CN103917552B - 具有短半衰期和高活性的合成五糖 - Google Patents
具有短半衰期和高活性的合成五糖 Download PDFInfo
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- CN103917552B CN103917552B CN201280040007.5A CN201280040007A CN103917552B CN 103917552 B CN103917552 B CN 103917552B CN 201280040007 A CN201280040007 A CN 201280040007A CN 103917552 B CN103917552 B CN 103917552B
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
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- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide pyridine complex Chemical compound O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 1
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- FRACPXUHUTXLCX-BELIEFIBSA-N tert-butyl N-{1-[(1S)-1-{[(1R,2S)-1-(benzylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-2-cyclopropylethyl]-2-oxopyridin-3-yl}carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CN(C1=O)[C@@H](CC2CC2)C(=O)N[C@@H](C[C@@H]3CCNC3=O)[C@H](C(=O)NCC4=CC=CC=C4)O FRACPXUHUTXLCX-BELIEFIBSA-N 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
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- C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
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Abstract
本发明涉及式(I)的五糖化合物及其盐。本发明还涉及包含式(I)的合成五糖化合物及其盐的药物组合物。本发明进一步涉及这些化合物作为药物的用途、尤其是旨在用于:对血液凝固障碍进行治疗;对与实体器官移植相关的缺血再灌注损伤进行预防;或者降低心脏外科手术、体外膜氧合期间或循环辅助(如人工心脏)期间的体外血液循环中的血液凝固风险。
Description
技术领域
本发明涉及抗凝血剂(即,防止血液凝固的物质)。具体而言,本发明涉及抗血栓形成的寡糖。
背景技术
作为天然硫酸化多糖的肝素是属于糖胺聚糖家族的抗凝剂。在凝血级联系统中,肝素的抗凝血活性归因于肝素加速抑制多种蛋白酶(特别是凝血因子Xa和凝血酶)的能力。
肝素及肝素衍生的药物通过附着至抗凝血酶(AT)的特定结合域而抑制凝血因子Xa的活性。一旦肝素或肝素衍生的药物附着至抗凝血酶的特定结合域,就会诱发抗凝血酶(AT)的构型发生变化。AT中的这一构型变化导致凝血因子Xa受到抑制。研究表明,能够显著结合AT并抑制凝血因子Xa的最小结构单元是五糖。
此类诱发构型变化的产品的原型是磺达肝素(fondaparinux)。磺达肝素钠(ArixtraTM-GlaxoSmithKline)是首个新型抗血栓形成制剂。磺达肝素钠在大鼠体内的半衰期为约1小时,在人体内的半衰期为约17小时。将磺达肝素钠以每日一次向需要抗凝血治疗的患者给予。磺达肝素钠为模拟肝素的抗凝血酶结合位点的化学合成五糖。磺达肝素钠是凝血因子Xa的选择性抑制剂,因此是凝血酶生成的抑制剂。
磺达肝素的合成时间长且复杂。因此,为了简化该化学过程并保留同样的活性和药代动力学性质,设计出了在US 5,543,403或WO 99/36428中所述的新系列的五糖。
US 5,543,403公开了合成五糖,其中,用烷氧基基团和O-硫酸根基团取代N-硫酸根基团、N-乙酸根基团和羟基基团。WO 99/36428公开了类似的合成五糖,将其中的L-艾杜糖醛单元固定为2S0构型,并且其中的D-葡萄糖醛单元E最终在5位上具有乙基基团。
然而,尽管这些五糖单元上存在的烷基基团显著简化了五糖的制备模式,但是它却还增长了半衰期,使得临床使用成为问题。
EP 2074131也尝试提供合成五糖。在这一申请中认为,五糖穿过肠道屏障的能力对于作为抗凝血药的应用而言很重要。
然而,看起来EP 2074131公开的许多化合物也具有过长的半衰期。
抗凝血五糖的半衰期(药物的血浆浓度减半所需的时间)是非常重要的药代动力学参数。事实上,例如在发生出血的情况下,有时候需要尽可能快地关闭抗凝血作用,从而可停止出血。
抗凝血剂在人体内的合适的半衰期为约5小时至约20小时,相应地,在大鼠体内的半衰期为0.5小时至约3小时。
在五糖上引入生物素部分使得能够通过注射亲和素(强力结合至生物素的蛋白质)而快速抑制抗凝血活性。
生物素基团(IUPAC名称为:5-[(3aS,4S,6aR)-2-氧代六氢化-1H-噻吩并[3,4-d]咪唑-4-基]戊酸;也被称为维生素B7)表示如下基团:
由EP 1322673得知此类生物素化的五糖。亲和素可阻碍化合物对其靶标的作用并加速所述化合物的清除。EP 1322673的生物素化化合物(biotinylated compounds)的抗凝血因子Xa活性与相应的未生物素化化合物的活性相当。
因此,通过给予亲和素可使生物素化化合物的抗凝血活性失效,最终使得能够使用半衰期长的抗凝血五糖。
然而,生物素酶存在于血浆中,切开生物素羧酸端的酰胺键,能够与生物素化化合物反应使所述化合物去生物素化。作为结果,去生物素化的化合物不会再被亲和素失效,同时保持所述化合物的抗凝血活性直至其在生理上被排出。由于抗凝血治疗可进行较长时间,并且去生物素化的化合物可在血浆中积累,上述状况成为实际的问题。因此,仍旧高度期望采用半衰期短的生物素化化合物,从而使得所述化合物能够在紧急情况下迅速失效,并能够使所述化合物在被生物素酶去生物素化后避免在血浆中积累。
本发明人出乎预料地发现,可通过改变D单元的取代基来调控烷基化/O-硫酸化五糖的半衰期。
在2位上引入氨基官能团可缩短半衰期。
该2位氨基官能团的生物素化可增长半衰期。
在D-单元引入一个游离羟基官能团缩短了半衰期。
将这些不同的观察结果进行组合,使得本发明人能够识别出具有短半衰期的、作为凝血因子Xa的强效抑制剂的生物素化五糖。
因此,本发明的一个目的是提供易于合成且具有短半衰期的五糖、尤其是生物素化五糖。
本发明的另一目的是提供具有高的抗凝血因子Xa活性(即,IC50的值低)的生物素化五糖。
因此,使用本发明所述的化合物、尤其是生物素化化合物,克服了现有技术的全部缺陷。
发明内容
本发明涉及式(I)的合成五糖化合物及其盐:
其中:
R1为C1-C3烷基基团;
