Substituted sulphonyl cyanamides, their use and pharmaceutical compositions containing them

Description

The compounds inhibit the sodium-dependent bicarbonate / chloride exchange mechanism and can therefore be used for the treatment and prevention of many diseases. The invention relates to compounds of general formula (I) in which X is a group of general formula (a), R1 is an alkyl group having 1, 2, 3 or 4 carbon atoms or a phenyl group which is unsubstituted or singly substituted by fluorine, chlorine, trifluoromethyl, methyl or methoxy; R2 and R3 are independently hydrogen, fluorine, chlorine, trifluoromethyl, cyano, -CO-R24 or -O-R25, where R24 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, -OR26 or phenyl which is unsubstituted or singly substituted by fluorine, chlorine, trifluoromethyl, methyl or methoxy; R26 is hydrogen, methyl or ethyl; R25 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl which is unsubstituted or singly substituted by fluorine, chlorine, trifluoromethyl, methyl or methoxy; or R25 is a heteroaryl group which is unsubstituted or singly substituted by fluorine, chlorine, trifluoromethyl, methyl or methoxy; or R2 and R3 are independently alkyl of 1, 2, 3 or 4 carbon atoms, cycloalkyl of 3, 4, 5, 6 or 7 carbon atoms; or R2 and R3 independently represent a phenyl group which is unsubstituted or singly substituted by fluorine, chlorine, trifluoromethyl, methyl or methoxy; or R2 and R3 are independently a heteroaryl group of 1,2,3,4,5,6,7,8 or 9 carbon atoms, which is unsubstituted or singly substituted with fluorine, chlorine, trifluoromethyl, methyl or methoxy; or R2 and R3 are independently -SOrR37, where R37 is alkyl of 1, 2, 3 or 4 carbon atoms or phenyl unsubstituted or substituted by fluorine, chlorine, trifluoromethyl, methyl or methoxy, and f is 0 or 2; R13, R14 and R15 are independently hydrogen, methyl, fluorine, chlorine, trifluoromethyl, cyano, SO2-R79, -CO-R80 or -O-R81; R79 and R81 are independently alkyl of 1, 2, 3 or 4 carbon atoms or phenyl, which is unsubstituted or singly substituted by fluorine, chlorine, trifluoromethyl, methyl or methoxy; a group in which R84 is hydrogen or alkyl of 1-8 carbon atoms, and R80 is hydrogen, methyl, -OR84, in which R84 is an alkyl group having 1, 2, 3 or 4 carbon atoms or a hydrogen atom. The invention also relates to physiologically tolerable salts of the above compounds. Preferred are compounds of formula (I) and their acid addition salts in which R13, R14 and R15 are hydrogen. Alkyl groups can have straight or branched carbon chains. Examples of alkyl groups having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, isobutyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl, sec-butyl, tert-butyl, tert-pentyl. Cycloalkyl groups also include rings substituted with alkyl groups. Cycloalkyl groups are mainly cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl groups, which can, however, also be substituted by, for example, alkyl groups having 1, 2, 3 or 4 carbon atoms. Substituted cycloalkyl groups are, for example, 4-methylcyclohexyl and 2,3-dimethylcyclopentyl. Heteroaryl groups with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms are mainly understood to mean groups derived from the phenyl and naphthyl groups, in which one or more CH groups are replaced by a nitrogen atom and / or in which at least two adjacent CH groups (resulting in a five-membered aromatic ring) are combined with a sulfur atom, oxy2 HU 225 377 β1 substituted with a gene atom or an SH group. Furthermore, one or both atoms of the condensation site of bicyclic groups may also be nitrogen atoms (as in the indolizinyl group). Heteroaryl groups are mainly understood to mean furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl groups. The present invention encompasses all stereoisomeric forms of the compounds of formula (I). The asymmetric centers in the compounds of formula (I) can each independently have the S- or R-configuration. The invention also encompasses all possible enantiomers and diastereomers, as well as mixtures of two or more stereoisomeric forms, for example mixtures of enantiomers and / or diastereomers in all ratios. Enantiomers are therefore subject to the invention in enantiomerically pure form, both as dextrorotatory and levorotatory antipodes, in the form of racemates and mixtures of the two enantiomers in all ratios. In the case of cis / trans isomerism, the cis-form, the trans-form and any mixtures of the two forms are subject to the invention.The individual stereoisomers can be prepared, if desired, by separation of mixtures in known manner, for example by chromatography or crystallization or by using stereochemically uniform starting materials during the synthesis, or by stereoselective synthesis. If appropriate, derivatives can be formed before the separation of the stereoisomers. The separation of a stereoisomeric mixture can be carried out at the stage of the compounds of formula (I) or at the stage of an intermediate during the synthesis. If a compound of formula (I) contains a mobile hydrogen atom, all tautomeric forms of the compound also form part of the subject matter of the invention. If the compounds of the formula (I) contain one or more acidic or basic groups, the corresponding physiologically or toxicologically acceptable salts, in particular pharmaceutically acceptable salts, are also subject to the invention. Compounds of the formula (I) containing acidic groups can be present, for example, in the form of alkali metal salts, alkaline earth metal salts or ammonium salts, and can be used in this form according to the invention. Examples of such salts include: sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of the formula (I) containing one or more basic groups can be present in the form of acid addition salts with physiologically acceptable inorganic or organic acids, and can be used in this form according to the invention.Examples of acids suitable for salt formation include: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, etc. If the compounds of general formula (I) contain both acidic and basic groups, in addition to the already mentioned salt forms, internal salts and betaines (zwitterions) are also subject to the