Aminoquinazolines and their use as medicaments
First Claim
Patent Images
1. A compound of the formula:
-
wherein X denotes a nitrogen atom, Ra denotes a hydrogen atom or a methyl group, Rb denotes a phenyl, benzyl or 1-phenylethyl group, wherein the phenyl nucleus in each case is substituted by the groups R1 to R3, where R1 and R2, which may be identical or different, each denote a hydrogen, fluorine, chlorine, bromine or iodine atom, a methyl, ethyl, hydroxy, methoxy, ethoxy, amino, cyano, vinyl or ethynyl group, an aryl, aryloxy, arylmethyl or arylmethoxy group, a methyl or methoxy group substituted by 1 to 3 fluorine atoms or R1 together with R2, if they are bound to adjacent carbon atoms, denotes a —
CH═
CH—
CH═
CH, —
CH═
CH—
NH or —
CH═
N—
NH group and R3 denotes a hydrogen, fluorine, chlorine or bromine atom, one of the groups Rc or Rd denotes an —
A—
B group and the other group Rc or Rd denotes a —
C—
D group, where A denotes a C1-6-alkylene group, a —
O—
C1-6-alkylene group, where the alkylene moiety is linked to the group B, or an oxygen atom, with the proviso that if A is an oxygen atom it may not be linked to the group B via a nitrogen atom of the group B, and B denotes a pyrrolidino group wherein the two hydrogen atoms in the 2 position are replaced by a group E, wherein E represents a —
CH2—
O—
CO—
CH2, —
CH2CH2—
O—
CO, —
CH2—
O—
CO—
CH2CH2, —
CH2CH2—
O—
CO—
CH2 or —
CH2CH2CH2—
O—
CO—
bridge optionally substituted by one or two C1-2-alkyl groups, a pyrrolidino group wherein the two hydrogen atoms in the 3 position are replaced by a group F wherein F denotes an —
O—
CO—
CH2CH2, —
CH2—
O—
CO—
CH2, —
CH2CH2—
O—
CO, —
O—
CO—
CH2CH2CH2, —
CH2—
O—
CO—
CH2CH2, —
CH2CH2—
O—
CO—
CH2, —
CH2CH2CH2—
O—
CO, —
O—
CO—
CH2—
NR4—
CH2, —
CH2—
O—
CO—
CH2—
NR4, —
O—
CO—
CH2—
O—
CH2 or —
CH2—
O—
CO—
CH2—
O—
bridge optionally substituted by one or two C1-2-alkyl groups, where R4 denotes a hydrogen atom or a C1-4-alkyl group, a piperidino or hexahydroazepino group, wherein the two hydrogen atoms in the 2 position are replaced by a group E, where E is as hereinbefore defined, a piperidino or hexahydroazepino group, wherein in each case the two hydrogen atoms in the 3 position or in the 4 position are replaced by a group F, where F is as hereinbefore defined, a piperazino or 4-(C1-4-alkyl)-piperazino group, wherein the two hydrogen atoms in the 2 position or in the 3 position of the piperazino ring are replaced by a group E, where E is as hereinbefore defined, a pyrrolidino or piperidino group, wherein two neighbouring hydrogen atoms are replaced by a —
O—
CO—
CH2, —
CH2—
O—
CO, —
O—
CO—
CH2CH2, —
CH2—
O—
CO—
CH2, —
CH2CH2—
O—
CO, —
O—
CO—
CH2—
NR4 or —
O—
CO—
CH2—
O—
bridge optionally substituted by one or two C1-2-alkyl groups, where R4 is as hereinbefore defined and the heteroatoms of the abovementioned bridges are not bound to the 2 or 5 position of the pyrrolidino ring and are not bound to the 2 or 6 position of the piperidino ring, a piperazino or 4-(C1-4-alkyl)-piperazino group, wherein a hydrogen atom in the 2 position together with a hydrogen atom in the 3 position of the piperazino ring are replaced by a —
CH2—
O—
CO—
CH2 or —
CH2CH2—
O—
CO—
bridge optionally substituted by one or two C1-2-alkyl groups, a piperazino group wherein a hydrogen atom in the 3 position together with the hydrogen atom in the 4 position are replaced by a —
CO—
O—
CH2CH2 or —
CH2—
O—
CO—
CH2—
bridge optionally substituted by one or two C1-2-alkyl groups, where in each case the left-hand end of the abovementioned bridges is bound to the 3 position of the piperazino ring, a pyrrolidino, piperidino or hexahydroazepino group substituted by the group R5 wherein R5 represents 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, a pyrrolidino group substituted in the 3 position by a 2-oxo-morpholino group, while the 2-oxo-morpholino group may be substituted by one or two C1-2-alkyl groups, a piperidino or hexahydroazepino group substituted in the 3 or 4 position by a 2-oxo-morpholino group, while the 2-oxo-morpholino group may be substituted by one or two C1-2-alkyl groups, a 4-(C1-4-alkyl)-piperazino or 4-(C1-4-alkyl)-homopiperazino group substituted at a cyclic carbon atom by R5, wherein R5 is as hereinbefore defined, a piperazino or homopiperazino group substituted in the 4 position by the group R6, wherein R6 represents 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 pyrrolidino group substituted in the 3 position by an (R4NR6), R6O, R6S, R6SO or R6SO2 group, where R4 and R6 are as hereinbefore defined, a piperidino or hexahydroazepino group substituted in the 3 or 4 position by an (R4NR6), R6O, R6S, R6SO or R6SO2 group, wherein R4 and R6 are as hereinbefore defined, a pyrrolidino, piperidino or hexahydroazepino group substituted by an R5—
C1-4-alkyl, (R4NR6)—
C1-4-alkyl, R6O—
C1-4-alkyl, R6S—
C1-4-alkyl, R6SO—
C1-4-alkyl, R6SO2—
C1-4-alkyl or R4NR6—
