MXPA97006380A - Guarides of alkenil-carboxylic acids replaced with phenyl, procedures for preparation, use as a medicine or diagnostic agent, as well as a medication that contains them - Google Patents

Abstract

The present invention relates to compounds of the formula I: wherein T is equal to and R (A), R (B), R (C), R (D), R (E), R (F), x and y with the meanings, which are indicated, as well as their pharmaceutically compatible salts, are effective inhibitors of the cellular antiporter between sodium and protons (exchanger between Na + and H +). Therefore, they are outstandingly suitable for the treatment of diseases that are to be attributed to an increased exchange between Na + and

Description

Guanidides of phenyl-substituted alkenyl carboxylic acids, processes for their preparation, their use as a medicament or diagnostic agent, as well as a medicament containing them The invention concerns guanidides of phenyl-substituted alkenylcarboxylic acids of the formula I where: T means R (A) means hydrogen, F, Cl, Br, I, CN, OH, OR (6), alkyl (Cx-C4), Or < CH2) aCbF2b + 1, cycloalkyl (C3-C8) or NR (7) R (8) r means zero or 1; a means zero, 1, 2, 3 or 4, • b means 1, 2, 3 or 4; R (6) means (C 1 -C 4) alkyl, perfluoro (C 1 -C 4) alkyl, (C 3 -C 6) alkenyl, (C3-C8) cycloalkyl, phenyl or benzyl, the phenyl nucleus being unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR (9) R (10); R (9) and R (10) denote H, (C1-C4) alkyl or perfluoroalkyl (Cj ^ -C ^; R (7) and R (8) independently of one another, are defined such as R (6); or R (7) and R (8), mean in common 4 or 5 methylene groups, of which a CH2 group can be replaced by oxygen, sulfur, NH, N-CH3 or N-benzyl, R (B), R (C) and R (D) independently of each other, are defined as R (A) x means zero, 1 or 2, • and means zero, l or 2; R (F) means hydrogen, F, Cl , Br, I, CN, OR (12), alkyl (C1-Cß), Op (CH2) fCgF2g + 1, cycloalkyl (C3-C8) or heteroaryl (Cj ^ -8); p means zero or 1; f means zero, 1, 2, 3 or 4, g means 1, 2, 3, 4, 5, 6, 7 or 8, R (12) means alkyl (C ^ Cg), perfluoroalkyl (C1-C4), alkenyl (C3) -C8), (C3-C8) cycloalkyl, phenyl or benzyl, the phenyl nucleus being unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR (13) R (14); R (13) and R (14) mean H, (C? -C4) alkyl or perfluoroalkyl (C? ~ C4); R (E) independently, is defined as R (F); R (I) independently is defined as T; or, R (l) means hydrogen, -On (CH2) pCqF2q4.?, F, Cl, Br, I, CN, - (C = 0) -N = C (NH2) 2, -S0rR (17), -SOr2NR (31) R (32); -Ou (CH2) vC6H5, -O ^ -heteroaryl (C1-C9) or -S ^ -heteroaryl (C1-C9); k means zero or 1; m means zero, 1, 2, 3, 4, 5, 6, 7 or 8; n means zero or 1; p means zero, 1, 2, 3 or 4; q means 1, 2, 3, 4, 5, 6, 7 or 8; r2 represents zero, 1, 2; R (31) and R (32) independently represent among them hydrogen, Ci to Ce alkyl, or perfluoroalkyl of. a Ce or R (31) and R (32) together represent 4 to 5 methylene groups, of which a CH2 group may be substituted by oxygen, S, NH, N-CH3 or N-benzyl; R (17) means alkyl (Ci-Cß); u means zero or 1; u2 means zero or 1; v means zero, 1, 2, 3 or 4; the phenyl nucleus being unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy, - (CH2) "NR (21) R (22), NR (18) R (19) and hete. roaril (C1-C9); R (18), R (19), R (21) and R (22) independently of each other, mean alkyl (C? -C4) or perfluoroalkyl (C? -C4); w means 1, 2, 3 or 4; the heteroaryl of the (C1-C9) heteroaryl unsubstituted or sus- substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl or methoxy; R (2), R (3), R (4) and R (5) Independently of one another, are defined such R (l), or R (l) and (R (2) or R (2) and R (3) in each case mean in ccirain -CH-CH = CH-CH-, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy, - (CH2) "2NR (24) R (25) and RN (2β) R (27); R (24), R (25), R (26) and R (27) mean H, (C 1 -C 4) alkyl or perfluoroalkyl (C? ~ C4), w2 means 1, 2, 3 or 4, the radical T being present in the molecule at least twice, but only three times as high as the pharmaceutically compatible salts thereof. the compounds of the formula I, in which: T means R (A) means hydrogen, F, Cl, CN, OH, OR (6), alkyl (C? _-C4), Or (CH2) aCbF2b + 1, Cycloalkyl (C3-C8)? NR (7) R (8); r means zero or 1; a means zero, l or 2 b means 1, 2, 3 64; R (6) means alkyl (C ^ j), perfluoro (C 1 -C 4) alkyl, phenyl or benzyl, the phenyl nucleus being unsubstituted or substituted with 1-3 substituents selected from the group consisting of group consisting of F, Cl, CF3, methyl, methoxy and NR (9) R (10); R (9) and R (10) independently of one another mean H, CH 3 or CF 3; R (7) and R (8) independently of one another are defined such as R (6); or R (7) and R (8) mean in common 4 or 5 methylene groups, of which a CH2 group can be replaced by oxygen, sulfur, NH, N-CH3 or N-benzyl; R (B), R (C) and R (D) independently, are defined as R (A), - x means -cero or í; and means zero or 1; R (F) means hydrogen, F, Cl, CN, OR (12), alkyl (C? -C4), Op (CH2) fCgF2g + 1, cycloalkyl (C3-C8) or heteroaryl (C? Cg); p means zero or 1; f means zero, 1 or 2; g means l, 2, 3 64; R (12) means (C1-C4) alkyl, perfluoroalkyl .Cx-C4), (C3-C8) cycloalkyl, phenyl or benzyl, wherein? 1 unsubstituted or substituted phenyl nucleus of 1-3 substituents selected from the group consisting of it consists of F, Cl, CF3, methyl, methoxy and NR (13) R (14); R (13) and R (14) independently of one another mean H, CH 3 or CF 3; R (E) independently, is defined as RÍF); R (I) independently is defined as T; or R (l) means hydrogen, -OkC i, F, Cl, Br, I, CN, - (C = 0) -N = C (NH2) 2, -SOrR (17). -SOr2NR (31) R (32); - CH ^ vCeHs, -C -heteroari (C1-C9) or -Su2-heteroaryl (C1-C9); means zero or 1; m means zero, 1, 2, 3 or 4; n means zero or 1; q means 1, 2, 3 or 4; r2 represents zero, 1, 2; R (31) and R { 32) independently of one another means hydrogen, C 1 -C 4 alkyl, or C 1 to C 4 perfluoroalkyl; or R (31) and R (32) together represent 4 to 5 methylene groups, of which a CH2 group can be substituted by oxygen, S, NH, N-CH3 or N-benzyl; R (17) means alkyl (d-); u means zero or 1; u2 means zero or l; v means zero, 1 or 2; the phenyl nucleus being unsubstituted or substituted with 1-3 substituents and seleko-icnadps between the group consisting of F, Cl, CF3, irethyl, - rp_te? i, - (CH2) v ^ (21) R (22 ), NR (18) R (19) or teterocaril (C1-C9); R (18), R (19), R (21) and R (22) mean H, (Ci-) alkyl or perfluoroalkyl (Cr-C ^); means 1, 2, 3 or 4; the heteroaryl heterocycle (C 1 -C 9) being unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3, irethyl or methoxy; R (2), R (3), R (4) and R (5) i _ _ _ ependiente_rente of each other are defined such as R (l), or R (l) and RÍ2) or R (2) and R (3) mean in each case in cerrún -CH-CH = CH-CH-, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy; - (CH2) v_NR (24) R (25) and NR (26) R (27); ,, and they mean H, CH3 or CF3; w2 means l, 2, 3 or 4; the radical T being present in the molecule, however, only twice; as well as its pharmaceutically compatible salts. Especially preferred are compounds of formula I, in which T means x means zero; and means zero; R (F) means hydrogen, F, Cl, CN, OR (12), alkyl (C ^ -C ^, -OpCgF2g + 1, cycloalkyl (C3-C8) or heteroaryl (C ^ Cg), p means zero or 1 g means l, 2, 3 or 4, R (12) means alkyl (CLC ^, CF3, (C3-C8) cycloalkyl, phenyl or benzyl, the phenyl nucleus being in each case unsubstituted or substituted 3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR (13) R (14); R (13) and R (14) mean H, CH3 or CF3; R (E) independently, is defined such as R (F); R (l) independently, is defined such as T; or R (l) means hydrogen, -OkC-H2_ + ?, -0-CqF2q + 1, F, Cl, CN, - (C = 0) -N = C (NH2) 2, ~ S02CH3, -S02NR (31 ) R (32), -0U (CH2) vCßHs, -Ou2-heteroaryl. { C1-C9) or -Su2-heteroaryl (C1-C9); k means zero or 1; m means zero, 1, 2, 3, or 4; n means zero or 1; q means 1, 2, 3 or 4; R (31) and R (32) independently represent among them hydrogen, or C4-C4 alkyl, or R (31) and R (32) together represent 4 to 5 methylene groups, of which a CH2 group can be substituted by oxygen, S, NH, N-CH3 or N-benzyl; u means zero or 1; u2 means zero or 1; v means zero ß 1; the phenyl nucleus being unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy, - (CH2) WNR (21) R (22), NR (18) R (19); R (18), R (19), R (21) and R (22) Independently from each other, mean H, alkyl (Ci-C *) or perfluoroalkyl (C 1 -C 4); means 1, 2, 3 or 4; the (C1-C9) heteroaryl heterocycle being unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF, methyl or methoxy; R (2), R (3), R (4) and R (5) Independently from each other, are defined such as R (l), or R (l) and R (2) or R (2) and R (3) In each case they mean in. common -CH-CH = CH-CH-, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy, - (CH2) w2NR (24) R. { 25) and NR (26) R { 27); R (24), R (25), R (26) and R (27) independently denote H, (C1.-C4) alkyl, or perfluoroalkyl (Cj-Ci); w2 means 1, 2, 3 or 4; the radical T being present in the molecule, however only twice; as well as its pharmaceutically compatible salts. The following compounds are very particularly preferred: l, 2-bis- [3- (E-2-methyl-propenoic acid guanidide)] benzene dihydrochloride, 1,3-bis- [3- (guanidide dihydrochloride E-2-methyl-propenoic acid)] benzene, 1,4-bis- [3- (E-2-methyl-propenoic acid guanidide)] benzene dihydrochloride, 2,3-bis- [3- ( guanidide of E-2-methyl-propenoic acid]] naphthalene, 1,2-bis- [3- (guanidide of Z-2-fluoro-propenoic acid)] benzene, 1- [3- (guanidide dihydrochloride Z-2-fluoro-propenoic acid)] -2- [3- (E-2-methyl-propenoic acid guanidide)] -benzene, 1,3-bis- [3- (guanidide of Z-2 acid, dihydrochloride -fluoro-propenoic acid)] benzene, 3- (4-chloro-3-guanidinocarbonyl-5-phenyl) -phenyl-2-methyl-propenoic acid guanidide, 1,3-bis- [3- (acid guanidide hydrochloride E-2-methyl-propenoic)] -2-methoxy-5-methyl-benzene, 1,2-bis- [3- (guanidide of E-2-methyl-propenoic acid)] -4-methyl-benzene dihydrochloride or, 1, 2-bis- [3- (E-2-methyl-propenoic acid)] -4,5-dichloro-benzene dihydrochloride, 1,3-bis- [3- (acid guanidide dihydrochloride E-propenoi-co)] benzene, 1,2-bis- [3- (E-2-methyl-propenoic acid guanidide)] -4-bromobenzene, 1,2-bis- [3-dihydrochloride] dihydrochloride - (E-2-methyl-propenoic acid guanidide)] -4- (4-methoxy-phenoxy) benzene, 1,2-bis- [3- (E-2-methyl-propenoic acid guanidide) dihydrochloride] -4- (4-methyl-phenoxy) benzene, 1,3-bis- [3- (guanidide of E-2-methyl- propenoic)] -5-methoxy-benzene, 1,3-bis- [3- (guanidide of E-2-methyl-propenoic acid)] -4- t-butyl-benzene hydrochloride, 1,4-bis-dihydrochloride - [3- (E-2-methyl-propenoic acid guanidide)] -2,5-dichloro-benzene, 1,2-bis- [3- (guanidide of E-2-methyl-propenoic acid) dihydrochloride] -4- (phenoxy) -benzene, 1,2-bis- [3- (E-2-methyl-propenoic acid guanidide)] -4- (methoxy) -benzene dihydrochloride, 1,2-bis- dihydrochloride [3- (E-2-methyl-propenoic acid guanidide)] -4- (ethoxy) -benzene and l, 2-bis- [3- (E-2-methyl-propenoic acid guanidide) dihydrochloride] -4- (3-pyridyloxy) -benzene. If one of the compounds of the formula I contains one or more centers of asymmetry, these can be configured as both S and R. The compounds can be present as optical isomers, as diastereomers, as racemates or as mixtures thereof. The double bond geometry of the compounds of the formula I can be both E and Z. The compounds can be present as isomers of double bonds in admixture.

