WO2001087829A1

WO2001087829A1 - Bisacylguanidine

Info

Publication number: WO2001087829A1
Application number: PCT/EP2001/004425
Authority: WO
Inventors: Rolf Gericke; Norbert Beier
Original assignee: Merck Patent Gmbh
Priority date: 2000-05-17
Filing date: 2001-04-19
Publication date: 2001-11-22
Also published as: DE10024319A1; AU2001258349A1

Abstract

The invention relates to bisacylguanidine of formula (I), wherein one of radicals is R?1, R2, R3, R4, or R5¿ and one of the radicals is R?6, R7, R8, R9 or R10¿, and to its physiologically acceptable salts and/or solvates. Said compounds exhibit cardioprotective properties and act as inhibitors of sub-type 1, cellular Na+/H+ antiporter.

Description

Bisacylguanidine

The invention relates to bisacylguanidines of the formula I.

wherein

one of the radicals R ¹ , R ² , R ³ , R ⁴ or R ⁵ and one of the radicals R ⁶ , R ⁷ , R ⁸ , R ⁹ or R ¹⁰

the other radicals each independently i

H, A, CN, shark, -SA, OA, -S0 ₂ A, Ph, OPh, Het, OH, NH ₂ , NHA, NA ₂ or -CO-A,

X is missing or S, S0 ₂ , (CH ₂ ) _n , CO, O or OCH ₂ ,

A alkyl with 1-8 C atoms,

Shark F, CI, Br or I,

Ph unsubstituted or mono-, di- or trisubstituted by A, OA, NH ₂ , NHA, NA ₂ , F, CI, Br and / or CF ₃ ,

Het mononuclear unsubstituted or mono- or polysubstituted by shark, A, OA, COOA, CN and / or carbonyl oxygen saturated or unsaturated heterocyclic ring system, which contains one or two identical or different heteroatoms such as nitrogen, oxygen and sulfur, n 1, 2 or 3,

and their physiologically acceptable salts and / or solvates.

Of the compounds of formula I according to the invention, all tautomeric and cis-trans isomers as well as all prodrugs are included.

The object of the invention was to find new compounds with valuable properties, in particular those which can be used for the production of medicaments.

It has been found that the compounds of the formula I and their physiologically acceptable salts have valuable pharmacological properties with good tolerability.

The new compounds are inhibitors of the cellular Na ⁺ / H ⁺ antiporter of subtype 1, ie active substances which inhibit the Na ⁺ / H ⁺ exchange mechanism of the cells (Düsing et al., Med. Klin. 87, 378-384 (1992)) and thus represent good antiarrhythmics which are particularly suitable for the treatment of arrhythmias which occur as a result of lack of oxygen.

The new compounds can also be used to treat insulin-independent diabetes meilitus (NIDDM).

The best-known active ingredient in the group of acylguanidines is amiloride. However, this substance primarily shows an antihypertensive and saluretic effect, which is particularly undesirable in the treatment of cardiac arrhythmia, while the antiarrhythmic properties are only very weak.

Benzoylguanidines are described, for example, in DE 44 04 183. However, the compounds described in the prior art are structurally distinctly different from those claimed here. The invention relates to compounds of the formula I and their physiologically acceptable salts.

The substances according to the invention of the present application show a good cardioprotective effect and are therefore particularly suitable for

Infarct treatment, infarct prophylaxis and for the treatment of angina pectoris. Furthermore, the substances counteract all pathological hypoxic and ischemic damage, so that the diseases caused primarily or secondarily can be treated. The active ingredients are also well suited for preventive applications.

Due to the protective effects of these substances in pathological, hypoxic or ischemic situations, there are further possible uses in surgical interventions to protect temporarily under-supplied organs, in organ transplants to protect the removed organs, in angioplasty vascular or cardiac interventions, in ischemia of the nervous system, in the therapy of Shock conditions and preventive prevention of essential hypertension.

Furthermore, the compounds can also be used as therapeutic agents in diseases caused by cell proliferation, such as arteriosclerosis, late diabetic complications, tumor diseases, fibrotic diseases, in particular of the lungs, liver and kidneys, and organ hypertrophies and hyperplasias. In addition, the

Diagnostic substances for the detection of diseases which are accompanied by increased activity of the Na ⁺ / H ⁺ antiporter, for example in erythrocytes, thrombocytes or leukocytes.

The effects of the compounds can be known per se with the help

Methods are determined as described, for example, by N. Escobales and J. Figueroa in J. Membrane Biol. 120, 41-49 (1991) or by L. Counillon, W. Scholz, H. Lang and J. Pouyssegur in Mol. Pharmacol. 44, 1041-1045 (1993). Suitable experimental animals are, for example, mice, rats, guinea pigs, dogs, cats, monkeys or pigs.

The effects of the compounds for the treatment of NIDDM can be determined analogously to the methods described in WO 99-08795.

The invention relates to the compounds of the formula I according to claims 1 to 2 and to their physiologically acceptable salts and solvates as medicaments.

The compounds can therefore be used as active pharmaceutical ingredients in human and veterinary medicine. They can also be used as intermediates for the production of further active pharmaceutical ingredients.

The invention therefore also relates to the drugs mentioned as inhibitors of the cellular Na ⁺ / H ⁺ antiporter of subtype 1 and to these drugs for the treatment of arrhythmias, angina pectoris, infarcts and insulin-independent diabetes mellitus (NIDDM).