CO group, wherein R4 to R6 are as hereinbefore defined, a pyrrolidino group substituted in the 3 position by an R5—
CO—
NR4, R5—
C1-4-alkylene-CONR4, (R4NR6)—
C1-4-alkylene-CONR4, R6O—
C1-4-alkylene-CONR4, R6S—
C1-4-alkylene-CONR4, R6SO—
C1-4-alkylene-CONR4, R6SO2—
C1-4-alkylene-CONR4, 2-oxo-morpholino-C1-4-alkylene-CONR4, R5—
C1-4-alkylene-Y or C2-4-alkyl-Y group, where the C2-4-alkyl moiety of the C2-4-alkyl-Y group in each case is substituted from position 2 by an (R4NR6), R6O, R6S, R6SO or R6SO2 group and the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups, wherein R4 to R6 are as hereinbefore defined and Y represents an oxygen or sulphur atom, an imino, N—
(C1-4-alkyl)-imino, sulphinyl or sulphonyl group, a piperidino or hexahydroazepino group substituted in the 3 or 4 position by an R5—
CO—
NR4, R5—
C1-4-alkylene-CONR4, (R4NR6)—
C1-4-alkylene-CONR4, R6O—
C1-4-alkylene-CONR4, R6S—
C1-4-alkylene-CONR4, R6SO—
C1-4-alkylene-CONR4, R6SO2—
C1-4-alkylene-CONR4, 2-oxo-morpholino-C1-4-alkylene-CONR4, R5—
C1-4-alkylene-Y or C2-4-alkyl-Y group, wherein Y is as hereinbefore defined, the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups and the C2-4-alkyl moiety of the C2-4-alkyl-Y group is substituted in each case from position 2 by an (R4NR6), R6O, R6S, R6SO or R6SO2 group, where R4 to R6 are as hereinbefore defined, a 4-(C1-4-alkyl)-piperazino or 4-(C1-4-alkyl)-homopiperazino group substituted at a cyclic carbon atom by an R5—
C1-4-alkyl, (R4NR6)—
C1-4-alkyl, R6O—
C1-4-alkyl, R6S—
C1-4-alkyl, R6SO—
C1-4-alkyl, R6SO2—
C1-4-alkyl or R4NR6—
CO group, wherein R4 to R6 are as hereinbefore defined, a piperazino or homopiperazino group substituted in the 4 position by an R5—
C1-4-alkyl, R5—
CO, R5—
C1-4-alkylene-CO, (R4NR6)—
C1-4-alkylene-CO, R6O—
C1-4-alkylene-CO, R6S—
C1-4-alkylene-CO, R6SO—
C1-4-alkylene-CO or R6SO2—
C1-4-alkylene-CO group, wherein R4 to R6 are as hereinbefore defined, a piperazino or homopiperazino group substituted in the 4 position by a C2-4-alkyl group, wherein the C2-4-alkyl group is substituted in each case from position 2 by an (R4NR6), R6O, R6S, R6SO or R6SO2 group, where R4 and R6 are as hereinbefore defined, a pyrrolidino. piperidino or hexahydroazepino group substituted by a 2-oxo-morpholino-C1-4-alkyl group, wherein the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups, a pyrrolidino group substituted in the 3 position by a C2-4-alkyl-Y group, wherein Y is as hereinbefore defined and the C2-4-alkyl moiety of the C2-4-alkyl-Y group is substituted in each case from position 2 by a 2-oxo-morpholino group optionally substituted by one or two C1-2-alkyl groups, a piperidino or hexahydroazepino group substituted in the 3 or 4 position by a C2-4-alkyl-Y group, wherein Y is as hereinbefore defined and the C2-4-alkyl moiety of the C2-4-alkyl-Y group is substituted in each case from position 2 by a 2-oxo-morpholino group optionally substituted by one or two C1-2-alkyl groups, a 4-(C1-4-alkyl)-piperazino or 4-(C1-4-alkyl)-homopiperazino group substituted at a cyclic carbon atom by a 2-oxo-morpholino-C1-4-alkyl group, wherein the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups, a piperazino or homopiperazino group substituted in the 4 position by a 2-oxo-morpholino-C1-4-alkylene-CO group, wherein the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups, a piperazino or homopiperazino group substituted in the 4 position by a C2-4-alkyl group, wherein the C2-4-alkyl moiety is substituted in each case from position 2 by a 2-oxo-morpholino group optionally substituted by one or two C1-2-alkyl groups, a pyrrolidinyl or piperidinyl group substituted in the 1 position by the group R6, by an R5—
C1-4-alkyl, R5—
CO, R5—
C1-4-alkylene-CO, (R4NR6)—
C1-4-alkylene-CO, R6O—
C1-4-alkylene R6S—
C1-4-alkylene-CO, R6SO—
C1-4-alkylene-CO, R6SO2—
C1-4-alkylene-CO or 2-oxo-morpholino-C1-4-alkylene-CO group, wherein R4 to R6 are as hereinbefore defined and the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups, a pyrrolidinyl or piperidinyl group substituted in the 1 position by a C2-4-alkyl group, wherein the C2-4-alkyl moiety is substituted in each case from position 2 by an (R4NR6), R6O, R6S, R6SO, R6SO2 or 2-oxo-morpholino group, where R4 and R6 are as hereinbefore defined and the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups, a pyrrolidin-3-yl-NR4, piperidin-3-yl-NR4 or piperidin-4-yl-NR4 group substituted in each case at the cyclic nitrogen atom by the group R6, by an R5—
C1-4-alkyl, R5—
CO, R5—
C1-4-alkylene-CO, (R4NR6)—
C1-4-alkylene-CO, R6O—
C1-4-alkylene-CO, R6S—
C1-4-alkylene-CO, R6SO—
C1-4-alkylene-CO, R6SO2—