R2为C1-C3烷氧基基团;R7为氢原子,或者R2和R7形成-O-CH2-或-O-CH2-CH2-桥联基团,其中,-O-连接至带有R2基团的碳原子,且-CH2-连接至带有R7基团的碳原子;
R3为氢原子或乙基基团;
R4为-OH、-NH2或-NH-LC-生物素;其中,LC表示接头,所述LC优选具有式-(C=O)-(CH2)n-NH-,n为1-10,更优选具有式-(C=O)-(CH2)4-NH;
当R5和R6基团不同时,R5和R6选自氢原子、甲基基团、乙基基团、丙基基团、丁基基团或戊基基团;
当R5和R6基团相同时,R5和R6选自氢原子、甲基基团、乙基基团、丙基基团和戊基基团;
但是,R1不同于R5或R6中的至少一个。
优选地,本发明所述的合成五糖化合物具有下述的式(II):
其中:
R1、R2、R3、R4、R5和R6如上所定义。
R4可为-NH2或-NH-LC-生物素,LC如上所定义。
在一个实施方式中,R5和R6表示相同的基团。
在另一实施方式中,R5或R6中的一个为氢原子,另一个为C1-C5烷基基团。
在上述所有实施方式的一个变型中,R2和R7形成-O-CH2-桥联基团,其中,-O-连接至带有R2基团的碳原子,-CH2-连接至带有R7基团的碳原子,且R3为乙基基团。
在上述所有实施方式的另一变型中,R2为C1-C3烷氧基基团,R3和R7为氢原子。
本发明还涉及药物组合物,所述药物组合物包含药学上可接受的稀释剂或载体以及上述的合成五糖化合物及其盐。
本发明进一步涉及合成五糖化合物及其盐作为药物的用途,所述药物例如旨在预防和治疗血液凝固障碍(blood clotting disorder)。
血液凝固障碍尤其是静脉血栓形成或动脉血栓形成中的一种,包括深静脉血栓形成、肺栓塞、急性冠状动脉综合征、心肌梗塞和中风。血液凝固障碍也可由心房颤动引起。
本发明还涉及合成五糖化合物及其盐作为用于对与实体器官移植相关的缺血再灌注损伤进行预防的药物的用途。
本发明进一步涉及对心脏外科手术期间、体外膜氧合期间、或循环辅助(如人工心脏)期间的体外血液循环中的血液凝固进行预防或者降低所述血液凝固风险的方法,其中,所述方法包括给予上文所述的合成五糖化合物及其盐。
本发明还涉及试剂盒,所述试剂盒包含:上述的合成五糖化合物及其盐、或上述的药物组合物;以及亲和素。
定义
本发明的化合物还可以药学上可接受的盐的形式存在。当用在药物中时,本发明的化合物的盐是指无毒的“药学上可接受的盐”。FDA批准的药学上可接受的盐的形式包括药学上可接受的酸式盐/阴离子盐或碱式盐/阳离子盐(Gould,P.L.,InternationalJ.Pharm.,1984,33,201-271;Berge,S.M.等,J.Pharm.Sci.,1977,66(1),1-19)。
当然,本发明的酸性化合物或碱性化合物的药学上可接受的盐可通过传统工序制备,例如通过将游离碱或游离酸与至少化学计量的期望成盐的酸或碱进行反应。
本发明酸性化合物的药学上可接受的盐包括:与无机阳离子形成的盐,如钠盐、钾盐、钙盐、镁盐、锌盐、铵盐;以及与有机碱形成的盐。合适的有机碱包括:N-甲基-D-葡糖胺、精氨酸、苄星青霉素、二乙醇胺、乙醇胺、普鲁卡因和氨丁三醇。
本发明碱性化合物的药学上可接受的盐包括由有机酸或无机酸衍生的盐。合适的阴离子包括:乙酸根、己二酸根、苯磺酸根、溴化物、樟脑磺酸根、氯化物、柠檬酸根、乙二磺酸根、丙酸酯十二烷基硫酸根、富马酸根、葡庚糖酸根、葡糖酸根、葡糖醛酸根、马尿酸根、海克酸根、氢溴化物(hydrobromide)、氢氯化物(hydrochloride)、碘化物、羟乙基磺酸根、乳酸根、乳糖醛酸根(lactiobionate)、马来酸根、甲磺酸根、甲基溴化物、甲基硫酸根、萘磺酸根、硝酸根、油酸根、双羟萘酸根、磷酸根、聚半乳糖醛酸根、硬脂酸根、琥珀酸根、硫酸根、磺基水杨酸根、单宁酸根、酒石酸根、对苯二甲酸根、甲苯磺酸根和三乙基碘化物。特别优选硫酸盐。
在本发明的治疗方法中,词语“给予”应涵盖用明确公开的化合物对所述各种疾病进行的治疗。
预期的是,本发明的化合物可通过口服途径或胃肠道外途径给予,所述给予包括:静脉内给予、肌内给予、腹膜内给予、皮下给予、经皮给予、直肠给予和局部给予、以及吸入给予。
对于口服给予,本发明的化合物通常以片剂、胶囊剂、水溶液或混悬液的形式提供。
口服用片剂可包括与药学上可接受的赋形剂混合的活性成分,所述赋形剂例如:惰性稀释剂、崩解剂、粘合剂、润滑剂、甜味剂、矫味剂、着色剂和防腐剂。合适的惰性稀释剂包括:碳酸钠和碳酸钙、磷酸钠和磷酸钙以及乳糖。合适的崩解剂为玉米淀粉和海藻酸。粘合剂可包括淀粉和明胶。如果存在的话,润滑剂通常为硬脂酸镁、硬脂酸或滑石粉。如果期望的话,可用材料(如,单硬脂酸甘油酯或是二硬脂酸甘油酯)对片剂进行包衣处理,以延缓在胃肠道中的吸收。
口服用胶囊剂包括硬明胶胶囊剂和软明胶胶囊剂,在硬明胶胶囊剂中,活性成分与固态稀释剂混合;而在软明胶胶囊剂中,活性成分与水或油混合,所述油例如花生油、液体石蜡或橄榄油。
对于胃肠道外使用,其包括肌内使用、腹膜内使用、皮下使用和静脉内使用,本发明化合物通常以无菌水溶液或混悬液提供,并被缓冲至合适的pH和等渗性。合适的水性辅料包括林格氏溶液(Ringer’s solution)和等渗氯化钠。本发明所述的水性混悬液可包括:混悬剂,如纤维素衍生物、海藻酸钠、聚乙烯吡咯烷酮、黄芪胶;湿润剂,如卵磷脂。适用于水性混悬液的防腐剂包括:羟基苯甲酸乙酯或羟基苯甲酸丙酯。
给予方式
本领域公知的是,本发明的化合物可被直接递送或以包含赋形剂的药物组合物(参见上文)递送。目前的治疗方法包括向受试者给予治疗上有效量的本发明化合物。
本文中使用的术语“治疗上有效量”或“治疗上有效剂量”是指为治疗、缓解、预防目标疾病症状、显示出可检测的治疗效果或预防效果、延长患者的生存时间所需要的本发明所述化合物的量。此类分子的毒性和疗效可通过在细胞培养物或实验动物中进行的标准药学程序来确定,所述标准药学程序例如测定LD50(使群体中的50%致死的剂量)和ED50(对群体中的50%在治疗上有效的剂量)。毒性相对于疗效的剂量比是治疗指数,可以LD50/ED50比进行表示。优选显示出高治疗指数的药剂。
治疗上有效量或治疗上有效剂量是引发组织、系统、动物或人体的生物学响应或医学响应的化合物或药物组合物的量,所述生物学响应或医学响应由研究人员、兽医、医生、或其他临床医师观察到。例如抗凝血活性和对血液凝固障碍的治疗。所述血液凝固障碍例如:深静脉血栓栓塞(包括深静脉血栓形成)、肺栓塞、术后深静脉血栓形成、冠状动脉综合征、心肌梗塞、中风等。
在考虑了患者病症详情的情况下,应根据本领域已知的方法对确切的剂型、给予途径、剂量和给药间隔进行选择。
任何特定患者所需的具体剂量水平都取决于许多因素,所述因素包括:所治疗病症的严重程度、给予途径、患者的总体健康情况(即,年龄、体重和饮食)、患者性别、给予时间和频率、处方医师的判断以及对治疗的耐受/响应。然而,通常来说日剂量(无论以单剂量给予或以分剂量给予)为每日0.01-500毫克、更通常为每日0.1-50毫克、最通常为每日1-10毫克。或者,剂量可按单位体重进行给予,在这种情况下,剂量通常为0.001-3毫克/千克、尤其是0.01-0.2毫克/千克、以及0.02-0.1毫克/千克。
化学定义
出于简洁的目的,本文中常用于指代一价基团(如“烷基”)的术语也被用来指代二价桥联基团、三价桥联基团或四价桥联基团,所述二价桥联基团、三价桥联基团或四价桥联基团由相应的一价基团通过失去一个或多个氢原子形成。由上下文可明白该术语是指一价基团还是指多价基团。根据正常的化合价规则,当由环状部分形成多价桥联基团时,连接键可处于任何合适的环原子上。
