CN110678473A - 核苷类抗癌药或抗病毒药的5’位二苄基单磷酸酯衍生物 - Google Patents
核苷类抗癌药或抗病毒药的5’位二苄基单磷酸酯衍生物 Download PDFInfo
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- CN110678473A CN110678473A CN201880031751.6A CN201880031751A CN110678473A CN 110678473 A CN110678473 A CN 110678473A CN 201880031751 A CN201880031751 A CN 201880031751A CN 110678473 A CN110678473 A CN 110678473A
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Abstract
本发明要解决的问题是提供一种药物,其代替临床中使用的作为癌症或病毒感染的治疗药的注射剂(核苷类抗癌药或抗病毒药),具有针对各种水解代谢酶的高稳定性,可以通过口服给药在体内被吸收,嵌入DNA和RNA的生物合成途径,抑制DNA和RNA的修饰、延伸或抑制反转录酶,抑制蛋白质合成,表现出细胞毒性。解决技术问题的方法是由通式(I)(其中,D是核苷类抗癌药或抗病毒药的5’位部分,R1和R2相同或不同,各自独立地是可以具有取代基的苄基)所表示的新型化合物。
Description
技术领域
本发明涉及一种化合物,这种化合物具有针对各种水解代谢酶的高稳定性,并且可以用作核苷类抗癌药或抗病毒药的5′位单磷酸酯的前药。
背景技术
目前,作为临床中使用的抗癌性核苷类,可以列举阿糖胞苷(Cytarabine)(胞嘧啶阿拉伯糖苷(Cytosine arabinoside),阿糖胞嘧啶(Ara-C),“Cytosar-U(注册商标)”,“Depocyt(注册商标)”),氟尿苷(Floxuridine)(“FUDR(注册商标)”),喷司他汀(Pentostatin)(脱氧柯福霉素(Deoxycoformycin),“Nipent(注册商标)”),氟达拉滨(Fludarabine)(“Fludara(注册商标)”),克拉屈滨(Cladribine)(“Leustatin(注册商标)”),吉西他滨(Gemcitabine)(“Gemzar(注册商标)”),5-氮杂胞苷(5-Azacytidine)(阿扎胞苷(Azacitidine),“Vidaza(注册商标)”),2’-脱氧-5-氮杂胞苷(地西他滨(Decitabine),“Dacogen(注册商标)”),氯法拉滨(Clofarabine)(“Clolar(注册商标)”,“Evoltra(注册商标)”),奈拉滨(Nelarabine)(“Arranon(注册商标)”,“Atriance(注册商标)”),三氟胸苷(Trifluorothymidine)(TFT,曲氟尿苷(Trifluridine),“Viroptic(注册商标)”,“Lonsurf(注册商标)”)等。在频繁分裂的癌细胞中,这些核苷类的5’位羟基通过各自相应的核苷激酶(2’-脱氧胞苷激酶,胸苷激酶1和2,或2-脱氧鸟苷激酶)单磷酸酯化后,经核酸生物合成途径嵌入DNA和RNA,抑制DNA和RNA的修饰、延伸,从而抑制相应的蛋白质合成,表现出细胞毒性,因此被用作各种癌症治疗药剂(非专利文献1)。
另外,目前,作为临床中使用的抗病毒性核苷类,可以列举齐多夫定(Zidovudine)(ZDV、叠氮胸苷(Azidothymidine)、AZT、“Retrovir(注册商标)”),拉米夫定(Lamivudine)(3TC、“Epivir(注册商标)”),司他夫定(Stavudine)(Sanilvudine、d4T、“Zerit(注册商标)”),阿巴卡韦(Abacavir)(ABC、“Ziagen(注册商标)”),恩曲他滨(Emtricitabine)(FTC、“Emtriva(注册商标)”、“Coviraci(注册商标)”),地丹诺辛(Didanosine)(ddI、“Videx(注册商标)”),扎西他滨(Zalcitabine)(ddC、“Hivid(注册商标)”)等。在感染了病毒的细胞中,这些核苷类均在5’位羟基通过各自相应的核苷激酶被单磷酸酯化,经核酸生物合成途径嵌入DNA和RNA,抑制与DNA和RNA合成相关的反转录酶,表现出细胞毒性,因此被用作抗病毒药(非专利文献2~3)。
