KR970700649A - 금속단백질 분해효소 억제제 - Google Patents

금속단백질 분해효소 억제제 Download PDF

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KR970700649A
KR970700649A KR1019960703916A KR19960703916A KR970700649A KR 970700649 A KR970700649 A KR 970700649A KR 1019960703916 A KR1019960703916 A KR 1019960703916A KR 19960703916 A KR19960703916 A KR 19960703916A KR 970700649 A KR970700649 A KR 970700649A
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alkyl
acid
dimethyl
hydroxy
methyl
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레이몬드 포올 벡키트
마아크 위트테이커
앤드류 밀러
피온나 미첼 마틴
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포올 리틀우드
브리티쉬 바이오테크 파마슈티칼스 리미티드
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Abstract

매트릭스 금속단백질분해 효소를 억제하는 다음 일반식(Ⅰ)의 화합물;
상기 식에서 X는 -CO2H 또는 -CONHOH기이고; R4는 페닐 또는 -이나 6원환 헤테로아릴 환이고 여기서 어느 환질소원자는 N-산화물로 산화될 수 있고, 이는 벤젠환에 또는 5-6 6-또는 7-원환헤테로고리환에 임의로 융합될 수 있고, 여기서 환중 어느 것은 임의로 치환될 수 있다.

Description

금속단백질 분해효소 억제제
본 내용은 요부공개 건이므로 전문내용을 수록하지 않았음

Claims (27)

  1. 다음 일반식(1)의 화합물 또는 이의염, 수화물이나 용매 화합물
    상기식에서 X는 -CO2H 또는 -CONHOH에 있고 : R1은 수소; (C1-C6)알킬; (C1-C6)알켄일; 페닐; 치환페닐; 페닐(C1-C6)알킬; 헤테로시클리일; 치환 헤테로시클리일; 헤테로시클리일(C1-C6)알킬, 치환 헤테로클리일(C1-C6)알킬; BSOn-A(여기서 n은 0.1 또는 2이고 B는 수소 또는 (C1-C6)알킬, 페닐, 치환페닐, 헤테로시클리일, (C1-C6)아실, 펜아실 또는 치환 펜아실기이고; A는 (C1-C6)알킬을 나타낸다) ; 아미노; 보호아미노; 아실아미노; OH; SH; (C1-C6)알콕시; (C1-C6)알킬아미노; 디-(C1-C6)알킬아미노; (C1-C6)알킬티오; 아릴(C1-C6)알킬; 아미노(C1-C6)알킬; 히드록시(C1-C6)알킬, 머캅토(C1-C6)알킬 또는 카르복시(C1-C6)알킬, 여기서 아미노-, 히드록시-, 머캅토- 또는 카르복실기는 임의로 보호되거나 또는 카르복실기는 아미드화 된다; 카르바모일, 모노(저급알킬) 카르바모일, 디(저급알킬)카르바모일, 디(저급알킬)아미노 또는 카르복시-저급 알카노일아미노에 의하여 치환된 저급 알킬이고; R2는 (C1-C6)알킬, (C1-C6)알켄일, (C1-C6)알킨일, 페닐(C1-C6)알킬, 헤테로아릴 (C1-C6)알킬, 시크로알킬(C1-C6)알킬 또는 실클로알켄일(C1-C6)알킬기 이고, 이중 하나는 (C1-C6)알킬, -O(C1-C6)알킬, -S(C1-C6)알킬, 할로와 시아노(-CN)에서 선택한 하나 또는 그이상의 치환기에 의하여 임의로 치환될 수 있다; R3는 기능기가 보호될 수 있는 천연 또는 비-천연 α아미노산의 특성기 이고; R4는 환질소 원자가 벤젠환 또는 5-, 6- 또는 7-원환 헤테로 고리환에 임의로 융합되는 N-산화물로서 산화될 수 있고, 환의 어느 것이 다음 기에 의하여 임의로 치환될 수 있는 페닐 또는 5-또는 6-원환 헤테로아릴환이다. (a)리드록실, 할로겐, -CN, CO2H, -CO2(C1-C6)알킬, -(C1-C6)-알킬-CO2(C1-C6)알킬, -CONH2-CONH(C1-C6)알킬, -CON(C1-C6)알킬2, -CHO, CH2OH, -(C1-C4)플루오로알킬, -O(C1-C6)알킬, -S(C1-C6)알킬, -SO(C1-C6)알킬, -SO2(C1-C6)알킬, -NO2, -NH2, -NH(C1-C6)알킬, -N(C1-C6)알킬2와, -NHCO(C1-C6)알킬에서 독립적으로 선택한 하나 또는 그 이상의 치환기, (b)기를 할로겐, 히드록실, 아미노, 카르복실 (C1-C4)-퍼플루오로알킬, (C1-C6)알킬, -O(C1-C6)알킬 또는 -S(C1-C6)알킬에서 선택한 하나 또는 그 이상의 치환기로 임의로 치환한, (C1-C6)알킬, (C2-C6)알켄일, (C2-C6)알킨일, (C3-C8)시크로알킬, (C4-C8)시클로알켄일, 페닐, 벤질, 헤테로아릴 또는 헤테로아릴케틸에서 선택한 기; R5는 수소 또는 (C1-C6)알킬기이다.
