CN1738665A - Pharmaceutical combination for the prevention or treatment of cardiovascular, cardiopulmonary, pulmonary, or renal diseases - Google Patents

Abstract

The invention relates to a method for the prophylaxis or treatment of cardiovascular, cardiopulmonary, pulmonary or renal diseases, achieved by the improvement of endothelial function and the protection of organs, tissues and vessels when indications require a blood pressure check and a lipid level check, especially in patients that have been diagnosed with type 2 diabetes mellitus or if prediabetes is suspected. Said method is also used for preventing diabetes and prediabetes and for the treatment of metabolic syndrome and insulin resistance in patients with normal blood pressure. Said method involves the common administration of effective quantities of telmisartan or a polymorph or salt thereof and simvastatin. The invention also relates to suitable pharmaceutical compositions, containing telmisartan or a polymorph or salt thereof and simvastatin, as a combined preparation for simultaneous, separate or sequential use in the prophylaxis or treatment of said diseases.

Description

The pharmaceutical composition of prevention or treatment cardiovascular disease, heart and lung diseases, pneumonopathy or nephropathy

The present invention relates to the method for a kind of prevention and treatment cardiovascular disease, heart and lung diseases, pneumonopathy or nephropathy, particularly suffers from the patient that diabetes or suspection have pre-diabetes (Pradiabete) for diagnosing, be used for prevent diabetes and pre-diabetes, perhaps treatment has normotensive patient's metabolic syndrome and insulin resistance.This method comprises to people's co-administered of need treatments angiotensin ii receptor antagonist telmisartan (Telmisartan) or its polymorph or salt and simvastatin (Simvastatin) with effective dose.The invention still further relates to the suitable pharmaceutical compositions that contains telmisartan or its polymorph or salt and simvastatin, as combination preparation with simultaneously, separately or be used for prevention successively or treat described disease, also relate to telmisartan or its polymorph or salt and simvastatin and be used to prepare a kind of combined use that prevents or treat the pharmaceutical composition of these diseases.

Angiotensin II (ANG II) plays an important role in pathophysiology, and particularly conduct is to the potent preparation of people's hypertension.Known, ANG II also has the effect that promotes growth except the effect of rising blood pressure, can cause that left ventricle blood supply insufficiency, blood vessel thicken, atherosclerosis, the depletion of kidney function and apoplexy.On the other hand, play the effect of Kallidin I vasodilation and protective tissue.Therefore, the ANGII-antagonist is suitable for treating mammiferous hypertension and congestive heart failure.The example of ANG II antagonist is described in EP 0502314A, EP 0253310A, EP 0323841A, EP 0324377A, US 4355040A and US 4880804A to some extent.The example of ANG II antagonist is CARDESARTAN (Candesartan), eprosartan (Eprosartan), irbesartan (Irbesartan), losartan (Losartan), Ao Mishatan (Olmesartan), Te Suoshatan (Tasosartan), valsartan (Valsartan) or telmisartan.

The effect of the resisting hypertension of ANG II-antagonism profit and protection kidney is for example described in following document to some extent:

● W.Wienen etc.: Antihypertensive and renoprotective effects of telmisartanafter long term treatment in hypertensive diabetic (D) rats, 2nd Int.Symposium onAngiotensin II Antagonism, February 15-18,1999, Elizabethan queen II conference centre, London, Britain, Book of Abstracts, Abstract No.50;

● J.Wagner etc.: Effects of AT 1 receptor blockade on blood pressure and therenin angiotensin system in spontaneously hypertensive rats of the stroke pronestrain, Clin.Exp.Hypertens., Bd.20 (1998), S.205-221; With

● M.Bohm etc.: Angiotensin II receptor blockade in TGR (mREN2) 27:effects of rennin-angiotensin-system gene expression and cardiovascular functions, J.Hypertens., Bd.13 (8) (1995), S.891-899.

Clinical research has confirmed that ANG II-antagonist protects the effect of kidney in addition in early days, for example is described in the following document:

● S.Andersen etc.: Renoprotctive effects of angiotensin II receptor blockadein type 1 diabetic patients with diabetic nephropathy, Kidney Int., Bd.57 (2) (2000), S.601-606;

● L.M.Ruilope:Renoprotction and rennin-angiotensin system blockade indiabetes mellitus, Am.J.Hypertens., Bd.10 (12 PT 2) Suppl. (1997), S.325-331; With

●J.F.E.Mann：Valsartan and the kidney：Present and future，J.Cardiovasc.Pharmacol.，Bd.33，Suppl.1(1999)，S.37-40。

In addition, ANG II-antagonist for example is described in the following document for the effect of endothelial dysfunction:

● E.L.Schiffrin etc.: Correction of arterial structure and endothelialdysfunction in human essential hypertension by the angiotensin-receptor antagonistIosartan Circulation, Bd.101 (14) (2000), S.1653-1659;

● R.M.Touyz etc.: Angiotensin II stimulates DNA and protein synthesis invascular smooth muscle cells from human arteries:role of extracellularsignal-regulated kinases, J.Hypertens., Bd.17 (7) (1999), S.907-916;

● E.L.Schiffrin:Vascular remodelling and endothelial function inhypertensive patients:Effects of antihypertensive therapy, Scand.Cardiovasc.J., Bd.32, Suppl 47 (1998) is S.15-21; With

●Prasad：Acute and chronic angiotensin-1 receptor antagonism reversesendothelial dysfunction in atherosclerosis，Circulation，Bd.101(2000)，S：2349 ff.。

Also disclose ANG II-antagonist and optionally blocked the AT1-receptor, the AT2-receptor that wherein plays antigrowth and tissue regeneration effect is unaffected.

EP 1013273A has also described AT1-receptor-antagonists or the AT2-receptor-regulator purposes to the treatment disease, described disease along with the increase of the AT1-receptor of subcutaneous area or in epithelium the AT2-receptor increase and occur, particularly treat the purposes of various pneumonopathy.

On the other hand, confirmed hypertension usually and hyperlipemia exist simultaneously.These two kinds of phenomenons are considered to take place usually to cause producing unfavorable cardiovascular cardiovascular diseases's main hazard factor.High blood cholesterol level and hyperlipidemia level participate in atherosclerotic beginning, and atherosclerosis is a kind of with at tremulous pulse, comprise that the lipidosis of irregular distribution on the inner membrance of coronary artery, carotid artery and peripheral arterial is the symptom of feature.This irregular lipid profile also is coronary heart disease, cardiovascular diseases's a feature, influential (the Wilson etc. of left ventricular hypertrophy that its order of severity and sickness rate occur as complication during also because of the existence of diabetes, patient's sex, smoking and hypertension, Am.J.Cardiol., Bd.59 (14) (1987), S.91G-94G).

Type ii diabetes is the disease of two pathological phenomenons, that is, the insulin secretion of pancreatic beta cell reduces the insulin resistance with Target organ liver, skeletal musculature and fatty tissue.Usually exist the compound pathological changes of two kinds of compositions.Following disease is diagnosed as empty stomach-hyperglycemia, that is, after fasting in 10-12 hour, blood sugar concentration surpasses the marginal value of every dl blood plasma 125mg glucose.(lattice row ketone, Glitazone) chemical compound of material type can effectively be treated type ii diabetes by thiazolidinedione.These chemical compounds improve the utilization of circulation insulin, therefore make blood glucose value decline (insulin sensitivity agent).Simultaneously, because feedback principle, the amount of insulin of rising is lowered, thereby has alleviated the burden of pancreas.The insulin sensitivity agent, as troglitazone (Troglitazone), rosiglitazone (Rosiglitazone) or pioglitazone (Pioglitazone), play a role by the nuclear receptor that is called as PPAR-γ (Peroxisomal Proliferator Activated Receptor) in conjunction with some.

WO 95/06410 discloses angiotensin ii receptor antagonist and has been used for the treatment of chronic inflammatory disease, comprises the purposes of systemic autoimmune disease.Diabetes are one of multiple whole body self property immune diseases.This type i diabetes is included into autoimmune disease, and majority is that the adolescence below 30 years old suffers from, wherein, when corresponding inherited genetic factors, under different factor affecting, cause causing subsequently the cytopathic pancreatitis of B-, pancreas can only produce on a small quantity or not produce insulin as a result.Type ii diabetes is not regarded as autoimmune disease.

