KR101610005B1 - Ｆａｂ 관련 질환의 치료에 사용하기 위한 푸린 유도체 - Google Patents
Ｆａｂ 관련 질환의 치료에 사용하기 위한 푸린 유도체 Download PDFInfo
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- KR101610005B1 KR101610005B1 KR1020107003508A KR20107003508A KR101610005B1 KR 101610005 B1 KR101610005 B1 KR 101610005B1 KR 1020107003508 A KR1020107003508 A KR 1020107003508A KR 20107003508 A KR20107003508 A KR 20107003508A KR 101610005 B1 KR101610005 B1 KR 101610005B1
- Authority
- KR
- South Korea
- Prior art keywords
- methyl
- xanthine
- quinazolin
- international publication
- treatment
- Prior art date
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Abstract
본원은 과증식성 질환의 치료를 위한 선택된 푸린 유도체의 용도를 설명한다.
Description
본원은 모든 종류의 병리학적 상태의 치료를 위한 억제 능력을 갖는 물질의 용도를 설명한다.
세프라제(seprase)라고도 알려진 섬유아세포 활성 단백질(FAP)은 세린 프로테아제의 부류에 속한다. FAP는 예컨대 DPP Ⅳ(디펩티딜펩티다제 Ⅳ) 효소와 같이, 화학식 X-Pro-XAA를 갖는 기존 단백질 또는 펩타이드로부터 디펩타이드를 분해시키는 효소에 속한다. FAP는 760개의 아미노산으로 이루어진 막투과 단백질이다. FAP는 DPP Ⅳ와의 높은 상동성을 나타내며 이 단백질과 함께 이종 이량체를 형성한다. DPP Ⅳ와 달리, FAP의 발현과 활성은 매우 제한된다. 따라서, FAP는 정상의 성인 조직에서는 발현되지 않는다. FAP는 외상 또는 조직 손상 후 활성화된 섬유아세포에서 유도된다. FAP는 모든 종류의 사람 상피성 종양의 종양 간질 조직 및 각종 골 및 연조직 육종의 악성 세포에서도 발현된다. 이들은 특히 90% 이상의 유방암종, 비-소세포 폐암종 및 결장직장암종을 포함한다. 여기서 FAP는 바람직하게는 새로 형성되고 있거나 형성된 혈관 가까이에서 발생한 섬유아세포에서 발견되고, 종양 모세혈관 내피세포와 실제의 악성 상피 세포 및 세포 집락 사이에서 특정한 세포 구획을 형성한다.
FAP-양성 섬유아세포는 원발성 암종과 전이성 암종 둘 다에서 발견된다. FAP의 발현 프로파일은 FAP가 건강한 조직에의 종양 침습과 종양 형성 및 전이에서 일부 역할을 담당한다는 것을 제안한다.
FAP 억제제, 즉 FAP의 단백질 분해 활성을 감소 또는 억제시킬 수 있는 물질은 모든 종류의 종양 질환의 치료를 위한 유용한 치료제이다. FAP 억제제는 바람직하게는 유방종양, 비-소세포 폐암종, 결장직장암종 및 연조직암종과 같은 상피 기원의 종양을 치료하는 데 사용될 수 있다. FAP 억제제는 예컨대 흑색종과 같은 모든 종류의 전이성 종양에도 지시된다.
또한, FAP 억제제는 다른 과증식성 질환에도 지시된다. 이들은 특히 심장 비대, 간경변 및 섬유종증을 포함한다. 추가로, FAP 억제제는 예컨대 관절염 또는 골관절염과 같은 류마티스성 질환 및 신경외상성 질환의 치료를 위한 매우 유용한 치료제로서 사용될 수도 있다. FAP 억제제는 상처 치유 장애 및 여드름, 및 예컨대 건선과 같은 증식성 피부 질환의 치료에도 지시된다. 추가로, FAP 억제제는 모든 기원의 통증 및 편두통의 치료에도 지시된다.
본 발명에 따른 선택된 푸린 유도체는 화학식 Ⅰ, Ⅱ, Ⅲ 또는 Ⅳ의 화합물, 이들의 토오토머, 에난티오머 및 염 및 이들의 혼합물로 정의될 수 있다.
