AU2004289057A1

AU2004289057A1 - AT1-receptor antagonists for treating nephrotic syndrome

Info

Publication number: AU2004289057A1
Application number: AU2004289057A
Authority: AU
Inventors: William Lionel Daley; Francis Plat; Suraj Shivappa Shetty
Original assignee: Novartis AG
Current assignee: Novartis AG
Priority date: 2003-11-14
Filing date: 2004-11-12
Publication date: 2005-05-26
Also published as: WO2005046677A3; TW200518747A; CN1882334A; WO2005046677A2; BRPI0416588A; CA2544747A1

Description

WO 2005/046677 PCT/EP2004/012877 Additional pharmaceutical use The enzyme cascade of the renin-angiotensin system (RAS) comprises a series of biochemi cal sequences and, as is known, there are different approaches for opening up possibilities for the treatment of, for example, hypertension by regulatory intervention. Angiotensinogen, a a2-macroglycoprotein, is split by the renin enzyme into the decapitate angiotensin I, which itself is biologically only very weakly active. The next step in the cascade is the removal of a further two amino acids by the action of the angiotensin-converting enzyme (ACE), bonded mainly in the endothelium, with formation of angiotensin 11. This latter is held to be one of the strongest natural vasoconstrictors. The vasoconstrictive effects of angiotensin I are produced by its action on the non-striated muscle cells, the stimulation of the formation of the adrenergenic hormones epinephrine and norepinephrine as well as by the increase of the activity of the sympathetic nervous system as a result of the formation of norepinephrine. Angiotensin Il also has an influence on the electrolytic balance, produces e.g. antinatriuretic and antidiuretic effects in the kidney and accordingly promotes the release of, on the one hand, the vasopressin peptide from the pituitary gland and, on the other hand, of aldosterone from the adrenal glomerulosa. These influences all play an important part in the regulation of blood pressure. Angiotensin il interacts with specific receptors on the surface of the target cell. It has been possible to identify receptor subtypes which are termed e.g. AT- and AT 2 -receptors. Great efforts have been made lately to identify substances that bind to ATr-receptors. Such active ingredients are often termed angiotensin il antagonists or blockers. Because of the inhibition of the AT,-receptor such antagonists can be used e.g. as antihypertensives or for the treatment of congestive heart failure. Angiotensin Il receptor antagonists are understood to mean those active ingredients which bind to the ATI-receptor subtype and inhibit its activity. These include compounds having different structural features. Compounds to be mentioned are, for example, those cited in the compound claims of EP-443983, the subject matter of which is herewith incorporated by reference in this application.

WO 2005/046677 PCT/EP2004/012877 -2 A compound to be highlighted is (S)-N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'(1 H tetrazol-5-yl)biphenyl-4-yl-methyl]amine (hereinafter termed valsartan) of formula CH CH O CH CH CH C CH

CH

2

CH

2 N COOH CH2 HN N \ / N N cited in European patent application having the publication no. EP-443983, Example 16, or a salt thereof, preferably a pharmaceutically acceptable salt thereof. Furthermore, the compounds cited in the compound claims of European patent application having the publication no. EP-25331 0 are incorporated by reference in this application. A compound to be highlighted is that of the following formula Cl N- OH N N NH N=N and the pharmaceutically acceptable salts thereof. Furthermore, the compounds cited in the compound claims of European patent application having the publication no. EP-403159 are incorporated by reference in this application. A compound to be highlighted is that of the following formula WO 2005/046677 PCT/EP2004/012877 -3 S N COOH N \-a COOH and the pharmaceutically acceptable salts thereof. Furthermore, the compounds cited in the compound claims of PCT patent application WO 91114679 are, with reference to this literature, herewith also included in this application. A compound to be highlighted is that of the following formula N 0 N O N NH N N and the pharmaceutically acceptable salts thereof. Furthermore, the compounds cited in the compound claims of European patent application having the publication no. EP-420 237 are incorporated by reference in this application. A compound to be highlighted is that of the following formula WO 2005/046677 PCT/EP2004/012877 -.4 N N N COOH and the pharmaceutically acceptable salts thereof. Furthermore, the compounds cited in the compound claims of European patent application having the publication no. EP-502314 are incorporated by reference in this application. A compound to be highlighted is that of the following formula NN NN N N COOH and the pharmaceutically acceptable salts thereof. Furthermore, the compounds cited in the compound claims of European patent application having the publication no. EP-459136 are incorporated by reference in this application. A compound to be highlighted is that of the following formula WO 2005/046677 PCT/EP2004/012877 -5 N I CO 0 0 N N N-HN and the pharmaceutically acceptable salts thereof. Furthermore, the compounds cited in the compound claims of European patent application having the publication no. EP-504888 are incorporated by reference in this application. A compound to be highlighted is that of the following formula N N N

-

N N INH \ / N N and the pharmaceutically acceptable salts thereof. Furthermore, the compounds cited in the compound claims of European patent application having the publication no. EP-514198 are incorporated by reference in this application. A compound to be highlighted is that of the following formula WO 2005/046677 PCT/EP2004/012877 -6 N Br N CONH

--

NH-SO 2CFa and the pharmaceutically acceptable salts thereof. Furthermore, the compounds cited in the compound claims of European patent application having the publication no. EP-475206 are incorporated by reference in this application. A compound to be highlighted is that of the following formula COOH N N N NH N=N and the pharmaceutically acceptable salts thereof. Furthermore, the compounds cited in the compound claims of PCT patent application WO 93/20816 are incorporated by reference included in this application. A compound to be highlighted is that of the following formula WO 2005/046677 PCT/EP2004/012877 -7 N 0 N NH N=N and the pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts of valsartan, for example, are typically acid addition salts. These acid addition salts are formed, for example, with strong inorganic acids, typically mineral acids, such as sulfuric acid, a phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, typically with 1

