CN100404517C - Bicyclic heterocycles, medicaments containing these compounds, their use, and methods for the production thereof - Google Patents

Bicyclic heterocycles, medicaments containing these compounds, their use, and methods for the production thereof Download PDF

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CN100404517C
CN100404517C CNB01814635XA CN01814635A CN100404517C CN 100404517 C CN100404517 C CN 100404517C CN B01814635X A CNB01814635X A CN B01814635XA CN 01814635 A CN01814635 A CN 01814635A CN 100404517 C CN100404517 C CN 100404517C
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amino
quinazoline
chloro
fluorophenyl
methyl
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CN1449390A (en
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弗兰克·希梅尔斯巴赫
埃尔克·兰格科普夫
伯吉特·琼
斯蒂芬·布莱克
弗莱维奥·索尔卡
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Boehringer Ingelheim Pharma GmbH and Co KG
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Abstract

The invention relates to bicyclic heterocycles of general formula (I), in which Ra to Rc are defined as referred to in Claims Nos. 1 to 7, to their tautomers, their stereoisomers, and to their salts, particularly their physiologically compatible salts with inorganic or organic acids or bases, which have valuable pharmacological properties, in particular, an inhibitive effect on the signal transduction imparted by tyrosine kinases. The invention also relates to the use of said bicyclic heterocycles for treating diseases, especially tumor diseases, disorders of the lung and of the respiratory tract, and to the production thereof.

Description

Bicyclic heterocycle, contain the pharmaceutical composition of these compounds, its purposes and preparation method
The bicyclic heterocycle of the relevant following general formula of the present invention:
Figure C0181463500061
Its tautomer, steric isomer and salt thereof, particularly itself and physiologically acceptable salt inorganic or organic acid or alkali, it has valuable pharmacological properties, especially the kinase mediated signal conduction tool of Tyrosine is suppressed effect, it is used for the treatment of the especially purposes of tumor disease, lung and respiratory tract disease of disease, and preparation method thereof.
In the last general formula I,
R aRepresent benzyl or 1-phenylethyl or through R 1And R 2The phenyl that base replaces, wherein
R 1Represent hydrogen, fluorine, chlorine or bromine atom, methyl, trifluoromethyl, cyano group or ethynyl, and
R 2Represent hydrogen or fluorine atom,
R bOr R cOne of base is represented R 3-(CH 2) m-O base, and R bOr R cAnother basic representation methoxy, cyclobutoxy group, cyclopentyloxy, cyclo propyl methoxy, cyclobutyl methoxy base, cyclopentyl methoxyl group, tetrahydrofuran (THF)-3-base oxygen base, tetrahydropyran-3-base oxygen base, tetrahydropyran-4-base oxygen base, tetrahydrofuran (THF) ylmethoxy or tetrahydropyrans ylmethoxy, wherein
R 3Represent N-(2-oxo-tetrahydrofuran-4-yl) methylamino-or N-(2-oxo-tetrahydrofuran-4-yl) ethylamino,
The R that on methylene radical, replaces through 1 or 2 methyl or ethyl 4-O-CO-CH 2-N-CH 2CH 2-OH base, wherein
R 4Represent hydrogen atom or C 1-4-alkyl,
Or the 2-oxo morpholine-4-base that can replace through 1 or 2 methyl or ethyl and
M represents 2,3 or 4 number,
Condition is except the following compounds:
4-[(3-chloro-4-fluorophenyl) amino]-6-cyclopentyloxy-7-(2-{N-(2-hydroxy-2-methyl third-1-yl)-N-[(ethoxycarbonyl) methyl] amino } oxyethyl group) quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-cyclopentyloxy-7-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group] quinazoline,
The 4-[(3-bromophenyl) amino]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline, and
The 4-[(3-bromophenyl) amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methylamino] oxyethyl group }-7-methoxyl group quinazoline,
Its tautomer, steric isomer and salt.
Preferred above-mentioned compound of Formula I is for wherein:
R aRepresent benzyl or 1-phenylethyl or through R 1And R 2The phenyl that base replaces, wherein
R 1Represent hydrogen, fluorine, chlorine or bromine atom, methyl, trifluoromethyl, cyano group or ethynyl, and
R 2Represent hydrogen or fluorine atom,
R bOr R cOne of base is represented R 3-(CH 2) m-O base and R bOr R cAnother basic representation methoxy of base, cyclobutoxy group, cyclopentyloxy, cyclo propyl methoxy, cyclobutyl methoxy base, cyclopentyl methoxyl group, tetrahydrofuran (THF)-3-base oxygen base, tetrahydropyran-3-base oxygen base, tetrahydropyran-4-base oxygen base, tetrahydrofuran (THF) ylmethoxy or tetrahydropyrans ylmethoxy, wherein
R 3Represent N-(2-oxo-tetrahydrofuran-4-yl) methylamino-or N-(2-oxo-tetrahydrofuran-4-yl) ethylamino,
The R that on methylene radical, replaces through 1 or 2 methyl or ethyl 4-O-CO-CH 2-N-CH 2CH 2-OH base, wherein
R 4Represent hydrogen atom or C 1-4-alkyl,
Or the 2-oxo morpholine-4-base that can replace through 1 or 2 methyl or ethyl and
M represents 2,3 or 4 number,
Condition is except the following compounds:
4-[(3-chloro-4-fluorophenyl) amino]-6-cyclopentyloxy-7-(2-{N-(2-hydroxy-2-methyl third-1-yl)-N-[(ethoxycarbonyl) methyl] amino } oxyethyl group) quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-cyclopentyloxy-7-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group] quinazoline,
The 4-[(3-bromophenyl) amino]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
The 4-[(3-bromophenyl) amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methylamino] oxyethyl group }-7-methoxyl group quinazoline,
The 4-[(3-bromophenyl) amino]-6-(2-{N-(2-hydroxy-2-methyl third-1-yl)-N-[(ethoxy carbonyl) methyl] amino } oxyethyl group)-7-methoxyl group quinazoline,
The 4-[(3-bromophenyl) amino]-6-[2-(3-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
The 4-[(3-bromophenyl) amino]-6-[2-(5,5-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-cyclobutoxy group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-cyclopentyloxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-cyclo propyl methoxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-cyclopentyl methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methylamino] oxyethyl group }-7-methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methylamino] oxyethyl group }-7-cyclopentyloxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methylamino] oxyethyl group }-7-cyclopentyl methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-7-methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-7-cyclopentyloxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-7-cyclopentyl methoxyl group quinazoline,
(R)-and the 4-[(1-phenylethyl) amino]-6-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-7-cyclopentyloxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-6-methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-6-cyclobutoxy group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-6-cyclopentyloxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-6-cyclo propyl methoxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-6-cyclopentyl methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methylamino] oxyethyl group }-6-methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methylamino] oxyethyl group }-6-cyclopentyloxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methylamino] oxyethyl group }-6-cyclopentyl methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-6-methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-6-cyclopentyloxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-6-cyclopentyl methoxyl group quinazoline, and
(R)-and the 4-[(1-phenylethyl) amino]-7-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-6-cyclopentyloxy quinazoline,
Its tautomer, steric isomer and salt.
The preferred particularly following compound of compound, wherein:
R aRepresent the 1-phenylethyl or through R 1And R 2The phenyl that base replaces, wherein
R 1Represent fluorine, chlorine or bromine atom, methyl or ethynyl, and
R 2Represent hydrogen or fluorine atom,
R bOr R cOne of base is represented R 3-(CH 2) m-O base reaches R bOr R cAnother basic representation methoxy of base, cyclobutoxy group, cyclopentyloxy, cyclo propyl methoxy, cyclobutyl methoxy base, cyclopentyl methoxyl group, tetrahydrofuran (THF)-3-base oxygen base, tetrahydropyran-3-base oxygen base, tetrahydropyran-4-base oxygen base, tetrahydrofuran (THF) ylmethoxy or tetrahydropyrans ylmethoxy, wherein
R 3Represent N-(2-oxo-tetrahydrofuran-4-yl) methylamino-,
On methylene radical through 1 or 2 methyl substituted R 4-O-CO-CH 2-N-CH 2CH 2-OH base,
Wherein
R 4Represent C 1-4-alkyl,
Or can through 1 or 2 methyl substituted 2-oxo morpholine-4-base and
M represents 2,3 or 4 number,
Condition is except the following compounds:
4-[(3-chloro-4-fluorophenyl) amino]-6-cyclopentyloxy-7-(2-{N-(2-hydroxy-2-methyl third-1-yl)-N-[(ethoxycarbonyl) methyl] amino } oxyethyl group) quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-cyclopentyloxy-7-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group] quinazoline,
The 4-[(3-bromophenyl) amino]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
The 4-[(3-bromophenyl) amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methylamino] oxyethyl group }-7-methoxyl group quinazoline,
The 4-[(3-bromophenyl) amino]-6-(2-{N-(2-hydroxy-2-methyl third-1-yl)-N-[(ethoxy carbonyl) methyl] amino } oxyethyl group)-7-methoxyl group quinazoline,
The 4-[(3-bromophenyl) amino]-6-[2-(3-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
The 4-[(3-bromophenyl) amino]-6-[2-(5,5-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-cyclobutoxy group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-cyclopentyloxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-cyclo propyl methoxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-cyclopentyl methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methylamino] oxyethyl group }-7-methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methylamino] oxyethyl group }-7-cyclopentyloxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methylamino] oxyethyl group }-7-cyclopentyl methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-7-methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-7-cyclopentyloxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-7-cyclopentyl methoxyl group quinazoline,
(R)-and the 4-[(1-phenylethyl) amino]-6-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-7-cyclopentyloxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-6-methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-6-cyclobutoxy group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-6-cyclopentyloxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-6-cyclo propyl methoxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-6-cyclopentyl methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methylamino] oxyethyl group }-6-methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methylamino] oxyethyl group }-6-cyclopentyloxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methylamino] oxyethyl group }-6-cyclopentyl methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-6-methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-6-cyclopentyloxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-6-cyclopentyl methoxyl group quinazoline, and
(R)-and the 4-[(1-phenylethyl) amino]-7-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-6-cyclopentyloxy quinazoline,
Its tautomer, steric isomer and salt.
Particularly preferred compound of Formula I is for wherein:
R aRepresent the 1-phenylethyl or through R 1And R 2The phenyl that base replaces, wherein
R 1Represent fluorine, chlorine or bromine atom, and
R 2Represent hydrogen or fluorine atom,
R bOr R cOne of base is represented R 3-(CH 2) m-O base, and R bOr R cAnother basic representation methoxy of base, cyclobutoxy group, cyclopentyloxy, cyclo propyl methoxy, cyclobutyl methoxy base, cyclopentyl methoxyl group, tetrahydrofuran (THF)-3-base oxygen base, tetrahydropyran-3-base oxygen base, tetrahydropyran-4-base oxygen base, tetrahydrofuran (THF) ylmethoxy or tetrahydropyrans ylmethoxy, wherein
R 3Represent N-(2-oxo-tetrahydrofuran-4-yl) methylamino-or through one or two methyl substituted 2-oxo morpholine-4-base, and
M represents 2,3 or 4 number,
Condition is except the following compounds:
4-[(3-chloro-4-fluorophenyl) amino]-6-cyclopentyloxy-7-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group] quinazoline,
The 4-[(3-bromophenyl) amino]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
The 4-[(3-bromophenyl) amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methylamino] oxyethyl group }-7-methoxyl group quinazoline,
The 4-[(3-bromophenyl) amino]-6-[2-(3-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
The 4-[(3-bromophenyl) amino]-6-[2-(5,5-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-cyclobutoxy group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-cyclopentyloxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-cyclo propyl methoxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-cyclopentyl methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methylamino] oxyethyl group }-7-methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methylamino] oxyethyl group }-7-cyclopentyloxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methylamino] oxyethyl group }-7-cyclopentyl methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-7-methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-7-cyclopentyloxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-7-cyclopentyl methoxyl group quinazoline,
(R)-and the 4-[(1-phenylethyl) amino]-6-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-7-cyclopentyloxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-6-methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-6-cyclobutoxy group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-6-cyclopentyloxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-6-cyclo propyl methoxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-6-cyclopentyl methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methylamino] oxyethyl group }-6-methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methylamino] oxyethyl group }-6-cyclopentyloxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methylamino] oxyethyl group }-6-cyclopentyl methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-6-methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-6-cyclopentyloxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-6-cyclopentyl methoxyl group quinazoline, and
(R)-and the 4-[(1-phenylethyl) amino]-7-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-6-cyclopentyloxy quinazoline,
Its tautomer, steric isomer and salt.
Most preferred compound of Formula I is following compound, wherein:
R aRepresent 1-phenylethyl, 3-bromophenyl or 3-chloro-4-fluorophenyl,
R bRepresent R 3-(CH 2) m-O base, wherein
R 3Representative reaches through one or two methyl substituted 2-oxo morpholine-4-base
M represents 2 or 3 number, and
R cRepresentation methoxy, cyclobutoxy group, cyclopentyloxy, cyclo propyl methoxy, tetrahydrofuran (THF)-3-base oxygen base or tetrahydrofuran (THF) ylmethoxy,
Condition is except the following compounds:
The 4-[(3-bromophenyl) amino]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
The 4-[(3-bromophenyl) amino]-6-[2-(3-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
The 4-[(3-bromophenyl) amino]-6-[2-(5,5-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
4-[(3-ammonia-4-fluorophenyl) amino]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-cyclobutoxy group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-cyclo propyl methoxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-7-methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-cyclopentyloxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-7-cyclopentyloxy quinazoline, and
(R)-and the 4-[(1-phenylethyl) amino]-6-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-7-cyclopentyloxy quinazoline,
Its tautomer, steric isomer and salt.
