CN101218217A - 具有改善性质的新的1,4-苯并硫氮杂䓬-1,1-二氧化物衍生物、制备它们的方法、包含所述化合物的药物以及它们的用途 - Google Patents
具有改善性质的新的1,4-苯并硫氮杂䓬-1,1-二氧化物衍生物、制备它们的方法、包含所述化合物的药物以及它们的用途 Download PDFInfo
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- A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
本发明涉及式(A)化合物及其生理学可接受的盐。所述的化合物适合作为例如降血脂药。
Description
本发明涉及取代的1,4-苯并硫氮杂(benzothiazepine)-1,1-二氧化物衍生物及其生理学可接受的盐。
1,4-苯并硫氮杂-1,1-二氧化物衍生物及其用于治疗高脂血症和动脉硬化以及高胆固醇血症已经被描述(EP 1 169 313)。
本发明的目的是提供与EP 1 169 313中描述的化合物相比具有更好功效的化合物。
因此,本发明涉及式A化合物及其可药用盐。
由于它们比起始化合物或基础化合物在水中更可溶,可药用盐特别适用于医学应用。这些盐必须具有可药用阴离子或阳离子。本发明化合物的适合的可药用酸加成盐是无机酸盐,所述的无机酸例如盐酸、氢溴酸、磷酸、偏磷酸、硝酸和硫酸,以及有机酸盐,所述的有机酸例如乙酸、苯磺酸、苯甲酸、柠檬酸、乙磺酸、富马酸、葡糖酸、羟基乙酸、羟乙磺酸、乳酸、乳糖酸、马来酸、苹果酸、甲磺酸、琥珀酸、对甲苯磺酸和酒石酸。
包含不可药用阴离子的盐(例如三氟乙酸盐)也属于本发明的范围,该盐用作中间体用于制备或纯化可药用盐和/或用于非治疗应用(例如体外应用)。
本发明化合物还可以以不同的多晶型形式存在,例如作为无定形和晶状多晶型形式。本发明化合物的所有多晶型形式属于本发明范围并且是本发明的另一个方面。
在下文中所有涉及“式A化合物”的指的是以上描述的式A化合物及其盐和溶剂化物。
式A化合物还可以与其它活性化合物组合施用。
为了获得所需的生物学作用而需要的式A化合物的量取决于很多因素,例如所选的特别化合物、预期的用途、施用类型和患者的临床状态。通常,日剂量在0.01mg至100mg(通常在0.05mg至50mg)/天/千克体重范围内,例如0.1-10mg/kg/天。
可以口服施用的单剂量制剂,例如片剂或胶囊剂例如可以包含1.0至1000mg,通常是10至600mg。当式A化合物本身可以用作治疗上述病症的化合物时,它们优选与可接受载体一起以药物组合物形式存在。载体当然必须是可接受的,这意味着它与其它组合物的成分是相容的并且对患者的健康没有危害。载体可以是固体或液体或两种均可并且优选与化合物配制成单剂量,例如包含0.05%至95%体重活性化合物的片剂。还可以存在其它药物活性物质,包括其它式A化合物。本发明药物组合物可以使用已知的制药方法中的一种方法来制备,该方法实质上包括将组分与可药用载体物质和/或辅助物质混合。
本发明药物组合物是适合口服和经口(例如舌下)施用的那些,即使最适合的施用方式(在每个单独情况中)取决于所治疗病症的性质和严重程度以及每个情况中使用的式A化合物的性质。糖包衣制剂和糖包衣缓释制剂也属于本发明的范围。优选抗酸和抗胃液的制剂。适合的抗胃液包衣包括醋酞纤维素、聚醋酸乙烯邻苯二甲酸酯、羟丙基甲基纤维素邻苯二甲酸酯和甲基丙烯酸和甲基丙烯酸甲酯的阴离子聚合物。
用于口服施用的适合的药物化合物可以以单独单位存在,例如胶囊剂、扁囊剂、锭剂或片剂,其在每个情况中包含特别量的式A化合物;散剂或颗粒剂;在水或非水液体中的溶液剂或混悬剂;或水包油型或油包水型乳剂。正如已经提及的,这些组合物可以使用任何适合的制药方法来制备,其包括其中将活性化合物和载体(其可以包括一种或多种另外的成分)接触的步骤。通常,组合物通过将活性化合物与液体和/或细微分开的固体载体进行均匀并且均相混合,如果需要再将产物模制来制备。因此,片剂可以例如借助将化合物的粉末或颗粒(如果适合的话,与一种或多种另外的成分一起)压制或模制来制备。压制片剂可以通过将自由流动形式的化合物(例如粉末或颗粒)压片来制备,如果适合的话,将化合物与粘合剂、润滑剂、惰性稀释剂和/或(几种)表面活性剂/分散剂在适合的机器中混合。模制片可以通过将粉状的化合物(将其用惰性、液体稀释剂在适合的机器中润湿)模制来制备。