화학식 Ⅰ
화학식 Ⅱ
화학식 Ⅲ
화학식 Ⅳ
위 화학식 Ⅰ, Ⅱ, Ⅲ 및 Ⅳ에서,
R1은 피리디닐메틸, 피리미디닐메틸, 퀴놀리닐메틸, (2-옥소-1,2-디하이드로-퀴놀리닐)메틸, 이소퀴놀리닐메틸, 퀴나졸리닐메틸, (4-옥소-3,4-디하이드로-퀴나졸리닐)메틸, 퀴녹살리닐메틸, [1,5]나프티리디닐메틸, (1H-페리미디닐)메틸, 페난트리디닐메틸, (11H-디벤조[b,e]아제피닐)메틸, (디벤조[b,f][1,4]옥사제피닐)메틸, (5H-디벤조[b,e][1,4]디아제피닐)메틸 또는 (이미다조[1,2-a]퀴놀리닐)메틸이고, 상기 언급된 그룹의 헤테로사이클릭 그룹은 Ra에 의해 일치환 또는 이치환될 수 있고, 여기서 치환체는 동일하거나 상이하고, Ra는 불소, 염소, 브롬, 시아노, 메틸, 에틸, 프로필, 이소프로필, 사이클로프로필, 페닐, 메톡시, 에틸옥시, 아미노, 메틸아미노, 디메틸아미노, 피롤리디노, 피페리디노, 모르폴리노, 피페라지노 또는 N-메틸피페라지노이고,
R2는 메틸, 에틸, 프로필, 이소프로필, 사이클로프로필 또는 페닐이고, 상기 메틸, 에틸, 프로필 및 이소프로필 그룹은 카복시, 메톡시카보닐, 에틸옥시카보닐, 아미노카보닐, 메틸아미노카보닐, 디메틸아미노카보닐, 피롤리디노카보닐, 피페리디노카보닐, 모르폴리노카보닐, 피페라지노카보닐 또는 N-메틸피페라지노카보닐에 의해 치환될 수 있고,
R3는 2-부텐-1-일, 3-메틸-2-부텐-1-일, 2-부틴-1-일, 벤질, 플루오로벤질, 클로로벤질, 브로모벤질 또는 시아노벤질이고,
R4는 피페라지노, 호모피페라지노, 3-(R)-아미노-피페리딘-1-일, 3-(S)-아미노-피페리딘-1-일, (2-아미노-에틸)-메틸아미노, (2-아미노-2-메틸-프로필)-메틸아미노, ((R)-2-아미노-프로필)-메틸아미노 또는 ((S)-2-아미노-프로필)-메틸아미노이다.
화학식 Ⅰ내지 Ⅳ의 푸린 유도체 중 화학식 Ⅰ 및 Ⅱ의 것들이 특히 바람직하다.
