MXPA97003921A - 1-naftoilguanidinas substitute, procedure for its preparation, its employment as a medicine or diagnostic agent, as well as a medication that the - Google Patents

Abstract

The present invention relates to: substituted 1-naphthoylguanidines of the formula I (See Formula), wherein R 2 to R 8 have the meanings indicated in the claims, are suitable, as a consequence, as antiarrhythmic drugs with a cardioprotective component for the prophylaxis of infarction and infarction treatment, as well as for the treatment of angina. They also preventively inhibit the pathophysiological processes in the appearance of ischemia-induced lesions, particularly in the development of ischemia-induced heart arrhythmias

Description

Substituted 1-naphthoylguanidines, process for its preparation, its use as a medicine or diagnostic agent, as well as medicine containing them The invention relates to substituted l-naphthoylguanidines of the formula I wherein R2, R3, R4, R5, R6, R7 and R8 stand for, independently of one another, H, F, Cl, Br, I, CN, N02, CF3, C2F5 or XaYbZ; X means O, S, NR (10), CR (ll) R (12), C = 0, C (= O) NR (10), C (= 0) 0, SO, S02, SO2NR (10), OC = 0, NR (10) C = O or NR (10) SO2, bonding with the naphthalene ring in each case through the atom on the left; R (10), R (ll) and R (12) signify, independently of one another, H, alkyl with 1, 2, 3, 4, 5 or 6 C atoms, perfluoroalkyl with 1, 2, 3 or 4 C atoms or cycloalkyl with 3, 4, 5, 6 or 7 C atoms; a means zero or 1; Y means alkylene with 1, 2, 3, 4, 5, 6, 7 or 8 groups CH2, one of these CH2 groups may be replaced by 0, S, NR (13) or o-, p- or m- -phenylene, -R (13) means H, alkyl with 1, 2, 3, 4, 5 or 6 C atoms, perfluoroalkyl with 1, 2, 3 or 4 C atoms or cycloalkyl with 3, 4, 5 or 6 C atoms, -b means zero or 1; Z means H, alkyl with 1, 2, 3, 4, 5, 6 or 7 C atoms, cycloalkyl with 3, 4, 5, 6 or 7 C atoms, C (= 0) R (15), S0- RCL5), NR (16) R (17) O phenyl, which is unsubstituted or substituted by 1-3 substituents chosen from the group consisting of F, Cl, Br, CF3, methyl, methoxy, NR (21) R (22); R (21) and R (22) signify, independently of one another, H or alkyl with 1, 2, 3 or 4 C atoms or perfluoroalkyl with 1, 2, 3 or 4 C atoms; R (15) means N = C (NH2) 2, NR (18) R < 19), N (CH2) CNR (18) R (19) or OR (20); c means 2 or 3, - R (18) and R (19) signify, independently of one another, H, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C atoms or perfluoroalkyl with 1, 2, 3 or 4 C atoms; or R (18) and R (19) together mean 4 or 5 methylene groups, of which a CH2 group can be replaced by oxygen, S, NH, N-CH3, N-benzyl or N- (p-chlorophenol). ); R (20) means H, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, perfluoroalkyl with 1, 2, 3 or 4 carbon atoms or cycloalkyl with 3, 4, 5, 6 or 7 carbon atoms. C; R (16) and R (17) signify, independently of one another, H, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C atoms or perfluoroalkyl with 1, 2, 3 or 4 carbon atoms. C; R (16) and R (17) together mean 4 or 5 methylene groups, of which a CH2 group can be replaced by oxygen, S, NH, N-CH3, N-benzyl or N- (p-chlorophenyl); or Z means a heterciclo with content in N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 atoms of C, the heterocycle being linked with N content through N or C and not being substituted or being substituted with 1-3 substituents selected from the group consisting of F, Cl, Br, CF3, methyl, methoxy and NR (21) R (22); wherein, however, for the case that R (4) represents an alkoxy radical, at least one of the substituents R (2), R (3), R (5), R (6), R (7) and R (8) are other than hydrogen; as well as its pharmaceutically compatible salts. Preference is given to compounds of the formula I, in which all substituents and indices are defined as above, but at least one of the substituents R 2, R 3, R 4, R 5, R 6, R 7 and R 8 is other than hydrogen; as well as its pharmaceutically compatible salts. Particularly preferred are compounds of the formula I, in which R.sub.2, R.sub.3, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are defined as in the beginning and R.sub.4 is H, F, Cl, Br, I, CN, N02, CF.sub.3, C2FS or Z , Z being defined as in the beginning, as well as its pharmaceutically compatible salts. Also preferred are compounds of the formula I, wherein: at least one of the substituents R 2, R 3, R 4, R 5, R 6, R 7 and R 8 signify XaYbZ; X means 0, S, NR (10), CR (11) R (12), C = 0, C (»O) NR (10), C (= 0) 0, SO, S02, SO2NR (10), 0C = 0, NR (10) C = 0 or NR (10) S02, bonding with the naphthalene ring in each case through the atom on the left; R (10), R (n) and R (12) signify, independently of one another, H, alkyl having 1, 2, 3 or 4 carbon atoms, perfluoroalkyl with 1 or 2 carbon atoms or cycloalkyl with 3, 4 , 5 or 6 C atoms; a means zero or 1; Y means alkylene with 1, 2, 3, 4 or 5 CH2 groups, one of these CH2 groups may be replaced by O, S, NR (13) or o-, p- or m- -phenylene, -R (13) means H, alkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl with 3, 4, 5 or 6 carbon atoms; b means zero or 1; Z means cycloalkyl with 3, 4, 5, 6 or 7 C atoms, C (= 0) R (15), S0, R (15), NR (16) R (17) or phenyl, which is unsubstituted or is substituted with 1-3 sub-substituted β-βββββ of the group consisting of F, Cl, Br, CF 3 / methyl, methoxy, NR (21) R (22); R (21) and R (22) signify, independently of one another, H, alkyl with 1, 2, 3 or 4 C atoms or perfluoroalkyl with 1 or 2 C atoms; R (15) means N = C (NH2) 2, NR (18) R (19), N (CH2) CNR (18) R (19) OR OR (20); R (18) and R (19) signify, independently of one another, H, alkyl with 1, 2, 3, 4 or 5 C atoms; or R (18) and R (19) together mean 4 or 5 methylene groups, of which a CH2 group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl; c means 2 or 3; R (20) means H or alkyl with 1, 2, 3, 4, 5 or 6 C atoms; R (16) and R (17) signify, independently of one another, H, alkyl having 1, 2, 3, 4 or 5 carbon atoms or perfluoroalkyl with 1 or 2 carbon atoms; or R (16) and R (17) together mean 4 or 5 methylene groups, of which a CH2 group can be replaced by oxygen, S, NH, N-CH3, N-benzyl or N- (p-chlorophenyl); or Z means a heterocycle with N content containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, which is linked through N or C and which is unsubstituted or substituted by 1; -3 substituents chosen from the group consisting of F, Cl, Br, CF3, methyl, methoxy and NR (21) R (22); and the respective remaining substituents R2, R3, R4, R5, R6, R7 and R8, which are not yet defined by the definition given above, mean, independently of one another, H, F, Cl, Br, I, CN, N02 , CF3, C2F5 or XaYbZ; X means O, S, NR (10), C = 0, C (= O) NR (10), C (= 0) 0, SO, S02, SO2NR (10), OC = 0, NR (10) C = O or NR (10) SO2, bonding with the naphthalene ring in each case through the atom on the left; R (10) means H, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, perfluoroalkyl