SK84195A3 - Orto-aminosubstituted benzoylguanidines, method of their manufacture, their use as medicament or diagnostic agent and a medicament containing them - Google Patents

Abstract

2-Amino-benzoylguanidines (I) and their salts are new. R1 = NR6R7; R2-R5 = H, F, Cl, Br, I, CN, SOaR10, ZNR11R12, COR13, SR21, OR22, NR23R24, CR25R26R27, (X)c-CdH2d+1, (X)c-(CH2)b-CeF2e+1, 3-8C alkenyl, CbH2bR30 or -X-(CH2)bR19; R6, R7 = H or opt. perfluorinated 1-8C alkyl; R10 = opt. perfluorinated 1-8C alkyl, 3-6C alkenyl or CbH2b-R16; R11-R13 = H, opt. perfluorinated 1-8C alkyl, 3-6C alkenyl or CbH2b-R16; or R11+R12 = (CH2)4 or (CH2)5 (both opt. with one CH2 replaced by O, S, NH, N-Me or N-benzyl); R16 = phenyl (opt. mono-, di- or tri-substd. by F, Cl, CF3, Me, OMe or NR17R18) or 3-7C cycloalkyl; R17, R18 = H, CF3 or 1-4C alkyl; R19 = phenyl (opt. mono-, di- or tri-substd. by F, Cl, CF3, Me, OMe, NR17R18 or -X-(CH2)f-(X')R16); R21-R23, R25 = CaH2a-1-9C heteroaryl (opt. mono-, di- or tri-substd. by F, Cl, CF3, Me, OH, NH2, NHMe or NMe2); X, X' = O, S or NR33; Z = bond, CO or SO2; R24,R26, R27, R31-R33 = H or opt. perfluorinated 1-4C alkyl; R30 = phenyl, biphenylyl or naphthyl (all opt. mono-, di- or tri-substd. by F, Cl, CF3, Me, OMe or NR31R32) or 3-8C cycloalkyl; a = 0-2; b = 0-4; c = 0 or 1; d = 0-8; e = 0-7; f = 1-4; cpds. where R<3> = R<4> = H are excluded.

Description

Ortho-amino-substituted benzoylguanidines, process for their preparation, their use as medicament or diagnostic agent and medicament containing them

Technical field

The invention relates to ortho-amino substituted benzoylguanidines, to a process for their preparation, to their use as a medicament or a diagnostic agent and to a medicament containing them.

BACKGROUND OF THE INVENTION

BACKGROUND OF THE INVENTION Compounds which are the subject of European patent no. However, these do not contain an ortho-amino group.

SUMMARY OF THE INVENTION

The invention relates to ortho-amino-substituted benzoylguanidines of the formula I

in which they mean

R ¹ NR ⁵⁰ R ⁶

R ^a and R ^p, independently of one another hydrogen, alkyl having 1 to 8 carbon atoms or perfluoroalkyl of 1 to 8 carbon uhl'íka,

R ² , R ³ , R ⁴ and R ⁵ independently of one another R ^{x 0} -SO-, R ^XX R ^{X 2} N-CO-, R ^{X 3} -CO- or R ^{X 4} R ^{x with} N-SO-, and zero, 1 or 2 , la

R ^xo, R ^xx, R ^X2, R ^X3, R ¹⁴ and R ^X each independently an alkyl group having atoms, perfluoroalkyl having atoms, alkenyl having 3 to 6 or CH-R ^xe, b ^y and b is zero, 1, 2, 3 or 4

P ¹⁶ to 8 to 8 carbon atoms C 3 to C 7 cycloalkyl, phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, CF ₃ , methyl , methoxy or NR ¹⁷ R ^ia ,

R ^1D and R ⁱ independently of one another are hydrogen, _CF3 or alkyl having 1 to 4 carbon atoms, or

R ^xx , R ¹² as well as R ¹⁴ and R ^x together with 4 or 5 methylene groups, of which one CH 3 group can be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH ₃ group or an N-benzyl group or

R ^xx , R ¹² , R ¹⁴ and R ^xs independently of one another are hydrogen, or

R ^2, R ^3, R ⁴ and R ^s independently of one SR ^21, -OR ^22, -NR ²³ R ²⁴ or -CH ² R R ^2-7, R ^21, R ^22, R ^23, and R ^{2 S} independently of the itself -C (H, -C (-C (-C) -C) -heteroaryl, which is unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of fluorine, chlorine, CF ₃ , CH ₃ , methoxy, hydroxyl , amino, methylamino and dimethylamino, b is zero, 1 or 2,

R ( ²⁴⁾ , R ( ²⁶⁾ and R ( ^2-7) independently of one another are hydrogen, (C1-C4) alkyl or (C1-C4) perfluoroalkyl, or

R ^2, R ^3, R ⁴ and R ^s independently of one another are hydrogen, I, CN, - (X) _{<C c and g} ~ cle or -CF (X)

2DE + L '

-CH H <atom

R ³³ is fluorine, bromine,

H, - (Xb)

2da ^{9-f in} the alkenyl group of 3 to 8 atoms,

R ³ °,

2df. oxygen, sulfur atom or NR ³³ , carbon dg (Xb) zero atom

R ( ³⁴⁾ is O, C1 -C4 or perfluoroalkyl (C1 -C4), R (O), S, or NR ( ³⁴⁾ , -C4, C1 -C4 alkyl or (C1 -C4) with 1 to 4

dh zero or 1 will give zero 1 2 3 4. 5 6. 7 db zero 1 2 3 4. de zero I 2 3 4. 5 6. 7 df zero I 2 3 4. R ³ °

8, a C 3 -C 8 group, a cycloalkyl phenyl group, a biphenylyl group or a naphthyl group, wherein the biphenylyl group or the methoxy group and the NR

R ^3X , phenyl, or naphthyl aromatic groups are unsubstituted substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, CF ₃ , methyl,