本发明中使用的术语“烷基”是指直链或支链的饱和一价烃基,所述烃基具有所示出的碳原子数。例如,术语“C1~C5烷基”包括C1烷基、C2烷基、C3烷基、C4烷基和C5烷基。通过非限制性实例,合适的烷基基团包括:甲基(-Me)、乙基(-Et)、丙基(-Pr)、异丙基、丁基(-Bu)、异丁基、叔丁基、戊基(-Pent)。
烷氧基是指“烷基-O-”基团,其中,烷基如上所定义。通过非限制性实例,合适的烷氧基基团包括:甲氧基、乙氧基、丙氧基和异丙氧基。
能够理解的是,本发明包括彼此不同的分离的非对映异构体及其混合物。
反离子(抵消了本发明化合物的带电形式)是药学上可接受的反离子,如氢、或更优选碱金属离子或碱土金属离子(包括钠、钙、镁和钾)。
基于前文的定义和常见的命名约定,本领域技术人员将能容易地理解其它“化合物”基团的定义。
将会明白的是,上述与本发明任一方面相关的任何可选特征也可被应用至本发明的任意其它方面。
在示例性化合物的描述中,“IC50”表示抗凝血因子Xa的活性。
应用
可将上文所述的化合物用作药物。更具体而言,可将所述化合物用作旨在用于对血液凝固障碍进行治疗的药物。
血液凝固障碍尤其是静脉血栓形成或动脉血栓形成中的一种,包括深静脉血栓形成、肺栓塞、急性冠状动脉综合征、心肌梗塞和中风。血液凝固障碍也可由心房颤动引起。
化合物还可在ECC(体外血液循环)期间使用。因此,重要的是抗凝血作用能够得到抑制或阻抑。
还可将化合物用作对与实体器官移植相关的缺血(由于血管堵塞导致供血不足)再灌注损伤进行预防的药物。
通过下述的实施例对本发明做出了进一步的阐述。
所使用的缩写
-DMF:N,N-二甲基甲酰胺;
-DCM:二氯甲烷;
-EtOAc:乙酸乙酯;
-THF:四氢呋喃;
-MTBE:甲基-叔丁基醚;
-TFA:三氟乙酸;
-TfOH:三氟甲磺酸;
-Ac2O:乙酸酐;
-Bn:苄基;
-Ph:苯基;
-Bz:苯甲酰基;
-Me:甲基,Et:乙基,Pr:丙基,Bu:正丁基,Pent:戊基,Hex:己基;以及
-Ac:乙酸盐/酯。
第1部分:单糖D单元的合成
方案1
a)Rb-X、NaH、DMF;b)NaN3、NH4Cl、H2O/(CH3)2CH-OH;c)Ra-X、NaH、DMF;d)Ac2O、TFA;e)HSPhCl、BF3·OEt2、甲苯;f)1N NaOH、THF/CH3OH;g)p-CH3OBzCl、吡啶。
化合物3的制备
化合物2(1,6:2,3-二脱水-4-ORb-[β]-D-吡喃甘露糖)以与Brill和Tirefort在Tetrahedron Lett.,(1998),39,pp.787-790中所述的类似方式通过Cerny Epoxide 1合成。将化合物2(17.5mmol)溶于130毫升N,N-二甲基甲酰胺/水混合物中[4/1(v/v)],然后向其中加入叠氮化钠(22.8克,350mmol)。将反应介质在100℃下加热6小时。在经硅藻土(Celite)过滤后,将滤液用乙酸乙酯稀释,再用水进行洗涤。将有机相用硫酸钠进行干燥、过滤并在真空下浓缩。将剩余物在乙酸乙酯/环己烷(20毫升/7毫升)混合物中重结晶,从而得到处于晶体形式的化合物3。
化合物4的制备
在氩气气氛下,向处于无水N,N-二甲基甲酰胺(80毫升)中的化合物3(11mmol)和Ra-X(33mmol)的经冷却(0℃)的混合物中,分批加入氢化钠(1.3克,33mmol)。将混合物在室温下搅拌20小时。用甲醇将过量的氢化钠去除。将反应混合物在真空下浓缩,并将剩余物溶于EtOAc中。将有机相用水洗涤、用硫酸钠干燥、过滤并在真空下浓缩。将粗产物通过硅胶柱色谱(正己烷/EtOAc)进行纯化,从而得到处于白色固体形式的化合物4。
化合物5的制备:乙酰解(acetolysis)的通用方法
在0℃下于干燥的圆底烧瓶中,将化合物4(11mmol)溶于乙酸酐(73毫升,770mmol,70eq.)和三氟乙酸(12.3毫升,165mmol,15eq.)的混合物中。将反应混合物液在室温下搅拌过夜,并在减压下移除溶剂,随后与甲苯共蒸馏。将剩余物通过硅胶柱快速色谱进行纯化来产生期望的化合物5;或者在用饱和的NaHCO3水溶液洗涤后,直接用于下一步骤中而无需任何进一步的纯化。
化合物6的制备:异头对氯苯硫酚基团(anomeric p-chlorothiophenol group)的引入
在0℃下,向处于甲苯(55毫升)中的化合物5(11mmol)和4-对氯苯硫酚(4.8克,33mmol)搅拌后的混悬液中加入BF3·OEt2(4.19毫升,33mmol),将混合物在室温下搅拌7小时。向其中加入NaHCO3饱和溶液至pH=7,将反应混合物在-20℃下冷却过夜。将有机层分离,用EtOAc稀释,并用水进行洗涤。将有机层用MgSO4进行干燥,在真空下移除溶剂,并将剩余物通过柱色谱(正己烷/乙酸乙酯)进行纯化,从而得到化合物6。
下文对两个化合物6f(Ra=OEt,Rb=OBn)和6h(Ra=OEt,Rb=OEt)的NMR数据进行了描述:
化合物6f
1H NMR(400MHz,CDCl3,ppm)δ7.77-7.41(m,10H arom.),5.73(d,1H,J=5.46Hz,H-1α),5.14-5.02(m,2H,CH2-Bn),4.56(d,1H,J=9.5Hz,H-1β),4.48-4.45(m,2H,H-6a/b),4.08-3.82(m,2H,R-CH2-CH3),4.06-3.94(m,2H,H-2,H-3),3.55-3.51(m,2H,H-4,H-5),2.25(s,3H,CH3-Ac),1.42(t,3H,J=7.1Hz,R-CH2-CH3)。
化合物6h
1H NMR(400MHz,CDCl3,ppm)δ7.45-7.40(m,2H arom.),7.30-7.27(m,2H arom.),5.48(d,1H,J=5.2Hz,H-1),4.30-4.26(m,2H,H-6a/b),3.81(dd,1H,J=5.2Hz,J=10.3Hz,H-2),3.72,3.57(2s,6H,2×OMe),3.50(t,1H,J=10.3Hz,H-3),2.08(s,3H,CH3-Ac)。
化合物7的制备:6-OAc基团的皂化作用
在搅拌下,于0℃向处于450毫升THF/甲醇(2/1)中的化合物6(120.9mmol)的溶液中,滴加1N氢氧化钠(120毫升)。将反应混合物在室温下搅拌3小时,然后在真空下浓缩。将剩余物溶于水中并用EtOAc进行萃取。将有机层用MgSO4进行干燥,并将溶剂蒸发,从而得到化合物7。将化合物7直接用于下一步骤中,而无需任何进一步的纯化。
化合物8的制备:6-(对甲氧基苯甲酰基基团)的引入
在0℃下,向处于吡啶(10毫升)中的化合物7(3.1mmol)搅拌后的溶液中滴加对甲氧基苯甲酰氯(0.635克,3.72mmol)。将反应混合物在室温下搅拌3小时。将反应混合物用DCM(20毫升)进行稀释、用1N HCl(10毫升)进行洗涤、用MgSO4进行干燥并在真空下进行浓缩,从而产生粗产物8。通过柱色谱(正己烷/乙酸乙酯)进行纯化,以良好的收率得到白色固体的纯化合物8。
化合物 | 8a | 8b | 8c | 8d | 8e | 8f |
ORa | OBn | OBn | OBn | OBn | OMe | OEt |
ORb | OBn | OMe | OEt | OPr | OBn | OBn |
化合物 | 8g | 8h | 8i | 8j | 8k | 8l |
ORa | OMe | OEt | OPr | OBu | OPent | OPr |
ORb | OMe | OEt | OPr | OBu | OPent | OBn |
制备出了12个化合物8a-8l,并在下文中描述了一些实例的NMR数据:
化合物8a
1H NMR(400MHz,CDCl3,ppm)δ7.83-7.77(m,2H arom.),7.36-7.16(m,12H arom.),7.09-7.03(m,2H arom.),6.86-6.80(m,2H arom.),5.51(d,1H,J=5.3Hz,H-1α),4.92-4.74(m,4H,2×CH2-Bn),4.31(d,1H,J=9.8Hz,H-1β),3.93-3.85(m,1H,H-2),3.84-3.70(m,3H,H-3,H-4,H-5),3.79(s,3H,OMe)。
化合物8f
1H NMR(400MHz,CDCl3,ppm)δ8.13-8.08(m,2H arom.),7.69-7.51(m,7H arom.),7.38-7.33(m,2H arom.),7.15-7.09(m,2H arom.),5.79(d,1H,J=5.46Hz,0.79H-1α),5.15-5.05(m,2H,CH2-Bn),4.79-4.65(m,2H,H-6a/b),4.58(d,1H,J=9.5Hz,0.21H-1β),4.12-3.87(m,2H,R-CH2-CH3),4.11-4.01(m,3H,H-2,H-3,H-4),4.08(s,3H,OMe),3.64-3.58(m,1H,H-5),1.45(t,3H,J=7.1Hz,R-CH2-CH3)。
化合物8g
1H NMR(400MHz,CDCl3,ppm)δ8.15-8.06(m,2H arom.),7.70-7.50(m,7H arom.),7.38-7.32(m,2H arom.),7.15-7.09(m,2H arom.),5.15-5.05(m,2H,CH2-Bn),5.80(d,1H,J=5.46Hz,H-1α),4.56(m,1H,H-1β),4.13-3.99(m,2H,H-2,H-3),3.74-3.70(m,3H,H-5,H-4),4.78-4.57(m,2H,H-6a/b),4.03-3.71(m,2H,R-CH2-CH2-CH3),1.92-1.76(m,2H,R-CH2-CH2-CH3),1.12(t,3H,J=7.1Hz,R-CH2-CH2-CH3)。
化合物8h
1H NMR(400MHz,CDCl3,ppm)δ7.94-7.90(m,2H arom.),7.41-7.38(m,2H arom.),7.17-7.14(m,2H arom.),6.96-6.91(m,2H arom.),5.54(d,1H,J=5.2Hz,H-1),4.56(m,2H,H-6a/b),4.44(m,2H,H-4,H-5),3.84(dd,1H,J=5.2Hz,J=10.3Hz,H-2),3.79,3.75,3.61(3s,9H,3×OMe),3.50(t,1H,J=10.3Hz,H-3)。
第2部分:五糖13和五糖15的合成
方案2
a)TfOH、溴烯杀(bromodan)、CH2Cl2/MTBE;b)2N KOH、CH3OH/THF;c)Py·SO3、吡啶;d)H2、Pd/C、t-BuOH/H2O;e)iPr2NEt、DMF。
化合物10的制备:苷化步骤
将WO 2008/041131中描述的四糖9(9.59mmol)和上述制备的单糖8(19.2mmol,2equiv.)溶于1/3(v/v)的二氯甲烷/甲基叔丁基醚混合物中(267毫升)。在加入4A分子筛粉末(1重量当量/四糖9)后,将混悬液在室温下搅拌2小时。将混合物于-50℃下冷却,依次加入溴烯杀(28.77mmol,3当量)和三氟甲磺酸(13.43mmol,1.4当量),将反应混合物在-50℃下搅拌2小时。加入另外量的单糖8(1equiv.),将反应混合物在-50℃下搅拌1小时,并在-20℃下储存过夜。然后,通过加入三乙胺,将反应混合物中和至pH 7-8,在真空下浓缩,将剩余物通过硅胶柱色谱(甲苯/丙酮:90/10至80/20)进行纯化,从而以60%-84%的收率得到五糖10。
化合物11的制备:脱乙酰作用和皂化作用
在0℃下,向处于2/1(v/v)的四氢呋喃/甲醇(15毫升)中的化合物10(0.14mmol)的溶液中加入2M氢氧化钾水溶液(6.2毫升),将混合物在室温下搅拌过夜。然后,用酸性树脂Dowex 50x8-100将反应混合物中和至pH 4。通过过滤将树脂移除,将滤液在真空下浓缩至干,从而以定量收率得到化合物11。
化合物12的制备:硫酸化
向处于无水吡啶(3毫升)中的化合物11(0.14mmol)的溶液中加入三氧化硫-吡啶复合物(4.2mmol,30equiv.)。将混合物在80℃下避光加热16小时。在冷却至0℃后,加入甲醇(2毫升),然后将溶液搅拌1小时。然后,加入5%的NaHCO3水溶液至pH 7-8,将混合物在室温下搅拌过夜,并浓缩至干。将剩余物溶于水中,并在Sephadex G-25柱上用水进行洗脱来脱盐,从而以70%-80%的收率得到化合物12。
化合物13的制备:氢解作用
在氢气气压下,在10%钯炭(1重量当量)存在的情况下,对处于叔丁醇(8毫升)/水(8毫升)混合物中的化合物12(0.16mmol)的溶液处理16小时。在过滤(Millipore(R)LSWP 5[mu]m滤器)后,将溶液浓缩至干,从而以定量收率产生化合物13。
化合物13a(OR5=OH,OR6=OH):[α]D=+52.4(c=0.82,H2O);质谱(ESI法,负离子模式);m/z 480.6[M-3H]3-;1H NMR(400MHz,D2O,ppm)δ5.64(d,1H,J=3.7Hz,H-1GlcIII),5.43(s,1H,H-1IdoUAII),5.21-5.19(m,2H,H-1GlcI,H-1GlcV),5.07(d,1H,J=7.8Hz,H-1GlcUAIV),3.75-3.57(5s,15H,5×OMe),2.26/1.87(m,2H,R-CH2-CH3),1.06(t,3H,J=6.9Hz,R-CH2-CH3)。
化合物13b(OR5=OH,OR6=OMe):质谱(ESI法,负离子模式);922.8055[M+3DBA-5H]2-,857.7206[M+2DBA-4H]2-,793.1449[M+DBA-3H]2-,528.4258[M+DBA-4H]3-,485.3701[M-3H]3-。
化合物13c(OR5=OH,OR6=OEt):质谱(ESI法,负离子模式);m/z929.8[M+3DBA-5H]2-,864.7[M+2DBA-4H]2-,760.2[M-2H]2-,490.0[M-3H]3-;1H NMR(400MHz,D2O,ppm)δ5.49(d,1H,J=3.7Hz,H-1GlcIII),5.28(d,1H,J=1.4Hz,H-1ManUAII),5.21(d,1H,J=3.4Hz,H-1GlcV),5.07(d,1H,J=3.7Hz,H-1GlcI),4.84(d,1H,J=7.4Hz,H-1GlcIV),3.93-3.74(m,2H,R-CH2-CH3),3.60,3.53,3.45,3.44,3.42(5s,15H,5×OMe),2.07/1.71(m,2H,-CH2-CH3),1.19(t,3H,J=6.9Hz,R-CH2-CH3),0.90(t,3H,J=7.2Hz,-CH2-CH3)。
化合物13d(OR5=OH,OR6=OPr):质谱(ESI法,负离子模式);m/z872.1984[M+2DBA-4H]2-,807.6226[M+1DBA-3H]2-,767.6424[M-2H]2-。
化合物13e(OR5=OMe,OR6=OH):质谱(ESI法,负离子模式);m/z857.66[M+2DBA-4H]2-,793.09[M+1DBA-3H]2-,486.10[M-3H]3-。