with 1, 2, 3 or 4 carbon atoms or cycloalkyl with 3, 4, 5, 6 or 7 carbon atoms C; a means zero or 1, - b means zero; Z stands for H, alkyl with 1, 2, 3, 4 or 5 C atoms; as well as its pharmaceutically compatible salts. Particularly preferred are compounds of the formula I, in which: at least one of the substituents R 2, R 3, R 4, R 5, R 6, R 7 and R 8 mean XaYbZ, - X means 0, NR (10), C (= O) NR (10), C (= 0) 0 or SO-NRUO), bonding with the naphthalene ring in each case through the atom on the left; R (10) means H or methyl, - a means 1, - Y means alkylene with 1, 2, 3, 4 or 5 CH2 groups; wherein one of these CH2 groups can be replaced by o-, p- or m-phenylene, -b means 1; Z means C (= 0) R (15), NR (16) R (17) or a heterocycle with N content with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, being linked the heterocycle with N content through N or C and not being substituted; R (15) means N = C (NH2) 2, NR (18) R (19) or OR (20); R (18) and R (19) signify, independently of one another, H, alkyl with 1, 2, 3 or 4 C atoms; or R (18) and R (19) together mean 4 or 5 methylene groups, of which a CH2 group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl; R (20) means H, alkyl having 1, 2 or 3 C atoms (16) and R (17) signifies, independently of one another, H or alkyl with 1, 2, 3, 4 or 5 C atoms; or R (16) and R (17) together mean 4 or 5 methylene groups, of which a CH2 group can be replaced by oxygen, S, NH, N-CH3, N-benzyl or N- - (p-chlorophenyl) , and the respective remaining substituents R2, R3, R4, R5, R6, R7 and R8 which are not yet defined by the definition given above, mean, independently of one another, H, F, Cl, Br, I, CF3 or XaYbZ; X means 0, NR (10), C (= O) NR (10), C (= 0) 0, S02, S02NR (10), 0C = 0 or NR (10) C = O, the link being made with the Naphthalene ring in each case through the atom on the left, - R (10) means H or alkyl with 1, 2 or 3 C atoms; a means zero or 1; b means zero; Z means H or alkyl with 1, 2, 3 or 4 C atoms; as well as its pharmaceutically compatible salts. If the compounds of the formula I contain one or more centers of asymmetry, then these can have the configuration of both S and R. The compounds can be present in the form of optical isomers, as diastereoisomers, as racemates or as mixtures thereof. The alkyl radicals and the named perfluoroalkyl radicals can be present in both straight chain and branched form. As heterocycles containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms are in particular pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl. , isoindolyl, benzimide-zolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinolinyl. Particularly preferred are heterocycles containing N-pyrrolyl, imidazolyl, quinolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl. The invention also relates to a process for the preparation of compound I, characterized in that a compound of formula II wherein L represents a slightly nucleophilic substitutable leaving group and the remaining substituents have the above-mentioned meaning, is reacted with guanidine. 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-ridylthio, a nitrogenous heterocycle, preferably 1-imi-dazolyl, 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 again be prepared in a manner known per se from the carboxylic acids in which they are fused (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 naphthoic 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-C00C2H5 or tosyl chloride in the presence of triethylamine in an inert solvent; or the activation of carboxylic acids can be carried out with dicyclohexylcarbodiimide (DCC) or with 0- [(cyano (ethoxycarbonyl) methylene) amino] -1,1,3,3-tetramethyl-nio ("TOTU") tetrafluoroborate [Proceedings of the 21. European Peptide Symposium, 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 indication of the literature source, in J. March, Advanced Organic Chemistry, third edition (John Wiley &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 naphthoic acid (II, L = OMe) with guanidine, methanol, isopropanol or THF have been proved at 20 ° C up to the boiling point of these solvents. In the majority of the reactions of compounds II with guanidine free of salts, advantageous work was carried out in inert aprotic solvents, such as THF, dimethoxyethane, dioxane or DMF. However, water can also be used with the use of a base, such as for example NaOH as solvent in the reaction of II with guanidine. When L means Cl, the addition of an acid scavenger is advantageously carried out, for example in the form of excess guanidine for the disunion of the halogenated hydrazide. A part of the naphthoic acid derivatives of the formula II in which they are melted is known and is described in the literature. The unknown compounds of formula II can be prepared according to methods known from the literature. 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, methylsulphonates, p-toluenesulfonates, malonates, fumarates. . The compounds I are substituted acylguanidines. The most relevant representative of acylguanidines is the pyrazine derivative Amiloride, 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 ethyl isopropylamiloride. r Amiloride: R ', R "= H dimethylamiloride: R', R" = CH3 ethylisopropylamiloride: R '= C2H5, R "= CH (CH3) 2 In addition, investigations have been reported which point to anti-arrhythmic properties of Amiloride (Cir-culation 79, 1257-63 (1989)). However, it opposes broad application as antiarrhythmic, the fact that this effect is only weakly marked and manifests itself as a blood hypotensive and saluretic effect, and these side effects are undesirable in the treatment of heart rhythm disorders Indications on antiarrhythmic properties of Amiloride were also obtained in experiments in isolated animal hearts [Eur. Heart J. 9 (supl.l): 167 (1988), (book of abstracts).] Thus, for example, it was found in rat hearts that it could be completely suppressed by Amilorida an artificially triggered ventricular fibrillation, more potent than the Amiloride was in this model the aforementioned Amiloride ethylisopropyl amyloride derivative. 545 are known l-naphthoylguanidines which in the 4-position are substituted with long-chain alkoxy groups. For these compounds, an application as fungicides in phytoprotection is described. From the patent applications WO 94/26709 and EP-OS 682 017 exclusively 2-naphthoylguanidines but no 1-naphthoylguanidine are known. As the only example, unsubstituted 2-naphthoylguanidine is mentioned in these applications. However, the compounds known from the mentioned publications do not meet all the requirements that are necessary for the development of a drug from a pharmacologically effective compound. Thus, for example, better resorption, more favorable half-disintegration times, better water solubility, lower toxicity or greater selectivity would be desirable.

