MXPA06010416A - Use of organic compounds - Google Patents

Abstract

The present is directed to a method for the prevention of, delay progression to or treatment of a condition or disease selected from diabetes type 2 (associated with or without hypertension), severe hypertension, PH, malignant hypertension, isolated systolic hypertension, familial dyslipidemic hypertension, endothelial dysfunction (with or without hypertension), survival post-MI, increase of formation of collagen and other extracellular matrix proteins, restenosis after stenting, PVD including PAD and peripheral venous disorders, CAD, morbidity, mortality, cerebrovascular diseases, metabolic disorder (Syndrome X), AF, renoprotection, reduction of proteinuria, renal failure, glomerulonephritis, nephrotic syndrome, renal fibrosis, AIN, ATN, acute tubulo-interstitial nephritis, PKD, vascular inflammation, rennin secreting tumors, vasculitides or closure, restenosis of dialysis access grafts comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof alone or in combination with another active ingredient.

Description

USE OF RENIN INHIBITORS IN THERAPY Aliskyrene inhibits the action of the natural renin enzyme. The latter passes from the kidneys into the blood, where it dissociates the angiotensinogen, releasing the decapeptide of angiotensin I, which then dissociates in the lungs, kidneys, and other organs, to form the octapeptide of angiotensinogen I I. The octapeptide increases the blood pressure both directly by arterial vasoconstriction, and indirectly by the release from the adrenal glands of the sodium ion retention hydrometer, aldosterone, accompanied by an increase in extracellular fluid volume. This increase can be attributed to the action of aldosterone. Inhibitors of the enzymatic activity of renin cause a reduction in the formation of angiotensin I. As a result, a proportionally smaller amount of angiotensin I I is produced. The reduced concentration of this active peptide hormone is the direct cause, for example, of the hypotensive effect of renin inhibitors. Other evaluations revealed that renin inhibitors can be used for a greater number of therapeutic indications. The invention relates to a method for the prevention, delay of progress, overcoming, or treatment of a condition or disease selected from: (a) Type 2 diabetes (associated with or without hypertension). For an example of a useful model to demonstrate the treatment of renal protection in type 2 diabetes with hypertension, see Kelly et al., Kid Int., Volume 54, pages 343-352 (1998); and for renal protection of db / db mice with diabetes mellitus without hypertension, see Ziyadeh et al., Proc. Nati Acad. Sci. USA, Volume 97, Number 14, pages 801 5-8020 (2000); (b) Severe hypertension, pulmonary hypertension (PH), malignant hypertension, isolated hypertension, and familial dyslipidemic hypertension. For an example of a useful model for demonstrating the treatment of severe hypertension and malignant hypertension, see Park et al., Am. J. Hypertens, Volume 15, Number 1, Part 1, pages 78-84 (2002); and for pulmonary hypertension, see Jones et al., Am. J. Physiol. Heart Circ. Physiol. (2004); (c) Endothelial dysfunction (with or without hypertension). For an example of a useful model for demonstrating the treatment of endothelial dysfunction (with or without hypertension), see Shinozaki et al., Diabetes, Volume 48, pages 2437-2445 (1999); (d) Survival after myocardial infarction (Ml); increase in the formation of collagen and other extracellular matrix proteins, and aortic coarctation. For an example of a useful model to demonstrate the treatment of survival after myocardial infarction and increased collagen formation, see Villarreal et al., Circulation, Volume 108, Number 12, pages 1487-1492 (2003); (e) Restenosis after vascular implantation (stents). For an example of a model useful for demonstrating the treatment of angioplasty, see Huang et al., Heart, Volume 90, pages 1 95-1 99 (2004); (f) Peripheral vascular disease (PVD), including peripheral arterial disease (PAD) and peripheral venous disorders; (g) Coronary artery disease (CAD). For an example of a model useful for demonstrating the treatment of coronary artery disease, see Gerríty et al., Diabetes, Volume 50, Number 7, pages 1654-1 655 (2001); (h) Pathology and mortality; (i) Cerebrovascular diseases. For an example of a useful model to demonstrate the treatment of this indication, see Park et al. (2002), supra; (j) Metabolic disorder (Syndrome X). See Wang et al., Circulation, Volume 107, pages 1923-1 929 (2003); (k) Atrial fibrillation (AF); (I) Renoprotection and proteinuria reduction; (m) Renal insufficiency, for example chronic renal failure; (n) Glomerulonephritis (may be associated with nephrotic syndrome, high blood pressure, and reduced renal function), focal segmental glomerulonephritis, and minimal change nephropathy; (o) S nephrotic syndrome and renal fibrosis; (p) Acute interstitial nephritis (AIN), acute tubular nephritis (ATN), and acute tubulo-interstitial nephritis; (q) P KD. See M artínez et al., Am. J. Kidney Dis. , Volume 29, pages 435-444 (1 997); (r) vascular inflammation; (s) renin secreting tumors; (t) migraine headaches; (u) vasculitides; and (v) closure and restenosis of dialysis access grafts, which comprises administering to a warm-blooded animal, an effective amount of a renin inhibitor or a pharmaceutically acceptable salt thereof. A further object of the present invention is to provide therapeutic compositions and a method that further aids in the stabilization of plaques, which comprises administering to a warm-blooded animal an effective amount of a renin inhibitor or a pharmaceutically acceptable salt thereof. Plaque stabilization means the inhibition of the plaque passing through a phase where the lipid core has grown and the fibrous cap is very thin and vulnerable to rupture due to an increase in the density of the macrophages. In a preferred aspect of the present invention, a method for preventing, delaying progress, overcoming, or treating a condition or disease selected from type 2 diabetes (associated with or without hypertension), isolated systolic hypertension, dysfunction is provided. endothelial (with or without hypertension), survival after infarction of myocardium, restenosis after vascular implantation (stents), peripheral vascular disease (PVD), coronary artery disease (CAD), pathology, mortality, cerebrovascular diseases, metabolic disorder (Syndrome X), renoprotection, and vascular inflammation. The prevention, delay of progress, overcoming, or treatment of a condition or disease that is different from category (b), as described hereinbefore or later herein, is understood to be made in patients with or without hypertension. A renin inhibitor is a drug that effectively inhibits the renin enzyme pharmacologically, resulting in the prevention, delay of progress, and treatment of conditions and diseases associated with inhibition of renin, especially the conditions and diseases specified above. in the present and later in the present. The renin inhibitors comprise, for example, peptide renin inhibitors, and preferably non-peptide inhibitors. A non-peptidic renin inhibitor is, for example, ditequirene, terlaquirene, sanquirene, SPP-100, or a compound of Formula (I): (I) or in each case, a pharmaceutically acceptable salt thereof.

