NZ245895A - Benzoylguanidine derivatives, medicaments and diagnostic reagents - Google Patents

Abstract

Ortho-substituted benzoylguanidines of the formula I <IMAGE> where: R(1) is equal to halogen, alkyl, -X-R(6), where X is equal to O, S, NR(7) or Y-ZO and R(6) is equal to H, (cyclo)(halo)alkyl(methyl), -CnH2n-phenyl, R(3) is equal to H, -X-R(6), R(2) and R(4) are equal to R(11)-SO1-2-, (di)-alkyl-N-SO2-, or one of the two radicals R(2) or R(4) is equal to hydrogen or is defined as R(1), R(5) is equal to H, methyl, F, Cl, methoxy, and their pharmaceutically acceptable salts. They are obtained by a process in which compounds of the formula II <IMAGE> in which R(1) to R(5) have the meaning mentioned and L represents a leaving group which can be easily substituted nucleophilically, are reacted with guanidine. The compounds I are used for producing a medicament for the treatment and the prophylaxis of heart-rhythm disorders and ischaemically induced damage, as well as for producing a medicament for the inhibition of cell proliferation.

Description

New Zealand Paient Spedficaiion for Paient Number £45895 245895 Patents Form 5 C'nc^ ... .. i c<?n<r2&s>\^;. | oaappL^Jif.; /fc/^/oo., y.'S- :....- .2ff.FEB.ro ! P.P. J;.; ::. ...!>$.% , .

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NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION ORTHO-SI JBSTITIJTED BENZOYLGUANI DINES. PROCESS FOR THEIR PREPARATION. THEIR USE AS A MEDICAMENT OR DIAGNOSTIC AND MEDICAMENTS CONTAINING THEM We, HOECHST AKTIENGESELLSHAFT, a Joint Stock Company existing under the laws of the Federal Republic of Germany, of D-6230 Frankfurt am Main 80, Federal Republic of Germany do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - (Followed by 1A) Description Ortho-substituted benzoylguanidines, process for their preparation, their use as a medicament or diagnostic and medicaments containing them The invention relates to ortho-substituted benzoylguanidines of the formula I R(2) R(4) R(5) where: R(1) is F, CI, Br, I, Cj-CB-alkyl or -X-R(6), 10 X is 0, S, NR(7) or Y-ZO and Y is 0 or NR(7) and Z is C or SO, R (6) is H, C1-C6-alkyl, C3-C7-cycloalkyl, cyclohexylmethyl, cyclopentylmethyl, 15 " (CH2) mCpF2?rl or -C^-RfS), m is 2ero or 1, p is 1 - 3, n is zero to 4, R(8) is phenyl which is unsubstituted 20 or substituted by 1-3 substituents selected from the groups F, CI, CF3, methyl, methoxy or NR(9)R(10) where R(9) and R(10) 245895 are H or C,-C4-alkyl, R(7) is H or C1-C3-alkyl, where R(6) and R{7) can also together be 4 or 5 5 methylene groups and a CHZ group can be replaced by 0, S, NH, N-CH3 or N-benzyl, R(3) is H or -X-R(6) where X is 0, S, NR(7) or Y-ZO, H(7) is H or C1-C3-alkyl, Y is 0 or NR(7), Z is C or SO, where Y is bonded to the phenyl radical in the formula I, R(6) is H, Cl-C6-alkyl, C5-C7-cycloalkyl, cyclohexylinethyl, cy c 1 open ty line thyl ~(CH2)0CpF2p+1 or -C^-RfS), m is zero or 1, p is 1 - 3, 20 n is zero to 4, R(8) is phenyl which is unsubstituted or substituted by 1-3 substituents selected from the group comprising F, Cl, CF3, methyl, 25 methoxy and NR(9)R(10), R(9) and R(10) are H or Cj-C^-alkyl, R(6) and R(7) can also together be 4 or 5 methylene groups and a CH2 group can be replaced by 0, S, NH, N-CH3 or N-benzyl, R(2) and R(4) - identical or different - are R(ll)-S0q- or R( 12)R( 13)N-S02-, where q is zero - 2, R(11) is Ci-C^-alkyl which is unsubstituted or carries phenyl as a substituent, where phenyl 35 is unsubstituted or substituted by 1 - 3 substituents from the group comprising F, Cl,/\xxV CF3, methyl, methoxy and NR(9)R(10) where R(9A^r and R( 10) are H or C^C^-alkyl, R(12) and R(13) are defined as R(6) and R(7); or one of the two radicals R(2) or R(4) is hydrogen or is defined as R(1), R(5) is H, methyl, F, CI or methoxy, and their pharmaceutical^ tolerable salts.

