KR960017658A - 알파₁-아드레날린수용체 길항물질로서의 [3-(4-페닐피페라진-1-일)프로필-아미노, 티오 및 옥시］-피리딘, 피리미딘 및 벤젠 유도체 - Google Patents

알파₁-아드레날린수용체 길항물질로서의 [3-(4-페닐피페라진-1-일)프로필-아미노, 티오 및 옥시］-피리딘, 피리미딘 및 벤젠 유도체 Download PDF

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KR960017658A
KR960017658A KR1019950040349A KR19950040349A KR960017658A KR 960017658 A KR960017658 A KR 960017658A KR 1019950040349 A KR1019950040349 A KR 1019950040349A KR 19950040349 A KR19950040349 A KR 19950040349A KR 960017658 A KR960017658 A KR 960017658A
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어니스트 클라크 데이비드
리챠드 엘워씨 토드
존 모간스 쥬니어 데이비드
롤란드 파이스터 외르그
브루스 렙크 데이비드
브라이안 스조그렌 에릭
엔-휴이 우 헬렌
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프리돌린 클라우스너·롤란드 보러
에프. 호프만-라 롯슈 아크티엔게젤샤프트
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Abstract

본 발명은 하기 일반식(Ⅰ)의 신규한 α1-아드레날린 수용체 길항물질 및 그의 약학적으로 허용되는 염 및 N-산화물에 관한 것이다:
상기식에서, p는 0 또는 1이고; t는 0, 1 또는 2이고; X는 0, S 또는 NR6(이때, R6은 하이드로 또는 (C1-C6)알킬이다)이고; Y 및 Z는 독립적으로 CH 또는 N이고; R1은 하이드로, 하이드록시, 할로, 니트로, 아미노, 시아노, (C1-4)알킬티오, 아세틸아미노, 트리플루오로아세틸아미노, 메틸설포닐아미노, (C1-6)알킬, (C3-6)사이클로알킬, (C3-6)사이클로알킬(C1-4)알킬, 옥사졸-2-일, 아릴, 헤테로아릴, 아릴(C1-4)알킬, 헤테로아릴(C1-4)알킬, (C1-6)알킬옥시, (C3-6)사이클로알킬옥시, (C3-6)사이클로알킬(C1-4)알킬옥시, 2-프로피닐옥시, 아릴옥시, 헤테로아릴옥시, 아릴(C1-4)아킬옥시 또는 헤테로아릴(C1-4)알킬옥시(여기서, 알킬은 1 내지 3개의 할로 원자로 임의로 치환되며, 아릴 또는 헤테로아릴은 할로 및 시아노중에서 독립적으로 선택된 1 내지 2개의 치환제로 임의로 치환된다)이고; R2는 하이드로, 하이드록시, 할로, 시아노, (C1-6)알킬 또는 (C1-6)알킬옥시(여기서, 알킬은 1 내지 3개의 할로 원자로 임의로 치환된다)이고; R3은 -C(O)R7(여기서, R7은 (C1-6)알킬, (C3-6)사이클로알킬, 디(C1-4)알킬아미노, N-(C1-4)알킬-N-(C1-4)알킬옥시아미노, (C1-4)알킬((C1-4)알킬옥시)아미노, 피롤리딘-1-일, 피레리딘-1-일, 모로폴린-4-일 또는 피페라진-1-일이다)이고; R4는 할로, 하이드록시, 시아노, (C1-6)일킬 또는 (C1-6)알킬옥시이고; 및 R5는 (C1-6)알킬이다.

