CN1182436A - 基于水蛭素氨基酸序列的凝血酶抑制剂 - Google Patents
基于水蛭素氨基酸序列的凝血酶抑制剂 Download PDFInfo
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Abstract
一种凝血酶抑制剂,它包括:大体积疏水性的第一部分,该部分能与负责蛋白酶解的凝血酶催化位点作用;和能维持下述氨基酸的疏水性和酸性的第二部分,其中的氨基酸是指天然水蛭素在C端非催化区N-乙酰—水蛭素45—65处的氨基酸55—60。在第一部分和第二部分之间是共价键连接部分。该化合物实用于治疗血栓形成类疾病。
Description
本发明涉及用作凝血酶抑制剂的肽衍生物,具体涉及基于含氨基酸45-65的水蛭素片段序列的肽衍生物。
凝血酶是凝血级联系统的一种重要的丝氨酸蛋白酶组分。除了分裂血纤蛋白原而引发血液凝固之外,凝血酶还激活其它凝血剂因子,包括凝血因子V、VIII和XIII,并激活抗凝血酶蛋白C。凝血酶也是一种有效的血小板激活物,它可减少活体内由组织纤溶酶原激活物介导的血栓溶解。所以,凝血酶的正反馈调节起增强止血作用,但引起血管畸变和脑血管动脉畸变而导致形成危及生命的血栓。
已知该酶有多种功能,它若被有效的专一性化合物抑制,则会对血栓形成相关疾病的治疗起不可估量的作用。这类疾病包括:冠状动脉疾病、脑血管疾病、末梢动脉堵塞疾病、深处静脉血栓形成和肺栓塞。
已知最有效的凝血酶抑制剂是水蛭素,它是一类从医用水蛭这种水蛭的腺分泌物中分离而得的同工蛋白质。很久以前人们就知道水蛭素的抗凝血性能。然而,迄今为止其治疗价值很小,因为其肠内吸收和皮肤吸收均相当少,故难于将该蛋白质配制成易于生效和易于施药的形式,因此该蛋白质不可能在血流中形成适当的浓度。
此外,不可能临床应用从水蛭提取物中分离的水蛭素,这是由于受其有限质量、费用和变应性反应的限制,其中的变应性反应系施药水蛭素大小的外源蛋白质时会经常出现的反应。
在其题为“Pharmacology of selective thrombin inhibitors”,(1988),Nouv.Rev.Fr.Hematol.30,pp.161-165的出版物中,Markwardt基于对天然的和合成的凝血酶抑制剂的药理研究结果而进一步提供有关水蛭素的临床资料。
该作者对水蛭素作了全面实验,指出含强酸性C端部分的肽对α-凝血酶有高度专一性。然后他推断出:水蛭素的C端部分有可能结合到该酶的阴离子结合位点区,而其致密的N端部分似乎结合到该酶的活性中心区。
业已发现,天然的脱硫水蛭素45-65以剂量相关的方式抑制牛α-凝血酶和人α-凝血酶引起的血纤蛋白原凝血。牛α-凝血酶的IC50值为940±200nM,它与有关同样片段形成血浆血纤蛋白血块的报道值相当吻合,且比水蛭素55-65低3倍,后者被指定为抗凝血活性所要求的极限核心(minimum core)。还有人证实此肽抗人α-凝血酶比抗牛α-凝血酶始终更为有效。
各种现有技术文献也阐述了,水蛭素氨基酸序列的活性片段好象是包括氨基酸46-65的氨基酸序列。于是,人们试图通过取代该序列中的某些氨基酸以增强此肽的抑制活性。
Krstenansky等人在“Antithrombin properties of C-terminus ofhirudin using synthetic unsulfated Nα-acetyl-hirudin”,(1987),FebsLetters,Vol.211,No.1,pp.10-16中描述了未脱硫Nα-乙酰基水蛭素45-65的C端片段的合成。作者们参照先前的工作(Chang,J.-V.,FEBS Letters,164,307(1983))并提到该片段可能含两个专一性结合区,一个结合到凝血酶的催化位点,而另一个结合到凝血酶的另一识别位点。两组作者也推断事实并非如此。
作者们还是阐明了水蛭素的45-65序列具有抑制凝血活性和凝血酶释放血纤肽A的能力。他们还提议,水蛭素45-65的同样序列可能不直接参与同凝血酶的催化位点的结合,因为凝血酶对合成底物的酰胺分解性能未受干扰。
在Krstenansky等人的标题为“Anticoagulant peptides:nature ofthe interaction of the C-terminal region of hirudin with a noncatalytic siteon thrombin”,(1987),J.Med.chem.,30,pp.1688-1691的论文中,作者们报道了在凝血酶的非催化结合位点处最小活性序列是水蛭素56-64。作者们基于这一设想报道了几种C端水蛭素54-65类似物的合成及其抑制凝血酶引起的形成血纤蛋白凝血的能力,目的在于确定水蛭素56-64和凝血酶的非催化结合位点之间的性质。
在结论中,作者们提到水蛭素的C端区可能结合到与凝血酶连接的纤维蛋白原区,它不是迄今文献中提出的区。
在下列文献中:Dodt等人(Interaction of site specific hirudinvariants withα-thrombin,(1988),Febs Letters,Vol.229,No.1,pp.87-90),Degryse等人(Point mutations modifying the thrombin inhibitionkinetics and antithrombotic activity in vi vo of recombinant hirudin,(1989),Protein Engineering,Vol.2,No.6,pp.459-465)和Braun等人(Use of site-directed mutagenesis to investigate the basis for the specificityof hirudin,(1988),Biochemistry,27,pp.6517-6522),作者们报道了在水蛭素基因上进行的定位诱变结果,研究了突变体水蛭素肽对凝血酶的抑制作用。
