MXPA01005295A - Use of benzoylguanidines for the treatment of non-insulin-dependent diabetes mellitus - Google Patents

Abstract

The invention relates to the use of benzoylguanidines of formula (I) wherein R1 is A;R2 is Het, CnFmH2n+1-mOp, R4, OR4, OH, benzyl, CN, Hal, SOq-R5, Ph, O-Ph, O-Het, NH-Het, NH2, NHA, NA2 or NH-Ph;R3 is SO2A';R4 is a straight-chain or branched alkyl radical having 1 to 8 C atoms or cycloalkyl having 3 to 8 C atoms which can beunsubstituted or mono-, di- or trisubstituted by A;R5 is A or Ph;A, A'in each case independently of one another are alkyl having 1 to 6 C atoms;Het is a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having from 1 to 4 N, O and/or S atoms, which can be substituted once, twice or three times by Hal, CF3, A, CN, NO2, NH2 and/or carbonyl oxygen;Hal is F, Cl, Br or I;Ph is unsubstituted phenyl or substituted once, twice or three times by A, OA, Hal, CF3, NH2, NHA or NA2;m is 1, 2, 3, 4, 5, 6, 7, but at most 2n+1;n is 1, 2 or 3;p is 0 or 1;q is 0, 1 or 2, 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 BENZOILGUANIDINAS TO TREAT DIABETES MELLITUS NO INSULINODEPENDIENTE The present invention relates to the use of benzoylguanidines of formula I wherein R1 represents A; R2 represents Het, CnFmH2n +? - mOp, R4, OR4, OH, benzyl, CN, Hal, R5, Ph, O-PH, O-Het, NH-Het, NH2, NHA, NA2 or NH-Ph; R3 represents S02-A '; R4 represents a straight or branched chain alkyl radical and from 1 to 8 carbon atoms, or cycloalkyl of 3 to 8 carbon atoms, unsubstituted or substituted one, two or three times with A; R5 represents A or Ph; A and A 'independently represent alkyl of 1 to 6 C atoms; Ref: 128816 Het represents a mono or bicyclic heterocycle, saturated, unsaturated or aromatic, with 1 to 4 N, 0 and / or S atoms, optionally substituted one, two or three times with Hal, CF3, A, CN, N02, NH2, and / or carbonyloxy; Hal represents F, Cl, Br, or I; Ph represents phenyl unsubstituted or substituted, one or two times with A, OA, Hal, CF3, NH2, NHA or NA2; m represents 1,2,3,4,5,6,7, but at most 2n + l; n represents 1, 2 or 3; p represents 0 or 1; and q represents 0, 1 or 2, and / or their physiologically acceptable salts and solvates, to produce a medicament for treating non-insulin-dependent diabetes mellitus. The compounds of formula I are known from EP 0 699 666, EP 0 699 663, EP 0 743 301, EP 0 704 431, EP 0 758 644, EP 0 699 660, EP 0 725 062, EP 0 708 088, EP 0 694 537 and EP 0 723 963. They are potent inhibitors of the cell sodium-proton antiporter (Na + / H + exchanger). In EP 0 589 336, for example, substituted benzoylguanidines are described according to other guidelines, as inhibitors of the sodium-cell proton antiporter, whose level is increased in diabetes. The use of pyrazinoylguanidines to treat diabetes mellitus is disclosed in WO 97/21438. The invention was based on the objective of finding compounds that had useful properties, in particular those that could be used to produce drugs. It was found that the compounds of formula I and their salts have particularly useful pharmacological properties, being well tolerated, and that, in particular, they can be used to produce a medicament for treating non-insulin-dependent diabetes mellitus (NIDDM). Moreover, the compounds of formula I and their salts can be used to produce a