CN101146528A - Pharmaceutical composition comprising hydroxylated nebivolol - Google Patents

Abstract

Hydroxylated nebivolol metabolites increase NO release from human endothelial cell preparations in a concentration dependent fashion following acute administration. In addition, hydroxylated nebivolol metabolites, including but not limited to 4-hydroxy- 6,6'difluoro-, 4-hydroxy-5-phenol-6,6'difluoro-, and 4-hydroxy-8-pheno-6,6'difluoro-, have the ability to increase the capacity for NO release in human endothelial cells following chronic administration. This invention provides hydroxylated nebivolol metabolites and compositions comprising nebivolol and/or at least one hydroxylated metabolite of nebivolol and/or at least one additional compound used to treat cardiovascular diseases or a pharmaceutically acceptable salt thereof, In addition, this invention provides methods of treating and/or preventing vascular diseases by administering at least one hydroxylated metabolite of nebivolol that is capable of releasing a therapeutically effective amount of nitric oxide to a targeted site affected by the vascular disease. Also, this invention is directed to the treatment and/or prevention of migraine headaches administering at least one hydroxylated metabolite of nebivolol. This invention may also be used in conjunction with or as a single treatment of metabolic syndrome disorders.

Description

The pharmaceutical composition that comprises hydroxylated nebivolol

John P.O ' Donnell, Walter Owens, Joseph Duncan, Andrew Shaw all belongs to Morgantown, WV; Jinn Wu belongs to Princeton Junction, NJ

According to 35USC § 119, the sequence number that the application requires on January 31st, 2005 to submit to is that 60/648,551 U.S. Provisional Application and the sequence number submitted on January 3rd, 2006 are 60/755,856 U.S. Provisional Application No..

Technical field

The metabolite of nebivolol has pharmacological property, and this pharmacological property may be favourable in the multiple disease of treatment in as cardiovascular disease, and described cardiovascular disease can comprise hypertension, atherosclerosis and congestive heart failure.Especially, metabolism has effect to NO for nebivolol and crucial metabolite thereof, does not rely on β ₁-selectivity interacts, and the nebivolol metabolite is associated with its application in cardiovascular disease therapies to the advantageous effect that endothelial NO discharges.The invention describes the hydroxylated nebivolol metabolite, contain the compositions of at least a hydroxyl nebivolol metabolite, and use said composition to treat and/or prevent the method for cardiovascular disease or obstacle.

Background of invention

The nitric oxide production normal generation of endothelium is important for keeping vascular function.Increase endothelial NO release and cause the smooth muscle cell contractility to reduce, vascular resistance reduces.Yet under the situation of hypertension and hyperlipemia, the dysfunction of endothelium causes the remarkable reduction that NO discharges, and it causes: 1) vasoconstriction and vasospasm increase; 2) more mononuclear cell and LDL soak into; 3) propagation of vascular smooth muscle cell; 4) oxidative stress increases; And 5) platelet aggregation increases.According to prompting, recover endothelial function and the metabolic material of NO and in the multiple cardiovascular diseases treatment of (comprising coronary artery disease and heart failure), have benefit.

Summary of the invention

After the acute administration, the NO that the mode that the hydroxylated nebivolol metabolite relies on concentration increases in the human endothelial cell prepared product discharges.In addition, after the long term administration, multiple hydroxylated nebivolol metabolite (includes but not limited to 4-hydroxyl-6,6 ' two fluoro-, 4-hydroxyl-5-phenol-6,6 ' two fluoro-and 4-hydroxyl-8-phenol (pheno)-6,6 ' two fluoro-) has the ability that NO discharges in the human endothelial cell that increases.The invention provides hydroxylated nebivolol metabolite and at least a hydroxylation metabolism product and/or at least a compositions that is used for the treatment of chemical compound or its pharmaceutically acceptable salt of cardiovascular disease that contain nebivolol and/or nebivolol.In addition, the invention provides by giving at least a hydroxylation metabolism product of nebivolol, treating and/or preventing with the nitric oxide deficiency is the method for the angiopathy of feature, and described hydroxylation metabolism product can discharge the nitric oxide of treatment effective dose to the target site that influenced by angiopathy.In addition, the present invention relates to give at least a hydroxylation metabolism product of nebivolol, treat and/or prevent migraine.The present invention can also unite or be used for the treatment of separately the metabolism syndrome obstacle.

The accompanying drawing summary

Fig. 1: acute treatment (50 μ M processing) afterwards, the effect that nebivolol and metabolite discharge peak NO in the human endothelial cell.

Fig. 2: acute treatment (50 μ M processing) afterwards, the effect that nebivolol and metabolite discharge peak NO in the human endothelial cell.

Fig. 3: acute treatment (10 μ M treatment) afterwards, the effect that nebivolol and metabolite discharge peak NO in the human endothelial cell.

Fig. 4: shown that handling peak NO afterwards with acetylcholine, nebivolol and nebivolol metabolite (5 μ M treatment) discharges.

Fig. 5: shown with the concentration-response effect after the nebivolol metabolite acute treatment.

Fig. 6: shown with the concentration-response after nebivolol, nebivolol enantiomer and the 4-hydroxyl nebivolol acute treatment.

Fig. 7: the amount that has shown NO release that use hydroxylated nebivolol acute drug processing (1.0 μ M) is measured after the isolated HUVECs from the white American's (hollow strips) and Black people's (solid bars) donor.Value is meansigma methods ± S.D. (n=5).

Fig. 8: synthetic target chirality metabolite-(R, S, S, S)-10 kinds of chemical compounds of series.

Fig. 9: amine 1 synthetic.

Figure 10: epoxide 1 synthetic.

Figure 11: amine 2 synthetic, part 1.

Figure 12: amine 2 synthetic, part 2.

Figure 13: epoxide 2 synthetic.

Figure 14: amine 3 synthetic.

Figure 15: epoxide 3 synthetic.

Figure 16: amine 4 synthetic.

Figure 17: epoxide 4 synthetic.

The coupling of Figure 18 a: amine-X and epoxide-Y is to produce target hydroxylated nebivolol metabolite, part 1.

The coupling of Figure 18 b: amine-X and epoxide-Y is to produce target hydroxylated nebivolol metabolite, part 2.

Detailed Description Of The Invention

Definition

For convenience, before further specifying the present invention, collected some used in description, embodiment and additional claim term at this.Should assign to read and understand these definition according to the remainder of the disclosure content by those skilled in the art.Unless otherwise defined, whole technology used herein has the conventional identical implication of understanding with those of ordinary skills with scientific terminology.

Article used herein " one (a) " and " one (an) " are meant the phraseological object of this article of one or more than one (that is, at least one).For instance, " element (anelement) " refers to an element or a more than element.

" about identical time " means, and is giving to give other reactive compound to this patient within about 30 minutes of a kind of chemical compound (nebivolol) to the patient." about identical time " also comprises and gives described chemical compound simultaneously.

Phrase used herein " angiotensin-convertion enzyme inhibitor " or " ACE inhibitor " are meant that inhibition changes into angiotensin the chemical compound of any enzyme of any other form. Blood vessel is tight Open plain invertase (ACE) inhibitor

ACE inhibitor is effective hypotensive agent, and its competitive inhibition angiotensin converting enzyme also stops angiotensin I to change into Angiotensin II.The limiting examples of ACE inhibitor comprises alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, perindopril, quinapril, ramiprilat, ramipril, spirapril, temocapril and trandolapril.Can use the known standard test technology of those of ordinary skills to differentiate other ACE inhibitor.

Phrase " angiotensin ii receptor antagonist " or " ARB " be meant with acceptor site on the Angiotensin II and combine, unless but there is other receptors ligand, otherwise do not cause the chemical compound that any physiology changes.

Angiotensin ii receptor antagonist (ARB): ARB is effective hypotensive agent, and it has very favorable side effect feature.Their mechanism of action is relevant with the vasoconstriction and the aldosterone-secretion effect of selective exclusion angiotensin.The limiting examples of ARB comprises Candesartan, Eprosartan, irbesartan, losartan and valsartan.Can use the known standard test technology of those of ordinary skills to identify other ARB.

Term " antagonist " is art-recognized, refers to the bind receptor site, unless but there is other receptors ligand, otherwise do not cause the chemical compound that the physiology changes.

Term " biological available " is art-recognized, and experimenter or patient that a part that refers to the form of related theme invention or administered dose is given it absorb, incorporate into or otherwise can be utilized by described experimenter or patient.

" Black people " are meant African blood lineage's people or non-descendants American, but are not necessarily limited to African those people that come from (for example, Carribean).

" treatment effective dose " is meant the chemical compound of effective its intended purposes of realization and/or the amount of compositions.

Phrase " cardiovascular agents " or " cardiovascular drug " are meant the therapeutic compound that is applicable to treatment or angiocardiopathy preventing.The limiting examples of the chemical compound that is fit to comprises that (1) thiazide diuretic (comprises chlorothiazide (Diuril), chlortalidone, hydrochlorothiazide, polythiazide (Renese), indapamide (Lozol) and metolazone (Mykrox, Zaroxolyn)); (2) loop diuretic (comprising bumetanide (Bumex) and furosemide (Lasix), torsemide (Demadex)); (3) diuretic (comprising amiloride (Midamor) and triamterene (Dyrenium)) of guarantor's potassium; (4) aldosterone receptor blocker (comprising eplerenone (Inspra) and spironolactone (Aldactone)); (5) beta blocker class (Propranolol (Inderal LA) and the timolol (Blocadren) that comprise atenolol (Tenormin), betaxolol (Kerlone), bisoprolol (Zebeta), metoprolol (Lopressor), the metoprolol (Toprol XL) that prolongs release, nadolol (Corgard), Propranolol (Inderal), long-acting); (6) has the beta blocker class (comprising acebutolol (Sectral), penbutolol (Levatol) and pindolol) of intrinsic sympathomimetic activity; (7) Zu He α and beta-blocker class (comprise carvedilol (Coreg) and labetalol (Normodyne, Trandate)); (8) the ACE inhibitor class (comprises benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace) and trandolapril (Mavik)); (9) Angiotensin II antagonist (Candesartan (Atacand), Eprosartan (Teveten), irbesartan (Avapro), losartan (Cozaar), Olmesartan (Benicar), telmisartan (Micardis) and valsartan (Diovan); (10) calcium channel blocker-non-dihydropyridines (comprises and prolongs the diltiazem (Cardizem CD, Dilacor XR, Tiazac) that discharges, the verapamil (Calan that prolongs the diltiazem (Cardizem LA) of release, discharges immediately, Isoptin), long lasting verapamil (Calan SR, Isoptin SR) and verapamil-Coer (Covera HS, VerelanPM)); (11) calcium channel blocker-dihydropyridines (comprising amlodipine (Norvasc), felodipine (Plendil), isradipine (DynaCirc CR), lasting nicardipine (Cardene SR), long lasting nifedipine (Adalat CC, Procardia XL) and the nisoldipine (Sular) that discharges); (12) α 1-blocker class (comprising doxazosin (Cardura), prazosin (Minipress) and terazosin (Hytrin)); (13) medicine (comprising clonidine (Catapres), clonidine patch (Catapres-TTS), methyldopa (Aldomet), reserpine and guanfacine) that works of maincenter α 2-agonist class and other maincenter; (14) directly vasodilation (comprises hydralazine (Apresoline) and minoxidil (Loniten); (15) ACEIs and CCBs (comprising amlodipine/benazepril hydrochloride, enalapril maleate/felodipine and trandolapril/verapamil); (16) ACEIs and diuretic (comprise benazepril/hydrochlorothiazide, captopril/hydrochlorothiazide, enalapril maleate/hydrochlorothiazide, lisinopril/hydrochlorothiazide, moexipril HCl/ hydrochlorothiazide and quinapril/hydrochlorothiazide; (17) ARBs and diuretic (comprise Candesartan ring plug/hydrochlorothiazide in heptan, methanesulfonic acid Eprosartan/hydrochlorothiazide, irbesartan/hydrochlorothiazide, Losartan Potassium/hydrochlorothiazide, telmisartan/hydrochlorothiazide, valsartan/hydrochlorothiazide; (18) beta-Blocking agent class and diuretic (comprise atenolol/chlortalidone, Bisoprolol/hydrochlorothiazide, metoprolol tartrate/hydrogen ammonia thiazine, nadolol/bendrofluthiazide and timolol maleate/hydrochlorothiazide; (19) medicine and the diuretic (comprising methyldopa/hydrochlorothiazide, reserpine/chlorothiazide and reserpine/hydrochlorothiazide) that work of maincenter; (20) diuretic and diuretic (amiloride HCl/ hydrochlorothiazide, spironolactone/hydrochlorothiazide and triamterene/hydrochlorothiazide).

Cardiovascular disease or obstacle are meant any cardiovascular disease known in the art or obstacle, include but not limited to that wherein said cardiovascular disease is selected from congestive heart failure, hypertension, pulmonary hypertension, cardiac muscle and cerebral infarction, atherosclerosis, atheroma forms, thrombosis, ischemic heart desease, postangioplasty restenosis, coronary artery disease, renal failure, stable, instability and anomaly (Prinzmetal) angina pectoris, cardiac edema, renal insufficiency, renal edema, hepatic edema, apoplexy, the outbreak of instantaneity ischemia, cerebrovascular accident, restenosis, blood pressure in the control hypertension, platelet adhesion, platelet aggregation, smooth muscle cell proliferation, pulmonary edema and with use the relevant vascular complication of medical apparatus and instruments.

Term " combination " is meant two or more different activities agent, they at roughly identical approximately time administration (for example, wherein activating agent is in single pharmaceutical preparation) or different time administrations (for example, a kind of medicine gave the experimenter before another kind of medicine).

It can be to use interchangeably that term " medicine ", " activating agent pharmaceutically ", " bioactivator ", " therapeutic agent " reach " activating agent ", refer to a kind of material such as chemical compound or complex, when with the effective dose administration, it has measurable useful physiological effect to health, as the treatment effect in disease or the treating dysfunction.Further, when using these terms, or when specific activating agent be when differentiating specially with title or type, be to be understood that such narration expection comprises activating agent itself and pharmaceutically acceptable, the last active derivant of pharmacology thereof, or with its obvious relevant chemical compound, include but not limited to salt, pharmaceutically acceptable salt, N-oxide, prodrug, active metabolite, isomer, fragment, analog, solvate, hydrate, radiosiotope etc.

Phrase " effective dose " is meant under the rational interests/risk ratio applicable to any treatment and produces the part of some expectations or the amount of substance of systemic effect.The effective dose of this material will be according to being changed by the experimenter that treated and disease condition, experimenter's body weight and age, the seriousness of disease condition, the mode of administration etc., and it can be determined easily by those of ordinary skill in the art.

" endothelial function disturbance " is meant that the ability in any physiological processes of being implemented by endothelium (no matter especially reason produces nitric oxide) is impaired.It can be assessed the reaction of acetylcholine or methacholine chloride etc. by for example invasive technique such as coronary artery, perhaps measures, uses on the elbow by Noninvasive technology such as blood flow or the expansion of brachial artery flow, brachial artery ultrasonography, imaging technique, measurement circulating biological labelling such as the asymmetric diethylarginine (ADMA) etc. of the cuff closure of elbow underarm are assessed.With regard to the latter measured, it was lower that the expansion of endothelium-dependent relaxation flow mediated has among the patient of endothelial function disturbance in diagnosis.

Phrase " endothelial nitric oxide synthase " or " eNOS " are meant and produce nitric oxide production enzyme.

Term " pharmaceutically acceptable salt " is art-recognized and refers to nontoxic, the inorganic and organic acid-addition salts of going up relatively of chemical compound, for example is included in contained those in the compositions of the present invention.

Term " pharmaceutically acceptable carrier " is art-recognized and refers to pharmaceutically acceptable material, component or medium such as liquid or solid filler, diluent, excipient, solvent or encapsulating substance, relates to the part of any theme composition or its component being transported or are transported to another organ or health from the part of an organ or health.With the meaning of theme composition and component compatibility thereof on, each 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 such as lactose, dextrose plus saccharose; (2) starch based is as corn starch and potato starch; (3) cellulose and derivant thereof such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragakanta; (5) Fructus Hordei Germinatus; (6) gelatin; (7) Talcum; (8) excipient such as cupu oil and suppository wax class; (9) oils such 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 is as magnesium hydroxide and aluminium hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline solution; (18) IV liquid includes but not limited to Ringer's solution, 5% D/W and manages saline half a lifetime; (19) ethanol; (20) phosphate buffer; And spendable other nontoxic compatible material in (21) pharmaceutical preparation.

" patient " is meant animal, and preferably mammal is more preferably the people, and comprises masculinity and femininity.

" quality of life " refers to people's walking, stair climbing, handles affairs, does housework, participates in recreation, and/or do not need within one day to have a rest, and/or do not have sleeping problems or breathe in the ability that shortens one or more.

Term " preventative " or " therapeutic " treatment is art-recognized and refers to and give the host one or more theme compositions.If (for example in undesirable patient's condition, the disease of host animal or other undesirable state) clinical manifest before administration, treatment is preventative so, be that it prevents that the host from undesirable patient's condition taking place, if administration after undesirable patient's condition performance on the contrary, treatment be curative (that is, its be intended to reduce, improve keep undesirable patient's condition of existence or by its side effect that causes).

Term " structure activity relationship " or " (SAR) " are art-recognized and refer to the interactional mode that the molecular structure that changes medicine or other chemical compound changes itself and receptor, enzyme, nucleic acid or other target etc.

Should understand, " replacement " or " being substituted " comprises condition in secret, and promptly such replacement is consistent with the quantivalence of substituted atom or substituent group permission, and replaces the stable chemical compound of generation, for example, its can be not spontaneous experience transform as by rearrangement, cyclisation, elimination or other reaction.

Considered that also term " substituted " includes the substituent group of all permissions of organic compounds.Aspect widely, the substituent group of permission includes the substituent group of non-annularity and cyclic, ramose and branchiess, isocyclic and heterocyclic, aromatic and the non-aromatic of organic compounds.Illustrational substituent group comprises, for example mentioned above those.For suitable organic compound, admissible substituent group can be one or more and identical or different.With regard to purpose of the present invention, hetero atom such as nitrogen can have the substituent group of any permission of hydrogen substituent group and/or organic compound as herein described, and it satisfies heteroatomic quantivalence.The present invention does not think to be subject to by any way the admissible substituent group of organic compound.

Term " synthetic " is art-recognized and refers to by external chemistry or enzymatic synthesis production.

Phrase " curative effect " is art-recognized and refers to animal, particularly mammal and the more especially part or the systemic effect that are caused by pharmacological active substance of philtrum.Therefore, this term mean be intended for use in the animal or human, to diagnose, cure, alleviate, treatment or prevent disease or strengthen the health of expectation or any material of spirit development and/or situation.Phrase " treatment effective dose " means under the rational interests/risk ratio applicable to any treatment and produces the part of some expectations or this amount of substance of systemic effect.The treatment effective dose of this material will be according to being changed by the experimenter that treated and disease condition, experimenter's body weight and age, the seriousness of disease condition, the mode of administration etc., and it can be determined easily by those of ordinary skills.

Term " treatment " is art-recognized and refers at least a symptom of curing and improving any patient's condition or disease.

The one or more locational hydroxyl that the term used as text " metabolite " or " nebivolol metabolite " are included in 3-8 and 3 '-8 ' position replaces, position 3-8 shown in wherein on parent nebivolol chemical compound and 3 '-8 ' can be a hydroxyl independently of one another, position 3-8 and 3 '-8 ' can be halogen atom such as fluorine independently of one another simultaneously, perhaps is hydrogen atom independently of one another.For example, chemical compound can be 4,4 ', 5,5 ', 8 or 8 ' monohydroxylated and 6 and 6 ' last two-fluorizated.In another embodiment, chemical compound can also be 4,5 ' in all these examples; 4 ', 5; 4,8 '; 4 ', 8 or 4 ', 8 ' last two-hydroxylated and be two on 6 and 6 '-fluorizated.The present invention envisions within its scope and comprises constitutional isomer that all are such and stereoisomer and composition thereof, and clearly do not describe those.Term " metabolite " and " nebivolol metabolite " are envisioned within its scope and are comprised constitutional isomer that all are such and stereoisomer and composition thereof, and clearly do not describe those.

Term " curative effect " is art-recognized and refers to animal, particularly mammal and the more especially part or the systemic effect that are caused by pharmacological active substance of philtrum.Therefore, this term be meant be intended for use in the animal or human, to diagnose, cure, alleviate, treatment or prevent disease or strengthen the health of expectation or any material of spirit development and/or situation.Phrase " treatment effective dose " is meant under the rational interests/risk ratio applicable to any treatment and produces the part of some expectations or this amount of substance of systemic effect.The treatment effective dose of this material will be according to being changed by the experimenter that treated and disease condition, experimenter's body weight and age, the seriousness of disease condition, the mode of administration etc., and it can be determined easily by those of ordinary skills.

Those skilled in the art can synthesize parent nebivolol chemical compound and hydroxylated metabolite thereof according to the method described in the following document, described document is U.S. Patent number 4 for example, 654,362,5,759,580,6,075,046,6,545,040 and EP0145067, EP0334429 and WO95/22325 and WO96/19987; People such as Van Lommen, J.Pharm.Belg., 45 (6): 355-360 (1990); Chandrasekhar, people such as S., Tetrahedron, 56 (34): 6339-6344 (2000); And people such as Kendrick, J.Chromatogram.A., 729:341-354 (1996); Its disclosed separately content is incorporated herein by reference with it in full at this.

Can also make hydroxylated metabolite by the synthesis program of finding in the appendix 1.Be reflected in the solvent that is suitable for reagent and carry out, used material is to be suitable for the conversion that will realize.The technical staff in organic synthesis field should be appreciated that the degree of functionality that exists on the molecule must be consistent with the chemical conversion that proposes.Sometimes, this will need scientist to judge the order about synthesis step, required blocking group and deprotection condition.Substituent group on the raw material can be incompatible with required some reaction conditions in some described method, but will be tangible easily with the alternative and the substituent group of this reaction condition compatibility to those skilled in the art.During synthetic operation, for the reaction of protecting mercaptan and alcohol groups to avoid not expecting, the use of sulfur and oxygen blocking group is as known in the art, and a lot of blocking groups like this are known, for example T.H.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, John Wiley﹠amp; Sons, New York (1999) is incorporated herein by reference with it in full at this.

Hydroxylated metabolite has alkaline nature, and therefore, they can be by being converted to the nontoxic acid-addition salts form of its therapeutic activity with suitable acid treatment, described acid for example, mineral acid such as halogen acids, for example hydrochloric acid, hydrobromic acid etc., and sulphuric acid, nitric acid, phosphoric acid etc.; Or organic acid, as acetic acid, propanoic acid, glycolic, 2 hydroxy propanoic acid, 2-oxo propanoic acid, ethanedioic acid, malonic acid, succinic acid, (Z)-2-butylene diacid, (E)-2-butylene diacid, 2-hydroxyl succinic acid, 2,3-dyhydrobutanedioic acid, 2-hydroxyl-1,2,3-propane-tricarboxylic acids, methanesulfonic acid, ethyl sulfonic acid, benzenesulfonic acid, 4-toluene sulfonic acide, cyclohexylsulfamic acid, 2 hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid and similarly acid.On the contrary, salt form is by changing into free alkali form with alkali treatment.

