SK148796A3 - Diguanides of subsituted benzenedicarboxylic acids, preparation method thereof, their use as a drug or diagnostic agent, as well as a drug containing them - Google Patents

Abstract

Benzenedicarboxylic acid diguanidide compounds of formula (I) and their salts are new. One of R1-R4 = -CO-N=C(NH2)2; and the others are as follows; R1 = H, 1-4C alkyl, F, Cl, OR32, NR33R34 or CF3; R2, R4 = H, halo, OH, CN, CF3, 1-8C alkyl, 2-8C alkenyl, (CH2)mR14, 1-, 2- or 3-pyrrolyl (optionally substituted by 1-4 of halo, CN, 2-8C alkanoyl, 2-8C alkoxycarbonyl, CHO, COOH, CF3, Me and OMe), SO2R22, CONH2, CONHMe, CONMe2, COR28, SO2NH2, SO2NHMe, SO2NMe2, OR35 or NR35R36; R3 = H, SR25, OR25, NR25R26 or CR25R26R27; R5 =1-4C alkyl, halo, (CH2)yCF3, O(CH2)yCF3, or phenyl (optionally substituted by 1-3 of F, Cl, CF3, Me, OMe, NH2, NHMe and NMe2); R32-R34 = H or 1-4C alkyl; m, y = 0-2; R14 = phenyl (optionally substituted by 1-3 of F, Cl, CF3, Me, OMe, NH2, NHMe or NMe2) or 3-8C cycloalkyl; R22, R28 = Me or CF3; R23, R24, R29, R30 = H or Me; R35, R36 = H or 1-6C alkyl; or R35+R36 = 4-7 (CH2)(4-7) optionally with one CH2 replaced by O, S, NH, NMe or N-benzyl; R25 = H, 1- 8C alkyl, phenyl (optionally substituted by 1-3 of F, Cl, CF3, Me, OMe, OH, NH2, NHMe and NMe2) or 1-9C heteroaryl (optionally substituted by 1-3 of F, Cl, CF3, Me, OMe, OH, NH2, NHMe and NMe2); R26, R27 = groups as defined for R25, or H, 1-8C alkyl (sic).

Description

Diguanidides of substituted benzenedicarboxylic acids, processes for their preparation, their use as medicaments or diagnostics, and medicaments containing them

Technical field

The invention relates to substituted benzenedicarboxylic acid diguanides, to a process for their preparation, to their use as a medicament or to a diagnosis, and to medicaments containing them.

BACKGROUND OF THE INVENTION

International Application Publication Number WO 94/26709 discloses diguanidide benzoic dicarboxylic acids, and yet none of the compounds described in this document does not contain any of the following substituents ^R, corresponding to the international application that R @ ^3rd

SUMMARY OF THE INVENTION

The present invention relates to the benzenedicarboxylic acid diguanides of the formula I

wherein one of R ^x, R ^2, R ^3, and R ¹ represents -C 0-N = C (NH _{2) 2,} and the remaining of R ^1, R ^2, R ³ and R have the following meanings:

R ¹ is H, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, I, -OR ^32, -NR ³³ R ³⁴ or trifluoromethyl, the radicals R ^32, R ^33, and R ( ³⁴⁾ independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms, R ( ²⁾ and R ( ⁴⁾ independently of one another are hydrogen, fluorine, chlorine, bromine or iodine, hydroxyl, cyano , trifluoromethyl, -CO-N = C (NH4) ₂ , alkyl of 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl of 2, 3, 4, 5, 6, 7 or 8 carbon atoms or a group

- (CH ₂ ) _m R ¹⁴ , where m is 0, 1 or 2,

R ¹⁴ is C 3 -C 8 cycloalkyl or phenyl which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine and chlorine, trifluoromethyl, methyl, methoxy and -NR ¹⁵ R ¹⁶ wherein: the symbols R ^{1 S,} and R ¹⁶ are hydrogen or methyl, or the radicals R ² and R ⁴ independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl which is unsubstituted or substituted 1-4 substituents selected from fluorine, chlorine, bromine, iodine, cyano, C 2 -C 8 alkanoyl, C 2 -C 8 alkoxycarbonyl, formyl, carboxyl, trifluoromethyl, methyl and methoxy, or the radicals R ² and R ⁴ independently of one another are a group

R ²² -SO 2, R ²³ R ²⁴ N-CO-, R ²⁸ -CO- or R ²⁹ R ^{3 O-N} S0a, the radicals R ²² and R ^{2 S} independently of one another are methyl or trifluoromethyl, and the symbols R ²³ , R ²⁴ , R ²⁹ and R ³ are each independently hydrogen or methyl, or R ² and R ⁴ are each independently

-OR ³⁵ or -NR ³⁵ R ³⁶ , wherein R ³⁵ and R ³⁶ each independently represent a hydrogen atom or an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, or R ^3S and R ³⁶ together are 4-7 methylene groups, of which one CH group may be replaced by O _2, sulfur, -NH-, -NCH ₃ or -N-benzyl;

R ³ is H, -SR ^25, -0R ^{2 S,} -NR ^{2 S} R ²⁶ or -CR ² R ^{2 S <S} R ^2.7, wherein

