SK281567B6 - Alkaline substituted benzoyl-guanidines, method for their production, their use as a medicament or diagnostic agent - Google Patents

Abstract

Disclosed are benzoylguanidines of formula (I) wherein the meaning of the substituents is given in the description. The process for preparing said compounds is based on the reaction of a compound of formula (II) wherein the substituents are as described in formula (I) with guanidine, optionally converting the product into a pharmacologically acceptable salt. Benzoylguanidines are used as medicaments for the treatment of heart and circulatory diseases

Description

Technical field

The invention relates to basic substituted benzoylguanidines, to processes for their preparation, to their use as a medicament or diagnostic agent, as well as to medicaments containing them.

BACKGROUND OF THE INVENTION

Pyrazine derivatives of amiloride which belong to the group of substituted acylguanidines are described e.g. v Eur. Heart J. 9 (suppl. 1): 167 (1988), where the antiarrhythmic properties of amiloride are shown.

U.S. Pat. Nos. 5,091,394 and 3,781,007 disclose further benzoylguanidines, respectively. carboxylquanidines.

EP 0 556 674 discloses 3,5-substituted benzoylguanidines in which the substituent R® is not as defined herein.

SUMMARY OF THE INVENTION

The invention relates to a benzoylguanidine of formula (I) r ¹¹¹

rW o NH 3 wherein one of the three substituents R ⁽¹⁾ , R ⁽²⁾ and R ⁽³⁾ is R ⁽⁶⁾ -ABD-, wherein:

R ^<6) represents a basic protonatable radical, i.e. an amino group of the formula -NR ⁽⁷⁾ R ^<8> , an amidino group of the formula R < ⁷ ) r < ⁸ IN-C [= NR ^] - or a guanidino group of the formula _R f) R ¹¹⁰¹ R ⁽⁷⁾ , R ⁽⁸⁾ , R ⁽⁹⁾ and R ^{(10) are} each independently hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms, or R ⁽⁷⁾ and R ^{(8); )} together are C _a H _2a where a is 4, 5, 6 or 7, wherein, if a = 5, 6 or 7 may be one methyl group of the group C _a H _2a replaced by a heteroatom or a heteroatom O , SO _m or NR ^(II) , or R ⁽⁸⁾ and R ™ or R ⁽⁹⁾ and R ⁽¹⁰⁾ or R ⁽⁷⁾ and R ⁽¹⁰⁾ are C _and H _2a> where a is 2 , 3,4 or 5, wherein when a is 3, 4 or 5, one methylene group in the group may be replaced by a heteroatom or a hetero group of O, SO _m or NR ^{(I 1)} , m being 0, 1 or 2 , and

R ^{( 19)} is hydrogen or methyl or R ⁽¹⁾ is a basic heteroaromatic ring system having 1 to 9 carbon atoms,

A is CbH _2b) wherein b is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, wherein in CbH _2b one or two methylene groups may be replaced by a group selected from - O-, -CO-, -CH [OR ⁽²⁰⁾ ] -, -SOm-, -NR * ²⁰ * -, -NR ⁽²⁰⁾ -CO-, -NR ⁽²⁰⁾ -CO-NH-, -NR * ²⁰⁾ -CO-NH-SO2-, ⁽ ϊ '' * hr ' ^xb '] _m .

and wherein in the group Ct, _H2b one methylene group may be replaced by -CH-R * ⁹⁹ *, wherein R ⁽⁹⁹⁾ together with R * ⁷⁾ form a pyrrolidine or piperidine group. aa, aa is 1 or 2, bb is 0 or 1, and aa + bb = 2,

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

R * ²⁰ * represents a hydrogen atom or a methyl group, B represents a phenylene or naphthylene radical

K1121 R ™

wherein the symbols R ¹² and R ¹³ * independently of one another, are hydrogen, methyl, fluoro, chloro, bromo, iodo, trifluoromethyl or -SO _w -R ^(14>.

R * ¹ > is methyl or NR ⁽¹⁵⁾ 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 0.1 or 2,

D is -C _d H _2d -X _r , where d is 0, 1, 2, 3, or 4,

X is -O-, -CO-, -CH [OR ^(2I) ] -, -SO _m - or -NR ⁽²¹⁾ -, f is 0 or 1,

R * ² '* represents a hydrogen atom or a methyl group, m has a value of 0,1 or 2, and the remainder of the substituents R * ⁹ , R * ²⁾ and R * ³ * each independently represent a hydrogen atom, a fluorine atom, an atom chlorine, bromine, iodine, cyano, (C 1 -C 8) alkyl, (C 2 -C 8) alkenyl, -NR ( ³⁵⁾ R ^(36), or R ⁽¹⁷⁾ -C (H) -Z '; - wherein g is 0, 1, 2, 3 or 4, h is 0 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 * together represent 4-7 methylene groups, of which one methylene group may be replaced by oxygen, sulfur, -NH-, -NCH ₃ or - N-benzyl,

Z represents O, -CO-, -SO _{H -,} -NR ¹⁸ '-, -NR ⁽ⁱ⁸ CO-, -NR ^<I8, -CO-NH- or -NR ⁽⁸⁾ -SO ₂ -, where

R ⁽¹⁸⁾ is hydrogen or methyl and is 0, 1 or 2,

R * ¹⁷ * represents a hydrogen atom, a cycloalkyl group having 3, 5 or 6 carbon atoms or a C group _to F _{2k + 1} - where k is 1, 2 or 3, or R * ¹⁷ * represents pyrrol-1-yl, a pyrrol-2-yl or pyrrol-3-yl group which is unsubstituted or is substituted by one to four substituents selected from the group consisting of fluorine atom, chlorine atom,

Bromine, iodine, cyano, (C 2 -C 8) alkanoyl, (C 2 -C 8) alkoxycarbonyl, formyl, carboxyl, trifluoromethyl, methyl and methoxy, or R * ¹⁷ 'means cycloalkyl (C až-C 8) group or phenyl group which is unsubstituted or substituted by one to three substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, hydroxyl group, methoxy group, -NR group ⁽³⁷⁾ R ( ³⁸⁾ , CH ₃ SO ₂ - and H ₂ NO ₂ S - and R ⁽³⁷⁾ and R ⁽³⁸⁾ are each hydrogen or methyl; R ⁽⁴⁾ and R ^{(5) are} independently in each case a hydrogen atom, an alkyl group having 1, 2, 3 or 4 carbon atoms, a fluorine atom, a chlorine atom, a group -OR ^(32> , -NR ^(33, R ⁽³⁴⁾ or -QF _{2r + 1} ) where R ^{< 32)} , R ^(33, and R ^(J4) independently of p are each hydrogen or alkyl having 1, 2 or 3 carbon atoms; and ar is 1, 2, 3 or 4, as well as their pharmacologically acceptable salts.

Preferred are compounds of formula (I) in which

R ⁽¹⁾ represents a hydrogen atom, a fluorine atom, a chlorine atom, a C 1 -C 4 alkyl group, a C 2 -C 4 alkenyl group, an -NR ⁽³⁵⁾ R ⁽³⁶⁾ or R ⁽¹⁷⁾ -C 8 H group _2g -Zi "wherein R * ³⁵ 'and R ⁽³⁶⁾ independently of one another represent a hydrogen atom, a methyl group or an ethyl group, or R' ³⁵⁾ and R ⁽³⁶⁾ together represent 4-5 methylene groups, of which one methylene group can be replaced by oxygen, sulfur, -NH- or -NCH ₃ ,

R ^<17> represents a hydrogen atom, a cycloalkyl group having 5 or 6 carbon atoms or a group C _to F _{2k + r} , where k has a value of 1,2 or 3, g has a value of 0,1,2,3 or 4, h has a 0 or 1

Z represents O, -CO-, -SO _{H -,} -NR ¹⁸ '-, -NR ⁽¹⁸⁾ -CO-, -NR ^(1!' -CO-NH- or -NR ⁽¹⁸⁾ -SO ₂ -, wherein R ^(1s) represents a hydrogen atom or a methyl group and av is 0, 1 or 2, or, when g and h are always 0,

R ⁽¹⁷⁾ represents a pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl group which is unsubstituted or substituted by one to two substituents selected from the group consisting of fluorine atom, chlorine atom, alkanoyl group having 2 to 5 carbon atoms; C 5 -C 5 alkoxycarbonyl, C 2 -C 5 alkoxycarbonyl, formyl, carboxyl, trifluoromethyl, methyl and methoxy, or R ⁽¹⁷⁾ is C 3 -C 8 cycloalkyl or phenyl which is unsubstituted or substituted by one to two substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group, -NR ( ³⁷⁾ R ^<38) , CH ₃ SO ₂ - and H ₂ NO ₂ groups with the symbols R ^{< 37)} and R ^{<38> are} each independently hydrogen or methyl, one of R ⁽²⁾ and R ⁽³ ') is R ⁽⁶⁾ -ABD-, wherein

R * ⁶ ) represents a group of the formula -NR ⁽⁷⁾ R ⁽⁸⁾ , an amidino group of the formula R ^<7) R ^(8> NC [= NR ⁽⁹⁾ ] - or a guanidino group of the formula r17) ₍ I10)

II R ⁽⁷⁾ , R ⁽⁸⁾ , R ⁽⁹⁾ and R ^{<1 (),} independently of one another, are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms, or R ⁽⁷⁾ and R ⁽⁸⁾ together represent a C ⁸ H ⁷ group, wherein a is 4,5,6 or 7, and when a is 5, 6 or 7, one methyl group in C _and H _{21 may} be replaced by a heteroatom or a hetero group O, _SOa or NR ⁽¹¹⁾ , R ^(tl) represents a hydrogen atom or a methyl group, or R ^(s) and R ⁽⁹⁾ together represent a CaH2 group, wherein a is 2,3, 4, or 5, wherein when a is 3, 4 or 5, one methylene group in the group may be replaced by a heteroatom or a hetero group of O, SO _m or NR ⁽¹¹⁾ , m is 0.1 or 2, or R ^{(s) )} means an imidazolyl, pyridyl, quinolinyl or isoquinolinyl group,

A is C _b H _2b , where b is 1, 2, 3, 4, or 5, wherein in the group CH ₂ B, one or two methylene groups may be replaced by a group selected from the group consisting of -O-, -CO-, - CH [OR ⁽²⁰⁾ ] -, -SO 2 -, -NR ⁽²⁰⁾ -, -NR ^(M) -CO-, -NR ⁽²⁰⁾ -CO-NH-, -NR ⁽²⁰⁾ -CO-NH- SO2-,

R ^C> NS 'and -SO ^ ⁹ ^ fnr -, and wherein in CBH _2b may be one methylene group replaced by -CH-R ⁽⁹⁹⁾ where R ⁽⁹⁹ * together with the symbol R ^<7) consists of a pyrrolidine or piperidine ring, aa is 1 or 2, bb is 0 or 1, and aa + bb = 2,

R < ⁹ > represents a hydrogen atom or an alkyl group having 1,

2, 3 or 4 carbon atoms; and

R ⁽² °) represents a hydrogen atom or a methyl group,

B represents a phenylene or naphthylene residue "(13

1 (113)

wherein R ⁽¹²⁾ and R ⁽¹³⁾ are each independently hydrogen, methyl, fluoro, chloro, trifluoromethyl or -SO ₂ -R ⁽¹⁴⁾ ,

R ⁽¹⁴⁾ is methyl or nr ⁵ > r < ¹⁶ , R ^{(16 )} and R ⁽¹⁶⁾ independently of each other are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms,

D is -C _d H _M -X (-, wherein d is 0, 1, 2, 3, or 4,

X is -O-, -CO-, -CH [OR ⁽²¹⁾ ] -, -SO _m - or -NR ⁽²¹⁾ -, f is 0 or 1,

SK 281567 Β6

R ^<211 represents a hydrogen atom or a methyl group, m is 0, 1 or 2, and the other of R ⁽²⁾ and R ^<3) represents a hydrogen atom, an alkyl group having 1, 2, 3 or 4 carbon atoms, an atom R ⁽⁴⁾ and R ^(5), independently of one another, are hydrogen, alkyl having 1, 2 or 3 carbon atoms, fluorine, chlorine or trifluoromethyl and their pharmacological means acceptable salts.

Particularly preferred are compounds of formula (I) in which

R ⁽¹⁾ is hydrogen, F, Cl, alkyl having 1, 2, 3 or 4 carbon atoms, -NR ⁽³⁵⁾ R ⁽³⁶⁾ and R ⁽¹⁷⁾ -C _g H _{2 g} Z _b - where g is 0, 1, 2, 3 or 4, h is 0 or 1,

Z is O, -CO-, -SOy-, -NR ⁽¹⁸⁾ -, -NR ⁽¹⁸⁾ -CO-, -NR ^, 18'-CO-NH- or -NR ⁽¹⁸⁾ -SO ₂ - wherein R ⁽¹⁸⁾ is hydrogen or methyl and is 0, 1 or 2,

R ⁽¹⁷⁾ represents a hydrogen atom, a cycloalkyl group having 5 or 6 carbon atoms or a trifluoromethyl group or, when g and h are each 0,

R ^<17) represents a pyrrol-1-yl group which is unsubstituted or is substituted by one to two substituents selected from the group consisting of fluorine atom, chlorine atom, C2 -C5 alkanoyl group, C2 -C5 alkoxycarbonyl group , trifluoromethyl and methyl, or R ⁽¹⁷⁾ represents a cycloalkyl group having 5 to 6 carbon atoms or a phenyl group which is unsubstituted or substituted by one substituent selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, CH ₃ SO ₂ -and H ₂ NO ₂ R ⁽³⁵⁾ and R ^{(36) are} each independently hydrogen, methyl or ethyl, or R ^'35> and R ^(3C) together represent 4 -5 methylene groups of which one methylene group may be replaced by oxygen, sulfur, -NH-, or -NCH ₃ , one of R ⁽²⁾ and R ⁽³⁾ is R ⁽⁶⁾ -ABD-, wherein

R ^<6) represents a group of the formula -NR ^<7) R ⁽⁸⁾ , an amidino group of the formula R ( ⁷ * R ^<8 * NC [= NR ⁽⁹⁾ J- ⁾ or a guanidino group of the formula rT7> R ¹¹⁰¹

R ' ⁷ ' represents a hydrogen atom or an alkyl group having 1, 2, 3 or 4 carbon atoms, R ⁽⁸⁾ , R ⁽⁹⁾ and R * ¹⁰ 'independently represent a hydrogen atom, a methyl group or an ethyl group, or R ⁽⁷⁾ and R ^(8> together represent C _and H _2a where a is 4 or 5, and if a is 5, one methylene group in C _and H _{2a may} be replaced NR ^(II) , R ⁽¹¹⁾ is hydrogen or methyl, or R ⁽⁶⁾ is imidazolyl or pyridyl,

A represents a C 1 H _2b group wherein b is 1, 2, 3, 4 or 5, wherein in the C ₂ H _2b group one or two methylene groups may be replaced by a group selected from the group consisting of -CO-, -CH [OR ⁽²⁰⁾ ] -, -NR ^<20) -CO-, (0) «·

R <»o> HS-SOJNR ^ V-SO, .-, and wherein in CBH _2b may be one methylene group replaced by -CH-R ^(991, where R ^(<W), together with the symbol R ^{<7 )} form a pyrrolidine or piperidine ring, aa is 1 or 2, bb is 0 or 1, and aa + bb = 2,

R ⁽⁹ ) represents a hydrogen atom or an alkyl group having 1,

2,3 or 4 carbon atoms; and

R ⁽²⁰⁾ represents a hydrogen atom or a methyl group or, if b is 2, 3, 4 or 5, one carbon atom in the group ΟΗ _{21) may} be replaced by -O-, -S-, -NR ^<20) -, -NR ⁽²⁰⁾ -CO- or -NR ⁽²⁰⁾ -CO-NH-,

B represents a phenylene residue, 1121

, (131 wherein R ^<12) and R ⁽¹³⁾ independently of one another are hydrogen, methyl, fluorine, chlorine, trifluoromethyl or -SO2-R ⁽¹⁴⁾ , R < ¹⁴ »represents a methyl group or NH2,

D is -CH ₂ -, -O-, -CO-, -SO _m - or -NR ^(2I) -, m is 0 or 2,

R ⁽²¹⁾ represents a hydrogen atom or a methyl group, and the remainder of the substituents R ⁽²⁾ and R ⁽³ 'represents a hydrogen atom, R ⁽⁴⁾ and R ⁽⁵⁾ independently of each other represent a hydrogen atom, an alkyl group having 1 , 2 or 3 carbon atoms, fluorine atom, chlorine atom or trifluoromethyl group, as well as their pharmacologically acceptable salts.