The renin inhibitor of Formula (I), chemically defined as 2 (S), 4 (S), 5 (S), 7 (S) -N- (3-amino-2,2-dimethyl-3-oxopropyl ) -2,7-di- (1-methyl-ethyl) -4-hydroxy-5-amino-8- [4-methoxy-3- (3-methoxy-propoxy) -phenyl-octanamide, is given to know specifically in European Patent Number EP 678503 A. Its hemi-fumarate salt is especially preferred. The non-peptidic renin inhibitor comprises those disclosed in International Publication Number WO 97/09311, especially the corresponding renin inhibitors disclosed in the claims and in the processing examples, especially SSP100 of the Formula : especially R respectively, in International Publication Number WO 04/002957, in particular the renin inhibitors disclosed in the processing examples and in the claims. The corresponding subject matter of these International Applications WO is incorporated by reference to the present invention. The structure of the active agents identified hereinabove or hereinafter by generic or commercial names, can be taken from the current edition of the standard "The Merck Index" compendium, or from the databases, for example Patent Focus , for example IMS Life Cycle - IMS World Publications. The corresponding content thereof is incorporated herein by reference. Any person skilled in the art is absolutely qualified to identify the active agents and, based on these references, in the same way is able to manufacture and test the indications and pharmaceutical properties in conventional test models, both in vitro and in vivo.

