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A series of novel isoxazolo analogues 11 of the dibenzazonine alkaloid protostephanine (1) has been prepared. A new regiospecific and potentially general aza macrocyclic ring forming process was developed where the first step was the 1,3-dipolar cycloaddition of benzonitrile oxide to the readily available examine 6. The product, isoxazoline 9a, under solvolytic conditions that normally convert monocyclic 5-aminoisoxazolines to isoxazoles failed to give the desired aza macrocycle 14. Alternate sequences involving quaternization of 9a with methyl iodide followed by either solvolysis in polar solvents or base-induced elimination were successful and gave the target structure 11a in excellent overall yield. X-ray crystallographic analysis of the quaternized intermediate 10a corroborated the assignment of structure and defined the crystal-state conformation

A series of analogues of the 5-lipoxygenase inhibitor 1-phenyl-3-pyrazolidinone (phenidone, 1a) has been prepared via two complementary new synthetic methods. The reaction of various electgrophiles with the dianion of 1a or with an N-silylpyrazolidinone anion gave the desired 4-substituted pyrazolidinones (Scheme I and II). A new procedure was developed for the resolution of 4-substitued pyrazolidinones (Scheme V). A regression study on 21 compounds in this series showed a correlation of increased inhibitor potency (pIC 50 ) with increased compound lipophilicity (log P) and with an N-phenyl electronic effect as measured by the 13 C NMR chemical shift parameter CNMR1' (R 2 =0.79). The most potent 5-lipoxygenase inhibitor in this series was 4-(ethylthio)-1-phenyl-3-pyrazolidinone (1n) with an IC 50 of 60 nM. Another member of this series, 4-(2-methoxyethyl)-1-phenyl-3-pyrazolidinone (1f, IC 50 =0.48 μM), although less potent than 1n, was betgter tolerated in the whole animal relative to phenidone (1a) and also displayed good oral activity in two models of 5-lipoxygenase inhibition. On the basis of a structure-activity relationship study, a mechanism for the inhibition of 5-lipoxygenase by this class of inhibitors was proposed

Reaction of benzamides and N-substituted benzamides with appropriate o-alkenyl and -alkynyl side-chains and (chlorocarbonyl)phenyl ketene gives transient anhydro-1,3-oxazinium hydroxides which readily undergo intramolecular 1,4-dipolar cycloaddition; loss of CO2 from these 1:1-cycloadducts, isolable with N-substituted systems and alkenyl side-chains, gives chromeno[4,3-b]pyridin-2-ones.

Thermal rearrangement of the ω-azidobutyl-p-benzoquinone (I) gives the bicyclic reaction products (III) and (IV) via the fused triazole (II).

The Ni(II) complex of 1,1-diethyl-3-(2-chlorobenzoyl) thiourea (L) was synthesized and its crystal structure determined by X-ray crystallography. NiL2 is monoclinic, space group P2l/c(#14), with a=8.229, b=39.277, c=8.485 A, β=96.8°. The Ni(II) is coordinated in a planar fashion by two S and two O atoms in a cis arrangement. The NiS and NiO bond lengths are approximately 2.14 and 1.84 A respectively, with the two bonds of each type differing only slightly. The SNiS and O NiO bond angles are 87.6° and 83.0° respectively, but with considerable expansion of the ligand bond angles in the chelate ring. The crystal structure of the free ligand was also determined to compare free and complex bond lengths and angles. It is orthorhombic, space group Pbca(#61), with a=9.856, b=10.128 and c= 26.848 A.