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 ALPHA(1)-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]quinazoli n-5(6H)-ones (5), 3-substituted methyl 2,3-dihydro-5H-thiazolo[2,3-b]q uinazolin-5-ones (15a,b), 3-substituted methyl 2,3-dihydroimidazo[2,1- b]quinazolin-5(1H)-ones (16a,b), 3-substituted methyl -dihydro-1H-imid azo-[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 m ethyl 5H-thiazolo[2,3-b]quinazolin-5-ones (55-56a,b), and 3-substitute d methyl 5-(methylthio)-2,3-dihydroimidazo[1,2-c] (57) were synthesize d as compound 1 conformational rigid congeners for pharmacological eva luation as potential alpha(1)-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 alpha(1)-adrenoceptor. Compounds 5 and 57 were the m ost highly selective and potent al antagonists with K-i = 0.21 +/- 0.0 2 and 0.90 +/- 0.08 nM, respectively. The S-enantiomers of these two c ompounds (K-i = 0.13 +/- 0.01 nM for (S)-(-)-5; K-i = 1.0 +/- 0.2 nM f or (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). C ompound 4 showed 8-fold higher affinity to alpha 1A-AR better than alp ha 1B-AR. These compounds possessed weak to no activity against the 5- HT1A receptor.