CN107929273A - 肝脏靶向药物 - Google Patents
肝脏靶向药物 Download PDFInfo
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- CN107929273A CN107929273A CN201711248185.8A CN201711248185A CN107929273A CN 107929273 A CN107929273 A CN 107929273A CN 201711248185 A CN201711248185 A CN 201711248185A CN 107929273 A CN107929273 A CN 107929273A
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- medicine
- liver
- small molecule
- galactosamine
- tba
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Abstract
本发明涉及生物医药领域,更具体涉及一种肝靶向药物。该药物为连接了半乳糖胺的化学小分子药物:所述的化学小分子药物为治疗肝脏疾病或与肝脏疾病有关的药物,所述的化学小分子药物包括但不限于甲状腺素T3、索拉菲尼、紫杉醇、瑞戈非尼、拉米夫定、恩替卡韦、替比夫定、他汀类、贝特类、烟酸类、胆酸螯合剂、其他肝炎病毒的DNA(RNA)聚合酶抑制化合物等;所述的半乳糖胺为三价乙酰半乳糖胺;所述的连接为半乳糖胺与化学小分子药物直接连接或通过链接片段连接,所述的链接片段包括但不限于碳链,二硫键,焦磷酸二酯,半胱氨酸,多肽,硫醚或缬氨酸‑瓜氨酸。本发明提供的这些药物,肝脏靶向性提高,药物疗效增强,对其他非靶组织的毒副反应减少。
Description
技术领域
本发明涉及生物医药领域,更具体涉及一种肝靶向药物。
背景技术
肝病是一种常见的危害性极大的疾病,常见肝脏疾病包括乙肝、甲肝、丙肝、肝硬化、脂肪化、肝癌、酒精肝等。现在临床治疗肝脏疾病的药物,大部分都不是靶向的,除可进入肝脏,还可以进入到身体的其他部位,带来不必要的副作用。临床上治疗肝脏疾病或与肝脏疾病有关的已经获批的药物,如乙肝治疗的核苷 (酸)药物,治疗肝癌、丙肝、肝硬化等药物,都由于非靶向性产生不必要的副作用;有些临床实验失败的药物,不是因为疗效,而是因为副作用太大,使其不能够应用于临床。
肝脏靶向药物的研究是一个热点,肝脏靶向药物不但可以使药物的疗效提高,而且可以减少副作用。近年来,各种肝靶向药物治疗肝脏疾病均取得很大进展,载体选择、运输途径、释放途径日趋多样化。肝靶向给药***主要包括被动靶向制剂、主动靶向制剂和物理靶向制剂。被动靶向制剂,如脂质体等纳米颗粒药物;主动靶向制剂,如半乳糖受体及三硝基苯基-抗生物素蛋白链菌素介导的肝主动靶向制剂。除以脂质体外为代表的被动靶向制剂外,主动靶向的药物制剂还很少见,研究主要集中在大分子药物的靶向研究,如蛋白质药物,核酸药物等。主动靶向分子也用于纳米药物的靶向研究,增加纳米药物对肝脏的靶向作用。据报道,常用于肝脏的靶向分子有甘草次酸和甘草酸,两者均有较好的肝组织分布特征。 Negishi证实了大鼠肝细胞膜上含有甘草次酸及甘草酸结合位点,随后的研究也证实甘草次酸/甘草酸修饰的载体有趋肝性。因此,甘草次酸/甘草酸可作为肝靶向载药***中的导向基团。细胞膜的糖受体,包括甘露糖、葡萄糖、和半乳糖等和肝肿瘤的叶酸受体等,虽然体外的细胞学研究和动物体内研究报道了这些分子的靶向作用,但是这些主动靶向应用于临床的还很少。