In the formulas given, A denotes a branched or unbranched alkyl group having 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4, in particular 1, 2 or 3, carbon atoms, in particular preferably methyl, furthermore preferably Ethyl, propyl, isopropyl, butyl, isobutyl, further preferably sec-butyl, tert-butyl, pentyl, isopentyl (3-methylbutyl), hexyl or isohexyl (4-methylpentyl). In A 1-7 H atoms can also be replaced by fluorine or chlorine. A therefore means e.g. also trifluoromethyl or pentafluoroethyl.

Preferably one of the radicals R ¹ , R ² , R ³ , R ⁴ or R ⁵ , and also one of the radicals R ⁶ , R ⁷ , R ⁸ , R ⁹ or R ¹⁰

one and / or two other radicals H, alkyl having 1, 2, 3 or 4 carbon atoms or alkylsulfonyl having 1, 2, 3 or 4 carbon atoms, and the remaining radicals H.

X is preferably S, S0 ₂ , CH ₂ , CH ₂ CH ₂ , CO or X is absent.

Ph preferably means e.g. Phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p- tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino) - phenyl, o-, m- or p- (N-methylaminocarbonyl) phenyl, o-, m- or p- acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p- (N, N-dimethylamino) phenyl, o-, m- or p- (N-ethylamino) phenyl, o-, m- or p- (N, N-diethylamino ) -phenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, more preferably 2,3-, 2,4-, 2,5- , 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-,

2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2 , 5- or 3,4-dimethoxyphenyl, 3-amino-4-chloro, 2-amino-3-chloro, 2-amino-4-chloro, 2-amino-5-chloro or 2-amino 6-chlorophenyl, 2-nitro-4-N, N-dimethylamino or 3-nitro-4-N, N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2 , 3,6-, 2,4,6- or 3,4,5-trichlorophenyl,

2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, 3,6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2,5- Difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl or 2, 5-dimethyl-4-chlorophenyl.

Het means, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5- Pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4- Pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, further preferably 1, 2,3-triazol-l-, -4- or -5-yl, 1, 2,4-triazol-1-, -3 - or 5-yl, 1- or 5-tetrazolyl, 1, 2,3-oxadiazol-4- or -5-yl, 1, 2,4-oxadiazol-3- or - 5-yl, 1, 3,4-thiadiazol-2- or -5 -yl, 1, 2,4-thiadiazol-3- or -5-yl, 1, 2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyi, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-,

5-, 6- or 7- benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1, 3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6- Quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo [1, 4] oxazinyl, more preferably 1, 3-benzodioxol-5-yl, 1, 4-benzodioxan-6-yl , 2,1, 3-benzothiaediazol-4- or -5-yl or 2,1, 3-benzoxadiazol-5-yl.

The heterocyclic radicals can also be partially or completely hydrogenated. Het can, for. B. also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl,

2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or -3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2- or -3 -thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4 - or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1, 4-dihydro-1-, -2-, -3- or -4-pyridyl, 1, 2,3,4 Tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, Tetrahydro-2-, -3- or - 4-pyranyl, 1, 4-dioxanyl, 1, 3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4- pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1, 2,3,4-tetrahydro-1-, -2-, -3- , -4-, -5-, -6-, -7- or -8-quinolyl, 1, 2,3,4-tetrahydro-1 -, - 2 -, - 3-, -4-, -5- , -6-, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or 8- 3,4-dihydro-2H-benzo [1, 4] oxazinyl, more preferably 2 , 3-methylenedioxyphenyl, 3,4-methylenedioxyphen yl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4- (difluoromethylenedioxy) phenyl, 2,3-dihydrobenzofuran-5- or 6-yl, 2,3- (2-oxo-methylenedioxy) - phenyl or 3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, more preferably 2,3-dihydro-benzofuranyl or 2,3-dihydro-2-oxo-furanyl.

"Multiple" means two, three, four or five times. Solvates are understood to mean, for example, hydrates, such as the hemi, mono- or dihydrates, or, for example, alcohol addition compounds, such as, for example, with methanol or ethanol.

Shark preferably means F, CI or Br.

In general, all residues such as e.g. A that can appear multiple times in the molecule, the same or different, i.e. can be independent of each other.

The invention relates in particular to the compounds of the formula Ia below

R ¹

R ³

wherein

one of the radicals R ¹ , R ² or R ³

and R ⁶

as well as all tautomeric forms and cis-trans isomers, the other residues each independently

H, A, or -S0 ₂ A,

X is missing or S, S0 ₂ , (CH ₂ ) _n , CO,

A is alkyl with 1-8 C atoms, n is 1 or 2,

and their physiologically acceptable salts and / or solvates.

The invention further relates to a process for the preparation of the compounds of the formula I according to claim 1, and of their salts and / or solvates, characterized in that

a) a compound of formula II

wherein

and Q CI, Br, I or a free or reactive functional OH group,

mean,

the other radicals each independently have the meanings given in claim 1

reacted with guanidine,

or

b) liberating them from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent, by

replacing a conventional amino protecting group with hydrogen by treatment with a solvolysing or hydrogenolysing agent or releasing an amino group protected by a conventional protecting group,

and / or that a base of formula I obtained is converted into one of its salts by treatment with an acid.

The compounds of the formula I are otherwise prepared by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart; Organic Reactions, John Wiley & Sons , Inc., New York; and in the above-mentioned patent application), under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made of variants which are known per se and are not mentioned here in detail.

