A series of 4(3H)-quinazolinones structurally related to 2-methyl-3-o-tolyl-4(3H)-quinazolinone (methaqualone, 3) were synthesized and evaluated for anticonvulsant activity. Preliminary screening of these compounds revealed that 2-[2-oxo-2-(4-pyridyl)ethyl]-3-aryl-4(3H)-quinazolinones 6l and 8i, 8k, and 8p-r having a single ortho substituent on the 3-aryl group had the most promising anticonvulsant activity. Compounds 6l and 8i possessing 3-o-tolyl and 3-o-chlorophenyl groups, respectively, showed good protection against MES- and scMet-induced seizures, combined with relatively low neurotoxicity after intraperitoneal administration in mice. They also exhibited low toxicity in tests for determining the mean hypnotic dose (HD50) and the median lethal dose (LD50). Although these compounds were markedly more potent as anticonvulsants when administered orally in mice and rats, they were also more neurotoxic. This neurotoxicity was particularly acute in oral tests with rats, which resulted in marginal protective indices. In drug differentiation tests, compound 6l was ineffective against seizures induced by bicuculline, picrotoxin, and strychnine, while 8i showed some protection against picrotoxin-induced seizures.

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Photostimulated reactions of 2,6-, 2,3-, 3,5-, and 2,5-dihalopyridines (la-e) with pinacolone potassium enolate (2) in liquid NH3 lead to facile replacement of both halogens via a modified SRN1 mechanism, which does not involve intermediate formation of monosubstitution products. The potassium salts of phenylacetonitrile (12a) and a-ethylphenylacetonitrile (12b) react with 2,6-dibromopyridine (la) under similar conditions to afford a mixture of mono-and disubstituted products via a related SRN1 process. 4,7-Dichloroquinoline ( 16) undergoes radical-chain displacement of chloride from C4 with enolate 2. 2,6-Dichloropyrazine (18) and 2,3-dichloropyrazine (20) also undergo monosubstitution with 2 and diisopropyl ketone potassium enolate ( 22), but these reactions appear to be mainly addition-elimination (SNAr) processes. Treatment of 3,6-dichloropyridazine ( 27) with 22 results in addition of 22 to C4 of the substrate. Photoassisted reaction of 2,4-dichloropyrimidine (31) with 12a leads to exclusive chloride displacement from C4 via the SRN1 mechanism.In a recent study1 2 of heteroaromatic SRN1 reactions,3 we found that 2,6-dibromopyridine (la) and 2,6-dichloropyridine (lb) reacted with pinacolone potassium enolate (2) under irradiation with near-ultraviolet light in liquid NH3 to afford disubstitution product 3a in excellent yield. la, X = Br (2,6) 3a (2,6) b, X = Cl (2,6) b (2,3) c, X = Cl (2,3) c (3,5) d, X = Cl (3,5) d (2,5) e, X= Br (2,5)

[Reaction: see text]. 2-iodobenzenesulfonamide (1a) underwent photostimulated S(RN)1 reactions in liquid NH3 with the potassium enolates derived from acetone, pinacolone, butanone, and 3-methyl-2-butanone to give fair to good yields of 2H-1,2-benzothiazine 1,1-dioxides 2. Reductive dehalogenation of 1a was found to predominate in photoinduced reactions of 1a with 3-pentanone, 2-methyl-3-pentanone, and 2,4-dimethyl-3-pentanone, the extent of reduction being proportional to the number of beta-hydrogen atoms present in the ketone enolate. Isotopic labeling studies with 2,4-dimethyl-3-pentanone-d14 (24) confirmed the major role of the beta-hydrogens in the reduction process. Reactions of 1a with cyclopentanone, cyclohexanone, and cyclooctanone enolates afforded new tricyclic benzothiazine derivatives 26-29. Attempts to extend the heteroannulation reaction to the preparation of 2H-1,2-benzothiazin-3(4H)-one 1,1-dioxides 3 (R = H, Ph) through reactions of 1a with tert-butyl acetate and ethyl phenylacetate enolates resulted only in hydrodehalogenation of 1a. However, oxazoline anion 30, a synthetic equivalent of ethyl phenylacetate, was successfully employed in an alternative S(RN)1-based synthesis of benzothiazine 3 (R = Ph).