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2005
Pyrazine derivatives
R 0550
Identification of 4-Piperazin-1-yl-quinazoline Template Based Aryl and Benzyl
as Potent, Selective, and Orally Bioavailable Inhibitors of Platelet-De03- 154 Thioureas
rived Growth Factor (PDGF) Receptor. — The thiourea analogues are prepared following three routes: i) coupling of piperazine derivatives (I) with isothiocyanates (II),
ii) reaction of amines (IV) with thiocarbonyl diimidazole (V) and subsequent treatment
of the resulting mixture of isothiocyanate/amino thiocarbonyl imidazole with (I), iii)
treatment of (I) with thiophosgene and subsequent reaction of the resulting chloro-thio-carbamate with amines. Benzyl and aryl thioureas (III) display the desired potency/
selectivity profile. These compounds reveal significant selectivity towards β-PDGFR.
Side chain optimization of the quinazoline ring affords compounds with basic side
chains possessing improved water solubility and a favorable pharmacokinetic profile
including high oral bioavailability and long plasma half life (no yields given). —
(HEATH*, J. A.; MEHROTRA*, M. M.; CHI, S.; YU, J.-C.; HUTCHALEELAHA,
A.; HOLLENBACH, S. J.; GIESE, N. A.; SCARBOROUGH, R. M.; PANDEY, A.;
Bioorg. Med. Chem. Lett. 14 (2004) 19, 4867-4872; Dep. Med. Chem., Millenium
Pharm., Inc., South San Francisco, CA 94080, USA; Eng.) — H. Hoennerscheid
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