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An eight membered cyclic sulfone 1,4-dihydropyridine, RWJ 22726, 1, with remarkable cardiovascular activity was prepared by isomerization of an exocyclic double bond isomer using various reaction conditions. Under acidic and thermal isomerization conditions, an equilibrium mixture of products in an optimum ratio of 1:3.5 in favor of the desired 1,4-dihydropyridine was obtained. Equilibration using basic reaction conditions could not be effected. Complete conversion to the 1,4-dihydropyridine during the isomerization reaction was ultimately achieved by selective precipitation of the hydrochloride salt of the desired isomer.

A series of novel cyclic sulfone dihydropyridines with five to nine membered rings have been synthesized. Anomalous intermediates isolated from the Hantzch condensation were found to vary depending on the sulfone ring size and aromatic substitution. Tin tetrachloride has been shown to be a superior Lewis acid catalyst for ethyl diazoacetate ring expansion of the requesite β-keto cyclic sulfone precursors.

An eight membered cyclic sulfone 1,4-dihydropyridine, RWJ 22726, 1, with remarkable cardiovascular activity was prepared by isomerization of an exocyclic double bond isomer using various reaction conditions. Under acidic and thermal isomerization conditions, an equilibrium mixture of products in an optimum ratio of 1:3.5 in favor of the desired 1,4-dihydropyridine was obtained. Equilibration using basic reaction conditions could not be effected. Complete conversion to the 1,4-dihydropyridine during the isomerization reaction was ultimately achieved by selective precipitation of the hydrochloride salt of the desired isomer.

A series of novel cyclic sulfone dihydropyridines with five to nine membered rings have been synthesized. Anomalous intermediates isolated from the Hantzch condensation were found to vary depending on the sulfone ring size and aromatic substitution. Tin tetrachloride has been shown to be a superior Lewis acid catalyst for ethyl diazoacetate ring expansion of the requesite β-keto cyclic sulfone precursors.

Methods for the synthesis of 3-[2-aminoethyl]-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridin-5-ones and 3-[2-aminopropyl]-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridin-5-ones are described. The scope and limitations of the various methods are discussed.

Allergic mediator release inhibitors such as cromolyn sodium have been reported to act by blockade of antigen-induced uptake of extracellular calcium. They also promote the formation of a phosphoprotein during inhibition of mediator release. Since alkaline phosphatase is associated with calcium uptake mechanisms in certain tissues as well as with phosphoprotein phosphatase action, inhibition studies with a series of mediator release inhibitors were done. The mediator release inhibitors, cromolyn sodium, doxantrazole, AA-344, M & B-22948, ICI-74917, and W-13560, were shown to uncompetitively inhibit human leucocyte alkaline phosphatase. The most potent inhibitor, W13560, had a K i of 7.9 × 10 −6 M. Cromolyn sodium was the least effective inhibitor of the series while ICI-74917 and W-13560 were the most potent. Doxantrazole, AA-344, and M & B-22948 were intermediate in their inhibitory activities against alkaline phosphatase. Since uncompetitive inhibitors are known to inhibit, activate, or have no effect on an enzyme, depending upon conditions, the unpredictable clinical activity observed with this class of agent may be explained by their incompetitive nature of inhibition.

Eighteen known nonsteroidal antiinflammatory drugs (NSAID) were tested for their action against soybean lipoxygenase (E.C.1.13.11.12) using linoleic acid as substrate. It was found that the best inhibitors of lipoxygenase were naproxen, BW 755C, indomethacin and isoxicam. Drugs with intermediate potency were meclofenamic acid, phenyl-butazone and benoxaprofen. Other drugs such as ibuprofen and zomepirac were only weakly active in the test.

Synthesis of 1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridin-5-ones via a Pechmann condensation of 3-carbethoxy-1-methyl-4-piperidone with various phenols is described. The limitations of this method are discussed. Synthesis of the parent ring system 3a via reduction of 1,2,3,4-tetrahydro-3-(phenylmethyl)-8-[(1-phenyl-1H-tetrazol-5-yl)oxy]-5H-[1]benzopyrano[3,4-c]pyridin-5-one (5) is also described.

A series of 8-amino-9-substituted guanines was synthesized and their activity evaluated against human purine nucleoside phosphorylase (PNP). All compounds were found to be potent inhibitors of human PNP (IC50s: 0.17-126 microM). They were also selectively cytotoxic to MOLT-4 lymphoblasts in the presence of a nontoxic amount (10 microM) of the PNP substrate, 2'-deoxyguanosine (GdR). The most potent of these analogs, 2,8-diamino-1,9-dihydro-9-(2-thienylmethyl)-6H-purin-6-one (8-amino-9-(2-thienylmethyl)guanine; PD 119,229) has an IC50 of 0.17 microM (Ki = 0.067 microM), significantly more potent than the known standard, 8-aminoguanosine (IC50 = 1.40 microM). Thus it represents the most potent PNP inhibitor known to date when tested without limiting the concentration of inorganic phosphate.

Eight known antipsoriatic drugs of diverse structures were tested on the basis of their structural similarity with arachidonic acid and known inhibitors of lipoxygenase. A correlation was observed between their antipsoriatic activity and lipoxygenase inhibition suggesting that a common underlying mechanism of action might be involved.