CN110382514B - Hcv ns5b聚合酶抑制剂的前药及其生产和使用方法 - Google Patents
Hcv ns5b聚合酶抑制剂的前药及其生产和使用方法 Download PDFInfo
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- CN110382514B CN110382514B CN201780085962.3A CN201780085962A CN110382514B CN 110382514 B CN110382514 B CN 110382514B CN 201780085962 A CN201780085962 A CN 201780085962A CN 110382514 B CN110382514 B CN 110382514B
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Abstract
本发明涉及用于治疗患者的丙型肝炎病毒的前药及其在治疗患者的丙型肝炎病毒中的用途。式1的前药、其立体异构体、同位素富集的类似物、或晶形或多晶形。
Description
发明领域
本发明涉及化疗剂及其在治疗病毒和癌症疾病中的应用。这些化合物是HCV NS5B聚合酶抑制剂的前药,并且预期用于治疗哺乳动物中的丙型肝炎。
发明背景
HCV引起的丙型肝炎是世界上传播最广泛的肝脏疾病之一。根据世界卫生组织(WHO)的年度报告,超过130-150mln人感染了HCV,并且超过70万人死于HCV[WHO.HepatitisC.WHO fact sheet №164.2016年7月更新http://www.who.int/mediacentre/factsheets/fs164/en/]。HCV表现出高遗传多样性,且其特征在于(gT)HCV基因型的区域变异。基因型1(gT1)是世界上最常见的(83.4mln人,或占所有HCV感染者的46.2%;其中约三分之一在东亚)。基因型3(gT3)是第二常见的基因型。在全球范围内,有54.3mln人(30.1%)感染了gT3。基因型2、4和6占所有HCV感染者的22.8%,而基因型5(gT5)占<1%。虽然基因型1和3在大多数国家中占优势,而不论其经济状况如何,但基因型4和5的最大发生率是低收入国家[Messina,J.P.等人,Global Distribution and Prevalence of Hepatitis CVirus Genotypes.Hepatology 2015,61(1),77-87.]
近年来在丙型肝炎治疗方面取得的相当大进展主要与索非布韦(PSI-7977,GS-7977)的发现有关,其为HCV NS5B抑制剂的核苷前药和前药PSI-7851的Sp异构体[Sofia,M.J.等人,Discovery of aβ-D-20-Deoxy-20-rfluoro-20-β-C-methyluridine Sovaldi Nucleotide Prodrug(PSI-7977)for the Treatment ofHepatitis C Virus.J.Med.Chem.2010,53,7202-7218.Sofia,M.J.等人,Nucleosidephosphoramidate prodrugs.专利US7964580(2011),专利US8334270(2012)。专利RU2478104(2013)],
现已广泛应用于丙型肝炎的联合疗法,包括与HCV NS5A抑制剂共同使用。/>已成为FDA和EC监管机构批准的第一个核苷酸,用于联合治疗感染各种HCV基因型(gT)的丙型肝炎患者。在临床研究中,它显示出对六种HCV基因型(gT1-gT6)的高效能[I.M.Jacobson等人,Sofosbuvir for hepatitis C genotype 2or 3in patientswithout treatment options.Engl.J.Med.2013,368,1867-1877.E.Lewirz等人,Sofosbuvir for previously untreated chronic hepatitis Cinfection.Engl.J.Med.2013,368,1878-1887]。/>
PSI-7851及其立体异构体PSI-7976和PSI-7977代谢成三磷酸PSI-7409,其实际上是HCV NS5B聚合酶抑制剂[E.Murakami等人,Mechanism of activation of PSI-7851andits diastereoisomer PSI-7977.J.Biol.Chem.2010,285(45),34337-34347],
还存在其他已知的类似物[专利US8334270(2012)。M.J.Sofia等人,Discovery of aβ-D-20-Deoxy-20-r-fluoro-20-β-C-methyluridine NucleotideProdrug(PSI-7977)for the Treatment of Hepatitis C Virus.J.Med.Chem.2010,53,7202-7218.],包括式A1的(S)-2-{[(2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢-2Н-嘧啶-1-基)-4-氟-3-羟基-4-甲基-四氢呋喃-2-基甲氧基]-苯氧基-磷酰基氨基}-丙酸环己酯,例如PSI-7851及其磷光体立体异构体PSI-7976和PSI-7977/>它们代谢成三磷酸PSI-7409,
然而,尽管最近在丙型肝炎的疗法方面取得了进展,但寻求具有改善特性的HCVNS5B抑制剂的新前药仍然是一项重大挑战。
发明概述
本发明人惊奇地发现,之前未知的式1的化合物及其式1.1(Sp立体异构体)或1.2(Rp立体异构体)的磷立体异构体是HCV NS5B聚合酶抑制剂的有效前药和有希望使用的抗病毒剂,尤其是,用于治疗丙型肝炎,
下面列出的是用于描述本发明的各种术语的定义。这些定义单独地或作为较大部分的组成部分适用于贯穿于本说明书和权利要求书中使用的术语,除非在特定情况下另外限制。
术语“晶形(crystalline form)”是指其中分子排列形成晶格的物质结构。
术语“多晶形(polycrystalline form)”是指由多个单晶或某些晶形的微晶组成的多晶物质结构。
术语“活性成分”(药物物质)是指合成或其他(生物技术,植物,动物,细菌等)来源的生理活性化合物,其表现出药理活性并且是药物组合物的活性成分。
术语“药物”是指片剂,胶囊,注射剂,软膏剂形式或预期用于恢复,改善或改变人类和动物生理功能并且用于治疗和预防疾病、用于诊断、麻醉、避孕、美容等的其他成品剂型的化合物(或形成药物组合物的化合物的混合物)。
术语“治疗性混合物”是指同时施用两种或更多种药物的组合,所述药物表现出不同的药理作用机制并且针对参与疾病发病机理的各种生物靶标。