Because from the diagnosis angle, one routine coronary heart disease appears in for example per two type ii diabetes philtrums, therefore think, it is the reason that diabetes increase in the Metabolic disorder of complexity, it can be by a series of risk factor performances, anti-glucose, the fasting glucose of rising, insulin resistance, hypertension, dyslipidemias disease or trunk obesity as disorder.For patient with high triglyceride and low HDL-cholesterol, the forerunner of insulin resistance tire (Pravalenz) be outstanding especially.Be referred to as forerunner (Pra) type ii diabetes, metabolic syndrome, syndrome X or glucagon syndrome.In the phase I, the insulin response of Target organ reduces to cause the amount of insulin secretion of pancreas to raise, so that blood sugar level remained in normal range.For many years, the insulin discharge that insulin generation too high or that raise makes insulin pass through the beta cell of pancreas no longer raises and discharges.So anti-glucose sexual stage that gets muddled.Body no longer can reach glucose peak fast enough.Final fasting blood sugar remains on high value, has suffered from diabetes.

Angina pectoris is a kind of symptom because of the strong girdle pain of chest, takes on left and radiates to left arm downwards from pareordia usually, uses the combination treatment of beta blocker, nitrate or calcium channel blocker and a kind of lipid lowerers to treat usually.Usually angina pectoris is based on that cardiac ischemia causes, and causes because of coronary artery disease usually.The experience surgical method is treated anginal patient usually can be with complication such as restenosiss; described restenosis can show as in the short-term breeder reaction by the caused wound of angioplasty, perhaps also can show as the long-run development in the arteriosclerosis process of grafting vessel and angioplasty part.

Several Therapeutic Method that reduce lipid and cholesterol are based on the enzymatic activity that hinders 3-hydroxy-3-methyl glutaryl base-coenzyme A-reductase (HMG-CoA-reductase); this reductase catalysis is converted into mevalonate from 3-hydroxy-3-methyl glutaryl base-coenzyme A, and this conversion is the early stage step of the approach of biosynthesis cholesterol.Known HMG-CoA-reductase inhibitor for example is such chemical compound, and this chemical compound is from the fungus metabolism, and its title that adopts ends up with " his spit of fland (statin) ".For example, Pravastatin (Pravastatin), lovastatin (Lovastatin), fluvastatin (Fluvastatin), simvastatin (Simvastatin) or atorvastatin (Atorvastatin).

Known simvastatin is the potent inhibitor of the enzyme of 3-hydroxy-3-methyl glutaryl base-coenzyme A-reductase (HMG-CoA-reductase), is cholesterol-biosynthetic inhibitor, and its effect is to reduce by LDL-C (LDL-C) to disappear.The attraction activity of this molecule when this effect is based on the compound hyperlipemia of treatment (a kind of common clinically atherogenic pathological changes), and so atherosis development process of prevention of arterial.

Research is also found; the decline of LDL-C-level to coronary heart disease play a protective role (for example referring to; " Scandinavian Simvastatin Survival Study " or 4S-Studie; be disclosed in The Lancet; Bd.344 (1994); S.1383-1389; perhaps paper " Prevention of coronary heart disease withprivastatin in men with hypercholesterolemia "; be published in The NewEngland Journal of Medicine by Shepherd etc.; Bd.333 (1995), S.1301-1307) in.

Prevent that in order to determine that Statins has the protective effect of heart failure, apoplexy and coronary heart disease from appearring in the noninsulindependent diabetes patient, also carried out other researchs; " Collaborative Atorvastatin DiabetesStudy " or CARDS research " Atorvastatin Versus Pevascularisation Treatment ", AVERT research and " Anglo-Scandinavian Cardiac Outcomes trial " or ASCOT research.

As mentioned above, because hypertension usually occurs with hyperlipemia or type ii diabetes sign, and because this phenomenon is the main hazard factor that (causing disadvantageous cardiovascular pathological changes usually) cardiovascular disease occurs, therefore if can provide a kind of monotherapy that prevents and treat this disease, be favourable to the patient.

In addition, if combination treatment also improves prevention or treatment heart and lung diseases, pneumonopathy or nephropathy, then be favourable, confirm that ANG II-antagonist is effective to these diseases.

The objective of the invention is, a kind of hypertension that both had been suitable for treating is provided, also be suitable for treating the medicine of hyperlipemia, this medicine can be treated metabolic syndrome and insulin resistance, can be used in the tangible type ii diabetes of treatment simultaneously, and the initial sign for the treatment of prediabetic compound metabolism disorder, therefore be used to prevent type ii diabetes.

Proposed combination treatment and corresponding compositions, said composition contains HMG-CoA-reductase-inhibitor and ANG II-antagonist.

● WO-95/26188 has described a kind of method for the treatment of atherosclerosis and cholesterol reducing, has wherein used HMG-CoA-reductase-inhibitor and ANG II-antagonist.Mention Pravastatin, simvastatin and lovastatin, as effective HMG-CoA-reductase-inhibitor.Mention losartan, as effective ANG II-antagonist.

● WO 97/37688 has described the combined use that HMG-CoA-reductase-inhibitor and ANG II-antagonist are used for the treatment of the multiple disease that is caused by hypertension and atherosclerosis.Mention Pravastatin, simvastatin, lovastatin and fluvastatin, as effective HMG-CoA-reductase-inhibitor.

● WO 99/11260 has described that a kind of specific HMG-CoA-reductase-inhibitor and ANGII-antagonist are used to bring high blood pressure down and lipid level and be used for the treatment of mammiferous angina pectoris and atherosclerotic combined use.Specific HMG-CoA-reductase-inhibitor is that atropic cuts down Sha Ting.As effective ANG II-antagonist, preferably mention losartan, irbesartan and valsartan.The ANG II-antagonist of mentioning also has Candesartan and eprosartan.

● WO 00/45818 has described HMG-CoA-reductase-inhibitor and ANG II-antagonist is used to improve diabetic neuropathy, especially improves the combined use of the nerve conduction velocity and the neural blood flow of diabetics.The example of mentioning that may make up is by the Pravastatin of Statins, simvastatin, simvastatin (Cerivastatin), fluvastatin, atorvastatin and his spit of fland (E) the formed mixture of losartan, irbesartan, valsartan and Candesartan (wherein preferred Candesartan) with ANG II-antagonist class.

● WO 01/15674 has described the combination of inhibitor and other antihypertensives, pravastatin, diuretic or the aspirin of renin angiotensin-system, be used to prevent the cardiovascular disease incident, as apoplexy, congestive heart failure, cardiovascular death, myocardial infarction, angor aggravation, asystole, revascularization process etc., diabetes and diabetic complication.The example of effective combination of mentioning is the inhibitor by angiotensin-conversion-enzyme (ACE), promptly the title of Cai Yonging is with the chemical compound of " pril " ending, as captopril (Captopril), imidapril (Imidapril), ramipril (Ramipril) etc., with the formed mixture of lovastatin, Pravastatin, simvastatin or fluvastatin of cholesterol reducing content.

Be surprisingly found out that among the present invention that angiotensin ii receptor antagonist telmisartan and salt thereof can also make the gene expression in the cell system raise except known hypotensive activity, known is to control by PPAR γ receptor by this gene transcription.For comparable condition to guarantee this effect, the present invention observes and quantification by the cell line (referring to embodiment 2) of stable conversion.Here relate to the CHO-cell, its expression has the conversion results of two gene components (Genkonstrukten).First configuration is luciferase genes (the de Wet JR of coding Photinus pyralis, Mol Cell Biol (1987) 7:725), it is under a kind of synthetic promoter control, with Hefe Gal4-binding site repeat for five times (referring to Genbank-Sequenz AF058756).Second component code by the ligand binding domain of people PPAR γ 2 transcription factor (referring to, Genbank-Sequenz U79012) and Hefe GAL4DNA in conjunction with territory (amino acid/11-147; Sadowski I, Nucleic Acids Res (1989) 17:7539) formed fusion rotein.

