OA13285A - Pentafluorosulfanyl benzoylguanidines, method for their production, their use as medicaments or diagnostic agents and medicament containing the same. - Google Patents

Abstract

The invention relates to pentafluorosulfanyl benzoylguanidines of formula (I), in which R1 to R4 are defined as cited in the claims. Said substances are suitable for use as anti-arrhythmic medicaments comprising cardio-protective components for the prophylaxis and treatment of infarcts, in addition to the treatment of angina pectoris. They also preventatively inhibit the pathophysiological events that occur during ischaemically induced traumas, in particular during the triggering of ischaemically induced cardiac arrhythmia.

Description

1 3285

Pentafluorosulfanyl benzoylguanidines, method for their production, theiruse as médicaments or diagnostic agents and médicament containing thesame

Pentafluorosulfanylbenzoylguanidines of the formula l

in which R1 to R4 hâve the meanings indicated in the daims, and thepharmaceutically acceptable salts thereof are substituted acylguanidinesand inhibit the cellular sodium-proton antiporter (Na+/H+ exchanger, NHE).

Because of the NHE-inhibitory properties, the compounds of the formula Iand the pharmaceutically acceptable salts thereof are suitable for theprévention and treatment of diseases caused by activation or activatedNHE, and of diseases caused secondarily by the NHE-related damage.

Compared with known compounds, the compounds of the invention aredistinguished by an extremely high activity in the inhibition of Na+/H+ exchange, and by improved ADMET properties. The xenobiotic structure (inparticular the introduction of the rather “unnatural/manmade” SF5substituents) advantageously influences tissue distribution. This leads interalia to increased exposures in vivo. This involves no signifîcant influence onthe absorption characteristics, and the high bioavailability of theacylguanidines is retained.

In contrast to some acylguanidines described in the literature, thecompounds of the formula I described herein and their pharmaceutically 2 13285 acceptable salts show no unwanted and disadvantageous salidureticproperties.

The invention relates to pentafluorosulfanylbenzoylguanidines of theformula I

in which R1 is hydrogen, alkyl having 1,2, 3 or 4 carbon atoms, alkoxy having 1,2, 3 or 4 carbon atoms, F, Cl, Br, I, -CN, NR5R6, -Op-(CH2)n- (CF2)O-CF3 or-(SOm)q -(CH2)r(CF2)s-CF3; R5 and R6 are, independently of one another, hydrogen, alkylhaving 1,2, 3 or 4 carbon atoms or-CH2-CF3; m is zéro, 1 or 2n, o, p, q, r and s are, independently of one another, zéro or 1; R2 is hydrogen, alkyl having 1,2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, I, -CN, NR7R8,-Ot-(CH2)U-(CF2)V-CF3 or -(SOw)x-(CH2)y-(CF2)z-CF3; R7 and R8 are, independently of one another, hydrogen, alkylhaving 1,2, 3 or 4 carbon atoms or -CH2-CF3; w is zéro, 1 or 2t, u, v, x, y and z are, independently of one another, zéro or 1; 3 1 3285 R3 is Cl, Br, I, -CN, -SO2CH3, alkoxy having 1,2, 3 or 4 carbon atoms, NR9R10, -Oa-(CH2)b-(CF2)c-CF3, -(SOd)e-(CH2>(CF2)g-CF3, alkylhaving 1,2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6,7 or 8 carbon atoms, in which 1,2, 3 or 4 hydrogen atoms may bereplaced by fluorine atoms; R9 and R10 are, independently of one another, hydrogen, alkyihaving 1,2, 3 or 4 carbon atoms or -CH2-CF3; a, b and c are, independently of one another, zéro or 1 ;d is zéro, 1 or 2; e iszeroorl; f is zéro, 1, 2, 3 or 4; g is zéro or 1 ; or R3 is -(CH2)h-phenyl or -O-phenyl, in which the phenyl radicals are unsubstituted or substituted by 1, 2or 3 radicals selected from the group consisting of F, Cl, Br, I,-Oj-(CH2)k-CF3, alkoxy having 1,2, 3 or 4 carbon atoms, alkyl having 1,2, 3 or 4 carbon atoms and -SO2CH3; j iszeroorl; k is zéro, 1,2 or 3; h is zéro, 1,2, 3 or 4;or R3 is -(CH2)aa-heteroaryl, which is unsubstituted or substituted by 1,2 or 3 radicals selectedfrom the group consisting of F, Cl, Br, I, -Obb-(CH2)cc-CF3, alkoxyhaving 1,2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbonatoms and -SO2CH3; bb is zéro or 1 ;is zéro, 1, 2 or 3; cc 1 3285 aa is zéro, 1,2, 3 or 4; R4 is hydrogen, F, Cl, Br, I, -CN, -SO2CH3, alkoxy having 1,2, 3 or 4 carbon atoms, NR11R12, -Odd-(CH2)ee-(CF2>CF3; -(SOgg)hh- (CH2)jj-(CF2)kk-CF3, alkyl having 1,2, 3, 4, 5 or 6 carbon atoms orcycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, in which 1, 2, 3 or 4hydrogen atoms may be replaced by fluorine atoms; R11andR12 are, independently of one another, hydrogen, alkylhaving 1, 2, 3 or 4 carbon atoms or -CH2-CF3; dd, ee and ff are, independently of one another, zéro or 1 ;gg is zéro, 1 or 2;hh is zéro or 1 ;jj is zéro, 1,2, 3 or 4;kk is zéro or 1 ; or R4 is -(CH2)n-phenyl or -O-phenyl, in which the phenyl radicals are unsubstituted or substituted by 1,2or 3 radicals selected from the group consisting of F, Cl, Br, I,-Omrrr(CH2)nn-CF3, alkoxy having 1,2, 3 or 4 carbon atoms, alkylhaving 1,2, 3 or 4 carbon atoms and -SO2CH3; mm is zéro or 1 ;nn is zéro, 1,2 or 3;

Il is zéro, 1, 2, 3 or 4;or R4 is -(CH2)oo-heteroaryl, which is unsubstituted or substituted by 1,2 or 3 radicals selectedfrom the group consisting of F, Cl, Br, I, -OpP-(CH2)rrCF3, alkoxyhaving 1,2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbonatoms and -SO2CH3; 1 3285 5 ρρ is zéro or 1 ;rr is zéro, 1,2 or 3; oo is zéro, 1, 2, 3 or 4;and the pharmaceuticaliy acceptable salts thereof.

Preference is given to compounds of the formula I, in which the meaningsare: R1 hydrogen, alkyl having 1,2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, I, -CN, NR5R6,-Op-(CH2)n-(CF2)o-CF3 or -(SOm)q-(CH2)r(CF2)s-CF3; R5 and R6 independently of one another hydrogen, alkylhaving 1,2, 3 or 4 carbon atoms or -CH2-CF3; m zéro,1 or 2η, o, p, q, r and s independently of one another zéro or 1 ; R2 hydrogen or F; R3 Cl, Br, I, -CN, -SO2CH3, alkoxy having 1,2, 3 or 4 carbon atoms,NR9R10, -Oa-(CH2)b-(CF2)c-CF3, -(SOd)e-(CH2)f-(CF2)g-CF3, alkylhaving 1,2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, in which 1, 2, 3 or 4 hydrogen atoms may bereplaced by fluorine atoms; R9 and R10 independently.of one another hydrogen, alkyl having 1,2, 3 or 4 carbon atoms or -CH2-CF3; a, b and c independently of one another zéro or 1 ;d zéro, 1 or 2; e zéro or 1 ; f zéro, 1, 2, 3 or 4; g zéro or 1 ; or 6 13285 R3 -(CH2)h-phenyl or-O-phenyl, in which the phenyl radicals are unsubstituted or substituted by 1,2or 3 radicals selected from the group consisting of F, CI, Br, I,-Oj-(CH2)k-CF3, alkoxy having 1,2, 3 or 4 carbon atoms, alkyl having 1,2, 3 or 4 carbon atoms and -SO2CH3;j zéro or 1 ; k zéro, 1,2 or 3; h zéro, 1,2, 3 or 4;or R3 -(CH2)aa_heteroaryl, which is unsubstituted or substituted by 1,2 or 3 radicals selectedfrom the group consisting of F, Cl, Br, I, -Obb-(CH2)cc-CF3, alkoxyhaving 1,2, 3 or 4 carbon atoms, alkyl having 1,2, 3 or 4 carbonatoms and -SO2CH3; bb zéro or 1 ; cc zéro, 1,2 or 3; aa zéro, 1, 2, 3 or 4; R4 hydrogen or F; and the pharmaœutically acceptable salts thereof.

Particular preference is given to compounds of the formula I, in which themeanings are: R1 hydrogen, alkyl having 1,2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, I, -CN, NR5R6, -O-CH2-CF3 or -(SOm)q-(CH2)r-CF3; R5 and R6 independently of one another hydrogen, alkylhaving 1,2, 3 or 4 carbon atoms or-CH2-CF3; m zéro, 1 or 2q and r independently of one another zéro or 1 ; 7 1 3285 R2 hydrogen or F; R3 Cl, Br, I, -CN, -SO2CH3, alkoxy having 1,2, 3 or 4 carbon atoms, NR9R10, -O-CH2-CF3, -(SOd)e-CF3, alkyl having 1,2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, inwhich 1,2, 3 or 4 hydrogen atoms may be replaced by fluorineatoms; R9 and R10 independently of one another hydrogen, alkyl having 1,2, 3 or 4 carbon atoms or-CH2-CF3; d zéro, 1 or 2; e zéro or 1; or R3 phenyl, which is unsubstituted or substituted by 1,2 or 3 radicals selectedfrom the group consisting of F, Cl, Br, I, -Oj-(CH2)k-CF3, alkoxyhaving 1, 2, 3 or 4 carbon atoms, alkyl having 1,2, 3 or 4 carbonatoms and -SO2CH3; j zéro or 1 ; k zéro, 1,2 or 3; R3 heteroaryl, which is unsubstituted or substituted by 1,2 or 3 radicals selectedfrom the group consisting of F, Cl, Br, I, -Obtr(CH2)cc-CF3, alkoxyhaving 1,2, 3 or 4 carbon atoms, alkyl having 1,2, 3 or 4 carbonatoms and -SO2CH3; bb zéro or 1 ; cc zéro, 1,2 or 3; R4 hydrogen or F; and the pharmaceutically acceptable salts thereof.

Very particular preference is given to compounds of the formula I in which the meanings are: 8 13285 R1 hydrogen, alkyl having 1,2, 3 or 4 carbon atoms, methoxy, ethoxy,F, Cl, NR5R6, -O-CH2-CF3 or-(SOm)q-(CH2)rCF3; R5 and R6 independently of one another hydrogen, alkyl having 1,2, 3 or 4 carbon atoms or -CH2-CF3; m zéro, 1 or 2q and r independently of one another zéro or 1 ; R2 hydrogen or F; R3 Cl, -CN, -SC>2CH3, methoxy, ethoxy, NR9R10, -O-CH2-CF3,-(SOd)e-CF3, alkyl having 1,2, 3,4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, in which 1,2, 3 or 4hydrogen atoms may be replaced by fluorine atoms; R9 and R10 independently of one another hydrogen, methyl, ethylor-CH2-CF3; d zéro, 1 or 2; e zéro or 1 ; or R3 phenyl, which is unsubstituted or substituted by 1 or 2 radicals selectedfrom the group consisting of F, Cl, -Oj-(CH2)k-CF3, methoxy, ethoxy, alkyl having 1,2, 3 or 4 carbon atoms and -SC>2CH3;j and k independently of one another zéro or 1 ;or R3 heteroaryl, which is unsubstituted or substituted by 1 or 2 radicals selected fromthe group consisting of F, Cl, -Obb-(CH2)Cc-CF3, methoxy, ethoxy,alkyl having 1,2, 3 or 4 carbon atoms and -SO2CH3; bb and cc 13285 y independently of one another zéro or 1 ; R4 hydrogen or F; and the pharmaceutically acceptable salts thereof.

