MXPA96005675A - Diguanididas of bencenodicarboxilicos substitute acids, procedure for its preparation, its employment as a diagnostic medicine or agent, as well as a medication that the - Google Patents

Abstract

Diabenanidides benzenedicarboxylic acids of the formula I (See Formula) wherein R (1) to R (5) have the meanings indicated in the claims, are valuable antiarrhythmic drugs with a cardioprotective component, also for the prevention of ischemia-induced lesions, in particularly in the triggering of heart arrhythmias induced by ischemia. As a consequence of the inhibition of the cellular exchange mechanism of Na + / H +, they are used for the treatment of acute or chronic lesions triggered by ischemia. In addition, they are distinguished by a strong inhibitory effect on cell proliferations. They are adequate to avoid the genesis of blood hypertension

Description

Diguanidides of substituted benzenedicarboxylic acids, process for their preparation, their use as a medicament or diagnostic agent, as well as medicament containing them The invention relates to diguanidides of benzenedicarboxylic acids of the formula I where one of the radicals R (l), R (2), R (3) and R (5) means -CO-N = C (NH2) 2; and the respective other radicals R (l), R (2), R (3) and R (5): R (1) and R (5) signify, independently of one another, hydrogen, alkyl with 1, 2, 3 or 4 C atoms, F, Cl, -OR (32), -NR (33) R (34) or CF3; R (32), R (33) and R (34) signify, independently of one another, hydrogen or alkyl with 1, 2, 3 or 4 C atoms; R (2) means hydrogen, F, Cl, Br, I, OH, -CN, CF3, -CO-N '= 0 (NH2) 2, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, alkenyl with 2, 3, 4, 5, 6, 7 or 8 C atoms or - (CH 2) a R (14); m means zero, 1 or 2; R (14) means cycloalkyl (C ^ -C) or phenyl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F and Cl, -CF} . methyl, methoxy and -VR (15) R (16); R (15) and R (16) signify, independently of one another, hydrogen or -CH 3; or R (2) means R (22) -SOj-, R (23) (2) N-CO-, R (28) -CO- or R (29) R (30) N-SO2-; R (22) and R (28) signify, independently of one another, 1 methyl or -CF,; R 23), R (24), R (29) and R (30) signify, independently of one another, hydrogen or meth; or R (2) means -OR (35) or -NR (35) R (36); R (35) and R (36) signify, independently of one another, hydrogen or alkyl with 1, 2, 3, 4, 5 or 6 C atoms; or R (35) and R (36) together mean 4-7 metal groups, of which a CH group can be replaced with oxygen, -S-, -NH-, -NCH3 or -N-benzyl; R (3) means hydrogen, -SR (25), -OR (25), -NR (25) R (26), -CR (25) R (26) R (27); R (25) means hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms or phenyl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F , Cl, CF < CH3, ethoxy, hydroxy, amino, methylamino and dimethylamino; or R (25) means heteroaryl (C, -C5), which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxy, amino, methylamino and dimethyl i miss; R (26) and R (27), independently of one another, are defined as R (25) or denote hydrogen or alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C atoms; R (4) means CFj, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, alkenium with 2, 3, 4, 5, 6, 7 or 8 C atoms, 1-alkyl (CJ-CJ) or - (CHj) "R (14); m means 1 or 2; R (14) means cycloalkyl (Cj-Cj) or phenyl, which is unsubstituted or substituted by 1-3 its thiomers chosen from the group consisting of F and Cl, -CF3, methyl, methoxy and -NR (15). ) R (16); R (15) and R (16) signify, independently of one another, hydrogen or -CHj; or R (4) means phenyl which is substituted with 2, 3, 4 or five substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and -NR (15) R (16); R (15) and R (16) signify, independently of one another, hydrogen or CHj; as well as its pharmaceutically compatible salts. Preference is given to compounds of the formula I, in which: one of the radicals R (l), R (2), R (3) and R (5) means -CO-N = C (NH2) 2; and the respective other radicals R (1), R (2), R (3) and R (5): R (1) and R (5) mean, independently of one another, hydrogen, alkyl with 1, 2, 3 or 4 atoms of C, F, Cl, -OR (32) or CF3; R (32) means hydrogen or alkyl with 1, 2, 3 or 4 C atoms; R (2) means hydrogen, F, Cl, Br, I. OH, CF3, alkyl with 1, 2, 3 or 4 C atoms, alkenyl with 2. 