SI9600027A - Base-substituted benzoylguanidines, process for their preparation, use thereof as a medicament or diagnostic as well as a medicament containing them - Google Patents

Abstract

Basic substd. benzoylguanidine derivs. of formula (I) and their salts are new. One of R1-R3 = Xf-CdH2d-B-A-R6 and the others of R1-R3 = H, F, Cl, Br, I, CN, 1-8C alkyl, 2-8C alkenyl, NR35R36 or Zh-CgH2g-R17; R6 = NR7R8, C(=NR9)NR7R8, NR10-C(=NR9)NR7R8 or basic heteroaromatic ring system with 1-9C; R7-R10 = H or 1-4C alkyl; or R7+R8 = C4H8 or CaH2a (opt. with one CH2 replaced by O, S(O)m or NR11; or R8+R9+R10 or R7+R10 = C2H4 or CcH2c (opt. with one CH2 replaced by O, S(O)m or NR11); A = CbH2b (opt. with one or two CH2 replaced by O, CO, CH(OR20), S(O)m, NR20, CONR20, NHCONR20, SO2NHCONR20, S(=O)(=NR19)NR20 or SO2NR20, or one CH2 replaced by CHR99); R7+R99 form pyrrolidine or piperidine; B = opt. substd. phenylene or naphthylene gp. of formula (i) or (ii); R12, R13 = H, Me, F, Cl, Br, I, CF3 or S(O)mR14; R14, R19 = H or 1-4C alkyl; X = O, CO, CH(OR21), SOm or NR21; R35, R36 = H or 1-6C alkyl; or R35+R36 = (CH2)4-7, with one CH2 opt. replaced by S, NH, NMe or N-benzyl; Z = O, CO, SOm, NR18, CONR18, NHCONR18 or SO2NR18; R17 = H, cyclopropyl, cyclopentyl, cyclohexyl, 1-3C perfluoroalkyl, 1-, 2- or 3-pyrrolyl (opt. substd. by 1-4 of F, Cl, Br, I, CN, 2-8C alkanoyl, 2-8C alkoxycarbonyl, CHO, COOH, CF3, Me and OMe) or 3-8C cycloalkyl or phenyl (both opt. substd. by 1-3 of F, Cl, CF3, Me, OH, OMe, NR37R38, SO2Me and SO2NH2); R11, R18, R20, R21, R37, R38 = H or Me; R4, R5 = H, 1-4C alkyl, F, Cl, OR32, NR33R34 or 1-4C perfluoroalkyl; R32-R34 = H or 1-3C alkyl; a = 5-7; b = 1-10; c = 3-5; d = 0-5; g = 0-4; f, h = 0 or 1; m = 0-2.

Description

HOECHST AKTIENGESELLSCHAFT

Basic substituted benzoylguanidines, process for their preparation, use as medicaments or diagnostics, as well as medicaments containing

The invention relates to benzoylguanidines of formula I

R (i)

R (2)

R (3) where:

one of the three substituents R (1), R (2) and R (3)

R (6) -A-B-D-;

R (6) is a protonable basic moiety called an amino group

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

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

or

R (7) and R (8) together are CH _h ; a 4, 5,6 or 7;

wherein in the case of a = 5, 6 or 7, one methylene group of the group C _fl H _{2a may be} replaced by a heteroatom group O, SO _m or NR (11), or

R (8) and R (9) or R (9) and R (10) or R (7) and R (10) represent the group C _a H _2a ; a is 2, 3, 4 or 5;

wherein in the case of a = 3, 4 or 5, one methylene group of the group may be replaced by a heteroatom group O, SO _m or NR (11);

m is zero, 1 or 2;

R (11) is hydrogen or methyl;

or

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

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

wherein in the group C _fc H _2h, one or two methylene groups may be replaced by one of the groups selected from the group consisting of -O-, -CO-, -CH [OR (20)] -, -SO _m - , -NR (20) -, -NR (20) -CO-, -NR (20) -CO-NH-, -NR (20) -CO-NH-SO ₂ (°) a «

INR (19) 1 _bb and -SOJNRCl ^ and wherein in the group one methylene group may be replaced by -CH-R (99), wherein R (99) together with R (7) forms a pyrrolidine or piperidine ring;

aa 1 or 2;

bb 0 or 1;

aa + bb = 2;

R (19) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms R (20) is hydrogen or methyl;

B phenylene or naphthylene residue,

R (I2)

R (13)

R (I2)

R (I3)

R (12) and R (13) independently of one another are hydrogen, methyl, F, Cl, Br, J, CF, or -SO _w R (14));

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

R (15) and R (16) independently of one another are hydrogen or alkyl having 1, 2,3 or 4 carbon atoms;

w is zero, 1 or 2;

^D -cftA;

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

X -O-, -C0-, -CH [O R (21)] -, -SO _m - or -NR (21) -;

f is zero or 1;

R (21) is hydrogen or methyl; m is zero, 1 or 2;

and in each case different substituents R (1) and R (2) and R (3) are independently hydrogen, F, Cl, Br, J, -CN, - (C 1 -C 4 -alkyl, - (C ₂ - C ₈ ) -alkenyl, -NR (35) R (36) or R (17) -C _g H _2g -Z _h -;

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

h is zero or 1;

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

R (35) and R (36) total 4-7 methylene groups, of which one CH ₂ -group may be replaced by oxygen, -S-, -NH-, -NCH ₃ or -N-benzyl;

Z-O-, -CO-, -SO _v -; -NR (18) -, -NR (18) -C0-, -NR (18) -C0-NH- or -NR (18) -SO ₂ -;

R (18) is hydrogen or methyl; to zero, 1 or 2;

R (17) is hydrogen, cycloalkyl having 3,5 or 6 C atoms or C _k F _{2k + 1} -;

k 1,2 or 3, or

R (17) pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl, which is unsubstituted or substituted by 1-4 substituents selected from the group consisting of F, Cl, Br, J, -CN , (C ₂ -C ₈ ) -alkanoyl, (C ₂ -C ₈ ) -alkoxycarbonyl, formyl, carboxy, -CF ₃ , methyl and methoxy;

or

R (17) - (C ₃ -C _g) -cycloalkyl or phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F and Cl, _-CF3, methyl, hydroxyl, methoxy, - NR (37) R (38), CH ₃ SO ₂ - and H ₂ NO ₂ S-;

R (37) and R (38) are hydrogen ah -CH ₃ ;

R (4) and R (5) independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, -OR (32), -NR (33) R (34) or-CF _{2r + 1} ;

R (32), R (33) and R (34) independently of one another are hydrogen or alkyl having 1 or 2 C atoms; r is 1,2,3 or 4;

as well as their pharmacologically tolerable salts.

Preferred are compounds of formula I, where they mean:

R (1) hydrogen, F, Cl, - (C _f C ₄ ) -alkyl, - (C ₂ -C ₄ ) -alkenyl, -NR (35) R (36) ah ^ 17) -¾¾

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

R (35) and R (36) total 4-5 methylene groups, of which one CH ₂ -group may be replaced by oxygen, -S-, -NH-, ah -NCH ₃ ;

R (17) is hydrogen, cycloalkyl having 5 ah 6 C atoms ah C _fc F _{2k + 1} -; k 1,2 ah 3, g zero, 1,2,3 ah 4;

h zero ah 1;

Z -0-, -C0-, -SO _v -, -NR (18) -, -NR (18) -C0-, -NR (18) -C0-NH- ah

-NR (18) -SO ₂ -;

R (18) is hydrogen or methyl;

to zero, 1 or 2; or when g and h are zero,

R (17) pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl, which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F, Cl, (C ₂ -C ₅ ) -alkanoyl, (C ₂ -C ₅ ) -alkoxycarbonyl, formyl, carboxy, -CF ₃ , methyl and methoxy;

or

R (17) - (C ₃ -C _g) -cycloalkyl or phenyl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F and Cl, _-CF3, methyl, methoxy, -NR (37 ) R (38), CH ₃ SO ₂ - and H ₂ NO ₂ S-;

R (37) and R (38) are independently hydrogen or -CH ₃ ; is one of the substituents R (2) and R (3)

R (6) -A-B-D-;

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

R (10)

R (7), R (8), R (9) and R (10) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 C atoms;

or

R (7) and R (8) together are 4,5, 6 or 7;

or

R (8) and R (9) mean that in the case of a = 5,6 or 7, one methylene group of group C may be replaced by a heteroatom group O, SO _m or NR (11);

R (11) is hydrogen or methyl;

total OH ^; a is 2,3, 4 or 5;

wherein in the case of a = 3,4 or 5, one methylene group of the group CH2 can be replaced by a heteroatom group O, SO _m or NR (11); m is zero, 1 or 2;

or

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

^{A c} b ^H 2b;

b 1, 2,3,4 or 5;

wherein in the group C _b H _2b, one or two methylene groups may be replaced by one of the groups selected from the group consisting of -O-, -CO-, -CH [OR (20)] -, -SO _m - , NR (20), -NR (20) -CO-, -NR (20) -CO-NH-, -NR (20) -CO-NH-SO ₂ -,

-R (20) N-SII lNR (l9) J _bb in-SOJNR ^ V;

wherein in the group C _b H _2b one methylene group may be replaced by -CH-R (99), wherein R (99) together with R (7) forms a pyrrolidine or piperidine ring; aa 1 or 2;

bb O or 1; aa + bb = 2;

R (19) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R (20) is hydrogen or methyl;

B phenylene or naphthylene residue

R (12) R (I2)

R (13)

R (12) and R (13) are independently hydrogen, methyl, F, Cl, CF ₃ or -SO ₂ -R (14); R (14) is methyl or NR (15) is R (16);

R (15) and R (16) independently of one another are hydrogen or alkyl having 1,

2,3 or 4 C atoms;

D -ςΗ ^, - Χ, -;

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

X -O-, -C0-, -CH [O R (21)] -, -SO _m - or -NR (21) -;

f is zero or 1;

R (21) is hydrogen or methyl; m is zero, 1 or 2;

and, in each case, a different residue R (2) and R (3) is hydrogen, alkyl having 1, 2, 3 or 4 C atoms, F, Cl or CF ₃ ;

R (4) and R (5) independently of one another are hydrogen, alkyl having 1 or 2 C atoms, F,

ClaI-CF _3;

as well as their pharmacologically tolerable salts.

Particularly preferred are the compounds of formula I, where they mean:

R (1) is hydrogen, F, Cl, alkyl having 1,2,3 or 4 C atoms, NR (35) R (36) or R (17) -C FL, -Z _h g zero, 1,2, 3 or 4;

zero or 1;

-O-, -C0-, -SO _in -, -NR (18) -, NR (18) -CO-, -NR (18) -C0-NH-, or -NR (18) -SO ₂ -;

R (18) is hydrogen or methyl; to zero, 1 or 2;

R (17) is hydrogen, cycloalkyl having 5 or 6 C atoms or CF ₃ -; or when g and h are zero,

R (17) pyrrol-1-yl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, (C ₂ -C ₅ ) -alkanoyl, (C ₂ -C ₅ ) - alkoxycarbonyl, -CF ₃ and methyl, or

R (17) - (C ₅ -C ₆ ) -cycloalkyl or phenyl which is unsubstituted or substituted by a substituent selected from the group consisting of F and Cl, -CF ₃ , methyl, CH ₃ SO ₂ - and

Η, ΝΟ ^;

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

or

R (35) and R (36) together are 4-5 methylene groups, of which one CH ₂ group may be replaced by oxygen, -S-, -NH-, or -NCH ₃ ;

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

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

R (7) «(10)

R (7) is hydrogen or alkyl having 1, 2, 3 or 4 C atoms;

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

R (7) and R (8) together are C ^; a 4 or 5;

wherein in the case of a = 5, one methylene group of the group CH2 can be replaced by NR (11), 2R (11) hydrogen or methyl;

R (6) imidazolyl or pyridyl;

^{A c} A _b ;

b 1,2, 3,4 or 5, wherein in group C _b H _2b, one or two methylene groups may be replaced by one of the groups selected from the group consisting of -CO-, -CH [OR (20) ] -, -NR (20) -CO-, (0) 00

II

INR (19) l _bb

-SO _aa [NR (19)] _bb in-SO ₂ -;

and wherein in the group C _2b H _2b, one methylene group may be replaced by -CH-R (99), wherein R (99) together with R (7) forms a pyrrolidine or piperidine ring;

aa 1 or 2; bb 0 or 1; aa + bb = 2;

R (19) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R (20) is hydrogen or methyl;

or when b is 2,3,4 or 5, one C atom in C _b H _{2b may be} replaced by the group -O-, -S-. NR (20) -, -NR (20) -CO- or -NR (20) -CO-NH-;

B phenylene residue R (1 2)

R (13)

R (12) and R (13) are independently hydrogen, methyl, F, Cl, CF ₃ or -SO ₂ R (14);

R (14) is methyl or NH ₂ ;

D -CH ₂ , -O-, -C0-, -SO _m - or -NR (21) -; m is zero or 2;

R (21) is hydrogen or methyl;

and in each case the other residue R (2) and R (3) is hydrogen;

R (4) and R (5) independently of one another are hydrogen, alkyl having 1 or 2 C atoms, F, Cl or -CF ₃ ; as well as their pharmaceutically acceptable salts.

