CA2196388A1 - Substituted diaryldicarboxylic acid diguanidides, processes for their preparation, their use as a medicament or diagnostic, and medicament containing them - Google Patents
Substituted diaryldicarboxylic acid diguanidides, processes for their preparation, their use as a medicament or diagnostic, and medicament containing themInfo
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- CA2196388A1 CA2196388A1 CA002196388A CA2196388A CA2196388A1 CA 2196388 A1 CA2196388 A1 CA 2196388A1 CA 002196388 A CA002196388 A CA 002196388A CA 2196388 A CA2196388 A CA 2196388A CA 2196388 A1 CA2196388 A1 CA 2196388A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
- C07C279/22—Y being a hydrogen or a carbon atom, e.g. benzoylguanidines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
- C07C311/52—Y being a hetero atom
- C07C311/54—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea
- C07C311/57—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea having sulfur atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings
- C07C311/60—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea having sulfur atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings having nitrogen atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings
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- Urology & Nephrology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
Diaryldicarboxylic acid diguanidides of the formula I
(see fig. I) I
in which R(1) to R(10) have the meanings indicated in the claims, are suitable as antiarrhythmic pharmaceuticals having a cardioprotective component for infarct prophylaxis and infarct treatment and also for the treatment of angina pectoris.They also inhibit, in a preventive manner, the pathophysiological processes in the formation of ischemically induced damage, in particular in the elicitation of ischemically induced cardiac arrhythmias.
(see fig. I) I
in which R(1) to R(10) have the meanings indicated in the claims, are suitable as antiarrhythmic pharmaceuticals having a cardioprotective component for infarct prophylaxis and infarct treatment and also for the treatment of angina pectoris.They also inhibit, in a preventive manner, the pathophysiological processes in the formation of ischemically induced damage, in particular in the elicitation of ischemically induced cardiac arrhythmias.
Description
2l~63~&
noechst Aktiengesellschaft HOE 96/F 013 Description 5 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
~R,~R8 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 atoms, F, Cl, -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, Cl, 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 Cl, -CF3, methyl, methoxy and -NR(1 5)R(1 6);
R(15) and R(16) are hydrogen or -CH3;
~lgfi38~
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, which is unsubstituted or substituted by 1 - 4 substituents selected from the group consisting of F, Cl, Br, I, -CN, (C2-C8)-alkanoyl, (C2-C8)-alkoxycarbonyl, formyl, carboxyl, -CF3, methyl, methoxy;
or the other radicals R(2) and R(4) in each case are R(22)-SO2-, 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) independently of one another are hydrogen or methyl;
or 15 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 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, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino and dimethylamino;
or R(25) is-(C1-Cg)-heteroaryl, which is unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, ~9638~
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, Cl, -OR(132), -NR(1 33)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 r~diçAIs R(7) and R(9) in each case independently of one another are hydn~gen, F, Cl, 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;
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 Cl, -CF3, methyl, methoxy and -NR(11 5)R(11 6);
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, Cl, 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 are R(1 22)-SO2-, R(1 23)R(1 24)N-CO-, R(1 28)-CO- or R(1 29)R(1 30)N-SO2;
219~38~
R(122) and R(128) independently of one another are methyl or -CF3;
R(123), R(124), R(129) and R(130) indepe,ndently of one another are hydrogen or methyl;
5 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;
15 the other radical R(8) in each case is h~d~gen, -SR(125), -OR(125), -NR(125)R(126) or-CR(125)R(126)R(127);
R( 1 25) is hydrogei), 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, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino and dimethylamino;
or R(1 25) is -(C1-Cg)-heteroaryl, which is unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F, Cl, 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(1 1 )-CO-, -NR(1 2)-CO-NR(13)-, -NR(1 7)-CO-NR(1 8)-SO2-, -NR(1 9)-SO2-, -SO2-NR(1 9)-SO2-, -SO2-NR(1 9)-CO-, -O-CO-NR(1 9)-SO2- or -CR(20)=CR(21 )-;
R(11), R(12), R(13), R(17), R(18), R(19), R(20) and R(21) indepe"denlly of one another are hydrogen or alkyl having 1, 2, 3, 4, S, 6, 7 or 8 carbon atoms and their pharmaceutically tolerable salts.
Preferred co",pounds 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 i"dependently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, Cl,-O R(32),-N R(33)R(34) or CF3;
R(32), R(33) and R(34) independently of one another are hydrogen or methyl;
the other Pdic~ls R(2) and R(4) in each case independenlly of one another are hydrogen, F, Cl, 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)-cycloalkylor phenyl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F and Cl, -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, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, 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 independently of one another are R(22)-SO2-, R(28)-C O- or R(29)R(30)N-SO2-;
R(22) and R(28) independently of one another are methyl or -CF3;
21963~
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, 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, phenyl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy and dimethylamino;
or R(25) is-(C1-Cg)-heteroaryl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, 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 independently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, Cl, -OR(132), -NR(133)R(134) or CF3;
R(132), R(133) and R(134) independently of one another are hydrogen or methyl;
2I 963g8 the other radicals R(7) and R(9) in each case independently of one another are hydrogen, F, Cl, Br, l, 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 iszero,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 Cl, -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, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, Br, l, -CN, (C2-C5)-alkanoyl, (C2-C5)-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)-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) 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 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, Cl, CF3, CH3, methoxy and dimethylamino;
or R(125) is -(C1-Cg)-heteroaryl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, 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)-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 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, Cl, -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, Cl, OH, CF3, -CO-N=C(NH2)2, 21~6~88 g 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, Cl, Br,1, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxyl, -CF3 and methyl;
or the other r~dic~ls R(2) and R(4) in each case are R(22)-SO2-;
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(3~)R(36);
R(35) and R(36) indep~nde, Itl~ of one another are hydrogen, methyl or ethyl;
the other radical R(3) in each case is hf~rogen, -SR(25), -OR(25), -NR(2~)R(26) or -CR(23)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or pheny!, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, CF3 and CH3;
or R(25) is -(C1 -Cg)-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, 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, Cl, -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 orie another are hydrogen, F, Cl, 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, Cl, Br, l, -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)-SO2-;
R(122) is methyl or -CF3;
or the other r~diçAIs 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, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, CF3 and CH3;
or R(125) is -(C1-Cg)-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, 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)-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 of one another are hydrogen, methyl or ethyl and their pharmaceutically tolerable salts.
