KR20030024914A - 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 PDFInfo
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Abstract
본 발명은 유용한 약물학적 특성, 특히 티로신 키나제에 의해 매개되는 신호 전달에 대한 억제 효과를 나타내는 화학식 I의 이환식 헤테로사이클, 이의 토토머, 이의 입체이성체 및 이의 염, 특히 무기 산, 유기 산, 무기 염기 또는 유기 염기와의 생리학적으로 허용되는 이의 염에 관한 것이다. 또한, 본 발명은 질환, 특히 종양성 질환과 폐 및 호흡관 질환을 치료하기 위한 당해 이환식 헤테로사이클의 용도 및 이의 제조방법에 관한 것이다.The present invention provides bicyclic heterocycles of formula I, tautomers thereof, stereoisomers and salts thereof, in particular inorganic acids, organic acids, inorganic bases, which exhibit useful pharmacological properties, in particular an inhibitory effect on signal transduction mediated by tyrosine kinases. Or a physiologically acceptable salt thereof with an organic base. The invention also relates to the use of the bicyclic heterocycle for the treatment of diseases, in particular neoplastic and pulmonary and respiratory tract diseases, and to methods for their preparation.
화학식 IFormula I
위의 화학식 I에서,In Formula I above,
Ra내지 Rc는 청구의 범위의 제1항 내지 제7항에서 정의한 바와 같다.R a to R c are as defined in claims 1 to 7.
Description
본 발명은 유용한 약물학적 특성, 특히 티로신 키나제에 의해 매개되는 신호 전달(signal transduction)에 대한 억제 효과를 나타내는 화학식 I의 이환식 헤테로사이클, 이의 토토머, 이의 입체이성체 및 이의 염, 특히 무기 산, 유기 산, 무기 염기 또는 유기 염기와의 생리학적으로 허용되는 이의 염, 질환, 특히 종양성 질환과 폐 및 호흡관 질환을 치료하기 위한 이의 용도 및 이의 제조방법에 관한 것이다.The present invention provides bicyclic heterocycles of formula I, their tautomers, their stereoisomers and salts thereof, in particular inorganic acids, organics, which exhibit useful pharmacological properties, in particular their inhibitory effect on signal transduction mediated by tyrosine kinases. It relates to physiologically acceptable salts, diseases thereof, especially tumorous diseases and lung and respiratory tract diseases with acids, inorganic bases or organic bases, and methods for their preparation.
위의 화학식 I에서,In Formula I above,
Ra는 벤질 또는 1-페닐에틸 그룹이거나, R1및 R2그룹에 의해 치환된 페닐그룹(여기서, R1은 수소원자, 불소원자, 염소원자 또는 브롬원자이거나, 메틸, 트리플루오로메틸, 시아노 또는 에티닐 그룹이고, R2는 수소원자 또는 불소원자이다)이고,R a is benzyl or 1-phenylethyl group, or a phenyl group substituted by R 1 and R 2 groups, wherein R 1 is hydrogen, fluorine, chlorine or bromine or methyl, trifluoromethyl, Cyano or ethynyl group, R 2 is a hydrogen atom or a fluorine atom),
Rb및 Rc그룹 중 하나는 R3-(CH2)m-O 그룹[여기서, R3은 N-(2-옥소-테트라하이드로푸란-4-일)-메틸아미노 또는 N-(2-옥소-테트라하이드로푸란-4-일)-에틸아미노 그룹이거나, 메틸렌 그룹이 1 또는 2개의 메틸 또는 에틸 그룹에 의해 치환된 R4-O-CO-CH2-N-CH2CH2-OH 그룹(여기서, R4는 수소원자 또는 C1-4-알킬 그룹이다) 또는 1 또는 2개의 메틸 또는 에틸 그룹에 의해 치환된 2-옥소-모르폴린-4-일 그룹이고, m은 2, 3 또는 4이다]이고, Rb및 Rc그룹 중 나머지 하나는 메톡시, 사이클로부틸옥시, 사이클로펜틸옥시, 사이클로프로필메톡시, 사이클로부틸메톡시, 사이클로펜틸메톡시, 테트라하이드로푸란-3-일옥시, 테트라하이드로피란-3-일옥시, 테트라하이드로피란-4-일옥시, 테트라하이드로푸라닐메톡시 또는 테트라하이드로피라닐메톡시 그룹이고,One of the R b and R c groups is an R 3- (CH 2 ) m -O group wherein R 3 is N- (2-oxo-tetrahydrofuran-4-yl) -methylamino or N- (2- Oxo-tetrahydrofuran-4-yl) -ethylamino group, or a R 4 —O—CO—CH 2 —N—CH 2 CH 2 —OH group, wherein the methylene group is substituted by one or two methyl or ethyl groups Wherein R 4 is a hydrogen atom or a C 1-4 -alkyl group or a 2-oxo-morpholin-4-yl group substituted by 1 or 2 methyl or ethyl groups, m is 2, 3 or 4], and the other of the R b and R c groups is methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, Tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group,
단, 화학식 Ⅰ의 화합물 중 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로펜틸옥시-7-(2-{N-(2-하이드록시-2-메틸-프로프-1-일)-N-[(에톡시카보닐)-메틸]-아미노}-에톡시)-퀴나졸린,Provided that 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2- {N- (2-hydroxy-2-methyl-prop in the compound of formula (I) -1-yl) -N-[(ethoxycarbonyl) -methyl] -amino} -ethoxy) -quinazolin,
4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로펜틸옥시-7-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] Quinazoline,
4-[(3-브로모-페닐)아미노]-6-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-7-메톡시-퀴나졸린 및4-[(3-Bromo-phenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline and
4-[(3-브로모-페닐)아미노]-6-{2-[N-(2-옥소-테트라하이드로푸란-4-일)-N-메틸-아미노]-에톡시}-7-메톡시-퀴나졸린은 제외된다.4-[(3-Bromo-phenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy} -7-meth Toxy-quinazoline is excluded.
바람직한 화학식 I의 화합물은Preferred compounds of formula (I)
Ra가 벤질 또는 1-페닐에틸 그룹이거나, R1및 R2그룹에 의해 치환된 페닐 그룹(여기서, R1은 수소원자, 불소원자, 염소원자 또는 브롬원자이거나, 메틸, 트리플루오로메틸, 시아노 또는 에티닐 그룹이고, R2는 수소원자 또는 불소원자이다)이고,R a is benzyl or 1-phenylethyl group, or a phenyl group substituted by R 1 and R 2 groups, wherein R 1 is hydrogen, fluorine, chlorine or bromine or methyl, trifluoromethyl, Cyano or ethynyl group, R 2 is a hydrogen atom or a fluorine atom),
Rb및 Rc그룹 중 하나가 R3-(CH2)m-O 그룹[여기서, R3은 N-(2-옥소-테트라하이드로푸란-4-일)-메틸아미노 또는 N-(2-옥소-테트라하이드로푸란-4-일)-에틸아미노 그룹이거나, 메틸렌 그룹이 1 또는 2개의 메틸 또는 에틸 그룹에 의해 치환된 R4-O-CO-CH2-N-CH2CH2-OH 그룹(여기서, R4는 수소원자 또는 C1-4-알킬 그룹이다) 또는 1 또는 2개의 메틸 또는 에틸 그룹에 의해 치환된 2-옥소-모르폴린-4-일 그룹이고, m은 2, 3 또는 4이다]이고, Rb및 Rc그룹 중 나머지 하나가 메톡시, 사이클로부틸옥시, 사이클로펜틸옥시, 사이클로프로필메톡시, 사이클로부틸메톡시, 사이클로펜틸메톡시, 테트라하이드로푸란-3-일옥시, 테트라하이드로피란-3-일옥시, 테트라하이드로피란-4-일옥시, 테트라하이드로푸라닐메톡시 또는 테트라하이드로피라닐메톡시 그룹이고,One of the R b and R c groups is an R 3- (CH 2 ) m -O group wherein R 3 is N- (2-oxo-tetrahydrofuran-4-yl) -methylamino or N- (2- Oxo-tetrahydrofuran-4-yl) -ethylamino group, or a R 4 —O—CO—CH 2 —N—CH 2 CH 2 —OH group, wherein the methylene group is substituted by one or two methyl or ethyl groups Wherein R 4 is a hydrogen atom or a C 1-4 -alkyl group or a 2-oxo-morpholin-4-yl group substituted by 1 or 2 methyl or ethyl groups, m is 2, 3 or 4], and the other of the R b and R c groups is methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, Tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group,
단, 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로펜틸옥시-7-(2-{N-(2-하이드록시-2-메틸-프로프-1-일)-N-[(에톡시카보닐)-메틸]-아미노}-에톡시)-퀴나졸린,Provided that 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2- {N- (2-hydroxy-2-methyl-prop-1-yl) -N-[(ethoxycarbonyl) -methyl] -amino} -ethoxy) -quinazolin,
4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로펜틸옥시-7-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] Quinazoline,
4-[(3-브로모-페닐)아미노]-6-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-7-메톡시-퀴나졸린,4-[(3-bromo-phenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
4-[(3-브로모-페닐)아미노]-6-{2-[N-(2-옥소-테트라하이드로푸란-4-일)-N-메틸-아미노]-에톡시}-7-메톡시-퀴나졸린,4-[(3-Bromo-phenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy} -7-meth Oxy-quinazoline,
4-[(3-브로모-페닐)아미노]-6-(2-{N-(2-하이드록시-2-메틸-프로프-1-일)-N-[(에톡시카보닐)메틸]-아미노}-에톡시)-7-메톡시-퀴나졸린,4-[(3-bromo-phenyl) amino] -6- (2- {N- (2-hydroxy-2-methyl-prop-1-yl) -N-[(ethoxycarbonyl) methyl ] -Amino} -ethoxy) -7-methoxy-quinazolin,
4-[(3-브로모-페닐)아미노]-6-[2-(3-메틸-2-옥소-모르폴린-4-일)에톡시]-7-메톡시-퀴나졸린,4-[(3-bromo-phenyl) amino] -6- [2- (3-methyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazolin,
4-[(3-브로모-페닐)아미노]-6-[2-(5,5-디메틸-2-옥소-모르폴린-4-일)에톡시]-7-메톡시-퀴나졸린,4-[(3-bromo-phenyl) amino] -6- [2- (5,5-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-7-메톡시-퀴나졸린,4-[(3-Chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy- Quinazolin,
4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-7-사이클로부틸옥시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclobutyloxy Quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-7-사이클로펜틸옥시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopentyloxy Quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-7-사이클로프로필메톡시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopropylme Oxy-quinazoline,
4-[(3-클로로-4-플루오로페닐]아미노]-6-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-7-사이클로펜틸메톡시-퀴나졸린,4-[(3-chloro-4-fluorophenyl] amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopentylme Oxy-quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-6-{2-[N-(2-옥소-테트라하이드로푸란-4-일)-N-메틸-아미노]-에톡시}-7-메톡시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 7-methoxy-quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-6-{2-[N-(2-옥소-테트라하이드로푸란-4-일)-N-메틸-아미노]-에톡시}-7-사이클로펜틸옥시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 7-cyclopentyloxy-quinazolin,
4-[(3-클로로-4-플루오로페닐)아미노]-6-{2-[N-(2-옥소-테트라하이드로푸란-4-일)-N-메틸-아미노]-에톡시}-7-사이클로펜틸메톡시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 7-cyclopentylmethoxy-quinazolin,
4-[(3-클로로-4-플루오로페닐)아미노]-6-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-메톡시-퀴나졸린,4-[(3-Chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-methoxy- Quinazolin,
4-[(3-클로로-4-플루오로페닐)아미노]-6-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-사이클로펜틸옥시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentyloxy Quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-6-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-사이클로펜틸메톡시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentylme Oxy-quinazoline,
(R)-4-[(1-페닐-에틸)아미노]-6-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-사이클로펜틸옥시-퀴나졸린,(R) -4-[(1-phenyl-ethyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentyloxy Quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-7-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-6-메톡시-퀴나졸린,4-[(3-Chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-methoxy- Quinazolin,
4-[(3-클로로-4-플루오로페닐)아미노]-7-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-6-사이클로부틸옥시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclobutyloxy Quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-7-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-6-사이클로펜틸옥시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopentyloxy Quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-7-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-6-사이클로프로필메톡시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopropylme Oxy-quinazoline,
4-[(3-클로로-4-플루오로페닐]아미노]-7-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-6-사이클로펜틸메톡시-퀴나졸린,4-[(3-chloro-4-fluorophenyl] amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopentylmeth Oxy-quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-7-{2-[N-(2-옥소-테트라하이드로푸란-4-일)-N-메틸-아미노]-에톡시}-6-메톡시-퀴나졸린,4-[(3-Chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 6-methoxy-quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-7-{2-[N-(2-옥소-테트라하이드로푸란-4-일)-N-메틸-아미노]-에톡시}-6-사이클로펜틸옥시-퀴나졸린,4-[(3-Chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 6-cyclopentyloxy-quinazolin,
4-[(3-클로로-4-플루오로페닐)아미노]-7-{2-[N-(2-옥소-테트라하이드로푸란-4-일)-N-메틸-아미노]-에톡시}-6-사이클로펜틸메톡시-퀴나졸린,4-[(3-Chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 6-cyclopentylmethoxy-quinazolin,
4-[(3-클로로-4-플루오로페닐)아미노]-7-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-6-메톡시-퀴나졸린,4-[(3-Chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-methoxy- Quinazolin,
4-[(3-클로로-4-플루오로페닐)아미노]-7-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-6-사이클로펜틸옥시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentyloxy Quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-7-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-6-사이클로펜틸메톡시-퀴나졸린 및4-[(3-chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentylme Oxy-quinazolin and
(R)-4-[(1-페닐-에틸)아미노]-7-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-6-사이클로펜틸옥시-퀴나졸린을 제외한 화합물, 이의 토토머, 이의 입체이성체 및 이의 염이고,(R) -4-[(1-phenyl-ethyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentyloxy -Compounds other than quinazoline, tautomers thereof, stereoisomers thereof and salts thereof,
특히Especially
Ra가 1-페닐에틸 그룹이거나 R1및 R2그룹에 의해 치환된 페닐 그룹(여기서, R1은 불소원자, 염소원자 또는 브롬원자이거나, 메틸 또는 에티닐 그룹이고, R2는 수소원자 또는 불소원자이다)이고,R a is a 1-phenylethyl group or a phenyl group substituted by R 1 and R 2 groups, wherein R 1 is a fluorine atom, a chlorine atom or a bromine atom, a methyl or ethynyl group, and R 2 is a hydrogen atom or Fluorine atom),
Rb및 Rc그룹 중 하나가 R3-(CH2)m-O 그룹[여기서, R3은 N-(2-옥소-테트라하이드로푸란-4-일)-메틸아미노 그룹이거나, 메틸렌 그룹이 1 또는 2개의 메틸 그룹에 의해 치환된 R4-O-CO-CH2-N-CH2CH2-OH 그룹(여기서, R4는 C1-4-알킬 그룹이다) 또는 1 또는 2개의 메틸 그룹에 의해 치환된 2-옥소-모르폴린-4-일 그룹이고, m은 2, 3 또는 4이다]이고, Rb및 Rc그룹 중 나머지 하나가 메톡시, 사이클로부틸옥시, 사이클로펜틸옥시, 사이클로프로필메톡시, 사이클로부틸메톡시, 사이클로펜틸메톡시, 테트라하이드로푸란-3-일옥시, 테트라하이드로피란-3-일옥시, 테트라하이드로피란-4-일옥시, 테트라하이드로푸라닐메톡시 또는 테트라하이드로피라닐메톡시 그룹이고,One of the R b and R c groups is an R 3- (CH 2 ) m -O group wherein R 3 is an N- (2-oxo-tetrahydrofuran-4-yl) -methylamino group, or the methylene group is R 4 —O—CO—CH 2 —N—CH 2 CH 2 —OH groups substituted by 1 or 2 methyl groups, wherein R 4 is a C 1-4 -alkyl group or 1 or 2 methyl 2-oxo-morpholin-4-yl group substituted by a group, m is 2, 3 or 4], and the other of the R b and R c groups is methoxy, cyclobutyloxy, cyclopentyloxy, Cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydro Pyranylmethoxy group,
단, 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로펜틸옥시-7-(2-{N-(2-하이드록시-2-메틸-프로프-1-일)-N-[(에톡시카보닐)-메틸]-아미노}-에톡시)-퀴나졸린,Provided that 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2- {N- (2-hydroxy-2-methyl-prop-1-yl) -N-[(ethoxycarbonyl) -methyl] -amino} -ethoxy) -quinazolin,
4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로펜틸옥시-7-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] Quinazoline,
4-[(3-브로모-페닐)아미노]-6-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-7-메톡시-퀴나졸린,4-[(3-bromo-phenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
4-[(3-브로모-페닐)아미노]-6-{2-[N-(2-옥소-테트라하이드로푸란-4-일)-N-메틸-아미노]-에톡시}-7-메톡시-퀴나졸린,4-[(3-Bromo-phenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy} -7-meth Oxy-quinazoline,
4-[(3-브로모-페닐)아미노]-6-(2-{N-(2-하이드록시-2-메틸-프로프-1-일)-N-[(에톡시카보닐)메틸]-아미노}-에톡시)-7-메톡시-퀴나졸린,4-[(3-bromo-phenyl) amino] -6- (2- {N- (2-hydroxy-2-methyl-prop-1-yl) -N-[(ethoxycarbonyl) methyl ] -Amino} -ethoxy) -7-methoxy-quinazolin,
4-[(3-브로모-페닐)아미노]-6-[2-(3-메틸-2-옥소-모르폴린-4-일)에톡시]-7-메톡시-퀴나졸린,4-[(3-bromo-phenyl) amino] -6- [2- (3-methyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazolin,
4-[(3-브로모-페닐)아미노]-6-[2-(5,5-디메틸-2-옥소-모르폴린-4-일)에톡시]-7-메톡시-퀴나졸린,4-[(3-bromo-phenyl) amino] -6- [2- (5,5-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-7-메톡시-퀴나졸린,4-[(3-Chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy- Quinazolin,
4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-7-사이클로부틸옥시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclobutyloxy Quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-7-사이클로펜틸옥시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopentyloxy Quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-7-사이클로프로필메톡시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopropylme Oxy-quinazoline,
4-[(3-클로로-4-플루오로페닐]아미노]-6-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-7-사이클로펜틸메톡시-퀴나졸린,4-[(3-chloro-4-fluorophenyl] amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopentylme Oxy-quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-6-{2-[N-(2-옥소-테트라하이드로푸란-4-일)-N-메틸-아미노]-에톡시}-7-메톡시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 7-methoxy-quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-6-{2-[N-(2-옥소-테트라하이드로푸란-4-일)-N-메틸-아미노]-에톡시}-7-사이클로펜틸옥시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 7-cyclopentyloxy-quinazolin,
4-[(3-클로로-4-플루오로페닐)아미노]-6-{2-[N-(2-옥소-테트라하이드로푸란-4-일)-N-메틸-아미노]-에톡시}-7-사이클로펜틸메톡시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 7-cyclopentylmethoxy-quinazolin,
4-[(3-클로로-4-플루오로페닐)아미노]-6-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-메톡시-퀴나졸린,4-[(3-Chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-methoxy- Quinazolin,
4-[(3-클로로-4-플루오로페닐)아미노]-6-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-사이클로펜틸옥시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentyloxy Quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-6-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-사이클로펜틸메톡시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentylme Oxy-quinazoline,
(R)-4-[(1-페닐-에틸)아미노]-6-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-사이클로펜틸옥시-퀴나졸린,(R) -4-[(1-phenyl-ethyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentyloxy Quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-7-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-6-메톡시-퀴나졸린,4-[(3-Chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-methoxy- Quinazolin,
4-[(3-클로로-4-플루오로페닐)아미노]-7-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-6-사이클로부틸옥시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclobutyloxy Quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-7-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-6-사이클로펜틸옥시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopentyloxy Quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-7-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-6-사이클로프로필메톡시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopropylme Oxy-quinazoline,
4-[(3-클로로-4-플루오로페닐]아미노]-7-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-6-사이클로펜틸메톡시-퀴나졸린,4-[(3-chloro-4-fluorophenyl] amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopentylmeth Oxy-quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-7-{2-[N-(2-옥소-테트라하이드로푸란-4-일)-N-메틸-아미노]-에톡시}-6-메톡시-퀴나졸린,4-[(3-Chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 6-methoxy-quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-7-{2-[N-(2-옥소-테트라하이드로푸란-4-일)-N-메틸-아미노]-에톡시}-6-사이클로펜틸옥시-퀴나졸린,4-[(3-Chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 6-cyclopentyloxy-quinazolin,
4-[(3-클로로-4-플루오로페닐)아미노]-7-{2-[N-(2-옥소-테트라하이드로푸란-4-일)-N-메틸-아미노]-에톡시}-6-사이클로펜틸메톡시-퀴나졸린,4-[(3-Chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 6-cyclopentylmethoxy-quinazolin,
4-[(3-클로로-4-플루오로페닐)아미노]-7-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-6-메톡시-퀴나졸린,4-[(3-Chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-methoxy- Quinazolin,
4-[(3-클로로-4-플루오로페닐)아미노]-7-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-6-사이클로펜틸옥시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentyloxy Quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-7-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-6-사이클로펜틸메톡시-퀴나졸린 및4-[(3-chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentylme Oxy-quinazolin and
(R)-4-[(1-페닐-에틸)아미노]-7-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-6-사이클로펜틸옥시-퀴나졸린을 제외한 화합물, 이의 토토머, 이의 입체이성체 및 이의 염이다.(R) -4-[(1-phenyl-ethyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentyloxy -Compounds other than quinazoline, tautomers thereof, stereoisomers thereof and salts thereof.
특히 바람직한 화학식 I의 화합물은Particularly preferred compounds of formula I are
Ra가 1-페닐에틸 그룹이거나, R1및 R2그룹에 의해 치환된 페닐 그룹(여기서, R1은 불소원자, 염소원자 또는 브롬원자이고, R2는 수소원자 또는 불소원자이다)이고,R a is a 1-phenylethyl group or is a phenyl group substituted by R 1 and R 2 groups, wherein R 1 is a fluorine atom, a chlorine atom or a bromine atom, and R 2 is a hydrogen atom or a fluorine atom,
Rb및 Rc그룹 중 하나가 R3-(CH2)m-O 그룹[여기서, R3은 N-(2-옥소-테트라하이드로푸란-4-일)-메틸아미노 그룹이거나, 1 또는 2개의 메틸 그룹에 의해 치환된 2-옥소-모르폴린-4-일 그룹이고, m은 2, 3 또는 4이다]이고, Rb및 Rc그룹 중 나머지 하나가 메톡시, 사이클로부틸옥시, 사이클로펜틸옥시, 사이클로프로필메톡시, 사이클로부틸메톡시, 사이클로펜틸메톡시, 테트라하이드로푸란-3-일옥시, 테트라하이드로피란-3-일옥시, 테트라하이드로피란-4-일옥시, 테트라하이드로푸라닐메톡시 또는 테트라하이드로피라닐메톡시 그룹이고,One of the R b and R c groups is an R 3- (CH 2 ) m -O group wherein R 3 is an N- (2-oxo-tetrahydrofuran-4-yl) -methylamino group, or 1 or 2 2-oxo-morpholin-4-yl group substituted by 2 methyl groups, m is 2, 3 or 4] and the other of the R b and R c groups is methoxy, cyclobutyloxy, cyclopentyl Oxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or Tetrahydropyranylmethoxy group,
단, 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로펜틸옥시-7-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-퀴나졸린,Provided that 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl)- Oxy] -quinazoline,
4-[(3-브로모-페닐)아미노]-6-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-7-메톡시-퀴나졸린,4-[(3-bromo-phenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
4-[(3-브로모-페닐)아미노]-6-{2-[N-(2-옥소-테트라하이드로푸란-4-일)-N-메틸-아미노]-에톡시}-7-메톡시-퀴나졸린,4-[(3-Bromo-phenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy} -7-meth Oxy-quinazoline,
4-[(3-브로모-페닐)아미노]-6-[2-(3-메틸-2-옥소-모르폴린-4-일)-에톡시]-7-메톡시-퀴나졸린,4-[(3-bromo-phenyl) amino] -6- [2- (3-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazolin,
4-[(3-브로모-페닐)아미노]-6-[2-(5,5-디메틸-2-옥소-모르폴린-4-일)에톡시]-7-메톡시-퀴나졸린,4-[(3-bromo-phenyl) amino] -6- [2- (5,5-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-7-메톡시-퀴나졸린,4-[(3-Chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy- Quinazolin,
4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-7-사이클로부틸옥시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclobutyloxy Quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-7-사이클로펜틸옥시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopentyloxy Quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-7-사이클로프로필메톡시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopropylme Oxy-quinazoline,
4-[(3-클로로-4-플루오로페닐]아미노]-6-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-7-사이클로펜틸메톡시-퀴나졸린,4-[(3-chloro-4-fluorophenyl] amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopentylme Oxy-quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-6-{2-[N-(2-옥소-테트라하이드로푸란-4-일)-N-메틸-아미노]-에톡시}-7-메톡시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 7-methoxy-quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-6-{2-[N-(2-옥소-테트라하이드로푸란-4-일)-N-메틸-아미노]-에톡시}-7-사이클로펜틸옥시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 7-cyclopentyloxy-quinazolin,
4-[(3-클로로-4-플루오로페닐)아미노]-6-{2-[N-(2-옥소-테트라하이드로푸란-4-일)-N-메틸-아미노]-에톡시}-7-사이클로펜틸메톡시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 7-cyclopentylmethoxy-quinazolin,
4-[(3-클로로-4-플루오로페닐)아미노]-6-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-메톡시-퀴나졸린,4-[(3-Chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-methoxy- Quinazolin,
4-[(3-클로로-4-플루오로페닐)아미노]-6-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-사이클로펜틸옥시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentyloxy Quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-6-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-사이클로펜틸메톡시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentylme Oxy-quinazoline,
(R)-4-[(1-페닐-에틸)아미노]-6-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-사이클로펜틸옥시-퀴나졸린,(R) -4-[(1-phenyl-ethyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentyloxy Quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-7-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-6-메톡시-퀴나졸린,4-[(3-Chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-methoxy- Quinazolin,
4-[(3-클로로-4-플루오로페닐)아미노]-7-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-6-사이클로부틸옥시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclobutyloxy Quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-7-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-6-사이클로펜틸옥시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopentyloxy Quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-7-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-6-사이클로프로필메톡시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopropylme Oxy-quinazoline,
4-[(3-클로로-4-플루오로페닐]아미노]-7-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-6-사이클로펜틸메톡시-퀴나졸린,4-[(3-chloro-4-fluorophenyl] amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopentylmeth Oxy-quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-7-{2-[N-(2-옥소-테트라하이드로푸란-4-일)-N-메틸-아미노]-에톡시}-6-메톡시-퀴나졸린,4-[(3-Chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 6-methoxy-quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-7-{2-[N-(2-옥소-테트라하이드로푸란-4-일)-N-메틸-아미노]-에톡시}-6-사이클로펜틸옥시-퀴나졸린,4-[(3-Chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 6-cyclopentyloxy-quinazolin,
4-[(3-클로로-4-플루오로페닐)아미노]-7-{2-[N-(2-옥소-테트라하이드로푸란-4-일)-N-메틸-아미노]-에톡시}-6-사이클로펜틸메톡시-퀴나졸린,4-[(3-Chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 6-cyclopentylmethoxy-quinazolin,
4-[(3-클로로-4-플루오로페닐)아미노]-7-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-6-메톡시-퀴나졸린,4-[(3-Chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-methoxy- Quinazolin,
4-[(3-클로로-4-플루오로페닐)아미노]-7-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-6-사이클로펜틸옥시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentyloxy Quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-7-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-6-사이클로펜틸메톡시-퀴나졸린 및4-[(3-chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentylme Oxy-quinazolin and
(R)-4-[(1-페닐-에틸)아미노]-7-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-6-사이클로펜틸옥시-퀴나졸린을 제외한 화합물, 이의 토토머, 이의 입체이성체 및 이의 염이다.(R) -4-[(1-phenyl-ethyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentyloxy -Compounds other than quinazoline, tautomers thereof, stereoisomers thereof and salts thereof.