去唾液酸糖蛋白受体(asialoglycoproteinreceptor,ASGPR)亦称半乳糖受体,是哺乳动物肝实质细胞特有的一种高效内吞受体,可专一性识别、结合并内吞循环血液中一些末端带有半乳糖残基或乙酰半乳糖胺残基的寡糖或寡糖蛋白,并与之结合,主动转运至肝细胞内部,使其在肝细胞内进行代谢。其中,乙酰半乳糖胺与ASGPR结合的亲和性比半乳糖胺高约50倍左右。ASGPR广泛地应用于肝靶向药物的研究中,但是目前为止,ASGPR主要应用于小干扰核酸(siRNA) 分子药物的研究中,2010年,Akinc等证明乙酰半乳糖胺修饰的脂质体可以实现高效的siRNA体内肝脏递送。一方面,在本领域已经被验证了,靶向分子可能(有的确实)会影响其所连接的药物分子的活性;另一方面,连接了药物分子的靶向分子的靶向效果也会一定程度被削弱;在一方面,靶向分子和药物分子采用何种连接方式能够使二者的功能均得到较好的发挥也并非通过简单地有限次实验能够轻易获知。也就是说在公开之前,本领域技术人员无法预测某种未使用过的靶向分子和药物分子的连接方式是否能获得令人满意的效果。
基于对于已经在临床应用的治疗肝脏疾病的小分子药物,尚未有人考虑到可以用半乳糖胺修饰来改善其靶向性,进而改善药物功效和减少副作用;此外,单个分子的半乳糖胺的靶向作用也十分有限;因此发明人实施并公开了本发明的内容。
发明内容
为解决上述问题,本发明的一个目的在于提供一种药物,该药物的设计原理为乳糖化衍生物或合成大分子与相关药物结合后,能将药物靶向转运至肝脏,既增强了药物的疗效,又减少了药物对其他非靶组织的毒副反应。由于单个分子的半乳糖胺的靶向作用有限,本发明采用多价糖分子作为肝脏的靶向分子。
本发明的另一个目的在于提供一种半乳糖胺在制备肝脏靶向药物中的用途。
本发明提供了一种药物,该药物为连接了半乳糖胺的化学小分子药物。本发明所述的化学小分子药物为治疗或辅助治疗肝脏疾病或肝脏相关疾病的药物,所述的肝脏疾病包括但不限于肝癌、病毒性肝炎、非酒精性脂肪肝、高脂血症、肝脏遗传性疾病等。
优选地,所述的半乳糖胺为乙酰半乳糖胺;
更优选地,所述的半乳糖胺为三价乙酰半乳糖胺,其基本结构式如式Ⅰ所示;其中,n=0-50,X1、Y1、Z1、X2、Y2、Z2、X3、Y3、Z3可以为氢基、乙酰基中的任一种;其中,链接三个乙酰半乳糖胺的碳链上可以带有亚氨基、氧基或羧基基团中的一种或多种。
优选地,所述的化学小分子药物包括但不限于甲状腺素T3、索拉菲尼、紫杉醇、瑞戈非尼、拉米夫定、恩替卡韦、替比夫定、他汀类、贝特类、烟酸类、胆酸螯合剂、肝炎病毒的DNA(RNA)聚合酶抑制化合物等。
优选地,所述的连接了半乳糖胺的化学小分子药物中的连接方式为半乳糖胺与化学小分子药物直接连接或通过链接片段连接;
优选地,所述的链接片段为但不限于碳链、二硫键、焦磷酸二酯、半胱氨酸、多肽、硫醚、缬氨酸-瓜氨酸、赖氨酸-γ-谷氨酸或这些化学结构的组合结构;
其中,所述的链接片段上还可带有亚氨基、氧基或羧基基团中的一种或多种;
优选地,所述的碳链的长度为2-40。
本发明还提供了半乳糖胺在制备肝脏靶向药物中的用途,所述的用途指将半乳糖胺通过直接连接或通过链接片段与化学小分子药物相连接来制备肝脏靶向药物。
进一步地,所述的用途中,化学小分子药物为治疗或辅助治疗肝脏疾病或肝脏相关疾病的药物。
进一步地,所述的肝脏疾病包括肝癌、病毒性肝炎、非酒精性脂肪肝、高脂血症、肝脏遗传性疾病等。
优选地,本发明所述的半乳糖胺为乙酰半乳糖胺;
更优选地,本发明所述的半乳糖胺为三价乙酰半乳糖胺。
再一方面,本发明还提供了一种药物组合物,该药物组合物包括上述的连接了半乳糖胺的化学小分子药物以及药学上可接受的辅料。
其中,所述的辅料为本领域常规使用的辅料,包括但不限于粘合剂、填料、涂膜聚合物、增塑剂、助流剂、崩解剂、润滑剂、防腐剂、乳化剂等。
另一方面,本发明的提供的药物组合物的剂型为注射剂、口服制剂或喷雾剂;
进一步地,所述的注射剂包括静脉、肌肉或皮下注射剂;
进一步地,所述的口服制剂包括片剂、胶囊剂、颗粒剂、缓释片剂、舌下含片、口腔速崩片、分散片、肠溶片、肠溶胶囊、缓释胶囊、含有微丸的胶囊或口服液。
