HRP960041A2 - Basically substituted benzoylguanidines, process for their preparation, their use as medicaments or diagnostics as well as medicaments containing them - Google Patents

Description

The invention relates to benzoylguanidines of formula I

[image]

where:

one of the three substituents R(1), R(2) and R(3) is R(6)-A-B-D-;

R(6) is a residue that can be basicly protonated, i.e. amino group -NR(7)R(8), amidino group R(7)R(8)N-C[=N-R(9)]- or guanidino group

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R(7), R(8), R(9) and (10) are independently hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms;

or

R(7) and R(8) together are CaH2a;

a is 4, 5, 6 or 7;

wherein if a = 5, 6 or 7, one methylene group of the group CaH2a can be substituted with a heteroatom group O, SOm or NR(11);

or

R(8) and R(9) or R(9) and R(10) or R(7) and R(10) represent the group CaH2a;

a is 2, 3, 4 or 5;

where if a = 3, 4 or 5, one methylene group of the group CaH2a can be substituted with a heteroatom group O, SOm or NR(11);

m is zero, 1 or 2;

R(11) is hydrogen or methyl;

or

R(6) is a basic heteroaromatic ring system with 1 - 9 C-atoms;

A is CbH2b,

b is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

wherein in the group CbH2b one or two methylene groups can be substituted with one of the groups selected from the group consisting of -O-, -CO-, -CH[OR(20)]-, -SOm-, -NR(20 )-, -NR(20)-CO-, -NR(20)-CO-NH-, -NR(20)-CO-NH-SO2-,

[image]

and -SOaa[NR(19)]bb-;

and wherein in the group CbH2b one methylene group can be replaced by -CH-R(99), whereby R(99) together with R(7) forms a pyrrolidine or piperidine ring;

aa is 1 or 2;

bb is 0 or 1;

aa + bb = 2;

R(19) is hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms;

R(20) is hydrogen or methyl;

B is a phenylene or naphthylene residue,

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R(12) and R(13) are independently hydrogen, methyl, F, Cl, Br, J, CF3 or -SOw-R(14);

R(14) is methyl or NR(15)R(16);

R(15) and R(16) are independently hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms;

w is zero, 1 or 2;

D is -CdH2d-Xf-;

d is zero, 1, 2, 3 or 4;

X is -O-, -, -CH[OR(21)]-, -SOm- or -NR(21)-;

f is zero or 1;

R(21) is hydrogen or methyl;

m is zero, 1 or 2;

and the remaining substituents R(1) and R(2) and R(3) independently of each other are hydrogen, F, Cl, Br, J, -CN, -(C1-C8)-alkyl, -(C2-C8)-alkenyl , -NR(35)R(36) or R(17)-CgH2g-Zh-;

g is zero, 1, 2, 3 or 4;

h is zero or 1;

R(35) and R(36) are independently hydrogen or alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms;

or

R(35) and R(36) together represent 4-7 methylene groups, one of which CH2-group can be substituted with oxygen, -S-, -NH-, -NCH3 or -N-benzyl;

Z is -O-, -CO-, -SOv-, -NR(18)-, -NR(18)-CO-, -NR(18)-CO-NH- or -NR(18)-SO2;

R(18) is hydrogen or methyl;

v is zero, 1 or 2;

R(17) is hydrogen, cycloalkyl with 3, 5 or 6 C-atoms or CkF2k+1,

k is 1, 2 or 3;

or

R(17) is pyrrole-1-yl, pyrrole-2-yl or pyrrole-3-yl, which is unsubstituted or substituted with 1-4 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C8)-Alkanoyl, (C2-C8)-Alkoxycarbonyl, formyl, carboxy, -CF3, methyl and methoxy;

or

R(17) -(C3-C8)-cycloalkyl or phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F and Cl, -CF3, methyl, hydroxy, methoxy, -NR(37)R (38), CH3SO2- and H2NO2S-;

R(37) and R(38) are hydrogen or -CH3;

R(4) and R(5) are independently hydrogen, alkyl with 1, 2, 3 or 4 C-atoms, F, Cl, -OR(32), -NR(33)R(34) or -CrF2r+ 1;

R(32), R(33) and R(34) are independently hydrogen or alkyl with 1, 2 or 3 carbon atoms;

r is 1, 2, 3 or 4;

and their pharmacologically tolerable salts.

Compounds of formula I are primarily those in which:

R(1) is hydrogen, F, Cl, -(C1-C4)-alkyl, -(C2-C4)-alkenyl, -NR(35)R(36) or R(17)-CgH2g-Zh-;

R(35) and R(36) are independently hydrogen, methyl or ethyl;

or

R(35) and R(36) together represent 4-5 methylene groups, one of which CH2-groups can be substituted with oxygen, -S-, -NH-, or -NCH3;

R(17) is hydrogen, cycloalkyl with 5 or 6 carbon atoms or CkF2k+1-;

k is 1, 2 or 3;

g is zero, 1, 2, 3 or 4;

h is zero or 1;

Z is -O-, -CO-, -SOv-, -NR(18)-, -NR(18)-CO-, -NR(18)-CO-NH- or -NR(18)-SO2;

R(18) is hydrogen or methyl;

v is zero, 1 or 2;

or, if g and h are zero,

R(17) is pyrrole-1-yl, pyrrole-2-yl or pyrrole-3-yl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, (C2-C5)-alkanoyl , (C2-C5)-Alkoxycarbonyl, formyl, carboxy, -CF3, methyl and methoxy;

or

R(17) is -(C3-C8)-cycloalkyl or phenyl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F and Cl, -CF3, methyl, methoxy, -N(R37)R( 38), CH3SO2- and H2NO2S-;

R(37) and R(38) are independently hydrogen or -CH3;

or

one of the substituents R(2) and R(3) represents R(6)-A-B-D;

R(6) is -NR(7)R(8), one amidino group R(7)R(8)N-C[=N-R(9)]-or one guanidino group

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R(7), R(8), R(9) and R(10) are independently hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms;

or

R(7) and R(8) together are CaH2a;

a is 4, 5, 6 or 7;

whereby if a = 5, 6 or 7 one methylene group of the group CaH2a can be substituted with a heteroatomic group O, SOm or NR(11);

R(11) is hydrogen or methyl;

or

R(8) and R(9) together represent the group CaH2a;

a is 2, 3, 4 or 5;

whereby if a = 3, 4 or 5 one methylene group of the group CaH2a can be substituted with a heteroatomic group O, SOm or NH(11);

m is zero, 1 or 2;

or

R(6) is imidazolyl, pyridyl, quinolinyl or isoquinolinyl;

A is CbH2b;

b is 1, 2, 3, 4 or 5,

whereby in the group CbH2b one or two methylene groups can be replaced by one of the groups selected from the group consisting of -O-, -CO-, -CH[OR(20)]-, -SOm-, -NR(20)-, -NR(20)-CO-, -NR(20)-CO-NH-SO2-,

[image]

and -SOaa[NR(19)]bb-;

and wherein in the group CbH2b one methylene group can be replaced by -CH-R(99), whereby R(99) together with R(7) forms a pyrrolidine or piperidine ring;

aa is 1 or 2;

bb is 0 or 1;

aa + bb = 2;

R(19) is hydrogen or alkyl with 1,2,3 or 4 carbon atoms;

R(20) is hydrogen or methyl;

B is a phenylene or naphthylene residue,

[image]

R(12) and R(13) are independently hydrogen, methyl, F, Cl, CF3 or -SO2-R(14);

R(14) is methyl or NR(15)R(16);

R(15) and R(16) are independently hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms;

D is -CdH2d-Xf-

d is zero, 1, 2, 3 or 4;

X is -O-, -, -CH[OR(21)]-, -SOm- or -NR(21)-;

f is zero or 1;

R(21) is hydrogen or methyl;

m is zero, 1 or 2;

and the remaining substituents R(2) and R(3) are hydrogen, alkyl with 1, 2, 3 or 4 C-atoms, F, Cl or CF3;

R(4) and R(5) are independently hydrogen, alkyl with 1, 2 or 3 carbon atoms, F, Cl or -CF3;

and their pharmacologically tolerable salts.

Of particular advantage are the compounds of formula I in which:

R(1) is hydrogen, F, Cl, alkyl with 1, 2, 3 or 4 C-atoms, -NR(35)R(36) or R(17)-CgH2g-Zh-;

g is zero, 1, 2, 3 or 4;

h is zero or 1;

Z is -O-, -CO-, -SOv-, -NR(18)-, -NR(18)-CO-, -NR(18)-CO-NH- or -NR(18)-SO2;

R(18) is hydrogen or methyl;

v is zero, 1 or 2;

R(17) hydrogen, cycloalkyl with 5 or 6 carbon atoms or -CF3;

or, if g and h are zero,

R(17) is pyrrole-1-yl, which is unsubstituted or substituted with 1 - 2 substituents selected from the group consisting of F, Cl, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, -CF3 and methyl;

or

R(17) is (C5-C6)-cycloalkyl or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F and Cl, -CF3, methyl, CH3SO2- and H2NO2S-;

R(35) and R(36) are independently hydrogen, methyl or ethyl;

or

R(35) and R(36) together represent 4-5 methylene groups, one of which CH2-group can be substituted with oxygen, -S-, -NH- or -NCH3;

or one of the substituents R(2) and R(3) represents R(6)-A-B-D;

R(6) is -NR(7)R(8), one amidino group

R(7)R(8)N-C[=N-R(9)]- or one guanidino group

[image]

R(7) is hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms;

R(8), R(9) and R(10) are independently hydrogen, methyl or ethyl; or

R(7) and R(8) together are CaH2a;

a is 4 or 5;

whereby if a = 5 one methylene group of the group CaH2a can be substituted with NR(11);

R(11) is hydrogen or methyl;

or

R(6) is imidazolyl- or pyridyl;

A is CbH2b;

b is 1, 2, 3, 4 or 5,

whereby in the group CbH2b one or two methylene groups can be replaced by one of the groups selected from the group consisting of -, -CH[OR(20)]-, -NR(20)-,

[image]

-SOaa[NR(19)]bb- and -SO2-;

and wherein in the group CbH2b one methylene group can be replaced by -CH-R(99), whereby R(99) together with R(7) forms a pyrrolidine or piperidine ring;

aa is 1 or 2;

bb is 0 or 1;

aa + bb = 2;

R(19) is hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms;

R(20) is hydrogen or methyl;

or, if b is equal to 2, 3, 4 or 5 one C-atom in CbH2b can be replaced by one group -O-, -S-, -NR(20)-, -NR(20)-CO- or - NR(20)-CO-NH-;

B is a phenylene residue

[image]

R(12) and R(13) are independently hydrogen, methyl, F, Cl, CF3 or -SO2-R(14);

R(14) is methyl or NH2;

D is -CH2-, -O-, -, -SOm- or NR(21)-;

m is zero or 2;

R(21) is hydrogen or methyl;

and the other substituents R(2) and R(3) are hydrogen;

R(4) and R(5) are independently hydrogen, alkyl with 1, 2 or 3 carbon atoms, F, Cl or -CF3;

and their pharmacologically tolerable salts.

Of particular advantage are the compounds of formula I in which:

R(1) is hydrogen, F, Cl, alkyl with 1, 2, 3 or 4 C-atoms, -NR(35)R(36) or R(17)-CgH2g-Zh-;

g is zero or 1;

h is zero or 1;

Z is -O-, -, -NR(18)-, -NR(18)-CO- or -NR(18)-SO2;

R(18) is hydrogen or methyl;

or, if g equals 1,

Z is -SO2-;

R(17) is hydrogen or CF3-;

R(35) and R(36) are independently hydrogen, methyl or ethyl;

or

R(35) and R(36) together are 4-5 methylene groups, one of which CH2-group can be substituted with oxygen, -S-, -NH-, or -NCH3;

one of the substituents R(2) and R(3) is R(6)-A-B-O-;

R(6) is -NR(7)R(8) or a guanidino group

[image]

R(7) is hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms;

R(8), R(9) and R(10) independently of each other are hydrogen, methyl or ethyl;

or

R(7) and R(8) together are CaH2a;

a is 4 or 5;

where if a = 5 one methylene group of the group CaH2a can be replaced by -NH- or -NCH3-,

or

R(6) is imidazolyl;

A is CbH2b;

b is 1, 2, 3 or 4;

whereby in the group CbH2b one or two methylene groups can be replaced by one of the groups selected from the group consisting of -,

[image]

-SOaa[NR(19)]bb- and -SO2-;

and wherein in the group CbH2b, one methylene group can be replaced by -CH-R(99), wherein R(99) together with R(7) forms a pyrrolidine or piperidine ring; or, if b is equal to 2, 3 or 4, one methylene group of the group CbH2b may be replaced by one group -O-, -S-;

aa is 1 or 2;

bb is 0 or 1;

aa + bb = 2;

R(19) is hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms;

R(20) is hydrogen or methyl;

B is a phenylene residue,

[image]

R(12) and R(13) are hydrogen;

and the second residue of R(2) and R(3) is hydrogen;

R(4) and R(5) are hydrogen;

and their pharmacologically tolerable salts.