化合物13f(OR5=OEt,OR6=OH):质谱(ESI法,负离子模式);m/z929.3[M+3DBA-5H]2-,864.7[M+2DBA-4H]2-,800.1[M+DBA-3H]2-,760.2[M-2H]2-,490.0[M-3H]3-。
化合物13g(OR5=OPr,OR6=OH):质谱(ESI法,负离子模式);m/z871.6919[M+2DBA-4H]2-,807.1179[M+DBA-3H]2-,767.1397[M-2H]2-。
化合物13h(OR5=OMe,OR6=OMe):[α]D=+71.6(c=1,H2O);质谱(ESI法,负离子模式);m/z 864.6[M+2DBA-4H]2-,800.0[M+DBA-3H]2-,533.0[M+DBA-4H]3-,590.0[M-3H]3-。
化合物13i(OR5=OEt,OR6=OEt):[α]D=+79.3(c=1,H2O);质谱(ESI法,负离子模式);m/z 943.3[M+3DBA-5H]2-,878.7[M+2DBA-4H]2-,814.2[M+DBA+3H]2-。
化合物13j(OR5=OPr,OR6=OPr):[α]D=+64.5(c=1,H2O);质谱(ESI法,负离子模式);m/z 508.7[M-3H]3-。
化合物13k(OR5=OBu,OR6=OBu):质谱(ESI法,负离子模式);m/z906.6991[M+2DBA-4H]2-,561.0756[M+DBA-4H]3-,518.0267[M-3H]3-。
化合物13l(OR5=OPent,OR6=OPent):[α]D=+66.9(c=1,H2O);质谱(ESI法,负离子模式);m/z 985.3[M+3DBA-5H]2-,920.8[M+2DBA-4H]2-,570.4[M+DBA-4H]3-,527.4[M-3H]3-。
化合物15的制备:LC-生物素化
向处于无水DMF(8mL)中的化合物13(0.086mmol)的溶液中加入琥珀酰亚胺基6-(生物素酰胺基)己酸酯14(58.6mg,0.129mmol)和二异丙基乙胺(22.5μL,0.129mmol),将混合物在室温下搅拌20小时。然后加入5%的NaHCO3水溶液(3.6毫升),将混合物在室温下搅拌过夜,并浓缩至干。将剩余物溶于水中,并在Sephadex G-25柱上用水进行洗脱来脱盐,从而以68%-87%的收率产生化合物15。
化合物15a(OR5=OH,OR6=OH):[α]D=+64.8(c=1,H2O);质谱(ESI法,负离子模式);m/z 1149.9[M+4DBA-6H]2-,1084.8[M+3DBA-5H]2-,1020.3[M+2DBA-4H]2-,679.8[M+2DBA-5H]3-,636.8[M+DBA-4H]3-;1H NMR(400MHz,D2O,ppm)δ5.66(d,1H,J=3.5Hz,H-1GlcIII),5.42(s,1H,H-1ManUAII),5.32(d,1H,J=3.6Hz,H-1GlcV),5.22(d,1H,J=3.8Hz,H-1GlcI),5.17(d,1H,J=7.4Hz,H-1GlcIV),4.54(m,1H,H-6生物素),4.42(m,1H,H-2生物素),3.75-3.54(5s,15H,5×OMe),3.33(m,1H,H-1生物素),2.99(dd,1H,J=5.0Hz,J=13.2Hz,H-7a生物素),2.76(d,1H,J=13.2Hz,H-7b生物素),2.28/1.93(m,2H,R-CH2-CH3),1.19(t,3H,J=6.9Hz,R-CH2-CH3)。
化合物15b(OR5=OH,OR6=OMe):[α]D=+59.2(c=1,H2O);质谱(ESI法,负离子模式);m/z 1156.9768[M+4DBA-6H]2-,1092.9164[M+3DBA-5H]2-,1027.3103[M+2DBA-4H]2-。
化合物15c(OR5=OH,OR6=OEt):质谱(ESI法,负离子模式);m/z1163.9[M+4DBA-6H]2-,1098.9[M+3DBA-5H]2-,1034.3[M+2DBA-4H]2-,969.7[M+DBA-3H]2-,689.2[M+2DBA-5H]3-,646.1[M+DBA-4H]3-;1H NMR(400MHz,D2O,ppm)δ5.49(d,1H,J=3.5Hz,H-1GlcIII),5.26(s,1H,H-1ManUAII),5.16(d,1H,J=3.6Hz,H-1GlcV),5.06(d,1H,J=3.8Hz,H-1GlcI),5.01(d,1H,J=7.4Hz,H-1GlcIV),4.54(m,1H,H-6生物素),4.42(m,1H,H-2生物素),3.98-3.73(m,2H,R-CH2-CH3),3.59,3.47,3.44,3.43,3.38(5s,15H,5×OMe),3.33(m,1H,H-1生物素),2.99(dd,1H,J=5.0Hz,J=13.2Hz,H-7a生物素),2.76(d,1H,J=13.2Hz,H-7b生物素),1.19(t,3H,J=6.9Hz,R-CH2-CH3)。
化合物15e(OR5=OMe,OR6=OH):质谱(ESI法,负离子模式);m/z1156.9[M+4DBA-6H]2-,1091.9[M+3DBA-5H]2-,1027.3[M+2DBA-4H]2-,962.7[M+DBA-3H]2-;1H NMR(400MHz,D2O,ppm)δ7.9(d,1H,J=9.1Hz,NH GlcV),5.50(d,1H,J=3.5Hz,H-1GlcIII),5.27(s,1H,H-1ManUAII),5.12(d,1H,J=3.6Hz,H-1GlcV),5.06(d,1H,J=3.8Hz,H-1GlcI),5.01(d,1H,J=7.4Hz,H-1GlcIV),4.59(m,1H,H-6生物素),4.41(m,1H,H-2生物素),3.59,3.55,3.47,3.44,3.43,3.37(6s,18H,6×OMe),3.33(m,1H,H-1生物素),2.99(dd,1H,J=5.0Hz,J=13.2Hz,H-7a生物素),2.76(d,1H,J=13.2Hz,H-7b生物素)。
化合物15f(OR5=OEt,OR6=OH):质谱(ESI法,负离子模式);m/z1163.9[M+4DBA-6H]2-,1098.9[M+3DBA-5H]2-,1034.3[M+2DBA-4H]2-,969.7[M+DBA-3H]2-,745.2[M+3DBA-6H]3-,646.1[M+DBA-4H]3-。
化合物15h(OR5=OMe,OR6=OMe):质谱(ESI法,负离子模式);m/z1164.5[M+4DBA-6H]2-。
化合物15i(OR5=OEt,OR6=OEt):质谱(ESI法,负离子模式);m/z1178.5[M+4DBA-6H]2-,1048.8[M+2DBA-4H]2-,984.2[M+DBA-3H]2-,698.9[M+2DBA-5H]3-,655.8[M+DBA-4H]3-。
化合物15j(OR5=OPr,OR6=OPr):[α]D=+47.4(c=1.6,H2O);质谱(ESI法,负离子模式);m/z 707.8[M+2DBA-5H]3-,664.8[M+DBA-4H]3-,621.7[M-3H]3-,466.0[M-4H]4-。
