CN1078070C - 苯并噻吩衍生物在制备抑制凝血酶药物中的用途 - Google Patents
苯并噻吩衍生物在制备抑制凝血酶药物中的用途 Download PDFInfo
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Abstract
Description
导致凝血酶形成的复杂的蛋白水解级联反应触发血凝过程、血栓形成。凝血酶通过蛋白水解作用从溶于血浆中的纤维蛋白原Aα和Bβ链上除去活化肽,引起不溶性纤维蛋白形成。
目前通过施用肝素类和香豆素类获取抗凝作用。非经胃肠道给药的药理学控制凝血和血栓形成是基于通过使用肝素类抑制凝血酶。肝素类通过促进内源性抗凝血酶III(主要的生理上的凝血酶抑制剂)的抑制作用间接地作用于凝血酶。由于抗凝血酶III水平在血浆中变化并且由于表面结合的凝血酶似乎对这种间接机制有抗性,因此肝素类可能是无效的治疗。因为据信凝血试验关系到效果和安全,因此应当用凝血试验(特别是活化部分凝血致活酶时间(APTT)试验)监测肝素水平。香豆素类通过在凝血酶原和其它此类蛋白的合成中阻滞转录后γ-羧化作用而防碍凝血酶的生成。由于其作用机制,香豆素类的效果仅能在给药后6-24小时才慢慢地表现出来。此外,它们不是有选择的抗凝血剂。香豆素类也需要用凝血试验(特别是凝血酶原时间试验)监测。
本发明涉及发现如下定义的本发明化合物,它们是具有口服生物利用度的凝血酶抑制剂。
本发明提供了抑制凝血酶的方法,该方法包括给需要这种治疗的人施用有效剂量的式I化合物及其药学上适用的盐和溶剂化物,其中R1和R3各自独立地为氢、-CH3、
(C1-C6烷基)或,这里Ar为任意取代的苯基,
R2系选自吡咯烷子基(pyrrolidino)、六亚甲基亚氨基和哌啶子基。
本发明涉及发现式I的一组经选择的2-苯基-3-芳酰基苯并噻吩类(苯并噻吩类)化合物可用于抑制凝血酶。本发明还包括应用所述化合物作为抗凝剂用于预防和治疗血栓栓塞性疾病,例如静脉血栓形成,肺栓塞,动脉血栓形成,特别是心肌缺血、心肌梗死和脑血栓形成,例如血管成形术和冠状旁路手术后的全身高凝状态和局部高凝状态,以及当涉及炎症过程的全身组织损伤。本发明提供的使用方法是通过给需要这种治疗的人或哺乳动物施用一定剂量的对于抑制凝血酶或其有关疾病和症状有效的式I化合物或其药学上适用的盐或溶剂化物来实现。术语抑制指包括其通常已被接受的意义,它包括对人或哺乳动物预防给药以及控制和/或治疗有关疾病或症状中的过量凝血酶。因此,当合适时,本发明方法包括预防和/或治疗。
雷洛昔芬是本发明的一个化合物,它是其中R1和R3为氢并且R2为1-哌啶基的式I化合物的盐酸盐。
一般来讲,本发明化合物可以与常用的赋形剂、稀释剂或载体进行配方并且可压制成片剂,或者也可以配制成方便口服给药的酏剂或溶液剂,或通过肌内或静脉途径给药。本发明化合物还可以经皮给药,并且可以配制缓释剂型等。
可以按照已有的方法制备本发明方法中使用的化合物,如按美国专利4,133,814、4,418,068和4,380,635所述方法进行制备,所有这些文献均收编在本发明中作为参考。一般来讲,该方法从带有6-羟基和2-(4-羟基苯基)基团的苯并[b]噻吩开始。起始化合物被保护,酰化,并进行脱保护,生成式I化合物。以上美国专利叙述了制备上述化合物的实施例。任意取代的苯基包括苯基和用C1~C6烷基、C1~C4烷氧基、羟基、硝基、氯、氟或三(氯或氟)甲基一次或二次取代的苯基。
用于本发明方法的化合物可以与多种有机和无机酸、碱生成药学上适用的酸和碱加成盐,药学上适用的酸和碱加成盐包括通常用于药物化学上的生理上适用的盐。所述盐也包括在本发明的范围内。用于生成上述盐的典型的无机酸包括盐酸、氢溴酸、氢碘酸、硝酸、硫酸、磷酸、连二磷酸等。可以应用由有机酸生成的盐,有机酸例如有脂肪族一或二羧酸、苯基取代的链烷酸、羟基链烷酸和羟基链烷二酸,以及芳香族酸、脂肪族和芳香族磺酸。因此所述药学上适用的盐包括乙酸盐、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、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、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、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。
