CN105504007B - 氨基磷酸酯衍生物、其制备方法及其在制药中的用途 - Google Patents
氨基磷酸酯衍生物、其制备方法及其在制药中的用途 Download PDFInfo
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- UAUIUKWPKRJZJV-MDJGTQRPSA-N paritaprevir Chemical compound C1=NC(C)=CN=C1C(=O)N[C@@H]1C(=O)N2C[C@H](OC=3C4=CC=CC=C4C4=CC=CC=C4N=3)C[C@H]2C(=O)N[C@]2(C(=O)NS(=O)(=O)C3CC3)C[C@@H]2\C=C/CCCCC1 UAUIUKWPKRJZJV-MDJGTQRPSA-N 0.000 description 1
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- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
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- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
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- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
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Abstract
本发明涉及制药领域,具体涉及式I或式II所示的氨基磷酸酯衍生物、其制备方法及其在制药中的用途,尤其涉及氨基磷酸酯衍生物在制备抗丙型肝炎病毒药物中的用途。
Description
技术领域
本发明涉及制药领域,具体涉及氨基磷酸酯衍生物及其制备方法与在制药中的用途,尤其涉及氨基磷酸酯衍生物在制备抗丙型肝炎病毒药物中的用途。
背景技术
慢性丙型肝炎是由丙型肝炎病毒(HCV)引起的严重肝病。HCV感染机体后,肝组织脂代谢紊乱并伴有慢性炎症,造成肝损伤、脂肪肝并可能导致肝硬化或肝细胞癌。有约四分之一的肝硬化和原发性肝癌是由HCV引起。据统计全球约有1.8亿慢性丙肝感染者,然而慢性丙型肝炎起病隐匿,症状不明显,公众认知度低,被喻为“隐形杀手”,因此实际患者数量要远大于统计数据。我国丙肝患者约为1000万例,2012年全国丙肝病例报告已从2006年的7万多例增至20多万例,其中仅有约4万人接受抗病毒治疗。近年来我国突发性群体性丙肝事件屡有发生,总之,丙型肝炎给人民群众的健康带来极大威胁。
丙肝患者若能及时接受规范的抗病毒治疗,可以实现治愈。长效干扰素和利巴韦林联合治疗是目前我国治疗丙肝的标准疗法。但是该标准疗法给药依从性差,产生局部、全身甚至精神上的副作用;此外,半数以上的患者在联合治疗后并不能够完全治愈,且治疗费用高。目前,通过抑制HCV生命周期中的关键蛋白进行抗病毒治疗成为抗丙肝治疗的热点。HCV丝氨酸蛋白酶NS3/4A是丙肝病毒复制过程中的关键酶,其通过催化丙肝病毒原蛋白的水解从而生成丙肝病毒复制生命周期的各种酶类,同时研究表明HCV丝氨酸蛋白酶抑制宿主细胞对丙肝病毒的自身免疫应答,因此对HCV丝氨酸蛋白酶抑制剂的研究是抗HCV病毒的研究热点之一。
