KR950702525A - 금속단백질 분해효소 억제제로서 히드록삼산 유도체 - Google Patents

금속단백질 분해효소 억제제로서 히드록삼산 유도체 Download PDF

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KR950702525A
KR950702525A KR1019950700232A KR19950700232A KR950702525A KR 950702525 A KR950702525 A KR 950702525A KR 1019950700232 A KR1019950700232 A KR 1019950700232A KR 19950700232 A KR19950700232 A KR 19950700232A KR 950702525 A KR950702525 A KR 950702525A
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조나톤 필립 딕켄스
미첼 죤 크림민
레이몬드 포올 백킷
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포올 리틀우드
브리티시 바이오테크 파마슈티칼즈 리미티드
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Abstract

다음 일반식(I)의 화합물은 매트릭스 금속단백질 분해효소억제활성을 갖는다.
상기 식에서 R2는 R6-A기를 나타내고, 여기서 A는 O 또는 S원자에 의하여 차단될 수 있는 6개 이하의 탄소원자를 갖는 2가의 곧은형 또는 분지형, 포화 또는 불포화 탄화수소 사슬을 나타내고, R6는 수소 또는 임의로 치환된 페닐, 시클로알킬 또는 시클로알켄일기를 나타내며; R3는 R7-(B)n기를 나타내고, 여기서 n는 0 또는 1이고, B는 0또는 S원자에 의하여 차단될 수 있는 6개 이하의 탄소원자를 갖는 2가의 곧은형 또는 분지형, 포화 또는 불포화 탄화수소 사슬을 나타내고, R7은 -CONHOH, 카르복실, 에스테르화 또는 아미드화된 카르복실, 시클로알킬, 시클로알켄일, 헤테로시클일, 페닐, 나프틸 또는 치환기를 페닐, 히드록시, C1-C6알콕시, 벤질옥시 또는 R8-(C=0)-(C1-C6알킬)-0-(여기서, R7는 히드록시, 아미노 또는 아미드결합을 통하여 결합되는 아미노산 잔기이다)에서 선택한 치환된 페닐이나 나프틸이고; 또는 (n=0인때를 제외하고)R7는 수소이며; R4는 수소 또는 메틸을 나타내며; R5는 수소, C1-C6알킬 또는 D-(C1-C6알킬)기를 나타내고, 여기서 D는 히드록시, (C1-C6)알콕시, (C1-C6)알킬티오, 아실아미노, 임의로 치환된 페닐이나 헤테로고리기, NH2또는 모노-나디-(C1-C6알킬)아민이나 헤테로고리기를 나타내며; 또는 R3와 R5는 함께 O, S 또는 N 헤테로원자에 의하여 차단될 수 있는 8-16개의 탄소원자를 갖는 2가의 포화 또는 불포화 탄화수소 사슬을 나타내며; 이때 R3는 천연알파-아미노산의 고유걸사슬 또는 어떠한 기능치환기가 보호되고, 어떠한 아미노기가 아실화되고, 카르복실기가 에스테르화되는 천연 알파-아미노산의 공유걸사슬이 아니다.

Description

금속단백질 분해효소 억제제로서 히드록삼산 유도체
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Claims (33)

