NZ314145A

NZ314145A - Substituted diaryldicarboxylic acid diguanidides, preparation and pharmaceutical compositions

Info

Publication number: NZ314145A
Application number: NZ314145A
Authority: NZ
Inventors: Heinz-Werner Kleeman; Joachim Brendel; Jan-Robert Schwark; Andreas Weichert; Hans Joachen Lang; Udo Albus; Wolfgang Scholz
Original assignee: Hoechst Ag
Priority date: 1996-01-31
Filing date: 1997-01-29
Publication date: 1997-11-24
Also published as: HUP9700277A3; PL317844A1; IL120093A0; CZ27197A3; NO970406L; HRP970057A2; EP0787717A1; KR970059165A; TR199700059A2; NO970406D0; DE19603425A1; SK12797A3; TW430642B; HUP9700277A2; JPH09221465A; ZA97770B; AU1239097A; CA2196388A1; AR005596A1; HU9700277D0

Description

New Zealand Paient Spedficaiion for Paient Number 314145 V New Zealand No. 314145 International No. PCT/ TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION Priority dates: 31.01.1996; Complete Specification Filed: 29.01.1997 Classification: (6) CJ7C279/22; C07C317/32; A61K31/155 Publication date: 24 November 1997 Journal No.: 1422 NO DRAWINGS new zealand patents act 1953 COMPLETE SPECIFICATION Title of Invention: Substituted diaryldicarboxylic acid diguanidides, processes for their preparation, their use as a medicament or diagnostic, and medicament containing them Name, address and nationality of applicant(s) as in international application form: HOECHST AKTIENGESELLSCHAFT, a German company of D-65926 Frankfurt am Main, Germany 314 14 5 Patents Form 5 N.Z. No.

NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION SUBSTITUTED DIARYLDICARBOXYLIC ACID DIGUANIDIDES. PROCESSES FOR THEIR PREPARATION. THEIR USE AS A MF,DTCAMF,NT OW DIAGNOSTIC. AND MEDICAMENT CONTAINING THEM We, HOECHST AKTIENGESELLSCHAFT, a Company existing under the laws of the Federal Republic of Germany of, D-65926 Frankfurt am Main, Federal Republic of Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- ■g^ATEMTOmCE £9 1997 -1 - (Followed by 1A) Hooohst AkUfcJTiyBJpllaU iafl IA hoe gfi if nn 31 4 1 Description Substituted diaryldicarboxylic acid diguanidides, processes for their preparation, their use as a medicament or diagnostic, and medicament containing them The invention relates to diaryldicarboxylic acid diguanidides of the formula I •R7 R6 in which: one of the radicals R(1), R(2), R(3), R(4) and R(5) is -co-n=c(nh2)2; the other radicals R(1) and R(5) in each case independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon 20 atoms, F, CI, -OR(32), -NR(33)R(34) or CF3; R(32), R(33) and R(34) independently of one another are hydrogen or alkyl having 1,2, 3 or 4 carbon atoms; the other radicals R(2) and R(4) in each case independently of one another are hydrogen, F, CI, Br, I, OH, -CN, CF3, -CO-N=C(NH2)2. alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms or -(CH2)mR(14); m is zero, 1 or 2; R(14) is -(C3-C8)-cycloalkyl or phenyl, which is unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F and CI, -CF3, methyl, methoxy and -NR(15)R(16); R(15) and R(16) are hydrogen or -CH3; 31 4 1 or the other radicals R(2) and R(4) in each case independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrroi-3-yl, which is unsubstituted or substituted by 1 - 4 substituents selected from the group consisting of F, CI, Br, I, -CN, (C2-C8)-alkanoyl, (C2-C8)-alkoxycarbonyl, formyl, carboxyl, -CF3, methyl, methoxy; or the other radicails R(2) and R(4) in each case are R(22)-S02-, R(23)R(24)N-CO-, R(28)-CO- or R(29)R(30)N-S02; 10 R(22) and R(28) independently of one another are methyl or -CF3; R(23), R(24), R(29) and R(30) independently of one another are hydrogen or methyl; or the other radicals R(2) and R(4) in each case independently of one another are -OR(35) or -NR(35)R(36); R(35) and R(36) independently of one another are hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; or R(35) and R(36) together are 4 - 7 methylene groups, of which one CH2 group can be replaced by oxygen, -S-, -NH-, -NCH3 or -N-benzyl; the other radical R(3) in each case 25 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 substituted by 1 - 3 substituents selected from the group consisting of F, CI, CF3, CH3, methoxy, hydroxyl, amino, methylamino and dimethylamino; or R(25) is -(C-j-CgHieteroaryl, which is unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F, CI, CF3, CH3> methoxy, hydroxyl, 31 4 1 4- n amino, methylamino and dimethylamino; R(26) and R(27) independently of one another are defined as R(25) or are hydrogen or alkyl 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) is -CO-N=C(NH2)2 the other radicals R(6) and R(10) in each case independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, CI, -OR(132), -NR(133)R(134) or CF3; R(132), R(133) and R(134) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; the other radicals R(7) and R(9) in each case independently of one another are hydrogen, F, CI, Br, I, OH, -CN, CF3, 15 -CO-N=C(NH2)2, alkyl having 1, 2,3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms or -(CH2)mfnR(114); mm is zero, 1 or 2; R(114) a is -(C3-C8)-cycioalkyl or phenyl, which is unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F and CI, -CF3, methyl, methoxy and -NR(115)R(116); R(115) and R(116) are hydrogen or -CH3; or the other radicals R(7) and R(9) in each case independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl, which is unsubstituted or substituted by 1 - 4 substituents selected from the group consisting of F, CI, Br, I, -CN, (C2-C8)-alkanoyl, (C2-C8)-30 alkoxycarbonyl, formyl, carboxyl, -CF3, methyl and methoxy; or the other radicals R(7) and R(9) in each case are R(122)-SOr, R(123)R(124)N-CQ- R(128)-CO- or R(129)R(130)N-S02; 4 314 14 5 R(122) and R(128) independently of one another are methyl or -CF3; R(123), R(124), R(129) and R(130) independently of one another are hydrogen or methyl; or the other radicals R(7) and R(9) in each case independently of one another are -OR(135) or -NR(135)R(136); 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 are 4-7 methylene groups, of which one CH2 group can be replaced by oxygen, -S-, -NH-, -NCH3 or -N-benzyl; the other radical R(8) in each case is hydrogen, -SR(125), -OR(125), -NR(125)R(126) or-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 substituted by 1 - 3 substituents selected from the group consisting of F, CI, CF3, CH3, methoxy, hydroxyl, amino, methylamino and dimethylamino; or R(125) is -(C^CgJ-heteroaryl, which is unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F, CI, CF3, CH3, methoxy, hydroxyl, amino, methylamino and dimethylamino; R(126) and R(127) independently of one another are defined as R(125) or are hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; A is absent or is -NR(11)-CO-, -NR(12)-CO-NR(13)-t -NR(17)-C0-NR(18)-S02--NR(19)-S02-, -S02-NR(19)-S02-, -S02-NR(19)-C0-t -0-C0-NR(19)-S02- or -CR(20)=CR(21)-; 314 14 5 R(11), R(12), R(13), R(17), R(18), R(19), R(20) and R(21) independently of one another are hydrogen or alkyl having 1,2, 3, 4, 5, 6, 7 or 8 carbon atoms and their pharmaceutically tolerable salts.

