HRP970057A2 - Substituted diaryl dicarboxylic acid diguanidines, process for their preparation, their use as medicament or diagnostic agents as well as medicaments containing them - Google Patents

Description

The invention relates to diaryldicarboxylic acid diguanides of formula I

[image]

where:

one of the residues R(1), R(2), R(3), R(4) and R(5) represents -CO-N=C (NH2)2;

always different residues

R(1) and R(5) independently represent hydrogen, alkyl with 1, 2, 3 or 4 carbon atoms, F, Cl, -OR(32), -NR(33)R(34) or CF3;

R(32), R(33) and R(34) independently represent hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms;

always different residues

R(2) and R(4) independently represent hydrogen, F, Cl, Br, J, OH, -CN, CF3, -CO-N=C(NH2)2, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, alkenyl with 2, 3, 4, 5, 6, 7 or 8 C-atoms or -(CH2)m-R(14); m is zero, 1 or 2;

R(14) represents -(C3-C8)-cycloalkyl or phenyl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F and Cl, -CF3, methyl, methoxy and -NR(15)R( 16);

R(15) and R(16) represent hydrogen or -CH3; or always different residues

R(2) and R(4) independently represent pyrrole-1-yl, pyrrole-2-yl or pyrrole-3-yl, which is unsubstituted or substituted with 1-4 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C8)-Alkanoyl, (C2-C8)-Alkoxycarbonyl, Formyl, Carboxy, -CF3, Methyl, Methoxy; or always different residues

R(2) and R(4) independently represent R(22)-SO2-, R(23)R(24)N-CO-, R(28)-CO- or R(29) R(30)N -SO2-;

R(22) and R(28) independently represent methyl or -CF3;

R(23), R(24, R(29) and R(30) independently represent hydrogen or methyl;

or always different residues

R(2) and R(4) independently represent -OR(35) or -NR(35)R(36);

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

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

always a different remainder

R(3) represents hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);

R(25) represents hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms or phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, inethoxy, hydroxy, amino, methylamino and diethylamino; or

R(25) represents -(C1-C9)-heteroaryl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxy, amino, methylamino and dimethylamino;

R(26) and R(27) are independently defined as R(25) or represent hydrogen or alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;

one of the residues R(6), R(7), R(8), R(9) and R(10) represents -CO-N=C (NH2)2;

always different residues

R(6) and R(10) independently represent hydrogen, alkyl with 1, 2, 3 or 4 carbon atoms, F, Cl, -OR(132), -NR(133)R(134) or CF3;

R(132), R(133) and R(134) independently represent hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms;

always different residues

R(7) and R(9) independently represent hydrogen, F, Cl, Br, J, OH, -CN, CF3, -CO-N=C (NH2) 2, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, alkenyl with 2, 3, 4, 5, 6, 7 or 8 C-atoms or - (CH2)mmR(114) ;

mm is zero, 1 or 2;

R(114) represents -(C3-C8)-cycloalkyl or phenyl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F and Cl, -CF3r methyl, methoxy and -NR(115) R(116 ) ;

R(115) and R(116) represent hydrogen or -CF3; or always different residues

R(7) and R(9) independently represent pyrrole-1-yl, pyrrole-2-yl or pyrrole-3-yl, which is unsubstituted or substituted with 1-4 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C8)-Alkanoyl, (C2-C8)-Alkoxycarbonyl, tormyl, carboxy, -CF3, methyl and methoxy;

or always different residues

R(7) and R(9) represent R(122)-SO2-, R(123)R(124)N-CO-, R(128)-CO- or R(129) R(130)N-SO2 -;

R(122) and R(128) independently represent methyl or -CF3;

R(123), R(124), R(129) and R(130) independently represent hydrogen or methyl;

or always different residues

R(7) and R(9) independently represent -OR(135) or -NR(135)R(136);

R(135) and R(136) independently represent hydrogen or alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms;

or

R(135) and R(136) together represent 4-7 methylene groups of which one CH2 group can be substituted with oxygen, -S-, -NH-, -NCH3 or -N-benzyl;

always a different remainder

R(8) represents hydrogen, -SR(125), -OR(125), -NR(125)R(126) or -CR(125) R(126) R(127);

R(125) represents hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms or phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxy, amino, methylamino and dimethylamino; or

R(125) represents -(C1-C9)-heteroaryl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxy, amino, methylamino and dimethylamino;

R(126) and R(127) are independently defined as R(125) or represent hydrogen or alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;

A, absent, represents -NR(11)-CO-, -NR(12)-CO-NR(13)-, -NR(17)-CO-NR(18)-SO2-, -NR(19)- SO2-, -SO2-NR(19)-SO2-, -SO2-NR(19)-CO-, -O-CO-NR(19)-SO2- or -CR(20)=CR(21);

R(11), R(12), R(13), R(17), R(18), R(19) and R(20) and R(21) independently represent hydrogen or alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; and their pharmaceutically acceptable salts.

Particular preference is given to compounds of formula I in which one of the residues R(1), R(2), R(3), R(4) and R(5) represents -CO-N=C (NH2)2;

always different residues

R(1) and R(5) independently represent hydrogen, alkyl with 1, 2 or 3 carbon atoms, F, Cl, -OR(32), -NR(33)R(34) or CF3;

R(32), R(33) and R(34) independently represent hydrogen or methyl;

always different residues

R(2) and R(4) independently represent hydrogen, F, Cl, Br, J, OH, CF3, -CO-N=C(NH2)2, alkyl with 1, 2, 3 or 4 C-atoms, alkenyl with 2, 3 or 4 carbon atoms or -(CH2)m-R(14);

m is zero, 1 or 2;

R(14) represents -(C3-C6)-cycloalkyl or phenyl, which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F and Cl, -CF3, methyl and methoxy; or

always different residues

R(2) and R(4) independently represent pyrrole-1-yl, pyrrole-2-yl or pyrrole-3-yl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C5)-Alkanoyl, (C2-C5)-Alkoxycarbonyl, formyl, carboxy, -CF3 and methyl; or always different residues

R(2) and R(4) independently represent R(22)-SO2-, R(28)-CO- or R(29)R(30)N-SO2-;

R(22) and R(28) independently represent methyl or -CF3;

R(29) and R(30) independently represent hydrogen or methyl;

or always different residues

R(2) and R(4) independently represent -OR(35) or -NR(35)R(36);

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

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

always a different remainder

R(3) represents hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);

R(25) represents hydrogen or alkyl with 1, 2, 3 or 4 C-atoms or phenyl, which is not substituted or is substituted with 1-2 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy and dimethylamino; or

R(25) represents -(C1-C9)-heteroaryl which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy and dimethylamino;

R(26) and R(27) independently represent hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms;

one of the residues R(6), R(7), R(8), R(9) and R(10) represents -CO-N=C(NH2)2, always different residues

R(6) and R(10) independently represent hydrogen, alkyl with 1, 2 or 3 carbon atoms, F, Cl, -OR(132), -NR(133)R(134) or CF3;

R(132), R(133) and R(134) independently represent hydrogen or methyl;

always different residues

R(7) and R(9) independently represent hydrogen, F, Cl, Br, J, OH, -CN, CF3, -CO-N=C(NH2)2, alkyl with 1, 2, 3 or 4 C -atom, alkenyl with 2, 3 or 4 carbon atoms or -(CH2)mmR(114);

mm is zero, 1 or 2;