Preferred compounds of the formula I are those where: R(l) is F, CI, Cj-Cj-alkyl, CF3 or -X-R(6) where X is 0, S or NR(7), R(6) is H, C1-Cs-alkyl, -(CH2)mCpF2p+1 or -CnH2n-R(8), m is zero or 1, p is 1 - 3, n is zero to 4, R(8) is phenyl which is unsubstituted or 15 substituted by 1 - 3 substituents selected from the group comprising F, CI, CF3, methyl, methoxy and NR(9)R(10) where R(9) and R(10) are H or Cx-C,,-alkyl, R(7) is H or methyl, where R(6) and R(7) can also together be 4 or 5 methylene groups and a CH2 group can be replaced by 0, S, NH, N-CHj or N-benzyl, R(3) is H, R(2) and R(4) - identical or different - are CH3-S0(J- or R(12)R(13)N-S02-, g is zero - 2, R{12) and R(13) are R(6) and R(7), or one of the two radicals R(2) or R(4) is H or is defined as R(1), R(5) is H, 245895 and their pharmaceutically tolerable salts.

Particularly preferred compounds of the formula I are those where: R(1) is F, CI, Cj-C3-alkyl or -X-R(6), 5 X is 0, S or NR(7), R(6) is H, Ci-C^-alkyl or -CnH2n-R(8), n is zero to 3, R(8) is phenyl which is unsubstituted or substituted by 1-3 substituents selected from 10 the group comprising F, Cl, CF3, methyl/ methoxy and NR(9)R(10) where R(9) and R(10) are H or methyl, R(7) is H or methyl, where R(6) and R(7) can also together be 4 or 15 5 methylene groups and a CH2 group can be replaced by 0, S, N-CH3 or N-benzyl, R(2), R(3) and R(5) are hydrogen, R(4 ) is CH3-S02- or R( 12 )R( 13 )N-S02- where R (12 ) is ""CjjH^-Rf 8 ) , n is 1 to 3, R(8) is phenyl which is unsubstituted or substituted by 1-3 substituents selected from the groups F, Cl, CF3, methyl, methoxy or NR(9)R(10) where R(9) and R(10) have the 25 meaning of H or methyl, R(13) is H, or R(12) and R(13) can also together be 4 or 5 methylene groups, and their pharmaceutically tolerable salts.

If one of the substituents R(l) to R(13) contains a center of asymmetry, the invention includes compounds ^ o i-having both the S and R configuration. The compounds cap be present as optical isomers, as diastereomers, afe*" racemates or as mixtures thereof.

The designated alkyl radicals can be present either in straight-chain or branched form.

The invention furthermore relates to a process for the 5 preparation of the compounds I, which comprises reacting compounds of the formula II with guanidine, in which R(1) to R(5) have the given meaning and L is a leaving group which can be easily 10 nucleophilically substituted.

The activated acid derivatives of the formula II in which L is an alkoxy group, preferably a methoxy group, a phenoxy group, or phenylthio, methylthio or 2-pyridylthio group, or a nitrogen heterocycle, preferably 1-15 imidazolyl, are advantageously obtained in a manner known per se from the carbonyl chlorides (formula II, L = Cl) on which they are based, which for their part can in turn be prepared in a manner known per se from the carboxylic acids (formula II, L = OH) on which they are based, for 20 example using thionyl chloride.

In addition to the carbonyl chlorides of the formula II (L = Cl), other activated acid derivatives of the formula II can also be prepared in a manner known per se directly from the benzoic acid derivatives (formula II, L = OH) on 25 which they are based, such as, for example, the methyl esters of the formula II where L = OCH3 by treatment with gaseous HCl in methanol, the imidazolides of the formula II by treatment with carbonyldiimidazole (L = 1-imidazolyl, Staab, Angew. Chem. Int. Ed. Engl. 1, 24 15 8 9 5 351 - 367 (1962)), the mixed anhydrides II using Cl-COOC2H5 or tosyl chloride in the presence of triethylamine in an inert solvent, and also the activation of benzoic acids using 5 dicyclohexylcarbodiimide (DCC) or using 0-6-[(cyano-(ethoxycarbonyl)methylene)amino]-1 , 1, 3,3-tetra-methyluronium tetrafluoborate ("TOTU") (Weiss and Krommer, Chemiker Zeitung 98, 817 (1974)). A number of suitable methods for the preparation of activated 10 carboxylic acid derivatives of the formula II are given under details of source literature in J. March, Advanced Organic Chemistry, Third Edition (John Wiley & Sons, 1985), p. 350.

