Synthesis and anticonvulsant activity of enaminones. 4. Investigations on isoxazole derivatives.

Due to the exceptional anticonvulsant activity displayed by substituted aniline enaminones, related pyridine derivatives and phenothiazines synthesised in our laboratories, the further investigation of various aromatic heterocycles was undertaken. Condensation of cyclic 1,3-diketo esters with 3-, and 5-aminoisoxazole derivatives led to a series of potent anti-maximal electroshock (MES) analogues, three of which occurred in the 3-amino series: ethyl ester (10), orally (po) active in rats [ED(50) 68.9 mg kg(-1), TD(50) > 500 mg kg(-1), protective index (PI = TD(50)/ED(50)) > 49.6]; methyl ester (9), ED(50) 68.9 mg kg(-1) intraperitoneally (ip) in mice, TD(50) > 500 mg kg(-1), PI > 7.3, and tert-butyl ester (8), ED(50) 28.1 mg kg(-1) po in rats, TD(50) > 500 mg kg(-1), PI > 17.8. Sodium channel binding studies, as well as evaluations against pentylenetetrazol, bicuculline, and picrotoxin on isoxazole 10 were all negative, leading to an unknown mechanism of action. X-ray diffraction patterns of a representative of the 3-amino series (isoxazoles 6-11) unequivocally display the existence of intramolecular hydrogen bonding of the nitrogen to the vinylic proton in the cyclohexene ring, providing a pseudo three ring structure which was also shown previously with the vinylic benzamides. Physicochemical-permeability across the BBB suggested an efflux mechanism for the previously synthesised aniline enaminones, but not with isoxazole 10.

Reactions of (Triphenylsilyl)ethylene Oxide with Grignard Reagents (and with MgBr(2)). A Reinvestigation.

Reactions of (triphenylsilyl)ethylene oxide (1) with simple Grignard reagents such as EtMgBr and PhMgBr have been reported to yield crystalline hydroxysilanes assigned as the alpha-hydroxy silanes expected from beta opening of the epoxide. Reinvestigation of these reactions showed that the hydroxysilanes were the beta-hydroxy silanes 4 and 7 expected from a rearrangement-trapping sequence; a bromohydrin, assigned as the alpha-bromo-beta-hydroxy silane 9 from alpha opening, and (triphenylsilyl)acetaldehyde (8) were also formed.

The synthesis of heterocyclic compounds of pharmaceutical interest from conjugated acetylenic and allenic nitriles

The reaction of hydroxyacetylenic nitriles with 2-aminoethanethiol gives 3-(2-aminoethylthio)-4-hydroxy-alkyl-2-enenitriles. These do not cyclise directly to a furan but isomerise directly to the corresponding N-adducts which then cyclise to give 5-amino-3-(2-thioethylamino)-2,2-dialkyl-2,3-dihydrofurans in > 90 percent yield. After protecting the hydroxyl function of a 3-(2-aminoethylthio)-4-hydroxyalkyl-2-enenitrile as a tetrahydropyranyl derivative, this S-adduct isomerised to the corresponding N-adduct on keeping. Three new 5,6-dihydro-3H-furo [3,4-b]-1,4-thiazines were prepared from the 5-(1-alkyl-1-tetrahydropyranyl-oxyalkyl)-6-cyano-2,3-dihydro-4H-1,4-thiazines by hydrolysis to the corresponding 5-(1-hydroxyalkyl)-6-cyano-2,3-dihydro-1,4-thiazines followed by base catalysed cyclisation. The addition of half molar amounts of a-phenylethylamine to two allenic nitriles resulted in the isolation of recovered allenic nitrile with low optical purity. In both cases the absolute configuration of the recovered allene was related to that of the resolving agent(Summary)