If desired, the starting materials can also be formed in situ in such a way that they are not isolated from the reaction mixture, but instead are immediately converted further into the compounds of the formula I. Compounds of the formula I are preferably prepared by using an activated carboxylic acid derivative of the formula II, Q being particularly preferably CI, Br, I or a reactively modified OH group such as, for example, an activated ester, an imidazolide or alkylsulfonyloxy with 1-6 C-

Atoms (preferably methylsulfonyloxy) or arylsulfonyloxy having 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy) is reacted with guanidine. Also particularly suitable are reaction variants in which the free carboxylic acid II (Q = OH) is converted to the respective activated derivative in a manner known per se and then directly, without this

Intermediate insulation, is reacted with guanidine or protected guanidine. Methods in which intermediate isolation is unnecessary are, for example, activation with carbonyldiimidazoi, dicyclohexylcarbodiimide or the Mukaiyama variant (Angew. Chem. 9_1, 788-812 (1979)).

Some of the carboxylic acids of the formula II used as intermediates, in which two of the radicals R ¹ -R ^{10 are} COOH, are known or can be prepared by customary methods. The compounds with the 2-methyl-propenoic acid guanidide structure are generally also produced from the dicarboxylic acid: a) by reduction to the dialcohols (for example with LiAIH), b) subsequent oxidation to the dialdehydes (for example with DMSO / oxalyl chloride) Swern), c) olefination with 2-phosphonopropionic acid triethyl ester according to Horner-Emmons (as described in Eur. J. Physiol. 1998, 436, 797-800), d) saponification of the diesters to give the dicarboxylic acids (eg with NaOH), e) guanylation of unsaturated dicarboxylic acids to the bisacylguanidines.

The reactions given are standard reactions in organic chemistry and are described, for example, in J. March, Adv. Org. Chemistry, 3rd. Ed., John Wiley & Sons (1985).

The reaction of a reactive carboxylic acid derivative of the formula II with guanidine is preferably carried out in a manner known per se in one protic or aprotic polar or non-polar inert organic solvents.

However, a preferred variant also consists in reacting the reactants directly with one another without the addition of a solvent.

When preparing II or when reacting II with guanidine, it is also expedient to work in the presence of a base or with an excess of the basic component. Suitable bases are preferably e.g. Alkali metal or alkaline earth metal hydroxides, carbonates, alcoholates or organic bases such as triethylamine, pyridine or N-ethyldiisopropylamine, which can also be used in excess and can then simultaneously serve as solvents.

Alcohols such as methanol, ethanol, isopropanol, n-butanol or tert-butanol are particularly suitable as inert solvents; Ethers such as diethyl ether, diisopropyl ether, THF or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Nitriles such as acetonitrile; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate; Amides such as phosphoric acid hexamethyl triamide; Sulfoxides such as dimethyl sulfoxide (DMSO); chlorinated hydrocarbons such as dichloromethane, chloroform, trichlorethylene, 1, 2-dichloroethane or carbon tetrachloride; Hydrocarbons such as benzene, toluene or xylene. Mixtures of these solvents with one another are also suitable.

Particularly suitable solvents are methanol, THF, dimethoxyethane,

Dioxane, water or mixtures made therefrom. The reaction temperature is, for example, temperatures between 20 ° and

Boiling point of the solvent suitable. The response times are between 5 minutes and 12 hours.

It is also often advisable to use guanidine in a protected form, e.g. as

Implement Boc or as a Cbz derivative. In this case, the compounds of the formula I can be obtained by liberating them from their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogenolysis.

Preferred starting materials for solvolysis or hydrogenolysis are those which otherwise correspond to the formula I, but instead of one or more free amino groups contain corresponding protected amino groups (prodrugs), preferably those which instead of an H atom which is connected to an N atom is an amino protective group, especially those which carry an R'-N group instead of an HN group, in which R 'is an amino protective group. There may also be several - identical or different - protected amino groups in the molecule of the starting material. If the existing protective groups are different from one another, they can in many cases be split off selectively.

The term "amino protecting group" is generally known and refers to groups which are suitable for protecting (blocking) an amino group from chemical reactions, but which are easily removable after the desired chemical reaction at another point in the

Molecule has been carried out. Typical of such groups are in particular unsubstituted or substituted acyl, aryl (for example 2,4-dinitrophenyl (DNP)), aralkoxymethyl (for example benzyloxymethyl (BOM)) or aralkyl groups (for example benzyl, 4-nitrobenzyl, triphenylmethyl). Since the amino protective groups are removed after the desired reaction (or reaction sequence), their type and size is otherwise not critical; however, preference is given to those having 1-20, in particular 1-8, carbon atoms. The term "acyl group" is to be understood in the broadest sense in connection with the present process. It encompasses acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluoyl; Aryloxyalkanoyl such as phenoxyacetyl; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl (BOC), 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as benzyloxycarbonyl (CBZ), 4-methoxybenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl (FMOC). Preferred amino protecting groups are BOC, DNP and BOM, furthermore CBZ, benzyl and acetyl.

The liberation of the compounds of formula I from their functional derivatives succeeds - depending on the protective group used - e.g. with strong acids, suitably with trifluoroacetic acid or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary.

Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran (THF) or dioxane, amides such as dimethylformamide (DMF), halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol and water. Mixtures of the abovementioned solvents are also suitable. Trifluoroacetic acid is preferably used in excess without the addition of another solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9: 1. The reaction temperatures for the cleavage are advantageously between about 0 and about 50 °; preferably one works between 15 and 30 ° (room temperature).

The BOC group can e.g. preferably with 40% trifluoroacetic acid in dichloromethane or with about 3 to 5N HCl in dioxane at 15-60 °, the FMOC group with an about 5-20% solution of dimethylamine, diethylamine or piperidine in DMF at 15- 50 °. The DNP group can be split off e.g. also with an approximately 3-10% solution of 2-mercaptoethanol in DMF / water at 15-30 °.

