摘要
过敏反应是指过高的异常的免疫反应,是一类严重威胁公众健康的慢性疾病。过敏反应病是临床多发病,且近年来其发病率有逐年增加的趋势。对过敏反应病的治疗,目前有多种方法,其中行之有效的方法之一是利用H_1受体拮抗剂(抗组胺药)进行的非特异性治疗。传统抗组胺药大都时效短且有中枢神经抑制等副作用,新一代抗组胺药在一定程度上克服了上述缺点,但近年来临床发现它们当中有些具有潜在的心血管系统不良反应及其它副作用。因此研究和开发药效更好、副作用更小的抗组胺新药意义深远。
西替利嗪是具有较好疗效的哌嗪类药物之一,近年来发现左西替利嗪较其混旋体药效更强,因而以左西替利嗪为先导化合物,本文合成了19个左旋二苯甲基哌嗪类化合物。同时,鉴于扑尔敏也是药效很好的抗组胺药物,所以用吡啶环取代了其中一个苯环合成了2个苯杂环哌嗪类化合物。所合成的目标化合物经元素分析、质谱、红外、核磁共振氢谱等确证其化学结构。
初步的抗过敏性哮喘和止痒的活性测试表明:有15个化合物有平喘作用,在扑尔敏组给药0.5mg/kg,WTW系列化合物组给药50mg/kg情况下,WTW-08、WTW-10、WTW-13、WTW-17和WTW-19活性与阳性对照药扑尔敏相当,化合物WTW-04、WTW-09、WTW-18和WTW-20与扑尔敏相比有较高的活性;有17个化合物有止痒作用,在扑尔敏组给药0.5mg/kg,WTW系列化合物组给药50mg/kg情况下,WTW-11、WTW-15和WTW-18活性与阳性对照药扑尔敏相当,化合物WTW-07和WTW-19与扑尔敏相比有较高的活性。
Allergy is a kind of excessive immune reaction. Allergic diseases are abroad in clinic. However, the incidence of the kind of disease tends to increase recently. Among the therapies for it, H_1 receptor antagonists (antihistamines) have shown to be effective clinically in the treatment of allergies. The classical antihistamines have some side effects such as restraining the central nervous system (CNS) and lasting shortly. Although the new antihistamines have no such side effect, some of them still have other side effects such as the latent harm to the heart and vessel system. It is important to study and explore the new antihistamines that have more significant effect and less side effect.
Cetirizine is an kind of excellent antihistaminic drug, bearing diphenylmethylpiperazine skeleton. Recently, it was repoted that levocetirizine displayed a better pharmacological profile than the racemic mixture. Therefore, we decided to synthesize some levogyrate enantiomers of them. Nineteen levogyrate compounds were synthesized. At the same time, through investigating the antihistaminic drugs of Chlorpheniramine, we replaced pyridine ring to one phenyl ring of diphenylmethylpiperazine skeleton, two compounds which include pyridine ring were synthesized. All the compounds were identified by MS, IR, ~1H-NMR and elemental analysis.
The results of the initial anti-allergic asthma and antipruritic tests showed that seventeen compounds had significant effect in asthma, the activities of WTW-08, WTW-10, WTW-13, WTW-17 and WTW-19 was equel to the activities of the positive comparison drug Chlorpheniramine, the activities of WTW-04, WTW-09, WTW-18 and WTW-20 was higher than Chlorpheniramine; fifteen compounds had significant antipruritic effect, the activities of WTW-11, WTW-15 and WTW-18 was equel to the activities of the positive comparison drag Chlorpheniramine, the activities of WTW-07 and WTW-19 was higher than Chlorpheniramine.
引文
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