550-54-9Relevant articles and documents
Novel prodrugs with a spontaneous cleavable guanidine moiety
Hamada, Yoshio
supporting information, p. 1685 - 1689 (2016/07/29)
Water-soluble prodrug strategy is a practical alternative for improving the drug bioavailability of sparingly-soluble drugs with reduced drug efficacy. Many water-soluble prodrugs of sparingly-soluble drugs, such as the phosphate ester of a drug, have been reported. Recently, we described a novel water-soluble prodrug based on O–N intramolecular acyl migration. However, these prodrug approaches require a hydroxy group in the structure of their drugs, and other prodrug approaches are often restricted by the structure of the parent drugs. To develop prodrugs with no restriction in the structure, we focused on a decomposition reaction of arginine methyl ester. This reaction proceeds at room temperature under neutral conditions, and we applied this reaction to the prodrug strategy for drugs with an amino group. We designed and synthesized novel prodrugs of representative sparingly soluble drugs phenytoin and sulfathiazole. Phenytoin and sulfathiazole were obtained as stable salt that were converted to parent drugs under physiological conditions. Phenytoin prodrug 3 showed a short half-life (t1/2) of 13?min, whereas sulfathiazole prodrug 7 had a moderate t1/2of 40?min. Prodrugs 3 and 7 appear to be suitable for use as an injectable formulation and orally administered drug, respectively.
Mechanistic investigations into the enantioselective Conia-ene reaction catalyzed by cinchona-derived amino urea pre-catalysts and CuI
Sladojevich, Filippo,Fuentes De Arriba, ángel L.,Ortín, Irene,Yang, Ting,Ferrali, Alessandro,Paton, Robert S.,Dixon, Darren J.
supporting information, p. 14286 - 14295 (2015/03/30)
The enantioselective Coniaene cyclization of alkyne-tethered β-ketoesters is efficiently catalyzed by the combination of cinchona-derived amino-urea pre-catalysts and copper(I) salts. The reaction scope is broad and a series of substrates can be efficiently cyclized with high yields and enantioselectivities. Herein, we present a detailed mechanistic study based on experimental considerations and quantum mechanical calculations. Several variables, such as the nature of the organic pre-catalyst and the metal-ion source, have been thoroughly investigated. Kinetic studies, as well as kinetic isotope effects and deuterium labeling experiments have been used to gain further insights into the mechanism and prove the cooperative nature of the catalytic system. Our studies suggest that the rate-limiting step for the reaction involves the β-ketoester deprotonation and that the active species responsible for the enantiodeterming step is monomeric in amino-urea pre-catalyst. Computational studies provide a quantitative understanding of the observed stereoinduction and identify hydrogen bonding from the urea group as a crucial factor in determining the observed enantioselectivity.
Easy access to 9-epimers of cinchona alkaloids: One-pot inversion by mitsunobu esterification-saponification
Sidorowicz, Lukasz,Skarzewski, Jacek
experimental part, p. 708 - 710 (2011/04/24)
Cinchona alkaloids were efficiently converted into their 9-epi diastereomers. The applied one-pot procedure was based on the Mitsunobu esterification with 4-nitrobenzoic acid followed by in situ saponification of the ester. This method requires only one column chromatography, easily separating the epi-isomer from the native alkaloid and the Mitsunobu byproducts. The procedure gives higher yields and is operationally simpler than the previously used stereoselective hydrolysis of the corresponding sulfonic acid esters. Georg Thieme Verlag Stuttgart New York.