3 or 4 C atoms or - (CH,), RI 14); m means zero, 1 or 2; R (14) means cycloalkyl (Cj-Cg) or phenyl, which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F and Cl, -CF3, methyl and methoxy; or R (2) means R (22) -SOj-, R (23) R (24) N-CO-, R (28) -CO- or R (29) R (30) N-SO2-; R (22) and R (28) signify, independently of one another, methyl or -CF,; R (23), R (24), R (29) and R (30) signify, independently of one another, hydrogen or meth; or R (2) means -OR (35) or -NR (35) R (6); R (35) and R (36) signify, independently of one another, hydrogen, methyl or ethyl; or R (35) and R (36) together mean 4-5 metal groups, of which a CH2 group can be replaced with oxygen, -S-, -NH- or -NCH ,; R (3) means hydrogen, -SR (25), -OR (25), -NR (25) R (26) or -CR (25) R (26) R (27); R (25) means hydrogen, alkyl having 1, 2, 3 or 4 C atoms or phenyl, which is unsubstituted or substituted with 1-2 substituents chosen from the group consisting of F, Cl, CFj, CHj , methoxy and dimethylam not; or R (25) means heteroaryl (Cj-C9, which is unsubstituted or is substituted by 1-2 its titerants chosen from the group consisting of F. Cl, CFj, CH-, methoxy and dimethylamine; R (26) and R (27) signify, independently of one another, hydrogen or alkyl with 1, 2, 3 or 4 C atoms; R (4) means -CFj, alkyl with 1, 2, 3, 4, 5 or 6 C atoms, alkenyl with 2, 3, 4, 5 or 6 C atoms, cycloalkyl (Cj-Cg) or - CH2R (14); R (14) means cycloalkyl (Cj-Cg) or phenyl, which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F and Cl, -CFj, methyl and methoxy; or R (4) means phenyl which is substituted with 2, 3, 4 or five substituents selected from the group consisting of F, Cl, CF,, methyl and methoxy; as well as its pharmaceutically compatible salts. Particularly preferred are compounds of the formula I, wherein: one of the radicals R (l), R (2), R (3) and R (5) means -CO-N = C (NH2) 2; and the respective other radicals Rll), R (2), R (3) and R (5): R (l) and R (5) signify, independently of one another, hydrogen, alkyl with 1, 2, 3 or 4 C, F, Cl, OH, methoxy or CFj atoms; R (2) means hydrogen, F, Cl, OH, CF,, alkyl having 1, 2, 3 or 4 carbon atoms, alkenium having 2, 3 or 4 carbon atoms or - (CHj) "R (14); m means zero, 1 or 2; R (14) means cycloalkyl (Cj-C or phenyl, which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F and cl, -CFj, methyl and methoxy; or R (2) means R (22) -SO, - .R (23) R (24) N-CO- .R (2S) -CO- or R (29) R (30) N-SO2; R (22) and R (28) signify, independently of one another, methyl or -CF,; R (23), R (24), R (29) and R (30) signify, independently of one another, hydrogen or meth; or R (2) means -OP (35) or -NR (5) R (6); R (35) and R (36) signify, independently of one another, hydrogen, methyl or ethyl; or R (35) and R (36) together mean 4-5 metal groups, of which a CH2 group can be replaced with oxygen, -S-, -NH- or -NCH3; R (3) means hydrogen, -SR (25), -OR (25), -NR (25) R (26) or -CR (25) R (26) R (27); R (25) means hydrogen, alkyl having 1, 2, 3 or 4 C atoms or phenyl, which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F, Cl, CFj, CHj, methoxy and dimethylamino; or R (25) means heteroaryl (Cj-C *), which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F, Cl, CFj, CHj, methoxy and dimethylamine; R (26) and R (27) signify, independently of one another, hydrogen or alkyl with 1, 2, 3 or 4 C atoms; R (4) means CF.,, alkyl with 1, 2, 3, 4, 5 or 6 C atoms, alkenyl with 2, 3, 4, 5 or 6 C atoms, cycloalkyl (C-C3) or -CH2R (14); R (14) dignifies cycloalkyl IC-C ^) or fenium. which is not substituted or substituted by 1-2 substituents selected from the group consisting of F and Cl, -CF, methyl and methoxy; or R (4) means phenyl which is substituted with 2, 3, 4 or five substituents selected from the group consisting of F, Cl, CF,, methyl and methoxy; as well as its pharmaceutically compatible salts. Particularly preferred are compounds of formula I, wherein: one of the radicals R (l), R (2), R (3) and R (5) means -C0-N = C (NH,) ,; and the respective other radicals R (1), R (2), R (3) and R (5): R (1) and R (5) mean, independently of one another, hydrogen, alkyl with 1, 2, 3 or 4 atoms of C, F, Cl, OH, methoxy or CFj; R (2) means hydrogen, F, Cl, OH, CF,, alkyl having 1, 2, 3 or 4 carbon atoms or - (CHj) BR (14); m means zero, 1 or 2; R (14) means cycloalkyl (Cj-Cg) or phenyl, which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F and Cl, -CF3, methyl and methoxy; or R (2) means -OR (35) or -NR (35) R (36); R (35) and R (36) signify, independently of one another, hydrogen, methyl or ethyl; or R (35) and R (36) together mean 4-5 methylene groups, of which a CH2 group can be replaced with oxygen, -S-, -NH- or -NCH,; R (3) means hydrogen or -OR (25): R (25) means hydrogen, alkyl having 1, 2, 3 or 4 C atoms or phenyl, which is unsubstituted or substituted by 1-2 substituents of the group of F, Cl, CF ,, CH, and methoxy: or R (25) means heteroaryl (Cjj), which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F, Cl, CF,, CH ^ and methoxy; R (4) means CFj, alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, alkenyl with 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl (Cj-Cg) or -CH2R14); R (14) means cycloalkyl (Cj-C8) or phenyl, which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F and Cl, -CFj, methyl and methoxy; or R (4) means phenyl which is substituted with 2, 3, 4 or five substituents selected from the group consisting of F, Cl, CFj, methyl and methoxy; as well as its pharmaceutically compatible salts. The designated alkyl radicals can be present in straight-chain or branched form. Heteroaryl (C.sup.