The indicated alkyl and perfluoroalkyl radicals can be present with both straight chain and branched chain. Heteroaryl (C ^ Cg) 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 are replaced by S, NH or O (mediating the formation of a five-membered aromatic ring). Otherwise, also one or both atom (s) of the condensation site of the bicyclic radicals (such as in indolizinyl) can be N atoms. As heteroaryl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxali-nyl, quinazolinyl and cinolinyl. The invention also relates to a process for the preparation of compound I, characterized in that a compound of formula II R (4) is reacted with guanidine. where R (l), R (2), R (3), R (4), R (5), R (A), R (B), R (C), R (D), R ( E), R (F), x and y have the indicated meanings and L represents a readily substitutable labile group in a nucleophilic manner. 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-pyridylthio, a heterocycle with nitrogen, preferably 1-imidazolyl, are advantageously obtained in a manner known per se from the chlorides of carboxylic acids (formula II, L = Cl) which are presented as their basis, which, in turn, can be prepared in a manner known per se from carboxylic acids (formula II, L = OH) which are presented as its foundation, 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 alkenyl acid derivatives (formula II, L = OH) that are presented as its foundation, such as for example the methyl esters of the formula II with L = OCH 3 by treatment with gaseous HCl in methanol, the imidazolides of formula II by treatment with carbonyldiimidazole [L = 1-imidazolyl, Staab, Angew. Chem. International Edition in English, 1, 351-367 (1962)], mixed anhydrides II with Cl-COOC2H5 or tosyl chloride in the presence of triethylamine in an inert solvent, as well as activations of alkenyl acids with dicyclohexylcarbodiimide (DCC) or with 0- [(cyano (ethoxycarbonyl) methylene) amino] -1, 1, 3,3-tetramethyluronium ("TOTU") tetrafluoroborate [Proceedings of the, 21. European Peptide Symposiu, Peptides 1990, compilers E. Giral t and D. Andreu, Esco, Leiden, 1991]. A number of methods suitable for the preparation of activated carboxylic acid derivatives of the formula II are set forth in the literature. source in J. March, Advanced Organic Chemistry, third edition (John Wiley &Sons, 1985), page 350. The reaction of an activated carboxylic acid derivative of formula II with guanidine is carried out in a manner known per se of a polar but inert protic or aprotic organic solvent. In this case, in the reaction of the methyl esters of alkenyl acids (II, L = OMe) with guanidine, methanol, isopropanol or THF have been proved at temperatures of 20 ° C. up to the boiling point of these solvents. the reactions of compounds II with guanidine free of salts were advantageously worked in inert aprotic solvents, such as THF, dimethoxyethane or dioxane, but water can also be used by using a base, such as for example NaOH, as the solvent in the reaction of compound II with guanidine When L means = Cl, the addition of an acid scavenger, eg in the guanidine form in excess, is advantageously carried out to fix the halogenated hydrazide A part of the alkenyl acid derivatives of the formula II, which are presented as a basis, is known and has been described in the literature The unknown compounds of the formula II can be prepared according to methods known from the bibliography. The alganelic acids obtained are reacted according to one of the process variants described above to give the compounds I according to the invention. The introduction of some substituents is achieved by methods known from the literature, from palladium-mediated cross-coupling of aryl halides or aryl triflates with, for example, organostannanes, organoboronic acids or organoboranes, or organic copper or zinc compounds. Alkenylguanidines I are generally weak bases and can bind acids by forming salts. Salts of acid addition are salts of all pharmacologically compatible acids, for example halides, especially hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulphonates or p-toluenesulphonates. The compounds of the formula I are substituted acylguanidines. The most prominent representatives of the acylguanidines are the guanidides of the pyrazinecarboxylic acid and the benzoic acid of the general formulas V and VI.

Amiloride: R, R '= H Dimethyl-amiloride: R, R' = CH 3 Ethyl-isopropyl-amiloride: R = CH (CH 3) 2, R '= C 2 H 5 The compounds of the formula V are designated in the literature generally as amilorides . The amiloride itself (R, R '= H) finds use in therapy as a potassium-sparing diuretic agent. Numerous other compounds of the amiloride type are described in the literature, such as, for example, dimethyl-amiloride or ethyl-isopropyl-amiloride. There are investigations that point to the antiarrhythmic properties of amiloride [Circulation 79, 1 .257-63 (1989)]. However, it is opposed to a wide use as an antiarrhythmic agent, the fact that this effect is only weakly pronounced and is accompanied by a hypotensive and salutary effect, and these side effects are undesirable in the treatment of heart rhythm disorders. In experiments with isolated animal hearts, indications of antiarrhythmic properties of amiloride were obtained [Eur. Heart J. 9 (supplement 1): 167 (1988) (book of abstracts)]. Thus, for example, in rat hearts it was found that an artificially caused ventricular fibrillation could be totally repressed by amiloride. Still more potent than amiloride was in this model the derivative of amiloride, ethyl-isopropyl-amiloride, mentioned above. The compounds of formula VI are selective inhibitors of the ubiquitous exchanger between sodium and protons (subtype 1, NHE-1) [NHE is short for Natrium-Hydrogen-Bxchanger = sodium and hydrogen exchanger]. Known representatives of the literature are HOE 694 and HOE 642, which are described as antiarrhythmics and under ischemic conditions as cardioprotectors [a) Scholz W, Albus U, Linz W, Martorana P, Lang HJ, Scholkens BA. Effects of Na * / H * exchange inhibitors in cardiac ischaemia. J. Mol. Cell. Cardiol. 1992; 24: 731-739; b) Scholz W, Albus U. Na * / H * exchange and its inhibition in cardiac ischemia and reperfusion. Basic Res. Cardiol. 1993; 88: 443-455; c) Scholz W, Albus U, Councell L, Gógelein H, Lang HJ, Linz W, Weichert A, Scholkens BA. Protective effects of HOE 642, a selective sodium-hydrogen exchange sub type 1 inhibitor, on cardiac ischaemia and reperfusion. Cardiovasc. Res. 1995; 29: 260-268; d) Bugge, E. and Ytrehus, K. Inhibition of sodium -hydrogen exchange reduces infarct size in the isolated rat heart - -A protective additive to ischaemic preconditioning. Cardiovasc. Res. 29: 269-274, 1995]. In addition, the guanidides of 3-phenyl- and 3-thiophenyl-propenoic acids VII as NHE inhibitors are known from the literature [US-2,734,904, WO 84/00875, DE-OS-44.21.536.3 (HOE 94 / F 168)], but no bisguanidine compound of the formula I is disclosed or suggested in these publications.