Inducing of the gene transcription of known PPAR γ control be to be undertaken by known thiazolidinedione (for example, rosiglitazone (Rosiglitazone)) as antidiabetic drug, and be combined on the PPAR γ receptor and activation is worked by it.Test system used herein can be quantitatively as the effect of the inductive luciferase activity of cell transformed system.Against one's expectation, telmisartan is to be attached to receptor PPAR γ by active substance to carry out to inducing of luciferase activity as expected equally.In different test systems, can not confirm combining of telmisartan and PPAR γ receptor.Therefore imagination when the synthetic PPAR γ that does not have high affinity-part, is caused that by the angiotensin ii receptor antagonist telmisartan the proteinic affinity of cofactor of PPAR γ improves, and can cause also that cofactor is proteinic to be replenished.This causes a kind of activation to genetic transcription by the cofactor mediation, and this gene is controlled by PPAR γ receptor.Because inducing of this gene is responsible for the antidiabetic effect of thiazolidinedione, therefore draws, and induces same gene to carry out a kind of comparable antidiabetic effect by telmisartan.Therefore, telmisartan not only is suitable for treating hypertension, and is suitable for treatment and prevention type ii diabetes.Comprising treatment and prevention metabolic syndrome, syndrome X or insulin resistance syndrome.

This new therapeutical effect of finding telmisartan and salt thereof means, available its a kind of treatment people of preparation or mammiferous medicine, with its prevention or treatment cardiovascular disease, heart and lung diseases, pneumonopathy or nephropathy, especially when being diagnosed as type ii diabetes or suspect for prediabetes, although perhaps blood pressure is normal, comprise the remainder data that metabolic syndrome or insulin resistance exist.It also is suitable for treatment and prevention type ii diabetes and forerunner's type ii diabetes.Comprising treatment and prevention metabolic syndrome, syndrome X or insulin resistance syndrome.Especially meaningfully treat the people, wherein the bonded hypertension of prevention or treatment and hyperlipemia or atherosclerosis is perhaps treated asthma, bronchitis or interstitial lung disease.

Confirm type ii diabetes with fasting blood sugar (every dl blood plasma surpasses the 125mg glucose), the mensuration of dextrose equivalent is a kind of standard method in the medicine conventional analysis in the blood.The property testing of anti-the glucose is performed such, and takes on an empty stomach behind the 75g glucose 2 hours, and the blood glucose value in every dl blood plasma of diabetes patient surpasses the 200mg glucose.In the property testing of anti-the glucose, treat research worker oral 75g glucose after fasting in 10-12 hour, 1 or 2 hour direct blood glucose value of measuring before taking glucose and after taking.For the people of health, before taking the blood glucose value of every dl blood plasma be 60 and 110mg between, the blood glucose value of taking back one hour every dl blood plasma is lower than 200mg, the blood glucose value of taking back 2 hours every dl blood plasma is lower than 140mg.If should value after 2 hours 140 and 200mg between, then also showing has disorderly anti-glucose.

The special distinguishing mark that prediabetes exists is to be confirmed by insulin resistance.If when people keeps the homoiostasis of glucose the amount of required insulin be other 2-3 doubly, and direct pathological phenomenon does not appear, then this people suffers from prediabetes.Blood glucose is normal-and the Clamp-test of hyperinsulinemia is the method for the most effective mensuration insulin resistance.In the insulin-glucose-infusion techniques scope of combination, measure the ratio of insulin and glucose.If the glucose index be lower than test background field 25%, then this people has insulin resistance (WHO definition).Than Clamp-test more economical be so-called mini Mod, in this model, in intravenous anti-glucose-test process, insulin concentration and the concentration of glucose in the interval measurement blood at a fixed time, and calculate insulin resistance thus.Another kind of assay method is the HOMA-model of mathematics.Calculate insulin resistance by empty stomach-blood plasma-glucose and empty stomach-insulin-concentration.Be impossible distinguish liver and insulin resistance periphery in these methods.These methods seldom are applicable to the insulin resistance evaluation in the daily reality.Clinically daily, introduce other parameters usually and estimate insulin resistance.For this reason, preferably introduce triglyceride-concentration of patient, because the triglyceride-level that raises is obviously relevant with the existence of insulin resistance.

When fasting blood sugar surpasses the maximum normal value of every dl blood plasma 110mg glucose, but when being no more than the marginal value of the every dl blood plasma 125mg glucose relevant, suspect to have prediabetes with diabetes.Prediabetic another sign is disorderly anti-glucose, that is, in anti-glucose property testing, (medicine) being taken before meal with the 75g glucose after 2 hours, blood glucose value is that every dl blood plasma has the 140-200mg glucose.

Also may there be prediabetes in the blood values of triglyceride during greater than 150mg/dl.The blood values of low HDL-cholesterol has further been strengthened this suspection.For the women, every dl blood plasma is lower than the value of 40mg, and for the male, every dl blood plasma is lower than the value of 50mg, is considered to low.The method of triglyceride and HDL-cholesterol is the standard method of medicine analysis equally in the mensuration blood, for example at ThomasL (Hrsg.): Labor und Diagnose "; TH-Books Verlagsgesellschaft mbH, Frankfurt/Main describes in 2000 to some extent.If fasting blood sugar surpasses every dl blood plasma 110mg glucose simultaneously, then more strengthened prediabetic suspection.If the blood values that records also can be with the ratio of waistline and hip circumference as auxiliary judging means in critical value range.If this ratio surpasses 0.8 or the male surpassed 1 to the women, then showing needs treatment.

If also must treat hypertension, then particularly point out, telmisartan can be used for treating diabetes or possible prediabetes.When the value that surpasses 140mm Hg and diastolic blood pressure when the value of systolic blood pressure surpasses 90mm Hg, be exactly this situation.If a patient has suffered from tangible diabetes, to recommend at present the value of systolic blood pressure is dropped to below the 130mm Hg, the value of diastolic blood pressure drops to below the 80mm Hg.In order to reach above-mentioned value, look concrete condition separately, can use the combination of angiotensin ii receptor antagonist and diuretic or calcium antagonist.Term " diuretic " comprises thiazine (Thiazide) or thiazine analog, as hydrochlorothiazide (HCTZ), gram chlorine handkerchief rice (Clopamide), benefit furosemide (Xipamide) or chlortalidone (Chlorthalidone), aldosterome-antagonist, as spironolactone (Spironolacton) or Eplerenone, as being suitable for treating hypertensive other diuretic, as furosemide (Furosemide) and pirbuterol (Piretanide), with and with the combination of amiloride (Amiloride) and triamterene (Triamteren).

The present invention shows that for the people who treats because of hypertension, if need the prediabetic development of prevention or treat tangible diabetes, then the angiotensin ii receptor antagonist telmisartan is desirable all the time.

Have only 10% can determine clear and definite reason, for example nephropathy in all hypertension (secondary hypertension).By treating and getting rid of this reason, can eliminate secondary hypertension usually.But relate to all situations nearly 90% of essential hypertension, also do not know its reason accurately, therefore directly healing.Hypertensive negative influence can be by changing living habit and correctly treating and reduce.Seem that respectively or simultaneously the synergism of the various risk factors that occur causes hypertension.Especially, the situation of answering close observation hypertension and lipid metabolism and carbohydrate metabolism disturbance to occur simultaneously.These pathological changes but can be learned by the higher blood values of triglyceride and glucose and the lower blood values of HDL-cholesterol in beginning usually and not obvious.In back one period, can see the obesity that slowly increases.Show that this pathological changes is caused by the insulin resistance that increases.Insulin is few more to work, and lipid metabolism and carbohydrate metabolism are just chaotic more.At last, the combination of all these pathological changes has increased the probability of suffering from diabetes and suffering from or die from heart disease or angiopathy too early.

Because constitutional or spontaneously hypertensive are multi-factor diseases, therefore, it seems that insulin resistance or hyperinsulinism unlikely are hypertensive single factors.But a large amount of the observation shows that the defective of insulin metabolism makes hyperpiesia, therefore is easy to suffer from hypertension.Be referred to as the hypertensive cerebral glucagon herein.So the hypertensive patient of about 50% normal type and the normotensive relatives of first order have been proved and have had insulin resistance.Compare with thin hypertensive patient, in adiposis patient, not only find higher insulin resistance, and close ties are also arranged between hypertension and the hyperinsulinism.