-C

4 alkanecarboxylic acids which may be substituted, e.g. by halogen, typically acetic acid, for example with dicarboxylic acids which may be unsaturated, such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or terephthalic acid, for example with hydroxycarboxylic acids, such as ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric acid, for example with amino acids, such as aspartic acid or glutaminic acid, or e.g. benzoic acid, or with organic sulfonic acids, for example with C1 C 4 alkanesulfonic acids or arylsulfonic acids which may be substituted, e.g. by halogen, for example with methane- or p-toluenesulfonic acid. Suitable salts with bases are typically metal salts, such as alkali metal salts or alkaline earth metal salts, typically sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, typically ethylamine, tert-butylamine, diethylamine, diisoopropylamine, triethylamine, tributylamine or dimethylpropylamine, or a mono-, di- or trihydroxy-lower alkylamine, typically mono-, di- or triethanolamine. Corresponding internal salts can also be used. Nephrotic syndrome Nephrotic syndrome is a clinical complex characterized by a number of renal and extrarenal features, the most prominent of which are proteinuria of >3.5 g per 1.73 m2 per 24 h (in WO 2005/046677 PCT/EP2004/012877 -8 practice, >3.0 to 3.5 g per 24 h), hypoalbuminemia, edema, hyperlipidemia, lipiduria, and hypercoagulability. It should be stressed that the key component is proteinuria, which results from altered permeability of the glomerular filtration barrier for protein, namely the glomerular basement membrane (GBM) and the podocytes and their slit diaphragms. The other components of the nephrotic syndrome and the ensuing metabolic complications are all secondary to urine protein loss and can occur with lesser degrees of proteinuria or may be absent even in patients with massive proteinuria. In general, the greater the proteinuria, the lower the serum albumin level. Hypoalbuminemia is compounded further by increased renal catabolism and inadequate, albeit usually increased, hepatic synthesis of albumin. Edema is defined as a swelling from excessive accumulation of serous fluid in tissue. The pathophysiology of edema formation in nephrotic syndrome is poorly understood. The hypothesis is that hypoalbuminemia results in decreased intravascular oncotic pressure, leading to leakage of extracellular fluid from blood to the interstitium. Intravascular volume falls, thereby stimulating activation of the renin-angiotensin-aldosterone axis and the sympathetic nervous system and release of vasopressin (antidiuretic hormone), and suppressing atrial natriuretic peptide release. These neural and hormonal responses promote renal salt and water retention, thereby restoring intravascular volume and triggering further leakage of fluid to the interstitium. Hyperlipidemia is believed to be a consequence of increased hepatic lipoprotein synthesis that is triggered by reduced oncotic pressure and may be compounded by increased urinary loss of proteins that regulate lipid homeostasis. Low-density lipoproteins and cholesterol are increased in the majority of patients, whereas very low density lipoproteins and triglycerides tend to rise in patients with severe disease. Lipiduria is caused by the filtration of lipoproteins across the damaged glomerular barrier. On urine microscopy lipiduria might appear as free fat, or as fat droplets in tubular cells or casts where they are referred to as oval fat bodies or fatty casts respectively. Hypercoagulability is probably multifactorial in origin and is caused, at least in part, by increased urinary loss of antithrombin III, altered levels and/or activity of proteins C and S, hyperfibrinogenemia due to increased hepatic synthesis, impaired fibrinolysis, and increased WO 2005/046677 PCT/EP2004/012877 platelet aggregability. As a consequence of these perturbations, patients can develop spontaneous peripheral arterial or venous thrombosis, renal vein thrombosis, and pulmonary embolism. Clinical features that suggest acute renal vein thrombosis include sudden onset of flank or abdominal pain, gross hematuria, a left-sided varicocele (the left testicular vein drains into the renal vein), increased proteinuria, and an acute decline in glomerular filtration rate(GFR). Chronic renal vein thrombosis is usually asymptomatic. Renal vein thrombosis is particularly common (up to 40%) in patients with nephrotic syndrome due to membranous glomerulopathy, membranoproliferative glomerulonephritis, and amyloidosis. Other metabolic complications of nephrotic syndrome include protein malnutrition and iron resistant microcytic hypochromic anemia due to transferrin loss. Hypocalcemia and secondary hyperparathyroidism can occur as a consequence of vitamin D deficiency due to enhanced urinary excretion of cholecalciferol-binding protein, whereas loss of thyroxine binding globulin can result in depressed thyroxine levels. An increased susceptibility to infection may reflect low levels of IgG that result from urinary loss and increased catabolism. In addition, patients are prone to unpredictable changes in the pharmacokinetics of therapeutic agents that are normally bound to plasma proteins. Nephrotic syndrome can complicate any disease that perturbs the negative electrostatic charge or architecture of the glomerular basement membrane and the podocytes and their slit diaphragms. Six entities account for greater than 90% of cases of nephrotic syndrome in adults: minimal change disease (MCD), focal and segmental glomerulosclerosis (FSGS), membranous glomerulopathy, membranoproliferative glomerulonephritis (MPGN), diabetic nephropathy, and amyloidosis. Renal biopsy is a valuable tool in adults with nephrotic syndrome for establishing a definitive diagnosis, guiding therapy, and estimating prognosis. Minimal Change Disease This glomerulopathy accounts for about 80% of nephrotic syndrome in children of younger than 16 years and 20% in adults .The peak incidence is between 6 and 8 years. Patients typically present with nephrotic syndrome and benign urinary sediment. Microscopic hematuria is present in 20 to 30%. Hypertension and renal insufficiency are very rare. MCD (also called nil disease, lipoid nephrosis, or foot process disease) is so named because glomerular size and architecture are normal by light microscopy. Immunofluorescence WO 2005/046677 PCT/EP2004/012877 -10 studies are typically negative for immunoglobulin and C3. Mild mesangial hypercellularity and sparse deposits of C3 and IgM may be detected. Occasionally, mesangial proliferation is associated with scanty IgA deposits, similar to those found in IgA nephropathy. However, the natural history of this variant and response to therapy resemble classic MCD. Electron microscopy reveals characteristic diffuse effacement of the foot processes of visceral epithelial cells . Focal and Segmental Glomerulosclerosis with Hyalinosis The pathognomonic morphologic lesion in FSGS is sclerosis with hyalinosis involving portions (segmental) of fewer than 50% (focal) of glomeruli on a tissue section. The incidence of idiopathic (primary) FSGS has increased over the past two decades so that it now accounts for about one-third of cases of nephrotic syndrome in adults and as many as one-half of cases of nephrotic syndrome in blacks. FSGS can complicate a number of systemic diseases and sustained glomerular capillary hypertension following nephron loss from any cause. Idiopathic FSGS typically presents as nephrotic syndrome (-66%) or subnephrotic proteinuria (-33%) in association with hypertension, mild renal insufficiency, and an abnormal urine sediment that contains red blood cells and leukocytes. Proteinuria is nonselective in most cases. Membranous Glomerulopathy This lesion is a leading cause of idiopathic nephrotic syndrome in adults (30 to 40%) and a rare cause in children (<5%). It has a peak incidence between the ages of 30 to 50 years and a male-female ratio of 2:1. Membranous glomerulopathy derives its name from the characteristic light-microscopic appearance on renal biopsy, namely diffuse thickening of the glomerular basement membrane which is most apparent upon staining with periodic acid Schiff (PAS). Most patients (>80%) present with nephrotic syndrome, proteinuria usually being nonselective. Microscopic hematuria is present in up to 50% of cases, but red blood cells casts, macroscopic hematuria, and leukocytes are extremely rare. Hypertension is documented in only 10 to 30% of patients at the outset but is common later in patients with progressive renal failure. Serologic tests such as antinuclear antibody, antineutrophil cytoplasmic antibody, anti-GBM antibody, cryoglobulin titers, and complement levels are normal in the idiopathic form.

