SK117996A3 - Pharmaceutical composition for treatment of diabetic nephropathy - Google Patents

Abstract

The angiotensin II antagonist of formula (I) and the pharmaceutically acceptable salts thereof can be used for the therapeutic treatment of diabetic nephropathy.

Description

Technical field

Renal vascular disorders are often observed in patients who have suffered from diabetes mellitus for a relatively long time. One symptom is diabetic nephropathy, also called diabetic glomerulosclerosis. Nodular thickening in the glomerular loop causes vascular lumen narrowing, fibrinoid deposits in capillary walls, and microaneurysms. These pathological symptoms manifest themselves clinically in the form of massive proteinuria and hypertension. If diabetic nephropathy is not adequately treated, renal function will deteriorate until the end stage requiring dialysis.

Therefore, it is considered very important to find active drug ingredients that are able to either prevent in the appropriate way in arresting the course of diabetic nephropathy or in reducing its symptoms.

BACKGROUND OF THE INVENTION

PCT application WO 92/10182 (published on 25.06.92) discloses the use of angiotensin II antagonists in the treatment of diabetic nephropathy. It is stated in this application that nitrogen-containing heterocycles, especially imidazole derivatives, as well as peptide angiotensin II antagonists, are particularly preferred for the treatment of diabetic nephropathy.

Extensive pharmacological studies have shown that angiotensin II antagonist of formula I

and its pharmaceutically acceptable salts are surprisingly suitable for the treatment of diabetic nephropathy. The compound of formula I and its pharmaceutically acceptable salts can also be used prophylactically. Said properties are obtained in particular by the overall application of the active ingredient.

In particular, the compound of formula I may be in the form of pharmaceutically acceptable salts. Since the compound of formula I, for example, has at least one basicity center, it can form acid addition salts. The salts are formed for example with strong inorganic acids such as mineral acids, e.g. sulfuric acid, a phosphoric or hydrohalic acid, with strong organic carboxylic acids, unsubstituted or substituted, e.g. halo-substituted, a C _x _ ₄ alkanecarboxylic acid, acetic acid, unsaturated or saturated dicarboxylic acids, for example oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or terephthalic acid, hydroxycarboxylic acids, for example ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric acid, with amino acids, for example aspartic acid or glutamic acid or benzoic acid, or with organic sulfonic acids, nesubstituo Bathtub or substituted, e.g. halo-substituted, a C _x _ _A -alkán- or arylsulfonic acids, e.g., the example metánsulfdnovou acid or p-toluénsulfdnovou acid. Suitable salts with bases are, for example, metal salts such as alkali metal or alkaline earth metal salts, for example sodium, magnesium or potassium salts, or salts with amdnium or organic amines, such as morpholine, thiomorpholine, piperidine, pyrrolidine, with mono-, di - or a tri-lower alkylamine, for example ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine, or with a mono-, di- or tri-hydroxy-lower alkylamine, for example with mono-, with di- or triethanolamine. Internal salts may also be formed.

In European patent application published no. 443 983 (published on 28.08.91) is an explicitly described compound of formula I (S) -N- (1-carboxy-2-methylprop-1-yl) -N-pentanoyl-N- (2 '- (1H)) in Example 16 (tetrazol-5-yl) biphenyl-4-ylmethyl) amine) and its salts, which compound differs only structurally from the compounds disclosed in WO 92/10182, and which compound is characterized as an angiotensin II antagonist. Also described in this application are angiotensin II antagonist properties of said compound.

Furthermore, the compound of the formula I or its salts are characterized by excellent tolerability and unexpectedly markedly potent activity.

The possibility of treating diabetic nephropathy with a compound of Formula I, or a pharmaceutically acceptable salt thereof, can be demonstrated in the following animal model known to those skilled in the art.

For example, the short-term and long-term effects of angiotensin II blockade on glomerular lesion formation can be determined after administration of the test compound to hyperglycemic diabetic rats. The method used is analogous to the assay method described in J. Am. Nephrol. 1993, 4:40-49. A therapeutic effect occurs, for example, when increasing the glomerular filtration rate (GFR) in these diabetic rats and avoiding proteinuria and glomerulosclerosis.

The effect of prolonged treatment with an angiotensin II blocker may be seen in normotensive rats who have been diagnosed with diabetes by injection of streptozotocin (e.g. 45 mg / kg i.v.).

Glomerular filtration rate and renal plasma flow can be measured as clereance of ³ H-inulin or ¹³ I-hipurate. The antitropic effect of the angiotensin II blocker of formula I on vascular hypertrophy, a secondary symptom of diabetes, can be determined by measuring both mesenteric vascular weight and glomerular volume analogously to Diabetes 1990, 39, 1575

- 1579.

Similarly beneficial effects may be obtained in the treatment of glomerulosclerosis associated with hyperlipidemia.

In prophylaxis, a compound of formula I that can be used according to the invention and its pharmaceutically acceptable salts can help or prevent pathological symptoms that occur in diabetic nephropathy, such as the occurrence of lesions of the vascular system in the kidneys and increased pressure in the glomerular capillaries, against glomerular, hemodynamic, and structural abnormalities in the kidneys, thereby ensuring stabilization of renal function. Further, by the compound of formula I which may be used according to the invention and its pharmaceutically acceptable salts, the incidence of pathological symptoms occurring in diabetic nephropathy, such as proteinuria, glomerulosclerosis, glomerular hypertrophy and high pressure in glomerular capillaries, can be reduced. Thus, abnormal glomerular and hemodynamic effects can be corrected and normalized.

SUMMARY OF THE INVENTION

The invention relates to the use of a compound of formula I and pharmaceutically acceptable salts thereof for the preparation of pharmaceutical compositions for the treatment of diabetic nephropathy.