适合经口(舌下)施用的药物组合物包括锭剂(其包含式A化合物以及矫味剂,通常是蔗糖和阿拉伯胶或黄蓍胶)和软锭剂(其包括在惰性基质中的化合物,所述的惰性基质例如明胶和甘油或蔗糖和阿拉伯胶)。
本发明的药物组合物的另一个实施方案包含适合的金属盐,例如钙、铝、铁、铜、锌、镁、锰或锌盐。优选的是钙和锌盐,例如磷酸钙、乳酸钙、碳酸钙、葡糖酸钙、乙酸钙、磷酸锌、乳酸锌、碳酸锌、葡糖酸锌或乙酸锌。向药物组合物中加入这些盐可以减少或预防患者腹泻的发生。
以下适合用作组合制剂的另外的活性化合物:
在Roten Liste[Red List]2005的第12章中命名的所有抗糖尿病药。它们可以与本发明式A化合物组合,特别用于协同改善作用的目的。该活性化合物组合可以通过给患者单独施用活性化合物来施用或以组合制剂形式(其中在一个药物制剂中存在数个活性化合物)施用来施用。以下引用的大多数活性化合物公开于USP Dictionary of USAN and InternationalDrug Names,US Pharmacopeia,Rockville,2001)中。
抗糖尿病药包括胰岛素和胰岛素衍生物(例如Lantus(参见www.lantus.com)或HMR 1964)、快速作用胰岛素(参见US 6,221,633)、GLP-1衍生物(例如WO 98/08871中Novo Nordisk A/S公开的、WO/04156中Zealand公开的以及WO 00/34331中Beaufour-Ipsen公开的那些)以及还包括口服有效降血糖的活性化合物。
口服有效降血糖的活性化合物优选包括磺酰脲类、双胍类、氯茴苯酸类、二唑烷二酮类、噻唑烷二酮类、葡萄糖苷酶和糖原磷酸化酶抑制剂、胰高血糖素拮抗剂、GLP-1-激动剂、钾通道开放剂(例如WO 97/26265和WO 99/03861中Novo Nordisk A/S公开的那些)、胰岛素增敏剂、肝酶(涉及刺激糖异生和/或糖原分解)抑制剂、葡萄糖摄取、葡萄糖转运和葡萄糖重吸收的调节剂、改变脂肪代谢的化合物(例如抗高血脂活性化合物和抗血脂活性化合物)、降低食物摄取的化合物、PPAR激动剂和PXR激动剂以及作用于β细胞的ATP-依赖性钾通道的活性化合物。
在本发明的一个实施方案中,式A化合物与HMGCoA还原酶抑制剂组合施用,所述的HMGCoA还原酶抑制剂例如辛伐他汀、氟伐他汀、普伐他汀、洛伐他汀、阿托伐他汀、西立伐他汀或罗苏伐他汀。
在本发明的一个实施方案中,式I化合物与胆固醇吸收抑制剂例如依泽替米贝、替奎安、帕马苷组合施用,或与PCT/EP 2004/00269、PCT/EP2003/05815、PCT/EP 2003/05814、PCT/EP 2003/05816、EP 0114531或US 6,498,156中描述的化合物组合施用。
在本发明的一个实施方案中,式A化合物与PPARγ激动剂组合施用,所述的PPARγ激动剂例如罗格列酮、吡格列酮、JTT-501或GI 262570。
在本发明的一个实施方案中,式A化合物与PPARα激动剂组合施用,所述的PPARα激动剂例如GW 9578或GW 7647。
在本发明的一个实施方案中,式A化合物与混合的PPARα/γ激动剂组合施用,所述的混合的PPARα/γ激动剂例如GW 1536、AVE 8042、AVE 8134或AVE 0847或PCT/US 00/11833、PCT/US 00/11490或WO03/020269中描述的。
在本发明的一个实施方案中,式A化合物与贝特类组合施用,所述的贝特类例如非诺贝特、氯贝特或苯扎贝特。
在本发明的一个实施方案中,式A化合物与MTP抑制剂组合施用,所述的MTP抑制剂例如英普他派、BMS-201038或R-103757。
在本发明的一个实施方案中,式A化合物与CETP抑制剂组合施用,所述的CETP抑制剂例如JTT-705。
在本发明的一个实施方案中,式A化合物与聚胆汁酸吸收剂组合施用,所述的聚胆汁酸吸收剂例如考来烯胺或考来维仑。
在本发明的一个实施方案中,式A化合物与LDL受体诱导剂(参见US6,342,512)组合施用。