invention. Salts of the compounds of formula (I) can be formed in a manner known to those skilled in the art, for example by reacting the compound with an organic or inorganic acid or base in a solvent or dispersant, or by subjecting another salt to anion or cation exchange.The present invention also includes salts which are not directly suitable for use as pharmaceuticals due to their poor physiological acceptability, but which can be used as intermediates in chemical reactions or for the preparation of physiologically acceptable salts. Physiologically acceptable salts of the compounds of formula (I) are understood to mean, for example, their organic and inorganic salts, as described in Remington's Pharmaceutical Sciences [17th edition, page 1418 (1985)]. For acidic groups, sodium, potassium, calcium and ammonium salts are preferred due to physical and chemical stability and solubility; for basic groups, salts of hydrochloric acid, sulfuric acid, phosphoric acid or carboxylic or sulfonic acids, such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p-toluenesulfonic acid are preferred, among others. The present invention also extends to all solvates of the compounds of formula (I), such as hydrates, alcohol adducts, derivatives of the compounds of formula (I), such as esters, prodrugs and active metabolites. The invention further relates to a process for the preparation of the novel compounds of the general formula (I) and their physiologically acceptable salts. The process is characterized in that a compound of the general formula (II), in which the symbols have the meanings given above, is reacted with cyanogen bromide. For the reaction, a dipolar, aprotic solvent stable to cyanogen bromide, such as acetonitrile, DMA, TMU or NMP, is used together with a strong, slightly nucleophilic auxiliary base, such as potassium carbonate or cesium carbonate. The reaction temperature may be between 0 °C and the boiling point of the solvent used, preferably between 60 °C and 120 °C. Sulfonamide derivatives of general formula (II) containing a group of formula (a) in place of X can be prepared by reacting a compound of general formula (III) in which Y, R13, R14 and R15 are as defined above and G is, for example, a group of formula -CH2Cl, -CH2BR, -CH2OH or -CH2OMs, and the sulfonamide group is preferably present in a protected form, for example as a dimethylaminomethylene derivative, with a compound of general formula (IV) in a manner known from the literature (nucleophilic substitution or Mitsunobu reaction, see J. Med. Chem. 1995, 38, 2357). Suitable processes for the preparation of compounds of formula (IV) are described, for example, in EP-A 253310, EP-A 324377, US 5482957 and J. Med. Chem. 1995, 38, 2357-2377. HU 225 377 B1 The compounds of general formula (III) can be prepared using methods known from the literature by reacting suitable, for example methyl, carboxylic acid ester, formyl substituted aryl derivatives, from which the above-mentioned G groups can be prepared in a manner known to the person skilled in the art, for example in situ formed benzyl zinc derivatives (see J. Org. Chem. 1977, 42, 1821; J. Org. Chem. 1988, 53, 5789) with substituted aryl halides in the presence of a Pd(0) catalyst. The compounds of general formula (I) according to the invention inhibit sodium-dependent bicarbonate / chloride exchange (NCBE) and the sodium / bicarbonate symporter. The authors of EP 855392 propose imidazole derivatives with a biphenylsulfonylcyanamide side chain as NCBE inhibitors. According to EP-A 903339 and DE 19804251.5, substituted biphenylsulfonylcyanamide derivatives can be used as NCBE inhibitors. Structurally similar compounds to the compounds of the invention of formula (I) are known from U.S. Patents 5,482,957 and 5,604,251 and from European Patent Application EP-A 479479, but the compounds are described as antihypertensive angiotensin II antagonists and do not have the sulfonylcyanamide side chain which is always present in the invention. WO9523792, WO9523791, EP-A 465368, EP-A 648763 describe imidazole biphenyl derivatives. These known compounds are antagonists of the AT1 subtype of angiotensin II receptor; this effect is not observed or is only observed to a small extent in the compounds of the invention. The invention further relates to the use of compounds of general formula (I) for the preparation of a pharmaceutical composition suitable for the prevention and treatment of diseases caused by ischemic conditions; further relates to the use of compounds of general formula (I) for the preparation of a pharmaceutical composition for the treatment and prevention of myocardial infarction; further relates to the use of compounds of general formula (I) for the preparation of a pharmaceutical composition for the treatment and prevention of angina pectoris; further relates to the use of compounds of general formula (I) for the preparation of a pharmaceutical composition for the treatment and prevention of ischemic conditions of the heart; further relates to the use of compounds of general formula (I) for the preparation of a pharmaceutical composition for the treatment and prevention of ischemic conditions of the peripheral and central nervous system and of stroke; further relates to the use of compounds of general formula (I) for the preparation of a pharmaceutical composition for the treatment and prevention of ischemic conditions of peripheral organs and limbs; further relates to the use of compounds of general formula (I) for the preparation of a pharmaceutical composition for the treatment and prevention of shock conditions; further relates to the use of compounds of general formula (I) for the preparation of a pharmaceutical composition for use in surgical operations and organ transplantation; further relates to the use of compounds of general formula (I) for the preparation of a pharmaceutical composition suitable for the preservation and storage of transplants for surgical purposes; further relates to the use of compounds of general formula (I) for the preparation of a pharmaceutical composition suitable for the treatment of diseases whose primary or secondary cause is cell proliferation, such as the use of the compounds for the preparation