Most preferred compound of Formula I is following compound, wherein
R aRepresent 3-chloro-4-fluorophenyl,
R bRepresent cyclopentyloxy, cyclo propyl methoxy, cyclopentyl methoxyl group, tetrahydrofuran (THF)-3-base oxygen base or tetrahydrofuran (THF) ylmethoxy, and
R cRepresent R 3-(CH 2) m-O base, wherein
R 3Representative reaches through one or two methyl substituted 2-oxo morpholine-4-base
It is several 2 that m represents,
Condition is except the following compounds:
4-[(3-chloro-4-fluorophenyl) amino]-6-cyclopentyloxy-7-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group] quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-6-cyclopentyloxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-7-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-6-cyclo propyl methoxy quinazoline, and
4-[(3-chloro-4-fluorophenyl) amino]-7-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-6-cyclopentyl methoxyl group quinazoline,
Its tautomer, upright this isomer and salt.
Following compound of giving an example is a most preferred compound:
(1) amino 4-[(3-chloro-4-fluorophenyl)]-6-cyclopentyl methoxyl group-7-[2-(2,2-dimethyl-6-oxo morpholine-4-yl) oxyethyl group] quinazoline,
(2) amino 4-[(3-chloro-4-fluorophenyl)]-6-cyclopentyloxy-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methylamino] oxyethyl group } quinazoline,
(3) amino 4-[(3-chloro-4-fluorophenyl)]-6-cyclo propyl methoxy-7-[2-(2,2-dimethyl-6-oxo morpholine-4-yl) oxyethyl group] quinazoline,
(4) amino 4-[(3-chloro-4-fluorophenyl)]-7-cyclobutoxy group-6-[3-(2,2-dimethyl-6-oxo morpholine-4-yl) propoxy-] quinazoline,
(5) amino 4-[(3-chloro-4-fluorophenyl)]-7-cyclo propyl methoxy-6-[3-(2,2-dimethyl-6-oxo morpholine-4-yl) propoxy-] quinazoline,
(6) amino 4-[(3-chloro-4-fluorophenyl)]-6-cyclo propyl methoxy-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methylamino] oxyethyl group } quinazoline,
(7) amino 4-[(3-bromophenyl)]-6-[2-((S)-6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
(8) amino 4-[(3-bromophenyl)]-6-[2-((R)-6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
(9) amino 4-[(3-chloro-4-fluorophenyl)]-6-[2-((R)-6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
(10) amino 4-[(3-chloro-4-fluorophenyl)]-6-[3-((R)-6-methyl-2-oxo morpholine-4-yl) propoxy-]-7-methoxyl group quinazoline,
(11) 4-[(R)-1-(phenylethyl) amino]-6-[3-((S)-6-methyl-2-oxo morpholine-4-yl) propoxy-]-7-methoxyl group quinazoline,
(12) 4-[(R)-1-(phenylethyl) amino]-6-[2-((S)-6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline, and
(13) amino 4-[(3-chloro-4-fluorophenyl)]-6-[2-((S)-6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
Its tautomer, steric isomer and salt.
Compound of Formula I can be prepared by following method, for example:
A) make down general formula compound:
Figure C0181463500171
Wherein
R aDefinition as described above,
R b' or R cOne of ' base representation methoxy, cyclobutoxy group, cyclopentyloxy, cyclo propyl methoxy, cyclobutyl methoxy base or cyclopentyl methoxyl group, and R b' or R cAnother base of ' base is represented Z 1-(CH 2) m-O base, wherein
M defines as described above, and
Z 1Represent leaving group such as halogen atom or sulfonyloxy such as chlorine or bromine atom, mesyloxy or right-tosyloxy,
React with following general formula compound:
H-R 3 (III)
Wherein
R 3Definition as described above.
Reaction is chosen wantonly at solvent or solvent mixture such as methylene dichloride, acetonitrile, dimethyl formamide, dimethyl sulfoxide (DMSO), tetramethylene sulfone, benzene, toluene, chlorobenzene, tetrahydrofuran (THF), benzene/tetrahydrofuran (THF) Huo diox, should be in the presence of uncle's organic bases such as triethylamine or N-ethyl diisopropylamine (and these organic basess can simultaneously as solvent) or in the presence of mineral alkali such as yellow soda ash or salt of wormwood, be desirably in-20 to 200 ℃ temperature, preferably under 0 to 150 ℃ temperature, carry out.
B) make and choose the following general formula compound cyclisation that in reaction mixture, forms wantonly:
Figure C0181463500172
Wherein
R aDefinition as described above,
R b" or R c" one of base representation methoxy, cyclobutoxy group, cyclopentyloxy, cyclo propyl methoxy, cyclobutyl methoxy base or cyclopentyl methoxyl group, and R b" or R c" another base of base is represented R 3'-(CH 2) m-O base, wherein
M defines as described above, and
R 3The R that ' representative replaces through 1 or 2 methyl or ethyl on methylene radical 4-O-CO-CH 2-N-CH 2CH 2-OH base, wherein
R 4Represent hydrogen atom or C 1-4-alkyl.
Reaction is chosen wantonly at solvent or solvent mixture such as methylene dichloride, acetonitrile, dimethyl formamide, dimethyl sulfoxide (DMSO), tetramethylene sulfone, benzene, toluene, chlorobenzene, tetrahydrofuran (THF), in benzene/tetrahydrofuran (THF) Huo diox, should be at anhydrous acid such as trifluoroacetic acid, methylsulfonic acid or sulfuric acid exist down, or at dewatering agent such as isobutyl chlorocarbonate, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, Vanadium Pentoxide in FLAKES, N, N '-dicyclohexyl carbon imide, N, N '-dicyclohexyl carbon imide/N-hydroxy-succinamide or I-hydroxybenzotriazole, N, N-carbonyl dimidazoles or triphenyl phosphine/tetracol phenixin exists down,-20 to 200 ℃ temperature, preferably under-10 to 160 ℃ temperature, carry out.
In the previous reaction, any reactive group of existence such as hydroxyl, carboxyl or imino-can be during reaction through reacting after the general protecting group protection of fracture.
For example, hydroxyl protecting group can be trimethyl silyl, ethanoyl, benzoyl, methyl, ethyl, the tertiary butyl, trimethylphenyl, benzyl or THP trtrahydropyranyl,
Carboxyl-protecting group can be trimethyl silyl, methyl, ethyl, the tertiary butyl, benzyl or THP trtrahydropyranyl, and
The imino-protecting group can be formyl radical, ethanoyl, trifluoroacetyl group, ethoxycarbonyl, tertbutyloxycarbonyl, carbobenzoxy-(Cbz), benzyl, methoxybenzyl or 2,4-diethoxy benzyl.
Used any protecting group is optional subsequently by for example in water-containing solvent such as water, isopropanol, acetic acid/water, tetrahydrofuran (THF)/water Huo diox/water; acid as trifluoroacetic acid, hydrochloric acid or sulfuric acid in the presence of or in the presence of alkali metal base such as sodium hydroxide or potassium hydroxide; or proton inertia ground is as in the presence of the iodine trimethyl silane; 0 to 120 ℃ temperature, preferably hydrolysis and rupturing under 10 to 100 ℃ temperature.
Yet, benzyl, methoxy-benzyl or carbobenzoxy-(Cbz) by for example in the presence of catalyzer such as the palladium/carbon in suitable solvent such as methyl alcohol, ethanol, ethyl acetate or Glacial acetic acid, the sour example hydrochloric acid of optional interpolation, temperature at 0 to 100 ℃, preferably 20 to 60 ℃ room temperature,, preferably under 3 to 5 crust hydrogen-pressure, rupture at 1 to 7 crust with hydrogen with hydrogen hydrogenation.But 2, the 4-dimethoxy-benzyl is preferable over fracture in the presence of methyl-phenoxide in the trifluoroacetic acid.
The tertiary butyl or tertbutyloxycarbonyl preferably by with acid as trifluoroacetic acid or salt acid treatment or with the iodine trimethyl silane, choose wantonly in solvent such as methylene dichloride, diox, methyl alcohol or ether, to handle and rupture.
Trifluoroacetyl group is preferably chosen in the presence of solvent such as acetate in 50 to 120 ℃ Temperature Treatment wantonly with sour example hydrochloric acid, or uses sodium hydroxide solution, chooses wantonly in the presence of solvent such as tetrahydrofuran (THF) 0 to 50 ℃ Temperature Treatment and ruptures.
Moreover gained formula I compound can resolve to its enantiomer and/or diastereomer, as described above.Therefore, for example the cis/trans mixture can resolve to its cis and trans-isomer(ide), and the compound with at least one optically active carbon is separable into its enantiomer.
Therefore, for example the cis/trans mixture can resolve to its cis and trans-isomer(ide) by chromatogram, the formula I compound that exists with racemic modification that obtains can separate (with reference to " stereochemistry introduction " (Topics in stereochemisery) of AllingerN.L. and Eliel E.L. by currently known methods own, the 6th volume, WileyInterscience, 1971), obtaining its optically active enantiomorph and have the formula I compound of at least 2 unsymmetrical carbons can be according to the currently known methods of its physical chemistry difference use own as resolving to its diastereomer with chromatogram and/or fractional crystallization, and if these compounds obtain with racemic modification, then it can resolve to above-mentioned enantiomer subsequently.
Enantiomer is preferably separated or is separated with the fit reaction of racemization (especially acid and activated derivatives thereof or alcohol) from the optically-active solvent recrystallization or with the optical rotatory substance that can form salt or derivative such as ester or acid amides with the post of chirality phase, and according to the separating obtained salt of dissolubility difference or the non-enantiomer mixture of derivative, and free enantiomorph can separate with suitable reagent effect from pure diastereo-isomerism salt or derivative.Habitual optically-active acid is tartrate or dibenzoyl tartaric acid, two-neighbour-tolyl tartrate, oxysuccinic acid, amygdalic acid, camphorsulfonic acid, L-glutamic acid, aspartic acid or the quinic acid of for example D-and L-type.Optically-active alcohols for example can be the optically-active acyl group of (+) or (-)-menthol and acid amides and for example can be (+)-or (-)-menthyl oxygen base carbonyl.
Moreover formula I compound can change into its salt, especially changes into and inorganic or organic acid physiologically acceptable salt with regard to pharmaceutical use.This purpose available acid comprises for example hydrochloric acid, Hydrogen bromide, sulfuric acid, methylsulfonic acid, phosphoric acid, formic acid, succsinic acid, lactic acid, citric acid, tartrate or toxilic acid.
In addition, if when the new compound of gained formula I contains carboxyl, hydroxyl phosphoryl, sulfo group or 5-tetrazyl,, especially during pharmaceutical use, change into its physiologically acceptable salt if need available subsequently inorganic or organic bases to change into its salt.With regard to the suitable alkali of this purpose, comprise for example sodium hydroxide, potassium hydroxide, spermine acid, cyclo-hexylamine, thanomin, diethanolamine and trolamine.
Some is that the known or available document currently known methods of document obtains (referring to example I to XIV) as formula II to the IV compound of initiator.
Address as the front, formula I compound of the present invention and physiologically acceptable salt thereof have valuable pharmacological character, especially to the inhibition effect of the signal conduction of EGF-R ELISA (EGF-R) mediation, simultaneously its available for example suppress ligand in conjunction with, receptor dimerization closes or Tyrosine kinases itself and reaching.Also may block signal is passed to and is positioned at the more composition in downstream.
The biological property research of compounds of the present invention is as follows:
The signal conduction restraining effect of EGF-R-mediation can be proved with for example expressing human EGF-R and its survival and the propagation cell relevant with EGF or TGF-α hormesis.Use through genetic modification to the relevant mouse source cell system of the white element-3-of Jie (IL-3) of the human EGF-R of expressive function herein.Be called F/L-HERc these cell proliferations can with mouse IL-3 or with EGF stimulate (referring to von Ruden, people such as T., EMBO J. 7, 2749-2756 (1998) and Pierce, people such as J.H., Science 239, 628-631 (1998)).
The initiator that is used for the F/L-HERc cell is clone FDC-P 1, its manufacturing has been described in Dexter, people such as T.M., J.Exp.Med. 152, 1036-1047 (1980).Yet another kind of mode also can use other somatomedin relevant cells (referring to for example Pierce, people such as J.H., Science 239, 628-631 (1988), Shibuya, people such as H., Cell 70, 57-67 (1992) and Alexander, people such as W.S., EMBO J. 10, 3683-3691 (1991)).With regard to expressing human EGF-R cDNA (referring to Ullrich, people such as A., Nature 309, 418-425 (1984)), as von Ruden, people such as T., EMBO J. 7, the described use recombinant retrovirus of 2749-2756 (1988), but retroviral vector LXSN (referring to Miller, people such as A.D., BioTechniques 7, 980-990 (1989)) be used in express EGF-R cDNA and use GP+E86 system as packing cell (referring to Markowitz, people such as D., J.Virol. 62, 1120-1124 (1988)).
Test following carrying out:
The F/L-HERc cell in the RPMI/1640 substratum (BioWhittaker) that is supplemented with the human EGF of 10% foetal calf serum (FCS, Boehringer Mannbeim), 2mM glutamine (BioWhittaker), standard antibiotic and 20 nanograms/milliliter (Promega) at 37 ℃ and 5%CO 2The following cultivation.In order to test the inhibition activity of The compounds of this invention, every cave 1.5 * 10 4Cultivate in 96 orifice plates of cell in above-mentioned substratum (200 microlitre), triplicate, stimulate cellular proliferation with EGF (20 nanograms/milliliter) or mouse IL-3.Used IL-3 from the culture supernatant of clone X63/0mIL-3 obtain (referring to Karasuyama, people such as H., Eur.J.Immunol. 18, 97-104 (1988)).The compounds of this invention is dissolved in 100% dimethyl sulfoxide (DMSO) (DMSO) and makes an addition in the substratum with various extent of dilution, and maximum DMSO concentration is 1%.Substratum was cultivated 48 hours at 37 ℃.
