KR20170010439A - 히단토인 유도체 함유 의약 조성물 - Google Patents
히단토인 유도체 함유 의약 조성물 Download PDFInfo
- Publication number
- KR20170010439A KR20170010439A KR1020177000115A KR20177000115A KR20170010439A KR 20170010439 A KR20170010439 A KR 20170010439A KR 1020177000115 A KR1020177000115 A KR 1020177000115A KR 20177000115 A KR20177000115 A KR 20177000115A KR 20170010439 A KR20170010439 A KR 20170010439A
- Authority
- KR
- South Korea
- Prior art keywords
- phenyl
- compound
- dione
- group
- triazaspiro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
Description
도 2는 정상 랫트로의 4주간 반복투여에 있어서의 요추 및 하퇴골의 골밀도를 나타내는 도면이다. 즉, 정상 랫트에 비히클, 화합물 7 또는 hPTH(1-34)를 4주간 1일 1회 반복투여한 경우에 있어서의 요추 및 하퇴골의 골밀도를 이중 X선 골염량 측정장치를 사용하여 측정한 결과를 나타내는 도면이다.
도 3은 정상 랫트로의 4주간 반복투여에 있어서의 하악골의 골밀도를 나타내는 도면이다. 즉, 정상 랫트에 비히클, 화합물 7 또는 hPTH(1-34)를 4주간 1일 1회 반복투여한 경우의 하악골의 골밀도를 이중 X선 골염량 측정장치를 사용하여 측정한 결과를 나타내는 도면이다.
도 4는 토끼 하퇴골 관절연골세포의 최종 분화에 대한 화합물 7의 억제작용을 나타내는 도면이다. 즉, 토끼 하퇴골 관절연골세포의 최종 분화에 대한 화합물 7 및 hPTH(1-34)의 억제작용을 알칼리포스파타아제 염색(A), 알리자린 레드 S 염색(B)에 의해 평가한 결과를 나타내는 도면이다.
도 5는 인간 연골세포에 있어서의 프로테오글리칸 합성량을 나타내는 도면이다. 즉, 인간 연골세포에 있어서의 프로테오글리칸 합성에 대한 화합물 7 및 hPTH(1-34)의 촉진작용을 평가한 결과를 나타내는 도면이다.
도 6은 토끼 반월판 부분 절제 모델의 하퇴골 관절연골의 병변부 면적 비율을 나타내는 도면이다. 즉, 토끼 반월판 부분 절제 모델의 관절 내에 비히클 또는 화합물 7을 지속 투여한 경우의 하퇴골 관절연골의 병변부 면적 비율을 측정한 결과를 나타내는 도면이다.
도 7은 토끼 반월판 부분 절제 모델의 하퇴골 관절연골의 수술 후 2주간에서의 육안적 변화를 나타내는 도면이다. 즉, 토끼 반월판 부분 절제 모델의 관절 내에 비히클 또는 화합물 7을 지속 투여한 경우의 수술 후 2주간에서의 하퇴골 관절연골의 변화를 육안적으로 관찰한 결과를 나타내는 도면이다.
도 8은 정상 랫트로의 4주간 반복 경구투여 후의 대표예의 대퇴골 원위단(distal end) 관절연골의 조직 화상을 나타내는 도면이다. 즉, 정상 랫트에 비히클 또는 화합물 7을 4주간 1일 1회 반복 경구투여한 후, 대표예의 대퇴골 원위단 관절연골을 광학 현미경으로 병리조직학적으로 관찰한 결과를 나타내는 도면이다.
도 9는 TPTX 랫트 모델에 30 ㎎/㎏의 용량으로 경구투여했을 때의 각 화합물의 투여 후 24시간까지의 혈청 Ca 농도 평균 변화량을 나타내는 도면이다.
