MXPA97001618A - Benzoilguanidinas replaced in orthodous position, procedure for its preparation, its use as a diagnostic medicine or agent, as well as a medication that conti - Google Patents

Abstract

Ortho-substituted benzoylguanidines of the formula I: wherein R (1) to R (4) have the meanings indicated in the claims, are suitable as antiarrhythmic drugs with a cardioprotective component for the prophylaxis of infarction and the treatment of infarction, as well as for the treatment of angina. They also preventively inhibit pathophysiological processes by forming ischemically induced lesions, especially in the case of the provocation of ischemic-induced cardiac arrhythmias.

Description

Benzoylguanidines substituted in the ortho position, a process for its preparation, its use as a medicine or diagnostic agent, as well as medicine containing them The invention concerns benzoylguanidines of general formula I where they mean: R (l) H, F, Cl, Br, I, CN, N02, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, alkoxy with 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, cycloalkoxy with 3, 4, 5, 6, 7 or 8 C atoms or Xa- (CH2) b- (CF2) c-CF3; X oxygen, S, NR (5), zero or 1; b zero, 1 or 2, - c zero, 1, 2 or 3; R (5) H, alkyl having 1, 2, 3 or 4 carbon atoms or -CdH2dR (b): d, 1, 2, 3 or 4; R (6) cycloaikyl with 3, i, 5, 6, 7 or 8 C atoms, phenyl, biphenylyl or naphthyl, the aromatic radicals being phenyl, biphenylyl or naphthyl unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR (7) R (8); Preferred are compounds of formula I, in which they mean: R (l) H, F, Cl, Br, I, CN, N02, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 atoms of C, alkoxy with 1, A, 3, 4, 5, 6, 7 or 8 C atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, cycloalkoxy with 3, 4, 5, 6 , 7 or 8 C atoms or Xa- (CH2) b- (CF2) c-CF3; X oxygen, at zero or 1; b zero, 1 or 2; c zero, 1, 2 or 3; or R (l) -SR (10) or -OR (10); R { 10) -CfH2f-cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms in the cycloalkyl ring, or phenyl, the phenyl being unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3, CH 3, methoxy, hydroxy, amino, methylamino and dimethylamino; f zero or 1, -or R (l) phenyl, naphthyl, biphenylyl or heteroaryl with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, the latter being linked through a C or N of the ring, which are unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxy, amino, methylamino and dimethylamino, or R (l) -SR (13), -OR (13), -NHR (13), -NR (13) R (14), -C = CR (18) or -C [R (19)] = CHR (18), R ( 13) and R (14) equal or different, - (CH 2) g- (CHOH) h- (CH 2) i- (CHOH) -R (17) O - < CH2) g-0- (CH2-CH20) h-R (24); R (17) hydrogen or methyl, g, h and i equal or different, zero, 1 or 2, - j 1 6 2; R (18) phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR (25) R (26); R (25) and R (26) H or alkyl with 1, 2, 3 or 4 C atoms; or R (18) heteroaryl with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, which is unsubstituted or substituted the same as phenyl; or R (18) alkyl having 1, 2, 3, 4, 5 or 6 C atoms, which is unsubstituted or substituted with 1-3 OH; or R (18) cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms; R (19) hydrogen or methyl, -R (2) and R (3) as defined R (l); R (4) alkyl having 1 or 2 C atoms; as well as its pharmaceutically compatible salts. Especially preferred are compounds of the formula I, in which they mean: R (l) H, F, Cl, alkyl with 1, 2, 3 or 4 as C, alkoxy with 1, 2, 3 or 4 carbon atoms C, cycloalkyl with 5 or 6 C atoms, cycloalkoxy with 5 or 6 C atoms or xa "(CF2) C-CF3; X oxygen, at zero or 1; c zero or 1; R (l) -SR (10) or -OR (IO), R (10) cycloalkyl having 4, 5 or 6 C atoms, or phenyl, the phenyl being unsubstituted or substituted with 1-3 its isomers selected from the group which consists of F, Cl, CF3, CH3, methoxy, hydroxy, amino, methylamino and dimethylammo; or R (l) quinolyl, isoquinolyl, pyridyl, which are attached through a C or N ring atom; and are unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF-, CH 3, methoxy, hydroxy, amino, methylamino and dimethylamino, or R (1) phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxy, amino, methylamino and dimethylamino, or R (l) -CSCR (18); R (18) phenyl or cycloalkyl, with five or 6 carbon atoms; R (2) and R (3) as defined R (l); R (4) methyl; as well as its pharmaceutically compatible salts. Particularly preferred are the compounds of the formula I, in which they mean: R (l) H, F, Cl, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 C atoms, cycloalkyl with 5 or 6 C atoms, cycloalkoxy with 5 or 6 C atoms or X -, - CFt, - X oxygen at zero or 