MXPA97001163A - Guidelines of substitute thiophenyl alcoholic substitute acids, procedure for its preparation, its employment as a medicine or diagnostic agent, as well as a medication that contains them - Google Patents

Abstract

The present invention relates to substituted thiophenylalkenylcarboxylic acid guanidines of the formula I: wherein R (1) to R (5) have the meanings indicated in the claims, are extraordinarily active antiarrhythmic drugs with a cardioprotective component and are extremely suitable for prophylaxis of the infarction and the treatment of the infarction, as well as for the treatment of the angina of chest, inhibiting or reducing strongly also of preventive form the pathophysiological processes in the appearance of injuries induced by ischemia, especially in the triggering of arrhythmias of the heart induced by ischemia.

Description

Guanidides of substituted thiophenyl uenylcarboxylic acids, process for their preparation, their use as a medicament or diagnostic agent, as well as medicament containing them The invention concerns guanidides of substituted thiophenylalkenylcarboxylic acids of the formula I wherein: at least one of the substituents R (l); R (2) and R (3) mean • On (CH2) ß-CqF2qtl, R (40) CO- OR R (31) SOk-; p means zero or 1; s means zero, 1, 2, 3 or 4 means 1, 2, 3, 4, 5, 6, 7 or 8; k. means zero, 1 or 2; R (40) means alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, perfluoroalkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, cycloalkyl with 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, CF3, methyl and methoxy; R (31) means alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, perfluoroalkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, cycloalkyl with 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, CF3, methyl or methoxy; or R (31) means NR (41) R (42); R (41) and R (42) signify, independently of one another, hydrogen, alkyl with 1, 2, 3 or 4 carbon atoms, perfluoroalkyl with 1, 2, 3 or 4 carbon atoms, or R (41) and R (42), together, mean 4 or 5 methylene groups, of which one CH2 group can be replaced with oxygen, S, NH, N-CH3 or N-benzyl, and the respective other substituents R (I), R (2) and R (3) signify, independently of one another, H, F, Cl, Br, I, CN, -0na-CmaH2Ba + 1O -Og, Cr, H2r, R (10); na means zero or l; a means zero, 1, 2, 3, 4, 5, 6, 7 or 8; ga means zero or 1; ra means zero, 1, 2, 3 or 4; R (10) means cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms or phenyl, the phenyl being unsubstituted or being substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl and methoxy; R (4) and R (5) signify, independently of one another, hydrogen, F, Cl, Br, I, CN, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, perfluoroalkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, or phenyl, which is unsubstituted or substituted by 1- 3 substituents chosen from the group consisting of F, Cl, CF3, methyl, methoxy and NR (14) R (15); R (14) and R (15) signify, independently of one another, H, alkyl having 1, 2, 3 or 4 carbon atoms or perfluoroalkyl with 1, 2, 3 or 4 carbon atoms; as well as its pharmaceutically compatible salts. Preference is given to compounds of the formula I, in which: at least one of the substituents R (l), R (2) and R (3) means -Op- (CH2) a-CqF2q + 1, R (40) CO - OR (31) S0k-; p means zero or 1; s means zero, l or 2, - q means 1, 2, 3 or 4; k means zero or 2; R (40) means alkyl having 1, 2, 3 or 4 carbon atoms, perfluoroalkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of in F, Cl, CF3, methyl and methoxy; R (31) means alkyl having 1, 2, 3 or 4 carbon