SK12797A3 - Substituted diarylcarboxylic acid diguanidines, preparation method thereof, their use as a drug or a diagnostic agent, as well as drug containing the same - Google Patents

Abstract

Diaryl dicarboxylic acid diguanidines of formula (I) and their salts are new. One of R1-R5 and one of R6-R10 = CON=C(NH2)2; of the others, R1, R5, R6, R10 = H, 1-4C alkyl, F, Cl, OR32, NR33R34 or CF3; R32-R34 = H or 1-4C alkyl; R2, R4, R7, R9 = H, F, Cl, Br, I, OH, CN, CF3, CON=C(NH2)2, 1-8C alkyl, 2-8C alkenyl, (CH2)mR14, pyrrol-(1, 2 or 3)-yl (optionally mono- to tetra-substituted by F, Cl, Br, I, CN, 2-8C alkanoyl, 2-8C alkoxycarbonyl, formyl, carboxy, CF3, methyl or methoxy), SO2R22, CONR23R24, COR28, SO2N(R29)R30, OR35 or N(R35)R36; m = 0-2; R14 = 3-8C cycloalkyl or phenyl (optionally mono- - tri-substituted with F, Cl, CF3, methyl, methoxy or N(R15)R16); R15, R16, R23, R24, R29, R30 = H or CH3; R22, R28 = methyl or CF3; R35, R36 = H or 1-6C alkyl; or R35+R36 = 4-7 methylene (optionally with one group substituted by O, S, NH, NCH3 or N-benzyl); R3 = H, SR25, OR25, N(R25)R26, C(R25)(R26)R27; R25 = H, 1-8C alkyl, phenyl (optionally mono- to tri-substituted with F, Cl, CF3, CH3, methoxy, hydroxy, amino, methylamino or dimethylamino), or 1-9C heteroaryl (optionally mono- to tri-substituted by F, Cl, CF3, CH3, OMe, OH, NH2, NHCH3, N(CH3)2); R26, R27 = as R25, or H or 1-8C alkyl; A = bond, N(R11)CO, N(R12)CON(R13), N(R17)CON(R18)SO2, N(R19)SO2, SO2, SO2N(R19)CO, OCON(R19)SO2 or C(R20)=C(R21); and R11 - R21 = H or 1-8C alkyl.

Description

(54) Title of the invention: Diaryldicarboxylic acid substituted diguanidides, process for their preparation, their use as a medicament or a diagnosis, as well as a medicament containing them (57)

The diaryldicarboxylic acid diguanidides of the formula (I) in which R ¹ to R ¹⁰ have the meanings given in the claims are suitable as antiarrhythmic drugs having a cardioprotective component for the prophylaxis and treatment of infarction as well as for the treatment of angina pectoris. It has an inhibitory effect on pathophysiological processes in the development of ischemic-induced damage, particularly in ischemic-induced cardiac arrhythmias.

(I)

ΉΊ- ι

Substituted diaryldicarboxylic acid diguanidides, process for their preparation, use as medicaments or diagnostics, as well as medicaments containing them

Techniques

The present invention relates to novel diaryldicarboxylic acid diquanidides and their use in the medical field.

BACKGROUND OF THE INVENTION

U.S. Patent 5,091,394 (HOE 89 / F 288) and European Patent Publication 0 556 674 (HOE 92 / F 034) disclose certain benzoylgunidines, but not diaryldicarboxylic acid diguanidides. WO 94/26 709 (PCT / JP94 / 00786) describes the use of already places the phenyl ring as a substituent of R ² in the meta position benzoylguanidine (beside many other possibilities) and the second phenyl ring may be (among many other possibilities) also carry guanidinyl- substituent. However, these known compounds are not satisfactory for several applications.

SUMMARY OF THE INVENTION

The invention relates to diaryldicarboxylic acid diguanides of the formula I

wherein they are one of the radicals R ¹ , r ² , R ³ , R ⁴ and R ⁵

-CO-N = C (NH ₂ ) ₂ 'other radicals R ¹ and R 3 independently of one another hydrogen atom, alkyl group having 1, 2, 3 or 4 carbon atoms, fluorine atom, chlorine atom, -OR ³² , -NR ³³ _and R ^34] p _ _{much a} trifluoromethyl group, R ^32, R ³³ and R ³⁴ independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms,

A me radicals R and R independently of one another are H, F, Cl, Br, I, hydroxyl, cyanide, trifluoromethyl, -CO-N-C _(NH2) 2, HL having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, an alkenyl group containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms or - (CH ₂ ) _m R ¹⁴ , m zero, number 1 or 2

R ^{14 is} C 3 -C 8 cycloalkyl or phenyl which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine and chlorine, trifluoromethyl, methyl, methoxy and -NR ¹⁵ R ¹⁶ ,

R ¹⁵ and R ^{1 S} is H or methyl and other radicals R ² and R ⁴ independently of one another pyrrol-l-yl, pyrrol-2-yl or pyrrol-3-yl which is unsubstituted or substituted by 1 up to 4 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, cyanide group, C 2 -C 8 alkanoyl group, C 2 -C 8 alkoxycarbonyl group, formyl group, carboxyl group, trifluoromethyl group methyl, methoxy, or other radicals R ² and R ⁴ , 23 _D 24 _T

R ²² -SO 2 -, R ²³ R ²⁴ N-CO-, R ²⁸ -CO- or R ²⁹ R ³⁰ N-SO 2,

R ( ²²⁾ and R ( ²⁸⁾ independently of one another are methyl or trifluoromethyl,

R ( ²³⁾ , R ( ²⁴⁾ , R ( ²⁹⁾ and R ( ³⁰⁾ independently of one another are hydrogen or methyl or other radicals R ( ²⁾ and R ( ⁴⁾ independently of one another -OR ³⁵ or -NR ³⁵ R ³⁸ ,

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) may} each contain 4 to 7 methylene groups, one methylene group being replaced by an oxygen atom , sulfur, imino, -NCH _3, or -N-benzyl, another R ³ hydrogen, -SR ²⁵ , -OR ²⁵ , -NR ²⁵ R ²⁶ , -CR ²⁵ R ²⁶ R ²⁷ , hydrogen, alkyl a group containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, methoxy, hydroxyl, amino, methylamino and dimethylamino, or a heteroaryl group having 1 to 9 carbon atoms which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluoro ru, chloro, trifluoromethyl, methyl, methoxy, hydroxyl, amino, methylamino, and dimethylamino,

R ²⁶ and R ²⁷ independently of one another as defined R ²³ or a hydrogen atom or an alkyl group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, one of the radicals R 6, R ⁷ , R 6, R ° and R ¹ ®

-CO-N = C (NH _{2) 2} other radicals R and R @ ¹⁰ independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, -OR · '· ²² -'- -NR ³³ R @ ³⁴ or trifluoromethyl, R ^132, R ¹³³ and R ¹³⁴ independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms, other groups R ⁷ and R independently of one another hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom, hydroxyl group, cyanide group, trifluoromethyl group, -CO-N = C (NH ₂ ) ₂ > alkyl group containing 1, 2, 3, 4, 5, 6 , 7 or 8 carbon atoms, an alkenyl group containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms or - (CH ₂ ) _mm R ¹¹⁴ , mm zero, number one or two,

¹¹⁴ R is cycloalkyl having 3 to 8 carbon atoms or phenyl, which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine and chlorine, trifluoromethyl, methyl, methoxy and NR ¹¹⁵ R ^treatment.

