【作者】 李芳；

【导师】 王恩思；

【作者基本信息】 吉林大学 ， 药物化学， 2012， 硕士

【摘要】 免疫系统是人体内一个特殊的能识别异己、排出异己物质的系统，由天然免疫系统（非特异性免疫系统）和获得性免疫系统（特异性免疫系统）共同组成。人体免疫系统的三大功能全是凭借免疫应答反应来实现的，而免疫抑制剂则是一类通过影响免疫应答反应，抑制机体免疫功能并且治疗疾病的药物。在临床上，免疫抑制剂主要用于抑制各种对机体不利的免疫反应，如器官移植排斥反应和自身免疫性疾病，具有深远的实际意义。但是，免疫抑制剂的治疗大多需要终身用药，所以对整个免疫系统的非特异抑制就会产生很多严重的不良反应，这也是目前免疫抑制剂治疗过程中所遇到的一些普遍问题，如：诱发感染、治疗指数低、诱导恶性肿瘤、肾毒性等等，这就在一定程度上限制了它的临床应用。人类在追求一种选择性更强、抑制作用快速、停药后作用可逆、不良反应少的免疫抑制剂。正是因为如此，新型免疫抑制剂的研发就更加迫在眉睫。随着免疫药理学、免疫生物学等学科的发展和人们对免疫抑制剂研究的深入，逐渐诞生了一些新型的免疫抑制剂。1995年，由Fujita教授与Yoshitomi制药有限公司共同合成的一种新型的免疫抑制剂FTY-720在世界上诞生，其化学名为：2-amino-2-〔2-(4-octylphenyl)ethy1〕-1,3propanediol hydrochloride，该药在短暂的时间里表现出显著的免疫抑制效果和独特的作用。FTY-720的免疫抑制作用是基于以下两个因素：（1）加速外周组织内成熟淋巴细胞归巢，抑制淋巴组织内细胞的游出。（2）诱导淋巴细胞的凋亡，它是一种和现有免疫抑制剂作用机制完全不同的新型药物，FTY-720主要适用于器官移植的排斥反应、免疫性疾病、肿瘤等方面。FTY-720的诞生引发了无数科学家的思考，正是基于它的构效关系，我们设计与合成了新型免疫的抑制剂—FC系列化合物：以四氢萘环为母体，苯环5,6,7位为烷基、芳基、烷氧基和苯氧基取代，2位为羟甲基和氨基取代。本文中所论述的分子（FC-022和FC-028）的合成路线是以间溴苯乙酸为原料和四氢萘酮为中间体，经过环合反应、羰基乙二醇保护与脱保护反应、Ullmann反应、Bucherer-Berg,s反应、螺海因水解等多个步骤合成。其中，路线中所得到的各中间体都由核磁共振氢谱和碳谱确认，目标分子由核磁共振氢谱、碳谱、红外、质谱共同表征确认。在合成过程中我们发现，利用Ullmann反应合成二芳醚类分子时，此时2-萘满酮在碱性条件下相对不稳定。为此，我们将实验路线改为先将2-四氢萘酮羰基保护后，再进行成醚反应，最后再脱掉保护基而得到了目标产物。虽然这一路线增加了反应步骤，但在产量上却有着收率高的优点，而且也易于操作。此外，对于终产物的成盐过程可以不经过分离提纯直接进行，因为它的极性较大不易于分离，这样也就简化了实验操作。本文中设计合成了含有胺基和醇羟基结构的2-萘满酮的衍生物，其结构与免疫抑制剂FTY-720的活性基团相似，这为以2-萘满酮衍生物为基础的新型免疫抑制剂的进一步开发奠定了基础，也为新型免疫抑制剂的研发提供了一条新的思路。更多还原

【Abstract】 The immune system is a special system，which can identify and exclude aliensubstances in the body，it is composed of natural immune system (non-specific immunesystem) and acquired immune system (specific immune system). The three functions ofhuman immune system are realized by the immune response，and immunosuppressive agentis a kind of the drug by influencing immune response，inhibiting immune function andtreating the diseases. In the clinic, immunosuppressive agents can inhibit various of adverseimmune reactions in organ transplant rejection and autoimmune diseases. However，immunosuppressive therapy mostly need lifelong medication，so there will be a lot of seriousadverse reactions from inhibiting the non-specific immune system，which are the ordinaryproblems we encountered in the process of the immunosuppressive treatment，such as：induction of infection，low therapeutic index，induction of malignant tumors，renal toxicityand so on，so that its clinical application is largely restricted. Now humans are in the pursuitof immunosuppressive agents with a faster reaction and a less adverse reactions. Because ofthis，the development of new immunosuppressive agents is more imminent.With the development of immune pharmacology and immune biology，some newimmunosuppressants appear. FTY-720was synthesized by Professor Fujita in1995withYoshitomi Pharmaceutical Company and become a brandnew immunosuppressant. Thechemical name is called2-amino-2-[2-(4-octyl-phenyl)ethyl]-1,3-propanediol hydrochloride.In a short time，the drug showed significant immunosuppressive effects and played a uniquerole in the clinic. The immunosuppressive effects of FTY-720is based on two factors，whichare different from the current immunosuppressants. It can reduce the number of B and Tlymphocytes in the peripheral blood, thereby weakening the attack on the graft. The decreasein peripheral blood lymphocyte will "homing" in the lymph nodes and intestinal lymph nodeset，which will not affect the NK cells、granulocyte and monocyte function. FTY-720couldaffect chemokine functions，decreasing the access number of T and B cells to transplantationby70%to80%, therefore，Xenotransplantation could significantly prolong the survivaltime，which prevent the occurrence of acute rejection and reverse the occurred rejection. The birth of FTY-720led to many scientists,s thinking. Basing on the structure-activityrelationship of ISP-1and FTY-720, we designed and synthesized a series of compoundsnamed FC. The synthetic route of the molecules (FC-022and FC-028) discussed in thisarticle is based on inter-bromo phenylacetic acid as a raw material, after the cyclizationreaction，carbonyl protection and deprotection with ethylene glycol, Ullmann reaction,Bucherer-Berg’s reaction，we got the target compound. The key intermediates and targetcompound are identified by1H-NMR,13C-NMR, MS and IR.Synthesis results indicated that，in the synthesis process of the diaryl ethers molecules(Ullmann reaction)，2-tetralone is relatively unstable under alkaline conditions，such asK2CO3、Na2CO3or NaOH. So2-tetralone etherification reaction should be carried out aftercarbonyl protected and then deprotection to give target product. Although this routeincreases the reaction steps，but it has a high yield in production，and it is easy to operate.Inaddition, the end product into a salt can be used directly without the separation andpurification，because its polarity can not be easily separated，at the same time，it simplifiesthe experimental operations.In this article we designed and synthesized a2-tetralone derivatives, they contained agroup of amine and alcoholic hydroxyl，which is similar to the active groups of FTY-720.Above all, this article has provided a new mentality for the immunity inhibitor’s research anddevelopment.更多还原