Particularly preferred are compounds of formula (I) in which

R ⁽¹⁾ is hydrogen, F, Cl, alkyl having 1, 2, 3 or 4 carbon atoms, -NR ⁽³⁵⁾ R ⁽³⁶⁾ and R ^(l7) -C _g H _{2 g} Z _h - where g is 0 or 1, h is 0 or 1,

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

R ⁽¹⁸ ) represents a hydrogen atom or a methyl group or, when g is 1,

Z is -SO ₂ -,

R * ¹⁷ ) is hydrogen or trifluoromethyl, R ⁽³⁵ 'and R ^<36 ' independently of each other are hydrogen, methyl or ethyl, or R ^'35) and R * ³⁶ * together are 4- 5 methylene groups, of which one methylene group can be replaced by oxygen, sulfur,

-NH- or -NCH ₃ , one of R ⁽²⁾ and R * ³ * is R ^(D) -ABO-, wherein

R ⁽⁶⁾ is -NR ^(7, R ^<8) or guanidino

SK 281567 Β6

B ™ '

R ⁽⁷⁾ is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms, R ⁽⁸ ', R ⁽⁹⁾ and R * ¹⁰ ) are each independently hydrogen, methyl or ethyl, or R ⁽⁷⁾ and R ⁽⁸⁾ together represent a C group Jija where a is 4 or 5, and if a is 5, one methylene group in C _and H _{2a may} be replaced by -NH or -NCH ₃ -, or R ⁽⁶⁾ is an imidazolyl group,

A represents Cy-I _2b , wherein b is 1, 2, 3 or 4, wherein in the CbH _2b group one or two methylene groups may be replaced by a group selected from -CO-, (O) u ··

- «'• a-sINN' ¹ ''!» »

-SO ^ 'V-SO, and wherein the CBH _2b group can be a methylene group is replaced by -CH-R ^<99), where R ^<99), together with the symbol R® may form a pyrrolidine or piperidine ring, or where b is 2, 3 or 4, one methylene group in CbH _{2b may} be replaced by -O or -S-, aa is 1 or 2, bb is 0 or 1, and aa + bb = 2,

R * ¹⁹ »represents a hydrogen atom or an alkyl group having 1,

2, 3 or 4 carbon atoms; and

R ⁽²⁰ > represents a hydrogen atom or a methyl group,

B represents a phenylene residue (R)

, t13) wherein R ⁽¹²⁾ and R ⁽¹³⁾ are each hydrogen, and the rest of R @ 1 and R @ ^{2 are} hydrogen, and R * ⁴ 'and R @ ² are both hydrogen and pharmacologically acceptable salts.

Particularly preferred are compounds selected from the group consisting of

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

4- [4- (4-metylpiperazinosulfonyl) phenoxy] -3-triíluórmetylbenzoylguanidín dihydrochloride,

4- [4- (2-pyrolidínetylaminosulfonyl) phenoxy] -3-trifluónnetylbenzoylguanidín-dimaleate

4- [4- (2-piperidínetylaminosulfonyl) phenoxy] -3- trifluoromethylbenzoylguanidine dimaleate

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

4- [4- (N-dimethylaminoethyl) sulfamoyl] phenoxy-3-trifluónnetylbenzoylguanidin,

4- (4-imidamidosulfonyl) phenoxy-3-trifluoromethylbenzoylguanidine,

3-Trifluoromethyl-4- (4-N-methylimidamidosulfonyl) phenoxybenzoylguanidine,

3-Methyl-4- (4- (1-methylpiperazin-4-ylsulfonyl) phenoxy) benzoylguanidine

4- (4-guanidinosulfonyl) phenoxy-3-trifluoromethylbenzoylguanidine,

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

4- [4-N, N-dimethyl-S-isothiouronylacetyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride;

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

4- [4- (2-N-imidazolyl-1-hydroxyethyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride,

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

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

4- [4- (4-imidazolylethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride;

4- [4- (3-N-imidazolyl-1-propyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoylguanidine-dihydrochloride,

4- (4- (1-methyl-2-pyrrolidinylethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride;

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

4- [4- (2-dimethylaminoethyl) sulfonylmethylphenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride; and

4- [4- (2-dimethylaminoethyl) sulfonylmetylfenoxy] -3-trifluoromethylbenzoylguanidine dihydrochloride. _

Said alkyl radicals may be either straight-chain or branched. . _μ

The basic heteroaromatic ring system having 1 to 9 carbon atoms is understood in particular to be radicals. which are derived from a cyclopentyl, phenyl or naphthyl group in which one or more CH groups have been replaced with nitrogen. In particular, the term heteroaryl means an imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, quinolyl or isoquinolyl group. Halogen is fluorine, chlorine, bromine or iodine.

When the compounds of formula (I) contain centers of asymmetry, formula (I) includes both the individual optical antipodes and their possible enantiomeric mixtures.

The invention further relates to a process for the preparation of compounds of formula (I), characterized in that the compound of formula (II)

(II), wherein the radicals R @ 1 to R @ 2 are as defined above and L represents a readily nucleophilically substitutable leaving group, is reacted with guanidine and that the product is optionally converted to a pharmacologically acceptable salt.

The activated acid derivatives of the formula (II) in which L represents an alkoxy group, in particular a methoxy group, a phenoxy group, a phenylthio group, a methylthio group, a 3-pyridyloxy group, a 2-pyridylthio group or a nitrogen heterocyclic group, especially a 1-imidazolyl group starting carboxylic acid chlorides (general formula (II), L represents a chlorine atom), which in turn can be produced

In a known manner starting from carboxylic acids (general formula (II), L represents a hydroxyl group), for example by reaction with thionyl chloride.

In addition to the carboxylic acid chlorides of formula (II) (where L is a chlorine atom), other activated acid derivatives of formula (II), for example methyl esters, can be directly prepared from the starting benzoic acid derivatives (formula (II), L is hydroxyl). of formula (II), wherein L is OCH 3, by reaction with hydrogen chloride gas in methanol, imidazolides of formula (II), by reaction with carbonyldiimidazole (L is 1-imidazolyl, Staab, Angew. Chem. Int. Ed. Engl. 1, 351-367 (1962)), mixed anhydrides of formula (II) by reaction with CICOOC 2 H 5 or tosyl chloride in the presence of triethylamine in an inert solvent, and also activation of benzoic acids with dicyclohexylcarbodiimide (DCC) or O - [(cyano (ctoxycarbonyl) methylene) amino] -1,1,3,3-tetramethylsuronium 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 producing activated carboxylic acid derivatives of formula (II) are listed in the literature list: J. March, Advanced Organic Chemistry, Third Edition (John Wiley and Sons, 1985), page 350.

The reaction of the activated carboxylic acid derivative of formula (I) with guanidine is carried out in a known manner in a protic or aprotic polar but inert organic solvent. In the reaction of methyl benzoate (formula II), L is OCH 3) with guanidine, methanol, isopropanol or tetrahydrofuran are conveniently used at a temperature of from 20 ° C to the boiling point of these solvents. Most often, the reaction of the compounds of formula (II) with salt-free guanidine is preferably carried out in an aprotic inert solvent such as tetrahydrofuran, dimethoxyethane, dioxane or isopropanol. However, water can also be used as a solvent in the reaction of a compound of formula (II) and (III) using a base such as sodium hydroxide.

When L represents a chlorine atom, it is preferable to add an acid-binding agent, for example in the form of excess guanidine, to bind the hydrohalic acid.

The starting derivatives of benzoic acids are partly known. They are prepared by methods known in the literature when, for example, the finished residue R ^(6, -ABC _d H _{2 d} -X _r or its precursor is introduced in exchange for halogen into the benzoic acid derivative of the general formula (III).

Wherein R 'represents a lower alkyl radical such as a methyl or ethyl group and R represents a halogen atom. The reactions are described in the literature, for example as a nucleophilic substitution reaction, as a radical Ullmann reaction or as a palladium catalyzed reaction.

The introduction of benzolsulfonamide derivatives substituted on the phenyl moiety nucleophilically with sulfur, oxygen or nitrogen is accomplished by methods of nucleophilic substitution of aromatics known in the literature. The halide and trifluoromethanesulfonate groups have proven to be cleavable groups on the benzoic acid derivatives in these substitutions. The reaction is preferably carried out in a dipolar aprotic solvent such as N, N-dimethylformamide (DMF) or N, N, N ', N'-tetramethylurea (TMU) at a temperature of from 0 ° C to the boiling point of the solvent, preferably from 80 ° C. to the boiling point of the solvent. Preferred acid binding agents are alkali metal or alkaline earth metal salts with an anion of higher basicity and lower nucleophilicity, for example potassium carbonate or cesium carbonate.

The compounds R ⁽⁶⁾ -ABC _d H _{2d R-X} used as precursors are largely known and can be also purchased as reagents. Their preparation is carried out by methods known from the literature known to the skilled person.

The introduction of certain substituents at the 4 and 5 positions is accomplished by methods known in the literature by means of palladium-mediated cross-coupling of aryl halides with, for example, organostanates, organic boron acids or organoborates or organic copper or zinc compounds.

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

The compounds of formula (I) are substituted acylguanidines.

The most prominent representative of the acylguanidines is the pyrazine derivative amiloride, which is used in therapy as a potassium-sparing diuretic. A number of other amiloride-type compounds have been described in the literature, such as dimethylamiloride or ethylisopropylamiloride.

R '

NH

II II

Amiloride: R and R are each hydrogen

Dimethylamiloride: R and R are each methyl

Ethylisopropylamiloride: R is C ₂ H _5, R is CH _{(CH}) 2}

In addition, studies are known which point to the antiarrhythmic properties of amiloride (Circulation 79, 1257-1263 (1989)). However, wider use as an antiarrhythmic agent is hampered by the fact that the antiarrhythmic effect is only weak and is accompanied by blood pressure lowering and saluretic effects, and these side effects are undesirable in the treatment of cardiac rhythm disorders.

References to the antiarrhythmic properties of amiloride have also been obtained in experiments on isolated animal hearts (Eur. Heart J. 9 (suppl. 1): 167 (1988) (book of abstracts)). Thus, for example, it has been found in the rat's heart that artificially induced cardiac oscillations can be completely suppressed by amiloride. Even more potent than amiloride, the amiloride derivative, ethylisopropylamiloride, was reported in this model.

U.S. Pat. No. 5,091,394 (HOE 89 / F 288) describes benzoylguanidines which, in the position corresponding to the radical R ^(1), carry only a hydrogen atom and in which none of the substituents represents the group R ^(5, -ABD). 556,674 A (HOE 92 / F 034) proposes 3,5-substituted benzoylguanidines in which

However, the substituent R ^p) does not have the meaning of R ^(s) -ABD- according to the invention.

U.S. Pat. No. 3,780,027 claims acylguanidines which are structurally similar to the compounds of formula (I) and are derived from commercially available diuretics such as bumetanide. Accordingly, these compounds have a strong salidiuretic activity.

It is therefore surprising that the compounds of the invention exhibit no undesirable and unfavorable salidiuretic properties, but exhibit very good antiarrhythmic properties against such arrhythmias, which occur, for example, in symptoms of oxygen deficiency. Due to their pharmacological properties, the compounds of the invention are very suitable as antiarrhythmic drugs with a cardioprotective component for the prophylaxis of infarction and the treatment of infarction as well as for the treatment of angina pectoris, while also preventing or severely inhibiting pathophysiological processes. cardiac arrhythmias. Because of their protective effects against pathological hypoxic or ischemic conditions, the compounds of the formula (I) can be used as medicaments for the treatment of all acute or chronic disorders caused by ischemia or primary or secondary induced diseases due to inhibition of the cellular Na ⁺ / H ⁺ exchange mechanism. . This relates to their use as medicines for surgical procedures, for example in organ transplants, which compounds can be used as protection of organs in the body of the donor before and during organ removal, for protection of organs taken, for example in handling or storing organs in physiological fluids as well as in transmission to the recipient organism. These compounds are also valuable protective drugs for performing angioplastic surgeries, for example on the heart as well as on peripheral vessels. In view of their protective action against ischemic-induced disorders, the compounds of the invention are also useful as medicaments for the treatment of ischemia of the nervous system, in particular of the central nervous system, for example useful for the treatment of stroke or cerebral edema. In addition, the compounds of the formula I according to the invention are also suitable for the treatment of various forms of shock, such as allergic, cardiogenic, hypovolemic and bacterial shock.

In addition, the compounds of the formula (I) according to the invention are characterized by a potent inhibitory action on cell proliferation, for example fibroblast cell proliferation and vascular smooth muscle cell proliferation. Therefore, the compounds of formula (I) are suitable as effective therapeutics for diseases in which cell proliferation is a primary or secondary cause and can therefore be used as anti-atherosclerotic agents, anti-late diabetic complications, anti-cancer, anti-fibrotic diseases such as lung fibrosis, liver fibrosis or kidney fibrosis and against hypertrophies and hyperplasia of organs, in particular hyperplasia of the officers, and possibly hypertrophies of the officers.

