MXPA02010091A

MXPA02010091A - Combination of organic compounds.

Info

Publication number: MXPA02010091A
Application number: MXPA02010091A
Authority: MX
Inventors: Ronald Edward Steele
Original assignee: Novartis Ag
Priority date: 2000-04-12
Filing date: 2001-04-10
Publication date: 2003-02-12
Also published as: CN1422152A; AU2001273938B2; IL152081A0; CA2405895A1; AR032316A1; KR20020089437A; WO2001076574A2; HUP0301335A2; NZ521855A; NO20024920L; EP1282410A2; AU7393801A; HUP0301335A3; RU2002129569A; SK14612002A3; WO2001076574A3; ZA200208204B; BR0110079A; JP2003530343A; PE20020082A1

Abstract

The invention relates to a pharmaceutical composition, of (i) an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof either alone or in combination with (ii) an AT1 receptor antagonist combined with a diuretic, or in each case, a pharmaceutically acceptable salt thereof and (iii) a pharmaceutically acceptable carrier.

Description

NOVEDOSO MEDICAL USE OF ALDOSTERONE SYNTHASE INHIBITORS ONLY OR IN COMBINATION WITH ANTAGONISTS OF THE AT-1 RECEIVER The invention relates to a pharmaceutical composition comprising: (i) an aldosterone tapese inhibitor or a pharmaceutically acceptable salt thereof alone or in combination with: (i) an ATi receptor antagonist or an ATi receptor antagonist combined with a diuretic or, in each case, a pharmaceutically acceptable salt thereof and (ii) a pharmaceutically acceptable carrier. The invention further relates to a method for preventing, delaying the progress of, treating a disease or condition selected from the group consisting of: (a) hypertension, congestive heart failure, renal insufficiency, especially chronic renal failure, restenosis after of percutaneous transluminal angioplasty and restenosis after coronary artery bypass surgery; (b) atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, for example chronic renal failure, hypothyroidism, survival after myocardial infarction (Ml), coronary heart disease, hypertension in the old age, familial dyslipidemic hypertension, increased collagen formation, fibrosis and remodeling that follows hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension; and (c) endothelial dysfunction with or without hypertension, which comprises administering the pharmaceutical composition of the present invention. In a preferred embodiment the present invention relates to a method of preventing, delaying the progress of or treating endothelial dysfunction with or without hypertension comprising administering to a warm-blooded animal, including man, in need thereof an effective amount of an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof. It is understood that ATi receptor antagonists (also called angiotensin II receptor antagonists) are those active ingredients that bind to the ATi receptor subtype of the angiotensin II receptor, but do not result in receptor activation. As a consequence of the inhibition of the AT-i receptor, these antagonists can, for example, be used as antihypertensive agents or to treat congestive heart failure. The class of ATi receptor antagonists comprises compounds that have differential structural aspects, essentially preferred are non-peptidic ones. For example, mention may be made of the compounds that are selected from the group consisting of valsaran, losarian, candesartan, eprosartan, irbesartan, saprisartan, fasosarian, iodide, the compound with the designation E-1477 of the following formula: the compound with the designation SC-52458 of the following formula: and the compound with the designation compound ZD-8731 of the following formula: or, in each case, a pharmaceutically acceptable salt thereof. Preferred ATi receptor antagonists are those agents that have been marketed, the most preferred one being valsartan or a pharmaceutically acceptable salt thereof. A diurenic is, for example, a derivative of liazide selected from the group consisting of chloroiazide, hydrochloroiazide, meiylclothiazide, and chlorothalidon. The most preferred is hydrochloroiazide. The aldoseerone synphase inhibitor is an enzyme that converts corticoserone to aldosterone to mediate the hydroxylation of corylserone to form 18-OH-corycosterone and 18-OH-corycoserone to aldosterone. The class of aldosterone synase inhibitors known to be applied for the synthesis of hypertension and primary aldosteronism comprises spheroidal aldoseferone syndase inhibitors as non-steroidal, with the latter being the most preferred. Preference is given to commercially available aldosterone synthase inhibitors or those aldosterone synthase inhibitors that have been approved by health authorities. The class of aldosterone synthase inhibitors comprises compounds having differential structural aspects. For example, mention may be made of the compounds that are selected from the group consisting of the non-steroidal aromatase inhibitors anasirozole, fadrozole (including the (+) - enanfimer thereof), as well as the spheroidal aromatase inhibitor. exemesta, or, in each case where applicable, a pharmaceutically acceptable salt thereof. The most preferred non-steroidal aldosterone synthase inhibitor is the (+) - enantiomer of fadrozole hydrochloride (U.S. Patent Nos. 4,617, 307 and 4, 889, 861) of the formula: Surprisingly, the pharmaceutical compositions according to the present invention exhibit a beneficial ephemeral effect, especially a synergistic (= more than additive), plus benefits resulting from combined irradiation such as a surprising prolongation of efficacy, a wider variety of treatment therapeutic and surprising beneficial effects in diseases and conditions associated with inhibitors of receptors ATi or sindasa aldosíerona, respectively. The compositions according to the present invention can be used for the prevention of, the progression of, and the progression of a disease or condition selected from the group consisting of: (a) hypertension, congestive heart failure, renal insufficiency , especially chronic renal failure, restenosis after percutaneous transluminal angioplasty and restenosis after coronary artery bypass surgery; (b) atherosclerosis, insulin resistance and syndrome X, diabetes mellilus lipo 2, obesity, nephropathy, renal insufficiency, for example chronic renal failure, hypoliroidismo, survival after myocardial infarction (Ml), coronary heart diseases, hypertension in the old age, familial dyslipidemic hypertension, increased collagen formation, fibrosis and remodeling that follows hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension; and (c) endothelial dysfunction with or without hypertension. The person skilled in the pertinent art is fully qualified to select a relevant animal test model to test the therapeutic indications and beneficial effects indicated heretofore and subsequently herein. These beneficial effects can, for example, be demonstrated in the test model as described by G. Jeremic et al. In J. Cardovasc. Pharmacol. 27: 347-354, 1996.

