CN112979734B - 三乙酰基-3-羟基苯基腺苷的晶型、制备方法及其用途 - Google Patents
三乙酰基-3-羟基苯基腺苷的晶型、制备方法及其用途 Download PDFInfo
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Abstract
本发明涉及治疗高脂血症的药物三乙酰基‑3‑羟基苯基腺苷的晶型、制备方法及其用途，本发明所述晶型包括具有调血脂作用的2’,3’,5’‑三‑O‑乙酰基‑N6‑(3‑羟基苯基)腺苷的Ⅰ型结晶和Ⅱ型结晶，其中Ⅰ型结晶具有如附图1所示的X射线粉末衍射图谱，其中Ⅱ型结晶，具有如附图4所示的X射线粉末衍射图谱。
Description
技术领域
本发明涉及治疗高脂血症的药物化合物2’，3’，5’-三-O-N6-(3-羟基苯基)腺苷的晶型及其制备方法，本发明还包括上述晶型的药物组合物，以及所述晶型及其药物组合物在治疗高脂血症的药物中的用途，属医药技术领域。
背景技术
大量的基础研究资料和临床实践证明，高脂血症，包括高胆固醇血症、高甘油三酯血症及复合性高脂血症是脑卒中、冠心病、心肌梗死、心脏猝死的重要危险因素。此外，高脂血症也是促进高血压、糖耐量异常、糖尿病的一个重要危险因素。高脂血症还可导致脂肪肝、肝硬化、胰腺炎、眼底出血、失明、周围血管病变、高尿酸血症等并发症。
目前临床上应用的调血脂药物包括以他汀类为代表的胆固醇生物合成酶抑制剂，这类药物通过抑制HMG-CoA还原酶，使体内内源性胆固醇的合成减少，减少低密度脂蛋白胆固醇 (LDL-C)的来源。同时，该类药物增加或激活肝细胞表面的LDL受体表达的水平而减少血液中LDL的含量。另一类是以激活过氧化物酶增生因子活化受体(PPARs)转录因子从而降低甘油三酯水平的贝特类药物，上述两类药物是当今调血脂药物的主流，其临床药效确切，服用剂量小，生物利用度较好，但二者产生的肝损伤和横纹肌溶解症等严重不良反应均已成为当今他汀类和贝特类药物最为令人担优和关注的安全性问题。
虫草素有调节血脂的作用，以虫草素为先导化合物，通过化学结构修饰合成虫草素的衍生物，从中筛选效果好且毒副作用小的药物。中国专利CN101712709A公开了一种以次黄嘌呤核苷为原料，经过醋酐乙酰化、氯化亚砜氯化、3-羟基苯胺取代而获得的化合物2’,3’,5’- 三-O-乙酰基-N6-(3-羟基苯基)腺苷即三乙酰基-3-羟基苯基腺苷(代号为：IMM-H007)， IMM-H007是一种新型调血脂化合物，化学结构为腺苷类似物。药理学研究表明，IMM-H007 (10μM)可抑制十八烯酸诱导的脂肪性变HepG2细胞内脂质的堆积。体内药效学研究发现，IMM-H007(2mg/kg)可降低高血脂症黄金地鼠升高的血清甘油三酯、总胆固醇、低密度脂蛋白和肝脏甘油三酯、总胆固醇水平。机制研究提示，IMM-H007可以上调十八烯酸诱导的脂肪病变HepG2细胞内或高血脂症黄金地鼠肝细胞内AMPK的磷酸化水平，是一种新型AMP-激活蛋白激酶(AMP-activated protein kinase，AMPK)激活剂。由此可见，IMM-H007作为一种与他汀类药物化学结构、作用靶点和代谢途径不同的新型调血脂化合物，有望成为临床预防和治疗心血管疾病的新药。目前对IMM-H007的进一步的研究包括不同治疗用途，例如抗炎症(CN104546887A)、治疗胰岛素抵抗(CN105663152A)、治疗高血脂症所伴随的单核细胞增多、动脉粥样硬化(CN107334775A)、治疗血管炎症、血管内皮功能紊乱(CN107412248A)、非酒精性脂肪肝(CN106943420A)等。
现有技术还公开了IMM-H007的以下合成路线：
所得产物为一种白色粉末状物质。
晶体通常以特定的立体几何物理形态成单个或簇状存在，在工业化生产中相对于油状或无定形在取用、称量、配制、干燥、过滤等方面均更具优势，而且晶体本身即是一种相对稳定的形态，更易保存和运输，此外，基于从溶液中结晶析出的特性，也能进一步降低最终产物中杂质的含量，获得更纯的产品。多晶型现象在药物中广泛存在，同一药物的不同晶型在溶解度、熔点、密度、稳定性等方面都有显著的差异，从而不同程度的影响药物的稳定性、生物利用度、疗效和安全性。
本发明人在对IMM-H007化合物的研究中发现，采用现有技术制备的IMM-H007为一种白色粉末状物质，经检测为混合结晶，或无定形结晶，本发明进一步研究发现IMM-H007还具有不同的结晶形式，为此本发明对这些晶型进行了筛选，最终获得两种具有良好的稳定性，口服生物利用度高的晶型，特别有利于制备成口服的药物制剂，还可以提高降低小鼠血清总胆固醇水平的能力。