Particularly preferred are the compounds of formula I where they are meant

R (1) is hydrogen, F, Cl, alkyl having 1, 2, 3 or 4 C atoms, -NR (35) R (36) or g is zero or 1;

h is zero or 1;

Z-O-, -CO-, -NR (18) -CO-, -NR (18) -CO-NH-, or -NR (18) -SO ₂ -;

R (18) is hydrogen or methyl;

or when g is 1; mean

Z -SO ₂ -;

R (17) is hydrogen or CF ₃ -;

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

R (35) and R (36) together are 4-5 methylene groups, of which one CH ₂ -group may be replaced by oxygen, -S-, -NH-, or -NCH ₃ ;

one of the substituents R (2) and R (3)

R (6) -A-B-O-;

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

R (7) R (10) _{R (} «)

R (7) ^{R (S) / N is} hydrogen or alkyl having 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 CH2, a4 or 5;

wherein in the case of a = 5, one methylene group may be the group

C _a H _{2a is} replaced by -NH- or -NCH ₃ -, or

R (6) is imidazolyl-;

AC _b H _a ;

1,2,3 or 4;

wherein in the group C _b H _2b, one or two methylene groups may be replaced by one of the groups selected from the group consisting of -CO-,

lnr (1 9) 1 _bb

-SO _aa [NR (19)] _bb - and-SO ₂ , and in which one methylene group in the group may be replaced by -CH-R (99), where R (99) together with R (7) may form a pyrrolidine or piperidine ring;

or, when b is 2,3 or 4, one methylene group in the group C _b H _{2b may be} replaced by the group -O-, -S-; aa 1 or 2;

bb O or 1;

aa + bb = 2;

R (19) is hydrogen or alkyl having 1, 2, 3 or 4 C atoms

R (20) is hydrogen or methyl;

a phenylene residue,

R (1 2)

R (1 3)

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

and in each case the other residue R (2) and R (3) is hydrogen;

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

as well as their pharmacologically tolerable salts.

Particularly preferred is a compound selected from the group in which they are

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

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

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

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

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

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-ylsulfonyl) phenoxy) -benzoylguanidine;

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

4- [4- (2-imidazoylthio-acetyl) phenoxy] -3-methylsulfonyl-benzoyl-guanidine, dihydrochloride;

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

4- [4- (2-Benzimidazolylthio-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-methylsulfonylbenzoyl-guanidine dihydrochloride;

4- [4- (N, N-Diethylaminoethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride;

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

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

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

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

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

4- [4- (2-Dimethylaminoethyl) sulfonylmethyl-phenoxy] -3-trifluoromethylbenzoylguanidine dihydrochloride.

Labeled alkyl residues can be both unbranched and branched.

The basic heteroaromatic ring system with 1-9 C atoms is understood to mean particularly residues derived from cyclopentyl, phenyl or naphthyl, in which one or more CH groups are replaced by N. In particular, imidazolyl, pyrazolyl, oxazolyl are considered heteroaryl. , isoxazolyl, thiazolyl, isothiazolyl, pyridyl, quinolyl, isoquinolyl.

Halogen means F, Cl, Br or J.

If the compounds of formula I contain asymmetric centers, formula I describes both the individual optical antipodes and their possible enantiomeric mixtures.

The invention further relates to a process for the preparation of compound I, wherein the compound of formula II

is reacted with guanidine, where R (1) to R (5) have the indicated meaning, and L stands for a leaving group that is readily nucleophilic to substitute, and optionally converted into a pharmacologically tolerable salt.

Activated acid derivatives of formula II, wherein L is alkoxy, preferably methoxy, phenoxy, phenylthio, methylthio, 3-pyridyloxy-, 2-pyridylthio, nitrogen heterocycle, preferably 1-imidazolyl, are preferably obtained in a known manner from known carboxylic chlorides acids (formula II, L = Cl) which can again be prepared in a known manner from known carboxylic acids (formula II, L = OH), e.g. with thionyl chloride.

In addition to the carboxylic acid chlorides of formula II (L = Cl), further activated acid derivatives of formula II can be prepared in a known manner directly from known benzoic acid derivatives (formula II, L = OH), e.g. methyl esters of formula II with L = OCH ₃ by treatment with gaseous HC1 in methanol, imidazolides of formula II by ob14 treatment with carbonyldiimidazole (L = 1-imidazolyl, Staab, Angew. Chem. Int. Ed. Engl. 1, 351 - 367 (1962)], mixed anhydrides II with C1COOC ₂ H ₅ or sued chloride in the presence of triethylamine, in an inert solvent, as well as activation of benzoic acids with dicyclohexylcarbodiimide (DCC) or with O [(cyano (ethoxycarbonyl) methylene) amino] 1,1 , 3,3-tetramethyluronium tetrafluoroborate (TOTU) [Proceedings of the 21st European Peptide Symposium, Peptides 1990, Editors E. Giralt and D. Andreu, Escom, Leiden, 1991]. A number of suitable methods for the preparation of activated carboxylic acid derivatives of the formula II is cited under the references in J. March, Advanced Organic Chemistry, Third Edition (John Wiley & Sons, 1985), p. 350.

The conversion of the activated carboxylic acid derivative of formula I with guanidine is carried out in a known manner in an aprotic or aprotic polar but inert organic solvent. In the process of metabolizing benzoic acid methyl esters (II, L = OMe) with guanidine, methanol, isopropanol or THF, a temperature of 20 ° C is maintained until the boiling point of these solvents. Most metabolites of compounds II with saltless guanidine are preferably acted in aprotic inert solvents such as THF, dimethoxyethane, dioxane or isopropanol. In metabolism II and III, however, water can also be used, using a base, e.g. NaOH as solvents.

When L = Cl, it is preferable to work with the addition of an acid inhibitor, e.g. in the form of excess guanidine for the cleavage of hydrochloric acid.

The subject benzoic acid derivatives are partially known. They are prepared according to methods known in the literature such that e.g. the finished residue R (6) -ABC _d H _2d -X _f - or its precursor is converted by the exchange of halogen into a benzoic acid derivative of formula III

wherein the substituent R 'has the meaning of a lower alkyl residue, such as e.g. methyl or ethyl and R represents halogen. The reactions have been described in the literature, e.g. as a nucleophilic substitution reaction, as a radical Ullmann reaction, or with a palladium catalyzed reaction.

The introduction of benzenesulfonamide derivatives, which in the phenyl moiety are nucleophilically substituted by sulfur, oxygen or nitrogen, is carried out in the literature known by the methods of nucleophilic aromatic substitution. The leaving group on the benzoic acid derivative was halides and trifluoromethanesulfonates. Preferably, we operate in a dipole aprotic solvent, such as DMF or TMU, at a temperature from 0 ° C to the boiling point of the solvent, preferably from 80 ° C to the boiling point of the solvent. Preferably, the alkali metal or alkaline earth alkali salt with the anion of higher basicity and lower nucleophilicity, e.g. K ^ CC ^ or CsCO ₃ .

The R (6) -ABC _d H _2d -X _f - compounds used are the predominantly known compounds and can be partially purchased as reagents. Their preparation is carried out according to methods known in the art, which are known to the person skilled in the art.

The introduction of one of the substituents into the 4- and 5-positions is accomplished by methods known in the literature, palladium-mediated cross-coupling of aryl halides with e.g. organostanes, organoboric acids ah organoborans or organobacaric or. zinc compounds.

Benzoylguanidines I are generally weak bases and can bind acids when salt is formed. Acid addition salts include salts of all pharmacologically tolerable acids, e.g. halides, in particular hydrochlorides, lactates, sulfates, citrates, tartrates, ascorbates, acetates, phosphates, methylsulfonates, p-toluenesulfonates.

Compounds I are substituted acylguanidines.

The most representative acylguanidine is the pyrazine derivative amiloride, which is used in treatment as a potassium-preserving diuretic. A number of further amiloride-type compounds have been described in the literature, such as e.g. dimethylamiloride or ethylisopropylamiloride.

II

NH

II

II

R '' amiloride: R ', R = H dimethylamiloride: R', R = CH ₃ ethylisopropylamiloride: R '= C ₂ H ₅ , R = CH (CH ₃ ) ₂

In addition, studies have been known to indicate the antiarrhythmic properties of amiloride (Circulation 79, 1257 to 1263 (1989)). However, we still face widespread use as antiarrhythmics, as this effect is only poorly expressed and is accompanied by a blood pressure lowering and saluretic effect, and these side effects are undesirable in the treatment of cardiac rhythm disorders.

Euratom Heart J. 9 (suppl. 1): 167 (1988) (book of abstracts) was also hinted at the antiarrhythmic properties of amiloride, for example, in rats' hearts, for example, they were found to be artificially triggered. The tremor of the ventricles was completely interrupted by amiloride, and even stronger than amiloride, the above mentioned amiloride derivative was ethylisoproplamiloride in this model.

U.S. Patent No. 5,091,394 (HOE 89 / F 288) discloses benzoylguanidines which, in the position corresponding to the residue R (1), carry only one hydrogen atom and in which none of the substituents has the significance of R (5) -ABD -. Publication of European Patent Application 0 556 674 A (HOE 92 / F 034) proposes 3,5-substituted benzoylguanidines in which the substituent R (2) has a meaning for R (5) -ABD- for which the present invention is not required protection.

US Patent No. 3,780,027 requires protection for acylguanidines, which are structurally similar to compounds of formula I and are derived from commercially available Henley loop diuretics such as bumetanide. Accordingly, these compounds are reported to have potent salidiuretic activity.

As a result, it was surprising that the compounds of the invention do not have any undesirable and noxious salidiuretic but have very good antiarrhythmic properties against such arrhythmias, such as those occurring e.g. when oxygen deficiency occurs. Due to their pharmacological properties, these compounds are extremely suitable as antiarrhythmic agents with a cardioprotective component for infarction prophylaxis and treatment, as well as for the treatment of angina, preventing or severely inhibiting pathophysiological transitions in the production of ischemically induced injury, especially when triggering ischemic induced cardiac arrhythmias. Due to their protective action against pathological hypoxic and ischemic situations, the compounds of the invention of Formula I may be used as a medicament for the treatment of all acute or chronic ischemia-triggered injuries, or primary, to inhibit the cellular Na ⁺ / H ⁺ exchange mechanism. or secondary-induced diseases. This concerns their use as a cure for surgery, e.g. organ transplants, wherein the compounds can be used both to protect the organs in the donor from before and during collection, to protect the organs removed, e.g. when handling or storing them in a bath of saline fluids, as well as when being converted to a receiving organism. The compounds are also valuable, protectively acting drugs in performing angioplasty surgeries, e.g. on the heart as well as on the peripheral scar. Due to their protective action against ischemically induced damage, the compounds are also suitable as medicaments for the treatment of ischemia of the nervous system, in particular the central nervous system of the ZNS, for example. to treat stroke or brain edema. In addition, the compounds of the invention of formula I are also suitable for the treatment of shock forms, such as e.g. allergic, cardiogenic, hypovolemic and bacterial shock.

In addition, the compounds of the invention of Formula I are characterized by a potent inhibitory effect on cell proliferation, e.g. cell proliferation of fibroblasts and proliferation of smooth muscle cells. In addition, compounds of Formula I are considered to be valuable therapists for diseases in which cell proliferation is a primary or secondary pattern and can therefore be used as anti-arteriosclerotic agents, agents for later diabetic complications, cancers, fibrotic diseases, such as pulmonary fibrosis, liver fibrosis or renal fibrosis, hypotrophies and organ hyperplasia, especially in prostate hyperplasia or. prostate hypertrophy.

The compounds of the invention are effective inhibitors of the cellular antiporter sodium protons (Na ⁺ / H ⁺ exchanger), which is elevated in many diseases (essential hypertension, atherosclerosis, diabetes, etc.) even in such cells, measurements may be feasible as e.g. in erythrocytes, platelets or leukocytes. The compounds of the invention are therefore suitable as outstanding and simple scientific tools, e.g. in its use as a diagnostic tool to identify and differentiate certain forms of hypertension, but also atherosclerosis, diabetes, proliferative diseases, etc. In addition, the compounds of formula I are suitable for preventative treatment to prevent the genesis of high blood pressure, e.g. essential hypertension.