在这些出版物中,作者们研究了在整个蛋白质进行的突变且其自身并不限制于水蛭素的45-65片段。此外,对45-65片段进行的修饰均局限于单个修饰,常在47号位置,虽然这些出版物还显示了在位置51、57、58、61和62处的突变,但它说明该残基不与活性中心相互作用。
Dodt等人以类似方式在论文“Distinct binding sites of Ala48-Hirudin1-47 and Ala48-Hirudin48-65 on α-thrombin”,(1990),The Journal ofBiological Chemistry,Vol.265,No.2,pp.713-718中描述了一些实验,旨在进行在水蛭素序列48号位置上的定位诱变。Dodt等人在此处所做的工作似乎被局限于在该位置上用脯氨酸取代丙氨酸,以促进他们的实验中所需的蛋白酶解。
最后,Maraganore等人,在“Anticoagulant activity of synthetichirudin peptides”,(1989),The Journal of Biological Chemistry,Vol.264,No.15,pp.8692-8698中,Dennis等人在“Use of fragments of hirudinto investigate thrombin-hirudin interaction”,(1990),Eur.J.Biochem.188,pp.61-66中,以及Chang等人在“The structural elements ofhirudin which bind to the fibrinogen recognition site of thrombin areexclusively located within its acidic C-terminal tail”,(1990),Febs.,Vol.26l,No.2,pp.287-290中描述了一些肽的合成和抗凝血性能,这些肽的序列基于天然水蛭素不同片段的序列。
具有抗凝血性能的化合物是有用的治疗剂,它们可用于活体内治疗各种病理状态。其中抗凝血疗法将会实用的最重要病例有心肌梗塞、肺栓塞和脑血管疾病、深处静脉血栓形成和血栓形成类疾病的其它指征。
目前可获得的抗凝血剂在很多方面不理想。例如,业已应用肝素来抑制凝血酶的活性因而治疗如静脉血栓形成和血栓栓塞的疾病。但是,肝素表现出许多种不利副作用,说明要求表现更合意的毒性水平的抗凝血剂。
低分子量和专一性凝血酶抑制剂的设计中利用远离或连接催化中心的辅助性结合位点,这类似于纤维蛋白原或水蛭素与凝血酶的结合方式,在蛋白质化学中构成挑战。可以想象,这种多功能抑制剂结合两个或多个被适当的间隔臂分离的识别性单元,有利于多种同时的相互作用,因而可显示效果和专一性的提高。结合具有低分子量结构的“外源”化学单元可赋与对蛋白酶解的抗性和良好的生物利用率。而且,因为它们比水蛭素小,所以这些化合物在用它们进行治疗的病人体内不大可能刺激不良的免疫响应。
PCT申请WO91/02750指出,某些凝血酶抑制剂具有可被缓慢分裂或根本不能分裂的CSDMs。然而,它们都是在Arg和Gly或Pro之间有修饰键,例如Arg [psiCH2-NH]-Gly、β-HomoArg-Gly、β-HomoArg-Pro、β-HomoArg-Val或Arg-[ψCO-CH2]-CH2-(CONH)-Gly。但没指示Gly或Pro氨基酸可被完全消去再接上完全抗凝血酶分裂的合成接头。
本发明的化合物是式(D)-Phe-Pro-Arg-(CH2)4(CO)-[NH-(CH2)4CO]2-DFEPIPL的肽衍生物(I),它模拟含残基45-65的水蛭素的羧基区。字母D、F、E、P、I和L表示按已知的单字母密码表示的氨基酸。
本发明的另一个方面是提供治疗血栓形成类疾病的药物组合物,它包括有效量的肽衍生物(I)(D)-Phe-Pro-Arg-(CH2)4(CO)-[NH(CH2)4CO]2-DFEPIPL及其药物上可接受的盐。
本发明的又一个方面是提供治疗或预防与血栓形成有关的血管疾病的方法,它包括对病人施药有效量的组合物,该组合物包含有效量的肽衍生物(I)D-Phe-Pro-Arg-(CH2)4(CO)-[NH(CH2)4CO]2-DFEPIPL。
在进一步的方面,本发明的化合物也可用于以下方面的组合物和方法中:活体内诊断成像、体外贮存体外的血液和涂敷外来器具(invasivedevices),以及来自体内的血液处理。
本发明涉及用作凝血酶抑制剂的肽衍生物。业已发现包括残基45-65的水蛭素天然片段能与凝血酶上两个独立且相隔较远的位点同时相互作用,其中的一个位点是推定的阴离子外位点(exosite),而另一个是负责蛋白酶解的催化位点。这种结合方式模拟但不同于天然水蛭素分子的机制,现已证实天然水蛭素分子是通过其N端三个残基与凝血酶的活性位点相互作用的。因此,好象是残基45、46和47在天然蛋白质中不起结合作用,而是在缺乏N端核心时尽管较弱地,但在空间上先倾向于恰当地相互作用。
基于该观察,我们合成了在分子的两个抑制性组分上进行了修饰的肽衍生物,且该衍生物表现的抗凝血酶活性高于任一部分单独的水平。此外,新形成易断裂键的化学修饰提供更活泼的化合物,它对凝血酶具有蛋白酶解稳定性优点。该肽衍生物用作抗凝血剂和血小板凝聚的抑制剂,于是降低动脉血栓形成和其它有关心血管病的指征中的危险因素。本发明的化合物也可用于治疗肿瘤转移如癌的病例。