发明内容
本发明提供了具有调血脂作用的2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷的Ⅰ型结晶和Ⅱ型结晶。
其中Ⅰ型结晶当使用粉末X射线衍射分析时(CuKα辐射)，衍射峰位置：2-Theta值(°) 具有如下特征：：
更进一步的，本发明提供的2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷的Ⅰ型结晶，其特征还在于，具有如附图1所示的X射线粉末衍射图谱。
更进一步的，本发明提供的2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷的Ⅰ型结晶，其特征在于：所述晶型的差示扫描量热曲线在165-175℃范围内有吸热熔融峰，差示扫描量热分析图见附图2。
更进一步的，本发明提供的2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷的Ⅰ型结晶，其特征在于：其红外光谱(IR)图具有如下特征吸收峰：1746.3，1621.9，1588.2，1470.2，1445.6， 1370.5，1229.2，1067.4，1031.7，928.8，915.2，866.2，854.8，829.2，775.6，759.5，691.1， 645.5cm-1，其红外光谱见附图3。
本发明的另一个目的是提供2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷的Ⅰ型结晶的制备方法，其特征在于，使用乙酸乙酯、丙酮、二氯甲烷、氯仿、甲苯、石油醚、正己烷等单一或任意两种或多种经不同配比组合制成的混合溶剂进行重结晶得到。
优选的，其制备方法包括如下步骤：将2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷粉末加热溶解于乙酸乙酯、丙酮、二氯甲烷、氯仿、甲苯、石油醚、正己烷等单一或任意两种或多种经不同配比组合制成的混合溶剂中，室温或低温下析出晶体，或在室温条件下，通过缓慢挥发的方法得到Ⅰ型结晶固态物质。
同时本发明提供了具有调血脂作用的2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷的Ⅱ型结晶，当使用粉末X射线衍射分析时(CuKα辐射)，衍射峰位置：2-Theta值具有如下特征：/>
更进一步的，本发明提供的2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷的Ⅱ型结晶，其特征还在于，具有附图4所示的X射线粉末衍射图谱。
更进一步的，本发明提供的2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷的Ⅱ型结晶，其特征在于：所述晶型的差示扫描量热曲线在145-155℃范围内有吸热熔融峰，差示扫描量热分析图见附图5。
更进一步的，本发明提供的2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷的Ⅱ型结晶，其特征在于：其红外光谱(IR)图具有如下特征吸收峰：1746.8，1626.2，1587.5，1474.0，1443.9， 1374.5，1230.2，1100.8，962.3，920.7，907.0,863.7，772.4，758.1，687.7，642.7，601.3,570.7cm-1，其红外光谱见附图6。
本发明的另一个目的是提供2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷的Ⅱ型结晶的制备方法，其特征在于，使用乙醇、正丙醇、异丙醇、正丁醇、甲醇、乙腈等单一溶剂或任意两种或多种经不同配比组合制成的混合溶剂重结晶得到。
优选的，其制备方法包括如下步骤：将2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷加热溶解于乙醇、正丙醇、异丙醇、正丁醇、甲醇、乙腈等单一或任意两种或多种经不同配比组合制成的混合溶剂中，室温或低温下析出晶体，或室温条件下通过缓慢挥发的方法得到晶体。