C1-4-alkylene-CO or 2-oxo-morpholino-C1-4-alkylene-CO group, wherein R4 to R6 are as hereinbefore defined and the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups, a pyrrolidin-3-yl-NR4, piperidin-3-yl-NR4 or piperidin-4-yl-NR4 group substituted in each case at the cyclic nitrogen atom by a C2-4-alkyl group, wherein the C2-4-alkyl moiety is substituted in each case from position 2 by an (R4NR6), R6O, R6S, R6SO, R6SO2 or 2-oxo-morpholino group, where R4 and R6 are as hereinbefore defined and the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups, a R5—
C1-4-alkylene-NR4 group wherein R4 and R5 are as hereinbefore defined, or a C2-4-alkyl-NR4 group wherein the C2-4-alkyl moiety is substituted in each case from position 2 by an (R4NR6), R6O, R6S, R6SO, R6SO2 or 2-oxo-morpholino group, where R4 and R6 are as hereinbefore defined and the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups, a 2-oxo-morpholin-4-yl group substituted by the group R7 or by the group R7 and a C1-4-alkyl group, where R7 represents a C3-4-alkyl, hydroxy-C1-4-alkyl, C1-4-alkoxy-C1-4-alkyl, di-(C1-4-alkyl)-amino-C1-4-alkyl, pyrrolidino-C1-4-alkyl, piperidino-C1-4-alkyl, morpholino-C1-4-alkyl, 4-(C1-4-alkyl)-piperazino-C1-4-alkyl, C1-4-alkylsulphanyl-C1-4-alkyl, C1-4-alkylsulphinyl-C1-4-alkyl, C1-4-alkyl-sulphonyl-C1-4-alkyl, cyano-C1-4-alkyl, C1-4-alkoxycarbonyl-C1-4-alkyl, aminocarbonyl-C1-4-alkyl, C1-4-alkyl-aminocarbonyl-C1-4-alkyl, di-(C1-4-alkyl)-aminocarbonyl-C1-4-alkyl, pyrrolidinocarbonyl-C1-4-alkyl, piperidinocarbonyl-C1-4-alkyl, morpholinocarbonyl-C1-4-alkyl or a 4-(C1-4-alkyl)-piperazinocarbonyl-C1-4-alkyl group, a 2-oxo-morpholin-4-yl group substituted by two groups R7, where R7 is as hereinbefore defined and the two groups R7 may be identical or different, a 2-oxo-morpholin-4-yl group wherein the two hydrogen atoms of a methylene group are replaced by a —
(CH2)m, —
CH2—
Y—
CH2, —
CH2—
Y—
CH2—
CH2, —
CH2CH2—
Y—
CH2CH2 or —
CH2CH2—
Y—
CH2CH2CH2—
bridge optionally substituted by one or two C1-2-alkyl groups, where Y is as hereinbefore defined and m represents the number 2, 3, 4, 5 or 6, a 2-oxo-morpholin-4-yl group wherein a hydrogen atom in the 5 position together with a hydrogen atom in the 6 position is replaced by a —
(CH2)n, —
CH2—
Y—
CH2, —
CH2—
Y—
CH2CH2 or —
CH2—
CH2—
Y—
CH2—
bridge, where Y is as hereinbefore defined and n denotes the number 2, 3 or 4, or, if C together with D represents a group Rc, it may also represent a 2-oxo-morpholin-4-yl group which may be substituted by 1 to 4 C1-2-alkyl groups, C denotes an —
O—
C1-6-alkylene group, where the alkylene moiety is linked to the group D, or an oxygen atom, while this may not be linked to a nitrogen atom of the group D, and D denotes an amino group substituted by 2 C1-4-alkyl groups wherein the alkyl groups may be identical or different and each alkyl moiety may be substituted from position 2 by a C1-4-alkoxy or di-(C1-4-alkyl)-amino group or by a 4- to 7-membered alkyleneimino group, while in the abovementioned 6- or 7-membered alkyleneimino groups a methylene group in each case may be replaced in the 4 position by an oxygen or sulphur atom of by a sulphinyl, sulphonyl or N—
(C1-4alkyl)-imino group, a 4- or 7-membered alkyleneimino group optionally substituted by 1 to 4 methyl group, a 6- to 7-membered alkyleneimino group optionally substituted by 1 to 2 methyl group where in each case a methylene group in the 4 position is replaced by an oxygen of sulphur atom, by a sulphinyl, sulphonyl, or N—
(C1-4-alkyl)-imino group, an imidazolyl group optionally substituted by 1 to 3 methyl group, a C5-7-cycloalkyl group wherein a methylene group is replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl or N—
(C1-4-alkyl)-imino group, or C together with D denotes a hydrogen atom, a C1-6-alkoxy group optionally substituted from position 2 by a hydroxy or C1-4-alkyl group, a C3-7-cycloalkoxy or C3-7-cycloalkyl-C1-4-alkoxy group, a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, or a group Rc, where Rc denotes a C2-6-alkoxy group which is substituted from position 2 by a C4-7-cycloalkoxy or C3-7-cycloalkyl-C1-3-alkoxy group, a C4-7-cycloalkoxy or C3-7-cycloalkyl-C1-6-alkoxy group, wherein the cycloalkyl moiety is substituted in each case by a C1-4-alkyl, C1-4-alkoxy, di-(C1-4-alkyl)-amino, pyrrolidino, piperidino, morpholino, piperazino, N—
(C1-2-alkyl)-piperazino, C1-4-alkoxy-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, where the abovementioned cycloalkyl moieties may additionally be substituted by a methyl or ethyl group, while, unless stated otherwise, the aryl moieties mentioned in the definition of the abovementioned groups denote a phenyl group which may be mono- or disubstituted by R′
, while the substituents may be identical or different, and R′
represents a fluorine, chlorine, bromine or iodine atom, a C1-2-alkyl, trifluoromethyl or C1-2-alkoxy group, or wherein if a phenyl group is disubstituted by R′ and
the two groups R′
are bound to adjacent carbon atoms of the phenyl group then the two groups R′
may together denote a C3-4-alkylene, methylenedioxy or 1,3-butadien-1,4-ylene group, or a tautomer or salt thereof.