In addition to the very potent inhibitory action on the Na ⁺ / H ⁺ exchanger, the compounds of the invention, in comparison with known compounds, significantly improve water solubility18. This makes them significantly better for iv applications.

Medicaments containing compound I may be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred administration being dependent on the particular appearance of the disease. Compounds I can be used alone or together with galenic auxiliaries, both in veterinary and human medicine.

Which of the excipients are suitable for the desired pharmaceutical formulations is known to one skilled in the art based on his or her expertise. In addition to solvents, gel formers, suppository substrates, tablet excipients, and other carriers of the active substance, e.g. antioxidants, dispersants, emulsifiers, antifoams, flavorants, preservatives, solubilizers or colorants are used.

For the oral dosage form, the active compounds are mixed with suitable excipients such as carrier materials, stabilizers or inert diluents, and by conventional methods are converted to the dosage forms, such as tablets, dragees, plug caps, aqueous, alcoholic or oily solutions. As inert stretchers, for example, gum arabicum, magnesium oxide, magnesium carbonate, potassium phosphate, milk sugar, glucose or starches, in particular maize starch. The preparation may be obtained either as a dry or as a wet granulate. As oily carrier materials or as solvents, e.g. vegetable or animal oils such as sunflower oil or fish oil.

For subcutaneous or intravenous administration, the active compounds are optionally converted with conventional substances, such as mediated solubilities, emulsifiers or further excipients, into solution, suspension or emulsion. As solvents, for example, for example: water, saline or alcohols, e.g. ethanol, propanol, glycerin, and also sugar solutions, such as glucose or mannitol solutions, or a mixture of the various solvents mentioned.

As a pharmaceutical preparation for administration in the form of aerosols or sprays, e.g. solutions, suspensions, or emulsions of the active substance of formula I in pharmaceutically non-problematic solvents, such as in particular ethanol or water, or in a mixture of such solvents.

The preparation may also contain, if necessary, other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as propellants. Such a preparation contains the active substance typically in a concentration of from about 0.1 to 10, especially from about 0.3 to 3% by weight.

The dosage of the active substance of formula I to be administered and the frequency of administration depend on the potency and the duration of effect of the compound used; and the manner and severity of the disease to be treated, as well as the sex, age, weight and individual acceptability of the mammal to be treated.

On average, the daily dose of a compound of Formula I in about 75 kg of a patient is at least 0.001 mg / kg, preferably 0.01 mg / kg, up to a maximum of 10 mg / kg, preferably 1 mg / kg body weight. Acute outbreaks, approximately immediately after the survival of a heart attack, may require even higher and more frequent doses, e.g. up to 4 individual doses per day. Especially with i.v. up to 200 mg per day may be required in patients with intensive care infarction.

List of abbreviations

AIBN ofja-azo-bis-isobutyronitrile

Bn benzyl brine a saturated aqueous NaCl solution

021 ^ 02 dichloromethane

DCI Desorption-Chemical Ionization

DEP diisopropyl ether

DMA dimethylacetamide

DME dimethoxyethane

DMF N, N-dimethylformamide

EE ethyl acetate (EtOAc)

El electronic shock eq equivalent

ES electrospray ionization

Et ethyl

FAB rapid bombardment of atoms

HEP n-heptane

HOAc acetic acid

Methyl

MeOH methanol m.p. melting point

MTB methyltetrabutyl ether

NBS

NMP

RT

THF

TMU

ZNS

N-Bromosuccinimide

N-methylpyrrolidone room temperature tetrahydrofuran

Ν, Ν, Ν ′, Ν′-tetramethylurea central nervous system

The experimental part

General regulation for the preparation of benzoyl guanidines (I)

Variant A: from benzoic acids (II, L = OH)

The 0.01 M benzoic acid derivative of formula II is dissolved or solubilized. suspended in 60 ml of anhydrous THF and then 1.78 g (0.011 M) of carbonyldiimidazole were added. After stirring for 2 hours at RT, 2.95 g (0.05 M) of guanidine was added to the reaction solution. After stirring overnight, the THF was distilled off under reduced pressure (rotary evaporator), made up with water, adjusted with 2 N HCl to pH 6 to 7, and the corresponding benzoyl guanidine (formula I) filtered. The benzoyl guanidines thus obtained can be converted to the corresponding salts by treatment with aqueous, methanolic or ether hydrochloric acid or other pharmacologically tolerated salts.

General regulation for the preparation of benzoyl guanidines (I)

Option B: Dissolve benzoic acid (II, L = O-alkyl) alkyl esters of benzoic acid alkyl ester of Formula II as well as 25 mmol of guanidine (free base) in 15 ml of isopropanol or suspend in 15 ml of THF and boil under reflux complete metabolism (thin layer control) (typical reaction time 2 to 5 h). Under reduced pressure (rotary evaporator), the solvent is distilled off, taken up in 300 ml of EE and washed 3 times with 50 ml of NaHCO _r solution _. Dry over Na ₂ SO ₄ , the solvent is distilled off and chromatographed on silica with a suitable eluting agent, e.g. EE / MeOH 5: 1.

(Salt formation, compare variant A).

EXAMPLE 1: 4- (4-Aminosulfonyl) phenoxy-3-trifluoromethyl-benzoylguanidine

a) 4-Fluoro-3-trifluoromethyl-benzoic acid methyl ester g of 4-fluoro-3-trifluoroethyl-benzoic acid and 9 ml of SOCl _{2 were} stirred in 50 ml of MeOH for 8 h at 60 ° C. The volatile constituents were then removed in vacuo to give 5.1 g of a colorless oil, which was further used without purification.

Rf (EE / MeOH 10: 1) = 0.74 MS (DCI) 223 (M + H) < ⁺ >

b) 4- (4-Aminosulfonyl) phenoxy-3-trifluoromethyl-benzoic acid methyl ester 890 mg of fluoride a), 690 mg of 4-hydroxybenzenesulfonamide and 1.1 g of K 2 CO 2 were stirred in 5 ml of DMF for 2 h at 120 ° C. Allow to cool to RT, add 100 ml brine and extract 3 times with 50 ml EE each. Dry over Na ₂ SO ₄ and remove the solvent in vacuo. 1.2 g of a colorless oil are obtained.

R f (MTB) = 0.45 MS (DCI) 376 (M + H) ⁺

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

550 mg of methyl ester 1b) is guanylated 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.

Tal. > 270 ° C

EXAMPLE 2: 4- [4- (N-t-Butylimido-N'-t-butyl) sulfamoyl] -3-trifluoromethylbenzoylguanidine, dihydrochloride

a) 4-Fluoro-benzenesulfonic acid-N, N'-bis-t-butyl-imidamide

900 ml of t-butylamine are added at -30 ° C to 10.3 ml of bromine. Allow to warm to 5 ° C and add 6.6 ml of 4-fluorothiophenol. The mixture was heated to RT and then stirred at this temperature for another 4 h. It is then poured onto 600 g of ice, 500 ml of EE is added and washed 3 times with 100 ml of saturated aqueous Na ₂ SO _{3 each} . The organic phases are then combined in vacuo, taken up again with 500 ml and washed 3 times with 200 ml of 0.6 M aqueous KH ₂ PO _{4 each} . The organic phase is then stirred for one hour with 100 ml of 2 N aqueous HCl and then the EE phase is separated immediately. The aqueous phase was adjusted with Na ₂ CO ₃ to pH = 9 and extracted 3 times with 200 ml EE each. Dry over Na ₂ SO ₄ and remove the solvent in vacuo. 6.4 g of a colorless oil are obtained.

R _f (DIP) = 0.46 MS (DCI); 287 (M + H) < ⁺ > ^.

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

2.9 g of 4-fluoro-benzenesulfonic acid N, N'-bis-t-butyl-imidamide and 3.4 g of CsOH (monohydrate) were stirred in 25 ml of TMU for 8 h at 160-170 ° C. It is then allowed to cool to RT, 100 ml of water and 50 ml of saturated aqueous NaHCO ₃ solution are added and extracted 3 times with 100 ml of EE each. Dry over Na ₂ SO ₄ and remove the solvent in vacuo. Chromatography on silica with EE / HEP 1: 1 gave 700 mg of a colorless oil.

R _f (MTB / DIP 1.1) = 0.27 MS (E): 285 (M + H) ⁺

c) 4- [4- (N-t-Butylimido-N'-t-butyl) sulfamoyl] phenoxy-3-trifluoromethylbenzoic acid methyl ester

600 mg of 4-hydroxy-benzenesulfonic acid N, N'-bis-t-butyl-imidamide, 468 mg of 4-fluoro-3-trifluoromethyl-benzoic acid methyl ester and 2.1 g of Cs ₂ CO _{3 were} mixed in 10 ml of TMU 1. 5 h at 160 ° C. Allow to cool to RT, add 100 ml of saturated aqueous NaHCO ₃ solution and extract 3 times with 100 ml EE each. Dry over Na ₂ SO ₄ and remove the solvent in vacuo. DIP chromatography gave 400 mg of a colorless oil.

R _f (DIP) = 0.28 MS (ES): 487 (M + H) ⁺

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

300 mg of 4- [4- (Nt-butylimido-N'-t-butyl) sulfamoyl] -3-trifluoromethylbenzoic acid methyl ester and 182 mg of guanidine are converted into 10 ml of isopropanol according to general regulation for the preparation of benzoylguanidines, variant B. 120 is obtained mg of colorless oil.

R _f (EE) = 0.24 MS (FAB): 587 (M + H) ⁺ m.p. (dihydrochloride) = 165 -168 ° C.

EXAMPLE 3: 4- [4-N- (dimethylaminoethyl) -methylsulfamoyl] phenoxy-3-trifluoromethylbenzoylguanidine, dihydrochloride

a) 4-Phenoxy-3-trifluoromethyl-benzoic acid methyl ester g 4-chloro-3-trifluoromethyl-benzoic acid methyl ester, 5.9 g of phenol and 17.4 g of K ^ COj were stirred in 100 ml of DMF for 14 h at 110 h ° C. Allow to cool to RT, dilute with 11 EE, wash 2 xs with 200 ml of water, 2 xs with 200 ml of 0.1 N aqueous NaOH solution and 2 xs with 300 ml of saturated aqueous NaCl solution. Dry over Na ₂ SO ₄ and remove the solvent in vacuo. Chromatography on silica with EE / HEP 1: 8 gave 11 g of a colorless oil.

R _f (EE / HEP 1: 8) = 0.24 MS (DCI): 297 (M + H) < ⁺ >

b) 4-Phenoxy-3-trifluoromethyl-benzoic acid g of 4-phenoxy-3-trifluoromethyl-benzoic acid methyl ester was dissolved in 200 ml of MeOH and supplemented with 41 ml of 1 N aqueous NaOH solution and stirred at RT for 24 h. Immediately remove MeOH, dilute with 11 water with an aqueous HCl solution, adjust to pH = 2 and filter the precipitate. Dry for 48 h in air to give 9.2 g of an amorphous solid.

R _f (EE) = 0.10

MS (DCI): 283 (M + H) < ⁺ > ^.

c) 4- (4-Chlorosulfonyl) phenoxy-3-trifluoromethyl-benzoic acid g of 4-phenoxy-3-trifluoromethyl-benzoic acid was dissolved in 15 ml of CHC1 ₃ and 710 μΐ of chlorosulfonic acid was added dropwise. The mixture was stirred for 3 h at RT and the solvent was removed in vacuo immediately. Then 50 g of ice and 50 ml of water are added, the mixture is stirred and the precipitate is filtered off for 10 minutes. 0.96 g of an amorphous solid is obtained.

R _f (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 was dissolved in 10 ml of acetone and 160 μl of trimethylethylenediamine and 350 μΐ of triethylamine were added. The mixture was stirred for 2 h at RT, immediately diluted with 100 ml of water and acetone was removed in vacuo. Adjust the pH to 6-7 with 0.1 N aqueous HCl and extract 6 xs per 100 ml EE. Dry over Na ₂ SO ₄ and remove the solvent in vacuo. 330 mg of an amorphous solid are obtained.

R _f (CH 2 / MeOH / HOAc / 1 H 8: 4: 1: 1) = 0.42 MS (EI): 447 (M + H) ⁺

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

330 mg of 4- [4-N- (dimethylaminoethyl) -methylsulfamoyl] phenoxy-3-trifluoromethyl-benzoic acid and 1 ml of SOCl _{2 was} heated in 10 ml of MeOH for 8 h under reflux. The volatile components of the mixture were removed in vacuo, taken up with 100 ml of saturated aqueous Na ₂ CO ₃ and 100 ml of EE each, and extracted 3 xs with 100 ml of EE each. Dry over Na ₂ SO ₄ and remove the solvent in vacuo. Silica chromatography with EE / MeOH 2: 1 gave 150 mg of a colorless gum.

