MXPA96003999A - Treatment of diabetic nephropathy with valsar - Google Patents

Abstract

The angiotensin II antagonist of the Formula: (See Formula) and the pharmaceutically acceptable salts thereof, can be used for the therapeutic treatment of diabetic nephropathy.

Description

TREATMENT OF DIABETIC NEPHROPATHY WITH VALSARTAN In patients who, for example, have been suffering from diabetes mellitus for a relatively long time, vascular disorders of the kidneys are often observed. One of the symptoms observed is diabetic nephropathy, also called diabetic glomerulosclerosis. Nodular lubrications in the glomerular tubes cause constrictions of the vascular lumen, fibrinoid deposits in the capillary walls, and microaneurysms. These pathological symptoms manifest clinically in the form of massive proteinuria and hypertension. If diabetic nephropathy is not adequately treated, renal function will deteriorate to the terminal stage, which requires dialysis. Therefore, great importance is attached to the search for active ingredients that can, either act in a preventive manner to stop the course of diabetic nephropathy in an appropriate manner, or reduce symptoms. The TCP Application WO 92/10182 (publication date: . 06.92) describes the use of angiotensin II antagonists, for the treatment of diabetic nephropathy. In that Application, heterocycles containing N more especially imidazole derivatives, and also peptide angiotensin II antagonists, are particularly described as being suitable for the treatment of diabetic nephropathy.

Extensive pharmacological studies have shown that the angiotensin II antagonist of the formula: and the pharmaceutically acceptable salts thereof are suitable, to a surprising degree, for the therapeutic treatment of diabetic nephropathy. The compound of the formula (I) and the pharmaceutically acceptable salts thereof can also be used in prophylaxis. These properties are obtained especially by means of the systemic administration of the active ingredient. The compound (I) can be especially in the form of pharmaceutically acceptable salts. Since the compound (I) has, for example, at least one basic center, it can form acid addition salts. These salts are formed, for example, with strong inorganic acids, such as mineral acids, for example. sulfuric acid, a phosphoric acid, to a halohydric acid, with strong organic carboxylic acids, such as alkane acids of 1 to carbon atoms unsubstituted or substituted, for example, substituted with halogen, for example, acetic acid, dicarboxylic acids unsaturated or saturated, for example, oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acids, hydroxycarboxylic acids, for example, ascorbic, glycolic, lactic, malic, tartaric, or citric acid, amino acids, for example, aspartic acid or glutathione, or benzoic acid, or with organic sulphonic acids, such as alkane acids of 1 to 4 carbon-sulphonic or aryl of 1 to 4 carbon atoms-unsubstituted or substituted, for example, substituted by halogen atoms, example, methanesulfonic or p-toluenesulfonic acid. Salts with suitable bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example, sodium, potassium, or magnesium salts, or salts with ammonium or an organic amine, such as morpholine, thio orfoline, piperidine, pyrrolidine, a mono-, di-, or tri-lower alkyl amine, for example, ethyl amine, tertiary butyl, diethyl, di-isopropyl, triethyl, tributyl, or dimethylpropyl, or a mono-, di-, or lower tri-hydroxyalkyl, eg, amine, di-, or tri-ethanolic amine. The corresponding internal salts can also be formed. In the European Patent Application Published under No. 443,983 (publication date: 28.08.91), in Example 16, the compound of the formula (I) and the salts thereof, said compound differs not only structurally from the compounds shown in WO 92/10182, it is specifically disclosed (amine [(S) -N- (1-carboxy-2-methylprop-1-yl) -N-pentanoyl-N- [2 '(1H-tetrazol-5-yl ) biphenyl-4-ylmethyl]], and is characterized as an angiotensin II antagonist. In this Application, the angiotensin II antagonist properties of that compound are described in the same manner. In addition, the compound of the formula (I) or the salts thereof are distinguished by an excellent tolerability and an unexpectedly pronounced activity force. The ability to treat diabetic nephropathy with the aid of the compound of the formula (I) or the pharmaceutically acceptable salts thereof can be demonstrated, for example, in the following animal model, which is known to the person skilled in the relevant field of the art. technique. Accordingly, for example, short-term and long-term effects, induced by blockade of angiothenet II, on the development of globular lesions can be determined after administration of the test compound to hyperglycemic diabetic rats. The method employed is analogous to the test method described in J. Am. Nephrol. 1993, ü: U0-H9. A therapeutic effect is present, for example, when, in those diabetic rats, the increase in the glomerular filtration rate (GFR) is prevented, and proteinuria and glomerulosclerosis are avoided.