药学上适用的酸加成盐一般可通过式I化合物与等摩尔或过量的酸反应制得。反应物通常于互溶剂如乙醚或苯中进行反应。盐一般在约1小时~10天内从溶液中析出,并且可以经过滤分离,或者按常规方法除去溶剂。
通常用于生成盐的碱包括氢氧化铵、碱金属和碱土金属氢氧化物、碳酸盐,以及脂肪族的伯、仲、叔胺和脂肪族二胺。用于制备加成盐的碱尤其包括氢氧化铵、碳酸钾、甲胺、二乙胺、乙二胺和环己胺。
与化合物(由该化合物衍生得到盐)相比较,药学上适用的盐一般具有提高溶解度的性质,因此它们通常更适用于配制液剂或乳剂。
药物制剂可以按本技术领域已知的方法制备。例如,将化合物与常用的赋形剂、稀释剂或载体一起配制,并可配制成片剂、胶囊剂、混悬液剂、粉剂等。适用于上述制剂的赋形剂、稀释剂和载体包括:填充剂和增量剂如淀粉、糖、甘露糖醇以及硅衍生物;粘合剂如羧甲基纤维素和其他的纤维素衍生物,藻酸盐、明胶和聚乙烯吡咯烷酮;湿润剂如甘油;崩解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以及固体聚乙二醇。
本发明化合物也可以配制成方便口服的酏剂或溶液剂,或者配制成适于非经胃肠道(如经肌内、皮下或静脉途径)给药的溶液剂。另外,本发明化合物还非常适用于配制成缓释剂型等。缓释制剂可以这样构成,以使它们仅仅或最好在肠道的特定部位并可能在一定时间内释放活性成分。包衣材料、包袋材料和保护材料可以由例如聚合物质或蜡制得。
为抑制合适疾病和症状中凝血酶需应用的本发明式I化合物的具体剂量将取决于由主治医师决定的病症的严重性和性质、给药途径以及有关的因素。一般来讲,每天接受的有效剂量为约0.1~1000mg,更一般的是约50~200mg。该剂量每天将对需治疗的患者一次或分大约三次、或按需要更经常施用,以有效地抑制凝血酶或其有关的疾病或症状。
正如施用带有碱性基团(如哌啶子基环)的药物时习惯使用其酸加成盐一样,优选以酸加成盐的形式施用式I化合物。通过口服途径施用这种化合物也是有益的。为此,可利用下列口服剂型。
制剂
在下述制剂中“活性成分”是指式I化合物。
制剂1:明胶胶囊剂
硬明胶胶囊剂按下面方法制备:
成分 量(mg/胶囊)活性成分 0.1-1000淀粉,NF 0-650可流动的淀粉粉末 0-650聚硅氧烷流体(350厘沲) 0-15将上述成分混合,通过美国45号筛并将其装入硬明胶胶囊。已经制备的雷洛昔芬的具体胶囊剂实施例包括下述制剂:制剂2:雷洛昔芬胶囊剂成分 量(mg/胶囊)雷洛昔芬 1淀粉,NF 112可流动的淀粉粉末 225.3聚硅氧烷流体(350厘沲) 1.7制剂3:雷洛昔芬胶囊剂成分 量(mg/胶囊)雷洛昔芬 5淀粉,NF 108可流动的淀粉粉末 225.3聚硅氧烷流体(350厘沲) 1.7制剂4:雷洛昔芬胶囊剂成分 量(mg/胶囊)雷洛昔芬 10淀粉,NF 103可流动的淀粉粉末 225.3聚硅氧烷流体(350厘沲) 1.7制剂5:雷洛昔芬胶囊剂成分 量(mg/胶囊)雷洛昔芬 50淀粉,NF 150可流动的淀粉粉末 397聚硅氧烷流体(350厘沲) 3.0按照合理的改变,还可以将上述具体的制剂进行变化。用下述成分制备片剂:制剂6:片剂成分 量(mg/片)活性成分 0.1-1000微晶纤维素 0-650煅制的二氧化硅 0-650硬脂酸 0-15将上述成分混合并压制成片剂。另外,每片含0.1~1000mg活性成分的片剂可以按下法制备:制剂7:片剂成分 量(mg/片)活性成分 0.1-1000淀粉 45微晶纤维素 35聚乙烯吡咯烷酮(为10%的水溶液) 4羧甲基纤维素钠 4.5硬脂酸镁 0.5滑石 1
将活性成分、淀粉和纤维素通过美国45号筛,并充分地混合。使聚乙烯吡咯烷酮溶液与得到的粉末混合,然后再通过美国14号筛。得到的颗粒于50~60℃干燥并通过美国18号筛。将预先通过美国60号筛的羧甲基纤维素钠、硬脂酸镁和滑石加到颗粒中,在混合以后将其在压片机上压制成片剂。
