CN116239640B - 吉西他滨前药及其医药用途 - Google Patents
吉西他滨前药及其医药用途 Download PDFInfo
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- CN116239640B CN116239640B CN202310066476.4A CN202310066476A CN116239640B CN 116239640 B CN116239640 B CN 116239640B CN 202310066476 A CN202310066476 A CN 202310066476A CN 116239640 B CN116239640 B CN 116239640B
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- gemcitabine
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- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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- Y02P20/00—Technologies relating to chemical industry
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Abstract
本发明属于生物医药领域,具体涉及一种吉西他滨前药及其医药用途。本发明首先提供了一种结构式如式(I)的化合物或其药学上可接受的盐、互变异构体、内消旋体、外消旋体、立体异构体或溶剂化物。本发明提供的吉西他滨前药具有理想的抗肿瘤活性;前药能够被NQO1酶代谢,肿瘤靶向性更强;前药受胞苷脱氨酶及核苷转运体影响更小。
Description
技术领域
本发明属于生物医药领域,具体涉及一类吉西他滨前药,本发明还涉及该类化合物作为抗肿瘤药物的医药用途。
背景技术
癌症将成为21世纪死亡的首要原因,并且将是世界各国提高预期寿命的最重要障碍。临床上虽然有多种抗肿瘤药物可供使用,但是由于肿瘤病因的复杂性、肿瘤的耐药性以及抗肿瘤药物的毒副作用等因素,现有的药物仍然不能满足临床治疗的需要。因此,寻找药效强、靶向性强、毒副作用小的新型抗肿瘤药物具有重要意义。核苷衍生物是一种广泛用于癌症治疗的化疗药物,而吉西他滨(Gemcitabine)是一种胞嘧啶核苷衍生物,1996年被美国FDA批准上市,临床上主要用于乳腺癌、膀胱癌、胰腺癌、卵巢癌以及其他各种实体瘤的治疗。在临床使用中,00吉西他滨极易被肝脏和血液中大量存在的胞苷脱氨酶(CDA)代谢失活,导致其在体内的半衰期较短(30~90min),又因其具有较强的亲水性,难以扩散入胞,导致其生物利用度较低。2009年,礼来公司用丙戊酸修饰吉西他滨的氨基,得到前药LY2334737。该化合物表现出优良的化学稳定性和酶稳定性;而活性研究表明,口服LY2334737的抗肿瘤活性优于吉西他滨。2014年,McGuigan团队将ProTide前药策略应用于吉西他滨,并筛选出最理想的前药NUC-1031。NUC-1031的代谢活化并不依赖脱氧胞苷激酶,而吸收入胞不依赖核苷转运体,此外还可抵抗CDA的降解失活,目前该药正在开展临床III期试验。
NQO1(依赖还原型辅酶I/II醌氧化还原酶1,NAD(P)H:quinone oxidoreductase1)是一种黄素蛋白酶,以NADH或NADPH为辅因子,催化醌类及其衍生物失去两个电子,发生还原反应。NQO1在诸多实体瘤(如乳腺癌、肺癌、前列腺癌、胃癌、结肠癌、胰腺癌等)中高表达,约为正常组织的5-200倍。本发明在吉西他滨上引入NQO1响应的醌丙酸或同时引入ProTide策略,期望能获得抗肿瘤活性理想的化合物。
发明内容
针对现有技术存在的问题,本发明的第一个目的是提供一种新型吉西他滨前药,该类前药能够被肿瘤组织及肿瘤微环境内高表达的NQO1酶激活,释放出活性代谢物,进而产生良好的抗肿瘤作用,且有较高的肿瘤特异性,安全性理想。
本发明的第二个目的是提供前述吉西他滨前药的制备方法。
本发明的第三个目的是提供前述吉西他滨前药的医药用途。
为了实现上述目的,本发明解决其技术问题采用的技术方案是:
第一方面,本发明保护一种吉西他滨前药,所述吉西他滨前药为结构式如式(I)的化合物或其药学上可接受的盐、互变异构体、内消旋体、外消旋体、立体异构体或溶剂化物:
其中,W选自:
X选自:H、卤素原子、C1-3烷基、C1-3烷氧基、氰基、硝基或羧基;X可以是任意位置的单取代或多取代;
Y选自:O、S、NH或NCH3;
Q选自:H或
R1或R2各自独立的选自:氢、1-6个碳的直链或支链烷基、苄基或苯环含取代基的苄基;
R3选自:1-6个碳的直链或支链烷基、苄基或苯环含取代基的苄基;
Ar选自:苯基、含取代基的苯基、1-萘基或2-萘基。
进一步的,
其中,W选自:
X选自:H、F、Cl、Br、I、CH3、CH3O、CN、NO2或COOH;X可以是任意位置的单取代或多取代。
更进一步的,W选自:
Y选自:O、S、NH或NCH3。
进一步的,Q选自:H或R1或R2各自独立的选自:氢、甲基、乙基、异丙基或苄基。