R _f (EE / MeOH 1: 1) = 0.30 MS (EI): 461 (M + H) ⁺

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

140 mg of 4- [4-N- (dimethylaminoethyl) -methylsulfamoyl] phenoxy-3-trifluoromethylbenzoic acid methyl ester and 90 mg of guanidine are converted to 3 ml of isopropanol according to the general rule for the preparation of benzoyl guanidines, variant B. 130 mg of an amorphous solid is obtained. .

R _f (EE / MeOH 1: 1) = 0.12 MS (EI): 488 (M + H) ⁺ m.p. (dihydrochloride) = 203 ° C

The title compounds of Examples 4 - 8 are synthesized analogously to Example 3:

EXAMPLE 4: 4- [4- (4-Methylpiperazinosulfonyl) phenoxy] -3-trifluoromethylbenzoylguanidine, dihydrochloride

R _f (EE / MeOH 1: 1) = 0.15 MS (EI): 486 (M + H) ⁺ m.p .: (dihydrochloride> 250 ° C)

EXAMPLE 5: 4- [4- (2-Pyrrolidinethylaminosulfonyl) phenoxy] -3-trifluoromethylbenzoylguanidine, dimaleinate

R _f (CH ₂ Cl ₂ / MeOH / HOAc / H ₂ O 8: 4: 1: 1) = 0.37 MS (FAB): 500 (M + H) ⁺

EXAMPLE 6: 4- [4- (2-Piperidinethylaminosulfonyl) phenoxy] -3-trifluoromethylbenzoylguanidine, dimaleinate

R _f (CH 2 / MeOH / HOAc / H 2 O 8: 4: 1: 1) = 0.40 MS (FAB): 514 (M + H) ⁺

EXAMPLE 7: 4- [4- (N-Dimethylamino-n-propyl) sulfamoyl] phenoxy-3-trifluoromethylbenzoylguanidine

R _f (EE / MeOH 1: 1) = 0.06

MS (EI): 488 (M + H) ⁺

EXAMPLE 8: 4- [4- (N-Dimethylaminoethyl) sulfamoyl] phenoxy-3-trifluoromethylbenzoylguanidine

R _{ (EE / MeOH 1: 1) = 0.17 MS (EI): 474 (M + H) ⁺

EXAMPLE 9: 4- (4-Imidamidosulfonyl) phenoxy-3-trifluoromethyl-benzoylguanidine

a) 4- [4- (N-t-Butylimido-N'-t-butyl) sulfamoyl] phenoxy-3-trifluoromethylbenzoic acid

4- [4- (Nt-Butylimido-N'-t-butyl) sulfamoyl] phenoxy-3-trifluoromethylbenzoic acid methyl ester (Example 2c) was dissolved in 100 ml of MeOH and 40 ml of 2 N aqueous NaOH was added. Boil for 3 h under reflux, remove MeOH in vacuo and transfer the residue to a mixture of 100 ml water and 100 ml EE. Add 500 ml of saturated aqueous NaH ₂ PO ₄ solution and extract 3 xs with 200 ml EE each. Dry over Na ₂ SO ₄ and remove the solvent in vacuo. 7.2 g of white crystals are obtained,

R _f (MTB) = 0.25 MS (ES): 473 (M + H) ⁺

Tal. = 200 ° C

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

6.6 g of 4- [4- (Nt-butylimido-N'-t-butyl) sulfamoyl] phenoxy-3-trifluoromethylbenzoic acid were dissolved in 140 ml of anhydrous CH ₂ C1 ₂ , 3.7 ml of trifluoromethanesulfonic acid were added and stirred for 24 h at RT. The mixture was stirred in 11 0.66 M aqueous solution of KH ₂ PO ₄ , the methylene chloride phase was separated and extracted 3 xs with 300 ml EE each. The combined organic phases were dried over Na ₂ SO ₄ and the solvents were removed in vacuo. 6.7 g of a crude oil are obtained which is used without further purification.

R _f (EE / MeOH 5: 1) = 0.21 MS (ES): 361 (M + H) ⁺

c) 4- (4-Imidosulfamoyl) phenoxy-3-trifluoromethyl-benzoic acid methyl ester; 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 were dissolved in 100 ml of MeOH, 20 ml of 2 N trimethylsilyldiazomethane in HEP was added dropwise and stirred for 6 h at RT. 200 ml of 20% acetic acid aqueous solution were then added immediately and then stirred for 30 minutes. Then 200 ml of EE was added and 9 x was extracted with 100 ml of 1N aqueous HC1 solution each. The aqueous phase was immediately adjusted to pH = 10 with NajCOg and extracted 3 times with 200 ml of EE each. Dry over Na ₂ SO ₄ and remove the solvent in vacuo. The silica residue with EE / HEP 1: 1 is chromatographed to give 1.2 g of product c) in addition to 890 mg of product d), in both cases oil.

c) R _f (EE) = 0.32 MS (ES): 375 (M + H) ⁺

d) R _f (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 are converted into 10 ml of THF according to the general regulation for the preparation of benzoyl-guanidines, variant B. After chromatography on silica with EE / MeOH 5: 1 yields 80 mg of colorless crystals.

R _f (EE / MeOH 5: 1) = 0.22 MS (ES): 402 (M + H) ⁺

Tal. = 156 ° C

EXAMPLE 10: 3-Trifluoromethyl-4- (4-N-methylimidamidosulfonyl) phenoxybenzoylguanidine

490 mg of 4- (4-N-methyl-imidosulfamoyl) phenoxy-3-trifluoromethylbenzoic acid methyl ester (Example 9 d) and 373 mg of guanidine are converted to 20 ml of THF according to the general regulation for the preparation of benzoyl-guanidines, variant B. According to chromatography on silica with EE / MeOH 5: 1 gives 370 mg of colorless crystals.

R _f (EE / MeOH 5: 1) = 0.33 MS (ES): 416 (M + H) ⁺

Tal. (dihydrochloride) = 233 ° C

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

EXAMPLE 11: 3-Methyl-4- (4- (1-methylpiperazin-4-ylsulfonyl) phenoxy) -benzoylguanidine

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

3.4 g of 4-fluoro-3-methyl-benzoic acid methyl ester, 2.4 g of phenol and 19.5 g of Cs ₂ CO _{3 were} stirred in 100 ml of NMP for 20 minutes at 160 ° C. The mixture is poured into 400 ml of saturated aqueous NaHCO ₃ solution, diluted with 400 ml of water and extracted 3 times with 200 ml of MTB each. Dry over Na ₂ SO ₄ and remove the solvent in vacuo. Chromatography of the residue on silica with EE / HEP 1: 4 yields 2.0 g of a colorless oil.

R _f (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

R _f (EE / MeOH 5: 1) = 0.24 MS (ES): 412 (M + H) ⁺

EXAMPLE 13: 4- (4-guanidinosulfonyl) phenoxy-3-trifluoromethyl-benzoylguanidine

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

13.5 g of 4-phenoxy-3-trifluoromethyl-benzoic acid (Example 3b) was dissolved in 150 ml of CHCl ₃ , 3.3 ml of chlorosulfonic acid was added dropwise at RT and then stirred for 3 h. The solvent was removed in vacuo, 300 g of ice and 100 ml of water were added and stirred for 10 minutes. Immediately then 400 ml was added to 0 ° C of cooled saturated aqueous NaCl solution, stirred for a further 15 minutes at 0 ° C and the precipitate was filtered off with suction. At 40 ° C, they were dried in vacuo to give 16.5 g of a white solid, which was used without further 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 were dissolved in 250 ml of SOCl ₂ and heated for 8 h under reflux. About half of the excess SOC1 ₂ is then removed in vacuo and the solution is added to 1 kg of ice. It is extracted 3 times with 500 ml CH ₂ Cl _{2 each,} dried over MgSO ₄ and the solvent removed in vacuo. 18.0 g of an oil are obtained which is used without further purification. R _f (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-benzoyl chloride were dissolved in 150 ml of acetone, 3.7 g of 3-hydroxypyridine and 11.0 g of K2 CO3 were added and stirred for 3 h at RT. The reaction mixture was poured onto 500 ml of water and extracted 3 times with 300 ml of EE each. Dry over Na ₂ SO ₄ , remove the solvent in vacuo and chromatograph on silica with MTB / 2% HOAc. 8.0 g of a yellowish oil are obtained.

R _f (MTB / 2% HOAc) = 0.29 MS (FAB): 517 (M + H) ⁺

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

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 h under reflux. The solvent was removed in vacuo, taken up with 400 ml of water, adjusted to pH = 8 with aqueous HCl and stirred for 2 h at RT. The precipitate was filtered off and chromatographed on silica with EE / MeOH 5: 1. 272 mg of amorphous solid are obtained.

R _f (EE / MeOH 5: 1) = 0.33 MS (ES): 445 (M + H) ⁺

EXAMPLE 14: 3-Methylsulfonyl-4- (4- (2-dimethylaminoethyl) phenoxy] benzoylguanidine bis-methanesulfonate

a) 5-Carboxy-2-fluorobenzenesulfonic acid

Dissolve 15.6 g (0.124 M) of sodium sulfite at 70 ° C in 120 ml of water. While maintaining the temperature, 23.8 g (0.1 M) of 4-fluoro-3-chlorosulfonylbenzoic acid and 10 N NaOH were added simultaneously and gradually while maintaining the pH between 9 and 10 (exothermic reaction). It was stirred for a further 3 hours at 70 ° C, allowed to stir for a minute with A-charcoal and then filtered. The external filtrate was cooled with concentrated hydrochloric acid to pH 0-1 and the crystalline 5-carboxy-2fluorobenzenesulfinic acid was filtered off. Colorless crystals,

Melting point: 167-170 ° C.

b) 5-Carboxy-2-fluorobenzenesulfonic acid disodium salt

It 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) NaOH in a mixture of 150 ml of methanol and 30 ml of water: after filtration of the sediment, distill off the solvent and the residue under acetone lead to crystallization.

Colorless crystalline substance, melting point:> 320 ° C.

c) 4-Fluoro-3-methylsulfonylbenzoic acid methyl ester

To a suspension of 15 g (0.06 M) of 5-carboxy-2-fluorobenzenesulfonic acid disodium salt in 80 ml of dry DMF was added 30 g (0.21 M) of methyl iodide, stirred for 6 hours at 60 ° C, the solvent was distilled off and the residue was supplemented with water. The mixture is stirred for 30 minutes under ice-cooling and the precipitate is filtered off.

Colorless crystalline substance.

Melting point: 102-105 ° C.

d) 3-Methylsulfonyl-4- [4- (2-dimethylaminoethyl) phenoxy] -benzoic acid methyl ester

4.64 g (0.02 M) of 4-fluoro-3-methylsulfonylbenzoic acid methyl ester are 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 and the suspension was stirred for 4 hours at 90 ° C.

After the solvent is distilled off and the residue is supplemented with water, it is extracted several times with acetic acid ethyl ester, the combined organic phases are concentrated under reduced pressure to give the substance as a yellow oily liquid.

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

1.88 g (0.005 M) of 3-methylsulfonyl-4- [4- (2-dimethylaminoethyl) phenoxy] benzoic acid methyl ester is boiled in 40 ml of half-concentrated hydrochloric acid for 5 hours under reflux, the aqueous hydrochloric acid is distilled off and the residue is under acetone lead to crystallization.

Colorless crystalline substance, melting point: 246-248 ° C.

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

It is obtained analogous to the regulation given in variant A of 3-methylsulfonyl-4- [4- (2-dimethylaminoethyl) phenoxy] benzoic acid at a pH between 7 and 8.

Colorless crystals, melting point: 214-218 ° C.

3-Methylsulfonyl-4- [4- (2-dimethylaminoethyl) phenoxy] benzoylguanidine bis-methanesulfonate is prepared analogously to the regulation given in variant A of 3-methylsulfonyl-4- [4- (2-dimethylaminoethyl) phenoxy] benzoylguanidine by treatment with 2, 5 equivalents of methanesulfonic acid in ethanol.

Colorless solid.

Melting point: 102 ° C.