O NH- VII R (l) = phenyl, thiophenyl Surprisingly, the compounds according to the invention of formula I inhibit the exchanger between sodium and protons of subtype 3. The NHE inhibitors known hitherto are hardly active in this subtype. The claimed compounds of the formula I act hypotensively and are therefore suitable as medicaments for the treatment of primary and secondary hypertonia. Because of their salidiuretic effect they are suitable as diuretic agents. In addition, the compounds act anti-ischemically on their own or in conjunction with NHE inhibitors with another specificity for substrates. These compounds protect organs insufficiently supplied with acute oxygen - or chronically by reduction or avoidance of ischemically induced lesions, and are therefore suitable as medicaments, for example in the case of thrombosis, vascular spasms, atherosclerosis or in surgical interventions. (for example, in the case of organ, kidney and liver 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 treatment with, or in its storage in, bath liquids, as well as in the transference to the recipient organism) or chronic or acute faults in the kidneys. Corresponding to its 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), with p. ex. for the treatment of stroke or cerebral edema. In addition to this, the compounds according to the invention of the formula I are also suitable for the treatment of shock forms, such as, for example, allergic, cardiogenic, hypovolemic and bacterial shocks. In addition, the compounds induce an improvement of the respiratory drive and are therefore used for the treatment of respiratory states in the following clinical conditions and diseases: disturbed central respiratory drive (eg, central apneas during sleep, sudden death of children, postoperative hypoxia), muscle-conditioned respiratory disorders, respiratory disorders after long-term artificial respiration, respiratory disorders in high mountain adaptation, obstructive and mixed forms of apneas during sleep, acute and chronic pulmonary diseases with hypoxia and hypercapnia. A combination of an NHE inhibitor with a carboanhydrase inhibitor (eg acetazolamide), causing the latter a metabolic acidosis and thereby increasing the respiratory activity, is shown as a favorable combination with reinforced effect and decreased use of active substances. In addition to this, the compounds according to the invention of the formula I are distinguished by a strong inhibitory effect on the proliferation of cells, for example on the proliferation of fibroblasts and the proliferation of the vascular smooth muscle cells. Therefore, the compounds of 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 antiatherosclerotic agents, as agents against late diabetic complications, cancerous diseases, fibrotic diseases such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, endothelial dysfunction, hypertrophies and hyperplasias of organs, especially in prostate hyperplasia or prostate hypertrophy. In addition, the compounds produce a decrease in cholesterol level and thus are suitable as medicines for the prevention and treatment of atherosclerosis. The compounds according to the invention are effective inhibitors of the cellular antiporter between sodium and protons (exchanger between Na + and H +), subtypes I and 3, which is increased in numerous diseases (essential hypertonia, atherosclerosis, diabetes, etc.) also in those cells which are easily accessible to measurements, such as e.g. 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, diabetes, proliferative diseases, etc. In addition to this, the compounds of the formula are suitable for preventive therapy in order to avoid the genesis of blood hypertension, for example, of essential hypertonia. In addition, it was found that the compounds of formula I have a favorable influence on serum lipoproteins. It is generally recognized that for the formation of arteriosclerotic vascular disorders, especially coronary heart disease, too high values of blood fats, the so-called hyperlipoproteinemia, constitute an essential risk factor. For the prophylaxis and the regression of atherosclerotic alterations, therefore, an extraordinary importance corresponds to the decrease of high amounts of lipoproteins in serum. Along with the reduction of total cholesterol in the serum, to the decrease in the proportion of specific atherogenic lipid fractions of this total cholesterol, especially of low density lipoproteins (LDL) and very low density lipoproteins (VLDL) It is of special importance, since these lipid fractions constitute an atherogenic risk factor. On the contrary, high-density proteins are attributed a protective function against coronary heart disease. Correspondingly, the hypolipidemic agents must be in a position to decrease not only the total cholesterol, but especially the serum LDL and VLDL cholesterol fractions. It was finally discovered that the compounds of the formula I show valuable, therapeutically utilizable properties, in relation to the influence on the level of serum lipids. Thus, these significantly decrease the increased serum concentration of LDL and VLDL, as seen for example due to an increased dietary intake of a meal rich in cholesterol and lipids or in the case of pathological alterations of metabolism, for example genetically conditioned hyperlipidemias. . Therefore, they can be used for the prophylaxis and regression of atherosclerotic alterations, suppressing them a causal risk factor. To this belong not only the primary hyperlipidemias, but also certain secondary hyperlipidemias, as they appear p. ex. in the case of diabetes. In addition to this, the compounds of the formula I lead to a manifest reduction of the infarcts induced by metabolic anomalies, and especially to a significant decrease in the induced magnitude of an infarct and its degree of severity. In addition, the compounds of the formula I lead to effective protection against epithelial lesions induced by metabolic abnormalities. With this protection of the vessels against the syndrome of endothelial dysfunction, the The compounds of formula I are valuable drugs for the prevention and treatment of coronary vascular spasms, atherogenesis and atherosclerosis, left ventricular hypertrophy and dilated cardiomyopathy, as well as thrombotic diseases. Said compounds find use, therefore, advantageously for the preparation of a medicament for the treatment of hypercholesterolemia; for the preparation of a medicine intended for the prevention of atherogenesis; for the preparation of a medicament for the prevention and treatment of atherosclerosis, for the preparation of a medicament for the prevention and treatment of diseases, which are caused by an increased level of cholesterol, for the preparation of a medicament intended for to the prevention and treatment of diseases that are caused by endothelial dysfunction, for the preparation of a medicament for the prevention and treatment of atherosclerosis-induced hypertonia, for the preparation of a medicament for the prevention and treatment of thrombosis induced by atherosclerosis, for the preparation of a drug for the prevention and treatment of ischemic lesions induced by hypercholesterolemia and endothelial dysfunction and post-ischemic reperfusion injury, for the preparation of a drug for the prevention and treatment of cardiac hypertrophies and cardiomyo atias induced by hypercholesterolemia and endothelial dysfunction, for the preparation of a drug for the prevention and treatment of coronary vascular spasms and myocardial infarctions induced by hypercholesterolemia and endothelial dysfunction, for the preparation of a drug for the prevention and treatment of the aforementioned ailments in combinations with hypotensive substances, preferably with angiotensin-converting enzyme (ACE) inhibitors and with angiotensin receptor antagonists, a combination of an inhibitor of NHE of the formula I with a depressant substance of the level of fats in blood, preferably with a HMG-CoA reductase inhibitor (eg lovastatin or pravastatin), the latter causing a hypolipidemic effect and thereby increasing the hypolipidemic properties of the NHE inhibitor of the formula I, manifests as a favorable combination with an increased effect and decreased use of active substances. The administration of inhibitors of the exchange between sodium and protons of the formula I is claimed as new drugs to decrease the increased level of fats in blood, as well as the combination of inhibitors of the exchange between sodium and protons with drugs with hypotensive and / or hypolipidemic effects . The medicaments, which contain a compound I, can be administered, in this case, by the oral, parenteral, intravenous, rectal or inhalation routes, the preferred application depending on the respective clinical picture of the disease. The compounds I can be applied, in such case, alone or in common with galenic adjuvants, and specifically in both veterinary and human medicine. To establish which coadjuvant substances are appropriate for the desired drug formulation is known to a person skilled in the art by virtue of his or her knowledge in the art. In addition to solvents, gel formers, suppository bases, tablet compression adjuvants and other active substance carriers, antioxidants, dispersants, emulsifiers, antifoams, flavor correctors, preservatives, solubilizers or dyes can be used, for example. For a form of oral application, the active compounds are mixed with suitable additive materials, such as vehicle materials, stabilizers or inert diluents and are brought by the usual methods to the appropriate presentation forms, such as tablets. , dragees, nestable capsules, 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. Suitable oily vehicle materials or solvents are, for example, vegetable or animal oils, such as sunflower oil or cod liver oil. For application subcutaneously or intravenously, the active compounds, if desired together with the substances customary therefor, such as solubilizers, emulsifiers or other adjuvants, are brought into the form of a solution, suspension or emulsion. Suitable solvents are p. ex. : water, a physiological solution of sodium chloride or alcohols, p. ex. ethanol, propanol, glycerol, together with these also sugar solutions, such as glucose or mannitol solutions, or also a mixture of the different solvents mentioned. As a pharmaceutical formulation for administration in the form of aerosols or nebulizations, 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 in a mixture of such solvents. The formulation may also contain, as necessary, other pharmaceutical adjuvants, such as surfactants, emulsifiers and stabilizers, as well as a propellant gas. One such preparation contains the active substance usually in a concentration of about 0.1 to 10, especially about 0.3 to 3% by weight. The dosage of the active substance of formula I to be administered and the frequency of administration depend on the intensity of the effect, and the duration of this effect, of the compounds used; In addition, they also depend on the type and intensity of the disease that is It must treat, as well as sex, age, weight and the individual capacity of response 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 from at least 0.001 mg / kg, preferably 0.01 mg / kg, up to a maximum of 10 mg / kg, preferably 1 mg / kg of body weight. In the case of acute outbreaks of diseases, 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 intravenous (i.v.) application, for example in the case of a heart attack patient in the intensive surveillance stage, up to 200 mg per day may be necessary.

List of abbreviations: MeOH methanol DMF N, N-dimethylformamide The impact of electrons DCI ionization with chemical desorption TA room temperature AE ethyl acetate (EtOAC) p. F. melting point HEP n-heptane DME dimethoxyethane ES electron projection FAB bombardment with fast atoms CH2C12 dichloromethane THF tetrahydrofuran eq. equivalent (s) EM mass spectrum Experimental part General requirements for the preparation of guanidines of alkenylcarboxylic acids (I) Alternative 1 A: from alkenylcarboxylic acids (II, L = OH) 1.0 eq. of the carboxylic acid derivative of the formula II is dissolved or suspended in anhydrous THF (5 ml / mmol) and then 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 (in a rotary evaporator), mixed with water, adjusted to a pH of 6 to 7 with 2 N HCl, and the corresponding guanidide is filtered off. (formula I). The carboxylic acid guanidides thus obtained can be transformed by treatment with aqueous, methanolic or ethereal hydrochloric acid, or other pharmacologically compatible acids, into the corresponding salts.

