AU2004288758B2 - Pentafluorosulfanyl benzoylguanidines, method for their production, their use as medicaments or diagnostic agents and medicament containing the same - Google Patents
Pentafluorosulfanyl benzoylguanidines, method for their production, their use as medicaments or diagnostic agents and medicament containing the same Download PDFInfo
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- AU2004288758B2 AU2004288758B2 AU2004288758A AU2004288758A AU2004288758B2 AU 2004288758 B2 AU2004288758 B2 AU 2004288758B2 AU 2004288758 A AU2004288758 A AU 2004288758A AU 2004288758 A AU2004288758 A AU 2004288758A AU 2004288758 B2 AU2004288758 B2 AU 2004288758B2
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Description
WO 2005/047239 PCT/EP2004/012393 1 Pentafluorosulfanyl benzoylguanidines, method for their production, their use as medicaments or diagnostic agents and medicament containing the same 5 Pentafluorosulfanylbenzoylguanidines of the formula I F R3 F,\ /F s R2 F / F N NH2 R4X2 R1 0
NH
2 in which R1 to R4 have the meanings indicated in the claims, and the pharmaceutically acceptable salts thereof are substituted acylguanidines 10 and inhibit the cellular sodium-proton antiporter (Na+/H+ exchanger, NHE). Because of the NHE-inhibitory properties, the compounds of the formula I and the pharmaceutically acceptable salts thereof are suitable for the prevention and treatment of diseases caused by activation or activated NHE, and of diseases caused secondarily by the NHE-related damage. 15 Compared with known compounds, the compounds of the invention are distinguished by an extremely high activity in the inhibition of Na/H+ exchange, and by improved ADMET properties. The xenobiotic structure (in particular the introduction of the rather "unnatural/manmade" SF 5 20 substituents) advantageously influences tissue distribution. This leads inter alia to increased exposures in vivo. This involves no significant influence on the absorption characteristics, and the high bioavailability of the acylguanidines is retained. 25 In contrast to some acylguanidines described in the literature, the compounds of the formula I described herein and their pharmaceutically 2 acceptable salts show no unwanted and disadvantageous saliduretic properties. The invention relates to pentafluorosulfanylbenzoylguanidines of the 5 formula I F R3 FN\ /F F -R2 F N
NH
2 R45 r R1 0
NH
2 in which R1 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 10 2, 3 or 4 carbon atoms, F, Cl, Br, I, -CN, NR5R6, -Op-(CH2)n (CF2)o-CF 3 or -(SOm)q -(CH2)r-(CF2)s-CF3; R5 and R6 are, independently of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH2-CF 3 ; 15 m is zero, 1 or 2 n, o, p, q, r and s are, independently of one another, zero 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, 20 -Ot-(CH2)u-(CF2)v-CF3 or -(SOw)x-(CH2)y-(CF2)z-CF3; R7 and R8 are, independently of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH2-CF3; w is zero, 1 or 2 25 t,u,v, x,y and z are, independently of one another, zero or 1; 3 R3 is Cl, Br, I, -CN, -SO2CH 3 , alkoxy having 1, 2, 3 or 4 carbon atoms, NR9R10, -Oa-(CH2)b-(CF2)c-CF3, -(SOd)e-(CH2)f-(CF2)g-CF3, alkyl having 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 be 5 replaced by fluorine atoms; R9 and R10 are, independently of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH 2
-CF
3 ; a, b and c 10 are, independently of one another, zero or 1; d is zero, 1 or 2; e is zero or 1; f is zero, 1, 2, 3 or 4; g is zero or 1; 15 or R3 is -(CH2)h-phenyl or -O-phenyl, in which the phenyl radicals are unsubstituted or substituted by 1, 2 or 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 20 having 1, 2, 3 or 4 carbon atoms and -SO 2
CH
3 ; j is zero or 1; k iszero,1,2or3; h is zero, 1, 2, 3 or 4; or 25 R3 is -(CH2)aa-heteroaryl, which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, Cl, Br, I, -Obb-(CH2)cc-CF3, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -SO 2
CH
3 ; 30 bb is zero or 1; cc iszero,1,2or3; 4 aa is zero, 1, 2, 3 or 4; R4 is hydrogen, F, CI, Br, I, -CN, -SO2CH 3 , alkoxy having 1, 2, 3 or 4 carbon atoms, NR1 1 R1 2, -Odd-(CH2)ee-(CF2)ff-CF3; -(SOgg)hh 5 (CH2)jj-(CF2)kk-CF3, alkyl having 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 be replaced by fluorine atoms; R11 and R12 are, independently of one another, hydrogen, alkyl 10 having 1, 2, 3 or 4 carbon atoms or -CH 2
-CF
3 ; dd, ee and ff are, independently of one another, zero or 1; gg is zero, 1 or 2; hh is zero or 1; 15 jj is zero, 1, 2, 3 or 4; kk is zero or 1; or R4 is -(CH2)11-phenyl or -0-phenyl, in which the phenyl radicals are unsubstituted or substituted by 1, 2 20 or 3 radicals selected from the group consisting of F, CI, Br, I, -Omm-(CH2)nn-CF3, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -SO2CH 3 ; mm is zero or 1; nn is zero, 1, 2 or 3; 25 11 is zero, 1, 2, 3 or 4; or R4 is -(CH2)oo-heteroaryl, which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, Cl, Br, 1, -Opp-(CH2)rr-CF 3 , alkoxy 30 having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -SO2CH 3
;
5 pp is zero or 1; rr is zero, 1, 2 or 3; 00 is zero, 1, 2, 3 or 4; and the pharmaceutically acceptable salts thereof. 5 Preference is given to compounds of the formula 1, in which the meanings 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, 10 -Op-(CH2)n-(CF2)o-CF3 or -(SOm)q-(CH2)r(CF2)s-CF3; R5 and R6 independently of one another hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH2-CF 3 ; m zero, 1 or 2 15 n,o, p, q, rand s independently of one another zero or 1; R2 hydrogen or F; R3 Cl, Br, I, -CN, -S02CH 3 , alkoxy having 1, 2, 3 or 4 carbon atoms, NR9R10, -Oa-(CH2)b-(CF2)c-CF3, -(SOd)e-(CH2)f-(CF2)g-CF3, alkyl 20 having 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 be replaced by fluorine atoms; R9 and R10 independently of one another hydrogen, alkyl having 1, 25 2, 3 or 4 carbon atoms or -CH2-CF 3 ; a, b and c independently of one another zero or 1; d zero, 1 or 2; e zero or 1; 30 f zero, 1, 2, 3 or 4; g zero or 1; or 6 R3 -(CH2)h-phenyl or -0-phenyl, in which the phenyl radicals are unsubstituted or substituted by 1, 2 or 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 5 having 1, 2, 3 or 4 carbon atoms and -S02CH 3 ; j zero or 1; k zero, 1, 2 or 3; h zero,1,2,3or4; or 10 R3 -(CH2)aa-heteroaryl, which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, Cl, Br, I, -Obb-(CH2)cc-CF3, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -SO 2
CH
3 ; 15 bb zero or 1; cc zero, 1, 2 or 3; aa zero, 1, 2, 3 or 4; R4 hydrogen or F; and the pharmaceutically acceptable salts thereof. 20 Particular preference is given to compounds of the formula 1, in which the meanings 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-CF 3 or 25 -(SOm)q-(CH2)r-CF3; R5 and R6 independently of one another hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH 2
-CF
3 ; m zero, 1 or 2 30 qand r independently of one another zero or 1; 7 R2 hydrogen or F; R3 CI, Br, I, -CN, -SO 2
CH
3 , alkoxy having 1, 2, 3 or 4 carbon atoms, NR9R1O, -O-CH 2
-CF
3 , -(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, in 5 which 1, 2, 3 or 4 hydrogen atoms may be replaced by fluorine atoms; R9 and R10 independently of one another hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH2-CF 3 ; 10 d zero,1 or2; e zero or 1; or R3 phenyl, which is unsubstituted or substituted by 1, 2 or 3 radicals selected 15 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 -SO 2
CH
3 ; j zero or 1; k zero, 1, 2 or 3; 20 or R3 heteroaryl, which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, Cl, Br, I, -Obb-(CH2)cc-CF3, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon 25 atoms and -SO 2
CH
3 ; bb zero or 1; cc zero, 1, 2 or 3; R4 hydrogen or F; and the pharmaceutically acceptable salts thereof. 30 Very particular preference is given to compounds of the formula I in which the meanings are: 8 R1 hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, methoxy, ethoxy, F, Cl, NR5R6, -O-CH 2
-CF
3 or -(SOm)q-(CH2)r-CF3; R5 and R6 independently of one another hydrogen, alkyl having 1, 5 2, 3 or 4 carbon atoms or -CH2-CF3; m zero, 1 or 2 q and r independently of one another zero or 1; R2 hydrogen or F; 10 R3 Cl, -CN, -SO2CH 3 , methoxy, ethoxy, NR9R1O, -O-CH2-CF 3 , -(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 4 hydrogen atoms may be replaced by fluorine atoms; R9 and R10 15 independently of one another hydrogen, methyl, ethyl or -CH 2
-CF
3 ; d zero, 1 or 2; e zero or 1; or 20 R3 phenyl, which is unsubstituted or substituted by 1 or 2 radicals selected from the 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 zero or 1; or R3 heteroaryl, which is unsubstituted or substituted by 1 or 2 radicals selected from the group consisting of F, Cl, -Obb-(CH2)cc-CF3, methoxy, ethoxy, 30 alkyl having 1, 2, 3 or 4 carbon atoms and -SO2CH 3 ; bb and cc 9 independently of one another zero or 1; R4 hydrogen or F; and the pharmaceutically acceptable salts thereof. 5 In one embodiment, preference is given in this connection to the compounds of the formula I in which R1 is described by 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, where R5 and R6 are, independently of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH2-CF 3 , or 10 -O-CH 2
-CF
3 or -(SOm)q-(CH2)r-CF3, where m is zero, 1 or 2, and q and r are, independently of one another, are zero or 1; particular preference is given to compounds in which R1 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 4 15 carbon atoms or -CH2-CF 3 , -O-CH 2 -CF3 or -(SOm)q-(CH2)rCF3, where m is zero, 1 or 2, and q and r are, independently of one another, zero or 1; very particular preference is given to compounds in which R1 is described by hydrogen, methyl, ethyl, CF 3
-CH
2 -0-, F, Cl or CF 3 . In a further embodiment, preference is given to compounds in which R1 is described 20 by hydrogen, methyl or ethyl, in particular methyl or ethyl. In a further embodiment, preference is given to compounds of the formula I in which R2 is described by hydrogen or F; particular preference is given to compounds in which R2 is described by hydrogen. 25 In a further embodiment, preference is given to compounds of the formula I in which R3 is described by Cl, -CN, -SO 2
CH
3 , methoxy, ethoxy, NR9R1O, where R9 and R10 are, independently of one another, hydrogen, methyl, ethyl or -CH2-CF 3 , or -O-CH 2
-CF
3 , -(SOd)e-CF3, where d is zero, 1 or 2, 30 and e is zero 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 be replaced by fluorine atoms, phenyl which is unsubstituted or 10 substituted by 1,2 or 3 radicals selected from the group consisting of F, Cl, Br, I, -Oj-(CH2)k-CF3, where j is zero or 1 and k is zero, 1, 2 or 3, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -SO 2
CH
3 , or heteroaryl which is unsubstituted or substituted by 1, 2 or 5 3 radicals selected from the group consisting of F, Cl, Br, I, -Obb (CH2)cc-CF3, where bb is zero or 1 and cc is zero, 1, 2 or 3, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -SO2CH 3 ; particular preference is given to compounds in which R3 is described by Cl, -CN, -SO2CH 3 , methoxy, ethoxy, NR9R1O, where R9 and 10 R10 are, independently of one another, hydrogen, methyl, ethyl or -CH2-CF 3 , or -O-CH 2
-CF
3 , -(SOd)e-CF3, where d is zero, 1 or 2, and e is zero 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 be replaced by fluorine atoms, phenyl which is unsubstituted or substituted by 15 1-2 radicals selected from the group consisting of F, Cl, -Oj-(CH2)k-CF3, where j and k are, independently of one another, zero or 1, methoxy, ethoxy, alkyl having 1, 2, 3 or 4 carbon atoms and -SO 2
CH
