79. Thiohydantoins. Part III. The N- and S-methyl derivatives of 5 : 5-disubstituted hydantoins and their mono- and di-thioanalogues

Carrington, H. C.; Waring, Worden

doi:10.1039/jr9500000354

Cited by 36 publications

(16 citation statements)

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“…Although it is tempting to speculate that X might be 1 -methylphenytoin (1 -MP), it must be emphasized that the present data do not offer any clues about the identity of X. We have attempted to synthesize 1-MP according to Cattelain and Chabrier (9), but the product obtained was identified to be 3 MP instead, confirming the previous findings (10). Alternatively, X could be the hydroxyl ated metabolite of 1,3-DMP.…”

Section: Discussionmentioning

confidence: 56%

N-Demethylation of Methyl and Dimethyl Derivatives of Phenytoin and Their Anticonvulsant Activities in Mice

Wong

Tan

Lee

1988

Japanese Journal of Pharmacology

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Abstract-Anticonvulsant activities of 3-methylphenytoin (3-MP) and 1 ,3 dimethylphenytoin (1,3-DMP) were observed to peak 3 hr after i .p. administration of the drugs dissolved in dimethylsulphoxide (DMSO), while maximal activity was obtained within 15 min with phenytoin. HPLC was employed to monitor the plasma concentrations of all three compounds at various time intervals after injecting 3-MP or 1,3-DMP. In both cases, phenytoin appeared in the plasma, gradually reaching 14-15 /ag/ml in 3 hr. The time course of increase in plasma phenytoin levels correlated with that of anticonvulsant activities. It was also found that 1 ,3 DMP gave rise to a major unidentified metabolite as well as 3-MP and phenytoin . This unidentified metabolite eluted only half a minute in front of 3-MP in the HPLC . Mice injected with high doses of 3-MP (100 mg/kg) in DMSO exhibited severe epileptiform activities. Phenobarbital, diazepam and clonazepam were found to protect against such seizures, but not phenytoin, carbamazepine and valproic acid. This shows that 3-MP is at least a pro-convulsant, taking into account that its effects might have been enhanced by DMSO. Unlike phenytoin, 3-MP lacked the ability to inhibit synaptosomal uptakes of both glutamate and GABA. This difference may be related to the fact that phenytoin, but not 3-MP, possesses potent anticonvulsant activity.Phenytoin (5,5-diphenylhydantoin) is a widely used drug in the treatment of most forms of epilepsy. In laboratory animals, its anticonvulsant activity is characterized by the effectiveness against maximal electroshock seizure (MES) but not pentylenetetrazole induced seizure. The ED50 is approx. 8 mg/kg in mice (1, 2). In our hands, the ED50 is 11 mg/kg (P.T.-H. Wong and S.-F. Tan, un published). Vida et al. (3) reported that two methyl derivatives of phenytoin, 3-methyl phenytoin (3-MP) and 1,3-dimethylpheny toin (1,3-DMP), are effective against MES in mice with ED50 values of about 5 and 50 mg/kg, respectively. Peak activities for 3-MP, 1,3-DMP and phenytoin were obtained at 2-3 hr post-administration, probably because the drugs were administered by the oral route as suspensions in 10% aqueous acacia. It is well known that mephenytoin (3-methyl-5 ethyl 5-phenylhydantoin), a phenytoin ana logue with clinical efficacy, is N-demethylated to an active metabolite 5-ethyl-5-phenyl hydantoin (4). This means that there is a distinct possibility of phenytoin being formed from its methyl derivatives, particularly when there is a considerable time lapse of 2-3 hr between drug administration and the meas urement of anticonvulsant activities. By using a suitable vehicle and route of admin istration to ensure rapid absorption and penetration into the brain, we reevaluated the actions of these phenytoin analogues. Materials and MethodsChemical synthesis: 3-MP was prepared by adding with continuous stirring 2 ml of NaOH (10%) followed by 1 ml of dimethyl sulphate to 10 ml of phenytoin sodium (0.2 g/ml). After standing for 30 min at room temp., the mixture was cooled in an ice ...

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Section: Discussionmentioning

confidence: 56%

N-Demethylation of Methyl and Dimethyl Derivatives of Phenytoin and Their Anticonvulsant Activities in Mice

Wong

Tan

Lee

1988

Japanese Journal of Pharmacology

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“…In fact, with an excess of diazomethane both aand P-compounds formed a dimethyl derivative, and with one mole of diazomethane both formed a monomethyl derivative which could be expected to be the 3'-derivative (19); this was confirmed by the pK, values of the compounds (8). The a-and P-isomers proved to be essentially identical in acid strength although one has its ionizing group in an axial position and the other in an equatorial position (cf.…”

Section: -Tert-butylcyclohexane-1-mentioning

confidence: 99%

Stereochemistry of the Bucherer–Bergs and Strecker Reactions of 4-tert-Butylcyclohexanone

Edward¹,

Jitrangsri²

1975

Can. J. Chem.

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The spirohydantoin (α-isomer) obtained from 4-tert-butylcyclohexanone by the Bucherer–Bergs reaction has been shown by n.m.r., u.v., and considerations of steric hindrance to have the tert-butyl group and 1′-nitrogen atom cis; the β isomer obtained via the Strecker reaction, or via modified Bucherer–Bergs reactions employing carbon disulfide or carbon oxysulfide, has these groups trans. The differing stereochemical courses of the various reactions can be explained by a detailed consideration of their mechanisms.

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“…We found the amino-nitrile 2 (R = Ph) unusually resistant to acid hydrolysis, perhaps because of the presence of the large phenyl group gauche to the axial nitrile, and so for convenience chose as our "Strecker" product the 2,4-dithiohydantoin 6 (R= Ph), produced by the modified reaction using CS,. This reaction went in very poor yield (another indication of hindrance), and the dithiohydantoin 6 (R = Ph) was more readily available by preparing first the monothiohydantoin 5 (R = Ph) by the COS modification of the Bucherer-Bergs reaction (8) (a reaction known to go well with hindered ketones such as adamantanone (13)), followed by sulfuration of the monothiohydantoin to the dithiohydantoin by phosphorus pentasulfide (14). The corresponding 2,4-dithiohydantoin 7 (R = Ph) of the ci-series was prepared by sulfuration of the normal Bucherer-Bergs product 4 (R = Ph).…”

Section: Resultsmentioning

confidence: 99%

Stereochemistry of the conventional and modified Bucherer–Bergs reactions of 2-substituted cyclohexanones

Sacripante¹,

Edward²

1982

Can. J. Chem.

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The configurations of the spiro-hydantoins produced from 2-methyl- and 2-phenylcyclohexanone, 2,6-dimethylcyclohexanone, and dl-menthone by either the conventional Bucherer–Bergs (B•–B•) reaction, or a variant employing COS or CS2 in place of CO2, have been established by 13C nmr. In all cases the conventional B•–B• reaction gave the hydantoin having the 4′-carbonyl group equatorial, and the COS or CS2 variant, the mono- or dithiohydantoin having the 4′-thiocarbonyl group, axial.

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79. Thiohydantoins. Part III. The N- and S-methyl derivatives of 5 : 5-disubstituted hydantoins and their mono- and di-thioanalogues

Cited by 36 publications

References 0 publications

N-Demethylation of Methyl and Dimethyl Derivatives of Phenytoin and Their Anticonvulsant Activities in Mice

N-Demethylation of Methyl and Dimethyl Derivatives of Phenytoin and Their Anticonvulsant Activities in Mice

Stereochemistry of the Bucherer–Bergs and Strecker Reactions of 4-tert-Butylcyclohexanone

Stereochemistry of the conventional and modified Bucherer–Bergs reactions of 2-substituted cyclohexanones

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