R ^2S represents a hydrogen atom, an alkyl group having 1,

2, 3, 4, 5, 6, 7 or 8 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from fluorine, chlorine, trifluoromethyl, methyl, methoxy, hydroxyl, amino , methylamino and dimethylamino, or R ²⁵ represents a heteroaryl group having 1 to 9 carbon atoms which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group, hydroxyl group, amino group, methylamino and dimethylamino, and R ²⁶ and R ²⁷ independently of each other are as defined for R ^2S or are hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and

^R is alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, I, a group -X- (CH _{2) y} -CF ₃ or phenyl, which is unsubstituted or substituted by 1 to 3 substituents selected from the group of fluorine and chlorine, trifluoromethyl, methyl, methoxy and -NR ⁶ R ^7, wherein the symbols R ⁶ and R ⁷ independently of one another are hydrogen or methyl;

X is a bond or an oxygen atom, and y is 0, 1 or 2, as well as pharmaceutically acceptable salts thereof.

Preferred compounds of formula I wherein one of R ^x, R ^2, R ³ and R ⁴ is -CO-N-C _{(NH2) 2,} and the remaining of R ^1, R ^2, R ^3, and R ⁴ have the following meanings:

R ¹ is H, alkyl having 1, 2, or 3 carbon atoms, F, Cl, Br, -OR ^32, -NR ³³ R ³⁴ or a trifluoromethyl radical, wherein the radicals R ^32, R ³³ and R ³⁴ independently, R ² and R ⁴ are each independently hydrogen, fluoro, chloro, bromo or iodo, hydroxyl, trifluoromethyl, -CO-N = C (NH ₂ ) _2, alkyl having 1, 2, 3 or 4 carbon atoms, alkenyl having 2, 3 or 4 carbon atoms or - (CH _{2) m} R ^14, wherein m is 0, 1 or 2,

R ¹⁴ is C 3 -C 6 cycloalkyl or phenyl which is unsubstituted or substituted by 1 or 2 substituents selected from fluoro and chloro, trifluoromethyl, methyl and methoxy, or R ² and R ⁴ independently are in each case a pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl group which is unsubstituted or substituted by 1 to 2 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, cyano, (C 2 -C 5) alkanoyl, (C 2 -C 5) alkoxycarbonyl, formyl, carboxyl, trifluoromethyl, methyl, or R ² and R ⁴ are each independently

R ²² -SO 2 -, R ²⁸ -CO- or R ²⁹ R ³ ° N-SO =, wherein R ²² and R ^{28 are} each independently methyl or trifluoromethyl, and R ²⁹ and R ³ independently of each other each independently represent a hydrogen atom or a methyl group, or R @ ² and R @ ⁴ each independently represent a group

-OR ³⁵ or -NR ³ R ³⁶ , wherein R ³⁵ and R ^{36 are} each independently hydrogen, methyl or ethyl, or R ³⁵ and R ³⁶ together represent 4 to 5 methylene groups of which one CH ₂ group replaced by O, S, -NH- or -NC _and,

R ³ represents a hydrogen atom, -SR ^{2 S} , -OR ^{2 S} , -NR ^{2 S} R ^{2 S} or -CR ²⁵ R ^2e R ² ' ⁷ , wherein:

R ^2S represents a hydrogen atom, an alkyl group having 1, 2, 3 or 4 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 2 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy and dimethylamino , or or R ²⁵ represents a heteroaryl group having 1 to 9 carbon atoms which is unsubstituted or substituted by 1 to 2 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and dimethylamino group, R ²⁶ and R ²⁷ each independently represents a hydrogen atom or an alkyl group having 1, 2, 3

Ί or 4 carbon atoms, and

^R is alkyl having 1, 2, 3 or 4 carbon atoms, fluorine, chlorine, bromine, trifluoromethyl or phenyl, which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F and Cl, CF , methyl, methoxy and dimethylamino as well as pharmaceutically acceptable salts thereof.

Particularly preferred are compounds of formula I wherein one of R ¹ , R ² , R ³ and R ⁴ is a group

-CO-N = C (NH ₂ ) ₂ , and the rest of R ³ -, R ² , R ³ and R ⁴ have the following meanings:

R ¹ is hydrogen, alkyl having 1,2,3, or carbon atoms, F, Cl, -OR ^32, -NR ³³ R ³⁴ or trifluoromethyl, the radicals R ^32, R ³³ and R ³⁴ independently of R ( ²⁾ and R ( ⁴⁾ independently of one another are hydrogen, fluoro, chloro, hydroxyl, trifluoromethyl, -CO-N = C (NH ₂ ) 4, alkyl having 1, 2, 3 or 4 carbon atoms or a pyrrol-1-yl group which is unsubstituted or substituted by 1 to 2 substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, alkanoyl groups of 2 to 2 C 5 -C 5 alkoxycarbonyl, C 2 -C 5 alkoxycarbonyl, formyl, carboxyl, trifluoromethyl and methyl, or R ² and R ⁴ are each independently R ²² -SO ₂ - _z in each case what

R ( ²²⁾ is methyl or trifluoromethyl, or R ( ²⁾ and R ( ⁴⁾ independently of one another are -OR ( ³⁵⁾ or -N (R ³⁾ R ³⁶ , wherein R ( ^{3 S)} and R ( ^{36) are} each independently hydrogen, methyl or ethyl,

R ³ represents a hydrogen atom, -SR ²⁵ , -OR ²⁵ , -NR ^{2 S} R ²⁶ or-alebo ²³ Η ^2β Η ^2-7 ·, wherein:

R ²⁵ is H, alkyl having 1, 2 or 3 carbon atoms or phenyl, which is unsubstituted or substituted by a substituent selected from the group consisting of fluoro, chloro, trifluoromethyl and methyl, or R ²⁵ represents a heteroaryl group, (1 to 9) carbon atoms which is unsubstituted or substituted by one substituent selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group and methyl group, and R ²⁶ and R ^2-7 each independently represent a hydrogen atom or a methyl group, and

^R is alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, trifluoromethyl, or phenyl which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine and chlorine, trifluoromethyl, methyl and methoxy groups, as well as pharmaceutically acceptable salts thereof.