DEFINITIONS Type 2 diabetes mellitus, including type 2 diabetes mellitus associated with hypertension, is a disease in which the pancreas does not secrete enough insulin due to impaired pancreatic (ß) -beta cell function, and / or where there is Insensitivity to the insulin produced (insulin resistance). Typically, fasting plasma glucose is less than 126 milligrams / deciliter, while pre-diabetes is, for example, a condition that is characterized by one of the following conditions: impaired fasting glucose (from 1 1 to 125) milligrams / deciliter), and impaired glucose tolerance (fasting glucose levels less than 126 milligrams / deciliter, and post-prandial glucose level between 140 milligrams / deciliter and 199 milligrams / deciliter). Type 2 diabetes mellitus can be associated with or without hypertension. Diabetes mellitus occurs frequently, for example, in African-Americans, Latin / Hispanic Americans, Native Americans, Asian-Americans, and Pacific Islanders. Markers of insulin resistance include HbA1 C, HOMA IR, measurement of collagen fragments, TG F-β in urine, PAI-1 and pro-renin. Severe hypertension is characterized by a systolic blood pressure of > . 180 mm Hg, and a diastolic blood pressure of > 1 10 mm Hg. Pulmonary hypertension (PH) is a disorder of the blood vessels of the lung, where the pressure in the pulmonary artery rises above the normal level of < 25/10 (especially the primary and secondary pulmonary hypertension), for example, because the small vessels that supply blood to the lungs constrict or tighten. According to the World Health Organization, pulmonary hypertension can be divided into five categories: pulmonary arterial hypertension (PAH), a pulmonary hypertension that occurs in the absence of a known cause is referred to as primary pulmonary hypertension, while hypertension Secondary pulmonary disease is caused by a condition selected, for example, from emphysema; bronchitis; vascular diseases by collagen, such as scleroderma, Crest syndrome, or systemic lupus erythematosus (SLE); pulmonary hypertension associated with disorders of the respiratory system; pulmonary hypertension due to thrombotic or chronic embolic disease; pulmonary hypertension due to disorders that directly affect the pulmonary blood vessels; and pulmonary venous hypertension (HPV). Malignant hypertension is usually defined as a very high blood pressure with optic nerve lining behind the eye, termed as papilledema (grade IV Keith-Wagner hypertension retinopathy). This also includes the malignant HTN of childhood. Isolated systolic hypertension is characterized by a systolic blood pressure of > _ 140 mm Hg, and a diastolic blood pressure of < 90 mm Hg. Familial dyslipidemic hypertension is characterized by disorders dyslipidemic mixed. Biomarkers include oxidized LDL, HDL, glutathione, and LPA homocysteine. Renovascular hypertension (renal arterial stenosis) is a condition in which the narrowing of the renal artery is significant, which leads to an increase in blood pressure, resulting from the signals sent by the kidneys. Biomarkers include renin, PRA, and pro-renin. Endothelial dysfunction with or without hypertension is a condition in which normal dilatation of blood vessels is impaired due to a lack of vasodilators-endothelium derivatives. The biomarkers include CRP, IL6, ET1, BIG ET1, VCAM and ICAM. Biomarkers of survival after myocardial infarction include BNP and pro-collagen factors. Fibrosis of the anus / renal / cardiac is defined as an abnormally high accumulation of collagen and other extracellular matrix proteins, due to the higher production or the lower degradation of these proteins. Biomarkers include BNP, pro-collagen factors, LVH, AGE, RAGE and CAGE. Coarctation of the aorta is an area of localized narrowing of the major artery (aorta). The narrowing can be caused by a "ledge" tissue inside the blood vessel that reduces its area. In an alternative way, it may be caused by a sub-development of a part of the aorta itself, which houses a longer area of reduced diameter. Restenosis after percutaneous transluminal ankioplasty is it defines as the closing of an artery following a procedure to open that artery that is totally or partially blocked by the accumulation of plaque or another disease. Biomarkers include coronary flow reserve. Peripheral vascular disease (PVD) refers to damage or dysfunction of peripheral blood vessels. There are two types of peripheral vasculopathies: peripheral arterial disease (PAD) that refers to diseased peripheral arteries, and peripheral venous disorders that can be measured by a brachial index of the ankle. Peripheral artery disease (PAD) is a condition that progressively hardens and narrows the arteries due to a g radic accumulation of plaque, and refers to conditions that affect blood vessels, such as arteries, veins, and capillaries, of the body outside the heart. It is also known as peripheral venous disorder. Trom bophlebitis is a condition in which an obstructing blood clot has formed which causes the surrounding veins to become inflamed. Veins - varicose veins is a condition in which an enlarged veins swell, darken and twist or contort. This occurs normally in the legs. Chronic venous insufficiency is an advanced stage of leg vein disease, where the veins become incompetent, causing blood to build up in the veins. legs and that they feed and sometimes they leak backwards. Coronary artery disease (CAP) is a condition that progressively hardens and narrows arteries due to a gradual buildup of plaque, and refers to conditions that affect blood vessels, such as the arteries within the heart. Coronary artery disease is a peculiar form of atherosclerosis that occurs in the three small arteries that supply oxygen-rich blood to the heart muscle. Biomarkers include CPK and troponin. Cerebrovascular diseases comprise attack conditions, such as embolic and thrombotic attack; thrombosis of large vessels and disease of small vessels; and hemorrhagic attack. Embolic attack is characterized by the formation of blood clots, for example in the heart, when clots travel through the bloodstream and into the brain. This can lead to a blockage of small blood vessels and cause an embolism. Thrombotic attack is a condition where blood flow is impaired due to a block of one or more of the arteries that supply blood to the brain. This process usually leads to thrombosis, causing thrombotic attacks. Biomarkers include PAI 1, TPA, and the function of platelets. Metabolic disorder (Syndrome X): Among different definitions of the metabolic syndrome that are known, three of them They are of particular relevance. Metabolic syndrome is characterized by three or more of the following criteria: 1. Abdominal obesity: waist circumference > 102 centimeters in men, and > 88 centimeters in women. 2. Hypertriglyceridemia: > 150 milligrams / deciliter (1,695 millimoles / liter). 3. Low HDL cholesterol < 40 milligrams / deciliter (1,036 millimoles / liter) in men, and < 50 milligrams / deciliter (1,295 millimoles / lítro) in women. 4. High blood pressure: > 130/85 mm Hg. 5. High fasting glucose: > 110 milligrams / deciliter (&g; 6.1 millimoles / liter). Metabolic syndrome can also be characterized by three or more of the following criteria: Triglycerides > 150 milligrams / deciliter, systolic blood pressure (BP) > _ 130 mm Hg, or diastolic blood pressure > .85 mm Hg, or a treatment against hypertension, high density lipoprotein cholesterol < 40 milligrams / deciliter, fasting blood sugar (FBS) > 110 milligrams / deciliter, and a body mass index (BMI) > 28.8 kilograms / square meter. Metabolic syndrome can also be characterized by diabetes, impaired glucose tolerance, impaired fasting glucose, or insulin resistance plus two or more of the following abnormalities: 1. High blood pressure: > _ 160/90 mm Hg. 2. Hyperlipidemia: concentration of triglycerides > _ 150 mg / deciliter (1,695 m unlimited / liter), and / or high density lipoprotein cholesterol < 35 milligrams / deciliter (0.9 m ilimoles / liter) in men, and < 39 m iligram os / deciliter (1.0 millimoles / liter) in women. 3. Or central kiss: ratio of the waist to the hip of > 0.90 in men, or > 0.85 in women, and / or body mass index > 30 kilograms / square meter or. 4. Microalbuminuria: index of excretion of urinary albumin > . 20 mg / m in uto, or a ratio of the albumin to the creatin ina of > . 