CZ20011785A3 - Use of benzoylguanidines for treating diabetes mellitus independent on insulin - Google Patents

Abstract

(57) Abstract The invention relates to the use of benzoylguanidines of formula (I) wherein R<1> is A; R<2> is Het, CnFmH2n+1-mOp, R<4>, OR<4>, OH, benzyl, CN, Hal, SOq-R<5>, Ph, O-Ph, O-Het, NH-Het, NH2, NHA, NA2 or NH-Ph; R<3> is SO2A'; R<4> is a straight-chain or branched alkyl radical having 1 to 8 C atoms or cycloalkyl having 3 to 8 C atoms which can be unsubstituted or mono-, di- or trisubstituted by A; R<5> is A or Ph; A, A' in each case independently of one another are alkyl having 1 to 6 C atoms, and/or their physiologically acceptable salts and solvates for the production of a medicament for the treatment of non-insulin-dependent diabetes mellitus.

Description

Use of benzoylguanidines for the treatment of non-insulin dependent diabetes mellitus

Technical field

The invention relates to the use of the benzoylguanidines of the formula I

(I) where is

R ¹ A,

R ² Het CnFmHzn-MOP + 1, R ⁴ 0R ^4, OH, benzyl, CN, Hal, ^SOq-R5,

Ph, Ph-O, O-Het, Het-NH, NH _2, NHA, NA ₂ or NH-Ph

R ³ SO ₂ A ',

R ⁴ is a straight or branched alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms which are unsubstituted or substituted by one, two or three A groups,

R ⁵ A or Ph,

A, A 'independently C 1 -C 6 alkyl,

Het a monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic group having one to four nitrogen, oxygen and / or sulfur atoms, optionally substituted by one, two or three of the group consisting of Hal, CF3, A, CN, NO2, NH2 and oxo,

Hal F, Cl, Br or J,

Ph unsubstituted phenyl or phenyl substituted with one, two or three of A, OA, Hal, CF 3, NH 2, NHA and NA 2, m 1, 2, 3, 4, 5, 6, 7 but not more than 2n + 1 , n 1,2 or 3,

P 0 or 1, q 0, 1 or 2, and physiologically acceptable salts and solvates thereof for the manufacture of a medicament for the treatment of non-insulin dependent diabetes mellitus.

BACKGROUND OF THE INVENTION

The compounds of formula (I) are known from European Patent Publication Nos. EP 0 699666, EP 0 699663, EP 0 743301, EP 0 704431, EP 0 758644, EP 0 699660, EP 0 725062, EP 0

708088, EP 0 694537 and EP 0 723963. They are potent inhibitors of the cellular sodium-proton antiporter (Na ⁺ / H ⁺ exchange).

Benzoylguanidines, otherwise substituted, are described, for example, in EP 0 589336 as inhibitors of the cellular sodium-proton antiporter, which shows an elevated level in diabetes.

• · ·

-.

The use of pyrazinoylguanidines for the treatment of diabetes mellitus is described in WO 97/21438.

SUMMARY OF THE INVENTION

The invention is based on the discovery that the compounds described above have useful properties, particularly suitable for the manufacture of medicaments. It has been found that the compounds of formula I and their salts have particularly useful pharmacological properties with good tolerability, especially when used for the manufacture of medicaments for the treatment of non-insulin-dependent diabetes mellitus (NIDDM).

In addition, the compounds of formula I and their salts can be used for the manufacture of medicaments for lowering and / or controlling the blood sugar level of a person suffering from NIDDM.

The compounds of formula I and their salts can be used for the manufacture of medicaments for lowering and / or controlling the levels of insulin, free fatty acids and triglycerides of a person suffering from NIDDM.

The efficacy of the compounds of formula I can be used for the manufacture of medicaments for the treatment of non-insulin dependent diabetes mellitus, as experimentally confirmed for some representative compounds of formula I. The pharmacological results of the tests of compounds of formula I are shown in Table I.