The compounds of the invention are potent inhibitors of the Na ⁺ / H ⁺ cellular exchange system, which in numerous diseases (essential hypertonia, atherosclerosis, diabetes, etc.) is also increased in cells readily accessible for measurement, such as erythrocytes, platelets or leukocytes. Thus, the compounds of the invention are useful as excellent and simple scientific tools, for example in their use as diagnostic agents to determine and distinguish certain forms of hypertonia, but also atherosclerosis, diabetes, proliferative diseases, etc. In addition, the compounds of formula (I) are useful in preventive therapies to prevent the development of high blood pressure, such as essential hypertonia.

In addition to the very strong Na ⁺ / H ⁺ exchange inhibitory action, the compounds of the invention exhibit substantially improved aqueous solubility over the known compounds. Therefore, they are substantially more suitable for intravenous administration.

Drugs containing a compound of formula (I) may be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred route of administration being dependent on the particular disease manifestations. The compounds of formula (I) may be used alone or together with galenic auxiliaries used in both veterinary and human medicine.

The person skilled in the art is familiar on the basis of his expert knowledge with which excipients are suitable for the desired drug formulation. In addition to solvents, gelling agents, suppository bases, tablet excipients and other active compound carriers, for example, antioxidants, dispersants, emulsifiers, antifoams, flavorants, preservatives, solubilizers or colorants can be used.

For oral use, the active compounds are admixed with excipients suitable for this purpose, such as carriers, stabilizers or inert diluents, and are converted into suitable dosage forms such as tablets, dragees, push-fit capsules and aqueous, alcoholic or oily solutions by conventional means. As inert carriers, for example, gum arabic, magnesium, magnesium carbonate, potassium phosphate, milk sugar, glucose or starches, in particular corn starch. The preparation can be carried out in the form of both dry and wet granules. Suitable oil carriers or solvents, for example, vegetable or animal oils such as sunflower oil or fish oil.

For subcutaneous or intravenous administration, the active compounds, if desired together with substances customary for this purpose, such as solubilizers, emulsifiers or other excipients, are formulated as a solution, suspension or emulsion. Suitable solvents are, for example, water, physiological saline or an alcohol, for example ethanol, propanol, glycerin, and also sugar solutions, such as glucose or mannitol solutions, or mixtures of the various solvents mentioned.

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

If desired, the formulation may also contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers as well as a propellant. Such a preparation usually contains the active ingredient in a concentration of from about 0.1 to 10, in particular, from about 0.3 to 3% by weight.

The dosages of the active compound of the formula I administered and the frequency of administration depend on the potency and duration of action of the compounds used and, moreover, on the type and severity of the disease to be treated as well as the sex, age, weight and individual response of the mammal being treated.

On average, the daily dose of a compound of formula (I) in a patient weighing about 75 kg is at least 0.001 mg / kg, preferably 0.01 mg / kg, up to at most 10 mg / kg, preferably up to 1 mg / kg body weight. In the event of an acute outbreak of the disease, for example immediately after

However, even higher and, in particular, more frequent doses, for example up to 4 sub-doses per day, may be required. In particular for intravenous use, for example in patients with an infarction in an intensive care unit, doses of up to 200 mg per day may be necessary.

DETAILED DESCRIPTION OF THE INVENTION

General process for the preparation of benzoylguanidines of the general formula (I)

Variant A: from benzoic acids (general formula (II) in which L is a hydroxyl group)

0.01 mol of the benzoic acid derivative of the formula (Π) is dissolved or suspended in 60 ml of anhydrous tetrahydrofuran and then 1.78 g (0.011 mol) of carbonyldiimidazole are added. The mixture was stirred at room temperature for two hours and then 2.95 g (0.05 mol) of guanidine was added to the reaction solution. The mixture is stirred overnight, then tetrahydrofuran is distilled off under reduced pressure on a rotary evaporator, water is added, the pH is adjusted to 6-7 with 2N hydrochloric acid and the corresponding benzoylguanidine (I) is filtered off. The benzoylguanidines thus obtained can be converted to the corresponding salts by treatment with aqueous, methanolic or ethereal hydrochloric acid or other pharmacologically acceptable acids.

General process for the preparation of benzoylguanidines of the general formula (I)

Variant B: from benzoic acid alkyl esters (Formula II) wherein L is O-alkyl) mmol of benzoic acid alkyl ester of Formula (II) and 25 mmol of guanidine (free base) are dissolved in 15 mL of isopropanol or suspended in 15 ml of tetrahydrofuran and the solution or suspension obtained is heated to reflux until the reaction is complete (thin layer chromatography is used to control the reaction), typically a reaction time of 2 to 5 hours. The solvent was distilled off under reduced pressure on a rotary evaporator, the residue was taken up in 300 ml of ethyl acetate and washed three times with 50 ml of sodium bicarbonate solution each time. It is dried over sodium sulphate, the solvent is distilled off in vacuo and the residue is chromatographed on silica gel using a suitable eluent, for example a 5: 1 mixture of ethyl acetate and methanol. (Salt formation takes place as in variant A).

Example 1

4- (4-aminosulfonyl) phenoxy-3-trifluoromethylbenzoylguanidine

a) 4-Fluoro-3-trifluoromethylbenzoic acid methyl ester g 4-Fluoro-3-trifluoromethylbenzoic acid and 9 ml SOCl 3 are stirred in 50 ml methanol for 8 hours at 60 ° C. To this end, the volatiles were removed in vacuo to give 5.1 g of a colorless oil which was used without further purification.

Rf (eluent; ethyl acetate / methanol 10: 10: 1) = 0.74

Mass spectrometry (desorption chemical ionization, DCI): 223 (M + H) ⁺

b) 4- (4-Aminosulfonyl) phenoxy-3-trifluoromethylbenzoic acid methyl ester

890 mg of fluoride a), 690 mg of 4-hydroxybenzenesulfonamide and 1.1 g of potassium carbonate are stirred in 5 ml of N, N-dimethylformamide for 2 hours at 120 ° C. The mixture is allowed to cool to room temperature, 100 ml of saturated aqueous sodium chloride solution are added and extracted three times with 50 ml of ethyl acetate each time. After drying over sodium sulfate and removing the solvent in vacuo, 1.2 g of a colorless oil are obtained.

_Rf (eluent: dichloromethane), 0.45 MS (DCI): 376 (M + H) ⁺

c) 4- (4-Aminosulfonyl) phenoxy-3-trifluoromethylbenzoylguanidine

550 mg of methyl ester 1b) is guanylated by the method of variant B. 170 mg of amorphous powder are obtained.

Rf (eluent: ethyl acetate / methanol 10: 10: 1) = 0.50

Mass spectrometry (electrospray ionization, ES): 403 (M + H) ⁺

This material was converted to the hydrochloride. Mp> 270 ° C.

Example 2

4- [4- (N-tert-Butylimido-N'-tert-butyl) sulfainoyl] -3-trifluoromethylbenzoylguanidine dihydrochloride

a) 4-Fluorobenzenesulfonic acid Ν, Ν'-bis-tert-butylimidamide

To 900 ml of t-butylamine is added at -30 ° C 103 ml of bromine. The mixture was allowed to warm to -5 ° C and 6.6 mL of 4-fluorothiophenol was added. The mixture was warmed to room temperature and stirred at this temperature for 4 hours. It is then poured into 600 g of ice, 500 ml of ethyl acetate are added and the mixture is washed three times with 100 ml of a saturated aqueous sodium sulfite solution each time. The organic phase is then concentrated in vacuo, taken up in 500 ml of ethyl acetate and washed three times with 200 ml of a 0.6 M aqueous potassium dihydrogen phosphate solution each time. The organic phase was then stirred with 100 ml of 2N aqueous hydrochloric acid for 1 hour and then the ethyl acetate phase was removed. The aqueous phase is adjusted to pH 9 with sodium carbonate and extracted three times with 200 ml of ethyl acetate each time. After drying over sodium sulfate and removing the solvent in vacuo, it is obtained

6.4 g of a colorless oil.

_Rf (eluent: DIP) = 0.46 MS (DCI): 287 (M + H) ⁺

b) 4-hydroxybenzenesulfonic acid Ν, Ν'-tert-butylimidamide

2.9 g of 4-fluorobenzenesulfonic acid Ν, Ν'-tert-butylimidamide and 3.4 g of cesium hydroxide (monohydrate) are stirred in 25 ml of Ν, Ν, Ν ', Ν'-tetramethylurea for 8 hours at 160-170 C. The mixture was then allowed to cool to room temperature, water (100 ml) and saturated aqueous sodium bicarbonate (50 ml) were added and the mixture was extracted with ethyl acetate (3.times.100 ml). It was dried over sodium sulfate and the solvent was removed in vacuo. Chromatography on silica gel using ethyl acetate / n-heptane (1: 1) yielded 700 mg of a colorless oil.

SK 281567 Β6

_Rf (eluent: methyl tert-butyl diisopropyl ether 1: 1) = 0.27

Electron impact mass spectrometry (EI): 285 (M + H) ⁺

c) 4- [4- (N-tert-Butylimido-N'-tert-butyl) sulfamoyl] phenoxy-3-trifluoromethylbenzoic acid methyl ester

600 mg of 4-hydroxybenzenesulfonic acid Ν, Ν'-tert-butylimidamide, 468 mg of 4-fluoro-3-trifluoromethylbenzoic acid methyl ester and 2.1 g of cesium carbonate are stirred in 10 ml of Ν, Ν, Ν ', Ν'-tetramethylurea for 1.5 hours at 160 ° C. The mixture is then allowed to cool to room temperature, 100 ml of saturated aqueous sodium bicarbonate solution are added and extracted three times with 100 ml of ethyl acetate each time. After drying over sodium sulfate, the solvent is removed in vacuo. Chromatography on silica gel using diisopropyl ether as eluent gave 400 mg of a colorless oil.

_Rf (eluent: DIP) = 0.28 MS (ES): 487 (M + H) ⁺

d) 4- [4- (N-tert-Butylimido-N'-tert-butyl) sulfamoyl] phenoxy-3-trifluoromethylbenzoylguanidine

300 mg of 4- [4- (N-tert-butylimido-N'-tert-butyl) sulfamoyl] -3-trifluoromethylbenzoic acid methyl ester and 182 mg of guanidine are reacted in 10 ml of isopropanol according to the general procedure for the preparation of benzoylguanidines, variant B. to 120 mg of a colorless oil. _Rf (eluent: ethyl acetate) = 0.24 MS (FAB neutral particles, FAB): 587 (M + H) ⁺ Melting point of the dihydrochloride was 165-168 ° C.

Example 3

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

a) 4-Phenoxy-3-trifluoromethylbenzoic acid methyl ester g of 4-chloro-3-trifluoromethylbenzoic acid methyl ester, 5.9 g of phenol and 17.4 g of potassium carbonate are stirred in 100 ml of Ν, Ν-dimethylformamide for 14 hours at 110 C. The mixture was allowed to cool to room temperature, diluted with 1 L of ethyl acetate, washed twice with 200 ml of water, twice with 200 ml of 0.1 N aqueous sodium hydroxide solution and twice with 300 ml of saturated aqueous sodium chloride solution each time. After drying over sodium sulfate, the solvent is removed in vacuo. Chromatography on silica gel using ethyl acetate / n-heptane (1: 8) as eluent gave 11 g of a colorless oil.

R _r (eluent: ethyl acetate: n-heptane = 1: 8) = 0.24

Mass spectrometry (DCI): 297 (M + H) &lt; ⁺ &gt; ^.

b) 4-Phenoxy-3-trifluoromethylbenzoic acid g 4-Phenoxy-3-trifluoromethylbenzoic acid methyl ester was dissolved in 200 ml methanol, 41 ml 1 N aqueous sodium hydroxide solution was added and the mixture was stirred for 24 hours at room temperature. The methanol was then removed in vacuo, the residue diluted with water, adjusted to pH 2 with aqueous hydrochloric acid, and the precipitate was filtered off. After drying in air for 48 hours, 9.2 g of an amorphous solid is obtained.

Rf (eluent: ethyl acetate) = 0.10

Mass Spectrometry (DCI): 283 (M + H) &lt; ⁺ &gt; ^.

c) 4- (4-Chlorosulfonyl) phenoxy-3-trifluoromethylbenzoic acid 4-Phenoxy-3-trifluoromethylbenzoic acid was dissolved in 15 ml of trichloromethane and 710 µg of chlorosulfonic acid was added dropwise. The mixture was stirred for 3 hours at room temperature and then the solvent was removed in vacuo. 50 g of ice and 50 ml of water are then added, the mixture is stirred for 10 minutes and the precipitate is filtered off. 0.96 g of an amorphous solid is obtained.

Rf (eluent: diisopropyl ether with 2% acetic acid) = 0.38

MS (EI): 381 (M + H) &lt; ^{+ &gt;}

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

475 mg of 4- (4-chlorosulfonyl) phenoxy-3-trifluoromethylbenzoic acid are dissolved in 10 ml of acetone and 160 µl of trimethylethylenediamine and 350 µl of triethylamine are added. The mixture is stirred for 2 hours at room temperature, then diluted with 100 ml of water and the acetone is removed in vacuo. The pH was adjusted to 6-7 with a 0.1N aqueous hydrochloric acid solution and extracted six times with 100 ml of ethyl acetate each time. After drying over sodium sulfate and removing the solvent in vacuo, 330 mg of an amorphous solid is obtained.

Rf (8: 4: 1: 1 dichloromethane / methanol / acetic acid / water) = 0.42 MS (EI): 447 (M + H) &lt; ^{+ &gt;}

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

330 mg of 4- [4-N- (dimethylaminoethyl) methylsulfuric acid. sulfamoyl] phenoxy-3-trifluoromethylbenzoic acid and 1 ml of SOCl ₂ is _f s 10 ml of methanol for 8 hours, heated to reflux. The volatiles were removed in vacuo, the residue was taken up in 100 mL of saturated aqueous sodium carbonate solution and 100 mL of ethyl acetate, and extracted three times with 100 mL of ethyl acetate each time. After drying over sodium sulfate, the solvent is removed in vacuo. Chromatography on silica gel using ethyl acetate / methanol (2: 1) yielded 150 mg of a colorless resin.

Rf (1: 1 ethyl acetate / methanol) = 0.30

Mass spectrometry (EI): 461 (M + H) &lt; ⁺ &gt; ^.

f) 4- [4-N- (Dimethylaminoethyl) methylsulfamoyl] phenoxy-3-trifluoromethylbenzoylguanidine

140 mg of 4- [4-N- (dimethylaminoethyl) methylsulfamoyl] phenoxy-3-trifluoromethylbenzoic acid methyl ester and 90 mg of guanidine are reacted in 3 ml of isopropanol according to the general procedure for the preparation of benzoylguanidines variant B. 130 mg of amorphous solid are obtained.