-C?) Is understood to mean 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 a ring) five-membered aromatic) are replaced by S, NH or O. In addition to this, also one or both atoms of the condensation site of cyclic b-radicals (such as in indo 1 iz ini lo) can be N atoms. As heteroaryl particularly suitable are furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl-1, pyridyl. pyrazinyl, pyrimidinyl, pyridazinyl. indolyl, indazolyl, quinolyl, i soqu i no 1 i 1o, phthalazinyl, quinoxal ini lo, quinazo 1 ini lo, cinolinilo. If one of the substituents Rl l) to R (5) contains one or more centers of asymmetry, then these can have, independently of one another, both the S configuration and also the R. The compounds can be in the form of isomers optical, as diastereoisomers, as racemates or as mixtures thereof. The invention also relates to a process for the preparation of compounds I, characterized in that compounds of formula II R (2 ') wherein R (l ') to R (5') have the meanings indicated above for R (l) to R (5), but of which at least one of the substituents R (l ') to R (5) ') is the COL group drawn, where L represents substitutable and slightly nucleophilic labile groups, are reacted with guanidine. The activated acid derivatives of the formula II, wherein L means an alkoxy group, preferably a methoxy group or a phenoxy group, a phenylthio group, methylthio, 2-pyridylthio, or a nitrogen heterocycle, preferably 1-imidazole are advantageously obtained in a manner known per se from the carboxylic acid chlorides on which they are based (formula II, L = Cl) which, in turn, can again be prepared in a manner known per se from the carboxylic acids on which they are based (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 benzenedicarboxylic acid derivatives in which are based (formula II, L = OH), such as for example the methyl esters of the formula II with L = OCHj by treatment with gaseous HC1 in methanol, the imidazolides of the formula II by treatment with carboni ldi imidazole [L = 1 --imidazole i, Staab, Angew. Che. Int. Ed. Engl. 1, 351-367 (1962)], the mixed anhydrides II with Cl-COOC ^ tosyl chloride in the presence of triet and lamin in an inert solvent, as well as the activations of benzenedicarboxylic acid 1 i-cos with dicyclohexyl 1 carbodi i ida (DCC) or with O- [t et raf luoro-borato de (cyano (ethoxycarboni Pmet i len) amino] -1,1, 3,3-tetramet i luronium] ("TOTU") [Proceedings of the 21. European Peptide Symposium, Peptides 1990. Editors E. Giralt and D. Andreu, Escom, Leiden, 1991. A number of methods suitable for the preparation of activated carboxylic acid derivatives of the general formula II are indicated with the reference to the source literature in J. March, Advanced Organic Chemistry, third edition (John Wiley &Sons, 1985), page 350. The reaction of an activated carboxylic acid derivative of formula I with guanidine is effected by known in a polar organic solvent, protic or aprotic, but inert, in this case, in the The methyl esters of benzenedicarboxylic acids (II, L = OMe) with guanidine have proved to be methanol, isopropanol or THF between 208C and the boiling point of these solvents. In the majority of the reactions of the compounds II with guanidine free of salts it was advantageously worked in inert solvents, such as THF, dimethoxyethane, dioxane or isopropanol. However, water can also be used as a solvent. When L means Cl, it is advantageously carried out with the addition of an acid scavenger, for example in the guanidine form in excess, for the liberation of the halogenated hydrazide. The introduction of the substituted compounds in the phenyl part with nucleophiles of sulfur, oxygen or nitrogen is achieved by methods known in the literature for nucleophilic substitution in derivatives of dialkyl esters of benzenediolic acids. As a labile group in the benzenedicarboxylic acid derivative, halides and t rif luoromethanesulphonates have been proven in this substitution. Advantageously, it is worked in an aprotic dipolar solvent, such as DMF or TMU, at a temperature of OQC up to the boiling point of the solvent, preferably of 80 ° C. up to the boiling point of the solvent. Advantageously, an alkaline metal or alkaline earth metal salt with an anion of high basicity and low nucleophilicity, for example CO, or CsCO, is advantageously used as acid scavengers. The introduction of the alkyl or aryl substituents is achieved by methods known from the palladium-induced cross coupling literature of aryl halides. for example with organic zinc compounds, tannanal organoes, organoboronic acids or organoboranes. Diguanidides of benzene carboxylic acids I are usually 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, ascorbates, lactates, sulfates, citrates, tartrates, acetates, phosphates, methyl sulphates, p-to luenosul fonatos.