The invention therefore relates to the use of the benzoylguanidines of the general formula I in particular from the group consisting of

(a) N-diaminomethylene-2-methyl-4- (1-pyrrolyl) -5-methylsulphonylbenzamide;

b) N-diaminomethylene-2-methyl-4-trifluoromethyl-5-methylsulfo-4,444,444 4,444 44,444

4 444444 • 44 ··· 4 · 444 4 · 44 · nylbenzamide

c) N-diaminomethylene-2-methyl-4-isopropyl-5-methylsulfonylbensamide and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment of insulin-independent diabetes mellitus.

By solvates is meant addition compounds with, for example, water or alcohols.

All symbols which occur several times in the compound of the formula I, for example A, have independent meanings.

The alkyl group has 1 to 6 carbon atoms, preferably 1, 2, 3, 4, 5 or 6 carbon atoms. In particular, it is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl but also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or a 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl group.

R @ ¹ is preferably C1 -C6 alkyl, preferably methyl, ethyl, propyl or isopropyl, in particular methyl.

The symbol R ³ represents a radical · SO2A wherein A is A 'preferably, for example methyl, ethyl, propyl, isopropyl or butyl, but particularly R ³ represents SO2CH3.

Het is preferably 2- or 3-furyl, 2,444,444,444

4 4 444 · 44

444444 44 «444444

444 4444 4 «444 44 ··· or 3-thienyl,

1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl,

1-, 3-, 4- or 5-pyrazolyl,

2-, 4 or 5-oxazolyl,

5-thiazolyl, 3-,

3-, 4- or 5-isoxazolyl,

4- or 5-isothiazolyl,

2-,

4- or

2-,

3- or

4-pyridyl, 2-, 4-, 5- or

6-pyrimidinyl, further preferably 1,2,3-triazol-1 -,

-4- or -5-yl,

1,2,4-triazol-1-, 3- or -5-yl, 1 or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or - 5-yl, 2-, 3-, 4-, 5 or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl,

3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6 or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2- 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4 or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2 -, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-,

5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzthiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-,

7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 2- ,

A 4-, 5-, 6-, 7- or 8-quinazolinyl group. The heterocyclic groups may also be partially or fully hydrogenated. Het may also be, for example, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-

-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-,

-4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-,

-3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl,

1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl,

-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl,

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · To ·

1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-,

-3-, -4-, -5-, -6-, -7- or -8-quinolinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolinyl. In particular, Het is 1-imidazolyl, 1-piperazinyl, 1-piperidinyl, 1-pyrrolidinyl, 1-pyrrolyl, pyridyl, oxodihydropyridyl or benzimidazolyl, and most preferably 1-pyrrolyl.

The formula CnFmH2n + i-n0p is preferably OCF3. OCH 2 F, OCHF 2, CF 3, C 2 F 5 or a partially fluorinated C 1 -C 4 alkyl group, CH 2 F, CHF 2, C 2 HF 4, C 2 H 2 F 3 or C 2 H 4 F.

R ^{@ 4} is preferably a straight or branched chain alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms. When R ^{4 is a} non-cyclic group, it is an alkyl group, which is also referred to as a preferred meaning of A. Particularly preferred cycloalkyl groups of R ⁴ are cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl or derivatives thereof substituted with one A group, especially methyl, ethyl or isopropyl.

R @ ² is, for example, preferably fluorine, chlorine or bromine, methyl, ethyl, propyl, isopropyl, 2-butyl, - (CH2) 4-CH3, cyclobutyl, cyclohexyl, p-tolyl, 4-chlorophenyl, 2,4 -dichlorophenyl, 4-fluorophenyl, 3,5-bis (trifluoromethyl) phenyl, 3,5-dichlorophenyl, phenyl, 2-furyl, SMe, SEt, SPr, S-isopropyl, S-tert-butyl, S- (3) -chlorophenyl), S- (2-chlorophenyl), S- (4-chlorophenyl), S-phenyl, S- (4-pyridyl), benzyloxy, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopentyloxy7 ·· ·· ·· ·· ·· ··