R ¹¹⁵ and R ^{116 are} hydrogen or methyl, or other radicals R ⁷ and R 6 independently of one another pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl not substituted or substituted 1-4 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, cyanide group, C 2 -C 8 alkanoyl group, C 2 -C 8 alkoxycarbonyl group, formyl group, carboxyl group, trifluoromethyl, methyl and methoxy, or other radicals R? and

R ¹²² -SO 2 -, R ¹²³ R ¹²⁴ N-CO-, R ¹²⁸ -CO- or R ¹²⁹ R ¹³⁰ N-SO 2 -, R ¹²² and R ¹²⁸ independently of each other a methyl or trifluoromethyl group, _r 123, _r 124 _r 129 _{and R} 130 independently of each other a hydrogen atom or a methyl group, or other radicals R ⁷ and R ⁹ independently of one another -OR ¹³⁵ or -NR ¹³⁵ R ¹³⁸ ,

R ( ¹³⁵⁾ and R ( ¹³⁶⁾ independently of one another are hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, or

R ¹³⁵ and R ¹³⁶ together the 4 to 7 methylene groups, of which one methylene group can be replaced by oxygen, S, NH, a group -NC ^ or N-benzyl, the other radical R ⁸ is H, -SR ^ ² -OR ', ^2', 126 -Nr125 _{r N e} p _a _ _CR 125 _R 126 _R 127

R ( ¹²⁵⁾ is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl which is unsubstituted or is substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy, hydroxyl, amino, methylamino and dimethylamino, or

R ¹²⁵ is a C 1 -C 9 heteroaryl group which is unsubstituted or is substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group, hydroxyl group, amino group, methylamino group and dimethylamino group,

R ¹²⁶ and R ¹²⁷ independently of one another as defined by R or a hydrogen atom or an alkyl group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,

A absent, -NR ^{1; L} -CO-, -NR ¹² -CO-NR ¹³ -, -NR ¹⁷ -CO-NR ¹⁸ -SO 2 - nr ¹⁹ -so2-, -so ₂ -nr ¹⁹ -so2-, - so2-nr ¹⁹ -co-, -O-CO-NR ¹⁹ -SO 2 - or -CR ²⁰ = CR ²¹ -,

R ( ¹¹⁾ , R ( ¹²⁾ , R ( ¹³⁾ , R ( ¹⁷⁾ , R ( ¹⁸⁾ , R ( ¹⁹⁾ , R ( ²⁰⁾ and R ( ²¹⁾ independently of one another hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; as well as pharmaceutically acceptable salts thereof.

Preferred compounds of formula I are those in which one of R ^1, R ^2, R ^3, R ⁴ and R ⁸ -CO-N = C _{(NH2) 2,} other radicals R ¹ and R ^9, independently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, fluorine atom, chlorine atom, -OR ³² , -NR ³³ R ³⁴ or trifluoromethyl,

R ( ³³⁾ and R ( ³⁴⁾ independently of one another are hydrogen or methyl, the other radicals R ( ²⁾ and R ( ⁴⁾ independently of one another are hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, trifluoromethyl, -CO-N = C (NH ₂ ) _{2 -} alkyl having 1, 2, 3 or 4 carbon atoms, alkenyl having 2, 3 or 4 carbon atoms or - (CH ₂ ) _m R ¹⁴ , m zero, the number 1 or 2,

R ^{14 is} C 3 -C 6 cycloalkyl or phenyl which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine and chlorine, trifluoromethyl, methyl and methoxy, or other radicals R ² and R ⁴ independently of one another a pyrrol-1-yl group, a pyrrol-2-yl group or a pyrrol-3-yl group which is unsubstituted or substituted by substituents selected from fluorine, chlorine, bromine, iodine, cyanide, (C 2 -C 5) alkanoyl, (C 2 -C 5) alkoxycarbonyl, formyl group. carboxyl, trifluoromethyl and methyl, or other radicals R ² and R ⁴ independently of one another R ²² -SO ₂ -, R ²⁸ -CO- or 2

R ²² and R ²⁸ r ²⁹ r ³⁰ n- ₂ - _z independently methyl or trifluoromethyl group,

R ( ²⁹⁾ and R ( ³⁰⁾ independently of one another are hydrogen or methyl or other radicals R ( ²⁾ and R ( ⁴⁾ independently of one another -OR ³⁵ or -NR ³⁵ R ³⁸ ,

R ( ³⁵⁾ and R ( ³⁶⁾ independently of one another are hydrogen, methyl or ethyl or 4 or 5 methylene groups, of which one methylene group may be replaced by an oxygen atom, a sulfur atom, an imino group or a group -nch ₃ , another R ³ a hydrogen atom, -SR ²⁵ , -OR ²⁵ , -NR ²⁵ R ²⁶ , -CR ²⁵ R ²⁶ R ²⁷ ,

R ( ²⁵⁾ is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, phenyl which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy and dimethylamino, or

R ^{25 is} a C 1 -C 9 heteroaryl group which is unsubstituted or is substituted by 1 or 2 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and dimethylamino group,

R ( ²⁶⁾ and R ( ²⁷⁾ independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, one of the radicals R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰

-CO-N = C (NH ₂ ) ₂ other radicals R ⁸ and R ¹⁸ independently of one another hydrogen, alkyl having 1, 2 or 3 carbon atoms, fluorine atom, chlorine atom,

-OR ¹³² , -NR ^{133, 34,} or trifluoromethyl,

R ( ¹³²⁾ , R ( ¹³³⁾ and R ( ¹³⁴⁾ independently of one another are hydrogen or methyl; in R (7), X and R are each independently hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, trifluoromethyl, -CO-N = C (ΝΉ2) 2 - alkyl having 1, 2, 3 or 4 carbon atoms, alkenyl having 2, 3 or 4 carbon atoms, or - (CH ₂ ) _mm R ¹¹⁴ , mm zero, number one or two,

