- 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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- Synthesis and in vitro antitumor activity of novel diaryl urea derivatives
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A series of novel diaryl ureas containing 4-[(2-amino-6-trifluromethyl) pyrimidine-4-yl]piperazine-1-yl group were synthesized and evaluated for their cytotoxic activities in a panel of human cancer cell lines. Compared with the reference drug Sorafenib, some compounds showed more potent and a broader spectrum of anti-cancer activities. Among them, compound 2p demonstrated significant inhibitory activities against MDA-MB-231, HT-29 and MCF-7 cell lines with IC50 values of 0.016, 0.63, 0.001 μmol/L, respectively.
- Zhao, Yan-Fang,Liu, Zi-Jian,Zhai, Xin,Ge, Dan-Dan,Huang, Qiang,Gong, Ping
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p. 386 - 388
(2013/07/19)
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- Studies on synthesis of novel triazolalkyl tagged trifluoromethyl substituted pyrimidine derivatives and their evaluation for cytotoxic activity
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The 2-amino-6-trifluoromethyl-3H-pyrimidin-4-one 1 was propargylated to give two regioisomers 2, 3 in definite proportions. Both regioisomers 2 and 3 were independently reacted with alkyl, aryl or cycloalkyl substituted azides under Sharpless conditions a
- Nagender, Punna,Reddy, Gannarapu Malla,Kumar, Royya Naresh,Reddy, Anugu Chandrashekar,Velatooru, Loka Reddy,Pamanji, Rajesh,Rao, Janapala Venkateswara,Narsaiah, Banda
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p. 865 - 871
(2013/12/04)
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- New fluoro intermediates for herbicidal sulfonylureas
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New pyrimidine and triazine intermediates for herbicidal sulfonylureas are prepared as follows: 2,4-dichloro-6-methylpyrimidine is converted via a halogenation, halogen exchange and substitution sequence to 2-amino-4-trifluoromethyl-6-trifluoromethoxypyrimidine. New fluoromethyl-triazines are available starting from guanidine, trichloroacetonitrile and difluoroacetic anhydride, or alternatively from thiocarbamoyl guanidine and chlorodifluoroacetic ester ring closure. To obtain new o-fluoroalkyl-benzenesulfonamide precursors, o-chlorobenzaldehyde was fluorinated with sulfur tetrafluoride, or a bromobenzene derivative was subjected to a substitution reaction with sodium pentafluoropropionate. Sulfonylureas derived from trifluoromethylpyrimidines with an m-methylthio substituent are selective post-emergence herbicides in cotton, presumably due to sulfone metabolization. Selectivity in wheat is obtained by combining 4-methoxy-6-trifluoromethyl-pyrimidine with a lipophilic difluoromethylbenzenesulfonamide moiety. Also in the difluoromethyl-triazine series, the combination with the difluoromethyl-benzenesulfonamide moiety is a good choice for wheat selectivity. Chlorodifluoromethyl- and trifluoromethyltriazines, however, combine better with an aromatic ester for best activity and selectivity in wheat. Selected compounds are undergoing broad field tests in wheat.
- Hamprecht, Gerhard,Mayer, Horst,Westphalen, Karl-Otto,Walter, Helmut
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p. 566 - 570
(2007/10/03)
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- Strong dimerization of ureidopyrimidones via quadruple hydrogen bonding
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6-Methyl-2-butylureidopyrimidone dimerizes via four hydrogen bonds in the solid state as well as in CHCl3 solution via a donor-donor-acceptor-acceptor (DDAA) array of hydrogen bonding sites in the 4[1H]-pyrimidinone tautomer. An intramolecular hydrogen bond from the pyrimidine NH group to the urea oxygen atom preorganizes the molecules for dimerization. The dimerization constant of the dimer in CHCl3 exceeds 106 M-1. In CHCl3 containing DMSO, the dimer is in equilibrium with the monomeric G[1H]-pyrimidinone tautomer. In 6-phenyl-2-butylureidopyrimidone, the 4[1H]-pyrimidinone tautomer coexists with the pyrimidin-4-ol form, which dimerizes with similar high dimerization constants via four hydrogen bonds in a DADA array. The latter tautomer predominates in derivatives with electronegative 6-substituents, like 6-nitrophenyl- and 6-trifluoromethyl-2-butylureidopyrimidone Due to its simple preparation and high dimerization constant, the ureidopyrimidone functionality is a useful building block for supramolecular chemistry.
- Beijer, Felix H.,Sijbesma, Rint P.,Kooijman, Huub,Spek, Anthony L.,Meijer
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p. 6761 - 6769
(2007/10/03)
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