가장 특히 바람직한 화학식 I의 화합물은Most particularly preferred compounds of formula I are
Ra가 1-페닐에틸, 3-브로모페닐 또는 3-클로로-4-플루오로페닐 그룹이고,R a is 1-phenylethyl, 3-bromophenyl or 3-chloro-4-fluorophenyl group,
Rb가 R3-(CH2)m-O 그룹(여기서, R3은 1 또는 2개의 메틸 그룹에 의해 치환된 2-옥소-모르폴린-4-일 그룹이고, m은 2 또는 3이다)이고,R b is a R 3- (CH 2 ) m -O group wherein R 3 is a 2-oxo-morpholin-4-yl group substituted by one or two methyl groups, m is 2 or 3 ego,
Rc가 메톡시, 사이클로부틸옥시, 사이클로펜틸옥시, 사이클로프로필메톡시, 테트라하이드로푸란-3-일옥시 또는 테트라하이드로푸라닐메톡시 그룹이고,R c is a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, tetrahydrofuran-3-yloxy or tetrahydrofuranylmethoxy group,
단, 4-[(3-브로모-페닐)아미노]-6-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-7-메톡시-퀴나졸린,Provided that 4-[(3-bromo-phenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quina Sleepy,
4-[(3-브로모-페닐)아미노]-6-[2-(3-메틸-2-옥소-모르폴린-4-일)에톡시]-7-메톡시-퀴나졸린,4-[(3-bromo-phenyl) amino] -6- [2- (3-methyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazolin,
4-[(3-브로모-페닐)아미노]-6-[2-(5,5-디메틸-2-옥소-모르폴린-4-일)에톡시]-7-메톡시-퀴나졸린,4-[(3-bromo-phenyl) amino] -6- [2- (5,5-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-7-메톡시-퀴나졸린,4-[(3-Chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy- Quinazolin,
4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-7-사이클로부틸옥시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclobutyloxy Quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-7-사이클로프로필메톡시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopropylme Oxy-quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-6-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-메톡시-퀴나졸린,4-[(3-Chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-methoxy- Quinazolin,
4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-7-사이클로펜틸옥시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopentyloxy Quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-6-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-사이클로펜틸옥시-퀴나졸린 및4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentyloxy Quinazoline and
(R)-4-[(1-페닐-에틸)아미노]-6-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-사이클로펜틸옥시-퀴나졸린을 제외한 화합물, 이의 토토머, 이의 입체이성체 및 이의 염이다.(R) -4-[(1-phenyl-ethyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentyloxy -Compounds other than quinazoline, tautomers thereof, stereoisomers thereof and salts thereof.
가장 특히 바람직한 화학식 I의 화합물은Most particularly preferred compounds of formula I are
Ra가 3-클로로-4-플루오로페닐 그룹이고,R a is a 3-chloro-4-fluorophenyl group,
Rb가 사이클로펜틸옥시, 사이클로프로필메톡시, 사이클로펜틸메톡시, 테트라하이드로푸란-3-일옥시 또는 테트라하이드로푸라닐메톡시 그룹이고,R b is cyclopentyloxy, cyclopropylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy or tetrahydrofuranylmethoxy group,
Rc가 R3-(CH2)m-O 그룹(여기서, R3은 1 또는 2개의 메틸 그룹에 의해 치환된 2-옥소-모르폴린-4-일 그룹이고, m은 2이다)이고,R c is an R 3 — (CH 2 ) m —O group wherein R 3 is a 2-oxo-morpholin-4-yl group substituted by one or two methyl groups, m is 2, and
단, 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로펜틸옥시-7-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-퀴나졸린,Provided that 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl)- Oxy] -quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-7-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-6-사이클로펜틸옥시-퀴나졸린,4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopentyloxy Quinazoline,
4-[(3-클로로-4-플루오로페닐)아미노]-7-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-6-사이클로프로필메톡시-퀴나졸린 및4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopropylme Oxy-quinazolin and
4-[(3-클로로-4-플루오로페닐]아미노]-7-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-6-사이클로펜틸메톡시-퀴나졸린을 제외한 화합물, 이의 토토머, 이의 입체이성체 및 이의 염이다.4-[(3-chloro-4-fluorophenyl] amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopentylmeth Compounds except oxy-quinazolin, tautomers thereof, stereoisomers thereof and salts thereof.
가장 특히 바람직한 화합물로서 다음의 화합물을 예시한다:As the most particularly preferred compounds the following compounds are exemplified:
(1) 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로펜틸메톡시-7-[2-(2,2-디메틸-6-옥소-모르폴린-4-일)-에톡시]-퀴나졸린,(1) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy-7- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -Ethoxy] -quinazolin,
(2) 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로펜틸옥시-7-{2-[N-(2-옥소-테트라하이드로푸란-4-일)-N-메틸-아미노]-에톡시}-퀴나졸린,(2) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N- Methyl-amino] -ethoxy} -quinazolin,
(3) 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로프로필메톡시-7-[2-(2,2-디메틸-6-옥소-모르폴린-4-일)-에톡시]-퀴나졸린,(3) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -Ethoxy] -quinazolin,
(4) 4-[(3-클로로-4-플루오로페닐)아미노]-7-사이클로부틸옥시-6-[3-(2,2-디메틸-6-옥소-모르폴린-4-일)-프로필옥시]-퀴나졸린,(4) 4-[(3-chloro-4-fluorophenyl) amino] -7-cyclobutyloxy-6- [3- (2,2-dimethyl-6-oxo-morpholin-4-yl)- Propyloxy] -quinazolin,
(5) 4-[(3-클로로-4-플루오로페닐)아미노]-7-사이클로프로필메톡시-6-[3-(2,2-디메틸-6-옥소-모르폴린-4-일)-프로필옥시]-퀴나졸린,(5) 4-[(3-chloro-4-fluorophenyl) amino] -7-cyclopropylmethoxy-6- [3- (2,2-dimethyl-6-oxo-morpholin-4-yl) -Propyloxy] -quinazolin,
(6) 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로프로필메톡시-7-{2-[N-(2-옥소-테트라하이드로푸란-4-일)-N-메틸-아미노]-에톡시}-퀴나졸린,(6) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N -Methyl-amino] -ethoxy} -quinazolin,
(7) 4-[(3-브로모-페닐)아미노]-6-[2-((S)-6-메틸-2-옥소-모르폴린-4-일)-에톡시]-7-메톡시-퀴나졸린,(7) 4-[(3-bromo-phenyl) amino] -6- [2-((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-meth Oxy-quinazoline,
(8) 4-[(3-브로모-페닐)아미노]-6-[2-((R)-6-메틸-2-옥소-모르폴린-4-일)-에톡시]-7-메톡시-퀴나졸린,(8) 4-[(3-bromo-phenyl) amino] -6- [2-((R) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-meth Oxy-quinazoline,
(9) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-((R)-6-메틸-2-옥소-모르폴린-4-일)-에톡시]-7-메톡시-퀴나졸린,(9) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2-((R) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy]- 7-methoxy-quinazoline,
(10) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[3-((R)-6-메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-메톡시-퀴나졸린,(10) 4-[(3-chloro-4-fluorophenyl) amino] -6- [3-((R) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy]- 7-methoxy-quinazoline,
(11) 4-[(R)-(1-페닐-에틸)아미노]-6-[3-((S)-6-메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-메톡시-퀴나졸린,(11) 4-[(R)-(1-phenyl-ethyl) amino] -6- [3-((S) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy]- 7-methoxy-quinazoline,
(12) 4-[(R)-(1-페닐-에틸)아미노]-6-[2-((S)-6-메틸-2-옥소-모르폴린-4-일)-에톡시]-7-메톡시-퀴나졸린 및(12) 4-[(R)-(1-phenyl-ethyl) amino] -6- [2-((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy]- 7-methoxy-quinazoline and
(13) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-((S)-6-메틸-2-옥소-모르폴린-4-일)-에톡시]-7-메톡시-퀴나졸린, 및(13) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2-((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy]- 7-methoxy-quinazoline, and
이의 토토머, 이의 입체이성체 및 이의 염.Tautomers thereof, stereoisomers thereof and salts thereof.
화학식 I의 화합물은, 예를 들면, 아래의 방법들로 제조할 수 있다.Compounds of formula (I) can be prepared, for example, by the following methods.
(a) 화학식 II의 화합물을 화학식 III의 화합물과 반응시키는 방법.(a) A method of reacting a compound of Formula II with a compound of Formula III.
위의 화학식 II에서,In Formula II above,
Ra은 위에서 정의한 바와 같고,R a is as defined above,
Rb' 및 Rc' 그룹 중 하나는 메톡시, 사이클로부틸옥시, 사이클로펜틸옥시, 사이클로프로필메톡시, 사이클로부틸메톡시 또는 사이클로펜틸메톡시 그룹이고, Rb'및 Rc' 그룹 중 나머지 하나는 Z1-(CH2)m-O 그룹(여기서, m은 위에서 정의한 바와 같고, Z1은 이탈 그룹, 예를 들면, 할로겐 원자 또는 설포닐옥시 그룹, 예를 들면, 염소원자, 브롬원자, 메탄설포닐옥시 그룹 또는 p-톨루엔설포닐옥시 그룹이다)이다.One of the R b 'and R c ' groups is a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy group, the other of the R b 'and R c ' groups Is a Z 1- (CH 2 ) m -O group wherein m is as defined above and Z 1 is a leaving group, for example a halogen atom or a sulfonyloxy group, for example a chlorine atom, a bromine atom, Methanesulfonyloxy group or p-toluenesulfonyloxy group).
위의 화학식 III에서,In Formula III above,
R3은 위에서 정의한 바와 같다.R 3 is as defined above.
반응은 용매 또는 용매 혼합물, 예를 들면, 메틸렌 클로라이드, 아세토니트릴, 디메틸포름아미드, 디메틸설폭사이드, 설폴란, 벤젠, 톨루엔, 클로로벤젠, 테트라하이드로푸란, 벤젠/테트라하이드로푸란 또는 디옥산 속에서, 편리하게는 3급 유기 염기, 예를 들면, 트리에틸아민 또는 N-에틸-디이소프로필아민의 존재하에(반면에 이들 유기 염기는 동시에 용매로서도 작용할 수 있다) 또는 무기 염기, 예를 들면, 탄산나트륨 또는 탄산칼륨의 존재하에, 편의상 -20 내지 200℃, 바람직하게는 0 내지 150℃의 온도에서 임의로 수행한다.The reaction is carried out in a solvent or solvent mixture, for example methylene chloride, acetonitrile, dimethylformamide, dimethylsulfoxide, sulfolane, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, Conveniently in the presence of a tertiary organic base such as triethylamine or N-ethyl-diisopropylamine (whereas these organic bases can also act as solvent at the same time) or an inorganic base such as sodium carbonate Or in the presence of potassium carbonate, optionally at a temperature of −20 to 200 ° C., preferably 0 to 150 ° C. for convenience.
(b) 반응 혼합물 속에서 임의로 형성된 화학식 IV의 화합물을 폐환시키는 방법.(b) ring closure of the compound of formula IV optionally formed in the reaction mixture.
위의 화학식 IV에서,In Formula IV above,
Ra는 위에서 정의한 바와 같고,R a is as defined above,
Rb" 및 Rc" 그룹 중 하나는 메톡시, 사이클로부틸옥시, 사이클로펜틸옥시, 사이클로프로필메톡시, 사이클로부틸메톡시 또는 사이클로펜틸메톡시 그룹이고, Rb" 및 Rc" 그룹 중 나머지 하나는 R3'-(CH2)m-O 그룹[여기서, m은 위에서 정의한 바와 같고, R3'은 메틸렌 그룹이 1 또는 2개의 메틸 또는 에틸 그룹에 의해 치환된 R4-O-CO-CH2-N-CH2CH2-OH 그룹(여기서, R4는 수소원자 또는 C1-4-알킬 그룹이다)이다]이다.One of the R b "and R c " groups is a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy group, and the other of the R b "and R c " groups Is a R 3 '-(CH 2 ) m -O group wherein m is as defined above and R 3 ' is a R 4 -O-CO-CH wherein the methylene group is substituted by one or two methyl or ethyl groups 2 -N-CH 2 CH 2 -OH group wherein R 4 is a hydrogen atom or a C 1-4 -alkyl group.
반응은 용매 또는 용매 혼합물, 예를 들면, 메틸렌 클로라이드, 아세토니트릴, 디메틸포름아미드, 디메틸 설폭사이드, 설폴란, 벤젠, 톨루엔, 클로로벤젠, 테트라하이드로푸란, 벤젠/테트라하이드로푸란 또는 디옥산 속에서, 편의상 무수 산, 예를 들면, 트리플루오로아세트산, 메탄설폰산 또는 황산의 존재하에 또는 탈수제, 예를 들면, 이소부틸 클로로포르메이트, 티오닐 클로라이드, 트리메틸클로로실란, 삼염화인, 오염화인, N,N'-디사이클로헥실카보디이미드, N,N'-디사이클로헥실-카보디이미드/N-하이드록시석신이미드 또는 1-하이드록시-벤조트리아졸, N,N'-카보닐디이미다졸 또는 트리페닐포스핀/사염화탄소의 존재하에, -20 내지 200℃, 바람직하게는 -10 내지 160℃의 온도에서 임의로 수행한다.The reaction is carried out in a solvent or solvent mixture, for example methylene chloride, acetonitrile, dimethylformamide, dimethyl sulfoxide, sulfolane, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, For convenience, in the presence of anhydrous acids such as trifluoroacetic acid, methanesulfonic acid or sulfuric acid or dehydrating agents such as isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentachloride, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexyl-carbodiimide / N-hydroxysuccinimide or 1-hydroxy-benzotriazole, N, N'-carbonyldiimidazole or Optionally in the presence of triphenylphosphine / carbon tetrachloride at a temperature of -20 to 200 ° C, preferably -10 to 160 ° C.
위에 기재한 반응에서, 존재하는 임의의 반응성 그룹, 예를 들면, 하이드록시, 카복시 또는 이미노 그룹은 반응 후에 다시 분해되는 통상적인 보호 그룹에 의해 반응 동안 보호될 수 있다.In the reactions described above, any reactive groups present, such as hydroxy, carboxy or imino groups, may be protected during the reaction by conventional protecting groups which decompose again after the reaction.
예를 들면, 하이드록시 그룹에 대한 보호 그룹은 트리메틸실릴, 아세틸, 벤조일, 메틸, 에틸, 3급-부틸, 트리틸, 벤질 또는 테트라하이드로피라닐 그룹일 수 있고, 카복시 그룹에 대한 보호 그룹은 트리메틸실릴, 메틸, 에틸, 3급-부틸, 벤질 또는 테트라하이드로피라닐 그룹일 수 있고, 이미노 그룹에 대한 보호 그룹은 포르밀, 아세틸, 트리플루오로아세틸, 에톡시카보닐, 3급-부톡시카보닐, 벤질옥시카보닐, 벤질, 메톡시벤질 또는 2,4-디메톡시벤질 그룹일 수 있다.For example, a protecting group for a hydroxy group can be a trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert-butyl, trityl, benzyl or tetrahydropyranyl group and the protecting group for a carboxy group is trimethyl May be silyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl groups, and the protecting group for the imino group is formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxy Carbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl groups.
사용된 임의의 보호 그룹은, 예를 들면, 수성 용매, 예를 들면, 물, 이소프로판올/물, 아세트산/물, 테트라하이드로푸란/물 또는 디옥산/물 속에서 산, 예를 들면, 트리플루오로아세트산, 염산 또는 황산의 존재하에 또는 알칼리 금속 염기, 예를 들면, 수산화나트륨 또는 수산화칼륨의 존재하에 또는 비양성자성 용매, 예를 들면, 요오도트리메틸실란의 존재하에 0 내지 120℃, 바람직하게는 10 내지 100℃의 온도에서 가수분해시킴으로써 이후에 임의로 분해시킨다.Any protecting group used is, for example, an acid, for example trifluoro, in an aqueous solvent such as water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water. 0 to 120 ° C., preferably in the presence of acetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as sodium or potassium hydroxide or in the presence of an aprotic solvent such as iodotrimethylsilane It is then optionally decomposed by hydrolysis at a temperature of 10 to 100 ° C.
그러나, 벤질, 메톡시벤질 또는 벤질옥시카보닐 그룹은, 예를 들면, 가수소분해에 의해, 예를 들면, 수소를 사용하여 적합한 용매, 예를 들면, 메탄올, 에탄올, 에틸 아세테이트 또는 빙초산 속에서 촉매, 예를 들면, 팔라듐/목탄의 존재하에, 임의로 산, 예를 들면, 염산을 가하여 0 내지 100℃, 바람직하게는 20 내지 60℃의 온도 및 1 내지 7bar, 바람직하게는 3 내지 5bar의 수소압에서 분해시킨다. 그러나, 2,4-디메톡시벤질 그룹은 바람직하게는 아니솔의 존재하에 트리플루오로아세트산 속에서 분해시킨다.However, benzyl, methoxybenzyl or benzyloxycarbonyl groups can be, for example, by hydrogenolysis, for example with hydrogen, in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid. In the presence of a catalyst, for example palladium / charcoal, optionally an acid, for example hydrochloric acid, is added to a temperature of 0 to 100 ° C., preferably 20 to 60 ° C. and hydrogen of 1 to 7 bar, preferably 3 to 5 bar. Decompose at pressure. However, the 2,4-dimethoxybenzyl group is decomposed in trifluoroacetic acid, preferably in the presence of anisole.
바람직하게는 3급-부틸 또는 3급-부틸옥시카보닐 그룹은 용매, 예를 들면, 메틸렌 클로라이드, 디옥산, 메탄올 또는 디에틸 에테르를 임의로 사용하여 요오도트리메틸실란으로 처리하거나 산, 예를 들면, 트리플루오로아세트산 또는 염산으로 처리하여 분해시킨다.Preferably tert-butyl or tert-butyloxycarbonyl groups are treated with iodotrimethylsilane or optionally acidic, for example using a solvent such as methylene chloride, dioxane, methanol or diethyl ether. Decompose by treating with trifluoroacetic acid or hydrochloric acid.
바람직하게는 트리플루오로아세틸 그룹은 50 내지 120℃의 온도에서 임의로 용매, 예를 들면, 아세트산의 존재하에 산, 예를 들면, 염산으로 처리하거나, 0 내지 50℃의 온도에서 임의로 용매, 예를 들면, 테트라하이드로푸란의 존재하에 수산화나트륨 용액으로 처리하여 분해시킨다.Preferably the trifluoroacetyl group is treated with an acid, for example hydrochloric acid, optionally in the presence of a solvent, for example acetic acid, at a temperature of 50 to 120 ° C., or optionally at a temperature of 0 to 50 ° C. For example, it is decomposed by treatment with sodium hydroxide solution in the presence of tetrahydrofuran.
게다가, 수득된 화학식 I의 화합물을 위에서 언급한 바와 같이 이들의 거울상이성체 및/또는 부분입체 이성체로 분할할 수 있다. 따라서, 예를 들면, 시스/트랜스 혼합물을 이들의 시스 및 트랜스 이성체로 분할할 수 있고 하나 이상의 광학 활성 탄소원자를 갖는 화합물을 이들의 거울상이성체로 분리할 수 있다.In addition, the compounds of formula (I) obtained can be divided into their enantiomers and / or diastereomers as mentioned above. Thus, for example, the cis / trans mixtures can be divided into their cis and trans isomers and the compounds with one or more optically active carbon atoms can be separated into their enantiomers.
따라서, 예를 들면, 시스/트랜스 혼합물을 크로마토그래피로 이들의 시스 및 트랜스 이성체로 분할할 수 있고, 라세미체로서 수득된 화학식 I의 화합물을 본래 공지된 방법[참조: Allinger N. L. and Eliel E. L., "Topics inStereochemistry", Vol. 6, Wiley Interscience, 1971]으로 이들의 광학 대장체로 분리할 수 있고, 둘 이상의 비대칭 탄소원자를 갖는 화학식 I의 화합물을 본래 공지된 방법, 예를 들면, 크로마토그래피 및/또는 분별 결정법으로 이들의 물리화학적 차이를 기준으로 하여 이들의 부분입체 이성체로 분할할 수 있고, 이들 화합물들이 라세미 형태로 수득되는 경우에는 위에서 언급한 바와 같이 이후에 거울상이성체로 분할할 수 있다.Thus, for example, the cis / trans mixtures can be chromatographically divided into their cis and trans isomers, and the compounds of formula (I) obtained as racemates can be obtained from the methods known per se by the known methods [Allinger NL and Eliel EL, "Topics inStereochemistry", Vol. 6, Wiley Interscience, 1971], wherein the compounds of formula I, which have two or more asymmetric carbon atoms, can be separated by their optical cognate, and their physicochemical properties are inherently known by methods such as chromatography and / or fractional crystallization. On the basis of the differences can be divided into their diastereomers, and if these compounds are obtained in racemic form, they can be subsequently divided into enantiomers as mentioned above.
바람직하게는 거울상이성체는 키랄 상(chiral phase)에 대한 컬럼 분리 또는 광학 활성 용매로부터의 재결정화로 분리하거나, 라세미 화합물과 염 또는 유도체, 예를 들면, 에스테르 또는 아미드를 형성하는 광학 활성 물질, 특히 산 및 이들의 활성화 유도체 또는 알콜과 반응시키고, 이렇게 하여 수득된 염 또는 유도체의 부분입체 이성체성 혼합물을, 예를 들면, 이들의 용해도 차이를 기준으로 하여 분리하는 반면, 유리 대장체는 적합한 제제의 작용에 의해 순수한 부분입체 이성체성 염 또는 유도체로부터 방출시킬 수 있다. 통상 사용되는 광학 활성 산은, 예를 들면, D- 및 L-형태의 타르타르산 또는 디벤조일타르타르산, 디-o-톨릴타르타르산, 말산, 만델산, 캄포르설폰산, 글루탐산, 아스파르트산 또는 퀸산이다. 광학 활성 알콜은, 예를 들면, (+) 또는 (-)-멘톨이고, 아미드 내의 광학 활성 아실 그룹은, 예를 들면, (+)- 또는 (-)-메틸옥시카보닐일 수 있다.Preferably, the enantiomers are separated by column separation for the chiral phase or recrystallization from the optically active solvent, or optically active substances, in particular, which form salts or derivatives, eg esters or amides, with racemic compounds Reactions with acids and their activating derivatives or alcohols and diastereomeric mixtures of the salts or derivatives thus obtained are separated, for example, on the basis of their solubility difference, whereas the free colon is a By action can be released from pure diastereomeric salts or derivatives. Commonly used optically active acids are, for example, tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid in the D- and L-forms. The optically active alcohol is, for example, (+) or (-)-menthol, and the optically active acyl group in the amide can be, for example, (+)-or (-)-methyloxycarbonyl.
또한, 화학식 I의 화합물을 무기 산 또는 유기 산을 사용하여 이의 염, 특히 약제학적 용도의 생리학적으로 허용되는 이의 염으로 전환시킬 수 있다. 이러한 목적으로 사용할 수 있는 산은, 예를 들면, 염산, 브롬화수소산, 황산, 메탄설폰산, 인산, 푸마르산, 석신산, 락트산, 시트르산, 타르타르산 또는 말레산을 포함한다.In addition, the compounds of formula (I) can be converted into salts thereof, in particular physiologically acceptable salts thereof, for pharmaceutical use using inorganic or organic acids. Acids that can be used for this purpose include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
또한, 이렇게 하여 수득된 화학식 I의 화합물이 카복시, 하이드록시포스포릴, 설포 또는 5-테트라졸릴 그룹을 함유하는 경우, 이후에, 경우에 따라, 이들을 무기 염기 또는 유기 염기를 사용하여 이의 염, 특히 약제학적 용도의 생리학적으로 허용되는 이의 염으로 전환시킬 수 있다. 이러한 목적에 적합한 염기는, 예를 들면, 수산화나트륨, 수산화칼륨, 아르기닌, 사이클로헥실아민, 에탄올아민, 디에탄올아민 및 트리에탄아민을 포함한다.In addition, when the compounds of the formula (I) thus obtained contain carboxy, hydroxyphosphoryl, sulfo or 5-tetrazolyl groups, then, if desired, these are optionally used using inorganic bases or organic bases, salts thereof, in particular Conversion to physiologically acceptable salts thereof for pharmaceutical use. Suitable bases for this purpose include, for example, sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanamine.
출발 물질로서 사용된 화학식 II 내지 IV의 화합물은 특정 경우 문헌에 공지되어 있거나 문헌에 공지된 방법으로 수득할 수 있다(참조: 실시예 I 내지 XIV).The compounds of the formulas (II) to (IV) used as starting materials can in some cases be known in the literature or obtained by methods known in the literature (see Examples I to XIV).
이미 위에서 언급한 바와 같이, 본 발명에 따르는 화학식 I의 화합물 및 생리학적으로 허용되는 이의 염은 유용한 약물학적 특성, 특히 표피 성장인자 수용체(EGF-R)에 의해 매개되는 신호 전달에 대한 억제 효과를 갖는데, 이는 예를 들면, 리간드 결합, 수용체 이량체화 또는 티로신 키나제 그 자체를 억제함으로써 달성할 수 있다. 또한, 더욱 아래쪽에 위치하는 성분에 대한 신호 전달을 차단할 수 있다.As already mentioned above, the compounds of formula (I) and the physiologically acceptable salts thereof according to the invention exhibit useful pharmacological properties, in particular their inhibitory effect on signal transduction mediated by epidermal growth factor receptor (EGF-R). Which can be achieved, for example, by inhibiting ligand binding, receptor dimerization or tyrosine kinase itself. It is also possible to block signal transmission for components located further down.
신규한 화합물의 생물학적 특성은 아래와 같이 조사한다:The biological properties of the novel compounds are investigated as follows:
EGF-R-매개된 신호 전달의 억제는, 예를 들면, 사람 EGF-R을 발현하고 그 생존 및 증식이 EGF 또는 TGF-알파에 의한 촉진에 따라 달라지는 세포를 사용하여 입증할 수 있다. 본원에서는 기능성 사람 EGF-R을 발현하도록 유전적으로 개질된 인터루킨-3(IL-3)에 의존하는 마우스 기원의 세포주를 사용한다. 따라서, F/L-HERc로서 공지된 이들 세포의 증식은 마우스 IL-3 또는 EGF 중 어느 하나에 의해 촉진시킬 수 있다[참조: von Ruden, T. et al., EMBO J.7, 2749-2756(1988); Pierce, J. H. et al., Science239, 628-631(1988)].Inhibition of EGF-R-mediated signal transduction can be demonstrated using, for example, cells which express human EGF-R and whose survival and proliferation depend on palpation by EGF or TGF-alpha. We use cell lines of mouse origin that rely on interleukin-3 (IL-3) genetically modified to express functional human EGF-R. Thus, the proliferation of these cells, known as F / L-HERc, can be promoted by either mouse IL-3 or EGF. Von Ruden, T. et al., EMBO J. 7 , 2749-2756 (1988); Pierce, JH et al., Science 239 , 628-631 (1988).