20 m iligrams / gram o. The biomarkers include proteinuria, TG F-β, TNF-a, and adiponectin. Biomarkers include low density lipoproteins, high density lipoproteins, and all markers of endothelial dysfunction. Atrial fibrillation (AF) is a type of heartbeat that is irregular or "upright," or that can cause blood to collect in the heart and potentially form a clot that can travel to the brain and cause an embolism. Organ protection is the prevention of the loss of the function of restoring a deteriorated function of a body organ. Renoprotection is a reduction of proteinuria. Biomarkers include fragments of collagen and TGF-β in the urine. Renal insufficiency, for example chronic renal failure; HE characterized for example by proteinuria and / or slight elevation of plasma creatinine concentration (106-177 milligrams / liter, corresponding to 1.2-2.0 milligrams / deciliter). Glomerulonephritis may be associated with nephrotic syndrome, high blood pressure, and reduced renal function; focal segmental glomerulonephritis; minimal change nephropathy, lupus nephritis, post-streptococcal glomerulonephritis, and IgA nephropathy. Nephrotic syndrome is a compilation of conditions that include massive proteinuria, edema, and central nervous system irregularities. Biomarkers include urinary protein excretion. Stabilization of plaque means making a plaque less dangerous by preventing thinning / rupture of the fibrous cap, loss of smooth muscle cells, and the accumulation of inflammatory cells. Renal fibrosis is an abnormal accumulation of collagen and other extracellular matrix proteins, which leads to loss of kidney function. The biomarkers include fragments of collagen and TGF-a in the urine. End-stage renal disease (ESRD) is the loss of kidney function to the extent that dialysis or renal replacement is needed. Biomarkers include glomerular filtration rate and creatinine clearance. Polycystic kidney disease (PKD) is a disorder genetic characterized by the growth of numerous cysts in the kidney. Cysts of polycystic kidney disease can slowly reduce much of the kidney mass, reducing kidney function, and leading to kidney failure. Polycystic kidney disease can be classified as two major inherited forms of polycystic kidney disease which are: autosomal dominant polycystic kidney disease, and autosomal recessive polycystic kidney disease, while non-inherited polycystic kidney disease can be termed as an acquired cystic kidney disease. Biomarkers include reduction of renal cysts by non-invasive imaging. Obesity is a condition of overweight defined by a body mass index of > 30. The term "prevention" means the prophylactic administration to healthy patients, to prevent the presentation of the conditions mentioned herein. Moreover, the term "prevention" means the prophylactic administration to patients who are in a previous stage of the conditions, to be treated. The term "delay, progress, improvement", as used herein, means administration to patients who are in a previous stage of the condition to be treated, in whose patients a pre-condition of the condition is diagnosed. correspondent. The term "treatment" is understood as the management and care of a patient for the purpose of fighting the disease, condition, or disorder. An "effective amount" will mean the amount of the compound that will elicit the biological or medical response of a tissue, system, or animal (including man) that is being sought by a researcher or clinician. The terms "warm-blooded animal or patient" are used interchangeably herein, and include, but are not limited to, humans, dogs, cats, horses, pigs, cattle, monkeys, rabbits, mice, and animals. laboratory. The preferred mammals are humans. A "pharmaceutically acceptable salt" refers to a non-toxic salt commonly used in the pharmaceutical industry, which is prepared by methods well known in the art. Surprisingly, the present invention has a longer duration of action than ACE or ARB, while maintaining the same efficacy. Furthermore, renin is a direct vasodilator, and has direct profibrotic effects. By blocking the activity of renin, anti-inflammatory and α-fibrotic effects would be expected in addition to what is seen with ACE and ARBs, due to the additive effect of Rl on ANGII and renin blockade. In addition, renin block affects ANG4 and ANG1-7. It is suspected that ANG1-7 has beneficial effects that affect inflammation, thrombosis, fibrosis, and cell proliferation. Most surprising is the experimental discovery that the combined administration of the renin inhibitor of Formula (I) or a salt thereof, with a therapeutic agent selected from the group consisting of (i) - (xiv), as defined below, results not only in a beneficial therapeutic effect, especially synergistic, or an enhancement of at least one of the components of the combination, but also additional benefits resulting from the combined treatment, and the additionally surprising beneficial effects, compared with a monotherapy that applies only one of the pharmaceutically active compounds used in the combinations disclosed in I presented. The invention relates in a similar manner to combinations, for example pharmaceutical combinations, containing a renin inhibitor of the present invention, or in each case, a pharmaceutically acceptable salt thereof, in combination with at least one active ingredient, or in each case, a pharmaceutically acceptable salt thereof. The combination can be made, for example, with the following compositions, selected from the group consisting of: (i) an angiotensin receptor I I antagonist, or a pharmaceutically acceptable salt thereof; (Ii) an inhibitor of the angiotensin converting enzyme, or a pharmaceutically acceptable salt thereof; (ii) a calcium channel blocker, or a pharmaceutically acceptable salt thereof; (iv) an HMG-Co-A-reductase inhibitor, or a salt pharmaceutically acceptable thereof; (v) an aldosterone synthase inhibitor, or a pharmaceutically acceptable salt thereof; (vi) an aldosterone antagonist, or a pharmaceutically acceptable salt thereof; (vii) a double ACE / N EP inhibitor, or a pharmaceutically acceptable salt thereof; (vii) a β-blocker, or a pharmaceutically acceptable salt thereof; (ix) an endothelin (ET) antagonist, or a pharmaceutically acceptable salt thereof; (x) a diuretic, or a pharmaceutically acceptable salt thereof; (xi) an oral hypoglycemic agent, or a pharmaceutically acceptable salt thereof; (xii) an inhibitor of M rp2; (xiii) furosemide or a pharmaceutically acceptable salt thereof; and (xiv) Gleevec, or a pharmaceutically acceptable salt thereof. The combination according to the present invention can be used, for example, for the prevention, delay of progress, overcoming, or treatment of a condition or disease selected from: (a) type 2 diabetes (associated with or without hypertension ); (b) severe hypertension, pulmonary hypertension, malignant hypertension, isolated systolic hypertension, and familial dyslipidemic hypertension; (c) endothelial dysfunction (with or without hypertension); (d) survival after myocardial infarction, increased collagen formation, and coarctation of the aorta; (e) restenosis after percutaneous transluminal angioplasty; (f) peripheral vasculopathy, including peripheral arteriopathy and peripheral venous disorders; (g) coronary artery disease; (h) pathology and mortality; (i) cerebrovascular diseases; (j) metabolic disorder (Syndrome X); (k) atrial fibrillation; (I) organ protection; (m) renoprotection; (n) renal failure, for example chronic renal failure; (o) glomerulonephritis (may be associated with nephrotic syndrome, high blood pressure, and reduced renal function), focal segmental glomerulonephritis, and minimal change nephropathy; (p) nephrotic syndrome and renal fibrosis; (q) AIN, ATN, and acute tubulo-interstitial nephritis; (r) end-stage renal disease (ESRD); (s) polycystic kidney disease (P KD); (t) vascular inflammation; (u) obesity; (v) migraine headaches; (w) renin-secreting tumors; and (x) vasculitides. The combination according to the present invention can be used in a method for plate stabilization, which comprises administering to a warm-blooded animal, an effective amount of a combination, of the invention or a pharmaceutically acceptable salt thereof. The combination according to the present invention, which comprises a renin inhibitor or a pharmaceutically acceptable salt thereof, can be administered by different routes of administration. Each agent can be tested over a wide range of dosages to determine the optimal level of the drug for each agent in combination, in order to elicit maximum response. For these studies, it is preferred to use treatment groups consisting of at least six animals per group. Each study is best conducted where the effects of the combination treatment group are determined at the same time as the individual components are evaluated. Although the effects of the drug can be observed with an acute administration (such as a day), it is preferable to observe the responses in a chronic setting, as shown below, where They did experiments during an observation period of two to three weeks. The long-term study is of sufficient duration to allow for the full development of the compensatory responses that arise, and therefore, the observed effect will most likely show the real responses of the test system representing the sustained or persistent It is understood that AT-i receptor antagonists (also referred to as angiotensin receptor 11 antagonists) are the active ingredients that bind to the AT-i receptor subtype of the angiotensin II receptor, but do not result in activation of the receiver. As a consequence of the inhibition of the AT ^ receptor, these antagonists, for example, can be used as anti-hypertensives, or for the treatment of congestive heart failure. The class of AT receptor? it comprises compounds having different structural characteristics, and non-peptidic ones are essentially preferred. For example, mention may be made of the compounds that are selected from the group consisting of Walloon (see European Patent Number EP 443983), they would be listed (see European Patent Number EP253310), candésartan (see European Patent Number EP 459136). ), eprosartan (see European Patent Number EP 403159), irbesartan (see European Patent Number EP 45451 1), olmesartan (see European Patent Number EP 503785), tasosartan (see European Patent EP number 539086), felmisartan (see European Patent Number EP 522314), the compound with the designation E-1477 of the Formula: the compound with the designation SC-52458 of the Formula: and the compound with the designation ZD-8731 of the Formula: or in each case, a pharmaceutically acceptable salt thereof.