更进一步的,所述R1或R2为氢。
进一步的,R3选自:甲基、乙基、异丙基、环己基或苄基。
更进一步的,R3选自:异丙基或苄基。
进一步的,Ar选自:苯基或1-萘基。
更进一步的,Ar选自:苯基。
第二方面,本发明还提供以下化合物:
及其药学上可接受的盐、互变异构体、内消旋体、外消旋体、立体异构体或溶剂化物。
第三方面,本发明提供一种前述化合物的制备方法,其合成路线如图7所示,其中,G1或G2各自独立的选自:氢或羟基保护基;所述羟基保护基可以是:叔丁氧羰基(Boc)、苄氧羰基(Cbz)、芴甲氧羰基(Fmoc)、苄基(Bn)、乙酰基(Ac)、三甲基硅基(TMS)、二叔丁基甲基硅基(TBS)、三异丙基硅基(TIS)或三苯基硅基;
W-Z1结构式如下所示:
其中,W选自:
X选自:H、F、Cl、Br、I、CH3、CH3O、CN、NO2或COOH;X可以是任意位置的单取代或多取代;
Y选自:O、S、NH或NCH3;
Z1或Z2各自独立的选自:氢或离去基团;所述离去基团可以是:Cl、Br、苯氧基、4-硝基苯氧基或五氟苯氧基;
Q选自:H或
R1或R2各自独立的选自:氢、1-6个碳的直链或支链烷基、苄基或苯环含取代基的苄基;
R3选自:1-6个碳的直链或支链烷基、苄基或苯环含取代基的苄基;
Ar选自:苯基、含取代基的苯基、1-萘基或2-萘基。
本发明提供前述化合物的制备方法,其选自如下(A1)-(A4)中的任一种:
(A1):对吉西他滨的羟基进行保护,合成化合物II;化合物II在缩合剂和碱的作用下酰化合成化合物III;移除化合物III的保护基,得到目标化合物Ia;
(A2):对吉西他滨的羟基进行保护,合成化合物II;化合物II经磷酰化得到化合物IV;化合物IV在缩合剂和碱的作用下酰化合成化合物V;移除化合物V的保护基,得到目标化合物Ib;
(A3):化合物Ia经磷酰化得到化合物Ib;
(A4):吉西他滨可直接选择性酰化,得到目标化合物Ic。
在一些具体的实施方案中,引入羟基保护基的方法是本领域技术人员众所周知的;其实例可参见Peter G.M.Wuts,Greene's Protective Groups in Organic Synthesis(第5版),JohnWiley&Sons,NY(2015),在此将其全部引入作为参考。
在一些具体的实施方案中,酰化反应所用碱为三乙胺、二异丙基乙基胺、N-甲基吗啉、DMAP或DBU;优选为三乙胺;所用溶剂包括但不限于:二氯甲烷、四氢呋喃、乙腈、N,N-二甲基甲酰胺、二甲基亚砜或者用这些溶剂任选组成的混合溶剂;反应温度为-50℃至100℃,优选的,所述反应温度为-10℃至70℃;更具体的,酰化反应中所用缩合剂为新戊酰氯、氯甲酸异丁酯、DCC或EDCI;所用添加剂为HOBt或氯化锂。
在一些具体的实施方案中,移除羟基保护基的方法是本领域技术人员众所周知的;其实例可参见Peter G.M.Wuts,Greene's Protective Groups in Organic Synthesis(第5版),JohnWiley&Sons,NY(2015),在此将其全部引入作为参考。
在一些具体的实施方案中,磷酰化所采用的溶剂包括但不限于:甲苯、四氢呋喃、乙腈、N,N-二甲基甲酰胺、二甲基亚砜、N-甲基吡咯烷酮、吡啶或者用这些溶剂任选组成的混合溶剂;所采用的碱为钠氢、叔丁醇钾、叔丁醇钠、叔丁基氯化镁、甲基氯化镁、苯基氯化镁、二甲基氯化铝、DMAP或DBU;反应温度为-50℃至80℃,优选的,所述反应温度为-10℃至30℃。
第四方面,本发明还保护一种药物组合物,包含前文所述的化合物或其药学上可接受的盐、互变异构体、内消旋体、外消旋体、立体异构体或溶剂化物,以及药学上可接受的载体。
本发明的药物可以是前文所述的化合物本身与药学上可接受的稀释剂、辅助剂和/或载体等混合的药物,也可以是以本发明的化合物或其药学上可接受的盐、互变异构体、内消旋体、外消旋体、立体异构体或溶剂化物作为活性成分之一的组合物与药学上可接受的稀释剂、辅助剂和/或载体等混合的药物。
第五方面,本发明还保护前文所述的化合物或其药学上可接受的盐、互变异构体、内消旋体、外消旋体、立体异构体或溶剂化物作为有效成分,在制备抗肿瘤药物中的应用。
本发明中,所述:
DBU是指:1,8-二氮杂双环[5.4.0]十一碳-7-烯(CAS:6674-22-2)
DCC是指:二环己基碳二亚胺(CAS:538-75-0)
DMAP是指:4-二甲氨基吡啶(CAS:1122-58-3)
EDCI是指:1-乙基-3-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(CAS:25952-53-8)
HATU是指:2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(CAS:148893-10-1)
HBTU是指:O-苯并三氮唑-四甲基脲六氟磷酸盐(CAS:94790-37-1)
HOBt是指:1-羟基苯并三唑(CAS:2592-95-2)
NBS是指:N-溴代琥珀酰亚胺(CAS:128-08-5)
NMM是指:N-甲基吗啉(CAS:109-02-4)
定义
除非另有说明,本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照本领域普通的含义去理解。当本文中出现商品名时,意在指代其对应的商品或其活性成分。