Rf (1: 1 ethyl acetate / methanol) = 0.12

MS (EI): 488 (M + H) &lt; ⁺ &gt;

The compounds listed in the titles of Examples 48 were synthesized in analogy to Example 3:

Example 4 4- [4- (4-Methylpiperazinosulfonyl) phenoxy] -3-trifluoromethylbenzoylguanidine dihydrochloride

SK 281567 Β6

Rf (1: 1 ethyl acetate / methanol) = 0.15

Mass spectrometry (EI): 486 (M + H) ⁺ The melting point of the dihydrochloride is more than 250 ° C.

Example 5

4- [4- (2-Pirolidínetylammosulfonyl) phenoxy] -3- trifluoromethylbenzoylguanidine dimaleate

Rf (eluent: 8: 4: 1: 1 dichloromethane / methanol / acetic acid / water) = 0.37

FAB: 500 (M + H) &lt; ⁺ &gt; ^.

Example 6

4- [4- (2-Piperidinoethylammosulfonyl) phenoxy] -3-trifluoromethylbenzoylguanidine dimaleinate

Rf (eluent: dichloromethane / methanol / acetic acid / water = 8: 4: 1: 1) = 0.40

MS (FAB): 514 (M + H) &lt; ^{+ &gt;}

Example 7

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

Rf (1: 1 ethyl acetate / methanol) = 0.06

MS (EI): 488 (M + H) &lt; ⁺ &gt; ^.

Example 8

4- [4- (N-dimethylaminoethyl) sulfamoyl] phenoxy-3-trifluoromethylbenzoylguanidine

Rf (1: 1 ethyl acetate / methanol) = 0.17

MS (EI): 474 (M + H) &lt; ^{+ &gt;}

Example 9

4- (4-Imidamidosulfonyl) phenoxy-3-trifluoromethylbenzoylguanidine

a) 4- [4- (N-tert-Butylimido-N'-tert-Butyl) sulfamoyl] phenoxy-3-trifluoromethylbenzoic acid

7.9 g of 4- [4- (N-tert-butylimido-N'-tert-butyl) sulfamoyl] phenoxy-3-trifluoromethylbenzoic acid methyl ester (Example 2c) are dissolved in 100 ml of methanol and 40 ml of 2N aqueous solution are added. sodium hydroxide. The mixture was refluxed for 3 hours, the methanol was removed in vacuo and the residue was taken up in a mixture of 100 ml of water and 100 ml of ethyl acetate. A saturated aqueous solution of sodium hydrogen phosphate (500 ml) was added and the mixture was extracted three times with 200 ml of ethyl acetate each time. After drying over sodium sulfate and removal of the solvent in vacuo, 7.2 g of white crystals are obtained.

_Rf (eluent: dichloromethane), 0.25 MS (ES): 473 (M + H) ⁺ Melting point: 200 ° C.

(b) 4- (4-Imidosulfamoyl) phenoxy-3-trifluoromethylbenzoic acid

6.6 g of 4- [4- (N-tert-butylimido-N'-tert-butyl) sulfamoyl] phenoxy-3-trifluoromethylbenzoic acid are dissolved in 140 ml of anhydrous dichloromethane, 3.7 ml of trifluoromethanesulfonic acid are added and the mixture is stirred for 24 hours at room temperature. The mixture is stirred into 1 l of a 0.66 M aqueous potassium dihydrogen phosphate solution, the methylene chloride phase is separated, and extracted three times with 300 ml of ethyl acetate each time. The combined organic phases were dried over sodium sulfate and the solvents were removed in vacuo. 6.7 g of an oily solid are obtained, which product is used without further purification.

_Rf (eluent: ethyl acetate: methanol 5: 1) = 0.21

MS (ES): 361 (M + H) &lt; ^{+ &gt;}

(c) 4- (4-Imidosulfamoyl) phenoxy-3-trifluoromethylbenzoic acid methyl ester; and

d) 4- (4-N-methylimidosulfamoyl) phenoxy-3-trifluoromethylbenzoic acid methyl ester

6.7 g of 4- (4-imidosulfamoyl) phenoxy-3-trifluoromethylbenzoic acid are dissolved in 100 ml of methanol, added dropwise with 20 ml of a 2N solution of trimethylsilyldiazuomethane in n-heptane and stirred for 6 hours at room temperature. 200 ml of a 20% aqueous acetic acid solution are then added and the mixture is stirred for 30 minutes. 200 ml of ethyl acetate are then added and the mixture is extracted nine times with 100 ml of 1N aqueous hydrochloric acid each. The pH of the aqueous vase was adjusted to 10 with sodium carbonate, and the mixture was extracted three times with 200 ml of ethyl acetate each time. After drying over sodium sulfate, the solvent is removed in vacuo. The residue was chromatographed on silica gel using 1: 1 ethyl acetate: n-heptane as eluent to give 1.2 g of product c) and 890 mg of product d), both of which were oily.

c) R _f (eluent: ethyl acetate) = 0.32 MS (ES): 375 (M + H) ⁺

d) R _f (eluent: ethyl acetate) = 0.38 MS (ES): 389 (M + H) ⁺

e) 4- (4-Imidamidosulfonyl) phenoxy-3-trifluoromethylbenzoylguanidine

220 mg of 4- (4-imidosulfamoyl) phenoxy-3-trifluoromethylbenzoic acid methyl ester and 174 mg of guanidine are treated with

The reaction is carried out in 10 ml of tetrahydrofuran according to the general procedure for the preparation of benzoylguanidines, variant B. After chromatography on silica gel with a 5: 1 mixture of ethyl acetate and methanol, 80 mg of colorless crystals are obtained.

Rf (eluent: ethyl acetate / methanol 5: 1) = 0.22

MS (ES): 402 (M + H) &lt; ⁺ &gt;

Example 10

3-Trifluoromethyl-4- (4-N-metylimidamidosulfonyl) fenoxybenzoylguanidín

HH ⁰ MKj

490 mg of 4- (4-N-methylimidosulfamoyl) phenoxy-3-trifluoromethylbenzoic acid methyl ester (Example 9d) and 373 mg of guanidine are reacted in 20 ml of tetrahydrofuran according to the general method for producing benzoylguanidines, variant B. After chromatography on silica gel using a mixture ethyl acetate: methanol (5: 1) gave 370 mg of colorless crystals.

Rf (eluent: ethyl acetate / methanol 5: 1) = 0.33

MS (ES): 416 (M + H) ⁴ dihydrochloride mp is 233 ° C.

The title compound of Example 11 is synthesized analogously to Example 3 from 3-methyl-4-phenoxybenzoic acid methyl ester:

Príkladll

3-Methyl-4- (4- (1-methylpiperazin-4-ylsulfonyl) phenoxy) benzoylguanidine

(a) 3-Methyl-4-phenoxybenzoic acid methyl ester

3.4 g of 4-fluoro-3-methylbenzoic acid methyl ester,

2.4 g of phenol and 19.5 g of cesium carbonate are stirred in 100 ml of NMP for 20 min at 160 ^e C. The mixture was poured into 400 mL of saturated aqueous sodium bicarbonate solution, diluted with 400 ml of water and extracted three times 200 ml of methyl tert-butyl ether each. After drying over sodium sulfate, the solvent is removed in vacuo. Chromatography of the residue on silica gel using ethyl acetate / n-heptane (1: 4) as eluent gave 2.0 g of a colorless oil.

Rf (eluent: ethyl acetate / n-heptane 1: 4) = 0.33

Mass spectrometry (EI): 243 (M + H) &lt; ⁺ &gt; ^.

The title compound of Example 12 is synthesized in analogy to Example 9:

Example 12

3-methylsulphonyl-4- (4-imidamidosulfonyl) fenoxybenzoylguanidín

Rf (eluent: ethyl acetate / methanol 5: 1) = 0.24

MS (ES): 412 (M + H) &lt; ^{+ &gt;}

Example 13

4- (4-Guamdinosulfonyl) phenoxy-3-trifluoromethylbenzoylguanidine

a) 4- (4-Hydroxysulfonyl) phenoxy-3-trifluoromethylbenzoic acid

13.5 g of 4-phenoxy-3-trifluoromethylbenzoic acid (Example 3b) are dissolved in 150 ml of trichloromethane, 3.3 ml of chlorosulfonic acid are added dropwise at room temperature, and the mixture is stirred for 3 hours. The solvent is removed in vacuo, 300 g of ice and 100 ml of water are added and the mixture is stirred for 10 minutes. Then, 400 ml of saturated aqueous sodium chloride solution cooled to 0 ° C are added, the mixture is stirred for an additional 15 minutes at 0 ° C and the precipitate is filtered off with suction and dried at 40 ° C in vacuo to give 16.5 g. g of a white solid which is used without further purification.

b) 4- (4-Chlorosulfonyl) phenoxy-3-trifluoromethylbenzoyl chloride

14.0 g of 4- (4-hydroxysulfonyl) phenoxy-3-trifluoromethylbenzoic acid and 1 ml of Ν, Ν-dimethylformamide are dissolved in 250 ml of SOCl ₂ and the mixture is heated under reflux for 8 hours. Approximately half of the excess SOC1 ₂ was removed in vacuo and the solution was added dropwise to 1 kg of ice. The mixture was extracted three times with 500 ml of dichloromethane each time and after drying over sodium sulfate, the solvent was removed in vacuo. 18.0 g of an oily substance are obtained, which product is used without further purification.

Rf (eluent: diisopropyl ether with 2% acetic acid) = 0.51

c) 4- [4- (3-Pyridyloxy) sulfonyl] phenoxy-3-trifluoromethylbenzoic acid 3-hydroxypyridylester

18.0 g of 4- (4-chlorosulfonyl) phenoxy-3-trifluoromethylbenzoyl chloride are dissolved in 150 ml of acetone, 3.7 g of 3-hydroxypiridine and 11.0 g of potassium carbonate are added and the mixture is stirred for 3 hours at room temperature. The reaction mixture is poured into 500 ml of water and extracted three times with 300 ml of ethyl acetate. After drying over sodium sulfate, the solvent is removed in vacuo and chromatographed on silica gel using methyl tert-butyl ether with 2% acetic acid as the eluent to give 8.0 g of a yellowish oil.

Rf (eluent: methyl tert-butyl ether with 2% acetic acid) = 0.29

MS (FAB): 517 (M + H) &lt; ⁺ &gt; ^.

d) 4- (4-Guanidinosulfonyl) phenoxy-3-trifluoromethylbenzoylguanidine

3.0 g of 4- [4- (3-pyridyloxy) sulfonyl] phenoxy-3-trifluoromethylbenzoic acid 3-hydroxypyridyl ester and 3.4 g of guanidine are dissolved in 10 ml of isopropanol and the mixture is heated under reflux for 3 hours. The solvent is removed in vacuo, the residue is taken up in 400 ml of water, the pH is adjusted with an aqueous acid solution.

The mixture was stirred at room temperature for 2 hours. The precipitate was filtered off and subjected to silica gel chromatography using a 5: 1 mixture of ethyl acetate and methanol as eluent. 272 mg of an amorphous solid are obtained.

Rf (eluent: ethyl acetate / methanol 5: 1) = 0.33

MS (ES): 445 (M + H) &lt; ^{+ &gt;}

Example 14

3-Methylsulfonyl-4- [4- (2-dimethylaminoethyl) phenoxy] benzoyl-guanidine-bismethanesulfonate

14a) 5-Carboxy-2-fluorobenzenesulfinic acid

Sodium sulfite (15.6 g, 0.124 mol) was dissolved in water (120 ml) at 70 ° C. While maintaining the temperature, 23.8 g (0.1 mol) of 4-fluoro-3-chlorosulfonylbenzoic acid and 10N sodium hydroxide are added simultaneously and in portions, maintaining the pH between 9 and 10 (an exothermic reaction occurs). The mixture is stirred for an additional 3 hours at 70 ° C, boiled for 15 minutes with activated carbon and then filtered. The pH of the filtrate is adjusted to 0-1 with concentrated hydrochloric acid under external cooling and the crystalline 5-carboxy-2-fluorobenzenesulfinic acid is filtered off. The product is obtained in the form of colorless crystals, m.p. 167-170 ° C.

14b) 5-Carboxy-2-fluorobenzenesulfinic acid disodium salt is obtained by introducing 17.2 g (0.084 mol) of carboxy-2-fluorobenzenesulfinic acid into a stirred solution of 6.72 g (0.168 mol) of sodium hydroxide in a mixture of 150 ml methanol and 30 ml water. After filtering off the suspended solids, the solvent was distilled off and the residue was crystallized from acetone. The product is obtained in the form of a colorless crystalline substance having a melting point greater than 320 ° C.

14c) 4-Fluoro-3-methylsulfonylbenzoic acid methyl ester

To a suspension of 15 g (0.06 mol) of 5-carboxy-2-fluorobenzenesulfonic acid disodium salt in 80 ml of dry N, N-dimethylformamide is added 30 g (0.21 mol) of methyl iodide, stirred for 6 hours at 60 ° C. ° C, the solvent was distilled off and water was added to the residue. The mixture was stirred and cooled for 30 minutes and the precipitate was filtered off. The product is obtained in the form of a colorless crystalline substance, m.p. 102-105 ° C.

14d) 3-Methylsulfonyl-4- [4- (2-dimethylaminoethyl) phenoxy] benzoic acid methyl ester

4.64 g (0.02 mol) of 4-fluoro-3-methylsulfonylbenzoate are added to a mixture of 60 ml of dimethylacetamide, 3.6 g (0.022 mol) of N, N-dimethyl-2- (4-hydroxyphenyl) ethylamine and 9.08 g (0.066 mol) of powdered anhydrous potassium carbonate and the suspension is stirred for 4 hours at 90 ° C. After distilling off the solvent, water was added to the residue and extracted several times with ethyl acetate, the combined organic phases were concentrated under reduced pressure, and the title compound was obtained as a yellow oil.

14e) Preparation of 3-methylsulfonyl-4- [4- (2-dimethylaminoethyl) phenoxy] benzoic acid hydrochloride

1.88 g (0.005 mol) of 3-methylsulfonyl-4- [4- (2-dimethylaminoethyl) phenoxy] benzoic acid in 40 ml of half-concentrated hydrochloric acid is heated to reflux for 5 hours, the aqueous hydrochloric acid is distilled off and the residue is crystallized from acetone. The product is obtained in the form of a colorless crystalline substance, m.p. 246-248 ° C.

14f) 3-Methylsulfonyl-4- [4- (2-dimethylaminoethyl) phenoxy] benzoylguanidine is obtained analogously to variant A from 3-methylsulfonyl-4- [4- (2-dimethylaminoethyl) phenoxy] benzoic acid at pH Between 7 and 8. The product is obtained in the form of colorless crystals, m.p. 214-218 ° C.

