KR960703124A - Pde-iv 억제활성을 갖는 신규한 화학적 화합물 - Google Patents

Pde-iv 억제활성을 갖는 신규한 화학적 화합물 Download PDF

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KR960703124A
KR960703124A KR1019950705789A KR19950705789A KR960703124A KR 960703124 A KR960703124 A KR 960703124A KR 1019950705789 A KR1019950705789 A KR 1019950705789A KR 19950705789 A KR19950705789 A KR 19950705789A KR 960703124 A KR960703124 A KR 960703124A
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purine
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cyclopropyl
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ethylamino
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카발라 데이비드
호퍼 피터
게릭 안드레
윈터게스트 피터
체신 마크
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마틴 그리네
유로셀티크, 에스. 에이.
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Abstract

본 발명은 퓨린 유도체 및 그의 이소구아닌 및 디티오크산틴 전구체 화합물에 관계한다. 이들 화합물들은 기관지 및 기관 이완 및/또는 항염증 활성을 갖는다. 본 발명은 또한 이들의 제조방법, 이들을 포함하는 약제 조성물, 및 이들의 의학적 용도에 관계한다. 특정한 바람직한 실시예에 있어서, 본 발명은 3-치환 및 3,8-비치환 6-아미노 퓨린 유도체들에 관계한다.

Description

PDE-IV 억제활성을 갖는 신규한 화학적 화합물
본 내용은 요부공개 건이므로 전문내용을 수록하지 않았음

Claims (57)

  1. 하기 식(I)의 화합물:
    상기 식에서, R3, R6및 R8은 동일하거나 서로 상이하고, 각각 H 또는 분지상 는 비분지상이며 치환되지 않았거나 OH, 알콕시, CO2H, =NOH, -NOCONH2또는 =O로 치환된 C1-8의 알킬기; 치환되지 않았거나 OH, 알콕시, CO2H, =NOH, -NOCONH2또는 =O로 치환된 C3-8의 시클로알킬기; 시클로알킬 부분이 치환되지 않았거나 OH, 알콕시, CO2H, =NOH, -NOCONH2또는 =O로 치환된 C4-8의 시클로알킬알킬기; 치환되지 않았거나 Cl, NH2, 알킬아미노, 디알킬아미노, 아미도, C1-C8의 알킬아미도 및 C1-C3디알킬아미도, OH, 알콕시, C=NOH, C=NOCONH2, C1-C3알킬, 페닐 또는 벤질로 치환된 아릴; 아르알킬(C1-4), 헤테로시클일; 헤테로시클일알킬 (C1-C4); 및 헤테로아릴을 나타내고; R6a는 H 또는 R6a를 나타내고, 또는 R6b, N 및 R6a는 함께 1 내지 3개의 질소원자, 0 내지 두 개의 산소원자, 0 내지 두 개의 황원자를 포함하고 알콕시, CO2H, CONH2, =NOH, =NOCONH2또는 =O를 포함하는 C3-8고리를 형성하며; 그리고 아릴이 페닐 또는 나프틸인 경우에 헤테로시클일은 1 내지 3개의 질소원자, 0 내지 두 개의 산소원자, 0 내지 두 개의 황원자를 포함하는 5, 6 또는 7원고리이고 아릴에서와 같이 고리사의 탄소원자 또는 질소원자가 치환될 수 있고; 또는 R3이 벤질기이고, R6a는 메틸 또는 이소프로필기이며 R6b는 수소원자이거나 또는 R3, R6a및 R6b는 모두 메틸기이며 R8은 수소원자 이외의 것인 경우에 그의 제약학상 허용되는 염.
  2. 제1항에 있어서, 상기 R3은 C1-8알킬, C3-7시클로알킬, C4-8시클로알킬알킬, 아릴 또는 아르(C1-4)알킬기를 나타내고; R6a는 C1-8알킬, C3-7시클로알킬, C4-8시클로알킬알킬, 아릴 아르(C1-4)알킬기, 또는 헤테로시클일(C1-4)알킬기를 나타내며; R6b는 수소원자 또는 C1-8알킬, C3-7시클로알킬, C4-8시클로알킬알킬, 아릴 또는 아르(C1-4) 알킬기를 나타내거나; 또는 -NR6aR6b는 함께 선택적으로 하나 이상의 추가의 헤테로 원자를 포함하는 5-원 또는 6-원 고리를 형성하며; 그리고 R8은 수소원자 또는 C1-8알킬, C3-7시클로알킬, C4-8시클로알킬알킬, 아릴, 아르(C1-4)알킬, 피리딜 또는 피리딜(C1-4)알킬기인 화합물.
