Synthesis of 2-N,N-Dimethylaminomethyl-2,3,3a,12b-tetrahydrodibenzo-[b,f]furo[2,3-d]oxepin Derivatives as Potential Anxiolytic Agents

Abstract

We have recently described the synthesis of two new series of 2-(aminomethyl)-2, 3,3a,8-tetrahydrodibenzo[c,f]isoxazolo[2,3-a]azepine derivatives (I) and 2-(aminomethyl)- 3,3a,8,12b-tetrahydrodibenzo[3,4:6,7]cyclohepta [1,2-b]furan derivatives (II) as novel 5-HT 2A/2C receptor blockers ( Fig. 1).1-5) Some of those tetracyclic isoxazolidines/tetrahydrofurans were potent mCPP (m-chlorophenylpiperazine) antagonists as shown in our in vivo mCPP challenge test, [3][4][5] and therefore could be considered as potential anxiolytic/antidepressants. [6][7][8][9][10][11][12] One enantiomer within this isoxazolidine series, R107500, was selected for clinical evaluation as an anxiolytic agent.Following our research program on modifications of these tetracyclic structures, we now report the synthesis of the corresponding dibenzoxepine (III) analogues. The described synthetic pathway allowed us to synthesize the four different diastereoisomers of the THF core. Results and Discussiontrans-Fused analogues were prepared following a similar methodology to that used for the synthesis of 2-(aminomethyl) -3,3a,8,12b-tetrahydrodibenzo[3,4:6,7]cyclohepta[1,2-b]furan derivatives (II). 4,5,13,14) Thus, epoxidation of dibenzo [b,f]oxepine (1) 15) with meta-chloroperbenzoic acid (MCPBA) gave dibenzo[b,f]oxepin-10,11-epoxide (2) in 79% yield (Chart 1). Epoxide ring opening with allylmagnesium bromide resulted in the desired trans-type b-allylic alcohol 3. The cyclization of 3 to form the tetrahydrofuran ring was carried out under the reaction conditions shown in Table 1. Bromine or pyridinium bromide perbromate in chloroform afforded with good yield (80% and 78% respectively) and diastereoselectivity (95 : 5) the trans-fused diastereoisomer 4b. When the cyclization step was performed with I 2 under basic reaction conditions the expected tetrahydrofuran derivatives 4a and 5a were obtained in satisfactory yield (80%), although the diastereoselectivity outcome of the cyclization was somewhat lower (4a : 5a; 90 : 10). The use of IPy 2 BF 4 (bis(pyridine)iodonium(I) tetrafluoroborate; Barluenga's reagent) 16) or MCPBA resulted in slightly increased yields (92% for 4c, 5c and 99% for 4a, 5a) but not diastereoselectivity at all. Remarkable is the fact that the cyclization reaction with Barluenga's reagent reached completion in two minutes affording the expected products in nearly quantita-

Microwave-Assisted Syntheses of Bioactive Seven-Membered, Macro-Sized Heterocycles and Their Fused Derivatives

“…These molecules belong to the family of the natural oxepinochromones. However, these authors do not take advantage of the MWirradiation for the closure of the seven-membered heterocycle, but they used a MW-assisted Claisen re-arrangement, which occurs concomitantly with a Boc deprotection leading to the key intermediate The dibenz [b,f]oxepines are characterized by an oxepane fused with two aromatic moieties: this is a relevant pharmacophore present in the structure of numerous therapeutic agents which can be used for several therapeutic applications such as antidepressant, antipsychotic and antiinflammatory indications ( Figure 5) [24][25][26][27][28]. Very few MW-assisted syntheses of dibenzoxazepines have been reported.…”

“…Nevertheless, two very interesting approaches, based (i) on an intramolecular SNAr; and (ii) on a McMurry reaction, each occurring with MW-activation, have been described by Moreno and co-workers [29] (Scheme 10A). The dibenz [b,f ]oxepines are characterized by an oxepane fused with two aromatic moieties: this is a relevant pharmacophore present in the structure of numerous therapeutic agents which can be used for several therapeutic applications such as antidepressant, antipsychotic and anti-inflammatory indications ( Figure 5) [24][25][26][27][28].…”

“…The dibenz[b,f]oxepines are characterized by an oxepane fused with two aromatic moieties: this is a relevant pharmacophore present in the structure of numerous therapeutic agents which can be used for several therapeutic applications such as antidepressant, antipsychotic and antiinflammatory indications ( Figure 5) [24][25][26][27][28]. Very few MW-assisted syntheses of dibenzoxazepines have been reported.…”

New Short Strategy for the Synthesis of the Dibenz[b,f]oxepin Scaffold

“…The dibenz[ b , f ]oxepin scaffold is an important synthetic target because a large number of compounds having this skeleton present relevant biological activities; such as antidepressant [1], anxiolytic [2], antipsychotic [3,4], angiotensin-II-receptor-antagonist [5], and anti-inflammatory properties [6]. Additionally, a number of natural occurring dibenz[ b , f ]oxepins have been isolated from plants of the genus Bauhinia (fam.…”

Synthesis of new seven-membered benzo-fused heterocyclic ortho-dicarbonitriles

“…For instance, tricyclic dibenz-[b,f]oxepine is an important structural fragment present in natural compounds [2,3] capable of inhibiting the cancer cells growth [4], exhibiting the antiphlogistic [5], neuroleptic [6], and other types of action [7,8]. Another no less important specimen of these heterocyclic class, dibenz[b,f] [1,4]oxazepine, also is one of key components of psychoactive drugs [9], antagonists of prostaglandin receptors [10], progesterone [11], inhibitors of kinase [12] and histone deacetylase [13].…”