Protective groups which can be removed hydrogenolytically (for example BOM, CBZ or benzyl) can be expediently, for example, by treatment with hydrogen in the presence of a catalyst (for example a noble metal catalyst such as palladium. be split off moderately on a support such as coal). Suitable solvents are those mentioned above, in particular, for example, alcohols such as methanol or ethanol or amides such as DMF. Hydrogenolysis is generally carried out at temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 °

1-10 bar carried out. Hydrogenolysis of the CBZ group succeeds e.g. good on 5-10% Pd-C in methanol at 20-30 °.

A base of the formula I can also be converted into the associated acid addition salt using an acid. Come for this implementation

Acids in question that provide physiologically acceptable salts. So inorganic acids can be used, e.g. Sulfuric acid. Nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. Formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2- or 3-phenylpropionic acid, citric acid, gluconic acid, asotonic acid, ascorbic acid - Tic acid, methane or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl sulfuric acid.

The compounds of formula I and their physiologically acceptable

Salts and / or solvates can be used for the production of pharmaceutical preparations, especially in a non-chemical way. They can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and optionally in combination with one or more further active ingredient (s). The invention thus also relates to pharmaceutical preparations containing at least one medicament according to one of the claims 5 to 6 and optionally carriers and / or auxiliaries and optionally other active ingredients.

These preparations can be used as medicinal products in human or veterinary medicine. Suitable carriers are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, lanolin, petroleum jelly. For oral use, tablets, dragees, capsules, syrups, juices or drops are used, for rectal use suppositories, for parenteral use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, for topical use, ointments, creams, pastes, Lotions, gels, sprays, foams, aerosols, solutions (e.g. solutions in alcohols such as ethanol or isopropanol, acetonitrile, DMF, dimethylacetamide, 1, 2-propanediol or their mixtures with one another and / or with water) or powder. The new compounds can also be lyophilized and the lyophilizates obtained e.g. can be used for the production of injectables.

Liposomal preparations are also particularly suitable for topical use. The specified preparations can be sterilized and / or contain auxiliaries such as conductors, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or flavoring substances. If desired, they can also contain one or more other active ingredients, e.g. one or more vitamins.

The compounds of the formula I and their physiologically acceptable salts can be administered to humans or animals, in particular mammals such as monkeys, dogs, cats, rats or mice, and can be used in the therapeutic treatment of the human or animal body and in combating diseases, in particular in the case of the therapy and / or prophylaxis of disorders of the cardiovascular system. They are therefore suitable for the treatment of arrhythmias, in particular especially if these are caused by lack of oxygen, from angina pectoris, infarcts, ischemia of the nervous system such as stroke or cerebral edema, from shock conditions and for preventive treatment.

The invention also relates to the use of compounds according to claims 1 and 2 and / or their physiologically acceptable salts for the manufacture of a medicament for combating diseases, preferably arrhythmias, angina pectoris, infarcts and insulin-independent diabetes mellitus (NIDDM).

The substances can also be used as therapeutic agents for diseases in which cell proliferation plays a role, such as arteriosclerosis, late diabetic complications, tumor diseases, fibroses, and organ hypertrophies and hyperplasias, especially in diseases of the prostate.

The substances according to the invention are generally used in analogy to known antiarrhythmics, e.g. Aprindine administered, preferably in dosages between about 0.01 and 5 mg, in particular between 0.02 and 0.5 mg per dosage unit. The daily dosage is preferably between about 0.0001 and 0.1, in particular between 0.0003 and 0.01 mg / kg body weight. However, the specific dose for each particular patient depends on a wide variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of excretion and on the combination of drugs and severity of the respective disease to which the therapy applies. Oral application is preferred.

In the examples below, "customary workup" means:

If necessary, water is added, the mixture is extracted with an organic solvent such as ethyl acetate, the organic phase is separated off and dried the organic phase over sodium sulfate, filtered, evaporated and purified by chromatography and / or crystallization.

example 1

A solution of 1.0 g of 3- [2- (3-carboxyphenyl) ethyl] benzoic acid in 30 ml of 1-methyl-2-pyrrolidone is mixed with 1.89 g of 2-chloro-1-methylpyridinium iodide and 2 h at RT stirred. 1.788 g of Boc-guanidine and 3.15 ml of N-ethyl-diisopropylamine are added and the mixture is stirred for 2 hours (Mukaiyama reaction). After customary working up, 1.85 g Λ / - {3- [2- (3-N-Boc-guanidino-carbonyl-phenyl) -ethyl] -benzoyl} -N'-Boc-guanidine ("AA")

Example 2

0.5 g of "AA" is mixed with 20 ml of 25% hydrochloric acid and heated under reflux for 2 h. After customary working up, 0.37 g of Λ / - {3- [2- (3- guanidinocarbonylphenyl) ethyl] benzoyl} guanidine, dihydrochloride, mp. 295-297 ° (decomposition).