WO 2005/046677 PCT/EP2004/012877 - 11 Membranoproliferative Glomerulonephritis This morphologic entity, also known as mesangiocapillary glomerulonephritis, is characterized by thickening of the glomerular basement membrane (GBM) and proliferative changes on light microscopy. Two major types are identified; both are characterized by a diffuse increase in mesangial cellularity and matrix, and by thickening and reduplication of the GBM such that the lobular pattern of the glomerular tuft is exaggerated. The hallmark of type Imembranoproliferative glomerulonephritis (MPGN) is the presence of subendothelial and mesangial deposits on electron microscopy that contain C3 and IgG or igM; rarely, IgA deposits are demonstrated by immunofluorescence microscopy. The hallmark of type I MPGN (dense deposit disease) is the presence of electron-dense deposits within the GBM and other renal basement membranes (shown by electron microscopy) that stain for C3, but little or no immunoglobulin. Most patients with type I MPGN present with heavy proteinuria or nephrotic syndrome, active urinary sediment, and normal or mildly impaired glomerular filtration rate (GFR). C3 levels are usually depressed, and Clq and C4 levels are borderline or low. Type I MPGN is an immune-complex glomerulonephritis and can be associated with a variety of chronic infections (e.g., bacterial endocarditis, HIV, hepatitis B and C), systemic immune-complex diseases (e.g., SLE, cryoglobulinemia), and malignancies (e.g., leukemias, lymphomas). Type I MPGN is a relatively benign disease, and 70 to 85% of patients survive without clinically significant impairment of GFR. Type 11 MPGN can also present with proteinuria and nephrotic syndrome; however, some patients present with nephritic syndrome,rapidly progressive glomerulonrphritis (RPGN), or recurrent macroscopic hematuria. Type 11 MPGN is an autoimmune disease in which patients have an IgG autoantibody, termed C3 nephritic factor that binds to C3 convertase, the enzyme that metabolizes C3, and renders it resistant to inactivation . It has been surprisingly found that AT1 -receptor antagonist, especially valsartan, can be used in therapeutically effective amount for the prevention, delay of progression or treatment of nephrotic syndrome and complications of metabolic syndrome.

WO 2005/046677 PCT/EP2004/012877 - 12 In the present description the terms "treatment" or "treat" refer to both prophylactic or preventative treatment as well as curative or disease modifying treatment, including treatment of patients at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition. Complications of nephrotic syndrome that may require treatment include edema, hyperlipidemia, thromboembolism, malnutrition, and vitamin D deficiency. Edema should be managed cautiously by moderate salt restriction, usually I to 2 g/day, and the judicious use of loop diuretics. It is unwise to remove >1.0 kg of edema per day as more aggressive diuresis may precipitate intravascular volume depletion and prerenal azotemia. Thromboembolism is defined as an occlusion of a blood vessel by an embolus that has broken away from a thrombus. Anticoagulation is indicated for patients with deep venous thrombosis, arterial thrombosis, and pulmonary embolism. Patients may be relatively resistant to heparin as a consequence of antithrombin Ill deficiency. Renal vein and vena caval angiography are indicated only when embolization occurs on anticoagulation and insertion of a caval filter is contemplated. Malnutrition which is defined as a state of poor nutrition can result from insufficient or excessive or unbalanced diet or from inability to absorb foods. Vitamin D deficiency exists when the concentration of 25-hydroxy-vitamin D (25-OH-D) in the blood serum occurs at 12 ng/ml (nanograms/milliliter), or less. The normal concentration of 25-hydroxy-vitamin D in the blood serum is 25-50 ng/ml. When vitamin D deficiency continues for many months in growing children, the disease commonly referred to as rickets will occur. A prolonged deficiency of the vitamin in adults results in osteomalacia. Both diseases involve defects in bones. A vitamin D deficiency disease of infancy or childhood with a disturbance of the normal process of ossification and bone growth. Often manifests with bone deformity. Vitamin D supplementation is advisable in patients with clinical or biochemical evidence of vitamin D deficiency.