The reaction of an activated carboxylic acid derivative 15 of the formula I with guanidine is carried out in a manner known per se in a protic or aprotic polar but inert organic solvent. Methanol or THF between 20°C and the boiling point of these solvents have proven suitable in the reaction of the methyl benzoates (II, L = OMe) 20 with guanidine between 20°C and the boiling point of these solvents. In most reactions of compounds II with salt-free guanidine, the reaction was advantageously carried out in aprotic inert solvents such as THF, dimethoxyethane or dioxane. However, water can also be 25 used as a solvent in the reaction of II with guanidine.

If L = Cl, the reaction is advantageously carried out with the addition of an acid scavenger, for example in the form of excess guanidine for binding the hydrohalic acid.

Some of the underlying benzoic acid derivatives of the formula II are known and described in the literature. The unknown compounds of the formula II can be prepared by methods known from the literature, by converting, for example, 2-chloro- or 2-fluoro-5-chlorosulfonylbenzoic 35 acid with ammonia or an amine into a 5-aminosulfonyl-2- U (, chloro- or -fluorobenzoic acid or with a weak reductant such as sodium bisulfite and subsequent alkylation into a 5-alkylsulfonyl-2-chloro- or -2-fluorobenzoic acid and reacting the benzoic acid derivatives thus obtained by 5 one of the process variants described above to give the compounds I according to the invention.

Carboxylic acids of this type or their esters of the formula II, where L = -OH or, for example, -O-methyl and where R(1) and/or R(3) have the meaning of halogen, can 10 also be used, however, as starting compounds for other carboxylic acids, it being possible to replace the halogen in the R (1) and/or R(4) position very conveniently in the known manner by numerous nucleophilic reagents, such as mercaptans R(6)-SH or primary amines 15 R(6)R(7)NH, with the formation of further benzoic acid derivatives II where L = -OH or -O-methyl.

In a similar manner, starting from 5-nitro-2-chlorobenzoic acid, further benzoic acid derivatives (II, L = -OH) can be prepared by nucleophilic introduction of 20 a radical R(l) in position 2 (replacement by Cl) and further modification of the nitro group, such as reduction to NH2 and subsequent alkylation or displacement, for example by diazotization and Sandmeyer reaction.

In general, benzoylguanidines I are weak bases and can bind acid with the formation of salts. Possible acid addition salts are salts of all pharmacologically tolerable acids, for example halides, in particular hydrochlorides, lactates, sulfates, citrates, tartrates, 30 acetates, phosphates, methanesulfonates and p-toluene-sulfonates.

The compounds I are substituted acylguanidines. 24 5 8 A prominent ester representative of the acylguanidines is the pyrazine derivative amiloride, which is used in therapy as a potassium-sparing diuretic. Numerous other compounds of the amiloride type are described in the 5 literature, such as, for example, dimethylamiloride or ethylisopropylamiloride. 0 NH R " Amiloride: R', R" = H Dimethylamiloride: R', R" = CH3 Ethylisopropylamiloride: R' = C2H5, R" = CH(CH3)2 Investigations have moreover been disclosed which point to antiarrhythmic properties of amiloride (Circulation 79, 1257 - 63 ( 1989)). Obstacles to wide use as an antiarrhythmic are, however, that this effect is only slightly pronounced and occurs accompanied by a hypoten- sive and saluretic action and these side effects are undesired in the treatment of cardiac arrhythmias.

Indications of antiarrhythmic properties of amiloride were also obtained in experiments on isolated animal hearts (Eur. Heart J. 9 (suppl.l): 167 (1988) (book of abstracts)). For instance, it was found in rat hearts that an artificially induced ventricular fibrillation could be suppressed completely by amiloride. The above-mentioned amiloride derivative ethylisopropylamiloride was even more potent than amiloride in this model.