atoms, perfluoroalkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of - Try F, Cl, CF3, methyl and methoxy; or R (31) means NR (41) R (42); R (41) and R (42) signify, independently of one another, hydrogen, CH 3 or CF 3; or R (41) and R (42), together, mean 4 or 5 methylene groups, of which a CH2 group can be replaced with oxygen, S, NH, N-CH3 or N-benzyl; and the respective other substituents R (l), R (2) and R (3) signify, independently of one another, H, F, Cl, Br, I, CN, -Ona-CmaH2ma + 1 O -OgaCraH2raR (10); na means zero or 1; ma means zero, 1, 2, 3 or 4; ga means zero or 1; ra means zero, 1 or 2; R (10) means cycloalkyl with 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, CF3, methyl and methoxy; R (4) and R (5) signify, independently of one another, hydrogen, F, Cl, alkyl having 1, 2, 3 or 4 carbon atoms, perfluoroalkyl with 1, 2, 3 or 4 carbon atoms, cycloalkyl with 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, CF3 / methyl, methoxy and NR (14) R (15); R (14) and R (15) signify, independently of one another, hydrogen, CH 3, CF 3; as well as its pharmaceutically compatible salts. Particularly preferred are compounds of the formula I, wherein: at least one of the substituents R (l), R (2) and R (3) mean -Op- (CH2) a-CqF2q + 1 or R (31) SOk-; p means zero or l; s means zero; q means 1, - k means zero or 2; R (3l) means CH 3, CF 3, or phenyl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF 3, methyl and methoxy; or R (31) means NR (41) R (42); R (41) and R (42) signify, independently of one another, hydrogen, CH 3 or CF 3; or R (41) and R (42), together, mean 4 or 5 methylene groups, of which a CH- group can be replaced with oxygen, S, NH, N-CH3 or N-benzyl; and the respective other substituents R (l), R (2) and R (3) signify, independently of one another, H, F, Cl, CN, -Ona-CmaH2ma + 1 O -OgaCraH2raR (10); na means zero or 1; ma means zero, 1, 2, 3 or 4; ga means zero or 1; ra means zero or 1; R (10) means phenyl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3; methyl and methoxy; R (4) and R (5) signify, independently of one another, hydrogen, F, C-L, CH, CF3; as well as its pharmaceutically compatible salts. Particularly preferred are compounds of formula I, wherein: at least one of the substituents R (l), R (2) and R (3) signifies R (31) SOk-; k means zero or 2; R (31) means CH 3, CF 3, or phenyl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF 3, methyl and methoxy; or R (31) means NR (41) R (42); R (4l) and R (42) signify, independently of one another, hydrogen, CH 3 or CF 3; or R (41) and R (42), together, mean 4 or 5 methylene groups, of which a CH2 group can be replaced with oxygen, S, NH, N-CH3 or N-benzyl; and the respective other substituents R (l), R (2) and R (3) signify, independently of one another, H, F, Cl, CN, -Ona-CmaH2ma + l O -OgaCraH2riáR (10); na means zero or 1; ma means zero, 1, 2, 3 or 4; ga means zero or 1; ra means zero or 1; R (10) means phenyl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl and methoxy; R (4) and R (5) signify, independently of one another, hydrogen, F, -, CH 3, F 3; as well as its pharmaceutically compatible salts. Particularly preferred are the following compounds: E-3- [2- (4-methylsulfonyl-thiophenyl) jpropenoic acid guanidide guanidide of E-3- [2- (5-methylthio-thiophenyl)] -2- methyl-propenoic guanidide of E-3- [2- (5-methylsulfonyl-thiophenyl)] -2-methyl-propenoic acid guanidide of E-3- [2- (3-chloro-4-isopropylsulfonyl-5 -methylthio-thiophenyl)] -2-methyl-propenoic guanidide of E-3- [2- (3-chloro-4-isopropylsulfonyl-5-methylsulfonyl-thiophenyl)] -2-methyl-propenoic acid, as its pharmaceutically compatible salts.