In one embodiment, preference is given in this connection to thecompounds of the formula l in which R1 is described by hydrogen, alkylhaving 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, I, -CN, NR5R6, where R5 and R6 are, independently of oneanother, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH2-CF3, or -O-CH2-CF3 or -(SOn)q-(CH2)rCF3, where m is zéro, 1 or 2, and q and rare, independently of one another, are zéro or 1; particular preference isgiven to compounds in which RI is described by hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, methoxy, ethoxy, F, Cl, NR5R6, where R5 and R6,are independently of one another, hydrogen, alkyl having 1, 2, 3, or 4carbon atoms or -CH2-CF3, -O-CH2-CF3 or -(SOm)q-(CH2)rCF3, where mis zéro, 1 or 2, and q and r are, independently of one another, zéro or 1;very particular preference is given to compounds in which R1 is describedby hydrogen, methyl, ethyl, CF3-CH2-O-, F, Cl or CF3. In a furtherembodiment, preference is given to compounds in which R1 is describedby hydrogen, methyl or ethyl, in particular methyl or ethyl.

In a further embodiment, preference is given to compounds of the formula Iin which R2 is described by hydrogen or F; particular preference is given tocompounds in which R2 is described by hydrogen.

In a further embodiment, preference is given to compounds of the formula Iin which R3 is described by Ci, -CN, -SO2CH3, methoxy, ethoxy, NR9R10,where R9 and R10 are, independently of one another, hydrogen, methyl,ethyl or -CH2-CF3, or -O-CH2-CF3, -(SO<j)e-CF3, where d is zéro, 1 or 2, and e is zéro or 1, alkyl having 1,2, 3, 4, 5 or 6 carbon atoms or cycloalkylhaving 3, 4, 5, 6 or 7 carbon atoms, in which 1,2, 3 or 4 hydrogen atomsmay be replaced by fluorine atoms, phenyl which is unsubstituted or 1 3285 10 substituted by 1,2 or 3 radicals selected from the group consisting of F, CI,Br, I, -Oj-(CH2)k-CF3, where j is zéro or 1 and k is zéro, 1,2 or 3, alkoxyhaving 1,2, 3 or 4 carbon atoms, alkyl having 1,2, 3 or 4 carbon atomsand -SO2CH3, or heteroaryl which is unsubstituted or substituted by 1, 2 or3 radicals selected from the group consisting of F, Cl, Br, I, -Obtr (CH2)cc-CF3, where bb is zéro or 1 and cc is zéro, 1,2 or 3, alkoxy having1,2, 3 or 4 carbon atoms, alkyl having 1,2, 3 or 4 carbon atoms and-SO2CH3; particular preference is given to compounds in which R3 is described by Cl, -CN, -SO2CH3, methoxy, ethoxy, NR9R10, where R9 andR10 are, independently of one another, hydrogen, methyl, ethyl or-CH2-CF3, or -O-CH2-CF3, -(SOd)e-CF3, where d is zéro, 1 or 2, and e iszéro or 1, alkyl having 1,2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3,4, 5, 6 or 7 carbon atoms, in which 1,2, 3 or 4 hydrogen atoms may bereplaced by fluorine atoms, phenyl which is unsubstituted or substituted by1-2 radicals selected from the group consisting of F, Cl, -Oj-(CH2)k-CF3, where j and k are, independently of one another, zéro or 1, methoxy,ethoxy, alkyl having 1,2, 3 or 4 carbon atoms and -SO2CH3, or heteroarylwhich is unsubstituted or substituted by 1-2 radicals selected from thegroup consisting of F, Cl, -Obb-(CH2)cc-CF3, where bb and cc are,independently of one another, zéro or 1, methoxy, ethoxy, alkyl having 1,2,3 or 4 carbon atoms and -SO2CH3; very particular preference is given tocompounds in which R3 is described by Cl, -CN or -SO2CH3.

In a further embodiment, preference is given to compounds of theformulae I in which R4 is described by hydrogen and F, with particularpreference for compounds in which R4 is described by hydrogen.

In a further embodiment, preference is given to compounds of the formula Iin which p, t, a and dd are, independently of one another, 1. 11 1 3285

If the substituents R1 to R4 contain one or more centers of asymmetry,these may independently of one another hâve both the S and the Rconfiguration. The compounds may be in the form of optical isomers, ofdiastereomers, of racemates or of mixtures thereof.

The présent invention encompasses ail tautomeric forms of the compoundsof the formula I.

Alkyl radicals may be straight-chain or branched. This also applies if theycarry substituents or occur as substituents of other radicals, for example influoroalkyl radicals oralkoxy radicals. Examples of alkyl radicals aremethyl, ethyl, n-propyl, isopropyf(= 1-methylethyl), n-butyl, isobutyl (= 2-methylpropyl), sec-butyl (= 1-methylpropyl), tert-butyl (= 1,1-dimethylethyl),n-pentyl, isopentyl, tert-pentyl, neopentyl and hexyl. Preferred alkyl radicalsare methyl, ethyl, n-propyl and isopropyl. One or more, for example 1, 2, 3,4 or 5, hydrogen atoms in alkyl radicals may be replaced by fluorine atoms.Examples of such fluoroalkyl radicals are trifluoromethyl, 2,2,2-trifluoroethyland pentafluoroethyl. Substituted alkyl radicals may be substituted in anypositions. Examples of cycloalkyl radicals are cyclopropyl, eyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. One or more, for'example1, 2, 3 or 4, hydrogen atoms in cycloalkyl radicals may be replaced byfluorine atoms. Substituted cycloalkyl radicals may be substituted in anypositions.

Phenyl radicals may be unsubstituted or be substituted one or more times,for example once, twice or three times, by identical or different radicals. If aphenyl radical is substituted, it preferably has one or two identical ordifferent substituents. This likewise applies to substituted phenyl radicals ingroups such as, for example, phenylalkyl or phenyloxy. The substituent inmonosubstituted phenyl radicals may be in position 2, position 3 or position4. Disubstituted phenyl may be substituted in the 2,3 position, 2,4 position, 2.5 position, 2,6 position, 3,4 position or 3,5 position. The substituents intri s u bstituted phenyl radicals may be in the 2,3,4 position, 2,3,5 position, 2.4.5 position, 2,4,6 position, 2,3,6 position or 3,4,5 position. 12 13285

Heteroaryl radicals are aromatic ring compounds in which one or more ringatoms are oxygen atoms, sulfur atoms or nitrogen atoms, e.g. 1, 2 or 3nitrogen atoms, 1 or 2 oxygen atoms, 1 or 2 sulfur atoms or a combinationof various heteroatoms. The heteroaryl radicals may be attached by ailpositions, for example by the 1 position, 2 position, 3 position, 4 position, 5position, 6 position, 1 position or 8 position. Heteroaryl radicals may beunsubstituted or be substituted one or more times, for example once, twiceor three times, by identical or different radicals. This applies likewise toheteroaryl radicals such as, for example, in the radical heteroarylalkyl.Examples of heteroaryl are furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl,phthalazinyl, quinoxalinyl, quinazolinyl and cinnolinyl.

Heteroaryl radicals are, in particular, 2- or 3-thienyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 1,2,3-triazol-1-, - 4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 2-, 4- or 5-oxazolyl,3-, 4- or 5-isoxazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1.3.4- oxadiazol-2-yl or -5-yl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 1.3.4- thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or-5-yl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 3- or 4-pyridazinyl,pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazoiyl, 1-,3-, 4-, 5-, 6- or 7-indazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-,7- or 8-isoquinolyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl. Also encompassed are the corresponding N-oxides of thesecompounds, i.e. for example 1-oxy-2-, 3- or 4-pyridyl.

Particularly preferred heteroaromatic radicals are 2- or 3-thienyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4- or 5-pyrazolyi, 2-, 3- or 4-pyridyl, 2- or 3-pyrazinyl, 2-, 4-, 5- or 6-pyrimidinyl and 3- or 4-pyridazinyl. 1 3285

The invention further relates to a process for preparing the compounds ofthe formula I which comprises reacting a compound of the formula II

II in which R1 to R4 hâve the stated meaning, and L is a leaving group whichcan undergo nucleophilic substitution, with guanidine.

The activated acid dérivatives of the formula II in which L is an alkoxy,preferably a methoxy, group, a phenoxy group, phenylthio, methylthio,2-pyridylthio group, a nitrogen heterocycle, preferably 1-imidazolyl, areadvantageously obfained in a manner known to those skilled in the artfrom the underlying carbonyl chlorides (formula II; L = Cl), which in turn canthemselves be prepared in a known manner from the underlying carboxylicacids (formula II; L = OH), for example using thionyl chloride.

Besides the carbonyl chlorides of the formula II (L = Cl) it is also possible topréparé other activated acid dérivatives of the formula II in a known mannerdirectlyfrom the underlying benzoic acids (formula II; L = OH), such as themethyl esters of the formula II with L = OCH3 by treatment with gaseousHCl in methanol, the imidazolides of the formula II by treatment withcarbonyldiimidazole, the mixed anhydrides of the formula II by treatmentwith CI-COOC2H5 or tosyl chloride in the presence of triethylamine in aninert solvent, and activations of benzoic acids with dicyclohexylcarbodiimide (DCC) or with 0-[(cyano(ethoxycarbonyl)-methylene)amino]-1,1,3,3-tetramethyluronium tetrafluoroborate (“TOTU")are also possible. A number of suitable methods for preparing activatedcarboxylic acid dérivatives of the formula II are indicated in J. March,Advanced Organic Chemistry, third édition (John Wiley &amp; Sons, 1985,page 350), indicating source literature. 14 1 3285

Reaction of an activated carboxyiic acid dérivative of the formula II withguanidine preferably takes place in a known manner in a protic or aproticpolar but inert organic solvent. Those which hâve proved suitable for thereaction of the methyl benzoates (formula II; L = OCH3) with guanidine are 5 methanol, isopropanol or THF at températures from 20°C to the boilingpoint of these solvents. Most reactions of compounds of the formula II withsalt-free guanidine are, for example, carried out in aprotic inert solventssuch as THF, dimethoxyethane, dioxane. However, it is also possible touse water in the presence of a base such as, for example, NaOH as 10 solvent in the reaction of compounds of the formula II with guanidine.

If L is Cl, it is advantageous to add an acid scavenger, for example in theform of excess guanidine, to bind the hydrohalic acid. 15 The compounds of the formula II can be prepared as follows, by 15 13285

XII II a) reducing a 4-nitrophenylsulfur pentafluoride dérivative of the formula IIIto the amine of the formula IV, b) halogenating the compound of the formula IV in the ortho position to the5 amino group with a halogenating agent to give the compound of the formula V, c) replacing the halogen substituent in the compound of the formula V witha suitable nucleophile or an organoelement compound, for example analkylboron compound, where appropriate with catalysis, by a substituent R1 10 and d) replacing the amino function in the compound of the formula VI by ahalogen substituent, 1 3285 16 e) replacing the halogen substituent in the compound of the formula VII bya nitrile function, f) hydrolyzing the nitrile function of the compound of the formula VIII to thecarboxylic acid, g) nitrating the compound of the formula IX in the ortho position to thepentafluorosulfanyl group to give the compound of the formula X, h) reducing the nitro compound of the formula X to the aniline, i) replacing the amino function in the compound of the formula XI by R3using a suitable nucleophile and

k) converting the compound of the formula XII into the compound of theformula II, where in the compounds of the formulae II, III, IV, V, VI, VII, VIII,IX, X, XI and XII

R1 to R4 are defined as in formula I L is defined as in formula II and X and Y are, independently of one another, F, Cl, Br or I.

The procedure for preparing the compounds of the formula II is initially instep a to convert the compounds of the formula III by methods known inprinciple for the réduction of aromatic nitro compounds to aromatic aminesinto compounds of the formula IV. Such methods are described, forexample, in: R.C. Larock, Comprehensive Organic Transformations: AGuide to Functional Group Préparations, VCH Publishers, New York,Weinheim, 1999, 821-828 and the literature cited therein.

Subsequently (step b), the compounds of the formula IV are dissolved in anorganic solvent A and reacted with a halogenating agent, for example abrominating agent. The reaction température in this case is generally from-30°C to +150°C, preferably 0°C to 40°C. The reaction time is generallyfrom 10 min to 20 h, depending on the composition, of the mixture and thechosen température range. The resulting reaction mixture can be workedup by subséquent filtration through a layer of silica gel, washing withorganic solvent A and, after removal of the solvent in vacuo, purifying theproduct by conventional purification methods such as recrystaliization,distillation or chromatography.