R ( ³²⁾ is hydrogen, (C1-C4) alkyl or (C1-C4) perfluoroalkyl, or

R ^2, R ^3,

R ⁴ and R ^s independently NR ^{4 O} R ⁴¹ or - (Xe) - (CH) R ^{4 S,}

R ⁴⁰ and R ⁴¹ independently of one another are H, alkyl of 1 to 8 carbon atoms, perfluoroalkyl having up to 8 carbon atoms or _{(CH2) e} ~ R ^42, e is zero, 1, 2, 3 or 4,

R ^{42 is} C 3 -C 7 cycloalkyl, phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, CF, ₃ , methyl, methoxy and NR ⁴³ R ⁴⁴ ,

R ⁴³ and R ⁴⁴ independently of one another are H, _CF3 or alkyl having 1 to 4 carbon atoms, or

R ⁴ ° and R ⁴¹ together 4 or 5 methylene groups of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH ₃ group or an N-benzyl group, (Xe) an oxygen atom, an atom sulfur or NR ^4V ,

R ( ⁴⁷⁾ is hydrogen, (C1-C4) -alkyl or (C1-C4) perfluoroalkyl, or zero, 1, 2, 3 or 4,

R ⁴⁵ is cycloalkyl of 3 to 7 carbon atoms, phenyl, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of fluoro, chloro, CF _3, methyl, methoxy, NR ^{a R L} and - (Xfa) - _{(CH2) e {a} - (XFB) R ^46,

Xfa is CH ₂ , oxygen, sulfur or

NR ^4S ,

Xfb oxygen, sulfur or NR ⁴⁹ , ed 1,2,3,4,

R ( ⁴⁶⁾ is hydrogen, alkyl of 1 to 4 carbon atoms or perfluoroalkyl of 1 to 4 carbon atoms,

R ^43, R ^49, R ^a and R @ ⁵³ independently of one another are H or alkyl of 1 to 4 carbon atoms or perfluoroalkyl of 1 to 4 carbon atoms, wherein R ³ and R ⁴ but can not be hydrogen, and their pharmaceutically acceptable salts.

Preferred are compounds of formula I wherein:

R ¹ NR ^SO R ⁶

R ⁵ and R ⁶ independently of one another are H, _CF3 or alkyl having 1 to 4 carbon atoms,

R ² and R ^a is H,

R ⁴ R ¹⁰ -SO R ^{1, L,} R ¹² N-CO-, R ¹³ -CO- or R ¹⁴ R ^ls N-SO -, a is zero, 1 or 2,

R 10, _R 1 = _{f R} 13, _R 1A _{and R} 15, independently of one another, an alkyl group having 1 to 8 carbon atoms, a perfluoroalkyl group having 1 to 8 carbon atoms, an alkenyl group having 3 to 8 carbon atoms or -CH-R ¹⁶ ,

2ab and b are zero, 1, 2, 3 or 4,

R ^{16 is} C 3 -C 7 cycloalkyl or phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, CF ₃ , methyl, methoxy or NR ^1,7 R ^ie ,

R ^1D and R ⁱ independently of one another, H, _CF or C 1 -C 4 alkyl, or

R ¹³ - and R ¹² and R ^14, and R ^{1 S} together 4 or 5 methylene groups, of which one CH ₂ group can be replaced by oxygen, S, NH, _N-CH3 or N-benzyl, or

RX1, _{R12 | R (} 14) _{and R (} 15) independently of one another are also hydrogen,

R ³ SR ^2X , -OR ²² , - NR ²³ R ^{2 4,} or -CR 1 R 2 R ² · ⁷ ,

R ^21, R ^22, R ²³ and R ²⁵ independently of one another C _{fc> 2to} H - _{(Ci-C &)} -heteroaryl group which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, chlorine, _a group CF, CH _3, methoxy, hydroxyl, amino, methylamino and dimethylamino, b is zero, 1 or 2,

R ^24, R ²⁶ and R ^{2 V} independently is H, alkyl of 1 to 4 carbon atoms or perfluoroalkyl having 1 to 4 carbon atoms, or

R ³ and R ⁴ independently of one another is F, Cl, Br, I, CN, - (X) or CH

- (X b) - (CH) -CF, alkenyl of 3-8 'dri' 2 'Caio 2DE-l' * · ^x carbon atoms, or -CHR ³ °, 2DF df '(Xa) is oxygen, S or NR ³³ ,

R ( ³³⁾ is hydrogen, (C1-C4) alkyl or (C1-C4) perfluoroalkyl, dg is zero, 1 (Xb) is oxygen, sulfur or NR ³⁴ ,

R ( ³⁴⁾ is hydrogen, (C1-C4) -alkyl or perfluoroalkyl;

1-4 carbon atoms, dh zero or 1, will give zero, 1, 2, 3, 4, 5, 6, 7, or 8, db zero, 1, 2, 3 or 4 de zero, 1, 2, 3-, 4, 5, 6 or 7 df zero, 1, 2, 3 or 4 R ³ °

C 3 -C 8 cycloalkyl, phenyl, biphenylyl or naphthyl, the phenyl, biphenylyl or naphthyl aromatic groups being unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of fluorine, chlorine, CF ₃ , methyl, methoxy and NR ^3X R ³² ,

R ( ³¹⁾ and R ( ³²⁾ independently of one another are hydrogen, (C1-C4) -alkyl or (C1-C4) perfluoroalkyl, or

NR ³ R ^{4 O} or R ^4X (Xe) - (CH) R ^{4 S,}

R ⁴ ° and R ^4X independently of one another hydrogen, C 1 -C 8 alkyl, C 1 -C 8 perfluoroalkyl or (CH) -R ⁴² , zero, 1, 2, 3 or 4,

R ^{42 is} C 3 -C 7 cycloalkyl, phenyl which is unsubstituted or

R ⁴ ° and (Xe) eb

R ⁴⁵ or is substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, CF ₃ , methyl, methoxy and NR ⁴³ R ⁴⁴ ,

R ⁴³ and R ⁴⁴ independently of one another are H, _CF3 or alkyl having 1 to 4 carbon atoms,

1 R 4 together 4 or 5 methylene groups, of which one _CH2 group ~ can be replaced by oxygen, S, NH, _N-CH3 or N-benzil, O, S or NR ^47,

R ⁴⁷ is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl, zero, 1, 2, 3 or 4, C 3 -C 7 cycloalkyl, unsubstituted phenyl, or is substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, CF ₃ , methyl, methoxy, NR ^SO R ^{S 3} - and - (Xfa) - (CH) - (Xfb) R ^4e , (Xfa) ) CH ₂ , oxygen, sulfur or NR ⁴ , (Xfb) oxygen, sulfur or NR ⁴⁹ , ed 1, 2, 3 or 4,

R ( ^4e) is hydrogen, (C1-C4) alkyl or (C1-C4) perfluoroalkyl,

R ( ⁴³⁾ , R ( ⁴⁹⁾ , R ( ⁵ ) and R ( ^S) independently of one another are hydrogen, C1-C4alkyl or C1-C4fluoroalkyl, and their pharmaceutically acceptable salts.