3 , or heteroaryl which is unsubstituted or substituted by 1-2 radicals selected from the group consisting of F, Cl, -Obb-(CH2)cc-CF3, where bb and cc are, 20 independently of one another, zero or 1, methoxy, ethoxy, alkyl having 1, 2, 3 or 4 carbon atoms and -SO2CH 3 ; very particular preference is given to compounds in which R3 is described by Cl, -CN or -SO2CH3. In a further embodiment, preference is given to compounds of the 25 formulae I in which R4 is described by hydrogen and F, with particular preference for compounds in which R4 is described by hydrogen. In a further embodiment, preference is given to compounds of the formula I in which p, t, a and dd are, independently of one another, 1. 30 11 If the substituents R1 to R4 contain one or more centers of asymmetry, these may independently of one another have both the S and the R configuration. The compounds may be in the form of optical isomers, of diastereomers, of racemates or of mixtures thereof. 5 The present invention encompasses all tautomeric forms of the compounds of the formula 1. Alkyl radicals may be straight-chain or branched. This also applies if they 10 carry substituents or occur as substituents of other radicals, for example in fluoroalkyl radicals or alkoxy radicals. Examples of alkyl radicals are methyl, ethyl, n-propyl, isopropyl (= 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 radicals 15 are 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-trifluoroethyl and pentafluoroethyl. Substituted alkyl radicals may be substituted in any positions. Examples of cycloalkyl radicals are cyclopropyl, cyclobutyl, 20 cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. One or more, for example 1, 2, 3 or 4, hydrogen atoms in cycloalkyl radicals may be replaced by fluorine atoms. Substituted cycloalkyl radicals may be substituted in any positions. 25 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 a phenyl radical is substituted, it preferably has one or two identical or different substituents. This likewise applies to substituted phenyl radicals in groups such as, for example, phenylalkyl or phenyloxy. The substituent in 30 monosubstituted phenyl radicals may be in position 2, position 3 or position 4. 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 in trisubstituted 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 Heteroaryl radicals are aromatic ring compounds in which one or more ring atoms are oxygen atoms, sulfur atoms or nitrogen atoms, e.g. 1, 2 or 3 nitrogen atoms, 1 or 2 oxygen atoms, 1 or 2 sulfur atoms or a combination 5 of various heteroatoms. The heteroaryl radicals may be attached by all positions, for example by the 1 position, 2 position, 3 position, 4 position, 5 position, 6 position, 7 position or 8 position. Heteroaryl radicals may be unsubstituted or be substituted one or more times, for example once, twice or three times, by identical or different radicals. This applies likewise to 10 heteroaryl 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. 15 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, 20 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-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 25 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 these compounds, i.e. for example 1-oxy-2-, 3- or 4-pyridyl. 30 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-pyrazolyl, 2-, 3- or 4-pyridyl, 2- or 3-pyrazinyl, 2-, 4-, 5- or 6-pyrimidinyl and 3- or 4-pyridazinyl.
13 The invention further relates to a process for preparing the compounds of the formula I which comprises reacting a compound of the formula I F R3 F /F R2 F / F R4 R1 0 in which R1 to R4 have the stated meaning, and L is a leaving group which 5 can undergo nucleophilic substitution, with guanidine. The activated acid derivatives of the formula 11 in which L is an alkoxy, preferably a methoxy, group, a phenoxy group, phenylthio, methylthio, 2-pyridylthio group, a nitrogen heterocycle, preferably 1-imidazolyl, are 10 advantageously obtained in a manner known to those skilled in the art from the underlying carbonyl chlorides (formula 11; L = Cl), which in turn can themselves be prepared in a known manner from the underlying carboxylic acids (formula 11; L = OH), for example using thionyl chloride. Besides the carbonyl chlorides of the formula II (L = Cl) it is also possible to 15 prepare other activated acid derivatives of the formula Il in a known manner directly from the underlying benzoic acids (formula 11; L = OH), such as the methyl esters of the formula il with L = OCH 3 by treatment with gaseous HCI in methanol, the imidazolides of the formula 11 by treatment with carbonyldiimidazole, the mixed anhydrides of the formula 11 by treatment 20 with Cl-COOC2H 5 or tosyl chloride in the presence of triethylamine in an inert 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 activated 25 carboxylic acid derivatives of the formula 11 are indicated in J. March, Advanced Organic Chemistry, third edition (John Wiley & Sons, 1985, page 350), indicating source literature.
14 Reaction of an activated carboxylic acid derivative of the formula Il with guanidine preferably takes place in a known manner in a protic or aprotic polar but inert organic solvent. Those which have proved suitable for the reaction of the methyl benzoates (formula 11; L = OCH3) with guanidine are 5 methanol, isopropanol or THF at temperatures from 20*C to the boiling point of these solvents. Most reactions of compounds of the formula II with salt-free guanidine are, for example, carried out in aprotic inert solvents such as THF, dimethoxyethane, dioxane. However, it is also possible to use water in the presence of a base such as, for example, NaOH as 10 solvent in the reaction of compounds of the formula 11 with guanidine. If L is Cl, it is advantageous to add an acid scavenger, for example in the form of excess guanidine, to bind the hydrohalic acid. 15 The compounds of the formula 11 can be prepared as follows, by 15 F H F F H F F H R2 F" FN 2F, F R2 FF R2 Fj a - F I NH b R4 .. o a R4 NH2 b R4C NH c - H X H 0 III IV V F H F H F N R2 F F R2 -F H F F F R2 F F Fd _e f R4 NH 2 R4 Y R4 R1 R1 R1 vi ViI Vill F FH F N F NH 2 N R2 F' R2 F N 2 F 0 F 0 h F R4 / g R45 / R4 R1 OH R1 OH R1 OH X XH Ix x xi F ,F R3 F -F R3 F' F / N R2 F | F~ F - 0 k F0 R4 R4 R1 OH R1 L XIl Il a) reducing a 4-nitrophenylsulfur pentafluoride derivative of the formula Ill to the amine of the formula IV, b) halogenating the compound of the formula IV in the ortho position to the 5 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 with a suitable nucleophile or an organoelement compound, for example an alkylboron compound, where appropriate with catalysis, by a substituent R1 10 and d) replacing the amino function in the compound of the formula VI by a halogen substituent, 16 e) replacing the halogen substituent in the compound of the formula VII by a nitrile function, f) hydrolyzing the nitrile function of the compound of the formula VIII to the carboxylic acid, 5 g) nitrating the compound of the formula IX in the ortho position to the pentafluorosulfanyl 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 X by R3 using a suitable nucleophile 10 and k) converting the compound of the formula XII into the compound of the formula Il, where in the compounds of the formulae 11, Ill, IV, V, VI, VII, VIII, IX, X, XI and X11 R1 to R4 are defined as in formula 1 15 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 in step a to convert the compounds of the formula Ill by methods known in 20 principle for the reduction of aromatic nitro compounds to aromatic amines into compounds of the formula IV. Such methods are described, for example, in: R.C. Larock, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, VCH Publishers, New York, Weinheim, 1999, 821-828 and the literature cited therein. 25 Subsequently (step b), the compounds of the formula IV are dissolved in an organic solvent A and reacted with a halogenating agent, for example a brominating agent. The reaction temperature in this case is generally from -30 0 C to +1500C, preferably 0*C to 40*C. The reaction time is generally 30 from 10 min to 20 h, depending on the composition of the mixture and the chosen temperature range. The resulting reaction mixture can be worked up by subsequent filtration through a layer of silica gel, washing with organic solvent A and, after removal of the solvent in vacuo, purifying the product by conventional purification methods such as recrystallization, 35 distillation or chromatography. From 0.1 to 10 mol of the compound of the formula IV for example are 17 dissolved in 1000 ml of organic solvent A. For example, from 0.8 to 1.2 equivalents of the halogenating agent are used for 1 mol of the compound of the formula IV to be halogenated. The term "halogenating agent" means for example elemental halogens, 5 halogen-amine complexes, cyclic and acyclic N-halogenated carboxamides and -imides, and ureas, as described, for example, in R.C. Larock, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, VCH Publishers, New York, Weinheim, 1999, 619-628, and the literature cited therein or M.B. Smith and J. March, March's Advanced 10 Organic Chemistry: Reactions, Mechanisms, and Structure, Wiley, New York, 2001, 704-707, and the literature cited therein, such as, for example, N-bromosuccinimide, N-chlorosuccinimide, HBr in H 2
SO
4 or 1,3-dibromo 5,5-dimethylimidazolidine-2,4-dione. The term "brominating agent" means, for example, elemental bromine, bromine-amine complexes, cyclic and 15 acyclic N-brominated carboxamides and -imides, and ureas, as described, for example, in R.C. Larock, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, VCH Publishers, New York, Weinheim, 1999, 622-624, and the literature cited therein or M.B. Smith and J. March, March's Advanced Organic Chemistry: Reactions, 20 Mechanisms, and Structure, Wiley, New York, 2001, 704-707, and the literature cited therein, for example N-bromosuccinimide, HBr in H 2
SO
4 or 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione, the latter being able to transfer 2 bromine atoms per molecule. The term "organic solvent A" preferably means aprotic solvents such as, for 25 example, 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 inorganic bases. 30 In step c, the compounds of the formula V are subsequently dissolved in an organic solvent B and reacted with a nucleophile R1 or an element compound comprising the substituent R1 to give compounds of the formula VI. It is possible in this case to add a base A and to add a catalyzing metal 35 salt A. The reaction temperature in this case is generally between -20*C and +150 0 C, preferably between 30 0 C and 100*C. The reaction time is generally from 0.5 h to 20 h, depending on the composition of the mixture and the chosen temperature range. The resulting reaction mixture can be 18 worked up by subsequent filtration through a layer of silica gel, washing with an organic solvent B and, after removal of the solvent in vacuo, purifying the product by conventional purification processes such as recrystallization, chromatography, for example on silica gel, distillation or 5 steam distillation. From 0.1 to 10 mol of the compound of the formula V for example are dissolved in 1000 ml of organic solvent B. For example, from 0.8 to 3 equivalents of the nucleophile R1 or of the element compound comprising the substituent R1 are used for 1 mol of the starting compound of the 10 formula V. The term "nucleophile R1" means compounds which result on deprotonation of a compound R1-H with strong bases such as, for example, alkyl- or aryllithium compounds, organomagnesium compounds, alcoholates or lithium diisopropylamide. 15 "Organoelement compounds comprising the substituent R1" mean for example organolithium compounds Ri-Li, organomagnesium compounds Ri-Mg-Hal, with Hal = Cl, Br, I, organoboron compounds such as R1-B(OH) 2 , R1-boronic esters such as, for example, R1-',0 0 20 Ri-boronic anhydrides such as, for example, R1 , B - BR1 I II UB BU OB' R1 or organozinc compounds R1-Zn-Z, with Z = Cl, Br, I. The term "base A" means bases like those used as auxiliary bases in 25 cross-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 the literature cited therein in each case, for example Na 2
CO
3 , Cs2CO3, KOH, NaOH, K 3
PO
4 , N(ethyl)3. 30 The term "organic solvent B" means protic or aprotic solvents such as diethyl ether, dimethoxyethane, THF, alcohols, water or mixtures thereof. In one embodiment, mixtures with water are preferred.
