CN1173821A - 抑制细胞-细胞粘连的方法 - Google Patents
抑制细胞-细胞粘连的方法 Download PDFInfo
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- CN1173821A CN1173821A CN96191839A CN96191839A CN1173821A CN 1173821 A CN1173821 A CN 1173821A CN 96191839 A CN96191839 A CN 96191839A CN 96191839 A CN96191839 A CN 96191839A CN 1173821 A CN1173821 A CN 1173821A
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Abstract
一种抑制细胞-细胞粘连的方法,其包括对需要治疗的人施用有效量的式Ⅰ化合物或其药用盐和溶剂化物,其中R1和R3独立地是氢、-CH3,(a)或(b),其中Ar是任意取代的苯基;R2选自吡咯烷、六亚甲基亚氨基和哌啶子基。
Description
血管内皮构成一种主要器官,该器官作为血液凝集、炎症的调节物起作用,并在血管内和实体组织之间的液体和介质的交换中发挥作用。因此,内皮的适当的功能在于全身的体内平衡。由重要的表面分子表达发生改变而引起的内皮机能障碍,将导致凝集障碍、局部或全身性血管炎症、以及动脉粥样硬化斑的发展和破裂的增强。这些作用可进一步导致这样一些病症,比如心肌梗塞、深层静脉栓塞、传播性血管内栓塞和中风。
某些细胞表面蛋白会因血管损伤或损害而改变,并可用作内皮机能障碍的标记物。这些蛋白中的关键的一类是介导细胞-细胞粘连的受体/配体,包括粘连蛋白、选择蛋白(例如ELAM)和免疫球蛋白超家族成员,如ICAM和VCAM。在不同的刺激物的作用下,这些分子增加,并且除了作为内皮机能障碍的重要的标记物外,还在血栓形成、炎症以及血管壁粥样化过程中起关键作用。其他活性,比如表面抗凝血剂反应,也在内皮机能障碍状态下受到损害。能够阻遏内皮机能障碍的化合物,如通过测量其抑制细胞-细胞粘连的能力或前凝血剂活性的表达所确定的,能够治疗这样一些病症,比如脓毒症、损伤(包括主要组织损害或创伤)、全身性炎症反应综合症、脓毒症综合症、脓毒性休克和多发性器官机能障碍综合症(包括DIC)以及动脉粥样硬化斑破裂及其相关后遗症。因为细胞-细胞粘连是广泛的生物学重要方面的基本过程,因此特异性调节粘连蛋白的能力具有许多血管组织外临床应用的潜力,包括用作抗炎药。
R2选自吡咯烷子基(pyrrolidino)、六亚甲基亚氨基和哌啶子基。
本发明涉及这样一个发现,即一类特定的2-苯基-3-芳酰基苯并噻吩(苯并噻吩),也就是式I化合物,可以用于抑制细胞-细胞粘连,特别是血管细胞-细胞粘连。而且,这些化合物可用于抑制血管内皮机能障碍。
本发明所提供的应用方法是通过向需要治疗的人施用一定剂量的式I化合物或其药用盐或溶剂化物来完成的,所述剂量可以有效地抑制细胞-细胞粘连及其影响。术语“抑制”包括其通常被接受的含义,包括阻止、预防、遏制、减缓、终止或逆转。如此,如果需要的话,本方法包括药物治疗和/或预防性施用。
雷洛昔芬是核调节分子,它是本发明式I化合物的盐酸盐,其中R1和R2是氢,R2是1-哌啶基。已表明雷洛昔芬结合***受体,它起先被认为是一种具有抗***功能和药性的分子,能够阻遏***激活子宫组织和***依赖性乳癌的能力。实际上,雷洛昔芬确实阻遏***在一些细胞中的作用;但是,在其他细胞类型中,雷洛昔芬与***激活同样的基因,并表现出同样的药性,例如使骨质疏松,血脂过高。结果,雷洛昔芬被认为是具有激动剂-拮抗剂混合特性的抗***物质。雷洛昔芬表现出的独特的作用方式及其与***的差异目前被认为是来自于雷洛昔芬-***受体复合物对不同基因功能的独特的激活和/或抑制作用,该作用与***-***受体复合物对基因的激活和/或抑制作用不同。因此,虽然雷洛昔芬和***利用和竞争同一受体,但二者由基因调节所产生的药理作用是难以预测的,而且是各自不同的。
一般说来,将本发明化合物与普通的赋形剂、稀释剂或载体一起配制并压成片剂,或制成适于口服的酏剂或溶液,或通过肌肉或静脉内途径施用。该化合物可以透皮施用,也可以制成持续释放的剂型等。
本发明方法所用的化合物可用已经建立的方法来制备,如美国专利4,133,814、4,418,068和4,380,635所述,在此引入作为参考。一般说来,制备过程开始于一个带有6-羟基和2-(4-羟苯基)基团的苯并[b]噻吩。起始化合物被保护、酰基化、去保护,形成式I化合物。这样的化合物的制备实例见上述美国专利。术语“任意取代的苯基”包括苯基和被C1-C6烷基、C1-C4烷氧基、羟基、硝基、氯、氟或三(氯或氟)甲基取代一次或两次的苯基。