medicament for reducing and / or regulating the blood sugar levels of NIDDM people. The compounds of formula I and their salts can also be used to produce a medicament for reducing and / or regulating the levels of insulin, free fatty acids and triglycerides of NIDDM people. The activity of the compounds of formula I that can be used to produce a medicament for treating non-insulin-dependent diabetes mellitus was experimentally confirmed for some representative compounds of formula I. The results of the tests have been compiled in table I. thus, the invention relates to the use of benzoylguanidines of formula I, wherein the compounds have been selected from the group consisting of a) N-diaminomethylene-2-methyl-4- (1-pyrrolyl) -5-methylsulfonyl-benzamide; b) N-diaminomethylene-2-methyl-4-trifluoromethyl-5-methylsulfonyl-benzamide; c) N-diaminomethylene-2-methyl-4-isopropyl-5-methylsulfonyl-benzamide, and / or its salts and solvates, physiologically acceptable, to produce a medicament for treating non-insulin-dependent diabetes mellitus. Solvates are the compounds of addition of water or alcohols, for example. For all the remains of several times appear, such as for example A, it is taken for granted that its meaning in each case is independent of that of the others. Alkyl has from 1 to 6 C atoms, preferably 1,2,3,4,5 or 6. Thus, alkyl represents in particular, for example, methyl, and also ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and in addition, pentyl , 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylphenyl, 1-1 / 2-, 1 / 3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 1,2- or 1,2,2-trimethylpropyl. R1 preferably represents alkyl of 1 to 6 carbon atoms, preferably, for example, methyl, ethyl, propyl or isopropyl; more preferably methyl. R3 signifies S02A ', where A' is preferably, for example, methyl, ethyl, propyl, isopropyl or butyl; R3 more preferably denotes S02CH3. Het preferably means 2- or 3-furyl, 2- 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, 3-, 4- or 5-isoxazolyl, 2-, - or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4- pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, and also preferably 1, 2, 3-triazole-l-, -4- or -5-yl, 1,2,4-triazole-1-, - 3 or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2-oxadiazol-3- or -5-yl, 1, 3, - thiadiazol-2-or-5-yl, l, 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-, 4-4H-thio-pyranyl, 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-benzoimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzoisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6 - or 7-benzo-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolino, 1-, 3-, 4-, 5-, 6- , 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl. The heterocyclic moieties may also be partially or totally hydrogenated. Thus, for example, Het can also mean 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-l-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-l-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2-, or 3-pyrrolidinyl, tetrahydro-1- , -2- or -4-imidazolyl, 2,3-dihydro-l-, -2-, -3-, -4- or 5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, , -dihydro-l-, -2-, -3- or -4-pyridyl, 1, 2, 3, -tetrahydro-l-, -2-, -3-, -4-, -5-, ó- 6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 