WO 2005/046677 PCT/EP2004/012877 -13 The favourable effect of AT1 -receptor antagonists on nephrotic syndrome , e.g. by the use of valsartan, can be manifested, for example, by the following experimental procedure: Administration of puromycin to rats induces progressive renal disease characterized by proteinuria, edema, sodium retention and hyperlipidemia. Thus, this experimental model of nephrotic syndrome is often used to study the potential beneficial effects of pharmacological interventions in the disease condition (Arevalo et al. Clin Chim Acta, 191:175, 1990; Diamond and Anderson, Am J Pathol, 137:1323, 1990). Male Sprague-Dawley rats weighing about 200 g are housed in a temperature- and light controlled room with 12 h light and dark cycles. The rats are allowed free access to food and water. Animals are randomized into the following groups: normal vehicle controls, drug treated (monotherapy or combination therapy) normal (non-nephrotic) groups, nephrotic untreated controls, and drug-treated (monotherapy or combination therapy) nephrotic groups. The rats assigned to the nephrotic group receive sequential intraperitoneal injections (i.p.) of puromycin aminonucleoside (PAN) on day 1 (130 mg/kg) and day 14 (60 mg/kg). The rats assigned to the control group receive intraperitoneal injections of equivalent amounts of water. Animals are then placed in individual metabolic cages for daily 24-h urine collections. Drugs are administered by oral gavage, subcutaneous osmotic pumps, inclusion in drinking water, or admixed with food, as appropriate. Typical dosages for valsartan in drinking water range from 3 to 30 mg/kg/day and those of the HMG-CoA reductase inhibitor is highly dependent upon the specific agent used. For example, with lovastatin, a dose of 15 mg/kg/day (oral gavage) is used. Urinary sodium concentration, serum and urinary creatinine concentrations, as well as urinary protein concentrations are measured. Blood pressure is measured by tail plethysmography. Blood samples are obtained from the tail vein for additional blood chemistry. All parameters are evaluated at baseline and periodically during the subsequent twelve weeks. At the end of the experiment, rats are sacrificed (pentobarbital 40mg/kg, i.p.) and kidneys are excised for histological studies. It can be shown that urinary protein concentration is significantly lower in valsartan-treated nephrotic animals relative to that in untreated nephrotic animals. Consistent with this observation, it can also be shown that renal structure and function is better preserved in valsartan-treated nephrotic animals relative to that in untreated nephrotic animals. It can be further shown that combination therapy of PAN-treated animals with valsartan and an HMG CoA reductase inhibitor elicits further improvement in renal structure and function relative to WO 2005/046677 PCT/EP2004/012877 -14 monotherapy with valsartan. This is manifested as further significant reductions in urinary protein excretion and concomitant amelioration of tubulointerstitial morphologic derangements relative to monotherapy with valsartan. The person skilled in the pertinent art is fully enabled to select a relevant test model to prove the efficacy of a combination of the present invention in the hereinbefore and hereinafter indicated therapeutic indications. It is the object of this invention to provide pharmaceutical compositions for the prevention delay of progression or treatment of nephrotic syndrome and its complications, which composition comprises an ATI-receptor antagonist, in particular valsartan, or a pharmaceutically acceptable salt thereof. It has been surprisingly found that compositions of valsartan and antihyperlipidemia agent show a particular potentiation, synergism, in the prevention, delay of progression or treatment of nephrotic syndrome and its complications. In a preferred embodiment of the invention, the antihyperlipidemia agent are statins. HMG-CoA reductase inhibitors, also called p-hydroxy-p-methylglutaryl-co-enzyme-A reductase inhibitors and also called statins) are understood to be those active agents which may be preferably used to lower the lipid levels including cholesterol in blood and can be used e.g. for the prevention or treatment of hyperlipidemia and artheriosclerosis. The class of HMG-Co-A reductase inhibitors comprises compounds having differing structural features HMG-CoA reductase inhibitor compounds are disclosed, e.g., in the following commonly assigned patents, published patent applications and publications which are all hereby incorporated herein by reference: Preferred are compounds which are selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin (formerly itavastatin), pravastatin, rosuvastatin, and simvastatin, or, in each case, a pharmaceutically acceptable salt thereof.

WO 2005/046677 PCT/EP2004/012877 - 15 Especially preferred HMG-Co-A reductase inhibitors are those agents which have been marketed. Most preferred are atorvastatin, fluvastatin, pitavastatin, rosuvastatin or simvastatin or a pharmaceutically acceptable salt thereof, in the first line pitavastatin or a pharmaceutically acceptable salt thereof. Only salts that are pharmaceutically acceptable and non-toxic are used therapeutically and those salts are therefore preferred. The corresponding active ingredient or a pharmaceutically acceptable salts thereof may also be used in form of a solvate, such as a hydrate or including other solvents, used for crystallization. The structure of the active agents identified hereinbefore or hereinafter by generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g. Patents International (e.g. IMS World Publications). The corresponding content thereof is hereby incorporated by reference. Any person skilled in the art is fully enabled to identify the active agent and, based on these references, likewise enabled to manufacture and test the pharmaceutical indications and properties in standard test models, both in vitro and in vivo. The term "potentiation" shall mean an increase of a corresponding pharmacological activity or therapeutical effect, respectively. Potentiation of one component of the combination according to the present invention by co-administration of an other component according to the present invention means that an effect is being achieved that is greater than that achieved with one component alone or that is greater than the sum of effects of each component. The term "synergistic" shall mean that the drugs, when taken together, produce a total joint effect that is greater than the sum of the effects of each drug when taken alone. Further benefits 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 the dosages need not only often be smaller but are also applied less frequently, thereby diminishing the incidence of side effects. This is in accordance with the desires and requirements of the patients to be treated.