F/L-HERc 세포에 사용되는 출발 물질은 세포주 FDC-P1이고 이의 제조는 문헌에 기재되어 있다[참조: Dexter, T. M. et al. J. Exp. Med.152,1036-1047 (1980)]. 그러나, 또한 다른 성장인자-의존성 세포도 사용할 수 있다[참조: Pierce, J. H. et al., Science239, 628-631 (1988), Shibuya, H. et al., Cell70, 57-67 (1992) and Alexander, W. S. et al., EMBO J.10, 3683-3691 (1991)]. 사람 EGF-R cDNA[참조: Ullrich, A. et al., Nature309, 418-425(1984)]를 발현시키기 위해서는 재조합 레트로바이러스를 문헌[참조: von Ruden, T. et al., EMBO J.7, 2749-2756(1988)]에 기재된 바와 같이 사용하되, 단 레트로바이러스 벡터 LXSN[참조: Miller, A. D. et al., BioTechniques7, 980-990(1989)]을 EGF-R cDNA의 발현을 위해 사용하고 세포주 GP+E86[참조: Markowitz, D. et al., J. Virol.62, 1120-1124(1988)]을 팩키징 세포로서 사용한다.The starting material used for F / L-HERc cells is cell line FDC-P 1 and its preparation is described in the literature. Dexter, TM et al. J. Exp. Med. 152, 1036-1047 (1980). However, other growth factor-dependent cells can also be used. Pierce, JH et al., Science 239 , 628-631 (1988), Shibuya, H. et al., Cell 70 , 57-67 (1992). and Alexander, WS et al., EMBO J. 10 , 3683-3691 (1991). For expressing human EGF-R cDNA (Ullrich, A. et al., Nature 309 , 418-425 (1984)), recombinant retroviruses are described in von Ruden, T. et al., EMBO J. 7 , 2749-2756 (1988), except that the retroviral vector LXSN (Miller, AD et al., BioTechniques 7 , 980-990 (1989)) was used for the expression of EGF-R cDNA. Cell line GP + E86 [Markowitz, D. et al., J. Virol. 62 , 1120-1124 (1988), are used as packaging cells.
시험은 아래와 같이 수행한다:The test is performed as follows:
F/L-HERc 세포를 RPMI/1640 배지[바이오위타커(BioWhittaker)]에서 배양하고 37℃ 및 5% CO2에서 10% 태아소 혈청[FCS, 베링거 만하임(Boehringer Mannheim)], 2mM의 글루타민(비오비타커), 표준 항생제 및 20ng/㎖의 사람EGF[프로메가(Promega)]를 보충시킨다. 본 발명에 따르는 화합물의 억제 활성을 조사하기 위해, 웰당 1.5×104개의 세포를 상기 배지(200㎕) 중에서 96-웰 디쉬에서 3반복 배양하고 세포 증식은 EGF(20ng/㎖) 또는 마우스 IL-3으로 촉진시킨다. 사용된 IL-3은 세포주 X63/0 mIL-3의 배양 상등액으로부터 수득한다[참조: Karasuyama, H. et al., Eur. J. Immunol.18, 97-104(1988)]. 본 발명에 따르는 화합물을 100% 디메틸설폭사이드(DMSO)에 용해시키고 각종 농도로 희석시켜(최대 DMSO 농도는 1%이다) 배양물에 첨가한다. 배양물을 37℃에서 48시간 동안 배양한다.F / L-HERc cells were cultured in RPMI / 1640 medium [BioWhittaker] and 10% fetal bovine serum [FCS, Boehringer Mannheim], 2 mM glutamine at 37 ° C. and 5% CO 2 . Biobiter), standard antibiotics and 20 ng / ml of human EGF (Promega). To investigate the inhibitory activity of the compounds according to the invention, 1.5 × 10 4 cells per well were cultured three times in 96-well dishes in the medium (200 μl), and cell proliferation was determined by EGF (20 ng / ml) or mouse IL −. Promote to 3. IL-3 used is obtained from the culture supernatant of cell line X63 / 0 mIL-3. Karasuyama, H. et al., Eur. J. Immunol. 18 , 97-104 (1988). The compounds according to the invention are dissolved in 100% dimethylsulfoxide (DMSO) and diluted to various concentrations (maximum DMSO concentration is 1%) and added to the culture. Cultures are incubated at 37 ° C. for 48 hours.
본 발명에 따르는 화합물의 억제 활성을 측정하기 위해 상대적인 세포 수를 셀 타이터(Cell Titer) 96TM수성 비방사능 세포 증식 검정(AQueous Non-Radioactive Cell Proliferation Assay)(프로메가)을 사용하여 O.D. 단위로 측정한다. 상대적인 세포 수는 대조군(억제제를 사용하지 않은 F/LHERc 세포)에 대한 백분율로서 계산하고 이로부터 세포 증식을 50% 억제하는 활성 물질의 농도(IC50)를 유도한다. 아래의 결과가 수득된다:Relative cell numbers were measured in OD units using the Cell Titer 96 TM Aqueous Non-Radioactive Cell Proliferation Assay (Promega) to determine the inhibitory activity of the compounds according to the invention. Measure Relative cell number is calculated as a percentage of the control (F / LHERc cells without inhibitor) and from which results in a concentration of active substance (IC 50 ) that inhibits cell proliferation 50%. The following results are obtained:
따라서, 본 발명에 따르는 화학식 I의 화합물은 사람 EGF 수용체를 예로 들어 입증한 바와 같이 티로신 키나제에 의한 신호 전달을 억제하여 티로신 키나제의기능항진(hyperfunction)에 의해 유발되는 병리생리학적 과정을 치료하는 데 유용하다. 이들은, 예를 들면, 양성 또는 악성 종양, 특히 상피 및 신경상피 기원의 종양, 전이(metastasisation) 및 혈관 내피 세포의 비정상적 증식(신혈관생성)이다.Accordingly, the compounds of formula (I) according to the invention inhibit the signal transduction by tyrosine kinases, as demonstrated for example with human EGF receptors, to treat pathophysiological processes caused by the hyperfunction of tyrosine kinases. useful. These are, for example, benign or malignant tumors, especially tumors of epithelial and neuroepithelial origin, metastasisation and abnormal proliferation of neovascular endothelial cells (neovascularization).
본 발명에 따르는 화합물은 티로신 키나제에 의한 자극에 의해 점액 생성이 증가 또는 변경되어 수반되는 기도 및 폐 질환, 예를 들면, 기도의 염증성 질환, 예를 들면, 만성 기관지염, 만성 폐쇄성 기관지염, 천식, 기관지확장증, 알레르기성 또는 비알레르기성 비염 또는 정맥동염, 낭성섬유증, α1-항트립신 결핍증 또는 기침, 폐기종, 폐섬유증 및 반응항진성 기도를 예방 및 치료하는 데에도 유용하다.The compounds according to the invention are used for airway and lung diseases, such as inflammatory diseases of the airways, for example chronic bronchitis, chronic obstructive bronchitis, asthma, bronchus, accompanied by increased or altered mucus production by stimulation by tyrosine kinases. It is also useful for preventing and treating bloat, allergic or nonallergic rhinitis or sinusitis, cystic fibrosis, α1-antitrypsin deficiency or cough, emphysema, pulmonary fibrosis, and reactive airways.
당해 화합물은 또한 티로신 키나제의 붕괴된 활성과 관련된 위장관, 담관 및 담낭 질환, 예를 들면, 만성 염증성 변화시 나타날 수 있는 것들, 예를 들면, 담낭염, 크론병, 궤양성 대장염 및 위장관 궤양 또는 분비 증가와 관련된 위장관 질환에서 나타날 수 있는 것들, 예를 들면, 메네트리에 병(Menetrier's disease), 분비 선종(secreting adenoma) 및 단백질 상실 증후군의 치료에 적합하고, 또한 비강 폴립, 각종 기원의 위장관 폴립, 예를 들면, 대장의 융모성 또는 선종성 폴립 뿐만 아니라, 가족성 결장 폴립증에서의 폴립, 가아드너 증후군(Gardner's syndrome)에서의 소장 폴립, 포이츠-예거 증후군(Peutz-Jeghers syndrome)에서의 전체 위장관에 걸친 폴립, 염증성 가폴립(pseudopolyp), 연소성 폴립, 심층낭종성대장염 및 장벽낭상기종 치료에도 적합하다.The compound also contains gastrointestinal, bile duct and gallbladder diseases associated with the disrupted activity of tyrosine kinases, such as those that may appear upon chronic inflammatory changes, such as cholecystitis, Crohn's disease, ulcerative colitis and increased gastrointestinal ulcers or increased secretion. What may appear in gastrointestinal diseases associated with, for example, Mentrier's disease, secreting adenoma and protein loss syndrome, and also suitable for the treatment of nasal polyps, gastrointestinal polyps of various origins, eg For example, colonic chorionic or adenomatous polyps, as well as polyps in familial colon polyps, small intestine polyps in Gardner's syndrome, and the entire gastrointestinal tract in Peutz-Jeghers syndrome. It is also suitable for treating polyps, inflammatory pseudopolyps, combustible polyps, deep cystic colitis and barrier cystic carcinoma over time.
또한, 화학식 I의 화합물 및 생리학적으로 허용되는 이의 염을 사용하여 특히 낭신에서와 같은 낭성 변화시의 신장 질환을 치료하거나, 본래 특발성이거나 예를 들면, 결핵성 경화증과 같은 증후군, 본-히펠-린다우 증후군(von-Hippel-Lindau Syndrome), 신결석증 및 해면 신장에서 나타나는 신낭 및 티로신 키나제의 이상 기능에 의해 유발되는 다른 질환, 예를 들면, 표피 과증식(건선), 염증성 과정, 면역계 질환, 조혈 세포의 과증식 등을 치료할 수 있다.In addition, compounds of formula (I) and physiologically acceptable salts thereof can be used to treat kidney disease, especially in cystic changes, such as in the cysts, or to be idiopathic in nature or, for example, syndromes such as tuberculous sclerosis, Bon-Hiffel-Linda Von-Hippel-Lindau Syndrome, nephrolithiasis and other diseases caused by dysfunction of the kidney and tyrosine kinases in the cavernous kidney, such as epidermal hyperplasia (psoriasis), inflammatory processes, immune system diseases, hematopoietic cells Overgrowth can be treated.
본 발명에 따르는 화합물은 이들의 생물학적 특성으로 인해 그 자체로 사용하거나, 예를 들면, 종양 치료, 모노테라피(monotherapy)에서 기타 약물학적 활성 화합물과 함께, 또는 기타 항종양 치료제, 예를 들면, 토포이소머라제 억제제(예: 에토포시드), 유사분열 억제제(예: 빈블라스틴), 핵산과 상호작용하는 화합물(예: 시스-플라틴, 사이클로포스파미드, 아드리아마이신), 호르몬 길항제(예: 타목시펜), 대사과정 억제제(예: 5-FU 등), 시토킨(예: 인터페론), 항체 등과 혼합하여 사용할 수 있다. 호흡관 질환을 치료하기 위해서는, 이들 화합물을 그 자체로 사용하거나 기타 기도 치료제, 예를 들면, 분비분해(secretolytic), 기관지분해(broncholytic) 및/또는 항염증 활성을 갖는 물질과 함께 사용할 수 있다. 위장관 영역에서의 질환을 치료하기 위해서는, 이들 화합물을 그 자체로 투여하거나 운동 또는 분비에 영향을 미치는 물질 또는 항염증성 물질과 함께 투여할 수 있다. 이들 혼합물은 동시에 또는 연속적으로 투여할 수 있다.The compounds according to the invention can be used on their own due to their biological properties, or for example in combination with other pharmacologically active compounds in tumor therapy, monotherapy, or other anti-tumor agents such as topo Isomerase inhibitors (e.g. etoposide), mitosis inhibitors (e.g. vinblastine), compounds that interact with nucleic acids (e.g. cis-platin, cyclophosphamide, adriamycin), hormonal antagonists (e.g. Tamoxifen), metabolic inhibitors (eg 5-FU), cytokines (eg interferon), antibodies, etc. To treat respiratory tract diseases, these compounds may be used on their own or in combination with other airway therapeutics, such as substances with secretolytic, broncholytic and / or anti-inflammatory activity. To treat diseases in the gastrointestinal tract, these compounds may be administered on their own or in combination with substances or anti-inflammatory substances that affect exercise or secretion. These mixtures can be administered simultaneously or sequentially.
이들 화합물은 그 자체로 또는 기타 활성 물질과 함께 정맥내, 피하, 근육내, 복강내 또는 비강내 경로로 투여하거나, 흡입에 의해 또는 경피적 또는 경구적으로 투여할 수 있으며, 에어로졸 제형은 흡입에 특히 적합하다.These compounds may be administered on their own or in combination with other active substances by the intravenous, subcutaneous, intramuscular, intraperitoneal or intranasal route, by inhalation or percutaneously or orally, and aerosol formulations are particularly suitable for inhalation. Suitable.
약제학적 용도의 경우, 일반적으로 본 발명에 따르는 화합물은 온혈 척추동물, 특히 사람에게 0.01 내지 100mg/체중kg, 바람직하게는 0.1 내지 15mg/kg의 투여량으로 사용한다. 투여를 위해, 이들은 하나 이상의 통상적인 불활성 담체/또는 희석제, 예를 들면, 옥수수 전분, 락토스, 글루코스, 미세결정성 셀룰로즈, 마그네슘 스테아레이트, 폴리비닐피롤리돈, 시트르산, 타르타르산, 물, 물/에탄올, 물/글리세롤, 물/소르비톨, 물/폴리에틸렌 글리콜, 프로필렌 글리콜, 스테아릴 알콜, 카복시메틸셀룰로즈 또는 지방 물질, 예를 들면, 고형 지방 또는 이들의 적합한 혼합물과 함께 통상적인 생약 제제, 예를 들면, 플레인 정제(plain tablet) 또는 제피정, 캡슐, 산제, 현탁액, 용액제, 분무제 또는 좌제로 제형화된다.For pharmaceutical use, the compounds according to the invention are generally used in warm blood vertebrates, especially humans, in dosages of 0.01 to 100 mg / kg body weight, preferably 0.1 to 15 mg / kg. For administration, they are one or more conventional inert carriers or diluents, for example corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol Conventional herbal preparations, such as water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethylcellulose or fatty substances such as solid fats or suitable mixtures thereof It is formulated as a plain tablet or as a tablet, capsule, powder, suspension, solution, spray or suppository.
아래의 실시예는 본 발명을 설명하기 위한 것으로 본 발명을 제한하지는 않는다:The following examples are intended to illustrate the invention but do not limit the invention:
출발 화합물의 제조:Preparation of Starting Compounds:
실시예 IExample I
4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로펜틸메톡시-7-(2-브로모-에톡시)-퀴나졸린4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy-7- (2-bromo-ethoxy) -quinazoline
탄산칼륨 4.84g을 N,N-디메틸포름아미드 40ml 중의 1,2-디브로모에탄 6.89ml 및 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로펜틸-메톡시-7-하이드록시-퀴나졸린 3.50g에 가한다. 반응 혼합물을 질소 대기하에 1.5시간 동안 80℃에서 교반한다. 주위 온도로 냉각시킨 후, 반응 혼합물을 여과하고 여액을 진공하에 증발시킨다. 갈색 오일성 잔사를 빙욕 속에서 냉각시키고 소량의 메탄올을 사용하여 분쇄하고, 이 때 황색을 띠는 고체가 결정석출된다. 침전물을 흡인여과하고 냉각 메탄올로 세척한 후, 진공 데시케이터 속에서 건조시킨다.4.84 g of potassium carbonate was added to 6.89 ml of 1,2-dibromoethane in 40 ml of N, N-dimethylformamide and 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyl-methoxy- To 3.50 g of 7-hydroxy-quinazoline. The reaction mixture is stirred at 80 ° C. for 1.5 h under a nitrogen atmosphere. After cooling to ambient temperature, the reaction mixture is filtered and the filtrate is evaporated in vacuo. The brown oily residue is cooled in an ice bath and triturated with a small amount of methanol, at which time a yellowish solid precipitates. The precipitate is suction filtered, washed with cold methanol and dried in a vacuum desiccator.
수득량: 2.60g (이론치의 58%),Yield: 2.60 g (58% of theory),
Rf값: 0.82 (실리카 겔, 메틸렌 클로라이드/메탄올 9:1)R f value: 0.82 (silica gel, methylene chloride / methanol 9: 1)
질량 스펙트럼 (ESI+): m/z = 494, 496, 498 [M+H]+ Mass spectrum (ESI + ): m / z = 494, 496, 498 [M + H] +
아래의 화합물을 실시예 I과 유사하게 수득한다.The following compounds are obtained similar to Example I.
(1) 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로프로필메톡시-7-(2-브로모에톡시)-퀴나졸린 (반응은 용매로서 아세토니트릴 속에서 수행한다)(1) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (2-bromoethoxy) -quinazolin (reaction is carried out in acetonitrile as solvent )
Rf값: 0.72 (실리카 겔, 메틸렌 클로라이드/메탄올/진한 암모니아 수용액 = 90:10:0.1)R f value: 0.72 (silica gel, methylene chloride / methanol / aqueous ammonia solution = 90: 10: 0.1)
질량 스펙트럼 (ESI-): m/z = 464, 466, 468 [M-H]- Mass spectrum (ESI -): m / z = 464, 466, 468 [MH] -
(2) 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로펜틸옥시-7-(2-브로모에톡시)-퀴나졸린(2) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2-bromoethoxy) -quinazoline
Rf값: 0.65 (실리카 겔, 메틸렌 클로라이드/메탄올/진한 암모니아 수용액 = 90:10:0.1)R f value: 0.65 (silica gel, methylene chloride / methanol / aqueous ammonia solution = 90: 10: 0.1)
질량 스펙트럼 (ESI-): m/z = 478, 480, 482 [M-H]- Mass spectrum (ESI -): m / z = 478, 480, 482 [MH] -
(3) 4-[(3-클로로-4-플루오로페닐)아미노]-7-사이클로부틸옥시-6-(3-브로모프로필옥시)-퀴나졸린 (반응은 용매로서 아세토니트릴 속에서 수행한다)(3) 4-[(3-chloro-4-fluorophenyl) amino] -7-cyclobutyloxy-6- (3-bromopropyloxy) -quinazolin (reaction is carried out in acetonitrile as solvent )
Rf값: 0.62 (실리카 겔, 메틸렌 클로라이드/메탄올 9:1)R f value: 0.62 (silica gel, methylene chloride / methanol 9: 1)
질량 스펙트럼 (ESI-): m/z = 478, 480, 482 [M-H]- Mass spectrum (ESI -): m / z = 478, 480, 482 [MH] -
(4) 4-[(3-클로로-4-플루오로페닐)아미노]-7-사이클로프로필메톡시-6-(3-브로모프로필옥시)-퀴나졸린 (반응은 용매로서 아세토니트릴 속에서 수행한다)(4) 4-[(3-chloro-4-fluorophenyl) amino] -7-cyclopropylmethoxy-6- (3-bromopropyloxy) -quinazolin (reaction is carried out in acetonitrile as solvent do)
Rf값: 0.74 (실리카 겔, 메틸렌 클로라이드/메탄올 9:1)R f value: 0.74 (silica gel, methylene chloride / methanol 9: 1)
질량 스펙트럼 (ESI-): m/z = 478, 480, 482 [M-H]- Mass spectrum (ESI -): m / z = 478, 480, 482 [MH] -
(5) 4-[(3-브로모-페닐)아미노]-6-(2-브로모에톡시)-7-메톡시-퀴나졸린(5) 4-[(3-bromo-phenyl) amino] -6- (2-bromoethoxy) -7-methoxy-quinazoline
융점: 244℃Melting Point: 244 ℃
질량 스펙트럼 (ESI+): m/z = 452, 454, 456 [M+H]+ Mass spectrum (ESI + ): m / z = 452, 454, 456 [M + H] +
(6) 4-[(R)-(1-페닐-에틸)아미노]-6-(3-브로모프로필옥시)-7-메톡시-퀴나졸린 (반응은 염기로서 칼륨 3급-부톡사이드를 사용하여 수행한다)(6) 4-[(R)-(1-phenyl-ethyl) amino] -6- (3-bromopropyloxy) -7-methoxy-quinazolin (reaction with potassium tert-butoxide as base Perform using)
Rf값: 0.60 (실리카 겔, 에틸 아세테이트/메탄올 9:1)R f value: 0.60 (silica gel, ethyl acetate / methanol 9: 1)
(7) 4-[(R)-(1-페닐-에틸)아미노]-6-(2-브로모에톡시)-7-메톡시-퀴나졸린 (반응은 염기로서 칼륨 3급-부톡사이드를 사용하여 수행한다)(7) 4-[(R)-(1-phenyl-ethyl) amino] -6- (2-bromoethoxy) -7-methoxy-quinazolin (reaction using potassium tert-butoxide as base To be performed)
융점: 255℃Melting point: 255 ℃
질량 스펙트럼 (ESI+): m/z = 402, 404 [M+H]+ Mass spectrum (ESI + ): m / z = 402, 404 [M + H] +
(8) 4-[(3-클로로-4-플루오로페닐)아미노]-6-(3-하이드록시-프로필옥시)-7-사이클로부틸옥시-퀴나졸린(8) 4-[(3-chloro-4-fluorophenyl) amino] -6- (3-hydroxy-propyloxy) -7-cyclobutyloxy-quinazoline
Rf값: 0.50 (실리카 겔, 메틸렌 클로라이드/메탄올 = 90:10)R f value: 0.50 (silica gel, methylene chloride / methanol = 90:10)
질량 스펙트럼 (ESI+): m/z = 418, 420 [M+H]+ Mass spectrum (ESI + ): m / z = 418, 420 [M + H] +
(9) 4-[(3-클로로-4-플루오로페닐)아미노]-6-(3-하이드록시-프로필옥시)-7-사이클로프로필메톡시-퀴나졸린(9) 4-[(3-chloro-4-fluorophenyl) amino] -6- (3-hydroxy-propyloxy) -7-cyclopropylmethoxy-quinazoline
Rf값: 0.21 (실리카 겔, 메틸렌 클로라이드/메탄올 = 95:5)R f value: 0.21 (silica gel, methylene chloride / methanol = 95: 5)
질량 스펙트럼 (ESI+): m/z = 418, 420 [M+H]+ Mass spectrum (ESI + ): m / z = 418, 420 [M + H] +
(10) 4-[(3-클로로-4-플루오로페닐)아미노]-6-(2-브로모-에톡시)-7-사이클로펜틸옥시-퀴나졸린(10) 4-[(3-chloro-4-fluorophenyl) amino] -6- (2-bromo-ethoxy) -7-cyclopentyloxy-quinazoline
Rf값: 0.67 (실리카 겔, 메틸렌 클로라이드/메탄올 = 90:10)R f value: 0.67 (silica gel, methylene chloride / methanol = 90:10)
질량 스펙트럼 (ESI+): m/z = 480, 482, 484 [M+H]+ Mass spectrum (ESI + ): m / z = 480, 482, 484 [M + H] +
(11) 4-[(3-클로로-4-플루오로페닐)아미노]-6-(2-브로모-에톡시)-7-사이클로프로필메톡시-퀴나졸린(11) 4-[(3-chloro-4-fluorophenyl) amino] -6- (2-bromo-ethoxy) -7-cyclopropylmethoxy-quinazoline
Rf값: 0.68 (실리카 겔, 메틸렌 클로라이드/메탄올 = 90:10)R f value: 0.68 (silica gel, methylene chloride / methanol = 90:10)
질량 스펙트럼 (ESI+): m/z = 466, 468, 470 [M+H]+ Mass spectrum (ESI + ): m / z = 466, 468, 470 [M + H] +
(12) 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로프로필메톡시-7-(3-하이드록시-프로필옥시)-퀴나졸린(12) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (3-hydroxy-propyloxy) -quinazoline
Rf값: 0.53 (실리카 겔, 메틸렌 클로라이드/메탄올 = 90:10)R f value: 0.53 (silica gel, methylene chloride / methanol = 90:10)
질량 스펙트럼 (ESI+): m/z = 418, 420 [M+H]+ Mass spectrum (ESI + ): m / z = 418, 420 [M + H] +
(13) 4-[(3-클로로-4-플루오로페닐)아미노]-6-(4-하이드록시-부틸옥시)-7-사이클로펜틸옥시-퀴나졸린(13) 4-[(3-chloro-4-fluorophenyl) amino] -6- (4-hydroxy-butyloxy) -7-cyclopentyloxy-quinazoline
Rf값: 0.46 (실리카 겔, 에틸 아세테이트)R f value: 0.46 (silica gel, ethyl acetate)
(14) 4-[(3-클로로-4-플루오로페닐)아미노]-6-(2-브로모-에톡시)-7-((R)-테트라하이드로푸란-3-일옥시)-퀴나졸린(14) 4-[(3-chloro-4-fluorophenyl) amino] -6- (2-bromo-ethoxy) -7-((R) -tetrahydrofuran-3-yloxy) -quina Sleepy
Rf값: 0.37 (실리카 겔, 메틸렌 클로라이드/메탄올 = 9:1)R f value: 0.37 (silica gel, methylene chloride / methanol = 9: 1)
질량 스펙트럼 (ESI-): m/z = 480, 482, 484 [M-H]- Mass spectrum (ESI -): m / z = 480, 482, 484 [MH] -
(15) 4-[(3-클로로-4-플루오로페닐)아미노]-6-(2-브로모-에톡시)-7-[(R)-(테트라하이드로푸란-2-일)메톡시]-퀴나졸린(15) 4-[(3-chloro-4-fluorophenyl) amino] -6- (2-bromo-ethoxy) -7-[(R)-(tetrahydrofuran-2-yl) methoxy ] -Quinazolin
질량 스펙트럼 (ESI-): m/z = 494, 496, 498 [M-H]- Mass spectrum (ESI -): m / z = 494, 496, 498 [MH] -
(16) 4-[(3-클로로-4-플루오로페닐)아미노]-7-(2-브로모-에톡시)-6-[(S)-(테트라하이드로푸란-2-일)메톡시]-퀴나졸린(16) 4-[(3-chloro-4-fluorophenyl) amino] -7- (2-bromo-ethoxy) -6-[(S)-(tetrahydrofuran-2-yl) methoxy ] -Quinazolin
질량 스펙트럼 (ESI-): m/z = 494, 496, 498 [M-H]- Mass spectrum (ESI -): m / z = 494, 496, 498 [MH] -
실시예 IIExample II
4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로펜틸메톡시-7-하이드록시-퀴나졸린4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy-7-hydroxy-quinazolin
4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로펜틸메톡시-7-메틸카보닐옥시-퀴나졸린 4.99g을 메탄올 80ml에 현탁시키고 진한 암모니아 수용액 1.80ml를 가한다. 반응 혼합물을 주위 온도에서 밤새 교반한다. 후처리를 위해 반응 혼합물을 메틸렌 클로라이드 500ml로 희석시키고 물 및 포화 염화나트륨 용액으로 세척한 후, 황산마그네슘 상에서 건조시키고, 증발시켜 농축시킨다. 갈색을 띠는 고체 4.30g이 수득된다. 조 생성물을 3급-부틸 메틸 에테르와 함께 교반하고 흡인여과한 후, 소량의 3급-부틸 메틸 에테르로 세척하고 주위 온도에서 진공건조시킨다.4.99 g of 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy-7-methylcarbonyloxy-quinazolin are suspended in 80 ml of methanol and 1.80 ml of concentrated aqueous ammonia solution is added. The reaction mixture is stirred overnight at ambient temperature. For workup the reaction mixture is diluted with 500 ml of methylene chloride and washed with water and saturated sodium chloride solution, then dried over magnesium sulphate and evaporated to concentrate. 4.30 g of a brownish solid are obtained. The crude product is stirred with tert-butyl methyl ether, suction filtered, washed with a small amount of tert-butyl methyl ether and dried in vacuo at ambient temperature.