EXAMPLE 15: 4- [4- (2-Dimethylaminoethyl) thiomethyl-phenoxy] -3-methylsulfonyl-benzoylguanidine dihydrochloride

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 hydrochloride and 12.4 g (0.1 M) of 4-hydroxybenzylalcohol in 250 ml of toluene was boiled for approximately 5 hours on a Kutsche water separator and the Steudel under reflux, the solvent is removed and the residue is filtered off after dissolution in methanol. After re-concentration, the residue is taken up in acetone until crystallization, the crystalline product is filtered off and the hygoscopic mass can be dried over NaOH with air to dry.

Melting point: 134-140 ° C.

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

Mixture of 3.48 g (0.015 M) of 4- (2-dimethylaminoethyl) thiomethyl-phenol, 40 ml of anhydrous tetramethylurea, 6.8 g (0.049 M) of anhydrous powdered KjCC ^ and 3.48 g (0.015 M) of methyl ester 4 -fluoro-3-methylsulfonylbenzoic acid was stirred for 6 hours at 90-100 ° C, the solvent was distilled off and the residue was made up with water. After extraction with acetic ester, drying and concentration of the combined organic phases, the desired product is obtained as an oil.

c) 4- [4- (2-dimethylaminoethyl) thiomethyl-phenoxy] -3-methylsulfonyl-benzoic acid hydrochloride

It is obtained analogous to the regulation described in Example 14 (d) by hydrolysis of 4-fluoro-3-methylsulfonylbenzoic acid methyl ester in 20% HCl.

Colorless to light yellow crystalline substance,

Melting point: 179-185 ° C.

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

It is obtained analogous to the regulation described in Example 14 e) from 4- [4- (234 dimethylaminoethyl) -thiomethyl-phenoxy] -3-methylsulfonylbenzoic acid hydrochloride. Hygroscopic substance, melting point: 230 ° C.

EXAMPLE 16: 4- [4- (2-Dimethylaminoethylthio) phenoxy] -3-methylsulfonyl-benzoylguanidine dihydrochloride

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

To a solution of 12.6 g (0.1 M) of 4-mercaptophenol in 100 ml of anhydrous DMF was added under a protective atmosphere of gas (argon) 17.28 g (0.11 M) of 2-diethylaminoethyl chloride hydrochloride and immediately thereafter 19.38 g (0.15 M) ethyldiisopropylamine and the reaction mixture was stirred for 12 hours with magnetic stirring at 110 ° C. After distilling off the solvent, the residue is made up with water, adjusted to pH 8-9 with 2 N NaOH, the amorphous precipitate is extracted several times with ethyl acetate and the combined organic phases are dried over sodium phosphate. The solvent was distilled off and the residue on silica was eluted column chromatographically with a mixture consisting of 8 parts of ethyl acetate and 1 part of methanol.

Colorless crystals,

Melting point: 108-110 ° C.

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

It is obtained as a yellow oil analogous to the rule described in 14 d) by the reaction of N, N-dimethyl-2- (4-hydroxyphenylthio) ethylamine with 4-fluoro-3-methylsulfonylbenzoic acid methyl ester, using DMF instead of dimethylacetamide.

Yellow oily liquid.

c) 4- [4- (2-Dimethylaminoethylthio) phenoxy] -3-methylsulfonylbenzoic acid 6.8 g of 4- [4- (2-dimethylaminoethylthio) phenoxy] -3-methylsulfonylbenzoic acid methyl ester is boiled in 10 ml of ice and 70 ml. half-concentrated HC1 for 5 hours under reverse flow conditions. After distillation of the solvent, the desired substance is obtained as an amorphous solid with no defined melting point.

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

It is obtained by analogy to the regulation given as variant A.

Colorless solid,

Decomposition point: 160 ° C when foaming.

EXAMPLE 17: 4- [4- (2-Dimethylaminoethylsulfonyl) phenoxy] -3-methylsulfonyl-benzoylguanidine dihydrochloride

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-methylsulfonylbenzoic acid in 50 ml of glacial acetic acid was added in portions at 5-10 ° C 6.9 g (0.028 M) of 3 chloroperbenzoic acid and stirred for 12 hours at RT. After addition of water, a precipitate of 3-chlorobenzoic acid is filtered off and extracted from the further impurity filtrate with acetic ester. The aqueous phase was concentrated and the amorphous residue was brought to crystallization under ethyl acetate.

Colorless crystals,

Melting point: 167-171 ° C.

b) 4- [4- (2-dimethylaminoethylsulfonyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

It is obtained analogous to the regulation given in variant A of 4- [4- (2-dimethylaminoethylsulfonyl) phenoxy] -3-methylsulfonylbenzoic acid in TMU as the reaction medium, the dihydrochloride is brought to crystallization under methanol.

Colorless crystals,

Melting point: 233-240 ° C (decomposition).

EXAMPLE 18: 4 - [(4-guanidinocarbonyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

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

Metabolism of 4-hydroxybenzoic acid ethyl ester with 4-fluoro-3methylsulfonylbenzoic acid methyl ester yields an analogous to the rule given under 14 d) 4- (4-ethoxycarbonylphenoxy) benzoic acid methyl ester as a colorless to light yellow oil, which is further removed without further action in the analogous manner indicated in regulation 16 c), hydrolyzed to 4- (4-carboxyphenoxy) -3-methylsulfonylbenzoic acid. Colorless crystals,

Melting point: 272-275 ° C.

b) 4 - [(4-guanidinocarbonyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride This is obtained analogous to the regulation described in variant A with a metabolism of 0.74 g (0.0022 M) (4-carboxyphenoxy) -3-methylsulfonylbenzoic acid with 0.78 g (0.0048 M) of carbonyldiimidazole and 1.55 g (0.026 M) of guanidine in DMA.

Colorless crystals,

Melting point: 252 ° C (decomposition).

EXAMPLE 19: 4- [4- (2-Dimethylaminoethyl) thiomethyl-phenoxy] -3-trifluoromethylbenzoylguanidine dihydrochloride

a) 4- [4- (2-Dimethylaminoethyl) thiomethyl-phenoxy] -3-trifluoromethylbenzoic acid methyl ester

It is prepared analogously to the regulation described in Example 15b) from 4- (2-dimethylaminoethyl) thiomethyl-phenol and 4-fluoro-3-trifluoromethylbenzoic acid methyl ester in DMU as the reaction medium, as an amorphous oily product.

b) 4- [4- (2-dimethylaminoethyl) thiomethyl-phenoxy] -3-trifluoromethyl-benzoic acid Prepared analogously to the procedure described in Example 14 d) by acid hydrolysis of 4- [4- (2-dimethylaminoethyl) thiomethyl methyl ester] -phenoxy] -3-trifluoromethylbenzoic acid. Colorless, hygroscopic crystals,

Melting point: 158-168 ° C (decomposition).

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

It is prepared analogously to the regulation described in variant A, from 4- [4- (2-dimethylaminoethyl) thiomethyl-phenoxy] -3-trifluoromethylbenzoic acid in TMU as the reaction medium. Amorphous, strongly hygroscopic solid,

Decomposition at 80-85 ° C.

EXAMPLE 20: 4- [4- (2-Dimethylaminoethylthio) phenoxy] -3-trifluoromethyl-benzoylguanidine dihydrochloride

H /

C — N

a) 4- [4- (2-Dimethylaminoethylthio) phenoxy] -3-trifluoromethyl-benzoic acid methyl ester

It is obtained analogous to the regulation described in Example 15b) from 4- (2-dimethylaminoethylthio) phenol and 4-fluoro-3-trifluoromethylbenzoic acid methyl ester in DMU as the reaction medium as an amorphous oily product.

b) 4- [4- (2-dimethylaminoethylthio) phenoxy] -3-trifluoromethyl-benzoic acid Prepared analogously to the procedure described in Example 14 d) by acid hydrolysis of 4- [4- (2-dimethylaminoethylthio) phenoxy] methyl ester] -3-Trifluoromethylbenzoic acid. The desired 4- [4 (2-dimethylaminoethylthio) phenoxy] -3-trifluoromethyl-benzoic acid is brought under acetone to crystallization.

Colorless crystals,

Melting point: 174-182 ° C (decomposition).

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

It is obtained analogous to the regulation described in variant A from 4- [4- (2-dimethylaminoethylthio) phenoxy] -3-trifluoromethyl-benzoic acid in THF as the reaction medium. Amorphous, hygroscopic crystalline solid,

Melting point: 240 ° C.

EXAMPLE 21 3-Trifluoromethyl-4- [4- (2-dimethylaminoethyl) phenoxy] benzoylguanidine dihydrochloride

a) 4-Chloro-3-trifluoromethyl-benzoic acid

Grignard compound was first prepared from 100 g of 5-bromo-2-chloro-benzotrifluoride and 10.2 g of magnesium in 600 ml of diethyl ether. Immediately, a stream of 60 g of anhydrous CO _{2 is} introduced into this solution at RT. 500 ml of saturated aqueous NaHSO ₄ solution are added dropwise, the phases are separated and another is extracted with 2 x 100 ml of diethyl ether. The organic phase was extracted 3 xs with 300 ml of 1 n NaOH, and then the aqueous phase was washed 3 xs with 100 ml of diethyl ether. The aqueous phase is then brought to pH 2 with HCl and diluted to 4 with water. The product is sucked off and dried in vacuo.

g of white powder.

R _f (MTB 2% HOAc) = 0.68.

b) 4-Chloro-3-trifluoromethyl-benzoic acid methyl ester g of 4-chloro-3-trifluoromethyl-benzoic acid was dissolved in 500 ml of MeOH and 75 ml of SOCl _{2 was} added dropwise. Cook for 5 hours under reflux, then remove the volatile components in vacuo. Take up with 11 EE and wash with 500 ml of saturated aqueous Na ₂ CO ₃ solution. Dry over Na ₂ SO ₄ , remove the solvent in vacuo and distill in vacuo.

Boiling point: 94 ° C (2 mPaS)

R _f (DIP) = 0.49 MS (DCI): 239 (M + H) ⁺

c) 4- [4- (2-Dimethylamino) ethyl] phenoxy-3-trifluoromethyl-benzoic acid methyl ester 1.9 g of 4-chloro-3-trifluoromethyl-benzoic acid methyl ester, 1.3 g of 4- (2-dimethylamino) of ethylphenol, 7.8 g of Cs ₂ CO _{3 was} stirred in 50 ml of tetramethylurea for 5 h at 140 ° C. Allow to cool, then add 300 ml of saturated aqueous NaHCO ₃ and 150 ml of water, and extract 3 times with 100 ml of EE each. Dry over Na ₂ SO ₄ , then remove the solvents in vacuo. Acetone / water chromatography 10: 1 gave 2.0 g of a colorless oil.

R _f (acetone / water 10: 1) = 0.15

MS (DCI): 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 by 1 , 6 g of guanidine in 60 ml of isopropanol according to variant B. The crude product is converted to dihydrochloride and recrystallized from 1,2-dimethoxyethane / water 9: 1. Melting point: 164 ° C Melting point (dihydrochloride): 236 ° C MS (DCI): 395 (M + H) ⁺

Water solubility of dihydrochloride 49 mg / ml (pH = 5.3).

EXAMPLE 22: 4- (4-N, N-Dimethylaminoethylphenoxy] -3-sulfamoylbenzoylguanidine bismethanesulfonate

It is obtained analogous to the regulation described in variant A from

4- [4- (2-Dimethylaminoethyl) phenoxy] -3-sulfamoylbenzoic acid in dimethylacetamide or N-methylpyrrolidone as the reaction medium. Amorphous hygroscopic solid,

Melting point: 183 ° C.

a) 4- [4- (2-Dimethylaminoethyl) phenoxy] -3-sulfamoylbenzoic acid methyl ester It is obtained by heating 0.011 mol of N, N-dimethyl-2- (4-hydroxyphenyl) ethylamine, 0.033 mol of potassium carbonate (ground) and 0.01 mol of 4-fluoro-3sulfamoylbenzoic acid methyl ester in 40 ml of dimethylacetamide over 90 hours at 90-100 ° C. After distilling off the solvent, the residue is mixed with water, the brown amorphous product is treated with acetic ester, filtered off from a crystalline precipitate and the solvent is distilled off from the filtrate. Amorphous oil product.

b) 4- [4- (2-dimethylaminoethyl) phenoxy] -3-sulfamoylbenzoic acid

It is digested by hydrolysis of 0.0066 mol of the corresponding methyl ester (a) in 60 ml of boiling half-concentrated hydrochloric acid for 5 hours. After evaporation of the aqueous hydrochloric acid in vacuo, the residue is treated with acetone and the precipitate is filtered off. The solvent was distilled off to give the desired benzoic acid. Softening point from 60 ° C.