WO 2005/046677 PCT/EP2004/012877 - 16 It is another object of this invention to provide pharmaceutical compositions for the prevention, delay of progression or treatment of nephrotic syndrome and its complications, which composition comprises an ATI-receptor antagonist, in particular valsartan, or a pharmaceutically acceptable salt thereof in combination with an antihyperlipidemia agent, especially a statin . It is another object of this invention to provide pharmaceutical compositions for the prevention, delay of progression or treatment of nephrotic syndrome and its complications, which composition comprises an AT1 -receptor antagonist, in particular valsartan, or a pharmaceutically acceptable salt thereof in combination with a statin selected from the group consisting of atorvastatin, fluvastatin, pitavastatin, simvastatin and rosuvastatin or a pharmaceutically acceptable salt thereof . In another embodiment, the invention provides a combination, such as a combined preparation or pharmaceutical composition for the prevention, delay of progression or treatment of nephrotic syndrome and its complications, wherein the combination comprises an AT1 -receptor antagonist, in particular valsartan, or a pharmaceutically acceptable salt thereof in combination with atorvastatin or a pharmaceutically acceptable salt thereof. In another embodiment, the invention provides a combination, such as a combined preparation or pharmaceutical composition for the prevention, delay of progression or treatment of nephrotic syndrome and its complications, wherein the combination comprises an AT1 -receptor antagonist, in particular valsartan, or a pharmaceutically acceptable salt thereof in combination with simvastatin or a pharmaceutically acceptable salt thereof. In another embodiment, the invention provides a combination, such as a combined preparation or pharmaceutical composition for the prevention, delay of progression or treatment of nephrotic syndrome and its complications, wherein the combination comprises an AT1 -receptor antagonist, in particular valsartan, or a pharmaceutically acceptable salt thereof in combination with rosuvastatin or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the invention provides a combination, such as a combined preparation or pharmaceutical composition for the prevention, delay of progression or WO 2005/046677 PCT/EP2004/012877 -17 treatment of nephrotic syndrome and its complications, wherein the combination comprises an ATI-receptor antagonist, in particular valsartan, or a pharmaceutically acceptable salt thereof in combination with fluvastatin or a pharmaceutically acceptable salt thereof . In a preferred embodiment, the invention provides a combination, such as a combined preparation or pharmaceutical composition for the prevention, delay of progression or treatment of nephrotic syndrome and its complications, wherein the combination comprises an AT1 -receptor antagonist, in particular valsartan, or a pharmaceutically acceptable salt thereof in combination with pitavastatin or a pharmaceutically acceptable salt thereof . The invention also relates to the use of an AT1-receptor antagonist, in particular valsartan, or a pharmaceutical salt thereof for the preparation of a pharmaceutical composition for the prevention, delay of progression or treatment of nephrotic syndrome and its complications. The invention also relates to the use of an AT1-receptor antagonist, in particular valsartan, or a pharmaceutical salt thereof for the preparation of a pharmaceutical composition for the prevention, delay of progression or treatment of nephrotic syndrome and its complications by administering to a mammal in need thereof a therapeutically effective amount of valsartan or a pharmaceutically acceptable salt thereof in combination with an antihyperlipidemia agent, especially a statin. The invention also relates to the use of an AT1 -receptor antagonist, in particular valsartan, or a pharmaceutical salt thereof for the preparation of a pharmaceutical composition for the prevention, delay of progression or treatment of nephrotic syndrome and its complications by administering to a mammal in need thereof a therapeutically effective amount of valsartan or a pharmaceutically acceptable salt thereof in combination with a statin selected from the group consisting of atorvastatin, fluvastatin, pitavastatin, rosuvastatin and simvastatin, or a pharmaceutically acceptable salt thereof. In a preferred embodiment the invention relates to the use of an ATI-receptor antagonist, in particular valsartan, or a pharmaceutical salt thereof for the preparation of a pharmaceutical composition for the prevention, delay of progression or treatment of nephrotic syndrome and its complications by administering to a mammal in need thereof a therapeutically effective WO 2005/046677 PCT/EP2004/012877 - 18 amount of valsartan or a pharmaceutically acceptable salt thereof in combination with fluvastatin or a pharmaceutically acceptable salt thereof. In a preferred embodiment the invention relates to the use of an AT1-receptor antagonist, in particular valsartan, or a pharmaceutical salt thereof for the preparation of a pharmaceutical composition for the prevention, delay of progression or treatment of nephrotic syndrome and its complications by administering to a mammal in need thereof a therapeutically effective amount of valsartan or a pharmaceutically acceptable salt thereof in combination with pitavastatin or a pharmaceutically acceptable salt thereof. The invention also relates to a method for the prevention, delay of progression or treatment of nephrotic syndrome and its complications, which method comprises administering to a mammal in need thereof a therapeutically effective amount of valsartan or a pharmaceutical salt thereof. The invention also relates to a method for the prevention, delay of progression or treatment of nephrotic syndrome and its complications, which method comprises administering to a mammal in need thereof a therapeutically effective amount of valsartan or a pharmaceutical salt thereof in combination with an antihyperlipidemia agent, especially a statin . The invention also relates to a method for the prevention, delay of progression or treatment of nephrotic syndrome and its complications, which method comprises administering to a mammal in need thereof a therapeutically effective amount of valsartan or a pharmaceutical salt thereof in combination with a statin selected from the group consisting of atorvastatin, fluvastatin, pitavastatin, rosuvastatin and simvastatin, or a pharmaceutically acceptable salt thereof. In a preferred embodiment the invention relates to a method for the prevention, delay of progression or treatment of nephrotic syndrome and its complications, which method comprises administering to a mammal in need thereof a therapeutically effective amount of valsartan or a pharmaceutical salt thereof in combination fluvastatin or a pharmaceutically acceptable salt thereof .