每5ml剂量含0.1-1000mg药物的各个混悬液剂可按下示制备:制剂8:混悬液剂成分 量(mg/5ml)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调味剂 适量着色剂 适量纯水 加至 5ml
将药物通过美国45号筛并与羧甲基纤维素钠和糖浆混合,得到调匀的糊状物。用一些水将苯甲酸溶液、调味剂、着色剂稀释,然后于搅拌下加入。再加入足量的水至所需体积。
本发明的一个方面是提供抑制哺乳动物中凝血酶的方法,该方法包括给需要治疗的哺乳动物施用有效(抑制凝血酶有效)剂量的式I化合物。
本发明方法设想的凝血酶抑制作用包括在需要时进行治疗和/或预防治疗。
进一步的具体实施方案中,本发明涉及治疗其中需要抑制凝血酶的人或动物。预期本发明化合物可用于动物(包括人)中治疗或预防血栓形成和血液及组织中的高凝状态。其中本发明化合物具有的有效用途是治疗或预防血栓形成和血液及组织中的高凝状态。可用本发明化合物治疗和/或预防的疾病包括静脉血栓形成和肺栓塞,动脉血栓形成,例如在心肌缺血、心肌梗死、不稳定心绞痛、基于血栓形成所致中风中的动脉血栓形成,以及外周动脉血栓形成。此外,本发明化合物在治疗或预防动脉粥样硬化例如冠状动脉疾病、脑动脉疾病和外周动脉疾病中具有预期效用。而且,预期本发明化合物可与溶栓药物一起用于心肌梗死。另外,本发明化合物在预防血栓溶解、经皮经腔冠状动脉成形术(PCTA)和冠状旁路手术后的再闭塞具有预期效用。而且,本发明化合物在预防显微外科后的血栓症复发中具有预期效用。此外,预期本发明化合物可用于有关人造器官和心脏瓣膜的抗凝治疗。而且,本发明化合物在血液透析和弥散性血管内凝血的抗凝治疗中具有预期效用。进一步的预期效用是用于冲洗在患者体内使用的导管和机械装置,以及作为抗凝剂用于体外保存血液、血浆及其它血液产品。而且,在其中血液凝固可能是第二种病理学之基本作用过程或来源的其它疾病例如癌症(包括转移)、炎性疾病(包括关节炎)和糖尿病中,本发明化合物还具有预期效用。本发明抗凝化合物可口服给药,或非经胃肠道给药,例如通过静脉输注(iv)、肌内注射(im)或经皮(sc)给药。
本发明方法还可与凝块溶解素例如组织纤维蛋白溶酶原激活剂(tPA)、改性tPA、链激酶或尿激酶组合实施。当凝块形成已经发生并且部分或完全阻塞了动脉或静脉的情况下,通常使用凝块溶解素。本发明化合物可在使用凝块溶解素之前施用或与之一起施用,或者在施用凝块溶解素之后单独施用或与凝块溶解素一起施用,进一步优选与阿斯匹林一起施用,以预防凝块形成的复发。
本发明方法还可与抑制血小板聚集的血小板糖蛋白IIb-IIIa受体拮抗剂组合实施。本发明化合物在使用该IIb-IIIa受体拮抗剂之前施用或与之一起施用,或者在使用IIb-IIIa受体拮抗剂之后施用,以防止凝块形成的发生或复发。
本发明方法还可与阿斯匹林组合实施。本发明化合物可在使用阿斯匹林之前施用或与之一起施用,或者在使用阿斯匹林之后施用,以防止凝块形成的发生或复发。如上文所述,本发明化合物优选与凝块溶解素和阿斯匹林组合施用。
在下列一个或多个实验中,评价了本发明化合物作为有效的凝血酶抑制剂的性能。
本发明提供的化合物(式I)具有抑制哺乳动物中凝血酶的作用。在凝血酶水解色原性底物N-苯甲酰-D-苯丙氨酰-L-缬氨酰-L-精氨酰-对硝基苯胺(N-苯甲酰-D-Phe-L-Val-L-Arg-对硝基苯胺)的实验中,通过测定体外凝血酶的酰胺酶活性的抑制试验,可阐明抑制凝血酶的作用。
按下述方法进行实验:将50μl缓冲液(0.03M Tris、0.15MNaCl,pH7.4)与25μl人凝血酶溶液(纯化的人凝血酶,EnzymeResearch Laboratories,South Bend,Indiana,8NIH单位/ml)和25μl受试化合物在溶剂(50%水和50%甲醇(viv))中混合,然后加入150μl色原性底物的水溶液(0.25mg/ml),通过在405nm处监测反应中对硝基苯胺的释放,测量底物的水解速率。绘制游离凝血酶浓度对水解速率的标准曲线。然后用标准曲线,将各个实验中使用试验化合物所观测的水解速率转换成“游离凝血酶”值。从实验中使用的凝血酶的已知初始量减去各实验中观测的游离凝血酶的量,计算出结合的凝血酶(与试验化合物结合)。从加入的抑制剂(试验化合物)的摩尔数减去结合的凝血酶的摩尔数,计算出各实验中游离抑制剂的数量。