Particularly preferred are compounds of formula I wherein one of R ¹ , R ² , R ^3, and R ⁴ is

-CO-N = C (NH ₂ ) ₂ , and the remainder of R ¹ , R ² , R ³ and R ⁴ have the following meanings:

R ¹ is H, alkyl having 1, 2, 3 or carbon atoms, fluorine, chlorine, trifluoromethyl or methoxy; R ² and R ^4, independently of one another, are hydrogen, hydroxyl group, trifluoromethyl group, -CO-N = C (NH _{z) 2,} alkyl having 1, 2, 3 or 4 carbon atoms or pyrrol-l-yl that is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl , bromine, iodine, cyano, C 2 -C 5 alkanoyl, C 2 -C 5 alkoxycarbonyl, formyl, carboxyl, trifluoromethyl and methyl,

R ³ represents a hydrogen atom, -OR ²⁵ or -CR ²⁵ R ²⁶ R ²⁷ , wherein

R ^2S represents a hydrogen atom, an alkyl group having 1 or 3 carbon atoms or a phenyl group which is unsubstituted or substituted by one substituent selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group and a methyl group, or R ^2S represents a heteroaryl (C 1 -C 9) group which is unsubstituted or substituted by one substituent selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group and methyl group, and R ²⁶ and R ^2V each independently represent a hydrogen atom or a methyl group, and

^R is alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, trifluoromethyl or phenyl, which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluoro and chloro, trifluoromethyl, and methyl group, as well as pharmaceutically acceptable salts thereof.

Said alkyl radicals may be straight-chain or branched.

C 1 -C 9 heteroaryl means radicals which are derived from a phenyl or naphthyl group in which one or more CH groups are replaced by nitrogen and / or in which at least two adjacent CH groups (to form a five-membered aromatic ring) are replaced by sulfur, NH or oxygen. Further, they may also be one or both of the atoms that form the condensation sites of the bicyclic moieties, nitrogen atoms (as in the case of the indolizinyl group).

Heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indazolyl, indazolyl, indazolyl, indazolyl, indazolyl, indazolyl, indazolyl, indazolyl, indazolyl, indazolyl, indazolyl, indazolyl, indazolyl, a cinnolinyl group.

If one of the substituents R ¹ to ^R contains one or more centers of asymmetry, these may independently of one another either the S or R configuration. The compounds of the invention may exist as optical isomers, diastereomers, racemates, or mixtures thereof.

The invention further encompasses a process for the preparation of compounds of formula I, wherein the compounds of formula II

in which R ¹ 'to ^R' as defined above for the radicals R ^x and R ^a, wherein, however, at least one of R ^x 'and R ^5' is given COL group, and L is an easily nucleophilically substituted leaving group, react with guanidine.

The activated acid derivatives of the formula II in which L represents an alkoxy group, in particular a methoxy or phenoxy group, a phenylthio group, a methylthio group, a 2-pyridylthio group or a nitrogen heterocyclic radical, especially a 1-imidazolyl group, are advantageously obtained in known manner from the starting carboxylic acid chlorides of formula (II) wherein L is a chlorine atom) which can in turn be prepared in a manner known per se from the starting carboxylic acids (compounds of formula (II) wherein L represents a hydroxyl group), for example by reaction with thionyl chloride. In addition to the carboxylic acid chlorides of the formula II (in which L is a chlorine atom), other activated acid derivatives of the formula II, such as, for example, can be directly prepared in a manner known per se from the starting benzenedicarboxylic acid derivatives (compounds of the formula II methyl ester of formula II wherein L is methoxy, by reaction with hydrogen chloride gas in methanol, imidazolide of formula II by reaction with carbonyldiimidazole (L represents 1-imidazolyl, Staab, Angew. Chem. Int. Ed. Engl. 1, 351-367 ( 1962)) or mixed anhydrides of formula II by reaction with Cl-COOC _and H _with or tosyl chloride in the presence of triethylamine in an inert solvent. Activation of benzenedicarboxylic acids can also be carried out with dicyclohexylcarbodiimide (DCC) or O - [(cyano (ethoxycarbonyl) methylene) amino] -1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU) (Proceedings of the 21st European Peptide Symposium, 1990, edited by E. Giralt and D. Andreu, Escom, Leiden, 1991). A number of suitable methods for preparing activated carboxylic acid derivatives of formula (II) are described in the literature listed in J. March, Advanced Organic Chemistry, Third Edition (John Wiley and Sons, 1985), page 350.