WO 2005/046677 PCT/EP2004/012877 - 19 In a preferred embodiment the invention relates to a method for the prevention, delay of progression or treatment of nephrotic syndrome and its complications, which method comprises administering to a mammal in need thereof a therapeutically effective amount of valsartan or a pharmaceutical salt thereof in combination pitavastatin or a pharmaceutically acceptable salt thereof . The present invention relates to a package comprising an AT 1- receptor blocker, especially valsartan together with instructions for use for the prevention, delay of progression or treatment of nephrotic syndrome and its complications. The present invention relates to a package comprising an AT 1- receptor blocker together with instructions for use in combination with an antihyperlipidemia agent for the prevention , delay of progression or treatment of nephrotic syndrome and its complications . The invention also relates to a "kit of parts" in the sense that the components can be dosed independently or by use of different fixed combinations with distinguished amounts of the components at different time points. The parts of the "kit of parts" can then, e.g., be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the "kit of parts". Preferably, the time intervals are chosen such that the effect on the treated disease or condition in the combined use of the parts is larger than the effect that would be obtained by use of only any one of the components. Preferably, there is at least one beneficial effect, e.g., a mutual enhancing of the effect of at least two therapeutic agents selected from the group consisting of (i) an AT 1- receptor blocker, specially valsartan and (ii) an antihyperlipiemia agent, especially a statin. The present invention provides a kit comprising in separate containers in a single package pharmaceutical compositions comprising in one container a pharmaceutical composition comprising the AT 1- receptor blocker valsartan and in a second container a pharmaceutical composition comprising an antihyperlipidemia agent especially a statin. In a preferred embodiment the present invention provides a kit comprising in separate containers in a single package pharmaceutical compositions comprising in one container a WO 2005/046677 PCT/EP2004/012877 - 20 pharmaceutical composition comprising the AT 1- receptor blocker valsartan and in a second container a pharmaceutical composition comprising the antihyperlipidemia agent fluvastatin. In another preferred embodiment the present invention provides a kit comprising in separate containers in a single package pharmaceutical compositions comprising in one container a pharmaceutical composition comprising the AT 1- receptor blocker valsartan and in a second container a pharmaceutical composition comprising the antihyperlipidemia agent pitavastatin . Said pharmaceutical compositions are those for enteral, such as oral, and also rectal or parenteral administration to mammals (warm-blooded animals), including man, the pharmacological active ingredient being present on its own or together with the usual pharmaceutical excipients. The pharmaceutical compositions contain, for example, from about 0.1 % to 100 %, preferably from about 1 % to about 80 %, of the active ingredient. Pharmaceutical compositions for enteral or parenteral and also for ocular administration are typically those in unit dose forms, such as drag6es, tablets, capsules or suppositories and also ampoules. These are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar-coating, dissolving or lyophilising methods. Accordingly, pharmaceutical compositions for oral use can be obtained by combining the active ingredient with solid carriers, if desired granulating a mixture obtained, and processing the mixture or granules, if desired or necessary after the addition of suitable excipients, to give tablets or drag6e cores. Suitable carriers are preferably fillers, typically sugars, such as lactose, saccharose, mannitol or sorbitol, cellulose compositions and/or calcium phosphates, e.g. tricalcium phosphate or calciumhydrogen phosphate, furthermore binders, such as starch paste, typically using e.g. corn starch, wheat starch, rice starch or potato starch, gelatin, traga canth gum, methylcellulose and/or polyvinylpyrrolidone and, if desired, disintegrants, such as the above-mentioned starches, furthermore carboxymethyl starch, crosslinked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof, typically sodium alginate. Excipients are primarily flow regulators and lubricants, typically silica gel, talcum, stearic acid or salts thereof, typically magnesium stearate or calcium stearate, and/or polyethylene glycol. Drag6e cores are provided with suitable coatings which, if desired, are resistant to gastric juice, using, inter alia, concentrated sugar solutions which optionally contain gum arabic, talcum, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, coating solutions in WO 2005/046677 PCT/EP2004/012877 -21 suitable organic solvents or solvent mixtures or, for the preparation of gastric juice-resistant coatings, solutions of suitable cellulose compositions, typically acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Colorants or pigments may be added to the tablets or drag6e coatings, for example to identify or indicate different doses of active ingredient. Other pharmaceutical compositions for oral administration are dry-filled gelatin capsules as well as soft closed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The dry-filled capsules may contain the active ingredient in the form of granules, typically in admixture with fillers, such as lactose, binders, such as starches, and/or lubricants, such as talcum or magnesium stearate. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, and stabilisers can also be added. Suitable pharmaceutical compositions for rectal administration are typically suppositories consisting of a combination of the active ingredient with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons and higher alkanols. Furthermore, gelatin rectal capsules containing a combination of the active ingredient with a base substance may also be used. Suitable base substances are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons. Suitable compositions for parenteral administration are primarily aqueous solutions of an active ingredient in water-soluble form, typically a water-soluble salt, and also suspensions of the active ingredient, such as appropriate oily injection suspensions, using suitable lipophilic solvents or vehicles, typically fatty oils, e.g. sesame oil, or synthetic fatty acid esters, typically ethyl oleate or triglycerides, or aqueous injection suspensions containing viscosity-increasing substances, e.g. sodium carboxymethylcellulose, sorbitol and/or dextran and, optionally, also stabilisers. For preventive treatments, unit dosage forms for oral administration are preferred, typically tablets or capsules and, in acute treatments, i.v. application forms. The dose of the active ingredient can depend of various factors, e.g. mode of application, species of warm-blooded animal, age and/or individual state. The estimated normal dose for WO 2005/046677 PCT/EP2004/012877 - 22 oral administration to a patient weighing about 75 kg is an approximate dose of about 10 mg to about 640 mg of AT1-receptor antagonist. In a preferred embodiment of this invention, pharmaceutically acceptable compositions comprising valsartan are used. The daily dose for oral administration of AT 1 -antagonist valsartan in a unit dose form is preferably about 20 mg to about 320 mg, more preferably about 40 mg or about 80 mg. The following Example illustrates the above invention without, however, limiting it in its scope in any way. Formulation Example 1: Film-Coated Tablets: Components Compostion Per Unit (mg) Standards Granulation Valsartan [= active ingredient] 80.00 Microcrystalline cellulose/ 54.00 NF, Ph. Eur Avicel PH 102 Crospovidone 20.00 NF, Ph. Eur Colloidal anhydrous silica / 0.75 Ph. Eur/ colloidal silicon dioxide / Aerosil 200 NF Magnesium stearate 2.5 NF, Ph. Eur Blending Colloidal anhydrous silica / 0.75 Ph. Eur/ colloidal silicon dioxide / Aerosil 200 NF Magnesium stearate 2.00 NF, Ph. Eur Coating Purified water') DIOLACK pale red 00F34899 7.00 Total tablet mass 167.00 * Removed during processing.