然而,这些核苷类的5’位羟基的单磷酸酯化是在核酸生物合成途径中最决定速度的步骤,并且当长期使用这些抗癌药和抗病毒药时,会引起与该单磷酸酯化步骤相关的核苷激酶的下调,倾向于成为对这些核苷系抗癌药和抗病毒药的耐药性的原因(非专利文献4)。
因此,作为临床中使用的药物,更理想的是使用这些核苷类抗癌药和抗病毒药的5’位单磷酸酯,即单核苷酸水平的化合物。然而,由于相应的5’位单磷酸酯类均含有极性较高的游离磷酸残基,因此在生物体内均无法顺利穿过细胞膜,据推测无论通过哪种方法给药都不能达到预期的临床效果。
在以上背景下,关于核苷类抗癌药和抗病毒药已研究了相应的5’位单磷酸酯的各种前药化。例如,作为磷酸残基的保护基,研究了在侧链中使用含有容易被羧酸酯酶水解代谢的酯的官能团,以及使用容易被磷酸酰胺酶水解代谢的磷酰胺官能团(非专利文献5)。
然而,在多次尝试中,由于对血液中或肝脏中存在的各种水解酶的稳定性极低,或在脱保护过程中生成的化合物的细胞毒性较高,无法表现出所期望的临床效果。另外,由这些尝试的结果发现,作为能够用于临床的药物,可列举替诺福韦酯(Tenofovir DF)(“Viread(注册商标)”)(专利文献1),帕拉德福韦(Pradefovir)(PDV、“Remofovir(注册商标)”、”Hepavir(注册商标)”)(专利文献2),索非布韦(Sofosbuvir)(“Sovaldi(注册商标)”)(专利文献3)等抗病毒药。
因此,作为用于核苷类抗癌药或抗病毒药的5’位单磷酸酯的前药,期望获得一种衍生物,其本身具有针对多种水解代谢酶的高稳定性,在细胞内非酶促地或酶促地发生脱保护,能够很容易地游离出核苷类抗癌药或抗病毒药的5’位单磷酸酯,并且在脱保护过程中生成的化合物的细胞毒性较低。
现有技术文献
专利文献
专利文献1:美国专利5977089号
专利文献2:国际专利03095665号公报
专利文献3:美国专利2010016251号公报
非专利文献
非专利文献1:Chemical Reviews,2016年,第116卷,第23期,14379-14455页
非专利文献2:Clinical Microbiology Reviews,2016年,第29卷,第3期,695-747页
非专利文献3:Medical Research Reviews,2016年,第36卷,第6期,1127-1173页
非专利文献4:Biochemical and Biophysical Research Communications),2012年,第421卷,第1期,98-104页
专利文献5:Chemical Reviews,2014年,第114卷,第18期,9154-9218页
发明内容
发明要解决的问题
本发明的目的在于提供一种核苷类抗癌药或抗病毒药的5’位单磷酸酯的衍生物,这些衍生物本身具有针对多种水解代谢酶的高稳定性,能够在细胞内顺利地非酶促或酶促地发生脱保护,进入核酸生物合成途径,并且在脱保护过程中生成的化合物的细胞毒性较低。
解决问题的手段
为了提供用于预防或治疗癌症或病毒感染的更有用的药物,本发明人已经认真开展了寻找新型化合物的研究,这些化合物具有针对代谢酶胞苷脱氨酶等水解代谢酶的高稳定性,并且能够在生物体内进入核酸生物合成途径中,既具有优异的药理学作用,又具有优异的物理化学特性。本发明人因此合成了包括5-氮杂胞苷在内的多种核苷类抗癌药或抗病毒药的5′位二烷基单磷酸酯衍生物,并且研究了其化学反应性,结果本发明人发现,具有特定结构的核苷类抗癌药或抗病毒药的5′位二烷基单磷酸酯衍生物出乎意料地表现出以下作为药物的优异特性:本身具有针对多种水解代谢酶的高稳定性,而且能在细胞内顺利地非酶促或酶促地发生脱保护,进入核酸生物合成途径中,并且在脱保护过程中生成的化合物的细胞毒性较低。经过进一步研究,本发明人最终完成了本发明。
即,上述技术问题已通过下文中所记载的发明而得以解决。
[1]一种由通式(I)表示的化合物或其盐
(其中,D是核苷类抗癌药或抗病毒药的5’位部分,R1和R2相同或不同,各自独立地是可以具有取代基的苄基)。
[2]根据[1]中所述的化合物或其盐,其中R1和R2各自独立地是可以具有烷基或卤素原子作为取代基的苄基。
[3]根据[2]中所述的化合物或其盐,其中烷基是C1-C6烷基。
[4]根据[2]中所述的化合物或其盐,其中烷基是甲基或乙基。
[5]根据[2]中所述的化合物或其盐,其中卤素原子是氟原子、氯原子或溴原子。
[6]根据[2]中所述的化合物或其盐,其中R1和R2是苄基。
[7]根据[1]中所述的化合物或其盐,其中D表示的核苷类抗癌药是阿糖胞苷、氟尿苷、喷司他汀、氟达拉滨、克拉屈滨、吉西他滨、氯法拉滨、奈拉滨、三氟胸苷、DFP-10917、虫草素、8-氯腺苷、RX-3117、曲西立滨、呋咯地辛、5-氟脱氧胞苷、利巴韦林或阿卡地新。