本文中的C1-3,是该部分具有给定范围中的1-3个碳原子。具体是指该基团可具有1个碳原子、2个碳原子或3个碳原子。
术语“烷基”是指通式为CnH 2n+1的烃基。该烷基可以是直链或支链的。例如,术语“C1-3烷基”指含有1至3个碳原子的烷基(例如甲基、乙基、正丙基、异丙基)。
术语“药学上可接受的”,是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。
作为药学上可接受的盐,例如,可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。
术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。
本申请还包括与本文中记载的那些相同的,但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本申请化合物。可结合到本申请化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素,诸如分别为2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、123I、125I和36Cl等。
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备,例如可配制成固态、半固态、液态或气态制剂,如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本申请化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本申请的药物组合物可以采用本领域众所周知的方法制造,如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
在一些实施方案中,药物组合物是口服形式。对于口服给药,可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合,来配制该药物组合物。这些辅料能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等,用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如,可通过下述方法获得:将所述的活性化合物与固体辅料混合,任选地碾磨所得的混合物,如果需要则加入其它合适的辅料,然后将该混合物加工成颗粒,得到了片剂或糖衣剂的核心。适合的辅料包括但不限于:粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
药物组合物还可适用于肠胃外给药,如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。
本申请的化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式,优选的实施方式包括但不限于本申请的实施例。
本申请具体实施方式的化学反应是在合适的溶剂中完成的,所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物,有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
有益效果
与现有技术相比,本发明提供的吉西他滨前药具有理想的抗肿瘤活性;前药能够被NQO1酶代谢,肿瘤靶向性更强;前药受胞苷脱氨酶及核苷转运体影响更小。
附图说明
图1为化合物I-1的氢谱。
图2为化合物I-2的氢谱。
图3为化合物I-5的氢谱。
图4为化合物I-6的氢谱。
图5为化合物I-2与I-6的稳定性研究。
图6为化合物I-2与I-6的体内抗肿瘤活性。
图7为本发明的化合物的合成路线。
具体实施方式
下面通过实施例具体说明本发明的内容。在本发明中,以下所述的实施例是为了更好的阐述本发明,并不是用来限制本发明的范围。在不背离本发明的精神和范围的前提下,可以对本发明进行各种变化和修饰。
实施例1
步骤一
将2,3,5-三甲基苯-1,4-二醇(W-1,2000mg,13mmol)、3-甲基丁-2-烯酸(1513mg,15mmol)置于双颈瓶并氩气保护,注入甲磺酸(20mL)后,85℃下回流3小时。反应结束后,将反应液倒入100g冰水,乙酸乙酯萃取三次,合并有机相,并依次用饱和食盐水洗涤、无水硫酸钠干燥。减压蒸干溶剂,用石油醚:乙酸乙酯=2:1重结晶,得白色固体(W-2)2430mg,产率84%。1H NMR(300MHz,DMSO)δ7.98(s,1H),2.57(s,2H),2.27(s,3H),2.10(s,3H),1.35(s,6H).
将上述固体(W-2,703mg,3mmol)置于单颈瓶,依次加入乙腈-水(9mL,乙腈:水=5:1)和NBS(587mg,3.3mmol),室温下反应1小时。反应结束后,反应液用乙酸乙酯萃取三次,合并有机相,并依次用饱和食盐水洗涤、无水硫酸钠干燥。减压蒸干溶剂,得到化合物W-3,黄色固体(702mg),产率94%。1H NMR(300MHz,DMSO)δ2.82(s,2H),2.06(s,3H),1.88(s,6H),1.36(s,6H).
