KR970707083A - 매트릭스 메탈로프로테아제 억제제(Matrix metalloprotease inhibitors) - Google Patents

매트릭스 메탈로프로테아제 억제제(Matrix metalloprotease inhibitors) Download PDF

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KR970707083A
KR970707083A KR1019970703394A KR19970703394A KR970707083A KR 970707083 A KR970707083 A KR 970707083A KR 1019970703394 A KR1019970703394 A KR 1019970703394A KR 19970703394 A KR19970703394 A KR 19970703394A KR 970707083 A KR970707083 A KR 970707083A
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compound
formula
phenyl
salt
carboxy
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KR1019970703394A
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KR100432602B1 (ko
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알린도 엘 카스텔하노
스티븐 엘 벤더
주디쓰 지 딜
스티븐 혼
텡 제이 리악
젠규 유안
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크루비너 알란 엠
신텍스(유 에스 에이)인코포레이티드
진저 글렌
아고우론 파마슈티칼즈, 인코포레이티드
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Abstract

화학식(I)의 화합물 및 약제학적으로 허용되는 이의 염은 스트로멜리신, 젤라티나제, 마트릴리신 및 콜라게나제와 같은, 매트릭스 메탈로프테아제를 억제하며, 당해 매트릭스 메탈로프테아제의 억제에 의해 완화되는 질환 상태를 갖고 있는 포유동물의 치료시 유용하다.

Description

매트릭스 메탈로프로테아제 억제제(Matrix metalloprotease inhibitors)
본 내용은 요부공개 건이므로 전문내용을 수록하지 않았음

Claims (34)

