MXPA94006545A - Ortho-substituted benzoylguanidines, a process for their preparation, their use as a medicament or diagnostic agent, and a medicament comprising them - Google Patents

Abstract

Benzoylguanidines of the formula I in which:R(1) to R(4) have the meanings given in the claims, are antiarrhythmic pharmaceuticals, having a cardioprotective component, which are also valuable for the prevention of ischemically induced damage, in particular in association with the triggering of ischemically induced cardiac arrhythmias. As a consequence of inhibiting the cellular Na+/H+ exchange mechanism, they are used for treating acute or chronic damage triggered by ischemia. In addition to this, they are notable for their strong inhibitory effect on the proliferation of cells. They are suitable for preventing the genesis of high blood pressure.

Description

I.

# BENZ03XGUANIDINAS REPLACED IN ORDINARY POSITION, PROCEDURE f * FOR PREPARATION, ITS EMPLOYMENT AS A MEDICATION OR AGENT OF I - DIAGNOSIS, AS WELL AS A MEDICATION THAT CONTAINS THEM.

F - INVENTORS: ANDREAS EICHERT, HANS-JOCHEN LANG, JAN-ROBERT SCHWARK, WOLFGANG SCHOLZ, and UDO ALBUS, German citizens, domiciled in Leipziger Strasse 21, D-63329 Egelsbach, Rüdesheimer Strasse 7, - D-65719 Hofheim, An der Hohlen Eiche 3, D-61350 Bad? Ombujrg, Loreleistrasse 63, D-65929 Frankfurt / Mam, Onterortstrasse 30, D-65760 Eschborn, and in Am Rdmerkastell 9, D-61197 Florstadt, Federal Republic of Germany, cede all • your rights to HO CHST AKTIENGESELLSCHAFT, a duly organized and incorporated company in accordance with the laws of the Federal Republic of Germany, domiciled at D-65926 Frankfurt am Main, Federal Republic of Germany, for the invention described below.

Ka) - SUMMARY OF THE INVENTION.