European Offenlegungsschrift 416,499 (HOE 89/F 288) describes benzoylguanidines which carry hydrogen in the positions corresponding to the radicals R(1) and R(2). In £ :' U US Patent 3,780,027, acylguanidines are described which are structurally similar to the compounds of the formula I and are derived from commercially available loop diuretics, such as bumetanide. A strong salidiuretic 5 activity is correspondingly reported for these compounds. The N-ainidino-3-furfurylamino-4-chloro-5-methylsulfonyl-benzamide described in this patent was resynthesized and in our models showed no antiarrhythmic action.

It was therefore surprising that the compounds according 10 to the invention have no undesired and disadvantageous salidiuretic properties, but very good antiarrhythmic properties, as occur, for example, in the case of oxygen deficiency symptoms. As a result of their pharmacological properties, the compounds are outstandingly suitable as 15 antiarrhythmic pharmaceuticals having a cardioprotective component for infarct prophylaxis and infarct treatment and for the treatment of angina pectoris, where they also preventively prohibit or greatly decrease the pathophysiological processes in the formation of ischemically 20 induced damage, in particular in the production of ischemically induced cardiac arrhythmias. Because of their protective actions against pathological hypoxic and ischemic situations, the compounds of the formula I according to the invention can be used as a result of 25 inhibition of the cellular Na+/H+ exchange mechanism as a pharmaceutical for the treatment of all acute or chronic damage caused by ischemia or primary or secondary diseases induced thereby. This relates to their use as pharmaceuticals for surgical interventions, for example 30 in organ transplantation, where the compounds can be used both for the protection of the organs in the donor before and during removal, for the protection of removed organs, for example during treatment with or storage thereof in physiological bath fluids, and during transfer to the 35 body of the recipient. The compounds are also useful protective pharmaceuticals during the performance of angioplastic surgical interventions, for example in the 24 58 95 heart and in peripheral vessels. In accordance with their protective action against ischemically induced damage, the compounds are also suitable as pharmaceuticals for the treatment of ischemias of the nervous system, in 5 particular the central nervous system, where they are suitable, for example, for the treatment of stroke or of cerebral edema. Moreover, the compounds of the formula I according to the invention are also suitable for the treatment of forms of shock, such as, for example, 10 allergic, cardiogenic, hypovolemic and bacterial shock.

Moreover, the compounds of the formula I according to the invention are distinguished by potent inhibitory action on the proliferation of cells, for example fibroblast cell proliferation and the proliferation of vascular 15 smooth muscle cells. The compounds of the formula I can therefore be considered as useful therapeutics for diseases in which cell proliferation is a primary or secondary cause, and can therefore be used as antiathero-sclerotics, agents against late-onset diabetic complica-20 tions, cancers, fibrotic diseases such as pulmonary fibrosis, fibrosis of the liver or fibrosis of the kidneys, organ hypertrophy and hyperplasia, in particular in prostate hyperplasia or prostate hypertrophy.

The compounds according to the invention are active 25 inhibitors of the cellular sodium-proton antiporter (Na+/FT exchanger), which is raised in numerous diseases (essential hypertension, atherosclerosis, diabetes, etc.) even in those cells which are easily accessible to measurements, such as, for example, in erythrocytes, 30 thrombocytes or leucocytes. The compounds according to the invention are therefore suitable as excellent and simple scientific tools, for example in their use as diagnostics for the determination and differentiation of certain forms of hypertension, but also of atherosclero-35 sis or of diabetes, proliferative diseases etc. Moreover, the compounds of the formula I are suitable for n > r ' c'... \ y; preventive therapy for the prevention of the formation of high blood pressure, for example of essential hypertension.

Pharmaceuticals which contain a compound I can be administered orally, parenterally, intravenously, 5 rectally or by inhalation, the preferred administration being dependent on the particular type of the disease. The compounds I can be used on their own or together with pharmaceutical auxiliaries, to be precise in veterinary and in human medicine.

The auxiliaries which are suitable for the desired pharmaceutical formulation are familiar to the person skilled in the art on the basis of his knowledge. In addition to solvents, gelling agents, suppository bases, tabletting auxiliaries and other active compound exci-15 pients, antioxidants, dispersants, emulsifiers, anti-foams, flavor correctants, preservatives, solubilizers or colorants, for example, can be used.