Preferred compounds of the formula I are those in which: one of the radicals R(1), R(2), R(3), R(4) and R(5) is -CO-N=C(NH2)2 the other radicals R(1) and R(5) in each case 10 independently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, CI, -OR(32), -NR(33)R(34) or CF3; R(32), R(33) and R(34) independently of one another are hydrogen or methyl; the other radicals R(2) and R(4) in each case 15 independently of one another are hydrogen, F, CI, Br, I, OH, CF3, -CO- N=C(NH2)2, alkyl having 1, 2, 3 or 4 carbon atoms, alkenyl having 2, 3 or 4 carbon atoms or -(CH2)mR(14); m is zero, 1 or 2; R(14) is-{C3-C6)-cycloalkyl or phenyl, '20 which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F and CI, -CF3, methyl and methoxy; or the other radicals R(2) and R(4) in each case independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl, 25 which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, CI, Br, I, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxyl, -CF3 and methyl; or the other radicals R(2) and R(4) in each case 30 independently of one another are R(22)-S02-, R(28)-CO- or R(29)R(30)N-S02~; R(22) and R(28) independently of one another are methyl or -CF3; 31 4 ' R(29) and R(30) independently of one another are hydrogen or methyl; or the other radical's R(2) and R(4) in each case independently of one another are -OR(35) or -NR(35)R(36); R(35) and R(36) independently of one another are hydrogen, methyl or ethyl; or R(35) and R(36) together are 4 - 5 methylene groups, of which one CH2 group can be replaced by oxygen, -S-, -NH- or -NCH3; the other radical R(3) in each case 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 or 4 carbon atoms, 15 phenyl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, CI, CF3, CH3, methoxy and dimethylamino; or R(25) "20 is -(C1-C9)-heteroarylt which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, CI, CF3, CH3, methoxy and dimethylamino; R(26) and R(27) independently of one another are hydrogen or alkyl having 1,2, 3 or 4 carbon atoms; one of the radicals R(6), R(7), R(8), R(9) and R(10) is -CO-N=C(NH2)2 the other radicals R(6) and R(10) in each case 30 independently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, CI. -OR(132), -NR(133)R(134) or CF3; R(132), R(133) and R(134) independently of one another are hydrogen or methyl; 314 145 7 the other radicals R(7) and R(9) in each case independently of one another are hydrogen, F, CI, Br, I, OH, CF3, -CO-N=C(NH2)2. alkyl having 1, 2, 3 or 4 carbon atoms, alkenyl having 2, 3 or 4 carbon atoms or -(CH2)mmR(114); mm is zero, 1 or2; R(114) is-(C3-C6)-cycloalkyl or phenyl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F and CI, -CF3, methyl and methoxy; or the other radicals R(7) and R(9) in each case independently of one another are pyrrol-1-yl, pyn-ol-2-yl or pyrrol-3-yl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, CI, Br, I, -CN, (C2-C5)-alkanoyl, (C2-C5)-15 alkoxycarbonyl, formyl, carboxyl, -CF3 and methyl; or the other radicals R(7) and R(9) in each case independently of one another are R(122)-S02-, R(128)-C0- or R(129)R( 130)N-S02-; R(122) and R(128) independently of one another are methyl or -CF3; R(129) and R(130) independently of one another are hydrogen or methyl; or the other radicals R(7) and R(9) in each case independently of one another are -OR(135) or -NR(135)R(136); R(135) and R(136) independently of one another are hydrogen, methyl or ethyl; or R(135) and R(136) together are 4 - 5 methylene groups, of which one CH2 group can be replaced by oxygen, -S-, -NH- or -NCH3; the other radical R(8) in each case 3? 4 t l: 8 is hydrogen, -SR(125), -OR(125), -NR(125)R(126) or -CR(125)R(126)R(127); R(125) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, CI, CF3, CH3, methoxy and dimethylamino; or R(125) is -(C-, -C9)-heteroaryl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, CI, CF3, CH3, methoxy and dimethylamino; R(126) and R(127) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 15 carbon atoms; A is absent or is -NR(11)-CO-, -NR(12)-CO-NR(13)-, -NR(17)-C0-NR(18)-S02-t -NR(19)-S02-, -S02-NR(19)-S02-, -S02-NR(19)-CO-, -0-C0-NR(19)-S02- or -CR(20)=CR(21)-; R(11), R(12), R(13), R(17), R(18), R(19), R(20) and R(21) "20 independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; and their pharmaceutically tolerable salts.

Particularly preferred compounds of the formula I are those in which: one of the radicals R(1), R(2), R(3), R(4) and R(5) is -CO-N=C(NH2)2; the other radicals R(1) and R(5) in each case independently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, CI, -OR(32), -NR(33)R(34) or CF3; R(32), R(33) and R(34) independently of one another are hydrogen or methyl; the other radicals R(2) and R(4) in each case independently of one another are hydrogen, F, CI, Oh'. CF3, -CO-N=C(NH2)2, 31 4 1 4 alkyl having 1, 2, 3 or 4 carbon atoms or pyrrol-1-yl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, CI, Br, I, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxyl, -CF3 and methyl; or the other radicals R(2) and R(4) in each case are R(22)-S02-; R(22) is methyl or -CF3; or the other radicals R(2) and R(4) in each case independently of one another are -OR(35) or -NR(35)R(36); R(35) and R(36) independently of one another are hydrogen, mothyl or ethyl; the other radical R(3) in each case 15 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 a substituent selected from the group consisting of F, CI, CF3 and CH3; ~0 R(25) is -(C^CgJ-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, CI, CF3 and CH3; R(26) and R(27) independently of one another are hydrogen or methyl; one of the radicals R(6), R(7), R(8), R(9) and R(10) is -CO-N=C(NH2)2; the other radicals R(6) and R(10) in each case independently of one another are hydrogen, alkyl having 1, 2 or 3 carbon 30 atoms, F, CI, -OR(132), -NR(133)R(134) or CF3; R(132), R(133) and R(134) independently of one another are hydrogen or methyl; the other radicals R(7) and R(9) in each case 314 14 5 independently of one another are hydrogen, F, CI, OH, CF3, -CO-N=C(NH2)2, alkyl having 1, 2, 3 or 4 carbon atoms or pynrol-1 -yl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, CI, Br, I, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxyl, -CF3 and methyl; or the other radicals R(7) and R(9) in each case are R(122)-S02-; R(122) is methyl or -CF3; or the other radicals R(7) and R(9) in each case independently of one another are -OR(135) or -NR(135)R(136); R(135) and R(136) independently of one another are hydrogen, methyl or ethyl; the other radical R(8) in each case is hydrogen, -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, 20 which is unsubstituted or substituted by a substituent selected from the group consisting of F, CI, CF3 and CH3; or R(125) is -(C1 -C9)-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, CI, CF3 and CH3; R(126) and R(127) independently of one anoiher are hydrogen or methyl; A is absent or is -NR(11)-CO-, -NR(12)-CO-NR(13)-, -NR(17)-C0-NR(18)-S02-, 30 -NR(19)-SOr, -S02-NR(19)-S02-, -S02-NR(19)-C0-, -0-C0-NR(19)-S02- 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, methyl or ethyl 314 14 11 and their pharmaceutical^ tolerable salts.

Very particularly preferred compounds of the formula I are those in which: one of the radicals R(1), R(2), R(3), R(4) and R(5) is -CO-N=C(NH2)2; the other radicals R(1) and R(5) in each case independently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, CI, or CF3; the other radicals R(2) and R(4) in each case 10 are hydrogen, OH, CF3, -CO-N=C(NH2)2, alkyl having 1, 2, 3 or 4 carbon atoms or pyrrol-1-yl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, CI, Br, I, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxyl, -CF3 and methyl; the other radical R(3) in each case is hydrogen, -OR(25) Oder -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 a substituent selected from the group consisting of F, CI, CF3 and CH3; "20 or R(25) is -(C1-C9)-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, CI, CF3 and CH3; R(26) and R(27) independently of one another are hydrogen or methyl; one of the radicals R(6), R(7), R(8), R(9) and R(10) is -CO-N=C(NH2)2; the other radicals R(6) and R(10) in each case independently of one another are hydrogen, alkyl having 1, 2 or 3 carbon 30 atoms, F, CI or CF3; the other radicals R(7) and R(9) in each case are hydrogen, OH, CF3, -CO-N=C(NH2)2, alkyl having 1, 2, 3 or 4 carbon atoms or pyrrol-1-yl, 314 14 5 12 which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, CI, Br, I, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxyl, -CF3 and methyl; the other radical R(8) in each case is hydrogen, -OR(125) 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 substituted by a substituent selected from the group consisting of F, CI, CF3 and CH3; or R(125) is -<C1-C9)-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, CI, CF3 and CH3; R(126) and R(127) independently of one another are hydrogen or methyl; A is absent or is -NR(11 )-CO-, -NR(12)-CO-NR(13)-, -NR(17)-C0-NR(18)-S02-, -NR(19)-SOr, -S02-NR(19)-S02-, -S02-NR(19)-CO-, -0-C0-NR(19)-S02-0r -CR(20)=CR(21)-; "20 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 their pharmaceutically tolerable salts.