The reaction of the activated carboxylic acid derivative of the formula II with guanidine is carried out in a manner known per se in a protic or aprotic polar but inert organic solvent. In the reaction of methyl benzenedicarboxylic acid ester (a compound of formula II wherein L is methoxy) with guanidine, methanol, isopropanol or tetrahydrofuran are conveniently used at a temperature of from 20 ° C to the boiling point of these solvents. Most of the reactions of compounds of formula II with salt-free guanidine are preferably carried out in inert solvents such as tetrahydrofuran, dimethoxyethane, dioxane or isopropanol. However, water can also serve as a solvent.

When L represents a chlorine atom, it is preferable to add an acid-binding agent, for example in the form of excess guanidine, to bind the hydrohalic acid.

The introduction of compounds substituted on the phenyl moiety by sulfur, oxygen or nitrogen containing nucleophiles is accomplished by methods known in the literature for nucleophilic substitution on benzenedicarboxylic acid dialkyl ester derivatives. As the leaving group on the benzenedicarboxylic acid derivative, a halide and trifluoromethanesulfonate moiety is suitable for this substitution. The reaction is preferably carried out in a dipolar aprotic solvent such as N, N-dimethylformamide (DMF) or N, N, N ', N'-tetramethylurea (TMU) at a temperature of from 0 ° C to the boiling point of the solvent, preferably from 80 ° C. to the boiling point of the solvent. The acid-binding agent is preferably an alkali metal or alkaline earth metal salt with an anion of higher basicity and lower nucleophilicity, for example potassium carbonate or calcium carbonate.

The introduction of alkyl or aryl substituents is accomplished by methods known in the literature by means of palladium-mediated cross-coupling of aryl halides with, for example, organic zinc compounds, organostannates, organic boron acids or organoborates.

The benzenedicarboxylic acid diguanidides of formula (I) are generally weak bases and can bind acids to form salts. Suitable acid addition salts are salts of all pharmacologically acceptable acids, for example halides, in particular hydrochlorides, ascorbates, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates and p-toluenesulfonates.

It is surprisingly found that the introduction of certain substituents R ¹ and / or R ^with substantially enhance the effectiveness of the compounds and also positively affects its pharmacokinetics.

Due to their pharmacological properties, the compounds of the formula I are very 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, while also preventing or severely inhibiting pathophysiological processes ischemic induced cardiac arrhythmias. Due to their protective effects against pathological hypoxic and ischemic conditions, the compounds of the formula I according to the invention can be used as medicaments for the treatment of all acute or chronic disorders caused by ischemia or such primary or secondary induced diseases due to inhibition of the cellular Na ⁺ / H exchange mechanism. This relates to their use as medicaments for surgical procedures, for example in organ transplants, which compounds can be used to protect organs in a donor from and during organ harvesting, to protect organs taken from, for example, handling or storing organs. in physiological fluids as well as in transfer to the recipient organism. These compounds are also valuable, protective-acting drugs in performing angioplastic surgeries, for example on the heart as well as on peripheral vessels. Because of their protective action against ischemic-induced disorders, these compounds are also useful as medicaments in the treatment of ischemia of the nervous system, in particular of the central nervous system, for example, for the treatment of stroke or cerebral edema. In addition, the compounds of the formula I according to the invention are also suitable for the treatment of various forms of shock, such as allergic, cardiogenic, hypovolaemic and bacterial shock.

In addition, the compounds of the formula I according to the invention are characterized by a potent inhibitory action on cell proliferation, for example fibroblast cell proliferation and vascular smooth muscle cell proliferation. Therefore, compounds of formula I are useful as therapeutics for diseases in which cell proliferation is a primary or secondary cause and can therefore be used as anti-atherosclerotic agents, anti-later diabetic complications, cancer diseases, fibrotic diseases such as fibrosis. lung, liver fibrosis or kidney fibrosis, and against hypertrophy and hyperplasia of organs, in particular hyperplasia of the uterine or hypertrophy of the uterine.

The compounds of the invention are potent inhibitors of the Na ⁺ / H * cellular exchange system, which is also elevated in many diseases (essential hypertonia, atherosclerosis, diabetes, etc.) in cells readily accessible for measurement, such as erythrocytes, thrombocytes or leukocytes. The compounds of the invention are therefore suitable as excellent and simple scientific tools, for example in their use as diagnostic agents to determine and distinguish certain forms of hypertonia, but also atherosclerosis, diabetes, proliferative diseases, etc. In addition, the compounds of formula I are useful in preventive therapy to prevent high blood pressure, such as essential hypertonia.

Compared to most known compounds, the compounds of the invention exhibit substantially improved aqueous solubility. Therefore, they are substantially more suitable for intravenous administration.

The compounds of the invention differ from the known water-soluble compounds by their better bioavailability and pharmacokinetics.

Medicaments containing a compound of the formula I can be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred route of administration being dependent on the present manifestations of the disease. The compounds of the formula I can be used alone or together with galenic auxiliaries, both in veterinary and in human medicine.

The person skilled in the art will recognize, based on his expert knowledge, which excipients are suitable for the desired drug formulation. In addition to solvents, gelling agents, lace bases, tablet excipients and other active compound carriers, for example, antioxidants, dispersants, emulsifiers, antifoams, flavorants, preservatives, solubilizers or colorants can be used.