This has been achieved by the compounds according to the invention which, furthermore, do not have any undesired and disadvantageous salidiuretic properties, but they have very good antiarrhythmic properties, such as those which are important for example for the treatment of diseases that are caused for an oxygen deficiency. As a result of its pharmacological properties, the compounds are extraordinarily 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 pectoris, being able to inhibit or reduce strongly also preventively the 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 pathological ischemic situations, the compounds of 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 medicaments for surgical interventions, for example in the case of organ transplants, the compounds can be used both for the protection of the organs in the donor before and during the extraction, for the protection of 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 a protective effect in the performance of angioplasty 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 treatment of shock forms, such as, for example, allergic shock, car-diogen, hypovolemic shock and bacterial shock. Furthermore, the compounds of the formula I according to the invention are distinguished by a strong inhibitory effect on the proliferation of cells, 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 antiatherosclerotic drugs, 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 effective inhibitors of the sodium proton cell antiporter (Na + / H + exchanger) which in numerous diseases (essential hyper tone, atherosclerosis, diabetes, etc.) is also increased in cells whose measurements are easily accessible , such as for example in erythrocytes, thrombocytes or leukocytes. Therefore, the compounds according to the invention are suitable as extra-ordinary 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 , proliferating diseases, etc. In addition, the compounds of the formula I are suitable for preventive therapy to prevent the genesis of blood hypertension, for example of essential hypertonia.

