-1,6-dihydro-pyrazolo (4,3-d) pyrimidin-7-ones, 5-(4-chloro-benzyl)-3-isopropyl-1,6-dihydro-pyrazolo (4,3-d) pyrimidin-7-ones, 5-(4-benzyloxy-benzyl)-3-isopropyl-1,6-dihydro-pyrazolo (4,3-d) pyrimidin-7-ones, 5-[2-(2-chloro-benzyl)-ethyl]-3-isopropyl-1,6-dihydro-pyrazolo (4,3-d) pyrimidin-7-ones, or its pharmaceutically acceptable salt, be preferably 5-(3-chloro-benzyl)-3-isopropyl-1 especially, 6-dihydro-pyrazolo (4,3-d) pyrimidin-7-ones, or its pharmaceutically acceptable salt; Preferred especially sldenafil, Vardenafil, tadalafil or its pharmaceutically acceptable salt.Patent documentation CN03814574.X, CN02819046.7, CN200380105260.5, CN200480027660.3, CN200680044730.5, CN02821152.9 disclosed those, be incorporated herein by reference in its entirety.
(6), another aspect of the present invention has also related to prevention, delay of progression or treatment are selected from the following disease or the method for disease: hypertension, hypertensive patients disease, diabetes, diabetic complication, dyslipidemia, ischemic diseases, coronary heart disease, angina pectoris, congestive heart failure, arrhythmia, apoplexy, atherosclerosis, cerebral infarction, cerebrovascular disease, cardiovascular disease, coronary artery disease, ventricular dysfunction, pulmonary vascular disease, renal vascular, nephropathy, the visceral vessel disease, the vascular flow occlusive disease, inflammatory diseases, autoimmune disease, the immunologic function disease, pulmonary disease, the antioxidant disease, sexual dysfunction, cognitive dysfunction, endothelial function disturbance, cardiac insufficiency, glaucoma, vascular dementia, edema, thrombosis, hypothyroidism, peripheral vascular disease, diseases of eye, ear, nose and throat section disease, aneurysm, renin secreting tumor, cataract, post-stroke depression, depression after cerebral infarction, the hypertensive cerebral hemorrhage aftertreatment, vertebral-basilar artery insufficiency, polycystic ovary syndrome, vascular compliance is impaired, schistosomicide or cancer, it comprises to its patient of needs uses pharmaceutical composition as (1).
In order to estimate antihypertensive active, for example can adopt Lovenberg/W: " animal model of hypertension research ", Prog.Clin.Biol.Res.1987,229, the described method of 225-240 according to combination of the present invention.Can be used for treating congestive heart failure for estimating combination of the present invention, for example can adopt Smith/HJ, NuttallA: " heart failure experimental model ", Cardiovasc/Res/1985,19, the disclosed method of 181-186.And (Cardiovasc/Res/1998,39:89-105) rat model of described hypertension and heart failure also can be used for the pharmacological evaluation of the present invention's combination for Doggrell/SA and Brown/L.Molecule means such as transgenic method also have description, for example people such as Luft: the inductive terminal organ's damage of hypertension; A kind of new transgenic means of old topic new explanation, Hypertension/1999,33,212-218.Can also according to respectively for example Chinese patent CN98808463.5 or CN98808465.1 disclosed method measured.
According to enhanced propertied can the mensuration of insulin secretion of the present invention combination according to the disclosed method of publication, people such as Tlkenoue for example, Biol.Pharm.Bull, 29 (4), 354-359 (1997).
Estimate when giving or making up the cardiovascular effect of the activating agent that gives and glucose utilization effect separately and can adopt people such as model such as Nawano, the zucker obese rat model described in the Metabolism/48:1248-1255,1999 publications carries out.And people such as Sato, Metabolism/45:457-462 has also described the research of using the diabetic spontaneous hypertensive rat in 1996 publications.In addition, rat model such as Cohen-Rosenthal diabetic hypertension rat (people such as Rosenthal, Hypertension/1997; 29:1260-1264) also be used for estimating simultaneously the effect of this combination to blood pressure and glucose metabolism.
Be to estimate the anti-high blood ester activity of the present invention's combination, can according to respectively for example US4739073, US5354772, Chinese patent CN98808463.5 or CN98808465.1 disclosed method measured.
Can be used for treating atherosclerosis and angina pectoris for estimating combination of the present invention or compositions, can be respectively measured according to for example Chinese patent CN98808463.5 or CN98808465.1 disclosed method.
The corresponding theme of these all documents is introduced this description as a reference.
The present invention can use the known corresponding pharmacological model of association area, proves combination of using active substance used in the present invention or the pharmaceutically active that compositions realized.Various equivalent modifications can be selected the animal test model of being correlated with fully, to confirm above and hereinafter pointed treatment disease or disease and beneficial effect.
