N-substituted tetrahydro-2,4-dioxoquinazolin-1-yl acetic acids as aldose reductase inhibitors.

Novel N-substituted tetrahydro-2,4-dioxoquinazolin-1-yl acetic acids characterized by formal replacement of the substituted benzyl moiety by cyclohexylmethyl and n-heptyl residues, respectively, were synthesized and evaluated as aldose reductase inhibitors.

Pyridazines 91. Synthesis of substituted tri- and tetracyclic compounds bearing a pyridazine core and their biological evaluation as antimycobacterial agents.

Starting from substituted 3,6-dichloropyridazine-4-carboxamides (2, 3) tri- and tetracyclic compounds (4, 5) could be smoothly prepared. Structural modifications of interest with regard to biological activity were performed by N-alkylation and reductive dehalogenation. The new substituted heterocyclic compounds were screened as antimycobacterial agents; the influence of the substitution pattern on activity is discussed.

1-substituted 4-[chloropyrazolyl][1,2,4]triazolo[4,3-a]quinoxalines: synthesis and structure-activity relationships of a new class of benzodiazepine and adenosine receptor ligands.

Starting from 3-(3-chloro-1H-pyrazol-5-yl)-1H-quinoxalin-2-one (2) a series of substituted [1,2,4]triazolo[4,3-a]quinoxalines (3a-f) was prepared via a multistep reaction sequence. Affinities of the novel derivatives 3a-f for benzodiazepine as well as for adenosine A1- and A2A-receptors of rat brain were determined by radioligand binding assays. 1-Methyl-4-(3-chloro-1H-pyrazol-5-yl) derivative 3a exhibited submicromolar affinity for the benzodiazepine binding site of GABAA receptors (Ki = 340 nM) and was less potent at A1-(Ki = 7.85 microM) and A2A-(Ki = 1.43 microM) adenosine receptors (AR). Derivatives with larger substituents in the 1-position showed reduced binding to benzodiazepine and A2A-AR, but increased A1-AR affinity, the 2-thienylmethyl derivative 3f being the most potent and selective A1-AR ligand of the present series (Ki = 200 nM).

Synthesis of N-aryl-N'-heteroaryl-substituted urea and thiourea derivatives and evaluation of their anticonvulsant activity.

Starting from amino(di)azines and 2-chloro-6-methyliso(thio)cyanate a series of aryl-substituted urea and thiourea derivatives was prepared and screened as potential antiepileptics. Among the new derivatives tested, only 2b and 3c exhibited adequate anticonvulsant effects, whereas 3d and 4d were found to be convulsants per se.

Pyridazines 82. Synthesis of pyridazino [3,4-b][1,5]benzodiazepin-5-ones and their biological evaluation as non-nucleoside HIV reverse transcriptase inhibitors.

Starting from 3,6-dichloro-N-(2-chloro-5-nitrophenyl)-pyridazine-4-carboxamide (7) a series of 6,11-dialkylated pyridazino- [3,4-b][1,5]benzodiazepin-5-ones with a 3-chloro-8-nitro, 8-amino, 8-acetylamino, or 8-chloro substitution pattern was prepared via N-alkyl-3-alkylamino-6-chloro-N-(2-chloro-5-nitrophenyl) -pyridazine-4-carboxamides. The new compounds were screened as non-nucleoside reverse transcriptase inhibitors. The influence of the substitution pattern in compounds 10-13 on inhibitory potency is discussed.

On the synthesis of pyridazomycin congeners. Part 2: L-alpha-Amino acids bearing a terminal azinium or diazinium system.

The synthesis of a variety of novel compounds structurally related to the antimicrobial natural product pyridazomycin via alkylation of appropriate azine and diazine derivatives is reported. Based on the results of preliminary antimicrobial tests the dependence of antimicrobial activity from several structural features of pyridazomycin is discussed.

Pyridazines, LXXII: On the synthesis of azinium and diazinium compounds structurally related to pyridazomycin.

Preparation of series of pyridine-, pyridazine-, and pyrazine-derived carboxamides bearing at the ring N-atom an alkyl side-chain with a terminal carboxylic group (7-11) or with a terminal acetylamino malonic ester moiety (13-17, 19-23) is described. Two desaza-pyridazomycin derivatives (24, 26) and homologs thereof (25, 27) were synthesised. The novel compounds which are structurally related to the antifungal antibiotic pyridazomycin were screened for antifungal activity: preliminary in vitro tests showed no activity.