바람직한 R1은 피리딘-2-일메틸, 피리딘-3-일메틸, 피리딘-4-일메틸, 피리미딘-2-일메틸, 피리미딘-4-일메틸, 퀴놀린-2-일메틸, 퀴놀린-3-일메틸, 퀴놀린-4-일메틸, 퀴놀린-5-일메틸, 퀴놀린-6-일메틸, 퀴놀린-7-일메틸, 퀴놀린-8-일메틸, (2-옥소-1,2-디하이드로-퀴놀린-6-일)메틸, 이소퀴놀린-1-일메틸, 이소퀴놀린-3-일메틸, 이소퀴놀린-4-일메틸, 이소퀴놀린-8-일메틸, 퀴나졸린-2-일메틸, 퀴나졸린-4-일메틸, 퀴나졸린-6-일메틸, 퀴나졸린-7-일메틸, (4-옥소-3,4-디하이드로-퀴나졸린-2-일)메틸, 퀴녹살린-2-일메틸, 퀴녹살린-5-일메틸, 퀴녹살린-6-일메틸, [1,5]나프티리딘-2-일메틸, [1,5]나프티리딘-3-일메틸, [1,5]나프티리딘-4-일메틸, (1H-페리미딘-2-일)메틸, 페난트리딘-6-일메틸, (11H-디벤조[b,e]아제핀-6-일)메틸, (디벤조[b,f][1,4]옥사제핀-11-일)메틸, (5H-디벤조[b,e][1,4]디아제핀-11-일)메틸 또는 (이미다조[1,2-a]퀴놀린-2-일)메틸이고, 상기 언급된 그룹의 헤테로사이클릭 그룹은 시아노, 에틸, 사이클로프로필, 페닐 또는 모르폴리노에 의해 일치환되거나 메틸에 의해 일치환 또는 이치환될 수 있고,
특히 바람직한 R1은 3-시아노-피리딘-2-일메틸, (4-페닐-피리미딘-2-일)메틸, (4,6-디메틸-피리미딘-2-일)메틸, 3-시아노-퀴놀린-2-일메틸, 3-메틸-이소퀴놀린-1-일메틸, 4-시아노-이소퀴놀린-3-일메틸, 퀴나졸린-2-일메틸, (1-메틸-2-옥소-1,2-디하이드로-퀴놀린-6-일)메틸, (4-메틸-퀴나졸린-2-일)메틸, (4,5-디메틸-퀴나졸린-2-일)메틸, (4-에틸-퀴나졸린-2-일)메틸, (4-사이클로프로필-퀴나졸린-2-일)메틸, (4-시아노-퀴나졸린-2-일)메틸, (4-모르폴리노-퀴나졸린-2-일)메틸, (4-페닐-퀴나졸린-2-일)메틸, (4-옥소-3,4-디하이드로-퀴나졸린-2-일)메틸, 퀴녹살린-2-일메틸, 퀴녹살린-6-일메틸, [1,5]나프티리딘-2-일메틸, (1H-페리미딘-2-일)메틸, 페난트리딘-6-일메틸, (11H-디벤조[b,e]아제핀-6-일)메틸, (디벤조[b,f][1,4]옥사제핀-11-일)메틸, (5-메틸-5H-디벤조[b,e][1,4]디아제핀-11-일)메틸 또는 (이미다조[1,2-a]퀴놀린-2-일)메틸이다.
바람직한 R2는 메틸, 카복시메틸, 메톡시카보닐메틸, 에틸옥시카보닐메틸, 사이클로프로필 및 페닐, 특히 메틸, 카복시메틸 및 페닐이다.
바람직한 R3는 2-부텐-1-일, 3-메틸-2-부텐-1-일, 2-부틴-1-일, 벤질, 2-클로로벤질, 2-브로모벤질 또는 2-시아노벤질, 특히 3-메틸-2-부텐-1-일, 2-부틴-1-일 또는 벤질이다.
바람직한 R4는 피페라지노, 호모피페라지노, 3-(R)-아미노-피페리딘-1-일, 3-(S)-아미노-피페리딘-1-일, (2-아미노-에틸)-메틸아미노, ((R)-2-아미노-프로필)-메틸아미노 또는 ((S)-2-아미노-프로필)-메틸아미노이다.
화학식 Ⅰ내지 Ⅳ의 푸린 유도체는 문헌으로부터 공지된 방법을 사용하여 제조할 수 있다. 화학식 Ⅰ의 푸린 유도체는 예컨대 국제 공개 공보 WO 제2002/068420호, WO 제2004/018468호, WO 제2004/041820호, WO 제2005/051950호, WO 제2005/082906호, WO 제2005/085246호, WO 제2006/027204호 및 WO 제2006/029769호에 설명된 바와 같이 제조할 수 있다.
화학식 Ⅱ의 푸린 유도체는 예컨대 국제 공개 공보 WO 제2004/050658호, WO 제2004/111051호, WO 제2005/058901호, WO 제2005/097798호 및 WO 제2005/110999호에 설명된 바와 같이 제조할 수 있다.
화학식 Ⅲ 및 Ⅳ의 푸린 유도체는 예컨대 국제 공개 공보 WO 제2006/068163호 및 WO 제2007/071738호에 설명된 바와 같이 제조할 수 있다.