术语“药物组合物”是指包含式1的化合物和如下成分的至少一种的组合物,所述成分的至少一种选自药学上可接受的和药理学相容的填充剂,溶剂,稀释剂,载体,辅助剂,分布剂和接受剂,赋形剂,递送剂,如防腐剂,稳定剂,填充剂,崩解剂,润湿剂,乳化剂,悬浮剂,增稠剂,甜味剂,矫味剂,芳香剂,抗菌剂,杀真菌剂,润滑剂和延长递送控制剂,其选择和比例这取决于施用的性质和途径以及剂量。适合的悬浮剂的实例是乙氧基化异硬脂醇,聚氧乙烯,山梨醇和山梨醇醚,微晶纤维素,偏氢氧化铝,膨润土,琼脂和西黄蓍胶,以及它们的混合物。可以使用各种抗细菌剂和抗真菌剂如对羟基苯甲酸酯,三氯叔丁醇,山梨酸等提供对微生物的防护。所述组合物还可包括等渗剂,例如糖,氯化钠等。使用减慢活性成分吸收的试剂,例如单硬脂酸铝和明胶,可以实现组合物的持续作用。适合的载体,溶剂,稀释剂和递送剂的实例包括水,乙醇,多元醇及其混合物,天然油(例如橄榄油)和用于注射的有机酯(例如油酸乙酯)。填料的实例是乳糖,奶糖,柠檬酸钠,碳酸钙,磷酸钙等。崩解剂和分配剂的实例是淀粉,海藻酸及其盐和硅酸盐。润滑剂的实例是硬脂酸镁,十二烷基硫酸钠,滑石粉和高分子量的聚乙二醇。用于口服,舌下,透皮,肌内,静脉内,皮下和局部或直肠施用活性成分的药物组合物单独或与另一种活性化合物组合,可以作为与传统的医药载体的混合物以标准施用形式施用于动物和人。适合的标准施用形式包括口服形式,例如片剂,胶囊,丸剂,粉剂,颗粒剂,口香糖和口服溶液或悬浮液;舌下和经口含的施用形式;气雾剂;植入物;透皮,透皮,皮下,肌内,静脉注射,鼻内或眼内形式;和直肠施用形式。
如本文所用的术语“惰性填充剂”是指用于形成药物组合物并且通常是安全的、无毒的、既不是生物学上也不是其他方面不合乎需要的的化合物,并且包含兽医和人类药物用途可接受的赋形剂。本发明化合物可以单独施用,但通常与一种或多种药学上可接受的赋形剂,稀释剂或载体混合物的形式施用,这取决于预期的施药途径和标准药学实践。
如本文所用,术语“治疗有效量”是指减轻受试者中疾病症状所需的物质,前药或药物的量。物质,前药或药物的剂量将满足每种特定情况下的个体需求。所述剂量可以在很宽的范围内变化,这取决于许多因素,例如待治疗的疾病的严重程度,患者的年龄和一般状况,用于患者治疗的其他药物,施用方式和途径,以及主治医生的经验。对于口服施用,在单一疗法和/或联合疗法中,日剂量约为0.01-10g,包括其间的所有值。优选的日剂量约为0.1-7g。通常,为了减轻或消除病毒,在治疗开始时给予较高的负荷剂量,随后将剂量减少至足以防止感染爆发的水平。
术语“受试者”是指哺乳动物,包括但不限于牛,猪,绵羊,鸡,火鸡,水牛,羊驼属(lama),鸵鸟,狗,猫和人;人类受试者是最优选的。推定受试者的治疗可涉及式1的前药,其立体异构体,同位素富集的类似物,药学上可接受的盐,水合物,溶剂合物和晶形或多晶形或它们与另一种化合物包括与HCV NS5A抑制剂的组合的用途。
本发明的主题为式1的(S)-2-{[(2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢-2Н-嘧啶-1-基)-4-氟-3-羟基-4-甲基-四氢呋喃-2-基甲氧基]-苯氧基-磷酰基氨基}-丙酸环丁酯、其磷立体异构体(式1.1的Sp立体异构体或式1.2的Rp立体异构体)、其同位素富集的类似物、或晶形或多晶形。
本发明的主题为式1的HCV NS5B聚合物抑制剂、其磷立体异构体(式1.1的Sp立体异构体或式1.2的Rp立体异构体)、其同位素富集的类似物、或晶形或多晶形,它们作为医疗用药物,用于治疗有此需要的人或温血动物的丙型肝炎。
优选的前药为(S)-2-{(S)-[(2R,3R,4R,5R)-5-(3,4-二氢-2,4-二氧代-2H-嘧啶-1-基)-3-羟基-4-甲基-4-氟-四氢呋喃-2-基甲氧基]-苯氧基-磷酰基氨基}-丙酸环丁酯(1.1)、其同位素富集的类似物、或晶形或多晶形。
令人惊奇地,式1的新型前药,其磷立体异构体,其同位素富集的类似物,以及晶形和多晶形显然为比已知的HCV NS5B抑制剂前药更有效的HCV NS5B抑制剂前药,并且特别是比和式A1的环己酯更有效的前药。
实际上,具有针对HCV的基因型1b(gT1b)的ЕС50=0.045-0.170μM[http://www.hcvdruginfo.ca/downloads/HCV_Sofosbuvir.pdf]和ЕС90=0.59μM,而式1.1的新型前药具有ЕС50=15.0-27.0nM和ЕС90=128.0nM(表1а),这意味着式1.1的新型前药的活性比/>高3倍以上。式1.1的前药在人肝脏微粒体S9部分中的半衰期为T1/2 hS9=0.05h,而/>具有T1/2 hS9=0.54h(表2),这意味着式1.1的新型前药在肝脏微粒体S9部分中的代谢速率比/>快11倍。此外,因式1.1的前药的代谢过程导致的三磷酸PSI-7409在大鼠肝脏中的浓度和AUC24h分别为Сmax=3224.0ng/g和AUC24h=30487.0ng·h/g,而Sovaldi的类似代谢导致Сmax=1934.0ng/g和AUC24h=16796.0ng·h/g(表3)。这证明了如下事实:式1.1的新型前药在肝脏中几乎两倍的更有效地代谢成必需的三磷酸PSI-7409(药物)。
与已知的式А1环己酯相比,式1.1的新型前药具有更高的效率,因为所述前药已知[M.J.Sofia等人,J.Med.Chem.2010,53,7202-7218]具有如下参数:ЕС90=250.0nM,T1/2 hS9=1.4h,Сmax=557ng/g和AUC24h=6484.0ng·h/g。
获得的结果(效果)是令人惊讶的,因为式1.1的前药(环丁酯)不仅比其类似物—式А1的环己酯更有效,而且比另一种类似物—式А2的环丙酯更具活性(ЕС90=73.0nM,ЕС90=410.0nM,参见表1a),其由本发明人专门制备以更好地示例所述令人惊奇的效果,
令人惊讶的是,在一系列环烷基酯中,最有效的一种显然是具有中等尺寸环烷基的式1.1的环丁酯,而具有较大尺寸环烷基的酯(具有式А1的已知环己酯)和较小大小的环烷基(由发明人特别制备的式A.2的环丙酯)显然有效性较低。
上述数据是本发明的新颖性和水平(有效性)的令人信服的证据。
本发明的主题是具有HCV NS5B聚合酶抑制剂特性的药物,所述药物是治疗有效量的式1的化合物、其立体异构体、同位素富集的类似物、或晶形或多晶形,预期其用于治疗有此需要的人类或温血动物的丙型肝炎。
本发明的主题是药物组合物,其以治疗有效量包含式1的前药、其立体异构体、同位素富集的类似物、晶形或多晶形,任选地与药学上可接受的填充剂,载体,添加剂或稀释剂组合,所述药物组合物用于治疗哺乳动物丙型肝炎病毒。
所述式1的前药、其立体异构体、同位素富集的类似物、晶形或多晶形可以以各种口服剂型和载体制备;口服施用可以以片剂,薄膜包衣片剂,硬和软明胶胶囊,溶液,乳液,糖浆或悬浮液的形式进行。当以栓剂的形式施用时,本发明的化合物是有效的。通常,最方便的施用途径是口服,使用常见的每日剂量方案,其可以根据疾病的严重程度和患者的抗病毒或抗肿瘤药物反应进行调整。
式1的前药、其立体异构体、同位素富集的类似物、或晶形或多晶形与一种或多种常见赋形剂,载体或稀释剂组合可以是药物组合物和其单位剂型的形式。药物组合物和标准剂型可以由通常比例的普通成分与或不与另外的活性化合物和剂型组成。根据规定的日剂量的不同,药物组合物可包含任何适当有效量的活性成分。药物组合物可以以固体物质的形式使用,例如片剂或填充胶囊;半固体粉末形式,具有持续释放的活性剂或液体如悬浮液,乳液或填充胶囊,其用于口服施用;或用于直肠或阴道施用的栓剂形式。典型的药物包含约5wt%-95wt%的活性化合物或化合物。术语“药物”或“剂型”意在包括活性化合物的固体和液体组合物,使得本领域技术人员显而易见,活性成分可以以不同药物的形式存在,视所需剂量和药代动力学参数的不同而定。