再一方面,递送本发明提供的药物组合物的方式不受任何限制,可以采用已知的各种递送***。
本发明的有益效果在于:
(1)本发明首次提出在治疗肝脏疾病或与肝脏疾病有关的化学小分子药物前连接上半乳糖胺,尤其是三价乙酰半乳糖胺,提高了这些药物的肝脏靶向性,增强了药物的疗效,减少了药物对其他非靶组织的毒副反应。
(2)本发明提供的肝脏靶向药物,除提高了药物靶向性外,对化学小分子药物的活性并没有影响,且本发明提供的肝脏靶向药物在到达肝脏细胞后,化学小分子药物能很好地与三价乙酰半乳糖胺分离,以化学小分子药物的形式在肝脏中发挥作用,解决了这些化学小分子药物连接了三价乙酰半乳糖胺后结构式改变可能影响药物活性以及到达肝脏细胞后无法从三价乙酰半乳糖胺上释放的问题。
(3)本发明提供的连接了三价乙酰半乳糖胺的甲状腺素T3药物,创造性地发现其中几种链接基团的靶向性优异,甲状腺素T3在肝脏的活性高,药效好。
附图说明
图1实施例1中制备三价乙酰半乳糖胺TBA-3流程图。
图2实施例1中TBA-1的制备流程图。
图3实施例3中T3-1、实施例4中T3-2及实施例5中T3-3的制备流程图。
图4实施例2-6中由三价乙酰半乳糖胺制备肝脏靶向药物TBA-4,TBA-5, TBA-6,TBA-7,TBA-8流程图。
图5实验例3降脂效果检测结果。
具体实施方式
下面参考具体实施例,对本发明进行描述,需要说明的是,这些实施例仅仅是描述性的,而不以任何方式限制本发明。
除特殊说明外,本发明实施例中所用化学试剂均为实验室常规商用试剂。
实施例1
制备三价乙酰半乳糖胺TBA-3
以下述顺序的步骤制备三价乙酰半乳糖胺TBA-3,其结构式及制备流程图见图1,其中:
(1)制备化合物PTT-1:
取乙酰半乳糖胺盐酸盐(购自梯希爱(上海)化成工业发展有限公司,产品编码:G0007)10.0g(55.8mmol),加入100mL二氯甲烷中,室温下边搅拌边加入0.16g(1.3mmol)4-二甲氨基吡啶(DMAP)以及20mL的三乙胺,溶解后,开始冰浴;冰浴的同时向其中滴加60mL(635.2mmol)的乙酸酐,滴加完毕后,室温反应,用薄层层析法(TLC)监测反应完全后;100mL水洗有机层,重复3次,将有机层干燥,减压蒸干后得白色固体18.0g,其结构式如图1所示,命名为PTT-1化合物。
(2)制备PTT-2化合物;
氮气保护下,用1,2-二氯乙烷溶解PTT-1 16.0g(41.1mmol),后向其中加入8.0g4A型分子筛(购自国药集团化学试剂有限公司,产品编号:40035066 (沪试));继续向其中滴加三氟甲磺酸三甲基硅酯,滴加完毕后升温至50℃,在50℃保温反应过夜,用薄层层析法(TLC)(展开剂为二氯甲烷:甲醇=10:1) 监测反应完全后;依序加入水,二氯甲烷,再加饱和NaHCO3至碱性,分层;干燥,减压蒸干;过柱(洗脱液为二氯甲烷:甲醇=1%-10%)得黄色油状物7.2g,其结构式如图1所示,命名为PTT-2化合物。
(3)制备PTT-3化合物;
取6.0g(9.1mmol)PTT-2,加入无水1,2-二氯乙烷120mL和4A分子筛 (购自国药集团化学试剂有限公司,产品编号:40035066(沪试))12.0g,室温下搅拌5min;向其中加入5-己烯-1-醇3.6g(36.8mmol),室温搅拌10min;继续向其中滴加三氟甲磺酸三甲基硅酯4.4mL(24.0mmol)20分钟,室温下搅拌 4h;继续向其中加入预冷的饱和NaHCO3溶液,分层;其中,水层加二氯甲烷萃取,合并有机层,水洗,用无水Na2SO4干燥,减压蒸干得粗品;得到的粗品用正己烷打浆,抽滤,减压烘干,得棕黄色固体5.6g,其结构式如图1所示,命名为PTT-3化合物。
(4)制备PTT-4化合物:
取5.6g(13mmol)PTT-3,加到80mL的二氯甲烷和乙腈的混合溶液(二氯甲烷和乙腈体积比为1:1)中,得溶液A;