在本发明的一个实施方案中,式A化合物与ACAT抑制剂组合施用,所述的ACAT抑制剂例如阿伐麦布。
在本发明的一个实施方案中,式A化合物与抗氧化剂组合施用,所述的抗氧化剂例如OPC-14117。
在本发明的一个实施方案中,式A化合物与脂蛋白脂肪酶抑制剂组合施用,所述的脂蛋白脂肪酶抑制剂例如NO-1886。
在本发明的一个实施方案中,式A化合物与ATP柠檬酸裂解酶抑制剂组合施用,所述的ATP柠檬酸裂解酶抑制剂例如SB-204990。
在本发明的一个实施方案中,式A化合物与角鲨烯合成酶抑制剂组合施用,所述的角鲨烯合成酶抑制剂例如BMS-188494。
在本发明的一个实施方案中,式A化合物与脂蛋白(a)拮抗剂组合施用所述的脂蛋白(a)拮抗剂例如CI-1027或烟酸。
在本发明的一个实施方案中,式A化合物与脂肪酶抑制剂组合施用,所述的脂肪酶抑制剂例如奥利司他。
在本发明的一个实施方案中,式A化合物与胰岛素组合施用。
在一个实施方案中,式A化合物与磺酰脲类组合施用,所述的磺酰脲类例如甲苯磺丁脲、格列本脲、格列吡嗪或格列美脲。
在一个实施方案中,式A化合物与双胍类组合施用,所述的双胍类例如二甲双胍。
在另一个实施方案中,式A化合物与氯茴苯酸类组合施用,所述的氯茴苯酸类例如瑞格列奈。
在一个实施方案中,式A化合物与噻唑烷二酮类组合施用,所述的噻唑烷二酮类例如曲格列酮、环格列酮、吡格列酮、罗格列酮或WO 97/41097中Dr.Reddy’s Research Foundation公开的化合物,特别是5-[[4-(3,4-二氢-3-甲基-4-氧代-2-喹唑啉基甲氧基)苯基]甲基]-2,4-噻唑烷二酮)。
在一个实施方案中,式A化合物与α-葡萄糖苷酶抑制剂组合施用,所述的α-葡萄糖苷酶抑制剂例如米格列醇或阿卡波糖。
在一个实施方案中,式A化合物与腺苷A1激动剂组合施用,所述的腺苷A1激动剂例如EP 0912520或PCT/EP 06749中描述的那些。
在一个实施方案中,式A化合物与作用于β细胞的ATP依赖性钾通道的活性化合物组合施用,所述的作用于β细胞的ATP依赖性钾通道的活性化合物例如甲苯磺丁脲、格列本脲、格列吡嗪、格列美脲或瑞格列奈。
在一个实施方案中,式A化合物与多于一种的上述化合物组合施用,例如与磺酰脲类和二甲双胍、磺酰脲类和阿卡波糖、瑞格列奈和二甲双胍、胰岛素和磺酰脲类、胰岛素和二甲双胍、胰岛素和曲格列酮、胰岛素和洛伐他汀等组合施用。
在另一个实施方案中,式A化合物与以下物质组合施用:CART调节剂(参见“cocaine-amphetamine-regulated transcript influences energymetabolism,anxiety and gastric emptying in mice”Asakawa,A等人,M.Hormone and Metabolic Research(2001),33(9),554-558)、NPY拮抗剂(例如萘-1-磺酸-{4-[(4-氨基喹唑啉-2-基氨基)甲基]环己基-甲基}酰胺盐酸盐(CGP 71683A))、大麻素受体1拮抗剂(参见例如EP 0656354、WO 00/15609或WO 02/076949)、MC4激动剂(例如1-氨基-1,2,3,4-四氢萘-2-甲酸[2-(3a-苄基-2-甲基-3-氧代-2,3,3a,4,6,7-六氢吡唑并[4,3-c]吡啶-5-基)-1-(4-氯苯基)-2-氧代乙基]酰胺;(WO 01/91752))、食欲肽拮抗剂(例如1-(2-甲基苯并唑-6-基)-3-[1,5]二氮杂萘-4-基脲盐酸盐(SB-334867-A))、H3激动剂(3-环己基-1-(4,4-二甲基-1,4,6,7-四氢咪唑并[4,5-c]吡啶-5-基)-丙-1-酮草酸盐(WO 00/63208))、TNF激动剂、CRF拮抗剂(例如[2-甲基-9-(2,4,6-三甲基苯基)-9H-1,3,9-三氮杂芴-4-基]二丙胺(WO 00/66585))、CRF BP拮抗剂(例如尿皮质素(urocortin))、尿皮质素激动剂、β3-激动剂(例如1-(4-氯-3-甲磺酰基甲基苯基)-2-[2-(2,3-二甲基-1H-吲哚-6-基氧基)乙基氨基]乙醇盐酸盐(WO 