Paper
Synthesis of 4H‐Imidazo[2,1‐c][1,4]benzoxazin‐4‐yl Acetic Acids and Esters as Possible COX‐2 Inhibitors.
Published Jul 11, 2006 · K. N. Jayaveera, S. Sailaja, P. Reddanna
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Abstract
Although, non-steroidal anti-inflammatory drugs (NSAIDS), have been used in the treatment of various inflammatory diseases, their usage is limited by the side effects produced by them, thereby necessitating the need for searching new molecular entities. A number of aryl and heteroaryl substituted acetic acids such as Diclofenac 1, Lumiracoxib 2, Lonazolac 3, Etodolac 4 have been commercialized as NSAIDS. Several imidazoazines have been reported to possess significant pharmacological activities. Otsuka et al. isolated a number of 1,4-benzoxazinone derivatives from the roots of Coix lachryma – jobi which have been used in treatment of neuralgia, rheumatism and inflammatory diseases. Furthermore, recently several 2-substituted benzoxazinones have been reported as smooth muscle relaxants, anticoagulant and antibacterial agents. In addition, a new series of benzoxazinones were reported useful in the treatment of type 2 diabetes which does not contain thiazolidenedione. In view of these observations and in continuation of our work on new benzoxazines, it was considered of interest to synthesize some new imidazobenzoxazinyl acetic acids and evaluate their COX-2 inhibitor activity. Methyl α-(3,4-dihydro-3-oxo-2H-1,4-benzoxazin2-yl)acetates 5 required as starting materials in the present work, were prepared by the reaction of substituted 2-aminophenols with maleic anhydride in refluxing methanol in the presence of triethylamine according to the procedure described earlier. Reaction of 5 with various ω-haloacetophenones in refluxing acetone in the presence of anhydrous potassium carbonate and tetrabutylammonium bromide as phase transfer catalyst gave the N-alkylated benzoxazinones 6 in excellent yields. H NMR spectra of 6 exhibited characteristic signals around δ 3.76-3.78 (CO2CH3), 2.98-3.06 (2 × dd, CH2CO2CH3), 5.0-5.03 (m, OCH) and 5.31-5.34(ABq, -NCH2-CO) apart from other aromatic protons. IR spectra of 6 exhibited characteristic ester, amide and ketone carbonyl in the region 1735, 1690 cm. Cyclocondensation of 6 in acetic acid in presence of ammonium acetate gave the targeted imidazobenzoxazinyl acetates 7 in good yields (IR 1737 cm). Hydrolysis of representative 7 in aqueous methanolic NaOH furnished the corresponding acetic acids 8 as colourless crystalline solids (Scheme I). Structures of compounds 7 were established based on their H NMR, IR, mass spectra and correct elemental analyses. In the H NMR spectra of 7, the ester group appeared as a singlet at δ 3.76, the methylene protons of ester group appeared as two sets of double doublets at δ 3.06 and 3.42 whereas OCH proton appeared as a double doublet at δ 5.74 apart from C1-imidazoproton (δ 7.4-7.5, singlet) and other aromatic protons.
New imidazobenzoxazinyl acetic acids show potential as COX-2 inhibitors, offering potential for new NSAIDs and other treatments.
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