EXAMPLE 23 3-Chloro-4-fluoro-4-dimethylaminoethyl) phenoxy] -5-methylsulfonyl-benzoylguanidine bismethanesulfonate

It is prepared analogously to the regulation described in variant A from 3-chloro-4- [4- (2-dimethylaminoethyl) phenoxy] -5-methylsulfonylbenzoic acid in dimethylacetamide or N-methylpyrrolidone as the reaction medium.

Hydro-crystalline solid,

Melting point 200 ° C

a) 3-Chloro-4- [4- (2-dimethylaminoethyl) phenoxy] -5-methylsulfonylbenzoic acid methyl ester

This is obtained analogous to Example 22 a) by metabolizing 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-methylsulfonylbenzoic acid Prepared analogously to Example 22a). Crystalline solid, decomposition: 238-244 ° C.

EXAMPLE 24: 4 - [(4-guanidinocarbonyl) phenoxy] -3-methylsulfonylbenzoylguanidine

H ₂ H h ₂ n

It is obtained as the unsaturated base of Example 18 by treating 4 - [(4-guanidinocarbonyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride with triethylamine in DMF. Colorless crystalline solid, melting point: 237 ° C.

EXAMPLE 25: 4- [4- (2-N-imidazolyl-1-oxo-ethyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

It is obtained analogous to the regulation described in variant A from 4- [4- (2-N-imidazolyl-oxo-ethyl) phenoxy] -3-methylsulfonylbenzoic acid in dry dimethylacetamide or N-methylpyrrolidone as the reaction medium. Colorless crystalline solid, decomposition: 255 ° C.

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

0.02 mol of 3-methylsulfonyl-4-phenoxybenzoic acid was introduced into a mixture of 0.08 mol of chloroacetyl chloride, 16 g of anhydrous aluminum chloride and 150 ml of 1,2 dichloroethane at 0-5 ° C, stirred for 2 hours at room temperature. stirred for another 2 hours at 40 to 45 ° C. After stirring overnight, the reaction mixture was poured under stirring into ice water, the crystalline precipitate was filtered off, washed with water and dried. Yellow crystals, melting point: 184-187 ° C.

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

A solution of 0.005 mol of 4- (4-chloroacetylphenoxy) -3-methylsulfonyl-benzoic acid (25 a) in 25 ml of anhydrous DMF was stirred with 0.0225 mol of imidazole for 4 hours at 60 ° C and then the solvent was distilled off. After treating the amorphous residue with water and adjusting the pH to 2-3 with 2 N hydrochloric acid, the mixture is stirred for 1 hour and the crystalline precipitate is filtered off. Crystals, decomposition 235-241 ° C.

EXAMPLE 26 4- [4- (2-Imidazolylthio-acetyl) phenoxy] -3-methylsulfonyl-benzoylguanidine dihydrochloride

This is obtained analogous to the regulation described in variant A of 4- [4- (2-imidazolylthioacetyl) phenoxy] -3-methylsulfonylbenzoic acid in a mixture of 50 ml THF and 10 ml dimethylacetamide as the reaction medium. Colorless crystalline solid, melting point: 220 ° C

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

It is obtained by the reaction of 4- (4-chloroacetylphenoxy) -3-methylsulfonylbenzoic acid (Example 25a) and a mole of 2-mercaptoimidazole in 20 ml of acetone and heating briefly to boiling. The mixture was stirred at room temperature for about 5 days and the crystalline precipitate was filtered off.

Decomposition: 202-205 ° C.

EXAMPLE 27: 4- [4- (4,5-Dihydro-2-imidazolylthio-a, cetyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

It is prepared according to the procedure described in variant A from 4- [4- (4,5-dihydro-2-imidazolylthioacetyl) phenoxy] -3-methylsulfonylbenzoic acid in a mixture of 50 ml THF and 10 ml dimethylacetamide as the reaction medium.

Colorless crystalline solid, melting point: 210 ° C.

a) Preparation of 4- (4- (4,5-dihydro-2-imidazolylthio-acetyl) phenoxy] -3-methylsulfonylbenzoic acid is carried out analogously to regulation 26a) by reaction of 4- (4chloroacetylphenoxy) -3-methylsulfonylbenzoic acid (Example 25 a) with 2-mercapto-4,5 dihydroimidazole. Decomposition: 305-310 ° C.

EXAMPLE 28: 4- [4- (N, N'-Dimethyl-S-isothuronyl-acetyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

This is obtained analogous to the regulation described in variant A from 4- [4- (N, N'-dimethyl-Sizothironyl-acetyl) phenoxy] -3-methylsulfonylbenzoic acid in a mixture of 50 ml THF and 10 ml dimethylacetamide as the reaction medium.

Colorless crystalline solid,

Melting point: 150 ° C

a) 4- [4- (N, N'-Dimethyl-S-isothuronyl-acetyl) phenoxy] -3-methylsulfonylbenzoic acid Prepared analogously to regulation 26a) by reaction of 4- (4-chloroacetylphenoxy) -3methylsulfonylbenzoic acid (Example 25 a ) with Ν, Ν'-dimethylthiourea at room temperature. Colorless crystals.

Decomposition: 185-190 ° C.

EXAMPLE 29: 4- [4- (2-Benzimidazolylthio-acetyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

It is obtained analogous to the regulation described in variant A from 4- [4- (2-benzimidazolylthioacetyl) phenoxy] -3-methylsulfonylbenzoic acid THF as the reaction medium. Colorless crystalline solid,

Melting point: 228 ° C.

a) 4- [4- (2-Benzimidazolylthio-acetyl) phenoxy] -3-methylsulfonylbenzoic acid Prepared according to regulation 26a) by reaction of 4- (4-chloroacetylphenoxy) -3-methyl sulfonylbenzoic acid (Example 25 a) with 2- mercaptobenzimidazole in DMF. Melting point: 182 ° C.

EXAMPLE 30: 4- [4- (2-Pyridylthio-acetyl) phenoxy] -3-methylsulfonyl-benzoylguanidine dihydrochloride

It is obtained analogous to the regulation described in variant A from 4- [4- (2-pyridylthio-acetyl) phenoxy] -3-methylsulfonylbenzoic acid in THF as the reaction medium. Colorless crystalline solid,

Melting point: 203 ° C.

a) 4- [4- (2-Pyridylthio-acetyl) phenoxy] -3-methylsulfonylbenzoic acid This is obtained analogous to regulation 26a) by reaction of 4- (4-chloroacetylphenoxy) -3methylsulfonylbenzoic acid (Example 25 a) with 2-mercaptopyridine. Melting point: 194-196 ° C.

EXAMPLE 31: 4- [4- (2-Quinolylthio-acetyl) phenoxy] -3-methylsulfonyl-benzoylguanidine dihydrochloride

It is obtained analogous to the regulation described in variant A from 4- [4- (2-quinolylthio-acetyl) phenoxy] -3-methylsulfonylbenzoic acid in THF as the reaction medium. Colorless crystalline solid. Melting point: 192 ° C.

a) Preparation of 4- [4- (2-quinolylthio-acetyl) phenoxy] -3-methylsulfonylbenzoic acid proceeds analogously to regulation 26a) by reaction of 4- (4-chloroacetylphenoxy) -3-methylsulfonylbenzoic acid (example 25 a) with 2-mercaptoquinoline in the DMF. Melting point: 210-214 ° C.

EXAMPLE 32: 4- [4- (2-N-imidazolyl-1-hydroxyethyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

OH

HCI

It is obtained analogous to the regulation described in variant A from 4- [4- (2-N-imidazolyl-hydroxyethyl) phenoxy] -3-methylsulfonylbenzoic acid in dimethylacetamide or Nmethylpyrrolidine as the reaction medium. Colorless crystalline solid.

Decomposition point: 260 ° C.

a) 4- [4- (2-N-imidazolyl-1-hydroxyethyl) phenoxy] -3-methylsulfonylbenzoic acid It 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 distilling off the solvent, supplementing the residue with water and adjusting the pH to 4 with 2N HCl, it was stirred for a few hours at room temperature and the crystals were filtered off.

Melting point: 240-248 ° C.

EXAMPLE 33: 3-Methylsulfonyl-4- (4-sulfamoylphenoxy) benzoylguanidine hydrochloride

It is prepared analogously to the regulation described in variant A from 3-methylsulfonyl-4- (4sulfamoylphenoxy) benzoic acid in dimethylacetamide as the reaction medium. Colorless crystalline solid,

Decomposition point: 267 ° C.

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

It is obtained by metabolizing 0.03 mol of 4-phenoxy-3-methylsulfonyl-benzoic acid with 0.15 mol of chlorosulfonic acid in 60 ml of methylene chloride at 0-5 ° C and stirring for a further 4 hours at room temperature. After treatment with ice water, the methylene chloride phase is separated, washed with water, dried over magnesium sulfate and the solvent distilled off. Crystals,

Melting point: 167-170 ° C.

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

It is obtained by reacting 3-methylsulfonyl-4- (4-chlorosulfonylphenoxy) -benzoic acid with an aqueous concentrated ammonia solution for 24 hours at room temperature, distilling the ammonia and acidifying the aqueous solution with 2N HCl to pH 1-2. The crystals are filtered off, washed with water and dried. Colorless crystalline substance, Melting point: 240-245 ° C.

EXAMPLE 34: 4- [4- (1-Hydroxy-2- (2-pyridylthio) ethyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

It is obtained analogous to the regulation described in variant A from 4- [4- (1-hydroxy-2- (2-pyridyl thio) ethyl) phenoxy] -3-methylsulfonylbenzoic acid in THF as the reaction medium. Colorless crystalline solid.

Melting point: 116 ° C.

a) 4- [4- (1-hydroxy-2- (2-pyridylthio) ethyl) phenoxy] -3-methylsulfonylbenzoic acid Prepared analogously to Example 32 a). Colorless crystalline substance.

Melting point: 169-174 ° C.

EXAMPLE 35 4- [4- (1-Hydroxy-2- (2-benzimidazolylthio) ethyl) phenoxy] -3-methylsulfonylbenzoyl-guanidine dihydrochloride

It is obtained analogous to the regulation described in variant A from 4- [4- (1-hydroxy-2- (2-benzimidazolylthio) ethyl) phenoxy] -3-methylsulfonylbenzoic acid in dimethylacetamide as the reaction medium. Colorless, crystalline solid.

Melting point: 213 ° C.

a) 4- [4- (1-Hydroxy-2- (2-benzimidazolylthio) ethyl) phenoxy] -3-methylsulfonylbenzoic acid

It is obtained analogous to Example 32 a). Colorless crystalline substance.

Melting point: 186-188 ° C.

EXAMPLE 36: 4- [4- (1-Hydroxy-2- (2-quinolylthio) ethyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

It is obtained analogous to the regulation described in variant A from 4- [4- (1-hydroxy-2- (2quinolylthio) ethyl) phenoxy] -3-methylsulfonylbenzoic acid in THF as the reaction medium. Colorless crystalline solid.

Melting point: 180 ° C.

a) 4- [4- (1-hydroxy-2- (2-quinolylthio) ethyl) phenoxy] -3-methylsulfonylbenzoic acid Prepared analogously to example 32 a) from 4- [4- (2-quinolylthio-acetyl) phenoxy] -3-methylsulfonyl-benzoic acid (Example 31 a).

Colorless crystalline substance.

EXAMPLE 37: 4- [4- (N, N-dimethylglycylamino) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

It is obtained analogous to the regulation described in variant A from 4- [4- (N, N-dimethylglycylamino) phenoxy] -3-methylsulfonylbenzoic acid in THF as the reaction medium. Colorless crystalline solid.

Melting point: 223 ° C.

a) The preparation of 3-methylsulfonyl-4- (4-nitrophenoxy) benzoic acid is carried out by the reaction 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 acetanhydride and 4 ml. of ice, at -10 ° C. After stirring at this temperature for 1.5 hours, it was stirred for 24 hours at room temperature and for a further 6 hours at 40 ° C.

Pour onto ice water, stirring to bring the amorphous oily product to crystallization. Yellow crystalline substance,

Melting point: 140-150 ° C.

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

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

c) N, N-dimethylglycine-imidazolid hydrochloride

It is obtained by the reaction of Ν, dim-dimethylglycine hydrochloride with carbonyldiimidazole in the anhydrous dimethylacetamide from which the product is taken. The mixture is further metabolised without further processing steps.

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

It is obtained by the reaction of Ν, dim-dimethylglycine-imidazolid hydrochloride (Example 37 c) with 4- (4-aminophenoxy) -3-methylsulfonyl benzoic acid (Example 37 b) by stirring for 5 hours in dimethylacetamide at room temperature. The solvent was distilled off, adjusted with HCl to pH 1-2 and extracted with ethyl acetate. The aqueous phase is distilled off and the residue is treated with methanol. After filtration of the insoluble part, the desired compound is obtained as a colorless oil.