In order to measure the inhibition activity of The compounds of this invention, use cell titrator 96 TMMoisture non-radioactive cell proliferation analysis (Promega) is measured relative cell count with O.D. unit.Relative cell count of percentage calculation and the active material concentration (IC when it releases inhibition cell proliferation 50% with control group (the F/LHERc cell of unrestraint agent) 50).Obtain following result:
Compound (embodiment numbering) The inhibited proliferation IC that EGF-is relevant 50[nM]
1 59
I(1) 29
1(2) 29
2(1) 36
Formula I compound of the present invention thereby can suppress by the conduction of the kinase whose signal of Tyrosine proves as the embodiment of human EGF acceptor, therefore can be in order to treat the pathologic process that causes because of the superfunction of Tyrosine kinases.These are for example optimum or malignant tumour, especially the abnormality proliferation of tumour, metastases and the vascular endotheliocyte in epidermis and neural epidermis source (blood vessel is superfluous gives birth to).
The compounds of this invention also can be used for preventing and treats because of the Tyrosine kinases stimulates causing that mucus produces and increasing or change air flue and the lung disease that causes, as air flue inflammatory disease for example chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergy or non-allergic rhinitis or sinusitis paranasal sinusitis, tumour fibrosis, alpha1-antitrypsin deficiency or cough, pulmonary emphysema, pnemnofibrosis and air flue allergy.
This compound also is applicable to that treatment destroys gi tract and biliary tract and the gallbladder disease that causes because of the Tyrosine kinase activity, as be found in the chronic inflammation change as cholecystitis, the Ke Longshi disease, colonic ulcer, and gastrointestinal ulceration maybe can betide because of increasing the gastrointestinal tract disease that secretion causes, as Menetrier ' s disease, secretion adenoma and protein loss syndrome, also can be used for treating the pipe intestinal polyp in nasal polyp and various sources, as the fine hair and the gland polyp of large intestine, but also can be familial polyposis, the syndromic polyp intestinal of Ge Dengna, the whole pipe intestinal polyp of Pu Zi-Jie He Cotard, the inflammatory pseudopolyp, juvenile polyp, dark artery of colon capsule and intestines airsac disease.
In addition, formula I compound and physiologically acceptable salt thereof can be used for treating the kidney disease, especially the tumour of tumour kidney changes, be used for the treatment of and can be the special renal cyst of sending out the property source or in syndrome, taking place, disease that causes because of Tyrosine kinases abnormal function as tubercle sclerosis, von Hippel-Lindau syndrome, glomerule ephritis and sponge kidney and other such as epidermis hyperplasia (psoriasis), inflammatory process, disease of immune system, hematopoietic cell hyper-proliferative etc.
Based on its biological property, The compounds of this invention can itself use or be used in combination with other pharmaceutically active compounds, for example be used for oncotherapy, monotherapy or be used in combination with other anti-tumor therapeutic agents is for example with topology isomerase inhibitors (as according to dragging plug (etoposide)), mitotic inhibitor (as Bin Puliesiting (vinblastine)), can with the interactional compound of Nucleotide (as Platinol (cisplatin)), endoxan, pacify big mycin (adriamycin)), hormone antagonist (as Tan Moxifen (tamoxifen)), metabolic process inhibitor (as 5-FU etc.), cytokine (as Interferon, rabbit), combined therapies such as antibody.With regard to the treatment respiratory tract disease, these compounds can itself use or be used in combination with other air flue therapeutical agents, as have the material of secretion inhibitor, inhibition segmental bronchus and/or antiphlogistic activity.With regard to the disease of treatment gastrointestinal region, these compounds can use own also can with reactivity or secretion are had the material of effect or use with the anti-inflammatory combinations of substances.These medicinal composition can while or administration in regular turn.
These compounds can itself or with other active substance combination with path in intravenously, subcutaneous, intramuscular, intraperitoneal or the nose, suction or through skin or oral administration medicine supplying, and aerosol preparations is particularly useful for sucking.
With regard to pharmaceutical use, The compounds of this invention generally is used for warm-blooded vertebrate, and especially human, dosage is 0.01-100 milligram/kg body weight, preferred 0.1-15 milligram/kilogram.With regard to administration, can allocate with one or more general inert support and/or thinner, as with W-Gum, lactose, glucose, Microcrystalline Cellulose, Magnesium Stearate, polyvinylpyrrolidone, citric acid, tartrate, water, water/ethanol, water/glycerine, water/Sorbitol Powder, water/polyoxyethylene glycol, propylene glycol, stearyl alcohol, carboxymethyl cellulose or fatty substance such as stearic fat or its suitable mixture, be deployed into general galenical, as plain sheet or coating tablet, capsule, pulvis, suspension agent, solution, syrup or suppository.
The following example in order to the explanation the present invention and not in order to the restriction the present invention.
The initial compounds preparation:
Example I
4-[(3-chloro-4-fluorophenyl) amino]-6-cyclopentyl methoxyl group-7-(2-bromine oxethyl) quinazoline
4.84 gram salt of wormwood is added into 3.50 gram 4-[(3-chloro-4-fluorophenyls) amino]-40 milliliters of N of 6-cyclopentyl methoxyl group-7-hydroxyl quinazoline and 6.89 milliliters of glycol dibromides, in the dinethylformamide solution.Reaction mixture stirred 1.5 hours in nitrogen at 80 ℃.After being cooled to room temperature, filter reaction mixture and filtrate vacuum-evaporation.The brown residue of oiliness cools off in ice bath and with the small amount of methanol development, crystallization goes out yellow solid.The suction filtration throw out is with cooling methanol wash and dry in vacuum drier.
Output: 2.60 grams (theoretical value 58%),
R fValue: 0.82 (silica gel, methylene chloride=9: 1),
Mass spectrum (ESI +): m/z=494,496,498[M+H] +
Be similar to example I and prepare following compounds:
(1) amino 4-[(3-chloro-4-fluorophenyl)]-6-cyclo propyl methoxy-7-(2-bromine oxethyl) quinazoline (be reflected in the acetonitrile solvent and carry out),
R fValue: 0.72 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1),
Mass spectrum (ESI -): m/z=464,466,468[M-H] -
(2) amino 4-[(3-chloro-4-fluorophenyl)]-6-cyclopentyloxy-7-(2-bromine oxethyl) quinazoline,
R fValue: 0.65 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1),
Mass spectrum (ESI -): m/z=478,480,482[M-H] -
(3) amino 4-[(3-chloro-4-fluorophenyl)]-7-cyclobutoxy group-6-(3-bromine propoxy-) quinazoline (be reflected in the acetonitrile solvent and carry out),
R fValue: 0.62 (silica gel, methylene chloride=9: 1),
Mass spectrum (ESI -): m/z=478,480,482[M-H] -
(4) amino 4-[(3-chloro-4-fluorophenyl)]-7-cyclo propyl methoxy-6-(3-bromine propoxy-) quinazoline (be reflected in the acetonitrile solvent and carry out),
R fValue: 0.74 (silica gel, methylene chloride=9: 1),
Mass spectrum (ESI -): m/z=478,480,482[M-H] -
(5) amino 4-[(3-bromophenyl)]-6-(2-bromine oxethyl)-7-methoxyl group quinazoline,
Fusing point: 244 ℃
Mass spectrum (ESI +): m/z=452,454,456[M+H] +
(6) amino 4-[(R)-(1-phenylethyl)]-6-(3-bromine propoxy-)-7-methoxyl group quinazoline (reaction is carried out as alkali with potassium tert.-butoxide),
R fValue: 0.60 (silica gel, ethyl acetate/methanol=9: 1).
(7) amino 4-[(R)-(1-phenylethyl)]-6-(2-bromine oxethyl)-7-methoxyl group quinazoline (reaction is carried out as alkali with potassium tert.-butoxide),
Fusing point: 255 ℃
Mass spectrum (ESI +): m/z=402,404[M+H] +
(8) amino 4-[(3-chloro-4-fluorophenyl)]-6-(3-hydroxyl propoxy-)-7-cyclobutoxy group quinazoline,
R fValue: 0.50 (silica gel, methylene chloride=90: 10),
Mass spectrum (ESI +): m/z=418,420[M+H] +
(9) amino 4-[(3-chloro-4-fluorophenyl)]-6-(3-hydroxyl propoxy-)-7-cyclo propyl methoxy quinazoline,
R fValue: 0.21 (silica gel, methylene chloride=95: 5),
Mass spectrum (ESI +): m/z=418,420[M+H] +
(10) amino 4-[(3-chloro-4-fluorophenyl)]-6-(2-bromine oxethyl)-7-cyclopentyloxy quinazoline,
R fValue: 0.67 (silica gel, methylene chloride=90: 10),
Mass spectrum (ESI +): m/z=480,482,484[M+H] +
(11) amino 4-[(3-chloro-4-fluorophenyl)]-6-(2-bromine oxethyl)-7-cyclo propyl methoxy quinazoline,
R fValue: 0.68 (silica gel, methylene chloride=90: 10),
Mass spectrum (ESI +): m/z=466,468,470[M+H] +
(12) amino 4-[(3-chloro-4-fluorophenyl)]-6-cyclo propyl methoxy-7-(3-hydroxyl propoxy-) quinazoline,
R fValue: 0.53 (silica gel, methylene chloride=90: 10),
Mass spectrum (ESI +): m/z=418,420[M+H] +
(13) amino 4-[(3-chloro-4-fluorophenyl)]-6-(4-hydroxyl butoxy)-7-cyclopentyloxy quinazoline,
R fValue: 0.46 (silica gel, ethyl acetate).
(14) amino 4-[(3-chloro-4-fluorophenyl)]-6-(2-bromine oxethyl)-7-((R)-(tetrahydrofuran (THF)-3-base oxygen base) quinazoline,
R fValue: 0.37 (silica gel, methylene chloride=9: 1),
Mass spectrum (ESI -): m/z=480,482,484[M-H] -
(15) amino 4-[(3-chloro-4-fluorophenyl)]-6-(2-bromine oxethyl)-7-[(R)-(tetrahydrofuran (THF)-2-yl) methoxyl group] quinazoline,
Mass spectrum (ESI -): m/z=494,496,498[M-H] -
(16) amino 4-[(3-chloro-4-fluorophenyl)]-7-(2-bromine oxethyl)-6-[(S)-(tetrahydrofuran (THF)-2-yl) methoxyl group] quinazoline,
Mass spectrum (ESI -): m/z=494,496,498[M-H] -
Example II
4-[(3-chloro-4-fluorophenyl) amino]-6-cyclopentyl methoxyl group-7-hydroxyl quinazoline
4.99 amino gram 4-[(3-chloro-4-fluorophenyl)]-6-cyclopentyl methoxyl group-7-methyl carbonyl oxygen base quinazoline is suspended in 80 ml methanol and 1.80 milliliters of concentrated ammonia solutions of interpolation.Reaction mixture is in stirred overnight at room temperature.After the termination, reaction mixture dilutes with 500 milliliters of methylene dichloride, with water and saturated nacl aqueous solution washing, with dried over mgso and evaporation concentration.Obtain 4.30 gram brown solids.Crude product stirs in t-butyl methyl ether, and suction filtration is with a small amount of t-butyl methyl ether washing and in room temperature vacuum-drying.
Output: 3.59 grams (theoretical amount 80%),
R fValue: 0.48 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1),
Mass spectrum (ESI +): m/z=388,340[M+H] +
Similar embodiment II prepares following compounds:
(1) amino 4-[(3-chloro-4-fluorophenyl)]-6-cyclo propyl methoxy-7-hydroxyl quinazoline,
R fValue: 0.56 (silica gel, methylene chloride=9: 1),
Mass spectrum (ESI -): m/z=358,360[M-H] -
(2) amino 4-[(3-chloro-4-fluorophenyl)]-6-cyclopentyloxy-7-hydroxyl quinazoline,
R fValue: 0.53 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1),
Mass spectrum (ESI +): m/z=374,376[M+H] +
(3) amino 6-benzyloxy-4-[(3-chloro-4-fluorophenyl)]-7-hydroxyl quinazoline,
R fValue: 0.54 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1),
Mass spectrum (ESI +): m/z=396,398[M+H] +
(4) amino 4-[(3-bromophenyl)]-6-hydroxyl-7-methoxyl group quinazoline (reaction is carried out in alcohol solvent with sodium hydroxide solution),
R fValue: 0.23 (silica gel, ethyl acetate),
Mass spectrum (ESI +): m/z=346,348[M+H] +
(5) amino 4-[(3-chloro-4-fluorophenyl)]-7-hydroxyl-6-((S)-tetrahydrofuran (THF)-3-base oxygen base) quinazoline,
R fValue: 0.57 (silica gel, methylene chloride=9: 1),
Mass spectrum (ESI +): m/z=376,378[M+H] +
(6) amino 4-[(3-chloro-4-fluorophenyl)]-methoxyl group of 7-hydroxyl-6-[(S)-(tetrahydrofuran (THF)-2-yl)] quinazoline,
R fValue: 0.42 (silica gel, methylene chloride=9: 1).
EXAMPLE III
4-[(3-chloro-4-fluorophenyl) amino]-6-cyclopentyl methoxyl group-7-methyl carbonyl oxygen base quinazoline
4.03 gram 4-chloro-6-cyclopentyl methoxyl group-7-methyl carbonyl oxygen base quinazoline is suspended in 70 milliliters of Virahols and adds 1.95 gram 3-chloro-4-fluoroanilines.Reaction mixture refluxed in nitrogen 2 hours.After being cooled to room temperature, the formed light color precipitation of suction filtration is with a small amount of washed with isopropyl alcohol and in air drying.
Output: 4.99 grams (theoretical amount 92%),
R fValue: 0.80 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1),
Mass spectrum (ESI +): m/z=430,432[M+H] +
Similar embodiment III prepares following compounds:
(1) amino 4-[(3-chloro-4-fluorophenyl)]-6-cyclo propyl methoxy-7-methyl carbonyl oxygen base quinazoline,
R fValue: 0.86 (silica gel, methylene chloride=9: 1),
Mass spectrum (ESI +): m/z=402,404[M+H] +
(2) amino 4-[(3-chloro-4-fluorophenyl)]-6-cyclopentyloxy-7-methyl carbonyl oxygen base quinazoline,
R fValue: 0.73 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1),
Mass spectrum (ESI +): m/z=416,418[M+H] +
(3) amino 6-benzyloxy-4-[(3-chloro-4-fluorophenyl)]-7-methyl carbonyl oxygen base quinazoline,
R fValue: 0.76 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1),
Mass spectrum (ESI +): m/z=438,440[M+H] +
(4) amino 4-[(3-bromophenyl)]-6-methyl carbonyl oxygen base-7-methoxyl group quinazoline,
R fValue: 0.50 (silica gel, ethyl acetate),
Mass spectrum (ESI +): m/z=388,390[M[+H] +
(5) amino 4-[(R)-(1-phenylethyl)]-6-hydroxyl-7-methoxyl group quinazoline (the acetoxyl group protecting group ruptures under reaction conditions),
R fValue: 0.46 (silica gel, ethyl acetate),
Mass spectrum (ESI +): m/z=296[M+H] +
(6) amino 6-benzyloxy-4-[(3-chloro-4-fluorophenyl)]-7-cyclopentyloxy quinazoline (adding pyridine) as auxiliary alkali,
R fValue: 0.51 (silica gel, methylene chloride=95: 5).