Kass值是凝血酶和试验化合物(I)之间反应的假设平衡常数。
计算了一系列试验化合物浓度的Kass值并以1/mol为单位报告其平均值。
基本上按上述人凝血酶所述方法,并用下述确定的合适的色原性底物,使用其它的人血液凝固系统丝氨酸蛋白酶,测定本发明化合物关于凝血因子丝氨酸蛋白酶的选择性。
从Enzyme Research Laboratories,South Bend,Indiana购得人凝血因子Xa、IXa、XIa和XIIa;从Leo Pharmaceuticals,Denmark购买人尿激酶;基本上按美国专利4,981,952(作为一个整体,该文献收编在本文中作为参考)在Eli Lilly and Co.制备重组的活化蛋白C(aPC);从KabiVitrum,Strockholm,Sweden,或从Midwest Biotech,Fishers,Indiana购买色原性底物:N-苯甲酰-Ile-Glu-Gly-Arg-对硝基苯胺(用于因子Xa)、N-Cbz-D-Arg-Gly-Arg-对硝基苯胺(作为因子Xa底物用于因子IXa实验)、焦谷氨酰-Pro-Arg-对硝基苯胺(用于因子XIa及用于aPC)、H-D-Pro-Phe-Arg-对硝基苯胺(用于因子XIIa)、以及焦谷氨酰-Gly-Arg-对硝基苯胺(用于尿激酶);从Worthington Biochemicals,Freehold,New Jersey购买牛胰蛋白酶;从Kabi Vitrum,Stockholm,Sweden得到人血浆激肽释放酶。从KabiVitrum,Stockholm,Sweden购买用于血浆激肽释放酶的色原底物H-D-Pro-Phe-Arg-对硝基苯胺。按上文对本发明化合物所述的方法,利用公知的肽偶联方法,从市售反应物开始,合成用于凝血酶和用于胰蛋白酶的底物:N-苯甲酰-Phe-Val-Arg-对硝基苯胺。
从Boehringer Mannheim,Indianopolis,Indiana购买人纤维蛋白溶酶;从American Diagnostica,Greenwich,Connecticut购买nt-PA作为单链活性对照;按本领域公知的方法(参见Burck等人,J.Biol.Chem.,265,5120-5177(1990))在Eli Lilly and Company制备改性的t-PA6(mt-PA6);从Kabi Vitrum,Stockholm,Sweden购买纤维蛋白溶酶色原性底物H-D-Val-Leu-Lys-对硝基苯胺和组织纤维蛋白溶酶原激活剂(t-PA)底物H-D-Ile-Pro-Arg-对硝基苯胺。
上述色原性底物中,所述的由三个字母构成的符号Ile、Glu、Gly、Pro、Arg、Phe、Val、Leu和Lys分别用于代表相应的氨基酸基团异亮氨酸、谷氨酸、甘氨酸、脯氨酸、精氨酸、苯丙氨酸、缬氨酸、亮氨酸和赖氨酸。
凝血酶抑制剂应当优选不影响由尿激酶、组织纤维蛋白溶酶原激活剂(t-PA)和链激酶引起的纤维蛋白溶解作用。这对于该药作为链激酶、t-PA或尿激酶溶栓治疗的辅助治疗用途,以及对于该药作为一种不影响(有关t-PA和尿激酶)内源性纤维蛋白溶解作用的抗凝药的用途都将是重要的。除了不干扰溶解纤维蛋白的蛋白酶的酰胺酶活性外,所述溶解纤维蛋白系统的不影响可应用人血浆凝血块及其被各溶解纤维蛋白的纤维蛋白溶酶原激活剂溶解实验进行研究。
原材料
由清醒的混合品种的狗(两性均可,Hazelton-LRE,Kalamazoo,Michigan,U.S.A.)通过静脉穿刺得到狗血并置于3.8%柠檬酸盐中。根据现有方法和详细说明(Smith,Biochem.J.,185,1-11(1980);和Smith等人,Biochemistry,11,2958-2967(1972))由新鲜的狗血浆制备纤维蛋白原,并且由有效期的ACD人血以成分I-2形式制备人血纤维蛋白原。人血纤维蛋白原(纯度98%/没有血纤维蛋白溶酶)得自于American Diagnostica,Greenwich,Connecticut。按已报告的方法(Smith等人,Biochemistry,11,2958-2967,(1972))完成血纤维蛋白原I-2制品的放射标记。从Leo Pharmaceuticals,Demark购买2200Ploug单位/瓶的尿激酶。从Hoechst-Roussel Pharmaceuticals,Somerville,NewJersey购买链激酶。