19 The term "catalyzing metal salt A" means inter alia Pd and Ni catalysts like those used for Suzuki and Negishi reactions and described 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, 5 54, 263 or G.C. Fu et al., J. Am. Chem. Soc. 2001, 123, 10099 or G.C. Fu et al., J. Am. Chem. Soc. 2002, 124, 13662 and the literature cited therein in each case, including the added ligands such as Pd(OAc) 2 , PdCl2(dppf) or Pd 2 (dba) 3 . 10 In step d, the compounds of the formula VI are subsequently converted into the compounds of the formula VII by a diazotization-halogenation process with a diazotizing-halogenating agent, for example with a diazotizing brominating agent, as described for other aromatic amines to replace the amine function by a halogen function for example in M.B. Smith and 15 J. 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 Group Preparations, VCH Publishers, New York, Weinheim, 1999, 678-679 and the literature cited therein, for example by the Sandmeyer or Gattermann 20 reaction. The process of M. Doyle et al., J. Org. Chem. 1977, 42, 2426 or of S. Oae et al., Bull. Chem. Soc. Jpn. 1980, 53,1065 is preferred. In step e, the compounds of the formula VII are reacted in a solvent C with a cyanidating agent, for example with addition of a catalyzing metal salt B. 25 The reaction temperature is generally from 20*C to 200'C, preferably 80*C to 150 0 C. The reaction time is generally from 1 h to 20 h, depending on the composition of the mixture and the chosen temperature range. The resulting reaction mixtures can be filtered with suction through a layer of silica gel or kieselguhr and the filtrate can be worked up by aqueous 30 extraction. After evaporation of the solvent in vacuo, the compound of the formula Vill is purified by conventional purification processes such as recrystallization, chromatography on silica gel, distillation or steam distillation. From 0.1 to 10 mol of the compound of the formula VII for example are 35 dissolved in 1000 ml of organic solvent C. For example, from 1 to 10 equivalents of the cyanidating agent are used for 1 mol of the compounds having the formula VII to be reacted. The term "cyanidating agent" means, for example, alkali metal cyanides or Zn(CN)2 either alone or mixed with metallic zinc, preferably in the form of 20 zinc dust. The term "organic solvent C" preferably means aprotic polar solvents such as, for example, DMF, dimethylacetamide, NMP, DMSO. The term "catalyzing metal salt B" means inter alia Pd and Ni catalysts like 5 those employed in Suzuki reactions and described 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 and the literature cited therein, for example PdCI2(dppf), Pd(OAc)2, Pd2(dba) 3 . 10 The resulting compounds of the formula VIII are subsequently hydrolyzed in step f to the carboxylic acids of the formula IX, for example in the presence of a base. This can take place by processes known to the skilled worker for hydrolyzing aromatic nitriles, as described, for example, in R.C. Larock, Comprehensive Organic Transformations: A Guide to 15 Functional Group Preparations, VCH Publishers, New York, Weinheim, 1999, 1986-1987 or M.B. Smith and J. March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Wiley, New York, 2001, 1179-1180 and the literature cited therein. 20 In step g, compounds of the formula IX are nitrated with a nitrating agent as described, for example, in Houben-Weyl, Methoden der organischen Chemie 4th edition, Organo-Stickstoff-Verbindungen IV, part 1, Georg Thieme Verlag Stuttgart 1992, pages 262-341. 25 In step h, the nitro compounds of the formula X are converted into compounds of the formula XI by methods known in principle for reducing aromatic nitro compounds to aromatic amines. Such methods are described for example in: R.C. Larock, Comprehensive Organic Transformations: a Guide to Functional Group Preparations, VCH 30 Publishers, New York, Weinheim, 1999, 821-828 and the literature cited therein. In step i, the anilines of the formula XI are converted by the diazotization replacement route into the compounds of the formula XII with replacement 35 of the amine group by R3. Such methods are known to the skilled worker and are described for example in Houben-Weyl, Methoden der organischen Chemie 4th edition, Organo-Stickstoff-Verbindungen I, part 2, Georg Thieme Verlag Stuttgart 1990, pages 1087-1136 and the references cited therein.
21 For example, an aniline of the formula XI can be converted by the diazotization-replacement route into a sulfochloride of the formula XII (R3 = SO 2 CI) as described, for example, in Houben-Weyl, Methoden der organischen Chemie 4th edition, Organo-Schwefel-Verbindungen, part 2, 5 Georg Thieme Verlag Stuttgart 1985, pages 1069-1070. In step k, the compounds of the formula XII are derivatized to the compounds of the formula Il by methods known to the skilled worker and as described above. 10 It is possible in this step for example for the sulfochlorides of the formula XII (R3 = SO2CI) to be converted initially into the corresponding sulfinic acids (as described for example in Houben-Weyl, Methoden der organischen Chemie 4th edition, Organo-Schwefel-Verbindungen, part 1, Georg Thieme Verlag Stuttgart 1985, pages 620-621 and Houben-Weyl, 15 Methoden der organischen Chemie, Schwefel-, Selen-, Tellur Verbindungen, Georg Thieme Verlag Stuttgart 1955, pages 304-309) and subsequently alkylated to give the methyl sulfone as described for example in Houben-Weyl, Methoden der organischen Chemie 4th edition, Organo Schwefel-Verbindungen, part 2, Georg Thieme Verlag Stuttgart 1985, 20 pages 1145-1149. Simultaneous esterification of the carboxylic acid to the methyl ester takes place. Compounds of the formula I in which R1 is hydrogen are prepared by carrying out the synthesis without steps b and c. 25 Compounds of the formula I in which R3 is NR9R10 are prepared by carrying out the synthesis without step i. Functional groups in the starting compounds may also be present in protected form or in the form of precursors, and then be converted into the desired groups in the compounds of the formula 11 prepared by the process 30 described above. Corresponding protective group techniques are known to the skilled worker. It is likewise possible for appropriate functional groups to be derivatized by methods known to the skilled worker. For example, compounds in which R3 is NH 2 can be converted by reaction with appropriate alkyl halides or 35 2,2,2-trifluoroethyl halides, for example methyl iodide, ethyl iodide or 2,2,2-trifluoroethyl iodide, into compounds in which R3 is NR9R1O, where R9 and R10 are, independently of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH2-CF 3 and are not both simultaneously hydrogen.
22 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 all pharmaceutically acceptable acids, for example halides, in 5 particular hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates, p-toluenesulfonates. The compounds of the formula I are substituted acylguanidines and inhibit the 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 I and/or the pharmaceutically acceptable salts thereof are suitable for the prevention and treatment of diseases caused by activation of or by an 15 activated NHE, and of diseases caused secondarily by the NHE-related damage. The compounds of the formula I may also be used for treating and preventing diseases by the NHE being only partially inhibited, for example by use of a low dosage. 20 Since NHE inhibitors predominantly act via their effect on cellular pH regulation, they can generally be combined beneficially with other compounds which regulate the intracellular pH, with suitable combination partners being inhibitors of the carbonic anhydrase enzyme group, 25 inhibitors of systems transporting bicarbonate ions, such as of the sodium bicarbonate cotransporter (NBC) or of the sodium-dependent chloride bicarbonate exchanger (NCBE), and NHE inhibitors with inhibitory effect on other NHE subtypes, because it is possible through them to enhance or modulate the pharmacologically relevant pH-regulating effects of the NHE 30 inhibitors described herein. The use of the compounds of the invention relates to the prevention and treatment of acute and chronic diseases in veterinary and human medicine.
23 Thus, the NHE inhibitors of the invention are suitable for the treatment of diseases caused by ischemia and by reperfusion. The compounds described herein are suitable because of their 5 pharmacological properties as antiarrhythmic medicaments. Owing to their cardioprotective component, the NHE inhibitors are outstandingly suitable for infarction prophylaxis and infarction treatment and for the treatment of angina pectoris, in which cases they also preventively inhibit or greatly reduce the pathophysiological processes 10 associated with the development of ischemia-induced damage, in particular in the triggering of ischemia-induced cardiac arrhythmias. Because of their protective effects against pathological hypoxic and ischemic situations, the compounds of the formula I and/or the pharmaceutically acceptable salts thereof used according to the invention can, because of inhibition of the 15 cellular Na+/H+ exchange mechanism, be used as medicaments for the treatment of all acute or chronic ischemia-induced damage or diseases induced primarily or secondarily thereby. This also relates to their use as medicaments for surgical interventions. 20 Thus, the compounds can be used during organ transplantations, it being possible to use the compounds both to protect the organs in the donor before and during the removal, to protect removed organs for example during treatment with or storage thereof in physiological bath liquids, and during transference to the recipient organism. 25 The compounds of the invention are likewise valuable medicaments with a protective effect when performing angioplastic surgical interventions, for example on the heart as well as on peripheral organs and vessels. 30 The compounds of the invention may also be used when performing bypass operations, for example bypass operations on coronary vessels and in Coronary Artery Bypass Graft (CABG).