1; R (2) and R (3) as defined R (l); R (4) methyl; as well as its pharmaceutically compatible salts. Heteroaryl with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms means the 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 (mediating formation of a five-membered aromatic ring) are replaced by S, NH or 0. Otherwise, also one or both atoms of the bicyclic radical condensation site (such as in the indolizinyl) can be N atoms. As heteroaryl with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms are especially considered furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyridinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazo-linyl, cinolinyl, - in particular furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, pyridyl, indolyl, quinolyl and isoquinol ilo. If one of the substituents R { 1) to R (4) contains one or several centers of asymmetry, these can be configured both S and R. The compounds can be presented as optical isomers, as disistereoisomers, as racemates or as mixtures thereof. The alkyl radicals designated can be straight chain or branched. The invention also relates to a process for the preparation of compound I, characterized in that a compound of formula II is reacted with guanidine. wherein R (l) to R (4) have the indicated meaning and L represents a labile group easily substituted nucleophilically. The activated acid derivatives of the formula II, wherein L means an alkoxy group, preferably a methoxy group, a phenoxy, phenylthio, methylthio, 2-pyridylthio group, a heterocycle with nitrogen, preferably 1-imidazolyl, are advantageously obtained, in a manner known per se, from the chlorides of carboxylic acids which are presented as their base (formula II, L = Cl), which in turn can be prepared from the carboxylic acids which are presented as their base ( formula II, L = OH), in a manner known per se, 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 which are presented as base (formula II, L = OH), such as the methyl esters of the formula II in which L = OCH 3 by treatment with gaseous HC1 in methanol, the imidazolides of the formula II by treatment with carbonyl-diimidazole [L = 1-imidazolyl, Staab, Angew. Chem. International ed. In English 1, 351 -367 (1962)], mixed anhydrides II with Cl-COOC2H5 or tosyl chloride (toluenesulfonyl) in the presence of triethylamine in an inert solvent, as well as activations of benzoic acids with dicyclohexyl-carbodiimide (DCC) or with 0- [(cyano (ethoxycarbonyl) methylene) -amino] -1,3,3-tetramethyl-uronium ("TOTU") [Weiss and Krommer, Chemiker Zeitung] 98, 817 (1974)]. A number of methods suitable for the preparation of activated carboxylic acid derivatives of formula II are indicated by reference to the source literature in J. March, Advanced Organi c Chemistry, third edition (John Wiley &Sons, 1985) , page 350. The reaction of an activated carboxylic acid derivative of the formula II with guanidine is carried out in a manner known per se in a polar protic or aprotic organic solvent, but inert. In this case, in the case of the reaction of methyl esters of benzoic acid (II, L = OMe) with guanidine, methanol, isopropanol or THF at 20'C 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 it was advantageously worked in inert aprotic solvents such as THF, dimethoxyethane and dioxane. However, water can also be used by using a base such as for example NaOH as solvent in the reaction of II with guanidine. When L means = Cl, it is advantageously worked with the addition of an acid scavenger, e.g. ex. in the form of excess guanidine, for the fixation of the hydrogen halide. A part of the benzoic acid derivatives of the formula II, which are presented as a basis, is known and described in the literature. The unknown compounds of the formula II can be prepared according to methods known from the literature. The benzoic acids obtained are reacted according to one of the above-described process variants to give compounds I according to the invention. The introduction of some substituents in positions 3, 4 and 5 is achieved according to methods known from the literature, palladium-mediated cross coupling of aryl halides or aryl triflates (trifluorosulfonates) with, for example, organo-stapes, organo-boronic acids or organo-boranes or organic compounds of copper or zinc. The benzoylguanidines I are generally weak bases and can fix an acid by forming salts. Suitable salts for the addition of acids are the salts of all pharmacologically compatible acids, for example halides, especially hydrochlorides, lactams, sulfates, citrates, tartrates, acetates, phosphates, methylsulphonates and p-toluenesulphonates.