Hydroxylated nebivolol metabolite

After (for a long time) administration, the hydroxylation metabolism product of nebivolol has the ability that NO discharges in the human endothelial cell that increases.Although be not bound by theory, think that the hydroxylation metabolism product of nebivolol works by activating L-arginine/nitric oxide approach.They are vasodilations of endothelium-dependent relaxation, has other heart-selectivity (promptly, beta-selective) blocking ability, it has the potentiality of keeping endothelial function or improving endothelial function disturbance and is effective medication for treatment cardiovascular disease such as atherosclerosis, hypertension, coronary artery disease and congestive heart failure.The hydroxylated nebivolol metabolite can be used as monotherapy and is used for the treatment of or prevents above-mentioned disease, or unite other medical substance that is fit to and use, they are in same dosage form/product or with the administration of accompanying of independent dosage form/product, with the above-mentioned obstacle of treatment/prevention sufficiently.Because these chemical compounds have the ability that increases the endothelium nitric oxide concentration, they can be suffered from the patient of acute coronary syndrome (ACS), coronary heart disease (CHD), metabolism syndrome and suffer the people of obesity to bring benefit for specific crowd such as diabetics, long-term smoker, Black American.

Observe the direct endothelium benefit of the hydroxylation metabolism product of nebivolol in the concentration that is low to moderate 250nM.By improving the ability that cell discharges NO, these nebivolol metabolites can have the ability of the abnormity of the strong vasodilator effect endothelial function relevant with hypertension with recovery.In addition, these metabolites may have appreciable impact in specific crowd of easily suffering from cardiovascular disease such as Black American, and these metabolites can have effect in HUVEC (Human umbilical vein endothelial cells) when being low to moderate the concentration of 250nM.

Following formula (I) expression hydroxylated nebivolol metabolite

Wherein the position 3-8 that shows on the parent nebivolol chemical compound and 3 '-8 ' can be independently of one another hydroxyl (and they at least one be-OH), position 3-8 and 3 '-8 ' can be halogen atom such as fluorine independently of one another simultaneously, perhaps is hydrogen atom independently of one another.For example, chemical compound can be 4,4 ', 5,5 ', 8 or 8 ' go up monohydroxylated and 6 and 6 ' last two-fluorizated.In another embodiment, chemical compound can be 4,5 ' in all these examples; 4 ', 5; 4,8 '; 4 ', 8 or 4 ', 8 ' last two-hydroxylated and be two on 6 and 6 '-fluorizated.The present invention envisions within its scope and comprises constitutional isomer that all are such and stereoisomer and composition thereof, and clearly do not describe those.

Should be understood that the hydroxylated nebivolol metabolite can exist with the form of mixtures of optically pure enantiomer, pure diastereomer, the mixture of enantiomer, the mixture of diastereomer, the racemic mixture of enantiomer, diastereomeric racemic modification or diastereomeric racemic modification.Should be understood that described chemical compound has minimum 4 stereocenters, and if pyranoid ring replaced by hydroxy functionality, this chemical compound has minimum 5 stereocenters.The present invention expects all combinations of stereoisomer.

For example, after acute administration, the nebivolol metabolite 4 that hydroxyl replaces, 5 '-dihydroxy-6,6 '-difluoro, 4,8 '-dihydroxy-6,6 '-two fluoro-and 4-hydroxyl-6, the NO that the mode that 6 '-two fluoro-rely on concentration increases in the human endothelial cell discharges.For example, 4,5 '-dihydroxy-6,6 '-two fluoro-, and 4,8 '-dihydroxy-6,6 '-two fluoro-are agonist that NO discharges, under the drug level of 50 μ M, have about 330-350nM NO maximum (referring to, Fig. 1 and Fig. 2).Think that the metabolite of hydroxylated nebivolol works as antioxidant and prevents lipid peroxidation.

The compositions that comprises nebivolol

To a certain extent, the present invention is characterised in that the compositions that comprises nebivolol metabolite and at least a other cardiovascular drug.In addition, the present invention is characterised in that the compositions that comprises nebivolol metabolite and at least a other activating agent.The amount that is present in each cardiovascular drug in the compositions and/or other activating agent can change according to a plurality of variablees such as age, body weight, sex and healthy relevant problem.Usually, the dosage of cardiovascular drug normally at about 0.01ng to about 10g/ kg body weight, particularly about 1ng is about 0.1g/ kilogram extremely, more especially about 100ng is about 10mg/ kilogram extremely.In another embodiment, the amount of nebivolol can roughly be that about 0.125mg is to about 40mg in the present composition.When other cardiovascular drug was ACE inhibitor, the amount of ACE inhibitor can roughly be that 0.5mg is to about 80mg.When other cardiovascular drug was ARB, the amount of ARB can roughly be that about 1mg is to about 1200mg.The amount of other cardiovascular drug will depend on used specific cardiovascular drug to a certain extent.

Except ACE inhibitor and ARBs, other cardiovascular drug includes, but are not limited to adrenergic blocking drug, 2-adrenergic agonist components, is used for the medicament of pheochromocytoma, anti-anginal drug, anti-arrhythmic, antiplatelet drug, anticoagulant, antihypertensive, antilipemic, antidiabetic drug, anti-inflammatory agent, calcium channel blocker, CETP inhibitor, cox 2 inhibitor, directly thrombin inhibitor, diuretic, endothelin receptor antagonists, HMG

Co-A reductase inhibitor, inotropic agent, feritin (rennin) inhibitor, vasodilation, vasopressor, the crosslinked clastogen of AGE (breaker) (crosslinked clastogen of high-grade advanced glycation end products such as alagebrium, referring to USP6,458,819), and AGE forms inhibitor (high-grade advanced glycation end products forms inhibitor, as pimagedine).The cardiovascular drug that falls within these general categorys is to illustrate by following.

" tonin (ACE ' s) and angiotensin ii receptor antagonist (ARB ' s) "

" angiotensin ii receptor antagonist " (ARB ' s) is such chemical compound, and it is by in conjunction with angiotensin-ii receptor and disturb its activity, thereby disturbs the activity of Angiotensin II.Angiotensin I and Angiotensin II are synthetic by enzyme renin angiotensin approach.When the nervous element of enzyme feritin vasoactive former (pseudoglobulin in the blood plasma), the beginning building-up process is to generate the decapeptide angiotensin I.By angiotensin converting enzyme (ACE), angiotensin I changes into Angiotensin II (angiotensin-[1-8] octapeptide).The latter is active pressor substance, has hinted that it is for example people's the hypertensive morbid substance of several forms of multiple mammalian species.

(ARB ' s) know comprises peptide compounds and non-peptide compound to angiotensin ii receptor antagonist.Most angiotensin ii receptor antagonist is the congener of modifying a little (congener), wherein by the agonist activity of decaying of the phenylalanine on other aminoacid replaces 8 with some; Can enhanced stability by slowing down other replacement of degenerating in vivo.

The example of angiotensin ii receptor antagonist comprises: telmisartan; Olmesartan; Peptide compounds (for example, Saralasin and relevant analog); Imidazoles-2-ketone (U.S. Patent number 5 that N-replaces, 087,634), the acetic acid imdazole derivatives comprises that 2-N-butyl-4-chloro-1-(2-chlorine benzile) imidazoles-5-acetic acid is (referring to people such as Long, J.Pharmacol.Exp.Ther.247 (1), 1-7 page or leaf (1988)); 4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-6-carboxylic acid and analog derivant (U.S. Patent number 4,816,463); The similar thing of N2-tetrazolium β-glucosiduronic acid (U.S. Patent number 5,085,992); Pyroles, pyrazoles and the triazole type (tryazoles) (U.S. Patent number 5,081,127) that replace; Phenol and Hete rocyclic derivatives be as 1,3-imidazoles (U.S. Patent number 5,073,566); Imidazo-first the ring of condensed 7-heterocycle (U.S. Patent number 5,064,825); Peptide class (for example, U.S. Patent number 4,772,684); The antibody class of Angiotensin II (for example, U.S. Patent number 4,302,386); And aralkyl imidazolium compounds such as xenyl-methyl substituted imidazoles (for example, EP253, on January 20th, 310,1988); ES8891 (N-morpholino acetyl group-(1-naphthyl)-L-alanyl-(4, thiazolyl)-L-alanyl (35,45)-4-amino-3-hydroxyl-5-encircles six valeryls-N-caproamide, Sankyo Company, and Ltd., Tokyo, Japan); SKF108566 (E-α-2-[2-butyl-1-(carboxyl phenyl) methyl] 1H-imidazoles-5-base [methylane]-2-thiophene propanoic acid, SmithKline Beecham Pharmaceuticals, Pa.); Losartan (DUP753/MK954, DuPont Merck Pharmaceutical Company); Remikirin (RO42-5892, F.Hoffman LaRoche A G); A2 (A.sub.2) agonist (Marion Merrill Dow) and some non-peptide heterocycle (G.D.Searle and Company).Other limiting examples of ARBs comprises Candesartan, Eprosartan, irbesartan, losartan and valsartan.Can use standard analytical techniques well known by persons skilled in the art to differentiate other ARBs.

" angiotensin converting enzyme " is the enzyme that a kind of catalysis angiotensin I is transformed into Angiotensin II (ACE).ACE inhibitor comprises that aminoacid and derivant thereof, peptide class comprise two-and the antibody of three-peptide and ACE, and it gets involved renin-angiotensin system by the activity that suppresses ACE, thereby reduces or eliminates the formation of pressor substance Angiotensin II.ACE inhibitor medically is being used for the treatment of hypertension, congestive heart failure, myocardial infarction and nephropathy.The known classification that is suitable for the chemical compound of making ACE inhibitor comprises acyl group sulfydryl and sulfydryl alkanoyl proline such as captopril (U.S. Patent number 4; 105,776) and zofenopril (U.S. Patent number 4,316; 906); carboxyalkyl dipeptide such as enalapril (U.S. Patent number 4,374,829); lisinopril (U.S. Patent number 4; 374; 829); quinapril (U.S. Patent number 4,344,949); ramipril (U.S. Patent number 4; 587; 258) and perindopril (U.S. Patent number 4,508,729); carboxyalkyl dipeptide analogue such as cilazapril (U.S. Patent number 4; 512,924) and benazepril (U.S. Patent number 4,410; 520); phosphinyl alkanoyl proline such as fosinopril (U.S. Patent number 4,337,201) and trandolapril.Other non-limiting instance of ACE inhibitor includes but not limited to alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, perindopril, quinapril, ramipril, ramiprilat, spirapril, temocapril, trandolapril.

Other activating agent also comprises following material:

Adrenergic blocking drug

The non-limiting instance that can be used for the adrenergic blocking drug (α-and beta-adrenergic blocking agent) in the present composition; comprise the B-adrenergic receptor blocker; include but not limited to atenolol; acebutolol; alprenolol; befunolol; betaxolol; bunitrolol; carteolol; celiprolol; hedroxalol; indenolol; labetalol; levobunolol; mepindolol; metipranolol; indomethacin; metoprolol; metrizoranolol; oxprenolol; pindolol; Propranolol; practolol; sotalolnadolol; tiprenolol; tolamolol; timolol; bupranolol; penbutolol; trimepranol; Yohimbine; (3-(1 for 2-; the 1-dimethyl ethyl)-amino-2-hydroxyl propoxyl group)-3-pyridine (pyridene) nitrile HCl; 1-fourth amino-3-(2, the 5-dichlorophenoxy)-2-propanol; 1-isopropyl amino-3-(4-(2-cyclo propyl methoxy ethyl) phenoxy group)-2-propanol; 3-isopropyl amino-1-(7-methyl indan-4-base oxygen)-2-butanols; 2-(3-tert-butyl group amino-2-hydroxyl-rosickyite base)-4-(5-carbamyl-2-thienyl) thiazole; 7-(the amino propoxyl group of 2-hydroxyl-3-tert-butyl group) benzo [c] furanone.More than the chemical compound of Jian Bieing can use with the admixture of isomeric compound form, or uses with its left-handed separately or dextral form.

2-adrenergic agonist components

Can be used for the limiting examples of the 2-adrenergic agonist components (α-and beta-adrenergic agonist) in the present composition, comprising: adrafinil, Adrenalone, albuterol, Nalde (amidephrine), apraclonidine, bitolterol, budralazine, carbuterol, clenbuterol, clonidine, clorprenaline, clonidine, cyclopentamine, denopamine, detomidine, dimetofrine, Dioxethedrine, dipivefrine, dopexamine, ephedrine, epinephrine, etafedrine, ethylnorephinephrine, fenoterol, fenoxazoline, formoterol, guanabenz, guanfacine, hexoprenaline, hydroxyamphetamine, ibopamine, indanazoline, neoisuprel, isometheptene, isoproterenol, Mabuterol, mephentermine, orciprenaline, metaradrine, Benazoline, methoxamedrine, 2-amino-4-methylhexane, methoxiphenadrin, the midodrine, modafinil, moxonidine, naphazoline, norepinephrine, norfenefrine, octodrine, octopamine, oxyfedrine, oxymetazoline, phenylephrine hydrochloride, the hydrochloric acid Super Odrinex, phenpromethamine, pholedrine, pirbuterol, prenalterol, procaterol, propylhexedrine, protokylol, pseudoephedrine, reproterol, rilmenidine, rimiterol, ritodrine, salmaterol, solterenol, synephrine, talipexole, terbutaline, the tetrahydrochysene tolazoline, tiamenidine, tramazoline, tretoquinol, tuaminoheptane, tulobuterol, tymazoline, tyramine, xamoterol, xylometazoline and composition thereof.

The medicine that is used for pheochromocytoma

Include but not limited to chemotherapeutics.

Anti-anginal drug

Include but not limited to Amlodipine Besylate Tablet, amlodipine maleate, betaxolol hydrochloride, bevantolol hydrochloride, butoprozine hydrochloride, carvedilol, cinepazic acid ethyl ester maleate, metroprolol succinate, molsidomine, monatepil maleate, nitrate esters (includes but not limited to glyceryl trinitrate (GTN, nitroglycerin, Nitro-Bid), 5-Ismo 20 (5-ISMN, Ismo), amyl nitrate and nicorandil (Icorel)), primidolol, ranolazine hydrochloride, tosifen, verapamil hydrochloride).

Anti-arrhythmic

Can be used for the limiting examples of the anti-arrhythmic in the present composition, comprising: acebutolol, acecainide, adenosine, ajmaline, alprenolol, amiodarone, amoproxan, aprindine, aprotinolol, atenolol, azimilide, bevantolol, bidisomide, the toluenesulfonic acid bretylium tosylate, bucumolol, butetolol, bunaftine, bunitrolol, bupranolol, butydrine hydrochloride, butobendine, capobenic acid, carazolol, carteolol, cibenzoline, cloranolol, Dimpyramidum, dofetilide, encainide, esmolol, flecainide, dihydrochinidin, ibutilide, indecainide, indenolol, the bromination ipratropium, lignocaine, lorajmine, lorcainide, meobentine, mexiletine, moracizine, nadoxolol, nifenazone, oxprenolol, penbutolol, pentisomide, pilsicainide, pindolol, pirmenol, practolol, neo-gilurytmal, procamide, pronetalol, Propafenone, Propranolol, pyrinoline, quinidine, sematilide, sotalol, talinolol, tilisolol, timolol, tocainide, verapamil, viquidil, xibenolol and composition thereof.

Antiplatelet drug

The limiting examples that can be used for the antiplatelet drug in the present composition comprises: clopidogrel, dipyridamole, abciximab and ticlopidine.

Anticoagulant

Anticoagulant is by negatively influencing the medicine that the generation, deposition, cracking and/or the activation that form the essential factor of blood clot suppress the hemopexis approach.The limiting examples that can be used for the anticoagulant (that is the relevant treatment of blood coagulation) in the present composition comprises brain Kangping (Aggrenox), anagrelide, aminocaproic acid, sulphinpyrazone, pentosan sodium (Arixtra), warfarin sodium, Fragmin, heparin sodium, Enoxaparin, Vitamin K1 preparation, anisindione, persantin, Bo Liwei, Pletal, ticlid see ticlopidine, Trental, warfarin.The medicament of other " anti--blood coagulation " and/or " solution fibrin " comprises plasminogen (becoming fibrinolysin by interacting with prekallikrein, kininogen, factor XI, plasma thromboplastin antecedent I, XIIIa, plasminogen activator precursor and tissue plasminogen activator [TPA]) streptokinase; Urokinase: (Anisoylated) plasminogen-streptokinase activator complex of Fructus Foeniculi acidylate, pro-urokinase, (Pro-UK), rTPA (alteplase (alteplase) or organized enzyme (activase); R represents recombinant), rPro-UK, Abbokinase (Abbokinase), Eminase (Eminase), streptokinase anagrelide hydrochloride, bivalirudin, dalteparin sodium, Danaparoid sodium, dazoxiben hydrochloride, efegatran sulfate, Enoxaparin Sodium, ifetroban, ifetroban sodium, tinzaparin sodium (Tinzaparin Sodium), reteplase (reteplase), trifenagrel, warfarin, dextran.

Other anticoagulant that also has includes, but are not limited to ancrod, anticoagulant citrate glucose solution, anticoagulant citrate glucose 1-phosphate1-adenine solution, anticoagulant citrate glucose 1-phosphate1-solution, anticoagulant heparin solution, anticoagulant sodium citrate solution, Ardeparin Sodium, bivalirudin, bromindione, dalteparin sodium, desirudin, dicoumarol, calciparine, heparin sodium, sodium apolate, Nafamostat Mesilate, phenprocoumon, tinzaparin sodium.

Platelet function inhibitor is the medicine that damage fully-developed platelet is carried out its normal physiological role (that is its normal function) ability.Platelet participates in a large amount of physiological processes usually, for example adhere to (for example adhering to cell and acellular entity), assemble (for example for forming the purpose of blood clot) and the factor such as somatomedin the release of (for example, platelet-derived somatomedin (PDGF)) and the granular component of platelet.An inhibitor that the subspecies class is a platelet aggregation of platelet function inhibitor, its be reduce or stop platelet with himself or with other cell and acellular component physical bond, thereby eliminate the chemical compound of ability of the ability of platelet formation thrombosis.

The example of useful platelet function inhibitor includes but not limited to acadesine, anagrelide (if giving) with the dosage that exceeds 10mg/ days, anipamil, argatroban, aspirin, clopidogrel, cyclooxygenase-2 inhibitors such as nonsteroidal anti-inflammatory agent and synthetic compound F 17-hydroxy-corticosterone R-122047, Danaparoid sodium, dazoxiben hydrochloride, two adenosines 5 ', 5 ' " P1; P4-tetraphosphate (Ap4A) analog; difibrotide; two hydrochloric acid dilazeps; 1; 2-and 1,3-dinitric acid glycerol, dipyridamole, dopamine and 3-methoxytyramine, efegatran sulfate, Enoxaparin Sodium, glucagon, glycoprotein iib/iiia antagonist such as Ro-43-8857 and L-700,462, ifetroban, ifetroban sodium, iloprost, integrilin (eptifibatide), the isocarbacyclin methyl ester, isosorbide-5-Mononitrate, itazigrel, ketanserin and BM-13.177, lamifiban, lifarizine, molsidomine, nifedipine, oxagrelate, PGE, platelet activating factor antagonist such as lexipafant, prostacyclin (PGI2), pyrazinamide, pyridinolum carbamtum, ReoPro (promptly, abciximab), sulfinpyrazone, synthetic compd B N-50727, BN-52021, CV-4151, E-5510, FK-409, GU-7, KB-2796, KBT-3022, KC-404, KF-4939, OP-41483, TRK-100, TA-3090, TFC-612 and ZK-36374,2,4,5,7-four thia octanes, 2,4,5,7-four thia octanes 2, the 2-dioxide, 2,4,5-three thia hexanes, theophylline, pentoxifylline, thromboxane and thromboxane synthetase inhibitor such as G-137 and sulotroban, ticlopidine, tirofiban, trapidil and ticlopidine, trifenagrel, trilinolein phosphoramide, 5 of 3-replacement, 6-two (4-methoxyphenyl)-1,2, the antibody of 4-triazines and glycoprotein iib/iiia, and U.S. Patent number 5,440, those disclosed in 020, and antiserotonin, clopidogrel, sulfinpyrazone, aspirin, dipyridamole, clofibrate, pyridinolum carbamtum, PGE, glucagon, antiserotonin, caffeine, theophylline, pentoxifylline, ticlopidine.

Antihypertensive

The limiting examples that can be used for the antihypertensive in the present composition comprises amlodipine, benidipine, benazepril, Candesartan, captopril, darodipine, diltiazem HCl, diazoxide, doxazosin HCl, enalapril, Eprosartan, the methanesulfonic acid losartan, felodipine, fenoldopam, fosinopril, guanabenz acetate, irbesartan, isradipine, lisinopril, mecamylamine, minoxidil, nicardipine HCl, nifedipine, nimodipine, nisoldipine, phenoxy group benzamine HCl, prazosin HCl, quinapril, reserpine, terazosin HCl, telmisartan and valsartan.

Antilipemic

The limiting examples that can be used for the antilipemic in the present composition comprises acipimox, aluminum nicotinate, atorvastatin, colestyramine, Colestid, DEAE-sephadex, beclobrate, fluvastatin, gemfibrozil, lovastatin, lysosomal sour lipase, icofibrate, nicotinic acid, the special class (fibrates) of PPAR alfa agonists such as shellfish, include but not limited to fenofibrate, chlorine Bei Te, pirifibrate, ciprofibrate, bezafibrate, clinofibrate, Ronifibrate, Etophylline Clofibrate, clofibric acid, etofibrate and gemfibrozil, pravastatin sodium, simfibrate, simvastatin, niceritrol, niclonate, cholexamin, oxiniacic acid, etiroxate, thyropropic acid, thyroxine, acifran, azacosterol, benfluorex, β-benzylidene butyramide, carnitine, the chondroitin sulfate clomestrone, dextran, dextran sodium sulfate, 5,8,11,14, the 17-eicosapentaenoic acid, eritadenine, furazabol, meglutol, AC-233, mytatrienediol, ornithine, gamma oryzanol, pantethine, the tetraacethyl tetramethylolmethane, phenylbutyramide, pirozadil, probucol, cupreol, sultosilic acid (piperazine salt), tiadenol, triparanol, xenbucin and composition thereof.

