SKF-105809

[¹⁴C]Formaldehyde was used in a nucleophile-assisted iminium ion cyclization with N-benzyl-3-butynylamine to provide N-benzyl-4-iodo-1,2,5,6-tetrahydro[2,6-¹14C₂]pyridine.Palladium-catalyzed coupling of this vinyl iodide with the organozinc derivative I gave the corresponding 4-arylated tetrahydropyridine.Treatment of this compound at elevated temperatures with Pd/Al₂O₃ in nitrobenzene solution caused hydrogenolysis of the benzyl group and aromatization, generating 1-benzyl-4-iodo-1,2,4,5-tetrahydro[2,6-¹⁴C₂]pyrimidine (II) in good overall radiochem. yield from [¹⁴C]formaldehyde.In high yields, II was converted via the methylsulfide [¹⁴C]SK&F 105561 to the methylsulfinyl compound [¹⁴C]SK&F 105809.It is proposed that, during the iminium ion cyclization, randomization of label between the 2- and 6-positions of the tetrahydropyridine ring occurs as the result of rapid equilibration between alkynyl and allenyl iminium ions, prior to cyclization.

A series of 1-alkyl- or -aryl-4-aryl-5-pyridinylimidazoles (A) were prepared and tested for their ability to bind to a recently discovered protein kinase termed CSBP and to inhibit lipopolysaccharide (LPS)-stimulated TNF production in mice. The kinase, CSBP, appears to be involved in a signaling cascade initiated by a number of inflammatory stimuli and leading to the biosynthesis of the inflammatory cytokines IL-1 and TNF. Two related imidazole classes (B and C) had previously been reported to bind to CSBP and to inhibit LPS-stimulated human monocyte IL-1 and TNF production. The members of the earlier series exhibited varying degrees of potency as inhibitors of the enzymes of arachidonic acid metabolism, PGHS-1 and 5-LO. Several of the more potent CSBP ligands and TNF biosynthesis inhibitors among the present series of N-1-alkylated imidazoles (A) were tested as inhibitors of PGHS-1 and 5-LO and were found to be weak to inactive as inhibitors of these enzymes. One of the compounds, 9 (SB 210313) which lacked measureable activity as an inhibitor of the enzymes of arachidonate metabolism, and had good potency in the binding and in vivo TNF inhibition assays, was tested for antiarthritic activity in the AA rat model of arthritis. Compound 9 significantly reduced edema and increased bone mineral density in this model.