  1. 다음 일반식(I)의 화합물 또는 이의 염, 용매화물이나 수화물.
    상기 식에서, R2는 R6-A기를 나타내고, 여기서 A는 O 또는 S원자에 의하여 차단될 수 있는 6개 이하의 탄소원자를 갖는 2가의 곧은형 또는 분지형, 포화 또는 불포화 탄화수소 사슬을 나타내고, R6는 수소 또는 임의로 치환된 페닐, 시클로알킬 또는 시클로알켄일기를 나타내며; R3는 R7-(B)n기를 나타내고, 여기서 n는 0 또는 1이고, B는 0또는 S원자에 의하여 차단될 수 있는 6개 이하의 탄소원자를 갖는 2가의 곧은형 또는 분지형, 포화 또는 불포화 탄화수소 사슬을 나타내고, R7은 -CONHOH, 카르복실, 에스테르화 또는 아미드화된 카르복실, 시클로알킬, 시클로알켄일, 헤테로시클일, 페닐, 나프틸 또는 치환기를 페닐, 히드록시, C1-C6알콕시, 벤질옥시 또는 R8-(C=0)-(C1-C6알킬)-0-(여기서, R7는 히드록시, 아미노 또는 아미드결합을 통하여 결합되는 아미노산 잔기이다)에서 선택한 치환된 페닐이나 나프틸이고; 또는 (n=0인때를 제외하고)R7는 수소이며; R4는 수소 또는 메틸을 나타내며; R5는 수소, C1-C6알킬 또는 D-(C1-C6알킬)기를 나타내고, 여기서 D는 히드록시, (C1-C6)알콕시, (C1-C6)알킬티오, 아실아미노, 임의로 치환된 페닐이나 헤테로고리기, NH2또는 모노-나디-(C1-C6알킬)아민이나 헤테로고리기를 나타내며; 또는 R3와 R5는 함께 O, S 또는 N 헤테로원자에 의하여 차단될 수 있는 8-16개의 탄소원자를 갖는 2가의 포화 또는 불포화 탄화수소 사슬을 나타내며; 이때 R3는 천연알파-아미노산의 고유걸사슬 또는 어떠한 기능치환기가 보호되고, 어떠한 아미노기가 아실화되고, 카르복실기가 에스테르화되는 천연 알파-아미노산의 공유걸사슬이 아니다.
  2. 제1항에 있어서, 입체화학이 다음과 같은 화합물; 히드록시기와 히드록삼산 부분을 갖는 C 원자-S, R2기를 갖는 C원자 -R, R3기를 갖는 C원자 -S.
  3. 제1항 또는 제2항에 있어서, R2가 C3-C6알킬, 시클로알킬(C3-C6알킬), 페닐(C2-C6알킬), C2-C4알콕시(C1-C3알킬)n, 또는 C-C4알킬술판일(C-C3알킬)m기(여기서 m는 0 또는 1이다)를 나타내는 화합물.
  4. 제3항에 있어서, R2가 n-펜틸, 시클로헥실프로필, 시클로헥실부틸, 시클로헥실펜틸, 페닐에틸, 페닐프로필, 페닐부틸, 페닐펜틸, 프로필옥시메틸 또는 프로필술판일을 나타내는 화합물.
  5. 제3항에 있어서, R2가 이소부틸을 나타내는 화합물.
  6. 전술한 항중 어느 한 항에 있어서, R3가 페닐, C1-C6알킬, C2-C6알켄일, 페닐(C1-C6알킬), 치환된 페닐(C1-C6알킬), 시클로알킬, 시클로알킬(C-C6알킬), 티에닐, 티에닐(C1-C6알킬), 피리딜(C1-C6알킬). 티아졸일(C1-C6알킬)티오푸란일(C1-C6알킬), 벤조티오푸란일(C1-C6알킬) 또는 이미다졸일(C1-C6알킬)기를 나타내고, R3와 R5과 함께 O,S 또는 N헤테로원자에 의하여 임의로 차단되는 C7-C12알킬렌사슬을 형성하는 화합물.
  7. 제6항에 있어서, R3가 페닐, t-부틸, 시클로헥실프로필, 시클로헥실부틸, 시클로헥실펜틸, 임의로 치환된 페닐에틸, 페닐프로필, 페닐부틸과 페닐펜틸기를 나타내고, 여기서 임의의 치환기는 페닐고리에 있고, 페닐, 히드록시, C1-C6알콕시, 벤질옥시, 테트라플루오로메틸, 할로(예를들어 클로로)와 R8-(C=0)-(C1-C6알킬)-O-(여기서 R8는 히드록시, 아미노 또는 아미드결합을 통하여 결합된 아미노산 잔기이다)에서 선택하는 화합물.
