KR20080031738A - 1,4-벤조티아제핀 1,1-디옥사이드 유도체, 이의 제조방법,이를 포함하는 약제 및 고지혈증 치료제로서의 이의 용도 - Google Patents
1,4-벤조티아제핀 1,1-디옥사이드 유도체, 이의 제조방법,이를 포함하는 약제 및 고지혈증 치료제로서의 이의 용도 Download PDFInfo
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- KR20080031738A KR20080031738A KR1020087001183A KR20087001183A KR20080031738A KR 20080031738 A KR20080031738 A KR 20080031738A KR 1020087001183 A KR1020087001183 A KR 1020087001183A KR 20087001183 A KR20087001183 A KR 20087001183A KR 20080031738 A KR20080031738 A KR 20080031738A
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- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
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- C07H13/12—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by acids having the group -X-C(=X)-X-, or halides thereof, in which each X means nitrogen, oxygen, sulfur, selenium or tellurium, e.g. carbonic acid, carbamic acid
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Abstract
본 발명은 화학식 A의 화합물 및 생리학적으로 허용되는 이의 염에 관한 것이다. 당해 화합물은, 예를 들면, 고지혈증 치료제로서 적합하다.
화학식 A
지질 대사, 고지혈증, 동맥경화증, 혈청 콜레스테롤 농도 저하, 인슐린 내성
Description
본 발명은 치환된 1,4-벤조티아제핀 1,1-디옥사이드 유도체 및 생리학적으로 허용되는 이의 염에 관한 것이다.
1,4-벤조티아제핀 1,1-디옥사이드 유도체, 및 고지혈증, 동맥경화증 및 고콜레스테롤혈증을 치료하기 위한 이의 용도는 이미 기재되어 있다[참조: EP 1169313].
본 발명의 목적은 EP 1169313에 기재된 화합물에 비해 상당히 우수한 효능을 갖는 화합물을 제공하는 것이다.
따라서, 본 발명은 화학식 A의 화합물 및 약제학적으로 허용되는 이의 염에 관한 것이다.
이들은 출발 화합물 또는 기본 화합물보다 더 수용성이기 때문에 약제학적으로 허용되는 염은 의약용으로 특히 적합하다. 이들 염은 약제학적으로 허용되는 음이온 또는 양이온을 가져야 한다. 본 발명에 따르는 화합물의 적합한 약제학적으로 허용되는 산 부가염은 무기산, 예를 들면, 염산, 브롬화수소산, 인산, 메타인산, 질산 및 황산의 염 및 유기산, 예를 들면, 아세트산, 벤젠설폰산, 벤조산, 시트르산, 에탄설폰산, 푸마르산, 글루콘산, 글리콜산, 이세티온산, 락트산, 락토비온산, 말레산, 말산, 메탄설폰산, 석신산, p-톨루엔설폰산 및 타르타르산의 염이다.
약제학적으로 허용되지 않는 음이온을 함유하는 염(예: 트리플루오로아세테이트)이 또한 약제학적으로 허용되는 염을 제조하거나 정제하기 위해 유용한 중간체로서 및/또는 비치료용, 예를 들면, 시험관 용도로 사용하기 위해 본 발명의 범위에 속한다.
본 발명에 따르는 화합물은 또한 상이한 다형으로, 예를 들면, 무정형 및 결정형 다형으로 존재할 수 있다. 본 발명에 따르는 모든 다형은 본 발명의 범위 내에 속하고 본 발명의 또 다른 양상이다.
다음 설명에서, "화학식 A에 따르는 화합물(들)"이라고 하는 것은 모두 상기한 바와 같이 화학식 A의 화합물 및 이의 염 및 용매화물에 관한 것이다.
화학식 A의 화합물은 또한 다른 활성 화합물과 함께 투여될 수 있다.
목적하는 생물학적 효과를 성취하기 위해서 요구되는 화학식 A에 따르는 화합물의 양은 다수의 인자, 예를 들면, 선택된 특정 화합물, 의도되는 용도, 투여 유형 및 환자의 임상 상태에 좌우된다. 일반적으로, 1일 투여량의 범위는 0.01mg 내지 100mg(통상적으로 0.05mg 내지 50mg)/체중(kg)/일, 예를 들면, 0.1 내지 10mg/kg/일이다.
경구 투여될 수 있는 단일 투여 제형, 예를 들면, 정제 또는 캡슐제는, 예를 들면, 1.0 내지 1000mg, 통상적으로 10 내지 600mg을 함유할 수 있다. 화학식 A에 따르는 화합물은 그 자체가 상기 질환을 치료하기 위한 화합물로서 사용될 수 있지만, 바람직하게는 허용되는 담체와 함께 약제학적 조성물의 형태로 존재한다. 담체는 물론 조성물의 다른 성분들과 상용성이고 환자의 건강에 유해하지 않다는 점에서 허용되는 것이어야 한다. 담체는 고형 또는 액체 또는 둘 다일 수 있고, 바람직하게는, 단일 투여형으로서, 예를 들면, 활성 화합물을 0.05 내지 95중량% 함유할 수 있는 정제로서 화합물과 함께 제형된다. 화학식 A에 따르는 다른 화합물을 포함하는 다른 약제학적으로 활성 물질이 또한 존재할 수 있다. 본 발명에 따르는 약제학적 조성물은 본질적으로 성분들을 약리학적으로 허용되는 담체 물질 및/또는 보조제 물질과 함께 혼합하는 것으로 이루어진 공지된 약제학적 방법 중 하나를 사용하여 제조할 수 있다.
