POTENTIAL ANTIPSYCHOTIC AGENTS .8. ANTIDOPAMINERGIC PROPERTIES OF A POTENT SERIES OF 5-SUBSTITUTED (-)-(S)-N-[(1-ETHYLPYRROLIDIN-2-YL)METHYL]-2,3-DIMETHOXYBENZAMIDES - SYNTHESIS VIA COMMON LITHIO INTERMEDIATES

A series of 5‐substituted (−)‐(S)‐N‐[(1‐ethylpyrrolidin‐2‐yl)methyl]‐2,3‐diniethoxybenzanndes were made by reaction of the corresponding benzoyl chlorides with (S)‐1‐ethylpyrrolidine‐2‐methylaruine (→ 14–16, 18–21). The acids required were prepared in a regiospecific manner from 5‐bromo‐2,3‐dimethoxybenzoic acid which was protected as dihydrooxazole (→ 4–8), metalated, reacted with various electrophiles (MeI, EtI, BuBr, CC13CCl3 or MeSSMe), and hydrolyzed (→9–13). Alternatively, (‐)‐(S)‐5‐bromo‐N‐[(1‐ethylpyrrolidin‐2‐yl)methyl]‐2,3‐di‐methoxybenzamide was treated with KH followed by BuLi and an electrophile (I2 or Me3SiCl) to give the 5‐iodo and 5‐(trimethylsilyl) derivatives 17 and 22, respectively. All 5‐substituted amides were highly potent inhibitors of [3H]spiperone binding in rat striatal membranes with IC50 values of 0.5 to 5 nM (Table 3). Thus, a relatively large steric bulk can be accomodated in the position para to the 2‐MeO group. This work also supports the notion that a positive as well as negative electrostatic potential can be located in this position. A selected number of derivatives were also investigated in vivo and found to inhibit apomorphine‐induced behavioural responses in the same dose range as haloperidol and raclopride (Table 4). This new group of benzamides is suitable for investigations of dopamine D‐2 receptors in labelled or unlabelled form. Copyright © 1990 Verlag GmbH & Co. KGaA, Weinheim