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-l-, -2-, -3-, -4-, -5-, -6-, -7- or 8-quinolyl, 1, 2, 3, 4-tetrahydro-l-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolyl. More preferably, Het means l-imidazolyl, 1-piperazinyl, 1-piperidyl, 1-pyrrolidinyl, 1-pyrrolyl, pyridyl, oxodihydropyridyl or benzoimidazolyl; the most preferred one is 1-pyrrolyl. CnFmH2n +? - mOp preferably means OCF3, OCH2F, OCHF2, CF3, C2F5 or partially fluorinated alkyl of 1 to 4 carbon atoms, CH2F, CHF2, C2HF4, C2H2F3 or C2H4F. R 4 preferably represents a straight or branched chain alkyl radical and from 1 to 8 carbon atoms, or cycloalkyl of from 3 to 8 carbon atoms of C. If R 4 is acyclic, then the radical is one of the alkyl radicals also preferred for A. Particularly preferred cycloalkyl radicals which can preferably represent R 4 are cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl or derivatives thereof, substituted once with A, particularly with methyl, ethyl or isopropyl. R 2 preferably means, for example, F, Cl, Br, methyl, ethyl, propyl, isopropyl, 2-butyl, - (CH 2) 4-CH 3 cyclobutyl, cyclohexyl, p-tolyl, 4-chlorophenyl, 2,4-dichlorophenyl, 4-fluorophenyl, 3,5-bis (trifluoromethyl) -phenyl, 3,5-dichlorophenyl, phenyl, 2-furyl, S-methyl, S-ethyl, S-propyl, S-isopropyl, S-tert-butyl, S - (3-chlorophenyl), S- (2-chlorophenyl), S- (4-chlorophenyl), S-phenyl, S- (4-pyridyl), benzyloxy, OH, methoxy, ethoxy, isopropyloxy, cyclopentyloxy, cyclohexyloxy,, tert-butyloxy, phenoxy, 2-chlorophenoxy, 3-chlorophenoxy, 4-chlorophenoxy, 3-pyridyloxy, 1-pyrrolidinyl, 1-piperidinyl, 3-hydroxy-1-piperidinyl, 4-amino-1-piperidinyl, 1-imidazolyl, 1-benzoimidazolyl, 2-methyl-1-imidazolyl, 1-pyrazolyl, 1-pyrrolyl, amino, anilino, 2-pyridylamino or 2-pyrimidylamino. In relation to the whole invention it is assumed that all the remains that appear several times may be the same or different, that is, they are independent of each other. Accordingly, the invention relates in particular to the use of those compounds of formula I for which at least one of the mentioned moieties has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following sub-formulas, from a to Ii, corresponding to formula I, and for which the residues not described in more detail have the meanings indicated for formula I, but in which: In R1 it is methyl or ethyl, In Ib R3 is S02CH3. In the RR11 it is methyl or ethyl, and R3 S02CH3. In Id Het is l-imidazolyl, 1-piperazinyl, 1-piperidyl, 1-pyrrolidinyl, 1-pyrrolyl, pyridyl, oxodihydropyridyl or benzoimidazolyl. In R 1 it is methyl or ethyl; R 3 S0 2 CH 3, and R 2 l-imidazolyl, 1-piperazinyl, 1-piperidyl, 1-pyrrolidinolo, 1-pyrrolyl, pyridyl, oxodihydropyridyl or benzoimidazolyl. In If R1 is methyl or ethyl; R3 is S02A '; R2 is Het, CnFmH2n +? - m0p, R4, OR4, OH, benzyl, CN, F, Cl, SOqR5, Ph, O-Ph, O-Het, NH-Het, NH2, NHA, NA2 NH-Ph; R 4 is straight or branched chain alkyl and from 1 to 6 C atoms, or cycloalkyl of 3 to 6 C atoms, unsubstituted or substituted once with A; R5 is A or Ph; A, A 'is alkyl of 1 to 6 C atoms; «MlMBll ^^ tlIto Het is a mono or bicyclic heterocycle, saturated, unsaturated or aromatic, with 1 to 4 N, O and / or S atoms, optionally substituted one, two or three times with Hal, CF3, A, CN, N02, NH2, and / or carbonyl oxygen, Hal, F, Cl, Br, or I; Ph is phenyl unsubstituted