抗病毒药物PMEA和Ribavirin衍生物合成研究
摘要
抗病毒药物PMEA(9-(2’-膦酰甲氧乙基)腺嘌呤)作为一种逆转录酶抑制剂，在临床应用中显示出其极大的优势：不易引起抗药性、较长的服用时间间隔、可与其它药物方便的联用等，但同时有一定的细胞毒性(尤其现有的口服前药Adefovir)，透膜性差导致的吸收利用度低等缺点。因此，本文设计PMEA的一种口服前药双(5-十一烷氧基戊酰甲氧基)PMEA，并对之进行了全合成。首先合成了PMEA的几种关键原料，之后合成了氯甲基化的5-十一烷基戊酸，并最终得到目标化合物。由于长链取代基的引入能够提高其脂溶性，可能会提高其透膜能力，同时长链取代基本身具有的抗癌、抗病毒效力，希望籍此改善PMEA的使用。另外，我们利用计算机进行量子计算，从静态构象和反应阈能两方面论证了由PMEA合成聚磷酸酯是可行的。同时本文尝试了长链醚合成及对羧酸进行氯甲基化的反应。
与此同时，本文合成了一系列利巴韦林(Ribavirin)结构类似物。利巴韦林是一种次黄嘌呤脱氢酶抑制剂，它是目前对丙型肝炎(HCV)治疗中唯一的小分子药物，但其毒性不可忽视。尤其，它在治疗SARS中也有积极的效果。在实验中，我们首先合成了一系列的1，2，4-三唑的衍生物，5-X-1，2，4-三唑酰甲酯(X=氯，溴、碘、氰、硫氰等)，这些化合物本身是很好的生物医药中间体，且具有一定的抗菌生物活性。此外本文由这些化合物出发，对利巴韦林结构类似物的合成进行尝试，并最终得到一系列化合物：3(5)-氯-1-(β-呋喃核糖基)-1，2，4-三唑-5(3)-酰胺、3(5)-溴-1-(β-呋喃核糖基)-1，2，4-三唑-5(3)-酰胺、3(5)-叠氮-1-(β-呋喃核糖基)-1，2，4-三唑-5(3)-酰胺、5-氨基-1-(β-呋喃核糖基)-1，2，4-三唑-3-酰胺等。此外，还对合成中的若干问题进行了初步讨论，例如同分异构体的区分等。
PMEA, 9-[2'-(phosphonomethoxy)ethyl]adenine, as a nucleotide analogue, is one kind of reverse transcriptase inhibitors. The oral prodrug of PMEA, that is its bis(pivaloyloxymethyl)ester (also named Adefovir dipivoxil or Preveon), has being evaluated in patients infected with human immunodeficiency viruses (HIV-1 and HIV-2) or the hepatitis B virus (HBV), and shown great advantages. Inevitabiely, there are some flaws with it, cytotoxinic, low bioavailablity, difficulty in permeating membrane. So, a new prodrug of PMEA, bis(5-undecyloxopentanoyloxymethyl)ester of PMEA ,was designed and synthesized, which is expected to overcome the disadvantages of other prodrugs of PMEA for adopting long-chain substitutes.
In addition, we want to change PMEA to a new kind of drug with low side-effect, good absorbability, and long-life controlled releasing feature by condensed polymerization with diols. With the help of computer, a positive conclusion of the feasibility of the esterification process was drawn through the results of quantum chemical calculation.
As to Ribavirin , inhibitor of inosine 5'-monophosphate dehydrogenase, the first synthetic drug with broad antiviral spectrum. It is used in combination with interferon a to treat HCV patient. Recently, it is used to against SARS and has found favorable response at the early stage of infection. Here several kinds of analogues of Ribavirin were synthesized . And we expect some of them having more antiviral bioactivity.
Meantime, several derivatives of 1,2,4-trizole were synthesized, which are highly expected to be used as biomedical intermediates.
与此同时，本文合成了一系列利巴韦林(Ribavirin)结构类似物。利巴韦林是一种次黄嘌呤脱氢酶抑制剂，它是目前对丙型肝炎(HCV)治疗中唯一的小分子药物，但其毒性不可忽视。尤其，它在治疗SARS中也有积极的效果。在实验中，我们首先合成了一系列的1，2，4-三唑的衍生物，5-X-1，2，4-三唑酰甲酯(X=氯，溴、碘、氰、硫氰等)，这些化合物本身是很好的生物医药中间体，且具有一定的抗菌生物活性。此外本文由这些化合物出发，对利巴韦林结构类似物的合成进行尝试，并最终得到一系列化合物：3(5)-氯-1-(β-呋喃核糖基)-1，2，4-三唑-5(3)-酰胺、3(5)-溴-1-(β-呋喃核糖基)-1，2，4-三唑-5(3)-酰胺、3(5)-叠氮-1-(β-呋喃核糖基)-1，2，4-三唑-5(3)-酰胺、5-氨基-1-(β-呋喃核糖基)-1，2，4-三唑-3-酰胺等。此外，还对合成中的若干问题进行了初步讨论，例如同分异构体的区分等。
PMEA, 9-[2'-(phosphonomethoxy)ethyl]adenine, as a nucleotide analogue, is one kind of reverse transcriptase inhibitors. The oral prodrug of PMEA, that is its bis(pivaloyloxymethyl)ester (also named Adefovir dipivoxil or Preveon), has being evaluated in patients infected with human immunodeficiency viruses (HIV-1 and HIV-2) or the hepatitis B virus (HBV), and shown great advantages. Inevitabiely, there are some flaws with it, cytotoxinic, low bioavailablity, difficulty in permeating membrane. So, a new prodrug of PMEA, bis(5-undecyloxopentanoyloxymethyl)ester of PMEA ,was designed and synthesized, which is expected to overcome the disadvantages of other prodrugs of PMEA for adopting long-chain substitutes.
In addition, we want to change PMEA to a new kind of drug with low side-effect, good absorbability, and long-life controlled releasing feature by condensed polymerization with diols. With the help of computer, a positive conclusion of the feasibility of the esterification process was drawn through the results of quantum chemical calculation.
As to Ribavirin , inhibitor of inosine 5'-monophosphate dehydrogenase, the first synthetic drug with broad antiviral spectrum. It is used in combination with interferon a to treat HCV patient. Recently, it is used to against SARS and has found favorable response at the early stage of infection. Here several kinds of analogues of Ribavirin were synthesized . And we expect some of them having more antiviral bioactivity.
Meantime, several derivatives of 1,2,4-trizole were synthesized, which are highly expected to be used as biomedical intermediates.
引文
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