수득량: 3.59g (이론치의 80%),Yield: 3.59 g (80% of theory),
Rf값: 0.48 (실리카 겔, 메틸렌 클로라이드/메탄올/진한 암모니아 수용액 = 90:10:0.1)R f value: 0.48 (silica gel, methylene chloride / methanol / aqueous ammonia solution = 90: 10: 0.1)
질량 스펙트럼 (ESI+): m/z = 388, 340 [M+H]+ Mass spectrum (ESI + ): m / z = 388, 340 [M + H] +
아래의 화합물을 실시예 II와 유사하게 수득한다:The following compounds are obtained similarly to Example II:
(1) 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로프로필메톡시-7-하이드록시-퀴나졸린(1) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7-hydroxy-quinazoline
Rf값: 0.56 (실리카 겔, 메틸렌 클로라이드/메탄올 9:1)R f value: 0.56 (silica gel, methylene chloride / methanol 9: 1)
질량 스펙트럼 (ESI-): m/z = 358, 360 [M-H]- Mass spectrum (ESI -): m / z = 358, 360 [MH] -
(2) 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로펜틸옥시-7-하이드록시-퀴나졸린(2) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7-hydroxy-quinazoline
Rf값: 0.53 (실리카 겔, 메틸렌 클로라이드/메탄올/진한 암모니아 수용액 = 90:10:0.1)R f value: 0.53 (silica gel, methylene chloride / methanol / aqueous ammonia solution = 90: 10: 0.1)
질량 스펙트럼 (ESI+): m/z = 374, 376 [M+H]+ Mass spectrum (ESI + ): m / z = 374, 376 [M + H] +
(3) 6-벤질옥시-4-[(3-클로로-4-플루오로페닐)아미노]-7-하이드록시-퀴나졸린(3) 6-benzyloxy-4-[(3-chloro-4-fluorophenyl) amino] -7-hydroxy-quinazolin
Rf값: 0.54 (실리카 겔, 메틸렌 클로라이드/메탄올/진한 암모니아 수용액 = 90:10:0.1)R f value: 0.54 (silica gel, methylene chloride / methanol / aqueous ammonia solution = 90: 10: 0.1)
질량 스펙트럼 (ESI+): m/z = 396, 398 [M+H]+ Mass spectrum (ESI + ): m / z = 396, 398 [M + H] +
(4) 4-[(3-브로모-페닐)아미노]-6-하이드록시-7-메톡시-퀴나졸린 (반응은 용매로서 에탄올 중의 수산화나트륨 용액을 사용하여 수행한다)(4) 4-[(3-bromo-phenyl) amino] -6-hydroxy-7-methoxy-quinazolin (reaction is carried out using a solution of sodium hydroxide in ethanol as solvent)
Rf값: 0.23 (실리카 겔, 에틸 아세테이트)R f value: 0.23 (silica gel, ethyl acetate)
질량 스펙트럼 (ESI+): m/z = 346, 348 [M+H]+ Mass spectrum (ESI + ): m / z = 346, 348 [M + H] +
(5) 4-[(3-클로로-4-플루오로페닐)아미노]-7-하이드록시-6-((S)-테트라하이드로푸란-3-일옥시)-퀴나졸린(5) 4-[(3-chloro-4-fluorophenyl) amino] -7-hydroxy-6-((S) -tetrahydrofuran-3-yloxy) -quinazoline
Rf값: 0.57 (실리카 겔, 메틸렌 클로라이드/메탄올 = 9:1)R f value: 0.57 (silica gel, methylene chloride / methanol = 9: 1)
질량 스펙트럼 (ESI+): m/z = 376, 378 [M+H]+ Mass spectrum (ESI + ): m / z = 376, 378 [M + H] +
(6) 4-[(3-클로로-4-플루오로페닐)아미노]-7-하이드록시-6-[(S)-(테트라하이드로푸란-2-일)메톡시]-퀴나졸린(6) 4-[(3-chloro-4-fluorophenyl) amino] -7-hydroxy-6-[(S)-(tetrahydrofuran-2-yl) methoxy] -quinazoline
Rf값: 0.42 (실리카 겔, 메틸렌 클로라이드/메탄올 = 9:1)R f value: 0.42 (silica gel, methylene chloride / methanol = 9: 1)
실시예 IIIExample III
4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로펜틸메톡시-7-메틸카보닐옥시-퀴나졸린4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy-7-methylcarbonyloxy-quinazolin
4-클로로-6-사이클로펜틸메톡시-7-메틸카보닐옥시-퀴나졸린 4.03g을 이소프로판올 70ml에 현탁시키고 3-클로로-4-플루오로-아닐린 1.95g을 가한다. 반응 혼합물을 질소 대기하에 2시간 동안 환류시킨다. 주위 온도로 냉각시킨 후, 형성된 연한 색상의 침전물을 흡인여과하고 소량의 이소프로판올로 세척한 후 공기 중에서 건조시킨다.4.03 g of 4-chloro-6-cyclopentylmethoxy-7-methylcarbonyloxy-quinazolin is suspended in 70 ml of isopropanol and 1.95 g of 3-chloro-4-fluoro-aniline are added. The reaction mixture is refluxed for 2 hours under a nitrogen atmosphere. After cooling to ambient temperature, the pale colored precipitate formed is suction filtered, washed with a small amount of isopropanol and dried in air.
수득량: 4.99g (이론치의 92%),Yield: 4.99 g (92% of theory),
Rf값: 0.80 (실리카 겔, 메틸렌 클로라이드/메탄올/진한 암모니아 수용액 = 90:10:0.1)R f value: 0.80 (silica gel, methylene chloride / methanol / aqueous ammonia solution = 90: 10: 0.1)
질량 스펙트럼 (ESI+): m/z = 430, 432 [M+H]+ Mass spectrum (ESI + ): m / z = 430, 432 [M + H] +
아래의 화합물을 실시예 III과 유사하게 수득한다:The following compounds are obtained similarly to Example III:
(1) 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로프로필메톡시-7-메틸카보닐옥시-퀴나졸린(1) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7-methylcarbonyloxy-quinazolin
Rf값: 0.86 (실리카 겔, 메틸렌 클로라이드/메탄올 = 9:1)R f value: 0.86 (silica gel, methylene chloride / methanol = 9: 1)
질량 스펙트럼 (ESI+): m/z = 402, 404 [M+H]+ Mass spectrum (ESI + ): m / z = 402, 404 [M + H] +
(2) 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로펜틸옥시-7-메틸카보닐옥시-퀴나졸린(2) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7-methylcarbonyloxy-quinazolin
Rf값: 0.73 (실리카 겔, 메틸렌 클로라이드/메탄올/진한 암모니아 수용액 = 90:10:0.1)R f value: 0.73 (silica gel, methylene chloride / methanol / aqueous ammonia solution = 90: 10: 0.1)
질량 스펙트럼 (ESI+): m/z = 416, 418 [M+H]+ Mass spectrum (ESI + ): m / z = 416, 418 [M + H] +
(3) 6-벤질옥시-4-[(3-클로로-4-플루오로페닐)아미노]-7-메틸-카보닐옥시-퀴나졸린(3) 6-benzyloxy-4-[(3-chloro-4-fluorophenyl) amino] -7-methyl-carbonyloxy-quinazolin
Rf값: 0.76 (실리카 겔, 메틸렌 클로라이드/메탄올/진한 암모니아 수용액 = 90:10:0.1)R f value: 0.76 (silica gel, methylene chloride / methanol / aqueous ammonia solution = 90: 10: 0.1)
질량 스펙트럼 (ESI+): m/z = 438, 440 [M+H]+ Mass spectrum (ESI + ): m / z = 438, 440 [M + H] +
(4) 4-[(3-브로모-페닐)아미노]-6-메틸카보닐옥시-7-메톡시-퀴나졸린(4) 4-[(3-bromo-phenyl) amino] -6-methylcarbonyloxy-7-methoxy-quinazoline
Rf값: 0.50 (실리카 겔, 에틸 아세테이트)R f value: 0.50 (silica gel, ethyl acetate)
질량 스펙트럼 (ESI+): m/z = 388, 390 [M+H]+ Mass spectrum (ESI + ): m / z = 388, 390 [M + H] +
(5) 4-[(R)-(1-페닐-에틸)아미노]-6-하이드록시-7-메톡시-퀴나졸린 (반응 조건하에 아세톡시 보호 그룹이 이미 분해되었다)(5) 4-[(R)-(1-phenyl-ethyl) amino] -6-hydroxy-7-methoxy-quinazolin (acetoxy protecting group has already been degraded under reaction conditions)
Rf값: 0.46 (실리카 겔, 에틸 아세테이트)R f value: 0.46 (silica gel, ethyl acetate)
질량 스펙트럼 (ESI+): m/z = 296 [M+H]+ Mass spectrum (ESI + ): m / z = 296 [M + H] +
(6) 6-벤질옥시-4-[(3-클로로-4-플루오로페닐)아미노]-7-사이클로펜틸옥시-퀴나졸린(6) 6-benzyloxy-4-[(3-chloro-4-fluorophenyl) amino] -7-cyclopentyloxy-quinazoline
(피리딘을 보조 염기로서 가한다)(Pyridine is added as auxiliary base)
Rf값: 0.51 (실리카 겔, 메틸렌 클로라이드/메탄올 = 95:5)R f value: 0.51 (silica gel, methylene chloride / methanol = 95: 5)
질량 스펙트럼 (ESI+): m/z = 464, 466 [M+H]+ Mass spectrum (ESI + ): m / z = 464, 466 [M + H] +
(7) 4-[(3-클로로-4-플루오로페닐)아미노]-7-메틸카보닐옥시-6-((S)-테트라하이드로푸란-3-일옥시)-퀴나졸린(7) 4-[(3-chloro-4-fluorophenyl) amino] -7-methylcarbonyloxy-6-((S) -tetrahydrofuran-3-yloxy) -quinazoline
Rf값: 0.67 (실리카 겔, 메틸렌 클로라이드/메탄올 = 9:1)R f value: 0.67 (silica gel, methylene chloride / methanol = 9: 1)
질량 스펙트럼 (ESI-): m/z = 416, 418 [M-H]- Mass spectrum (ESI -): m / z = 416, 418 [MH] -
(8) 4-[(3-클로로-4-플루오로페닐)아미노]-7-메틸카보닐옥시-6-[(S)-(테트라하이드로푸란-2-일)메톡시]-퀴나졸린-하이드로클로라이드(8) 4-[(3-chloro-4-fluorophenyl) amino] -7-methylcarbonyloxy-6-[(S)-(tetrahydrofuran-2-yl) methoxy] -quinazolin- Hydrochloride
융점: 274 내지 276℃Melting Point: 274-276 ° C
질량 스펙트럼 (ESI+): m/z = 432, 434 [M+H]+ Mass spectrum (ESI + ): m / z = 432, 434 [M + H] +
실시예 IVExample IV
4-클로로-6-사이클로펜틸메톡시-7-메틸카보닐옥시-퀴나졸린4-Chloro-6-cyclopentylmethoxy-7-methylcarbonyloxy-quinazolin
4-하이드록시-6-사이클로펜틸메톡시-7-메틸카보닐옥시-퀴나졸린 3.80g을 티오닐 클로라이드 90ml에 현탁시키고 질소 대기하에 가열하여 비등시킨다. N,N-디메틸포름아미드 4방울을 가한 후, 반응 혼합물을 추가로 2시간 동안 환류시킨다. 주위 온도로 냉각시킨 후, 과량의 티오닐 클로라이드를 수분사 진공(water jet vacuum)하에 증류제거한다. 갈색 잔사를 톨루엔 30ml와 함께 교반한다. 용매를 증류제거하여 회갈색 고체 4.30g을 수득하고, 이를 더 이상 정제하지 않고 추가로 반응시킨다.3.80 g of 4-hydroxy-6-cyclopentylmethoxy-7-methylcarbonyloxy-quinazolin is suspended in 90 ml of thionyl chloride and heated to boiling under nitrogen atmosphere. After adding 4 drops of N, N-dimethylformamide, the reaction mixture is refluxed for a further 2 hours. After cooling to ambient temperature, the excess thionyl chloride is distilled off under water jet vacuum. The brown residue is stirred with 30 ml of toluene. The solvent is distilled off to give 4.30 g of an off-brown solid, which is further reacted without further purification.
Rf값: 0.89 (실리카 겔, 메틸렌 클로라이드/메탄올/진한 암모니아 수용액 =90:10:0.1)R f value: 0.89 (silica gel, methylene chloride / methanol / condensed aqueous ammonia = 90: 10: 0.1)
아래의 화합물을 실시예 IV와 유사하게 수득한다:The following compounds are obtained analogously to Example IV:
(1) 4-클로로-6-사이클로프로필메톡시-7-메틸카보닐옥시-퀴나졸린(1) 4-chloro-6-cyclopropylmethoxy-7-methylcarbonyloxy-quinazolin
Rf값: 0.84 (실리카 겔, 메틸렌 클로라이드/메탄올 = 9:1)R f value: 0.84 (silica gel, methylene chloride / methanol = 9: 1)
(2) 4-클로로-6-사이클로펜틸옥시-7-메틸카보닐옥시-퀴나졸린(2) 4-chloro-6-cyclopentyloxy-7-methylcarbonyloxy-quinazolin
Rf값: 0.69 (실리카 겔, 메틸렌 클로라이드/메탄올/진한 암모니아 수용액 = 90:10:0.1)R f value: 0.69 (silica gel, methylene chloride / methanol / aqueous ammonia solution = 90: 10: 0.1)
(3) 6-벤질옥시-4-클로로-7-메틸카보닐옥시-퀴나졸린(3) 6-benzyloxy-4-chloro-7-methylcarbonyloxy-quinazolin
Rf값: 0.77 (실리카 겔, 메틸렌 클로라이드/메탄올/진한 암모니아 수용액 = 90:10:0.1)R f value: 0.77 (silica gel, methylene chloride / methanol / aqueous ammonia solution = 90: 10: 0.1)
(4) 6-벤질옥시-4-클로로-7-사이클로펜틸옥시-퀴나졸린(4) 6-benzyloxy-4-chloro-7-cyclopentyloxy-quinazolin
Rf값: 0.91 (실리카 겔, 메틸렌 클로라이드/메탄올 = 9:1)R f value: 0.91 (silica gel, methylene chloride / methanol = 9: 1)
(5) 4-클로로-7-메틸카보닐옥시-6-((S)-테트라하이드로푸란-3-일옥시)-퀴나졸린(5) 4-chloro-7-methylcarbonyloxy-6-((S) -tetrahydrofuran-3-yloxy) -quinazoline
Rf값: 0.83 (실리카 겔, 에틸 아세테이트/메탄올 = 9:1)R f value: 0.83 (silica gel, ethyl acetate / methanol = 9: 1)
(6) 4-클로로-7-메틸카보닐옥시-6-[(S)-(테트라하이드로푸란-2-일)메톡시]-퀴나졸린(6) 4-chloro-7-methylcarbonyloxy-6-[(S)-(tetrahydrofuran-2-yl) methoxy] -quinazoline
Rf값: 0.48 (실리카 겔, 사이클로헥산/에틸 아세테이트 = 1:1)R f value: 0.48 (silica gel, cyclohexane / ethyl acetate = 1: 1)
실시예 VExample V
4-하이드록시-6-사이클로펜틸메톡시-7-메틸카보닐옥시-퀴나졸린4-hydroxy-6-cyclopentylmethoxy-7-methylcarbonyloxy-quinazolin
피리딘 100ml 중의 4,7-디하이드록시-6-사이클로펜틸메톡시-퀴나졸린 4.30g을 질소 대기하에 80℃로 가열한다. 아세트산 무수물 1.80ml를 당해 암갈색 현탁액에 가한다. 반응 혼합물을 3시간 동안 80℃에서 교반하며, 그 동안 전체 용액이 형성된다. 주위 온도로 냉각시킨 후, 반응 혼합물을 빙수 약 800ml에 붓는다. 형성된 침전물을 흡인여과하고 물로 완전히 세척한다. 연갈색 고체를 진공 데시케이터 속에서 건조시킨다.4.30 g of 4,7-dihydroxy-6-cyclopentylmethoxy-quinazolin in 100 ml of pyridine is heated to 80 ° C. under a nitrogen atmosphere. 1.80 ml of acetic anhydride are added to the dark brown suspension. The reaction mixture is stirred at 80 ° C. for 3 hours during which time the entire solution is formed. After cooling to ambient temperature, the reaction mixture is poured into about 800 ml of ice water. The formed precipitate is suction filtered and washed thoroughly with water. The light brown solid is dried in a vacuum desiccator.
수득량: 3.82g (이론치의 77%),Yield: 3.82 g (77% of theory),
Rf값: 0.49 (실리카 겔, 메틸렌 클로라이드/메탄올 = 9:1)R f value: 0.49 (silica gel, methylene chloride / methanol = 9: 1)
질량 스펙트럼 (ESI-): m/z = 301 [M-H]- Mass spectrum (ESI -): m / z = 301 [MH] -
아래의 화합물을 실시예 V와 유사하게 수득한다:The following compounds are obtained analogously to Example V:
(1) 4-하이드록시-6-사이클로프로필메톡시-7-메틸카보닐옥시-퀴나졸린(1) 4-hydroxy-6-cyclopropylmethoxy-7-methylcarbonyloxy-quinazolin
Rf값: 0.53 (실리카 겔, 메틸렌 클로라이드/메탄올 = 9:1)R f value: 0.53 (silica gel, methylene chloride / methanol = 9: 1)
질량 스펙트럼 (ESI-): m/z = 273 [M-H]- Mass spectrum (ESI -): m / z = 273 [MH] -
(2) 4-하이드록시-6-사이클로펜틸옥시-7-메틸카보닐옥시-퀴나졸린(2) 4-hydroxy-6-cyclopentyloxy-7-methylcarbonyloxy-quinazolin
융점: 209 내지 212 ℃Melting Point: 209-212 ° C
질량 스펙트럼 (ESI-): m/z = 287 [M-H]- Mass spectrum (ESI -): m / z = 287 [MH] -
(3) 6-벤질옥시-4-하이드록시-7-메틸카보닐옥시-퀴나졸린(3) 6-benzyloxy-4-hydroxy-7-methylcarbonyloxy-quinazolin
Rf값: 0.48 (실리카 겔, 메틸렌 클로라이드/메탄올/진한 암모니아 수용액 = 90:10:0.1)R f value: 0.48 (silica gel, methylene chloride / methanol / aqueous ammonia solution = 90: 10: 0.1)
질량 스펙트럼 (ESI-): m/z = 309 [M-H]- Mass spectrum (ESI -): m / z = 309 [MH] -
(4) 4-하이드록시-7-메틸카보닐옥시-6-((S)-테트라하이드로푸란-3-일옥시)-퀴나졸린(4) 4-hydroxy-7-methylcarbonyloxy-6-((S) -tetrahydrofuran-3-yloxy) -quinazoline
Rf값: 0.62 {시판 역상 TLC 판[이. 머크(E. Merck)], 아세토니트릴/물/트리플루오로아세트산 = 50:50:1}R f value: 0.62 {commercial reverse phase TLC plate]. E. Merck], acetonitrile / water / trifluoroacetic acid = 50: 50: 1}
질량 스펙트럼 (ESI+): m/z = 291 [M+H]+ Mass spectrum (ESI + ): m / z = 291 [M + H] +
(5) 4-하이드록시-7-메틸카보닐옥시-6-[(S)-(테트라하이드로푸란-2-일)메톡시]-퀴나졸린(5) 4-hydroxy-7-methylcarbonyloxy-6-[(S)-(tetrahydrofuran-2-yl) methoxy] -quinazoline
Rf값: 0.50 (실리카 겔, 메틸렌 클로라이드/메탄올 = 9:1)R f value: 0.50 (silica gel, methylene chloride / methanol = 9: 1)
질량 스펙트럼 (ESI+): m/z = 305 [M+H]+ Mass spectrum (ESI + ): m / z = 305 [M + H] +
실시예 VIExample VI
4,7-디하이드록시-6-사이클로펜틸메톡시-퀴나졸린4,7-dihydroxy-6-cyclopentylmethoxy-quinazoline
에탄올 140ml 중의 2-아미노-5-사이클로펜틸메톡시-4-하이드록시-벤조산 5.76g 및 포름아미딘 아세테이트 6.52g을 약 3시간 동안 환류시킨다. 후처리를 위해 반응 혼합물을 약 100ml가 되도록 증발시키고 빙수 300ml를 가하며, 이 때 회색 침전물이 형성된다. 침전물을 흡인여과하고 물로 세척한 후, 진공 데시케이터 속에서 건조시킨다.5.76 g of 2-amino-5-cyclopentylmethoxy-4-hydroxy-benzoic acid and 6.52 g of formamidine acetate in 140 ml of ethanol are refluxed for about 3 hours. For workup the reaction mixture is evaporated to about 100 ml and 300 ml of ice water is added, whereby a gray precipitate is formed. The precipitate is suction filtered, washed with water and dried in a vacuum desiccator.
수득량: 4.57g (이론치의 77%),Yield: 4.57 g (77% of theory),
Rf값: 0.25 (실리카 겔, 메틸렌 클로라이드/메탄올 = 95:5)R f value: 0.25 (silica gel, methylene chloride / methanol = 95: 5)
질량 스펙트럼 (ESI-): m/z = 259 [M-H]- Mass spectrum (ESI -): m / z = 259 [MH] -
아래의 화합물을 실시예 VI과 유사하게 수득한다:The following compounds are obtained analogously to Example VI:
(1) 4,7-디하이드록시-6-사이클로프로필메톡시-퀴나졸린(1) 4,7-dihydroxy-6-cyclopropylmethoxy-quinazoline
Rf값: 0.45 (실리카 겔, 메틸렌 클로라이드/메탄올/진한 암모니아 수용액 = 90:10:0.1)R f value: 0.45 (silica gel, methylene chloride / methanol / aqueous ammonia solution = 90: 10: 0.1)
질량 스펙트럼 (ESI-): m/z = 231 [M-H]- Mass spectrum (ESI -): m / z = 231 [MH] -
(2) 4,7-디하이드록시-6-사이클로펜틸옥시-퀴나졸린(2) 4,7-dihydroxy-6-cyclopentyloxy-quinazoline
Rf값: 0.42 (실리카 겔, 메틸렌 클로라이드/메탄올/진한 암모니아 수용액 = 90:10:0.1)R f value: 0.42 (silica gel, methylene chloride / methanol / aqueous ammonia solution = 90: 10: 0.1)
질량 스펙트럼 (EI): m/z = 246 [M]+ Mass spectrum (EI): m / z = 246 [M] +
(3) 6-벤질옥시-4,7-디하이드록시-퀴나졸린(3) 6-benzyloxy-4,7-dihydroxy-quinazoline
Rf값: 0.44 (실리카 겔, 메틸렌 클로라이드/메탄올/진한 암모니아 수용액 = 90:10:0.1)R f value: 0.44 (silica gel, methylene chloride / methanol / aqueous ammonia solution = 90: 10: 0.1)
질량 스펙트럼 (ESI-): m/z = 267 [M-H]- Mass spectrum (ESI -): m / z = 267 [MH] -
(4) 6-벤질옥시-7-사이클로펜틸옥시-4-하이드록시-퀴나졸린(4) 6-benzyloxy-7-cyclopentyloxy-4-hydroxy-quinazolin
융점: 221 내지 223℃Melting Point: 221-223 DEG C
질량 스펙트럼 (ESI+): m/z = 337 [M+H]+ Mass spectrum (ESI + ): m / z = 337 [M + H] +
(5) 4,7-디하이드록시-6-((S)-테트라하이드로푸란-3-일옥시)-퀴나졸린(5) 4,7-dihydroxy-6-((S) -tetrahydrofuran-3-yloxy) -quinazoline
Rf값: 0.69 [시판 역상 TLC 판(이. 머크), 아세토니트릴/물/트리플루오로아세트산 = 50:50:1]R f value: 0.69 [commercial reverse phase TLC plate (E. Merck), acetonitrile / water / trifluoroacetic acid = 50: 50: 1]
질량 스펙트럼 (ESI-): m/z = 247 [M-H]- Mass spectrum (ESI -): m / z = 247 [MH] -
(6) 4,7-디하이드록시-6-[(S)-(테트라하이드로푸란-2-일)메톡시]-퀴나졸린(6) 4,7-dihydroxy-6-[(S)-(tetrahydrofuran-2-yl) methoxy] -quinazoline
Rf값: 0.56 (실리카 겔, 메틸렌 클로라이드/메탄올 = 9:1)R f value: 0.56 (silica gel, methylene chloride / methanol = 9: 1)
질량 스펙트럼 (ESI-): m/z = 261 [M-H]- Mass spectrum (ESI -): m / z = 261 [MH] -
실시예 VIIExample VII
2-아미노-5-사이클로펜틸메톡시-4-하이드록시-벤조산2-Amino-5-cyclopentylmethoxy-4-hydroxy-benzoic acid
5-사이클로펜틸메톡시-4-하이드록시-2-니트로-벤조산 6.50g을 메탄올 130ml에 용해시키고 라니 니켈 2.00g을 가한 후, 당해 혼합물을 약 3시간 동안 수소압 50psi 하에 대략 주위 온도에서 수소화시켜 계산된 양의 수소를 흡수시킨다. 촉매를 여과제거하고 가열된 메탄올로 세척한다. 여액을 진공하에 증발시킨다. 갈색을 띠는 고체가 잔류하며, 이를 더 이상 정제하지 않고 추가로 반응시킨다.After dissolving 6.50 g of 5-cyclopentylmethoxy-4-hydroxy-2-nitro-benzoic acid in 130 ml of methanol and adding 2.00 g of Raney nickel, the mixture was hydrogenated at approximately ambient temperature under hydrogen pressure of 50 psi for about 3 hours. Absorb the calculated amount of hydrogen. The catalyst is filtered off and washed with heated methanol. The filtrate is evaporated in vacuo. A brownish solid remains, which is further reacted without further purification.