# ? Oligo-substituted benzoylguanidines of formula I are described in doncje: R (l) means H, Hal, CN. NO ,, (cyclo) alkyl. (O) (S) [NR (5) 3 (CH2) b- (CF2) c-CF3; * R (5) means H. alkyl (Cj-Cj), -CdH2dR (6). R (61) means cycloalkyl, (bi) phenyl (ilo), naphthyl, or.,.,.,., - R (1) means -SR (10), -OR (10) r, -CR (10) ) R (11) (12), • -. (10) means -CjH ^ -cycloalkyl (C3-C5). "Eteroaryl (C ^ -Cg) or phenyl., R. (il), R (12) they are defined as R (10) or signi- -Kb) -fican hydrogen, alkyl (C ^ -C ^). . or R (l) means -SR (13). -0R (13), -NHR (13), -NR (13) R (14). -CHR (13) R (15), -C [R (15) R (16)] 0Hr -C = CR (18). -C [R (19)] = CR (18) f [CR (20) R (2D) j .- (CO) - [CR (22) R (23) R (24)] 1 R (13), R (14) mean - (CH2) - (CHOH) h ~ (CH2) j- (CHOH) - -R (17), R (17) means hydrogen, methyl, - (CH,) - O- (CH -, - CHoO) ,, - R (24), RÍ15), R (16) mean hydrogen, alkyl or together with the carbon atom carrying them, mean cycloalkyl, R (18) means phenyl , heteroaryl. (cyclo) alkyl, R (19) f R (20), R (21), R (22), R (23) mean hydrogen. methyl, R (24) means H, (cyclo) alkyl. -CBH2fi-R (18). R (2) and R (3) are defined as R (l). R (4) means alkyl. Hal, CN, - (CH2) n ~ (CFJ 0-CF3) as well as their pharmaceutically compatible salts Compounds I have no undesired salidiurotic properties, but very good antiarrhythmic properties.They are extraordinarily suitable as antiarrhythmic drugs. with a cardioprotective component for the prophylaxis (c) -xis of infarction and the treatment of infarction, as well as for the treatment of angina pectoris, also strongly inhibiting or reducing the pathophysiological processes in case for the formation of ischemia-induced lesions Due to their protective effects against hypoxic and ischemic pathological conditions, the compounds of the formula I according to the invention can be used as a consequence of the inhibition of the cellular exchange mechanism of Na + / H as medicines for the treatment of all acute or chronic injuries triggered by the ischemia or of diseases induced in a primary or secondary school for them. -1 (d) # The invention concerns benzoylsuanidines of the formula wherein: R (l) means H. F, Cl. Br. I, CN, 02, alkyl (Cj-C8). cycloalkyl (C-Cj), Xa- (CH2) b- (CF2) C-CF3, X means oxygen, S, NR (5), a means zero, 1, b means zero, 1, 2, c means zero, 1 r 2, 3, R (5) means H, alkyl (Cj-C ^). -CdH2¡, R (6), d means zero, 1, 2, 3 p 4. R (6) means cycloalkyl (C3-C1). phenyl, biphenylyl, naphthyl, the aromatic-2-cos components being unsubstituted or substituted with 1 to 3 substituents of the group F. Cl, CF 3, methyl, methoxy or NR (7) R (8), where R (7) and R (8) independently equal to H, or alkyl IC ^ -C ^), or R (l) means -SR (IO), -OR (IO), -CR (10) III) R (12), R (10) means -CfH2j-cycloalkyl (C3-C1) r heteroaryl (CJ-CJ) or phenyl, the aromatic systems being unsubstituted or substituted with 1 to 3 substituents of the group Fr Cl, CF3. CH3, methoxy, hydroxy, amino, methylamino, dimethylamino, f means zero, 1, 2, R (ll), R (12), independently of one another, are defined as R (10) O mean hydrogen, alkyl- R (l) means phenyl, naphthyl, biphenylyl, heteroaryl (Cj-Cg), the latter linked through C or N, and which are unsubstituted or substituted with 1 to 3 substituents of the group F, Cl, CF3 , CH3, methoxy, hydroxy, amino, methylamino or dimethylamino, R (l) means -SR (13), -OR (13), -NHR (13), -NR (13) R (14), -CHR (13 ) R (15). -C [R (15) R (16)] OH, -CaCR (18), -C [R (19)] = CR (18), - [CR (20) R (21)] k- (CO) - - [CR (22) R (23) R (24)] j, R (13), R (14), same or different, mean - (CH2) g- (CHOH) h- (CH2) i- ( CHOH) jR (17). R (17) means hydrogen, methyl. - (CH2) 0-O- (CH2-CH2O) h-R (24). g, h, i, equal or different, mean, zero, 1, 2, 3, 4, j means 1, 2, 3, 4, R (15), R (16), same or different, mean hydrogen, alkyl (C ^ -Cg) or, together with the carbon atom carrying them, mean a cycloalkyl (C3-Cg), R (18) means phenyl, which is unsubstituted or substituted with 1 to 3 substituents of the group F, Cl , CF3, methyl, methoxy or NR (25) R (26), where R (25) and R (26) are equal to H or alkyl (C ^ -C ^), or R (18) means heteroaryl (Cj-Cg) ), which is unsubstituted or substituted as phenyl, or R (18) means alkyl (C ^ -Cg), - 4 - which is unsubstituted or substituted by 1 to 3 OH, or R (18) means cycloalkyl (C3-) C i) and R (19), R (20), R (21), R (22) and R (23) mean hydrogen, methyl, k means zero, 1, 2, 3, 4. 1 means zero, 1, 2, 3, 4, R (24) means H, alkyl (Cj-Cg), cycloalkyl (C3-C y), -CsH2? -R (18) 'm means 1, 2, 3, 4, R (2) and R (3) are defined as R (l), and R (4) means alkyl (Cj-C ^, F , Cl, Br, I, CN.- (CH 2) n- (CF 2) 0-CF 3, n means zero, 1, or means zero, 1, 2, as well as their pharmaceutically compatible salts, Preference is given to compounds of the formula I , in which: R) means H, F, Cl, Br, CN, N02, alkyl (Cj-Cj¡), cycloalkyl (C3-Cj), Xa- (CF2) C-CF3, X means oxygen, S, a means zero, 1, c means zero, 1, 2, 3, R (l) means -SR (10), -OR (10), R (10) means -C. { H2j-cycloalsuyl (C3-C,), hetero-5-aryl (C, -Cg) or phenyl. the aromatic systems being unsubstituted or substituted with 1 to 3 substituents of the group F, Cl, CF3, CH3, methoxy, hydroxy, amino, methylamino, dimethylamino, f means zero, 1, or R (l) means phenyl, naphthyl, biphenylyl , heteroaryl (Cj-Cg), the latter bonded through C or N, and which are unsubstituted or substituted with 1 to 3 substituents of the group F, Cl, CF3, CH3, methoxy, hydroxy, amino, methylamino or dimethylamino, R { 1) means -SR (13), -OR (13), -NHRÍ13), -NR (13) R (14), -C = CR (18), -C [R (19)] = CR (18) , R (13), R (14), same or different, mean - (CH2) g- (CHOH) h- (C ^ ij- (CHOH) jR (17), R (17) means hydrogen, methyl, - ÍCH2) a-0-. { CH2-CH20) h-R (24), g, h, i, equal or different, mean, zero, 1, 2, j means 1, 2, R { 18) means phenyl, which is unsubstituted or substituted with 1 to 3 -6-substituents of the group F, Cl, CF3, methyl, methoxy or NR (25) R (26), where R (25) and R (26) are is -ual to H or alsuyl (Ci, -CLt). or R (18) means heteroaryl (C-C8), which is unsubstituted or substituted as phenyl, or R (18) means alkyl (C ^ -Cg), which is unsubstituted or substituted by 1 to 3 OH, or R (18) means cycloalkyl (Cj-Cg), and R (19) means hydrogen, methyl, R (2) and R (3) are defined as R (l). and R (4) means alkyl (Cj-C ^), F, Cl, Br, CN, - (CH2) n- (CF2) 0-CF3, n means zero, 1, or means zero, 1, as well as their pharmaceutically compatible salts. Particularly preferred are compounds of the formula to H, F, Cl, alsuyl (Cj-Cg), cycloalsuyl (Cj-Cg). Xa- (CF2) C-CF3, X means oxygen, a means zero, 1, c means zero, 1, or - 7 -R (l) means -SR (10), -OR (IO), R (10) means cycloalsuyl (C ^ -Cg), quinolyl, isoquinolyl. pyridyl, phenyl, which is unsubstituted or substituted by 1 to 3 substituents of the group F, Cl, CF 3, CH 3, methoxy, hydroxy, amino, methylamino. dimethylamino, or Rd) means phenyl, quinolyl, isoquinolyl, pyridyl, imidazolyl, linked through C or N, which are unsubstituted or substituted with 1 to 3 substituents of the group F, Cl, CF3, CH3, methoxy, hydroxy, amino, methylamino or dimethylamino. or R (l) means -C = CR (18), R (18) means phenyl. cycloalsuyl. { C¡¡-Cg). R (2) and R (3) are defined as Rd), and R (4) means methyl, F, Cl, CF3, as well as their pharmaceutically compatible salts. By heteroaryl (C ^ -Cg) are meant radicals which are derived from phenyl or naphthyl, in which one or more CH groups are replaced by N and / or in which at least two contiguous CH groups (with formation of an aromatic ring) of five members) are replaced by S. NH or O. In addition, - 8 - one or both atoms of the condensation point of bicyclic radicals (such as in indolizinyl), can be N atoms. As heteroaryl ( Cj-Cg) are particularly suitable furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl. pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, fatalazi-nyl, quinoxalinyl, quinazolinyl, cinolinyl. If one of the substituents Rd) to R (4) contains one or more centers of asymmetry, then these can have the configuration of both S and R. The compounds can be presented as optical isomers, as diastereomers, as racemates or as mixtures of the same. The alkyl radicals can be present in both straight chain and branched form. The invention also relates to a process for the preparation of compound I, characterized in that a compound of formula II - 9 - is reacted with guanidine, where Rd) to R (4) have the indicated meanings and L represents a slightly nucleophilic substitutable leaving group. The activated acid derivatives of the formula II. wherein L means an alkoxy group, preferably a methoxy group, a phenoxy group, a phenylthio group, methylthio. 