It was further found that the compounds of formula I show a favorable influence of serum lipoproteins. It is generally recognized that the formation of arteriosclerotic variations of the vessels, particularly coronary heart disease, too high blood fat values, the so-called hyperlipoproteine-mias, represent an essential risk factor. For the prophylaxis and regression of atherosclerotic variations, therefore, an extraordinary importance is given to the reduction of increased serum lipoproteins. Along with the reduction of total cholesterol in the serum, particular importance is attached to the reduction of the proportion of the atherogenic lipid fractions specific to this total cholesterol, in particular to low density lipoproteins (LDL) and lipoproteins of very low density (VLDL), since these lipid fractions represent an atherogenic risk factor. In contrast, high-density lipoproteins are given a protective function against coronary heart disease. Correspondingly, the hypolipidemics should be able to reduce not only the total cholesterol, but in particular the cholesterol fractions in the serum of VLDL and LDL. It has now been found that compounds of the formula I show, in relation to the influence of the level of lipids in the serum, valuable therapeutically usable properties. Thus, they significantly reduce the increased concentration in serum of LDL and VLDL, such as can be seen for example by increased dietary intake of a food rich in cholesterol and lipids or in the case of pathological variations of metabolism, for example genetically conditioned hyperlipidemias. Therefore, it is possible to resort to them for the prophylaxis and regression of atherosclerotic variations, suppressing a causal risk factor. They not only include primary hyperlipidemias, but also certain secondary hyperlipidemias, such as those that occur, for example, in the case of diabetes. In addition, the compounds of the formula I lead to a clear reduction of the infarcts induced by abnormalities of the metabolism and, in particular, to a significant decrease in the magnitude of the infarction induced and its degree of severity. In addition, the compounds of formula I lead to an effective protection against lesions by abnormalities in the metabolism of induced endothelial lesions. With this protection of the vessels against the syndrome of endothelial dysfunction, the compounds of the formula I are valuable drugs for the prevention and treatment of coronary vascular spasms, of atherogenesis and atherosclerosis, of left ventricular hypertrophy and of dilated cardiomyopathy, and thrombotic diseases. Said compounds are therefore advantageously used for the manufacture of a medicament for the treatment of hypercholesterinemia; for the manufacture of a medicament for the prevention of atherogenesis; for the manufacture of a medicament for the prevention and treatment of atherosclerosis, for the manufacture of a medicament for the prevention and treatment of diseases that are triggered by an increased level of cholesterol, for the manufacture of a medicament for the prevention and treatment of diseases that are triggered by an endothelial dysfunction, for the manufacture of a medicament for the prevention and treatment of hyperthermia induced by atherosclerosis, for the manufacture of a drug for the prevention and treatment of thrombosis induced by atherosclerosis, for the manufacture of a medicament for the prevention and treatment of ischemic lesions and post-ischemic reperfusion injuries induced by hypercholesterinemia and endothelial dysfunction, for the manufacture of a medicament for the prevention and treatment of cardiac hypertrophies and cardiomyopathies induced by hypercholesterol inemia and endothelial dysfunction, for the manufacture of a medicament for the prevention and treatment of coronary vascular spasms and myocardial infarctions induced by hypercholesterinemia and endothelial dysfunction, for the manufacture of a medicament for the treatment of the mentioned ailments in combinations with blood hypotensive substances, preferably with angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor antagonists, a combination of an NHE inhibitor of formula I with an active ingredient reducing the level of fat in blood, preferably with an inhibitor of HMG- CoA reductase (for example, lovastatin or pravastatin), causing the latter a hi-polypidemic effect and thereby increasing the hipoli-pidémicas properties of the NHE inhibitor of formula I, manifests as a favorable combination with reinforced effect and use reduced of the active principle. Therefore, the administration of sodium proton exchange inhibitors of the formula I is also claimed as medicaments for the reduction of increased levels of blood fat, as well as the combination of inhibitors of the exchange of sodium protons with medicaments. blood hypotensive and / or hypolipidemic action. 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 for the desired drug formulation are suitable 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, for example antioxidants, dispersing agents, emulsifiers, defoamers, flavor regulators, preservatives, dissolving agents or dyes can 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 oil-containing substances or solvents include, for example, vegetable or animal oils, such as sunflower oil or cod liver oil. For subcutaneous or intravenous administration, the active compounds are brought into 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 saline 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 dispersions. Solvent reds 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 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 outbreaks 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.

Experimental part List of abbreviations CDI carbonyldiimidazole DMF N, N-dimethylformamide TA room temperature p.f. melting point FC flash chromatography THF tetrahydrofuran eq. equivalent EE ethyl acetate (EtOAc) General requirements for the preparation of naphthoylguanidines (I) Variant 1 A: from naphthoic acids (II, L = OH) 1.0 eq. of the naphthoic acid derivative of the formula II are dissolved or suspended in anhydrous tetrahydrofuran (THF) (5 ml / millimole) and then mixed with 1.2 eq. of carbonyl-diimidazole. After stirring for 2 hours at RT, 5.0 eq. Are added to the reaction solution. of guanidine. After stirring overnight, the THF is distilled off under reduced pressure (rotary evaporator), mixed with water and the corresponding guanidide (formula I) is filtered off. 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 I B: from alkyl esters of naphthoic acid (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 or suspended in isopropanol or in THF and boiled under reflux (typical reaction time, 2 to 5 h) until complete conversion (control by thin layer). The solvent is distilled off under reduced pressure (rotary evaporator), taken up in EA and washed 3 times with NaHCO 3 solution. It is dried over Na 2 SO 4, the solvent is distilled off in vacuo and chromatographed on silica gel with a suitable eluent agent, for example EE / MeOH 5: 1. (Formation of salt, see Variant A) General prescription for hydroxynaphthoic acid alkylacetate gives a solution of l eq. of an ester of hydroxynaphthoic acid (for example 6-hydroxynaphthoic acid methyl ester or 2-hydroxynaphthoic acid methyl ester) in DMF (3 ml / ml) is added 1.5 eq. of sodium methylate and stirred for 30 min at 40 ° C. Then 1.7 eq. of the alkylating agent (for example N- (2-chloroethylmorpholine)) and is stirred, depending on the reactivity of the alkylating agent used, at temperatures between 40 ° C and 120 ° C until the complete reaction (control by CD, reaction time typical: 1-15 h).