or substituted one, two or three times with A, OA, Hal, CF3, NH2, NHA or NA2; m is 1,2,3,4,5,6,7, but at most 2n + 1; n is 1, 2 or 3; p is 0 or 1, and q is 0 or 2. R1 is methyl or ethyl; R1 is S02CH3; R is l-imidazolyl, 1-piperazinyl, 1-piperidyl, 1-pyrrolidinyl, 1-pyrrolyl, pyridyl, oxodihydropyridyl, benzoimidazolyl, CnFmH2n +? - mOp, or R4; R 4 is straight or branched chain alkyl and from 1 to 6 C atoms, or cycloalkyl of 3 to 6 C atoms, unsubstituted or substituted once with A; A is alkyl of 1 to 6 C atoms; m is 1,2,3,4,5,6,7, but at most 2n + 1; n is 1, 2 or 3, and p is O or 1. In Ih Ri it is methyl or ethyl; R3 is S02CH3, and R2 is l-imidazolyl, 1-piperazinyl, 1-piperidyl, 1-pyrrolidinyl, 1-pyrrolyl, pyridyl, oxydihydropyridyl, benzoimidazolyl, CF3, OCF3 or alkyl of 1 to 6 carbon atoms. In Ii R1 is methyl or ethyl; R3 is S02CH3, and R2 is 1-pyrrolyl, CF3, OCF3 or alkyl of 1 to 4 carbon atoms. In Ij R1 is methyl or ethyl; R3 is S02A; R2 is Het, CnFmH2n + 1-mOP, R4, OR4, OH, benzyl, CN, F, Cl, SOqR5, Ph, O-Ph, O-Het, NH-Het, NH2, NHA, NA2 NH-Ph; R 4 is straight or branched chain alkyl and from 1 to 6 C atoms, or cycloalkyl of 3 to 6 C atoms, unsubstituted or substituted once with A; R5 is A or Ph; A, A 'is alkyl of 1 to 6 C atoms; Het is l-imidazolyl, 1-piperazinyl, 1-pyrrolidinyl, 1-pyrrolyl, pyridyl, oxodihydropyridyl, benzoimidazolyl, optionally substituted one, two or three times with Hal, CF3, A, CN, N02, NH2 and / or carbonyloxygen; Hal is F, Cl, Br or I; Ph is phenyl unsubstituted or substituted one, two or three times with A, OA, Hal, CF3, NH2, NHA or NA2; m is 1,2,3,4,5,6,7, but at most 2n + 1; n is 1, 2 or 3; p is 0 or 1, and q is 0 or 2. and / or of the salts and solvates acceptable from the physiological point of view of these compounds. The compounds of formula I can be used in the state of their salts derived from inorganic or organic acids or bases. A base of formula I can be transformed into the respective acid addition salt, using an acid, for example, by reacting equivalent amounts of the base and the acid, in an inert solvent such as ethanol which is then evaporated. Possible acids for this reaction are, in particular, those which give salts acceptable from the physiological point of view. Thus inorganic acids can be used, for example sulfuric, nitric; Hydrogen halides such as hydrochloric or hydrobromic; phosphorics such as orthophosphoric; sulfamics, and in addition, organic acids, in particular carboxylic, sulphonic or sulfuric, aliphatic, alicyclic, arylaliphatic, aromatic, or heterocyclic, mono or polybasic, for example formic, acetic, propionic, pivalic, diethylacetic, malonic, succinic, pimelic, fumaric, maleic, lactic, tartaric, malic, citric, gluconic, ascorbic, nicotinic, isonicotinic, matanesulfonic, ethanesulfonic, ethanedisulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalene monosulfonic, naphthalene disulfonic and lauryl sulfuric. Salts of physiologically unacceptable acids, such as picrates, can be used to isolate and / or purify the compounds of formula I. On the other hand, the compounds of formula I can be transformed, using bases ( for example, sodium or potassium hydroxide or carbonate) in the corresponding metal salts, in particular in alkali metal or alkaline earth metal salts, or in the corresponding ammonium salts.