3 Assignments
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Accused Products
Abstract
Compounds of the formula
having an inhibitory effect on signal transduction mediated by tyrosine kinases, their use in the treatment of diseases, especially tumoral diseases and diseases of the lungs and air-ways, and the preparation thereof.
65 Citations
8 Claims
-
1. A compound of the formula:
-
wherein X denotes a nitrogen atom, Ra denotes a hydrogen atom or a methyl group, Rb denotes a phenyl, benzyl or 1-phenylethyl group, wherein the phenyl nucleus in each case is substituted by the groups R1 to R3, where R1 and R2, which may be identical or different, each denote a hydrogen, fluorine, chlorine, bromine or iodine atom, a methyl, ethyl, hydroxy, methoxy, ethoxy, amino, cyano, vinyl or ethynyl group, an aryl, aryloxy, arylmethyl or arylmethoxy group, a methyl or methoxy group substituted by 1 to 3 fluorine atoms or R1 together with R2, if they are bound to adjacent carbon atoms, denotes a —
CH═
CH—
CH═
CH, —
CH═
CH—
NH or —
CH═
N—
NH group andR3 denotes a hydrogen, fluorine, chlorine or bromine atom, one of the groups Rc or Rd denotes an —
A—
B group andthe other group Rc or Rd denotes a —
C—
D group, whereA denotes a C1-6-alkylene group, a —
O—
C1-6-alkylene group, where the alkylene moiety is linked to the group B, or an oxygen atom, with the proviso that if A is an oxygen atom it may not be linked to the group B via a nitrogen atom of the group B, andB denotes a pyrrolidino group wherein the two hydrogen atoms in the 2 position are replaced by a group E, wherein E represents a —
CH2—
O—
CO—
CH2, —
CH2CH2—
O—
CO, —
CH2—
O—
CO—
CH2CH2, —
CH2CH2—
O—
CO—
CH2 or —
CH2CH2CH2—
O—
CO—
bridge optionally substituted by one or two C1-2-alkyl groups,a pyrrolidino group wherein the two hydrogen atoms in the 3 position are replaced by a group F wherein F denotes an —
O—
CO—
CH2CH2, —
CH2—
O—
CO—
CH2, —
CH2CH2—
O—
CO, —
O—
CO—
CH2CH2CH2, —
CH2—
O—
CO—
CH2CH2, —
CH2CH2—
O—
CO—
CH2, —
CH2CH2CH2—
O—
CO, —
O—
CO—
CH2—
NR4—
CH2, —
CH2—
O—
CO—
CH2—
NR4, —
O—
CO—
CH2—
O—
CH2 or —
CH2—
O—
CO—
CH2—
O—
bridge optionally substituted by one or two C1-2-alkyl groups, where R4 denotes a hydrogen atom or a C1-4-alkyl group,a piperidino or hexahydroazepino group, wherein the two hydrogen atoms in the 2 position are replaced by a group E, where E is as hereinbefore defined, a piperidino or hexahydroazepino group, wherein in each case the two hydrogen atoms in the 3 position or in the 4 position are replaced by a group F, where F is as hereinbefore defined, a piperazino or 4-(C1-4-alkyl)-piperazino group, wherein the two hydrogen atoms in the 2 position or in the 3 position of the piperazino ring are replaced by a group E, where E is as hereinbefore defined, a pyrrolidino or piperidino group, wherein two neighbouring hydrogen atoms are replaced by a —
O—
CO—
CH2, —
CH2—
O—
CO, —
O—
CO—
CH2CH2, —
CH2—
O—
CO—
CH2, —
CH2CH2—
O—
CO, —
O—
CO—
CH2—
NR4 or —
O—
CO—
CH2—
O—
bridge optionally substituted by one or two C1-2-alkyl groups, whereR4 is as hereinbefore defined and the heteroatoms of the abovementioned bridges are not bound to the 2 or 5 position of the pyrrolidino ring and are not bound to the 2 or 6 position of the piperidino ring, a piperazino or 4-(C1-4-alkyl)-piperazino group, wherein a hydrogen atom in the 2 position together with a hydrogen atom in the 3 position of the piperazino ring are replaced by a —
CH2—
O—
CO—
CH2 or —
CH2CH2—
O—
CO—
bridge optionally substituted by one or two C1-2-alkyl groups,a piperazino group wherein a hydrogen atom in the 3 position together with the hydrogen atom in the 4 position are replaced by a —
CO—
O—
CH2CH2 or —
CH2—
O—
CO—
CH2—