01/83451))、MSH(促黑素细胞激素)激动剂、MCH(浓缩黑色素激素)受体拮抗剂(参见例如WO 03/15769)、CCK-A激动剂(例如{2-[4-(4-氯-2,5-二甲氧基苯基)-5-(2-环己基乙基)噻唑-2-基氨基甲酰基]-5,7-二甲基吲哚-1-基}乙酸三氟乙酸盐(WO 99/15525)或SR-146131(WO 0244150)或SSR-125180)、5-羟色胺重摄取抑制剂(例如右芬氟拉明)、混合的5-羟色胺能和去甲肾上腺素能化合物(例如WO 00/71549)、5HT激动剂(例如1-(3-乙基苯并呋喃-7-基)哌嗪草酸盐(WO 01/09111))、铃蟾肽激动剂、甘丙肽拮抗剂、生长激素(例如人生长激素)、释放生长激素的化合物(6-苄氧基-1-(2-二异丙基氨基乙基氨基甲酰基)-3,4-二氢-1H-异喹啉-2-甲酸叔丁酯(WO01/85695))、TRH激动剂(参见例如EP 0 462 884)、解偶联蛋白2或蛋白3调节剂、瘦蛋白激动剂(参见例如Lee,Daniel W.Leinung,Matthew C.Rozhavskaya-Arena,Marina;Grasso,Patricia.Leptin agonists as apotential approach to the treatment of obesity.Drugs of the Future(2001),26(9),873-881)、DA激动剂(溴隐亭、doprexin)、脂肪酶/淀粉酶抑制剂(例如WO 00/40569)、PPAR调节剂(例如WO 00/78312)、11β-HSD1(11-β-羟基类固醇脱氢酶1型)抑制剂(参见例如WO 01/90094或T.Barf等人,J.Med.Chem.(2002),45,3813-3815)、乙酰辅酶A羧化酶(ACC;参见例如WO 99/46262)抑制剂、二肽基肽酶IV(DPP-IV;参见例如EP 1259246)抑制剂、RXR调节剂或TR-β-激动剂。
在本发明的一个实施方案中,其它活性化合物是瘦蛋白,参见例如“Perspectives in the therapeutic use of leptin”,Salvador,Javier;Gomez-Ambrosi,Javier;Fruhbeck,Gema,Expert Opinion onPharmacotherapy(2001),2(10),1615-1622。
在一个实施方案中,其它活性化合物是右苯丙胺或苯丙胺。
在一个实施方案中,其它活性化合物是芬氟拉明或右芬氟拉明。
在另一个实施方案中,其它活性化合物是西布曲明。
在一个实施方案中,其它活性化合物是奥利司他。
在一个实施方案中,其它活性化合物是马吲哚或芬特明。
在一个实施方案中,式A化合物与压载物质(ballast substance),优选不溶性的压载物质(参见例如carob/Caromax(Zunft H J等人,Carob pulppreparation for treatment of hypercholesterolemia,ADVANCES INTHERAPY(2001 Sep-Oct),18(5),230-6)组合施用。Caromax是含角豆的产物,来源于Nutrinova,Nutrition Specialties & Food Ingredients GmbH,Industriepark Hoechst,65926 Frankfurt/Main。与Caromax的组合可以在一个制剂中或通过分别施用式A化合物和Caromax来发挥作用。关于这一点,Caromax也可以以食品(例如以面包、饼和软点心或早餐棒(muesli bar))形式施用。
应当理解的是本发明化合物与一种或多种上述化合物以及(如果需要)一种或多种另外的药物活性物质的每个适合的组合被认为包括在本发明的被保护范围内。
实施例A
化合物A制备如下:
结构式流程图1
结构式流程图2(异氰酸酯2的合成)
化合物1a的合成:
对映异构体纯的化合物1a是通过手性色谱法由外消旋苯胺(anilide)1(EP 1169313化合物8a/b)获得的,手性色谱法使用ChiralpakAS-H76,流动相是正庚烷/甲醇/乙醇10/1/1加0.1%DEA。通过从THF/EA/正庚烷中结晶,进一步纯化化合物1a(ee 99.9%)是可能的。优对映体具有正的旋光性,并且绝对立体化学通过单晶X-射线结构来确定。
