SYNTHESIS OF NEW 1,2,4-TRIAZOLOQUINAZOLINE DERIVATIVES AS CNS MODULATORS

Abstract

A series of 1,2,4-triazolo4,3-cJquinazoline-3-thiol was synthesized by reacting isatoic anhydrides (Ia, Ib) with thiosemicarbazide to yield the appropriate 2-acylhydrazinocarbothioamides (IIab ,IIb) which were cyclized to afford 5-(2- substituted aminophenyl)-1,2,4-triazol-3-thiols (IIIab ,IIIb) using sodium hydroxide. The triazol derivatives (IIIab,IIIb) were cyclized to the new 1,2,4-riazolo4,3-cquinazoline-3-thiol (IV) upon condensation with aromatic aldehydes. Whereas, cyclization of (IIIab,IIIb) with formaldehyde unexpectedly afforded 3-hydroxymethyl-1,2,4-triazolo1,5-cquinazolin-2-thione (VIa, VIb). The last reaction is the role-play to the formation of a series of 1,2,4-triazolo 1,5-cquinazoline-2-thiol (VLc, VId, VII) upon boiling of the appropriate 1,2,4-triazolo4,3-cquinazoline-3-thiol in ethanol with acidified formaldehyde. Also, alkylation of 3-thiol derivatives (IV) with the appropriate alkyl halide in alkaline medium afforded a new series of 3-alkyl (or 3-aralkyl) thio-1,2,4-triazolo4,3-cquinazolines (Va-b). Otherwise, alkylation of 5-(2-methylaminophenyl)-1,2,4-triazol-3-thiol (IIIa) was affected firstly and followed by condensation with either carbon disulfide or hydroxybenzaldehyde to produce 3-alkylthio-6- methyl-1,2,4-triazolo(4,3-cquinazolin-5(6H)-thione (IX) or 3-alkylthio-5-(hydroxyphenyl)-6-methyl-1,2,4-triazolo4,3- c]quinazoline (V1-1) respectively. Oxo-desulfuration was the key-procedure for preparation of 3-hydroxy-6-methyl-5-(4- nitrophenyl)-1,2,4-triazolo4,3-cquinazoline (X) from its thione analogue. The new triazoloquinazoline derivatives were subjected to preliminary pharmacological screening, where compounds (VIf, Vb, VIa, VIb, VId, X) produced a moderate to high CNS stimulant effect when tested on mice. Furthermore, compound (VIa) was tested by recording the electroencephalographic changes induced by its intravenous injection in conscious rabbits which gave noticeable results.