Particularly preferred are compounds of formula I in which:

R ¹ NR ^SO R ^G

R ^a and R @ ⁶ independently of one another, H or CH _3,

R ² and R ⁵ is H,

R ⁴ R ¹⁰ —SO R ¹¹ R ¹² N —CO--, R ¹³ -CO- or R ¹³ R ¹¹ N-SO-, a '2 and represents 2

R 10, _R XX, _R X 2, _R 13, _R X 4 _{and R} XS independently of one another have a C 1 -C 8 alkyl group, a C 1 -C 8 perfluoroalkyl group or -CH-R ^{1 s} , ab 2 and ab ab is zero, 1 or 2, _R s is phenyl, which is unsubstituted or substituted with 1 to 3 substituents from the group consisting of fluoro, chloro, CF _3, methyl, methoxy and NR ^l R ^i,

R ¹ and R ^1a independently of one another are hydrogen, CF ₃ , or CH, or

R ¹¹ and R ¹² and R ^14, and R ^{1 S} together 4 or 5 methylene groups, of which one _CH2 ~ group can be replaced by oxygen, S, NH, N-CH _a or N-benzyl, or

R ^11, R ^12, R ^14, and R ^{1 S,} independently of one another H,

R ³ -OR ²² or -NR ²³ R ^24,

R ²² and R ²³ independently of each other a -CH - (C -C) -heteroaryl group which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a CF ₃ group, a CH ₃ group, a methoxy group , hydroxyl, amino, methylamino and dimethylamino, b is zero, 1 or 2,

R ²⁴ hydrogen, CH ₃ or CF ₃ ,

or

R ³ and R ⁴ independently of one another is F, Cl, Br, I, CN, (Xa) _(J ^ ^c 2 that ^H (i + 1, or - (X b) - (CH) -CF (Xa) an oxygen atom, a sulfur atom or NR ³³ , R ³³ a hydrogen atom, a C 1 -C 4 alkyl group or a C 1 -C 4 perfluoroalkyl group, dg zero (Xb) an oxygen atom, a sulfur atom or a NR ³⁴ , R ³⁴ hydrogen atom, a C 1 -C 4 alkyl group or a C 1 -C 4 perfluoroalkyl group, dh zero will give 1 2 3 4 db zero de 1 2 3 4

or

NR ³ R ^{4 O} R ⁴¹ or (Xe) - _{(CH2) t>} ^R4S,

R ⁴ and R ⁴¹ independently of one another are H, alkyl having 1 to 8 carbon atoms, perfluoroalkyl of 1 to 8 carbon atoms, or (CH ^ R ^42, e is zero, 1 or 2,

R ^{42 is} C 3 -C 7 cycloalkyl, phenyl which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, CF ₃ group, methyl group, methoxy group and NR ⁴³ R ⁴⁴ ,

R ⁴³ and R ¹⁴ independently of one another, H, CF ₃ or CH _3, or

R ⁴ ° and R ^4X together 4 or 5 methylene groups of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH ₃ group or an N-benzyl group, (Xe) an oxygen atom, a sulfur atom or NR ^4V ,

R ( ⁴⁾ is hydrogen, (C1-C4) -alkyl or CF _(a ) or zero, 1 or 2,

R ^{45 is} C 3 -C 7 cycloalkyl or phenyl which is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, CF ₃ group, methyl group, methoxy group,

pins, ^SO NR R ^SX and - (Xfa) - _{(CH2) EEI} - (XFB) R ^{4 S,} (Xfa) CH 2, O, S or nr ^4S , (XFB) oxygen atom, sulfur atom, NR ⁴ ®, ed 1 or 2, R ^4e hydrogen atom; 4 ató carbon or CF ₃

R ^4e, R ^49, R ^a and R ^5x independently is hydrogen, alkyl of 1 to 4 carbon atoms or CF _3, and their pharmaceutically-acceptable salts thereof.

The heteroaryl group having 1 to 9 carbon atoms means in particular radicals derived from a phenyl or naphthyl group in which one or more CH-groups are replaced by a nitrogen atom and / or in which at least two adjacent CH-groups (in the formation of a five-membered group) aromatic ring) replaced by a sulfur atom, an NH group or an oxygen atom. Further, one or both of the condensation site of the bicyclic moiety (as in the indolizinyl moiety) may be nitrogen atoms.

Suitable heteroaryl groups are, in particular, furanyl, thienyl, pyrrole, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrazinyl, pyrimidinyl, pyrimidinyl an indolyl group, an indazolyl group, a quinolyl group, an isoquinolyl group, a phthalazinyl group, a quinoxazolinyl group, a cinolinyl group, a quinazolinyl group.

Where it said one of R ^x and ^R one or more asymmetric centers, these can have the S or R configuration well. The compounds may be in the form of optical isomers, diastereomers, racemates or mixtures thereof.

Said alkyl groups and perfluoroalkyl groups may be straight or branched.

The invention further relates to a process for the preparation of compounds of the formula I, which process comprises the preparation of compounds of the formula II

in which

R ¹ and ^R are defined above, and

L represents a weak nucleophilically substituted leaving group, reacted with guanidine.

