KR900014424A - 아미노산 유도체 - Google Patents

아미노산 유도체 Download PDF

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KR900014424A
KR900014424A KR1019900004090A KR900004090A KR900014424A KR 900014424 A KR900014424 A KR 900014424A KR 1019900004090 A KR1019900004090 A KR 1019900004090A KR 900004090 A KR900004090 A KR 900004090A KR 900014424 A KR900014424 A KR 900014424A
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compound
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amino acid
imidazol
alkyl
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브랑카 퀴리코
페터 매르키 한스
나이다르트 베르너
라무즈 헨리
보스틀 볼프강
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쟝-쟈크 오가이, 롤란드 보러
에프, 호프만-라 로슈 에이지
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract

내용 없음

Description

아미노산 유도체
본 내용은 요부공개 건이므로 전문내용을 수록하지 않았음

Claims (25)

  1. 광학적으로 순수한 부분입체이성체, 부분입체이성체의 혼합물, 부분입체이성체의 라세미체 또는 부분입체 이서체 라세미체의 혼합물 형태의 하기 일반식(Ⅰ)의 아미노산 유도체 및 약제학적으로 허용되는 이의 염.
    상기식에서, R1은 수소 또는 메틸이고, R2는 에틸, 프로필, 이소프로필, 이미다졸-2-일, 이미다졸-4-일피라졸-3-일, 티아졸-4-일, 티엔-2-일, 에톡시카보닐, t-부틸카보닐메틸, 벤질옥시카보닐메틸 또는 t-부톡시이고, R3은 이소부틸, 사이클로헥실메틸 또는 벤질이고, R4는 니트로, 아미노 또는 일반식-N(R5)(R6)인 그룹이고,
    중의 하나이고, R5는 알킬, 알콕시알킬 또는 임의로 치환된 페닐, 페닐알킬 또는 페닐설포닐알킬이고, R6은 알킬, 알콕시알킬, 임의로 치환된 페닐, 페닐알킬 또는 페닐설포닐알킬, 알카노일, 알콕시카보닐, 아릴알콕시카보닐, 임의로 치환된 벤즈이미다졸론일 또는 임의로 아실화된 아미노산이 잔기 또는 임의로 아실화된 디펩티드의 잔기이거나, R5와 R6은 이들이 결합한 진소원자와 함께 5원 또는 6원 헤티로사이클, 5원 또는 6원 락탐 또는 5원 또는 6원 이미드를 나타내고, 단, R6이 알카노일,알콕시카보닐 또는아릴알콕시카보닐이고, 점선이 추가의 결합인 경우, A는 그룹(b)일수 없고, R7은 페닐, 치환된 페닐, 벤질 또는 나프틸이고, R8은 수소, 알콕시카보닐알킬, 알킬카보닐알킬, 사이클로알칼카보닐알킬, 헤테로사이클로알킬카보닐알킬, 아릴카보닐알킬, 아미노카보닐알킬, 치환된 아미도 카보닐알킬, 아미노알킬카보닐알킬, 치환된 아미노알킬보닐알킬, 아미노알킬설포닐알킬, 치환된 아미노알킬 설포닐알킬, 알톡시카보닐하이드록시알킬, 알킬카보닐하이드록시 알킬, 사이클로 알킬 카보닐 하이드록시알킬, 헤테로사이클로 알킬카보닐하이드록시알킬, 아릴카보닐하이드록시알킬, 아미노카보닐하이드록시알킬, 치환된 아미노카보닐하이드록시알킬, 디알콕시포스포르옥시알킬, 