步骤二
将盐酸吉西他滨(Gem HCl,899mg,3mmol)置于双颈瓶中,加入DMF-DMSO混合溶剂(8mL,DMF:DMSO=3:1),在氩气气流下,依次加入NMM(304mg,3.3mmol)、HOBt(406mg,3mmol)、化合物W-3(825mg,3.3mmol)和EDCI(748mg,3.9mmol),65℃下反应过夜。反应结束后,反应液用乙酸乙酯萃取三次,合并有机相,并用饱和碳酸氢钠洗涤三次,饱和食盐水洗涤一次,有机相用无水硫酸钠干燥。减压蒸干溶剂,经硅胶柱层析(二氯甲烷:甲醇=30:1)得化合物I-1,黄色固体669mg,产率45%。1H NMR(300MHz,DMSO)δ11.05(s,1H),8.20(d,J=7.6Hz,1H),7.12(d,J=7.6Hz,1H),6.30(d,J=6.5Hz,1H),6.16(t,J=7.4Hz,1H),5.27(t,J=5.4Hz,1H),4.17(tt,J=12.9,7.4Hz,1H),3.94–3.74(m,2H),3.64(ddd,J=12.7,5.9,3.5Hz,1H),3.08(d,J=3.0Hz,2H),2.07(s,3H),1.94–1.82(m,6H),1.38(s,6H).
实施例2
步骤一
将吉西他滨(Gem,1000mg,3.8mmol)与咪唑(780mg,11.5mmol)置于单颈瓶,加入叔丁基二甲基氯硅烷(1500mg,9.6mmol)和DMF(25mL),室温反应24小时。反应结束后,反应液用乙酸乙酯萃取三次,合并有机相,并用饱和碳酸氢钠洗涤三次,饱和食盐水洗涤一次,有机相用无水硫酸钠干燥。减压蒸干溶剂,得化合物II-1,白色固体1700mg,产率92%。1H NMR(300MHz,CDCl3)δ7.69–7.63(m,1H),6.32(dd,J=10.4,4.8Hz,1H),5.84(d,J=7.6Hz,1H),4.31(ddd,J=12.3,10.6,7.8Hz,1H),3.99(dt,J=11.8,2.2Hz,1H),3.90(d,J=7.8Hz,1H),3.81(dd,J=11.7,2.2Hz,1H),0.94(d,J=8.9Hz,18H),0.18–0.09(m,12H).
步骤二
将化合物W-3(2433mg,9.7mmol)置于双颈瓶,氩气置换3次,加入THF(30mL),移至0℃,依次加入NMM(1.2mL,10.6mmol)和氯甲酸异丁酯(1.3mL,10.6mmol)并反应30分钟,加入(4-(甲基氨基)苯基)甲醇(2000mg,14.6mmol),0℃下反应过夜。反应结束后,反应液用乙酸乙酯萃取三次,合并有机相,并用盐酸(1N)和饱和碳酸氢钠洗涤三次,饱和食盐水洗涤一次,有机相用无水硫酸钠干燥。减压蒸干溶剂,乙醚打浆,得化合物W-4,黄色固体2500mg,产率70%。1H NMR(300MHz,DMSO)δ7.42(d,J=7.9Hz,2H),7.22(d,J=7.8Hz,2H),4.54(s,2H),2.65(s,2H),2.02(s,3H),1.91(d,J=5.5Hz,6H),1.24(s,6H).
将化合物W-4(554mg,1.5mmol)和4-硝基苯基碳酰氯(907mg,4.5mmol)置于双颈瓶,氩气置换3次,加入DCM(12mL),移至0℃,滴加DIPEA(1.3mL,7.5mmol),0℃下反应过夜。反应结束后,反应液用二氯甲烷萃取三次,合并有机相,并用饱和碳酸氢钠洗涤三次,饱和食盐水洗涤一次,有机相经无水硫酸钠干燥。减压蒸干溶剂,经硅胶柱层析(石油醚:乙酸乙酯=2:1)得黄色油状物W-5,710.1mg,产率88.6%。1H NMR(300MHz,CDCl3)δ8.36–8.23(m,2H),7.54(d,J=7.9Hz,2H),7.48–7.36(m,2H),7.28(s,2H),5.35(s,2H),3.19(s,3H),2.78(s,2H),2.12(s,3H),1.99(d,J=10.2Hz,6H),1.33(s,6H).
