Bermudez J, Dabbs S, King F D
Beecham Pharmaceuticals Research Division, Harlow, Essex, England.
J Med Chem. 1990 Jul;33(7):1932-5. doi: 10.1021/jm00169a018.
A novel series of potent 5-HT3 receptor antagonists, ortho-substituted phenylureas 6a-z, is described in which the 5-membered ring of the previously reported indazoles and indolines has been replaced by an intramolecular hydrogen bond. High potency was found both for carbamate 6a and urea 6b. Granatane 6c was less potent than the equivalent tropane. Phenylurea 11c lacking the ortho substituent was inactive. Whereas further substitution could not be tolerated in the aromatic ring, activity was retained with a range of O-alkyl groups, compounds 6k-t. In addition, good activity was found for ortho ester 6u and sulfonamide 6x. The ortho-substituted phenylureas can therefore be regarded as bioisosteres of the 6,5-heterocycles indole, indazole, and indoline.
本文描述了一系列新型强效5-羟色胺3（5-HT3）受体拮抗剂，即邻位取代苯基脲6a-z，其中先前报道的吲唑和吲哚啉的五元环已被分子内氢键取代。发现氨基甲酸酯6a和脲6b均具有高效能。石榴烷6c的效能低于等效的托烷。缺乏邻位取代基的苯基脲11c无活性。虽然芳环中不能耐受进一步取代，但一系列O-烷基化合物6k-t仍保留了活性。此外，原酸酯6u和磺酰胺6x具有良好活性。因此，邻位取代苯基脲可被视为6,5-杂环吲哚、吲唑和吲哚啉的生物电子等排体。