본 발명에 따르는 약제학적 조성물은 가장 적합한 투여 방식이 각각의 개별적인 경우에 치료될 질환의 특징 및 중증도 및 각각의 경우에 사용되는 화학식 A에 따르는 화합물의 특성에 좌우되는 경우에도 경구 및 경구적(예: 설하) 투여에 적합하다. 당의 제형 및 당의 서방출 제형도 본 발명의 범위에 속한다. 내산성 및 내위액성(gastric juice-resistant)인 제형이 바람직하다. 적합한 내위액성 코팅으로는 셀룰로스 아세테이트 프탈레이트, 폴리비닐 아세테이트 프탈레이트, 하이드록시프로필메틸 셀룰로스 프탈레이트 및 메타크릴산과 메틸 메타크릴레이트의 음이온성 중합체가 있다.
경구 투여용으로 적합한 약제학적 화합물은 독립된 단위로, 예를 들면, 각각의 경우에 화학식 A에 따르는 화합물을 특정량 함유하는 캡슐제, 카세제, 로젠지제 또는 정제로; 산제 또는 과립제로서; 수용성 또는 비수용성 액체 중의 용액제 또는 현탁액제로서; 또는 수중유 또는 유중수 유액으로서 존재할 수 있다. 이미 언급한 바와 같이, 이들 조성물은 활성 화합물과 담체(이는 하나 이상의 추가 성분으로 이루어질 수 있다)를 접촉시키는 단계를 포함하는 모든 적합한 약제학적 방법을 사용하여 제조할 수 있다. 일반적으로, 조성물은 활성 화합물과 액체 및/또는 미분 고형 담체를 균일하고 균질하게 혼합한 후, 필요한 경우, 생성물을 성형함으로써 제조한다. 따라서, 정제는, 예를 들면, 필요한 경우, 하나 이상의 추가 성분과 함께 압축되거나 성형되는 화합물의 분말 또는 과립을 통해 제조할 수 있다. 압축 정제는 적합한 기계에서, 필요한 경우, 결합제, 윤활제, 불활성 희석제 및/또는 하나의(수 개의) 계면활성제/분산제(들)과 함께 화합물을 자유 유동 형태로, 예를 들 면, 분말 또는 과립으로 타정함으로써 제조할 수 있다. 성형 정제는 불활성 액체 희석제에 의해 습윤된 분말 화합물을 적합한 기계에서 성형함으로써 제조할 수 있다.
경구적(설하) 투여에 적합한 약제학적 조성물로는 화학식 A에 따르는 화합물을 향미제, 통상적으로 수크로즈 및 아라비아 고무 또는 트라가칸트와 함께 함유하는 로젠지제, 및 불활성 염기, 예를 들면, 젤라틴 및 글리세롤 또는 수크로스 및 아라비아 고무 속에 화합물을 포함하는 파스틸(pastil)이 있다.
본 발명에 따르는 약제학적 조성물의 추가의 양태는 적합한 금속염, 예를 들면, 칼슘, 알루미늄, 철, 구리, 아연, 마그네슘, 망간 또는 아연염을 포함한다. 칼슘염 및 아연염, 예를 들면, 인산칼슘, 칼슘 락테이트, 탄산칼슘, 칼슘 글루코네이트, 칼슘 아세테이트, 인산아연, 아연 락테이트, 탄산아연, 아연 글루코네이트 또는 아연 아세테이트가 바람직하다. 이들 염을 약제학적 조성물에 첨가함으로써 환자에게서 설사 발생을 감소시키거나 방지할 수 있다.
다음은 배합 제제용 추가 활성 화합물로서 사용하기에 적합하다: 로텐 리스트(Roten Liste)[Red List] 2005의 12장에 명명되어 있는 모든 항당뇨병약. 이들은 특히 효과를 상승적으로 향상시키려는 목적으로 본 발명에 따르는 화학식 A의 화합물과 배합될 수 있다. 활성 화합물 배합물은 활성 화합물을 환자에게 따로 투여하거나 이들을 수 개의 활성 화합물이 하나의 약제학적 제제에 존재하는 배합 제제의 형태로 투여함으로써 투여할 수 있다. 아래에서 언급되는 대부분의 활성 화합물은 문헌[참조: USP Dictionary of USAN & International Drug Names, US Pharmacopeia, Rockville 2001]에 기재되어 있다.
항당뇨병약에는 인슐린 및 인슐린 유도체, 예를 들면, 란투스(Lantus®)[참조: www.lantus.com] 또는 HMR 1964, 신속 작용성 인슐린(참조: 6,221,633), GLP-1 유도체, 예를 들면, 노보 노르디스크 아/에스(Novo Nordisk A/S)가 WO 98/08871에 기재하고 있는 것들, 질랜드(Zealand)가 WO/04156에 기재하고 있는 것들 및 뷰포-입센(Beaufour-Ipsen)이 WO 00/34331에 기재하고 있는 것들이 포함되고, 경구 활성 혈당 강하 활성 화합물도 포함된다.