Of particular advantage is the compound selected from the group they comprise

4-[4-N-(dimethylaminoethyl)-methylsulfamoyl]phenoxy-3-trifluoromethyl-benzoylguanidine, dihydrochloride;

4-[4-(4-methylpiperazinosulfonyl)phenoxy]-3-trifluoromethyl-benzoylguanidine, dihydrochloride;

4-[4-(2-pyrrolidineethylaminosulfonyl)phenoxy]-3-trifluoromethyl-benzoylguanidine dimaleinate;

4-[4-(2-piperidineethylaminosulfonyl)phenolsy]-3-trifluoromethyl-benzoylguanidine, dimaleinate;

4-[4-N-(dimethylamino-n-propyl)sulfamoyl]phenoxy-3-trifluoromethyl-benzoylguanidine;

4-[4-(N-dimethylaminoethyl)sulfamoyl]phenoxy-3-trifluoromethyl-benzoylguanidine;

4-(4-imidamidosulfonyl)phenoxy-3-trifluoromethyl-benzoylguanidine;

3-trifluoromethyl-4-(4-N-methylimidamidosulfonyl)phenoxy-benzoylguanidine;

3-methyl-4-(4-(1-methylpiperazin-4-yl-sulfonyl)phenoxy)-benzoylguanidine;

4-(4-guanidinosulfonyl)phenoxy-3-trifluoromethyl-benzoylavanidine;

4-[4-(2-imidazolylthio-acetyl)phenoxy]-3-methylsulfonyl-benzoylguanidine, dihydrochloride;

4-[4-(N,N'-dimethyl-S-isothiouronyl-acetyl)phenoxy]-3-methylsulfonyl-benzoylguanidine dihydrochloride;

4-[4-(2-benzimidazolthio-acetyl)phenoxy]-3-methylsulfonyl-benzoylguanidine dihydrochloride;

4-[4-(2-N-imidazolyl-1-hydroxyethyl)phenoxy]-3-methylsulfonyl-benzoylguanidine dihydrochloride;

4-[4-(N,N-dimethylglycylamino)phenoxy]-3-methylsulfonyl-benzoylguanidine dihydrochloride;

4-[4-(N,N-diethylaminoethyl)aminosulfonylphenoxy]-3-methylsulfonyl-benzoylguanidine dihydrochloride;

4-[4-(4-imidazolylethyl)aminosulfonyl-phenoxy]-3-methylsulfonyl-benzoylguanidine dihydrochloride;

4-[4-(3-N-imidazolyl-1-propyl)aminosulfonyl-phenoxy]-3-methylsulfonyl-benzoylguanidine dihydrochloride;

4-[4-(1-methyl-2-pyrrolidinylethyl)aminosulfonyl-phenoxy]-3-methylsulfonyl-benzoylguanidine dihydrochloride;

4-[4-(N-piperidinoethyl)aminosulfonyl-phenoxy]-3-methylsulfonyl-benzoylguanidine dihydrochloride;

4-[4-(2-dimethylaminoethyl)sulfonylmethyl-phenoxy]-3-methylsulfonyl-benzoylguanidine dihydrochloride;

4-[4-(2-dimethylaminoethyl)sulfonylmethyl-phenoxy]-3-trifluoromethyl-benzoylguanidine dihydrochloride.

The indicated alkyl residues can be present both straight-chain and branched.

A basic heteroaromatic ring system with 1 - 9 C-atoms means in particular residues derived from cyclopentyl, phenyl or naphthyl, in which one or more CH-groups are replaced by N. Heteroaryls are especially imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, quinolyl, isoquinolyl.

Halogens are F, Cl, Br or J.

If the compounds of formula I have asymmetric centers, then formula I also describes the individual optical antipodes as well as their possible mixtures of enantiomers.

The invention further relates to the process for the production of compound I, characterized in that the compound of formula II

[image]

chemically converted with guanidine, where R(1) to R(5) have the stated meaning, and L represents a leaving group that can be easily substituted with a nucleophile, and to be translated into a pharmacologically tolerable salt if necessary.

Activated acid derivatives of the formula II, in which L represents alkoxy, preferably a methyloxy group, a phenyloxy group, a phenylthio, a methylthio, a 3-pyridinyloxy group, a 2-pyridylthio group, a heterocycle with nitrogen, preferably a 1-imidazolyl group, are obtained in a known manner from the basic chlorides of carboxylic acids (formula II, L = Cl), which in turn can be produced in a known manner from basic carboxylic acids (formula II, L = OH), for example with thionyl chloride.

In addition to chlorides of carboxylic acids of formula II (L = Cl), further activated acid derivatives of formula II can also be produced in a known manner from basic derivatives of benzoic acid (formula II, L = OH), for example methyl esters of formula II with L = OCH3 by treatment with gaseous HCl in methanol, imidazoles of formula II by treatment with carbonylimidazole [L = 1-imidazolyl, Staab, Angew. Chem. Int. Ed. English 1, 351-367 (1962)], from mixed anhydrides II with ClCOOC2H5 or tosyl chloride in the presence of triethylamine in an inert solvent, as well as by activating benzoic acid with dicyclohexylcarbodiimide (DCC) or with O[(cyano(ethoxycarbonyl)methylene)amino]-1 ,13,-tetramethyl-uronium tetrafluorocarbonate ("TOTU") [Proceedings of the 21st European Peptide Symposium, Peptides 1990, published by E. Gilard and D. Andreu, Escom, , 1991]. A number of suitable methods for the production of activated derivatives of carboxylic acids of formula II are listed in the literature review in J. March, Advanced Organic Chemistry, 3rd edition (John Wiley & Sons, 1985), p. 350.

The chemical conversion of activated carboxylic acid derivatives of formula I with guanidine is carried out in a known manner in a protic or aprotic polar but inert organic solvent. For the chemical conversion of benzoic acid methyl ester (II, L = OMe) with guanidine, methanol, isopropanol or THF are recommended at temperatures of 20ºC up to the boiling point of that solvent. In most of the chemical transformations of compounds II with salt-free guanidine, it was done primarily in aprotic solvents, such as THF, dimethoxyethane, dioxane or isopropanol. However, with the use of a base, for example NaOH, water can also be used as a solvent in the chemical conversion of II and III.

If L stands for Cl, it is preferably done with the addition of an acid acceptor, eg in the form of excess guanidine to bind the hydrohalic acid.

The basic derivatives of benzoic acid are partially known. They are produced according to methods known from the literature, by which, for example, the finished residue R(6)-A-B-Cd-H2d-Xf- or its previous step is converted by replacing the halogen into a benzoic acid derivative of formula III

[image]

in which the substituent R' represents a lower alkyl residue, such as methyl or ethyl, and R'' represents halogen. The reactions are described in the literature, for example, as a nucleophilic substitution reaction, as a radical Ullman reaction or reactions catalyzed by palladium.

The introduction of benzenesulfonamide derivatives substituted in the phenyl part with sulfur, oxygen or nitrogen nucleophiles takes place according to methods of nucleophilic substitution on aromatics known from the literature. Halides and trifluoromethanesulfonates proved to be good starting groups on the benzoic acid derivative for this substitution. It is preferably carried out in a dipolar aprotic solvent, such as DMF or TMU, at a temperature from 0ºC to the boiling point of the solvent, preferably from 80ºC to the boiling point of the solvent. An alkaline or alkaline earth salt with an anion of greater basicity and less nucleophilicity, for example K2CO3 or CsCO3, serves as an acid acceptor.

The compounds used as precursors R(6)-A-B-Cd-H2d-Xf- are mostly known and are partially commercially available as reagents. Their production takes place according to methods known from the literature, which are known to experts.

The introduction of several substituents in positions 4 and 5 takes place according to methods known from the literature by cross-linking aryl halides through palladium with, for example, organostanas, organoboric acids or organoboranes or organocopper or organozinc compounds.

Benzoylguanidines are generally weak bases and can bind acids to form salts. Suitable acid addition salts are salts of all pharmacologically tolerable acids, for example halides, especially hydrochlorides, lactates, sulfates, citrates, tartrates, ascorbates, acetates, phosphates, methylsulfonates, p-toluenesulfonates.

Compounds I are substituted alkylguanidines.

The most prominent representative of acylguanidine is the pyrazine derivative amiloride, which is used in therapy as a potassium-sparing diuretic. Numerous further amiloride-type compounds are described in the literature, such as dimethylamiloride or ethylisopropylamiloride.

[image]

Amiloride: R', R'' = H,

dimethylamiloride: R', R'', = CH3,

ethylisopropylamiloride: R' = C2H5, R'' = CH(CH3)2.

For this reason, there are known studies that point to the antiarrhythmic properties of amiloride (Circulation 79, 1257 to 1253 (1989). However, its widespread use as an antiarrhythmic is opposed by the fact that these effects are expressed only very weakly and are accompanied by a decrease in blood pressure and a saluretic effect, and these side effects are undesirable in the treatment of heart rhythm disorders.

Experiments on isolated animal hearts also indicated the antiarrhythmic properties of amiloride (Eur. Heart J. 9 (suppl. 1): 167 (1988) (book of abstracts). Thus, for example, it was found on rat hearts that amiloride artificially induced ventricular fibrillation can completely suppress In that model, even stronger than amiloride was the above-mentioned amiloride derivative ethylisopropylamiloride.

In patent document 5 091 394 (HOE 89/F 288) benzoylguanidines are described, which in the position corresponding to the residue R(1) carries only one hydrogen atom, and in which none of the substituents has the meaning R(5)-A-B-D. In European published document 0 556 674 A (HOE 92/F 034) 3,5-substituted benzoylguanidines are proposed, but in which the substituent R(2), according to the proposed disclosure, does not have the required meaning of R(5)-A-B-D.

Patent document 3 780 027 claims acylguanidines, which are structurally similar to the compounds of formula I and are derived from commercially available sliding diuretics, such as bumetanide. Correspondingly strong salidiuretic efficacy is reported for these compounds.

Therefore, it was surprising that the compounds according to the invention do not show any undesirable and harmful salidiuretic properties, but rather very good antiarrhythmic properties against such arrhythmias as occur, for example, in cases of oxygen deficiency. Due to their pharmacological properties, the compounds are extremely suitable as antiarrhythmic drugs with cardioprotective components for the prophylaxis of infarction and the treatment of infarction, and for the treatment of angina pectoris, whereby they also preemptively inhibit or greatly interfere with the pathophysiological processes induced by the occurrence of ischemic damage, especially when causing ischemia-induced cardiac arrhythmia . Due to their protective action against pathological hypoxic and ischemic situations due to the inhibition of the cellular exchange mechanism of Na+/H+ compounds according to the invention of formula I can be used as drugs for the treatment of all acute or chromic damage caused by ischemia or primary or secondary diseases induced thereby. This also applies to their use in surgical procedures, e.g. in organ transplantation, where these compounds can also be used to protect organs in the donor before and during collection, to protect the taken organ, for example during processing, or its disposal in physiological liquids, as well as when being transferred to the recipient's organism. These compounds are also valuable drugs with a protective effect during angioplasty operations on the heart as well as on peripheral vessels. In accordance with their protective action against damage induced by ischemia, these compounds are also suitable as drugs for the treatment of ischemia of the nervous system, in particular of the central nervous system, where they are suitable, for example, for the treatment of stroke or brain edema. Furthermore, the compounds according to the invention of formula I are also suitable for the treatment of forms of shock, such as allergic, cardiogenic, hypovolemic and bacterial shock.

The compounds according to the invention of formula I are further characterized by a strong inhibitory effect on cell proliferation, for example cell proliferation of fibroblasts and proliferation of vascular smooth muscle cells. For this reason, the compounds of formula I come into consideration as valuable agents for the therapy of diseases in which cell proliferation is the primary or secondary cause, and for this reason they can be used as antiatherosclerotics, agents against diabetic late complications, cancer diseases, fibrotic diseases such as pulmonary fibrosis, liver fibrosis or renal fibrosis, hypertrophy and hyperplasia of organs, especially in case of prostatic hyperplasia or prostatic hypertrophy.

The compounds according to the invention are effective inhibitors of cellular sodium proton antiporters (Na+/H+-exchanger), which in many diseases (essential hypertension, atherosclerosis, diabetes, etc.) are also elevated in such cells that are not easily accessible for measurements, such as in erythrocytes, platelets or leukocytes.

The compounds according to the invention are therefore suitable as a distinguished and simple scientific tool, for example for use as diagnostics in certain forms for the determination and research of hypertension, but also atherosclerosis, diabetes, proliferative diseases, etc. The compounds according to the invention of formula I are also suitable for preventive therapy, to prevent the genesis of high blood pressure, for example essential hypertension.

In addition to a very strong inhibitory effect on Na+/H+-exchangers compared to known compounds, the compounds according to the invention also show a significantly improved solubility in water. They are therefore significantly better for i.v. applications.

Medicines containing the compounds of formula I can be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred application depending on the respective disease presentation. The compounds of formula I can be used alone or together with galenic excipients, both in veterinary medicine and in human medicine.

Excipients suitable for the desired drug formulation are available to those skilled in the art. In addition to solvents, gel-forming agents, suppository bases, auxiliaries for tablets and other active substance carriers, antioxidants, dispersing agents, emulsifiers, anti-foaming agents, flavoring agents, preservatives, and solubility-improving agents can also be used. or dyes.

For the oral form of administration, the active compounds are mixed with suitable additional substances, such as carriers, stabilizers or inert diluents, and are brought into suitable dosage forms, such as tablets, dragees, capsules, aqueous, alcoholic or oily solutions, using usual methods. Gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, especially corn starch, can be used as inert carriers. At the same time, preparations can be made both as dry and also as wet granulate. Vegetable or animal oils, such as sunflower oil or fish oil, come into consideration as carrier oils or wastes.

For subcutaneous or intravenous administration, the active compounds are brought, as desired, into a solution, suspension or emulsion with the usual substances for this as auxiliaries for solutions, emulsifiers or other auxiliaries. As solvents, for example, water, physiological saline solution or alcohols, for example ethanol, propanol, glycerine, and in addition also sugar or glucose solutions or mannitol solutions, or also a mixture of the various mentioned solvents, can be considered.

Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active substance of formula I in a pharmaceutically acceptable solvent, such as ethanol or water or a mixture of such solvents.

If necessary, the formulation may also contain other pharmaceutical auxiliary substances such as surfactants, emulsifiers and stabilizers, and propellant gas. Such a preparation contains the active substance usually in a concentration of approximately 0.1 to 10, especially approximately 0.3 to 3 wt. %.