데페닐옥시포스포르옥시아킬, 아릴알킬, 알콕시카보닐아미노, 아릴알콕시카보닐아미노, 알킬티오알킬, 알킬설피닐알킬, 알킬설포닐아킬 아릴티오알킬, 아릴설피닐알킬, 아릴설포닐알킬, 아릴알킬티오알킬, 아릴아킬설피닐아킬 또는 아릴알킬설포닐알킬이고, 단 R7이 페닐, 벤질 또는 α-나프틸인 경우, R8은 알콕시카보닐아미노 또는 아릴알콕시카보닐아미노일 수 없고, Y는 N-말단에서 Z와 결합하는, 임의로 Z-및/또는 α-메틸화된 페닐글리신, 사이클로헥실글리신, 페닐알라닌, 사이클로헥실알라닌, 4-플루오로페닐알라닌, 4-클로로페닐알라닌, 티로신, 0-메틸티로신, α-나프틸알라닌 또는 호모페닐알라닌의 2가 잔기이고, N는 수소 또는 아실이다.
  2. 제1항에 있어서, R1이 수소인 화합물.
  3. 제1항 또는 제2항에 있어서, R2가 이미다졸 -2-일, 이미다졸-4-일 또는 티아졸-4-일, 바람직하게 이미다졸-4-일인 화합물.
  4. 제1항 내지 제3항중의 어느 한항에 있어서, R3이 사이클로헥실메틸인 화합물
  5. 제1항 내지 제4항중의 어느 한항에 있어서, R4가 그룹 -N(R5)(R6)인 화합물.
  6. 제5항에 있어서, R5가 알킬, 바람직하게는 메틸이고, R6은 임의로 아실화된 아미노산 잔기 또는 임의로 아실화된 디펩티드 잔기, 바람직하게는 히스티딘 또는 페닐알라닌의 아실화 잔기 또는 히스티딘과 페닐알라닌으로 이루어지는 디펩티드의 아실화 잔기이거나 R5와 R6이 이들이 결합한 질소원자와 함께 5원 또는 6원 락탐을 이루는 화합물.
  7. 제1항 내지 제6항중의 어느 한항에 있어서, A가 그룹(a)인 화합물.
  8. 제1항 내지 제7항중의 어느 한항에 있어서, R7이 페닐 또는 치환된 페닐, 바람직하게는 페닐인 화합물.
  9. 제1항 내지 제8항중의 어느 한항에 있어서, R8이 바람직하게는 알킬카보닐알킬, 아미노알킬바코닐알킬, 치환된 아미노알킬 카보닐알킬, 아미노알킬설포닐알킬, 치환된 아미노알킬설포닐알킬 또는 알킬설포닐알킬, 바람직하게는 알킬카보닐알킬 또는 알킬설포닐알킬, 특히 C1-C4-알킬카보닐메틸 또는 C1-C4-알킬설포닐케닐인 화합물
  10. 제1항 내지 제6항중의 어느 한항에 있어서, A가 그룹(b)인 경우, T가 N-말단에서 Z와 결합된 페닐알라닌이 2가 잔기인 화합물.
  11. 제1항 내지 제6항 및 제10항중의 어느 한항에 있어서, Z가 Ra가 임의로 치횐된 탄소수 10이하인 포화 지방족 탄화수소 잔기 또는 임의로 치환된 탄소수 18이하인 헤테로방향족 탄화수소 잔기인 그룹 Ra-O-CO-, 바람직하게는, Ra가 탄소수 6이하인 포화 지방족 탄화수소, 잔기 또는 탄소수 10이하의 헤테로방향족 잔기인 그룹 Ra-O-CO-인 화합물.
  12. 제1항 내지 제9항중의 한항에 있어서, R1이 수소이고, R2가 이미다졸 -4-일이고, R3이 사이클로 헥실메틸이고, R4가 -N(R5)(R6)이고 R5가 메틸이고, R6이 히스티딘 또는 페닐알라닌의 아실화 잔기이거나 히스티딘과 페닐알라닌으로 이루어지는 디펩티드의 아실화 잔기이고, R7이 페닐이고, R8이 C1-C4-알킬카보닐메틸 또는 C1-C4-알킬설로닐메틸인 화합물.
