CN1199337A - 抑制血纤维蛋白溶酶原激活剂抑制剂1的方法 - Google Patents
抑制血纤维蛋白溶酶原激活剂抑制剂1的方法 Download PDFInfo
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Abstract
抑制血纤维蛋白溶酶原激活剂抑制剂1的方法,该方法包括给予需要进行抑制的人有效量的式(Ⅰ)化合物或其可药用盐或溶剂化物,其中R1和R3独立地为氢、-CH3、-CO-(C1-C6烷基)或-CO-Ar,其中Ar是取代或未取代的苯基;R2选自1-吡咯烷基、六亚甲基亚胺基和哌啶子基。
Description
发明背景
溶解血纤维蛋白系统在维持正常止血平衡中起重要作用。该系统中的一个关键的因子是血纤维蛋白溶酶原激活剂抑制剂I(PAI-1),它通过抑制血纤维蛋白溶酶原激活剂如组织型血纤维蛋白溶酶原激活剂(tPA)而减小内源除去血纤维蛋白的能力。研究表明深处静脉血管中血栓形成危险性的增加与PAI-1的升高有关。而且,发现在患有心肌梗塞和败血症的病人中PAI-1升高。因为增加心血管危险与减少溶解血纤维蛋白能力有关,降低PAI-1应当导致心脏保护作用。事实上,目前在FraminhamOffspring Study中对绝经前和后的妇女的PAI-1水平的分析研究表明绝经后妇女具有明显较高的PAI-1水平,用雌激素治疗可将其水平减少到绝经前的水平。相信减小PAI-1的作用有助于对减少心脏疾病危险进行雌激素替代治疗的总体效果。
尽管PAI-1可在各种组织中产生,但主要由血管内皮细胞产生。血管内皮构成了起血液凝固调节、炎症调节和血管内腔和实质组织之间的液体和介质的交换作用的主要器官。因此,内皮的合适功能是体内总体平衡的关键。因为PAI-1可因内皮细胞对某些刺激(包括细胞激活素(cytokines))产生反应而增加,所以产生功能障碍,导致凝血缺损、局部和全身血管炎和增加动脉粥样硬化斑的发展和破裂。这些作用可进一步导致疾病,包括心肌梗塞、深处静脉血栓形成和弥漫的血管内血栓形成。
由于在内皮细胞/血浆界面局部控制PAI-1可在许多疾病过程中起重要作用,因此抑制在内皮中表达PAI-1的试剂可用于治疗疾病,如脓毒症、损伤包括重要组织损伤和创伤、系统炎性反应综合症、脓毒综合症、脓毒性休克和多器官功能障碍综合症(包括DIC)以及心肌梗塞、深处静脉形成血栓、弥漫的血管内形成血栓、动脉粥样硬化斑破裂及其相关的后遗症。而且由于血纤维蛋白在肿瘤细胞生物学中的关键作用,发现PAI-1调节剂可用作抗转移瘤药物。
发明概述
本发明提供抑制血纤维蛋白溶酶原激活剂抑制剂1的方法,该方法包括给予需要进行抑制的人有效量的式I化合物及其可药用盐和溶剂化物
其中R1和R3独立地为氢、-CH3、-CO-(C1-C6烷基)或-CO-Ar,其中Ar是取代或未取代的苯基;
R2选自1-吡咯烷基(pyrrolidino)、六亚甲基亚胺基和哌啶子基。
发明详细描述
本发明发现选择出的一组2-苯基-3-芳酰基苯并噻吩(苯并噻吩类),由式I所示,可用于抑制PAI-1。
本发明提供的使用方法通过给予需要抑制的人一定剂量的式I化合物或其可药用盐或溶剂化物来进行,它可有效地抑制PAI-1或与其过量有关的生理疾病。术语“抑制”包括其通常可接受的意思,它包括阻止、防止、制止和减缓、停止或逆转其进行、严重性或所导致的症状或作用。
雷洛昔芬是本发明的一种化合物,是式I化合物的盐酸盐,其中R1和R3为氢且R2为1-哌啶基,它是一种核调节分子。雷洛昔芬已经显示与雌激素受体结合且最初认为它是一种具有抗雌激素功能和药理的分子,其中阻断雌激素激活子宫组织和雌激素依赖的乳房癌。的确,雷洛昔芬在某些细胞中阻断雌激素的作用,而在其它细胞中雷洛昔芬激活与雌激素相同的基因并且显示相同的药理作用,如骨质疏松、血脂过高。因此,雷洛昔芬已被称作具有激动和拮抗混合特性的抗雌激素剂。现在认为雷洛昔芬所显示的不同于雌激素的独特作用是由于与由雌激素-雌激素受体复合物激活和/或抑制基因相反的通过雷洛昔芬-雌激素受体复合物独特激活和/或抑制各种基因功能。所以,尽管雷洛昔芬和雌激素利用并竞争相同的受体,但由这两种物质调节基因所产生的药理结果是不容易预见的而且是各自独特的。
通常,将所述化合物与常规的赋形剂、稀释剂或载体配制并压制成片剂,或者配制成常规口服给药或通过肌内或静脉内途径给药的酏剂或溶液剂。所述化合物可经皮给药,并且可配制成持续释放剂型等。