From 0.1 to 10 mol of the compound of the formula IV for example are 17 1 3285 dissolved in 1000 ml of organic solvent A. For example, from 0.8 to 1.2équivalents of the halogenating agent are used for 1 mol of the compoundof the formula IV to be halogenated.

The term “halogenating agent” means for example elemental halogens,halogen-amine complexes, cyclic and acyclic N-halogenated carboxamidesand -imides, and ureas, as described, for example, in R.C. Larock,Comprehensive Organic Transformations: A Guide to Functional GroupPréparations, VCH Publishers, New York, Weinheim, 1999, 619-628, andthe literature cited therein or M.B. Smith and J. March, March’s AdvancedOrganic Chemistry: Reactions, Mechanisms, and Structure, Wiley, NewYork, 2001, 704-707,. and the literature cited therein, such as, for example,N-bromosuccinimide, N-chlorosuccinimide, HBr in H2SO4 or 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione. The term “brominating agent” means,for example, elemental bromine, bromine-amine complexes, cyclic andacyclic N-brominated carboxamides and -imides, and ureas, as described,for example, in R.C. Larock, Comprehensive Organic Transformations: AGuide to Functional Group Préparations, VCH Publishers, New York,Weinheim, 1999, 622-624, and the literature cited therein or M.B. Smithand J. March, March’s Advanced Organic Chemistry: Reactions,Mechanisms, and Structure, Wiley, New York, 2001,704-707, and theliterature cited therein, for example N-bromosuccinimide-, HBr in H2SO4 or1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione, the latter being abte totransfer 2 bromine atoms per molécule.

The term “organic solvent A” preferably means aprotic solvents such as, forexample, dichloromethane, chloroform, tetrachloromethane, pentane,hexane, heptane, octane, benzene, toluene, xylene, chlorobenzene, 1,2-dichloroethane, trichloroethylene or acetonitrile.

Any HX produced in the reaction can be trapped by organic or inorganicbases.

In step c, the compounds of the formula V are subsequently dissolved in anorganic solvent B and reacted with a nucleophile R1 or an elementcompound comprising the substituent R1 to give compounds of the formulaVI. It is possible in this case to add a base A and to add a catalyzing métalsait A.

The reaction température in this case is generally between -20°C and+150°C, preferably between 30°C and 100°C. The reaction time isgenerally from 0.5 h to 20 h, depending on the composition of the mixtureand the chosen température range. The resulting réaction mixture can be 1 3285 18 worked up by subséquent filtration through a layer of silica gel, washjngwith an organic solvent B and, after removal of the solvent in vacuo,purifying the product by conventional purification processes such asrecrystallization, chromatography, for example on silica gel, distillation orsteam distillation.

From 0.1 to 10 mol of the compound of the formula V for example aredissolved in 1000 ml of organic solvent B. For example, from 0.8 to 3équivalents of the nucleophile R1 or of the element compound comprisingthe substituent RI are used for 1 mol of the starting compound of theformula V.

The term “nucleophile R1 “ means compounds which resuit ondeprotonation of a compound R1-H with strong bases such as, forexample, alkyl- or aryllithium compounds, organomagnesium compounds,alcoholates or lithium diisopropylamide. “Organoelement compounds comprising the substituent R1” mean forexample organolithium compounds R1 -Li, organomagnesium compoundsR1-Mg-Hal, with Hal = Cl, Br, I, organoboron compounds such asR1-B(OH)2, R1-boronic esters such as, for example, R1-boronic anhydrides such as, for example,

I R1 ororganozinc compounds R1-Zn-Z, with Z = Cl, Br, I.

The term “base A” means bases like those used as auxiliary bases incross-coupling reactions and mentioned for example in A. Suzuki et al.,Chem. Rev. 1995, 95, 2457-2483 or M. Lamaire et al., Chem. Rev. 2002,102, 1359-1469 or S.P. Stanforth, Tetrahedron 1998, 54, 263-303 and theliterature cited therein in each case, for example Na2CC>3, CS2CO3, KOH,NaOH, K3PO4, N(ethyl)3.

The term “organic solvent B" means protic or aprotic solvents such asdiethyl ether, dimethoxyethane, THF, alcohols, water or mixtures thereof. Inone embodiment, mixtures with water are preferred. 19 1 3285

The term “catalyzing métal sait A” means inter alia Pd and Ni catalysts likethose used for Suzuki and Negishi reactions and described for example inA. Suzuki et al., Chem. Rev. 1995, 95, 2457-2483 or M. Lamaire et al.,Chem. Rev. 2002, 102, 1359-1469 or S.P. Stanforth, Tetrahedron 1998, 54, 263 or G.C. Fu et al., J. Am. Chem. Soc. 2001, 123, 10099 or G.C. Fuet al., J. Am. Chem. Soc. 2002, 124, 13662 and the literature cited thereinin each case, including the added ligands such as Pd(OAc)2, PdCl2(dppf)or Pd2(dba)3.

In step d, the compounds of the formula VI are subsequently converted intothe compounds of the formula VII by a diazotization-halogenation processwith a diazotizing-halogenating agent, for example with a diazotizing-brominating agent, as described for other aromatic amines to replace theamine function by a halogen function for example in M.B. Smith andJ. March, March’s Advanced Organic Chemistry: Reactions, Mechanisms,and Structure, Wiley, New York, 2001, 935-936 or R.C. Larock,Comprehensive Organic Transformations: A Guide to Functional GroupPréparations, VCH Publishers, New York, Weinheim, 1999, 678-679 andthe literature cited therein, for example by the Sandmeyer or Gattermannreaction. The process of M. Doyle et al., J. Org. Chem. 1977, 42, 2426 or ofS. Oaeetal., Bull. Chem. Soc. Jpn. 1980, 53, 1065 is preferred.;

In step e, the compounds of the formula VII are reacted in a solvent C witha cyanidating agent, for example with addition of a catalyzing métal sait B.The réaction température is generally from 20°C to 200°C, preferably 80°Cto 150°C. The reaction time is generaily from 1 h to 20 h, depending on thecomposition of the mixture and the chosen température range. Theresulting reaction mixtures can be filtered with suction through a layer ofsilica gel or kieselguhr and the filtrate can be worked up by aqueousextraction. After évaporation of the solvent in vacuo, the compound of theformula VIII is purified by conventional purification processes such asrecrystallization, chromatography on silica gel, distillation or steamdistillation.

From 0.1 to 10 moi of the compound of the formula VII for example aredissolved in 1000 ml of organic solvent C. For example, from 1 to 10équivalents of the cyanidating agent are used for 1 mol of the compoundshaving the formula VII to be reacted.

The term “cyanidating agent” means, for example, alkali métal cyanides orZn(CN)2 either alone or mixed with metallic zinc, preferably in the form of 20 1 3285 zinc dust.

The term “organic solvent C” preferably means aprotic polar solvents suchas, for example, DMF, dimethylacetamide, NMP, DMSO.

The term “catalyzing métal sait B" means inter alia Pd and Ni catalysts likethose employed in Suzuki reactions and described for example in A. Suzukiet al., Chem. Rev. 1995, 95, 2457-2483 or M. Lamaire et al., Chem. Rev.2002, 102, 1359-1469 or S.P. Stanforth, Tetrahedron 1998, 54, 263 andthe literature cited therein, for example PdCl2(dppf), Pd(OAc)2, Pd2(dba)3.

The resulting compounds of the formula VIII are subsequently hydrolyzedin step f to the carboxylic acids of the formula IX, for example in thepresence of a base. This can take place by processes known to the skilledworker for hydrolyzing aromatic nitriles, as described, for example, inR.C. Larock, Comprehensive Organic Transformations: A Guide toFunctional Group Préparations, VCH Publishers, New York, Weinheim,1999, 1986-1987 orM.B. Smith and J. March, March’s Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, Wiley, New York, 2001,1179-1180 and the literature cited therein.

In step g, compounds of the formula IX are nitrated with a nitrating agent asdescribed, for example, in Houben-Weyl, Methoden der organischenChemie 4th édition, Organo-Stickstoff-Verbindungen IV, part 1, GeorgThieme Verlag Stuttgart 1992, pages 262-341.

In step h, the nitro compounds of the formula X are converted intocompounds of the formula XI by methods known in principle for reducingaromatic nitro compounds to aromatic amines. Such methods aredescribed for example in: R.C. Larock, Comprehensive OrganicTransformations: a Guide to Functional Group Préparations, VCHPublishers, New York, Weinheim, 1999, 821-828 and the literature citedtherein.

In step i, the anilines of the formula XI are converted by the diazotization -replacement route into the compounds of the formula XII with replacementof the amine group by R3. Such methods are known to the skilled workerand are described for example in Houben-Weyl, Methoden der organischenChemie 4th édition, Organo-Stickstoff-Verbindungen I, part 2, GeorgThieme Verlag Stuttgart 1990, pages 1087-1136 and the référencés citedtherein. 21 1 3285

For example, an aniline of the formula XI can be converted by thediazotization-replacement route into a sulfochloride of the formula XII(R3 = SO2CI) as described, for example, in Houben-Weyl, Methoden derorganischen Chemie 4th édition, Organo-Schwefel-Verbindungen, part 2,GeorgThieme Verlag Stuttgart 1985, pages 1069-1070.

In step k, the compounds of the formula XII are derivatized to thecompounds of the formula II by methods known to the skilled worker and asdescribed above.

It is possible in this step for example for the sulfochlorides of the formulaXII (R3 = SO2CI) to be converted initially into the côrresponding sulfinicacids (as described for example in Houben-Weyl, Methoden derorganischen Chemie 4th édition, Organo-Schwefel-Verbindungen, part 1,Georg Thieme Verlag Stuttgart 1985, pages 620-621 and Houben-Weyl,Methoden der organischen Chemie, Schwefel-, Selen-, Tellur-Verbindungen, Georg Thieme Verlag Stuttgart 1955, pages 304-309) andsubsequently alkylated to give the methyl sulfone as described for examplein Houben-Weyl, Methoden der organischen Chemie 4th édition, Organo-Schwefel-Verbindungen, part 2, Georg Thieme Verlag Stuttgart 1985,pages 1145-1149. Simultaneous estérification of the carboxylic acid to themethyl ester takes place.

Compounds of the formula I in which R1 is hydrogen are prepared bycarrying out the synthesis without steps b and c.

Compounds of the formula I in.which R3 is NR9R1Û are prepared bycarrying out the synthesis without step i.

Functional groups in the starting compounds may also be présent inprotected form or in the form of precursors, and then be converted into thedesired groups in the compounds of the formula II prepared by the processdescribed above. Corresponding protective group techniques are known tothe skilled worker.

It is likewise possible for appropriate functional groups to be derivatized bymethods known to the skilled worker. For example, compounds in which R3is NH2 can be converted by reaction with appropriate alkyl halides or2,2,2-trifluoroethyl halides, for example methyl iodide, ethyl iodide or2,2,2-trifluoroethyl iodide, into compounds in which R3 is NR9R10, whereR9 and R10 are, independently ofone another, hydrogen, alkyl having 1,2,3 or 4 carbon atoms or -CH2-CF3 and are not both simultaneouslyhydrogen. - 22 13285

Pentafluorosulfanylbenzoylguanidines of the formula I are generally weak bases and are able to bind acids to form salts. Suitable acid addition salts are salts of ail pharmaceutically acceptable acids, for example halides, in 5 particular hydrochlorides, lactates, sulfates, citrates, tartrates, acétates, phosphates, methylsulfonates, p-toluenesulfonates.

The compounds of the formula I are substituted acylguanidines and inhibitthe cellular sodium-proton antiporter (Na+/H+ exchanger, NHE), in 10 particular the subtype NHE-1.

Because of the NHE-inhibitory properties, the compounds of the formula Iand/or the pharmaceutically acceptable salts thereof are suitable for theprévention and treatment of diseases caused by activation of or by an -15 activated NHE, and of diseases caused secondarily by the NHE-relateddamage.