9 9 · 9 9 9 9 99

9 · 9,999 9 · 9 9 9 9 9 99

999 9999 99 999 99999 pin, cyclohexyloxy, tert-butyloxy, phenoxy, 2-chlorophenoxy, 3-chlorophenoxy, 4-chlorophenoxy, 3-pyridyloxy, 1-pyrrolidinyl, 1-piperidinyl, 3-piperidinyl, 3-piperidinyl, 3-piperidinyl, 3-piperidinyl, amino-1-piperidinyl, 1-imidazolyl, 1-benzimidazolyl, 2-methyl-1-imidazolyl, 1-pyrazolyl, 1-pyrrolyl, amino, or 1-amino, 2-pyridylamino, or 2-pyrimidyl and amino.

The groups which occur several times in the general formulas can be independently of one another or different.

Accordingly, the invention relates in particular to compounds of the formula I in which at least one of the symbols has the above-mentioned preferred meaning. Some preferred groups of compounds of formula (I) are the following compounds of formulas (Ia) to (Ij), wherein not particularly indicated symbols have the meanings given in formula (I).

AND. however, in the general formulas: Ia R ¹ group methyl or ethyl, [0057] Ib R ³ group SO2CH3, Ic R ¹ group methyl or ethyl, R ³ group SO2CH3, Id Het 1-imidazolyl, 1-piperazinyl, 1-piperidinyl, 1-pyrrolidinyl, 1-pyrrolyl, pyridyl, oxodihydropyridyl or benzimidazolyl, Ie R ¹ group methyl or ethyl, R ³ group SO2CH3, R ² group 1-imidazolyl, 1-piperazinyl, 1-pipe-

pyridyl, 1-pyrrolidinyl, 1-pyrrolyl, pyri-

4444

4 44

4f

4444 • 4 4

444 ··· 4 · 4 · 4 · 4-yl, oxodihydropyridyl or benzimidazolyl,

If R ¹ is methyl or ethyl,

R ³ group Sosa *

R ² is Het, CnFmH2n + 1-MOP, ^{R4, OR4,} OH, benzyl, CN, F, Cl, SOcjR ^5, Ph, O-Ph, O-Het, NH-Het, _NH2, NHA, NA2 or NH-Ph,

R ⁴ is a straight or branched alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms which are unsubstituted or monosubstituted by group A,

R ⁵ A or Ph,

A, A 'alkyl having 1 to 6 carbon atoms,

Het a monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic group having one to four nitrogen, oxygen and / or sulfur atoms, optionally substituted with one, two or three groups selected from Hal, CF3, A, CN, NO2, NH2 and oxo ,

Hal F, Cl, Br or J,

Ph unsubstituted phenyl or phenyl substituted with one, two or three of A, OA, Hal, CF 3, NH 2, NHA and NA 2, m 1, 2, 3, 4, 5, 6, 7 but not more than 2n + 1 , n 1,2 or 3,

P 0 or 1, q 0 or 2

ig R ¹ group methyl or ethyl, R ³ group SO2CH3, R ² group 1-imidazolyl, 1-piperazinyl, 1-pipe

a pyridyl, 1-pyrrolidinyl, 1-pyrrolyl, pyridyl, or oxodihydropyridylovou benzimidazolylo9 • 9 9999 acid, CnFmH2n-MOP + 1 or R ^4,

R ⁴ is a straight or branched alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms which are unsubstituted or monosubstituted by group A,

A is an alkyl group having 1 to 6 carbon atoms, m 1, 2, 3, 4, 5, 6, 7 but not more than 2n + 1, n 1, 2 or 3,

P O or 1,

Ih

R ¹ is methyl or ethyl,

R ³ radical

SO2CH3,

R ² group,

-imidazolyl, 1-piperazinyl, 1-piperidinyl, 1-pyrrolidinyl, 1-pyrrolyl, pyridyl, oxodihydropyridyl or benzimidazolyl, CF 3, OCF 3 or an alkyl group having 1 to 6 carbon atoms,

