Pharmaceutical compositions for the treatment of systemic inflammatory response syndrome

Pharmaceutical composition comprised of

• (a) at least one active substance selected from the group of benzimidazoles of general formula (I)
• 10
• wherein
• Ar denotes a phenylene or naphthylene group optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C1-3-alkyl or C1-3-alkoxy group,
• a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally substituted in the carbon skeleton by a C-3-alkyl group,
• A denotes a C1-3-alkylene group,
• B denotes an oxygen or sulphur atom, a methylene, carbonyl, sulphinyl or sulphonyl group, an imino group optionally substituted by a C1-3-alkyl group wherein the alkyl moiety may be mono- or disubstituted by a carboxy group,
• Ra denotes a R1-CO-C3-5-cycloalkyl group wherein
• R1 denotes a C1-3-alkoxy, amino, C1-4-alkylamino or di-(C14-alkyl)-amino group, wherein in each case the alkyl moiety may be substituted by a carboxy group,
• a 4- to 7-membered cycloalkyleneimino or cycloalkenyleneimino group which may be substituted by one or two C1-3-alkyl groups, while an alkyl substituent may simultaneously be substituted by a hydroxy, C1-3-alkoxy, carboxy, carboxy-C1-3-alkoxy, carboxy-C1-3-alkylamino, N-(C1-3-alkyl)-N-(carboxy-C1-3-alkyl)-amino, carboxy-C1-3-alkylaminocarbonyl, N-(C1-3-alkyl)-N-(carboxy-C1-3-alkyl)-aminocarbonyl, carboxy-C1-3-alkylaminocarbonylamino, 1-(C1-3-alkyl)-3-(carboxy-C1-3-alkyl)-aminocarbonylamino, 3-(C1-3-alkyl)-3-(carboxy-C1-3-alkyl)-aminocarbonylamino or 1,3-di-(C1-3-alkyl)-3-(carboxy-C1-3-alkyl)-aminocarbonylamino group,
• a 4- to 7-membered cycloalkyleneimino group substituted by a hydroxy group,
• a 5- to 7-membered cycloalkyleneimino group optionally substituted by a C1-3-alkyl group, to which a phenyl ring is fused via two adjacent carbon atoms,
• a morpholino, piperazino, N-(C1-3-alkyl)-piperazino, pyrrolino, 3,4-dehydro-piperidino or pyrrol-1-yl group,
• a R2-CX-C3-5-cycloalkyl group wherein
• R2 denotes a phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl group optionally substituted by a C1-3-alkyl group, while the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C1-3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C1-3-alkyl group and an oxygen or sulphur atom or one or two nitrogen atoms and the abovementioned alkyl substituent may be substituted by a carboxy, carboxy-C1-3-alkoxy, carboxy-C1-3-alkylamino or N-(C1-3-alkyl)-carboxy-C1-3-alkylamino group, and
• X denotes an oxygen atom, a C1-3-alkylimino, C1-3-alkoxyimino, C1-3-alkylhydrazino, di-(C1-3-alkyl)-hydrazino, C2-4-alkanoylhydrazino, N-(C1-3-alkyl)-C2-4-alkanoylhydrazino or C1-3-alkylidene group each of which may be substituted by a carboxy group in the alkyl or alkanoyl moiety or in the alkyl and alkanoyl moiety,
• a C1-3-alkyl or C3-5-cycloalkyl group substituted by an imidazole or imidazolone group, wherein
• the imidazole ring may be substituted by a phenyl or carboxy group and by one or two C1-3-alkyl groups or by one, two or three C1-3-alkyl groups, while the substituents may be identical or different and one of the abovementioned alkyl substituents may simultaneously be substituted by a carboxy group or in the 2 or 3 position by an amino, C2-4-alkanoylamino, C1-3-alkylamino, N-(C2-4-alkanoyl)-C1-3-alkylamino or di-(C1-3-alkyl)-amino group, and
• the imidazolone ring may be substituted by a C1-3-alkyl group, while the alkyl substituent may be substituted by a carboxy group or in the 2 or 3 position by an amino, C2-4-alkanoylamino, C1-3-alkylamino, N-(C2-4-alkanoyl)-C1-3-alkylamino or di-(C1-3-alkyl)-amino group, and