The compounds of the formula I may also be used for treating andpreventing diseases by the NHE being only partially inhibited, for exampleby use of a low dosage. 20

Since NHE inhibitors predominantly act via their effect on cellular pHrégulation, they can generally be combined beneficially with othercompounds which regulate the intracellular pH, with suitable combinationpartners being inhibitors of the carbonic anhydrase enzyme group,

25 inhibitors of Systems transporting bicarbonate ions, such as of the sodiumbicarbonate cotransporter (NBC) or of the sodium-dependent chloride-bicarbonate exchanger (NCBE), and NHE inhibitors with inhibitory effect onother NHE subtypes, because it is possible through them to enhance ormodulate the pharmacologically relevant pH-regulating effects of the NHE 30 inhibitors described herein.

The use of the compounds of the invention relates to the prévention andtreatment of acute and chronic diseases in veterinary and human medicine. 23 1 3 285

Thus, the NHE inhibitors of the invention are suitable forthe treatment ofdiseases caused by ischemia and by reperfusion.

The compounds described herein are suitable because of theirpharmacological properties as antiarrhythmic médicaments.

Owing to their cardioprotective component, the NHE inhibitors areoutstandingly suitable for infarction prophylaxis and infarction treatmentand for the treatment of angina pectoris, in which cases they alsopreventively inhibit or greatly reduce the pathophysiological processesassociated with the development of ischemia-induced damage, in particularin the triggering of ischemia-induced cardiac arrhythmias. Because of theirprotective effects against pathological hypoxie and ischémie situations, thecompounds of the formula I and/orthe pharmaceutically acceptable saltsthereof used according to the invention can, because of inhibition of thecellular Na+/H+ exchange mechanism, be used as médicaments for thetreatment of ail acute or chronic ischemia-induced damage or diseasesinduced primarily or secondarily thereby.

This also relates to their use as médicaments for surgical interventions.Thus, the compounds can be used during organ transplantations, it beingpossible to use the compounds both to protect the organs in the donorbefore and during the removal, to protect removed organs for exampleduring treatment with or storage thereof in physiological bath liquids, andduring transference to the récipient organism.

The compounds of the invention are likewise valuable médicaments with aprotective effect when performing angioplastie surgical interventions, forexample on the heart as well as on peripheral organs and vessels.

The compounds of the invention may also be used when performingbypass operations, for example bypass operations on coronary vessels andin Coronary Artery Bypass Graft (CABG). 1 3285

Depending on their activity with regard to ischemia-induced damage, thecompounds of the invention I may similarly be used in resuscitation after acardiac arest.

The compounds of the invention are of interest for médicaments for life-threatening arrhythmias. Ventricular fibrillation is terminated and thephysiological sinus rhythm of the heart is restored.

Since NHE1 inhibitors of human tissue and organs, especially the heart,protect effectively not only against damage caused by ischemia andreperfusion but also against the cytotoxic effect of médicaments like thoseused in particular in cancer therapy and the therapy of autoimmunediseases, combined administration with compounds of the formula I and/orthe pharmaceutically acceptable salts thereof is suitable for inhibiting thecytotoxic, especially cardiotoxic, side effects of said compounds. Theréduction in the cytotoxic effects, especially the cardiotoxicity, resultingfrom comedication with NHE1 inhibitors makes it additionally possible toincrease the dose of the cytotoxic therapeutic agents and/or to prolong themédication with such médicaments. The therapeutic benefits of such acytotoxic therapy can be considerably increased by combination with NHEinhibitors.

In addition, the NHE1 inhibitors of the invention of the formula I and/or thepharmaceutically acceptable salts thereof can be used when there is heart-damaging overproduction of thyroid hormones, thyrotoxicosis, or onexternal supply of thyroid hormones. The compounds of the formula Iand/or the pharmaceutically acceptable salts thereof are thus suitable forimproving therapy with cardiotoxic médicaments.

In accordance with their protective effect against ischemia-induceddamage, the compounds of the invention are also suitable as médicamentsfor the treatment of ischemias of the nervous System, especially of thecentral nervous System, being suitable for example for the treatment ofstroke or of cérébral edema. 25 1 3285

The compounds of the formula I and/orthe pharmaceutically acceptablesalts thereof are also suitable for the therapy and prophylaxis of diseasesand disorders induced by overexcitability of the central nervous System, inparticularforthe treatment of epileptic disorders, centrally induced clonieand tonie spasms, States of psychological dépréssion, anxiety disordersand psychoses. In these cases it is possible to use the NHE inhibitorsdescribed herein alone or in combination with other substances withantiepileptic activity or antipsychotic active ingrédients, or carbonicanhydrase inhibitors, for example with acetazolamide, and with otherinhibitors of NHE or of the sodium-dependent chloride-bicarbonateexchanger (NCBE).

The compounds used according to the invention ofthe formula I and/orthepharmaceutically acceptable salts thereof are additionally likewise suitablefor the treatment of types of shock such as, for example, of allergie,cardiogenic, hypovolémie and bacterial shock.

The compounds of the formula I and/or the pharmaceutically acceptablesalts thereof can likewise be used for the prévention and treatment ofthrombotic disorders because they, as NHE inhibitors, are able to inhibitplatelet aggregation themselves. They are additionally able to inhibit orpreventthe excessive release, occurring after ischemia and reperfusion, ofmediators of inflammation and coagulation, especially of von Willebrandfactor and of thrombogenic selectin proteins. It is thus possible to reduceand eliminate the pathogenic effect of significant thrombogenic factors. TheNHE inhibitors ofthe présent invention can therefore be combined withother anticoagulant and/or thrombolytic active ingrédients such as, forexample, recombinant or naturel tissue plasminogen activator,streptokinase, urokinase, acetylsalicylic acid, thrombin antagonists, factorXa antagonists, médicinal substances with fibrinolytic activity, thromboxanereceptor antagonists, phosphodiesterase inhibitors, factor Vlla antagonists,clopidogrel, ticlopidine etc. Combined use ofthe présent NHE inhibitorswith NCBE inhibitors and/or with inhibitors of carbonic anhydrase such as,for example, with acetazolamide, is particularly bénéficiai. 26 1 3285 NHE1 inhibitors are additionally distinguished by a strong inhibitory effecton the prolifération of cells, for example fibroblast prolifération and theprolifération of smooth vascular muscle cells. The compounds of theformula I and/or the pharmaceutically acceptable salts thereof are thereforesuitable as valuable therapeutic agents fordiseases in which proliférationrepresents a primary or secondary cause, and can therefore be used asa ntiathero scie rôties, agents for chronic rénal failure, cancers.

It was possible to show that cell migration is inhibited by NHE inhibitors.

The compounds of the formula I and/or the pharmaceutically acceptablesalts thereof are therefore suitable as valuable therapeutic agents fordieases in which cell migration represents a primary or secondary cause,such as, for example, cancers with a pronounced tendency to metastasis. NHE1 inhibitors are further distinguished by a retardation or prévention offibrotic disorders. Compounds of the formula I and/or the pharmaceuticallyacceptable salts thereof are thus suitable as agents for the treatment ofcardiac fibroses, and of pulmonary fibrosis, hepatic fibrosis, rénal fibrosisand other fibrotic disorders. They can thus be used for the treatment oforgan hypertrophies and hyperplasias, for example of the heart and theprostate. They are therefore suitable for the prévention and treatment ofheart failure (congestive heart failure = CHF) and for the treatment andprévention of prostate hyperplasia or prostate hypertrophy.

Since there is significant élévation in NHE in essential hypertensives, thecompounds of the formula I and/or the pharmaceutically acceptable saltsthereof are suitable for the prévention and treatment of high blood pressureand for the treatment of cardiovascülar disorders. In these cases they canbe used alone or with a suitable combination and formulation partner forthe treatment of high blood pressure and for the treatment ofcardiovascülar disorders. Thus, for example, one or more diuretics with athiazide-like action, loop diuretics, aldostérone and pseudoaldosteroneantagonists, such as hydrochlorothiazide, indapamide, polythiazide, 1 3285 27 furosemide, piretanide, torasemide, bumetanide, amiloride, triamterene,spironolactone oreplerone, can be combined. The NHE inhibitors of theprésent invention can further be used in combination with calcium channelblockers such as verapamil, diltiazem, amlodipine or nifedipine, and withACE inhibitors such as, for example, ramipril, enalapril, lisinopril, Josinoprilor captopril, Further bénéficiai combination partners are also beta-blockerssuch as metoprolol, albuterol etc., antagonists of the angiotensin receptorand its receptor subtypes such as losartan, irbesartan, valsartan,omapatrilat, gemopatrilat, endothelin antagonists, renin inhibitors,adenosine receptor agonists, inhibitors and activators of potassiumchannels such as glibenclamide, glimepiride, diazoxide, cromakalim,minoxidil and dérivatives thereof, activators of the mitochondrial ATP-sensitive potassium channel (mitoK(ATP) channel), inhibitors of Kv1.5 etc.

It has emerged that NHE1 inhibitors hâve a significant antiinflammatoryeffect and can thus be used as antiinflammatory drugs. Inhibition of therelease of mediators of inflammation is noteworthy in this connection. Thecompounds can thus be used alone or in combination with anantiinflammatory drug for the prévention or treatment of chronic and acuteinflammatory disorders. Combination partners advantageously used arestéroïdal and non-steroidal antiinflammatory drugs. The compounds of theinvention can additionaliy be employed for the prévention or treatment ofdisorders caused by protozoa, such as malaria and coccidiosis in poultry.

It has additionaliy been found that NHE1 inhibitors show a bénéficiai effecton sérum lipoproteins. It is generally acknowledged that blood fat levelswhich are too high, called hyperlipoproteinemias, represent an essentialrisk factor for the development of arteriosclerotic vascular lésions,especially coronary heart disease. The réduction of elevated sérumlipoproteins therefore has exceptional importance for the prophylaxis andrégression of atherosclerotic lésions. Besides the réduction in total sérumcholestérol, it is partîcularly important to reduce the proportion of spécifieatherogenic lipid fractions ofthis total cholestérol, in particular of the lowdensity lipoproteins (LDL) and of the very low density lipoproteins (VLDL), 28 1 3285 because these lipid fractions represent an atherogenic risk factor. Bycontrast, a protective function against coronary heart disease is ascribed tothe high density lipoproteins. Accordingly, hypolipidémies should be able toreduce not only total cholestérol but, in particular,'the VLDL and LDL sérumcholestérol fractions. It has now been found that NHE1 inhibitors showvaluable therapeutically utilizable properties in relation to influencing thesérum lipid levels. Thus, they significantly reduce the elevated sérumconcentrations of LDL and VLDL as are to be observed, for example, dueto increased dietary intake of a cholestérol- and lipid-rich diet or in cases ofpathological metabolic alterations, for example genetically relatedhyperlipidemias. They can therefore be used for the prophylaxis andrégression of atherosclerotic lésions by eliminating a causal risk factor.Included herein are not only the primary hyperlipidemias but also certainsecondary hyperlipidemias occurring, for example, in association withdiabètes. In addition, the NHE1 inhibitors lead to a marked réduction in theinfarctions induced by metabolic abnormalities and, in particular, to asignificant réduction in the induced infarct size and the severity thereof.

The compounds of the formula I and/orthe pharmaceutically acceptablesalts thereof are therefore advantageously used for producing amédicament for the treatment of hypercholesterolemia; for producing amédicament for the prévention of atherogenesis; for producing amédicament for the prévention and treatment of atherosclerosis, forproducing a médicament for the prévention and treatment of diseasesinduced by elevated cholestérol levels, for producing a médicament for theprévention and treatment of diseases induced by endothélial dysfunction,for producing a médicament for the prévention and treatment ofatherosclerosis-induced hypertension, for producing a médicament for theprévention and treatment of atherosclerosis-induced thromboses, forproducing a médicament for the prévention and treatment of hypercholesterolemia-induced and endothélial dysfunction-inducedischémie damage and post-ischemic reperfusion damage, for producing amédicament for the prévention and treatment of hypercholesterolemia-induced and endothélial dysfunction-induced cardiac hypertrophies andcardiomyopathies and of congestive heart failure (CHF), for producing a 1 3285 29 médicament for the prévention and treatment of hypercholesterolemia-induced and endothélial dysfunction-induced coronary vasospasms andmyocardial infarctions, for producing a médicament for the treatment ofsaid disorders in combinations with hypotensive substances, preferablywith angiotensin converting enzyme (ACE) inhibitors and angiotensinreceptor antagonists. A combination of an NHE inhibitor of the formula Iand/or the pharmaceutically acceptable salts thereof with an activeingrédient lowering the blood fat levels, preferably with an HMG-CoAreductase inhibitor (for example lovastatin or pravastatin), the latterbringing about a hypolipidémie effect and thus increasing the hypolipidémieproperties of the NHE inhibitor of the formula I and/or the pharmaceuticallyacceptable salts thereof, proves to be a favorable combination withenhanced effect and reduced use of active ingrédients.