bridge optionally substituted by one or two C1-2-alkyl groups, where in each case the left-hand end of the abovementioned bridges is bound to the 3 position of the piperazino ring,a pyrrolidino, piperidino or hexahydroazepino group substituted by the group R5 wherein R5 represents 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, a pyrrolidino group substituted in the 3 position by a 2-oxo-morpholino group, while the 2-oxo-morpholino group may be substituted by one or two C1-2-alkyl groups, a piperidino or hexahydroazepino group substituted in the 3 or 4 position by a 2-oxo-morpholino group, while the 2-oxo-morpholino group may be substituted by one or two C1-2-alkyl groups, a 4-(C1-4-alkyl)-piperazino or 4-(C1-4-alkyl)-homopiperazino group substituted at a cyclic carbon atom by R5, wherein R5 is as hereinbefore defined, a piperazino or homopiperazino group substituted in the 4 position by the group R6, wherein R6 represents 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 pyrrolidino group substituted in the 3 position by an (R4NR6), R6O, R6S, R6SO or R6SO2 group, where R4 and R6 are as hereinbefore defined, a piperidino or hexahydroazepino group substituted in the 3 or 4 position by an (R4NR6), R6O, R6S, R6SO or R6SO2 group, wherein R4 and R6 are as hereinbefore defined, a pyrrolidino, piperidino or hexahydroazepino group substituted by an R5—
C1-4-alkyl, (R4NR6)—
C1-4-alkyl, R6O—
C1-4-alkyl, R6S—
C1-4-alkyl, R6SO—
C1-4-alkyl, R6SO2—
C1-4-alkyl or R4NR6—
CO group, wherein R4 to R6 are as hereinbefore defined,a pyrrolidino group substituted in the 3 position by an R5—
CO—
NR4, R5—
C1-4-alkylene-CONR4, (R4NR6)—
C1-4-alkylene-CONR4, R6O—
C1-4-alkylene-CONR4, R6S—
C1-4-alkylene-CONR4, R6SO—
C1-4-alkylene-CONR4, R6SO2—
C1-4-alkylene-CONR4, 2-oxo-morpholino-C1-4-alkylene-CONR4, R5—
C1-4-alkylene-Y or C2-4-alkyl-Y group, where the C2-4-alkyl moiety of the C2-4-alkyl-Y group in each case is substituted from position 2 by an (R4NR6), R6O, R6S, R6SO or R6SO2 group and the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups, whereinR4 to R6 are as hereinbefore defined and Y represents an oxygen or sulphur atom, an imino, N—
(C1-4-alkyl)-imino, sulphinyl or sulphonyl group,a piperidino or hexahydroazepino group substituted in the 3 or 4 position by an R5—
CO—
NR4, R5—
C1-4-alkylene-CONR4, (R4NR6)—
C1-4-alkylene-CONR4, R6O—
C1-4-alkylene-CONR4, R6S—
C1-4-alkylene-CONR4, R6SO—
C1-4-alkylene-CONR4, R6SO2—
C1-4-alkylene-CONR4, 2-oxo-morpholino-C1-4-alkylene-CONR4, R5—
C1-4-alkylene-Y or C2-4-alkyl-Y group, whereinY is as hereinbefore defined, the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups and the C2-4-alkyl moiety of the C2-4-alkyl-Y group is substituted in each case from position 2 by an (R4NR6), R6O, R6S, R6SO or R6SO2 group, where R4 to R6 are as hereinbefore defined, a 4-(C1-4-alkyl)-piperazino or 4-(C1-4-alkyl)-homopiperazino group substituted at a cyclic carbon atom by an R5—
C1-4-alkyl, (R4NR6)—
C1-4-alkyl, R6O—
C1-4-alkyl, R6S—
C1-4-alkyl, R6SO—
C1-4-alkyl, R6SO2—
C1-4-alkyl or R4NR6—
CO group, wherein R4 to R6 are as hereinbefore defined,a piperazino or homopiperazino group substituted in the 4 position by an R5—
C1-4-alkyl, R5—
CO, R5—
C1-4-alkylene-CO, (R4NR6)—
C1-4-alkylene-CO, R6O—
C1-4-alkylene-CO, R6S—
C1-4-alkylene-CO, R6SO—
C1-4-alkylene-CO or R6SO2—
C1-4-alkylene-CO group, wherein R4 to R6 are as hereinbefore defined,a piperazino or homopiperazino group substituted in the 4 position by a C2-4-alkyl group, wherein the C2-4-alkyl group is substituted in each case from position 2 by an (R4NR6), R6O, R6S, R6SO or R6SO2 group, where R4 and R6 are as hereinbefore defined, a pyrrolidino. piperidino or hexahydroazepino group substituted by a 2-oxo-morpholino-C1-4-alkyl group, wherein the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups, a pyrrolidino group substituted in the 3 position by a C2-4-alkyl-Y group, wherein Y is as hereinbefore defined and the C2-4-alkyl moiety of the C2-4-alkyl-Y group is substituted in each case from position 2 by a 2-oxo-morpholino group optionally substituted by one or two C1-2-alkyl groups, a piperidino or hexahydroazepino group substituted in the 3 or 4 position by a C2-4-alkyl-Y group, wherein Y is as hereinbefore defined and the C2-4-alkyl moiety of the C2-4-alkyl-Y group is substituted in each case from position 2 by a 2-oxo-morpholino group optionally substituted by one or two C1-2-alkyl groups, a 4-(C1-4-alkyl)-piperazino or 4-(C1-4-alkyl)-homopiperazino group substituted at a cyclic carbon atom by a 2-oxo-morpholino-C1-4-alkyl group, wherein the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups, a piperazino or homopiperazino group substituted in the 4 position by a 2-oxo-morpholino-C1-4-alkylene-CO group, wherein the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups, a piperazino or homopiperazino group substituted in the 4 position by a C2-4-alkyl group, wherein the C2-4-alkyl moiety is substituted in each case from position 2 by a 2-oxo-morpholino group optionally substituted by one or two C1-2-alkyl groups, a pyrrolidinyl or piperidinyl group substituted in the 1 position by the group R6, by an R5—