The compounds I are substituted acylguanidines. From European patent application publication EP-640 583.Al (HOE 93 / F 254), compounds similar to compounds I are known. However, the known compounds do not contain any alkoxy radical in the 2-position, which distinguishes the compounds according to the invention from those known. Furthermore, similar compounds are known from the publication document for German patent application DE-OS 44.21.495, which, however, always have a heteroaryloxy substituent, the compounds according to the invention do not, on the contrary, have this substituent heteroaryloxy. Compared with the known compounds, the compounds according to the invention are distinguished by an extraordinarily high activity in the inhibition of the exchange between Na + and H +. Like the known compounds, they do not have undesirable and disadvantageous salidiuretic properties of any kind, but they have very good antiarrhythmic properties, such as are important, for example, for the treatment of diseases, which appear in the case of deficiency phenomena. oxygen. The compounds, due to their pharmacological properties, are outstandingly suitable as antiarrhythmic drugs with a cardioprotective component for the prophylaxis of infarcts and the treatment of infarcts, as well as for the treatment of angina pectoris, inhibiting or diminishing them strongly. also in a preventive way, the pathophysiological processes resulting in ischemically induced lesions, especially in the case of the provocation of ischemically induced cardiac arrhythmias. Because of their protective effects against hypoxic and pathological ischemic situations, the compounds of the formula I according to the invention, as a consequence of the inhibition of the cellular mechanism of exchange between Na + and H +, can be used as medicaments for the treatment of all lesions acute or chronic caused by ischemia, or diseases induced primarily or secondarily in this way. This implies its use as medicines for surgical interventions, p. ex. in cases of organ transplants, the compounds can be used both for the protection of organs in the donor before and during extraction, for the protection of extracted organs, for example in the case of treatment with physiological bath liquids or in the of their storage in them, as well as when making the transfer to the recipient's organism. The compounds are also valuable drugs, which act in a protective manner, in the performance of angioplastic surgical interventions, for example in the heart, as well as in peripheral vessels. Corresponding to their protective effect against ischemically induced lesions, the compounds are also suitable as medicaments for the treatment of ischemias of the nervous system, especially of the CNS (central nervous system), and they are suitable for this purpose. ex. for the treatment of stroke or cerebral edema. In addition, the compounds according to the invention of formula I are also suitable for treatment of shock forms, such as, for example, allergic, cardiogenic, hypovolemic and bacterial shocks. Furthermore, the compounds according to the invention of formula I are distinguished by a strong inhibitory effect on cell proliferations, for example the cell proliferation of fibroblasts and the proliferation of smooth muscle cells of the vessels. Therefore, the compounds of the formula I come into question as valuable therapeutic agents for diseases, in which cell proliferation is a primary or secondary cause and, therefore, can be used as antiatherotropic agents, as anti-inflammatory agents. late diabetic complications, cancerous diseases, fibrotic diseases, such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, hypertrophies and hyperplasias of organs, especially in the case of prostatic hyperplasia or hypertrophy of the prostate. The compounds according to the invention are effective inhibitors of the sodium and proton cell antiporter (exchanger between Na4 and H +), which is increased in numerous diseases (essential hypertension, atherosclerosis, diabetes, etc.) also in cells that are easily accessible to measurements, such as for example in erythrocytes, thrombocytes or leukocytes. The compounds according to the invention are, therefore, suitable as outstanding and simple scientific tools, for example in their use as diagnostic agents for the determination and differentiation of certain forms of hypertonia, but also of atherosclerosis, of diabetes, proliferative diseases, etc. In addition, the compounds of formula I are suitable for preventive therapy in order to prevent the genesis of blood hypertension, for example, essential hypertonia. The drugs, which contain a compound I, can be applied in such cases orally, parenterally, intravenously, rectally or by inhalation, depending on the preferred application of the respective symptomatic picture of the disease. The compounds I can be applied in this case by themselves or in common with galenic adjuvants, and certainly both in veterinary medicine and also in medicine! human A person skilled in the art knows, by virtue of his specialized knowledge, which coadjuvant substances are suitable for the desired drug formulation. In addition to solvents, gel-forming agents, suppository bases, adjuvants for tablets, and other vehicles of active substances, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor correctors, preservatives, solubilizers or dyes. . For an oral form of application, the active compounds are mixed with the adjuvants suitable for this purpose, such as vehicle materials, stabilizers or inert diluents, and by the usual methods are brought into the appropriate forms of presentation and administration, such as as tablets, dragees, nestable capsules and aqueous solutions, alcoholic or oily. As inert vehicles, p. ex. gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. In this case, the preparation can be carried out in the form of both dry and wet granules. Oily vehicle materials or solvents include, for example, animal or vegetable oils, such as sunflower oil or cod liver oil. For subcutaneous application, the active compounds, if desired together with the usual substances for this, such as solubilizers, emulsifiers or other adjuvants, are brought into solution, suspension or emulsion. Suitable solvents are p. ex. in question: water, a physiological solution of sodium chloride or alcohols, p. ex. ethanol, propanol, glycerol, together with them also solutions of sugars such as glucose or mannitol solutions, or also a mixture of the various solvents mentioned. As a pharmaceutical formulation for administration in the form of aerosols or sprays, p. ex. solutions, suspensions or emulsions of the active substance of formula I in a pharmaceutically innocuous solvent, such as especially ethanol or water, or a mixture of such solvents. The formulation can, if necessary, also contain other pharmaceutical adjuvants, such as surfactants, emulsifiers and stabilizers, as well as a driving gas. One such preparation contains the active substance usually in a concentration of about 0, From 1 to 10, in particular from approximately 0.3 to 3% by weight. The dosage of the active substance of the formula I to be administered and the frequency of administration depend on the intensity of the effect and the duration of such effect of the compounds used.; in addition, they also depend on 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 the case of a patient weighing 75 kg is at least 0.001 mg / kg, preferably 0.01 mg / kg, up to a maximum of 10 mg / kg. kg, preferably 1 mg / kg of body weight. In the case of acute outbreaks of the disease, for example immediately after suffering a cardiac infarction, even higher and, above all, more frequent dosages may be necessary, eg. ex. of up to 4 individual doses per day. Especially, in the case of the application via i.v. (intravenous), for example in the case of a heart attack patient in the intensive care phase, up to 200 mg per day may be necessary.

