SYNTHESIS AND ANTI-INFLAMMATORY ACTIVITY OF SOME FUSED PYRIMIDINES

Abstract

Seeking new anti-inflammatory agents and based on molecular modeling studies, design and synthesis of pyrimidoazepine and pyrimidopyrimidoazepine derivatives substituted in the polymethylene ring with different alicyclic secondary amines was performed. Thus, reacting 2-dicyanomethylidenoperhydroazepine 1 with sulphuryl chloride furnished the 6-chloro derivative 2.The oiminonitriles 3 were obtained via the reaction of 2 with isopropyl or phenyl isocyanate. Refluxing 3 with morpholine or piperidine afforded the 5-morpholino or piperidino 3-imino derivatives 4. Reduction of the latter compounds furnished the corresponding 3amino derivatives 5. Preparation of the 3-chloromethyl pyrimidoazepine derivatives 6 was achieved via the reaction of 5 with chloroacetyl chloride. Reacting 6 with thiourea and further decomposition of the methyl isothiourea salts gave the 3-thiomethyl derivatives 7. Preparation of thioethers 8 and 9 was done through the reaction of 7 with methyl iodide, chloroacetic acid or ethyl chloroacetate. Refluxing the 3-thiomethyl compounds 7 with acetyl or benzoyl chloride yielded the 3-thioester compounds 10. The uncyclized (4-chlorobutanamide) derivatives 11 were obtained through the reaction of the enaminonitriles 5 with chlorobutyryl chloride. Refluxing compounds 11 with alcoholic hydrochloric acid solution yielded the 3-chloropropyl pyrimidopyrimidoazepine derivatives 12.These tricycles when reacted with different primary or secondary amines yielded the tetracyclic ring system pyrrolopyrimidopyrimidoazepines 13. Reacting 5 with oxalyl chloride gave the 3-chlorocarbonyl derivatives, which were reacted without separation with different alcohols and amines affording the corresponding 3-carbamoylformate 14 and 1-N-substituted -2oxoacetamide 15, respectively. Intramolecular cyclization of these latter compounds yielded their tricyclic counterparts 16 and 17, respectively. Eighteen representative compounds were screened for their anti-inflammatory activity using diclofenac as reference drug. Also, molecular modelling was performed.