R ^{114 is} C 3 -C 6 cycloalkyl or phenyl which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine and chlorine, trifluoromethyl, methyl and methoxy, or; the radicals R and R independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl which is unsubstituted or substituted by one or two substituents selected from the group consisting of fluorine atom, chlorine atom, atom bromine, iodine, cyanide, C 2 -C 5 alkanoyl, C 2 -C 5 alkoxycarbonyl, formyl, carboxyl, trifluoromethyl and methyl, or other radicals R ⁷ and R 6 independently wearing. R ¹²² -SO ₂ -, -CO-, or R ¹²⁸ _R 129 _R 130 _{N S} _ q _ _{EXAMPLE 2}

R ¹²² and R ^{128 are} each independently methyl or trifluoromethyl,

R ( ¹²⁹⁾ and R ( ¹³⁰⁾ independently of one another are hydrogen or methyl, or other radicals R ( ⁷⁾ and R ( ⁹⁾ independently of one another -OR ¹³⁵ or -NR ¹³³ R ¹³⁸ ,

R ( ¹³⁵⁾ and R ( ¹³⁶⁾ independently of one another are hydrogen, methyl or ethyl;

R ¹³⁵ and R ^{13S can} carry 4 to 5 methylene groups, one methylene group of which can be replaced by an oxygen atom, a sulfur atom, an imino group or an -NCH 4 group, the other R ⁸ is a hydrogen atom, -SR ²³ , -OR ²³ , -NR ²³ R · '· _ ²⁸ or _CR 125 _R 126 _R 127

R ( ¹²³⁾ is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl which is unsubstituted or substituted by 1 to 2 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and dimethylamino, or

R ¹²³ is a C 1 -C 9 heteroaryl group which is unsubstituted or is substituted by 1 or 2 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and dimethylamino group,

R ( ¹²⁶⁾ and R ( ¹²⁷⁾ independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms,

A absent, -NR 4 - CO-, -NR ¹² -CO-NR ¹³ -, -NR ¹⁷ -CO-NR ¹⁸ -SO2-nr ¹⁹ -so2-, -so ₂ -nr ¹⁹ -so ₂ -, - Sat ₂ -nr ¹⁹ -co-, -O-CO-NR ¹⁹ 11

-SO ₂ - or -CR ²⁰ = CR ²¹ -,

R ¹¹ , R ¹² , R ¹³ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ and independently of each other a hydrogen atom containing 1, 2, 3 or 4, as well as pharmaceutically acceptable salts or alkyl carbon atoms thereof, are particularly preferred of formula I are those in which one of R ^1, R ^2, R ^3, R ⁴ and R ⁵ -CO-N = C _{(NH2) 2,} other radicals R ³ and R · ³ independently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, fluoro, chloro, -OR ³² , -NR ³³ R ^34, or trifluoromethyl,

R ( ³²⁾ , R ( ³³⁾ and R ( ³⁴⁾ independently of one another are hydrogen or methyl; - 9 and RΛ are independently hydrogen, fluorine, chlorine, hydroxyl, trifluoromethyl,

-CO-N = C (NH ₂ ) ₂ , alkyl having 1, 2, 3 or 4 carbon atoms or pyrrol-1-yl not substituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine and a chlorine atom, a bromine atom, an iodine atom, a cyanide group, a C2 -C5 alkanoyl group, a C2 -C5 alkoxycarbonyl group, a formyl group, a carboxyl group, a trifluoromethyl group and a methyl group, or other radicals R @ ² and R ⁴ r ²² -so ₂ -,

R ^{22 is} methyl or trifluoromethyl, or other radicals R ² and R ⁴ independently of one another -OR ³⁸ or -NR ³³ R ^{3 '} ,

R ( ³⁵⁾ and R ( ³⁸⁾ independently of one another are hydrogen or methyl

12 · or ethyl, another radical R ³ is hydrogen, -SR ²⁵ , -OR ²⁵ , -NR ²⁵ R ²⁶ or -CR ²⁵ R ²⁶ R ²⁷ ,

R ( ²⁵⁾ is hydrogen, alkyl having 1, 2 or 3 carbon atoms or phenyl which is unsubstituted or substituted by one substituent selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group and methyl group, or

R ^{25 is} a C 1 -C 9 heteroaryl group which is unsubstituted or substituted by one substituent selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group and methyl group,

R ( ²⁶⁾ and R ( ²⁷⁾ independently of one another are hydrogen or methyl, one of R ⁵ , R ⁷ , R ⁵ , R ⁹ and R ⁸ ;

-CO-N = C (NH ₂ ) ₂ other radicals R ⁵ and R ¹ independently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, fluorine atom, chlorine atom, -OR '* · ³² , - NR ³³ R @ ^3, or 4 trifluoromethyl,

R ( ¹³²⁾ , R ( ¹³³⁾ and R ( ¹³⁴⁾ independently of one another are hydrogen or methyl, the other radicals R ( ⁷⁾ and R ( ⁹⁾ independently of one another are hydrogen, fluorine, chlorine, hydroxyl, trifluoromethyl,

-CO-N = C (NH ₂ ) 2 'alkyl having 1, 2, 3 or 4 carbon atoms or pyrrol-1-yl not substituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine, a chlorine atom, a bromine atom, an iodine atom, a cyanide group, 2 to 5 carbon atoms, a 2 to 5 carbon atom alkoxy group, a formyl group, a carboxyl group, a trifluoromethyl group and a methyl group, or other radicals R ⁷ and R ⁹ R ¹²² -SO ₂ -, _R 122 methyl or trifluoromethyl, or other radicals R ⁷ and R ⁹ independently of one another -OR ¹³⁵ or -NR ¹³⁵ R ¹³⁶ ,

R ( ¹³⁵⁾ and R ( ^136), independently of one another, a hydrogen atom, a methyl group or an ethyl group, another radical R ³ is a hydrogen atom, -SR ¹²⁵ , -OR ¹²⁵ , -NR ¹²⁵ R ¹²⁶ or _cr 125 _r 126 _r 127

R ( ¹²⁵⁾ is hydrogen, alkyl having 1, 2 or 3 carbon atoms or phenyl which is unsubstituted or is substituted by one substituent selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group and methyl group, or

R ¹²⁵ is a C 1 -C 9 heteroaryl group which is unsubstituted or substituted by one substituent selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group and methyl group,

R ( ¹²⁶⁾ and R ( ¹²⁷⁾ independently of one another are hydrogen or methyl,

A absent, ¹ -NR ^L CO-, -NR ¹² -CO-NR ¹³ -, -NR ¹⁷ -CO-NR ¹⁸ -SO 2 -NR ¹⁹ -SO 2 ~, -SO ₂ -NR ¹⁹ -SO 2, -so2-nr ¹⁹ -co-, -O-CO-NR ¹⁹ -SO 2 - or -CR ²⁰ = CR ²¹ -,

R ¹¹ , R ¹² , R ¹³ , R ¹⁷ , independently of or ethyl, as well as their pharmaceutical, 18, 19, atom, acceptable ²⁰ and R ²¹ hydrogen, salts.

