盐酸替洛隆的制备及其诱导干扰素能力的研究

Study on preparation and interferon inducing activity of tilorone dihydrochloride

[目的]高效合成盐酸替洛隆,对盐酸替洛隆进行质量研究并简略探究其诱导干扰素的作用强度与特点。[方法]通过2,7-二羟基-9-芴酮与2-二乙氨基氯乙烷盐酸盐发生取代反应合成替洛隆,进一步酸化得到盐酸替洛隆。目标化合物的结构经红外光谱(IR)、核磁(1HMNR)和质谱(MS)确证,并依据药典规定的方法,依次检验盐酸替洛隆的各项理化性质及含量。盐酸替洛隆以250 mg·kg^(-1)的剂量灌胃SPF小鼠,分别在给药后不同时间采血,采用ELISA法检测血清中α1干扰素水平,评估盐酸替洛隆干扰素诱导作用。[结果]盐酸替洛隆合成收率达到93%;其理化性质稳定,制备方法可靠;给小鼠灌胃12 h后,诱导其机体产生干扰素达到峰值约2 000 pg·m L^(-1),且持续时间长达24 h。[结论]建立的盐酸替洛隆合成方法收率高,盐酸替洛隆质量稳定可控;所得产物诱导干扰素能力显著,研发前景好。

[ Objectives] The aim of this paper was to make preparation and quality investigation of tilorone dihydrochloride. On the other hand, drug effect on induction of interferon was also primarily proved. [ Methods ] Tilorone was synthesized by the substitution reaction of 2,7-dihydroxy-9H-fluoren-9-one with 2-diethylaminoethyl chloride hydrochloride, which was then acidified to give tilorone dihydrochloride. The structure of target compound was characterized by Infrared Spectroscopy（IR） , ^1H Nuclear Magnetic Resonance （^1H MNR）and mass spectrum （MS）. By the method of pharmacopeia, physiochemical properties and content determination were identified in sequence for primary specification establishment. Tilorone dihydrochloride was dissolved at suitable concentration permitting an inoculum of 250 mg· kg^-1（mice） orally. After tilorone challenged, mice were bled for IFN-α1 assay via ELISA method. [ Results] Tilorone dihydrochloride was synthesized in good yield of 93% and stable for quality control. In addition, tilorone could characteristically induce an unusually delayed and prolonged interferon response with peak level of 2 000 pg· mL^-1 observed from 12 h to 24 h. [ Conclusions] The compound was efficient to prepare, and was stable and effective to induce obvious interferon responses, which will have broader prospects of development.