2-pi-Ridylthio, a nitrogenous heteroscycle, preferably 1-imidazolyl. they are advantageously obtained in a manner known per se from the carboxylic acid chlorides in which they are melted (formula II, L = Cl) which. for their part, they can again be prepared in a manner known per se from the carboxylic acids in which they are melted (formula II, L = OH), for example with thionyl chloride. In addition to the carboxylic acid 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 in which they are melted ( formula II, L = OH), such as for example the methyl esters of the formula II with L = 0CH3 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. 351 to 367 (1962)], the mixed anhydrides II with C1-C00C2H5 or tosyl chloride, in the presence of triethylamine in an inert solvent, as well as the activations of ben-10 -zoic acids with dicyclohexylcarbodiimide (DCC ) or with O- [(cyano (ethoxycarbonyl) methylene) amino] -1,1,3, 3-te-tramethyluronium tetrafluoroborate ("TOTU") [Proceedings of the 21. European Peptide Symposium. Peptides 1990, Editors E. Giralt and D. Andreu, Escom, Leiden, 1991]. A number of suitable methods for the preparation of activated carboxylic acid derivatives of the formula II are indicated, with indication of the literature source, in J. March, Advanced Organic Chemistry, third edition (John Wiley &Sons, 1985), p. . 350. The reaction of an activated carboxylic acid derivative of formula II with guanidine is carried out, in a manner known per se, in a polar but inert protic or aprotic organic solvent. In this case, in the reaction of the benzoic acid methyl ester (II, L = OMe) with guanidine, methanol, isopropanol or THF of 20dC have been proved up to the boiling point of these solvents. In the majority of the reactions of compounds II with guanidine free of salts, advantageous work was carried out in inert aprotic solvents. such as THF, dimethoxyethane. dioxane However, water can also be used with the use of a base, such as for example NaOH as solvent in the reaction of II with guanidine. When L means Cl, the addition of an acid scavenger is advantageously carried out, for example in the form of-11-excess guanidine for the dissociation of the halogenated hydrazide. A part of the benzoic acid derivatives of the formula II in which they are melted is known and is described in the literature. The unknown compounds of formula II can be prepared according to methods known from the literature. The benzoic acids obtained are reacted, according to one of the variants of the process described above, to give compounds I according to the invention. The incorporation of some substituents at positions 3, 4, 5 and 6 is achieved by methods known from the literature of palladium-induced cross coupling of aryl halides or aryl triflates, for example with organostannanes, organoboronic acids or organoboranes or organic compounds of copper or zinc. The benzoylguanidines I are, generally, weak bases and can bind acid with salt formation. Suitable salts by the addition of acids are salts of all pharmacologically compatible acids, for example halides, in particular hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates, p-toluenesulfonates. The compounds I are substituted acylguanidines. The most prominent representative of acylguanidines is the pyrazine derivative amiloride, which finds application - 12 - in therapy as a potassium-sparing diuretic. Numerous other compounds of the amiloride type are described in the literature, such as, for example, dimethylamiloride or ethylisopropyl iloride. amiloride: R *, R "= H dimethylamiloride: R ', R" = CH3 ethylisopropyl iloride: R' = C2H5, R "= CH (CH3) 2 In addition, studies have been reported which point to antiarrhythmic properties of Amiloride (Circulation 79, 1257 to 1263 (1989)) However, it is opposed to a wide application as an antiarrhythmic agent that this effect is only weakly marked and that it is accompanied by a blood hypotensive and saliuretic effect, and these effects Seizures are undesirable in the treatment of heart rhythm disorders Indications about the antiarrhythmic properties of amiloride were also obtained in the case of experiments in - 13 - isolated hearts of animals (Eur. Heart J. 9 (supl.l): 167 ( 1988) (Book of abstracts)) Thus, for example, in rat hearts it was found that an artificially triggered ventricular fibrillation could be completely suppressed by amiloride, and even more powerful than amiloride was in this model the amiloride ethylisopropylamine-loride ratio mentioned above. In the U.S. patent specification 5 091 394 (HOE 89 / F 288) and German patent application P 42 04 575.4 (HOE 92 / F 034) describe benzoylguanidines which, however, do not carry any substituent in the ortho position in the aromatic nucleus. In U.S. Pat. 3 780 027 acylguanidines are claimed which are structurally similar to the compounds of the formula I and which are derived from commercially available diuretics of the loop of Henle, such as burmetanide. Correspondingly, strong salidiuretic activity is indicated for these compounds. Therefore, it was surprising that the compounds according to the invention did not have any undesired and disadvantageous salidiuretic properties, but very good antiarrhythmic properties, as they occur, for example, in oxygen deficiency manifestations. As a consequence of its pharmacological properties as antiarrhythmic drugs with a cardioprotective component, the compounds are extraordinarily suitable for the prophylaxis of infarction, and the treatment of infarction as well as for the treatment of angina pectoris, also strongly inhibiting or reducing preventive treatment of pathophysiological processes when ischemia-induced lesions are formed, particularly when cardiac arrhythmias induced by ischemia are triggered. Due to their protective effects against hypoxic and ischemic pathological situations, the compounds of the formula I according to the invention can be used, as a consequence of the inhibition of the cellular exchange mechanism of Na / H, as medicaments for the treatment of all the acute or chronic injuries triggered by ischemia or primary or secondary diseases induced by them. This concerns their use as medicaments for surgical interventions, for example in the case of organ transplants, the compounds being able to be used both for the protection of the organs in the donor before and during the extirpation, for the protection of extirpated organs, for example in the treatment with or storage in physiological bath liquids, as well as in the transfer to the recipient organism. The compounds are also valuable drugs with a protective effect in the performance of angioplastic surgical interventions, for example in the heart as well as in the peripheral vessels. Corresponding to its protective effect against ischemia-induced lesions, the compounds are also suitable as medicaments for the treatment of ischemia of the nervous system, in particular of the central nervous system (SNZ), and are suitable, for example, for the treatment of Stroke or cerebral edema. In addition, the compounds of the formula I according to the invention are also suitable for treatment of shock forms, such as, for example, allergic, cardiogenic, hypovolemic shock and bacterial shock.

