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KR960704842A - 저콜레스테롤혈증제로서 유용한 하이드록시-치환된 아제티디논 화합물 (Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents) - Google Patents

저콜레스테롤혈증제로서 유용한 하이드록시-치환된 아제티디논 화합물 (Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents)

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KR960704842A
KR960704842A KR1019960701555A KR19960701555A KR960704842A KR 960704842 A KR960704842 A KR 960704842A KR 1019960701555 A KR1019960701555 A KR 1019960701555A KR 19960701555 A KR19960701555 A KR 19960701555A KR 960704842 A KR960704842 A KR 960704842A
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hydroxy
phenyl
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비. 로젠블룸 스튜어트
듀가 선딥
에이. 버네트 듀안
더블유. 클라더 죤
에이. 맥키트릭 브라이언
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쉐링 코포레이션
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Abstract

본 발명은 일반식(Ⅰa)의 하이드록시-치환된 아제티디논 저콜레스테롤혈증제 또는 이의 약제학적으로 허용 되는 염, 이들 화합물을 단독으로 또는 콜레스테롤 생합성 억제제와 배합하여 투여함으로서 혈청 콜레스테롤을 낮추는 방법, 이들 화합물을 함유하는 약제학적 조성물, 및 그들 화합물을 제조하는 방법에 관한 것이다.
상기 식에서Ar1및 Ar2는 아릴 및 R4-환된 아릴이고; Ar3또는 Ar5-치환된 아릴이며; X,Y 및 Z는 -CH2-, CH(저급 알킬)-또는 -C(디저급 알킬)-이고; R 및 R2는 -OR6, -O(CO)R6-O(CO)OR9또는 -O(CO)NR6R7이며; R1및 R3은 수소 또는 저급 알킬이고; q는 0 또는 1이며; r은 0 또는 1이고; m,n 및 p는 0 내지 4이며; 단, q 및 r 중의 하나 이상은 1이고 m,n,p,q 및 r의 합은 1 내지 6이며; p가 0이고 r이 1일때 m,q 및 n의 합은 1 내지 5이고; R4는 저급 알킬, -CF3,-CN, -NO2및 할로겐중에서 선택되고; R5는 -OR6, -O(CO)R6, -O(CO)OR9, -O(CH2)1-5OR6, -O(CO)NR6R7, -NR6R7,-NR6(CO)R7, -NR6(CO)OR9, -NR6(CO)R7R8, -NR6SO2R9, -COOR6, CONR6R7, - COR6, -SO2NR6R7, S(O)0-2R9, -O(CH2)1-10-COOR6, -O(CH2)1-10-CONR6R7, -(저급 알킬렌)COOR6및 -CH=CH-COOR6중에서 선택되고; R6, R7및 R8은 수소, 저급 알킬, 아릴 및 아릴-치환된 저급 알킬이며; R9는 저급 알킬, 아릴 또는 아릴-치환된 저급 알킬이다.

Description

저콜레스테롤혈증제로서 유용한 하이드록시-치환된 아제티디논 화합물(Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents)
본 내용은 요부공개 건이므로 전문내용을 수록하지 않았음

Claims (22)

  1. 하기 일반식(Ⅰ)의 화합물 또는 이의 약제학적으로 허용되는 염.
