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KR970705983A - 나프틸 화합물, 그의 중간체, 제조방법, 조성물 및 사용방법(naphthylcompounds, intermediates, processes, compo sitions, and methods) - Google Patents

나프틸 화합물, 그의 중간체, 제조방법, 조성물 및 사용방법(naphthylcompounds, intermediates, processes, compo sitions, and methods)

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KR970705983A
KR970705983A KR1019970701827A KR19970701827A KR970705983A KR 970705983 A KR970705983 A KR 970705983A KR 1019970701827 A KR1019970701827 A KR 1019970701827A KR 19970701827 A KR19970701827 A KR 19970701827A KR 970705983 A KR970705983 A KR 970705983A
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compound
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헨리 울만 브리안트
조지 죠셉 쿨리난
제프리 알란 도지
케난 죠셉 파헤이
찰스 데이비드 존스
찰스 윌리스 3세 루가
브라이언 스티븐 뮤엘
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피터 쥐. 스트링거
일라이 릴리 앤드 캄파니
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Abstract

본 발명은 골다공증, 과지질혈증 및 에스트로겐-의존성 암을 포함하는 폐경후 증후군의 증상을 경감시키고 또한 자궁 섬유종 질환, 자궁내막증 및 대동맥 평활근 세포 증식을 억제하는데 유용한 특정 신규의 나프틸 및 디하이드로 화합물을 제공한다. 이들 화합물을 재조하는 방법도 제공한다.

Description

나프틸화합물, 그의중간체, 제조방법, 조성물 및 사용방법 (NAPHTHYLCOMPOUNDS, INTERMEDIATES, PROCESSES, COMPO SITIONS, ANDMETHODS)
본 내용은 요부공개 건이므로 전문내용을 수록하지 않았음

Claims (46)