Activated acid derivatives of the formula II in which L is alkoxy, preferably methoxy, phenoxy, phenylthio, methylthio, 2-pyridylthio, nitrogen heterocycle, preferably 1-imidazolyl, are obtained in a known manner from carboxylic acid chlorides (formula II) , L = Cl), which in turn can be prepared in known manner from carboxylic acids (formula II, L = OH), for example by reaction with thionyl chloride. In addition to the carboxylic acid chlorides of formula II (L = Cl), other activated acid derivatives of formula II can be prepared in a known manner directly from benzoic acid derivatives (formula II, L = OH), such as methyl esters of formula II with L = OCH ₃ by treatment with gaseous hydrogen chloride in methanol, imidazolides of formula II by carbonyldiimidazole (L = 1-imidazolyl, Staab, Angew, Chem. Int. Ed. Engl. 1, 351-367 (1962)), mixed anhydrides of formula II by Cl- COOC ₂ H _with or tosyl chloride in the presence of triethylamine in an inert solvent, as well as activation of benzoic acids with dicyclohexylcarbodiimide (DCC) or O - ((cyano (ethoxycarbonyl) methylene) amino) -1,1,3,3-tetramethyluronium tetrafluoroborate (”TOTU) Proceedings of the 21st European Peptide Symposium, Peptides 1990, Editors E. Giralt and D. Andreu, Escom, Leiden, 1991).

In J. March, Advanced Organic Chemistry, Third Edition (John Wiley and Sons, 1985), p. 350, reference is made to a number of suitable methods for making activated carboxylic acid derivatives of formula II with reference to the literature.

The reaction of the activated carboxylic acid derivative of the formula II with guanidine is carried out in a known manner in a protic or aprotic polar but inert organic solvent. Methanol, isopropanol or THF at a temperature between 20 ° C and the boiling point of these solvents have proven useful in the reaction of methyl benzoate (formula II, L = OMe) with guanidine. Most of the reactions of the compounds of formula II with guanidine without salts are preferably carried out in inert solvents such as THF, dimethoxyethane or isopropanol. Water may also be used as the solvent.

If L = C1, the addition of an acid-binding agent, e.g. in the form of excess guanidine to bind hydrohalic acid.

Introduction of substituted sulfur, oxygen, or nitrogen nucleophiles is accomplished by nucleophilic substitution methods on the aromatic hydrocarbon. Halides and trifluoromethanesulfonates have proven to be suitable as leaving groups in this substitution. Preferably, the reaction is carried out in a dipolar aprotic solvent such as DMF or TMU at a temperature ranging from 0 ° C to the boiling point of the solvent, preferably between 80 ° C and the boiling point of the solvent. The alkali metal salt or alkaline earth salt with an anion of high alkalinity and low nucleophilia such as K ₂ CO ₃ is preferably used as the acid-binding agent.

The introduction of alkyl or aryl substituents is well known in the literature by known methods of cross-linking aryl halides with, for example, organic zinc compounds, organic tin compounds, organic boron acids, or palladium-mediated organic borates.

The benzoylguanidines of formula I are generally weak bases and can bind acids in salt formation. Suitable acid addition salts are salts of all pharmacologically acceptable acids, for example halides, in particular hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates, p-toluenesulfonates.

The compounds of formula I are substituted acylguanidines.

The most prominent representative of the acylguanidines is the pyrazine derivative amiloride, a non-potassium loss inducing diuretic used in medicine. A number of other amiloride-type compounds such as dimethylamiloride or ethylisopropylamiloride are described in the literature.

NH

NH ₂ amiloride: R ', R''= H dimethylamiloride: R', R * '= CH ₃ ethylisopropylamiloride: R' = C ₂ H _s , R '' = CH (CH ₃ ) ₂

In addition, experiments have been reported which show the antiarrhythmic properties of amiloride (Circulation 79, 1257-1263 (1989)). However, its widespread use as antiarrhythmics is hampered by the fact that this effect is only slightly pronounced and is accompanied by lowering blood pressure and leaching salts, and that these side effects are undesirable in the treatment of cardiac rhythm disorders.

Evidence of the antiarrhythmic properties of amiloride has also been obtained in experiments on isolated animal hearts (Eur. Heart J. 9 (suppl. 1); 167 (1988), book of abstracts). For example, it has been found in rat hearts that artificially induced ventricular fibrillation can be completely suppressed by amiloride. Even more potent in this model was the above amiloride derivative ethylisopropylamiloride.

U.S. Pat. No. 3,780,027 discloses acylguanidines which are structurally similar to the compounds of Formula I and which are derived from commercially available loop diuretics such as bumetanide. These compounds are said to have a potent salt secretion effect.

The compounds of the invention have unexpectedly no undesirable and disadvantageous saliduretic properties but have very good antiarrhythmic properties. They are therefore well suited for the treatment of conditions such as occur, for example, in the absence of oxygen. Due to their pharmacological properties, these compounds are extremely useful as antiarrhythmic drugs with a cardioprotective component for the prophylaxis of infarction and for the treatment of infarction as well as for the treatment of angina pectoris, while also suppressing or severely reducing preventive pathophysiological processes in ischemic-induced damage, in particular cardiac arrhythmias. Because of their protective effects against pathological hypoxic and ischemic situations, the compounds of the formula I can be used as medicaments for the treatment of all acute and chronic ischemia-induced lesions or primary or secondary-induced diseases due to inhibition of the cellular Na * / H * exchange mechanism. . This applies to their use as medicaments for surgical procedures, for example in organ transplants, which compounds may be used as protection of organs in the donor before or during collection, for protection of organs taken, for example, in saline or saline, and when transferred to the recipient organism. The compounds of the invention are also valuable, protective-acting drugs in performing angioplastic procedures, for example, on the heart as well as on peripheral vessels. Because of their protective effect against ischemic induced damage, the compounds of the invention are also useful as medicaments for the treatment of ischemia of the nervous system, in particular of the central nervous system, e.g. suitable for the treatment of stroke or brain edema. In addition, the compounds of the formula I according to the invention are also suitable for the treatment of various types of shock, such as allergic, cardiogenic, hypovolaemic and bacterial.