For oral use, the active compounds are admixed with excipients suitable for this purpose, such as carriers, stabilizers or inert diluents, and formulated into suitable dosage forms such as tablets, dragees, pourable capsules and aqueous, alcoholic or oily solutions by conventional means. . As inert carriers, for example, gum arabic, magnesium, magnesium carbonate, potassium phosphate, milk sugar, glucose or starches, in particular corn starch, can be used. In this case, the preparation can be carried out in the form of dry or wet granules. Suitable oily carriers or solvents are, for example, vegetable or animal oils, such as sunflower oil or fish oil.

For subcutaneous or intravenous administration, the active compounds, if desired together with substances customary for this purpose, such as solubilizers, emulsifiers or other excipients, are formulated as a solution, suspension or emulsion. Suitable solvents are, for example, water, physiological sodium chloride solution or alcohols, for example ethanol, propanol, glycerine, and also sugar solutions, such as glucose or mannitol solutions, or mixtures of the various solvents mentioned.

Suitable pharmaceutical compositions for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active compound of the formula I in a pharmaceutically acceptable solvent, in particular ethanol or water, or in a mixture of such solvents. If desired, the composition may also contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers as well as a propellant. Such a preparation contains the active ingredient usually in a concentration of from about 0.1 to 10, in particular from about 0.3 to 3% by weight.

Dosage of the active compound to be administered

The frequency of administration depends on the strength and duration of action of the compounds used, moreover, on the type and severity of the disease being treated, as well as on the sex, age, weight and individual responses of the mammal being treated.

On average, the daily dose of a compound of formula I in a patient weighing about 75 kg is at least 0.001 mg / kg body weight, in particular at least 0.01 mg / kg body weight, up to a maximum of 10 mg / kg body weight, in particular 1 mg / kg body weight. weight. In an acute outbreak of the disease, for example immediately after a heart attack, even higher and, in particular, more frequent doses, for example up to 4 sub-doses per day, may be necessary. Especially for intravenous use, for example in patients with an infarction in an intensive care unit, up to 100 mg per day may be required.

DETAILED DESCRIPTION OF THE INVENTION

General process for preparing benzenedicarboxylic acid diguanides of formula I from benzenedicarboxylic acid dialkyl esters (compounds of formula II wherein L is O-alkyl) mmol of benzenedicarboxylic acid dialkyl ester of formula II and 50 mmol of guanidine (free base) are dissolved in 5 ml of isopropanol and the resulting solution is heated to reflux until the reaction is complete (thin layer chromatography is controlled), typically 5 minutes to 5 hours. The mixture is then diluted with 150 ml of water and the product is filtered off with suction. Optionally, the product is chromatographed on silica gel using a suitable eluent, for example a 5: 1 mixture of ethyl acetate and methanol.

Example 1

4-Chloro-5-phenylisophthalic acid diguanide

(a) 3-Bromo-2-chloro-5-methylbenzoic acid 2-amino-3-bromo-5-methylbenzoic acid is diazotized at 0 ° C with 8.3 g of sodium nitrite in 500 ml of 6N aqueous hydrochloric acid, then The mixture is stirred for 30 minutes at room temperature and a solution of 22 g of copper (I) chloride in 200 ml of saturated aqueous hydrochloric acid at 40 ° C is added in portions. The mixture was stirred for 20 minutes at 40-50 ^and C, the precipitate is suction filtered, washed with water to neutral pH and at 40 ° C, dried under reduced pressure. 23.3 g of pale yellow crystals with a melting point of 170-172 ° C are obtained.

R _£ (ethyl acetate-methanol = 5: 1) = 0.51

Mass spectrometry (DCI, desorption chemical ionization):

249 (M + H) &lt; ^{+ &gt;}

b) 5-Bromo-4-chloroisophthalic acid g. magnesium sulfate heptahydrate was dissolved in 600 ml of water and then 20 g of 3-bromo-2-chloro-5-methylbenzoic acid was added. The mixture is heated to 90 ° C, then 63 g of potassium permanganate are added portionwise at 90-100 ° C and the mixture is heated to reflux for 2 hours with stirring. The mixture was then allowed to cool to room temperature, saturated aqueous sodium sulfate was added dropwise until the violet color disappeared, the saturated aqueous sodium carbonate solution was adjusted to pH 12 and the manganese dioxide was filtered off with suction. Wash with saturated aqueous sodium carbonate solution and hot water, adjust the pH of the filtrate to 1 with aqueous hydrochloric acid, and filter the precipitate with suction. 13.5 g of a colorless solid are obtained, m.p.> 275 ° C.

R _£ (DIP 2% HOAc) = 0.18

Mass Spectrometry (DCI): 279 (M + H) · * c 5-Bromo-4-chloroisophthalic acid dimethyl ester

13.5 g of 5-bromo-4-chlórizoftalovej was dissolved in 200 ml of methanol, added dropwise with 20 ml of SOC1 ₂ and the mixture was stirred and heated to reflux for 5 hours. The volatiles were then removed in vacuo and the residue dried under gentle vacuum. 14 g of colorless crystals of melting point 99 DEG C. are obtained.