R(114) represents -(C3-C6)-cycloalkyl or phenyl, which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F and Cl, -CF3, methyl and methoxy; or

always different residues

R(7) and R(9) independently represent pyrrole-1-yl, pyrrole-2-yl or pyrrole-3-yl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C5)-Alkanoyl, (C2-C5)-Alkoxycarbonyl, formyl, carboxy, -CF3 and methyl;

or always different residues

R(7) and R(9) independently represent R(122)-SO2-, R(128)-CO- or R(129)R(130)N-SO2-;

R(122) and R(128) independently represent methyl or -CF3;

R(129) and R(130) independently represent hydrogen or methyl;

or always different residues

R(7) and R(9) independently represent -OR(135) or -NR(135)R(136);

R(135) and R(136) independently represent hydrogen, methyl or ethyl; or

R(135) and R(136) together represent 4-5 methylene groups of which one CH2 group can be substituted with oxygen, -S-, -NH- or -NCH3;

always a different remainder

R(8) represents hydrogen, -SR(125), -OR(125), -NR(125)R(126) or -CR(125)R(126)R(127);

R(125) represents hydrogen, alkyl with 1, 2, 3 or 4 C-atoms or phenyl, which is not substituted or is substituted with 1-2 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy or dimethylamino; or

R(125) represents -(C1-C9)-heteroaryl which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy and dimethylamino;

R(126) and R(127) independently represent hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms;

A, absent, represents -NR(11)-CO-, -NR(12) -CO-NR(13)-, -NR(17)-CO-NR(18)-SO2-, -NR(19)- SO2-, -SO2-NR(19) -SO2-, -SO2-NR(19)-CO-, -O-CO-NR(19)-SO2- or -CR(20)=CR(21);

R(11), R(12), R(13), R(17), R(18), R(19), R(20) and R(21) independently represent hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms; and their pharmaceutically acceptable salts.

Compounds of the formula I are particularly preferred, in which one of the residues R(1), R(2), R(3), R(4) and R(5) represents -CO-N=C(NH2)2;

always different residues

R(1) and R(5) independently represent hydrogen, alkyl with 1, 2 or 3 carbon atoms, F, Cl, -OR(32), -NR(33)R(34) or CF3;

R(32), R(33) and R(34) independently represent hydrogen or methyl;

always different residues

R(2) and R(4) independently represent hydrogen, F, Cl, Br, J, OH, CF3, -CO-N=C(NH2)2, alkyl with 1, 2, 3 or 4 C-atoms or pyrrole-1-yl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxy-carbonyl , formyl, carboxy, -CF3 and methyl; or

always different residues

R(2) and R(4) represent R(22)-SO2-;

R(22) represents methyl or -CF3;

or always different residues

R(2) and R(4) independently represent -OR(35) or -NR(35)R(36);

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

or always a different remainder

R(3) represents hydrogen, -SR(25), -OR(25), -NR(25)R(26) , -CR(25) R(26) R(27) ;

R(25) represents hydrogen, alkyl with 1, 2 or 3 C-atoms or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3; or

R(25) represents -(C1-C9)-heteroaryl which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3;

R(26) and R(27) independently represent hydrogen or methyl;

one of the residues R(6), R(7), R(8), R(9) and R(10) represents -CO-N=C(NH2)2,

always different residues

R(6) and R(10) independently represent hydrogen, alkyl with 1, 2 or 3 carbon atoms, F, Cl, -OR(132), -NR(133)R(134) or CF3;

R(132), R(133) and R(134) independently represent hydrogen or methyl;

always different residues

R(7) and R(9) independently represent hydrogen, F, Cl, OH, CF3,-CO-N=C(NH2)2, alkyl with 1, 2, 3 or 4 C-atoms, pyrrole-1- il, which is not substituted or is substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxy, - CF3 and methyl;

or always different residues

R(7) and R(9) independently represent R(122)-SO2-;

R(122) represents methyl or -CF3;

or always different residues

R(7) and R(9) independently represent -OR(135) or -NR(135)R(136);

R(135) and R(136) independently represent hydrogen, methyl or ethyl;

always a different remainder

R(8) represents hydrogen, -SR(125), -OR(125), -NR(125)R(126) or -CR(125)R(126)R(127);

R(125) represents hydrogen, alkyl with 1, 2 or 3 C-atoms or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3; or

R(125) represents -(C1-C9)-heteroaryl which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3;

R(126) and R(127) independently represent hydrogen or methyl;

A, absent, represents -NR(11)-CO-, -NR(12)-CO-NR(13)-, -NR(17)-CO-NR(18)-SO2-, -NR (19)- SO2-, -SO2-NR(19)-SO2-, -SO2-NR(19)-CO-, -O-CO-NR(19)-SO2- or -CR(20)=CR(21)-;

R(11), R(12), R(13), R(17), R(18), R(19), R(20) and R(21) independently represent hydrogen, methyl or ethyl, and their pharmaceutically acceptable salts.

Compounds of formula 1 are particularly preferred, in which one of the residues R(1), R(2), R(3), R(4) and R(5) represents -CO-N=C(NH2)2;

always different residues

R(1) and R(5) independently represent alkyl with 1, 2 or 3 carbon atoms, F, Cl or CF3;

always different residues

R(2) and R(4) represent hydrogen, OH, CF3, -CO-N=C(NH2)2, alkyl with 1, 2, 3 or 4 C-atoms or pyrrol-1-yl, which is not substituted or is substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxy, -CF3 and methyl;

always a different remainder

R(3) represents hydrogen, -OR(25) or -CR(25)R(26)R(27);

R(25) represents hydrogen, alkyl with 1, 2 or 3 C-atoms or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3; or

R(25) represents -(C1-C9)-heteroaryl which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3;

R(26) and R(27) independently represent hydrogen or methyl;

one of the residues R(6), R(7), R(8), R(9) and R(10) represents -CO-N=C(NH2)2;

always different residues

R(6) and R(10) independently represent hydrogen, alkyl with 1, 2 or 3 carbon atoms, F, Cl or CF3;

always different residues

R(7) and R(9) represent hydrogen, OH, CF3, -CO-N=C(NH2)2, .alkyl with 1, 2, 3 or 4 C-atoms, pyrrol-1-yl, which is not substituted or is substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxy, -CF3 and methyl;

always a different remainder

R(8) represents hydrogen, -OR(125) or -CR(125)R(126)R(127);

R(125) represents hydrogen, alkyl with 1, 2 or 3 C-atoms or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3; or

R(125) represents -(C1-C9)-heteroaryl which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3;

R(126) and R(127) independently represent hydrogen or methyl;

A, absent, represents -NR(11)-CO-, -NR(12)-CO-NR(13)-, -NR(17)-CO-NR(18)-SO2-, -NR(19)- SO2-, -SO2-NR(19)-SO2-, -SO2-NR(19)-CO-, -O-CO-NR(19)-SO2- or -CR(20)=CR(21)-;

R(11), R(12), R(13), R(17), R(18), R(20) and R(21) independently represent hydrogen or methyl; and their pharmaceutically acceptable salts.