3-Methylsulfonyl-4- [4- (2-dimethylaminoethyl) phenoxy] benzoyguanidine bismethanesulfonate is obtained in an analogous manner to that described in Variant A from 3-methylsulfonyl-4- [4- (2-dimethylaminoethyl) phenoxy] benzoylguanidine by reaction with 2 , 5 equivalents of methanesulfonic acid in ethanol. The product is a colorless solid with a melting point of 102 ° C.

Example 15

4- [4- (2-Dimethylaminoethyl) thiomethylphenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

15a) Preparation of 4- (2-dimethylaminoethyl) thiomethylphenol

A mixture of 200 mg of p-toluenesulfonic acid, 14.1 g (0.1 mol) of 2-dimethylaminoethyl mercaptan hydrochloride and 12.4 g (0.1 mol)

The 4-hydroxybenzyl alcohol in 250 ml of toluene was refluxed for about 5 hours using a water trap, the solvent was removed and the residue was filtered after dissolution in methanol. After re-concentration, the residue is crystallized from acetone, the crystalline product is filtered off and the slightly hygroscopic mass is dried over sodium hydroxide in the absence of air. Melting point 134-140 ° C.

15b) 4- [4- (2-Dimethylamino-ethyl) -thiomethyl-phenoxy] -3-methylsulfonyl-benzoic acid methyl ester

A mixture of 3.48 g (0.015 mol) of 4- (2-dimethylaminoethyl) thiomethylphenol, 40 ml of anhydrous tetramethylurea, 6.8 g (0.049 mol) of anhydrous potassium carbonate powder and 3.48 g (0.015 mol) of 4-fluoro-methyl ester. 3-Methylsulfonylbenzoate is stirred for 6 hours at 90-100 ° C, the solvent is distilled off and water is added to the residue. Extraction with ethyl acetate, drying and concentration of the combined organic phases gave the desired product as an oil.

15c) 4- [4- (2-Dimethylaminoethyl) thiomethylphenoxy] -3-methylsulphonylbenzoic acid hydrochloride is obtained in an analogous manner to that described in Example 14d) by hydrolyzing methyl 4-fluoro-3-methylsulphonylbenzoate in 20% hydrochloric acid. The product is obtained as a colorless to pale yellow crystalline solid, m.p. 179-185 ° C.

15d) 4- [4- (2-Dimethylaminoethyl) thiomethylphenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride is obtained in an analogous manner to that described in Example 14e) from hydrochloride

4- [4- (2-Dimethylaminoethyl) thiomethylphenoxy] -3-methylsulfonylbenzoic acid Β 6. The product is obtained in the form of a hygroscopic substance having a melting point of 230 ° C.

Example 16

4- [4- (2-Dimethylaminoethylthio) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

16a) N, N-Dimethyl-2- (4-hydroxyphenylthio) ethylamine

To a solution of 12.6 g (0.1 mol) of 4-mercaptophenol in 100 ml of anhydrous Ν, Ν-dimethylformamide was added, under argon, as a shielding gas, 17.28 g (0.11 mol) of 2-diethylaminoethyl chloride hydrochloride and then 19.38 g (0.15 mol) of ethyldiisopropylamine and the reaction mixture was heated and stirred with a magnetic stirrer at 110 ° C for 12 hours. After distilling off the solvent, water was added to the residue, the pH was adjusted to 8-9 with 2N sodium hydroxide, the amorphous precipitate was extracted several times with ethyl acetate, and the combined organic phases were dried over sodium sulfate. The solvent was distilled off and the residue was subjected to silica gel column chromatography using a mixture of 8 parts of ethyl acetate and 1 part of methanol as eluent. The product is obtained in the form of colorless crystals, m.p. 108-110 ° C.

16b) 4- [4- (2-Dimethylaminoethylthio) phenoxy] -3-methylsulfonylbenzoic acid methyl ester is obtained as a yellow oil in an analogous manner to that described in Example 14d) by reaction of N, N-dimethyl-2- (4- hydroxyphenylthio) ethylamine with 4-fluoro-3-methylsulfonylbenzoate, using N, N-dimethylformamide as the reaction medium instead of dimethylacetamide. The product is obtained as a yellow oil.

16c) 4- [4- (2-Dimethylaminoethylthio) phenoxy] -3-methylsulfonylbenzoic acid

6.8 g of methyl 4- [4- (2-dimethylaminoethylthio) phenoxy] -3-methylsulfonylbenzoate were refluxed for 5 hours in 10 ml of glacial acetic acid and 70 ml of half-concentrated hydrochloric acid. After distilling off the solvent, the desired compound is obtained in the form of an amorphous solid without defining a melting point.

(iod) 4- [4- (2-Dimethylaminoethylthio) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride is obtained in an analogous manner to that described in Variant A as a colorless solid which decomposes at 160 ° C when foaming.

Example 17

4- [4- (2-Dimetylaminoetylsulfonyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

17a) 4- [4- (2-Dimethylaminoethylsulfonyl) phenoxy] -3-methylsulfonylbenzoic acid

To a solution of 3.8 g (0.008 mol) of 4- [4- (2-dimethylaminoethylthio) phenoxy] -3-methylsulfonylbenzoic acid in 50 ml of glacial acetic acid was added portionwise at 5 -10 ° C 6.9 g (0.028) mol) of 3-chloroperbenzoic acid and the mixture is stirred for 12 hours at room temperature. After addition of water, the precipitate of 3-chlorobenzoic acid is filtered off and other impurities are extracted from the filtrate with ethyl acetate. The aqueous phase is concentrated and the amorphous residue is crystallized from ethyl acetate. The product is obtained in the form of colorless crystals, m.p. 167-171 ° C.

17b) 4- [4- (2-Dimethylaminoethylsulfonyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride is obtained analogously to variant A from 4- [4- (2-dimethylammoethylsulfonyl) phenoxy] -3-methylsulfonylbenzoic acid in Ν , Ν, Ν ', Ν'-tetramethylurea as the reaction medium. The dihydrochloride is crystallized from methanol. The product is obtained in the form of colorless crystals which melt under decomposition at 233-240 ° C.

Example 18

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

18a) 4- (4-Carboxyphenoxy) -3-methylsulfonylbenzoic acid

Reaction of ethyl 4-hydroxybenzoate with ethyl 4-fluoro-3-methylsulphonylbenzoate affords 4- (4-ethoxycarbonylphenoxy) -3-methylsulphonylbenzoic acid methyl ester as a colorless to pale oily substance in an analogous manner to that described in Example 14dj. Further purification is hydrolyzed in an analogous manner to that described in Example 16c) to give 4- (4-carboxyphenoxy) -3-methylsulfonylbenzoic acid. The product is obtained in the form of colorless crystals, m.p. 272-275 ° C.

18b) 4 - [(4-Guanidinocarbonyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride is obtained in an analogous manner to that described in Variant A by reacting 0.74 g (0.0022 mol) of (4-carboxyphenoxy) -3-methylsulfonylbenzoic acid with 0.78 g (0.0048 mol) of carbonyldiimidazole and 1.55 g (0.026 mol) of guanidine in dimethylacetamide. The product is obtained in the form of colorless crystals melting with decomposition at 252 ° C.

Example 19

4- [4- (2-dimethylaminoethyl) thiomethylphenoxy] -3-trifluoromethylbenzoylguanidine dihydrochloride

19a) 4- [4- (2-Dimethylaminoethyl) thiomethylphenoxy] -3-trifluoromethylbenzoic acid methyl ester is obtained in analogy to

By the method as described in Example 15b) from 4- (2-dimethylaminoethyl) thiomethylphenol and methyl 4-fluoro-3-fluoromethylbenzoate in Ν, Ν, Ν ', Ν'-tetramethylurea as the reaction medium in the form of amorphous oil product.

19b) 4- [4- (2-Dimethylaminoethyl) thiomethylphenoxy] -3-trifluoromethylbenzoic acid is obtained in an analogous manner to that described in Example 14d) by acid hydrolysis of 4- [4- (2-dimethylaminoethyl) thiomethylphenoxy] -3- trifluoromethylbenzoic. The product is obtained in the form of colorless hygroscopic crystals melting at 158-168 ° C with decomposition.

19c) 4- [4- (2-Dimethylaminoethyl) thiomethylphenoxy] -3-trifluoromethylbenzoylguanidine dihydrochloride is obtained analogously to variant A from 4- [4- (2-dimethylaminoethyl) thiomethylphenoxy] -3-trifluoromethylbenzoic acid in Ν , Ν, Ν ', Ν'-tetramethylurea as the reaction medium. The product is obtained as an amorphous, strongly hygroscopic solid decomposing at 80-85 ° C.

Example 20

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

20a) 4- [4- (2-Dimethylaminoethylthio) phenoxy] -3-trifluoromethylbenzoic acid methyl ester was obtained in an analogous manner to that described in Example 15b) from 4- (2-dimethylaminoethylthio) phenol and 4-fluoro-3- methyl ester trifluoromethylbenzoic acid in N, N, N ', N'-tetramethylurea as the reaction medium in the form of an amorphous oily product.

20b) 4- [4- (2-Dimethylaminoethylthio) phenoxy] -3-trifluoromethylbenzoic acid was obtained in an analogous manner to that described in Example 14d) by acid hydrolysis of 4- [4- (2-dimethylaminoethylthio) phenoxy] -3- trifluoromethylbenzoic. The desired 4- [4- (2-dimethylaminoethylthio) phenoxy] -3-trifluoromethylbenzoic acid is crystallized from acetone. The product is obtained in the form of colorless crystals melting at 174-182 ° C with decomposition.

20c) 4- [4- (2-Dimethylaminoethylthio) phenoxy] -3-trifluoromethylbenzoylguanidine dihydrochloride is obtained analogously to variant A from 4- [4- (2-dimethylaminoethylthio) phenoxy] -3-trifluoromethylbenzoic acid in tetrahydrofuran as a reaction medium. The product is obtained as an amorphous, hygroscopic crystalline solid, m.p. 240 ° C.

Example 21

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

21a) 4-Chloro-3-trifluoromethylbenzoic acid

From 100 g of 5-bromo-2-chlorobenzotrifluoride and 10.2 g of magnesium in 600 ml of diethyl ether, the Gngnard compound is first prepared. A stream of 60 g of anhydrous carbon dioxide is then introduced into this solution at room temperature. 500 ml of saturated aqueous sodium hydrogen sulphate solution are added dropwise, the phases are separated and extracted twice more with 100 ml of diethyl ether. The organic phase is extracted three times with 300 ml of 1N sodium hydroxide each and then the aqueous phase is washed three times with 100 ml of diethyl ether each time. The pH of the aqueous phase is adjusted to 2 with hydrochloric acid and the mixture is diluted to 4 L with water. The product is filtered off with suction and dried in vacuo. 75 g of a white powder are obtained.

Rf (eluent: methyl tert-butyl ether with 2% acetic acid) = 0.68

21 b) Methyl 4-chloro-3-trifluónnetylbenzoovej g of 4-chloro-3-trifluórmetylbenzoovcj was dissolved in 500 ml of methanol and added dropwise to 75 ml SOC1 _second The mixture was refluxed for 5 hours and then the volatiles were removed in vacuo. After removal of 1 L of ethyl acetate, washing with 500 ml of saturated aqueous sodium carbonate solution and drying over sodium sulfate, the solvent is removed in vacuo and distillation is carried out in vacuo. The boiling point of the product is 94 [deg.] C. (at a pressure of 266.6 Pa). Rf (eluent: diisopropyl ether) = 0.49 Mass Spectrometry (DCI): 239 (M + H) ⁺

21c) 4- [4- (2-Dimethylamino) ethyl] phenoxy-3-trifluoromethylbenzoic acid methyl ester

1.9 g of 4-chloro-3-trifluoromethylbenzoic acid methyl ester, 1.3 g of 4- (2-dimethylamino) ethylphenol and 7.8 g of cesium carbonate are stirred in 50 ml of tetramethylurea for 5 hours at 140 ° C. The mixture is allowed to cool, then 300 ml of saturated aqueous sodium bicarbonate solution and 150 ml of water are added and the mixture is extracted three times with 100 ml of ethyl acetate each time. After drying over sodium sulfate, the solvents are removed in vacuo. Chromatography using acetone: water (10: 1) as eluent gave 2.0 g of a colorless oil.

Rf (eluent: acetone / water 10: 1) = 0.15 mass spectrometry (DCI): 368 (M + H) &lt; ^{+ &gt;}

d) 4- [4- (2-Dimethylamino) ethyl] phenoxy-3-trifluoromethylbenzoylguanidine

2.0 g of methyl 4- [4- (2-dimethylamino) ethyl] phenoxy-3-trifluoromethylbenzoic acid ester are guanylated with 1.6 g of guanidine in 60 ml of isopropanol according to variant B. The crude product is converted to the dihydrochloride and recrystallized from 1 2: 2-dimethoxyethane / water 9: 1. The melting point of the free base is 164 ° C, the melting point of the dihydrochloride is 236 ° C.

Mass spectrometry (DCI): 395 (M + H) ⁺ The water solubility of the dihydrochloride is 49 mg / ml (pH = 5.3).

SK 281567 Β6

Example 22

4- (4-N, N-Dimethylaminoethylphenoxy) -3-sulfamylbenzoyl-guanidine bis-methanesulfonate

is obtained in an analogous manner to that described for Variant A from 4- [4- (2-dimethylaminoethyl) phenoxy] -3-sulfamoylbenzoic acid in dimethylacetamide or N-methylpyrrolidone as the reaction medium. The product is obtained as an amorphous, hygroscopic, crystalline solid, m.p. 183 ° C.

a) 4- [4- (2-Dimethylaminoethyl) phenoxy] -3-sulfamoylbenzoic acid methyl ester is obtained by heating 0.011 mol of N, N-dimethyl-2- (4-hydroxyphenyl) ethylamine, 0.033 mol of ground potassium carbonate and 0.01 mol methyl ester of the acid

Of 4-fluoro-3-sulfamoylbenzoic acid in 40 ml of dimethylacetamide for 5 hours at 90-100 ° C. After distilling off the solvent, the residue is stirred with water, ethyl acetate is added to the brown amorphous product, the crystalline precipitate is filtered off and the solvent is distilled off from the filtrate. An amorphous oily product is obtained.

b) 4- [4- (2-Dimethylaminoethyl) phenoxy] -3-sulfamoylbenzoic acid is obtained 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, acetone was added to the residue and the precipitate was filtered off. The solvent was distilled off to give the desired benzoic acid softening at 60 ° C.