固体剂型包括粉末,片剂,丸剂,胶囊,栓剂和可分散的颗粒。固体载体是指一种或多种可用作稀释剂,矫味剂,增溶剂,润滑剂,助悬剂,粘合剂,防腐剂,崩解剂或包封材料的物质。粉末载体通常是与细粒活性组分混合的细粒固体。在片剂中,活性成分通常以适当的比例与具有必要粘合能力的载体混合并压制成所需的形状和大小。适合的载体包括但不限于碳酸镁,硬脂酸镁,滑石粉,糖,乳糖,果胶,糊精,淀粉,明胶,西黄蓍胶,甲基纤维素,羧甲基纤维素钠,低熔点蜡,可可脂等。除活性成分外,固体制剂还可包含染料,矫味剂,稳定剂,缓冲剂,人造和天然甜味剂,分散剂,增稠剂,增溶剂等。
液体组合物也适用于口服施用。液体剂型包括乳液,糖浆,酏剂和水性悬浮液。它们包含固体药物形式,在使用前立即转化为液体药物。乳液可以在溶液中制备,例如在丙二醇的水溶液中制备,或者它们可以包含乳化剂,例如卵磷脂,山梨醇单油酸酯或阿拉伯树胶。水悬浮液可以通过用延展性材料如天然或合成树胶,树脂,甲基纤维素,羧甲基纤维素钠和其它众所周知的助悬剂将细粒活性成分分散在水中来制备。
式1的前药、其立体异构体、同位素富集的类似物、晶形或多晶形可以制备成栓剂形式施用。首先熔化低熔点蜡,例如脂肪酸甘油酯或可可脂的混合物,然后通过例如搅拌使活性成分均匀分散。将熔融的均匀混合物倾入适合尺寸的模具中并使其冷却和固化。
可以制备式1的前药、其立体异构体、同位素富集的类似物、晶形或多晶形用于阴道施用。除了活性成分外,还应用栓剂,棉塞,乳膏,凝胶,糊剂,泡沫体或喷雾剂,其中包括本领域众所周知的载体。
本发明的主题是式1的前药、其立体异构体、同位素富集的类似物、晶形或多晶形在生产用于治疗丙型肝炎病毒的药物中的应用。推定式1的前药、其立体异构体、同位素富集的类似物、晶形或多晶形用于生产用于治疗本文所述的任何病毒性疾病的药物,其可以是选自如下的任意式1的化合物:
(S)-2-{[(2R,3R,4R,5R)-5-(3,4-二氢-2,4-二氧代-2H-嘧啶-1-基)-3-羟基-4-甲基-4-氟-四氢呋喃-2-基甲氧基]-苯氧基-磷酰基氨基}-丙酸环丁酯(1),
(S)-2-{(S)-[(2R,3R,4R,5R)-5-(3,4-二氢-2,4-二氧代-2H-嘧啶-1-基)-3-羟基-4-甲基-4-氟-四氢呋喃-2-基甲氧基]-苯氧基-磷酰基氨基}-丙酸环丁酯(1.1),和
(S)-2-{(R)-[(2R,3R,4R,5R)-5-(3,4-二氢-2,4-二氧代-2H-嘧啶-1-基)-3-羟基-4-甲基-4-氟-四氢呋喃-2-基甲氧基]-苯氧基-磷酰基氨基}-丙酸环丁酯(1.2),
其同位素富集的类似物、或晶形或多晶形,单独地或与一些另外的本发明化合物组合。
本发明的主题是在有此需要的受试者中联合治疗和/或预防病毒和癌症疾病的方法,所述方法包括向受试者施用治疗有效量的式1的前药、其立体异构体、同位素富集的类似物、或晶形或多晶形和治疗有效量的一些另外的抗病毒药或抗癌药,其中所述药物同时或交替施用。应理解,在连续的药剂施用之间可存在1至24小时的任何时间跨度。
“另外的抗病毒药”的实例包括、但不限于HCV NS3蛋白酶抑制剂[US20140296136、US8,987,195、US7973040、US2012214783]、HCV NS4抑制剂[EP1497282]、HCV NS3/NS4抑制剂EP 2364984]和HCV NS5A抑制剂[C.Wang等人,Hepatitis C virus RNA eliminationand development of resistance in replicon cells treated with BMS-790052.Antimicrob.Agents Chemother.2012,56,1350-1358.https://en.wikipedia.org/wiki/Daclatasvir;A.V.Ivachtchenko等人,Discovery of NovelHighly Potent Hepatitis C Virus NS5A Inhibitor(AV4025)。J.Med.Chem.2014,57,7716-7730;专利申请US14/845,333);Toll-样受体激动剂(WO2015023958、WO2012097012);和另外的抑制剂(WO2014106019、WO2014033176、WO2014033170、WO2014033167、WO2013006394、US20090163545]。
更优选的是抗病毒药物组合物,其与式1的新型前药或其式1.1的立体异构体,同位素富集的类似物,晶形或多晶形一起另外包含治疗有效量的抗病毒或抗癌药物。
更优选的是抗病毒药物组合物,其与式1的新型前药或其式1.1的立体异构体,同位素富集的类似物,晶形或多晶形一起另外包含治疗有效量的HCV NS5A抑制剂,所述HCVNS5A抑制剂选自下组:
达卡他韦(Daclatasvir)(Daklinza,BMS790052)[Belema,M.等人,Discovery andDevelopment of Hepatitis C Virus NS5A Replication ComplexInhibitors.J.Med.Chem.2014,57,1643-1672.Bachand,C.等人,Hepatitis C virusinhibitors.专利WO2008/021927,2008.Bachand,C.等人,Hepatitis C virusinhibitors.专利WO2008/021928,2008.Bachand,C.等人,Hepatitis C virusinhibitors.专利WO2008/021936,2008.http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_Public_assessmentreport/human/003768/WC500172849.pdf.]
Hepavivir(AV-4025)[Ivachtchenko,A.V.等人,Discovery of Novel HighlyPotent Hepatitis C Virus NS5A Inhibitor(AV4025)。J.Med.Chem.2014,57,7716-7730.专利WO2012/074437,2012。专利US9428491,2016.]
AV-4056和AV-4058[US9428491。]
AV-4067和AV-4084[专利申请US14/845,333.]
奥比他韦(ABT-267)[Gardelli,C.等人,Phosphoramidate Prodrugs of 20-C-methylcytidine for Therapy of Hepatitis C Virus Infection.J.Med.Chem.2014,57,2047-2057。专利WO2010/144646,2010.]