Example 1: 4-fluoro-l-naphthoylguanidine hydrochloride From 1 g of 4-fluoro-l-naphthoic acid, 0.75 g of 4-fluoro-l-naphthoylguanidine hydrochloride were obtained according to General Requirement 1A. P.f .: 245 ° C. 'H-NMR (DMS0-d6): d [ppm] = 7.5 (1H), 7.75 (2H), 8.1 (2H), 8.45 (1H), 8.7 (4H), 12.4 (1H).

Example 2: 5-Bromo-6-methoxy-l-naphthoylguanidine hydrochloride To a suspension of 4.2 g of 5-bromo-6-methoxy-1-naphthoic acid (obtained from the methyl ester described in DE 4318069 by saponification) in 90 ml of THF, 3.2 g are added. of CDI and stirred overnight at RT. It is mixed with 4.4 g of guanidine, stirred for 4 h at RT, the THF is distilled off in a rotary evaporator and the residue is mixed with 100 ml of water. The resulting precipitate is filtered with suction, dried and suspended in 60 ml of methanol. After the addition of 3 ml of saturated isopropanolic hydrochloric acid and stirring for 30 minutes, the hydrochloride is filtered off with suction. 4.8 g of 5-bromo-6-methoxy-1-naphthoylguanidine hydrochloride, -p.f. are obtained. : > 260 ° C. XH-NMR (DMS0-d6): d [ppm] = 4.0 (3H), 7.6 (1H), 7.7 (1H), 7.9 (1H), 8.2-8.4 ( 6H), 12.1 (1H).

Example 3: 6-Methoxy-5-trifluoromethyl-1-naphthoylguanidine hydrochloride From 4.0 g of 6-methoxy-5-trifluoromethyl-1-naphthoic acid (cf. EP 0059596, US 4590010), 4.7 g of 6-methoxy hydrochloride were obtained analogously to Example 2. -5-trifluoromethyl-l-naphthoylguanidine, -pf. : > 260 ° C. XH-NMR (DMS0-d6): d [ppm] = 4.0 (3H), 7.7 (2H), 7.9 (1H), 8.3 (1H), 8.5 (3H), 8 , 7 (2H), 12.3 (1H).

Example 4: 6-methoxy-l-naphthoylguanidine hydrochloride From 2.0 g of 6-methoxy-1-naphthoic acid, 1.2 g of 6-methoxy-1-naphthoylguanidine hydrochloride were obtained analogously to Example 2; p.f. : 235-236 ° C. XH-NMR (DMSO-d6): d [ppm] = 3.9 (3H), 7.3 (1H), 7.5 (1H), 7.6 (1H), 7.85 (1H), 8 , 1 (1H), 8.25 (1H), 8.6 (4H), 12.0 (1H).

Example 5: 6- (2-diethylaminoethoxy) -l-naphthoylguanidine a) 200 g of 6-hydroxy-l-naphthoic acid are heated at reflux for 2 h in anhydrous methanol, which is saturated with HCl gas. Concentrate, the residue is recrystallized from methanol and 50 g of 6-hydroxy-l-naphthoic methyl ester are obtained. b) 5 g of 6-hydroxy-1-naphthoic acid methyl ester and 2.0 g of sodium methylate are stirred in 50 ml of DMF for 20 min at 40 ° C and under N,. Then 5.7 g of diethylaminoethyl chloride (free base) are added and the mixture is stirred for 1 h at 40 ° C. The DMF is removed on a rotary evaporator, the residue is taken up in dilute hydrochloric acid and extracted with ethyl acetate. The aqueous phase is made alkaline with sodium hydroxide solution and extracted again with ethyl acetate. After concentrating this extract, 6.2 g of 6- (2-diethylaminoethoxy) -1-naphthoic acid methyl ester are obtained. c) 6 g of 6- (2-diethylaminoethoxy) -1- -naphthoic acid methyl ester and 6.8 g of KOH are dissolved in 150 ml of methanol and heated to reflux for 6 h. After adjusting the pH to 5.0, the methanol is distilled off in vacuo and the residue is stirred with 500 ml of methylene chloride. After filtration and concentration of the filtrate, 2.2 g of 6- (2-diethylaminoethoxy) -1-naphthoic acid are obtained. d) To a suspension of 2.0 g of 6- (2-diethylaminoetho-xi) -l-naphthoic acid in 50 ml of THF is added 1.5 g of CDI, and the reaction mixture is stirred overnight. TA. It is then mixed with 2.0 g of guanidine, stirred again overnight, concentrated and the residue is mixed with 100 ml of water. The precipitate formed is filtered off with suction and purified by CF with methylene chloride / methanol 1: 1. 0.66 g of 6- (2-diethylaminoethoxy) -l-naphthoylguanidine are obtained; p.f .: 168-169 ° C. : H-NMR (DMS0-d6): d [ppm] = 1.0 (6H), 2.6 (4H), 2.85 (2H), 4.15 (2H), 7.15 (1H), 7.3 (1H), 7.4 (1H), 7.75 (2H), 8.7 (1H).