Study Design In the study to be performed, permanent coronary artery occlusion (CAO) was used in rats as a model of acute myocardial infarction. The experiments are carried out with 5 treatment groups characterized by the following aspects: • simulated operated animals • CAO + vehicle • CAO + wallocks • CAO + aldoserone synase inhibitor • CAO + aniolygonism of ATi receptor + aldosterone synase inhibitor. The following doses and routes of administration may be applied: For example, for the valsare ATi receptor antagonist, a) -3d to + 2d: s.c. injections. of 2.5 mg / kg BW / 12 h b) + 3d to + 28d: s.c. Osmotic minipumps Boost 5 mg / kg / d For the (+) - enantiomer of fadrozole hydrochloride: Osmoic minipumps Boost 0.4 mg / kg / d. During the examination, the following variables were measured: • size of the infarction, • volume of the LV chamber, • density of the inlersíicial and perivascular collagen in duplicated LV myocardium, • conence of proiein in COL-I and COL-11 in myocardium LV of duplication mediated wesíern blot, • cross-sectional area of cardiomyocytes and length in myocardial sections LV, • plasma concentrations of Ang II and aldosterone, • concentration of sodium, potassium and aldosterone in urine, • blood pressure in consieníes animals, • blood pressure in LV and carotid in anesthetized animals.

