KR950702979A - 티로신 키나제 억제제로서의 아릴리덴 및 헤테로아릴리덴 옥신돌 유도체(Arylidene and heteroarylidene oxindole derivatives as tyrosine kinase inhibitors) - Google Patents

티로신 키나제 억제제로서의 아릴리덴 및 헤테로아릴리덴 옥신돌 유도체(Arylidene and heteroarylidene oxindole derivatives as tyrosine kinase inhibitors) Download PDF

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KR950702979A
KR950702979A KR1019950700742A KR19950700742A KR950702979A KR 950702979 A KR950702979 A KR 950702979A KR 1019950700742 A KR1019950700742 A KR 1019950700742A KR 19950700742 A KR19950700742 A KR 19950700742A KR 950702979 A KR950702979 A KR 950702979A
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methylene
hydroxy
tetralyl
oxindol
oxindole
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부젯티 프랑코
롱고 안토니오
가브리엘라 브라스차 마리아
오르치 파브리치오
크루그놀라 안젤로
발리나리 다리오
마리안니 마리안젤라
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비토리노 페라리오
파마치아 에스. 피. 에이.(Pharmacia S. p. A.)
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Abstract

본 발명은 티로신 키나제 억제제로서 유용한 일반식(I)의 아릴리덴 및 헤테로아릴리덴 옥신돌 유도체 및 약제학적으로 허용되는 이의 염에 관한 것이다.
상기식에서, Y는 나프탈렌, 테트랄린, 퀴놀린 및 이소퀴놀린으로부터 선택된 바이사이클릭 환 시스템이고; R은, Y가 테트랄린일때는 수소 또는 옥소(=0) 그룹이거나, Y가 나프탈렌, 퀴놀린 또는 이소퀴놀린일때는 수소이고; R1과 R2는 각각 독립적으로 수소, C1-C6알킬 또는 C2-C6알카노일이며; m은 0,1 또는 2이고; n은 0,1,2 또는 3이며; R3와 R4는 각각 독립적으로 수소, 할로겐, 시아노, C1-C6알킬, 카복시, 니트로 또는 -NR6R7이고, 여기에서 R6와 R7은 각각 독립적으로 수소 또는 C1-C6알킬이며; R5는 수소 또는 C1-C6알킬이다.

Description

티로신 키나제 억제제로서의 아릴리덴 및 헤테로아릴리덴 옥신돌 유도체(Arylidene and heteroarylidene oxindole derivatives as tyrosine kinase inhibitors)
본 내용은 요부공개 건이므로 전문내용을 수록하지 않았음

Claims (13)