The preferred AT1 receptor aniiagonias are the agents that have been traded, and the Walster, or a salt, is more preferred.

Accepted Acceptance of the same. It is understood that inhibitors of H M G-CoA-uctase network (also referred to as ß-hydroxy-ß-mephile-glucopylic-enzyme-A-reductase inhibitors) are the active agents that can be used to reduce lipid levels, including blood cholesterol. The class of HMG-CoA reductase inhibitors comprises compounds that have different styrene-like characteristics. For example, mention may be made of the compounds that are selected from the group consisting of atorvasiaine, cerivasfafina, compacfine, dalvasfaina, dihydrocompacline, fluindosatin, fl grapesiaina, lovasiaina, piiavastatin, mevasfafina, pravastatin, rivasiafina, simvasfaina, rosuvasiaina, and velosfain, or in each case, a pharmaceutically acceptable salt thereof. The preferred HMG-CoA reductase inhibitors are the commercially available agents, and more preferred are fluvasiaine and pifavasiaine, or in each case, a pharmaceutically acceptable salt thereof. The interruption of the enzymatic degradation of angiotensin | up to angiotensin II with the so-called inhibitors of the angiogenesis-converting enzyme, it is a success variant for the regulation of blood pressure, and therefore, it also makes available a therapeutic method for the treatment of cardiac insufficiency congesfiva. The class of inhibitors of the enzyme converíidora of Angiotensin comprises com positions that have different structural characteristics. For example, mention may be made of the compounds that are selected from the group consisting of alacepril, benazepril, benazeprilat, captopril, ceronapril, cilazapril, delapril, enalapril, enaprilai, fosinopril, imidapril, lisinopril, m ovelipril, perindopril, quinapril. , ramipril, spirapryl, em ocapril, and trandolapril, or in each case a pharmaceutically acceptable salt of the same. Preferred angioinensin converting enzyme inhibitors are the agents that have been traded, and more benazepril and enalapril are preferred. The class of blockers in the calcium channel essentially comprises the dihydropyridines (DHPs) and those that are not hydropyridines, such as the blockers of the calcium channel of the dilifiazem and the verapamil type. The calcium combination in this combination is preferably a representative of dihydropyridine selected from the group consisting of amlodipine, felodipine, riosidine, isradipine, lacidipine, nicardipine, nedipipine, nigulipipine, niludipine, nimodipine, nisoldipine, niirendipine, and nidipipine. , and preferably is a representative other than dihydropyridine selected from the group consisting of flunarizine, prenylamine, diltiazem, fendiline, gallopamil, mibefradil, anipamil, tiapamil, and verapamil, and in each case, a pharmaceutically acceptable salt of the These calcium channel blockers are used therapeutically, for example, as drugs confers hyperfunction, against angina, and anti-arrhythmics. Preferred calcium channel blockers comprise amlodipine, diltiazem, isradipine, nlcardipine, nifedipine, nimodipine, nizoldipine, nitrendipine, and verapamil, or, for example, depending on the specific calcium channel blocker, a pharmaceutically acceptable salt thereof. Especially preferred is dihydropyridine, amlodipine, or a pharmaceutically acceptable salt, especially the besylate thereof. An especially preferred representative of those which are not dihydropyridines is verapamil or a pharmaceutically acceptable salt, especially hydrochloride, thereof. The aldosterone synase is an enzyme that converts corticosterone to aldosterone by hydroxylation of corticoserone to form 18-OH-corycoserone, and from 18-OH-corticosterone to aldosterone. It is known that the class of aldosterone synthase inhibitors is applied for the treatment of hyper-tension and primary aldosleronism, and comprises 'inhibitors of spheroidal and non-spheroidal aldoserone syndeses, the latter being more preferred. Preference is given to commercially available aldoseerone synase inhibitors, or to aldosterone synthase inhibitors that have been approved by health authorities.