  1. 하기 화학식(I)의 화합물 또는 약제학적으로 허용되는 이의 염.
    상기 화학식에서, R1은 머캅토, 아세틸티오, 카복시, 하이드록시카바모일, N-하이드록시포밀아미노, 알콕시카보닐, 아릴옥시카보닐, 아르알콕시카보닐, 벤질옥시카바모일 또는 화학식의 그룹(여기서, R6은 아릴 또는 헤테로아릴이다)이고, R2는 알킬, 사이클로알킬, 아릴, 헤테로사이클로알킬 또는 헤테로아릴이며, R3은 알킬, 사이클로알킬, 아르알킬 또는 헤테로아르알킬이고, R7은 아릴, 헤테로아릴 또는 헤테로사이클로알킬이며, X는 화학식 -(CH2)m-Y-(CH2)n-의 그룹(여기서, Y는 0, S 또는 단일 결합이고, m은 0 내지 4의 정수이며, n은 0 내지 4의 정수이고, m+n은 0 내지 4의 정수이다)이고, p는 0 내지 4의 정수이되, 단 p가 0이 아닌 경우에, R2-X는 비페닐알킬이다.
  2. 제1항에 있어서, R1이 카복시이고, R3이 사이클로헥실이며, R7이 치환되거나 비치환된 페닐 또는 N-모노폴리노이며, X가 프로판-1, 3-디일이고, p가 2 또는 3인 화합물 또는 이의 염.
  3. 제2항에 있어서, R7이 4-(아미노설포닐) 페닐 또는 N-모르폴리노인 화합물 이의 염.
  4. 제1항에 있어서, R2가 알킬, 치환되거나 비치환된 페닐 또는 하기 화학식의 그룹인 화합물 또는 이의 염.
    상기 식에서, A는 CH2, O, NH, S, CH2-CH2또는 NH-CH2이고 R10은 H, 알킬, 알콕시, 알킬아미노 또는 아실아미노이며, R11은 H 또는 할로이고,R7은 4-피리딜 또는 치환되거나 비치환된 페닐이며, p는 0이다.
  5. 제4항에 있어서, R1은 카복시, 하이드록시카바모일 또는 N-하이드록시포밀아미노이고, R2가 페닐, 비페닐, 4-(피리딜) 페닐 또는 2-메틸프로필이며, R3이 3급 부틸, 4-아미노부틸, 디메틸아미노부틸, 4-(N, N'-디에틸구아니도) 부틸, 프로필, 2-메틸프로필, 1-하이드록시이소프로필, 1-하이드록시에틸 또는 사이클로헥실이고, X가 단일 결합, 에틸렌 또는 프로판-1, 3-디일인 화합물 또는 이의 염.
  6. 제4항에 있어서, R2가 비페닐인 화합물 또는 이의 염.
  7. 제6항에 있어서, R1이 카복시, N-하이드록시포밀아미노 또는 하이드록시카바모일이고, R3이 알킬이며, R7이 4-피리딜인 화합물 또는 이의 염.
  8. 제7항에 있어서, R3이 3급 부틸이고, X가 프로판-1, 3-디일인 화합물 또는 이의 염.
  9. 제8항에 있어서, R1이 카복시, N-하이드록시포밀아미노 또는 하이드록시카바모일인 화합물 또는 이의 염.
  10. 제4항에 있어서, R2가 하기 화학식의 그룹인 화합물 또는 이의 염.
    상기 식에서, A는 CH2이고, R10은 H 또는 아실아미노이여, R11은 H이고, R7은 치환되거나 비치환된 페닐이며, X는 프로판-1, 3-디일이다.
  11. 제10항에 있어서, R1이 카복시, 하이드록시카바모일 또는 N-하이드록시포밀아미노이고, R3이 알킬이며, R7이 알콕시카보닐페닐인 화합물 또는 이의 염.
  12. 제11항에 있어서, R1이 카복시이고, R3이 2-메틸프로필이며, R7이 4-(메톡시카보닐) 페닐인 화합물 또는 이의 염.
  13. 제6항에 있어서, R7이 치환되거나 비치환된 페닐인 화합물 또는 이의 염.
  14. 제13항에 있어서, R1이 카복시이고, R3이 알킬 또는 사이클로알킬이며, X가 프로판-1, 3-디일인 화합물 또는 이의 염.
  15. 제14항에 있어서, R3이 사이클로헥실이고, R7이 4-(하이드록시에틸아미노설포닐) 페닐 또는 4-(디메틸아미노에틸아미노설포닐) 페닐이거나, R3이 4-(아미노)부틸 또는 4-(이소프로필아미노) 부틸이고 R7이 4-(에톡시카보닐) 페닐이거나, R3이 1-하이드록시이소프로필이고 R7이 페닐이거나, R3이 3급 부틸인 화합물 또는 이의 염.