Compounds of formula I are particularly preferred, in which one of the residues R(1), R(3) and R(5) represents -CO-N=C(NH2)2;

always different residues

R(1) and R(5) independently represent alkyl with 1, 2 or 3 carbon atoms, F, Cl or CF3;

R(2) and R(4) represent hydrogen, OH, CF3, alkyl with 1, 2, 3 or 4 C-atoms or pyrrol-1-yl, which is unsubstituted or substituted with 1-2 substituents selected from the group consist of F, Cl, Br, J, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxy, -CF3 and methyl; always a different remainder

R(3) represents hydrogen, -OR(25) or -CR(25)R(26)R(27);

R(25) represents hydrogen or alkyl with 1, 2 or 3 C-atoms or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3; or

R(25) represents -(C1-C9)-heteroaryl which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3;

R(26) and R(27) independently represent hydrogen or methyl;

one of the residues R(6), R(8) and R(10) represents -CO-N=C(NH2)2,

always different residues

R(6) and R(10) independently represent hydrogen, alkyl with 1, 2 or 3 carbon atoms, F, Cl or CF3;

R(7) and R(9) represent hydrogen, OH, CF3, alkyl with 1, 2, 3 or 4 C-atoms, pyrrole-1-yl, which is unsubstituted or substituted with 1-2 substituents selected from the group consist of F, Cl, Br, J, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxy, -CF3 and methyl;

always a different remainder

R(8) represents hydrogen, -OR(125) or -CR(125)R(126)R(127);

R(125) represents hydrogen, alkyl with 1, 2 or 3 C-atoms or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3; or

R(125) represents -(C1-C9)-heteroaryl which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3;

R(126) and R(127) independently represent hydrogen or methyl;

A, absent, represents -NR(11)-CO-, -NR(12)-CO-NR(13)-, -NR(17)-CO-NR(18)-SO2-, -NR(19)- SO2-, -SO2-NR(19)-SO2-, -SO2-NR(19)-CO-, -O-CO-NR(19)-SO2- or -CR(20)=CR(21)-;

R(11), R(12), R(13), R(17), R(18), R(19), R(20) and R(21) independently represent hydrogen or methyl; and their pharmaceutically acceptable salts.

Compounds of formula I in which one of the residues R(1), R(2), R(3), R(4) and R(5) represents -CO-N=C(NH2)2 are particularly preferred;

always different residues

R(1) and R(5) independently represent alkyl with 1, 2 or 3 carbon atoms, F, Cl or CF3; always different residues

R(2) and R(4) independently represent hydrogen, OH, CF3, -CO-N=C(NH2)2, alkyl with 1, 2, 3 or 4 C-atoms or pyrrol-1-yl, which is not substituted or is substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxy, -CF3 and methyl; always a different remainder

R(3) represents hydrogen, -OR(25) or -CR(25)R(26)R(27);

R(25) represents hydrogen, alkyl with 1, 2 or 3 C-atoms or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3; or

R(25) represents -(C1-C9)-heteroaryl which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3;

R(26) and R(27) independently represent hydrogen or methyl;

one of the residues R(6), R(7), R(8), R(9) and R(10) represents -CO-N=C(NH2)2; always different residues

R(6) and R(10) independently represent hydrogen, alkyl with 1, 2 or 3 carbon atoms, F, Cl or CF3; always different residues

R(7) and R(9) independently represent hydrogen, OH, CF3, -CO-N=C(NH2)2, alkyl with 1, 2, 3 or 4 C-atoms, pyrrol-1-yl, which is not substituted or is substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxy, -CF3 and methyl; always a different remainder

R(8) represents hydrogen, -OR(125) or -CR(125)R(126)R(127);

R(125) represents hydrogen, alkyl with 1, 2 or 3 C-atoms or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3; or

R(125) represents -(C1-C9)-heteroaryl which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3;

R(126) and R(127) independently represent hydrogen or methyl;

A represents -NR(11)-CO-, -NR(12)-CO-NR(13), -NR(17)-CO-NR(18)-SO2-, -NR(19)-SO2-, - SO2-NR(19)-SO2-, -SO2-NR(19)-CO-, -O-CO-NR(19)-SO2- or -CR(20)=CR(21)-;

R(11), R(12), R(13), R(17), R(18), R(19), R(20) and R(21) independently represent hydrogen or methyl; and their pharmaceutically acceptable salts.

The labeled alkyl residues can be straight or branched chain.

(C1-C9)-heteroaryl means residues derived from phenyl or naphthyl, in which one or more CH groups are replaced by N and/or in which at least two adjacent CH groups (with the formation of a five-membered aromatic ring) are replaced by S, NH or O. Of the others, one or both atoms of the condensation site may also be N-atoms of a bicyclic residue (as in indolizinyl).

Heteroaryls include, in particular, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oskazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinoxazolinyl, quinolinyl .

If one of the substituents R(1) to R(10) has one or more centers of asymmetry, they can independently be in the S or R configuration. The compounds may also exist as optical isomers, as diastereomers, as racemates or as mixtures thereof.

Carbon-carbon double bonds can be connected both in cis and also in trans configuration.

The invention further relates to the process for the production of compounds I, which is characterized by the fact that the compound of formula II

[image]

in which R(1') to R(10') have the meanings given above for R(1) to R(10), of which however at least one of the substituents R(1') to R(5') and at least one of of the substituents R(6') to R(10') represents a labeled COL group, and in which L represents a nucleophilic leaving group that can easily be substituted, chemically converted with guanidine.

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

In addition to the chlorides of carboxylic acids of formula II (L=Cl), further activated acid derivatives can also be produced directly from basic derivatives of diaryldicarboxylic acids (formula II, L=OH), such as methyl ester of formula II with L= OCH3 by treatment with gaseous HCl in methanol, imidazole of formula II by treatment with carbonyldiimidazole [L=1-imidazole, Staab, Angew. Chem. Int. Ed. English 1351-367 (1962)], mixed anhydrides II with Cl-COOC2H5 or tosyl chloride in the presence of triethylamine in an inert solvent, as well as by activating the diaryl-dicarboxylic acid with dicyclohexyl-carbodiimide (DCC) or with O-[(cyano(ethoxycarbonyl)-methylene )amino]-1, 1,3,3-tetramethyluronium tetrafluoroborate ("TOTU") [Proceedings of the 21. Europien Peptide Symposium, Peptides 1990, Publishers E. Giralt and D. Andreu, Escom, Leiden, 1991]. A number of suitable methods for the production of activated derivatives of carboxylic acids of general formula II are listed in the literature review in J. March, Advanced Organic Chemistry, Third Edition (John Wiley & Sons, 1985), p. 350.

The chemical conversion of activated derivatives of carboxylic acids of formula II with guanidine takes place in a manner known per se in a protic or aprotic polar but inert organic solvent. At the same time, when converting the methyl ester of diaryldicarboxylic acid (II, L=OMe) with guanidine, methanol, isopropanol or THF between 20°C and the boiling point of that solvent proved to be good. In most chemical transformations of compounds II with guanidine, when not in salt form, it is useful to work in inert solvents such as THF, dimethoxyethane, dioxane or isopropanol. Water can also serve as a solvent.

When L=Cl, it is useful to work with the addition of an acid acceptor, eg in the form of excess guanidine to bind the hydrohalic acid.

The introduction of compounds, substituted in the phenyl part with sulfur, oxygen or nitrogen nucleophiles, is carried out by nucleophilic substitution on dialkylester derivatives of diaryldicarboxylic acid according to methods known from the literature. With this substitution, halides and trifluoromethanesulfonates proved to be good starting groups on the diaryl-dicarboxylic acid derivative. It is preferably carried out in a dipolar aprotic solvent, such as DMF, or TMU, at a temperature from 0°C to the boiling point of the solvent, preferably from 80°C to the boiling point of the solvent. An alkaline or alkaline earth salt with an anion of high basicity and slight nucleophilicity, for example K2CO3 or CsCO3, serves as an acid acceptor.