(7), another aspect of the present invention also related to the purposes as each pharmaceutical composition in (1) to (5), it is characterized in that the medicine that is used to prepare prevention, delay of progression or treats following disease or disease:
Hypertension, hypertensive patients disease, diabetes, diabetic complication, dyslipidemia, ischemic diseases, coronary heart disease, angina pectoris, congestive heart failure, arrhythmia, apoplexy, arteriosclerosis, cerebral infarction, cerebrovascular disease, cardiovascular disease, coronary artery disease, ventricular dysfunction, pulmonary vascular disease, renal vascular, nephropathy, the visceral vessel disease, the vascular flow occlusive disease, inflammatory diseases, autoimmune disease, the immunologic function disease, pulmonary disease, the antioxidant disease, sexual dysfunction, cognitive dysfunction, endothelial function disturbance, cardiac insufficiency, glaucoma, vascular dementia, edema, thrombosis, hypothyroidism, peripheral vascular disease, diseases of eye, ear, nose and throat section disease, aneurysm, renin secreting tumor, cataract, post-stroke depression, depression after cerebral infarction, the hypertensive cerebral hemorrhage aftertreatment, vertebral-basilar artery insufficiency, polycystic ovary syndrome, vascular compliance is impaired, schistosomicide or cancer.
(8), another aspect of the present invention has also related to as (1) to (5) described pharmaceutical composition, as (6) described method, as (7) described purposes, it is characterized in that, the pharmaceutically acceptable salt of described Ai Lishatan ester is the potassium salt of Ai Lishatan ester, and wherein:
Described calcium channel blocker is selected from Levamlodipine, amlodipine, lacidipine, lercanidipine, nicardipine, cilnidipine, nitrendipine, nimodipine, felodipine, nifedipine, nisoldipine, benidipine, diltiazem, verapamil;
Described angiotensin converting enzyme inhibitor is selected from perindopril, ramipril, fosinopril, lisinopril, quinapril, enalapril, imidapril, trandolapril, delapril, benazepril, zofenopril, enalaprilat;
Described B-adrenergic receptor blocker is selected from metoprolol, bisoprolol, Propranolol, dexpropranolol, levobetaxolol, betaxolol, esmolol, atenolol, oxprenolol, pindolol, celiprolol, arotinolol, sotalol, dexsotalol, labetalol, carvedilol;
Described alpha-adrenergic receptor blocker is selected from terazosin, alfuzosin, doxazosin, prazosin, minoxidil, urapidil, naftopidil, trapidil, nicorandil, Alprostadil, buflomedil, fasudil;
Described diuretic is selected from hydrochlorothiazide, chlortalidone, indapamide, methyclothiazide, triamterene, spironolactone, furosemide, amiloride, torasemide, eplerenone, bumetanide;
Described renin inhibitor is selected from aliskiren, terlakiren, ditekiren, zankiren, enalkiren;
Described neutral endopeptidase inhibitor is selected from candoxatril, candoxatrilat, ecadotril;
Described Na +/ Ca 2+The exchange transporter inhibitors is selected from 2-[4-[(2, the 5-difluorophenyl) methoxyl group] phenoxy group]-5-phenetidine, the disclosed SEA0064 of Chinese patent CN03803728.9;
The CLN-1 that described antihypertensive is selected from that Daglutril, Phosphoramidon, omapatrilat, fasidotril, fasidotril draw, describe among sampatrilat, gemopatrilat, bosentan, ambrisentan, sitaxentan, atrasentan, the international monopoly Wo2004/108764;
Described dipeptidyl peptidase/IV inhibitor is selected from: vildagliptin, sitagliptin, Sha Gelieting, Rui Gelieting, Bei Gelieting, denagliptin, sulphostin;
Described antidiabetic drug is selected from Nateglinide, repaglinide, Mitiglinide, acarbose, voglibose, miglitol, vildagliptin, sitagliptin, Sha Gelieting, Rui Gelieting (Retagliptin), Bei Gelieting, denagliptin, sulphostin, ciglitazone, englitazone, darglitazone, darglitazone, balaglitazone, Li Gelie ketone, netoglitazone, gliclazide, glibenclamide, glimepiride, glipizide, gliquidone, metformin, the Mo Geta azoles, Luo Lige pricks, according to the lattice Liezong, Fa Gelietazha, fenofibrate, bezafibrate, etofibrate, clinofibrate, ciprofibrate, gemfibrozil, clofibrate;
Described HMG-CoA reductase inhibitor is selected from atorvastatin, Rosuvastatin, simvastatin, Pitavastatin, fluvastatin, pravastatin, lovastatin;
Described antihyperlipidemic is selected from according to Ezetimibe, colestyramine, colestipol, examine come rice, avasimibe, Yi Lumaibu, lecimibide;
Described PDE inhibitor is selected from sldenafil, Vardenafil, tadalafil;
The acceptable salt of its pharmacy of perhaps respectively doing for oneself.
(9), the invention still further relates to a kind of pharmaceutical composition, it is characterized in that, it comprises pharmaceutically acceptable salt and a certain amount of at least a following active matter that is selected from of a certain amount of Ai Lishatan ester: calcium channel blocker, angiotensin converting enzyme inhibitor, B-adrenergic receptor blocker, alpha-adrenergic receptor blocker, diuretic or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier.