Especially preferred compounds of the formula I are those in which: one of the radicals R(1), R(3) and R(5) is -CO-N=C(NH2)2; the other radicals R(1) and R(5) in each case independently of one another are hydrogen, alkyl having 1,2 or 3 carbon atoms, F, CI or CF3; R(2) and R(4) ere hydrogen, OH, CF3, alkyl having 1, 2, 3 or 4 carbon atoms or pyrrol-1-yl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, CI, Br, I, -CN, (C2-C5)-alkanoyl, (C2-C5)- 314 1 13 alkoxycarbonyl, formyl, carboxyl, -CF3 and methyl; the other radical R(3) in each case is hydrogen, -OR(25) 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 a substituent selected from the group consisting of F, CI, CF3 and CH3; or R(25) is -(Ci-C9)-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, CI, CF3 and CH3; R(26) and R(27) independently of one another are hydrogp-1 or methyl; one of the radicals R(6), R(8) and R(10) is -CO-IM=C(NH2)2; the other radicals R(6) and R(10) in each case independently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, CI or CF3; R(7) and R(9) are hydrogen, OH, CF3, alkyl having 1, 2, 3 or 4 carbon atoms or pyrrol-1-yl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, CI, Br, I, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxyl, -CF3 and methyl; the other radical R(8) in each case is hydrogen, -OR(125) 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 substituted by a substituent selected from the group consisting of F, CI, CF3 and CH3; or R(125) is -(C1-C9)-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, CI, CF3 and CH3; 314 14 5 R(126) and R(127) independently of one another are hydrogen or methyl; A is absent or is -NR(11 )-C0-, -NR(12)-CO-NR(13)-, -NR(17)-CO-NR(18)-SOr, -NR(19)-S02-, -S02-NR(19)-S02-, -S02-NR(19)-C0-f -0-C0-NR(19)-S02-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 their pharmaceutically tolerable salts.

Very especially preferred compounds of the formula I are those in which: one of the radicals R(1), R(2), R(3), R(4) and R(5) is -CO-N=C(NH2)2; the other radicals R(1) and R(5) in each case independently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, CI or CF3; the other radicals R(2) and R(4) in each case are hydrogen, OH, CF3, -CO-N=C(NH2)2, alkyl having 1, 2, 3 or 4 carbon atoms or pyrrol-1-yl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, CI, Br, I, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxyl, -CF3 and methyl; the other radical R(3) in each case is hydrogen, -OR(25) 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 a substituent selected from the group consisting of F, CI, CF3 and CH3; or R(25) is -(C^CgJ-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, CI, CF3 and CH3; R(26) and R(27) independently of one another are hydrogen or methyl; one of the radicals R(6), R(7), R(8), R(9) and R(10) 31 4 1 is -CO-N=C(NH2)2; the other radicals R(6) and R(10) in each case independently of one another are hydrogen, alkyl having 1,2 or 3 carbon atoms, F, CI, or CF3; the other radicals R(7) and R(9) in each case are hydrogen, OH, CF3, -CO-N=C(NH2)2, alkyl having 1, 2, 3 or 4 carbon atoms or pyrrol-1 -yI, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, CI, Br, I, -CN, (C2-C5)-alkanoyl, (C2-C5)-10 alkoxycarbonyl, formyl, carboxyl, -CF3 and methyl; the other radical R(8) in each case is hydrogen, -OR(125) or -CR(125)R(126)R(127); R(125) is hydrogen, alkyl having 1,2 or 3 carbon atoms or phenyl, 15 which is unsubstituted or substituted by a substituent selected from the group consisting of F, CI, CF3 and CH3; or R(125) is -(C1 -Cg)-heteroary I, which is unsubstituted or substituted by a substituent selected from the group consisting of F, CI, CF3 and CH3; R(126) and R(127) independently of one another are hydrogen or methyl; A is -NR(11 )-CO-, -NR(12)-CO-NR(13)-, -NR(17)-C0-NR(18)-SOr, 25 -NR(19)-S02-, -S02-NR(19)-S02-, -S02-NR(19)-C0-, -0-C0-NR(19)-S02- 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 their pharmaceutically tolerable salts.

The designated alkyl radicals can be straight-chain or branched.

(Ci-C9)-Heteroaryl is understood as meaning radicals which are derived from phenyl or naphthyl, in which one or more CH groups are replaced by N and/or in 314 145 16 which at least two adjacent CH groups are replaced by S, NH or 0 (with formation of a five-membered aromatic ring). In addition, one or both atoms of the condensation site of bicyclic radicals (such as in indolizinyl) can also be nitrogen atoms.

Heteroaryl counts in particular as furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl or cinnolinyl.

If one of the substituents R(1) to R(10) contains one or more centers of asymmetry, these, independently of one another, can have either the S or the R configuration. The compounds can be present as optical isomers, as H!astereomers, as racemates or as mixtures thereof. Carbon-carbon double bonds can be either cis- or trans-linked.

The invention furthermore relates to a process for the preparation of the compounds I, which comprises reacting compounds of the formula II in which R(1') to R(10') have the meanings indicated 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 the substituents R(6') to R(10') is the marked COL group, and in which L represents leaving groups which can be easily nucleophilically substituted, with guanidine.

The activated acid derivatives of the formula II, in which L is an alkoxy group, preferably a methoxy group or phenoxy group, a phenylthio, methylthio or 2-pyridylthio group, or a nitrogen heterocycle, preferably 1-imidazolyl, are advantageously obtained, in a manner known per se, from the underlying carbonyl 314 14 17 chlorides (formula II, L = CI), which, for their part, can in turn be prepared, in a manner known per se, from the underlying carboxylic adds (formula II, L = OH), for example using thionyl chloride.

In addition to the carbonyl chlorides of the formula II (L = CI), further activated acid derivatives of the formula II can also be prepared, in a manner known per se, directly from the underlying diaryldicarboxylic acid derivatives (formula II, L = OH), such as, for example, the methyl esters of the formula II with L = OCH3 by treating with gaseous HCI in methanol, the imidazolides of the formula II by treating with carbonyldiimidazole [L = 1-imidazolyl, Staab, Angew. Chem. Int. Ed. Engl. 1, 351 to 10 367 (1962)], the mixed anhydrides II with CI-COOC2H5 or tosyl chloride in the presence of triethylamine in an inert solvent, as well as the activation of diaryldicarboxylic acids with dicyclohexylcarbodiimide (ZCC) or with 0-[(cyano(ethoxycarbonyl)methylene)amino]-1,1,3,3-tetramethyluronium tetrafluoroborate ("TOTU") [Proceedings of the 21st European Peptide Symposium, 15 Peptides 1990, Editors E. Giralt and D. Andreu, Escom, Leiden, 1991]. A series of suitable methods for preparing activated carboxylic acid derivatives of the formula II are given, with citation of the source literature, in J. March, Advanced Organic Chemistry, Third Edition (John Wiley & Sons, 1985), p. 350.