The introduction of alkyl and aryl substituents is done by crosslinking aryl halides with, for example, organic compounds of zinc, organic compounds of tin, organic compounds of boric acid or organoborane by means of palladium, according to methods known from the literature.

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

US Patent 5 091 394 (HOE 89/F 288) and European Patent Application 0 556 674 (HOE 92/F 034) describe benzoylguanides, but not diguanides of diaryldicarboxylic acids. WO 94/26 709 (PTC/JP94/00786) already describes the possibility of introducing a phenyl nucleus in the meta position of benzoylguanidine as a substituent R(2) (among many other possibilities), and this second phenyl nucleus can (among many other possibilities) also carry a guanidyl group as a substituent. However, these known compounds are not satisfactory for many application possibilities.

Due to their pharmacological properties, the compounds according to the invention are extremely suitable as antiarrhythmics with a cardioprotective component for the prophylaxis of heart attacks and the treatment of heart attacks, as well as for the treatment of angina pectoris, whereby they also preventively inhibit or greatly reduce pathophysiological processes in the occurrence of ischemia-induced injuries, especially in the occurrence of heart attacks arrhythmias induced by ischemia. Due to their protective action against pathological hypoxic and ischemic situations, the compounds according to the invention of formula I, due to the inhibition of the cellular mechanism of Na*/H+ exchange, can be used as drugs for the treatment of all acute or chronic injuries caused by ischemia or primary or secondary diseases induced thereby. This refers to their use as drugs in surgical procedures, for example in organ transplants, where the compounds can be used to protect organs in the donor, before and during collection, to protect extracted organs, for example during processing or when they are disposed of in physiological fluids baths, as well as when transferring it to the recipient's body. The compounds are also valuable drugs with a protective effect during angioplasty operations, for example on the heart, as well as on peripheral blood vessels. In accordance with their protective effect against ischemia-induced injuries, the compounds are also suitable as drugs for the treatment of ischemia of the nervous system, in particular of the central nervous system, where they are suitable, for example, for the treatment of stroke or cerebral edema. The compounds according to the invention of formula I are also suitable for the treatment of forms of shock, such as allergic, cardiogenic, hypovolemic and bacterial shock.

Furthermore, the compounds according to the invention of formula I are characterized by a strong inhibitory effect on cell proliferation, for example cell proliferation of fibroblasts and proliferation of smooth muscle cells of blood vessels. Therefore, the compounds of formula I come into consideration as valuable therapeutics for diseases in which cell proliferation is the primary or secondary cause, and therefore can be used as antiatherosclerotics, agents against diabetic late complications, cancer, fibrotic diseases such as pulmonary fibrosis, liver fibrosis or fibrosis kidney, organ hypertrophy and hyperplasia, especially in prostate hyperplasia, i.e. prostate hypertrophy.

The compounds according to the invention are effective inhibitors of cellular sodium-proton antiporters (Na+/H+ exchangers) which are also elevated in numerous diseases (essential hypertension, atherosclerosis, diabetes, etc.) in such cells for which measurements are easily available, such as in erythrocytes, platelets or leukocytes. The compounds according to the invention are therefore suitable as a prominent and simple scientific tool, for example for use in diagnostics to determine and differentiate certain forms of hypertension, but also for atherosclerosis, diabetes, proliferative diseases, etc. Furthermore, the compounds of formula I are suitable for

preventive therapy to prevent the genesis of high blood pressure, for example essential hypertension.

Compared to most known compounds, the compounds according to the invention have significantly better water solubility. This is why they are much better for i.v. application.

Compared to known water-soluble compounds, the compounds according to the invention are characterized by excellent bioavailability and pharmacokinetics.

In this case, drugs containing compound I can be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred application depending on the respective disease presentation. Here, compounds I can be used alone or together with galenic excipients, both in veterinary medicine and in human medicine.

Excipients suitable for the desired drug formulation are known to the expert based on his professional knowledge. In addition to solvents, agents for forming gels, bases for suppositories, excipients for tablets and other active substance carriers, antioxidants, dispersants, emulsifiers, anti-foaming agents, taste correction agents, preservatives, and dissolution enhancers can also be used. or dyes.

For oral application, the active compounds are mixed with suitable additional substances, such as carriers, stabilizers or inert diluents, and converted into suitable forms for administration, such as tablets, dragees, capsules, aqueous, alcoholic or oily solutions, by the usual methods. Gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, especially corn starch, can be used as inert carriers. At the same time, the preparation can be dry or also a wet granulate. Vegetable or animal oils, such as sunflower oil or fish liver oil, can be used as oil carriers or solvents.

For subcutaneous or intravenous administration, the active compounds are, if desired, converted into solutions, suspensions or emulsions with the usual solubilizers, emulsifiers or other excipients. Suitable solvents include, for example, water, physiological saline solution or alcohols, for example ethanol, propanol, glycerin, and also sugar solutions, such as glucose or mannitol solutions, or also a mixture of different mentioned solvents.

For example, solutions, suspensions or emulsions of the active substance of formula I in a pharmaceutically acceptable solvent, especially ethanol or water, or a mixture of such solvents are suitable as pharmaceutical formulations for administration in the form of an aerosol or spray. If necessary, the formulation can also contain other pharmaceutical auxiliary substances such as surfactants, emulsifiers and stabilizers, and propellant gas. Such a preparation contains the active substance usually in a concentration of about 0.1 to 10, especially from about 0.3 to 3 wt. %.

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

On average, the daily dose of the compound of formula I in a patient weighing approximately 75 kg is at least 0.001 mg/kg body weight, preferably at least 0.01 mg/kg body weight, up to 10 mg/kg body weight, preferably up to 1 mg/kg body weight weight. In case of acute disease outbreaks, approximately immediately after a heart attack, higher and above all more frequent dosages may be required, for example up to 4 individual doses per day. Especially with i.v. application, possibly in a patient with a heart attack in the intensive care unit, up to 100 mg per day may be necessary.

List of abbreviations:

ATBN α,α-azo-bis-isobutyronitrile

Bn benzyl

A saturated aqueous solution of NaCl is concerned

CH2Cl2 dichloromethane

DCI desorption chemical ionization

DIP diisopropyl ether

DMA dimethylacetamide

DME dimethoxyethane

DMF N,N-dimethylformamide

EE ethyl acetate (EtOAc)

EI electron impact

eq. equivalent

ES ionization by electrospray

Et ethyl

FAB bombing with fast atoms

HEP n-heptane

HOAc acetic acid

Me methyl

MeOH methanol

Mp melting point

MTB methyl tert.butyl ether

NBS N-bromosuccinimide

NMP N-methylpyrrolidone

RT room temperature

THF tetrahydrofuran

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

Tol toluene

CNS central nervous system

Experimental, part

General regulation for the production of diaryldicarboxylic acid diguanide (I) from benzodicarboxylic acid dialkylester (II, L=O-alkyl)

5 mmoles of benzodicarboxylic acid dialkylester of formula II as well as 50 mmoles of guanidine (free base) are dissolved in 5 ml of isopropanol and boiled under reflux until complete chemical conversion (thin-layer control) (depending on the activity of the carbonyl, the typical reaction time is from 5 minutes to 10 hours ). At the end, it is diluted with 150 ml of water and the product is sucked off. If necessary, chromatograph on silica gel with a suitable eluent, eg EE/MeOH 5:1 or with acetone/water 10:1.