List of abbreviations: MeOH methanol DMF N, N-dimethylformamide TA room temperature AE ethyl acetate (? TOñc) P.f. melting point THF tetrahydrofuran eq. equivalent Experimental part General prescription for the preparation of bepzoyl-guanidines (I) Variant A: from benzoic acids (II, L = OH) 1.0 eq. Is dissolved or suspended. of the benzoic acid derivative of the formula II in anhydrous THF (5 ml / mmol) and then mixed with 1.1 eq. of carbonyl-diii '' ^ ñ zol. After stirring for a period of 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 a pH of 6 to 7 with 2N HC1 and the corresponding benzoylguanidine is filtered off ( formula I). The benzoylguanidines obtained in this manner 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) Alternative B: From alkyl esters of benzoic acid (II, L = O-alkyl) They are dissolved in isopropanol or suspended in THF 1.0 eq. of the benzoic acid alkyl ester of the formula II, as well as 5.0 eq. of guanidine (free base) and are heated to boiling until the reaction is complete (control by thin layer chromatography) (typical reaction time of 2 to 5 h). The solvent is removed by distillation under reduced pressure (evaporated rotary), collected in EA and washed 3 times with a solution of NaHCO3. Dry over Na 2 SO 4, remove the solvent by vacuum distillation and chromatograph on silica gel with an appropriate eluent, for example, AE / MeOH 5: 1. (formation of salt, compare variant A) Example 1: 2,3-dimethoxy-5-trifluoromethyl-benzoylguanidine hydrochloride: colorless crystals P.f. 166 * C (with decomposition) Synthesis path: a) 2-Chloro-3-iodo-5-trifluoromethyl-benzoic acid methyl ester from 2-chloro-5-trifluoromethyl-benzoic acid methyl ester by reaction with 1 equivalent of N-iodo-succinimide in 5 equivalents of trifluoromethosulfonic acid at RT for 24 h, colorless oil, (M + H) +: 364 b) 2,3-dimethoxy-5-trifluoromethyl-benzoic acid from ester 2-Chloro-3-iodo-5-trifluoromethyl-benzoic acid methyl ester (1 a) by reaction with 10 equivalents of a 30% sodium methylate solution in the presence of 0.25 equivalents of copper (II) chloride in Absolute DMF at reflux in the course of 1 h. Aqueous treatment and extraction with EA provide a brownish oil. (M + H) +: 251 c) 2, 3-dimethoxy-5-trifluoromethyl-benzoylgua-nidine hydrochloride from 1) according to process A, colorless crystals, P.f. 166 * C (with decompositions: .tion).

Example 2: 2-Methoxy-3-iodo-5-trifluoromethyl-benzoylguanidine hydrochloride: colorless crystals, P.f. 150 'C (with decomposition) Synthetic route: a) 2-Methoxy-3-iodo-5-trifluoromethyl-benzoic acid from 1 a) by reaction with 1.1 equivalents of a 30% sodium methylate solution in the presence of 0.3 equivalents of copper (II) chloride in absolute DMF at room temperature within 2 h. Aqueous treatment and extraction with EA provide colorless crystals, P.f. 120-125 * C b) 2-Methox: .- 3-iodo-5-trifluoromethyl-benzoyl-guanidine hydrochloride from 2a) according to process A, colorless crystals, P.f. 150 'C (with decomposition) Example 3: Hydrochloride of; 2-methoxy-3-cyclopentyl-5-rifluorome-il-benzoylguanidine: colorless crystals, P.f. 210"C (with decomposition) Synthetic route: a) 2-Chloro-3-cyclopentyl-5-trifluoromethyl-benzoic acid methyl ester from 1 a) by cross-coupling with 1.5 equivalents of cyclopentyl-zinc chloride (from cyclopentyl-magnesium chloride by transmetallation with zinc chloride (II) -theory in THF) by stirring at room temperature in the presence of [1, 1 '-bis- (diphenylphosphino) -ferrocene] aladium (II) chloride ) catalytic and copper iodide (I), aqueous treatment, extraction with ethyl acetate and column chromatography on silica gel with ethyl acetate / n-heptane (3: 7), colorless oil (M + H) + : 306 b) 2-Methoxy-3-cyclopentyl-5-trifluoromethyl-benzoic acid by reaction with 10 equivalents of a 30% sodium methylate solution in the presence of 0.25 equivalents of copper (II) chloride in absolute DMF at reflux in the course of 1 h. Aqueous treatment and extraction with EA provide a colorless oil, (M + H) +: 289 c) 2-Methoxy-3-cyclopentyl-5-trifluoromethyl-benzoylguanidine hydrochloride starting from 3b) according to process A, colorless crystals, P.f. 210 * C (with decomposition) Example 4: 2-Methoxy-5-trifluoromethyl-benzoylguanidine hydrochloride: colorless crystals P.f. 208 * C (with decomposition) Synthesis route: a) 2-Methoxy-5-trifluoromethyl-benzoic acid from 2-chloro-5-trifluoromethyl-benzoic acid methyl ester by reaction with 10 equivalents of a 30% sodium methylate solution in the presence of 0.25 equivalents of copper (II) chloride in absolute DMF at 100 * C over the course of 1.5 h.