将化合物II-1(154mg,0.3mmol)置于双颈瓶,氩气置换3次,加入DCM(4mL),移至0℃,分别加入化合物W-5(250mg,0.5mmol)和DIPEA(0.3mL),0℃下反应过夜。反应结束后,反应液用二氯甲烷萃取三次,合并有机相,并用饱和碳酸氢钠洗涤三次,饱和食盐水洗涤一次,有机相用无水硫酸钠干燥。减压蒸干溶剂,经硅胶柱层析(二氯甲烷:甲醇=50:1)得化合物III-1,黄色油状物232mg,产率83.9%。1H NMR(300MHz,CDCl3)δ8.11–8.00(m,1H),7.48(d,J=7.9Hz,2H),7.22(d,J=8.1Hz,3H),6.40–6.27(m,1H),5.27(s,2H),4.35(td,J=11.5,7.9Hz,1H),4.11–3.91(m,2H),3.82(dd,J=11.9,1.9Hz,1H),3.16(s,3H),2.76(s,2H),2.10(s,3H),2.00(s,6H),1.31(s,6H),0.94(d,J=15.5Hz,18H),0.17–0.09(m,12H).
将化合物III-1(450mg,0.5mmol)置于单颈瓶,加入THF(2mL),滴加三乙胺三氢氟酸盐(2mL),室温反应过夜。反应结束后,反应液用乙酸乙酯萃取三次,合并有机相,并用饱和碳酸氢钠洗涤三次,饱和食盐水洗涤一次,有机相用无水硫酸钠干燥。减压蒸干溶剂,经硅胶柱层析(二氯甲烷:甲醇=30:1)得黄色固体(I-2)230mg,产率68.9%。1H NMR(300MHz,MeOD)δ8.32(d,J=7.6Hz,1H),7.56(d,J=7.8Hz,2H),7.32(dd,J=16.8,7.7Hz,3H),6.25(t,J=7.3Hz,1H),5.28(s,2H),4.30(td,J=12.1,8.2Hz,1H),3.96(q,J=5.5Hz,2H),3.81(dd,J=13.3,3.4Hz,1H),3.13(s,3H),2.74(s,2H),2.07(s,3H),1.96(d,J=6.6Hz,6H),1.29(s,6H).
实施例3
按照实施例2方法,将起始原料中的(4-(甲基氨基)苯基)甲醇替换为4-氨基苯甲醇,最终得到化合物I-3。HRMS(ESI)calcd.for C31H34N4O9F2Na[M+Na]+667.2186;found667.2194.
实施例4
按照实施例2方法,将起始原料中的(4-(甲基氨基)苯基)甲醇替换为4-羟基苯甲醇,最终得到化合物I-4。HRMS(ESI)calcd.for C31H33N3O10F2Na[M+Na]+668.2026;found668.2038.
实施例5
步骤一
将L-丙氨酸苄酯盐酸盐(2157mg,10mmol)和苯基二氯磷酸酯(2110mg,10mmol)置于双颈瓶,氩气置换3次,加入DCM(50mL),移至-78℃,滴加TEA(2780μL,20mmol)并反应30分钟,移至室温反应3小时。再移至0℃,加入五氟苯酚(1840mg,10mmol)和DCM(10mL),滴加TEA(1529μL,11mmol),0℃下反应过夜。反应结束后,蒸干反应液,再用乙酸乙酯萃取三次,合并有机相,并用饱和碳酸氢钠洗涤三次,饱和食盐水洗涤一次,有机相用无水硫酸钠干燥。减压蒸干溶剂,得白色固体3220mg(Q-1),产率64%。1H NMR(300MHz,DMSO)δ7.43–7.27(m,6H),7.27–7.14(m,3H),6.91(dd,J=14.1,9.9Hz,1H),5.09(d,J=2.2Hz,2H),4.05(tq,J=10.2,7.1Hz,1H),1.35–1.26(m,3H).
步骤二
将I-1(350mg,0.7mmol)和Q-1(531mg,1.1mmol)置于双颈瓶,氩气置换3次,加入无水吡啶(3mL),移至0℃,滴加二甲基氯化铝(1M,0.4mL,0.4mmol),室温反应过夜。反应结束后,反应液用乙酸乙酯萃取三次,并用盐酸(1N)洗涤一次,饱和食盐水洗涤一次,有机相用无水硫酸钠干燥。减压蒸干溶剂,经硅胶柱层析(二氯甲烷:甲醇=30:1)得化合物I-5,黄色固体140mg,产率24.6%。1H NMR(300MHz,MeOD)δ8.00–7.82(m,1H),7.42–7.10(m,11H),6.27(q,J=7.6Hz,1H),5.17(s,2H),4.55–3.98(m,5H),3.16(d,J=3.5Hz,2H),2.12(d,J=7.3Hz,3H),1.90(d,J=10.6Hz,6H),1.46(d,J=2.1Hz,6H),1.37(d,J=7.3Hz,3H).
