新型2-溴苯酰胺类小分子CCR5拮抗剂的合成及其GTPγS结合性

Synthesis and GTPγS Binding Activity of Novel 2-Bromo-benzamides Small Molecule CCR5 Antagonists

以2-羟基-5-溴苯甲醛为起始原料,经取代,还原和NBS溴化反应制得5-溴-2-(4-氯苯甲氧基)溴甲苯(3);以4-哌啶酮盐酸盐为原料,经保护,还原和缩合反应制得N-烯丙基-2-溴-N-哌啶基苯酰胺(7);3和7经取代反应合成了一个新型的非肽类小分子CCR5拮抗剂——N-烯丙基-2-溴-N-{N-[2-(4-氯苯甲氧基)-5-溴苄基]-4-哌啶基}苯酰胺(8),总产率32.5%,其结构经1H NMR,13C NMR,IR和ESI-MS表征。用GTPγS法测试了8的生物结合性。结果表明:8的生物结合性与TD0232接近,其IC50为(8.12±0.3)nmol·L-1。

5-Bromo-1-[(4-chlorobenzyl)oxy]-2-bromotoluene(3) was obtained by substitution reaction,reduction and NBS bromination from 5-bromo-2-hydroxybenzaldehyde. N-allyl-2-bromo-N-( 4-piperidinyl)benzamide(7) was prepared by protection,reduction and condensation reaction from 4-piperidone hydrochlorid. A novel non-peptide small molecule compound,N-allyl-2-bromo-N-【1-{ 2-[( 4-chlorobenz)oxyyl]-5-bromobenz}-4-piperidin】benzamide(8) with total yield of 32. 5%,was synthesized by substitution reaction of 3 with 7. The structure was characterized by1 H NMR,13 C NMR,IR and ESIMS. The biological activity of 8 was detected by the SPA GTPγS assay. The results indicated that the biological binding activity of 8 approach to TD0232 with IC50of(8. 12 ± 0. 3) nmol·L- 1.