Mass spectrum (ESI +): m/z=464,466[M+H] +
(7) amino 4-[(3-chloro-4-fluorophenyl)]-7-methyl carbonyl oxygen base-6-((S)-tetrahydrofuran (THF)-3-base oxygen base) quinazoline,
R fValue: 0.67 (silica gel, methylene chloride=9: 1),
Mass spectrum (ESI -): m/z=416,418[M-H] -
(8) amino 4-[(3-chloro-4-fluorophenyl)]-methoxyl group of 7-methyl carbonyl oxygen base-6-[(S)-(tetrahydrofuran (THF)-2-yl)] the quinazoline hydrochloride,
Fusing point: 274-276 ℃,
Mass spectrum (ESI +): m/z=432,434[M+H] +
EXAMPLE IV
4-chloro-6-cyclopentyl methoxyl group-7-methyl carbonyl oxygen base quinazoline
3.80 gram 4-hydroxyl-6-cyclopentyl methoxyl group-7-methyl carbonyl oxygen base quinazoline is suspended in 90 milliliters of thionyl chloride and is heated to boiling in nitrogen.Add 4 N, behind the dinethylformamide, reaction mixture refluxed 2 hours again.After being cooled to room temperature, in jet of water vacuumizes, steaming and remove excessive thionyl chloride.Brown residue stirs with 30 milliliters of toluene.Steaming desolventizes and stays 4.30 gram taupe brown solids, its not purified and further reaction.
R fValue: 0.89 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1).
Similar embodiment IV prepares following compounds:
(1) 4-chloro-6-cyclo propyl methoxy-7-methyl carbonyl oxygen base quinazoline,
R fValue: 0.84 (silica gel, methylene chloride=9: 1).
(2) 4-chloro-6-cyclopentyloxy-7-methyl carbonyl oxygen base quinazoline,
R fValue: 0.69 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1).
(3) 6-benzyloxy-4-chloro-7-methyl carbonyl oxygen base quinazoline,
R fValue: 0.77 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1).
(4) 6-benzyloxy-4-chloro-7-cyclopentyloxy quinazoline,
R fValue: 0.91 (silica gel, methylene chloride=9: 1).
(5) 4-chloro-7-methyl carbonyl oxygen base-6-((S)-tetrahydrofuran (THF)-3-base oxygen base) quinazoline,
R fValue: 0.83 (silica gel, ethyl acetate/methanol=9: 1).
(6) methoxyl group of 4-chloro-7-methyl carbonyl oxygen base-6-[(S)-(tetrahydrofuran (THF)-2-yl)] quinazoline,
R fValue: 0.48 (silica gel, cyclohexane/ethyl acetate=1: 1).
EXAMPLE V
4-hydroxyl-6-cyclopentyl methoxyl group-7-methyl carbonyl oxygen base quinazoline
4.30 restrain 4,100 milliliters of pyridine solutions of 7-dihydroxyl-6-cyclopentyl methoxyl group quinazoline are heated to 80 ℃ in nitrogen.In burgundy suspension, add 1.80 ml acetic anhydride.Reaction mixture stirred 3 hours at 80 ℃, during form whole solution.After being cooled to room temperature, reaction mixture is to about 800 milliliters of frozen water.The precipitation that suction filtration forms reaches with the water thorough washing.The light gray solid is dry in vacuum drier.
Output: 3.82 grams (theoretical amount 77%),
R fValue: 0.49 (silica gel, methylene chloride=9: 1),
Mass spectrum (ESI -): m/z=301[M-H] -
Similar embodiment V prepares following compounds:
(1) 4-hydroxyl-6-cyclo propyl methoxy-7-methyl carbonyl oxygen base quinazoline
R fValue: 0.53 (silica gel, methylene chloride=9: 1),
Mass spectrum (ESI -): m/z=273[M-H] -
(2) 4-hydroxyl-6-cyclopentyloxy-7-methyl carbonyl oxygen base quinazoline
Fusing point: 209-212 ℃,
Mass spectrum (ESI -): m/z=287[M-H] -
(3) 6-benzyloxy-4-hydroxyl-7-methyl carbonyl oxygen base quinazoline
R fValue: 0.48 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1),
Mass spectrum (ESI -): m/z=309[M-H] -
(4) 4-hydroxyl-7-methyl carbonyl oxygen base-6-((S)-tetrahydrofuran (THF)-3-base oxygen base) quinazoline
R fValue: 0.62 (anti-phase ready-formed TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50: 50: 1),
Mass spectrum (ESI +): m/z=291[M+H] +
(5) methoxyl group of 4-hydroxyl-7-methyl carbonyl oxygen base-6-[(S)-(tetrahydrofuran (THF)-2-yl)] quinazoline,
R fValue: 0.50 (silica gel, methylene chloride=9: 1),
Mass spectrum (ESI +): m/z=305[M+H] +
Example VI
4,7-dihydroxyl-6-cyclopentyl methoxyl group quinazoline
5.76 gram 2-amino-5-cyclopentyl methoxyl group-4-hydroxy-benzoic acid and 6.52 gram formamidine acetates refluxed about 3 hours in 140 milliliters of ethanol.After the termination, reaction mixture is evaporated to about 100 milliliters and add 300 milliliters of frozen water, forms gray precipitate.The suction filtration throw out is with water washing and dry in vacuum drier.
Output: 4.57 grams (theoretical amount 77%),
R fValue: 0.25 (silica gel, methylene chloride=95: 5),
Mass spectrum (ESI -): m/z=259[M-H] -
Similar embodiment VI prepares following compounds:
(1) 4,7-dihydroxyl-6-cyclo propyl methoxy quinazoline
R fValue: 0.45 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1),
Mass spectrum (ESI -): m/z=231[M-H] -
(2) 4,7-dihydroxyl-6-cyclopentyloxy quinazoline
R fValue: 0.42 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1),
Mass spectrum (EI): m/z=246[M] +
(3) 6-benzyloxy-4,7-dihydroxyl quinazoline
R fValue: 0.44 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1),
Mass spectrum (ESI -): m/z=267[M-H] -
(4) 6-benzyloxy-7-cyclopentyloxy-4-hydroxyl quinazoline
Fusing point: 221-223 ℃
Mass spectrum (ESI +): m/z=337[M+H] +
(5) 4,7-dihydroxyl-6-((S)-tetrahydrofuran (THF)-3-base oxygen base) quinazoline
R fValue: 0.69 (anti-phase ready-formed TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50: 50: 1),
Mass spectrum (ESI -): m/z=247[M-H] -
The methoxyl group of (6) 4,7-dihydroxyl-6-[(S)-(tetrahydrofuran (THF)-2-yl)] quinazoline,
R fValue: 0.56 (silica gel, methylene chloride=9: 1),
Mass spectrum (ESI-): m/z=261[M-H] -
Example VII A
2-amino-5-cyclopentyl methoxyl group-4-hydroxy-benzoic acid
6.50 gram 5-cyclopentyl methoxyl group-4-hydroxyl-2-nitrobenzoic acid is dissolved in 130 ml methanol, add 2.00 gram Buddhist nun Ruan nickel, and mixture consumes at about 3 hours hydrogen until calculated amount of about room temperature hydrogenation under the 50psi hydrogen-pressure.Filtration catalizer reaches and washs with hot methanol.Vacuum-evaporation filtrate.Stay brown solid, its not purified and further reaction.
Output: 5.79 grams (theoretical amount 100%),
R fValue: 0.67 (silica gel, methylene chloride=9: 1),
Mass spectrum (ESI -): m/z=250[M-H] -
Similar embodiment VII prepares following compounds:
(1) 2-amino-5-cyclo propyl methoxy-4-hydroxy-benzoic acid
R fValue: 0.51 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1),
Mass spectrum (ESI -): m/z=222[M-H] -
(2) 2-amino-5-ring the eleventh of the twelve Earthly Branches oxygen base-4-hydroxy-benzoic acid
R fValue: 0.38 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1),
Mass spectrum (ESI +): m/z=238[M+H] +
(3) 2-amino-5-benzyloxy-4-hydroxy-benzoic acid
R fValue: 0.52 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1),
Mass spectrum (ESI -): m/z=258[M-H] -
(4) 2-amino-5-benzyloxy-4-cyclopentyloxy phenylformic acid ring pentyl ester (this reacts in 1: 1 methyl alcohol and the tetrahydrofuran compound and carries out)
R fValue: 0.84 (silica gel, ethyl acetate/hexanaphthene=1: 1),
Mass spectrum (ESI +): m/z=396[M+H] +
(5) 2-amino-4-hydroxy-5-((S)-tetrahydrofuran (THF)-3-base oxygen base) phenylformic acid
R fValue: 0.70 (anti-phase ready-formed TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50: 50: 1),
Mass spectrum (ESI -): m/z=238[M-H] -
(6) methoxyl group of 2-amino-4-hydroxy-5-[(S)-(tetrahydrofuran (THF)-2-yl)] phenylformic acid
R fValue: 0.59 (anti-phase ready-formed TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50: 50: 1),
Mass spectrum (ESI -): m/z=252[M-H] -
Example VII A I
5-cyclopentyl methoxyl group-4-hydroxyl-2-nitrobenzoic acid
15.37 restrain 4,5-methylene-dioxy-2-nitrobenzoic acid and 51.84 milliliters of cyclopentyl carbinols are dissolved in reaching in 100 milliliters of dimethyl sulfoxide (DMSO) and cool off under nitrogen in ice bath.Then portion-wise addition 3.90 restrains sodium.Reaction mixture stirs 30 minutes simultaneously with the ice bath cooling, then simply is heated to 35-40 ℃ and subsequently with restir under the ice bath cooling 3 hours.Then remove ice bath and reaction mixture in stirred overnight at room temperature.Red burgundy reaction soln is poured in about 800 milliliters of acetone, formed the burgundy precipitation.The suction filtration throw out with washing with acetone, is dissolved in the 300-400 ml water and transfers to pH about 2 with 60 milliliters of 2N hydrochloric acid.The aqueous solution with dichloromethane extraction for several times.The extraction liquid that merges washs with saturated nacl aqueous solution, with dried over sodium sulfate and evaporation concentration.The burgundy oil residue is dissolved in 800 milliliters of methylene dichloride and through silica gel purification, uses methylene chloride (9: 1) wash-out in the bottle.Obtain brown oil, itself and water stir the crystallization with the ice bath cooling simultaneously.The brown precipitate thing that forms is through suction filtration, with less water washing and dry in vacuum drier.
Output: 9.55 grams (theoretical amount 47%),
R fValue: 0.67 (silica gel, toluene/diox/ethanol/Glacial acetic acid=90: 10: 10: 6),
Mass spectrum (ESI -): m/z=280[M-H] -
Similar embodiment VIII prepares following compounds:
(1) 5-cyclo propyl methoxy-4-hydroxyl-2-nitrobenzoic acid
R fValue: 0.61 (silica gel, toluene/diox/ethanol/Glacial acetic acid=90: 10: 10: 6),
Mass spectrum (ESI -): m/z=252[M-H] -
(2) 5-cyclopentyloxy-4-hydroxyl-2-nitrobenzoic acid
R fValue: 0.62 (silica gel, toluene/diox/ethanol/Glacial acetic acid=90: 10: 10: 6),
Mass spectrum (ESI -): m/z=266[M-H] -
(3) 5-benzyloxy-4-hydroxyl-2-nitrobenzoic acid
Fusing point: 176-178 ℃
Mass spectrum (ESI -): m/z=288[M-H] -
(4) 4-hydroxyl-2-nitro-5-((S)-tetrahydrofuran (THF)-3-base oxygen base) phenylformic acid
R fValue: 0.58 (anti-phase ready-formed TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50: 50: 1),
Mass spectrum (ESI -): m/z=268[M-H] -
(5) methoxyl group of 4-hydroxyl-2-nitro-5-[(S)-(tetrahydrofuran (THF)-2-yl)] phenylformic acid
R fValue: 0.53 (anti-phase ready-formed TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50: 50: 1),
Mass spectrum (ESI -): m/z=282[M-H] -
Example I X
(2-hydroxy-2-methyl third amino) ethyl acetate
100.00 the cooling of gram yellow soda ash is added in 100 milliliters of unsaturated carbonate potassium solutions of 50.00 gram glycine ethyl ester hydrochlorides down.The material that forms with the about 600 milliliters of extracted with diethyl ether of total amount for several times.The ether extraction liquid that merges is with dried over sodium sulfate and be evaporated to dried.Stay 28.60 gram glycine ethyl esters.Mix with 26.00 milliliters of epoxy Trimethylmethanes and 40 milliliters of dehydrated alcohols and in the Roth ball 90 ℃ of heating 6 hours.After being cooled to room temperature, the reaction mixture evaporation concentration stays mobiloil.
Output: 45.80 grams (theoretical amount 73%),
Mass spectrum (ESI +): m/z=176[M+H] +
Embodiment X
4-methylamino dihydrofuran-2-ketone
2.00 25 ml methanol solution of gram 4-(N-benzyl-N-methylamino) dihydrofuran-2-ketone are in 250 milligrams of palladiums (10%, on activated carbon) about 2 hours of hydrogenation under room temperature in the 50psi hydrogen-pressure, until the hydrogen of consumption calculations amount.After the termination reaction, filtration catalizer and filtrate are evaporated in vacuum.Stay water white oil, its not purified directly further reaction.