The class of aldosterone synthase inhibitors comprises compounds having different esírucfural characteristics. By example, mention may be made of the compounds that are selected from the group consisting of the non-spheroidal aromatase inhibitors anastrozole, fadrozole (including its (-) enantiomer), as well as the steroidal aromatase inhibitor exemestane, or in each case case, where applicable, a pharmaceutically acceptable salt thereof. The most preferred non-spheroidal aldospherone synase inhibitor is the enantiomer - (+) of the (US Patents Nos. 4,617,307 and 4,889,861), or a pharmaceutically acceptable salt thereof, for example the fadrozole hydrochloride of the formula: A preferred anabolic steroidal aldosterone is eplerenone of the Formula: or spironolactone. A preferred dual ACE / NEP inhibitor is, for example, omapatrilat (see European Patent No. EP 629627), fasidotril, or fasidotrilaine, or Z 1 3752A (see International Publication No. WO 97/24342), or if appropriate, a pharmaceutically acceptable salt of the same. The β-blockers suitable for use in the present invention include β-adrenergic blocking agents (β-blockers), which compete with epinephrine for β-adrenergic receptors, and interfere with the action of epinephrine. Preferably, β-blockers are selective for the β-adrenergic receptor, compared to (a) -adrenergic receptors, and thus do not have a significant α-blocker effect. Suitable β-blockers include the compounds selected from acebutolol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, esmolol, labelalol, meoprolol, nadolol, oxprenoiol, penbuololol, pindolol, propranolol, soolol, and imolol. When the β-blocker is an acid or a base, or is capable of a way to form pharmaceutically acceptable salts or prodrugs, it is considered that these forms are encompassed herein, and it is understood that the compounds can be administered in free form. or in the form of a pharmaceutically acceptable salt or a prodrug, such as a physiologically hydrolysable and acceptable ester. For example, meipoprolol is suitably administered as its tartrate salt, propranolol is suitably administered as the hydrochloride salt, etc. The endoíelina (ET) is a highly vasoconsíricfor péplido Poienie, synthesized and released by the vascular endothelium. Endothelin exists in three isoforms (ET-1, ET-2, and ET-3). ET endothelin will mean any or all of the other isoforms of endothelin. High plasma endothelin levels have been reported in patients with, for example, essential hypertension. The antagonism of the endophine receptfor can be used to inhibit vasoconstriction effects induced by endothelin. A preferred endothelin antagonist is, for example, bosentan (see European Pafenia Number EP 526708 A), enrasing (see International Publication Number WO 94/25013), arsenals (see International Publication Number WO 96/06095), in particular the hydrochloride of Afrasenia, Darusenfan (see European Patent Number EP 785926 A), BMS 193884 (see European Patent Number EP 702012 A), sifaxenían (see the United States of America Number 5,594,021), especially siliaxsenia-sodium , YM 598 (see European Patent Number EP 882719 A), S 0139 (see International Publication Number WO 97/27314), J 104132 (see European Patent Number EP 714897 A or International Publication Number WO 97/37665 ), and also tezosenfan (see International Publication Number WO 96/19459), or in each case, a pharmaceutically acceptable salt thereof. A diuretic is, for example, a thiazide derivative selected from the group consisting of chlorothiazide, hydrochlorothiazide, methylclothiazide, amiloride, triamterene, and chlorothalidone. The most preferred is hydrochloroxyzide.