In the U.S. patent specification 5 091 394 (HOE 89 / F 288) and in European publication specification 0 556 674 (HOE 92 / F 034) there are described benzoyl lguanidines, but not diguanidides of benzenedicarboxylic acids. From WO 94/26709 a benzo i Iguanid i na is known which in position 5 contains a nitrophenyl substituent. However, from these documents, 5-pheni-1-benzoi-1 guanidines are not known to be released several times. The compounds are extraordinarily suitable, as a result of their pharmacological properties, 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 pectoris, and can also inhibit or reduce strongly Preventive the pathophysiological processes in the formation of ischemia-induced lesions, particularly in the development of • heart arrhythmias induced by ischemia. Due to their protective effects against hypoxic and pathological ischemic situations, the compounds of the formula I according to the invention can be used, as a consequence of the inhibition of the cellular Naf / Hf exchange mechanism, as medicaments for the treatment of all Acute or chronic injuries triggered by ischemia or diseases induced in a primary or secondary way by the previous ones. This affects their employment as medicines for surgical interventions, for example in the case of organ transplants, the compounds can be used both for the protection of the organs in the donor, before and during the extraction, for the protection of the extracted organs, for example in the treatment with or its storage in physiological bath liquids, as well as in the transplant in the recipient organism. The compounds are also valuable drugs with protective action 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 (CNS), for example being suitable for the treatment of apoplexy or of cerebral edema. In addition, the compounds of the formula I according to the invention are also suitable for treatment of forms of shock, such as, for example, allergic shock, cardiogenic, hypovolemic and bacterial shock. In addition, the compounds of the formula I according to the invention are distinguished by a strongly inhibitory effect on cell proliferation, for example the proliferation of fibroblast cells and the proliferation of the smooth muscle of the vessels. Therefore, the compounds of the formula I come into consideration as valuable therapeutic agents for diseases in which the proliferation of cells is a primary or secondary cause and, therefore, can be used as an antiatherosclerosis. - agents, agents against late diabetic complications, carcinogenic diseases, fibrotic diseases, such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, hypertrophies and hyperplasias of the organs, in particular in the case of prostate hyperplasia or hypertrophy of the prostate . The compounds according to the invention are very active inhibitors of the sodium proton cell antiporter (Na / H exchanger), which is increased in numerous diseases (essential hypertension, atherosclerosis, diabetes, etc.), also in those cells which are easily accessible for measurements, such as e.g. in erythrocytes, thrombocytes or leukocytes. Therefore, the compounds according to the invention are suitable as extraordinary and simple scientific tools, for example in their use as diagnostic agents to determine and differentiate certain forms of hypertonia, but also of atherosclerosis, diabetes, pro-active 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. With respect to most of the known compounds, the compounds according to the invention have a significantly improved water solubility. Therefore, they are essentially better suited for the application i.v .. The compounds according to the invention are distinguished, with respect to the known compounds with good solubility in water, by their better bioavailability and pharmacokinetics. The drugs containing a compound I can be administered in this case orally, parenterally, intravenously, rectally or by inhalation, depending on the preferred administration of the respective clinical picture of the disease. In this case, the compounds I can be used alone or together with galenic adjuvants, namely in veterinary medicine as well as in human medicine. By virtue of their scientific knowledge, it is usual for the expert in the field to know which adjuvants are suitable for the desired drug formulation. In addition to solvents, gel formers, suppository bases, tablet adjuvants and other active ingredients, antioxidants, dispersants, emulsifiers, defoamers, flavor correctors, preservatives, dissolving agents or dyes can be used. For an oral administration form, the active compounds are mixed with the additives suitable for eyl, such as support substances, stabilizers or inert diluents and are taken to suitable administration forms, such as tablets, dragees, plug-in capsules, solutions watery, alcoholic or oily, by the usual methods. Suitable inert carriers are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. In this case, the preparation can be carried out either in the form of dry granules or also in the form of wet granules. 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 to solution, suspension or emulsion, if desired with the usual substances for this, such as dissolution promoters, emulsifiers or other adjuvants. Suitable solvents are, for example, water, physiological sodium chloride solution or alcohols, for example ethanol, propanol, glycerol and, together with them, also sugar solutions, such as glucose or mannitol solutions, or else a mixture based on the different solvents mentioned. As a pharmaceutical formulation for administration in the form of aerosols or sprays, for example, solutions, suspensions or emulsions of the active compound of the formula I in a pharmaceutically innocuous solvent, such as in particular ethanol or water, or in a mixture of such solvents are suitable. As required, the formulation may also contain other pharmaceutical adjuvants, such as tsectives, emulsifiers and stabilizers, as well as a propellant gas. A preparation of this type contains the active ingredient usually in a concentration of from about 0.1 to 10, in particular from about 0.3 to 3% by weight. The dosage of the active principle of the formula I to be administered and the periodicity of the administration depend on the power of action and the duration of the effect of the compounds used.; in addition, also the type and severity of the disease to be treated, as well as the sex, age, weight and individual response capacity of the mammal to be treated. On average, the daily dose of a compound of the formula I amounts, in a patient of approximately 75 kg in weight, to at least 0.001 mg / kg of body weight, preferably at least 0.01 mg / kg of body weight. body weight up to at most 10 mg / kg of body weight, preferably up to at most 1 mg / kg of body weight. In the case of acute manifestations of the disease, for example immediately after having suffered a heart infarction, even higher and, above all, more periodic dosages may be necessary, for example up to 4 individual doses per day. In particular, in the case of an i.v. application, for example in a heart attack patient in the Intensive Care Unit, up to 100 mg per day may be necessary.