Output: 1.20 grams,
R fValue: 0.13 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=116[M+H] +
Embodiment XI
4-(N-benzyl-N-methylamino) dihydrofuran-2-ketone
23.20 milliliter N-methyl-benzyl amine is added in 150 milliliters of dichloromethane solutions of 15.00 gram 5H-furans-2-ketone.Reaction mixture about 48 hours in stirring at room.After the termination, reaction mixture evaporation concentration and content on silicagel column with ethyl acetate/petroleum ether (3: 1) as eluent and chromatographic separation.Obtain the required product of yellow oil.
Output: 19.77 grams (theoretical amount 54%),
R fValue: 0.67 (silica gel, ethyl acetate)
Mass spectrum (ESI +): m/z=228[M+Na] +
Embodiment XII
4-[(3-chloro-4-fluorophenyl) amino]-7-cyclobutoxy group-6-hydroxyl quinazoline
10 milliliters of trifluoroacetic acids under agitation drop to 5.60 gram 6-benzyloxy-4-[(3-chloro-4-fluorophenyls) amino]-7-cyclobutoxy group quinazoline in.Reaction mixture is heated to about 40 ℃.After 20 hours, add 3 milliliters of trifluoroacetic acids in stirring at room again.Even still almost do not carry out at 3 hours afterreactions of room temperature restir owing to react, so reaction mixture is heated to 50 ℃.After 4 hours, reaction is finished and is used rotatory evaporator to steam basically and remove excessive trifluoroacetic acid.Residue mixes with water and with concentrated ammonia solution furnishing alkalescence.The light brown precipitation that forms is washed and drying in moisture eliminator with massive laundering through suction filtration.Products therefrom still contains trifluoroacetic acid.
Output: 5.82 grams,
R fValue: 0.61 (silica gel, methylene chloride=9: 1)
Mass spectrum (ESI +): m/z=360,362[M+H] +
Similar embodiment XII prepares following compounds:
(1) amino 4-[(3-chloro-4-fluorophenyl)]-7-cyclo propyl methoxy-6-hydroxyl quinazoline
R fValue: 0.65 (silica gel, methylene chloride=9: 1)
Mass spectrum (ESI +): m/z=360,362[M+H] +
(2) amino 4-[(3-chloro-4-fluorophenyl)]-7-cyclopentyloxy-6-hydroxyl quinazoline
R fValue: 0.65 (silica gel, methylene chloride=9: 1)
Mass spectrum (ESI +): m/z=374,376[M+H] +
(3) amino 4-[(3-chloro-4-fluorophenyl)]-6-hydroxyl-7-((R)-tetrahydrofuran (THF)-3-base oxygen base) quinazoline
R fValue: 0.32 (silica gel, methylene chloride=9: 1),
(4) amino 4-[(3-chloro-4-fluorophenyl)]-methoxyl group of 6-hydroxyl-7-[(R)-(tetrahydrofuran (THF)-2-yl)] quinazoline
Mass spectrum (ESI -): m/z=388,390[M-H] -
Embodiment XIII
6-benzyloxy-4-[(3-chloro-4-fluorophenyl) amino]-7-cyclobutoxy group quinazoline
7.50 gram salt of wormwood and 4.50 gram methylsulfonic acid ring butyl esters are added into 7.00 gram 6-benzyloxy-4-[(3-chloro-4-fluorophenyls) amino]-60 milliliters of N of 7-hydroxyl quinazoline, in the dinethylformamide solution.Reaction mixture stirred 2 hours at 80 ℃.Add 2.00 gram methylsulfonic acid ring butyl esters and 3.00 gram salt of wormwood and mixture again and stir a weekend (weekend) at 60 ℃.Incomplete because of reaction, add 3.50 gram methylsulfonic acid ring butyl esters and 5.00 gram salt of wormwood again.At 80 ℃ again after 20 hours, reaction is almost finished.After the termination, reaction mixture and 300 milliliters of ethyl acetate merge to reach with water and saturated nacl aqueous solution washs.Organic phase is with dried over mgso and evaporation concentration.Residue stirs with methyl alcohol, produces brown precipitate.Suction filtration is with methanol wash and dry in moisture eliminator.
Output: 5.10 grams (theoretical amount 64%),
R fValue: 0.69 (silica gel, methylene chloride=9: 1)
Mass spectrum (ESI -): m/z=448,450[M-H] -
Similar embodiment XIII prepares following compounds:
(1) amino 6-benzyloxy-4-[(3-chloro-4-fluorophenyl)]-7-cyclo propyl methoxy quinazoline (using the brooethyl cyclopropane)
R fValue: 0.72 (silica gel, methylene chloride=9: 1)
Mass spectrum (ESI -): m/z=448,450[M-H] -
(2) amino 6-benzyloxy-4-[(3-chloro-4-fluorophenyl)]-7-cyclopentyloxy quinazoline (using the bromine pentamethylene)
R fValue: 0.78 (silica gel, methylene chloride=9: 1)
Mass spectrum (ESI +): m/z=464,466[M+H] +
Embodiment XIV
(S)-(2-hydroxyl third amino) tert.-butyl acetate
15.00 gram (S)-(+)-1-amino-2-propyl alcohol is dissolved in 100 milliliters of N, dinethylformamide and add 6.97 milliliters of diisopropylethylamine.Follow in 30 minutes with Dropwise 5 .91 milliliter bromo-acetic acid tert-butyl under the ice bath cooling.Remove cooling bath and reaction mixture in stirred overnight at room temperature.After the termination, reaction mixture vacuum-evaporation.Residue is dissolved in 50 ml waters and saturated with 15 gram sodium-chlor in the bottle.The aqueous solution with ethyl acetate extraction for several times.The extraction liquid that merges washs with saturated nacl aqueous solution, with dried over mgso and vacuum-evaporation, obtains yellow oil.
Output: 7.36 grams (theoretical amount 97%),
R fValue: 0.46 (silica gel, ethyl acetate/methanol=9: 1)
Mass spectrum (ESI +): m/z=190[M+H] +
Similar embodiment XIV prepares following compounds:
(1) (R)-(2-hydroxyl third amino) tert.-butyl acetate
R fValue: 0.46 (silica gel, ethyl acetate/methanol=9: 1)
Mass spectrum (ESI +): m/z=190[M+H] +
(2) (1,1-dimethyl-2-hydroxyl ethylamino) tert.-butyl acetate
Mass spectrum (ESI +): m/z=204[M+H] +
R fValue: 0.47 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1).
Embodiment XV
4-[(3-chloro-4-fluorophenyl) amino]-6-(3-mesyloxy propoxy-)-7-cyclobutoxy group quinazoline
In the presence of diisopropylethylamine, make 4-[(3-chloro-4-fluorophenyl in room temperature) amino]-6-(3-hydroxyl propoxy-)-7-cyclobutoxy group quinazoline and methylsulfonyl chloride reaction, obtain this compound.
R fValue: 0.37 (silica gel, methylene chloride=95: 5),
Mass spectrum (ESI -): m/z=494,496[M-H] -
Similar embodiment XV prepares following compounds:
(1) amino 4-[(3-chloro-4-fluorophenyl)]-6-(3-mesyloxy propoxy-)-7-cyclo propyl methoxy quinazoline
R fValue: 0.65 (silica gel, methylene chloride=90: 10),
Mass spectrum (ESI -): m/z=494,496[M-H] -
(2) amino 4-[(3-chloro-4-fluorophenyl)]-6-cyclo propyl methoxy-7-(3-mesyloxy propoxy-) quinazoline
R fValue: 0.73 (silica gel, methylene chloride=90: 10),
Mass spectrum (ESI +): m/z=496,498[M+H] +
(3) amino 4-[(3-chloro-4-fluorophenyl)]-6-(4-mesyloxy butoxy)-7-cyclopentyloxy quinazoline
R fValue: 0.76 (silica gel, methylene chloride=90: 10),
Mass spectrum (ESI +): m/z=524,526[M+H] +
Embodiment XVI
4-[(3-chloro-4-fluorophenyl) amino]-6-hydroxyl-7-cyclo propyl methoxy quinazoline
In the mixture of methylene dichloride, ethanol and concentrated hydrochloric acid (500: 210: 3.5), in the Parr device, in the presence of 10%Pd/C, make 6-benzyloxy-4-[(3-chloro-4-fluorophenyl) amino]-hydrogenation of 7-cyclo propyl methoxy quinazoline, obtain this compound.
Productive rate: 73% of theoretical amount,
Mass spectrum (ESI +): m/z=360,362[M+H] +
Embodiment XVII
5-benzyloxy-4-cyclopentyloxy-2-nitrobenzoic acid ring pentyl ester
In the presence of salt of wormwood as auxiliary alkali, in dimethyl sulfoxide (DMSO), make 5-benzyloxy-4-hydroxyl-2-nitrobenzoic acid and the reaction of 2.2 equivalent bromine pentamethylene in room temperature, obtain this compound.
Productive rate: 87% of theoretical amount,
R fValue: 0.92 (silica gel, ethyl acetate/hexanaphthene=1: 1),
Mass spectrum (ESI +): m/z=426[M+H] +
Embodiment XVIII
4-[(3-chloro-4-fluorophenyl) amino]-6-benzyloxy-7-((R)-tetrahydrofuran (THF)-3-base oxygen base) quinazoline
5.03 the milliliter diethyl azodiformate drops to 8.00 gram 4-[(3-chloro-4-fluorophenyls) amino]-160 milliliters of tetrahydrofuran solutions of 6-benzyloxy-7-hydroxyl quinazoline (referring to WO 0055141A1) and 2.42 milliliters of (S)-(+)-3-hydroxyl tetrahydrofurans and 7.95 gram triphenyl phosphines in.Be reflected at stirred overnight at room temperature and use the rotatory evaporator evaporation.The bottle in residue on silicagel column with dichloromethane/ethyl acetate (2: 1 to 1: 2 gradients) as the eluent chromatogram purification.
Output: 7.34 grams (theoretical amount 78%),
Fusing point: 165-168 ℃,
Mass spectrum (ESI +): m/z=466,468[M+H] +
Similar embodiment XVIII prepares following compounds:
(1) amino 4-[(3-chloro-4-fluorophenyl)]-methoxyl group of 6-benzyloxy-7-[(R)-(tetrahydrofuran (THF)-2-yl)] quinazoline
Mass spectrum (ESI +): m/z=480,482[M+H] +
R fValue: 0.38 (silica gel, methylene chloride=15: 1).
(2) amino 4-[(3-chloro-4-fluorophenyl)]-7-(2-bromine oxethyl)-6-((S)-(tetrahydrofuran (THF)-3-base oxygen base) quinazoline
R fValue: 0.35 (silica gel, methylene chloride=20: 1).
The preparation of final compound:
Embodiment 1
4-[(3-chloro-4-fluorophenyl) amino]-6-cyclopentyl methoxyl group-7-[2-(2,2-dimethyl-6-oxo morpholine-4-yl) Oxyethyl group] quinazoline
250 milligrams of 4-[(3-chloro-4-fluorophenyls) amino]-6-cyclopentyl methoxyl group-7-(2-bromine oxethyl) quinazoline and 341 milligrams of (2-hydroxy-2-methyl third amino) ethyl acetate be dissolved in 20 milliliters of acetonitriles and mix with 50 milligrams of sodium iodides, 275 milligrams of salt of wormwood and 0.70 milliliter of diisopropylethylamine.About 90 hours of reaction mixture refluxed.After being cooled to room temperature, filter reaction mixture and filtrate vacuum-evaporation.The bottle in residue on silicagel column with petrol ether/ethyl acetate (50: 50,0: 100 afterwards) chromatogram.Obtain beige solid cyclisation product.
Output: 62 milligrams (theoretical amount 23%),
R fValue: 0.29 (silica gel, ethyl acetate),
Mass spectrum (ESI -): m/z=541,543[M-H] -
Similar embodiment 1 preparation following compounds:
(1) amino 4-[(3-chloro-4-fluorophenyl)]-6-cyclo propyl methoxy-7-[2-(2,2-dimethyl-6-oxo morpholine-4-yl) oxyethyl group] quinazoline
R fValue: 0.58 (silica gel, methylene chloride=9: 1),
Mass spectrum (ESI -): m/z=513,515[M-H] -
(2) amino 4-[(3-chloro-4-fluorophenyl)]-7-cyclobutoxy group-6-[3-(2,2-dimethyl-6-oxo morpholine-4-yl) propoxy-] quinazoline
Fusing point: 212-214 ℃,
Mass spectrum (ESI -): m/z=527,529[M-H] -
(3) amino 4-[(3-chloro-4-fluorophenyl)]-7-cyclo propyl methoxy-6-[3-(2,2-dimethyl-6-oxo morpholine-4-yl) propoxy-] quinazoline
Fusing point: 200-202 ℃,
Mass spectrum (ESI -): m/z=527,529[M-H] -
(4) amino 4-[(3-chloro-4-fluorophenyl)]-6-[3-(2,2-dimethyl-6-oxo morpholine-4-yl) propoxy-]-7-methoxyl group quinazoline
Fusing point: 222-224 ℃,
Mass spectrum (ESI -): m/z=487,489[M-H] -
Embodiment 2
4-[(3-chloro-4-fluorophenyl) amino]-6-cyclo propyl methoxy-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N- Methylamino] oxyethyl group } quinazoline
300 milligrams of 4-[(3-chloro-4-fluorophenyls) amino]-20 milliliters of acetonitrile solutions of 6-cyclo propyl methoxy-7-(2-bromine oxethyl) quinazoline and 400 milligrams of 4-methylamino-dihydrofuran-2-ketone and 240 milligrams of salt of wormwood and 70 milligrams of sodium iodides mix and refluxed 24 hours.After being cooled to room temperature, filter reaction mixture and filtrate vacuum-evaporation.In the bottle residue in silicagel column with methylene chloride/concentrated ammonia solution (97: 3: 0.05) as eluent and chromatogram.Obtain ficelle solid title compound.