The dosage of the active substance of formula I when administered and the frequency of administration depends on the strength of action and the duration of action of the compound used; in addition, it also depends on the type and severity of the disease being treated, and on the type, age, weight and individual irritability of the treated mammal.

On average, the daily dose of the compound of formula I in a patient weighing approximately 75 kg is at least 0.001 mg/kg, preferably 0.01 mg/kg, up to a maximum of 10 mg/kg, preferably 1 mg/kg of body weight. In acute disease outbreaks, approximately immediately after suffering a heart attack, even higher and above all more frequent dosages may be necessary, for example up to 4 individual doses per day. Especially with i.v. administration, approximately in a patient with a heart attack in the intensive care unit, up to 200 mg per day may be required.

List of abbreviations:

AIBN α,α-azo-bis-isobutyronitrile,

Bn benzyl,

Brine saturated aqueous NaCl solution,

CH2Cl2 dichloromethane,

DCl desorption chemical ionization,

DIP diisopropyl ether,

DMA dimethylacetamide,

DME dimethoxyethane,

DMF N,N-dimethylformamide,

EE ethyl acetate (EtOAc),

EI electronic shock,

eq equivalent,

ES ionization by electrospray,

Ethyl,

FAB fast atom bombing,

HEP n-heptane,

HOAc acetic acid,

Me methyl,

MeOH methanol,

mp melting point,

MTB methyl tert.butyl ether,

NBS N-bromosuccinimide,

NMP N-methylpyrrolidone,

RT room temperature,

THF tetrahydrofuran,

TMU N,N,N',N'-tetramethylurea,

CNS central nervous system.

Experimental part

General regulation for the production of benzoyl-guanidine (I)

Version A: from benzoic acid (II, L = OH)

0.01 M of the benzoic acid derivative of formula II is dissolved or suspended in 60 ml of aqueous THF and then mixed with 1.78 g (0.011 M) of carbonyldiimidazole. After stirring for 2 hours at room temperature, 2.95 g (0.05 M) of guanidine was added to the reaction solution. After stirring overnight, the THF is removed by distillation under reduced pressure (rotary evaporator), mixed with water, adjusted to pH 6 to 7 with 2N HCl, and the corresponding benzoylguanidine (formula I) is filtered off. The benzoyl-guanidines thus obtained can be converted into the corresponding salts by treatment with water, methanolic or etheric hydrochloric acid or with other pharmacologically tolerable acids.

General regulation for the production of benzoyl-guanidine (I)

Version B: from the alkyl ester of benzoic acid (II, Z = O-alkyl)

5 mmol of benzoic acid alkyl ester of formula II and 25 ml of guanidine (anhydrous base) are dissolved in 15 ml of isopropanol or suspended in 15 ml of THF and boiled under reflux until complete chemical conversion (thin layer control) (typical reaction time 2 to 5 hours) ). The solvent was removed by distillation under reduced pressure (rotary evaporator), taken up in 300 ml of EE and washed three times with 50 ml of NaHCO3 solution each. Dry over Na2SO4, remove the solvent by distillation and chromatograph on silica gel with a suitable solvent, eg EE/MeOH 5:1. (For salt formation, compare version A).

Example 1

4-(4-aminosulfonyl)phenoxy-3-trifluoromethyl-benzoylguanidine

[image]

a) 4-fluoro-3-trifluoromethyl-benzoic acid methyl ester

5 g of 4-fluoro-3-trifluoromethyl-benzoic acid and 9 ml of SOCl2 are mixed in 50 ml of MeOH for 8 hours at 60ºC. Finally, the volatile components are removed in vacuo and 5.1 g of colorless oil is obtained, which is further used without purification.

Rf (EE/MeOH 10:1) = 0.74;

MS (DCl) 223 (M+H) + .

b) 4-(4-aminosulfonyl)phenoxy-3-fluoromethyl-benzoic acid methyl ester

890 mg of fluoride a), 690 mg of 4-hydroxybenzenesulfonamide and 1.1 g of K2CO3 are mixed in 5 ml of DMF for 2 hours at 120ºC. Let it cool to room temperature, add 100 ml of saturated NaCl aqueous solution, and extract 3 times with 50 ml of EEa each. It was dried over Na2SO4 and the solvent was removed in vacuo. 1.2 g of colorless oil is obtained.

Rf (MTB) = 0.45;

MS (DCl) 367 (M+H) + .

c) 4-(4-aminosulfonyl)phenoxy-3-fluoromethyl-benzoylguanidine

550 g of methyl ester 1 b) is granulated according to variant B. 170 mg of amorphous powder is obtained.

Rf (EE/MeOH 10:1) = 0.50;

MS (ES) 403 (M+H) + .

It is converted into hydrochloride.

Melting point: >270ºC.

Example 2

4-[4-(N-t-butylimido-N'-t-butyl)sulfonyl]-3-trifluoromethyl-benzoylguanidine, dihydrochloride

[image]

a) N-N'-bis-t-butyl-imidamide of 4-fluoro-benzenesulfonic acid

900 ml of t-butylamine is mixed at -30ºC with 10.3 ml of bromine. Let it warm up to 5ºC and add 6.6 ml of 4-fluorothiophenol. The mixture is heated to room temperature and stirred at that temperature for another 4 hours. Finally, it is poured onto 600 g of ice, 500 ml of EE is added and it is washed 3 times with 100 ml of saturated aqueous Na2SO3 solution each. Now the organic phase is concentrated in a vacuum, taken up again in 500 ml of EE and washed 3 times with 200 ml of 0.6 M aqueous solution of KH2PO4. Then the organic phase is mixed for 1 hour with 100 ml of 2N aqueous HCl solution and finally the phase is separated in EE. The aqueous phase is adjusted to pH - 9 with Na2CO3 and extracted 3 times with 200 ml of EE each. It was dried over Na2SO4 and the solvent was removed in vacuo. 6.4 g of colorless oil is obtained.

Rf (DIP) = 0.46;

MS (DCl) 287 (M+H) + .

b) N-N'-bis-t-butyl-imidamide of 4-hydroxy-benzenesulfonic acid

2.9 g of N-N'-bis-t-butyl-imidamide of 4-fluoro-benzenesulfonic acid and 3.4 g of CsOH (monohydrate) are mixed in 25 ml of TMU for 8 hours at 160-170ºC. It is finally allowed to cool to room temperature, mixed with 100 ml of water and 50 ml of saturated aqueous NaHCO3 solution and extracted 3 times with 100 ml of EE each. It was dried over Na2SO4 and the solvent was removed in vacuo. Chromatography on silica gel with EE/HEP 1:1 yields 700 g of colorless oil. Rf (MTB/DIP 1.1) = 0.27;

MS (EI) 285 (M+H) + .

c) 4-[4-(N-t-butylimido-N'-t-butyl)sulfamoyl]-phenoxy-3-trifluoromethyl-benzoic acid methyl ester

600 mg of N-N'-bis-t-butyl imidamide of 4-hydroxy-benzenesulfonic acid, 468 mg of 4-fluoro-3-trifluoromethyl-benzoic acid methyl ester and 2.1 g of Cs2CO3 are mixed in 10 ml of TMU 1, 5 hours at 160ºC. Allow to cool to room temperature, add 100 ml of saturated aqueous NaHCO3 solution and extract 3 times with 100 ml of EE each. It was dried over Na2SO4 and the solvent was removed in vacuo. Chromatography on silica gel with DIP gives 400 g of colorless oil.

Rf (DIP) = 0.28;

MS (ES): 487 (M+H) + .

d) 4-[4-(N-t-butylimido-N'-t-butyl)sulfamoyl]-3-trifluoromethyl-benzoylguanidine

300 mg of 4-[4-(N-t-butylimido-N'-t-butyl)sulfamoyl]-3-trifluoromethyl-benzoic acid methyl ester and 182 mg of guanidine are chemically converted according to the general recipe for the production of benzoyl-guanidine, version B. It is obtained 120 mg of colorless oil.

Rf (EE) = 0.24;

MS (FAB): 587 (M+H) + ;

melting point (dihydrochloride) = 165-168ºC.

Example 3

4-[4-(N-dimethylaminoethyl)-methylsulfamoyl]-phenoxy-3-trifluoromethyl-benzoic acid, dihydrochloride

[image]

a) Methyl ester of 4-phenoxy-3-trifluoromethyl-benzoic acid

15 g of 4-chloro-3-trifluoromethyl-benzoic acid methyl ester, 5.9 g of phenol and 17.4 g of K2CO3 were mixed in 100 ml of DMF for 14 hours at 110ºC. Allow to cool to room temperature, dilute with 1 1 EE, wash 2 times with 200 ml of water, 2 times with 200 ml of 0.1 N aqueous NaOH solution and 2 times with 300 ml of saturated aqueous NaCl solution. It was dried over Na2SO4 and the solvent was removed in vacuo. Chromatography on silica gel with EE/HEP 1:8 gives 11 g of a colorless oil.

Rf (EE/HEP 1:8) = 0.24;

MS (DCl): 297 (M+H) + .

b) 4-phenoxy-3-trifluoromethyl-benzoic acid

11 g of 4-phenoxy-3-trifluoromethyl-benzoic acid methyl ester is dissolved in 200 ml of MeOH and mixed with 41 ml of 1N aqueous NaOH solution and stirred for 24 hours at room temperature. At the end, the MeOH is removed under vacuum, diluted with 1 1 of water, adjusted to pH = 2 with an aqueous HCl solution and the precipitate is filtered off. It is air-dried for 48 hours and 9.2 g of an amorphous solid is obtained.

Rf (EE) = 0.10;

MS (DCl): 283 (M+H) + .

c) 4-(4-chlorosulfonyl)phenoxy-3-trifluoromethyl-benzoic acid

1 g of 4-phenoxy-3-trifluoromethyl-benzoic acid is dissolved in 15 ml of CHCl3 and 710 μl of chlorosulfonic acid are added dropwise. It was stirred for 3 hours at room temperature and finally the solvent was removed under vacuum. Then add 50 g of ice and 50 ml of water, mix for 10 minutes and filter off the precipitate. 0.96 g of an amorphous solid is obtained.

Rf (DIP 2% HOAc) = 0.38;

MS (EI): 381 (M+H) + .

d) 4-[4-(N-dimethylaminoethyl)-methylsulfamoyl]-phenoxy-3-trifluoromethyl-benzoic acid

475 mg of 4-(4-chlorosulfonyl)phenoxy-3-trifluoromethyl-benzoic acid is dissolved in 10 ml of acetone and mixed with 160 μl of trimethylethylenediamine and 350 μl of triethylamine. The mixture is stirred for 2 hours at room temperature, at the end it is diluted with 100 ml of water and the acetone is removed under vacuum. With a 0.1 N aqueous solution of HCl, it is adjusted to pH = 6-7 and extracted 6 times with 100 ml of EE. It was dried over Na2SO4 and the solvent was removed in vacuo. 330 mg of amorphous solid is obtained.

Rf (CH2Cl2/MeOH/HOAc/H2O) 8:4:1:1) = 0.42;

MS (EI): 447 (M+H) + .

e) 4-[4-(N-dimethylaminoethyl)-methylsulfamoyl]-phenoxy-3-trifluoromethyl-benzoic acid methyl ester

330 g of 4-[4-(N-dimethylaminoethyl)-methylsulfamoyl]-phenoxy-3-trifluoromethyl-benzoic acid and 1 ml of SOCl2 are heated in 10 ml of MeOH for 8 hours under reflux. The volatile ingredients of the mixture are removed in a vacuum, taken up in 100 ml of saturated aqueous Na2CO3 solution and 100 ml of EE and extracted 3 times with 100 ml of EE each. It was dried over Na2SO4 and the solvent was removed in vacuo. Chromatography on silica gel with EE/MeOH 2:1 gives 150 mg of a colorless resin.

Rf (EE/MeOH/1:1) = 0.30;

MS (EI): 461 (M+H) + .

f) 4-[4-(N-dimethylaminoethyl)-methylsulfamoyl]phenoxy-3-trifluoromethyl-benzoguanidine

140 mg of 4-[4-(N-dimethylaminoethyl)-methylsulfamoyl]phenoxy-3-trifluoromethyl-benzoic acid methyl ester and 90 mg of guanidine are chemically converted into 3 ml of isopropanol according to the general recipe for the production of benzoyl-guanidine, version B. 130 mg of amorphous solid tari.

Rf (EE/MeOH/1:1) = 0.12;

MS (EI): 488 (M+H) + ;

melting point (dihydrochloride) = 203ºC.

The title compounds of examples 4 - 8 are synthesized analogously to example 3:

Example 4

4-[4-(4-methylpiperazinosulfonyl)-phenoxy]-3-trifluoromethyl-benzoylguanidine, dihydrochloride

[image]

Rf (EE/MeOH/1:1) = 0.15;

MS (EI): 486 (M+H) + ;

melting point (dihydrochloride), = >250ºC.

Example 5

4-[4-(2-pyrrolidineethylaminosulfonyl)phenoxy]-3-trifluoromethyl-benzoylguanidine, dimaleinate

[image]

Rf (CH2Cl2/MeOH/HOAc/H2O 8:4:1:1) = 0.37;

MS (FAB): 500 (M+H) + .

Example 6

4-[4-(2-piperidineethylaminosulfonyl)phenoxy]-3-trifluoromethyl-benzoylguanidine, dimaleinate

[image]

Rf (CH2Cl2/MeOH/HOAc/H2O 8:4:1:1) = 0.40;

MS (FAB): 514 (M+H) + .

Example 7

4-[4-(N-dimethylamino-n-propyl)sulfamoyl]phenoxy-3-trifluoromethyl-benzoylguanidine

[image]

Rf (EE/MeOH 1:1) = 0.06;

MS (EI): 488 (M+H) + .

Example 8

4-[4-(N-dimethylaminoethyl)sulfamoyl]phenoxy-3-trifluoromethyl-benzoylguanidine

[image]

Rf (EE/MeOH 1:1) = 0.17;

MS (EI): 474 (M+H) + .