Variant IB: from alkenyl esters of alkenylcarboxylic acids (II, L = O-alkyl) 1.0 eq. of the carboxylic 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 refluxed until complete conversion (according to a control by thin layer chromatography) (typical reaction time of 2 to 5 h). The solvent is distilled off under reduced pressure (rotary evaporator), taken up 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 gel of silica with a suitable eluting agent, eg AE / MeOH 5: 1. (about the formation of a salt, see Variant A) Example 1: 1,2-bis- [3- (E-2-methyl-propenoic acid)] benzene dihydrochloride] l a) l eq. of the 2-phosphono-propionic acid triethyl ester was deprotonated to O'C with 1 eq. of n-butyl lithium in hexane and then mixed at RT with 0.5 eq. of 1,2-phthalodialdehyde. After complete reaction of the dialdehyde, it was treated with water and extracted by stirring three times with toluene. After drying the combined organic phases over magnesium sulfate, the solvent was removed in vacuo and the remaining crude product was separated by chromatography on silica gel with mixtures of AE and HEP as eluent. It was isolated: l, 2-di- [3- (ethyl ester of E-2-methyl-propenoic acid)] benzene. Colorless oil; MS (DCI): 303 (M + l +) 1 b) The ester from 1 a) was saponified according to a conventional method (sodium hydroxide in methanol). It was isolated: 1,2-di- [3- (E-2-methyl-propenoic acid)] benzene. Colorless solid material; P.f .: > 187'C; MS (DCI): 246 (M +) 1 c) The dicarboxylic acid from 1 b) was transformed according to Variant 1 A into the diguanidide dihydrochloride. Colorless solid material, -P.f .: > 200 * C; MS (DCI): 329 (M + l) + Example 2: 1,3-Bis- [3- (E-2-methyl-propenoic acid)] benzene dihydrochloride] 2 a) 1 eq. of the 2-phosphono-propionic acid triethyl ester was deprotonated at 0 * C with 1 eq. of n-butyl lithium in hexane and then it was mixed at RT with 0.5 eq. of l, 3-isophthalodial-dehyde. After complete reaction of the dialdehyde, it was treated with water and extracted by stirring three times with toluene. After drying the combined organic phases over magnesium sulfate, the solvent was removed in vacuo and the remaining crude product was separated by chromatography on silica gel with mixtures of AE and HEP as eluent. It was isolated: l, 3-di- [3- (ethyl ester of E-2-methyl-propenoic acid)] benzene. Colorless oil; MS (DCI): 303 (M + l +) 2 b) The ester from 2 a) was saponified according to a conventional method (sodium hydroxide in methanol). It was isolated: 1,3-di- [3- (E-2-methyl-propenoic acid)] benzene. Colorless solid material, -P.f .: > 190 * C; MS (DCI): 247 (M + l +) 2 c) The dicarboxylic acid from 2 b) was transformed according to Variant 1 A into the diguanidide dihydrochloride. Colorless solid material, -P.f .: 175 'C; MS (DCI): 329 (M + l) + Example 3: Dihydrochloride of 1, -bis- [3- (E-2-methyl-propenoic acid guanidide)] benzene 3 a) 1 eq. of the 2-phosphono-propionic acid triethyl ester was deprotonated to O'C with 1 eq. of n-butyl lithium in hexane and then it was mixed at RT with 0.5 eq. of 1,4-terephthalo-dialdehyde. After complete reaction of the dialdehyde, it was treated with water and extracted by stirring three times with toluene. After drying the combined organic phases over magnesium sulfate, the solvent was removed in vacuo and the remaining crude product was separated by chromatography on silica gel with mixtures of AE and HEP as eluent. It was isolated: l, 4-di- [3- (ethyl ester of E-2-methyl-propenoic acid)] -benzene. Colorless solid material; P.f .: 41 ° C; MS (DCI): 303 (M + l +) 3 b) The ester from 3 a) was saponified according to a conventional method (sodium hydroxide in methanol). It was isolated: 1,4-di- [3- (E-2-methyl-propenoic acid)] benzene. Colorless solid material, -P.f .: > 190 * C; MS (DCI): 247 (M + l *) 3 c) The dicarboxylic acid from 3 b) was transformed according to Variant 1 A into the diguanidide dihydrochloride. Yellow solid material, -P.f .: 255'C; MS (DCI): 329 (M + l) + Example 4: 2,3-bis- [3- (E-2-methyl-propenoic acid)] naphthalene dihydrochloride] 4 a) l eq. of the 2-phosphono-propionic acid triethyl ester was deprotonated to O'C with 1 eq. of n-butyl lithium in hexane and then it was mixed at RT with 0.5 eq. of 2, 3-naphthalene-dialdehyde. After complete reaction of the dialdehyde, it was treated with water and extracted by stirring three times with toluene. After drying the combined organic phases over magnesium sulfate, the solvent was removed in vacuo and the remaining crude product was separated by chromatography on silica gel with mixtures of AE and HEP as eluent. It was isolated: 2,3-di- [3- (ethyl ester of E-2-methyl-propenoic acid)] - naphne german. Colorless oil: MS (DCI): 353 (M + l +) 4 b) The ester from 4 a) was saponified according to a conventional method (sodium hydroxide in methanol). It was isolated: 2,3-di- [3- (E-2-methyl-propenoic acid)] naphthalene. Colorless solid material; P.f .: > 210 #C; MS (DCI): 295 (M-H) " 4 c) The dicarboxylic acid from 4 b) was converted according to the variant 1 A into the diguanidide dihydrochloride. Colorless solid material; P.f .: > 200 * C; MS (DCI): 379 (M + l) + Example 5: 1, 2-bis- [3- (Z-2-fluoro-propenoic acid)] benzene dihydrochloride a) With the aid of a known method of the literature (Cousseau et al., Tetrahedron Letters 34, 1993, 6,903), starting with 1,2-phthalodialdehyde, 1,2-di- [3- (ethyl ester of Z-2-fluoro-propenoic acid]] benzene and purified on silica gel with mixtures of AE and HEP and isolated. Colorless solid material P.f .: amorphous; MS (DCI): 311 (M + l) + B) The diester from 5 a) was reacted according to Variant 1 B to give the diguanidide and transformed into the dihydrochloride. P.f .: > 235 * C; MS (DCI): 337 (M + l) + Example 6: 1- [3- (Guanidide of Z-2-fluoro-propenoyl) acid]] -2- [3- (E-2-methyl-propenoic acid guanidide)] benzene dihydrochloride 6 a) Monoaldehyde monoester 6 a) also isolated e? the preparation of 7 a) was transformed into the diester 6 b) with the help of 4 a). yellowish oil yellowish oil EM (Cl): 223 (M + l) + MS (Cl): 307 (M + l) + 6 c) The diester from 6 b) was reacted according to Variant 1 B to give the diguanidide and transformed into the dihydrochloride. P.f .: > 200'C; MS (ES): 333 (M + l) + Example 7: 1, 3-bis- [3- (Z-2-fluoro-propenoic acid)] benzene dihydrochloride 7 a) Using a known method of the literature (Cousseau et al., Tetrahedron Letters 34, 1993, 6.903), starting from 1,3-isophthalodialdehyde, 1,3-di- [3- (ethyl ester of Z-2-fluoro-propenoic acid]] benzene and purified on silica gel with mixtures of AE and HEP and isolated. Colorless solid material P.f .: amorphous; MS (Cl): 311 (M + 1) + 7 b) The diester from 7 a) was reacted according to Variant 1 B to give the diguanidide and transformed into the dihydrochloride. Yellow / orange solid material P.f .: > 180'C; MS (Cl): 337 (M + 1) + Example 8: Guanidide of 3- acid. { 4-chloro-3-gruanidinocarbonyl-5-phenyl) phenyl-2-methyl-propenoic acid 8 a) 3-Bromo-2-chloro-5-methyl-benzoic acid 25 g of 2-amino-3-bromo-5-methyl-benzoic acid were dissolved in 500 ml of a 6 N aqueous solution of HCl. they mixed O'C with 8.25 g of NaN02 and diazotized for 30 minutes at this temperature. This diazonium salt solution was then poured onto a warm solution at 40 ° C of 22 g of CuCl in 200 ml of a saturated aqueous solution of HCl and subsequently stirred for 20 minutes at this temperature. The product was filtered with suction, washed with 500 ml of water and dried at 40 ° C. in a thin vacuum, 23.3 g of white crystals were obtained, MP 170-172 * C, Rf: (AE / MeOH 5: 1) = 0.51, MS (DCI): 249 (M + H) + 8 b) 3-Bromo-2-chloro-5-dibromomethyl-benzoic acid 10 g of 3-bromo-2-chloro-5-methyl-benzoic acid were dissolved in 150 ml of chlorobenzene and heated to reflux. At this temperature, 7.2 g of N-bromo-succinimide and 0.5 g of benzoyl peroxide were added and refluxed for 30 minutes. Next, 7.2 g of N-bromo-succinimide and 0.5 g of benzoyl peroxide were added a second time and the mixture was refluxed for a further 3 hours. After cooling, 200 ml of EA were added, washed with 50 ml of a saturated aqueous solution of Na 2 SO 3 and 300 ml of a saturated aqueous solution of KH 2 PO 4 and the aqueous phase was extracted 2 times, each time with 200 ml of EA . It dried on Na 2 SO 4 and the solvent was removed in vacuo. Obtained 14.1 g of a yellow oil. Rf (DIP / 2% of HOAc) = 0.32 8 c) 3-Bromo-2-chloro-5-formyl-benzoic acid 11.7 g of AgN03 were dissolved in 150 ml of water and 150 ml of MeOH and a solution of 14 g of 3-aq. Acid was added dropwise. Bromo-2-chloro-5-dibromomethyl-benzoic acid in 100 ml of MeOH. It was subsequently stirred for 30 minutes at RT, 100 ml of a saturated aqueous solution of NaCl was added, the silver salts were filtered off with suction and the solvents were removed in vacuo. The residue was taken up in 200 ml of a 5% aqueous solution of KHS04 and extracted 3 times, each time with 200 ml of EA. It was dried over Na2SO4 and the solvent was removed in vacuo. Chromatography on silica gel with DIP / 2% HOAc gave 3.6 g of colorless crystals. P.f .: 148 * C; Rf (DIP / 2% HOAc) = 0.12; MS (DCI): 263 (M + H) + 8 d) 3-Bromo-2-chloro-5-formyl-benzoic acid ethyl ester 3.6 g of 3-bromo-2-chloro-5-formyl-benzoic acid were dissolved in 100 ml of EtOH, dropwise added dropwise 2.9 ml of S0C12, and boil at reflux for 5 hours. Then, the volatile components were removed in vacuo and the residue was chromatographed on silica gel with AE / HEP 1: 8. 2.7 g of a colorless oil were obtained. Rf (AE / HEP 1: 8) = 0.24; MS (DCI): 291 (M + H) + 8 e) 3- (3-Bromo-4-chloro-5-ethoxycarbonyl) phenyl-2-methyl-propenoic acid ethyl ester 2.7 g of the 3-bromo-2-chloro-3-ethyl ester 5-formyl-benzoic, analogously to Example 4 a), to a Wittig-Horner reaction and 3.4 g of a colorless oil were obtained. Rf (AE / HEP 1: 8) = 0.24; MS (DCI): 374 (M + H) + 8 f) 3- (4-Chloro-3-ethoxycarbonyl-5-phenyl) phenyl-2-ethyl-propenoic acid ethyl ester 3.3 g of 3- (3-bromo-4-chloro) ethyl ester were dissolved -5-ethoxycarbonyl) phenyl-2-methyl-propenoic acid, 1.23 g of phenylboronic acid, 2.14 g of Na2CO3, 576 mg of triphenylphosphine and 227 mg of Pd (0Ac) 2 in 150 ml of toluene and 40 ml of water and heated to reflux for 7 hours. It was then cooled to RT, mixed with 200 ml of EA and washed twice, each time with 100 ml of a saturated aqueous solution of Na 2 CO 3 as well as with 100 ml of a saturated aqueous solution of NaCl, dried over Na 2 SO 4. and the solvent was removed in vacuo. Chromatography on silica gel with AE / HEP 1: 8 gave 800 mg of a colorless oil. Rf (AE / HEP 1: 8) = 0.25 MS (DCI): 372 (M + H) + 8 g) 3- (4-Chloro-3-guanidinocarbonyl-5-phenyl) phenyl-2-methyl-propenoic acid guanidide 1.8 g of potassium t-butylate were dissolved in 100 ml of DMF, added thereto 1.82 g of guanidine hydrochloride and stirred for 1 hour at RT. Next, 700 mg of 3- (4-chloro-3-ethoxycarbonyl-4-phenyl) phenyl-2-methyl-propenoic acid ethyl ester was added and stirred for 5 hours at 100 ° C. The reaction mixture was poured into 200 ml of water and extracted 3 times, each time with 200 ml of EA. It was dried over Na2SO4 and the solvent was removed in vacuo. Chromatography on silica gel with acetone / water 10: 1 gave 170 mg of an amorphous foam. Rf (acetone / water 10: 1) = 0.23; MS (FAB): 399 (M + H) + Example 9: 1,3-Bis- [3- (E-2-methyl-propenoic acid)] -2-methoxy-5-methyl-benzene hydrochloride 9 a) 1 eq. of the 2-phosphono-propionic acid triethyl ester was deprotonated to O'C with 1 eq. of n-butyl-lithium in hexane and then it was mixed at RT with 0.5 eq. of 2-methoxy-5-methyl-l, 3-isophthalodialdehyde. After complete reaction of the dialdehyde, it was treated with water and extracted by stirring three times with toluene. After the combined organic phases were dried over magnesium sulfate, the solvent was removed in vacuo and the remaining crude product was separated by chromatography on silica gel with mixtures of AE and HEP as eluent. It was isolated: 1,3-di- [3- (ethyl ester of E-2-methyl-propenoic acid)] -2-methoxy-5-methyl-benzene. Colorless oil; MS (Cl): 347 (M + 1 +) 9 b) The diester from 9 a) was saponified according to a conventional method (sodium hydroxide in methanol). It was isolated: 1,3-di- [3- (E-2-methyl-propenoic acid)] -2-methoxy-5-methyl-benzene. Colorless solid material; P.f .: 196'C; MS (DCI): 290 (M +) 9 c) The dicarboxylic acid from 9 b) was transformed according to Variant 1 A into the diguanidide and isolated as hydrochloride. Colorless solid material; P.f .: 279 * C; MS (NIB): 373 (M + l) + Example 10: 1, 2-bis- (3- (guanidide of E-2-methyl-propenoic acid)] -4-methyl-benzene hydrochloride a, b) The diester of 4-methyl phthalic acid was converted according to a conventional method (eg reduction with lithium aluminum hydride) into the dialcohol 10 a). The alcohol was then oxidized in classical conditions (eg by oxidation of S ern) to give the dialdehyde 10 b).

Dialcohol 10 a): colorless oil: MS (DCI): 153 (M + l +) and 135 (M + l-H-O). Dialdehyde 10 b): dark oil, MS (Cl): 149 (M + l +) c) 1 eq. of the 2-phosphono-propionic acid triethyl ester was deprotonated at 0 * C with 1 eq. of n-butyl-lithium in hexane and then it was mixed at RT with 0.5 eq. of 4-methyl-1,2-phthalodialdehyde 10 b). After complete reaction of the dialdehyde it was treated with water and extracted by stirring three times with toluene. After the combined organic phases were dried over magnesium sulfate, the solvent was removed in vacuo and the remaining crude product was separated by chromatography on silica gel with mixtures of EA and HEP as eluent. It was isolated: 4-methyl-l, 2-di- [3- (ethyl ester of E-2-methyl-propenoic acid)] benzene. Colorless oil; MS (Cl) .- 317 (M + l +) D) The ester from 10 c) was saponified according to a conventional method (sodium hydroxide in methanol). It was isolated: 4-methyl-1,2-di- [3- (E-2-methyl-propenoic acid)] benzene.