Antidiabetic drug

The limiting examples that can be used for the antidiabetic drug in the present composition comprises biguanides such as buformin, metformin and phenformin, hormones such as insulin, sulfonyl urea derivates such as acetohexamide, 1-butyl-3-metanilyl urea, carbutamide, chlorpropamide, glibornuride, gliclazide, glimepiride, glipizide, gliquidone, glisoxepide, glibenclamide, glybuthiazole, glybuzole, glyhexamide, Glycodiazine, glypinamide, Phenbutamide, tolazamide, tolbutamide, metahexamide, the HDL agonist, PPAR gamma agonist such as thiazolidinediones such as pioglitazone, rosiglitazone and troglitazone, and other, comprise acarbose, calcium mesoxalate, miglitol and repaglinide.

Anti-inflammatory agent

The limiting examples that can be used for the anti-inflammatory agent in the present composition comprises alclofenac, Aclovate, algestone acetonide, alpha amylase, amcinafal, amcinafide, amfenac sodium, amiprilose hydrochloride, Antril (Synergen), anirolac, anitrazafen, azapropazone, balsalazide disodium, bendazac benoxaprofen, benzydamine hydrochloride, bromelain, broperamole, budesonide, carprofen, cicloprofen, cinnopentazone, cliprofen, Clobesol, clobetasone butyrate, clopirac, the propanoic acid cloticasone, cormethasone acetate, cortodoxone, deflazacort, desonide, desoximetasone, dexamethasone dipropionate, diclofenac potassium, diclofenac sodium, diflorasone diacetate, diflumidone sodium, diflunisal, difluprednate, diftalone, dimethyl sulfoxine, drocinonide, endrysone, enlimomab, enolicam sodium, epirizole, etodolac, etofenamate, felbinac, fenamole, fenbufen, fenclofenac, fenclorac, fendosal fenpipalone, fentiazac, flazalone, Fluazacort, flufenamic acid, flumizole, flunisolide acetate, flunixin, flunixin meglumine, fluocortin butyl, fluorometholone acetate, fluquazone, flurbiprofen, fluretofen, fluticasone propionate, furaprofen, furobufen, halcinonide, halobetasol propionate, halopredone acetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol, ilonidap, indomethacin, Indomethacin sodium, indoprofen, indoxole, intrazole, isoflupredone acetate, Isoxepac, isoxicam, ketoprofen, lofemizole hydrochloride, lornoxicam, loteprednol etabonate, meclofenamate sodium, meclofenamic acid, the meclorisone dibutyrate, mefenamic acid, mesalazine, meseclazone, methylprednisolone suleptanate, morniflumate, nabumetone, naproxen, naproxen sodium, naproxol, nimazone, olsalazine sodium, orgotein, orpanoxin, oxaprozin, oxyphenbutazone, the hydrochloric acid paranyline, Pentosan Polysulfate Sodium, phenbutazone sodium glycerate, pirfenidone, piroxicam, piroxicam cinnamate, piroxicam olamine, pirprofen, prednazate, prifelone, prodolic acid, proquazone, proxazole, proxazole citrate, rimexolone, romazarit, salcolex, Salnacedin, salsalate, salicylate, Sanguinarium Chloride, seclazone, sermetacin, sudoxicam, sulindac, suprofen, talmetacin, talniflumate, talosalate, tebufelone, tenidap, tenidap sodium (TenidapSodium), tenoxicam, tesicam, tesimide, tetrydamine, tiopinac, tixocortol cuts down ester, tolmetin, tolmetin sodium, triclonide, triflumidate, zidometacin, glucocorticoids, McN 2783-21-98.A preferred anti-inflammatory agent is an aspirin.

Calcium channel blocker

" calcium channel blocker " is at chemically inhomogeneous chemical compound, in the control that various diseases is comprised several cardiovascular disease, has important therapeutic value, described cardiovascular disease is hypertension, angina pectoris for example, and arrhythmia (Fleckenstein, Cir.Res.v.52, (suppl.1), 13-16 page or leaf (nineteen eighty-three); Fleckenstein, Experimental Facts andTherapeutic Prospects, John Wiley, New York (1983); McCall, D., Curr Pract Cardiol, 10 volumes, 1-11 page or leaf (1985)).Calcium channel blocker is different types of medicine, and it prevents by adjusting cell calcium passage or the calcium that slows down enters cell (Remington, The Science and Practice of Pharmacy, the 19th edition, Mack PublishingCompany, Eaton, Pa., 963 pages (1995)).Most of present available calcium channel blockers and being suitable for according to the present invention belong to one of three big chemical classes of medicine, dihydropyridines, nifedipine for example, the phenylalkyl amine, for example verapamil, and benzothiazepine class (benzothiazepines) is as diltiazem .The limiting examples that can be used for the calcium channel blocker in the present composition comprises bepridil, clentiazem , diltiazem , fendiline, gallopamil, mibefradil, prenylamine, semotiadil, terodiline, verapamil, amlodipine, aranidipine, barnidipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine, isradipine, lacidipine, lercanidipine, Manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine, bencyclane, etafenone, fantofarone, perhexiline and composition thereof.

The CETP inhibitor

The limiting examples that can be used for the CETP inhibitor in the present composition comprises Tuo Chepu (torcetrapib) and JT7-705.

Cox 2 inhibitor

The limiting examples that can be used for the cox 2 inhibitor in the present composition comprises following chemical compound: at all chemical compounds and the material of the 8th page of beginning of the WO99/20110 of Winokur, as the member of the selective COX-2-inhibitor 2 chemical compound of three different structures classification; And at exercise question the U.S. Patent number 6 on 24 days October in 2000 of the Nichtberger of " Combination therapy for treating; preventing; orreducing the risks associated with acute coronary ischemic syndromeand related conditions ", in 136,804 the chemical compound and the material of optionally cox 2 inhibitor; And exercise question is that PCT/US9509905, the PCT of December in 1996 announcement on the 27th that people such as " Combination of a Cyclooxygenase-2Inhibitor and a LeukotrieneB4Receptor Antagonist for the Treatment of Inflammations. ", Isakson submit on June nineteen ninety-five 12 applies for being the chemical compound of selective COX-2-inhibitor 2 and material among the WO/09641645.The implication of cox 2 inhibitor should comprise chemical compound and the material of wherein quoting and incorporate into the WO99/20110 of Winokur by reference technique in the present invention, wherein quote and incorporate into the U.S. Patent number 6 in the 24 days October in 2000 of Nichtberger by reference technique, 136,804 chemical compound and material, and quote and incorporate the PCT/US9509905 that people such as Isakson submit on June nineteen ninety-five 12 into, the PCT application WO/09641645 of December in 1996 announcement on the 27th, exercise question is to be the chemical compound of cox 2 inhibitor and material in " Combination of a Cyclooxygenase-2In hibitor and a Leukotriene B4Receptor Antagonist for theTreatment of Inflammations. ".The implication of cox 2 inhibitor in the present invention also comprises rofecoxib and celecoxib, is sold with trade name VIOXX and CELEBREX respectively by Merck and Searle/Pfizer.Rofecoxib is discussed in the WO99/20110 of Winokur, as the 9th page chemical compound 3.Celecoxib is discussed in identical list of references and is SC-58635, and discuss at T.Penning, 1, synthetic and biological assessment: 4-[5-(4-tolyl)-3-(the trifluoromethyl)-1H-pyrozo1-1-yl of 5-diaryl pyrazole azole cyclooxygenase-2 inhibitor] benzsulfamide (SC-58635, celecoxib) discriminating "; J.Med.Chem.Apr.25,1997:40 (9): among the 1347-56.The implication of cox 2 inhibitor also comprises the SC299 that is called as the fluorescence diaryl oxazole in the present invention.People such as C.Lanzo " Fluorescence quenching analysis of theassociationanddissociationofadiarylheterocycletocyclo oxygenasel-1andcyclooxygenase-2:dynamicbasisofcycloxygen ase-2selectivity ", Biochemistry May23,2000, vol.39 (20): 6228-34, with people such as J.Talley, " 4; 5-two aryloxazole inhibitors ofcyclooxygenase-2 (COX-2) ", Med.Res.Rev.May1999; 19 (3): 199-208.The implication of cox 2 inhibitor also comprises valdecoxib among the present invention; referring to " 4-[5-methyl-3-phenyl-isoxazole azoles-1-yl] benzsulfamide; valdecoxib: A Potent and SelectiveInhibitor of COX-2 "; J.Med.Chem.2000; Vol.43:775-777; and parecoxib; sodium salt or parecoxib sodium; referring to N-[[(5-methyl-3-phenyl-isoxazole azoles-4 base)-phenyl] sulfonyl] the propionyl imines; sodium salt; parecoxib sodium: A Potent and Selective Inhibitorof COX-2for Parenteral Administration ", J.Med.Chem.2000, Vol.43:1661-1663.The implication of cox 2 inhibitor also comprises the replacement as the suitable metathetical sulfonamide part of mesyl part among the present invention.Referring to, people such as J.Carter, Synthesisand activity of sulfonamide-substituted4,5-diaryl thiazoles asselective cyclooxygenase-2inhibitors. " Bioorg.Med.Chem.Lett Apr.19; 1999:Vol.9 (8): 1171-74; and article " Design and synthesis ofsulfonyl-substituted4,5-two arylthiazoles as selective cyclooxygenase-2inhibitors "; Bioorg.Med.Chem.Lett Apr.19,1999:Vol.9 (8): the chemical compound of quoting among the 1167-70.Implication of the present invention comprises cox 2 inhibitor, the people's such as NS398:Attiga that in two pieces of literary compositions, quote " Inhibitors of Prostaglandin Synthesis InhibitHuman Prostate Tumor Cell Invasiveness and Reduce the Release ofMatrix Metalloproteinases ", 60Cancer Research4629-4637, Aug.15,2000 and " The cyclooxygenase-2inhibitor celecoxib induces apoptosisbyblockingAktactivationinhumanprostatecancercel lsindependently of Bc1-2; " people such as Hsu, 275 (15) J.Biol.Chem.11397-11403 (2000).The implication of cox 2 inhibitor comprises and quotes people such as Mitchell " Cyclo-oxygenase-2:pharmacology; physiology; biochemistryandrelevancetoNSAIDtherapy " among the present invention, ring-oxygenase-2 alternative cpd among Brit.J.ofPharmacology (1999) vol.128:1121-1132 is especially referring to the 1126th page.The implication of cox 2 inhibitor comprises so-called NO-NSAIDs or nitric oxide-release-NSAIDs among the present invention, people such as L.Jackson " COX-2Selective Nonsteroidal Anti-Inflammatory Drugs:Do TheyReally Offer Any Advantages? " Drugs, June, 2000 vol.59 (6): mention among the 1207-1216 and in the article of footnote 27 and 28.Also be included in any material that comprises in the implication of cox 2 inhibitor of the present invention, it is with greater than 10 to 1 ratio and preferably optionally suppress COX-2 isozyme (with respect to the COX-1 isozyme) with at least 40 to 1 ratio, mention among the WO99/20110 as Winokur, and has a substituent group that is positioned on the cyclic ring, theoretical according to traditional quantivalence-shell-electronics-right-repulsion, it has two atoms that the contain free electron sulfylamine of celecoxib (as be arranged in), its second substituent group is positioned at sufficiently away from this first substituent different ring, do not have significant electron interaction with first substituent group.Second substituent group should have electronegativity in greater than such substituent group of 0.5, perhaps second substituent group should be the atom that is positioned on the periphery of chemical compound, and it is selected from halogen F, Cl, Br or I, or VI family element S or O.Therefore, with regard to this meaning that comprises at last, the part of cox 2 inhibitor should be hydrophilic and other parts are lipophilic with regard to cox 2 inhibitor.What also comprise as cox 2 inhibitor is at Pharmacotherapy:A Pathophysiologic Approach, and the 553rd page of chemical compound of listing of people such as Depiro (McGraw Hill1999) comprises nabumetone and etodolac.Admit that exist overlappingly in the selective COX-2-inhibitor 2 that proposes, the purpose of term cox 2 inhibitor is to comprise institute's cox 2 inhibitor selectively all sidedly, is optionally on the meaning that suppresses COX-2 (with respect to COX-1) in this section.The inventor adds the medicine that name is called etoricoxib to being applicable to such cox 2 inhibitor of the present invention, and it is at Wall Street Journal, and Dec.13 quotes in 2000, is produced by Merck.Also referring to, people's such as Chauret " In vitro metabolism considerations; including activitytesting of metabolites; in the discovery and selection of the COX-2inhibitor etoricoxib (MK-0663); " Bioorg.Med.Chem.Lett.11 (8): 1059-62 (Apr.23,2001).Another kind optionally cox 2 inhibitor is DFU[5,5-dimethyl-3-(3-fluoro phenyl)-4-(4-methyl sulphonyl) phenyl-2 (5H)-furanone], quote in people's such as Yergey Drug Metab.Dispos.29 (5): 638-44 (May2001).The inventor also comprises flavone compound antioxidant silymarin with cox 2 inhibitor optionally, and the active component in the silymarin, silybinin, and its proof suppresses to have significant COX-2 inhibitory action with respect to COX-1.Silymarin also shows the protection to glutathion peroxidase depletion.People's such as Zhao " Significant Inhibition by the FlavonoidAntioxidantSilymarinagainst12-O-tetracecanoylph orbol13-acetate-causedmodulationofantioxidantandinflamma toryenzymes; and cyclooxygenase2and interleukin-1alpha expression inSENCAR mouse epidermis:implications in the prevention of stage Itumorpromotion; " Mol.Carcinog.December1999, Vol26 (4): 321-33PMID10569809.Be used for the treatment of hepatopathy at European silymarin.

A large amount of above cox 2 inhibitors of identifying are prodrugs of selective COX-2-inhibitor 2, bring into play its effect by changing into activity and selective COX-2-inhibitor 2 in vivo.The activity that forms by the cox 2 inhibitor prodrug of above evaluation and optionally cox 2 inhibitor be described in detail in disclosed WO95/00501 on January 5 nineteen ninety-five, the U.S. Patent number 5 of July 13 nineteen ninety-five disclosed WO95/18799 and the announcement on the 12nd of nineteen ninety-five December, in 474,995.Known U.S. Patent number 5,543,297 (name be called: " Human cyclooxygenase-2cDNAand assays for evaluating cyclooxygenase-2activity; ") instruction, those of ordinary skills can determine that whether a kind of medicament is the precursor of cox 2 inhibitor or cox 2 inhibitor optionally, be parts of the present invention therefore.

" directly thrombin inhibitor "

Directly the limiting examples of thrombin inhibitor comprises hirudin, hirugen, bivalirudin, argatroban, PPACK and thrombin aptamers.

Diuretic

The limiting examples that can be used for the diuretic in the present composition comprises althiazide, bendroflumethiazide, benzthiazide, butizide, chlortalidone, cyclopenthiazide, cyclothiazide, epitizide, ethiazide, fenquizone, indapamide, hydroflumethiazide, methyclothiazide, meticrane, metolazone, paraflutizide, polythiazide, quinethazone, teclothiazide, trichlormethiazide, chlormerodrin, meralluride, mercurophylline, Diucardyn sodium (Ayerst), mercumatilin sodium, calomel, mersalyl, vinegar tea alkali, 7-morpholino methyl-theophylline, pamabrom, protheobromine, theobromine, canrenone, oleandrine, spironolactone, acetazolamide, ambuside, azosemide, bumetanide, butazolamide, clopamide, the clorexolone, disulfamide, ethoxzolamide, furosemide, mefruside, methazolamide, piretanide, torsemide, tripamide, xipamide, aminometradine, amisometradine, amanozine, amiloride, Arbutin, chlorazanil, etacrynic acid, etozolin, hydracarbazine, isosorbide, mannitol, metochalcone, muzolimine, perhexiline, ticrynafen, triamterene, urea and composition thereof.Diuretic according to using can also give potassium so that the fluid balance optimization is avoided hypokalemia alkalosis simultaneously to the patient.Using of potassium can be form or food such as the Fructus Musae or the orange juice by absorbing high potassium content every day of potassium chloride.

Endothelin receptor antagonists

The limiting examples that can be used for the endothelin receptor antagonists in the present composition comprise bosentan, sulfonamide endothelin antagonist, BQ-123, SQ28608 etc., and composition thereof.

HMG-CoA reductase inhibitor (Statins (Statins))

HMG-CoA (3-hydroxy-3-methyl glutaryl-coenzyme A) reductase is the microsomal enzyme of the rate-limiting reaction (HMG-CoA6 mevalonic acid) in a kind of catalysis cholesterol biosynthetic process.The HMG-CoA reductase inhibitor suppresses the HMG-CoA reductase, and therefore suppresses the synthetic of cholesterol.Many HMG-CoA reductase inhibitors have been used to treat the individuality of hypercholesterolemia.Recently, show the HMG-CoA reductase inhibitor in the treatment apoplexy be useful (Endres M, etc., Proc Natl Acad Sci U S A, 1998,95:8880-5).

The HMG-CoA reductase inhibitor that can be used for together using with medicine of the present invention includes but not limited to simvastatin (U.S. Patent number 4,444,784), lovastatin (U.S. Patent number 4,231,938), pravastatin sodium (U.S. Patent number 4,346,227), Fluvastatin (U.S. Patent number 4,739,073), atorvastatin (U.S. Patent number 5,273,995), cerivastatin and U.S. Patent number 5,622,985,5,135,935,5,356,896,4,920,109,5,286,895,5,262,435,5,260,332,5,317,031,5,283,256,5,256,689,5,182,298,5,369,125,5,302,604,5,166,171,5,202,327,5,276,021,5,196,440,5,091,386,5,091,378,4,904,646,5,385,932,5,250,435,5,132,312,5,130,306,5,116,870,5,112,857,5,102,911,5,098,931,5,081,136,5,025,000,5,021,453,5,017,716,5,001,144,5,001,128,4,997,837,4,996,234,4,994,494,4,992,429,4,970,231,4,968,693,4,963,538,4,957,940,4,950,675,4,946,864,4,946,860,4,940,800,4,940,727,4,939,143,4,929,620,4,923,861,4,906,657,4,906,624 and 4,897, a large amount of other materials described in 402, the content of above-mentioned patent disclosure is hereby incorporated by.

Other limiting examples that can be used for the HMG-CoA reductase inhibitor in the present composition comprises mevastatin, Pitavastatin, rosuvastatin, gemcabene and probucol.

Inotropic agent

The limiting examples that can be used for the inotropic agent in the present composition comprises vinegar tea alkali, acetyldigitoxin, 2-amino-4-picoline, amrinone, the hemisuccinic acid benfurodil, bucladesine, Camphotamide, convallatoxin, alvonal, denopamine, deslanoside, lanatoside, Folium Digitalis Purpureae, Digitoxin, digoxin, dobutamine, docarpamine, dopamine, dopexamine, enoximone, erythrophleine, fenalcomine (fenalsomine), gitalin, bigitalin, glycocyamine, Heptaminol, hydrastine (hydrastinine), ibopamine, the lanatoside class, loprinone, milrinone, cerberoside, oleandrine, strophanthin, oxyfedrine, pimobendan, prenalterol, Proscillaridin, Resibufogenin, Scillaren, scillarenin, strophanthin K, sulmazole, theobromine, vesnarinone, xamoterol, and composition thereof.

" renin inhibitor "

Renin inhibitor is the chemical compound that disturbs renin activity.Renin inhibitor comprises aminoacid and derivant thereof, peptide and derivant thereof, and the antibody of feritin.For the example of the renin inhibitor of United States Patent (USP) theme as follows: the urea derivative of peptide (U.S. Patent number 5,116,835); By the continuous aminoacid (U.S. Patent number 5,114,937) of non-peptide bond; Dipeptides and tripeptide derivative (U.S. Patent number 5,106,835); Aminoacid and derivant thereof (U.S. Patent number 5,104,869 and 5,095,119); Glycol sulfonamides and sulfenyl class (U.S. Patent number 5,098,924); The peptide of modifying (U.S. Patent number 5,095,006); Peptidyl β-aminoacyl aminodiol carbamate (U.S. Patent number 5,089,471); Pyrrolo-imidazolone (pyrolimidazolones) (U.S. Patent number 5,075,451); The peptide (U.S. Patent number 5,066,643) of fluorine-containing and chlorine Shi Deding (statine) or statone; Peptidyl aminodiol (U.S. Patent number 5,063,208 and 4,845,079); N-morpholino derivant (U.S. Patent number 5,055,466); Gastric inhibitory polypeptide derivant (U.S. Patent number 4,980,283); N-heterocyclic alcohol (U.S. Patent number 4,885,292); The monoclonal antibody of feritin (U.S. Patent number 4,780,401); With multiple other peptide and analog thereof (U.S. Patent number 5,071,837,5,064,965,5,063,207,5,036,054,5,036,053,5,034,512, and 4,894,437).

Vasodilation

The vasodilation limiting examples that can be used in the present composition comprises bencyclane, cinnarizine, citicoline, cyclandelate, ciclonicate, DIEDI, vinpocetine, fasudil, fenoxedil, flunarizine, ibudilast, ifenprodil, sorbide nitrate, isosorbide mononitrate, lomerizine, nafronyl, Nicopile, nicergoline, nimodipine, papaverine, pentifylline, tinofedrine, vancamine, vinpocetine, viquidil, Win-5494, bendazol, the hemisuccinic acid benfurodil, benziodarone, chlorazisin, carbocromene, clobenfurol, clonitrate, cloricromen, dilazep, dipyridamole, droprenilamine, efloxate, Eritrityl Tetranitrate, etafenone, fendiline, floredil, ganglefene, the cardiac muscle extract, hexestrol bis (α-diethyl amino ethyl group ether), hexobendine, the hydralazine compounds, itramine tosilate (itramin tosylate) khellin, lidoflazine, mannitol hexanitrate, medibazine, nitroglycerin, isosorbide mononitrate, sorbide nitrate and other nitrate esters, four pentaerythritol tetranitrates, pentrinitrol, perhexiline, pimefylline, prenylamine, etrynit, pyridofylline, trapidil, methylchromone, trimetazidine, thibetine, visnadine, aluminum nicotinate, bamethan, bencyclane, betahistine, Kallidin I, brovincamine; bufeniode; buflomedil; butalamine; cetiedil; ciclonicate; cinepazide; cinnarizine; cyclandelate; DIEDI; eledoisin; fenoxedil; flunarizine (flunazine); hepronicate; ifenprodil; iloprost; inositol niacinate; cardilan; kallidin; kallikrein; thymoxamine; nafronyl; nicametate nicergoline; nicofuranose; nicotinyl alcohol; arlidin; pentifylline; pentoxifylline; piribedil; PGE1; suloctidil; tolazoline; xantinol nicotinate and composition thereof.

Notice that " hydralazine compounds " is meant the chemical compound of following formula:

Wherein a, b and c independently are singly-bound or two key separately; R ₁And R ₂Independently be hydrogen, alkyl, ester or heterocycle separately; R ₃And R ₄Independently be lone pair electrons or hydrogen separately, condition is R ₁, R ₂, R ₃And R ₄In at least one is not a hydrogen.The example of hydralazine compounds includes but not limited to budralazine, cadralazine, dihydralazine, endralazine, hydralazine, pildralazine, todralazine etc.