Example 9

4-(4-Imidamidosulfonyl)phenoxy-3-trifluoromethyl-benzoylguanidine

[image]

a) 4-[4-(N-t-butylimido-N'-t-butyl)sulfamoyl]phenoxy-3-trifluoromethyl-benzoic acid

7.9 g of 4-[4-(N-t-butylimido-N'-t-butyl)sulfamoyl]phenoxy-3-trifluoromethyl-benzoic acid methyl ester (example 2c) was dissolved in 100 ml of MeOH and 40 ml of 2 N aq. of NaOH solution. It is boiled for 3 hours at reflux, the MeOH is removed in vacuo and the residue is taken up in a mixture of 100 ml of water and 100 ml of EE. Add 500 ml of saturated aqueous solution of NaH2PO4 and extract 3 times with 200 ml of EE each. It was dried over Na2SO4 and the solvent was removed in vacuo. 7.2 g of white crystals are obtained.

Rf (MTB) = 0.25;

MS (ES): 473 (M+H) + ;

melting point: 200ºC.

b) 4-(4-imidosulfamoyl)phenoxy-3-trifluoromethyl-benzoic acid

6.6 g of 4-[4-(N-t-butylimido-N'-t-butyl)sulfamoyl]phenoxy-3-trifluoromethyl-benzoic acid is dissolved in 140 ml of anhydrous CH2Cl2, 3.7 ml of trifluoromethanesulfonic acid is added and mixed 24 hours at room temperature. The mixture is mixed in 1 1 0.66 M aqueous solution of KH2PO4, the phase is separated in methylene chloride and extracted 3 times with 300 ml of EE each. The combined organic phases were dried over Na2SO4 and the solvent was removed in vacuo. 6.7 g of viscous oil is obtained, which is further used without cleaning.

Rf (EE/MeOH 5:1) = 0.21;

MS (IS): 361 (M+H) + .

c) Methyl ester of 4-(4-imidosulfamoyl)phenoxy-3-trifluoromethyl-benzoic acid and

d) 4-(4-N-methyl-imidosulfamoyl)phenoxy-3-trifluoromethyl-benzoic acid methyl ester

6.7 g of 4-(4-imidosulfamoyl)phenoxy-3-trifluoromethyl-benzoic acid is dissolved in 100 ml of MeOH, 20 ml of a 2N solution of trimethylsilyldiazomethane in HEP is added dropwise and stirred for 6 hours at room temperature. At the end, 200 ml of 20% aqueous acetic acid solution is added and mixed for another 30 minutes. Then 200 ml of EE is added and extracted 9 times with 100 ml of 1 N aqueous HCl solution. The aqueous phase is finally adjusted to pH = 10 and extracted 3 times with 200 ml EEa each. It was dried over Na2SO4 and the solvent was removed in vacuo. The residue is chromatographed on silica gel with EE/HEP 1:1 and 1.2 g of product c) is obtained in addition to 890 mg of product d), in both cases oil.

c) Rf (EE) = 0.32; MS (ES): 375 (M+H) + ;

d) Rf (EE) = 0.38; MS (ES): 389 (M+H) + .

e) 4-(4-imidamidosulfonyl)phenoxy-3-trifluoromethyl-benzoylguanidine

220 mg of 4-(4-imidosulfamoyl)phenoxy-3-trifluoromethyl-benzoic acid methyl ester and 174 mg of guanidine in 10 ml of THF are chemically converted according to the general recipe for the production of benzoyl-guanidine, version B. After chromatography on silica gel with EE/MeOH 5:1, 80 mg of benzoic crystals are obtained.

Rf (EE/MeOH 5:1) = 0.22;

MS (ES): 402 (M+H) + ;

melting point: 156ºC.

Example 10

3-trifluoromethyl-4-(4-N-methylimidamidosulfonyl)-phenoxy-benzoylguanidine

[image]

490 mg of 4-(4-N-methyl-imidosulfonyl)phenoxy-3-trifluoromethyl-benzoic acid methyl ester (example 9d) and 373 mg of guanidine in 20 ml of THF are chemically converted according to the general recipe for the production of benzoyl-guanidine, version B After chromatography on silica gel with EE/MeOH 5:1, 370 mg of benzoic crystals are obtained.

Rf (EE/MeOH 5:1) = 0.33;

MS (ES): 416 (M+H) + ;

melting point (dihydrochloride): 233ºC.

The title compound of example 11 was synthesized analogously to example 3 from the methyl ester of 3-methyl-4-phenoxy-benzoic acid:

Example 11

3-methyl-4-(4-(1-methylpiperazin-4-yl-sulfonyl)-phenoxy-benzoylguanidine

[image]

a) Methyl ester of 3-methyl-4-phenoxy-benzoic acid

3.4 g of methyl ester of 4-fluoro-3-methyl-benzoic acid, 2.4 g of phenol and 19.5 g of Cs2CO3 are mixed in 100 ml of NMP for 20 minutes at 160ºC. The mixture is poured into 400 ml of saturated aqueous NaHCO3 solution, diluted with 400 ml of water and extracted 3 times with 200 ml of MTB. It was dried over Na2SO4 and the solvent was removed in vacuo. Chromatography of the residue on silica gel with EE/HEP 1:4 gave 2.0 g of a colorless oil.

Rf (EE/HEP 1:4) = 0.33;

MS (EI): 243 (M+H) + .

The title compound of Example 12 was synthesized analogously to Example 9:

Example 12

3-Methylsulfonyl-4-(4-imidamidosulfonyl)phenoxy-benzoylguanidine

[image]

Rf (EE/MeOH 5:1) = 0.24;

MS (ES): 412 (M+H) + .

Example 13

4-(4-guanidinosulfonyl)phenoxy-3-trifluoromethyl-benzoylguanidine

[image]

a) 4-(4-hydroxysulfonyl)phenoxy-3-trifluoromethyl-benzoic acid

13.5 g of 4-phenoxy-3-trifluoromethyl-benzoic acid (example 3b) is dissolved in 150 ml of CHCl3, 3.3 ml of chlorosulfonic acid is added dropwise at room temperature and stirred for another 3 hours. The solvent is removed under vacuum, 300 g of ice and 100 ml of water are added and mixed for 10 minutes. Finally, 400 ml of saturated aqueous NaCl solution cooled to 0ºC is added, it is stirred for a further 15 minutes at 0ºC and the precipitate is suctioned off. It was dried in vacuo at 40ºC to give 16.5 g of a white solid which was further used without purification.

b) 4-(4-chlorosulfonyl)phenoxy-3-trifluoromethyl-benzoyl chloride

14.0 g of 4-(4-hydroxysulfonyl)phenoxy-3-trifluoromethyl-benzoic acid and 1 ml of DMF are dissolved in 250 ml of SOCl 2 and heated under reflux for 8 hours. About half of the excess SOCl2 is finally removed in vacuo and the solution is poured dropwise onto 1 kg of ice. It is extracted 3 times with 500 ml of CH2Cl2 each, dried over MgSO4 and the solvent is removed in vacuo. 18.0 g of oil is obtained, which is used without further purification.

Rf (DIP/2% HOAc) = 0.51.

c) 4-[4-(3-pyridyloxy)sulfonyl]-phenoxy-3-trifluoromethyl-benzoic acid 3-hydroxypyridyl ester

18.0 g of 4-(4-chlorosulfonyl)phenoxy-3-trifluoromethyl-benzyl chloride is dissolved in 150 ml of acetone, mixed with 3.7 g of 3-hydroxypyridine and 11.0 g of K2CO3 and stirred for 3 hours at room temperature. The reaction mixture is poured over 500 ml of water and extracted 3 times with 300 ml of EE each. It is dried over Na2SO4, the solvent is removed in vacuo and chromatographed on silica gel with MTB/2% HOAc. 8.0 g of yellowish oil is obtained.

Rf (MTP/2% HOAc) = 0.29;

MS (FAB): 517 (M+H) + .

d) 4-(4-guanidinosulfonyl)phenoxy-3-trifluoromethyl-benzoyl-guanidine

3.0 g of 4-[4-(3-pyridyloxy)-sulfonyl]phenoxy-3-trifluoromethyl-benzoic acid 3-hydroxypyridyl ester and 3.4 g of guanidine are dissolved in 10 ml of i-propanol and heated for 3 hours under reflux. The solvent is removed in a vacuum, taken up with 400 ml of water, adjusted to pH = 8 with an aqueous solution of hydrochloric acid and stirred for 2 hours at room temperature. The precipitate is filtered off and chromatographed on silica gel with EE/MeOH 5:1. 272 mg of amorphous solid is obtained.

Rf (EE/MeOH 5:1) = 0.33;

MS (ES): 445 (M+H) + .

Example 14

3-methylsulfonyl-4-[4-(2-dimethylaminoethyl)phenoxy]-benzoylguanidine bis-methanesulfonate

[image]

a) 5-carboxy-2-fluorobenzenesulfinic acid

15.6 g (0.124 M) of sodium sulfite is dissolved at 70ºC in 120 ml of water. With heating, 23.8 g (0.1 mol) of 4-fluoro-3-chlorosulfonylbenzoic acid and 10 n NaOH are added in portions so that the pH is kept between 9 and 10 (exothermic reaction). It is stirred for a further 3 hours at 70ºC, allowed to stir for a further 15 minutes with A-carbon and then filtered. The pH of the filtrate is adjusted to 0 - 1 with external cooling with concentrated hydrochloric acid and the crystalline 5-carboxy-2-fluorobenzenesulfinic acid is filtered off. Colorless crystals.

Melting point: 167-170ºC.

b) Disodium salt of 5-carboxy-2-fluorobenzenesulfinic acid

is obtained by introducing 17.2 g (0.084 M) of carboxy-2-fluorobenzenesulfinic acid into a mixed solution of 6.72 g (0.168 M) of NaOH in a mixture of 150 ml of methanol and 30 ml of water. After filtering the fluffy substances, the solvent is removed by distillation and the residue is crystallized using acetone.

Colorless crystalline substance, melting point: >320ºC.

c) Methyl ester of 4-fluoro-3-methylsulfonylbenzoic acid

30 g (0.21 M) methyl iodide is added to a suspension of 15 g (0.06 M) of the disodium salt of 5-carboxy-2-fluorobenzenesulfinic acid in 80 ml of dry DMF, it is stirred for 6 hours at 60ºC, the solvent is removed by distillation and the rest is mixed with water. It is stirred for 30 minutes while cooling with ice and the precipitate is filtered off.

Colorless crystalline substance, melting point: 102-105ºC.

d) Methyl ester of 3-methylsulfonyl-4-[4-(2-dimethylaminomethyl)phenoxy]-benzoic acid

4.64 g (0.02 M) of 4-fluoro-3-methylsulfonyl-benzoic acid methyl ester was added to a mixture of 60 ml of dimethylacetamide, 3.6 g (0.022 M) of N,N-dimethyl-2-(4 -hydroxyphenyl)-ethylamine and 9.08 g (0.066 M) of powdered anhydrous K2CO3 and the suspension was stirred for 4 hours at 90ºC. After removal of the solvent by distillation, the residue is mixed with water and repeatedly extracted with ethyl acetic acid, the combined organic phases are concentrated under reduced pressure to obtain a substance as a yellow oily liquid.

e) Preparation of 3-methylsulfonyl-4-[4-(2-dimethylaminoethyl)phenoxy]-benzoic acid, dihydrochloride

1.88 g (0.005 M) of 3-methylsulfonyl-4-[4-(2-dimethylaminoethyl)phenoxy]-benzoic acid methyl ester is boiled in 40 ml of semi-concentrated hydrochloric acid for 5 hours under reflux, the aqueous hydrochloric acid is removed by distillation and the residue is crystallized with acetone.

Colorless crystalline substance, melting point: 246-248ºC.

f) 3-methylsulfonyl-4-[4-(2-dimethylaminoethyl)phenoxy]-benzoylguanidine

it is obtained analogously to the prescription specified in version A from 3-methylsulfonyl-4-[4-(2-dimethylaminoethyl)phenoxy]-benzoic acid at a pH value between 7 and 8.

Colorless crystals, melting point: 214-218ºC.

g) 3-methylsulfonyl-4-[4-(2-dimethylaminoethyl)phenoxy]-benzoylguanidine bis-methanesulfonate

it is obtained analogously to the prescription specified in version A from 3-methylsulfonyl-4-[4-(2-dimethylaminoethyl)phenoxy]-benzoylguanidine by treatment with 2.5 equivalents of methanesulfonic acid in ethanol.

Colorless solid, melting point: 102ºC.

Example 15

4-[4-(2-dimethylaminoethyl)thiomethyl-phenoxy]-3-methylsulfonyl-benzoylguanidine dihydrochloride

[image]

a) Preparation of 4-(2-dimethylaminoethyl)thiomethyl-phenol

A mixture of 200 mg of p-toluenesulfonic acid, 14.1 g (0.1 M) of 2-dimethylaminoethyl mercaptan dihydrochloride and 12.4 g (0.1 M) of 4-hydroxybenzyl alcohol in 250 ml of toluene is boiled for approx. 5 hours on a water separator according to Kutscher and Steudel under reflux, the solvent is removed and the residue is filtered after dissolving in methanol. After re-concentration, the residue is brought to crystallization using acetone, the crystalline product is filtered off and the easily hygroscopic mass is dried over NaOH with the exclusion of air.