  16. 제15항에 있어서, R7이 4-(N-모르폴리노프로필아미노설포닐) 페닐, 4-(메틸아미노설포닐) 페닐, 4-(하이드록시에틸아미노설포닐) 페닐 또는 4-(메틸설피닐) 페닐인 화합물 또는 이의 염.
  17. 제4항에 있어서, R1이 카복시이고, R2가 페닐이며, R3이 알킬 또는 사이클로알킬이고, R7이 치환되거나 비치환된 페닐인 화합물 또는 이의 염.
  18. 제17항에 있어서, R3이 4-(아미노)부틸이고 R7이 4-(에톡시카보닐) 페닐이며 X가 프로판-1, 3-디일이거나, R3이 (N, N'-디에틸구아니도)-N-부틸이고 R7이 4-(에톡시카보닐) 페닐이며 X가 프로필렌이거나, R3이 사이클로헥실이고 R7이 4-(N, N-디메틸아미노에틸아미노설포닐) 페닐이며 X가 에틸렌인 화합물 또는 이의 염.
  19. 제4항에 있어서, R1이 머캅토, 카복시, 하이드록시카바모일 또는 N-하이드록시포밀아미노이고, R2가 2-메틸프로필이며, R3이 알킬, 사이클로알킬 또는 헤테로아르알킬이고, R7이 치환되거나 비치환된 페닐이며, X가 단일 결합인 화합물 또는 이의 염.
  20. 제19항에 있어서, R1이 하이드록시카바모일이고, R3이 프로필, 2-메틸프로필, 사이클로헥실 또는 3-메닐인돌릴이며, R7이 4-(메톡시) 페닐, 4-(카복시) 페닐, 4-(메톡시카보닐) 페닐 또는 4-(디메틸아미노에틸카바모일) 페닐인 화합물 또는 이의 염.
  21. 제20항에 있어서, R7이 4-(디메틸아미노에틸카바모일) 페닐 또는 4-(메톡시카보닐) 페닐인 화합물 또는 이의 염.
  22. 제19항에 있어서, R1이 N-하이들고시포밀아미노이고, R3이 2-메틸프로필이며 R7이 4-(메톡시카보닐) 페닐이거나, R1이 카복시이고 R3이 사이클로헥실 또는 2-메틸프로필이며 R7이 4-(메톡시카보닐) 페닐이거나, R1이 머캅토이고 R3이 2-메틸프로필이며 R7이 4-(메톡시카보닐) 페닐인 화합물 또는 이의 염.
  23. 제4항에 있어서, R1이 카복시이고, R2가 4-(2-하이드록시에틸) 페닐, 4-(2-하이드록시프로필) 페닐, 4-(2-하이드록시부틸) 페닐, 4-피리딜페닐, 비페닐, 4'-(아미노에톡시) 비페닐, 4'-(시아노) 비페닐 또는 4'-(하이드록시) 비페닐이며, R3이 2-메틸프로필이고, R7이 4-(메톡시카보닐) 페닐이며, X가 프로판-1, 3-디일인 화합물 또는 이의 염.
  24. 제23항에 있어서 R2가 나-(피리딜) 페닐인 화합물 또는 이의 염.
  25. 제1항의 화합물 또는 이의 염 및 약제학적으로 허용되는 부형제를 포함하는 약제학적 조성물.
  26. 치료학적 유효량의 제1항의 화합물 또는 이의 염을 이를 필요로 하는 포유동물에 투여함을 포함하는, 포유동물의 매트릭스 메탈로프로테이나제 활성의 억제 방법.
  27. 치료학적 유효량의 제1항의 화합물 또는 이의 염을 이를 필요로 하는 포유동물에 투여함을 포함하는, 관절염, 비정상적 창상 유합, 조직 궤향화, 골 흡수성 질환, 당뇨병, 종양 침윤, 종양 전이 및 치근막 질환으로 이루어진 그룹으로부터 선택되는 매트릭스 메틸로프로테이나제 매개된 질환의 치료 방법.
  28. 하기 화학식의 화합물.
    상기 화학식에서, R2는 알킬, 아릴 또는 헤테로아릴이고, X는 화학식-(CH2)m-Y-(CH2)n의 그룹(여기서, Y는 0, S 또는 단일 결합이고, m은 0 내지 4의 정수이며, n은 0 내지 4의 정수이고, m+n은 0 내지 4의 정수이다)이거나 R2와 X는 함께 저급 알케닐이다.
