Synthesis and antibacterial activities of new dibenzothiazepine derivatives

The development of heterocyclic scaffolds is a fast emerging subject in the medicinal chemistry. Imidazole, triazole, benzimidazole and their fused compounds are extensively studied because of their significant pharmacological activities 1 . Another class of heterocyclic scaffolds containing nitrogen, oxygen and sulphur with eminent biological activities in central nervous system is dibenzothiazepines (Figure 1), which are of great interest in the area of drug discovery and development due to their broad spectrum of pharmacological activities. These compounds are used in antihistaminic 2 , potential high ceiling diuretics 3 . Especially C-11Nsubstituted analogues were studied and found to be active 4 . Dibenzo[b,f][1,4]thiazepine is a class of antipsychotic drug. 11-[4-{2-(2-Hydroxyethoxy)ethyl}-1piperazinyl] dibenzo[b,f][1,4] thiazepine (trade name Quetiapine), a typical antipsychotic drug that is practiced for the treatment of schizophrenia and bipolar disorder for many years 5 . As Horrom et al. disclosed that dibenzothiazepine derivatives were useful for the antischizophrenics and also being useful for variety of medical application including as neuroleptic, antidepressant 2,6 . Recently these drugs have been used to treat delirium and agitation 7 . The compound used as antipsychotic and neuroleptics have, however been plagued by the problems of undesired side effects, such as acute dyskinesias, acute dystopias, pseudo-parkinsonism and tardive dyskinesias 8 . Thus there still remains a need for compounds which exhibit antidopaminergic activity and pharmaceutical activity to overcome such undesired side effect. The synthesis of new derivatives possessing antibacterial activity has considerable attention owing to the continue increase in bacterial resistance. It has been reported that benzodiazepine and substituted benzodiazepine-2-one exhibited the strong antibacterial activity 9,10 . Dibenzothiazepine derivatives were synthesized using various methods such as reaction of iminochloride with the different basic moiety especially piperazine and substituted piperazine derivatives 4,6 . Furthermore compounds containing the dibenzothiazepine basic skeleton with different morpholino, thiomorpholino, piperidino, 1pipirazinyl, pyrrolidinyl were also reported. It was therefore reasoned that the fusion of imidazole, triazole and benzimidazole with dibenzothiazepine may lead to a novel tricyclic heterocyclic scaffolds with interesting biological activities. Herein we report compound carrying imidazole, triazole and their substituted moieties at C-11 position and their antibacterial activity. The synthetic reaction sequence for the preparation of C-11 substituted dibenzo[b,f][1,4]thiazepines is depicted in Scheme I. The intermediate 5 was prepared by following literature procedure with optimized conditions. Initially reduction of 2-nitro diphenylsulfide 1 using Fe/HCl gave poor yield, but hydrogenation of 1 with Raney-nickel in MeOH at 80 psi afforded 2 in very good yield (98%). The carbamate 3 was prepared from amine 2 and phenyl chloroformate in the presence of bases such as NaOH,