특히 바람직한 푸린 유도체는 다음과 같은 화합물, 이들의 토오토머, 에난티오머 및 치료학적으로 유효한 염이다.
ㆍ 1-[(퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-((R)-3-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2004/018468호, 실시예 2(80)):
ㆍ 1-[(3-메틸-이소퀴놀린-1-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-((R)-3-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2004/018468호, 실시예 2(130)):
ㆍ 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-((S)-3-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2004/018468호, 실시예 2(141)):
ㆍ 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2004/018468호, 실시예 2(142)):
ㆍ 1-[(4-페닐-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2004/018468호, 실시예 2(217)):
ㆍ 2-((R)-3-아미노-피페리딘-1-일)-3-(부트-2-이닐)-5-(4-메틸-퀴나졸린-2-일메틸)-3,5-디하이드로-이미다조[4,5-d]피리다진-4-온 (참조: 국제 공개 공보 WO 제2004/050658호, 실시예 136)):
ㆍ 1-[([1,5]나프티리딘-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-((R)-3-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2004/018468호, 실시예 2(252)):
ㆍ 1-[(1H-페리미딘-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2004/041820호, 실시예 1(29)):
ㆍ 1-[(4-에틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2005/085246호, 실시예 1(22)):
ㆍ 1-[(4-사이클로프로필-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2005/085246호, 실시예 1(23)):
ㆍ 1-[(4-페닐-피리미딘-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2005/085246호, 실시예 1(31)):
ㆍ 1-[(4-시아노-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2005/085246호, 실시예 1(37)):
ㆍ 1-[(11H-디벤조[b,e]아제핀-6-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2004/041820호, 실시예 1(5)):
ㆍ 1-[(페난트리딘-6-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2004/041820호, 실시예 1(33)):
ㆍ 1-[(디벤조[b,f][1,4]옥사제핀-11-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2004/041820호, 실시예 1(8)):
ㆍ 1-[(5-메틸-5H-디벤조[b,e][1,4]디아제핀-11-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2004/041820호, 실시예 1(12)):
ㆍ 1-[(4,5-디메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2005/085246호, 실시예 1(28)):
ㆍ 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-[(2-아미노-에틸)-메틸아미노]-크산틴 (참조: 국제 공개 공보 WO 제2006/029769호, 실시예 1(1)):
ㆍ 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-페닐-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2005/082906호, 실시예 1(8)):
ㆍ 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(3-메틸-2-부텐-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2004/018468호, 실시예 2(20)와 유사한 방법):
ㆍ 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-벤질-8-(3-(R)-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2004/018468호, 실시예 2(294)와 유사한 방법):
ㆍ 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(피페라진-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2005/051950호, 실시예 1):
ㆍ 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(호모피페라진-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2005/051950호, 실시예 1(3)):
ㆍ 1-[(3-시아노-퀴놀린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2005/085246호, 실시예 1(30)):
ㆍ 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-[(S)-(2-아미노-프로필)-메틸아미노]-크산틴 (참조: 국제 공개 공보 WO 제2006/029769호, 실시예 2(4)):
ㆍ 1-[(이미다조[1,2-a]퀴놀린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2004/041820호, 실시예 1(32)):
ㆍ 1-[(4-옥소-3,4-디하이드로-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2004/018468호, 실시예 2(71)):
ㆍ 1-[(퀴녹살린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2004/018468호, 실시예 2(169)):
ㆍ 1-[(퀴녹살린-6-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-((R)-3-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2005/085246호, 실시예 1(83)):
ㆍ 1-[(4-모르폴리노-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2004/018468호, 실시예 2(180)):
ㆍ 1-[(1-메틸-2-옥소-1,2-디하이드로-퀴놀린-6-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2004/018468호, 실시예 2(227)):
ㆍ 1-[(4-시아노-이소퀴놀린-3-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-((R)-3-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2005/085246호, 실시예 1(88)):
ㆍ 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-카복시메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2006/027204호, 실시예 2):
ㆍ 1-[(4,6-디메틸-피리미딘-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-((R)-3-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2005/085246호, 실시예 1(82)):
ㆍ 1-[(3-시아노-피리딘-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-((R)-3-아미노-피페리딘-1-일)-크산틴 (참조: 국제 공개 공보 WO 제2005/085246호, 실시예 1(52)):
당해 화합물의 생물학적 특성을 다음과 같이 조사한다.