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 the formula I are suitable as valuable drugs for diseases in which cell proliferation is a primary or secondary cause and can therefore be used as anti-atherosclerotic agents, anti-later complications of diabetes, cancer, fibrotic diseases such as lung fibrosis, liver fibrosis or kidney fibrosis, hypertrophy and hyperplasia of organs, especially in hyperplasia or hypertrophy of the prostate.

The compounds of the invention are potent inhibitors of the cellular sodium proton antiporter (Na * / H * -exchanger), which is elevated in many diseases (essential hypertonia, atherosclerosis, diabetes, etc.) even in cells readily accessible to measurements such as erythrocytes , thrombocytes or leukocytes. The compounds of the invention are therefore suitable as excellent and simple scientific tools, especially when used as a diagnostic means for the determination and differentiation of certain types of hypertonia, but also atherosclerosis, diabetes, proliferative diseases, etc. In addition, the compounds of formula (I) are suitable for preventive treatment to prevent the development of high blood pressure, such as essential hypertonia.

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

Which excipients are suitable for the desired drug form is well known to those skilled in the art on the basis of their expert knowledge. In addition to solvents, gelling agents, suppository bases, tablet excipients and other active compound carriers, for example, antioxidants, dispersants, emulsifiers, antifoams, flavoring agents, preservatives, solubilizers or colorants can be used.

For oral use, the active compounds are admixed with suitable excipients, such as carriers, stabilizers or inert diluents, and formulated in a convenient dosage form, such as tablets, dragees, capsules, aqueous, alcoholic or oily solutions, by conventional methods. As an inert carrier, gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, in particular corn starch, can be used. The preparation can be in the form of both dry granules and 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, optionally together with substances usually used for this purpose, such as solubilizers, emulsifiers or other excipients, are brought into solution, suspension or emulsion. Suitable solvents are, for example, water, saline or alcohols, e.g. ethanol, propanol, glycerin, in addition also a sugar solution such as glucose or mannitol solution, but also a mixture of the various solvents mentioned.

Suitable pharmaceutical preparations for application in the form of aerosols or sprays are e.g. solutions, suspensions or emulsions of the active compound of the formula I in a pharmaceutically acceptable solvent, such as, in particular, ethanol or water or a mixture of these solvents. If desired, the formulation may also contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a carrier gas. Such a preparation usually contains the active compound in a concentration of about 0.1 to 10, in particular about 0.3 to 3% by weight.

The dosage of the active compound of the formula I to be administered and how often it is to be administered depends on the efficacy and duration of action of the compounds used, in addition on the type and severity of the disease to be treated and on sex, age, weight and from the individual's access to treatment.

On average, the daily dose of a compound of Formula I in a patient weighing about 75 kg is at least 0.001 mg, preferably 0.01 mg to 10 mg, preferably 1 mg. In the event of an acute outbreak of the disease, such as immediately after a heart attack, higher doses may be required and, in particular, more frequently administered, e.g. up to 4 individual doses per day. Especially i.v. use, as in a heart attack patient at an intensive care station, up to 100 mg per day may be required.

The compounds of the formula I according to the invention, or their acceptable salts, can be prepared analogously to the examples given in the examples.

List of abbreviations

MeOH methanol

DMF N, N-dimethylformamide

TNU N, N, N ', N'-tetramethylurea

NBS N-bromosuccinimide

AIBN alpha, alpha-azo-bis-isobutyronitrile

E1 electron impact

DC1 desorption chemical ionization

RT room temperature

EE ethyl acetate

DIP diisopropyl ether

MTB methyl tert-butyl ether mp melting point

HEP

DME n-heptane dimethoxyethane

FAB fast atom bombardment CH C1 2 2 THF dichloromethane tetrahydrofuran eq ES equivalent electrospray ionization Me methyl et ethyl Bn benzyl ZNS central nervous system Brine saturated aqueous sodium chloride solution

DETAILED DESCRIPTION OF THE INVENTION

General formula for the production of acylguanidines of the general formula

I

Variant A: from carboxylic acids of formula II (L = OH) eq. of a carboxylic acid derivative of the general formula

II is dissolved or suspended in 5 ml / mmol of anhydrous THF, then mixed with 1.1 eq of carbonyldiimidazole. It is stirred at room temperature for 2 hours and then 5 eq is added to the reaction solution. guanidine. Stir overnight, then THF is distilled off under reduced pressure (Rotavapor), water is added, pH is adjusted to 6-7 with 2N HCl and the corresponding acylguanidine of formula II is filtered off. The acylguanidines thus obtained can be converted into the corresponding salts by treatment with aqueous, methanolic or ethereal hydrochloric acid or other pharmacologically acceptable acids.

General formula for the production of acylguanidines of the formula I

Variant B: from alkyl carboxylic acid esters of formula II (L = O-alkyl) eq. of an alkyl ester of the carboxylic acid of the formula II as well as 5 eq. guanidine (free base) is dissolved in isopropanol or suspended in THF and refluxed (typical reaction time 2-5 hours) until complete reaction (thin layer chromatography control). The solvent was distilled off under reduced pressure (Rotavapor), taken up in EE and washed 3 times with sodium bicarbonate solution. It is dried over sodium sulphate, the solvent is distilled off in vacuo and chromatographed on silica gel using a suitable eluent, for example a 5: 1 mixture of ethyl acetate and methanol.

(For salt formation see variant A)

Example 1

2-Amino-4-chloro-5-sulfamoylbenzoylguanidine dihydrochloride was prepared according to variant B from the corresponding benzoic ester.

mp: 288-290 ° C

Example 2

2-Amino-4-chloro-5- (N-ethylsulfamoyl) benzoylguanidine dihydrochloride was prepared according to variant B from the corresponding benzoic acid ester.

mp 242 ° C

Example 3

2- (N-Butylamino) -4-chloro-5-sulfamoylbenzoylguanidine dihydrochloride was prepared according to variant B from the corresponding acid ester melting point: 286 ° C

Example 4

2- (N-ethylamino) -4-chloro-5-sulfamoylbenzoylguanidine dihydrochloride was prepared according to variant B from the corresponding benzoic acid ester.

mp 290 ° C

Example 5

2-Amino-5- (1-piperidyl) benzoylguanidine dihydrochloride was prepared according to variant B from the corresponding benzoic acid ester.