For a form for oral administration, the active compounds are mixed with the additives suitable for this purpose, 20 such as excipients, stabilizers or inert diluents, and are brought by the customary methods into the suitable administration forms, such as tablets, coated tablets, hard gelatine capsules, or aqueous, alcoholic or oily solutions. Inert excipients which can be used are, for 25 example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. Preparation can be carried out here both as dry and as moist granules. Suitable oily excipients or solvents are, for example, vegetable or 30 animal oils, such as sunflower oil or fish liver oil.

For subcutaneous or intravenous administration, the active compounds are brought into solution, suspension or emulsion, if desired using the substances customary for this purpose such as solubilizers, emulsifiers or other 24 5 8 9 auxiliaries. Suitable solvents are, for example: water, physiological saline solution or alcohols, for example ethanol, propanol, glycerol, and also sugar solutions such as glucose or mannitol solutions, or alternatively 5 a mixture of the various solvents mentioned.

Pharmaceutical formulations suitable for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active compound of the formula I in a pharmaceutically acceptable 10 solvent, such as, in particular, ethanol or water, or a mixture of these solvents.

If required, the formulation can also contain still other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant gas. Such 15 a preparation contains the active compound customarily in a concentration from about 0.1 to 10, in particular from about 0.3 to 3 % by weight.

The dose of the active compound of the formula I to be administered and the frequency of administration depend 20 on the potency and duration of action of the compounds used and additionally on the type and severity of the disease to be treated and on the sex, age, weight and individual responsiveness of the mammal to be treated.

On average, the daily dose of a compound of the formula 25 I in a patient of weight about 75 kg is at least 0.001 mg/kg, preferably 0.01 mg/kg to 10 mg/kg, preferably 1 mg/kg of body weight. In acute episodes of the disease, for example immediately after suffering a cardiac infarct, even higher and in particular more frequent dosages may be necessary, for example up to 4 individual doses per day. In particular when administered 1.v., for example in the case of an infarct patient in the intensive care ward, up to 200 mg per day may be necessary. 2 4 5 fi fi $ 13 Experimental Section General procedure for the preparation of benzoylguanidines (I) from benzoic acids (II, L = OH) 0.01 mol of the benzoic acid derivative of the formula II 5 is dissolved or suspended in 60 ml of anhydrous tetra-hydrofuran (THF) and then treated with 1.78 g (0.011 mol) of carbonyldiimidazole. After stirring for 2 hours at room temperature, 2.95 g (0.05 mol) of guanidine are introduced into the reaction solution. After stirring 10 overnight, the THF is distilled off under reduced pressure (Rotavapor), the residue is treated with water, the mixture is adjusted to pH 6-7 with 2N HCl and the corresponding benzoylguanidine (formula I) is filtered The benzoylguanidines thus obtained can be converted into the corresponding salts by treatment with aqueous or methanolic hydrochloric acid or other pharmacologically tolerable acids.

Example 1: 2-Chloro-5-methylsulfonylbenzoylguanidine hydrochloride, colorless crystals, melting point 208-210°C, from 2-chloro-5-methylsulfonylbenzoic acid (melting point 182-186°C).

Example 2: 2-Chloro-5-piperidylsulfonylbenzoylguanidine, off.

HCl 0 NH2 u " " 2 colorless crystals, melting point 226-229°C, O Sr r r V $ 3 from 2-chloro-5-piperidylsulfonylbenzoic acid (melting point 207-210°C) .

Example 3: 2-Chloro-5-(1-pyrrolidinylsulfonyl)benzoylguanidine, colorless crystals, melting point 195-198°C, from 2-chloro-5-(1-pyrrolidinylsulfonyl)benzoic acid (melting point 205°C).

Example 4: 2-Chloro-5-N-methylsulfamoylbenzoylguanidine hydrochloride, colorless crystals, melting point 201-203°C, from 2-chloro-5-N-methylsulfamoylbenzoic acid (melting point 169-170°C).

Example 5: 2-Chloro-5-N,N-dipropylsulfamoylbenzoylguanidine hydrochloride, hc i 0 nh colorless crystals, melting point 170-173°C, from 2-chloro-5-N,N-dipropylsulfamoylbenzoic (melting point 102-104°C). acid 24 58 9 5 - 15 Example 6: 2-Chloro-5-(2-phenylethylsulfamoyl)benzoylguanidine hydrochloride, n 0 2 s .NCX/NH2 l| • hc 0 nh, colorless cyrstals, melting point 70°C, from 2-chloro-5-(2-phenylethylsulfamoyl)benzoic acid (melting point 160-163°C).