of an anti-arteriosclerotic agent, late complications of diabetes, cancer, fibrotic diseases such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, and prostatic hyperplasia; and also relates to the use of compounds of general formula (I) for the preparation of a pharmaceutical composition for the treatment of respiratory distress. The invention also relates to a pharmaceutical composition comprising an effective amount of a compound of formula (I). Given that the compounds of the invention inhibit the Na+-dependent CI- / HCO3-exchange mechanism and therefore have potential antiarrhythmic properties - these are important for the treatment of diseases occurring in oxygen deficiency phenomena, for example - the compounds of general formula (I) are suitable as antiarrhythmic active ingredients with a cardioprotective component for the prevention and treatment of infarction and for the treatment of angina pectoris. In doing so, the compounds can completely prevent or greatly reduce the pathological physiological processes involved in the development of ischemia-induced damage, especially ischemia-induced cardiac arrhythmia. Based on their protective effect against pathological hypoxic and ischemic situations, the compounds of general formula (I) according to the invention, because they inhibit the intracellular Na+-dependent CI- / HCO3 exchange mechanism or the sodium / bicarbonate symporter, are suitable for the treatment of acute or chronic damage or primary or secondary diseases caused by ischemia. They protect organs with insufficient oxygen supply by reducing or preventing damage caused by ischemia, therefore, for example, as a drug against thrombosis, vasospasm, atherosclerosis, or during surgical interventions (for example, during organ transplantation, such as kidney and liver transplantation during and after organ removal, then for the protection of the organ stored in physiological solutions and during implantation), and in case of acute or chronic renal failure.The compounds of general formula (I) are also potentially valuable, protective medicinal substances that can be used during vascular surgery and cardiac surgery. Based on their potential protective effect against damage caused by ischemia, the compounds are useful in the treatment of ischaemic disorders of the nervous system, especially the central nervous system. HU 225 377 Β1 mia conditions, for example in case of stroke or cerebral edema. In addition, the compounds of general formula (I) according to the invention can be used for the treatment of shock conditions, for example allergic shock, cardiac shock, hypovolemic and bacterial shock. The compounds of general formula (I) according to the invention strongly inhibit cell proliferation, for example the proliferation of fibroblasts and smooth muscle cells, and are therefore valuable therapeutic agents in diseases whose primary or secondary cause is cell proliferation, and therefore can be used against atherosclerosis, late complications of diabetes, cancers, fibrotic diseases such as pulmonary fibrosis, liver fibrosis or kidney fibrosis, organ hypertrophy and hyperplasia, in particular prostate hyperplasia and hypertrophy. We found that substances that inhibit the Na+-dependent CI_ / HCO3_exchange mechanism and the sodium / bicarbonate symporter can stimulate breathing by increasing the chemosensitivity of respiratory chemoreceptors. These chemoreceptors play a major role in maintaining regular breathing. Hypoxia, decreased pH, and increased CO2 levels in the body activate these receptors, and minute respiratory volume adapts. During sleep, breathing is particularly prone to disturbance and is highly dependent on the activity of chemoreceptors. Improving respiratory priming by stimulating chemoreceptors with substances that inhibit the Na+-dependent CI_ / HCO3_exchange mechanism leads to improved breathing in the following clinical conditions and diseases: disturbed central respiratory priming (e.g. central sleep apnea, sudden infant death syndrome, postoperative hypoxia), muscle-induced respiratory distress, respiratory distress after prolonged artificial ventilation, respiratory distress during high altitude adaptation, obstructive and mixed forms of sleep apnea, acute and chronic lung diseases associated with hypoxia and CO2 accumulation. Pharmaceutical compositions containing the compound of general formula (I) can be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred route of administration depending on the pathology of the disease in question. The compounds of general formula (I) can be administered alone or in combination with excipients, both in human and veterinary medicine. The excipients suitable for the desired pharmaceutical form are selected by the specialist based on their expertise. In addition to solvents, gelling agents, suppository bases, tableting excipients and other carriers, antioxidants, dispersants, emulsifiers, antifoams, flavor enhancers, preservatives, solubilizers or colorants can be used. In the case of a pharmaceutical preparation for oral administration, the active ingredient is mixed with suitable additives, such as carriers, stabilizers or inert diluents, and is formulated into a suitable preparation by conventional methods. Suitable preparation forms include, for example, tablets, dragees, capsules, aqueous, alcoholic or oily solutions. Inert carriers include, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. The substances can be granulated dry or wet. Oily carriers or solvents include, for example, vegetable or animal oils, such as sunflower oil and cod liver oil. For subcutaneous or intravenous administration, the active compound is dissolved, suspended or emulsified, if desired, together with the usual additives, such as solubilizers, emulsifiers or other excipients. Examples of solvents that can be used are: water, physiological NaCl solution or alcohols, such as ethanol, propanol, glycerol, and sugar solutions, such as glucose or mannitol solution or mixtures thereof. Aerosol or spray formulations may be, for example, solutions, suspensions or emulsions of the active ingredient of formula (I) in a pharmaceutically acceptable solvent, in particular ethanol or water or a mixture