Example 23

3-Chloro-4- [4- (2-dimethylaminoethyl) phenoxy] -5-methylsulphonylbenzoylguanidine-bismethanesulphonate H-H is obtained in an analogous manner to that described in Variant A from 3-chloro-4-acid. - [4- (2-dimethylaminoethyl) phenoxy] -5-methylsulfonylbenzoic acid in dimethylacetamide or N-methylpyrrolidone as reaction medium. The product is obtained as a hygroscopic crystalline solid with a melting point of 200 ° C.

a) 3-Chloro-4- [4- (2-dimethylaminoethyl) phenoxy] -5-methylsulfonylbenzoic acid methyl ester was obtained in a manner analogous to Example 22a) by reaction of 3,4-dichloro-5-methylsulfonylbenzoic acid methyl ester with N, N- dimethyl 2- (4-hydroxyphenyl) ethylamine as an amorphous oil.

b) 3-Chloro-4- [4- (2-dimethylaminoethyl) phenoxy] -5-methylsulfonylbenzoic acid was obtained analogously to Example 22a) as a crystalline solid decomposing at 238-240 ° C.

Example 24

4 - [(4-Guanidinocarbonyl) phenoxy] -3-methylsulfonylbenzoylguanidine

is obtained as a base which is not in the form of the salt of Example 18 by reaction of 4 - [(4-guanidinocarbonyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride with triethylamine in Ν, Ν-dimethylformamide. The product is obtained as a colorless crystalline solid, m.p. 237 ° C.

Example 25

4- [4- (2-N-Imidazolyl-1-oxoethyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

o HH, obtained in an analogous manner to that described in variant A from 4- [4- (2-N-imidazolyl-1-oxoethyl) phenoxy] -3-methylsulfonylbenzoic acid in dry dimethylacetamide or N-methylpyrrolidone as the reaction medium in the form of colorless crystalline solid decomposing at 255 ° C.

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

To a mixture of 0.08 mol of chloroacetyl chloride, 16 g of anhydrous aluminum chloride and 150 ml of 1,2-dichloroethane at 0-5 ° C was added portionwise 0.02 mol of 3-methylsulfonyl-4-phenoxybenzoic acid, the mixture was stirred for 2 hours. hours at room temperature and then stirred for 2 hours at 40-45 ° C. The reaction mixture was allowed to stand overnight, then poured into ice water with stirring, the crystalline precipitate was filtered off, washed with water and dried. The product is obtained in the form of yellow crystals, m.p. 184-187 ° C.

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

A solution of 0.005 mol of 4- (4-chloroacetylphenoxy) -3-methylsulfonylbenzoic acid (from Example 25a) in 25 ml of anhydrous Ν, Dim-dimethylformamide is stirred with 0.0225 mol of imidazole for 4 hours at 60 ° C and then the solvent is distilled off. . Water is added to the amorphous residue, the pH is adjusted to 2-3 with 2N hydrochloric acid, and then the mixture is stirred for 1 hour and the crystalline precipitate is filtered off. The product is obtained in the form of crystals decomposing at 235-241 ° C.

Example 26

4- [4- (2-imidazolylthioacetyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

NH 2 was obtained analogously to variant A from 4- [4- (2-imidazolylthioacetyl) phenoxy] -3-methylsulfonylbenzoic acid in a mixture of 50 mL of tetrahydrofuran and 10 mL of dimethylacetamide as reaction medium as a colorless crystalline solid with mp 220 ° C.

a) 4- [4- (2-Imidazolylthioacetyl) phenoxy] -3-methylsulfonylbenzoic acid is obtained by reacting 4- (4-chloroacetylphenoxy) -3-methylsulfonylbenzoic acid (from Example 25a) and 1 mol of 2-mercaptobenzimidazole in 20 ml of acetone with by brief heating to boiling. The mixture is stirred for about 5 days at room temperature and the crystalline precipitate is filtered off. The product decomposes at 202-205 ° C.

Example 27

4- (4- (4,5-dihydro-2-imidazolylthioacetyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

by HM, obtained in an analogous manner to that described in Variant A from 4- (4- (4,5-dihydro-2-imidazolylthioacetyl) phenoxy] -3-methylsulfonylbenzoic acid in a mixture of 50 ml of tetrahydrofuran and 10 ml of dimethylacetamide as reaction medium in Colorless crystalline solid, m.p. 210 ° C.

a) Preparation of 4- (4- (4,5-dihydro-2-imidazolylthioacetyl) phenoxy] -3-methylsulfonylbenzoic acid is carried out analogously to Example 26a) by reaction of 4- (4-chloroacetylphenoxy) -3-methylsulfonylbenzoic acid (from Example 25a) with 2-mercapto-4,5-dihydroimidazole. The product decomposes at 305-310 ° C.

Example 28

4- [4- (N, N-dimethyl-2-isothiouronylacetyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

is obtained in an analogous manner to that described in Variant A from 4- [4- (N, N'-dimethyl-S-isothiuronylacetyl) phenoxy] -3-methylsulfonylbenzoic acid in a mixture of 50 ml of tetrahydrofuran and 10 ml of dimethylacetamide as the reaction medium in the form of colorless crystalline solid, m.p. 150 ° C.

a) 4- [4- (N, N'-Dimethyl-S-isothiuronylacetyl) phenoxy] -3-methylsulfonylbenzoic acid is obtained analogously to Example 26a) by reaction of 4- (4-chloroacetylphenoxy) -3-methylsulfonylbenzoic acid (from Example 25a) with N, N'-dimethylthiourea at room temperature in the form of colorless crystals decomposing at 185-190 ° C.

Example 29

4- [4- (2-Benzimidazolyltioacetyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

a) 4- [4- (2-Benzimidazolylthioacetyl) phenoxy] -3-methylsulfonylbenzoic acid is obtained analogously to Example 26a) by reaction of 4- (4-chloroacetylphenoxy) -3-methylsulfonylbenzoic acid (from Example 25a) with 2-mercaptobenzimidazole in N, N-dimethylformamide. The melting point of the product is 182 ° C.

Example 30

4- [4- (2-pyridylthioacetyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

was obtained in an analogous manner to that described for Variant A from 4- [4- (2-pyridylthioacetyl) phenoxy] -3-methylsulfonylbenzoic acid in tetrahydrofuran as the reaction medium as a colorless crystalline solid, m.p. 203 ° C.

a) 4- [4- (2-Pyridylthioacetyl) phenoxy] -3-methylsulfonylbenzoic acid is obtained analogously to Example 26a) by reacting 4- (4-chloroacetylphenoxy) -3-methylsulfonylbenzoic acid (from Example 25a) with 2-mercaptopyridine. Mp 194-196 ° C.

Example 31

4- [4- (2-Quinolylthioacetyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

was obtained in an analogous manner to that described for Variant A from 4- [4- (2-quinolylthioacetyl) phenoxy] -3-methylsulfonylbenzoic acid in tetrahydrofuran as the reaction medium as a colorless crystalline solid, m.p. 192 ° C.

a) Preparation of 4- [4- (2-quinolylthioacetyl) phenoxy] -3-methylsulfonylbenzoic acid is carried out analogously to Example 26a) by reaction of 4- (4-chloroacetylphenoxy) -3-methylsulfonylbenzoic acid (from Example 25a) with 2-mercaptoquinoline in Ν, Ν-dimethylformamide. Mp 210-214 ° C.

Example 32

4- [4- (2-N-Imidazolyl-1-hydroxyethyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

NH,

NH, is obtained in an analogous manner to that described in Variant A from 4- (4- (2-benzimidazolylthioacetyl) phenoxy] -3-methylsulfonylbenzoic acid in tetrahydrofuran as the reaction medium as a colorless crystalline solid, m.p. 228 ° C.

is obtained in an analogous manner to that described in Variant A from 4- [4- (2-N-imidazolyl-1-hydroxyethyl) phenoxy] -3-methylsulfonylbenzoic acid in dimethylacetamide or N-methylpyrrolidone as the reaction medium in the form of a colorless crystalline solid decomposing at 260 ° C.

SK 281567 Β6

a) 4- [4- (2-N-imidazolyl-1-hydroxyethyl) phenoxy] -3-methylsulfonylbenzoic acid is obtained by reducing 0.0034 mol of 4- [4- (2-N-imidazolyl-1-oxoethyl) phenoxy ] -3-methylsulfonylbenzoate 0.0068 mol of sodium borate in 40 ml of ethanol. After distilling off the solvent, adding water to the residue and adjusting the pH to 4 with 2N hydrochloric acid, the mixture was stirred for several hours at room temperature and the crystals were filtered off. Mp 240-248 ° C.

Example 33 3-Methylsulfonyl-4- (4-sulfamoylphenoxy) benzoylguanidine-

was obtained in an analogous manner to that described for Variant A from 3-methylsulfonyl-4- (4-sulfamoylphenoxy) benzoic acid in dimethylacetamide as the reaction medium as a colorless crystalline solid decomposing at 267 ° C.

a) 3-Methylsulfonyl-4- (4-chlorosulfonylphenoxy) benzoic acid is obtained by reacting 0.03 mol of 4-phenoxy-3-methylsulfonylbenzoic acid with 0.15 mol of chlorosulfonic acid in 60 ml of methylene chloride at 0-5 ° C with additional stirring for 4 hours at room temperature. After addition of ice water, the methylene chloride phase is separated, washed with water, dried over magnesium sulphate and the solvent is distilled off. The product is obtained in the form of crystals of m.p. 167-170 ° C.

b) 3-Methylsulfonyl-4- (4-sulfamoylphenoxy) benzoic acid is obtained by reacting 3-methylsulfonyl-4- (4-chlorosulfonylphenoxy) benzoic acid with aqueous concentrated ammonia solution for 24 hours at room temperature, distilling off ammonia and acidifying the aqueous 2N solution hydrochloric acid to pH 1-2. The crystals are filtered off, washed with water and dried. The product is obtained in the form of a colorless crystalline substance, m.p. 240-245 ° C.

Example 34

4- [4- (l-hydroxy-2- (2-pyridylthio) ethyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

MH, obtained analogously to variant A from 4- [4- (1-hydroxy-2- (2-pyridylthio) ethyl) phenoxy] -3-methylsulfonylbenzoic acid in tetrahydrofuran as reaction medium in the form of a colorless crystalline solid mp 116 ° C.

a) 4- [4- (1-Hydroxy-2- (2-pyridylthio) ethyl) phenoxy] -3-methylsulfonylbenzoic acid is obtained in analogy to Example 32a) as a colorless crystalline substance, m.p. 169-174 ° C.

Example 35

4- [4- (1-Hydroxy-2- (2-benzimidazolylthio) ethyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

HH, obtained analogously to variant A from 4- [4- (1-hydroxy-2- (2-benzimidazolylthio) ethyl) phenoxy] -3-methylsulfonylbenzoic acid in dimethylacetamide as reaction medium as a colorless crystalline solid mp 213 ° C.

a) 4- [4- (1-hydroxy-2- (2-benzimidazolylthio) ethyl) phenoxy] -3-methylsulfonylbenzoic acid is obtained in analogy to Example 32a) as a colorless crystalline substance, m.p. 186-188 ° C.

Example 36

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

o hh ₂ is obtained in an analogous manner to that described in Variant A from 4- (4- (1-hydroxy-2- (2-quinolylthio) ethyl) phenoxy] -3-methylsulfonylbenzoic acid in tetrahydrofuran as the reaction medium in the form of a colorless crystalline solid mp 180 ° C.

a) 4- [4- (1-Hydroxy-2- (2-quinolylthio) ethyl) phenoxy] -3-methylsulfonylbenzoic acid was obtained analogously to Example 32a) from 4- [4- (2-quinolylthioacetyl) phenoxy] -3-methylsulfonylbenzoic acid (from Example 31a) as a colorless crystalline solid.

Example 37 4- [4- (N, N-Dimethylglycylamino) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

o hh ₂ is obtained analogously to variant A from 4- [4- (N, N-dimethylglycylamino) phenoxy] -3-methylsulfonylbenzoic acid in tetrahydrofuran as reaction medium as a colorless crystalline solid, m.p. 223 ° C .

a) The preparation of 3-methylsulfonyl-4- (4-nitrophenoxy) benzoic acid is carried out by reacting 0.02 mol of 3-methylsulfonyl-4-phenoxybenzoic acid with 0.96 ml of 100% nitric acid in a mixture of 8 ml of acetic anhydride and 4 ml of glacial acid. acetic acid at -10 ° C. After stirring at this temperature for 1.5 hours, the mixture was stirred at room temperature for 24 hours and at 40 ° C for a further 6 hours. The mixture is poured into ice water and the amorphous oily product is crystallized by stirring in water. The product is obtained as a yellow crystalline solid, m.p. 140-150 ° C.

b) 4- (4-Aminophenoxy) -3-methylsulfonylbenzoic acid is obtained by catalytic hydrogenation of 3-methylsulfonyl-4- (4-nitrophenoxy) benzoic acid (from Example 37a) with Raney17

SK 281567 Β6

- in methanol at normal pressure until hydrogen uptake is complete. After evaporation of the solvent, a uniform amorphous oil is obtained.

c) Ν, Ν-Dimethylglycine imidazole hydrochloride is obtained by reacting Ν, Ν-dimethylglycine hydrochloride with carbonyldiimidazole in anhydrous dimethylacetamide, from which the product is separated. The mixture was subjected to the following reaction without further purification.

d) 4- [4- (N, N-dimethylglycylamino) phenoxy] -3-methylsulfonylbenzoic acid was obtained by reacting N, N-dimethylglycine imidazolidide hydrochloride (from Example 37c) with 4- (4-aminophenoxy) -3-methylsulfonylbenzoic acid (from Example 37b) stirring for 5 minutes in dimethylacetamide at room temperature. The solvent was distilled off, the pH was adjusted to 1-2 with hydrochloric acid and extracted with ethyl acetate. The aqueous phase was distilled off and methanol was added to the residue. After filtering off the insoluble material, the title compound is obtained as a colorless oil.

Example 38

4- [4- (N, N-diethylaminoethyl) ammosulfonylfenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride ^chloro j \ q __

H

CH 2 Cl 2 S 2 HCl

HH ₂ was obtained analogously to variant A from 4- [4- (N, N-diethylaminoethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoic acid in anhydrous dimethylacetamide as reaction medium as a colorless crystalline solid, m.p. 206 ° C. .

a) 4- [4- (N, N-Diethylaminoethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoic acid was obtained by reacting 0.05 mol of 3-methylsulfonyl-4- (4-chlorosulfonylphenoxy) benzoic acid (from Example 33a) with 0.06 mol of N, N-diethylaminoethylamine in the presence of excess triethylamine (about 0.015 mol) in methanol as the reaction medium. After distilling off the solvent mixture, a small amount of water was added and the pH was adjusted to 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 o

NH 3 is obtained in an analogous manner to that described in Variant A from 4- [4- (1-methyl-4-piperazino) sulfonylphenoxy] -3-methylsulfonylbenzoic acid in tetrahydrofuran as the reaction medium as a colorless crystalline solid decomposing at 234 - 244 ° C.

a) 4- (4- (1-Methyl-4-piperazino) sulfonylphenoxy) -3-methylsulfonylbenzoic acid was obtained by reacting 3-methylsulfonyl-4- (4-chlorosulfonylphenoxy) benzoic acid (from Example 33a) with N-methylpiperazine in an analogous manner as in Example 38a) in the form of colorless crystals decomposing at 287-292 ° C.