경구 활성 혈당 강하 활성 화합물에는 바람직하게는 설포닐우레아, 비구아니딘(biguanidines), 메글리티니드(meglitinides), 옥사디아졸리딘디온(oxadiazolidinediones), 티아졸리딘디온(thiazolidinediones), 글루코시다제 및 글리코겐 포스포릴라제 억제제, 글루카곤 길항제, GLP-1 작용제, 칼륨 채널 개방제(opener), 예를 들면, 노보 노르디스크 아/에스가 WO 97/26265 및 WO 99/03861에 기재하고 있는 것들, 인슐린 민감제, 글루코스신합성 및/또는 당원분해의 자극에 관여하는 간 효소의 억제제, 글루코스 흡수 조절자, 글루코스 수송 및 글루코스 재흡수, 지방 대사를 변경시키는 화합물, 예를 들면, 항고지혈증 활성 화합물 및 항지혈증(antilipidaemic) 활성 화합물, 식품 흡수를 감소시키는 화합물, PPAR 작용제 및 PXR 작용제, 및 베타 세포에서 ATP 의존성 칼륨 채널에 대해 작용하는 활성 화합물이 포함된다.
본 발명의 한 양태로서, 화학식 A의 화합물은 HMGCoA 리덕타제 억제제, 예를 들면, 심바스타틴(simvastatin), 플루바스타틴(fluvastatin), 프라바스타 틴(pravastatin), 로바스타틴(lovastatin), 아토르바스타틴(atorvastatin), 세리바스타틴(cerivastatin) 또는 로수바스타틴(rosuvastatin)과 함께 투여된다.
본 발명의 한 양태로서, 화학식 I의 화합물은 콜레스테롤 흡수 억제제, 예를 들면, 에제티미브(ezetimibe), 티퀘시드(tiqueside), 파마퀘시드(pamaqueside) 또는 PCT/EP 2004/00269, PCT/EP 2003/05815, PCT/EP 2003/05814, PCT/EP 2003/05816, EP 0114531 또는 US 6,498,156에 기재되어 있는 화합물과 함께 투여된다.
본 발명의 한 양태로서, 화학식 A의 화합물은 PPAR 감마 작용제, 예를 들면, 로시클리타존(rosiglitazone), 피오글리타존(pioglitazone), JTT-501 또는 GI 262570과 함께 투여된다.
본 발명의 한 양태로서, 화학식 A의 화합물은 PPAR 알파 작용제, 예를 들면, GW 9578 또는 GW 7647과 함께 투여된다.
본 발명의 한 양태로서, 화학식 A의 화합물은 혼합된 PPAR 알파/감마 작용제, 예를 들면, GW 1536, AVE 8042, AVE 8134 또는 AVE 0847 또는 PCT/US 00/11833, PCT/US 00/11490 또는 WO 03/020269에 기재되어 있는 것들과 함께 투여된다.
본 발명의 한 양태로서, 화학식 A의 화합물은 피브레이트(fibrate), 예를 들면, 페노피브레이트(fenofibrate), 클로피브레이트(clofibrate) 또는 베자피브레이트(bezafibrate)와 함께 투여된다.
본 발명의 한 양태로서, 화학식 A의 화합물은 MTP 억제제, 예를 들면, 임플 리타피드(implitapide), BMS-201038 또는 R-103757과 함께 투여된다.
본 발명의 한 양태로서, 화학식 A의 화합물은 CETP 억제제, 예를 들면, JTT-705와 함께 투여된다.
본 발명의 한 양태로서, 화학식 A의 화합물은 중합체성 담즙산 흡착제, 예를 들면, 콜레스티라민(cholestyramine) 또는 콜레세벨람(colesevelam)과 함께 투여된다.
본 발명의 한 양태로서, 화학식 A의 화합물은 LDL 수용체 유도 인자(참조: US 6,342,512)와 함께 투여된다.
본 발명의 한 양태로서, 화학식 A의 화합물은 ACAT 억제제, 예를 들면, 아바시미베(avasimibe)와 함께 투여된다.
본 발명의 한 양태로서, 화학식 A의 화합물은 항산화제, 예를 들면, OPC-14117과 함께 투여된다.
본 발명의 한 양태로서, 화학식 A의 화합물은 지단백 리파제 억제제, 예를 들면, NO-1886과 함께 투여된다.
본 발명의 한 양태로서, 화학식 A의 화합물은 ATP 시트레이트 리아제 억제제, 예를 들면, SB-204990과 함께 투여된다.
본 발명의 한 양태로서, 화학식 A의 화합물은 스쿠알렌 신타제 억제제, 예를 들면, BMS-188494와 함께 투여된다.
본 발명의 한 양태로서, 화학식 A의 화합물은 지단백(들) 길항제, 예를 들면, CI-1027 또는 니코틴산과 함께 투여된다.
본 발명의 한 양태로서, 화학식 A의 화합물은 리파제 억제제, 예를 들면, 오를리스타트(orlistat)와 함께 투여된다.
본 발명의 한 양태로서, 화학식 A의 화합물은 인슐린과 함께 투여된다.