[8]根据[1]中所述的化合物或其盐,其中D表示的核苷类抗病毒药是齐多夫定、拉米夫定、司他夫定、阿巴卡韦、恩曲他滨、地丹诺辛或司他夫定。
[9]根据[1]所述的化合物或其盐,其中化合物是
[10]一种制备[1]中所述的化合物或其盐的方法,其包括:使核苷类抗癌药或抗病毒药与氯氧化磷反应,然后在脱卤化氢剂的存在下使其与可以具有取代基的苯甲醇反应,或者包括使核苷类抗癌药或抗病毒药在脱卤化氢剂的存在下与可以具有取代基的二苄基卤代磷酸酯衍生物反应。
[11]一种药物组合物,其包含[1]至[9]中任一项所述的化合物或其盐。
[12]根据[11]中所述的药物组合物,其是癌细胞或病毒感染细胞的增殖抑制剂。
[13]根据[11]中所述的药物组合物,其是用于预防或治疗癌症或病毒感染的药物。
[14]一种抑制哺乳动物中癌细胞或病毒感染细胞增殖的方法,包括:将有效量的[1]至[9]中任一项所述的化合物或其盐给药至哺乳动物。
[15]一种用于预防或治疗哺乳动物中癌症或病毒感染的方法,包括:将有效量的[1]至[9]中任一项所述的化合物或其盐给药至哺乳动物。
发明效果
根据本发明,核苷类抗癌药或抗病毒药的5′位二苄基单磷酸酯衍生物变得比相应的核苷类抗癌药或抗病毒药的脂溶性更高,因此可用于口服给药,在肠部被吸收后,它们不受血液或肝脏中的各种水解代谢酶(例如:羧酸酯酶、胞苷脱氨酶、核酸酶、磷酸酶、磷酸二酯酶等)的影响,而穿过频繁分裂的癌细胞和病毒感染细胞的细胞膜,在细胞膜内或细胞内逐渐非酶促地水解,然后通过磷酸二酯酶进行酶促水解,游离出相应的核苷类抗癌药或抗病毒药的5′位单磷酸酯。推测这些5′位单磷酸酯衍生物经由核酸生物合成途径嵌入DNA和RNA中,从而抑制DNA和RNA的修饰、延伸,抑制相应的蛋白质合成,抑制反转录酶,表现出细胞毒性,因此它们可预期起到用于治疗或预防各种癌症和病毒感染的药物的作用。另外,它们可预期起到也对因核苷激酶下调而产生耐药性的癌症和病毒感染细胞有效的治疗剂作用。
具体实施方式
除非另有特别说明,在本说明书和权利要求所使用的术语具有以下含义。
本发明的化合物或其盐
本发明的化合物是由下通式(I)表示的化合物。
其中,D是核苷类抗癌药或抗病毒药的5’位部分,R1和R2各自独立地是可以具有取代基的苄基。R1和R2可以相同或不同。
如D所示的核苷类抗癌药包括阿糖胞苷(Cytarabine),氟尿苷(Floxuridine),喷司他汀(Pentostatain),氟达拉滨(Fludarabine),克拉屈滨(Cladribine),吉西他滨(Gemcitabine),氯法拉滨(Clofarabine),奈拉滨(Nelarabine),三氟胸苷(Trifluorothymidine,TFT),DFP-10917,虫草素(Cordycepin),8-氯腺苷(8-Chloro-adenosine),RX-3117,曲西立滨(Triciribine),呋咯地辛(Forodesine),5-氟-2’-脱氧胞苷(5-氟-2’-脱氧胞苷),利巴韦林(Ribavirin),阿卡地新(Acadecine)等。这些核苷类抗癌药的化学结构如下所示:
另外,如D所示的核苷类抗病毒药,可以列举齐多夫定(Zidovudine),拉米夫定(Lamivudine),司他夫定(Stavudine),阿巴卡韦(Abacavir),恩曲他滨(Emtricitabine),地丹诺辛(Didanosine),司他夫定(Stavudine)等,这些核苷类抗病毒药的化学结构如下所示:
本发明的由通式(I)所示的化合物例如可列举由以下式(ⅰ)~(xⅵ)所示的化合物等:
在上述式(ⅰ)-(xⅵ)中,R1和R2各自独立地是可以具有取代基的苄基。R1和R2可以相同或不同。
“可以具有取代基的苄基”是指苄基可以具有取代基,也可以不具有取代基。在苄基的可取代的位置处的取代基数目可以是1至5,优选为1至3,当取代基的数目是2或更多时,各取代基可以相同,也可以不同。取代基的实例包括烷基、卤素原子、氰基、硝基等,优选的实例包括烷基和卤素原子。
“烷基”是指(但不限于)饱和脂肪族烃基,例如碳原子数为1-20的直链或支链烷基或环烷基。作为直链或支链烷基,可以列举甲基,乙基,丙基,异丙基,丁基,仲丁基,异丁基,叔丁基,戊基,己基等C1-C6烷基,庚基,1-甲基己基,5-甲基己基,1,1-二甲基戊基,2,2-二甲基戊基,4,4-二甲基戊基,1-乙基戊基,2-乙基戊基,1,1,3-三甲基丁基,1,2,2-三甲基丁基,1,3,3-三甲基丁基,2,2,3-三甲基丁基,2,3,3-三甲基丁基,1-丙基丁基,1,1,2,2-四甲基丙基,辛基,1-甲基庚基,3-甲基庚基,6-甲基庚基,2-乙基己基,5,5-二甲基己基,2,4,4-三甲基戊基,1-乙基-1-甲基戊基,壬基,1-甲基辛基,2-甲基辛基,3-甲基辛基,7-甲基辛基,1-乙基庚基,1,1-二甲基庚基,6,6-二甲基庚基,癸基,1-甲基壬基,2-甲基壬基,6-甲基壬基,1-乙基辛基,1-丙基庚基,正壬基,正癸基等取代基,优选C1-C6烷基。C1-C6烷基的优选的实例为甲基和乙基。环烷基可列举环丙基,环丁基,环戊基,环己基,环庚基,环辛基等。另外,环烷基的优选的实例为环戊基和环己基。