C1-4-alkyl, R5—
CO, R5—
C1-4-alkylene-CO, (R4NR6)—
C1-4-alkylene-CO, R6O—
C1-4-alkylene R6S—
C1-4-alkylene-CO, R6SO—
C1-4-alkylene-CO, R6SO2—
C1-4-alkylene-CO or 2-oxo-morpholino-C1-4-alkylene-CO group, whereinR4 to R6 are as hereinbefore defined and the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups, a pyrrolidinyl or piperidinyl group substituted in the 1 position by a C2-4-alkyl group, wherein the C2-4-alkyl moiety is substituted in each case from position 2 by an (R4NR6), R6O, R6S, R6SO, R6SO2 or 2-oxo-morpholino group, where R4 and R6 are as hereinbefore defined and the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups, a pyrrolidin-3-yl-NR4, piperidin-3-yl-NR4 or piperidin-4-yl-NR4 group substituted in each case at the cyclic nitrogen atom by the group R6, by an R5—
C1-4-alkyl, R5—
CO, R5—
C1-4-alkylene-CO, (R4NR6)—
C1-4-alkylene-CO, R6O—
C1-4-alkylene-CO, R6S—
C1-4-alkylene-CO, R6SO—
C1-4-alkylene-CO, R6SO2—
C1-4-alkylene-CO or 2-oxo-morpholino-C1-4-alkylene-CO group, whereinR4 to R6 are as hereinbefore defined and the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups, a pyrrolidin-3-yl-NR4, piperidin-3-yl-NR4 or piperidin-4-yl-NR4 group substituted in each case at the cyclic nitrogen atom by a C2-4-alkyl group, wherein the C2-4-alkyl moiety is substituted in each case from position 2 by an (R4NR6), R6O, R6S, R6SO, R6SO2 or 2-oxo-morpholino group, where R4 and R6 are as hereinbefore defined and the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups, a R5—
C1-4-alkylene-NR4 group wherein R4 and R5 are as hereinbefore defined, ora C2-4-alkyl-NR4 group wherein the C2-4-alkyl moiety is substituted in each case from position 2 by an (R4NR6), R6O, R6S, R6SO, R6SO2 or 2-oxo-morpholino group, where R4 and R6 are as hereinbefore defined and the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups, a 2-oxo-morpholin-4-yl group substituted by the group R7 or by the group R7 and a C1-4-alkyl group, where R7 represents a C3-4-alkyl, hydroxy-C1-4-alkyl, C1-4-alkoxy-C1-4-alkyl, di-(C1-4-alkyl)-amino-C1-4-alkyl, pyrrolidino-C1-4-alkyl, piperidino-C1-4-alkyl, morpholino-C1-4-alkyl, 4-(C1-4-alkyl)-piperazino-C1-4-alkyl, C1-4-alkylsulphanyl-C1-4-alkyl, C1-4-alkylsulphinyl-C1-4-alkyl, C1-4-alkyl-sulphonyl-C1-4-alkyl, cyano-C1-4-alkyl, C1-4-alkoxycarbonyl-C1-4-alkyl, aminocarbonyl-C1-4-alkyl, C1-4-alkyl-aminocarbonyl-C1-4-alkyl, di-(C1-4-alkyl)-aminocarbonyl-C1-4-alkyl, pyrrolidinocarbonyl-C1-4-alkyl, piperidinocarbonyl-C1-4-alkyl, morpholinocarbonyl-C1-4-alkyl or a 4-(C1-4-alkyl)-piperazinocarbonyl-C1-4-alkyl group, a 2-oxo-morpholin-4-yl group substituted by two groups R7, where R7 is as hereinbefore defined and the two groups R7 may be identical or different, a 2-oxo-morpholin-4-yl group wherein the two hydrogen atoms of a methylene group are replaced by a —
(CH2)m, —
CH2—
Y—
CH2, —
CH2—
Y—
CH2—
CH2, —
CH2CH2—
Y—
CH2CH2 or —
CH2CH2—
Y—
CH2CH2CH2—
bridge optionally substituted by one or two C1-2-alkyl groups, whereY is as hereinbefore defined and m represents the number 2, 3, 4, 5 or 6, a 2-oxo-morpholin-4-yl group wherein a hydrogen atom in the 5 position together with a hydrogen atom in the 6 position is replaced by a —
(CH2)n, —
CH2—
Y—
CH2, —
CH2—
Y—
CH2CH2 or —
CH2—
CH2—
Y—
CH2—
bridge, whereY is as hereinbefore defined and n denotes the number 2, 3 or 4, or, if C together with D represents a group Rc, it may also represent a 2-oxo-morpholin-4-yl group which may be substituted by 1 to 4 C1-2-alkyl groups, C denotes an —
O—
C1-6-alkylene group, where the alkylene moiety is linked to the group D, or an oxygen atom, while this may not be linked to a nitrogen atom of the group D, andD denotes an amino group substituted by 2 C1-4-alkyl groups wherein the alkyl groups may be identical or different and each alkyl moiety may be substituted from position 2 by a C1-4-alkoxy or di-(C1-4-alkyl)-amino group or by a 4- to 7-membered alkyleneimino group, while in the abovementioned 6- or 7-membered alkyleneimino groups a methylene group in each case may be replaced in the 4 position by an oxygen or sulphur atom of by a sulphinyl, sulphonyl or N—