You get analog

from 3- [2- (2-carboxyphenyl) ethyl] benzoic acid

Λ / - {3- [2- (2-guanidinocarbonylphenyl) ethyl] benzoyl} guanidine, dihydrochloride, mp 180 °;

from 4- [2- (2-carboxyphenyl) ethyl] benzoic acid

Λ / - {4- [2- (2-guanidinocarbonylphenyl) ethyl] benzoyl} guanidine, dihydrochloride, mp 190 °; from 2 - [(2-carboxyphenyl) sulfanyl] benzoic acid

Λ / - {2 - [(2-guanidinocarbonylphenyl) sulfanyl] benzoyl} guanidine, dihydrochloride, mp 335.4 °;

from 2- [2- (2-carboxyphenyl) ethyl] benzoic acid

Λ / - {2- [2- (2-guanidinocarbonylphenyl) ethyl] benzoyl} guanidine, dihydrochloride, mp 280-283 °;

from 4 - [(2-carboxyphenyl) sulfanyl] benzoic acid

Λ / - {4 - [(2-guanidinocarbonylphenyl) sulfanyl] benzoyl} guanidine, dihydrochloride, mp 269.7 °;

from 4 - [(2-carboxyphenyl) sulfanyl] -2-methyl-5-methylsulfonylbenzoic acid

Λ / - {4 - [(2-guanidinocarbonylphenyl) sulfanyl] -2-methyl-5-methylsulfonylbenzoyl} guanidine, dihydrochloride, mp 289.5 °;

from 3 - [(2-carboxyphenyl) sulfanyl] benzoic acid Λ / - {3 - [(2-guanidinocarbonylphenyl) sulfanyl] benzoyl} guanidine,

Dihydrochloride, mp 288 °;

from 3 - [(4-carboxyphenyl) sulfanyl] benzoic acid

Λ / - {3 - [(4-guanidinocarbonylphenyl) sulfanyl] benzoyl} guanidine, dihydrochloride, mp 287 °;

from 3 - [(3-carboxyphenyl) sulfanyl] benzoic acid

Λ / - {3 - [(3-guanidinocarbonylphenyl) sulfanyl] benzoyl} guanidine, dihydrochloride, mp. 275 °.

Example 3

Analogously to Examples 1 and 2, one obtains

from biphenyl-2,2'-dicarboxylic acid Λ / - {2- (2-guanidinocarbonylphenyl) benzoyl} guanidine, dihydrochloride, mp. 302 ° (decomposition);

from biphenyl-4,4'-dicarboxylic acid

Λ / - {4- (4-guanidinocarbonylphenyl) benzoyl} guanidine, dihydrochloride, mp. 347 ° (decomposition);

from biphenyl-3,3'-dicarboxylic acid

Λ / - {3- (3-guanidinocarbonylphenyl) benzoyl} guanidine, dihydrochloride, mp 271-273 ° (decomposition);

from 3- [2 '- (2-carboxypropenyl) biphenyl-2-yl] -2-methyl-acrylic acid

^^ - [^ - (S-Guanidino ^ -methyl-S-oxo-propeny -biphenyl ^ -yl] ^ - methyl-acryloyl} -guanidine

Dihydrochloride, mp 230 ° (decomposition);

from 3- [4 '- (2-carboxypropenyl) biphenyl-4-yl] -2-methyl-acrylic acid

Λ- {3- [4 '- (3-Guanidino-2-methyl-3-oxo-propenyl) biphenyl-4-yl] -2-methyl-acryloylj-guanidine, dihydrochloride, mp 312-315 °;

from 3- {4- [4- (2-carboxypropenyl) benzyl] phenyl} -2-methyl-acrylic acid

Λ / - (3- {4- [4- (3-Guanidino-2-methyl-3-oxo-propenyl) benzyl] phenyl} -2-methyl-acryloyl) guanidine, dihydrochloride, mp. 269.2 °;

from 3- {4- [3- (2-carboxypropenyl) benzyl] phenyl} -2-methyl-acrylic acid Λ / - (3- {4- [3- (3-guanidino-2-methyl-3 -oxo-propenyl) -benzyl] -phenyl} -2-methyl-acryloyl) -guanidine, dihydrochloride, mp. 285.7 °; from 3- {3- [2- (2-carboxypropenyl) benzenesulfonyl] phenyl} -2-methyl-acrylic acid

Λ / - (3- {3- [2- (3-Guanidino-2-methyl-3-oxo-propenyl) benzenesulfonyl] phenyl} -2-methyl-acryloyl) guanidine, dihydrochloride, mp. 104.1 °;

from 3- {2- [4- (2-carboxypropenyl) benzyl] phenyl} -2-methyl-acrylic acid

Λ / - (3- {2- [4- (3-Guanidino-2-methyl-3-oxo-propenyl) benzyl] phenyl} -2-methyl-acryloyl) guanidine, dihydrochloride, mp. 184-187 °;

from 3- {2- [2- (2-carboxypropenyl) benzoyl] phenyl} -2-methyl-acrylic acid

Λ / - (3- {2- [2- (3-guanidino-2-methyl-3-oxo-propenyl) benzoyl] phenyl} -2-methyl-acryloyl) guanidine, dihydrochloride, mp 189 ° ( Decomposition);

from 3- {2- [4- (2-carboxypropenyl) benzoyl] phenyl} -2-methyl-acrylic acid

Λ / - (3- {2- [4- (3-Guanidino-2-methyl-3-oxo-propenyl) benzoyl] phenyl} -2-methyl-acryloyl) guanidine, dihydrochloride, mp 189-190 °;

from 3- {2- [2- (2-carboxypropenyl) benzenesulfanyl] phenyl} -2-methyl-acrylic acid

A / - (3- {2- [2- (3-guanidino-2-methyl-3-oxo-propenyl) benzenesulfanyl] phenyl} -2-methyl-acryloyl) guanidine, dihydrochloride, mp 259.0 °;

from 3- {2- [2- (2-carboxypropenyl) benzyl] phenyl} -2-methyl-acrylic acid Λ / - (3- {2- [2- (3-guanidino-2-methyl-3 -oxo-propenyl) -benzyl] -phenyl} -2-methyl-acryloyl) -guanidine, dihydrochloride, mp. 194-197 °;

from 3- {4- [2- (2-carboxypropenyl) benzenesulfanyl] phenyl} -2-methyl-acrylic acid Λ / - (3- {4- [2- (3-guanidino-2-methyl-3 -oxo-propenyl) -benzenesulfanyl] - phenyl} -2-methyl-acryloyl) -guanidine, dihydrochloride, mp. 285 °;

from 3- {2- [2- (2-carboxypropenyl) benzenesulfonyl] phenyl} -2-methyl-acrylic acid Λ / - (3- {2- [2- (3-guanidino-2-methyl-3 -oxo-propenyl) -benzenesulfonyl] - phenyl} -2-methyl-acryloyl) -guanidine, dihydrochloride, mp. 315 °; from 3- {4- [2- (2-carboxypropenyl) benzenesulfonyl] phenyl} -2-methyl-acrylic acid