Melting point: 134-140ºC.

b) Methyl ester of 4-[4-(2-dimethylaminoethyl)thiomethyl-phenoxy]-3-methylsulfonyl-benzoic acid

A mixture of 3.48 g (0.015 M) 4-(2-dimethylaminoethyl)-thiomethylphenol, 40 ml anhydrous tetramethylurea, 6.8 g (0.049 M) anhydrous powdered K2CO3 and 3.48 g (0.015 M) methyl ester of 4-fluoro- of 3-methylsulfonylbenzoic acid is stirred for 6 hours at 90-100ºC, the solvent is removed by distillation and the residue is mixed with water. After extraction with acetic ester, drying and thickening of the combined organic phases, the desired product is obtained as an oil.

c) Hydrochloride of 4-[4-(2-dimethylaminoethyl)thiomethylphenoxy]-3-methylsulfonyl-benzoic acid

is obtained analogously to the prescription described in example 14d) by hydrolysis of the methyl ester of 4-fluoro-3-methylsulfonylbenzoic acid in 20% HCl.

Colorless to light yellow crystalline substance,

melting point: 179-185ºC.

d) Dihydrochloride 4-[4-(2-dimethylaminoethyl)thiomethyl-phenoxy]-3-methylsulfonyl-benzoylguanidine

is obtained analogously to the recipe described in example 14e) from 4-[4-(2-dimethylaminoethyl)thiomethyl-phenoxy]-3-methylsulfonylbenzoic acid hydrochloride.

Hygroscopic substance, melting point: 230ºC.

Example 16

4-[4-(2-dimethylaminoethylthio-phenoxy]-3-methyl-sulfonyl-benzoguanidine dihydrochloride

[image]

a) N,N-dimethyl-2-(4-hydroxyphenylthio)ethylamine

17.28 g (0.11 M) of 2-diethylaminoethyl chloride hydrochloride was added to a solution of 12.6 g (0.1 M) of 4-mercaptophenol in 100 ml of anhydrous DMF under a protective atmosphere (argon) and finally 19, 38 g (0.15 M) of ethyldiisopropylamine and the reaction mixture is heated for 12 hours with a magnetic stirrer at 110ºC. After removing the solvent by distillation, the residue is mixed with water, the pH is adjusted to 8-9 with 1 N NaOH, the amorphous precipitate is extracted several times with ethyl acetate and the combined organic phases are dried over sodium sulfate. The solvent is removed by distillation and the residue is chromatographed on a silica gel column with an eluent consisting of 8 parts ethyl acetate and 1 part methanol.

Colorless crystals, melting point: 108-110ºC.

b) 4-[4-(2-dimethylaminoethylthio)phenoxy]-3-methylsulfonylbenzoic acid methyl ester

is obtained as a yellow oil analogously to the procedure described in 14d) chemical conversion of methyl ester of N,N-dimethyl-2-(4-hydroxyphenylthio)ethylamine with methyl ester of 4-fluoro-3-methylsulfonyl-benzoic acid, whereby as a reaction agent instead of dimethylacetate uses DMF.

Yellow oily liquid.

c) 4-[4-(2-dimethylaminoethylthio)phenoxy]-3-methylsulfonyl-benzoic acid

6.8 g of 4-[4-(2-dimethylaminoethylthio)phenoxy]-3-methylsulfonylbenzoic acid methyl ester is boiled in 10 ml of acetic acid and 70 ml of semi-concentrated HCl for 5 hours under reflux conditions. After removing the solvent by distillation, the desired substance is obtained as an amorphous solid without a defined melting point.

d) 4-[4-(2-dimethylaminoethylthio)phenoxy]-3-methylsulfonyl-benzoguanidine dihydrochloride

is obtained analogously to the regulation specified as variant A.

A colorless solid,

decomposition temperature: 160ºC with foaming.

Example 17

4-[4-(2-dimethylaminoethylsulfonyl)phenoxy]-3-methylsulfonyl-benzoylguanidine dihydrochloride

[image]

a) 4-[4-(2-dimethylaminoethylsulfonyl)phenoxy]-3-methylsulfonyl-benzoic acid

To a solution of 3.8 g (0.008 M) of 4-[4-(2-dimethylaminoethylthio)phenoxy]-3-methylsulfonyl-benzoic acid in 50 ml of glacial acetic acid is added at 5-10ºC in portions 6.9 g (0.028 M) of 3-chloroperbenzoic acid and stirred for 12 hours at room temperature. After adding water, the precipitate of 3-chlorobenzoic acid is filtered off and further impurities are extracted from the filtrate. The aqueous phase is concentrated and the amorphous residue is crystallized with ethyl acetate. Colorless crystals, melting point: 167-171ºC.

b) 4-[4-(2-dimethylaminoethylsulfonyl)phenoxy]-3-methylsulfonyl-benzoyl-guanidine dihydrochloride

is obtained analogously to the prescription specified in version A from 4-[4-(2-dimethylaminoethylsulfonyl)phenoxy]-3-methyl-sulfonyl-benzoic acid in TMU as a reaction medium. The dichloride is crystallized with methanol.

Colorless crystals, melting point: 233-240º (decomposition).

Example 18

4-[(4-guanidinocarbonyl)phenoxy]-3-methylsulfonylbenzoylguanidine dihydrochloride

[image]

a) From 4-(4-carboxyphenoxy)-3-methylsulfonylbenzoic acid

Chemical conversion of methyl ester of 4-hydroxybenzoic acid with methyl ester of 4-fluoro-3-methylsulfonylbenzoic acid analogously to the regulation specified under 14d) yields methyl ester of 4-(4-ethoxycarbonylphenoxy)-benzoic acid as a colorless to light yellow oil which is hydrolyzed without further cleaning procedures analogously according to the method specified in regulation 16c) in (4-carboxyphenoxy)-3-methylsulfonyl-benzoic acid.

Colorless crystals, melting point: 227-275ºC.

b) 18b) 4-[(4-guanidinocarbonyl)phenoxy]-3-methylsulfonyl-benzoyl-guanidine dihydrochloride

it is obtained analogously to the prescription given in version A by chemical conversion of 0.74 g (0.0022) of (4-carboxyphenoxy)-3-methylsulfonylbenzoic acid with 0.78 g (0.0048 M) of carbonyl-di-imidazole and 1.55 g ( 0.026 M) guanidine in DMA.

Colorless crystals, melting point: 252ºC.

Example 19

4-[4-(2-dimethylaminoethyl)thiomethyl-phenoxy]-3-trifluoromethylbenzoylguanidine dihydrochloride

[image]

a) Methyl ester of 4-[4-(2-dimethylaminoethyl)thiomethyl-phenoxy]-3-trifluoromethylbenzoic acid

is obtained analogously to the recipe described in example 15b) from 4-(2-dimethylaminoethyl)thiomethyl-phenol and methyl ester of 4-fluoro3-trifluoromethylbenzoic acid in DMU as a reaction medium as an amorphous, oily product.

b) 4-[4-(2-dimethylaminoethyl)thiomethyl-phenoxy]-3-trifluoromethyl-benzoic acid

obtained analogously to the recipe described in example 14d) by acid hydrolysis of methyl ester

4-[4-(2-dimethylaminoethyl)thiomethyl-phenoxy]-3-trifluoromethylbenzoic acid.

Colorless, hygroscopic crystals, melting point: 158-168º (decomposition).

c) 4-[4-(2-dimethylaminoethyl)thiomethyl-phenoxy]-3-trifluoromethylbenzoylguanidine dihydrochloride

is obtained analogously to the recipe described in variant A from 4-[4-(2-dimethylaminoethyl)thiomethyl-phenoxy]-3-trifluoromethyl-benzoic acid in TMU as a reaction medium. Amorphous, highly hygroscopic solid, decomposition at 80-85ºC.

Example 20

4-[4-(2-dimethylaminoethylthio)phenoxy]-3-trifluoromethylbenzoylguanidine dihydrochloride

[image]

a) Methyl ester of 4-[4-(2-dimethylaminoethylthio)phenoxy]-3-trifluoromethyl-benzoic acid

is obtained analogously to the recipe described in example 15b) from 4-(2-dimethylaminoethylthio)phenol and 4-fluoro-3-trifluoromethyl-benzoic acid methyl ester in DMU as a reaction medium as an amorphous, oily product.

b) 4-[4-(2-dimethylaminoethylthio)phenoxy]-3-trifluoromethylbenzoic acid

is obtained analogously to the recipe described in example 14d) by acid hydrolysis of 4-[4-(2-dimethylamino ethylthio)phenoxy]-3-trifluoromethyl benzoic acid methyl ester. The desired 4-[4-(2-dimethylaminoethylthio)phenoxy]-3-trifluoromethyl-benzoic acid crystallizes with acetone.

Colorless crystals, melting point: 174-182ºC (decomposition).

c) 4-[4-(2-dimethylaminoethylthio)phenoxy]-3-trifluoromethyl-benzoylguanidine dihydrochloride

is obtained analogously to the recipe described in variant A from 4-[4-(2-dimethylaminoethylthio)phenoxy]-3-trifluoromethyl-benzoic acid in THF as a reaction medium.

Amorphous, hygroscopic crystalline solid, decomposition at 240ºC.

Example 21

3-Trifluoromethyl-4-[4-(2-dimethylaminoethyl)phenoxy]benzoylguanidine dihydrochloride

[image]

a) 4-chloro-3-trifluoromethylbenzoic acid

The Grignard compound is first prepared from 100 g of 5-bromo-2-chloro-benzotrifluoride and 10.2 g of magnesium in 600 ml of diethyl ether. Finally, a current of 60 g of anhydrous CO2 is introduced into that solution at room temperature. 500 ml of saturated aqueous solution of NaHSO4 are added dropwise, the phases are separated and extracted 2 more times with 100 ml of diethyl ether each. The organic phase is extracted 3 times with 300 ml of 1 n NaOH, finally the aqueous phase is washed 3 times with 100 ml of diethyl ether. Now the aqueous phase is brought to pH 2 with HCl and diluted to 4 l with water. The product is sucked off and dried in a vacuum.

75 g of white powder, Rf (MTB 2% HOAc) = 0.68.

b) 4-chloro-3-trifluoromethylbenzoic acid methyl ester

75 g of 4-chloro-3-trifluoromethylbenzoic acid is dissolved in 500 ml of MeOH and 75 ml of SOCl2 is added dropwise. It is boiled for 5 hours under reflux, finally the volatile ingredients are removed in a vacuum. It is taken with 1 liter of EE and washed with 500 ml of saturated aqueous solution of Na2CO3. It is dried over Na2SO4, the solvent is removed and distilled under vacuum.

Boiling point: 94ºC (2 tor);

Rf (DIP) = 0.49; MS (DCl): 239 (M+H) + .

c) 4-[4-(2-dimethylamino)ethyl]phenoxy-3-trifluoromethyl-benzoic acid methyl ester

1.9 g of methyl ester of 4-chloro-3-trifluoromethyl-benzoic acid, 1.3 g of 4-(2-dimethylamino) ethyl-phenol, 7.8 g of Cs2CO3 are mixed in 50 ml of tetramethylurea for 5 hours at 140ºC. Allow to cool, then add 300 ml of saturated aqueous solution of NaHCO3 and 150 ml of water, and extract 3 times with 100 ml of EE each. It is dried over Na2SO4 and finally the solvent is removed in vacuo. Chromatography with acetone/water 10:1 gave 2.0 g of a colorless oil.

Rf (acetone/water 10:1) = 0.15; MS (DCl): 368 (M+H) + .

d) 4-[4-(2-dimethylamino)ethyl]phenoxy-3-trifluoromethyl-benzoylguanidine

2.0 g of 4-[4-(2-dimethylamino)ethyl]phenoxy-3-trifluoromethyl-benzoic acid methyl ester is guanylated with 1.6 g of guanidine in 60 ml of isopropanol according to variant B. The crude product is converted into the dihydrochloride and recrystallized from 1,2-dimethoxyethane/water 9:1.

Melting point (free base): 164ºC;

melting point (dihydrochloride): 236ºC;

MS (DCl): 395 (M+H) + .

Solubility in water of dihydrochloride: 49 mg/ml (pH = 5.3).

Example 22

4-(4-N,N-dimethylaminoethylphenoxy)-3-sulfamoyl-benzoylguanidine bismethanesulfonate

[image]

is obtained analogously to the procedure described in version A from 4-[4-(2-dimethylaminoethyl)phenoxy]-3-sulfamoyl benzoic acid in dimethylacetamide or N-methylpyrrolidone as a reaction medium. Amorphous, hygroscopic crystalline solid.

Melting point: 183ºC.

a) Methyl ester of 4-[4-(2-dimethylaminoethyl]phenoxy-3-sulfamoyl-benzoic acid)

obtained by heating 0.011 moles of N,N-dimethyl-2-(4-hydroxyphenyl)-ethylamine, 0.033 moles of potassium carbonate (ground) and 0.01 moles of 4-fluoro-3-sulfamoyl-benzoic acid methyl ester in 40 ml of dimethylacetamide for 5 hours at 90-100ºC. After removing the solvent by distillation, the residue is mixed with water, the brown amorphous product is treated with acetic ester, filtered from the crystalline precipitate and the solvent is separated from the filtrate by distillation. Amorphous oily product.

b) 4-[4-(2-dimethylaminoethyl]phenoxy-3-sulfamoyl-benzoic acid).

is obtained by hydrolysis of 0.0066 mol of the corresponding methyl ester (a) in 60 ml of boiling semi-concentrated hydrochloric acid for 5 hours. After evaporation of aqueous hydrochloric acid in a vacuum, the residue is treated with acetone and the precipitate is filtered off. The solvent is removed by distillation and the desired benzoic acid is obtained. Softening point above 60ºC.

Example 23

3-chloro-4-[4-(2-dimethylaminoethyl]phenoxy-5-methylsulfonyl-benzoylguanidine bismethanesulfonate

[image]

is obtained analogously to the recipe described in version A from 3-chloro-4-[4-(2-dimethylaminoethyl]phenoxy-5-methylsulfonyl-benzoic acid in dimethylacetamide or N-methylpyrrolidone as a reaction medium).

