Compounds which inhibit beta-secretase activity and methods of use thereof
a beta-secretase and compound technology, applied in the direction of biocide, amide active ingredients, drug compositions, etc., can solve the problems of loss of memory, confusion and disorientation,
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example 1
Preparation of Selected Beta-Secretase Inhibitor Compounds
example 1.1
Synthesis of tert-butyl 3-hydroxy-4-(3-methoxybenzylamino)-1-phenylbutan-2-ylcarbamate
[0228]Methylthiazole (1.0 g, 10.1 mmol) in THF at −78° C. was treated with n-BuLi (1.6 M, 7.56 mL) for 30 min, DMF (1.4 mL, 18.2 mmol) was added dropwise. The resulting reaction mixture was warmed to r.t. After the starting material was disappeared (by TLC), the reaction mixture was recooled to 0° C. and LAH (0.69 g, 18.5 mmol) was added. The mixture was warmed to r.t. and stirred for 1 h, the reaction was quenched with aqueous NH4Cl, diluted with EtOAc. The organic solution was separated, extracted twice with EtOAc, dried with Na2SO4, and concentrated. The residue was purified with flash chromatography to give the corresponding alcohol as a light yellow oil. 1H-NMR: (300 MHz, CDCl3), δ: 6.89 (s, 1H); 4.95 (s, 2H); 2.48 (s, 3H).
[0229]Methylthiazole methanol (0.57 g, 4.4 mmol) was treated with mesyl chloride (0.42 mL, 5.4 mmol) and triethyl ethylamine at 0° C. in dichloromethane. The resulting mixtu...
example 1.2
Synthesis of N1-(3-hydroxy-4-(3-methoxybenzylamino)-1-phenylbutan-2-yl)-5-(N-methylmethylsulfonamido)-N3-(1-phenylethyl)isophthalamide
[0233]Tert-butyl 3-hydroxy-4-(3-methoxybenzylamino)-1-phenylbutan-2-ylcarbamate was obtained in a single step by the ring opening reaction of tert-butyl-(1-oxiranyl-2-phenylethyl)-carbamnate with 3-methoxybenzylamine under reflux condition in 2-propanol. Deprotection of Boc group by treatment of TFA in CH2Cl2 or methanolic HCl provided 3-amino-1-(3-methoxybenzylamino)-4-phenylbutan-2-ol, which was directly exposed to peptide coupling reaction with 3-(N-methylmethylsulfonamido)-5-(1-phenylethylcarbamoyl)benzoic acid in presence of N-ethyl-N′-(dimethylaminopropyl)carbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole hydrate and diisopropylethylamine in a mixture of DMF and CH2Cl2 to afford N1-(3-hydroxy-4-(3-methoxybenzylamino)-1-phenylbutan-2-yl)-5-(N-methylmethylsulfonamido)-N3-(1-phenylethyl)isophthalamide.
[0234]Dimethyl 5-aminoisophthalate was me...
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