수득량: 5.79g (이론치의 100%),Yield: 5.79 g (100% of theory),
Rf값: 0.67 (실리카 겔, 메틸렌 클로라이드/메탄올 = 9:1)R f value: 0.67 (silica gel, methylene chloride / methanol = 9: 1)
질량 스펙트럼 (ESI-): m/z = 250 [M-H]- Mass spectrum (ESI -): m / z = 250 [MH] -
아래의 화합물을 실시예 VII과 유사하게 수득한다:The following compounds are obtained similarly to Example VII:
(1) 2-아미노-5-사이클로프로필메톡시-4-하이드록시-벤조산(1) 2-Amino-5-cyclopropylmethoxy-4-hydroxy-benzoic acid
Rf값: 0.51 (실리카 겔, 메틸렌 클로라이드/메탄올/진한 암모니아 수용액 = 90:10:0.1)R f value: 0.51 (silica gel, methylene chloride / methanol / aqueous ammonia solution = 90: 10: 0.1)
질량 스펙트럼 (ESI-): m/z = 222 [M-H]- Mass spectrum (ESI -): m / z = 222 [MH] -
(2) 2-아미노-5-사이클로펜틸옥시-4-하이드록시-벤조산(2) 2-Amino-5-cyclopentyloxy-4-hydroxy-benzoic acid
Rf값: 0.38 (실리카 겔, 메틸렌 클로라이드/메탄올/진한 암모니아 수용액 = 90:10:0.1)R f value: 0.38 (silica gel, methylene chloride / methanol / aqueous ammonia solution = 90: 10: 0.1)
질량 스펙트럼 (ESI+): m/z = 238 [M+H]+ Mass spectrum (ESI + ): m / z = 238 [M + H] +
(3) 2-아미노-5-벤질옥시-4-하이드록시-벤조산(3) 2-Amino-5-benzyloxy-4-hydroxy-benzoic acid
Rf값: 0.52 (실리카 겔, 메틸렌 클로라이드/메탄올/진한 암모니아 수용액 = 90:10:0.1)R f value: 0.52 (silica gel, methylene chloride / methanol / aqueous ammonia solution = 90: 10: 0.1)
질량 스펙트럼 (ESI-): m/z = 258 [M-H]- Mass spectrum (ESI -): m / z = 258 [MH] -
(4) 사이클로펜틸 2-아미노-5-벤질옥시-4-사이클로펜틸옥시-벤조에이트(4) cyclopentyl 2-amino-5-benzyloxy-4-cyclopentyloxy-benzoate
(반응은 메탄올과 테트라하이드로푸란의 1:1 혼합물 속에서 수행한다)(The reaction is carried out in a 1: 1 mixture of methanol and tetrahydrofuran)
Rf값: 0.84 (실리카 겔, 에틸 아세테이트/사이클로헥산 = 1:1)R f value: 0.84 (silica gel, ethyl acetate / cyclohexane = 1: 1)
질량 스펙트럼 (ESI+): m/z = 396 [M+H]+ Mass spectrum (ESI + ): m / z = 396 [M + H] +
(5) 2-아미노-4-하이드록시-5-((S)-테트라하이드로푸란-3-일옥시)-벤조산(5) 2-Amino-4-hydroxy-5-((S) -tetrahydrofuran-3-yloxy) -benzoic acid
Rf값: 0.70 [시판 역상 TLC 판(이. 머크), 아세토니트릴/물/트리플루오로아세트산 = 50:50:1]R f value: 0.70 [commercial reverse phase TLC plate (E. Merck), acetonitrile / water / trifluoroacetic acid = 50: 50: 1]
질량 스펙트럼 (ESI-): m/z = 238 [M-H]- Mass spectrum (ESI -): m / z = 238 [MH] -
(6) 2-아미노-4-하이드록시-5-[(S)-(테트라하이드로푸란-2-일)메톡시]-벤조산(6) 2-Amino-4-hydroxy-5-[(S)-(tetrahydrofuran-2-yl) methoxy] -benzoic acid
Rf값: 0.59 [시판 역상 TLC 판(이. 머크), 아세토니트릴/물/트리플루오로아세트산 = 50:50:1]R f value: 0.59 [commercial reverse phase TLC plate (E. Merck), acetonitrile / water / trifluoroacetic acid = 50: 50: 1]
질량 스펙트럼 (ESI-): m/z = 252 [M-H]- Mass spectrum (ESI -): m / z = 252 [MH] -
실시예 VIIIExample VIII
5-사이클로펜틸메톡시-4-하이드록시-2-니트로-벤조산5-cyclopentylmethoxy-4-hydroxy-2-nitro-benzoic acid
4,5-메틸렌디옥시-2-니트로-벤조산 15.37g 및 사이클로펜틸메탄올 51.84ml를 디메틸 설폭사이드 100ml에 용해시키고 질소 대기하에 빙욕 속에서 냉각시킨다. 이어서, 나트륨 3.90g을 배치식으로 가한다. 반응 혼합물을 빙욕으로 냉각시키면서 30분 동안 교반한 후, 간단히 35 내지 40℃로 가열하고, 이어서 빙욕으로 냉각시키면서 추가로 3시간 동안 교반한다. 이어서, 빙욕을 제거하고 반응 혼합물을 주위 온도에서 밤새 교반한다. 적색을 띠는 암갈색 반응 용액을 아세톤 약 800ml에 부으면, 이 때 암갈색 침전물이 형성된다. 침전물을 흡인여과하고 아세톤으로 세척한 후, 물 300 내지 400ml에 용해시키고 2N 염산 60ml을 사용하여 약 pH 2로 조정한다. 당해 수용액을 메틸렌 클로라이드로 수회 추출한다. 합한 추출물을 포화 염화나트륨 용액으로 세척하고 황산나트륨 상에서 건조시킨 후, 증발시켜 농축시킨다. 암갈색 오일성 플라스크 잔사를 메틸렌 클로라이드 800ml에 용해시키고 메틸렌 클로라이드/메탄올(9:1)로 실리카 겔 충전물을 통해 정제한다. 갈색 오일이 수득되며, 이를 빙욕으로 냉각시키면서 물과 함께 교반하여 결정화시킨다. 갈색을 띠는 형성된 침전물을 흡인여과하고 소량의 물로 세척한 후, 진공 데시케이터 속에서 건조시킨다.15.37 g of 4,5-methylenedioxy-2-nitro-benzoic acid and 51.84 ml of cyclopentylmethanol are dissolved in 100 ml of dimethyl sulfoxide and cooled in an ice bath under a nitrogen atmosphere. Then, 3.90 g of sodium is added batchwise. The reaction mixture is stirred for 30 minutes while cooling in an ice bath, then briefly heated to 35-40 ° C. and then stirred for an additional 3 hours while cooling in an ice bath. The ice bath is then removed and the reaction mixture is stirred overnight at ambient temperature. Pour the reddish dark brown reaction solution into about 800 ml of acetone, at which time a dark brown precipitate is formed. The precipitate is suction filtered, washed with acetone, dissolved in 300-400 ml of water and adjusted to about pH 2 with 60 ml of 2N hydrochloric acid. The aqueous solution is extracted several times with methylene chloride. The combined extracts are washed with saturated sodium chloride solution, dried over sodium sulfate and then evaporated to concentrate. The dark brown oily flask residue is dissolved in 800 ml of methylene chloride and purified through silica gel charge with methylene chloride / methanol (9: 1). A brown oil is obtained, which is crystallized by stirring with water while cooling in an ice bath. The brownish precipitate formed is suction filtered, washed with a small amount of water and dried in a vacuum desiccator.
수득량: 9.55g (이론치의 47%),Yield: 9.55 g (47% of theory),
Rf값: 0.67 (실리카 겔, 톨루엔/디옥산/에탄올/빙초산 = 90:10:10:6)R f value: 0.67 (silica gel, toluene / dioxane / ethanol / glacial acetic acid = 90: 10: 10: 6)
질량 스펙트럼 (ESI-): m/z = 280 [M-H]- Mass spectrum (ESI -): m / z = 280 [MH] -
아래의 화합물을 실시예 VIII과 유사하게 수득한다:The following compounds are obtained analogously to Example VIII:
(1) 5-사이클로프로필메톡시-4-하이드록시-2-니트로-벤조산(1) 5-cyclopropylmethoxy-4-hydroxy-2-nitro-benzoic acid
Rf값: 0.61 (실리카 겔, 톨루엔/디옥산/에탄올/빙초산 = 90:10:10:6)R f value: 0.61 (silica gel, toluene / dioxane / ethanol / glacial acetic acid = 90: 10: 10: 6)
질량 스펙트럼 (ESI-): m/z = 252 [M-H]- Mass spectrum (ESI -): m / z = 252 [MH] -
(2) 5-사이클로펜틸옥시-4-하이드록시-2-니트로-벤조산(2) 5-cyclopentyloxy-4-hydroxy-2-nitro-benzoic acid
Rf값: 0.62 (실리카 겔, 톨루엔/디옥산/에탄올/빙초산 = 90:10:10:6)R f value: 0.62 (silica gel, toluene / dioxane / ethanol / glacial acetic acid = 90: 10: 10: 6)
질량 스펙트럼 (ESI-): m/z = 266 [M-H]- Mass spectrum (ESI -): m / z = 266 [MH] -
(3) 5-벤질옥시-4-하이드록시-2-니트로-벤조산(3) 5-benzyloxy-4-hydroxy-2-nitro-benzoic acid
융점: 176 내지 178℃Melting point: 176-178 ° C
질량 스펙트럼 (ESI-): m/z = 288 [M-H]- Mass spectrum (ESI -): m / z = 288 [MH] -
(4) 4-하이드록시-2-니트로-5-((S)-테트라하이드로푸란-3-일옥시)-벤조산(4) 4-hydroxy-2-nitro-5-((S) -tetrahydrofuran-3-yloxy) -benzoic acid
Rf값: 0.58 [시판 역상 TLC 판(이. 머크), 아세토니트릴/물/트리플루오로아세트산 = 50:50:1]R f value: 0.58 [commercial reverse phase TLC plate (E. Merck), acetonitrile / water / trifluoroacetic acid = 50: 50: 1]
질량 스펙트럼 (ESI-): m/z = 268 [M-H]- Mass spectrum (ESI -): m / z = 268 [MH] -
(5) 4-하이드록시-2-니트로-5-[(S)-(테트라하이드로푸란-2-일)메톡시]-벤조산(5) 4-hydroxy-2-nitro-5-[(S)-(tetrahydrofuran-2-yl) methoxy] -benzoic acid
Rf값: 0.53 [시판 역상 TLC 판(이. 머크), 아세토니트릴/물/트리플루오로아세트산 = 50:50:1]R f value: 0.53 [commercial reverse phase TLC plate (E. Merck), acetonitrile / water / trifluoroacetic acid = 50: 50: 1]
질량 스펙트럼 (ESI-): m/z = 282 [M-H]- Mass spectrum (ESI -): m / z = 282 [MH] -
실시예 IXExample IX
에틸 (2-하이드록시-2-메틸-프로필아미노)-아세테이트Ethyl (2-hydroxy-2-methyl-propylamino) -acetate
탄산나트륨 100.00g을 포화 탄산칼륨 용액 100ml 중의 글리신 에틸 에스테르 하이드로클로라이드 50.00g에 냉각시키면서 가한다. 형성된 매스를 총 약 600ml의 디에틸 에테르로 수회 추출한다. 합한 에테르 추출물을 황산나트륨 상에서 건조시키고 증발건조시킨다. 글리신 에틸 에스테르 28.60g가 잔류한다. 이를 이소부틸렌 옥사이드 26.00ml 및 무수 에탄올 40ml와 혼합하고 로트 봄(Roth bomb) 속에서 6시간 동안 90℃로 가열한다. 주위 온도로 냉각시킨 후, 반응 혼합물을 증발시켜농축시키면 유동성 오일이 잔류한다.100.00 g of sodium carbonate is added to 50.00 g of glycine ethyl ester hydrochloride in 100 ml of saturated potassium carbonate solution while cooling. The formed mass is extracted several times with a total of about 600 ml of diethyl ether. The combined ether extracts are dried over sodium sulphate and evaporated to dryness. Remains 28.60 g of glycine ethyl ester. It is mixed with 26.00 ml of isobutylene oxide and 40 ml of anhydrous ethanol and heated to 90 ° C. for 6 hours in a Roth bomb. After cooling to ambient temperature, the reaction mixture is evaporated and concentrated to leave a flowable oil.
수득량: 45.80g (이론치의 73%),Yield: 45.80 g (73% of theory),
질량 스펙트럼 (ESI+): m/z = 176 [M+H]+ Mass spectrum (ESI + ): m / z = 176 [M + H] +
실시예 XExample X
4-메틸아미노-디하이드로-푸란-2-온4-methylamino-dihydro-furan-2-one
메탄올 25ml 중의 4-(N-벤질-N-메틸-아미노)-디하이드로-푸란-2-온 2.00g을 팔라듐 250mg(활성탄 상의 10%)의 존재하에 수소압 50psi에서 약 2시간 동안 주위 온도에서 수소화시켜 계산된 양의 수소를 흡수시킨다. 후처리를 위해 촉매를 여과제거하고 진공하에 증발시킨다. 무색 오일이 잔류하며, 이를 더 이상 정제하지 않고 추가로 반응시킨다.2.00 g of 4- (N-benzyl-N-methyl-amino) -dihydro-furan-2-one in 25 ml of methanol at ambient temperature for about 2 hours at 50 psi hydrogen pressure in the presence of 250 mg of palladium (10% on activated carbon) Hydrogenation absorbs the calculated amount of hydrogen. The catalyst is filtered off and evaporated under vacuum for workup. Colorless oil remains and is reacted further without further purification.
수득량: 1.20gYield: 1.20 g
Rf값: 0.13 (실리카 겔, 에틸 아세테이트)R f value: 0.13 (silica gel, ethyl acetate)
질량 스펙트럼 (ESI+): m/z = 116 [M+H]+ Mass spectrum (ESI + ): m / z = 116 [M + H] +
실시예 XIExample XI
4-(N-벤질-N-메틸-아미노)-디하이드로-푸란-2-온4- (N-benzyl-N-methyl-amino) -dihydro-furan-2-one
N-메틸벤질아민 23.20ml를 메틸렌 클로라이드 150ml 중의 5H-푸란-2-온 15.00g에 첨가한다. 반응 혼합물을 약 48시간 동안 주위 온도에서 교반한다. 후처리를 위해, 반응 혼합물을 증발시켜 농축시키고 용출액으로서 에틸 아세테이트/석유 에테르(3:1)를 사용하여 실리카 겔 컬럼 상에서 배치식으로 크로마토그래피를 수행한다. 목적하는 생성물을 황색을 띠는 오일로서 수득한다.23.20 ml of N-methylbenzylamine is added to 15.00 g of 5H-furan-2-one in 150 ml of methylene chloride. The reaction mixture is stirred at ambient temperature for about 48 hours. For workup, the reaction mixture is concentrated by evaporation and chromatographically performed on a silica gel column using ethyl acetate / petroleum ether (3: 1) as eluent. The desired product is obtained as a yellowish oil.
수득량: 19.77g (이론치의 54%),Yield: 19.77 g (54% of theory),
Rf값: 0.67 (실리카 겔, 에틸 아세테이트)R f value: 0.67 (silica gel, ethyl acetate)
질량 스펙트럼 (ESI+): m/z = 228 [M+Na]+ Mass spectrum (ESI + ): m / z = 228 [M + Na] +
실시예 XIIExample XII
4-[(3-클로로-4-플루오로페닐)아미노]-7-사이클로부틸옥시-6-하이드록시-퀴나졸린4-[(3-chloro-4-fluorophenyl) amino] -7-cyclobutyloxy-6-hydroxy-quinazolin
트리플루오로아세트산 10ml를 6-벤질옥시-4-[(3-클로로-4-플루오로페닐)아미노]-7-사이클로부틸옥시-퀴나졸린 5.60g에 교반하면서 적가한다. 반응 혼합물을 약 40℃까지 가열한다. 주위 온도에서 20시간 동안 교반한 후, 추가로 트리플루오로아세트산 3ml를 가한다. 주위 온도에서 3시간 동안 추가로 교반한 후에도 반응은 거의 진행되지 않기 때문에, 반응 혼합물을 50℃로 가열한다. 4시간 후, 반응이 완료되고, 과량의 트리플루오로아세트산을 회전 증발기를 사용하여 실질적으로 증류제거한다. 잔사를 물과 혼합하고 진한 암모니아 수용액을 사용하여 알칼리성으로 만든다. 형성된 연갈색 침전물을 흡인여과하고 다량의 물로 세척한 후, 데시케이터 속에서 건조시킨다. 수득된 생성물은 여전히 트리플루오로아세트산을 함유한다.10 ml of trifluoroacetic acid is added dropwise to 5.60 g of 6-benzyloxy-4-[(3-chloro-4-fluorophenyl) amino] -7-cyclobutyloxy-quinazolin with stirring. The reaction mixture is heated to about 40 ° C. After 20 hours of stirring at ambient temperature, additional 3 ml of trifluoroacetic acid is added. The reaction mixture is heated to 50 ° C., since the reaction hardly proceeds after further stirring at ambient temperature for 3 hours. After 4 hours, the reaction is complete and the excess trifluoroacetic acid is substantially distilled off using a rotary evaporator. The residue is mixed with water and made alkaline using concentrated aqueous ammonia solution. The light brown precipitate formed is suction filtered and washed with plenty of water and then dried in a desiccator. The product obtained still contains trifluoroacetic acid.
수득량: 5.82gYield: 5.82 g
Rf값: 0.61 (실리카 겔, 메틸렌 클로라이드/메탄올 = 9:1)R f value: 0.61 (silica gel, methylene chloride / methanol = 9: 1)
질량 스펙트럼 (ESI+): m/z = 360, 362 [M+H]+ Mass spectrum (ESI + ): m / z = 360, 362 [M + H] +
아래의 화합물을 실시예 XII와 유사하게 수득한다:The following compounds are obtained analogously to Example XII:
(1) 4-[(3-클로로-4-플루오로페닐)아미노]-7-사이클로프로필메톡시-6-하이드록시-퀴나졸린(1) 4-[(3-chloro-4-fluorophenyl) amino] -7-cyclopropylmethoxy-6-hydroxy-quinazolin
Rf값: 0.65 (실리카 겔, 메틸렌 클로라이드/메탄올 = 9:1)R f value: 0.65 (silica gel, methylene chloride / methanol = 9: 1)
질량 스펙트럼 (ESI+): m/z = 360, 362 [M+H]+ Mass spectrum (ESI + ): m / z = 360, 362 [M + H] +
(2) 4-[(3-클로로-4-플루오로페닐)아미노]-7-사이클로펜틸옥시-6-하이드록시-퀴나졸린(2) 4-[(3-chloro-4-fluorophenyl) amino] -7-cyclopentyloxy-6-hydroxyquinazolin
Rf값: 0.65 (실리카 겔, 메틸렌 클로라이드/메탄올 = 9:1)R f value: 0.65 (silica gel, methylene chloride / methanol = 9: 1)
질량 스펙트럼 (ESI+): m/z = 374, 376 [M+H]+ Mass spectrum (ESI + ): m / z = 374, 376 [M + H] +
(3) 4-[(3-클로로-4-플루오로페닐)아미노]-6-하이드록시-7-((R)-테트라하이드로푸란-3-일옥시)-퀴나졸린(3) 4-[(3-chloro-4-fluorophenyl) amino] -6-hydroxy-7-((R) -tetrahydrofuran-3-yloxy) -quinazoline
Rf값: 0.32 (실리카 겔, 메틸렌 클로라이드/메탄올 = 9:1)R f value: 0.32 (silica gel, methylene chloride / methanol = 9: 1)
(4) 4-[(3-클로로-4-플루오로페닐)아미노]-6-하이드록시-7-[(R)-(테트라하이드로푸란-2-일)메톡시]-퀴나졸린(4) 4-[(3-chloro-4-fluorophenyl) amino] -6-hydroxy-7-[(R)-(tetrahydrofuran-2-yl) methoxy] -quinazoline
질량 스펙트럼 (ESI-): m/z = 388, 390 [M-H]- Mass spectrum (ESI -): m / z = 388, 390 [MH] -
실시예 XIIIExample XIII
6-벤질옥시-4-[(3-클로로-4-플루오로페닐)아미노]-7-사이클로부틸옥시-퀴나졸린6-benzyloxy-4-[(3-chloro-4-fluorophenyl) amino] -7-cyclobutyloxy-quinazolin
탄산칼륨 7.50g 및 사이클로부틸 메탄설포네이트 4.50g을 N,N-디메틸포름아미드 60ml 중의 6-벤질옥시-4-[(3-클로로-4-플루오로페닐)아미노]-7-하이드록시-퀴나졸린 7.00g에 가한다. 반응 혼합물을 2시간 동안 80℃에서 교반한다. 이어서, 사이클로부틸 메탄설포네이트 2.00g 및 탄산칼륨 3.00g을 가하고 혼합물을 주말에 걸쳐 60℃에서 교반한다. 여전히 반응이 완료되지 않은 상태이므로 추가로 사이클로부틸 메탄설포네이트 3.50g 및 탄산칼륨 5.00g을 가한다. 추가로 20시간 동안 80℃에서 교반한 후, 반응이 거의 종결된다. 후처리를 위해 반응 혼합물을 에틸 아세테이트 300ml와 합하고 물 및 포화 염화나트륨 용액으로 세척한다. 유기 상을 황산마그네슘 상에서 건조시키고 증발시켜 농축시킨다. 잔사를 메탄올과 함께 교반하면 갈색을 띠는 침전물이 생성된다. 이것을 흡인여과하고 메탄올로 세척한 후, 데시케이터 속에서 건조시킨다.7.50 g of potassium carbonate and 4.50 g of cyclobutyl methanesulfonate were added to 6-benzyloxy-4-[(3-chloro-4-fluorophenyl) amino] -7-hydroxy-quina in 60 ml of N, N-dimethylformamide. Add 7.00 g sleepy. The reaction mixture is stirred at 80 ° C. for 2 hours. Then 2.00 g of cyclobutyl methanesulfonate and 3.00 g of potassium carbonate are added and the mixture is stirred at 60 ° C. over the weekend. Since the reaction is still incomplete, 3.50 g of cyclobutyl methanesulfonate and 5.00 g of potassium carbonate are added. After a further 20 hours of stirring at 80 ° C., the reaction is almost complete. The reaction mixture is combined with 300 ml of ethyl acetate for workup and washed with water and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated by evaporation. Stirring the residue with methanol gives a brownish precipitate. This is suction filtered, washed with methanol and dried in desiccator.
수득량: 5.10g (이론치의 64%),Yield: 5.10 g (64% of theory),
Rf값: 0.69 (실리카 겔, 메틸렌 클로라이드/메탄올 = 9:1)R f value: 0.69 (silica gel, methylene chloride / methanol = 9: 1)
질량 스펙트럼 (ESI-): m/z = 448, 450 [M-H]- Mass spectrum (ESI -): m / z = 448, 450 [MH] -
아래의 화합물을 실시예 XIII과 유사하게 수득한다:The following compounds are obtained analogously to Example XIII:
(1) 6-벤질옥시-4-[(3-클로로-4-플루오로페닐)아미노]-7-사이클로프로필메톡시-퀴나졸린 (브로모메틸사이클로프로판을 사용한다)(1) 6-benzyloxy-4-[(3-chloro-4-fluorophenyl) amino] -7-cyclopropylmethoxy-quinazolin (using bromomethylcyclopropane)
Rf값: 0.72 (실리카 겔, 메틸렌 클로라이드/메탄올 = 9:1)R f value: 0.72 (silica gel, methylene chloride / methanol = 9: 1)
질량 스펙트럼 (ESI-): m/z = 448, 450 [M-H]- Mass spectrum (ESI -): m / z = 448, 450 [MH] -
(2) 6-벤질옥시-4-[(3-클로로-4-플루오로페닐)아미노]-7-사이클로펜틸옥시-퀴나졸린(2) 6-benzyloxy-4-[(3-chloro-4-fluorophenyl) amino] -7-cyclopentyloxy-quinazoline
(브로모사이클로펜탄을 사용한다)(Use bromocyclopentane)
Rf값: 0.78 (실리카 겔, 메틸렌 클로라이드/메탄올 = 9:1)R f value: 0.78 (silica gel, methylene chloride / methanol = 9: 1)
질량 스펙트럼 (ESI+): m/z = 464, 466 [M+H]+ Mass spectrum (ESI + ): m / z = 464, 466 [M + H] +
실시예 XIVExample XIV
3급-부틸 (S)-(2-하이드록시-프로필아미노)-아세테이트Tert-butyl (S)-(2-hydroxy-propylamino) -acetate
(S)-(+)-1-아미노-2-프로판올 15.00g을 N,N-디메틸포름아미드 100ml에 용해시키고 디이소프로필에틸아민 6.97ml를 가한다. 이어서, 여기에 3급-부틸 브로모아세테이트 5.91ml를 30분 내에 적가하면서, 빙욕으로 냉각시킨다. 빙욕을 제거하고 반응 혼합물을 주위 온도에서 밤새 교반한다. 후처리를 위해 반응 혼합물을 진공하에 증발시킨다. 플라스크 잔사를 물 50ml에 용해시키고 염화나트륨 15g으로 포화시킨다. 당해 수용액을 에틸 아세테이트로 수회 추출한다. 합한 추출물을 포화 염화나트륨 용액으로 세척하고 황산마그네슘 상에서 건조시킨 후, 진공하에 증발시키면 황색을 띠는 오일이 잔류한다.15.00 g of (S)-(+)-1-amino-2-propanol is dissolved in 100 ml of N, N-dimethylformamide and 6.97 ml of diisopropylethylamine are added. Subsequently, 5.91 ml of tert-butyl bromoacetate is added dropwise within 30 minutes, followed by cooling in an ice bath. The ice bath is removed and the reaction mixture is stirred overnight at ambient temperature. The reaction mixture is evaporated under vacuum for workup. The flask residue is dissolved in 50 ml of water and saturated with 15 g of sodium chloride. The aqueous solution is extracted several times with ethyl acetate. The combined extracts are washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated under vacuum to leave a yellowish oil.
수득량: 7.36g (이론치의 97%),Yield: 7.36 g (97% of theory),
Rf값: 0.46 (실리카 겔, 에틸 아세테이트/메탄올 = 9:1)R f value: 0.46 (silica gel, ethyl acetate / methanol = 9: 1)
질량 스펙트럼 (ESI+): m/z = 190 [M+H]+ Mass spectrum (ESI + ): m / z = 190 [M + H] +
아래의 화합물을 실시예 XIV와 유사하게 수득한다:The following compounds are obtained analogously to Example XIV:
(1) 3급-부틸 (R)-(2-하이드록시-프로필아미노)-아세테이트(1) tert-butyl (R)-(2-hydroxy-propylamino) -acetate
Rf값: 0.46 (실리카 겔, 에틸 아세테이트/메탄올 = 9:1)R f value: 0.46 (silica gel, ethyl acetate / methanol = 9: 1)
질량 스펙트럼 (ESI+): m/z = 190 [M+H]+ Mass spectrum (ESI + ): m / z = 190 [M + H] +
(2) 3급-부틸 (1,1-디메틸-2-하이드록시-에틸아미노)-아세테이트(2) tert-butyl (1,1-dimethyl-2-hydroxy-ethylamino) -acetate
질량 스펙트럼 (ESI+): m/z = 204 [M+H]+ Mass spectrum (ESI + ): m / z = 204 [M + H] +
Rf값: 0.47 (실리카 겔, 메틸렌 클로라이드/메탄올/진한 암모니아 수용액 = 90:10:0.1)R f value: 0.47 (silica gel, methylene chloride / methanol / aqueous ammonia solution = 90: 10: 0.1)
실시예 XVExample XV
4-[(3-클로로-4-플루오로페닐)아미노]-6-(3-메탄설포닐옥시-프로필옥시)-7-사이클로부틸옥시-퀴나졸린4-[(3-chloro-4-fluorophenyl) amino] -6- (3-methanesulfonyloxy-propyloxy) -7-cyclobutyloxy-quinazoline
당해 화합물은 4-[(3-클로로-4-플루오로페닐)아미노]-6-(3-하이드록시-프로필옥시)-7-사이클로부틸옥시-퀴나졸린을 주위 온도에서 디이소프로필에틸아민의 존재하에 메틸렌 클로라이드 중의 메탄설폰산 클로라이드와 반응시켜 제조한다.This compound is a mixture of 4-[(3-chloro-4-fluorophenyl) amino] -6- (3-hydroxy-propyloxy) -7-cyclobutyloxy-quinazolin at ambient temperature of diisopropylethylamine. Prepared by reaction with methanesulfonic acid chloride in methylene chloride in the presence.