of such solvents. The formulation may optionally contain other pharmaceutical excipients, such as surfactants, emulsifiers and stabilizers, and a propellant. Such formulations generally contain the active ingredient in a concentration of about 0.1 to 10% by weight, in particular about 0.3 to 3% by weight. The dosage of the active ingredient of general formula (I) and the frequency of administration depend on the strength and duration of the effect of the active ingredient used, the nature and severity of the disease to be treated, and the sex, age, body weight and individual response of the mammal to be treated. On average, the daily dose of the compounds of the general formula (I) for a patient with a body weight of about 75 kg is at least 0.001 mg / kg, preferably 0.01 mg / kg body weight. In the case of an acute onset of the disease, for example immediately after a heart attack, the necessary dose may be higher, the administration being in particular more frequent, for example up to 4 single doses per day. Especially during iv. administration, in the case of a heart attack patient in the intensive care unit, up to 200 mg may be required per day. The compounds of formula (I) can be used as sole active ingredients or in combination with other pharmaceutically active compounds. The compounds of the general formula (I) and / or their physiologically acceptable salts can be used together with other pharmaceutically active compounds to achieve a beneficial therapeutic effect for the prevention of the above-mentioned pathologies, in particular for the treatment of cardiovascular diseases. The active compounds according to the invention are preferably combined with sodium / hydrogen exchange inhibitors (NHE) and / or with active substances belonging to other classes of cardiovascular active compounds. The invention further a) NCBE inhibitors of general formula (I) and / or physiologically acceptable salts thereof and NHE inhibitors and / or physiologically acceptable salts thereof; b) active substances belonging to the classes of NCBE inhibitors of general formula (I) and / or their physiologically tolerable salts and other cardiovascular active substances and / or their physiologically tolerable salts; and HU 225 377 B1 c) (I) also applies to combinations of NCBE inhibitors and / or their physiologically acceptable salts and NHE inhibitors and / or their physiologically acceptable salts and other active substances belonging to the classes of cardiovascular active substances and / or their physiologically acceptable salts. The active substances known and identified as NHE inhibitors are guanidine derivatives, preferably acylguanidines, among others those described in the book “DIURETICS, Chemistry, Pharmacology and Medicine” by Edward J. Cragoe, Jr. [J. WILEY & Sons (1983), 303-341] and listed in patent EP 98115754.8. Suitable NHE inhibitors include, for example, benzoylguanidines, see US 5292755, US 5373024, US 5364868, US 5591754, US 5516805, US 5559153, UD 5571842, US 5641792, US 5631293, EP-A 577024, EP-A 602522, EP-A 602523, EP-A 603650, EP-A 604852, EP-A 612723, EP-A627413, EP-A 628543, EP-A 640593, EP-A640588, EP-A 702001, EP-A 713864, EP-A 723956, EP-A 754680, EP-A 765868, EP-A 774459, EP-A 794171, EP-A814077, EP-A 869 116; ortho-substituted benzoylguanidine derivatives, see EP-A 556673, EP-A 791577, EP-A 794172; ortho-amino-substituted benzoylguanidine derivatives, see EP-A 690048, isoquinoline derivatives, see EP-A 590455; benzofused 5-ring heterocycles, see EP-A 639573; diacyl-substituted guanidines, see EP-A 640587; acyl guanidines, see US 5547953; phenyl-substituted alkyl or alkenyl carboxylic acid guanidines bearing a perfluoroalkyl group, see US 5567734, EP-A 688766; heteroaroyl guanidines, see EP-A 676395; bicyclic heteroaroyl guanidines, see EP-A 682017;indenoylguanidines, see EP-A 738712; benzyloxycarbonylguanidines, see EP-A 748795; phenyl-substituted alkenylcarboxylic acid guanidines bearing fluorophenyl groups, see EP-A 744397; substituted cinnamic acid guanidines, see EP-A 755919; sulfonamides, see EP-A 771788; benzenedicarboxylic acid diguanidines, see EP-A 774458, EP-A 774457; diarylcarboxylic acid diguanidines, see EP-A 787717; substituted thiophenylalkenylcarboxylic acid guanidines, see EP-A 810207; substituted 1- or 2-naphthylguanidines, see EP-A 810205 and EP-A 810206; indanilidineacetylguanidines, see EP-A837055; phenylsubstituted alkenylcarboxylic acid guanidines, see EP-A 825178; aminopiperidylbenzoylguanidines, see EP-A 667341; heterocycloxybenzylguanidines, see EP-A 694537; orthosubstituted benzoylguanidines, see Ep704431; orthosubstituted alkylbenzylguanidines, see EP-A 699660; orthosubstituted heterocyclylbenzoylguanidines, see EP-A 699666;orthosubstituted 5-methylsulfonylbenzoylguanidines, see EP-A 708088; orthosubstituted 5-alkylsulfonylbenzoylguanidines bearing a 4-amino substituent, see EP-A 723963; orthosubstituted 5-alkylsulfonylbenzoylguanidines bearing a 4-mercapto substituent, see EP-A 743301; 4-sulfonyl or 4-sulfinylbenzylguanidines, see EP-A 758644; alkenylbenzoylguanidines, see EP-A 760365; benzoylguanidines fused to a cyclic sulfone, see DE 19548708; benzoyl, polycyclic aroyl and heteroaroylguanidines, see WO 9604241; 3-phenylbenzoylguanidines containing a basic amide group in the 5-position, see WO 9725310; 3-(dihalothienyl)- or 3-(dihalophenyl)benzoylguanidines containing a basic substituent in the 5-position, see WO 9727183; 3-methylsulfonylbenzoylguanidines containing certain amino substituents in the 4-position, see WO 9512584; amiloride derivatives, see WO 9512592;3-methylsulfonylbenzoylguanidines containing certain amino substituents in the 4-position, see WO9726253; indoloylguanidines, see EP-A 622356 and EP-A 708091; indoloylguanidines fused to other ring systems, see EP 787728; methylguanidine derivatives, see WO 9504052; 1,4-benzoxazinoylguanidines, see EP-A 719766; 5-bromo-2-naphthoylguanidines, see JP 8225513; quinoline-4-carbonylguanidines bearing a phenyl group in the 2-position, see EP-A 726254; cinnamoylguanidines, see JP 09059245; propenoylguanidines bearing a naphthalene substituent, see JP 9067332; propenoylguanidines bearing an indole substituent, see JP 9067340; or acryloylguanidines