(C1-4alkyl)-imino group,a 4- or 7-membered alkyleneimino group optionally substituted by 1 to 4 methyl group, a 6- to 7-membered alkyleneimino group optionally substituted by 1 to 2 methyl group where in each case a methylene group in the 4 position is replaced by an oxygen of sulphur atom, by a sulphinyl, sulphonyl, or N—
(C1-4-alkyl)-imino group,an imidazolyl group optionally substituted by 1 to 3 methyl group, a C5-7-cycloalkyl group wherein a methylene group is replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl or N—
(C1-4-alkyl)-imino group, orC together with D denotes a hydrogen atom, a C1-6-alkoxy group optionally substituted from position 2 by a hydroxy or C1-4-alkyl group, a C3-7-cycloalkoxy or C3-7-cycloalkyl-C1-4-alkoxy group, a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, or a group Rc, where Rc denotes a C2-6-alkoxy group which is substituted from position 2 by a C4-7-cycloalkoxy or C3-7-cycloalkyl-C1-3-alkoxy group, a C4-7-cycloalkoxy or C3-7-cycloalkyl-C1-6-alkoxy group, wherein the cycloalkyl moiety is substituted in each case by a C1-4-alkyl, C1-4-alkoxy, di-(C1-4-alkyl)-amino, pyrrolidino, piperidino, morpholino, piperazino, N—
(C1-2-alkyl)-piperazino, C1-4-alkoxy-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, where the abovementioned cycloalkyl moieties may additionally be substituted by a methyl or ethyl group,while, unless stated otherwise, the aryl moieties mentioned in the definition of the abovementioned groups denote a phenyl group which may be mono- or disubstituted by R′
, while the substituents may be identical or different, andR′
represents a fluorine, chlorine, bromine or iodine atom, a C1-2-alkyl, trifluoromethyl or C1-2-alkoxy group, or wherein if a phenyl group is disubstituted by R′ and
thetwo groups R′
are bound to adjacent carbon atoms of the phenyl group then the two groups R′
may together denote a C3-4-alkylene, methylenedioxy or 1,3-butadien-1,4-ylene group,or a tautomer or salt thereof. - View Dependent Claims (2, 3, 4, 6, 7, 8)
X denotes a nitrogen atom, Ra denotes a hydrogen atom, Rb denotes a 1-phenylethyl, 3-methylphenyl, 3-chlorophenyl, 3-bromophenyl or 3-chloro-4-fluorophenyl group, Rc denotes an — - A—
B group wherein
A denotes a —
OCH2CH2, —
OCH2CH2CH2 or —
OCH2CH2CH2CH2 group, where the alkylene moiety in each case is linked to the group B, andB denotes a piperidino group wherein the two hydrogen atoms in the 4 position are replaced by a —
CH2—
O—
CO—
CH2, —
CH2CH2—
O—
CO, —
CH2CH2—
O—
CO—
CH2, —
O—
CO—
CH2—
NCH3—
CH2 or —
O—
CO—
CH2—
O—
CH2—
bridge,a piperazino group wherein a hydrogen atom in the 3 position together with the hydrogen atom in the 4 position are replaced by a —
CO—
O—
CH2—
CH2 or —
CH2—
O—
CO—
CH2—
bridge, where in each case the left-hand end of the abovementioned bridges is bound to the 3 position of the piperazino ring,a piperidino group which is substituted in the 4 position by a 2-oxo-morpholino or 2-oxo-morpholinomethyl group, where the 2-oxo-morpholino moiety may be substituted in each case by one or two methyl groups, a piperazino group which is substituted in the 4 position by a 2-oxo-tetrahydrofuran-3-yl or 2-oxo-tetrahydrofuran-4-yl group, a piperidino group which is substituted in the 4 position by an R6S group, where R6 denotes a 2-oxo-tetrahydrofuran-3-yl or 2-oxo-tetrahydrofuran-4-yl group, a piperazino group which is substituted in the 4 position by a 2-oxo-tetrahydrofuranylmethyl or 2-oxo-tetrahydrofuranylcarbonyl group, a piperazino group which is substituted in the 4 position by a [2-(2-oxo-tetrahydrofuran-3-ylsulphenyl)ethyl] group, a piperidin-4-yl group which is substituted in the 1 position by a 2-oxo-tetrahydrofuran-3-yl or 2-oxo-tetrahydrofuran-4-yl group, a 2-oxo-morpholin-4-yl group which is substituted by a methoxymethyl or methoxyethyl group, a 2-oxo-morpholin-4-yl group wherein the two hydrogen atoms of a methylene group are replaced by a —
CH2CH2CH2CH2, —
CH2CH2CH2CH2CH2, —
CH2—
O—
CH2CH2 or —
CH2CH2—
O—
CH2CH2—
bridge,and Rd represents a methoxy, cyclopropylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, or a tautomer or salt thereof.