方法——对t-PA溶解人血浆凝血块的效果
通过向内含0.0229uCi125I标记的纤维蛋白原的100μl人血浆中加入50μl凝血酶(73NIH单位/ml),在微量试管中形成人血浆凝血块。用50μl尿激酶或链激酶(50、100或1000单位/ml)覆盖凝血块并于室温保温20小时,研究凝血块溶解。保温后于BeckmanMicrofuge中将试管离心。取25μl上清液加到1.0ml体积的0.03MTris/0.15M NaCl缓冲液中,用于γ射线计数。通过不加凝血酶(并以缓冲液代替),得到100%溶解的计数对照值。在覆盖溶液中以1、5和10μg/ml浓度加入化合物,评价凝血酶抑制剂可能的纤维蛋白溶解作用的干扰。通过线性外推法由数据点推知代表特定浓度的纤维蛋白溶解剂50%溶解作用的点值。评估IC50大致的近似值。
抗凝活性
原材料
由清醒的混合品种的狗(两性均或,hazelton-LRE,Kalamazoo,Michigen,U.S.A.)或由麻醉的Sprague-Dawley雄性大鼠(Harlan Sprague-Dawley,Inc.,Indianapolis,Indiana,U.S.A.),通过静脉穿刺术在3.8%柠檬酸盐中制得狗血浆和大鼠血浆。按照已有方法和详细说明(Smith,Biochem.J.,185,1-11(1980);和Smith等人,Biochemistry,11,2958-2967(1972)),由有效期的ACD人血以成分I-2形式制备纤维蛋白原。从AmericanDiagnostica,Greenwich,Connecticut购买98%纯度/没有纤维蛋白溶酶的人纤维蛋白原。从Baxter Healthcare Corp.,Dade Division,Miami,Florida得到凝血试剂ACTIN、凝血致活酶和人血浆。从Parke-Davis(Ann Detroit,Michigan)得到牛凝血酶用于血浆中凝血实验。
方法
抗凝作用测定
凝血实验按以前所述的方法(Smith等人,ThrombosisResearch,50,163-174(1988))进行。所有凝血实验测定均使用一种CoAScreener凝血仪(American LABor,Inc.)。向0.05ml试验血浆中加入0.05ml盐水和0.05ml凝血致活酶-C试剂,测定凝血酶原时间(PT)。将0.05ml ACTIN试剂与0.05ml试验血浆一起保温120秒,然后加入0.05mlCaCl2(0.02M),测定活化部分凝血致活酶时间(APTT)。向0.05ml试验血浆中加入0.05ml盐水和0.05ml凝血酶(10NIH单位/ml),测定凝血酶时间(TT)。在广泛的浓度范围内,将式I化合物加至人或动物血浆中以测定对APTT、PT和TT实验的延长效果。使用线性外推法,评估使每个实验凝血时间加倍延长所需的浓度。
动物
用甲苯噻嗪(20mg/kg,经皮)和氯胺酮(120mg/kg,经皮)麻醉Sprague Dawley雄性大鼠(350~425g,Harlan Sprague Dawley Inc.,Indianapolis,IN),并保持在加热的水垫(37℃)上。颈静脉插导管用于输注。
动静脉旁路模型
左颈静脉和右颈动脉均用20cm长的聚乙烯PE60导管插管。一根内隙带有棉线(5cm)的6cm长的较大导管(PE 190)中心管段被摩擦装配在上述较长管段之间,以构成动静脉旁路循环。在小心取出棉线并称重之前,血液经该旁路循环15min。用棉线和血栓总重量减去湿棉线的重量(参见J.R.Smith,Br J Pharmacol,77:29,1982)。
FeCl3动脉损伤的模型。
