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)

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The synthesis and some pharmacological effects of cis- and trans-2-substituted 2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole derivatives are described. In these derivatives, the substituents of the 2, 5 and 8 position, together with the relative configuration of the 4a and 9b position, influenced the potency of the central nervous system activities. A cis-2-[3-(p-fluorobenzoyl)propyl] analogue (5k) of carbidine (1) possessed not only thymoleptic-like biological activity but had more potent neuroleptic activity than the parent drug.

A series of 3-phenyl-2-piperazinyl-5H-1-benzazepines and related compounds were synthesized and evaluated for potential neuroleptic activity. The preparation of these compounds was carried out by 2,3-dichlorination of 3-phenyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-ones with phosphorus pentachloride followed by amination and concurrent dehydrochlorination. Compounds having the 4-chloro or 4-fluoro substituent in the 3-phenyl group were found to possess the neuroleptic-like activity. Among them, 2-(4-methyl-1-piperazinyl)-3-(4-fluorophenyl)-5H-1-benzazepine dihydrochloride (23) was comparable to chlorpromazine in inhibiting exploratory activity, conditioned avoidance response, and self-stimulation response and more potent than chlorpromazine in antagonizing apomorphine-induced emesis. These neuroleptic effects may be based on an antidopaminergic property of the compound. In causing catalepsy or ptosis, however, 23 was weaker than chlorpromazine. Therefore, this ring system is of interest as a novel class of neuroleptics. Some compounds having the 7-chloro or 7-bromo substituent showed potent anticonvulsant effects against maximal seizures induced by electroshock or pentylenetetrazole.

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