  1. 일반식(I)의 화합물 또는 약제학적으로 허용되는 이의염.
    상기식에서, Y는 나프탈렌, 테트랄린, 퀴놀린 및 이소퀴놀린으로부터 선택되는 바이사이클릭(bicyclic)환 시스템이고; R은 Y가 테트랄린일때는 수소 또는 옥소(=0) 그룹이거나, Y가 나프탈렌, 퀴놀린 또는 이소퀴놀린일때는 수소이며; R1과 R2는 각각 독립적으로 수소, C1-C6알킬 또는 C2-C6알카노일이고; m은 0,1 또는 2이며; n은 0,1,2 또는 3이고; R3과 R4는 각각 독립적으로 수소, 할로겐, 시아노, C1-c6알킬, 카복시, 니트로 또는 -NR6R7이고, 여기에서 R6과 R7은 각각 독립적으로 수소 또는 C1-C6알킬이며; R5는 수소 또는 C1-C6알킬이며; 단 a) 동시에, Y가 나프탈렌이고; R3가 수소, 할로겐 시아노 또는 C1-C6알킬이고; R5가 수소이며; m이 0이고, R 및 R1이 상기 정의한 바와 같을때, R4는 수소 이외의 것이며; b) 동시에, Y가 퀴놀린 또는 이소퀴놀린이고; R3가 수소, 할로겐, 시아노 또는 C1-C6알킬이고; n이 0,1 또는 2이며; R5가 수소이고; m이 0이며, R 및 R1이 상기 정의한 바와 같을때, R4는 수소 이외의 것이며; c) 동시에, Y가 벤젠 잔기만이 치환된 텐트랄린이고, R4가 수소, 할로겐, 시아노 또는 C1-C4알킬이고; n이 0,1 또는 2이며; R5가 수소이고; m이 0이며 R이 수소이고 R1이 상기 정의한 바와 같을때, R4는 수소 이외의 것이며; d) 동시에, Y가 나프탈렌이고, m과 n이 0이고; R과 R3가 수소이며; C-4 탄소원자에 결합된 R4가 할로겐 또는 C1-C4, 알킬일때, R5는 C1-C2알킬 이외의 것이다.
  2. 제1항에 있어서, Y가 테트랄린, 퀴놀린 또는 이소퀴놀린이고; n이 0,1,2 또는 3이며; m이 0 또는 1이고; R1과 R2가 각각 독립적으로 수소 또는 C1-C4알킬이며; R3과 R4가 각각 독립적으로, 수소, 할로겐, 시아노, 카복시 또는 아미노이고; R5가 수소이며; R이 제1항에서 정의한 바와 같은 일반식(I)의 화합물 또는 약제학적으로 허용되는 이의 염.
  3. 제1항에 있어서, Y가 테트랄린 또는 퀴놀린이고; n이 0,1,2 또는 3이며; m이 0 또는 1이고; R1, R2및 R5가 수소이며; R3와 R4가 각각 독립적으로 수소, 아미노 또는 카복시이고; R이 제1항에서 정의한 바와 같은 일반식(I)의 화합물 또는 약제학적으로 허용되는 이의 염.
  4. 각각 Z 또는 E 부분입체이성체 또는 이들의 혼합물 형태로 존재하는, 3-[(4′-아미노-1′-테트랄릴)메틸렌]-2-옥신돌; 3-[(4′-디메딜아미노-1′-데트랄릴)메틸렌]-2-옥신돌; 3-[(4′-카복시-1′-테트랄릴)메틸렌]-2-옥신돌; 5-하이드록시-3-[(1′-테트랄릴)메틸렌]-2-옥신돌; 5-아미노-3-[(1′-테트랄틸)메틸렌]-2-옥신돌; 5-카복시-3-[(1′-테트랄릴)메틸렌]-2-옥신돌; 5-하이드록시-3-[(2′-하이드록시-1′-테트탈릴)메틸렌]-2-옥신돌; 5-하이드록시-3-[(2′-하이드록시-1′-테트랄릴)메틸렌]-2-옥신돌; 5-아미노-3-[(2′-하이드록시-1′-테트랄릴)메틸렌]-2-옥신돌; 5-아미노-3-[(4′-하이드록시-1′-테트랄릴)메틸렌]-2-옥신돌; 5-카복시-3-[(2′-하이드록시-1′-테트랄린)메틸렌]-2-옥신돌; 5-카복시-3-[(4′-하이드록시-1′-테트랄릴)메틸렌]-2-옥신돌; 5-하이드록시-3-[(4′,5′-디하이드록시-1′-테트랄릴)메틸렌]-2-옥신돌; 5-하이드록시-3-[(4′,8′-디하이드록시-1′-테트랄릴)메틸렌]-2-옥신돌; 5-아미노-3-[(4′,5′-디하이드록시-1′-테트랄릴)메틸렌]-2-옥신돌; 5-아미노-3-[(4′,8′-디하이드록시-1′-테트랄릴)메틸렌]-2-옥신돌; 5-카복시-3-[(4′,5′-디하이드록시-1′-테트랄릴)메틸렌]-2-옥신돌; 3-[(4′-아미노-2′-테트랄릴)메틸렌]-2-옥신돌; 3-[(4′-카복시-2′-테트랄릴)메틸렌]-2-옥신돌; 5-하이드록시-3-[(2′-테트랄릴)메틸렌]-2-옥신돌; 5-아미노-3-[(2′-테트랄릴)메틸렌]-2-옥신돌; 5-카복시-3-[(2′-테트랄릴)메틸렌]-2-옥신돌; 5-하이드록시-3-[(1′-하이드록시-2′-테트랄릴)메틸렌]-2-옥신돌; 