Very particularly prefer,ed cor"pounds of the formula I are those in which: one of the r~di~ls 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 ,ndependently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, Cl, 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, Cl, 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, Cl, CF3 and CH3;
or R(25) is-(C1-Cg)-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, 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, Cl 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, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, Br, l, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarL.o, lyl, 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, Cl, 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, Cl, 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)-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 of one another are hydrogen or methyl;
and their pharmaceutically tolerable salts.
Especially prerer,ed compounds of the formula I are those in which:
25 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, Cl or CF3;~0 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, Cl, Br, l, -CN, (C2-C5)-alkanoyl, (C2-C5)-21!~638~
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, Cl, CF3 and CH3;
or R(25) is-(C1-Cg)-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, CF3 and CH3;
R(26) and R(27) independently of one another are hydrogen or methyl;
one of the r~di~ls R(6), R(8) and R(10) is -CO-N=C(NH2)2;
the other radicals R(6) and R(10) in each case incJepe"der,lly of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, Cl 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, Cl, Br, l, -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, Cl, CF3 and CH3;
or R(125) is -(C1 -Cg)-heteroaryl, which is unsubstituted or substituted by a substituent seleded from the group consisting of F, Cl, 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)-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 of one another are hydrogen or methyl;
and their pharmaceutically tolerable salts.
10 Very especially prefel, ed 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 indep~"cJe"tly of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, Cl 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, Cl, Br, l, -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, Cl, CF3 and CH3;
or R(25) is-(C1-Cg)-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, 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) ~l96~88 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, Cl, or CF3;
5 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, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, Br, l, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxyc~rL,onyl, 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, Cl, CF3 and CH3;
or R(125) is -(C1 -Cg)-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, 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)-SO2-, -NR(19)-SO2-, -SO2-NR(19)-SO2-, -SO2-NR(19)-CO-, -O-CO-NR(19)-SO2- or ~ D ~ r D ~
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.
30 The designated alkyl radicals can be straight-chain or branched.
(C1-Cg)-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 which at least two ~ cent CH groups are replaced by S, NH or O (with formation of a five-",e"~bered 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, indepe"denlly of one another, can have either the S or the R configuration.
The compounds can be present as optical isomers, as diastereomers, 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 1, which comprises reacting compounds of the formula ll ~(2l) (9l) ~(7,, (5') (6') 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 ll, 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 21g638~
chlorides (formula ll, L = Cl), which, for their part, can in turn be prepared, in a manner known per se, from the underlying carboxylic acids (formula ll, L = OH), for example using thionyl chloride.
In addition to the ca~ nyl chlorides of the formula ll (L = Cl), further activated aci 5 derivatives of the formula ll can also be prepared, in a manner known per se, directly from the underlying diaryldicarboxylic acid derivatives (formula ll, L = OH), such as, for exa""~la, the methyl esters of the formula ll with L = OCH3 by treating with g~seo! ~s HCI in methanol, the imidazolides of the formula ll by treating with carLonyldiimidazole [L = 1-imidazolyl, Staab, Angew. Chem. Int. Ed. Engl. 1, 351 to 367 (1962)], the mixed anhydrides ll with Cl-COOC2H5 or tosyl chloride in the presence of triethylamine in an inert solvent, as well as the activation of diaryldicarboxylic acids with dicyclohexylcarbodiimide (DCC) or with O-[(cyano(ethoxycarbonyl)methylene)amino]-1, 1 ,3,3-tetramethyluronium tetrafluoroborate ("TOTU") [Proceedings of the 21 st European Peptide Symposium,1 5 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 ll are given, with citation of the source literature, in J. March, Advanced OrganicChemistry, Third Edition (John Wiley & Sons, 1985), p. 350.
20 The reaction of an activated carboxylic acid derivative of the formula I withguanidine is effected, in a manner known pe! 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 (Il, L = OMe) with 25 guanidine. Most reactions of compounds ll 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 = Cl, the reaction is advantageously carried out with addition of an acid30 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 2l9~388 involving nucleophilic 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 advantageolJsly carried out in a dipolar aprotic solvent, such as DMF or TMU, at a 5 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 nuc'eophilicity, for example K2CO3 or CsC03.
1 0 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 co"",ounds, organostannanes, organoboronic acids or organoborar,es.
15 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, asc~rL,ates, 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 25 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 manyapplication possibilities.
30 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 21~63~'8 reducing, in a preventive manner, the pathophysiological processes in the formation of ische~ ly 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 accotding to the5 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 phar",aceuticals for surgical interventions, e.g. in organ transplantations, it being possible to use the compounds both to protect the organs 10 in the donor before and during removal and to protect removed organs, for example during ~,eall"enl with physiological bath fluids or storage thereof in these fluids, and also during Ira"srer into the recipient body. The co",pounds 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 15 action against ischemically induced damage, the compounds are also suitable for use as pha""aceuticals 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,20 cardiogenic, hypovolemic and bacterial shock.
Moreover, the co,npounds of the formula I according to the invention are distinguished by their strong inhibitory effect on the proliferation of cells, for example the proliferation of fibroblast cells and the proliferation of vascular smooth muscle 25 cells. The co",pounds 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, fibrotic disorders, such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, and against organ 30 hypertrophy and hyperplasia, in particular in hyperplasia or hypertrophy of the prostate.
The compounds according to the invention are efficacious inhibitors of the cellular 21S~388 sodium/~,roton antipoi ler (Na+/H+ exchanger), which, in numerous disorders (essential hypertension, atherosclerosis, diabetes, etc.), is also raised in cells which are readily ~~essible to measurement, such as, for example, in erythrocytes, platelets or leukocytes. The co""~ounds according to the invention are therefore5 suitable for use as outstanding and simple scientific tools, for example in their use as diayl)oslics for Jeter,.,ii,ing and dir~ere"liating 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 signitlcantly improved water solubility. They are therefore essentially more highly suitable for i.v. administration.
15 Co",pared to the known readily water-soluble compounds, the compounds according to the invention are distinguished by their better bioavailability andphar" ,acokinetics.
In this context, pharmaceuticals which contain a compound I can be administered 20 orally, parenlerally, 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 2196~8~
tablets, coated tablets, hard gelatin capsules or aqueous, alcoholic or oily solutions.
Gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, g~ucose 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 5 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 sllh~n~leous or intravenous administration, the active compounds, if desiredtogether with the substances which are customary for the purpose, such as 10 solubilizers, emulsifiers 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, and 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 apharmaceutically acceptal,le solvent, such as, in particular, ethanol or water, or a mixture of such solvents, are suitable for use as a pharmaceutisal 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, emulsifiers and stabilizers, as well as a propellant. Such a preparation customarily contains the active compound in a co"cenlralion of about 0.1 to 10, in particular of about 0.3 to 3% by weight.