Example 6: l-naphthoylguanidine hydrochloride; p.f. 160- -162 ° C.

Example 7: 2-Hydroxy-naphthoylguanidine hydrochloride monohydrate; p.f. 310 ° C.

Example 8: 2-methoxy-l-naphthoylguanidine hydrochloride; p.f. : 263-264 ° C.

The following compounds were obtained analogously to the methods described above, by alkylation of 1-hydroxynaphthoic acid methylester and subsequent reaction with guanidine according to the general prescription, Variant IB, or subsequent saponification to give the corresponding naphthoic acid, followed by guanidation according to Variant 1A: Example 9: 2- (4-Bromobenzyloxy) -naphthoylguanidine hydrochloride hemihydrate, -P.f. : 198-202 ° C.

Example 10: 2- [4- (1-piperidinomethyl) benzyloxy] -l-naphthoylguanidine; p.f. : 205-210 ° C Example 11: 2- [4- (N, -dimethylaminomethyl) benzyloxy] -l-naphthoylguanidine hydrochloride monohydrate, - p.f. 240 ° C.

Example 12: 2- [3- (N, N-dimethylaminomethyl) benzyloxy] -l-naphthoylguanidine hydrochloride sesquihydrate; p.f. 209 ° C.

Example 13: 2-propyloxy-l-naphthoylguanidine hydrochloride; p.f. 235-237 ° C.

Example 14: 2-Butyloxy-l-naphthoylguanidine hydrochloride; p.f. 215-216 ° C.

Example 15: 2-isopentyloxy-l-naphthoylguanidine hydrochloride; p.f. 235-237 ° C.

Example 16: 2-sec-Butyloxy-l-naphthoylguanidine hydrochloride; p.f. 189-190 ° C.

Example 17: 2-Ethoxy-1-naphthoylguanidine hydrochloride hemihydrate, -p.f. 247-248 ° C.

Example 18: 2-isopropyloxy-l-naphthoylguanidine hydrochloride; p.f. 219-223 ° C.

Example 19: 2-Benzyloxy-l-naphthoylguanidine hydrochloride, -p.f. 210-215 ° C.

Example 20: 2-Heptyloxy-l-naphthoylguanidine hydrochloride; p.f. 180-185 ° C.

Example 21: 2-Cyclopentoxy-l-naphthoylguanidine hydrochloride; p.f. 263-264 ° C.

Example 22: 4-dimethylamino-l-naphthoylguanidine hydrochloride Starting from 1.0 g of 4-dimethylamino-l-naphthoic acid, 1.0 g of 4-dimethylamino-l-naphthoylguanidine hydrochloride are obtained according to general requirement 1A; XH-NMR (DMS0-d6): d [ppm] = 3.0 (s, 6H), 7.2 (d, 1H), 7.6 (m, 2H), 8.1 (d, 1H), 8.3 (m, 1H), 8.5 (m, 1H), 8.7 (broad s, 4H), 12, 1 (s, 1H). .

Example 23: Naphthalene-1,4-dicarboxylic acid diguanidide a) 5 g of naphthalene-1,4-dicarboxylic acid are dissolved in 50 ml of methanol, mixed with 10 ml of S0C12 and boiled under reflux for 6 h. The volatile components are removed in vacuo and the product is dried in vacuo. 5 g of dimethyl ester of naphthalene-1,4-dicarboxylic acid are obtained in the form of a colorless oil, -EM (DCI): 245 (M + H). b) 1.2 g of naphthalene-1,4-dicarboxylic acid dimethyl ester and 3 g of guanidine are dissolved in 10 ml of anhydrous isopropane-nol and boiled under reflux for 4 h. The solvent is removed in vacuo, suspended with water and the product separated by filtration. 450 mg of diguanidide of naphthalene-1,4-dicarboxylic acid are obtained; mp .: 270"C (with decomposition); Rf (acetone / water 10: 1) = 0.14; MS (FAB): 299 (M + H) +.