Hygroscopic crystalline solid, melting point: 200ºC.

a) Methyl ester of 3-chloro-4-[4-(2-dimethylaminoethyl]phenoxy-5-methylsulfonylbenzoic acid)

obtained analogously to example 22a) by chemical conversion of 3,4-dichloro-5-methylsulfonylbenzoic acid methyl ester with N,N-dimethyl-2-(4-hydroxyphenyl)-ethylamine. Amorphous, oily substance.

b) 3-chloro-4-[4-(2-dimethylaminoethyl]phenoxy-5-methylsulfonyl-benzoic acid)

is obtained analogously to example 22a). Crystalline solid, decomposition: 238-244ºC.

Example 24

4-[(4-guanidinocarbonyl)phenoxy]-3-methyl-sulfonylbenzoylguanidine

[image]

is obtained as a salt-free base from example 18 by treating 4-[(4-guanidinocarbonyl)phenoxy]-3-methylsulfonylbenzoyl-guanidine dihydrochloride with triethylamine in DMF.

Colorless crystalline solid; melting point: 237ºC.

Example 25

4-[4-(2-N-imidazolyl-1-oxo-ethyl)phenoxy]-3-methylsulfonylbenzoylguanidine dihydrochloride

[image]

is obtained analogously to the recipe described in version A from 4-[4-(2-N-imidazolyl-1-oxo-ethyl)phenoxy]-3-methylsulfonylbenzoic acid in dry dimethylacetamide or N-methylpyrrolidone as a reaction medium. Colorless crystalline solid, decomposition: 255ºC.

a) 4-(4-chloroacetylphenoxy)-3-methylsulfonylbenzoic acid

0.02 mol of 3-methylsulfonyl-4-phenoxybenzoic acid is added in portions to a mixture of 0.08 mol of chloroacetyl chloride, 16 g of anhydrous aluminum chloride and 150 ml of 1,2-dichloroethane at 0-5ºC, stirred for 2 hours at room temperature and finally stirred for 2 hours at 40-45ºC. It is allowed to stand overnight and after that the reaction mixture is poured onto ice water with stirring, the crystalline precipitate is filtered off, washed with water and dried. Yellow crystals, melting point:

184-187ºC.

b) 4-[4-(2-N-imidazolyl-1-oxo-ethyl)phenoxy]-3-methylsulfonylbenzoic acid

A solution of 0.005 mol of 4-(4-chloroacetylphenoxy)-3-methylsulfonylbenzoic acid (25a) in 25 ml of anhydrous DMF was stirred with 0.0225 mol of imidazole for 4 hours at 60ºC and then the solvent was removed by distillation. After treating the amorphous residue with water and adjusting the pH to 2-3 with 2N hydrochloric acid, it is stirred for one hour and the crystalline precipitate is filtered off. Crystals, decomposition 235-241ºC.

Example 26

4-[4-(2-N-imidazolylthio-acetyl)phenoxy]-3-methylsulfonyl-benzoylguanidine dihydrochloride

[image]

is obtained analogously to the recipe described in variant A from 4-[4-(2-imidazolylthio-acetyl)]-3-methylsulfonylbenzoic acid in a mixture of 50 ml of THF and 10 ml of dimethylacetamide as a reaction medium. Colorless crystalline substance, melting point: 220ºC.

a) 4-[4-(2-imidazolylthio-acetyl)phenoxy]-3-methylsulfonylbenzoic acid

it is obtained by chemical conversion of 4-(4-chloroacetylphenoxy)-3-methylsulfonylbenzoic acid (example 25a) and moles of 2-mercaptoimidazole in 20 ml of acetone and heating for a short time until boiling. Mix approx. 5 days at room temperature and the crystalline precipitate is filtered off. Decomposition: 202-205ºC.

Example 27

4-[4-(4,5-dihydro-2-imidazolylthio-acetyl)phenoxy]-3-methylsulfonyl-benzoylguanidine

[image]

is obtained analogously to the recipe described in version A from 4-[4-(4,5-dihydro-2-imidazolylthio-acetyl)phenoxy]-3-methyl-sulfonylbenzoic acid in a mixture of 50 ml of THF and 10 ml of dimethylacetamide as a reaction media.

Colorless crystalline solid, melting point: 210ºC.

a) 4-[4-(4,5-dihydro-2-imidazolylthio-acetyl)phenoxy]-3-methylsulfonylbenzoic acid

it is prepared analogously to regulation 26a) by the reaction of 4-(4-chloroacetylphenoxy)-3-methylsulfonylbenzoic acid (example 25a) with 2-mercapto-4,5-dihydroimidazole. Decomposition: 305-310ºC.

Example 28

4-[4-(N,N'-dimethyl-S-isothiouronyl-acetyl)phenoxy]-3-methylsulfonyl-benzoylguanidine dihydrochloride

[image]

is obtained analogously to the recipe described in version A from 4-[4-(N,N'-dimethyl-S-isothiouronyl-acetyl)phenoxy]-3-methyl-sulfonylbenzoic acid in a mixture of 50 ml of THF and 10 ml of dimethylacetamide as reaction medium.

Colorless crystalline solid, melting point: 150ºC.

a) 4-[4-(N,N'-dimethyl-S-isothiouronyl-acetyl)-phenoxy]-3-methylsulfonyl-benzoic acid

is obtained analogously to regulation 26a) by the reaction of 4-(4-chloroacetylphenoxy)-3-methylsulfonylbenzoic acid (example 25a) with N,N'-dimethylthiourea at room temperature. Colorless crystals.

Decomposition: 185-190ºC.

Example 29

4-[4-(2-benzimidazolylthio-acetyl)-phenoxy]-3-methylsulfonyl-benzoylguanidine dihydrochloride

[image]

is obtained analogously to the recipe described in version A from 4-[4-(2-benzimidazolylthio-acetyl)-phenoxy]-3-methylsulfonyl-benzoic acid in THF as a reaction medium. Colorless crystalline solid, melting point: 228ºC.

a) 4-[4-(2-benzimidazolylthio-acetyl)-phenoxy)-3-methyl-sulfonyl-benzoic acid

is obtained analogously to recipe 26a) by the reaction of 4-(4-chloroacetyl-phenoxy)-3-methylsulfonylbenzoic acid (example 25a) with 2-mercaptobenzimidazole in DMF.

Melting point: 182ºC.

Example 30

4-[4-(2-pyridylthio-acetyl)-phenoxy]-3-methyl-sulfonyl-benzoylguanidine dihydrochloride

[image]

is obtained analogously to the recipe described in version A from 4-[4-(2-pyridylthio-acetyl)phenoxy]-3-methyl-sulfonyl-benzoic acid in THF as a reaction medium. Colorless crystalline solid, melting point: 203ºC.

a) 4-[4-(2-pyridylthio-acetyl)phenoxy]-3-methylsulfonyl-benzoic acid

is obtained analogously to recipe 26a) by the reaction of 4-(4-chloroacetylphenoxy)-3-methylsulfonyl-benzoic acid (example 25a) with 2-mercaptopyridine.

Melting point: 194-196ºC.

Example 31

4-[4-(2-quinolylthio-acetyl)phenoxy]-3-methyl-sulfonyl-benzoylguanidine dihydrochloride

[image]

is obtained analogously to the recipe described in version A from 4-[4-(2-quinolylthio-acetyl)phenoxy]-3-methylsulfonyl-benzoic acid in THF as a reaction medium. Colorless crystalline solid, melting point: 192ºC.

a) 4-[4-(2-quinolylthio-acetyl)phenoxy]-3-methyl-sulfonyl-benzoic acid

it is prepared analogously to regulation 26a) by the reaction of 4-(4-chloroacetylphenoxy)-3-methylsulfonyl-benzoic acid (example 25a) with 2-mercaptoquinoline in DMF. Melting point: 210-214ºC.

Example 32

4-[4-(2-N-imidazolyl-1-hydroxyethyl)phenoxy]-3-methylsulfonyl-benzoylguanidine dihydrochloride

[image]

is obtained analogously to the recipe described in version A from 4-[4-(2-N-imidazolyl-1-hydroxyethyl)phenoxy]-3-methylsulfonyl-benzoic acid in dimethylacetamide or N-methylpyrrolidine as a reaction medium. Colorless crystalline solid, decomposition temperature: 260ºC.

a) 4-[4-(2-N-imidazolyl-1-hydroxyethyl)phenoxy]-3-methylsulfonyl-benzoic acid

is obtained by reducing 0.0034 mol of 4-[4-(2-N-imidazolyl-1-oxo-ethyl)phenoxy]-3-methylsulfonyl-benzoic acid with 0.0068 mol of sodium borate in 40 ml of ethanol. After removing the solvent by distillation, mixing the residue with water and adjusting the pH to 4 with 2N hydrochloric acid, it is stirred for several hours at room temperature and the crystals are filtered off. Melting point: 240-248ºC.

Example 33

Methylsulfonyl-4-(4-sulfamoylphenoxy)benzoylguanidine hydrochloride

[image]

is obtained analogously to the recipe described in version A from 3-methylsulfonyl-4-(4-sulfamoylphenoxy)benzoic acid in dimethylacetamide as a reaction medium. Colorless crystalline solid, decomposition temperature: 267ºC.

a) 3-methylsulfonyl-4-(4-chlorosulfonylphenoxy)benzoic acid

obtained by chemical conversion of 0.03 mol of 4-phenoxy-3-methylsulfonyl-benzoic acid with 0.15 mol of chlorosulfonic acid in 60 ml of methylene chloride at 0-5ºC and further stirring for 4 hours at room temperature. After treatment with ice water, the phase is separated in methylene chloride, washed with water, dried over magnesium sulfate and the solvent is removed by distillation. Crystals, melting point: 167-170ºC.

b) 3-methylsulfonyl-4-(4-sulfamoylphenoxy)benzoic acid

it is obtained by the reaction of 3-methylsulfonyl-4-(4-chlorosulfonylphenoxy)benzoic acid with an aqueous concentrated ammonia solution for 24 hours at room temperature. Ammonia is removed by distillation and the aqueous solution is acidified with 2N HCl to pH 1-2. The crystals are filtered off, washed with water and dried. Colorless crystalline substance,

melting point: 240-245ºC.

Example 34

4-[4-(1-hydroxy-2-(pyridylthio)ethyl)phenoxy]-3-methylsulfonyl-benzoylganidine dihydrochloride

[image]

is obtained analogously to the prescription of version A from 4-[4-(1-hydroxy-2-(2-pyridylthio)ethylphenoxy)-3-methylsulfonyl-benzoic acid in THF as a reaction medium. Colorless crystalline solid, melting point: 116ºC.

a) 4-[4-(1-hydroxy-2-(2-pyridylthio)ethyl)phenoxy]-3-methylsulfonyl-benzoic acid

it is obtained analogously to example 32a). Colorless crystalline solid, melting point: 169-174ºC.

Example 35

4-[4-(1-hydroxy-2-(2-benzimidazolylthio)ethyl)phenoxy]-3-methylsulfonyl-benzoylganidine dihydrochloride

[image]

is obtained analogously to the prescription of version A from 4-[4-(1-hydroxy-2-(2-benzimidazolylthio)ethyl)phenoxy]-3-methyl-sulfonyl-benzoic acid in dimethylacetamide as a reaction medium. Colorless crystalline solid, melting point: 213ºC.

a) 4-[4-(1-hydroxy-2-(2-benzimidazolylthio)ethyl)phenoxy]-3-methylsulfonyl-benzoic acid

it is obtained analogously to example 32a). Colorless crystalline solid, melting point: 186-188ºC.

Example 36

4-[4-(1-hydroxy-2-(2-quinolylthio)ethyl)phenoxy]-3-methylsulfonyl-benzoylnidine dihydrochloride

[image]

is obtained analogously to the prescription of version A from 4-[4-(1-hydroxy-2-(2-quinolylthio)ethyl)phenoxy]-3-methylsulfonyl-benzoic acid in THF as a reaction medium. Colorless crystalline solid, melting point: 180ºC.

a) 4-[4-(1-hydroxy-2-(2-quinolylthio)ethyl)phenoxy]-3-methylsulfonyl-benzoic acid

obtained analogously to example 32a) from 4-[4-(2-quinolylthio-acetyl)phenoxy]-3-methylsulfonyl-benzoic acid (example 31a).

Colorless crystalline substance.

Example 37

4-[4-(N,N-dimethylglycylamino)phenoxy]-3-methyl-sulfonyl-benzoylguanidine dihydrochloride

[image]

is obtained analogously to the prescription of version A from 4-[4-(N,N-dimethylglycylamino)phenoxy]-3-methylsulfonyl-benzoic acid in THF as a reaction medium. Colorless crystalline solid, melting point: 223ºC.

a) 3-methylsulfonyl-4-(4-nitrophenoxy)benzoic acid

it is prepared by chemical conversion of 0.02 mol of 3-methylsulfonyl-4-phenoxybenzoic acid with 0.96 ml of 100% nitric acid in a mixture of 8 ml of acetic anhydride and 4 ml of glacial acetic acid at -10ºC. After mixing for 1.5 hours at that temperature, it is mixed for 24 hours at room temperature and a further 6 hours at 40ºC. It is poured onto ice water, and the oily amorphous product is brought to crystallization by mixing with water. Yellow crystalline substance,

melting point: 140-150ºC.

b) 4 (4-aminophenoxy)-3-methylsulfonylbenzoic acid

is obtained by catalytic hydrogenation of 3-methylsulfonyl-4-(4-nitrophenoxy)benzoic acid (example 37a) with Raney nickel in methanol under normal pressure until complete hydrogen uptake. After evaporation of the solvent, a unique amorphous oil is obtained.

c) N.N-dimethylglycine-imidazolide hydrochloride

it is obtained by chemical conversion of N,N-dimethylglycine hydrochloride with carbonyldiimidazole in anhydrous dimethylacetamide, from which the product is excreted. The mixture is further chemically converted without further processing procedures.

d) 4-[4-(N,N-dimethylglycylamino)phenoxy]-3-methylsulfonyl-benzoic acid

obtained by chemical conversion of N,N-dimethylglycine-imidazolide hydrochloride (example 37c) with 4-(4-aminophenyl)-3-methylsulfonylbenzoic acid (example 37b) by stirring for 5 hours in dimethylacetamide at room temperature. The solvent was removed by distillation, the pH was adjusted to 1-2 with hydrochloric acid and extracted with ethyl acetate. The aqueous phase is separated by distillation and the residue is treated with methanol. After separating the insoluble ingredients by filtration, the desired compound is obtained as a colorless oil.