The reaction of an activated carboxylic acid derivative of the formula I with guanidine is effected, in a manner known per se, in a protic or aprotic organic solvent which is polar but inert. In this context, methanol, isopropanol or THF, between 20° C and the boiling temperature of these solvents, have proven to be suitable for use in the reaction of the dimethyl diaryldicarboxylates (II, L = OMe) with 25 guanidine. Most reactions of compounds II with salt-free guanidine were advantageously carried out in inert solvents such as THF, dimethoxyethane, dioxane or isopropanol. However, water can also be used as solvent.

When L = CI, the reaction is advantageously carried out with addition of an acid 30 scavenger, e.g. in the form of excess guanidine, to bind the hydrohalic acid.

The introduction of the compounds substituted in the phenyl moiety by sulfur, oxygen or nitrogen nucleophiles is achieved by methods known from the literature 31 4 1 18 involving nucieophilic substitution of derivatives of dialkyl diaryldicarboxylates. In this substitution, suitable leaving groups on the diaryldicarboxylic acid derivative have proven to be halides and trifluoromethanesulfonates. The reaction is advantageously carried out in a dipolar aprotic solvent, such as DMF or TMU, at a temperature of 0°C up to the boiling point of the solvent, preferably from 80°C up to the boiling point of the solvent. Acid scavengers advantageously used are an alkali metal or alkaline earth metal salt having an anion of high basicity and low nucleophilicity, for example K2CO3 or CsC03.

The introduction of the alkyl or aryl substituents is achieved by methods known from the literature involving palladium-mediated cross-coupling of aryl halides with, for example, organozinc compounds, organostannanes, or; ^noboronic acids or organoboranes.

Diaryldicarboxylic acid diguanidides I are in general weak bases and are able to bind acid with the formation of salts. Suitable acid addition salts are salts of all pharmacologically tolerable acids, for example halides, in particular hydrochlorides, ascorbates, lactates, sulfates, citrates, tartrates, acetates, phosphates, ^ methylsulfonates and p-toluenesulfonates.

US Patent 5 091 394 (HOE 89/F 288) and European Offenlegungsschrift 0 556 674 (HOE 92/F 034) describe benzoylguanidines, but not diaryldicarboxylic acid diguanidides. WO 94/26 709 (PCT/JP94/00786) even describes the possibility of attaching a phenyl nucleus as a substituent R(2) in the meta-position of a benzoylguanidine (besides many other possibilities), and this second phenyl nucleus can (besides many other possibilities) also carry a guanidyl group as a substituent. These known compounds, however, are still not satisfactory for many application possibilities.

As a consequence of their pharmacological properties, the compounds according to the invention are outstandingly suitable for use as antiarrhythmic pharmaceuticals having a cardioprotective component for infarct prophylaxis and infarct treatment as well as for the treatment of angina pectoris, the compounds also inhibiting or greatly 314 14 19 reducing, in a preventive manner, the pathophysiological processes in the formation of ischemically induced damage, in particular in the elicitation of ischemically induced cardiac arrhythmias. Because of their protective effects against pathological hypoxic and ischemic situations, the compounds of the formula I according to the invention can be used, as a consequence of inhibition of the cellular Na+/H+ exchange mechanism, as pharmaceuticals for treating all acute or chronic damage elicited by ischemia, or diseases which are primarily or secondarily induced thereby. This applies to their use as pharmaceuticals for surgical interventions, e.g. in organ transplantations, it being possible to use the compounds both to protect the organs in the donor before and during removal and to protect removed organs, for example during treatment with physiological bath fluids or storage thereof in these fluids, and also during transfer into the recipient body. The compov-.ids are likewise valuable protective pharmaceuticals when carrying out angioplastic surgical interventions, for example on the heart or on peripheral vessels. In accordance with their protective action against ischemically induced damage, the compounds are aiso suitable for use as pharmaceuticals for treating ischemias of the nervous system, in particular of the CNS, being suitable, e.g. for the treatment of stroke or of cerebral edema. Moreover, the compounds of formula I according to the invention are likewise suitable for the treatment of forms of shock, such as, for example, of allergic, cardiogenic, hypovolemic and bacterial shock.

Moreover, the compounds of the formula I according to the invention are distinguished by their strong inhibitory effect on the proliferation of ceils, for example the proliferation of fibroblast cells and the proliferation of vascular smooth muscle cells. The compounds of the formula I are therefore suitable as valuable therapeutics for illnesses in which cell proliferation represents a primary or secondary cause, and may therefore be used as antiatherosclerotics, agents against diabetic late complications, carcinomatous disorders, fibrotiu disorders, such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, and against urgan hypertrophy and hyperplasia, in particular in hyperplasia or hypertrophy of the prostate.

The compounds according to the invention are efficacious inhibitors of the cellular 31 4 14 sodium/proton antiporter (Na+/H+ exchanger), which, in numerous disorders (essential hypertension, atherosclerosis, diabetes, etc.), is also raised in cells which are readily accessible to measurement, such as, for example, in erythrocytes, platelets or leukocytes. The compounds according to the invention are therefore suitable for use as outstanding and simple scientific tools, for example in their use as diagnostics for determining and differentiating certain forms of hypertension, but also atherosclerosis, diabetes, proliferative disorders, etc. Moreover, the compounds of formula I are suitable for use in preventive therapy for preventing the genesis of high blood pressure, for example of essential hypertension.

Compared to most known compounds, the compounds according to the invention have a significantly improved water solubility. They are tnerefore essentially more highly suitable for i.v. administration.

Compared to the known readily water-soluble compounds, the compounds according to the invention are distinguished by their better bioavailability and pharmacokinetics.

In this context, pharmaceuticals which contain a compound i can be administered 20 orally, parenterally, intravenously, rectally or by inhalation, the preferred route of administration being dependent on how the disorder manifests itself in each case. In this context, the compounds I may be used alone or together with pharmaceutical auxiliaries, both in the case of veterinary medicine and in the case of human medicine.

On the basis of his expert knowledge, the person skilled in the art is familiar with which auxiliary substances are suitable for the desired pharmaceutical formulation. In addition to solvents, gel-formers, suppository bases, tableting auxiliaries, and other active-compound excipients, antioxidants, dispersants, emulsifiers, defoamers, 30 taste corrigents, preservatives, solubilizers or colorants, for example, can be used. For an oral administration form, the active compounds are mixed with the additives which are suitable for the purpose, such as excipients, stabilizers or inert diluents, and converted by the customary methods into suitable administration forms, such as 314 14 5 21 tablets, coated tablets, hard gelatin capsules or aqueous, alcoholic or oily solutions. Gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch, for example, can be used as inert excipients. In this context, the preparation can be effected both as dry or moist i granules. Vegetable or animal oils, for example, such as sunflower oil or cod-liver oil, are suitable for use as oily excipients or as solvents.

For subcutaneous or intravenous administration, the active compounds, if desired together with the substances which are customary for the purpose, such as 10 solubilizers, emuisifiers or further auxiliaries, are brought into solution, suspension or emulsion. Examples of suitable solvents are: water, physiological saline solution or alcohols, for example ethanol, propanol or glycerol, u. .d in addition sugar solutions, such as glucose or mannitol solutions, or alternatively a mixture of the different solvents mentioned.

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 such solvents, are suitable for use as a pharmaceutical formulation for administration in the form of aerosols or sprays. If required, the formulation can also 20 contain other further pharmaceutical auxiliaries, such as surfactants, emuisifiers and stabilizers, as well as a propellant. Such a preparation customarily contains the active compound in a concentration of about 0.1 to 10, in particular of about 0.3 to 3% by weight.

The dosage of the active compound of the formula I to be administered and the frequency of administration depend on the potency and duration of action of the compounds used; additionally also on the nature and severity of the disease to be treated, as well as on the sex, age, weight and individual responsiveness of the mammal to be treated.

