Five-Membered Heterocycles Fused to Benzene

Though the therapeutic utility of aspiri n has been recognized for well over a century, this venerable drug was not classified as a nonsteroid antiinflammatory until recently. The first drug to be so classified was in fact, indomethacin (1), a very useful agent introduced 

Replacement of chlorine on the pendant benzoyl group by azide is apparently consistent with antiinflammatory activity. Acylation of indomethacin intermediate with p-nitrobenzoyl chloride leads to the corresponding amide (7). Saponification ( ) followed by reduction of the nitro group gives the amine 9. The diazonium salt (10) obtained on treatment with nitrous acid is then reacted with sodium azide there is thus obtained zidomethacin (11). 

Serotonin (12) is a ubiquitous endogenous compound that has a multitude of biological activities. For 

Two closely related indoles fused to an additional saturated ring have been described as CNS agents. The first of these is obtained in straightforward manner by Fischer indole condensation of functionalized cyclohexanone 0 with phenyl hydrazine (19). The product, cyclindole (21) shows antidepressant activity. The fluorinated analogue flucindole (26) can be prepared by the same scheme. An alternate route starting from a somewhat more readily available intermediate involves as the first step Fischer condensation of substituted phenyl hydrazine with 4-hydroxycyclohexanone (23). The resulting alcohol (24) is then converted to its tosylate (25). Displacement by means of dimethyl amine leads to the antipsychotic agent flucindole (26).  

Changing the functionality on the alicyclic ring from an amine to a carboxylic acid leads to a compound that shows antiallergic activity, acting possibly by means of inhibition of the release of allergic mediators. Thus, condensation of acylated indole with cyclohexanone carboxylic acid affords directly oxarbazole (29).  

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FIVE-MEMBERED HETEROCYCLES FUSED TO BENZENE intermediate 52 affords domperidone (66), a very... 

Chapter 10. Five-Membered Heterocycles Fused to Benzene 165... 

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