  3. 제2항에 있어서, 상기 R3이 C1-8알킬기, 아르(C1-4)알킬기 또는 C3-7시클로알킬기인 화합물.
  4. 제2항에 있어서, 상기 R6a가 C1-8알킬기이고, R6b는 수소원자인 화합물.
  5. 제2항에 있어서, 상기 R8이 수소원자인 화합물.
  6. 제2항에 있어서, 상기 R8이 C3-7시클로알킬기인 화합물.
  7. 제5항에 있어서, 상기 R8이 시클로프로필기인 화합물.
  8. 제2항에 있어서, 상기 R8이 C1-8알킬기인 화합물.
  9. 제7항에 있어서, 상기 R8이 이소프로필기인 화합물.
  10. 제1항에 있어서, 상기 화합물이 6-에틸아미노-3-헥실-3H-퓨린; 3-헥실-6-메틸아미노-3H-퓨린; 3-벤질-6-메틸아미노-3H-퓨린; 8-시클로프로필-6-에틸아미노-3-(3-메틸 부틸)-3H-퓨린; 8-시클로프로필-3-에틸-6-프로필아미노-3H-퓨린; 8-시클로프로필-3-에틸-6-메틸아미노-3H-퓨린; 3-부틸-6-에틸아미노-3H-퓨린; 3-부틸-8-시클로프로필-6-에틸아미노-3H-퓨린; 6-에틸아미노-3-프로필-3H-퓨린; 8-시클로프로필-6-에틸아미노-3-프로필-3H-퓨린; 8-시클로프로필-3-시클로프로필메틸-6-에틸아미노-3H-퓨린; 3-벤질-6에틸아미노-3H-퓨린; 8-시클로프로필-6-시클로프로필아미노-3-프로필-3H-퓨린; 3-((2-메틸)부틸)-6-(2-피페라진-1-일)에틸아미노)-3H-퓨린; 3-시클로헥실메틸-6-에틸아미노-3H-퓨린; 3-((2-메틸)부틸)-6-(2-피페라진-1-일)에틸아미노)-3H-퓨린; 3-시클로헥실메틸-6-에틸아미노-3H-퓨린; 3-벤질-6-에틸아미노-8-(1-메틸에텔)-3H-퓨린; 3-시클로헥실메틸-8-시클로프로필-6-에틸아미노-3H-퓨린; 3-시클로프로필메틸-8-이소프로필-6-에틸아미노-3H-퓨린; 3-에틸-8-이소프로필-6-에틸아미노-3H-퓨린; 3-에틸-8-시클로펜틸-6-벤질아미노-3H-퓨린; 3-에틸-8-이소프로필-6-벤질아미노-3H-퓨린; 3-에틸-8-시클로펜틸-6-에틸아미노-3H-퓨린; 3-(4-클로로벤질)-6-에틸아미노-3H-퓨린; 3-(4-클로로벤질)-6-에틸아미노-8-이소프로필-3H-퓨린; 6-벤질아미노-8-시클로프로필-3-프로필-3H-퓨린; 8-시클로프로필-6-헥실아미노-3-프로-3H-퓨린; 8-시클로프로필-3-프로필-6-(4-피리딜메틸아미노)-3H-퓨린; 6-시클로펜틸-8-시클로프로필-3-프로필-3H-퓨린; 6-부틸아미노-8-시클로프로필-3-프로필-3H-퓨린; 8-시클로프로필-6-(2-히드록시에틸아미노)-3-프로필-3H-퓨린; 6-(3-시클로펜틸옥시-4-메톡시벤질아미노)-8-시클로프로필-3-프로필-3H 퓨린; 6-아미노-8-시클로프로필-3-프로필-3H-퓨린; 3-에틸-6-시클로펜틸아미노-8-이소프로필-3H-퓨린; 