实施例6
步骤一
将吉西他滨(263mg,1mmol)和碳酸钠(530mg,5mmol)置于单颈瓶,加入二氧六环-水(二氧六环:水=4:1,25mL)和二碳酸二叔丁酯(218mg,1mmol),室温反应48小时。反应结束后,反应液用乙酸乙酯萃取三次,合并有机相,并用饱和食盐水洗涤一次,有机相用无水硫酸钠干燥。减压蒸干溶剂,经硅胶柱层析(二氯甲烷:甲醇=20:1)得II-2白色固体243mg,产率67%。1H NMR(300MHz,DMSO)δ7.65(d,J=7.5Hz,1H),7.43(d,J=5.4Hz,2H),6.22(t,J=9.3Hz,1H),5.82(d,J=7.5Hz,1H),5.30–5.11(m,2H),4.15(dt,J=7.0,3.5Hz,1H),3.80–3.59(m,2H),1.46(s,9H).
步骤二
将化合物II-2(545mg,1.5mmol)置于双颈瓶,氩气置换3次,加入THF(10mL),滴加叔丁基氯化镁(1.7M,1.1mL,1.8mmol)并搅拌30分钟,加入化合物Q-1(1613mg,3mmol),室温反应过夜。反应结束后,加入饱和氯化铵水溶液(10mL)淬灭,反应液用乙酸乙酯萃取三次,合并有机相,并用饱和食盐水洗涤一次,有机相用无水硫酸钠干燥。减压蒸干溶剂,经硅胶柱层析(二氯甲烷:甲醇=30:1)得化合物IV-1,白色固体921mg,产率78%。1H NMR(300MHz,DMSO)δ7.46(d,J=7.4Hz,3H),7.33(d,J=7.9Hz,7H),7.19(d,J=7.3Hz,3H),6.30–6.12(m,2H),5.74(d,J=7.5Hz,1H),5.22(d,J=7.2Hz,1H),5.10(d,J=3.0Hz,2H),4.40–4.21(m,3H),4.02–3.88(m,1H),1.44(s,9H),1.27(d,J=7.1Hz,3H).
将化合物IV-1(340mg,0.5mmol)和中间体W-5(400mg,1.5mmol)置于双颈瓶,氩气置换3次,加入DCM(3mL),移至0℃,缓慢滴加DIPEA(435μL,2.5mmol),室温反应过夜。反应结束后,反应液用二氯甲烷萃取三次,合并有机相,并用饱和食盐水洗涤一次,有机相用无水硫酸钠干燥。减压蒸干溶剂,经硅胶柱层析(二氯甲烷:甲醇=60:1)得化合物V-1,黄色固体364mg,产率68%。1H NMR(300MHz,CDCl3)δ7.66(d,J=7.6Hz,1H),7.47(d,J=7.9Hz,2H),7.33(d,J=8.7Hz,7H),7.26–7.15(m,6H),6.45–6.34(m,1H),5.27(s,2H),5.17(d,J=4.7Hz,2H),4.45(dt,J=10.1,5.8Hz,1H),4.34–4.25(m,2H),4.13–4.02(m,2H),3.16(s,3H),2.76(s,2H),2.11(s,3H),2.00(s,6H),1.51(s,9H),1.43(d,J=6.0Hz,3H),1.31(s,6H).
将化合物V-1(320mg,0.3mmol)置于单颈瓶,加入DCM(5mL),移至-10℃,滴加TFA(3mL),-10℃反应5小时。反应结束后,加入饱和碳酸氢钠调节pH至中性,反应液用二氯甲烷萃取三次,合并有机相,并用饱和食盐水洗涤一次,有机相用无水硫酸钠干燥。加压蒸干溶剂,经硅胶柱层析(二氯甲烷:甲醇=25:1)得化合物I-6,黄色固体130mg,产率48%。1H NMR(300MHz,DMSO)δ11.01(s,1H),7.94(d,J=8.1Hz,1H),7.51(d,J=8.1Hz,2H),7.40–7.00(m,13H),6.47(d,J=6.4Hz,1H),6.29–6.12(m,2H),5.23(s,2H),5.08(d,J=4.3Hz,2H),4.43–4.13(m,3H),4.12–3.86(m,2H),3.05(s,3H),2.65(s,2H),2.00(s,3H),1.88(s,6H),1.30–1.16(m,9H).
实施例7
按照实施例5与实施例6方法,将起始原料中的L-丙氨酸苄酯盐酸盐替换为L-丙氨酸异丙酯盐酸盐,最终得到化合物I-7。HRMS(ESI)calcd.for C44H53N5O13F2P[M+H]+928.3340;found 928.3352.