• additionally a phenyl or pyridine ring may be fused to the abovementioned imidazole and imidazolone rings via two adjacent carbon atoms,
• an imidazolidin-2,4-dion-5-yl group which may be substituted by one or two C1-3-alkyl groups, while simultaneously an alkyl substituent may be substituted by a carboxy group,
• a C1-4-alkyl group which is substituted
• by a C1-3-alkyl-Y1-C1-3-alkyl, HOOC-C1-3-alkyl-Y,-C1-3-alkyl, tetrazolyl-C1-3-alkyl-Y2, R3NR4 or R3NR4-C1-3-alkyl group and
• by an isoxazolidinylcarbonyl group optionally substituted by a C1-3-alkyl group, by a pyrrolinocarbonyl, 3,4-dehydro-piperidinocarbonyl, pyrrol-1-yl-carbonyl, carboxy, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl or 4- to 7-membered cycloalkyleneiminocarbonyl group, while in the abovementioned groups the cycloalkyleneimino moiety may be substituted by one or two C1-3-alkyl groups and simultaneously in each case an alkyl moiety or alkyl substituent of the abovementioned C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl or cycloalkyleneiminocarbonyl groups may be substituted by a carboxy group, and the remaining hydrogen atoms of the C, 4-alkyl group may be wholly or partly replaced by fluorine atoms, wherein
• R3 denotes a hydrogen atom or a C1-3-alkyl group optionally substituted by a carboxy group and
• R4 denotes a hydrogen atom, a C1-3-alkyl-Y1-C1-3-alkyl-Y2, carboxy-C1-3-alkyl-Y1-C1-3-alkyl-Y2, C1-3-alkyl-Y2 or carboxy-C1-3-alkyl-Y2 group or
• R3 and R4 together with the nitrogen atom between them denote a 4-to 7-membered cycloalkyleneimino group optionally substituted by a carboxy, C1-3-alkyl or carboxy-C1-3-alkyl group, wherein
• Y1 denotes a carbon-carbon bond, an oxygen atom, a sulphenyl, sulphinyl, sulphonyl, —NH, —NH—CO or —NH—CO—NH group and
• Y2 denotes a carbon-nitrogen bond or a carbonyl, sulphonyl, imino or —NH—CO group, while the carbonyl group of the —NH—CO group is linked to the nitrogen atom of the R3NR4 group, and the imino groups mentioned in the definition of the groups Y, and Y2 may each additionally be substituted by a C1-3-alkyl or carboxy-C1-3-alkyl group,
• a C1-3-alkyl or C3-5-cycloalkyl group substituted by a R5NR6 group, wherein
• R5 denotes a hydrogen atom, a C1-3-alkyl, C5-7-cycloalkyl, phenylcarbonyl, phenylsulphonyl or pyridinyl group and
• R6 denotes a C1-3-alkyl, carboxy-C1-3-alkyl or carboxy-C1-3-alkylcarbonyl group,
• a C1-3-alkyl group which is substituted by a C2-4-alkanoyl or C5-7-cycloalkanoyl group and by a C1-3-alkyl group substituted by a chlorine, bromine or iodine atom,
• Rb denotes a hydrogen atom or a C1-3-alkyl group and
• Rc denotes a cyano group or an amidino group optionally substituted by one or two C1-3-alkyl groups, wherein
• the carboxy groups mentioned in the definition of the abovementioned groups may also be replaced by a group which may be converted in vivo into a carboxy group or by a group which is negatively charged under physiological conditions or
• the amino and imino groups mentioned in the definition of the abovementioned groups may also be substituted by a group which can be cleaved in vivo, wherein