  2. 제1항에 있어서, 입체화학이 다음과 같은 화합물;
    R1과 X기를 갖는 C원자 -S, R2기를 갖는 C원자 -R, R3기를 갖는 C원자 -S,
  3. 제1항에 있어서, 제2항에 있어서, R1이 수소, 케닐, 에틸, 히드록실, 알릴, 티에닐술판일메탄, 티에닐술폰일메틸과 프탈이미도메틸인 화합물,
  4. 전술한 항중 어느 한 항에 있어서, R2가 이소-부틸, n-펜틸, n-헥실, n-헵틸, n-옥틸, n-논일, n-데실, 시클로헥실프로필, 페닐프로필, 4-클로페닐프로필, 4-메틸페닐프로필, 4-메톡시페닐프로필, 페닐부틸, 프로필메틸 또는 프로필술판일인 화합물.
  5. 전술한 항중 어느 한 항에 있어서, R3가 (C1-C6)알킬, 벤질, 히드록시벤질, 벤질옥시벤질, (C1-C6)알콕시벤질이나 벤질옥시 (C1-C6)알킬기; 또는 기능기가 보호될 수 있고, 존재하는 카르복실기가 아미드화 될 수 있는 천연 α아미노산의 특성기; -[Alk]n R6[여기서 Alk 하나 또는 그 이상의 -O 또는 -S- 원자 또는 -N (R1)-기(여기서 R7은 수소 원자 또는 (C1-C6)알킬기 이다)에 의하여 임의로 차단되는 (C1-C6)알킬 또는 (C2-C6)알킬렌일기이다]; 또는 식 -OCH2COR8기에 의하여 페틸환이 치화노딘 벤질기, 여기서 R8은 히드록실, 아미노, (C1-C6)알콕시, 페닐-(C1-C6)알콕시, (C1-C6)알킬아미노, 디[(C1-C6)알킬]아미노, 페닐(C1-C6)알킬아미노, 아미노산 또는 산할라이드의 잔기, 에스테르 또는 이의 아미드 유도체이고, 이 잔기는 아미드 결합을 통하여 연결되고, 상기 아미노산은 글리신, α또는 β알라닌, 빌린, 류신, 이소류신, 페닐알라딘, 티로신, 트립토판, 세린, 트레오닌, 시스테인, 메티오닌, 아스파라긴, 글루타긴, 글루타민, 리신, 히스티딘, 알기닌, 글루탐산과 아스파르트산에서 선택한다; 또는 헤테로고리 환이 비치환 되거나 아니면 할로, 니트로, 카르복시, (C1-C6)알콕시, 시아노, (C1-C6)알카노일, 트리플루오로메틸-(C1-C6)알킬, 히드록시, 프로밀, 아미노 (C1-C6)알킬아미노, 디-(C1-C6)알킬아미노, 머캅토, (C1-C6)알킬티오, 히드록시 (C1-C6)알킬, 머캅토(C1-C6)알킬 또는 (C1-C6)-알킬페닐메틸로 일-또는 이치환되는, 헤테로고리(C1-C6)알킬기.
