Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used as analgesic or antipyretic agents for the clinical treatment of inflammatory diseases such as arthritis, lumbago and rheumatism. These NSAIDs (e.g., ibuprofen, aspirin, and indomethacin) exhibit an inhibitory action on the cyclooxygenase (COX) that catalyzes the biosynthesis of prostaglandins and thromboxane from arachidonic acid. There are two isoforms of the membrane-bound COXs, COX-1 expressed constitutively, and COX-2 induced by stimuli of cytokines, mitogens or hormones. The constitutive COX-1 has also been reported to be induced by the stimulus of an angiogenic cytokine vascular endothelial growth factor (VEGF) 1) or by shear stress in vascular endothelial cells.
2)Recently, several COX-2 selective inhibitors such as meloxicam 3) and celecoxib 4) have been developed as NSAIDs because these substances show little gastropathy, a typical side effect of NSAIDs.We have previously reported the synthesis of a number of novel oximes and their derivatives, with several compounds showing anti-inflammatory activities in carrageenan-induced rat foot-pad swelling assay and histamine-induced rat vascular permeability assay. 5,6) We also reported the COX-1 inhibitory effect of the 4Ј-piperidinoacetophenone oxime (POx), 4Ј-morpholinoacetophenone oxime (M-Ox) and their Oacetyl derivatives (P-Ox-Ac or M-Ox-Ac).
6)The metabolic products of arachidonic acid catalyzed by 5-lipoxygenase (LOX) are leukotrienes (LTs) which function as important mediators in many types of inflammation reaction including allergy, asthma, and arthritis. For instance, LTC 4 and LTD 4 , well-known components of the slow-reacting substance of anaphylaxis (SRS-A), induce severe bronchoconstriction and increase vascular permeability, and LTB 4 causes leukocyte chemotaxis.7-10) Therefore, the development of dual inhibitors of COX and 5-LOX should be promising for the treatment of several inflammatory and allergy symptoms. Many investigations have shown that the enzymes catalyzing the arachidonic acid cascade (COX, 5-LOX, and/or 12-LOX) were inhibited by various hydroxamic acids and their derivatives. [11][12][13][14] Kramer et al. have reported a dual inhibitory action to COX and 5-LOX by hydroxylamine analogs of 2, 6 di-tert-butylphenols.
15)The purpose of the present study is to search more effective anti-inflammatory or anti-allergic drugs such as COX-2 selective and/or 5-LOX inhibitors. Hydroxylamine derivatives, which are substances reduced from anti-inflammatory oximes, are potential candidates for both anti-inflammatory and anti-allergic agents. Thus, anti-inflammatory oximes (POx and M-Ox) were reduced to the corresponding hydroxylamines; (1-hydroxylamino-1-(4Ј-piperidinophenyl) ethane, P-HA, and 1-hydroxylamino-1-(4Ј-morpholinophenyl) ethane, M-HA). 16,17) We also prepared N,O-diacetyl hydroxylamine derivatives, i.e., 1-(N,O-diacetyl hydroxylamino)-1-(4Ј-piperidinophenyl) ethane (P-HA-Ac) and 1-(N,O-diacetyl hydroxylamino)-1-(4Ј-morpholinophenyl) ethane (M-HA-Ac), as O-acetyl oximes ...