HCV丝氨酸蛋白酶抑制剂通过模拟HCV丝氨酸蛋白酶底物或产物发挥其抗HCV作用,目前上市或处于临床研究的HCV丝氨酸蛋白酶抑制剂主要为含有2-4个非天然氨基酸的拟肽,目前已有4个拟肽类HCV丝氨酸蛋白酶抑制剂成功上市,它们是Telaprevir、Boceprevir、Simeprevir和Asunaprevir。此外,还有若干拟肽类HCV丝氨酸蛋白酶抑制剂处于临床研究阶段,它们包括:ABT450、Faldaprevir、BILN-2061、GS9256、danoprevir、ACH1625、mk-5172、Vaniprevir和GS9451。临床研究表明,HCV丝氨酸蛋白酶抑制剂联合标准治疗方法可以有效的减少患者体内的病毒数目,与其它抗HCV在研药物联用的临床试验也表现出积极效果。但是,该类化合物仍存在一些不足:首先该类化合物的活性还有进一步提高的空间以降低药物剂量;拟肽类化合物由于其类肽性,药代动力学性质还有待进一步提高,主要包括口服生物利用度、肝脏组织药物浓度与血管中药物浓度比等;HCV属于正链RNA病毒,变异发生率高,患者长期用药容易诱发病毒变异并产生耐药,这也是抗病毒药物研发及临床应用中面临的严峻挑战,尤其是目前处于上市或临床研究的HCV丝氨酸蛋白酶抑制剂由于其结构差异小,作用机制相似,存在交叉耐药性,对于某个药物产生耐药性后,其他类型的化合物均有可能无效。此外,部分临床在研的抗HCV药物还存在严重的副作用。因此,研制具有新结构类型的HCV丝氨酸蛋白酶抑制剂具有重大意义。
发明内容
本发明所要解决的技术问题在于克服上述不足之处,研制新型的氨基磷酸酯衍生物,以开发疗效好、剂量低且副作用小的抗丙型肝炎病毒药物。
本发明公开了一系列氨基磷酸酯衍生物或其药学上可接受的盐或酯或溶剂化物或其立体异构体,所述衍生物是式I或式II化合物:
其中,R1为氢、1~6个碳的直链或支链烷基、3~6个碳的环烷基、苄基、苯基或卤素;
R2为1~6个碳的直链或支链烷基、3~6个碳的环烷基或苄基;R1与R2可以通过0~10个原子的链相连;
R3、R4分别为氢、1~10个碳的非取代或取代的直链或支链烷基、3~10个碳的非取代或取代的环烷基、苄基、苯乙基、苯乙烯基、苯基或取代苯基;
R6、R7为氢、卤素、CN、NO2、CF3、OCF3、1~6个碳的直链或支链烷基或3~6个碳的环烷基;
Y为氧或NH;
Z为芳基、取代的芳基、杂环芳基或取代的杂环芳基。
本发明化合物优选R1为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、环丙基、环戊基、环己基、苄基或苯基;优选R2为1~6个碳的直链或支链烷基、3~6个碳的环烷基;或R1与R2可以通过0~10个原子的链相连;优选R3、R4分别为1~10个碳的非取代或取代的直链或支链烷基或3~6个碳的环烷基;优选X为 其中,优选R5为氢、1~6个碳的直链或支链烷基或3~6个碳的环烷基;优选Y为氧;优选Z为取代的芳基或取代的杂环芳基;优选R6、R7为氢、卤素、CN、NO2、CF3或OCF3;
进一步地,本发明化合物更优选R1为氢;更优选R2为环己基、叔丁基、异丙基;或R1与R2可以通过4~6个原子的链相连;更优选R3、R4分别为甲基、乙基、异丙基或叔丁基;更优选X为其中,更优选R5为氢、1~6个碳的直链或支链烷基或3~6个碳的环烷基;更优选R6、R7为氢或卤素;更优选Z为取代的杂环芳基。部分优选的Z具有如下结构:
本发明通式I和通式II的优选化合物如下:
本发明的另一目的是提供了氨基磷酸酯类衍生物的制备方法,如下反应式所示:
式I化合物的制备:
具体包括下列步骤:
式III化合物或其盐与相应的亚磷酸二酯发生偶联反应得到式I化合物,所采用的溶剂选自苯、甲苯、氯仿、正己烷、环己烷、二氯甲烷、1,2-二氯乙烷、甲基叔丁基醚、***、乙酸乙酯、四氢呋喃、四氯化碳、丙酮、乙腈、乙醇、甲醇、N,N-二甲基甲酰胺或二甲亚砜中的一种或多种的混合溶剂,优选四氢呋喃、乙腈或二氯甲烷;偶联反应所使用的碱选自吡啶、三乙胺、二异丙基乙胺、4-二甲氨基吡啶(DMAP)、碳酸钾或碳酸钠;反应温度为零下20℃至100℃,优选温度为0℃至60℃;式III化合物的盐为其盐酸盐、三氟乙酸盐、硫酸盐、硝酸盐、三氟甲烷磺酸盐、甲烷磺酸盐或对甲苯磺酸盐。
式II化合物的制备:
式IV化合物或其盐与相应的亚磷酸二酯发生偶联反应得到式I化合物,所采用的溶剂选自苯、甲苯、氯仿、正己烷、环己烷、二氯甲烷、1,2-二氯乙烷、甲基叔丁基醚、***、乙酸乙酯、四氢呋喃、四氯化碳、丙酮、乙腈、乙醇、甲醇、N,N-二甲基甲酰胺或二甲亚砜中的一种或多种的混合溶剂,优选四氢呋喃、乙腈或二氯甲烷;偶联反应所使用的碱选自吡啶、三乙胺、二异丙基乙胺、4-二甲氨基吡啶(DMAP)、碳酸钾或碳酸钠;反应温度为零下20℃至100℃,优选温度为0℃至60℃;式IV化合物的盐为其盐酸盐、三氟乙酸盐、硫酸盐、硝酸盐、三氟甲烷磺酸盐、甲烷磺酸盐或对甲苯磺酸盐。