取高碘酸钠11.2g(52.4mmol),加到28mL水中,得溶液B;
在冰浴中(小于10℃)搅拌混合溶液A和溶液B,搅拌15min,得溶液C;溶液C放水浴中,向溶液C中加入46.0mg(0.088mmol)氯化钌,加入期间,水浴锅中温度控制在35℃之下,加完后,室温下搅拌1h,再加入高碘酸钠6.8g (31.6mmol),在室温下继续搅拌反应1h得溶液D,TLC监测反应完全;溶液 D中加入水80mL,用固体NaHCO3调节pH至7.5;分开有机层,水层用40mL 二氯甲烷洗3次,弃掉有机层;水层用柠檬酸调节pH至3,酸化的化合物被萃取进二氯甲烷(160mL/次,重复3次);有机层中加入饱和食盐水80mL,然后滴加3%Na2S溶液,直到有机层由墨绿色变成淡黄色;分层,有机层用无水 Na2SO4干燥,然后减压蒸干得类白色固体3.6g,其结构式如图1所示,命名为 PTT-4化合物。
(5)制备TBA-2化合物:
取1.56g(2.44mmol)的化合物TBA-1(其结构式如图1所示)和3.6g (8.04mmol)的PTT-4,加到60mL二甲基甲酰胺(DMF)中;然后向其中加入2.24g(0.012mmol)的1-羟基苯并***(HOBt)和3.36g(8.84mmol)O- (苯并三氮唑-1-基)-二(二甲胺基)碳鎓六氟磷酸盐(HBTU),然后缓慢加入 4.16mL(24.12mmol)的N,N-二异丙基乙胺(DIEA);室温搅拌3h;然后加入水,水层用二氯甲烷萃取(10mL/次,重复2次);合并有机层,然后依次用饱和80mL的NaHCO3,水(60mL/次,2次),60mL饱和食盐水洗;用无水 Na2SO4干燥,减压蒸干,用硅胶柱层析纯化(洗脱液为甲醇∶二氯甲烷=3%-15%);得淡黄色固体2.36g,其结构式如图1所示,命名为TBA-2化合物。
(6)制备TBA-3化合物:
2.36g(1.2mmol)的TBA-2用120mL甲醇溶解,再加入1.0g 10%的Pd-C 催化剂(湿式Degussa型E101NE/W)以及2.0mL乙酸,常压下加氢,反应过夜得反应液A;反应液A用硅藻土过滤,滤液减压蒸干,得油状物1.8g,其结构式如图1所示,命名为TBA-3化合物,TBA-3化合物即为三价乙酰半乳糖胺。
其中,步骤(5)中的TBA-1化合物,其由下述顺序的步骤制备得到,制备流程图见图2:
A.称取三羟甲基氨基甲烷30.25g(0.25mol)加入50mL二甲基亚砜(DMSO) 以及5mLNaOH溶液(浓度为1g/mL),降温到0℃,滴加丙烯酸叔丁酯125mL (0.86mol),2小时加完,室温反应过夜,加乙酸乙酯,水洗2次,有机层干燥。过层析柱(洗脱液为乙酸乙酯∶石油醚=5%-20%),得无色油状物53.4g,其结构式如图2所示,命名为TBA-1a。
B.称取TBA-1a 50.0g(0.099moL),加二氯甲烷180mL及碳酸钠溶液(25%) 140mL,室温滴加氯甲酸苄酯50mL(0.35moL),2小时滴加完,室温反应过夜,饱和食盐水洗涤3次,无水Na2SO4干燥,蒸干溶剂,得产物47.8g,其结构式如图2所示,命名为TBA-1b。
C.取TBA-1b 47.8g(0.075moL),加甲醇300mL和三氟乙酸30mL,室温反应过夜,减压蒸干溶剂,加DMF 100mL,TBTU 83g,DIEA 104mg,降温到 0℃,滴加N-叔丁氧羰基-1,3-丙二胺70g(0.40moL)(购自安耐吉化学,货号: B010011),2小时滴加完毕,室温反应过夜,加水300mL洗涤有机层,有机层用无水Na2SO4干燥,蒸干溶剂,得TBA-1c 43.2g。
D.取TBA-1c 43.2g(0.046moL)加甲醇400mL和三氟乙酸40mL,室温反应过夜,减压蒸干溶剂,得产物20g,其结构式如图1所示,命名为TBA-1。
