Synthesis of Pent-aza Phenoxazines: A New Group of Anti-inflammatory Heterocycles. Their Effect and Other Analgesics on Pain

Abstract

The synthesis of novel 1-amino-7-methyl-2,4,6,8,9-pent-azaphenoxazine (13) and 2-aldehyde-7-methyl-4-phenyl-3,4,6,8,9-pent-aza phenoxazine (17) is reported. The pent-aza compound (13) was prepared by suspending acetamidine hydrochloride (8) in ethanol and treated with anhydrous hydrazine at 0°C to afford a pink solid compound acetamidrazone (9). Treatment of compound (9) with oxalyl chloride and heated at reflux, yielded 6-methyl-1,4,5-triazine-2,3-dione (10). This compound when reacted with 4,5-diamino-6-hydroxypyrimidine (12) in ethanol, provided a solid 1-amino-7-methyl-2,4,6,8,9- pent-azaphenoxazin (13) in excellent yield. The 2-aldehyde-7-methyl-4-phenyl-3,4,6,8,9- pent-aza phenoxazine (17) was obtained utilizing 3-aldehyde-5-amino-6-hydrxy-1-phenylpyridazine (16) which was produced by refluxing a mixture of furfural and phenylhydrazine in toluene. Treatment of compound (16) with 6-methyl-1,4,5-triazine-2,3.dione (10) in ethanol  gave the pent-aza-phenoxazine (17) in good yield. These compounds were confirmed by IR,1H NMR,13C NMR spectroscopy and MS spectrometry.  The two novel products (13) and (17) were investigated for analgesic actions. The result compared favorably with three known analgesics: Paracetamol, Aspirin and Alabukun (a local analgesic). The doses of 0.125 to 0.150 g/kg injected into adult rabbits intraperetoneally lead to reduction of pain threshold. The result of the anti-inflammatory screening data revealed the dose and time dependant effect of these compounds in the carrageenan induced paw oedema. At time of 120mins, there was complete inhibition of oedema by 95.36% and 97.51% from the compounds 13 and 17 respectively, while the standard drug Zerodol (Aceclofenac) showed inhibition by 57.79%. The ability of these two compounds to antagonize carrageenan-induced oedema was correlated with anti-inflammatory potential.