    상기 식에서, Ar1및 Ar2는 독립적으로 아릴 및 R4- 치환된 아릴로 이루어진 그룹중에서 선택되고; Ar3은 아릴 또는 R5- 치환된 아릴이며; X,Y 및 Z는 독립적으로 -CH2-, CH(저급 알킬)- 및 -C(디저급 알킬)-로 이루어진 그룹중에서 선택되고;R 및 R2는 독립적으로 -OR6, -O(CO)R6-O(CO)OR9및 -O(CO)NR6R7으로 이루어진 그룹중에서 선택되며; R1및 R3은 독립적으로 수소, 저급 알킬 및 아릴로 이루어진 그룹중에서 선택되고; -q는 0 또는 1이며; r은 0 또는 1이고; m,n 및 p는 독립적으로 0,1,2,3, 또는 4이며; 단, q 및 r 중의 하나 이상은 1이고 m,n,p,q 및 r의 합은 1,2,3,4,5 또는 6이며; p가 0이고 r이 1일때 m,q 및 n의 합은 1,2,3,4 또는 5이며; R4는 독립적으로 저급 알킬, -OR6, -O(CO)R6, -O(CO)OR9, -O(CH2)1-5OR6, -O(CO)NR6R7, -NR6R7,-NR6(CO)R7, -NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO2R9, -COOR6, CONR6R7, - COR6, -SO2NR6R7, S(O)0-2R9, -O(CH2)1-10-COOR6, -O(CH2)1-10-CONR6R7, -(저급 알킬렌)COOR6-CH=CH=COOR6-CF3,-CN, -NO2및 할로겐으로 이루어진 그룹중에서 선택된 1 내지 5개의 치환체이고; R5는 독립적으로 -OR6, -O(CO)R6, -O(CO)OR9, -O(CH2)1-5OR6, -O(CO)NR6R7, -NR6R7,-NR6(CO)R7, -NR|6(CO)OR9, -NR6(CO)NR7R8, -NR6SO2R9, -COOR6, CONR6R7, - COR6, -SO2NR6R7, S(O)0-2R9, -O(CH2)1-10-COOR6, -O(CH2)1-10-CONR6R7, -(저급 알킬렌)COOR6및 -CH=CH=COOR6으로 이루어진 그룹중에서 선택된 1 내지 5개의 치환체이며; R6, R7및 R8은 독립적으로 수소, 저급 알킬, 아릴 및 아릴-치환된 저급 알킬로 이루어진 그룹중에서 선택되고; R9는 저급 알킬, 아릴 또는 아릴-치환된 저급 알킬이다.
  2. 제1항에 있어서 Ar1이 페닐 또는 R4-치환된 페닐이고,Ar2가 페닐 또는 R4-치환된 페닐이며, Ar3이 R5-치환된 페닐인 화합물.
  3. 제2항에 있어서 Ar1이 R4-치환된 페닐(여기서,R6는 할로겐이다)이고, Ar2가 R4-치환된 페닐[여기서,R4는 할로겐 또는 -OR5(여기서, R6는 저급 알킬 또는 수소이다)이다]이며, Ar3이 R5-치환된 페닐[여기서,R5는 -OR6(여기서, R5는 저급 알킬 또는 수소이다)이다]인 화합물.
  4. 제1항 내지 제3항 중 어느 한 항에 있어서, X,Y 및 Z가 각각 -CH2-이고,R1및 R3가 각각 수소이며, R 및 R2가 각각 -OR5(여기서, R5는 수소이다)이고, m,n,p,q, 및 r의 합이 2,3,또는 4인 화합물.
  5. 제1항 내지 제4항 중 어느 한 항에 있어서, m,n 및 r이 각각 0이고, q가 1이며, p가 2인 화합물.
  6. 제1항 내지 제4항 중 어느 한 항에 있어서, p,q 및 n이 각각 0이고, r이 1이며, m이 2 또는 3인 화합물.
