title: 1-Alkyl-3-amino-5-aryl-1H-[1,2,4]triazoles: novel synthesis via cyclization of N-acyl-S-methylisothioureas with alkylhydrazines and their potent corticotropin-releasing factor-1 (CRF(1)) receptor antagonist activities.
abstract: Cyclizations of alkylhydrazines with N-acyl-S-methylisothioureas, readily synthesized from acyl chlorides, sodium thioisocyanate, dialkylamines then methyl iodide in a one-pot reaction, gave 1-alkyl-3-dialkylamino-5-phenyltriazoles 7 as major products. The regioisomers were assigned through the use of NOE NMR experiments. While bearing a N-bis(cyclopropyl)methyl-N-propylamino group, this series of compounds shows very good binding affinity on the human CRF(1) receptor. Among them, 1-methyl-3-[N-bis(cyclopropyl)methyl-N-propylamino]-5-(2,4-dichlorophenyl)-1H-[1,2,4]triazole 7a had the best binding affinity for the CRF(1) receptor (K(i)=9 nM).
authors.affiliation: Neurocrine Biosciences, Inc., 10555 Science Centre Drive, San Diego, CA 92121, USA. cchen@neurocrine.com
authors.forename: C
authors.initials: C
authors.lastname: Chen
authors.forename: R
authors.initials: R
authors.lastname: Dagnino
authors.forename: C Q
authors.initials: CQ
authors.lastname: Huang
authors.forename: J R
authors.initials: JR
authors.lastname: McCarthy
authors.forename: D E
authors.initials: DE
authors.lastname: Grigoriadis
mesh_terms: D006801:Humans; D006834:Hydrazines / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D013890:Thiourea / Q000737:chemistry*; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000099052:CRF Receptor, Type 1
chemical_list: D006834:Hydrazines; D018019:Receptors, Corticotropin-Releasing Hormone; D014230:Triazoles; D000099052:CRF Receptor, Type 1; D013890:Thiourea