24 Depending on their activity with regard to ischemia-induced damage, the compounds of the invention I may similarly be used in resuscitation after a cardiac arest. The compounds of the invention are of interest for medicaments for life 5 threatening arrhythmias. Ventricular fibrillation is terminated and the physiological sinus rhythm of the heart is restored. Since NHEI inhibitors of human tissue and organs, especially the heart, protect effectively not only against damage caused by ischemia and 10 reperfusion but also against the cytotoxic effect of medicaments like those used in particular in cancer therapy and the therapy of autoimmune diseases, combined administration with compounds of the formula I and/or the pharmaceutically acceptable salts thereof is suitable for inhibiting the cytotoxic, especially cardiotoxic, side effects of said compounds. The 15 reduction in the cytotoxic effects, especially the cardiotoxicity, resulting from comedication with NHE1 inhibitors makes it additionally possible to increase the dose of the cytotoxic therapeutic agents and/or to prolong the medication with such medicaments. The therapeutic benefits of such a cytotoxic therapy can be considerably increased by combination with NHE 20 inhibitors. In addition, the NHE1 inhibitors of the invention of the formula I and/or the pharmaceutically acceptable salts thereof can be used when there is heart damaging overproduction of thyroid hormones, thyrotoxicosis, or on 25 external supply of thyroid hormones. The compounds of the formula I and/or the pharmaceutically acceptable salts thereof are thus suitable for improving therapy with cardiotoxic medicaments. In accordance with their protective effect against ischemia-induced 30 damage, the compounds of the invention are also suitable as medicaments for the treatment of ischemias of the nervous system, especially of the central nervous system, being suitable for example for the treatment of stroke or of cerebral edema.
25 The compounds of the formula I and/or the pharmaceutically acceptable salts thereof are also suitable for the therapy and prophylaxis of diseases and disorders induced by overexcitability of the central nervous system, in particular for the treatment of epileptic disorders, centrally induced clonic 5 and tonic spasms, states of psychological depression, anxiety disorders and psychoses. In these cases it is possible to use the NHE inhibitors described herein alone or in combination with other substances with antiepileptic activity or antipsychotic active ingredients, or carbonic anhydrase inhibitors, for example with acetazolamide, and with other 10 inhibitors of NHE or of the sodium-dependent chloride-bicarbonate exchanger (NCBE). The compounds used according to the invention of the formula I and/or the pharmaceutically acceptable salts thereof are additionally likewise suitable 15 for the treatment of types of shock such as, for example, of allergic, cardiogenic, hypovolemic and bacterial shock. The compounds of the formula I and/or the pharmaceutically acceptable salts thereof can likewise be used for the prevention and treatment of 20 thrombotic disorders because they, as NHE inhibitors, are able to inhibit platelet aggregation themselves. They are additionally able to inhibit or prevent the excessive release, occurring after ischemia and reperfusion, of mediators of inflammation and coagulation, especially of von Willebrand factor and of thrombogenic selectin proteins. It is thus possible to reduce 25 and eliminate the pathogenic effect of significant thrombogenic factors. The NHE inhibitors of the present invention can therefore be combined with other anticoagulant and/or thrombolytic active ingredients such as, for example, recombinant or natural tissue plasminogen activator, streptokinase, urokinase, acetylsalicylic acid, thrombin antagonists, factor 30 Xa antagonists, medicinal substances with fibrinolytic activity, thromboxane receptor antagonists, phosphodiesterase inhibitors, factor VIIa antagonists, clopidogrel, ticlopidine etc. Combined use of the present NHE inhibitors with NCBE inhibitors and/or with inhibitors of carbonic anhydrase such as, for example, with acetazolamide, is particularly beneficial.
26 NHE1 inhibitors are additionally distinguished by a strong inhibitory effect on the proliferation of cells, for example fibroblast proliferation and the proliferation of smooth vascular muscle cells. The compounds of the 5 formula I and/or the pharmaceutically acceptable salts thereof are therefore suitable as valuable therapeutic agents for diseases in which proliferation represents a primary or secondary cause, and can therefore be used as antiatherosclerotics, agents for chronic renal failure, cancers. 10 It was possible to show that cell migration is inhibited by NHE inhibitors. The compounds of the formula I and/or the pharmaceutically acceptable salts thereof are therefore suitable as valuable therapeutic agents for dieases in which cell migration represents a primary or secondary cause, such as, for example, cancers with a pronounced tendency to metastasis. 15 NHE1 inhibitors are further distinguished by a retardation or prevention of fibrotic disorders. Compounds of the formula I and/or the pharmaceutically acceptable salts thereof are thus suitable as agents for the treatment of cardiac fibroses, and of pulmonary fibrosis, hepatic fibrosis, renal fibrosis 20 and other fibrotic disorders. They can thus be used for the treatment of organ hypertrophies and hyperplasias, for example of the heart and the prostate. They are therefore suitable for the prevention and treatment of heart failure (congestive heart failure = CHF) and for the treatment and prevention of prostate hyperplasia or prostate hypertrophy. 25 Since there is significant elevation in NHE in essential hypertensives, the compounds of the formula I and/or the pharmaceutically acceptable salts thereof are suitable for the prevention and treatment of high blood pressure and for the treatment of cardiovascular disorders. In these cases they can 30 be used alone or with a suitable combination and formulation partner for the treatment of high blood pressure and for the treatment of cardiovascular disorders. Thus, for example, one or more diuretics with a thiazide-like action, loop diuretics, aldosterone and pseudoaldosterone antagonists, such as hydrochlorothiazide, indapamide, polythiazide, 27 furosemide, piretanide, torasemide, bumetanide, amiloride, triamterene, spironolactone or eplerone, can be combined. The NHE inhibitors of the present invention can further be used in combination with calcium channel blockers such as verapamil, diltiazem, amlodipine or nifedipine, and with 5 ACE inhibitors such as, for example, ramipril, enalapril, lisinopril, fosinopril or captopril. Further beneficial combination partners are also beta-blockers such as metoprolol, albuterol etc., antagonists of the angiotensin receptor and its receptor subtypes such as losartan, irbesartan, valsartan, omapatrilat, gemopatrilat, endothelin antagonists, renin inhibitors, 10 adenosine receptor agonists, inhibitors and activators of potassium channels such as glibenclamide, glimepiride, diazoxide, cromakalim, minoxidil and derivatives thereof, activators of the mitochondrial ATP sensitive potassium channel (mitoK(ATP) channel), inhibitors of Kv1.5 etc. 15 It has emerged that NHE1 inhibitors have a significant antiinflammatory effect and can thus be used as antiinflammatory drugs. Inhibition of the release of mediators of inflammation is noteworthy in this connection. The compounds can thus be used alone or in combination with an antiinflammatory drug for the prevention or treatment of chronic and acute 20 inflammatory disorders. Combination partners advantageously used are steroidal and non-steroidal antiinflammatory drugs. The compounds of the invention can additionally be employed for the prevention or treatment of disorders caused by protozoa, such as malaria and coccidiosis in poultry. 25 It has additionally been found that NHE1 inhibitors show a beneficial effect on serum lipoproteins. It is generally acknowledged that blood fat levels which are too high, called hyperlipoproteinemias, represent an essential risk factor for the development of arteriosclerotic vascular lesions, especially coronary heart disease. The reduction of elevated serum 30 lipoproteins therefore has exceptional importance for the prophylaxis and regression of atherosclerotic lesions. Besides the reduction in total serum cholesterol, it is particularly important to reduce the proportion of specific atherogenic lipid fractions of this total cholesterol, in particular of the low density lipoproteins (LDL) and of the very low density lipoproteins (VLDL), 28 because these lipid fractions represent an atherogenic risk factor. By contrast, a protective function against coronary heart disease is ascribed to the high density lipoproteins. Accordingly, hypolipidemics should be able to reduce not only total cholesterol but, in particular, the VLDL and LDL serum 5 cholesterol fractions. It has now been found that NHE1 inhibitors show valuable therapeutically utilizable properties in relation to influencing the serum lipid levels. Thus, they significantly reduce the elevated serum concentrations of LDL and VLDL as are to be observed, for example, due to increased dietary intake of a cholesterol- and lipid-rich diet or in cases of 10 pathological metabolic alterations, for example genetically related hyperlipidemias. They can therefore be used for the prophylaxis and regression of atherosclerotic lesions by eliminating a causal risk factor. Included herein are not only the primary hyperlipidemias but also certain secondary hyperlipidemias occurring, for example, in association with 15 diabetes. In addition, the NHE1 inhibitors lead to a marked reduction in the infarctions induced by metabolic abnormalities and, in particular, to a significant reduction in the induced infarct size and the severity thereof. The compounds of the formula I and/or the pharmaceutically acceptable salts thereof are therefore advantageously used for producing a 20 medicament for the treatment of hypercholesterolemia; for producing a medicament for the prevention of atherogenesis; for producing a medicament for the prevention and treatment of atherosclerosis, for producing a medicament for the prevention and treatment of diseases induced by elevated cholesterol levels, for producing a medicament for the 25 prevention and treatment of diseases induced by endothelial dysfunction, for producing a medicament for the prevention and treatment of atherosclerosis-induced hypertension, for producing a medicament for the prevention and treatment of atherosclerosis-induced thromboses, for producing a medicament for the prevention and treatment of 30 hypercholesterolemia-induced and endothelial dysfunction-induced ischemic damage and post-ischemic reperfusion damage, for producing a medicament for the prevention and treatment of hypercholesterolemia induced and endothelial dysfunction-induced cardiac hypertrophies and cardiomyopathies and of congestive heart failure (CHF), for producing a 29 medicament for the prevention and treatment of hypercholesterolemia induced and endothelial dysfunction-induced coronary vasospasms and myocardial infarctions, for producing a medicament for the treatment of said disorders in combinations with hypotensive substances, preferably 5 with angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor antagonists. A combination of an NHE inhibitor of the formula I and/or the pharmaceutically acceptable salts thereof with an active ingredient lowering the blood fat levels, preferably with an HMG-CoA reductase inhibitor (for example lovastatin or pravastatin), the latter 10 bringing about a hypolipidemic effect and thus increasing the hypolipidemic properties of the NHE inhibitor of the formula I and/or the pharmaceutically acceptable salts thereof, proves to be a favorable combination with enhanced effect and reduced use of active ingredients. Thus, compounds of the formula I and/or the pharmaceutically acceptable 15 salts thereof lead to effective protection against endothelial damage of various origins. This protection of the vessels against the syndrome of endothelial dysfunction means that the compounds of the formula I and/or the pharmaceutically acceptable salts thereof are valuable medicaments for the prevention and treatment of coronary vasospasms, peripheral vascular 20 diseases, in particular intermittent claudication, atherogenesis and atherosclerosis, left ventricular hypertrophy and dilated cardiomyopathy and thrombotic disorders. It has additionally been found that NHE1 inhibitors are suitable in the 25 treatment of non-insulin-dependent diabetes (NIDDM), with the insulin resistance being restrained. It may in this connection be beneficial, to enhance the antidiabetic activity and quality of the effect of the compounds of the invention, to combine them with a biguanide such as metformin, with an antidiabetic sulfonylurea such as glyburide, glimepiride, tolbutamide 30 etc., with a glucosidase inhibitor, with a PPAR agonist such as rosiglitazone, pioglitazone etc., with an insulin product of different administration form, with a DB4 inhibitor, with an insulin sensitizor or with meglitinide.