25 The dosage of the active compound of the formula I to be administered and thefrequency 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 themammal to be treated.
On average, the daily dose of a compound of the formula I for a patient of about75 kg in weight is at least 0.001 mg/kg of body weight, preferably at least 0.01 mglkg of body weight, up to at most 10 mg/kg of body weight, preferably up to ~ 21g63~
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 doses per day. On i.v. use, in particular, for example in the case of an infarct patient in intensive care, 5 up to 100 mg per day may be necessary.
List of abbreviations:
AIBN ~, ~ -azo-bis-isobutyronitrile Bn benzyl Brine saturated aqueous NaCI solution CH2CI2 dichloromethane DCI desorption~hemical ionization DIP diisopropyl ether DMA di",ethylacetamide 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-bromosuccinimide NMP N-methylpyrrolidone RT room temperature THF tetrahydrofuran TMU N,N,N',N'-tetramethylurea 2196~88 Tol toluene CNS central nervous system 5 Experimental section General procedure for the preparation of diaryldicarboxylic acid diguanidides (I) from dialkyl benzenedicarboxylates (Il, L = O-alkyl) 5 mmol of the dialkyl benzenedicarboxylate of the formula ll and 50 mmol of 10 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 15 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 ~~'~
H2N ~ N N ~ NH2 NH2 ~ NH2 25 a. Ethyl 3-(4-formyl)phenylbenzoate 3.4 9 of ethyl 3-bromobenzoate, 170 mg of palladium(ll) acetate, 390 mg of triphenylphosphine, 2.5 9 of 4-formylphenylboronic acid, 15 ml of a 2 N aqueous Na2CO3 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 NaHCO3 solution are then added and 30 the mixture is extracted 3 times using 150 ml of EA each time. The organic phase is dried over Na2SO4 and the solvent is removed in vacuo. Chromatography on silica gel using EA/HEP 1:8 yields 2.4 9 of white crystals, mp 81 ~C.
Rf (DIP) = 0.55 MS (DCI): 255 (M+H)+
219638~
b. Ethyl 3-(4-ethoxycarbonyl)phenylbenzoate 2.4 9 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, a5 clear solution is obtained, to which 18.9 9 of MnO2 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 agueous Na2CO3 solution and extracted 3 times with 300 ml ofEA each time. The organic phase is dried over Na2CO3 and the solvent is removed in vacuo. Chromatography on silica gel using EA/HEP 1:4 yields 2.5 9 of a colorless 1 0 oil.
Rf (DIP) = 0.59 MS (ES): 299 (M+H)+
c. 3-(4-Guanidinocarbonyl)phenylbenzoylguanidine 1.1 9 of ethyl 3-(4-ethoxycarbonyl)phenylbenzoate are reacted according to the 15 general procedure for the preparation of diaryldicarboxylic acid diguanidides and 760 mS Of colorless crystals are obtained, mp 11 3~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 2 5 o~3~N ~ NH2 O NH
mp 283~C.
Rf(acetone/water 10:1) = 0.25 MS (FAB): 325 (M+H)+
Example 3: 4-(4-Guanidinoc~rbonyl)phenylsulfamoylber,~oylguanidine H,N N,J~ HN~ NH2 a. Ethyl 4-sulfamoylbenzoate 20 9 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 Na2CO3 solution and the mixture is extracted 3 times with 200 ml of EA each time. The organic phase is dried over Na2SO4 the solvent is removed in vacuo and 21 9 of colorless crystals are obtained, mp 108~C.
Rf (DIP) = 0.24 MS (DCI): 230 (M+H)+
b. Ethyl 4-(4~thoxycarbonyl)phenylsulfamoylbenzoate 1.1 9 of ethyl 4-sulfamoylbenzoate, 840 mg of ethyl 4-fluorobenzoate and 4.9 g of Cs2CO3 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 Na2SO4 and the solvent is removed in vacuo. Chromatography on silica gel using EA/HEP 1:1 yields 2.6 9 of a colorlessoil.
Rf(EA/HEP 1:1) = 0.38 MS (DCI): 378 (M+H)+
c. 4-(4-Guanidinocarl,onyl)phenylsulfamoylbenzoylguanidine 2.5 9 of ethyl 4-(4-ethoxycarbonyl)phenylsulfamoylbenzoate are reacted accordingto 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 21963~
diaryldicarboxylic acid diguanidides:
Example 4: Biphenyl-4,4'-dicarboxylic acid diguanidide ~, l~, N~ NH2 Rf (acetoneh~ater 10:1 ) = 0.09 MS (FAB): 325 (M+H)+
Example 5: 4[3-(Guanidinocarbonyl)phenylaminocarbonylaminosulfonyl]-1 5 benzoylguanidine N
~ X
~ 5--NH l~NH~
a) Methyl 4~thoxycarbGnylaminosulfonylbenzoate 6.0 9 of methyl 4-aminosulfonylbenzoate and 7.7 9 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 syringe, 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 NaHSO4 solution and 200 ml of water.
The product is filtered off with suction and dried at 50~C in vacuo. 7.1 9 of colorless crystals, mp. 146~C
Rf(EA) 0.41 MS (DCI): 288 (M + H)+
b) 4-Ethoxycarbonylaminosulfonylbenzoic acid 6 9 of methyl 4-ethoxyca,l,onylaminosulfonylbenzoate and 42 ml of a 1 N 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 is5 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 9 of colorless crystals are obtained, mp.: 189~C
Rf (DIP/2% HOAc) = 0.28 MS (ES): 274 (M ~ H)+
1 0 c) 4-[3-(Hydroxycarbonyl)phenylaminocarbonylaminosulfonyl]benzoic acid 2 9 of 4-ethoxycarbonylaminosulfonylbenzoic acid and 1 9 of 3-aminobenzoic acid are boiled under reflux for 10 h in 50 ml of anhydrous toluene.1 ne solvent is removed in vacuo, and 2.8 9 of a crude product are obtained which is directly employed further.
d) 4-[3-(Guanidinocarbonyl)phenylaminocarbonylaminosulfonyl]-benzoylguanidine 1.4 9 of 4-(3-(hydroxycarbonyl)phenylaminocarbonylaminosulfonyl]benzoic acid and1.4 9 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 9 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+/H+ exchange and thus to be 21963&8 able to determine, by flame photometry, the Na+ influx into the erythrocytes viaNa+/H+ exchange. The blood was removed from the aural arteries and rendered inco~g~ le using 25 lU/ml of potassium heparin. A part of each sample was used for the duplicate deler",indtion of the hematocrit by means of centrifugation. Aliquots 5 of in each case 100 1~l were used for measuring the initial Na+ content of the erythrocytes.
