Aminoquinazolines which inhibit signal transduction mediated by tyrosine kinases
First Claim
Patent Images
1. A compound of the formula Ra denotes a hydrogen atom or a methyl group, Rb denotes a phenyl, benzyl- or 1-phenylethyl group wherein the phenyl nucleus is substituted in each case by the groups R1 to R3, while R1 and R2, which may be identical or different, in each case 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, denote a —
- CH═
CH—
CH═
CH, —
CH═
CH—
NH—
or —
CH═
N—
NH group and R3 denotes a hydrogen, fluorine, chlorine or bromine atom, Rc denotes a hydrogen atom or a methyl group, X denotes a nitrogen atom, A denotes a 1,1- or 1,2-vinylene group which may be substituted in each case by one or two methyl groups or by a trifluoromethyl group, an ethynylene group or a 1,3-butadien-1,4-ylene group optionally substituted by a methyl or trifluoromethyl group, B denotes an alkylene or —
CO-alkylene group wherein the alkylene moiety in each case contains 1 to 4 carbon atoms, while the linking of the —
CO-alkylene group to the adjacent group A in each case must take place via the carbonyl group, a —
CO—
O-alkylene- or —
CO—
NR4-alkylene group wherein the alkylene moiety in each case contains 1 to 4 carbon atoms, while the linking to the adjacent group A in each case must take place via the carbonyl group, wherein R4 denotes a hydrogen atom or a methyl or ethyl group, or a carbonyl group, C denotes a 2-oxo-morpholin-4-yl group substituted by the group R5 or by the group R5 and a C1-4-alkyl group, while R5 denotes 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-alkylsulphonyl-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 R5, where R5 is as hereinbefore defined and the two groups R5 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, while m denotes the number 2, 3, 4, 5 or 6 and Y denotes an oxygen or sulphur atom, a sulphinyl, sulphonyl or C1-4-alkylimino group, 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 —
CH2CH2—
Y—
CH2-bridge, while Y is as hereinbefore defined and n denotes the number 2, 3 or 4, or, if D together with E denotes a group Rd, it may also denote a 2-oxo-morpholin-4-yl group which may be substituted by 1 to 4 C1-2-alkyl groups, D denotes a —
O—
C1-6-alkylene group, while the alkylene moiety is linked to the group E, or an oxygen atom, while this may not be linked to a nitrogen atom of the group E, and E 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 the 2 position 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- to 7-membered alkyleneimino groups in each case a methylene group may be replaced in the 4 position by an oxygen or sulphur atom or by a sulphinyl, sulphonyl- or N—
(C1-4-alkyl)-imino group, a 4- to 7-membered alkyleneimino group optionally substituted by 1 to 4 methyl groups, a 6- to 7-membered alkyleneimino group optionally substituted by 1 or 2 methyl groups, wherein in each case a methylene group in the 4 position is replaced by an oxygen or sulphur atom or by a sulphinyl, sulphonyl- or N—
(C1-4-alkyl)-imino 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 or by a sulphinyl, sulphonyl or N—
(C1-4-alkyl)-imino group, or D together with E denotes a hydrogen atom, a C1-6-alkoxy group optionally substituted from the 2 position by a hydroxy- or C1-4-alkoxy group, a C3-7-cycloalkoxy- or C3-7-cycloalkyl-C1-4-alkoxy group, or a group Rd, where Rd denotes a C2-6-alkoxy group which is substituted from the 2 position 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 in each case is substituted by a C1-4-alkyl, C1-4-alkoxy, di-(C1-4-alkyl)-amino, pyrrolidino, piperidino, morpholino, piperazino, 4-(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 4-(C1-2-alkyl)-piperazino-C1-2-alkyl group, while the abovementioned cycloalkyl moieties may additionally be substituted by a methyl or ethyl group, while, unless otherwise stated, by the aryl moieties mentioned in the definition of the abovementioned groups is meant a phenyl group which may be mono- or disubstituted by R6, while the substituents may be identical or different and R6 denotes a fluorine, chlorine, bromine or iodine atom, a C1-2-alkyl, trifluoromethyl or C1-2-alkoxy group, or two groups R6, if they are bound to adjacent carbon atoms, together represent a C3-4-alkylene, methylenedioxy or 1,3-butadien-1,4-ylene group, or a tautomer or salt thereof.
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Accused Products
Abstract
Compounds of the formula
having an inhibitory effect on signal transduction mediated by tyrosine kinases, and the use thereof for treating diseases, particularly tumoral diseases, diseases of the lungs and respiratory tract.
