CN111909205B - 一种替诺福韦双丙酸酯基氨基磷酸酯化合物及其药物组合物和用途 - Google Patents
一种替诺福韦双丙酸酯基氨基磷酸酯化合物及其药物组合物和用途 Download PDFInfo
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Abstract
本发明公开了一种替诺福韦双丙酸酯基氨基磷酸酯化合物，还公开了制备方法以及含有该组化合物的药物组合物。试验证明本发明化合物具有抑制HBV病毒复制的活性，同时所述化合物具有比目前治疗艾滋病药物替诺福韦酯富马酸盐(TAF)活性高、开发系数大等优点。实验还证明本发明化合物还具有抑制HIV‑1病毒复制的活性，可用于治疗艾滋病药物或乙型肝炎药物的开发。
Description
技术领域
本发明涉及医药技术领域，特别涉及一种替诺福韦双丙酸酯基氨基磷酸酯化合物，以及含有该化合物的药物组合物和用途。
背景技术
中国市场治疗乙肝的一类用药ETV(恩替卡韦)、TDF(韦瑞德)、TAF(韦立得)，自上市以来，各有优缺点。
ETV的优点：副作用小；缺点：有一定的耐药，孕妇禁用；
TDF优点：抗病毒效果好，极少耐药；缺点：有一定的肾毒性，长期应用会对骨骼和肾脏有一定的副作用；
TAF优点：与TDF抗病毒效果相当，提高了肾脏和骨骼实验室安全参数，极少耐药，使用剂量仅为一代替诺福韦的十二分之一。
韦立得(TAF)是治疗乙肝的新型口服方案，虽不能完全治愈乙肝，但是其功效有了大大的提升，能够很好的控制乙肝病毒量。在临床效果上，TAF和TDF在治疗乙肝有相同的临床效果，但是TAF的用量更小，毒性更低，在耐药性和联合治疗中会发挥更大的作用。但由于TAF进入人体后要脱落一分子的苯酚，所以TAF复方制剂上市以来逐渐表现出来了不容忽视的毒副作用：乳酸中毒及严重肝脏肿大合并脂肪肝。
因此开发新的TAF的类似物，保持结构的微小变化，维持TAF优秀的抗病毒活性，同时具有在血浆中更好的稳定性和口服生物利用度意义重大。
综上，虽然目前全球的艾滋病/乙肝治疗药物，吉利德公司的TDF、TAF复方制剂仍然独霸市场，但是我们的基于TNF的治疗艾滋病/乙肝药物研究仍然意义巨大。进一步改善其人体的生物利用度、提高活性、降低毒副作用而充分发挥治疗乙肝和艾滋病的药效仍然具有重要的价值。
发明内容
在对TAF类似物的前药研究过程中，意外地发现把TAF的苯环链替换成氨基NHR链后，活性有所升高，生物活性选择系数SI也有所升高，这样使得研究样品的使用剂量比较TAF可以进一步降低，即可以进一步降低TAF的毒性，同时保持TAF的活性，在组织细胞特别是肝细胞中药物浓度与TAF相比有显著的增加。所以本发明的替诺福韦双丙酸酯基氨基磷酸酯化合物由于可以显著提高对乙肝和艾滋病的治疗效果，并极大的降低TDF或TAF引起的肾毒性和骨毒性。由此提出了下述发明。
一种替诺福韦双丙酸酯基氨基磷酸酯化合物，包括：
a)化合物(Ia)，其结构如下所示，
其中，R1＝R2＝C4-C12烷基；或
b)由如a)所述化合物(Ia)与酸制得的药学上可接受的盐。
进一步，当所述R1、R2基团选自异丁基、新戊基、正丁基、环己基或叔丁基时，化合物的结构式分别为下列结构式：
进一步，所述药学上可接受的盐为草酸盐、丙二酸盐、琥珀酸盐、富马酸盐、天冬氨酸盐、柠檬酸盐、水杨酸盐、盐酸盐、硫酸盐或磷酸盐，酸和化合物(Ia)摩尔比的范围为(0.5～1):1。
进一步，当所述R1、R2基团选自异丁基、新戊基、正丁基、环己基或叔丁基时，所述富马酸盐的结构式分别为下列结构式：
进一步，所述富马酸盐是由富马酸与化合物按照0.5:1的摩尔比制得。
另一方面，本发明还提供了一种药物组合物，包含治疗有效量的替诺福韦双丙酸酯基氨基磷酸酯化合物，以及至少一种药学上可接受的载体或赋形剂。
进一步，所述药物组合物还包含治疗有效量的额外治疗剂，所述额外治疗剂选自抑制HIV蛋白酶的化合物、逆转录酶的HIV非核苷抑制剂、逆转录酶的HIV核苷抑制剂、逆转录酶的HIV核苷酸抑制剂、HIV整合酶抑制剂、gp41抑制剂、CXCR4抑制剂、gp120抑制剂、CCR5抑制剂、病毒壳体聚合抑制剂、非催化部位HIV整合酶部位抑制剂的至少一种。
进一步，所述药物组合物的剂型为片剂或胶囊。
本发明所述的替诺福韦双丙酸酯基氨基磷酸酯化合物可应用于制备用于预防或治疗病毒疾病的药物。具体的病毒疾病为HIV-1感染或HBV感染或HIV-1与HBV同时感染。
经测定，本发明化合物具有成为治疗艾滋病/乙肝的药物所需的优良属性，具体如下：
在一体外抗乙肝病毒活性筛选中，化合物C0P3232的IC50是TAF(阳性对照)的1.16倍，生物活性选择系数SI是TAF(阳性对照)的2.48倍。其表明本发明所述化合物比一类抗乙肝药物TAF抑制病毒复制的活性高，开发生物活性选择系数大，有望成为治疗HBV感染的药物。本发明所述化合物集高活性、低毒性、高生物利用度等各种良好属性于一体，有着成为新一代治疗艾滋病或治疗乙型肝炎的药物的前景。