  13. (S)-N-[(1S,2S)-1-(사이클로헥실메틸)-2-하이드록시-3-(2-옥소피페리디노)프로필]-α-[(R)-α-(3,3-디메틸-2-옥소부틸)-하이드로신남아미도]이미다졸-4-프로피온아미드, (S)-N-[(1S,2S)-1-(사이클로헥실메틸)-3-[(S)-α-[(R)-α-(3,3-디메틸-2-옥소부틸)하이드로 신남아미도]-N-이소프로필이미다졸-4-프로피온아미도]-2-하이드록실프로필]-α-[(R)-α-(3,3-디메틸-2-옥소부틸)-하이드로신남아미도]이미다졸-4-프로피온아미드, (S)-N-[(1S,2S)-1-(사이클로헥실메틸)-2-하이드록시-3-[[(S)-1-[-α-(3,3-디메틸-2-옥소부틸)하이드로신남아미도]-2-이미다졸-4-일-에틸-]메틸아미노-]프로필-]α-[(R)-α-(3,3-디메틸-2-옥소부틸)-하이드로신남아미도]이미다졸-4-프로피온아미드, (S)-N-[(1S,2S)-1-(사이클로헥실메틸)-2-하이드록시-3-[(S)-3-(이미다졸-4-일)-2-하이드로신남아미도-N-메틸프로피온아미도]프로필]-α-[(R)-α-(3,3-디메틸-2-옥소부틸)-하이드로신남아미도]이미다졸-4-프로피온아미드, t-부틸[(S)-α-[[(S)-1-[[(1S,2S)-3-[[(S)-1-[(S)-α-(1-t-부톡시포릉아미도)하이드로신남아미도]-2-이미다졸-4-일-에틸]메틸카바모일]-1-(사이클로헥실메틸)-2-하이드록시프로필]카바모일]-2-이미다졸-4-일-에틸]카바모일]펜에틸]카바메이트, t-부틸[(S)-α-[[(2S,3S)-3-[(S)-2-[(S)-α-(1-t-부톡시포름아미도)하이드로신남아미도]-3-이미다졸-프로피온아미도]-4-사이클로헥실-2-하이드록시부틸]메틸카바모일]펜에틸]카바메이트 및 (S)-N-[(1S,2S)-1-(사이클로헥실메틸)-2-하이드록시-3-프탈이미도프로필]-α-[(R)-α-(3,3-디메틸-2-옥소부틸)-하이드로신남아미도]이미다졸-4-프로피온아미드.
  14. 하기 일반식(Ⅱ),(Ⅲ) 및 (Ⅴ)의 화합물.
    상기식에서, B는 아미노 보호그룹, 바람직하게는 t-부톡시카보닐 또는 벤질옥시카보닐이고, R1는 수소 또는 메틸이고, R2는 에틸, 프로필, 이소프로필, 이미다졸-2-일, 이미다졸-4-일, 피라졸-3-일, 티아졸-4-일, 티엔-2-일, 에톡시카보닐, t-부틸카보닐메틸, 벤질옥시카보닐메틸 또는 t-부톡시이고, R3은 이소부틸, 사이클로헥실메틸 또는 벤질이고, R4는 니트로, 아미노 또는 일반식N(R5)(R6)인 그룹이고, R5는 알킬, 알콕시알킬 또는 임의로 치환된 페닐, 페닐알킬 또는 페닐설포닐알킬이고, R6은 알킬, 알콕시알킬, 임의로 치환된 페닐, 페닐알킬 또는 페닐설포닐알킬, 알카노일, 알콕시카보닐, 아릴알콕시카보닐, 임의로 치환된 벤즈이미다졸론일 또는 임의로 아실화된 아미노산의 잔기 또는 임의로 아실화된 디펩티드의 잔기이거나, R5와 R6은 이들이 결합한 질소원자와 함께 5원 또는 6원 헤테로사이클, 5원 또는 6원 락탐 또는 6원 이미드를 나타낸다.
  15. 치료학적 활성 물질로서 사용하기 위한 제1항 내지 제13항중 어느 한항에 따르는 아미노산 유도체.
  16. 고혈압 및 심장기능부전의 억제 또는 예방에 사용하기 위한 제1항 내지 제13항중의 어느 한항에 따르는 아미노산 유도체.
  17. a)하기 일반식(Ⅱ)의 화합물을 그룹
    및 -Y-Z(b)[여기서, R7,R8,Y,Z 및 점선은 상기에서 정의한 바와같다]를 제공하는 아실화제와 반응시키거나, b)하기 일반식(Ⅲ)의 화합물과 하기 일반식(Ⅳ)의 화합물 또는 활성화된 이의 유도체를 반응시키거나, c)Z가 수소이고, 다른 기호는 상기에서 정의한 바와 같은 일반식(Ⅰ)의 화합물과 임의로 아실화된 아미노산 또는 임의로 아실화된 디펩티드를 반응시키거나, d)A가 N-보호된 아미노 그룹을 함유하고/하거나 R4가 N-보호된 아미노 그룹이고/이거나 R2가 N-보호된 이미다졸-2-일, 이미다졸-4-일 또는 피라졸-3-일인 일반식(Ⅰ)의 화합물로부터 N-보호그룹(들)을 절단함으로써, A가 자유 아미노그룹이고/이거나 R4가 아미노 그룹이고/이거나 R2가 이미다졸-2-일, 이미다졸-4-일 