Preferably, the therapeutically co-effective amounts of the active agents according to the combination of the present invention can be administered simultaneously or in sequence in any order, separately, or in a fixed combination. The pharmaceutical composition according to the present The invention, as described hereinabove and further in the present, may be used for simultaneous use or use in sequence in any order, for separate use, or as a fixed combination. The corresponding active ingredients, or pharmaceutically acceptable salts thereof, can also be used in the form of a solvate, such as a hydrate, or including other solvents used for chilling. The compounds to be combined may be present as pharmaceutically acceptable salts. If you have compues you have, for example, at least a basic ceníre, can form acid addition salts. The corresponding acid addition salts can also be formed which, if desired, additional basic chromatography is present. Compounds having an acid group, for example COOH, can also form salts with bases. In a variation of the same, the present invention in the same way refers to a "case of parts", for example in the sense that the components to be combined According to the present invention, they can be dosed independently, or by using different fixed combinations with distinguished quantities of the components, that is, in a simulated manner or at different points of time. The loudspeaker loudspeaker loops can then be administered, for example, in a simultaneous or chronologically staggered manner, that is, at different points of time, and with equal or different time intervals for any part of the kit of parts. Preferably, the inflows of time are selected in such a way that the effect on the disease or condition brought about in the combined use of the paries is greater than the effect that would be obtained through the use of only one of the components. The invention further relates to a commercial package comprising the combination according to the present invention, June with instructions for simultaneous, separate, or sequential use. The dosage may depend on different factors, such as the mode of application, the species, the age and / or the individual condition. For oral application, the doses to be administered daily are 10 milligrams and 1 gram. The term "synergistic", as used in the present, means that the effect achieved with the methods and compositions of the present invention is greater than the sum of. the effects that dissolve from the individual methods and compositions that comprise the ingredients of this invention. separated. The person skilled in the pertinent art is absolutely qualified to select a relevant and standard animal test model to test the therapeutic indications and beneficial effects indicated earlier in the present and more in the present. These pharmaceutical preparations are for enteral admi- nistration, such as oral, and also rectal or parenteral, to homeotherms, including preparations to the pharmacological agent as well as either June or June with the auxiliary pharmacist auxiliaries acosfum bradas. For example, pharmaceutical preparations are from about 0.1 to 90 per cent, preferably from about 1 per cent to about 80 per cent of the active compound. Pharmaceutical preparations for parenteral or parenteral administration, and also ocular, are, for example, in uniform dosage forms, such as coated tablets, tablets, capsules, or suppositories, and also ampoules. They are prepared in a way that is known by itself, for example using conventional mixing, granulation, coating, solubilization, or lyophilization processes. As a result, pharmaceutical preparations for oral use can be obtained by combining the active compound with solid excipients, if desired a mixture that has been obtained is granulated, and if required or necessary, the mixture is processed. or the g ranulated in tablets or cores of coated tablets after of having added suitable auxiliary substances. The dosage of the active compound may depend on a variety of factors, such as the mode of administration, the homeothermic species, the age, and / or the individual condition. Preferred dosages for the active ingredients of the pharmaceutical combination according to the present invention are the effective ferapéuíicamenfe dosages, especially those that are commercially available. Normally, in the case of oral administration, an approximate daily dose of about 1 milligram to about 360 milligrams is to be estimated, for example for a patient weighing approximately 75 kilograms. The dosage of the active compound may depend on a variety of favors, such as the mode of administration, the homeothermic species, age, and / or the individual condition. The pharmaceutical preparation will be supplied in a suitable unit dosage form, for example a capsule or tablet, and comprising a cartridge, which, in conjunction with the additional components, will be jointly effecive. The doses of the renin inhibitor of Formula (I) which are to be administered to warm-blooded animals, for example humans, for example of a body weight of approximately 70 kilograms, in particular the effective doses in inhibiting the Renin enzyme, for example to reduce blood pressure and / or to improve the symptoms of glaucoma, are approximately 3 m iligram to approximately 3 g ram, preferably from approximately 10 milligrams to approximately 1 gram, for example approximately 20 to 200 mm ilig ram / person / day, preferably divided into 1 to 4 individual doses, which, for example, can be of the same size. Usually, children receive approximately half the dose for adults. The necessary dose for each individual can be monitored, for example, by measuring the serum concentration of the active ingredient, and can be adjusted to an optimum level. Individual doses include, for example, 75 milligrammes, 150 milligrams, or 300 milligrams per patient. The valsartan, as a representative of the class of AT-i receptor antagonists, will be supplied in a suitable unit dosage form, for example a capsule or tablet, and comprising an effective therapeutic amount, eg, from about 20 milligrams to about 320. milligrams of walruses, which can be applied to patients. The application of the active ingredient can occur up to three times a day (tid.), Starting, for example, with a daily dose of 20 milligrams or 40 milligrams of walruses, increasing up to 80 milligrams a day, and also up to 1 60 milligrams. per day, and up to 320 milligrams per day. Preferably, the waltz is applied twice a day (b.i.d.), with a dose of 80 milligrams or 160 milligrams, respectively, each. The corresponding doses can be added, for example, in the morning, at noon, or in the night. Administration twice a day is preferred. In the case of the HMG-CoA reductase inhibitors, the preferred unit dosage forms of HMG-CoA reductase inhibitors are, for example, tablets or capsules comprising, for example, from about 5 milligrams to about 120 milligrams, preferably, when fluvastatin is used, for example 20 milligrams, 40 milligrams, or 80 milligrams (equivalent to free acid) of fluvastain, for example administered once a day. In the case of angiotensin converting enzyme inhibitors, the preferred unit dosage forms of the angioinensin converting enzyme inhibitors are, for example, tablets or capsules comprising, for example, from about 5 milligrams to about 20 milligrams. , preferably 5 milligrams, 10 milligrams, 20 milligrams, or 40 milligrams of benazepril; from approximately 6.5 to 100 milligrams, preferably 6.25 milligrams, 12.5 milligrams, 25 milligrams, 50 milligrams, 75 milligrams, or 100 milligrams of captopril; from about 2.5 milligrams to about 20 milligrams, preferably 2.5 milligrams, 5 milligrams, 10 milligrams, or 20 milligrams of enalapril; from about 10 milligrams to about 20 milligrams, preferably 10 milligrams or 20 milligrams of fosinopril; from about 2.5 milligrams to about 4 milligrams, preferably 2 milligrams or 4 milligrams of perindopril; Approximately 5 milligrams to approximately 20 milligrams, preferably 5 milligrams, 10 milligrams, or 20 milligrams of quinapril; or from about 1.25 milligrams to about 5 milligrams, preferably 1.25 milligrams, 2.5 milligrams, or 5 milligrams of ramipril. Administration is preferred three times a day. For example, suitable daily dosages of β-blockers for adults, of the corresponding compounds for oral administration, are as indicated: acebutolol - 200-1,200 milligrams; atenolol - 25-100 milligrams; betaxolol - 10-20 milligrams; Bisoprolol - 5-10 milligrams; carteolol - 2.5-10 milligrams; labetalol - 100-1,800 milligrams; Meoprolol - 50-450 milligrams; nadolol - -40-240 milligrams; oxprenolol - 60-480 milligrams; penbuolol - 20-80 milligrams; pindolol - 10-80 milligrams; Propanolol - 40-320 milligrams or 60-320 milligrams for the long-acting formulation; sotalol - 160-320 milligrams; Iimolol - 20-60 milligrams. Especially preferred β-blockers for use in the present invention are atenolol, metoprolol, and propranolol. Low-dose combinations are especially preferred.