FAP 분석:
사용되는 FAP 공급원은 CD8huFAP 세포의 균일화된 제조물이고 이것을 완충액에 1:100 비율로 희석한다. 반응을 위해 사용되는 기질은 H-Ala-Pro_7-아미도-4-트리플루오로메틸쿠마린(AlaPro-AFC)(제조원: Bachem, Prod. No I-1680)이다.
시험 물질을 DMSO(디메틸설폭사이드) 및 완충액에 희석하고 96-웰 플레이트에 피펫팅한다. 여기에 효소 70㎕ 및 기질 20㎕를 첨가한다. 플레이트를 주위 온도에서 1시간 동안 배양한 후 Wallac Victor 1420 Multilabel Counter를 사용하여 405㎚의 여기 파장 및 535㎚의 방출 파장에서 형광성을 측정한다. 시험 물질 존재하의 형광성을 대조군의 형광성과 비교함으로써 결과를 산출한다. 기본 형광성은 공제한다.
본 발명에 따른 화합물은 100μM의 농도에서 50% 초과의 FAP 억제율을 갖는다. 바람직하게, 본 발명에 따른 화합물은 3μM의 농도에서 50% 초과의 FAP 억제율을 갖는다.
약제학적 용도를 위해, 본 발명에 따른 화합물은 일반적으로 온혈 척추 동물, 특히 사람에게 0.001 내지 100㎎/㎏(체중), 바람직하게는 0.1 내지 15㎎/㎏의 용량으로 1일 1 내지 4회 사용된다. 이 목적을 위해 화합물을 임의로 다른 활성 물질과 병용되어 1종 이상의 통상의 불활성 담체 및/또는 희석제, 예컨대 옥수수 전분, 락토오스, 글루코오스, 미세결정성 셀룰로오스, 마그네슘 스테아레이트, 폴리비닐피롤리돈, 시트르산, 타르타르산, 물, 물/에탄올, 물/글리세롤, 물/소르비톨, 물/폴리에틸렌글리콜, 프로필렌글리콜, 세틸스테아릴알코올, 카복시메틸셀룰로오스, 또는 경질 지방과 같은 지방 물질 또는 이들의 적합한 혼합물과 제형화하여 비피복 또는 피복 정제, 캡슐, 분말, 현탁액 또는 좌약과 같은 통상의 생약 제제를 형성한다.
약제학적 제제는 목적하는 투여 방법(경구, 정맥내, 비경구 등)에 따라서 고안되는데, 바람직한 제형은 경구 제제이다.
상기 언급된 푸린 유도체를 함유하는 본 발명에 따른 약제학적 조성물은 종래 기술에 설명된 바와 같은 방법에 의해 당업자가 허가된 제형화 부형제를 사용하여 제조한다. 이러한 부형제의 예는 희석제, 결합제, 담체, 충전제, 윤활제, 유동제, 결정화 지연제, 붕해제, 용해제, 착색제, pH 조절제, 계면활성제 및 유화제이다.
적합한 희석제의 예로는 셀룰로오스 분말, 칼슘 하이드로겐 포스페이트, 에리트리톨, (저-치환) 하이드록시프로필셀룰로오스, 만니톨, 전젤라틴화 전분, 또는 크실리톨이 포함된다.
적합한 결합제의 예로는 비닐피롤리돈과 다른 비닐 유도체(코포비돈), 하이드록시프로필메틸셀룰로오스(HPMC), 하이드록시프로필셀룰로오스(HPC), 폴리비닐피롤리돈(포비돈), 전젤라틴화 전분, 또는 저-치환 하이드록시프로필셀룰로오스가 포함된다.
적합한 윤활제의 예로는 탈크, 폴리에틸렌글리콜, 칼슘 베헤네이트, 칼슘 스테아레이트, 수소화 피마자유 또는 마그네슘 스테아레이트가 포함된다.