Methodology Infarct size: transverse hemi - ological sections of six μm thickness of the left ventricle with blue nylon tissue were acquired and acquired by means of a video camera (Sony) B / W XC-77CE CCD. The resulting image is processed in a KS 300 image analysis system (Cari Zeiss Vision) using specially developed software (Porzio et al., nineteen ninety five). A single blind operator for treatment defines in an irrational way the borders of the intervenlricular septal, and the infarcted area in each section is identified semiautomatically as the area of unstained ventricular tissue. The soffware calculates automatically for each component of the ventricular section defined as the chamber, sepio, infarcted area, infarcted LV wall and viable LV wall, a set of geometric parameters (Porzio et al., 1 995). Histology: Hearts are fixed in situ, by retrograde perfusion with formaldehyde at 4% regulated after stopping in diastole by i.v. of KCl 0.5 M. After fixation, the left ventricle (LV) and the free wall of the right ventricle are weighed separately; The longest diameter of the LV is measured with a calibrator. The histological sections of the LV are stained with hematoxylin & amp; eosin for qualitative examination and to quantify the cross-sectional area of cardiomyocytes with a semi-automated image analysis ruin. The deposition of interstitial collagen in LV in sections dyed red is evaluated Sirius with a semi-automated image analysis routine (Masson et al., 1998). Collagen content in duplicate myocardium of LV: The tissue of LV in the duplicate myocardium is homogenized, subjected to electrophoresis SDS-PAGE and electro-blotted on nitrocellulose membrane. The spots are exposed to primary antibodies, i.e., antiserum of type I collagen or type I1 (Chemicon) rabbit anti-rala. Primary antibodies are recognized by secondary antibodies conjugated with alkaline phosphatase (for type I collagen) or peroxidase (type I collagen l). Volume of the left ventricular chamber: The volume of the LV chamber is determined in hearts arrested in diastole (KCl) and fixed in formalin under a hydrostatic pressure equivalent to the final diastolic pressure of LV measured. A metric rod is inserted into the LV to measure the internal length of the LV. The transverse diameters of the LV chamber are measured in two cross sections of 1 mm thickness near the base and the apex of the ventricle (Jeremic et al., 1996). The volume of the chamber is calculated from an equation that integrates the cross-sectional diameters and interior length. Left Systemic and Ventricular Hemodynamics: A microtip pressure transducer (M illar S PC-320) connected to a recorder (Windograf, Gould Electronics) is inserted into the right carotid artery to record the systolic and dialytic blood pressures. The pressure transducer is advanced in LV to measure systolic LV (LVSP) and end-diastolic (LVEDP) pressures, the first derivative of LV pressure with respect to time (+ dP / dt) and heart rate. Noninvasive blood pressure: Systolic blood pressure and heart index are measured by the tail bend method (Leica LE 5002) in conscious rats. Urine electrolytes, hormones: Rats are housed individually in metabolic cages and urine is collected in 24 h in 1 ml of 6N HCl. The water intake is measured. Urine catecholamines are extracted in Bondelut C-? 8 columns (Varian), separated by HPLC (Apex-l l C18 50x4.5 mm, 3 μm analytical column, Jones Chromatography) and quantified with an electrochemical detector ( Coulochem II, ESA) (Goldstein et al., 1981 ). Plasma and urine aldosterone and plasma angiotensin I I are determined with specific radioimmunoassays (Aldoctk-2, DiaSorin and Angiotensin I I, N ichols Diagnostics). Sodium and potassium are measured in urine by flame photometry. Sample size 1 0 analyzable animals in each treatment group are sufficient to detect biologically significant differences. Only rats with an infarct size of at least 10% of the area of the LV section are included in the final analysis. Accordingly, the composition of the present invention can be used for the prevention of, delay in prog, and survival treatment after myocardial infarction (M l).

Endothelial dysfunction is recognized as a critical factor in vascular diseases. The endothelium plays a bimodal role as the source of several hormones or by-products with opposite effects: vasodilation and vasoconstriction, inhibition or promotion of growth, fibrinolysis or thrombogenesis, production of anaerobic agents or oxidants. Genetically predisposed hypertensive animals with endothelial dysfunction are a valid model to evaluate the effectiveness of cardiovascular therapy. Endothelial dysfunction is characterized, for example, by increased oxidative stress, causing decreased nitric oxide, factors involved in coagulation or increased fibrinolysis such as plasminogen activation inhibitor-1 (PAI-1), tissue factor (TF), activator of tissue plasminogen (tPA), increased adhesion molecules such as ICAM and VCAM, increased growth factors such as bFGF, TGFβ, VEGF, all factors that cause cell growth, inflammation and fibrosis. The trafficking for example of endothelial dysfunction can be demonstrated in the following test: Male SHR material and methods 20-24 weeks old, purchased from RCC Ltd. (Fullingsdorf, Switzerland), were kept in a room with controlled temperature and light with free access to rat food and tap water. The experiment is carried out in accordance with the NIH guide and approved by the Canton Veterinary office (Bew 161, Kantonales Veterináramt, Liestal, Switzerland). All rats are treated with the NO L-NAME synthase inhibitor (Sigma Chemicals) administered in drinking water (50 mg / L) for 12 weeks. The average daily dose of L-NAME calculated from the water consumed was 2.5 mg / kg / d (range 2.1 -2.7). The rats are divided into 5 groups: group 1, control (n = 40); Group 2, valsartan (5 mg / kg / d, n = 40); Group 3, the (+) - enantiomer of fadrozole hydrochloride (n = 30); Group 4, a combination of the (+) - enantiomer of fadrozole hydrochloride and valsartan (5 mg / kg / d, n = 30); and Group 5, valsartan (50 mg / kg / d, n = 30). The drugs are administered in fluid to drink. The pressor effect of Ang I I at 1 mg / kg obtained in normotensive rats of conirols is reduced by 49% and 73% after treatment with valsartan 5 and 50 mg / kg / d, respectively (Gervais et al., 1999). The response to Ang I injected into Wistar Kyoto rats previously treated with the (+) - enantiomer of fadrozole hydrochloride or valsarían 5 mg / kg / d is similar. Body weight is measured every week. Systolic blood pressure and heart rate are recorded by tail fold plethysmography 3 and 2 weeks before the start of the study and 2 weeks after the administration of the drug. The urine is collected in a 24-hour period from rats kept in individual (metabolic) cages the week before starting treatment and at weeks 4 and 12 for measurement of volume and determination of protein, creatine, sodium and potassium using normal laboratory methods. At the same time, samples of points are withdrawn, blood from the retroorbital plexus (maximum 1 ml) for creatinine, Na * and KJ assays. Ten rats are sacrificed from each group at four weeks for liver and heart collection for morphological analysis.