The invention also relates to a method of treating diabetic nephropathy, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

The invention also relates to pharmaceutical compositions for the treatment of diabetic nephropathy, comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient particularly suitable for systemic administration.

The invention therefore also relates to corresponding systemically administrable compositions which contain as active ingredient a compound of formula I or a pharmaceutically acceptable salt thereof.

A therapeutically effective amount is an amount that prevents or hinders the progression of a diabetic nephropathy disorder or completely cures the disorder, or that acts preventively. Such amount can be readily determined by one skilled in the art.

Said pharmaceutical compositions are intended for enteral as well as oral or rectal administration or for parenteral administration to a warm-blooded animal, said preparations comprising a pharmacologically active ingredient alone or together with the usual pharmaceutical auxiliaries. The pharmaceutical compositions contain, for example, about 0.1% to 100%, preferably 1% to 60%, of the active ingredient. Pharmaceutical compositions for enteral and parenteral as well as for ocular administration are, for example, in unit dose form, such as dragees, tablets, capsules or lace, as well as ampoules. They are produced in a manner known per se, for example by conventional mixing, granulating, dissolving or lyophilizing. Pharmaceutical compositions for oral use can thus be obtained by mixing the active ingredient with solid carriers, optionally granulating the resulting mixture and processing the mixture or granules after optionally adding suitable excipients to form tablets or dragee cores.

Suitable carriers are, in particular, fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example calcium phosphate or dibasic phosphate, and also binders such as starch pastes using, for example, corn, wheat, rice or potato starch. gelatin, tragacanth gum, methylcellulose and / or polyvinylpyrrolidone, and optionally disintegrants such as the aforementioned starches, also carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate. The excipients are in particular glidants and lubricants, for example silicic acid, talc, stearic acid or salts thereof such as magnesium or calcium stearate, and / or polyethylene glycol. Dragee cores are provided with suitable, suitably enteric coatings, using, inter alia, concentrated sugar solutions which may contain gum arabic, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, or coating solutions in suitable organic solvents or mixed solvents or for the preparation of enteric coating solutions suitable cellulose preparations such as ethylcellulose phthalate or hydroxypropylcellulose phthalate. Dyestuffs or pigments may be added to the tablet or dragee coatings, for example for identification purposes or to indicate different doses of the active ingredient.

In addition, dry-filled capsules made of gelatin and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol are dry-filled capsules. The dry-filled capsules may contain the active ingredient in the form of granules, for example in admixture with fillers such as lactose, binders such as starches and / or glidants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, to which stabilizers may also be added.

Suitable rectally applicable pharmaceutical compositions are, for example, lace, which consist of a combination of the active ingredients and a lace base. Suitable lace bases are, for example, natural or synthetic triglycerides, aliphatic hydrocarbons, polyethylene glycols or higher alkanols. Gelatin rectal capsules containing a combination of the active ingredient and a base material can also be used. Suitable base materials are, for example, liquid triglycerides, polyethylene glycols or aliphatic hydrocarbons.

Particularly suitable for parenteral administration are aqueous solutions of the active ingredient in water-soluble form, for example a water-soluble salt, as well as suspensions of the active ingredient, as the corresponding oily injection suspension, using suitable lipophilic solvents or carriers such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or aqueous injection suspensions containing viscosity enhancers, for example sodium carboxymethylcellulose, sorbitol and / or dextran, and optionally other stabilizers.

The dose of the active ingredient may depend on various factors, such as the mode of administration, the species of warm-blooded animal, the age and / or condition of the individual patient. Normally, the approximate daily dose for a patient weighing 75 kg is estimated to be approximately 10 mg to 250 mg for oral administration.

The invention also relates to a process for the preparation of pharmaceutical compositions for the treatment of diabetic nephropathy, which composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The following example illustrates the invention described above without limiting its scope in any way.

Example of dosage form

Hard gelatin capsule containing as active ingredient, for example, (S) -N- (1-carboxy-2-methylprop-1-yl) -N-pentanoyl-N- (2 (1H-tetrazol-5-yl) biphenyl-4- ylmethyl) amine, can be prepared, for example, as follows:

composition

(1) active ingredient (2) microcrystalline cellulose (3) polyvidone K30 (4) sodium lauryl sulfate (5) crospovidone (6) magnesium stearate 80.0 mg 110.0 mg 45.2 mg 1.2 mg 26.0 mg 2.6 mg Components (1) and (2) are granulated with solution of the components

and (4) in water. Components (5) and (6) are added to the dry granules and the resulting mixture is filled into size 1 hard gelatin capsules.

Claims (6)

Use of a compound of formula I CH ₃ CH _3, or a pharmaceutically acceptable salt thereof for the preparation of pharmaceutical compositions for the treatment of diabetic nephropathy. 2. A method of treating diabetic nephropathy, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. 3. A pharmaceutical composition for the treatment of diabetic nephropathy, comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Use of a compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 for the preparation of a pharmaceutical composition for the therapeutic and prophylactic treatment of glomerular, hemodynamic and structural abnormalities in the kidney, proteinuria, glomerulosclerosis, glomerular hypertrophy and high pressure in glomerular capillaries. The method of claim 2 for the therapeutic and prophylactic treatment of glomerular, hemodynamic and structural abnormalities in the kidney, proteinuria, glomerulosclerosis, glomerular hypertrophy and high pressure in glomerular capillaries. A pharmaceutical composition according to claim 3 for the treatment of glomerular, hemodynamic and structural abnormalities in the kidney, proteinuria, glomerulosclerosis, glomerular hypertrophy and high pressure in the glomerular capillaries.