本发明方法所用的化合物可以与多种有机和无机的酸和碱形成药用酸和碱加成盐,包括在药物化学中经常应用的生理可接受盐。这样的盐也是本发明的一部分。用于形成这样的盐的典型无机酸包括盐酸、氢溴酸、氢碘酸、硝酸、硫酸、磷酸、连二磷酸等。也可以使用从有机酸,比如脂肪族一或二羧酸、苯基取代的链烷酸、羟基链烷酸以及羟基链烷二酸、芳香族酸、脂肪酸和芳香族磺酸获得的盐。这样的药用盐包括乙酸盐、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、延胡索酸盐、羟基乙酸盐、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、杏仁酸盐、甲磺酸盐、尼克酸盐、异尼克酸盐、硝酸盐、草酸盐、邻苯二甲酸盐、对苯二甲酸盐、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、氯代苯磺酸盐、乙烷磺酸盐、2-羟基乙烷磺酸盐、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。
药用酸加成盐典型地是通过将式I化合物与等摩尔或过量的酸反应形成的。反应物一般于互溶剂如***或苯中进行反应。盐通常在大约1小时至10天内从溶液中析出,并可通过过滤分离,或用常规方法去掉溶剂。
通常用于形成盐的碱包括氢氧化铵、碱金属及碱土金属氢氧化物、碳酸盐,以及脂肪族的伯、仲、叔胺、脂肪族二胺。在制备加成盐中特别有用的碱包括氢氧化铵、碳酸钾、甲胺、乙二胺、二乙胺和环己胺。
与形成它们的化合物相比,药用盐一般具有更强的溶解特性,因此更适于制成液体或乳剂。
药物制剂可以用本领域已知的方法制备。例如,这些化合物可以与常用的赋形剂、稀释剂或载体制成片剂、胶囊剂、悬液剂、粉剂等。适于这些制剂的赋形剂、稀释剂和载体的例子包括:填充剂和增量剂,如淀粉、糖、甘露醇和硅衍生物;结合剂,如羧甲基纤维素和其他纤维素衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮;保湿剂,如甘油;崩散剂,如碳酸钙和碳酸氢钠;阻滞溶解剂,如石蜡;吸收促进剂,如季铵化合物;表面活性剂,如十六烷醇、单硬脂酸甘油酯;吸附载体,如陶土和皂土;润滑剂,如滑石、硬脂酸钙和硬脂酸镁,固体聚乙二醇。
这些化合物也可制成酏剂或溶液剂,使之适于口服,或制成适于胃肠外(如肌肉内、皮下或静脉内)给药的溶液。此外,这些化合物也适于制成持续释放的剂型等。这些制剂可以这祥制成,使得它们可能在一段时间内,仅仅或优选地在肠道的特定部位释放出活性成分。包衣、包膜和保护性基质可以由例如聚合物质和蜡制成。
根据本发明,抑制细胞-细胞粘连或其作用,或本文所公开的任何其他应用所需的式I化合物的具体剂量,依赖于病惰的严重程度、施用途径、以及由主治医师决定的相关因素。一般说来,可接受的有效的日剂量为大约0.1至1000毫克/天,更典型的是大约50至200毫克/天。用这样的剂量对患者施用,每天要进行一次至大约三次,如果需要,可以施用更多次,以有效地抑制细胞-细胞粘连或其作用,或本文所公开的任何其他应用。
如施用带有碱性基团(如哌啶子基环)的药物时惯用其酸加成盐一样,通常优选的是以酸加成盐的形式施用式I化合物。通过口服途径施用该化合物也是有利的。为此,下述口服剂型是适用的。
制剂
在下述制剂中,“活性成分”指的是式I化合物。
制剂1:明胶胶囊
硬明胶胶囊以如下方式制备:
成分 量(毫克/胶囊)
活性成分 0.1-1000
淀粉,NF 0-650
淀粉可流动粉末 0-650
350厘斯聚硅氧烷流体 0-15
各成分混合后,通过45号筛孔的U.S.筛,填入硬明胶胶囊中。
已制成的具体的雷洛昔芬胶囊制剂包括以下这些:制剂2:雷洛昔芬胶囊成分 量(毫克/胶囊)雷洛昔芬 1淀粉,NF 112淀粉可流动粉末 225.3350厘斯聚硅氧烷流体 1.7
制剂3:雷洛昔芬胶囊成分 量(毫克/胶囊)雷洛昔芬 1淀粉,NF 108淀粉可流动粉末 225.3350厘斯聚硅氧烷流体 1.7
制剂4:雷洛昔芬胶囊成分 量(毫克/胶囊)雷洛昔芬 1淀粉,NF 103淀粉可流动粉末 225.3350厘斯聚硅氧烷流体 1.7
制剂5:雷洛昔芬胶囊成分 量(毫克/胶囊)雷洛昔芬 50淀粉,NF 150淀粉可流动粉末 397350厘斯聚硅氧烷流体 3.0上述具体的制剂可依照所提供的合理的变化而改变。用如下成分可以制备片剂:
制剂6:片剂
成分 量(毫克/片)
活性成分 0.1-1000
微晶纤维素 0-650
煅制二氧化硅 0-650
硬脂酸 0-15
将各成分混合,压成片剂。
可选地,每片含有0.1-1000毫克活性成分的片剂可如下制成:
制剂7:片剂
成分 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%水溶 4液)
羧甲基纤维素钠 4.5
硬脂酸镁 0.5
滑石 1
将活性成分、淀粉和纤维素通过45号筛孔的U.S.筛并充分混合。所得的粉末与聚乙烯吡咯烷酮溶液混合,然后通过14号筛孔的U.S.筛。所得颗粒在50°-60℃下干燥,通过18号筛孔的U.S.筛。将羧甲基淀粉钠、硬脂酸镁和滑石预先通过60号的U.S.筛,然后加入到颗粒中,混合后,用压片机压成片剂。
每5毫升剂量含有0.1-1000毫克药物的悬液剂可如下制备:
制剂8:悬液剂
成分 量(毫克/5毫升)
活性成分 0.1-1000毫克
羧甲基纤维素钠 50毫克
糖浆 1.25毫升
苯甲酸溶液 0.10毫升
调味剂 q.v.
着色剂 q.v.
加纯水至 5毫升