6-아미노-8-시클로프로필-3-프로필-3H-퓨린; 3-에틸-6-시클로펜틸아미노-8-이소프로필-3H-퓨린; 6-시클로헥실아미노-8-이소프로필-3-프로필-3H-퓨린; 6-시클로펜틸아미노-8-이소프로필-3-프로필-3H-퓨린; 3-에틸-6-시클로펜틸아미노-8-시클로프로필-3H-퓨린; 3-(4-클로로벤질)-6-시클로펜틸아미노-8-시클로프로필-3H-퓨린; 6-시클로펜틸아미노-3-(3-시클로펜틸옥시-4-메톡시벤질)-8-이소프로필-3H-퓨린; 3-(2-클로로벤질)-6-시클로펜틸아미노-8-이소프로필-3H-퓨린; 8-시클로프로필-6-디에틸아미노-3-프로필-3H-퓨린 히드로클로리드; 8-시클로프로필-6-(3-펜틸아미노)-3-프로필-3H-퓨린 히드로클로리드; 6-에틸아미노-8-이소프로필-3-(4-피리딜메틸)-3H-퓨린; 3-에틸-8-이소프로필-6-에틸아미노-3H-퓨린; 3-에틸-8-시클로펜틸-6-벤질아미노-3H-퓨린; 3-에틸-8-시클로펜틸-6-에틸아미노-3H-퓨린; 3-시클로헥실메틸-6-에틸아미노-3H-퓨린; 3-시클로헥실메틸-8-시클로프로필-6-에틸아미노-3H-퓨린; 3-시클로프로필-6-에틸아미노-3-(3-메틸부틸)-3H-퓨린; 3-시클로프로필-3-에틸-6-프로필아미노-3H-퓨린; 8-시클로프로필-3-시클로프로필메틸-6-에틸아미노-3H-퓨린; 3-헥실-6-메틸아미노-3H-퓨린; 3-벤질-6-메틸아미노-3H-퓨린; 3-시클로프로필메틸-8-이소프로필-6-에틸아미노-3H-퓨린; 3-에틸-8-시클로프로필-6-에틸아미노-3H-퓨린; 8-시클로프로필-6-에틸아미노-3-프로필-3H-퓨린; 8-시클로프로필-6-시클로프로필아미노-3-프로필-3H-퓨린; 3-(3-시클로펜틸옥시-4-메톡시벤질)-6-에틸아미노-8-이소프로필-3H-퓨린; 3-(4-클로로벤질)-6-에틸아미노-3H-퓨린; 및 3-에틸-6-에틸아미노-8-((3-시클로펜틸옥시-4-메톡시)벤질)-3H-퓨린으로 구성되는 군으로부터 선택되는 화합물.
  11. 제1항에 있어서, 상기 화합물이 3-(3-시클로펜틱옥시-4-메톡시벤질)-6-에틸아미노-3H-퓨린; 3-(4-클로로벤질)-6-에틸아미노-8-이소프로필-3H-퓨린; 3-(3-시클로펜틸옥시-4-메톡시벤질)-6-에틸아미노-8-이소프로필-3H-퓨린; 6-시클로펜틸-8-시클로프로필-3-프로필-3H-퓨린 및 이들의 제약학상 허용되는 염으로 구성되는 군으로부터 선택되는 화합물.
  12. 제3항에 있어서, 상기 R3이 C1-3알킬기인 화합물.
  13. 제2항에 있어서, 상기 R6a가 메틸기 또는 에틸기이고, R6b는 수소원자인 화합물.
  14. 제2항에 있어서, 상기 R3이 프로필기인 화합물.
  15. 제2항에 있어서, 상기 R3이 치환 또는 비치환 벤질인 화합물.
  16. 제2항에 있어서, 상기 R3이 시클로프로필메틸인 화합물.
  17. 하기 식(II)의 화합물.