도 10은 성숙령의 난소 적출 랫트에 비히클, 화합물 7 또는 hPTH(1-34)를 3개월간 1일 1회 반복투여한 경우의 요추 및 대퇴골의 골밀도를 이중 X선 골염량 측정장치에 의해 측정한 결과를 나타내는 도면이다.
도 11은 토끼 반월판 부분 절제 모델의 관절 내에 비히클 또는 화합물 7을 투여하고 4주간 후의 무릎관절 연골의 변화를 조직학적으로 평가한 결과를 나타내는 도면이다.
Claims (14)
- 하기 화학식 1로 표시되는 화합물 또는 그의 약리학적으로 허용되는 염을 유효 성분으로서 포함하는 뼈 및/또는 연골 동화작용(anabolism)을 유도하기 위한 의약 조성물;
[화학식 1]
〔화학식 중,
R1 및 R2는 R1과 R2가 모두 수소원자가 아니라는 조건하에 각각 독립적으로
1) 수소원자,
2) 할로겐원자,
3) 1~5개의 불소원자로 치환되어 있어도 되는 탄소수 1~2개의 알킬기, 또는
4) 1~5개의 불소원자로 치환되어 있어도 되는 탄소수 1~2개의 알콕시기
이거나; 또는
R1 및 R2는 서로 결합하여 형성되는 하기 식:
(식 중 각 *는 페닐 부분과의 결합 위치를 나타낸다.)으로 표시되는 기이고;
또한 R3 및 R4는 각각 독립적으로 1~3개의 불소원자로 치환되어 있어도 되는 메틸기이거나; 또는
R3 및 R4는 그들이 결합하는 탄소원자와 함께 탄소수 3~6의 고리(여기서 고리를 형성하는 탄소원자 중 하나는 산소원자; 황원자; 또는 메틸기로 치환되어 있어도 되는 질소원자로 치환되어 있어도 된다.)를 형성한다.〕. - 제1항에 있어서,
상기 화학식 1로 표시되는 화합물 또는 그의 약학적으로 허용되는 염의 R1 및 R2가 아래의 조합에서 선택되고:
1) R1이 수소원자 또는 할로겐원자이며, 또한 R2가 수소원자, 트리플루오로메틸기 또는 트리플루오로메톡시기이다(단, R1과 R2가 모두 수소원자가 되는 경우를 제외한다);
2) R1이 트리플루오로메틸기 또는 트리플루오로메톡시기이고, 또한 R2가 수소원자 또는 할로겐원자이다;
3) R1 및 R2가 서로 결합하여 형성되는 하기 식:
(식 중 각 *는 페닐 부분과의 결합 위치를 나타낸다.)으로 표시되는 기이다;
또한 R3 및 R4가 메틸기이거나; 또는
R3 및 R4가 그들이 결합하는 탄소원자와 함께 아래에서 선택되는 고리:
(식 중 *는 이미다졸리딘-2,4-디온 부분과의 결합 위치를 나타낸다.)를 형성하는 의약 조성물. - 제1항에 있어서,
상기 화학식 1로 표시되는 화합물 또는 그의 약학적으로 허용되는 염의 R1, R2가 아래의 조합에서 선택되고:
1) R1이 트리플루오로메톡시기이며, 또한 R2가 불소원자이다;
2) R1이 브롬원자이고, 또한 R2가 수소원자이다;
3) R1이 트리플루오로메틸기이고, 또한 R2가 불소원자이다;
4) R1이 불소원자이고, 또한 R2가 트리플루오로메톡시기이다;
5) R1이 트리플루오로메틸기이고, 또한 R2가 수소원자이다;
6) R1이 수소원자이고, 또한 R2가 트리플루오로메톡시기이다;
7) R1, R2는 서로 결합하여 형성되는 하기 식:
(식 중 각 *는 페닐 부분과의 결합 위치를 나타낸다.)으로 표시되는 기이다;