Example 38

4-[4-(N,N-diethylaminoethyl)aminosulfonyl-phenoxy]-3-methylsulfonyl-benzoyl-guanidine dihydrochloride

[image]

is obtained analogously to the procedure described in version A from 4-[4-(N,N-diethylaminoethyl)aminosulfonylphenoxy]-3-methyl-sulfonyl-benzoic acid in anhydrous dimethylacetamide as a reaction medium. Colorless crystalline solid,

melting point: 206ºC.

a) 4-[4-(N,N-diethylaminoethyl)aminosulfonylphenoxy]-3-methylsulfonyl-benzoic acid

is obtained by reacting 0.05 mol of 3-methylsulfonyl-4-(4-chlorosulfonylphenoxy)benzoic acid (example 33a) with 0.06 mol of N,N-diethylaminoethylamine in the presence of excess triethylamine (approx. 0.015 mol) in methanol as a reaction medium. After removing the solvent mixture, it is mixed with a little water and the pH is adjusted to 4-5. The crystalline precipitate is filtered off.

Melting point: 263-268ºC.

Example 39

4-[4-(1-methyl-4-piperazino)sulfonylphenoxy]-3-methylsulfonyl-benzoyl-guanidine dihydrochloride

[image]

is obtained analogously to the procedure described in version A from 4-[4-(1-methyl-4-piperazine)sulfonylphenoxy]-3-methylsulfonyl-benzoic acid in THF as a reaction medium. Colorless crystalline solid, decomposition: 234-244ºC.

a) 4-[4-(1-methyl-4-piperazino)sulfonylphenoxy]-3-methylsulfonyl-benzoic acid

is obtained by chemical conversion of methylsulfonyl-4-(4-chlorosulfonylphenoxy)-benzoic acid (example 33a) with N-methylpiperazine analogously to example 38a. Colorless crystals, decomposition: 287-292ºC.

Example 40

4-[4-(4-imidazolylethyl)aminosulfonylphenoxy]-3-methylsulfonyl-benzoyl-guanidine dihydrochloride

[image]

is obtained analogously to the procedure described in version A from 4-[4-(4-imidazolylethyl)aminosulfonylphenoxy)-3-methylsulfonyl-benzoic acid in dimethylacetamide as a reaction medium. Colorless crystalline solid, melting point: 264ºC.

a) 4-[4-(4-imidazolylethyl)aminosulfonylphenoxy]-3-methylsulfonyl-benzoic acid

obtained analogously to example 38a) by chemical conversion of methylsulfonyl-4-(4-chlorosulfonylphenoxy)benzoic acid (example 33a) with histamine. Colorless, amorphous solid, decomposition: 265ºC.

Example 41

4-[4-(3-N-imidazolyl-1-propyl)aminosulfonyl-phenoxy]-3-methylsulfonyl-benzoyl-guanidine dihydrochloride

[image]

is obtained analogously to the procedure described in version A from 4-[4-(3-N-imidazolyl-1-propyl)aminosulfonylphenoxy]-3-methylsulfonyl-benzoic acid in THF as a reaction medium. Colorless crystalline solid, decomposition: 257ºC.

a) 4-[4-(3-N-imidazolyl-1-propyl)aminosulfonylphenoxy]-3-methylsulfonyl-benzoic acid

obtained analogously to example 38a) by chemical conversion of methylsulfonyl-4-(4-chlorosulfonylphenoxy)-benzoic acid (example 33a) with 1-(3-aminopropyl)imidazole. Colorless amorphous solid, melting point: 250ºC.

Example 42

4-(4-(1-methyl-2-pyrrolidinylethyl)aminosulfonyl-phenoxy]-3-methylsulfonyl-benzoyl-guanidine dihydrochloride

[image]

is obtained analogously to the procedure described in version A from 4-[4-(1-methyl-2-pyrrolidinylethyl)aminosulfonylphenoxy]-3-methylsulfonyl-benzoic acid in dimethylacetamide as a reaction medium. Colorless crystalline solid, melting point: 254ºC.

a) 4-[4-(1-methyl-pyrrolidinylethyl)aminosulfonylphenoxy]-3-methylsulfonyl-benzoic acid

obtained analogously to example 38a) by chemical conversion of methylsulfonyl-4-(4-chlorosulfonylphenoxy)benzoic acid (example 33a) with 2-(2-aminoethyl)-1-methylpyrrolidine. Melting point: 242-247ºC.

Example 43

4-[4-(N-morpholinoethyl)aminosulfonyl-phenoxy]-3-methylsulfonyl-benzoyl-guanidine dihydrochloride

[image]

is obtained analogously to the procedure described in version A from 4-[4-(N-morpholinoethyl)aminosulfonylphenoxy]-3-methylsulfonyl-benzoic acid in dimethylacetamide as a reaction medium. Colorless crystalline solid, melting point: 272ºC.

a) 4-[4-(N-morpholinoethyl)aminosulfonylphenoxy]-3-methylsulfonyl-benzoic acid

obtained analogously to example 38a) by chemical conversion of methylsulfonyl-4-(4-chlorosulfonylphenoxy)benzoic acid (example 33a) with N-(2-aminoethyl)-morpholine. Colorless

crystalline compound, melting point: 220-224ºC.

Example 44

4-[4-(N-piperidinoethyl)aminosulfonyl-phenoxy]-3-methylsulfonyl-benzoyl-guanidine dihydrochloride

[image]

is obtained analogously to the procedure described in version A from 4-[4-(N-piperidinoethyl)aminosulfonylphenoxy]-3-methylsulfonyl-benzoic acid in dimethylacetamide as a reaction medium. Colorless crystalline solid, melting point: 266ºC.

a) 4-[4-(N-piperidinoethyl)aminosulfonylphenoxy]-3-methylsulfonyl-benzoic acid

obtained analogously to example 38a) by chemical conversion of methylsulfonyl-4-(4-chlorosulfonylphenoxy)benzoic acid (example 33a) with N-(2-aminoethyl)piperidine.

Colorless crystalline solid, melting point: 271-273ºC.

Example 45

4-[4-(2-pyridylethyl)aminosulfonylphenoxy]-3-methylsulfonyl-benzoyl-guanidine dihydrochloride

[image]

is obtained analogously to the procedure described in version A from 4-[4-(2-pyridylethyl)aminosulfonylphenoxy]-3-methylsulfonyl-benzoic acid in anhydrous dimethylacetamide as a reaction medium. Colorless crystalline solid, melting point: 257ºC.

a) 4-[4-(2-pyridylethyl)aminosulfonylphenoxy]-3-methyl-sulfonyl-benzoic acid

obtained analogously to example 38a) by chemical conversion of methylsulfonyl-4-(4-chlorosulfonylphenoxy)benzoic acid (example 33a) with 2-(2-aminoethyl)pyridine. Colorless crystals, melting point: 268-270ºC.

Example 46

4-[4-(2-dimethylaminoethylethyl)sulfonylmethyl-phenoxy]-3-methylsulfonyl-benzoyl-guanidine dihydrochloride

[image]

obtained by oxidation with peracid analogously to the procedure described in example "4" from 4-[4-(2-dimethylaminoethyl)-thiomethyl-phenoxy)-3-methylsulfonyl-benzoylguanidine dihydrochloride (example 15). Colorless crystals. Melting point: 245ºC.

Example 47

4-[4-(2-dimethylaminoethylethyl)sulfonylmethyl-phenoxy]-3-trifluoromethyl-benzoyl-guanidine dihydrochloride

[image]

obtained by oxidation with peracid analogously to the procedure described in example 17 from 4-[4-(2-dimethylaminoethyl)-thiomethyl-phenoxy]-3-trifluoromethyl-benzoylguanidine dihydrochloride (example 19). Colorless crystals.

Melting point: 140ºC.

Pharmacological data:

Inhibition of the Na+/H+-exchanger of rabbit erythrocytes, white New Zealand rabbits (Ivanovas) reaches a standard diet with 2% cholesterol in six weeks, in order to activate the Na+/H+-exchange and thus through the Na+/H+-exchange could be determined by flame photometry Na+ influx into erythrocytes. Blood was taken from the ear arteries and made non-coagulable with 25 IU of potassium heparin. One part of each sample was used for double determination of hematocrit by centrifugation. Aliquots of 100 μl were used to measure the N+ output content of erythrocytes.

To determine amiloride-sensitive sodium influx, 100 μl of each blood sample was incubated in 5 ml of hyperosmotic salt-sucrose medium (mmol/l: 140 NaCl, 3 KCl, 150 sucrose, 0.1 ouabain, 20 tris-hydroxymethylaminomethane) at pH 7.4 and 37ºC. After that, the erythrocytes were washed three times with ice-cold MgCl2-ouabain solution (mmol/l: 112 MgCl2, 0.1 ouabain) and hemolyzed in 2.0 ml of distilled water. Intracellular sodium content was determined by flame photometry.

Net Na+-influx was calculated from the difference between the initial sodium values and the sodium content of erythrocytes after incubation. Sodium influx suppressed by amiloride is obtained from the difference of sodium content in erythrocytes after incubation and without amiloride 3 x 10-4 mol/l. Compounds according to the invention were also treated in this way.

the results

Inhibition of Na+/H+-exchanger:

[image]

Claims (19)

