Xanthine derivatives, their preparation and their use in pharmaceutical compositions

A compound of formula (I)

• 5
• wherein:
• R1 is a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by R10 and R11, wherein:
• R10 is a formylamino, a C3-7-cycloalkyl-carbonylamino, C3-7-cycloalkyl-C1-3-alkyl-carbonylamino, C6-9-bicycloalkyl-carbonylamino, C6-9-bicycloalkyl-C1-3-alkyl-carbonylamino, C4-7-cycloalkenyl-carbonylamino, C4-7-cycloalkenyl-C1-3-alkyl-carbonylamino, C3-7-cycloalkyl-sulfonylamino, C3-7-cycloalkyl-C1-3-alkyl-sulfonylamino, arylsulfonylamino, aryl-C1-3-alkyl-sulfonylamino, or a heteroarylcarbonylamino group,
• a C5-7-cycloalkyl-carbonylamino group wherein a methylene group is replaced by an oxygen or sulfur atom or by an imino, sulfinyl, or sulfonyl group,
• a C5-7-cycloalkyl-carbonylamino group wherein a —CH2—CH2 group is replaced by a —NH—CO or —NH—NH group,
• a C5-7-cycloalkyl-carbonylamino group wherein a —CH2—CH2—CH2 group is replaced by a —NH—CO—NH, —NH—CO—O, or —O—CH2—O group,
• a C6-7-cycloalkyl-carbonylamino group wherein a —CH2—CH2—CH2—CH2 group is replaced by a —NH—CH2—CH2—NH, —NH—CO—CH2—NH, —NH—CH2—CH2—O, —NH—CO—CH2—O, or —O—CH2—CH2—O group,
• a cycloheptyl-carbonylamino group wherein a —CH2—CH2—CH2—CH2—CH2 group is replaced by a —NH—CH2—CH2—CH2—NH, —NH—CO—CH2—CH2—NH, —NH—CH2—CH2—CH2—O, —NH—CO—CH2—CH2—O, or —O—CH2—CH2—CH2—O group, or
• a C5-7-cycloalkyl-carbonylamino group wherein one or two methylene groups are replaced by carbonyl groups,
• wherein the imino groups in the abovementioned groups are optionally independently substituted by a C1-3-alkyl group;
• and
• R11 is a hydrogen, fluorine, chlorine, bromine, or iodine atom or a C1-3-alkyl, C1-3-alkyloxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, or cyano group;
• R2 is a hydrogen atom, or a C1-6-alkyl, C2-4-alkenyl, C3-4-alkynyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C1-3-alkyl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranylmethyl, tetrahydropyranylmethyl, aryl, aryl-C1-4-alkyl, aryl-C2-3-alkenyl, arylcarbonyl-C1-2-alkyl, heteroaryl-C1-3-alkyl, furanylcarbonylmethyl, thienylcarbonylmethyl, thiazolylcarbonylmethyl, pyridylcarbonylmethyl, C1-4-alkyl-carbonyl-C1-2-alkyl, or C3-6-cycloalkyl-carbonyl-C1-2-alkyl group,
• an aryl-D-C1-3-alkyl group, wherein D is an oxygen or sulfur atom, or an imino, C1-3-alkylimino, sulfinyl, or sulfonyl group,
• a C1-4-alkyl group substituted by a group Ra, wherein Ra is a cyano, carboxy, C1-3-alkyloxy-carbonyl, aminocarbonyl, C1-3-alkylamino-carbonyl, di-(C1-3-alkyl)-amino-carbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, or 4-ethylpiperazin-1-ylcarbonyl group, or
• a C2-4-alkyl group substituted by a group Rb, wherein Rb is a hydroxy, C1-3-alkyloxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, or 4-ethylpiperazin-1-yl group and is isolated from the cyclic nitrogen atom in the 3 position of the xanthine skeleton by at least two carbon atoms;
• R3 is a C3-8-alkyl, C3-8-alkenyl, C3-8-alkynyl, aryl, or aryl-C2-4-alkenyl group,
• a C1-3-alkyl group substituted by a group Rc, wherein:
• Rc is a C3-7-cycloalkyl group optionally substituted by one or two C1-3-alkyl groups, a C5-7-cycloalkenyl group optionally substituted by one or two C1-3-alkyl groups, or an aryl group, or
• a furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidyl, or pyrazinyl group, optionally substituted by one or two C1-3-alkyl groups or by a fluorine, chlorine, bromine, or iodine atom or by a trifluoromethyl, cyano, or C1-3-alkyloxy group, or
• a C3-6-alkenyl group substituted by a fluorine, chlorine, or bromine atom, or a trifluoromethyl group;
• R4 is an azetidin-1-yl or pyrrolidin-1-yl group substituted in the 3 position by an amino, C1-3-alkylamino, or a di-(C1-3-alkyl)amino group optionally additionally substituted by one or two C1-3-alkyl groups,
• a piperidin-1-yl or hexahydroazepin-1-yl group is substituted in the 3 position or 4 position by an amino, C1-3-alkylamino, or a di-(C1-3-alkyl)amino group and optionally additionally substituted by one or two C1-3-alkyl groups,