  7. 제1항에 있어서 rel 3(R)-(2-(R)-하이드록시-2-페닐에틸)-4(R)-(4 메톡시페닐)-1-페닐-2-아제티디논; rel 3(R)-(2-(R)-하이드록시-2-페닐에틸)-4(S)-(4-메톡시페닐)-1-페닐-2-아제티디논; 3(S)-(1-(S)-하이드록시-3-페닐프로필)-4(S)-(4 메톡시페닐)-1-페닐-2-아제티디논;3(S)-(1-(R)-하이드록시-3-페닐프로필)-4(S)-(4 메톡시페닐)-1-페닐-2-아제티디논;3(R)-(1(R)-하이드록시-3-페닐프로필)-4(S)-(4-메톡시페닐)-1-페닐_2-아제티디본;rel-3(R)-[(S)-하이드록시-2-나프탈레닐)메틸]-4(S)-(4-메톡시페닐)-1-페닐-2-아제티디논; rel-3(R)-[(R)-하이드록시-2-나프탈레닐)메틸]4(S)-(4 메톡시페닐)-1-페닐-2-아제티디논; 3(R)-(3(R)-하이드록시-3-페닐프로필)-1,4(S)-비스-(4-메톡시페닐)-1-페닐-2-아제티디논; 3(R)-(3(S)-하이드록시-3-페닐프로필)-1,4(S)-비스-(4-메톡시페닐)-2-아제티디논;4(S)-(4-하이드록시페닐)-3(R)-(3(R)하이드록시-3-페닐프로필)-1-(4-메톡시페닐)-2-아제티디논;4(S)-(4-하이드록시페닐)-3(R)-(3(S)하이드록시-3-페닐프로필)-1-(4-메톡시페닐)-2-아제티디논; rel-3(R)-[3(RS)-하이드록시-3-[4-메톡시메톡시)-페닐]프로필]-1,4(S)-비스-(4-메톡시페닐)-2-아제티디논; 1-(4-플루오로페닐)-3(R)-[3(S)-(4-플루오로페닐)-3-하이드록시프로필)]-4(S)-(4-하이드록시페닐)-2-아제티디논;1-(4-플루오로페닐)-3(R)[3(R)-(4-플루오로페닐)-3-하이드록시프로필)]-4(S)-(4-하이드록시페닐)-2-아제티디논;4(S)-[4-(아세틸옥시)페닐]-3(R)-(3(R)-하이드록시-3-페닐프로필)-1-(4-메톡시페닐)-2-아제티디논;4(S)-[4-(아세틸옥시)페닐]-3(R)-(3(S)-하이드록시-3-페닐프로필)-1-(4-메톡시페닐)-2-아제티디논;1-(4-플루오로페닐)-3(R)-[3(S)-(4-플루오로페닐)-3-하이드록시프로필)]-4(S)-(4-페닐메톡시)페닐]-2-아제티디논;3(R)-[3(R)-(아세틸옥시)-3-페닐프로필]-1,4(S)-비스-(4-메톡시페닐)-2-아제티디논;3(R)-[3(S)-(아세틸옥시)-3-페닐프로필]-1,4(S)-비스-(4-메톡시페닐)-2-아제티디논;3(R)-[3(R)-(아세틸옥시)-3-(4-플루오로페닐)프로필]-4(S)-[4-(아세틸옥시)-페닐]-1-(4-플루오로페닐)-2-아제티디논;3(R)-[3(S)-(아세틸옥시)-3-(4-플루오로페닐)프로필]-4(S)-[4-(아세틸옥시)-페닐]-1-(4-플루오로페닐)-2-아제티디논;3(R)-[3(R)-(아세틸옥시)-3-(4-클로로페닐)프로필]-4(S)-[4-(아세틸옥시)-페닐]-1-(4-클로로페닐)-2-아제티디논;3(R)-[3(S)-(아세틸옥시)-3-(4-클로로페닐)프로필]-4(S)-[4-(아세틸옥시)-페닐]-1-(4-클로로페닐)-2-아제티디논 및 rel 1-(4-플루오로페닐)-4(S)-(하이드록시페닐)-3(R)-(1(R)-하이드록시-3-페닐프로필)-2-아제티디논으로 이루어진 그룹중에서 선택된 화합물.
  8. 약제학적으로 허용되는 담체중에 유효량의 제1항 내지 제7항 중 어느 한 항의 화합물을 단독으로 또는 클레스테롤 생합성 억제제와 배합하여 포함하는, 아테롬성 동맥경화증을 치료 또는 예방하거나 혈장 콜레스테롤 수준을 감소시키기 위한 약제학적 조성물.