    상기 식에서, R2는 O 또는 S이고; R3, R6a및 R8은 동일하거나 서로 상이하고, 각각 H 또는 분지상 또는 비분지상이며 치환되지 않았거나 OH, 알콕시, CO2H, =NOH, -NOCONH2또는 =O로 치환되는 C1-8의 알킬기; 치환되지 않았거나 OH, 알콕시, CO2H, =NOH, -NOCONH2또는 =O로 치환된 C3-8의 시클로알킬기; 시클로알킬 부분이 치환되지 않았거나 OH, 알콕시, CO2H, =NOH, -NOCONH2또는 =O로 치환된 C4-8의 시클로알킬알킬기; 치환되지 않았거나 Cl, NH2, 알킬아미노, 디알킬아미노, 아미도, C1-C8알킬아미도 및 C1-C3디알킬아미도, OH, 알콕시, C=NOH, C=NOCONH2, C1-C3알킬, 페닐 또는 벤질로 치환된 아릴; 아르알킬(C1-4), 헤테로시클일, 헤테로이클일알킬 (C1-C4); 및 헤테로아릴을 나타내고; R6b는 H 또는 R6a를 나타내거나, 또는 R6b, N 및 R6a는 함께 1 내지 3개의 질소원자, 0 내지 두 개의 산소원자, 0 내지 두 개의 황원자, 알콕시, CO2H, CONH2, =NOH, =NOCONH2또는 =O를 포함하는 C3-C8고리를 형성하며; 그리고 아릴이 페닐 또는 나프틸인 경우에 헤테로시클일을 1 내지 3개의 질소원자, 0 내지 두 개의 산소원자, 0 내지 두 개의 황원자를 포함하는 5, 6 또는 7원고리이고 아릴에서와 같이 고리상의 탄소원자 또는 질소원자가 치환될 수 있고; 또는 R3이 벤질기이고, R6a는 메틸 또는 이소프로필기이며 R6b는 수소원자이거나 또는 R3, R6a및 R6b는 메틸기이며 R8은 수소원자 이외의 것인 경우에 그의 제약학상 허용되는 염.
  18. 제17항에 있어서, 상기 R3은 C1-8알킬, C3-7시클로알킬, C4-8시클로알킬알킬, 아릴 또는 아르(C1-4)알킬기를 나타내고; R6a는 C1-8알킬, C3-7시클로알킬, C4-8시클로알킬알킬, 아릴 아르 (C1-4)알킬기, 또는 헤테로시클일(C1-4) 알킬기를 나타내며; R6b는 수소원자 또는 C1-8알킬, C3-7시클로알킬, C4-8시클로알킬알킬, 아릴 또는 아르(C1-4)알킬기를 나타내거나; 또는 -NR6aR6b는 함께 선택적으로 하나 이상의 추가의 헤테로 원자를 포함하는 5-원 또는 6-원 고리를 형성하며; 그리고 R8은 수소원자 또는 C1-8알킬, C3-7시클로알킬, C4-8시클로알킬알킬, 아릴, 아르(C1-4)알킬, 피리딜 또는 피리딜(C1-4)알킬기인 화합물.
  19. 제18항에 있어서, 상기 R3이 C1-8알킬기, 아르(C1-4)알킬기 또는 C3-7시클로알킬기인 화합물.
  20. 제18항에 있어서, 상기 R6a가 C1-8알킬기이고, R6b는 수소원자인 화합물.
  21. 제18항에 있어서, 상기 R8이 수소원자인 화합물.
  22. 제18항에 있어서, 상기 R8이 C3-7시클로알킬기인 화합물.
  23. 제22항에 있어서, 상기 R8이 시클로프로필기인 화합물.
  24. 제18항에 있어서, 상기 R8이 C1-8알킬기인 화합물.
  25. 제18항에 있어서, 상기 R8이 이소프로필기인 화합물.
  26. 제19항에 있어서, 상기 R3이 C1-4알킬기인 화합물.
  27. 제18항에 있어서, 상기 R6a가 메틸기 또는 에틸기이고, R6b는 수소원자인 화합물.
  28. 제18항에 있어서, 상기 R3이 프로필기인 화합물.
  29. 제18항에 있어서, 상기 R3이 치환 또는 비치환 벤질인 화합물.