Furthermore, the compounds of the formula I according to the invention are distinguished by a strong inhibitory effect on cell proliferation, for example the proliferation of fibroblast cells and the proliferation of the cells of smooth muscle vessels. For this reason, the compounds of the formula I come into consideration as valuable therapeutic agents for diseases in which the proliferation of cells represents a primary or secondary cause and, therefore, agents against late diabetic complications can be used as anti-roesclerotic agents. , cancer diseases, fibrotic diseases, such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, hypertrophies and hyperplasias of the organs, in particular in the hyperplasia of the prostate or the hypertrophy of the prostate. The compounds according to the invention are effective - 16 - inhibitors of the sodium proton cell antiporter (Na + / H + exchanger) which, in the case of numerous diseases (essential hypertonia, atherosclerosis, diabetes, etc.), is also increased in cells whose measurements are easily accessible, such as for example in erythrocytes, thrombocytes or leukocytes. Therefore, the compounds according to the invention are suitable as extraordinary and scientifically simple tools, for example in their use as diagnostic agents for the determination and differentiation of certain forms of hypertonia, but also of atherosclerosis, of the diabetes, proliferative diseases, etc. In addition, the compounds of the formula I are suitable for preventive therapy to prevent the genesis of blood hypertension, for example of essential hypertonia. The drugs containing a compound I can in this case be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred administration depending on the respective symptoms of the disease. In this case, the compounds I can be used alone or together with galenical auxiliaries, namely both in veterinary medicine and also in human medicine. What kind of auxiliary substances are suitable for the desired drug formulation is familiar to the expert - 17 - by virtue of his knowledge. In addition to solvents, gel formers, suppository bases, tablet auxiliaries and other active substance carriers, for example antioxidants, dispersing agents, emulsifiers, defoamers, flavor correctors, preserving agents, dissolving agents or dyes can be used. For an oral administration form, the active compounds are mixed with suitable additives for this, such as support substances, stabilizers or inert diluents and are brought, by the usual methods, to suitable administration forms, such as tablets, Dragees, plug-in capsules, aqueous, alcoholic or oily solutions. Inert media used are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. In this case, the preparation can be carried out both in the form of dry granulate and also of wet granulation. Suitable oil-containing substances or solvents include, for example, vegetable or animal oils, such as sunflower oil or cod liver oil.