Aqueous work-up and column chromatography provide colorless crystals, P.f. 108-110'C b) 2-methoxy-5-trifluoromethyl-benzoylguanidine hydrochloride starting from 4a) according to process A, colorless crystals, P.f. 208 'C (with decomposition) Example 5: 2-Methoxy-4-methyl-benzoylguanidine hydrochloride: colorless crystals P.f. 213'C. Synthesis path: a) 2-Methoxy-4-methyl-benzoic acid from 2-chloro-4-methyl-benzoic methyl ester analogously to 3b), colorless solid material, P.f. 212 * C. b) 2-methoxyl hydrochloride: L-4-methyl-benzoylguanidine from 5a) according to the general prescription.

Example 6: 3,5-bis-t-bu-il-2-methoxybenzoylguanidin hydrochloride: colorless crystals, P.f. 114 * C. Synthesis route • a) 2,5-bis-t-butyl-2-methoxy-benzoic acid methyl ester from 3,5-bis-t-butyl-salicylic acid methyl ester by methyl iodide in presence of potassium carbonate in DMF, colorless oil, vM + H) + = 278. b) 3, 5-bis-t-butyl-2-methoxy-benzoylguanidine hydrochloride starting from 6a) according to the general prescription.

Example 7: 2,4-dimethoxy-5-trifluoromethyl-benzoylguanidine hydrochloride: colorless crystals, P.f. 207 ° C. Synthesis route: a) 2,4-dimethoxy-5-bromo-benzoic acid methyl ester from 5-bromo-2,4-hydroxy-benzoic acid by means of methyl iodide in DMF in the presence of potassium carbonate, crystals colorless, Pf 115'C. b) 2-4-Dimethoxy-5-tpfluoromethyl-benzoic acid methyl ester from 7a) by heating to 90 ° C with potassium trifluoroacetate in NMP in the presence of copper iodide (I), colorless crystals, Pf .: 125"C. c) 2,4-Dimethoxy-5-trifluoromethyl-benzoylgua-nidine hydrochloride from 7a) according to the general prescription.

Pharmacological data: Inhibition of the exchanger between Na + and H + of rabbit erythrocytes White rabbits of New Zealand (Ivanovas) received a standard diet with 2% cholesterol for six weeks, in order to activate the exchange between Na + and H + and thus determine the incoming Na + flow in the erythrocytes through the exchange between Na + and H +, by flame photometry. The blood was extracted from the arteries of one ear and made uncoagulable by 25 IU heparin-potassium. A part of each sample was used for the double determination of the hematocrit by centrifugation. Aliquots in each case of 100 μl were used for the measurement of the starting Na + content of the erythrocytes. To determine the incoming influx of amiloride sensitive sodium, 100 μl of each blood sample was incubated in each case in 5 ml of a hyperosmolar medium of common salt and sucrose (mmol / l: 140 NaCl, 3 KC1, 150 sucrose, 0.1 ouabain, 2 tris-hydroxymethyl aminomethane) at a pH of 7.4 and 37"C. The erythrocytes were then washed three times with an ice-cold solution of MgCl2 and ouabain (mmol / l). 1: 112 MgCl2, 0.1 ouabain) and hemolyzed in 2.0 ml of distilled water The intracellular sodium content was determined by flame photometry The net inflow of Na + was calculated from the difference between the sodium starting values and the sodium content of the erythrocytes after incubation The incoming sodium influx inhibitable with amiloride was established from the difference in the sodium content of the erythrocytes, after incubation with and without amyloid, 3 x 10 ~ 4 mmol / 1. In this way, the compounds according to the invention were also used.