Mass Spectrometry (DCI): 307 (M + H) &lt; + &gt;

d) 4-Chloro-5-phenylisophthalic acid dimethyl ester

3.1 g of 5-bromo-4-chloroisophthalic acid dimethyl ester,

1.2 g of benzeneboronic acid (dihydroxyphenylborane), 2.1 g of sodium carbonate, 230 mg of palladium acetate and 500 mg of triphenylphosphine are heated to reflux in 50 ml of toluene and 10 ml of water for 6 hours with stirring. The mixture is allowed to cool to room temperature, diluted with 300 ml of toluene and washed three times with 100 ml of saturated aqueous sodium carbonate solution each time. The mixture was dried over sodium sulfate, the solvent was removed in vacuo and the residue was chromatographed on silica gel using ethyl acetate / n-heptane 1: 4 as eluent. 1.5 g of a colorless oil are obtained.

R _£ (ethyl acetate-n-heptane 1: 4) = 0.22

Mass Spectrometry (DCI): 305 (M + H) &lt; + &gt;

e) 4-Chloro-5-phenylisophthalic acid diguanide

2.6 g of potassium tert-butoxide are dissolved in 50 ml of anhydrous N, N-dimethylformamide and 2.6 g of guanidine hydrochloride are added. The mixture is stirred for 1.5 hours at room temperature, 700 mg of 4-chloro-5-phenylisophthalic acid dimethyl ester is added and the mixture is further stirred for 2 hours at 100 ° C. The mixture was poured into 1 L of water, adjusted to pH 8 with aqueous sodium bicarbonate solution and aqueous hydrochloric acid solution, and then extracted three times with 200 ml of ethyl acetate each time. The extract was dried over sodium sulfate and the solvent was removed in vacuo. The residue is suspended in 100 ml of water and filtered off with suction, and then the precipitate is resuspended in 50 ml of ethyl acetate and filtered off with suction. The product was dried under vacuum to give 350 mg of colorless crystals melting at 235 ° C.

R _£ (acetone: water = 10: 1) = 0.063

Mass spectrometry (ES, electrospray ionization):

359 (M + H) &lt; + &gt;

Pharmacological data:

Inhibition of Na * / H * exchange system in rabbit erythrocytes

White New Zealand rabbits (Ivanovas) are given a standard 2% cholesterol diet for six weeks to activate Na * / H * exchange and to be able to determine by flame photometry of the Na * influx into erythrocytes via Na * / H * exchange. Blood is drawn from the ear artery to prevent clotting of 25 IU potassium-heparin. A portion of each sample is used for duplicate determination of hematocrit by centrifugation. Samples of 100 μΐ each are used to measure the initial Na * content of erythrocytes.

To determine the sodium influx sensitive to amiloride, 100 μΐ of each blood sample is incubated in 5 ml of hyperosmolar saline sucrose medium (140 mmol / l sodium chloride, 3 mmol / l potassium chloride, 150 mmol / l sucrose, 0.1 mmol). (1 ouabain, 20 mmol / l trishydroxymethylaminomethane) at pH 7.4 and 37 ° C. The erythrocytes are then washed three times with an ice-cold solution of magnesium chloride and ouabain (112 mmol / l magnesium chloride, 0.1 mmol / l ouabain) and hemolyzed in 2.0 ml of distilled water. Intracellular sodium content is determined by flame photometry.

The net influx of Na * is calculated from the difference between the initial sodium content and the sodium content of erythrocytes after incubation. Amiloride-inhibiting sodium influx is determined from the difference in sodium contents in erythrocytes after incubation in the presence and absence of amiloride at a concentration of 3 x 10 ^-4 mol / l. The same applies to the compounds of the invention.

Results: Inhibition of Na * / H * exchange system:

Example compound IC _sq (mmol / l) 1 0.9

Claims (18)