Claims (10)

CLAIMING IS

1 . A method for the prevention, delay of progress, or withdrawal of a condition or disease selected from type 2 diabetes (associated with or without hypertension), severe hypertension, pulmonary hypertension (PH), malignant hypertension, isolated systolic hypertension, dyslipidemic hypertension familial, endothelial dysfunction (with or without hypertension), survival after myocardial infarction (M l), increased formation of collagen and other ex-cellular matrix proteins, restenosis after vascular implantation (stení), peripheral vascular disease (PVD), including peripheral arteriopay (PAD) and peripheral venous transitions, coronary arteriography (CAD), paology, morbidity, cerebrovascular diseases, metabolic disorder (Syndrome X), atrial fibrillation (AF), renoprotection, reduction of profeinuria, renal insufficiency, glomerulonephritis, syndrome nephrotic, renal fibrosis, acute interstitial nephritis (AI N), nephritis acute tubular ritis (ATN), tubulo-inferstic nephritis, polycystic kidney disease (PKD), vascular inflammation, secretory renin tumors, vasculiides or closure, resenosis of dialysis access ingestions, which comprises administering a warm-blooded animal , an effective amount of a renin inhibitor, or a pharmaceutically acceptable salt thereof. 2. A method of assisting the stabilization of plaque, which comprises administering to a warm-blooded animal, a

Effectiveness of a renin inhibitor or a pharmaceutically acceptable salt thereof.

3. The method of claim 1, wherein the renin inhibitor is a compound of Formula (I): or a pharmaceutically acceptable salt thereof.

4. The method of claim 2, wherein the renin inhibitor is a compound of Formula (II): or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition, which comprises a renin inhibitor in combination with at least one additional active agent selected from the group consisting of: (i) an angiotensin II receptor antagonist, or a pharmaceutically acceptable salt thereof; (ii) an inhibitor of the angiotensin converting enzyme, or a pharmaceutically acceptable salt thereof; (iii) a calcium channel blocker, or a pharmaceutically acceptable salt thereof; (iv) an HMG-Co-A-reductase inhibitor, or a pharmaceutically acceptable salt thereof; (v) an inhibitor of aldosterone synthase, or a pharmaceutically acceptable salt thereof; (vi) an aldosterone antagonist, or a pharmaceutically acceptable salt thereof; (vii) a double inhibitor of ACE / NEP, or a pharmaceutically acceptable salt thereof; (viii) a β-blocker, or a pharmaceutically acceptable salt thereof; (ix) an endothelin (ET) antagonist, or a pharmaceutically acceptable salt thereof; (x) a diuretic, or a pharmaceutically acceptable salt thereof; (xi) an oral hypoglycemic agent, or a pharmaceutically acceptable salt thereof; (xii) an inhibitor of Mrp2; (xiii) furosemide or a pharmaceutically acceptable salt thereof; and (xiv) Gleevec, or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition of claim 5, wherein the renin inhibitor is a compound of the Formula (I), or a pharmaceutically acceptable salt thereof.

7. A method for the prevention, delay of progress, overcoming, or treatment of a condition or disease selected from: (a) type 2 diabetes (associated with or without hypertension); (b) severe hypertension, pulmonary hypertension, elevated blood pressure, isolated systolic hypertension, and familial dyslipidemic hypertension; (c) endothelial dysfunction (with or without hypertension); (d) survival after myocardial infarction, increase in the formation of collagen, and coarctation of the aorta; (e) restenosis after percutaneous transluminal angioplasty; (f) peripheral vasculopaphy, including peripheral arteriopathy and peripheral venous disorders; (g) coronary artery disease; (h) paphology and mortality; (i) cerebrovascular diseases; (j) Metabolic trasforne (S syndrome X); (k) atrial fibrillation; (I) organ protection; (m) renoprotection; (n) Kidney failure, for example kidney failure chronicle; (o) glomerulonephritis (may be associated with nephrotic syndrome, high blood pressure, and reduced renal function), focal segmental glomerulonephritis, and minimal change nephropathy; (p) nephrotic syndrome and renal fibrosis; (q) AIN, ATN, and acute tubulointerstitial nephritis; (r) end-stage renal disease (ESRD); (s) polycystic kidney disease (PKD); (í) vascular inflammation; (u) obesity; (v) migraine headaches; (w) renin secretory nodes; and (x) vasculifides, which comprises administering to a warm-blooded animal, an effective amount of the pharmaceutical composition of claim 5.

8. The method of claim 7, wherein the renin inhibitor is a compound of the Formula (I), or a pharmaceutically acceptable salt thereof.

9. A method for assisting the stabilization of plaque, which comprises administering to a warm-blooded animal, an effective amount of the pharmaceutical composition of claim 5. The method of claim 9, wherein the renin inhibitor is a compound of the Formula (I): or a pharmaceutically acceptable salt thereof.