Description

알파1-아드레날린수용체 길항물질로서의 ［3-(4-페닐피페라진-1-일)프로필-아미노, 티오 및 옥시］-피리딘, 피리미딘 및 벤젠 유도체
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Claims (21)

  1. 하기 일반식(Ⅰ)의 화합물 및 이들의 약학적으로 허용되는 염 및 N-산화물:
    상기식에서, p는 0 또는 1이고; t는 0, 1 또는 2이고; X는 0, S 또는 NR6(이때, R6은 하이드로 또는 (C1-C6)알킬이다)이고; Y 및 Z는 독립적으로 CH 또는 N이고; R1은 하이드로, 하이드록시, 할로, 니트로, 아미노, 시아노, (C1-4)알킬티오, 아세틸아미노, 트리플루오로아세틸아미노, 메틸설포닐아미노, (C1-6)알킬, (C3-6)사이클로알킬, (C3-6)사이클로알킬(C1-4)알킬, 옥사졸-2-일, 알릴, 헤테로아릴, 아릴(C1-4)알킬, 헤테로아릴(C1-4)알킬, (C1-6)알킬옥시, (C3-6)사이클로알킬옥시, (C3-6)사이클로알킬(C1-4)알킬옥시, 2-프로피닐옥시, 아릴옥시, 헤테로아릴옥시, 아릴(C1-4)알킬옥시 또는 헤테로아릴(C1-4)알킬옥시(여기서, 알킬은 1 내지 3개의 할로 원자로 임의로 치환되며, 아릴 또는 헤테로아릴은 할로 및 시아노중에서 독립적으로 선택된 1 내지 2개의 치환제로 임의로 치환된다)이고; R2는 하이드로, 하이드록시, 할로, 시아노, (C1-6)알킬 또는 (C1-6)알킬옥시(여기서, 알킬은 1 내지 3개의 할로 원자로 임의로 치환된다)이고; R3은 -C(O)R7(여기서, R7은 (C1-6)알킬, (C3-6)사이클로알킬, 디(C1-4)알킬아미노, N-(C1-4)알킬-N-(C1-4)알킬옥시아미노, (C1-4)알킬((C1-4)알킬옥시)아미노, 피롤리딘-1-일, 피레리딘-1-일, 모로폴린-4-일 또는 피페라진-1-일이다)이고; R4는 할로, 하이드록시, 시아노, (C1-6)일킬 또는 (C1-6)알킬옥시이고; 및 R5는 (C1-6)알킬이다.
  2. 제1항에서, p는 0이고, t가 0 또는 1이고, X가 NH이고, Z가 CH이고, R1이 메티티오, 메틸설포닐아미노, (C1-4)알킬, 사이크로프로필, 옥사졸-2-일, (C1-3)알킬옥시 또는 사이클로프로필메톡시(여기서, 알킬은 3개의 할로 원자로 임의로 치환된다)이고, R2가 하이드로, 풀루오로 또는 메틸이고, R3이 디메틸아미노카보닐 또는 N-메틸-N-메톡시아미노카보닐이고, 존재하는 R4가 할로, 시아노 또는 메틸중에서 선택된, 5-위치의 치환제인 화합물.
  3. 제2항에 있어서, t가 0이고, Y가 N이고, R1이 메틸티오, n-프로필, 사이클로프로필, 옥사졸-2-일메톡시, 트리플루오로메톡시, 2-(2,2,2-트리플루오로)에톡시 또는 사이클로프로필메톡시인 화합물.
  4. 제3항에 있어서, R1이 메톡시이고, R2가 하이드로이고, R3이 데메틸아미노카보닐인 화합물 즉, 2-{3-〔4-(2-메톡시페닐)피페라진-1-일〕-프로필아미노}-N,N-디메틸니코틴아미드 및 그의 약학적으로 허용되는 염의 화합물.
  5. 제4항에 있어서, 2-{3-〔4-(2-메톡시페닐)피페라진-1-일〕-프로필아미노}-N,N-디메틸니코틴아미드 하이드로클로라이드인 화합물,
  6. 제3항에 있어서, R1이 2-(2,2,2-트리플루오로)에톡시이고, R2가 하이드로이고, R3이 데메틸아미노카보닐인 화합물, 즉 2-(3-{4-〔2-(2,2,2-트리플루오로-에톡시)페닐〕피페라진-1-일}-프로필아미노)-N,N-디메틸니코틴아미드 및 그의 약학적으로 허용되는 염인 화합물.
  7. 제6항에 있어서, 2-(3-{4-〔2-(2,2,2-트리플루오로에톡시)페닐〕피페라진-1-일}-프로필아미노)-N,N-디메틸니코틴아미드 하이드로클로라이드인 화합물.