EXAMPLE 38: 4- [4- (N, N-Diethylaminoethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoyl-guanidine dihydrochloride

HC1

NH ₂

It is prepared analogously to the regulation described in variant A from 4- [4- (N, N -diethylaminoethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoic acid in anhydrous dimethylacetamide as the reaction medium. Colorless crystalline solid, Melting point: 206 ° C.

a) 4- [4- (N, N-Diethylaminoethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoic acid This is obtained by reacting 0.05 mol of 3-methylsulfonyl-4- (4-chlorosulfonylphenoxy) benzoic acid (Example 33 a) with 0, 06 moles of Ν, diet-diethylaminoethylamine in the presence of excess triethylamine (approx. 0.015 mol) in methanol as the reaction medium. After distilling off the solvent mixture, a little water is added and adjusted to pH 4-5. The crystalline precipitate was filtered off.

Melting point: 263-268 ° C.

EXAMPLE 39: 4- [4- (1-Methyl-4-piperazino) sulfonylphenoxy-3-methylsulfonylbenzoylguanidine dihydrochloride

It is obtained analogous to the regulation described in variant A from 4- [4- (1-methyl-4-piperazino) sulfonylphenoxy] -3-methylsulfonylbenzoic acid in THF as the reaction medium. Colorless crystalline solid, decomposition: 234-244 ° C.

a) 4- [4- (1-Methyl-4-piperazino) sulfonylphenoxy] -3-methylsulfonylbenzoic acid It is obtained by the reaction of methylsulfonyl-4- (4-chlorosulfonylphenoxy) -benzoic acid (Example 33 a) with N-methylpiperazine analogous to the example 38 a).

Colorless crystals, decomposition: 287-292 ° C.

EXAMPLE 40: 4- [4- (4-Imidazolylethyl) aminosulfonyl-phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

This is obtained analogous to the regulation described in variant A from 4- [4- (4-imidazolylethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoic acid in dimethylacetamide as the reaction medium. Colorless crystalline solid,

Melting point: 264 ° C.

a) 4- [4- (4-imidazolylethyl) aminosulfonyl] phenoxy] -3-methylsulfonylbenzoic acid is obtained analogous to Example 38 a) by reacting methylsulfonyl-4- (4-chlorosulfonylphenoxy) benzoic acid (Example 33 a) with histamine. Colorless amorphous solid. Decomposition: 265 ° C.

EXAMPLE 41 4-4- (3-N-imidazolyl-1-propyl) aminosulfonyl-phenoxy] -3-methylsulfonylbenzoyl-guanidine dihydrochloride

CH ₃ 0 ₂ S

It is obtained analogous to the regulation described in variant A from 4- [4- (3-N-imidazolyl-1-propyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoic acid in THF as the reaction medium. Colorless crystalline solid, decomposition: 257 ° C.

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

This is obtained analogous to Example 38 a) by reacting methylsulfonyl-4- (4-chlorosulfonylphenoxy) benzoic acid (Example 33 a) with 1- (3-aminopropyl) imidazole. Colorless amorphous solid,

Melting point: 250 ° C.

EXAMPLE 42: 4- [4- (1-Methyl-2-pyrrolidinylethyl) aminosulfonyl-phenoxy] -3-methylsulfonylbenzoyl-guanidine dihydrochloride

It is prepared analogously to the regulation described in variant A from 4- [4- (1-methyl-2-pyrrolidinylethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoic acid in dimethylacetamide as the reaction medium. Colorless crystalline solid,

Melting point: 254 ° C.

a) 4- [4- (1-Methyl-2-pyrrolidinylethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoic acid

This is obtained analogously to Example 38 a) by reacting methylsulfonyl-4- (4-chlorosulfonylphenoxy) benzoic acid (Example 33 a) with 2- (2-aminoethyl) -1-methylpyrrolidine.

Melting point: 242-247 ° C.

EXAMPLE 43: 4- [4- (N-morpholinoethyl) aminosulfonyl-phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

This is obtained analogous to the regulation described in variant A, from 4- [4- (N-morpholinoethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoic acid in dimethylacetamide as the reaction medium. Colorless crystalline solid, melting point: 272 ° C.

a) 4- [4- (N-morpholinoethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoic acid Prepared analogously to Example 38 a) by reacting methylsulfonyl-4- (4-chlorosulfonylphenoxy) benzoic acid (Example 33 a) with N- (2- aminoethyl) morpholine. Colorless crystalline compound, melting point: 220-224 ° C.

EXAMPLE 44: 4- [4- (N-Piperidinoethyl) aminosulfonyl-phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

It is obtained analogous to the regulation described in variant A from 4- [4- (Npiperidinoethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoic acid in anhydrous dimethylacetamide as the reaction medium. Colorless crystalline solid, melting point: 266 ° C.

a) 4- [4- (N-piperidinoethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoic acid Prepared analogously to Example 38 a) by reacting methylsulfonyl-4- (4-chlorosulfonylphenoxy) benzoic acid (Example 33 a) with N- (2- aminoethyl) piperidine. Colorless crystalline substance, melting point: 271-273 ° C.

EXAMPLE 45: 4- [4- (2-Pyridylethyl) aminosulfonyl-phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

It is prepared analogously to the regulation described in variant A from 4- [4- (2-pyridylethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoic acid in anhydrous dimethylacetamide as the reaction medium. Colorless crystalline solid, melting point: 257 ° C.

a) 4- [4- (2-pyridylethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoic acid is obtained analogous to example 38 a) by reacting methylsulfonyl-4- (4-chlorosulfonylphenoxy) benzoic acid (example 33 a) with 2- (aminoethyl) pyridine.

Colorless crystals.

Melting point: 268-270 ° C.

EXAMPLE 46: 4- [4- (2-Dimethylaminoethyl) sulfonylmethyl-phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

It is obtained by oxidation with peracid analogous to the regulation described in Example 4 from 4-] 4- (2-dimethylaminoethyl) thiomethyl-phenoxy] -3-methylsulfonylbenzoyl-guanidine dihydrochloride (Example 15). Colorless crystals.

Melting point: 245 ° C.

EXAMPLE 47: 4- [4- (2-Dimethylaminoethyl) sulfonylmethyl-phenoxy] -3-trifluoromethylbenzoylguanidine dihydrochloride

It is obtained by peracid oxidation analogous to that described in Example 17 from 4- [4- (2-dimethylaminoethyl) thiomethyl-phenoxy] -3-trifluoromethylbenzoyl-guanidine dihydrochloride (Example 19).

Colorless crystals. Melting point: 140 ° C.

Pharmacological information:

Inhibition of the Na ⁺ / H ⁺ 'rabbit erythrocyte exchanger

White New Zealand rabbits (Ivanovas) were given a standard diet with 2% cholesterol for 6 weeks to activate the Na ⁺ / H ⁺ exchange and thus to flame photometrically determine Na ⁺ flux into erythrocytes via Na ⁺ / H ⁺ exchange. Blood was drawn from the ear arteries and made undiluted with 25 IE of potassium heparin. A portion of each sample was used for double determination of hematocrit by centrifugation. Aliquots of 100 μΐ each were used to measure the Na ⁺ source content in erythrocytes.

For determination of amiloride-sensitive sodium influx, 100 μΐ of each blood sample was incubated in each case with 5 ml of hyperosmolam sol-sucrose medium (mmol / 1: 140 NaCl, 3 KC1, 150 sucrose, 0.1 ouabain, 20 tris-hydroxymethyl-aminomethane ) at pH 7.4 and 37 ° C. The erythrocytes were then washed 3 times with ice-cold MgCl ₂ ouabain solution (mmol / 1: 112 MgC1, 0.1 ouabain) and hemolyzed in 2.0 ml distilled water. The intracellular sodium content was determined by flame photometry.

Na ⁺ -net influx was calculated from the difference between sodium baseline and erythrocyte sodium content after incubation. Amyloride-inhibitory sodium influx is obtained from the difference in sodium content of erythrocytes after incubation with and without amiloride 3 χ 10 ⁴ mol / l. In this way, the compounds of the invention were also treated.

Results

Inhibition of Na ⁺ / H ⁺ exchanger:

Example IC50 (/ imol / l)

7

0.8

0.32

0.05

0,082

0.3

0.1

0.06

0.005 θ, Ι

0.05

0.01

0.16

0.2

0.008

0.04

0.014

0.12

0.44

0.20

0.09

0.07

HOECHST AKTIENGESELLSCHAFT:

For

CJUGLJAN A

Claims (19)

