New pyrimido[5,4-e]pyrrolo[1,2-c]pyrimidines were synthesized. A series of ylidene carbohydrazides 14a-i, and hydrazonate 15, were obtained from the prepared 3-carbohydrazide derivative 13. Pyrazole derivatives 12, 16a,b, 18, 19, 20, were also prepared through different reactions. The anti-inflammatory and analgesic activities of all new compounds were evaluated and most of them exerted comparable activity to indomethacin and celecoxib. Ulcer indexes for the most active compounds were calculated and most of them showed less ulcerogenic effect than the reference drugs. The most potent anti-inflammatory compound 12 showed an IC(50) of 6.00 μmol/kg and low ulcer index. COX-1/COX-2 activity ratio of compounds 12 and 16b showed almost equal inhibitory effect on both isoenzymes. 2D-QSAR studies revealed good predictive and statistically significant QSAR models.