R ¹ is methyl or ethyl,

Ij

R ³

R ²

R ¹

R ³

R ² group group group group group group

SO2CH3,

1-pyrrolyl, CF 3, OCF 3 or C 1 -C 6 alkyl, methyl or ethyl,

SO2A,

Het, CnFmH2n + l-aOp,

CN, F, Cl, SO 2 R ⁵ , Ph, O-Ph,

R ⁴ , OR ⁴ , OH, benzyl,

O-Het, NH2, NHA,

NA2 or NH-Ph,

R ⁴ is a straight or branched chain alkyl group R ⁵

AND,

Monosubstituted with 1 to 3 carbon atoms or up to 6 carbon atoms up to 6 carbon atoms

A or Ph, an alkyl group having 1 to or cycloalkyl groups which are unsubstituted A, carbon atoms,

Het 1-imidazolyl,

1-piperazinyl, 1-pipe-

φφ ·· φ φ φ φ φ φ φφ • φ «φφ

Ridyl, 1-pyrrolidinyl, 1-pyrrolyl, pyridyl, oxodihydropyridyl or benzimidazolyl, which are optionally substituted by one, two or three of Hal, CF3, A; , CN, NO 2, NH 2 and oxo,

Hal F, Cl, Br or J,

Ph unsubstituted phenyl or phenyl substituted with one, two or three of A, OA, Hal, CF 3, NH 2, NHA and NA 2, m 1, 2, 3, 4, 5, 6, 7 but not more than 2n + 1 , n 1, 2 or 3, p 0 or 1, q 0 or 2, and physiologically acceptable salts and solvates thereof.

The compounds of the formula I can be used in the form of salts derived from inorganic and organic acids or bases.

The base of formula (I) can be converted into an appropriate acid addition salt by acid, for example by reacting an equivalent amount of base and acid in an inert solvent such as ethanol and then evaporating the solvent. Particularly suitable acids for this reaction are those which give physiologically acceptable salts. Inorganic acids such as sulfuric, nitric, hydrohalic acids such as hydrochloric or hydrobromic acids, phosphoric acids such as orthophosphoric acid, sulfamic acid and ogranic acids may be used, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polyhydric carboxylic, sulfonic acids or sulfuric acids such as formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic, wine, apple, lemon, gluconic, ascorbic, nicotinic, isonicotinic, methanesulfonic, ethanesulfonic, ethanedisulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalene monosulfonic, and naphthalenedisulfonic acid. Salts with physiologically unacceptable acids, for example picrates, can be used for the isolation and / or purification of the compounds of formula I.

On the other hand, the compounds of the formula I can be converted by using bases (such as sodium or potassium hydroxide or carbonate) into the corresponding metal salts, in particular the alkali metal or alkaline earth metal salts or the corresponding ammonium salts.

The results of the antidiabetic activity tests of some representative compounds of Formula I are shown in Table I. The compounds were administered orally via animal models of diabetes (NOSTZ rats) in their moderate diabetic state. Adult male rats weighing 300-500 g, bred in groups of five individuals under standard conditions, were used for the tests.

Diabetes is induced by injection of streptozotocin (100 mg / kg body weight, intravenously) on the day of birth. In adulthood, NOSTZ rats exhibit NIDDM with the following characteristics (Portha-Diabetologia 17: 313-377, 1979) ^:

- fasting hyperglycemia 180 to 200 mg / dl

- glucose intolerance

- specific failure of insulin secretion in response to glucose.

All drugs tested are suspended in Arabic gum solution and administered orally once daily for four days. Compounds are studied by basal glycemia, lactatemia and insulinemia before treatment day 0.2 hours after acute (day 1) and two hours after the last treatment.

• 4 • · ·

··· · · 4 • 4

4 • 44 «

444 • 4

• 4 treatment (once daily for four days) with 20 mg / kg of compounds.