In order to determine the amiloride-sensitive sodium influx, 100 ,ul of each blood sample were in each case incubated, at pH 7.4 and 37~C, in 5 ml of a hyperosmolar salVsucrose medium (mmol/l: 140 NaCI, 3 KCI, 150 sucrose, 0.1 ouabain, 20 tris(hydroxymethyl)aminomethane). The erythrocytes were then washed three times with ice-cold MgCI2/ou~h~ solution (mmol/l: 112 MgCI2, 0.1 ouabain) and hemolyzed in 2.0 ml of distilled water. The intracellular sodium content was determined by flame pl ,oto",etry.
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 x 10~ mol/l.
20 This ll.ettlod was also employed in the case of the compounds according to the Inventlon.
Results Inhibition of the Na+/H+ exchanger:
Example lC~n ~mol/l ~ .5 4 2.C
noechst Aktiengesellschaft HOE 96/F 013 Description 5 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
~R,~R8 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 atoms, F, Cl, -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, Cl, 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 Cl, -CF3, methyl, methoxy and -NR(1 5)R(1 6);
R(15) and R(16) are hydrogen or -CH3;
~lgfi38~
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, which is unsubstituted or substituted by 1 - 4 substituents selected from the group consisting of F, Cl, Br, I, -CN, (C2-C8)-alkanoyl, (C2-C8)-alkoxycarbonyl, formyl, carboxyl, -CF3, methyl, methoxy;
or the other radicals R(2) and R(4) in each case are R(22)-SO2-, 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) independently of one another are hydrogen or methyl;
or 15 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 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, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino and dimethylamino;
or R(25) is-(C1-Cg)-heteroaryl, which is unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, ~9638~
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, Cl, -OR(132), -NR(1 33)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 r~diçAIs R(7) and R(9) in each case independently of one another are hydn~gen, F, Cl, 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;
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 Cl, -CF3, methyl, methoxy and -NR(11 5)R(11 6);
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, Cl, 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 are R(1 22)-SO2-, R(1 23)R(1 24)N-CO-, R(1 28)-CO- or R(1 29)R(1 30)N-SO2;
219~38~
R(122) and R(128) independently of one another are methyl or -CF3;
R(123), R(124), R(129) and R(130) indepe,ndently of one another are hydrogen or methyl;
5 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;
15 the other radical R(8) in each case is h~d~gen, -SR(125), -OR(125), -NR(125)R(126) or-CR(125)R(126)R(127);
R( 1 25) is hydrogei), 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, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino and dimethylamino;
or R(1 25) is -(C1-Cg)-heteroaryl, which is unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F, Cl, 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(1 1 )-CO-, -NR(1 2)-CO-NR(13)-, -NR(1 7)-CO-NR(1 8)-SO2-, -NR(1 9)-SO2-, -SO2-NR(1 9)-SO2-, -SO2-NR(1 9)-CO-, -O-CO-NR(1 9)-SO2- or -CR(20)=CR(21 )-;
R(11), R(12), R(13), R(17), R(18), R(19), R(20) and R(21) indepe"denlly of one another are hydrogen or alkyl having 1, 2, 3, 4, S, 6, 7 or 8 carbon atoms and their pharmaceutically tolerable salts.
Preferred co",pounds 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 i"dependently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, Cl,-O R(32),-N R(33)R(34) or CF3;
R(32), R(33) and R(34) independently of one another are hydrogen or methyl;
the other Pdic~ls R(2) and R(4) in each case independenlly of one another are hydrogen, F, Cl, 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)-cycloalkylor phenyl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F and Cl, -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, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, 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 independently of one another are R(22)-SO2-, R(28)-C O- or R(29)R(30)N-SO2-;
R(22) and R(28) independently of one another are methyl or -CF3;
21963~
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, 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, phenyl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy and dimethylamino;
or R(25) is-(C1-Cg)-heteroaryl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, 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 independently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, Cl, -OR(132), -NR(133)R(134) or CF3;
R(132), R(133) and R(134) independently of one another are hydrogen or methyl;
2I 963g8 the other radicals R(7) and R(9) in each case independently of one another are hydrogen, F, Cl, Br, l, 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 iszero,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 Cl, -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, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, Br, l, -CN, (C2-C5)-alkanoyl, (C2-C5)-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)-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) 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 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, Cl, CF3, CH3, methoxy and dimethylamino;
or R(125) is -(C1-Cg)-heteroaryl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, 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)-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 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, Cl, -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, Cl, OH, CF3, -CO-N=C(NH2)2, 21~6~88 g 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, Cl, Br,1, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxyl, -CF3 and methyl;
or the other r~dic~ls R(2) and R(4) in each case are R(22)-SO2-;
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(3~)R(36);
R(35) and R(36) indep~nde, Itl~ of one another are hydrogen, methyl or ethyl;
the other radical R(3) in each case is hf~rogen, -SR(25), -OR(25), -NR(2~)R(26) or -CR(23)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or pheny!, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, CF3 and CH3;
or R(25) is -(C1 -Cg)-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, 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, Cl, -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 orie another are hydrogen, F, Cl, 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, Cl, Br, l, -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)-SO2-;
R(122) is methyl or -CF3;
or the other r~diçAIs 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, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, CF3 and CH3;
or R(125) is -(C1-Cg)-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, 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)-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 of one another are hydrogen, methyl or ethyl and their pharmaceutically tolerable salts.
Very particularly prefer,ed cor"pounds of the formula I are those in which: one of the r~di~ls 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 ,ndependently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, Cl, 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, Cl, 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, Cl, CF3 and CH3;
or R(25) is-(C1-Cg)-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, 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, Cl 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, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, Br, l, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarL.o, lyl, 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, Cl, 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, Cl, 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)-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 of one another are hydrogen or methyl;
and their pharmaceutically tolerable salts.
Especially prerer,ed compounds of the formula I are those in which:
25 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, Cl or CF3;~0 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, Cl, Br, l, -CN, (C2-C5)-alkanoyl, (C2-C5)-21!~638~
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, Cl, CF3 and CH3;
or R(25) is-(C1-Cg)-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, CF3 and CH3;
R(26) and R(27) independently of one another are hydrogen or methyl;
one of the r~di~ls R(6), R(8) and R(10) is -CO-N=C(NH2)2;
the other radicals R(6) and R(10) in each case incJepe"der,lly of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, Cl 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, Cl, Br, l, -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, Cl, CF3 and CH3;
or R(125) is -(C1 -Cg)-heteroaryl, which is unsubstituted or substituted by a substituent seleded from the group consisting of F, Cl, 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)-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 of one another are hydrogen or methyl;
and their pharmaceutically tolerable salts.