bearing a heteroaryl substituent, see WO 9711055, and physiologically acceptable salts of these compounds.; Preference is given to those NHE inhibitors which are preferred in the publications listed. In particular, the following compounds are preferred: cariporide (HOE642), EMD 96785, FR 168888, FR 183998, SM-20550, KBR-9032, and their physiologically acceptable salts. Most preferred are cariporide or N-(4-isopropyl-3-methanesulfonylbenzoyl)guanidine, and their physiologically acceptable salts. Groups of active agents with respect to the heart and circulation that can be combined therapeutically advantageously with NCBE inhibitors or with a combination of NCBE inhibitors and NHE inhibitors are, for example, the following: beta-receptor blockers, calcium antagonists, angiotensin converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers, loop diuretics, thiazide diuretics, potassium-sparing diuretics, aldosterone antagonists used to lower blood pressure, cardiac glycosides or other agents used in the treatment of heart failure and congestive heart failure that increase the force of contraction, class I-IV antiarrhythmics, nitrates, KATP openers, KATP blockers, veratridine-activated sodium channel inhibitors, etc.For example, the following active substances can be used: beta-blockers: propranolol, atenolol, metoprolol; calcium antagonists; dithiazem hydrochloride, verapamil hydrochloride, nifedipine; ACE inhibitors: captopril, enalapril, ramipril, trandolapril, quinapril, spirapril, preferably ramipril or trandolapril; angiotensin II receptor antagonists: losartan, valsartan, telmisartan, eprosartan, tasosartan, candesartan, irbesartan; loop diuretics: furosemide, oiretanide, torasemide; thiazide diuretics: hydrochlorothiazide, metolazone, indapamide; potassium-sparing diuretics: amiloride, triameterene, spironolactone; cardiac glycosides: digoxin, digitoxin, strophanthin; antiarrhythmics: amiodarone, solatol, bretylium, flecainide; nitrate: glyceryl trinitrate; K+(ATP)-openers: cromacaline, lemakalin, nocorandil, pinakidil, minoxidil; Inhibitors of the Na+-channel that can be activated by veratridine. HU 225 377 B1 Examples of compounds that can be combined particularly advantageously with NCBE inhibitors of the general formula (I) are blockers of the non-inactivating sodium channel (veratridine-activated sodium channel). The combination of an NCBE inhibitor of the general formula (I) and a blocker of the non-inactivating sodium channel (veratridine-activated sodium channel) is useful for the prevention of infarction and recurrent infarction, for the treatment of infarction and angina pectoris, for the inhibition of the onset and maintenance of cardiac arrhythmias of ischemic origin, tachycardia, and ventricular fibrillation. In this case, the combination of the compound of the general formula (I) and the non-inactivating sodium channel blocker can completely prevent or greatly reduce the pathological physiological processes involved in the development of ischemia-induced damage, especially ischemia-induced cardiac arrhythmias.Based on their protective effect against pathological hypoxic and ischemic situations, the combination of the NCBE inhibitor of general formula (I) and the non-activating sodium channel blocker according to the invention, because it increases the inhibition of sodium influx into the cell, is suitable for the treatment of acute or chronic damage or diseases caused by primary or secondary ischemia. This also applies to use in surgical interventions (for example, during organ transplantation, during and after organ removal, and then for the protection of the organ stored in physiological solutions, as well as during implantation). The combinations of the NCBE inhibitor of general formula (I) and the non-activating sodium channel blocker are also potentially valuable, protective drugs that can be used during vascular surgery and heart surgery.Based on their potential protective effect against ischemia-induced damage, the combinations can be used to treat ischemic conditions of the nervous system, especially the central nervous system, such as stroke or cerebral edema. In addition, the combination of the NCBE inhibitor of general formula (I) and the non-activating sodium channel blocker according to the invention can be used to treat shock conditions, such as allergic shock, cardiac shock, hypovolemic and bacterial shock. The invention also relates to a pharmaceutical composition which a) an NCBE inhibitor of general formula (I) and a NHE inhibitor and / or physiologically tolerable salts thereof; b) an NCBE inhibitor of the general formula (I) and active substances belonging to other classes of cardiovascular active substances and / or their physiologically tolerable salts; or c) contains an NCBE inhibitor of the general formula (I), an NHE inhibitor and active substances belonging to other classes of cardiovascular active substances and / or their physiologically tolerable salts. Due to the combined use, the effect of one of the combination partners can be enhanced by the other partner, i.e. the effect and / or duration of the effect of a combination or preparation according to the invention is stronger and / or more durable than the effect and / or duration of the effect of the individual components (synergistic effect). The combined use leads to the fact that the dosage of the combination partners can be reduced compared to the dosage required for separate use. The combinations and preparations according to the invention therefore have the advantage that the amount of active ingredient to be used can be greatly reduced, so that undesirable side effects are eliminated or at least greatly reduced. The pharmaceutical compositions of the invention can be prepared, for example, by mixing the individual components together in the form of a fine powder, or by dissolving the components, for example in a lower alcohol, followed by removal of the solvent. The weight ratio of the NCBE inhibitor to the NHE inhibitor or other cardio-circulatory active substance in the combinations and compositions according to the invention is suitably 1:0.01-1:100, preferably 1:0.1-1:10. The combinations and compositions according to the invention