한 양태로서, 화학식 A의 화합물은 설포닐우레아, 예를 들면, 톨부타미드(tolbutamide), 글리벤클라미드(glibenclamide), 글리피지드(glipizide) 또는 글리메피리드(glimepiride)와 함께 투여된다.
한 양태로서, 화학식 A의 화합물은 비구아니드(biguanide), 예를 들면, 메트포르민(metformin)과 함께 투여된다.
또 다른 양태로서, 화학식 A의 화합물은 메글리티니드(meglitinide), 예를 들면, 레파글리니드(repaglinide)와 함께 투여된다.
한 양태로서, 화학식 A의 화합물은 티아졸리딘디온, 예를 들면, 트로글리타존(troglitazone), 시글리타존(ciglitazone), 피오글리타존(pioglitazone), 로시글리타존(rosiglitazone) 또는 닥터 레디스 리서치 파운데이션(Dr. Reddy's Research Foundation)이 WO 97/41097에 기재하고 있는 화합물, 특히 5-[[4-[(3,4-디하이드로-3-메틸-4-옥소-2-퀴나졸리닐메톡시]페닐]메틸]-2,4-티아졸리딘디온과 함께 투여된다.
한 양태로서, 화학식 A의 화합물은 α-글루코시다제 억제제, 예를 들면, 미글리톨(miglitol) 또는 아카르보스(acarbose)와 함께 투여된다.
한 양태로서, 화학식 A의 화합물은 아데노신 A1 작용제, 예를 들면, EP 0912520 또는 PCT/EP06749에 기재되어 있는 것들과 함께 투여된다.
한 양태로서, 화학식 A의 화합물은 베타 세포의 ATP-의존성 칼륨 채널에 대해 작용하는 활성 화합물, 예를 들면, 톨부타미드(tolbutamide), 글리벤클라미드(glibenclamide), 글리피지드(glipizide), 글리메피리드 또는 레파글리니드(repaglinide)와 함께 투여된다.
한 양태로서, 화학식 A의 화합물은 상기 화합물들 중의 1개를 초과하는 화합물과 함께, 예를 들면, 설포닐우레아와 메트포르민, 설포닐우레아와 아카르보스, 레파글리니드와 메트포르민, 인슐린과 설포닐우레아, 인슐린과 메트포르민, 인슐린과 트로글리타존, 인슐린과 로바스타틴 등과 함께 투여된다.
또 다른 양태로서, 화학식 A의 화합물은 CART 조절자(참조: "cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice" Asakawa, A. et al., M.: Hormone and Metabolic Research (2001), 33(9), 554-558), NPY 길항제, 예를 들면, 나프탈렌-1-설폰산-{4-[(4-아미노퀴나졸린-2-일아미노)메틸]사이클로헥실-메틸}아미드 하이드로클로라이드(CGP 71683A), 칸나비노이드 수용체 1 길항제(참조: EP 0656354, WO 00/15609 또는 WO 02/076949), MC4 작용제(예: 1-아미노-1,2,3,4-테트라하이드로나프탈렌-2-카복실산 [2-(3a-벤질-2-메틸-3-옥소-2,3,3a,4,6,7-헥사하이드로피라졸로[4,3-c]피리딘-5-일)-1-(4-클로로페닐)-2-옥소에틸]아미드; (WO 01/91752)), 오렉신 길항제(예: 1-(2-메틸벤즈옥사졸-6-일)-3-[1,5]나프티리딘-4-일 우레아 하이드로클로라이드(SB-334867-A)), H3 작용제(3-사이클로헥실-1-(4,4-디메틸-1,4,6,7-테트라하이드로이미다조[4,5-c]피리딘-5-일)-프로판-1-온 옥살산 염(WO 00/63208)); TNF 작용 제, CRF 길항제(예: [2-메틸-9-(2,4,6-트리메틸페닐)-9H-1,3,9-트리아자플루오렌-4-일]디프로필아민(WO 00/66585)), CRF BP 길항제(예: 우로코르틴(urocortin)), 우로코르틴 작용제, β3-작용제(예: 1-(4-클로로-3-메탄설포닐메틸페닐)-2-[2-(2,3-디메틸-1H-인돌-6-일옥시)에틸아미노]에탄올 하이드로클로라이드(WO 01/83451)), MSH(멜라닌 세포 자극 호르몬) 작용제, MCH(멜라닌-농축 호르몬) 수용체 길항제(참조: WO 03/15769), CCK-A 작용제(예: {2-[4-(4-클로로-2,5-디메톡시페닐)-5-(2-사이클로헥실에틸)티아졸-2-일카바모일]-5,7-디메틸인돌-1-일}아세트산 트리플루오로아세트산 염(WO 99/15525) 또는 SR-146131(WO 0244150) 또는 SSR-125180), 세로토닌 재흡수 억제제(예: 덱스펜플루라민(dexfenfluramine)), 혼합 세로토닌성 및 노르아드레날린성 화합물(예: WO 00/71549), 5HT 작용제, 예를 들면, 1-(3-에틸벤조푸란-7-일)피페라진 옥살산염(WO 01/09111), 봄베신(bombesin) 작용제, 갈라닌 길항제, 성장 호르몬(예: 사람 성장 호르몬), 성장 호르몬 방출 화합물(3급-부틸 6-벤질옥시-1-(2-디이소프로필아미노에틸카바모일)-3,4-디하이드로-1H-이소퀴놀린-2-카복실레이트(WO 01/85695)), TRH 작용제(참조: EP 0462884), 디커플링(decoupling) 단백질 2 또는 단백질 3 조절자, 렙틴 작용제(참조: Lee, Daniel W.; Leinung, Matthew C.; Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as a potential approach to the treatment of obesity. Drugs of the Future (2001), 26(9), 873-881), DA 작용제(브로모크립틴(bromocriptine), 도프렉신(doprexin)), 리파제/아밀라제 억제제(예: WO 00/40569), PPAR 조절자(예: WO 00/78312), 11β-HSD1(11-베타-하이드록시스테로이드데하이드로게나제 유형 1) 억 제제[참조: WO 01/90094 또는 문헌(T. Barf et al., J. Med. Chem. (2002), 45, 3813-3815], 아세틸-CoA 카복실라제(ACC; 참조: WO 99/46262) 억제제, 디펩티딜펩티다제 IV(DPP-IV; 참조: EP 1259246) 억제제, RXR 조절자 또는 TR-β-작용제와 함께 투여된다.
