摘要
抗胆碱能药物是一类重要的外周神经系统药物,它能阻滞胆碱受体,使递质乙酰胆碱不能与受体结合。临床上,是治疗有机磷中毒的主要药物之一,此外还用作散瞳药、制止分泌药、解痉止痛药以及肌肉松弛剂等:军事上,用来对付化学武器的袭击,作为反恐药物对付恐怖分子。近年来,对此类药物的研究已经成为全球的热点。
最初,抗胆碱能药是从天然药物中提取,目前研究重点以合成为主。但是,许多抗胆碱能药物起效慢并且副作用大,限制了此类药物的临床应用。因此,寻找活性好,选择性高,作用强,毒性低及具有新适应症的新型抗胆碱药物成为当前药物合成工作者的热点之一。抗胆碱能药物的主要是胆碱能神经递质乙酰胆碱竞争M受体和N受体,所以抗胆碱能药的结构一定要契合M受体和N受体的结构才能显示高效生物活性。大多数抗胆能化合物具有较强的抗M作用而没有强的抗N作用。其中,三环类抗胆碱能药物是一类具有较强抗胆碱能活性的药物。
文献报道过的呫吨类抗胆碱药物多为氨基醇酯类化合物,其结构可以分为环状基团、含氮基团和酯基三个部分,但根据M受体拮抗剂的构效关系我们知道,环状基团与M受体上相应的亲酯性区域通过疏水键或范德华力发生附加结合,阻断乙酰胆碱对受体的作用。而且酯键并不是抗胆碱活性所必需的,也可以是醚键,即氨基醇醚类化合物。我们根据三取代乙氧基羟胺类抗胆碱能药物的合成方法设计合成了9-羟基呫吨-9-甲氧基胺类化合物。以期待获得选择性高,作用强,毒性低及具有新适应症的新型抗胆碱药物。
我们在参考文献的基础上,设计了合成路线,以邻氯苯甲酸为起始原料经过Ullmann缩合和脱水闭环得到呫吨酮,然后在硫叶立德作用下合成出其环氧乙烷中间体;目标化合物的阳离子头部分我们选用哌啶环状基团,以异烟酸为原料,经过酯化、氢化还原合成了1-甲基-4-哌啶甲醇,最后在氢化钠的作用下合成了目标化合物。由于时间原因,未能针对该化合物建立动物模型开展活性测试工作。尽管如此,实验还是为将来药物筛选、组合以及药理学研究提供了参考依据。
另外,我们用三氯氧磷为酰氯化试剂合成了水杨酸酯类紫外线吸收剂水杨酸苯酯和水杨酸对辛基苯酯,实验证明该方法具有操作简便、条件温和、环境友好等优点,是一条适合工业化生产的合成路线。
Anticholinergic drugs are a class of important peripheral nervous system drugs,which block cholinergic receptors,so that neurotransmitter acetylcholine receptor-binding and should not. Clinically,it is the treatment of organophosphate poisoning,one of the main drugs,in addition to drugs used to stop the secretion,mydriatics,spasmolytic and muscle relaxant analgesic agent,etc. Militarily,to deal with chemical weapons attacks,as the anti-terror drug dealing with terrorists. In recent years,studies of such drugs has become a global hot spots.
Initially,the anti-cholinergic drugs are extracted from natural substances,and the present study mainly focuses on synthesis.However,many anti-cholinergic drugs have the effect to be slow and the side effect is big,which limited the clinical application of these drugs.Therefore, looking for good activity,high selectivity,the role of strong,low toxicity and a new indication for a new anticholinergic drags has become the one of the hot spots for drug synthetic workers. Anticholinergic drags are the main cholinergic neurotransmitter acetylcholine receptor M and N competition receptors,so its structure must fit M to N receptor and receptor in order to show the efficiency of the structure of biological activity.The majority of anti-cholinergic drugs has strong anti-M role but not the role of strong anti-N.Among them,the tricyclic anti-cholinergic drugs are a class of strong activity of anticholinergic drugs.
Have been reported in the literature category xanthene anticholinergic drugs for many amino alcohol esters,and its ring structure can be divided into groups,nitrogen-containing ester groups and three parts.However,according to M-receptor antagonist structure-activity relationship of us know that the cyclic group with M receptor on the corresponding region of the pro-ester bond or through hydrophobic van der Waals force additional happen combination of blocking acetylcholine receptors.Ester and anti-cholinergic activity is not necessary,it could be ether bond,that is,amino-alcohol compounds.We according to the three types of ethoxy hydroxylamine anticholinergic drug design and synthesis 9-hydroxyl-xanthene-9-ethyl(cycloalkylamino)ethers to look forward to the high selectivity,the role of strong,low toxicity and a new indication for a new type of anti-cholinergic drugs.
At our reference on the basic design of the synthetic route to o-chlorobenzoic acid as the starting material through Ullmann condensation and dehydration have been xanthene-one closed-loop,and then at the role of sulfur ylides under its ethylene oxide synthesis intermediates. We chose piperidine ring for the cationic compound,isonicotinic acid as raw material,after esterification,hydrogenation reduction synthesized 1-methyl-4-piperidine methanol,and finally at the role of sodium synthesized target compounds.Because of time reasons,we can not set up for the compounds to carry out activity in animal model testing.Nevertheless,it is providing a refference for future drug screening,combinatorial and pharmacological research.
In addition,we used phosphorus oxychloride reagent for synthesis of the UV absorber of salicylic acid esters,phenyl salicylate and p-octylphenyl salicylate.Experiments show that the method is simple and mild conditions,the advantages of environmentally friendly,and is a suitable synthetic route for industrial production.
引文
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