艾尔巴韦(MK-8742),[Coburn,C.A.等人,ChemMedChem.2013,8,1930-1940。专利WO2012/040923,2012。专利WO2012/041014,2012]
维帕他韦(VEL,GS-5816),[专利WO2015/110048,2015.http://www.accessdata.fda.gov/drugsatfdadocs/nda/2016/208341O rig1s000PharmR.pdf].http://www.gilead.com/~/media/files/pdfs/medicines/liver-disease/epclusa/epclusa_pi.pdf]
那拉匹韦(SCH 900518),HCV非结构蛋白3(NS3)抑制剂[Arasappan A.等人,Discovery of Narlaprevir(SCH 900518):A Potent,Second Generation HCV NS3SerineProtease Inhibitor.ACS Med.Chem.Lett.,2010,1(2),64-69]
西美瑞韦(Olysio),HCV非结构蛋白NS3/NS4抑制剂[https://www.tga.gov.au/sites/default/files/auspar-simeprevir-141027-pi.docx]
本发明的主题是在有此需要的受试者中联合治疗病毒和癌症疾病的方法,所述方法包括连续或同时施用治疗有效量的式1的前药、其立体异构体、同位素富集的类似物、晶形或多晶形,或一些另外的抗病毒药或抗癌药。应理解,在连续的药物施用之间可能存在任何时间跨度。
推定另外的抗病毒药为,但不限于,干扰素α,干扰素β,聚乙二醇化干扰素α,利巴韦林,左旋韦林(levovirin),塔利韦林,另一种核苷HCV聚合酶抑制剂,非核苷HCV聚合酶抑制剂,HCV蛋白酶抑制剂,HCV解旋酶抑制剂或HCV融合抑制剂,HBV DNA聚合酶抑制剂和HIV1逆转录酶(RT)抑制剂。当前药或其衍生物或盐与另一种抗病毒药或抗癌药联合施用时,活性相对于前药的初始活性可以增加。在联合疗法中,药剂的施用可以是关于式1的前药的同时或连续施用。本文所用的“同时给药施用”的概念因此意指同时或在不同时间施用。同时施用两种或更多种药剂可以通过使用一种包含两种或更多种活性成分的制备形式进行,或者实质上通过同时施用两种或更多种具有一种活性剂的剂型来进行。应当理解,本文所用的任何对治疗的提及也包括预防。此外,如本文所用,术语病毒感染的“疗法”包括治疗或预防与介导的病毒感染或其临床症状相关的疾病或病症。
本发明涉及制备式1的前药和立体异构体、同位素富集的类似物及其晶形和多晶形的方法,所述方法涉及使用之前未知的式2的(S)-2-(五氟苯基氧基-苯氧基-磷酰基氨基)-丙酸环丁酯或其立体异构体式2.1的(S)-2-((S)-五氟苯基氧基-苯氧基-磷酰基氨基)-丙酸环丁酯和式2.2的(S)-2-((R)-五氟苯基氧基-苯氧基-磷酰基氨基)-丙酸环丁酯,它们也为本发明的主题,
本发明人惊奇地发现,式1的新型前药及其磷立体异构体(式1.1的Sp-立体异构体和式1.2的Rp-立体异构体)是比例如已知的和式A1的环己酯以及之前未知的式A2的环丙酯(对比物)更有效的HCV NS5B抑制剂的前药。
因此,具有抗HCV基因型1b(gT1b)ЕС50=0.045-0.170μM和ЕС90=590nM,式А1的环己酯具有ЕС90=250.0nM,而式А2的环丙酯具有ЕС90=73.0nM和ЕС90=410.0nM(表1)。式1.1的新型前药具有ЕС50=15.0-27.0nM和ЕС90=128.0nM(表1а),这意味着式1.1的新型前药比/>的活性高三倍以上,比式А1化合物活性高两倍,比式А2的化合物活性高三倍。
式1.1的前药在人肝微粒体S9部分中的半衰期为T1/2 hS9=0.05h,而具有T1/2 hS9=0.54h,式А1的环己基酯,T1/2 hS9=1.4h(表2),这意味着人肝微粒体S9部分中式1.1的新前药的代谢速率比/>快11倍,比式А1的环己酯的快28倍。此外,由式1.1前药的代谢过程产生的大鼠肝脏中三磷酸PSI-7409的浓度和AUC24h分别为Сmax=3224.0ng/g和AUC24h=30487.0ng·h/g,而Sovaldi的类似的代谢导致Сmax=1934.0ng/g和AUC24h=16796.0ng·h/g(表3)。这证明了如下事实:式1.1的新型前药在肝脏中代谢成必需的三磷酸PSI-7409(药物)的有效性几乎是/>的两倍,并且比式А1的环己酯有效地高4.7倍。
获得的结果(效果)是令人惊讶的,因为式1.1的前药(环丁酯)不仅比其类似物—式А1的环己酯更有效,而且比另一种类似物—式А2的环丙酯更具活性(ЕС90=73.0nM,ЕС90=410.0nM,参见表1a),其由本发明人专门制备以更好地示例所述令人惊奇的效果。
最佳实施方案
现在将根据某些实施方案描述本发明,并不预期这些实施方案是为了限制其范围。相反,本发明涵盖可包括在权利要求范围内的所有替代,变型和等效方案。因此,包括具体实施方案的以下实施例将示例本发明而不限制本发明。
实施例1.式1的前药(S)-2-{[(2R,3R,4R,5R)-5-(3,4-二氢-2,4-二氧代-2H-嘧啶-1-基)-3-羟基-4-甲基-4-氟-四氢呋喃-2-基甲氧基]-苯氧基-磷酰基氨基}-丙酸环丁酯及其立体异构体1.1和1.2的合成方案(方案1)。
方案1
在0℃向N-Boc-L-丙氨酸(4:15.5g,81.9mmol)在二氯甲烷(300ml)中的溶液中加入DCC(16.9g,81.9mmol),5min后,加入环丁醇(3:5.6g,78.0mmol)和DMAP(2.0g,16.4mmol)。将该混合物在室温搅拌过夜,真空蒸发,用乙酸乙酯(300ml)处理残余物。过滤出残余物,用乙酸乙酯洗涤。用5%柠檬酸溶液(2x 100ml)、饱和NaHCO3溶液(2x 100ml)和盐水洗涤滤液,用Na2SO4干燥,真空蒸发,得到19.6g(98%)(S)-2-(叔丁氧羰基氨基)丙酸环丁酯(5),为白色粉末。1H NMR(400MHz,DMSO-d6)δ7.22(d,J=7.2Hz,0.85H),6.87(m,0.15H),4.89(p,J=7.2Hz,1H),3.94(m,1H),2.26(m,2H),1.98(m,2H),1.74(m,1H),1.59(m,1H),1.38(s,7.5H),1.34(brs,1.5H),1.22(d,J=7.2Hz,3H)。
向化合物5(19.6g,80.6mmol)在二噁烷(50ml)中的溶液中加入HCl(230ml,3M)的二噁烷溶液,将该混合物搅拌过夜,真空蒸发。用乙醚(400ml)处理残余物,搅拌过夜。过滤出残余物,用乙醚洗涤,真空干燥,得到14.1g(97%)(S)-2-氨基-丙酸环丁酯盐酸盐(6),为白色粉末。1H NMR(400MHz,DMSO-d6)δ8.56(brs,3H),5.00(p,J=7.6Hz,1H),4.02(q,J=7.2Hz,1H),2.31(m,2H),2.07(m,2H),1.78(m,1H),1.62(m,1H),1.41(d,J=7.2Hz,3H)。