30 Besides the acute antidiabetic effects, the compounds of the formula I and/or the pharmaceutically acceptable salts thereof counteract the development of late complications of diabetes and can therefore be used as medicaments for the prevention and treatment of late damage from 5 diabetes, such as diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy and other disorders occurring as a consequence of diabetes. They can in this connection be advantageously combined with the antidiabetic medicaments just described under NIDDM treatment. The combination with a beneficial dosage form of insulin should be particularly 10 important in this connection. NHEI inhibitors show, besides the protective effects against acute ischemic events and the subsequent equally acutely stressing reperfusion events, also direct therapeutically utilizable effects against diseases and 15 disorders of the entire mammalian organism which are associated with the manifestations of the chronically progressive aging process and which occur independently of acute hypoperfusion states and under normal, non ischemic conditions. These pathological, age-related manifestations induced over the long aging period, such as illness, invalidity and death, 20 which can now be made amenable to treatment with NHE inhibitors, are diseases and disorders which are essentially caused by age-related changes in vital organs and the function thereof and become increasingly important in the aging organism. Disorders connected with an age-related functional impairment or with age 25 related manifestations of wear of organs are, for example, the inadequate response and reactivity of the blood vessels to contraction and relaxation reactions. This age-related decline in the reactivity of vessels to constricting and relaxing stimuli, which are an essential process of the cardiovascular system and thus of life and health, can be significantly eliminated or 30 reduced by NHE inhibitors. One important function and a measure of the maintenance of the reactivity of vessels is the blockade or retardation of the age-related progression in endothelial dysfunction, which can be eliminated highly significantly by NHE inhibitors. The compounds of the formula I and/or the pharmaceutically acceptable salts thereof are thus outstandingly 31 suitable for the treatment and prevention of the age-related progression in endothelial dysfunction, especially of intermittent claudication. An example of another variable characterizing the aging process is the 5 decline in the contractability of the heart and the decline in the adaptation of the heart to a required pumping output of the heart. This diminished efficiency of the heart as a consequence of the aging process is in most cases connected with a dysfunction of the heart which is caused inter alia by deposition of connective tissue in the myocardial tissue. This deposition 10 of connective tissue is characterized by an increase in the weight of the heart, by an enlargement of the heart and by restrictive cardiac function. It was surprising that it was possible almost completely to inhibit such aging of the heart organ. The compounds of the formula I and/or the pharmaceutically acceptable salts thereof are thus outstandingly suitable 15 for the treatment and prevention of heart failure, of congestive heart failure (CHF). Not only is it possible to cure a cancer which has already occurred through inhibition of proliferation, but there is also reduction and highly significant 20 retardation of the age-related incidence of cancer through NHE inhibitors. A particularly noteworthy finding is that the disorders, occurring as a result of aging, of all organs and not only certain types of cancer are suppressed or occur with a highly significant delay. The compounds of the formula I and/or the pharmaceutically acceptable salts thereof are thus suitable for the 25 treatment and, in particular, the prevention of age-related types of cancer. With NHE inhibitors, a delay, shifted highly significantly in time is found in the occurrence of age-related disorders of all 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 no other group of medicaments or by any natural products. This unique effect of NHE inhibitors also makes it possible, besides the use of the active ingredients alone on humans and animals, to combine these NHE inhibitors 32 with other active principles, measures, substances and natural products which are used in gerontology and which are based on a different mechanism of action. Such classes of active ingredients used in gerontological therapy are: in particular vitamins and substances with 5 antioxidant activity. Since there is a correlation between caloric load or food intake and the aging process, the combination with dietary measures can take place for example with appetite suppressants. It is likewise possible to consider a combination with hypotensive medicaments such as with ACE inhiibitors, angiotensin receptor antagonists, diuretics, Ca+ 2 antagonists etc. 10 or with metabolism-normalizing medicaments such as cholesterol-lowering agents. The compounds of the formula I and/or the pharmaceutically acceptable salts thereof are thus outstandingly suitable for the prevention of age related tissue changes and for prolonging life while retaining a high quality 15 of life. The compounds of the invention are effective inhibitors of the cellular sodium-proton antiporter (Na/H exchanger) which in a large number of disorders (essential hypertension, atherosclerosis, diabetes etc.) is also 20 increased in cells which are readily amenable to measurements, such as, for example, in erythrocytes, platelets or leucocytes. The compounds used according to the invention are therefore suitable as outstanding and simple scientific tools, for example in their use as diagnostic agents for determining and distinguishing different types of hypertension, but also of 25 atherosclerosis, diabetes and the late complications of diabetes, proliferative 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 the 30 pharmaceutically acceptable salts thereof, together with pharmaceutically acceptable carriers and additives, alone or in combination with other active pharmaceutical ingredients or medicaments. Medicaments which comprise a compound of the formula I and/or the pharmaceutically acceptable salts thereof can in this connection be 33 administered, for example, orally, parenterally, intravenously, rectally, transdermally or by inhalation, the preferred administration being dependent on the particular characteristics of the disorder. The compounds of the formula I may moreover be used alone or together with 5 pharmaceutical excipients, both in veterinary medicine and in human medicine. The medicaments generally comprise active ingredients of the formula I and/or the pharmaceutically acceptable salts thereof in an amount of from 0.01 mg to 1 g per dose unit. 10 The excipients suitable for the desired pharmaceutical formulation are familiar to the skilled worker on the basis of his expert knowledge. Besides solvents, gel formers, suppository bases, tablet excipients, and other active ingredient 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 with additives suitable for this purpose, such as carriers, stabilizers or inert diluents, 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 are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. It is moreover possible for the preparation to take place both as dry granules and as wet granules. 25 Examples of suitable oily carriers or solvents are vegetable or animal oils such as sunflower oil or fish liver oil. For subcutaneous, intramuscular or intravenous administration, the active compounds used are converted, if desired with the substances customary 30 for this purpose, such as solubilizers, emulsifiers or other excipients, into a solution, suspension or emulsion. Examples of suitable solvents are: water, physiological saline or alcohols, e.g. ethanol, propanol, glycerol, as well as sugar solutions such as glucose or mannitol solutions, or else a mixture of the various solvents mentioned.
34 Suitable as pharmaceutical formulation for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active ingredient of the formula I and/or the pharmaceutically 5 acceptable salts thereof in a pharmaceutically acceptable solvent such as, in particular, ethanol or water, or a mixture of such solvents. The formulation may, if required, also contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers, and a propellant gas. Such a preparation normally contains the active ingredient in a concentration of 10 about 0.1 to 10, in particular of about 0.3 to 3% by weight. The dosage of the active ingredient of the formula I to be administered, and the frequency of administration, depend on the potency and duration of action of the compounds used; additionally also on the nature and severity 15 of the disorder to be treated and on the sex, age, weight and individual responsiveness of the mammal to be treated. On average, the daily dose of a compound of the formula I and/or the pharmaceutically acceptable salts thereof for a patient weighing about 20 75 kg is at least 0.001 mg/kg, preferably 0.01 mg/kg, to a maximum of 10 mg/kg, preferably 1 mg/kg, of body weight. For acute episodes of the disorder, 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, in 25 particular on i.v. administration, for example for a patient with infarction in the intensive care unit, and the compounds of the invention can be administered by infusion. List of abbreviations: 30 ADMET absorption - distribution - metabolism - excretion - toxicology CDI diimidazol-1-ylmethanone dba dibenzylideneacetone DIP diisopropyl ether DIPEA diisopropylethylamine 35 DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EA ethyl acetate 5 eq. equivalent HOAc acetic acid KOtBu potassium 2-methylpropan-2-olate MeOH methanol mp melting point 10 MTB tert-butyl methyl ether NMP N-methyl-2-pyrrolidone OAc acetate dppf 1,1'-bis(diphenylphosphino)ferrocene RT room temperature 15 THF tetrahydrofuran TMEDA N,N,N',N'-tetramethylethane-1,2-diamine Experimental part 20 Example 1: N-(5-Methanesulfonyl-2-methyl-4-pentafluorosulfanyl benzoyl)guanidine F F,\ ,F FO N
NH
2
NH
2 a) 4-Aminophenylsulfur pentafluoride 25 NH 2 A solution of tin(II) chloride (1465 g, 7.73 mol) in concentrated (32 percent) aqueous HCI solution was heated with stirring to 80 0 C and then, with ice 36 cooling, 4-nitrophenylsulfur pentafluoride (584 g, 2.344 mol) was introduced in 8 portions over the course of 1 h. The internal temperature was kept below 100*C during this. Subsequently, the mixture was stirred at an internal temperature of 850C for 1.5 h and then cooled to 450C over the 5 course of a further hour. A mixture of ice (12 kg), NaOH (2 kg) and dichloromethane (1.5 I) was prepared and the reaction mixture was added with vigorous stirring. The phases were separated, the aqueous phase was extracted 3 times with 1 1 of dichloromethane each time, and the combined organic phases were dried over Na2SO4 and evaporated in vacuo. 510 g of 10 4-aminophenylsulfur pentafluoride were obtained as a pale yellow crystalline powder, m.p. 63-65*C b) 4-Amino-3-bromophenylsulfur pentafluoride
F
5 S Br N H2 15 4-Aminophenylsulfur pentafluoride (510 g, 2.327 mol) was dissolved in dichloromethane (7 1), the solution was cooled to 50C and, while stirring, 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (326 g, 1.14 mol) was introduced in several portions with ice cooling so that the internal temperature was kept at 3-80C (approx. 1 h). The mixture was then left to 20 stir and warm to room temperature without external cooling for 1 h. The mixture was filtered through a bed of silica gel (volume about 1 1) and washed with dichloromethane (5.5 I), and the filtrate was evaporated in vacuo. About 700 g of a red-brown crystalline mass was obtained and was dissolved in n-heptane (600 ml) at 600C and then crystallized in a 25 refrigerator at 40C. Filtration with suction resulted in 590 g (85%) of 4-amino-3-bromophenylsulfur pentafluoride as brownish crystals, m.p. 59-59.5*C. c) 4-Amino-3-methylphenylsulfur pentafluoride 30 FSS CH H 3
NH
2 A mixture of Cs2CO3 (794 g, 2.7 mol), dimethoxyethane (2 1), water (300 ml) and trimethylboroxine (50 percent solution in THF, 225 g, 0.9 mol) 37 was heated to 700C, PdC 2 (dppf) x CH 2
CI
2 (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 over the course of 2 h while the reaction mixture was heated to reflux. It was subsequently 5 heated under reflux for a further 3 h and then cooled to room temperature, diluted with MTB ether (500 ml), filtered through a silica gel column (14 x 7 cm, 70-200 pm) and washed with MTB ether (2500 ml). The filtrate was evaporated in vacuo. 490 g of a black, semicrystalline mass was obtained and was subjected to a steam distillation. A total of 5.5 1 of 10 condensate was collected, from which the crystals of the product separated out. The condensate was extracted 3 x with MTB ether, and the combined organic phases were dried over Na 2
SO
4 and evaporated in vacuo. 4-Amino-3-methylphenylsulfur pentafluoride (181 g, 76%) was obtained as colorless crystals, m.p. 65-66*C, 15 d) 4-Bromo-3-methylphenylsulfur pentafluoride
F
5 S
CH
3 aBr 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 50C and, while 20 stirring and cooling with ice, a solution of 4-amino-3-methylphenylsulfur pentafluoride (30.9 g, 132.5 mmol) in MTB ether (140 ml) was added dropwise at 5-80C over the course of 1 h. Evolution of nitrogen started after about 2 min. The mixture was then allowed to warm with stirring to room temperature over the course of 1 h, a mixture of ice (250 g), 26 percent 25 aqueous NH3 solution (50 ml) and MTB ether (250 ml) was added, and the mixture was stirred for 10 min. The phases were separated, the aqueous was extracted 3 x with MTB ether (150 ml each time), and the combined organic phases were shaken once with 400 ml of water. Drying with Na2SO4 and evaporation of the organic phase resulted in 39 g of 4-bromo 30 3-methylphenylsulfur pentafluoride as a red-brown oil which was contaminated with 8 mol% of 4,5-dibromo-3-methylphenylsulfur pentafluoride, but was used further without further purification. Yield 89% based on a purity of 90%.