Output: 70 milligrams (theoretical amount 22%),
R fValue: 0.47 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1),
Mass spectrum (ESI +): m/z=501,503[M+H] +
Similar embodiment 2 obtains following compounds:
(1) amino 4-[(3-chloro-4-fluorophenyl)]-6-cyclopentyloxy-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methylamino] oxyethyl group } quinazoline
R fValue: 0.42 (silica gel, methylene chloride/concentrated ammonia solution=90: 10: 0.1),
Mass spectrum (ESI +): m/z=515,517[M+H] +
(2) amino 4-[(3-chloro-4-fluorophenyl)]-6-{3-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methylamino] propoxy-}-7-cyclobutoxy group quinazoline
Fusing point: 147.5-151 ℃,
Mass spectrum (ESI +): m/z=515,517[M+H] +
Embodiment 3
4 -[(3-bromophenyl) amino]-6-[2-((S)-6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinoline azoles Quinoline
90 microlitre methylsulfonic acids are added into 380 milligrams of 4-[(3-bromophenyls) amino]-6-(2-{N-[(tertbutyloxycarbonyl) methyl]-N-((S)-2-hydroxypropyl) amino oxyethyl group)-8 milliliters of acetonitrile solutions of 7-methoxyl group quinazoline in.About 3 hours of reaction mixture refluxed is then added another normal methylsulfonic acid and is continued and refluxes until reacting completely.After the termination, reaction mixture is with the ethyl acetate dilution and with saturated sodium bicarbonate solution and saturated nacl aqueous solution washing.Organic phase is with dried over mgso and vacuum-evaporation.Residue and ether stir and suction filtration in the bottle.Obtain the title compound of white solid.
Output: 280 milligrams (theoretical amount 85%),
Fusing point: 190 ℃,
Mass spectrum (ESI -): m/z=485,487[M-H] -
Similar embodiment 3 obtains following compounds:
(1) amino 4-[(3-bromophenyl)]-6-[2-((R)-6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline
Fusing point: 193 ℃,
Mass spectrum (ESI +): m/z=487,489[M+H] +
(2) amino 4-[(3-chloro-4-fluorophenyl)]-6-[2-((R)-6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline (reaction is carried out in acetonitrile with trifluoroacetic acid)
Fusing point: 208 ℃,
Mass spectrum (ESI -): m/z=459,461[M-H] -
(3) amino 4-[(3-chloro-4-fluorophenyl)]-6-[3-((R)-6-methyl-2-oxo morpholine-4-yl) propoxy-]-7-methoxyl group quinazoline (reaction is carried out in acetonitrile with trifluoroacetic acid)
R fValue: 0.33 (silica gel, ethyl acetate),
Mass spectrum (ESI -): m/z=473,475[M-H] -
(4) amino 4-[(R)-(1-phenylethyl)]-6-[3-((S)-6-methyl-2-oxo morpholine-4-yl) propoxy-]-7-methoxyl group quinazoline (reaction is carried out in acetonitrile with trifluoroacetic acid)
R fValue: 0.41 (silica gel, ethyl acetate/methanol=9: 1),
Mass spectrum (ESI -): m/z=449[M-H] -
(5) amino 4-[(R)-(1-phenylethyl)]-6-[2-((S)-6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline (reaction is carried out in acetonitrile with trifluoroacetic acid)
R fValue: 0.49 (silica gel, ethyl acetate/methanol/concentrated ammonia solution=9: 1: 0.1),
Mass spectrum (ESI -): m/z=435[M-H] -
(6) amino 4-[(3-chloro-4-fluorophenyl)]-6-[3-((R)-6-methyl-2-oxo morpholine-4-yl) propoxy-]-7-cyclobutoxy group quinazoline (reaction is carried out in acetonitrile with trifluoroacetic acid)
Fusing point: 185.5-189.5 ℃,
Mass spectrum (ESI +): m/z=515,517[M+H] +
(7) amino 4-[(3-chloro-4-fluorophenyl)]-6-[3-(5,5-dimethyl-2-oxo morpholine-4-yl) propoxy-]-7-cyclobutoxy group quinazoline (reaction is carried out in acetonitrile with trifluoroacetic acid)
Fusing point: 214-216 ℃,
Mass spectrum (ESI -): m/z=527,529[M-H] -
(8) amino 4-[(3-chloro-4-fluorophenyl)]-6-[3-((R)-6-methyl-2-oxo morpholine-4-yl) propoxy-]-7-cyclo propyl methoxy quinazoline (reaction is carried out in acetonitrile with trifluoroacetic acid)
Fusing point: 160.5-163 ℃,
Mass spectrum (ESI +): m/z=515,517[M+H] +
(9) amino 4-[(3-chloro-4-fluorophenyl)]-6-[3-((S)-6-methyl-2-oxo morpholine-4-yl) propoxy-]-7-cyclo propyl methoxy quinazoline (reaction is carried out in acetonitrile with trifluoroacetic acid)
Fusing point: 160-162 ℃,
Mass spectrum (ESI +): m/z=515,517[M+H] +
(10) amino 4-[(3-chloro-4-fluorophenyl)]-6-[2-((S)-6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-cyclopentyloxy quinazoline (reaction is carried out in acetonitrile with trifluoroacetic acid)
R fValue: 0.31 (silica gel, ethyl acetate),
Mass spectrum (ESI +): m/z=515,517[M+H] +
(11) amino 4-[(3-chloro-4-fluorophenyl)]-6-[2-((R)-6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-cyclopentyloxy quinazoline (reaction is carried out in acetonitrile with trifluoroacetic acid)
Fusing point: 176-178 ℃,
Mass spectrum (ESI +): m/z=515,517[M+H] +
(12) amino 4-[(3-chloro-4-fluorophenyl)]-6-[2-((S)-6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-cyclo propyl methoxy quinazoline (reaction is carried out in acetonitrile with trifluoroacetic acid)
R fValue: 0.37 (silica gel, ethyl acetate),
Mass spectrum (ESI +): m/z=501,503[M+H] +
(13) amino 4-[(3-chloro-4-fluorophenyl)]-6-[2-((R)-6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-cyclo propyl methoxy quinazoline (reaction is carried out in acetonitrile with trifluoroacetic acid)
R fValue: 0.37 (silica gel, ethyl acetate),
Mass spectrum (ESI +): m/z=501,503[M+H] +
(14) amino 4-[(3-chloro-4-fluorophenyl)]-6-cyclo propyl methoxy-7-[2-((S)-6-methyl-2-oxo morpholine-4-yl) oxyethyl group] quinazoline (reaction is carried out in acetonitrile with trifluoroacetic acid)
R fValue: 0.48 (silica gel, ethyl acetate/methanol=9: 1),
Mass spectrum (ESI +): m/z=501,503[M+H] +
(15) amino 4-[(3-chloro-4-fluorophenyl)]-6-cyclo propyl methoxy-7-[2-((R)-6-methyl-2-oxo morpholine-4-yl) oxyethyl group] quinazoline (reaction is carried out in acetonitrile with trifluoroacetic acid)
Mass spectrum (ESI +): m/z=501,503[M+H] +
(16) amino 4-[(3-chloro-4-fluorophenyl)]-6-cyclo propyl methoxy-7-[3-((R)-6-methyl-2-oxo morpholine-4-yl) propoxy-] quinazoline (reaction is carried out in acetonitrile with trifluoroacetic acid)
R fValue: 0.67 (silica gel, ethyl acetate/methanol=9: 1),
Mass spectrum (ESI -): m/z=513,515[M-H] -
(17) amino 4-[(3-chloro-4-fluorophenyl)]-6-cyclo propyl methoxy-7-[3-((S)-6-methyl-2-oxo morpholine-4-yl) propoxy-] quinazoline (reaction is carried out in acetonitrile with trifluoroacetic acid)
R fValue: 0.67 (silica gel, ethyl acetate/methanol=9: 1),
Mass spectrum (ESI -): m/z=513,515[M-H] -
(18) amino 4-[(3-chloro-4-fluorophenyl)]-6-[2-(2,2-dimethyl-6-oxo morpholine-4-yl) oxyethyl group]-7-cyclopentyloxy quinazoline (reaction is carried out in acetonitrile with trifluoroacetic acid)
R fValue: 0.56 (silica gel, ethyl acetate),
Mass spectrum (ESI +): m/z=529,531[M+H] +
(19) amino 4-[(3-chloro-4-fluorophenyl)]-6-cyclopentyloxy-7-[2-((S)-6-methyl-2-oxo morpholine-4-yl) oxyethyl group] quinazoline (reaction is carried out in acetonitrile with trifluoroacetic acid)
R fValue: 0.60 (silica gel, ethyl acetate/methanol=9: 1),
Mass spectrum (ESI +): m/z=515,517[M+H] +
(20) amino 4-[(3-chloro-4-fluorophenyl)]-6-cyclopentyloxy-7-[2-((R)-6-methyl-2-oxo morpholine-4-yl) oxyethyl group] quinazoline (reaction is carried out in acetonitrile with trifluoroacetic acid)
Mass spectrum (ESI +): m/z=515,517[M+H] +
(21) amino 4-[(3-chloro-4-fluorophenyl)]-6-[4-((S)-6-methyl-2-oxo morpholine-4-yl) butoxy]-7-cyclopentyloxy quinazoline (reaction is carried out in acetonitrile with trifluoroacetic acid)
R fValue: 0.51 (silica gel, ethyl acetate),
Mass spectrum (ESI +): m/z=543,545[M+H] +
(22) amino 4-[(3-chloro-4-fluorophenyl)]-6-[4-((R)-6-methyl-2-oxo morpholine-4-yl) butoxy]-7-cyclopentyloxy quinazoline (reaction is carried out in acetonitrile with trifluoroacetic acid)
Mass spectrum (ESI +): m/z=543,545[M+H] +
(23) amino 4-[(3-chloro-4-fluorophenyl)]-6-[3-((S)-6-methyl-2-oxo morpholine-4-yl) propoxy-]-7-methoxyl group quinazoline (reaction is carried out in acetonitrile with trifluoroacetic acid)
Fusing point: 183-186 ℃,
Mass spectrum (ESI +): m/z=475,477[M+H] +
(24) amino 4-[(3-chloro-4-fluorophenyl)]-6-[3-(5,5-dimethyl-2-oxo morpholine-4-yl) propoxy-]-7-methoxyl group quinazoline (reaction is carried out in acetonitrile with trifluoroacetic acid)
R fValue: 0.43 (silica gel, ethyl acetate),
Mass spectrum (ESI -): m/z=487,489[M-H] -
(25) amino 4-[(3-chloro-4-fluorophenyl)]-6-[2-((S)-6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline (reaction is carried out in acetonitrile with trifluoroacetic acid)
Fusing point: 212-213 ℃,
Mass spectrum (ESI +): m/z=461,463[M+H] +
(26) amino 4-[(3-chloro-4-fluorophenyl)]-6-{2-[N-(carboxymethyl)-N-((S)-2-hydroxypropyl) amino] oxyethyl group }-7-methoxyl group quinazoline (producing 3 (25) by products)
Fusing point: 187-190 ℃,
Mass spectrum (ESI +): m/z=479,481[M+H] +
(27) amino 4-[(3-chloro-4-fluorophenyl)]-6-[2-(2,2-dimethyl-6-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline (reaction is carried out in acetonitrile with trifluoroacetic acid)
Fusing point: 229-232 ℃,
Mass spectrum (ESI -): m/z=473,475[M-H] -
(28) amino 4-[(3-chloro-4-fluorophenyl)]-6-[2-(2,2-dimethyl-6-oxo morpholine-4-yl) oxyethyl group]-7-((R)-tetrahydrofuran (THF)-3-base oxygen base) quinazoline (reaction is carried out in acetonitrile with trifluoroacetic acid)
Fusing point: 195-196 ℃,
Mass spectrum (ESI +): m/z=531,533[M+H] +
(29) amino 4-[(3-chloro-4-fluorophenyl)]-6-[2-(2,2-dimethyl-6-oxo morpholine-4-yl) oxyethyl group]-7-[(R)-(tetrahydrofuran (THF)-2-yl) methoxyl group] quinazoline (reaction is carried out in acetonitrile with trifluoroacetic acid)
Fusing point: 184 ℃,
Mass spectrum (ESI +): m/z=545,547[M+H] +
(30) amino 4-[(3-chloro-4-fluorophenyl)]-7-[2-(2,2-dimethyl-6-oxo morpholine-4-yl) oxyethyl group]-6-((R)-tetrahydrofuran (THF)-3-base oxygen base) quinazoline
Fusing point: 202-205 ℃,
Mass spectrum (ESI +): m/z=531,533[M+H] +
(31) amino 4-[(3-chloro-4-fluorophenyl)]-7-[2-(2,2-dimethyl-6-oxo morpholine-4-yl) oxyethyl group]-6-[(S)-(tetrahydrofuran (THF)-2-yl) methoxyl group] quinazoline
Fusing point: 182 ℃,
Mass spectrum (ESI +): m/z=545,547[M+H] +
Embodiment 4
The 4-[(3-bromophenyl) amino]-6-(2-{N-[(tertbutyloxycarbonyl) methyl]-N-((S)-2-hydroxypropyl) amino } second The oxygen base)-7-methoxyl group quinazoline
0.25 the milliliter diisopropylethylamine is added into 650 milligrams of 4-[(3-bromophenyls) amino]-15 milliliters of acetonitrile solutions of 6-(2-bromine oxethyl)-7-methoxyl group quinazoline and 1.10 gram (S)-(2-hydroxyl third amino) tert.-butyl acetates in.Reaction mixture spends the night 50 ℃ of stirrings.Because do not detect reaction, so the evaporation concentration reaction mixture, with 20 milliliters of N, dinethylformamide mixes and stirred 8 hours at 60 ℃.Then temperature rises to 80 ℃.After 8 hours, react completely again.The reaction mixture evaporation concentration and on silicagel column with ethyl acetate as the eluent chromatographic separation.Obtain the required product of white solid.