  6. 제1항 내지 제4항중 어느 한 항에 있어서, R3가 -CRaRbRc기인 화합물; 상기식에서 Ra, Rb와 Rc는 각각 독립적으로 수소, (C1-C6)알킬, (C2-C6)알켄일, (C1-C6)알킨일, 페닐(C1-C6)알킬, (C3-C8)시클로알킬이고, 단 상기에서 Ra, Rb와 Rc는 모두가 수소는 될수 없다; 또는 Rc는 수소, (C1-C6)알킬, (C2-C6)알켄일, (C2-C6)알킨일, 페닐(C1-C6)알킬, 또는 (C3-C8)시클로알킬이고, Ra와 Rb는 이들에 결합되는 탄소원자와 함께 3∼8원환 시클로알킬는 5-내지 6-원환 헤테로고리 환을 형성한다; Ra, Rb와 Rc는 이들에 결합되는 탄소원자와 함께 삼환(예를 들면 아다만틸)을 형성하며; 또는 Ra와 Rb는 각각 독립적으로 (C1-C6)알킬, (C2-C6)알켄일, (C2-C6)알킨일, 페닐(C1-C6)알킬 또는 수소이외의 하기 Rc로 정의되는 기, 또는 Ra와 Rb는 이들에 결합되는 탄소원자와 함께 3∼8 원환 시클로알킬 또는 3-내지 8원한 헤테로고리 환을 형성하고, Rc는 수소, -OH, -SH, 할로겐, -CN, CO2H, (C1-C4)퍼플루오로알킬, -CH2OH, -CO2(C1-C6)알킬, -O(C1-C6)알킬, -O(C2-C6)알켄일, -S(C1-C6)알킬, -SO(C1-C6)알킬, -OS2(C1-C6)알킬, -S(C2-C6)알켄일, -SO(C2-C6)알켄일, -SO(C2-C6)알켄일, -SO2(C2-C6)알켄일 또는 -Q-W-기이고 Q는 -O-, -S-, -SO- 또는 -SO2-의 결합을 나타내고 W는 페닐, 페닐알킬, (C3-C8)시클로알킬, (C4-C8)시클로알킬알킬, (C4-C8)시클로알켄일, (C4-C8)시클로알켄일알킬,헤테로아릴 또는 헤테로아릴알킬기이고, 이 W기는 히드록시, 할로겐, -CN, -CO2H, -CO2(C1-C6)알킬, -CONH(C1-C6알킬)2, -CHO, -CH2OH, (C1-C4)퍼플루오로알킬, -O(C1-C6)알킬, -S(C1-C6)알킬, -SO(C1-C6)알킬, -SO2(C1-C6)알킬, -NO2, -NH2, -NH(C1-C6)알킬, -N(C1-C6)알킬2, -NHCO(C1-C6)알킬, (C1-C6)알킬, (C2-C6)알켄일, (C2-C6)알킨일, (C3-C8)시클로알킬, (C4-C8)시클로알켄일, 페틸 또는 벤질에서 독립적으로 선택한 하나 또는 그이상의 치환기에 의하여 임의로 치환될 수 있다.
  7. 제1항 내지 제4항중 어느 한 항 에 있어서, R3가 벤질, 이소-부틸 또는 t-부틸, 1-벤질티오-1-1메틸에틸과, 1-머캅토-1-메틸에틸인 화합물.
  8. 전술한 항중 어느 한 항에 있어서, R4가 페닐, 나프틸, 푸란일, 티에닐, 필로린일, 테트라히이드로푸란일, 이미다졸일, 옥사디아졸일, 티아졸일, 티아디아졸일, 피리딘일, 피리딘일 N-산화물, 피페라진일, 인돌일, 벤즈이미다 졸일, 벤조트리아졸일, 피라진일, 피리다진일, 피리미딘일, 디티아닐, 벤조[b]티에닐, 이소옥사졸일 또는 퀴놀린일이고, 이게중 어느것은 제1항의 R4에 관하여 명시된 치환기에 의하여 이므이로 치환되는 화합물.