Example 1

3-(4-guanidinocarbonyl)phenyl-benzoylguanidine

[image]

a) Ethyl ester of 3-(4-formyl)phenyl-benzoic acid

3.4 g of ethyl ester of 3-bromobenzoic acid, 170 mg of palladium(II)-acetate, 390 mg of triphenylphosphine, 2.5 g of 4-formyl-phenylboronic acid, 15 ml of 2N aqueous solution of Na2CO3, 90 ml of toluene and 25 ml of boiling ethanol for 2 hours under reflux in an argon atmosphere. At the end, 150 ml of saturated aqueous solution of Na2CO3 is added and extracted 3 times with 150 ml of EE each. It was dried over Na2SO4 and the solvent was removed in vacuo. Chromatography on silica gel with EE/HEP 1:8 gives 2.4 g of white crystals, melting point 81°C.

Rf(DIP)=0.55

MS(DCI): 255 (M+H) +

b) Ethyl ester of 3-(4-ethoxycarbonyl)phenyl-benzoic acid

2.4 g of 3-(4-formyl)phenyl-benzoic acid ethyl ester are dissolved in 190 ml of ethanol and 2.3 g of NaCN and 1.1 ml of glacial acetic acid are added at room temperature. After 15 minutes a clear solution is obtained, 18.9 g of MnO2 is added at room temperature. It is stirred for 7 hours at room temperature, the precipitate is filtered off and the filtrate is poured into 300 ml of saturated aqueous Na2CO3 solution and extracted 3 times with 300 ml of EE each. It was dried over Na2CO3 and the solvent was removed in vacuo. Chromatography on silica gel with EE/HEP 1:4 gives 2.5 g of colorless oil.

Rf(DIP)=0.59 MS(ES): 299(M+H)+

c) 3-(4-guanidinocarbonyl)phenyl-benzoylguanidine

1.1 g of ethyl ester of 3-(4-ethoxycarbonyl)phenyl-benzoic acid is chemically converted according to the general recipe for the production of diaryldicarboxylic acid diguanide and 760 mg of colorless crystals are obtained, melting point 113°C. Rf(acetone/water 10:1)=0.21

MS(FAB): 325 (M+H) +

The title compound of Example 2 was synthesized analogously to Example 1:

Example 2

2-(4-guanidinocarbonyl)phenyl-benzoylguanidine

[image]

Melting point 283°C.

Rf(acetone/water 10:1)=0.25

MS(FAB): 325(M+H)+

Example 3

4-(4-guanidinocarbonyl)phenylsulfamoyl-benzoylguanidine

[image]

a) Ethyl ester of 4-sulfamoyl-benzoic acid

Dissolve 20 g of 4-sulfamoyl-benzoic acid in 500 ml of ethanol, add 36 ml of SOCl2 and boil for 5 hours under reflux. At the end, the volatile ingredients are removed in a vacuum, adjusted to pH 9 with a saturated aqueous solution of Na2CO3 and extracted 3 times with 200 ml of EE each. It is dried over Na2SO4, the solvent is removed in vacuo and 21 g of colorless crystals are obtained, melting point 108°C.

Rf(DIP)=0.24

MS(DCI): 230(M+H)+

b) Ethyl ester of 4-(4-ethoxycarbonyl)phenylsulfamoyl-benzoic acid

1.1 g of ethyl ester of 4-sulfamoyl-benzoic acid, 840 mg of ethyl ester of 4-fluorobenzoic acid and 4.9 g of Cs2CO3 are mixed in 10 ml of NMP for 10 hours at 130°C. Finally, let it cool to room temperature, add 200 ml of EE and wash 3 times with 100 ml of water each. It was dried over Na2SO4 and the solvent was removed in vacuo. Chromatography on silica gel with EE/HEP 1:1 gives 2.6 g of a colorless oil.

Rf (EE/HEP 1:1)=0.38

MS(DCI): 378 (M+H) +

c) 4-(4-guanidinocarbonyl)phenylsulfamoyl-benzoylguanidine

2.5 g of ethyl ester of 4-(4-ethoxycarbonyl)phenylsulfamoyl-benzoic acid is chemically converted according to the general procedure for the production of diaryldicarboxylic acid diguanide (reaction time 10 hours) and 560 mg of a white amorphous solid is obtained.

Rf(acetone/water 10:1)=0.16

MS(FAB): 446 (M+H) +

The title compound of Example 4 was synthesized according to the general procedure for the production of diaryldicarbon diguanides

acids from the dimethyl ester of biphenyl-4,4-dicarboxylic acid:

Example 4

Biphenyl-4,4'-dicarboxylic acid-diguanidide

[image]

Rf(acetone/water 10:1)=0.09

MS(FAB): 325 (M+H) +

Example 5

4-[3-(guanidinocarbonyl)phenylarinocarbonylarinosulfonyl]-benzoylguanidine

[image]

a) Methyl ester of 4-ethoxycarbonylaminosulfonyl-benzoic acid

6.0 g of 4-aminosulfonyl-benzoic acid methyl ester and 7.7 g of K2CO3 in 100 ml of anhydrous DME are boiled for 5 minutes under reflux. At the end, 5.3 ml of methyl ester of chloroformic acid is injected and boiled for another 2 hours under reflux. It is allowed to cool, the solid substance is suctioned off and the product is released by mixing with 100 ml of saturated aqueous NaHSO4 solution and 200 ml of water. The product is sucked off and dried in a vacuum at 50°C. 7.1 g of colorless crystals are obtained. Melting point 146°C.

Rf(EE)=0.41

MS(DCI): 288(M+H)+

b) 4-ethoxycarbonylarainosulfonyl-benzoic acid

6 g of methyl ester of 4-ethoxycarbonylaminosulfonyl-benzoic acid and 42 ml of 1 N aqueous NaOH solution in 50 ml of MeOH are mixed for 24 hours at room temperature. The solvent is removed in a vacuum, taken up in 100 ml of water, adjusted to pH 1-2 with a dilute aqueous solution of hydrochloric acid and the product is suctioned off. It is dried in vacuum and 5.5 g of colorless crystals are obtained.

Melting point 189°C.

Rf(DIP/2% HOAc)=0.28

MS(ES): 274(M+H)+

c) 4-[3-hydroxycarbonyl)phenylaminocarbonylaminosulfonyl]-benzoic acid

7.4 g of 4-ethoxycarbonylaminosulfonyl-benzoic acid and 1 g of 3-aminobenzoic acid in 50 ml of anhydrous toluene are boiled for 10 hours under reflux. The solvent is removed in vacuo to give 2.8 g of crude product, which is converted directly further.

d) 4-[3-(guanidinocarbonyl)phenylaminocarbonylaminosulfonyl]-benzoylguanidine

1.4 g of 4-[3-hydroxycarbonyl)phenylaminocarbonylamino-sulfonylbenzoic acid and 1.4 g of carbonyldiuraidazole are dissolved in 60 ml of a mixture of anhydrous THF and anhydrous DMF and stirred for 24 hours at room temperature. Finally, 2.5 g of guanidine is added and the mixture is stirred for another 24 hours at room temperature. Solvents are removed in a vacuum, the product is suspended in 100 ml of water, then adjusted to pH 7 with a dilute aqueous hydrochloric acid solution and stirred for 1 hour at room temperature. The product is sucked off and dried in a vacuum. 820 mg of colorless crystals are obtained. Melting point 207°C.