PATENT CLAIMS Substituted benzenedicarboxylic acid diguanidides of the general formula I in which one of the radicals R ¹ , R ² , -CO-N = C (NH _{2) 2,} R ³ and R ⁴ represent a group and the rest of R ¹ , R ^2, R ³ and R ⁴ have the following meanings: R ¹ is H, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, I, -OR ^32, -NR ³³ R ³⁴ or trifluoromethyl, the radicals R ^32, R ^33, and R ( ³⁴⁾ independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms, R ( ²⁾ and R ( ⁴⁾ independently of one another are hydrogen, fluorine, chlorine, bromine or iodine, hydroxyl, cyano , trifluoromethyl, -CO-N = C (NH ₂ ) _a , alkyl group with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl group with 2, 3, 4, 5, 6, 7 or 8 carbon atoms or a group - (CH _{2) ro} R ^{X 4} where m is 0, 1 or 2, R ¹⁴ is C 3 -C 8 cycloalkyl or phenyl which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine and chlorine, trifluoromethyl, methyl, methoxy and -NR ^XS R ^{X 6} , wherein: the symbols R ^X and R ¹⁶ are hydrogen or methyl, or the radicals R ² and R ⁴ independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl which is unsubstituted or substituted 1-4 substituents selected from fluorine, chlorine, bromine, iodine, cyano, C 2 -C 8 alkanoyl, C 2 -C 8 alkoxycarbonyl, formyl, carboxyl, trifluoromethyl, methyl a methoxy group, or the radicals R ² and R ⁴ independently of one another are a group R ²² -SO 2 -, R ²³ R ²⁴ N-CO-, R ^{2 S} -CO- or R ²⁹ R ³ N-SO 2, wherein R ²² and R ^{28 are} each independently methyl or trifluoromethyl, and R ²³ , R ²⁴ , R ²⁹ and R ³ are each independently hydrogen or methyl, or R ² and R ⁴ are each independently -OR ^3S or -NR ^3S R ³⁶ , wherein R ^3S and R ^{36 are} each independently hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, or R ^3S and R ³⁶ together are 4-7 methylene groups, of which one CH group may be replaced _out by O, S, -NH-, -NCH ₃ or -N-benzyl; R ³ represents a hydrogen atom, -SR ²⁵ , -OR ²⁵ , -NR ²⁵ R ²⁶ or -CR ²⁵ R ^2e R ²⁷ , wherein: R ²⁵ represents a hydrogen atom, an alkyl group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from fluorine, chlorine, trifluoromethyl R ²⁵ represents a heteroaryl group having 1 to 9 carbon atoms which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group, a hydroxyl group, an amino group, a methylamino group and dimethylamino group; , methyl, methoxy, hydroxyl, amino, methylamino and dimethylamino, and R ²⁶ and R ²⁷ independently of each other are as defined for R ^2S or are hydrogen or alkyl having 1, 2, 3, 4, 5 , 6, 7 or 8 carbon atoms, and R ⁵ is alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, I, a group -X- (CH?) _P -CF _yl or phenyl, which is unsubstituted or substituted by 1 to 3 substituents selected from the group of fluorine and chlorine, trifluoromethyl, methyl, methoxy and -NR ^e R ^7, wherein the symbols R ⁶ and R ^v independently of one another are hydrogen or methyl; X is a bond or an oxygen atom, and y is 0, 1 or 2, as well as pharmaceutically acceptable salts thereof. Substituted benzenedicarboxylic acid diguanidides of the formula I according to claim 1, wherein one of the radicals R ¹ , R ² , R ³ and R ⁴ represents the group -CO-N = C (NH ₂ ) ₂ , and the rest of the symbols R ¹ , R ^2, R ³ and R ⁴ have the following meanings: R ¹ is H, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, -OR ^32, -NR ³³ R ³⁴ or trifluoromethyl, the radicals R ^32, R ³³ and R ³⁴ each independently represents a hydrogen atom or a methyl group, R ² and R ⁴ independently represent a hydrogen atom, a fluorine, chlorine, bromine or iodine atom, a hydroxyl group, a trifluoromethyl group, a -CO-N = C (NH _{2) group} ) _2, alkyl having 1, 2, 3 or 4 carbon atoms, alkenyl having 2, 3 or 4 carbon atoms or - (CH _{2) y} R ^14, wherein m is 0, 1 or 2, R ⁴ is C 3 -C 6 cycloalkyl or phenyl which is unsubstituted or substituted with 1 to 2 substituents selected from fluoro and chloro, trifluoromethyl, methyl and methoxy, or R ² and R ⁴ independently are in each case a pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl group which is unsubstituted or substituted by 1 to 2 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, cyano group, (C 2 -C 5) alkanoyl, (C 2 -C 5) alkoxycarbonyl, formyl, carboxyl, trifluoromethyl and methyl groups, or R ² and R ⁴ are each independently R 22 -SO ₂ -, R ²⁸ -CO- or R ²⁹ R ³ N-SO _a , wherein R ²² and R ^2S independently of each other are methyl or trifluoromethyl, and R ²⁹ and R ³ independently of one another each independently represent a hydrogen atom or a methyl group, or R @ ² and R @ ⁴ each independently represent a group -OR ^{3 S} or -NR ^{3 S} R ³⁶ , wherein R ^{3 S} and R ^{36 are} each independently hydrogen, methyl or ethyl, or R ³⁵ and R ³⁶ together represent 4 to 5 methylene groups of which one _{of the} CH sku27 pina replaced by O, S, -NH- or -NC _and, R ³ is H, -SR ^{2 S, 2 S} -0R, -NR ^{2 S 2 S} R ^{2 S,} or -CR a R ^{2 e} R ^27, wherein R ²⁵ represents a hydrogen atom, an alkyl group having 1, 2, 3 or 4 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 2 substituents selected from fluorine, chlorine, trifluoromethyl, methyl, methoxy and dimethylamino or R ^2S represents a C 1 -C 9 heteroaryl group which is unsubstituted or substituted by 1 to 2 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group and a dimethylamino group, and R ²⁶ and R ^Each independently represents a hydrogen atom or an alkyl group having 1, 2, 3 or 4 carbon atoms, and ^R is alkyl having 1, 2, 3 or 4 carbon atoms, fluorine, chlorine, bromine, trifluoromethyl or phenyl, which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F and Cl, CF , methyl, methoxy and dimethylamino. Substituted benzenedicarboxylic acid diguanidides of the formula I according to claim 1 or 2, wherein one of the radicals R ¹ , R ² , R ³ and R ⁴ represents a group -CO-N = C (NH ₂ ) ₂ and the rest of the symbols R ^x, R ^2, R ³ and R ⁴ have the following meanings: R ^x