91 Citations
8 Claims
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1. A compound of the formula
Ra denotes a hydrogen atom or a methyl group, Rb denotes a phenyl, benzyl- or 1-phenylethyl group wherein the phenyl nucleus is substituted in each case by the groups R1 to R3, while R1 and R2, which may be identical or different, in each case 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, denote a — - CH═
CH—
CH═
CH, —
CH═
CH—
NH—
or —
CH═
N—
NH group andR3 denotes a hydrogen, fluorine, chlorine or bromine atom, Rc denotes a hydrogen atom or a methyl group, X denotes a nitrogen atom, A denotes a 1,1- or 1,2-vinylene group which may be substituted in each case by one or two methyl groups or by a trifluoromethyl group, an ethynylene group or a 1,3-butadien-1,4-ylene group optionally substituted by a methyl or trifluoromethyl group, B denotes an alkylene or —
CO-alkylene group wherein the alkylene moiety in each case contains 1 to 4 carbon atoms, while the linking of the —
CO-alkylene group to the adjacent group A in each case must take place via the carbonyl group,a —
CO—
O-alkylene- or —
CO—
NR4-alkylene group wherein the alkylene moiety in each case contains 1 to 4 carbon atoms, while the linking to the adjacent group A in each case must take place via the carbonyl group, whereinR4 denotes a hydrogen atom or a methyl or ethyl group, or a carbonyl group, C denotes a 2-oxo-morpholin-4-yl group substituted by the group R5 or by the group R5 and a C1-4-alkyl group, while R5 denotes 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-alkylsulphonyl-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 R5, where R5 is as hereinbefore defined and the two groups R5 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, whilem denotes the number 2, 3, 4, 5 or 6 and Y denotes an oxygen or sulphur atom, a sulphinyl, sulphonyl or C1-4-alkylimino group, 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 —
CH2CH2—
Y—
CH2-bridge, whileY is as hereinbefore defined and n denotes the number 2, 3 or 4, or, if D together with E denotes a group Rd, it may also denote a 2-oxo-morpholin-4-yl group which may be substituted by 1 to 4 C1-2-alkyl groups, D denotes a —
O—
C1-6-alkylene group, while the alkylene moiety is linked to the group E, oran oxygen atom, while this may not be linked to a nitrogen atom of the group E, and E 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 the 2 position 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- to 7-membered alkyleneimino groups in each case a methylene group may be replaced in the 4 position by an oxygen or sulphur atom or by a sulphinyl, sulphonyl- or N—
(C1-4-alkyl)-imino group,a 4- to 7-membered alkyleneimino group optionally substituted by 1 to 4 methyl groups, a 6- to 7-membered alkyleneimino group optionally substituted by 1 or 2 methyl groups, wherein in each case a methylene group in the 4 position is replaced by an oxygen or sulphur atom or by a sulphinyl, sulphonyl- or N—
(C1-4-alkyl)-imino 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 or by a sulphinyl, sulphonyl or N—
(C1-4-alkyl)-imino group, orD together with E denotes a hydrogen atom, a C1-6-alkoxy group optionally substituted from the 2 position by a hydroxy- or C1-4-alkoxy group, a C3-7-cycloalkoxy- or C3-7-cycloalkyl-C1-4-alkoxy group, or a group Rd, where Rd denotes a C2-6-alkoxy group which is substituted from the 2 position 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 in each case is substituted by a C1-4-alkyl, C1-4-alkoxy, di-(C1-4-alkyl)-amino, pyrrolidino, piperidino, morpholino, piperazino, 4-(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 4-(C1-2-alkyl)-piperazino-C1-2-alkyl group, while the abovementioned cycloalkyl moieties may additionally be substituted by a methyl or ethyl group, while, unless otherwise stated, by the aryl moieties mentioned in the definition of the abovementioned groups is meant a phenyl group which may be mono- or disubstituted by R6, while the substituents may be identical or different and R6 denotes a fluorine, chlorine, bromine or iodine atom, a C1-2-alkyl, trifluoromethyl or C1-2-alkoxy group, or two groups R6, if they are bound to adjacent carbon atoms, together represent 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)
Ra denotes a hydrogen atom, Rb denotes a benzyl or 1-phenylethyl group or a phenyl group substituted by the groups R1 and R2, while R1 denotes a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyano or ethynyl group and R2 denotes a hydrogen or fluorine atom, Rc denotes a hydrogen atom, X denotes a nitrogen atom, A denotes a 1,2-vinylene group, B denotes a C1-4-alkylene group, C denotes a 2-oxo-morpholin-4-yl group substituted by the group R5 or by the group R5 and a C1-4-alkyl group, while R5 denotes a C3-4-alkyl, C1-2-alkoxy-C1-4-alkyl, di-(C12-alkyl)-amino-C1-4-alkyl, pyrrolidino-C1-4-alkyl, piperidino-C1-4-alkyl, morpholino-C1-4-alkyl, 4-(C1-2-alkyl)-piperazino-C1-4-alkyl, C1-2-alkylsulphanyl-C1-4-alkyl, C1-2-alkylsulphinyl-C1-4-alkyl, C1-2-alkylsulphonyl-C1-4-alkyl, cyano-C1-4-alkyl, C1-2-alkoxycarbonyl-C1-4-alkyl, aminocarbonyl-C1-4-alkyl, C1-2-alkyl-aminocarbonyl-C1-4-alkyl, di-(C1-2-alkyl)-aminocarbonyl-C1-4-alkyl, pyrrolidinocarbonyl-C1-4-alkyl, piperidinocarbonyl-C1-4-alkyl, morpholinocarbonyl-C1-4-alkyl- or a 4-(C1-2-alkyl)-piperazinocarbonyl-C1-4-alkyl group, a 2-oxo-morpholin-4-yl group substituted by two groups R5, while R5 is as hereinbefore defined and the two groups R5 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—
or —
CH2CH2—
Y—
CH2CH2-bridge, while
m denotes the number 2, 3, 4 or 5 and Y denotes an oxygen or sulphur atom, a sulphinyl, sulphonyl or C1-2-alkylimino group, 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 —
CH2CH2—
Y—
CH2-bridge, whereY is as hereinbefore defined and n denotes the number 2, 3 or 4, or, if D together with E denotes a group Rd, it may also denote a 2-oxo-morpholin-4-yl group which may be substituted by 1 or 2 methyl or ethyl groups, D denotes a —
O—
C1-4-alkylene group, while the alkylene moiety is linked to the group E, andE denotes a dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino, 4-methyl-piperazino- or 4-ethyl-piperazino group or D together with E denotes a hydrogen atom, a methoxy, ethoxy, 2-methoxy-ethoxy, 3-methoxy-propyloxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, a cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy or cyclohexylmethoxy group or a group Rd, where Rd denotes a 2-(cyclobutyloxy)-ethoxy, 2-(cyclopentyloxy)-ethoxy, 2-(cyclopropylmethoxy)-ethoxy or 2-(cyclobutylmethoxy)-ethoxy group, or a tautomer or salt thereof.