Example 7: 2-Chloro-5-N-methyl-N- (2-phenylethyl) sulf ainoylbenzoyl-guanidine hydrochloride, . hcl 0 nh2 colorless crystals, melting point 186-188°C, from 2-chloro-5-N-methyl-N-(2-phenylethyl)sulfamoylbenzoic acid (melting point 127-129°C).

Example 8: 2-Piperidyl-5-sulfamoylbenzoylguanidine, H2N02S colorless crystals, melting point 247°C, from 2-piperidyl-5-sulfamoylbenzoic acid (melting point 248°C, prepared from 2-chloro-5-sulfamoylbenzoic acid in 10 mol of piperidine under inert gas for 24 hours by boiling under reflux, distilling off the excess piperidine and treating the residue with water/dilute hydrochloric acid at pH 1-2).

Example 9: 2-Benzylamino-5-sulfamoylbenzoylguanidine, HjN02S NH 0 colorless crystals, melting point 191-193°C, from 2-benzylamino-5-sulfamoylbenzoic acid (melting point 246°C, prepared from 2-chloro-5-sulfamoylbenzoic acid in 20 equivalents of benzylamine over the course of 8 hours at 130°C/inert gas and treatment with water/dilute HCl at pH 1-2 ) .

Example 10: 2-N-Methyl-N-(2-phenylethyl) amino-5-sulfamoylbenzoyl-guanidine hydrochloride, colorless crystals, melting point 180°C, from 2-N-methyl-N-(2-phenylethyl)amino-5-sulfamoylbenzoic acid (melting point 240°C, preparation by heating 2-fluoro-5-sulfamoylbenzoic acid and N-methyl-2-phenyl-ethylamine for 10-15 hours in dimethylacetamide in the presence of 4 equivalents of ethyldiisopropylamine at 120°C, evaporating the solvent and treating the residue with water and dilute HCl at pH 1-2).

Example 11: 2-N-Methyl-N-(2-phenylethyl)amino-5-methylsulfonylbenzoylguanidine hydrochloride, h c i ch • hc i 24 5 8 9 colorless crystals, melting point 123°C, from 2-N-methyl-N-(2-phenylethyl)amino-5-methylsulfonyl-benzoic acid (amorphous oil, preparation from 2-chloro-5-methylsulfonylbenzoic acid and N-methyl-2-phenylethylamine analogously to Example 10 over the course of 8 hours at 140°C).

Example 12: -N-Methy1-N-(2-phenylethyl)sulfamoyl-2-piperidino-benzoylguanidine, colorless crystals, melting point 85°C, from 5-N-methyl-N-(2-phenylethyl)sulfamoyl-2-piperidino-benzoic acid (amorphous intermediate without defined melting point, preparation from 2-chloro-5-N-methyl-N-(2-phenylethyl)sulfamoylbenzoic acid and piperidine analogously to Example 8).

Example 13: 2- (2-Chlorophenylthio) -5-methylsulfonylbenzoylguanidine hydrochloride, colorless crystals, melting point 284-286°C, from 2-(2-chlorophenylthio)-5-methylsulfonylbenzoic acid (melting point 210-216°C, prepared by reaction of methyl 2-chloro-5-methylsulfonylbenzoate with 1 eq. of 2-chlorothiophenol and excess KzC03 in DMF at 90 °C for 7 hours and hydrolysis of the methyl 2-(2-chlorophenylthio) -5-methylsulfonylbenzoate (melting point 145°C) thus obtained in a mixture of dioxane and sodium hydroxide 18 solution at room temperature) .

Example 14: 2-(2,6-Dichlorophenylthio)-5-methylsulfonylbenzoylguanidine hydrochloride, colorless crystals, melting point 288-290°C, from 2-(2,6-dichlorophenylthio)-5-methylsulfonylbenzoic acid (melting point 244°C, prepared analogously to Example 13 from methyl 2-chloro-5-methylsulfonylbenzoate with 1 eq. of 2,6-dichlorothiophenol and hydrolysis of the methyl 2-(2,6-dichlorophenylthio)-5-methylsulfonyl-benzoate (melting point 139°C) thus obtained analogously to Example 13.