  8. 제3항에 있어서, R1이 2-(2,2,2-트리플루오로)에톡시이고, R2가 하이드로이고, R3이 N-메틸-N-메톡시아미노카보닐인 화합물, 즉 2-(3-{4-〔2-(2,2,2-트리플루오로-에톡시)페닐〕피페라진-1-일}-프로필아미노)-N-메틸-N-메톡시니코틴아미드 및 그의 약학적으로 허용되는 염인 화합물.
  9. 제8항에 있어서, 2-(3-{4-〔2-(2,2,2-트리플루오로에톡시)페닐〕피페라진-1-일}-프로필아미노)-N-메틸-N-메톡시니코틴아미드 하이드로클로라이드인 화합물.
  10. 제3항에 있어서, R1이 메톡시이고, R2가 4-위치의 메틸이고, R3이 디메틸아미노카보닐인 화합물, 즉 2-{3-〔4-(2-메톡시-4-메틸페닐)피페라진-1-일〕-프로필아미노}-N,N-디메틸니코틴아미드 및 그의 약학적으로 허용되는 염.
  11. 제10항에 있어서, 2-{3-〔4-(2-메톡시-4-메틸-페닐)피페라진-1-일〕-프로필아미노}-N,N-디메틸니코틴아미드 옥살레이트인 화합물.
  12. 제3항에 있어서, R1이메틸티오이고, R2가 하이드로이고, R3이 디메틸아미노카보닐인 화합물, 즉 2-{3-〔4-(2-메틸티오페닐)피페라진-1-일〕-프로필아미노}-N,N-디메틸니코틴아미드 및 그의 약학적으로 허용되는 염.
  13. 제12항에 있어서, 2-{3-〔4-(2-메틸티오페닐)피페라진-1-일〕-프로필아미노}-N,N-디메닐니코틴아미드 하이드로클로라이드인 화합물.
  14. 제3항에 있어서, R1이 n-프로필이고, R2가 하이드로이고, R3가 디메틸아미노카보닐인 화합물, 즉 2-{3-〔4-〔2-n-프로필페닐)피페라진-1-일〕프로필아미노}-N,N-디메틸니코틴 및 그의 약학적으로 허용되는 염인 화합물.
  15. 제14항에 있어서, 2-{3-〔4-(2-n-프로필페닐)피페라진-1-일〕-프로필아미노}-N,N-디메틸니코틴아미드 하이드로클로라이드인 화합물.
  16. 제3항에 있어서, R1이 사이클로프로필메톡시이고, R2가 하이드로이고, R3가 디메틸아미노카보닐인 화합물, 즉 2-{3-〔4-〔2-사이클로프로필메톡시페닐)피페라진-1-일〕프로필아미노}-N,N-디메틸니코틴아미드 및 그의 약학적으로 허용되는 염인 화합물.
  17. 제16항에 있어서, 2-{3-〔4-〔2-사이클로프로필메톡시페닐)피페라진-1-일〕프로필아미노}-N,N-디메틸니코틴아미드 옥살레이트인 화합물.
  18. 제3항에 있어서, R1이 옥사졸-2-일이고, R2가 하이드로이고, R3가 디메틸아미노카보닐인 화합물, 즉 2-{3-〔4-〔2-옥사졸-2-일페닐)피페라진-1-일〕프로필아미노}-N,N-디메틸니코틴아미드 및 그의 약학적으로 허용되는 염인 화합물.
  19. 제18항에 있어서, 2-{3-〔4-(2,2-옥사졸-2-일-페닐)피페라진-1-일〕프로필아미노}-N,N-디메틸니코틴아미드 하이드로클로라이드인 화합물.
  20. 제1 내지 19항 중 어느 한 항의 화합물 치료 효과량을 약학적으로 허용되는 부형제와 함께 포함하는, 양성 전립선 과형성에 의해 야기된 하부 요로의 폐색과 직 간접적으로 관련된 질환을 치료하기 위한 약학 조성물.