  9. 제9항에 있어서, R4가 페닐 2-메톡시페닐, 3-메톡시페닐, 4-메톡시페닐, 3,4-디메톡시페닐, 2-플루오로페닐, 3-플루오로페닐, 4-플루오로페닐, 2-클로로페닐, 3-클로로페닐, 4-클로로페닐, 3,4-디클로로페닐, 3,5-디클로로페닐, 2-브로모페닐, 3-브로모페닐, 4-브로모페닐, 2-요오드페닐, 3-요오드페닐, 4-요오드페닐, 2-메틸페닐, 3-메틸페닐, 4-메틸페닐, 3,4-디메틸, 2-t-부틸페닐, 3-t-부틸페닐, 4-t-부틸페닐, 4-t-부틸-2,6-디메틸페닐, 2-니트로페닐, 3-니트로페닐, 4-니트로페닐, 2-시아노페닐, 3-시아노페닐, 4-시아노페닐, 2-아세틸페닐, 3-아세틸페닐, 4-아세틸페닐, 2-메틸술폰일페닐, 3-메틸술폰일페닐, 4-메틸술폰일페닐, 2-트리플루오로메틸페닐, 3-트루플루오로메틸페닐, 4-트리플루오로메틸페닐, 3,5-디트리플루오로메틸페닐, 2-아미노페닐, 3-아미노페닐, 4-아미노페닐, 2-N,N-디메틸-아미노페닐, 3-N,N-디메틸아미노페닐, 4-N,N-디메틸아미노페닐, 2-히드록시페닐, 3-히드록시페닐, 4-히드록시페닐, 2-나프틸, 푸탄-2-일, 티엔-2-일, 피롤-2-일, 테트라하이드로푸탄-2-일, 이미다졸-2-일, 티아졸-2-, 4-에톡시카르보닐메틸티아졸-2-일, 4-페닐티아졸-2-일, 4,5-디메틸티아졸-2-일, 5-브로모티아졸-2-일, 4-tert-부틸티아졸-2-일, 벤조티아질-2-일, 1,2,4-옥사디아졸-5-일, 1,2,4-옥사이다졸-3-일, 3-메틸-1,2,4-옥사이다졸-5-일,3-페닐-1,2,4-옥사디아졸-5-일, 1,3,4-옥사디아졸-2-일, 1,2,4-티아디아졸-5-일, 1,3,4-티아디아졸-2-일, 5-메틸-1,3,4-티아디아졸-2-일, 피리딘-2-일, 피리딘-3-일, 피리딘-4-일, 피리딘-2-일, 피리딘-3-일, 피리딘-4-일의 N-산화물, 피페라진-1-일, 인돌-2-일, 벤즈이미다졸일-2-일, 벤조트리아졸-2-일, 피라진-2-일, 1,2-피리다진-3-일, 1,3-피리미딘-5-일, 1,3-디티안-2-일, 벤조[b]티엔-2-일, 이소옥사졸-5-일, 퀴놀린-3-일인 화합물.
  10. 전술한 항중 어느 한 항에 있어서, R4가 3-메톡시페닐, 피리딘-2-일, 피리딘-3-일, 티아졸-2-일, 4-에톡시카르보닐메틸티아졸-2-일, 5-메틸-1,3,4-티아디아졸-2-일, 또는 4-tert-부틸티아졸-2-일인 화합물.
  11. 전술한 항중 어느 한 항에 있어서, R5가 수소인 화합물.
  12. 다음 화합물에서 선택한 화합물; 3R-(2,2-디메틸-1S-피리딘-2-일 카르바모일-프로필카르바모일)-5-메틸-2S-프로펜-2-일-헥사노히드록삼산, 3R(2,2-디메틸-IS-피리딘-2-일 카르바모일-프로필카르바모일)-2S-히드록시-5-메틸헥사히드록삼산, 3R-(2,2-디메틸-IS-(5-메틸-1,3,4-티아디아졸-2-일 카르바모일)-프로필카르바모일)-2S-히드록시-5-메틸헥사노-히드록삼산. 3R-(2,2-디메틸-IS-(3-메톡시페닐)카르바모일-프로필-카르바모일)-2S-히드록시-5-메틸헥사노-히드록삼산, 3R-(2,2-디메틸-IS-피리딘-3-일 카르바모일-프로필카르바모일)-2S-히드록시-5-메틸 헥사노히드록삼산. 3R-(2,2-디메틸-IS-피리딘-2-일 카르바모일-프로필카르바모일)-5-메틸-2S-프탈이미도메틸헥사노히드록삼산. 3R(2,2-디메틸-IS-(티아졸-2-일 카르바모일)-프로필카르바모일)-5-메틸-2S-프로펜-2-일-헥사노히드록삼산. 3R-(2,2-디메틸IS-(티아졸-2-일 카르바모일)-프로필카르바모일)-2A-히드록시-5-미텔헥사히드록삼산. 3R-(2,2-디메틸-IS-(4-에톡시카르보닐메틸티아졸-2-일 카르바모일)프로필카르바모일)-2S-히드록시-5-메틸힉사노히드록삼산. 과 이들의 염, 용매 화합물 또는 수화물.