또는 피라졸-3-일인 일반식(Ⅰ)의 화합물을 제조하거나, e)R4가 아미노인 일반식(Ⅰ)의 화합물과 2염기산의 무수물을 반응시킴으로써 R4가 5원 또는 6원 이미드인 일반식(Ⅰ)의 화합물을 제조하거나, f)R6이 수소이고 R5가 알킬, 알콕시알킬 또는 임의로 치환된 페닐, 페닐알킬 또는 페닐설포닐알킬인 일반식(Ⅰ)의 화합물과 R6잔기를 제공하는 아실화제를 반응시킴으로써 R5가 알킬, 알콕시알킬 또는 임의로 치환된 페닐, 페닐알킬 또는 페닐설포닐알킬이고 R6이 알킬, 알콕시알킬, 임의로 치환된 페닐, 페닐알킬 또는 페닐설포닐알킬, 알카노일, 알콕시카보닐, 아릴알콕시카보닐 또는 임의로 아실화된 아미노산의 잔기 또는 임의로 아실화된 디펩티드의 잔기인 일반식(Ⅰ)의 화합물을 제조하고, g)경우에 따라, 부분입체이성체의 라세미체의 혼합물을 부분입체이성체의 라세미체 또는 광학적으로 순수한 부분입체이성체로 분리시키고/시키거나, h)경우에 따라, 부분입체이성체의 혼합물을 광학적으로 순수한 부분입체이성체로 분리시키고/시키거나, i)경우에 따라, 수득한 화합물을 약제학적으로 허용되는 염으로 전환시킴을 포함하여 제1항 내지 제13항중의 어느 한항에 따르는 화합물을 제조하는 방법.
    상기식에서, R1, R2, R3, R4및 A는 제1항에서 정의한 바와같다.
  18. 제1항 내지 제13항중의 어느 한항에 따르는 아미노산 유도체와 치료학적으로 불활성인 부형제를 함유하는 의약품.
  19. 제1항 내지 제13항중의 어느 한항에 따르는 아미노산 유도체와 치료학적으로 불활성인 부형제를 함유하는 고혈압 및 심장기능부전의 억제 또는 예방용 의약품.
  20. 제1항 내지 제13항중의 어느 한항에 따르는 아미노산 유도체의 질병 억제 또는 예방용 용도.
  21. 제1항 내지 제13항중의 어느 한항에 다르는 아미노산 유도체의 고혈압 및 심장기능부전의 억제 또는 예방용 용도.
  22. 제1항 내지 제13항중의 어느 한항에 따르는 아미노산 유도체의 고혈압 및/또는 심장기능부전에 대한 의약품 제조용 용도.
  23. 제17항에서 청구한 방법 또는 이의 명백한 화학적 등가물에 의해 제조된 제1항 내지 제13항중의 어느 한항에 따르는 아미노산 유도체.
  24. 상술한 방법.
  25. 치료를 요하는 환자에게 유효량의 제1항 내지 제13항중의 어느 한항에 따르는 아미노산 유도체를 투여함을 포함함을 특징으로 하여 고혈압 및/또는 심장기능부전을 치료 또는 예방하는 방법.
    ※ 참고사항 : 최초출원 내용에 의하여 공개하는 것임.
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IL93845A0 (en) 1990-12-23
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AU634526B2 (en) 1993-02-25
CA2012306A1 (en) 1990-09-28
PT93573A (pt) 1990-11-07
US5278148A (en) 1994-01-11
YU58190A (en) 1992-05-28
JPH02289540A (ja) 1990-11-29
NO901399L (no) 1990-10-01
HUT53662A (en) 1990-11-28
EP0389898A2 (de) 1990-10-03
NO901399D0 (no) 1990-03-27
FI901490A0 (fi) 1990-03-26
AU5218890A (en) 1990-10-04
HU901802D0 (en) 1990-07-28

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