preferably contain a total of 0.5-99.5% by weight, particularly preferably 4-99% by weight, of active ingredient(s). When the compositions are used on mammals, preferably humans, the dosage of the various active ingredient components is, for example, 0.001-100 mg / kg / day. List of abbreviations: BCECF 2',7'-bis(2-carboxyethyl)-5,6-carboxy-fluorescein BN benzyl DCI Desorption-Chemical ionisation DIP diisopropyl ether DMA dimethylacetamide DME dimethoxyethane DMF Ν,Ν-dimethylformamide EE ethyl acetate Ei electron impact eq equivalent ES electrospray ionisation Esneg electrospray, negative ionisation et ethyl EtOH ethanol FAB Fást Atom Bombardment Fmoc 9-fluorenylmethoxycarbonyl HEP n-heptane HOAc acetic acid Me methyl HEP n-heptane HOAc acetic acid Me methyl MeOH methanol MTB methyl tert-butyl ether NCBE sodium dependent chloride / bicarbonate exchange mechanism NHE sodium / hydrogen exchange mechanism TMU N, N, N ', N '-tetramethyl urea Tol toluene Examples General procedure for the preparation of sulfonylcyanamides from sulfonamides The starting sulfonamide is dissolved in 10 ml / mmol anhydrous acetonitrile, 3 equivalents of potassium carbonate and 1 equivalent of cyanogen bromide (as a 5 N solution in acetonitrile) are added, and the mixture is refluxed. HU 225 377 Β1 is stirred under refrigeration until complete conversion (typical reaction time: 10 minutes to 6 hours). The reaction mixture is chromatographed on silica gel without further work-up. Example 1 2-Butyl-5-methylsulfanyl-3-[4-(3'-cyanoaminosulfonylbenzyl)benzyl]-3H-imidazole-4-carboxylic acid ethyl ester; compound of formula (1) Synthesis route a) 3-Bromo-N-dimethylamino-methane-benzenesulfonamide: A mixture of 20.3 g of 3-bromo-benzenesulfonamide and 57 ml of dimethylformamide-dimethylacetal in 120 ml of dimethylformamide was allowed to stand at room temperature for 3 days. After aqueous work-up, the precipitate was filtered. The product was dried in vacuo at 50 °C to give 20.5 g of a colorless solid. Melting point: 122 °C, MS (ES): 291 (M+H)+ b) 4-[3-(Dimethylaminomethylenesulfamoyl)benzyl]benzoic acid methyl ester: 3.5 g of 3-bromo-N-dimethylaminomethylenebenzenesulfonamide (1a) and 3 equivalents of 4-bromomethylbenzoic acid methyl ester zinc reagent were cross-esterified in the presence of 0.1 equivalent of Pd(II) acetate, 0.2 equivalent of triphenylphosphine and 0.12 equivalent of copper(I) iodide at 80 °C in 200 ml of dimethylformamide. Reaction time 3 days. After aqueous work-up, the solvent was removed in vacuo and the residue was chromatographed on silica gel. 4.1 g of product was obtained as a colorless solid, melting point: 36-37 °C, MS (ES): 291 (M+H)+ c) 4-(3-Sulfamoylbenzyl)-benzyl alcohol: 3.0 g of the product from 1b) are reduced with 1.2 g of lithium alanate in 140 ml of tetrahydrofuran at 0 °C for 30 minutes, then the reaction mixture is refluxed for 2 hours. After aqueous work-up, 1.47 g of a colorless solid is obtained. Melting point: 113-115 °C d) 4-[3-(Dimethylaminomethylenesulfamoyl)benzyl]benzyl alcohol: prepared as described under 1a) from 1.7 g of compound 1c). Yield: 1.98 g of colorless crystals, Melting point: 92 °C, MS (ES): 333 (M+H)+ e) 2-Butyl-5-methylsulfanyl-3-[4-(3-dimethylaminomethylenesulfamoylbenzyl)benzyl]-3H-imidazole-4-carboxylic acid ethyl ester From 4-[3-(Dimethylaminomethylenesulfamoyl)benzyl]benzylmethanesulfate [prepared in situ as follows: 0.7 g of compound 1d) was reacted with 1 equivalent of methanesulfonic acid chloride in the presence of 2 equivalents of triethylamine in dichloromethane at 60 °C for two hours, then the mixture was stirred at room temperature for another 1 hour, then the solvent was removed] and 2 equivalents of 2-butyl-5-methylsulfamoyl-3H-imidazole-4-carboxylic acid ethyl ester (J. Med. Chem. 1995, 38, 2357) by nucleophilic substitution. The starting materials were kept in 18 ml of dimethylformamide in the presence of 6 equivalents of potassium carbonate for 16 hours at 60 °C. After aqueous work-up and column chromatography purification, 0.31 g of a colorless oil is obtained. MS (ES): 557 (M+H)+ f) 2-Butyl-5-methylsulfanyl-3-[4-(3-sulfamoylbenzyl)benzyl]-3H-imidazole-4-carboxylic acid ethyl ester: 0.3 g of compound 1 e) was hydrolyzed with 1 ml of semi-concentrated hydrochloric acid in 1 ml of glacial acetic acid under reflux for 2 hours. After addition of water and drying, 0.27 g of a colorless resin was obtained. MS (ES): 502 (M+H)+ g) 2-Butyl-5-methylsulfanyl-3-[4-(3'-cyanoaminosulfonylbenzyl)benzyl]-3H-imidazole-4-carboxylic acid ethyl ester: 0.17 g of compound 1 f) was cyanated according to the general procedure. 0.1 g of a colorless resin was obtained, melting point: 62 'C, MS (ES): 527 (M+H)+ Example 2 2-Butyl-5-methylsulfanyl-3-[3-(3'-cyanoaminosulfonylbenzyl)benzyl]-3H-imidazole-4-carboxylic acid ethyl ester; compound of formula (2) Synthesis route a) 3-[3-(Dimethylaminomethylenesulfamoyl)benzyl]benzoic acid methyl ester: prepared according to 1b) from 3.1 g of compound 1a), but starting from 3 equivalents of 3-bromomethylbenzoic acid methyl ester. 3.05 g of colorless solid, melting point: 95 'C, MS (ES): 361 (M+H)+ b) 3-(3-Sulfamoylbenzyl)benzyl alcohol: Prepared from 2.97 g of compound 2a) by reduction according to 1c). 1.9 g of a colorless solid are obtained, melting point: 94 °C. MS (Cl): 277 (M)+ c) 3-[3-Dimethylaminomethylenesulfamoyl)benzyl]benzyl alcohol: 1.39 g of compound 2b) was prepared according to 1 a). 1.41 g of colorless crystals, melting point: 99-100 'C, MS (ES): 333 (M+H)+ d) 2-Butyl-5-methylsulfanyl-3-[-(3-dimethylaminomethylenesulfamoylbenzyl)benzyl]-3H-imidazole-4-carboxylic acid ethyl ester: prepared in situ from 3-[3-(3-dimethylaminomethylenesulfamoylbenzyl)benzyl]methanesulfonate [0.28 g prepared from compound 2c)] according to example 1e). 0.15 g colorless resin, MS (ES): 557 (M+H)+ e) 2-Butyl-5-methylsulfanyl-3-[3-(3-sulfamoylbenzyl)benzyl]-3H-imidazole-4-carboxylic acid ethyl ester: 0.15 g of compound 2d) was hydrolyzed according to Example 1f) to give 0.13 g of colorless crystals. Melting point: 49 °C, MS (ES): 502 (M+H)+ f) 2-Butyl-5-methylsulfanyl-3-[3-(3'-cyanoaminosulfonylbenzyl)benzyl]-3H-imidazole-4-carboxylic acid ethyl ester: 0.12 g of compound 2e) was cyanated according to the general procedure. 