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KR100859107B1 - 도파민 ｄ2 수용체 및 세로토닌 재흡수 부위에 대한친화도가 높은8-｛4-[3-(5-플루오로-1ｈ-인돌-3-일)-프로필]-피페라진-1-일｝-2-메틸-4ｈ-벤조[1,4]옥사진-3-온 메실레이트 - Google Patents

도파민 ｄ2 수용체 및 세로토닌 재흡수 부위에 대한친화도가 높은8-｛4-[3-(5-플루오로-1ｈ-인돌-3-일)-프로필]-피페라진-1-일｝-2-메틸-4ｈ-벤조[1,4]옥사진-3-온 메실레이트 Download PDF

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KR100859107B1
KR100859107B1 KR1020037010907A KR20037010907A KR100859107B1 KR 100859107 B1 KR100859107 B1 KR 100859107B1 KR 1020037010907 A KR1020037010907 A KR 1020037010907A KR 20037010907 A KR20037010907 A KR 20037010907A KR 100859107 B1 KR100859107 B1 KR 100859107B1
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mesylate
dopamine
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serotonin reuptake
oxazin
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박커코르넬리스
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솔베이 파마슈티칼스 비. 브이
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Abstract

본 발명은 화학식 I의 신규한 페닐피페라진 유도체인 메실레이트에 관한 것이다.
화학식 I
Figure 112003030616081-pct00003
당해 염은 페닐피페라진의 유리 염기에 비해 유리한 특성을 나타낸다.
페닐피페라진 유도체, CNS 장애, 정신분열증, 기타 정신병적 장애, 생체이용율

Description

도파민 Ｄ2 수용체 및 세로토닌 재흡수 부위에 대한 친화도가 높은 8-｛4-[3-(5-플루오로-1Ｈ-인돌-3-일)-프로필]-피페라진-1-일｝-2-메틸-4Ｈ-벤조[1,4]옥사진-3-온 메실레이트 {8-｛4-[3-(5-Fluoro-1H-indol-3-yl)-propyl]-piperazin-1-yl｝-2-methyl-4H-benzo[1,4]oxazin-3-one mesylate with high affinity for the dopamine D2 receptor and the serotonin reuptake site}
본 발명은 화학식 I의 신규한 페닐피페라진 유도체에 관한 것이다.
Figure 112003030616081-pct00001
WO 01/14330에는 신규한 페닐 피페라진 그룹이 기재되어 있다. 당해 그룹의 화합물은 도파민 D2 수용체 및 세로토닌 재흡수 부위 둘 다에 대해 높은 친화도를 나타낸다. 이러한 조합은 정신분열증 및 기타 정신병적 장애의 치료에 유용하여 모든 질환 증상[예: 양성 증상(positive symptom) 및 음성 증상(negative symptom)]을 보다 완전하게 치료할 수 있다.
당해 화합물은 마우스에게서 아포모르핀 유발된 클라이밍 거동(climbing behaviour)을 잠재적으로 길항시킬 수 있으므로, 도파민 D2 수용체에서 길항제로서의 활성을 나타낸다. 당해 화합물은 또한 마우스에게서 5-HTP 유발된 거동을 일으킬 수 있으므로 세로토닌 재흡수 억제제로서의 활성을 나타낸다.
당해 화합물은 임상 관련 항정신병약에 민감한 치료 모델[예: 조건화된 회피 반응(참조: Van der Heyden & Bradford, Behav. Brain Res., 1988, 31:61-67)] 및 항우울제 또는 불안 완화제에 민감한 치료 모델[예: 스트레스 유발된 발성 억제(참조: van der Poel et al., Psychopharmacology, 1989, 97: 147-148)]에 있어서 활성이다.
임상 관련 도파민 D2 수용체 길항제와는 대조적으로, 당해 화합물은 설치류에 대해서는 강직증을 유발하는 경향이 낮고, 이로써 현존 항정신병약보다 추체외 부작용을 덜 유발시키는 경향이 있다.
이들 화합물 고유의 세로토닌 재흡수 억제 활성은 항우울제 또는 불안 완화제에 민감한 거동 모델들에게서 관찰된 치료학적 효과의 원인이 될 수 있다.
당해 화합물은 도파민 또는 세로토닌 작용계에서의 장애에 의해 유발되는 중추 신경계 질병 또는 질환, 예를 들면, 공격성, 불안 장애, 자폐증, 현기증, 우울증, 인지 또는 기억 장애, 파킨슨병 및 특히 정신분열증 및 기타 정신병적 장애의 치료에 사용될 수 있다.
본 발명에 이르러, 위의 화학식 I의 메실레이트가 이의 유리 염기(즉, WO 01/14330의 89번 화합물)에 비해 특히 유리한 특성을 나타내는 것으로 밝혀졌다.
당해 메실레이트 화합물은 물에 대한 용해도가 유리 염기보다 훨씬 우수하여 우수한 생체이용율을 나타낸다.
당해 화합물은 키랄 중심을 가지므로, 라세미체 혼합물 및 개별 에난티오머 둘 다 본 발명에 속한다.
당해 화합물은 액체 및 고형 담체 물질과 같은 보조 물질을 사용하여 적합한 공정을 통해서 투여하는 데 적합한 형태로 될 수 있다.
당해 화합물의 유리 염기는 WO 01/14330에 기재된 바와 같이 제조될 수 있다.
유리 염기를 공지되어 있는 염 형성 방법에 따라서 메실레이트로 전환시킬 수 있다.
본 발명은 다음 실시예를 통해서 설명된다.
실시예
WO 01/14330에 기재되어 있는 바와 같이 수득 가능한 유리 염기(89번 화합물) 2.0g(4.7mmol)을 메탄올 40ml에 현탁시켰다. 현탁액을 60℃로 가온하고, 메탄올 10ml 속의 메탄설폰산 0.45g(4.7mmol) 용액을 약 2분 이내에 가하였다. 투명한 용액이 수득되었다. 60℃에서 5분 동안 교반한 후, 결정화되기 시작하였다. 용액을 60분 이내에 20℃로 서서히 냉각시키고, 동일한 온도에서 30분 동안 교반하였다. 60분 이내에 0℃로 추가로 냉각시키고 90분 동안 교반하였다. 고형 물질을 여과하여 분리하고, 메탄올 5ml로 세척한 후, 하룻밤 동안 50℃에서 감압하에 건조시켰다. 백색 메실레이트의 수율은 2.17g(88%)이었다.

Claims (3)

  1. 화학식 I의 화합물.
    화학식 I
    Figure 112003030616081-pct00002
  2. 삭제
  3. 삭제
KR1020037010907A 2001-02-21 2002-02-19 도파민 ｄ2 수용체 및 세로토닌 재흡수 부위에 대한친화도가 높은8-｛4-[3-(5-플루오로-1ｈ-인돌-3-일)-프로필]-피페라진-1-일｝-2-메틸-4ｈ-벤조[1,4]옥사진-3-온 메실레이트 Expired - Fee Related KR100859107B1 (ko)

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