methyl group

Preferred are especially compounds of formula I are those in which one of R ^1, R ^2, R ^3, R ⁴ and R ³

-CO-N = C (NH ₂ ) 2 'other radicals R ¹ and R ⁵ independently of one another hydrogen, alkyl having 1, 2 or 3 carbon atoms, fluorine, chlorine or trifluoromethyl, other radicals R ² and R ⁴ is hydrogen, hydroxyl, trifluoromethyl, -CO-N = C (NH ₂ ) ₂ 'alkyl having 1, 2, 3 or 4 carbon atoms or pyrrol-1-yl not substituted or substituted 1 or 2 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, cyanide group, C 2 -C 5 alkanoyl group, C 2 -C 5 alkoxycarbonyl group, formyl group, carboxyl group, trifluoromethyl and methyl, another radical R ³ is hydrogen, -OR ²³ or -CR ²³ R ²³ R ²⁷ ,

R ( ²⁵⁾ is hydrogen, alkyl having 1, 2 or 3 carbon atoms or phenyl which is unsubstituted or substituted by one substituent selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group and methyl group, or

R ^{25 is} a C 1 -C 9 heteroaryl group which is unsubstituted or is substituted by one substituent selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group and a methyl group,

R ²⁶ and R ²⁷ independently of one another are hydrogen or methyl, one of R ^, ^R7, R®, R ^ and R ^

-co-n = c (nh ₂ ) ₂ other radicals R ⁶ and R ¹⁰ independently of one another hydrogen, alkyl having 1, 2 or 3 carbon atoms, fluorine, chlorine or trifluoromethyl, other radicals R ⁷ and ³ a hydrogen atom, a hydroxyl group, a trifluoromethyl group, -CO-N = C (NH ₂ ) ₂ , an alkyl group containing 1, 2, 3 or 4 carbon atoms or a pyrrol-1-yl group which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, cyanide group, C 2 -C 5 alkanoyl group, C 2 -C 5 alkoxycarbonyl group, formyl group, carboxyl group, trifluoromethyl group and methyl, another R @ ⁸ radical hydrogen, --OR ^{@ 125} or --CR @ ¹² R @ ¹² R @ ¹² R @ ¹²⁷ ,

R ( ¹²⁵⁾ is hydrogen, alkyl having 1, 2 or 3 carbon atoms or phenyl which is unsubstituted or is substituted by one substituent selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group and methyl group, or

R ¹²⁵ is a C 1 -C 9 heteroaryl group which is unsubstituted or substituted by one substituent selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group and methyl group,

R ( ¹²⁶⁾ and R ( ¹²⁷⁾ independently of one another are hydrogen or methyl,

A absent, NR ^{1, L,} -CO-, -NR ¹² -CO-NR ¹³ -, -NR ¹⁷ -CO-NR ¹⁸ -SO 2 NR ¹⁹ -SO 2, -SO ₂ -NR ¹⁹ -SO 2 - SO 2 -NR ¹⁹ -CO-, -O-CO-NR ¹⁹ -SO 2 - or -CR ²⁰ = CR ²¹ -,

R ( ¹¹⁾ , R ( ¹²⁾ , R ( ¹³⁾ , R ( ¹⁷⁾ , R ( ¹⁸⁾ , R ( ¹⁹⁾ , R ( ²⁰⁾ and R ( ²¹⁾ independently of one another are hydrogen or methyl, and pharmaceutically acceptable salts thereof.

Particularly preferred are compounds of formula I are those in which one of R ^1, R ³ and R ⁵

-co-n = c (nh ₂ ) ₂ , other radicals R ¹ and R ⁵ independently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, fluorine atom, chlorine atom or trifluoromethyl group,

R ² and R ^{4 are} hydrogen, hydroxyl, trifluoromethyl, alkyl having 1, 2,3 or 4 carbon atoms or pyrrol-1-yl not substituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, cyanide, C 2 -C 5 alkanoyl, C 2 -C 5 alkoxycarbonyl, formyl, carboxyl, trifluoromethyl and methyl, other R ³ is hydrogen, -OR ²⁵ or -CR ²⁵ R ²⁶ R ²⁷ ,

R ( ²⁵⁾ is hydrogen, alkyl having 1, 2 or 3 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 and methyl group, or

R ^{25 is} a C 1 -C 9 heteroaryl group which is unsubstituted or substituted by one substituent selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group and methyl group,

R ²⁶ and R ²⁷ independently of one another are hydrogen or methyl, one of the radicals R ⁸ , R ® and R ® · ®

-CO-N = C (NH ₂ ) ₂ other radicals R ⁸ and R ¹⁰ independently of one another hydrogen atom, alkyl group having 1, 2 or 3 carbon atoms, fluorine atom, chlorine atom and trifluoromethyl group, hydrogen atom, hydroxyl group, trifluoromethyl, alkyl having 1, 2, 3 or 4 carbon atoms or pyrrol-1-yl not substituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, cyanide, C 2 -C 5 alkanoyl, C 2 -C 5 alkoxycarbonyl, formyl, carboxyl, trifluoromethyl and methyl, other R ⁸ is hydrogen, -OR ¹²⁸ or -CR ' ²⁸ R®- ²⁸ R® · ²⁷

R ¹²⁵ is H, alkyl having 1, 2 or 3 carbon atoms or phenyl, which is unsubstituted or substituted by one substituent selected from skúpi18 ny consisting of fluoro, chloro, trifluoromethyl and methyl, or R ¹²⁵ heteroaryl, containing 1 to 9 carbon atoms which is unsubstituted or substituted by one substituent selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group and methyl group,

R ( ¹²⁶⁾ and R ( ¹²⁷⁾ independently of one another are hydrogen or methyl,

A absent, ¹ -NR ^L CO-, -NR ¹² -CO-NR ¹³ -, -NR ¹⁷ -CO-NR ¹⁸ S02-NR ¹⁹ -SO 2, -SO ₂ -NR ¹⁹ -SO 2 - so2-nr ¹⁹ -co-, -O-CO-NR ¹⁹ -SO 2 - or -CR ²⁰ = CR ²¹ -,

NR ¹¹ , NR ¹² , NR ¹³ , NR ¹⁷ , NR ¹⁸ , NR ¹⁹ , NR ²⁰ and NR ²¹ independently of one another hydrogen atom or methyl group, as well as pharmaceutically acceptable salts thereof.

