Novel pyrrolo[2,3-d]pyrimidines and pyrrolo[2,3-b]pyridines: design, synthesis, and in vivo TNF-α inhibitory activity

Novel pyrrolo[2,3-d]pyrimidines 5a–j, 6a–j and pyrrolo[2,3-b]pyridines 7a–h; incorporating the common vicinal diaryl motif of tumor necrosis factor-α (TNF-α) inhibitors, were synthesized starting from 2-amino-pyrrole-3-carbonitriles 1a–h. The structures of synthesized compounds were elucidated by spectral data (IR, NMR, and MS) and elemental analyses. Representative compounds were evaluated for their ability to inhibit lipopolysaccharide-induced TNF-α production in vivo in rat at 25 mg/kg p.o. Structure activity relationships are described. The pyrrolo[2,3-d]pyrimidines displayed better inhibitory activity than the pyrrolo[2,3-b]pyridines. The most potent among the biologically tested compounds was the pyrrolopyrimidine 5h (N-(4-ethoxyphenyl)-2-(4-oxo-6-phenyl-7-(pyridine-4-yl)-4H-pyrrolo[2,3-d]pyrimidin-3(7H)-yl)acetamide),showing TNF-α inhibitory activity (96 %) comparable to that of dexamethasone (91 %).