또한 R3 및 R4가 메틸기이거나; 또는
R3 및 R4가 그들이 결합하는 탄소원자와 함께 아래에서 선택되는 고리:
(식 중 *는 이미다졸리딘-2,4-디온 부분과의 결합 위치를 나타낸다.)를 형성하는 의약 조성물. - 제1항에 있어서,
상기 화학식 1로 표시되는 화합물 또는 그의 약학적으로 허용되는 염의 R3 및 R4가 메틸기인 의약 조성물. - 제1항에 있어서,
아래의 것으로 이루어진 군으로부터 선택되는 화합물 또는 그의 약리학적으로 허용되는 염을 유효 성분으로서 포함하는 의약 조성물:
1-(4-(2-((2-(4-플루오로-3-(트리플루오로메톡시)페닐)-4-옥소-1,3,8-트리아자스피로[4.5]데카-1-엔-8-일)설포닐)에틸)-3,5-디메틸페닐)-5,5-디메틸이미다졸리딘-2,4-디온;
1-(4-(2-((2-(3-브로모페닐)-4-옥소-1,3,8-트리아자스피로[4.5]데카-1-엔-8-일)설포닐)에틸)-3,5-디메틸페닐)-5,5-디메틸이미다졸리딘-2,4-디온:
1-(4-(2-((2-(4-플루오로-3-(트리플루오로메틸)페닐)-4-옥소-1,3,8-트리아자스피로[4.5]데카-1-엔-8-일)설포닐)에틸)-3,5-디메틸페닐)-5,5-디메틸이미다졸리딘-2,4-디온;
1-(4-(2-((2-(3-플루오로-4-(트리플루오로메톡시)페닐)-4-옥소-1,3,8-트리아자스피로[4.5]데카-1-엔-8-일)설포닐)에틸)-3,5-디메틸페닐)-5,5-디메틸이미다졸리딘-2,4-디온;
1-(4-(2-((2-(2,2-디플루오로벤조[d][1,3]디옥솔-5-일)-4-옥소-1,3,8-트리아자스피로[4.5]데카-1-엔-8-일)설포닐)에틸)-3,5-디메틸페닐)-5,5-디메틸이미다졸리딘-2,4-디온;
1-(3,5-디메틸-4-(2-((4-옥소-2-(3-(트리플루오로메틸)페닐)-1,3,8-트리아자스피로[4.5]데카-1-엔-8-일)설포닐)에틸)페닐)-5,5-디메틸이미다졸리딘-2,4-디온;
1-(3,5-디메틸-4-(2-((4-옥소-2-(4-(트리플루오로메톡시)페닐)-1,3,8-트리아자스피로[4.5]데카-1-엔-8-일)설포닐)에틸)페닐)-5,5-디메틸이미다졸리딘-2,4-디온);
1-(3,5-디메틸-4-(2-((4-옥소-2-(4-(트리플루오로메톡시)페닐)-1,3,8-트리아자스피로[4.5]데카-1-엔-8-일)설포닐)에틸)페닐)-1,3-디아자스피로[4.4]노난-2,4-디온;
1-(3,5-디메틸-4-(2-((4-옥소-2-(4-(트리플루오로메톡시)페닐)-1,3,8-트리아자스피로[4.5]데카-1-엔-8-일)설포닐)에틸)페닐)-8-메틸-1,3,8-트리아자스피로[4.5]데칸-2,4-디온;
5-(3,5-디메틸-4-(2-((4-옥소-2-(4-(트리플루오로메톡시)페닐)-1,3,8-트리아자스피로[4.5]데카-1-엔-8-일)설포닐)에틸)페닐)-2-옥사-5,7-디아자스피로[3.4]옥탄-6,8-디온; 및
4-(3,5-디메틸-4-(2-((4-옥소-2-(4-(트리플루오로메톡시)페닐)-1,3,8-트리아자스피로[4.5]데카-1-엔-8-일)설포닐)에틸)페닐)-4,6-디아자스피로[2.4]헵탄-5,7-디온. - 제1항에 있어서,