본 발명의 한 양태로서, 다른 활성 화합물은 렙틴이다[참조: "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2(10), 1615-1622)].
한 양태로서, 다른 활성 화합물은 덱삼페타민(dexamphetamine) 또는 암페타민(amphetamine)이다.
한 양태로서, 다른 활성 화합물은 펜플루라민(fenfluramine) 또는 덱스펜플루라민(dexfenfluramine)이다.
또 다른 양태로서, 다른 활성 화합물은 시부트라민(sibutramine)이다.
한 양태로서, 다른 활성 화합물은 오를리스타트(orlistat)이다.
한 양태로서, 다른 활성 화합물은 마진돌(mazindol) 또는 펜테르민(phentermine)이다.
한 양태로서, 화학식 A의 화합물은 밸러스트 물질(ballast substances), 바람직하게는 불용성 밸러스트 물질(예: 카로브(carob)/카로맥스(Caromax®))(참조: Zunft H J; et al., Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct), 18(5), 230-6)과 함께 투여된다. 카로맥스는 독일 65926 프랑크푸르트/마인 인두스트리파크 훽스트에 소재하는 누트리노파, 누트리티온 스페시알티스 운트 푸드 인그레딘츠 게엠베하(Nutrinova, Nutrition Specialties & Food Ingredients GmbH)의 카로브 함유 제품이다. 카로맥스와의 배합은 하나의 제제에서 달성될 수 있거나 화학식 A의 화합물과 카로맥스를 따라 투여함으로써 달성될 수 있다. 이와 관련하여, 카로맥스는 또한 식료품의 형태로, 예를 들면, 빵, 케익 및 빵과자 또는 뮤즐리 바(muesli bar) 형태로 투여될 수 있다.
본 발명에 따르는 화합물과 하나 이상의 상기 화합물 및, 필요한 경우, 하나 이상의 추가의 약리학적 활성 물질과의 각각 적합한 배합물도 본 발명의 보호 범위에 속하는 것으로 간주됨을 이해할 것이다.
실시예 A
화학식 A
화합물(A)는 다음과 같이 제조하였다.
화합물(1a)의 합성:
에난티오머적으로 순수한 화합물(1a)를 라세미체 아닐리드(1)(EP 1169313 화합물 8a/b)로부터 키랄팩 AS-H96을 사용하여 이동상 n-헵탄/메탄올/에탄올(10/1/1)과 0.1% DEA로 키랄 크로마토그래피하여 수득한다. THF/EA/n-헵탄으로부터 결정화함으로써 화합물(1a)를 더욱 더(ee 99.9%) 정제시킬 수 있다. 유토머(eutomer)는 포지티브 광학 회전성을 갖고, 절대 입체화학은 단일 결정 X선 구조로 측정되었다.
화합물(3)의 합성:
실온에서 아닐리드(1a) 6g과 이소시아네이트(2)(Synlett 2003, 1, 47-50) 7.5g을 메틸렌 클로라이드 150ml에 용해시킨다. 실온에서 1시간 후, 혼합물을 농축시키고, 잔사를 섬광 크로마토그래피로 정제한다. 화합물(3)을 무색 고체로서 10.5g(95%) 수득한다. TLC(n-헵탄/에틸 아세테이트 1:2). Rf=0.3. C40H56N4O12S(816.98). MS(M+H)+=817.33.
화합물(A)의 합성:
화합물(3) 9.7g을 메탄올 120ml와 트리에틸아민 40ml에 용해시키고, 실온에서 16시간 동안 방치한다. 용액을 농축시키고, 잔사를 고온 에틸 아세테이트 60ml에 용해시킨다. 실온으로 냉각시킨 후, 에틸 아세테이트/n-헵탄(4:1) 50ml를 가한다. 현탁액을 30분 동안 교반하고, 침전물을 흡인 여과한 후, 에틸 아세테이트/n-헵탄(4:1) 30ml로 세척한다. 화합물(A)를 무정형 고체로서 7.01g(91%) 수득하고 모액(화합물(A) 40 내지 50% 함유) 450mg을 수득한다. TLC(메틸렌 클로라이드/메탄올/진한 암모니아 30/10/3). Rf=0.5. C32H48N4O8S(648.83). MS(M+H)+=649.26.