  13. 다음 화합물에서 선택한 화합물: 5-메틸-3R-(2-페닐-IS-페닐키르바모일-에틸카르바모일)-헥사노히드록삼산. 3R-(2,2-디메틸-IS-페닐카르바모일-프로필카르바모일)-5-메틸-헥사노히드록삼산, 3R(2,2-디메틸-IS-피리딘-2-일 카르바모일-프로필카르바모일)-5-메틸-헥사노히드록삼산. 3R-(2-2-디메틸-IS-페닐카르바모일-프로필카르바모일)-2S-히드록시-5-메틸헥사하사노히드록삼산, 2S-히드록시-3R-(3-메틸-IS-나프-2-일 카르바모일-부틸카르바모일)-5-메틸-헥사노히드록삼산, 2S-히드록시-3R-(3-메틸-IS(4-메톡시페닐)카르바모일-부틸카르바모일)-5-메틸헥사노히드록삼산. 3R-(2,2-디메틸-IS-(4-ter-부틸-2,6-디메틸페닐)카르바모일-프로필카르바모일)-2s-히드록시-5-메틸힉사노히드록삼산. 3R-(2,2-디메틸-IS-(4-메톡시페닐)카르바모일-프로필카르바모일)-2S-히드록시-5-메틸헥사노히드록삼산. 3R-(2,2-디메틸-IS-피리딘-4-일카르바모일-프로필카르바모일)-2S-히드록시-5-메틸헥사 노히드록삼산, 3R-(2,2-디메틸-IS-(4-히드록시페닐)카르바모일-프로필카르바모일)-2S-히드록시-5-메틸헥사노히드록삼산. 3R-(2-벤질티오-2-메틸-IS-(피리딘-2-일카르바모일)프로필카르바모일)-2S-히드록시-5-메틸헥사노히드록삼산, 3R-(2,2-디메틸-IS-페닐카르바모일-프로필카르바모일)-2S-히드록시-5-페닐헥사노히드록삼산, 3R-(2,2-디메틸-IS-(4,5-디메틸티아졸-2-일카르바모일)-프로필카르바모일)-2S-히드록시-5-메틸헥사노히드록삼산. 3R-(2,2-디메틸-IS-(5-브로모-티아졸-2-일카르바모일)-2S-히드록시-5-메틸헥사노히드록삼산, 3R-(2,2-디메틸-IS(4-페닐-티아졸-2-일카르바모일)-프로필카르바모일)-2S-히드록시-5-메틸헥사노히드록삼산. 3R-(2,2-디메틸-1S-(4tert-부틸티아디아졸-2-일카르바모일)-프로필카르모일)-2S-히드록시-5-메틸헥사노히드록삼산. 3R-(2,2-디메틸-1S-페닐카르바모일-프로필카르바모일)-5-메틸-2S-프로펜-2-일-헥사노히드록삼산. 3R-(2,2-디메틸-1S-(4-메톡시페닐카르바모일)-프로필카르바모일)-5-메틸-2S-프로펜-2-일-헥사노히드록삼산. 3R-(2-벤질티오-2-메틸-1S-(피리딘-2-일카르바모일)-프로필카르바모일)-5-메틸-2S-프로펜-2-일-헥사노히드록 삼산. 3R(2,2-디메틸-1S-(피리딘-3-알카르바모일)-프로필카르바모일)-5-메틸-2S-프로펜-2-일-헥사노히드록삼산. 3R-(2,2-디메틸-1S-(4-히드록시페닐카르바모일)-프로필카르바모일)-5-메틸-2S-프로펜-2-일-헥사노히드록삼산, 3R-(2,2-디메틸-1S-(3-메톡시페닐카르바모일)-프로필카르바모일)-5-메틸-2S-프로펜-2-일-헥사노히드록삼산. 3R-(2,2-디메틸-1S-(피리딘-4-일카르바모일)-프로필카르바모일-5-메틸-2S-프로펜-2-일-헥사노히드록삼산, 3R-(2,2-디메틸-1S-(2-메톡시페닐카르바모일)-프로필카르바모일)-5-메틸-2S-태엔-2-일술판일메틸-헥사노히드록삼산. 3R-(2,2-디메틸-1S-(피리딘-2-일카르바모일)-프로필카르바모일)-5-메틸-2S-태엔-2-일술판일메틸-헥사노히드록삼산. 3R-(2,2-디메틸-1S-(2-메톡시페닐카르바모일)-프로필카르바모일-5-메틸-2S-태엔-2-일술판일메틸-헥사노히드록삼산, 3R-(2,2-디메틸-1S-(피리딘-2-일카르바모일)-프로필카르바모일)-5-메틸-2S-태엔-2-일술판일메틸-헥사노히드록삼산, 3R-(2,2-디메틸-1S-페닐카르바모일-프로필카르바모일)-2S-히드록시-5-페닐헥사노산. 3R-(2,2-디메틸-1S-(N-옥시-피리딘-2-일)카르바모일-프로필카르바모일)-2s-히드록시-5-메틸헥사노히드록삼산,과 이들의 염, 용매 화합물 또는 수화물.