Table I

Antidiabetic activity of representative compounds of formula I on NOSTZ diabetic rats (20 mg / kg p.o.,% effect)

R ‘ R ^z R ⁴ Glycemia Insulinemia Lactatemia D1 D4 D1 D4 · 01 D4 ch ₃ cf ₃ -so ₂ ch ₃ -19 -21 -39 -22 -26 -20 ch ₃ 1-pyrrolyl -so ₂ ch ₃ -16 -29 · -17 -43 -15 -22 ch ₃ isopropyl -so ₂ ch ₃ -14 -25 19 Dec -14 7 5

Pharmacological data confirm that test compounds at 20 mg / kg significantly reduce fasting plasma glucose following acute and chronic treatment.

The invention also relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production, in particular by a non-chemical route, of pharmaceutical compositions for the treatment of non-insulin-dependent diabetes mellitus. For this purpose, the compounds of the invention may be converted into a suitable dosage form with at least one solid or liquid and / or semi-liquid carrier or excipient and optionally in admixture with one or more other active ingredients.

The invention also relates to pharmaceutical compositions comprising at least one compound of the formula I and / or a physiologically acceptable salt or solvate thereof for the treatment of non-insulin-dependent diabetes mellitus.

• 4 4

44

4 4 4

44 4444 44 4 * 4 • 4 4 4 4 4 4 4 4 4 4 4 4 4 · 4 4 4 • 4 44 4 4 4 44

The invention also relates to pharmaceutical compositions for the treatment of non-insulin dependent diabetes mellitus comprising at least one compound selected from the group consisting of:

(a) N-diaminomethylene-2-methyl-4- (1-pyrrolyl) -5-methylsulphonylbenzamide;

(b) N-diaminomethylene-2-methyl-4-trifluoromethyl-5-methylsulphonylbenzamide;

c) N-diaminomethylene-2-methyl-4-isopropyl-5-methylsulfonyl benzamide and / or their physiologically acceptable salts or solvates.

These compositions of the invention may be used as medicaments in human and veterinary medicine. Suitable carriers are inorganic or organic substances which are suitable for enteral (e.g. oral) or parenteral or topical administration and which do not react with the compounds of formula I, such as water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerin triacetate, gelatin, carbohydrates such as lactose or starches, magnesium stearate, talc and petrolatum. Especially suitable for oral use are tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops, suppositories for rectal use, solutions for parenteral use, especially oily or aqueous solutions, further suspensions, emulsions or implants, for topical use ointments, creams or powders. The compounds of the invention may also be lyophilized and the resulting lyophilizates used, for example, for the preparation of injectables. The compositions may be sterilized and / or may contain adjuvants such as glidants, preservatives, stabilizing agents and / or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffers, coloring agents, flavoring agents and / or one or more more active ingredients such as vitamins.

As a rule, the compounds of the formula I according to the invention are:

14- · «·» »» »

·· ·· «· ·· • • • • • • • ··· • • • • • • · • • • ·· • ··· • • ··

Uses in doses similar to other known commercially available means for said indication (such as metformin or amiloride), preferably at a dose of 0.1 to 500 mg, especially 5 to 300 mg per dosage unit. The daily dose is preferably about 0.01 to 250 mg / kg, in particular 0.02 to 100 mg / kg body weight.

The compound of the formula I according to the invention is generally preferably administered in a dosage of about 1 to 500 mg, in particular 5 to 100 mg per dosage unit. The daily dose is preferably 0.02 to 10 mg / kg body weight. The dose for each individual depends on a variety of factors, such as the efficacy of the particular compound used, age, body weight, general health, sex, diet, time and route of administration, excretion rate, drug combination, and severity of the disease. . Oral administration is preferred.

The following examples illustrate pharmaceutical compositions ¹

DETAILED DESCRIPTION OF THE INVENTION

Example A

Injection ampoules

A solution of 100 g of an active compound of the formula I and 5 g of disodium hydrogen phosphate in 3 l of double-distilled water is adjusted to pH 6.5 with 2N hydrochloric acid, sterile filtered and filled into injection vials, lyophilized under sterile conditions and vials close. Each vial contains 5 mg of active substance.