mp 170 ° C

Example 6

2-Amino-3-bromo-5-methylbenzoylguanidine dihydrochloride was prepared according to variant A from the corresponding benzoic acid.

mp> 300 ° C

Example 7

2-Amino-3-methylbenzoylguanidine dihydrochloride was prepared according to variant B from the corresponding benzoic acid ester.

mp> 270 ° C

Example 8

2-Amino-3,5-dichlorobenzoylguanidine dihydrochloride was prepared according to variant A from the corresponding benzoic acid.

mp: 190 ° C

Example 9

2-Amino-5-chlorobenzoylguanidine dihydrochloride was prepared according to variant A from the corresponding benzoic acid.

m.p.> 390 ° C with decomposition = 0.27 (ethyl acetate)

Example 10

2-Amino-4,5-dimethoxybenzoylguanidine dihydrochloride was prepared according to variant A from the corresponding benzoic acid.

mp 177 ° C

Example 11

2-Amino-4,5-dibromobenzoylguanidine was prepared according to variant B from the corresponding benzoic acid methyl ester.

mp 158 ° C

Example 12

2-Dimethylamino-5-chlorobenzoylguanidine dihydrochloride was prepared according to variant B from the corresponding benzoic acid methyl ester.

mp: 135-145 ° C

Pharmacological data:

Inhibition of rabbit erythrocyte Na * / H * -exchanger

White New Zealand rabbits were given a standard diet of 2% cholesterol for six weeks to activate Na * / H * exchange so that a flame photometer could determine the supply of Na * to the erythrocytes via Na * / H * exchange. Blood was collected from the ear arteries and 25 IU potassium heparin was added to avoid clotting. A portion of each sample was used to duplicate the hemocrystalline assay by centrifugation. Aliquots of 100 μΐ were used to measure the initial Na * content in erythrocytes.

To determine amiloride-sensitive sodium intake, 100 μΐ of each blood sample was incubated at pH 7.4 and 37 ° C in 5 ml each of salt and sucrose hyperosmolar media (mmol / 1: 140 NaCl, 3 KCl, 150 sucrose, 0, 1 ouabain, 20 trishydroxymethylaminomethane). The erythrocytes were then washed three times with an ice solution of magnesium chloride and ouabain (mmol / 1: 112 MgCl ₂ , 0.1 ouabain) and hemolyzed in 2 ml of distilled water. The intracellular sodium content was determined by a flame photometer.

Net Na + feed was calculated from the difference between baseline sodium and sodium content in erythrocytes after incubation. The sodium supply, which can be inhibited by amiloride, resulted from the difference between the sodium content of erythrocytes after incubation with and without 3 x 10 ^-4 mol / l amiloride. The compounds of the invention have also been used in this manner.

The results

Inhibition of Na * / H * -exchanger

Example ^Ic _so (Mmol / 1)

1 2 to 3 9 1 to 2 11 0.1 12 1 to 2

Claims (17)