Vasopressor

The limiting examples that can be used for the vasopressor in the present composition comprise methylsulfuric acid amezinium, angiotensinamide, dimetofrine, dopamine, etifelmine, etilefrine, gepefrine, metaradrine, methoxamedrine, midodrine, norepinephrine, pholedrine, synephrine, and composition thereof.

The crosslinked clastogen of AGE (the crosslinked clastogen of advanced glycosylation end product)

The limiting examples that can be used for the crosslinked clastogen of AGE in the present composition comprises Alagebrium.

AGE forms inhibitor (advanced glycosylation end product formation inhibitor)

The limiting examples that can be used for the AGE formation inhibitor in the present composition comprises pimagedine.

Other activating agent:

The limiting examples of other active component that can share with these nebivolol compositionss includes, but are not limited to the chemical compound of following representative category, with and pharmaceutically acceptable salt, isomer, ester, ether and other derivant:

Analgesic and antibiotic medicine are as aloxiprin, auranofin, azapropazone, benorylate, capsaicin, celecoxib, diclofenac, diflunisal, etodolac, fenbufen, Fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, leflunomide, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, crovaril, Phenylbutazone, piroxicam, rofecoxib, sulindac, tetrahydrocannabinol, tramadol and trometamol;

Anthelmintic is as albendazole, bephenium hydroxynaphthoate, cambendazole, dichlorophen, ivermectin, mebendazole, oxamniquine, oxfendazole, oxantel, praziquantel, Pyrantel Pamoate and thiabendazole;

Antasthmatic is as Zileuton, zafirlukast, terbutaline sulphate, montelukast and albuterol;

Antimicrobial drug is as Alatrofloxacin., azithromycin, baclofen, benzathine benzylpenicillin, cinoxacin, ciprofloxacin, clarithromycin, clofazimine, cloxacillin, demeclocycline, dirithromycin, doxycycline, erythromycin, ethionamide, furazolidone, grepafloxacin, imipenum, levofloxacin, lorefloxacin, moxifloxacin hydrochloride, nalidixan, nitrofurantoin, norfloxacin, ofloxacin, rifampicin, rifabutin, rifapentine, Sparfloxacin, spiramycin, sulfbenzamide, sulfadoxine, sulfamerazine, ulphacetamide, sulfadiazine, sulfafurazole, sulfamethoxazole, sulfapyridine, tetracycline, trimethoprim, trovafloxacin and vancomycin;

Antiviral agents is as Abacavir, amprenavir, Delavirdine, efavirenz, indinavir, lamivudine, nelfinavir, nevirapine, ritonavir, Saquinavir and stavudine;

Antidepressants are as amoxapine, BUP, citalopram, clomipramine, fluoxetine Hydrochloride, aueural, mianserin hydrochloride, psychostyl, paroxetine hydrochloride, sertraline hydrochloride, trazodone hydrochloride, trimipramine maleate and VENLAFAXINE HCL;

Anti-epileptics is as beclamide, carbamazepine, clonazepam, ethotoin, felbamate, fosphenytoin sodium, lamotrigine, mephenytoin, mesuximide, enphenemal, oxcarbazepine, paramethadione, phenacal, phenobarbital, phenytoin, phensuximide, primidone, sultiame, hydrochloric acid tiagabine, topiramate, valproic acid and vigabatrin;

Antifungal is as amphotericin, butenafine hydrochloride, Nitric acid butoconazole, clotrimazole, econazole nitrate, fluconazol, flucytosine, griseofulvin, itraconazole, ketoconazole, miconazole, natamycin, nystatin, Sulconazole Nitrate, oxiconazole, terbinafine HCl (erbinafine HCI), terconazole (triaconazole), tioconazole and undecylenic acid;

Antigout drug is as allopurinol, probenecid and sulfinpyrazone;

Antimalarial is as amodiaquine, chloroquine, Lapudrine (ICI)., hydrochloric acid Halofantrine, Mefloquine Hydrochloride, chloroguanide hydrochloride, pyrimethamine and quinine sulfate;

Antimigraine is as agit, gynergen, frovatriptan, desernil, naratriptan hydrochloride, Pizotifen Maleate, rizatriptan benzoate, Sumatriptan Succinate and Zomitriptan;

Muscarine antagonist is as atropine, benzhexol hydrochloride, biperiden, ethopropazine hydrochloride, Daturine, mepenzolate bromide, oxyphencyclimine hydrochloride and tropicamide;

Antineoplastic agent and immunosuppressant are as aminoglutethimide, amsacrine, azathioprine, bicalutamide, bisantrene, busulfan, camptothecine, capecitabine, chlorambucil, cyclosporin, dacarbazine, Ellipticine, estramustine, etoposide, irinotecan, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitoxantrone, mofetil Mycophenolate Mofetil (mofetil mycophenolate), nilutamide, paclitaxel, procarbazine hydrochloride, sirolimus, tacrolimus, Tamoxifen Citrate, teniposide, testolactone, hydrochloric acid hycamtin and Toremifene Citrate;

Antiprotozoal is as atovaquone, benznidazole, clioquinol, decoquinate, diiodohydroxyquinoline (Iodoquinol), diloxanide furoate, dinitolmide, furazolidone, metronidazole, nimorazole, nitrofural, ornidazole and tinidazole;

Psychosis is as Aripiprazole, clozapine, Ziprasidone, haloperidol fourth, molindone, loxapine, thioridazine, molindone, tiotixene, pimozide, fluphenazine, risperidone, mesoridazine, Quetiapine, trifluoperazine, chlorprothixene, chlorpromazine, perphenazine, triflupromazine, olanzapine;

Antithyroid drug is as carbimazole, paricalcitol 19-Nor-1,25-dihydroxyvitamin D2 and propylthiouracil;

Cough medicine is as benzonatate;

Antianxiety drug, tranquilizer, sleeping pill and neuroleptic are as alprazolam, amobarbital, barbital, bentazepam, bromazepam, bromperidol, brotizolam, butobarbital, carbromal, chlorine nitrogen , clomethiazole, chlorpromazine, chlorprothixene, clonazepam, clobazam, clotiazepam, clozapine, diazepam, droperidol, ethinamate, fluanisone, flunitrazepam, triflupromazine, Flupentixol Decanoate, fluphenthixol decanoate, flurazepam, gabapentin, haloperidol, lorazepam, lormetazepam, medazepam, meprobamate, mesoridazine, methaqualone, methylphenidate, midazolam, molindone, nitrazepam, olanzapine, oxazepam, pentobarbital, perphenazine, pimozide, prochlorperazine, pseudoephedrine, Quetiapine, risperidone, Sertindole, sulpiride, temazepam, thioridazine, triazolam, zolpidem and zopiclone;

17-hydroxy-11-dehydrocorticosterone is as beclometasone, betamethasone, budesonide, cortisone acetate, desoximetasone, dexamethasone, fludrocortisone acetate, flunisolide, fluocortolone, fluticasone propionate, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone;

Antiparkinsonian drug is as apomorphine, bromocriptine methanesulfonate, lisuride maleate, pramipexole, SKF-101468A and tolcapone;

Gastrointestinal drug is as nigalax (bisacodyl), cimetidine, cisapride, diphenoxylate hydrochloride, domperidone, famotidine, lansoprazole, loperamide, mesalazine, nizatidine, omeprazole, Zofran, RABEPRAZOLE SODIUM, ranitidine hydrochloride and sulfasalazine;

Keratolytic agent is as Acitretin, calcipotriene, calcifediol, calcitriol, vitamin D3, ergocalciferol, etretinate, retinoid, targretin and tazarotene;

Lipid regulating agent is as atorvastatin, bezafibrate, cerivastatin, ciprofibrate, clofibrate, fenofibrate, fluvastatin, gemfibrozil, pravastatin, probucol and simvastatin;

Muscle relaxant is as dantrolene sodium and tizanidine hydrochloride;

Nutrient is as calcitriol, carotene, dihydrotachysterol, essential fatty acid, non-essential fatty acid, dihydrovitamin K1, vitamin A, vitamin B2, vitamin D, vitamin E and vitamin K;

Opium kind analgesics is as codeine, dextropropoxyphene, diamorphine, dihydrocodeine, fentanyl, meptazinol, methadone, morphine, nalbuphine and pentazocine;

Sex hormones is as clomifene citrate, Cortisone, danazol, dehydroepiandrosterone, ethinylestradiol, finasteride, fludrocortisone, fluoxymesterone, medroxyprogesterone acetate, megestrol acetate, mestranol, methyltestosterone, norethindrone, norgestrel, estradiol, conjugated estrogen hormone, progesterone, rimexolone, stanozolol, diethylstilbestrol, testosterone and tibolone;

Beta stimulant is as amfetamine, dextro-amphetamine, dexfenfluramine, fenfluramine and Mazindol;

The medicine that is used for rheumatoid arthritis is as methotrexate, auranofin, aurothioglucose and sodium aurothiomalate;

Be used for osteoporotic medicine, as alendronate and raloxifene;

Local anesthetic;

Antiherpetic is as aciclovir, valaciclovir and famciclovir;

Bendectin is as ondansetron and granisetron;

The flavone compound and isoflavonoid, proanthocyanidins, flavan-3-alcohol class, flavonols, flavonoid, flavanone, isoflavan ketone, its salt and the esters that comprise anthocyan and anthocyanidin glycoside.Yet this exploitation is not limited to isolating flavone compound from part of Radix Astragali (AstragalusMembranaceus) plant, plant or extract, but comprises and separating from difference source or any suitable flavone compound of chemosynthesis.In addition, any suitable flavone compound and isoflavonoid thereof known or that find not yet are within the scope of the present invention.A large amount of flavone compounds and isoflavonoid thereof are described in USDA-Iowa State University Database on the IsoflavoneContent of Foods, Release1.3-2002, and USDA Database for theFlavonoid Content of Selected Foods-2003 (http://www.n al.usda.gov/fnic/foodcomp/Data/isoflav/isoflav.html) and (http://www.nal.usda.gov/fnic/foodcomp/Data/Flav/flav.html) (both are hereby incorporated by in the lump).How to be used for flavone compound and/or isoflavonoid that the present invention develops purpose be tangible for the technical staff in selection.For example, the flavone compound that is used for this exploitation purpose can be, but be not limited to (-)-epicatechin (epictechin), (+)-catechin, procyanidin B2, Quercetin dehydrate, taxifolin, resveratrol etc.

Carotenoid, it normally derives from the tetraterpenes of mevalonic acid and phosphoric acid deoxy-D-xylulose sugar approach (older source is meant its source as " isoprenoid " approach sometimes).Two molecule condensations of the busy cattle busy cattle base bisphosphate of base of C20 chemical compound (GGDP) form symmetric carotenoid skeleton.

Carotenoid is divided into two subclass, promptly is called the more polar compound of phylloxanthin class or oxygen carotenoid, and nonpolar hydrocarbon carotene.

Similar thing of term such as carotenoid and carotenoid derivatives typically refer to derived from the chemical compound or the compositions of naturally occurring carotenoid or are meant synthetic carotenoid simply in some embodiments.In some embodiments, similar thing of term such as carotenoid and carotenoid derivatives can typically refer to chemical compound or compositions chemically, and it is synthetic deutero-by the parent compound based on non-carotenoid; Yet, the deutero-analog of its finally similar in fact carotenoid.In certain embodiments, term can refer to the synthesis of derivatives of naturally occurring carotenoid as similar thing of carotenoid and carotenoid derivatives.The example of carotenoid is provided at book " carotenoid handbook (CarotenoidsHandbook) ", and people such as G.Britton edit, and 2004, it was hereby incorporated by.

To be fit to carotenoid compounds be tangible for the technical staff according to how selecting the present invention to develop purpose.

The example of carotenoid comprises astaxanthin, cryptoxanthin, phylloxanthin, lycopene, beta-carotene.

Other non-limiting instance of naturally occurring carotenoid comprises Aaptopurpurin, actinerythrin (Actinioerythrin), Actinioerythrol, Flos Inulae red pigment (adonirubin), ADX (Adonixanthin), A.g.470, A.g.471, Agelaxanthin C, net spore cup fungi flavin (Aleuriaxanthin), different flavin (Alloxanthin), Amarouciaxanthin A, Amarouciaxanthin B, cryptoxanthin (Anchovyxanthin), 3 ', 4 '-diatoxanthin anhydrates, the deoxidation flexixanthin anhydrates, the Eschscholtzia californica carotenoid, phylloxanthin anhydrates, peridinin anhydrates, rhodovibrin anhydrates, saproxanthin anhydrates, warmingol anhydrates, warmingone anhydrates, antheraxanthin, aphanicin, Aphanicol, aphanin, Aphanol, aphanizophyll, 8 '-apo--β-Radix Dauci Sativae-8 '-aldehyde, 10 '-apo--β-Radix Dauci Sativae-10 '-aldehyde, 12 '-apo--β-Radix Dauci Sativae-12 ' aldehyde, 14 '-apo--β-Radix Dauci Sativae-14 '-aldehyde, 6 '-apo--Ψ-Radix Dauci Sativae-6 '-aldehyde, 8 '-apo--Ψ-Radix Dauci Sativae-8 '-aldehyde, β-apo--2-Radix Dauci Sativae aldehyde (carotenal), β-apo--3-Radix Dauci Sativae aldehyde, β-apo--4-Radix Dauci Sativae aldehyde, β-apo--2 '-Radix Dauci Sativae aldehyde, β-apo--8 '-Radix Dauci Sativae aldehyde, β-apo--10 '-Radix Dauci Sativae aldehyde, β-apo--12 '-Radix Dauci Sativae aldehyde, β-apo--14 '-Radix Dauci Sativae aldehyde, apo--8,8 '-the Radix Dauci Sativae dialdehyde, 8 '-apo--beta-carotene-3,8 '-glycol, 4 '-apo--β-Radix Dauci Sativae-4 '-acid (oic acid), 8 '-apo--β-Radix Dauci Sativae-8 '-acid, 10 '-apo--β-Radix Dauci Sativae-10 '-acid, 12 '-apo--beta-carotene-12 '-acid, β-apo--2 '-daucic acid (carotenoic acid), β-apo--2 '-the daucic acid methyl ester, β-apo--8 '-daucic acid, β-apo--10 '-daucic acid, β-apo--12 '-daucic acid, 8 '-apo--β-Radix Dauci Sativae-3-alcohol, β-apo--2 '-carotenol, apo--7-fucoxanthol (fucoxanthinol), apo--2-Fructus Lycopersici esculenti olefine aldehydr (lycopenal), apo--3-lycopene, apo--6 '-lycopene, apo--8 '-lycopene, apo--10 '-the yellow aldehyde (violaxanthal) of violet, apo--12 '-the yellow aldehyde of violet, the yellow aldehyde of apo-violet, apo--2-cryptoxanthin aldehyde (zeaxanthinal), apo--3-cryptoxanthin aldehyde, apo--4-cryptoxanthin aldehyde, 3,4,3',4'-tetraketo-.beta.-carotene (Astacein), 3,4,3',4'-tetraketo-.beta.-carotene, the 3,4,3',4'-tetraketo-.beta.-carotene dipalmitate, astaxanthin, asterinic acid, Asteroidenone, asymmetric sigma carotene, aurochrome, auroxanthin, azafrin, azafrin aldehyde (Azafrinaldehyde);

The antibacterial phytoene, bacterioruberin α, bacterioruberin β, bacteriopurpurin α, antibacterial rubine element, α-Xi Junyuhongsu, the plain disaccharidase glycosides of antibacterial rubine, the plain monoglycosides of antibacterial rubine, the α-Xi Junyuhongsu monomethyl ether, two dehydration antibacterial rubine elements, 3,4,3 ', 4 '-two dehydrogenations-beta-carotene, two dehydrogenation lycopenes, 2,2 '-two (4-hydroxy-3-methyl-crotyl)-β, beta-carotene, 2,2 '-two [3-(glucityl oxygen base)-3-methyl butyl]-3,4,3 ', 4 '-four dehydrogenations-1,2,1 ', 2 '-tetrahydrochysene-Ψ, Ψ-carotene-1,1 '-glycol, 2,2 '-two [4-(β, D-glycopyranosyl oxygen base)-3-methyl-2-butene base]-γ, gamma carotene, 2,2 '-two (4-hydroxy-3-methyl-crotyl)-γ, gamma carotene, 2,2 '-two (4-hydroxy-3-methyl-crotyl)-[ε], [ε]-carotene, 2,2 '-two (3-hydroxy-3-methyl butyl-3,4,3 ', 4 '-four dehydrogenations-1,2,1 ', 2 ' tetrahydrochysene-Ψ, Ψ-carotene-1,1 '-glycol, 2,2 '-two (3-methyl-2-butene base)-[ε], [ε]-carotene, 2,2 '-two (3-methyl-2-butene base-3,4,3 ', 4 '-four dehydrogenations-1,2-dihydro-Ψ, Ψ-Radix Dauci Sativae-1-alcohol, 2,2 '-two (3-methyl-2-butene bases)-3,4,3 ', 4 '-four dehydrogenations-1,2,1 ', 2 '-tetrahydrochysene-Ψ, Ψ-carotene-1,1 '-glycol, 2,2 '-two (3-methyl-2-butene bases)-1,2,1 ', 2 '-tetrahydrochysene-Ψ, Ψ-carotene-1,1 '-glycol, 2,2 '-two (O-methyl-5-C-methylpent glycosyl oxygen base)-3,4,3 ', 4 '-four dehydrogenations-1,2,1 ', 2 '-tetrahydrochysene-Ψ, Ψ-carotene-1,1 '-glycol, 3,3 '-two (rhamanopyranosyl oxygen base)-β, beta-carotene, 2,2 '-two (rhamanopyranosyl oxygen bases)-3,4,3 ', 4 '-four dehydrogenations-1,2,1 ', 2 '-tetrahydrochysene-Ψ, Ψ-carotene-1,1 '-glycol, bixin;

Echinenone, Echininone, eloxanthin, 6-Epikarpoxanthin, 3 '-Biao phylloxanthin (Epilutein), 5,6-epoxy-alpha-carotene, 5,8-epoxy-alpha-carotene, 5,8-epoxy-beta-carotene, 1,2-epoxy-1,2,7,8,11,12,7 ', 8 ', 11 ', 12 '-decahydro-Ψ, Ψ-carotene, 5,6-epoxy-7 ', 8 '-two dehydrogenations-5,6-dihydro-β, beta-carotene-3,3 '-glycol, 5,8-epoxy-7 ', 8 '-two dehydrogenations-5,8-dihydro-β, beta-carotene-3,3 '-glycol, 1 ', 2 '-epoxy-3 ', 4 '-two dehydrogenations-1,2 '-dihydro-β, Ψ-carotene-2-alcohol, 5 ', 6 '-epoxy-6,7-two dehydrogenations-5,6,5 ', 6 '-tetrahydrochysene-β, beta-carotene-3,5,19 (or 19 '), 3 '-tetrol, 5 ', 6 '-epoxy-6,7-two dehydrogenations-5,6,5 ', 6 '-tetrahydrochysene-β, beta-carotene-3,5,3 '-triol, 5 ', 6 '-epoxy-6,7-two dehydrogenations-5,6,5,6 '-tetrahydrochysene-β, beta-carotene-3,5,3 '-triol 3-acetate, 5 ', 8 '-epoxy-6,7-two dehydrogenations-5,6,5 ', 8 '-tetrahydrochysene-β, beta-carotene-3,5,3 '-triol, 5,6-epoxy-5,6-dihydro-12 '-apo--beta-carotene-3,12 '-glycol, 5,8-epoxy-5,8-dihydro-10 '-apo--beta-carotene-3,10 '-glycol, 5,8-epoxy-5,8-dihydro-12 '-apo--beta-carotene-3,12 '-glycol, 5,6-epoxy-5,6-dihydro-β, beta-carotene, 5,8-epoxy-5,8-dihydro-β, beta-carotene, 5,6-epoxy-5,6-dihydro-β, [ε]-E carotene, 5,8-epoxy-5,8-dihydro-β, [ε]-carotene, 1 ', 2 '-epoxy-1 ', 2 '-dihydro-β, Ψ-carotene, 1 ', 2 '-epoxy-1 ', 2 '-dihydro-[ε], Ψ-carotene, 1,2-epoxy-1,2-dihydro-Ψ, Ψ-carotene, 5,6-epoxy-5,6-dihydro-Ψ, Ψ-carotene, 5,6-epoxy-5,6-dihydro-β, beta-carotene-3,3 '-glycol, 5,8-epoxy-5,8-dihydro-β, beta-carotene-3,3 '-glycol, 5,6-epoxy-5,6-dihydro-β, [ε]-carotene-3,3 '-glycol, 5,6-epoxy-5,6-dihydro-β, [ε]-carotene-3,3 '-the glycol dipalmitate, 5,8-epoxy-5,8-dihydro-β, [ε]-carotene-3,3 '-glycol, 5,6-epoxy-5,6-dihydro-β, [ε]-carotene-3,3 ', 6 '-triol, 5,8-epoxy-5,8-dihydro-β, [ε]-carotene-3,3 ', 6 '-triol, 5,6-epoxy-5,6-dihydro-β, β-Radix Dauci Sativae-2-alcohol, 5,6-epoxy-5,6-dihydro-β, β-Radix Dauci Sativae-3-alcohol, 5 ', 8 '-epoxy-5 ', 8 '-dihydro-β, β-Radix Dauci Sativae-3-alcohol, 5,6-epoxy-5,6-dihydro-β, [ε]-Radix Dauci Sativae-2-alcohol, 5,6-epoxy-5,6-dihydro-β, Ψ-Radix Dauci Sativae-3-alcohol, 5,8-epoxy-5,8-dihydro-β, Ψ-Radix Dauci Sativae-3-alcohol, 5,8-epoxy-3,3 '-dihydroxy-alpha-carotene, 5,6-epoxy-3,3 '-dihydroxy-7 ', 8 ' two dehydrogenations-5,6,7,8-tetrahydrochysene-β, β-Radix Dauci Sativae-8-ketone, 5 ', 6 '-epoxy-3,3 '-dihydroxy-7,8-two dehydrogenations-5 ', 6 '-dihydro-10,11,20-three nor--β, beta-carotene-19 ', 11 '-lactone, 5 ', 6 '-epoxy-3,3 '-dihydroxy-4,7-two dehydrogenations-5 ', 6 '-dihydro-10,11,20-three nor--β, beta-carotene-19 ', 11 '-lactone 3-acetate, 5 ', 6 '-epoxy-3,3 '-dihydroxy-7,8-two dehydrogenations-5 ', 6 '-dihydro-10,11,20-three nor--β, beta-carotene-19 ', 11 '-lactone 3-acetate, 5,6-epoxy-3,3 '-dihydroxy-5,6-dihydro-β, X-Radix Dauci Sativae-6 '-ketone, 5,8-epoxy-3,3 '-dihydroxy-5,8-dihydro-β, X-Radix Dauci Sativae-6 '-ketone, 5,6-epoxy-3,3 '-dihydroxy-5,6,7 ', 8 '-tetrahydrochysene-β, [ε]-carotene-11 ', 19 '-lactone, 1 ', 2 '-epoxy-2 '-(2,3-epoxy-3-methyl butyl)-2-(3-hydroxy-3-methyl butyl)-3 ', 4 '-two dehydrogenations-1,2,1 ', 2 '-tetrahydrochysene-Ψ, Ψ-Radix Dauci Sativae-1-alcohol, 1,2-epoxy-1,2,7,8,7 ', 8 '-six hydrogen-Ψ, Ψ-carotene, 5,6-epoxy-3-hydroxyl-8 '-apo--β-Radix Dauci Sativae-8 '-aldehyde, 5,6-epoxy-5,6-dihydro-10 '-apo--beta-carotene-3,10 '-glycol, 5,8-epoxy-3-hydroxyl-gamma carotene, 5,8-epoxy-3-hydroxyl-5,8-dihydro-8 '-apo--β-Radix Dauci Sativae-8 '-aldehyde, 5,6-epoxy-3-hydroxyl-5,6-dihydro-10 '-apo--β-Radix Dauci Sativae-10 '-aldehyde 502,5,6-epoxy-3-hydroxyl-5,6-dihydro-12 '-apo--β-Radix Dauci Sativae-12 '-aldehyde, 5,6-epoxy-3-hydroxyl-5,6,7 ', 8 '-tetrahydrochysene-7 '-apo--β-Radix Dauci Sativae-8 '-ketone, 5,8-epoxy phylloxanthin, 1,2-epoxy-1,2,7,8,11,12,7 ', 8 ' octahydro-Ψ, Ψ-carotene, 1,2-epoxy-1,2,7,8,7 ', 8 ', 11 ', 12 ' octahydro-Ψ, Ψ-carotene, 1 ', 2 '-epoxy-7,8,11,12,1 ', 2 ', 7 ', 8 '-octahydro-β, Ψ-Radix Dauci Sativae-2-alcohol, 1,2-epoxy phytoene, 5,8-epoxy Rubixanthin, 5 ', 8 '-epoxy-5,6,5 ', 8 '-tetrahydrochysene-β, beta-carotene-3,5,6,3 '-tetrol, 5 ', 6 '-epoxy-5,6,5 ', 6 '-tetrahydrochysene-β, beta-carotene-3,5,6,3 '-tetrol, 5,6-epoxy-3 ', 4 ', 7 ', 8 '-four dehydrogenations-5,6-dihydro-β, β-Radix Dauci Sativae-4-ketone, 5,6-epoxy-3 ', 3 ', 5 ', 19 '-four-hydroxyl-6 ', 7 '-two dehydrogenations-5,6,7.8,5 ', 6 '-six hydrogen-β, β-Radix Dauci Sativae-8-ketone 3-acetate 19 '-alkyl caproate, 5,6-epoxy-3,3 ', 5 '-trihydroxy-6 ', 7 '-two dehydrogenations-5,6,7,8,5 ', 6 '-six hydrogen-β, β-Radix Dauci Sativae-8-ketone, 5,6-epoxy-3,3 ' 5 '-trihydroxy-6 ', 7 '-two dehydrogenations-5,6,7,8,5 ', 6 '-six hydrogen-β, β-Radix Dauci Sativae-8-ketone 3 '-acetate, 5 ', 6 '-epoxy-3,5,3 '-trihydroxy-6,7-two dehydrogenations-5,6,5 ', 6 '-tetrahydrochysene-10,11,20-three nor--β, beta-carotene-19 ', 11 '-lactone, 5 ', 6 '-epoxy-3,5,3 '-trihydroxy-6,7-two dehydrogenations-5,6,5 ', 6 '-tetrahydrochysene-10,11,20-three nor--β, beta-carotene-19 ', 11 '-lactone 3-acetate, 4 ', 5 '-epoxy-3,6,3 '-trihydroxy-7,8,4 ', 5 ', 7 ', 8 '-six hydrogen-γ, [ε]-Radix Dauci Sativae-8-ketone, 5, the 6-antheraxanthin, 5, the 8-antheraxanthin, the Eschscholtzia californica phylloxanthin, Eschscholtzia californica ketone, 4 '-epoxy-β, β-Radix Dauci Sativae-4-ketone, 4 '-epoxy-4-ketone-beta-carotene, Euglenanone, euglenarhodone, Eutreptiellanone;