Results Inhibition of the Na + / H + exchanger: Example Cl50 (mol / l) 1 0.053 x 1 0 ~ 6 2 0.01 7 x 1 0 ~ 6 5 1 0"6 6 1 x 10" 6 7 0.2 x 10"6

Claims (16)

1. Claims i.- Ortho-substituted benzoylguanidines of the formula I where they mean: R (l) H, F, Cl, Br, I, CN, N02, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, alkoxy with 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, cycloalkoxy with 3, 4 , 5, 6, 7 or 8 C atoms or
2. Xa- (CH2) b- (CF2) c-CF3; X oxygen, S, NR (5), zero or 1; b zero, 1 or 2; c zero, 1, 2 or 3; R (5) H, alkyl having 1, 2, 3 or 4 carbon atoms or -CdH2dR (6): d, 1, 2, 3 or 4; R (6) cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, phenyl, biphenylyl or naphthyl, the aromatic radicals being phenyl, biphenylyl or naphthyl unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR (7) R (8); R (7) and R (8), independently of one another, H or alkyl with 1, 2, 3 or 4 C atoms; or R (l) -SR (10), -OR (IO) OR -CR (10) R (11) R (12); R (10) -CfH2f-cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms in the cycloalkyl ring, or phenyl, the phenyl being unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxy, amino, methylamino and dimethylamino; f zero, 1 or 2; R (ll) and R (12) are defined independently from each other as R (10) or denote hydrogen or alkyl having 1, 2, 3 or 4 C atoms; or R (l) phenyl, naphthyl, biphenylyl or heteroaryl with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, the latter being linked through a C or N ring atom , which in each case are unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxy, amino, methylamino and dimethylamino, or R (l) -SR (13) , -0R (13), -NHR (13), -NR (13) R (14), -CHR (13) R (15), -C [R (15) R (16) OH], -C = CR (18), -C [R (19)] = CHR (18), -C [R (20) R (21)] k- (CO) - [CR (22) R (23)]? - R (24), zero k, 1, 2, 3 or i; 1 zero, 1, 2, 3 or 4; R (13) and R (14) equal or different, - (CH2) g- (CH0H) h- (CH2) i- (CHOH) jR (17) or - (CH2) g-0- (CH2-CH20) hR (24): R (17) hydrogen or methyl, g, hei equal or different, zero, 1, 2, 3 or 4; j zero, 1, 2, 3 or 4;
3. R (15) and R (16) equal or different, hydrogen, alkyl with 1, 2, 3, 4, 5 or 6 C atoms or, in common with the carbon atom carrying them, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms; R (18) phenyl, which is ein substituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR (25) R (26); R (25) and R (26) H or alkyl with 1, 2, 3 or 4 C atoms; or R (18) heteroaryl with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, which is unsubstituted or substituted the same as phenyl; or R (18) alkyl having 1, 2, 3, 4, 5 or 6 C atoms, which is unsubstituted or substituted with 1-3 OH; or R (18) cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms; R (19), R (20), R (21), R (22) and R (23) equal or different, hydrogen or methyl; R (24) H, alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 carbon atoms or
4. -CmH2m-R < 18 >; m 1, 2, 3 0 4; R (2) and R (3) as defined R (l); R (4) alkyl having 1, 2, 3 or 4 C atoms; as well as its pharmaceutically compatible salts. 2. Compounds of the formula I according to the claim 1, characterized because e. this means: R (l) H, F, Cl, Br, I, CN, N02, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, alkoxy with 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, cycloalkoxy or C 3, 4, 5, 6, 7 or 8 C atoms or
5. Xa- (CH2) b- (CF c-CF3; X oxygen, at zero or 1; b zero, 1 or 2; c zero, 1, 2 or 3; or R (l) -SR { 10) Ó -OR (10); R (10) -CfH2f-cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms in the cycloalkyl ring, or phenyl, the phenyl being unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxy, amino, methylamino and dimethylamino; f zero or 1; or R (l) phenyl, naphthyl, biphenylyl or heteroaryl with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, the latter being linked through a C or N ring atom, which are unsubstituted or substituted with 1-3 selected substituents of the group consisting of F, Cl, CF3, CH3, methoxy, hydroxy, amino, methylamino and dimethylamino, or R (l) -SR (13), -ORU3), -NHRÜ3), -NR (13) R (14 ), -CSCR (18) OR -C [R (19)] = CHR (18), R (13) and R (14) equal or different, - (CH2) - (CHOH) h- (CH2) i- (CHOH) jR (17) or - (CH2) g-0- (CH2-CH20) hR (24); R (17) hydrogen or methyl, g, h and i equal or different, zero, 1 or 2, • j 1 or 2;