PATENT CLAIMS Ortho-amino-substituted benzoylguanidines of the general formula I in which they are R ¹ NR ^SO R ⁶ R ^a and R ^e, independently of one another hydrogen, alkyl having 1 to 8 carbon atoms or perfluoroalkyl of 1 to 8 carbon atoms, R ² , R ³ , R ' ¹ and R ⁵ independently of one another R ¹⁰ -SO-, R ¹² -R ¹² N-CO-, R ¹³ -CO- or R ¹⁴ R ³ - ^with N-SO and zero, 1 or 2, R ^10, R ^11, R ^13, R ^13, R ^14, and R ^{1 S} independently of one another alkyl having 1 to 8 carbon atoms, perfluoroalkyl of 1 to 8 carbon atoms, alkenyl having 3 to 6 carbon atoms or a -CH - R ^s, 2ato ato b is zero, 1, 2, 3 or 4, R ^{16 is} C 3 -C 7 cycloalkyl, phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, CF ₃ , methyl, methoxy or NR ¹⁷ R ^{1 S} , R ^xv and R ^{e are} independently hydrogen, CF or C 1 -C 4 alkyl, or R ^11, _R i = _a j _{as R} i4 _{and R} = l together 4 or 5 methylene groups, of which one CH ₂ -group can be replaced by O ,, by S, NH, N-CH ₃ group joining or N-benzyl, or R ( ¹¹⁾ , R ( ¹²⁾ , R ( ¹⁴⁾ and R ( ¹⁵⁾ independently of one another are hydrogen, or R ^2, R ^3, R ⁴ and R ^s independently of one SR ^2T, -OR ^22, -NR ²³ R ^24, or 31 ²⁵ ¢ ¾ ¾ ^{2-7 2,} R ^2X, R ^22, R ^23, and R ^{2 S} independently of the -CH- (C -C) -heteroaryl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, CF ₃ , CH ₃ , methoxy, hydroxyl, amino, methylamino and dimethylamino, b is zero, 1 or 2, R ( ²⁴⁾ , R ( ^2e) and R ^{( 27)} independently of one another are hydrogen, (C1-C4) alkyl or (C1-C4) perfluoroalkyl, or R ^2, R ^3, R ⁴ and R ^s independently of one another are H, F, Cl, Br, I, CN, - (Xa) - (Xb) ^ - _{(CH2) eie DTJ-C 2} F _<ae ^ _i , C3-C8 alkenyl or-C HR ³ °, (Xa) oxygen, sulfur or NR ³³ , R ( ³³⁾ is O, C1 -C4 alkyl or (C1 -C4) perfluoroalkyl, dg is zero or 1, (X b) O, S or NR ³⁴ ; R ( ³⁴⁾ is hydrogen, (C1-C4) alkyl or (C1-C4) perfluoroalkyl, dh is zero or 1, will give zero 1 2 μ, 4. 5 6, 7, 8 db zero 1 2 3 4. de zero 1 2 3 4. 5 6, 7, df zero I 2 3 4. R ^{3 is} C 3 -C 8 cycloalkyl, phenyl, biphenylyl or naphthyl, the phenyl, biphenylyl or naphthyl aromatic groups being unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, CF ₃ , methyl, methoxy and NR ³¹ R ³² , R ( ³¹⁾ , R ( ^{32) are} hydrogen, (C1-C4) alkyl or (C1-C4) perfluoroalkyl, or R ^2, R ^3, R ⁴ and R ^s independently NR ^{4 O} R ⁴¹ or - (Xe) - (CH _a) R ^{4 S} _EFA. R ⁴ and R ⁴¹ independently of one another are H, alkyl of 1 to 8 carbon atoms, perfluoroalkyl having up to 8 carbon atoms or (CH _{2) e} -R ^42, e is zero, 1, 2, 3 or 4, R ^{42 is} C 3 -C 7 cycloalkyl, phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, CF ₃ group, methyl group, methoxy group and NR ⁴³ R ⁴⁴ . R ( ⁴³⁾ and R ( ⁴⁴⁾ independently of one another are hydrogen, CF or C1 -C4 -alkyl _; or R ⁴ ° and R ⁴¹ together 4 or 5 methylene groups of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH ₃ group or an N-benzyl group, (Xe) an oxygen atom, an atom sulfur or NR ^4V , R ( ⁴⁾ is hydrogen, alkyl of 1 to 4 carbon atoms or perfluoroalkyl of 1 to 4 carbon atoms, or zero, 1, 2, 3 or 4, R ^{45 is} C 3 -C 7 cycloalkyl, phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, CF ₃ group, methyl group, methoxy group, NR ⁵⁰ R ^SX and - (Xfa) - _{(CH2) p <or} - (XFB) R ^46, Xfa is CH ₂ , oxygen, sulfur or NR ^4a , Xfb is oxygen, sulfur or NR ⁴⁹ , ed 1, 2, 3, 4, R ( ⁴⁶⁾ is hydrogen, alkyl of 1 to 4 carbon atoms or perfluoroalkyl of 1 to 4 carbon atoms, R ^4, R ^49, R ^a and R ^{with x} independently of one another are H or alkyl of 1 to 4 carbon atoms or perfluoroalkyl of 1 to 4 carbon atoms, wherein R ³ and R ⁴ but can not be hydrogen, and their pharmaceutically acceptable salts. Compounds of the general formula I according to claim 1, characterized in that they represent R ^x NR ⁵⁰ R ⁶ , R ⁵ and R ⁶ independently of one another are H, _CF3 or alkyl having 1 to 4 carbon atoms, R ² and R ⁵ is H, R ⁴ R ^x -SO-, R ^XX R ^{X 2} N -CO-, R ¹³ -CO-, or R ^{X 4} R ^XS N-SO-, and zero, 1 or 2, R ^x0 , R ^xx , R ^x2 , R ^x3 , R ^x4 and R ^x5 independently of one another are C 1 -C 8 alkyl, C 1 -C 8 perfluoroalkyl, C 3 -C 8 alkenyl or -CH - R ^xs , to 2ab and b to zero, 1, 2, 3 or 4, R ^{16 is a} C 3 -C 7 cycloalkyl group or a phenyl group which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a CF ₃ group, a methyl group, a methoxy group or NR ^{x in} R ^xa . R ^x and R ^x, independently of one another, H, _CF or C 1 -C 4 alkyl, or R ^xx and R ¹² as well as R ¹⁴ and R ^x together with 4 or 5 methylene groups, of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH ₃ group or an N-benzyl group, or R ^xx , R ^x2 , R ^x4 and R ^xs independently of one another also represent a hydrogen atom, R ^2X SR ^3, -OR ^23, -NR ^{23 »34} or -CR ^{2 S} R ²⁶ R ^23, R ^2X, R ^22, R ^23, and R ^{2 S} independently -CH - (C -C) -heteroaryl is 2to '19' ⁴ group which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, a chlorine atom, a CF ₃ group, a CH ₃ group, a methoxy group, a hydroxyl group, an amino group, a methylamino group and a dimethylamino group, b is zero, 1 or 2, R ^24, R ²⁶ and R ^{2 V} independently is H, alkyl of 1 to 4 carbon atoms or perfluoroalkyl having 1 to 4 carbon atoms, or R ³ and R ⁴ independently of one another is F, Cl, Br, I, CN, - (X) o CH, or that 2da + l ^{(X b)} ^ ^<CH JÄb- ^c <e ^F _{2 £ ä} C 3 -C 8 alkenyl or -CHR ³ °, (Xa) oxygen, sulfur or NR ³³ ; R ( ³³⁾ is hydrogen, (C1-C4) alkyl or (C1-C4) perfluoroalkyl, dg is zero, 1 (Xb) is oxygen, sulfur or NR ³⁴ , R ( ³⁴⁾ is hydrogen, (C1-C4) alkyl or (C1-C4) perfluoroalkyl, dh zero or 1, will give zero 1 2, 3, 4, 5, 6, 7 or db zero 1 2, 3 or 4 de zero I 2, 3, 4, 5, 6, or 7 df zero I 2, 3 or 4 r ₃ ° C 3 -C 8 cycloalkyl, phenyl, biphenylyl or naphthyl, the phenyl, biphenylyl or naphthyl aromatic groups being unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of fluorine, chlorine, CF ₃ , methyl, methoxy and NR ^3X R ³² , R ( ³⁾ and R ( ³²⁾ independently of one another are hydrogen, alkyl of 1 to 4 carbon atoms