Rf(CH2Cl2/MeOH/water/HOAc 8:4:1:1)=0.56

M3(ES): 447(M+H)+

Pharmacological data

Inhibition of Na+/H+-exchanger in rabbit erythrocytes

White New Zealand rabbits (Ivanovas) were fed a standard diet with 2% cholesterol for six weeks to activate the Na+/H+-exchange and thus the entry of Na+ into erythrocytes by Na+/H+-exchange could be determined by flame photometry. Blood was taken from the ear arteries and clotting was prevented with 25 IU potassium heparin. One part of each sample was used for double determination of hematocrit by centrifugation. Aliquots of 100 µl each were used to measure the initial content of Na+ in erythrocytes.

To determine amiloride-sensitive sodium entry, 100 µl of each blood sample was incubated in 5 ml of hyperosmotic salt-sucrose solution (mmol/1: 140 NaCl, 3 KCl, 150 sucrose, 0.1 oubain, 20 tris-hydroxymethyl- aminomethane) at pH 7.4 and 37°C. After that, the erythrocytes were washed three times with an ice-cold solution of MgCl2-oubain (mmol/1: 112 MgCl2, 0.1 oubain) and hemolyzed in 2.0 ral of distilled water. Intracellular sodium content was determined by flame photometry.

Na+ entry was calculated as the difference between the initial value of sodium content and the sodium content of erythrocytes after incubation. Sodium entry that can be suppressed with amiloride was obtained from the difference in sodium content in erythrocytes after incubation with and without 3 x 10-4 mol/I amiloride. This was also the case with the compounds according to the invention.

the results

Inhibition of Na+/H+-exchanger:

[image]

Claims (20)