The remaining rats are sacrificed at 12 weeks. The heart and liver weights are recorded. Sampling of terminal blood was performed in 5% EDTA in weeks 4 (morphometry study) and 12 (end of study) for aldosterone, radioimmunoassay de-sterilization using aldosterone-RIA DPC cover-bill equipment (Bühlmann , Switzerland). Statistical analysis: All data are expressed as the mean ± SEM. Statistical analysis is performed using a one-way ANOVA, followed by a Duncan multiple-range test and a Newman-Keuls test, for comparison between the different groups. The results with a probability value of less than 0.05 are deeply significant statistically. A regression improvement of atherosclerosis without affecting serum lipid levels can, for example, be demonstrated by using the animal model as described by H. Kano and collaborators in Biochemical and Biophysical Research Communications 259, 414-419 (1999). That the compounds or combinations according to the present invention can be used for the regression of a Atherosclerosis induced with cholesterol diet, can be demonstrated using the test model described, for example, by C. Jiang et al in Br. J. Pharmacol, (1991), 104, 1033-1037. That the compounds or combinations according to the present invention can be used for the eradication of renal insufficiency, especially chronic renal failure, can be demonstrated using the test model described, for example, by D. Cohen et al. In Journal of Cardiovascular Pharmacology , 32: 87-95 (1998). Additional benefits when applying the composition of the present invention are that lower doses of the individual drugs to be combined according to the present invention can be used to reduce the dosage, for example, that dosages need not only to be minor frequently but also to be applied less frequently, or they can be used in order to decrease the incidence of side effects. This according to the wishes and requirements of patients to be trafados. Most surprising is the experimental finding that the combined administration of the combination according to the present invention results in a beneficial effect, especially synergistic, therapeutic, but also in benefits that result from combined treatment and surprising beneficial effects in addition compared to a monotherapy applying only one of the pharmaceutically active compounds used in the combinations described in the present. In particular, the most surprising is the experimental finding that the combination of the present invention results in a therapeutic effect, especially synergistic, beneficial, but also in benefits resulting from combined tracing such as a surprising prolongation of efficacy, a variety broader therapeutic treatment and surprising beneficial effects in diseases and conditions as specified hereinbefore or hereinbelow. Additional benefits when applying the composition of the present invention are that lower doses of the individual drugs to be combined according to the present invention can be used to network the dosage, for example, that the dosages need not only be smaller frequently, but also applied less frequently, or can be used in order to decrease the incidence of side effects. This according to the wishes and requirements of patients to be treated. The results of the studies clearly show that the composition in accordance with the present invention can be used for the prevention of, delay in the progress of, the tracing of a disease or condition selected from the group consisting of: (a) hypertension, congestive cardiac insufficiency, renal insufficiency, and especially chronic renal insufficiency, restenosis after percutaneous transluminal angioplasty and restenosis after coronary artery bypass surgery; (b) atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, for example chronic renal failure, hypothyroidism, survival after myocardial infarction (Ml), coronary heart disease, hypertension in the old age, familial dyslipidemic hypertension, increased collagen formation, fibrosis and remodeling that follows hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension; and (c) endothelial dysfunction with or without hypertension. The compositions of the present invention can also be used for the prevention and delay of progress and preferably the treatment of other diseases. A preferred composition comprises the combination of the (+) enantiomer of fadrozole hydrochloride and valsartan or valsartan combined with hydrochlorothiazide. Preferably, the therapeutically effective amounts together of an ATi receptor antagonist or an ATi receptor antagonist combined with a diuretic, in each case, in free or pharmaceutically acceptable salt form and an aldosterone synthase inhibitor in free or pharmaceutically acceptable salt can be administered simultaneously or sequentially in any order, of separately or in a fixed combination. In addition, the invention relates to a method for the prevention of, delay in the progress of, trafficking in a disease or condition selected from the group consisting of: (a) hypertension, congestive heart failure, renal insufficiency, especially chronic renal failure, restenosis after percutaneous transluminal angioplasty and restenosis after coronary artery bypass surgery; (b) atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, for example chronic renal failure, hypothyroidism, survival after myocardial infarction (M l), coronary heart disease, hypertension in old age, familial dyslipidemic hypertension, increased collagen formation, fibrosis and remodeling that follows hypertension (antiproliferative effect of the combination), all diseases or conditions associated with or without hyperlension; and (c) endoihelial dysfunction with or without hypertension, which comprises administering to a warm-blooded animal, including man, a therapeutically effective amount of an aldosterone synthase inhibitor in free form or pharmaceutically acceptable salt either alone or in combination with an ATi receptor antagonist or in combination with an ATi receptor antagonist combined with a diuretic, in each case, in free or pharmaceutically acceptable salt form.