Infer that thus pampered philtrum has 1/3rd people that the situation that hypertension and lipid metabolism and carbohydrate metabolism disturbance occur together takes place approximately in the world, and this numerical value is increasing also.Therefore need a kind of medicine, help with this medicine in this case, the stage delays and stops the development of described metabolism disorder as far as possible in early days, and the effect of avoiding hypertension to be harmful to health simultaneously.

The present invention discloses a kind of medicine, not only can treat hypertension and hyperlipemia disease simultaneously with this medicine, and can treat the initial sign of tangible type ii diabetes or the compound metabolism disorder of prediabetes.This novel pharmaceutical combination thing is particularly suitable for treating and preventing above-mentioned hypertensive cerebral glucagon, and it is meant the insufficient utilization of circulation insulin in the blood circulation, and with the hypertension that causes thus.Therefore, the present invention also is included in prevent diabetes among the patient of treatment patient's hypertension and hyperlipemia.When also having described coindication outside forerunner's diabetes, the compositions of using telmisartan (Telmisartan) and simvastatin (Simvastatin) immediately is with control hypertension, hyperlipemia or hypertensive cerebral glucagon, can delay thus or avoids occurring tangible type ii diabetes.

Telmisartan and suitable salt thereof also show:

● not at the external ligand binding domain that is combined in people's PPAR γ receptor, but

● when in the culture medium of the PPAR γ that it is added stable conversion-recipient cell system, cause the inducing of luciferase activity, it

A) express a kind of by people PPAR γ transcription factor ligand binding domain and the fusion rotein that constitutes in conjunction with the territory of Hefe GAL4 DNA and

B) contain luciferase genes under five multiple Hefe GaL4 binding sites control.

The preparation of this PPAR γ-recipient cell system has been described in embodiment 2.

If in α screening (Ullmann EF etc., Proc Natl Acad Sci USA (1994) 91:5426-5430), can not be confirmed, then at the external ligand binding domain that is attached to people PPAR γ 2 receptors that do not exist.Replace the α screening, also can carry out SPA-test (Mukherjee R etc., J Steroid Biochem Mol Biol (2002) 81:217-225) or NMR-test (Johnson BA etc., J Mol Biol (2000) 298:187-194).Usually, there is not a kind of method can confirm combination in these methods at receptor.

Unite that to use angiotensin-ii receptor blockers and one or more other treatment active substance be significant or necessary, telmisartan is a kind of preferred angiotensin-ii receptor blockers, because it has blood pressure lowering and diabetes compound action with independent active substance, but perhaps prevent diabetes.Therefore, is great improvement by the active substance compositions of telmisartan and HMG-CoA reductase inhibitor simvastatin preparation being used for the treatment of aspect cardiovascular disease, heart and lung diseases, pneumonopathy or the nephropathy, wherein must treat hypertension, hyperlipemia, prediabetes or the significantly prevention of type ii diabetes, osteoporosis or Alzheimer and diabetes at the same time, all the more so.

According to observations, compare with individually dosed ANG II-antagonist or HMG-CoA-reductase-inhibitor, by the telmisartan of co-administered effective dose or the simvastatin of its polymorph or salt and effective dose, for cardiovascular disease, heart and lung diseases, pneumonopathy or the nephropathy of preventing or treatment needs therapist to suffer from, can reach wonderful advantage with high effective degree, do not rely on the known hypotensive activity of active substance telmisartan, do not rely on the known hyperlipidemia disease of active substance simvastatin activity yet.Like this, for example expression of may command substrate-metalloproteases MMP-9, this protease is strengthened expression chronic bronchitis or type ii diabetes.Also can resist the blood plasma value of the raising of the cytokines CD40L that promotes inflammation.The blood plasma value of the raising of CD40L is known cardiovascular diseases's a risk factor.

Also observe, described compositions can be improved prevention or the treatment to endothelial function, for the patient who should controlling blood pressure controls lipid level again, can play the effect of protection patient's organ, tissue and blood vessel.Like this, can improve the elasticity of tremulous pulse, and can strengthen generation NO in skin, NO is the genetic marker of endothelial function.

Also observe, said composition can effectively prevent or treat following symptom especially:

Indication (A), it is to affirm mode, by suppressing the receptor-mediated effect of AT1-, with the effect that keeps by the receptor-mediated Angiotensin II of AT2-(ANG II), with suppress the HMG-CoA-reductase-effect, and be affected, therefore, it also strengthens the effect by the Kallidin I mediation, and can reach the effect of hyperlipidemia disease; Perhaps

Indication (B), it is along with the increase of AT2-receptor in the increase of subcutaneous area AT1-receptor or the epithelium and occur.

Suitable indication (A) is selected from following indication:

Treatment mixed type hypertension and hyperlipemia;

Apoplexy, acute myocardial infarction or cardiovascular death appear in minimizing, particularly for having the patient that higher defective cardiovascular diseases or risk of stroke take place;

Provide the kidney protective effect, for example renal insufficiency or diabetic nephropathy;

Prevent that left ventricular hypertrophy, blood vessel from thickening, for example prevent the vessel wall thickening after the vascular surgery, improve the probability of surviving after the heart transplantation, prevent the postangioplasty arterial restenosis, prevention or treatment activate arteries and veins gruel type pathological changes, as atherosclerosis, the protection coronary artery disease prevents atheroma development and prevention of diabetic vascular disease;

Cholesterol reducing, reduce blood plasma-Fibrinogen and blood plasma-viscosity, hinder the propagation of smooth muscle cell, reduce the ability of oxidative macrophage LDL, protecting myocardial cell anoxia (hypoxische) pathological changes and reduction plasminogen activator-inhibitor-1 (PAI-1);

Prevention or treatment ischemic peripheral circulation pathological changes and myocardial ischaemia (angina pectoris); With

Prevent from cardiac insufficiency to occur after the myocardial infarction.

Suitable indication (B) is selected from following indication:

Obstructive respiration road disease, chronic obstructive pulmonary disease, as bronchitis or chronic bronchitis, emphysema, for example because asthma, cystic fibrosis, intermittence pneumonopathy, pulmonary carcinoma, pulmonary vascular disease, and the resistance that raises of the air-flow of respiratory organ (forcierter) when breathing;

Adult's Respiratory distress syndrome (ARDS), the multiplication capacity of epithelium, treatment deteriorated blood syndrome, injury of lung when reducing pulmonary carcinoma and breast carcinoma are as pneumonia, suction (Absaugen) gastric material, thoracic trauma, shock, burn, fat embolism, cardiopulmonary bypass art, O ₂-poisoning, hemorrhagic pancreatitis, intermittence and bronchovesicular inflammation, especially, when its along with substrate-metalloproteases, the expression that raises as MMP-9 and when occurring, the propagation of epithelial cell and intermittence cell, ossein enrichment and fibrosis propagation.

Therefore, the invention provides the method for a kind of prevention or treatment hypertension and hyperlipemia, especially be prediabetic mammal for being diagnosed as diabetes or suspecting, wherein, this method comprises the HMG-GoA-reductase-inhibitor simvastatin of a kind of effective dose of co-administered and a kind of ANGII-antagonist telmisartan or its polymorph or salt of effective dose.

The invention still further relates to simvastatin and telmisartan or its polymorph or salt at a kind of combined use that is used for preventing or treating the hypertensive pharmaceutical composition that is combined with hyperlipemia of preparation, especially when being diagnosed as diabetes or suspect for prediabetes.

Therefore, the advantageous effect of the inventive method relates generally to combined therapy for the protective effect of organ, tissue and blood vessel and for the preventive effect of diabetes.

Above-mentioned beyond thought advantage is attributable to, effectively block because of the receptor-mediated ANG II of AT1-effect by simvastatin, effect because of the receptor-mediated ANG II of AT2-, it keeps not influencing by specific ANG II-antagonist, improve because of the effect of Kallidin I mediation is common, the effect of similar transcription activating of PPAR γ and realization hyperlipidemia disease.