Described calcium channel blocker, angiotensin converting enzyme inhibitor, B-adrenergic receptor blocker, alpha-adrenergic receptor blocker, diuretic or its pharmaceutically acceptable salt are selected from the corresponding example described in the context respectively.
(10), in another preference, as (9) described pharmaceutical composition, it is characterized in that it comprises pharmaceutically acceptable salt and a certain amount of calcium channel blocker or its pharmaceutically acceptable salt of a certain amount of Ai Lishatan ester, and pharmaceutically acceptable carrier.
The invention still further relates to be used to prevent, delay of progression or treatment be according to the medicine box of disease of the present invention or disease, it is characterized in that it comprises:
(a) the acceptable salt of pharmacy and the pharmaceutically acceptable carrier of a certain amount of Ai Lishatan ester of first unit dosage forms;
(b) a certain amount of at least a cardiovascular and cerebrovascular medicine of second unit dosage forms or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier; And
(c) be used to hold the container of first, second unit dosage forms.
In a kind of alternatives of the present invention, the present invention relates to equally a kind of " component medicine box ", and for example meaning promptly can be separately according to component that the present invention made up or by using the different fixing combination medicine-feeding of specified quantitative component, i.e. while or in the different time points administration.Thus, the each several part in the component medicine box can for example interlock simultaneously or in chronological order and use, and promptly the each several part in the component medicine box is used in different time points and with identical or different interval.Preferably, the selection of interval should make be used in combination each component to the effect of treatment disease or disease greater than the effect of only using arbitrary component and being obtained.
Therefore, the invention further relates to a kind of component medicine box, it comprises:
(a) the acceptable salt of pharmacy and the pharmaceutically acceptable carrier of a certain amount of Ai Lishatan ester of first unit dosage forms;
(b) two or three or the individual form of more kinds of components, a certain amount of at least a cardiovascular and cerebrovascular medicine or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier; And
(c) be used to hold the container of constituent parts dosage form.
Typical medicine box also contains the description that is used for while, difference or uses in succession to the administration of different activities thing.
More surprisingly, test is found: combined administration comprises the acceptable salt of pharmacy and a certain amount of at least a cardiovascular and cerebrovascular medicine or its pharmaceutically acceptable salt and the pharmaceutically acceptable carrier of a certain amount of Ai Lishatan ester, not only can produce useful, collaborative therapeutic effect particularly, but also can produce bring by combined administration with only use combination shown here in single medication of employed pharmaceutically active substances other benefits and other the wonderful beneficial effects compared.
The active substance that the present invention will unite can exist with pharmaceutically acceptable salt or ester.If these chemical compounds have for example at least one basic center, then they can form acid-addition salts.If necessary, can form the acid-addition salts of the correspondence of basic center with extra existence.Chemical compound with acidic-group (for example COOH) can also form salt with alkali.
In context, the structure of the active substance of being distinguished by adopted name or trade name can derive from the standard outline " The/Merck/Index " of current edition, or derive from data base, for example international monopoly data base (for example IMS/world/Publications).Its corresponding contents is hereby incorporated by.Any those skilled in the art can differentiate active substance fully, and can make it equally based on these lists of references, and in the external of standard and in vivo test model testing drug indication and character.
Route of administration:
That suitable route of administration can comprise is for example oral, rectum, part, nose, lung, eye, enteral and parenteral; Main parenteral approach comprises intravenous, intramuscular and subcutaneous administration; Accessory route of administration comprises in intraperitoneal, intra-arterial, intraarticular, intracardiac, the brain pond, in the Intradermal, intralesional, ophthalmic, pleura, in the sheath, administration in intrauterine and the ventricle.The administration of route of administration preferred oral, intravenous, intramuscular and subcutaneous administration, the more preferably oral administration of pharmaceutical composition of the present invention.
Preparation type that uses and route of administration and be preferred topical or preferred whole body administration are decided according to physics, the chemistry and biology characteristic of the indication that will treat and medicine.
Pharmaceutical preparation:
The preparation of pharmaceutical composition of the present invention is pharmaceutically acceptable various dosage form, can be selected from: non-slow control release type, slow control release type or injection.Non-slow control release type is selected from: tablet, capsule, dispersible tablet, oral cavity disintegration tablet, chewable tablet, drop pill, granule, suspensoid, oral solution, buccal tablet, tincture, suppository, ointment, pill, aerosol, spray, membrane, Emulsion, powder, liniment, gel, the agent of transdermal card; Slow control release type is selected from: slow releasing tablet, slow releasing capsule, controlled release controlled release tablet and controlled release capsule; Injection is selected from: small-volume injection, aseptic freeze-dried powder pin, sterilized powder packing and bulk capacity injection.
Pharmaceutical composition of the present invention can and be that those are suitable for being applied to the patient's who comprises the people pharmaceutical composition through intestinal such as oral or rectum and through parenteral with known method preparation itself, its comprise treatment effective dose with at least two kinds of pharmacological active substances one or more pharmaceutically acceptable carrier combinations; Especially be suitable for through intestinal or parenteral application and at least two kinds of pharmacological active substances one or more pharmaceutically acceptable carrier combinations, for example, pharmaceutical preparation is for example about 0.1% to 100% by containing, and preferred about 1% to about 90%, and more preferably from about 10% to about 60% active substance is formed.