当用于α-氨基酸时,术语“残基”指通过脱去其羧基的羟基和α-氨基的一个氢而得自相应的α-氨基酸的基团。
文中所用指单个的残基的缩写是基于the IUPAC-IUB Commission onBiochemical Nomenclature[Biochemistry,11,1726-1732,(1972)]的推荐。文中所用的术语“氨基酸”包括天然生成的氨基酸和非天然的类似物如化学合成和肽化学领域中技术人员常用的那些非天然类似物。非天然氨基酸一览表可参见“The Peptides”,vol.5,1983,Academic Press,Chapter 6by D.C.Roberts and F.Vellaccio。
本发明还涉及治疗或预防与血栓形成有关的血管疾病的方法,该方法包括对病人施药有效量的组合物,此组合物含与药物上可接受的载体掺和的肽衍生物。
本发明还涉及在用溶栓剂医治病人时减少再灌注时间或提高再闭塞(reocclusion)时间的方法。该方法包括对病人施药有效量的组合物,此组合物含本发明的肽衍生物和与药物上可接受的载体掺合的溶栓剂。
依本发明的另一方面,本发明的肽衍生物可用于治疗肿瘤转移。此衍生物治疗肿瘤时的效果通过对转移生长的抑制来体现。这基于某些癌细胞中存在的促凝血酶。该酶激活凝血级联系统中凝血因子X和凝血因子Xa的转化,导致血纤蛋白沉积,它反过来又作为肿瘤生长的底物。通过抑制凝血酶而抑制纤维蛋白沉积,本发明的分子可作为有效的抗转移瘤剂。可用本发明的凝血酶抑制剂治疗的转移瘤实例包括但不限于:脑癌、肝癌、肺癌、骨癌和瘤形成的浆细胞癌。
依本发明的另一方面,凝血酶抑制剂可用于涂敷外来器具表面用的组合物和方法中,致使接受这类器具的病人体内血块形成或血小板活化的危险性更低。可用本发明的组合物涂敷的表面例如有:假体、人造瓣膜、血管移植物、斯坦特固定模和导管。涂敷这些器具的方法和组合物是本领域中的技术人员已知的,它们包括使含凝血酶抑制剂的组合物化学交联或物理吸附在器具表面。
依本发明的进一步实施方案,凝血酶抑制剂可用于病人的诊断用血栓成像。在该实施方案中,用放射性同位素标记凝血酶抑制剂。放射性同位素的选择基于人们熟悉的一些因素例如:毒性、生物半衰期和鉴别率。优选的同位素包括但不限于:125I、123I和111In。标记凝血酶抑制剂的方法是本领域中为人熟知的。最优选地,放射性同位素是123I且用123I-Bolton-Hunter试剂来进行标记。将已标记的凝血酶抑制剂施药给病人并让其与含于血块中的凝血酶结合。然后利用人们熟知的方法如利用联到计算机成像系统上的可检测放射性的摄像机来观测此血块。该技术也产生血小板结合的凝血酶和meizothrombin的成像。
在另一方面,上述凝血酶抑制剂或其组合物可用作来自体内处理血液或体外血液用的抗凝血剂。文中用到的术语“来自体内”处理包括从病人体内抽出血液,接受体外处理,再返回到病人的过程,如渗析法、血液过滤或外科手术时的血液分流术。文中用到的“体外血液”这一术语是指体外贮存的、最终用于病人的血液制品,也指收集自病人、有待用于各种测定的血液。这类制品包括全血、血浆或需要抑制凝血的任意血液组分。
本发明的肽衍生物可用本领域中技术人员熟悉的各种方法合成。例如,此肽类可用Stewart et.al.在“Solid phase peptide synthesis”,Freeman & Co.,San Francisco,1969中描述的固相法,在合适的肽合成仪上合成。肽衍生物的非氨基酸区要求在将该部分通过惯常的固相合成法与其它氨基酸连接以生成所需的肽之前先进行化学合成。本领域中的技术人员将会懂得,熟练的有机化学家容易制备此肽衍生物的合成区。肽衍生物的合成
可用BOC-GlnPAM树脂(Applied Biosystems;0.64mmol/克)作固相载体,在Applied Biosystems 430A肽合成仪上合成肽衍生物。氨基酸偶联可由二环己基碳化二亚胺/N-羟基苯并三唑介导,再如下进行脱保护:先与50%三氟乙酸(TFA)的二氯甲烷作用3分钟,接着循环20分钟。侧链保护基为:Asp(Chx)、Arg(Tos)。然后可用含苯甲醚和甲硫醚(10vol.%)的液态氟化氢在-5℃下对充分保护的肽树脂处理60分钟。接着用氮气流除去过量的HF,并用醚提取残留固体,再过滤。然后用冰醋酸和水提取树脂,接着冷冻干燥。肽衍生物的纯化和分析
所得冻干的粗肽可利用惯常认可的肽纯化技术纯化成匀质物。一种合适的方法是反相色谱法:在Vydac十八烷基二氧化硅玻璃柱(15,1.5×30cm,40psi)上利用如下线性梯度溶剂系统:A,500ml 500ml 0.1%TFA/H2O和B,含0.1%TFA的1L 60%乙腈(Acelonitrite)/H2O。各级分的分析可用反相HPLC在Varian LC上进行,其中利用Vvdac C18分析柱,在215nm处测定。可合并纯度在99%以上的各级分并冷冻干燥。肽含量可通过氨基酸分析法在Beckman model 6300氨基酸分析仪上进行测定。然后在Waters Pico-Tag Work Station中干燥试样。往小瓶中加入含1%苯酚的恒沸HCl(200μl),并交替(用干燥的氮气)吹洗,吹洗三次后抽真空。最后,将含试样的小瓶在150℃下的真空中加热1小时。可在装有离子喷射入口源的SCIEXAPI III谱仪上进行质谱分析。
这样,可由正确的氨基酸组成和质谱确认合成的肽的结构和序列,其中的质谱是为了证明与计算的分子量相符。药物组合物