Pharmacological data: Rabbit erythrocyte Na * / H + exchanger inhibitors: New Zealand white rabbits (Ivanovas) received a standard diet with 2% cholesterol for six weeks in order to activate Na * / H * Y exchange, thus, to determine by flame photometry the influx of Na * in the erythrocytes through NaVH exchange. '"The blood was taken from the arteries of the ear and made uncoagulable by 25 IU / ml of potassium heparin. Part of each sample was used for the double determination of the hematocrit by centrifugation Aliquots of 100 μl in each case were used to measure the Na * content of the erythrocytes, in order to determine the influx of sensitive sodium to Amiloride, 100 μl of each blood sample was incubated at pH 7.4 and 37 ° C in each case in 5 ml of a hyperosmolar salt-sucrose medium (millimoles / 1: 140 of NaCl, 3 of KC1, 150 of sucrose, 0.1 huabain, 20 Tris-hydroxymethylaminometa-no) Then, the erythrocytes were washed three times with ice-cold MgCl2-uabaine solution (millimoles / 1: 112 MgCl2, 0.1 barley) and hemolyzed in 2.0 ml of distilled water. The intracellular sodium content was determined by flame photometry. The net influx of Na + se. calculated from the difference between the starting values of sodium and the sodium content of the erythrocytes after incubation. The inhibitory sodium influx by Amiloride was deduced from the difference in the sodium content of the erythrocytes after incubation with and without Amiloride 3 x 10"4 moles / 1. Thus, the compounds were also proceeded according to the invention.

Results for the inhibition of the Na * / H * exchanger

Claims (1)

CLAIMS l.- Substituted l-naphthoylguanidines of the formula I wherein R2, R3, R4, R5, R6, R7 and R8 mean, independently of one another, H, F, Cl, Br, I, CN, N02, CF3, C2F5 or XaYbZ; X means O, S, NR (10), CR (11) R (12), C = 0, C (= 0) NR (10), C (= 0) 0, SO, S02, SO-NR (IO ), 0C = 0, NR (10) C = O or NR (10) SO2, bonding with the naphthalene ring in each case through the atom on the left; R (10), R (ll) and R (12) signify, independently of one another, H, alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, perfluoroalkyl with 1, 2, 3 or 4 atoms of C or cycloalkyl with 3, 4, 5, 6 or 7 C atoms; a means zero or 1; Y means alkylene with 1, 2, 3, 4, 5, 6, 7 or 8 CH2 groups, one of these CH2 groups being replaced by O, S, NR (13) or o-, p- or m- -phenylene; R (13) means H, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, perfluoroalkyl with 1, 2, 3 or 4 carbon atoms or cycloalkyl with 3, 4, 5 or 6 carbon atoms; b means zero or 1; Z means H, alkyl with 1, 2, 3, 4, 5, 6 or 7 C atoms, cycloalkyl with 3, 4, 5, 6 or 7 C atoms, C (= 0) R (15), S02R ( 15), NR (16) R (17) or phenyl, which is unsubstituted or substituted by