Particular preference is given to compounds of the formula I in which one of the radicals R ^{@ 1} , R ^{@ 2} , R @ ³ , R @ ⁴ and R @ ^{8 are as follows.}

-co-n = c (nh ₂ ) ₂ , other radicals R ¹ and R ⁵ independently of one another hydrogen, alkyl having 1, 2 or 3 carbon atoms, fluorine, chlorine or trifluoromethyl, other radicals R ² and R ⁴ is H, hydroxy, trifluoromethyl, -CO-N = C (NH ₂₎ 2 Z is alkyl having 1, 2, 3 or 4 carbon atoms or pyrrol-l-yl which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, cyanide group, C 2 -C 5 alkanoyl group, C 2 -C 5 alkoxycarbonyl group, formyl group, carboxyl group, tri19 atoter _d 25 one of fluoromethyl and methyl, another radical of R ³ hydrogen, -OR ²⁵ or -CR ²⁵ R ²⁶ R ²⁷ , a hydrogen atom, an alkyl group containing 1, 2 or 3 carbon atoms or a phenyl group, ora is unsubstituted or is substituted by one substituent selected from the group consisting of fluorine, chlorine, trifluoromethyl and methyl, or a heteroaryl group having 1 to 9 carbon atoms which is unsubstituted or substituted by one substituent selected from the group fluorine , a chlorine atom, a trifluoromethyl group and a methyl group, and R ²⁷ independently of one another a hydrogen atom or a methyl group, the radicals R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰

-CO-N = C (NH ₂ ) ₂ other radicals R ⁶ and R ¹⁰ independently of one another hydrogen, alkyl having 1, 2 or 3 carbon atoms, fluorine atom, chlorine atom and trifluoromethyl group, in 7 Q other radicals R and R is H, hydroxy, trifluoromethyl, -CO-N-C _(NH2) 2> is alkyl having 1, 2, 3 or 4 carbon atoms or pyrrol-l-yl which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, cyanide group, C 2 -C 5 alkanoyl group, C 2 -C 5 alkoxycarbonyl group, formyl group, carboxyl group, trifluoromethyl and methyl, the other R ⁸ is hydrogen, -OR ¹²⁵ or -CR ¹²⁵ R ¹²⁸ R ¹²⁷ ,

R ( ¹²⁵⁾ is hydrogen, alkyl having 1, 2 or 3 carbon atoms or phenyl which is unsubstituted or is substituted by one substituent selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group and methyl group, or

R ¹²⁵ is a C 1 -C 9 heteroaryl group which is unsubstituted or is substituted by one substituent selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group and a methyl group,

R ( ¹²⁶⁾ and R ( ¹²⁷⁾ independently of one another are hydrogen or methyl,

-NR ¹¹ -CO-, -NR ¹² -CO-NR ¹³ -, -NR ¹⁷ -CO-NR ¹⁸ -SO 2, -NR ¹⁹ -SO 2 -NR ¹⁹ SO ₂ -SO 2, -SO 2 NR ¹⁹ - CO-, -O-CO-NR ¹⁹ -SO ² - or

-CR ²⁰ = CR ²¹ -

R ( ¹¹⁾ , R ( ¹²⁾ , R ( ¹³⁾ , R ( ¹⁷⁾ , R ( ¹⁸⁾ , R ( ¹⁹⁾ , R ( ²⁰⁾ and R ( ²¹⁾ independently of one another are hydrogen or methyl or their pharmaceutically acceptable salts.

Said alkyl groups may be straight or branched.

C 1 -C 9 heteroaryl groups refer to radicals derived from phenyl or naphthyl in which one or more CH groups are replaced by a nitrogen atom and / or in which at least two adjacent CH groups (in the formation of a five-membered aromatic group) ring) is replaced by a sulfur atom, an imino group or an oxygen atom. In addition, one or both of the condensation atoms of the bicyclic residue (as in indolizinyl) may also be nitrogen atoms.

Suitable heteroaryl groups are, in particular, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl an indolyl group, an indazolyl group, a quinolyl group, an isoquinolyl group, a phthalazinyl group, a quinoaxalinyl group, a quinazolinyl group, a cinolinyl group.

When one of the substituents R @ ¹⁸ to R @ ¹⁸ contains one or more asymmetric centers, these may independently have both S and R configurations. The compounds may exist as optical isomers, as diastereomers, as racemates or mixtures thereof. The carbon-carbon double bonds may be both cis and trans.

The invention further relates to a process for the preparation of compounds of the formula I, which process comprises the preparation of compounds of the formula II

wherein R ^ to R ^ -θ 'are as defined above for R ³ to R ¹⁰ · of which however at least one of R ¹ to R ⁵ and at least one of R ⁶ to R ^10' is a group represented by COL and wherein L represents readily nucleophilically substitutable eliminable groups are reacted with guanidine.

Activated acid derivatives of the formula II in which L is alkoxy, preferably methoxy or phenoxy, phenylthio, methylthio, 2-pyridylthio or nitrogen heterocycle, preferably 1-imidazolyl, are obtained in a manner known per se from the corresponding carboxylic acid chlorides of general formula of formula II in which L represents a chlorine atom, which in turn can be prepared in a manner known per se from the corresponding carboxylic acids of formula II in which L represents a hydroxyl group, for example with thionyl chloride.

In addition to the carboxylic acid chlorides of the formula II in which L is a chlorine atom, other acid derivatives of the formula II can be prepared in a manner known per se directly from the corresponding diaryldicarboxylic acid derivatives of the formula II in which L is OH, e.g. wherein L is OCH3, by treatment with hydrogen chloride in methanol, imidazolides of formula II by treatment with carbonyldiimidazole (L = 1-imidazolyl, Staab, Angew. Chem. Int. Ed. Engl. 1, 351-367 (1962)), mixed anhydrides of formula II with Cl-COOC ₂ H ₅ or tosyl chloride in the presence of triethylamine in an inert solvent, as well as activation of diaryldicarboxylic acids with dicyclohexylcarbodiimide or with O - ((cyano (ethoxycarbonyl) methylene) amino) -1,1,3,3-tetramethyluronium tetrafluoride (Proceedings of the 21st European Peptide Symposium, Peptides 1990, ed. E. Giralt and D.Andre) (Escom, Leiden, 1991). In J.March, Advanced Organic Chemistry, Third Edition (John Wiley and Sons, 1985), p. 350 a series of suitable methods for the production of activated carboxylic acid derivatives of formula (II) with reference literature.

The reaction of the activated carboxylic acid derivative of the formula I with guanidine takes place in a manner known per se in a protic or aprotic polar or inert organic solvent. Methanol, isopropanol or tetrahydrofuran between 20 ° C and the boiling point of these solvents have proved to be useful in the reaction of the diaryldicarboxylic acid dimethyl ester of the formula II in which L L represents OMe with guanidine.

Most of the reactions of the compounds of formula II with salt-free guanidine were preferably carried out in inert solvents such as tetrahydrofuran, dimethoxyethane, dioxane or isopropanol. Water may also serve as a solvent.

When L is a chlorine atom, the addition of an acid-binding agent is advantageously carried out, for example in the form of excess guanidine to bind the hydrohalic acid.