WO 2005/046677 PCT/EP2004/012877 - 23 The film-coated tablet is manufactured e.g. as follows: A mixture of valsartan, microcrystalline cellulose, crospovidone, part of the colloidal anhydrous silica/colloidal silicon dioxide/Aerosile 200, silicon dioxide and magnesium stearate is premixed in a diffusion mixer and then sieve through a screnning mill. The resulting mixture is again pre-mixed in a diffusion mixer, compacted in a roller compacter and then sieve through a screening mill. To the resulting mixture, the rest of the colloidal anhydrous silica/colloidal silicon dioxide/Aerosile 200 are added and the final blend is made in a diffusion mixer. The whole mixture is compressed in a rotary tabletting machine and the tablets are coated with a film by using Diolack pale red in a perforated pan. Formulation Example 2: Film-coated tablets: Components Compostion Per Unit (mg) Standards Granulation Valsartan {= active ingredient] 160.00 Microcrystalline cellulose/ 108.00 NF, Ph. Eur Avicel PH 102 Crospovidone 40.00 NF, Ph. Eur Colloidal anhydrous silica / 1.50 Ph. Eur/ colloidal silicon dioxide / Aerosil 200 NF Magnesium stearate 5.00 NF, Ph. Eur Blending Colloidal anhydrous silica / 1.50 Ph. Eur/ colloidal silicon dioxide / Aerosil 200 NF Magnesium stearate 4.00 NF, Ph. Eur Coating Opadry Light Brown 00F33172 10.00 Total tablet mass 330.00 The film-coated tablet is manufactured e.g. as described in Formulation Example 1.

WO 2005/046677 PCT/EP2004/012877 -24 Formulation Example 3: Film-Coated Tablets: Components Compostion Per Unit (mg) Standards Core: Internal phase Valsartan 40.00 [= active ingredient] Silica, colloidal anhydrous 1.00 Ph. Eur, USP/NF (Colloidal silicon dioxide) [= Glidant] Magnesium stearate 2.00 USP/NF [= Lubricant] Crospovidone 20.00 Ph. Eur [Disintegrant] Microcrystalline cellulose 124.00 USP/NF [= Binding agent] External phase Silica, colloidal anhydrous, 1.00 Ph. Eur, USP/NF (Colloidal silicon dioxide) [= Glidant] Magnesium stearate 2.00 USP/NF [Lubricant] Film coating Opadry* brown OOF 167119 9.40 Purified Water" Total tablet mass 199.44 ' The composition of the Opadry* brown OOF16711 coloring agent is tabulated below. "I Removed during processing Opadry* Composition: WO 2005/046677 PCT/EP2004/012877 - 25 Ingredient Approximate % Composition Iron oxide, black (C.I. No. 77499, E 172) 0.50 Iron oxide, brown (C.I. No. 77499, E 172 0.50 Iron oxide, red (C.I. No. 77491, E 172) 0.50 Iron oxide, yellow (C.I. No. 77492, E 172) 0.50 Macrogolum (Ph. Eur) 4.00 Titanium dioxide (C.. No. 77891, E 171) 14.00 Hypromellose (Ph. Eur) 80.00 The film-coated tablet is manufactured e.g. as described in Formulation Example 1. Formulation Example 4: Capsules: Components Compostion Per Unit (mg) Valsartan [= active ingredient] 80.00 Microcrystalline cellulose 25.10 Crospovidone 13.00 Povidone 12.50 Magnesium stearate 1.30 Sodium lauryl sulphate 0.60 Shell Iron oxide, red 0.123 (C.I. No. 77491, EC No. E 172) Iron oxide, yellow 0.123 (C.1. No. 77492, EC No. E 172) Iron oxide, black 0.245 (C.I. No. 77499, EC No. E 172) Titanium dioxide 1.540 Gelatin 74.969 Total tablet mass 209.50 WO 2005/046677 PCT/EP2004/012877 - 26 The tablet is manufactured e.g. as follows: Granulation/Drying Valsartan and microcrystallin cellulose are spray-granulated in a fluidised bed granulator with a granulating solution consisting of povidone and sodium lauryl sulphate dissolved in purified water. The granulate obtained is dried in a fluidised bed dryer. Milling/Blending The dried granulate is milled together with crospovidone and magnesium stearate. The mass is then blended in a conical srew type mixer for approximately 10 minutes. Encapsulation The empty hard gelatin capsules are filled with the blended bulk granules under controlled temperature and humidity conditions. The filed capsules are dedustee, visually inspected, weightchecked and quarantied until by Quality assurance department. Examples 7 to 11: WO 2005/046677 PCT/EP2004/012877 - 27 Example 7 8 9 10 11 Components COMPOSITION PER COMPOSITION COMPOSITION COMPOSITION COMPOSITION UNIT (mg) PER UNIT (mg) PER UNIT (mg) PER UNIT (mg) PER UNIT (mg) Granulation Valsartan Drug Substance 80.000 160.000 40.000 320.000 320.000 Microcrystalline Cellulose 54.000 108.000 27.000 216.000 216.000 (NF, Ph.Eur.)/ Avicel PH 102 Crospovidone (NF, Ph.Eur.) 15.000 30.000 7.500 80.000 60.000 Colloidal Anhydrous Silica 1.500 3.000 0.750 3.000 6.000 (Ph. Eur.)/Colloidal Silicon Dioxide (NF)/Aerosil 200 Magnesium Stearate ( NF, 3.000 6.000 1.500 10.000 12.000 Ph.Eur.) Blending Colloidal Anhydrous Silica --- - --- 3.000 (Ph. Eur.)/Colloidal Silicon Dioxide (NF)/Aerosil 200 Magnesium Stearate, NF, 1.500 3.000 0.750 8.000 6.000 Ph.Eur. Core Weight/mg 155.000 310.000 77.500 640.000 620.000 Coating - - 3.800 15.000 16.000 Formulation Example 5: Capsules: Components Composition Per Unit (mg) Valsartan [= active ingredient] 160.00 Microcrystalline cellulose 50.20 Crospovidone 26.00 Povidone 25.00 Magnesium stearate 2.60 Sodium lauryl sulphate 1.20 Shell Iron oxide, red 0.123 (C.I. No. 77491, EC No. E 172) Iron oxide, yellow 0.123 (C.I. No. 77492, EC No. E 172) WO 2005/046677 PCT/EP2004/012877 - 28 Iron oxide, black 0.245 (C.I. No. 77499, EC No. E 172) Titanium dioxide 1.540 Gelatin 74.969 Total tablet mass 342.00 The formulation is manufactured e.g. as described in Formulation Example 4. Formulation Example 6: Hard Gelatine Capsule: Components Compostion Per Unit (mg) Valsartan [= active ingredient] 80.00 Sodium laurylsulphate 0.60 Magnesium stearate 1.30 Povidone 12.50 Crospovidone 13.00 Microcrystalline cellulose 21.10 Total tablet mass 130.00 Formulation Example 6 bis: A hard gelatin capsule, comprising as active ingredient e.g. (S)-N-(1-carboxy-2-methylprop 1 -yl)-N-pentanoyl-N-[2'(1 H-tetrazol-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 WO 2005/046677 PCT/EP2004/012877 - 29 Components (1) and (2) are granulated with a solution of components (3) and (4) in water. The components (5) and (6) are added to the dry granulate and the mixture is filled into size 1 hard gelatin capsules.

