CN105399771B - 替诺福韦前药晶型及其制备方法和用途 - Google Patents
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Abstract
本发明涉及9‑[(R)‑2‑[[(S)‑[[[1‑(异丙氧基羰基)‑1‑甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐新晶形及其制备方法和用途。具体地，本发明涉及式(I)所示9‑[(R)‑2‑[[(S)‑[[[1‑(异丙氧基羰基)‑1‑甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的新晶型，其特征在于，所述晶型XRPD图谱中至少包含2θ±0.20°为：5.08，12.44，13.18，22.37，23.37，28.56的衍射峰。本发明晶型具有生物利用度高，药效显著，稳定性好，收率高，纯度高等特点，有助于药物给药途径的选择与设计，以及药物制剂工艺参数的确定，从而提高药品生产质量。
Description
技术领域
本发明涉及医药化学领域，具体涉及替诺福韦前药9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐新晶型及其制备方法，含有治疗有效量的该化合物的药物组合物及其制药用途。
背景技术
9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐(I)。具备如下结构：
9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐(I)是一种核苷类逆转录酶抑制剂，是替诺福韦(PMPA)的前药。PMPA结构类似天然核苷单磷酸，在体内迅速转化为活性代谢产物PMPA二磷酸(PMPApp)；PMPApp与天然5′三磷酸脱氧腺苷竞争，掺入到病毒DNA链中，但由于PMPApp缺乏3′OH基团，无法再进行5′，3′磷酸二酯键偶联，从而导致DNA链延长受阻，最终阻断病毒的复制(图1)。研究证明PMPA具有抗人免疫缺陷病毒(HIV)和乙型肝炎病毒(HBV)活性。
但PMPA含有磷酸基团，在生理pH条件下通常带负电荷而极性太强不易通过生物膜，导致该类药物口服生物利用度差、组织分布系数低，并且具有一定的肾毒性。因此在开发该类药物时，需要运用前药原理将磷酸基团的负电荷掩蔽，消除该类药物的不足。吉利德公司开发的PMPA的双酯前药，富马酸PMPA二吡伏酯(tenofovirdisoproxilfumarate,TDF)分别于2001年被美国食品药品管理局(FDA)批准用于治疗HIV感染。
TDF在一定程度上显著改善了PMPA的药代动力学属性，但它在体内还是很快被血浆中广泛存在的非特异性酯酶水解，尤其是在肠黏膜上皮细胞碳酸酯酶作用下迅速水解释放出PMPA。血浆中高浓度PMPA由于其膜透过性差而被迅速排出体外，难以在感染部位保持足够的浓度；此外，PMPA是肾近端小管上皮细胞有机阴离子转运体(hOAT)的底物，血浆中高浓度PMPA易在肾近端小管上皮细胞中累积，造成一定的肾毒性风险。
而新一代的单磷酰胺单酯类前药克服了上述TDF的缺点，在血浆中很稳定，不易被酯酶水解；但被吸收进入细胞内；立即在丝氨酸蛋白酶(cathepsinA)以及体内特异性酰胺酶的作用下转化为PMPA，因此有更好的组织透过性及淋巴组织和细胞靶向性。吉利德公司开发的单磷酰胺单酯类前药GS7340(参考专利WO2013052094A2)已经顺利进入Ⅲ期临床试验，结果显示GS7340与30倍剂量的TDF相比，还具有更强的抗病毒能力和更好的安全性。
9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐(I)和GS7340一样，在细胞内都会释放出活性成分PMPA。其辅助基团设计巧妙，结构上和GS7340只有一个甲基的区别，辅助基团在细胞内的脱落机制和方式与GS7340基本相同。可以预见，HS-10234由于吸收和分布上优势，将比TDF等前药更为有效地发挥其活性成分PMPA的药效，作为最有潜力的新一代PMPA前药造福于广大患者。
本领域技术人员知道，药物的多晶型已经成为药物研究过程和药品成品质量控制及检测过程中必不可少的重要组成部分。对药物多晶型的研究有助于新药化合物生物活性的选择，有助于提高生物利用度，增进临床疗效，有助于药物给药途径的选择与设计，以及药物制剂工艺参数的确定，从而提高药品生产质量。同一药物晶型不同，生物利用度可能差异显著。同一种药物，某些晶型可能比其他晶型具备更高的生物活性。获得一种生物活性更高，更适合医药应用的替诺福韦前药晶型是医药领域一直期待解决的技术问题。
发明内容
本发明的目的在于解决上述技术问题，提供9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的一种新晶型，本发明将其命名为晶型A。
本发明所述晶型A的XRPD图谱中至少包含2θ±0.20°为：5.08，12.44，13.18，22.37，23.37，28.56的衍射峰。
优选的，所述的9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型A的XRPD图谱中至少包含2θ±0.20°为：5.08，7.42，10.15，12.44，13.18，22.37，23.37，28.56的衍射峰。更优选的，还包含2θ±0.20°为16.35，18.23，21.36，25.00，31.68的衍射峰。
特别优选的，所述晶型A的XRPD图谱如图1所示。
本发明所述的9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型A的差热分析结果表明，在110.9℃出现一个尖锐的吸热熔融峰。
