HUT76542A - Use of valsartan for the preparation of pharmaceutical composition serving for the treatment of diabetic nephropathy - Google Patents

Description

^ DIABETIC NEPHROPATHY TREATMENT'S APPLICATION ^ APPLICATION2 * 5A

Patients with a history of, for example, Diabetes Mellitus have, in many cases, experienced renal vascular (vascular) disorders. One of the symptoms seen is nephropathy diabetica (a kidney disease caused by diabetes), also called diabetic glomerulosclerosis. The nodular thickening of the capillary mucosa causes constriction of the vessel cavities, creating fibrinous deposits and microaneurysms (circumscribed dilatation of the vessel) on the walls of the capillaries.

These pathological manifestations are in the form of clinically severe proteinuria (protein urination) and hypertension. If nephropathy diabetica is not properly treated, renal function deteriorates to the final stage, which already requires dialysis.

Therefore, great attention is being paid to the research of active substances that have a preventive effect and are thus capable of arresting the progress of nephropathy diabetica or ameliorating symptoms.

• · · · ·

International Patent Application WO 92/10182, issued June 25, 1992, discloses the use of angiotensin II antagonists for the treatment of nephropathy diabetica. According to this application, nitrogen-containing hetero-ring compounds, more preferably imidazole derivatives and peptide angiotensin II antagonists are preferred for the treatment of nephropathy diabetica.

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

CH, CH, <Z CH

and pharmaceutically acceptable salts thereof are surprisingly useful in the therapeutic treatment of nephropathy diabetica. The compounds of the formula I and their pharmaceutically acceptable salts can also be used for prophylaxis. These properties are particularly pronounced when the active ingredient is administered systemically.

Preferably, the compound of formula I is in the form of its pharmaceutically acceptable salts. For example, since (I) • · · · · ·

I

The compound of formula 3 has at least one basic center, which forms acid addition salts. Such salts are formed, for example, with strong inorganic acids such as mineral acids such as sulfuric acid, a phosphoric acid or a hydrogen halide, strong organic carboxylic acids such as unsubstituted or halogen-substituted C 1-4 alkanecarboxylic acids such as acetic acid, saturated or saturated oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic or terephthalic acid, hydroxycarboxylic acids such as ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric acid, amino acids such as aspartic acid, glutamic acid or glutamic acid for example halogen substituted C 1-4 alkane or aryl sulfonic acids such as methane or p-toluenesulfonic acid.

Suitable bases include, for example, metal salts such as alkali metals or alkaline earth metals such as sodium, potassium or magnesium, and ammonia or an organic amine such as morpholine, thiomorpholine, piperidine, pyrrolidine, a lower mono-, di- or a trialkylamine such as ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl or dimethylpropylamine, or a hydroxy (lower carbon mono-, di- or trialkyl) amine such as mono , di- or triethanolamine salts. Suitable internal salts may also be formed.

In European Patent Application Publication No. 443983, issued August 28, 1991, in Example 16, (S) -N- (1-carboxy-2-methylprop-1-yl) -N-pentanoyl-N- [2'- (1 H-Tetrazol-5-yl) -biphenyl-4-ylmethyl] -amine, which is not only structurally different from International Patent Application WO 92/10182 · * ·· ···· and salts thereof and are described as angiotensin II antagonists. This application also discloses the angiotensin II antagonist properties of the compound.

Furthermore, the compounds of formula I and their salts are characterized by excellent tolerability and surprisingly potent activity.

The utility of the compounds of formula I and their pharmaceutically acceptable salts in the treatment of nephropathy diabetica is illustrated, for example, by the following animal model known to those skilled in the art.

For example, by blocking angiotensin II, short- and long-term effects on vascular lesions can be determined after administration of the test compound to diabetic rats with hyperglycaemia (elevated blood glucose). The method is described in [J. Am. Nephrol. 4: 40-49 (1993)]. A therapeutic effect is present if, for example, in such diabetic rats, the growth of glomerular filtration (GFR) stops, and proteinuria and glomerulosclerosis do not occur. The long-term effect of treatment with angiotensin II blockers can be determined in rats with normal blood pressure, where diabetes was induced by intravenous injection of 45 mg / kg streptozotocin.

The extent of glomerular filtration and plasma flow in the kidney can be measured as the clearance of 1 H-inulin or 1311-hippurate (the renal excretion of a substance). The antitrophic effect of an angiotensin II blocking compound of formula I on vascular hypertrophy, which is a secondary symptom of diabetes, can be determined by the method described in Diabetes 39: 1575-1579 (1990). ], the vascular mass and glomerular volume of the gonad is measured.

Similarly beneficial effects can be achieved in the treatment of hyperlipidemia-related glomerulosclerosis.

In prophylaxis, the compound of formula (I) and pharmaceutically acceptable salts thereof can be used according to the present invention to prevent pathological symptoms of nephropathy diabetica, such as renal vascular injury, increased glomerular capillary pressure, and thus protect the glomerular !) and structural abnormalities, thereby stabilizing renal function. Furthermore, the compounds of formula (I) and their pharmaceutically acceptable salts used in the present invention can be used to slow, reduce or reverse the development of pathological symptoms of nephropathy diabetica such as proteinuria, glomerulosclerosis, glomerular hypertrophy and increased glomerular capillary pressure. Thus, abnormal glomerular and hemodynamic effects can be corrected and normalized.

It is a further object of the present invention to provide a compound of formula (I) and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment of nephropathy diabetica.

The present invention further provides a method of treating nephropathy diabetica comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. in.

The present invention also provides pharmaceutical compositions for the treatment of nephropathy diabetica comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient specifically adapted for systemic administration.