Claims

1. Use of an ATrreceptor antagonist or a pharmaceutically acceptable salt thereof alone or in combination with an antihyperlipidemia agent, especially a statin for the preparation of a pharmaceutical composition for the prevention, delay of progression or treatment of nephrotic syndrome and its complications.

2. Use according to claim 1 for the treatment of nephrotic syndrome.

3. Use of an ATrreceptor antagonist selected from the group consisting of: CH CH 0 CH CH CH C CH OHCH N COOH (a) 2 CH2 C CH 2 HN N \ / N N C1 N OH N N NH (b) N=N WO 2005/046677 PCT/EP2004/012877 - 31 / ~ COOH N 0 N N NH N (f -- N N COOH WO 2005/046677 PCT/EP2004/012877 -32 N 7 00 co 0 0 (g) /N N N N N N CN (N=N NH-SO 2CF 3 WO 2005/046677 PCT/EP2004/012877 -33 COOH N N ) --- und \ / N N N 0 (k) N NH N=N or, in each case, of a pharmaceutically acceptable salt thereof alone or in combination with an antihyperlipidemia agent, especially a statin selected from the group consisting of atorvastatin, fluvastatin, pitavastatin, rosuvastatin and simvastatin, or a pharmaceutically acceptable salt thereof according to any one of claims 1-2.

4. Use of valsartan of formula CH CH S/ 3 0 CH |1 T CH 3 C /C CH CH 2 CH 2 N COOH CH 2 HN N \ / N- N or a salt thereof according to any one of claims 1-2. WO 2005/046677 PCT/EP2004/012877 - 34

5. Use according to anyone of claims 1-4 wherein the statin is fluvastatin or a pharmaceutically acceptable salt thereof.

6. Use according to anyone of claims 1-4 wherein the statin is pitavastatin or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition for the prevention, delay of progression or treatment of nephrotic syndrome, comprising a therapeutically effective amount of an AT-receptor antagonist or a pharmaceutically acceptable salt thereof alone or in combination with an antihyperlipidemia agent, especially a statin.

8. The pharmaceutical composition according to claim 7 wherein the statin is selected from the group consisting of atorvastatin, fluvastatin, pitavastatin, rosuvastatin and simvastatin, or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition according to claim 8 wherein the statin is fluvastatin or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition according to claim 9 wherein the statin is pitavastatin or a pharmaceutically acceptable salt thereof.

11. A method for the prevention, delay of progression or treatment of nephrotic syndrome and its complications, which comprises administering to a mammal in need thereof a therapeutically effective amount of an AT1 -receptor antagonist or a pharmaceutically acceptable salt thereof alone or in combination with an antihyperlipidemia agent, especially a statin.

12. The method according to claim 11 wherein the statin is selected from the group consisting of atorvastatin, fluvastatin, pitavastatin, rosuvastatin and simvastatin, or a pharmaceutically acceptable salt thereof.

13. The method according to claim 12 wherein the statin is fluvastatin or a pharmaceutically acceptable salt thereof. WO 2005/046677 PCT/EP2004/012877 - 35

14. The method according to claim 12 wherein the statin is pitavastatin or a pharmaceutically acceptable salt thereof.