化合物5的合成:
在80℃下,将4.5g的葡糖胺4(Aldrich)溶于100mL的DMF中,然后加入5g的N-(苄氧基羰基氧基)琥珀酰亚胺(ABCR)。20分钟后,滴加100mL的乙酸酐/吡啶(1∶1),并且将反应溶液在50℃下保持1小时。将溶剂在高真空下蒸馏,并且将残留物经快速色谱纯化。产量10.1g(77%)的5,其为无色固体。TLC(正庚烷/乙酸乙酯1∶2),Rf=0.4。C24H31NO12(525.51)。MS(M+H)+=525.25。
化合物6的合成:
将17.45g的五乙酸酯5溶于200mL的0.25M甲醇盐酸中,并且在氩气气氛下加入1.3g的10%钯活性碳。在5bar的氢气压下,在室温下将混合物氢化1小时。将催化剂除去并且蒸馏出约150mL的甲醇。加入MTB醚后,将盐酸盐6沉淀出来。获得13g(92%)的无色固体6。C16H25NO10×HCl(427.84)。MS(M+H)+=392.21。
化合物2的合成:
将1.5g的盐酸盐6悬浮于50mL的二氯甲烷中并且在氩气下冷却至0℃。在该悬浮液中依次加入1.5g的三光气和3mL的三乙胺,并且将混合物在0℃下搅拌1小时。将反应溶液用50mL的正庚烷/乙酸乙酯(1∶1)稀释并且通过少量硅胶过滤。将溶剂蒸馏,得到1.52g的无定形固体2,其为粗产物,其不经进一步纯化直接用于下一步。
化合物3的合成:
在室温下,将5.45g(12.3mmol)的苯胺1a和3.58g(8.5mmol)的异氰酸酯2溶于150mL的二氯甲烷中。室温下1小时后,将混合物浓缩并且将残留物经快速色谱纯化。产量4.72g(64%)的3,其为无色固体。TLC(正庚烷/乙酸乙酯1∶2),Rf=0.3。C42H60N4O13S(861.03)。MS(M+H)+=861.59。
化合物A的合成:
将4.7g的3溶于60mL的甲醇和20mL的三乙胺中并且在室温下放置16小时。将溶液浓缩并且将残留物经快速色谱纯化(二氯甲烷/甲醇/浓氨30/10/3)。产量2.17g(60%)的A,其为无定形固体。TLC(二氯甲烷/甲醇/浓氨30/10/3),Rf=0.4。C32H50N4O8S(650.84)。MS(M+H)+=651.34。
本发明的化合物A的生物学试验是应用体外IBAT抑制试验来进行的。该试验检查了本发明化合物对重组表达的人钠依赖性回肠胆汁酸转运体的转运活性的作用(IBAT=回肠Na+/胆汁酸共转运体,ASBT=顶端钠依赖性胆汁酸转运体,SLC10A2=溶质载体家族10,成员2)。
体外IBAT抑制试验的准备和实践
1.人IBAT表达载体的克隆
使用例如Joseph Sambrook和David Russell的Molecular Cloning:ALaboratory Manual中描述的分子生物学标准方法克隆人IBAT的cDNA(互补脱氧核糖核酸)并且将其引入到pcDNA1载体(来自Invitrogen)中。引入片段的随后测序显示其与P.A.Dawson描述的并且存放在GenBank序列数据库(GenBank Accesion Number:U10417)中的人IBAT的碱基序列的碱基599至1645完全一致。碱基599至1645相应于人IBAT的完全编码区。
2.组成性表达人IBAT的重组细胞系的制备
将人IBAT表达载体通过稳定转染引入到CHO(中国仓鼠卵巢)细胞中。为了挑选单细胞克隆,将400μg/mL的遗传霉素加入到细胞培养基(Ham’s F12培养基,补充有10%胎牛血清、100单位/mL的青霉素、100单位/mL的链霉素)中。由筛选获得的单细胞克隆的功能性通过它们对放射性标记的牛磺胆酸([3H]-TCA)的摄取活性进行试验。将对[3H]-TCA具有最高摄取活性的细胞克隆(后面以CHO-hIBAT表示)挑选出来进行进一步试验并且在400μg/mL的遗传霉素的存在下进一步培养。
3.本发明化合物对IBAT依赖性摄取牛磺胆酸进入细胞的抑制作用的测量