本发明的肽衍生物可以治疗上可接受的盐的形式获得。由于肽衍生物的残基具有酸和/或碱的官能,那么就可以衍生出有机酸(如乙酸、三氟乙酸、乳酸、丁二酸或苹果酸)或碱(如钠、钾或钙)的盐。肽衍生物的这些盐具有充分的生物活性。可以用R.A.Boissonas等人,Helv.Chim.Acta.43,1849(1960)描述的方法,应用合适的离子交换树脂将治疗上可接受的盐从一种盐形式转变成另一种形式。
本发明的肽衍生物或其治疗上可接受的盐,可单独地或组合地用于治疗或预防血栓形成引起的血管病。将它与药物上可接受的载体系统施药给温血动物如人、马或狗,其组成比例依溶解性和选用的施药方法而定。本发明的肽衍生物与药物上可接受的载体组合后可以静脉内、皮下或肌肉注射来施药。合适的载体实例见于权威药学教材,如“Remington’sPharmaceutical Sciences”,16th edition,Mack Publishing Company,Easton,Penn.,1980。
肽衍生物的剂量将随施药方式并可能随具体的盐形式而变化。至于注射,肽衍生物的治疗有效剂量是在约0.05mg/kg~10mg/kg体重的剂量范围内。除了活性成分外,组合物通常还含合适的缓冲剂例如磷酸盐缓冲剂,以维持适当的pH;并含有氯化钠、葡萄糖或甘露糖醇以使溶液具有等渗性。
本发明的肽衍生物可单独地或与其它药物组合施药。例如,肽衍生物可与溶纤剂如组织纤溶酶原激活物、链激酶或尿激酶组合施药以防止冠状动脉的再闭塞。肽衍生物也可与肝素或低分子量肝素一起施药,这是一种可有利地减少肝素或低分子量肝素的剂量的组合形式。可与肽衍生物一起施用的其它化合物包括血栓烷和EPII b3a。
下述实施例中用到的缩写包括,BOC:叔丁氧基羰基;Tos:对-甲苯磺酰;CH2Cl2:二氯甲烷;TEA:三乙胺;BOP:苯并三唑基N-氧化三(二甲氨基)鏻六氟磷酸盐;DMF:二甲基甲酰胺;EtOAc:乙酸乙酯;DCC:N,N’-二环己基碳化二亚胺;DPPA:二苯基磷酰叠氯化物:THF:四氢呋喃;HF:氟化氢;CBZ:苄氧基碳酰。实施例1
合成(2S)-2-(BOC)-N-甲氧基-N-甲基-5-甲苯磺酰胍基(guanadino)戊酰胺
在0℃的冰浴中,向含有TEA(0.4ml,3mmol)和N,O-二甲基羟基胺盐酸化物(146mg,1.5mmol)的Nα-BOC-NG-甲苯磺酰精氨酸(428mg,1mmol)于30ml DMF的溶液中,加入BOP试剂(500mg,1.1mmol)(B.Castro,J.R.Dormoy,G.Elvin,C.Selve,TetrahedronLetters#14,pp.1219-1222,1975)。在4℃下搅拌反应达15小时,然后高真空蒸发掉溶剂。残余物溶于50ml EtOAc并用水洗涤。有机相进一步用5%NaHCO3、1N HCl各萃取三次,再在Na2SO4上干燥。溶剂在硅藻土上过滤后真空浓缩。往浓缩物中加入少量己烷,沉积的白色固体(500mg)为标题化合物。质谱分析:
M/Z=472(M+H)+。
实施例2
合成6-BOC-9-甲苯磺酰胍基-1-壬烯-5-酮
往实施例1的产物(600mg,1.3mmol)于25ml THF的溶液中加入10当量制备自4-溴-1-丁烯的格利雅试剂(制备释注:滴加1.75g 4-溴-1-丁烯处理312mg镁屑(13mmol)于50ml无水乙醚的溶液维持缓慢回流),待金属全部消耗后用注射器将此格利雅溶液在氩气中转入THF混合物。用NH4Cl水溶液使整个THF混合物骤冷,TLC之后显示起始原料已消失(是在Kieselgel60F 254,Merck,玻璃板上进行TLC的)。进行相分离,有机相进一步用1N HCl和H2O洗涤,干燥(Na2SO4)并真空蒸发。在硅胶上进行色谱分离(用4∶1EtOAc/己烷洗脱)得清亮的油状标题化合物。质谱分析:M/Z=469(M+H)+。
实施例3
合成5-BOC-4-氧基-8-甲苯磺酰胍基辛酸
将实施例2的产物(2.5g,5.3mmol)溶于50ml乙腈,接着加入高碘酸钠(8g,37.5mmol)于50ml水中的溶液。用100mg氯化钌处理此混合物。室温下强烈搅拌一小时后,用TLC未测出起始原料。用100ml H2O和100ml乙醚稀释该混合物。进行相分离,水相进一步用乙醚萃取。合并的有机萃取物用H2O洗涤,干燥(Na2SO4)并蒸发至干,得1.5g标题化合物的泡沫体。M/Z=485(M+H)+。
实施例4
合成6-BOC-5-氧基-9-甲苯磺酰胍基壬酸
本实施例的标题化合物以类似于实施例1~3的方法合成。简言之,用制备自镁和5-溴-1-戊烯的格利雅试剂与实施例1的产物反应。分离生成的加合物得类似于实施例3的油状产物,接着用高碘酸钠和氯化钌的组合处理得本实施例的标题同系物。M/Z=499(M+H)+。
实施例5
合成7-BOC-6-氧基-10-甲苯磺酰胍基癸酸
本实施例的标题化合物以类似于实施例1~4的方法制备。在本实施例中,用制备自镁和6-溴-1-己烯的格利雅试剂与实施例1的产物反应。接着如实施例2中所述用硅胶凝胶色谱分离该加合物,再将此加合物与高碘酸钠和氯化钌反应。分离产物得油状的标题化合物。M/Z=513(M+H)+。
实施例6
4N-t-BOC-3-氧基-7-甲苯磺酰胍硫代庚酸乙酯(混合酐法)
混合酐的形成:于-20℃下,在搅拌时往1g(2.4mmol)(L)-Nα-BOC-Arg(Nw)TOS)OH和0.66ml(0.48mmol)三乙胺于15ml无水四氢呋喃的溶液中,滴加0.40ml(0.3mmol)氯甲酸异丁酯达15分钟。1小时后用15ml乙醚稀释该混合物,滤去沉淀出的固体物。含混合酐的滤液于0℃下贮存。