Λ / - (3- {4- [2- (3-Guanidino-2-methyl-3-oxo-propenyl) benzenesulfonyl] phenyl} -2-methyl-acryloyl) guanidine, dihydrochloride, mp. 234 °;

from 3- {3- [4- (2-carboxypropenyl) benzenesulfonyl] phenyl} -2-methyl-acrylic acid

Λ / - (3- {3- [4- (3-Guanidino-2-methyl-3-oxo-propenyl) benzenesulfonyl] phenyl} -2-methyl-acryloyl) guanidine, dihydrochloride, mp 279 °;

from 3- {3- [2- (2-carboxypropenyl) benzenesulfanyl] phenyl} -2-methyl-acrylic acid

Λ / - (3- {3- [2- (3-Guanidino-2-methyl-3-oxo-propenyl) benzenesulfanyl] phenyl} -2-methyl-acryloyl) guanidine, dihydrochloride, mp 223 °;

from 3- {3- [4- (2-carboxypropenyl) benzenesulfanyl] phenyl} -2-methyl-acrylic acid

Λ / - (3- {3- [4- (3-Guanidino-2-methyl-3-oxo-propenyl) benzenesulfanyl] phenyl} -2-methyl-acryloyl) guanidine, dihydrochloride, mp. 211 °;

from 3- (2- {2- [4- (2-carboxypropenyl) phenyl] ethyl} phenyl) -2-methyl-acrylic acid

Λ / - [3- (2- {2- [4- (3-Guanidino-2-methyl-3-oxo-propenyl) phenyl] ethyl} phenyl) -2-methyl-acryloyl] guanidine, mp 160-165 °;

from 3- {3- [3- (2-carboxypropenyl) benzenesulfanyl] phenyl} -2-methyl-acrylic acid

Λ / - (3- {3- [3- (3-Guanidino-2-methyl-3-oxo-propenyl) benzenesulfanyl] phenyl} -2-methyl-acryloyl) guanidine, dihydrochloride, mp. 237 °;

from 3- {3- [3- (2-carboxypropenyl) benzenesulfonyl] phenyl} -2-methyl-acrylic acid

Λ / - (3- {3- [3- (3-Guanidino-2-methyl-3-oxo-propenyl) benzenesulfonyl] phenyl} -2-methyl-acryloyl) guanidine, dihydrochloride, mp 240 °; from 3- (3- {2- [3- (2-carboxypropenyl) phenyl] ethyl} phenyl) -2-methyl-acrylic acid

Λ / - [3- (3- {2- [3- (3-Guanidino-2-methyl-3-oxo-propenyl) phenyl] ethyl} phenyl) -2-methyl-acryloyl] guanidine, mp 156 ° (decomposition);

from 3- (3- {2- [2- (2-carboxypropenyl) phenyl] ethyl} phenyl) -2-methyl-acrylic acid

Λ / - [3- (3- {2- [2- (3-guanidino-2-methyl-3-oxo-propenyl) phenyl] ethyl} phenyl) -2-methyl-acryloyl] guanidine, mp . 175-180 °.

Example 4

A suspension of 1.0 g of 4- [2- (3-carboxyphenyl) ethyl] benzoic acid in 35 ml of THF is mixed with 1.2 g of 1,1'-carbonyldiimidazole and stirred and stirred for 2 hours. A mixture of 2.12 g of guanidinium chloride in 4.1 ml of sodium methylate (30% solution in methanol) is concentrated and the benzoic acid solution is added and the mixture is stirred for 2 hours. The mixture is worked up in the customary manner and 0.84 g of A / - {4- [2- (3-guanidinocarbonylphenyl) ethyl] benzoyl} guanidine, dihydrochloride, mp. 262-266 ° (decomposition).

You get analog

from 4 - [(4-carboxyphenyl) methyl] benzoic acid Λ / - {4 - [(4-guanidinocarbonylphenyl) methyl] benzoyl} guanidine,

Dihydrochloride, mp 269.3 °;

from 3 - [(3-carboxyphenyl) methyl] benzoic acid

Λ / - {3 - [(3-guanidinocarbonylphenyl) methyl] benzoyl} guanidine, dihydrochloride, mp 224.2 °;

from 3 - [(4-carboxyphenyl) carbonyl] benzoic acid

Λ / - {3 - [(4-guanidinocarbonylphenyl) carbonyl] benzoyl} guanidine, dihydrochloride, mp 273-275 °;

from 4 - [(4-carboxyphenyl) carbonyl] benzoic acid Λ / - {4 - [(4-guanidinocarbonylphenyl) carbonyl] benzoyl} guanidine, dihydrochloride, mp 295-297 °;

from 2 - [(4-carboxyphenyl) methyl] benzoic acid Λ / - {2 - [(4-guanidinocarbonylphenyl) methyl] benzoyl} guanidine,

