KR940005271A - 표지된 피브리노겐 수용체 길항제, 이의 용도 및 이의 제조방법 - Google Patents

표지된 피브리노겐 수용체 길항제, 이의 용도 및 이의 제조방법 Download PDF

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KR940005271A
KR940005271A KR1019930006959A KR930006959A KR940005271A KR 940005271 A KR940005271 A KR 940005271A KR 1019930006959 A KR1019930006959 A KR 1019930006959A KR 930006959 A KR930006959 A KR 930006959A KR 940005271 A KR940005271 A KR 940005271A
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phenyl
substituted
amidino
carboxymethyl
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바이센베르거 요하네스
슈베르트 한스-디이터
스비테크 칼-하인즈
린즈 귄터
힘멜스바흐 프랑크
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디터 라우딘, 게르하르트 후버
닥터 칼 토매 게엠베하
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Publication of KR940005271A publication Critical patent/KR940005271A/ko

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    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

본 발명은 수용체에 대한 친화성이125Ⅰ-피브리노겐의 친화성에 필적하거나 그 이상이고 외인성 단백질에 의해 결합을 방해받지 않는 신규한 표지된 피브리노겐 수용체 길항제, 보다 특히 알부민 또는 피브리노겐과 같은 외인성 단백질의 존재하에서 수용체에 대해 500nM미만의 친화도(KD)를 갖는 제3항에 따른 삼중수소-표지된 피브리노겐 수용체 길항제, 피브리노겐 수용체 결합 시험에서 리간드로서 또는 피브리노겐 수용체 길항제의 농도 측정을 위한 이들의 용도 및 이들의 제조방법에 관한 것이다.

Description

표지된 피브리노겐 수용체 길항제, 이의 용도 및 이의 제조방법
본 내용은 요부공개 건이므로 전문내용을 수록하지 않았음
제1도는 혈장존재하에서 BIBU 52에 의한 사람 전구에 대한3H-BIBU 52D의 결합 억제 그래프이다.

Claims (12)