PATENT APPLICATIONS Compounds of formula I R (t) R C 3) R (4) where: one of the three substituents R (1), R (2) and R (3) R (6) -A-B-D-; R (6) is a protonable basic residue, i.e. amino group -NR (7) R (8), amidino group R (7) R (8) N-C [= N-R (9) j- or guanidino group "t") -γ ____ / N R (7), R (8), R (9) and R (10) independently of one another are hydrogen or alkyl having 1, 2,3 or 4 carbon atoms; or R (7) and R (8) together are C _a H _2a ; a 4,5, 6 or 7; wherein in the case of a = 5,6 or 7, one methylene group of group C H < 1 > may be replaced by a heteroatom group O, SO _m or NR (11), or R (8) and R (9) or R (9) and R (10) or R (7) and R (10) are OH ^; a 2,3,4 or 5; wherein in the case of a = 3,4 or 5, one methylene group of group C may be replaced by one heteroatom group O, SO _m or NR (11); m is zero, 1 or 2; R (11) is hydrogen or methyl; or R (6) a basic heteroaromatic ring system of 1-9 C atoms; AC _b H _2b ; b 1,2,3,4,5,6,7,8,9 or 10; wherein in the group C _b H _2b, one or two methylene groups may be replaced by one of the groups selected from the group consisting of -O-, -CO-, -CH [OR (20)] -, -SO _m - , -NR (20) -, -NR (20) -CO-, -NR (20) -CO-NH-, -NR (20) -CO-NH-SO ₂ - -R (20) N-SlHR (19) l _bb and-SO _aa [NR (19)] _bb and wherein in the group C _b H _2b one methylene group may be replaced by -CH-R (99), wherein R (99) together with R (7) forms a pyrrolidine or piperidine ring; aa 1 or 2; bb 0 or 1; aa + bb = 2; R (19) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R (20) is hydrogen or methyl; B phenylene or naphthylene residue R (12) R (I2) R (I 3) R (12) and R (13) independently of one another are hydrogen, methyl, F, Cl, Br, J, CF ₃ or -SO _w -R (14); R (14) is methyl or NR (15) is R (16); R (15) and R (16) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; w is zero, 1 or 2; ^D - ^C d ^H 2d - ^X P d zero, 1,2,3 or 4; X -O-, -C0-, -CH [O R (21)] -, -SO _m - or -NR (21) -; f is zero or 1; R (21) is hydrogen or methyl; m is zero, 1 or 2; and in each case different substituents R (1) and R (2) and R (3) are independently hydrogen, F, Cl, Br, J, -CN, - (C 1 -C 6 -alkyl, - (C ₂ -C) _g ) -alkenyl, -NR (35) R (36) or R (17) -CH2-Zp g zero, 1,2,3 or 4; h is zero or 1; R (35) and R (36) are independently hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; or R (35) and R (36) together, 4 - 7 methylene groups, of which one CH ^ group is replaced by oxygen, -S-, -NH-, -NCH ₃ or -N-benzyl; Z-O-, -CO-, -SO _v , -NR (18) -, -NR (18) -C0-, -NR (18) -C0-NH- ah NR (18) -SO ₂ -; R (18) is hydrogen or methyl; to zero, 1 or 2; R (17) is hydrogen, cycloalkyl having 3,5 or 6 C atoms or C _fe F _{2k + 1 +} ; k 1,2 or 3, or R (17) pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl, which is unsubstituted or substituted by 1-4 substituents selected from the group consisting of F, Cl, Br, J, -CN , (C ₂ -C _g ) alkanoyl, (C ₂ -C _g ) -alkoxycarbonyl, formyl, carboxy, -CF ₃ , methyl and methoxy; or R (17) - (C 1 -C 4 -cycloalkyl or phenyl is unsubstituted or substituted with 1 - 3 substituents selected from the group consisting of F and Cl, -CF _r methyl, hydroxy, methoxy, -NR (37) R (38), CH ₂ SO ₂ - and H ₂ NO ₂ S-, R (37) and R (38) is hydrogen or _-CH?; R (4) and R (5) independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, -OR (32), -NR (33) R (34), or -CF _{2r + y} ; R (32), R (33) and R (34) independently of one another are hydrogen or alkyl having 1, 2 or 3 carbon atoms; r is 1, 2, 3 or 4; as well as their pharmacologically tolerable salts. 2. A compound of formula I according to claim 1, characterized in that: R (l) is hydrogen, F, Cl, - _(C, -C ₄₎ -alkyl, - (C ₂ -C ₄₎ -alkenyl, -NR (35) R (36) or ^R ( ¹⁷ ) - ^C A ' ^Z »> R (35) and R (36) independently of one another are hydrogen, methyl or ethyl; or R (35) and R (36) total 4-5 methylene groups, of which one CH ₂ group may be replaced by oxygen, -S-, -NH-, or -NCH _? ; R (17) is hydrogen, cycloalkyl having 5 or 6 carbon atoms or C 1 -C 2 _{alkyl + 7} ; k is 1, 2 or 3, g is zero, 1, 2, 3 or 4; h is zero or i; Z -O-, -CO-, -SO _v -, -NR (18) -, -NR (18) -CO-, -NR (18) -CO-NH- or -NR (18) -SO ₂ -; R (18) is hydrogen or methyl; to zero, 1 or 2; or, when g and h are zero, R (17) pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl, which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F, Cl, (C ₂ -C ₅ ) -alkanoyl, (C ₂ -C ₅ ) -alkoxycarbonyl, formyl, carboxy, -CF ₃ , methyl and methoxy; or R (17) - (C ₃ -C ₈ ) -cycloalkyl or phenyl, which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F and Cl, -CF ₃ , methyl, methoxy, -NR ( 37) R (38), CH ₃ SO ₂ - and F ^ NO ^ -; R (37) and R (38) are independently hydrogen or -CH ₃ ; is one of the substituents R (2) and R (3) R (6) -A-B-D-; R (6) -NR (7) R (8), amidino group R (7) R (8) N-C [= N-R (9)] - or guanidino group R (7) R (IO) (s) - V ____ R (7), R (8), R (9) and R (10) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 C atoms; or R (7) and R (8) together are CH2; a 4,5,6 or 7; wherein in the case of a = 5,6 or 7, one methylene group of the CH _h group may be replaced by a heteroatom group O, SO or NR (11); R (11) is hydrogen or methyl; R (8) and R (9) together are 0, ¾ a 2,3,4 or 5; wherein in the case of a = 3, 4 or 5, one methylene group of group C may be replaced by a heteroatom group O, SO _m or NR (11), m zero, 1 or 2; or R (6) imidazolyl-, pyridyl-, quinolinyl or isoquinolinyl; AC _b H _a ; bl, 2,3,4 or 5, wherein in the group C _b H _2b, one or two methylene groups may be replaced by one of the groups selected from the group consisting of -0-, -C0-, -CH [OR (20 )] -, -SO _m -, NR (20), -NR (20) -CO-, -NR (20) -CO-NH-, -NR (20) -CO-NH-SO ₂ -, (0 ) oo II R (20) N-Sl NR (1 9) 1 _bb in-SO _M [NR (19)] _bb -; and wherein in the group one methylene group may be replaced by -CH-R (99), forming R (99) together with R (7) a pyrrolidine or piperidine ring; aa 1 or 2; bb 0 or 1; aa + bb = 2; R (19) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R (20) is hydrogen or methyl; phenylene or naphthylene residue R (12) R (15) R (12) R (1 3> R (12) and R (13) are independently hydrogen, methyl, F, Cl, CF ₃ or -SO ₂ -R (14); R (14) is methyl or NR (15) is R (16); R (15) and R (16) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; D d zero, 1,2,3 or 4; X -O-, -C0-, -CH [O R (21)], -SO _m - or -NR (21) -; f is zero or 1; R (21) is hydrogen or methyl; m is zero, 1 or 2; and in each case the other radical R (2) and R (3) is hydrogen, alkyl having 1,2,3 or 4 carbon atoms, F, C1, or CF _3; R (4) and R (5) independently of one another are hydrogen, alkyl having 1, 2 or 3 C atoms, F, Clali-CF ₃ . Compound of formula I according to claims 1 or 2, characterized in that: R (1) is hydrogen, F, Cl, alkyl having 1, 2, 3 or 4 carbon atoms, -NR (35) R (36) or R 1 -CH 2 -; ² g zero, 1,2,3 or 4; h is zero or 1; Z-O-, -CO-, -SO _v -, -NR (18) -, -NR (18) -C0-, -NR (18) -C0-NH-, or -NR (18) -SO ₂ -; R (18) is hydrogen or methyl; to zero, 1 or 2; R (17) is hydrogen, cycloalkyl having 5 or 6 C atoms or CF ₃ -; or when g and h are zero, R (17) pyrrol-1-yl, which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F, Cl, (C ₂ C ₅ ) -alkanoyl, (C ₂ -C ₅ ) -alkoxycarbonyl, -CF ₃ and methyl; or R (17) - (C ₅ -C ₆ ) -cycloalkyl or phenyl, which is unsubstituted or substituted by a substituent selected from the group consisting of F and Cl, -CF ₃ , methyl, CH ₃ SO ₂ - and F ^ NC ^ S R (35) and R (36) are independently hydrogen, methyl or ethyl; or R (35) and R (36) together are 4-5 methylene groups, of which one CH ₂ group may be replaced by oxygen, -S-, -NH-, or -NCH ₃ ; one of the substituents R (2) and R (3) R (6) -A-B-D-; R (6) -NR (7) R (8), amidino group R (7) R (8) N-C [= N-R (9)] - or guanidino group R (7) B (tO) K.) ^{/ H} Y ' R (9) R (7) is hydrogen or alkyl having 1, 2, 3 or 4 C atoms; R (8), R (9) and R (10) independently of one another are hydrogen, methyl or ethyl; or R (7) and R (8) together are C _a H _2a ; a 4 or 5; wherein in the case of a = 5, one methylene group of group C _a H _{2a may be} replaced by NR (11), R (11) is hydrogen or methyl; or R (6) imidazolyl or pyridyl; ^A 5, ¾ b 1,2,3,4 or 5, wherein in group C _b H _2b, one or two methylene groups may be replaced by one of the groups selected from the group consisting of -CO-, -CH [ OR (20)] -, -NR (20) -CO-, S ” -R (20) N-SII (HR (19) l _bb -SOJNR (19)] _bb in-SO ₂ -; and wherein in the group C _2b H _2b, one methylene group may be replaced by -CH-R (99), wherein R (99) together with R (7) forms a pyrrolidine or piperidine ring; aa 1 or 2; bb 0 or 1; aa + bb = 2; R (19) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms R (20) is hydrogen or methyl; or when b is 2,3,4 or 5, one C atom in C _b H _{2b may be} replaced by the group -O-, -S-, NR (20) -, -NR (20) -CO- or - NR (20) -CO-NH-; B phenylene residue R (1 2) R (13) R (12) and R (13) independently of one another are hydrogen, methyl, F, Cl, CF ₃ or -SO ₂ R (14); R (14) is methyl or NH ₂ ; D -CH ₂ -, -O-, -C0-, -SO _m - or -NR (21) -; m is zero or 2; R (21) is hydrogen or methyl; and in each case another residue R (2) and R (3) is hydrogen; R (4) and R (5) independently of one another are hydrogen, alkyl having 1, 2 or 3 C atoms, F, Cl, or CF ₃ . Compounds of formula I according to at least one of claims 1 - 3, characterized in that they mean: R (1) is hydrogen, F, Cl, alkyl having 1, 2, 3 or 4 C atoms, -NR (35) R (36), or R (17) -CH _{2 g} -Z _h -; g is zero or 1; h is zero or 1; Z-O-, -CO-, -NR (18) -CO-, -NR (18) -CO-NH-, or -NR (18) -SO ₂ -; R (18) is hydrogen or methyl; or when g is 1; mean Z -SO ₂ -; R (17) is hydrogen or CF ₃ -; R (35) and R (36) independently of one another are hydrogen, methyl or ethyl; or R (35) and R (36) together are 4 - 5 methylene groups of which one CH ₂ group may be replaced by oxygen, -S-, -NH-, or -NCH ₃ ; one of the substituents R (2) and R (3) R (6) -A-B-O-; R (6) -NR (7) R (8) or guanidino group R (7) R (10) R (8) V R (9) ^{/ N} R (7) is hydrogen or alkyl having 1, 2, 3 or 4 C atoms; R (8), R (9) and R (10) independently of one another are hydrogen, methyl or ethyl; or R (7) and R (8) together are C H 2; a 4 or 5; wherein in the case of a = 5, one methylene group of group C H < 3 > may be replaced by -NH- or -NCH ₃ -, or R (6) imidazolyl-; ^A b 1,2,3 or 4; wherein in the group C _b H _2b, one or two methylene groups may be replaced by one of the groups selected from the group consisting of -C0-, -R (20) N-SII I NR (19) l _bb -SO _aa [NR (19)] _bb - and -SO ₂ and in which one methylene group may be replaced by -CH-R (99) in the group, where R (99) together with R (7) can be pyrrolidine or a piperidine ring; or when b is 2, 3 or 4, one methylene group of group C _b H _{2b may be} replaced by group -O-, -S-; aa 1 or 2; bb O or 1; aa + bb = 2; R (19) is hydrogen or alkyl having 1, 2, 3 or 4 C atoms R (20) is hydrogen or methyl; B is a phenylene residue, R (12) R (13) R (12) and R (13) are hydrogen, and each other is R (2) and R (3) is hydrogen; R (4) and R (5) are hydrogen. A compound of formula I according to claim 1, 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-Pyrrolidinethylaminosulfonyl) phenoxy] -3-trifluoromethyl-benzoylguanidine. dimaleinate; 4- [4- (2-piperidinethylaminosulfonyl) 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-ylsulfonyl) phenoxy) -benzoylguanidine; 4- (4-guanidinosulfonyl) phenoxy-3-trifluoromethyl-benzoylguanidine; 4- [4- (2-imidazolylthio-acetyl) phenoxy] -3-methylsulfonyl-benzoyl-guanidine dihydrochloride; 4- [4- (N, N'-dimethyl-S-isothionyl-acetyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride; 4- [4- (2-Benzimidazolylthio-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-methylsulfonylbenzoyl-guanidine dihydrochloride; 4- [4- (N, N-Diethylaminoethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride; 4- [4- (4-imidazolylethyl) aminosulfonyl-phenoxy] -3-methylsulfonyl-benzoylguanidine dihydrochloride; 4- [4- (3-N-imidazolyl-1-propyl) aminosulfonyl-phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride; 4- [4- (1-methyl-2-pyrrolidinylethyl) aminosulfonyl-phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride; 4- [4- (N-piperidinoethyl) aminosulfonyl-phenoxy] -3-methylsulfonyl-benzoylguanidine dihydrochloride; 4- [4- (2-dimethylaminoethyl) sulfonylmethyl-phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride; 4- [4- (2-Dimethylaminoethyl) sulfonylmethyl-phenoxy] -3-trifluoromethylbenzoylguanidine dihydrochloride. A process for the preparation of compound I according to claim 1, characterized in that the compound of formula II wherein R (1) to R (5) has a given meaning and is L for a readily nucleophilic leaving group, is reacted with guanidine, and optionally converted into a pharmacologically acceptable salt. Use of compound I according to claim 1 for the preparation of a medicament for the treatment of arrhythmias. Use of an effective amount of compound I according to claim 1 together with conventional additives for the preparation of suitable dosage forms for the treatment of arrhythmias. Use of compound I according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of a heart attack. Use of compound I according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of angina. Use of compound I according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of ischemic heart conditions. Use of compound I according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of ischemic conditions of the peripheral and central nervous system and heart attack. Use of compound I according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of ischemic conditions of peripheral organs and extremities. Use of compound I according to claim 1 for the preparation of a medicament for the treatment of conditions in shock. Use of compound I according to claim 1 for the preparation of a medicament for use in surgery and organ transplants. Use of compound I according to claim 1 for the preparation of a medicament for the preservation and storage of transplants for surgical measures. Use of compound I according to claim 1 for the preparation of a medicament for the treatment of diseases in which cell proliferation is the primary or secondary cause, and thus its use as anti-arteriosclerotic agents, agents for subsequent diabetic complications, cancers, fibrotic diseases, such as pulmonary fibrosis, liver fibrosis or renal fibrosis, prostate hyperplasia. Use of compound I according to claim 1 for the preparation of a scientific tool for inhibiting the Na ⁺ / H ⁺ exchanger for the diagnosis of hypertension and proliferative disorders. A medicament comprising an effective amount of compound I according to one or more of claims 1 to 4.