“卤素原子”是指氟原子、氯原子、溴原子、碘原子等。优选的实例是氟原子、氯原子和溴原子。
本发明的由通式(I)所示的化合物的盐可以是药学上可接受的任何盐。这些盐可以列举无机酸盐(例如,盐酸盐、硫酸盐、氢溴酸盐、磷酸盐等)和有机酸盐(例如,乙酸盐、三氟乙酸盐、琥珀酸盐、马来酸盐、富马酸盐、丙酸盐、柠檬酸盐、酒石酸盐、乳酸盐、草酸盐、甲磺酸盐、对甲苯磺酸盐等)等酸加成盐等,但不限制于这些盐。
本发明的由通式(I)所示的化合物可以是晶体,它可以呈单晶形式或多种结晶形式的混合物。可以根据公知的结晶方法通过结晶来制备晶体。
此外,本发明的由通式(I)所示的化合物可以是溶剂合物(例如,水合物等),溶剂合物和非溶剂合物(例如,非水合物等)两者均包括在化合物(I)中。
本发明的核苷类抗癌药或抗病毒药的5′位二苄基单磷酸酯衍生物可以作为核苷类抗癌药或抗病毒药的5′位单磷酸酯的前药。
对于水解代谢酶例如羧酸酯酶、胞苷脱氨酶、核酸酶、磷酸酶、磷酸二酯酶等而言,核苷类抗癌药或抗病毒药的5′位二苄基单磷酸酯衍生物本身是非常稳定的,并且,由消化道吸收的核苷类抗癌药或抗病毒药的5′位二苄基单磷酸酯衍生物在癌细胞或病毒感染细胞的细胞内非酶促或酶促地发生水解,游离出相应的核苷类抗癌药或抗病毒药的5′位单磷酸酯。这些5′位单磷酸酯衍生物经由核酸生物合成途径嵌入DNA和RNA,抑制DNA和RNA的修饰、延伸,抑制相应的蛋白质合成,或者抑制反转录酶,从而预期表现出细胞毒性。
因此,本发明中的核苷类抗癌药或抗病毒药的5′位二苄基单磷酸酯衍生物预期具有针对水解代谢酶的高稳定性,可以作为各种核苷类抗癌药或抗病毒药的5′位单磷酸酯的前药。
本发明的由通式(I)所示的化合物的制备方法
例如,本发明的由通式(I)所示的化合物可以根据以下方法或其他类似方法制备。
方法A
通式(I)的化合物或其盐可以根据公知的方法或其他类似方法而制备(参照Bulletin of the Chemical Society,1969,42(12),3505-8,Nucleic Acids Research,1984,12,5025-36,Chemical&Pharmaceutical Bulletin,1995,43(2),210-215,以及WO-2011113173)。例如,将商购的核苷类抗癌药或抗病毒药(有时称作核苷类)在合适的溶剂中用氯氧化磷活化,然后在脱卤化氢剂的存在下与可以具有取代基的苯甲醇反应,能够得到作为目标化合物的核苷类抗癌药或抗病毒药的5′位二苄基单磷酸酯衍生物(参照化学式(I))。
方法B
可以通过例如,在合适的溶剂中且在脱卤化氢剂的存在下,使商购的核苷类抗癌药或抗病毒药与二苄基氯磷酸酯衍生物反应来制备通式(I)的化合物或其盐,能够得到作为目标化合物的核苷类抗癌药或抗病毒药的5′位二苄基磷酸酯衍生物(参照化学式(I))。
(脱卤化氢剂)
所使用的脱卤化氢剂包括有机碱和无机碱。有机碱的实例包括但不限于三乙胺、N,N-二异丙基乙胺、吡啶、4-二甲基氨基吡啶(DMAP)、正丁基锂和叔丁醇钾。无机碱的实例包括但不限于氢化钠、碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾和碳酸铯。优选地,碱的用量为原料化合物的2当量以上。此外,可以列举出,相对于1摩尔原料化合物,通常为2.0至50.0当量的范围,优选5.0至20.0当量的范围,更优选5.0~10.0当量的范围。
(反应溶剂)
从反应顺利进行等观点来看,本发明的反应优选在溶剂中进行。只要反应能够进行,任何溶剂均可以用于本发明的反应中。
在使用方法A时,反应溶剂的实例可列举磷酸三甲酯、磷酸三乙酯、磷酸三丁酯、磷酸三苯酯、磷酸三甲苯酯等磷酸酯;在使用方法B时,反应溶剂的实例可列举吡啶。此外,只要反应能够进行,溶剂可以以任何量使用。本领域技术人员可以适当地调整用于本发明反应中的溶剂的用量。
(反应温度)