同时,在0℃和氩气保护下,往二异丙胺(3.4ml,24mmol)于25ml无水乙醚的溶液中,在搅拌下滴加一当量正丁基Li的THF溶液达30分钟。然后,冷却该反应混合物至-60℃并用2.5ml硫代乙酸乙酯处理。于60℃下搅拌30分钟后,用6g MgBr2乙醚配合物处理,且继续搅拌30分钟。最后,用预先形成的混合酐处理此混合物,继续搅拌5小时直至反应完全(依HPLC测定)。
滴加6M NH4Cl处理该反应混合物并进行相分离。有机相用50mlEtOAc稀释,再用1N HCl(3X)、H2O(3X)萃取,用Na2SO4干燥后高真空蒸发得油状标题化合物,M/Z=515(M+H)+。
实施例7
偶联实施例6的硫代酯至α-氨基酸酯和去保护的氨基乙酰聚苯乙烯树脂。
将得自实施例6已保护的精氨酰statone(2当量)溶于CH2Cl2,并加入到含生长多肽链的α-氨基酸酯(1当量)或聚苯乙烯树脂混合物中。向该混合物中加入碘化亚铜(2当量)和三乙胺(2当量)。至于氨基酸酯,用HPLC监测反应;或者在聚苯乙烯结合的肽的情况下,则用惯常的水合茚三酮试验监测反应。
实施例8
制备式II:-〔NH-CH2-CH=CH-CH2-(CO)〕3-的合成间隔基亚基
模拟(Cox M.T.,Heston D.W.and Horbury J.,J.Chem.Soc.Chem.Comm.,1980,799-800)进行合成并作大量修改。全过程略述如下:
a)合成反-β-氢化粘康酸二甲酯。
将22g(153mmol)反-β-氢化粘康酸溶于含500mg对甲苯磺酸和100ml甲醇的200ml苯中。溶液保持回流达5小时,再用100ml水处理。进行相分离,有机层进一步用5%NaHCO3和H2O萃取。干燥(Na2SO4)后,真空蒸发掉溶剂,蒸馏(83~85℃,0.5mmHg)残余物得19g标题化合物。
b)合成反-β-氢化粘康酸单甲酯
将5g(27.5mmol)步骤a)的产物悬浮于0.1M KH2PO4的100ml溶液,接着加入20mg猪肝酯酶。滴加1M NaOH溶液而维持溶液的pH为7。在加入相当于1摩尔当量二酯的1M NaOH后,用活性炭处理溶液,搅拌5分钟并用硅藻土过滤。用乙醚萃取滤液,废弃合并的有机萃取物。用3N HCl调节水相至酸性,再用乙醚萃取。合并的乙醚萃取物被干燥(Na2SO4)后真空蒸发。减压蒸馏(105-110℃,0.5mmHg)残余物,余留4g油状标题化合物。
c)合成4-甲氧基羰基-2-脱氢异氰酸丁酯
将1.22g(7.3mmol)步骤b)的单酯溶于25ml苯。滴加0.76ml(8.7mmol)草酰氯达15分钟,剧烈搅拌溶液3小时。真空蒸发此溶液,将残余物溶于10ml丙酮后加入预先冷却的(0℃)叠氮化钠lg于20ml 50%水/丙酮的溶液。30分钟后用水(50ml)稀释此混合物,并用每份20ml的苯萃取3次。将合并的有机提取物干燥(Na2SO4)并过滤。滤液在80℃的油浴中加热直至无氮气放出为止。真空蒸发溶剂,再减压蒸馏(80-85℃,0.5mmHg)残余物得700mg标题化合物。
d)合成4-N-丁氧基羰基-戊-3-烯酸
将890mg(12.2mmol)叔丁醇加入含步骤c)的产物(1g,6.1mmol)的25ml苯溶液中。全部溶液被回流10小时,然后真空蒸发。残余物用步骤b)中所述的猪肝酯酶处理,再用该步骤中所述方法处理得700mg标题化合物。
然后将得自步骤d)的产物用作制备合成的间隔臂II的单元。利用本领域中技术人员熟悉的技术组合这些单元而形成间隔臂(II)。
实施例9
制备P79
Ac-(D)Phe-Pro45-Arg-(COCH2)CH2-(CO)-Gln-Ser50-His-Asn-Asp-Gly-Asp55-Phe-Glu-Glu-Ile-Pro60-Glu-Glu-Tyr-Leu-GlnOH
将1g叔丁氧基羰基-Gln苯基乙酰氨基甲基树脂(AppliedBiosystems;0.64mmol/g)进行16轮合成,其中包括nα-侧链去保护(50%TFA于CH2Cl2中)和利用2.5meq被保护的氨基酸/DCC与N-羟基苯并三唑的偶联。标准氨基酸的侧链保护基如下:Asp(环己基)、Glu(苄基)、His(苄氧基甲基)、Tyr(溴苄基)、Ser(苄基)。
也用DCC/N-羟基苯并三唑将得自实施例3的合成保护氨基酸偶联至Gln49。为得到最佳结果,N-BOC-(D)-Phe-Pro-OH可代替各氨基酸以单个的单元加入。
在-5℃的特氟隆容器中,用含苯甲醚和二甲硫(10vol%)的氟化氢处理已完全保护的肽树脂(500mg)达60分钟。通N2气流除去过量的HF,残余物用乙醚萃取后过滤。用冰醋酸和水萃取该树脂三次,接着冷冻干燥。
冻干后的粗肽利用反相色谱在十八烷基二氧化硅(15,Vydac)玻璃柱(1.5×30cm,40psi)上纯化至均质物,它利用的线性梯度溶剂系统包括(a)500ml 0.1%TFA/H2O和(B)含0.1%TFA的1升60%乙腈H2O溶液。合并纯度达98%或更高的各级分并冷冻干燥。
氨基酸分析指示:Asp(3),Ser(1),Glu(6),Gly(1),Ile(1),Leu(1),Tyr(1),Phe(2),His(1),Pro(2)。
所得的肽表现为假分子离子,相应于2548.6。
实施例10
制备P183。
Ac-(D)-Phe-Pro-Arg-[(CO)-CH2]-CH2CH2CH2-(CO)-[NH-CH2-CH=CH-CH2-(CO)]-Asp-Phe-Glu-Pro-Ile-Pro-Leu-OH。