Example 15: -Methylsulfonyl-2-piperidinobenzoylguanidine hydrochloride, colorless crystals, melting point 124-130°C/ prepared from 5-methylsulfonyl-2-piperidinobenzoic acid (melting point 198°C, preparation by reaction of 2-chloro-5-methylsulfonylbenzoic acid by boiling for several hours in 10 eqivalents of piperidine under a reflux condenser, evaporation of the excess piperidine and subsequent treatment with water/dilute HCl at pH 1- Example 16 2,4-Dichloro-5-sulfamoylbenzoylguanidine hydrochloride c i h c i 2) Me 02S A L! U 2 colorless crystals, melting point 240°C, by reaction of 2,4-dichloro-5-sulfamoylbenzoic acid with guanidine according to the general procedure described above.

Example 17 2-Amino-4-chloro-5-sulfamoylbenzoylguanidine hydrochloride C TV /NH2 H 2 N 0 2 s j| N H 2 N ={ x H C 0 colorless cyrstals, melting point 318-320°C, by reaction of 2-amino-4-chloro-5-sulfamoylbenzoic acid with guanidine according to the general procedure described above.

Example 18 -Methylsulfamoyl-2-piperidylbenzoylguanidine hydrochloride NyNH2 x HCI 0 nh2 colorless crystals, melting point 212-214°C, by reaction of 5-methylsulfamoyl-2-piperidylbenzoic acid with guanidine according to the general procedure described above. 2 4 5 8 Example 19 2,3-Dichloro-5-methylsulfonylbenzoylguanidine hydrochloride C I "HCI o nh2 colorless crystals, melting point 280°C, by reaction of 2,3-dichloro-5-methylsulfonylbenzoic acid with guanidine according to the general procedure described above.

Example 20 2-Methy1-5-methylsuIfonylbenzoylguanidine hydrochloride Me 02S HC I colorless crystals, melting point 212°C, by reaction of 2-methyl-5-methylsulfonylbenzoic acid with guanidine according to the general procedure described above.

Example 21 2- ( 2-Chlorobenzylami.no ) - 5-sulf amoyl benzoyl guanidine hydrochloride 0 colorless crystals, melting point 137°C, by reaction of 2-(2-Chlorobenzylamino)-5-sulfamoylbenzoic acid with guanidine according to the general procedure described above.

R E3*3 p«i u h k 0 R

Claims (3)

1. WHAT WE CLAIM IS: 10 15 20 An ortho-substituted benzoylguanidine of the formula j R ( 2 ) R(3) R(4) I R(5) wherein the substituents are defined as follows: R(l) is F, Cl, Br, I, C1-C6-alkyl or -X-R(6), X is Of S, NR(7) or Y-ZO and Y is 0 or NR(7) and Z is C or SO, R (6) is H, Ci-Cg-alkyl, C5-C7-cycloalkyl, cyclohexylmethyl, cyclopentylmethyl, -(CH2)aCpF2pn or -CJJ^-RfS), m is zero or 1, p is 1 - 3, n is zero to 4, R (8) is phenyl which is unsubstituted or substituted by 1-3 substituents selected from the groups F, Cl, CF3, methyl, methoxy or NR(9) R (10) where R(9) and R(10) are H or C,-C4-alkyl, R(7) is H or C^Cj-alkyx, 25 where R(6) and R(7) can also together be 4 or 5 methylene groups and a CH2 group can be replaced by 0, S, NH, N-CH3 or N-benzyl, 30 R(3) is H or -X~R(6) where X is 0, S, NR(7) or Y-ZO, R(7) is H or C1-C3-alkyl, Y is 0 or NR(7), 345895 - 22 - Z is C or SO, where Y is bonded to the phenyl radical in the formula I, R(6) is H, Cj-Cg-alkyl, C5-C7-cycloalkyl, 5 cyclohexylmethyl, cyclopentylmethyl, -(CH2)DCpF2pTl or -CnH2n-R(8), m is zero or 1, p is 1 - 3, r. is zero to 4, 10 R(8) is phenyl which is unsubstituted or substituted by 1-3 substituents selected from the group comprising F, Cl, CF3, methyl, methoxy and NR(9)R(10), 15 R(9) and R(10) are H or C^C*- alkyl, R(6) and R(7) can also together be 4 or 5 methylene groups and a CH2 group can be replaced by 0, S, NH, N-CH3 or N-benzyl, 20 R(2) and R(4) - identical or different - are R(ll)- S0q- or R(12)R( 13 )N-SO,- , where q is zero - 2, R (11) is C^C^-alkyl which is unsubstituted or carries phenyl as a substituent, where phenyl 25 is unsubstituted or substituted by 1 - 3 substituents from the group comprising F, Cl, CF3, methyl, methoxy and NR(9)R(10) where R(9) and R (10) are H or C^C^-alkyl, R(12) and R(13) are defined as R(6) and R(7); 30 or one of the two radicals R(2) or R(4) is hydrogen or is defined as R(l), and R(5) is H, methyl, F, Cl or methoxy, and their pharmaceutically tolerable salts.