If the compounds of the formula I contain one or more centers of asymmetry, then these can be configured as both S and R. The compounds can be present as optical isomers, as diastereoisomers, 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 in a mixture as double-bond isomers.

The alkyl radicals and the designated perfluoroalkyl radicals can be present in both straight chain and branched form. The invention also relates to a process for the preparation of compound I, characterized in that a compound of formula II is reacted with guanidine, wherein R (1) to R (5) have the indicated meanings and L represents a substitutable and slightly nucleophilic leaving group. The activated acid derivatives of the formula II, wherein L means an alkoxy group, preferably a methoxy group, a phenoxy group, a phenylthio group, methylthio, 2-pi-luthylthio, a nitrogen heterocycle, preferably 1-imidazolyl, they are advantageously obtained, in a manner known per se, from the carboxylic acid chlorides in which they are melted (formula II, L = Cl) which, in turn, can be prepared, again in a manner known per se, to starting from the carboxylic acids in which they are melted (formula II, L = OH), for example with thionyl chloride. In addition to the carboxylic acid chlorides of the formula II (L = Cl), other activated acid derivatives of the formula II can also be prepared in a manner known per se, directly from the benzoic acid derivatives in which they are melted ( formula II, L = OH), such as for example the methyl esters of the formula II with L = 0CH3 by treatment with gaseous HCl in methanol, the imidazolides of the formula II by treatment with carbonyldiimidazole [L = 1-imidazolyl, Staab Angew Chem. Int. Ed. Engl. 1, 351-367 (1962)], mixed anhydrides II with C1-C00C2HS or tosyl chloride in the presence of triethylamine in an inert solvent, as well as activations of benzoic acids with di-cyclohexylcarbodiimide (DCC) or with tetrafluoroborate of 0 - [(cyano (ethoxycarbonyl) methylene) amino] -1,1,3,3-tetramethylidene ("TOTU") [Proceedings of the 21. European Peptide Sym-posium, Peptides 1990, Editors E. Giralt and D Andreu, Escom, Leiden, 1991]. A number of suitable methods for the preparation of activated carboxylic acid derivatives of the formula II are indicated with reference to the source literature in J. March, Advanced Organic Chemistry, third edition (John Wiley & amp;; Sons, 1985), p. 350. The reaction of an activated carboxylic acid derivative of formula II with guanidine is carried out in a manner known per se in a polar, but inert, protic or aprotic organic solvent. In this case, in the reaction of the methyl esters of benzoic acid (II, L = OMe) with guanidine, methanol, isopropanol or THF of a temperature of 20 ° C at the boiling point of these solvents have been proved. In the majority of the reactions of compounds II with guanidine free of salts, it was advantageously worked in inert aprotic solvents, such as THF, dimethoxyethane, dioxane. However, also water, with the use of a base, such as for example NaOH, can be used as a solvent in the reaction of II with guanidine. When L means Cl, it is advantageous to work with the addition of an acid scavenger, for example in the guanidine form in excess, for the dissociation of the halogenated hydrazide. A part of the propenoic acid derivatives of the formula II on which they are based are known and are described in the literature. The unknown compounds of formula II can be prepared according to methods known in the literature. The obtained alkenylcarboxylic acids are reacted according to one of the above-described process variants to give the compounds I according to the invention. The introduction of some substituents is achieved by methods known from the palladium-induced cross-coupling literature, aryl halides or aryl triflates, for example with organostannanes, organoboronic acids or organoboranes or organic compounds of copper or zinc The guanidines of carboxylic acids I are generally weak bases and can bind acids with salt formation. Suitable salts by the addition of acids are salts of all pharmacologically compatible acids, for example halides, in particular hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates, p-toluenesulfonates. The compounds I are substituted acylguanidines. The most relevant representative of acylguanidines is the derivative of pyrazine to iloride, which finds application in therapy as a potassium-sparing diuretic. Numerous other compounds of the amiloride type are described in the literature, such as for example dimethylamiloride or ethylisopropylamiloride. 0 NH R "amiloride: R ', R" = H dimethylamiloride: R', R "= CH3 ethylisopropylamiloride: R '= C2H5, R" = CH (CH3) 2 In addition, investigations have been made that point to properties Amiloride antiarrhythmics [Circulation 79, 1257-63 (1989)] However, it is opposed to a wide application as an antiarrhythmic agent, the fact that this effect is only weakly marked and manifests itself as a blood hypotensive and saluretic effect, and these Secondary effects are undesirable in the treatment of heart rhythm disorders Indications on antiarrhythmic properties of amiloride were also obtained in experiments on isolated hearts of animals [Eur. Heart J. 9 (supl.l): 167 (1988), (book of abstracts)] * Thus, for example, it was found in rat hearts that an artificially triggered ventricular fibrillation could be completely suppressed by amiloride, more potent than amiloride in this model. or of aforementioned amiloride etilisopropilamilorida. Known from WO 84/00875 are cinnamic acid guanidides (Ra and Rc, or Rb and Rd = double bond, R (l) = substituted phenyl); however, it does not describe or suggest thiophene compounds. From U.S. Patent Specification 2 734 904 are known cinnamic acid guanidides (R = substituted phenyl, alkyl = alkenylene), but thiophene compounds of the type described are not described or suggested. It is known that guanidides of thiophene-alkenylcarboxylic acids but without the essential substituents -Op- (CH 2) β-CqF 2 q + 1, R (40) CO- or R (31) S 0 k- are certainly known. In DE-OS 44 21 536.3 (HOE 94 / F 168) cinnamic acid guanidides are described, however, this document also does not disclose thiophene compounds. The known compounds and also those proposed do not, however, fulfill all the desired requirements, thus, their solubility in water leaves still to be desired.