• a 3-aminopiperidin-1-yl group wherein the piperidin-1-yl moiety is optionally additionally substituted by an aminocarbonyl, C1-2-alkyl-aminocarbonyl, di-(C1-2-alkyl)aminocarbonyl, pyrrolidin-1-ylcarbonyl, (2-cyanopyrrolidin-1-yl)carbonyl, thiazolidin-3-ylcarbonyl, (4-cyanothiazolidin-3-yl)carbonyl, piperidin-1-ylcarbonyl, or morpholin-4-ylcarbonyl group,
• a 3-aminopiperidin-1-yl group wherein the piperidin-1-yl moiety is additionally substituted in the 4 position or 5 position by a hydroxy or methoxy group,
• a 3-aminopiperidin-1-yl group wherein the methylene group in the 2 position or 6 position is replaced by a carbonyl group,
• a piperidin-1-yl or hexahydroazepin-1-yl group substituted in the 3 position by an amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group, wherein in each case two hydrogen atoms on the carbon skeleton of the piperidin-1-yl or hexahydroazepin-1-yl group are replaced by a straight-chain alkylene bridge, this bridge containing 2 to 5 carbon atoms if the two hydrogen atoms are on the same carbon atom, or 1 to 4 carbon atoms if the hydrogen atoms are on adjacent carbon atoms, or 1 to 4 carbon atoms if the hydrogen atoms are on carbon atoms which are separated by one atom, or 1 to 3 carbon atoms if the hydrogen atoms are on carbon atoms which are separated by two atoms,
• an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, or hexahydroazepin-1-yl group substituted by an amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl, or a di-(C1-3-alkyl)amino-C1-3-alkyl group,
• a piperazin-1-yl or [1,4]diazepan-1-yl group optionally substituted on the carbon skeleton by one or two C1-3-alkyl groups,
• a 3-iminopiperazin-1-yl, 3-imino-[1,4]diazepan-1-yl, or 5-imino-[1,4]diazepan-1-yl group optionally substituted on the carbon skeleton by one or two C1-3-alkyl groups,
• a [1,4]diazepan-1-yl group optionally substituted by one or two C1-3-alkyl groups substituted in the 6 position by an amino group,
• a C3-7-cycloalkyl group substituted by an amino, C1-3-alkylamino, or di-(C1-3-alkyl)-amino group,
• a C3-7-cycloalkyl group substituted by an amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl, or a di-(C1-3-alkyl)amino-C1-3-alkyl group,
• a C3-7-cycloalkyl-C1-2-alkyl group wherein the cycloalkyl moiety is substituted by an amino, C1-3-alkylamino, or di-(C1-3-alkyl)-amino group,
• a C3-7-cycloalkyl-C1-2-alkyl group wherein the cycloalkyl moiety is substituted by an amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl, or a di-(C1-3-alkyl)amino-C1-3-alkyl group,
• a C3-7-cycloalkylamino group wherein the cycloalkyl moiety is substituted by an amino, C1-3-alkylamino, or di-(C1-3-alkyl)-amino group, and the two nitrogen atoms on the cycloalkyl moiety are separated from one another by at least two carbon atoms,
• an N—(C3-7-cycloalkyl)-N—(C1-3-alkyl)-amino group wherein the cycloalkyl moiety is substituted by an amino, C1-3-alkylamino, or di-(C1-3-alkyl)-amino group, and the two nitrogen atoms on the cycloalkyl moiety are separated from one another by at least two carbon atoms,
• a C3-7-cycloalkylamino group wherein the cycloalkyl moiety is substituted by an amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl, or a di-(C1-3-alkyl)amino-C1-3-alkyl group,
• an N—(C3-7-cycloalkyl)-N—(C1-3-alkyl)-amino group wherein the cycloalkyl moiety is substituted by an amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl, or a di-(C1-3-alkyl)amino-C1-3-alkyl group,
• a C3-7-cycloalkyl-C1-2-alkyl-amino group wherein the cycloalkyl moiety is substituted by an amino, C1-3-alkylamino, or di-(C1-3-alkyl)-amino group,
• an N—(C3-7-cycloalkyl-C1-2-alkyl)-N—(C1-2-alkyl)-amino group wherein the cycloalkyl moiety is substituted by an amino, C1-3-alkylamino, or di-(C1-3-alkyl)-amino group,
• a C3-7-cycloalkyl-C1-2-alkyl-amino group wherein the cycloalkyl moiety is substituted by an amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl, or a di-(C1-3-alkyl)amino-C1-3-alkyl group,