Thus, compounds of the formula I and/or the pharmaceutically acceptablesalts thereof lead to effective protection against endothélial damage ofvarious origins. This protection of the vessels against the syndrome ofendothélial dysfunction means that the compounds of the formula I and/orthe pharmaceutically acceptable salts thereof are valuable médicaments forthe prévention and treatment of coronary vasospasms, peripheral vasculardiseases, in particular intermittent claudication, atherogenesis andatherosclerosis, left ventricular hypertrophy and dilated cardiomyopathyand thrombotic disorders.

It has additionally been found that NHE1 inhibitors are suitable in thetreatment of non-insulin-dependent diabètes (NIDDM), with the insulinrésistance being restrained. It may in this connection be bénéficiai, toenhance the antidiabetic activity and quality of the effect of the compoundsof the invention, to combine them with a biguanide such as metformin, withan antidiabetic sulfonylurea such as glyburide, glimepiride, tolbutamideetc., with a glucosidase inhibitor, with a PPAR agonist such asrosiglitazone, pioglitazone etc., with an insulin product of differentadministration form, with a DB4 inhibitor, with an insulin sensitizor or withmeglitinide. 30 1 3285

Besides the acute antidiabetic effects, the compounds of the formula Iand/or the pharmaceutically acceptable salts thereof counteract thedevelopment of late complications of diabètes and can therefore be usedas médicaments for the prévention and treatment of late damage fromdiabètes, such as diabetic nephropathy, diabetic retinopathy, diabeticcardiomyopathy and other disorders occurring as a conséquence ofdiabètes. They can in this connection be advantageously combined withthe antidiabetic médicaments just described under NIDDM treatment. Thecombination with a bénéficiai dosage form of insulin should be particularlyimportant in this connection. NHE1 inhibitors show, besides the protective effects against acuteischémie events and the subséquent equally acutely stressing reperfusionevents, also direct therapeutically utilizable effects against diseases anddisorders of the entire mammalian organism which are associated with themanifestations of the chronically progressive aging process and whichoccur independently of acute hypoperfusion States and under normal, non-ischemic conditions. These pathological, age-related manifestationsinduced overthe long aging period, such as iiiness, invalidity and death,which can now be made amenable to treatment with NHE inhibitors, arediseases and disorders which are essentially caused by age-relatedchanges in vital organs and the function thereof and become increasinglyimportant in the aging organism.

Disorders connected with an age-related functional impairment or with age-related manifestations of wear of organs are, for example, the inadéquateresponse and reactivity of the blood vessels to contraction and relaxationreactions. This age-related décliné in the reactivity of vessels to constrictingand relaxing stimuli, which are an essential process of the cardiovascularSystem and thus of life and health, can be significantly eliminated orreduced by NHE inhibitors. One important function and a measure of themaintenance of the reactivity of vessels is the blockade or retardation of theage-related progression in endothélial dysfunction, which can be eliminatedhighly significantly by NHE inhibitors. The compounds of the formula Iand/or the pharmaceutically acceptable salts thereof are thus outstandingly 1 3285 suitable forthe treatment and prévention of the age-reiated progression inendothélial dysfunction, especially of intermittent claudication.

An example of another variable characterizing the aging process is the5 décliné in the contractability of the heart and the décliné in the adaptation of the heart to a required pumping output ofthe heart. This diminishedefficiency ofthe heart as a conséquence ofthe aging process is in mostcases connected with a dysfunction of the heart which is caused inter aliaby déposition of connective tissue in the myocardial tissue. This déposition 10 of connective tissue is characterized by an increase in the weight of theheart, by an enlargement ofthe heart and by restrictive cardiac function. Itwas surprising that it was possible almost completely to inhibit such agingof the heart organ. The compounds of the formula I and/or thepharmaceutically acceptable salts thereof are thus outstandingly suitable 15 . for the treatment and prévention of heart failure, of congestive heart failure(CHF).

Not only is it possible to cure a cancer which has already occurred throughinhibition of prolifération, but there is also réduction and highly significant 20 retardation ofthe age-related incidence of cancer through NHE inhibitors. Aparticularly noteworthy finding is that the disorders, occurring as a resuit ofaging, of ail organs and not only certain types of cancer are suppressed oroccur with a highly significant delay. The compounds ofthe formula I and/orthe pharmaceutically acceptable salts thereof are thus suitable for the 25 treatment and, in particular, the prévention of age-related types of cancer.

With NHE inhibitors, a delay, shifted highly significantly in time is found inthe occurrence of age-related disorders of ail the organs investigated,including the heart, vessels, liver etc., and a highly significant delay in 30 cancer of the elderly. On the contrary, there is also surprisingly a prolongation of life to an extent which has to date been achievable by noother group of médicaments or by any natural products. This unique effectof NHE inhibitors also makes it possible, besides the use ofthe activeingrédients a.lone on humans and animais, to combine these NHE inhibitors 32 1 3285 with other active principles, measures, substances and natural productswhich are used in gerontology and which are based on a differentmechanism of action. Such classes of active ingrédients used ingerontological therapy are: in particular vitamins and substances withantioxidant activity. Since there is a corrélation between calorie load orfoodintake and the aging process, the combination with dietary measures cantake place for example with appetite suppressants. It is likewise possible toconsider a combination with hypotensive médicaments such as with ACEinhiibitors, angiotensin receptor antagonists, diuretics, Ca+2 antagonists etc.or with metaboiism-normalizing médicaments such as cholesterol-loweringagents.

The compounds of the formula I and/orthe pharmaceutically acceptablesalts thereof are thus outstandingly suitable for the prévention of age-related tissue changes and for prolonging life while retaining a high qualityoflife. . . ..

The compounds of the invention are effective inhibitors of the cellularsodium-proton antiporter (Na/H exchanger) which in a large number ofdisorders (essential hypertension, atherosclerosis, diabètes etc.) is alsoincreased in cells which are readily amenable to measurements, such as,for example, in érythrocytes, platelets or leucocytes. The compounds usedaccording to the invention are therefore suitable as outstanding and simplescientific tools, for example in thëir use as diagnostic agents fordetermining and distinguishing different types of hypertension, but also ofatherosclerosis, diabètes and the late complications of diabètes,proliférative disorders etc.

Also claimed is a medicine for human, veterinary or phytoprotective use,comprising an effective amount of a compound of the formula I and/or thepharmaceutically acceptable salts thereof, together with pharmaceuticallyacceptable carriers and additives, alone or in combination with other activepharmaceutical ingrédients or médicaments. Médicaments which comprise a compound of the formula I and/orthepharmaceutically acceptable salts thereof can in this connection be 1 3285 33 ' administered, for example, orally, parenterally, intravenously, rectally,transdermaliy or by inhalation, the preferred administration beingdépendent on the particular characteristics of the disorder. The compoundsof the formula I may moreover be used alone or together with 5 pharmaceutical excipients, both in veterina'ry medicine and in humanmedicine. The médicaments generally comprise active ingrédients of theformula I and/orthe pharmaceutically acceptable salts thereof in an amountof from 0.01 mg to 1 g per dose unit. 10 The excipients suitable for the desired pharmaceutical formulation are familiarto the skilled worker on the basis of his expert knowledge. Besidessolvents, gel formers, suppository bases, tablet excipients, and other activeingrédient carriers, it is possible to use, for example, antioxidants,dispersants, emulsifiers, antifoams, flavorings, preservatives, solubilizers or 15 colors.

For a form for oral administration, the active compounds are mixed withadditives suitable for this purpose, such as carriers, stabilizers or inertdiluents, and converted by conventional methods into suitable dosage 20 forms such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily solutions. Examples of inert carriers which can be used aregum arable, magnesia, magnésium carbonate, potassium phosphate,lactose, glucose or starch, especially corn starch. It is moreover possiblefor the préparation to take place both as dry granules and as wet granules. 25 Examples of suitable oily carriers or solvents are vegetable or animal oilssuch as sunflower oil or fish liver oil.

For subeutaneous, intramuscuiar or intravenous administration, the activecompounds used are converted, if desired with the substances customary 30 for this purpose, such as solubilizers, emulsifiers or other excipients, into asolution, suspension or émulsion. Examples of suitable solvents are: water,physiological saline oralcohols, e.g. éthanol, propanol, glycerol, as well assugar solutions such as glucose or mannitol solutions, or else a mixture ofthe various solvents mentioned. . 1 3285 34

Suitable as pharmaceutical formulation for administration in the form ofaérosols or sprays are, for example, solutions, suspensions or émulsions ofthe active ingrédient of the formula I and/orthe pharmaceuticallyacceptable salts thereof in a pharmaceutically acceptable solvent such as,in particular, éthanol or water, or a mixture of such solvents. Theformulation may, if required, also contain other pharmaceutical excipientssuch as surfactants, emulsifiers and stabilizers, and a propellant gas. Sucha préparation normally contains the active ingrédient in a concentration ofabout 0.1 to 10, in particular of about 0.3 to 3% by weight.

The dosage of the active ingrédient of the formula I to be administered, andthe frequency of administration, dépend on the potency and duration ofaction of the compounds used; additionally also on the nature and severityof the disorderto be treated and on the sex, âge, weight and individualresponsiveness of the mammal to be treated.

On average, the daily dose of a compound ofthe formula I and/orthepharmaceutically acceptable salts thereof for a patient weighing about75 kg is at least 0.001 mg/kg, preferably 0.01 mg/kg, to a maximum of10 mg/kg, preferably 1 mg/kg, of body weight. For acute épisodes ofthedisorder, for example immediately after suffering a myocardial infarction,higher and, in particular, more frequent dosages may also be necessary,e.g. up to 4 single doses a day. Up to 700 mg a day may be necessary, inparticular on i.v. administration, for example for a patient with infarction inthe intensive care unit, and the compounds ofthe invention can beadministered by infusion.

