Potential antipsychotic agents. Part 8. Antidopaminergic properties of a potent series of 5-substituted (−)-(S)-N-[(1-ethylpyrrolidin-2-yl)methyl]-2,3-dimethoxybcnzaimides. Synthesis via common lithio intermediates
✍ Scribed by Thomas Högberg; Peter Ström; Håkan Hall; Sven Ove Ögren
- Publisher
- John Wiley and Sons
- Year
- 1990
- Tongue
- German
- Weight
- 583 KB
- Volume
- 73
- Category
- Article
- ISSN
- 0018-019X
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✦ Synopsis
A series of 5-substituted (-)-(S)-N-[( l-ethylpyrrolidin-2-yl)methyl]-2,3-dimethoxybenzamides were made by reaction of the corresponding benzoyl chlorides with (S)-l-ethylpyrrolidine-2-methylamine (+ 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 (+ U ) , metalated, reacted with various electrophiles (MeI, EtI, BuBr, CC13CC13 or MeSSMe), and hydrolyzed (+ 9-13). Alternatively, (-)-(S)-S-bromo-N-[( 1 -ethylpyrrolidin-2-yI)methyl]-2,3-dimethoxybenzamide was treated with KH followed by BuLi and an electrophile (I2 or Me3SiC1) 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 IC,, values of 0.5 to 5 nM (Table ) . Thus, a relatively large steric bulk can be accomodated in the positionpara to the 2-Me0 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 uiuo and found to inhibit apomorphine-induced behavioural responses in the same dose range as haloperidol and raclopride (Table ) . This new group of benzamides is suitable for investigations of dopamine D-2 receptors in labelled or unlabelled form. ') Part 7: [I].