On average, the daily dose of a compound of the formula I for a patient of about 75 kg in weight is at least 0.001 mg/kg of body weight, preferably at least 0.01 mg/kg of body weight, up to at most 10 mg/kg of body weight, preferably up to 31 4 1 22 at most 1 mg/kg of body weight. In acute episodes of the disease, for example immediately after suffering a cardiac infarct, even higher, and in particular more frequent, dosages may also be necessary, e.g. up to 4 individual dose? per day. On i.v. use, in particular, for example in the case of an infarct patient in intensive care, up to 100 mg per day may be necessary. w List of abbreviations: AIBN «,« -azo-bis-isobutyronitrile Bn benzyl Brine saturated aqueous NaCI solution CH2CI2 dichloromethane DCI desorption-chemical ionization DIP diisopropyl ether DMA dimethylacetamide DME dimethoxyethane DMF N, N-dimethylformamide EA ethyl acetate (EtOAc) El electron impact • eq equivalent ES electrospray-ionization Et ethyl FAB fast atom bombardment • HEP n-heptane HOAc acetic acid Me methyl MeOH methanol mp melting point MTB methyl tertiary-butyl ether NBS N-bromosuccinirnide NMP N-methylpyrrolidone RT room temperature THF tetrahydrofuran TMU N, N, N\ N'-tetramethylurea 314 14 5 23 Tol CNS toluene central nervous system Experimental section General procedure for the preparation of diaryldicarboxylic acid diguanidides (I) from dialkyl benzenedicarboxylates (II, L - O-alkyl) mmol of the dialkyl benzenedicarboxylate of the formula II and 50 mmol of guanidine (free base) are dissolved in 5 ml of isopropanol and the solution is boiled under reflux (typical reaction time, depending on carbonyl activity of the carboxylic acid derivative, 5 minutes to 10 h) until conversion is complete (thin-layer checking).

The mixture is then diluted with 150 ml of water and the product is filtered off with suction. If appropriate, it is chromatographed on silica gel using a suitable eluent, e.g. EA/MeOH 5: 1 or acetone/water 10:1.

Example 1:3-(4-Guanidinocarbonyl)phenylbenzoylguanidine a. Ethyl 3-(4-formyl)phenylbenzoate 3.4 g of ethyl 3-bromobenzoate, 170 mg of palladium(ll) acetate, 390 mg of triphenylphosphine, 2.5 g of 4-formylphenylboronic acid, 15 ml of a 2 N aqueous Na2C03 solution, 90 ml of toluene and 25 ml of ethanol are boiled under reflux for 2 h under argon. 150 ml of a saturated aqueous NaHC03 solution are then added and the mixture is extracted 3 times using 150 ml of EA each time. The organic phase is dried over Na2S04 and the solvent is removed in vacuo. Chromatography on silica gel using EA/HEP 1:8 yields 2.4 g of white crystals, mp 81°C.

Rf (DIP) = 0.55 MS (DCI): 255 (M+H)+ NHj o NH. 31 4 1 24 4 b. Ethyl 3-(4-ethoxycarbonyl)phenylbenzoate 2.4 g of ethyl 3-(4-formyl)phenylbenzoate are dissolved in 190 ml of ethanol and 2.3 g of NaCN and 1.1 ml of glacial acetic acid are added at RT. After 15 minutes, a clear solution is obtained, to which 18.9 g of Mn02 are added at RT. The mixture is stirred at RT for 7 h, the precipitate is filtered off and the filtrate is poured onto 300 ml of saturated aqueous I^CC^ solution and extracted 3 times with 300 ml of EA each time. The organic phase is dried over Na2C03 and the solvent is removed in vacuo. Chromatography on silica gel using EA/HEP 1:4 yields 2.5 g of a colorless oil.

Rf (DIP) = 0.59 MS (ES): 299 (M+H)+ c. 3-(4-Guanidinocarbonyl)phenyibenzoylguanidine 1.1 g of ethyl 3-(4-ethoxycarbonyl)phenylbenzoate are reacted according to the general procedure for the preparation of diaryldicarboxylic acid diguanidides and 760 mg of colorless crystals are obtained, mp 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)phenylbenzoylguanidine mp 283°C.

Rf (acetone/water 10:1) = 0.25 MS (FAB): 325 (M+H)4 31 4 14 5 Example 3:4-(4-Guanidinocarbonyl)phenylsulfamoylbenzoylguanidine h.n o X h2n n nh, =< // o a. Ethyl 4-sulfamoylbenzoate g of 4-sulfamoylbenzoic acid are dissolved in 500 ml of ethanol, 36 ml of SOCI2 are added dropwise and the mixture is boiled under reflux for 5 h. The volatile constituents are then removed in vacuo, the residue is adjusted to pH = 9 using saturated aqueous Na2C03 solution and the mixture is extracted 3 times with 200 ml of EA each time. The organic phase is dried over Na2S04 the solvent is removed in vacuo and 21 g of colorless crystals are obtained, mp 108°C.

(DIP) = 0.24 MS (DCI): 230 (M+H)+ b. Ethyl 4-(4-ethoxycarbonyl)phenylsulfamoylbenzoate 1.1 g of ethyl 4-sulfamoylbenzoate, 840 mg of ethyl 4-fluorobenzoate and 4.9 g of Cs2C03 are stirred at 130°C for 10 h in 10 ml of NMP. The mixture is then allowed to cool to RT, 200 ml of EA are added and it is washed 3 times with 100 ml of water each time. The organic phase is dried over Na2S04 and the solvent is removed in vacuo. Chromatography on silica gel using EA/HEP 1:1 yields 2.6 g of a colorless oil.

Rf (EA/HEP 1:1) = 0.38 MS (DCI): 378 (M+H)+ c. 4-(4-Guanidinocarbonyl)phenylsulfamoylbenzoylguanidine 2.5 g of ethyl 4-(4-ethoxycarbonyl)phenylsulfamoylbenzoate are reacted according to the general procedure for the preparation of diaryldicarboxylic acid diguanidides (reaction time 10 h), and 560 mg of a white amorphous solid are obtained. Rf (acetone/water 10:1) = 0.16 MS (FAB): 446 (M+H)+ The title compound of Example 4 was synthesized from dimethyl biphenyl-4,4'-dicarboxylate according to the general procedure for the preparation of 314 14 26 diaryldicarboxylic acid diguanidides: Example 4: Biphenyl-4,4'-dicarboxylic acid diguanidide h2n o .X h2n n ^NH2 (acetone/water 10:1) = 0.09 MS (FAB): 325 (M+H)+ Example 5:4[3-(Guanidinocarbonyl)phenylaminocarbonylaminosulfonyl]-15 benzoylguanidine v^-NH2 h,n V=N v=/ § h2n a) Methyl 4-ethoxycarbonylaminosulfonylbenzoate 25 6.0 g of methyl 4-aminosulfonylbenzoate and 7.7 g of K2CO3 are boiled under reflux for 5 minutes in 100 ml of anhydrous DME. 5.3 ml of methyl chloroformate are then added by means of a syinge, and the mixture is boiled under reflux for a further 2 h. It is allowed to cool, the solid is filtered off with suction and the product is liberated by stirring with 100 ml of saturated aqueous NaHS04 solution and 200 ml of water. 30 The product is filtered off with suction and dried at 50°C in vacuo. 7.1 g of colorless crystals, mp. 146°C Rf(EA) 0.41 MS (DCI): 288 (M + H)+ 314) 27 b) 4-Ethoxycarbonylaminosuifonylbenzoic acid 6 g of methyl 4-ethoxycarbonylaminosulfonylbenzoate and 42 ml of a 1N aqueous NaOH solution are stirred at RT for 24 h in 50 ml of MeOH. The solvents are removed in vacuo, the residue is taken up using 100 ml of water, the solution is 5 adjusted to pH = 1 -2 using dilute aqueous HCI solution and the product is filtered off with suction. It is dried in vacuo, and 5.5 g of colorless crystals are obtained, mp.: 189°C Rf (DIP/2% HOAc) = 0.28 MS (ES): 274 (M + H)+ c) 4-[3-(Hydroxycarbonyl)phenylaminocarbonylaminosulfonyl]benzoic acid 2 g of 4-ethoxycarbonylaminosuffcnylbenzoic acid and 1 g of 3-aminobenzoic acid are boiled under reflux for 10 h in 50 ml of anhydrous tr'-jene. The solvent is removed in vacuo, and 2.8 g of a crude product are obtained which is directly employed further. d) 4-[3-(Guanidinocarbonyl)phenylaminocarbonylaminosulfonyl]-benzoylguanidine 1.4 g of 4-(3-(hydroxycarbonyl)phenylaminocarbonylaminosulfonyl]benzoic acid and 1.4 g of carbonyldiimidazole are dissolved in 60 ml of a mixture of anhydrous THF and anhydrous DMF and the solution is stirred at RT for 24 h. 2.5 g of guanidine are 20 then added, and the mixture is stirred at RT for a further 24 h. The solvents are removed in vacuo, the product is suspended in 100 ml of water and then adjusted to pH = 7 using dilute aqueous HCI solution, and the mixture is stirred at RT for 1 h. The product is filtered off with suction and dried in vacuo. 820 mg of colorless crystals are obtained, mp: 207°C Rf(CH2CI2/MeOH/water/HOAc 8:4:1:1) = 0.56 MS (ES): 447 (M + H)+ Pharmacological data: Inhibition of the Na+/H+ exchanger of rabbit erythrocytes New Zealand White rabbits (Ivanovas) received a standard diet containing 2% cholesterol for six weeks in order to activate the Na"l7H+ exchange and thus to be 314 14 5 28 able to determine, by flame photometry, the Na+ influx into the erythrocytes via Na+/H+ exchange. The blood was removed from the aural arteries and rendered incoagulable using 25 lU/ml of potassium heparin. A part of each sample was used for the duplicate determination of the hematocrit by means of centrifugation. Aliquots of in each case 100 |j| were used for measuring the initial Na+ content of the erythrocytes.