本发明的另一目的在于提供9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的晶型A的制备方法，包括如下步骤：
①将任意形态的9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐在有机溶剂中加热溶解；
②将9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的溶解液冷却析晶；
③过滤晶体得到晶型A。
优选的，所述有机溶剂选自乙腈、无水甲醇、无水乙醇、异丙醇、无水甲醇/正庚烷、无水乙醇/正庚烷、异丙醇/正庚烷、无水甲醇/甲基叔丁基醚、无水乙醇/甲基叔丁基醚、异丙醇/甲基叔丁基醚、无水甲醇/异丙醚、无水乙醇/异丙醚、异丙醇/异丙醚、无水甲醇/乙醚、无水乙醇/乙醚或异丙醇/乙醚，其中优选无水甲醇/正庚烷。
优选的，有机溶剂加热溶解温度一般为30℃至回流温度，优选回流温度；析晶温度优选-40～40℃，最优选0℃～10℃。
本发明的另一目的还在于提供一种包含有效量的所述晶型A的药物组合物，任选的，所述组合物中还包含药学上可接受的载体。
本发明的组合物包括适于口服和注射等给药途径，优选口服给药途径。剂型包括片剂，胶囊，分散剂和混悬剂，优选片剂。
本发明的另一目的还在于提供所述晶型A及含有晶型A的药物组合物在在制备治疗艾滋病或乙型病毒性肝炎药物中的应用。
本发明的新晶型A具有生物利用度高，药效显著，稳定性好，收率高，纯度高等特点。本发明的新晶型有助于药物给药途径的选择与设计，以及药物制剂工艺参数的确定，从而提高药品生产质量。
附图说明
图1是本发明9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐新晶型的XRPD图谱。
图2是本发明9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐新晶型的DSC图谱。
具体实施方式
为体现本发明的技术方案及其所取得的效果，下面将结合具体实施例对本发明做进一步说明，但本发明的保护范围并非局限于具体实施例。
实施例一：
将9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐5.0g，无水甲醇20.0ml和正庚烷5ml置于反应瓶中，加热至回流，使固体完全溶解，关闭加热，降温至0～10℃搅拌析晶2h，过滤固体得到晶型A。
经检测验证，其X射线粉末衍射图谱如图1所示，其DSC图谱与图2吻合，证明了所得晶型为晶型A。
实施例二：
将9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐5.0g，无水乙醇20.0ml置于反应瓶中，加热至回流，使固体完全溶解，关闭加热，降温至0～10℃搅拌析晶2h，过滤固体得到晶型A。
经检测验证，其X射线粉末衍射图谱与图1吻合，其DSC图谱与图2吻合，证明了所得晶型为晶型A。
实施例三：
将9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐5.0g，异丙醇20.0ml和甲基叔丁基醚5ml置于反应瓶中，加热至回流，使固体完全溶解，关闭加热，降温至0～10℃搅拌析晶2h，过滤固体得到晶型A。
经检测验证，其X射线粉末衍射图谱与图1吻合，其DSC图谱与图2吻合，证明了所得晶型为晶型A。
实验例：稳定性考察
对本发明实施例一的方法制备的新晶型进行稳定性考察，结果表明，本发明的新晶型晶型A在稳定性试验中没有发生转晶，同时也没有发生化学降解，在室温下是稳定的，符合药物及制剂需求，详见下表：
Claims (6)
1.式(I)所示9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的新晶型的制备方法，
其特征在于，所述晶型具有与图1基本一致的X射线衍射图，包括如下步骤：
1)将任意形态的9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐在有机溶剂中加热溶解；
2)将9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的溶解液冷却析晶；
3)过滤晶体得到目标晶型；
其中，所述有机溶剂选自无水甲醇、无水乙醇、异丙醇、无水甲醇/正庚烷、无水乙醇/正庚烷、异丙醇/正庚烷、无水甲醇/甲基叔丁基醚、无水乙醇/甲基叔丁基醚、异丙醇/甲基叔丁基醚、无水甲醇/异丙醚、无水乙醇/异丙醚、异丙醇/异丙醚、无水甲醇/乙醚、无水乙醇/乙醚或异丙醇/乙醚。
2.根据权利要求1所述的式(I)所示9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的新晶型的制备方法，其特征在于，所述晶型的差热分析结果表明，在110.9℃出现一个尖锐的吸热熔融峰。
3.根据权利要求1所述的式(I)所示9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的新晶型的制备方法，其特征在于，有机溶剂加热溶解温度为30℃至回流温度。
4.根据权利要求1所述的式(I)所示9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的新晶型的制备方法，其特征在于，有机溶剂加热溶解温度为回流温度。
5.根据权利要求1所述的式(I)所示9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的新晶型的制备方法，其特征在于，冷却析晶温度为-40～40℃。
6.根据权利要求1所述的式(I)所示9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的新晶型的制备方法，其特征在于，冷却析晶温度为0～10℃。
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