List of abbreviations: ADMET absorption - distribution - metaboiism - excrétion - toxicology CDI diimidazol-1-ylmethanone dba dibenzylideneacetone DIP diisopropyl ether DIPEA diisopropylethylamine 1 3285 35 DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EA ethyl acetate eq. équivalent HOAc acetic acid KOtBu potassium 2-methylpropan-2-olate MeOH methanol mp melting point MTB tert-butyl methyl ether NMP N-methyl-2-pyrrolidone OAc acetate dppf 1 ,T-bis(diphenylphosphino)f&amp;rrocene RT room température THF· tetrahydrofuran TMEDA N,N,N',N'-tetramethylethane-1,2-diamine

Experimental part

Example 1 : N-(5-Methanesulfonyl-2-methyl-4-pentafluorosulfanyl-benzoyi)guanidine

a) 4-Aminophenylsulfur pentafluoride

NH2 A solution of tin(il) chloride (1465 g, 7.73 moi) in concentrated (32 percent)aqueous HOI solution was heated with stirring to 80°C and then, with ice 36' 1 3285

cooling, 4-nitrophenylsulfur pentafluoride (584 g, 2.344 mol) was introducedin 8 portions over the course of 1 h. The internai température was keptbelow 100°C during this. Subsequently, the mixture was stirred at aninternai température of 85°C for 1.5 h and then cooled to 45°C over thecourse of a further hour. A mixture of ice (12 kg), NaOH (2 kg) anddichloromethane (1.5 I) was prepared and the reaction mixture was addedwith vigorous stirring. The phases were separated, the aqueous phase wasextracted 3 times with 1 I of dichloromethane each time, and the combinedorganic phases were dried over Na2SO4 and evaporated in vacuo. 510 g of4-aminophenylsulfur pentafluoride were obtained as a pale yellowcrystalline powder, m.p. 63-65°C b) 4-Amino-3-bromophenylsulfur pentafluoride

4-Aminophenylsulfur pentafluoride (510 g, 2.327 mol) was dissolved indichloromethane (7 I), the solution was cooled to 5°C and, while stirring, l, 3-dibromo-5,5-dimethylimidazoli.dine-2,4-dione (326 g, 1.14 mol) wasintroduced in several portions with ice cooling so that the internaitempérature was kept at 3-8°C (approx. 1 h). The mixture was then left tostir and warm to room température without external cooling for 1 h. Themixture was filtered through a bed of silica gel (volume about 1 I) andwashed with dichloromethane (5.5 I), and the filtrate was evaporated invacuo. About 700 g of a red-brown crystalline mass was obtained and wasdissolved in n-heptane (600 ml) at 60°C and then crystallized in arefrigerator at 4°C. Filtration with suction resulted.in 590 g (85%) of4-amino-3-bromophenylsulfur pentafluoride as brownish crystals, m. p. 59-59.5°C. c) 4-Amino-3-methylphenylsulfur pentafluoride

A mixture of CS2CO3 (794 g, 2.7 mol), dimethoxyethane (2 I), water(300 m!) and trimethylboroxine (50 percent solution in THF, 225 g, 0.9 mol) 37 13255 was heated to 70°C, PdCl2 (dppf) x CH2CI2 (37 g, 45 mmol) was added,and a solution of 4-amino-3-bromophenylsulfur pentafluoride (270 g, 0.9 mol) in dimethoxyethane (400 ml) was added dropwise overrthe courseof 2 h while the reaction mixture was heated to reflux. It was subsequentlyheated under reflux for a further 3 h and then cooled to room température,diluted with MTB ether (500 ml), filtered through a silica gel column(14><7 cm, 70-200 pm) and washed with MTB ether (2500 ml). The filtratewas evaporated in vacuo. 490 g of a black, semicrystalline mass wasobtained and was subjected to a steam distillation. A total of 5.5 I ofcondensate was collected, from which the crystals of the product separatedout. The condensate was extracted 3 * with MTB ether, and the combinedorganic phases were dried over Na2SC>4 and evaporated in vacuo.4-Amino-3-methylphenyIsulfur pentafluoride (181 g, 76%) was obtained ascolorless crystals, m.p. 65-66°C, d) 4-Bromo-3-methylphenylsulfur pentafluoride

A mixture of tert-butyl nitrite (90 percent pure, 37 ml, 280 mmol) and CuBr2(35.8 g, 160 mmol) in acetonitrile (260 ml) was cooled to 5°C and, whilestirring and cooling with ice, a solution of 4-amino-3-methylphenylsulfurpentafluoride (30.9 g, 132.5 mmol) in MTB ether (140 ml) was addeddropwise at 5-8°C over the course of 1 h. Evolution of nitrogen started afterabout 2 min. The mixture was then allowed to warm with stirring to roomtempérature over the course of 1 h, a mixture of ice (250 g), 26 percentaqueous NH3 solution (50 ml) and MTB ether (250 ml) was added,. and themixture was stirred for 10 min. The phases were separated, the aqueouswas extracted 3 χ with MTB ether (150 ml each time), and the combinedorganic phases were shaken once with 400 ml of water. Drying withNa2SÛ4 and évaporation of the organic phase resulted in 39 g of 4-bromo-3-methylphenylsulfur pentafluoride as a red-brown oil which wascontaminated with 8 mol% of 4,5-dibromo-3-methylphenylsu!furpentafluoride, but was used further without further purification. Yield 89%based on a purity of 90%. 38 1 3285 e) 4-Cyano-3-methylphenylsulfur pentafluoride

A mixture of 4-bromo-3-methylphenylsulfur pentafluoride (136.4 g.'purity80%, 0.367 mol), Zn(CN)2 (72.8 g, 0.62 mol) and Zn dust (7.2 g, 0.11 mol)in dimethylacetamide (900 ml) and water (40 ml) was heated with stirringand nitrogen blanketing to 125°C, and PdCI2(dppf) x CH2CI2 (32.7 g, 40 mmol) was added. After stirring at 125°C for one hour,

PdCI2(dppf) * CH2CI2 (16.3 g, 20 mmol) and Zn dust (3.6 g, 55 mmol)were again added, and stirring was continued at 125°C for 2 h. The mixturewas then cooled to room température, diluted with n-heptane (400 ml) andstirred vigorously with addition of 5 N aqueous NH4CI solution (250 ml) andwater (450 ml) for 15 min. The mixture was filtered with suction through alayer of kieselguhr, the phases were separated, and the aqueous wasextracted 2 χ with n-heptane (200 ml). The combined organic phases wereshaken with water (450 ml), dried over MgSC>4 and evaporated in vacuo.The resulting black residue was dissolved in 200 ml of n-heptane, filteredand again evaporated in vacuo. 78 g of a dark brown liquid were obtainedand were purified by chromatography on a silica gel column (7 χ 55 cm,60-200 pm, n-heptane/dichloromethane 4:1 to 3:2). The first fractionobtained was 6.5 g of 4-bromo-3-methylphenylsulfur pentafluoride(precursor) as yellowish liquid, and then 71.1 g (80%) of 4-cyano-3-methyl-phenylsulfur pentafluoride as pale yellow oil. f) 2-Methyl-4-pentafluorosulfanyIbenzoic acid

A mixture of 4-cyano-3-methylphenylsulfur pentafluoride (41.2 g, 169.4 mmol), NaOH (20.4 g, 510 mmol) and water (60 ml) in ethyleneglycol (160 ml) was heated to 130°C and stirred at this température for 4 h.It was then cooled to room température and diluted with MTB ether(150 ml) and water (250 ml), and the mixture was filtered with suction. Thephases of the filtrate were separated, and the aqueous was acidified withconcentrated aqueous HCl solution, and the precipitated solid was filteredoff with suction. 41.1 g (93%) of.2-methyl-4-pentafluorosulfanylbenzoic acid 39 1 3 285 were obtained as colorless crystals, m.p. 138-139°C. g) 2-Methyl-5-nitro-4-pentafluorosulfanylbenzoic acid

5 6.0 g of 2-methyl-4-pentafluorosulfanylbenzoic acid were dissolved in 60 ml of a 90% aqueous HNO3 solution and, at RT, 6 ml of a 96% H2SO4 were added dropwise. The mixture was left to stand at.RT for 28 h and thenpoured into 300 g of ice, 300 ml of water were added and, after stirring for1 h, the product was filtered off. Drying in air resulted in 6.5 g of a pale 10 yellow solid, mp. 218-220°C.

Rf (DIP/2%HOAc) = 0.27 MS (ES'): 306 h) 5-Amino-2-methy!-4-pentafluorosulfanylbenzoic acid

15 6.5 g of 2-methyl-5-nitro-4-pentafluorosulfanylbenzoic acid were dissolved in 100 ml of MeOH and 20 ml of HOAc, and 500 mg of 10% Pd/C wereadded. Hydrogénation was carried out under hydrogen at atmosphericpressure and RT for 20 h. The reaction was incomplète and thereforehydrogénation was continued under a pressure of 6 bar of hydrogen and at 20 RT for 48 h. The catalyst was then filtered off and the solvents wereremoved in vacuo. 5.7 g of a pale grey solid were obtained, mp. 187-189°C.

Rf (DIP/2%HOAc) = 0.23 MS (ES'): 276 40 1 3285 i) 5-Chlorosulfonyl-2-methyl-4-pentafluorosulfanylbenzoic acid

1.0 g of 5-amino-2-methyl-4-pentafluorosulfanylbenzoic acid was dissolvedin 30 mi of HOAc, and 30 g of ice and 30 ml of a saturated aqueous HClsolution were added. Then, at 0°C, a solution of 274 mg of NaNÜ2 in 1 mlof water was added dropwise overthe course of one minute. The mixturewas stirred at 0°C for 15 minutes. The resulting suspension was thenadded in portions to a suspension, cooled to 0°C, of 6.1 mg of CuCI and61.5 mg of CuCl2 χ 2H2O in 30 ml of a saturated solution of SO2 in HOAc.

The mixture was stirred at 0°C for 1 h and then at RT for 1 h. The reactionmixture was subsequently extracted 3 times with 200 ml of diethyl ethereach time. MgSO4 was used for drying, and the volatile constituents were removed in vacuo. 1.3 g of the product were obtained and immediatelyreacted further. k) 2-Methyl-5-sulfino-4-pentafluorosulfanylbenzoic acid

1.2 g of 5-chlorosulfonyl-2-methyl-4-pentafluorosulfanylbenzoic acid wereadded in portions to a solution, heated to 70°C, of 4.2 g of Na2SO3 in 50 ml of water and, during this, the pH of the solution was kept between pH = 9and pH = 11 with a 2N aqueous NaOH solution. The mixture was stirred at70°C for 20 minutes, cooled to RT and adjusted to pH = 1-2 with anaqueous HCl solution. The mixture was left to stand at RT for 16 h and thenthe product was filtered off and dried in vacuo. 1.0 g of a white solid was 41 1 3285 obtained, mp. 288-290°C (with décomposition).

Rf (EA/MeOH 1:1) = 0.52 I) Methyl 5-methanesulfonyl-2-methyl-4-pentafluorosulfanylbenzoate

1.0 g of 2-methyl-5-sulfino-4-pentafluorosulfanylbenzoic acid wassuspended in 10 ml of water, and 3.1 ml of an aqueous 2N NaOH solutionwere added (phenolphthalein: basic). The water was removed in vacuo andthen coevaporated twice with 20 ml of toluene each time. The disodium saitwas then dissolved in 40 ml of anhydrous DMF and, after addition of0.69 ml of methyl iodide, stirred initially at 60°C for 4 h and then at RT for15 h. The reaction mixture was poured into 100 ml of water and a firstportion of the product (500 mg) was filtered off with suction. The filtrate wasadjusted to pH = 2 with aqueous HCl solution and extracted 3 times with30 ml of EA each time. MgSCU was used for drying, and the solvent was removed in vacuo. Chromatography on silica gel with DIP afforded a further460 mg of white crystals, mp 127°C.

Rf (DIP) = 0.36 m) N-(5-Methanesulfonyl-2-methyl-4-pentafluorosulfanylbenzoyl)guanidine0.70 g of guanidine chloride and 0.68 g of KOtBu were stirred in 20 ml ofanhydrous DMF at RT for 30 minutes. This suspension was then added to0.43 g of methyl 5~methanesulfonyI-2-methyl-4-pentafluorosulfanyl-benzoate and stirred at RT for 16 h. The reaction mixture was then pouredinto 200 ml of water, adjusted to pH = 8 with aqueous HCl solution andextracted 3 times with 100 ml of EA each time. MgSO4 was used for drying,and the solvent was removed in vacuo. The residue was suspended in 5 mlof CH2CI2 and the product was filtered off. 190 mg of colorless crystals 42 were obtained, mp. 254-256°C.

Rf (EA) = 0.22 1 3285 MS (ES+): 382

Example 2: N-(5-Methanesulfonyl-2-methyl-4-pentafluorosu!fanylbenzoyl)-5 guanidine methanesulfonic acid sait

NH2 9.3 g of the title compound of example 1 were suspended in 100 ml ofwater and a solution of 2.3 g of methanesulfonic acid in 10 ml of water was 10 added. The mixture was subsequently stirred at RT for 30 minutes and thenthe water was removed under reduced pressure to obtain 11.7 g of themethanesulfonic acid sait, which was subsequently recrystallized from110 ml of water to obtain 10.0 g of N-(5-methanesulfonyl-2-methyl-4-pentafluorosulfanylbenzoyl)guanidine methanesulfonic acid sait as white 15 crystals, m.p. 230°C.