本发明还提供了药用组合物，含有治疗有效量的2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基) 腺苷的I型结晶或Ⅱ型结晶和药用辅料的药用组合物。将治疗有效量的2’,3’,5’-三-O-乙酰基 -N6-(3-羟基苯基)腺苷的I型结晶或Ⅱ型结晶与一种或多种药用辅料混合或接触制成药用组合物或制剂，该药用组合物或制剂是以制药领域中熟知的方式进行制备的，在制成药物制剂时可以制成任何可药用的剂型，这些剂型选自：片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、混悬剂、溶液剂、注射剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、贴剂等。
进一步的，本发明所述药物组合物还含有药学上可接受的载体。
所述药学上可接受的的载体包括但不限于：甘露醇、山梨醇、山梨酸或钾盐、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、维生素A、维生素C、维生素E、维生素D、氮酮、EDTA二钠、EDTA钙钠，一价碱金属的碳酸盐、醋酸盐、磷酸盐或其水溶液、盐酸、醋酸、硫酸、磷酸、氨基酸、氯化钠、氯化钾、乳酸钠、木糖醇、麦芽糖、葡萄糖、果糖、右旋糖苷、甘氨酸、淀粉、蔗糖、乳糖、甘露糖醇、硅衍生物、纤维素及其衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、丙二醇、乙醇、土温60-80、司班 -80、蜂蜡、羊毛脂、液体石蜡、十六醇、没食子酸酯类、琼脂、三乙醇胺、碱性氨基酸、尿素、尿囊素、碳酸钙、碳酸氢钙、表面活性剂、聚乙二醇、环糊精、β－环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁等。
本发明的药物组合物在使用时根据病人的情况确定用法用量。
更进一步的，2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷的晶Ⅰ型或晶Ⅱ型固态物质可用于制备用于预防和/或治疗高血脂症相关的心脑血管疾病的药物。
附图说明：
图1是晶Ⅰ型固态物质的X射线粉末衍射图谱
图2是晶Ⅰ型固态物质的的DSC图
图3是晶Ⅰ型固态物质的红外光谱图
图4是晶Ⅱ型固态物质的X射线粉末衍射图谱
图5是晶Ⅱ型固态物质的的DSC图
图6是晶Ⅱ型固态物质的红外光谱图
图7是大鼠口服不同晶型原料药后代谢产物M1血药浓度-时间曲线
具体实施方式
下面结合具体实施例对本发明作进一步的说明。
实施例1：2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷化合物的制备
1)5.36g次黄嘌呤腺苷悬浮于25ml吡啶中，冰浴至0℃，滴加醋酐16ml，滴加完毕，室温搅拌6h，TLC检测反应结束，减压蒸去绝大部分吡啶，冷却，加水，抽滤，水洗，得白色固体(3-0乙酰基次黄嘌呤腺苷)7.55g。
2)取上述产物5.5g，加入二氯甲烷50ml和1ml DMF，升温至40℃，滴加3.3g SOCl2的二氯甲烷溶液，回流，6h后TLC检测反应结束，将反应液用二氯甲烷稀释，饱和碳酸氢钠溶液洗两次，饱和氯化钠洗两次，加入无水硫酸钠干燥，减压蒸尽溶剂，得三-0-乙酰基-6- 氯腺苷5.4g。
3)取三-O-乙酰基-6-氯腺苷5.4g、3-氨基苯酚4.28g，加入无水乙醇30ml、三乙胺3.96g， 60℃条件下反应8h，减压蒸除溶剂，残余物经硅胶柱层析纯化，洗脱剂：乙酸乙酯：石油醚＝2:1，收集所需组分，减压浓缩，得2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷1.51g。
实施例2. 2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷I型结晶的制备
将1.0g 2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷加入8mL乙酸乙酯中，加热回流使澄清，过滤，得澄清溶液，缓慢搅拌下降至室温析晶2h，抽滤，得白色或类白色晶体，即晶Ⅰ型固态物质，当使用粉末X射线衍射分析时(CuKα辐射)，衍射峰位置：2-Theta值具有如下特征：：/> 29.64±0.2，X射线粉末衍射图谱见附图1，DSC图见附图2，红外光谱图见附图3。
实施例3. 2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷I型结晶的制备
将1.0g 2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷加入10mL乙酸乙酯中，加热回流使澄清，滴加10mL石油醚，缓慢搅拌下降至室温析晶1h，抽滤，得白色或类白色晶体，即晶Ⅰ型固态物质。X射线粉末衍射图谱与实施例2相同，DSC图见附图2，红外光谱图见附图3。