The introduction of compounds substituted in the phenyl moiety nucleophilically with sulfur, oxygen or nitrogen is well known in the literature by known methods of nucleophilic substitution on diaryldicarboxylic acid dialkyl ester derivatives. Halides and trifluoromethanesulfonates have proven to be a leaving group on a diaryldicarboxylic acid derivative in this substitution.

a dipolar aprotic solvent, such as N, N, N ', N'-tetramethylurea, is preferably used in dimethylformamide or lotion at 0 ° C to the boiling point of the solvent, preferably at 80 ° C to the boiling point of the solvent. The alkali metal salt or alkaline earth metal salt with an anion of high basicity and low nucleophilia, for example potassium carbonate or cesium carbonate, is preferably used as the acid binding agent.

The introduction of alkyl and aryl substituents is successful in the literature by known methods of palladium-mediated cross-coupling of aryl halides with, for example, organic zinc compounds, organostannanes, organic boron acids or organoborates.

The diaryl carboxylic acid diguanidides of formula (I) are generally weak bases and are capable of acid binding in salt formation. Suitable acid addition salts are salts of all pharmacologically acceptable acids, for example halides, in particular hydrochlorides, ascorbates, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates, p-toluenesulfonates.

Due to their pharmacological properties as antiarrhythmic drugs with a cardioprotective component, the compounds of the invention are extremely suitable for the prophylaxis of infarction and for the treatment of infarction, as well as for the treatment of angina pectoris and preventively inhibit or severely reduce pathophysiological processes in ischemically induced damage. cardiac arrhythmias due to ischemia. In view of their protective effects against pathological hypoxic and ischemic conditions, the compounds of the formula I according to the invention can be used as medicaments for the treatment of all acute or chronic ischemia-induced damage or primary or secondary diseases due to inhibition of the cellular Na ⁺ / H ⁺ exchange mechanism. . This relates to their use as medicaments used in surgical procedures, e.g. In organ transplants, these compounds can be used both for protecting organs in a donor before and during harvesting, for protecting organs harvested, for example, by treating them with a saline bath or placing them in the bath, and also for implantation into a recipient organism. The compounds of the invention are also valuable, protective-acting drugs in performing angioplastic surgical procedures, for example, on the heart as well as on peripheral vessels. Because of their protective effect against ischemic induced damage, the compounds of the invention are useful as medicaments for the treatment of ischemia of the nervous system, in particular of the central nervous system, for example for the treatment of stroke or brain edema. In addition, the compounds of the formula I according to the invention are also suitable for the treatment of various types of shock, such as allergic, cardiogenic, hypovolemic and bacterial shock.

In addition, the compounds of formula (I) according to the invention are characterized by a potent inhibitory effect on cell proliferation, for example fibroblast cell proliferation and smooth vascular muscle cell proliferation. Therefore, compounds of the formula I are suitable as valuable drugs for diseases in which cell proliferation is a primary or secondary cause and can therefore be used as anti-atherosclerotics, agents for late diabetic complications, cancerous diseases, fibrotic diseases such as β25 lung bronze, fibrosis liver or kidney fibrosis, organ hypertrophies and organ hyperplasia, particularly against prostate hyperplasia or prostate hypertrophy.

The compounds of the invention are potent inhibitors of the cellular antiporter sodium protons (Na ⁺ / H ⁺ -exchanger), which is elevated in a variety of diseases (essential hypertension, atherosclerosis, diabetes, etc.) even in cells readily accessible to measurements, such as erythrocytes, thrombocytes or leukocytes. The compounds of the invention are therefore suitable as excellent and simple diagnostic means, for example in their use for the determination and differentiation of certain types of hypertension, but also atherosclerosis, diabetes, proliferative diseases, etc. In addition, the compounds of formula I are suitable for preventive treatment to prevent the development of high blood pressure, such as essential hypertension.

Compared to most known compounds, the compounds of the invention are characterized by significantly improved water solubility. Therefore, it is substantially more suitable for intravenous administration.

Compounds of the invention exhibit improved bioavailability and pharmacokinetics over known well-soluble compounds.

Drugs containing a compound of formula I may be administered orally, parenterally, intravenously or by inhalation, with the preferred administration being dependent on the clinical picture of the disease. The compounds of the formula I can be used alone or together with auxiliaries, both in veterinary and in human medicine.

Which excipients are suitable for the desired form of drug is well known to the person skilled in the art on the basis of his expert knowledge. In addition to solvents, gelling agents, suppository bases, tablet excipients and other active compound carriers, for example, antioxidants, dispersants, emulsifiers, antifoams, taste corrigents, preservatives, dissolution aids or colorants can be used. For an oral dosage form, the active compounds are admixed with excipients suitable for this purpose, such as carriers, stabilizers, or inert diluents, and formulated into suitable dosage forms such as tablets, dragees, capsules, aqueous, alcoholic or oily solutions by conventional methods. As inert carriers, e.g. gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, in particular corn starch. In this case, the preparation can be obtained both as dry and as wet granules. Suitable oily carriers or solvents are, for example, vegetable or animal oils, such as sunflower oil or fish oil.

For subcutaneous or intravenous administration, the active compounds, optionally with substances customary for this purpose, such as solubilizers, emulsifiers or other auxiliaries, are dissolved, suspended or emulsified. Suitable solvents are, for example, water, saline or alcohols, e.g. ethanol, propanol, glycerin, in addition also sugar solutions such as glucose or mannitol solutions, or else a mixture of the various solvents mentioned.

Suitable pharmaceutical preparations for application in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active compound of the formula I in a pharmaceutically acceptable solvent, such as, in particular, ethanol or water or a mixture of these solvents. If desired, the formulation may also contain pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a carrier gas. Such a preparation usually contains the active compound in a concentration of approximately 0.1 to 10, in particular approximately 0.3 to 3% by weight.

The dosage of the active compound of the formula I and the frequency of its administration depend on the efficacy and duration of action of the compounds used, in addition on the type and intensity of the disease to be treated and the sex, age, weight and individual reactivity of the mammal to be 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 body weight, preferably at least 0.01 mg / kg body weight, to a maximum of 10 mg / kg body weight, preferably at most 1 mg / kg body weight. In an acute outbreak of the disease, such as immediately after the onset of a heart attack, even higher and especially more frequent doses, e.g. up to 4 individual doses per day. In particular, for intravenous use, for example in a heart attack patient in an intensive care unit, up to 100 mg per day may be required.

Experimental part

DETAILED DESCRIPTION OF THE INVENTION

General formula for the preparation of diaryldicarboxylic acid diguanides of the general formula I from the benzenedicarboxylic acid dialkyl esters of the general formula II in which L represents O-alkyl:

Dissolve 5 mmol of the benzenedicarboxylic acid dialkyl ester of formula II as well as 50 mmol of guanidine (free base) in 5 ml of isopropanol and heat to reflux until the reaction is complete by TLC. A typical reaction time is 5 minutes to 10 hours, depending on the carbonyl reactivity of the carboxylic acid derivative. It is then diluted with 150 ml of water and the product is filtered off with suction. Alternatively, it is chromatographed on silica gel using a suitable eluent, for example a 5: 1 mixture of ethyl acetate and methanol or a 10: 1 mixture of acetone and water.

