Butler D E, Leonard J D, Caprathe B W, L'Italien Y J, Pavia M R, Hershenson F M, Poschel P H, Marriott J G
J Med Chem. 1987 Mar;30(3):498-503. doi: 10.1021/jm00386a010.
A series of dihydro-1H-pyrrolizine-3,5(2H,6H)-diones were synthesized and evaluated for their ability to reverse electroconvulsive shock (ECS) induced amnesia in mice. Among the structure-activity relationships explored were the effects of ring size, the presence of heteroatoms (sulfur) in the ring system, and the introduction of alkyl substituents. The optimal ring size for the bicyclic system was 5.5 with dihydro-1H-pyrrolizine-3,5(2H,6H)-dione (3), although some activity was present in the corresponding 5.6 [hexahydro-3,5-indolizinedione (7)] and 6.6 [tetrahydro-2H-quinolizine-4,6(3H,7H)-dione (9)] analogues. Replacement of the C-1 carbon atom in compound 3 with a sulfur [dihydropyrrolo[2,1-b]thiazole-3,5(2H,6H)-dione (10)] abolished activity, and the introduction of methyl groups resulted in poorer biological profiles except when the substitution was made at the 7a position [dihydro-7a-methyl-1H-pyrrolizine-3,5(2H,6H)-dione (4)]. In several instances, hydrolysis of the parent bicyclic compound was carried out to furnish the corresponding lactam acids, which were further derivatized. Several exhibited interesting activity, especially the 5-oxo-2-pyrrolidinepropanoic acid derivatives such as 5-oxo-2-pyrrolidinepropanoic acid (12), 5-oxo-2-pyrrolidinepropanoic acid phenylmethyl ester (17), 5-oxo-2-pyrrolidinepropanoic acid (3-chlorophenyl)methyl ester (20), N-4-pyridyl-5-oxo-2-pyrrolidinepropanoic acid amide (25), and N-(2,6-dimethylphenyl)-5-oxo-2-pyrrolidinepropanoic acid amide (27). Compound 3 (CI-911; rolziracetam) was also observed to improve performance on a delayed-response task in aged rhesus monkeys and was selected for evaluation in cognitively impaired human subjects on the basis of its biological profile and a wide margin of safety in animals.
合成了一系列二氢-1H-吡咯嗪-3,5(2H,6H)-二酮，并评估了它们逆转小鼠电惊厥休克（ECS）诱导失忆的能力。在探索的构效关系中，包括环大小的影响、环系统中杂原子（硫）的存在以及烷基取代基的引入。双环系统的最佳环大小为5.5，即二氢-1H-吡咯嗪-3,5(2H,6H)-二酮（3），尽管相应的5.6 [六氢-3,5-吲哚嗪二酮（7）] 和6.6 [四氢-2H-喹嗪-4,6(3H,7H)-二酮（9）] 类似物也有一些活性。用硫取代化合物3中的C-1碳原子 [二氢吡咯并[2,1-b]噻唑-3,5(2H,6H)-二酮（10）] 会消除活性，引入甲基会导致较差的生物学特性，除非在7a位进行取代 [二氢-7a-甲基-1H-吡咯嗪-3,5(2H,6H)-二酮（4）]。在一些情况下，对母体双环化合物进行水解以提供相应的内酰胺酸，这些内酰胺酸进一步衍生化。有几种表现出有趣的活性，特别是5-氧代-2-吡咯烷丙酸衍生物，如5-氧代-2-吡咯烷丙酸（12）、5-氧代-2-吡咯烷丙酸苄酯（17）、5-氧代-2-吡咯烷丙酸（3-氯苯基）甲酯（20）、N-4-吡啶基-5-氧代-2-吡咯烷丙酰胺（25）和N-(2,6-二甲基苯基)-5-氧代-2-吡咯烷丙酰胺（27）。还观察到化合物3（CI-911；罗拉西坦）可改善老年恒河猴在延迟反应任务中的表现，并基于其生物学特性和在动物中的广泛安全边际被选用于认知受损人类受试者的评估。