5-하이드록시-3-[(3′-하이드록시-2′-테트랄릴)메틸렌]-2-옥신돌; 5-하이드록시-3-[(3′-하이드록시-2′-테트랄릴)메틸렌]-2-옥신돌; 5-아미노-3-[(1′- 하이드록시-2′-테트랄릴)메틸렌]-2-옥신돌; 5-아미노-3-[(3′-하이드록시-2′-테트랄릴)메틸렌]-2-옥신돌; 5-아미노-3-[(3′-하이드록시-2′-테트랄릴)메틸렌]-2-옥신돌; 5-카복시-3-[(1′-하이드록시-2′-테트랄릴)메틸렌]-2-옥신돌; 5-카복시-3-[(3′-하이드록시-2′-테트랄릴)메틸렌]-2-옥신돌; 5-카복시-3-[(4′-하이드록시-2′-테트랄릴)메틸렌]-2-옥신돌; 5-하이드록시-3-[(1′,4′-디하이드록시-2′-테트랄릴)메틸렌]-2-옥신돌; 5-하이드록시-3-[(4′,5′-디하이드록시-2′-테트랄릴)메틸렌]-2-옥신돌; 5-하이드록시-3-[(4′,8′-디하이드록시-2′-테트랄릴)메틸렌]-2-옥신돌; 5-하이드록시-3-[(3′,5′-디하이드록시-2′-테트랄릴)메틸렌]-2-옥신돌; 5 - 하이드록시-3-[(3′,8′-디하이드록시-2′-테트랄릴)메틸렌]-2-옥신돌; 5-아미노-3-[(1′,4′-디하이드록시-2′-테트랄릴)메틸렌]-2-옥신돌; 5-아미노-3-[(4′,5′-디하이드록시-2′-테트랄릴)메틸렌]-2-옥신돌; 5-아미노-3-[(3′,5′-디하이드록시-2′-테트랄릴)메틸렌]-2-옥신들; 5-아미노신-[(3′,8′-디하이드록시-2′-테트랄릴)메틸렌]-2-옥신돌; 5-아미노-3-[(3′,8′-디하이드록시-2′-테트랄릴)메틸렌]-2-옥신돌; 5-카복시-3-[(1′,4′-디하이드록시-2′-테트랄릴)메틸렌]-2-옥신돌; 5-카복시-3-[(4′,5′-디하이드록시-2′-테트랄릴)메틸렌]-2-옥신돌; 5-카복시-3-[(4′,8′-디하이드록시-2′-테트랄릴)메틸렌]-2-옥신돌; 5-카복시-3-[(3′,5′-디하이드록시-2′-테트랄릴)메틸렌]-2-옥신돌; 5-카복시-3-[(3′,8′-디하이드록시-2′-테트트랄릴)메틸렌]-2-옥신돌; 5-하이드록시-3-[(1′,4′,5′-트리하이드록시-2′-테트랄릴)메틸렌]-2-옥신돌; 5-하이드록시-3-[(1′,4′,8′-트리하이드록시-2′-테트랄릴)메틸렌]-2-옥신돌; 3-[(8′-옥소-1′,4′-디하이드록시-2′-테트랄릴)메틸렌]-2-옥신돌; 5-하이드록시-3-[(5′-퀴놀릴)메틸렌]-2-옥신돌; 5-아미노-3-[(5′-퀴놀릴)메틸렌]-2-옥신돌; 5-카복시-3-[(5′-퀴놀릴)메틸렌]-2-옥신돌; 5-하이드록시-3-[(4′-퀴놀틸)메틸렌]-2-옥신돌; 5 - 아미노-3-[(4′-퀴놀릴)메틸렌]-2-옥신돌; 5-카복시-3-[(4′-퀴놀릴)메틸렌]-2-옥신돌; 5-하이드록시-3-[(8′-하이드록시-5′-퀴놀릴)메틸렌]-2-옥신돌; 5-아미노-3-[(8′-하이드록시-5′-퀴놀릴)메틸렌]-2-옥신돌; 5-카복시-3-[(8′-하이드록시-5′-퀴놀릴)메틸렌]-2-옥신돌; 5-하이드록시-3-[(8′-하이드록시-4′-퀴놀릴)메틸렌]-2-옥신돌; 및 5-아미노-3-[(8′-하이드록시-4′-퀴놀릴)메틸렌]-2-옥신돌; 5-카복시-3-[(8′-하이드록시-5′-퀴놀릴)메틸렌]-2-옥신돌; 5-브로모-3-[(9-하이드록시-9-퀴놀릴)메틸렌]-2-옥신돌; 5-플루오로-3-[(9-하이드록시-5′-퀴놀릴)메틸렌]-2-옥신돌; 5-메톡시-3-[(2′-테트랄릴)메틸렌]-2-옥신돌; 5-아세톡시-3-[(2′-테트랄릴)메틸렌]-2-옥신돌;및5-하이드록시-3-[(8′-하이드록시-1′-테트랄릴)메틸렌]-2-옥신돌로부터 선택되는 화합물 및 약제학적으로 허용되는 이의 염.
  5. 각각 Z 또는 E 부분입체이성체 또는 이들의 혼합물 형태로 존재하는, 3-[(8′-하이드록시-7′-퀴놀릴)메틸렌]-2-옥신돌; 3-[(5′-하이드록시-4′-퀴놀릴)메틸렌]-2-옥신돌; 3-[(8′-하이드록시-4′-퀴놀릴)메틸렌]-2-옥신돌; 5-하이드록시-3-[(5′-메톡시-3′-인돌릴)메틸렌]-2-옥신돌; 5-아미노-3-[(5′-메톡시-3′-인돌릴)메틸렌]-2-옥신돌; 5-하이드록시-3-[(2′-메틸-3′-인돌릴)메틸렌]-2-옥신돌; 3-[(2′-메틸-3′-인돌릴)메틸렌]-2-옥신돌; 3-[(9-시아노-3′-인돌릴)메틸렌]-2-옥신돌; 3-[(5′-하이드록시-3′-인돌릴)메틸렌]-2-옥신돌;및 3-[(5′-메톡시-3′-인돌릴)에틸렌]-2-옥신돌로부티 선택되는 화합물 및 약제학적으로 허용되는 이의 염.