List of abbreviations: Bn bencilo sa lmuera so l uc l onal water of NaC l sétturada CH? 2 C I? idiclo rome t ano DCI chemical ionization by desorption DIP di isopropi 1 ether DMA di eilacet mide DME imethoxy DMF N, Nd? met i 1 for amide EE ethyl acetate (EtOAcí The impact of electrons eq equivalent ES ionization by e lect roaton Ethyl FAB bombardment with fast atoms HEP n-heptane HOAc acetic acid Me meth i lo MeOH methanol pf melting point MTB methyl tertiary butyl io-ether NBS N-bromosuccinimide NMP N-met i Ipirrol idona TA room temperature THF tetrahydrofuran TUN, N, N ', N'-tetramet i 1urea Tol toluene SNC central nervous system Experimental part General prescription for the preparation of diguanidides of benzenedicarboxylic acids (I) from dialkyl esters of benzenedicarboxylic acids (II, L = O-alkylo) mmol of the dialkylene ester of benzenedi-carboxylic acid of the formula II, as well as 50 millimoles of guanidine (free base) are dissolved in 5 ml of isopropanol and boiled under reflux (typical reaction time, 5 minutes to 5 h) until Complete conversion (thin layer control). It is then diluted with 150 ml of water and the product is filtered off with suction. Eventually, it was chromatographed on silica gel with a suitable eluent, for example EE / MeOH 5: 1.

Example 1: djaguanidide of 5-t-butyl and i-isophtalic acid 2.9 g of dimethyl ester of 5-t-butyl-1-γ-sophone are reacted (reaction time, 10 minutes) according to the general prescription for the preparation of diguanidides of benzenedicarboxylic acids (I). 2.7 g of white crystals, m.p. > 270QC. Rf (acetone / water 10: 1) = 0.13 MS (ES): 305 (M + H) * Example 2: diguanidide of 5- [3,5-bis (trifluoromethyl) phenyl] -isophthalic acid 600 mg of dimethyl ester of 5- [3,5-bis (t-ri-romoet-i-1-phenyl-1-isophthalic acid) are reacted (reaction time, 10 minutes) according to the general prescription for the preparation of diguanidides of benzenedicarboxylic acids 5 (I). 580 mg of white crystals, m.p. 248OC with decomposition. Rf (acetone / water 10: 1) = 0.21 MS (FAB): 461 (M + H) 1- 2a: Dimethyl acid 5- [3,5-bis (trifluoromet i 1) fe-10 nor 1] -isophtalic ester 3,73 g of 5-bromo-isophtalic acid dimethyl ester, 2.74 g of acid 3, 5-bis (t ri f luoro et i 1) feni lbórico, 2.1 g of Na 2 CO 3, 225 mg of acetate of t > ú l) and 525 mg of triphenylphosphine are stirred in 100 ml of toluene and 20 ml of water for 3 h at 100QC. Allow to cool, dilute with 200 ml of EA and extract twice, in each case with 100 ml of saturated aqueous NaHCO solution. Dry over Na 2 SO 4, and remove the solvent in vacuo. Silica gel chromatography with EE / HEP 1: 8 provides 1.3 g of a material pale yellow solid, m.p. 151QC. Rf (EE / HEP 1: 8) = 0.21 MS (FAB): 407 (M + H) * The compounds of the statement of Examples 3-5 are synthesized analogously to Example 2, and the previous steps of dimethyl ester are they obtain analogously to 2a. '' s Example 3: diguanidide of 5- (3,5-dichloropheni-1) -isophthalic acid H r2N p.f. 250QC with decomposition Rf (acetone / water 10: 1) = 0.13 MS (ES): 393 (M + H) Example 4: diguanidide of 5- (2,4-dichlorophenyl) -isophthalic acid p.f. > 250QC with decomposition Rf (acetone / water 10: 1) = 0.15 MS (ES): 393 (M + H) f Example 5: diguanidide of 5- (-cioro-4-fluorofeni 1) • -isophtal ico acid p.f. 231QC with decomposition R acetone / water 10: 1) = 0.L4 MS (ES): 37"(M + H) 1 Example 6: diguanidide of 5-cyclohexene 1-isophthalic acid a) Dimethyl 5-cyclohexene 1-isophthalic acid ester To 100 ml of a 0.5 M ZnC solution in THF, 22 ml of a 2 M solution of cyclohexylmagnesium chloride in diethyl ether are added dropwise. It is stirred for 5 h at 50 ° C., and the organic zinc compound is subsequently directly reacted as solution A. 39 g of 5- isophthalic acid dimethyl ester, 420 mg of [1, 1-bis (diffe-ni Ifosf ino) ferrocen] Pd (11) chloride and 130 mg of Cul are suspended in 70 ml of THF. At RT the solution A is then added dropwise and stirred for S h at this temperature. The reaction mixture is poured into 300 ml of saturated NaHCO aqueous solution, diluted with 100 ml of water, the precipitate is separated by filtration and extracted 4 times in each case with 200 ml of EA. Dry over Na2SOj, and remove the solvent in vacuo. Chromatography on silica gel with EE / HEP 1: 4 provides 2.7 g of a colorless oil. Rf (EE / HEP 1: 4) = 0.40 MS (FAB): 277 (M + H) b) diguanidide of 5-cyclohexy-1-isophthalic