经中线腹侧颈切口分离各颈动脉。每一动脉下均放置一个热温差电偶并在转筒记录器上连续记录血管温度。将纵向切开的导管套箍(0.058ID×0.077OD×4mm,Baxter Med.Grade Silicone)置于正好在热温差电偶之上的每一颈动脉周围。FeCl3六水合物溶解在水中,其浓度(20%)仅根据FeCl3的实际重量表示。为了损伤动脉并诱发血栓形成,用移吸管移吸2.85μl至套箍以润湿热温差电偶探头之上的动脉。温度的快速下降表明动脉闭塞发生。闭塞时间用分钟记录,并由FeCl3的应用和血管温度快速下降之间的消逝时间表示(参见K.D.Kurz,Thromb.Res.,60:269,1990)。
自发的血栓溶解模型
体外数据表明,肽凝血酶抑制剂抑制凝血酶和其它的丝氨酸蛋白酶例如纤维蛋白溶酶和组织纤维蛋白溶酶原激活剂。为评估本发明化合物是否抑制体内纤维蛋白溶解作用,通过在肺循环内植入标记的全血凝块测定自发的血栓溶解速率。将大鼠血液(1ml)与牛凝血酶(4IU,Parke Davis)和125I人纤维蛋白原(5uCi,ICN)快速混合立即吸入硅化橡胶管内并于37℃保温1小时。从管中取出老化的血栓,切成1cm的段,在生理盐水中洗3次,每段均用γ射线计数器计数。将已知计数值的一段提吸到导管中,该导管随后被插入到颈静脉。将该导管前端推进至右心房附近并推出血凝块以使之飘流到肺循环中。植入后1小时,收集心脏和肺并分别计数,以百分数表示血栓溶解,其中:
植入的凝血块的纤维蛋白溶解作用呈时间依赖性(参见J.P.Clozel,Cardiovas.Pharmacol.,12:520,1988)。
凝血参数
血浆凝血酶时间(TT)和活化部分凝血致活酶时间(APTT)用纤维测定仪测定。血样取自颈静脉导管并收集在含有柠檬酸钠(3.8%,1份配9份血液)的注射器中。为测定TT,将大鼠血浆(0.1ml)与盐水(0.1ml)和牛凝血酶(0.1ml、30μ/ml、在TRIS缓冲液中;ParkeDavis)于37℃混合。为测定APTT,将血浆(0.1ml)和APTT溶液(0.2ml,Organon Teknika)保温5分钟(37℃)并加入CaCl2(0.025M)以开始凝血。实验一式两份,取其平均值。
生物利用度指数
生物活性的测定、血浆凝血酶时间(TT)用以代替母体化合物实验,其设想依据是:凝血酶时间(TT)的增长仅是由母体化合物抑制凝血酶所致。在对麻醉的大鼠静脉单次快速给药后以及对禁食的清醒大鼠作口服给药治疗后,测定凝血酶抑制剂对TT的作用时间过程。由于血液体积和测定时间过程(从治疗时间到应答恢复至治疗前的值的时间)所需点数的限制,使用两群大鼠。各样品群代表交替的顺序时间点。使用时间过程的平均TT计算曲线下面积(AUC)。用下文所示等式计算生物利用度指数并以百分相对活性表示。
测定血浆TT时间过程的曲线下面积(AUC)并调整剂量。生物利用度指数被称为“%相对活性”并按下式计算:
化合物
每天在生理盐水中新配制化合物溶液并作为一种制剂注射,或者于实验15分钟之前开始输注并连续贯穿于整个实验过程。单次快速静脉注射的体积为1ml/kg,口服为5ml/kg,输注体积是3ml/hr。
统计资料
结果以均值+/-SEM表示。使用一元(one-way)方差分析以检测统计学上的显著差异,然后应用Dunnetts检验以检测哪些均值是有差异的。对于相等均值的无效假设的否决,显著性水平为P<0.05。
动物
使雄性狗(Beagles;18月~2年;12-13Kg,Marshall Farms,North Rose,New York 14516)禁食过夜,在给药后240分钟喂饲Purina certified Prescription Diet(Purina Mills,St.Louis,Missouri)。水可任意饮用。室温保持在66-74°F之间;45-50%相对湿度;06.00~18.00点钟光照。
药代动力学模型
在给药之前,使试验化合物溶解在无菌的0.9%盐水中立即配制成5mg/ml制剂。通过口服(管饲法)给狗施用单次2mg/kg剂量的试验化合物。于给药后0.25、0.5、0.75、1、2、3、4和6小时从头部静脉抽取血样(4.5ml)。血样收集在内含柠檬酸盐的Vacutainer管中,在离心使之成为血浆之前保存于冰上。用二硝基苯基肼衍生血浆样品,用HPLC(Zorbax SB-C8柱)分析,以甲醇/500mM乙酸钠(60:40,V/V)(用磷酸调节至pH7)洗脱。记录试验化合物的血浆浓度并用于计算药代动力学参数:清除速率常数(Ke)、总体清除率(Clt)、分布容积(VD)、最高血浆试验化合物浓度时间(Tmax)、Tmax的试验化合物最高浓度(Cmax)、血浆半衰期(t0.5)、时量曲线下面积(A.U.C)、吸收的试验化合物份量(F)。