- CH═
-
3. A compound of the formula I according to claim 1, wherein
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 hydrogen atom, X denotes a nitrogen atom, A denotes a 1,2-vinylene group, B denotes a methylene group, C denotes a 2-oxo-morpholin-4-yl group which is substituted by a methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl, diethylaminoethyl, cyanomethyl or cyanoethyl group, a 2-oxo-morpholin-4-yl group, wherein the two hydrogen atoms of a methylene group are replaced by a — - CH2CH2, —
CH2CH2CH2, —
CH2CH2CH2CH2, —
CH2CH2CH2CH2CH2, —
CH2—
O—
CH2CH2, —
CH2—
NCH3—
CH2CH2, —
CH2—
NC2H5—
CH2CH2, —
CH2CH2—
O—
CH2CH2, —
CH2CH2—
NCH3—
CH2CH2—
or —
CH2CH2—
NC2H5—
CH2CH2—
bridge,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 —
CH2CH2CH2, —
CH2CH2CH2CH2, —
CH2—
O—
CH2, —
CH2—
NCH3—
CH2, —
CH2—
NC2H5—
CH2, —
CH2—
O—
CH2CH2, —
CH2—
NCH3—
CH2CH2, —
CH2—
NC2H5—
CH2CH2, —
CH2CH2—
O—
CH2, —
CH2CH2—
NCH3—
CH2—
or —
CH2CH2—
NC2H5—
CH2—
bridge,or, if D together with E denotes a group Rd, it may also denote a 2-oxo-morpholin-4-yl group which is substituted by 1 or 2 methyl groups, and D together with E denotes a hydrogen atom, a methoxy, ethoxy, 2-methoxy-ethoxy, 3-methoxy-propyloxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy or tetrahydrofuranylmethoxy group, a cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy group or a group Rd, where Rd denotes a 2-(cyclobutyloxy)-ethoxy, 2-(cyclopentyloxy)-ethoxy, 2-(cyclopropylmethoxy)-ethoxy or 2-(cyclobutylmethoxy)-ethoxy group, or a tautomer or salt thereof.
- CH2CH2, —
-
4. A compound of the formula I according to claim 1, wherein
Ra denotes a hydrogen atom, Rb denotes a 3-chloro-4-fluorophenyl group, Rc denotes a hydrogen atom, X denotes a nitrogen atom, A denotes a 1,2-vinylene group, B denotes a methylene group, C denotes a 2-oxo-morpholin-4-yl group which is substituted by a methoxymethyl or methoxyethyl group, or a 2-oxo-morpholin-4-yl group, wherein the two hydrogen atoms of a methylene group are replaced by a — - CH2CH2—
O—
CH2CH2—
bridge, andD together with E denotes a hydrogen atom, a methoxy or cyclopropylmethoxy group, or a tautomer or salt thereof.
- CH2CH2—
-
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.
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8. A method of treating a malignant tumour or a disease of the respiratory tract or lungs which is accompanied by increased or altered production of mucus caused by stimulation of tyrosine kinases, 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-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(2-oxo-1,9-dioxa-4-aza-spiro[5,5]undec-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline and (3) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-({4-[2-(2-methoxy-ethyl)-6-oxo-morpholin-4-yl]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, or a tautomer or salt thereof.
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Specification
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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)Raymond, Richard L.
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Assistant Examiner(s)Liu, Hong
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Application NumberUS09/934,631Publication NumberTime in Patent Office1,007 DaysField of Search544/119, 544/71, 514/234.5, 514/228.8US Class Current514/228.8CPC Class CodesA61P 35/00 Antineoplastic agentsC07D 413/12 linked by a chain containin...