Flavacin, flavochrome, flavorhodin, flavaxanthin, flexixanthin, Foliachrome, Foliaxanthin;

A word used for translation is praised flavin (Gazaniaxanthin), β, D-gentiobiose base β, D-glucityl 8,8 '-two apo-carotene-8,8 '-two acid esters, gentiobiose base hydrogen-8,8 '-two acid esters, gentiobiose base neapolitanosyl8,8 '-two apo-carotene-8,8 '-two acid esters, β, D-glucityl hydrogen-4,4 '-two apo-carotene-4,4 '-two acid esters, 4 '-β, D-glucityl 4-hydrogen-7 ', 8 '-dihydro-4,4 '-two apo-carotene-4,4 '-two acid esters, β, D-glucityl hydrogen-8,8 '-two apo-carotene-8,8 '-two acid esters, β, D-glucityl methyl-8,8 '-two apo-carotene-8,8 '-two acid esters, glycopyranosyl oxygen base (referring to glucityl oxygen base), 4-glucityl oxygen base-4,4 ' two apo-neurosporenes, 1 '-glucityl oxygen base-3 ', 4 '-two dehydrogenations-1 ', 2 '-dihydro-β, Ψ-carotene, 1-glucityl oxygen base-3,4-two dehydrogenations-1,2-dihydro-Ψ, Ψ-carotene, 2 '-glucityl oxygen base-3 ', 4 '-two dehydrogenations-1 ', 2 '-dihydro-β, Ψ-carotene-3,1 '-glycol, 1 '-glucityl oxygen base-3 ', 4 '-two dehydrogenations-1 ', 2 '-dihydro-β, Ψ-Radix Dauci Sativae-3-alcohol, 1 '-glucityl oxygen base-3 ', 4 '-two dehydrogenations-1 ', 2 '-dihydro-β, Ψ-Radix Dauci Sativae-2 '-alcohol, 1 '-glucityl oxygen base-3 ', 4 '-two dehydrogenations-1 ', 2 '-dihydro-β, Ψ-Radix Dauci Sativae-4-ketone, 1-glucityl oxygen base-3,4-two dehydrogenations-1,2,7 ', 8 '-tetrahydrochysene-Ψ, Ψ-carotene, 1-glucityl Oxy-1,2-dihydro-Ψ, Ψ-Radix Dauci Sativae-20-aldehyde, 1-glucityl Oxy-1 ', 2 '-dihydro-β, Ψ-carotene, 1 '-the glucityl Oxy-1 ', 2 '-dihydro-[], Ψ-carotene, 1-glucityl Oxy-1,2-dihydro-Ψ, Ψ-carotene, 4-glucityl oxygen base-7 ', 8 '-dihydro-4,4 '-two apo-carotene, 1 '-glucityl oxygen base-2 '-hydroxyl-3 ', 4 '-two dehydrogenations-1 ', 2 '-dihydro-β, Ψ-Radix Dauci Sativae-4-ketone, 2-(4-glucityl oxygen base-3-methyl-2-butene base)-2 '-(4-hydroxy-3-methyl-crotyl)-γ, gamma carotene, 2-(4-glucityl oxygen base-3-methyl-2-butene base)-2 '-(4-hydroxy-3-methyl-crotyl)-[ε], [ε]-carotene, 2-(4-glucityl oxygen base-3-methyl-2-butene base)-2 '-(4-hydroxy-3-methyl-crotyl)-7,8-dihydro-[ε], [ε]-carotene, 2 '-(4-glucityl oxygen base-3-methyl-2-butene base)-2-(3-methyl-2-butene base)-[ε], [ε]-Radix Dauci Sativae-18-alcohol, 2-[3-(glucityl oxygen base)-3-methyl butyl]-2 '-(3-hydroxy-3-methyl butyl)-3,4,3 ', 4 '-four dehydrogenations-1,2,1 ', 2 '-tetrahydrochysene-Ψ, Ψ-carotene-1,1 '-glycol, 1 '-glucityl oxygen base-3,4,3 ', 4 '-four dehydrogenations-1 ', 2 '-dihydro-β, Ψ-carotene, Glycymerin, Guaraxanthin;

Different phylloxanthin, different agelaxanthin A, different bixin, different carotene, different-sigma carotene, different-sigma carotene, different Xi Honghuasuan, different kryptoxanthin, different phycophaein, different fucoxanthol, different phylloxanthin, different methyl bixin, different mussel phylloxanthin, 2-isopentene group-3,4-dehydrogenation rhodopin, different renieratene, β-different renieratene, 3, the 3 '-different renieratenol of different renieratenediol, 3-, different tedaniaxantbin, different tedanin, different cryptoxanthin;

Karpoxanthin, ketone-, also referring to oxo or-ketone ketone capsanthin, 4-ketone capsanthin, 4-ketone-alpha-carotene, 4-ketone-beta-carotene, 4-ketone-gamma carotene, 4-ketone pectenoxanthin, 4-ketone-3 ', 4 '-dehydrogenation-beta-carotene, 4-ketone-1 ', 2 '-dihydro-1 '-hydroxyl torulene, 2-ketone-7 ', 8 '-the dihydro rhodovibrin, 4-ketone-3,3 '-dihydroxy-alpha-carotene, 4 '-ketone-3-hydroxyl-gamma carotene, 4-ketone-3 '-the hydroxyl lycopene, 4-Ketolutein 3324-ketone myxol2 '-(methylpent glucosides), 4-ketone mucus phylloxanthin, 2-ketone-OH-spirillum phylloxanthin, 4-ketone phleixanthophyll, 2-ketone rhodovibrin, 4 '-the ketone Rubixanthin, 2-ketone spirillum phylloxanthin, 4-ketone torulene, 4-ketone cryptoxanthin;

The Lactuca phylloxanthin, Latochrome, Latoxanthin, leprotene, Lilixanthin, Loniceraxanthin, Loroxanthin, Lusomycin, phylloxanthin, the phylloxanthin dimethyl ether, lutein dipalmitate, the phylloxanthin epoxide, luteochrome, Luteol, corpus luteum xanthin (Luteoxanthin), lycopene, lycopene-20-aldehyde, lycopene, lycopene-16,16 '-glycol, lycopene 1, the 2-epoxide, lycopene 5, the 6-epoxide, lycopene-16-alcohol, lycopene-20-alcohol, lycopersene, Lycophyll, lycoxanthin;

Mactraxanthin, Manixanthin, 1-mannose group oxygen base-3,4-two dehydrogenations-1,2-dihydro-8 '-apo--Ψ-carotene-8 '-alcohol, 3 '-methoxyl group-β, beta-carotene-3-alcohol, 3-methoxyl group-β, X-carotene, 1-methoxyl group-1,2,7,8,11,12,7 ', 8 ', 11 ', 12 '-decahydro-Ψ, Ψ-carotene, 1 '-methoxyl group-1,2,7,8,11,12,1 ', 2 ', 7 ', 8 '-decahydro-Ψ, Ψ-Radix Dauci Sativae-1-alcohol, 1-methoxyl group-3,4-two dehydrogenations-1,2-dihydro-Ψ, Ψ-Radix Dauci Sativae-20-aldehyde, 1 '-methoxyl group-3 ', 4 '-two dehydrogenations-1 ', 2 '-dihydro-β, Ψ-carotene, 1-methoxyl group-3,4-two dehydrogenations-1,2-dihydro-Ψ, Ψ-carotene, 1-methoxyl group-3,4-two dehydrogenations-1,2,7 ', 8 ', 11 ', 12 '-six hydrogen-Ψ, Ψ-carotene, 1 '-methoxyl group-3 ', 4 '-two dehydrogenations-1,2,7,8,1 ', 2 '-six hydrogen-Ψ, Ψ-carotene-1-alcohol, 1-methoxyl group-3,4-two dehydrogenations-1,2,7 ', 8 '-tetrahydrochysene-Ψ, Ψ-carotene, 1 '-methoxyl group-3 ', 4 '-two dehydrogenations-1,2,1 ', 2 '-tetrahydrochysene-Ψ, Ψ-carotene-1-alcohol, 1-methoxyl group-3,4-two dehydrogenations-1,2,7 ', 8 '-tetrahydrochysene-Ψ, Ψ-Radix Dauci Sativae-2-ketone, 1-methoxyl group-1,2-dihydro-Ψ, Ψ-Radix Dauci Sativae-20-aldehyde, 1-methoxyl group-1,2-dihydro-Ψ, Ψ-carotene, 1 '-methoxyl group-1 ', 2 '-dihydro-β, Ψ-Radix Dauci Sativae-4 '-ketone, 1 '-methoxyl group-1 ', 2 '-dihydro-X, Ψ-carotene-4 '-ketone, 1-methoxyl group-1,2-dihydro-Ψ, Ψ-Radix Dauci Sativae-4-ketone, 1 '-methoxyl group-1 ', 2 '-dihydro-3 ', 4 '-dehydrogenation-gamma carotene, 1-methoxyl group-1,2-dihydro-3,4-dehydrogenation lycopene, 1-methoxyl group-1,2-dihydro-3,4-two dehydrogenations lycopene-20-aldehyde, 1-methoxyl group-1,2-dihydro lycopene, 4-methoxyl group-5,6-dihydro lycopene, 1-methoxyl group-1,2-dihydro neurosporene, 1-methoxyl group-1,2-dihydro phytoene, 1-methoxyl group-1,2-dihydro phytofluene, 1 '-methoxyl group-1 ', 2 '-dihydro sphere (red utmost point hair bacillus) alkene, 3-methoxyl group-19,3 '-dihydroxy-7,8-two dehydrogenations-β, X-carotene-6 ', 8 '-diketone, 1-methoxyl group-1,2,7 ', 8 ', 11 ', 12 '-six hydrogen-Ψ, Ψ-carotene, 1 '-methoxyl group-1,2,7,8,1 ', 2 '-six hydrogen-Ψ, Ψ-Radix Dauci Sativae-1-alcohol, 1-methoxyl group-1,2,7 ', 8 ', 11 ', 12 '-six hydrogen-Ψ, Ψ-Radix Dauci Sativae-4-ketone, 1-methoxyl group-1 '-hydroxyl-1,2,1 ', 2 '-the tetrahydrochysene phytofluene, 1-methoxyl group-2-ketone-7 ', 8 '-dihydro-3,4-dehydrogenation lycopene, methoxyl group tomato red aldehyde, 1-methoxyl group-1,2,7,8,7 ', 8 ', 11 ', 12 '-octahydro-Ψ, Ψ-carotene, 1 '-methoxyl group-1,2,7,8,11,12,1 ', 2 '-octahydro-Ψ, Ψ-Radix Dauci Sativae-1-alcohol, 1-methoxyl group-4-oxo-1,2-dihydro-8 '-apo--Ψ-Radix Dauci Sativae-8 '-aldehyde, 1-methoxyl group-4-oxo-1,2-dihydro-12 '-apo--Ψ-Radix Dauci Sativae-12 '-aldehyde, the methoxy phytoene, the methoxy phytofluene, methoxy sphere (red utmost point hair bacillus) alkene, 1 '-methoxyl group-3,4,3 ', 4 '-four dehydrogenations-1,2,1 ', 2 '-tetrahydrochysene-Ψ, Ψ-Radix Dauci Sativae-1-alcohol, 1-methoxyl group-1,2,7 ', 8,-tetrahydrochysene-Ψ, Ψ-carotene, 1-methoxyl group-1,2,7 ', 8 '-tetrahydrochysene-Ψ, Ψ-Radix Dauci Sativae-4-ketone, 1-methoxyl group-1,2,7 ', 8 '-tetrahydrochysene-3,4-dehydrogenation lycopene, 3 methoxyl groups-19,3 ', 8 '-trihydroxy-7,8-two dehydrogenations-β, X-Radix Dauci Sativae-6 '-ketone, methyl 4 '-apo--β-Radix Dauci Sativae-4 '-acid esters, methyl 8 '-apo--β-Radix Dauci Sativae-8 '-acid esters, methyl 6 '-apo--Ψ-Radix Dauci Sativae-6 '-acid esters, methyl apo--6 '-the lycopene acid esters, methyl bixin, 2-(3-methyl-2-butene base)-β, β-Radix Dauci Sativae-18 (or 18 ')-alcohol, 2-(3-methyl-2-butene base)-3,4-two dehydrogenations-1,2-dihydro-Ψ, Ψ-Radix Dauci Sativae-1-alcohol, 2-(3-methyl-2-butene base)-7,8,7 ', 8 '-tetrahydrochysene-[ε], Ψ-Radix Dauci Sativae-18-alcohol, 3 ', 4 '-two dehydrogenations-β, Ψ-Radix Dauci Sativae-16 '-acid esters, methyl 1-hexose-based-1,2-dihydro-3,4-two dehydrogenations-apo--8 '-lycopene acid methyl ester, methyl hydrogen 6,6 '-two apo-carotene-two acid esters, 1-mannose group oxygen base-3,4-two dehydrogenations-1,2-dihydro-8 '-apo--Ψ-carotene-8 '-the acid methyl ester, 1 '-methoxyl group-4 '-oxo-1 ', 2 '-dihydro-X, Ψ-carotene-16 (or 17 or 18)-sour methyl ester, 2 '-(O-methyl-5-C-methylpent glycosyl oxygen base)-3 ', 4 '-two dehydrogenations-1 ', 2 '-dihydro-β, Ψ-carotene-3,1 '-glycol, Metridene, Mimulaxanthin, monadoxanthin, the antibacterial rubine of singly anhydrating element, single dehydrogenation-beta-carotene, single dehydrogenation lycopene, single demethyl (change) spirillum phylloxanthin, monocycle oxygen-, also referring to epoxy-monohydroxy ring phytoene, monohydroxy ring phytofluene, citroxanthin, mutatoxanthin, Mytiloxanthin, Mytiloxanthinone, Myxobactin, Myxobactone, sticking 2 '-glucoside, sticking 2 '-O-methyl-methylpent glucosides, sticking 2 '-rhamnoside, the mucus phylloxanthin, Myxoxanthophyll 3',4'-Didehydro-2'-((6-deoxy-alpha-L-mannopyranosyl)oxy)-1',2'-dihydro-1',3-dihydroxy-beta,psi-Carotene, the mucus phylloxanthin;

Neocarotene, Neochrome, Neo-3-CaroteneB, new-beta-cryptoxanthin A, neoxanthin, neoxanthin 3-acetate, neurospora phylloxanthin, neurospora phylloxanthin methyl ester, neurosporene;

Octahydro-beta-carotene, 1,2,7,8,11,12,7 ', 8 '-octahydro-Ψ, Ψ-carotene, 7,8,11,12,7 ', 8 ', 11 ', 12 '-octahydro-Ψ, Ψ-carotene, 1,2,7,8,11,12,7 ', 8 '-octahydro-Ψ, Ψ-carotene-1,2-glycol, 1,27,8,1 ', 2 ', 7 ', 8 '-octahydro-Ψ, Ψ-carotene-1,1 '-glycol, 1,2,7,8,11,12,7 ', 8 '-octahydro-Ψ, Ψ-Radix Dauci Sativae-1-alcohol, 7,8,11,12,7 ', 8 ', 11 ', 12 '-octahydro-β, Ψ-Radix Dauci Sativae-2-alcohol, 1,2,7,8,7 ', 8 ', 11 ', 12 '-octahydro-Ψ, Ψ-Radix Dauci Sativae-1-alcohol, 7,8,11,12,7 ', 8 ', 11 ', 12 '-octahydro-4,4 '-two apo-carotene, phytoene, 5,6,7,8,5 ', 6 ', 7 ', 8 '-phytoene, 7,8,11,12,7 ', 8 ', 11 ', 12 '-phytoene, 3,4,3 ', 4 ', 7 ', 8 ', 11 ', 12 '-octahydro spirillum phylloxanthin, OH, also referring to hydroxyl-or-pure OH-chlorobactene, OH-chlorobactene glucoside, the OH-lycopene, 2-OH-monocycle phytoene, 2-OH-monocycle phytofluene, the OH-neurosporene, OH-Okenone, OH-P481, OH-P482, OH-P511, OH-R, the OH-rhodopin, OH-Sintaxanthin5, the 6-epoxide, OH-sphere (red utmost point hair bacillus) alkene, OH-sphere (red utmost point hair bacillus) ketenes, OH-7,8,11, the 12-neurosporene, OH-Y, Okenone, Ophioxanthin, Oscillaxanthin, Oscillol2,2 '-two (O-methyl-methylpent glucosides), Oscillol2,2 '-two rhamnosides, Ovoester, oxo-, also referring to ketone or-ketone 3-oxo canthaxanthin, 4 '-oxo-4,4 '-two apo-carotene-4-acid, 8 '-oxo-8,8 '-two apo-daucic acid, 3-oxygen echinenone, 4-oxygen saproxanthin, 16 '-oxo torulene, 6 '-the oxygen chrysanthemaxanthin, P412, P444, P450, P452, P481, P500, P518,1 '-[(χ-O-palmityl-β, D-glucityl) oxygen base]-3 ', 4 '-two dehydrogenations-1 ', 2 '-dihydro-β, Ψ-Radix Dauci Sativae-2 '-alcohol, the butterfly red pigment, papilioerythrinone, Paracentrone, Parasiloxanthin, Pectenol, Pectenolone, pectenoxanthin, pentaxanthin, peridinin, peridinin alcohol, Persicachrome, Persicaxanthin, Phillipsiaxanthin, Philosa miaxanthin, Phleixanthophyll, Palmic acid Phleixanthophyll, Phoeniconone, Phoenicopterone, phoenicoxanthin, physalin, the leaves of plants flavin, phytoene, C (30)-phytoene, phytoene 1,2-(ring) oxide, Phytoenol, phytofluene, the phytofluene epoxide, Phytofluenol, pigment R, pigment X, pigment Y, Plectaniaxanthin, poly--suitable-gamma carotene, poly--suitable-Ψ-carotene, poly--suitable-lycopene, Prasinoxanthin, lycopersene before the pyrophosphoric acid, phytoene before the pyrophosphoric acid, before-gamma carotene, prolycopene, preceding neurosporene, preceding neurosporene, vacation-alpha-carotene, pyrenoxanthin, Pyrrhoxanthin, Pyrrhoxanthinol;