In order to determine the amiloride-sensitive sodium influx, 100 pi of each blood sample were in each case incubated, at pH 7.4 and 37°C, in 5 ml of a hyperosmolar 10 salt/sucrose medium (mmol/l: 140 NaCI, 3 KCI, 150 sucrose, 0.1 ouabain, tris(hydroxymethyl)aminomethane). The erythrocytes were then washed three times with ice-cold MgCl^ouabain solution (mmol/l: 112 .V)gCI2, 0.1 ouabain) and hemolyzed in 2.0 ml of distilled water. The intracellular sodium content was determined by flame photometry.

The net influx of Na+ was calculated from the difference between the initial sodium values and the sodium content of the erythrocytes following incubation. The amiloride-inhibitable sodium influx resulted from the difference in the sodium content of the erythrocytes following incubation with and without amiloride 3 * 10"* mol/l. 20 1 his method was also employed in the case of the compounds according to the invention.

Results Inhibition of the Na+/H+ exchanger Example ICcn Mmol/l 1 1.5 2 .0 3 1.5 4 2.0 I—JL™. o i 4 1 29

Claims

WHAT WE CLAIM IS:

1. A diaryldicarboxylic acid diguanidide of the formula I 5 I 10 in which: one of the radicals R(1), R(2), R(3), R(4) and R(5) is -CO-N=C(NH2)2; the other radicals R(1) and R(5) in each case 15 independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbor. atoms, F, CI, -OR(32), -NR(33)R(34) or CF3; R(32), R(33) and R(34) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; 20 the other radicals R(2) and R(4) in each case independently of one another are hydrogen, F, CI, Br, I, OH, -CN, CF3, -CO-N=C(NH2)2, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms or -(CH2)mR(14); m is zero, 1 or 2; 25 R(14) is -(C3-C8)-cycloalkyl or phenyl, which is unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F and CI, -CF3, methyl, methoxy and -NR(15)R(16); R(15) and R(16) 30 are hydrogen or -CH3; or the other radicals R(2) and R(4) in each case independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl, 314 145 30 which is unsubstituted or substituted by 1 - 4 substituents selected from the group consisting of F, CI, Br, I, -CN, (C2-C8)-alkanoyl, (C2-C8)-alkoxycarbonyl, formyl, carboxyl, -CF3, methyl, methoxy; or i the other radicals R(2) and R(4) in each case are R(22)-SOr, R(23)R(24)N-CO-, R(28)-CO- or R(29)R(30)N-S02; R(22) and R(28) independently of one another are methyl or -CF3; R(23), R(24), R(29) and R(30) 10 independently of one another are hydrogen or methyl; or the other radicals R(2) and R(4) in each case independently of one another are -OR(35) or -NR(35)R(36); R(35) and R(36) 15 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 are 4-7 methylene groups, of which one CH2 group can be 20 replaced by oxygen, -S-, -NH-, -NCH3 or -N-benzyl; the other radical R(3) in each case 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 substituted by 1 - 3 substituents 25 selected from the group consisting of F, CI, CF3, CH3, methoxy, hydroxyl, amino, methylamino and dimethylamino; or R(25) is -(C-pCgHieteroaryl, which is unsubstituted or substituted by 1 - 3 substituents selected 30 from the group consisting of F, CI, CF3, CH3, methoxy, hydroxyl, amino, methylamino and dimethylamino; R(26) and R(27) independently of one another are defined as R(25) or are hydrogen or 314 14 5 31 alkyl 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) is -CO-N=C(NH2)2. the other radicals R(6) and R(10) in each case independently of one another are hydrogen, alkyl having 1,2,3 or 4 carbon atoms, F, CI, -OR(132), -NR(133)R(134) or CF3; R(132), R(133) and R(134) independently of one another are hydrogen or alkyl having 1,2, 3 or 4 carbon atoms; 10 the other radicals R(7) and R(9) in each case independently of one another are hydrogen, F, CI, Br, I, OH, -CN, CF3, -CO-N=C(NH2)2, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl having 2, 3, 4, 5,6, 7 or 8 carbon atoms or -(CH2)mmR(114); mm is zero, 1 or 2; 15 r(114) is -(C3-C8)-cycloalkyl or phenyl, which is unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F and CI, -CF3, methyl, methoxy and -) NR(115)R(116); 20 R(115) and R(116) are hydrogen or -CH3; or the other radicals R(7) and R(9) in each case independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl, 25 which is unsubstituted or substituted by 1 - 4 substituents selected from the group consisting of F, CI, Br, I, -CN, (C2-C8)-alkanoyl, (C2-C8)-alkoxycarbonyl, formyl, carboxyl, -CF3, methyl and methoxy; or the other radicals R(7) and R(9) in each case 30 are R(122)-S02-, R(123)R(124)N-CO-, R(128)-CO- or R(129)R(130)N-S02; R(122) and R(128) independently of one another are methyl or -CF3; R(123), R(124), R(129) and R(130) 314 14 5 \ 32 independently of one another are hydrogen or methyl; or the other radicals R(7) and R(9) in each case independently of one another are -OR(135) or -NR(135)R(136); 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 are 4 - 7 methylene groups, of which one CH2 group can be replaced by oxygen, -S-, -NH-, -NCH3 or -N-benzyl; the other radical R(8) in each case is hydrogen, -SR('<25), -OR(125), -NR(125)R(126) or -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 substituted by 1 - 3 substituents selected from the group consisting of F, CI, CF3, CH3, methoxy, hydroxyl, amino, methylamino and dimethylamino; or R(125) is -{C1 -C9)-heteroaryl, which is unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F, CI, CF3, CH3, methoxy, hydroxyl, amino, methylamino and dimethylamino; R(126) and R(127) independently of one another are defined as R(125) or are hydrogen or alkyl having 1, 2, 3, 4, 5,6, 7 or 8 carbon atoms; A is absent or is -NR(11)-CO-, -NR(12)-CO-NR(13)-, -NR(17)-CO-NR(18)-SOr, -NR(19)-S02- -S02-NR(19)-S02-, -S02-NR(19)-C0-, -0-C0-NR(19)-S02-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 alkyl having 1,2, 3, 4, 5, 6, 7 or 8 carbon atoms 31 4 33 or its pharmaceutical^ tolerable salts.