For example, according to observations, the ANG II-antagonist telmisartan that co-administered is specific or its polymorph or salt and specific HMG-CoA-reductase-inhibitor simvastatin, with be used alone this active substance and compare, can play and prevent cardiovascular death and general mortality rate significantly, particularly relate to the effect of apoplexy and acute myocardial infarction.

Therefore, preferred the inventive method is, in order to reduce the people that needs treatment or inhuman mammal, apoplexy and acute myocardial infarction appear, particularly suffering from tangible type ii diabetes or suspection has prediabetes or the defective cardiovascular diseases of high-risk is arranged or the people of apoplexy, to its co-administered telmisartan or its polymorph or salt and simvastatin.

Also observe, combined therapy and corresponding compositions, said composition contains HMG-CoA-reductase-inhibitor simvastatin and a certain amount of ANG II-antagonist telmisartan or its polymorph or the salt of specified quantitative, has higher activity in mammiferous blood pressure of control and hyperlipemia.Expection can surpass the effect of corresponding conventional combination astoundingly by the synergism that particular combinations reached.

The synergistic combination that is used for controlling blood pressure and control lipid is interpreted as, this combination contains the polymorph or the salt of a certain amount of simvastatin and a certain amount of telmisartan or this active substance, wherein, the quantity not sufficient of each independent active substance is to reach the therapeutical effect that is reached by the drug regimen administration, and, the summation of the therapeutical effect that the compound action of a certain amount of medicine can reach greater than the single medicine that adopts this amount.

Another theme of the present invention is compositions and the preparation thereof that comprises the medicine of telmisartan or its salt and simvastatin.In treatment people or inhuman mammal, said composition is used for prevention or treats above-mentioned disease or indication, wherein, said composition comprises telmisartan and simvastatin, randomly contain medicine acceptable diluent and/or carrier simultaneously, and in prevention or when treating these diseases or indication, be with simultaneously, separately or the combination dosage forms that uses successively carry out administration.

The active substance combination has one or more formulation adjuvants usually, as mannitol, Sorbitol, xylitol, sucrose, calcium carbonate, calcium phosphate, lactose, cross-linking sodium carboxymethyl cellulose salt (cellulose gum sodium salt, crosslinked), crospolyvinylpyrrolidone, primojel, hydroxy propyl cellulose (low replacement), corn starch, polyvinylpyrrolidone, the copolymer of vinylpyrrolidone and other ethenyl derivatives (copolymerization of ethylene ketopyrrolidine), hydroxy propyl cellulose, HYDROXY PROPYL METHYLCELLULOSE, microcrystalline Cellulose or starch, magnesium stearate, stearyl fumarate, Talcum, HYDROXY PROPYL METHYLCELLULOSE, carboxymethyl cellulose, acetyl cellulose phthalate, polyvinyl acetate, water, water/ethanol, water/glycerol, water/Sorbitol, water/Polyethylene Glycol, propylene glycol, cetyl stearyl alcohol, carboxymethyl cellulose or fatty material, as tristearin, or its suitable mixture, the preparation that is mixed with by prescription commonly used is as tablet, dragee, capsule, powder, suspension or suppository.

By being mixed with effective substance and one or more auxiliary agents, suppress then, obtain tablet.This tablet also can be made of multilamellar.The example of auxiliary agent is:

● inert diluent, as mannitol, Sorbitol, xylitol, sucrose, calcium carbonate, calcium phosphate and lactose;

● disintegrating agent, as cross-linking sodium carboxymethyl cellulose salt (carboxymethyl cellulose ether sodium salt, crosslinked), crospolyvinylpyrrolidone, primojel, hydroxy propyl cellulose (low replacement) and corn starch;

● binding agent, as copolymer (copolymerization of ethylene ketopyrrolidine), hydroxy propyl cellulose, HYDROXY PROPYL METHYLCELLULOSE, microcrystalline Cellulose or the starch of polyvinylpyrrolidone, vinylpyrrolidone and other ethenyl derivatives;

● lubricant, as magnesium stearate, stearyl fumarate, Talcum;

● be used for the preparation of storage effect, as HYDROXY PROPYL METHYLCELLULOSE, carboxymethyl cellulose, Cellacefate and polyvinyl acetate; With

● the coloring agent that medicine allows, if any the ferrum oxide of color.

Of the present invention aspect all in, the ANG II-antagonist telmisartan that relates to is { 4 '-[2-just-propyl group-4-methyl-6-(1-tolimidazole-2-yl)-benzimidazole-1-ylmethyl]-diphenyl-2-carboxylic acid } or its polymorph or salt, is preferably sodium salt.Telmisartan is existing commercially available, as commodity Micardis  by name.

Telmisartan is for example described in EP 0502314 and US 5591762 to some extent.

The polymorph of telmisartan is for example described in WO 00/43370, US 6358986 and US 6410742 to some extent.The salt of telmisartan is for example described in WO 03/037876 to some extent.

As described in WO 03/037876, the telmisartan sodium salt of following formula is to make its polymorphic with selection mode by suitable selection preparation condition.

The crystal formation of telmisartan sodium salt is characterised in that its fusing point T=245 ± 5 ℃ (by determine with dsc method, uses Mettler-Toledo DSC82-device; The rate of heat addition: 10K/ minute).

In order to prepare telmisartan-sodium salt, can carry out according to following one or both preparation methoies.

Of the present invention aspect all in, HMG-CoA-reductase-inhibitor the simvastatin that relates to is { 2,2-dimethyl-butanoic acid, 1,2,3,7,8,8a-six hydrogen-3,7-dimethyl-8-[2-tetrahydrochysene-4-hydroxyl-6-oxo-2H-pyrans-2-yl)-and ethyl-1-naphthyl ester }, for example its trade name is Zocor .

Simvastatin is for example described in EP 0033538 and US 4444784 to some extent.

Two kinds of active substance of co-administered are interpreted as administration or administration simultaneously successively on the time, and wherein, administration simultaneously is preferred.For administration successively, telmisartan was used before or after the administration simvastatin.

Can with active substance by oral, through cheek, parenteral, by suction, rectum or topical, wherein, oral administration is preferred.That parenteral comprises is subcutaneous, intravenous, intramuscular and intrasternal injection and infusion means.

Active substance can multiple different dosage form pass through oral administration, that is, active substance can be mixed with tablet, capsule, pill, confection, powder, spray, aqueous suspension, elixir, syrup etc. with the acceptable inert carrier of different medicines.What belong to this carrier is solid diluent or filler, aseptic aqueous medium and multiple nontoxic organic solvent.In addition, these oral pharmaceutical preparatioies can suitable manner contain sweetener and/or correctives, wherein, can use to reach the different preparation of above purpose.Generally speaking, the concentration range of The compounds of this invention in this peroral dosage form counted the about 90 weight % of about 0.5-with total compositions, can form the preparation unit of hope with such amount.Being suitable for the preparation The compounds of this invention dosage form, that have controlled release and device is that the technical staff is known.For oral administration, can use tablet, it contains different carriers, as sodium citrate, calcium carbonate and calcium phosphate, and different disintegrating agents, as starch, be preferably potato starch or tapioca, alginic acid and some composition silicate, and binding agent, as polyvinylpyrrolidone, sucrose, gelatin and arabic gum.In addition, can make with lubricator, as the compositions of magnesium stearate, sodium lauryl sulfate and Talcum or similar type, equally as filler soft to fill-and hard gelatine capsule.Lactose or toffee and the high-molecular weight Polyethylene Glycol in addition that belong to this.If wish it is the aqueous suspension and/or the elixir of oral administration, can make active substance increase sweet substance or flavoring material, coloring agent or pigment and optional emulsifying agent and/or water, ethanol, propylene glycol, glycerol and inhomogeneous compositions thereof carried out combination with different.

For parenteral, can use the solution of chemical compound in Oleum sesami or Oleum Arachidis hypogaeae semen or the aseptic aqueous solution of solution in aqueous propylene glycol and the acceptable salt of relative medicine.This aqueous solution can randomly cushion with suitable manner, and liquid diluent randomly can reach isoosmotic pressure with the Sal or the glucose of q.s.This specific aqueous solution is particularly suitable for intravenous, intramuscular and subcutaneous injection.At this, be easy to obtain aseptic water-bearing media according to routine techniques known to the skilled.For example, generally use distilled water as liquid diluent.Final preparation is by suitable biofilter, and for example the filter that is got by sintered glass, kieselguhr or not vitrified ceramic obtains.Preferred filter type is Berkefeld filter, Chamberland filter and asbestos board-metal-Seitz-filter, by vacuum pump liquid is sucked in the sterility container.When carrying out the essential step in the injection whole process of preparation, make that final products are in the aseptic condition.