化合物15k(OR5=OBu,OR6=OBu):[α]D=+56.1(c=0.95,H2O);质谱(ESI法,负离子模式);m/z 1206.4319[M+4DBA-6H]2-,1141.9298[M+3DBA-5H]2-,717.5716[M+2DBA-5H]3-,674.5105[M+DBA-4H]3-,631.4722[M-3H]3-。
化合物15l(OR5=OPent,OR6=OPent):[α]D=+64.0(c=1,H2O);质谱(ESI法,负离子模式);m/z 1220.0267[M+4DBA-6H]2-,1155.4486[M+3DBA-5H]2-,1090.3690[M+2DBA-4H]2-,726.5686[M+2DBA-5H]3-,683.5173[M+DBA-4H]3-,640.4665[M-3H]3-。
第3部分:五糖17和18的合成
如下述方案3中所示,由单糖8和之前的WO 2006/067173中所述的四糖16起始,以与化合物13和化合物15(方案2)所述相似的方式制备化合物17和18。
方案3:化合物17和化合物18的合成途径
(由中间体8和中间体16起始)
以与以化合物13所述相似的方式制备化合物17。
化合物17a(OR5=OH,OR6=OH):质谱(ESI法,负离子模式);m/z837.6353[M+2DBA-4H]2-,773.0602[M+DBA-3H]2-,708.4929[M-2H]2-;1H NMR(400MHz,D2O,ppm)δ5.56(d,1H,J=3.4Hz,H-1GlcV),5.51(d,1H,J=3.5Hz,H-1GlcIII),5.20(d,1H,J=3.6Hz,H-1GlcI),4.99(s,1H,H-1IdoUAII),4.81(d,1H,J=7.8Hz,H-1GlcUAIV),3.76-3.57(6s,18H,6×OMe)。
化合物17b(OR5=OH,OR6=OMe):质谱(ESI法,负离子模式);m/z909.2[M+3DBA-5H]2-,844.7[M+2DBA-4H]2-,780.1[M+DBA-3H]2-,715.5[M-2H]2-;1H NMR(400MHz,D2O,ppm)δ5.35(d,1H,J=3.6Hz,H-1GlcIII),5.31(d,1H,J=3.5Hz,H-1GlcV),5.04(d,1H,J=3.7Hz,H-1GlcI),4.98(s,1H,H-1IdoUAII),4.64(d,1H,J=7.8Hz,H-1GlcUAIV),3.61(s,3H,OMe),3.55(2s,6H,OMe),3.50(2s,6H,OMe),3.48(s,3H,OMe),3.42(s,3H,OMe)。
化合物17c(OR5=OH,OR6=OEt):质谱(ESI法,负离子模式);m/z851.6870[M+2DBA-4H]2-,787.1106[M+DBA-3H]2-,722.5338[M-2H]2-,481.3487[M-3H]3-;1H NMR(400MHz,D2O,ppm)δ5.50(d,1H,J=3.5Hz,H-1GlcIII),5.42(d,1H,J=3.5Hz,H-1GlcV),5.19(d,1H,J=3.8Hz,H-1GlcI),5.13(s,1H,H-1IdoUAII),4.79(d,1H,J=7.7Hz,H-1GlcUAIV),3.98-3.91(m,2H,R-CH2-CH3),3.75-3.57(6s,18H,6×OMe),1.32(t,3H,J=6.9Hz,R-CH2-CH3)。
化合物17e(OR5=OMe,OR6=OH):质谱(ESI法,负离子模式);m/z844.6550[M+2DBA-4H]2-,780.0801[M+DBA-3H]2-,715.5092[M-2H]2-,476.6641[M-3H]3-。
化合物17f(OR5=OEt,OR6=OH):质谱(ESI法,负离子模式);m/z851.7[M+2DBA-4H]2-,787.1[M+DBA-3H]2-,722.5[M-2H]2-,481.3[M-3H]3-。
化合物17h(OR5=OMe,OR6=OMe):质谱(ESI法,负离子模式);m/z916.2817[M+3DBA-5H]2-,851.7057[M+2DBA+2Na-4H]2-,787.1298[M+DBA-3H]2-,722.5541[M-2H]2-,481.3654[M-3H]3-;1H NMR(400MHz,D2O,ppm),δ5.48(d,1H,J=3.5Hz,H-1GlcV),5.36(d,1H,J=3.4Hz,H-1GlcIII),5.04(m,2H,H-1IdoUAII,H-1GlcI),4.67(d,1H,J=7.8Hz,H-1GlcUAIV),3.64-3.42(8s,24H,8×OMe)。
以与化合物15所述相似的方式制备化合物18。
化合物18a(OR5=OH,OR6=OH):质谱(ESI法,负离子模式);m/z718.215[M+3DBA-6H]3-,671.528[M+2DBA-5H]3-,628.142[M+DBA-4H]3-,585.090[M-3H]3-;1H NMR(400MHz,D2O,ppm)δ5.35(d,1H,J=3.6Hz,H-1GlcIII),5.29(d,1H,J=3.9Hz,H-1GlcV),5.04(d,1H,=3.7Hz,H-1GlcI),4.99(s,1H,H-1IdoUAII),4.67(d,1H,J=7.8Hz,H-1GlcUAIV),3.60-3.42(6s,18H,6×OMe),4.61(m,1H,H-6生物素),4.42(m,1H,H-2生物素),3.33(m,1H,H-1生物素),3.01(dd,1H,J=4.9Hz,J=13.1Hz,H-7a生物素),2.77(d,1H,J=13.1Hz,H-7b生物素)。
化合物18c(OR5=OH,OR6=OEt):质谱(ESI法,负离子模式);m/z1150.8828[M+4DBA-6H]2-,1086.3187[M+3DBA-5H]2-,1021.2565[M+2DBA-4H]2-,956.6723[M+DBA-3H]2-,892.1098[M-2H]2-,594.3942[M-3H]3-。
化合物18e(OR5=OMe,OR6=OH):质谱(ESI法,负离子模式);m/z1143.8594[M+4DBA-6H]2-,1078.7886[M+3DBA-5H]2-,1014.2141[M+2DBA-4H]2-,949.6444[M+DBA-3H]2-,632.7502[M+DBA-4H]3-,589.7020[M-3H]3-。
化合物18f(OR5=OEt,OR6=OH):质谱(ESI法,负离子模式);m/z1151.4[M+4DBA-6H]2-,1085.8[M+3DBA-5H]2-,1021.2[M+2DBA-4H]2-,957.2[M+DBA-3H]2-,637.4[M+DBA-4H]3-,594.4[M-3H]3-。
化合物18h(OR5=OMe,OR6=OMe):质谱(ESI法,负离子模式);m/z637.4261[M+DBA-4H]3-,594.3792[M-3H]3-,445.0662[M-4H]4-;1H NMR(400MHz,D2O,ppm),δ5.36(d,1H,J=3.4Hz,H-1GlcIII),5.24(d,1H,J=3.9Hz,H-1GlcV),5.04(m,2H,H-1GlcI,H-1IdoUAII),4.66(d,1H,J=7.8Hz,H-1GlcUAIV),3.59-3.43(8s,24H,8×OMe),4.59(m,1H,H-6生物素),4.42(m,1H,H-2生物素),3.33(m,1H,H-1生物素),2.99(dd,1H,J=4.9Hz,J=13.1Hz,H-7a生物素),2.76(d,1H,J=13.1Hz,H-7b生物素)。