In addition, these compounds do not yet selectively act as desired. Therefore, it was desirable to make available compounds with improved water solubility and selectivity. This has been achieved by the compounds according to the invention, which do not have undesired and disadvantageous salidiuretic properties, but have very good antiarrhythmic properties, such as are important for the treatment of diseases that are caused by an oxygen deficiency. As a result of their pharmacological properties, the compounds are extremely suitable as antiarrhythmic drugs with a cardioprotective component for the prophylaxis of infarction and the treatment of infarction, as well as for the treatment of angina, also strongly inhibiting or reducing Pathophysiological processes in the appearance of lesions induced by ischemia, in particular in the triggering of heart arrhythmias induced by ischemia. Due to their protective effects against hypoxic and ischemic pathological situations, the compounds of the formula I according to the invention can be used, as a consequence of the inhibition of the cellular exchange mechanism of Na + / H *, as medicaments for the treatment of all acute or chronic injuries triggered by ischemia or diseases induced in a primary or secondary way by the previous ones. This concerns their use as drugs for surgical interventions, for example in the case of organ transplants, the compounds being able to 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 storage in physiological bath liquids, as well as in the transfer to the recipient organism. The compounds are also valuable drugs with protective effect in the performance of angioplastic surgical operations, 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), being suitable, for example, for the treatment of stroke. or cerebral edema. In addition, the compounds of the formula I according to the invention are also suitable for the treatment of forms of shock, such as, for example, allergic, cardiogenic, hypovolemic shock and bacterial shock. In addition, the compounds of the formula I according to the invention are distinguished by a strong inhibitory effect on cell proliferation, for example the proliferation of fibroblast cells and the proliferation of the cells of 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 represents a primary or secondary cause and, therefore, can be used as anti-choleretic agents, agents against late diabetic complications , carcinogenic diseases, fibrotic diseases, such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, hypertrophies and hyperplasias of organs, in particular in the hyperplasia of the prostate or in the hypertrophy of the prostate. The compounds according to the invention are valuable inhibitors of the sodium proton cell antiporter (Na + / H + exchanger) which in numerous diseases (essential hypertonia, atherosclerosis, diabetes, etc.) is also increased in cells whose measurements are easily accessible, such as as for example 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 for the determination and differentiation of certain forms of hypertonia, but also of atherosclerosis, diabetes, diseases proliferating, 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. Medicaments containing a compound I can in this case be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred administration depending on the respective phenotype of the disease. The compounds I can in this case be used alone or together with galenic auxiliaries, namely both in veterinary medicine and also in human medicine. Which auxiliary substances are suitable for the desired drug formulation is usual for the person skilled in the art by virtue of his scientific knowledge. In addition to solvents, gel formers, suppository bases, tablet auxiliaries and other active substance supports, antioxidants, dispersing agents, emulsifiers, defoamers, flavor correctors, preservatives, dissolving agents or dyes may be used. For an oral administration form, the active compounds are mixed with suitable additives, such as support substances, stabilizers or inert diluents and are brought, by the usual methods, to suitable administration forms, such as tablets, dragees, plug-in capsules, aqueous solutions, alcoholic or oily. 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 oils or solvents, for example, include 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 purpose, such as dissolution promoters, emulsifiers or other auxiliary substances. Suitable solvents are, for example, water, physiological sodium chloride solution or alcohols, for example ethanol, propanol, glycerol, and, 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 are suitable in a pharmaceutically innocuous solvent, such as in particular ethanol or water, or in a mixture of such solvents. The formulation may contain, as necessary, also other pharmaceutical auxiliaries, such as surfactants, emulsifiers and stabilizers, as well as a propellant gas. A preparation of this type contains the active principle usually in a concentration of about 0.1 to 10, in particular about 0.3 to 3% by weight. The dosage of the active principle of the formula I to be administered and the frequency of administration depend on the power of efficacy and the duration of the activity 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 in a patient of approximately 75 kg of weight is at least 0.001 mg / kg, preferably 0.01 mg / kg up to at most 10 mg / kg, Preference 1 mg / kg body weight. In the case of acute manifestations of the disease, for example immediately after suffering a heart infarction, even higher and, above all, more frequent dosages may be necessary, for example up to 4 individual doses per day. In particular, in the case of i.v. application, for example in a heart attack patient in the intensive care unit, up to 200 mg per day may be necessary.