• by a group which may be converted into a carboxy group in vivo is meant a hydroxymethyl group, a carboxy group esterified with an alcohol wherein the alcoholic moiety is a C1-6-alkanol, a phenyl-C1-3-alkanol, a C3-9-cycloalkanol, while a C5-8-cycloalkanol may additionally be substituted by one or two C1-3-alkyl groups, a C5-8-cycloalkanol wherein a methylene group in the 3 or 4 position is replaced by an oxygen atom or by an imino group optionally substituted by a C1-3-alkyl, phenyl-C1-3-alkyl, phenyl-C1-3-alkoxycarbonyl or C2-6-alkanoyl group and the cycloalkanol moiety may additionally be substituted by one or two C1-3-alkyl groups, a C4-7-cycloalkenol, a C3-5-alkenol, a phenyl-C3-5-alkenol, a C3-5-alkynol or phenyl-C3-5-alkynol,
• with the proviso that no bond to the oxygen atom starts from a carbon atom which carries a double or triple bond, a C3-8-cycloalkyl-C1-3-alkanol, a bicycloalkanol with a total of 8 to 10 carbon atoms which may additionally be substituted in the bicycloalkyl moiety by one or two C1-3-alkyl groups, a 1,3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of formula
• Rd—CO—O—(ReCRf)—OH,
• wherein
• Rd denotes a C1-alkyl, C5-7-cycloalkyl, phenyl or phenyl-C1-3-alkyl group
• Re denotes a hydrogen atom, a C1-3-alkyl, C5-7-cycloalkyl or phenyl group and
• Rf denotes a hydrogen atom or a C1-3-alkyl group,
• by a group which is negatively charged under physiological conditions is meant a tetrazol-5-yl, phenylcarbonylaminocarbonyl, trifluoromethylcarbonylaminocarbonyl, C1-6-alkylsulphonylamino, phenylsulphonylamino, benzylsulphonylamino, trifluoromethylsulphonylamino, C1-6-alkylsulphonylaminocarbonyl, phenylsulphonylaminocarbonyl, benzylsulphonylaminocarbonyl or perfluoro-C1-6-alkylsulphonylaminocarbonyl group
• and by a group which can be cleaved from an imino or amino group in vivo is meant a hydroxy group, a benzoyl group optionally mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C1-3-alkyl or C1-3-alkoxy groups, while the substituents may be identical or different, a pyridinoyl group or a C1-16-alkanoyl group, a 3,3,3-trichloropropionyl or allyloxycarbonyl group, a C1-16-alkoxycarbonyl or C1-16-alkylcarbonyloxy group, wherein hydrogen atoms may be wholly or partly replaced by fluorine or chlorine atoms, a phenyl-C1-6-alkoxycarbonyl group, a 3-amino-propionyl group wherein the amino group may be mono- or disubstituted by C1-6-alkyl or C3-7-cycloalkyl groups and the substituents may be identical or different, a C1-3-alkylsulphonyl-C2-4-alkoxycarbonyl, C1-3-alkoxy-C2-4-alkoxy-C2-4-alkoxycarbonyl, Rd—CO—O—(RdCRf)—O—CO, C1-6-alkyl-CO—NH—(RgCRh)—O—CO or C1-6-alkyl-CO—O—(RgCRh)—(RgCRh)—O—CO group, wherein Rd to Rf are as hereinbefore defined and
• Rg and Rh, which may be identical or different, denote hydrogen atoms or C1-3-alkyl groups,
• the tautomers, stereoisomers, mixtures thereof and the salts thereof, and
• (b) at least one active substance selected from the group consisting of inhibitors of platelet function such as in particular acetylsalicylic acid, fibrinogen receptor antagonists, inhibitors of ADP-induced aggregation, P2T receptor antagonists and combined thromboxane receptor antagonists/synthetase inhibitors, thrombolytically active substances, such as in particular alteplase, reteplase, tenecteplase, urokinase, staphylokinase and streptokinase, physiological activators and inhibitors of the clotting system and their recombinant analogues such as in particular Protein C, recombinant human activated Protein C, TFPI and antithrombin, substances with an antagonistic effect on endotoxins, interleukins, TNF, bradykinin, prostaglandins, cyclooxygenases, NO, platelet activating factor acetylhydrolases, inflammation inhibitors, immunosuppressant substances, antibiotics and catecholamines