  1. 하기 일반식(I)의 화합물 또는 그의 약학적으로 허용가능한 염:
    상기 식에서, R1은 -H, -OH,-O(C1-C4알킬),-OCOC6H5,-OCO(C1-C6알킬) 또는 -OSO2(C4-C6알킬)이고; R2은 -H, -OH, -O(C1-C4알킬), -OCOC6H5, -OCO(C1-C6알킬) 또는 -OSO2(C4-C6알킬)이고; n은 2또는 3이며; R3은 1- 피페리디닐, 1-피롤리디닐, 메틸-1-피롤리디닐, 디메틸-1-피롤리디닐, 4-모폴리노, 디메틸아미노, 디에틸아미노 또는 1-헥사메틸렌이미노이다.
  2. 제1항에 있어서, n은 2인 화합물 또는 그의 약학적으로 혀용가능한 염.
  3. 제2항에 있어서, R3이 1-피페리디닐인 화합물 또는 그의 약학적으로 혀용가능한 염.
  4. 제3항에 있어서, R1및 R2가 각각 -OH인 화합물 또는 그의 약학적으로 허용가능한 염.
  5. 제3항에 있어서, R1및 R2가 각각 -OCH3인 화합물 또는 그의 약학적으로 허용가능한 염.
  6. 제3항에 있어서, R1및 R2가 각각 -OSO2(C4-C6알킬)인 화합물 또는 그의 약학적으로 혀용가능한 염.
  7. 제6항에 있어서, R1및 R2가 각각 -OSO2(CH2)4CH3인 화합물 또는 그의 약학적으로 허용가능한 염.
  8. 제1항 내지 제7항 중 어느 한 항에 있어서, 상기 염이 염산염인 화합물.
  9. 하기 일반식(IV)의 혼합물 또는 그의 약학적으로 허용가능한 염;
    상기 식에서, R1a는 -H, -OH 또는 -O(C1-C4알킬)이고; R2a는 -H, -OH 또는 -O(C1-C4알킬)이고; R3은 1- 피페리디닐, 1-피롤리디닐, 디메틸아미노, 디에틸아미노 또는 1-헥사메틸렌이미노이고; n은 2또는 3이다.
  10. 제9항에 있어서, R3은 1- 피페리디닐이고 n인 2인 화합물 또는 그의 약학적으로 허용가능한 염.
  11. 제10항에 있어서, R1a및 R2a가 각각 -O(C1-C4알킬)인 화합물 또는 그의 약학적으로 허용가능한 염.
  12. 제11항에 있어서, R1a및 R2a가 각각 -OCH3인 화합물 또는 그의 약학적으로 허용가능한 염.
  13. 제10항에 있어서, R1a및 R2a가 각각 -OH 인 화합물 또는 그의 약학적으로 허용가능한 염
  14. 제9항 내지 제13항 중 어느 한 항에 있어서, 상기 염이 염산염인 화합물.
  15. 약학적으로 허용가능한 담체, 희석제 또는 부형제와 함께, 제1항 내지 제7항 중 어느 한 항에 따른 화합물 또는 그의 약학적으로 허용가능한 염, 및 임의적으로 유효량의 에스트로겐 또는 프로게스틴을 포함하는 약학 조성물.
  16. 제15항에 있어서, 상기 염이 염산염인 약학 조성물.
  17. 약학적으로 허용가능한 담체, 희석제 또는 부형제와 함께, 제9항 내지 제13항 중 어느 한 항에 따른 화합물 또는 그의 약학적으로 혀용가능한 염, 및 임의적으로는 유효쟝의 에스트로겐 또는 프로게스틴을 포함하는 약학 조성물.
  18. 제17항에 있어서, 상기 염이 염산염인 약학 조성물.
  19. 폐경후 증후군의 치료가 필요한 여성에게 제 1항 내지 제7항 중 어느 한 항에 따른 화합물 또는 그의 약학적으로 혀용가능한 염 유효량을 투여하는 것을 포함하는, 폐경후 증후군의 증상을 경감시키는 방법.
  20. 제19항에 있어서, 폐경후 증후군의 병리학적 상태가 골다공증인 방법.
  21. 제19항에 있어서, 폐경후 증후군의 병리학적 상태가 심혈관 질환과 과련된 방법.
  22. 제21항에 있어서, 상기 심혈관 질환이 과지질현증인 방법.
  23. 제19항에 있어서, 상기 페경후 증후군의 병리학적 상태가 에스트로겐-의존성 암인 방법.
  24. 제23항에 있어서, 상기 에스트로겐-의존성 암이 유방암 또는 자궁암인 방법.
  25. 자궁 섬유종 질환의 치료가 필요한 여성에게 제1항 내지 제7항 중 어느 한 항에 따른 화합물 또는 그의 약학적으로 혀용가능한 염 유효량을 투여하는 것을 포함하는, 자궁 섬유종 질환의 억제 방법.
