Nonsteroidal antiinflammatory agents. 1. 10,11-Dihydro-11-oxodibenz[b,f]oxepinacetic acids and related compounds

Abstract

10,ll-Dihydro-ll-oxodibenz[6,/]oxepinacetic acids and related compounds were synthesized as potential antiinflammatory agents. Among them,/]oxepin-2-yl)propionic acid (16b) and its thiepin analogue (16c) showed excellent antipyretic activity together with potent antiinflammatory and analgesic properties in biological tests. Structure-activity relationships are discussed, In recent years a number of arylacetic acid derivatives have been reported to possess potent antiinflammatory activity in animal tests,2 and several of them have been clinically used.3 Shen4 has proposed a hypothetical antiinflammatory receptor site for indomethacin-type nonsteroidal agents, and for optimal receptor interaction, the two aromatic rings in a molecule should be out of plane. We, therefore, carried out the synthesis of the arylacetic acid derivatives containing tricyclic systems, such as dibenz[b,/]oxepin and dibenzo[b,/]thiepin, their 10,11-dihydro-11-oxo and 10,11-dihydro-ll-hydroxy analogues, and 10.11-dihydro-ll-oxodibenz[6,/][l,4]oxazepin, in which the two benzene rings are held in a noncoplanar orientation by the two-atom bridge, and subjected them to biological tests. Consequently, it was found that 2-(8-methyl-10.11-dihydro-ll-oxodibenz[i>,/]oxepin-2-yl)propionic acid (16b) and its thiepin analogue (16c) were highly active as o 16b, X = O c, X= S antiinflammatory, analgesic, and antipyretic agents. Based on these data, they have been selected for further study.Recently, the Nippon Chemiphar group has reported an analogous study in a patent5 independently of our work.6Chemistry. Dibenz[6,/]oxepinacetic acid derivatives (8-10) have been synthesized by the route shown in Scheme I. Ullmann reaction between 2-iodobenzoic acids 1 and ethyl hydroxybenzoates 2 gave the diphenyl ethers 3, which were reduced with lithium aluminum hydride to afford the diols 4. On chlorination, followed by reaction with sodium cyanide, 4 gave the bis(cyanomethyl) derivatives 6. Hydrolysis of 6 and subsequent cyclization with(1)

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.…”

Microwave‐Assisted Cross‐Coupling for the Construction of Diaryl Sulfides

“…Aryl sulfides and their oxidized forms, sulfones and sulfoxides, are common functional groups in pharmaceutical agents such as nonsteroidal anti-inflammatory agents, 1 HIV protease inhibitors and antiviral agents, 2 selective M 2 muscarinic receptor antagonists, 3 leukocyte function-associated antigen-1/intracellular molecule-1 interaction antagonists, 4 leukotriene B 4 antagonists, 5 histone deacetylase inhibitors, 6 fatty acid amide hydrolase inhibitors, 7 a 2 -adrenoceptor antagonists, 8 and gonadotropin-releasing hormone antagonists. 9 Most importantly, diaryl sulfides serve as useful starting materials for the construction of heterocycles containing sulfur atom and precursors leading to sulfones and sulfoxides.…”

Synthesis of dibenzo[b,f][1,4]oxazepin-11(10H)-one and pyrido[2,3-b][1,4]benzoxazepin-10(11H)-one compounds based on o-nitrochloro derivatives of benzene and pyridine

“…4 Intramolecular acylation of 1-isocyanato-2-phenoxybenzenes 3 gives dibenzo[b,f] [1,4]oxazepin-11(10H)-ones 7a in good yields. 17,22,23 Another less popular method involves the heating of xanthen-9-one oximes 4 with phosphorus pentachloride 17 or polyphosphoric acid. 24 This results in a dibenzoxazepine system via Beckmann rearrangement.…”