Dihydrochloride, mp 247-249 °;

from 2 - [(3-carboxyphenyl) carbonyl] benzoic acid

Λ / - {2 - [(3-guanidinocarbonylphenyl) carbonyl] benzoyl} guanidine, dihydrochloride, mp 239-240 °;

from 2 - [(2-carboxyphenyl) sulfonyl] benzoic acid

Λ / - {2 - [(2-guanidinocarbonylphenyl) sulfonyi] benzoyl} guanidine, dihydrochloride, mp 300.4 °;

from 4 - [(2-carboxyphenyl) sulfonyl] benzoic acid

Λ / - {4 - [(2-guanidinocarbonylphenyl) sulfonyl] benzoyl} guanidine, dihydrochloride, mp 261, 8 °;

from 2 - [(2-carboxyphenyl) methyl] benzoic acid

A / - {2 - [(2-guanidinocarbonylphenyl) methyl] benzoyl} guanidine, dihydrochloride, mp 271-273 °.

The following examples relate to pharmaceutical preparations:

Example A: Injection glasses

A solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate are adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.

Example B: Suppositories

A mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.

Example C: solution

A solution of 1 g of an active ingredient is prepared of the formula I, 9.38 g of NaH ₂ P0 ₄ ^■ 2 H ₂ 0, 28.48 g Na ₂ HP0 ₄ • 12 H ₂ 0 and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D: ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E: tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient. Example F: coated tablets

Analogously to Example E, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.

Example G: capsules

2 kg of active ingredient of the formula I are filled into hard gelatin capsules in a conventional manner, so that each capsule contains 20 mg of the active ingredient.

Example H: ampoules

A solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.

Claims

claims

1. Compounds of formula I.

wherein

the other residues each independently

X is missing or S, S0 ₂ , (CH ₂ ) _n , CO, 0 or OCH ₂ ,

A alkyl with 1-8 C atoms,

Shark F, CI, Br or I,

Ph unsubstituted or mono-, bi- or trisubstituted by A, OA, NH ₂ , NHA, NA ₂ , F, CI, Br and / or CF ₃ phenyl or benzyl, Het mononuclear unsubstituted or mono- or polysubstituted by Shark, A. , OA, COOA, CN and / or carbonyl oxygen substituted saturated or unsaturated heterocyclic

Ring system, which one or two of the same or various heteroatoms such as nitrogen, oxygen and

Contains sulfur, n is 1, 2 or 3,

and their physiologically acceptable salts and / or solvates.

Compounds according to claim 1, wherein one of the radicals R ¹ , R ² , R ³ , R ⁴ or R ⁵ , and one of the radicals R ⁶ , R ⁷ , R ⁸ , R ⁹ or R ¹⁰

one and / or two other radicals H, alkyl with 1, 2, 3 or 4 carbon atoms or alkylsulfonyl with 1, 2, 3 or 4 carbon atoms, and the remaining radicals are H, and their physiologically acceptable salts and / or solvates.

3. Compounds according to claim 1, wherein

X is absent or S, S0 ₂ , CH ₂ , CH ₂ CH ₂ or CO, and their physiologically acceptable salts and / or solvates.

4. Compounds of formula la according to claim 1,

R ¹

R ³ wherein

one of the radicals R ¹ , R ² or R ³

and R ⁶

as well as all tautomeric forms and cis-trans isomers, the other radicals each independently

H, A, or -S0 ₂ A,

X is absent or is S, S0 ₂ , (CH ₂ ) _n , CO, A alkyl having 1-8 C atoms, n is 1 or 2,

and their physiologically acceptable salts and / or solvates.

5. Compounds according to claim 1 selected from the group Λ / - {3- [2- (3-guanidinocarbonylphenyl) ethyl] benzoyl} guanidine,

Λ / - {3- [2- (2-guanidinocarbonylphenyl) ethyl] benzoyl} guanidine, Λ / - {4- [2- (2-guanidinocarbonylphenyl) ethyl] benzoyl} guanidine, Λ / - {2 - [(2-guanidinocarbonylphenyl) sulfanyl] benzoyl} guanidine, Λ / - {2- [2- (2-guanidinocarbonyl phenyl) ethyl] benzoyl} guanidine, A / - {4 - [(2-Guanidinocarbonyl-phenyl) -sulfanyl] benzoyl} -guanidine, Λ / - {4 - [(2-guanidinocarbonylphenyl) sulfanyl] -2-methyl-5-methylsulfonylbenzoyl} guanidine,

Λ - {3 - [(2-guanidinocarbonylphenyl) sulfanyl] benzoyl} guanidine,

Λ / - {3 - [(4-Guanidinocarbonyl-phenyl) -sulfanyl] benzoyl} -guanidine,

Λ / - {3 - [(3-Guanidinocarbonyl-phenyl) -sulfanyl] benzoyl} -guanidine,

Λ / - {2- (2-Guanidinocarbonyl-phenyl) benzoyl} -guanidine,

Λ / - {4- (4-Guanidinocarbonyl-phenyl) benzoyl} -guanidine,

Λ / - {3- (3-guanidinocarbonylphenyl) benzoyi} guanidine, V- {3- [2 '- (3-guanidino-2-methyl-3-oxo-propenyl) biphenyl-2-yi] -2-methyl-acryloyl} guanidine,

Λ - {3- [4 '- (3-guanidino-2-methyl-3-oxo-propenyl) biphenyl-4-yl] -2-methyl-acryloyl} -guanidine, Λ / - (3- {4- [4- (3-guanidino-2-methyl-3-oxo-propenyl) benzyl] phenyl} -2-methyl-acryloyl) guanidine,

Λ / - (3- {4- [3- (3-guanidino-2-methyl-3-oxo-propenyl) benzyl] phenyl} -2-methyl-acryloyl) guanidine,