Furthermore, the invention relates to the use of a: (a) pharmaceutical composition comprising: (i): a receptor antagonist ATi or an ATi receptor antagonist combined with a diuretic or, in each case, a pharmaceutically acceptable salt thereof; (ii) an aldoserone tapese inhibitor or a pharmaceutically acceptable salt thereof and (i) a pharmaceutically acceptable vehicle; or (b) an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention of, delay in the progress of, a disease or condition selected from a group consisting of: (a) ) hypertension, congestive heart failure, renal failure, especially chronic renal failure, restenosis after percutaneous transluminal angioplasty and restenosis after coronary artery bypass surgery; (ß) atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, for example chronic renal failure, hypothyroidism, survival after myocardial infarction (M l), coronary heart disease, hypertension in old age, familial dyslipidemic hypertension, increased collagen formation, fibrosis and remodeling that follows hypertension (antiproliferative effect of the combination), all these diseases or associated conditions with or without hypertension; and (?) endothelial dysfunction with or without hypertension. The present invention is similarly referred to as a "package of parts", for example, in the sense that the components to be combined in accordance with the present invention can be dosed independently or through the use of different fixed combinations with amounts distinctive components, that is, simultaneously or at different time points. The parts of the package of parts can then, for example, be administered simultaneously or gradually chronologically, ie at different time points and with equal or different time intervals for any part of the package of parts. Preferably, the time intervals are selected such that the effect on the disease or condition brought about in the combined use of the pairs is greater than the effect that would be obtained by using only any one of the components. The invention further relates to a commercial package comprising the combination according to the present invention together with the instructions for simultaneous use, separately or sequentially. These pharmaceutical preparations are for enteral administration, such as oral, and also rectal or parenteral to homeotherms, with the preparations comprising the active pharmacological compound either alone or in conjunction with pharmaceutical substances auxiliary custom. For example, pharmaceutical preparations consist of from about 0.1% to 90%, preferably from about 1% to about 80%, of the active compound. Pharmaceutical preparations for enteral or parenteral administration, and also for ocular administration, are, for example, in the form of unit doses, such as coated tablets, tablets, capsules or suppositories and also ampoules. These are prepared in a manner that is known per se, for example using conventional mixing, granulating, solubilizing or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active component with solid excipients, if it is desired to granulate a mixture that has been obtained, and, if required or necessary, to process the mixture or granulate into coated tablets or cores. after having added suitable auxiliary auxiliaries. The dosage of the active compound may depend on a variety of factors, such as the mode of administration, homeothermic species, age and / or individual condition. Preferred dosages for the active ingredients of the pharmaceutical combination according to the present invention are therapeutically effective dosages, especially those which are commercially available. Normally, in the case of oral administration, an approximate daily dose of approximately 1 mg hasía approximately 360 mg is going to be estimated, for example, for a patient of approximately 75 kilograms of weight. The dosage of the active compound may depend on a variety of factors, such as mode of administration, homeothermic species, age and / or individual condition. Valsartan, as a representative of the class of AT-i receptor antagonists, will be provided in the manner of a suitable dosage unit, for example, a capsule or tablet, and comprising an epinephrically effective amount, for example, from approximately 20 to approximately 320 mg, of valsartan that can be applied to patients. The application of the active ingredient can occur up to three times a day, starting for example with a daily dose of 20 mg or 40 mg of valsartan, which increases to 80 mg per day and in addition to 160 mg per day up to 320 mg per day. Preferably, valsartan is applied twice daily with a dose of 80 mg or 160 mg, respectively, each. The corresponding doses can be taken, for example, in the morning, at midday or in the afternoon. The following examples illustrate the invention described above; however, it is not intended to restrict the scope of this invention in any way.