在上述反应式中,R1、R2、R3、R4、R6、R7、X、Y和Z如式I和式II化合物中所定义。
本发明的又一目的是提供了式I或式II化合物或其药学上可接受的盐或酯或溶剂化物或其立体异构体在制备抗丙型肝炎药物中的用途。
通过药效学实验,令人惊讶地发现,本发明的式I和式II化合物对野生型HCV的抑制效果显著优于抗丙型肝炎药物Telaprevir和Sofosbuvir,且具有很低的细胞毒性。实验结果提示,本发明化合物或其药学上可接受的盐可用于制备抗丙型肝炎药物。
本发明还提供了一种预防或治疗丙型肝炎的药物组合物,其中含有治疗有效量的式I或式II化合物或其药学上可接受的盐和药学上可接受的载体。所述药物组合物可以是普通片剂或胶囊、缓释片剂或胶囊、控释片剂或胶囊、颗粒剂、散剂、糖浆剂、口服液、注射剂等制剂学上常规的制剂形式。
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。
实施例1
化合物I-1的制备
将60mg化合物V溶解于2ml二氯甲烷中,室温下滴加0.5ml三氟乙酸,室温搅拌2小时,减压条件下蒸除溶剂以及过量的三氟乙酸。将残留物溶解于1ml乙腈中,加入1ml四氯化碳、50μL三乙胺和1mg 4-二甲氨基吡啶(DMAP),体系降温至-5℃,缓慢滴加20μL的亚磷酸二甲酯,滴毕室温搅拌过夜。浓缩反应液,向体系中加入1N盐酸溶液,乙酸乙酯(10ml x 3)萃取水相,无水硫酸钠干燥,蒸干有机相得粗品,经快速柱层析(二氯甲烷∶甲醇=60∶1)得化合物I-1(37.4mg,收率52%):1H NMR(300MHz,MeOD+CDCl3)δ7.98-7.95(m,1H),7.53(s,1H),7.13-7.06(m,2H),5.83-5.74(m,1H),5.51(s,1H),5.36-5.27(m,1H),5.17-5.10(m,1H),4.70-4.64(m,1H),4.26(d,J=12Hz,1H),4.15(d,J=6Hz,1H),4.11(d,J=9Hz,1H),3.86(d,J=9Hz,1H),3.62-3.57(m,4H),3.52-3.36(m,3H),3.27-3.18(m,1H),2.93-2.83(m,1H),2.69(s,3H),2.66-2.63(m,2H),2.18(s,1H),2.14-2.11(m,1H),2.05(s,4H),2.01-1.99(m,1H),1.99-1.83(m,1H),1.80-1.67(m,7H),1.41-1.35(m,10H);HRMS Calcd forC41H55N6O10NaPS2,[M+Na]+m/z 909.3056,found 909.3041.
实施例2
化合物I-2的制备
参照实施例1的制备方法,将亚磷酸二甲酯替换成亚磷酸二乙酯制得化合物I-2:1HNMR(300MHz,CDCl3)δ10.89(s,1H),8.13-8.10(m,2H),7.71(s,1H),7.29-7.23(m,1H),5.87-5.70(m,1H),5.61(s,1H),5.29(t,J=15Hz,1H),5.12(t,J=6Hz,1H),4.66-4.61(m,1H),4.31-4.27(m,1H),4.19-4.14(m,1H),3.99(s,3H),3.92-3.87(m,4H),3.71-3.69(m,2H),3.27-3.20(m,1H),2.96-2.87(m,2H),2.72-2.67(m,1H),2.64(s,3H),2.57-2.54(m,1H),2.23-2.18(m,1H),2.02(s,1H),1.94-1.92(m,2H),1.72-1.64(m,8H),1.41(d,J=3Hz,6H),1.31-1.09(m,9H);HRMS Calcd for C43H58N6O10PS2,[M-1]-m/z 913.3393,found913.3413.
