- 3-Ethyl-6-methyl-isocytosines: Synthesis and solid state structural analysis
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The syntheses and solid state structures of 3-ethyl-6- methyl-5-alkyl-isocytosines (alkyl=H, Me, Et, n-Pr, n-Bu) are presented. These heterocycles consistently self-assemble into N-H N hydrogen-bonded dimers, which further associate by N-H···O=C interactions, or N-H···O-H···O=C hydrogen bonds involving water of crystallization, generating extended supramolecular networks. Crystal packing analysis indicates that although hydrogen bonding is the primary intermolecular interaction in these molecular crystals, the dispersion forces may play a decisive role in determining their final three-dimensional arrangements. (C) 2000 Elsevier Science Ltd.
- Custelcean, Radu,Craciun, Liliana
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- Discovery and SAR of 6-alkyl-2,4-diaminopyrimidines as histamine H 4 receptor antagonists
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This report discloses the discovery and SAR of a series of 6-alkyl-2-aminopyrimidine derived histamine H4 antagonists that led to the development of JNJ 39758979, which has been studied in phase II clinical trials in asthma and atopic dermatitis. Building on our SAR studies of saturated derivatives from the indole carboxamide series, typified by JNJ 7777120, and incorporating knowledge from the tricyclic pyrimidines led us to the 6-alkyl-2,4-diaminopyrimidine series. A focused medicinal chemistry effort delivered several 6-alkyl-2,4-diaminopyrimidines that behaved as antagonists at both the human and rodent H4 receptor. Further optimization led to a panel of antagonists that were profiled in animal models of inflammatory disease. On the basis of the preclinical profile and efficacy in several animal models, JNJ 39758979 was selected as a clinical candidate; however, further development was halted during phase II because of the observation of drug-induced agranulocytosis (DIAG) in two subjects.
- Savall, Brad M.,Chavez, Frank,Tays, Kevin,Dunford, Paul J.,Cowden, Jeffery M.,Hack, Michael D.,Wolin, Ronald L.,Thurmond, Robin L.,Edwards, James P.
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p. 2429 - 2439
(2014/04/17)
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