基本上依关于P79及其类似物的作了较小修改的那样合成并纯化该标题肽衍生物。例如,用叔丁氧基羰基-Leu苯基乙酰氨基甲基聚苯乙烯树脂(Applied Biosystems,0.64mmol/g)开始固相合成。至于Asp残基后续的t-BOC基的脱保护,用到含10%甲基乙基硫醚、50%TFA于CH2Cl2中的溶液。这样,由HPLC(在215nm处的UV吸收)测得最佳化标题肽的产率大于60%。
以类似于P183的方法制备P184和P185
P184
Ac-(D)-Phe-Pro-Arg-[(CO)CH2]CH2CH2CH2(CO)-[NH-CH2-CH=CH-CH2-(CO)]2-Asp-Phe-Glu-Pro-Ile-Pro-Leu-OH。
氨基酸分析指示:Asp(1.00),Glu(1.08),Ile(0.96),Leu(1.01),Phe(1.91),Pro(3.48)。
假分子离子:1553。
P185
Ac-(D)-Phe-Pro-Arg-[(CO)CH2]CH2CH2CH2-(CO)-[NH-CH2-CH=CH=CH2-(CO)]3-Asp-Phe-Glu-Pro-Ile-Pro-Leu-OH。
氨基酸分析指示:Asp(1.00),Glu(1.06),Ile(0.93),Leu(0.98),Phe(1.88),Pro(3.6)。
假分子离子:1647
肽衍生物(I)
(D)-Phe-Pro-Arg-(CH2)4(CO)-[NH(CH2)4CO]2-DFEPIPL以类似于P183、P184和P185的方法制备,只是用合成残基氨基戊酸代替[NH-CH2-CH=CH-CH2-(CO)]。
氨基酸分析指示:Asp(0.97),Glu(1.00),Ile(1.04),Leu(1.02),Phe(1.96),Pro(2.86)。
实施例11
凝血酶活性的酰胺分解测定
Tos-Gly-Pro-Arg-pNA的凝血酶催化水解是在Varian Cary 2000双光束分光光度计上于405nm处监控的,其中利用底物浓度为2.5,3.5,5和10μM,终体积为1ml。水解反应的进行条件:于25℃下、pH7.8、含0.1MNaCl和0.1%PEG 6000的0.1M Tris-HCl缓冲液中。是这样开始反应的:将溶于pH7.8的0.1M Tris-HCl缓冲剂中的底物加至酶(0.4或0.04nM)和溶于相同缓冲剂中的各浓度抑制剂的预温育的溶液。记录初始速率,并依如下方法测定Ki值:对于竞争性抑制用图解法,通过Dixon图的加权线性回归;或者对于双曲线抑制用Baici的方法(Baici,1981)。采用与上述荧光操作方式中相同的条件和仪器来进行荧光团分析,以比率(λex=383nm,λem=455nm)表示。用已知浓度的7-氨基-4-甲基香豆素溶液校正荧光强度。本发明的合成肽衍生物对人α-凝血酶的专一性也可通过比较它对人α-凝血酶和牛α-凝血酶的相对抑制活性来测定,而对胰蛋白酶的专一性则通过比较凝血酶活性的酰胺分解分析中测得的Ki值来测定。
这样,本发明的肽衍生物对凝血酶的抑制活性也可通过测定已混合重构的正常人血浆的凝血酶原时间(PT,外源途径)或活化部分促凝血酶原激酶时间(APTT,内在途径)来检定,其中利用Coag-A-Mate 2001仪(General Diagnostics Inc.,Morris Planes,New Jersey)或其它合适的光谱仪。
因此,若测定凝血酶原时间,将50μl重构含柠檬酸盐的正常人血浆(Sigma,St-Louis,MO.)与50μl促凝血酶原激酶溶液在37℃下混合于400μl小容器中。然后用200μlpH7.8的Tris-HCl缓冲液(含0.1M NaCl,0.1%PEG 6000)或不同浓度抑制剂的相同缓冲液处理此混合物。用100μl25mM CaCl2再钙化后记录凝血时间。不含抑制剂时的凝血时间为19-22sec。
利用同样方法来测定活化部分促凝血酶原激酶时间,但需用脑磷脂(Sigma,St-Louis,MO.)活化重构血浆达3分钟。
肽衍生物对凝血酶的抑制活性可通过它抑制凝血酶介导的血小板凝聚的能力来表现,它由Bio Data PAP-4集合度计测得的透光度的增大而指示。
血纤蛋白原凝血分析
对血纤蛋白原凝血形成的抑制可用分光光度法在37℃下的VarianDMS 90上于405nm处测定。将300μl含0.1M NaCl、0.1%PEG600的0.1%血纤蛋白原(Sigma)于0.1M pH7.8 Tris-HCl中的溶液与不同浓度抑制剂于相同缓冲剂中的溶液混合于聚苯乙烯小容器中,加入酶(人或牛α-凝血酶0.4nM)引发反应,其中总体积为1mL。记录不同抑制剂浓度下从混合至因形成凝血而引起光线偏转的时间,并用对数概率值分析法计算IC50值。本分析中抑制剂的浓度基于肽含量。
也可用其它不同的分析法来测定本发明的肽衍生物的抗凝血活性。所以,肽衍生物对凝血酶的抑制活性也可通过抑制活化部分促凝血酶原激酶的时间(APTT内在途径或凝血酶原时间PT外源途径)来分析。因此,可用Coag-A-Mate 2001仪(General Diagnostics Inc.,Morris Plabes,New Jersey)分析已混合正常人血浆的APTT而测定抗凝血活性。
此外,本发明的肽衍生物对于凝血酶催化水解三肽基对-硝基苯胺(tripeptidyl P-nitroanilide)底物甲苯磺酰-Gly-Pro-Arg-对-硝基苯胺(Chromozym TH,Boehringer-Mannheim,Indianapolis,In.)的抑制作用可这样测试,即用分光光度法在Cary 219双光束分光光度计上于420nm处测定。将凝血酶溶液与Tris-HCl,pH7.4,NaCl缓冲液混合而预备该反应。