将药物通过45号筛孔的U.S.筛,与羧甲基纤维素钠和糖浆混合形成光滑的膏体。将苯甲酸溶液、调味剂、着色剂用一些水稀释,边搅动边加到膏体中。再加入足量的水以达到所需的体积。
体外细胞粘连试验
人脐静脉内皮细胞(HUVEC)或人主动脉内皮(HAE)得自Clonetics(San Diego)并在Clonetics提供的EBM培养基中生长。将细胞置于96孔平板上,其密度使得在37℃下过夜培养后得到汇合的单层。加入受试化合物,在无血清的培养基中培养8-20小时。在总体积为75至100微升的,有受试化合物存在的结合试验之前,将单层细胞在有或没有2ng/mlIL-1或有20纳克肿瘤坏死因子(TNF)的条件下培养4至24小时。培养后,加入50微升体积的氚标记的U937细胞,每孔1至3×10(6)细胞。U937细胞是通过加入3H-胸苷至终浓度每毫升1毫居里,然后培养18至20小时而被氚标记的。在使用之前用PBS洗细胞以除去过量的标记物。标记的U937细胞与内皮细胞一起培养20分钟之后,吸出每孔中的液体,用含钙的PBS将孔洗四次。通过加入0.25%SDS/0.1N NaOH搅动5分钟而将单层细胞和粘附的U937细胞溶解。通过对溶解的细胞进行闪烁计数而确定结合的水平。
抗凝血剂活性试验
将96孔平板中的用或未用IL-1(2ng/ml)处理的人内皮细胞的汇合培养物用HBSS洗一次,以除去血清蛋白,用含有400nM重组人蛋白C和10nM人凝血酶的无血清培养基(DMEM/F-12培养基,20mM-HEPES,pH7.5,50mg/ml庆大霉素,1mg/ml人转铁蛋白和1mg/ml人牛胰岛素)培养。将细胞在37℃下培养,在不同的时间移出培养基,加入等体积的下述溶液:20mM Tris-Hcl,pH7.5,150mM NaCl,1mg/ml BSA和10U/ml水蛭素。将样本在含水蛭素的缓冲液中培养5分钟以抑制凝血酶活性。通过加入生色底物(S-2366)至终浓度0.75mM,用ThermoMax动态微滴定平板计数器(Molecular Devices)在405nm处测量每分钟吸收单位的改变来测定所产生的活化蛋白C的量。在所有的实验中,蛋白C/凝血酶溶液样本是在没有细胞的孔中培养的,以便测定蛋白C凝血酶催化活性的基础水平。生成的活化蛋白C的量以每分钟每微克细胞蛋白的吸收值(mOD)表示。
结果
用化合物A处理人脐静脉血内皮细胞(HUVEC),同时由TNF诱导粘连分子的表达,其中R1和R3是氢,R3是吡咯烷基。如表I所示,在本试验中,100nM化合物A的存在将导致细胞-细胞粘连的水平降低大约40%。当细胞在用TNF诱导之前仅用10nM化合物A预处理大约20分钟时,观察到粘连大约减少65%(表2)。我们也用IL1同时处理了HUVEC和人主动脉表皮细胞(HAEC),IL1是在10nM化合物A存在下诱导粘连分子表达的另一种炎症介体。如表3所示,化合物A有效地抑制了两种细胞系中IL1诱导的粘连。因此,化合物可以在静脉和动脉细胞中阻遏由两种独立的方式介导的粘连分子表达的诱导。
作为该化合物调节内皮基本特性的能力的进一步的证据,我们测量了内皮细胞激活人蛋白C的能力,这个能力是在内皮机能障碍状态下进行向下调节的天然调节功能。如表4所示,细胞的IL1处理显著地降低了内皮支持蛋白C生成的能力。但是,在用化合物A处理细胞之后,IL1对该功能的抑制基本上消失。上面的数据表明化合物A保护细胞免于激活炎症和前凝血活性。
表1.化合物A对U937细胞粘连TNF激活的人脐静脉内皮细胞(HUVEC)的影响
条件 结合活性百分比a
未处理的对照 0±7.5
用TNF处理的 100±95
TNF加化合物A(100nM) 62±17
a结合水平以用TNF诱导前后与内皮结合的U937细胞数的百分比表示。
表2.用化合物A预处理对U937细胞粘连TNF激活的人脐静脉内皮细胞(HUVEC)的影响
条件 结合活性百分比a
未处理的对照 0±20
用TNF处理的 100±16
TNF加化合物A(100nM) 34±8
a结合水平以用TNF诱导前后与内皮结合的U937细胞数的百分比表示。
表3.用化合物A预处理对U937细胞粘连IL1激活的人主动脉内皮细胞(HAEC)和人脐静脉内皮细胞(HUVEC)的影响
条件 与下列细胞的结合活性百分比a
HUVEC HAEC
IL1处理的 100±14 100±8
IL1加化合物A(10 18±13 54±7nM)
a结合水平以用IL1诱导前后与内皮结合的U937细胞数的百分比表示。
表4.化合物A对人蛋白C激活用IL-1处理的内皮细胞的影响,所述激活是凝血酶催化的
条件 结合活性百分比a
未处理的对照 8.8±1.4
用IL1处理的 3.7±0.4
IL1加化合物A 7.6±.6
Claims (6)
2.权利要求1的方法,其中化合物是其盐酸盐。
5.权利要求4的方法,其中化合物是其盐酸盐。
6.权利要求4的方法,其中化合物是下式化合物或其盐酸盐:
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US08/385,934 US5484808A (en) | 1995-02-09 | 1995-02-09 | Methods of inhibiting cell-cell adhesion |