For subcutaneous or intravenous application. the active compounds are brought into solution, suspension or emulsion, if desired with the usual substances for this purpose, such as dissolution promoters, emulsifiers or other auxiliary substances. Suitable solvents are, for example, water, physiological sodium chloride solution or alcohols. for example ethanol, propanol. glycerol and with them also solutions of sugars, such as glucose or mannitol solutions. or also a mixture based on the different solvents mentioned. As a pharmaceutical formulation for administration in the form of aerosols or sprays, for example, solutions are suitable, suspensions or emulsions of the active ingredient of the formula I in a pharmaceutically innocuous solvent, such as in particular ethanol or water, or in a mixture of solvents of this type. The formulation may contain. as necessary, also other pharmaceutical auxiliaries, such as surfactants, emulsifiers and stabilizers, as well as a propellant gas. A preparation of this type contains the active principle usually in a concentration of about 0.1 to 10, in particular about 0.3 to 3% by weight. The dosage of the active principle of the formula I to be administered and the frequency of administration depend on the action power and the duration of action of the compounds used; in addition, the type and severity of the disease to be treated, as well as the sex, age, weight and individual responsiveness of the mammal to be treated. On average, the daily dose of a compound of the formula I in-19 - a patient of approximately 75 kg of weight is at least 0.001 mg / kg, preferably 0.01 mg / kg. up to at most 10 mg / kg, preferably 1 mg / kg of body weight. In the case of acute manifestations of the disease, for example immediately after suffering a cardiac infarction, higher and, above all, more frequent dosages may also be necessary, for example up to 4 individual doses per day. In particular, in the case of i.v. administration, for example in a heart attack patient, up to 200 mg per day may be necessary in the intensive monitoring unit.