1. Compounds of formula I, indicated by the fact that they are represented by formula (I) [image] where: one of the three substituents R(1), R(2) and R(3) is R(6)-A-B-D-; R(6) is a residue that can be basicly protonated, i.e. amino group -NR(7)R(8), amidino group R(7)R(8)N-C[=N-R(9)]- or guanidino group [image] R(7), R(8), R(9) and (10) are independently hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms; or R(7) and R(8) together are CaH2a; a is 4, 5, 6 or 7; wherein if a = 5, 6 or 7, one methylene group of the group CaH2a may be replaced with a heteroatom group O, SOm, or NR(11); or R(8) and R(9) or R(9) and R(10) or R(7) and R(10) represent the group CaH2a: a is 2, 3, 4 or 5; where if a = 3, 4 or 5, one methylene group of the group CaH2a can be substituted with a heteroatom group O, SOm or NR(11); m is zero, 1 or 2; R(11) is hydrogen or methyl; or R(6) is a basic heteroaromatic ring system with 1 - 9 C-atoms; A is CbH2b; b is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein in the group CbH2b one or two methylene groups can be substituted with one of the groups selected from the group consisting of -O-, -CO-, -CH[OR(20)]-, -SOm-, -NR(20 )-, -NR(20)-CO-, -NR(20)-CO-NH-, -NR(20)-CO-NH-SO2-, [image] and -SOaa[NR(19)]bb-; and wherein in the group CbH2b one methylene group can be replaced by -CH-R(99), whereby R(99) together with R(7) forms a pyrrolidine or piperidine ring; aa is 1 or 2; bb is 0 or 1; aa + bb = 2; R(19) is hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms; R(20) is hydrogen or methyl; B is a phenylene or naphthylene residue, [image] R(12) and R(13) are independently hydrogen, methyl, F, Cl, Br, J, CF3 or -SOw-R(14); R(14) is methyl or NR(15)R(16); R(15) and R(16) are independently hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms; w is zero, 1 or 2; D is -CdH2d-Xf-; d is zero, 1, 2, 3 or 4; X is -O-, -CO-, -CH[OR(21)]-, -SOm- or -NR(21)-; f is zero or 1; R(21) is hydrogen or methyl; m is zero, 1 or 2; and the remaining substituents R(1) and R(2) and R(3) independently of each other are hydrogen, F, Cl, Br, J, -CN, -(C1-C8)-alkyl, -(C2-C8)-alkenyl, -NR(35)R(36) or R(17)-CgH2g-Zh-; g is zero, 1, 2, 3 or 4; h is zero or 1; R(35) and R(36) are independently hydrogen or alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms; or R(35) and R(36) together represent 4-7 methylene groups, one of which CH2-group can be substituted with oxygen, -S-, -NH-, -NCH3 or -N-benzyl; Z is -O-, -CO-, -SOv-, -NR(18)-, -NR(18)-CO-, -NR(18)-CO-NH- or -NR(18)-SO2; R(18) is hydrogen or methyl; v is zero, 1 or 2; R(17) is hydrogen, cycloalkyl with 3, 5 or 6 C-atoms or CkF2k+1-; k is 1, 2 or 3; or R(17) is pyrrole-1-yl, pyrrole-2-yl or pyrrole-3-yl, which is unsubstituted or substituted with 1-4 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C8)-Alkanoyl, (C2-C8)-Alkoxycarbonyl, formyl, carboxy, -CF3, methyl and methoxy; or R(17) -(C3-C8)-cycloalkyl or phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F and Cl, -CF3, methyl, hydroxy, methoxy, -NR(37)R (38), CH3SO2- and H2NO2S-; R(37) and R(38) are hydrogen or -CH3; R(4) and R(5) are independently hydrogen, alkyl with 1, 2, 3 or 4 carbon atoms, F, Cl, -OR(32), -NR(33)R(34) or -CrF2r+ 1; R(32), R(33) and R(34) are independently hydrogen or alkyl with 1, 2 or 3 carbon atoms; r is 1, 2, 3 or 4; and their pharmacologically tolerable salts. 2. Compounds of formula I according to claim 1, characterized in that in them R(1) is hydrogen, F, Cl, -(C1-C4)-alkyl, -(C2-C4)-alkenyl, -NR(35)R(36) or R(17)-CgH2g-Zh-; R(35) and R(36) are independently hydrogen, methyl or ethyl; or R(35) and R(36) together represent 4-5 methylene groups, one of which CH2-groups can be substituted with oxygen, -S-, -NH-, or -NCH3; R(17) is hydrogen, cycloalkyl with 5 or 6 carbon atoms or CkF2k+1-; k is 1, 2 or 3; g is zero, 1, 2, 3 or 4; h is zero or 1; Z is -O-, -CO-, -SOv-, -NR(18)-, -NR(18)-CO-, -NR(18)-CO-NH- or -NR(18)-SO2; R(18) is hydrogen or methyl; v is zero, 1 or 2; or, if g and h are zero, R(17) is pyrrole-1-yl, pyrrole-2-yl or pyrrole-3-yl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, (C2-C5)-alkanoyl , (C2-C5)-Alkoxycarbonyl, formyl, carboxy, -CF3, methyl and methoxy; or R(17) is -(C3-C8)-cycloalkyl or phenyl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F and Cl, -CF3, methyl, methoxy, -N(R37)R( 38), CH3SO2- and H2NO2S-; R(37) and R(38) are independently hydrogen or -CH3; or one of the substituents R(2) and R(3) represents R(6)-A-B-D; R(6) is -NR(7)R(8), one amidino group R(7)R(8)N-C[=N-R(9)]- or one guanidino group [image] R(7), R(8), R(9) and R(10) are independently hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms; or R(7) and R(8) together are CaH2a; a is 4, 5, 6 or 7; whereby if a = 5, 6 or 7 one methylene group of the group CaH2a can be substituted with a heteroatomic group O, SOm or NR(11); R(11) is hydrogen or methyl; or R(8) and R(9) together represent the group CaH2a; a is 2, 3, 4 or 5; whereby if a = 3, 4 or 5 one methylene group of the group CaH2a can be substituted with a heteroatomic group O, SOm or NH(11); m is zero, 1 or 2; or R(6) is imidazolyl, pyridyl, quinolinyl or isoquinolinyl; A is CbH2b; b is 1, 2, 3, 4 or 5, whereby in the group CbH2b one or two methylene groups can be replaced by one of the groups selected from the group consisting of -O-, -CO-, -CH[OR(20)]-, -SOm-, -NR(20)-, -NR(20)-CO-, -NR(20)-CO-NH-, -NR(20)-CO-NH-SO2-, [image] and -SOaa[NR(19)]bb-; and wherein in the group CbH2b one methylene group can be replaced by -CH-R(99), whereby R(99) together with R(7) forms a pyrrolidine or piperidine ring; aa is 1 or 2; bb is 0 or 1; aa + bb = 2; R(19) is hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms; R(20) is hydrogen or methyl; B is a phenylene or naphthylene residue, [image] R(12) and R(13) are independently hydrogen, methyl, F, Cl, CF3 or -SO2-R(14); R(14) is methyl or NR(15)R(16); R(15) and R(16) are independently hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms; D is -CdH2d-Xf-; d is zero, 1, 2, 3 or 4; X is -O-, -CO-, -CH[OR(21)]-, -SOm- or -NR(21)-; f is zero or 1; R(21) is hydrogen or methyl; m is zero, 1 or 2; and the remaining substituents R(2) and R(3) are hydrogen, alkyl with 1, 2, 3 or 4 C-atoms, F, Cl or CF3; R(4) and R(5) are independently hydrogen, alkyl with 1, 2 or 3 carbon atoms, F, Cl or -CF3; and their pharmacologically tolerable salts. 3. Compounds of formula I according to claims 1 or 2, characterized in that in them R(1) is hydrogen, F, Cl, alkyl with 1, 2, 3 or 4 C-atoms, -NR(35)R(36) or R(17)-CgH2g-Zh-; g is zero, 1, 2, 3 or 4; h is zero or 1; Z is -O-, -CO-, -SOv-, -NR(18)-, -NR(18)-CO-, -NR(18)-CO-NH- or -NR(18)-SO2; R(18) is hydrogen or methyl; v is zero, 1 or 2; R(17) hydrogen, cycloalkyl with 5 or 6 carbon atoms or -CF3; or, if g and h are zero, R(17) is pyrrole-1-yl, which is unsubstituted or substituted with 1 - 2 substituents selected from the group consisting of F, Cl, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, -CF3 and methyl; or R(17) is (C5-C6)-cycloalkyl or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F and Cl, -CF3, methyl, CH3SO2- and H2NO2S-; R(35) and R(36) are independently hydrogen, methyl or ethyl; or R(35) and R(36) together represent 4-5 methylene groups, one of which CH2-group can be substituted with oxygen, -S-, -NH- or -NCH3; one of the substituents R(2) and R(3) represents R(6)-A-B-D; R(6) is -NR(7)R(8), one amidino group, R(7)R(8)N-C[=N-R(9)]- or one guanidino group [image] R(7) is hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms; R(8), R(9) and R(10) are independently hydrogen, methyl or ethyl; or R(7) and R(8) together are CaH2a; a is 4 or 5; whereby if a = 5 one methylene group of the group CaH2a can be substituted with NR(11); R(11) is hydrogen or methyl; or R(6) is imidazolyl- or pyridyl; A is CbH2b; b is 1, 2, 3, 4 or 5, where in the group CbH2b one or two methylene groups can be replaced by one of the groups selected from the group consisting of -CO-, -CH[OR(20)]-, -NR(20)-CO-, [image] -SOaa[NR(19)]bb- and -SO2-; and wherein in the group CbH2b one methylene group can be replaced by -CH-R(99), whereby R(99) together with R(7) forms a pyrrolidine or piperidine ring; aa is 1 or 2; bb is 0 or 1; aa + bb = 2; R(19) is hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms; R(20) is hydrogen or methyl; or, if b equals 2, 3, 4, or 5 one C-atom in CbH2b can be substituted with one group -O-, -S-, -NR(20)-, -NR(20)-CO- or -NR(20)-CO-NH-; B is a phenylene residue [image] R(12) and R(13) are independently hydrogen, methyl, F, Cl, CF3 or -SO2-R(14); R(14) is methyl or NH2; D is -CH2-, -O-, -CO-, -SOm- or NR(21)-; m is zero or 2; R(21) is hydrogen or methyl; and the other substituents R(2) and R(3) are hydrogen; R(4) and R(5) are independently hydrogen, alkyl with 1, 2 or 3 carbon atoms, F, Cl or -CF3. 4. Compounds of formula I according to at least one of claims 1 to 3, characterized in that in them R(1) is hydrogen, F, Cl, alkyl with 1, 2, 3 or 4 C-atoms, -NR(35)R(36) or R(17)-CgH2g-Zh-; g is zero or 1; h is zero or 1; Z is -O-, -CO-, -NR(18)-CO-, -NR(18)-CO-NH- or -NR(18)-SO2; R(18) is hydrogen or methyl; or, if g equals 1, Z is -SO2-; R(17) is hydrogen or CF3-; R(35) and R(36) are independently hydrogen, methyl or ethyl; or R(35) and R(36) together are 4-5 methylene groups, one of which CH2-group can be substituted with oxygen, -S-, -NH-, or -NCH3; one of the substituents R(2) and R(3) is R(6)-A-B-O-; R(6) is -NR(7)R(8) or a guanidino group [image] R(7) is hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms; R(8), R(9) and R(10) independently of each other are hydrogen, methyl or ethyl; or R(7) and R(8) together are CaH2a; a is 4 or 5; where if a = 5 one methylene group of the group CaH2a can be replaced by -NH- or -NCH3-, or R(6) is imidazolyl; A is CbH2b; b is 1, 2, 3 or 4; whereby in the group CbH2b one or two methylene groups can be replaced by one of the groups selected from the group consisting of -CO-, [image] -SOaa[NR(19)]bb- and -SO2-; and wherein in the group CbH2b one methylene group can be replaced by -CH-R(99), whereby R(99) together with R(7) forms a pyrrolidine or piperidine ring; or, if b equals 2, 3, or 4, one methylene group in the group CbH2b can be substituted with one group -O-, -S-; aa is 1 or 2; bb is 0 or 1; aa + bb = 2; R(19) is hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms; R(20) is hydrogen or methyl; B is a phenylene residue, [image] R(12) and R(13) are hydrogen; and the second residue of R(2) and R(3) is hydrogen; R(4) and R(5) are hydrogen. 5. The compound of formula I according to claim 1, characterized in that it is selected from the group consisting of 4-[4-N-(dimethylaminoethyl)-methylsulfamoyl]phenoxy-3-trifluoromethyl-benzoylguanidine, dihydrochloride; 4-[4-(4-methylpiperazinosulfonyl)phenoxy]-3-trifluoromethyl-benzoylguanidine, dihydrochloride; 4-[4-(2-pyrrolidineethylaminosulfonyl)phenoxy]-3-trifluoromethyl-benzoylguanidine, dimaleinate; 4-[4-(2-piperidineethylaminosulfonyl)phenoxy]-3-trifluoromethyl-benzoylguanidine, dimaleinate; 4-[4-N-(dimethylamino-n-propyl)sulfamoyl]phenoxy-3-trifluoromethyl-benzoylguanidine; 4-[4-(N-dimethylaminoethyl)sulfamoyl]phenoxy-3-trifluoromethyl-benzoylguanidine; 4-(4-imidamidosulfonyl)phenoxy-3-trifluoromethyl-benzoylguanidine; 3-trifluoromethyl-4-(4-N-methylimidamidosulfonyl)phenoxy-benzoylguanidine; 3-methyl-4-(4-(1-methylpiperazin-4-yl-sulfonyl)phenoxy)-benzoylguanidine; 4-(4-guanidinosulfonyl)phenoxy-3-trifluoromethyl-benzoylavanidine; 4-[4-(2-imidazolylthio-acetyl)phenoxy]-3-methylsulfonyl-benzoylguanidine, dihydrochloride; 4-[4-(N,N'-dimethyl-S-isothiouronyl-acetyl)phenoxy]-3-methylsulfonyl-benzoylguanidine dihydrochloride; 4-[4-(2-benzimidazolthio-acetyl)phenoxy]-3-methylsulfonyl-benzoylguanidine dihydrochloride; 4-[4-(2-N-imidazolyl-1-hydroxyethyl)phenoxy]-3-methylsulfonyl-benzoylguanidine dihydrochloride; 4-[4-(N,N-dimethylglycylamino)phenoxy]-3-methylsulfonyl-benzoylguanidine dihydrochloride; 4-[4-(N,N-diethylaminoethyl)aminosulfonylphenoxy)-3-methylsulfonyl-benzoylguanidine dihydrochloride; 4-[4-(4-imidazolylethyl)aminosulfonyl-phenoxy]-3-methylsulfonyl-benzoylguanidine dihydrochloride; 4-[4-(3-N-imidazolyl-1-propyl)aminosulfonyl-phenoxy]-3-methylsulfonyl-benzoylguanidine dihydrochloride; 4-[4-(1-methyl-2-pyrrolidinylethyl)aminosulfonyl-phenoxy]3-methylsulfonyl-benzoylguanidine dihydrochloride; 4-[4-(N-piperidinoethyl)aminosulfonyl-phenoxy]-3-methylsulfonyl-benzoylguanidine dihydrochloride; 4-[4-(2-dimethylaminoethyl)sulfonylmethyl-phenoxy]-3-methylsulfonyl-benzoylguanidine dihydrochloride; 4-[4-(2-dimethylaminoethyl)sulfonylmethyl-phenoxy]-3-trifluoromethyl-benzoylguanidine dihydrochloride. 6. Process for the production of compound I according to claim 1, characterized in that the compound of formula II [image] in which R(1) to R(5) have the stated meaning, and L represents a nucleophilic leaving group that can be easily substituted with a nucleophile, chemically converted with guanidine, and to be translated into a pharmacologically tolerable salt if necessary. 7. Use of the compound according to claim 1, characterized in that it is used for the production of a drug for the treatment of arrhythmias. 8. A method for the treatment of arrhythmias, characterized in that an effective amount of the compound I according to claim 1 is mixed with the usual additional substances and given in suitable administration forms. 9. Use of compound I according to claim 1, characterized in that it is used for the production of a drug for the treatment or prophylaxis of heart attack. 10. Use of compound I according to claim 1, characterized in that it is used for the production of a medicine for the treatment or prophylaxis of angina pectoris. 11. The use of compound I according to claim 1, characterized in that it is used for the production of a medicine for the treatment or prophylaxis of ischemic conditions of the heart. 12. Use of compound I according to claim 1, characterized in that it is used for the production of a drug for the treatment or prophylaxis of ischemic conditions of the peripheral and central nervous system and stroke. 13. Use of compound I according to claim 1, characterized in that it is used for the production of a medicine for the treatment or prophylaxis of ischemic conditions of peripheral organs and limbs. 14. The use of compound I according to claim 1, characterized in that it is used for the production of a medicine for the treatment of shock conditions. 15. Use of compound I according to claim 1, characterized in that it is used for the production of a medicine for use in surgical operations and organ transplantation. 16. Use of compound I according to claim 1, characterized in that it is used for the production of a medicine for the preservation and disposal of grafts for surgical operations. 17. The use of compound I according to claim 1, characterized by the fact that it is used for the production of a drug for the treatment of diseases, in which the primary or secondary cause is cell proliferation, and thus their use as antiatherosclerotics, agents against diabetic late complications, cancer, fibrotic diseases such as pulmonary fibrosis, liver fibrosis or renal fibrosis, prostate hyperplasia. 18. The use of compound I according to the claim, characterized by the fact that it is used for the production of a scientific agent for the inhibition of Na+/H+-exchangers, for the diagnosis of hypertension and proliferative diseases. 19. Medicine, characterized in that it contains an effective amount of compound I, according to one or more claims.