本发明的反应温度没有特殊限制。从提高产率、副产物控制及经济效益等观点来看,可以在一个实施方案中作为实例提及-20℃~50℃(即,负20℃~正50℃)的范围,优选-10℃~30℃(即,负10℃~正30℃)的范围,更优选-10℃~20℃(即,负10℃~正20℃)的范围,甚至更优选-5℃~15℃(即,负5℃~正15℃)的范围,特别优选-5℃~10℃(即,负5℃~正10℃)的范围。
(反应时间)
本发明的反应时间没有特殊限制。从提高产率、副产物控制及经济效益等观点来看,可以作为实例提及0.5小时~120小时的范围,优选1小时~72小时的范围,更优选1小时~48小时的范围,甚至更优选1小时~24小时的范围。然而,本领域技术人员可以适当地调整本发明的反应时间。
本发明的药物组合物
本发明的由通式(I)表示的化合物作为安全的药物可以直接地或者根据公知的方法与药学上可接受的载体混合形成药物组合物而用于哺乳动物(例如,人类、猴、猫、猪、马、牛、小鼠、大鼠、豚鼠、狗、兔等)。
在本发明中,作为药学上可接受的载体,可以使用各种常规有机或无机载体物质作为配制材料,例如可列举固体制剂中使用的赋形剂、润滑剂、粘结剂和崩解剂;液体制剂中使用的溶剂、增溶剂、悬浮剂、等渗剂和缓冲剂。此外,根据需要可以使用防腐剂、抗氧化剂、着色剂、甜味剂等配制添加剂。
作为药物组合物的剂型,例如可列举片剂、胶囊剂(包含软胶囊和微胶囊)、颗粒剂、粉剂、糖浆、乳剂、悬浮液、缓释剂等口服制剂,这些能够安全地口服给药。然而,不限于这些实例,因为还可以液体制剂给药。
可以根据制剂技术领域中的常规方法制备药物组合物,例如可以使用日本药典等中记载的方法。
本发明的通式(I)所表示的化合物的用途
本发明的通式(I)所表示的化合物具有多种治疗和预防的用途。在优选的实施方案中,用于治疗各种核苷类抗癌药或抗病毒药相应的适应症。例如,在使用吉西他滨的5′位二苄基单磷酸酯衍生物(参照上图中的结构式vi)的情况下,优选的适应症包括:非小细胞肺癌、胰腺癌、胆道癌、尿路上皮癌、无法手术或复发的乳腺癌、癌症化疗后恶化的卵巢癌、复发或难治性恶性淋巴肿瘤等。
在本发明中使用的合适的药物组合物包含有效量的活性成分,即在被治疗的症状(例如,血液学异常(诸如镰状细胞性贫血)、MDS和/或癌症(例如NSCL))中,活性成分以实现治疗和/或预防疾病的目的的有效量存在。
在本发明中使用的药物组合物被提供为用于口服给药的剂型。在本说明书中提供的药物组合物可以固体、半固体、或液体形式用于口服给药。本说明书中所述的使用情况下,口服给药包括经颊,经舌和舌下给药。用于口服给药的合适剂型包括片剂、胶囊剂、丸剂、药片、药用糖、芳香制剂、扁胶囊剂、粒剂、加药口香糖、颗粒剂、散装粉末、发泡制剂、或非发泡粉剂或颗粒剂、溶液、乳剂、悬浮液、溶液、薄片(wafer)、喷雾剂(sprinkles)、酏剂和糖浆制剂、但不限于这些实例。除了活性成分之外,药物组合物还可以包含粘结剂、填充剂、稀释剂、崩解剂、湿润剂、润滑剂、流动促进剂、着色剂、色素迁移抑制剂、甜味剂和调味剂,但不限于这些实例,药物组合物还可以含有一种或多种药学上可接受的载体或赋形剂。
在药物组合物或剂型中的本发明的通式(1)所表示的化合物的用量例如可以选自以下范围:约1mg~约2000mg,约10mg~约2000mg,约20mg~约2000mg,约50mg~约1000mg,约100mg~约500mg,约150mg~约500mg,或约150mg~约250mg。
当使用本发明的化合物作为抗癌药时,其有效给药量可以根据癌症的性质、癌症进展阶段、治疗方针、转移程度、肿瘤的量、体重、年龄、性别和患者的(遗传)种族背景等进行适当选择。药学上有效的剂量一般根据临床中观察到的症状,癌症的阶段等因素来确定。例如,在给予人类的情况下,每日剂量为约0.01mg/kg~约10mg/kg(对于体重为60kg的成年人,约0.5mg~约500mg),优选约0.05mg/kg~约5mg/kg,更优选约0.1mg/kg~约2mg/kg。可以一次给药,也可以分多次给药。
实施例
以下提供实施例对本发明进行进一步的详细说明,但本发明不限于下述实施例的范围。
在以下实施例中,室温是指约15~30℃。1H-NMR和13C-NMR使用日本电子JNM-ECZ400R进行测定,其中使用DMSO-d6或CD3OD作为溶剂,以ppm示出从内标物四甲基硅烷得出的化学位移δ。在本说明书中使用的其他标记具有以下含义。s:单峰;d:双重峰;t:三重峰;m:多重峰;br:宽峰;br s:宽单峰;J:耦合常数。此外,各化合物的质量使用Yamazen SmartFlash MS系统进行测定。
实施例1
用氯氧化磷活化核苷类并且随后与苯甲醇缩合