当利用本发明的肽衍生物来进行这些分析时,表明它起对凝血酶的双功能抑制剂作用。确实,已证实肽链上引入由合适的间隔臂分开的两个关键性区可提供强凝血酶抑制剂。结果如表I所示。
显然,在单分子中引入两个由合适的连接臂分开的结合区可大为增强该化合物对凝血酶的亲和性。事实上,两个独立区单独的IC50剂量的组合会导致凝血时间准确加倍;而如果这两个区通过连接臂相连,则可获得更大的活性。因此,看来当它们与凝血酶接触时,本发明的双功能抑制剂发生双重协同结合。连接臂作为适当的间隔臂用于跨接辅助位点(区(ii))和催化位点(区(i))以及邻接催化位点的非极性结合位点。
氯化铁损伤引起的血栓形成模型
种:大鼠,雄性,Sprague-Dawley
重:375-450g
FeCl3引起的动脉损伤模型试验依下列文献报道的进行:Karz,K.D.,Main,R.W.,Sandusky,G.E.,Thrombosis research 60;269-280,1990和Schumacher,W.A.等人J.pharmacology and experimental therapeutics267;1237-1242,1993。
用尿烷麻醉雄性Sprague-Dawley(375-450g)(1500mg/kg IP)。使动物躺在维持在37℃的热垫上。通过正中颈切开接近颈动脉,小心地用钝器解剖法揭开脉管并将其与颈动脉鞘分离。用镊子夹起动脉以让出间隙在其下插入两根小聚乙烯管(PE-205)。在PE-205和动脉之间放置温度探头(Physitemp MT23/3)TM。在应用FeCl3之后监测脉管的温度60分钟,用热敏电阻(Cole-Palmer Model 08533-41)记录脉管的温度变化。在温度探头上方颈动脉上敷贴预先浸入35%FeCl3溶液的WhatmanTM1号滤纸的小圆片(直径为3mm)而引起损伤。试验部位覆盖铝箔以防FeCl3被光降解。
记录介于敷贴氯化铁时和脉管温度剧降(>2.4℃)时之间的时间,作为脉管的闭塞时间(TTO)。
在开始实验前,将血样抽入(1ml)盛有0.105M柠檬酸盐缓冲溶液的试管(来自眼窦),最后将动物放血。所有的样本保存于冰上,并于4℃时在2000Rpm下尽可能迅速地离心10min。在止血分析仪(haemostasisanalyzer)(STAGO ST4TM)上分析血浆的活化部分促凝血酶原激酶时间,重复分析两次。
从一组4只动物所得两条动脉于-80℃下贮存供进一步分析,其它的动脉在40X的光学显微镜(LeicaTM)下观察以量化闭塞(完全的、部分的、未闭塞)。
血小板凝聚分析
从捐献的血液分离出人血小板,并依Packham等人描述的方法制备洗涤两次的悬浮液。利用心脏穿刺术采集大鼠血液至ACD(6∶1,v/v)。按Ardlie等人描述的方法(Br.J.Haematol.1970,19:7,Proc.Soc.Exp.Bio.Med.1971,136:1021)制备洗过的血小板悬浮液。最终悬浮介质是修饰的Tyrode溶液(NaCl 138mM,KCl 2.9mM,HEPES 20mM,NaH2PO40.42mM,CaCl2 1M,MgCl2 2mM,0.1%葡萄糖,0.35%白蛋白,腺苷三磷酸双磷酸酯(1μl/ml)pH7.4)。调节血小板数至5000,000/ul。为了能测定致密颗粒内含物的释放程度,用14C-血清紧张素标记第一次洗液中的血小板(1uCi/10ml洗液),并测定释出的14C-血清紧张素。加入Impramine(5uM最终浓度)以防释出的血清紧张素被再摄取。应用血小板集合度计来分析(4 channel BioData PAP4,Hatboro,PA,USA)。加入刺激剂(人的0.1U/ml最终浓度)3min后测定凝聚百分数。在加刺激剂前,于37℃下将抑制剂预保温1min。IC50值是指抑制血小板凝聚或分泌至对照样的50%的浓度。
表I
化合物 | Ki(pM) | IC50dTT(nM) | IC50血浆凝血时间(nM)** | 加倍有效时间的剂量(mg/kg) | IC50凝血酶引起的血小板凝聚(nM) |
Hirulog | 230 | 1.8 | 12 | 2 | 8 |
P184 | 1500 | 10.5 | 52 | 1-2 | 6 |
P183 | 300000 | - | - | - | - |
P185 | 3200 | - | - | - | - |
(I) | 100 | 1.3 | 3.1 | 1 | 0.7 |
引起加倍有效时间所需肝素的剂量是200U/kg。
“-”表示未测到。表中的数据表示3-5次观测平均值。对照组(盐水处理的)大鼠的有效时间为19±1min(n=11)。
“*”在含血纤蛋白原的缓冲液中加倍凝血酶时间所要求的化合物浓度。
“**”抑制人血浆凝血时间达50%所要求的化合物浓度。
Claims (3)
1.肽衍生物(I):
(D)-Phe-Pro-Arg-(CH2)4(CO)-[NH(CH2)4CO]2-DFEPIPL及其药物上可接受的盐。
2.治疗血栓形成类疾病的组合物,它包括有效量的肽衍生物(I)(D)-Phe-Pro-Arg-(CH2)4(CO)-[NH(CH2)4CO]2-DFEPIPL及其药物上可接受的盐。
3.治疗或预防与血栓形成有关的血管疾病的方法,该方法包括对病人施药有效量的、权利要求2的组合物。
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1996
- 1996-03-18 KR KR1019970706576A patent/KR19980703173A/ko not_active Application Discontinuation
