CN109608492B - 一种用于骨质疏松的二膦酸化合物及其制备方法 - Google Patents
一种用于骨质疏松的二膦酸化合物及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种结构新颖的二膦酸化合物，具有布洛芬结构单元和苯丙氨酸结构单元。药理试验表明其可以用于治疗骨质疏松，抑制破骨细胞活力与已经上市的二膦酸类药物如阿伦膦酸钠、唑来膦酸而言基本相当，同时本发明二膦酸化合物还具有较好的促进成骨细胞增殖作用的效果。
Description
技术领域
本申请涉及一种新的用于骨质疏松的二膦酸化合物，以及制备所述二膦酸化合物的方法，属于医药技术领域。
背景技术
二膦酸(Biphosphonates,BPs)又称为双膦酸、偕二膦酸，是一种人工合成的、代谢稳定的无机焦磷酸类似物，其基本结构单元如下式所示：
二膦酸类化合物临床上广泛用于治疗骨质疏松、变形性骨炎、恶性肿瘤引起的高钙血症、肿瘤骨转移及其它骨代谢疾病，而这些疾病的发生、发展与破骨细胞数目及活性异常密切相关，二膦酸化合物通过不同的作用方式抑制破骨细胞活化，诱导破骨细胞的凋亡，从而抑制骨吸收。
现有的研究表明，二膦酸结构中与碳原子相连的两条侧链是决定双膦酸盐类理化特性及生物效应的基础，各种双膦酸盐都有着各自不同的生化特点及生物活性；以及双膦酸盐的活性大小与碳链长度及链端结构有关，因而人们通过改变碳链长度及与碳原子连接的基团，从而引起其物化性质和生物特性的显著改变，其活性可相差近万倍，甚至于完全没有活性，而这类药物的构效关系尚在探索之中(参见1)《骨质疏松症骨基础理论研究》，罗先正等主编，哈尔滨出版社，第196-198页，1998年12月；2)“a-AMINO ACID DERIVEDBISPHOSPHONATES.SYNTHESIS AND ANTI-RESORFTIVE ACTIVITY”，DANA M.MIZRAHI等，《Phosphorus,Sulfur,and Silicon and the Related Elements》，第173卷，第1-25页，20061004.)。
在已经商品化的二膦酸药物中，取代基变换带来的药物活性改变可以参见下表1(参见3)“第三代双膦酸类药物的构效关系及其作用机制研究”，刘清竹，第5页，2016)：
表1：双膦酸类化合物的结构与骨吸收相对强度
尽管研究人员通过对侧链的修饰，引入各种具有生物活性的结构单元和元素种类例如硒等，不断开发出结构新颖的二膦酸化合物并验证了其活性(参见4)CN106083925A；5)CN105924470A；6)CN107365330A；7)CN106232612A)，但是开发更多种对于破骨细胞具有强抑制作用以及同时对于成骨细胞具有促进作用的二膦酸化合物仍然是必要的。
发明内容
本发明的目的在于克服现有技术的不足，提出一种结构新颖的二膦酸化合物及其制备方法与应用。该化合物具有更好的抗骨质疏松活性和更佳的生理效应，同时对肝肾等器官的毒副作用更小。
为了实现上述目的，本发明首先提出了涉及具有如下式I结构的化合物及其药学上可接受的盐：
本发明还提供了涉及上述式I化合物的制备方法，合成路线如下：
其中，步骤(1)中，氯化反应条件溶剂为二氯甲烷，催化剂为DMF，氯化试剂为氯化亚砜；其中，式a所示的布洛芬：氯化亚砜：DMF：二氯甲烷的投料比为1mmol:(2～10mmol):(0.05～0.5mmol):(0.5～5mL)。
步骤(2)中，式b的酰氯与苯丙氨酸发生缩合反应，所述缩合反应在碱存在的条件下进行。其中，所述碱为碳酸钠、碳酸氢钠、三乙胺、吡啶、碳酸钾中的任意一种。式b化合物与苯丙氨酸的摩尔比为(1～2):1，优选为(1.2～1.5):1。
步骤(3)中，式c化合物与亚磷酸、三氯化磷在加热条件下反应，制备得到式I的目标产物。其中，式c化合物与亚磷酸的摩尔比为1:1～1:6；式c化合物与三氯化磷的摩尔比为1:2～1:6。所述加热反应温度为80～120℃。
本发明还涉及上述式I化合物药学上可接受的盐，所述盐可以根据本领域公知的方法制备获得。如使用无机碱和/或有机碱，如氨、伯氨、仲氨、叔氨、碱金属氢氧化物、碱土金属氢氧化物等，优选的药学上接受的盐为钠盐、钾盐。
本发明还涉及包含上述式I化合物或其药学上可接受的盐的药物组合物，该药物组合物含有治疗有效量的本发明的式I化合物及其药学上可接受的盐，以及任选的含有药用载体。其中所述的药用载体指药学领域常用的药用载体。该药物组合物可以根据本领域公知的方法制备得到。
本发明的二膦酸化合物引入布洛芬结构单元、苯丙氨酸结构单元，结构新颖，未被现有技术所披露。药理试验表明其可以用于治疗骨质疏松，主要作用在于通过抑制破骨细胞活性、诱导破骨细胞凋亡起到抑制骨吸收，阻止骨吸收和骨微结构的破坏。细胞药理试验结果进一步表明，本发明的二膦酸化合物相对于已经上市的二膦酸类药物如阿伦膦酸钠、唑来膦酸而言，在保持基本相同的抑制破骨细胞活力的同时，还具有更好的促进成骨细胞增殖作用的效果。