The results of the trials of the antidiabetic activity of some representative compounds of the formula I have been compiled in table I below. The compounds were administered orally to an animal model of diabetes (NOSTZ rats) with a moderate diabetic state. The experiments were performed with adult male rats weighing between 300 and 500 g, housed in groups of 5 under standard conditions. Diabetes was induced by injecting extremophozotocin (100 grams per kg of body weight, intravenously), on the day of birth. At adulthood, NOSTZ rats have a NIDDM that has the following characteristics (Portha - Diabetology 17 (1979), 313-377): fasting hyperglycemia: 180-200 mg / dl - impaired glucose tolerance specific lack of insulin secretion in response to the glusosa. All drugs tested were suspended in a gum arabic solution and administered orally, once a day for four days. The compounds were studied using the following procedure: determination of glycemia, lactatemia and basal insulinemia, before the day of treatment (day 0); 2 hours after the acute treatment (day 1), and 2 hours after the last administration of the chronic treatment (once a day for 4 days) of the compounds, at a rate of 20 mg / kg. Table I. Antidiabetic activity of representative compounds of formula I, on diabetic NOSTZ rats (20 mg / kg, p.o, effects [%]).

The pharmacological data confirm that, with 20 mg / kg of the compounds tested, fasting plasma glucose significantly decreases after acute and chronic treatment. The invention also relates to the use of the compounds of formula I and / or their salts from the physiological point of view to produce pharmaceutical preparations intended for the treatment of non-insulin-dependent diabetes mellitus, in particular by a non-chemical route. In this context, the compounds can be brought into a suitable dosage form, together with at least one solid, liquid and / or semi-liquid excipient or adjuvant, and, if convenient, in combination with another or other active compounds. The invention also relates to a pharmaceutical preparation for treating diabetes mellitus not Insulin dependent, prepared containing at least one compound of formula I and / or one of its physiologically acceptable salts or solvates. The invention also relates to a pharmaceutical preparation for treating non-insulin dependent diabetes mellitus, which is characterized in that it contains at least one compound selected from the group: a) N-diaminomethylene-2-methyl-4- (1-pyrrolyl) -5-methylsulfonyl-benzamide; ühririMittiii b) N-diaminomethylene-2-methyl-4-trifluoromethyl-5-methylsulfonyl-benzamide; c) N-diaminomethylene-2-methyl-4-isopropyl-5-methylsulfonylbenzamide, and / or one of its physiologically acceptable salts or solvates. These preparations can be used as medicines in human or veterinary medicine. Possible excipients are organic or inorganic substances, suitable for enteral (for example oral) or parenteral administration or for local (topical) application, and which do not react with the new compounds, for example: water, vegetable oils, benzyl alcohols , alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin; carbohydrates such as lactose or starch; magnesium stearate, talc and solid petrolatum. For oral administration, tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops are used in particular; for rectal administration, suppositories; for parenteral administration, solutions, preferably oily or aqueous, and also suspensions, emulsions or implants; for local or topical application, ointments, creams and talcs. The compounds of formula I can also be lyophilized, and the lyophilized substances obtained can be used, for example, to produce injectable preparations. These preparations can be sterilized and / or contain adjuvants such as lubricants, preservatives, stabilizers and / or humectants.; emulsifiers, salts that alter the osmotic pressure, pH regulators, colorants, flavors and / or one or more other active compounds, for example, one or several vitamins. The compounds of formula I, according to the invention, are generally administered analogously to other known commercial preparations, available for the claimed uses (for example metformin or amiloride), preferably at doses between 0.1 and 500 mg, in particular between 5 and 300 mg per dosage unit. The daily dose is preferably between 0.02 and 10 mg per kg of body weight. However, the specific dose for each patient depends on all kinds of factors, for example, the efficacy of the specific compound used; of age, weight, general state of health, sex of the patient, diet, moment and route of administration of the preparation; of the rate of excretion, of the pharmaceutical combination and of the severity of the particular disorder to which the treatment is applied. Oral administration is preferred. The following examples refer to pharmaceutical preparations. Example A: vials-ampoules for injection. A solution of 100 g of an active compound of formula I and 5 g of hydrogen phosphate and disodium in 3 liters of double distilled water is brought to pH 6.5 using 2N hydrochloric acid, sterilized by filtration, filled into vials-ampoules for injectables and freeze-dried in sterile conditions; the blister-bottles are closed in aseptic conditions. Each bottle-vial contains 5 mg of the active compound. Example B: suppositories. A mixture of 20 g of an active compound of formula I is melted together with 100 g of soy lecithin and 1400 g of cocoa butter; It is poured into molds and left to cool. Each suppository contains 20 mg of active compound.