Being used for the specific compound of percutaneous dosing or the dosage form of compositions for example is solution, lotion, ointment, frost, gel, suppository, slow releasing agent, and the device that for this reason uses.These dosage forms are particularly including specific chemical compound and can contain ethanol, water, permeation enhanced dose and inert carrier, as becoming glue material, mineral oil, emulsifying agent, benzyl alcohol etc.

The form of medication that makes for example contains 2.5-40mg, and preferred 5,10,15,20,25,30,35 or the equivalent of the simvastatin of 40mg.The daily dose of simvastatin oral administration is that about 0.625mg (or count 0.009mg/kg body weight with the people of body weight 70kg) is to about 450mg (people with body weight 70kg counts the 6.43mg/kg body weight), the dosage of parenteral is about 20mg (people with body weight 70kg counts the 0.286mg/kg body weight), and the dosage of preferred oral administration is that about 1.25mg (people with body weight 70kg counts the 0.018mg/kg body weight) is to about 80mg (people with body weight 70kg counts the 1.428mg/kg body weight).The daily dose of special preferred oral administration is about 2.5mg (0.036mg/kg body weight, people in body weight 70kg), about 5mg (0.071mg/kg body weight, people in body weight 70kg), about 10mg (0.143mg/kg body weight, people in body weight 70kg), about 20mg (0.286mg/kg body weight, people in body weight 70kg) or about 40mg (0.571mg/kg body weight, the oral administration daily dose is about 10mg when the people in body weight 70kg), perhaps particularly beginning.

The form of medication that makes for example contains 20-200mg, and preferred 20,40,80,120,160 or the equivalent of 200mg telmisartan free acid.Active substance mixes with HCTZ or chlortalidone, and like this, this form of medication for example contains 10-50mg, and preferred 50,25 or the 12.5mg diuretic.Telmisartan or its polymorph or salt, the daily dose of oral administration is a 10mg (or 0.143mg/kg body weight, people in body weight 70kg) to 500mg (7.143mg/1g body weight, people in body weight 70kg), the dosage of parenteral is about 20mg (the 0.286mg/kg body weight is in the people of body weight 70kg), and the daily dose of preferred oral administration is a 20mg (0.286mg/kg body weight, people in body weight 70kg) to 100mg (the 1.429mg/kg body weight is in the people of body weight 70kg).The daily dose of special preferred oral administration is a 40mg (0.571mg/kg body weight, people in body weight 70kg) to 80mg (the 1.143mg/kg body weight is in the people of body weight 70kg), perhaps, particularly dosage is about 80mg (the 1.143mg/kg body weight is in the people of body weight 70kg).

In drug regimen, the ratio of preferred simvastatin and telmisartan or its polymorph or salt is 1: 100-100: 1 (by weight).

In particularly preferred embodiments, simvastatin with telmisartan or its polymorph or salt with following daily dose oral administration:

5mg simvastatin and 40mg telmisartan (or its polymorph or salt);

5mg simvastatin and 80mg telmisartan (or its polymorph or salt);

10mg simvastatin and 40mg telmisartan (or its polymorph or salt);

10mg simvastatin and 80mg telmisartan (or its polymorph or salt);

20mg simvastatin and 40mg telmisartan (or its polymorph or salt);

20mg simvastatin and 80mg telmisartan (or its polymorph or salt).

According to an embodiment preferred, contain the simvastatin of 0.625mg-450mg and the telmisartan of 10mg-500mg in the dosage unit of pharmaceutical composition of the present invention, optional one or more medicine acceptable diluent and/or carriers in addition.

According to another embodiment preferred, contain the simvastatin of 1.25mg-80mg and the telmisartan of 20mg-100mg in dosage unit of pharmaceutical composition of the present invention, optional one or more medicine acceptable diluent and/or carriers in addition.

Contain the simvastatin of 2.5mg-20mg and the telmisartan of 40mg-80mg in the dosage unit of another preferred group of pharmaceutical composition of the present invention, optional also have one or more medicine acceptable diluent and/or carriers.

Contain 5,10 or the simvastatin of 20mg and 40 or the telmisartan of 80mg in the dosage unit of another preferred group of pharmaceutical composition of the present invention, optional also have one or more medicine acceptable diluent and/or carriers.

As mentioned above, the invention still further relates to telmisartan and the simvastatin purposes when being used in combination, be used to prepare treatment people or inhuman mammiferous pharmaceutical composition, with prevention or treat above-mentioned indication.Purposes is interpreted as preparing above-mentioned all pharmaceutical compositions of the present invention.

Embodiment:

Embodiment 1: the external PPAR γ ligand binding domain that is not combined in of telmisartan, losartan and irbesartan

Preparation contains the protein of people PPAR γ-ligand binding domain (LBD) in escherichia coli, as the GST-fusion rotein, and carries out purification with the affinity tswett's chromatography methods.

Embed restriction fragment site BamH I and Xho I by other in expression vector pGEX-4T-1 (Amersham), and sub-clone one dna fragmentation, the aminoacid 205-505 of its coding people PPAR γ 2-transcription factor is (referring to Genbank-Eintrag U79012), and the control fragments sequence.Under 25 ℃, induce 4 hours with 0.2mM IPTG after, in the escherichia coli-StammBL21 (DE3) of the recommendation of pGEX carrier, carry out Expression of Fusion Protein.And then make bacterial precipitation after inducing, and at PBS, freezing among the pH7.4 (weggefroren).According to the explanation of French Press, dissolved GST-PPAR γ-LBD-fusion rotein is carried out purification by GSTrap-post (Pharmacia).Add the reductive glutathion of 20mM and carry out eluting.

GST-PPAR γ-LBD-protein portion is measured protein concentration by HiTrap desalting column (Pharmacia) desalination with ortho-test.

Preparation contains the protein of people RXR α-ligand binding domain (LBD) in escherichia coli, as the Histag-fusion rotein, and carries out purification with the affinity chromatography.Through in expression vector pET28c (Novagen), embedding restriction fragment site BamH I and Not I in addition, sub-clone one dna fragmentation, the aminoacid 220-461 of its coding people RXR α-transcription factor is (referring to Genbank-Eintrag NM-002957, nt729-1457), and control fragments sequence.Under 25 ℃, induce 4 hours with 0.2mM IPTG after, in the pET carrier of recommending escherichia coli-bacterial strain BL21 (DE3), carry out Expression of Fusion Protein.And then make bacterial precipitation after the expression, and at PBS, freezing among the pH7.4.According to the explanation of French Press, dissolved His-RXR α-LBD-fusion rotein is carried out purification by HiTrap chelate column (Pharmacia).Carry out eluting through 500mM imidazoles gradient (stufe).His-RXR α-LBD-protein portion is measured protein concentration by HiTrap desalting column (Pharmacia) desalination with ortho-test.

A) α screening

α screening-test is described in UllmannEF etc. at first, among Proc Natl Acad SciUSA (1994) 91:5426-5430.The measurement of carrying out in the present embodiment according to Glickman JFDeng, the description of JBiomol Screen (2002) 7:3-10 is carried out.Test-buffer is made of 25mM Hepes pH7.4,100mM NaCl, 1mM DTT, 0.1%Tween-20,0.1%BSA.With the biotinylation LXXLL-peptide of 3nMGST-PPAR γ-LBD-fusion rotein, 15nM cofactor CBP (with respect to Mukherjee R etc., 218 pages of disclosed peptides of J Steroid Biochem Moi Biol (2002) 81:217-225) with cysteine of another kind of N-terminal, resist-GST-acceptor bead or strepto-antibiosis albumin-donor bead (Applied Biosystems) with each 10 μ g/ml, in the 12.5 μ l cumulative volumes in the presence of the experimental compound (in DMSO) of variable concentrations, incubated at room temperature 4 hours.Testing final DMSO concentration is 1% (v/v).DMSO solution with 1% contrasts (NSB) as a setting.On Packard fusion-measuring instrument, measure.