实施例4. 2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷Ⅱ型结晶的制备
将1.0g 2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷加入5mL乙醇中，加热回流使澄清，过滤，得澄清溶液，缓慢搅拌下降至室温析晶1h，抽滤，得白色或类白色晶体即Ⅱ型结晶，测得X射线粉末衍射在2θ值为： 处具有特征峰。X射线粉.末衍射图谱见附图4，DSC图见附图5，红外光谱图见附图6。
实施例5.I型结晶的稳定性研究
按专利ZL 200810223639.4描述的方法制备混晶，将混晶与I型结晶分别放置于40℃±2℃,75％±5％RH(相对湿度)条件下，加速试验6个月之后取出测试DSC、IR，结果显示I型结晶在40℃±2℃，75％±5％RH(相对湿度)条件下，加速试验6个月，晶型保持不变，I型结晶具有良好的稳定性。结果如表1所示。
表1 I型结晶的稳定性研究结果
实施例6.Ⅱ型结晶的稳定性研究
按专利ZL 200810223639.4描述的方法制备混晶，将混晶与Ⅱ型结晶分别放置于40℃±2℃,75％±5％RH(相对湿度)条件下，6个月之后取出测试DSC、IR，结果表明Ⅱ型结晶保持不变，结果如表2所示。
表2 Ⅱ型结晶的稳定性研究结果
实施例7.I型结晶的药代动力学研究
1.动物给药和血样采集
雄性SD大鼠10只，分为两组，每组5只，分别为混晶组和I型结晶组，分别按50mg/kg/10mL剂量给药。动物实验前禁食12h，自由饮水。大鼠灌胃给药后于5min，15min，30min，1h，2h，4h，6h，8h和12h各时间点从眼眶静脉丛取血。血样收集到预先冰浴化并加有100mMNaF肝素化管中，4℃离心分离血浆，立即加入两倍体积乙腈沉淀或迅速放入-20℃冰箱中保存备用。
2.样品处理
取大鼠给药后血浆样品100μL，加入20μL内标和180μL乙腈沉淀蛋白，高速离心14000rpm×5min两次，取上清液5μL进行LC/MS/MS分析。
3.LC/MS/MS测定
色谱柱：Zorbax C18(2.1×100mm,3.5μm)；柱温：30℃，流动相：乙腈-水(10mM醋酸铵和0.1％甲酸)梯度洗脱，流速：0.2mL/min。检测离子对：m/z 486.200→228.100(样品)；m/z 360.1→228.0(活性代谢物M1)；m/z 374.1→242.0(内标)。
4.血药浓度及药动学参数
大鼠口服不同晶型药品CMC混悬液(50mg/kg)后，吸收较快，给药后5min血浆中即可检测到原型药及代谢产物M1，原型药血药浓度较低，主要为M1。I型结晶组M1的Cmax，Tmax，AUC(0-t)和MRT(0-t)分别为119.55±31.08ng/mL，0.5h，313.88±73.81ng/mL*h和2.68±0.30 h，混晶组相应参数分别为49.36±5.43ng/mL，0.5h，177.25±38.00ng/mL*h和3.63±0.41h。粉末组的Cmax和AUC(0-t)低于I型结晶组，结果如表3所示。大鼠口服不同晶型原料药后代谢产物M1血药浓度-时间曲线见附图7。
表3 大鼠口服不同晶型原料药后代谢产物M1血浆药代动力学参数(50mg/kg,n＝5)
大鼠口服药物(50mg/kg)I型结晶组代谢产物M1的AUC(0-t)和峰浓度Cmax平均值均高于混晶组，说明I型结晶在大鼠体内的吸收较好，口服生物利用度高于混晶。
实施例8.不同晶型对高血脂模型小鼠总胆固醇水平的影响
1.材料和方法
实验动物：昆明种小鼠，雄性，体重20～24g，由中国人民解放军军事医学科学院实验动物中心提供，许可证编号：SCXK-(军)2012-0004。
受试品：I型结晶与混晶，使用前用0.25％的CMC配成所需浓度。
试剂盒：总胆固醇试剂盒，中生北控生物科技股份有限公司。
仪器：SeperateTM Max 190酶标仪。
饲料：基础饲料与高脂饲料，均由北京华阜康生物科技股份有限公司提供，许可证号： SCXK京2009-0008。基础饲料配方：20％面粉，10％米粉，20％玉米，20％豆粉，25％麸皮， 2％骨粉，2％鱼粉。高脂饲料配方：78.6％基础饲料，10％猪油，10％蛋黄粉，1％胆固醇，0.4％胆盐。
分组与给药：动物随机分成4组，分别为正常对照组、模型对照组、I型结晶组与混晶组，每组10只。各给药组给药剂量均为50mg/kg，每天灌胃一次，体积均为0.1ml/10g，连续给药7天，正常对照组、模型对照组每天给予等体积蒸馏水。于第7天给药半小时后动物取血，测定血清中CHO含量测定方法按照CHO试剂盒说明书进行，以酶标仪在505nm 波长下测定吸光度。按下列公式计算总胆固醇含量：CHO(mg/dl)＝(待测血清OD值-空白OD 值)/(标准血清OD-空白OD值)*198。