- 1996-03-18 JP JP8527932A patent/JPH11502203A/ja not_active Ceased
- 1996-03-18 WO PCT/CA1996/000164 patent/WO1996029347A1/en not_active Application Discontinuation
- 1996-03-18 AT AT96905636T patent/ATE208401T1/de not_active IP Right Cessation
- 1996-03-18 AU AU49349/96A patent/AU695920B2/en not_active Ceased
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- 1996-03-18 ES ES96905636T patent/ES2168461T3/es not_active Expired - Lifetime
- 1996-03-18 HU HU9800727A patent/HUP9800727A3/hu unknown
- 1996-03-18 IL IL11752696A patent/IL117526A/xx not_active IP Right Cessation
- 1996-03-18 CN CN96193457A patent/CN1182436A/zh active Pending
- 1996-03-18 EA EA199700239A patent/EA000088B1/ru not_active IP Right Cessation
- 1996-03-18 CA CA002215702A patent/CA2215702A1/en not_active Abandoned
- 1996-03-18 EP EP96905636A patent/EP0815139B1/en not_active Expired - Lifetime
- 1996-03-18 BR BR9607839A patent/BR9607839A/pt not_active Application Discontinuation
- 1996-03-20 ZA ZA962267A patent/ZA962267B/xx unknown
-
1997
- 1997-09-19 NO NO974342A patent/NO974342L/no not_active Application Discontinuation
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1998
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102590490A (zh) * | 2010-12-30 | 2012-07-18 | 西门子医疗诊断产品有限责任公司 | 测定凝固抑制剂的方法 |
CN102590490B (zh) * | 2010-12-30 | 2015-12-16 | 西门子医疗诊断产品有限责任公司 | 测定凝固抑制剂的方法 |
CN102603881A (zh) * | 2011-01-20 | 2012-07-25 | 中国中医科学院中药研究所 | 一种抗凝血活性寡肽及宽体金线蛭中抗凝血活性寡肽类化合物的提取纯化 |
Also Published As
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US6060451A (en) | 2000-05-09 |
AU695920B2 (en) | 1998-08-27 |
CA2215702A1 (en) | 1996-09-26 |
ES2168461T3 (es) | 2002-06-16 |
KR19980703173A (ko) | 1998-10-15 |
AU4934996A (en) | 1996-10-08 |
HK1005511A1 (en) | 1999-01-15 |
DE69616770T2 (de) | 2002-08-01 |
JPH11502203A (ja) | 1999-02-23 |
IL117526A0 (en) | 1996-07-23 |
ZA962267B (en) | 1996-09-27 |
BR9607839A (pt) | 1998-06-16 |
NO974342D0 (no) | 1997-09-19 |
EP0815139B1 (en) | 2001-11-07 |
NO974342L (no) | 1997-11-19 |
IL117526A (en) | 1999-12-31 |
WO1996029347A1 (en) | 1996-09-26 |
ATE208401T1 (de) | 2001-11-15 |
EP0815139A1 (en) | 1998-01-07 |
HUP9800727A3 (en) | 1998-09-28 |
HUP9800727A2 (hu) | 1998-07-28 |
DE69616770D1 (de) | 2001-12-13 |
EA000088B1 (ru) | 1998-06-25 |
EA199700239A1 (ru) | 1998-02-26 |
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