6. R (18) phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR (25) R (26); R (25) and R (26) H or alkyl with 1, 2, 3 or 4 C atoms; or R (18) heteroaryl with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, which is unsubstituted or substituted the same as phenyl; or R (18) alkyl having 1, 2, 3, 4, 5 or 6 C atoms, which is unsubstituted or substituted with 1-3 OH; OR R (18) cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms; R (19) hydrogen or methyl, - R (2) and R (3) as defined Rll); R (4) alkyl with 1 or 2 C atoms. 3. Compounds of the formula I according to claim 1 or 2, characterized in that they mean: R (l) H, F, Cl, alkyl with 1, 2, 3 or 4 C atoms, alkoxy with 1, 2, 3 or 4 C atoms, cycloalkyl with 5 or 6 C atoms, cycloalkoxy with 5 or 6 C atoms or Xa- (CF2> c-CF3 'X oxygen , at zero or 1; c zero or 1; or R (l) -SR (10) or -OR (10); R (10) cycloalkyl with 4, 5 or 6 C atoms, or phenyl, the phenyl being substituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxy, amino, methylamino and dimethylamino; or R (l) quinolyl, isoquinolyl, pyridyl, which are attached through a C or N ring atom, and are unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxy, amino, methylamino and dimethylamino, or R (l) phenyl, which is unsubstituted or substituted with 1-3 substituyent is selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxy, amino, methylamino and dimethylamino, or R (l) -C = CR (18); R (18) phenyl or cycloalkyl, with five or 6 carbon atoms;
7. R (2) and R (3) as defined R (l); R (4) methyl. 4. - Compounds of the formula I according to one of claims 1 to 3, characterized in that they mean:
8. R (l) H, F, Cl, alkyl with 1, 2, 3 or 4 C atoms, alkoxy with 1, 2, 3 or 4 C atoms, cycloalkyl with 5 or 6 C atoms, cycloalkoxy with 5 or 6 C or Xa-CF3 atoms; X oxygen at zero or 1; R (2) and R (3) as defined R (l); R (4) methyl. 5. Process for the preparation of a compound I according to claim 1, characterized in that a compound of the formula II is reacted with guanidine in which R (l) to R (4) have the meanings indicated and L represents a group labile easily replaceable nucleophilically. 6. - Use of a compound I according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of diseases caused by ischemic conditions. 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. 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 intended for the treatment or prophylaxis of ischemic states of the peripheral and central nervous systems 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 extremities.
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 intended for use in surgical operations and organ transplants.
14. 14. - Use of a compound I according to claim 1 for the preparation of a medicament intended for the preservation and storage of transplanted organs for surgical measures.
15. 15. - Use of a compound I according to claim 1 for the preparation of a medicament for the treatment of diseases, in which cell proliferation is a primary or secondary cause, and therefore its use for the preparation of an antiatherosclerotic agent, an agent against late diabetic complications, cancerous diseases, fibrotic diseases, such as pulmonary fibrosis, liver fibrosis or renal fibrosis, and prostate hyperplasia.
16. 16. Medicament, characterized by an effective content of a compound of the formula I according to claims 1 to 4.