10 Very especially prefel, ed 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 indep~"cJe"tly of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, Cl 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, Cl, Br, l, -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, Cl, CF3 and CH3;
or R(25) is-(C1-Cg)-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, 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) ~l96~88 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, Cl, or CF3;
5 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, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, Br, l, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxyc~rL,onyl, 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, Cl, CF3 and CH3;
or R(125) is -(C1 -Cg)-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, 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)-SO2-, -NR(19)-SO2-, -SO2-NR(19)-SO2-, -SO2-NR(19)-CO-, -O-CO-NR(19)-SO2- or ~ D ~ r D ~
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.
30 The designated alkyl radicals can be straight-chain or branched.
(C1-Cg)-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 which at least two ~ cent CH groups are replaced by S, NH or O (with formation of a five-",e"~bered 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, indepe"denlly of one another, can have either the S or the R configuration.
The compounds can be present as optical isomers, as diastereomers, 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 1, which comprises reacting compounds of the formula ll ~(2l) (9l) ~(7,, (5') (6') 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 ll, 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 21g638~
chlorides (formula ll, L = Cl), which, for their part, can in turn be prepared, in a manner known per se, from the underlying carboxylic acids (formula ll, L = OH), for example using thionyl chloride.
In addition to the ca~ nyl chlorides of the formula ll (L = Cl), further activated aci 5 derivatives of the formula ll can also be prepared, in a manner known per se, directly from the underlying diaryldicarboxylic acid derivatives (formula ll, L = OH), such as, for exa""~la, the methyl esters of the formula ll with L = OCH3 by treating with g~seo! ~s HCI in methanol, the imidazolides of the formula ll by treating with carLonyldiimidazole [L = 1-imidazolyl, Staab, Angew. Chem. Int. Ed. Engl. 1, 351 to 367 (1962)], the mixed anhydrides ll with Cl-COOC2H5 or tosyl chloride in the presence of triethylamine in an inert solvent, as well as the activation of diaryldicarboxylic acids with dicyclohexylcarbodiimide (DCC) or with O-[(cyano(ethoxycarbonyl)methylene)amino]-1, 1 ,3,3-tetramethyluronium tetrafluoroborate ("TOTU") [Proceedings of the 21 st European Peptide Symposium,1 5 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 ll are given, with citation of the source literature, in J. March, Advanced OrganicChemistry, Third Edition (John Wiley & Sons, 1985), p. 350.
20 The reaction of an activated carboxylic acid derivative of the formula I withguanidine is effected, in a manner known pe! 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 (Il, L = OMe) with 25 guanidine. Most reactions of compounds ll 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 = Cl, the reaction is advantageously carried out with addition of an acid30 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 2l9~388 involving nucleophilic 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 advantageolJsly carried out in a dipolar aprotic solvent, such as DMF or TMU, at a 5 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 nuc'eophilicity, for example K2CO3 or CsC03.
1 0 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 co"",ounds, organostannanes, organoboronic acids or organoborar,es.
15 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, asc~rL,ates, 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 25 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 manyapplication possibilities.
30 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 21~63~'8 reducing, in a preventive manner, the pathophysiological processes in the formation of ische~ ly 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 accotding to the5 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 phar",aceuticals for surgical interventions, e.g. in organ transplantations, it being possible to use the compounds both to protect the organs 10 in the donor before and during removal and to protect removed organs, for example during ~,eall"enl with physiological bath fluids or storage thereof in these fluids, and also during Ira"srer into the recipient body. The co",pounds 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 15 action against ischemically induced damage, the compounds are also suitable for use as pha""aceuticals 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,20 cardiogenic, hypovolemic and bacterial shock.
Moreover, the co,npounds of the formula I according to the invention are distinguished by their strong inhibitory effect on the proliferation of cells, for example the proliferation of fibroblast cells and the proliferation of vascular smooth muscle 25 cells. The co",pounds 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, fibrotic disorders, such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, and against organ 30 hypertrophy and hyperplasia, in particular in hyperplasia or hypertrophy of the prostate.
The compounds according to the invention are efficacious inhibitors of the cellular 21S~388 sodium/~,roton antipoi ler (Na+/H+ exchanger), which, in numerous disorders (essential hypertension, atherosclerosis, diabetes, etc.), is also raised in cells which are readily ~~essible to measurement, such as, for example, in erythrocytes, platelets or leukocytes. The co""~ounds according to the invention are therefore5 suitable for use as outstanding and simple scientific tools, for example in their use as diayl)oslics for Jeter,.,ii,ing and dir~ere"liating 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 signitlcantly improved water solubility. They are therefore essentially more highly suitable for i.v. administration.
15 Co",pared to the known readily water-soluble compounds, the compounds according to the invention are distinguished by their better bioavailability andphar" ,acokinetics.
In this context, pharmaceuticals which contain a compound I can be administered 20 orally, parenlerally, 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 2196~8~
tablets, coated tablets, hard gelatin capsules or aqueous, alcoholic or oily solutions.
Gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, g~ucose 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 5 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 sllh~n~leous or intravenous administration, the active compounds, if desiredtogether with the substances which are customary for the purpose, such as 10 solubilizers, emulsifiers 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, and 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 apharmaceutically acceptal,le solvent, such as, in particular, ethanol or water, or a mixture of such solvents, are suitable for use as a pharmaceutisal 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, emulsifiers and stabilizers, as well as a propellant. Such a preparation customarily contains the active compound in a co"cenlralion of about 0.1 to 10, in particular of about 0.3 to 3% by weight.
25 The dosage of the active compound of the formula I to be administered and thefrequency 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 themammal to be treated.
On average, the daily dose of a compound of the formula I for a patient of about75 kg in weight is at least 0.001 mg/kg of body weight, preferably at least 0.01 mglkg of body weight, up to at most 10 mg/kg of body weight, preferably up to ~ 21g63~
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 doses per day. On i.v. use, in particular, for example in the case of an infarct patient in intensive care, 5 up to 100 mg per day may be necessary.