38 e) 4-Cyano-3-methylphenylsulfur pentafluoride
F
5 S
CH
3 CN A mixture of 4-bromo-3-methylphenylsulfur pentafluoride (136.4 g, purity 80%, 0.367 mol), Zn(CN) 2 (72.8 g, 0.62 mol) and Zn dust (7.2 g, 0.11 mol) 5 in dimethylacetamide (900 ml) and water (40 ml) was heated with stirring and nitrogen blanketing to 1250C, and PdCl 2 (dppf) x CH2Cl2 (32.7 g, 40 mmol) was added. After stirring at 1250C for one hour, PdCl2(dppf) x CH2Cl 2 (16.3 g, 20 mmol) and Zn dust (3.6 g, 55 mmol) were again added, and stirring was continued at 1250C for 2 h. The mixture 10 was then cooled to room temperature, diluted with n-heptane (400 ml) and stirred vigorously with addition of 5 N aqueous NH 4 CI solution (250 ml) and water (450 ml) for 15 min. The mixture was filtered with suction through a layer of kieselguhr, the phases were separated, and the aqueous was extracted 2 x with n-heptane (200 ml). The combined organic phases were 15 shaken with water (450 ml), dried over MgSO4 and evaporated in vacuo. The resulting black residue was dissolved in 200 ml of n-heptane, filtered and again evaporated in vacuo. 78 g of a dark brown liquid were obtained and were purified by chromatography on a silica gel column (7 x 55 cm, 60-200 lim, n-heptane/dichloromethane 4:1 to 3:2). The first fraction 20 obtained 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-pentafluorosulfanylbenzoic acid FSS
CH
3 CO2H 00 2 H 25 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 ethylene glycol (160 ml) was heated to 1300C and stirred at this temperature for 4 h. It was then cooled to room temperature and diluted with MTB ether 30 (150 ml) and water (250 ml), and the mixture was filtered with suction. The phases of the filtrate were separated, and the aqueous was acidified with concentrated aqueous HCI solution, and the precipitated solid was filtered off with suction. 41.1 g (93%) of 2-methyl-4-pentafluorosulfanylbenzoic acid 39 were obtained as colorless crystals, m.p. 138-139*C. g) 2-Methyl-5-nitro-4-pentafluorosulfanylbenzoic acid F F,\ /F F''/S 0,N0 II o OH 5 6.0 g of 2-methyl-4-pentafluorosulfanylbenzoic acid were dissolved in 60 ml of a 90% aqueous HNO 3 solution and, at RT, 6 ml of a 96% H 2
SO
4 were added dropwise. The mixture was left to stand at RT for 28 h and then poured into 300 g of ice, 300 ml of water were added and, after stirring for 1 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-methyl-4-pentafluorosulfanylbenzoic acid F F ,F
F'
F 0
H
2 N / OH 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 were added. Hydrogenation was carried out under hydrogen at atmospheric pressure and RT for 20 h. The reaction was incomplete and therefore hydrogenation 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 were removed in vacuo. 5.7 g of a pale grey solid were obtained, mp. 187 1890C. Rf (DIP/2%HOAc) = 0.23 MS (ES~): 276 40 i) 5-Chlorosulfonyl-2-methyl-4-pentafluorosulfanylbenzoic acid F F'I F 0 C-S 00 OH 1.0 g of 5-amino-2-methyl-4-pentafluorosulfanylbenzoic acid was dissolved 5 in 30 ml of HOAc, and 30 g of ice and 30 ml of a saturated aqueous HCI solution were added. Then, at 0*C, a solution of 274 mg of NaNO 2 in 1 ml of water was added dropwise over the course of one minute. The mixture was stirred at 0*C for 15 minutes. The resulting suspension was then added in portions to a suspension, cooled to 0*C, of 6.1 mg of CuCl and 10 61.5 mg of CuC12 x 2H20 in 30 ml of a saturated solution of S02 in HOAc. The mixture was stirred at 0CC for 1 h and then at RT for 1 h. The reaction mixture was subsequently extracted 3 times with 200 ml of diethyl ether each time. MgSO4 was used for drying, and the volatile constituents were removed in vacuo. 1.3 g of the product were obtained and immediately 15 reacted further. k) 2-Methyl-5-sulfino-4-pentafluorosulfanylbenzoic acid F F 0 OH 1.2 g of 5-chlorosulfonyl-2-methyl-4-pentafluorosulfanylbenzoic acid were 20 added in portions to a solution, heated to 700C, of 4.2 g of Na2SO 3 in 50 ml of water and, during this, the pH of the solution was kept between pH = 9 and pH = 11 with a 2N aqueous NaOH solution. The mixture was stirred at 70*C for 20 minutes, cooled to RT and adjusted to pH = 1-2 with an aqueous HCI solution. The mixture was left to stand at RT for 16 h and then 25 the product was filtered off and dried in vacuo. 1.0 g of a white solid was 41 obtained, mp. 288-290*C (with decomposition). Rf (EA/MeOH 1:1) = 0.52 1) Methyl 5-methanesulfonyl-2-methyl-4-pentafluorosulfanylbenzoate F F,\ ,F F' F 00 0 0 ~ 0 5 1.0 g of 2-methyl-5-sulfino-4-pentafluorosulfanylbenzoic acid was suspended in 10 ml of water, and 3.1 ml of an aqueous 2N NaOH solution were added (phenolphthalein: basic). The water was removed in vacuo and then coevaporated twice with 20 ml of toluene each time. The disodium salt 10 was then dissolved in 40 ml of anhydrous DMF and, after addition of 0.69 ml of methyl iodide, stirred initially at 600C for 4 h and then at RT for 15 h. The reaction mixture was poured into 100 ml of water and a first portion of the product (500 mg) was filtered off with suction. The filtrate was adjusted to pH = 2 with aqueous HCI solution and extracted 3 times with 15 30 ml of EA each time. MgSO4 was used for drying, and the solvent was removed in vacuo. Chromatography on silica gel with DIP afforded a further 460 mg of white crystals, mp 1270C. Rf (DIP) = 0.36 20 m) N-(5-Methanesulfonyl-2-methyl-4-pentafluorosulfanylbenzoyl)guanidine 0.70 g of guanidine chloride and 0.68 g of KOtBu were stirred in 20 ml of anhydrous DMF at RT for 30 minutes. This suspension was then added to 0.43 g of methyl 5-methanesulfonyl-2-methyl-4-pentafluorosulfanyl benzoate and stirred at RT for 16 h. The reaction mixture was then poured 25 into 200 ml of water, adjusted to pH = 8 with aqueous HCI solution and extracted 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 ml of CH2CI2 and the product was filtered off. 190 mg of colorless crystals 42 were obtained, mp. 254-256 0 C. Rf (EA) = 0.22 MS (ES+): 382 Example 2: N-(5-Methanesulfonyl-2-methyl-4-pentafluorosulfanylbenzoyl) 5 guanidine methanesulfonic acid salt F F, O HO 0 N
NH
2
NH
2 9.3 g of the title compound of example 1 were suspended in 100 ml of water 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 then the water was removed under reduced pressure to obtain 11.7 g of the methanesulfonic acid salt, which was subsequently recrystallized from 110 ml of water to obtain 10.0 g of N-(5-methanesulfonyl-2-methyl 4-pentafluorosulfanylbenzoyl)guanidine methanesulfonic acid salt as white 15 crystals, m.p. 2300C. Example 3: N-(5-Methanesulfonyl-2-methyl-4-pentafluorosulfanylbenzoyl) guanidine hydrochloride F F,\ ,F HCI N
NH
2 20 NH 2 300 mg of the title compound of example 2 were suspended in 50 ml of a saturated aqueous Na 2
CO
3 solution and extracted twice with 40 ml of EA each time. The EA phase was subsequently dried over MgSO 4 and the 43 solvent was removed under reduced pressure. The residue was dissolved in 10 ml of MeOH and admixed with 2 ml of a 10% aqueous HCI solution. The volatiles were removed under reduced pressure to leave 230 mg of white crystals, m.p. 276-278*C. 5 Determination of the NHE inhibition The inhibitory concentration IC50 for NHE-1 inhibition was determined as follows: 10 IC50 for NHE-1 inhibition was determined in an FLIPR assay by measurement of the pHi recovery in transfected cell lines which express human NHE-1. 15 The assay was carried out in an FLIPR (fluorometric imaging plate reader) with black-walled 96-well microtiter plates with clear bases. The transfected cell lines expressing the various NHE subtypes (the parental cell line LAP-1 shows no endogenous NHE activity as a result of mutagenesis and subsequent selection) were seeded the preceding day at a density of 20 -25 000 cells/well. The growth medium for the transfected cells (Iscove +10% fetal calf serum) additionally contained G418 as selection antibiotic in order to ensure the presence of the transfected sequences. 25 The actual assay started with the removal of the growth medium and addition of 100 ptl of loading buffer per well (5 pM BCECF-AM [2',7' bis(carboxyethyl)-5- (and -6-)carboxyfluorescein, acetoxymethyl ester] in 20 mM NH4CI, 115 mM choline chloride, 1 mM MgCI2, 1 mM CaCl2, 5 mM KCl, 20 mM HEPES, 5 mM glucose; pH 7.4 [adjusted with KOH]). The cells 30 were then incubated at 370C for 20 minutes. This incubation led to loading of the cells with the fluorescent dye whose fluorescence intensity depends on pHi, and with NH4CI which made the cells slightly alkaline. The nonfluorescent dye precursor BCECF-AM is, as ester, membrane- 44 permeable. The actual dye BCECF is not membrane-permeable but is liberated inside cells by esterases. After this incubation for 20 minutes, the loading buffer which contained 5 NH4CI and free BCECF-AM was removed by washing three times in a cell washer (Tecan Columbus) with in each case 400 pl of washing buffer (133.8 mM choline chloride, 4.7 mM KCl, 1.25 mM MgCl2, 1.25 mM CaC12, 0.97 mM K2HPO4, 0.23 mM KH 2
PO
4 , 5 mM HEPES, 5 mM glucose; pH 7.4 [adjusted with KOH]). The residual volume which remained in the wells 10 was 90 pl (50-125 pl possible). This washing step removed the free BCECF-AM and results, as a consequence of the removal of the external
NH
4 + ions, in intracellular acidification (- pHi 6.3 - 6.4). Since the equilibrium of intracellular NH 4 + with NH 3 and H+ was disturbed by the removal of the extracellular NH 4 + and by the subsequent 15 instantaneous passage of the NH 3 through the cell membrane, the washing process resulted in H+ remaining inside the cells, which was the cause of the intracellular acidification. This may eventually lead to cell death if it persists long enough. It was important at this point that the washing buffer was sodium-free 20 (<1 mM) because extracellular sodium ions would lead to an instantaneous recovery of the pHi through the activity of the cloned NHE isoforms. It was likewise important for all the buffers used (loading buffer, washing buffer, recovery buffer) not to contain any HCO 3 ions, because the presence of bicarbonate would lead to activation of interfering bicarbonate 25 dependent pHi regulatory systems present in the parental LAP-1 cell line. The microtiter plates with the acidified cells were then (up to 20 minutes after the acidification) transferred to the FLIPR. In the FLIPR, the intracellular fluorescent dye was excited by light with a wavelength of 30 488 nm generated by an argon laser, and the measured parameters (laser power, illumination time and aperture of the CCD camera incorporated in 45 the FLIPR) were chosen so that the average fluorescence signal per well is between 30 000 and 35 000 relative fluorescence units. The actual measurement in the FLIPR started with a photograph being 5 taken by the CCD camera every two seconds under software control. After ten seconds, the recovery of the intracellular pH was initiated by adding 90 pl of recovery buffer (133.8 mM NaCl, 4.7 mM KCI, 1.25 mM MgCl2, 1.25 mM CaC12, 0.97 mM K 2