将二氯磷酸苯酯(16.9g,80.2mmol)加入到化合物6(14.4g,80.2mmol)在二氯甲烷(214ml)中的溶液中。将该混合物冷却至-75至-70℃,滴加三乙胺(16.2g,160.4mmol)在二氯甲烷(16ml)中的溶液,同时维持温度在-75至-70℃。将该混合物在-70℃搅拌30min,然后加热至-20℃。在-20至-10℃加入五氟苯酚(14.6g,79.4mmol)在二氯甲烷(105ml)中的溶液,然后滴加三乙胺(8.1g,80.2mmol)在二氯甲烷(8ml)中的溶液,保持将该混合物在室温搅拌过夜。真空蒸发该混合物,加入乙酸乙酯(500ml)和水(500ml),分离有机层,用5%NaHCO3溶液、盐水洗涤,用Na2SO4干燥,真空蒸发。向残余物中加入己烷和乙酸乙酯的混合物(200ml,6:1),保持将该混合物搅拌过夜。过滤出得到的残余物,用6:1己烷/乙酸乙酯混合物(50ml)洗涤,风干,得到16.7g(S)-2-((全氟苯氧基)(苯氧基)磷酰基氨基)丙酸环丁酯(2)。
使得到的产物(2)从己烷/乙酸乙酯(4:1)混合物(500ml)中重结晶,得到13.8g(37%)(S)-2-((S)-(全氟苯氧基)-(苯氧基)-磷酰基氨基)丙酸环丁酯(2.1),为白色疏松粉末。1H NMR(300MHz,DMSO-d6)δ7.42(m,2H),7.24(m,3H),6.87(dd,J1=14.1Hz,J2=10.2Hz,1H),4.87(p,J=7.5Hz,1H),3.94(m,1H),2.23(m,2H),1.94(m,2H),1.71(m,1H),1.58(m,1H),1.27(d,J=7.2Hz,3H)。在式2.1的化合物重结晶过程中,用己烷/乙酸乙酯混合物(6:1)洗涤后得到标准溶液,真空蒸发,从己烷中重结晶3次,得到(S)-2-((R)-(全氟苯氧基)-(苯氧基)-磷酰基氨基)丙酸环丁酯(2.2),为白色疏松粉末。1H NMR(300MHz,DMSO-d6)δ7.42(m,2H),7.26(m,3H),6.85(dd,J1=13.8Hz,J2=10.2Hz,1H),4.88(p,J=7.5Hz,1H),3.95(m,1H),2.24(m,2H),1.93(m,2H),1.72(m,1H),1.59(m,1H),1.28(d,J=6.9Hz,3H)。
在氩气气氛中在0℃向(2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-2-(羟基甲基)-4-甲基-4-氟-四氢呋喃-3-基碳酸叔丁酯(7:5g,13.9mmol)在THF(165ml)中的溶液中加入1M氯化叔丁基镁在THF中的溶液(31.3ml,31.3mmol),将该混合物在室温搅拌30min。在0-5℃使用注射器加入式2.1的化合物(7.8g,16/7mmol)在THF(30ml)中的溶液,将该混合物在氩气气氛中搅拌24小时。在添加甲醇时(10ml),真空蒸发该混合物。将残余物溶于500ml乙酸乙酯,用5%柠檬酸溶液、5%NaHCO3溶液洗涤,用Na2SO4干燥,真空蒸发。用硅胶对残余物进行色谱,应用己烷/乙酸乙酯(1:2)作为洗脱液,得到5.89g(66%)(S)-2-((S)-(((2R,3R,4R,5R)-3-(叔丁氧羰基氧基)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-甲基-4-氟-四氢呋喃-2-基)甲氧基)(苯氧基)磷酰基氨基)丙酸环丁酯(8.1),显然为无色固化泡沫体。LC-MS(ESI)642(M+H)+。
类似地,以中间体7和2为原料制备(S)-2-((((2R,3R,4R,5R)-3-(叔丁氧羰基氧基)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-甲基-4-氟-四氢呋喃-2-基)甲氧基)(苯氧基)磷酰基氨基)丙酸环丁酯(8)(收率:52%,LC-MS(ESI)642(M+H)+);和(S)-2-((R)-(((2R,3R,4R,5R)-3-(叔丁氧羰基氧基)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-甲基-4-氟-四氢呋喃-2-基)甲氧基)(苯氧基)磷酰基氨基)丙酸环丁酯(8.2),以中间体7和2.2为原料(收率:59%,LC-MS(ESI)642(M+H)+)。
在0℃向式8.1的化合物(4.45g,6.9mmol)在二氯甲烷(60ml)中的溶液中加入三氟乙酸(60ml)。将该混合物在室温搅拌15h,真空蒸发,溶于250ml DCM,用300ml 5%NaHCO3洗涤,用Na2SO4干燥,真空蒸发,从乙酸乙酯和甲基-叔丁基醚的混合物(1:1)中重结晶,得到2.7g(71%)(S)-2-((S)-(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-3-羟基-4-甲基-4-氟-四氢呋喃-2-基)甲氧基)-(苯氧基)-磷酰基氨基)丙酸环丁酯(1.1),为白色结晶物质。LC-MS(ESI)542(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.51(brs,1H),7.56(d,J=8.0Hz,1H),7.38(m,2H),7.23(m,2H),7.19(m,1H),6.03(m,2H),5.84(d,J=6.8Hz,1H),5.55(dd,J1=8.0Hz,J2=1.2Hz,1H),4.85(p,J=7.2Hz,1H),4.37(m,1H),4.27(m,1H),4.01(m,1H),3.83(m,2H),2.23(m,2H),1.95(m,2H),1.71(m,1H),1.56(m,1H),1.25(d,J=22.8Hz,3H),1.23(d,J=6.8Hz,3H)。
使式1.1的前药从不同溶剂中重结晶,得到多晶形或晶形。因此,从乙酸乙酯与甲基-叔丁基醚的混合物(1:1)、乙醇、乙酸乙酯和乙酸与水的混合物中重结晶得到多晶形形式的前药1.1,其主要包含正交晶相,其具有的晶胞参数为:a=28.1056(8)А,b=16.8998(4)А,和c=5.25380(12)А;和单斜晶相,其具有的晶胞参数为:a=16.2770(6)А,b=16.9117(8)А,c=5.20429(15)А,和β=117.822(2)°。
使式1.1的前药从二甲亚砜与水的混合物中重结晶得到白色结晶物质,其由正交晶相组成,该正交晶相具有的晶胞参数为:a=28.1056(8)А,b=16.8998(4)А,和c=5.25380(12)А。
从在рН2和рН7下0.18-0.25mg/ml之间改变的不同溶剂中重结晶后,晶形和多晶形具有相似的溶解度值。例外的是从二甲亚砜中重结晶得到的多晶样品,其溶解度略高并且在0.63-0.67mg/ml之间变化(表1)。
表1. 260nm波长的式1.1的前药的多晶形和晶形的动力学溶解度
类似地,制备(S)-2-((((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-3-羟基-4-甲基-4-氟-四氢呋喃-2-基)甲氧基)-(苯氧基)-磷酰基氨基)丙酸环丁酯(1)(收率:58%;LC-MS(ESI)542(M+H)+和(S)-2-((R)-(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-3-羟基-4-甲基-4-氟-四氢呋喃-2-基)甲氧基)-(苯氧基)-磷酰基氨基)丙酸环丁酯(1.2)(收率:64%;LC-MS(ESI)542(M+H)+。1H NMR(300МHz,DМSО-d6)δ11.53(brs,1H),7.56(d,J=8.1Hz,1H),7.38(m,2H),7.19(m,3H),6.08(m,2H),5.91(d,J=6.3Hz,1H),5.57(d,J=8.1Hz,1H),4.85(p,J=7.5Hz,1H),4.41(m,1H),4.27(m,1H),4.05(m,1H),3.79(m,2H),2.23(m,2H),1.94(m,2H),1.70(m,1H),1.56(m,1H),1.24(d,J=23.4Hz,3H),1.21(d,J=6.0Hz,3H)。