acid 5.3 g of guanidine hydrochloride are dissolved in 55 ml of DMF and a solution of 5.6 g of potassium tert-butyllate is added dropwise at RT. dissolved in 50 ml of DMF. The mixture is subsequently stirred for 2 h at RT, then a solution of 1.4 g of 5-cyclohexyl-1-isophthalic acid dimethyl ester in 15 ml of DMF is added dropwise and the mixture is stirred for 24 h at RT. . The reaction mixture is poured into 1 1 of water and extracted 3 times in each case with 100 ml of EA. It is dried over NaSO (, and the solvent is removed in vacuo) The residue is suspended in 50 ml of EE and adjusted to pH = 2-3 with a saturated solution of maleic acid in the EA The crystalline residue is separated by filtration, it is washed with 50 ml of EE and then dissolved in each case in 50 ml of an aqueous solution of saturated NaCOj, an aqueous solution of saturated NaHCO and water, and the free base is isolated by extraction in each case 3 times with 100 ml. ml of EA is dried over a2SOj, and the solvent is removed in vacuo to obtain 1.1 g of colorless crystals, mp 219-220QC Rf (acetone / water 10: 1) = 0.23 MS (FAB): 331 (M + H) f Pharmacological data: Inhibition of the Na / H exchanger 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 of Naf / H + and 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 removed from the arteries of the ear and made uncoagulable by 25 IU of potassium heparin. A part of each sample was used for the double determination of the hematocrit by centrifugation. Aliquots of 100 μl in each case were used to measure the starting Na content of the erythrocytes. In order to determine the influx of sodium sensitive to Amiloride, 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-sucrose medium (1 μm). / 1: 140 of NaCl, 3 of KC1, 150 of sucrose, 0.1 of uabaína, 20 of Tr is-hidroximet i 1 - aminomethane). The erythrocytes were then washed 3 times with ice-cold MgCl-, -uabaine solution (millimoles / 1: 112 MgCl, 0.1, uabaine, and haemoiazed in 2.0 ml of distilled water. Sodium iptracellular 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 influx of sodium inhibited by Amiloride resulted from the difference of the sodium content of the erythrocytes after incubation with and without Amilopda 3 x 10 -4 moles / 1. Thus, the compounds according to the invention were also used.

Resulted Inhibition of the Na + / H * exchanger

Claims (4)

CLAIMS 1.- Diguanidides of benzene carboxylic acids of the formula I where one of the radicals R (l), R (2), R (3) and R (5) means -CO-N = C (NH,) ,; and the respective other radicals R (1), R (2), R (3) and R (5): R (1) and R (5) mean, independently of one another, hydrogen, alkyl with 1, 2, 3 or 4 C atoms, F, Cl, -OR (32), -NR (33) R (34) or CF3; R (32), R (33) and R (34) mean, independently of one another, hydrogen or alkyl having 1, 2, 3 or 4 C atoms; R (2) means hydrogen, F, Cl, Br, I, OH, -CN, CF ^, -CO-N = C (NH2) 2, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, alkenyl with 2, 3, 4, 5, 6, 7 or 8 C atoms or - (CH 2) R (14); m means zero, 1 or 2; R (14) means cycloaikyl (C ^ -C ^) or phenyl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F and Cl, -CF3, methyl, methoxy and -NR (15). ) R (16); R (15) and R (16) mean, independently of one another, hydrogen or -CH 3; R (2) means R (22) -SO, -, R (23) R (24) N-CO-, R (28) -CO- or R (29) R (30) N-SO2-; R (22) and R (28) signify, independently of one another, methyl or -CF,; R (23), R (24), R (29) and R (30) signify, independently of one another, hydrogen or et i lo; or R (2) means -OR (35) or ~ NR (35) R (6); R (35) and R { 36) signify, independently of one another, hydrogen or alkyl with 1, 2, 3, 4, 5 or 6 C atoms; or R (35) and R (36) mean together 4-7 metal groups, of which one group CH can be replaced with oxygen, -S-, -NH-, -NCH3 or -N-benzyl; R (3) means hydrogen, -SR25), -OR (25), -NR (25) R (26), -CR (25) R (26) R (27); R (25) means hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms or phenyl, which is unsubstituted or is substituted with 1-3 substituents selected from the group consisting of F , Cl, CFj, CHj, methoxy, hydroxy, amino, meth i lamino and dimet i lamino; or R (25) means heteroaryl (C ^ -CQ), which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CFj, CH-, methoxy, hydroxy, , methylamino and dimethylamino; R (26) and R (27), independently of each other, are defined as R (25) or denote hydrogen or alkyl with