Concentration/M	Telmisartan		Rosiglitazone
						MW	SD	MW	SD
NSB	619	21	573	17
					1.00E-08			820	18
3.00E-08	642	41	1720	48
					1.00E-07	606	10	8704	59
3.00E-07	644	56	27176	1232
					1.00E-06	677	14	43233	1083
3.00E-06	720	35	52691	3771
					1.00E-05	847	82	56366	4303
5.00E-05	1111	135

Different with rosiglitazone, a kind of document is known at the bonded PPAR γ-agonist of LBD, find to pass through telmisartan, losartan and the irbesartan of enrichment (concentration is to 50 μ M) gradually, do not have direct activation PPAR γ-LBD, therefore do not have replenishing of tangible LXXLL-peptide.

B) SPA-test

At Mukherjee R etc., among J Steroid Biochem Mol Biol (2002) 81:217-225 SPA-test procedure has been described.The test buffer is made up of 20mM Tris pH7.5,25mM KCl, 10mM DTT, 0.2%Triton X-100.With 30nM GST-PPAR γ-LBD-fusion rotein, 30nMHis-RXR α-LBD, anti--GST-antibody (1: 600, Amersham Pharmacia), 0.25mg a-protein SPA PVT antibody-in conjunction with pearl (Amersham Pharmacia), 30nM ³The rosiglitazone of H-labelling is in 100 μ l cumulative volumes with experimental compound dilution, incubated at room temperature 5 hours.

Replace radioactive rosiglitazone.Add the unlabelled rosiglitazone of 10 μ M and contrast (NSB) as a setting, replace experimental compound, add used solvent, as DMSO as maximum (Bmax).

And then with tester in Hettich Universal 30Rf-centrifuge under the 2000Upm centrifugal 5 minutes, and measure after the cultivation at Packard TopCount NXT.

	Telmisartan		Irbesartan		Losartan
							Concentration/M	MW	SD	MW	SD	MW	SD
NSB	217	9	217	9	217	9
							Bmax	911	15	911	15	911	15
1.00E-07	837	49	913	54	915	43
							3.00E-07	802	28	810	49	835	11
1.00E-06	818	27	815	51	901	10
							3.00E-06	818	20	779	26	814	53
1.00E-05	703	30	723	37	787	46
							3.00E-05	691	222	648	40	784	96
1.00E-04	545	18	510	81	611	17

Different with direct PPAR γ-agonist (combining) with PPAR γ-LBD, even big excessive telmisartan, losartan or irbesartan do not have the radioactivity rosiglitazone of concentration dependent ground inhibition by binding site yet.

C) NMR-test

With direct PPAR γ-part,, in the presence of the experimental compound telmisartan, measure PPAR γ-LBD's as the rosiglitazone difference ¹⁵During N TROSY-spectrum, exchange interaction does not take place in the aminoacid of experimental compound and binding site.In the presence of experimental compound, the amino acid whose location of binding site is the same when not having part.

Embodiment 2: the PPAR γ of preparation stable conversion-recipient cell system

The aminoacid 205-505 of coding people PPAR γ 2-transcription factor is (corresponding to Genbank-Sequenz U79012Nucleotide 703-1605) a dna fragmentation, restriction fragment site BamH I and Hind III through inserting in the multiple clone site of carrier pFA-CMV (Stratagene) in addition, and checking sequence.The N-terminal of the plasmid pFA-CMV/hPPAR γ 2-LBD coding PPAR γ-LBD of gained is identical with the frame of Gal4 DNA-land.This plasmid anti-neomycin of also encoding.

Cell line CHO-K1 (ATCC CCL-61) and plasmid pFA-CMV/hPPAR γ 2-LBD and pFR-Luc (Stratagene) cotransfection.PFR-Luc luciferase-the gene of encoding is repeating under five times the control in HefeGal4-site.According to the maker explanation, carry out transfection with Lipofectamin2000.

Cultured cell in medium (Ham ' s F12 is added with 10% N of embryo's serum fotalem Kalberserum) after the transfection, is being arranged in the presence of the 0.5mg/ml G-418.Cultivate after 6 days, passage, and in culture medium, kept again 10 days.Pick the clone body of the anti-neomycin that obtains at microscopically, and in 96-hole-plate, separate and cultivation.Obtain containing the different cell transformed system of plasmid (as clone numbers 10,11,13 etc.), it is continued to be retained in the culture medium.

About the inducibility of luciferase gene, by PPAR γ-agonist, as rosiglitazone, research cell line, and the luciferase signal reaction that raises with stimulating by PPAR γ-agonist.

Embodiment 3: the activatory cellulated PPAR γ of telmisartan, losartan and irbesartan

The CHO-K1 cell line of drawing from the clone body 11 of the conversion of embodiment 2 is placed in (ausgesat) 96-hole-flat underside, and its density is 3 * 10 ⁴Cell/200 μ l/ holes, and in having the Ham ' s F-12-culture medium of 10% N of cleer and peaceful 0.5mg/ml G-418 of fetal blood overnight incubation.Change in the culture medium that does not add G-418 after 24 hours.

With suitable solvent, make experimental compound reach 100 times as DMSO, and cell is diluted to 1: 00 with existing substrate to desirable concentration.With employed solvent such as DMSO, contrast as a setting with same concentrations.

Adding material abandoning supernatant (Uberstande) after 24 hours is with each 150 μ l lavation buffer solution (25mM Tricine, 16.3mM MgSO ₄, pH7.8) washed cell is twice.Behind the washing step, add 150 μ l luciferase-test buffer (25mM tricin (Tricine), 0.5mMEDTA, 0.54mM NaTPP, 16.3mM MgSO to each tester ₄, 1.2mM ATP, 0.05mM fluorescein, 56.8mM2-mercaptoethanol, 0.1%Trition X-100, pH7.8) and 50 μ l lavation buffer solutions.After waiting five minutes on the PackardTopCount NXT, measure luminosity.Carry out integration to beginning to measure the back plain enzyme unit of initial 10 seconds relative fluorescence (RLU), obtain luciferase-activity.

	Telmisartan		Irbesartan		Losartan		Rosiglitazone
									Concentration/M	MW	SD	MW	SD	MW	SD	MW	SD
NSB	466	188	466	188	466	188	741	141
									1.00E-08							2761	178
3.00E-08							8256	708
									1.00E-07							35265	2947
3.00E-07	760	255	491	70	874	475	86859	6139
									1.00E-06	2859	455	657	65	589	70	106252	30018
3.00E-06	24498	2290	1028	342	672	88	143232	14064
									1.00E-05	61397	7853	3292	556	709	163	150989	24245
3.00E-05	58790	2055	22133	4202	3271	585
									1.00E-04			29600	6939	1132	1668

By the angiotensin ii receptor antagonist telmisartan, can activate the PPAR γ-approach in PPAR γ-recipient cell system especially doughtily.By other angiotensin ii receptor antagonist,, at first realize activation in higher test concentrations and less degree ground as losartan and irbesartan etc.

Embodiment 4: example of formulations

Tablet 1

By telmisartan sodium salt and auxiliary agent and magnesium stearate are directly suppressed, obtain the tablet of following compositions:

Component:	mg
		The telmisartan sodium salt	41.708
Mannitol	149.542
		Microcrystalline Cellulose	50.000
Cross-linking sodium carboxymethyl cellulose salt	5.000
		Magnesium stearate	3.750
Amount to	250.000

Tablet 2

By telmisartan sodium salt and auxiliary agent and magnesium stearate are directly suppressed, obtain the tablet of following compositions:

Component:	mg
		The telmisartan sodium salt	83.417
Sorbitol	384.083
		Doubt vinylpyrrolidone K25	25.000
Magnesium stearate	7.500
		Amount to	500.000

Tablet 3

Hydrochlorothiazide (Hvdrochlorothiiazid), telmisartan sodium salt, Sorbitol and red iron oxide mix in freely falling body blender (" Free Fall Blender "), sieve by sieve O.8mm, after adding magnesium stearate, in the freely falling body blender, be processed into pulverous mixture.