将CHO-hIBAT细胞以40000个细胞/孔的浓度接种于在聚-D-赖氨酸包被的96孔板中的细胞培养基中并且培养24小时。然后将细胞用不含钠的转运试验缓冲液(140mM氯化胆碱、2mM氯化钾、1mM氯化镁、1mM氯化钙、10mM HEPES/Tris,pH 7.5)洗涤一次,然后在室温下用不含钠的转运试验缓冲液(作为阴性对照)或与含钠的转运试验缓冲液(140mM氯化钠、2mM氯化钾、1mM氯化镁、1mM氯化钙、10mM HEPES/Tris,pH 7.5)(作为阳性对照)培养30分钟。同时,将试验孔也在不同浓度的待测化合物的存在下在室温下、在含钠的转运试验缓冲液中培养30分钟。使用在二甲亚砜中的10mM储备液,将试验物质在转运试验缓冲液中适当稀释(40μL/孔)。然后通过加入10μL/孔的放射性标记的牛磺胆酸([3H]-TCA)和未标记的牛磺胆酸的混合物开始试验。试验中牛磺胆酸的终浓度是10μM。在室温下培养60分钟后,通过加入100μL/孔的不含钠的转运试验缓冲液(4℃)来终止反应,并且每孔用不含钠的转运试验缓冲液洗涤三次。最后,在每孔中加入100μL的闪烁液,并且在MicroBeta闪烁微量板读数器(来自Wallac)上确定摄入细胞中的放射性。
试验化合物的半最大抑制作用(IC50值,抑制浓度50)确定如下:
1.0%抑制值的确定。这是在物质不存在下,在含钠的转运试验缓冲液中测定的值。
2.100%抑制值的测定。这是在物质不存在下,在不含钠的转运试验缓冲液中测定的值。
3.测量的抑制值(百分数)的计算,该测量在不同浓度的待测化合物的存在下进行。使用这些数值,才可能确定牛磺胆酸摄取减少50%时的化合物浓度(IC50值)。
对于实施例A,IC50(人IBAT)为:0.155μM。
为了进行比较,还测定了来自EP 1 169 313的结构最相似的化合物。对于下式化合物11a(来自实施例5):
IC50(人IBAT)为:0.319μM。
本发明的化合物A的活性是来自EP 1 169 313的比较的实施例的活性的206%。
Claims (12)
2.药物,该药物包含权利要求1中要求的化合物。
3.药物,该药物包含权利要求1中要求的化合物以及至少一种其它活性化合物。
4.权利要求3中要求的药物,其包含作为其它活性化合物的一种或多种使脂质代谢正常化的化合物。
5.权利要求3或4中要求的药物,其包含作为其它活性化合物的一种或多种抗糖尿病药、降血糖活性化合物、减肥药、减食欲药、HMG-CoA还原酶抑制剂、胆固醇吸收抑制剂、PPARγ激动剂、PPARα激动剂、PPARα/γ激动剂、贝特类、MTP抑制剂、CETP抑制剂、聚胆汁酸吸收剂、LDL受体诱导剂、ACAT抑制剂、抗氧化剂、脂蛋白脂肪酶抑制剂、ATP柠檬酸裂解酶抑制剂、角鲨烯合成酶抑制剂、脂蛋白(a)拮抗剂、脂肪酶抑制剂、胰岛素、磺酰脲类、双胍类、氯茴苯酸类、噻唑烷二酮类、α-葡萄糖苷酶抑制剂、作用于β细胞的ATP-依赖性钾通道的活性化合物、CART激动剂、NPY激动剂、大麻素受体1拮抗剂、MCH受体拮抗剂、MC4激动剂、食欲肽激动剂、H3激动剂、TNF激动剂、CRF激动剂、CRF BP拮抗剂、GLP-1衍生物、urocortin激动剂、β3激动剂、MSH(促黑素细胞激素)激动剂、CCK-A激动剂、5-羟色胺重摄取抑制剂、混合的5-羟色胺和去甲肾上腺素能化合物、5HT激动剂、铃蟾肽激动剂、甘丙肽拮抗剂、生长激素、释放生长激素的化合物、TRH激动剂、解偶联蛋白-2或-3调节剂、瘦蛋白激动剂、DA激动剂(溴隐亭、doprexin)、脂肪酶/淀粉酶抑制剂、11β-HSD1抑制剂、ACC抑制剂、DPP-IV抑制剂、PPAR调节剂、RXR调节剂或TR-β-激动剂或苯丙胺。
6.权利要求2、3、4或5中任意一项要求的药物,其包含作为其它辅剂的一种或多种金属盐。
7.权利要求1中要求的化合物,其用作治疗脂质代谢障碍的药物。
8.制备包含权利要求1中要求的化合物的药物的方法,该方法包括将活性化合物与可药用载体混合并且将该混合物制成适合施用的形式。
9.权利要求1中要求的化合物在制备用于治疗高脂血症的药物中的用途。
10.权利要求1中要求的化合物在制备用于降低血清胆固醇浓度的药物中的用途。
11.权利要求1中要求的化合物在制备用于治疗动脉硬化症状的药物中的用途。
12.权利要求1中要求的化合物在制备用于治疗抗胰岛素性的药物中的用途。