在室温下将核苷类(0.5mM)悬浮在约1mL的磷酸三乙酯中,在冷却至0℃的条件下向其中加入93μL氯氧化磷(以摩尔计为原料的约2倍),搅拌约2小时。接着,将相应的苯甲醇(以摩尔计约10倍)和约0.4mL(以摩尔计约10倍)的吡啶加入该溶液,在冷却至0℃的条件下再搅拌1小时。将该反应溶液注入乙酸乙酯-水的混合液中,用稀碳酸氢钠溶液中和,然后用乙酸乙酯萃取。将萃取物用饱和盐水洗涤,并经无水硫酸镁干燥。将去除了不可溶的物质后的萃取物在减压下干燥,将得到的油状残留物用硅胶柱(Yamazen Smart Flash MS系统)分离纯化,由此得到作为目标化合物的核苷类的5′位二苄基单磷酸酯衍生物。这种方法在下文中称为合成方法A。
实施例2
核苷类和二苄基氯代磷酸酯衍生物的缩合
在室温下将核苷类(0.5mM)悬浮在1.0mL无水吡啶中,在冷却至0℃的条件下,加入约0.25mL(以摩尔计约1.2倍)的相应的二苄基氯代磷酸酯衍生物,并搅拌约1小时。将该反应溶液注入乙酸乙酯-水的混合液中,用稀碳酸氢钠溶液中和后,用乙酸乙酯萃取。将萃取液用饱和盐水洗涤,然后经无水硫酸镁干燥,将去除了不可溶的物质的萃取液在减压下干燥,将得到的油状残留物用硅胶柱(Yamazen Smart Flash MS系统)分离纯化,由此得到作为目标化合物的核苷类的5′位二苄基单磷酸酯衍生物。这种方法在下文中称为合成方法B。
以下示出了与通过上述合成方法A和合成方法B所合成的核苷类的5′位二苄基单磷酸酯化合物(1)~化合物(4)相关的硅胶柱分离系统、分离产率、由仪器获得的数据、分配系数。
化合物(1):吉西他滨-5′-单磷酸O,O’-二(4-氟)苄基酯(O,O’-二(4-氟)苄基2’-脱氧-2’,2’-二氟-5’-胞嘧啶核苷酸酯:在通式(I)中,D=2’-脱氧-2’,2’-二氟胞苷-5’-基,R1=R2=4-氟苄基):(合成方法A和合成方法B),硅胶柱的洗脱相:乙酸乙酯-甲醇,
产率:15%(合成方法A),50%(合成方法B)
质量=m/e 560.2(M++1),(对C23H22F4N3O7P进行计算,MW=559.11)。
1H-NMR(CD3OD)δ:4.02-4.07(1H,m),4.10-4.23(1H,m),4.25-4.42(2H,m),5.06(2H,s),5.08(2H,s),5.83(1H,d,J=7.7Hz),6.23(1H,brt,J=8.3Hz),7.05-7.13(4H,m),7.35-7.42(4H,m),以及7.52(1H,d,J=7.8Hz)ppm.
1H-NMR(DMSO-d6)
δ:3.95-4.05(1H,m),4.10-4.25(1H,m),4.25-4.32(2H,m),5.03(2H,br s),5.05(2H,br s),5.73(1H,d,J=7.3Hz),6.17(1H,br t),6.45(1H,d,J=6.4Hz),7.25-7.35(4H,m),7.37-7.42(4H,m),7.4(2H,br),以及7.49(1H,d,J=7.7Hz)ppm.
13C-NMR(CD3OD)δ:67.0(4.8Hz),70.3(t,4.8Hz),71.0,71.2,71.5,80.1,96.6,116.3,116.5,120.8,123.4,126.0,131.4,131.5,132.9(6.8Hz),133.0(6.8Hz),142.4,157.4,163.1,165.5,以及167.4ppm.
分配系数:log P(正辛醇/PBS)=2.288
化合物(2):吉西他滨-5’-单磷酸O,O’-二(4-氯)苄基酯(O,O’-二(4-氯)苄基2’-脱氧-2’,2’二氟-5’-胞嘧啶核苷酸酯:通式(I)中,D=2’-脱氧-2’,2’-二氟胞嘧啶核苷-5’-基,R1=R2=4-氯苄基):(合成方法A),硅胶柱的洗脱相:乙酸乙酯-甲醇,
产率:15.4%
质量=m/e592.2(M++1)(对C23H22Cl2F2N3O7P进行计算,MW=591.05)。
1H-NMR(CD3OD)δ:4.03-4.10(1H,m),4.14-4.25(1H,m),4.30-4.45(2,m),5.06(2H,s),5.09(2H,s),5.83(1H,d,J=7.3Hz),6.23(1H,br t,J=8.2Hz),7.25-7.40(8H,m),以及7.50(1H,d,J=7.8Hz)ppm.
1H-NMR(DMSO-d6)
δ:3.95-4.05(1H,m),4.10-4.25(1H,m),4.25-4.32(2H,m),5.04(2H,br s),5.06(2H,br s),5.74(1H,d,J=7.8Hz),6.20(1H,br t),6.45(1H,d,J=6.4Hz),7.34-7.40(4H,m),7.40-7.46(6H,m),以及7.49(1H,d,J=7.8Hz)ppm.