Use suitable tablet machine (as Korsch KEO or Fette P1200) that the compositions of active substance and auxiliary agent is pressed into tablet then.Make the tablet with following compositions, wherein, the amount of every telmisartan sodium salt that contains is equivalent to 80mg telmisartan free acid.

Content	The mg/ sheet	％
			The telmisartan sodium salt	83.417	13.903
Hydrochlorothiazide	12.500	2.083
			Sorbitol	494.483	82.414
Red iron oxide	0.600	0.100
			Magnesium stearate	9.000	1.500
Amount to	600.000	100.000

After stirring (75rpm) in 30 minutes, the telmisartan sodium salt of three reinforced tablets dissolves in 900ml0.1M phosphate buffer pH7.5 and reaches 92 ± 1.5%, 96 ± 1.8% or 100 ± 1.0%.After 30 minutes, the hydrochlorothiazide dissolving reaches 69 ± 6.3%, 72 ± 2.1% or 78 ± 1.8% in 900ml 0.1M HCl (100rpm).

Embodiment 5: prepare the telmisartan crystals of sodium salt by telmisartan

The raw material of preparation telmisartan crystals of sodium salt is the telmisartan free acid, and it obtains according to conventional method (for example according to EP-0502314).

In the 308.8ml toluene in the reaction vessel that the adding of 154.4g telmisartan is suitable, suspension and 27.8g 44.68% sodium hydroxide solution and 84.9ml ethanol merge, and heat about 30 minutes down at 78 ℃.Filtering mixt then.Randomly, when a large amount of solid residues are in filter, with the mixture washing filter of 61.8ml toluene and 15.3ml ethanol composition.

463.2ml toluene is added in another reaction vessel, and heating down refluxes.Under boiling temperature, slowly add the filtrate that obtains by said method, carry out azeotropic distillation simultaneously.After adding fully, add the solution that randomly obtains equally by the filter cleaning mixture, and azeotropic distillation once more.Distillating mixture is 103 ℃ up to temperature.Then with the suspension cool to room temperature.Under vacuum, filter crystal, use the 154.4ml toluene wash, and dry in 60 ℃ cyclic drying case.

Productive rate: 154.6g (96%)

Clear crystal

C ₃₃H ₂₉N ₄O ₂Na * 0.5H ₂O value of calculation: C72.51 H5.72 N10.25

Test value: C72.57 H5.69 N10.21

Embodiment 6: prepare the telmisartan crystals of sodium salt by the telmisartan hydrochlorate

Preparation telmisartan hydrochlorate:

With the 411g tert-butyl group-4 '-[[2-just-propyl group-4-methyl-6-(1-tolimidazole-2-yl)-benzimidazole-1-yl]-methyl]-the diphenyl-2-carboxylic acid ester is suspended in the 822ml glacial acetic acid, and merges with 213g concentrated hydrochloric acid (37%) aqueous solution.Heating blends down refluxes.Steam about 640ml solvent.The residue that keeps lentamente with 50-60 ℃ the hydration of about 620ml also.Mix 20g active carbon (as Norit SX2Ultra) in the mixture.Gained mixture stir about 10 minutes under constant temperature.After the filtration, residue 25ml glacial acetic acid and about 620ml water washing 3 times.Gained filtrate reheats about 50-60 ℃, and sneaks into about 2 premium on currency.At about 23 ℃ of following stir abouts after 12 hours, the formed crystal of sucking filtration, and with about 500ml water washing 2 times, with about 900ml washing with acetone 1 time, then about 60 ℃ dry down.

Productive rate: 367g (92.5%)

Clear crystal

Fusing point: 278 ℃

Prepare telmisartan-crystals of sodium salt by the telmisartan hydrochlorate:

55.1g telmisartan hydrochlorate is dissolved in 110.2ml toluene, 5.5ml water and the 55.1ml isopropyl alcohol.Mixture and 36.9g Feldalat NM (30%, in methanol) and 2.75g active carbon (as Norit SX 2 Ultra) merge.Then mixture heated is arrived about 75 ℃.Under constant temperature, in about 30 minutes, steam the solvent mixture of about 50ml.Filter the suspension of gained.With about 20ml toluene wash residue.Filtrate merges with about 5ml water and about 150ml toluene.Heating gained mixture under refluxing.Will about 150ml solvent mixture azeotropic distillation (up to 102 ℃).Make mixture 100 ℃ of following crystallizations 1 hour.The sucking filtration crystal, with about 50ml toluene wash, and dry under about 60 ℃.

Productive rate: 53.6g (99%)

Clear crystal

C ₃₃H ₂₉N ₄O ₂Na0.5H ₂O value of calculation: C72.51 H5.72 N10.25

Test value: C72.44 H5.68 N10.20.

Claims (18)

1. the purposes of angiotensin ii receptor antagonist telmisartan or its a kind of salt and HMG-CoA-reductase inhibitor simvastatin, it is used to prepare people or the employed medicine of mammal that is used for the treatment of when its demonstration need prevent or treat cardiovascular disease, heart and lung diseases, pneumonopathy or nephropathy.

2. according to the purposes of claim 1, be used for the treatment of the people when its demonstration needs prevention or treatment with hypertension that hyperlipemia or atherosclerosis combine.

3. according to the purposes of claim 1, be used for the treatment of the people when it shows needs treatment asthma, bronchitis or interstitial lung disease.

4. according to the purposes of claim 1, be used for the treatment of the people when it is diagnosed as type ii diabetes or suspects for prediabetes, be used for prevent diabetes and prediabetes, perhaps be used for the treatment of metabolic syndrome and insulin resistance with normotensive patient.

5. according to the purposes of claim 1, be used for the treatment of or the prophylaxis of hypertension insulin resistance.

6. according to the purposes of claim 1, be characterised in that, be used for surpassing the people of the need treatment of every dl blood plasma 110mg glucose at fasting blood sugar.

7. according to the purposes of claim 1, be characterised in that, be used for surpassing the people of the need treatment of 150mg/dl in the blood values of triglyceride.

8. according to the purposes of claim 7, be characterised in that, be used for the blood values at HDL, for the women, every dl blood plasma is lower than 40mg, and for the male, every dl blood plasma is lower than the people of the need treatment of 50mg.

9 purposes according to claim 4 are characterised in that, be used for surpassing 130mmHg in the systolic blood pressure value, and the diastolic blood pressure value surpass the people of the need treatment of 80mmHg.

10. purposes according to Claim 8, be characterised in that, the daily dose of simvastatin oral administration for about 0.009mg/kg body weight to the 6.43mg/kg body weight, the daily dose of telmisartan or its polymorph or salt oral administration is about 0.143mg/kg to 7.143mg/kg body weight.

11. purposes according to Claim 8 is characterised in that, the daily dose of simvastatin parenteral is about 0.286mg/kg body weight, and the daily dose of telmisartan or its polymorph or salt parenteral is about 0.286mg/kg body weight.

12. showing at it, treatment needs prevention or treatment cardiovascular disease, heart and lung diseases, pneumonopathy or nephropathy, the time people's method, be characterised in that with a kind of medicine that contains angiotensin ii receptor antagonist telmisartan or its a kind of salt and HMG-CoA-reductase inhibitor simvastatin and carry out administration.

13. be used for the treatment of people or mammal pharmaceutical compositions for use when it shows needs prevention or treatment cardiovascular disease, heart and lung diseases, pneumonopathy or nephropathy, said composition comprises telmisartan and makes up with simvastatin and optional one or more auxiliary agents.

14. the pharmaceutical composition according to claim 13 is characterised in that, pharmaceutical dosage form contains 20-200mg telmisartan and 2.5-40mg simvastatin.

15. the pharmaceutical composition according to claim 14 is characterised in that, the ratio of telmisartan and simvastatin or its polymorph or salt is 1: 2 to 1: 16 (by weight).

16. the pharmaceutical composition according to claim 13 is characterised in that, two kinds of active substance also mix with a kind of diuretic.

17. the pharmaceutical composition according to claim 16 is characterised in that, pharmaceutical dosage form contains 10-50mgHCTZ or chlortalidone.

18. the pharmaceutical composition according to claim 13 is characterised in that, with active substance with simultaneously, separately or successively mode is treated.