These pharmaceutical preparatioies are used for being applied to the patient through intestinal such as oral and rectum or through parenteral, and described preparation comprises the pharmacological active substance with pharmaceutically acceptable carrier.Be used for through intestinal or be unit dosage form for example, as coated tablet, tablet, capsule or granule and injection through the pharmaceutical preparation that parenteral is used.These preparations for example use conventional mixing, granulation, coating, dissolving or freeze drying process preparation with known method preparation itself.Therefore, the pharmaceutical preparation that is used to orally use can obtain by the following method: active matter mixed with solid excipient, if desired, with acquired granulating mixture, and if desired or necessary, mixture or granule are processed into tablet or coated cores after adding suitable adjuvant.
Drug dose:
Using of the present composition will be carried out with the amount that is enough to reach the treatment effect that those of ordinary skills generally acknowledge.The active substance effective dose separately that is used for compositions depends on multiple factor, the mode of for example using, species homoiothermous, age and/or individual situation, can according to used particular compound, method of application, the disease of being treated with the different of sanatory seriousness change.Therefore, use the dosage of the present composition to select, comprise experimenter's type, kind, age, general health situation, body weight, meals, sex and medical condition according to various factors; Sanatory seriousness; Patient's kidney and liver function; Drug regimen; With used particular compound and route of administration thereof.Any subject formulations can single dose or fractionated dose use.Generally speaking, the dosage of activating agent will be selected based on known other factors in age, health, body weight and the medical field by the doctor.
Active matter of the present invention in the context, patient for the about 60kg of body weight, the approximate daily dose that estimation is used is from the scope of 1ng to 100g/kg body weight, and preferred dose is the scope from 0.1 μ g to 10g/kg body weight, and more preferably dosage is the scope from 0.1mg to 50mg/kg body weight.
For example, to the homoiothermic animal of about 60kg body weight, comprise the daily dose of potassium salt, sodium salt or the calcium salt of the Ai Lishatan ester that the people uses, for example dosage is 1mg to 4g/ people/sky, be preferably 5mg to 800mg/ people/sky, 5mg-300mg/ people/sky more preferably, for example can be divided into every day and can be 1-4 time onesize single dose administration, be preferably 1～2 administration every day, more preferably 1 administration every day.Usually the child accepts to be about half of adult's dosage.For example, can monitor each individual necessary dosage and be adjusted to optimum level by the serum-concentration of measuring active component.Single dose comprises for example 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 80mg, 100mg, 150mg, 200mg, 300mg/ people/sky.
In given patient, will produce the accurate time of application of any particular topic compositions of the most effective treatment and amount and will depend on activity, pharmacokinetics and the bioavailability of theme composition, physiology's state of patient (comprise age, sex, disease type and stage, general physical condition, to the reactivity and the drug type of given dose), route of administration etc.Can be used for optimizing treatment in this explanation that provides, for example determine Best Times and/or the amount used, it need and regulate dosage and/or normal experiment that the time is formed by the monitoring experimenter.
Preferably, the active substance according to combination of the present invention of therapeutic alliance effective dose can distinguish or with fixed combination simultaneously or with any order sequential application.
Usually, according to the present invention, following activating agent carries out administration with following dosage:
Levamlodipine, about usually 0.5mg is to about 20mg;
Amlodipine, about usually 1mg is to about 40mg; Lacidipine, about usually 1mg is to about 50mg;
Cilnidipine, about usually 0.5mg is to about 40mg; Lercanidipine, about usually 2.5mg is to about 40mg;
Perindopril, about usually 0.5mg is to about 32mg; Ramipril, about usually 0.5mg is to about 40mg;
Fosinopril, about usually 2.5mg is to about 80mg; Lisinopril, about usually 1mg is to about 80mg;
Metoprolol http://bbs.idrug.cn/showtopic-346-1.aspx, about usually 2mg is to about 200mg; Bisoprolol, about usually 2.5mg is to about 40mg;
Arotinolol, about usually 1mg is to about 40mg; Carvedilol http://bbs.idrug.cn/showtopic-347-1.aspx, about usually 2mg is to about 100mg;
Terazosin, about usually 1mg is to about 20mg; Doxazosin, about usually 1mg is to about 16mg;
Aliskiren, about usually 37.5mg is to about 300mg; Hydrochlorothiazide, about usually 1mg is to about 200mg;
Sitagliptin, about usually 5mg is to about 200mg;
Sldenafil, about usually 10mg is to about 200mg; Vardenafil, about usually 1mg is to about 40mg;
Pioglitazone, about usually 3.75mg is to about 120mg; Rosiglitazone, about usually 0.25mg is to about 32mg;
Troglitazone, about usually 50mg is to about 400mg; Gliclazide, about usually 20mg is to about 160mg;
Glibenclamide, about usually 0.625mg is to about 10mg; Glimepiride, about usually 0.5mg is to about 16mg;
Glipizide, about usually 1.25mg is to about 20mg; Gliquidone, about usually 7.5mg is to about 120mg;
Glyclopyramide, about usually 0.5mg is to about 16mg; Repaglinide, about usually 0.25mg is to about 8mg;
Nateglinide, about usually 15mg is to about 240mg; Mitiglinide, about usually 1.25mg is to about 40mg;
Voglibose, about usually 0.1mg is to about 1.2mg; Acarbose, about usually 6.25mg is to about 200mg;
Atorvastatin calcium, about usually 10mg is to about 160mg; Simvastatin, about usually 10mg is to about 160mg;
Pitavastatin Calcium, about usually 0.1mg is to about 16mg; Auspicious his the spit of fland calcium that cuts down, about usually 10mg is to about 160mg;
Pravastatin sodium, about usually 10mg is to about 160mg; According to Ezetimibe, about usually 2.5mg is to about 40mg;
Particularly preferably be the low dosage combination.