7-cis: Renieracistene, Renierapurpurin, Renieratene, Reticulaxanthin, Retinylidenetiglic acid, anti-two dehydrogenations (β-) carotene, anti-dehydrogenation (β-) carotene, anti-dehydrogenation-gamma carotene, anti-dehydrogenation cryptoxanthin, rhamnopyranosyl-, referring to rhamanopyranosyl oxygen base-2 '-O-rhamanopyranosyl-4-ketone mucus, 2 '-O-rhamanopyranosyl mucus, 3 '-rhamanopyranosyl oxygen base-β, β-Radix Dauci Sativae-3-alcohol, 1-rhamanopyranosyl oxygen base-3 ', 4 '-two dehydrogenations-1 ', 2 '-dihydro-β, Ψ-carotene, 2 '-rhamanopyranosyl oxygen base-3 ', 4 '-two dehydrogenations-1 ', 2 '-dihydro-β, Ψ-carotene-3,1 '-glycol, 2 '-rhamanopyranosyl oxygen base-3 ', 4 '-two dehydrogenations-1 ', 2 '-dihydro-β, Ψ-carotene-3,4,1 '-triol, 1 '-rhamanopyranosyl oxygen base-3 ', 4 '-two dehydrogenations-1 ', 2 '-dihydro-β, Ψ-Radix Dauci Sativae-3-alcohol, Rhodoauranxanthin, rhodopin, rhodopin (20-) aldehyde, rhodopurpurin acetaldehyde glucoside, the rhodopin glucoside, rhodopurpurin ethanol, rose-red alizarinopurpurin, rose-red torulene, rhodovibrin, rhodoviolasin, rhodoxanthin, Roserythrin, rubichrome, Rubixanthin, Rubixanthin 5, the 6-epoxide, Rubixanthone;

Salmon acid, Salmoxanthin, saproxanthin, the sarcina phylloxanthin, sarcina phylloxanthin diglucoside, sarcina phylloxanthin list glucoside, sarcinene, 5,6-breaks-β, beta-carotene-5, the 6--diketone, 5,6-breaks-β, [ε]-carotene-5, the 6-diketone, half-α-carotenone, half-β-Hu Luobutong, Sidnyaxanthin, Sintaxanthin, siphonaxanthin, siphonein, 3,19-dihydroxy-7,8-two-dehydrogenation-β, X-carotene-3 ', 6 '-diketone 3-sodium sulfate, 3,19-dihydroxy-3 ', 6 '-dioxo-7,8-two dehydrogenations-β, X-carotene-17 '-aldehyde 3-sodium sulfate, 3,19,3 '-trihydroxy-7,8-two dehydrogenations-6 '-oxo-beta, X-carotene-17 '-acid esters 3-sodium sulfate, 3,19,17 '-trihydroxy-7,8-two dehydrogenations-β, X-carotene-3 ', 6 '-diketone 3-sodium sulfate, Sphaerobolin, spherical (red utmost point hair bacillus) alkene, spherical (red utmost point hair bacillus) ketenes, the spirillum phylloxanthin, Sulcatoxanthin;

Tangeraxanthin, taraxanthin, the taraxanthin dipalmitate, taraxigen, Tareoxanthin, Tedaniaxanthin, Tedanin, Ternstroemiaxanthin, Tethyatene, 7,8,7 ', 8 '-four dehydrogenation astaxanthins, 3,4,3 ', 4 '-four dehydrogenations-β, beta-carotene, 3,4,3 ', 4 '-four dehydrogenations-Ψ, Ψ-carotene, 7,8,7 ', 8 '-four dehydrogenations-β, beta-carotene-3,3 '-glycol, 3,4,3 ', 4 '-four dehydrogenations-β, beta-carotene-2,2 '-diketone, 3 ', 4 ', 7 ', 8 '-four dehydrogenations-β, beta-carotene-3-alcohol, 3,4,3 ', 4 '-four dehydrogenation lycopenes, 6,7,6 ', 7 '-four dehydrogenations-5,6,5 ', 6 '-tetrahydrochysene-β, beta-carotene-3,3 '-glycol, 6,7,6 ', 7 '-four dehydrogenations-5,6,5 ', 6 '-tetrahydrochysene-β, beta-carotene-3,5,3 ', 5 '-tetrol, 7,8,7 ', 8 '-four dehydrogenation cryptoxanthin, 3,4,3 ', the two dehydration of 4 '-four dehydrogenations antibacterial rubine element, 5,6,5 ', 6 '-the tetrahydrochysene canthaxanthin, 7,8,7 ', 8 '-the tetrahydrochysene capsorubin, tetrahydrochysene-beta-carotene, 7,8,7 ', 8 '-tetrahydrochysene-β, beta-carotene, 7 ', 8 ', 11 ', 12 '-tetrahydrochysene-β, Ψ-carotene, 7 ', 8 ', 11 ', 12 '-tetrahydrochysene-gamma carotene, 7 ', 8 ', 11 ', 12 '-tetrahydrochysene-γ, Ψ-carotene, 1,2,7,8-tetrahydrochysene-Ψ, Ψ-carotene, 1,2,1 ', 2 '-tetrahydrochysene-Ψ, Ψ-carotene, 7,8,11,12-tetrahydrochysene-Ψ, Ψ-carotene, 7,8,7 ', 8 '-tetrahydrochysene-Ψ, Ψ-carotene, 5,6,5 ', 6 '-tetrahydrochysene-β, beta-carotene-4,4 '-glycol, 7,8,7 ', 8 '-tetrahydrochysene-β, beta-carotene-3,3 '-glycol, 7 ', 8 ', 9 ', 10 '-tetrahydrochysene-β, Ψ-carotene-3,17 '-glycol, 1,2,1 ', 2 '-tetrahydrochysene-Ψ, Ψ-carotene-1,1 '-glycol, 5,6,5 ', 6 '-tetrahydrochysene-β, beta-carotene-4,4 '-diketone, 5,6,5 ', 6 '-tetrahydrochysene-β, beta-carotene-3,5,6,3 ', 5 ', 6 '-hexanol, 1,2,7,8-tetrahydrochysene-Ψ, Ψ-Radix Dauci Sativae-1-alcohol, 1,2,7 ', 8 '-tetrahydrochysene-Ψ, Ψ-Radix Dauci Sativae-1-alcohol, 7,8,11,12-tetrahydrochysene-4,4 '-two apo-carotene, 7,8,7 ', 8 '-tetrahydrochysene-4,4 '-two apo-carotene, neurosporene, 1,2,1 ', 2 '-neurosporene, 5,6,5 ', 6 '-neurosporene, 7,8,11, the 12-neurosporene, 7,8,7 ', 8 '-neurosporene, 7 ', 8 ', 11 ', 12 '-neurosporene, 1,2,1 ', 2 '-neurosporene-1,1 '-glycol, 1,2,1 ', 2 '-the tetrahydrochysene neurosporene, 3,4,11 ', 12 '-tetrahydrochysene sphere (red utmost point hair bacillus) alkene, 3,4,7,8-tetrahydrochysene spirillum phylloxanthin, 3,4,3 ', 4 '-tetrahydrochysene spirillum phylloxanthin, 3,4,3 ', 4 '-tetrahydrochysene spirillum phylloxanthin-20-aldehyde, 5,6,5 ', 6 '-tetrahydrochysene-3,4,3 ', 4 '-tetrol 4,4 '-di-sulfate, 2,3,2 ', 3 '-tetrahydroxy-β, beta-carotene-4,4 '-diketone, 2,3,2 ', 3 '-tetrahydroxy-β, echinenone, 3,19,3 ', 17 '-tetrahydroxy-β, χ-Radix Dauci Sativae-6 '-one 3-sulphate ester, 3,5,3 ', 5 '-tetrahydroxy-6 ', 7 '-two dehydrogenations-5,8,5 ', 6 '-tetrahydrochysene-β, β-Radix Dauci Sativae-8-ketone, 3,3 ', 5,5 '-tetrahydroxy-6 '-hydrogen-7-dehydrogenation-beta-carotene, 3,4,3 ', 4 '-tetrahydroxy pirardixanthin, 3,4,3 ', 4 '-tetrahydroxy-5,6,5 ', 6 '-tetrahydrochysene-β, beta-carotene, (3,4,3 ' 4 ')-tetraketone-beta-carotene, 4,5,4 ', 5 '-tetraketone-beta-carotene, Thiothece-425, Thiothece-460, Thiothece-474, Thiothece-478, Thiothece-484, Thiothece-OH-484, tilefiss phylloxanthin (Tilefishxanthin) I, tilefiss phylloxanthin II, tilefiss phylloxanthin III, tilefiss phylloxanthin IV, torularhodin, torularhodin aldehyde, the torularhodin methyl ester, Torulenal, Torulene, the Torulene carboxylic acid, 2,3,2 '-trihydroxy-β, echinenone, 3,3 ', 4 '-trihydroxy-β, β-Radix Dauci Sativae-4-ketone, 3,4,3 '-trihydroxy-β, χ-Radix Dauci Sativae-6 '-ketone, 3,3 ', 5 '-trihydroxy-6 ', 7 '-dehydrogenation-alpha-carotene, 3,3 ', 8 '-trihydroxy-7,8-two dehydrogenations-β, X-carotene-4,6 '-diketone, 3,3 ', 8 '-trihydroxy-7,8-two dehydrogenations-β, χ-Radix Dauci Sativae-6 '-ketone, 3,19,3 '-trihydroxy-7,8-two dehydrogenations-β, χ-Radix Dauci Sativae-6 '-one 3-sulphate ester, 3,1 ', 2 '-trihydroxy-3 ', 4 '-two dehydrogenations-1 ', 2 '-dihydro-β, Ψ-Radix Dauci Sativae-4-ketone, 3,5,19-trihydroxy-6,7-two dehydrogenations-5,6,7 ', 8 '-tetrahydrochysene-7 '-apo--β-Radix Dauci Sativae-8 '-ketone 3-acetate 19-alkyl caproate, 3,5,6 '-trihydroxy-6,7-two dehydrogenations-5,6,7 ', 8 '-tetrahydrochysene-β, [ε]-carotene-3 ', 8 '-diketone, 3,5,3 '-trihydroxy-5,6-dihydro-beta-carotene, 3,3 ', 5 '-trihydroxy-5 ', 6 '-dihydro-beta-carotene 5 ', 6 '-epoxide, 3,19,3 '-trihydroxy-7,8-dihydro-β, [ε]-Radix Dauci Sativae-8-ketone, 3,19,3 '-trihydroxy-7,8-dihydro-β, β-Radix Dauci Sativae-8-ketone 19-laurate, 3,6,3 '-trihydroxy-7,8-dihydro-γ, [ε]-Radix Dauci Sativae-8-ketone, 3,3 ', 19-trihydroxy-7,8-dihydro-8-oxo-alpha-carotene, 3,3 ', 6 '-trihydroxy-5,8-epoxy-alpha-carotene, 3,4,4 '-trihydroxy pirardixanthin, 1,1 ', 2 '-trihydroxy-3,4,3 ', 4 '-four dehydrogenations-1,2,1 ', 2 '-tetrahydrochysene-Ψ, Ψ-Radix Dauci Sativae-2-ketone, 3,4,4 '-trihydroxy-5,6,5 ', 6 '-tetrahydrochysene-β, beta-carotene, three kentriorhodin, 3,4,4 '-triketone-beta-carotene, 3,1 ', 2 '-trimethoxy-3 ', 4 '-two dehydrogenations-1 ', 2 ' dihydro-β, Ψ-Radix Dauci Sativae-4-ketone, Triophaxanthin, Triphasiaxanthin, the three antibacterial rubine elements that anhydrate, Trollein, the Flos Trollii chrome yellow, trollixanthin, the Flos Trollii flora, trollixanthin, Tunaxanthin, Uriolide, vaucheriaxanthin, violaxanthin, Violeoxanthin, Violerythrin, Warmingol, Warmingone, Webbiaxanthin, phylloxanthin, phylloxanthin K (1), phylloxanthin K (1) S, lutein dipalmitate, the phylloxanthin epoxide, α-Zeacarotene, β-Zeacarotene, β (1)-Zeacarotene, α-Zeacarotene-3,17 '-glycol, β-Zeacarotene-3,17 '-glycol, β-Zeacaroten-3-alcohol, Zeaxanthene, cryptoxanthin, the cryptoxanthin diepoxide, the cryptoxanthin dimethyl ether, cryptoxanthin two rhamnosides, the cryptoxanthin dipalmitate, cryptoxanthin 5, the 6-epoxide, cryptoxanthin 5, the 8-epoxide, cryptoxanthin furanoxide, the cryptoxanthin monomethyl ether, cryptoxanthin list rhamnoside, cryptoxanthin and Zeinoxanthin.

More than the inventory of naturally occurring carotenoid to mean be the limiting examples of naturally occurring carotenoid.This inventory is not comprehensive, because more naturally occurring molecule will be found, it will fall into the category of carotenoid.

Sulfonylurea

The limiting examples of sulfonylurea, include but not limited to acetohexamide, DiaBeta, glibenclamide, gliclazide, glipizide (Glucotrol), glyclopyramide, chlorpropamide, tolazamide, tolbutamide, glimepiride (Ya Moli), tolbutamide and the similar thing of meglitinide (for example, repaglinide, Nateglinide, meglitinide and Mitiglinide (KAD-1229)) etc.

Nicotinic acid and related derivatives

Term nicotinic acid is the general descriptor of nicotinic acid (pyridine-3-carboxylic acid) and derivant thereof.The limiting examples of nicotinic acid derivant comprises nicofuranose, acipimox (5-methylpyrazine-2-carboxylic acid 4-oxide), niceritrol, probucol, ftivazide, cholexamin, oxiniacic acid, nicoclonate, nicomol, NIASPAN, niceritrol and tocopheryl nicotinate.

Chemical compound of the present invention can be formulated as pharmaceutical composition, and it is suitable for oral, buccal, parenteral, transdermal or rectal administration or is suitable for sucking or being blown into the form of using.Parenteral is used and is comprised subcutaneous injection, intravenous injection, intramuscular injection, breastbone inner injection or infusion techniques.

Pharmaceutical composition can also be treated effective dose and is formulated as dosage unit form, and it is easy to use with dosage even.Used dosage unit form is meant and is suitable for the physically separated unit of making single dose in this explanation and the claim, and constituent parts comprises and the active component of the bonded calculating of required pharmaceutical carrier with the scheduled volume of the curative effect of generation expectation.The example of such dosage unit form is tablet (comprising impression sheet or coated tablet), capsule, pill, powder packaging, wafer, injectable solution or suspension, teaspoon amount (teaspoonful), table spoon amount (tablespoonful) etc., and the multidose that separates.As in the practice of routine, such dosage form can also comprise the material beyond the non-inert diluent, for example lubricant such as magnesium stearate.Under the situation of capsule, tablet, effervescent tablet and pill, dosage form can also comprise buffer agent.Perle can be prepared into the mixture that contains reactive compound of the present invention or compositions and vegetable oil.Hard gelatin capsule can contain the granule of the reactive compound that closes with the cellulose derivative group of solid, powder carrier such as lactose, sucrose, Sorbitol, mannitol, potato starch, corn starch, amylopectin, gelatin.Tablet and pill can make has casing.

Orally administered liquid dosage form can comprise and contains this area inert diluent commonly used such as pharmaceutically acceptable emulsion, solution, suspension, syrup and the elixir of water.Such compositions also comprises auxiliary agent, as wetting agent, emulsifying agent and suspending agent and sweeting agent, flavoring agent and spice.

The suppository of vagina or rectal administration chemical compound of the present invention and compositions can make like this: by chemical compound or compositions and the nonirritating excipient that is fit to such as cocoa butter and Polyethylene Glycol are mixed, they at room temperature are solids and be liquid under body temperature, like this their fusions and discharge medicine.

Injectable preparation, for example aseptic injectable aqueous or oil-based suspension can use the dispersant, wetting agent and/or the suspending agent that are fit to according to known technology preparation.Aseptic injectable formulation can also be nontoxic parenteral acceptable diluent or aseptic injectable solution or the suspension in the solvent, for example solution in the 1,3 butylene glycol.Among acceptable carrier and solvent, available is water, Ringer's solution and isoosmotic sodium chloride solution.Aseptic fixed oil also can be conventionally used as solvent or suspension medium.

Compositions of the present invention may further include conventional excipients, it is pharmaceutically acceptable organic or inorganic carrier mass, it is suitable for oral, buccal, parenteral, transdermal or rectal administration or for being suitable for sucking or being blown into the form of using, its not with reactive compound generation adverse reaction.The pharmaceutically acceptable carrier that is fit to comprises, for example water, saline solution, alcohol, vegetable oil, Polyethylene Glycol, gelatin, lactose, amylose, magnesium stearate, Talcum, surfactant, silicic acid, heavy-gravity paraffin, aromatic oil, glycerine monofatty ester and diglyceride, petroethral fatty acid ester, hydroxy methocel, polyvinylpyrrolidone etc.Pharmaceutical preparation can be aseptic, if desired, can mix adjuvant for example lubricant, antiseptic, stabilizing agent, wetting agent, emulsifying agent, the salt that influences osmotic pressure, buffer agent, coloring agent, flavoring agent and/or aromatic substance etc., its not with reactive compound generation adverse reaction.For parenteral application, particularly suitable carrier is by solution composition, preferably oily or aqueous solution, and suspension, emulsion or implants.Aqueous suspension can contain the material that increases suspension viscosity, comprises for example sodium carboxymethyl cellulose, Sorbitol and/or glucosan.Randomly, suspension can also contain stabilizing agent.

Tablet and capsule can also be prepared to the sustained release formulation form, so that it provides controlled lasting release chemical compound of the present invention in a few hours.

Compositions of the present invention will be to use with the amount that is enough to obtain the curative effect that those skilled in the art generally acknowledge.

The dosage of any compositions of the present invention will be according to patient's symptom, age and body weight, the form of the character of the disease that treat or prevent and seriousness, route of administration, theme composition and changing.Any subject formulations can single dose or is used with the dosage that separates.The dosage of the present composition can be determined easily by technology well known to those skilled in the art or as the instruction of this paper.

The dosage range of nebivolol is the about 100mg/ of about 0.1mg-days.In another embodiment, dosage range can be the about 50mg/ of about 0.75mg-days.And in another embodiment, dosage range can be the about 10mg of about 1.25mg-every day.

In certain embodiments, the dosage of common compounds effective is usually in the scope of the about 1g/ kg body weight of about 0.01ng-, particularly in the scope of the about 0.1g/ kg body weight of about 1ng-, more especially in the scope of the about 10mg/ kg body weight of about 100ng-.

Effective dose or amount and any possible influence to regularly using said preparation may need to differentiate for the specific compositions of the present invention.This can finish by normal experiment as herein described, uses one or more groups animal (every group preferably at least 5 animals), if or be adapted at finishing in the human test.The effect of the method for any theme composition and treatment or prevention can followingly be assessed: by using compositions, and by measuring the effect that one or more suitable index evaluations are used, and relatively after the processing of these indexs and the value before handling.

In given patient, produce the accurate time of application of any particular topic compositions of the most effective treatment and activity, pharmacokinetics and the bioavailability that amount will depend on theme composition, physiology's state of patient (comprise age, sex, disease type and stage, general physical condition, to the reactivity of given dose and drug type), route of administration etc.Can be used for optimizing treatment in this guilding principle 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.

When the experimenter treats, can measure the health that one or more indexs of correlation are monitored the patient by the scheduled time within treatment cycle.Treatment (comprising compositions, amount, time and the preparation used) can be according to the result optimizing of this monitoring.By measuring identical parameter, can periodically reevaluate the patient to determine improved degree.To the adjusting of the amount of the theme composition used and may can reevaluate based on these the adjusting of time of application and carry out.

Treatment can be begun by the less dosage less than the optimal dose of chemical compound.After this, increase dosage, until obtaining the suitableeest curative effect by few increment.

The use theme composition can reduce the dosage that needs of any single medicine contained in the compositions (for example, steroidal anti-inflammatory drugs), because the beginning of the effect of different pharmaceutical and persistent period can be (complimentary) that works in coordination with.

The toxicity of theme composition and curative effect can for example be measured LD by the standard pharmaceutical time-and-motion study in cell culture or the laboratory animal ₅₀And ED ₅₀

The scope that can be used to prepare the used dosage of people by the data of cell culture assays method and zooscopy acquisition.The dosage of any theme composition preferably is within the scope of circulation composition, and it comprises having seldom toxicity or avirulent ED ₅₀Dosage can change in this scope, depends on used dosage form and used route of administration.For compositions of the present invention, treat effective dosage and can estimate by the cell culture assays method at first.

Usually, 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.

Treatment suffers from the angiopathy result of the test that for example experimenter's of hypertension technical staff provides hereafter, can easily determine the treatment effective dose.Usually, effective every day of the dosage of the chemical compound of expectation formula (I) or its pharmaceutically-acceptable acid addition will be the about 50mg/ kg body weight of about 0.01mg/kg-, especially the about 10mg/ kg body weight of about 0.1mg/kg-, preferably about 0.1mg/ kilogram-Yue 1mg/ kg body weight.

The present invention also provides medicine kit, and it contains one or more one or more compositions that medicinal compound of the present invention and/or compositions are housed, and comprises the container of hydroxylated nebivolol metabolite.Such medicine kit (for example for example can also comprise other chemical compound and/or compositions, diuretic, digoxin, the chemical compound that is used for the treatment of cardiovascular disease, therapeutic agent, penetration enhancer, lubricant etc.), the device of administered compound and/or compositions, and the printed instructions of government bodies' prescribed form of production, use or the sale of management medicine or biological product, this description can also reflect that government bodies' approval is used for production, use or the sale that the people uses.

Another embodiment of the invention relates at least a hydroxylated metabolite of local application nebivolol, and the randomly at least a other treatment wounded tissue such as the therapeutic agent of damaged blood vessels.

Chemical compound of the present invention, and randomly other therapeutic agent can be impregnated in natural or synthetic substrate, this substrate can be applicable to target organism degree point then specifically.Therefore, the nebivolol metabolite " combines with substrate ", its mean the nebivolol metabolite together with a part of physics of other therapeutic agent and natural or synthetic substrate and/or chemical bond, with natural or synthetic substrate fusion, link or be included in the natural or synthetic substrate.

Any extensively multiple natural or synthetic polymer can be as the substrate in the context of the present invention.What only need is that substrate is biologically acceptable.The example that is applicable to substrate of the present invention is such polymer, comprise that for example TPO is (as polystyrene, polypropylene, polyethylene, high density polyethylene (HDPE), politef, polyvinylidene fluoride and polrvinyl chloride), polymine or derivatives thereof class, polyethers (as, Polyethylene Glycol), polyesters is (as poly--L-lactic acid, poly--D, L-lactic acid, poly--D-lactic acid, polyglycolic acid, poly--lactide/glycolides)), polyanhydrides, the poly butyric esters, polyamide-based (as nylon), polyurethanes, polyurethane copolymer class (as thermoplastic polyurethane polymer's class), polyacrylate is (as polymethacrylates, poly-(2-(methylacryoyloxyethyl)-2 '-(trimethyl ammonium) ethyl phosphonic acid inner salt-altogether-n-dodecyl methyl acrylate), polymer is (as polylactic acid/poly-D-lysine copolymer, polyurethane/polyester copolymer, polyurethane/copolyether, nylon/copolyether steps moral as the Vista) mixture, biopolymer is (as the peptide class, protein-based, oligonucleotides, antibody class, the peptide hormone class, glycoprotein, glycogen and nucleic acid class), the starburst dendritic macromole, natural fibre substrate (as filter paper), synthetic fiber matrix material (as the synthetic polymer and the copolymer of three-Wei lattice) etc.The polymer of example is described in U.S. Patent number 5,705, and 583,5,770,645 and 5,994,444, its disclosure is incorporated herein by reference in full at this.