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Families Citing this family (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6515009B1 (en) | 1991-09-27 | 2003-02-04 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
US5811447A (en) * | 1993-01-28 | 1998-09-22 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
US6251920B1 (en) | 1993-05-13 | 2001-06-26 | Neorx Corporation | Prevention and treatment of cardiovascular pathologies |
US5770609A (en) | 1993-01-28 | 1998-06-23 | Neorx Corporation | Prevention and treatment of cardiovascular pathologies |
US6491938B2 (en) | 1993-05-13 | 2002-12-10 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
US6197789B1 (en) | 1995-06-07 | 2001-03-06 | Neorx Corporation | Prevention and treatment of cardiovascular pathologies with tamoxifen analogues |
US20030083733A1 (en) * | 1997-10-10 | 2003-05-01 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
US6099562A (en) * | 1996-06-13 | 2000-08-08 | Schneider (Usa) Inc. | Drug coating with topcoat |
US5837313A (en) * | 1995-04-19 | 1998-11-17 | Schneider (Usa) Inc | Drug release stent coating process |
US20020091433A1 (en) * | 1995-04-19 | 2002-07-11 | Ni Ding | Drug release coated stent |
US5747509A (en) * | 1996-06-03 | 1998-05-05 | Schering Aktiengesellschaft | Method for lowering plasma levels of lipoprotein(a) |
US5773432A (en) * | 1996-10-30 | 1998-06-30 | Schering Aktiengesellschaft | Method for lowering plasma levels of lipoprotein(a) |
WO1998046588A2 (en) * | 1997-04-11 | 1998-10-22 | Neorx Corporation | Compounds and therapies for the prevention of vascular and non-vascular pathologies |
US6008232A (en) * | 1997-08-20 | 1999-12-28 | Eli Lilly And Company | Methods for preventing headaches |
AU3053199A (en) | 1998-04-01 | 1999-10-25 | Ono Pharmaceutical Co. Ltd. | Fused thiophene derivatives and drugs containing the same as the active ingredient |
ATE301129T1 (de) | 1999-05-04 | 2005-08-15 | Strakan Int Ltd | Androgen glykoside und die androgenische aktivität davon |
US6359015B1 (en) | 2000-02-28 | 2002-03-19 | The United States Of America As Represented By The Department Of Veterans Affairs | Method for antagonizing inhibition effects of alcohol on cell adhesion |