Rf값: 0.37 (실리카 겔, 메틸렌 클로라이드/메탄올 = 95:5)R f value: 0.37 (silica gel, methylene chloride / methanol = 95: 5)
질량 스펙트럼 (ESI-): m/z = 494, 496 [M-H]- Mass spectrum (ESI -): m / z = 494, 496 [MH] -
아래의 화합물을 실시예 XV와 유사하게 수득한다:The following compounds are obtained similar to Example XV:
(1) 4-[(3-클로로-4-플루오로페닐)아미노]-6-(3-메탄설포닐옥시-프로필옥시)-7-사이클로프로필메톡시-퀴나졸린(1) 4-[(3-chloro-4-fluorophenyl) amino] -6- (3-methanesulfonyloxy-propyloxy) -7-cyclopropylmethoxy-quinazoline
Rf값: 0.65 (실리카 겔, 메틸렌 클로라이드/메탄올 = 90:10)R f value: 0.65 (silica gel, methylene chloride / methanol = 90:10)
질량 스펙트럼 (ESI-): m/z = 494, 496 [M-H]- Mass spectrum (ESI -): m / z = 494, 496 [MH] -
(2) 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로프로필메톡시-7-(3-메탄설포닐옥시-프로필옥시)-퀴나졸린(2) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (3-methanesulfonyloxy-propyloxy) -quinazoline
Rf값: 0.73 (실리카 겔, 메틸렌 클로라이드/메탄올 = 90:10)R f value: 0.73 (silica gel, methylene chloride / methanol = 90:10)
질량 스펙트럼 (ESI+): m/z = 496, 498 [M+H]+ Mass spectrum (ESI + ): m / z = 496, 498 [M + H] +
(3) 4-[(3-클로로-4-플루오로페닐)아미노]-6-(4-메탄설포닐옥시-부틸옥시)-7-사이클로펜틸옥시-퀴나졸린(3) 4-[(3-chloro-4-fluorophenyl) amino] -6- (4-methanesulfonyloxy-butyloxy) -7-cyclopentyloxy-quinazoline
Rf값: 0.76 (실리카 겔, 메틸렌 클로라이드/메탄올 = 90:10)R f value: 0.76 (silica gel, methylene chloride / methanol = 90:10)
질량 스펙트럼 (ESI+): m/z = 524, 526 [M+H]+ Mass spectrum (ESI + ): m / z = 524, 526 [M + H] +
실시예 XVIExample XVI
4-[(3-클로로-4-플루오로페닐)아미노]-6-하이드록시-7-사이클로프로필-메톡시-퀴나졸린4-[(3-chloro-4-fluorophenyl) amino] -6-hydroxy-7-cyclopropyl-methoxy-quinazolin
당해 화합물은 파르장치(Parr apparatus) 내에서 메틸렌 클로라이드, 에탄올 및 진한 염산(500:210:3.5)의 혼합물 중에서 10% Pd/C의 존재하에 6-벤질옥시-4-[(3-클로로-4-플루오로페닐)아미노]-7-사이클로프로필메톡시-퀴나졸린을 수소화시켜 수득한다.This compound was prepared in the Parr apparatus in the presence of 10% Pd / C in a mixture of methylene chloride, ethanol and concentrated hydrochloric acid (500: 210: 3.5) in the presence of 6-benzyloxy-4-[(3-chloro-4 -Fluorophenyl) amino] -7-cyclopropylmethoxy-quinazolin is obtained by hydrogenation.
수득율: 이론치의 73%Yield: 73% of theory
질량 스펙트럼 (ESI+): m/z = 360, 362 [M+H]+ Mass spectrum (ESI + ): m / z = 360, 362 [M + H] +
실시예 XVIIExample XVII
사이클로펜틸 5-벤질옥시-4-사이클로펜틸옥시-2-니트로-벤조에이트Cyclopentyl 5-benzyloxy-4-cyclopentyloxy-2-nitro-benzoate
당해 화합물은 주위 온도에서 디메틸 설폭사이드 중의 보조 염기로서의 탄산칼륨의 존재하에 5-벤질옥시-4-하이드록시-2-니트로-벤조산을 브로모사이클로펜탄 2.2당량과 반응시켜 수득한다.The compound is obtained by reacting 5-benzyloxy-4-hydroxy-2-nitro-benzoic acid with 2.2 equivalents of bromocyclopentane at ambient temperature in the presence of potassium carbonate as an auxiliary base in dimethyl sulfoxide.
수득율: 이론치의 87%Yield: 87% of theory
Rf값: 0.92 (실리카 겔, 에틸 아세테이트/사이클로헥산 = 1:1)R f value: 0.92 (silica gel, ethyl acetate / cyclohexane = 1: 1)
질량 스펙트럼 (ESI+): m/z = 426 [M+H]+ Mass spectrum (ESI + ): m / z = 426 [M + H] +
실시예 XVIIIExample XVIII
4-[(3-클로로-4-플루오로페닐)아미노]-6-벤질옥시-7-((R)-테트라하이드로푸란-3-일옥시) 퀴나졸린4-[(3-chloro-4-fluorophenyl) amino] -6-benzyloxy-7-((R) -tetrahydrofuran-3-yloxy) quinazoline
디에틸 아조디카복실레이트 5.03ml를 테트라하이드로푸란 160ml 중의 4-[(3-클로로-4-플루오로페닐)아미노]-6-벤질옥시-7-하이드록시-퀴나졸린[참조: WO 제0055141 A1호] 8.00g, (S)-(+)-3-하이드록시-테트라하이드로푸란 2.42ml 및 트리페닐포스핀 7.95g의 용액에 적가한다. 반응 혼합물을 주위 온도에서 밤새 교반한 후, 회전 증발기를 사용하여 증발시킨다. 플라스크 잔사를 용출액으로서 메틸렌클로라이드/에틸 아세테이트(구배 2:1로부터 1:2)를 사용하여 실리카 겔 컬럼 상에서 크로마토그래피로 정제한다.5.03 ml of diethyl azodicarboxylate was added to 4-[(3-chloro-4-fluorophenyl) amino] -6-benzyloxy-7-hydroxy-quinazolin in 160 ml of tetrahydrofuran [see WO 0055141 A1. Arc] dropwise to a solution of 8.00 g, 2.42 ml of (S)-(+)-3-hydroxy-tetrahydrofuran and 7.95 g of triphenylphosphine. The reaction mixture is stirred at ambient temperature overnight and then evaporated using a rotary evaporator. The flask residue is purified by chromatography on a silica gel column using methylene chloride / ethyl acetate (gradient 2: 1 to 1: 2) as eluent.
수득량: 7.34g (이론치의 78%),Yield: 7.34 g (78% of theory),
융점: 165 내지 168℃Melting Point: 165-168 ° C.
질량 스펙트럼 (ESI+): m/z = 466, 468 [M+H]+ Mass spectrum (ESI + ): m / z = 466, 468 [M + H] +
아래의 화합물을 실시예 XVIII과 유사하게 수득한다:The following compounds are obtained analogously to Example XVIII:
(1) 4-[(3-클로로-4-플루오로페닐)아미노]-6-벤질옥시-7-[(R)-(테트라하이드로푸란-2-일)메톡시]-퀴나졸린(1) 4-[(3-chloro-4-fluorophenyl) amino] -6-benzyloxy-7-[(R)-(tetrahydrofuran-2-yl) methoxy] -quinazoline
질량 스펙트럼 (ESI+): m/z = 480, 482 [M+H]+ Mass spectrum (ESI + ): m / z = 480, 482 [M + H] +
Rf값: 0.38 (실리카 겔, 메틸렌 클로라이드/메탄올 = 15:1)R f value: 0.38 (silica gel, methylene chloride / methanol = 15: 1)
(2) 4-[(3-클로로-4-플루오로페닐)아미노]-7-(2-브로모-에톡시)-6-((S)-테트라하이드로푸란-3-일옥시)-퀴나졸린(2) 4-[(3-chloro-4-fluorophenyl) amino] -7- (2-bromo-ethoxy) -6-((S) -tetrahydrofuran-3-yloxy) -quina Sleepy
Rf값: 0.35 (실리카 겔, 메틸렌 클로라이드/메탄올 = 20:1)R f value: 0.35 (silica gel, methylene chloride / methanol = 20: 1)
최종 화합물의 제조:Preparation of the final compound:
실시예 1Example 1
4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로펜틸메톡시-7-[2-(2,2-디메틸-6-옥소-모르폴린-4-일)-에톡시]-퀴나졸린4-[(3-Chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy-7- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy ] -Quinazolin
4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로펜틸메톡시-7-(2-브로모에톡시)-퀴나졸린 250mg 및 에틸 (2-하이드록시-2-메틸-프로필아미노)-아세테이트 341mg을 아세토니트릴 20ml에 용해시키고 요오드화나트륨 50mg, 탄산칼륨 275mg 및 디이소프로필에틸아민 0.70ml와 합한다. 반응 혼합물을 약 90시간 동안 환류시킨다. 주위 온도로 냉각시킨 후, 반응 혼합물을 여과하고 여액을 진공하에 증발시킨다. 플라스크 잔사를 용출액으로서 석유 에테르/에틸 아세테이트(50:50, 이후에는 0:100)를 사용하여 실리카 겔 컬럼 상에서 크로마토그래피한다. 폐환 생성물을 베이지색 고체로서 수득한다.250 mg of 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy-7- (2-bromoethoxy) -quinazolin and ethyl (2-hydroxy-2-methyl-propyl 341 mg of amino) -acetate is dissolved in 20 ml of acetonitrile and combined with 50 mg of sodium iodide, 275 mg of potassium carbonate and 0.70 ml of diisopropylethylamine. The reaction mixture is refluxed for about 90 hours. After cooling to ambient temperature, the reaction mixture is filtered and the filtrate is evaporated in vacuo. The flask residue is chromatographed on a silica gel column using petroleum ether / ethyl acetate (50:50, then 0: 100) as eluent. The ring closure product is obtained as a beige solid.
수득량: 62mg (이론치의 23%),Yield: 62 mg (23% of theory),
Rf값: 0.29 (실리카 겔, 에틸 아세테이트)R f value: 0.29 (silica gel, ethyl acetate)
질량 스펙트럼 (ESI-): m/z = 541, 543 [M-H]- Mass spectrum (ESI -): m / z = 541, 543 [MH] -
아래의 화합물을 실시예 1과 유사하게 수득한다:The following compounds are obtained similarly to Example 1:
(1) 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로프로필메톡시-7-[2-(2,2-디메틸-6-옥소-모르폴린-4-일)-에톡시]-퀴나졸린(1) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -Ethoxy] -quinazoline
Rf값: 0.58 (실리카 겔, 메틸렌 클로라이드/메탄올 = 9:1)R f value: 0.58 (silica gel, methylene chloride / methanol = 9: 1)
질량 스펙트럼 (ESI-): m/z = 513, 515 [M-H]- Mass spectrum (ESI -): m / z = 513, 515 [MH] -
(2) 4-[(3-클로로-4-플루오로페닐)아미노]-7-사이클로부틸옥시-6-[3-(2,2-디메틸-6-옥소-모르폴린-4-일)-프로필옥시]-퀴나졸린(2) 4-[(3-chloro-4-fluorophenyl) amino] -7-cyclobutyloxy-6- [3- (2,2-dimethyl-6-oxo-morpholin-4-yl)- Propyloxy] -quinazolin
융점: 212 내지 214℃Melting Point: 212-214 ° C
질량 스펙트럼 (ESI-): m/z = 527, 529 [M-H]- Mass Spectrum (ESI -): m / z = 527, 529 [MH] -
(3) 4-[(3-클로로-4-플루오로페닐)아미노]-7-사이클로프로필메톡시-6-[3-(2,2-디메틸-6-옥소-모르폴린-4-일)-프로필옥시]-퀴나졸린(3) 4-[(3-chloro-4-fluorophenyl) amino] -7-cyclopropylmethoxy-6- [3- (2,2-dimethyl-6-oxo-morpholin-4-yl) -Propyloxy] -quinazoline
융점: 200 내지 202℃Melting point: 200-202 ° C
질량 스펙트럼 (ESI-): m/z = 527, 529 [M-H]- Mass Spectrum (ESI -): m / z = 527, 529 [MH] -
(4) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[3-(2,2-디메틸-6-옥소-모르폴린-4-일)-프로필옥시]-7-메톡시-퀴나졸린(4) 4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (2,2-dimethyl-6-oxo-morpholin-4-yl) -propyloxy] -7- Methoxy-Quinazoline
융점: 222 내지 224℃Melting Point: 222-224 ° C
질량 스펙트럼 (ESI-): m/z = 487, 489 [M-H]- Mass spectrum (ESI -): m / z = 487, 489 [MH] -
실시예 2Example 2
4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로프로필메톡시-7-{2-[N-(2-옥소-테트라하이드로푸란-4-일)-N-메틸-아미노]-에톡시}-퀴나졸린4-[(3-Chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl- Amino] -ethoxy} -quinazoline
아세토니트릴 20ml 중의 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로프로필메톡시-7-(2-브로모에톡시)-퀴나졸린 300mg 및 4-메틸아미노-디하이드로-푸란-2-온 400mg을 탄산칼륨 240mg 및 요오드화나트륨 70mg과 혼합하고 24시간 동안 환류시킨다. 주위 온도로 냉각시킨 후, 반응 혼합물을 여과하고 여액을 진공하에 증발시킨다. 플라스크 잔사를 용출액으로서 메틸렌 클로라이드/메탄올/진한 암모니아 수용액(97:3:0.05)을 사용하여 실리카 겔 컬럼 상에서 크로마토그래피한다. 표제 화합물을 연베이지색 고체로서 수득한다.300 mg of 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (2-bromoethoxy) -quinazolin in 20 ml of acetonitrile and 4-methylamino-dihydro- 400 mg of furan-2-one are mixed with 240 mg of potassium carbonate and 70 mg of sodium iodide and refluxed for 24 hours. After cooling to ambient temperature, the reaction mixture is filtered and the filtrate is evaporated in vacuo. The flask residue is chromatographed on a silica gel column using methylene chloride / methanol / rich aqueous ammonia solution (97: 3: 0.05) as eluent. The title compound is obtained as a light beige solid.
수득량: 70mg (이론치의 22%),Yield: 70 mg (22% of theory),
Rf값: 0.47 (실리카 겔, 메틸렌 클로라이드/메탄올/진한 암모니아 수용액 = 90:10:0.1)R f value: 0.47 (silica gel, methylene chloride / methanol / aqueous ammonia solution = 90: 10: 0.1)
질량 스펙트럼 (ESI+): m/z = 501, 503 [M+H]+ Mass spectrum (ESI + ): m / z = 501, 503 [M + H] +
아래의 화합물을 실시예 2와 유사하게 수득한다:The following compounds are obtained similarly to Example 2:
(1) 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로펜틸옥시-7-{2-[N-(2-옥소-테트라하이드로푸란-4-일)-N-메틸-아미노]-에톡시}-퀴나졸린(1) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N- Methyl-amino] -ethoxy} -quinazoline
Rf값: 0.42 (실리카 겔, 메틸렌 클로라이드/메탄올/진한 암모니아 수용액 = 90:10:0.1)R f value: 0.42 (silica gel, methylene chloride / methanol / aqueous ammonia solution = 90: 10: 0.1)
질량 스펙트럼 (ESI+): m/z = 515, 517 [M+H]+ Mass spectrum (ESI + ): m / z = 515, 517 [M + H] +
(2) 4-[(3-클로로-4-플루오로페닐)아미노]-6-{3-[N-(2-옥소-테트라하이드로푸란-4-일)-N-메틸-아미노]-프로필옥시}-7-사이클로부틸옥시-퀴나졸린(2) 4-[(3-chloro-4-fluorophenyl) amino] -6- {3- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -propyl Oxy} -7-cyclobutyloxy-quinazoline
융점: 147.5 내지 151℃Melting Point: 147.5-151 ° C
질량 스펙트럼 (ESI+): m/z = 515, 517 [M+H]+ Mass spectrum (ESI + ): m / z = 515, 517 [M + H] +
실시예 3Example 3
4-[(3-브로모-페닐)아미노]-6-[2-((S)-6-메틸-2-옥소-모르폴린-4-일)-에톡시]-7-메톡시-퀴나졸린4-[(3-Bromo-phenyl) amino] -6- [2-((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quina Sleepy
메탄설폰산 90㎕를 아세토니트릴 8ml 중의 4-[(3-브로모-페닐)아미노]-6-(2-{N-[(3급-부틸옥시카보닐)메틸]-N-((S)-2-하이드록시-프로필)-아미노}-에톡시)-7-메톡시-퀴나졸린 380mg에 가한다. 반응 혼합물을 약 3시간 동안 환류시킨 후, 추가 당량의 메탄설폰산을 가하고 계속 환류시켜 반응을 종결시킨다. 후처리를 위해 반응 혼합물을 에틸 아세테이트로 희석시키고 포화 탄산수소나트륨 용액 및 포화 염화나트륨 용액으로 세척한다. 유기 상을 황산마그네슘 상에서 건조시키고 진공하에 증발시킨다. 플라스크 잔사를 디에틸 에테르와 함께 교반하고 흡인여과한다. 표제 화합물을 백색 고체로서 수득한다.90 μl of methanesulfonic acid was added to 4-[(3-bromo-phenyl) amino] -6- (2- {N-[(tert-butyloxycarbonyl) methyl] -N-((S in 8 ml of acetonitrile. To 380 mg) -2-hydroxy-propyl) -amino} -ethoxy) -7-methoxy-quinazolin. After the reaction mixture is refluxed for about 3 hours, an additional equivalent of methanesulfonic acid is added and the reflux is continued to terminate the reaction. For workup the reaction mixture is diluted with ethyl acetate and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulphate and evaporated in vacuo. The flask residue is stirred with diethyl ether and suction filtered. The title compound is obtained as a white solid.
수득량: 280mg (이론치의 85%),Yield: 280 mg (85% of theory),
융점: 190℃Melting point: 190 ℃
질량 스펙트럼 (ESI-): m/z = 485, 487 [M-H]- Mass spectrum (ESI -): m / z = 485, 487 [MH] -
아래의 화합물을 실시예 3과 유사하게 수득한다:The following compounds are obtained similarly to Example 3:
(1) 4-[(3-브로모-페닐)아미노]-6-[2-((R)-6-메틸-2-옥소-모르폴린-4-일)-에톡시]-7-메톡시-퀴나졸린(1) 4-[(3-bromo-phenyl) amino] -6- [2-((R) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-meth Toxy-Quinazoline
융점: 193℃Melting point: 193 ℃
질량 스펙트럼 (ESI+): m/z = 487, 489 [M+H]+ Mass spectrum (ESI + ): m / z = 487, 489 [M + H] +
(2) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-((R)-6-메틸-2-옥소-모르폴린-4-일)-에톡시]-7-메톡시-퀴나졸린 (반응은 아세토니트릴 중의 트리플루오로아세트산을 사용하여 수행한다)(2) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2-((R) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy]- 7-methoxy-quinazolin (reaction is carried out using trifluoroacetic acid in acetonitrile)
융점: 208℃Melting point: 208 ℃
질량 스펙트럼 (ESI-): m/z = 459, 461 [M-H]- Mass spectrum (ESI -): m / z = 459, 461 [MH] -
(3) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[3-((R)-6-메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-메톡시-퀴나졸린 (반응은 아세토니트릴 중의 트리플루오로아세트산을 사용하여 수행한다)(3) 4-[(3-chloro-4-fluorophenyl) amino] -6- [3-((R) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy]- 7-methoxy-quinazolin (reaction is carried out using trifluoroacetic acid in acetonitrile)
Rf값: 0.33 (실리카 겔, 에틸 아세테이트)R f value: 0.33 (silica gel, ethyl acetate)
질량 스펙트럼 (ESI-): m/z = 473, 475 [M-H]- Mass spectrum (ESI -): m / z = 473, 475 [MH] -
(4) 4-[(R)-(1-페닐-에틸)아미노]-6-[3-((S)-6-메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-메톡시-퀴나졸린 (반응은 아세토니트릴 중의 트리플루오로아세트산을 사용하여 수행한다)(4) 4-[(R)-(1-phenyl-ethyl) amino] -6- [3-((S) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy]- 7-methoxy-quinazolin (reaction is carried out using trifluoroacetic acid in acetonitrile)
Rf값: 0.41 (실리카 겔, 에틸 아세테이트/메탄올 = 9:1)R f value: 0.41 (silica gel, ethyl acetate / methanol = 9: 1)
질량 스펙트럼 (ESI-): m/z = 449 [M-H]- Mass spectrum (ESI -): m / z = 449 [MH] -
(5) 4-[(R)-(1-페닐-에틸)아미노]-6-[2-((S)-6-메틸-2-옥소-모르폴린-4-일)-에톡시]-7-메톡시-퀴나졸린 (반응은 아세토니트릴 중의 트리플루오로아세트산을 사용하여 수행한다)(5) 4-[(R)-(1-phenyl-ethyl) amino] -6- [2-((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy]- 7-methoxy-quinazolin (reaction is carried out using trifluoroacetic acid in acetonitrile)
Rf값: 0.49 (실리카 겔, 에틸 아세테이트/메탄올/진한 암모니아 수용액 = 9:1:0.1)R f value: 0.49 (silica gel, ethyl acetate / methanol / condensed aqueous ammonia = 9: 1: 0.1)
질량 스펙트럼 (ESI-): m/z = 435 [M-H]- Mass spectrum (ESI -): m / z = 435 [MH] -
(6) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[3-((R)-6-메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-사이클로부틸옥시-퀴나졸린(반응은 아세토니트릴 중의 트리플루오로아세트산을 사용하여 수행한다)(6) 4-[(3-chloro-4-fluorophenyl) amino] -6- [3-((R) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy]- 7-cyclobutyloxy-quinazolin (reaction is carried out using trifluoroacetic acid in acetonitrile)
융점: 185.5 내지 189.5℃Melting Point: 185.5-189.5 ° C
질량 스펙트럼 (ESI+): m/z = 515, 517 [M+H]+ Mass spectrum (ESI + ): m / z = 515, 517 [M + H] +
(7) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[3-(5,5-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-사이클로부틸옥시-퀴나졸린(7) 4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (5,5-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7- Cyclobutyloxy-quinazoline
(반응은 아세토니트릴 중의 트리플루오로아세트산을 사용하여 수행한다)(Reaction is carried out using trifluoroacetic acid in acetonitrile)
융점: 214 내지 216℃Melting Point: 214-216 ° C
질량 스펙트럼 (ESI-): m/z = 527, 529 [M-H]- Mass Spectrum (ESI -): m / z = 527, 529 [MH] -
(8) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[3-((R)-6-메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-사이클로프로필메톡시-퀴나졸린(8) 4-[(3-chloro-4-fluorophenyl) amino] -6- [3-((R) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy]- 7-cyclopropylmethoxy-quinazoline
(반응은 아세토니트릴 중의 트리플루오로아세트산을 사용하여 수행한다)(Reaction is carried out using trifluoroacetic acid in acetonitrile)
융점: 160.5 내지 163℃Melting point: 160.5 to 163 ° C
질량 스펙트럼 (ESI+): m/z = 515, 517 [M+H]+ Mass spectrum (ESI + ): m / z = 515, 517 [M + H] +
(9) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[3-((S)-6-메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-사이클로프로필메톡시-퀴나졸린(9) 4-[(3-chloro-4-fluorophenyl) amino] -6- [3-((S) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy]- 7-cyclopropylmethoxy-quinazoline
(반응은 아세토니트릴 중의 트리플루오로아세트산을 사용하여 수행한다)(Reaction is carried out using trifluoroacetic acid in acetonitrile)
융점: 160 내지 162℃Melting point: 160-162 ° C
질량 스펙트럼 (ESI+): m/z = 515, 517 [M+H]+ Mass spectrum (ESI + ): m / z = 515, 517 [M + H] +
(10) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-((S)-6-메틸-2-옥소-모르폴린-4-일)-에톡시]-7-사이클로펜틸옥시-퀴나졸린(10) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2-((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy]- 7-cyclopentyloxy-quinazoline
(반응은 아세토니트릴 중의 트리플루오로아세트산을 사용하여 수행한다)(Reaction is carried out using trifluoroacetic acid in acetonitrile)
Rf값: 0.31 (실리카 겔, 에틸 아세테이트)R f value: 0.31 (silica gel, ethyl acetate)
질량 스펙트럼 (ESI+): m/z = 515, 517 [M+H]+ Mass spectrum (ESI + ): m / z = 515, 517 [M + H] +
(11) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-((R)-6-메틸-2-옥소-모르폴린-4-일)-에톡시]-7-사이클로펜틸옥시-퀴나졸린(반응은 아세토니트릴 중의 트리플루오로아세트산을 사용하여 수행한다)(11) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2-((R) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy]- 7-cyclopentyloxy-quinazolin (reaction is carried out using trifluoroacetic acid in acetonitrile)
융점: 176 내지 178℃Melting point: 176-178 ° C
질량 스펙트럼 (ESI+): m/z = 515, 517 [M+H]+ Mass spectrum (ESI + ): m / z = 515, 517 [M + H] +
(12) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-((S)-6-메틸-2-옥소-모르폴린-4-일)-에톡시]-7-사이클로프로필메톡시-퀴나졸린 (반응은 아세토니트릴 중의 트리플루오로아세트산을 사용하여 수행한다)(12) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2-((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy]- 7-cyclopropylmethoxy-quinazolin (reaction is carried out using trifluoroacetic acid in acetonitrile)
Rf값: 0.37 (실리카 겔, 에틸 아세테이트)R f value: 0.37 (silica gel, ethyl acetate)
질량 스펙트럼 (ESI+): m/z = 501, 503 [M+H]+ Mass spectrum (ESI + ): m / z = 501, 503 [M + H] +
(13) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-((R)-6-메틸-2-옥소-모르폴린-4-일)-에톡시]-7-사이클로프로필메톡시-퀴나졸린(13) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2-((R) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy]- 7-cyclopropylmethoxy-quinazoline
(반응은 아세토니트릴 중의 트리플루오로아세트산을 사용하여 수행한다)(Reaction is carried out using trifluoroacetic acid in acetonitrile)
Rf값: 0.37 (실리카 겔, 에틸 아세테이트)R f value: 0.37 (silica gel, ethyl acetate)
질량 스펙트럼 (ESI+): m/z = 501, 503 [M+H]+ Mass spectrum (ESI + ): m / z = 501, 503 [M + H] +
(14) 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로프로필메톡시-7-[2-((S)-6-메틸-2-옥소-모르폴린-4-일)-에톡시]-퀴나졸린(14) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- [2-((S) -6-methyl-2-oxo-morpholine-4- Yl) -ethoxy] -quinazoline
(반응은 아세토니트릴 중의 트리플루오로아세트산을 사용하여 수행한다)(Reaction is carried out using trifluoroacetic acid in acetonitrile)
Rf값: 0.48 (실리카 겔, 에틸 아세테이트/메탄올 = 9:1)R f value: 0.48 (silica gel, ethyl acetate / methanol = 9: 1)
질량 스펙트럼 (ESI+): m/z = 501, 503 [M+H]+ Mass spectrum (ESI + ): m / z = 501, 503 [M + H] +