Formulation Example 1: Film Coated Tablets: r) removed during processing The film coated tablet is manufactured, for example, as follows. A mixture of valsartan, microcpstalin cellulose, crospovidon, colloidal anhydrous silica / colloidal silicon dioxide / Aerosile 200, silicon dioxide and magnesium magnesium are pre-mixed in a diffusion mixer and then hovered through a sifting mill. The resulting mixture is previously mixed again in a diffusion mixer, compacted in a roller compactor and then hovered through a sifting mill. To the resulting mixture, the remainder of the colloidal anhydrous silica / colloidal silicon dioxide / Aerosile 200 is added and the final mixture is made in a diffusion mixer. The whole mixture is compressed in a revolving rotary machine and the tablets are coated with a film using pale red Diolack in a perforated tray.

Formulation Example 2: Film coated tablets: The film coated sheet is manufactured, for example, as described in Formulation Example 1.

Formulation Example 3: The composition of the brown coloring agent Opadry® OO F 1671 1 is calculated later. "] Removed during processing.

Composition of Opadry®: The film-coated tablet is manufactured, for example, as described in Formulation Example 1.

Formulation Example 4: Capsules: The board is manufactured, for example, as follows: Granulation / Drying The valsaran and the microcrystalline cellulose are granulated by spraying in a fluidized bed granulator with a solution of granulation consisting of povidone and sodium lauryl sulfate dissolved in purified water. The obtained granulate is dried in a fluidized bed dryer. Ground / Mixed The dry granulate is milled June crospovidón and eslearaío of magnesium. The mass is then mixed in a conical endless lomo lomo mixer lasting approximately 10 min. Encapsulation The empty hard gelatin capsules are filled with bulk granules mixed under controlled temperature and humidity conditions. The filled capsules are shaken, visually inspected, checked for weight and guaranteed by the Quality Assurance Department.

Formulation Example 5: Capsules: The formulation is manufactured, for example as described in Formulation Example 4 Formulation Example 6: Hard Gelatin Capsule: Formulation Example 7: A hard gelatin capsule, comprising an active ingredient, for example (S) -N- (1-carboxy-2-methylprop-2-yl) -N-penyanoyl-N- [2 '(1 H -etrazol-5-yl) biphenyl-4-yl-methyl] amine, can be formulated, for example, as follows: Composition: (1) valsartan 80.0 mg (2) microcrystalline cellulose 110.0 mg (3) polyvidone K30 45.2 mg (4) sodium lauryl sulfate 1.2 mg (5) crospovidone 26.0 mg (6) magnesium stearate 2.6 mg The component parts (1) and (2) are granulated with a solution of the componies (3) and (4) in water. The components (5) and (6) are added to the dry granulate and the mixture is poured into size 1 hard gelatin capsules.

Formulation Example 8: 1 .035 mg of hemihydrate CGS 16 949 A is equivalent to 1,000 mg of anhydrate.