is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, -OR ^32, -NR ³³ R ³⁴ or trifluoromethyl, the radicals R ^32, R ³³ and R ³⁴ independently of one another are hydrogen or methyl; R ² and R ^4, independently of one another, are hydrogen, fluorine, chlorine, hydroxyl, trifluoromethyl, -CO-N-C _{(NH2) 2,} alkyl having 1, 2, 3 or 4 carbon atoms or pyrrol-1 -yl which is unsubstituted or substituted by 1 to 2 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, cyano group, C2 -C5 alkanoyl group, C2 -C5 alkoxycarbonyl group, formyl group carboxy, trifluoromethyl and methyl, or R ² and R ⁴ are each independently R ²² -SO ₂ -, R ( ²²⁾ is methyl or trifluoromethyl, or R ( ²⁾ and R ( ⁴⁾ independently of one another are -OR ( ³⁵⁾ or -N (R ³⁾ R ³⁶ , wherein R ( ^{3 S)} and R ( ^{36) are} each independently hydrogen, methyl or ethyl, R ³ is H, -SR ^25, -OR ^25, -NR ²⁵ R ²⁵ -CR ^{2 e} and R ^{2 e} R ^{2 '7,} wherein R ²⁵ represents a hydrogen atom, an alkyl group having 1, 2 or 3 carbon atoms or a phenyl group which is unsubstituted or substituted by one substituent selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group and a methyl group, or R ^2S represents a heteroaryl group having 1 to 9 carbon atoms which is unsubstituted or substituted one substituent selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group and methyl group, and R ² ® and R ^{27 are} each independently hydrogen or methyl, and ^R is alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, trifluoromethyl, or phenyl which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine and chlorine, trifluoromethyl, methyl and methoxy. Substituted benzenedicarboxylic acid diguanidides of the general formula I according to claim 1, 2 or 3, in which one of the radicals R ¹ , R ² , R ³ , R ³ , R ³ , R ³ and R ³ . R ^2, R ³ and R ⁴ is a group -co-n = c (nh ₂ ) ₂ , and the rest of R ^x , R ² , R ³ and R ⁴ have the following meanings: R ^{@ 1} represents a hydrogen atom, an alkyl group having 1,2,3 or R @ ⁴ and R @ ^d are each independently hydrogen, hydroxyl, trifluoromethyl, trifluoromethyl or methoxy; -CO-N-C _{(NH2) 2,} alkyl having 1, 2, 3 or 4 carbon atoms or pyrrol-l-yl that is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl , bromine, iodine, cyano, C 2 -C 5 alkanoyl, C 2 -C 5 alkoxycarbonyl, formyl, carboxyl, trifluoromethyl and methyl, R ³ represents a hydrogen atom, -OR ²⁵ or -CR ²⁵ R ²⁶ R ²⁷ , wherein R ²⁵ represents a hydrogen atom, an alkyl group having 1, 2 or 3 carbon atoms or a phenyl group which is unsubstituted or substituted by one substituent selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group and a methyl group, or R ²⁵ represents a heteroaryl group having 1 to 9 carbon atoms which is unsubstituted or substituted one substituent selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group and methyl group, and R ²⁶ and R ^{27 are} each independently hydrogen or methyl, and ^R is alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, trifluoromethyl, or phenyl which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluoro and chloro, trifluoromethyl, and methyl group. A process for the preparation of a substituted benzenedicarboxylic acid diguanidide of the formula I according to claim 1, wherein the compound of the formula II R2, the symbols R ¹ 'to ^R' as defined above for ^R, but where at least one of the radicals in which R ¹ -C R ¹ to R ^s represents said COL group, and L is an easily nucleophilically substituted leaving group, with guanidine. Use of a substituted benzenedicarboxylic acid diguanidide of the formula I according to claim 1 for the manufacture of a medicament for the treatment of arrhythmias. The substituted benzenedicarboxylic acid diguanidide of the formula I according to claim 1 for use in the treatment of arrhythmias. Use of a substituted benzenedicarboxylic acid diguanidide of the formula I according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of a heart attack. Use of a substituted benzenedicarboxylic acid diguanidide of the formula I according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of angina pectoris. Use of a substituted benzenedicarboxylic acid diguanidide of the formula I according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of ischemic heart conditions. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of ischemic conditions of the peripheral and central nervous system and stroke. Use of a substituted benzenedicarboxylic acid diguanidide of the formula I according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of ischemic conditions of peripheral organs and limbs. Use of a substituted benzenedicarboxylic acid diguanidide of the formula I according to claim 1 for the manufacture of a medicament for the treatment of shock conditions. Use of a substituted benzenedicarboxylic acid diguanidide of the formula I according to claim 1 for the manufacture of a medicament for use in surgical operations and organ transplants. Use of a substituted benzenedicarboxylic acid diguanidide of the formula I according to claim 1 for the manufacture of a medicament for the preservation and storage of transplants for surgical procedures. Use of a compound of formula I as claimed in claim 1 for the manufacture of a medicament for the treatment of diseases whose primary or secondary cause is cell proliferation, i.e. for the manufacture of an anti-atherosclerotic agent for late diabetic complications, cancer diseases, fibrotic diseases such as fibrosis. lung, liver fibrosis or kidney fibrosis, and anti-uterine hyperplasia. Use of a substituted benzenedicarboxylic acid diguanidide of the formula I according to claim 1 for the preparation of a scientific tool for the inhibition of the Na 2 / H 2 exchange system, for the diagnosis of hypertonia and proliferative diseases. Medicament, characterized in that it comprises an effective amount of a substituted benzenediocarboxylic acid diguanidide of the formula I according to one or more of Claims 1 to 4.