实施例2.式А2的(S)-2-((S)-(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-3-羟基-4-甲基-4-氟-四氢呋喃-2-基)甲氧基)-(苯氧基)-磷酰基氨基)丙酸环丙酯的前药的合成方案(方案2)
方案2
将环丙基胺(9:4.06ml,58.8mmol)和Boc-L-丙氨酸(22.2g,58.8mmol)溶于250ml氯仿,在用冰冷却下加入亚硝酸异戊酯(7.9ml,58.8mmol)。在冷却下将该混合物搅拌16h,蒸发至干,进行硅胶色谱(用乙酸乙酯:己烷1:8洗脱),得到7.68g(57%)1:4之比的式10的环丙酯和式11的烯丙基醚的混合物(基于1H NMR数据)。将得到的酯10和醚11混合物溶于120ml乙腈,此时在氩气气氛中加入三苯膦(446mg,1.7mmol)和Pd(PPh3)4(984mg,0.85mmol)。用冰冷却该溶液,用吡咯烷(2.49g,35mmol)在乙腈(30ml)中的溶液稀释。将该混合物在氩气气氛中在0-4℃搅拌16h,蒸发至干,进行硅胶色谱(用乙酸乙酯:己烷1:8洗脱),得到1.38g(S)-2-(叔丁氧羰基氨基)丙酸环丙酯(15)。1H NMR(CDCl3,400MHz)δ5.04(br.s.,1H),4.26(m,1H),4.19(m,1H),1.46(с,9H),1.37(d,J=7.2Hz,3H),0.74(m,4H)。
向式12的化合物(3.5g,15.3mmol)在10ml二噁烷中的溶液中加入20ml 3МHCl的二噁烷溶液。将该混合物在室温搅拌2h,蒸发至干,得到2.53g(S)-2-氨基-丙酸环丙酯盐酸盐(13)。1H NMR(DMSO-d6,300MHz)δ8,65(br.s.,3H),4,19(m,1H),3,99(к,J=6.9Hz,1H),1.39(d,J=6.9Hz,3H),0.73(m,4H)。
向冷却至-70℃的式13的化合物((2.53g,15.3mmol)和苯基二氯磷酸酯(3.23g,15.3mmol)在50ml二氯甲烷的溶液中滴加三乙胺(4.26ml,30.6mmol)在10ml二氯甲烷中的溶液。然后使该混合物的温度升至-10℃,滴加预先已经制备的五氟苯酚(2.82g,15.3mmol)和三乙胺(2.13ml,15.3mmol)在15ml二氯甲烷中的混合物。添加完成时,将该反应混合物在室温搅拌12h,然后蒸发,用50ml苯处理残余物。过滤出残余物,用15ml苯洗涤。用饱和碳酸氢钠溶液洗涤滤液,用硫酸钠干燥,蒸发。向残余物中以8ml/1g的速率加入乙酸乙酯:己烷1:4的混合物,将得到的混合物剧烈搅拌16h。过滤出残余物,使其从乙酸乙酯:己烷1:4的混合物中重结晶,得到1.02g(14%)(S)-2-((S)-(全氟苯氧基)-磷酰基氨基)丙酸环丙酯(14)。LC-MS(ESI)452(M+H)+。1H NMR(CDCl3,300MHz)δ7.38(m,2H),7.26(m,3H),4.7(m,1H),3.96(m,1H),1.46(d,J=7.2Hz,3H),0.74(m,4H)。
向用冰冷却的(2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-2-(羟基甲基)-4-甲基-4-氟-四氢呋喃-3-基碳酸叔丁酯(820mg,1.85mmol)在25ml干THF中的溶液中滴加1Мt-BuMgCl的THF溶液(4ml,0.4mmol)。终止冷却,将该反应混合物在室温搅拌0.5h,然后再用冰冷却,滴加式14的化合物(1.02g,2.18mmol)在THF中的溶液。将该反应混合物在室温搅拌12h,然后用饱和氯化铵溶液处理。分离有机相,用二氯甲烷萃取水相。用硫酸钠干燥合并的萃取物,过滤,得到~1.16g(S)-2-((S)-(((2R,3R,4R,5R)-3-(叔丁氧羰基氧基)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-甲基-4-氟-四氢呋喃-2-基)甲氧基)-(苯氧基)-磷酰基氨基)丙酸环丙酯(15),照此用于下一步。LC-MS(ESI)628(M+H)+。
在用冰冷却下向式15的化合物(~1.16g,1.85mmol)在20ml二氯甲烷中的溶液中加入三氟乙酸(20ml)。将该反应混合物搅拌3h,然后真空浓缩。将残余物溶于二氯甲烷,用水稀释,用碳酸氢钠中和。分离有机层,用硫酸钠干燥,蒸发至干。对残余物进行硅胶色谱(氯仿:甲醇),使其从乙酸乙酯:MTBE中重结晶,得到505mg式А2的(S)-2-((S)-(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-3-羟基-4-甲基-4-氟-四氢呋喃-2-基)甲氧基)-(苯氧基)-磷酰基氨基)丙酸环丙酯(52%)。LC-MS(ESI)528(M+H)+。1H NMR(DMSO-d6,400MHz)δ11.24(br.s.,1H),7.56(d,J=8.1Hz,1H),7.38(m,2H),7.20(m,3H),6.05(m,2H),5.86(m,1H),5.54(d,J=8.1Hz,1H),4.36(m,1H),4.23(m,1H),4.02(m,2H),3.82(m,2H),1.25(d,J=22.2Hz,3H),1.21(d,J=6.6Hz,3H),0.66(m,2H),0.57(m,2H)。
实施例3.片剂形式的药物组合物的制备
将淀粉(500mg)、研磨的乳糖(800mg)、滑石粉(200mg)和1500mg式1.1的前药彼此混合,压制成棒形物。将得到的棒形物粉碎成颗粒,过筛,采集14-16目颗粒。使由此得到的颗粒成形为适合形式的片剂,每片重400或800mg。
实施例4.胶囊形式的药物组合物的制备
将式1.1的前药谨慎地与乳糖粉末按照1:1之比混合。将得到的粉末混合物包装入具有适当大小的胶囊,每粒胶囊中200或400mg。
实施例5.用于肌内、腹膜内或皮下注射的组合物形式的药物组合物的制备
将式1.1的前药(500mg)与氯丁醇(300ml)、丙二醇(2ml)和注射用水(100ml)混合。过滤得到的溶液,置于5ml安瓿中并且密封。
使用用HCV复制子稳定转染的Huh7人肝细胞癌细胞系评价包含前药的测试组合物的抗病毒活性。将完全培养基(DMEM 1X,Cellgro;目录号10-013-CV)中的细胞悬浮液转移到96-孔板(每孔50μl)中,最终密度为每孔7500个细胞。所测试的前药的连续稀释液由DMSO中新鲜的200倍通用溶液制备,具有11个浓度点和3倍增量,从完全培养基中的20nM开始,并且一式两份使用。铺板细胞后最少4小时,向每个孔中加入50μl连续前药稀释液。最终的前药浓度为10nM-0.1pM,DMSO的浓度为0.5%。将具有细胞的平板在37℃和加湿的5%CO2气氛中温育3天。温育完成时,通过将板翻转并谨慎摇动除去培养基。将细胞用100μl 1:1丙酮:甲醇溶液固定1分钟,用磷酸盐缓冲液(PBS)洗涤3次,并在室温下使用PBS中的10%胎牛血清(FBS)(150μl/孔)封闭1小时。将细胞用PBS洗涤3次,并使用Affinity BioReagents(目录号#MA1-080)和以在10%FBS-PBS中的比例为1:4000稀释通用溶液(1mg/ml))在37℃下与抗-NS5B HCV抗体(100μl/孔)一起温育2小时。将细胞用PBS洗涤3次并通过OPD溶液(100μl/孔)展开,每个板使用溶解在柠檬酸盐/磷酸盐缓冲液(12ml)中的一片OPD片剂,其中加入5μl 30%H2O2,用在室温下避光30分钟。用2N H2SO4(100μl/孔)终止反应,并使用多功能读数器Victor3V 1420(Perkin Elmer)测量OD490。根据使用GraphPad Prizm软件绘制的活性曲线测量测试的前药的ЕС50值。式1.1的新型前药对1b(gT1b)HCV基因型具有ЕС50=15.0-27.0nM和ЕС90=128.0nM;具有ЕС50=45-170nM和ЕС90=590nM;式А1的环己基酯,ЕС90=250.0nM;式А2的环丙酯,ЕС90=73.0nM和ЕС90=410.0nM(表1а)。因此,式1.1的新型前药的活性超过/>的3倍,为式А1化合物的2倍,并且为式А2化合物的3倍以上。