Colorless solid material; P.f .: 194-198 * C; MS (Cl): 260 (M +) e) The dicarboxylic acid from 10 d) was transformed according to Variant 1 A into the diguanidide dihydrochloride. Colorless solid material, -P.f .: 190"C MS (ES): 342 (M + l) + Example 11: 1,2-bis [3- (guanidide of E-2-methyl-propenoic acid)] -4,5-dichloro-benzene dihydrochloride 11 a, b) The diethyl ester of 4,5-dichloro-phthalic acid was transformed according to a conventional method (eg reduction with lithium aluminum hydride) into the dialcohol 11 a). The alcohol was then oxidized under conventional conditions (eg by Swern oxidation) to give dialdehyde 11 b).

Dialcohol 11 a): colorless solid material, P.f. 147"C; MS (Cl): 207 (M + 1 +) Dialdehyde 11 b): amorphous solid material, MS (Cl): 203 (M + 1 +) 11 c) 1 eq. of the ethyl ester of 2-phosphono-propionic acid was deprotonated at 0 * C with 1 eq. of n-butyl lithium in hexane and then it was mixed at RT with 0.5 eq. of 4, 5-dichloro-1,2-phthalodialdehyde 11 b). After complete reaction of the dialdehyde it was treated with water and extracted by stirring three times with toluene. After having dried the organic phases After concentrating them over magnesium sulfate, the solvent was removed in vacuo and the remaining crude product was separated by chromatography on silica gel with mixtures of AE and HEP as eluent. It was isolated: 4, 5-dichloro-l, 2-di- [3- (ethyl ester of E-2-methyl-propenoic acid)] -benzene. Colorless oil; P.f. > 230 ° C; MS (Cl): 371 (M + 1 +) 11 d) The diester from 11 c) was transformed according to Variant 1 B into the diguanidide dihydrochloride. Colorless solid material; P.F .: > 220 * C; MS (ES): 397 (M + l) + Example 12: L-3-bis- [3- (E-propenoic acid)] benzene dihydrochloride 12 a) 1 eq. of triethyl phosphonoacetate was deprotonated at 0 ° C with 1 eq. of n-butyl lithium in hexane and then it was mixed at RT with 0.5 eq. of l, 3-isophthalodialdehyde. After complete reaction of the dialdehyde it was treated with water and extracted by stirring three times with toluene. After the combined organic phases were dried over magnesium sulfate, the solvent was removed in vacuo and the remaining crude product was separated by chromatography on silica gel with mixtures of EA and HEP as eluent. It was isolated: 1,3-di- [3- (ethyl ester of E-2-methyl-propenoic acid)] -benzene. Colorless oil; EM (Cl) .- 275 (M + l +) 12 b) The diester from 12 a) was saponified according to a conventional method (sodium hydroxide in methanol). It was isolated: 1,3-di- [3- (E-propenoic acid)] benzene. Colorless solid material; P.f .: > 200 * C; MS (DCI): 217 (M-l +) 12 c) The dicarboxylic acid from 12 b) was transformed according to Variant 1 A into the diguanidide dihydrochloride. Colorless solid material; P.f .: 296 * C; MS (ES): 301 (M + l) + Example 13: Di 1,2-bis- [3- (guanidide of E-2-methyl-propenoic acid)] -4-bromo-benzene hydrochloride 13 a, b) The dimethyl ester of 4-bromo-phthalic acid was converted according to a conventional method (eg by reduction with lithium aluminum hydride) into the dialcohol 13 a). The alcohol was then oxidized under standard conditions (eg by oxidation of S ern) to give the dialdehyde 13 b).

Dialcohol 13 a): colorless oil; MS (DCI): 217 (M + l +) and 199 (M + 1-H-O). Dialdehyde 13 b): Amorphous solid material, MS (Cl): 213 (M + l +) 13 c) 1 eq. of the 2-phosphono-propionic acid triethyl ester was deprotonated to O'C with 1 eq. of n-butyl lithium in hexane and then mixed at room temperature with 0.5 eq. of 4-bromo-l, 2-phthalodialdehyde 13 b). After complete reaction of the dialdehyde it was treated with water and extracted by stirring three times with toluene. After the combined organic phases were dried over magnesium sulfate, the solvent was removed in vacuo and the remaining crude product was separated by chromatography on silica gel with mixtures of EA and HEP as eluent. It was isolated: 4-bromo-l, 2-di- [3- (ethyl ester of E-2-methyl-propenoic acid)] -benzene. Colorless oil; MS (Cl): 381 (M, + 1 +) 13 d) The ester from 13 c) was saponified according to a conventional method (sodium hydroxide in methanol). It was isolated: 4-bromo-l, 2-di- [3- (E-2-methyl-propenoic acid)] benzene. Amorphous and colorless solid material, - MS (ES): 325 (M + l +) 13 e) The dicarboxylic acid from 13 e) was converted according to Variant 1 A into the diguanidide dihydrochloride. Solid colorless material, -P.f .: 240'C; MS (FAB): 407 (M + l) + Example 14: 1,2-Bis- [3- (E-2-methyl-propenoic acid)] -4- (4-methoxy-phenoxy) -benzene dihydrochloride 14 a) The dimethyl ester of 4-nitro phthalic acid was reacted analogously to a process known from the literature (J. Org Chem. Volume 42, No. 21, 1977, 3419-3 425) in DMF with the sodium salt of 4-methoxy phenolate to give the 4- (4-methoxy-phenoxy) phthalic acid dimethyl ester. After conventional treatment and chromatography with hexane / EA, the diester was isolated as a brownish oil. MS (Cl): 316 (M +); 317 (M + l +). 14 b, c) The diester 14 a) was converted according to a conventional method (eg reduction with lithium aluminum hydride) into the dialcohol 14 b). The alcohol was then oxidized under conventional conditions (eg by Swern oxidation) to give dialdehyde 14 c).

Dialcohol 14 b): brownish oil; MS (Cl): 260 (M +). Dialdehyde 14 c): brownish oil; MS (Cl): 257 (M + 1 +). 14 d) 1 eq. of the triethyl 2-phosphono-propionic acid ester was deprotonated at 0 ° C with 1 eq of n-butyllithium in hexane and then mixed with 0.5 eq of 1,2-phthalo-dialdehyde 14 c at RT. After complete reaction of the dialdehyde, it was treated with water and extracted by stirring three times with toluene After the combined organic phases had been dried over magnesium sulfate, the solvent was removed in vacuo. and the remaining crude product was separated by chromatography on silica gel with mixtures of EA and HEP as eluent. It was isolated: 1,2-di- [3- (ethyl ester of E-2-methyl-propenoic acid)] -4- (4-methoxy-phenoxy) benzene. Slightly brownish oil; MS (NBA): 424 (M +) 14 e) The diester from 14 d) was saponified according to a conventional method (sodium hydroxide in methanol). It was isolated: 1,2-di- [3- (E-2-methyl-propenoic acid)] -4- (4-methoxy-phenoxy) -benzene. Light yellow solid material; P.f .: 112 ° C; MS (ES): 368 (M +) 14 f) The dicarboxylic acid from 14 e) was transformed according to Alternative 1 A into the diguanidide dihydrochloride. Colorless solid material, -P.f .: 212 * C; MS (IS): 451 (M + l) + Example 15: 1,2-Bis- [3- (E-2-methyl-propenoic acid)] -4- (4-methyl-phenoxy) -benzene dihydrochloride a) The dimethyl ester of 4-nitro phthalic acid was reacted analogously to a process known from the literature (J. Org Chem. Volume 42, No. 21, 1977, 3419-3 425) in DMF with the sodium salt of 4-methyl phenolate to give the 4- (4-methyl-phenoxy) phthalic acid dimethyl ester. After classical treatment and chromatography with hexane / EA, the diester was isolated as a yellowish oil. MS (Cl): 301 (M + 1 +). b, c) The diester 15 a) was converted according to a conventional method (eg reduction with lithium aluminum hydride) into the dialcohol 15 b). The alcohol was then oxidized under conventional conditions (eg by Swern oxidation) to give the dialdehyde 15 c).

Dialcohol 15 b): yellowish oil, MS (Cl): 244 (M +), 245 (M + l +). Dialdehyde 15 c): brownish oil, MS (Cl): 241 (M + l +). d) 1 eq. of the 2-phosphono-propionic acid triethyl ester was deprotonated at 0 * C with 1 eq. of n-butyl-lithium in hexane and then it was mixed at RT with 0.5 eq. of 1,2-phthalo-dialdehyde 15 c). After complete reaction of the dialdehyde it was treated with water and extracted by stirring three times with toluene. After the combined organic phases were dried over magnesium sulfate, the solvent was removed in vacuo and the remaining crude product was separated by chromatography on silica gel with mixtures of EA and HEP as eluent. It was isolated: 1,2-di- [3- (ethyl ester of E-2-methyl-propenoic acid)] -4- (4-methyl-phenoxy) benzene. Slightly brownish oil; MS (NBA): 408 (M +), 409 (M + l +) E) The diester from 15 d) was saponified according to a conventional method (sodium hydroxide in methanol). It was isolated: 1,2-di- [3- (E-2-methyl-propenoic acid)] -4- (4-methyl-phenoxy) -benzene. Colorless solid material, - P.f .: 185'C; MS (NBA): 352 (M +) f) The dicarboxylic acid from 15 e) was transformed according to Alternative 1 A into the diguanidide dihydrochloride. Colorless solid material, -P.f .: 186 * C; MS (ES): 435 (M + l) + Example 16: 1,3-Bis- [3- (E-2-methyl-propenoic acid)] -5-methoxy-benzene hydrochloride 16 a) 1 eq. of the 2-phosphono-propionic acid triethyl ester was deprotonated to O'C with 1 eq. of n-butyl lithium in hexane and then it was mixed at RT with 0.5 eq. of 5-methoxy-l, 3-phthalodialdehyde. After complete reaction of the dialdehyde it was treated with water and extracted by stirring three times with toluene. After the combined organic phases were dried over magnesium sulfate, the solvent was removed in vacuo and the remaining crude product was separated by chromatography on silica gel with mixtures of EA and HEP as eluent. It was isolated: 1,3-di- [3- (ethyl ester of E-2-methyl-propenoic acid)] -5-methoxy-benzene. Colorless oil; MS (Cl): 333 (M + 1 +) 16 b) The diester from 16 a) was saponified according to a conventional method (sodium hydroxide in methanol). It was isolated: 1,3-di- [3- (E-2-methyl-propenoic acid)] -5-methoxy-benzene. Colorless solid material; P.f .: > 200'C; MS (DCI): 276 (M +) 16 c) The dicarboxylic acid from 16 b) was transformed according to Variant 1 A into the diguanidide and isolated as hydrochloride. Colorless solid material; P.f .: 124 * C; MS (NBA): 359 (M + l) + Example 17: 1,3-Bis- [3- (E-2-methyl-propenoic acid)] -5-t-butyl-benzene hydrochloride 17 a) 1 eq. of the triethyl ester 2-phosphono-propionic acid was deprotonated at 0 * C with 1 eq. of n-butyl lithium in hexane and then it was mixed at RT with 0.5 eq. of 5-t-butyl-l, 3-isophthalodialdehyde. After complete reaction of the dialdehyde it was treated with water and extracted by stirring three times with toluene. After the combined organic phases were dried over magnesium sulfate, the solution was removed in vacuo and the remaining crude product was separated by chromatography on silica gel with mixtures of AE and HEP as eluent. It was isolated: 1,3-di- [3- (ethyl ester of E-2-methyl-propenoic acid)] -5-t-butyl-benzene. Colorless oil; MS (Cl): 359 (M + 1 +) 17 b) The diester from 17 a) was saponified according to a conventional method (sodium hydroxide in methanol). It was isolated: 1,3-di- [3- (E-2-methyl-propenoic acid)] - 5-t-butyl-benzene. Colorless solid material; P.f .: > 200'C; MS (DCI): 302 (M +) 17 c) The dicarboxylic acid from 17 b) was transformed according to Variant 1 A into the diguanidide and isolated as hydrochloride. Colorless solid material; P.f .: 115 * C; MS (NBA): 385 (M + l +) Example 18: 1,4-bis- [3- (E-2-methylpropenoic acid guanidide)] -2,5-dichlorobenzene dihydrochloride 18 a) 1 eq. of the 2-phosphono-propionic acid triethyl ester was deprotonated at 0 * C with 1 eq. of n-butyl lithium in hexane and then it was mixed at RT with 0.5 eq. of 1,4- (2, 5-dichloro) -terephthalodialdehyde. After complete reaction of the dialdehyde it was treated with water and extracted by stirring three times with toluene. After the combined organic phases were dried over magnesium sulfate, the solvent was removed in vacuo and the remaining crude product was separated by chromatography on silica gel with mixtures of EA and HEP as eluent. It was isolated: l, 4-di- [3- (ethyl ester of E-2-methyl-propenoic acid)] -2,5-dichloro-benzene. Colorless solid material, -P.f .: amorphous; MS (DCI): 371 (M + l +) B) The diester from 18 a) was saponified according to a conventional method (sodium hydroxide in methanol). It was isolated: 1,4-di- [3- (E-2-methyl-propenoic acid)] -2,5-dichloro-benzene. Colorless solid material, - MS (DCI): 315 (M + l +) 18 c) The dicarboxylic acid from 18 b) was transformed according to Variant 1 A into the diguanidide dihydrochloride. Yellow solid material P.f .: > 200 * C; MS (DCI): 397 (M + l) + Example 19: 1,2-Bis- [3- (E-2-methylpropenoic acid guanidide)] -4- (phenoxy) -benzene dihydrochloride 19 a) The dimethyl ester of 4-nitrophthalic acid was reacted analogously to a procedure known from the literature (J. Orgr. Chem. Tome 42, Nc 21, 1977, 3. 419-3 .425) in DMF with the sodium phenolate salt to give the 4-phenoxy-phthalic acid dimethyl ester. After conventional treatment and chromatography with hexane / EA, the diester was isolated as a yellowish oil. EM < CI): 287 (M + l +). 19 b, c) The diester 19 a) was converted according to a conventional method (eg reduction with lithium aluminum hydride) into the dialcohol 19 b). The alcohol was then oxidized under conventional conditions (eg by Swern oxidation) to give the dialdehyde 19 c).