2. A compound as claimed in claim 1, wherein the „ c c 35 substituents are defined as follows: -as**' 245895 - 23 - 10 15 R(l) is F, Cl, C1-C3-alkyl, CF3 or -X-R(6) where X is 0, S or NR(7), R(6) is H, C,-Cs-alkyl, - (CH2)mC?F2pTl or -CnH2n-R( 8 ) , m is zero or 1, p is 1 - 3, n is zero to 4, R(8) is phenyl which is unsubstituted or substituted by 1 - 3 substituents selected from the group comprising F, Cl, CF3/ methyl, methoxy and NR(9)R(10) where R(9) and R(10) are H or C1-Cll-alkyl, R(7) is H or methyl, where R(6) and R(7) can also together be 4 or 5 methylene groups and a CH2 group can be replaced by 0, S, NH, N-CH3 or N-benzyl, 20 R(3) is H, R (2 ) and R (4 ) - identical or different - are CH3-S0q-or R(12)R(13)N-S02-, q is zero - 2, R( 12) and R(13) are R(6) and R(7), or one of the two radicals R(2) or R (4) is H or is defined as R( 1) , and 25 R(5) is H,

3. A compound as claimed in claim 1, wherein the substituents are defined as follows: R(1) is F, Cl, C1-C3-alkyl or -X-R(6), X is 0, S or NR(7), 30 R(6) is H, Cj-C^-alkyl or -CnH2n-R(8), n is zero to 3, R(8) is phenyl which is unsubstituted substituted by 1-3 substituents selected from the group comprising F, Cl, CF3, 35 methyl, methoxy and NR(9)R(10) where 245895 - 24 - R(9 ) and R(10) are H or methyl, R ( 7) is H or methyl, where R(6) and R(7) can also together be 4 or 5 methylene groups and a CH2 group can be replaced by 0, S, N-CH, or N-benzyl, 10 15 R(2), R ( 3) and R ( 5) are hydrogen, an<^ R(4) is CH3-S02- or R (12 ) R (13 ) N-S02- where R( 12) is -C3H2a-R(8), n is 1 to 3, R(8) is phenyl which is unsubstituted or substituted by 1-3 substituents selected from the groups F, Cl, CF3, methyl, methoxy or NR(9)R(10) where R(9) and R(10) have the meaning of H or methyl, R ( 13 ) is H, or R(12) and R(13) can also together be 4 or 5 methylene groups, A process for the preparation of a compound I as claimed in claim 1, which comprises 20 25 5, reacting a compound of the formula II R(2) R(3) R(4) (II] R(5) with guanidine, in which R(1) to R 5) are as defined in cl and L is a leaving group which can be easily " nucleophilically substituted. The use of a compound I as claimed in claim 1 for preparing a medicament suitable for the treatment and for the prophylaxis of cardiac arrhythmias and of ischemically induced damage. 25 7. 5 8. 10 9. 15 10. The use of a compound I as claimed in claim 1 for preparing a medicament suitable for inhibiting the proliferation of cells. A medicament suitable for the treatment and for the prophylaxis of cardiac arrhythmias and of ischemically induced damage, which contains an effective amount of a compound I as claimed in claim 1 and pharmaceutically customary additives. A medicament suitable for inhibiting the proliferation of cells, which contains an effective amount of a compound I as claimed in claim 1 and pharmaceutically customary additives. An ortho-substituted benzoylguanidine of the formula I according to claim 1 substantially as herein described or exemplified. A process according to claim 4 substantially as herein described or exemplified. HOECHST AKTIENGESELLSCHAFT By Their Attorneys HENRY HUGHES Per :