Sauerberg P, Chen J, WoldeMussie E, Rapoport H
Department of Chemistry, University of California, Berkeley 94720.
J Med Chem. 1989 Jun;32(6):1322-6. doi: 10.1021/jm00126a030.
A number of pilocarpine analogues containing the (S)-3-ethyl-4-[(4'-imidazolyl)methyl]-2-oxazolidinone (9) structural feature were synthesized from L-histidine. With 1-benzyl-L-histidine as the key intermediate, a regiospecific synthetic route was developed to the N pi-methyl derivative 8. The regiochemistry of the alkylation of the imidazole nucleus was determined by measuring proton cross-ring coupling constants in the high-field 1H NMR. The effects on muscarinic receptors of these variously alkylated derivatives 6-10 were studied on isolated guinea pig ileum. The derivatives in which the imidazole nitrogen was unsubstituted (9), N tau-methylated (10), and N pi-methylated (8) were cholinergic muscarinic agonists with an increasing order of potency; compounds 6 and 7 were inactive. Analogue 8 with the same substitution pattern as pilocarpine was equipotent with pilocarpine, making these hydrolytically stable carbamate derivatives potentially useful drugs.
从L-组氨酸合成了一系列含有(S)-3-乙基-4-[(4'-咪唑基)甲基]-2-恶唑烷酮(9)结构特征的毛果芸香碱类似物。以1-苄基-L-组氨酸为关键中间体，开发了一条区域特异性合成路线，用于合成Nπ-甲基衍生物8。通过测量高场1H NMR中的质子交叉环耦合常数，确定了咪唑核烷基化的区域化学。在离体豚鼠回肠上研究了这些不同烷基化衍生物6-10对毒蕈碱受体的影响。咪唑氮未被取代的衍生物(9)、Nτ-甲基化的衍生物(10)和Nπ-甲基化的衍生物(8)是胆碱能毒蕈碱激动剂，其效力呈递增顺序；化合物6和7无活性。与毛果芸香碱具有相同取代模式的类似物8与毛果芸香碱等效，使得这些水解稳定的氨基甲酸酯衍生物成为潜在的有用药物。