Λ- (3- {3- [2- (3-guanidino-2-methyl-3-oxo-propenyl) benzenesulfonyl] phenyi} -2-methyl-acryloyl) guanidine,

Λ / - (3- {2- [4- (3-guanidino-2-methyl-3-oxo-propenyl) benzyl] phenyl} -2-methyl-acryloyl) guanidine,

Λ / - (3- {2- [2- (3-guanidino-2-methyl-3-oxo-propenyl) benzoyl] phenyi} -2-methyl-acryloyl) guanidine,

Λ / - (3- {2- [4- (3-guanidino-2-methyl-3-oxo-propenyl) benzoyl] phenyl} -2-methyl-acryloyl) guanidine,

Λ / - (3- {2- [2- (3-guanidino-2-methyl-3-oxo-propenyl) benzenesulfanyl] phenyl} -2-methyl-acryloyl) guanidine,

Λ / - (3- {2- [2- (3-guanidino-2-methyl-3-oxo-propenyl) benzyl] phenyl} -2-methyl-acryloyl) guanidine,

Λ / - (3- {4- [2- (3-guanidino-2-methyl-3-oxo-propenyl) benzenesulfanyl] phenyl} -2-methyl-acryloyl) guanidine, Λ / - (3- {2- [2- (3-guanidino-2-methyl-3-oxo-propenyl) benzenesulfonyl] phenyl} -2-methyl-acryloyl) guanidine,

Λ / - (3- {4- [2- (3-guanidino-2-methyl-3-oxo-propenyl) benzenesulfonyl] phenyl} -2-methyl-acryloyl) guanidine,

Λ / - (3- {3- [4- (3-Guanidino-2-methyl-3-oxo-propenyl) benzoisulfonyl] phenyl} -2-methyl-acryloyl) guanidine,

Λ / - (3- {3- [2- (3-guanidino-2-methyl-3-oxo-propenyl) benzenesulfanyl] phenyl} -2-methyl-acryloyl) guanidine, Λ / - (3> { 3- [4- (3-guanidino-2-methyl-3-oxo-propenyl) benzenesulfanyl] phenyl} -2-methyl-acryloyl) guanidine,

Λ / - [3- (2- {2- [4- (3-guanidino-2-methyl-3-oxo-propenyl) phenyl] ethyl} phenyl) -2-methyl-acryloyl] guanidine, Λ / - (3- {3- [3- (3-Guanidino-2-methyl-3-oxo-propenyl) benzenesulfanyi] phenyl} -2-methyl-acryloyl) guanidine,

Λ / - (3- {3- [3- (3-Guanidino-2-methyl-3-oxo-propenyl) benzenesulfonyl] phenyl} -2-methyl-acryloyl) guanidine,

Λ / - [3- (3- {2- [3- (3-guanidino-2-methyl-3-oxo-propenyl) phenyl] ethyl} phenyl) -2-methyl-acryloyl] guanidine,

Λ / - [3- (3- {2- [2- (3-guanidino-2-methyl-3-oxo-propenyl) phenyl] ethyl} phenyl) -2-methyl-acryloyl] guanidine,

Λ / - {4- [2- (3-guanidinocarbonylphenyl) ethyl] benzoyl} guanidine, Λ / - {4 - [(4-guanidinocarbonylphenyl) methyl] benzoyl} guanidine,

Λ / - {3 - [(3-Guanidinocarbonyl-phenyl) methyl] benzoyl} -guanidine,

Λ / - {3 - [(4-Guanidinocarbonyl-phenyl) carbonyl] benzoyl} -guanidine,

Λ / - {4 - [(4-guanidinocarbonylphenyl) carbonyl] benzoyl} guanidine, Λ / - {2 - [(4-guanidinocarbonylphenyl) methyl] benzoyl} guanidine,

Λ / - {2 - [(3-Guanidinocarbonyl-phenyl) carbonyl] benzoyl} -guanidine,

Λ / - {2 - [(2-Guanidinocarbonyl-phenyl) sulfonyl] benzoyl} -guanidine,

Λ / - {4 - [(2-Guanidinocarbonyl-phenyl) sulfonyl] benzoyl} -guanidine,

Λ / - {2 - [(2-guanidinocarbonylphenyl) methyl] benzoyl} guanidine, and their physiologically acceptable salts and / or solvates. Process for the preparation of bisacylguanidines of the formula I according to one or more of claims 1 to 4 and of their salts and / or solvates, characterized in that

a) a compound of formula II

wherein

and

Q CI, Br, I or a free or reactively functionally modified OH group,

mean,

the other radicals each independently have the meanings given in claim 1

reacted with guanidine,

or b) liberating them from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent, by

7. Compounds of formula I according to claims 1 to 5 and their physiologically acceptable salts and solvates as active pharmaceutical ingredients.

8. Active pharmaceutical ingredients according to claim 7 as an inhibitor of the cellular Na ⁺ / H ⁺ antiporter of subtype 1.

9. Active pharmaceutical ingredients according to claim 7 or 8 for the treatment of arrhythmias, angina pectoris, infarcts and insulin-independent diabetes mellitus (NIDDM).

10. Pharmaceutical preparation containing at least one compound according to one of claims 1 to 5 and optionally carriers and / or auxiliaries and optionally other active ingredients.

11. Use of compounds according to claims 1 to 5 and / or their physiologically acceptable salts for the manufacture of a medicament for combating diseases.

2. Use according to claim 11 for the manufacture of a medicament for combating arrhythmias, angina pectoris, infarcts and insulin-independent diabetes mellitus (NIDDM).