Example C: solution. A solution is prepared with 1 g of an active compound of formula I, 9.38 g of NaH2HP04.2H20, 28.48 g of Na2HP04.12H20, 0.1 g of benzalkonium chloride and 940 ml of double distilled water. The pH is brought to 6.8 and the volume to 1 liter. It is sterilized by irradiation.

Example D: ointment 500 mg of an active compound of formula are mixed I with 99.5 g of solid petrolatum, under aseptic conditions.

Example E: tablets. A mixture of 1 kg of an active compound of formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc, and 0.1 kg of magnesium stearate is converted in the usual way into tablets, so that each tablet contains 10 mg of the active compound.

Example F: coated tablets. Tablets are prepared as in Example E, which is then coated in the usual way with a cover of sucrose, potato starch, talc, tragacanth and dye.

Example G: capsules. In hard gelatin capsules, 2 kg of an active compound of formula I are packaged in the usual manner, such that each capsule contains 20 mg of the active compound.

Example H: ampoules. A solution of 1 kg of an active compound of formula I in 60 ml of double distilled water is sterilized by filtration, filled into ampoules and the ampoules are close aseptically. Each ampoule contains 10 mg of the active compound. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers. fifteen twenty ^^ smÉmttimmW ^^.

Claims (4)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. Benzoylguanidines of formula I wherein R1 represents A; R? Represents Het, CnFmH? N + i-mOp, R4, OR4, OH, benzyl, CN, Hal, SOq-R5, Ph, O-PH, O-Het, NH-Het, NH2, NHA, NA2 or NH -Ph; R3 represents S02-A '; R4 represents a straight or branched chain alkyl radical and from 1 to 8 carbon atoms, or cycloalkyl of 3 to 8 carbon atoms, unsubstituted or substituted one, two or three times with A; R5 represents A or Ph; A and A 'independently represent alkyl of 1 to 6 C atoms; Het represents a mono or bicyclic, saturated, unsaturated or aromatic heterocycle, with 1 to 4 N, 0 and / or S atoms, optionally substituted one, two or three times with Hal, CF3, A, CN, N02, NH2 , and / or carbonyloxy; Hal represents F, Cl, Br, or I; Ph represents phenyl unsubstituted or substituted one, two or three times with A, OA, Hal, CF3, NH2, NHA or NA2; m represents 1,2,3,4,5,6,7, but at most 2n + l; n represents 1, 2 or 3; p represents 0 or 1, and q represents 0, 1 or 2, and / or its physiologically acceptable salts and solvates, characterized in that they are used to produce a medicament for treating non-insulin-dependent diabetes mellitus.

2. Benzoylguanidines of formula I according to claim 1, chosen from the group consisting of a) N-diaminomethylene-2-methyl-4- (1-pyrrolyl) -5-methylsulfonyl-benzamide; b) N-diaminomethylene-2-methyl-4-trifluoromethyl-5-methylsulfoni-1-benzamide; c) N-diaminomethylene-2-methyl-4-isopropyl-5-methylsulfoni-1-benzamide, and / or physiologically acceptable salts and solvates thereof, characterized in that they are used to produce a medicament for the treatment of diabetes mellitus; insulin-dependent

3. Pharmaceutical preparation containing at least one compound of general formula I according to claim 1 and / or one of its physiologically acceptable salts or solvates, characterized in that it is used for the treatment of diabetes mellitus not insulin-dependent

4. Pharmaceutical preparation according to claim 3, which contains at least one compound selected from the group consisting of: a) N-diaminomethylene-2-methyl-4- (1-pyrrolyl) -5-methylsulfoni-1-benzamide; b) N-diaminomethylene-2-methyl-4-trifluoromethyl-5-methylsulfonylbenzamide; c) N-diaminomethylene-2-methyl-4-isopropyl-5-methylsulfonyl-benzamide, and / or its salts and solvates, physiologically acceptable, characterized in that the treatment of non-insulin-dependent diabetes mellitus is used. SUMMARY OF THE INVENTION The use of benzoylguanidines of formula I is proposed wherein R1 represents A; R2 represents Het, CnFmH2n +? - mOp, R4, OR4, OH, benzyl, CN, Hal, SOq-R5, Ph, O-PH, O-Het, NH-Het, NH2, NHA, NA2 or NH-Ph; R3 represents S02-A '; R4 represents a straight or branched chain alkyl radical and from 1 to 8 carbon atoms, or cycloalkyl of 3 to 8 carbon atoms, unsubstituted or substituted one, two or three times with A; R5 represents A or Ph; A and A 'independently represent alkyl of 1 to 6 C atoms; Het represents a mono or bicyclic heterocycle, saturated, unsaturated or aromatic, with 1 to 4 N, O and / or S atoms, optionally substituted one, two or three times with Hal, CF3, A, CN, N02, NH2 , and / or carbonyloxy; Hal represents F, Cl, Br, or I; Ph represents phenyl unsubstituted or substituted, one or two times with A, OA, Hal, CF3, NH2, NHA or NA2; m represents 1,2,3,4,5,6,7, but at most 2n + l; n represents 1, 2 or 3; p represents 0 or 1; and q represents 0, 1 or 2, and / or their physiologically acceptable salts and solvates, to produce a medicament for treating non-insulin-dependent diabetes mellitus. These compounds reduce and regulate blood sugar levels, and also those of insulin, free fatty acids and triglycerides, of people with NIDDM.