  1. 수용체에 대한 친화성이125Ⅰ-피브리노겐의 친화성에 필적하거나 그 이상이고 외인성 단백질의 존재하에서 수용체에 대한 친화도(KD)가 500nM미만이며 검정가능한 원자를 하나 이상을 포함함을 특징으로 하는 피브기노겐 수용체 길항제.
  2. 제1항에 있어서, 검정가능한 원자로서 수소를 대체하는 삼중수소를 사용함을 특징으로 하는 피브리노겐 수용체 길항제.
  3. 제1항 또는 제2항에 있어서, 일반식(I)이 아미딘, 이들의 토토머, 입체이성체(이들의 혼합물 포함) 및 이들의 염의 수소원자 하나 이상을 삼중수소를 대체시킴을 특징으로 하는 피브리노겐 수용체 길항제.
    (I) Ra-Rb 상기식에서. Ra는 4-아미디노페닐 또는 5-아미디노-피리미드-2-일 그룹이고, Rb는 HOOC-D-C-B-A-그룹(여기에서, A는 임의로 메톡시-치환된 페닐렌 그룹(이는 추가로 하나 또는 두개의 메탄 그룹이 질소원자에 의해 대체될 수 있다)을 나타내거나, 이미다졸리논-디-일, 이미다졸리디 논-디-일, 이미다졸리딘-디온-디-일, 트리아졸리논-디-일 또는 1, 1-디옥소-1,2,5-티아디아졸라딘-디-일 그룹(이들 각각은 탄소원자에서 메탈, 에틸 또는 트리플루오로메틸 그룹에 의해 임의로 치환된다)을 나타내거나, 하나의 질소원자에서 그룹 Rl에 의해 임의로 치환된 벤즈이미다졸-디-일 그룹을 니타내거나, 질소원자에 의해 그룹 B에 결합된 아미노카보닐 그룹을 나타내고; B는 메틸렌. 카로닐, 사이클로헥실렌, 페닐렌 또는 이미다졸-디-일 그룹, 질소원자를 통해 그룹 C에 결합된 아미노카보닐 그룹(이는 동시에 질소원자에서 메틸 그룹에 의해 치환될 수 있다), 또는 산소원자를 통해 그룹 A에 결합된 메틸렌 옥시 그룹을 나타내며; C는 그룹 R2에 의해 임의로 치환된 에틸렌 그룹, 사이클로헥실렌 그룹, 질소원자에서 그룹 R3에 의해 임의로 치환된 피롤리딘-디-일 또는 피롤리디논-디-일 그룹, 피페리딘-디-일 그룹 또는 질소원자를 통해 그룹 D에 결합된 아미노카보닐 그룹을 나타내고; D는 결합이거나 메틸렌 도는 에틸렌 그룹이며; R1은 메틸, 2-피페라디노에틸, 2-(3,4-디메톡시페닐)에틸 또는 3-티오모폴리노프로필 그룹이고; R2는 아미노 또는 하이드록시 그룹이며; R3는 3-페닐프로필, 아세틸, 메탄설포닐 또는 피롤리디노카보닐메틸 그룹이다]이다.
  4. 제3항에 있어서, Ra가 4-아미디노-페닐 그룹을 나타내거나, Rb가 4-위치에서 3-카복시메틸-피롤리단-2-온-5-일-메틸옥시 그룹에 의해 치환된 페닐 그룹을 나타내는 경우, 또한 5-아미디노-피리미드-2-일 그룹을 나타내고, Rb가 4-위치에서 4-카복시메틸-피롤리딘-2-일-메틸옥시, 3-카복시메틸-피롤리딘-2-온-5-일-메틸옥시, 4-카복시메틸-피페리디노메틸, 4-카복시메틸-피페리디카보닐, 4-카복시사이클로헥 실아미노카보닐 또는 N-메틸-N-(4-카복시사이클로헥실)-아미노카보닐 그룹에 의해 치환된 페닐 그룹(여기에서, 1-위치에서 각각의 피롤리딘 잔기는 아세틸 또는 메탄설포닐 그룹에 의해 치환될 수 있고 피롤리디논 잔기는 3-페닐-프로필 또는 피롤리디노카보닐 메틸 그룹에 의해 치환될 수 있다), 3-위치에서 4-카복시사이클로헥실-아미노카보닐-그룹에 의해 치환된 4-메특시-페닐 그룹, 6-위치에서 이미다졸-1-일 그룹에 의해 치환된 피리다진-3-일 그룹(여기에서, 이미다졸릴 잔기는 4-위치에서 2-아미노-2-카복시-에틸 또는 2-카복시-2하이드록시-에틸 그룹에 의해치환된다), 3-위치에서 4-(2-카복시에틸)-사이클로헥실 또는 4-(2-카복시에틸)-피닐 그룹에 의해 치환된 4-메틸-4-이미다졸린-2-온-1-일 그룹, 3-위치에서 4-(2-카복시-에틸)-페닐 그룹에 의해 치환된 4-메틸-4-이미다졸린-2-온-1-일 또는 이미다졸리딘-2,4-디온-1-일 그룹, 5-위치에서 임의로 메틸-또는 에틸-치환이고 4-위치에서 4-(2-카복시에틸)-페닐 그룹에 의해 치환된 1,2,4-트리아졸-5-인-3-온-2-일 그룹, 2-위치에서 4-(2-카복시에틸)-페닐 그룹에 의해 치환된 1,2,4-트리아졸-5-인-3-온-4-일 그룹, 5-위치에서 4-(2-카복시에틸)-페닐 그룹에 의해 치환된 1,1-디옥소-1,2,5-티아디아졸리딘-2-일-그룹, 1-위치에서 메틸, 2-피페라지노-에틸 또는 2-(3,4-디메톡시페닐)-에틸 그룹에 의해 임의로 치환되고 5-위치에서 2-카복시에틸아미노카보닐 그룹에 의해 치환된 벤즈이미다졸-2-일 그룹, 또는 3-위치에서 2-카복시에틸아미노카보닐 그룹에 의해 치환된 페닐아미노카보닐 그룹인 일반식(Ⅰ)의 피브리노겐 수용체 길항제, 이들의 토토머, 입체이성체(이들 혼합물을 포함함) 및 이들의 염의 수소원자 하나 이상을 삼중수소로 대체시킴을 특징으로 하는, 피브리노겐 수용체 길항제.