• an N—(C3-7-cycloalkyl-C1-2-alkyl)-N—(C1-2-alkyl)-amino group wherein the cycloalkyl moiety is substituted by an amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl, or a di-(C1-3-alkyl)amino-C1-3-alkyl group,
• an R19—C2-4-alkylamino group wherein R19 is separated from the nitrogen atom of the C2-4-alkylamino moiety by at least two carbon atoms,
• an R19—C2-4-alkylamino group wherein the nitrogen atom of the C2-4-alkylamino moiety is substituted by a C1-3-alkyl group and R19 is separated from the nitrogen atom of the C2-4-alkylamino moiety by at least two carbon atoms,
• an amino group substituted by R20,
• an amino group substituted by R20 and a C1-3-alkyl group, wherein R20 is optionally independently substituted by one or two C1-3-alkyl groups,
• an R19—C3-4-alkyl group wherein the C3-4-alkyl moiety is straight-chained and is optionally additionally substituted by one or two C1-3-alkyl groups,
• a 3-amino-2-oxopiperidin-5-yl or 3-amino-2-oxo-1-methylpiperidin-5-yl group,
• a pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, hexahydroazepin-3-yl, or hexahydroazepin-4-yl group substituted in the 1 position by an amino, C1-3-alkylamino, or di-(C1-3-alkyl)amino group, or
• an azetidin-2-yl-C1-2-alkyl, azetidin-3-yl-C1-2-alkyl, pyrrolidin-2-yl-C1-2-alkyl, pyrrolidin-3-yl, pyrrolidin-3-yl-C1-2-alkyl, piperidin-2-yl-C1-2-alkyl, piperidin-3-yl, piperidin-3-yl-C1-2-alkyl, piperidin-4-yl, or piperidin-4-yl-C1-2-alkyl group, optionally independently substituted by one or two C1-3-alkyl groups;
• R19 is an amino, C1-3-alkylamino, or di-(C1-3-alkyl)-amino group;
• and
• R20 is an azetidin-3-yl, azetidin-2-ylmethyl, azetidin-3-ylmethyl, pyrrolidin-3-yl, pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, piperidin-3-yl, piperidin-4-yl, piperidin-2-ylmethyl, piperidin-3-ylmethyl, or piperidin-4-ylmethyl group, each optionally substituted by one or two C1-3-alkyl groups,
• wherein:
• each alkyl, alkenyl, and alkynyl group is independently straight-chained or branched, unless otherwise stated,
• each aryl group is independently a phenyl or naphthyl group optionally mono- or disubstituted by Rh, where the substituents are identical or different, and
• each heteroaryl group is independently a pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl, or isoquinolinyl group,
• or a pyrrolyl, furanyl, thienyl, or pyridyl group wherein one or two methyne groups are replaced by nitrogen atoms,
• an indolyl, benzofuranyl, benzothiophenyl, quinolinyl, or isoquinolinyl group wherein one to three methyne groups are replaced by nitrogen atoms, or
• a 1,2-dihydro-2-oxopyridinyl, 1,4-dihydro-4-oxopyridinyl, 2,3-dihydro-3-oxopyridazinyl, 1,2,3,6-tetrahydro-3,6-dioxopyridazinyl, 1,2-dihydro-2-oxopyrimidinyl, 3,4-dihydro-4-oxopyrimidinyl, 1,2,3,4-tetrahydro-2,4-dioxopyrimidinyl, 1,2-dihydro-2-oxopyrazinyl, 1,2,3,4-tetrahydro-2,3-dioxopyrazinyl, 2,3-dihydro-2-oxoindolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxo-1H-benzimidazolyl, 2,3-dihydro-2-oxobenzoxazolyl, 1,2-dihydro-2-oxoquinolinyl, 1,4-dihydro-4-oxoquino-linyl, 1,2-dihydro-1-oxoisoquinolinyl, 1,4-dihydro-4-oxocinnolinyl, 1,2-dihydro-2-oxoquinazolinyl, 3,4-dihydro-4-oxoquinazolinyl, 1,2,3,4-tetrahydro-2,4-dioxoquinazolinyl, 1,2-dihydro-2-oxoquinoxalinyl, 1,2,3,4-tetrahydro-2,3-dioxoquinoxalinyl, 1,2-dihydro-1-oxophthalazinyl, 1,2,3,4-tetrahydro-1,4-dioxophthalazinyl, chromanyl, cumarinyl, 2,3-dihydrobenzo[1,4]dioxinyl, or 3,4-dihydro-3-oxo-2H-benzo[1,4]oxazinyl group,
• wherein each heteroaryl group is independently mono- or disubstituted by Rh, where the substituents are identical or different, and
• Rh is a fluorine, chlorine, bromine, or iodine atom, a trifluoromethyl, cyano, nitro, amino, aminocarbonyl, aminosulfonyl, methylsulfonyl, acetylamino, methylsulfonylamino, C1-3-alkyl, cyclopropyl, ethenyl, ethynyl, hydroxy, C1-3-alkyloxy, difluoromethoxy, or trifluoromethoxy group,
• or a prodrug or salt thereof.