使用ATPLite试剂盒(Perkin-Elmer,Boston,USA)根据制造商的说明在相同细胞系Huh7中同时评价包含前药的测试组合物的细胞毒性。将完全培养基(DMEM 1X,Cellgro;目录号10-013-CV)中的细胞悬浮液转移到具有黑色壁和透明底部(50μl/孔)的96孔板中,最终密度为每孔7500个细胞。铺板细胞后18小时,加入连续药物稀释液(50μl/孔)。将具有细胞的平板在37℃加湿的5%CO2气氛中温育4天。然后用PBS(200μl/孔)洗涤细胞两次,并通过加入裂解缓冲液(50μl/孔)裂解;所有试剂均取自ATPLite试剂盒。在振荡器上搅拌5分钟后,加入底物(50μl/孔)。再温育5分钟后,将板在黑暗中保持10分钟,并使用多功能读数器Victor3V 1420(Perkin Elmer)测量孔中的发光。从使用GraphPad Prizm软件绘制的细胞毒性曲线测量测试的前药的CС50值。特别地,对于式1.1的新型前药,将细胞毒性测定为СС50>100μM(表1a),且治疗窗(治疗指数TI=EC50/CC50)TI>6000.0。
实施例7.化合物的动力学溶解度的评价
方法原理.将测试的化合物溶解在DMSO中以达到10-mM浓度,然后倾入含水溶剂(磷酸盐缓冲液,水或不同pH值的通用缓冲液)中以使浓度降至200μM。将置于96-孔滤板(Millipore的MultiScreen溶解性滤板)中的所得溶液在室温下在摇床上温育1小时,并将残余物真空滤出。在分光光度计上记录化合物的吸收光谱,其范围为240-400nm,增量为10-nm。为了定量估计溶解度,使用包含40%乙腈的标准溶液(0-200μM)的校准曲线。估计浓度范围为3-200μM。测试程序一式两份进行。
校准标准品的制备.从在在含有40%乙腈的缓冲液中稀释的DMSO中的50倍储备溶液制备校准标准品,向其中加入以确保测试化合物在校准样品中的完全溶解。通过在DMSO中加入4μl相应的50x储备溶液至196μl包含40%乙腈的缓冲液,在UV 96-孔板的孔中制备浓度为0、3.125、12.5、50、100和200μM的六个标准样品。所有点中DMSO的浓度恒定且等于2%(v/v)。
为绘制校准曲线,在250-400nm的波长范围内UV板的光谱记录,增量为10-nm。基于每种化合物的光谱数据,选择波长以满足以下标准:
-对于最小化合物浓度,OD>0.1(AU);
-对于最大化合物浓度,OD<2.0.
对于每种化合物,绘制校准曲线,其中OD在选定波长下作为浓度的函数。
化合物的动力学溶解度的评价.如下在MultiScreen Solubility(MilliporeCorp.)滤板中评价溶解度:
·向MultiScreen Solubility滤板的每个孔中加入196μl缓冲液(不含乙腈)和4μl 10-mM化合物的DMSO溶液或4μl DMSO(用于空白基质)。将板在室温下在摇床(400rpm)上温育1小时。
·通过真空(10”Hg)将所得溶液通过滤板滤出到具有U形底部的聚丙烯板中。
·从U形底板上,将滤液(120μl/孔)转移到新的UV板中,向其中加入乙腈(80μl/孔)。
·测量每种化合物对于预选波长的所得溶液的光密度。
计算.滤液中最终化合物浓度如下计算:
C滤液=(ODλ滤液-ODλ空白)/斜率x 1.67
其中
ODλ滤液为选择的波长的滤液的光密度;
ODλ空白为空白基质的OD;
斜率为校准线梯度;
1.67为用乙腈稀释的滤液的稀释因子。
结果如表1中所示。
实施例8.前药样品的X-射线粉末相分析。
所有衍射图案在Bruker D8Advance Vario衍射仪上记录,该衍射仪配备有铜-阳极X射线管和Ge(111)单色器(CuKo^)和LynxEye位置敏感检测器,在窥视设置中。样品s5的照射范围为3-90°26,而其他样品的照射范围为5.7-90°26,且增量为0.01°26。使用BrukerTopas5软件进行分析['Bruker TOPAS 5 User Manual.—Karlsruhe,Germany:Bruker AXSGmbH,2015.]。
通过从乙酸乙酯和甲基-叔丁基醚(1:1)的混合物,乙醇,乙酸乙酯和乙酸与水的混合物中重结晶得到式1.1化合物的样品具有多晶形。这些样品的X射线粉末相分析揭示了它们的定性相结构的相似性和它们的相关系的微不足道的差异。样品具有斜方晶相,具有以下晶胞参数:a=28.1056(8)A,b=16.8998(4)A,c=5.25380(12)A。系统消光分析允许人们假设P212121的空间群。晶胞体积2495.45(11)А3相当于要求保护的组合物且Z'=1。样品也具有单斜晶相,具有以下晶胞参数:a=16.2770(6)А,b=16.9117(8)А,c=5.20429(15)А,β=117.822(2)°。系统消光分析允许人们假设P21的空间群。晶胞体积为1266.98(9)А3相当于要求保护的组合物且Z'=1。基于积分峰强度比较的位相关系评价启示单斜晶相的含量在30-50%之间变化。
通过从二甲基砜与水的混合物中重结晶式1.1化合物得到的样品是结晶形式的白色物质。根据X射线粉末分析数据,所述形式的样品是单相的并且由具有以下晶胞参数的斜方晶相组成:a=28.1056(8)A,b=16.8998(4)A,c=5.25380(12)A。系统消光分析允许人们假设P212121的空间群。晶胞体积2495.45(11)А3相当于要求保护的组合物且Z'=1。
实施例9.包含式1.1的前药的组合物在生物基质中的稳定性评价。
将包含式1.1前药(测试化合物)的初始组合物在DMSO中以10mM的浓度制备。从所述组合物中,以100μM的浓度在乙腈:水的混合物中以1:1的体积比制备100倍的工作溶液。
a)在S9部分中的稳定性.在0.1M磷酸钾缓冲液(pH 7.4BD Gentest)中制备反应混合物,总终体积为250μl,并含有1mM NADPH-四钠盐(AppliChem),7mM葡萄-6-磷酸钠盐(Sigma),1.5U/ml葡糖-6-磷酸脱氢酶(Sigma),3.3mM MgCl2(Sigma),5mM尿苷-5-二磷酸-葡糖醛酸三钠盐(UDPGluA,Sigma)和1μM测试化合物(这些是终浓度)。通过添加人肝S9部分(BD Gentest)的悬浮液启动代谢反应,并且蛋白质的终浓度为1mg/ml。将反应混合物在37℃下在Vortemp56振荡器上温育,同时以400rpm搅拌。在一定间隔(0、0.25、0.5、1、2、4、6、8、24小时)后,取30μl样品;通过向所取样品中加入包含内标的冷乙腈(180μl)终止反应。将蛋白质在冰上沉积15分钟。然后将样品以3000rpm离心10分钟,取上清液(150μl)进行分析。温育一式两份进行两次,每个样品测量两次。