  26. 자궁내막증의 치료가 필요한 여성에게 제1항 내지 제7항 중 어느 한 항에 따른 화합물 또는 그의 약학적으로 혀용가능한 염 유효량을 투여하는 것을 포함하는, 자궁내막증의 억제 방법.
  27. 대동맥 평활근 세포 증식의 억제가 필요한 여성에게 제1항 내지 제7항 중 어느 한 항에 따른 화합물 또는 그의 약학적으로 허용가능한 염 유효량을 투여하는 것을 포함하는, 대동맥 평활근 세포 증식의 억제 방법.
  28. 재발협착증의 치료가 필요한 여성에게 제1항 내지 제7항 중 어느 한항에 따른 화합물 또는 그의 약학적으로 허용가능한 염 유효량을 투여하는 것을 포함하는, 재발협착증의 억제 방법.
  29. 제19항의 방법을 포함하고, 폐경후 증후군의 치료가 필요한 여성에게 유효량의 에스트로겐을 투여하는 것을 추가로 포함하는, 폐경후 증후군의 증상을 경감시키는 방법.
  30. 제19항의 방법을 포함하고, 폐경후 증후군의 치료가 필요한 여성에게 유효량의 프로게스틴을 투여하는것을 추가로 포함하는, 폐경후 증후군의 증상을 경감시키는 방법.
  31. 제19항 내지 제30항 중 어느 한 항에 있어서, 상기 염이 염상염인 방법.
  32. 폐경후 증후군의 증상, 특히 골다공증, 과지질혈증을 포함하는 심혈과 질환, 및 유방암 및 자궁암을 포함하는 에스트로겐-의존성 암을 경감시키는 약제로 사용하기 위한, 임의적으로는 에스트로겐 또는 프로게스틴과 함께 제1항 내지 제7항 중 어느 한 항에 따른 화합물 또는 그의 약학적으로 허용가능한 염.
  33. 제 32항에 있어서, 상기 염이 염산염인 화합물.
  34. 자궁 섬유종 질환, 자궁내막증, 대동맥 평활근 세포증식 및 재발협착증을 억제하는 약제로서 사용하기위한, 임의적으로는 에스트로겐 또는 프로게스틴과 함께 제1항 내지 제7항 중 어느 한 항에 따른 화합물 또는 그의 약학적으로 허용가능한 염.
  35. 제34항에 있어서, 상기 염이 염산염인 화합물.
  36. a) 약 150℃ 내지 약 200℃ 범위의 비점을 갖는 용매의 존재하에 하기 일반식(Ⅲd)의 화합물을 환원제와 반응시키고, 그 혼합물을 환류할 때까지 가열하며; b) R1b및/또는 R2b가 -O(C1-C4알킬)인 경우에는, 임의적으로 R1b및/또는 R2b하이드록시 보호기를 제거하고; 또한 c) 임의적으로는 단계 a)또는 b)로부터의 반응생성물의 염을 생성시키는 것을 포함하는, 하기 일반식 (Ia)의 화합물 또는 그의 약학적으로 허용가능한 염을 제조하는 방법:
    상기 식에서, R1a는 -H, -OH 또는 -O(C1-C4알킬)이고; R2a-H, OH 또는 -O(C1-C4알킬)이고; R3은 1-피페리디디닐, 1-피롤리디닐, 디메틸아미노, 디에틸아미노 또는 1-헥사메틸렌이미노이고;n은 2또는 3이며; R1b는 -H 또는 -O(C1-C4알킬)이며; R2b는 -H 또는-O(C1-C4알킬)이다.
  37. 제36항에 있어서, 하나의 동일한 용기에서 수행하는 방법.
  38. 제37항에 있어서, 상기 일반식(Ia)의 화합물이, R1a및 R2a가 각각 메톡시이고, R3이 1-피페리디닐이며, n이 2인 화합물 또는 그의 약학적으로 허용가능한 염인 방법.
  39. 제38항에 있어서, 상기 일반식(Ia)의 화합물의 염이 염산염인 방법.
  40. 제39항에 있어서, 상기 환원제가 수소화알루미늄리튬인 방법.
  41. 제40항에 있어서, 약 150℃ 내지 약 200℃범위의 비점을 갖는 상기 용매가 n-프로필벤젠인 방법.
  42. a) 하기 일반식 (Ⅲd)의 화합물을 환원제와 반응시키고; b) R1b및/또는 R2b가 -O(C1-C4알킬)인 경우에는, 임의적으로 R1b및/또는 R2b하이드록시 보호기를 제거하고; c) R1및 R2가 -OH인 경우에는, 임의적으로 상기 하이드록시기를 구조식 -O(C1-C4알킬), -COC6H5, -OCO(C1-C6알킬)또는 -OSO2(C4-C6알킬)의 치환기로 치환하며; 또한 d)임의적으로는 단계 a),b) 또는 c)로부터의 반응생성물의 염을 생성시키는 것을 포함하는, 하기 일반식(I)의 화합물 또는 그의 약학적으로 허용가능함 염을 제조하는 방법;