  9. 아테롬성 동매경화증을 치료 또는 예방하거나 혈장 콜레스테롤 수준을 감소시키기 위한 약제의 제조에 있어서 제1항 내지 제7항 중 어느 한 항에 따른 화합물의 용도.
  10. 제1항 내지 제7항 중 어느 한 항에 정의된 화합물을 약제학적으로 허용되는 담체와 혼합함을 특징으로 하여, 제8항의 약제학적 조성물을 제조하는 방법.
  11. 제1항 내지 제7항 중 어느 한 항에 정의된 화합물 및 콜레스테롤 생합성 억제제를 약제학적으로 허용되는 담체와 혼합함을 특징으로 하여, 제8항의 약제학적 조성물을 제조하는 방법.
  12. 아테롬성 동매경화증의 치료 또는 예방에서 또는 혈장 클레스테롤 수준 감소를 위한 콜레스테롤 생합성 억제제와의 배합 사용용 약제 제조시 제1항 내지 제7항 중 어느 한 항에 따른 화합물의 용도.
  13. 아테롬성 동매경화증의 치료 또는 예방에서 또는 혈장 클레스테롤 수준 감소를 위한 제1항 내지 제7항 중 어느 한 항에 따른 화합물과의 배합 사용용 약제 제조시 콜레스테롤 생합성 억제제의 용도.
  14. 약제학적으로 허용되는 담체중의 유효량의 콜레스테롤 생합성 억제제를 함유하는 약제학적 조성물을 제1용기에 포함하고 약제학적으로 허용되는 담체중의 유효량의 제1항 내지 제7항 중 어느 한항에 정의된 화합물을 함유하는 약제학적 조성물을 제2용기에 포함하는, 아테롬성 동맥경화증을 치료 또는 예방하거나 혈장 콜레스테롤 수준을 감소시키기 위한 배합 사용용 약제학적 조성물을 단일 팩키지중의 분리 용기에 포함하는 키트.
  15. 제1항 내지 제7항 중 어느 한 항에 정의된 유효량의 화합물을 단독으로 또는 유효량의 콜레스테롤 생합성 억제제와 배합하여 아테롬성 동맥경화증의 치료를 필요로 하는 포유동물에게 투여함을 특징으로 하여, 아테롬성 동맥경화증을 치료 또는 에방하거나 혈장 코레스테롤 수준을 감소시키는 방법.
  16. 제8항, 제11항 또는 제14항에 있어서, 콜레스테롤 생합성 억제제가 HMG CoA환원효소 억제제, 스쿠알렌 합성 억제제 및 스쿠알렌 에폭시다제 억제제로 이루어진 그룹중에서 선택되는 약제학적 조성물.
  17. 제16항에 있어서, 콜레스테롤 생합성 억제제가 로바스타틴, 프라바스타틴, 플루바스타틴, 심바스타틴,CI-981,DMP-565,L-659,699, 스쿠알렌스타틴 1 및 NB-598로 이루어진 그룹중에서 선택되는 약제학적 조성물.
  18. 제12항 또는 제13항에 있어서, 콜레스테롤 생합성 억제제가 제16항 또는 제17항에 정의된 바와 같은 억제제인 용도.
  19. 제15항에 있어서, 콜레스테롤 생합성 억제제가 제16항 또는 제17항에 정의된 바와 같은 억제제인 방법.
  20. (a)일반식(A)의 락톤을 강 염기로 처리하고, (b)단계(a)의 생성물을 일반식
    의 이민(여기서, Ar20은 Ar2,적절히 보호된 하이드록시-치환된 아릴 또는 적절히 보호된 아미노-치환된 아릴이고;Ar30은 Ar3,적절히 보호된 하이드록시-치환된 아릴 또는 적절히 보호된 아미노-치환된 아릴이다)과 반응시키며,(c)반응물을 산으로 켄칭시키고,(d) R′,Ar10, Ar20및 Ar30으로부터 존재하는 보호그룹을 임의로 제거하며, (e)R3치환체가 부착되어 있는 탄소 및 R에서의 치환기, 및 Ar1, Ar2및 Ar3에서의 하이드록시 또는 아미노 치환기를 임의로 작용화시킴을 특징으로 하여, 일반식(ⅠA)의 화합물을 제조하는 방법.