Claims

1. The use of a pharmaceutical composition comprising: (i) an aldosleone synthase inhibitor or a pharmaceutically acceptable salt thereof alone or in combination with, (ii) an ATi receptor antagonism or an ATi receptor antagonist combined with a diuretic or , in each case, a pharmaceutically acceptable salt thereof and (iii) a pharmaceutically acceptable carrier; for the prevention of, delay in the progress of, treatment of a disease or condition selected from the group consisting of: (a) hypertension, congestive heart failure, renal insufficiency, especially chronic renal insufficiency, restenosis after percutaneous transluminal angioplasty and restenosis after short-circuit coronary artery surgery; (b) atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, for example chronic renal failure, hypothyroidism, survival after myocardial infarction (Ml), coronary heart disease, hypertension in the old age, familial dyslipidemic hypertension, increased collagen formation, fibrosis and remodeling that follows hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension; and (c) endothelial dysfunction with or without hypertension.

2. The use according to claim 1 wherein said receptor anolygonism ATi is selected from the group consisting of valsartan, losarían, candesartan, eprosartan, irbesartan, saprisartan, tasosarían, telmisartan, the compound with the designation E-1477 of the following formula : the compound with the designation SC-52458 of the following formula: and the compound with the designation compound ZD-8731 of the following formula: or, in each case, a pharmaceutically acceptable salt thereof.

3. The use according to claim 2 wherein said AT1 receptor agonist is valsartan or a pharmaceutically acceptable salt thereof.

4. The use according to any of claims 1 to 3 wherein said inhibitor of aldoseerone synase is selected from the group consisting of anastrozole, fadrozole (including the (+) - enantiomer thereof) and exemesfano, or, in each case where applicable, a salt of the same pharmaceutically acceptable.

5. The use according to any of claims 1 to 4 wherein said inhibitor of aldosterone synase is the (+) - enantiomer of fadrozole hydrochloride of the formula:

6. The use according to any of claims 1 to 5 wherein the diuretic is hydrochlorothiazide.

7. The use of a pharmaceutical composition comprising: an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention of, delay in the progress of, treatment of a disease or condition selected from the group which consists of: (a) hypertension, congestive heart failure, renal insufficiency, especially chronic renal failure, restenosis after percutaneous transluminal angioplasty and restenosis after short-circuit surgery of coronary arteries; (ß) aerosol, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, for example chronic renal failure, hypothyroidism, survival after myocardial infarction (M l), coronary heart disease, hypertension in old age, familial dyslipidemic hypertension, increased collagen formation, fibrosis and remodeling that follows hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension; and (?) endothelial dysfunction with or without hyperintense.

8. A pharmaceutical composition comprising: (i) an aldosterone synthase inhibitor or pharmaceutically acceptable salt thereof either alone or in combination with, (ii) an ATi receptor antagonist or an ATi receptor antagonist combined with a diuretic or, in each case, a pharmaceutically acceptable salt thereof and (ii) a pharmaceutically acceptable carrier; for the prevention of, delay in the progress of, treatment of a disease or condition selected from the group consisting of: (a) hypertension, congestive heart failure, renal insufficiency, especially chronic renal failure, restenosis after percutaneous transluminal angioplasty and resenosis after coronary artery corfo- ry surgery; (b) atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, for example chronic renal failure, hypothyroidism, survival after myocardial infarction (Ml), coronary heart disease, hypertension in the old age, familial dyslipidemic hypertension, increased collagen formation, fibrosis and remodeling that follows hypertension (antiproliferative effect of the combination), diseases or conditions associated with or without hyperintense; and (c) endothelial dysfunction with or without hypertension.

9. A method for preventing, reversing the progress of, treatment of a disease or condition selected from the group consisting of: (a) hypertension, congestive heart failure, renal insufficiency, especially chronic renal insufficiency, restenosis after percutaneous transluminal angioplasty and restenosis after coronary artery bypass surgery; (b) atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, for example chronic renal failure, hypothyroidism, survival after myocardial infarction (Ml), coronary heart disease, hypertension in the old age, familial dyslipidemic hypertension, increased collagen formation, fibrosis and remodeling that follows hypertension (amphiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension; and (c) endothelial dysfunction with or without hypertension; which comprises administering to a warm-blooded animal, including man, a therapeutically effective amount of an aldosterone synase inhibitor in free or pharmaceutically acceptable salt form.

10. A method according to claim 9 which further comprises administering a therapeutically effective amount of an ATi receptor antagonist or an ATi receptor antagonist combined with a diuretic, in each case, in free or pharmaceutically acceptable salt form.