·· ·· • · »·.

* · ···· ····

··· « ·· and * • • • • • ··· e · • ♦ ♦ • · • • · • • · ·· ···

Example B

Suppositories

A mixture of 20 g of an active compound of the formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.

Example C

Solution

A solution of 1 g of an active compound of the formula I, 9.38 g of sodium dihydrogen phosphate dihydrate, 28.48 g of sodium hydrogen phosphate with 12 water molecules and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water is prepared. The pH of the solution is adjusted to 6.8, made up to one liter and sterilized by irradiation. This solution can be used as eye drops.

Example D

Ointment

500 mg of an active compound of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E

Tablets

From a mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate, tablets are compressed in a conventional manner such that each tablet contains 10 mg of the active ingredient.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Example F

Dragee

Analogously to Example E, tablets are compressed and then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.

Example G

The capsules are filled into hard gelatine capsules in a manner known per se with 2 kg of the active ingredient of the formula I in such a way that each capsule contains 20 mg of active ingredient.

Example H

Ampoule

A solution of 1 kg of active compound of the formula I in 60 l of double-distilled water is sterile filtered and filled into ampoules, lyophilized under sterile conditions and the ampoules are sealed. Each ampoule contains 10 mg of the active substance.

Industrial applicability

The benzoylguanidine derivative and pharmaceutically acceptable salts thereof are suitable for the manufacture of pharmaceutical compositions for the treatment of non-insulin dependent diabetes mellitus.

Claims (4)

The use of the benzoylguanidines of the general formula I (I) wherein R1 is R1, R2 Het, CnFmH2n + 1-mOP) R4, OR4, OH, benzyl, CN, Hal, SOq-R5, Ph, O-Ph, O-Het, NH-Het, NH 2, NHA, NA 2 or NH-Ph, R 3 SO 2 A, R 4 is a straight or branched alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms which are unsubstituted or substituted once, two or three groups A, R5A or Ph, A, A ', independently of one another, an alkyl group having 1 to 6 carbon atoms, a Het monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic group having one to four nitrogen, oxygen and / or sulfur, optionally substituted with one, two or three of the group consisting of Hal, CF 3, A, CN, NO 2, NH 2 and oxo, Hal F, Cl, Br or J, or unsubstituted phenyl; or a phenyl group substituted with one, two or three groups from the group A, OA, Hal, CF 3, NH 2, NHA and NA2 1, 2 or 3 0 or 1 O, 1 or 2, and / or their physiologically acceptable salts and solvates for the manufacture of compositions independent of insulin-dependent diabetes mellitus. 1, 2, 3, 4, 5, 6, 7 but not more than 2n + 1, 2. Use of the benzoylguanidines according to claim 1 of the general formula Even from the file including (a) N-diaminomethylene-2-methyl-4- (1-pyrrolyl) -5-methylsulphonylbenzamide; (b) N-diaminomethylene-2-methyl-4-trifluoromethyl-5-methylsulphonylbenzamide; c) N-diaminomethylene-2-methyl-4-isopropyl-5-methylsulfonylbenzamide and / or their physiologically acceptable salts and solvates for the manufacture of insulin-independent agents for the treatment of diabetes mellitus. Pharmaceutical composition for the treatment of non-insulin-dependent diabetes mellitus, characterized in that it contains, as active ingredient, the benzoylguanidines according to claim 1 and / or their physiologically acceptable salts or solvates. 4. The pharmaceutical composition for the treatment of non-insulin dependent diabetes mellitustus according to claim 3, comprising at least one compound selected from the group consisting of: (a) N-diaminomethylene-2-methyl-4- (1-pyrrolyl) -5-methylsulphonylbenzamide; (b) N-diaminomethylene-2-methyl-4-trifluoromethyl-5-methylsulphonylbenzamide; c) N-diaminomethylene-2-methyl-4-isopropyl-5-methylsulfonylbenzamide and / or physiologically acceptable salts or solvates thereof.