  6. 각각 Z 또는 E 부분입체이성체 또는 이들의 혼합물 형태로 존재하는, 2-시아노-3-(4-퀴놀릴)아크릴아미드; 2-시아노-3-(3-인돌릴)아크틸아미드; 2-시아노-3-(1,4-디하이드록시-2-테트랄릴)아크릴아미드; 2-시아노-3-(1,4-디하이드록시-2-테트랄릴)티오아크릴아미드; 2-시아노-3-(2-하이드록시-1-나프틸)아크릴로니트릴; 2-시아노-3-(2-나프틸)아크릴아미드; 2-시아노-3-(2-나프틸)티오아크릴아미드; 2-시아노-3-(3,5-디하이드록시-2-나프틸)아크릴아미드 및 2-(4-하이드록시페닐)-3-(1,4-디메톡시-2-나프틸)아크릴로니트릴로부터 선택되는 화합물 및 약제학적으로 허용되는 이의 염.
  7. 일반식(II) 알데하이드를 일반식(III)의 화합물과 축합시키고, 필요할 경우, 일반식(I)의 화합물을 또다른 일반식(I)의 화합물로 전환시키고/시키거나, 필요할 경우, 일반식(I)의 화합물을 약제학적으로 허용되는 이의 염으로 전환시키고/시키거나, 필요할 경우, 염을 유리 화합물로 전환시키고/시키거나, 필요할 경우, 일반식(I)의 화합물의 이성체 혼합물을 단일 이성체로 분리시킴을 포함하여, 제1항에 따른 일반식(I)의 화합물 또는 약제학적으로 허용되는 이의 염을 제조하는 방법.
    상기식에서, Y, n, R, R1, R3, m, R2, R4및 R5는 제1항에서 정의한 바와 같다.
  8. 적절한 담체 및/또는 희석제와, 활성 성분으로서 제1항에 따른 일반식(I)의 화합물 또는 제5항 또는 제6항에 따른 화합물 또는 약제학적으로 허용되는 이의 염을 함유하는 약제학적 조성물.
  9. 티로신 키나제 억제제로서 사용하기 위한, 제1항, 제5항 또는 제6항에 따른 화합물 또는 약제학적으로 허용되는 이의 염.
  10. 제9항에 있어서, 증시억제제로서 사용하기 위한 화합물 또는 이의 염.
  11. 제9항에 있어서, 아테롬성 플라그 발생을 억제하거나 현관 형성을 조절하는데 있어서, 전이방지제 또는 항암제로서 사용하기 위한 화합물 또는 이의 염.
  12. 티로신 키나제 억제제로서 사용하기 위한 약제학적 조성물의 제조에 있어서, 다음 일반식(I)의 화합물 및 약제학적으로 허용되는 이의 염의 용도.
    상기식에서, Y는 나프탈렌, 테트랄린, 퀴놀린 및 이소퀴놀린으로부터 선택되는 바이사이클릭 환 시스템이고; R은, Y가 테트랄린일때는 수소 또는 옥소(=0) 그룹이거나, Y가 나프탈렌, 퀴놀린 또는 이소퀴놀린일때는 수소이며; R1과 R2는 각각 독립적으로 수소, C1-C6알킬 또는 C2-C6알카노일이고; m은 0,1 또는 2이며; n은 0,1,2 또는 3이고; R3과 R4는 각각 독립적으로 수소, 할로겐, 시아노, C1-C6알킬, 카복시, 니트로 또는 -NR6R7이며, 여기에서 R6과 R7은 각각 독립적으로 수소 또는 C1-C6알킬이고; R5는 수소 또는 C1-C6알킬이고; 단 a) 동시에 Y가 나프탈렌이고; R3가 수소, 할로겐, 시아노 또는 C1-C6알킬이며; R5가 수소이고; m이 0이며, n, R 및 R1이 상기 정의한 바와 같을때, R4는 수소 이외의 것이며; b) 동시에, Y가 퀴놀린 또는 이소퀴놀린이고; R3가 수소, 할로겐, 시아노 또는 C1-C6알킬이며; n이 0,1또는 2이고; R5가 수소이며; m이 0이며 R과 R1이 상기 정의한 바와 같을때, R4는 수소 이외의 것이며; c) 동시에 Y가 벤젠 잔기만이 치환된 테트랄린이고, R3가 수소, 할로겐, 시아노 또는 C1-C6알킬이며; n이 0,1 또는 2이고;R5가 수소이며; m이 0이고, R이 수소이며 R1이 상기 정의한 바와 같을때, R4는 수소 이외의 것이다.
  13. 제12항에서 정의한 바와 같은 일반식(I)의 화합물 또는 제5항 또는 제6항에서 정의한 바와 같은 화합물 또는 약제학적으로 허용되는 이의 염, 및 종양치료요법에서 동시, 별도 또는 순차적 사용을 위한 혼합 제제로서의 부가의 항암제를 함유하는 생성물.
    ※ 참고사항 : 최초출원 내용에 의하여 공개하는 것임.
KR1019950700742A 1993-07-01 1994-05-26 티로신 키나제 억제제로서의 아릴리덴 및 헤테로아릴리덴 옥신돌 유도체(Arylidene and heteroarylidene oxindole derivatives as tyrosine kinase inhibitors) KR950702979A (ko)