1-3 substituents selected from the group consisting of F, Cl, Br, CF3, methyl, methoxy, NR (21) R (22); R (2l) and R (22) signify, independently of one another, H or alkyl with 1, 2, 3 or 4 C atoms or perfluoroalkyl with 1, 2, 3 or 4 C atoms, - R (15) means N = C (NH2) 2, NR (18) R (19), N (CH2) CNR (18) R (19) or OR (20); c means 2 or 3; R (18) and R (19) signify, independently of one another, H, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C atoms or perfluoroalkyl with 1, 2, 3 or 4 carbon atoms. C, - or R (18) and R (19) together mean 4 or 5 methylene groups, of which a CH2 group can be replaced by oxygen, S, NH, N-CH3, N-benzyl or N- (p- chlorophenol), - R (20) means H, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, perfluoroalkyl with 1, 2, 3 or 4 carbon atoms or cycloalkyl with 3, 4, 5 6 or 7 C atoms; R (16) and R (17) signify, independently of one another, H, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C atoms or perfluoroalkyl with 1, 2, 3 or 4 carbon atoms. C; R (16) and R (17) together mean 4 or 5 methylene groups, of which a CH2 group can be replaced by oxygen, S, NH, N-CH3, N-benzyl or N- (p-chlorophenyl); or Z means a heterciclo with content in N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 atoms of C, the heterocycle being linked with N content through N or C and not being substituted or being substituted with 1-3 substituents selected from the group consisting of F, Cl, Br, CF3, methyl, methoxy and NR (21) R (22), -where, however, for the case where R (4) represents an alkoxy radical, at least one of the substituents R (2), R (3), R (5), R (6), R (7) and R (8) are other than hydrogen; as well as its pharmaceutically compatible salts. 2. Compound of the formula I according to claim 1, wherein all substituents and indices are defined as in claim 1, but at least one of the substituents R2, R3, R4, R5, R6, R7 and R8 is other than hydrogen. 3. Compound of the formula I according to claim 2, wherein R2, R3, R5, R6, R7 and R8 are defined as in claim 1; R4 means H, F, Cl, Br, I, CN, N02, CF3 / C2FS or Z, Z being defined as in claim 1. 4. Compound of formula I according to claim 1, wherein: at least one of the substituents R2, R3, R4, R5, R6, R7 and R8 mean XaYbZ; X means 0, S, NR (10), CR (11) R (12), C = 0, C (= O) NR (10), C (= 0) 0, SO, S02, S02NR (10), 0C = 0, NR (10) C = 0 or NR (10) S02, bonding with the naphthalene ring in each case through the atom on the left, - R (10), R { 11) and R (12) signify, independently of one another, H, alkyl having 1, 2, 3 or 4 carbon atoms, perfluoroalkyl with 1 or 2 carbon atoms or cycloalkyl with 3, 4, 5 or 6 carbon atoms.; a means zero or 1; Y means alkylene with 1, 2, 3, 4 or 5 CH2 groups, one of these CH2 groups can be replaced by 0, S, NR (13) or o-, p- or m- - phenylene, - R (13) means H, alkyl with 1, 2, 3 or 4 C atoms or cycloalkyl with 3, 4, 5 or 6 C atoms; b means zero or 1; Z means cycloalkyl with 3, 4, 5, 6 or 7 C atoms, C (= 0) R (15), S02R (15), NR (16) R (17) or phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, Br, CF3 / methyl, methoxy, NR (21) R (22), -R (21) and R (22) mean, independently of each other, H, alkyl with 1, 2, 3 or 4 carbon atoms or perfluoroalkyl with 1 or 2 carbon atoms; R (15) means N = C (NH2) 2, NR (18) R (19), N (CH2) CNR (18) R (19) or OR (20); R (18) and R (19) signify, independently of one another, H, alkyl with 1, 2, 3, 4 or 5 C atoms, - or R (18) and R (19) mean together 4 or 5 groups methylene, of which a CH2 group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl, • c means 2 or 3, - R (20) means H or alkyl with 1, 2, 3, 4 , 5 or 6 C atoms; R (16) and R (17) signify, independently of one another, H, alkyl having 1, 2, 3, 4 or 5 carbon atoms or perfluoroalkyl with 1 or 2 carbon atoms; or R (16) and R (17) together mean 4 or 5 methylene groups, of which a CH2 group can be replaced by oxygen, S, NH, N-CH3, N-benzyl or N- (p-chlorophenyl), - or Z means a heterocycle with N content containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, which is linked through N or C and which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, Br, CF3, methyl, methoxy and NR (21) R (22); and the respective remaining substituents R2, R3, R4, R5, R6, R7 and R8, which are not yet defined by the definition given above, mean, independently of one another, H, F, Cl, Br, I, CN, N02 , CF3, C2FS OR X, YbZ; X means O, S, NR (10), C = 0, C (= O) NR (10), C (= 0) 0, SO, S02, SO2NR (10), 0C = 0, NR (10) C = O or NR (10) S02, bonding with the naphthalene ring in each case through the atom on the left; R (10) means H, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, perfluoroalkyl with 1, 2, 3 or 4 carbon atoms or cycloalkyl with 3, 4, 5, 6 or 7 carbon atoms C; a means zero or 1, - b means zero; Z means H, alkyl with 1, 2, 3, 4 or 5 carbon atoms. 5. Compound of the formula I according to claim 4, wherein: at least one of the substituents R 2, R 3, R 4, R 5 , R6, R7 and R8 denote XaYbZ, - X means O, NR (10), C (= 0) NR (10), C (= 0) 0 or SO2NR (10), bonding with the naphthalene ring in each case through the atom on the left; R { 10) means H or methyl, - a means 1, - Y means alkylene with 1, 2, 3, 4 or 5 CH2 groups; wherein one of these CH2 groups can be replaced by o-, p- or m-phenylene, -b means 1; Z means C (= 0) R (15), NR (16) R (17) or a heterocycle with N content with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, being linked the heterocycle with N content through N or C and not being substituted, - R (15) means N = C (NH2) 2, NR (18) R (19) or OR (20); R (18) and R (19) signify, independently of one another, H, alkyl with 1, 2, 3 or 4 C atoms; or R (18) and R (19) together mean 4 or 5 methylene groups, of which a CH2 group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl, • R (2Q) means H, alkyl with 1, 2 or 3 C atoms; R (16) and R (17) signify, independently of one another, H or alkyl with 1, 2, 3, 4 or 5 C atoms; or R (16) and R (17) together mean 4 or 5 methylene groups, of which a CH2 group can be replaced by oxygen, S, NH, N-CH3, N-benzyl or N- - (p-chlorophenyl) , and the respective remaining substituents R2, R3, R4, R5, R6, R7 and R8 which are not yet defined by the definition given above, mean, independently of one another, H, F, Cl, Br, I, CF3 or XaYbZ, - X means O, NR (10), C (= O) NR (10), C (= 0) 0, S02, SO, NR (10), 0C = 0 or NR (10) C = O, the bond with the naphthalene ring being carried out in each case through the atom on the left, - R (10) means H or alkyl with 1, 2 or 3 C atoms; a means zero or 1; b means zero; Z means H or alkyl with 1, 2, 3 or 4 C atoms. 6. Process for the preparation of a compound I according to claim 1, characterized in that a compound of the formula II wherein L represents a light nucleophilic substitutable leaving group and the remaining substituents are defined as in claim 1, it is reacted with guanidine. 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 conditions 8. Use of a compound I according to claim 1 for the preparation of a medicament for the treatment of arrhythmias. 9. 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 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 of the attack of apoplexy. 14. 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 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 operations 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, consequently, their use as antiatherosclerotic agents against late complications diabetics, carcinogenic diseases, fibrotic diseases, such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, hyperplasia of the prostate. 19. Use of a compound I according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of disorders of the metabolism of fats. 20. Curative and therapeutic agent, characterized by an effective content of a compound of the formula I according to one or more of claims 1 to 5.