The specific embodiment
Describe the present invention in detail below in conjunction with embodiment, these embodiment are presented for purposes of illustration, do not limit the scope of the invention.
Embodiment 1: the agent of Ai Lishatan ester potassium salt levo-amlodipine
Figure G201010301112220100202D000281
Preparation method:
(I) the particulate granulation of Ai Lishatan ester potassium salt
1, various solid supplementary materials are crossed sieve respectively 5～No. 6, standby;
2, with half pre-paying of recipe quantity starch dissolution in 45 ℃～60 ℃ purified water and add hydroxypropyl emthylcellulose, make solution be cooled to room temperature;
3, in granulator, mix Ai Lishatan ester potassium salt, remaining pre-paying starch;
4, will mix from the mixture of powders of step 3 with from the solution of step 2 in granulator, the limit edged stirs, and makes suitable soft material, becomes wet granular with No. 2 sieve series;
5, dried particles in drying equipment, dry back makes moisture (loss on drying) be less than or equal to 2.0% with No. 2 sieve granulate at last;
(II), preparation at last
6, in the Ai Lishatan ester potassium salt granule that step (I) obtains, add Levamlodipine besylate and micropowder silica gel;
7, with the mill mixture of powders of milling, make it become satisfactory thin sprills;
8, in the mixture of powders of milling, add magnesium stearate, carboxymethylstach sodium, and in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer, mix from step 7;
9, use sheeting equipment in flakes, make 1000, get final product finally mixed granule compacting.
Embodiment 2: Ai Lishatan ester potassium salt amlodipine capsule
Figure G201010301112220100202D000291
Preparation method:
(I) the particulate granulation of Ai Lishatan ester potassium salt
1, various solid supplementary materials are crossed sieve respectively 5～No. 6, standby;
2, half recipe quantity pregelatinized Starch is dissolved in 50 ℃ of purified water and the adding hydroxypropyl cellulose, makes solution be cooled to room temperature;
3, in granulator, mix Ai Lishatan ester potassium salt, microcrystalline Cellulose and remaining pre-paying starch;
4, will mix from the mixture of powders of step 3 with from the solution of step 2 in granulator, the limit edged stirs, and makes suitable soft material, becomes wet granular with No. 2 sieve series;
5, dried particles in drying equipment, dry back makes moisture (loss on drying) be less than or equal to 2.0% with No. 2 sieve granulate at last;
(II), preparation at last
6, in the Ai Lishatan ester potassium salt granule that step (I) obtains, add Amlodipine Besylate Tablet, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and micropowder silica gel;
7, with the mill mixture of powders of milling, make it become satisfactory thin sprills;
8, in the mixture of powders of milling, add magnesium stearate, carboxymethylstach sodium, and in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer, mix from step 7;
9, behind the above-mentioned mixture of powders mix homogeneously, it is heavy to calculate grain, surveys intermediate content, qualified after, be distributed into 1000 capsules, get final product.
Embodiment 3: the antihypertensive activity experiment
Adopt rat spontaneously hypertensive model (SHR), Ai Lishatan ester potassium salt (dosage 0.5mg/kg), Levamlodipine besylate (dosage 0.5mg/kg) and Ai Lishatan ester potassium salt Levamlodipine besylate mixture (administering drug combinations dosage: 0.5mg/kg and 0.5mg/kg) are suspended in gastric infusion in the normal saline respectively, and the blood pressure situation is as follows before and after the administration:
The about 10mm mercury column of Ai Lishatan ester potassium salt blood pressure drops, the about 10mm mercury column of Levamlodipine besylate blood pressure drops, the about 25mm mercury column of Ai Lishatan ester potassium salt Levamlodipine besylate mixture blood pressure drops.
Experimental result shows: Ai Lishatan ester potassium salt, Levamlodipine besylate and Ai Lishatan ester potassium salt Levamlodipine besylate mixture all have tangible hypotensive effect to rat, the hypotensive effect of Ai Lishatan ester potassium salt Levamlodipine besylate mixture is obvious especially, illustrates that Ai Lishatan ester potassium salt and Levamlodipine besylate drug combination have very obvious synergistic or potentiation to blood pressure lowering.