  14. X 가 히드록삼산기(-CONHOH)인 제1항 화합물의 제조방법에 있어서, 본 발명의 다른 특징을 형성하는 이방법은 다음과 같이 이루어진다; (a) 다음 일반식(Ⅱ)의 산 또는 이의 활성화 유도체를
    R4와 R5는 히드록실아민, 0-보호히드록실아민 또는 N,O-이중 보호히드록실아민이나, 이의염과 반응 시킨다음, (상기식에서 R1,R2,R3,R4와 R5는 히드록실아민, O-보호 히드록실아민, N,O-이중보호히드록실아민 또는 이들의 염과 우수하게 반응하는 R1,R2,R3,R4와 R5의 어느 치환기가 이러한 반응에서 그들자신을 보호하는 것을 제외하고 일반식(Ⅰ)에서 정의한 바와 같다.) 히드록실아민, O-보호히드록시아민 또는 N,O-이중 보호히드록실아민이나, 이의 염과 반응시킨 다음 반응생성 히드록삼산기에서와 R1,R2,R3,R4와 R5의 보호 치환기에서 보호기를 제거하거나 또는, (b) 다음(Ⅱb)의 이중보호 히드록삼산유도체를 탈보호하는 방법.
    상기식에서 R1,R2,R3,R4와 R5는 일반식(Ⅰ)에서 정의한 바와 같고, R14는 아미노보호기이고 R15는 히드록실 보호기이다. 방법(a)에서 [화합물(1)의 R1이 히드록시인 특별한 경우에] 히드록시기 R1과 인접한 카르복실기를 다음식(Ⅱa)의 이온살온으로 동시에 보호하고;
    (상기식에서, R12과 R13기는 디올살은 형성시약으로부터 유도된다) 디옥살온환은 히드록시아민과의 반응에 의하여 개방되어 원하는 일반식(Ⅰ)의 히드록삼산을 얻는 방법.
  15. 내용 없음
  16. X가 카르복실산에(-COOH)인 제1항 화합물의 제조방법에 있어서 다음식(Ⅲ)의 산 또는 이의 활성화 유도체를 다음식(Ⅳ)의 아민과 커플링시킨 다음, 보호기 R11,R1,R2,R3,R4와 R5로부터 어떠한 보호기를 제거하여 하는 방법.
    상기 식에서 R1,R2,R3,R4와 R5는 일반식(Ⅰ)에 정의된 바와 같고, 그의 커플링 반응에서 우수한 반응성을 갖는 R1,R2,R3,R4와 R5의 치환기는 그들자체 이러한 반응에서 보호될수 있고, R11은 히드록시보호기를 나타낸다.
  17. 제16항에 있어서, [일반식(1)에서 R1이 히드록시인특별한 경우에 화합물(Ⅲ)이 다음식(Ⅴ)인 제조방법.
    상기식에서 R2,R3,R4와 R5는 일반식(Ⅰ)에서 정의한 바와 같고 R12과 R13기는 디옥살은 형성시약에서 유도된다.
  18. 유효량의 제1항 내지 제13항중 어느 한 항의 화합물을 포유동물에 투여하여서 하는 사람을 포함한 포유동물에 대한 MMPs와/또는 TNF에 의하여 매개돈 질명 또는 증상의 관리(이는 치료는 예방을 뜻한다)방법.