Dialcohol 19 b): yellowish oil, MS (Cl): 230 (M +), 231 (M + l +). Dialdehyde 19 c): brownish oil, MS (Cl): 227 (M + l +). 19 d) 1 eq. of the triethyl ester of 2-phosphono-propionic acid was deprotonated at 0 ° C with 1 eq of n-butyllithium in hexane and then mixed with 0.5 eq of 1,2-phthalo-dialdehyde at RT. 19 c) After complete reaction of the dialdehyde, it was treated with water and extracted by stirring three times with toluene After drying the combined organic phases over magnesium sulfate, the solvent was removed in vacuo. and the remaining crude product was separated by chromatography on silica gel with mixtures of EA and HEP as eluent. It was isolated: 1,2-di- [3- (ethyl ester of E-2-methyl-propenoic acid)] -4- (phenoxy) benzene. Slightly brownish oil; MS (NBA): 394 (M +), 395 (M + l +) 19 e) The diester from 19 d) was saponified according to a conventional method (sodium hydroxide in methanol). It was isolated: 1,2-di- [3- (E-2-methyl-propenoic acid)] -4- (phenoxy) benzene. Colorless solid material; P.f .: 160'C; MS (NBA): 338 (M +) 13 f) The dicarboxylic acid from 19 e) was transformed according to Variant 1 A into the diguanidide dihydrochloride. Colorless solid material, - P. f. : 170 * C; MS (IS): 421 (M + l) + Example 20: 1,2-Bis- [3- (E-2-methyl-propenoic acid)] -4- (methoxy) benzene dihydrochloride Analogously to Example 19, the compound of Example 20 was prepared by nucleophilic aromatic substitution of the ester of 4-nitro phthalic acid with sodium methylate, and subsequent reduction / oxidation / reaction of olefination, saponification and guanidation of the diacid. a) Diester of 4-methoxy phthalic acid EM (Cl): 225 (M + l +) Dialcohol 20 b): yellowish-brown oil; MS (Cl): 169 (M + 1 +) - Dialdehyde 20 c): dark oil, MS (Cl); 165 (M + l +). Diester 20 d): dark oil; MS (NIB): 333 (M + l +). 20 e) 1,2-di [3- (E-2-methyl-propenoic acid)] -4- (methoxy) -benzene colorless solid material; P.f .: > 200'C; MS (NBA): 276 (M +) F) The dicarboxylic acid from 20 e) was transformed according to Variant 1 A into the diguanidide dihydrochloride. Colorless solid material; P.f .: 170 * C; MS (ES): 359 (M + 1) +.

Example 21: 1,2-Bis- [3- (E-2-methyl-propenoic acid)] -4- (ethoxy) -benzene dihydrochloride 21 a) The diethyl ester of 4-ethoxy phthalic acid was prepared by ethylation of 4-hydroxy phthalic acid with 3.5 equivalents of ethyl iodide and 3.1 equivalents of potassium carbonate in DMF at 70 * C. Next, the diester was prepared by reduction / oxidation / olefination reaction, which was transformed according to Variant 1B into diguanidide 21. 21 a) Diethyl ester of 4-ethoxy phthalic acid, dark oil; MS (Cl): 267 (M + 1 +) Dialcohol 21 b): brownish-yellow oil; MS (Cl): 183 (M + 1") Dialdehyde 21 c): dark oil, MS (Cl) 179 (M + 1 +) Diester 21 d): yellowish oil MS (NBA): 347 (M + l + ) 21 f) The diester 20 d) was transformed according to Variant 1 B into the diguanidide dihydrochloride. Colorless solid material, -P.f .: 245'C; MS (ES): 373 (M + l) + Example 22: 1,2-bis- [3- (E-2-methyl-propenoic acid)] -4- (3-pyridyloxy) -benzene dihydrochloride 22 a) The dimethyl ester of 4-nitro phthalic acid was reacted analogously to a process known from the literature (J. Org.Chem.motion 42, No. 21, - 1977, 3. 419-3.425) in DMF with the sodium salt of 3-hydroxy-pyridine to give the 4- (3-pyridyloxy) phthalic acid dimethyl ester. After the classical treatment and chromatography with hexane / EA, the diester was isolated as a yellowish oil. MS: 288 (M + l +) 22 b, c) The diester 22 a) was converted according to a conventional method (for example, reduction with lithium aluminum hydride) into the dialcohol 22 b). The alcohol was then oxidized under conventional conditions to give dialdehyde 22 c) (eg by Swern oxidation) Dialcohol 22 b): yellowish oil, MS: 232 (M + l +). Dialdehyde 22 c): yellowish-brown oil, MS: 228 (M + l +). 22 d) 1 eq. of the 2-phosphono-propionic acid triethyl ester was deprotonated at 0 * C with 1 eq. of n-butyl lithium in hexane and then it was mixed at RT with 0.5 eq. of 1,2-phthalo-dialdehyde 22 c). After complete reaction of the dialdehyde it was treated with water and extracted by stirring three times with toluene. After the combined organic phases were dried over magnesium sulfate, the solvent was removed in vacuo and the remaining crude product was separated by chromatography on silica gel with mixtures of EA and HEP as eluent. It was isolated: 1,2-di- [3- (ethyl ester of E-2-methyl-propenoic acid)] -4- (3-pyridyloxy) benzene. Slightly brownish oil; MS: 396 (M + l +) 22 e) The diester from 22 d) was saponified according to a conventional method (sodium hydroxide in methanol). It was isolated: 1,2-di- [3- (E-2-methyl-propenoic acid)] -4- (3-pyridyloxy) -benzene. Colorless solid material; P.f. : 210 ° C; MS: 339 (M +) 22 f) The dicarboxylic acid from 22 e) was transformed according to Variant 1 A into the diguanidide dihydrochloride. Solid colorless material, -P.f .: 176'C; MS: 422 (M + l) + Example 23: 1,2-Bis- [3- (2-methyl-propenoic acid guanidide]] -4- [4- (2-dimethylamino-ethylene) -phenoxyl-benzene dihydrochloride 23 a) The dimethyl ester of 4-nitro phthalic acid was reacted analogously to a process known from the literature (J. Org Chem. Volume 42, N 21, 1977, 3419-3 425) in DMF with the sodium salt of 4- (2-dimethylamino-ethylene) -phenol to give the 4- [4- (2-dimethylamino-ethylene) -phenoxy] -phthalic acid dimethyl ester After classical treatment and chromatography with hexane / EA, it was isolated the diester, MS: 358 (M + 1 +). 23 b, c) The diester 23 a) was converted according to a conventional method (reduction with lithium aluminum hydride) into the dialcohol 23 b). The alcohol was then oxidized according to Dess-Martin (see Dess-Martin oxidation, JOC, 1994, 59, 7,549-7, 552) to give the dialdehyde 23 c).

Dialcohol 23 b): yellow-brown oil, MS: 340 (M + l +). Dialdehyde 23 c): yellowish oil, MS: 269 (M + l +). 23 d) 1 eq. of the 2-phosphono-propionic acid triethyl ester was deprotonated at 0 * C with 1 eq. of n-butyl lithium in hexane and then it was mixed at RT with 0.5 eq. of 1,2-phthalo-dialdehyde 23 c). After complete reaction of the dialdehyde it was treated with water and extracted by stirring three times with toluene. After the combined organic phases were dried over magnesium sulfate, the solvent was removed in vacuo and the remaining crude product was separated by chromatography on silica gel with mixtures of EA and HEP as eluent. It was isolated: 1,2-bis- [3- (ethyl ester of E-2-methyl-propenoic acid)] -4- [4- (2-dimethylamino-ethylene) -phenoxy] -benzene. Yellowish oil; MS: 466 (M + 1 +). 23 e) The diester from 23 d) was saponified according to a conventional method (sodium hydroxide in methanol). It was isolated: 1, 2-bis- [3- (E-2-methyl-propenoic acid)] -4- [4- (2-dimethylamino-ethylene) -phenoxy] -benzene. Colorless solid material, - P.f .: > 220 * C; MS: 409 (M +) 23 f) The dicarboxylic acid from 23 e) was converted according to Variant 1 A into the diguanidide dihydrochloride. MS: 410 (M + l) + Examples 24 and 25: 1,2-Bis- [3- (E-2-methyl-propenoic acid)] -4- [4-methoxy-benzyloxy] benzene dihydrochloride and 1,2-bis- dihydrochloride [1] 3 - (E-2-methyl-propenoic acid guanidide)] -4-hydroxy-benzene 24 a) 1 eq. of the dimethyl ester of 4-hydroxy phthalic acid, 1.1 eq. of potassium carbonate and 1.1 eq. of 4-methoxy-benzyl chloride were stirred in DMF at RT. After 4 days, it was treated according to a classic prescription. The 4- (4-methoxy-benzyloxy) phthalic acid dimethyl ester was isolated as a colorless oil. MS: 331 (M + 1 +) 24 b, c) The diester 24 a) was converted according to a conventional method (reduction with lithium aluminum hydride) into the dialcohol 24 b). The alcohol was then oxidized according to a classical prescription (Swern oxidation) to give the dialdehyde 24 c).