본 발명에 따르는 화합물(A)의 생물학적 시험을 시험관내 IBAT 억제 시험을 사용하여 수행하였다. 당해 시험은 재조합적으로 발현된 사람 나트륨 의존성 회장 담즙산 수송자의 수송 활성에 대한 본 발명에 따르는 화합물의 효과를 조사한다(IBAT=회장 Na+/담즙산 콘트랜스포터(contransporter), ASBT=정점(apical) 나트륨 의존성 담즙산 수송자, SLC10A2=용질 담체족 10, 멤버 2).
시험관내 IBAT 억제 시험을 위한 제조 및 실시:
1. 사람 IBAT에 대한 발현 벡터의 클로닝
사람 IBTA의 cDNA(상보적 데옥시리보핵산)를, 예를 들면, 조셉 샘브룩(Jeseph Sambrook)과 데이비드 러셀(David Russell)의 분자 클로닝: 실험실 매뉴얼에 기재되어 있는 분자 생물학의 표준 방법을 사용하여 클로닝하고, 인비트로겐(Invitrogen)으로부터 입수한 pcDNA1 벡터에 도입시켰다. 삽입물의 후속 서열화는 도슨 피.에이.(Dawson P.A.)가 기재하고 유전자은행 서열 데이타은행(GenBank sequence databank)(유전자은행 승인 번호: U10417)에 기탁된 사람 IBAT에 대한 염기 서열의 염기 599 내지 1645와 완전히 일치함을 나타냈다. 염기 599 내지 1645는 사람 IBAT의 완전한 코딩 영역에 상응한다.
2. 사람 IBAT를 구성적으로 발현하는 재조합 세포주의 제조
사람 IBAT에 대한 발현 벡터를 안정한 트랜스펙션(transfection)을 통해 CHO(중국 햄스터 난소) 세포에 도입시켰다. 단일 세포 클론을 선택하기 위해서, 제네티신(geneticin) 400㎍/㎖를 세포 배양 배지(10% 우태 혈청, 100단위/ml 페니실린, 100단위/ml 스트렙토마이신이 보충된 햄스(Ham's) F12 배지)에 가하였다. 당해 선택으로 인한 단일 세포 클론의 기능성을 방사선 표지된 토로콜산([3H]-TCA)에 대한 이들의 흡수 활성을 통해 시험하였다. 후속적으로 CHO-hIBAT로서 나타내는, [3H]-TCA에 대해 가장 높은 흡수 활성을 갖는 세포 클론을 추가 시험을 위해서 선택하고 제네티신 400㎍/㎖의 존재하에 추가로 배양시켰다.
3. 본 발명에 따르는 화합물의 세포로의 토로콜산의 IBAT-의존성 흡수에 대한 억제 효과의 측정
CHO-hIBAT 세포를 폴리-D-라이신 피복된 96웰 플레이트에 세포 배양 배지 속의 웰당 40,000개의 세포의 농도로 심고 24시간 동안 배양시켰다. 이어서, 세포를 나트륨 비함유 수송 검정 완충액(140mM 콜린 클로라이드, 2mM 염화칼륨, 1mM 염화마그네슘, 1mM 염화칼슘, 10mM HEPES/Tris, pH 7.5)으로 1회 세척하고, 네거티브 대조군으로서 나트륨 비함유 수송 검정 완충액 또는 포지티브 대조군으로서 나트륨 함유 수송 검정 완충액(140mM 염화나트륨, 2mM 염화칼륨, 1mM 염화마그네슘, 1mM 염화칼슘, 10mM HEPES/Tris, pH 7.5)을 사용하여 실온에서 30분 동안 배양하였다. 동시에, 시험 웰을 상이한 농도의 시험될 화합물의 존재하에 나트륨 함유 수송 검정 완충액 속에서 실온에서 30분 동안 배양하였다. 디메틸 설폭사이드 중의 10mM 원액을 사용하여 시험 물질을 수송 검정 완충액(40㎕/웰) 속에서 적합하게 희석시켰다. 이어서, 방사선 표지된 토로콜산([3H]-TCA)과 표지되지 않은 토로콜산의 혼합물 10㎕/웰을 첨가하여 시험을 개시시켰다. 시험에서 토로콜산의 최종 농도는 10μM이었다. 실온에서 60분 배양한 후, 나트륨 비함유 수송 검정 완충액(4℃) 100㎕/웰을 첨가하여 반응을 중단시키고, 각각의 웰을 나트륨 비함유 수송 검정 완충액으로 3회 세척하였다. 마지막으로, 신틸레이션 유체 100㎕를 각각의 웰에 가하고, 세포로 흡수된 방사선을 왈락(Wallac)으로부터 입수한 마이크로베타(MicroBeta) 신틸레이션 마이크로플레이트 판독기로 측정하였다.