  29. 하기 화학식(Ⅲ)의 화합물을 팔라듐/탄소 촉매의 존재하에서 수소화시킴을 포함하는, 화학식(Ⅴ)의 화합물의 제조 방법.
    상기 화학식에서, R2는 아릴 또는 헤테로아릴이다.
  30. 제29항에 있어서, 화학식(Ⅲ)의 화합물이 N-(2R)-(3급 부톡시키보닐) 메틸-4-펜테노일)-4S-페닐메틸-2-옥시졸리디논을 염기 및 팔라듐 촉매의 존재하에서 R2-할라이드와 접촉시킴으로써 제조되는 방법.
  31. 화학식(Ⅳ)의 화합물을 나트륨 헥사메틸디실라지드 및 3급 부틸브로모아세테이트와 접촉시킴을 포함하는, 화학식(Ⅴ)의 화합물의 제조 방법.
    상기 화학식에서, R2는 아릴 또는 헤테로아릴이다.
  32. 화학식 (Ⅵ)의 화합물.
    상기 화학식에서, R2는 아릴 또는 헤테로아릴이다.
  33. (a) 하기 화학식(Ⅶ)의 화합물을 피리딘 중의 과량의 메실 클로라이드와 접촉시킨 다음, 염기성 조건하에서 환류시키고, (b) 단계 (a)에서 R2가 수소인 경우에, 단계(a)의 생성물을 염기 및 팔라듐 촉매의 존재하에서 아릴 할라이드 또는 헤테로아릴 할라이드와 반응시킴을 포함하는, 화학식(Ⅵ)의 화합물의 제조 방법.
    상기 화학식에서, R2는 하기 화학식(Ⅶ)에서는 수소, 아릴 또는 헤테로아릴이고 화학식(Ⅵ)에서는 아릴 또는 헤테로아릴이다.
  34. (A) 하기 화학식(D)의 화합물을 염기 및 아미드 커플링 시약의 존재하에 화학식(F)의 화합물과 접촉시켜, 상응하는 화학식(I)의 화합물을 수득하거나, (B) X 및 R2가 함께 비치환되거나 아릴 또는 헤테로아릴 치환된 알케닐인, 상응하는 화합물을 촉매적으로 수소화시키니거나, (C) R1이 알콕시카보닐 또는 아르알콕시카보닐인 화학식(I)의 화합물을 온화한 산성 조건하에서 처리하여, R1이 카복시인 상응하는 화학식(I)의 화합물을 수득하거나, (D) R1이 카복시인 화학식(I)의 화합물을 O-벤질하이드록실아민과 접촉시켜, R1이 벤질옥시카바모일인 상응하는 화학식(I)의 화합물을 수득하거나, (E) R1이 벤질옥시카바모일인 화학삭(I)의 화합물을 촉매적으로 수소화시켜, R1이 벤질옥시카바모일인 상응하는 화학식(I)의 화합물을 수득하거나, (F) R1이 카복시인 화학식(I)의 화합물을 하이드록실아민과 접촉시켜, R1이 하이드록시카바모일인 상응하는 화학식 (I)의 화합물을 수득하거나, (G) 화학식(P-6)의 화합물을 촉매적으로 수소화시켜, R1이 N-하이드록시포밀아미노인 상응하는 화학식(I)의 화합물을 수득하거나, (H) R1이 아세틸티오인 화학식(I)의 화합물을 비양성자성 용매중에서 수산화 암모늄으로 처리하여, R1이 머캅토인 상응하는 화학식(I)의 화합물을 수득함을 포함하는, 화학식(I)의 화합물 제조 방법.
    상기 화학식에서, R1은 화학식(I)에서는 머캅토, 아세틸티오, 카복시, 벤질옥시카바모일, 하이드록시카바모일, N-하이드록시포밀아미노, 알콕시카보닐, 아르알콕시카보닐, 벤질옥시카바모일 또는 화학식(여기서, R6은 아릴 또는 헤테로아릴이다)의 그룹이고, 화학식(F)에서는 알콕시카보닐, 아르알콕시카보닐, 아릴- 또는 헤테로아릴티오메틸포스피노일 또는 아세틸티오이며, R2는 알킬, 아릴 또는 헤테로아릴이고, R3은 알킬, 사이클로알킬, 아르알킬 또는 헤테로아르알킬이며, X는 화학식 -(CH2)m-Y-(CH2)n의 그룹(여기서, Y는 0, S 또는 단일 결합이고, m은 0 내지 4의 정수이며, n은 0 내지 4의 정수이고, m+n은 0 내지 4의 정수이다)이며, R7은 아릴, 헤테로아릴 또는 헤테로사이클로알킬이고, p는 0 내지 4의 정수이다.
    ※ 참고사항 : 최초출원 내용에 의하여 공개하는 것임.
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