  8. 제6항에 있어서, R3가 페닐에틸, 시클로헥실, 티에닐(C1-C6알킬), 피리딜메틸, 티아졸일메틸, 티오푸란일메틸, 벤조티오푸란일메틸 또는 이미다졸릴메틸, 1-에텐일, 1-프로펜일, 1-프로핀일, 2,2-디메틸프로필, 나프틸, 나프틸메틸, 부틸옥시메틸과 프로필술판일메틸 또는 부틸술판일메틸을 나타내는 화합물.
  9. 제6항에 있어서, 시클로헥실메틸, t-부틸, 2-티에닐메틸, (4-히드록시카르보닐메톡시)페닐메틸, (4-페닐)페닐메틸, 메톡시카르보닐에틸, 또는 N-히드록시아미노카르보닐에틸을 나타내는 화합물.
  10. 전술한 항중 어느 한 항에 있어서, R4가 메틸 또는 에틸을 나타내는 화합물.
  11. 제1항 내지 제9항중 어느 한 항에 있어서, R4가 수소인 화합물.
  12. 전술한 항중 어느 한 항에 있어서, R5가 수소나 C1-C4알킬, 또는 D-(C1-C6알킬)기를 나타내고, 여기서 D는 히드록시, (C1-C6)알콕시, (C1-C6)알킬티오, 아실아미노, 임의로 치환된 페닐, 또는 헤테로고리기를 나타내는 화합물.
  13. 제12항에 있어서, R5가 프로필, 부틸, 히드록시에틸, 2-에틸티오에틸, 2-아세톡시에틸, N-아세틸-2-아미노에틸, 3-(2-피로리돈)프로필, 임의로 치환된 페닐에틸, 페닐프로필, 페닐부틸 또는 페닐펜틸을 나타내는 화합물.
  14. 제12항에 있어서, R5가 메틸 또는 메틸인 화합물.
  15. 다음 화합물이 이들의 염, 용매화물 또는수화물에 선택한 화합물.
    N2-[3S-히드록시-4-(N-히드록시아미노)-2R-이소부틸석신일]-L-(4-옥시메틸카르복시)페닐알라닌-N'-메틸아미드; N2-[3S-LEMFHR시-4-(N-히드록시아미노)-2R-이소부틸석신일]-L-페닐글리신-N'-메틸아미드; N2-[3S-히드록시-4-(N-히드록시아미노)-2R-이소부틸석신일]-L-(4-페닐)페닐알라닌-N'-메틸아미드; N2-[3S-히드록시-4-(N-히드록시아미노)-2R-이소부틸석신일]아미노-1-아자시클로트리데칸-2-온; N2-[2S-히드록시-4-(N-히드록시아미노)-2R-이소부틸석신일]-L-3-(1-피라졸일)알라닌-N'-메틸아미드; N2-[3S-히드록시-4-(N-히드록시아미노)-2R-이소부틸석신일]-L-4-(N-히드록시아미노)글루탐산-N'-메틸아미드; N2-[3S-히드록시-4-(N-히드록시아미노)-2R-이소부틸석신일]-L-3-(2-티엔일)알라닌-N'-메틸아미드; N2-[3S-히드록시-4-(N-히드록시아미노)-2R-이소부틸석신일]-L-시클로헥실 알라닌-N'-(3-(2-피로리돈)프로필)아미도.
  16. N2-[3S-히드록시-4-(N-히드록시아미노)-2R-이소부틸석신일]-L-시클로헥실알라닌-N'-메틸아미드 또는 이의 염, 용매화물이나 수화물.
  17. N2-[3S-히드록시-4-(N-히드록시아미노)-2R-이소부틸석신일]-L-tert-류신-N'-메틸아미드 또는 이의 염, 용매화물이나 수화물.
  18. (a)다음 일반식(II) 또는 이의 활성화 유도체를 히드록실아민, 0-보호 히드록실아민 또는 이들의 염과 결합시킨 다음,
    (상기식에서, R2,R3,R4와 R5는 히드록실아민, 0-보호 히드록실아민, 또는 이들의 염과 우수하게 반응하는 R2,R3,R4및 R5의 어떠한 치환기가 그들 자체 이와 같은 반응에서 보호될 수 있는 것을 제외하고 일반식(I)에 기재된 바와같다) 반응생성된 히드록삼산 부분에서와 R2,R3,R4와 R5의 보호치환기에서 보호기를 제거하고, (b)일반식(I)의 화합물을 일반식(I)의 다른 화합물로 변환시킴을 특징으로 하는 제1항의 화합물의 제조방법.
  19. 제18항에 있어서, 일반식(II)으로 표시되는 화합물의 활성화 유도체를 사용하고 이 활성화 유도체가 펜타플루오로페닐, 히드록시석신일 또는 히드록시벤즈트리아질 에스테르인 제조방법.
