Perregaard J, Andersen K, Hyttel J, Sánchez C
H. Lundbeck A/S, Cophenhagen-Valby, Denmark.
J Med Chem. 1992 Dec 25;35(26):4813-22. doi: 10.1021/jm00104a006.
A series of 1-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-2-imidazolidinones has been synthesized. The 1-position of the indole is substituted with phenyl groups and in the 2- or 6-positions are additional substituents. An analogous series with the imidazolidinone ring opened to corresponding urea derivatives was also prepared. High potency and selectivity for 5-HT2 receptors (as compared with D2 and alpha 1 receptor affinities) were obtained with medium-large substituents such as 6-chloro, 6-methyl, and 6-trifluoromethyl or a 2-methyl substituent. Larger 6-substituents such as isopropyl considerably reduced activity, while the smaller 6-fluoro substituent afforded unselective compounds. Selective 5-HT2 antagonists were found by combining 6-substitution with both unsubstituted 1-phenyl and substituted 1-phenyl groups (2-F, 4-F, 4-Cl). However, 3-substitution of the phenyl group markedly reduced 5-HT2 receptor affinity, especially with a 3-trifluoromethyl substituent. Introduction of a 3-(2-propyl) substituent in the imidazolidinone ring reduced binding to alpha 1 adrenoceptors with a factor of 3-8. Practically no influence on 5-HT2 and D2 receptor affinities were found by the presence of this substituent compared to the 3-unsubstituted derivatives. Compounds with potent receptor binding also potently inhibited the quipazine-induced head twitch syndrome in rats. The compounds were equally active after oral and subcutaneous administration and they had a long duration of action (> 24 h). Especially urea derivatives were found to be considerably more potent at 24 h than at 2 h after subcutaneous administration. Some of the compounds potently inhibited isolation-induced aggression in mice, an effect which, however, did not correlate to 5-HT2 receptor-mediated activities. On the basis of these structure-activity studies 1-[2-[4-[6-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1- piperidinyl]ethyl]-3-(2-propyl)-2-imidazolidinone (Lu 26-042, compound 4c) was selected for further pharmacological and toxicological investigations.
已合成了一系列1-[2-[4-(1H-吲哚-3-基)-1-哌啶基]乙基]-2-咪唑啉酮。吲哚的1-位被苯基取代，2-位或6-位有其他取代基。还制备了咪唑啉酮环开环形成相应脲衍生物的类似系列。对于5-HT2受体具有高效能和选择性（与D2和α1受体亲和力相比），通过中等大小的取代基如6-氯、6-甲基和6-三氟甲基或2-甲基取代基可实现。较大的6-取代基如异丙基会显著降低活性，而较小的6-氟取代基则产生非选择性化合物。通过将6-取代与未取代的1-苯基和取代的1-苯基（2-氟、4-氟、4-氯）组合发现了选择性5-HT2拮抗剂。然而，苯基的3-取代显著降低了5-HT2受体亲和力，尤其是3-三氟甲基取代基。在咪唑啉酮环中引入3-(2-丙基)取代基使与α1肾上腺素能受体的结合降低了3至8倍。与3-未取代的衍生物相比，该取代基的存在对5-HT2和D2受体亲和力实际上没有影响。具有强效受体结合能力的化合物也能有效抑制大鼠中喹哌嗪诱导的头部抽搐综合征。这些化合物经口服和皮下给药后活性相同，且作用持续时间长（>24小时）。特别是脲衍生物在皮下给药后24小时比2小时的效能显著更高。一些化合物能有效抑制小鼠隔离诱导的攻击行为，然而，这种作用与5-HT2受体介导的活性无关。基于这些构效关系研究，选择了1-[2-[4-[6-氯-1-(4-氟苯基)-1H-吲哚-3-基]-1-哌啶基]乙基]-3-(2-丙基)-2-咪唑啉酮（Lu 26-042，化合物4c）进行进一步的药理和毒理学研究。