1. 2, 3, 4, 5, 6, 7 or 8 C atoms: R (4) means CFj, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, alkenyl with 2, 3, 4, 5, 6, 7 or 8 C atoms, cycloalkyl (Cj- Cg) or - (CH2) aR (14); m means 1 or 2; R (14) means cycloalkyl (C ^ -Cg) or phenyl, which is unsubstituted or substituted by 1-3 substituents chosen from the group consisting of F and Cl, -CF,. methyl, methoxy and -NR (15) R (16); R (15) and R (16) signify, independently of one another, hydrogen or -CH,; or R (4) means phenyl which is substituted with 2, 3, or five substituents selected from the group consisting of F, Cl, CF, methyl, methoxy and -NR (15) R (16); R (15) and R (16) signify, independently of one another, hydrogen or CH,; as well as its pharmaceutically compatible salts.

2. Compound of formula I according to claim 1, wherein: one of the radicals R (l), R (2), R (3) and R (5) means -CO-N = C (NH2) 2; and the respective other radicals R (1), R (2), R (3) and R (5): R (1) and R (5) mean, independently of one another, hydrogen, alkyl with 1, 2, 3 or 4 atoms of C, F, Cl, -OR (32) or CF3; R (32) means hydrogen or alkyl with 1, 2, 3 or 4 C atoms; R (2) means hydrogen, F, Cl, Br, I, OH, CFj, alkyl with 1, 2, 3 or 4 carbon atoms, alkenyl with 2, 3 or 4 carbon atoms or - (CHj), R ( 14); m means zero. 1 or 2; R (14) means cycloalkyl (Cj-C3) or phenyl. which is not substituted or substituted by 1-2 substituents selected from the group consisting of F and Cl, -CF3, methyl and methoxy; R (2) means R (22) -S02-, R (23) R (24) N-CO-, R (28) -CO- or R (29) R (30) N-SO2; R (22) and R (28) signify, independently of one another, methyl or -CF,; R (23), R (24), R (29) and R (30) mean, independently of one another, hydrogen or me t i 1 o; or R (2) means -0R (35) or -NR (35) R (36): R (35) and R (36) signify, independently of one another, hydrogen, methyl or ethyl; or R (35) and R (36) together mean 4-5 metal groups, of which a CH group can be replaced with oxygen, -S-, -NH- or -NCH3; R (3) means hydrogen, -SR (25). -OR (25), -NR (25) R (26) or -CR (25) R (26) R (27); R (25) means hydrogen, alkyl having 1, 2, 3 or 4 C atoms or phenyl, which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F, Cl, CF3, CH, methoxy and dimet i lamino; or R (25) means heteroaryl (Cj-C ^), which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy and dimethylamine; R (26) and R (27) signify, independently of one another, hydrogen or alkyl with 1, 2, 3 or 4 C atoms; R (4) means CF3, alkyl with 1, 2, 3, 4, 5 or 6 C atoms, alkenyl with 2, 3, 4, 5 or 6 C atoms, cycloalkyl (C5-Cg or -CH2R (14) R (14) means cycloalkyl (Cj-Cg) or phenyl, which is unsubstituted is substituted with 1-2 substituents selected from the group consisting of F and Cl, -CF, methyl and methoxy; ) means phenyl which is substituted with 2, 3, 4 or five substituents selected from the group consisting of F, Cl, CF3, methyl and methoxy, and their pharmaceutically compatible salts

3.- Compound of formula I according to claim 1 or 2, characterized in that in it: one of the radicals R (l), R (2), R (3) and R (5) means -CO-N = C (NH2) 2; and the respective other radicals R (1), R (2), R (3) and R (5): R (1) and R (5) mean, independently of one another, hydrogen, alkyl with 1, 2, 3 or 4 C, F, Cl, OH, methoxy or CF3 atoms; R (2) means hydrogen, F, Cl, OH, CF3, alkyl having 1, 2, 3 or 4 C atoms, alkenyl having 2, 3 or 4 C atoms or - (CHj ^ RÍ); m means zero, 1 or 2; R (14) means cycloalkyl (Cj-Cg) or phenyl, which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F and Cl, -CF3, methyl and methoxy; R (2) means R (22) -SOj-, R (23) R (24) N-CO-, R (28) -CO-R (29) R (30) N-SO2; R (22) and R (28) signify, independently of one another, methyl or -CF; R (23), R (24), R (29) and R (30) independently of one another denote hydrogen or methyl; or R (2) means -OR (35) or -NR (35) R (36); R (35) and R (36) signify, independently of one another, hydrogen, methyl or ethyl; or R (35) and R (36) together mean 4-5 methylen groups, of which a CH2 group may be replaced with oxygen, -S-, -NH- or -NCH3; R (3) means hydrogen, -SR (25), -OR (25), -NR (25) R (26) or -CR (25) R (26) R (27); R (25) means hydrogen, alkyl having 1, 2, 3 or 4 C atoms or phenyl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy and di-ethylamino; or R (25) means heteroaryl (Cj-C9), which is unsubstituted or is substituted by 1-2 its selected twerers from the group consisting of F, Cl, CF3, CH3, methoxy and dimethylamine; R (26) and R (27) signify, independently of one another, hydrogen or alkyl with 1, 2, 3 or 4 C atoms; R (4) means CFj, alkyl with 1, 2, 3, 4, 5 or 6 C atoms, alkenyl with 2, 3, 4, 5 or 6 C atoms, cycloalkyl (Cj-Cg) or -CH2R (14 ); R (14) means cycloalkyl (Cj-Cg) or phenyl, which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F and Cl, -CF, methyl and methoxy; R (4) means phenyl which is substituted with 2, 3, 4 or five substituents selected from the group consisting of F, Cl, CF3, methyl and methoxy. 