0.07 g of a colorless resin was obtained, melting point: 172-174 'C, MS (ES): 527 (M+H)+ Example 3 2-Phenyl-4-formyl-5-chloro-3-[3-(3'-cyanaminosulfonylbenzyl)benzyl]-3H-imidazole; Compound of formula (3) Synthesis route a) 2-Phenyl-4-formyl-5-chloro-3-[3-(3-dimethylaminomethylenesulfamoylbenzyl)benzyl]-3H-imidazole: prepared in situ from 3-[3-(3-dimethylaminomethylenesulfamoylbenzyl)benzyl]-methanesulfonate [0.58 g from 2c)] by nucleophilic substitution according to example 1e) but using 0.72 g of 5-chloro-4-formyl-2-phenyl-3H-imidazole [Chem. Pharm. Bull. 1976, 24(5), 960]. 0.19 g of colorless oil MS (ES): 521 (M+H)+ b) 2-Phenyl-4-formyl-5-chloro-3-[3-(3-sulfamoylbenzyl)benzyl]-3H-imidazole: 0.17 g of compound 2a) was hydrolyzed according to example 1f). 0.13 g of colorless crystals were obtained. Melting point: 83-85 'C, MS (ES): 466 (M+H)+ HU 225 377 B1 c) 2-Phenyl-4-formyl-5-chloro-3-[3-(3-dimethylaminomethylenesulfamoylbenzyl)benzyl]-3H-imidazole: 0.13 g of compound 3b) was cyanated according to the general procedure. 0.08 g of a colorless solid was obtained, melting point 75 °C, MS (ES): 491 (M+H)+ Example 4 2-[4-(4-Chloro-5-formyl-2-phenylimidazol-1-ylmethyl)benzenesulfonyl]benzenesulfonic acid cyanamide; compound of formula (4) 3.0 g 2-chlorobenzenesulfonamide, 2.0 g thiocresol, A mixture of 6.5 g of potassium carbonate and 30 ml of dimethylformamide was stirred at 100 °C for 6 hours and then at 120 °C for 13 hours. The reaction mixture was poured into 200 ml of water and extracted with 500 ml of ethyl acetate. The organic phase was washed with 100 ml of saturated aqueous Na2CO3 solution, dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was chromatographed on silica gel with diisopropyl ether to give 1.4 g of white crystals, melting point: 122-124 °C. Rf=0.36 (diisopropyl ether), MS (ES): 280 (M+H)+ b) N-Dimethylaminomethylene-2-p-tolylsulfanylbenzenesulfonamide A mixture of 1.4 g of 2-p-tolylsulfanylbenzenesulfonamide and 10 ml of dimethoxymethyldimethylamine was stirred at room temperature for two hours. The reaction mixture was then poured into 500 ml of water, stirred for another two hours, the product was filtered off with suction and dried in vacuo. 1.6 g of white crystals were obtained, melting point: 151 °C. Rf=0.28 (MTB), MS (DCI): 335 (M+H) + c) N-Dimethylaminomethylene-2-(toluene-4-sulfonyl)benzenesulfonamide To a solution of 1.5 g of N-dimethylaminomethylene-2-p-tolylsulfanylbenzenesulfonamide in 50 ml of dichloromethane at 0 °C was added 2.6 g of m-chloroperbenzoic acid. The reaction mixture was stirred at room temperature for 3 hours, then 100 ml of saturated aqueous Na2SO3 solution was added and stirring was continued for another 5 minutes. The mixture was diluted with 150 ml of dichloromethane and washed with 2*50 ml of saturated aqueous Na2CO3 solution. It was then dried over magnesium sulfate and the solvent was removed in vacuo. 1.5 g of white crystals were obtained, melting point: 178 °C. Rf=0.44 (ethyl acetate), MS (ES): 367 (M+H)+ d) 2-(4-Bromomethylbenzenesulfonyl)-N-dimethylaminomethylenebenzenesulfonamide A mixture of 1.5 g of N-dimethylaminomethylene-2-(toluene-4-sulfonyl)benzenesulfonamide, 0.74 g of NBS and 20 mg of benzoyl peroxide in 15 ml of chlorobenzene was refluxed for 2 hours. The reaction mixture was allowed to cool, then diluted with 100 ml of toluene and washed with 20 ml of saturated aqueous Na2SO3 solution and then 2*50 ml of saturated aqueous Na2SO3 solution. The solution was dried over magnesium sulfate and the solvent was removed in vacuo. 1.6 g of amorphous solid was obtained, which was reacted further without purification. Rf=0.44 (ethyl acetate), MS (ES): 445 (M+H)+ e) 2-[4-(4-Chloro-5-formyl-2-phenylimidazol-1-ylmethyl)benzenesulfonyl]-N-dimethylaminomethylenebenzenesulfonamide A mixture of 1.6 g of 2-(4-bromomethylbenzenesulfonyl)-N-dimethylaminomethylenebenzenesulfonamide, 680 mg of 5-chloro-2-phenyl-3H-imidazole-4-carbaldehyde and 1.4 g of potassium carbonate in 15 ml of anhydrous dimethylformamide was stirred at room temperature for 3 days. The reaction mixture was then diluted with 200 ml of ethyl acetate and washed with 3*50 ml of saturated aqueous Na2CO3 solution. The solution was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was chromatographed on silica gel with methyl tert-butyl ether. 240 g of a colorless oil were obtained. Rf=0.08 (MTB) MS (ES): 571 (M+H) + f) 2-[4-(4-Chloro-5-formyl-2-phenylimidazol-1-ylmethyl)benzenesulfonyl]benzenesulfonamide 230 mg of 2-[4-(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)benzenesulfonyl]-N-dimethylaminomethylenebenzenesulfonamide were refluxed in a mixture of 3 ml of ethanol and 3 ml of saturated aqueous HCl solution for 2 hours. The cooled reaction mixture was poured into 10 ml of water and the product was filtered off. The crude product was chromatographed on silica gel with methyl tert-butyl ether. 151 mg of amorphous solid was obtained. Rf=0.41 (MTB) MS (ES): 516 (M+H) + g) 2-[4-(4-Chloro-5-formyl-2-phenylimidazol-1-ylmethyl)benzenesulfonyl]benzenesulfonic acid cyanamide A mixture of 145 mg of 2-[4-(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)benzenesulfonyl]benzenesulfonamide, 117 mg of potassium carbonate and 56 μΙ of acetonitrile 5 M cyanogen bromide solution in 2 ml of anhydrous acetonitrile was heated under reflux for 90 minutes. The reaction mixture was allowed to cool. Chromatography with a 10:1 mixture of ethyl acetate and methanol gave 90 mg of an amorphous solid. Rf=0.27 (EE / MeOH 10:1) MS (ES): 541 (M+H)+ Pharmacological studies Inhibition of sodium-dependent chloride / bicarbonate exchange (NCBE) in human endothelial cells Human endothelial cells were detached from the culture flasks with trypsin / EDTA buffer (0.05 / 0.02% in phosphate buffer) and, after centrifugation (100 g, 5 min), transferred to buffered saline (mmol / l: 115 NaCl, 20 NH4Cl, 5 KCl, 1 CaCl2, 1 MgSO4, 20 N-(2-hydroxyethyl)-piperazine-N-2-ethanesulfonic acid (HEPES), 5 glucose and 1 g / l bovine serum albumin). The cell suspension was incubated with 5 pm BCECF-acetoxymethyl ester at 37 °C for 20 min. Afterwards, the cells were washed and resuspended in sodium- and bicarbonate-free buffer (mmol / l: 5 HEPES, 133.8 choline chloride, 4.7 KCl, 1.25 MgCl2, 0.97 K2PO4, 5 glucose, pH 7.4). For fluorescence measurement in the FLIPR device (Fluorescent Imaging Plate Reader), 100 μΙ of cell suspension (=20,000 cells) was pipetted into each well of a 96-well microtiter plate and the microtiter plate was centrifuged (100 g, 5 min). 