    상기 식에서,Ar1, Ar2, Ar3,X,Y,Z,R,R1,R3,m,n,p및 q는 제1항에 정의한 바와 같고, 단, m,n,p및 q이 합은 1내지 6이며; R′는 보호된 하이드록시 그룹이고; Ar10은 상기 정의된 바와 같은 Ar1,적절히 보호된 하이드록시-치환된 아릴 또는 적절히 보호된 아미노-치환된 아릴이다.
  21. (a)일반식(B)의 락톤을 강 염기로 처리하고, (b)단계(a)의 생성물을 일반식
    의 이민(여기서, Ar20은 Ar2,적절히 보호된 하이드록시-치환된 아릴 또는 적절히 보호된 아미노-치환된 아릴이고;Ar30은 Ar3,적절히 보호된 하이드록시-치환된 아릴 또는 적절히 보호된 아미노-치환된 아릴이다)과 반응시키며,(c)반응물을 산으로 켄칭시키고,(d) R2′,Ar10, Ar20및 Ar30으로부터 존재하는 보호그룹을 임의로 제거하며, (e)R1치환체가 부착되어 있는 탄소에서의 치환기 및 Ar1, Ar2및 Ar3에서의 하이드록시 또는 아미노 치환기를 작용화시킴을 특징으로 하여, 일반식(ⅠB)의 화합물을 제조하는 방법.
    상기 식에서,Ar1, Ar2, Ar3,X,Y,Z,R,R1,R2,R3,m,n,p및 r은 제1항에 정의한 바와 같고, 단, m,n,p및 r의 합은 1내지 6이며;r 및 n이 각각 0이면, p는 1 내지 4이고; Ar10은 상기 정의된 Ar1,적절히 보호된 하이드록시-치환된 아릴 또는 적절히 보호된 아미노-치환된 아릴이고;R2′는 보호된 하이드록시 그룹이다.
  22. 공정 A:
    일반식(Ⅲ)의 에스테르(여기서,R1,R3,X,Y,Z,m,n,p,q및 r은 제1항에 정의한 바와 같고, R1및 Ar10은 제20항에 정의한 바와 같으며;R2′는 제21항에 정의한 바와 같고; R10은 저급 알킬, 메틸 또는 10-(디이소프로필설폰아미도)이소보르닐이다)를 강 염기로 처리하고, 이어서 일반식(Ⅱ)의 이민(여기서, Ar20및 Ar30은 제20항에 정의한 바와 같다)으로 처리하여 제1항에 정의된 바와 같은 일반식(Ⅰ)의 화합물을 수득하거나;
    공정 B:
    일반식(Ⅴ)의 아제티디논(여기서,Ar20및 Ar30은 제20항에 정의한 바와 같다)을 강 염기로 처리하고, 이어서 일반식(Ⅵ)의 알데하이드 또는 케톤(여기서,R1,R3,X,Y,m,n 및 q는 제1항에 정의한 바와 같고, R′ 및 Ar10은 제20항에 정의한 바와 같다)으로 처리하여 r이 1이고 p가 0이며 R2가 OH인 일반식(I)의 화합물인 일반식 (Ie)의 화합물을 수득하거나;
    공정 C:
    일반식(X)의 화합물(여기서, 변수는 상기 공정 A 및 공정 B에 정의한 바와 같다)을 트리알킬포스핀 및 디알킬아조디카복실레이트로 폐환시켜 일반식(I)의 상대적인 3,4-트란스 화합물인 일반식(Ia)의 화합물을 수득하거나;
    공정 D:
