A new group of 1-and 7-[ω-(benzhydryl-1-alkyl]-3methylxanthine derivatives with antihistamine activity

Abstract

Directed synthesis using the accessible compound 3-methylxanthine was used to obtain a new group of 1-and 7-[w-(benzhydryl-1)alkyl]-3-methylxanthine derivatives which functioned as histamine receptor blockers. The compound which was most active, had the longest duration of action, and the lowest toxicity was 7-[4-(4-benzhydrylpiperazinyl-1)butyl]-3-methylxanthine succinate, and this compound was selected for clinical trials.Key words: 1-and 7-[w-(benzhydryl-1)alkyl]-3-methylxanthine derivatives, synthesis, antihistamine activity, acute toxicity, further pharmacological study of 7-[4-(4-benzhydrylpiperazinyl-1)butyl]-3-methylxanthine succinate.The widespread occurrence of allergic disorders (more than 35% of the working population) makes the task of treating allergy a first-rank medical-social problem [1].According to the current classification, existing histamine H 1 receptor blockers are divided into two groups: first-generation agents such as diphenhydramine, clemastine, promethazine, chloropyramine, azelastine, Ksifenadin (a Russian phencarol formulation), and second-generation agents such as cetirizine, levocetirizine, loratadine, desloratadine, acrivastine, ebastine, fexofenadine, etc.; these, unlike first-generation agents, do not have marked sedative activity, while their durations of action are longer (cetirizine, loratadine).The most widely used agents in current medical practice are antiallergic agents of the first group, as they quite effectively eliminate or alleviate the symptoms of allergy in pathological states in whose development histamine plays a leading role [2]. However, these agents are not free of significant disadvantages (sedative actions, side effects associated with their anticholinergic actions, tachyphylaxis on prolonged use, arrythmogenic effects).The disadvantages of the existing arsenal of antiallergic agents include the limited number of antihistamines for local (intraconjunctival, intranasal) use -local agents produce side effects less frequently than agents for oral use. Given that most allergies are particularly characterized by individual sensitivity to one or another antihistamine agent, effective treatment requires a quite wide spectrum of antiallergic agents.With the aim of seeking new, highly effective and safe antiallergy agents with new structures, we have synthesized a large group of 1-and 7-xanthine derivatives with the general formulae I and II (scheme 1) and have studied their antihistamine activity; a new antiallergic substance -teoritin -has been identified. This is 3-methyl-7-[4-(benzhydrylpiperazinyl-1)butyl]xanthine (IIg) [3].In the planned synthesis of new compounds we retained the benzhydrylpiperazinylalkyl fragment at positions 1 and 7 of the xanthine molecule, which is the pharmacophore base of a series of second-generation antihistamines, and biogenic 1 0091-150X/11/4501-0001