100 μΙ of buffer solution was taken from another prepared microtiter plate in the FLIPR device and pipetted into the wells of the measuring plate. To observe the 100% control, i.e. the normalization of the intracellular pH (pHj), the sodium-dependent chloride / bicarbonate exchange mechanism was used. HU 225 377 Β1, a bicarbonate and Na-containing buffer solution was used, which contained 50 pm HOE 642 (other mmol / l: 5 HEPES, 93.8 NaCl, 40 NaHCO3, 4.7 KCl, 1.25 CaCl2, 1.25 MgCl2, 0.97 Na2HPO4, 0.23 NaH^ PO4, 5 glucose, pH 7.4). For the 0% control, i.e. no pHj-normalization, a bicarbonate-free, Na-containing buffer solution was used (mmol / l: 5 HEPES, 133.8 NaCl, 4.7 KCl, 1.25 CaCl2, 1.25 MgCl2, 0.97 Na2HPO4, 0.23 NaH2PO4, 5 glucose, pH 7.4), which also contained 50 pm HOE 642. The compounds of the invention of general formula (I) were added in different concentrations to the sodium and bicarbonate-containing solution. The buffer solutions were added to the acidified cells in the wells of the plate, and the increase in fluorescence intensity with increasing pH was measured. The kinetics were recorded at 35 °C for 2 minutes. The increase in fluorescence intensity measured at different concentrations of the compounds of the invention was compared to the two controls, and the inhibitory capacity of the given substance was calculated from this. Results Residual activity of NCBE at 10 pm inhibitor concentration Example Residual activity in % 1. 11.1 2. 35.2 3. 24.3 PATENT CLAIMS

Claims

PATENT CLAIMS 1. Compounds of formula (I) wherein X is a group of formula (a), R1 is an alkyl group having 1, 2, 3 or 4 carbon atoms or a phenyl group which is unsubstituted or singly substituted by fluorine, chlorine, trifluoromethyl, methyl or methoxy; R2 and R3 are independently hydrogen, fluorine, chlorine, trifluoromethyl, cyano, -CO-R24 or -O-R25, where R24 is hydrogen, an alkyl group having 1, 2, 3 or 4 carbon atoms, a group of formula -OR26 or a phenyl group which is unsubstituted or singly substituted by fluorine, chlorine, trifluoromethyl, methyl or methoxy; R26 is hydrogen, methyl or ethyl; R25 represents a hydrogen atom, an alkyl group having 1, 2, 3 or 4 carbon atoms or a phenyl group which is unsubstituted or singly substituted by a fluorine, chlorine, trifluoromethyl, methyl or methoxy group;or R25 is a heteroaryl group which is unsubstituted or singly substituted by fluorine, chlorine, trifluoromethyl, methyl or methoxy; or R2 and R3 are independently an alkyl group having 1,2,3 or 4 carbon atoms, a cycloalkyl group having 3,4,5,6 or 7 carbon atoms, or R2 and R3 are independently a phenyl group which is unsubstituted or singly substituted by fluorine, chlorine, trifluoromethyl, methyl or methoxy; or R2 and R3 are independently a heteroaryl group having 1,2,3, 4,5,6,7,8 or 9 carbon atoms, which is unsubstituted or singly substituted by fluorine, chlorine, trifluoromethyl, methyl or methoxy; or R2 and R3 independently represent a group of the formula -SOf-R37, wherein R37 represents an alkyl group of 1, 2, 3 or 4 carbon atoms or a phenyl group which is unsubstituted or singly substituted by fluorine, chlorine, trifluoromethyl, methyl or methoxy, and / is 0 or 2;R13, R14 and R15 are independently hydrogen, methyl, fluorine, chlorine, trifluoromethyl, cyano, SO2-R79, -CO-R80 or -O-R81; R79 and R81 are independently C1, C2, C3 or C4 alkyl or phenyl which is unsubstituted or monosubstituted by fluorine, chlorine, trifluoromethyl, methyl or methoxy; R80 is hydrogen, methyl or -OR84, in which R84 is C1, C2, C3 or C4 alkyl or hydrogen, and compounds or physiologically acceptable salts thereof.; 2. Compounds of general formula (I) according to claim 1, as well as physiologically acceptable salts of these compounds, for use as pharmaceuticals.

3. A pharmaceutical composition comprising an effective amount of one of the compounds of general formula (I) according to claim 1 and / or a physiologically tolerable salt thereof.

4. Pharmaceutical compositions according to claim 3, which additionally contain an effective amount of an NHE inhibitor and / or an active substance belonging to other classes of cardiovascular active substances and / or their physiologically tolerable salts.

5. Compounds of general formula (I) according to claim 1 and / or physiologically acceptable salts thereof for use in inhibiting the sodium-dependent bicarbonate / chloride exchanger (NCBE).

6. Compounds of general formula (I) according to claim 1 and / or physiologically acceptable salts of these compounds for the treatment and / or prevention of myocardial infarction, angina pectoris, diseases caused by ischemic conditions, respiratory distress, as well as for the treatment and prevention of ischemic conditions of the heart, central and peripheral nervous system, stroke, ischemic conditions of peripheral organs and limbs, and diseases whose primary or secondary cause is cell proliferation, as well as for the treatment of shock conditions or for the preservation and storage of transplants for surgical purposes.

7. Use of compounds of general formula (I) according to claim 1 and / or their physiologically acceptable salts for use in the treatment and / or prevention of cancer.

8. A pharmaceutical composition according to claim 3 or 4 for the treatment and / or prevention of myocardial infarction, angina pectoris, diseases caused by ischemic conditions, respiratory distress, as well as for the treatment and prevention of ischemic conditions of the heart, central and peripheral nervous system, stroke, ischemic conditions of peripheral organs and limbs, as well as diseases whose primary or secondary cause is cell proliferation, as well as for the treatment of shock conditions or for use in the conservation and storage of transplants for surgical purposes.

9. A pharmaceutical composition according to claim 3 or 4 for the treatment and / or prevention of cancer.