实施例8
吉西他滨前药的细胞活性评价
药品:前药化合物(上述实施例制备)、对照药吉西他滨(Gem,CAS:95058-81-4)、NUC-1031(CAS:840506-29-8)、双香豆素(DIC,CAS:66-76-2)。
实验材料:96孔细胞培养板购自康宁公司;CCK8试剂购自百赛生物;DMSO购自Sigma公司;肿瘤细胞株(A549和MCF-7);正常细胞株(LO-2)。
实验步骤:
1.将受试化合物用100% DMSO溶解配制成200mM的母液储存;将双香豆素用100%DMSO溶解配制成25mM的母液储存;
2.将细胞消化、计数,配置细胞悬浮液(A549:3.5×104个/mL,MCF-7:5×104个/mL,LO-2:3×104个/mL),在96孔细胞培养板中每孔加入100μl细胞悬浮液;
3.将96孔细胞培养板置于37℃,5%,CO2培养箱中培养24小时;
4.用培养基稀释受试药物至所需浓度,并使DMSO终浓度不超过0.1%,向96孔板中每孔加入100μl相应的含药培养基,同时设立阴性对照组;
5.若细胞实验中需用双香豆素(DIC)抑制细胞内NQO1活性,先用培养基稀释受试药物和双香豆素至所需浓度,并使DMSO终浓度不超过0.1%。将旧培养基吸去,并向96孔板中每孔加入100μL含双香豆素的培养基,共孵2小时后,再向每孔加入100μL相应的含药培养基,同时设立阴性对照组;
6.将96孔细胞培养板置于37℃,5%,CO2培养箱中培养72小时;
7.向每孔中加入10μl的CCK8溶液,并继续在培养箱中培养2-3小时;
8.使用酶标仪在450nm处读出每孔的OD值;
9.计算出每组的抑制率。
实验结果如表1所示,所有的化合物对所选肿瘤细胞株(A549和MCF-7)均有良好的抗肿瘤活性。其中前药I-2、I-4、I-6对肿瘤细胞的抗增殖活性均强于阳性药Gem;前药I-2~I-7对肿瘤细胞的抗增殖活性均强于阳性药NUC-1031。更值得注意的是,本发明所述的代表性前药对正常细胞(LO-2)的抗增殖活性均低于阳性药Gem与NUC-1031。这提示本发明所述化合物有良好的抗肿瘤活性,且对正常组织安全性较好。
另一方面,双香豆素(DIC)预处理的细胞内NQO1酶活性降低,所有化合物在该条件下的抗细胞增殖活性均有显著降低,这提示化合物活性受NQO1酶活性影响。化合物很有可能需要经NQO1酶活化,符合本发明的发明目的。
表1.化合物的体外抗细胞增殖活性(IC50,μM)
实施例9
吉西他滨前药的稳定性研究
受试药品:前药化合物(上述实施例制备);对照药物:吉西他滨(Gem,CAS:95058-81-4)、NUC-1031(CAS:840506-29-8);内标化合物:索非布韦(SOF,CAS:1190307-88-0)。
分析仪器:LC-20A型高效液相色谱仪;ZORBAX Eclipse XDB-C18(4.6×150mm,5μm);
实验步骤:
1.将受试药品用100%DMSO溶解配制成10mg/mL的母液储备;;将NADPH用PBS溶液溶解配制成1mg/mL的母液储备;
2.①PBS稳定性实验中,将前药化合物及对照药物母液分别用乙腈逐级稀释至400μg/mL;②NQO-1稳定性实验中,将受试化合物、NQO1和NADPH母液稀释并混合,使得三者终浓度分别为300μM、1μg/mL和700μM的混合液作为实验组;取化合物和NADPH终浓度分别为300μM和700μM的混合液作为对照组;上述①②两组样品均置于37℃恒温水浴中温孵;
3.分别于不同时间点取100μL样品加入至100μL乙腈(含索非布韦内标)中充分震荡混合;其中,预先将索非布韦母液用乙腈逐级稀释至200μg/mL,配成含内标乙腈溶液;
4.两次离心(12000rpm×5min)后,取60μL上清至进样瓶。使用高效液相色谱进行稳定性检测以及生成物的定量;
5.以索非布韦为内标,通过建立标准曲线得出受试化合物的稳定性。
实验结果如图5所示,化合物I-2(图5-A,●)在NQO1酶催化下能够迅速降解,并释放出吉西他滨(Gem,图5-A,■);而对照组中,化合物I-2在不含酶的空白溶液中稳定性良好(图5-A,○);此外,Gem在NQO1酶存在下稳定性较好(图5-A,X)。以上实验说明,化合物I-2能够被NQO1酶代谢活化并生成Gem,本发明所述前药具有NQO1靶向性。