  19. MMPs와/또는 TNF에 의하여 매개되는 질병 또는 증상의 관리(이는 치료는 예방을 뜻한다)에 사람 또는 동물약제로 사용하는 제1항 내지 제13항중 어느 한 항의 화합물.
  20. MMPs과/또는 TNF에 의하여 매개된 질병 도는 증상의 관리(이는 치료 또는 예방을 뜻한다)에 사람 또는 동물약재료로 사용하는 제1항 내지 제13항중 어느 한항의 화합물.
  21. MMPs와/또는 TNF에 의하여 매개된 질병 또는 증상을 관리(이는 치료 또는 예방을 뜻한다)하기 위한 약제의 제조에서 제1항 내지 제13항중 어느 한항의 화합물의 용도.
  22. 관련된 질병 또는 증상이 MMP에 매개도니 것인, 제18항의 방법, 제19항 또는 제20항에서 사용하는 화합물, 또는 제21항의 용도.
  23. 관련된 질병 또는 증상이 류우머티스성관절염, 골관절염, 치주염, 치은염, 각막궤양, 아차 혼합감염에 의한 고체종양성장과 종양칩입, 신혈관녹내장, 다종경화증, 또는 건선인 제18항의 방법. 제19항 또는 제120항에 사용하는 화합물 또는 제21항의 용도.
  24. 관련된 질병 또는 증성이 TNF에 의하여 매개돈 것인 제18항의 방법. 제19항 또는 제20항에 사용하는 화합물 또는 제21항의 용도.
  25. 관련된 질병 또는 증상이 염증, 열, 호흡순환작용, 출혈웅고와 급성기반응, 악태증과 식욕감퇴, 급성전염, 충격상태, 이식편 대 숙주 바능 또는 자가 면역질병인 제18항의 방법, 제19항 또는 제20항에 사용하는 화합물 또는 제21항의 용도.
  26. 약학적으로 또는 수의학적으로 수용할수 있는 부형제 또는 담체와 함께 제1항 내지 제13항중 어느 한 항에 따른 화합물로 이루어지는 약학적 또는 수의학적 조성물.
  27. 제26항에 있어서 경구 투여에 사용하는 약학적 또는 수의학적 조성물.
    ※ 참고사항 : 최초출원 내용에 의하여 공개하는 것임.
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US5859253A (en) 1999-01-12
UA43358C2 (uk) 2001-12-17
NO963030D0 (no) 1996-07-19
NO306396B1 (no) 1999-11-01
KR100418808B1 (ko) 2004-07-23
CZ211596A3 (cs) 1998-04-15
BR9506535A (pt) 1997-09-16
FI962904A (fi) 1996-07-19
DE69515702D1 (de) 2000-04-20
NZ278627A (en) 1997-04-24
ATE165817T1 (de) 1998-05-15
EP0822186A2 (en) 1998-02-04
AU682920B2 (en) 1997-10-23
ES2117400T3 (es) 1998-08-01
HUT75059A (en) 1997-03-28
GR3033209T3 (en) 2000-08-31
DE69502378D1 (en) 1998-06-10
DE19581347T1 (de) 1996-12-05
CN1138851A (zh) 1996-12-25
HU9601991D0 (en) 1996-09-30
DE69502378T2 (de) 1998-10-01
ES2144819T3 (es) 2000-06-16
PT822186E (pt) 2000-08-31
EP0740652B1 (en) 1998-05-06
SK281544B6 (sk) 2001-04-09
EP0822186A3 (en) 1998-03-04
FI962904A0 (fi) 1996-07-19
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DK0822186T3 (da) 2000-06-26
ATE190609T1 (de) 2000-04-15
EP0822186B1 (en) 2000-03-15
US5747514A (en) 1998-05-05
CZ290145B6 (cs) 2002-06-12
AU1459795A (en) 1995-08-08
EP0740652A1 (en) 1996-11-06
WO1995019956A1 (en) 1995-07-27
NO963030L (no) 1996-09-19
PL315745A1 (en) 1996-11-25
DK0740652T3 (da) 1999-02-01
JP3297053B2 (ja) 2002-07-02
PL179997B1 (pl) 2000-11-30
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CN1049651C (zh) 2000-02-23
JPH09508361A (ja) 1997-08-26

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