b)在人造胃液和肠液中的稳定性.将包含最终浓度为1μM的式1.1前药的测试组合物在人工胃液(在0.7%v/v HCl中的0.2%NaCl)和人造肠液(0.05M KH2PO4,pH 6.75)中温育。温育在Vortemp56振荡温育箱中于37℃进行,同时以300转/分钟的速率搅拌。在一定间隔(0、0.25、0.5、1、2、4、6、8、24小时)后,取30μl样品;通过向所取样品中加入包含内标的冷乙腈(180μl)终止反应。然后将样品离心,以3000转/分钟取样上清液(150μl)10分钟用于分析。温育一式两份进行两次,每个样品测量两次。
c)在血浆中的稳定性.将最终浓度为1μM的测试化合物在合并的人血浆中温育(Innovative Research)。温育在Vortemp56振荡温育箱中于37℃进行,同时以300转/分钟的速率搅拌。在一定间隔(0、0.25、0.5、1、2、4、6、8、24小时)后,取30μl样品;通过向所取样品中加入包含内标的冷乙腈(180μl)终止反应。然后将样品离心,以3000转/分钟10分钟取样上清液(150μl)用于分析。温育一式两份进行两次,每次样品测量两次。
样品分析.使用针对每种测试的前药开发的HPLC-MS/MS技术分析样品,其中将色谱系统1290Infinity II(Agilent Technologies)与串联质谱仪QTRAP5500(AB Sciex)组合。在开发质谱检测条件时,使用注射泵将测试化合物在浓度为100ng/ml的乙腈-水(1:1)混合物中的溶液直接注入质谱仪中,并在正离子模式下进行电喷雾电离。以总离子电流模式(MS1)扫描允许我们识别每种化合物的分子离子,并且以MS2模式记录碱性产物离子。然后,为了获得最大灵敏度,将MS/MS技术在MRM模式下进行优化。在定量色谱图处理中,最强烈的MRM转换用于分析物和内标。通过在YMC Triart C18柱(50x 2mm,1.9μm)上的线性梯度洗脱色谱在由0.1%甲酸水溶液和0.1%甲酸乙腈溶液组成的流动相中进行分离。甲苯磺丁脲(Fluka)用作内标。
计算.在生物基质中温育期间,根据抗病毒组合物中测试的前药消除动力学测定半衰期(Т1/2)。计算基于标准化为内标信号的测试样品中化合物的色谱峰面积值。根据色谱峰的对数归一化面积随时间的线性依赖性,计算消除速率的常数(k是线性截面斜率)。然后,测定半衰期:Т1/2=0.693/k。特别是(表2)发现,式1.1的前药、式А1的化合物和在人体肠液(Т1/2 SGF=12.7-17h)、人肠液(Т1/2 SIF>20h)和人体血浆(Т1/2 HPL>24h)中具有相差无几的稳定性。同时,式1.1的前药在人肝微粒体S9部分中更活跃地代谢并具有半衰期Т1/2 HS9=0.05h,而其原型/>具有Т1/2 HS9=0.57h,且式А1的环己酯具有Т1/2 HS9=1.4h(表2),这意味着式1.1的前药在人肝微粒体S9部分中代谢比/>快11倍,并且比式А1的化合物快28倍。
用于施用于大鼠的包含式1.1的前药和的组合物的制备.以50mg/kg的剂量施用测试的组合物。为此,在0.5%羟丙基甲基纤维素(HPMC)溶液中制备浓度为5.0mg/ml的式1.1的前药或/>的组合物,向其中加入5%乙醇,如下:向称重的部分式1.1的前药或/>中加入适量的HPMC,将该混合物在研钵中研磨干燥,然后逐渐加入适量的5%乙醇的蒸馏水溶液,并谨慎地将混合物搅拌以获得适于胃内施用的悬浮液。
包含式1.1的前药和的组合物在动物中的施用.血浆和肝样品的制备.本研究对Sprague Dawley大鼠进行。基于选定的时间点(1、2、4、6、8、10、12、16和24小时)将大鼠分成6只的组。称重大鼠,并通过饲管胃内施用包含式1.1前药或/>的组合物的体积。在施用于某一组动物的间隔期间,取肝脏和血液样品。在施用后适当的一段时间期限后,通过CO2吸入使大鼠安乐死。在安乐死之后,立即迅速打开动物,切割其肝上叶并立即置于液氮中。然后将冷冻的肝脏片段转移到用液氮冷却的标记试管中。将样品保持在液氮中直至实验结束,然后放入-80℃的超冷冰箱中。
样品制备.将重约1g的肝样品在研钵中研磨,同时用液氮冷却。将得到的粉末用三倍体积的甲醇和70%甲醇与EDTA一起倾入,并使用Omni Bead Ruptor 24均化器以6.3m/s的速率均化两次45秒(间隔10秒)。向360μl如此获得的匀浆中加入40μl含有PSI-7409和H027-4261(或实验样品中的甲醇)和100μl 25ng/ml浓度的内标溶液(5-溴尿苷三磷酸)的10倍标准溶液。搅拌和离心后,将400μl上清液用400μl1%甲酸在甲醇-水(1:1)的混合物中的溶液稀释。然后,使用Waters Oasis WAX柱进行固相萃取。用800μl 5%氨的甲醇溶液洗脱所得产物,蒸发洗脱液并重新溶解在200μl甲醇中。
HPLC-MS/MS分析条件.使用HPLC-MS/MS技术分析样品,其中HPLC系统Agilent1290Infinity II与AB Sciex QTrap 5500质谱仪组合。在Thermo Hypercarb柱(50x 3mm,5μm)上进行分离。使用25-mM乙酸铵与0.5%铵的溶液作为流动相A(MPA);使用25-mM的乙酸铵在水-异丙醇-乙腈(1:1:3)与0.5%铵的混合物中的溶液作为流动相B(MPB)。以梯度模式进行分离:0-0.3min-5%MPB;3-3.4min-50%MPB;3.6-4.5min-5%MPB。以MRM模式记录PSI-7409和H027-4261,其中离子跃迁分别为499/159和410/150。
药代动力学分析.使用PhoenixTM 6.3(Pharsight Corp.)和GraphPad Prizm软件通过非隔室技术进行“肝脏浓度对时间关系”数据的药代动力学分析。计算以下药代动力学参数:肝脏中的最大浓度(Сmax)及其实现时间(Tmax),半衰期(T1/2)和PK曲线下面积(AUC0-t,AUC0-inf)。结果在表3中给出。正如从表3中可以看出的,由大鼠肝脏中的式1.1的前药代谢产生的三磷酸PSI-7409的浓度和AUC24h分别为Сmax=3224.0ng/g和AUC24h=30487.0ng·h/g,而表现出相似的代谢的/>具有Сmax=1934.0ng/g和AUC24h=16796.0ng·h/g,式А1的环己酯具有Сmax=557ng/g和AUC24h=6484.0ng·h/g(表3)。这启示与/>相比,式1.1的新型前药在肝脏代谢中几乎两倍有效地成为期望的三磷酸PSI-7409(药物),而与式А1的环己酯相比,为4.7倍。
工业实用性
本发明可以在医学和兽医中使用。
Claims (8)
3.医疗用药物,具有HCV NS5B聚合酶抑制剂特性,并且是权利要求1的化合物,其预期用于治疗有此需要的人或温血动物的丙型肝炎。
5.药物组合物,包含治疗有效量的权利要求1的化合物和药学上可接受的载体。
6.权利要求5的药物组合物,用于治疗丙型肝炎病毒。
7.权利要求5或权利要求6的药物组合物或权利要求1的化合物、或其立体异构体、或其同位素富集的类似物、晶形或多晶形在制备用于治疗感染丙型肝炎病毒的受试者的药物中的用途。
8.权利要求7的用途,其中所述药物预期用于在有此需要的受试者中治疗由丙型肝炎病毒导致的感染。
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