List of abbreviations:
AIBN ~, ~ -azo-bis-isobutyronitrile Bn benzyl Brine saturated aqueous NaCI solution CH2CI2 dichloromethane DCI desorption~hemical ionization DIP diisopropyl ether DMA di",ethylacetamide 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-bromosuccinimide NMP N-methylpyrrolidone RT room temperature THF tetrahydrofuran TMU N,N,N',N'-tetramethylurea 2196~88 Tol toluene CNS central nervous system 5 Experimental section General procedure for the preparation of diaryldicarboxylic acid diguanidides (I) from dialkyl benzenedicarboxylates (Il, L = O-alkyl) 5 mmol of the dialkyl benzenedicarboxylate of the formula ll and 50 mmol of 10 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 15 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 ~~'~
H2N ~ N N ~ NH2 NH2 ~ NH2 25 a. Ethyl 3-(4-formyl)phenylbenzoate 3.4 9 of ethyl 3-bromobenzoate, 170 mg of palladium(ll) acetate, 390 mg of triphenylphosphine, 2.5 9 of 4-formylphenylboronic acid, 15 ml of a 2 N aqueous Na2CO3 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 NaHCO3 solution are then added and 30 the mixture is extracted 3 times using 150 ml of EA each time. The organic phase is dried over Na2SO4 and the solvent is removed in vacuo. Chromatography on silica gel using EA/HEP 1:8 yields 2.4 9 of white crystals, mp 81 ~C.
Rf (DIP) = 0.55 MS (DCI): 255 (M+H)+
219638~
b. Ethyl 3-(4-ethoxycarbonyl)phenylbenzoate 2.4 9 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, a5 clear solution is obtained, to which 18.9 9 of MnO2 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 agueous Na2CO3 solution and extracted 3 times with 300 ml ofEA each time. The organic phase is dried over Na2CO3 and the solvent is removed in vacuo. Chromatography on silica gel using EA/HEP 1:4 yields 2.5 9 of a colorless 1 0 oil.
Rf (DIP) = 0.59 MS (ES): 299 (M+H)+
c. 3-(4-Guanidinocarbonyl)phenylbenzoylguanidine 1.1 9 of ethyl 3-(4-ethoxycarbonyl)phenylbenzoate are reacted according to the 15 general procedure for the preparation of diaryldicarboxylic acid diguanidides and 760 mS Of colorless crystals are obtained, mp 11 3~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 2 5 o~3~N ~ NH2 O NH
mp 283~C.
Rf(acetone/water 10:1) = 0.25 MS (FAB): 325 (M+H)+
Example 3: 4-(4-Guanidinoc~rbonyl)phenylsulfamoylber,~oylguanidine H,N N,J~ HN~ NH2 a. Ethyl 4-sulfamoylbenzoate 20 9 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 Na2CO3 solution and the mixture is extracted 3 times with 200 ml of EA each time. The organic phase is dried over Na2SO4 the solvent is removed in vacuo and 21 9 of colorless crystals are obtained, mp 108~C.
Rf (DIP) = 0.24 MS (DCI): 230 (M+H)+
b. Ethyl 4-(4~thoxycarbonyl)phenylsulfamoylbenzoate 1.1 9 of ethyl 4-sulfamoylbenzoate, 840 mg of ethyl 4-fluorobenzoate and 4.9 g of Cs2CO3 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 Na2SO4 and the solvent is removed in vacuo. Chromatography on silica gel using EA/HEP 1:1 yields 2.6 9 of a colorlessoil.
Rf(EA/HEP 1:1) = 0.38 MS (DCI): 378 (M+H)+
c. 4-(4-Guanidinocarl,onyl)phenylsulfamoylbenzoylguanidine 2.5 9 of ethyl 4-(4-ethoxycarbonyl)phenylsulfamoylbenzoate are reacted accordingto 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 21963~
diaryldicarboxylic acid diguanidides:
Example 4: Biphenyl-4,4'-dicarboxylic acid diguanidide ~, l~, N~ NH2 Rf (acetoneh~ater 10:1 ) = 0.09 MS (FAB): 325 (M+H)+
Example 5: 4[3-(Guanidinocarbonyl)phenylaminocarbonylaminosulfonyl]-1 5 benzoylguanidine N
~ X
~ 5--NH l~NH~
a) Methyl 4~thoxycarbGnylaminosulfonylbenzoate 6.0 9 of methyl 4-aminosulfonylbenzoate and 7.7 9 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 syringe, 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 NaHSO4 solution and 200 ml of water.
The product is filtered off with suction and dried at 50~C in vacuo. 7.1 9 of colorless crystals, mp. 146~C
Rf(EA) 0.41 MS (DCI): 288 (M + H)+
b) 4-Ethoxycarbonylaminosulfonylbenzoic acid 6 9 of methyl 4-ethoxyca,l,onylaminosulfonylbenzoate and 42 ml of a 1 N 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 is5 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 9 of colorless crystals are obtained, mp.: 189~C
Rf (DIP/2% HOAc) = 0.28 MS (ES): 274 (M ~ H)+
1 0 c) 4-[3-(Hydroxycarbonyl)phenylaminocarbonylaminosulfonyl]benzoic acid 2 9 of 4-ethoxycarbonylaminosulfonylbenzoic acid and 1 9 of 3-aminobenzoic acid are boiled under reflux for 10 h in 50 ml of anhydrous toluene.1 ne solvent is removed in vacuo, and 2.8 9 of a crude product are obtained which is directly employed further.
d) 4-[3-(Guanidinocarbonyl)phenylaminocarbonylaminosulfonyl]-benzoylguanidine 1.4 9 of 4-(3-(hydroxycarbonyl)phenylaminocarbonylaminosulfonyl]benzoic acid and1.4 9 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 9 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+/H+ exchange and thus to be 21963&8 able to determine, by flame photometry, the Na+ influx into the erythrocytes viaNa+/H+ exchange. The blood was removed from the aural arteries and rendered inco~g~ le using 25 lU/ml of potassium heparin. A part of each sample was used for the duplicate deler",indtion of the hematocrit by means of centrifugation. Aliquots 5 of in each case 100 1~l were used for measuring the initial Na+ content of the erythrocytes.
In order to determine the amiloride-sensitive sodium influx, 100 ,ul of each blood sample were in each case incubated, at pH 7.4 and 37~C, in 5 ml of a hyperosmolar salVsucrose medium (mmol/l: 140 NaCI, 3 KCI, 150 sucrose, 0.1 ouabain, 20 tris(hydroxymethyl)aminomethane). The erythrocytes were then washed three times with ice-cold MgCI2/ou~h~ solution (mmol/l: 112 MgCI2, 0.1 ouabain) and hemolyzed in 2.0 ml of distilled water. The intracellular sodium content was determined by flame pl ,oto",etry.
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 x 10~ mol/l.