All publications and the patent mentioned in the present invention here all are incorporated herein by reference, and are just quoted as a reference separately as each piece document.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.

Claims (10)

1. a pharmaceutical composition is characterized in that, it comprises pharmaceutically acceptable salt and a certain amount of at least a cardiovascular and cerebrovascular medicine or its pharmaceutically acceptable salt and the pharmaceutically acceptable carrier of a certain amount of Ai Lishatan ester.
2. pharmaceutical composition as claimed in claim 1 is characterized in that, the pharmaceutically acceptable salt of described Ai Lishatan ester is the alkali metal salt or the alkali salt of Ai Lishatan ester.
3. as claim 1,2 described pharmaceutical compositions, it is characterized in that the pharmaceutically acceptable salt of described Ai Lishatan ester is a kind of in potassium salt, sodium salt or the calcium salt of Ai Lishatan ester.
4. as the described pharmaceutical composition of claim 1 to 3, it is characterized in that described cardiovascular and cerebrovascular medicine is selected from least a following active matter: calcium channel blocker, angiotensin converting enzyme inhibitor, the B-adrenergic receptor blocker, the alpha-adrenergic receptor blocker, diuretic, renin inhibitor, neutral endopeptidase inhibitor, Na+/Ca2+ exchanges transporter inhibitors, angiotensin ii receptor antagonist, antihypertensive, dipeptidyl peptidase/IV inhibitor, antidiabetic drug, the HMG-CoA reductase inhibitor, antihyperlipidemic, 2-adrenergic agonist components, anti-anginal drug, anti-arrhythmic, antiplatelet drug, anticoagulant, anti-inflammatory agent, the CETP inhibitor, cox 2 inhibitor, direct thrombin inhibitor, inotropic agent, vasodilation, vasopressor, the crosslinked blocker of AGE, sinuatrial node If electric current blocker, prostacyclin, the PDE inhibitor, or its pharmaceutically acceptable salt or ester.
5. as the described pharmaceutical composition of claim 1 to 4, it is characterized in that:
Described calcium channel blocker is selected from Levamlodipine, amlodipine, lacidipine, lercanidipine, nicardipine, cilnidipine, nitrendipine, nimodipine, felodipine, nifedipine, nisoldipine, benidipine, diltiazem, verapamil;
Described angiotensin converting enzyme inhibitor is selected from perindopril, ramipril, fosinopril, lisinopril, quinapril, enalapril, imidapril, trandolapril, delapril, benazepril, zofenopril, enalaprilat;
Described B-adrenergic receptor blocker is selected from metoprolol, bisoprolol, Propranolol, dexpropranolol, levobetaxolol, betaxolol, esmolol, atenolol, oxprenolol, pindolol, celiprolol, arotinolol, sotalol, dexsotalol, labetalol, carvedilol;
Described alpha-adrenergic receptor blocker is selected from terazosin, alfuzosin, doxazosin, prazosin, minoxidil, urapidil, naftopidil, trapidil, nicorandil, Alprostadil, buflomedil, fasudil;
Described diuretic is selected from hydrochlorothiazide, chlortalidone, indapamide, methyclothiazide, triamterene, spironolactone, furosemide, amiloride, torasemide, eplerenone, bumetanide;
Described renin inhibitor is selected from aliskiren, terlakiren, ditekiren, zankiren, enalkiren;
Described neutral endopeptidase inhibitor is selected from candoxatril, candoxatrilat, ecadotril;
Described Na+/Ca2+ exchange transporter inhibitors is selected from 2-[4-[(2, the 5-difluorophenyl) methoxyl group] phenoxy group]-5-phenetidine, the disclosed SEA0064 of Chinese patent CN03803728.9;
The CLN-1 that described antihypertensive is selected from that Daglutril, Phosphoramidon, omapatrilat, fasidotril, fasidotril draw, describe among sampatrilat, gemopatrilat, bosentan, ambrisentan, sitaxentan, atrasentan, the international monopoly Wo2004/108764;
Described dipeptidyl peptidase/IV inhibitor is selected from: vildagliptin, sitagliptin, Sha Gelieting, Rui Gelieting, Bei Gelieting, denagliptin, sulphostin;
Described antidiabetic drug is selected from Nateglinide, repaglinide, Mitiglinide, acarbose, voglibose, miglitol, ciglitazone, englitazone, darglitazone, darglitazone, balaglitazone, Li Gelie ketone, netoglitazone, gliclazide, glibenclamide, glimepiride, glipizide, gliquidone, metformin, the Mo Geta azoles, Luo Lige pricks, according to the lattice Liezong, Fa Gelietazha, fenofibrate, bezafibrate, etofibrate, clinofibrate, ciprofibrate, gemfibrozil, clofibrate;
Described HMG-CoA reductase inhibitor is selected from atorvastatin, Rosuvastatin, simvastatin, Pitavastatin, fluvastatin, pravastatin, lovastatin;
Described antihyperlipidemic is selected from according to Ezetimibe, colestyramine, colestipol, examine come rice, avasimibe, Yi Lumaibu, lecimibide;
Described PDE inhibitor is selected from sldenafil, Vardenafil, tadalafil;
The acceptable salt of its pharmacy of perhaps respectively doing for oneself.