13C-NMR(CD3OD)
δ:67.2(5.8Hz),70.3(t,4.8Hz),71.1,71.4,71.6,80.2,96.7,120.9,123.5,126.1,129.9,130.8,135.8(6.8Hz),142.5,157.5,以及167.5ppm.
分配系数:log P(正辛醇/PBS)=3.062
化合物(3):吉西他滨-5’-单磷酸O,O’-二(4-溴)苄基酯(O,O’-二(4-溴)苄基2’-脱氧-2’,2’-二氟-5’-胞嘧啶核苷酸酯):在通式(I)中,D=2’-脱氧-2’,2’-二氟胞嘧啶核苷-5’-基,R1=R2=4-溴-苄基):(合成方法A),硅胶柱的洗脱相:乙酸乙酯-甲醇,
产量=15.1%(1.0mM比例)
质量=m/e 682.1(M++1)(对C23H22Br2F2N307P进行计算,计算值681.22)
1H-NMR(CD3OD)
δ:4.05-4.10(1H,m),4.15-4.25(1H,m),4.30-4.45(2,m),5.04(2H,s),5.06(2H,s),5.84(1H,d,J=7.3Hz),6.24(1H,br t,J=8Hz),7.23-7.30(4H,m),以及7.45-7.53(5H,m)ppm.
13C-NMR(CD3OD)
δ:67.2(4.8Hz),70.2(t,4.9Hz),71.0,71.3,71.5,80.1,96.7,120.8,123.4,123.7,126.0,130.9,132.8,136.1(6.8Hz),142.4,157.6,以及167.5ppm.
分配系数:log P(正辛醇/PBS)=3.325
化合物(4):5-氟-2’-脱氧胞苷-5’-单磷酸O,O’-二(4-氟)苄基酯(O,O’-二(4-氟)苄基5-氟-2’-脱氧-5’-胞嘧啶核苷酸酯):通式(I)中,D=5-氟-2’-脱氧胞嘧啶核苷-5’-基,R1=R2=4-氟苄基):(合成方法A),硅胶柱的洗脱相:乙酸乙酯-甲醇,产率=13.0%
质量=m/e 542.2(M++1)(对C23H23F3N3O7P进行计算,MW=541.12)
1H-NMR(CD3OD)δ:2.00-2.10和2.30-2.40(每个1H,每个m),4.00-4.10(1H,m),4.18-4.32(3H,m),5.05(2H,br s),5.11(2H,br s),6.17(br t,J=6.0Hz),7.00-7.15(4H,m),7.30-7.45(4H,m),以及7.87(1H,d,J=6.4Hz)ppm.
分配系数:log P(正辛醇/PBS)=2.196
[试验实施例1]核苷类抗癌药或抗病毒药的5′位二苄基单磷酸酯衍生物对胞苷脱氨酶的稳定性
将约1mg的所得到的核苷类抗癌药或抗病毒药的5′位二苄基单磷酸酯衍生物(参照通式(I))溶解于1mL乙腈中,将10μL的上述溶液加入1mL的PBS中,在该溶液中加入10μL的胞苷脱氨酶的PBS溶液,在37℃的温度下搅拌约30分钟~1小时。向所得到的反应液中加入1mL乙腈,进行离心分离,对其上清液使用HPLC进行分析。例如,表1示出了胞苷、吉西他滨和O,O’-二(4-氟)苄基2’-脱氧-2’,2’-二氟-5’-胞嘧啶核苷酸酯(化合物(1))的分析结果。
胞苷脱氨酶:CDA(1-146aa),His标记的人类重组胞苷脱氨酶(ATGen公司)
HPLC测定条件
柱:ZORBAX Bonus-RP
4.6mm x 250mm粒径:5μm
洗脱:洗脱液A=含有10mM的甲酸铵的纯化水
洗脱液B=乙腈
梯度模式:A:B=99:1→20:80,30分钟
流速:1.0mL/分钟
箱温:40℃
检测器:UV240nm
[表1]
原料 | HPLC分析得知的变化 |
胞嘧啶核苷 | 原料的峰在30分钟后完全消失 |
吉西他滨 | 原料的峰在30分钟后完全消失 |
化合物(1) | 证实了原料的峰甚至在1小时后也几乎没有变化 |
由此可确认,本发明的核苷类抗癌药或抗病毒药的5′位二苄基单磷酸酯衍生物在生理条件下相对于胞苷脱氨酶极其稳定。另一方面,胞苷和吉西他滨在上述反应条件下均不稳定,且完全消失。
[试验实施例2]核苷类抗癌药或抗病毒药的5′位二苄基单磷酸酯衍生物的非酶促/酶促水解反应性
将约1mg所得到的核苷类抗癌药或抗病毒药的5′位二苄基单磷酸酯衍生物(参照通式(I))例如O,O’-二(4-氟)苄基2’-脱氧-2’,2’-二氟-5’-胞嘧啶核苷酸酯(化合物(1))溶解于1mL乙腈中,将10μL的该溶液加入1mL PBS中,加入下述各种水解酶PBS溶液10μL,在37℃的温度下搅拌约1小时。向这些反应液中加入1mL的乙腈,进行离心分离,各上清液使用HPLC进行分析,结果由表2示出。另外,HPLC测定条件与试验实施例1中的相同。