生物学试验
将理解的是,有许多测定方法适用于对本发明化合物的生物学活性进行测试。然而,将用于对本发明化合物的生物学活性进行测试的合适方法列于下文中。
确定化合物的抗凝血因子Xa活性(IC50)
本发明化合物通过激活抗凝血酶(AT)来抑制凝血因子Xa。在标准条件下,在AT存在的情况下比较各化合物抑制凝血因子Xa的活性。对于各化合物而言,绘制表示抑制百分率相对于浓度的曲线。确定抑制50%的凝血因子Xa活性的浓度(IC50)。将可商购的体系用于这一目的:Stachrom HP试剂盒(Diagnostica Stago)。在STA Compact(DiagnosticaStago)上进行这一测定。
对血浆中的化合物进行定量
基于各化合物的抗凝血因子Xa活性(如上述的Stachrom HP试剂盒,DiagnosticaStago),使用生物测定来确定化合物的大鼠血浆浓度(微克化合物/毫升血浆)。该测定在STA Compact(Diagnostica Stago)上进行。用大鼠血浆中待定量的各化合物作出具体的校正曲线。
静脉内给予后的药代动力学研究(清除半衰期,T1/2)
在静脉内给予后,于雌性Wistar Han大鼠中对本发明化合物的药代动力学进行研究。
在多个时间点进行血样采集,将9体积的血样与1体积的柠檬酸钠混合,并立即在冰上冷却。使样品在低温下接受3000×g离心10分钟(血浆通常在低于8℃的温度下保持稳定24小时),并在-20℃下冻存。使用上述的凝血因子Xa活性,通过化合物的抗凝血因子Xa的活性来测定化合物浓度(每毫升血浆)。
对于各化合物,从由此得到的浓度相对于时间的曲线计算出清除半衰期。
结果
第1家族(R2与R7形成桥联基团,R4=-NH2且R5=R6)
化合物 | OR5/OR6 | IC50(nM) | T1/2(h)(大鼠) |
13h | –OMe | 99 | 1.2±0.1 |
13i | –OEt | 45 | 1.5±0.1 |
13j | –OPr | 47 | 1.8±0.1 |
13k | –OBu | 34 | 2.2±0.1 |
13l | -OPent | 34 | 3.2±0.1 |
比较1
化合物PA01以与Petitou在WO 99/36428中所述相似的方式合成。
化合物PA01在大鼠中的半衰期T1/2为3.5±0.3小时,IC50活性为34nM。
化合物PA01与化合物13h的不同之处在于R4基团:化合物PA01具有-OMe基团,而化合物13h具有-NH2基团。当将二者进行比较时,观察到化合物13h的半衰期比起化合物PA01降低约66%。
还可与化合物13i至化合物13l进行比较。观察到这些化合物在保持了其凝血因子Xa抑制活性的同时,全部具有短于化合物PA01的半衰期。
比较2
化合物PA02以与EP 2074131中所述相似的方式合成。
化合物PA02在大鼠中的半衰期T1/2为4.8±0.5小时,IC50活性为108nM。
化合物13h至化合物13l与化合物PA02的不同之处在于:化合物13h至化合物13l在R5和R6中具有碳原子数更少的烷氧基基团。化合物13h至化合物13l在大鼠中的半衰期比起化合物PA02的半衰期更短,化合物13h至化合物13l的半衰期为1.2小时(-OMe)至3.2小时(-OPent)。
另外,与化合物PA02相比,化合物13h至化合物13l的抗凝血因子Xa活性增高,即化合物13h至化合物13l的IC50降低。化合物13h至化合物13l的IC50值为99nM(-OMe)至34nM(-OBu和-OPent)。
应注意的是,这一限制性选择产生了比起现有技术化合物具有短的半衰期的化合物。
第2家族(R2与R7形成桥联基团,R4=-NH2且R5≠R6)
化合物 | OR5/OR6 | IC50(nM) | T1/2T(h)(大鼠) |
13c | –OH/OEt | 84 | 1.4±0.1 |
13d | –OH/OPr | 94 | 0.9±0.1 |
再次观察到,这一限制性选择产生了比起现有技术化合物具有短的半衰期的化合物。
第3家族(R2与R7形成桥联基团,R4=-NH-LC-生物素且R5=R6)
化合物 | OR5/OR6 | IC50(nM) | T1/2T(h)(大鼠) |
15a | –OH | 56 | 1.7±0.2 |
15h | –OMe | 32 | 1.6±0.2 |
15i | –OEt | 21 | 2.8±0.1 |
15k | –OBu | 32 | 3.0±0.2 |
LC表示下式:
生物素(或IUPAC名称:5-[(3aS,4S,6aR)-2-氧代六氢化-1H-噻吩并[3,4-d]咪唑-4-基]戊酸,也被称为维生素B7)表示如下基团:
比较3
化合物PA01与化合物15h的不同之处在于R4基团,化合物PA01具有-OMe基团,化合物15h具有-NH-LC-生物素基团。当将二者进行比较时,观察到化合物15h的半衰期比起化合物PA01降低约54%。
还可与化合物15a和化合物15i进行比较,观察到这些化合物的半衰期均短于化合物PA01的半衰期。
另外,比起化合物PA01,化合物15h、化合物15i和化合物15k显示出更低的IC50活性,因而是更好的凝血因子Xa抑制剂。
比较4
化合物PA02与化合物15a的不同之处在于R5基团和R6基团,化合物PA02具有-OHex(己氧基)基团,而化合物15a具有-OH基团;这两个化合物的不同之处还在于R4基团,化合物PA02具有-NH2基团,而化合物15a具有-NH-LC-生物素基团。当对这两个化合物进行比较时,观察到化合物15a的半衰期比起化合物PA02降低约73%。
化合物15h至化合物15k与化合物PA02不同之处在于,化合物15h至化合物15k在R5和R6中具有碳原子数更少的烷氧基基团。化合物15h至化合物15k的半衰期比起化合物PA02的半衰期更短。
另外,与化合物PA02相比,化合物15h至化合物15k的活性增高。化合物15a的IC50值为56nM,而化合物15h至化合物15k的IC50值仍然低于33nM。
比较5
第1家族的化合物与第3家族的化合物的不同之处在于R4基团,第1家族的化合物具有-NH2基团,而第3家族具有-NH-LC-生物素基团。与第1家族的化合物相比,第3家族的化合物具有更高的抗凝血因子Xa活性(更低的IC50),并且还具有可接受的半衰期值。
因此,在第1家族化合物上接枝生物素基团出乎预料地增高了抗凝血因子Xa活性。
第4家族(R2与R7形成桥联基团,R4=-NH-LC-生物素且R5≠R6)
化合物 | OR5/OR6 | IC50(nM) | T1/2T(h)(大鼠) |
15b | –OH/OMe | 42 | 1.3±0.1 |
15e | –OMe/OH | 65 | 1.3±0.1 |
15c | –OH/OEt | 30 | 2.2±0.2 |
15f | –OEt/OH | 50 | 1.3±0.0 |
比较6
第2家族的化合物与第4家族的化合物的不同之处在于R4基团,第2家族化合物具有-NH2基团,而第4族的化合物具有-NH-LC-生物素基团。与第2家族的化合物相比,第4家族的化合物具有更高的抗凝血因子Xa活性(更低的IC50),并且还具有可接受的半衰期值。
因此,在第2家族化合物上接枝生物素基团出乎预料地增高了抗凝血因子Xa活性。
第5家族(R2=烷氧基,R7=H,R4=-NH2)
化合物 | OR5/OR6 | IC50(nM) | T1/2(h)(大鼠) |
17h | –OMe/OMe | 59 | 1.2±0.1 |