2. A compound of the formula I as claimed in claim 1, wherein: one of the radicals R(1), R(2), R(3), R(4) and R(5) is -CO-N=C(NH2)2 the other radicals R(1) and R(5) in each case independently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, CI, -OR(32), -NR(33)R(34) or CF3; R(32), R(33) and R(34) 10 independently of one another are hydrogen or methyl; the other radicals R(2) and R(4) in each case independently of one another are hydrogen, F, C., Br, I, OH, CF3> -CO-N=C(NH2)2, alkyl having 1, 2, 3 or 4 carbon atoms, alkenyl having 2, 3 or 4 carbon atoms or -(CH2)rnR(14); 15 m is zero, 1 or 2; R(14) is -(C3-C6)-cycloalkyl or phenyl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F and CI, -CF3, methyl and methoxy; I or 20 the other radicals R(2) and R(4) in each case independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, CI, Br, I, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxyl, -CF3 and methyl; 25 or the other radicals R(2) and R(4) in each case independently of one another are R(22)-S02-, R(28)-CO- or R(29)R(30)N-S0r; R(22) and R(28) 30 independently of one another are methyl or -CF3; R(29) and R(30) independently of one another are hydrogen or methyl; or 314 145 34 the other radicals R(2) and R(4) in each case independently of one another are -OR(35) or -NR(35)R(36); R(35) and R(36) independently of one another are hydrogen, methyl or ethyl; or R(35) and R(36) together are 4 - 5 methylene groups, of which one CH2 group can be replaced by oxygen, -S-, -NH- or -NCH3; the other radical R(3) in each case is hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27); R(25) or R(25) R(26) one of the radicals R(6), R(7), R(8), R(9) and R(10) is -CO-N=C(NH2)2 the other radicals R(6) and R(10) in each case independently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, CI,-OR(132),-NR(133)R(134) or CF3; R(132), R(133) and R(134) independently of one another are hydrogen or methyl; the other radicals R(7) and R(9) in each case independently of one another are hydrogen, F, CI, Br, I, OH, CF3, -CO-N=C(NH2)2. alkyl having 1, 2, 3 or 4 carbon atoms, alkenyl having 2, 3 or is hydrogen, alkyl having 1,2, 3 or 4 carbon atoms, phenyl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, CI, CF3, CH3, methoxy and dimethylamino; is -(C^CgJ-heteroaryl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, CI, CF3, CH3, methoxy and dimethylamino; and R(27) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; 3 i 4 1 35 4 carbon atoms or -(CH2)mmR(114); mm is zero, 1 or 2; R(114) is -(C3-C6)-cycloalkyl or phenyl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F and CI, -CF3, methyl and methoxy; or the other radicals R(7) and R(9) in each case independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl, 10 which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, CI, Br, I, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxyl, -CF3 and methyl; or the other radicals R(7) and R(9) in each case 15 independently of one another are R(122)-S02-, R(128)-CO- or R( 129)R( 130)N-S02-; R(122) and R(128) independently of one another are methyl or -CF3; R(129) and R(130) 20 independently of one another are hydrogen or methyl; or the other radicals R(7) and R(9) in each case independently of one another are -OR(135) or -NR(135)R(136); R(135) and R(136) 25 independently of one another are hydrogen, methyl or ethyl; or R(135) and R(136) together are 4-5 methylene groups, of which one CH2 group can be replaced by oxygen, -S-, -NH- or -NCH3; 30 the other radical R(8) in each case is hydrogen, -SR(125), -OR(125), -NR(125)R(126) or -CR(125)R(126)R(127); R(125) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl <>14 145 36 which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, CI, CF3, CH3, methoxy and dimethylamino; or R(125) is -(C^CgHieteroaryl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, CI, CF3, CH3, methoxy and dimethylamino; R(126) and R(127) independently of one another are hydrogen or alkyl having 1,2, 3 or 4 carbon atoms; A is absent or is -NR(11)-CO-, -NR(12)-CO-NR(13)-, -NR(17)-C0-NR(18)-S02-, -NR(19)-S02-, -S02-NR(19)-S02-, -SOrNR(19)-CO-, -0-C0-NR(19)-S02-0r -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 alkyl having 1,2, 3 or 4 carbon atoms.

3. A compound of the formula I as claimed in claim 1 or 2, in which: one of the radicals R(1), R(2), R(3), R(4) and R(5) is -CO-N=C(NH2)2; the other radicals R(1) and R(5) in each case independently of one another are hydrogen, alkyl having 1,2 or 3 carbon atoms, F, CI, -OR(32), -NR(33)R(34) or CF3; R(32), R(33) and R(34) independently of one another are hydrogen or methyl; the other radicals R(2) and R(4) in each case independently of one another are hydrogen, F, CI, OH, CF3, -CO-N=C(NH2)2, alkyl having 1, 2, 3 or 4 carbon atoms or pyrrol-1-yl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, CI, Br, I, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxyl, -CF3 and methyl; oi4 14: 37 or the other radicals R(2) and R(4) in each case are R(22)-SOr; R(22) is methyl or -CF3; i or the other radicals R(2) and R(4) in each case independently of one another are -OR(35) or -NR(35)R(36); R(35) and R(36) independently of one another are hydrogen, methyl or ethyl; 10 the other radical R(3) in each case 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 -iornsor phenyl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, CI, CF3 and CH3; 15 or R(25) is -(C^CgJ-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, CI, CF3 and CH3; 20 R(26) and R(27) independently of one another are hydrogen or methyl; one of the radicals R(6), R(7), R(8), R(9) and R(10) is -CO-N=C(NH2)2; the other radicals R(6) and R(10) in each case 25 independently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, CI, -OR(132), -NR(133)R(134) or CF3; R(132), R(133) and R(134) independently of one another are hydrogen or methyl; the other radicals R(7) and R(9) in each case 30 independently of one another are hydrogen, F, CI, OH, CF3, -CO-N=C(NH2)2, alkyl having 1, 2, 3 or 4 carbon atoms or pyrrol-1-yl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, CI, Br, I, -CN, (C2-C5)-alkanoyl, (C2-C5)- 314 14 5 38 alkoxycarbonyl, formyl, carboxyl, -CF3 and methyl; or the other radicals R(7) and R(9) in each case are R(122)-SOr; R(122) is methyl or -CF3; or the other radicals R(7) and R(9) in each case independently of one another are -OR(135) or -NR(135)R(136); 10 R(135) and R(136) independently of one another are hydrogen, methyl or ethyl; the other radical R(8) in each case is hydrogen, -SR(125), -OR(125), -NR(125)R(126) or -CR(125)R(126)R(127); R(125) 15 is hydrogen, alkyl having 1,2 or 3 carbon atoms or phenyl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, CI, CF3 and CH3; or ) R(125) 20 is -(C-j-CgJ-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, CI, CF3 and CH3; . R(126) and R(127) * independently of one another are hydrogen or methyl; 25 A is absent or is -NR(11)-CO-, -NR(12)-CO-NR(13)-, -NR(17)-C0-NR(18)-S02-t -NR(19)-S02-, -S02-NR(19)-S02-, -S02-NR(19)-C0- -0-C0-NR(19)-S02- 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, methyl or ethyl. 30 m 314 145 39

