Use of tyrosine kinase inhibitors for the treatment of inflammatory processes

A method for treating a disease of the airways or lungs or the intestines associated with inflammation, which method comprises administering to a host in need of such treatment a therapeutically effective amount of a substance selected from the group consisting of:

• (a) quinazolines of the formula
• 3
• wherein
• X denotes a nitrogen atom or a carbon atom substituted by a cyano group,
• Ra denotes a hydrogen atom or a C1-4-alkyl group,
• Rb denotes a phenyl, benzyl or 1-phenylethyl group, wherein the phenyl nucleus may be substituted in each case by the groups R1 and R2, while
• R1 and R2, which may be identical or different, in each case denote a hydrogen, fluorine, chlorine, bromine or iodine atom,
• a C1-4-alkyl, hydroxy, C1-4-alkoxy, C3-6-cycloalkyl, C4-6-cycloalkoxy, C2-5-alkeny or C2-5-alkynyl group,
• an aryl, aryloxy, arylmethyl or arylmethoxy group,
• a C3-5-alkenyloxy or C3-5-alkynyloxy group, while the multiple bond is isolated from the oxygen atom,
• a C1-4-alkylsulphenyl, C1-4-alkylsulphinyl, C1-4-alkylsulphonyl, C1-4-alkylsulphonyloxy, trifluoromethylsulphenyl, trifluoromethylsulphinyl or trifluoromethylsulphonyl group,
• a methyl or methoxy group substituted by 1 to 3 fluorine atoms,
• an ethyl or ethoxy group substituted by 1 to 5 fluorine atoms,
• a cyano or nitro group or an amino group optionally substituted by one or two C1-4-alkyl groups, while the substituents may be identical or different,
• A denotes an oxygen atom or an imino group optionally substituted by a C1-4-alkyl group,
• B denotes a bond, a carbonyl or sulphonyl group,
• C denotes a methylene, ethylene or ethenylene group,
• n denotes one of the numbers 0 or 1,
• D denotes an amino, C1-4-alkylamino, C3-5-cycloalkylamino or di-(C1-4-alkyl)-amino or di-(C3-5-cycloalkyl)-amino group wherein the alkyl and cycloalkyl moieties may be identical or different,
• a C2-4-alkylamino group wherein the alkyl moiety is substituted in the β, γ or δ position to the nitrogen atom of the amino group by the group R3, while
• R3 denotes a hydroxy, C1-4-alkoxy, C1-3-alkoxycarbonyl, amino, C1-4-alkylamino or di-(C1-4-alkyl)-amino group,
• a 4- to 7-membered alkyleneimino group optionally substituted by one or two methyl groups or
• a 6- to 7-membered alkyleneimino group optionally substituted by one or two methyl groups wherein in each case a methylene group in the 4 position is replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, imino or N—(C1-4-alkyl)-imino group,
• an N—(C1-4-alkyl)—N—(C2-4-alkyl)-amino group wherein the alkyl moieties in the β, γ or δ position to the nitrogen atom of the amino group may optionally be substituted by the group R3, where R3 is as hereinbefore defined,
• a di-(C2-4-alkyl)-amino group wherein the two C2-4-alkyl moieties in each case are substituted in the β, γ or δ position to the nitrogen atom of the amino group by the group R3, while the substituents may be identical or different and R3 is as hereinbefore defined,
• a C3-7-cycloalkylamino or C3-7-cycloalkyl-C1-3-alkylamino group, wherein in each case the nitrogen atom may be substituted by a further C1-4-alkyl group, an amino or C1-4-alkylamino group, wherein in each case the nitrogen atom is substituted by a tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranylmethyl, 1-(tetrahydrofuran-3-yl)-piperidin-4-yl, 1-(tetrahydropyran-3-yl)-piperidin-4-yl, 1-(tetrahydropyran-4-yl)-piperidin-4-yl, 3-pyrrolidinyl, 3-piperidinyl, 4-piperidinyl, 3-hexahydro-azepinyl or 4-hexahydro-azepinyl group optionally substituted by 1 to 3 C1-4-alkyl groups,
• a 4- to 7-membered alkyleneimino group optionally substituted by 1 to 4 C1-2-alkyl groups which may be substituted by the group R3 either at a cyclic carbon atom or at one of the alkyl groups, while R3 is as hereinbefore defined,
• a piperidino group substituted by a tetrahydrofuranyl, tetrahydropyranyl or tetrahydrofuranylmethyl group,
• a 6- to 7-membered alkyleneimino group optionally substituted by 1 or 2 C1-2-alkyl groups wherein in each case a methylene group in the 4 position is replaced by an oxygen or sulphur atom, by an imino group substituted by the group R4, by a sulphinyl or sulphonyl group, while
• R4 denotes a hydrogen atom, a C1-4-alkyl, 2-methoxy-ethyl, 3-methoxy-propyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-4-alkyl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranylmethyl, formyl, C1-4-alkylcarbonyl, C1-4-alkylsulphonyl, aminocarbonyl, C1-4-alkylaminocarbonyl or di-(C1-4-alkyl)-aminocarbonyl group,