Dialcohol 24 b): amorphous solid material, - MS: 275 (M + l +). Dialdehyde 24 c): yellowish oil, MS: 271 (M + l +). 24 d) 1 eq. of the 2-phosphono-propionic acid triethyl ester was deprotonated at 0 * C with 1 eq. of n-butyl lithium in hexane and then it was mixed at RT with 0.5 eq. of 1,2-phthalo-dialdehyde 24 c). After complete reaction of the dialdehyde it was treated with water and extracted by stirring three times with toluene. After the combined organic phases were dried over magnesium sulfate, the solvent was removed in vacuo and the remaining crude product was separated by chromatography on silica gel with mixtures of EA and HEP as eluent. It was isolated: 1,2-bis- [3- (ethyl ester of E-2-methyl-propenoic acid)] -4- [4-methoxy-benzyloxy) -benzene as a yellowish oil. MS: 439 (M + l +) 24 e) The diester from 24 d) was saponified according to a conventional method (sodium hydroxide in methanol). It was isolated: 1,2-bis- [3- (E-2-methyl-propenoic acid)] -4- [4-methoxy-benzyloxy] -benzene, solid colorless material. P.f .: 206-220'C; MS: 382 (M +) 24 f) The dicarboxylic acid from 24 e) was transformed according to Variant 1 A into the diguanidide dihydrochloride. P.f .: 210 'C; MS: 465 (M + l) + Example 25: 1,2-Bis- [3- (E-2-methyl-propenoic acid)] -4- hydroxy-benzene dihydrochloride The dicarboxylic acid from 24 e) was reacted according to Alternative 1 A for give the diguanidide dihydrochloride. Apart from the compound of Example 24, Product 25 was isolated. MS: 345 (M + 1) + Pharmacological data: Rabbit erythrocyte Na + and H + exchanger inhibitors (subtype I; NHE-l): New Zealand white rabbits (Ivanovas) received a classic diet with 2% cholesterol for six weeks, to activate the exchange between Na + and H + and thus determine by flame photometry the influx of Na + into the erythrocytes through the exchange between Na + and H +. The blood was extracted from the arteries of one ear and made uncoagulable with 25 IU / ml heparin-potassium. A part of each sample was used for the double determination of the hematocrit by centrifugation. Aliquots, in each case 100 μl, were used to measure the initial Na + content of the erythrocytes. To determine the influx of sodium sensitive to amiloride, 100 μl of each blood sample was incubated each time in 5 ml of a hyperosmolar salt and sucrose medium (mmol / L: 140 NaCl, 3 KCl, 150 sucrose, 0.1 ouabain, 20 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 MgCl 2 and ouabain (mmol / 1: 112 MgCl 2, 0.1 ouabain) 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 initial values of sodium and the sodium content of erythrocytes after incubation. The influx of inhibible sodium by amiloride was established from the difference of the sodium contents of the erythrocytes after incubation with and without amiloride 3 x 10"4 mol / 1. according to the invention.

Results of the inhibition of the exchanger between Na + and H + (subtype 1, NHE-1): Example (see experimental part) IC50 (μmol) 4 4 [IC50 = 50% inhibitory concentration] Most molecular biology techniques follow protocols taken from the works "Current Protocols in Molecular Biology (compilers Ausubel, FM, Brent, R., Kingston, RE, Moore, DD, Seidman, JG Smith, JA and Struhl, K, John Wiley &Sons) "or" Molecular Cloning: A Laboratory Manual (Sambroock, J., Fristsch, EF and Mania -tis, T., Cold Spring Harbor Laboratory Press (1989)) ". In the framework of the work of the present authors, stably transfected cell lines were produced, expressing in each case one of the following NHE subtypes: NHEl from a human being (Sardet et al., Cell 56, 271-280 (1989)); Rabbit NHE2 (Tse et al., J. Biol. Chem. 268, 11 917-11924 (1993)) or rat NHE3 (Orlowski et al., J. Biol. Chem. 267, 9. 331 -9.339 (1992) ). The cDNA clones, obtained by Professor Pouysségur, of the respective subtypes of NHE were introduced by cloning, after having added appropriate linker sequences, in the expression plasmid pMAMneo (obtainable, for example, through the CLONTECH entity, Heidelberg) in such a way that the NHE 1 recognition sequence of the plasmid is located at approximately 20-100 base pairs in front of the initiation codon of the respective subtype of NHE and that the entire coding sequence is present in the construction (artificial entity). With the so-called "calcium phosphate method" (described in chapter 9.1 of "Current Protocols in Molecular Biology"), the LAP1 cell line deficient in NHE was transfected (Franchi et al., Proc. Nati. Acad. Sci. USA 83 , 9.388-9.392 (1986)) with the plasmids, which obtain the respective coding sequences of the NHE subtypes. After selection for transfected cells through growth in a medium containing G418 (only cells, which have obtained by transfection a neo-gene, can survive under these conditions) was selected for functional expression of NHE. For this, the "Acid Load" technique described by Sardet (_7ardet eü., Cell 56, 271-280 (1989)) was used. The cells, which express a subtype of functional NHE, can compensate, also in the absence of C02 and HC03, for the acidification carried out in this assay and, on the other hand, untransfected LAP1 cells can not compensate for it. At the time of the "Acid Load" selection, the surviving cells were seeded in microtiter plates in such a way that, statistically, one cell per well should be presented, and after a microscope, after about 10 days, how many colonies grew per well? Cell populations from individual colonies were investigated with the XTT proliferation kit (Boehringer Mannheim entity) for their ability to survive according to "Acid Load." The best cell lines were used for subsequent trials and, in order to avoid a loss of the transfected sequence, were cultured under constant selection pressure in a medium containing G 418. For the determination of IC 50 values for the inhibition of individual NHE subtypes by specific substances, an assay developed by S. Faber (Faber et al.; Cell. Physiol. Biochem. 6, 39-49 (1996)), which is based on the "Acid Load" technique.

In this test the recovery of the intracellular pH was determined (pH ^ after acidification, which is established in the case of a functional NHE also under bicarbonate-free conditions.) For this, the pHi was determined with the fluorescent dye, sensitive to pH , BCECF (Calbiochem entity, the precursor compound BCECF-AM is used) The cells were first loaded with BCECF The fluorescence of BCECF was determined in a "Ratio Fluorescence Spectrometer = Fluorescence Ratio Spectrometer" (entity Photon Technology International, South Brunswick, N.J., USA) with excitation wavelengths of 505 and 440 nm and an emission wavelength of 535 nm and was converted by calculation into pH¿ by calibration curves. By deviating from the protocol described, the cells were already incubated when loading with BCECF in an NH4C1 buffer (pH 7.4) (NH4C1 buffer: 115 mM NaCl, 20 mM NH4C1, 5 mM KCl, 1 mM CaCl2, 1 mM MgSO4, 20 mM hepes, 5 mM glucose, 1 mg / ml BSA; with 1 M NaOH a pH of 7.4 is adjusted). Intracellular acidification was induced by the addition of 975 μl of an NH4C1-free buffer to 25 μl aliquots of cells incubated in NH4C1 buffer. The subsequent rate of recovery of the pH value was recorded in the case of NHEl at 2 minutes, in the case of NHE2 at 5 minutes and in the case of NHE3 at 3 minutes. To calculate the inhibitory potency of the tested substances, the cells were first investigated in buffers, in which a full pH recovery took place or no recovery of the pH took place at all. For total pH recovery (100%), the cells were incubated in a buffer containing Na + (133.8 mM NaCl, 4.7 mM KCl, 1.25 mM CaCl2, 1.25 mM MgCl2, 0.27 Na2HP02. mM, 0.23 mM NaH2P04, 5 mM Hepes, 5 mM glucose, a pH of 7.0 is adjusted with 1 M NaOH). For the determination of the 0% value, the cells were incubated in a Na + free buffer (133.8 mM choline chloride, 4.7 mM KCl, 1.25 mM CaCl2, 1.25 mM MgCl2, 0.97 mM K2HP02. , 0.23 mM KH2P04, 5 mM Hepes, 5 mM glucose, adjusted to a pH of 7.0 with 1 M NaOH). The substances to be tested were formulated in the buffer containing Na +. The Recovery of intracellular pH with each tested concentration of a substance was expressed as a percentage of maximum recovery. From the percentage values of the recovery of the pH, the Cl50 value of the respective substance for the individual NHE subtypes was calculated using the SigmaPlot program.

IC50, NHE-3 Example 1 0.7 Example 6 3.2 Example 9 1.75 Example 3 1.1

Claims (20)

Claims

1.- Guanidides of phenyl-substituted alkenyl carboxylic acids of the formula I where: T means R (A) means hydrogen, F, Cl, Br, I, CN, OH, OR (6), alkyl (Cx-C4), Or (CH2) aCbF2b + 1, cycloalkyl (C3-C8) or NR (7) R (8) r means zero or 1; a means zero, 1, 2, 3 or 4; b means 1, 2, 3 or 4, - R (6) means alkyl (CLC ^, perfluoroalkyl (C ^ Cj), alkenyl (C3-C6), cycloalkyl (C3-C8), phenyl or benzyl, the nucleus being phenyl unsubstituted or substituted with 1-3 substituents selected from group consisting of F, Cl, CF3, methyl, methoxy and NR (9) R (10); R (9) and R (10) mean H, (C 1 -C 4) alkyl or perfluoro (C 1 -C 4) alkyl; R (7) and R (8) independently of one another are defined such as R (6); or R (7) and R (8) mean in common 4 or 5 methylene groups, of which a CH2 group can be replaced by oxygen, sulfur, NH, N-CH3 or N-benzyl; R (B), R (C) and R (D) independently of each other, are defined such as R (A); x means zero, 1 or 2, -y means zero, 1 or 2; R (F) means hydrogen, F, Cl, Br, I, CN, 0R (12), alkyl (-C8), Op (CH2) fCgF2g + 1, cycloalkyl (C3-C8) or heteroaryl (C ^ Cg); p means zero or l; f means zero, 1, 2, 3 or 4; g means 1, 2, 3, 4, 5, 6, 7 or 8; R (12) means alkyl (CL-C8), perfluoroalkyl (CLC ^, (C3-C8) alkenyl, (C3-C8) cycloalkyl, phenyl or benzyl, the phenyl nucleus being unsubstituted or substituted with 1-3 selected substituents between the group consisting of F, Cl, CF3, methyl, methoxy and NR (13) R (14); R (13) and R (14) mean H, alkyl (C ^ Cj) or perfluoroalkyl (Cx-C4) , -R (E) independently, is defined such as R (F); R (I) independently is defined as T; or R (l) means hydrogen, -OkC-H2- + ?, -On (CH2) pCqF2q + 1, F, Cl, Br, I, Cn, - (C = 0) -N «C (NH2) 2, -SOrR (17), -SOr2NR (31) R (32); -Ou (CH2) VC6H5, -Ou2- (C1-C9) heteroaryl or -Su2-heteroaryl (C? -C9); means zero or 1; m means zero, 1, 2, 3, 4, 5, 6, 7 or 8; n means zero or 1; p means zero, 1, 2, 3 or 4; q means 1, 2, 3, 4, 5, 6, 7 or 8; r2 represents zero, 1, 2; R (31) and R (32) independently represent among them hydrogen, Ci to C8 alkyl, or perfluoroalkyl of Ci to Cß or R (31) and R (32) together represent 4 to 5 methylene groups, of which a CH2 group may be substituted by oxygen, S, NH, N-CH3 or N-benzyl; R (17) means alkyl (C? -C8); u means zero or 1; u2 means zero or 1; v means zero, 1, 2, 3 or 4; the phenyl nucleus being unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy, - (CH2) WNR (21) R (22), NR (18) R ( 19) and heteroaryl (C_-C9); R (18), R (19), R (21) and R (22) Independently from each other, mean (C 1 -C 4) alkyl or perfluoro (C 1 -C 4) alkyl; w means 1, 2, 3 or 4; the heteroaryl heterocycle (C ^ Cg) being unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, 'methyl or methoxy; R (2), R (3), R (4) and R (5) Independently of one another, are defined such as R (l), or R (l), R (2) or R (2) and R (3) mean in each case in common -CH-CH = CH-CH-, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy, - (CH2) w2NR (24) R (25) and NR (26) R (27); R (24), R (25), R (26) and R (27) mean H, (C 1 -C 4) alkyl or perfluoro (C 1 -C 4) alkyl, w 2 means 1, 2, 3 or 4, -the radical T in the molecule at least twice, but only at most three times; as well as its pharmaceutically compatible salts.

