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Use of tyrosine kinase inhibitors for the treatment of inflammatory processes

  • US 20030149062A1
  • Filed: 01/29/2003
  • Published: 08/07/2003
  • Est. Priority Date: 02/05/2002
  • Status: Abandoned Application
First Claim
Patent Images

1. 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 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.

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