4. A compound of the formula I as claimed in any one of claims 1 to 3, in which: one of the radicals R(1), R(2), R(3), R(4) and R(5) is -CO-N=C(NH2)2; the other radicals R(1) and R(5) in each case 5 independently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, CI, or CF3; the other radicals R(2) and R(4) in each case are hydrogen, OH, CF3, -CO-N=C(NH2)2, alkyl having 1, 2, 3 or 4 carbon atoms or pyrrol-1-yl, 10 which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, CI, Br, I, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxyl, -CF3 and methyl; the other radical R(3) in each case is hydrogen, -OR(25) Oder -CR(25)R(26)R(27); 15 R(25) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or phenyl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, CI, CF3 and CH3; or R(25) is -(C.|-C9)-heteroaryl, 20 which is unsubstituted or substituted by a substituent selected from the group consisting of F, CI, CF3 and CH3; R(26) and R(27) independently of one another are hydrogen or methyl; one of the radicals R(6), R(7), R(8), R(9) and"R(10) 25 is -CO-N=C(NH2)2; the other radicals R(6) and R(10) in each case independently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, CI or CF3; the other radicals R(7) and R(9) in each case 30 are hydrogen, OH, CF3, -C0-N=C(NH2)2, alkyl having 1, 2, 3 or 4 carbon atoms or pyrrol-1-yl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, CI, Br, I, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxyl, -CF3 and methyl; N.Z. PAT r- f 40 314 145 the other radical R(8) in each case is hydrogen, -OR(125) 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 substituted by a substituent selected from the group consisting of F, CI, CF3 and CH3; or R(125) is -(^-CgJ-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, CI, CF3 and CH3; R(126) and R(127) independently of one another are hydrogen or methyl; A is absent or is -NR(11 )-C0-, -NR(12)-CO-NR(13)-, -NR(17)-C0-NR(18)-SOr, -NR(19)-S02-, -S02-NR(19)-S02-, -S02-NR(19)-C0-, -0-C0-NR(19)-S02- 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.

5. A compound of the formula I as claimed in any one of claims 1 to 4, in which: one of the radicals R(1), R(3) and R(5) is -C0-N=C(NH2)2; the other radicals R(1) and R(5) in each case independently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, CI or CF3; R(2) and R(4) are hydrogen, OH, CF3, alkyl having 1, 2, 3 or 4 carbon atoms or pyrrol-1-yl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, CI, Br, I, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxyl, -CF3 and methyl; the other radical R(3) in each case is hydrogen, -OR(25) or-CR(25)R(26)R(27); R(25) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or phenjrt,„. 314 14 5 41 which is unsubstituted or substituted by a substituent selected from the group consisting of F, CI, CF3 and CH3; or R(25) is -(C^CgHieteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, CI, CF3 and CH3; R(26) and R(27) independently of one another are hydrogen or methyi; one of the radicals R(6), R(8) and R(10) is -CO-N=C(NH2)2; the other radicals R(6) and R(10) in each case independently of one another are hydrogen, alk>. having 1, 2 or 3 carbon atoms, F, CI or CF3; R(7) and R(9) are hydrogen, OH, CF3, alkyl having 1,2,3 or 4 carbon atoms or pyrrol-1-yl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, CI, Br, I, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxyl, -CF3 and methyl; the other radical R(8) in each case is hydrogen, -OR(125) 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 substituted by a substituent selected from the group consisting of F, CI, CF3 and CH3; or R(125) is -(C^CgJ-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, CI, CF3 and CH3; R(126) and R(127) independently of one another are hydrogen or methyl; A is absent or is -NR(11 )-CO-, -NR(12)-CO-NR(13)-, -NR(17)-CO-NR(18)-S02-, -NR(19)-S02-, -S02-NR(19)-S02-, -S02-NR(19)-C0-, -0-C0-NR(19)-S02- or 314 14!) 42 -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.

6. A compound of the formula I as claimed in any one of claims 1 to 4, in which: one of the radicals R(1), R(2), R(3), R(4) and R(5) is -CO-N=C(NH2)2; the other radicals R(1) and R(5) in each case independently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, CI or CF3; the other radicals R(2) and R(4) in each case are hydrogen, OH, CF3, -CO-N=C(NH2)2, alky' having 1, 2, 3 or 4 carbon atoms or pyrrol-1-yi, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, CI, Br, I, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxyl, -CF3 and methyl; the other radical R(3) in each case is hydrogen, -QR(25) 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 a substituent selected from the group consisting of F, CI, CF3 and CH3; or R(25) is -(C^CgJ-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, CI, CF3 and CH3; R(26) and R(27) independently of one another are hydrogen or methyl; one of the radicals R(6), R{7), R(8), R(9) and R(10) is -CO-N=C(NH2)2; the other radicals R(6) and R(10) in each case independently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, CI, or CF3; the other radicals R(7) and R(9) in each case are hydrogen, OH, CF3, -CO~N=C(NH2)2, alkyl having 1, 2, 3 or 4 carbon 43 atoms or pyrrol-1-yl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, CI, Br, i, -CN, (C2-C5)-atkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxyl, -CF3 and methyl; the other radical R(8) in each case is hydrogen, -OR(125) 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 substituted by a substituent selected from the group consisting of F, CI, CF3 and CH3; R(125) is -(C -C9)-heteroary I, which is unsubstituted or substituted by a substituent selected from the group consisting of F, CI, CF3 and CH3; R(126) and R(127) independently of one another are hydrogen or methyl; A is -NR(11 )-CO-, -NR(12)-CO-NR( 13)-, -NR(17)-CO-NR(18)-S02-, -NR(19)-S02-, -S02-NR(19)-S02-, -S02-NR(19)-CO-, -0-C0-NR(19)-S02-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.

7. A process for preparing a compound of the formula I as claimed in claim 1, which comprises reacting a compound of the formula II or *(6") II in which R(1') to R(10') have the meanings indicated 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 314 145 10 30 44 substituents R(6') to R(10') is the marked COL group, and in which L represents leaving groups which can be easily nucleophilically substituted, with guanidine.

8. The use of a compourJ as claimed in claim 1 for preparing a medicament for the treatment of illnesses caused by ischemic conditions.

9. The use of a compound I as claimed in claim 1 for preparing a medicament for treating arrhythmias.

10. A method for treating arrhythmias in non-human animals, wherein an effective amount of a compound I as claimed in claim 1 is mixed with the customary additives and administered in a suitable form for administration. 15

11. Use of a compound I as claimed in claim 1 for preparing a medicament for the treatment or prophylaxis of cardiac infarct.

12. The use of a compound I as claimed in claim 1 for preparing a medicament for the treatment or prophylaxis of angina pectoris. 20

13. The use of a compound I as claimed in claim 1 for preparing a medicament for the treatment or prophylaxis of ischemic conditions of the heart.

14. The use of a compound I as claimed in claim 1 for preparing a medicament for 25 the treatment or prophylaxis of ischemic conditions of the peripheral and central nervous system and of stroke.

15. The use of a compound I as claimed in claim 1 for preparing a medicament for the treatment or prophylaxis of ischemic conditions of peripheral organs ar.d limbs.

16. The use of a compound I as claimed in claim 1 for preparing a medicament for the treatment of states of shock. ' N.Z. PAT-;.;-;' OFFICE - 4 SFp 1997 314 14 3 45

17. The use of a compound I as claimed in claim 1 for preparing a medicament for employment in surgical operations and organ transplantations.

18. The use of a compound I as claimed in claim 1 for preparing a medicament for the preservation and storage of transplants for surgical measures.

19. The use of a compound I as claimed in claim 1 for preparing a medicament for the treatment of illnesses in which cell proliferation represents a primary or secondary cause, and thus their use as antiatherosclerotics, agents against diabetic secondary complications, carcinomatous disorders, fibrotic disorders, such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, and prostate hyperplasia.

20. A medicine, containing an effective amount of a compound of the formula I as claimed in one or more of claims 1 to 6.

21. A compound of formula I according to claim 1 substantially as herein described or exemplified.

22. A process according to claim 7 substantially as herein described or exemplified.

23. Use according to any one of claims 8, 9 and 11-19 substantially as herein described or exemplified.

24. A method according to claim 10 substantially as herein described or exemplified.

25. A medicine according to claim 20 substantially as herein described or exemplified. END OF CLAIMS HOECHST AKTIENGESELLSCHAFT By Their Attorneys HENRY HUGHES Per: fv.?. f