2. Compound of formula I according to claim 1, wherein T means R (A) means hydrogen, F, Cl, CN, OH, OR (6), alkyl (-d), Or (CH 2) aCbF 2b + 1, cycloalkyl (C 3 -C 8) or NR (7) R (8); r means zero or 1; a means zero, 1 or 2; b means 1, 2, 3 or 4; R (6) means (C 1 -C 4) alkyl, (C 1 -C 4) perfluoroalkyl, phenyl or benzyl, the phenyl nucleus being unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3, methyl, methoxy and NR (9) R (10); R (9) and R (10) independently of one another mean H, CH 3 or CF 3; R (7) and R (8) independently of one another, are defined such as R (6), - or R (7) and R (8) mean in common 4 or 5 methylene groups, of which a CH2 group it can be replaced by oxygen, sulfur, NH, N-CH3 or N-benzyl; R (B) # R (C) and R (D) independently, are defined such as R (A); x means zero or 1; and means zero or 1; R (F) means hydrogen, F, Cl, CN, OR (12), alkyl (-C ^, Op (CH2) fCgF2g + 1, cycloalkyl (C3-C8) or heteroaryl (C ^ Cg), - p means zero or 1; f means zero, l or 2, g means 1, 2, 3 or 4, R (12) means alkyl (CLC ^), perfluoroalkyl (^ - ^), cycloalkyl (C3-C8), phenyl or benzyl, the phenyl nucleus being unsubstituted or substituted of 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR (13) R (14); R (13) and R (14) independently one of another, they mean H, CH3 or CF3; R (E) independently, is defined such as R (F), -R (l) independently, is defined such as T, -o R (l) means hydrogen, -Oj -Cy ^,. ^, -OnCqF2q + 1, F, Cl, Br, I, CN, - (C = 0) -N = C (NH2) 2, -SOrR (17), -SOr2NR (31) R ( 32), -0_ (CH2) .C ^ s, -0u2-heteroaryl (C ^ Cg) or -Su2-heteroaryl (Ci-Cg); k means zero or 1; means zero, 1, 2, 3 or 4; n means zero or 1; q means 1, 2, 3 or 4; r2 represents zero, 1, 2; R (31) and R (32) independently of each other mean hydrogen, C 1 -C 4 alkyl, or perfluoroalkyl of Ci to C 4; or R (31) and R (32) together represent 4 to 5 methylene groups, of which a CH2 group can be substituted by oxygen, S, NH, N-CH3 or N-benzyl; R (17) means (C 1 -C 4) alkyl u means zero or 1; u2 means zero or .1; v means zero, 1 or 2; the phenyl nucleus being unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy, - (CH2) "NR (21) R (22), NR (18) R (19) or heteroaryl (C1-C9); R (18), R (19), R (21) and R (22) mean H, (C 1 -C 4) alkyl or perfluoro (C 1 -C 4) alkyl; w means 1, 2, 3 or 4; the (C1-C9) heteroaryl heterocycle being unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl or methoxy; R (2), R (3), R (4) and R (5) independently of one another are defined as R (1), or R (l) and R (2) or R (2) and R (3) they mean in each case in common -CH-CH = CH-CH-, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy, - (CH2) " 2NR (24) R (25) and NR (26) R (27); R (24), R (25), R (26) and R (27) mean H, CH 3, or CF 3; 2 means 1, 2, 3 or 4; the radical T is present in the molecule, however, only twice.

3. - Compound of the formula according to claim 1 or 2, wherein T means x means zero; and means zero; R (F) means hydrogen, F, Cl, CN OR (12), alkyl (C? -C4), -OpCgF2g + ?, (C3-C8) cycloalkyl (C1-C9) heteroaryl; p means zero or 1; g means 1, 2, 3 or 4; R (12) means (C1-C4) alkyl, CF3, (C3-C8) cycloalkyl, phenyl or benzyl, the phenyl nucleus being in each case unsubstituted or substituted of 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR (13) R (14); R (13) and R (14) mean H, CH 3 or CF 3; R (E) independently, is defined as R (F); R (I) independently is defined as T; or R (l) means hydrogen, -OkC i, -0"CqF2 < I + 1, F, Cl, CN, - (C = 0) -N = C (NH2) 2, -S02CH3, -S02NR (31) R (32), -Ou (CH2) VC6H5, -0 __- heteroaryl ( C1-C9) or -S ^ -heteroaryl (C1-C9); means zero or 1; means zero, 1, 2, 3 or 4; n means zero or 1; q means 1, 2, 3 or 4; R (31) and R (32) independently represent hydrogen, or C1-C4 alkyl, or R (31) and R (32) together represent 4 to 5 methylene groups, of which a CH2 group may be substituted by oxygen, S, NH, N-CH3 or N-benzyl; u means zero or 1; u2 means zero or 1; v means zero or 1; the phenyl nucleus being unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy, - (CH2) "NR (21) R (22), NR (18) R (19); R (18), R (19), R (21) and R (22) independently of each other, mean H, (C 1 -C 4) alkyl or perfluoro (C 1 -C 4) alkyl; w means 1, 2, 3 or 4; the (C1-C9) heteroaryl heterocycle being unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl or methoxy; R (2), R (3), R (4) and R (5) independently of each other, are defined such as R (1), or R (l) and R (2) or R (2) and ( R3) mean in each case in common -CH-CH = CH-CH-, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy, - (CH2) w2NR (24) R (25) and NR (26) R (27); R (24), R (25), R (26) and R (27) independently mean H, (C 1 -C 4) alkyl or perfluoro (C 1 -C 4) alkyl; w2 means 1, 2, 3 or 4; the radical T is present in the molecule, however, only twice.

4. - Compounds of the formula I according to one or more of claims 1 to 3, which are: 1, 2-bis- [3- (E-2-methyl-propenoic acid guanidine)] benzene dihydrochloride], 1,3-Bis- [3- (E-2-methyl-propenoic acid guanidide)] benzene, 1,4-bis- [3- (E-2-methyl-propenoic acid guanidide) dihydrochloride] benzene, 2,3-bis- [3- (E-2-methyl-propenoic acid)] naphthalene dihydrochloride, 1,2-bis- [3- (Z-2-fluoro-propenoic acid guanidide dihydrochloride )] benzene, 1- [3- (guanidide of Z-2-fluoro-propenoic acid)] -2- [3- (E-2-methyl-propenoic acid guanidide)] -benzene, l-dihydrochloride dihydrochloride, 3-bis- [3- (Z-2-fluoro-propenoic acid guanidide)] benzene, 3- (4-chloro-3-guanidinocarbonyl-5-phenyl) -phenyl-2-methyl-propenoic acid guanidide, hydrochloride of 1, 3-bis- [3- (E-2-methyl-propenoic acid guanidide)] -2-methoxy-5-methyl-benzene, 1,2-bis- [3- (E-guanidide dihydrochloride -2-methyl-propenoic acid)] -4-methyl-benzene, 1,2-bis- [3- (E-2-methyl-propenoic acid guanidide)] -4,5-dichloro-benzene dihydrochloride, dihydrochloride 1, 3-bis- [3- (guanidide from acid E-propenoi-co)] benzene, 1,2-bis- [3- (E-2-methyl-propenoic acid guanidide)] -4-bromobenzene, 1,2-bis- dihydrochloride 3- (E-2-methyl-propenoic acid guanidide)] -4- (4-methoxy-phenoxy) benzene, 1,2-bis- [3- (guanidide of E-2-methyl-propenoic acid) dihydrochloride) ] -4- (4-methyl-phenoxy) benzene, 1,3-bis- [3- (guanidide from E-2-methyl-propenoic acid)] -5-methoxy-benzene hydrochloride, hydrochloride from 1, 3- bis- [3- (E-2-methyl-propenoic acid guanidide)] -4-t-butyl-benzene, 1,4-bis- [3- (guanidide of E-2-methyl-propenoic acid) dihydrochloride) ] -2,5-dichlorobenzene, 1,2-bis- [3- (guanidide of E-2-methyl-propenoic acid)] -4- (phenoxy) -benzene dihydrochloride, 1, 2-bis- [3- (E-2-methyl-propenoic acid guanidide)] -4- (methoxy) -benzene dihydrochloride, 1,2-bis- [3- (E-acid guanidide dihydrochloride 2-methyl-propenoic)] -4- (ethoxy) -benzene and 1,2-bis- [3- (guanidide of E-2-methyl-propenoic acid)] -4- (3-pyridyloxy) - dihydrochloride benzene.

5. Process for the preparation of a compound I, characterized in that a compound of the formula II is reacted with guanidine where R (l), R (2), R (3), R (4), R (5), R (A), R (B), R (C), R (D), R ( E) and R (F) have the indicated meanings and X and y, L represents a labile group easily substitutable in a nucleophilic manner.

6. - Use of a compound I according to claim 1 for the preparation of a medicament for the treatment of arrhythmias.

7. 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 additive materials and administered in an appropriate presentation form.

8. Use of a compound I according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of cardiac infarction.

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 or prophylaxis of ischemic heart conditions. eleven . - 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. 12 - 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. 13 - Use of a compound according to claim 1, for the preparation of a medicament for the treatment of shock states. 14 - Use of a compound according to the claim 1, for the preparation of a medicine intended for use in surgical operations and organ transplants. fifteen . - Use of a compound 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 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. 17 - Use of a compound according to claim 1, for the preparation of a medicament for the treatment or prophylaxis of disorders of fat metabolism. 18 - Use of a compound according to claim 1 for the preparation of a medicament for the treatment or pro-filaxis of disturbed respiratory distress disorders. 19. The use of a compound I according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of acute and chronic diseases of the kidneys, especially for an acute or chronic inoperability of the kidneys. twenty . - Drug, which contains an effective amount of a compound 1 according to one or more of claims 1 to 4.