or perfluoroalkyl of 1 to 4 carbon atoms, or R ³ NR ⁴⁰ R ⁴¹ or (Xe) - (CH) R ^{4 S} , R ⁴ and R ⁴¹ independently of one another are H, alkyl having 1 to 8 carbon atoms, perfluoroalkyl of 1 to 8 carbon atoms or _{(CH2) q-R} ^42, e is zero, 1, 2, 3 or 4, R ^{42 is} C 3 -C 7 cycloalkyl, phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, CF ₃ group, methyl group, methoxy group and NR ⁴³ R ⁴⁴ , R ⁴³ and R ⁴⁴ independently of one another, H, _CF or C 1 -C 4 alkyl, or R ⁴ ° and R ⁴¹ together 4 or 5 methylene groups of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH ₃ group or an N-benzyl group, (Xe) an oxygen atom, an atom sulfur or NR ^4V , R ^{( 47)} is hydrogen, (C1-C4) alkyl or (C1-C4) fluoroalkyl, or zero, 1, 2, 3 or 4, R ^{45 is} C 3 -C 7 cycloalkyl, phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, CF ₃ group, methyl group, methoxy group, NR ^SO R ^S1 and - (Xfa) - (CH2) eei- (XFB) R ^46, (Xfa) is CH2, O, S or NR ^4, (XFB) O, S or NR ^43, ed 1, 2, 3 or 4, R ( ⁴⁶⁾ is hydrogen, alkyl of 1 to 4 carbon atoms or perfluoroalkyl of 1 to 4 carbon atoms, R ^4, R ^49, R ^a and R ^S1, independently of one another are H, alkyl having 1 to 4 carbon atoms or perfluoroalkyl having 1 to 4 carbon atoms. Compounds of formula (I) according to claims 1 and 2, characterized in that they are R ¹ R ² NR ^so R ^e R ^a and R @ ⁶ independently of one another H or and ^R R ⁴ is H, R ^xo -SO ^XX R R ^{X 2} N-CO-, R-CO- or ^{X 3 X 4} R N R ^X is -SO ^ 2 R ^xx , R ^x2 , R ^x3 , R ^x4 and R ^xs independently of one another are C 1 -C 4 alkyl, perfluoroalkyl carbon or -CH-R ato 2 a. to zero, rl · or 2, and R ^{x 0} , group with 1 16, up to atoms of ab R ¹⁶ which is not 1 to 3 phenyl, or substituted with a group consisting of a chlorine atom, a CF ₃ group, a methyl toxic group and NR ^{x in} R ^xa , R ^xv and R ^xa independently of each other are hydrogen, substituted with substituents. F, atóskupiny, meskupinu _CF or CH, 3 'or R ^xx and R ^X2 and R ^14, and R ^{1 S} together 4 or 5 methylene groups, one CH _{and the} A group may be replaced by S, NH, benzylic group or of which by O, N or CH-N 3 R ^xx , R ^X2 , R ¹⁴ and R ^xs independently of one another -OR ²² or -NR ²³ R ²⁴ , R ²² _and R ²³ independently of one another which is with 1 to 3 melting R ³ is H, -CH - (C -C) -heteroaryl substituted or substituted with substituents selected from the group consisting of fluorine atom, chlorine atom, CF _a , CH ₃ , methoxy, hydroxyl, amino, methylamino and dimethylamino, b is zero, 1 or 2, R ²⁴ is H, CH ₃ or CF _3, or R ³ and R ⁴ independently of one another is F, Cl, Br, I, CN, - (X) ^ -C _g H _{that 2da + L} and - (X b) - (CH) -CF (X ) an oxygen atom, a sulfur atom or NR ³³ , R ( ³³⁾ is hydrogen, (C1-C4) alkyl or (C1-C4) perfluoroalkyl, dg is zero, (Xb) is oxygen, sulfur or NR ³⁴ , R ( ³⁴⁾ is hydrogen, (C1-C4) -alkyl or (C1-C4) perfluoroalkyl, dh zero will give 1, 2, 3 4. db zero de 1, 2, 3 4. or NR ³ R ^{4 O} or R ^4X (Xe) - _{(CH2) ato} R ^45, R ( ⁴ ) and R ( ^4X) independently of one another are hydrogen, alkyl of 1 to 8 carbon atoms, perfluoroalkyl of 1 to 8 carbon atoms or (CH) -R ⁴² , zero, 1 or 2, R ^{42 is} C 3 -C 7 cycloalkyl, phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, CF ₃ group, methyl group, methoxy group and NR ⁴³ R ⁴⁴ . R ⁴³ and R ⁴⁴ independently of one another, H, CF ₃ or CH _3, or R ⁴ ° and R ^4X together 4 or 5 methylene groups of which one CH 4 group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH ₃ group or an Nbenzyl group, (Xe) an oxygen atom, a sulfur atom or NR ⁴⁷ , R ⁴⁷ is H, alkyl of 1 to 4 carbon atoms or CF _3, eb is zero, 1 or 2, R ^{4 S is a} C 3 -C 7 cycloalkyl group or a phenyl group which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, CF _a , methyl, methoxy- pins, NR R ^{S1 SO,} and - (Xfa) - _{(CH2) ECI} - (XFB) R ^46, (Xfa) CH ₂ , oxygen, sulfur or NR ⁴³ , (XFB) oxygen atom, sulfur atom, NR ⁴³ , ed 1 or 2, R ⁴⁶ a hydrogen atom, a (1-4C) alkyl group carbon or CF ₃ R ⁴³ , R ^43, R ^a and R ^S1 independently of one another a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a CF group. A process for the preparation of a compound of formula (I) according to claim 1, characterized in that the compound of formula (II) in which R ¹ and ^R are defined above, and L represents a weak nucleophilically substitutable leaving group, reacted with guanidine and optionally converted to a pharmaceutically acceptable salt. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment of arrhythmias. 6. A method for the treatment of arrhythmias which comprises admixing an effective amount of a compound of formula (I) according to claim 1 with conventional additives and administering it in a suitable dosage form. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of a heart attack. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of angina pectoris. Use of a compound of 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 of stroke. 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 peripheral organs and limbs. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment of shock conditions. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for use in surgical operations and organ transplants. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the preservation and storage of transplants for surgical purposes. Use of a compound of the formula I according to claim 1 for the manufacture of a medicament for the treatment of diseases in which cell proliferation is a primary or secondary cause and thus its use as an anti-atherosclerotic, anti-diabetic later complication, cancer, fibrotic diseases such as lung fibrosis, fibrosis liver or kidney fibrosis, prostatahyperplasia. Use of a compound of formula (I) according to claim 1 for the manufacture of a scientific means for inhibiting Na @ + / l @ + exchanger, for the diagnosis of hypertonia and proliferative diseases. A medicament comprising an effective amount of a compound of Formula 1 according to claims 1 to 3.