List of abbreviations: MeOH methanol DMF N, -dimethylformamide RT ambient temperature EE ethyl acetate (EtOAc) P.f. melting point THF tetrahydrofuran eq. ZNS equivalent central nervous system Experimental part General prescription for the preparation of benzoylguanidines (I) Alternative A: from benzoic acids (II, L = OH) - 20 - 1.0 eq. of the benzoic acid derivative of the formula II is dissolved or suspended in anhydrous THF (5 ml / millimole) and immediately mixed with 1.1 eq. of carbonyldiimidazole. After stirring for 2 hours at RT, 5.0 eq. of guanidine in the reaction solution. After stirring overnight, the THF is distilled off under reduced pressure (rotary evaporator), mixed with water, adjusted to pH 6 to 7 with 2N HCl and the corresponding benzoylguanidine (formula I) is filtered off . The benzoylguanidines thus obtained can be converted into the corresponding salts by treatment with aqueous, methanolic or ethereal hydrochloric acid or other pharmacologically compatible acids.

General prescription for the preparation of benzoylguanidines (I) Variant B: from alkyl esters of benzoic acid (II, L = O-alkyl) 1, A eq. of the benzoic acid alkyl ester of the formula II, as well as 5.0 eq. of guanidine (free base) are dissolved in isopropanol or suspended in THF and heated to boiling (typical reaction time 2 to 5 hours) until complete conversion (control in thin layer). The solvent is distilled off under reduced pressure (rotary evaporator), the residue is taken up in EA and washed - 21 - 3 times with NaHCO solution. It is dried over Na2SO4, and the solvent is distilled off in vacuo and the residue is chromatographed on silica gel with a suitable eluent, for example EE / MeOH 5: 1. (For ation of salts, see variant A) Example 1: 2,3-Dichloro-benzoylguanidine hydrochloride: colorless crystals, m.p. 232aC from 2,3-dichlorobenzoic acid according to variant A.

Example 2: 2-Fluoro-3-trifluoromethyl-benzoylguanidine hydrochloride: colorless crystals, vitreous from 2-fluoro-3-trifluoromethyl-benzoic acid according to variant B.

Example 3: 2,4-Dichloro-benzoylguanidine hydrochloride: colorless crystals, m.p. 242 ° C from 2,4-dichlorobenzoic acid according to variant A.