US7666588B2 (en) | 2001-03-02 | 2010-02-23 | Ibis Biosciences, Inc. | Methods for rapid forensic analysis of mitochondrial DNA and characterization of mitochondrial DNA heteroplasmy |
US20030027135A1 (en) * | 2001-03-02 | 2003-02-06 | Ecker David J. | Method for rapid detection and identification of bioagents |
US20040121309A1 (en) * | 2002-12-06 | 2004-06-24 | Ecker David J. | Methods for rapid detection and identification of bioagents in blood, bodily fluids, and bodily tissues |
US6613083B2 (en) * | 2001-05-02 | 2003-09-02 | Eckhard Alt | Stent device and method |
JP3887588B2 (ja) * | 2002-08-30 | 2007-02-28 | 株式会社リガク | X線回折による応力測定法 |
US6977272B2 (en) * | 2002-10-16 | 2005-12-20 | President And Fellows Of Harvard College | Method for antagonizing inhibition effects of alcohol on cell adhesion |
EP1578399A4 (en) * | 2002-12-06 | 2007-11-28 | Isis Pharmaceuticals Inc | METHODS FOR RAPID IDENTIFICATION OF PATHOGENS IN HUMANS AND BEETS |
US7964343B2 (en) * | 2003-05-13 | 2011-06-21 | Ibis Biosciences, Inc. | Method for rapid purification of nucleic acids for subsequent analysis by mass spectrometry by solution capture |
US8097416B2 (en) | 2003-09-11 | 2012-01-17 | Ibis Biosciences, Inc. | Methods for identification of sepsis-causing bacteria |
US8546082B2 (en) | 2003-09-11 | 2013-10-01 | Ibis Biosciences, Inc. | Methods for identification of sepsis-causing bacteria |
US20120122101A1 (en) * | 2003-09-11 | 2012-05-17 | Rangarajan Sampath | Compositions for use in identification of bacteria |
US8163895B2 (en) | 2003-12-05 | 2012-04-24 | Ibis Biosciences, Inc. | Compositions for use in identification of orthopoxviruses |
US20050266411A1 (en) * | 2004-05-25 | 2005-12-01 | Hofstadler Steven A | Methods for rapid forensic analysis of mitochondrial DNA |
AU2006272776B2 (en) * | 2005-07-21 | 2012-01-19 | Ibis Biosciences, Inc. | Methods for rapid identification and quantitation of nucleic acid variants |
CN107412248A (zh) | 2016-05-24 | 2017-12-01 | 中国医学科学院药物研究所 | 三乙酰基-3-羟基苯基腺苷在治疗血管炎症或改善血管内皮功能中的应用 |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4133814A (en) * | 1975-10-28 | 1979-01-09 | Eli Lilly And Company | 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents |
US4418068A (en) * | 1981-04-03 | 1983-11-29 | Eli Lilly And Company | Antiestrogenic and antiandrugenic benzothiophenes |
