During a search for benzodiazepine receptor modulators, a highly potent adenosine antagonist (CGS 15943) was discovered. The compound was defined as a resonance-stabilized hybrid of the canonical structures 9-chloro-2-(2-furyl)[1,2,4]triazolo[1,5-c]quinazolin-5-amine (2a) and 9-chloro-2-(2-furyl)-5,6-dihydro[1,2,4]triazolo[1,5-c]-quinazolin- 5-imine (2b). Spectroscopic evidence and chemical reactivity in polar media favor the amine form 2a as the major contributor of the two canonical structures. The synthesis of 2 and some of its analogues and the structure-activity relationships in four biological test systems are described. Replacement of the 9-chloro group by hydrogen, hydroxyl, or methoxyl gave compounds with comparable binding potency at the A1 and A2 receptors but much less activity as antagonists of 2-chloroadenosine in guinea pig tracheal strips. Alkylation of the 5-amino group caused, in general, a loss of binding activity, particularly at the A2 receptor, as well as complete loss of activity in the tracheal model. Modification of the 2-furyl group caused a pronounced loss of activity in all of the test systems.

3-Formylchromone(1) reacts with active methylene derivatives to yield condensation products 2a-d, 1 0 , l l and 12. Treatment of 2a-d with ammonia or methylamine gives pyridines 3-6. Alternatively, reaction of 1 with enamine derivatives yields pyrido compounds 15, 17, 19, 21, 23 and 28 in one step. Factors determining the formation and regiospecificity of the pyridine ring forming reactions are also discussed.1.

BA 41899 (5-methyl-6-phenyl-1,3,5,6-tetrahydro-3,6-methano-1,5- benzodiazocine-2,4-dione, 6) is a structurally novel 1,5-benzodiazocine derivative and represents the prototype of a hitherto unknown class of positive inotropic Ca(2+)-sensitizing agents. It is completely devoid of phosphodiesterase (PDE) III inhibitory activity or any other known inotropic mechanism. BA 41899 (6) exhibits a pharmacological in vitro profile comprising Ca(2+)-sensitizing, positive inotropic, and negative chronotropic effects. CGP 48506 ((+)-6), the (+)-enantiomer of BA 41899 (6), enantiospecifically carries Ca2+ sensitization by up to a full pCa unit and a corresponding positive inotropic effect. Conversely, the negative chronotropic action resides in the corresponding (-)-enantiomer, CGP 48508 ((-)-6). All the effects are exerted in the low micromolar range. The positive inotropic action of CGP 48506 ((+)-6) is associated with a decelerating effect on contraction and, more prominently, relaxation dynamics in isolated guinea pig atria. In contrast to Ca(2+)-sensitizing PDE inhibitors, CGP 48506 ((+)-6) does not increase maximum Ca(2+)-activated force in myocardial skinned fibers.

Five metabolites of diclofenac sodium (Voltarol) have been identified in human plasma. All five metabolites were more than 50 times less potent than diclofenac in inhibiting PGE2 production in zymosan-stimulated mouse macrophages and LTC4 synthesis was not inhibited in these cells. Anti-inflammatory activity (adjuvant arthritis and carragheenan-induced paw oedema in rats) and analgesic activity (phenyl-p-benzoquinone writhing, mouse) of the metabolites were at least 10 times lower when compared to diclofenac. There was a good correlation between in vitro PGE2 inhibition and in vivo activities for diclofenac and its metabolites indicating that inhibition of prostaglandin synthesis is a major mechanism responsible for their pharmacological actions.

A general synthesis of selectively 6‐(trifluoromethyl)‐substitued 2(1H)‐pyridinones is described. Further transformation of one of these compounds leads to the new CF3‐containing potassium‐channel openers 2a and 2b.