HPO
4 , 0.23 mM KH 2
PO
4 , 10 mM HEPES, 5 mM glucose; pH 7.4 [adjusted with NaOH]) by means of the 96-well 10 pipettor incorporated in the FLIPR. Positive control wells (100% NHE activity) were those to which pure recovery buffer is added, while negative controls (0% NHE activity) received washing buffer. Recovery buffer with twice the concentration of test substance was added to all the other wells. Measurement in the FLIPR 15 terminated after 60 measurements (two minutes). The raw data are exported into the ActivityBase program. This program firstly calculates the NHE activities for each tested substance concentration and, from these, the IC50 values for the substances. Since the progress of 20 pHi recovery was not linear throughout the experiment, but fell at the end owing to decreasing NHE activity at higher pHi values, it was important to select for evaluation of the measurement the part in which the increase in fluorescence of the positive controls was linear. Example NHE1 inhibition IC50 [nM] 1 49 25 In vivo pharmacokinetics - profiling with the "n in one method" The exposure data and the volumes of distribution were determined as characteristic pharmacokinetic data as follows: 30 46 The NHE-1 inhibitor of example 1 of the invention and, as reference substance, the known NHE-1 inhibitor cariporide with the formula 0 II
O=S
OH N
NH
2
NH
2 were dissolved in an aqueous, slightly acidic medium (water, pH 4, 5 adjusted with 1 M hydrochloric acid). The concentration of the aqueous formulation prepared in this way was about 1.5 mg of each substance per 1 g of solution. 10 ml of this formulation were administered as a single bolus by catheter into the jugular vein of a fasting male beagle dog (dose about 1 mg of each substance administered per kg of the dog's body 10 weight). Blood samples were taken by means of a second catheter after 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h and 24 h, and heparinized plasma was prepared by centrifugation at 1000 G in appropriate plasma tubes. The plasma samples were worked up and, after an HPLC separation, 15 quantified by MS/MS. The high specificity of this method permitted simultaneous determination of a plurality of substances. The exposures could be calculated using the WinNonlin computer program from the concentration-time plots (see figure 1) and compared with the exposure of the known NHE-1 reference substance. Since the various substances were 20 measured in the same animal at the same time, the result was an accurate comparison of the compounds, and a ranking of the volumes of distribution was possible. Compound Volume of distribution [I/kg of body weight] Example 1 1.67 Reference substance 2.94 cariporide 47 It is clearly evident 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 higher than with the reference substance 5 cariporide. Cariporide is no longer detectable 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 administration of in each case approx. 1 mg/kg of the compound of example 1 and of cariporide. 10 y axis: concentration of the measured compound in the pg/mi in plasma x axis: time in h Comprises/comprising and grammatical variations thereof when used in this specification are to be taken to specify the presence of stated features, integers, 15 steps or components or groups thereof, but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.
Claims (13)
1. A compound of the formula I F R3 FN\ /F S NR2 F N NH2 R45( R1 0 NH 2 5 in which R1 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, F, CI, Br, I, -CN, NR5R6, -Op-(CH2)n (CF2)o-CF3 or -(SOm)q -(CH2)r-(CF2)s-CF3; 10 R5and R6 are, independently of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH2-CF 3 ; m is zero, 1 or 2 n, o, p, q, r and s 15 are, independently of one another, zero or 1; R2 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, F, CI, Br, I, -CN, NR7R8, -Ot-(CH2)u-(CF2)v-CF3 or -(SOw)x-(CH2)y-(CF2)z-CF3; R7 and R8 20 are, independently of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH 2 -CF 3 ; w iszero,1or2 t, u, v, x, y and z are, independently of one another, zero or 1; 49 R3 is CI, Br, 1, -CN, -SO 2 CH 3 , alkoxy having 1, 2, 3 or 4 carbon atoms, NR9R10, -Oa-(CH2)b-(CF2)c-CF3, -(SOd)e-(CH2)f-(CF2)g-CF3, alkyl having 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 be 5 replaced by fluorine atoms; R9 and R10 are, independently of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH 2 -CF 3 ; a, b and c 10 are, independently of one another, zero or 1; d is zero, 1 or 2; e is zero or 1; f is zero, 1, 2, 3 or 4; g is zero or 1; 15 or R3 is -(CH2)h-phenyl or -0-phenyl, in which the phenyl radicals are unsubstituted or substituted by 1, 2 or 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 20 having 1, 2, 3 or 4 carbon atoms and -SO 2 CH 3 ; j is zero or 1; k is zero, 1, 2 or 3; h is zero, 1, 2, 3 or 4; or 25 R3 is -(CH2)aa-heteroaryl, which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, Cl, Br, I, -Obb-(CH2)cc-CF3, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -SO 2 CH 3 ; 30 bb is zero or 1; cc iszero,1,2or3; 50 aa is zero, 1, 2, 3 or 4; R4 is hydrogen, F, Cl, Br, I, -CN, -SO 2 CH 3 , alkoxy having 1, 2, 3 or 4 carbon atoms, NR1 1 R1 2, -Odd-(CH2)ee-(CF2)ff-CF3; -(SOgg)hh 5 (CH2)j-(CF2)kk-CF3, alkyl having 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 be replaced by fluorine atoms; R11 and R12 are, independently of one another, hydrogen, alkyl 10 having 1, 2, 3 or 4 carbon atoms or -CH 2 -CF 3 ; dd, ee and ff are, independently of one another, zero or 1; gg is zero, 1 or 2; hh is zero or 1; 15 jj is zero, 1, 2, 3 or 4; kk is zero or 1; or R4 is -(CH2)11-phenyl or -0-phenyl, in which the phenyl radicals are unsubstituted or substituted by 1, 2 20 or 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, alkyl having 1, 2, 3 or 4 carbon atoms and -SO 2 CH 3 ; mm is zero or 1; nn is zero, 1, 2 or 3; 25 11 is zero, 1, 2, 3 or 4; or R4 is -(CH2)oo-heteroaryl, which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, Cl, Br, I, -Opp-(CH2)rr-CF3, alkoxy 30 having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -SO 2 CH 3 ; 51 pp is zero or 1; rr is zero, 1, 2 or 3; 00 is zero, 1, 2, 3 or 4; and the pharmaceutically acceptable salts thereof. 5
2. A compound of the formula I as claimed in claim 1, in which the meanings 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, 10 -Op-(CH2)n-(CF2) 0 -CF3 or -(SOm)q-(CH2)r-(CF2)s-CF3; R5 and R6 independently of one another hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH 2 -CF 3 ; m zero, 1 or 2 15 n,o, p,q, rands independently of one another zero or 1; R2 hydrogen or F; R3 Cl, Br, I, -CN, -S0 2 CH3, alkoxy having 1, 2, 3 or 4 carbon atoms, NR9R10, -Oa-(CH2)b-(CF2)c-CF3, -(SOd)e-(CH2)f-(CF2)g-CF3, alkyl 20 having 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 be replaced by fluorine atoms; R9 and R10 independently of one another hydrogen, alkyl having 1, 25 2, 3 or 4 carbon atoms or -CH2-CF 3 ; a, b and c independently of one another zero or 1; d zero, 1 or 2; e zero or 1; 30 f zero, 1, 2, 3 or 4; g zero or 1; or 52 R3 -(CH2)h-phenyl or -0-phenyl, in which the phenyl radicals are unsubstituted or substituted by 1, 2 or 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 5 having 1, 2, 3 or 4 carbon atoms and -SO2CH 3 ; zero or 1; k zero, 1, 2 or 3; h zero, 1, 2, 3 or 4; or 10 R3 -(CH2)aa-heteroaryl, which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, Cl, Br, 1, -Obb-(CH2)cc-CF3, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -SO2CH 3 ; 15 bb zero or 1; cc zero, 1, 2 or 3; aa zero, 1, 2, 3 or 4; R4 hydrogen or F; and the pharmaceutically acceptable salts thereof. 20
3. A compound of the formula I as claimed in claim 1 or 2, in which the meanings 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-CH 2 -CF 3 or 25 -(SOm)q-(CH2)r-CF3; R5 and R6 independently of one another hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH 2 -CF 3 ; m zero, 1 or 2 30 qand r independently of one another zero or 1; 53 R2 hydrogen or F; R3 C, Br, I, -CN, -SO2CH3, alkoxy having 1, 2, 3 or 4 carbon atoms, NR9R1 0, -O-CH 2 -CF 3 , -(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, in which 1, 2, 3 or 4 hydrogen atoms may be replaced by fluorine 5 atoms; R9 and R1O independently of one another hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH 2 -CF 3 ; d zero, 1 or 2; 10 e zero or 1; or R3 phenyl, which is unsubstituted or substituted by 1, 2 or 3 radicals selected 15 from the group consisting of F, C1, 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 -S02CH 3 ; zero or 1; k zero, 1, 2or3; 20 or R3 heteroaryl, which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, C1, Br, I, -Obb-(CH2)cc-CF3, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -SO2CH 3 ; bb zero or 1 cc zero, 1, 2 or 3; R4 hydrogen or F; 30 and the pharmaceutically acceptable salts thereof. 4 A compound of the formula I as claimed in any one of claims 1 to 3, in vhich the meanings are: 54 R1 hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, methoxy, ethoxy, F, Cl, NR5R6, -O-CH2-CF 3 or -(SOm)q-(CH2)r-CF3; R5 and R6 independently of one another hydrogen, alkyl having 1, 5 2, 3 or 4 carbon atoms or -CH2-CF 3 ; m zero, 1 or 2 q and r independently of one another zero or 1; R2 hydrogen or F; 10 R3 Cl, -CN, -SO 2 CH 3 , methoxy, ethoxy, NR9R10, -O-CH 2 -CF 3 , -(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 4 hydrogen atoms may be replaced by fluorine atoms; R9 and R10 15 independently of one another hydrogen, methyl, ethyl or -CH 2 -CF 3 ; d zero, 1 or 2; e zero or 1; or 0 R3 phenyl, which is unsubstituted or substituted by 1 or 2 radicals selected from the group consisting of F, Cl, -Oj-(CH2)k-CF3, methoxy, ethoxy, alkyl having 1, 2, 3 or 4 carbon atoms and -S0 2 CH 3 ; jand k 5 independently of one another zero or 1; or R3 heteroaryl, which is unsubstituted or substituted by 1 or 2 radicals selected from the group consisting of F, CI, -Obb-(CH2)cc-CF3, methoxy, ethoxy, 30 alkyl having 1, 2, 3 or 4 carbon atoms and -S0 2 CH 3 ; bb and cc 55 independently of one another zero or 1; R4 hydrogen or F; And the pharmaceutically acceptable salts thereof. 5 . A compound of the formula I as claimed in any of claims 1 to 4 and selected from: N-(5-methanesulfonyl-2-methyl-4-pentafluorosulfanyl benzoyl)guanidine, and the pharmaceutically acceptable salts thereof. (i. A process for preparing a compound of the formula I as claimed in any one 10 of claims 1 to 5 and/or the pharmaceutically acceptable salts thereof, which comprises reacting a compound of the formula 11, F FR3 F N R2 F 15 R4 I 0 I which R1 to R4 have the meaning stated in claims 1 to 4 and L is a leaving Croup which can undergo nucleophilic substitution, with guanidine. 