Example 4: 2-Fluoro-4-trifluoromethyl-benzoylguanidine hydrochloride: colorless crystals, m.p. 143 to 145SC-22- from 2-fluoro-4-trifluoromethyl-benzoic acid according to variant B. * Example 5: 2,5-Dimethyl-benzoylguanidine hydrochloride: colorless crystals, m.p. 247ßC from 2,5-dimethyl-benzoic acid according to variant A.

Example 6: 2,5-Dichloro-benzoylguanidine hydrochloride: colorless crystals, m.p. 209SC from 2,5-dichloro-benzoic acid according to variant A.

Example 7: 2,5-bis (trifluoromethyl) -benzoylguanidine hydrochloride: colorless crystals, m.p. 240 to 242 ° C from 2,5-bis (trifluoromethyl) -benzoic acid according to variant A.

• Example 8: 2-Fluoro-5-trifluoromethyl-benzoylguanidine hydrochloride: colorless crystals, m.p. 168 to 170 ° C from 2-fluoro-5-trifluoromethyl-benzoic acid according to variant A. - 23 - Example 9: 2-Chloro-5-trifluoromethyl-benzoylguanidine hydrochloride: colorless crystals, m.p. 209-211 aC from 2-chloro-5-trifluoromethyl-benzoic acid according to variant A.

Example 10: 2-Fluoro-5-iodo-3-trifluoromethyl-benzoylguanidine hydrochloride: colorless crystals, m.p. 197-200SC Synthetic pathway: a) 2-fluoro-5-iodo-3-trifluoromethyl-benzoic acid nitrile from 2-fluoro-3-trifluoromethyl-benzonitrile by reaction with 1 equivalent of N-iodo-succinimide in 5 equivalents of trifluoromethanesulfonic acid at RT for 24 h, colorless crystals, mp 65-67 ° C. b) 2-fluoro-5-iodo-3-trifluoromethyl-benzoic acid from part a), by heating a mixture based on concentrated hydrochloric acid in glacial acetic acid, colorless crystals, m.p. 136-38 ° C. c) 2-fluoro-5-iodo-3-trifluoromethyl-benzoylguanidine hydrochloride starting from section b) according to variant A.

Example 11: 2,4-difluoro-benzoylguanidine hydrochloride: colorless crystals, m.p. 170-72aC - 24 - from 2,4-difluoro-benzoic acid according to variant A.

Example 12: 2,6-difluoro-benzoylguanidine hydrochloride: colorless crystals, m.p. 208-10aC from 2,6-difluoro-benzoic acid according to variant A.

Example 13: 4-Fluoro-2-trifluoromethyl-benzoylguanidine hydrochloride: colorless crystals, m.p. 155-57 ° C from 4-fluoro-2-trifluoromethyl-benzoic acid according to variant A.

Example 14: 6-Fluoro-2-trifluoromethyl-benzoylguanidine hydrochloride: colorless crystals, m.p. 178-80dC from 6-fluoro-2-trifluoromethyl-benzoic acid according to variant A.

Example 15: 4-imidazolyl-2-trifluoromethyl-benzoylguanidine hydrochloride: colorless, amorphous crystals from 4-imidazolyl-2-trifluoromethyl-benzoic acid according to variant A. - 25 - Example 16: 2-Trifluoromethyl-benzoylguanidine hydrochloride: colorless crystals, m.p. 225dC from 2-trifluoromethyl-benzoic acid according to the variant TO.

Example 17: 2-Chloro-benzoylguanidine hydrochloride: colorless crystals: m.p. 161dC from 2-chloro-benzoic acid according to variant A.

Example 18: 2,3-Dichloro-4-methoxy-benzoylguanidine hydrochloride: colorless crystals, m.p. 227aC from 2,3-dichloro-4-methoxy-benzoic acid according to variant A.

Example 19: 2-Chloro-5-methyl-benzoylguanidine hydrochloride: colorless crystals, m.p. 134SC from 2-chloro-5-methyl-benzoic acid according to the variant TO.

Pharmacological data: Inhibition of the Na / H exchanger of red-white erythrocytes New Zealand white rabbits (Ivanovas) received a standard diet with 2% cholesterol for six weeks in order to activate the exchange of Na-f / Hiy, thus, to be able to determine by flame photometry the influx of Na + in the erythrocytes through the exchange of Na / H *. The blood was taken from the auditory arteries and transformed into non coagulable by 25 IU of potassium heparin. A part of each sample was used for the double determination of the hematocrit by centrifugation. Aliquots of in each case 100 μl were used to measure the starting Na content of the erythrocytes. In order to determine the influx of amiloride sensitive sodium, 100 μl of each blood sample was incubated at pH 7.4 and at 37 ° C in each case in 5 ml of a hyperosmolar salt and sucrose medium (millimoles / 1: 140 NaCl 3 KCl, 150 sucrose, 0.1 uabaine, 20 Tris-hydroxymethyl-a-methane). The erythrocytes were then washed three times with ice cold MsCl? -uabain solution (millimoles / 1: 112 MgCl2, 0.1 uabaine) and hemolyzed in 2.0 ml of distilled water. The intracellular sodium content was determined by flame photometry. The net influx of Na + was calculated from the difference between the starting values of sodium and the sodium content of the erythrocytes after incubation. The sodium influx susceptible to being inhibited by amiloride was deduced from the difference in sodium content 'my. ? jß of erythrocytes after incubation with and without amiloride 3 x 10 moles / 1. Thus, the compounds according to the invention were also used.

