Roquinimex-related 3-quinolinecarboxamide derivatives were prepared and evaluated for treatment of autoimmune disorders. The compounds were tested in mice for their inhibitory effects on disease development in the acute experimental autoimmune encephalomyelitis model and selected compounds in the beagle dog for induction of proinflammatory reaction. Structure-activity relationships are discussed. Compound 8c, laquinimod, showed improved potency and superior toxicological profile compared to the lead compound roquinimex (1b, Linomide) and was selected for clinical studies (currently in phase II).
A fast and simple approach to novel cyclic isothioureas and related guanidine derivatives is presented in this study. The construction of the central basic scaffolds is achieved solely by the application of microwave-assisted chemistry, without any need of activating agents or protecting group manipulations. The product formation of various substituted guanidines from the corresponding isothiouronium salts was controlled by the nucleophilicity of the counterion and influenced by the reaction temperature. Further, a new fast-track access to tetrahydropyrimidin-2-ylamines was developed.
1,4]-Diazepan-6-ols are easily oxidized to ketones using Swern or Dess-Martin oxidation conditions. The fluorination of these [1,4]-diazepanones with diethylaminosulfur trifluoride (DAST) affords gem-difluorohomopiperazines. Detosylation under microwave conditions represents a rapid method to access the corresponding amines in high yields.
Pyrimidine derivatives R 0510Methods for the Construction of New Highly Functionalized Guanidines. -Reaction of the protected amino alcohols (II) generated from epoxides with the isothioronium salts (IV) leads to functionalized cyclic guanidines in good yields. In contrast, direct coupling of guanidines [cf. (IX)] with epoxides provides functionalized guanidines in low yields. -(WELLNER, E.; SANDIN*, H.; SWANSTEIN, M.-L.; Synlett 2004, 10, 1817-1819; Dep. Drug Discovery, Active Biotech AB, S-220 07 Lund, Swed.; Eng.) -Jannicke 01-135
Chemistry. -Interestingly treatment of the isothiouronium salt (XIIIa) with the amine (Xb) does not give the expected guanidine derivative but the cyclization product (XVI). -(SANDIN, H.; SWANSTEIN, M.-L.; WELLNER*, E.; J. Org. Chem. 69 (2004) 5, 1575-1580; Dep. Drug Discovery, Active Biotech AB, S-220 07 Lund, Swed.; Eng.) -Jannicke 29-144
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.