(15) 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로프로필메톡시-7-[2-((R)-6-메틸-2-옥소-모르폴린-4-일)-에톡시]-퀴나졸린(반응은 아세토니트릴 중의 트리플루오로아세트산을 사용하여 수행한다)(15) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- [2-((R) -6-methyl-2-oxo-morpholine-4- Yl) -ethoxy] -quinazolin (reaction is carried out using trifluoroacetic acid in acetonitrile)
질량 스펙트럼 (ESI+): m/z = 501, 503 [M+H]+ Mass spectrum (ESI + ): m / z = 501, 503 [M + H] +
(16) 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로프로필메톡시-7-[3-((R)-6-메틸-2-옥소-모르폴린-4-일)-프로필옥시]-퀴나졸린(16) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- [3-((R) -6-methyl-2-oxo-morpholine-4- Yl) -propyloxy] -quinazolin
(반응은 아세토니트릴 중의 트리플루오로아세트산을 사용하여 수행한다)(Reaction is carried out using trifluoroacetic acid in acetonitrile)
Rf값: 0.67 (실리카 겔, 에틸 아세테이트/메탄올 = 9:1)R f value: 0.67 (silica gel, ethyl acetate / methanol = 9: 1)
질량 스펙트럼 (ESI-): m/z = 513, 515 [M-H]- Mass spectrum (ESI -): m / z = 513, 515 [MH] -
(17) 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로프로필메톡시-7-[3-((S)-6-메틸-2-옥소-모르폴린-4-일)-프로필옥시]-퀴나졸린(17) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- [3-((S) -6-methyl-2-oxo-morpholine-4- Yl) -propyloxy] -quinazolin
(반응은 아세토니트릴 중의 트리플루오로아세트산을 사용하여 수행한다)(Reaction is carried out using trifluoroacetic acid in acetonitrile)
Rf값: 0.67 (실리카 겔, 에틸 아세테이트/메탄올 = 9:1)R f value: 0.67 (silica gel, ethyl acetate / methanol = 9: 1)
질량 스펙트럼 (ESI-): m/z = 513, 515 [M-H]- Mass spectrum (ESI -): m / z = 513, 515 [MH] -
(18) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-(2,2-디메틸-6-옥소-모르폴린-4-일)-에톡시]-7-사이클로펜틸옥시-퀴나졸린(18) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -7- Cyclopentyloxy-quinazoline
(반응은 아세토니트릴 중의 트리플루오로아세트산을 사용하여 수행한다)(Reaction is carried out using trifluoroacetic acid in acetonitrile)
Rf값: 0.56 (실리카 겔, 에틸 아세테이트)R f value: 0.56 (silica gel, ethyl acetate)
질량 스펙트럼 (ESI+): m/z = 529, 531 [M+H]+ Mass spectrum (ESI + ): m / z = 529, 531 [M + H] +
(19) 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로펜틸옥시-7-[2-((S)-6-메틸-2-옥소-모르폴린-4-일)-에톡시]-퀴나졸린(19) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- [2-((S) -6-methyl-2-oxo-morpholin-4-yl ) -Ethoxy] -quinazoline
(반응은 아세토니트릴 중의 트리플루오로아세트산을 사용하여 수행한다)(Reaction is carried out using trifluoroacetic acid in acetonitrile)
Rf값: 0.60 (실리카 겔, 에틸 아세테이트/메탄올 = 9:1)R f value: 0.60 (silica gel, ethyl acetate / methanol = 9: 1)
질량 스펙트럼 (ESI+): m/z = 515, 517 [M+H]+ Mass spectrum (ESI + ): m / z = 515, 517 [M + H] +
(20) 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로펜틸옥시-7-[2-((R)-6-메틸-2-옥소-모르폴린-4-일)-에톡시]-퀴나졸린(20) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- [2-((R) -6-methyl-2-oxo-morpholin-4-yl ) -Ethoxy] -quinazoline
(반응은 아세토니트릴 중의 트리플루오로아세트산을 사용하여 수행한다)(Reaction is carried out using trifluoroacetic acid in acetonitrile)
질량 스펙트럼 (ESI+): m/z = 515, 517 [M+H]+ Mass spectrum (ESI + ): m / z = 515, 517 [M + H] +
(21) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[4-((S)-6-메틸-2-옥소-모르폴린-4-일)-부틸옥시]-7-사이클로펜틸옥시-퀴나졸린(21) 4-[(3-chloro-4-fluorophenyl) amino] -6- [4-((S) -6-methyl-2-oxo-morpholin-4-yl) -butyloxy]- 7-cyclopentyloxy-quinazoline
(반응은 아세토니트릴 중의 트리플루오로아세트산을 사용하여 수행한다)(Reaction is carried out using trifluoroacetic acid in acetonitrile)
Rf값: 0.51 (실리카 겔, 에틸 아세테이트)R f value: 0.51 (silica gel, ethyl acetate)
질량 스펙트럼 (ESI+): m/z = 543, 545 [M+H]+ Mass spectrum (ESI + ): m / z = 543, 545 [M + H] +
(22) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[4-((R)-6-메틸-2-옥소-모르폴린-4-일)-부틸옥시]-7-사이클로펜틸옥시-퀴나졸린(22) 4-[(3-chloro-4-fluorophenyl) amino] -6- [4-((R) -6-methyl-2-oxo-morpholin-4-yl) -butyloxy]- 7-cyclopentyloxy-quinazoline
(반응은 아세토니트릴 중의 트리플루오로아세트산을 사용하여 수행한다)(Reaction is carried out using trifluoroacetic acid in acetonitrile)
질량 스펙트럼 (ESI+): m/z = 543, 545 [M+H]+ Mass spectrum (ESI + ): m / z = 543, 545 [M + H] +
(23) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[3-((S)-6-메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-메톡시-퀴나졸린(23) 4-[(3-chloro-4-fluorophenyl) amino] -6- [3-((S) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy]- 7-methoxy-quinazoline
(반응은 아세토니트릴 중의 트리플루오로아세트산을 사용하여 수행한다)(Reaction is carried out using trifluoroacetic acid in acetonitrile)
융점: 183 내지 186℃Melting point: 183-186 ° C
질량 스펙트럼 (ESI+): m/z = 475, 477 [M+H]+ Mass spectrum (ESI + ): m / z = 475, 477 [M + H] +
(24) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[3-(5,5-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-메톡시-퀴나졸린(24) 4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (5,5-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7- Methoxy-Quinazoline
(반응은 아세토니트릴 중의 트리플루오로아세트산을 사용하여 수행한다)(Reaction is carried out using trifluoroacetic acid in acetonitrile)
Rf값: 0.43 (실리카 겔, 에틸 아세테이트)R f value: 0.43 (silica gel, ethyl acetate)
질량 스펙트럼 (ESI-): m/z = 487, 489 [M-H]- Mass spectrum (ESI -): m / z = 487, 489 [MH] -
(25) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-((S)-6-메틸-2-옥소-모르폴린-4-일)-에톡시]-7-메톡시-퀴나졸린(25) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2-((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy]- 7-methoxy-quinazoline
(반응은 아세토니트릴 중의 트리플루오로아세트산을 사용하여 수행한다)(Reaction is carried out using trifluoroacetic acid in acetonitrile)
융점: 212 내지 213℃Melting Point: 212-213 ° C
질량 스펙트럼 (ESI+): m/z = 461, 463 [M+H]+ Mass spectrum (ESI + ): m / z = 461, 463 [M + H] +
(26) 4-[(3-클로로-4-플루오로페닐)아미노]-6-{2-[N-(카복시메틸)-N-((S)-2-하이드록시-프로필)-아미노]-에톡시}-7-메톡시-퀴나졸린(26) 4-[(3-chloro-4-fluorophenyl) amino] -6- {2- [N- (carboxymethyl) -N-((S) -2-hydroxy-propyl) -amino] -Ethoxy} -7-methoxy-quinazoline
[3(25)의 제조시의 부산물][By-products in the manufacture of 3 (25)]
융점: 187 내지 190℃Melting Point: 187 to 190 ° C
질량 스펙트럼 (ESI+): m/z = 479, 481 [M+H]+ Mass spectrum (ESI + ): m / z = 479, 481 [M + H] +
(27) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-(2,2-디메틸-6-옥소-모르폴린-4-일)-에톡시]-7-메톡시-퀴나졸린(27) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -7- Methoxy-Quinazoline
(반응은 아세토니트릴 중의 트리플루오로아세트산을 사용하여 수행한다)(Reaction is carried out using trifluoroacetic acid in acetonitrile)
융점: 229 내지 232℃Melting Point: 229-232 ° C
질량 스펙트럼 (ESI-): m/z = 473, 475 [M-H]- Mass spectrum (ESI -): m / z = 473, 475 [MH] -
(28) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-(2,2-디메틸-6-옥소-모르폴린-4-일)-에톡시]-7-((R)-테트라하이드로푸란-3-일옥시)-퀴나졸린(28) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -7- ((R) -tetrahydrofuran-3-yloxy) -quinazoline
(반응은 아세토니트릴 중의 트리플루오로아세트산을 사용하여 수행한다)(Reaction is carried out using trifluoroacetic acid in acetonitrile)
융점: 195 내지 196℃Melting point: 195-196 ° C
질량 스펙트럼 (ESI+): m/z = 531, 533 [M+H]+ Mass spectrum (ESI + ): m / z = 531, 533 [M + H] +
(29) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-(2,2-디메틸-6-옥소-모르폴린-4-일)-에톡시]-7-[(R)-(테트라하이드로푸란-2-일)메톡시]-퀴나졸린(29) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -7- [(R)-(tetrahydrofuran-2-yl) methoxy] -quinazoline
(반응은 아세토니트릴 중의 트리플루오로아세트산을 사용하여 수행한다)(Reaction is carried out using trifluoroacetic acid in acetonitrile)
융점: 184℃Melting Point: 184 ℃
질량 스펙트럼 (ESI+): m/z = 545, 547 [M+H]+ Mass spectrum (ESI + ): m / z = 545, 547 [M + H] +
(30) 4-[(3-클로로-4-플루오로페닐)아미노]-7-[2-(2,2-디메틸-6-옥소-모르폴린-4-일)-에톡시]-6-((S)-테트라하이드로푸란-3-일옥시)-퀴나졸린(30) 4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -6- ((S) -tetrahydrofuran-3-yloxy) -quinazoline
융점: 202 내지 205℃Melting Point: 202-205 ° C
질량 스펙트럼 (ESI+): m/z = 531, 533 [M+H]+ Mass spectrum (ESI + ): m / z = 531, 533 [M + H] +
(31) 4-[(3-클로로-4-플루오로페닐)아미노]-7-[2-(2,2-디메틸-6-옥소-모르폴린-4-일)-에톡시]-6-[(S)-(테트라하이드로푸란-2-일)메톡시]-퀴나졸린(31) 4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -6- [(S)-(tetrahydrofuran-2-yl) methoxy] -quinazoline
융점: 182℃Melting Point: 182 ℃
질량 스펙트럼 (ESI+): m/z = 545, 547 [M+H]+ Mass spectrum (ESI + ): m / z = 545, 547 [M + H] +
실시예 4Example 4
4-[(3-브로모-페닐)아미노]-6-(2-{N-[(3급-부틸옥시카보닐)메틸]-N-((S)-2-하이드록시-프로필)-아미노}-에톡시)-7-메톡시-퀴나졸린4-[(3-Bromo-phenyl) amino] -6- (2- {N-[(tert-butyloxycarbonyl) methyl] -N-((S) -2-hydroxy-propyl)- Amino} -ethoxy) -7-methoxy-quinazoline
디이소프로필에틸아민 0.25ml를 아세토니트릴 15ml 중의 4-[(3-브로모-페닐)아미노]-6-(2-브로모에톡시)-7-메톡시-퀴나졸린 650mg 및 3급-부틸 (S)-(2-하이드록시-프로필아미노)-아세테이트 1.10g에 가한다. 반응 혼합물을 50℃에서 밤새 교반한다. 어떠한 반응도 검출되지 않으므로 반응 혼합물을 진공하에 농축시키고 N,N-디메틸포름아미드 20ml와 합한 후, 8시간 동안 60℃에서 교반한다. 이어서, 온도를 80℃로 상승시킨다. 추가로 8시간 후, 반응이 종결된다. 반응 혼합물을 증발시켜 농축시키고 용출액으로서 에틸 아세테이트를 사용하여 실리카 겔 컬럼 상에서 크로마토그래피를 수행한다. 목적하는 생성물을 백색 고체로서 수득한다.0.25 ml of diisopropylethylamine was added to 650 mg of 4-[(3-bromo-phenyl) amino] -6- (2-bromoethoxy) -7-methoxy-quinazolin in 15 ml of acetonitrile and tert-butyl ( To 1.10 g of S)-(2-hydroxy-propylamino) -acetate. The reaction mixture is stirred at 50 ° C. overnight. No reaction is detected so the reaction mixture is concentrated in vacuo, combined with 20 ml of N, N-dimethylformamide and stirred at 60 ° C. for 8 hours. The temperature is then raised to 80 ° C. After an additional 8 hours, the reaction is terminated. The reaction mixture is concentrated by evaporation and chromatography is performed on a silica gel column using ethyl acetate as eluent. The desired product is obtained as a white solid.
수득량: 410mg (이론치의 51%),Yield: 410 mg (51% of theory),
Rf값: 0.27 (실리카 겔, 에틸 아세테이트)R f value: 0.27 (silica gel, ethyl acetate)
질량 스펙트럼 (ESI-): m/z = 559, 561 [M-H]- Mass spectrum (ESI -): m / z = 559, 561 [MH] -
아래의 화합물을 실시예 4와 유사하게 수득한다:The following compounds are obtained similarly to Example 4:
(1) 4-[(3-브로모-페닐)아미노]-6-(2-{N-[(3급-부틸옥시카보닐)-메틸]-N-((R)-2-하이드록시-프로필)-아미노}-에톡시)-7-메톡시-퀴나졸린(1) 4-[(3-bromo-phenyl) amino] -6- (2- {N-[(tert-butyloxycarbonyl) -methyl] -N-((R) -2-hydroxy -Propyl) -amino} -ethoxy) -7-methoxy-quinazoline
융점: 130℃Melting point: 130 ℃
질량 스펙트럼 (ESI-): m/z = 559, 561 [M-H]- Mass spectrum (ESI -): m / z = 559, 561 [MH] -
(2) 4-[(3-클로로-4-플루오로페닐)아미노]-6-(2-{N-[(3급-부틸옥시-카보닐)메틸]-N-((R)-2-하이드록시-프로필)-아미노}-에톡시)-7-메톡시-퀴나졸린 (반응은 N,N-디메틸포름아미드 속에서 수행한다)(2) 4-[(3-chloro-4-fluorophenyl) amino] -6- (2- {N-[(tert-butyloxy-carbonyl) methyl] -N-((R) -2 -Hydroxy-propyl) -amino} -ethoxy) -7-methoxy-quinazolin (reaction is carried out in N, N-dimethylformamide)
Rf값: 0.40 (실리카 겔, 에틸 아세테이트/석유 에테르 = 4:1)R f value: 0.40 (silica gel, ethyl acetate / petroleum ether = 4: 1)
(3) 4-[(3-클로로-4-플루오로페닐)아미노]-6-(3-{N-[(3급-부틸옥시-카보닐)메틸]-N-((R)-2-하이드록시-프로필)-아미노}-프로필옥시)-7-메톡시-퀴나졸린 (반응은 N,N-디메틸포름아미드 속에서 수행한다)(3) 4-[(3-chloro-4-fluorophenyl) amino] -6- (3- {N-[(tert-butyloxy-carbonyl) methyl] -N-((R) -2 -Hydroxy-propyl) -amino} -propyloxy) -7-methoxy-quinazolin (reaction is carried out in N, N-dimethylformamide)
Rf값: 0.37 (실리카 겔, 에틸 아세테이트/석유 에테르 = 4:1)R f value: 0.37 (silica gel, ethyl acetate / petroleum ether = 4: 1)
질량 스펙트럼 (ESI-): m/z = 547, 549 [M-H]- Mass spectrum (ESI -): m / z = 547, 549 [MH] -
(4) 4-[(R)-(1-페닐-에틸)아미노]-6-(3-{N-[(3급-부틸옥시카보닐)메틸]-N-((S)-2-하이드록시-프로필)-아미노}-프로필옥시)-7-메톡시-퀴나졸린 (반응은 N,N-디메틸포름아미드 속에서 수행한다)(4) 4-[(R)-(1-phenyl-ethyl) amino] -6- (3- {N-[(tert-butyloxycarbonyl) methyl] -N-((S) -2- Hydroxy-propyl) -amino} -propyloxy) -7-methoxy-quinazolin (reaction is carried out in N, N-dimethylformamide)
Rf값: 0.65 (실리카 겔, 에틸 아세테이트/메탄올 = 9:1)R f value: 0.65 (silica gel, ethyl acetate / methanol = 9: 1)
질량 스펙트럼 (EI): m/z = 524 [M]+ Mass spectrum (EI): m / z = 524 [M] +
(5) 4-[(R)-(1-페닐-에틸)아미노]-6-(2-{N-[(3급-부틸옥시-카보닐)메틸]-N-((S)-2-하이드록시-프로필)-아미노}-에톡시)-7-메톡시-퀴나졸린 (반응은 N,N-디메틸포름아미드 속에서 수행한다)(5) 4-[(R)-(1-phenyl-ethyl) amino] -6- (2- {N-[(tert-butyloxy-carbonyl) methyl] -N-((S) -2 -Hydroxy-propyl) -amino} -ethoxy) -7-methoxy-quinazolin (reaction is carried out in N, N-dimethylformamide)
Rf값: 0.57 (실리카 겔, 에틸 아세테이트/메탄올/진한 암모니아 수용액 = 9:1:0.1)R f value: 0.57 (silica gel, ethyl acetate / methanol / condensed aqueous ammonia = 9: 1: 0.1)
(6) 4-[(3-클로로-4-플루오로페닐)아미노]-6-(3-{N-[(3급-부틸옥시카보닐)메틸]-N-((R)-2-하이드록시-프로필)-아미노}-프로필옥시)-7-사이클로부틸옥시-퀴나졸린(6) 4-[(3-chloro-4-fluorophenyl) amino] -6- (3- {N-[(tert-butyloxycarbonyl) methyl] -N-((R) -2- Hydroxy-propyl) -amino} -propyloxy) -7-cyclobutyloxy-quinazoline
Rf값: 0.31 (실리카 겔, 메틸렌 클로라이드/메탄올 = 95:5)R f value: 0.31 (silica gel, methylene chloride / methanol = 95: 5)
(7) 4-[(3-클로로-4-플루오로페닐)아미노]-6-(3-{N-[(3급-부틸옥시카보닐)메틸]-N-(1,1-디메틸-2-하이드록시-에틸)-아미노}-프로필옥시)-7-사이클로부틸옥시-퀴나졸린(7) 4-[(3-chloro-4-fluorophenyl) amino] -6- (3- {N-[(tert-butyloxycarbonyl) methyl] -N- (1,1-dimethyl- 2-hydroxy-ethyl) -amino} -propyloxy) -7-cyclobutyloxy-quinazoline
Rf값: 0.29 (실리카 겔, 메틸렌 클로라이드/메탄올 = 95:5)R f value: 0.29 (silica gel, methylene chloride / methanol = 95: 5)
질량 스펙트럼 (ESI+): m/z = 603, 605 [M+H]+ Mass spectrum (ESI + ): m / z = 603, 605 [M + H] +
(8) 4-[(3-클로로-4-플루오로페닐)아미노]-6-(3-{N-[(3급-부틸옥시카보닐)메틸]-N-((R)-2-하이드록시-프로필)-아미노}-프로필옥시)-7-사이클로프로필메톡시-퀴나졸린(8) 4-[(3-chloro-4-fluorophenyl) amino] -6- (3- {N-[(tert-butyloxycarbonyl) methyl] -N-((R) -2- Hydroxy-propyl) -amino} -propyloxy) -7-cyclopropylmethoxy-quinazoline
Rf값: 0.37 (실리카 겔, 메틸렌 클로라이드/메탄올 = 95:5)R f value: 0.37 (silica gel, methylene chloride / methanol = 95: 5)
(9) 4-[(3-클로로-4-플루오로페닐)아미노]-6-(3-{N-[(3급-부틸옥시카보닐)메틸]-N-((S)-2-하이드록시-프로필)-아미노}-프로필옥시)-7-사이클로프로필메톡시-퀴나졸린(9) 4-[(3-chloro-4-fluorophenyl) amino] -6- (3- {N-[(tert-butyloxycarbonyl) methyl] -N-((S) -2- Hydroxy-propyl) -amino} -propyloxy) -7-cyclopropylmethoxy-quinazoline
Rf값: 0.50 (실리카 겔, 에틸 아세테이트)R f value: 0.50 (silica gel, ethyl acetate)
(10) 4-[(3-클로로-4-플루오로페닐)아미노]-6-(2-{N-[(3급-부틸옥시카보닐)메틸]-N-((S)-2-하이드록시-프로필)-아미노}-에톡시)-7-사이클로펜틸옥시-퀴나졸린(10) 4-[(3-chloro-4-fluorophenyl) amino] -6- (2- {N-[(tert-butyloxycarbonyl) methyl] -N-((S) -2- Hydroxy-propyl) -amino} -ethoxy) -7-cyclopentyloxy-quinazoline
Rf값: 0.54 (실리카 겔, 에틸 아세테이트/사이클로헥산 = 9:1)R f value: 0.54 (silica gel, ethyl acetate / cyclohexane = 9: 1)
(11) 4-[(3-클로로-4-플루오로페닐)아미노]-6-(2-{N-[(3급-부틸옥시카보닐)메틸]-N-((R)-2-하이드록시-프로필)-아미노}-에톡시)-7-사이클로펜틸옥시-퀴나졸린(11) 4-[(3-chloro-4-fluorophenyl) amino] -6- (2- {N-[(tert-butyloxycarbonyl) methyl] -N-((R) -2- Hydroxy-propyl) -amino} -ethoxy) -7-cyclopentyloxy-quinazoline
Rf값: 0.66 (실리카 겔, 에틸 아세테이트)R f value: 0.66 (silica gel, ethyl acetate)
(12) 4-[(3-클로로-4-플루오로페닐)아미노]-6-(2-{N-[(3급-부틸옥시카보닐)메틸]-N-((S)-2-하이드록시-프로필)-아미노}-에톡시)-7-사이클로프로필메톡시-퀴나졸린(12) 4-[(3-chloro-4-fluorophenyl) amino] -6- (2- {N-[(tert-butyloxycarbonyl) methyl] -N-((S) -2- Hydroxy-propyl) -amino} -ethoxy) -7-cyclopropylmethoxy-quinazoline
Rf값: 0.60 (실리카 겔, 에틸 아세테이트)R f value: 0.60 (silica gel, ethyl acetate)
(13) 4-[(3-클로로-4-플루오로페닐)아미노]-6-(2-{N-[(3급-부틸옥시카보닐)메틸]-N-((R)-2-하이드록시-프로필)-아미노}-에톡시)-7-사이클로프로필메톡시-퀴나졸린(13) 4-[(3-chloro-4-fluorophenyl) amino] -6- (2- {N-[(tert-butyloxycarbonyl) methyl] -N-((R) -2- Hydroxy-propyl) -amino} -ethoxy) -7-cyclopropylmethoxy-quinazoline
Rf값: 0.60 (실리카 겔, 에틸 아세테이트)R f value: 0.60 (silica gel, ethyl acetate)
(14) 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로프로필메톡시-7-(2-{N-[(3급-부틸옥시카보닐)메틸]-N-((S)-2-하이드록시-프로필)-아미노}-에톡시)-퀴나졸린(14) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (2- {N-[(tert-butyloxycarbonyl) methyl] -N- ((S) -2-hydroxy-propyl) -amino} -ethoxy) -quinazoline
Rf값: 0.30 (실리카 겔, 에틸 아세테이트)R f value: 0.30 (silica gel, ethyl acetate)
(15) 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로프로필메톡시-7-(2-{N-[(3급-부틸옥시카보닐)메틸]-N-((R)-2-하이드록시-프로필)-아미노}-에톡시)-퀴나졸린(15) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (2- {N-[(tert-butyloxycarbonyl) methyl] -N- ((R) -2-hydroxy-propyl) -amino} -ethoxy) -quinazoline
Rf값: 0.30 (실리카 겔, 에틸 아세테이트)R f value: 0.30 (silica gel, ethyl acetate)
(16) 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로프로필메톡시-7-(3-{N-[(3급-부틸옥시카보닐)메틸]-N-((R)-2-하이드록시-프로필)-아미노}-프로필옥시)-퀴나졸린(16) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (3- {N-[(tert-butyloxycarbonyl) methyl] -N- ((R) -2-hydroxy-propyl) -amino} -propyloxy) -quinazoline
Rf값: 0.35 (실리카 겔, 에틸 아세테이트)R f value: 0.35 (silica gel, ethyl acetate)
(17) 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로프로필메톡시-7-(3-{N-[(3급-부틸옥시카보닐)메틸]-N-((S)-2-하이드록시-프로필)-아미노}-프로필옥시])-퀴나졸린(17) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (3- {N-[(tert-butyloxycarbonyl) methyl] -N- ((S) -2-hydroxy-propyl) -amino} -propyloxy])-quinazoline
Rf값: 0.35 (실리카 겔, 에틸 아세테이트)R f value: 0.35 (silica gel, ethyl acetate)
(18) 4-[(3-클로로-4-플루오로페닐)아미노]-6-(2-{N-[(에톡시카보닐)메틸]-N-(2-하이드록시-2-메틸-프로필)-아미노}-에톡시)-7-사이클로펜틸옥시-퀴나졸린(18) 4-[(3-chloro-4-fluorophenyl) amino] -6- (2- {N-[(ethoxycarbonyl) methyl] -N- (2-hydroxy-2-methyl- Propyl) -amino} -ethoxy) -7-cyclopentyloxy-quinazoline
Rf값: 0.64 (실리카 겔, 메틸렌 클로라이드/메탄올 = 9:1)R f value: 0.64 (silica gel, methylene chloride / methanol = 9: 1)
질량 스펙트럼 (ESI+): m/z = 575, 577 [M+H]+ Mass spectrum (ESI + ): m / z = 575, 577 [M + H] +
(19) 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로펜틸옥시-7-(2-{N-[(3급-부틸옥시카보닐)메틸]-N-((S)-2-하이드록시-프로필)-아미노}-에톡시)-퀴나졸린(19) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2- {N-[(tert-butyloxycarbonyl) methyl] -N- ( (S) -2-hydroxy-propyl) -amino} -ethoxy) -quinazoline
Rf값: 0.51 (실리카 겔, 에틸 아세테이트)R f value: 0.51 (silica gel, ethyl acetate)
(20) 4-[(3-클로로-4-플루오로페닐)아미노]-6-사이클로펜틸옥시-7-(2-{N-[(3급-부틸옥시카보닐)메틸]-N-((R)-2-하이드록시-프로필)-아미노}-에톡시)-퀴나졸린(20) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2- {N-[(tert-butyloxycarbonyl) methyl] -N- ( (R) -2-hydroxy-propyl) -amino} -ethoxy) -quinazoline
Rf값: 0.51 (실리카 겔, 에틸 아세테이트)R f value: 0.51 (silica gel, ethyl acetate)
(21) 4-[(3-클로로-4-플루오로페닐)아미노]-6-(4-{N-[(3급-부틸옥시카보닐)메틸]-N-((S)-2-하이드록시-프로필)-아미노}-부틸옥시)-7-사이클로펜틸옥시-퀴나졸린(21) 4-[(3-chloro-4-fluorophenyl) amino] -6- (4- {N-[(tert-butyloxycarbonyl) methyl] -N-((S) -2- Hydroxy-propyl) -amino} -butyloxy) -7-cyclopentyloxy-quinazolin
Rf값: 0.61 (실리카 겔, 에틸 아세테이트)R f value: 0.61 (silica gel, ethyl acetate)
(22) 4-[(3-클로로-4-플루오로페닐)아미노]-6-(4-{N-[(3급-부틸옥시카보닐)메틸]-N-((R)-2-하이드록시-프로필)-아미노}-부틸옥시)-7-사이클로펜틸옥시-퀴나졸린(22) 4-[(3-chloro-4-fluorophenyl) amino] -6- (4- {N-[(tert-butyloxycarbonyl) methyl] -N-((R) -2- Hydroxy-propyl) -amino} -butyloxy) -7-cyclopentyloxy-quinazolin
Rf값: 0.61 (실리카 겔, 에틸 아세테이트)R f value: 0.61 (silica gel, ethyl acetate)
(23) 4-[(3-클로로-4-플루오로페닐)아미노]-6-(3-{N-[(3급-부틸옥시카보닐)메틸]-N-((S)-2-하이드록시-프로필)-아미노}-프로필옥시)-7-메톡시-퀴나졸린(23) 4-[(3-chloro-4-fluorophenyl) amino] -6- (3- {N-[(tert-butyloxycarbonyl) methyl] -N-((S) -2- Hydroxy-propyl) -amino} -propyloxy) -7-methoxy-quinazoline
Rf값: 0.46 (실리카 겔, 에틸 아세테이트)R f value: 0.46 (silica gel, ethyl acetate)
질량 스펙트럼 (ESI-): m/z = 547, 549 [M-H]- Mass spectrum (ESI -): m / z = 547, 549 [MH] -
(24) 4-[(3-클로로-4-플루오로페닐)아미노]-6-(3-{N-[(3급-부틸옥시카보닐)메틸]-N-(1,1-디메틸-2-하이드록시-에틸)-아미노}-프로필옥시)-7-메톡시-퀴나졸린(24) 4-[(3-chloro-4-fluorophenyl) amino] -6- (3- {N-[(tert-butyloxycarbonyl) methyl] -N- (1,1-dimethyl- 2-hydroxy-ethyl) -amino} -propyloxy) -7-methoxy-quinazoline
질량 스펙트럼 (ESI+): m/z = 563, 565 [M+H]+ Mass spectrum (ESI + ): m / z = 563, 565 [M + H] +
(25) 4-[(3-클로로-4-플루오로페닐)아미노]-6-(2-{N-[(3급-부틸옥시카보닐)메틸]-N-((S)-2-하이드록시-프로필)-아미노}-에톡시)-7-메톡시-퀴나졸린(25) 4-[(3-chloro-4-fluorophenyl) amino] -6- (2- {N-[(tert-butyloxycarbonyl) methyl] -N-((S) -2- Hydroxy-propyl) -amino} -ethoxy) -7-methoxy-quinazoline
Rf값: 0.66 (실리카 겔, 에틸 아세테이트/메탄올 = 9:1)R f value: 0.66 (silica gel, ethyl acetate / methanol = 9: 1)