犬动脉血栓形成模型
狗的外科手术准备及器械同Jackson等人文献所述(Circulation,82,930-940(1990))。用戊巴比妥钠(30mg/kg,静脉注射)麻醉混合品种的狗(6-7月龄,两性均可,Hazelton-LRE,Kalamazoo,MI,U.S.A),气管插管并通以空气。调节每次呼吸进出肺部的气量和呼吸频率,以便保持血液PO2、PCO2和pH在正常生理范围内。插入皮下针电极,用于记录导联II心电图。
经左中侧颈切口分离左颈静脉和颈总动脉。用插入于颈动脉的预校过的Millar换能器(型号MPC-500,Millar Instruments,Houston,TX,U.S.A.)连续测定动脉血压(ABP)。实验期间颈静脉插管取血样。另外,两后腿股静脉均插管用于给予试验化合物。
在第五肋间隔进行左胸廓造口术,并将心脏悬于位于心脏周围的支架上。在接近第一个主要的直线心室分支分离左冠状动脉旋支(LCX)的1~2cm区段。在该LCX中插入一个26号针装配的金属丝阳极(特氟隆包裹的,30号镀银的铜丝)3~4cm长,并使之与动脉内表面接触(于实验终止时证实)。
在皮下位置设置负极,完成刺激回路。在电极区域的LCX周围设置可调节的塑料咬合器。在接近于阳极的LCX周围设置预校过的电磁流量探针(Carolina Medical Electronics,King,NC,U.S.A),用于测定冠状血流(CBF)。调节咬合器,使得在LCX的机械闭塞10秒后产生40~50%观测到的充血血流反应的抑制。用数据获得系统(型号M3000,Modular Instruments,Malvern,PA.U.S.A)记录和分析全部的血液动力学和心电图测定结果。
血栓形成和化合物给药方法
通过向阳极接通100μA直流电(DC)产生LCX内膜的电解损伤。电流维持60分钟。然后观察血管是否闭塞而决定是否断电。血栓形成自发进行,直至LCX完全闭塞(CBF为零且S-T段增加)。使正闭塞的血栓老化1小时后开始给药。以0.5和1mg/kg/小时的剂量开始本发明化合物的2小时输注,同时输注血栓溶解剂(例如组织纤维蛋白溶酶原激活剂、链激酶、APSAC)。给予试验化合物后进行3小时再灌注。血栓成功溶解后冠状动脉的再闭塞定义为:零的CBF维持30分钟以上(包括30分钟)。
血液学和模板出血时间测定
用血液学分析仪(Cell-Dyn 900,Sequoia-Turner.MountView,CA,U.S.A),测定含柠檬酸盐(3.8%)的血液(1份柠檬酸盐:9份血液)的全血细胞计数、血红蛋白和血细胞比容值。用SimplateII出血时间装置(Organon Teknika Durham,N.C.,U.S.A)测定牙龈模板(template)出血时间。使用该装置在狗的左上或左下颌的齿龈部位造2个水平切口。每一切口为3mm宽×2mm深。切口造好后,用秒表测定出现出血的时间长短。当血液从切口渗出时,用棉拭子吸收血液。模板出血时间是从切口至出血停止的时间。给予试验化合物前(0分钟)、输注期间的第60分钟时、试验化合物的给药结束时(120分钟)、以及实验终止时,测定出血时间。
通过一元方差分析(ANOVA)分析所有数据,然后通过Student-Neuman-Kuels post hoc t检验测定显著性水平。重复ANOVA检验,以测定实验期间各时间点之间的显著性差异。至少在P<0.05的水平上检测数值统计学上的差异。所有数值都是均值±SEM。按照American Physiological Society的指导原则进行所有的研究。进一步的详细资料参见Jackson等人所述的方法(J.Cardiovasc.Pharmacol.,21,587-599(1993))。