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CN109415329A (zh) * | 2016-06-27 | 2019-03-01 | 葛兰素史克知识产权第二有限公司 | 合成方法 |
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KR20230106651A (ko) | 2020-11-12 | 2023-07-13 | 알비레오 에이비 | 진행성 가족성 간내 담즙정체증(pfic)을 치료하기 위한 오데빅시바트 |
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US6107494A (en) * | 1994-09-13 | 2000-08-22 | G.D. Searle And Company | Substituted 5-aryl-benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake |
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 |
DE10312963A1 (de) * | 2003-03-24 | 2004-10-07 | Aventis Pharma Deutschland Gmbh | Substituierte 4-Phenyltetrahydroisochinoline, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament, sowie sie enthaltendes Medikament |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN109415329A (zh) * | 2016-06-27 | 2019-03-01 | 葛兰素史克知识产权第二有限公司 | 合成方法 |
CN109415329B (zh) * | 2016-06-27 | 2023-05-12 | 葛兰素史克知识产权第二有限公司 | 合成方法 |
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DE502006002956D1 (de) | 2009-04-09 |
NZ565293A (en) | 2010-01-29 |
US20080207592A1 (en) | 2008-08-28 |
IL188606A0 (en) | 2008-04-13 |
ATE423774T1 (de) | 2009-03-15 |
AU2006272043A1 (en) | 2007-01-25 |
MX2008000355A (es) | 2008-03-07 |
TW200745070A (en) | 2007-12-16 |
JP2009501178A (ja) | 2009-01-15 |
AR058433A1 (es) | 2008-02-06 |
KR20080027841A (ko) | 2008-03-28 |
WO2007009656A2 (de) | 2007-01-25 |
WO2007009656A3 (de) | 2007-04-19 |
EP1907370B1 (de) | 2009-02-25 |
DE102005033100B3 (de) | 2007-01-25 |
MA29620B1 (fr) | 2008-07-01 |
BRPI0613041A2 (pt) | 2010-12-14 |
CA2614697A1 (en) | 2007-01-25 |
RU2008105741A (ru) | 2009-08-20 |
EP1907370A2 (de) | 2008-04-09 |
NO20080728L (no) | 2008-02-08 |
AR055076A1 (es) | 2007-08-01 |
ZA200710360B (en) | 2008-11-26 |
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