적합한 붕해제의 예로는 옥수수 전분 또는 크로스포비돈이 포함된다.
본 발명에 따른 DPP Ⅳ 억제제의 약제학적 제형의 적합한 제조 방법은,
ㆍ 활성 물질과 적합한 정제화 부형제의 분말 혼합물을 직접 정제화하거나,
ㆍ 적합한 부형제와 함께 과립화한 후 적합한 부형제와 함께 혼합하고 이어서 정제화 및 필름 피복하거나,
ㆍ 분말 혼합물 또는 과립을 캡슐 안에 충전시키는 것이다.
적합한 과립화 방법은,
ㆍ 고압력 혼합기에서 습윤 과립화한 후 유동층 건조시키거나,
ㆍ 한 반응기에서 과립화하거나,
ㆍ 유동층 과립화하거나,
ㆍ 적합한 부형제와 함께 건조 과립화(예: 롤러 압축에 의해)한 후 정제화하거나 캡슐에 충전시키는 것이다.
상이한 기능적 장애들이 흔히 동시에 발생하기 때문에, 다수의 상이한 활성 성분들을 함께 병용하는 것이 종종 권장할 만하다. 따라서, 진단되는 기능적 장애에 따라서, FAP 억제제를 문제의 질병에 통상적으로 사용되는 (허가된) 활성 물질, 예컨대 과증식 억제 특성을 갖는 활성 물질 또는 과증식성 질환(예: 암)의 치료에 사용될 수 있는 활성 물질과 함께 병용할 경우 개선된 치료 결과를 얻을 수 있다.
이러한 병용 치료는 활성 물질들의 비고정 병용물로서 또는 예컨대 정제 또는 캡슐과 같은 고정 병용물 형태로서 제공될 수 있다. 이를 위해 필요한 병용 상대의 약제학적 제형은 약제학적 조성물로서 상업적으로 구입하거나 당업자가 통상의 방법을 사용하여 제조할 수 있다. 약제학적 조성물로서 상업적으로 구입될 수 있는 활성 물질은 종래 기술의 여러 문헌들, 예컨대 연간 간행되는 약물 목록인 제약 산업 연방 연합회의 "Rote Liste®", 또는 "Physicians' Desk Reference"로 알려진 처방 약물에 대한 제조자 정보의 연간 개정 편집물에 설명되어 있다.
여기에 정의된 항암 치료는 단독 요법으로서 사용되거나, 본 발명에 따른 화합물과 함께 통상의 수술, 방사선요법 또는 화학요법을 포함할 수 있다. 상기 화학요법은 다음과 같은 종류의 화학요법 및/또는 표적 항종양제 1종 이상을 포함할 수 있다.
공지된 화학요법 항종양제의 예로는 다음과 같은 종류 및 이들의 일부 전형적인 예들을 들 수 있다: (ⅰ) 사이클로포스파미드(Endoxan), 이포스파미드(Holoxan), 티오테파, 멜팔란(Alkeran) 또는 클로로에틸니트로소우레아(CENU)와 같은 알킬화/카바밀화 활성 물질; (ⅱ) 시스플라틴(Platinex), 옥살리플라틴, 사트라플라틴 또는 카보플라틴(Carboplat)과 같은 백금 유도체; (ⅲ) 빈카 알칼로이드(Vincristin, Vinblastin, Vinorelbin), 파클리탁셀(Taxol), 도세탁셀(Taxotere) 또는 이의 유사체 또는 공액체와 같은 탁산, 에포틸론 B(Patupilone), 아자에포틸론(Ixabepilone) 또는 ZK-EPO와 같은 에포틸론 등의 항유사분열 활성 물질/튜불린 억제제; (ⅳ) 안트라사이클린(예: 독소루비신/아드리블라스틴), 에피포도필로톡신(예: 에토포시드/Etopophos) 및 캄프토테신 및 캄프토테신 유사체(예: Irinotecan/Camptosar 또는 Topotecan/Hycamtin)와 같은 토포이소머라제 억제제; (ⅴ) 5-플루오로우라실(5-FU), 카페시타빈(Xeloda), 아라비노실사이토신/사이타라빈(Alexan) 또는 겜시타빈(Gemzar)과 같은 피리미딘 길항제; (ⅵ) 6-머캅토푸린(Puri-Nethol), 6-티오구아닌 또는 플루다라빈(Fludara)과 같은 푸린 길항제, 및 (ⅶ) 메토트렉세이트(Farmitrexat) 또는 프레메트렉세드(Alimta)와 같은 폴산 길항제.