1. Diguanidides of diaryldicarboxylic acid of formula I [image] indicated by that one of the residues R(1), R(2), R(3), R(4) and R(5) represents -CO-N=C (NH2)2; always different residues R(1) and R(5) independently represent hydrogen, alkyl with 1, 2, 3 or 4 carbon atoms, F, Cl, -OR(32), -NR(33)R(34) or CF3; R(32), R(33) and R(34) independently represent hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms; always different residues R(2) and R(4) independently represent hydrogen, F, Cl, Br, J, OH, -CN, CF3, -CO-N=C (NH2)2, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, alkenyl with 2, 3, 4, 5, 6, 7 or 8 C-atoms or -(CH2)m-R(14); m is zero, 1 or 2; R(14) represents -(C3-C8)-cycloalkyl or phenyl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F and Cl, -CF3, methyl, methoxy and -NR(15)R( 16); R(15) and R(16) represent hydrogen or -CH3; or always different residues R(2) and R(4) independently represent pyrrole-1-yl, pyrrole-2-yl or pyrrole-3-yl, which is unsubstituted or substituted with 1-4 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C8)-Alkanoyl, (C2-C8)-Alkoxycarbonyl, Formyl, Carboxy, -CF3, Methyl, Methoxy; or always different residues R(2) and R(4) independently represent R(22)-SO2-, R(23)R(24)N-CO-, R(28)-CO- or R(29) R(30)N -SO2-; R(22) and R(28) independently represent methyl or -CF3; R(23), R(24, R(29) and R(30) independently represent hydrogen or methyl; or always different residues R(2) and R(4) independently represent -OR(35) or -NR(35)R(36); R(35) and R(36) independently represent hydrogen or alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms; or R(35) and R(36) represent 4-7 methylene groups of which one CH2 group can be substituted with oxygen, -S-, -NH-, -NCH3 or -N-benzyl; always a different remainder R(3) represents hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27); R(25) represents hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms or phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, inethoxy, hydroxy, amino, methylamino and diethylamino; or R(25) represents -(C1-C9)-heteroaryl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxy, amino, methylamino and dimethylamino; R(26) and R(27) are independently defined as R(25) or represent hydrogen or alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; one of the residues R(6), R(7), R(8), R(9) and R(10) represents -CO-N=C(NH2)2; always different residues R(6) and R(10) independently represent hydrogen, alkyl with 1, 2, 3 or 4 C-atoms, F, Cl, -OR(132), -NR(133)R(134) or CF3; R(132), R(133) and R(134) independently represent hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms; always different residues R(7) and R(9) independently represent hydrogen, F, Cl, Br, J, OH, -CN, CF3, -CO-N=C(NH2)2, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, alkenyl with 2, 3, 4, 5, 6, 7 or 8 C-atoms or -(CH2)mmR(114); mm is zero, 1 or 2; R(114) represents -(C3-C8)-cycloalkyl or phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F and Cl, -CF3r methyl, methoxy and -NR(115)R(116 ) ; R(115) and R(116) represent hydrogen or -CF3; or always different residues R(7) and R(9) independently represent pyrrole-1-yl, pyrrole-2-yl or pyrrole-3-yl, which is unsubstituted or substituted with 1-4 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C8)-Alkanoyl, (C2-C8)-Alkoxycarbonyl, Tormyl, Carboxy, -CF3, Methyl and Methoxy; or always different residues R(7) and R(9) represent R(122)-SO2-, R(123)R(124)N-CO-, R(128)-CO- or R(129)R(130)N-SO2 -; R(122) and R(128) independently represent methyl or -CF3; R(123), R(124), R(129) and R(130) independently represent hydrogen or methyl; or always different residues R(7) and R(9) independently represent -OR(135) or -NR(135)R(136); R(135) and R(136) independently represent hydrogen or alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms; or R(135) and R(136) together represent 4-7 methylene groups of which one CH2 group can be substituted with oxygen, -S-, -NH-, -NCH3 or -N-benzyl; always a different remainder R(8) represents hydrogen, -SR(125), -OR(125), -NR(125)R(126) or -CR(125)R(126)R(127); R(125) represents hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms or phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxy, amino, methylamino and dimethylamino; or R(125) represents -(C1-C9)-heteroaryl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxy, amino, methylamino and dimethylamino; R(126) and R(127) are independently defined as R(125) or represent hydrogen or alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; A, absent, represents -NR(11)-CO-, -NR(12)-CO-NR(13)-, -NR(17)-CO-NR(18)-SO2-, -NR(19)- SO2-, -SO2-NR(19)-SO2-, -SO2-NR(19)-CO-, -O-CO-NR(19)-SO2- or -CR(20)=CR(21); R(11), R(12), R(13), R(17), R(18), R(19) and R(20) and R(21) independently represent hydrogen or alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; and their pharmaceutically acceptable salts. 2. The compound of formula I according to claim 1, characterized by the fact that in it one of the residues R(1), R(2), R(3), R(4) and R(5) represents -CO-N=C( NH2)2; always different residues R(1) and R(5) independently represent hydrogen, alkyl with 1, 2 or 3 carbon atoms, F, Cl, -OR(32), -NR(33)R(34) or CF3; R(32), R(33) and R(34) independently represent hydrogen or methyl; always different residues R(2) and R(4) independently represent hydrogen, F, Cl, Br, J, OH, CF3, -CO-N=C(NH2)2, alkyl with 1, 2, 3 or 4 C-atoms, alkenyl with 2, 3 or 4 carbon atoms or -(CH2)m-R(14); m is zero, 1 or 2; R(14) represents -(C3-C6)-cycloalkyl or phenyl, which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F and Cl, -CF3, methyl and methoxy; or always different residues R(2) and R(4) independently represent pyrrole-1-yl, pyrrole-2-yl or pyrrole-3-yl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C5)-Alkanoyl, (C2-C5)-Alkoxycarbonyl, formyl, carboxy, -CF3 and methyl; or always different residues R(2) and R(4) independently represent R(22)-SO2-, R(28)-CO- or R(29)R(30)N-SO2-; R(22) and R(28) independently represent methyl or -CF3; R(29) and R(30) independently represent hydrogen or methyl; or always different residues R(2) and R(4) independently represent -OR(35) or -NR(35)R(36); R(35) and R(36) independently represent hydrogen, methyl or ethyl; or R(35) and R(36) together represent 4-5 methylene groups of which one CH2 group can be substituted with oxygen, -S-, -NH-, -NCH3; always a different remainder R(3) represents hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR (25) R (26) R (27); R(25) represents hydrogen or alkyl with 1, 2, 3 or 4 C-atoms or phenyl, which is not substituted or is substituted with 1-2 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy and dimethylamino; or R(25) represents -(C1-C9)-heteroaryl which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy and dimethylamino; R(26) and R(27) independently represent hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms; one of the residues R(6), R(7), R(8), R(9) and R(10) represents -CO-N=C (NH2)2, always different residues R(6) and R(10) independently represent hydrogen, alkyl with 1, 2 or 3 carbon atoms, F, Cl, -OR(132), -NR(133)R(134) or CF3; R(132), R(133) and R(134) independently represent hydrogen or methyl; always different residues R(7) and R(9) independently represent hydrogen, F, Cl, Br, J, OH, -CN, CF3, -CO-N=C(NH2)2, alkyl with 1, 2, 3 or 4 C -atom, alkenyl with 2, 3 or 4 C-atoms or -(CH2)mmR(114) ; mm is zero, 1 or 2; R(114) represents -(C3-C6)-cycloalkyl or phenyl, which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F and Cl, -CF3, methyl and methoxy; or always different residues R(7) and R(9) independently represent pyrrole-1-yl, pyrrole-2-yl or pyrrole-3-yl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C5)-Alkanoyl, (C2-C5)-Alkoxycarbonyl, formyl, carboxy, -CF3 and methyl; or always different residues R(7) and R(9) independently represent R(122)-SO2-, R(128)-CO- or R(129) R(130) N-SO2-; R(122) and R(128) independently represent methyl or -CF3; R(129) and R(130) independently represent hydrogen or methyl; or always different residues R(7) and R(9) independently represent -OR(135) or -NR(135)R(136); R(135) and R(136) independently represent hydrogen, methyl or ethyl; or R(135) and R(136) together represent 4-5 methylene groups of which one CH2 group can be substituted with oxygen, -S-, -NH- or -NCH3; always a different remainder R(8) represents hydrogen, -SR(125), -OR(125), -NR(125)R(126) or -CR(125) R(126) R(127); R(125) represents hydrogen, alkyl with 1, 2, 3 or 4 C-atoms or phenyl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy or dimethylamino; or R(125) represents -(C1-C9)-heteroaryl which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy and dimethylamino; R(126) and R(127) independently represent hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms; A, absent, represents -NR(11)-CO-, -NR(12)-CO-NR(13)-, -NR(17)-CO-NR(18)-SO2-, -NR(19) - SO2-, -SO2-NR(19)-SO2-, -SO2-NR(19)-CO-, -O-CO-NR(19)-SO2- or -CR(20)=CR(21); R(11), R(12), R(13), R(17), R(18), R(19), R(20) and R(21) independently represent hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms; and their pharmaceutically acceptable salts. 