    상기 식에서, R1은 -H, -OH, -O(C1-C4알킬), -OCOC6H5, -OCO(C1-C6알킬) 또는 -OSO2(C4-C6알킬)이고; R2은 -H, -OH, -O(C1-C4알킬), -OCOC6H5, -OCO(C1-C6알킬) 또는 -OSO2(C4-C6알킬)이고; R3은 1피페리디닐, 1-피롤리디닐, 메틸-1-피롤리디닐, 디메틸-1-피롤리디닐, 4-모폴리노, 디메틸아미노, 디에틸아미노 또는 1-헥사메틸렌이미노이며; M은 -CH(OH)- 또는 -CH2-이고; n은 2또는 3이고; R1b는 -H 또는 -O(C1-C4알킬)이고; R2b는 -H 또는 -O(C1-C4알킬)이다.
  43. 제42항에 있어서, 상기 반응 생성물이, R1및 R2가 각각 -OH이고, R3이 1-피페리디닐이고, M이 -CH2-이며, n이 2인 일반식(I)의 화합물 또는 그의 약학적으로 허용가능한 염인 방법.
  44. 제42항 또는 제43항에 있어서, 상기 일반식(I)의 화합물의 염이 염산염인 방법.
  45. 임의의 실시예를 참조하며 실질적으로 명세서에 기술한 바와 같이, 하기 일반식(I)의 화합물 또는 그의 약학적으로 허용가능한 염을 제조하는 방법:
    상기 식에서, R1은 -H, -OH, -O(C1-C4알킬), -OCOC6H5, -OCO(C1-C6알킬) 또는 -OSO2(C4-C6알킬)이고; R2는 -H, -OH, -O(C1-C4알킬), -OCOC6H5, -OCO(C1-C6알킬) 또는 -OSO2(C4-C6알킬)이고; M은 -CH(OH)- 또는 -CH2-이고; n은 2또는 3이고; R3은 1-피페리디닐, 1-피롤리디닐, 메틸-1-피롤리디닐, 디메틸-1-피롤리디닐, 4-모폴리노, 디메틸아미노, 디에틸아미노 또는 1-헥사메틸렌이미노이다.
  46. 임의의 실시예를 참조하여 실질적으로 명세서에 기재한 바와 같은 하기 일반식(I)의 화합물 또는 그의 약학적으로 혀용가능한 염:
    상기 식에서, R1은 -H, -OH, -O(C1-C4알킬), -OCOC6H5, -OCO(C1-C6알킬) 또는 -OSO2(C4-C6알킬)이고; R2는 -H, -OH, -O(C1-C4알킬), -OCOC6H5, -OCO(C1-C6알킬) 또는 -OSO2(C4-C6알킬)이고; M은 -CH(OH)- 또는 -CH2-이고; n은 2또는 3이고; R3은 1-피페리디닐, 1-피롤리디닐, 메틸-1-피롤리디닐, 디메틸-1-피롤리디닐, 4-모폴리노, 디메틸아미노, 디에틸아미노 또는 1-헥사메틸렌이미노이다.
    ※ 참고사항 : 최초출원 내용에 의하여 공개하는 것임.
KR1019970701827A 1994-09-20 1995-09-18 나프틸 화합물, 그의 중간체, 제조방법, 조성물 및 사용방법(naphthylcompounds, intermediates, processes, compo sitions, and methods) Abandoned KR970705983A (ko)

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MX9702154A (es) 1997-06-28
MY132075A (en) 2007-09-28
US5484795A (en) 1996-01-16
HUT77919A (hu) 1998-10-28
PE47496A1 (es) 1996-11-12
CZ82297A3 (en) 1997-12-17
EP0703228A1 (en) 1996-03-27
NO307929B1 (no) 2000-06-19
IL115335A0 (en) 1995-12-31

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