实施例3
化合物I-3的制备
参照实施例1的制备方法,将亚磷酸二甲酯替换成亚磷酸二异丙酯制得化合物I-3:1H NMR(300MHz,CDCl3)δ10.23(s,1H),8.36(s,1H),8.16(s,1H),7.98-7.93(m,1H),7.54(s,1H),7.17(d,J=3Hz,1H),7.06(s,1H),5.83-5.75(m,1H),5.53(s,1H),5.36-5.24(m,1H),5.14(d,J=6Hz,1H),4.84-4.76(m,1H),4.69-4.64(m,1H),4.61-4.57(m,1H),4.53-4.48(m,2H),4.27-4.16(m,2H),3.98(s,3H),3.24-3.19(m,1H),2.98-2.88(m,1H),2.69(s,3H),2.66-2.59(m,1H),2.21-2.10(m,1H),2.03-2.10(m,1H),1.83-1.59(m,8H),1.41-1.37(m,18H),1.26-1.20(m,8H);HRMS Calcd for C45H63N6O10NaPS2,[M+Na]+m/z 965.3682,found 965.3671.
实施例4
化合物I-4的制备
参照实施例1的制备方法,将亚磷酸二甲酯替换成亚磷酸二苯酯制得化合物I-4:1HNMR(300MHz,MeOD)δ7.75(d,J=9Hz,1H),7.59(s,1H),7.28(s,1H),7.20-7.15(m,5H),7.12-7.03(m,5H),6.98-6..92(m,2H),5.91-5.74(m,1H),5.53(s,1H),5.38-5.30(m,1H),5.16(d,J=9Hz,1H),4.60-4.53(m,1H),4.37(d,J=12Hz,1H),4.24-4.19(m,1H),3.98(s,3H),3.22-3.14(m,2H),3.01-2.94(m,1H),2.61(s,3H),2.48-2.40(m,1H),2.29-2.19(m,1H),2.05-1.92(m,1H),1.79-1.60(m,8H),1.41(d,J=9Hz,6H),1.13-1.11(m,8H);HRMSCalcd for C51H59N6O10NaPS2,[M+Na]+m/z 1033.3369,found1033.3383.
实施例5
化合物I-5的制备
参照实施例1的制备方法,将亚磷酸二甲酯替换成亚磷酸二苄酯制得化合物I-5:1HNMR(300MHz,MeOD)δ8.06(s,1H),7.63(s,1H),7.34-7.29(m,10H),7.26-7.24(m,2H),5.77-5.69(m,1H),5.57(s,1H),5.37-5.28(m,1H),5.18-5.13(m,1H),4.71-4.68(m,1H),4.37-4.34(m,1H),4.22-4.12(m,2H),3.99(s,3H),3.33(d,J=12Hz,4H),3.35-3.18(m,1H),3.02-2.94(m,1H),2.86-2.77(m,2H),2.63(s,3H),2.57-2.52(m,2H),2.46-2.36(m,1H),2.33-2.24(m,1H),2.19-1.99(m,1H),1.94-1.80(m,1H),1.40(d,J=6Hz,6H),1.18(s,9H).
实施例6
化合物I-6的制备
将40mg化合物I-5溶解于1ml甲醇中,加入1.5mg 10%Pd-C,室温下通入氢气搅拌10分钟,过滤,将滤液浓缩旋干得到化合物I-6(21.3mg,收率87%):1H NMR(300MHz,MeOD)δ8.08(d,J=12Hz,1H),7.64-7.63(m,1H),7.39(d,J=12Hz,1H),7.35(s,1H),5.82-5.69(m,1H),5.60(s,1H),5.43-5.28(m,1H),5.20-5.12(m,1H),4.71-4.66(m,1H),4.36(d,J=15Hz,1H),4.21(dd,J=12,3Hz),4.12(d,J=6Hz,1H),4.00(s,3H),3.30-3.17(m,1H),2.97-2.95(m,1H),2.79-2.72(m,1H),2.62(s,3H),2.69-2.62(m,2H),2.43-2.37(m,1H),2.32-2.23(m,1H),2.02(s,1H),1.91-1.80(m,1H),1.40(d,J=6Hz),1.71(s,10H).
