16071-28-6Relevant articles and documents
5-Cyanopyrimidine derivatives as a novel class of potent, selective, and orally active inhibitors of p38a MAP kinase
Liu, Chunjian,Wrobleski, Stephen T.,Lin, James,Ahmed, Gulzar,Metzger, Axel,Wityak, John,Gillooly, Kathleen M.,Shuster, David J.,McIntyre, Kim W.,Pitt, Sidney,Shen, Ding Ren,Zhang, Rosemary F.,Zhang, Hongjian,Doweyko, Arthur M.,Diller, David,Henderson, Ian,Barrish, Joel C.,Dodd, John H.,Schieven, Gary L.,Leftheris, Katerina
, p. 6261 - 6270 (2007/10/03)
A novel class of 5-cyanopyrimidine-based inhibitors of p38a MAP kinase has been investigated. Analogues optimized through SAR iterations display low nanomolar enzymatic and cellular activity. The in vivo efficacy of this class of p38 inhibitors was demonstrated by 3a and 3b (>50% reduction in TNF levels when orally dosed at 5 mg/kg, 5 h prior to LPS administration in an acute murine model of inflammation). For 3a and 3b, the previously identified N-methoxybenzamide moiety (1) was replaced with N-(isoxazol-3-yl)benzamide, thereby providing increased metabolic stability. Cyanopyrimidine 3a demonstrated 100% oral bioavailability in mouse. High p38 kinase selectivity versus over 20 kinases was observed for analogue 3b. Direct hydrogen bonding of the cyano nitrogen of the 5-cyanopyrimidine core to the backbone NH of Met109 was confirmed by X-ray crystallographic analysis of 3a bound to p38α.
Synthesis of Pyrimidine Derivatives by the Reaction of Ketene Dithioacetals with Amides
Kohra, Shinya,Tominaga, Yoshinori,Hosomi, Akira
, p. 959 - 968 (2007/10/02)
Reactions of methyl 2-cyano-3,3-bis(methylthio)acrylate (1a) with carboxamides 2a-g in the presence of sodium hydride in a mixture of benzene and N,N-dimethylacetamide took place displacement with the methylthio group to give the corresponding methyl 3-N-acylamino-2-cyano-3-(methylthio)acrylates 3a-g which were readily converted to the corresponding pyrimidine derivatives at reflux in methanol in good yields.Reactions of 2-cyano-3,3-bis(methylthio)acrylonitrile (1b) with the carboxamides 2a-f gave directly pyrimidine-5-carbonitrile derivatives 7a-f.Ketene dithioacetals 1a,b smoothly reacted with thioamide 2g or urea 2h,i to give the expected pyrimidine derivatives 9,10a,b.Polyfunctionalized pyrimidines, thus obtained, were also used for the synthesis of fused pyrimidine derivatives.