Example 1

3- (4-guanidinocarbonyl) phenylbenzoylguanidine

NK.

NH.

N H

ABOUT

a. 3- (4-Formyl) phenylbenzoic acid ethyl ester

3.4 g of ethyl bromobenzoate, 170 mg of palladium acetate, 390 mg of triphenylphosphine, 2.5 g of 4-formylphenylboronic acid, 15 ml of 2 N aqueous sodium carbonate solution, 90 ml of toluene and 25 ml of ethanol are heated under reflux for 2 hours. 150 ml of a saturated aqueous solution of sodium bicarbonate was added thereto, and extracted three times with 150 ml of ethyl acetate each time. It is dried over sodium sulfate and the solvent is distilled off in vacuo. Chromatography on silica gel (ethyl acetate / n-heptane 1: 8) gave 2.4 g of white crystals, m.p. 81 ° C.

Rf (diisopropyl ether) = 0.55

Mass spectrum (desorption chemical ionization):

255 (M + H) < ⁺ > ^.

b. 3- (4-Ethoxycarbonyl) phenylbenzoic acid ethyl ester

2.4 g of 3- (4-formyl) phenylbenzoate are dissolved in 190 ml of ethanol and 2.3 g of sodium cyanide and 1.1 ml of glacial acetic acid are added at room temperature. After 15 minutes a clear solution is obtained to which 18.9 g of manganese dioxide are added at room temperature. After stirring at room temperature for 7 hours, the precipitate is filtered off and the filtrate is poured onto 300 ml of saturated aqueous sodium carbonate solution and extracted three times with 300 ml of ethyl acetate each time. It is dried over sodium carbonate and the solvent is distilled off in vacuo. Chromatography on silica gel using ethyl acetate / n-heptane 1: 4 as eluent gave 2.5 g of a colorless oil. Rf (diisopropyl ether) = 0.59

Mass Spectrum (Electrospray Ionization):

299 (M + H) < ⁺ > ^.

c. 3- (4-Guanidinocarbonyl) phenylbenzoylguanidines

1.1 g of 3- (4-ethoxycarbonyl) phenylbenzoate are reacted according to the general procedure for the preparation of di-diaryldicarboxylic acid diguanidines to give 760 mg of colorless crystals, m.p. 113 ° C.

Rf (acetone / water 10: 1) = 0.21

Mass spectrum (fast atom bombardment):

325 (M + H) < ^{+ >}

The title compound of Example 2 was synthesized in analogy to Example 1.

Example 2

2- (4-guanidinocarbonyl) phenylbenzoylguanidine

N ^ NH,

N H,

Mp 283 ° C

Rf (acetone / water 10: 1) = 0.25

MS (fast atom bombardment): 325 (M + H) ⁺

Example 3

4- (4-guanidinocarbonyl) phenylsulfamoylbenzoylguanidine

a. 4-sulfamoylbenzoic acid ethyl ester g 4-sulfamoylbenzoic acid is dissolved in 500 ml of ethanol, 36 ml of SOCl ₂ are added dropwise and the reaction mixture is heated under reflux for 5 hours. The volatiles were removed in vacuo, the residue was adjusted to pH = 9 with saturated aqueous sodium carbonate solution and extracted three times with 200 ml of ethyl acetate, then dried over sodium sulfate, and the solvent was distilled off in vacuo to give 21 g of colorless crystals. mp 108 ° C.

Rf (diisopropyl ether) = 0.24

Mass spectrum (desorption chemical ionization):

230 (M + H) < ⁺ > ^.

b. 4- (4-ethoxycarbonyl) phenylsulfamoylbenzoic acid ethyl ester j

1.1 g of 4-sulfamoylbenzoic acid ethyl ester, 840 mg of 4-fluorobenzoic acid ethyl ester and 4.9 g of cesium carbonate are stirred for 10 hours at 130 DEG C. in 10 ml of N-methylpyrrolidone. The reaction mixture is then allowed to cool to room temperature, 200 ml of ethyl acetate are added and washed three times with 100 ml of water each time. It is dried over sodium sulphate and the solvent is distilled off in vacuo. Chromatography on silica gel using ethyl acetate / n-heptane (1: 1) gave 2.6 g of a colorless oil.

Rf (ethyl acetate / n-heptane 1: 1) = 0.38

Mass spectrum (desorption chemical ionization):

378 (M + H) < ⁺ > ^.

c. 4- (4-guanidinocarbonyl) phenylsulfamoylbenzoylguanidine

2.5 g of 4- (4-ethoxycarbonyl) phenylsulfamoylbenzoic acid ethyl ester was reacted according to the general procedure for the preparation of diarylcarboxylic acid diguanidines (reaction time 10 hours) to give 560 mg of a white amorphous solid.

_Rf (acetone / water 10: 1) = 0.16

Mass spectrum (fast atom bombardment):

446 (Μ + Η) ⁺

The title compound of Example 4 was synthesized according to the general formula for the preparation of diarylcarboxylic acid diguanidines from dimethyl biphenyl-4,4-dicarboxylic acid dimethyl ester.

Example 4

Biphenyl-4,4'-dicarboxylic acid diguanidide

Rf (acetone / water 10: 1) = 0.09

Mass spectrum (fast atom bombardment):

325 (M + H) < ^{+ >}

Example 5

4- (3- (guanidinocarbonyl) phenylaminocarbonylaminosulfonyl) benzoylguanidine

N

ABOUT

II

ABOUT

(a) methyl 4-ethoxycarbonylaminosulfonylbenzoate g methyl 4-aminosulfonylbenzoate and 7.7 g potassium carbonate are refluxed in 100 ml of anhydrous dimethyloxyethane for 5 minutes. Then, 5.3 ml of methyl chloroformate are added dropwise and the mixture is refluxed for a further 2 hours, allowed to cool, the solid is filtered off with suction and stirred with 100 ml of saturated aqueous sodium hydrogen sulphate solution and 200 ml of water to give the product. released. The product is filtered off with suction and dried under vacuum at 50 ° C to give 7.1 g of colorless crystals, m.p. 146 ° C.

Rf (ethyl acetate) 0.41

Mass spectrum (desorption chemical ionization):

288 (M + H) < ⁺ > ^.

(b) 4-ethoxycarbonylaminosulfonylbenzoic acid g of 4-ethoxycarbonylaminosulfonylbenzoic acid methyl ester and 42 ml of 1 N aqueous sodium hydroxide solution are stirred for 24 hours at room temperature in 50 ml of methanol. The solvents are distilled off in vacuo, the residue is taken up in 100 ml of water, adjusted to pH = 1-2 with dilute aqueous HCl and the product is filtered off with suction, dried in vacuo to give 5.5 g of colorless crystals, m.p. 189 ° C. .