6. prevention, delay of progression or treat the method for following disease or disease: hypertension, hypertensive patients disease, diabetes, diabetic complication, dyslipidemia, ischemic diseases, coronary heart disease, angina pectoris, congestive heart failure, arrhythmia, apoplexy, atherosclerosis, cerebral infarction, cerebrovascular disease, cardiovascular disease, coronary artery disease, ventricular dysfunction, pulmonary vascular disease, renal vascular, nephropathy, the visceral vessel disease, the vascular flow occlusive disease, inflammatory diseases, autoimmune disease, the immunologic function disease, pulmonary disease, the antioxidant disease, sexual dysfunction, cognitive dysfunction, endothelial function disturbance, cardiac insufficiency, glaucoma, vascular dementia, edema, thrombosis, hypothyroidism, peripheral vascular disease, diseases of eye, ear, nose and throat section disease, aneurysm, renin secreting tumor, cataract, post-stroke depression, depression after cerebral infarction, the hypertensive cerebral hemorrhage aftertreatment, vertebral-basilar artery insufficiency, polycystic ovary syndrome, vascular compliance is impaired, schistosomicide or cancer, it comprises to its pharmaceutical composition of claim 1 of patient's administering therapeutic effective dose of needs.
7. as the purposes of each pharmaceutical composition in the claim 1 to 5, it is characterized in that the medicine that is used to prepare prevention, delay of progression or treats following disease or disease:
Hypertension, hypertensive patients disease, diabetes, diabetic complication, dyslipidemia, ischemic diseases, coronary heart disease, angina pectoris, congestive heart failure, arrhythmia, apoplexy, arteriosclerosis, cerebral infarction, cerebrovascular disease, cardiovascular disease, coronary artery disease, ventricular dysfunction, pulmonary vascular disease, renal vascular, nephropathy, the visceral vessel disease, the vascular flow occlusive disease, inflammatory diseases, autoimmune disease, the immunologic function disease, pulmonary disease, the antioxidant disease, sexual dysfunction, cognitive dysfunction, endothelial function disturbance, cardiac insufficiency, glaucoma, vascular dementia, edema, thrombosis, hypothyroidism, peripheral vascular disease, diseases of eye, ear, nose and throat section disease, aneurysm, renin secreting tumor, cataract, post-stroke depression, depression after cerebral infarction, the hypertensive cerebral hemorrhage aftertreatment, vertebral-basilar artery insufficiency, polycystic ovary syndrome, vascular compliance is impaired, schistosomicide or cancer.
8. as the described pharmaceutical composition of claim 1 to 5, method as claimed in claim 6, purposes as claimed in claim 7, it is characterized in that the pharmaceutically acceptable salt of described Ai Lishatan ester is the potassium salt of Ai Lishatan ester, and wherein:
Described calcium channel blocker is selected from Levamlodipine, amlodipine, lacidipine, lercanidipine, nicardipine, cilnidipine, nitrendipine, nimodipine, felodipine, nifedipine, nisoldipine, benidipine, diltiazem, verapamil;
Described angiotensin converting enzyme inhibitor is selected from perindopril, ramipril, fosinopril, lisinopril, quinapril, enalapril, imidapril, trandolapril, delapril, benazepril, zofenopril, enalaprilat;
Described B-adrenergic receptor blocker is selected from metoprolol, bisoprolol, Propranolol, dexpropranolol, levobetaxolol, betaxolol, esmolol, atenolol, oxprenolol, pindolol, celiprolol, arotinolol, sotalol, dexsotalol, labetalol, carvedilol;
Described alpha-adrenergic receptor blocker is selected from terazosin, alfuzosin, doxazosin, prazosin, minoxidil, urapidil, naftopidil, trapidil, nicorandil, Alprostadil, buflomedil, fasudil;
Described diuretic is selected from hydrochlorothiazide, chlortalidone, indapamide, methyclothiazide, triamterene, spironolactone, furosemide, amiloride, torasemide, eplerenone, bumetanide;
Described renin inhibitor is selected from aliskiren, terlakiren, ditekiren, zankiren, enalkiren;
Described neutral endopeptidase inhibitor is selected from candoxatril, candoxatrilat, ecadotril;
Described Na+/Ca2+ exchange transporter inhibitors is selected from 2-[4-[(2, the 5-difluorophenyl) methoxyl group] phenoxy group]-5-phenetidine, the disclosed SEA0064 of Chinese patent CN03803728.9;
The CLN-1 that described antihypertensive is selected from that Daglutril, Phosphoramidon, omapatrilat, fasidotril, fasidotril draw, describe among sampatrilat, gemopatrilat, bosentan, ambrisentan, sitaxentan, atrasentan, the international monopoly Wo2004/108764;
Described dipeptidyl peptidase/IV inhibitor is selected from: vildagliptin, sitagliptin, Sha Gelieting, Rui Gelieting, Bei Gelieting, denagliptin, sulphostin;
Described antidiabetic drug is selected from Nateglinide, repaglinide, Mitiglinide, acarbose, voglibose, miglitol, ciglitazone, englitazone, darglitazone, darglitazone, balaglitazone, Li Gelie ketone, netoglitazone, gliclazide, glibenclamide, glimepiride, glipizide, gliquidone, metformin, the Mo Geta azoles, Luo Lige pricks, according to the lattice Liezong, Fa Gelietazha, fenofibrate, bezafibrate, etofibrate, clinofibrate, ciprofibrate, gemfibrozil, clofibrate;
Described HMG-CoA reductase inhibitor is selected from atorvastatin, Rosuvastatin, simvastatin, Pitavastatin, fluvastatin, pravastatin, lovastatin;
Described antihyperlipidemic is selected from according to Ezetimibe, colestyramine, colestipol, examine come rice, avasimibe, Yi Lumaibu, lecimibide;
Described PDE inhibitor is selected from sldenafil, Vardenafil, tadalafil;
The acceptable salt of its pharmacy of perhaps respectively doing for oneself.