US4380635A (en) * | 1981-04-03 | 1983-04-19 | Eli Lilly And Company | Synthesis of acylated benzothiophenes |
US5395842A (en) * | 1988-10-31 | 1995-03-07 | Endorecherche Inc. | Anti-estrogenic compounds and compositions |
JP3157882B2 (ja) * | 1991-11-15 | 2001-04-16 | 帝国臓器製薬株式会社 | 新規なベンゾチオフエン誘導体 |
US5356926A (en) * | 1992-02-24 | 1994-10-18 | Warner-Lambert Company | 3-alkyloxy-, aryloxy-, or arylalkyloxy-benzo [β]thiophene-2-carboxamides as inhibitors of cell adhesion |
TW383306B (en) * | 1992-12-22 | 2000-03-01 | Lilly Co Eli | New use of 2-phenyl-3-aroylbenzothiophenes in lowering serum cholesterol |
UA32427C2 (uk) * | 1993-10-15 | 2000-12-15 | Елі Ліллі Енд Компані | Застосування бензотіофенів або їх фармацевтично прийнятних солей або сольватів для інгібування ангіогенезу і/або ангіогенних захворювань |
US5457113A (en) * | 1993-10-15 | 1995-10-10 | Eli Lilly And Company | Methods for inhibiting vascular smooth muscle cell proliferation and restinosis |
US5441965A (en) * | 1993-12-21 | 1995-08-15 | Eli Lilly And Company | Methods of inhibiting thrombin |
US5574047A (en) * | 1993-12-21 | 1996-11-12 | Eli Lilly And Company | Methods of inhibiting imperfect tissue repair |
US5476862A (en) * | 1993-12-21 | 1995-12-19 | Eli Lilly And Company | Methods of increasing thrombomodulin expression |
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JPH10513475A (ja) | 1998-12-22 |
IL117079A0 (en) | 1996-06-18 |
MY132251A (en) | 2007-09-28 |
AU693021B2 (en) | 1998-06-18 |
EP0726071A3 (zh) | 1996-09-11 |
UA43391C2 (uk) | 2001-12-17 |
US5484808A (en) | 1996-01-16 |
RU2179021C2 (ru) | 2002-02-10 |
US5496851A (en) | 1996-03-05 |
CN1072931C (zh) | 2001-10-17 |
CZ248297A3 (cs) | 1998-06-17 |
NO973635D0 (no) | 1997-08-06 |
EP0726071A2 (en) | 1996-08-14 |
CA2212339A1 (en) | 1996-08-15 |
NO973635L (no) | 1997-09-29 |
IL117079A (en) | 1999-12-31 |
WO1996024384A1 (en) | 1996-08-15 |
HUP9801323A3 (en) | 1999-09-28 |
NZ305072A (en) | 2000-07-28 |
CZ286448B6 (en) | 2000-04-12 |
ZA961076B (en) | 1997-08-11 |
AU5299696A (en) | 1996-08-27 |
KR19980702079A (ko) | 1998-07-15 |
HUP9801323A2 (hu) | 1999-05-28 |
MX9706072A (es) | 1997-10-31 |
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