20 This ll.ettlod was also employed in the case of the compounds according to the Inventlon.
Results Inhibition of the Na+/H+ exchanger:
Example lC~n ~mol/l ~ .5 4 2.C
Claims (20)
1. A diaryldicarboxylic acid diguanidide of the formula I
I
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 atoms, F, Cl, -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, Cl, 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 Cl, -CF3, methyl, methoxy and -NR(15)R(16);
R(15) and R(16) 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, which is unsubstituted or substituted by 1 - 4 substituents selected from the group consisting of F, Cl, Br, I, -CN, (C2-C8)-alkanoyl, (C2-C8)-alkoxycarbonyl, formyl, carboxyl, -CF3, methyl, methoxy;
or the other radicals R(2) and R(4) in each case are 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 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 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, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino and dimethylamino;
or R(25) is -(C1-C9)-heteroaryl, which is unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F, Cl, 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 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, Cl, -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, Cl, 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;
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 Cl, -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, Cl, 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 are 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 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 carban 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, Cl, 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, Cl, 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)-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 of one another are hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or its pharmaceutically tolerable salts.
I
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 atoms, F, Cl, -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, Cl, 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 Cl, -CF3, methyl, methoxy and -NR(15)R(16);
R(15) and R(16) 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, which is unsubstituted or substituted by 1 - 4 substituents selected from the group consisting of F, Cl, Br, I, -CN, (C2-C8)-alkanoyl, (C2-C8)-alkoxycarbonyl, formyl, carboxyl, -CF3, methyl, methoxy;
or the other radicals R(2) and R(4) in each case are 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 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 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, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino and dimethylamino;
or R(25) is -(C1-C9)-heteroaryl, which is unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F, Cl, 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 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, Cl, -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, Cl, 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;
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 Cl, -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, Cl, 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 are 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 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 carban 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, Cl, 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, Cl, 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)-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 of one another are hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or its pharmaceutically 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, Cl, -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, Cl, 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 or2;
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 Cl, -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, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, 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 independently of one another are R(22)-SO2-, R(28)-CO- or R(29)R(30)N-SO2-;
R(22) and R(28) independently of one another are methyl or -CF3;
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) independantly 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, phenyl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy and dimethylamino;
or R(25) is -(C1-C9)-heteroaryl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, 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 independently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, Cl, -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, Cl, 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 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 Cl, -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, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, 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 independently of one another are R(122)-SO2-, R(128)-CO- or R(129)R(130)N-SO2-;
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 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, Cl, CF3, CH3, methoxy and dimethylamino;
or R(125) is -(C1-C9)-heteroaryl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, 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)-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 of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms.
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, Cl, -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, Cl, 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 or2;
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 Cl, -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, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, 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 independently of one another are R(22)-SO2-, R(28)-CO- or R(29)R(30)N-SO2-;
R(22) and R(28) independently of one another are methyl or -CF3;
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) independantly 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, phenyl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy and dimethylamino;
or R(25) is -(C1-C9)-heteroaryl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, 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 independently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, Cl, -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, Cl, 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 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 Cl, -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, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, 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 independently of one another are R(122)-SO2-, R(128)-CO- or R(129)R(130)N-SO2-;
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 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, Cl, CF3, CH3, methoxy and dimethylamino;
or R(125) is -(C1-C9)-heteroaryl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, 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)-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 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, Cl, -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, Cl, 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, Cl, 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)-SO2-;
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, methyl or ethyl;
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 atoms or phenyl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, CF3 and CH3;
or R(25) is -(C1-C9)-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, 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, Cl, -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, Cl, 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, Cl, 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)-SO2-;
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, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, 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, Cl, 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)-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 of one another are hydrogen, methyl or ethyl.
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, Cl, -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, Cl, 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, Cl, 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)-SO2-;
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, methyl or ethyl;
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 atoms or phenyl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, CF3 and CH3;
or R(25) is -(C1-C9)-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, 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, Cl, -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, Cl, 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, Cl, 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)-SO2-;
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, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, 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, Cl, 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)-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 of one another are hydrogen, methyl or ethyl.
4. A compound of the formula I as claimed in at least 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 independently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, Cl, 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, Cl, 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, Cl, CF3 and CH3;
or R(25) is-(C1-C9)-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, 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, Cl 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, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, 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, Cl, 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, Cl, 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)-SO2-, -NR(19)-SO2-, -SO2-NR(19)-SO2-, -SO2-NR(19)-CO-, -C-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 of one another are hydrogen or methyl.
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, Cl, 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, Cl, 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, Cl, CF3 and CH3;
or R(25) is-(C1-C9)-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, 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, Cl 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, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, 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, Cl, 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, Cl, 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)-SO2-, -NR(19)-SO2-, -SO2-NR(19)-SO2-, -SO2-NR(19)-CO-, -C-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 of one another are hydrogen or methyl.
5. A compound of the formula I as claimed in at least one of claims 1 to 4, 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, Cl 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, Cl, 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, Cl, CF3 and CH3;
or R(25) is-(C1-C9)-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, CF3 and CH3;
R(26) and R(27) independently of one another are hydrogen or methyl;
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 independenlly of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, Cl 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, Cl, 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, Cl, 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, Cl, 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)-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 of one another are hydrogen or methyl.
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, Cl 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, Cl, 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, Cl, CF3 and CH3;
or R(25) is-(C1-C9)-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, CF3 and CH3;
R(26) and R(27) independently of one another are hydrogen or methyl;
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 independenlly of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, Cl 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, Cl, 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, Cl, 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, Cl, 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)-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 of one another are hydrogen or methyl.
6. A compound of the formula I as claimed in at least 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, Cl 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, Cl, 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, Cl, CF3 and CH3;
or R(25) is-(C1-C9)-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, 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, Cl, 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, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, 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, Cl, 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, Cl, 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)-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 of one another are hydrogen or methyl.
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, Cl 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, Cl, 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, Cl, CF3 and CH3;
or R(25) is-(C1-C9)-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, 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, Cl, 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, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, 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, Cl, 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, Cl, 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)-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 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
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 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.
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 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 compound 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, 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.
as claimed in claim 1 is mixed with the customary additives and administered in a suitable form for administration.
11. Use of a compound I as claimed in claim 1 for preparing a medicament for thetreatment or prophylaxis of cardiac infarct.
12. The use of a compound I as claimed in claim 1 for preparing a medicament forthe treatment or prophylaxis of angina pectoris.
13. The use of a compound I as claimed in claim 1 for preparing a medicament forthe 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 forthe 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 forthe treatment or prophylaxis of ischemic conditions of peripheral organs and limbs.
16. The use of a compound I as claimed in claim 1 for preparing a medicament forthe treatment of states of shock.
17. The use of a compound I as claimed in claim 1 for preparing a medicament foremployment in surgical operations and organ transplantations.