시험 화합물의 반치(half-maximal) 억제 효과(IC50 값, 억제 농도 50)를 다음과 같이 측정하였다:
1. 0% 억제값을 측정한다. 이는 물질의 부재하에 나트륨 함유 수송 검정 완충액 속에서 측정된다.
2. 100% 억제값을 측정한다. 이는 물질의 부재하에 나트륨 비함유 수송 검정 완충액 속에서 측정된 값이다.
3. 각종 농도의 시험될 화합물의 존재하에 수행된 측정의 억제값(%)을 계산한다. 이들 값을 사용하여 토로콜산 흡수율이 50% 감소되는 화합물 농도를 측정할 수 있다.
실시예 A의 경우, IC50(사람 IBAT)이 0.057μM인 것으로 밝혀졌다.
비교를 위해서, EP 1169313으로부터의 구조적으로 가장 유사한 화합물을 또한 측정하였다. 화학식 11a의 (실시예 5로부터의) 화합물(11a)의 경우, IC50(사람 IBAT)이 0.319μM인 것으로 밝혀졌다.
EP 1169313으로부터의 화합물에 대한 당해 비교 실시예에 비해 본 발명에 따르는 화합물(A)의 활성이 560% 더 높다.
Claims (12)
- 화학식 A의 화합물 또는 약제학적으로 허용되는 이의 염.화학식 A
- 제1항에 따르는 화합물을 포함하는 약제.
- 제1항에 따르는 화합물과 하나 이상의 추가의 활성 화합물을 포함하는 약제.
- 제3항에 있어서, 추가의 활성 화합물로서 지질 대사를 정상화하는 하나 이상의 화합물을 포함하는 약제.
- 제3항 또는 제4항에 있어서, 추가의 활성 화합물로서 하나 이상의 항당뇨병약, 혈당강하 활성 화합물, 지방 억제(anti-adipose) 약물, 식욕감퇴제, HMG-CoA-리덕타제 억제제, 콜레스테롤 흡수 억제제, PPAR 감마 작용제, PPAR 알파 작용제, PPAR 알파/감마 작용제, 피브레이트, MTP 억제제, CETP 억제제, 중합체성 담즙산 흡착제, LDL 수용체 유도 인자, ACAT 억제제, 항산화제, 지단백질 리파제 억제제, ATP 시트레이트 리아제 억제제, 스쿠알렌 신테타제 억제제, 지단백질(a) 길항제, 리파제 억제제, 인슐린, 설포닐우레아, 비구아니드, 메글리티니드, 티아졸리딘디온, α-글루코시다제 억제제, 베타 세포의 ATP-의존성 칼륨 채널에 대해 작용하는 활성 화합물, CART 작용제, NPY 작용제, 칸나비노이드 수용체 1 길항제, MCH 수용체 길항제, MC4 작용제, 오렉신 작용제, H3 작용제, TNF 작용제, CRF 작용제, CRF BP 길항제, GLP-1 유도체, 우로코르틴 작용제, β3 작용제, MSH(멜라닌 세포 자극 호르몬) 작용제, CCK-A 작용제, 세로토닌 재흡수 억제제, 혼합 세로토닌 및 노르아드레날린성 화합물, 5HT 작용제, 봄베신 작용제, 갈라닌 길항제, 성장 호르몬, 성장 호르몬 방출 화합물, TRH 작용제, 디커플링 단백질-2 또는 -3 조절자, 렙틴 작용제, DA 작용제(브로모크립틴, 도프렉신), 리파제/아밀라제 억제제, 11β-HSD1 억제제, ACC 억제제, DPP-IV 억제제, PPAR 조절자, RXR 조절자 또는 TR-β작용제 또는 암페타민을 포함하는 약제.
- 제2항 내지 제5항 중의 어느 한 항에 있어서, 추가의 보조제로서 하나 이상의 금속염을 포함하는 약제.
- 제1항에 있어서, 지질 대사 질환 치료용 약제로서 사용하기 위한 화합물.
- 활성 화합물과 약제학적으로 허용되는 담체를 혼합하고, 혼합물을 투여하기에 적합한 형태로 형성시킴을 포함하는, 제1항에 따르는 화합물을 포함하는 약제의 제조방법.
- 고지혈증 치료용 약제를 제조하기 위한, 제1항에 따르는 화합물의 용도.
- 혈청 콜레스테롤 농도 저하용 약제를 제조하기 위한, 제1항에 따르는 화합물의 용도.
- 동맥경화증 치료용 약제를 제조하기 위한, 제1항에 따르는 화합물의 용도.