• a morpholino or 2-oxo-morpholin-4-yl group which may be substituted by a methyl, ethyl or C1-3-alkoxymethyl group,
• an imidazolyl group optionally substituted by 1 to 3 methyl groups,
• a C5-7-cycloalkyl group wherein a methylene group is replaced by an oxygen or sulphur atom, by an imino group substituted by the group R4, by a sulphinyl or sulphonyl group, while R4 is as hereinbefore defined,
• a hydroxy or C1-4-alkoxy group, or also
• a hydrogen atom, if n is the number 0, and
• Rc denotes a hydrogen atom, a C1-4-alkoxy-C1-4-alkoxy, C1-4-alkoxy, C4-7-cycloalkoxy or C3-7-cycloalkyl-C1-6-alkoxy group, wherein the cycloalkyl moiety may be substituted in each case by a C1-3-alkyl, hydroxy, C1-4-alkoxy, amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, pyrrolidino, piperidino, morpholino, piperazino, N—(C1-2-alkyl)-piperazino,
• hydroxy-C1-2-alkyl, C1-4-alkoxy-C1-2-alkyl, amino-C1-2-alkyl, C1-4-alkylamino-C1-2-alkyl, di-(C1-4-alkyl)-amino-C1-2-alkyl, pyrrolidino-C1-2-alkyl, piperidino-C1-2-alkyl, morpholino-C1-2-alkyl, piperazino-C1-2-alkyl or N—(C1-2-alkyl)-piperazino-C1-2-alkyl group, while the abovementioned monosubstituted cycloalkyl moieties may additionally be substituted by a C1-3-alkyl group, or
• a 3-pyrrolidinyloxy, 2-pyrrolidinyl-C1-4-alkyloxy, 3-pyrrolidinyl-C1-4-alkyloxy, 3-piperidinyloxy, 4-piperidinyloxy, 2-piperidinyl-C1-4-alkyloxy, 3-piperidinyl-C1-4-alkyloxy, 4-piperidinyl-C1-4-alkyloxy, 3-hexahydro-azepinyloxy, 4-hexahydro-azepinyloxy, 2-hexahydro-azepinyl-C1-4-alkyloxy, 3-hexahydro-azepinyl-C1-4-alkyloxy or 4-hexahydro-azepinyl-C1-4-alkyloxy group, wherein in each case the cyclic nitrogen atom is substituted by the group R4, where R4 is as hereinbefore defined,
• a piperazino or homopiperazino group substituted in the 4 position by an R6-C1-4-alkyl, R6—CO, R6-C1-4-alkylene-CO, (R5NR7)-C1-4-alkylene-CO, R7O—C1-4-alkylene-CO, R7S—C1-4-alkylene-CO, R7SO—C1-4-alkylene-CO or R7SO2-C1-4-alkylene-CO group, wherein
• R5 denotes a hydrogen atom or a C1-4-alkyl group,
• R6 denotes a 2-oxo-tetrahydrofuranyl, 2-oxo-tetrahydropyranyl, 2-oxo-1,4-dioxanyl or 2-oxo-4-(C1-4-alkyl)-morpholinyl group optionally substituted by one or two C1-2-alkyl groups and
• R7 denotes a 2-oxo-tetrahydrofuran-3-yl, 2-oxo-tetrahydrofuran-4-yl, 2-oxo-tetrahydropyran-3-yl, 2-oxo-tetrahydropyran-4-yl or 2-oxo-tetrahydropyran-5-yl group optionally substituted by one or two C1-2-alkyl groups,
• a morpholino-C1-4-alkoxy or 2-oxo-morpholin-4-yl-C1-6-alkoxy group which may be substituted by 1 or 2 methyl or ethyl groups, or
• a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, while
• by the aryl moieties mentioned in the definition of the abovementioned groups is meant a phenyl group, which may in each case be monosubstituted by R8, mono-, di- or trisubstituted by R9 or monosubstituted by R8 and additionally mono- or disubstituted by R9, while the substituents may be identical or different, wherein
• R8 denotes a cyano, carboxy, C1-4-alkoxycarbonyl, aminocarbonyl, C1-4-alkyl-aminocarbonyl, di-(C1-4-alkyl)-aminocarbonyl, C1-4-alkylsulphenyl, C1-4-alkylsulphinyl, C1-4-alkylsulphonyl, hydroxy, C1-4-alkylsulphonyloxy, trifluoromethyloxy, nitro, amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, C1-4-alkylcarbonylamino, N—(C1-4-alkyl)—C1-4-alkylcarbonylamino, C1-4-alkylsulphonylamino, N-(C1-4-alkyl)-C1-4-alkylsulphonylamino, aminosulphonyl, C1-4-alkylaminosulphonyl or di-(C1-4-alkyl)-aminosulphonyl group or a carbonyl group which is substituted by a 5- to 7-membered alkyleneimino group, while in the abovementioned 6- to 7-membered alkyleneimino groups in each case a methylene group in the 4 position may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, imino or N—(C1-4-alkyl)-imino group, and
• R9 denotes a fluorine, chlorine, bromine or iodine atom, a C1-4-alkyl, trifluoromethyl or C1-4-alkoxy group,
• (b) the compounds
• (1) 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-dimethylamino-cyclohexyl)amino]-pyrimido[5,4-d]pyrimidine,
• (2) 4-[(R)-(1-phenylethyl)amino]-6-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine, and
• (3) 4-{[3-chloro-4-(3-fluoro-4-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline,
• as well as tautomers and pharmaceutically acceptable salts of one of the foregoing substances,
• (c) the antibodies
• (1) Cetuximab C225,
• (2) Trastuzumab, ABX-EGF, and
• (3) Mab ICR-62, and
• (d) EGFR-antisense.