Rf (diisopropyl ether / 2% acetic acid) = 0.28

Mass Spectrum (Electrospray Ionization):

274 (M + H) < ⁺ > ^.

c) 4- (3- (hydroxycarbonyl) phenylaminocarbonylaminosulfonyl) benzoic acid 4-ethoxycarbonylaminosulfonylbenzoic acid and 1 g of 3-aminobenzoic acid are heated under reflux in 50 ml of anhydrous toluene for 10 hours. The solvent was distilled off in vacuo to give 2.8 g of crude product which was used directly further.

d) 4- (3- (guanidinocarbonyl) phenylaminocarbonylsulfonyl) benzoyl 33 guanidine

1.4 g of 4- (3- (hydroxycarbonyl) phenylaminocarbonylaminosulfonyl) benzoic acid and 1.4 g of carbonylimidazole are dissolved in 60 ml of a mixture of anhydrous tetrahydrofuran and anhydrous N, N-dimethylformamide and stirred at room temperature for 24 hours. 2.5 g of guanidine are then added and the mixture is stirred at room temperature for a further 24 hours. The solvents were distilled off under vacuum, the product was suspended in 10 ml of water, then adjusted to pH 7 with dilute aqueous HCl and stirred for 1 hour at room temperature. The product is filtered off with suction and dried under vacuum. 820 mg of colorless crystals of melting point 207 DEG C. are obtained.

Rg (CH ₂ Cl ₂ / methanol / water / acetic acid 8: 4: 1: 1) = 0.56 Mass spectrum (electrospray ionization):

447 (M + H) < ⁺ > ^.

Pharmacological data

Inhibition of Na ⁺ / H ⁺ exchanger of rabbit erythrocytes

White New Zealand rabbits received for six standard diet with 2% cholesterol in order to activate Na ⁺ / H ⁺ exchange and thus to be able to set flame photometry supply Na ⁺ influx into the erythrocytes via Na ⁺ / H ^+. Blood was drawn from their ear arteries and made uncoagulated with 25 µl of potassium heparin. A portion of each sample was used for duplicate determination of hematocrit by centrifugation. Aliquots of 100 L each were used to measure the initial Na ⁺ content of erythrocytes.

To determine the supply of amiloride-sensitive sodium, 100 L of each blood sample was incubated at pH 7.4 and 37 ° C in 5 ml each of a salt and sucrose-based hyperosmolar medium containing 140 mmol / l NaCl, 3 mmol / l KCl, 150 mmol / l sucrose, 0.1 mmol / l ouabain, 20 mmol / l trishydroxymethylaminomethane. The erythrocytes were then washed three times with an ice solution of magnesium chloride and ouabain containing 112 mmol / l MgCl ₂ and 0.1 mmol / l ouabain, and hemolyzed in 2 ml distilled water. The intracellular content of the sodium was determined by a flame photometer.

The net Na ⁺ feed was calculated from baseline sodium and sodium content in erythrocytes after incubation. The supply of amiloride-inhibiting sodium resulted from the difference in sodium content in the erythrocytes after incubation with and without 3 x 10 ⁴ mol / l amiloride. The compounds of the invention have also been used in this manner.

The results

Inhibition of Na ⁺ / H ⁺ exchanger

Example

IC ₅ (µmol)

1,5 5,0

1,5 2,0

Claims (1)

Substituted diaryldicarboxylic acid diguanidides of the formula I ## STR3 ## in which R @ 1, R @ 5 is one of the radicals R, R, R, R ⁴ and R ⁵ other others -co-n = c (nh ₂ ) ₂ , the radicals R ¹ and R ⁵ independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, fluorine atom, chlorine atom, -OR ³² , -NR ³³ R ( ³⁴⁾ or trifluoromethyl, R ( ³²⁾ , R ( ³³⁾ and R ( ^34), independently of one another, hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms, R ( ²⁾ and R ( ⁴⁾ independently of one another hydrogen, fluorine, chlorine , bromine, iodine, hydroxyl, cyanide, trifluoromethyl, -CO-N = C (NH ₂ ) ₂ , alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl a group containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms or - (CH ₂ ) _m R ¹⁴ , m zero, a number 1 or 2, a cycloalkyl group having 3 to 8 carbon atoms or a phenyl group which is not substituted or substituted with 1 to 3 substituents selected from the group consisting of fluorine and chlorine, trifluoromethyl, methyl a group, a methoxy group, and -NR 1 -R 1 R ⁸ , R ( ¹⁵⁾ R ( ¹⁶⁾ is hydrogen or methyl or other radicals R ( ²⁾ and R ( ⁴⁾ independently of one another pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl not substituted or substituted by 1 to 2 4 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, cyanide group, C 2 -C 8 alkanoyl group, C 2 -C 8 alkoxycarbonyl group, formyl group, carboxyl group, trifluoromethyl group , methyl and methoxy, or the other radicals R ² and R ⁴ R ²² -SO 7 -, R ²³ R ²⁴ N-CO-, R ²⁸ -CO- or R ²⁹ R ³⁰ N-SO 7, independently of one another, methyl or trifluoromethyl, R ( ²⁹⁾ and R ( ³⁰⁾ independently of one another are hydrogen or methyl or other radicals R ( ²⁾ and R ( ⁴⁾ independently of one another -OR ³⁵ or -NR ³⁸ R ³⁸ , R ³ 5 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 the 4 to 7 methylene groups, of which one methylene group can be replaced by oxygen, a sulfur atom, an imino group, an -NCH3 group, or a -N-benzyl, another radical R ³ is hydrogen, -SR ²⁵ , -OR ²⁵ , -NR ²⁵ R ²⁶ , -CR ²⁵ R ²⁶ R ²⁷ , R ( ²⁵⁾ is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl which is unsubstituted or is substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy, hydroxyl, amino, methylamino and dimethylamino, or R ^{25 is} a C 1 -C 9 heteroaryl group which is unsubstituted or is substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy, hydroxyl, amino, methylamino and dimethylamino, R ²⁶ and R ²⁷ independently of one another as defined R ²⁵ or a hydrogen atom or an alkyl group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, one of the radicals R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ other others -CO-N = C (NH _{2) 2} radicals R ⁶ and R ¹⁰ independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, -OR ^132, -NR ¹³³ R ¹³⁴ or trifluoromethyl, R ¹³² , R ¹³³ and R ¹³⁴ independently of one another hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms, the radicals R ⁷ and R ⁹ independently of one another are hydrogen, fluorine, chlorine, bromine atom, iodine atom, hydroxyl group, cyanide group, trifluoromethyl group, -CO-N = C (NH ₂ ) ₂ , alkyl-