具体实施方式
以下结合具体实施例，对本发明作进一步详述。
实施例1式b化合物的制备
将20.6g(0.1mol)布洛芬溶于二氯甲烷(100mL)中，加入0.77mL的DMF(约10mmol)，加热至回流，然后缓慢滴加氯化亚砜(60g,约0.5mol)，搅拌反应5小时后，经TLC监测反应完成。随后经真空旋转蒸发除去溶剂，补加甲苯，继续真空旋转蒸发除去多余氯化亚砜，得到式b所示的酰氯，可直接用于下一步反应(产率95％)。
实施例2式c化合物的制备
取实施例1制备得到的式b所示的酰氯11.5g(约0.05mol)，加入苯丙氨酸7.5g(约0.045mol)，再加入三乙胺10.1g(0.1mol)，溶于无水甲醇(50mL)中，于60℃搅拌反应4小时，经TLC监测反应完成。随后加入水淬灭，乙酸乙酯洗涤，无水硫酸钠干燥，旋转蒸发除去溶剂后经硅胶柱层析分离，得到式c所示的化合物(产率92％)。
实施例3式I化合物的制备
将实施例2制备的式c化合物7.06g(0.02mol)、亚磷酸8.2g(0.1mol)和甲苯(10mL)的混合物加热至80℃，缓慢滴加三氯化磷13.7g(0.1mol)，滴毕保温反应5小时后，加入水20mL，加热回流反应4小时。反应液冷却后加至无水乙醇20mL中，冷冻析晶，过滤，滤饼用去离子水洗涤，滤饼用去离子水重结晶，得到白色固体(产率72％)。1H-NMR(400MHz，CD3SOCD3)δ(ppm):8.05-8.16(m,1H),7.17-7.28-7.10(m,9H),5.25(s,1H),4.83(s,4H),4.02-4.08(m,1H),3.51-3.57(m,1H),2.65-2.93(m,2H),2.45(d,2H),1.79-1.85(m,1H),1.81(s,3H),0.94(s,6H)。
实施例4式I化合物效果评价
通过细胞试验评价式I化合物的抗骨质疏松能力。
促成骨细胞增殖试验:实验分为式I化合物组、唑来膦酸组、阿伦膦酸组和空白组，各实验组浓度为10-8mol/L。
大鼠成骨细胞以3*103/孔接种于48孔细胞培养板中，每孔体积100μL，每组设定10个平行孔进行测定。过夜培养后(37℃，5％CO2),待细胞贴壁完全，吸干培养基，按照实验分组每孔分别加入含对应药物的培养基100μL，继续培养后第1、2、3天取每组10孔样本进行检测成骨细胞增殖能力。
表1促成骨细胞增殖平均促进率
破骨细胞抑制率评价试验:实验分为式I化合物组、唑来膦酸组和阿伦膦酸组和空白组，各实验组浓度为10-8mol/L。
破骨细胞的骨吸收能力测定采用日本COSMOBIO公司的破骨细胞骨嫩滑检测试剂盒进行测定。取出试剂盒中的48孔板，沿孔壁每孔加入0.25mL试剂盒中的BON RESORPTIONASSAY FACS，每孔接种细胞悬液500μL，每孔接种细胞6.5*103/mL。每孔加入100*药物母液各5μL。连续培养4-7天，中间不换液。连续培养4天后，从骨吸收检测板各孔中取100μL细胞培养上清液至48孔板中。48孔板各孔中加入50μL试剂盒中的BON RESORPTION ASSAY FACS，轻轻混匀。用荧光酶标仪检测各孔的吸光度值。
表2破骨细胞活性平均抑制率
由上述药理试验可以看出，本发明的式I化合物相比于唑来膦酸及阿伦膦酸，两者具有基本相当的破骨细胞抑制率，但是本发明的式I化合物则显示出较好的促成骨细胞增殖的能力。可见本发明的式I化合物可以维持一个较佳的骨细胞生成和抑制的动态平衡，更适应于骨质疏松病症的治疗中。
Claims (7)
1.一种具有如下式I所示结构的化合物及其药学上可接受的盐：
2.根据权利要求1所述的式I所示结构的化合物的制备方法，其特征在于，所述方法制备路线如下：
3.根据权利要求2所述的方法，其特征在于，步骤(1)中，氯化反应条件溶剂为二氯甲烷，催化剂为DMF，氯化试剂为氯化亚砜；其中，式a所示的布洛芬：氯化亚砜：DMF：二氯甲烷的投料比为1mmol:(2～10mmol):(0.05～0.5mmol):(0.5～5mL)。
4.根据权利要求2所述的方法，其特征在于，步骤(2)中，式b的酰氯与苯丙氨酸发生缩合反应，所述缩合反应在碱存在的条件下进行；其中，所述碱为碳酸钠、碳酸氢钠、三乙胺、吡啶、碳酸钾中的任意一种；式b化合物与苯丙氨酸的摩尔比为(1～2):1。
5.根据权利要求2所述的方法，其特征在于，步骤(3)中，式c化合物与亚磷酸、三氯化磷在加热条件下反应，制备得到式I的目标产物；其中，式c化合物与亚磷酸的摩尔比为1:1～1:6；式c化合物与三氯化磷的摩尔比为1:2～1:6；所述加热反应温度为80～120℃。
6.一种药物组合物，其含有如权利要求1所述的具有式I所示结构的化合物及其药学上可接受的盐。
7.根据权利要求1所述的具有式I所示结构的化合物及其药学上可接受的盐在制备治疗骨质疏松的药物中的用途。
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