On April 2, 2009, Ghosh, Arun K.; Liu, Chunfeng; Devasamudram, Thippeswamy; Lei, Hui; Swanson, Lisa M.; Ankala, Sudha V.; Lilly, John C.; Bilcer, Geoffrey M. published a patent.Formula: C7H6F3NO The title of the patent was Preparation of (3-hydroxy-4-amino-butan-2-yl)-3-[2-(thiazol-2-yl)pyrrolidine-1-carbonyl]benzamide derivatives and related compounds as selective beta-secretase inhibitors. And the patent contained the following:
The title compounds [I; A1 = each (un)substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; A2 = each cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; X = CH2, O, (un)substituted NH, or S(O)w; or where X is CH or N, and is the attachment point for R6 or R7; L1, L5 = a bond, (un)substituted NH, S(O)q, (un)substituted alkylene; L4 = a bond, C(O), (un)substituted NH, S(O)q, (un)substituted alkylene; R2, R3 = S(O)2R11, C(O)R12, each (un)substituted NH2, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; R4, R5 = H, halogen, NO2, each (un)substituted OH, NH2, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, S(O)nR11, C(O)R12; R6, R7 = H, halogen, NO2, each (un)substituted OH, NH2, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, S(O)nR11, C(O)R12; R11 = H, each (un)substituted alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; R12 = H, each (un)substituted NH2, OH, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; m = 0-2] or pharmaceutically acceptable salts or solvates thereof were prepared The present invention provides novel β-secretase inhibitors which are capable of selectively reducing memapsin 2 catalytic activity relative to memapsin 1 catalytic activity or cathepsin D by greater than ∼5 or ∼10-fold. It also provides methods for their use, including methods of treating of Alzheimer’s disease. Thus, to 330 mg (R)-3-methyl-5-[2-(4-methylthiazol-2-yl)pyrrolidine-1-carbonyl]benzoic acid in CH2Cl2 at room temperature, 269 mg 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 162 mg HOBT were added, stirred at room temperature for 20 min, cooled to 0°, treated with a solution of (2R,3S)-3-amino-4-phenyl-1-[3-(trifluoromethyl)benzylamino]butan-2-ol and 2 mL diisopropylethylamine in CH2Cl2, and stirred at room temperature for 16 h to yield 60% N-[(2S,3R)-3-hydroxy-1-phenyl-4-[[3-(trifluoromethyl)benzyl]amino]butan-2-yl]-3-methyl-5-[[(R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl]carbonyl]benzamide (II). II showed Ki of 7.09, 1,079.9, and 825.73 nM, for inhibiting memapsin 2 (β-secretase), cathepsin D, memapsin 1 (β-secretase 2), resp., and showed IC50 of 23 nM against memapsin 2 (β-secretase). The experimental process involved the reaction of (6-(Trifluoromethyl)pyridin-3-yl)methanol(cas: 386704-04-7).Formula: C7H6F3NO
The Article related to thiazolylpyrrolidinecarbonylbenzamide preparation selective secretase inhibitor, alzheimer disease treatment thiazolylpyrrolidinecarbonylbenzamide preparation, hydroxyaminobutanylthiazolylpyrrolidinecarbonylbenzamide preparation secretase inhibitor and other aspects.Formula: C7H6F3NO
Referemce:
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