Studies on Quinazolines and 1,2,4-Benzothiadiazine 1,1-Dioxides. 8. , Synthesis and Pharmacological Evaluation of Tricyclic Fused Quinazolines and 1,2,4-Benzothiadiazine 1,1-Dioxides as Potential α1-Adrenoceptor Antagonists

A series of 2-substituted methyl 2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-ones (4), 3-substituted methyl 2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-ones (5), 3-substituted methyl 2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-ones (15a,b), 3-substituted methyl 2,3-dihydroimidazo[2,1-b]quinazolin-5(1H)-ones (16a,b), 3-substituted methyl 2,3-dihydro-1H-imidazo[1,2-b][1,2,4]benzothiadiazine 5,5-dioxides (33a,b), 2-substituted methyl imidazo[1,2-c]quinazolin-5(6H)-ones (42 − 45a,b), 3-substituted methyl imidazo[1,2-c]quinazolin-5(6H)-ones (50 − 53a,b), 3-substituted methyl 5H-thiazolo[2,3-b]quinazolin-5-ones (55 − 56a,b), and 3-substituted methyl 5-(methylthio)-2,3-dihydroimidazo[1,2-c]quinazoline (57) were synthesized as compound 1 conformational rigid congeners for pharmacological evaluation as potential α1-adrenoceptor antagonists. Compounds 4, 5, 33a,b, 44a,b, 45a,b, 52a,b, 53a,b, and 57 were found to possess high affinity for the α1-adrenoceptor. Compounds 5 and 57 were the most highly selective and potent α1 antagonists with K i = 0.21 ± 0.02 and 0.90 ± 0.08 nM, respectively. The S-enantiomers of these two compounds (K i = 0.13 ± 0.01 nM for (S)-(−)-5; K i = 1.0 ± 0.2 nM for (S)-(+)-57) were 144−200-fold more potent than the R-enantiomers (K i = 26 ± 8 nM for (R)-(+)-5; K i = 144 ± 23 nM for (R)-(−)-57). Compound 4 showed 8-fold higher affinity to α1A-AR better than α1B-AR. These compounds possessed weak to no activity against the 5-HT1A receptor.