具体实施方式
以下实施例可以使本专业技术人员更全面地理解本发明，但不以任何方式限制本发明。所有化合物的结构均经1H NMR或MS确定。
本发明所用原料：替诺福韦、L-丙氨酸酯盐酸盐、富马酸都由市场购买得到。
实施例1
9-[(R)-2-[[二[[(S)-(1-正丁氧基羰基)乙基]氨基]氧膦基]甲氧基]丙基]腺嘌呤(C0P3434)的制备。
称取市售的替诺福韦(C0P00)7.18g(25mmol)，加入250ml烧瓶中，再加入氯化亚砜50g，升温至55℃，10分钟后，再继续升温至70℃后搅拌1小时，减压蒸馏氯化亚砜，蒸馏结束后再加入100ml干燥乙腈并在85℃下回流10min后，减压蒸干乙腈，降温至室温，然后加入50ml干燥二氯甲烷，再继续搅拌0.5h后加入12.42g(75mmol，3eq)L-丙氨酸正丁酯盐酸盐(AH34)，再搅拌10min后滴加大约20ml三乙胺，滴加完毕，继续搅拌0.5h。
抽滤，滤液蒸干后再加入100ml乙酸乙酯。并分别用100g 5％碳酸氢钾水溶液洗涤两次、100g 20％氯化钠水溶液洗涤两次，无水硫酸钠干燥，干燥后抽滤，滤液蒸干。乙酸乙酯柱层析得C0P3434约6g(纯度98.2％)。
1H NMR(400MHz,CDCl3)δ,(ppm):0.84-0.92(6H,dt,2×CH3)，1.03-1.14(9H,m,3×CH3),1.26-1.40(4H,m,2×CH2)，1.44-1.68(4H,m,2×CH2),2.73-2.89(1H,m,OCH),3.02-3.56(4H,m,2×NH and OCH2P),3.70-4.11(6H,m,2×NCH and 2×COOCH2),4.15-4.33(2H,m,NCH2),6.25(2H,s,NH2),7.89(1H,s,嘌呤环上的H),8.33(1H,s,嘌呤环上的H)。
ESI-MS:[M+H]+542.6。
实施例2
9-[(R)-2-[[二[[(S)-(1-正丁氧基羰基)乙基]氨基]氧膦基]甲氧基]丙基]腺嘌呤富马酸盐(FC0P3434)的制备。
将等量9-[(R)-2-[[二[[(S)-(1-正丁氧基羰基)乙基]氨基]氧膦基]甲氧基]丙基]腺嘌呤(C0P3434)和富马酸溶于热的乙腈中,回流搅拌2小时,室温下冷却析晶，滤出析出的固体并用乙腈洗涤得白色固体:9-[(R)-2-[[二[[(S)-(1-正丁氧基羰基)乙基]氨基]氧膦基]甲氧基]丙基]腺嘌呤富马酸盐(FC0P3434)。
实施例3
本发明化合物抗HBV病毒活性的体外测定
1.体外细胞模型:HepG 2.2.15细胞
2.Dot blot法测定化合物抗乙肝病毒活性
2.1种HepG 2.2.15细胞(4×104细胞/孔)到96孔板，在37℃，5％培养过夜。
2.2第二天，稀释化合物，加不同浓度化合物到培养孔中。培养液中DMSO的终浓度为1％。1μM恩替卡韦(ETV)作为100％Inhibition对照；1％的DMSO作为0％Inhibition对照。
2.3第五天，更换含有化合物的新鲜培养液。
2.4第八天和第九天，去除培养孔中的培养液，收取细胞进行点杂交。
3.结果：见表一。
表一：化合物的细胞毒性，胞外抗HBV活性(HepG2.2.15)
4.实验结论：
4.1阳性化合物TAF在HepG 2.2.15细胞中对乙肝病毒复制符合预期的抑制效果，证明实验有效可信。
4.2抗乙肝病毒活性。在点杂交实验中,上表化合物C0P3232在抗乙肝病毒的活性都是TAF(阳性对照)的1.16倍。且开发系数SI是阳性对照TAF的2.48倍。
4.3这充分表明：本发明化合物比目前抗乙肝药物TAF抑制病毒复制的活性高，有望成为治疗HBV感染的新一代药物。
实施例4
制剂配方与工艺
本发明的药物组合物可按通用的口服药物制剂制备方法制成片剂或胶囊，5mg剂量的本发明化合物片剂或胶囊单位含量如下：
表二
| 名称 | 配比/mg |
| 本发明化合物 | 2.50 |
| 乳糖 | 1.65 |
| 淀粉 | 0.66 |
| 微晶纤维素 | 0.08 |
| 羧甲淀粉钠 | 0.08 |
| 硬脂酸鎂 | 0.03 |
。
Claims (3)
1.一种替诺福韦双丙酸酯基氨基磷酸酯化合物或其药学上可接受的盐，其特征在于，所述替诺福韦双丙酸酯基氨基磷酸酯化合物的结构式选自如下结构式之一：
所述药学上可接受的盐为富马酸盐，所述富马酸盐的结构式选自如下结构式之一：
2.一种药物组合物，其特征在于，包含治疗有效量的如权利要求1所述的替诺福韦双丙酸酯基氨基磷酸酯化合物或其药学上可接受的盐，以及至少一种药学上可接受的载体或赋形剂。
3.如权利要求1所述的替诺福韦双丙酸酯基氨基磷酸酯化合物或其药学上可接受的盐在制备用于预防或治疗HBV感染病毒疾病的药物中的应用。
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