Output: 410 milligrams (theoretical amount 51%),
R fValue: 0.27 (silica gel, ethyl acetate),
Mass spectrum (ESI -): m/z=559,561[M-H] -
Similar embodiment 4 preparation following compounds:
(1) amino 4-[(3-bromophenyl)]-6-(2-{N-[(tertbutyloxycarbonyl) methyl]-N-((R)-2-hydroxypropyl) amino } oxyethyl group)-7-methoxyl group quinazoline
Fusing point: 130 ℃,
Mass spectrum (ESI -): m/z=559,561[M-H] -
(2) amino 4-[(3-chloro-4-fluorophenyl)]-6-(2-{N-[(tertbutyloxycarbonyl) methyl]-N-((R)-2-hydroxypropyl) amino } oxyethyl group)-7-methoxyl group quinazoline (react on N, carry out in the dinethylformamide)
R fValue: 0.40 (silica gel, ethyl acetate/petroleum ether=4: 1).
(3) amino 4-[(3-chloro-4-fluorophenyl)]-6-(3-{N-[(tertbutyloxycarbonyl) methyl]-N-((R)-2-hydroxypropyl) amino } propoxy-)-7-methoxyl group quinazoline (react on N, carry out in the dinethylformamide)
R fValue: 0.37 (silica gel, ethyl acetate/petroleum ether=4: 1),
Mass spectrum (ESI -): m/z=547,549[M-H] -.
(4) amino 4-[(R)-(1-phenylethyl)]-6-(3-{N-[(tertbutyloxycarbonyl) methyl]-N-((S)-2-hydroxypropyl) amino } propoxy-)-7-methoxyl group quinazoline (react on N, carry out in the dinethylformamide)
R fValue: 0.65 (silica gel, ethyl acetate/methanol=9: 1),
Mass spectrum (EI): m/z=524[M] +
(5) amino 4-[(R)-(1-phenylethyl)]-6-(2-{N-[(tertbutyloxycarbonyl) methyl]-N-((S)-2-hydroxypropyl) amino } oxyethyl group)-7-methoxyl group quinazoline (react on N, carry out in the dinethylformamide)
R fValue: 0.57 (silica gel, ethyl acetate/methanol/concentrated ammonia solution=9: 1: 0.1).
(6) amino 4-[(3-chloro-4-fluorophenyl)]-6-(3-{N-[(tertbutyloxycarbonyl) methyl]-N-((R)-2-hydroxypropyl) amino } propoxy-)-7-cyclobutoxy group quinazoline
R fValue: 0.31 (silica gel, methylene chloride=95: 5).
(7) amino 4-[(3-chloro-4-fluorophenyl)]-6-(3-{N-[(tertbutyloxycarbonyl) methyl]-N-(1,1-dimethyl-2-hydroxyethyl) amino } propoxy-)-7-cyclobutoxy group quinazoline
R fValue: 0.29 (silica gel, methylene chloride=95: 5).
Mass spectrum (ESI +): m/z=603,605[M+H] +
(8) amino 4-[(3-chloro-4-fluorophenyl)]-6-(3-{N-[(tertbutyloxycarbonyl) methyl]-N-((R)-2-hydroxypropyl) amino } propoxy-)-7-cyclo propyl methoxy quinazoline
R fValue: 0.37 (silica gel, methylene chloride=95: 5).
(9) amino 4-[(3-chloro-4-fluorophenyl)]-6-(3-{N-[(tertbutyloxycarbonyl) methyl]-N-((S)-2-hydroxypropyl) amino } propoxy-)-7-cyclo propyl methoxy quinazoline
R fValue: 0.50 (silica gel, ethyl acetate).
(10) amino 4-[(3-chloro-4-fluorophenyl)]-6-(2-{N-[(tertbutyloxycarbonyl) methyl]-N-((S)-2-hydroxypropyl) amino } oxyethyl group)-7-cyclopentyloxy quinazoline
R fValue: 0.54 (silica gel, ethyl acetate/hexanaphthene=9: 1).
(11) amino 4-[(3-chloro-4-fluorophenyl)]-6-(2-{N-[(tertbutyloxycarbonyl) methyl]-N-((R)-2-hydroxypropyl) amino } oxyethyl group)-7-cyclopentyloxy quinazoline
R fValue: 0.66 (silica gel, ethyl acetate).
(12) amino 4-[(3-chloro-4-fluorophenyl)]-6-(2-{N-[(tertbutyloxycarbonyl) methyl]-N-((S)-2-hydroxypropyl) amino } oxyethyl group)-7-cyclo propyl methoxy quinazoline
R fValue: 0.60 (silica gel, ethyl acetate).
(13) amino 4-[(3-chloro-4-fluorophenyl)]-6-(2-{N-[(tertbutyloxycarbonyl) methyl]-N-((R)-2-hydroxypropyl) amino } oxyethyl group)-7-cyclo propyl methoxy quinazoline
R fValue: 0.60 (silica gel, ethyl acetate).
(14) amino 4-[(3-chloro-4-fluorophenyl)]-6-cyclo propyl methoxy-7-(2-{N-[(tertbutyloxycarbonyl) methyl]-N-((S)-2-hydroxypropyl) amino } oxyethyl group) quinazoline
R fValue: 0.30 (silica gel, ethyl acetate).
(15) amino 4-[(3-chloro-4-fluorophenyl)]-6-cyclo propyl methoxy-7-(2-{N-[(tertbutyloxycarbonyl) methyl]-N-((R)-2-hydroxypropyl) amino } oxyethyl group) quinazoline
R fValue: 0.30 (silica gel, ethyl acetate).
(16) amino 4-[(3-chloro-4-fluorophenyl)]-6-cyclo propyl methoxy-7-(3-{N-[(tertbutyloxycarbonyl) methyl]-N-((R)-2-hydroxypropyl) amino } propoxy-) quinazoline
R fValue: 0.35 (silica gel, ethyl acetate).
(17) amino 4-[(3-chloro-4-fluorophenyl)]-6-cyclo propyl methoxy-7-(3-{N-[(tertbutyloxycarbonyl) methyl]-N-((S)-2-hydroxypropyl) amino } propoxy-) quinazoline
R fValue: 0.35 (silica gel, ethyl acetate).
(18) amino 4-[(3-chloro-4-fluorophenyl)]-6-(2-{N-[(ethoxycarbonyl) methyl]-N-(2-hydroxy-2-methyl propyl group) amino } oxyethyl group)-7-cyclopentyloxy quinazoline
R fValue: 0.64 (silica gel, methylene chloride=9: 1),
Mass spectrum (ESI +): m/z=575,577[M+H] +
(19) amino 4-[(3-chloro-4-fluorophenyl)]-6-cyclopentyloxy-7-(2-{N-[(tertbutyloxycarbonyl) methyl]-N-((S)-2-hydroxypropyl) amino } oxyethyl group) quinazoline
R fValue: 0.51 (silica gel, ethyl acetate).
(20) amino 4-[(3-chloro-4-fluorophenyl)]-6-cyclopentyloxy-7-(2-{N-[(tertbutyloxycarbonyl) methyl]-N-((R)-2-hydroxypropyl) amino } oxyethyl group) quinazoline
R fValue: 0.51 (silica gel, ethyl acetate).
(21) amino 4-[(3-chloro-4-fluorophenyl)]-6-(4-{N-[(tertbutyloxycarbonyl) methyl]-N-((S)-2-hydroxypropyl) amino } butoxy)-7-cyclopentyloxy quinazoline
R fValue: 0.61 (silica gel, ethyl acetate).
(22) amino 4-[(3-chloro-4-fluorophenyl)]-6-(4-{N-[(tertbutyloxycarbonyl) methyl]-N-((R)-2-hydroxypropyl) amino } butoxy)-7-cyclopentyloxy quinazoline
R fValue: 0.61 (silica gel, ethyl acetate).
(23) amino 4-[(3-chloro-4-fluorophenyl)]-6-(3-{N-[(tertbutyloxycarbonyl) methyl]-N-((S)-2-hydroxypropyl) amino } propoxy-)-7-methoxyl group quinazoline
R fValue: 0.46 (silica gel, ethyl acetate),
Mass spectrum (ESI -): m/z=547,549[M-H] -
(24) amino 4-[(3-chloro-4-fluorophenyl)]-6-(3-{N-[(tertbutyloxycarbonyl) methyl]-N-(1,1-dimethyl-2-hydroxyethyl) amino } propoxy-)-7-methoxyl group quinazoline
Mass spectrum (ESI +): m/z=563,565[M+H] +
(25) amino 4-[(3-chloro-4-fluorophenyl)]-6-(2-{N-[(tertbutyloxycarbonyl) methyl]-N-((S)-2-hydroxypropyl) amino } oxyethyl group)-7-methoxyl group quinazoline
R fValue: 0.66 (silica gel, ethyl acetate/methanol=9: 1),
Mass spectrum (ESI +): m/z=535,537[M+H] +
(26) amino 4-[(3-chloro-4-fluorophenyl)]-6-(2-{N-[(ethoxycarbonyl) methyl]-N-(2-hydroxy-2-methyl propyl group) amino } oxyethyl group)-7-methoxyl group quinazoline (be with the mixture of the material of cyclisation)
R fValue: 0.44 (silica gel, ethyl acetate),
Mass spectrum (ESI +): m/z=521,523[M+H] +
(27) amino 4-[(3-chloro-4-fluorophenyl)]-6-(2-{N-[(ethoxycarbonyl) methyl]-N-(2-hydroxy-2-methyl propyl group) amino } oxyethyl group)-7-((R)-tetrahydrofuran (THF)-3-base oxygen base) quinazoline (be with the mixture of the material of cyclisation)
R fValue: 0.30 (silica gel, methylene chloride=9: 1),
(28) amino 4-[(3-chloro-4-fluorophenyl)]-6-(2-{N-[(ethoxycarbonyl) methyl]-N-(2-hydroxy-2-methyl propyl group) amino } oxyethyl group)-7-[(R)-(tetrahydrofuran (THF)-2-yl) methoxyl group] quinazoline
Mass spectrum (ESI -): m/z=589,591[M-H] -
(29) amino 4-[(3-chloro-4-fluorophenyl)]-7-(2-{N-[(ethoxycarbonyl) methyl]-N-(2-hydroxy-2-methyl propyl group) amino } oxyethyl group)-6-((S)-tetrahydrofuran (THF)-3-base oxygen base) quinazoline
R fValue: 0.16 (silica gel, methylene chloride=20: 1).
(30) amino 4-[(3-chloro-4-fluorophenyl)]-7-(2-{N-[(ethoxycarbonyl) methyl]-N-(2-hydroxy-2-methyl propyl group) amino } oxyethyl group)-6-[(S)-(tetrahydrofuran (THF)-2-yl) methoxyl group] quinazoline
R fValue: 0.68 (silica gel, ethyl acetate/methanol=15: 1).
Be similar to the known additive method of previous embodiment and document, can prepare following compounds:
(1) amino 4-[(3-chloro-4-fluorophenyl)]-7-[2-(6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-6-methoxyl group quinazoline,
(2) amino 4-[(3-chloro-4-fluorophenyl)]-7-[3-(6-methyl-2-oxo morpholine-4-yl) propoxy-]-6-methoxyl group quinazoline,
(3) amino 4-[(3-chloro-4-fluorophenyl)]-6-[2-((S)-6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
(4) amino 4-[(3-chloro-4-fluorophenyl)]-6-[3-((S)-6-methyl-2-oxo morpholine-4-yl) propoxy-]-7-methoxyl group quinazoline,
(5) amino 4-[(3-chloro-4-fluorophenyl)]-6-[3-(5,5-dimethyl-2-oxo morpholine-4-yl) propoxy-]-7-methoxyl group quinazoline,
(6) amino 4-[(3-chloro-4-fluorophenyl)]-6-[2-(5,5-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
(7) amino 4-[(3-chloro-4-fluorophenyl)]-6-[3-(3-methyl-2-oxo morpholine-4-yl) propoxy-]-7-methoxyl group quinazoline,
(8) amino 4-[(3-chloro-4-fluorophenyl)]-6-[2-(3-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
(9) amino 4-[(R)-(1-phenylethyl)]-6-[3-((R)-6-methyl-2-oxo morpholine-4-yl) propoxy-]-7-methoxyl group quinazoline,
(10) amino 4-[(R)-(1-phenylethyl)]-6-[2-((R)-6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
(11) amino 4-[(3-chloro-4-fluorophenyl)]-7-[4-(6-methyl-2-oxo morpholine-4-yl) butoxy]-6-methoxyl group quinazoline,
(12) amino 4-[(3-chloro-4-fluorophenyl)]-7-[3-(6-methyl-2-oxo morpholine-4-yl) propoxy-]-6-methoxyl group quinazoline,
(13) amino 4-[(3-chloro-4-fluorophenyl)]-6-[4-(6-methyl-2-oxo morpholine-4-yl) butoxy]-7-methoxyl group quinazoline,
(14) amino 4-[(3-chloro-4-fluorophenyl)]-6-[2-(6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-(tetrahydrofuran (THF)-3-base oxygen base) quinazoline,
(15) amino 4-[(3-chloro-4-fluorophenyl)]-6-[2-(6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-(tetrahydropyran-3-base oxygen base) quinazoline,
(16) amino 4-[(3-chloro-4-fluorophenyl)]-6-[2-(6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-(tetrahydropyran-4-base oxygen base) quinazoline,
(17) amino 4-[(3-chloro-4-fluorophenyl)]-6-[2-(6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-(tetrahydrofuran (THF)-2-ylmethoxy) quinazoline,
(18) amino 4-[(3-chloro-4-fluorophenyl)]-6-[2-(6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-(tetrahydropyran-4-base methoxyl group) quinazoline,
(19) amino 4-[(3-chloro-4-fluorophenyl)]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-(tetrahydrofuran (THF)-3-base oxygen base) quinazoline,
(20) amino 4-[(3-chloro-4-fluorophenyl)]-6-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-7-(tetrahydrofuran (THF)-3-base oxygen base) quinazoline,
(21) amino 4-[(3-chloro-4-fluorophenyl)]-6-[4-(6,6-dimethyl-2-oxo morpholine-4-yl) butoxy]-7-(tetrahydrofuran (THF)-3-base oxygen base) quinazoline,
(22) amino 4-[(3-chloro-4-fluorophenyl)]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-(tetrahydrofuran (THF)-2-ylmethoxy) quinazoline,
(23) amino 4-[(3-chloro-4-fluorophenyl)]-6-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-7-(tetrahydrofuran (THF)-2-ylmethoxy) quinazoline,
(24) amino 4-[(3-chloro-4-fluorophenyl)]-6-[4-(6,6-dimethyl-2-oxo morpholine-4-yl) butoxy]-7-(tetrahydrofuran (THF)-2-ylmethoxy) quinazoline,
(25) amino 4-[(3-chloro-4-fluorophenyl)]-7-[2-(6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-6-(tetrahydrofuran (THF)-3-base oxygen base) quinazoline,
(26) amino 4-[(3-chloro-4-fluorophenyl)]-7-[2-(6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-6-(tetrahydropyran-3-base oxygen base) quinazoline,
(27) amino 4-[(3-chloro-4-fluorophenyl)]-7-[2-(6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-6-(tetrahydropyran-4-base oxygen base) quinazoline,
(28) amino 4-[(3-chloro-4-fluorophenyl)]-7-[2-(6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-6-(tetrahydrofuran (THF)-2-ylmethoxy) quinazoline,
(29) amino 4-[(3-chloro-4-fluorophenyl)]-7-[2-(6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-6-(tetrahydropyran-4-base methoxyl group) quinazoline,
(30) amino 4-[(3-chloro-4-fluorophenyl)]-7-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-6-(tetrahydrofuran (THF)-3-base oxygen base) quinazoline,
(31) amino 4-[(3-chloro-4-fluorophenyl)]-7-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-6-(tetrahydrofuran (THF)-3-base oxygen base) quinazoline,
(32) amino 4-[(3-chloro-4-fluorophenyl)]-7-[4-(6,6-dimethyl-2-oxo morpholine-4-yl) butoxy]-6-(tetrahydrofuran (THF)-3-base oxygen base) quinazoline,
(33) amino 4-[(3-chloro-4-fluorophenyl)]-7-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-6-(tetrahydrofuran (THF)-2-ylmethoxy) quinazoline,
(34) amino 4-[(3-chloro-4-fluorophenyl)]-7-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-6-(tetrahydrofuran (THF)-2-ylmethoxy) quinazoline,
(35) amino 4-[(3-chloro-4-fluorophenyl)]-7-[4-(6,6-dimethyl-2-oxo morpholine-4-yl) butoxy]-6-(tetrahydrofuran (THF)-2-ylmethoxy) quinazoline.