질량 스펙트럼 (ESI+): m/z = 535, 537 [M+H]+ Mass spectrum (ESI + ): m / z = 535, 537 [M + H] +
(26) 4-[(3-클로로-4-플루오로페닐)아미노]-6-(2-{N-[(에톡시카보닐)메틸]-N-(2-하이드록시-2-메틸-프로필)-아미노}-에톡시)-7-메톡시-퀴나졸린(26) 4-[(3-chloro-4-fluorophenyl) amino] -6- (2- {N-[(ethoxycarbonyl) methyl] -N- (2-hydroxy-2-methyl- Propyl) -amino} -ethoxy) -7-methoxy-quinazoline
(이미 폐환된 물질과의 혼합물로서 나타남)(Appears as a mixture with already closed substances)
Rf값: 0.44 (실리카 겔, 에틸 아세테이트)R f value: 0.44 (silica gel, ethyl acetate)
질량 스펙트럼 (ESI+): m/z = 521, 523 [M+H]+ Mass spectrum (ESI + ): m / z = 521, 523 [M + H] +
(27) 4-[(3-클로로-4-플루오로페닐)아미노]-6-(2-{N-[(에톡시카보닐)메틸]-N-(2-하이드록시-2-메틸-프로필)-아미노}-에톡시)-7-((R)-테트라하이드로푸란-3-일옥시)-퀴나졸린(27) 4-[(3-chloro-4-fluorophenyl) amino] -6- (2- {N-[(ethoxycarbonyl) methyl] -N- (2-hydroxy-2-methyl- Propyl) -amino} -ethoxy) -7-((R) -tetrahydrofuran-3-yloxy) -quinazoline
(이미 폐환된 물질과의 혼합물로서 나타남)(Appears as a mixture with already closed substances)
Rf값: 0.30 (실리카 겔, 메틸렌 클로라이드/메탄올 = 9:1)R f value: 0.30 (silica gel, methylene chloride / methanol = 9: 1)
(28) 4-[(3-클로로-4-플루오로페닐)아미노]-6-(2-{N-[(에톡시카보닐)메틸]-N-(2-하이드록시-2-메틸-프로필)-아미노}-에톡시)-7-[(R)-(테트라하이드로푸란-2-일)메톡시]-퀴나졸린(28) 4-[(3-chloro-4-fluorophenyl) amino] -6- (2- {N-[(ethoxycarbonyl) methyl] -N- (2-hydroxy-2-methyl- Propyl) -amino} -ethoxy) -7-[(R)-(tetrahydrofuran-2-yl) methoxy] -quinazoline
질량 스펙트럼 (ESI-): m/z = 589, 591 [M-H]- Mass spectrum (ESI -): m / z = 589, 591 [MH] -
(29) 4-[(3-클로로-4-플루오로페닐)아미노]-7-(2-{N-[(에톡시카보닐)메틸]-N-(2-하이드록시-2-메틸-프로필)-아미노}-에톡시)-6-((S)-테트라하이드로푸란-3-일옥시)-퀴나졸린(29) 4-[(3-chloro-4-fluorophenyl) amino] -7- (2- {N-[(ethoxycarbonyl) methyl] -N- (2-hydroxy-2-methyl- Propyl) -amino} -ethoxy) -6-((S) -tetrahydrofuran-3-yloxy) -quinazoline
Rf값: 0.16 (실리카 겔, 메틸렌 클로라이드/메탄올 = 20:1)R f value: 0.16 (silica gel, methylene chloride / methanol = 20: 1)
(30) 4-[(3-클로로-4-플루오로페닐)아미노]-7-(2-{N-[(에톡시카보닐)메틸]-N-(2-하이드록시-2-메틸-프로필)-아미노}-에톡시)-6-[(S)-(테트라하이드로푸란-2-일)메톡시]-퀴나졸린(30) 4-[(3-chloro-4-fluorophenyl) amino] -7- (2- {N-[(ethoxycarbonyl) methyl] -N- (2-hydroxy-2-methyl- Propyl) -amino} -ethoxy) -6-[(S)-(tetrahydrofuran-2-yl) methoxy] -quinazoline
Rf값: 0.68 (실리카 겔, 에틸 아세테이트/메탄올 = 15:1)R f value: 0.68 (silica gel, ethyl acetate / methanol = 15: 1)
아래의 화합물을 앞에 기재된 실시예 및 문헌에 공지된 다른 방법과 유사하게 제조할 수 있다:The following compounds can be prepared analogously to the examples described above and other methods known in the literature:
(1) 4-[(3-클로로-4-플루오로페닐)아미노]-7-[2-(6-메틸-2-옥소-모르폴린-4-일)-에톡시]-6-메톡시-퀴나졸린(1) 4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -6-methoxy Quinazoline
(2) 4-[(3-클로로-4-플루오로페닐)아미노]-7-[3-(6-메틸-2-옥소-모르폴린-4-일)-프로필옥시]-6-메톡시-퀴나졸린(2) 4-[(3-chloro-4-fluorophenyl) amino] -7- [3- (6-methyl-2-oxo-morpholin-4-yl) -propyloxy] -6-methoxy Quinazoline
(3) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-((S)-6-메틸-2-옥소-모르폴린-4-일)-에톡시]-7-메톡시-퀴나졸린(3) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2-((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy]- 7-methoxy-quinazoline
(4) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[3-((S)-6-메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-메톡시-퀴나졸린(4) 4-[(3-chloro-4-fluorophenyl) amino] -6- [3-((S) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy]- 7-methoxy-quinazoline
(5) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[3-(5,5-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-메톡시-퀴나졸린(5) 4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (5,5-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7- Methoxy-Quinazoline
(6) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-(5,5-디메틸-2-옥소-모르폴린-4-일)-에톡시]-7-메톡시-퀴나졸린(6) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (5,5-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7- Methoxy-Quinazoline
(7) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[3-(3-메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-메톡시-퀴나졸린(7) 4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (3-methyl-2-oxo-morpholin-4-yl) -propyloxy] -7-methoxy Quinazoline
(8) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-(3-메틸-2-옥소-모르폴린-4-일)-에톡시]-7-메톡시-퀴나졸린(8) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (3-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy Quinazoline
(9) 4-[(R)-(1-페닐-에틸)아미노]-6-[3-((R)-6-메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-메톡시-퀴나졸린(9) 4-[(R)-(1-phenyl-ethyl) amino] -6- [3-((R) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy]- 7-methoxy-quinazoline
(10) 4-[(R)-(1-페닐-에틸)아미노]-6-[2-((R)-6-메틸-2-옥소-모르폴린-4-일)-에톡시]-7-메톡시-퀴나졸린(10) 4-[(R)-(1-phenyl-ethyl) amino] -6- [2-((R) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy]- 7-methoxy-quinazoline
(11) 4-[(3-클로로-4-플루오로페닐)아미노]-7-[4-(6-메틸-2-옥소-모르폴린-4-일)-부틸옥시]-6-메톡시-퀴나졸린(11) 4-[(3-chloro-4-fluorophenyl) amino] -7- [4- (6-methyl-2-oxo-morpholin-4-yl) -butyloxy] -6-methoxy Quinazoline
(12) 4-[(3-클로로-4-플루오로페닐)아미노]-7-[3-(6-메틸-2-옥소-모르폴린-4-일)-프로필옥시]-6-메톡시-퀴나졸린(12) 4-[(3-chloro-4-fluorophenyl) amino] -7- [3- (6-methyl-2-oxo-morpholin-4-yl) -propyloxy] -6-methoxy Quinazoline
(13) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[4-(6-메틸-2-옥소-모르폴린-4-일)-부틸옥시]-7-메톡시-퀴나졸린(13) 4-[(3-chloro-4-fluorophenyl) amino] -6- [4- (6-methyl-2-oxo-morpholin-4-yl) -butyloxy] -7-methoxy Quinazoline
(14) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-(6-메틸-2-옥소-모르폴린-4-일)-에톡시]-7-(테트라하이드로푸란-3-일옥시)-퀴나졸린(14) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7- (tetra Hydrofuran-3-yloxy) -quinazolin
(15) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-(6-메틸-2-옥소-모르폴린-4-일)-에톡시]-7-(테트라하이드로피란-3-일옥시)-퀴나졸린(15) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7- (tetra Hydropyran-3-yloxy) -quinazolin
(16) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-(6-메틸-2-옥소-모르폴린-4-일)-에톡시]-7-(테트라하이드로피란-4-일옥시)-퀴나졸린(16) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7- (tetra Hydropyran-4-yloxy) -quinazolin
(17) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-(6-메틸-2-옥소-모르폴린-4-일)-에톡시]-7-(테트라하이드로푸란-2-일메톡시)-퀴나졸린(17) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7- (tetra Hydrofuran-2-ylmethoxy) -quinazolin
(18) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-(6-메틸-2-옥소-모르폴린-4-일)-에톡시]-7-(테트라하이드로피란-4-일메톡시)-퀴나졸린(18) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7- (tetra Hydropyran-4-ylmethoxy) -quinazolin
(19) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-7-(테트라하이드로푸란-3-일옥시)-퀴나졸린(19) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7- (Tetrahydrofuran-3-yloxy) -quinazoline
(20) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-(테트라하이드로푸란-3-일옥시)-퀴나졸린(20) 4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7- (Tetrahydrofuran-3-yloxy) -quinazoline
(21) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[4-(6,6-디메틸-2-옥소-모르폴린-4-일)-부틸옥시]-7-(테트라하이드로푸란-3-일옥시)-퀴나졸린(21) 4-[(3-chloro-4-fluorophenyl) amino] -6- [4- (6,6-dimethyl-2-oxo-morpholin-4-yl) -butyloxy] -7- (Tetrahydrofuran-3-yloxy) -quinazoline
(22) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-7-(테트라하이드로푸란-2-일메톡시)-퀴나졸린(22) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7- (Tetrahydrofuran-2-ylmethoxy) -quinazoline
(23) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-7-(테트라하이드로푸란-2-일메톡시)-퀴나졸린(23) 4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7- (Tetrahydrofuran-2-ylmethoxy) -quinazoline
(24) 4-[(3-클로로-4-플루오로페닐)아미노]-6-[4-(6,6-디메틸-2-옥소-모르폴린-4-일)-부틸옥시]-7-(테트라하이드로푸란-2-일메톡시)-퀴나졸린(24) 4-[(3-chloro-4-fluorophenyl) amino] -6- [4- (6,6-dimethyl-2-oxo-morpholin-4-yl) -butyloxy] -7- (Tetrahydrofuran-2-ylmethoxy) -quinazoline
(25) 4-[(3-클로로-4-플루오로페닐)아미노]-7-[2-(6-메틸-2-옥소-모르폴린-4-일)-에톡시]-6-(테트라하이드로푸란-3-일옥시)-퀴나졸린(25) 4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -6- (tetra Hydrofuran-3-yloxy) -quinazolin
(26) 4-[(3-클로로-4-플루오로페닐)아미노]-7-[2-(6-메틸-2-옥소-모르폴린-4-일)-에톡시]-6-(테트라하이드로피란-3-일옥시)-퀴나졸린(26) 4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -6- (tetra Hydropyran-3-yloxy) -quinazolin
(27) 4-[(3-클로로-4-플루오로페닐)아미노]-7-[2-(6-메틸-2-옥소-모르폴린-4-일)-에톡시]-6-(테트라하이드로피란-4-일옥시)-퀴나졸린(27) 4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -6- (tetra Hydropyran-4-yloxy) -quinazolin
(28) 4-[(3-클로로-4-플루오로페닐)아미노]-7-[2-(6-메틸-2-옥소-모르폴린-4-일)-에톡시]-6-(테트라하이드로푸란-2-일메톡시)-퀴나졸린(28) 4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -6- (tetra Hydrofuran-2-ylmethoxy) -quinazolin
(29) 4-[(3-클로로-4-플루오로페닐)아미노]-7-[2-(6-메틸-2-옥소-모르폴린-4-일)-에톡시]-6-(테트라하이드로피란-4-일메톡시)-퀴나졸린(29) 4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -6- (tetra Hydropyran-4-ylmethoxy) -quinazolin
(30) 4-[(3-클로로-4-플루오로페닐)아미노]-7-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-6-(테트라하이드로푸란-3-일옥시)-퀴나졸린(30) 4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6- (Tetrahydrofuran-3-yloxy) -quinazoline
(31) 4-[(3-클로로-4-플루오로페닐)아미노]-7-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-6-(테트라하이드로푸란-3-일옥시)-퀴나졸린(31) 4-[(3-chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6- (Tetrahydrofuran-3-yloxy) -quinazoline
(32) 4-[(3-클로로-4-플루오로페닐)아미노]-7-[4-(6,6-디메틸-2-옥소-모르폴린-4-일)-부틸옥시]-6-(테트라하이드로푸란-3-일옥시)-퀴나졸린(32) 4-[(3-chloro-4-fluorophenyl) amino] -7- [4- (6,6-dimethyl-2-oxo-morpholin-4-yl) -butyloxy] -6- (Tetrahydrofuran-3-yloxy) -quinazoline
(33) 4-[(3-클로로-4-플루오로페닐)아미노]-7-[2-(6,6-디메틸-2-옥소-모르폴린-4-일)-에톡시]-6-(테트라하이드로푸란-2-일메톡시)-퀴나졸린(33) 4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6- (Tetrahydrofuran-2-ylmethoxy) -quinazoline
(34) 4-[(3-클로로-4-플루오로페닐)아미노]-7-[3-(6,6-디메틸-2-옥소-모르폴린-4-일)-프로필옥시]-6-(테트라하이드로푸란-2-일메톡시)-퀴나졸린(34) 4-[(3-chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6- (Tetrahydrofuran-2-ylmethoxy) -quinazoline
(35) 4-[(3-클로로-4-플루오로페닐)아미노]-7-[4-(6,6-디메틸-2-옥소-모르폴린-4-일)-부틸옥시]-6-(테트라하이드로푸란-2-일메톡시)-퀴나졸린(35) 4-[(3-chloro-4-fluorophenyl) amino] -7- [4- (6,6-dimethyl-2-oxo-morpholin-4-yl) -butyloxy] -6- (Tetrahydrofuran-2-ylmethoxy) -quinazoline
실시예 5Example 5
활성 물질 75mg을 함유하는 제피정Tablets containing 75 mg of active substance
정제 코어 1개는 다음을 함유한다:One tablet core contains:
활성 물질 75.0mgActive substance 75.0 mg
인산칼슘 93.0mgCalcium Phosphate 93.0mg
옥수수 전분 35.5mgCorn Starch 35.5mg
폴리비닐피롤리돈 10.0mgPolyvinylpyrrolidone 10.0mg
하이드록시프로필메틸셀룰로스 15.0mgHydroxypropylmethylcellulose 15.0mg
마그네슘 스테아레이트1.5mg Magnesium Stearate 1.5mg
230.0mg230.0mg
제조:Produce:
활성 물질을 인산칼슘, 옥수수 전분, 폴리비닐피롤리돈, 하이드록시프로필메틸셀룰로스 및 지정된 양의 절반량의 마그네슘 스테아레이트와 혼합한다. 직경이 13 mm인 블랭크를 타정기에서 제조한 후, 이들을 적합한 기계를 사용하여 메쉬 크기가 1.5mm인 체를 통과하도록 문지르고 잔량의 마그네슘 스테아레이트와 혼합한다. 당해 과립을 타정기에서 압착시켜 목적하는 형상의 정제를 성형한다.The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half the amount of magnesium stearate in the specified amount. After the blanks with a diameter of 13 mm are produced in a tablet press, they are rubbed through a sieve having a mesh size of 1.5 mm using a suitable machine and mixed with the remaining amount of magnesium stearate. The granules are pressed in a tablet press to form tablets of the desired shape.
코어 중량: 230mgCore weight: 230 mg
다이: 9mm, 볼록Die: 9 mm, convex
이렇게 하여 수득된 정제를 필수적으로 하이드록시프로필메틸셀룰로스로 이루어진 필름으로 피복시킨다. 최종 필름 피복된 정제를 밀랍을 사용하여 광택을 낸다.The tablets thus obtained are coated with a film consisting essentially of hydroxypropylmethylcellulose. The final film coated tablets are polished using beeswax.
제피정 중량: 245mg.Coating weight: 245 mg.
실시예 6Example 6
활성 물질 100mg을 함유하는 정제Tablets containing 100 mg of active substance
조성:Furtherance:
정제 1개는 다음을 함유한다:One tablet contains:
활성 물질 100.0mg100.0 mg of active substance
락토스 80.0mgLactose 80.0mg
옥수수 전분 34.0mgCorn Starch 34.0mg
폴리비닐피롤리돈 4.0mgPolyvinylpyrrolidone 4.0mg
마그네슘 스테아레이트2.0mg Magnesium Stearate 2.0mg
220.0mg220.0mg
제조방법:Manufacturing Method:
활성 물질, 락토스 및 전분을 함께 혼합하고 폴리비닐피롤리돈 수용액으로 균일하게 습윤화시킨다. 습윤 조성물을 체질하고(메쉬 크기: 2.0mm) 50℃에서 선반형 건조기 속에서 건조시킨 후, 다시 체질하고(메쉬 크기: 1.5mm) 윤활제를 가한다. 최종 혼합물을 압착시켜 정제를 성형한다.The active substance, lactose and starch are mixed together and uniformly wetted with aqueous polyvinylpyrrolidone. The wet composition is sieved (mesh size: 2.0 mm), dried in a shelf dryer at 50 ° C., then sieved again (mesh size: 1.5 mm) and lubricant is added. The final mixture is compressed to form tablets.
정제 중량: 220mgTablet weight: 220 mg
직경: 10mm, 이중 평면, 양면에 절단 면이 있고 한 면에는 새김(notch)이 있다.Diameter: 10 mm, double planes, with cut faces on both sides and notches on one side.
실시예 7Example 7
활성 물질 150mg을 함유하는 정제Tablets containing 150 mg of active substance
조성:Furtherance:
정제 1개는 다음을 함유한다:One tablet contains:
활성 물질 50.0mg50.0 mg of active substance
락토스 분말 89.0mgLactose Powder 89.0mg
옥수수 전분 40.0mgCorn Starch 40.0mg
콜로이드성 실리카 10.0mg10.0 mg colloidal silica
폴리비닐피롤리돈 10.0mgPolyvinylpyrrolidone 10.0mg
마그네슘 스테아레이트1.0mg Magnesium Stearate 1.0mg
300.0mg300.0mg
제조:Produce:
활성 물질을 락토스, 옥수수 전분 및 실리카와 혼합한 후, 20% 폴리비닐피롤리돈 수용액으로 습윤화시키고 메쉬 크기가 1.5mm인 체를 통해 통과시킨다. 당해 과립을 45℃에서 건조시키고 동일한 체를 통해 다시 통과시킨 후, 지정된 양의 마그네슘 스테아레이트와 혼합한다. 혼합물로부터 정제를 압착시킨다.The active material is mixed with lactose, corn starch and silica and then wetted with 20% aqueous polyvinylpyrrolidone solution and passed through a sieve with a mesh size of 1.5 mm. The granules are dried at 45 ° C. and passed again through the same sieve and then mixed with the specified amount of magnesium stearate. The tablet is compressed from the mixture.
정제 중량: 300mgTablet weight: 300 mg
다이: 10mm, 편평함Die: 10 mm, flat
실시예 8Example 8
활성 물질 150mg을 함유하는 경질 젤라틴 캡슐Hard gelatin capsules containing 150 mg of active substance
캡슐 1개는 다음을 함유한다:One capsule contains:
활성 물질 50.0mg50.0 mg of active substance
옥수수 전분(건조시킨 것) 약 80.0mgCorn starch (dried) approx. 80.0 mg
락토스(분말) 약 87.0mgLactose (powder) approx. 87.0 mg
마그네슘 스테아레이트3.0mg Magnesium Stearate 3.0mg
약 420.0mg420.0 mg
제조:Produce:
활성 물질을 부형제와 혼합하고 메쉬 크기가 0.75mm인 체를 통해 통과시킨 후, 적합한 장치를 사용하여 균질 혼합한다. 최종 혼합물을 크기 1의 경질 젤라틴 캡슐에 충전시킨다.The active material is mixed with excipients and passed through a sieve with a mesh size of 0.75 mm, followed by homogeneous mixing using a suitable apparatus. The final mixture is filled into size 1 hard gelatin capsules.
캡슐 충전량: 약 320mgCapsule Filling Capacity: Approximately 320mg
캡슐 쉘: 크기 1의 경질 젤라틴 캡슐Capsule Shell: Size 1, Hard Gelatin Capsules
실시예 9Example 9
활성 물질 150mg을 함유하는 좌제Suppositories containing 150 mg of active substance
좌제 1개는 다음을 함유한다:One suppository contains:
활성 물질 150.0mg150.0 mg of active substance
폴리에틸렌글리콜 1500 550.0mgPolyethylene glycol 1500 550.0mg
폴리에틸렌글리콜 6000 460.0mgPolyethylene Glycol 6000 460.0mg
폴리옥시에틸렌 소르비탄 모노스테아레이트840.0mg Polyoxyethylene Sorbitan Monostearate 840.0mg
2,000.0mg2,000.0mg
제조:Produce:
좌제 매스를 용융시킨 후, 여기에 활성 물질을 균질하게 분포시키고 당해 용융물을 냉각시킨 금형에 붓는다.After the suppository mass is melted, the active substance is distributed homogeneously therein and the melt is poured into a cooled mold.
실시예 10Example 10
활성 물질 50mg을 함유하는 현탁액Suspension containing 50 mg of active substance
현탁액 100ml는 다음을 함유한다:100 ml of the suspension contains:
활성 물질 1.00g1.00 g of active substance
카복시메틸셀룰로스-Na염 0.10g0.10 g of carboxymethylcellulose-Na salt
메틸 p-하이드록시벤조에이트 0.05g0.05 g of methyl p-hydroxybenzoate
프로필 p-하이드록시벤조에이트 0.01g0.01 g of propyl p-hydroxybenzoate
글루코스 10.00gGlucose 10.00 g
글리세롤 5.00g5.00 g of glycerol
70% 소르비톨 용액 20.00g20.00 g of 70% sorbitol solution
향미제 0.30gFlavor 0.30g
증류수 총 100ml가 되게 하는 양Volume to make 100 ml of distilled water
제조:Produce:
증류수를 70℃로 가열한다. 메틸 및 프로필 p-하이드록시벤조에이트를 글리세롤 및 카복시메틸셀룰로스의 나트륨 염과 함께 당해 증류수에 교반하면서 용해시킨다. 당해 용액을 주위 온도로 냉각시킨 후, 여기에 활성 물질을 가하여 교반하면서 균질하게 분산시킨다. 당, 소르비톨 용액 및 향미제를 가하여 용해시킨 후, 현탁액을 교반하면서 탈기시켜 공기를 제거한다.Distilled water is heated to 70 ° C. Methyl and propyl p-hydroxybenzoate are dissolved with stirring in the distilled water together with the sodium salts of glycerol and carboxymethylcellulose. After cooling the solution to ambient temperature, the active substance is added thereto and dispersed homogeneously with stirring. After sugar, sorbitol solution and flavoring agent are added to dissolve, the suspension is degassed while stirring to remove air.
현탁액 5ml는 활성 물질 50mg을 함유한다.5 ml of suspension contains 50 mg of active substance.
실시예 11Example 11
활성 물질 10mg을 함유하는 앰플Ampoule with 10 mg of active substance
조성:Furtherance:
활성 물질 10.0mg10.0 mg active substance
0.01N 염산 적당량0.01N hydrochloric acid
2차 증류수 총 2.0ml가 되게 하는 양Amount to make 2.0 ml of total distilled water
제조:Produce:
활성 물질을 필요량의 0.01N HCl에 용해시키고 통상적인 염으로 등장성으로 한 후, 여과 살균하고 2ml 앰플에 넣는다.The active material is dissolved in the required amount of 0.01 N HCl, isotonic with conventional salts, filtered sterilized and placed in a 2 ml ampoule.
실시예 12Example 12
활성 물질 50mg을 함유하는 앰플Ampoule with 50 mg of active substance
조성:Furtherance:
활성 물질 50.0mg50.0 mg of active substance
0.01N 염산 적당량0.01N hydrochloric acid
2차 증류수 총 10.0ml가 되게 하는 양Amount of 10.0 ml of secondary distilled water
제조:Produce:
활성 물질을 필요량의 0.01N HCl에 용해시키고 통상적인 염으로 등장성으로 한 후, 여과 살균하고 10ml 앰플에 넣는다.The active material is dissolved in the required amount of 0.01 N HCl, isotonic with conventional salts, filtered sterilized and placed in a 10 ml ampoule.
실시예 13Example 13
활성 물질 5mg을 함유하는 분말 흡입용 캡슐Powder inhalation capsule containing 5 mg of active substance
캡슐 1개는 다음을 함유한다:One capsule contains:
활성 물질 5.0mg5.0 mg of active substance
흡입용 락토스15.0mg Inhalation Lactose 15.0mg
20.0mg20.0 mg
제조:Produce:
흡입을 위해 활성 물질을 락토스와 혼합한다. 당해 혼합물을 캡슐 제조기에서 캡슐에 충전시킨다(빈 캡슐 중량: 약 50mg).The active substance is mixed with lactose for inhalation. The mixture is filled into capsules in a capsule maker (empty capsule weight: about 50 mg).
캡슐 중량: 70.0mgCapsule Weight: 70.0mg
캡슐 크기 = 3Capsule size = 3
실시예 14Example 14
활성 물질 2.5mg을 함유하는 손으로 들고 쓰는 분무기(hand-held nebuliser)용 흡입 용액Inhalation solution for hand-held nebulisers containing 2.5 mg of active substance
1회 분무액은 다음을 함유한다:The single spray solution contains:
활성 물질 2.500mg2.500 mg active substance
벤잘코늄 클로라이드 0.001mgBenzalkonium Chloride 0.001mg
1N 염산 적당량1N hydrochloric acid
에탄올/물(50/50) 총 15.000mg이 되게 하는 양Ethanol / water (50/50) for a total of 15.000 mg
제조:Produce:
활성 물질 및 벤잘코늄 클로라이드를 에탄올/물(50/50)에 용해시킨다. 용액의 pH를 1N 염산으로 조정한다. 수득된 용액을 여과하고 손으로 들고 쓰는 분무기용으로 적합한 용기(카트리지)에 넣는다.The active substance and benzalkonium chloride are dissolved in ethanol / water (50/50). The pH of the solution is adjusted with 1N hydrochloric acid. The resulting solution is filtered and placed in a container (cartridge) suitable for hand held sprayers.
용기 내용물: 4.5gContainer Content: 4.5g
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DE10042058A DE10042058A1 (en) | 2000-08-26 | 2000-08-26 | Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation |
PCT/EP2001/009532 WO2002018351A1 (en) | 2000-08-26 | 2001-08-18 | Bicyclic heterocycles, medicaments containing these compounds, their use, and methods for the production thereof |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100673775B1 (en) * | 2005-04-08 | 2007-01-24 | 엘지전자 주식회사 | Home bar door of refrigerator |
EP3182023A1 (en) | 2015-12-18 | 2017-06-21 | Lg Electronics Inc. | Air conditioner |
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