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GB939313638A GB9313638D0 (en) 1993-07-01 1993-07-01 Arylidene and heteroarylidene oxindole derivatives and process for their preparation
PCT/EP1994/001715 WO1995001349A1 (en) 1993-07-01 1994-05-26 Arylidene and heteroarylidene oxindole derivatives as tyrosine kinase inhibitors

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FI950859A (fi) 1995-02-24
AU6971994A (en) 1995-01-24
PL307741A1 (en) 1995-06-12
FI950859A0 (fi) 1995-02-24
DK0658159T3 (da) 2000-12-18
HU9500954D0 (en) 1995-05-29
DE69425637D1 (de) 2000-09-28
ZA944730B (en) 1995-07-13
EP0987263A2 (en) 2000-03-22
HUT72047A (en) 1996-03-28
MX9404885A (es) 1995-01-31
ES2152317T3 (es) 2001-02-01
GB9313638D0 (en) 1993-08-18
NZ267423A (en) 1996-03-26
DE69425637T2 (de) 2001-05-03
PT658159E (pt) 2001-01-31
JPH08500847A (ja) 1996-01-30
DE69434955D1 (de) 2007-05-31
ES2300132T3 (es) 2008-06-01
JP3737826B2 (ja) 2006-01-25
WO1995001349A1 (en) 1995-01-12
DE69434955T2 (de) 2008-01-17
IL110131A0 (en) 1994-10-07
EP0658159A1 (en) 1995-06-21
EP0987263A3 (en) 2003-10-15
AU679754B2 (en) 1997-07-10
RU95108244A (ru) 1997-03-20
CN1111454A (zh) 1995-11-08
ATE195734T1 (de) 2000-09-15
US5656654A (en) 1997-08-12
GR3034854T3 (en) 2001-02-28
EP0658159B1 (en) 2000-08-23
CA2142472A1 (en) 1995-01-12
EP0987263B1 (en) 2007-04-18
ATE360013T1 (de) 2007-05-15

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