  30. 제18항에 있어서, 상기 R3이 시클로프로필메틸인 화합물.
  31. 제17항에 있어서, 상기 화합물이 8-시클로프로필-3,7-디히드로-6-(4-피리딜메틸아미노)-2-티오-2H-퓨린-2-원; 6-시클로펜틸아미노-8-시클로프로필-3,7-디히드로-3-프로필-2-티오-2H-퓨린-2원; 8-시클로프로필-3,7-디히드로-6-(2-히드록시에틸아미노)-2티오-2H-퓨린-2-원; 및 그들의 제약학상 허용되는 염으로 구성되는 군으로부터 선택되는 화합물.
  32. 하기 식(III)의 화합물:
    상기 식에서, R3및 R8은 동일하거나 서로 상이하고, 각각 H 또는 분지상 또는 비분지상이며 치환되지 않았거나 OH, 알콕시, CO2H, =NOH, -NOCONH2또는 =O로 치환된 C1-8의 알킬기; 치환되지 않았거나 OH, 알콕시, CO2H, =NOH, -NOCONH2또는 =O로 치환된 C3-8의 시클로알킬기; 시클로알킬 부분이 치환되지 않았거나 OH, 알콕시 CO2H, =NOH, -NOCONH2또는 =O로 치환된 C4-8의 시클로알킬알킬기; 치환되지 않았거나 Cl, NH2, 알킬아미노, 디알킬아미노, 아미도, C1-C8알킬아미도 및 C1-C3디알킬아미도, OH, 알콕시, C-NOH, C=NOCONH2, C1-C3알킬, 페닐 또는 벤질로 치환된 아릴; 아르알킬(C1-4), 헤테로시클일; 헤테로시클일알킬 (C1-C4); 및 헤테로아릴을 나타낸다.
  33. 제32항에 있어서, 상기 R3은 C1-8알킬, C3-7시클로알킬, C4-8시클로알킬알킬, 아릴 또는 아르(C1-4)알킬기를 나타내고; R8은 수소원자 또는 C1-8알킬, C3-7시클로알킬, C4-8시클로알킬알킬, 아릴, 아르(C1-4)알킬, 피리딜 또는 피리딜(C1-4)알킬기인 화합물.
  34. 제32항에 있어서, 상기 R3이 C1-8알킬기, 아르(C1-4)알킬기 또는 C3-7시클로알킬기인 화합물.
  35. 제32항에 있어서, R3이 수소원자인 화합물.
  36. 제32항에 있어서, 상기 R8이 C3-7시클로알킬기인 화합물.
  37. 제32항에 있어서, 상기 R8이 시클로프로필기인 화합물.
  38. 제32항에 있어서, 상기 R8이 C1-8알킬기인 화합물.
  39. 제32항에 있어서, 상기 R8이 이소프로필기인 화합물.
  40. 제32항에 있어서, 상기 R3이 C1-4알킬기인 화합물.
  41. 제32항에 있어서, 상기 R3이 프로필기인 화합물.
  42. 제32항에 있어서, 상기 R3이 치환 또는 비치환 벤질인 화합물.
  43. 제32항에 있어서, 상기 R3이 시클로프로필메틸인 화합물.
  44. 제32항에 있어서, 상기 화합물이 3-벤질-3,7-디히드로-8-(1-메틸에틸)-2,6-디티오-1H-퓨린-2,6-디원; 3-시클로헥실메틸-8-시클로프로필-3,7-디히드로-2,6-디티오-1H-퓨린-2,6-디원;3-(4-클로로벤질)-8-이소프로필-3,7-디히드로-2,6-디티오-3,7-퓨린-2,6-디원; 8-시클로프로필-3-시클로프로필메틸-3,7-디히드로-2,6-디티오-1H-퓨린-2,6-디원; 3-(3-시클로펜틱옥시-4-메톡시벤질)-3,7-디히드로-8-이소프로필-2,6-디티오-1H-퓨린-2,6-디원; 8-시클로프로필-3,7-디히드로-1,3-디에틸-2,6-디티오-1H-퓨린-2,6-디원; 및 그들이 제약학상 허용되는 염으로 구성되는 군으로부터 선택되는 화합물.