The physics and the architectural feature that are applicable to substrate of the present invention are not crucial, but depend on application.When it will be apparent to one skilled in the art that substrate when nebivolol compositions of the present invention-metabolite expection is used for partial, relative short-term and using or similarly use, they need not be biodegradable.For some applications, as postangioplasty, coronary bypass or with blood vessel transplantation implant or similar relevant neointimal hyperplasia, substrate slowly dissolving or biodegradable or biological absorbable in physiological environment may be ideal.

In preventing and/or treating cardiovascular disease or disease, nebivolol metabolite of the present invention and randomly at least a therapeutic agent are by using intra-arterial or intravenous catheter, can directly be applied to the damaged blood vessels surface through intravenous, described conduit is suitable for transmitting chemical compound desired region at least.The position of impaired artery surface is determined by traditional diagnostic method such as X-ray angiography, uses available routine of those skilled in the art and the method for knowing to finish.

When using in vivo, chemical compound of the present invention and compositions can be used with the treatment effective dose in pharmaceutically acceptable carrier combination, and be as described herein.

When chemical compound of the present invention and compositions are used as the mixture of at least a hydroxylated nebivolol metabolite, its can also with one or more other therapeutic agent combined administrations, described therapeutic agent is known to be particular disease states such as the diuretic and/or different hypotensive agent such as beta blocker, calcium channel blocker or the ACE inhibitor of treatment-resistant targeting effectively.Should be understood that such therapeutic alliance has constituted further aspect of the present invention.

" use jointly " and comprise simultaneously or be alternative scheme with treatment and its Chinese medicine of the composition that makes up successively, perhaps wherein a kind of component chronic administration and other component is used off and on.Component can be used with identical compositions or the compositions of separating with by identical or different route of administration.

Nebivolol metabolite of the present invention can be used in combination with other medicines, and described other medicines are used for the treatment of/prevent/and suppress or improve the hydroxylated nebivolol metabolite its useful disease or the patient's condition.Other medicines comprise, antithrombotic agent for example, thrombolytic, fibrinolytic, the vasospasm inhibitor, potassium channel activator, calcium channel blocker, hypotensive agent, antimicrobial, antibiotic, antiplatelet drug, antimitotic drug, antiproliferative agents, the microtubule inhibitor, the secretion inhibitor agent, transform inhibitor, antisense nucleotide, anti-cancer chemotherapeutic agents, steroid, nonsteroidal antiinflammatory drug, selective COX-2-inhibitor 2, immunosuppressant, growth factor antagonist or antibody, dopamine agonist, radiotherapeutic agents, biological medicine, angiotensin-convertion enzyme inhibitor, angiotensin ii receptor antagonist, renin inhibitor, free radical scavenger, iron chelating agent, antioxidant, gonadal hormone, anti-polymerase, antiviral agent, the optical dynamic therapy agent, the antibody target therapeutic agent, gene therapeutic agents, diphosphonate or other osteoporosis drug, cholesterol lowering drug (includes but not limited to Statins, nicotinic acid or gemfibrozil), or its mixture.

Described other medicines can be by using for its conventional approach and amount of using, simultaneously or use the chemical compound of hydroxylated nebivolol metabolite successively.When nebivolol metabolite of the present invention and one or more other medicines used simultaneously, the pharmaceutical composition that also contains described other medicines except containing chemical compound of the present invention was preferred.Therefore, pharmaceutical composition of the present invention comprises those that also contain one or more other active component except containing nebivolol metabolite of the present invention.Can make up with nebivolol metabolite of the present invention, the example of separate administration or other active component of using with identical compositions, include but not limited to: (1) morphine and other opioid receptor agonist, comprise propoxyphene (Darvon), (2) nonsteroidal antiinflammatory drug (NSAIDs), comprise cox 2 inhibitor such as propanoic derivatives class (alminoprofen benoxaprofen, the bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid is Ji tioxaprofen), acetogenin class (indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, Isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin and zomepirac), fenamic acid derivative class (flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives class (diflunisal and flufenisal), former times health class (isoxicam, piroxicam, sudoxicam and tenoxicam), salicylic acid esters (aspirin, sulfasalazine) and pyrazolone (azapropazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, Phenylbutazone), and examine former times class (celecoxib, valecoxib, rofecoxib and etoricoxib), (3) corticosteroids such as betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone, (4) histamine H 1 receptor antagonist such as brompheniramine, chlorphenamine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, atarax, methdilazine, promethazine, alimemazine, azatadine, Cyproheptadine, antazoline, pheniramine, neo-antergan, astemizole, terfenadine, loratadine, alerlisin, Desloratadine, fexofenadine and levocetirizine, (5) histamine H2 receptor antagonist such as cimetidine, famotidine and ranitidine, (6) ionic pump inhibitor such as omeprazole, lansoprazole, pantoprazole and esomeprazole, (7) leukotriene antagonist and 5-fat oxidation enzyme inhibitor such as zafirlukast, montelukast, pranlukast and zileuton, (8) be used for angina pectoris, the medicine of myocardial infarction comprises nitrate esters such as nitroglycerin and isosorbidi dinitras, beta-Blocking agent such as atenolol, metoprolol, Propranolol, acebutolol, betaxolol, bisoprolol, carteolol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, sotalol and timolol thereof, calcium channel blocker such as diltiazem, verapamil, nifedipine, bepridil, felodipine, flunarizine, isradipine, nicardipine and nimodipine, (9) incontinence medication such as antimuscarinic medicine are (for example, tolterodine and oxibutynin), (10) the gastrointestinal spasmolytic is (as atropine, scopolamine, Neoquess, muscarine antagonist and diphenoxylate), skeletal muscle relaxant (cyclobenzaprine, carisoprodol, chlorphenesin, chlorzoxazone, metaxalone, methocarbamol, baclofen, dantrolene, diazepam or orphenadrine), (11) gout medication such as allopurinol, probenecid and colchicine, (12) be used for the medicine such as the methotrexate of rheumatoid arthritis, auranofin, aurothioglucose and Kidon (Ono), (13) be used for osteoporotic medicine such as alendronate and raloxifene, Decongestant such as pseudoephedrine and phenylpropanolamine, (14) local anesthetic, (15) antiherpetic such as acyclovir, valaciclovir and famciclovir, (16) Bendectin such as ondansetron and granisetron, (17) the crosslinked clastogen of advanced glycosylation end product (the crosslinked clastogen of AGE), alagebrium for example, and (18) advanced glycosylation end product forms inhibitor (AGE forms inhibitor), for example pimagedine.

Term " nitric oxide " comprises uncharged nitric oxide (NO) and charged nitric oxide class, and preferably charged nitric oxide class is as nitrous ion (NO+) and nitroxyl ion (NO-).The nitric oxide of release, transmission or transfer compounds has structure F--NO, wherein F is that nitric oxide discharges, transmits or the transfer part, and comprise chemical compound any and that all are such, its site to its predictive role is provided for the nitric oxide of the activity form of its intended purposes.

Using of nebivolol metabolite and hypotensor

Nebivolol metabolite of the present invention and acid-addition salts thereof can be before using hypotensor, during and use afterwards, condition is that the time of application of The compounds of this invention makes chemical compound of the present invention strengthen the effect of hypotensor effectively with respect to the using of hypotensor.

The hypotensor that its activity is reinforced therein, what can mention is the medicine with adrenergic activity and/or vasodilator activity.Especially, such medicine can be a U.S. Patent number 3,663, and the chemical compound that relates in 607 and 3,836,671 specifically is an atenolol, can be U.S. Patent number 3,337, and the chemical compound that relates in 628 and 3,520,919 specifically is a Propranolol; Can be U.S. Patent number 3,873, the chemical compound that relates in 600 specifically be a metoprolol; Can be U.S. Patent number 3,511, the chemical compound that relates in 836 specifically be a prazosin; Can be U.S. Patent number 2,484, the chemical compound that relates in 029 specifically be a hydralazine; U.S. Patent number 2,928, the chemical compound that relates in 829 specifically is a guanethidine; U.S. Patent number 2,503, the chemical compound that relates in 059 specifically is a phentolamine; U.S. Patent number 3,261, the chemical compound that relates in 859 specifically is a verapamil; U.S. Patent number 3,485, the chemical compound that relates in 847 specifically is a nifedipine; U.S. Patent number 3,910, the chemical compound that relates in 924 specifically is a carteolol; German patent 2,458, the chemical compound that relates in 624 and 2,458,625 specifically is a celiprolol.The patent of all references is hereby incorporated by.The purpose of listing the active component of these groups provides representational example, rather than limits the scope of the invention.

Preferably, nebivolol metabolite of the present invention and hypotensor are to use with the form of suitable compositions.The said composition meaning is also to comprise containing at the nebivolol metabolite of this definition and the product of hypotensor, as the preparation of combination be used for simultaneously, separately, regularly be released into/one or both, perhaps in the treatment that brings high blood pressure down, use successively.Such product for example can comprise, comprises the container with the suitable compositions that contains nebivolol metabolite of the present invention and contains the test kit of the container of the compositions with hypotensor with another.Such product has such benefit: based on treatment patient's diagnosis, the doctor who treats that wishes to bring high blood pressure down can select two kinds of compositions of suitable amount and the order of using.

When using in the process of using hypotensor, the composition of active components that contains hypotensor and nebivolol metabolite of the present invention can be especially easily.

Of the present invention further aspect, can provide contain the amount that can strengthen the hypotensor effect in the nebivolol metabolite of the present invention of this definition and the compositions of hypotensor.In said composition, the mol ratio between nebivolol metabolite and the hypotensor can not be about 1:1, perhaps can be about 1: 1.The amount of the active component of nebivolol metabolite will be the amount that obtains the effect of reinforcement hypotensor in such compositions; The amount of hypotensor will be such amount, when strengthening, just obtain to bring high blood pressure down effect in case use.Especially, the mol ratio of expectation formula (I) chemical compound and blood pressure lowering chemical compound can be to be positioned between about 50: 1 to about 1: 50, especially between about 20: about 1: 20 of 1-, or between about 10: 1 to about 1: 10, or between about 5: 1 to about 1: 5, more especially between about 2: 1 to about 1: 2.So especially compositions is that wherein hypotensor is to belong to one of medicine in the patent of above quoting, more particularly those compositionss of the medicine mentioned specially of this paper.

The present invention also provide contain pharmaceutically acceptable carrier and as the amount of the effect that can strengthen hypotensor of active component in the nebivolol metabolite of the present invention of this definition or the compositions of its pharmaceutically-acceptable acid addition.

In order to prepare such pharmaceutical composition, the specific compound of the alkali of effective dose or acid-addition salts form, as active component mix closely with pharmaceutically acceptable carrier and, these carriers can adopt extensively multiple type according to the form of using the preparation of expectation.These pharmaceutical compositions are the single dose form ideally, preferably are applicable to the injection of oral, rectum or parenteral.For example, in the compositions of preparation peroral dosage form, under the situation of oral liquid such as suspending agent, syrup, elixir and solution, can use any medicinal medium commonly used such as water, glycols, oils, alcohols etc.; Or under the situation of powder, pill, capsule and tablet, can use solid carrier such as starch, saccharide, Kaolin, lubricant, binding agent, disintegrating agent etc.Because its comfortableness in using, tablet and capsule have been represented best oral dosage unit form, under these circumstances, use the solid medicinal carrier apparently.For the gastrointestinal topical composition, carrier generally includes aseptic water (although other composition is arranged) at least to a great extent in order to improve dissolubility, can comprise.Injectable solution for example can prepare in the carrier of the mixture that comprises saline solution, glucose solution or saline and glucose solution.Injectable suspension can also prepare under the situation that can use suitable liquid-carrier, suspending agent etc.In being suitable for the compositions of applied dermally, carrier randomly comprises penetration enhancers and/or suitable wetting agent, randomly makes up the suitable additive of any character of less ratio, and this additive can not cause significant illeffects to skin.This additive can help using and/or can help to make compositions desired to skin.These compositionss can be used in many ways, for example as percutaneous plaster, spot-on, ointment.The acid-addition salts of nebivolol metabolite of the present invention is because its water-soluble with respect to the increase of corresponding alkali form obviously is to be more suitable for preparing Aquo-composition.

The invention still further relates to the method for strengthening the hypotensor effect in the homoiothermic animal that needs the hypotensor therapy, this method comprises hypotensor from effective dose to this homoiothermic animal and the nebivolol metabolite of the present invention defined above of using.

Perhaps optionally, the present invention relates to reduce the method for the homoiothermic animal blood pressure of suffering from hypertension, described method comprises hypotensor from effective dose to described homoiothermic animal and the nebivolol metabolite defined above of using.

Those technical staff that treat the experimenter who suffers from hypertension can easily determine safety and effective amount according to the result of the test that hereinafter provides.Usually, estimate that effective every day of the dosage of nebivolol metabolite of the present invention or its pharmaceutically-acceptable acid addition is 0.01mg/kg to 50mg/kg body weight, especially 0.1mg/kg to 10mg/kg body weight, preferably 0.1mg/kg to 1mg/kg body weight.

Nitric oxide in nebivolol metabolite and normotensive Black American and the white man's donor discharges

In the Black American of the U.S., observed the higher in vogue of cardiovascular risk factor (particularly hypertension).The CV danger that increases in the Black American may comprise the NO bioavailability of minimizing owing to the difference of angiological physiology.What support this notion is, the active clinical assessment of brachial artery proves, compares with the white man of age-matched, and the conduction blood vessel has reduced the responsiveness of endogenous and exogenous NO among the healthy Black American.The basis of this difference is because from the low bioavailability of the NO of Black American's endothelium, though there is the much higher endothelium-dependent relaxation NO synthase (eNOS) of level.The cell base of this paradox is following discovery: conciliate the excessive O that link coupled eNOS produces by NAD (P) H-oxidase ₂ ^-The loss (because itself and the O that cause functional NO ₂ ^-Reactivity, produce potent oxide peroxynitrite salt (ONOO ^-) form).

Six kinds of stereoselective hydroxy metabolite products have strengthened significantly from the NO bioavailability (Fig. 7) in the endotheliocyte of the white American and Black people's donor.Because the crucial layout of hydroxyl substituent on the nebivolol molecule, multiple metabolite have significantly greater than nebivolol, even the NO of l-nebivolol discharges active.Therefore, the stereo selectivity hydroxy metabolite product of nebivolol is the effective stimulus agent that NO discharges in the human endothelial cell.Also have, because select hydroxyl substituent, some hydroxy metabolite product has significantly active greater than the NO release of nebivolol or l-nebivolol.

Experiment is described in detail: the acute treatment with six kinds of stereo selectivity hydroxy metabolite products in from the endotheliocyte of the white American and Black people's donor shows that whole six kinds of hydroxy metabolite products have the activity that more is better than the d-nebivolol and is better than the nebivolol racemic modification most.Compare with nebivolol, 4 ' (R)-hydroxyl-7-fluoro-6-hydroxyl-l-nebivolol metabolite causes in white man and the Black people's donor that NO discharges about twice and increases, respectively to 476 ± 20 and 383 ± 18nmol/L.4 ' (R)-hydroxyl-5-fluoro-l-nebivolol metabolite also surpasses the activity of nebivolol even l-nebivolol〉50%.These discoveries show that the hydroxy metabolite product of nebivolol discharges the acute NO in the human endothelial cell and has obviously and highly reproducible effect.

Table 1. adopts the acute NO of chemical compound to discharge

Title	White man's donor NO (nM)	Black people's donor NO (nM)
			4 ' (R)-hydroxyl-7-fluoro-6-hydroxyl-l-nebivolol 4 ' (R)-hydroxyl-5-fluoro-6-hydroxyl-l-nebivolol 4 (S)-hydroxyl-7 '-fluoro-6 '-hydroxyl-l-nebivolol 5-fluoro-6-hydroxyl-l-nebivolol 4 ' (R)-hydroxyl-l-nebivolol 4 (S)-hydroxyl-l-nebivolol l-nebivolol nebivolol d-nebivolol	476±20 407±27 272±12 258±20 237±11 204±12 268±12 218±11 127±17	383±18 316±17 242±12 212±9 194±10 151±8 192±9 148±10 87±6

In table 1 and Fig. 7,, nebivolol, d-nebivolol, l-nebivolol and six kinds of relatively effects that stereo selectivity hydroxy metabolite product discharges NO have been shown for cell from the white American's (hollow strips) and the collection of Black people's (solid bars) donor.The release of NO from these endotheliocytes of having adopted the electrochemical nano sensor evaluation insert very much near cell surface.Whole six kinds of hydroxy metabolite products have remarkable activity greater than the d-nebivolol, and four kinds are better than the nebivolol racemic modification.Compare with nebivolol, 4 (R)-hydroxyl-7-fluoro-6-hydroxyl-l-nebivolol (1689-64A) metabolite causes in white man and the Black people's donor that NO discharges about twice and increases, respectively to 476 ± 20 and 383 ± 18nmol/L.4 ' (R)-hydroxyl-5-fluoro-l-nebivolol metabolite (1689-64B) also surpasses the activity of l-nebivolol〉50%.It is similar to nebivolol to have minimum active metabolite.These discoveries show that the hydroxy metabolite product of nebivolol discharges the acute NO in the human endothelial cell and has obviously and highly reproducible effect.

Other pharmacological examples

Method and material: the measurement that NO discharges in people's endothelium

All measured values that present are to use sensitive porphyrin (porphyrinic) probe at external record.Directly measuring N O discharges from Human umbilical vein endothelial cells (HUVEC).From American type culture collection (American Type Culture Collection, Manassas, VA) obtain the HUVEC cell, and it is grown in Ham ' s F12K culture medium, and this culture medium has and is adjusted to the 2mM L-glutaminate that contains the 1.5g/l sodium bicarbonate and endothelial cell growth additive (ECGS)=10% hyclone of heparin that has replenished 0.1mg/ml and 0.03-0.05mg/ml.The HUVEC cell is remained in the atmosphere of CO2 concentration (5%) of rising.From Mylan Laboratories (Morgantown, WV.) obtain nebivolol, its enantiomer and nebivolol metabolite and (comprise nebivolol glucosiduronic acid, 4-hydroxyl-5 ' phenol metabolism product, 4-hydroxyl-8 '-phenol metabolism product, 4-hydroxyl, 5-hydroxyl, 8-hydroxy metabolite product, N-DAD, N-DACA and N-DAAA.

At 37 ℃, in Hank ' s balance solution, carry out all measurements that endothelial NO discharges.Cell hole is transferred to faraday (Faraday) cage, and use inverted microscope (LeicaMicrosystems, Wetzler, Germany) and computer assisted micromanipulator, place porphyrin pick off (diameter 0.5mm) with the distance of distance endothelial cell surface 5 ± 2 μ m.Pick off is worked with three-electrode system: nano-sensor (working electrode), saturated calomel electrode (reference electrode) and platinum lead (antielectrode, 0.5mm diameter).Three electrodes are connected to potentiostat/galvanostat PAR273.Baseline is stable after about 20 seconds.With nano injection device (nanoinjector) test compound is expelled on the cell surface after the solubilization in the buffer agent.With sensor measurement and the proportional electric current of NO concentration, this pick off is worked with the galvanometer pattern under the constant potential of 0.63V.Use has been installed the ibm computer of customized software and amperograms (electric current is with respect to time graph) and has been obtained data and utilized Guniry FASl Femtostat that (Warminster PA) writes down this data.

Nano-sensor is made by carbon fiber.By the calcining of controlled temperature, the vertical size of carbon fiber is reduced to less than 1 μ m by 6 μ m.Make pick off to the NO sensitivity by the polymeric porphyrin of deposition conductivity, and cover the Nafion of thin layer.Under micromole NO concentration, the porphyrin microsensor has the response time of 0.1ms, has the response time of 10ms under the detectability of 1nM.

Be used for the nano-sensor of NO with saturated solution (the concentration 1.82mM that the power consumption analytic process confirms) calibration.Before measuring cytoactive and afterwards, make up the linearity correction curve of each pick off from 5x to 3x NO.Present data with each triplicate meansigma methods ± SEM that measures.With data (calculate and draw) be transferred to Microcal Origin Software (OriginLabCorp., Northampton, MA).

In these experimentations, the HUVEC prepared product is stable, and cell maintained vigour greater than 24 hours in culture medium.Under the non-irritating condition, the foundation level that NO discharges very low (＜30nM).In individual endotheliocyte, carry out measurement as the NO release of the function of handling.After of short duration refractory stage, can on individual cells, carry out the repeatedly measurement that NO discharges.For (robust) statistical analysis of requiring great effort,, use independent cell for each used in these analyses concentration and the type of medicine.

The relatively effect that NO in the human endothelial cell is discharged with the acute treatment of nebivolol metabolite

The result of these analyses confirms, β ₁Release has different effects to six kinds of metabolites of-adrenoceptor-selective antagonist nebivolol to the NO in the human endothelial cell within the finite concentration scope.Fig. 3 has compared after adding 10 μ M concentration medicines, and the peak NO in the HUVEC prepared product of six kinds of metabolites discharges.From then on be that under identical experiment condition, described metabolite discharges NO and has quantitatively different effect apparently among the figure.Under 10 high relatively μ M concentration, only there is a kind of metabolite (4-hydroxyl nebivolol) to produce the NO level that surpasses 400nM, yet even under this relative high concentration, three kinds of metabolites (N-DAD, N-DACA and N-DAAA) stimulate less than 90nM peak NO level.Remaining two kinds of metabolites (5-hydroxyl and 8-hydroxyl nebivolol) discharge NO and have medium effect, are about 220nM NO under 10 μ M concentration.Dihydroxy nebivolol metabolite (comprising 4-hydroxyl-5 '-phenol and 4-hydroxyl-8 '-phenol), and the glucuronidation metabolite all is being activated aspect the NO releasability.

In Fig. 4, directly the NO release action with some nebivolol metabolite and acetylcholine, nebivolol and nebivolol enantiomer compares then.These data show, compare with nebivolol or its enantiomer, and metabolite 4-hydroxyl nebivolol has maximum NO release action.Under the same concentration of 5 μ M, the NO that 4-hydroxyl nebivolol causes discharges and has surpassed 400nM, discharges yet nebivolol produces the NO peak of about 225nM level.Interesting is the approximate value of measuring with acetylcholine (the natural medium that NO discharges in the endothelium) of the NO release action that 4-hydroxyl nebivolol confirms.As shown in Fig. 1-6, handling afterwards with 5-hydroxyl or 8-hydroxyl nebivolol, the release of endothelial NO is similar to parent nebivolol chemical compound and enantiomer thereof.