The effect of long-term treatment with angiotensin II blocker can be determined in normotensive rats in which diabetes has been induced by the injection of streptozotocin (for example, 45 milligrams / kilogram, intravenously). The glomerular filtration rate and renal plasma flow can be measured as a 3H-inulin release or I-hipurate. The anti-trophic effect of the angiotensin II blocker of the formula (I) on vascular hypertrophy which is a secondary symptom of diabetes, can be determined by measuring both the mesenteric vascular weight and the glomerular volume analogously to Diabetes 1990, 39, pages 1575- 1579 In a similar way, convenient effects can be obtained in the treatment of glomerulosclerosis associated with hyperlipidemia. In prophylaxis, the compound of the formula (I) that can be used according to the invention, and the pharmaceutically acceptable salts thereof, can help to prevent the pathological symptoms that occur in diabetic nephropathy, for example, the formation of vascular system injuries in the kidney, and the increase in pressure in glomerular capillaries, and therefore, offers protection against glomerular, hemodynamic, and structural abnormalities in the kidney, and therefore, ensures the stabilization of functions kidney Furthermore, with the aid of the compound of the formula (I), which can be used according to the invention, and the pharmaceutically acceptable salts thereof, it can be slowed down, slow down, or reverse the presentation of the pathological symptoms that they occur in diabetic nephropathy, for example, proteinuria, glomerulosclerosis, glomerular hypertrophy, and high glomerular capillary pressure. Therefore, abnormal glomerular and hemodynamic effects can be corrected or normalized. The present invention relates to the use of the compound of the formula (I) and the pharmaceutically acceptable salts thereof, for the preparation of pharmaceutical compositions for the treatment of diabetic nephropathy. The present Application also relates to a method for the treatment of diabetic nephropathy, which comprises administering to patients requiring this treatment, a therapeutically effective amount of the compound of the formula (I) or a pharmaceutically acceptable salt thereof. The present Application also relates to pharmaceutical compositions for the treatment of diabetic nephropathy, said compositions comprising a therapeutically effective amount of the compound of the formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient suitable especially for administration systemic Accordingly, the invention also relates to the corresponding systemically administrable pharmaceutical compositions comprising, as an active ingredient, a compound of the formula (I) or a pharmaceutically acceptable salt thereof. It is understood that a therapeutically effective amount is the amount that stops or reduces the progress of the diabetic nephropathy disorder, or completely cures the disorder, or that acts in a preventive manner. This amount can be determined without difficulty by the person skilled in the relevant field. These pharmaceutical compositions are for enteral, such as oral or rectal, or parenteral administration to warm-blooded animals, the compositions comprising the pharmacological active ingredient by itself, or together with conventional pharmaceutical excipients. The pharmaceutical compositions comprise, for example, from about 0.1 percent to 100 percent, preferably from about 1 percent to about 60 percent of the active ingredient. Pharmaceutical compositions for parenteral and parenteral administration, and also ocular, are, for example, those which are in a unit dosage form, such as dragees, tablets, capsules, or suppositories, and also ampoules. These are manufactured in a manner known per se, for example, by means of conventional mixing, granulating, confectioning, dissolving, or lyophilizing processes.