  21. 하기 (A) 내지 (O) 단계를 포함하는 하기 일반식(Ⅰ)의 화합물 및 이들의 약학적으로 허용되는 염 및 N-산화물의 제조 방법; (A) p가 0이고, Y 및 Z중 하나 또는 둘다가 N인 일반식(Ⅰ)의 화합물은 하기 일반식(3)의 화합물을 하기 일반식(2)의 화합물과 반응시킨후 존재하는 임의의 P1보호기를 제거하므로써 제조하고, (B) Y 및 Z가 각각 CH인 일반식(Ⅰ)의 화합물은 (ⅰ) R9가 하이드록시인 일반식(3)의 화합물은 일반식(7)의 화합물로 전환시키고, (ⅱ) 일반식(7)의 화합물을 하기 일반식(8)의 화합물과 반응시킨후 존재하는 임의의 P1및 P3보호기를 제거하므로써 제조하고, (C) Y 및 Z가 각각 CH인 일반식(Ⅰ)의 화합물은 (ⅰ) 일반식(8)의 화합물을 3-브로모-1-프로판올과 반응시켜 일반식(10)의 화합물을 제조하고, (ⅱ) 일반식(10)의 화합물을 전화시켜 일반식(9)의 화합물을 수득하고, (ⅲ) 일반식(9)의 화합물을 하기 일반식(5)의 화합물과 반응시키고 존재하는 임의의 P1및 P3보호기를 제거하므로써 제조하고, (D) 임의로, R2가 하이드로인 일반식(Ⅰ)의 화합물을 할로겐화시켜 R2가 할로인 일반식(Ⅰ)의 화합물을 수득하고, (E-1) 임의로, Y 및 Z중 하나 또는 둘다가 N이고, t가 0인 일반식(Ⅰ)의 화합물을 할로겐화시켜 Y 및 Z중 하나 또는 둘다가 N이고, R4가 할로인 일반식(Ⅰ)의 화합물을 수득하고, (E-2) 임의로, Y 및 Z가 각각 CH이고, t가 0인 일반식(Ⅰ)의 화합물을 할로겐화시켜 Y 및 Z가 각각 CH이고, R4가 하로인 일반식(Ⅰ)의 화합물을 수득하고, (F) 임의로, R1이 메톡시인 일반식(Ⅰ)의 화합물을 탈메틸화시켜 R1이 하이드록시인 일반식(Ⅰ)의 화합물을 수득하고, (G) 임의로, R2또는 R4가 할로겐인 일반식(Ⅰ)의 화합물을 시아노-탈할로겐화시켜 R2또는 R4가 각각 시아노인 일반식(Ⅰ)의 화합물을 수득하고, (H) 임의로, R1이 니트로인 일반식(Ⅰ)의 화합물을 환원시켜 R1이 아미노인 일반식(1)의 화합물을 수득하고, (I) 임의로, R1이 아미노인 일반식(Ⅰ)의 화합물을 아세트산 무수물, 트리플루오로아세트산 무수물 또는 메탄설포닐 클로라이드와 반응시켜 R1이 각각 아세틸아미노, 트리플루오로아세틸아미노 또는 메틸설포닐아미노인 일반식(Ⅰ)의 화합물을 수득하고, (J) 임의로, p가 0인 일반식(Ⅰ)의 화합물을 알킬화시켜 R5가 (C1-6)알킬인 일반식(Ⅰ)의 화합물을 수득하고, (K) 임의로, R6이 하이드로인 일반식(Ⅰ)의 화합물을 알킬화시켜 R6이 (C1-6)알킬인 일반식(Ⅰ)의 화합물을 수득하고, (L) 임의로, 일반식(Ⅰ)의 화합물을 산화시켜 그의 N-산화물 유도체를 수득하고, (M) 임의로, 일반식(Ⅰ)의 화합물의 N-산화물 유도체를 비산화된 형태로 환원시키는 단계, (N) 임의로, 일반식(Ⅰ)의 화합물을 약학적으로 허용되는 염으로 전환시키고, (O) 임의로, 일반식(Ⅰ)의 화합물의 염 형태를 비 염 형태로 전환시키는 단계
    상기식에서, p는 0 또는 1이고; t는 0, 1 또는 2이고; X는 O, S 또는 NR6(이때, R6은 하이드로 또는 (C1-6)알킬이다)이고; Y 및 Z는 독립적으로 CH 또는 N이고; R1은 하이드로, 하이드록시, 할로, 니트로, 아미노, 시아노, (C1-4)알킬티오, 아세틸아미노, 트리플루오로아세틸아미노, 메틸설포닐아미노, (C1-6)알킬, (C3-6)사이클로알킬, (C3-6)사이클로알킬(C1-4)알킬, 옥사졸-2-일, 아릴, 헤테로아릴, 아릴(C1-4)알킬, 헤테로아릴(C1-4)알킬, (C3-6)알킬옥시, (C3-6)사이클로알킬옥시, (C3-6)사이클로알킬(C1-4)알킬옥시, 2-프로피닐옥시, 아릴옥시, 헤테로아릴옥시, 아릴(C1-4)알킬옥시 또는 헤테로아릴(C1-4)알킬옥시(여기서, 알킬은 1 내지 3개의 할로 