Embodiment 5
The coated tablet that contains 75 milligrams of active substances
1 core contains:
75.0 milligrams of active substances
93.0 milligrams in calcium phosphate
35.5 milligrams of W-Gums
10.0 milligrams of polyvinylpyrrolidones
15.0 milligrams of Vltra tearss
Magnesium Stearate 1.5 milligram
230.0 milligram
Preparation:
One meromict of active substance and calcium phosphate, W-Gum, polyvinylpyrrolidone, Vltra tears and specified amount Magnesium Stearate.The plain sheet and its sieve of following through 1.5 millimeters of meshes that make 13 millimeters of diameters with pelleter use the suitable device friction, and mix with the residual content Magnesium Stearate.This particle compresses the tablet that forms desired shape in pelleter.
Core weight: 230 milligrams
Mould: 9 millimeters, convexity
Prepared nuclear is with basically by film dressing that Vltra tears was constituted.The film coating tablet of making polishes through beeswax.
Coated tablet weight: 245 milligrams.
Embodiment 6
The tablet that contains 100 milligrams of active substances
Form:
1 tablet contains:
100.0 milligrams of active substances
80.0 milligrams of lactose
34.0 milligrams of W-Gums
4.0 milligrams of polyvinylpyrrolidones
Magnesium Stearate 2.0 milligram
220.0 milligram
The preparation method:
Active substance, lactose and starch mix and are evenly moistening with the aqueous solution of polyvinylpyrrolidone.Sieve at wet composition (2.0 millimeters meshes) and in 50 ℃ of netted drying machines, after the drying, sieve once again (1.5 millimeters meshes) and add lubricant.The compressed formation tablet of the mixture of making.
Tablet weight: 220 milligrams
Diameter: 10 millimeters, a double-deck bilateral facet and a side have indentation.
Embodiment 7
The tablet that contains 150 milligrams of active substances
Form:
1 tablet contains:
150.0 milligrams of active substances
89.0 milligrams of powder lactose
40.0 milligrams of W-Gums
10.0 milligrams of colloid silicas
10.0 milligrams of polyvinylpyrrolidones
Magnesium Stearate 1.0 milligram
300.0 milligram
The preparation method:
Active substance and lactose and W-Gum and silicon-dioxide mix and are evenly moistening and sieve through the sieve of 1.5 millimeters meshes with the 20% polyvinylpyrrolidone aqueous solution.Particle is 45 ℃ of dryings and pass through identical sieve once again, and mixes with the specified amount Magnesium Stearate.Be compressed into tablet from mixture.
Tablet weight: 300 milligrams
Mould: 10 millimeters, tabular
Embodiment 8
The hard gelatin capsule that contains 150 milligrams of active substances
1 capsule contains:
50.0 milligrams of active substances
About 80.0 milligrams of W-Gum (exsiccant)
About 87.0 milligrams of lactose (powder)
Magnesium Stearate 3.0 milligram
About 420.0 milligrams
Preparation:
Active substance mixes with excipient, by the sieve and the use suitable device uniform mixing of 0.75 millimeter mesh.The mixture of making is inserted hard gelatin capsule No. 1.
Capsule is filled: about 320 milligrams
Capsule shell: No. 1 gelatine capsule.
Embodiment 9
The suppository that contains 150 milligrams of active substances
1 suppository contains:
150.0 milligrams of active substances
Polyethylene glycol 1500 550.0 Bos gram
460.0 milligrams of polyethylene glycol 6000s
Tween-60 840.0 milligram
2,000.0 milligrams
Preparation:
After the fusion of suppository material, the active substance uniformly distributing in it and melts pour in the cooling die.
Embodiment 10
The suspension that contains 50 milligrams of active substances
100 milliliters of suspension contain:
Active substance 1.00 grams
Carboxymethyl cellulose-Na salt 0.10 gram
Right-methyl hydroxybenzoate 0.05 gram
Right-nipasol 0.01 gram
Glucose 10.00 grams
Glycerine 5.00 grams
70% sorbitol solution, 20.00 grams
Correctives 0.30 gram
Distilled water adds to 100 milliliters
Preparation:
Distilled water is heated to 70 ℃.Right-methyl hydroxybenzoate and right-nipasol stir with glycerine and Xylo-Mucine and are dissolved in it.Solution is cooled to room temperature and adds active substance and stir homodisperse in it down.After adding sugar, add sorbitol solution and correctives and dissolving, suspension stirs exhaust down to eliminate gas.
5 milliliters of suspension contain 50 milligrams of active substances.
Embodiment 11
The ampoule that contains 10 milligrams of active substances
Form:
10.0 milligrams of active substances
0.01N hydrochloric acid is an amount of
Two times distilled water is added into 2.0 milliliters
Preparation:
Active substance is dissolved among the 0.01N HCl of necessary amount, and is isoosmotic with the salt furnishing, filter sterilization and moving in 2 milliliters of ampoules.
Embodiment 12
The ampoule that contains 50 milligrams of active substances
Form:
50.0 milligrams of active substances
0.01N hydrochloric acid is an amount of
Two times distilled water is added into 10.0 milliliters
Preparation:
Active substance is dissolved among the 0.01N HCl of necessary amount, and is isoosmotic with the salt furnishing, filter sterilization and moving in 10 milliliters of ampoules.
Embodiment 13
The powder inhalation capsules that contains 5 milligrams of active substances
1 capsule contains:
5.0 milligrams of active substances
The suction lactose 15.0 milligram
20.0 milligram
Preparation:
Active substance mixes with lactose with suction.Mixture is inserted (about 50 milligrams of capsulae vacuus weight) in the capsule with the capsule maker.
Capsules weight: 70.0 milligrams
Capsule number=3
Embodiment 14
Contain the suction solution that the hand-held atomizer of 2.5 milligrams of active substances is used
1 sprays contains:
2.500 milligrams of active substances
0.001 milligram of benzalkonium chloride
1N hydrochloric acid is an amount of
Ethanol/water (50/50) is added into 15.000 milligrams
Preparation:
Active substance and benzalkonium chloride are dissolved in the ethanol/water (50/50).PH value of solution is adjusted with 1N hydrochloric acid.Gained solution reaches after filtration and moves to the appropriate containers (casket) that is used for hand-held atomizer.
Container contents: 4.5 grams

Claims (9)

1. compound of Formula I,
Figure C018146350002C1
Wherein
R aRepresent 1-phenylethyl, 3-bromophenyl or 3-chloro-4-fluorophenyl,
R bRepresent R 3-(CH 2) m-O base, wherein
R 3Representative reaches through one or two methyl substituted 2-oxo morpholine-4-base
M represents 2 or 3 number, and
R cRepresentation methoxy, cyclobutoxy group, cyclopentyloxy, cyclo propyl methoxy, tetrahydrofuran (THF)-3-base oxygen base or tetrahydrofuran (THF) ylmethoxy,
Condition is except the following compounds:
The 4-[(3-bromophenyl) amino]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
The 4-[(3-bromophenyl) amino]-6-[2-(3-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
The 4-[(3-bromophenyl) amino]-6-[2-(5,5-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-cyclobutoxy group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-cyclo propyl methoxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-7-methoxyl group quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[2-(6,6-dimethyl-2-oxo morpholine-4-yl) oxyethyl group]-7-cyclopentyloxy quinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-7-cyclopentyloxy quinazoline, and
(R)-and the 4-[(1-phenylethyl) amino]-6-[3-(6,6-dimethyl-2-oxo morpholine-4-yl) propoxy-]-7-cyclopentyloxy quinazoline,
Or its salt.
2. the following compounds of general formula I as claimed in claim 1:
(1) amino 4-[(3-chloro-4-fluorophenyl)]-7-cyclobutoxy group-6-[3-(2,2-dimethyl-6-oxo morpholine-4-yl) propoxy-] quinazoline,
(2) amino 4-[(3-chloro-4-fluorophenyl)]-7-cyclo propyl methoxy-6-[3-(2,2-dimethyl-6-oxo morpholine-4-yl) propoxy-] quinazoline,
(3) amino 4-[(3-bromophenyl)]-6-[2-((S)-6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
(4) amino 4-[(3-bromophenyl)]-6-[2-((R)-6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
(5) amino 4-[(3-chloro-4-fluorophenyl)]-6-[2-((R)-6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
(6) amino 4-[(3-chloro-4-fluorophenyl)]-6-[3-((R)-6-methyl-2-oxo morpholine-4-yl) propoxy-]-7-methoxyl group quinazoline,
(7) amino 4-[(R)-(1-phenylethyl)]-6-[3-((S)-6-methyl-2-oxo morpholine-4-yl) propoxy-]-7-methoxyl group quinazoline,
(8) amino 4-[(R)-(1-phenylethyl)]-6-[2-((S)-6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline, and
(9) amino 4-[(3-chloro-4-fluorophenyl)]-6-[2-((S)-6-methyl-2-oxo morpholine-4-yl) oxyethyl group]-7-methoxyl group quinazoline,
Or its salt.
3. as the compound and the physiologically acceptable salt inorganic or organic acid or alkali of each general formula I in the claim 1 to 2.
4. pharmaceutical composition contains compound and one or more inert support and/or thinner just like the general formula I of claim 1 or 2.
5. be used for preventing and treat the purposes that stimulates the mucus that causes to produce to increase or change the pharmaceutical composition of the air flue that causes and lung disease because of the Tyrosine kinases in manufacturing as the compound of the general formula I of claim 1 or 2.
6. the purposes of claim 5, wherein said air flue and lung disease are the air flue inflammatory disease.
7. the purposes of claim 6, wherein said air flue inflammatory disease is chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergy or non-allergic rhinitis or sinusitis paranasal sinusitis, tumour fibrosis, alpha1-antitrypsin deficiency or cough, pulmonary emphysema, pnemnofibrosis and air flue allergy.
8. the method for preparing pharmaceutical composition as claimed in claim 4 is characterized by the compound that makes claim 1 or 2 and sneaks in one or more inert support and/or the thinner.
9. method for preparing compound of Formula I as claimed in claim 1 or its salt is characterized by:
A) make down general formula compound:
Figure C018146350004C1
Wherein
R aDefinition as claimed in claim 1,
R b' or R c' one of representation methoxy, cyclobutoxy group, cyclopentyloxy, cyclo propyl methoxy, cyclobutyl methoxy base or cyclopentyl methoxyl group, and R b' or R cAnother base of ' base is represented Z 1-(CH 2) m-O base, wherein
M definition as claimed in claim 1, and
Z 1Represent leaving group,
React with following formula: compound:
H-R 3 (III)
Wherein
R 3Definition as claimed in claim 1, or
B) make and choose the following formula: compound cyclisation that in reaction mixture, forms wantonly:
Figure C018146350005C1
Wherein
R aDefinition as claimed in claim 1,
R b" or R c" one of representation methoxy, cyclobutoxy group, cyclopentyloxy, cyclo propyl methoxy, cyclobutyl methoxy base or cyclopentyl methoxyl group and R b" or R c" another base is represented R 3'-(CH 2) m-O base, wherein
M definition as claimed in claim 1, and
R 3The R that ' representative replaces through 1 or 2 methyl or ethyl on methylene radical 4-O-CO-CH 2-N-CH 2CH 2-OH base, wherein
R 4Represent hydrogen atom or C 1-4-alkyl,
Randomly, in the above-mentioned reaction used any protecting group rupture once again and/or
The gained compound of Formula I changes into its salt, randomly when being used to prepare medicine, changes into its physiologically acceptable salt.
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