Accordingly, pharmaceutical compositions for oral use can be obtained by combining the active ingredient with solid carriers, optionally granulating a resulting mixture, and processing the mixture or granules if desired or necessary, after the addition of suitable excipients, to form tablets or dragee cores. Suitable carriers are especially fillers, such as sugars, for example, lactose, sucrose, mannitol, or sorbitol, cellulose and / or calcium phosphate preparations, for example, calcium triphosphate or calcium acid phosphate, and also binders such as starch pastes, using, for example, corn starch, wheat starch, rice starch or potato starch, gelatin, tragacanth gum, methyl cellulose and / or polyvinyl pyrrolidone, and if desired, disintegrators, such as the aforementioned starches, also carboxymethyl starch, cross-linked polyvinyl pyrrolidone, ene, alginic acid or a salt thereof, such as sodium alginate. The excipients are especially flow conditioners and lubricants, for example, silicic acid, talc, stearic acid or their salts, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragee cores are provided with suitable, optionally enteric coatings, using, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol, and / or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations such as acetyl cellulose phthalate or hydroxypropylmethyl cellulose phthalate. Dyes or pigments may be added to tablets or dragee coatings, for example, for identification purposes or to indicate different doses of the active ingredient. Other pharmaceutical compositions that can be administered orally are dry filled capsules made of gelatin, and also sealed soft capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The dry filled capsules may comprise the active ingredient in the form of granules, for example, mixed with fillers, such as lactose, binders, such as starches, and / or brighteners, such as talc or magnesium stearate, and if desired , with 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 can be added in the same manner. They come into consideration as rectally administrable pharmaceutical compositions, for example, suppositories, which consist of a combination of the active ingredient and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols, or higher alkanols. It is also possible to use rectal gelatin capsules comprising a combination of the active ingredient and a base material. Suitable base materials are, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons. Suitable for parenteral administration are, in particular, aqueous solutions of an active ingredient in a water-soluble form, for example, a water-soluble salt, and also suspensions of the active ingredient, such as the corresponding oily suspensions for injection, using solvents or vehicles. liquefied, such as fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides, or aqueous suspensions for injection comprising viscosity-increasing substances, for example, sodium carboxymethyl cellulose , sorbitol, and / or dextran, and optionally also stabilizers. The dose of the active ingredient may depend on different factors, such as the mode of administration, the species of warm-blooded animal, the age and / or the individual condition. In normal cases, it is estimated that the approximate daily dose for a patient weighing approximately 75 kilograms is, in the case of oral administration, from approximately 10 milligrams to approximately 250 milligrams. The present Application also relates to a process for the preparation of pharmaceutical compositions for the treatment of diabetic nephropathy, said compositions comprising the compound of the formula (I) or a pharmaceutically acceptable salt thereof.

The following Example illustrates the invention described above, but is not intended to limit its scope in any way. Formulation Example 1: A hard gelatin capsule comprising, as an active ingredient, for example, amine (S) -N- (1-carboxy-2-methylprop-1-yl) -N-pentanoyl-N- can be formulated. [2 '(LH-tetrazol-5-yl) biphenyl-4-yl-methyl], for example, as follows: Composition (1) active ingredient 80.0 milligrams (2) microcrystalline cellulose 110.0 milligrams (3) polyvidone K30 45.2 milligrams ( 4) sodium lauryl sulfate 1.2 milligrams (5) crospovidone 26.0 milligrams (6) magnesium stearate 2.6 milligrams Components (1) and (2) are granulated with a solution of components (3) and (4) in water. Components are added (5) and (6) to the dry granules, and size 1 hard gelatin capsules are filled with the resulting formulation.

Claims (6)

1. The use of a compound of the formula (I): or a pharmaceutically acceptable salt thereof, for the preparation of pharmaceutical compositions for the treatment of diabetic nephropathy.

2. A method for the treatment of diabetic nephropathy, which comprises administering to patients requiring this treatment, a therapeutically effective amount of a compound of the formula (I): or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition for the treatment of diabetic nephropathy, which comprises a therapeutically effective amount of a compound of the formula (I): or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

4. The use of a compound of the 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 glomerular capillary pressure.

5. A method according to claim 2, for the therapeutic and prophylactic treatment of hemodynamic, structural, and kidney-related abnormalities in the kidney, of glomerulosclerosis proteinuria, of glomerular hypertrophy, and of high glomerular capillary pressure.

6. A pharmaceutical composition according to claim 3, for the treatment of glomerular, hemodynamic, and structural abnormalities in the kidney, of glomerulosclerosis proteinuria, of glomerular hypertrophy, and of high glomerular capillary pressure.