[表2]
此外,本试验中所使用的酶分别是磷酸二酯酶Ⅰ(来自衲脊响尾蛇蛇毒:WOR公司),磷酸二酯酶Ⅱ(来自牛脾脏:WOR公司),核酸酶(来自葡萄球菌:SIGMA公司),磷脂酶CB1(人类重组酶:ABV公司),磷脂酶CD 1(人类重组酶:ABV公司),磷脂酶CG 1(人类重组酶:ABV公司),碱性磷酸酶Ⅰ(OPCA00948:人类重组肠型酶:AVIVA Systems Biolog公司),碱性磷酸酶L(OPCA00950:人类重组非组织特异性同工酶:AVIVA Systems Biolog公司),酸性磷酸酶(1-158aa:来源于大肠杆菌的His标记的人类重组酶:ATGen公司)。
由此可知,核苷类抗癌药或抗病毒药的5′位二苄基单磷酸酯衍生物(参照通式(I))在任何水解酶的存在下均极其稳定。另一方面,这些核苷类抗癌药或抗病毒药的5′位二苄基单磷酸酯衍生物(例如,O,O’-二(4-氟)苄基2’-脱氧-2’,2’-二氟-5’-胞嘧啶核苷酸酯:化合物(1))在生理条件下(例如,在37℃下的PBS溶液中)逐渐水解,生成相应的5′位单苄基单磷酸酯衍生物,该单苄基酯衍生物在生理条件下被磷酸二酯酶Ⅰ顺利地水解,几乎定量地生成相应的5′位单磷酸酯(例如,2’-脱氧-2’,2’-二氟-5’-胞苷酸:吉西他滨5’-O-单磷酸酯)。
[试验实施例3]核苷类抗癌药或抗病毒药的5′位二苄基单磷酸酯衍生物的生物活性
在100μL的含有人胰脏癌细胞(MIA-Paca-2)(细胞数:约5x103个)的培养基中加入试验化合物(各种浓度的DMSO溶液),培养3天,用alamarBlue试剂通过荧光显色研究对细胞增殖的抑制效果,计算各IC50的值。表3示出了其结果。
[表3]
由此可知,核苷类抗癌药或抗病毒药的5′位二苄基单磷酸酯衍生物(参照通式(I))表现出与所用作原料的核苷类抗癌药或抗病毒药相似的生物活性。
工业上利用的可能性
根据本发明,可以为医疗实践提供一种能够代替在临床中用于治疗或预防各种癌症或病毒感染的核苷类抗癌药或抗病毒药的药物。
Claims (15)
2.根据权利要求1所述的化合物或其盐,其中,R1和R2各自独立地是可以具有烷基或卤素原子作为取代基的苄基。
3.根据权利要求2所述的化合物或其盐,其中,烷基是C1-C6烷基。
4.根据权利要求2所述的化合物或其盐,其中,烷基是甲基或乙基。
5.根据权利要求2所述的化合物或其盐,其中,卤素原子是氟原子、氯原子或溴原子。
6.根据权利要求1所述的化合物或其盐,其中,R1和R2是苄基。
7.根据权利要求1所述的化合物或其盐,其中,D所表示的核苷类抗癌药是阿糖胞苷、氟尿苷、喷司他汀、氟达拉滨、克拉屈滨、吉西他滨、氯法拉滨、奈拉滨、三氟胸苷、DFP-10917、虫草素、8-氯腺苷、RX-3117、曲西立滨、呋咯地辛、5-氟脱氧胞苷、利巴韦林或阿卡地新。
8.根据权利要求1所述的化合物或其盐,其中,D所表示的核苷类抗病毒药是齐多夫定、拉米夫定、司他夫定、阿巴卡韦、恩曲他滨、地丹诺辛或司他夫定。
10.一种制备权利要求1所述的化合物或其盐的方法,其包括:使核苷类抗癌药或抗病毒药与氯氧化磷反应,然后在脱卤化氢剂的存在下使其与可以具有取代基的苯甲醇反应,或者包括:使核苷类抗癌药或抗病毒药在脱卤化氢剂的存在下与可以具有取代基的二苄基卤代磷酸酯衍生物反应。
11.一种药物组合物,其包含权利要求1至9中任一项所述的化合物或其盐。
12.根据权利要求11所述的药物组合物,其是癌细胞或病毒感染细胞的增殖抑制剂。
13.根据权利要求11所述的药物组合物,其是用于预防或治疗癌症或病毒感染的药物。
14.一种抑制哺乳动物中癌细胞或病毒感染细胞增殖的方法,包括:将有效量的权利要求1-9中任一项所述的化合物或其盐给药至哺乳动物。
15.一种用于预防或治疗哺乳动物中癌症或病毒感染的方法,包括:将有效量的权利要求1-9中任一项所述的化合物或其盐给药至哺乳动物。
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CN114773417A (zh) * | 2022-04-06 | 2022-07-22 | 郑州大学 | 一种虫草素磷酸酯及其制备方法与应用 |
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