实施例2
一种肝脏靶向药物TBA-4,其结构式如图4所示,该药物为三价乙酰半乳糖胺与甲状腺素T3(其结构式如图4所示,以化合物T3表示)直接连接得到。
TBA-4的制备步骤如下:取0.38g(0.21mmol)的TBA-3,用20mL的二甲基甲酰胺(DMF)溶解,然后加入74.2mg(0.23mmol)的HBTU和0.12mL (0.69mmol)的DIEA,搅拌反应5min;然后加入用10mL DMF溶解的化合物 T3(0.15g,0.23mmol)(购自梯希爱(上海)化成工业发展有限公司,产品编码:T0453),室温搅拌反应过夜得反应液A;减压蒸干反应液A,蒸干后,用 50mL二氯甲烷溶解,依次用25mL饱和NaHCO3和25mL水洗;有机层用无水Na2SO4干燥,减压蒸干,加5mL甲胺乙醇溶液,室温反应2h;减压蒸干溶剂,用硅胶柱层析纯化(洗脱液为甲醇∶二氯甲烷=3%-15%),得类白色固体172.1 mg,其结构式如图4所示,命名为TBA-4化合物。
实施例3
一种肝脏靶向药物TBA-5,其结构式如图4所示,该药物为三价乙酰半乳糖胺与甲状腺素T3通过直链连接得到。
TBA-5的制备步骤如下:取TBA-3 0.38g(0.21mmol),用20mL的DMF 溶解,然后加入74.2mg(0.23mmol)HBTU和0.12mL(0.69mmol)的DIEA,搅拌反应5min;然后加入用10mL DMF溶解的化合物T3-1(0.15g,0.23mmol,其结构式如图4所示),室温搅拌反应过夜得反应液A;减压蒸干反应液A,蒸干后,用50mL二氯甲烷溶解,依次用25mL饱和NaHCO3和25mL水洗;有机层用无水Na2SO4干燥,减压蒸干,加5mL甲胺乙醇溶液,室温反应2h;减压蒸干溶剂,用硅胶柱层析纯化(洗脱液为甲醇∶二氯甲烷=3%-15%),得类白色固体181.6mg,其结构式如图4所示,命名为TBA-5化合物。
其中,T3-1化合物由下述顺序的步骤制备得到,其制备流程图如图3所示:
取6-氨基己酸55.0mg(0.42mmol)(购自安耐吉化学,货号:A010678),用20mL DMF溶解,然后加入148.4mg的HBTU(0.46mmol)和0.24mL的 DIEA(1.4mmol),搅拌反应5min,然后加入用10mL DMF溶解的化合物T3 (0.3g,46mmol),室温搅拌反应过夜;减压蒸干反应液,蒸干后,用50mL 二氯甲烷溶解,再用25mL的饱和NaHCO3和25mL水洗;有机层用无水Na2SO4干燥,蒸干溶剂,得类白色固体190.0mg,其结构式如图3所示,命名为T3-1。
实施例4
一种肝脏靶向药物TBA-6,其结构式如图4所示,该药物为三价乙酰半乳糖胺与甲状腺素T3通过较长的直链连接得到。
TBA-6的制备步骤如下:取TBA-3 0.30g(0.17mmol),用20mL的DMF 溶解,然后加入74.2mg(0.23mmol)HBTU和0.12mL(0.69mmol)的DIEA,搅拌反应5min;然后加入用10mL DMF溶解的化合物T3-2(0.16g,0.20mmol,其结构式如图4所示),室温搅拌反应过夜得反应液A;减压蒸干反应液A,蒸干后,用50mL二氯甲烷溶解,依次用25mL饱和NaHCO3和25mL水洗;有机层用无水Na2SO4干燥,减压蒸干,加5mL甲胺乙醇溶液,室温反应2h;减压蒸干溶剂,用硅胶柱层析纯化(洗脱液为甲醇∶二氯甲烷=3%-15%),得类白色固体205.4mg,其结构式如图4所示,命名为TBA-6化合物。
其中,T3-2化合物由下述顺序的步骤制备得到,其制备流程图如图3所示:
取8-氨基辛酸66.90mg(0.42mmol)(购自安耐吉化学,货号:B010409),用 20mLDMF溶解,然后加入148.4mg的HBTU(0.46mmol)和0.24mL的DIEA (1.4mmol),搅拌反应5分钟,然后加入用10mL DMF溶解的化合物T3(0.3g, 46mmol),室温搅拌反应过夜;减压蒸干反应液,蒸干后,用50mL二氯甲烷溶解,依次用25mL饱和NaHCO3和25mL水洗;有机层用无水Na2SO4干燥,蒸干溶剂,得类白色固体230.5mg,其结构式如图3所示,命名为T3-2。
实施例5
一种肝脏靶向药物TBA7,其结构式如图4所示;该药物为三价乙酰半乳糖胺与甲状腺素T3通过带有氨基的链接片段连接得到。
TBA-7的制备步骤如下:取TBA-3 0.30g(0.17mmol),用20mL的DMF 溶解,然后加入74.2mg(0.23mmol)HBTU和0.12mL(0.69mmol)的DIEA,搅拌反应5min;然后加入用10mL DMF溶解的化合物T3-3(0.17g,0.21mmol,其结构式如图4所示),室温搅拌反应过夜得反应液A;减压蒸干反应液A,蒸干后,用50mL二氯甲烷溶解,依次用25mL饱和NaHCO3和25mL水洗;有机层用无水Na2SO4干燥,减压蒸干,加5mL甲胺乙醇溶液,室温反应2h;减压蒸干溶剂,用硅胶柱层析纯化(洗脱液为甲醇∶二氯甲烷=3%-15%),得类白色固体211.6mg,其结构式如图4所示,命名为TBA-7化合物。
其中,T3-3化合物由下述顺序的步骤制备得到,其制备流程图如图3所示:
取β-氨基丙酸37.0mg(0.42mmol)(购自安耐吉化学,货号:A010136),用 20mL DMF溶解,然后加入148.4m g HBTU(0.46mmol)和0.24mL DIEA(1.4 mmol),搅拌反应5分钟,然后加入用10mL DMF溶解的化合物T3(0.3g,46 mmol),室温搅拌反应过夜;减压蒸干反应液,蒸干后,用50mL二氯甲烷溶解,依次用25mL饱和NaHCO3和25mL水洗;有机层用无水Na2SO4干燥,过滤,滤液中加115.0mg(0.60mmol)的1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(EDC.HCL),及12mg的DMAP及40.5mg(0.45mmol)3-羟基丙酸,室温反应过夜,加10%盐酸30mL洗涤有机层,有机层用无水Na2SO4干燥,过硅胶层析柱纯化(洗脱液为甲醇∶二氯甲烷=1%-10%),得类白色固体180.5mg,其结构式如图3所示,命名为T3-3。
实施例6
一种肝脏靶向药物TBA8,其结构式如图4所示;该药物为三价乙酰半乳糖胺与索拉菲尼(其结构式如图4所示)直接连接得到。
TBA-8的制备步骤如下:取TBA-3 0.40g(0.22mmol),用20mL的DMF 溶解,然后加入74.2mg(0.23mmol)HBTU和0.12mL(0.69mmol)的DIEA,搅拌反应5min;然后加入用10mL DMF溶解的索拉菲尼(0.12g,0.26mmol),室温搅拌反应过夜得反应液A;减压蒸干反应液A,蒸干后,用50mL二氯甲烷溶解,依次用25mL饱和NaHCO3和25mL水洗;有机层用无水Na2SO4干燥,减压蒸干,加5mL甲胺乙醇溶液,室温反应2h;减压蒸干溶剂,用硅胶柱层析纯化(洗脱液为甲醇∶二氯甲烷=3%-15%),得类白色固体143.4mg,其结构式如图4所示,命名为TBA-8化合物;
其中,索拉菲尼购自湖北胜天恒创生物科技股份有限公司,其结构式如图4 所示。
实验例1
肝脏靶向性测定
检测实施例2-6中提供的肝脏靶向药物的肝脏靶向性:
(1)荧光标记实施例2-6制备的肝脏靶向药物,分别记为F-TBA-4,F-TBA-5, F-TBA-6,F-TBA-7,F-TBA-8;
(2)准备16只雄性C57BL/6老鼠,饲养在恒温和恒湿的环境,不限制食物和水的摄入;2周龄时,取15只随机分为5组,每组3只,分别尾静脉注射 F-TBA-4,F-TBA-5,F-TBA-6,F-TBA-7,F-TBA-8(200μg/kg);余下的一只作为对照组,尾静脉注射游离的荧光分子;
