Clark J A, Clark M S, Gardner D V, Gaster L M, Hadley M S, Miller D, Shah A
J Med Chem. 1979 Nov;22(11):1373-9. doi: 10.1021/jm00197a018.
Following the discovery that 3-(dimethylamino)-1,1-diphenyl-2-propanol hydrobromide (1) possesses potent reserpine-prevention activity in mice, a series of analogues of 1 was synthesized and evaluated as potential antidepressant agents. Several routes to analogues of 1 were evaluated, the most generally applicable of which was the regiospecific ring opening of a suitably functionalized 1,1-diaryl-2,3-epoxypropane (obtained in three stages from the corresponding benzophenone) with the appropriate amine. The more interesting compounds of the series were evaluated for their propensity to cause undesirable peripheral anticholinergic effects, all compounds tested being markedly less active than imipramine on this parameter. On the basis of its good activity in biochemical and pharmacological animal models of depression, together with its relative lack of anticholinergic side effects, 1-(3-chlorophenyl)-3-(dimethylamino)-1-phenyl-2-propanol hydrochloride (20, BRL 14342) was chosen for further evaluation.
在发现3-(二甲基氨基)-1,1-二苯基-2-丙醇氢溴酸盐(1)在小鼠中具有有效的利血平预防活性后，合成了一系列1的类似物并作为潜在的抗抑郁药进行评估。评估了几种合成1类似物的路线，其中最普遍适用的是用适当的胺对适当官能化的1,1-二芳基-2,3-环氧丙烷(由相应的二苯甲酮分三步获得)进行区域特异性开环。对该系列中更有趣的化合物进行了引起不良外周抗胆碱能作用倾向的评估，所有测试的化合物在该参数上的活性均明显低于丙咪嗪。基于其在抑郁症生化和药理动物模型中的良好活性，以及相对缺乏抗胆碱能副作用，选择了1-(3-氯苯基)-3-(二甲基氨基)-1-苯基-2-丙醇盐酸盐(20，BRL 14342)进行进一步评估。