Example 40

4- [4- (4-imidazolylethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

was obtained in an analogous manner to that described for Variant A from 4- [4- (4-imidazolylethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoic acid in dimethylacetamide as the reaction medium as a colorless crystalline solid, m.p. 264 ° C.

a) 4- [4- (4-Imidazolylethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoic acid was obtained analogously to Example 38a) by reaction of methylsulfonyl-4- (4-chlorosulfonylphenoxy) benzoic acid (from Example 33a) with colorless amorphous histamine. solid decomposing at 265 ° C.

Example 41

4- [4- (3-N-Imidazolyl-1-propyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

x 2 HCl

HHj was obtained in an analogous manner to that described in Variant A from 4- [4- (3-N-imidazolyl-1-propyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoic acid in tetrahydrofuran as the reaction medium as a colorless crystalline solid decomposing at temperature 257 ° C.

a) 4- (4- (3-N-imidazolyl-1-propyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoic acid was obtained analogously to Example 38a) by reaction of methylsulfonyl-4- (4-chlorosulfonylphenoxy) benzoic acid (from Example 33a) with 1- (3-aminopropyl) -imidazole as a colorless amorphous solid, m.p. 250 ° C.

Example 42

4- [4- (l-methyl-2-pyrrolidinylethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

o hh ₂ is obtained analogously to variant A from 4- (4- (1-methyl-2-pyrrolidinylethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoic acid in dimethylacetamide as reaction medium in the form of a colorless crystalline solid, m.p. 254 C.

SK 281567 Β6

a) 4- [4- (1-Methyl-2-pyrrolidmylethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoic acid is obtained analogously to Example 38a) by reaction of methylsulfonyl-4- (4-chlorosulfonylphenoxy) benzoic acid (from Example 33a) with 2 - (2-aminoethyl) -l-methylpyrrolidine. Mp 242-247 ° C.

Example 43

4- [4- (N-morpholinoethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

ABOUT !

KHj was obtained analogously to variant A from 4- [4- (N-morpholinoethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoic acid in dimethylacetamide as reaction medium as a colorless crystalline solid, m.p. 272 ° C.

(a) 4- [4- (N-Morpholinoethyl) aminosulfonylphenoxy] -

3-Methylsulfonylbenzoic acid is obtained analogously to Example 38a) by reaction of methylsulfonyl-4- (4-chlorosulfonylphenoxy) benzoic acid (from Example 33a) with N- (2-aminoethylyl) morpholine as a colorless crystalline compound, m.p. 220-224 ° C. .

Example 44

4- [4- (N-Piperidinoethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

HCl

NH 3 is obtained in an analogous manner to that described for Variant A from 4- [4- (N-piperidinoethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoic acid in clueless dimethylacetamide as the reaction medium as a colorless crystalline solid, m.p. 266 ° C.

a) 4- [4- (N-piperidinoethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoic acid is obtained analogously to Example 38a) by reaction of methylsulfonyl-4- (4-chlorosulfonylphenoxy) benzoic acid (from Example 33a) with N- (2- aminoethylyl] piperidine as a colorless crystalline solid, m.p. 271-273 ° C.

Example 45

4- [4- (2-pyridylethyl) ammosulfonylfenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

was obtained in an analogous manner to that described in Variant A from 4- [4- (2-pyridyl-ethyl) -aminosulfonyl-phenoxy] -3-methylsulfonyl-benzoic acid in anhydrous dimethylacetamide as reaction medium as a colorless crystalline solid, m.p.

a) 4- [4- (2-Pyridylethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoic acid is obtained analogously to Example 38a) by reaction of methylsulfonyl-4- (4-chlorosulfonylphenoxy) benzoic acid (from Example 33a) with 2- (aminoethyl) pyridine in as colorless crystals, m.p. 268-270 ° C.

Example 46

4- [4- (2-dimethylaminoethyl) sulfonylmetylfenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

en \

was obtained by peroxoacid oxidation in an analogous manner to that described in Example 17 from 4- [4- (2-dimethylaminoethyl) thiomethylphenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride (from Example 15) as colorless crystals, m.p. 245 ° C.

Example 47

4- [4- (2-dimethylaminoethyl) sulfonylmetylfenoxy] -3-trifluoromethylbenzoylguanidine dihydrochloride

was obtained by oxidation with a peracid in an analogous manner to that described in Example 17 from 4- [4- (2-dimethylaminoethyl) thiomethylphenoxy] -3-trifluoromethylbenzoylguanidine dihydrochloride (from Example 19) as colorless crystals, m.p. 140 ° C.

Pharmacological data;

Inhibition of Na ⁺ / H ⁺ exchange system in rabbit erythrocytes

White New Zealand rabbits (Ivanovas) were given a standard 2% cholesterol diet for six weeks to activate Na ⁺ / H ⁺ exchange and to be able to determine by flame photometry of Na ⁺ influx into erythrocytes via Na7H ⁺ exchange. Blood was drawn from the ear artery and made uncoagulated with 25 IU potassium heparin. A portion of each sample was used for duplicate hematocrit determination by centrifugation. Parts with a volume of 100 μΐ each served to measure the initial Na ⁺ content of erythrocytes.

In order to determine the influx of amiloride-sensitive sodium, 100 µl of each blood sample was incubated in 5 ml of hyperosmolar saline sucrose medium (140 mmol / l sodium chloride, 3 mmol / l ouabain, 20 mmol / l trishydroxymethylaminomethane) at pH 7.4 and temperature 37 ° C. The erythrocytes are then washed three times with an ice-cold solution of magnesium chloride and ouabain (112 mmol / l magnesium chloride, 0.01 mmol / l ouabain) and hemolyzed in 2.0 ml of distilled water. Intracellular sodium content is determined by flame photometry.

The net influx of Na ⁺ is calculated from the difference between the initial sodium content and the sodium content of erythrocites

SK 281567 Β6 after incubation. Amiloride-inhibiting Na ⁺ influx is obtained from the difference in sodium contents in erythrocytes after incubation in the presence or absence of amiloride (3 x 10 ^-4 mol / L). The compounds of the invention have also been used in this manner.

The results

Inhibition of Na ⁺ / H ⁺ exchange system:

example IC ₅₀ (μπιοί / ΐ) 1 0.8 2 0.32 3 0.05 4 0,082 5 0.3 6 0.1 7 0.06 8 0,005 9 0.1 14 0.05 15 0.01 16 0.16 17 1 18 0.2 19 0,008 20 0.04 21 0,014 28 0.12 32 0.44 33 0.20 46 0.09 47 0.07

PATENT CLAIMS

Claims (18)