    일반식(Ⅱ)의 이민(여기서,Ar20및 Ar30은 공정 A에 정의한 바와 같다)을 일반식(Ⅶ)의 활성화된 카복실산(여기서, L은 Cl,OP(O)(Cl)OPh,2-옥시-N메틸피리디늄 요오다이드 또는 2-티오피리딜 에스테르이고, 나머지 변수는 공정 A 및 공정 B에 정의한 바와 같다)으로 3급 아민 염기의 존재하에 처리하거나;
    공정 E:
    일반식(ⅩⅢ) 의 화합물(여기서, 변수는 상기 공정 A 및 공정 B에 정의한 바와 같다)을 강 비-친핵성 염기로 처리하여 일반식(I)의 상대적인 3,4-트란스 화합물인 일반식(Ia)의 화합물을 수득하거나;
    공정 F:
    일반식 (ⅩⅥ)의 알데하이드 또는 케톤(여기서, 변수는 상기 공정 A및 공정 B에 정의한 바와 같다)을 Ar10-유기금속성 시약(여기서, Ar10은 상기 공정 A에 정의한 바와 같다)으로 처리하여 R이 OH인 일반식(I)의 화합물인 일반식(Ig)의 화합물을 수득하고, 이어서 보호 그룹을 임의로 제거하거나;
    공정 G:
    일반식(ⅩⅧ)의 화합물(여기서, Hal은 Cl,Br 또는 I이고, Ar1, Ar2, Ar3,R1,R2,R3,Y,Z,q,n,r및 p는 제1항에 정의한 바와 같다)을 테트라알킬-암모늄 염 또는 테트라 n-부틸암모늄 트리플루오로아세테이트로 처리하고, 이어서 온화한 염기로 처리하여 m이 0이고, R이 OH인 일반식(I)의 화합물인 일반식(Ii)의 화합물을 수득하거나;
    공정 H:
    일반식(ⅩⅩ)의 케톤(여기서,Ar10, Ar20, Ar30,R2′,R3,X,Y,Z,m,n,r및 p는 공정 A항에 정의한 바와 같다)을 환원시켜 q가 1이고 R이 OH이며 R1이 H이고 나머지 변수가 일반식(ⅩⅩ)에 정의한 바와 같은 일반식(I)의 화합물인 일반식(Ij)의 화합물을 수득하고, 이어서 보호 그룹을 임의로 제거하거나;
    공정 I:
    일반식(ⅩⅩⅥ) 의 알릴 알콜(여기서,Ar1, Ar2, Ar3및 R1는 제1항에 정의한 바와 같고, X′Y′중 및 하나는 -CH=CH-이고 다른 하나는 -CH=CH-,-CH2-,CH2CH2-,-CH(저급 알킬)-,-CH(디저급 알킬)또는 결합이다)을 수소화하여 Ar1, Ar2, Ar3및 R1이 상기 정의한 바와 같고 X″ 및 Y″중 하나가 -CH2=CH2-이고 다른 하나가 -CH2=CH2-,-CH2-,-CH(저급 알킬)-,-CH(디저급 알킬)또는 결합으로 이루어진 그룹중에서 선택되는 일반식(I)의 화합물인 일반식(Ik)의 화합물을 수득하거나;
    공정 I:
    일반식(ⅩⅩⅨ)의 알콜 (여기서, 변수는 공정 A에 정의한 바와 같다)을 트리스(트리메틸실릴)실란으로 라디칼개시제의 존재하에 탈할로겐화시켜 일반식(Im)및 (In) 의 이성체의 혼합물(여기서, 변수는 상기 정의한 바와 같다)을 수득하고, 이어서 임의로 이성체를 분리하고 보호 그룹을 제거함을 특징으로 하여, 일반식(I)의 화합물을 제조하는 방법.
    ※ 참고사항 : 최초출원 내용에 의하여 공개하는 것임.
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