A series of N-phenyl-N'-pyridinylureas was examined for anticonvulsant activity. Extensive structure/activity investigations revealed optimal activity in the N-(2,6-disubstituted-phenyl)-N'-(4-pyridinyl)urea series, with 37 exhibiting the best overall anticonvulsant profile. Compound 37 was effective against seizures induced by maximal electroshock but did not protect mice from clonic seizures produced by the convulsant pentylenetetrazol. The overall pharmacological profile suggests that 37 would be of therapeutic use in the treatment of generalized tonic-clonic and partial seizures. Compound 37 was selected for Phase 1 clinical trials.

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The reaction of various tetrahydro-0-carboline-3-carboxylic acids, 2a-c, with dimethyl acetylenedicarboxylate in acetic anhydride directly afforded the corresponding indolizino [6,7-6] indoles 4a-c, in moderate yields. Likewise, treatment of 1,2,3,4-tetrahydro-/3-carboline-1-carboxylic acid, 5, in acetic anhydride, with a variety of acetylenic dipolarophiles and less successfully with olefinic dipolarophiles furnished the corresponding indolizino-[8,7-b]indole derivatives. These reactions involve a 1,3-dipolar cycloaddition of the respective munchnone intermediates (3 and 6), respectively, formed in situ, with the dipolarophilic substrates.Huisgen and coworkers have recently reported a general synthesis of pyrroles1 and pyrrolines2 using mesoionic A2-oxazolium-5-olates (munchnones). These reactions involved a 1,3-dipolar cycloaddition of the munchnone, behaving like a cyclic azomethine ylide,3 to the corresponding acetylenic or olefinic dipolarophile, followed by C02 evolution, and aromatization or tautomerization.4 5678Most examples of the application of this reaction, to date, have involved the use of acyclic, JV-acyl -amino acids as the starting material,5-8 although Huisgen has converted L-proline to the pyrrolizine derivative, 1, in 76% yield by reaction with dimethyl acetylenedicarboxylate in acetic anhydride.1

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.