Synthesis and adenosine receptor binding studies of some novel triazolothienopyrimidines.

Abstract A new series of 5-alkyl/aryl-8,9-dimethyl/8,9,10,11-tetrahydro[1]benzothieno[3,2- e ][1,2,4]triazolo[4,3- c ]pyrimidine-3(2 H )-thiones ( 4a – k ) have been synthesized through a facile cyclization reaction of 4-hydrazino-2-alkyl/aryl-5,6-dimethyl/5,6,7,8-tetrahydro[1]benzothieno[2,3- d ]pyrimidines ( 3a – k ) using carbon disulphide under basic conditions. 4-Hydrazino-2-alkyl/aryl-5,6-dimethyl/5,6,7,8-tetrahydro[1]benzothieno[2,3- d ]pyrimidines ( 3a – k ) were prepared by replacing the chloro group of 4-chloro-2-substituted-5,6-dimethyl/5,6,7,8-tetrahydro[1]benzothieno[2,3- d ]pyrimidines ( 2a – k ) with hydrazine hydrate which were obtained by a known one-pot synthesis. The affinities of these compounds for adenosine A 1 /A 2A receptors were determined at 1 μM concentration. The test compounds which exhibited more than 20% inhibition were selected and further screened at six different concentration levels to estimate their EC 50 / K i values. The most potent compounds in the series were 4c and 4d having an ethyl side chain at C 5 position with dimethyl and cyclohexyl substitution at the C 8 –C 9 positions, exhibiting K i values of 2.1 and 1.1 μM, respectively, at A 1 ARs. The SAR indicates that by increasing or decreasing the alkyl chain length at C 5 led to reduced affinity. The remaining aryl/arylalkyl derivatives of the series were inactive showing that a simple alkyl side chain at C 5 is necessary for these ligands to bind at A 1 ARs. However, none of the compounds showed inhibition on A 2A receptors at 1 μM concentration indicating their selectivity. This communication describes the design, synthesis and evaluation of these new molecules.