(3)静脉注射后,分别在1,6和12小时做小鼠全身成像,并在各个时间点收集小鼠的器官,测量小鼠各个器官的荧光强度(相对荧光单位,RFU);实验数据记录见表1,由表1结果可知,实施例2-6的药物进入小鼠体内后,均迅速靶向肝脏。
表1
实验例2
检测甲状腺素活性
检测实施例2-5中提供的肝脏靶向药物进入肝脏细胞后甲状腺素T3的释放情况:甲状腺素可刺激肝细胞的基因表达活性,故通过检测肝细胞的基因表达强度来判断甲状腺素的活性,具体实验步骤如下:
(1)HAMF12/DEMEM培养液(含10%小牛血清)培养HEPG2细胞,收集培养细胞,离心去除原培养液,换新鲜培养液并按照5×104个细胞/孔培养在96孔细胞培养板中;
(2)培养24h后,根据Invitrogen公司的Lipofectamine 2000转染试剂使用说明书进行质粒转染,所用质粒为DR4-luciferase-TR质粒(购自安捷伦公司,产品编号240135),每孔转染0.45ng质粒;
(3)转染两天后,将实施例2-5制备的TBA-4,TBA-5,TBA-6,TBA-7以1 μM的浓度分别加入不同的孔中.;
(4)10h后停止反应,根据Promega公司的荧光素酶检测***(Luciferase AssaySystem)说明书,检测每孔细胞的Luciferase活性,实验数据见表2。由表2数据可知,实施例2-5制备的药物进入细胞后,甲状腺素均很好地释放并发挥作用,故能刺激肝细胞的基因表达,从而使得细胞Luciferase活性(相对荧光素酶单位,RLU)显著增强。
表2
实验例3
降脂效果检测
(1)C57BL/6J小鼠用高脂饲料喂养2个月后,腹腔注射实施例2-5提供的 TBA-4,TBA-5,TBA-6,TBA-7药物,每天1次,注射剂量为200nM/kg,连续2 周,对照组注射生理盐水;
(2)最后一次注射后24h,取血,测定血液中的脂质含量。实验结果见图 5。
Claims (10)
1.一种药物,该药物为连接了半乳糖胺的化学小分子药物。
2.如权利要求1所述的药物,其中,所述的化学小分子药物为治疗或辅助治疗肝脏疾病或肝脏相关疾病的药物,所述的肝脏疾病包括但不限于肝癌、病毒性肝炎、非酒精性脂肪肝、高脂血症、肝脏遗传性疾病等。
3.如权利要求2所述的药物,其中,所述的化学小分子药物包括但不限于甲状腺素T3、索拉菲尼、紫杉醇、瑞戈非尼、拉米夫定、恩替卡韦、替比夫定等,他汀类、贝特类、烟酸类、胆酸螯合剂、肝炎病毒的DNA/RNA聚合酶抑制化合物等。
4.如权利要求1所述的药物,其中,所述的半乳糖胺为三价乙酰半乳糖胺,其基本结构式如式Ⅰ所示,其中,n=0-50,X1、Y1、Z1、X2、Y2、Z2、X3、Y3、Z3可以为氢基、乙酰基中的任一种。
5.如权利要求4所述的药物,其中,所述的三价乙酰半乳糖胺,链接三个乙酰半乳糖胺的碳链上带有亚氨基、氧基或羧基基团中的一种或多种。
6.如权利要求1所述的药物,其中,所述的连接了半乳糖胺的化学小分子药物中的连接方式为半乳糖胺与化学小分子药物直接连接或通过链接片段连接。
7.如权利要求6所述的药物,其中,所述的链接片段为碳链、二硫键、焦磷酸二酯、半胱氨酸、多肽、硫醚、缬氨酸-瓜氨酸或这些化学结构的组合结构。
8.半乳糖胺在制备肝脏靶向药物中的用途,所述的用途指将乙酰半乳糖胺通过直接连接或通过链接片段与化学小分子药物相连接来制备肝脏靶向药物。
9.一种药物组合物,该药物组合物包括权利要求1-7任一项所述的药物以及药学上可接受的辅料。
10.如权利要求9所述的药物组合物,其中,所述的药物组合物为注射剂、口服制剂或喷雾剂。
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