List of abbreviations: MeOH methanol DMF N, N-dimethylformide The impact of electrons DCI chemical ionization by RT desorption room temperature EE ethyl acetate (EtOAc) p.f. melting point HEP n-heptane DME dimethoxyethane ES atomization of electrons FAB bombardment with fast atoms CH2C12 dichloromethane THF tetrahydrofuran eq. equivalent Experimental part General prescriptions for the preparation of guanidides of alkenylcarboxylic acids (I) Variant 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 / millimole) and then mixed with 1.1 eq. of carbonildii idazol. After stirring for 2 hours at RT, 5.0 eq are incorporated into the reaction solution. of guanidine. After stirring overnight, the THF is distilled off under reduced pressure (rotary evaporator), mixed with water, adjusted to pH 6 to 7 with 2 N HCl and the corresponding gua-nidide (formula I) it is separated by filtration. The carboxylic acid guanidines thus obtained can be converted into the corresponding salts by treatment with aqueous, methanolic or ethereal hydrochloric acid or other pharmacologically compatible acids.

Variant B: from alkyl 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 boiled under reflux (typical reaction time, 2 to 5 h) until the complete version (control by thin layer). The solvent is distilled off under reduced pressure (rotary evaporator), taken up in EA and washed 3 times with NaHCO3 solution. Dry over Na 2 SO 4, remove the solvent by vacuum distillation and chromatograph on silica gel with a suitable eluent, for example EE / MeOH 5: 1. (Salt formation, see variant A) Example 1: E-3- [2- (4-methylsulfonyl-thiophenyl)] propenoic acid guanidide 1 a) Methyl ester of E-3- [2- (4-methylsulfonyl-thiophe-nyl)] propenoic acid eq. of 3- [2- (4-bromothiopyl-nyl)] propenoic acid methyl ester, 2 eq. of sodium salt of methylsulfinic acid, 2 eq. were heated to reflux in toluene / DMF (2/3, 3 ml / millimole ester). Standard work-up and chromatography on silica gel (eluent: cyclohexane / EE) provided E-3- [2- (4-methylsulfonyl-thiophe-nyl)] propenoic acid methyl ester.

P.f .: amorphous MS: 247 (M + l) + 1 b) The carboxylic acid was released from ester 1 a) under standard conditions (MeOH / NaOH). P.f .: 203 ° C MS: 233 (M + l) + l e) i) was transformed, in accordance with the A prescription, into guanidide hydrochloride. P.f .: 200 ° C EM: 274 (M + l) + Example 2: Guanidide hydrochloride of E-3- [2- (5-methylthio-thiophenyl)] -2-methyl-propenoic acid hydrochloride 2 a) 1 eq. of 2-phosphonopropionic 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 1 eq. of 5-methylthiobenzaldehyde. After the complete reaction of the aldehyde, it was worked up with water and extracted three times with stirring 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 EA / HEP mixtures as eluent. E-3- [2- (5-methylthio-thiophenyl)] -2-methyl-propenoic acid ethyl ester was isolated. Colorless oil EM: 243 (M + l) + 2 b) The ester of 2 a) was converted, according to variant B, first into the guanidide and then to the hydrochloride. P.f. : 172 ° C MS: 256 (M + 1) + Example 3: Guanidide hydrochloride of E-3- [2- (5-ethylsulfonyl-thiophenyl)] -2-methyl-propenoic acid The ester of 2 a) was oxidized, according to a standard reaction, with 2.2 eq. of m-chloroperbenzoic acid in methylene chloride in the ethyl ester of E-3- [2- (5-methylsul-fonyl-thiophenyl)] -2-methyl-propenoic acid. Colorless oil EM: 275 (M + l) + 3 b) The ester of 3 a) was first converted with sodium hydroxide into methanol in the free acid and then, according to variant A, into the guanidide hydrochloride. Acid Amorphous solid substance MS: 247 (M + l) + Guanidide Hydrochloride: P.f .: > 210 ° C MS: 288 (M + l) + Example 4: Guanidide hydrochloride of E-3- [2- (3-chloro-4-isopropylsulfonyl-5-methylthio-thiophenyl)] -2-methyl-propenoic acid hydrochloride 4 a) In analogy to 2 a), commercially available 3-chloro-4-isopropylsulfonyl-5-methylthio-thiophenyl-2-carboaldehyde was converted to the corresponding propenoic acid ester. Colorless oil EM: 384 (M + l) + 4 b) The ester of 4 a) was transformed, according to variant B, into the guanidide and isolated as the hydrochloride. P.f .: 227-235 ° C MS: 396 (M + l) + Example 5: Guanidide hydrochloride of E-3- [2- (3-chloro-4-isopropylsulfonyl-5-methylsulfonyl-thiophenyl)] -2-ethyl-propenoic acid hydrochloride a) The ester of 4 a) was transformed, with a standard reaction with 2.2 eq. of m-chloroperbenzoic acid in methylene chloride, in the ethyl ester of E-3- [2- (3-chloro-4-isopropylsulfonyl-5-methylsulfonyl-thiophenyl)] -2-methyl-propenoic acid. MS: 416 (M + l) + b) The ester of 5 a) was transformed, according to variant B, into the guanidide and isolated as the hydrochloride. MS: 428 (M + l) +