PATENT CLAIMS Benzoylguanidines of the general formula (I) in which one of the three substituents R ^(1> , R ^p) and R ^<3) represents a group R ⁽⁶⁾ -ABD-, wherein: R ^<6) represents a basic protonatable radical, i.e. an amino group of the formula -NR ⁽⁷⁾ R ⁽⁸⁾ , an amidino group of the formula R ^ R ^ ⁸ NC [= NR * ⁹ ] - or a guanidino group of the formula "ffl. (10) I I> r <» ^{X the} symbols R ^<7) , R ^<s, ₍ R ^<9) and R ⁽¹⁰⁾ independently of one another represent a hydrogen atom or an alkyl group having 1, 2, 3 or 4 carbon atoms, or R6 and R® together represent C _and H _2a , where a is 4, 5, 6 or 7, and if a is 5, 6 or 7, one methylene group in the C group may be replaced by a heteroatom or a heteroaryl group of O, SO _m or NR ⁽ⁿ⁾ , or R ⁽⁸⁾ and R ^<9 'or R ⁽⁹⁾ and R ⁽¹⁰⁾ or R ⁽⁷⁾ and R ⁽¹⁰⁾ are C _and H _2a , where a is 2 , 3,4, or 5, wherein if a is 3, 4 or 5, one methylene group in groups C _and H _{2a may} be replaced by a heteroatom or a hetero group (O, SO _m or NR ⁽ⁿ⁾⁾ , m being 0,1 or 2 a R ⁽¹⁾ is hydrogen or methyl, or R ⁽⁶⁾ is a basic heteroaromatic ring system of 1 to 9 carbon atoms, A represents a group CbH _2b) wherein b has a value of 1,2,3,4, 5,6,7,8,9 or 10, wherein in the group CbH _21! one or two methylene groups may be replaced by a group selected from -O-, -CO-, -CH [OR ^po ]] -, -SOm-, -NR ⁽²⁰⁾ -, -NR ⁽²⁰⁾ -CO- , -NR ⁽²⁰⁾ -CO-NH-, -NR ⁽²⁰⁾ -CO-NH-SO 2 -, (0) II ** .R < O _> -Sa-SO ₁ JNR ⁽¹ ' ⁾ _{] bb} -, and wherein in the CbH _2b group one methylene group may be replaced by -CH-R ¹ ', where R * ⁹⁹ ' together with R ⁽⁷⁾ form a pyrrolidine or piperidine ring, aa is 1 or 2, bb is 0 or 1, and aa + bb = 2, R ⁽¹⁹⁾ represents a hydrogen atom or an alkyl group having 1, 2, 3 or 4 carbon atoms; and R ⁽²⁰ > represents a hydrogen atom or a methyl group, B is a phenylene or naphthylene radical where R ⁽¹²⁾ and R ⁽¹³⁾ independently of one another, are hydrogen, methyl, fluoro, chloro, bromo, iodo, trifluoromethyl or -SO _w -R ^{( I4)} , R ⁽¹⁴ 'is methyl or NR < ¹⁵ >R' ¹⁶ >, R ⁽¹⁵⁾ and R ⁽¹⁶⁾ independently of each other are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms, w 0, 1, or 2 D is -C _d H _2d -Xf-, wherein d has a value of 0,1,2,3 or 4, X is -O-, -CO-, -CH [OR ^(2I) ] -, -SO _r - or -NR ^(2I) -, f is 0 or 1, R ⁽²¹⁾ represents a hydrogen atom or a methyl group, m is 0, 1 or 2 and the other of R ⁽¹⁾ , R ⁽²⁾ and R ⁽³⁾ independently of one another are hydrogen, fluorine, chlorine , bromine, iodine, cyano, (C 1 -C 8) alkyl, (C 2 -C 8) alkenyl, -NR ⁽³⁵⁾ R ⁽³⁶⁾ or R ^{(7) C 8} H 6 -Zh-, where g is 0, 1, 2, 3 or 4, h is 0 or 1, R ^(35> and R ⁽³⁶⁾ independently of each other represent a hydrogen atom or an alkyl group with 1, 2, 3, 4, Or R ⁽³⁵⁾ and R ^(3S) together represent 4-7 methylene groups, one of which may be one methylene Replace with oxygen, sulfur, -NH-, -NCH ₃ or -N-benzyl, Z is O, -CO-, -SO, -, -NR ^(IS '-, -NR ^(1B) -CO-, -NR ⁽ 18'-CO-NH- or -NR ⁽¹⁸⁾ -SO ₂₎ - wherein R ⁽¹⁸⁾ represents a hydrogen atom or a methyl group and has a value of 0,1 or 2, R ⁽¹⁷⁾ represents a hydrogen atom, a cycloalkyl group having 3, 5 or 6 carbon atoms, or a group C _to F _{2k + 1} -> where k is 1, 2 or 3, or R ⁽ⁿ⁾ means pyrrol-1-yl , pyrrol-2-yl or pyrrol-3-yl not substituted or substituted by one to four substituents selected from fluorine, chlorine, bromine, iodine, cyano, C 2 -C 8 alkanoyl carbon, C 2 -C 8 alkoxycarbonyl, formyl, carboxyl, trifluoromethyl, methyl and methoxy, or R ⁽¹⁷⁾ means a C 3 -C 8 cycloalkyl or a phenyl group which is unsubstituted or is substituted with one to three substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, hydroxyl, methoxy, -NR ^(37), R ⁽³⁸⁾ , CH ₃ SO _{2 and} H ₂ NO ₂ R ⁽³⁷⁾ and R ⁽³⁸⁾ each represent a hydrogen atom or a methyl group, and R * ¹ * each independently represent a hydrogen atom, an alkyl group having 1, 2, 3 or with 4 carbon atoms, fluorine atom, chlorine atom, -OR ⁽³²⁾ , -NR ⁽³³ * R ^<34) or -QF (1), wherein R ⁽³²⁾ , R ⁽³³⁾ and R ⁽³⁴⁾ independently each represents a hydrogen atom or an alkyl group having 1, 2 or 3 carbon atoms; and ar is 1, 2, 3 or 4, as well as their pharmacologically acceptable salts. The benzoylguanidines of general formula (I) according to claim 1, in which R ⁽¹⁾ represents a hydrogen atom, a fluorine atom, a chlorine atom, a C1-C4 alkyl group, a C2-C4 alkenyl group, an -NR ⁽³⁵⁾ R ⁽³⁶⁾ group or a R ^-CLHjg-ZiB group wherein R ^& lt ^{; 35 >} and R &lt; ^{36 &gt}; independently represent hydrogen, methyl or ethyl, or R &lt; ³⁵ & gt ^; and R & lt ^{; 36 &gt}; together represent 4-5 methylene groups of which one may be methylene replace with oxygen, sulfur, -NH- or -NCH ₃ R < ⁷ > represents a hydrogen atom, a cycloalkyl group having 5 or 6 carbon atoms or a group C _to F _{2k + r} , where k is 1, 2 or 3, g is 0, 1, 2, 3 or 4, h 0 or 1 Z represents O, -CO-, -SO _{H -,} -NR ^<I8) -, -NR ^(I8 '-CO-, -NR ^(18' -CO-NH- or -NR ⁽¹⁸⁾ _-SO2- - where R ⁽¹⁸⁾ represents a hydrogen atom or a methyl group and av is 0, 1 or 2, or, when g and h are always 0, R ⁽¹⁷⁾ represents a pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl group which is unsubstituted or substituted by one to two substituents selected from the group consisting of fluorine atom, chlorine atom, alkanoyl group having 2 to 5 carbon atoms; C 5 -C 5 alkoxycarbonyl, C 2 -C 5 alkoxycarbonyl, formyl, carboxyl, trifluoromethyl, methyl and methoxy, or R ⁽¹⁷⁾ is C 3 -C 8 cycloalkyl or phenyl which is unsubstituted or substituted by one to two substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group, -NR ⁽³⁷⁾ R ^'38) , CH ₃ SO ₂ - and H ₂ NO ₂ S- groups, and R ⁽³⁷⁾ and R ^{(38) are} each independently hydrogen or methyl, one of R ⁽²⁾ and R ⁽³⁾ is R ^(S) -ABD-, wherein: R 6 represents a group of the formula -NR ⁷ R ⁽⁸⁾ , an amidino group of the formula R ⁽⁷⁾ R ^(I) NC [= NR ^<9) ] - or a guanidino group of the formula r (7), 110) I l _R (S < radicals R ^(7), R ^<8), R ^<9) and R ^(Io) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms, or the radicals R ⁽⁷⁾ and R ^<8> together represent a group C _and H _2a , where a has a value of 4,5,6 or 7 and if a has a value of 5, 6 or 7, one methylene group in the group CaH _{2a can} be replaced by a heteroatom or a hetero group O, _SOa or NR * ^{n '} R ⁽¹¹⁾ represents a hydrogen atom or a methyl group, or R ⁽⁸⁾ and R ⁽⁹⁾ together represent a group C1-C4 wherein a has a value of 2,3, 4, or 5, that a is 3, 4 or 5, one methylene group in the group may be replaced by a heteroatom or a hetero group of O, _SOa or NR ^(I1) , m is 0,1 or 2, or R ^(ä) is imidazolyl, pyridyl , quinolinyl or isoquinolinyl, A is CBH _{2 b,} wherein b is 1,2,3,4 or 5, wherein in CBH _2b, one or two methylene groups replaced by a group selected from the groups -O-, -CO-, -CH [ OR ⁽²⁰⁾ ] -, -SO 2 -, -NR ^{( 20)} -, -NR ⁽²⁰⁾ -CO-, -NR ⁽²⁾ -CO-NH-, -NR ⁽²⁰⁾ -CO-NH- SO2-, <o>"-R^{<, O)} NS _and -SOJNR ⁽ 19V, and wherein in group C _b H _2b one methylene group can be replaced by -CH-R ^<99) , where R ⁽⁹⁹⁾ together with R ⁽⁷⁾ form a pyrrolidine or piperidine ring, aa is 1 or 2, bb is 0 or 1, and aa + bb = 2, R < ¹⁹ * represents a hydrogen atom or an alkyl group having 1, 2,3 or 4 carbon atoms; and R ^<20) represents a hydrogen atom or a methyl group, B represents a phenylene or naphlylene residue 112 ²¹ | yy H3) where 1 (13) R * ¹² 'and R * ¹³ ' are each independently hydrogen, methyl, fluoro, chloro, trifluoromethyl or -SO ₂ -R ^(I4) , R ⁽¹⁴⁾ is methyl or NR ⁽¹³⁾ R ⁽¹⁶⁾ , R ⁽¹⁵⁾ and R ⁽¹⁶⁾ independently of each other are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms, D is -C _d H _M -X _r , where d is 0, 1, 2, 3, or 4, X is -O-, -CO-, -CH [OR ⁽²¹⁾ ] -, -SO _m - or -NR ^(2I) -, f is 0 or 1, R ⁽²¹⁾ is hydrogen or methyl, m is 0, 1 or 2, and the remainder of R ⁽²⁾ and R ⁽³⁾ is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, a fluorine atom, a chlorine atom or a trifluoromethyl group; and R ⁽⁴⁾ and R ⁽⁵⁾ independently of one another denote a hydrogen atom, an alkyl group having 1, 2 or 3 carbon atoms, a fluorine atom, a chlorine atom or a trifluoromethyl group. The benzoylguanidines of formula (I) according to claim 1 or 2, wherein: R ^(I) is hydrogen, F, Cl, alkyl having 1, 2, 3 or 4 carbon atoms, -NR ^35, R ⁽³⁶⁾ or a group R ^<7) -C _g H _{2 g} - Z _h - where g is 0, 1, 2, 3, or 4, h is 0 or 1, Z represents O, -CO-, -SO _{H -,} -NR ¹⁸ '-, -NR ⁽¹⁸⁾ -CO-, -NR ^(1S5 -CO-NH- or -NR ^(I8) -SO ₂ - where R < ¹⁸ * represents a hydrogen atom or a methyl group and has a value of 0,1 or 2, R @ ⁷ represents a hydrogen atom, a cycloalkyl group having 5 or 6 carbon atoms, or a trifluoromethyl group or, when g and h are each 0, R ' ¹⁷ ' represents a pyrrol-1-yl group which is unsubstituted or substituted by one to two substituents selected from the group consisting of fluorine atom, chlorine atom, C2 -C5 alkanoyl group, C2 -C5 alkoxycarbonyl group , trifluoromethyl and methyl, or R ⁽¹⁷⁾ is a C 5-6 cycloalkyl or phenyl group which is unsubstituted or substituted by one of fluorine, chlorine, trifluoromethyl, methyl, CH ₃ SO ₂ -and H ₂ NO ₂ , R ⁽³⁵⁾ and R ^(3S), independently of one another, are hydrogen, methyl or ethyl, or R ^{( 35)} and R ⁽³⁶⁾ together are 4 -5 methylene groups of which one methylene group may be replaced by oxygen, sulfur, -NH-, or -NCH ₃ , one of R ⁽²⁾ and R ⁽³⁾ is -ABD-, wherein R ⁽⁶⁾ is a group of the formula -NR ^(7> R ^<8 ·, amidino group of formula R ⁽⁷ 'R ⁽⁸ ^ NC [= NR ^{| 9>]} - or a guanidino group of formula J7l í ¹¹⁰ ' I 'H' (9I R ⁽⁷⁾ represents a hydrogen atom or an alkyl group having 1, 2, 3 or 4 carbon atoms, R (R), R ( ⁹ ') and R ( ¹⁰⁾ ' are each independently hydrogen, methyl or ethyl, or R ^<7> and R ⁽⁸⁾ together represent a group CaH 2, where a is 4 or 5, and if a is 5, one methylene group in the CaH 2 group can be replaced by NR ⁽¹¹⁾ , R ⁽¹¹⁾ represents a hydrogen atom or a methyl group, or R ^<6> represents an imidazolyl or pyridyl group, A is cbh ₂ t »wherein b is 1,2,3,4 or 5, wherein in CBH _2b, one or two methylene groups replaced by a group selected from the group consisting of -CO-, -CH [OR ^{(20 )]} -, - NR ⁽²⁰⁾ -CO-, <a) ._ -R 10 ' ^, H-S [NR ¹¹ ']] -SQJNR ^ 'V-SOj-, and wherein in CBH _2b may be one methylene group replaced by -CH-R ^(99), where R ^<99), together with the symbol R ⁽⁷⁾ form a pyrrolidine or piperidine ring, and on is 1 or 2, bb is 0 or 1, and aa + bb = 2, R <^19> represents a hydrogen atom or an alkyl group having 1, 2, 3 or 4 carbon atoms and R ⁽²⁰⁾ represents a hydrogen atom or a methyl group or, if b has a value of 2,3,4 or 5, one carbon atom in the group CJub can be replaced by -O-, -S-, -NR ⁽²⁰⁾ -, -NR ^(2b) -CO-, or -NR ^(M) -CO-NH-, B represents a phenylene residue wherein R ⁽¹²⁾ and R ⁽¹³⁾ are each independently hydrogen, methyl, fluoro, chloro, trifluoromethyl or -SO 2 -R · ¹⁴ *, R < ¹⁴ 'is methyl or NH 2 D is -CH ₂ -, -O-, -CO-, -SO _m - or -NR ⁽²¹⁾ -, m is 0 or 2, R ⁽²¹⁾ represents a hydrogen atom or a methyl group, and the rest of the substituents R ¹² 'and R ⁽³⁾ represent a hydrogen atom, R ⁽⁴⁾ and R ⁽⁵⁾ independently of each other represent a hydrogen atom, an alkyl group having 1, 2 or 3 carbon atoms, a fluorine atom, a chlorine atom or a trifluoromethyl group. Benzoylguanidines of formula (I) according to at least one of claims 1 to 3, in which R ⁽ * ⁾ represents a hydrogen atom, a fluorine atom, a chlorine atom, an alkyl group having 1, 2, 3 or 4 carbon atoms, an -NR ^{( 35)} R ^(36> or R ⁽¹⁷⁾ -C _g h _h -Z _{2 g} -, wherein g is 0 or 1, h is 0 or 1, Z is O, -CO-, -NR ⁽¹⁸ ) -CO-, -NR ⁽¹⁸⁾ -CO-NH-, or -NR ⁽¹⁸⁾ -SO ₂ -, wherein R ¹¹⁸⁾ represents a hydrogen atom or a methyl group or, when g is 1, Z represents a -SO ₂ - group, R ⁽¹⁷⁾ represents a hydrogen atom or a trifluoromethyl group, 286 R * ³³ * and R * ³⁶ * each independently represent a hydrogen atom, a methyl group or an ethyl group, or R ⁽³⁵ * and R * ³⁶ 'together represent 4-5 methylene groups from which one methylene group replaced by oxygen, sulfur, -NH-, or -NCH3, one of R ⁽²⁾ and R ⁽³⁾ being R ⁽⁶⁾ -ABO-, wherein R ⁽⁶⁾ is -NR ⁽⁷⁾ R ⁽⁸⁾ or guanidino (II) R ' ⁷ * represents a hydrogen atom or an alkyl group having 1, 2, 3 or 4 carbon atoms, R ^(8> , R ⁽⁹⁾ and R ^<10) independently of one another represent a hydrogen atom, a methyl group or an ethyl group, or R ⁽⁷⁾ and R ⁽⁸⁾ together represent a CaH 2 group, wherein a is 4 or 5, and when a is 5, one methylene group in the CaH ₂ group can be replaced by -NH or NCH 3 -, or R ^<6) represents an imidazolyl group, A is CBH _2BL wherein b is 1,2,3 or 4, wherein in CBH _2b, one or two methylene groups replaced by a group selected from the group consisting of -CO-, R ^{<, and NS-SO.tNRÍ} ^ - a-SOi-, and wherein the CBH _2b group can be a methylene group is replaced by -CH-R ^<W), wherein the symbol R ⁹⁹ * together with the symbol R ^{( 7)} may form a pyrrolidine or piperidine ring, and when b has a value of 2,3 or 4, can be a methylene group of the group CBH _2b replaced by -O- or -S-, aa is 1 or 2, the value bb 0 or 1 and aa + bb = 2 R ^<19) represents a hydrogen atom or an alkyl group having 1, 2, 3 or 4 carbon atoms and R ^<20) represents a hydrogen atom or a methyl group, B represents a phenylene radical (121/131) wherein R ⁽¹²⁾ and R ⁽¹³⁾ each represent a hydrogen atom and the remainder of the substituents R® and R ⁽³⁾ represent a hydrogen atom and R ⁽⁴⁾ and R ⁽⁵⁾ represent in each case a hydrogen atom. A compound of formula (I) according to claim 1 selected from the group consisting of 4- [4-N- (dimethylaminoethyl) methylsulfamoyl] phenoxy-3-trifluoromethylbenzoylguanidine dihydrochloride, 4- [4- (4-methylpiperazinosulfonyl) phenoxy] -3- trifluoromethylbenzoylguanidine dihydrochloride, 4- [4- (2-pyrolidínetylaminosulfbnyl) phenoxy] -3- trifluoromethylbenzoylguanidine dimaleate 4- [4- (2-piperidinethylaminosulfonyl) phenoxy] -3-trifluoromethylbenzoylguanidine dimaleinate, 4- [4- (N-dimethylamino-n-propyl) sulfamoyl] phenoxy-3-trifluoromethylbenzoylguanidine, 4- [4- (N-dimethylaminoethyl) ) sulfamoyl] phenoxy-3-trifluoromethylbenzoylguanidine, 4- (4-imidamidosulfonyl) phenoxy-3-trifluoromethylbenzoylguanidine, 3-Trifluoromethyl-4- (4-N-methylimidamidosulfonyl) phenoxy benzoylguanidine 3-Methyl-4- (4- (1-methylpiperazin-4-ylsulfonyl) phenoxy) benzoylguanidine, 4- (4-guanidinosulfonyl) phenoxy-3-trifluoromethylbenzoylguanidine, 4- [4- (2-imidazolylthioacetyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride, 4- [4-N, N'-dimethyl-S-isothiuronylacephyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride, 4- [4- ( 2-benzimidazolyltioacetyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride; 4- [4- (2-N-imidazolyl-1-hydroxyethyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride, 4- [4- (N, N-dimethylglycylamino) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride, 4- [4 - (N, N-diethylaminoethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride, 4- [4- (4-imidazolylethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride, 4- [4- (3-N-imidazolyl-1-propyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride, 4- [4- (1-methyl-2-pyrrolidinylethyl) aminosulfonylphenoxy] -3-. -methylsulfonylbenzoylguanidine dihydrochloride, 4- [4- (N-piperidinoethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride, 4- [4- (2-dimethylaminoethyl) sulfonylmethylphenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride, and 4- [4- (2-dimethylaminoethyl) sulfonylmethylphenoxy] -3-trifluoromethylbenzoylguanidine dihydrochloride. A process for the preparation of the benzoylguanidine of formula (I) according to claim 1, characterized in that the compound of formula (II) has the radicals R * ¹ * to R ^(s) and L represents a readily nucleophilically substitutable cleavable moiety. and reacting the product with a guanidine and optionally converting the product into a pharmacologically acceptable salt. Use of the benzoylguanidine of formula (I) according to claim 1 for the manufacture of a medicament for the treatment of arrhythmias. Use of a compound of formula (I) according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of a heart attack. Use of a compound of formula (I) according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of angina pectoris. Use of a compound of formula (I) according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of ischemic heart conditions. Use of the benzoylguanidine of formula (I) according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis23 EN 281567 x 6 xiu peripheral and central nervous system ischemic conditions and stroke. Use of a benzoylguanidine of formula (1) according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of ischemic conditions of peripheral organs and limbs. Use of a benzoylguanidine of formula (1) according to claim 1 for the manufacture of a medicament for the treatment of shock conditions. Use of the benzoylguanidine of formula (1) according to claim 1 for the manufacture of a medicament for use in surgical operations and organ transplants. Use of a benzoylguanidine of the general formula (1) according to claim 1 for the manufacture of a medicament for the preservation and storage of transplants for surgical procedures. Use of the benzoylguanidine of formula (1) according to claim 1 for the manufacture of a medicament for the treatment of diseases whose primary or secondary cause is cell proliferation, and thus its use as an anti-atherosclerotic agent for late diabetic complications, cancer diseases, fibrotic diseases such as is fibrosis of the lungs, fibrosis of the liver or fibrosis of the kidney and anti-hyperplasia of the uterine. Use of the benzoylguanidine of formula (1) according to claim 1 for the preparation of a scientific tool for inhibiting the Na ⁺ / H ⁺ exchange system, for the diagnosis of hypertonia and proliferative diseases. Medicament, characterized in that it contains an effective amount of the benzoylguanidines of the general formula (I) according to one or more of claims 1 to 4.