17c | –OH/OEt | 103 | 1.3±0.1 |
第6家族(R2=烷氧基,R7=H,R4=-NH-LC-生物素)
化合物 | OR5/OR6 | IC50(nM) | T1/2(h)(大鼠) |
18a | –OH/OH | 53 | 1.9±0.1 |
18b | –OH/OMe | 34 | 2.4±0.1 |
18e | –OMe/OH | 55 | 1.5±0.1 |
18f | –OEt/OH | 39 | 2.3±0.2 |
18c | –OH/OEt | 31 | 1.9±0.2 |
比较7
当将第5家族和第6家族的相应化合物进行比较,其不同之处在于R4基团:第5家族化合物具有-NH2基团,而第6家族化合物具有-NH-LC-生物素基团。第6家族化合物的抗凝血因子Xa活性比起第5家族化合物的抗凝血因子Xa活性更高,并且第6家族化合物仍具有可接受的半衰期值。
因此,在第5家族化合物上接枝生物素基团出乎预料地增高了抗凝血因子Xa活性。
Claims (8)
1.合成五糖化合物及其盐,所述合成五糖化合物选自如下化合物:
2.一种药物组合物,所述药物组合物包含:权利要求1所述的合成五糖化合物及其盐、以及药学上可接受的稀释剂或载体。
3.权利要求1所述的合成五糖化合物及其盐或者权利要求2所述的药物组合物在制备用于对血液凝固障碍进行预防和治疗的药物中的用途。
4.权利要求1所述的合成五糖化合物及其盐或者权利要求2所述的药物组合物在制备用于对血液凝固障碍进行治疗的药物中的用途。
5.权利要求1所述的合成五糖化合物及其盐或者权利要求2所述的药物组合物在制备用于对与实体器官移植相关的缺血再灌注损伤进行预防的药物中的用途。
6.权利要求1所述的合成五糖化合物及其盐或者权利要求2所述的药物组合物在制备用于对心脏外科手术期间、体外膜氧合期间、或循环辅助期间的体外血液循环中的血液凝固进行预防或者降低所述血液凝固的风险的药物中的用途。
7.如权利要求6所述的用途,其中,所述循环辅助为人工心脏。
8.一种试剂盒,所述试剂盒包含:权利要求1所述的合成五糖化合物及其盐或者权利要求2所述的药物组合物;以及亲和素。
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WO1999025720A1 (en) * | 1997-11-19 | 1999-05-27 | Akzo Nobel N.V. | Carbohydrate derivatives |
WO1999036428A1 (fr) * | 1998-01-19 | 1999-07-22 | Sanofi-Synthelabo | Nouveaux pentasaccharides, procedes pour leurs preparations et compositions pharmaceutiques les contenant |
EP1574516A1 (en) * | 2004-03-05 | 2005-09-14 | Sanofi-Aventis | Antithrombotic compound |
CN101535327A (zh) * | 2006-10-05 | 2009-09-16 | 恩多提斯药业公司 | 抗凝血化合物 |
WO2011073408A2 (en) * | 2009-12-18 | 2011-06-23 | Endotis Pharma | Pharmaceutical oral dosage form containing a synthetic oligosaccharide |
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US5378829A (en) | 1990-04-23 | 1995-01-03 | Akzo N.V. | Sulfated glycosaminoglycanoid derivatives of the heparin and heparan sulfate type |
FR2814463B1 (fr) * | 2000-09-22 | 2002-11-15 | Sanofi Synthelabo | Nouveaux polysaccharides a activite antithrombotique comprenant au moins une liaison covalente avec la biotine ou un derive de la biotine |
TWI403334B (zh) | 2004-12-23 | 2013-08-01 | Merck Sharp & Dohme | 包含生物素殘基之抗血栓雙重抑制劑 |
RU2434876C2 (ru) * | 2005-10-10 | 2011-11-27 | Н.В. Органон | Антитромботические двойные ингибиторы, включающие биотиновую метку |
TW201006479A (en) * | 2008-07-18 | 2010-02-16 | Sanofi Aventis | Use of idrabiotaparinux for decreasing the incidence of bleedings during an antithrombotic treatment |
FR2952935B1 (fr) * | 2009-11-20 | 2011-12-02 | Sanofi Aventis | Procede de preparation du n-biotinyl-6-aminocaproate de n succinimidyle |
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Publication number | Priority date | Publication date | Assignee | Title |
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WO1999025720A1 (en) * | 1997-11-19 | 1999-05-27 | Akzo Nobel N.V. | Carbohydrate derivatives |
WO1999036428A1 (fr) * | 1998-01-19 | 1999-07-22 | Sanofi-Synthelabo | Nouveaux pentasaccharides, procedes pour leurs preparations et compositions pharmaceutiques les contenant |
EP1574516A1 (en) * | 2004-03-05 | 2005-09-14 | Sanofi-Aventis | Antithrombotic compound |
CN101535327A (zh) * | 2006-10-05 | 2009-09-16 | 恩多提斯药业公司 | 抗凝血化合物 |
WO2011073408A2 (en) * | 2009-12-18 | 2011-06-23 | Endotis Pharma | Pharmaceutical oral dosage form containing a synthetic oligosaccharide |
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