원자로 임의로 치환되며, 아릴 또는 헤테로아릴은 할로 및 시아노중에서 독립적으로 선택된 1 내지 2개의 치환제로 임의로 치환된다)이고; R2는 하이드로, 하이드록시, 할로, 시아노, (C1-6)알킬 또는 (C1-6)알킬옥시(여기서, 알킬은 1 내지 3개의 할로 원자로 임의로 치환된다)이고; R3은 -C(O)R7(여기서, R7은 (C1-6)알킬, (C3-6)사이클로알킬, 디(C1-4)알킬아미노, N-(C1-4)알킬-N-(C1-4)알킬옥시아미노, (C1-4)알킬((C1-4)알킬옥시)아미노, 피롤리딘-1-일, 피페리딘-1-일, 모르폴린-4-일 또는 피페라진-1-일이다)이고;R4는 할로, 하이드록시, 시아노, (C1-6)알킬 또는 (C1-6)알킬옥시이고; 및 R5는 (C1-6)알킬이고, R9는 하이드록시, 메르캅토 또는 -NHR6이고, R10은 하이드록시, 메르캅토, -NHR6또는 -NHP3(여기서, P3은 보호기이다)이고, L은 이탈기이고, 일반식(3), (7) 및 (9)에서, R1, R2, R3및 R6은 상기 정의한 바와 같고(단, 하이드록시인 R1, R2및/또는 R3은 각각 P1보호기로 보호된다), 일반식(2), (8), (10) 및 (5)에서, t, Y, Z, R3및 R4는 상기 정의한 바와 같고(단, Y 및 Z중 하나 또는 둘다는 N이고, 각각의 존재하는 하이드록시기는 P1보호기로 보호된다.
    ※ 참고사항 : 최초출원 내용에 의하여 공개하는 것임.
KR1019950040349A 1994-11-08 1995-11-08 알파₁-아드레날린수용체 길항물질로서의 [3-(4-페닐피페라진-1-일)프로필-아미노, 티오 및 옥시］-피리딘, 피리미딘 및 벤젠 유도체 KR960017658A (ko)

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BRPI0910737A2 (pt) * 2008-04-23 2019-09-24 Takeda Pharmaceuticals Co composto, pró-droga, agente farmacêutico, método para profilaxia ou tratamento de doenças do trato urinário inferior em um mamífero, e, uso de um composto ou uma pró-droga do mesmo.
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PL311261A1 (en) 1996-05-13
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JPH08208614A (ja) 1996-08-13
MA23717A1 (fr) 1996-07-01
HU9503178D0 (en) 1996-01-29
FI955376A (fi) 1996-05-09
NO954453D0 (no) 1995-11-07
AU3459995A (en) 1996-05-16
NZ280396A (en) 1997-05-26
PE10997A1 (es) 1997-04-26
ZA959268B (en) 1997-01-31
SG70950A1 (en) 2000-03-21
CO4520230A1 (es) 1997-10-15
EP0711757A1 (en) 1996-05-15
HUT73843A (en) 1996-09-30
IL115844A0 (en) 1996-01-31
NO954453L (no) 1996-05-09
CN1136039A (zh) 1996-11-20
AR002244A1 (es) 1998-03-11
TR199501387A2 (tr) 1996-07-21
FI955376A0 (fi) 1995-11-08
CA2162089A1 (en) 1996-05-09
US5688795A (en) 1997-11-18

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