Example 3: N-(5-Methanesulfonyl-2-methyl-4-pentafluorosulfanylbenzoyl)-guanidine hydrochloride

300 mg of the title compound of example 2 were suspended in 50 ml of asaturated aqueous Na2CO3 solution and extracted twice with 40 ml of EAeach time. The EA phase was subsequently dried over MgSÛ4 and the 43 1 3285 solvent was removed under reduced pressure. The residue was dissolvedin 10 ml of MeOH and admixed with 2 ml of a 10% aqueous HCl solution.The volatiles were removed under reduced pressure to leave 230 mg ofwhite crystals, m.p. 276-278°C. Détermination of the NHE inhibition

The inhibitory concentration IC50 for NHE-1 inhibition was determined asfollows: IC50 for NHE-1 inhibition was determined in an FLIPR assay bymeasurement of the pHj recovery in transfected cell lines which expresshuman NHE-1.

The assay was carried out in an FLIPR (fluorometric imaging plate reader)with black-walled 96-well microtiter plates with clear bases. The transfectedcell lines expressing the various NHE subtypes (the parental cell line LAP-1shows no endogenous NHE activity as a resuit of mutagenesis andsubséquent sélection) were seeded the preceding day at a density of~25 000 cellsfwell.

The growth medium for the transfected cells (Iscove +10% fêtai calf sérum)additionally contained G418 as sélection antibiotic in order to ensure thepresence of the transfected sequences.

The actual assay started with the removal of the growth medium andaddition of 100 μΙ of loading buffer per well (5 μΜ BCECF-AM [2‘,7‘-bis(carboxyethyl)-5- (and -6-)carboxyfluorescein, acetoxymethyl ester] in20 mM NH4CI, 115 mM choline chloride, 1 mM MgCl2, 1 mM CaCl2, 5 mM KCI, 20 mM HEPES, 5 mM glucose; pH 7.4 [adjusted with KOH]). The cellswere then incubated at 37°C for 20 minutes. This incubation led to loadingof the cells with the fluorescent dye whose fluorescence intensity dépendson pHi, and with NH4CI which made the cells slightly alkaline.

The nonfluorescent dye precursor BCECF-AM is, as ester, membrane- 44 1 3285 permeable. The actual dye BCECF is not membrane-permeable but isliberated inside ceils by esterases.

Afterthis incubation for 20 minutes, the loading buffer which containedNH4CI and free BCECF-AM was removed by washing three times in a cellwasher (Tecan Columbus) with in each case 400 pl of washing buffer(133.8 mM choline chloride, 4.7 mM KCI, 1.25 mM MgCl2, 1.25 mM CaCl2,

0.97 mM K2HPO4, 0.23 mM KH2PO4, 5 mM HEPES, 5 mM glucose; pH 7.4 [adjusted with KOH]). The résiduel volume which remained in the wellswas 90 pl (50-125 pl possible). This washing step removed the freeBCECF-AM and results, as a conséquence of the removal of the externalNH44· ions, in intracellular acidification (- pHj 6.3 - 6.4).

Since the equilibrium of intracellular NH4+ with NH3 and H+ was disturbedby the removal of the extracellular NH4+ and by the subséquentinstantaneous passage of the NH3 through the cell membrane, the washing process resulted in H+ remaining inside the ceils, which was the cause ofthe intracellular acidification. This may eventually lead to cell death if itpersists long enough.

It was important at this point that the washing buffer was sodium-free(<1 mM) because extracellular sodium ions would lead to an instantaneousrecovery of the pHj through the activity of the cloned NHE isoforms. (t was likewise important for ail the buffers used (loading buffer, washingbuffer, recovery buffer) not to contain any HCO3 ions, because thepresence of bicarbonate would lead to activation of interfering bicarbonate-dependent pHj regulatory Systems présent in the parental LAP-1 cell line.

The microtiter plates with the acidified ceils were then (up to 20 minutesafterthe acidification) transferred to the FLIPR. In the FLIPR, theintracellular fluorescent dye was excited by light with a wavelength of488 nm generated by an argon laser, and the measured parameters (laserpower, illumination time and aperture of the CCD caméra incorporated in « 13285 the FLIPR) were chosen so that the average fluorescence signal per well isbetween 30 000 and 35 000 relative fluorescence units.

The actual measurement in the FLIPR started with a photograph beingtaken by the CCD caméra every two-seconds under software control. Afterten seconds, the recovery of the intracellular pH was initiated by adding90 pl of recovery buffer (133.8 mM.NaCI, 4.7 mM KCI, 1.25 mM MgCl2, 1.25 mM CaCI2, 0.97 mM K2HPO4, 0.23 mM KH2PO4, 10 mM HEPES, 5 mM glucose; pH 7.4 [adjusted with NaOH]) by means of the 96-wellpipettor incorporated in the FLIPR.

Positive control wells (100% NHE activity) were those to which purerecovery buffer is added, while négative Controls (0% NHE activity)received washing buffer. Recovery buffer with twice the concentration oftest substance was added to ail the other wells. Measurement in the FLIPRterminated -after 60 measurements (two minutes).

The raw data are exported into the ActivityBase program. This programfirstly calculâtes the NHE activities for each tested substance concentrationand, from these, the IC50 values for the substances. Since the progress ofpHj recovery was not linearthroughout the experiment, but fell at the endowing to decreasing NHE activity at higher pH; values, it was important to select for évaluation of the measurement the part in which the increase influorescence of the positive Controls was linear.

Example NHE1 inhibition IC50 [nM] 1 49

In vivo pharmacokinetics - profiling with the “n in one method”

The exposure data and the volumes of distribution were determined ascharacteristic pharmacokinetic data as follows: 1 3285

The NHE-1 inhibitorof example 1 of the invention and, as référencésubstance, the known NHE-1 inhibitor cariporide with the formula

were dissolved in an aqueous, slightly acidic medium (water, pH 4, 5 adjusted with 1M hydrochloric acid). The concentration of the aqueous formulation prepared in this way was about 1.5 mg of each substance per1 g of solution. 10 ml of this formulation were administered as a singlebolus by cathéter into the jugular vein of a fasting male beagle dog (doseabout 1 mg of each substance administered per kg of the dog’s body 10 weight). Blood samples were taken by means of a second cathéter after5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h and 24 h, and heparinized plasmawas prepared by centrifugation at 1000 G in appropriate plasma tubes.

The plasma samples were worked up and, after an HPLC séparation, 15 quantified by MS/MS. The high specificity of this method permitted simultaneous détermination of a plurality of substances. The exposurescould be calculated using the WinNonlin computer program from theconcentration-time plots (see figure 1) and compared with the exposure ofthe known NHE-1 référencé substance. Since the various substances were 20 measured in the same animal at the same time, the resuit was an accuratecomparison of the compounds, and a ranking of the volumes of distributionwas possible.

Compound Volume of distribution [l/kg of body weight] Example 1 1.67 Référencé substance cariporide 2.94 47 1 3285

It is clearly évident from the concentration-time plots in figure 1 that the compound of the invention is retained in the blood also over a longer period and thus the exposure is about 2-3 times higherthan with the reference 5 substance cariporide. Cariporide is no longer détectable in the plasma after 24 hours.

The captions and signs in the figure were as follows:

Fig. 1 : concentration-time plots in the blood plasma of dogs after 10 administration of in each case approx. 1 mg/kg of the compound ofexample 1 and of cariporide. y axis: concentration of the measured compound in the pg/ml in plasmax axis: time in h

Claims (16)

10 10 48 Patent daims

1. A compound of the formula I in which R1 R1 15 R2 1 3285 15 R2 20 20

N Y R1 O NH. NH, is hydrogen, alkyl having 1,2,3 or 4 carbon atoms, alkoxy having 1,2, 3 or 4 carbon atoms, F, Cl, Br, I, -CN, NR5R6, -Op-(CH2)n- (CF2)O-CF3 or -(SOm)q -(CH2)r(CF2)s-CF3; R5 and R6 are, independently of one another, hydrogen, alkylhaving 1,2, 3 or 4 carbon atoms or-CH2-CF3; m is zéro, 1 or 2n, o, p, q, r and s are-, independently of one another, zéro or 1 ;is hydrogen, alkyl having 1,2, 3 or 4 carbon atoms, alkoxy having 1,2, 3 or 4 carbon atoms, F, Cl, Br, I, -CN, NR7R8, -Ot-(CH2)u-(CF2)v-CF3 or-(SOw)x-(CH2)y-(CF2)z-CF3; R7 and R8 are, independently of one another, hydrogen, alkylhaving 1,2, 3 or 4 carbon atoms or -CH2-CF3; w is zéro, 1 or 2t, u, v, x, y and z are, independently of one another, zéro or 1 ; 49 1 3285 R3 is Cl, Br, I, -CN, -SO2CH3, alkoxy having 1,2, 3 or 4 carbon atoms, NR9R1.0, -Oa-(CH2)b-(CF2)c-CF3, -(SOd)e-(CH2)f-(CF2)g-CF3, alkylhaving 1,2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6,7 or 8 carbon atoms, in which 1,2, 3 or 4 hydrogen atoms may bereplaced by fluorine atoms; R9 and R10 are, independently of one another, hydrogen, alkylhaving 1,2, 3 or 4 carbon atoms or -CH2-CF3; a, b and c are, independently of one another, zéro or 1 ;d is zéro, 1 or 2; e is zéro or 1 ; f is zéro, 1,2, 3 or 4; g iszeroorl; or R3 is -(CH2)h-phenyl or -O-phenyl, in which the phenyl radicals are unsubstituted or substituted by 1,2or 3 radicals selected from the group consisting of F, Cl, Br, I,-Oj-(CH2)k-CF3, alkoxy having 1,2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -SO2CH3;j is zéro or 1 ;k is zéro, 1,2 or 3; h is zéro, 1,2, 3 or 4;or R3 is -(CH2)aa-heteroaryl1 which is unsubstituted or substituted by 1,2 or 3 radicals selectedfrom the group consisting of F, Cl, Br, I, -Obb-(CH2)cc-CF3, alkoxyhaving 1,2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbonatoms and -SO2CH3; bb is zéro or 1 ;is-zero, 1,2 or 3; cc 50 1 3285 aa is zéro, 1,2, 3 or 4; R4 is hydrogen, F, Cl, Br, I, -GN, -SO2CH3, alkoxy having 1,2, 3 or 4carbon atoms, NR11R12, -Odd-(CH2)ee-(CF2)ff-CF3; -(SOgg)hh- (CH2)jj-(CF2)kk"CF3, alkyl having 1,2, 3, 4, 5 or 6 carbon atoms orcycloalkyf having 3, 4, 5, 6, 7 or 8 carbon atoms, in which 1, 2, 3 or 4hydrogen atoms may be replaced by fluorine atoms; R11 and R12 are, independently of one another, hydrogen, alkylhaving 1,2, 3 or 4 carbon atoms or -CH2-CF3; dd, ee and ff are, independently of one another, zéro or 1 ;gg is zéro, 1 or2; hh is zéro or 1 ; jj is zéro, 1,2, 3 or 4;kk is zéro or 1 ; or R4 is -(CH2)n-phenyl or -O-phenyl, in which the phenyl radicals are unsubstituted or substituted by 1,2or 3 radicals selected from the group consisting of F, Cl, Br, I,-Omm-(CH2)nn-CF3, alkoxy having 1, 2, 3 or 4 carbon atoms, alkylhaving 1,2, 3 or 4 carbon atoms and -SO2CH3; mm is zéro or 1 ;nn is zéro, 1,2 or 3; Il is zéro, 1,2, 3 or 4;or R4 is -(CH2)oo-heteroaryl, which is unsubstituted or substituted by 1,2 or 3 radàcals selectedfrom the group consisting of F, Cl, Br, I, -OpP-(CH2)rrCF3, alkoxyhaving 1,2, 3 or 4 carbon atoms, alkyl having 1,2, 3 or 4 carbonatoms and -SO2CH3; 1 3285 pp is zéro or 1 ;rr is zéro, 1,2 or 3; oo is zéro, 1,2, 3 or 4;and the pharmaceutically acceptable salts thereof.