실험적 또는 표준 암 치료에 사용되는 표적 항종양제의 예로는 다음과 같은 종류 및 이들의 일부 전형적인 예들을 들 수 있다: (ⅰ) 이마티닙(Glivec), ZD-1839/페피티닙(Iressa), Bay43-9006(Sorafenib, Nexavar), SU11248/수니티닙(Sutent) 또는 OSI-774/에를로티닙(Tarceva), 다사티닙(Sprycel), 이라파티닙(Tykerb), 또는 바탈라닙, 반데타닙(Zactima) 또는 파조타닙과 같은 키나제(예: Abl, EGFR, VEGFR, PDGFR 등) 억제제; (ⅱ) PS-341/보르테주밉(Velcade)과 같은 프로테아솜 억제제; (ⅲ) 17-알릴아미노겔다나마이신(17-AAG)과 같은 열 충격 단백질 90 억제제; (ⅳ) 콤브레타스틴 A4 Phosphat 또는 AVE8062/AC7700과 같은 혈관 표적 약제(VTAs), 및 베바시주맙(Avastin)과 같은 VEGF 항체 등의 항-혈관형성 활성 물질, PTK787/ZK222584(Vatalanib) 또는 반데타닙(Zactima) 또는 파조파닙과 같은 안지오키나제 억제제 또는 KDR 티로신키나제 억제제; (ⅴ) 트라스투주맙(Herceptin), 리툭시맙(MabThera/Rituxan), 알렘투주맙(Campath), 토시투모맙(Bexxar), C225/세툭시맙(Erbitux), 아바스틴 또는 파니투무맙과 같은 단일클론 항체, 겜투주맙 오조가미신(Mylotarg) 또는 이브리투모맙 티욱세탄(Zevalin)과 같은 단일클론 항체의 변이체 및 공액체, 및 항체 단편; (ⅵ) G-3139/오블리메르센(Genasense)과 같은 올리고뉴클레오타이드-기재 활성 물질; (ⅶ) ProMune과 같은 톨(toll)-유사 수용체/TLR 9 작용제, 이미퀴모드(Aldara) 또는 이사토리빈 및 그의 유사체와 같은 TLR 7 작용제, 또는 레시퀴모드와 같은 TLR 7/8 작용제, 및 TLR 7/8 작용제인 면역자극성 RNA; (ⅷ) 프로테아제 억제제, (ⅸ) 항-에스트로겐(예: 타목시펜 또는 랄록시펜), 항-안드로겐(예: 플루타마이드 또는 카소덱스), LHRH 유사체(예: 류프롤라이드, 고세렐린 또는 트립토렐린) 및 아로마타제 억제제와 같은 호르몬 활성 물질.
암 치료에서 유용할 수 있는 다른 표적 항종양제의 예로는 다음과 같은 활성 물질을 들 수 있다: 블레오마이신, 올-트랜스 레티노산(ATRA)과 같은 레티노이드, 데시타빈(Docagen) 또는 5-아자사이티딘과 같은 DNA 메틸트랜스퍼라제 억제제, 알라노신, 인터류킨-2와 같은 사이토킨, 인터페론-알파2 또는 인터페론-감마와 같은 인터페론, TRAIL과 같은 사멸 수용체 작용제, DR4/5 작용성 항체, FasL 및 TNF-R 작용제(예: 마파투무맙 또는 렉사투무맙과 같은 TRAIL 수용체 작용제), 및 SAHA와 같은 HDAC 억제제.