Results Inhibition of the Na / H exchanger: NOVELTY OF THE INVENTION. Having described the invention, it is considered as a novelty and, therefore, what is contained in the following is claimed as its property.

Claims (16)

1. - 28 - CLAIMS • 1.- Benzoylguanidines of the formula I wherein: R (l) means H, F, Cl, Br, I, CN, N02, alsuyl IC ^ -C ^). cycloalkyl (C3-C8), Xa- (CH2) b- (CF2) c-CF3, X signifies oxygen, S, NR (5). a means zero, 1, b means zero, 1, 2, c means zero, 1, 2, 3, R (5) means H, alsuyl (C ^ -C ^), -C ^^ R (6), d means zero, 1, 2, 3, 4, R (6) means cycloalsuyl (CCi), phenyl, biphenylyl, naphthyl, the aromatic components being unsubstituted or substituted with 1 to 3 substituents of the group F, Cl, CF3, methyl, methoxy or NR (7) R (8), where R (7) and R (8) are independently isual to H, or-29 alkyl (C ^ -C ^), Rd) means -SR (10). -OR (IO), -CR (10) R (ll) R (12), R (10) means -CjH2f-cycloalkyl (Cj-Cj), heteroaryl (C ^ -Cg) or phenyl, the aromatic systems being substituted or substituted with 1 to 3 substituents of the group F. Cl, CF-,. CH3 methoxy, hydroxy. Not me. methylamino. dimethylamino, f means zero, 1, 2. R (ll). R (12). independently of one another, they are defined as R (10) or they mean hydrogen, alkyl (^ -Cj), or R (l) means phenyl, naphthyl, biphenylyl. heteroaryl (Cj-Cg), the latter linked through C or N. and which are unsubstituted or substituted with 1 to 3 substituents of the group F, Cl, CF3, CH3-methoxy. hydroxy, aminow methylamino or dimethylamino, R (l) means -SRÍ13), -ORÍ13), -NHRÍ13), -NR (13) RÍ14). -CHR (13) R (15), -C [R (15) R (16)] 0H. -CSCR (18), -C [R (19)] = CR (18), - [CR (20) R (21)] k- (CO) - [CR (22) R (23) R (24) ]? RI 13), R (14), same or different, mean - (CH2) - (CHOH) h- (CH2) - (CHOH) -R (17), R (17) is hydrogen, methyl. - (CH2) a-0- (CH2-CH20) hR (24), g, h, i, equal or different, mean, zero, 1, 2, 3, 4, j means 1, 2, 3, 4, R (15), R (16), same or different, mean hydrogen, alkyl (C ^ -Cg) or, together with the carbon atom carrying them, mean a cycloalsuyl (C-Cg), R (18) means phenyl, which is unsubstituted or substituted by 1 to 3 substituents of the group F, Cl, CF3, methyl, methoxy or NR (25) R (26), where R (25) and R (26) are equal to H or alkyl ( C ^ -C ^), or R (18), means heteroaryl (C ^ -Cg), which is unsubstituted or substituted as phenyl. or R (18) means alkyl (Cj-Cg), which is unsubstituted or substituted by 1 to 3 OH, or R (18) means cycloalkyl (C3-C1), and R (19), R (20) , R (21), R (22) R (23) mean hydrogen, methyl. - 31 - k means zero, 1, 2, 3, 4, 1 means zero, 1, 2, 3, 4, R (24) means H, alsuyl (C ^ -Cg), cycloalsuyl (C3-Cg), - CaH2a-R (18), m means 1, 2, 3, 4, R (2) and R (3) are defined as Rd), and R (4) means alkyl (CJ-CJ), F, Cl. Br. I, CN, - (CH2) n- (CF2) 0-CF3, n means zero, 1, or means zero, 1, 2, as well as their pharmaceutically compatible salts. 2. Compounds of the formula I according to claim 1, characterized in that therein: R (l) means H, F, Cl, Br, CN, NOj, alkyl (Cj-Cg). cycloalkyl (Cj-Cg), Xa ~ (CF2) C-CF3- X means oxygen, S, a means zero, 1, c means zero, 1, 2, 3, or R (l) means -SR (IO), -OR (IO), R (10) means -CjHjj-cycloalkyl (Cj-Cg). heteroaryl (Cj-Cg) or phenyl, the aromatic systems being unsubstituted or substituted by 1 to 3 substituents of the group F, Cl. CF3, CH3, methoxy, hydroxy, amino, methylamino, dimethyl-32-auno, f means zero, 1, R (l) means phenyl, naphthyl, biphenylyl, heteroaryl (C, -Cg), the latter linked through C or N, and which are unsubstituted or substituted with 1 to 3 substituents of the group F, Cl, CF3 , CH3, methoxy. hydroxy, amino, methylamino or dimethylamino. R (l) means -SR (13), -0RÍ13), -NHR (13), -NR (13) R (14), -CSCR (18), -C [R (19)] = CR (18) , R13), R (14), equal or different, mean - (CHj) - (CHOH) h- (CH2) i- (CHOH) jR (17), R (17) means hydrogen, methyl: - (CH2) g-0- (CH2-CHjO) hR (24), g, h, i, same or different, mean, zero, 1, 2, j means 1.
2. 2, R (18) means phenyl, which is unsubstituted or substituted with 1 to 3 substituents of group F, Cl, CF3. methyl, methoxy or NR (25) R (26), where R (25) and R (26) are equal to H or alkyl (Cj-C¿), or R (18) means heteroaryl (C ^ -Cg), - 33 - which is unsubstituted or substituted as phenyl, or R (18) means alkyl (C ^ -Cg). which is unsubstituted or substituted by 1 to 3 OH, or R (18) means cycloalkyl (C3 ~ Cg), and R (19) means hydrogen, methyl, R (2) and R (3) are defined as R (l) ). and R (4) means alsuyl (CJ-CJ), F. Cl. Br. CN, - (CH2) n- (CF2) 0-CF3. n means zero, 1, or means zero. 1, as well as its pharmaceutically compatible salts.
3. 3. Compounds of the formula I according to claim 1, characterized in that therein: R (l) mean. F, Cl, alkyl (Cj-Cg), cycloalkyl (Cj-Cg). Xa- (CF2) C-CF3. X means oxygen. a means zero. 1, c means zero, 1, R (l) means -SR (IO), -ORI 10), R (10) means cycloalkyl (C ^ -Cg). quinolyl, isoquinolyl, pyridyl, phenyl, which is unsubstituted or substituted with -34-1 to 3 substituents of group F, Cl, CF3, CH3, methoxy, hydroxy, amino, methylamino, dimethylamino. R (l) means phenyl, quinolyl, isosuinolyl, pyridyl, imidazolyl, linked through C or N, which are unsubstituted or substituted by 1 to 3 substituents of the group F, Cl, CF3, CH3, methoxy. hydroxy, amino, methylamino or dimethylamino, (l) means -C = CR (18), R (18) means phenyl, cycloalkyl (C5-Cg), R (2) and R (3) are defined as Rd), and R (4) means methyl, F , Cl, CF3, as well as their pharmaceutically compatible salts.
4. 4. Process for the preparation of a compound I according to claim 1, characterized in that wherein R (l) to R (4) possess the meanings set forth in the -3- claim 1 and L represents a slightly nucleophilic substitutable leaving group, is reacted with guanidine.
5. 5. Use of a compound I according to claim 1 for the preparation of a medicament for the treatment of arrhythmias.
6. 6. Method for the treatment of arrhythmias, characterized in that an effective amount of a compound I according to claim 1 is mixed with the usual additives and administered in a suitable administration form.
7. 7. Use of a compound I according to claim 1, for the preparation of a medicament for the treatment or prophylaxis of cardiac infarction.
8. 8. Use of a compound I according to claim 1, for the preparation of a medicament for the treatment or prophylaxis of angina pectoris.
9. 9. Use of a compound I according to claim 1. for the preparation of a medicament for the treatment or prophylaxis of ischemic heart conditions.
10. 10. Use of a compound I according to claim 1, for the preparation of a medicament for the treatment or prophylaxis of ischemic states of the peripheral and central nervous system and of apoplexy.
11. 11. Use of a compound I according to claim 1, for the preparation of a medicament for the treatment or prophylaxis of ischemic states of peripheral organs and - 36 - members of the body.
12. 12. Use of a compound I according to claim 1, for the preparation of a medicament for the treatment of shock states.
13. 13. Use of a compound I according to claim 1 for the preparation of a medicament for use in surgical procedures and organ transplants.
14. 14. Use of a compound I according to claim 1, for the preparation of a medicament for the preservation and storage of organs of transplants for surgical purposes.
15. 15. Use of a compound I according to claim 1 for the preparation of a medicament for the treatment of diseases in which the proliferation of cells represents a primary or secondary cause and, consequently, their use as antiatherosclerotic agents against complications late diabetics, cancer diseases, fibrotic diseases. such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, hyperplasia of the prostate.
16. 16. Use of a compound I according to claim 1, for the preparation of a scientific tool for the inhibition of the Na / H exchanger, for the diagnosis of hypertonia and proliferative diseases. 17.- Healing and therapeutic agent, characterized by an effective content of a compound I according to claim 1. 37 -. 37 - In testimony of which, I have signed the above description and novelty of the invention as an apdoerado of HOECHST AKTIENGESELLSCHAFT, in the City of Mexico, District Federal, today, August 26, 1994. p.p. of HOECHST AKTIENGESELLSCHAFT *