2. A compound of the formula I as claimed in claim 1, in which themeanings are: R1 hydrogen, alkyl having 1,2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, I, -CN, NR5R6,-Op-(CH2)n-(CF2)o-CF3 or -(SOm)q-(CH2)r(ÇF2)s-CF3; R5 and R6 independently of one another hydrogen, alkylhaving 1,2, 3 or 4 carbon atoms or-CH2-CF3; m zéro, 1 or 2n, o, p, q, r and s independently of one another zéro or 1 ; R2 hydrogen or F; R3 Cl, Br, I, -CN, -SO2CH3, alkoxy having 1, 2, 3 or 4 carbon atoms,NR9R10, -Oa-(CH2)b-(CF2)c-CF3, -(SOd)e-(CH2>(CF2)g-CF3, alkylhaving 1,2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, in which 1, 2, 3 or 4 hydrogen atoms may bereplaced by fluorine atoms; R9 and R10 independently of one another hydrogen, alkyl having 1,2, 3 or 4 carbon atoms or -CH2-CF3; a, b and c independently of one another zéro or 1 ;d zéro, 1 or 2; e zéro or 1 ; f zéro, 1,2, 3 or 4; g zéro or 1 ; or 52 1 3285 R3 . -(CH2)h-phenyl or-O-phenyl, in which the phenyl radicale are unsubstituted or substituted by 1,2or 3 radical.s selected from the group consisting of F, Cl, Br, I,-Oj-(CH2)k-CF3, alkoxy having 1,2, 3 or 4 carbon atoms, alkyl having 1,2, 3 or 4 carbon atoms and -SO2CH3;j zéro or 1 ; k zéro, 1,2 or 3; h zéro, 1,2, 3 or 4; or R3 -(CH2)aa-heteroaryl, which is unsubstituted or substituted by 1,2 or 3 radicals selectedfrom the group consisting of F, Cl, Br, I, -Obb-(CH2)cc-CF3, alkoxyhaving 1,2, 3 or 4 carbon atoms, alkyl having 1,2, 3 or 4 carbonatoms and -SO2CH3; bb zéro or 1 ; cc zéro, 1,2 or 3; aa zéro, 1,2, 3 or 4; R4 hydrogen or F; and the pharmaceutically acceptable salts thereof.

3. A compound of the formula I as claimed in claim 1 or 2, in which themeanings are: R1 hydrogen, alkyl having 1,2, 3 or 4 carbon atoms, alkoxy having 1,2, 3 or 4 carbon atoms, F, Cl, Br, I, -CN, NR5R6, -O-CH2-CF3 or -(SOm)q-(CH2)rCF3; R5 and R6 independently of one another hydrogen, alkyl having 1,2, 3 or 4 carbon atoms or -CH2-CF3; m zéro,1 or 2q and r independently of one another zéro or 1 ; 53 1 3285 R2 hydrogen or F; R3 Cl, Br, I, -CN, -SO2CH3, alkoxy having 1,2, 3 or 4 carbon atoms, NR9R10, -O-CH2-CF3, -(SOd)e'CF3, alkyl having 1,2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, inwhich 1, 2, 3 or 4 hydrogen atoms may be replaced by fluorineatoms; R9 and R10 independentiy of one another hydrogen, alkyl having 1,2, 3 or 4 carbon atoms or -CH2-CF3; d zéro, 1 or 2; e zéro or 1 ; or R3 phenyl, which is unsubstituted or substituted by 1,2 or 3 radicals selectedfrom the group consisting of F, Cl, Br, I, -Oj-(CH2)k-CF3, alkoxyhaving 1, 2, 3 or 4 carbon atoms, alkyl having 1,2, 3 or 4 carbonatoms and-SO2CH3; j zéro or 1 ; k zéro, 1,2 or 3; or R3 heteroaryl, which is unsubstituted or substituted by 1,2 or 3 radicals selectedfrom the group consisting of F, CI, Br, I, -Obb-(CH2)cc-CF3, alkoxy ’having 1, 2, 3 or 4 carbon atoms, alkyl having 1,2, 3 or 4 carbonatoms and -SO2CH3; bb zéro or 1 ; cc zéro, 1,2 or 3; R4 hydrogen or F; and the pharmaceutically acceptable salts thereof.

4. A compound of the formula I as claimed in one or more of daims 1,2 and 3, in which the meanings are: 54 1 3285 R1 hydrogen, alkyl having 1,2, 3 or 4 carbon atoms, methoxy, ethoxy,F, Cl, NR5R6, -O-CH2-CF3 or -(SOm)q-(CH2)rCF3; R5 and R6 independently of one another hydrogen, alkyl having 1,5 . 2, 3 or4 carbon atoms or-CH2-CF3; m zéro, 1 or 2q and r independently of one another zéro or 1 ; R2 hydrogen or F; 10 R3 Cl,-CN,-SO2CH3, methoxy, ethoxy, NR9R10,-O-CH2-CF3, -(SOd)e-CF3, alkyl having 1,2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, in which 1,2, 3 or 4hydrogen atoms may be replaced by fluorine atoms; R9 and R10 15 independently of one another hydrogen, methyl, ethyl or-CH2-CF3; d zéro, 1 or 2; e zéro or 1 ; or 20 R3 phenyl, which is unsubstituted or substituted by 1 or 2 radicals selected fromthe group consisting of F, Cl, -Oj-(CH2)k-CF3, methoxy, ethoxy, alkyl having 1,2, 3 or 4 carbon atoms and -SO2CH3;j and k 25 independently of one another zéro or 1 ; or R3 heteroaryl, which is unsubstituted or substituted by 1 or 2 radicals selected fromthe group consisting of F, Cl, -Obb-(CH2)cc-CF3, methoxy, ethoxy, 30 alkyl having 1,2, 3 or 4 carbon atoms and -SO2CH3; bb and cc 55 1 3285 independently of one another zéro or 1 ; R4 hydrogen or F; and the pharmaceuticaily acceptable salts thereof.

5. A compound of the formula I as claimed in any of daims 1 to 4 andselected from: N-(5-methanesulfonyl-2-methyl-4-pentafluorosulfanyl-benzoyl)guanidine, and the pharmaceuticaily acceptable salts thereof.

6. A process for preparing a compound of the formula I as claimed inone or more of daims 1,2,3, 4 and 5 and/or the pharmaceuticailyacceptable salts thereof, which comprises reacting a compound of theformula II,

II in which Ri to R4 hâve the meaning stated in daims 1 to 4 and L is aleaving group which can undergo nucleophilic substitution, with guanidine.

7. A compound of the formula I and/or the pharmaceuticaily acceptablesalts thereof as claimed in one or more of daims 1 to 5 for use asmédicament.

8. The use of a compound of the formula I and/or the pharmaceuticailyacceptable salts thereof as claimed in one or more of daims 1 to 5 forproducing a médicament for the treatment or prophylaxis of acute orchronic damage, disorders or indirect sequelae of organs and tissuescaused by ischémie or reperfusion events, for the treatment or prophylaxisof arrhythmias, of life-threatening cardiac ventricular fibrillation, ofmyocardiai infarction, of angina pectoris, for the treatment or prophylaxis ofischémie States of the heart, of ischémie States of the peripheral and centralnervous System or of stroke or of ischémie States of peripheral organs and 1 3285 56 tissues, for the treatment or prophylaxis of States of shock, of diseases inwhich cellular prolifération represents a primary or secondary cause, ofcancer, of metastasis, of prostate hypertrophy and of prostate hyperplasia,of atherosclerosis or of disturbances of lipid metabolism, of high bloodpressure, of essential hypertension, of disorders of the central nervousSystem, of disorders resulting from overexcitability of the CNS, epilepsy orcentrally induced convulsions, of disorders of the central nervous System, ,especially of anxiety States, dépréssions or psychoses, for the treatment orprophylaxis of non-insulin-dependent diabètes mellitus (NIDDM) or latedamage from diabètes, of thromboses, of disorders resulting fromendothélial dysfunction, of intermittent claudication, for the treatment orprophylaxis of fibrotic disorders of internai organs, fibrotic disorders of theliver, fibrotic disorders of the kidney, fibrotic disorders of vessels andfibrotic disorders of the heart, for the treatment or prophylaxis of heartfailure or of congestive heart fâilure, of acute or chronic inflammatorydisorders, of disorders caused by protozoa, of malaria and of coccidiosis inpoultry, and for use for surgical operations and organ transplantations, forpreserving and storing transplants for surgical procedures, for use inbypass operations, for use in resuscitation after a cardiac arrest, forpreventing age-related tissue change, for producing a médicament directedagainst aging or for prolonging life, for the treatment and réduction of thecardiotoxic effects in thyrotoxicosis or for producing a diagnostic aid.

9. The use of a compound of the formula I and/or the pharmaceuticallyacceptable salts thereof as claimed in one or more of daims 1 to 5 incombination with other médicaments or active ingrédients for producing amédicament for the treatment or prophylaxis of acute or chronic damage,disorders or indirect sequelae of organs and tissues caused by ischémie orreperfusion events, for the treatment or prophylaxis of arrhythmias, of life-threatening cardiac ventricular fibrillation, of myocardial infarction, of anginapectoris, for the treatment or prophylaxis of ischémie States of the heart, ofischémie States of the peripheral and central nervous System or of stroke orof ischémie States of peripheral organs and tissues, for the treatment orprophylaxis of States of shock, of diseases in which cellular prolifération 57 1 3285 represents a primary or secondary cause, of cancer, of metastasis, ofprostate hypertrophy and of prostate hyperplasia, of atherosclerosis orofdisturbances of lipid metabolism, of high blood pressure, of essentialhypertension, of disorders of the central nervous System, of disorders 5 resulting from overexcitability of the CNS, epilepsy or centrally inducedconvulsions, of disorders of the central nervous System, especially ofanxiety States, dépréssions or psychoses, for the treatment or prophylaxisof non-insulin-dependent diabètes mellitus (NIDDM) or late damage fromdiabètes, of thromboses, of disorders resulting from endothélial 10 dysfunction, of intermittent claudication, for the treatment or prophÿlaxis offibrotic disorders of internai organs, fibrotic disorders of the liver, fibroticdisorders of the kidney, fibrotic disorders of vessels and fibrotic disorders ofthe heart, for the treatment or prophylaxis of heart failure or of congestiveheart failure, of acute or chronic inflammatory disorders, of disorders 15 caused by protozoa, of malaria and of coccidiosis in poultry, and for use forsurgical operations and organ transplantations, for preserving and storingtransplants for surgical procedures, for use in bypass operations, for use inresuscitation after a cardiac arrest, for preventing age-related tissuechange, for producing a médicament directed against aging or for 20 prolonging life, for the treatment and réduction of the cardiotoxic effects inthyrotoxicosis or for producing a diagnostic aid.

10. The use of a compound of the formula I and/orthe pharmaceuticallyacceptable salts thereof as claimed in claim 9 in combination with 25 cardiotoxic and cytotoxic médicaments or active ingrédients for producing amédicament with reduced cardiotoxic and cytotoxic properties. '

11. The use of a compound of the formula I and/or the pharmaceuticallyacceptable salts thereof atone or in combination with other médicaments or 30 active ingrédients as claimed in claim 8 and/or 9 for producing a médicament for the treatment or prophylaxis of acute or chronic damage,disorders or indirect sequelae of organs and tissues caused by ischémie orreperfusion events. 1 3285 58

12. The use of a compound of the formula I and/or the pharmaceuticallyacceptable salts thereof alone or in combination with other médicaments oractive ingrédients as claimed in claim 8 and/or 9 for producing amédicament for the treatment of life-threatening cardiac ventricularfibrillation.

13. The use of a compound of the formula I and/or the pharmaceuticallyacceptable salts thereof alone or in combination with other médicaments oractive ingrédients as claimed in claim 8 and/or 9 for producing amédicament for the treatment or prophylaxis of metastasis.

14. The use of a compound of the formula I and/or the pharmaceuticallyacceptable salts thereof alone or in combination with other médicaments oractive ingrédients as claimed in claim 8 and/or 9 for producing amédicament for the treatment or prophylaxis of fibrotic disorders of theheart, of heart failure or of congestive heart failure.

15. A medicine for human, veterinary and/or phytoprotective usecomprising an effective amount of a compound of the formula I and/or thepharmaceutically acceptable salts thereof as claimed in one or more ofdaims 1 to 5, together with pharmaceutically acceptable carriers andadditives.

16. A medicine for human, veterinary and/or phytoprotective use comprising an effective amount of a compound of the formula I and/or thepharmaceutically acceptable salts thereof as claimed in one or more ofdaims 1 to 5, together with pharmaceutically acceptable carriers andadditives in combination with other pharmacological active ingrédients ormédicaments.