20 *. A compound of the formula I and/or the pharmaceutically acceptable salts t ereof as claimed in any one of claims 1 to 5 for use as medicament. E . The use of a compound of the formula I and/or the pharmaceutically 25 z cceptable salts thereof as claimed in any one of claims 1 to 5 for producing a r iedicament for the treatment or prophylaxis of acute or chronic damage, disorders or indirect sequelae of organs and tissues caused by ischemic or reperfusion events, for the treatment or prophylaxis of arrhythmias, of life t threatening cardiac ventricular fibrillation, of myocardial infarction, of angina 30 pectoris, for the treatment or prophylaxis of ischemic states of the heart, of ischemic states of the peripheral and central nervous system or of stroke or of ischemic states of peripheral organs and tissues, for the treatment or prophylaxis cf states of shock, of diseases in which cellular proliferation represents a primary 56 r secondary cause, of cancer, of metastasis, of prostate hypertrophy and of prostate hyperplasia, of atherosclerosis or of disturbances of lipid metabolism, of igh blood pressure, of essential hypertension, of disorders of the central nervous :ystem, of disorders resulting from overexcitability of the ONS, epilepsy or entrally induced convulsions, of disorders of the central nervous system, specially of anxiety states, depressions or psychoses, for the treatment or rophylaxis of non-insulin-dependent diabetes mellitus (NIDDM) or late damage rom diabetes, of thromboses, of disorders resulting from endothelial dysfunction, f intermittent claudication, for the treatment or prophylaxis of fibrotic disorders of nternal organs, fibrotic disorders of the liver, fibrotic disorders of the kidney, ibrotic disorders of the vessels and fibrotic disorders of the heart, for the reatment or prophylaxis of heart failure or of congestive heart failure, of acute or ,hronic inflammatory disorders, of disorders caused by protozoa, of malaria and of coccidiosis in poultry, and for use for surgical operations and organ ransplantations, for preserving and storing transplants for surgical procedures, or use in bypass operations, for use in resuscitation after a cardiac arrest, for >reventing age-related tissue change, for producing a medicament directed against aging or for prolonging life, for the treatment and reduction of the :ardiotoxic effects in thyrotoxicosis or for producing a diagnostic aid. 9 The use of a compound of the formula I and/or the pharmaceutically acceptable salts thereof as claimed in any one of claims 1 to 5 in combination vith other medicaments or active ingredients for producing a medicament of the reatment or prophylaxis of acute or chronic damage, disorders or indirect sequelae of organs and tissues caused by ischemic or reperfusion events, for the reatment or prophylaxis of arrhythmias, of life-threatening cardiac ventricular fibrillation, of myocardial infarction, of angina pectoris, for the treatment or rophylaxis of ischemic states of the heart, of ischemic states of peripheral and entral nervous system or of stroke or of ischemic states of peripheral organs and issues, for the treatment or prophylaxis of states of shock, of diseases in which ellular proliferation 57 0. The use of a compound of the formula I and/or the pharmaceutically acceptable salts thereof as claimed in claim 9 in combination with cardiotoxic and ytotoxic medicaments or active ingredients or producing a medicament with educed cardiotoxic and cytotoxic properties.
11. The use of a compound of the formula I and/or the pharmaceutically acceptable salts thereof alone or in combination with other medicaments or active ngredients as claimed in claim 8 and/or 9 for producing a medicament for the reatment or prophylaxis of acute or chronic damage, disorders or indirect equelae of organs and tissues caused by ischemic or reperfusion events.
12. The use of a compound of the formula I and/or the pharmaceutically acceptable salts thereof alone or in combination with other medicaments or active ngredients as claimed in claim 8 and/or 9 for producing a medicament for the reatment of life-threatening cardiac ventricular fibrillation.
13. The use of a compound of the formula I and/or the pharmaceutically acceptable salts thereof alone or in combination with other medicaments or active ngredients as claimed in claim 8 and/or 9 for producing a medicament for the reatment or prophylaxis of metastasis . 4. The use of a compound of the formula I and/or the pharmaceutically cceptable salts thereof alone or in combination with other medicaments or active ngredients as claimed in claim 8 and/or 9 for producing a medicament for the reatment or prophylaxis of fibrotic disorders of the heart, of heart failure or of ongestive heart failure. 5. A medicine for human, veterinary and/or phytoprotective use comprising in effective amount of a compound of the formula I and/or the pharmaceutically cceptable salts thereof as claimed in any one of claims 1 to 5, together with harmaceutically acceptable carriers and additives. 58
16. A medicine for human, veterinary and/or phytoprotective use comprising an effective amount of a compound of the formula I and/or the pharmaceutically acceptable salts thereof as claimed in any one of claims 1 to 5, together with pharmaceutically acceptable carriers and additives in combination with other pharmacological active ingredients or medicaments.
17. A method of medical treatment or prophylaxis of acute or chronic damage, disorders or indirect sequelae of organs and tissues caused by ischemic or reperfusion events, of treatment or prophylaxis of arrhythmias, of life-threatening ::ardiac ventricular fibrillation, of myocardial infarction, of angina pectoris, of reatment or prophylaxis of ischemic states of the heart, of ischemic states of the peripheral and central nervous system or of stroke or of ischemic states of peripheral organs and tissues, of treatment or prophylaxis of states of shock, of diseases in which cellular proliferation represents a primary or secondary cause, of cancer, of metastasis, of prostate hypertrophy and of prostate hyperplasia, of atherosclerosis or of disturbances of lipid metabolism, of high blood pressure, of essential hypertension, of disorders of the central nervous system, of disorders -esulting from overexcitability of the CNS, epilepsy or centrally induced -onvulsions, of disorders of the central nervous system, especially of anxiety states, depressions or psychoses, of treatment or prophylaxis of non-insulin dependent diabetes mellitus (NIDDM) or late damage from diabetes, of hromboses, of disorders resulting from endothelial dysfunction, of intermittent -laudication, of treatment or prophylaxis of fibrotic disorders of internal organs, ibrotic disorders of the liver, fibrotic disorders of the kidney, fibrotic disorders of he vessels and fibrotic disorders of the heart, of treatment or prophylaxis of heart ailure or of congestive heart failure, of acute or chronic inflammatory disorders, of disorders caused by protozoa, of malaria and of coccidiosis in poultry, of reatment or prophylaxis of a subject undergoing surgical operations and organ ransplantations, bypass operations, or cardiac arrest, of treating transplants for urgical procedures or age-related tissue change, of substantially preventing ging or prolonging life, of treatment and reduction of the cardiotoxic effects in hyrotoxicosis, wherein a subject in need, or a transplant, is administered an 59 effective amount of a compound as claimed in any one of claims 1 to 5 and/or the >harmaceutically acceptable salts thereof.
18. A method of medical treatment or prophylaxis of acute or chronic damage, Disorders or indirect sequelae of organs and tissues caused by ischemic or -eperfusion events, of treatment or prophylaxis of arrhythmias, of life-threatening :ardiac ventricular fibrillation, of myocardial infarction, of angina pectoris, of reatment or prophylaxis of ischemic states of the heart, of ischemic states of the >eripheral and central nervous system or of stroke or of ischemic states of >eripheral organs and tissues, of treatment or prophylaxis of states of shock, of diseases in which cellular proliferation represents a primary or secondary cause, Af cancer, of metastasis, of prostate hypertrophy and of prostate hyperplasia, of therosclerosis or of disturbances of lipid metabolism, of high blood pressure, of ssential hypertension, of disorders of the central nervous system, of disorders esulting from overexcitability of the CNS, epilepsy or centrally induced ,onvulsions, of disorders of the central nervous system, especially of anxiety ;tates, depressions or psychoses, of treatment or prophylaxis of non-insulin dependent diabetes mellitus (NIDDM) or late damage from diabetes, of hromboses, of disorders resulting from endothelial dysfunction, of intermittent ,laudication, of treatment or prophylaxis of fibrotic disorders of internal organs, ibrotic disorders of the liver, fibrotic disorders of the kidney, fibrotic disorders of he vessels and fibrotic disorders of the heart, of treatment or prophylaxis of heart failure or of congestive heart failure, of acute or chronic inflammatory disorders, of isorders caused by protozoa, of malaria and of coccidiosis in poultry, of reatment or prophylaxis of a subject undergoing surgical operations and organ ransplantations, bypass operations, or cardiac arrest, of treating transplants for urgical procedures or age-related tissue change, of substantially preventing ging or prolonging life, of the treatment and reduction of the cardiotoxic effects in hyrotoxicosis, wherein a subject in need, or a transplant, is administered an effective amount of a compound as claimed in any one of claims 1 to 5 and/or the harmaceutically acceptable salts thereof in combination with other medicaments r active ingredients. 60 9. The method of claim 17 or 18, when used for the treatment or prophylaxis >f acute or chronic damage, disorders or indirect sequelae of organs and tissues Jased by ischemic or reperfusion events.
20. The method of claim 17 or 18, when used for the treatment of life :hreatening cardiac ventricular fibrillation.
21. The method of claim 17 or 18, when used for the treatment or prophylaxis >f metastasis.
22. The method of claim 17 or 18, when for the treatment or prophylaxis of ibrotic disorders of the heart, heart failure or congestive heart failure.
23. A compound according to any one of claims 1 to 5, a process according to :laim 6, a use according to any one of claims 8 to 14, a medicine according to :laim 15 or 16, or a method according to any one of claims 17 to 22 substantially as hereinbefore described. SANOFI-AVENTIS DEUTSCHLAND GMBH WATERMARK PATENT & TRADE MARK ATTORNEYS :26952AU00
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