可按照建立的方法制备本发明方法中使用的化合物,如美国专利4133814、4418068和4380635所详细描述的,这些文献都引入本文供参考。这些方法通常都以具有6-羟基基团和2-(4-羟基苯基)基团的苯并[b]噻吩作为起始原料。将起始化合物保护、酰化并脱保护而形成式I化合物。在上文所述的美国专利中提供了制备这些化合物的实例。取代或未取代的苯基包括苯基和由一个或两个C1-C6烷基、C1-C4烷氧基、羟基、硝基、氯、氟或三(氯或氟)甲基取代的苯基。
本发明使用的化合物与各种各样的有机和无机酸和碱形成可药用的酸和碱加成的盐,包括常用于药物化学的生理可接受的盐。这些盐也是本发明的一部分。用于形成这些盐的典型的无机酸包括盐酸、氢溴酸、氢碘酸、硝酸、硫酸、磷酸和连二磷酸等。也可使用由有机酸衍生的盐,如脂族单和二羧酸、苯基取代的链烷酸、羟基链烷酸和羟基链烷二酸、芳香酸、脂族和芳族磺酸。因此可药用盐包括乙酸盐、苯基乙酸盐、三氟乙酸盐、丙烯酸盐、抗坏血酸盐、苯甲酸盐、氯代苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、甲基苯甲酸盐、邻乙酰氧基苯甲酸盐、萘-2-苯甲酸盐、溴化物、异丁酸盐、苯基丁酸盐、β-羟基丁酸盐、丁炔-1,4-二酸盐、己炔-1,4-二酸盐、癸酸盐、辛酸盐、氯化物、肉桂酸盐、柠檬酸盐、甲酸盐、富马酸盐、乙醇酸盐、庚酸盐、马尿酸盐、乳酸盐、苹果酸盐、马来酸盐、羟基马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、烟酸盐、异烟酸盐、硝酸盐、草酸盐、邻苯二甲酸盐、苯对二甲酸盐(teraphthalate)、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、丙炔酸盐、丙酸盐、苯基丙酸盐、水杨酸盐、癸二酸盐、琥珀酸盐、辛二酸盐、硫酸盐、硫酸氢盐、焦硫酸盐、亚硫酸盐、亚硫酸氢盐、磺酸盐、苯磺酸盐、对溴苯磺酸盐、氯苯磺酸盐、乙磺酸盐、2-羟基乙磺酸盐、甲磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐、对甲苯磺酸盐、二甲苯磺酸盐、酒石酸盐等。优选的盐是盐酸盐。
可药用酸加成的盐典型地是通过式I化合物与等摩尔或过量的酸反应来形成。通常将反应物在互溶剂如乙醚或苯中合并。该盐通常在1小时到10天内从溶液中沉淀出来并可通过过滤分离或可通过常规方式除去溶剂。
常用于形成盐的碱包括氢氧化铵和碱金属和碱土金属的氢氧化物、碳酸盐以及脂族胺和伯胺、仲胺和叔胺、脂族二胺。制备加成盐的特别有用的碱包括氢氧化铵、碳酸钾、甲基胺、二乙基胺、乙二胺和环己胺。
可药用盐与衍生它们的化合物相比通常具有增强的溶解性的特点,因此常常更易于配制成液体或乳剂。
可通过本领域已知的方法来制备药物制剂。例如,可将所述化合物与常规赋形剂、稀释剂或载体配制并形成片剂、胶囊、悬浮液、粉剂等。适用于这些制剂的赋形剂、稀释剂和载体的例子包括下列物质:填充剂和增容剂如淀粉、糖、山梨糖醇和硅的衍生物;粘合剂如羧甲基纤维素和其它纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮;润湿剂如甘油;崩解剂如碳酸钙和碳酸氢钠;延缓溶解剂如石蜡;再吸收促进剂如季铵化合物;表面活性剂如鲸蜡醇、单硬脂酸甘油酯;吸附载体如高岭土和膨润土;以及润滑剂 如滑石、硬脂酸钙和硬脂酸镁和固体聚乙二醇类。
也可将化合物配制成便于口服给药的酏剂或溶液剂或适于非胃肠道给药例如肌内、皮下或静脉途径给药的溶液。另外,该化合物非常适于配制成持续释放剂型等。可将制剂制成在合理的时间内仅释放活性成分的或优选在肠道特定部位。例如可由聚合物或蜡制备包衣、包封物和保护材料。
本发明抑制PAI-1或本文公开的其它任何用途所需的式I化合物的具体剂量将取决于疾病的严重性、给药途径和由临床医师所确定的相关因素。通常每日可接受的并且有效的剂量约为0.1-1000毫克/天,且更常用的是约50-200毫克/天。此剂量每天一次到约三次给予需要进行治疗的个体,或者按需要更频繁给予来有效地抑制PAI-1或本文所公开的任何其它用途。
通常优选以酸加成的盐的形式给予式I化合物,因为所给予的药物中通常携带有碱性基团,如哌啶子基环。通过口服途径给予本发明化合物也是有利的。为了此目的,可制备下列口服剂型。
制剂
在下列制剂中,“活性成分”意指式I化合物。
制剂1:明胶胶囊用下列成分制备硬明胶胶囊:
组分 量(毫克/胶囊)活性成分 0.1-1000淀粉,NF 0-650可流动的粉状淀粉 0-650350厘沲聚硅氧烷流体 0-15将组分混合、过45目美国筛并填充到硬明胶胶囊中。下文显示了已经制备的雷洛昔芬具体胶囊制剂的实例:制剂2:雷洛昔芬胶囊组分 量(毫克/胶囊)雷洛昔芬 1淀粉,NF 112可流动的粉状淀粉 225.3350厘沲聚硅氧烷流体 1.7制剂3:雷洛昔芬胶囊组分 量(毫克/胶囊)雷洛昔芬 5淀粉,NF 108可流动的粉状淀粉 225.3350厘沲聚硅氧烷流体 1.7制剂4:雷洛昔芬胶囊组分 量(毫克/胶囊)雷洛昔芬 10淀粉,NF 103可流动的粉状淀粉 225.3350厘沲聚硅氧烷流体 1.7制剂5:雷洛昔芬胶囊组分 量(毫克/胶囊)雷洛昔芬 50淀粉,NF 150可流动的粉状淀粉 397350厘沲聚硅氧烷流体 3.0上述具体制剂可随各种合理因素的变化而改变。使用下列组分来制备片剂:制剂6:片剂组分 量(毫克/片)活性组分 0.1-1000微晶纤维素 0-650二氧化硅,烘制的 0-650硬脂酸 0-15将组分混合并压制成片。另外,如下制得含有0.1-1000毫克活性成分的片剂:制剂7:片剂组分 量(毫克/片)活性成分 0.1-1000淀粉 45微晶纤维素 35聚乙烯吡咯烷酮(10%的水 4溶液)羧甲基纤维素钠 4.5硬脂酸镁 0.5滑石 1
将活性成分、淀粉和纤维素过45目美国筛并彻底混合。将聚乙烯吡咯烷酮溶液与所得粉末混合,然后过14目美国筛。在50-60℃温度下干燥所制得的颗粒并过18目美国筛。然后将预先过60目美国筛的羧甲基淀粉钠、硬脂酸镁和滑石加到颗粒中,混合后在压片机上压制成片。
如下制备每5毫升剂量含有0.1-1000毫克药物的悬浮液:制剂8:悬浮液组分 量(毫克/5毫升)活性成分 0.1-1000mg羧甲基纤维素钠 50mg糖浆 1.25mg苯甲酸溶液 0.10ml香料 适量色素 适量纯水到 5ml
将药物过45目美国筛并与羧甲基纤维素钠和糖浆混合形成均匀的糊剂。用一些水稀释苯甲酸溶液、香料和色素并在搅拌下加入糊剂中。然后加入足量的水以达到所需体积。内皮细胞PAI-1测定
用每孔5×104人内皮细胞(HUVEC)制备96孔组织培养板,所述细胞存在于补充有2%FBS的Clonetics’内皮细胞生长培养基(EGM)中。在37℃温度下培养过夜后,用有或没有化合物I(其中R1和R2为羟基且R2为1-吡咯烷基)和有或没有1nMIL-1-β的无血清培养基(DMEM/F-12介质,20mM-HEPES,pH7.5,50μg/ml庆大霉素,1μg/ml人铁传递蛋白和1μg/ml牛胰岛素)代替所述培养基。在37℃温度下培养过夜后,使用Imubind Plasma PAI-1 ELISA(AmericanDiagnostic Inc.#822/1S)测定培养基样品分泌的PAI-1。结果
用化合物1处理人脐静脉内皮细胞(HUVEC),同时用IL-1诱导PAI-1。在用从商业供应商(Clonetics)获得的某些批细胞进行的初期实验中,我们发现不是所有批的细胞都对17-β雌二醇有反应,因此不能用于化合物1对PAI-1分泌影响的测定实验中。如表1所示,使用雌激素-反应曲线,我们观察到化合物1明显降低0.5nM浓度的IL-1对PAI-1的诱导作用。如表2所示,使用不同批的雌激素反应细胞,化合物1以浓度依赖性方式抑制IL-1诱导的分泌作用。这些数据表明化合物1是自激活的内皮细胞的诱导PAI-1的非常强的抑制剂并且因增强溶解血纤维蛋白的能力而会产生心脏保护作用,即减少心血管疾病的发生。而且化合物1减少PAI-1的积极效果可在与浓度升高有关的疾病中作为急救药来使用。
表1 化合物1对人内皮细胞分泌PAI-1的作用处理方式 PAI-1浓度(ng/ml)平均
值+/-SE,n=4无IL-1的对照 328+/-46IL-1 735+/-11IL-1和0.5nM化合物1 521+/-52
表2 化合物1对人内皮细胞分泌PAI-1作用的浓度反应处理方式(M) PAI-1浓度(%抑制率)5×10-9M化合物1 82+/-175×10-10M化合物1 65+/-85×10-11M化合物1 48+/-115×10-12M化合物1 22+/-45×10-13M化合物1 -1+/-75×10-14M化合物1 0
Claims (3)
1、一种抑制血纤维蛋白溶酶原激活剂抑制剂1的方法,该方法包括给予需要进行抑制的人有效量的式I化合物或其可药用盐或溶剂化物
其中R1和R3独立地为氢、-CH3、-CO-(C1-C6烷基)或-CO-Ar,其中Ar是取代或未取代的苯基;
R2选自1-吡咯烷基、六亚甲基亚胺基和哌啶子基。
2、权利要求1的方法,其中所述化合物为其盐酸盐。
3、权利要求1的方法,其中所述化合物为:或其盐酸盐。