Claims (19)

1. - Guanidides of substituted thiophenylalkenylcarboxylic acids of the formula I wherein: at least one of the substituents R (l), R (2) and R (3) mean -Op- (CH2) a-CqqF1-: 2q + li R (40) CO- or R (31) SOk - P means zero, l; S means zero, 1, 2, 3, 4; q means 1, 2, 3, 4, 5, 6, 7 or 8; k means zero, 1 or 2; R (40) means alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, perfluoroalkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, cycloalkyl with 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, CF3, methyl and methoxy; R (31) means alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, perfluoroalkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, cycloalkyl with 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, CF3, methyl or methoxy; or R (31) means NR (41) R (42); R (41) and R (42) signify, independently of one another, hydrogen, alkyl with 1, 2, 3 or 4 carbon atoms, perfluoroalkyl with 1, 2, 3 or 4 carbon atoms, or R (41) and R (42), together, mean 4 or 5 methylene groups, from which a CH2 group can be replaced with oxygen, S, NH, N-CH- or N-benzyl; and the respective other substituents R (l), R (2) and R (3) signify, independently of one another, H, F, Cl, Br, I, CN, "Ona-CaaH2ma + 1 O -OgaCraH2raR (10) na means zero or 1; ma means zero, 1, 2, 3, 4, 5, 6, 7 or 8, ga means zero or 1; ra means zero, 1, 2, 3 or 4; R (10) means cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms or phenyl, the phenyl being unsubstituted or being substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3 / methyl and methoxy; R (4) and R (5) signify, independently of one another, hydrogen, F, Cl, Br, I, CN, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, perfluoroalkyl with 1, 2 , 3, 4, 5, 6, 7 or 8 C atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, or phenyl, which is unsubstituted or substituted by 1-3 substituents selected from group consisting of F, Cl, CF3, methyl, methoxy and NR (14) R (15); R (14) and R (15) signify, independently of each other, H, alkyl with 1, 2, 3 or 4 atoms of C or perfluoroalkyl with 1, 2, 3 or 4 C atoms; as well as its pharmaceutically compatible salts.

2. - Compound of formula I according to claim 1, wherein: at least one of the substituents R (1), R (2) and R (3) mean -Op- (CH 2) β-CqF 2 q + 1, R ( 40) CO-OR (31) SOk-; p means zero or l; s means zero, l or 2; q means 1, 2, 3 or 4; k means zero or 2; R (40) means alkyl having 1, 2, 3 or 4 carbon atoms, perfluoroalkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of - Try F, Cl, CF3, methyl and methoxy; R (31) means alkyl having 1, 2, 3 or 4 carbon atoms, perfluoroalkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of in F, Cl, CF3, methyl and methoxy; or R (31) means NR (41) R (42); R (41) and R (42) signify, independently of one another, hydrogen, CH 3, CF 3; or R (41) and R (42), together, mean 4 or 5 methylene groups, of which a CH2 group can be replaced with oxygen, S, NH, N-CH3 or N-benzyl; and the respective other substituents R (l), R (2) and R (3) signify, independently of one another, H, F, Cl, Br, I, CN, -Ona-CmaH2ma + 1 or -OgaCraH2raR (10); na means zero or 1; ma means zero, 1, 2, 3 or 4; ga means zero or 1; ra means zero, 1 or 2; R (10) means cycloalkyl with 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, CF3 / methyl and methoxy; R (4) and R (5) signify, independently of one another, hydrogen, F, Cl, alkyl having 1, 2, 3 or 4 carbon atoms, perfluoroalkyl with 1, 2, 3 or 4 carbon atoms, cycloalkyl with 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, CF3, methyl, methoxy and NR (14) R (15); R (14) and R (15) signify, independently of one another, hydrogen, CH 3, CF 3; as well as its pharmaceutically compatible salts.