화합물이 1-(3,5-디메틸-4-(2-((4-옥소-2-(3-(트리플루오로메틸)페닐)-1,3,8-트리아자스피로[4.5]데카-1-엔-8-일)설포닐)에틸)페닐)-5,5-디메틸이미다졸리딘-2,4-디온 또는 그의 약리학적으로 허용되는 염인 의약 조성물. - 제1항에 있어서,
화합물이 1-(3,5-디메틸-4-(2-((4-옥소-2-(4-(트리플루오로메톡시)페닐)-1,3,8-트리아자스피로[4.5]데카-1-엔-8-일)설포닐)에틸)페닐)-5,5-디메틸이미다졸리딘-2,4-디온 또는 그의 약리학적으로 허용되는 염인 의약 조성물. - 제1항에 있어서,
화합물이 1-(3,5-디메틸-4-(2-((4-옥소-2-(4-(트리플루오로메톡시)페닐)-1,3,8-트리아자스피로[4.5]데카-1-엔-8-일)설포닐)에틸)페닐)-1,3-디아자스피로[4.4]노난-2,4-디온 또는 그의 약리학적으로 허용되는 염인 의약 조성물. - 제1항에 있어서,
의약 조성물이 골다공증의 예방 또는 치료, 치주병에 있어서의 골량 감소의 개선, 발치 후의 치조골 결손의 회복 촉진, 변형성관절증의 예방 또는 치료, 관절연골 결손의 회복 촉진, 무형성골증의 예방 또는 치료, 연골무형성증의 예방 또는 치료, 연골저형성증의 예방 또는 치료, 골연화증의 예방 또는 치료, 또는 골절의 회복 촉진용인 의약 조성물. - 제1항 내지 제9항 중 어느 한 항에 기재된 화합물 또는 그의 약리학적으로 허용되는 염의 의약적으로 유효한 양을 골다공증의 예방 또는 치료, 치주병에 있어서의 골량 감소의 개선, 발치 후의 치조골 결손의 회복 촉진, 변형성관절증의 예방 또는 치료, 관절연골 결손의 회복 촉진, 무형성골증의 예방 또는 치료, 연골무형성증의 예방 또는 치료, 연골저형성증의 예방 또는 치료, 골연화증의 예방 또는 치료, 또는 골절의 회복 촉진을 필요로 하는 환자에게 투여하는 것을 포함하는, 뼈 및/또는 연골 동화작용의 유도방법.
- 제11항에 있어서,
뼈 및/또는 연골 동화작용의 유도방법이 골다공증의 예방 또는 치료방법, 치주병에 있어서의 골량 감소의 개선방법, 발치 후의 치조골 결손의 회복 촉진방법, 변형성관절증의 예방 또는 치료방법, 관절연골 결손의 회복 촉진방법, 무형성골증의 예방 또는 치료방법, 연골무형성증의 예방 또는 치료방법, 연골저형성증의 예방 또는 치료방법, 골연화증의 예방 또는 치료방법, 또는 골절의 회복 촉진방법인 방법. - 골다공증의 예방 또는 치료, 치주병에 있어서의 골량 감소의 개선, 발치 후의 치조골 결손의 회복 촉진, 변형성관절증의 예방 또는 치료, 관절연골 결손의 회복 촉진, 무형성골증의 예방 또는 치료, 연골무형성증의 예방 또는 치료, 연골저형성증의 예방 또는 치료, 골연화증의 예방 또는 치료, 또는 골절의 회복 촉진을 위한 의약 조성물을 제조하기 위한, 제1항 내지 제9항 중 어느 한 항에 기재된 화합물 또는 그의 약리학적으로 허용되는 염의 사용.
- 뼈 및/또는 연골 동화작용을 유도하기 위한 의약 조성물을 제조하기 위한, 제1항 내지 제9항 중 어느 한 항에 기재된 화합물 또는 그의 약리학적으로 허용되는 염의 사용.
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