Claims (11)
1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴 또는 이의 염을 포함하는, 심장 비대, 간경변, 섬유종증, 상처 치유 장애 및 여드름으로부터 선택되는, 섬유아세포 활성 단백질(Fibroblast Activation Protein;FAP)의 억제에 반응하는 과증식성 질환 치료용 약제학적 조성물.
삭제
삭제
삭제
삭제
제1항에 기재된 화합물을 사용함을 특징으로 하는, 제1항에 따른 과증식성 질환 치료용 약제학적 조성물의 제조 방법.
1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴 또는 이의 염을 포함하는 심장 비대 치료용 약제학적 조성물.
1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴 또는 이의 염을 포함하는 간경변 치료용 약제학적 조성물.
1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴 또는 이의 염을 포함하는 섬유종증 치료용 약제학적 조성물.
삭제
제1항에 기재된 화합물을 포함하는, 상처 치유 장애 또는 여드름의 치료에 사용하기 위한 FAP 억제용 약제학적 조성물.
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2008
- 2008-08-15 EP EP08787268.5A patent/EP2190434B1/en not_active Revoked
- 2008-08-15 KR KR1020107003508A patent/KR101610005B1/ko active IP Right Grant
- 2008-08-15 CA CA2696579A patent/CA2696579C/en active Active
- 2008-08-15 NZ NZ600126A patent/NZ600126A/en unknown
- 2008-08-15 US US12/673,176 patent/US20110112069A1/en not_active Abandoned
- 2008-08-15 BR BRPI0815405-8A2A patent/BRPI0815405A2/pt not_active Application Discontinuation
- 2008-08-15 RU RU2010109545/15A patent/RU2569749C2/ru active
- 2008-08-15 MX MX2010001821A patent/MX2010001821A/es active IP Right Grant
- 2008-08-15 WO PCT/EP2008/060740 patent/WO2009024542A2/en active Application Filing
- 2008-08-15 JP JP2010521404A patent/JP5769966B2/ja active Active
- 2008-08-15 EP EP19169300.1A patent/EP3542801A1/en not_active Withdrawn
- 2008-08-15 AU AU2008290582A patent/AU2008290582B2/en active Active
- 2008-08-15 ES ES08787268T patent/ES2733348T3/es active Active
- 2008-08-15 CN CN200880103199A patent/CN101784278A/zh active Pending
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2010
- 2010-01-05 ZA ZA201000075A patent/ZA201000075B/xx unknown
-
2016
- 2016-01-20 US US15/001,301 patent/US20160136180A1/en not_active Abandoned
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040138214A1 (en) | 2002-11-08 | 2004-07-15 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions |
| US20060058323A1 (en) | 2004-09-11 | 2006-03-16 | Boehringer Ingelheim International Gmbh | New 8-(3-amino-piperidin-1-yl)-7-(but-2-ynyl)-xanthines, the preparation thereof and their use as pharmaceutical compositions |
Also Published As
| Publication number | Publication date |
|---|---|
| JP5769966B2 (ja) | 2015-08-26 |
| MX2010001821A (es) | 2010-03-10 |
| EP2190434A2 (en) | 2010-06-02 |
| US20160136180A1 (en) | 2016-05-19 |
| AU2008290582B2 (en) | 2014-08-14 |
| RU2569749C2 (ru) | 2015-11-27 |
| RU2010109545A (ru) | 2011-09-27 |
| CA2696579A1 (en) | 2009-02-26 |
| ZA201000075B (en) | 2010-09-29 |
| ES2733348T3 (es) | 2019-11-28 |
| WO2009024542A3 (en) | 2009-05-22 |
| NZ600126A (en) | 2013-12-20 |
| AU2008290582A1 (en) | 2009-02-26 |
| BRPI0815405A2 (pt) | 2015-02-03 |
| CN101784278A (zh) | 2010-07-21 |
| US20110112069A1 (en) | 2011-05-12 |
| EP3542801A1 (en) | 2019-09-25 |
| EP2190434B1 (en) | 2019-04-17 |
| CA2696579C (en) | 2017-01-24 |
| JP2010536820A (ja) | 2010-12-02 |
| WO2009024542A2 (en) | 2009-02-26 |
| KR20100055423A (ko) | 2010-05-26 |
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