实施例7
化合物I-7的制备
参照实施例1的制备方法,将化合物VI用三氟乙酸脱Boc保护基,再与亚磷酸二甲酯反应制得化合物I-7:MS[M+1]+m/z 861.30.
实施例8
化合物I-13的制备
参照实施例1的制备方法,将化合物VII用三氟乙酸脱Boc保护基,再与亚磷酸二甲酯反应制得化合物I-13:MS[M+1]+m/z 771.23.
实施例9
化合物I-28的制备
参照实施例1的制备方法,将化合物VIII用三氟乙酸脱Boc保护基,再与亚磷酸二甲酯反应制得化合物I-28:MS[M+1]+m/z 797.25.
实施例10
化合物II-1的制备
参照实施例1的制备方法,将化合物IX用三氟乙酸脱Boc保护基,再与亚磷酸二甲酯反应制得化合物II-1:MS[M+1]+m/z 728.25.
实施例11
化合物II-3的制备
参照实施例1的制备方法,将化合物X用三氟乙酸脱Boc保护基,再与亚磷酸二甲酯反应制得化合物II-3:MS[M+1]+m/z 754.26.
实施例12
化合物I-17的制备
参照实施例1的制备方法,将化合物XI用三氟乙酸脱Boc保护基,再与亚磷酸二甲酯反应制得化合物I-17:MS[M+1]+m/z 754.26.
实施例13
抗HCV体外药效学试验
药品:受试化合物(上述实施例制备)、阳性对照药为Telaprevir和Sofosbuvir.
细胞模型:采用GT1b丙肝病毒复制子细胞***测定化合物的体外活性。将GT1bHCV基因(野生型)重新构建,剪切掉一部分片段,并增加了新的片段,这其中包括抗生素耐受基因和荧光素酶基因。将新构建的重组基因转染入人肝癌细胞系Huh-7中。通过在含有硫酸新霉素(G418)的培养基中培养后,可以获得G418耐受的细胞克隆,这些细胞克隆可以持续的表达HCV复制子RNA,从而建立有效复制的HCV细胞培养***。通过检测荧光素酶基因的表达高低可以确定丙肝病毒的复制水平。
实验步骤:
1.化合物与细胞共孵育:种GT1b复制子细胞到96孔板,每孔8000个细胞;每个化合物浓度进行复孔检测,3倍系列稀释10个点,DMSO终浓度为0.5%;二氧化碳培养箱培养细胞72小时;
2.向每孔细胞中加入细胞活力检测试剂,检测细胞活力。随后向细胞中加入荧光素酶发光底物,等5分钟用化学发光检测***检测。分析数据并计算化合物细胞毒性和抗丙肝病毒GT 1b基因型复制子的活性。
3.对数据进行非线性拟合,计算化合物的CC50或EC50。
结果:通过化学发光检测***检测受试化合物对HCV抑制活性。实验结果如表1所示。结果表明,本发明受试化合物的抗HCV活性(EC50范围在4nM~388nM)均显著优于抗丙型肝炎药物Telaprevir(EC50=1000nM),且均表现出较低的细胞毒性(CC50>10μM)。尤其令人惊喜的是,若干化合物(如化合物I-1:EC50=4nM)显示了极强的抗HCV活性,显著优于“重磅炸弹型”抗丙型肝炎药物Sofosbuvir(EC50=152nM)。以上结果提示本发明化合物有望开发成为安全、有效的新型抗丙型肝炎药物。
表1.受试化合物的抗HCV作用
实施例14
片剂
将实施例1中制得的化合物I-1(50g)、羟丙甲基纤维素E(150g)、淀粉(200g)、聚维酮K30适量和硬脂酸镁(1g)混合,制粒,压片。
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