  5. 제3항 또는 제4항에 있어서, (1) (3S,5S)-및 (3R,5R)-5-[[4-(5-아미디노피리미드-2-일)-페닐]-옥시메틸]-3-카복시메틸-피롤리딘-2-온, (2) (3S,5S)-및 (3R,5R)-1-아세틸-5-[(4'-아미디노-4-비페닐릴)-옥시메틸]-3-카복시메틸-피롤리딘,(3) (3S,5S)-및 (3R,5R)-5-[[4-(5-아미디노-4-비페닐릴)-옥시메틸]-3-카복시메틸-1-메탄설포닐-피롤리딘, (4) (3S,5S)-및 (3R,5R)-5-[[4'-(5-아미디노-4-비페닐릴)-옥시메틸]-3-카복시메틸-피롤리딘-2-온, (5) 4-아미디노-4'-[(트랜스-4-카복시사이클로헥실)-아미노카보닐)-비페닐, (6) 4-아미디노-4'-[N-(트랜스-4-카복시사이클로헥실)-N-메틸-아미노카보닐)-비페닐, (7) 1-(4-아미디노페닐)-3-(4-(2-카복시에틸)-페닐]-이미다졸리딘-2,4-디온, (8) 1-(4-아미디노페닐)-3-[4-(2-카복시에틸)-페닐]-4-메틸-4-이미다졸리딘-2-온, (9) 2-(4-아미디노페닐)-4-[4-(2-카복에틸)-페닐)-1,2,4-트리아졸-5-인-3-온, (10) 4-(4-아미디노페닐)-2-[4-(2-카복시에틸)-페닐)-1,2,4-트리아졸-5-인-3-온, (11) 2-(4-아미디노페닐)-4-[4-(2-카복시에틸)-페닐]-5-메틸 -1, 2, 4-트리아졸-5-인-3-온, (12) 2-(4-아미디노페닐)-4-[4-(2-카복시에틸)-페닐)-5-에틸-1,2,7-트리아졸-5-인-3-온, (13) 2-(4-아미디노페닐)-5-[4- (2-카복시에틸)-페닐)-1,2,5-티아디아졸리딘-1,1- 디옥사이드, (14) 1-(4-아미디노페닐)-3-[4-(2-카복시에틸)-사이클로헥실)-이미다졸리딘-2-온, (15) 2-(4-아미디 노페닐)-5-[(2-카복시에틸)-아미노카보닐)-1-[2-(피페라진-1-일)-에틸)-벤즈이미다졸, (16) 4-아미디노-4 '-[4-(카복시메틸)-피페리디노카보닐)-비페닐 및 이들의 염인 피브리노겐 수용체 길항제.
  6. 제3항 또는 제4항에 있어서, (1) (3S,5S)-및 (3R,5R)-5-[[(4-(5-아미디노피리미드-2-일)-페닐]-옥시메틸]-3-카복시메틸-피롤리딘-2-온, (2) (3S,5S)-및 (3R,5R)-1-아세틸-5-[(4'-아미디노-4-비페닐릴)옥시메틸]-3-카복시메틸-피롤리딘, (3) (3S,5S)-및 (3R,5R)-5-[[4'-(5-아미디노-4-비페닐릴)-옥시메틸]-3-카복시메틸-1-메탄설포닐-피롤리딘, (4) (3S,5S)-및 (3R,5R)-5-[(4'-아미디노-4-비페닐릴)-옥시메틸]-3-카복시메틸-피롤리딘-2-온, (5) 4-아미디노-4'-[4-(카복시메틸)-피페리디노카보닐]-비페닐 및 이들근 염인 피브리노겐 수용체 길항제.
  7. 제3항 내지 제6항중 어느 한 항에 있어서, 방향족 수소원자를 삼중수소로 대체시킴을 특징으로 하는 피브리노겐 수용체 길항제.
  8. (3S,5S)-5-[(4'-아미디노-4-비페닐릴)옥시메틸]-3-[(카복시)메틸]-피롤리디논[3-3H-비페닐릴] 및 이의 염.
  9. 피브리노겐 수용체에 대한 화학적 물질의 결합을 측정하기 위한 제1항 내지 제8항에 따른 표지된 피브리노겐 수용체 길항제의 용도.
  10. 피브리노겐 수용체 길항제의 농도를 측정하기 위한 제1항 내지 제8항에 따른 표지된 피브리노겐 수용체 길항제의 용도.
  11. 제9항 또는 제10항에 있어서, 외인성 알부민 및/또는 체액의 존재하에서 측정함을 특징으로 하는 표지된 피브리노겐 수용체 길항제의 용도.
  12. 수소 대신 삼중수소원자 하나 이상을 (a) 불포화된 탄소-탄소 결합을 촉매적 삼중수소 처리하거나, (b) 할로겐 원자를 가수소분해 교환시키거나, (c) 촉매적 수소/삼숭수소 교환하거나, (d) 삼중수소 처리된 용매중에서 촉매적 수소/삼중수소 교환하기나, (e) 생성되는 피브리노겐 수용체 길항제의 전구체를 삼중수소 처리한 후 피브리노겐 수용체 길항제를 합성하여 상응하는 비-표지된 피르기노겐 수용체 길항제를 도입시키고, 필요한경우 수득된 이성체 혼합물을 이들의 에난티오머로 분해시키고/시키거나 수득된 삼중수소 처리된 화합물을 이의 염으로 전화시킴을 특징으로 하는, 제2항 내지 제8항에 따른 삼중수소-표지된 피브리노겐 수용체 길항제의 제조방법.
    ※ 참고사항 : 최초출원 내용에 의하여 공개하는 것임.
KR1019930006959A 1992-04-28 1993-04-26 표지된 피브리노겐 수용체 길항제, 이의 용도 및 이의 제조방법 KR940005271A (ko)

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MX9302446A (es) 1994-03-31
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AU3715393A (en) 1993-11-04
EP0567967B1 (de) 1996-07-10
NO180046C (no) 1997-02-05
DK0567967T3 (da) 1996-11-18
GR3020740T3 (en) 1996-11-30
FI931881A (fi) 1993-10-29
NO180046B (no) 1996-10-28
ES2092170T3 (es) 1996-11-16
US5677466A (en) 1997-10-14
ATE140225T1 (de) 1996-07-15
FI931881A0 (fi) 1993-04-27
CA2094963A1 (en) 1993-10-29
NO931528D0 (no) 1993-04-27
AU670778B2 (en) 1996-08-01

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