Design and synthesis of a novel 2-oxindole scaffold as a highly potent and brain-penetrant phosphodiesterase 10A inhibitor.

Highly potent and brain-penetrant phosphodiesterase 10A (PDE10A) inhibitors based on the 2-oxindole scaffold were designed and synthesized. (2-Oxo-1,3-oxazolidin-3-yl)phenyl derivative 1 showed the high P-glycoprotein (P-gp) efflux (efflux ratio (ER)=6.2) despite the potent PDE10A inhibitory activity (IC50=0.94 nM). We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity by utilizing structure-based drug design (SBDD) techniques based on the X-ray crystal structure with PDE10A. Finally, 1-(cyclopropylmethyl)-4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (19e) was identified with improved P-gp efflux (ER=1.4) and an excellent PDE10A inhibitory activity (IC50=0.080 nM). Compound 19e also exhibited satisfactory brain penetration, and suppressed PCP-induced hyperlocomotion with a minimum effective dose of 0.3mg/kg by oral administration in mice.

Domino Pd-catalyzed Heck cyclization and bismuth-catalyzed hydroamination: formal synthesis of elacomine and isoelacomine.

The formal synthesis of hemiterpene spirooxindole alkaloids elacomine (1) and isoelacomine (2) is described. Heck reaction of protected iodoanilines with 5,6-dihydro-2H-pyran-2-one or six-membered unsaturated lactams was investigated. The coupling product was readily converted to a carbamoyl chloride with an incorporated diene unit. The spiro(pyrrolidine-3,3'-oxindole) skeleton, which corresponds to the carbon skeleton of 1 and 2, was efficiently constructed from this intermediate by using a domino palladium-catalyzed Heck reaction and bismuth-catalyzed hydroamination. An isolated byproduct of the reaction could also be converted to the spirooxindole skeleton.

Enantioselective synthesis of 3,3-disubstituted oxindoles through Pd-catalyzed cyanoamidation.

The first enantioselective cyanoamidation of olefins provides quick access to a variety of 3,3-disubstituted oxindoles. The combination of Pd(dba)2, an optically active phosphoramidite, and N, N-dimethylpropylene urea (DMPU) in decalin were found to be the best conditions.

Palladium-catalyzed intramolecular cyanoamidation of alkynyl and alkenyl cyanoformamides.

[reaction: see text] The five- to seven-membered alpha-alkylidene lactams were prepared in 45-99% yield by the palladium-catalyzed cyanoamidation of alkynyl cyanoformamides. The reaction proceeded exclusively in a 5-exo mode, giving the corresponding (Z)-alkenes as major products. The reaction was also applied to 1,1-disubstituted alkenes to afford oxindoles bearing a quaternary carbon center.

Flexible strategy for syntheses of spirooxindoles using palladium-catalyzed carbosilylation and Sakurai-type cyclization.

The intramolecular carbosilylation of N-[2-(1,3-butenyl)aryl]carbamoyl chloride has been investigated. The reaction with hexamethyldisilane proceeds smoothly in the presence of a catalytic amount of [Pd(η(3)-allyl)Cl](2) to give oxindoles with an allylsilane functional group in good yield. The subsequent subjection of the products to a Sakurai-type reaction provides more advanced tricyclic spirooxindoles by controlling the stereochemistry of three contiguous stereogenic centers.