在模板出血时间实验中还于0.25、0.50和1.0mg/kg·hr评估了本发明式I化合物。
通过上述任一实验所显示的对抑制凝血酶及其性质的正性效果,阐明了本发明化合物的效用。
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US08/171,394 US5441965A (en) | 1993-12-21 | 1993-12-21 | Methods of inhibiting thrombin |
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ATE268768T1 (de) | 1997-04-30 | 2004-06-15 | Lilly Co Eli | Antithrombosemittel |
CA2287993A1 (en) | 1997-04-30 | 1998-11-05 | Mary George Johnson | Antithrombotic agents |
US6103740A (en) * | 1997-08-21 | 2000-08-15 | Eli Lilly And Company | Methods for lowering platelet counts |
US6187777B1 (en) | 1998-02-06 | 2001-02-13 | Amgen Inc. | Compounds and methods which modulate feeding behavior and related diseases |
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AU8155894A (en) | 1995-06-29 |
DE69402173D1 (de) | 1997-04-24 |
NO313081B1 (no) | 2002-08-12 |
IL112048A (en) | 1999-03-12 |
EP0664126B1 (en) | 1997-03-19 |
JPH07223947A (ja) | 1995-08-22 |
GR3023537T3 (en) | 1997-08-29 |
US5508292A (en) | 1996-04-16 |
CZ287725B6 (en) | 2001-01-17 |
US5441965A (en) | 1995-08-15 |
EP0664126A1 (en) | 1995-07-26 |
ATE150308T1 (de) | 1997-04-15 |
UA29446C2 (uk) | 2000-11-15 |
NO944932L (no) | 1995-06-22 |
AU693822B2 (en) | 1998-07-09 |
ES2102154T3 (es) | 1997-07-16 |
NO944932D0 (no) | 1994-12-19 |
ZA9410084B (en) | 1996-06-19 |
CZ322694A3 (en) | 1995-09-13 |
CN1107704A (zh) | 1995-09-06 |
HU224915B1 (en) | 2006-04-28 |
DK0664126T3 (da) | 1997-09-01 |
IL112048A0 (en) | 1995-03-15 |
HU9403675D0 (en) | 1995-02-28 |
CA2138493A1 (en) | 1995-06-22 |
DE69402173T2 (de) | 1997-07-17 |
RU94045846A (ru) | 1996-10-20 |
US5688813A (en) | 1997-11-18 |
TW321601B (zh) | 1997-12-01 |
HUT71344A (en) | 1995-11-28 |
KR950016744A (ko) | 1995-07-20 |
NZ270185A (en) | 1997-07-27 |
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