  45. 유효량의 제1항 내지 제44항에 따른 화합물을 투여하는 과정을 포함하는 선택적인 PDE IV 억제를 필요로 하는 환자에 있어서 선택적인 PDE IV 억제를 달성하는 방법.
  46. 제1항 내지 제44항에 기술된 화학적 구조를 갖는 화합물을 포함하는 약제 조성물.
  47. 유효량의 제1항 내지 제44항에 따른 화합물을 투여하는 과정을 포함하는 천식, 알러지, 염증, 우울증, 아토피성 질병, 비염, 치매 및 시토킨의 비정상적으로 높은 생리적 농도와 관련된 질병상태로 구성되는 군으로부터 선택되는 질병상태로 고통을 받는 포유동물을 치료하는 방법.
  48. 적합한 반응매질의 존재 또는 부재하에서 약 0℃부터 약 100℃사이의 온도에서 하기 식(IV)의 화합물을
    식(V)의 화합물과 반응시키는 과정을 포함하는 식(I)의 화합물의 제조방법:
  49. 제48항에 있어서, 상기 반응을 위한 용매가 물, 알콜, 탄화수소 및 할로겐화 탄화수소로 구성되는 군으로부터 선택되는 방법.
  50. 제48항에 있어서, 상기 식(II)의 화합물이 대응하는 6-옥소-화합물의 가황에 의해 제조되는 방법.
  51. 제50항에 있어서, 상기 가황이 피리딘내의 6-옥소 화합물의 현탁액을 몰초추과량의 오황화인으로 처리함으로써 수행되는 방법.
  52. 적당한 환원제를 이용하여 하기 식(II)의 화합물을 환원시키는 과정을 포함하는 식(I)의 화합물의 제조 방법:
  53. 제52항에 있어서, 상기 환원이 촉매에 의해 이루어지는 방법.
  54. 제52항에 있어서, 상기 환원이 알콜, 탄화수소 또는 물로부터 선택된 적합한 용매내에서 수행되는 방법.
  55. 제52항에 있어서, 상기 환원이 염기의 존재하에서 액체 암모니아 또는 히드라진내의 알칼리 금속을 이요하여 달성되는 방법.
  56. 제52항에 있어서, 상기 식(II)의 화합물이 제46항의 방법에 따라 아민 R6aR6bNH와 반응시킴으로써 하기 식(III)의 화합물의 대응하는 2,6-디티오크산틴 유도체들로부터 제조되는 방법:
  57. 제52항에 있어서, 상기 식(III)의 화합물이 가황에 의해 대응하는 2-디오크산틴 유도체로부터 제조되는 방법.
    ※ 참고사항 : 최초출원 내용에 의하여 공개하는 것임.
KR1019950705789A 1993-06-22 1994-06-21 Pde-iv억제활성을갖는신규한화학적화합물 KR100349239B1 (ko)

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HUT74176A (en) 1996-11-28
BG100258A (bg) 1996-11-29
EP0916673A1 (en) 1999-05-19
AU6977194A (en) 1995-01-17
CN1045778C (zh) 1999-10-20
CA2165433A1 (en) 1994-12-23
CA2165433C (en) 2002-05-28
DE69432087D1 (de) 2003-03-06
ATE182593T1 (de) 1999-08-15
NO955219L (no) 1996-02-22
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KR100349239B1 (ko) 2003-01-24
EP0916673B1 (en) 2003-01-29
US5939422A (en) 1999-08-17
PL312225A1 (en) 1996-04-01
FI956168A (fi) 1996-02-01
JP3350550B2 (ja) 2002-11-25
ATE231863T1 (de) 2003-02-15
EP0705265B1 (en) 1999-07-28
ZA944463B (en) 1995-02-17
HU9503545D0 (en) 1996-02-28
CZ342595A3 (en) 1996-08-14
DE69419755D1 (de) 1999-09-02
DE69432087T2 (de) 2003-11-06
WO1995000516A1 (en) 1995-01-05
AU683270B2 (en) 1997-11-06
TW418208B (en) 2001-01-11
FI956168A0 (fi) 1995-12-21
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GB9312853D0 (en) 1993-08-04
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