3. Compound of formula I according to claim 1 or 2, characterized in that one of the residues R(1), R(2), R(3), R(4) and R(5) represents -CO-N=C( NH2)2; always different residues R(1) and R(5) independently represent hydrogen, alkyl with 1, 2 or 3 carbon atoms, F, Cl, -OR(32), -NR(33)R(34) or CF3; R(32), R(33) and R(34) independently represent hydrogen or methyl; always different residues R(2) and R(4) independently represent hydrogen, F, Cl, Br, J, OH, CF3, -CO-N=C(NH2)2, alkyl with 1, 2, 3 or 4 C-atoms or pyrrole-1-yl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxy-carbonyl , form1, carboxy, -CF3 and methyl; or always different residues R(2) and R(4) represent R(22)-SO2-; R(22) represents methyl or -CF3; or always different residues R(2) and R(4) independently represent -OR(35) or -NR(35)R(36); R(35) and R(36) independently represent hydrogen, methyl or ethyl; or always a different remainder R(3) represents hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27); R(25) represents hydrogen, alkyl with 1, 2 or 3 C-atoms or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3; or R(25) represents -(C1-C9)-heteroaryl which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3; R(26) and R(27) independently represent hydrogen or methyl; one of the residues R(6), R(7), R(8), R(9) and R(10) represents -CO-N=C(NH2)2, always different residues R(6) and R(10) independently represent hydrogen, alkyl with 1, 2 or 3 carbon atoms, F, Cl, -OR(132), -NR(133)R(134) or CF3; R(132), R(133) and R(134) independently represent hydrogen or methyl; always different residues R(7) and R(9) independently represent hydrogen, F, Cl, OH, CF3, -CO-N=C(NH2)2, alkyl with 1, 2, 3 or 4 C-atoms, pyrrole-1- il, which is not substituted or is substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxy, - CF3 and methyl; or always different residues R(7) and R(9) independently represent R(122)-SO2-; R(122) represents methyl or -CF3; or always different residues R(7) and R(9) independently represent -OR(135) or -NR(135)R(136); R(135) and R(136) independently represent hydrogen, methyl or ethyl; always a different remainder R(8) represents hydrogen, -SR(125), -OR(125), -NR(125)R(126) or -CR(125)R(126)R(127); R(125) represents hydrogen, alkyl with 1, 2 or 3 C-atoms or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3; or R(125) represents C1-C9)-heteroaryl which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3; R(126) and R(127) independently represent hydrogen or methyl; A, absent, represents -NR(11)-CO-, -NR(12)-CO-NR(13)-, -NR(17)-CO-NR(18)-SO2-, -NR(19)- SO2-, -SO2-NR(19)-SO2-, -SO2-NR(19)-CO-, -O-CO-NR(19)-SO2- or -CR(20)=CR(21)-; R(11), R(12), R(13), R(17), R(18), R(19), R(20) and R(21) independently represent hydrogen, methyl or ethyl. 4. Compound of formula I according to at least one of claims 1 to 3, characterized in that one of the residues R(1), R(2), R(3), R(4) and R(5) represents -CO-N =C(NH2)2; always different residues R(1) and R(5) independently represent alkyl with 1, 2 or 3 carbon atoms, F, Cl or CF3; always different residues R(2) and R(4) represent hydrogen, OH, CF3, -CO-N=C(NH2)2, alkyl with 1, 2, 3 or 4 C-atoms or pyrrol-1-yl, which is not substituted or is substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxy, -CF3 and methyl; always a different remainder R(3) represents hydrogen -OR(25) or -CR(25)R(26)R(27); R(25) represents hydrogen, alkyl with 1, 2 or 3 C-atoms or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3; or R(25) represents -(C1-C9)-heteroaryl which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3; K(26) and R(27) independently represent hydrogen or methyl; one of the residues R(6), R(7), R(8), R(9) and R(10) represents -CO-N=C(NH2)2, always different residues R(6) and R(10) independently represent hydrogen, alkyl with 1, 2 or 3 carbon atoms, F, Cl or CF3; always different residues R(7) and R(9) represent hydrogen, OH, CF3, -CO-N=C(NH2)2, alkyl with 1, 2, 3 or 4 C-atoms, pyrrole-1-yl, which is not substituted or is substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, J, -CM, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxy, -CF3 and methyl; always a different remainder R(8) represents hydrogen, -OR(125) or -CR(125)R(126)R(127); R(125) represents hydrogen, alkyl with 1, 2 or 3 C-atoms or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3; or R(125) represents -(C1-C9)-heteroaryl which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3; R(126) and R(127) independently represent hydrogen or methyl; A, absent, represents -NR(11)-CO-, -NR(12)-CO-NR(13)-, -NR(17)-CO-NR(18)-SO2-, -NR(19)- SO2-, -SO2-NR(19)-SO2-, -SO2-NR(19)-CO-, -O-CO-NR(19)-SO2- or -CR(20)=CR(21)-; R(11), R(12), R(13), R(17), R(18), R(20) and R(21) independently represent hydrogen or methyl. 5. Compound of formula I according to at least one of claims 1 to 4, indicated by that one of the residues R(1), R(3) and R(5) represents -CO-N=C(NH2)2; always different residues R(1) and R(5) independently represent alkyl with 1, 2 or 3 carbon atoms, F, Cl or CF3; R(2) and R(4) represent hydrogen, OH, CF3, alkyl with 1, 2, 3 or 4 C-atoms or pyrrol-1-yl, which is unsubstituted or substituted with -2 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C5)-Alkanoyl, (C2-C5)-Alkoxycarbonyl, formyl, carboxy, -CF3 and methyl; always a different remainder R(3) represents hydrogen, -OR(25) or -CR(25)R(26)R(27); R(25) represents hydrogen or alkyl with 1, 2 or 3 C-atoms or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF- and CH-; or R(25) represents -(C1-C9)-heteroaryl which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3; R(26) and R(27) independently represent hydrogen or methyl; one of the residues R(6), R(8) and R(10) represents -CO-N=C(NH2)2, always different residues R(6) and R(10) independently represent hydrogen, alkyl with 1, 2 or 3 carbon atoms, F, Cl or CF3; R(7) and R(9) represent hydrogen, OH, CF3, alkyl with 1, 2, 3 or 4 C-atoms, pyrrole-1-yl, which is unsubstituted or substituted with 1-2 substituents selected from the group consist of F, Cl, Br, J, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxy, -CF3 and methyl; always a different remainder R(8) represents hydrogen, -OR(125) or -CR(125)R(126)R(127); R(125) represents hydrogen, alkyl with 1, 2 or 3 C-atoms or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CK3; or R(125) represents -(C1-C9)-heteroaryl which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3; R(126) and R(127) independently represent hydrogen or methyl; A, absent, represents -NR(11)-CO-, -NR (12) -CO-NR(13)-, -NR(17)-CO-NR(18)-SO2-, -NR(19)-SO2-, -SO2-NR(19)-SO2-, -SO2-NR(19)-CO-, -O-CO-NR(19) -SO2- or -CR(20)=CR(21)-; R(11), R(12), R(13), R(17), R(18), R(19), R(20) and R(21) independently represent hydrogen or methyl. 6. Compound of formula I according to at least one of claims 1 to 4, characterized in that that one of the residues R(1), R(2), R(3), R(4) and R(5) represents -CO-N=C(NH2)2; always different residues R(1) and R(5) independently represent alkyl with 1, 2 or 3 carbon atoms, F, Cl or CF3; always different residues R(2) and R(4) independently represent hydrogen, OH, CF3 -CO-N=C(NH2)2, alkyl with 1, 2, 3 or 4 C-atoms or pyrrole-1-yl, if less substituted or is substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxy, -CF3 and methyl; always a different remainder R(3) represents hydrogen, -OR(25) or -CR(25)R(26)R(27); R(25) represents hydrogen, alkyl with 1, 2 or 3 C-atoms or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3; or R(25) represents -(C1-C9)-heteroaryl which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3; R(26) and R(27) independently represent hydrogen or methyl; one of the residues R(6), R(7), R(8), R(9) and R(10) represents -CO-N=C(NH2)2; always different residues R(6) and R(10) independently represent hydrogen, alkyl with 1, 2 or 3 carbon atoms, F, Cl or CF3; always different residues R(7) and R(9) independently represent hydrogen, OH, CF3, -CO-N=C(NH2)2, alkyl with 1, 2, 3 or 4 C-atoms, pyrrol-1-yl, which is not substituted or is substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxy, -CF3 and methyl; always a different remainder R(8) represents hydrogen, -OR(125) or -CR(125)R(126)R(127); R(125) represents hydrogen, alkyl with 1, 2 or 3 C-atoms or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3; or R(125) represents -(C1-C9)-heteroaryl which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3; R(126) and R(127) independently represent hydrogen or methyl; A represents -NR(11)-CO-, -NR(12)-CO-NR(13), -NR(17)-CO-NR(18)-SO2-, -NR(19)-SO2-, - SO2-NR(19)-SO2-, SO2-NR(19)-CO-, -O-CO-NR(19)-SO2- or -CR(20)=CR(21)-; R(11), R(12), R(13), R(17), R(18), R(19), R(20) and R(21) independently represent hydrogen or methyl. 7. Process for the production of compounds I, characterized in that the compound of formula II [image] in which R(1') to R(10') have the meanings specified in claim 1 for R(1) to R(10), of which however at least one of the substituents R(1') to R(5') and at least one of the substituents R(6') to R(10') represents a labeled COL group, and in which L represents a nucleophilic leaving group that can easily be substituted, chemically converted with guanidine. 8. Use of compound I according to claim 1, characterized in that it is used for the production of a drug for the treatment of diseases caused by ischemic conditions. 9. Use of compound I according to claim 1, characterized in that it is used for the production of a drug for the treatment of arrhythmias. 10. A method for the treatment of arrhythmias, characterized in that an effective amount of the compound I according to claim 1 is mixed with common additives and administered in a form suitable for administration. 11. Use of compound I according to claim 1, characterized in that it is used for the production of a drug for the treatment or prophylaxis of heart attack. 12. Use of compound I according to claim 1, characterized in that it is used for the production of a medicine for the treatment or prophylaxis of angina pectoris. 13. The use of compound I according to claim 1, characterized in that it is used for the production of a medicine for the treatment or prophylaxis of ischemic conditions of the heart. 14. The use of compound I according to claim 1, characterized in that it is used for the production of a drug for the treatment or prophylaxis of ischemic conditions of the peripheral and central nervous system and stroke. 15. Use of compound I according to claim 1, characterized in that it is used for the production of a medicine for the treatment or prophylaxis of ischemic conditions of peripheral organs and limbs. 16. The use of compound I according to claim 1, characterized in that it is used for the production of a medicine for the treatment of shock conditions. 17. Use of compound I according to claim 1, characterized in that it is used for the production of a medicine used in surgical operations and organ transplants. 18. Use of compound I according to claim 1, characterized in that it is used for the production of a drug used for preservation and disposal of transplants for surgical procedures. 19. The use of compound I according to claim 1, indicated ink, that it is used for the production of a drug for the treatment of diseases in which the primary or secondary cause is cell proliferation, and therefore it is used as an antiatherosclerotic agent, an agent against late complications of diabetes, cancer, fibrotic diseases such as pulmonary fibrosis, liver fibrosis or kidney fibrosis, prostate hyperplasia. 20. Medicine, characterized in that it contains an effective amount of compound I according to one or more claims 1 to 6.