4. Compound of the formula I according to claims 1 to 3, wherein: one of the radicals R (l), R (2), R (3) and R (5) means -CO-N = C (NH2) 2; and the respective other radicals R (1), R (2), R (3) and R (5): R (1) and R (5) mean, independently of one another, hydrogen, alkyl with 1, 2, 3 or 4 C, F, Cl, OH, methoxy or CF3 atoms; R (2) means hydrogen, F, CL, OH, CF3, alkyl having 1, 2, 3 or 4 carbon atoms or - (CH2) .R (14); m means zero, 1 or 2; R (14) means cycloalkyl (Cj-Cg) or phenyl, which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F and Cl, -CF3, methyl and methoxy; or R (2) means -OR (35) or -NR (5) R (36); R (35) and R (36) signify, independently of one another, hydrogen, methyl or ethyl; or R (35) and R (36) together mean 4-5 methylene groups, of which a CH group may be replaced with oxygen, -S-, -NH- or -NCH3; R (3) means hydrogen or -OR (25); R (25) means hydrogen, alkyl having 1, 2, 3 or 4 C atoms or phenyl, which is unsubstituted or substituted by 1-2 its members selected from the group consisting of F, Cl, Fj, CH3 and methoxy; R (25) means heteroaryl (Cj-Cg), which is unsubstituted or substituted by 1-2 substituents of the group of F, Cl, CF3, CH, and methoxy; R (4) means CF3, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkenyl with 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl (C5-Cg) or -CH2R (14 ); R (14) means cycloalkyl C Cj-Cg) or phenyl, which is unsubstituted or substituted by 1-2 its t i uents chosen from the group consisting of F and Cl, -CFj, methyl and methoxy; R (4) means phenyl which is substituted with 2, 3, 4 or five substituents selected from the group consisting of F, C, CF 3, methyl and methoxy. 5.- Procedure for the preparation of a compound I according to claim 1, characterized in that a compound of the formula II wherein R (l) to R (5) have the meanings indicated above and L represents substitutable and slightly nucleophilic labile groups, is reacted with guanidine. 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. Method for the treatment and prophylaxis of diseases caused by ischemic states, characterized in that an effective amount of a compound I according to claim 1 is combined with the usual additives and administered in a suitable administration form. 8. Use of a compound I according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of heart infarction and arrhythmias. 9. Use of a compound I according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of angina pectoris. 10. Use of a compound I according to claim 1 for the preparation of a medicament for the treatment 0 prophylaxis of ischemic heart conditions. 11.- Use of a compound I according to the claim 1 for the preparation of a medication for the treatment 0 the prophylaxis of ischemic states of the peripheral and central nervous system and of apoplexy. 12.- Use of a compound I according to the claim 1 for the preparation of a medication for the treatment 0 the prophylaxis of ischemic states of peripheral organs and my embryos. 13.- Use of a compound I according to the claim 1 for the preparation of a medication for the treatment of shock states. 14. Use of a compound I according to claim 1 for the preparation of a medicament for use in surgical operations and organ transplants. 15. Use of a compound I according to claim 1 for the preparation of a medicament for the preservation and storage of transplanted organs for surgical measures. 16. 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 antiatheric agents, agents against late diabetic complications, carcinogenic diseases, fibrotic diseases, such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, and hyperplasia of the prostate. 17. 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 proliferating diseases. 18. Medicament containing an effective amount of a compound I according to one or more of claims 1 to

4.