-
-
3. A compound of the formula I according to claim 1 wherein
X denotes a nitrogen atom, Ra denotes a hydrogen atom, Rb denotes a 1-phenylethyl, 3-methylphenyl, 3-chlorophenyl, 3-bromophenyl or 3-chloro-4-fluorophenyl group, Rc denotes a methoxy, cyclopentyloxy, cyclopropylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group and Rd denotes an — - A—
B group whereinA denotes an —
OCH2CH2, —
OCH2CH2CH2 or —
OCH2CH2CH2CH2 group, where the alkylene moiety in each case is linked to the group B, andB denotes a piperidino group wherein the two hydrogen atoms in the 4 position are replaced by a —
CH2—
O—
CO—
CH2, —
CH2CH2—
O—
CO, —
CH2CH2—
O—
CO—
CH2, —
O—
CO—
CH2—
NCH3—
CH2 or —
O—
CO—
CH2—
O—
CH2—
bridge,a piperazino group wherein a hydrogen atom in the 3 position together with the hydrogen atom in the 4 position are replaced by a —
CO—
O—
CH2—
CH2 or —
CH2—
O—
CO—
CH2—
bridge,where in each case the left-hand end of the abovementioned bridges is bound to the 3 position of the piperazino ring, a piperidino group which is substituted in the 4 position by a 2-oxo-morpholino or 2-oxo-morpholinomethyl group, while the 2-oxo-morpholino moiety may be substituted in each case by one or two methyl groups, a piperazino group which is substituted in the 4 position by a 2-oxo-tetrahydrofuran-3-yl or 2-oxo-tetrahydrofuran-4-yl group, a piperidino group which is substituted in the 4 position by an R6S group, where R6 represents a 2-oxo-tetrahydrofuran-3-yl or 2-oxo-tetrahydrofuran-4-yl group, a piperazino group which is substituted in the 4 position by a 2-oxo-tetrahydrofuranylmethyl or 2-oxo-tetrahydrofuranylcarbonyl group, a piperazino group which is substituted in the 4 position by a [2-(2-oxo-tetrahydrofuran-3-ylsulphenyl)ethyl] group, a piperidin-4-yl group which is substituted in the 1 position by a 2-oxo-tetrahydrofuran-3-yl or 2-oxo-tetrahydrofuran-4-yl group, a 2-oxo-morpholin-4-yl group which is substituted by a methoxymethyl or methoxyethyl group, a 2-oxo-morpholin-4-yl group wherein the two hydrogen atoms of a methylene group are replaced by a —
CH2CH2CH2CH2, —
CH2CH2CH2CH2CH2, —
CH2—
O—
CH2CH2 or —
CH2CH2—
O—
CH2CH2—
bridge,or a tautomer or salt thereof.
- A—
-
4. A compound of the formula I according to claim 1 wherein
X denotes a nitrogen atom, Ra denotes a hydrogen atom, Rb denotes a 3-chloro-4-fluorophenyl group, Rc denotes a cyclopentyloxy, cyclopropylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy or tetrahydrofuran-2-yl-methoxy group and Rd denotes an — - A—
B group whereinA denotes a —
OCH2CH2 group, where the alkylene moiety is linked to the group B, andB denotes a piperazino group wherein a hydrogen atom in the 3 position together with the hydrogen atom in the 4 position is replaced by a —
CH2—
O—
CO—
CH2—
bridge, while the left-hand end of the abovementioned bridge is bound to the 3 position of the piperazino ring,a piperazino group which is substituted in the 4 position by a 2-oxo-tetrahydrofuran-3-yl, 2-oxo-tetrahydrofuran-4-yl-,2-oxo-tetrahydrofuranylmethyl or 2-oxo-tetrahydrofuranylcarbonyl group, or a tautomer or salt thereof.
- A—
-
6. A physiologically acceptable salt of a compound according to claim 1, 2, 3, 4 or 5, formed with an inorganic or organic acid or base.
-
7. A pharmaceutical composition comprising a compound according to claim 1, 2, 3, 4 or 5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
-
8. A method of treating a benign or malignant tumour which comprises administering a therapeutically effective amount of a compound according claim 1, 2, 3, 4 or 5 or a pharmaceutically acceptable salt thereof.
-
5. A compound selected from the group consisting of:
-
(1) 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentylmethoxy-7-{2-[4-(2-oxo-tetrahydrofuran-4-yl)-piperazin-1-yl]-ethoxy}-quinazoline. (2) 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentyloxy-7-{2-[4-(2-oxo-tetrahydrofuran-4-yl)-piperazin-1-yl]-ethoxy}-quinazoline, (3) 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopropylmethoxy-7-{2-[4-(2-oxo-tetrahydrofuran-4-yl)-piperazin-1-yl]-ethoxy)}-quinazoline and (4) 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopropylmethoxy-7-(2-{4-[(R)-(2-oxo-tetrahydrofuran-5-yl)methyl]-piperazin-1-yl}-ethoxy)-quinazoline, or a tautomer or salts thereof.
-
Specification
-
- Resources
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Current AssigneeBoehringer Ingelheim Pharma GmbH & Company Kg (C.H. Boehringer Sohn AG & Co. KG)
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Original AssigneeBoehringer Ingelheim Pharmaceuticals Incorporated (C.H. Boehringer Sohn AG & Co. KG)
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InventorsHimmelsbach, Frank, Langkopf, Elke, Jung, Birgit, Solca, Flavio, Blech, Stefan
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Primary Examiner(s)Shah, Mukund J.
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Assistant Examiner(s)Balasubramanian, Venkataraman
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Application NumberUS09/938,314Publication NumberTime in Patent Office747 DaysField of Search544/284, 544/293, 544/111, 544/61, 544/115, 544/119, 540/596, 514/227.8, 514/234.8, 514/252.16, 514/252.15, 514/252.17, 514/211.15, 514/252.14US Class Current514/252.14CPC Class CodesA61K 31/505 Pyrimidines; Hydrogenated p...A61K 31/517 ortho- or peri-condensed wi...A61P 35/00 Antineoplastic agentsC07D 405/12 linked by a chain containin...C07D 405/14 containing three or more he...C07D 413/12 linked by a chain containin...C07D 413/14 containing three or more he...