18. The use of a compound I as claimed in claim 1 for preparing a medicament forthe preservation and storage of transplants for surgical measures.
19. The use of a compound I as claimed in claim 1 for preparing a medicament forthe 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 asclaimed in one or more of claims 1 to 6.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19603425.6 | 1996-01-31 | ||
| DE19603425A DE19603425A1 (en) | 1996-01-31 | 1996-01-31 | Substituted diaryldicarboxylic acid diguanidides, processes for their preparation, their use as medicaments or diagnostic agents and medicaments containing them |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2196388A1 true CA2196388A1 (en) | 1997-08-01 |
Family
ID=7784136
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002196388A Abandoned CA2196388A1 (en) | 1996-01-31 | 1997-01-30 | Substituted diaryldicarboxylic acid diguanidides, processes for their preparation, their use as a medicament or diagnostic, and medicament containing them |
Country Status (19)
| Country | Link |
|---|---|
| EP (1) | EP0787717A1 (en) |
| JP (1) | JPH09221465A (en) |
| KR (1) | KR970059165A (en) |
| AR (1) | AR005596A1 (en) |
| AU (1) | AU1239097A (en) |
| BR (1) | BR9700817A (en) |
| CA (1) | CA2196388A1 (en) |
| CZ (1) | CZ27197A3 (en) |
| DE (1) | DE19603425A1 (en) |
| HR (1) | HRP970057A2 (en) |
| HU (1) | HUP9700277A3 (en) |
| IL (1) | IL120093A0 (en) |
| NO (1) | NO970406L (en) |
| NZ (1) | NZ314145A (en) |
| PL (1) | PL317844A1 (en) |
| SK (1) | SK12797A3 (en) |
| TR (1) | TR199700059A2 (en) |
| TW (1) | TW430642B (en) |
| ZA (1) | ZA97770B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10024319A1 (en) * | 2000-05-17 | 2001-11-22 | Merck Patent Gmbh | New bis-acylguanidine compounds are subtype-1 cellular sodium ion-proton antiporter inhibitors useful e.g. for treating arrhythmia, angina pectoris, infarction and insulin-independent diabetes mellitus |
| AR065785A1 (en) * | 2007-03-19 | 2009-07-01 | Xenon Pharmaceuticals Inc | BIARETO AND BIHETEROARILE COMPOUNDS OF UTILITY IN THE TREATMENT OF IRON DISORDERS |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3929582A1 (en) | 1989-09-06 | 1991-03-07 | Hoechst Ag | BENZOYLGUANIDINE, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AS A MEDICINE AND THE MEDICINE CONTAINING IT |
| DE59302959D1 (en) | 1992-02-15 | 1996-07-25 | Hoechst Ag | 3,5-Substituted benzoylguanidines, with antiarrhythmic effects and inhibitory effects on cell proliferation |
| US5278933A (en) | 1992-06-30 | 1994-01-11 | Hunsinger Terrance D | Fiber optic splice organizer and associated method |
| EP0604852A1 (en) * | 1992-12-28 | 1994-07-06 | Hoechst Aktiengesellschaft | 2,4-Substituted 5-(N-substituted-sulfamoyl) benzoylguanidines, as antiarrhythmic agents, inhibitors of the proliferation of cells and inhibitors of sodium-hydrogen exchange |
| IL109570A0 (en) * | 1993-05-17 | 1994-08-26 | Fujisawa Pharmaceutical Co | Guanidine derivatives, pharmaceutical compositions containing the same and processes for the preparation thereof |
| DE4327244A1 (en) * | 1993-08-13 | 1995-02-16 | Hoechst Ag | Urea-substituted benzoyl guanedines, process for their preparation, their use as a medicament or diagnostic agent, and medicament containing them |
-
1996
- 1996-01-31 DE DE19603425A patent/DE19603425A1/en not_active Withdrawn
-
1997
- 1997-01-08 PL PL97317844A patent/PL317844A1/en unknown
- 1997-01-20 EP EP97100776A patent/EP0787717A1/en not_active Withdrawn
- 1997-01-29 TR TR97/00059A patent/TR199700059A2/en unknown
- 1997-01-29 SK SK127-97A patent/SK12797A3/en unknown
- 1997-01-29 HU HU9700277A patent/HUP9700277A3/en unknown
- 1997-01-29 IL IL12009397A patent/IL120093A0/en unknown
- 1997-01-29 NZ NZ314145A patent/NZ314145A/en unknown
- 1997-01-29 CZ CZ97271A patent/CZ27197A3/en unknown
- 1997-01-29 TW TW086100957A patent/TW430642B/en active
- 1997-01-29 AR ARP970100360A patent/AR005596A1/en unknown
- 1997-01-29 AU AU12390/97A patent/AU1239097A/en not_active Abandoned
- 1997-01-30 HR HR19603425.6A patent/HRP970057A2/en not_active Application Discontinuation
- 1997-01-30 NO NO970406A patent/NO970406L/en unknown
- 1997-01-30 CA CA002196388A patent/CA2196388A1/en not_active Abandoned
- 1997-01-30 ZA ZA97770A patent/ZA97770B/en unknown
- 1997-01-30 JP JP9016046A patent/JPH09221465A/en active Pending
- 1997-01-30 BR BR9700817A patent/BR9700817A/en not_active Application Discontinuation
- 1997-01-31 KR KR1019970003012A patent/KR970059165A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| TW430642B (en) | 2001-04-21 |
| DE19603425A1 (en) | 1997-08-07 |
| JPH09221465A (en) | 1997-08-26 |
| HU9700277D0 (en) | 1997-03-28 |
| NO970406L (en) | 1997-08-01 |
| NZ314145A (en) | 1997-11-24 |
| SK12797A3 (en) | 1998-02-04 |
| AR005596A1 (en) | 1999-06-23 |
| TR199700059A2 (en) | 1997-08-21 |
| HUP9700277A2 (en) | 1997-10-28 |
| IL120093A0 (en) | 1997-04-15 |
| AU1239097A (en) | 1997-08-07 |
| NO970406D0 (en) | 1997-01-30 |
| CZ27197A3 (en) | 1998-05-13 |
| ZA97770B (en) | 1997-07-31 |
| EP0787717A1 (en) | 1997-08-06 |
| HUP9700277A3 (en) | 1998-04-28 |
| KR970059165A (en) | 1997-08-12 |
| HRP970057A2 (en) | 1998-04-30 |
| PL317844A1 (en) | 1997-08-04 |
| BR9700817A (en) | 1998-07-07 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |