|Title:|| GABA and L-glutamic acid analogs for antiseizure treatment|
|Abstract:||A compound of the formula ##STR1## wherein R.sub.1 is a straight or branched alkyl group having from 1 to 6 carbon atoms, phenyl, or cycloalkyl having from 3 to 6 carbon atoms; R.sub.2 is hydrogen or methyl; and R.sub.3 is hydrogen, methyl or carboxyl; which is useful in the treatment of seizure disorders. Processes are disclosed for the preparation of the compound. Intermediates prepared during the synthesis of the compound are also disclosed.|
|Inventor(s):|| Silverman; Richard B. (Morton Grove, IL), Andruszkiewicz; Ryszard (Sopot, PL), Yuen; Po-Wai (Ann Arbor, MI), Sobieray; Denis M. (Holland, MI), Franklin; Lloyd C. (Hamilton, MI), Schwindt; Mark A. (Holland, MI) |
|Assignee:|| Northwestern University (Evanston, IL) Warner-Lambert Company (Ann Arbor, MI) |
|Filing Date:||Apr 12, 1995|
|Claims:||1. A process for preparing an S-isomer of a compound of the formula |
wherein R.sub.1 is a straight or branched alkyl of from 1 to 6 carbon atoms, phenyl, or cycloalkyl having from 3 to 6 carbon atoms; R.sub.2 is hydrogen, methyl, or carboxyl; individual enantiomers thereof; and pharmaceutically acceptable salts thereof; with the proviso that when R.sub.2 is hydrogen, R.sub.1 is other than methyl; said process comprising the steps of forming an acid chloride of an acid of the formula HOC(.dbd.O)CH(R.sub.1)(R.sub.2), the corresponding acid chloride having the formula ClC(.dbd.O)CH(R.sub.1)(R.sub.2), adding the acid chloride to a solution of (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone and n-butyllithium at -78.degree. C. under argon to produce an oxazolidinone derivative of the formula ##STR9## treating the oxazolidinone (II) with benzyl .alpha.-bromoacetate to produce an ester ##STR10## treating the ester (III) with hydrogen peroxide and lithium oxide followed by treatment with sodium metabisulfite to produce a compound of the formula ##STR11## treating the compound (IV) with borane dimethyl sulfide complex to produce the compound ##STR12## forming the corresponding tosylate from the compound (V), forming an azide from the corresponding tosoylate and reducing the azide to the amine of the formula ##STR13## wherein R.sub.1 and R.sub.2 have the meanings defined for formula (I), Ph is phenyl, Me is methyl, and Bn is benzyl.