  20. 제18항 또는 제19항에 있어서, 일반식(II)의 화합물을 다음 일반식(III)의 산 또는 이의 활성화 유도체와 다음 일반식(IV)의 아민가 결합시킨 다음, 보호기 또는 보호부분을 제거하여서 하는 제조방법.
    상기 식들에서, R2,R3,R4와 R5는 상기 일반식(I)에 기재된 바와같고, R10와 R11은 각가 히드록시 보호기를 나타내거나 이는 함께 동시에 두 히드록시기를 보호하는 2가 부분을 나타낸다.
  21. 제20항에 있어서, 일반식(III)으로 표시되는 화합물의 활성화 유도체를 사용하고 이 활성화 유도체가 펜타플루오로페닐 에스테르, 산무수물 또는 산 할로겐화물, 예를들어 염화물인 제조방법.
  22. 제20항 또는 제21항에 있어서, 화합물(III)이 다음 일반식(V)을 갖는 제조방법.
    상기 식에서, R,R3,R4와 R5는 일반식(I)에 기재된 바와같고 R12와 R13기는 디옥사론 형성시약에서 유도된다.
  23. 제22항에 있어서, R12과 R13이 수소, 알킬, 페닐 또는 치환된 페닐인 제조방법.
  24. 유효량의 제1항 내지 제16항중 어느 한 항의 화합물을 포유동물에 투여하여서 함을 특징으로 하는 사람을 포함한 포유동물의 MMPS와 또는 TNF에 의하여 매개되는 질병 또는 증상의 처리방법(이는 치료 또는 예방을 뜻한다).
  25. MMPS와/또는 TNF에 의하여 매개되는 질병 또는 증상을 처리(이는 치료 또는 예방을 뜻한다)하는데, 사람 또는 수의용 의약으로서의 제1항 내지 제17항중 어느 한 항에 따른 화합물의 용도.
  26. MMPS와/또는 TNF에 의하여 매개되는 질병 또는 증상을 처리(이는 치료 또는 예방을 뜻한다)하는데, 사람 또는 수의용 의약으로서의 제1항 내지 제17항중 어느 한 항에 따른 화합물의 용도.
  27. MMPS와/또는 TNF에 의하여 매개되는 질병 또는 증상을 처리(이는 치료 또는 예방을 뜻한다)하기 위한 약제를 제조하는데, 제1항 내지 제17항중 어느 한 항에 따른 화합물의 용도.
  28. 제24항에 있어서, 제25항 또는 제26항의 용도용 화합물을 언급한 질병 또는 증상이 MMP에의 매개된 것인 질병 또는 증상의 처리방법.
  29. 제24항에 있어서, 제25항 또는 제26항의 용도용 화합물로 언급한 질병 또는 증상이 류우머티스성 관절염, 골관절염, 치주조직염, 치은염, 위궤양 또는 이차 혼합감염에 의한 종양칩입인 질병 또는 증상의 처리방법.
  30. 제24항에 있어서, 제25항이나 제26항의 용도용 또는 제27항의 용도용 화합물로 언급한 질병 또는 증상이 TNF에 의여 매개된 것이 질병 또는 증상의 처리방법.
  31. 제24항에 있어서 제25항이나 제26항의 용도용, 또는 제27항의 용도용 화합물로, 언급한 질병 또는 증상이 염증, 발열증, 순환계작용, 출혈, 응고와 급성위상반응, 악태증과 식욕감퇴, 급성감염, 쇼크상태, 이식편대 숙주반응 또는 자기면역질병인 질병 또는 증상의 처리방법.
  32. 제1항 내지 제17항중 어느 한 항의 화합물과 제약학적으로 또는 수의학적으로 허용할 수 있는 부형제 또는 담체로 이루어지는 제약학적 또는 수의학적 조성물.
  33. 제32항에 있어서, 경구투여에 적합한 제약학적 또는 수의학적 조성물.
    ※ 참고사항 : 최초출원 내용에 의하여 공개하는 것임.
KR1019950700232A 1992-07-23 1993-07-23 금속단백질 분해효소 억제제로서 히드록삼산 유도체 KR100205710B1 (ko)

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