2-Pyrrolidinylideneureas, a new class of central nervous system agents

Abstract

A series of N-aryl-N'-(1-methyl-2-pyrrolidinylidene)ureas was prepared and screened for pharmacological activity. Congeners possessing either phenyl or phenyl substituted with 4-nitro, 3-bromo, 3-chloro, 3-fluoro, and 3-methyl groups were found to demonstrate anxiolytic activity. 2,6-Disubstitution of the phenyl ring with methyl, chloro, and bromo imparted potent muscle-relaxant properties which appear to be centrally mediated. A significant separation of the anxiolytic and muscle-relaxant properties from other CNS activities, e.g., anticonvulsant, sedative, and hypnotic, was achieved.

A new example of the three-component reaction: nucleophilic ring opening in cyclopropenones by cyanide ions in the presence of water or alcohols

“…17 Isopropyl 3 cyano 2 methyl 3 phenylpropionate (4c) was ob tained as a viscous yellowish oil (mixture of diastereomers) from cyclopropenone 1b (0.72 g, 5 mmol) and propan 2 ol (30 mL) as described for compound 4a. The yield of compound 4c was 0.86 g (75%).…”

Microwave-assisted cyclizations promoted by polyphosphoric acid esters: a general method for 1-aryl-2-iminoazacycloalkanes

“…These compounds have been described as selective inhibitors of the inducible form of human nitric oxide synthase (iNOS), which catalyzes the reaction to form nitric oxide via the oxidation of L-arginine to L-citrulline [3–6]. Some urea and thiourea derivatives have been studied as CNS agents [7] and anthelmintic drugs [8]. This heterocyclic core therefore represents the foundation for potential bioactive agents.…”

“…These methods usually require drastic reaction conditions and are generally limited to 2-iminopyrrolidines and/or to N -unsubstituted or N -alkyl derivatives. Other methods involve cyclic precursors such as lactams [4,6–7 16], thiolactams [3,6] or 2-aminopyridines [6]. …”

“…2-iminoazepanes [3,7,9–10], are very scarce, and no general method has been described for their synthesis. To our knowledge, N- aryl derivatives have not been hitherto reported.…”

Xilobam: Analysis, determination of decomposition products, and assessment of stability

“…Xilobam, N-(2,6-dimethylphenyl) -N'- (1-methyl-2 -pyrrolidinylidene)urea, a new class of central nervous system agents, is being evaluated clinically as a skeletal muscle relaxant (1,2). Xilobam is a sparingly soluble base with a spectrophotometrically determined pKa of 6.1.…”