Synthesis and Anti-Inflammatory Activity of 8H-1-Thia-8- aza-dibenzo[e,h]azulenes Ivana Ozimec Landek,* Dijana Pes ˇic ´, Mladen Merc ´ep [1], Barbara Stanic ´ [1], and Milan Mesic ´ GlaxoSmithKline Research Centre Zagreb Limited, Prilaz baruna Filipovic ´a 29, 10000 Zagreb, Croatia *E-mail: ivana.o.ozimec-landek@gsk.com Received April 21, 2010 DOI 10.1002/jhet.605 Published online 15 April 2011 in Wiley Online Library (wileyonlinelibrary.com). Synthesis of a novel class of fused heterotetracyclic compounds, 8H-1-thia-8-aza-dibenzo[e,h]azulenes (VII), is described. Starting N-benzoyl-protected 5H-dibenzo[b,f]azepine (XI, PG ¼ Bz) was oxidized to 5-benzoyl-10,11-epoxy-10,11-dihydro-5H-dibenzo[b,f]azepine (2), which subsequently rearranged in Lewis acid-induced epoxide ring opening to give 5-benzoyl-5,11-dihydro-10H-dibenzo[b,f]azepin-10- one (3). Vilsmeier reaction of 3 provided b-chlorovinyl aldehyde 4 that readily cyclized with ethyl 2- mercaptoacetate to form dibenzazepino[4,5]-fused thiophene structure 5. Further transformation of sub- stituent at C-2 position of 5 and N-deprotection led to final aminoalkoxy derivatives 9. All compounds with tetracyclic skeleton were tested in vitro for their anti-inflammatory activity. J. Heterocyclic Chem., 48, 856 (2011). INTRODUCTION Dibenzo[b,f]azepine framework is found within a num- ber of medicinally important compounds, particularly those acting at central nervous system (for example, see refs. 2–4). Antidepressants imipramine (Ia,Y ¼ H) and its 3-chloro analog clomipramine (Ia,Y ¼ Cl), as well as antiepileptics carbamazepine (Ib) and oxcarbazepine (Ic) are examples of compounds bearing such tricyclic moiety that are well known as widely prescribed drugs (Fig. 1). Furthermore, there is a growing pool of evidence that tri- cyclic antidepressants-like imipramine and its derivatives also possess pronounced anti-inflammatory and analgesic properties (for example, see refs. 5–13). On the other hand, some members of a series of 5- substituted 2,3-diaryl-thiophenes (II) were also reported to have significant anti-inflammatory activity through strong inhibition of necrosis factor alpha (TNF-a) pro- duction [14]. In our continuing efforts aimed toward synthesis and determination of anti-inflammatory activity of various heterocyclic dibenzo[e,h]azulenes, we recently reported on the synthesis, properties, structure determination, and preliminary biological results of dibenzo[e,h]azulenes characterized by furan III [15], pyrrole IV [16], thio- phene V [17], and imidazole ring VI [18] annulated to the central oxepine or thiepine ring (Fig. 1). Preliminary data revealed the ability of these polycyclic systems to inhibit TNF-a production in vitro. Herein, we wish to report on the continuation of our project with the study of 8H-1-thia-8-aza-dibenzo[e,h]azulenes [19], a series that embodies central azepine and [2,3]-fused thiophene ring VII (Fig. 1) and may be perceived as a combination of structural subunits I and II. Target molecules, both 8- N-substituted and 8-N-unsubstituted, bearing an alkoxy chain of variable length and a basic moiety at position C-2 are expected to possess significant anti-TNF-a activ- ity [20] and desirable pharmacokinetic properties. RESULTS AND DISCUSSION Chemistry. The tetracyclic structure VII is formed by annulation of the thiophene ring onto the existing tri- cyclic dibenzo[b,f]azepine moiety, as is shown by the retrosynthetic sequence in Scheme 1. To enable this, the V C 2011 HeteroCorporation 856 Vol 48