When tested in dog at mg kg

When tested in dog at 20mg/kg, showed a reduction of 56% of Aβ42 in the cerebrospinal fluid (CSF) 8h post doing, comparable to that of (see ). Upon evaluation of ap-1 in a one week repeated dose study in dog, at 10 and 20mg/kg/day, no increase in liver enzyme levels (ALT or AST) was observed. Only slight increase in bilirubin was present, which normalized within 24h after dosing. This represents an improvement versus , which in the same canine model showed increase in both liver enzymes and bilirubin at lower exposure levels. Most analogs from were prepared according to the route described in , . N-alkylation or arylation of dibromotriazole provided triazolo-derivatives – in good to excellent yields. Various substituents were then introduced at the 5-position of –, as depicted in . The resulting bromotriazoles – were then submitted to Suzuki reaction conditions in the presence of either boronate or potassium trifluoroborate salt to yield analogs , , , , , , . Compound was prepared in 68% yield from , via oxidation with manganese oxide. The synthesis of compounds and is shown in . Commercially available nitriles and were condensed with hydrazide to give and , respectively. Methylation of provided and its regioisomer , in a disappointing 1:6 ratio. Initially, the anilinotriazoles were prepared by addition of methyl hydrazine to thioureas, as exemplified in . Thus, starting from commercially available 4-F-benzonitriles, nucleophilic aromatic substitution with 4-Me-imidazole provided imidazo-aryl derivatives as the major regioisomers, in a moderate yield. Exposure of to ethanolic HCl provided iminoesters , isolated as HCl salts. When were treated with arylisothiocyanates , thioimidates were obtained. Upon treatment of with hydrazines, anilinotriazoles listed in were formed in yields varying from poor to excellent. This route could not provide all desired analogs, and thus formation of triazoles from cyanoimidates using a method developed by Webb and coworkers was investigated (). Addition of anilines to diphenyl cyanocarbonimidate provided cyano isoureas in low to moderate yields. This reaction needed to be performed at higher temperatures and proceeded with longer reaction times than the ones originally reported. The yields were improved when the addition was performed in the presence of a base, LiHMDS in particular. When treated with methyl hydrazine, cyclized to anilinotriazoles , usually as single regioisomers. For the 2-CF substituted cyanoisourea , the regioisomer was also formed in a low (22%) yield. When were subjected to Sandmeyer reaction conditions with t-butyl nitrite and Cu(II) bromide, bromotriazoles were formed in low to moderate yields. Side product was difficult to separate from the product mixtures, but its formation was diminished when NaNO and HBr were used in the Sandmeyer reaction. This synthetic pathway proceeded with low overall yields. Formation of the secondary products such as was another drawback. Given the beneficial effect of LiHMDS to the addition reaction of anilines to imidate , it was questioned whether this base would also help in adding anilines directly to bromotriazoles such as (). Previous attempts of introducing anilines on bromotriazole under classical Buchwald conditions failed. Gratifyingly, by addition of 3equiv of LiHMDS to a mixture of and anilines , at −78°C, bromoanilinotriazoles were obtained in high yields and as single regioisomers. When bromotriazoles were reacted with boronic esters under Suzuki reaction conditions, the desired anilinotriazoles were obtained, in moderate to good yields. A major side product of this reaction was the homocoupled product derived from (, ). Formation of was drastically decreased when the boronic ester was added dropwise at reflux to a solution of , base and catalyst. It was also found that using [1,1′-bisdiphenylphosphino)ferrocene]dichloropalladium (II) as catalyst provided better yields than tetrakis(triphenylphosphine)palladium(0).