Mutulis Felikss, Kreicberga Jana, Yahorava Sviatlana, Mutule Ilze, Borisova-Jan Larisa, Yahorau Aleh, Muceniece Ruta, Azena Sandra, Veiksina Santa, Petrovska Ramona, Wikberg Jarl E S
Department of Pharmaceutical Biosciences, Division of Pharmacology, Uppsala Biomedical center, Uppsala University, Uppsala, Sweden.
Bioorg Med Chem. 2007 Sep 1;15(17):5787-810. doi: 10.1016/j.bmc.2007.06.003. Epub 2007 Jun 8.
Two hundred and ten tertiary amides were prepared on solid phase. Diamines were coupled to activated carboxylated Wang polymer, and the polymeric substituted benzyloxycarbonyl protected diamines obtained were reacted with aldehydes or ketones in trimethyl orthoformate giving resin attached Schiff bases. Coupled resins were then reduced to secondary amines by sodium cyanoborohydride in 4% acetic acid/trimethyl orthoformate, followed by acylation with the carboxylic acid in the presence of PyBroP and diisopropylethylamine. Cleavage of tertiary amides from the resin was made by trifluoroacetic acid in the presence of scavengers (mainly 1,2-ethanedithiol). When indole derivatives were prepared, parallel alkylation with the linker fragment occurred, giving derivatives of 2-(4-hydroxybenzyl)-indole as side products. Solution synthesis or mixed liquid/solid phase preparation of title substances proved to be advantageous in cases when the above method did not give acceptable results. According to this approach an efficient formation of Schiff bases was achieved in the presence of TiCl(4). Substances were isolated by reversed phase chromatography; in some cases isomers were additionally separated by chiral chromatography on Chirobiotic T. When tested on human recombinant melanocortin receptors all the tertiary amides showed some binding affinities; for the highest affinity compounds the K(i)s reached 400 nM on MC(1), 2 microM on MC(3) and 1 microM on MC(4) and MC(5) receptors. cAMP assays of some of the title compounds showed that the tertiary amides are melanocortin receptor antagonists on the four MC receptor subtypes.
在固相上制备了210种叔酰胺。将二胺与活化的羧基化Wang聚合物偶联，所得的聚合物取代的苄氧羰基保护的二胺与醛或酮在原甲酸三甲酯中反应，得到树脂连接的席夫碱。然后将偶联的树脂在4%乙酸/原甲酸三甲酯中用氰基硼氢化钠还原为仲胺，接着在PyBroP和二异丙基乙胺存在下用羧酸进行酰化。在清除剂（主要是1,2 - 乙二硫醇）存在下，用三氟乙酸从树脂上裂解叔酰胺。当制备吲哚衍生物时，会发生与连接片段的平行烷基化反应，生成2-(4 - 羟基苄基)-吲哚衍生物作为副产物。当上述方法不能得到可接受的结果时，溶液合成或混合液/固相制备标题物质被证明是有利的。根据这种方法，在TiCl(4)存在下实现了席夫碱的有效形成。通过反相色谱分离物质；在某些情况下，异构体还通过手性Chirobiotic T色谱进一步分离。当在人重组黑皮质素受体上进行测试时，所有叔酰胺都表现出一定的结合亲和力；对于亲和力最高的化合物，其在MC(1)受体上的K(i)值达到400 nM，在MC(3)受体上为2 μM，在MC(4)和MC(5)受体上为1 μM。一些标题化合物的cAMP测定表明，叔酰胺是四种MC受体亚型上的黑皮质素受体拮抗剂。