- 인슐린 내성 치료용 약제를 제조하기 위한, 제1항에 따르는 화합물의 용도.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102005033099A DE102005033099A1 (de) | 2005-07-15 | 2005-07-15 | Neues 1,4-Benzothiazepin-1,1-Dioxidderivat mit verbesserten Eigenschaften, Verfahren zu dessen Herstellung, diese Verbindung enthaltende Arzneimittel und dessen Verwendung |
| DE102005033099.1 | 2005-07-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20080031738A true KR20080031738A (ko) | 2008-04-10 |
Family
ID=36997833
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020087001183A KR20080031738A (ko) | 2005-07-15 | 2006-07-13 | 1,4-벤조티아제핀 1,1-디옥사이드 유도체, 이의 제조방법,이를 포함하는 약제 및 고지혈증 치료제로서의 이의 용도 |
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| US (1) | US7615536B2 (ko) |
| EP (1) | EP1912960A1 (ko) |
| JP (1) | JP2009501177A (ko) |
| KR (1) | KR20080031738A (ko) |
| CN (1) | CN101223151A (ko) |
| AU (1) | AU2006272042A1 (ko) |
| BR (1) | BRPI0613462A2 (ko) |
| CA (1) | CA2614524A1 (ko) |
| DE (1) | DE102005033099A1 (ko) |
| IL (1) | IL188608A0 (ko) |
| MA (1) | MA29619B1 (ko) |
| MX (1) | MX2008000426A (ko) |
| NO (1) | NO20080789L (ko) |
| NZ (1) | NZ565292A (ko) |
| RU (1) | RU2008105756A (ko) |
| TW (1) | TW200745069A (ko) |
| UY (1) | UY29675A1 (ko) |
| WO (1) | WO2007009655A1 (ko) |
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| DE102006053636B4 (de) | 2006-11-14 | 2008-09-18 | Sanofi-Aventis Deutschland Gmbh | Neue mit Cyclohexylresten substituierte 1,4-Benzothiepin-1,1-Dioxidderivate und deren Verwendung |
| DE102006053637B4 (de) | 2006-11-14 | 2011-06-30 | Sanofi-Aventis Deutschland GmbH, 65929 | Neue mit Fluor substituierte 1,4-Benzothiepin-1,1-Dioxidderivate, diese Verbindungen enthaltende Arzneimittel und deren Verwendung |
| DE102006053635B4 (de) | 2006-11-14 | 2011-06-30 | Sanofi-Aventis Deutschland GmbH, 65929 | Neue mit Benzylresten substituierte 1,4-Benzothiepin-1,1-Dioxidderivate, diese Verbindungen enthaltende Arzneimittel und deren Verwendung |
| EP2083832B1 (de) | 2006-11-14 | 2011-01-05 | Sanofi-Aventis Deutschland GmbH | Neue 1,4-benzothiepin-1,1-dioxidderivate mit verbesserten eigenschaften, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung |
| DE102007005045B4 (de) | 2007-01-26 | 2008-12-18 | Sanofi-Aventis | Phenothiazin Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
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| SE441189B (sv) * | 1984-02-07 | 1985-09-16 | Boliden Ab | Forfarande for framstellning av metalliskt bly genom smeltreduktion |
| PT864582E (pt) * | 1997-03-14 | 2003-10-31 | Aventis Pharma Gmbh | 1,4-benzotiazepina-1,1-dioxidos hipolipidemicos |
| US6221897B1 (en) * | 1998-06-10 | 2001-04-24 | Aventis Pharma Deutschland Gmbh | Benzothiepine 1,1-dioxide derivatives, a process for their preparation, pharmaceuticals comprising these compounds, and their use |
| DE19916108C1 (de) * | 1999-04-09 | 2001-01-11 | Aventis Pharma Gmbh | Mit Zuckerresten substituierte 1,4-Benzothiazepin-1,1-dioxidderivate, Verfahren zu deren Herstellung und deren Verwendung |
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2005
- 2005-07-15 DE DE102005033099A patent/DE102005033099A1/de not_active Ceased
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2006
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- 2006-07-13 BR BRPI0613462-9A patent/BRPI0613462A2/pt not_active Application Discontinuation
- 2006-07-13 KR KR1020087001183A patent/KR20080031738A/ko not_active Application Discontinuation
- 2006-07-13 CN CNA2006800258356A patent/CN101223151A/zh active Pending
- 2006-07-13 CA CA002614524A patent/CA2614524A1/en not_active Abandoned
- 2006-07-13 AU AU2006272042A patent/AU2006272042A1/en not_active Abandoned
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- 2006-07-13 WO PCT/EP2006/006848 patent/WO2007009655A1/de active Application Filing
- 2006-07-13 TW TW095125565A patent/TW200745069A/zh unknown
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2008
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- 2008-01-08 MA MA30556A patent/MA29619B1/fr unknown
- 2008-02-13 NO NO20080789A patent/NO20080789L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| RU2008105756A (ru) | 2009-08-20 |
| DE102005033099A1 (de) | 2007-01-18 |
| WO2007009655A1 (de) | 2007-01-25 |
| MX2008000426A (es) | 2008-03-10 |
| UY29675A1 (es) | 2007-02-28 |
| US7615536B2 (en) | 2009-11-10 |
| US20080207534A1 (en) | 2008-08-28 |
| NZ565292A (en) | 2010-01-29 |
| AU2006272042A1 (en) | 2007-01-25 |
| NO20080789L (no) | 2008-02-13 |
| CN101223151A (zh) | 2008-07-16 |
| IL188608A0 (en) | 2008-04-13 |
| BRPI0613462A2 (pt) | 2011-01-11 |
| TW200745069A (en) | 2007-12-16 |
| EP1912960A1 (de) | 2008-04-23 |
| JP2009501177A (ja) | 2009-01-15 |
| CA2614524A1 (en) | 2007-01-25 |
| MA29619B1 (fr) | 2008-07-01 |
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