化合物I-6(图5-B,●)在NQO1酶催化下能够迅速降解,并释放出NUC-1031(图5-A,■);而对照组中,化合物I-6在不含酶的空白溶液中稳定性良好(图5-A,○);此外,NUC-1031在NQO1酶存在下稳定性较好(图5-A,X)。以上实验说明,化合物I-2能够被NQO1酶代谢活化并生成Gem,本发明所述前药具有NQO1靶向性。综上,上述实验提示化合物可被NQO1酶活化,符合本发明的发明目的。
实施例10
吉西他滨前药的体内抗肿瘤活性研究
受试样品:化合物I-2、化合物I-6、吉西他滨(Gem)、NUC-1031;溶媒选用含DMSO及吐温80的生理盐水;实验分组为溶媒组及给药组(给药剂量0.1mmol/kg,每周2次,连续3周,第1/5/8/12/15/19/22天给药)。
受试动物:Balb/c裸鼠,6周龄,雌性;每组8只,共5组,共40只。
实验方法:
1.收集培养的人肺癌细胞A549细胞悬液,浓度为2×107个/ml,以每只0.1ml接种于裸鼠右侧腋窝皮下;
2.裸鼠移植瘤用游标卡尺测量移植瘤直径,肿瘤生长至100mm3时将动物随机分组。同时,各组小鼠开始给药,并记为第0天(Day 0);实验结束后,随即处死裸鼠,手术剥取瘤块称重。
观测指标:
1.体重:Day 1/5/8/12/15/19/22记录一次动物体重;
2.肿瘤体积:Day 1/5/8/12/15/19/22记录一次肿瘤体积大小;
分别计算肿瘤体积(tumor volume,TV;TV=1/2×a×b2;其中a、b分别表示长宽)及相对肿瘤体积(relative tumor volume,RTV;RTV=Vt/V0;其中V0为第0天测量所得肿瘤体积,Vt为每一次测量时的肿瘤体积)。
3.抗肿瘤活性的评价指标:
①相对肿瘤增殖率T/C(%)
T/C(%)=TRTV/CRTV×100%,其中TRTV为给药组RTV,CRTV为溶媒组RTV。
②肿瘤生长抑制率TI(%)
TI(%)=(溶媒组平均瘤重-给药组平均瘤重)/溶媒组平均瘤重×100%。
4.统计处理:均值用X±SD表示,组间分析用t检验进行统计学处理,应用SPSS(Staffstical Package for the Social Science)17.0对结果进行统计分析。
实验结果如图6所示,溶媒组荷瘤鼠(图6-A,●)的肿瘤体积持续增加;与之相比,化合物I-2(图6-A,■)及化合物I-6(图6-A,▲)抑瘤效果明显,与现有阳性药Gem(图6-A,)与NUC-1031(图6-A,◆)相当;其中,化合物I-6有最强的抑瘤能力。在给药期间,荷瘤鼠的体重增长稳定(图6-B),提示受试化合物的安全性良好;此外,所有化合物均有理想的抑瘤率。综上,上述实验提示本发明专利所提供的化合物有理想的体内抗肿瘤效果,符合本发明的发明目的。
以上所述仅是本发明的优选实施方式,并不用于限制本发明,应当指出,对于本技术领域的普通技术人员来说,可以根据上述说明加以改进或变换,这些改进和变换应属于本发明所附权利要求的保护范围。
Claims (9)
1.一种结构式如式(I)的化合物或其药学上可接受的盐:
其中,W选自:
X选自:氢、卤素原子、C1-3烷基、C1-3烷氧基、氰基、硝基或羧基;X是任意位置的单取代或多取代;
Y选自:O、S、NH或NCH3;
Q选自:氢或
R1或R2各自独立的选自:氢、甲基、乙基或异丙基;
R3选自:甲基、乙基、异丙基或苄基;
Ar选自:苯基。
2.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,
W选自:
X选自:H、F、Cl、Br、I、CH3、CH3O、CN、NO2或COOH;X是任意位置的单取代或多取代。
3.根据权利要求2所述的化合物或其药学上可接受的盐,其特征在于,
W选自:
4.根据权利要求1-3任一所述的化合物或其药学上可接受的盐、互变异构体、内消旋体、外消旋体、立体异构体或溶剂化物,其特征在于,所述R1、R2为氢或甲基。
5.根据权利要求1-3任一所述的化合物或其药学上可接受的盐、互变异构体、内消旋体、外消旋体、立体异构体或溶剂化物,其特征在于,R3选自:异丙基或苄基。
6.根据权利要求4所述的化合物或其药学上可接受的盐,其特征在于,R3选自:异丙基或苄基。
7.如下化合物及其药学上可接受的盐:
8.一种药物组合物,包含权利要求1-3、或权利要求4、或权利要求5、或权利要求6、或权利要求7任一所述的化合物或其药学上可接受的盐,以及药学上可接受的载体。
9.权利要求1-3、或权利要求4、或权利要求5、或权利要求6、或权利要求7任一所述的化合物或其药学上可接受的盐作为有效成分,在制备抗肿瘤药物中的应用。
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