双膦酸盐类抗骨质疏松药物利塞膦酸钠及其衍生物的合成与表征
摘要
双膦酸盐类是目前治疗骨质疏松症的最重要药物,通常以口服或静脉注射用药。主要用于治疗骨质疏松症、变形性骨炎症、恶性肿瘤骨转移引起的高钙血症和骨痛等各种常见的骨病。随着人们对双膦酸盐类化合物的深入研究和广泛应用,其发展十分迅速,已形成三代产品。利塞膦酸钠为第三代双膦酸盐类抗骨质疏松药物中上市较早,疗效明显的强于一、二代产品。但作为目前治疗骨质疏松症的最主要药物之一,利塞膦酸钠的缺陷是双磷原子上的四个羟基易与食物中的Ca2+及人体内的微量金属离子(Co2+, Ni2+, Cu2+,Fe3+,Cr2+)鳌合形成配合物或沉淀,从而使其在体内的药物利用度大为降低。
为了克服这一问题,通过对该药物分子的结构进行优化,方案是基于利塞膦酸钠的双膦酸母体结构,对双膦酸分子进行脂化或／并环化且引入亲水性基团。按照这个实验方案,本论文主要完成了以下的研究内容：
1、合成第三代双膦酸盐类抗骨质疏松的原料药物利塞膦酸钠。
2、为探明利塞膦酸与金属离子的络合能力,设计合成了利塞膦酸与钙离子及系列过渡金属离子配合物。结果表明,利塞膦酸与过渡金属形成了1：1的配合物。
3、为研发利塞膦酸盐类的抗骨质疏松新药,设计合成单一取代、双一取代和环化的三个利塞膦酸衍生物,这些化合物的合成均未见文献报道。
4、成功将连接器基团引入利塞膦酸吡啶环的氮原子上,再进一步引入荧光试剂,获得了一种新颖的荧光探针型利塞膦酸药物分子,为研究其药物的作用机理提供了基础。
以上所有合成的化合物通过元素分析、红外、紫外、核磁共振等分析测试进行结构表征,并得以确认。
Bisphosphonates are one kind of the important antiosteoporosis drugs.They are widely used for the treatment of osteoporosis,deformation bone flammation, bone metastases from malignant hypercalcemia and so on.As the bisphosphonate compounds are in-depth studies and widely used on them, three generations of bisphosphonate products have been developed. Risedronate sodium, a third-generation bisphosphonate with pyridyl, is the earliest protein inhibitor of bone absorption on market and its effect was stronger than earlier the first and second-generation products. As a commercial drug, the disadvantage of the risedronate is that four hydroxyls on both phosphorus atoms of it can chelate easily Ca2+and transition metal ions such as Co2+, Ni+, Cu2+, Fe2+, and Cr2+to form complexes or precipitation, so that make it less effective in biological system. In order to overcome this problem, our strategy, based on the parent structure of residronate, is to modify its structure by esterification and cyclization of the hydroxyls of it and bring a hydrophilic group.
Based on this strategy, the following research has been down:(1) The risedronate sodium was synthesized for the third-generation bisphosphonates as anti-osteoporosis drugs.(2) To explore complexing capacity between risedronate and metal ions, the risedronate complexes with calcium ion and a serious of transition metal ions were synthesized, and the results indicated that the complexes have a 1:1 ration of ligand and metals, (3) To reasearch risedronate salts for anti-osteoporosis new drugs, three mono-and di-substituted and cyclic derivatives of risedronate were design and synthesized, which are not reported in lectures, and (4) a novel risedronate molecule with fluorescent group was successfully synthesized by a crosslink group which linking risedronate and fluorescent reagent, this will help to investigate the mechanism of the drug. All synthesized compounds were characterized by EA,IR,UV-Vis and 1HNMR and confirmed.
为了克服这一问题,通过对该药物分子的结构进行优化,方案是基于利塞膦酸钠的双膦酸母体结构,对双膦酸分子进行脂化或／并环化且引入亲水性基团。按照这个实验方案,本论文主要完成了以下的研究内容：
1、合成第三代双膦酸盐类抗骨质疏松的原料药物利塞膦酸钠。
2、为探明利塞膦酸与金属离子的络合能力,设计合成了利塞膦酸与钙离子及系列过渡金属离子配合物。结果表明,利塞膦酸与过渡金属形成了1：1的配合物。
3、为研发利塞膦酸盐类的抗骨质疏松新药,设计合成单一取代、双一取代和环化的三个利塞膦酸衍生物,这些化合物的合成均未见文献报道。
4、成功将连接器基团引入利塞膦酸吡啶环的氮原子上,再进一步引入荧光试剂,获得了一种新颖的荧光探针型利塞膦酸药物分子,为研究其药物的作用机理提供了基础。
以上所有合成的化合物通过元素分析、红外、紫外、核磁共振等分析测试进行结构表征,并得以确认。
Bisphosphonates are one kind of the important antiosteoporosis drugs.They are widely used for the treatment of osteoporosis,deformation bone flammation, bone metastases from malignant hypercalcemia and so on.As the bisphosphonate compounds are in-depth studies and widely used on them, three generations of bisphosphonate products have been developed. Risedronate sodium, a third-generation bisphosphonate with pyridyl, is the earliest protein inhibitor of bone absorption on market and its effect was stronger than earlier the first and second-generation products. As a commercial drug, the disadvantage of the risedronate is that four hydroxyls on both phosphorus atoms of it can chelate easily Ca2+and transition metal ions such as Co2+, Ni+, Cu2+, Fe2+, and Cr2+to form complexes or precipitation, so that make it less effective in biological system. In order to overcome this problem, our strategy, based on the parent structure of residronate, is to modify its structure by esterification and cyclization of the hydroxyls of it and bring a hydrophilic group.
Based on this strategy, the following research has been down:(1) The risedronate sodium was synthesized for the third-generation bisphosphonates as anti-osteoporosis drugs.(2) To explore complexing capacity between risedronate and metal ions, the risedronate complexes with calcium ion and a serious of transition metal ions were synthesized, and the results indicated that the complexes have a 1:1 ration of ligand and metals, (3) To reasearch risedronate salts for anti-osteoporosis new drugs, three mono-and di-substituted and cyclic derivatives of risedronate were design and synthesized, which are not reported in lectures, and (4) a novel risedronate molecule with fluorescent group was successfully synthesized by a crosslink group which linking risedronate and fluorescent reagent, this will help to investigate the mechanism of the drug. All synthesized compounds were characterized by EA,IR,UV-Vis and 1HNMR and confirmed.
引文
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