9. pharmaceutical composition, it is characterized in that, it comprises pharmaceutically acceptable salt and a certain amount of at least a following active matter that is selected from of a certain amount of Ai Lishatan ester: calcium channel blocker, angiotensin converting enzyme inhibitor, B-adrenergic receptor blocker, alpha-adrenergic receptor blocker, diuretic or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier.
10. pharmaceutical composition as claimed in claim 9 is characterized in that, it comprises pharmaceutically acceptable salt and a certain amount of calcium channel blocker or its pharmaceutically acceptable salt of a certain amount of Ai Lishatan ester, and pharmaceutically acceptable carrier.
CN201010301112A 2010-02-02 2010-02-02 Medicine composition containing allisartan isoproxil salts Pending CN101822837A (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105246512A (en) * 2013-04-30 2016-01-13 艾伯维公司 Methods for improving lipid profiles using atrasentan
CN105982891A (en) * 2015-01-30 2016-10-05 王召印 Medicinal composition of allisartan isoproxil and enkephalinase inhibitor or prodrug of enkephalinase inhibitor
CN109833481A (en) * 2017-11-24 2019-06-04 深圳信立泰药业股份有限公司 A kind of pharmaceutical composition of A Lishatan ester or its salt and diuretics
CN109865139A (en) * 2017-12-04 2019-06-11 深圳信立泰药业股份有限公司 A kind of compound medicament composition of A Lishatan ester or its salt and calcium-ion channel antagonists
CN110801452A (en) * 2015-03-12 2020-02-18 深圳信立泰药业股份有限公司 Pharmaceutical composition containing allisartan isoproxil hydrolysate or hydrolysate salt thereof and application thereof
CN113876768A (en) * 2020-11-13 2022-01-04 深圳信立泰药业股份有限公司 New application of compound medicinal composition of allisartan isoproxil and amlodipine

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105246512A (en) * 2013-04-30 2016-01-13 艾伯维公司 Methods for improving lipid profiles using atrasentan
CN105982891A (en) * 2015-01-30 2016-10-05 王召印 Medicinal composition of allisartan isoproxil and enkephalinase inhibitor or prodrug of enkephalinase inhibitor
CN110801452A (en) * 2015-03-12 2020-02-18 深圳信立泰药业股份有限公司 Pharmaceutical composition containing allisartan isoproxil hydrolysate or hydrolysate salt thereof and application thereof
CN109833481A (en) * 2017-11-24 2019-06-04 深圳信立泰药业股份有限公司 A kind of pharmaceutical composition of A Lishatan ester or its salt and diuretics
CN109833481B (en) * 2017-11-24 2021-07-27 深圳信立泰药业股份有限公司 Medicinal composition of allisartan isoproxil or salt thereof and diuretic
CN113289023A (en) * 2017-11-24 2021-08-24 深圳信立泰药业股份有限公司 Medicinal composition of allisartan isoproxil or salt thereof and diuretic
CN113289023B (en) * 2017-11-24 2023-02-28 深圳信立泰药业股份有限公司 Medicinal composition of allisartan isoproxil or salt thereof and diuretic
CN109865139A (en) * 2017-12-04 2019-06-11 深圳信立泰药业股份有限公司 A kind of compound medicament composition of A Lishatan ester or its salt and calcium-ion channel antagonists
CN109865139B (en) * 2017-12-04 2021-07-20 深圳信立泰药业股份有限公司 Compound pharmaceutical composition of allisartan isoproxil or salt thereof and calcium channel antagonist
CN113230411A (en) * 2017-12-04 2021-08-10 深圳信立泰药业股份有限公司 Compound pharmaceutical composition of allisartan isoproxil or salt thereof and calcium channel antagonist
CN113876768A (en) * 2020-11-13 2022-01-04 深圳信立泰药业股份有限公司 New application of compound medicinal composition of allisartan isoproxil and amlodipine
CN113876768B (en) * 2020-11-13 2023-05-02 深圳信立泰药业股份有限公司 New application of aliskirilowii and amlodipine compound pharmaceutical composition

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