ABSTRACT
The discovery of a novel series of CXCR3 antagonists is described. Starting from an HTS positive, iterative optimization gave potent compounds (IC(50) 15 nM in a chemotaxis assay). The strategy employed to improve the metabolic stability of these derivatives is described.
Subject(s)
Chemotaxis/drug effects , Receptors, CXCR3/antagonists & inhibitors , Animals , Cell Line , Humans , Inhibitory Concentration 50 , Mice , Microsomes , Rats , Structure-Activity Relationship , T-Lymphocytes/physiologyABSTRACT
Benzalaminoacetals (1), upon refluxing with trifluoroacetic acid, lead to 2-benzylpyrazines, rather than the expected isoquinolines. This unusual reaction represents another useful way to prepare a variety of 2-benzylpyrazines from the corresponding benzaldehydes.
Subject(s)
Acetals/chemistry , Benzene/chemistry , Pyrazines/chemical synthesis , Trifluoroacetic Acid/chemistry , Molecular Structure , Pyrazines/chemistryABSTRACT
A facile synthesis of alpha,beta-unsaturated carboxylic acids from gem-dibromomethylarenes is described. gem-Dibromomethylarenes are employed for the first time in the Knoevenagel-Doebner reaction as aldehyde equivalents for the efficient synthesis of alpha,beta-unsaturated carboxylic acids.
Subject(s)
Aldehydes/chemistry , Benzene Derivatives/chemistry , Carboxylic Acids/chemical synthesis , Malonates/chemistry , Carboxylic Acids/chemistry , Molecular Structure , StereoisomerismABSTRACT
2,2'-Diiodobiphenyl-4,4'-dicarboxylic acid dimethyl ester (3) undergoes either a ring-closure reaction with phenylacetylene to give 4 or hydrodeiodo phenylethynylation to give 5 under the catalytic conditions of Pd(OAc)(2)/CuI/phosphine in amines. In these reactions, the amine and the phosphine ligands play important roles in controlling the reactivity. Among the ligands we used, tris(o-tolyl)phosphine is the best ligand for hydrodeiodo phenylethynylation, while the bidentate phosphine ligand retards both of the reactions. On the basis of our results, we propose that 5 is formed through a fast hydrodeiodination, followed by a Sonogashira phenylethynylation. The results of the deuterium labeling experiments show that proton exchange between the acetylenic proton and the alkyl protons of amine occurs effectively under the reaction conditions. In addition, the hydrogen that replaces the iodide in the hydrodeiodination process arises mainly from the acetylenic proton.