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CA2207141A1 (en) * | 1996-07-15 | 1998-01-15 | David Thompson Berg | Benzothiophene compounds, and uses and formulations thereof |
US5792798A (en) * | 1996-07-29 | 1998-08-11 | Eli Lilly And Company | Method for inhibiting plasminogen activator inhibitor 1 |
US6025373A (en) * | 1997-04-22 | 2000-02-15 | Eli Lilly And Company | Methods for reducing fibrinogen |
EP1113007A1 (en) | 1999-12-24 | 2001-07-04 | Pfizer Inc. | Tetrahydroisoquinoline compounds as estrogen agonists/antagonists |
US6586453B2 (en) * | 2000-04-03 | 2003-07-01 | 3-Dimensional Pharmaceuticals, Inc. | Substituted thiazoles and the use thereof as inhibitors of plasminogen activator inhibitor-1 |
WO2006088011A1 (ja) * | 2005-02-15 | 2006-08-24 | Tokai University Educational System | プラスミノーゲンアクチベーターインヒビター-1阻害剤 |
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TW383306B (en) * | 1992-12-22 | 2000-03-01 | Lilly Co Eli | New use of 2-phenyl-3-aroylbenzothiophenes in lowering serum cholesterol |
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JPH11513665A (ja) | 1999-11-24 |
CZ106098A3 (cs) | 1999-03-17 |
ZA968444B (en) | 1998-04-07 |
PL326294A1 (en) | 1998-09-14 |
US5731328A (en) | 1998-03-24 |
HUP9802348A2 (hu) | 1999-08-30 |
EP0854715A4 (en) | 2001-12-19 |
ATE255414T1 (de) | 2003-12-15 |
EA001003B1 (ru) | 2000-08-28 |
HUP9802348A3 (en) | 1999-11-29 |
EA199800366A1 (ru) | 1998-10-29 |
AU716655B2 (en) | 2000-03-02 |
DE69630969D1 (de) | 2004-01-15 |
EP0854715B1 (en) | 2003-12-03 |
DE69630969T2 (de) | 2004-10-21 |
ES2211981T3 (es) | 2004-07-16 |
CO4750819A1 (es) | 1999-03-31 |
EP0854715A1 (en) | 1998-07-29 |
NO981578D0 (no) | 1998-04-07 |
NO981578L (no) | 1998-04-07 |
AU7259696A (en) | 1997-04-30 |
KR19990064099A (ko) | 1999-07-26 |
CA2234404A1 (en) | 1997-04-17 |
WO1997013511A1 (en) | 1997-04-17 |
AR003812A1 (es) | 1998-09-09 |
NZ319948A (en) | 2000-06-23 |
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