In Fig. 6, the most effective metabolite 4-hydroxyl nebivolol and parent nebivolol chemical compound and enantiomer thereof are compared.Consistent with previous figure, when administration under same experiment condition, on the relative effectivenes of described medicine and effect, there is significant difference.Compare nebivolol and other metabolite, 4-hydroxyl nebivolol shows maximum NO release action under wide in range drug level, has the EC of 500nM ₅₀Relatively with the processing of parent compound or its enantiomer, observe the significant difference of 4-hydroxyl nebivolol on effect under the 500nM concentration being low to moderate.

Claims (82)

1. pharmaceutical composition, it comprises at least a stereoisomer of the nebivolol metabolite that hydroxyl replaces, or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier, and wherein this nebivolol metabolite structural formula is:

Wherein 3-5,7,8 and 3 '-5 ', 7 ', one or more positions of 8 ' are hydroxyl independently of one another or are hydrogen atom independently of one another.

2. the pharmaceutical composition of claim 1, wherein 4 of nebivolol are replaced by hydroxyl.

3. the pharmaceutical composition of claim 1, wherein 4 ' of nebivolol is replaced by hydroxyl.

4. the pharmaceutical composition of claim 1, wherein nebivolol is replaced by hydroxyl two at 4 and 8,4 and 8 ', 4 ' and 8 or 4 ' and 8 '.

5. the pharmaceutical composition of claim 1, wherein 4 of nebivolol and 5 ' or nebivolol 4 ' and 5 replaced by hydroxyl.

6. method that treats and/or prevents this patient's central vessel disease that needs, it comprises the compositions of the claim 1 of drug treatment effective dose.

7. the method for claim 6, wherein said cardiovascular disease is selected from congestive heart failure, hypertension, pulmonary hypertension, cardiac muscle and cerebral infarction, atherosclerosis, atheroma forms, thrombosis, ischemic heart desease, postangioplasty restenosis, coronary artery disease, renal failure, stable, instability and anomaly (Prinzmetal) angina pectoris, cardiac edema, renal insufficiency, renal edema, hepatic edema, apoplexy, the outbreak of instantaneity ischemia, cerebrovascular accident, restenosis, blood pressure in the control hypertension, platelet adhesion, platelet aggregation, smooth muscle cell proliferation, pulmonary edema, with the relevant vascular complication of use medical apparatus and instruments, with the relevant wound of use medical apparatus and instruments, pulmonary thromboembolism, the brain thromboembolism, thrombophlebitis, thrombocytopenia and bleeding disorder.

8. the method for claim 7, wherein said cardiovascular disease is selected from congestive heart failure, hypertension, restenosis and atherosclerosis.

9. the hydroxylated nebivolol metabolite in the unit dosage forms, wherein each unit contains the nebivolol metabolite with the required amount of being predetermined of the bonded generation expectation of pharmaceutical carrier curative effect.

10. the method for claim 6, wherein intravenous, per os, through cheek, parenteral, by sucking spray, topical application or the described compositions of transdermal administration.

11. a pharmaceutical composition, it comprises at least a stereoisomer of the nebivolol metabolite of hydroxyl replacement, or its pharmaceutically acceptable salt and at least a other activating agent, and wherein nebivolol metabolite structural formula is:

Wherein 3-5,7,8 and 3 '-5 ', 7 ', one or more positions of 8 ' are hydroxyl independently of one another or are hydrogen atom independently of one another.

12. the pharmaceutical composition of claim 11, wherein at least a other activating agent is a cardiovascular drug.

13. the pharmaceutical composition of claim 12, wherein said cardiovascular drug is selected from ACE inhibitor, ARB ' s, adrenergic blocking drug, 2-adrenergic agonist components, the medicament that is used for pheochromocytoma, anti-arrhythmic, antiplatelet drug, anticoagulant, antihypertensive, antilipemic, antidiabetic drug, anti-inflammatory agent, calcium channel blocker, the CETP inhibitor, cox 2 inhibitor, direct thrombin inhibitor, diuretic, endothelin receptor antagonists, the HMGCo-A reductase inhibitor, inotropic agent, renin inhibitor, vasodilation, vasopressor, the crosslinked clastogen of AGE, AGE forms inhibitor and composition thereof.

14. the pharmaceutical composition of claim 12, wherein said cardiovascular drug is selected from ACE inhibitor, ARB and composition thereof.

15. the pharmaceutical composition of claim 14, wherein said cardiovascular drug is an ACE inhibitor.

16. the pharmaceutical composition of claim 15, wherein said ACE inhibitor is selected from alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, perindopril, quinapril, ramipril, ramiprilat, spirapril, temocapril, trandolapril and composition thereof.

17. the compositions of claim 15, wherein said ACE inhibitor is selected from enalapril, ramipril and ramiprilat and composition thereof.

18. the pharmaceutical composition of claim 14, wherein said cardiovascular drug is ARB.

19. the pharmaceutical composition of claim 18, wherein said ARB is selected from Candesartan, Eprosartan, irbesartan, losartan, valsartan and composition thereof.

20. the pharmaceutical composition of claim 12, wherein said cardiovascular drug are selected from the crosslinked clastogen of AGE, AGE forms inhibitor and composition thereof.

21. a compositions, it comprises at least a stereoisomer of nebivolol metabolite that hydroxyl replaces, or its pharmaceutically acceptable salt, and a kind of other activating agent is only arranged, and wherein nebivolol metabolite structural formula is:

Wherein 3-5,7,8 and 3 '-5 ', 7 ', one or more positions of 8 ' are hydroxyl independently of one another or are hydrogen atom independently of one another.

22. the compositions of claim 21, wherein said other activating agent is a cardiovascular drug.

23. the compositions of claim 22, wherein said cardiovascular drug is selected from ACE inhibitor, ARB ' s, adrenergic blocking drug, 2-adrenergic agonist components, the medicament that is used for pheochromocytoma, anti-arrhythmic, antiplatelet drug, anticoagulant, antihypertensive, antilipemic, antidiabetic drug, anti-inflammatory agent, calcium channel blocker, the CETP inhibitor, cox 2 inhibitor, direct thrombin inhibitor, diuretic, endothelin receptor antagonists, the HMGCo-A reductase inhibitor, inotropic agent, renin inhibitor, vasodilation, vasopressor, the crosslinked clastogen of AGE, AGE forms inhibitor and composition thereof.

24. the compositions of claim 22, wherein said cardiovascular drug is selected from ACE inhibitor and ARB ' s.

25. the compositions of claim 22, wherein said cardiovascular drug is selected from the ACE inhibitor of alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, perindopril, quinapril, ramipril, ramiprilat, spirapril, temocapril and trandolapril.

26. the compositions of claim 22, wherein said cardiovascular drug is ARB, is selected from Candesartan, Eprosartan, irbesartan, losartan and valsartan.

27. the compositions of claim 22, wherein said cardiovascular drug are selected from the crosslinked clastogen of AGE and AGE forms inhibitor.

28. pharmaceutical composition, it comprises at least a stereoisomer of the nebivolol metabolite of hydroxyl replacement, or its pharmaceutically acceptable salt and at least a other activating agent and pharmaceutically acceptable carrier, wherein nebivolol metabolite structural formula is:

Wherein 3-5,7,8 and 3 '-5 ', 7 ', one or more positions of 8 ' are hydroxyl independently of one another or are hydrogen atom independently of one another.

29. the pharmaceutical composition of claim 28, wherein at least a other activating agent is a cardiovascular drug.

30. the pharmaceutical composition of claim 29, wherein said cardiovascular drug is selected from ACE inhibitor, ARB ' s, adrenergic blocking drug, 2-adrenergic agonist components, the medicament that is used for pheochromocytoma, anti-arrhythmic, antiplatelet drug, anticoagulant, antihypertensive, antilipemic, antidiabetic drug, anti-inflammatory agent, calcium channel blocker, the CETP inhibitor, cox 2 inhibitor, direct thrombin inhibitor, diuretic, endothelin receptor antagonists, the HMGCo-A reductase inhibitor, inotropic agent, renin inhibitor, vasodilation, vasopressor, the crosslinked clastogen of AGE, AGE forms inhibitor and composition thereof.

31. the pharmaceutical composition of claim 29, wherein said cardiovascular drug is selected from ACE inhibitor, ARB ' s and composition thereof.

32. the pharmaceutical composition of claim 31, wherein said cardiovascular drug is an ACE inhibitor.

33. the pharmaceutical composition of claim 32, wherein said ACE inhibitor is selected from alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, perindopril, quinapril, ramipril, ramiprilat, spirapril, temocapril, trandolapril and composition thereof.

34. the pharmaceutical composition of claim 33, wherein said ACE inhibitor is selected from enalapril, ramipril and ramiprilat and composition thereof.

35. the pharmaceutical composition of claim 31, wherein said cardiovascular drug is ARB.

36. the pharmaceutical composition of claim 35, wherein said ARB is selected from Candesartan, Eprosartan, irbesartan, losartan, valsartan and composition thereof.

37. the pharmaceutical composition of claim 29, wherein said cardiovascular drug are selected from the crosslinked clastogen of AGE, AGE forms inhibitor and composition thereof.

38. method that treats and/or prevents the cardiovascular diseases, it comprises at least a stereoisomer for the treatment of the nebivolol metabolite that the hydroxyl of safety and effective dose replaces to the curee, or its pharmaceutically acceptable salt, and at least a other activating agent is to form mixture, wherein this mixture is enough to treat this patient's condition, and wherein nebivolol metabolite structural formula is:

Wherein 3-5,7,8 and 3 '-5 ', 7 ', one or more positions of 8 ' are hydroxyl independently of one another or are hydrogen atom independently of one another.

39. the method for claim 38, wherein at least a other activating agent is a cardiovascular drug.

40. the method for claim 39, wherein said cardiovascular drug is selected from ACE inhibitor, ARB ' s, adrenergic blocking drug, 2-adrenergic agonist components, the medicament that is used for pheochromocytoma, anti-arrhythmic, antiplatelet drug, anticoagulant, antihypertensive, antilipemic, antidiabetic drug, anti-inflammatory agent, calcium channel blocker, the CETP inhibitor, cox 2 inhibitor, direct thrombin inhibitor, diuretic, endothelin receptor antagonists, the HMGCo-A reductase inhibitor, inotropic agent, renin inhibitor, vasodilation, vasopressor, the crosslinked clastogen of AGE, AGE forms inhibitor and composition thereof.

41. the method for claim 38, wherein said cardiovascular diseases is selected from congestive heart failure, hypertension, pulmonary hypertension, cardiac muscle and cerebral infarction, atherosclerosis, atheroma forms, thrombosis, ischemic heart desease, postangioplasty restenosis, coronary artery disease, renal failure, stable, instability and anomaly (Prinzmetal) angina pectoris, cardiac edema, renal insufficiency, renal edema, hepatic edema, apoplexy, the outbreak of instantaneity ischemia, cerebrovascular accident, restenosis, blood pressure in the control hypertension, platelet adhesion, platelet aggregation, smooth muscle cell proliferation, pulmonary edema, with the relevant vascular complication of use medical apparatus and instruments, with the relevant wound of use medical apparatus and instruments, pulmonary thromboembolism, the brain thromboembolism, thrombophlebitis, thrombocytopenia and bleeding disorder.

42. the method for claim 40, wherein said cardiovascular drug are selected from ACE inhibitor, ARB ' s and composition thereof.

43. the method for claim 42, wherein said cardiovascular drug is an ACE inhibitor.

44. the method for claim 42, wherein said cardiovascular drug is ARB.

45. the method for claim 40, wherein said cardiovascular drug are selected from the crosslinked clastogen of AGE, AGE forms inhibitor and composition thereof.

46. the described pharmaceutical composition of claim 28, wherein said composition comprises medicine kit.

47. the pharmaceutical composition of claim 12, wherein said cardiovascular drug is a vasodilation.

48. the pharmaceutical composition of claim 47, wherein said vasodilation be selected from sorbide nitrate, isosorbide mononitrate and hydralazine compounds, and composition thereof.

49. the pharmaceutical composition of claim 11, wherein at least a other activating agent is a flavone compound.

50. the pharmaceutical composition of claim 49, wherein said flavone compound be selected from (-)-epicatechin, (+)-catechin, procyanidin B2, Quercetin dehydrate, taxifolin and resveratrol, and composition thereof.

51. the pharmaceutical composition of claim 11, wherein at least a other activating agent be selected from flavone compound, carotenoid, sulfonylurea and nicotinic acid and relevant derivant, and composition thereof.

52. the pharmaceutical composition of claim 51, wherein at least a other activating agent is a carotenoid.

53. the pharmaceutical composition of claim 52, wherein carotenoid is selected from astaxanthin, cryptoxanthin, phylloxanthin, lycopene, beta-carotene and composition thereof.

54. the pharmaceutical composition of claim 51, wherein at least a other activating agent is a sulfonylurea.

55. the pharmaceutical composition of claim 54, wherein said sulfonylurea be selected from the similar thing of acetohexamide, DiaBeta, glibenclamide, gliclazide, glipizide, glyclopyramide, chlorpropamide, tolazamide, tolbutamide, glimepiride, tolbutamide and meglitinide, and composition thereof.

56. the method for claim 39, wherein said cardiovascular drug is a vasodilation.

57. the method for claim 56, wherein said vasodilation be selected from sorbide nitrate, isosorbide mononitrate and hydralazine compounds, and composition thereof.

58. the method for claim 57, wherein said hydralazine compounds is selected from budralazine, cadralazine, two hydralazines, endralazine, hydralazine, pildralazine and todralazine, or its pharmaceutically acceptable salt, and composition thereof.

59. the method for claim 38, wherein at least a other activating agent is a flavone compound.

60. the method for claim 59, wherein said flavone compound chemical compound be selected from (-)-epicatechin, (+)-catechin, procyanidin B2, Quercetin dehydrate, taxifolin and resveratrol, and composition thereof.

61. the method for claim 38, wherein at least a other activating agent be selected from flavone compound, carotenoid, sulfonylurea and nicotinic acid and relevant derivant, and composition thereof.

62. one kind is improved the method that NO discharges in this Black people patient who needs is arranged, it comprises at least a stereoisomer for the treatment of the nebivolol metabolite that the hydroxyl of safety and effective dose replaces to Black people patient, or its pharmaceutically acceptable salt, and at least a other cardiovascular drug is to form mixture, wherein this mixture is enough to improve NO release, and wherein nebivolol metabolite structural formula is:

Wherein 3-5,7,8 and 3 '-5 ', 7 ', one or more positions of 8 ' are hydroxyl independently of one another or are hydrogen atom independently of one another.

63. the method for claim 62, wherein at least a other cardiovascular drug is selected from ACE inhibitor, ARB ' s, adrenergic blocking drug, 2-adrenergic agonist components, the medicament that is used for pheochromocytoma, anti-arrhythmic, antiplatelet drug, anticoagulant, antihypertensive, antilipemic, antidiabetic drug, anti-inflammatory agent, calcium channel blocker, the CETP inhibitor, cox 2 inhibitor, direct thrombin inhibitor, diuretic, endothelin receptor antagonists, the HMGCo-A reductase inhibitor, inotropic agent, renin inhibitor, vasodilation, vasopressor, the crosslinked clastogen of AGE, AGE forms inhibitor and composition thereof.

64. the method for claim 63, wherein at least a other cardiovascular drug is a vasodilation.

65. the method for claim 64, wherein said vasodilation are selected from sorbide nitrate, isosorbide mononitrate, hydralazine compounds and composition thereof.

66. the method for claim 65, wherein said hydralazine compounds be selected from budralazine, cadralazine, dihydralazine, endralazine, hydralazine, pildralazine and todralazine or its pharmaceutically acceptable salt, and composition thereof.

67. a method that reduces mortality rate relevant with cardiovascular disease among the Black people patient, it comprises following each component for the treatment of effective dose to Black people patient:

(i) at least a stereoisomer of the nebivolol metabolite of hydroxyl replacement, or its pharmaceutically acceptable salt, wherein nebivolol metabolite structural formula is:

Wherein 3-5,7,8 and 3 '-5 ', 7 ', one or more positions of 8 ' are hydroxyl independently of one another or are hydrogen atom independently of one another;

(ii) at least a hydralazine compounds or its pharmaceutically acceptable salt;

(iii) at least a sorbide nitrate and/or isosorbide mononitrate, and

(iv) randomly, be selected from one or more chemical compounds of Folium Digitalis Purpureae compounds, diuresis chemical compound, potassium, angiotensin-convertion enzyme inhibitor, beta-adrenergic blocking agent, cholesterol reducing agent, calcium channel blocker, angiotensin ii receptor antagonist and endothelin antagonist.

68. the method for claim 67, wherein said cardiovascular diseases is selected from congestive heart failure, hypertension, pulmonary hypertension, cardiac muscle and cerebral infarction, atherosclerosis, atheroma forms, thrombosis, ischemic heart desease, postangioplasty restenosis, coronary artery disease, renal failure, stable, instability and anomaly (Prinzmetal) angina pectoris, cardiac edema, renal insufficiency, renal edema, hepatic edema, apoplexy, the outbreak of instantaneity ischemia, cerebrovascular accident, restenosis, blood pressure in the control hypertension, platelet adhesion, platelet aggregation, smooth muscle cell proliferation, pulmonary edema, with the relevant vascular complication of use medical apparatus and instruments, with the relevant wound of use medical apparatus and instruments, pulmonary thromboembolism, the brain thromboembolism, thrombophlebitis, thrombocytopenia and bleeding disorder.

69. the method for claim 68, wherein said cardiovascular diseases is a hypertension.

70. the method for claim 69, wherein said hydralazine compounds be budralazine, cadralazine, dihydralazine, endralazine, hydralazine, pildralazine, todralazine or its pharmaceutically acceptable salt, and composition thereof.

71. the method for claim 67, wherein with every day about 1mg to every day about 10mg amount give nebivolol.

72. one kind is improved the method that NO discharges in this Black people patient who needs is arranged, it comprises following each component for the treatment of effective dose to this Black people patient:

(i) at least a stereoisomer of the nebivolol metabolite of hydroxyl replacement, or its pharmaceutically acceptable salt, wherein nebivolol metabolite structural formula is:

Wherein 3-5,7,8 and 3 '-5 ', 7 ', one or more positions of 8 ' are hydroxyl independently of one another or are hydrogen atom independently of one another;

(ii) at least a hydralazine compounds or its pharmaceutically acceptable salt;

(iii) at least a sorbide nitrate and/or isosorbide mononitrate, and

(iv) randomly, be selected from one or more chemical compounds of Folium Digitalis Purpureae compounds, diuresis chemical compound, potassium, angiotensin-convertion enzyme inhibitor, beta-adrenergic blocking agent, cholesterol reducing agent, calcium channel blocker, angiotensin ii receptor antagonist and endothelin antagonist.

73. the method for claim 72, wherein said hydralazine compounds be budralazine, cadralazine, dihydralazine, endralazine, hydralazine, pildralazine, todralazine or its pharmaceutically acceptable salt, and composition thereof.

74. the method for claim 73, wherein said hydralazine compounds is a hydralazine hydrochloride.

75. a method that in this Black people patient who needs is arranged, improves exercise tolerance or improve the quality of living, it comprise to this Black people patient treat effective dose following each component:

(i) at least a stereoisomer of the nebivolol metabolite of hydroxyl replacement, or its pharmaceutically acceptable salt, wherein nebivolol metabolite structural formula is:

Wherein 3-5,7,8 and 3 '-5 ', 7 ', one or more positions of 8 ' are hydroxyl independently of one another or are hydrogen atom independently of one another;

(ii) at least a hydralazine compounds or its pharmaceutically acceptable salt;

(iii) at least a sorbide nitrate and/or isosorbide mononitrate, and

(iv) randomly, be selected from one or more chemical compounds of Folium Digitalis Purpureae compounds, diuresis chemical compound, potassium, angiotensin-convertion enzyme inhibitor, beta-adrenergic blocking agent, cholesterol reducing agent, calcium channel blocker, angiotensin ii receptor antagonist and endothelin antagonist.

76. the method for claim 75, wherein said hydralazine compounds be budralazine, cadralazine, dihydralazine, endralazine, hydralazine hydrochloride, pildralazine, todralazine or its pharmaceutically acceptable salt, and composition thereof.

77. the method for claim 76, wherein said hydralazine compounds is a hydralazine hydrochloride.

78. one kind is improved the method that NO discharges in this Black people patient who needs is arranged, it comprises at least a stereoisomer that gives the nebivolol metabolite of hydroxyl replacement to this Black people patient, or its pharmaceutically acceptable salt, its the amount for every day about 1mg to about 10mg every day, and at least a other cardiovascular drug, wherein nebivolol metabolite structural formula is:

Wherein 3-5,7,8 and 3 '-5 ', 7 ', one or more positions of 8 ' are hydroxyl independently of one another or are hydrogen atom independently of one another.

79. the method for claim 78, wherein said cardiovascular drug are selected from sorbide nitrate, isosorbide mononitrate, hydralazine compounds and composition thereof.

80. method that treats and/or prevents cardiovascular disease, wherein this method comprises at least a stereoisomer that gives the nebivolol metabolite of hydroxyl replacement to the patient, or its pharmaceutically acceptable salt, its the amount for every day about 1mg to about 10mg every day, and at least a other cardiovascular drug, this cardiovascular drug is selected from sorbide nitrate, isosorbide mononitrate, hydralazine compounds and composition thereof, and wherein nebivolol metabolite structural formula is:

Wherein 3-5,7,8 and 3 '-5 ', 7 ', one or more positions of 8 ' are hydroxyl independently of one another or are hydrogen atom independently of one another.

81. a method that improves exercise tolerance or improve the quality of living in this Black people patient who needs is arranged, it comprises following each component for the treatment of effective dose to this Black people patient:

(i) at least a stereoisomer of the nebivolol metabolite that replaces of hydroxyl, or its pharmaceutically acceptable salt, its amount for every day about 1mg to about 10mg every day, wherein nebivolol metabolite structural formula is:

Wherein 3-5,7,8 and 3 '-5 ', 7 ', one or more positions of 8 ' are hydroxyl independently of one another or are hydrogen atom independently of one another;

(ii) at least a cardiovascular drug; With

(iii) randomly, be selected from one or more chemical compounds of Folium Digitalis Purpureae compounds, diuresis chemical compound, potassium, angiotensin-convertion enzyme inhibitor, beta-adrenergic blocking agent, cholesterol reducing agent, calcium channel blocker, angiotensin ii receptor antagonist and endothelin antagonist.

82. the method for claim 81, wherein said cardiovascular drug is selected from ACE inhibitor, ARB ' s, adrenergic blocking drug, 2-adrenergic agonist components, the medicament that is used for pheochromocytoma, anti-arrhythmic, antiplatelet drug, anticoagulant, antihypertensive, antilipemic, antidiabetic drug, anti-inflammatory agent, calcium channel blocker, the CETP inhibitor, cox 2 inhibitor, direct thrombin inhibitor, diuretic, endothelin receptor antagonists, the HMGCo-A reductase inhibitor, inotropic agent, renin inhibitor, vasodilation, vasopressor, the crosslinked clastogen of AGE, AGE forms inhibitor and composition thereof.

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