2.数据分析：数据以平均值±标准差表示，数据分析采取t检验。
结果：统计结果显示，与正常组小鼠血清总胆固醇(CHO)水平(123.4±20.7mg/dl)比较，模型对照组小鼠CHO水平(161.7±17.4mg/dl)明显升高(P<0.01)，表明造模成功。与模型组比较，混晶组CHO水平(138.3±13.5mg/dl)、晶Ⅰ型固态物质组CHO水平(139.7±15.6mg/dl) 明显降低(P<0.01)。I型结晶组与混晶组作用基本相当，未见明显差异。结果见表4
表4.不同晶型对高血脂模型小鼠总胆固醇的影响(n＝10)
与模型组比较，*P<0.05，**P<0.01
与空白组比较，#P<0.05，##P<0.01
实施例9.Ⅱ型结晶与混晶对高血脂模型小鼠总胆固醇水平的影响
1.材料和方法
实验动物：昆明种小鼠，雄性，体重20～24g，由中国人民解放军军事医学科学院实验动物中心提供，许可证编号：SCXK-(军)2012-0004。
受试品：Ⅱ型结晶与混晶，使用前用0.25％的CMC配成所需浓度。
试剂盒：总胆固醇试剂盒，中生北控生物科技股份有限公司。
仪器：SeperateTM Max 190酶标仪。
饲料：基础饲料与高脂饲料，均由北京华阜康生物科技股份有限公司提供，许可证号： SCXK京2009-0008。基础饲料配方：20％面粉，10％米粉，20％玉米，20％豆粉，25％麸皮，2％骨粉，2％鱼粉。高脂饲料配方：78.6％基础饲料，10％猪油，10％蛋黄粉，1％胆固醇，0.4％胆盐。
分组与给药：动物随机分成4组，分别为正常对照组、模型对照组、Ⅱ型结晶组与混晶组，每组10只。各给药组给药剂量均为50mg/kg，每天灌胃一次，体积均为0.1ml/10g，连续给药7天，正常对照组、模型对照组每天给予等体积蒸馏水。于第7天给药半小时后动物取血，测定血清中CHO含量测定方法按照CHO试剂盒说明书进行，以酶标仪在505nm波长下测定吸光度。按下列公式计算总胆固醇含量：CHO(mg/dl)＝(待测血清OD值-空白OD值)/(标准血清OD-空白OD值)*198。
2.数据分析：数据以平均值±标准差表示，数据分析采取t检验。
结果：统计结果显示，与正常组小鼠血清总胆固醇(CHO)水平(123.4±20.7mg/dl)比较，模型对照组小鼠CHO水平(161.7±17.4mg/dl)明显升高(P<0.01)，表明造模成功。与模型组比较，混晶组CHO水平(138.3±13.5mg/dl)、Ⅱ型结晶组CHO水平(136.5±17.1mg/dl)明显降低 (P<0.01)。Ⅱ型结晶组与混晶组作用基本相当，未见明显差异。在50mg/kg剂量下，Ⅱ型结晶组与混晶组均明显降低小鼠血清总胆固醇水平的作用，且降血脂程度基本相当，结果见表5。
表5.不同晶型对高血脂模型小鼠总胆固醇的影响(n＝10)
与模型组比较，*P<0.05，**P<0.01
与空白组比较，#P<0.05，##P<0.01。
Claims (4)
1.具有调血脂作用的2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷的Ⅰ型结晶，其特征在于，所述Ⅰ型结晶当使用粉末X射线衍射分析时，使用CuKα辐射，具有如图1所示的X射线粉末衍射图谱。
2.根据权利要求1所述的Ⅰ型结晶，其特征在于，所述晶型的差示扫描量热曲线在165-175℃范围内有吸热熔融峰，差示扫描量热分析图见图2。
3.根据权利要求1所述的Ⅰ型结晶，其特征在于，其红外光谱(IR)图具有如下特征吸收峰：1746.3，1621.9，1588.2，1470.2，1445.6，1370.5，1229.2，1067.4，1031.7，928.8，915.2，866.2，854.8，829.2，775.6，759.5，691.1，645.5cm-1，其红外光谱见图3。
4.根据权利要求1所述的Ⅰ型结晶，其特征在于，所述Ⅰ型结晶的制备方法，包括如下步骤：将2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷粉末加热溶解于乙酸乙酯、丙酮、二氯甲烷、氯仿、甲苯、石油醚、正己烷中单一或任意两种或多种经不同配比组合制成的混合溶剂，室温或低温下析出晶体，或在室温条件下，通过缓慢挥发的方法得到Ⅰ型结晶固态物质。
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