The invention also encompasses suitable systemically administrable pharmaceutical compositions containing as active ingredient a compound of formula (I) or a pharmaceutically acceptable salt thereof.

A therapeutically effective amount is the amount that stops or slows the progression of nephropathy to diabetica, or completely cures or has a preventive effect. This amount is readily determined by one of ordinary skill in the art.

These pharmaceutical compositions, which contain the active ingredient alone or together with conventional pharmaceutical excipients, are administered enterally, for example orally or rectally, or parenterally to warm-blooded animals. For example, the pharmaceutical compositions contain from about 0.1% to about 100%, preferably from about 1% to about 60%, of the active ingredient. Pharmaceutical formulations for enteral, parenteral and ocular administration may be presented, for example, in unit dosage forms such as dragees, tablets, capsules, suppositories or ampoules. The compositions are readily prepared, for example, by conventional mixing, granulating, confectioning, dissolving or lyophilizing processes. So it is for oral administration

Pharmaceutical compositions can be prepared by mixing the active ingredient with solid carriers, optionally granulating the resulting mixture, and processing the mixture or granulate, if desired or necessary, into tablets or dragee cores.

Carriers include excipients such as sugars such as lactose, sucrose, mannitol or sorbitol, cellulose formulations and / or calcium phosphates or calcium hydrogen phosphates; binders such as starch pastes made from corn, wheat, rice or potato starch, gelatin, tragacanth gum, methylcellulose and / or polyvinylpyrrolidone, and, if desired, disintegrating (tablet disintegrating) agents such as the aforementioned starches, carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid and salts thereof such as sodium alginate. The excipients may be fluidizing agents and lubricants such as silica, talc, stearic acid and its salts, such as magnesium or calcium stearate, and / or polyethylene glycol. The dragee cores may be coated with an appropriate enteric coating (which may be absorbed from the gut), including concentrated sugar solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol, and / or titanium dioxide. or coating solutions in a suitable organic solvent or solvent mixture, or solutions of cellulose formulations suitable for enteral coating, such as acetylcellulose phthalate or hydroxypropylmethylcellulose beverage. Dyestuffs or dyes may also be added to the coating of tablets or dragees, for example for identification or to indicate different doses of the active ingredient.

The pharmaceutical compositions for oral administration may also be dry-filled capsules made of gelatin or soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Dry-filled capsules may contain the active ingredient in granular form, for example, in admixture with excipients such as lactose, binders such as starches, lubricants 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 glycol, and a stabilizer may be added.

Pharmaceutical compositions for rectal administration include, for example, suppositories consisting of a mixture of the active ingredient and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffinic hydrocarbons, polyethylene glycols or higher alkanols. gelatin suppositories consisting of a mixture of the active ingredient and a suppository base may also be used.

Suitable suppository bases are, for example, liquid triglycerides, polyethylene glycols or paraffinic hydrocarbons.

For parenteral administration, aqueous solutions of a water-soluble form of the active ingredient, such as a water-soluble salt, or suspensions of the active ingredient, for example, oily injection suspensions containing suitable lipophilic solvents or carriers such as fatty oils such as sesame oil or synthetic fatty acid esters · · · · · · · · · · · · · · · · · · · · · · · · ···

9 rides are used, as well as aqueous injections or suspensions containing viscosity-increasing agents such as sodium carboxymethylcellulose, sorbitol and / or dextran, and optionally stabilizers.

The dosage of the active ingredient may vary depending on various factors such as the route of administration employed, the species, age and / or individual condition of the warm-blooded animal. Normally, in a patient weighing about 75 kg, a daily dose of about 10 mg to about 250 mg is administered orally.

It is a further object of the present invention to provide a process for the manufacture of a medicament for the treatment of nephropathy diabetica comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The following example is intended to illustrate the invention in more detail and is not intended to limit its scope.

Example 1 (preparation)

A hard gelatin capsule containing, for example, (S) -N- (1-carboxy-2-methylprop-1-yl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl as an active ingredient. -4-ylmethyl] -amine, can be formulated with the following composition:

(1) agent 80.0 mg (2) microcrystalline cellulose 110.0 mg (3) polyvidone K30 45.2 mg (4) sodium laureth sulfate 1.2 mg (5) crospovidone 26.0 mg

(6) magnesium stearate 2.6 mg

Components (1) and (2) are granulated with an aqueous solution of components (3) and (4). Components (5) and (6) are added to the dry granulate and the resulting composition is filled into size 1 hard gelatin capsules.

Claims (6)

PATENT CLAIMS A compound of formula (I) O ll ^C \ ^{2 3} / </ ch ₂ ^x ch ch ₃ ch ₃ </ ³ CH I The use of CH or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of nephropathy diabetica. 2. A method of treating nephropathy diabetica, wherein a patient in need thereof is treated with a compound of Formula (I). A therapeutically effective amount of 12 or a pharmaceutically acceptable salt thereof. 3. A pharmaceutical composition for the treatment of nephropathy diabetica, characterized in that a compound of the formula I CH CH X / O CH II Ϊ CH CH Or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 in the preparation of a medicament for the therapeutic and prophylactic treatment of glomerular, hemodynamic and structural renal disorders, proteinuria, glomerulosclerosis, glomerular hypertrophy and increased glomerular capillary pressure. 5. A method according to claim 2 for the therapeutic and prophylactic treatment of glomerular, hemodialysis and structural renal disorders, proteinuria, glomerulosclerosis, glomerular hypertrophy and increased capillary pressure. A pharmaceutical composition according to claim 3 for the therapeutic and prophylactic treatment of glomerular, hemodynamic and structural renal disorders, as well as proteinuria, glomerulosclerosis, glomerular hypertrophy and increased capillary pressure.