3. Compound of formula I according to claims 1 or 2, characterized in that therein: at least one of the substituents R (l), R (2) and R (3) mean -Op- (CH2) 8-CqF2q +1 or R (31) SOk-; p means zero or 1; s means zero; q means 1; k means zero or 2; R (31) means CH 3 / CF 3, or phenyl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF 3 / methyl and methoxy; or R (31) means NR (41) R (42); R (4l) and R (42) signify, independently of one another, hydrogen, CH 3 or CF 3; or R (41) and R (42), together, mean 4 or 5 methylene groups, of which a CH2 group can be replaced with oxygen, S, NH, N-CH3 or N-benzyl; and the respective other substituents R (l), R (2) and R (3) signify, independently of one another, H, F, Cl, CN, "Ona" CmaH2l-a + 1O-OgaCraH2raR (10); na means zero or i; ma means zero, 1, 2, 3 or 4; ga means zero or 1; ra means zero or 1; R (10) means phenyl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl and methoxy; R (4) and R (5) signify, independently of one another, hydrogen, F, Cl, CH 3, CF 3; as well as its pharmaceutically compatible salts.

4. Compound of the formula I according to one of claims 1 to 3, wherein: at least one of the substituents R (l), R (2) and R (3) mean R (31) S0k-; k means zero or 2; R (31) means CH 3, CF 3, or phenyl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF 3, methyl and methoxy; or R (31) means NR (41) R (42); R (41) and R (42) signify, independently of one another, hydrogen, CH 3 or CF 3; or R (41) and R (42), together, mean 4 or 5 methylene groups, of which one CH2 group may be replaced with oxygen, S, NH, N-CH3 or N-benzyl, and the respective other substituents R (l), R (2) and R (3) signify, independently of one another, H, F, Cl, CN, -Ona-CmaH2Ba + 1O-0gaCraH2raR (10); na means zero or 1; ma means zero, 1, 2, 3 or 4; ga means zero or 1; ra means zero or 1; R (10) means phenyl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl and methoxy; R (4) and R (5) signify, independently of one another, hydrogen, F, Cl, H3, CF3; as well as its pharmaceutically compatible salts.

5. Compound of formula I according to claim 1, characterized in that it is chosen from the group consisting of E-3- [2- (4-methylsulfonyl-thiophenyl)] propenoic acid guanidide guanidide of E-3- [ 2- (5-methylthio-thiophenyl)] -2-methyl--propenoic guanidide of E-3- [2- (5-methylsulfonyl-thiophenyl)] -2-methyl-propenoic acid guanidide of E-3- [2] - (3-Chloro-4-isopropylsulfonyl-5-methylthio-thiophenyl) -2-methyl-propenoic acid and guanidide of E-3- [2- (3-chloro-4-isopropylsulfonyl-5-methylsulfonyl) -thiophenyl)] -2-methyl-propenoic acid.

6. - Process for the preparation of a compound I according to claim 1, characterized in that a compound of the formula II is reacted with guanidine, wherein R (l) to R (5) have the indicated meanings and L represents a substitutable and slightly nucleophilic leaving group.

7. 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 states.

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

9. Method for treating arrhythmias, characterized in that an effective amount of a compound I according to claim 1 is mixed with the usual additives and administered in a suitable administration form.

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

11. Use of a compound I according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of angina pectoris.

12. Use of a compound I according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of ischemic heart conditions.

13. Use of a compound I according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of ischemic states of the peripheral and central nervous system and apoplectic attack.

14. - Use of a compound I according to claim 1 for the preparation of a medication for the treatment or prophylaxis of ischemic states of peripheral organs and limbs.

15. Use of a compound I according to claim 1 for the preparation of a medicament for the treatment of shock states.

16. Use of a compound I according to claim 1 for the preparation of a medicament for use in surgical operas and organ transplants.

17. 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.

18. 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, therefore, its use for the preparation of antiatherosclerotics, agents against late diabetic complications, carcinogenic diseases, fibrotic diseases, such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, hyperplasia of the prostate.

19. Medicament containing an effective amount of a compound I according to one or more of claims 1 to 5.