| 摘要 |
Disclosed are 1-oxo-isoindoline-4-carboxamide and 1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxamide derivatives as represented by the general formula (I), in which: R1 represents hydrogen, alkyl, cycloalkyl, (CH2)n-alkenyl, (CH2)n-alkynyl or alkyl-Z-alkyl, or else R1 represents a COOR, S(O)mR, aryl or aralkyl, wherein said alkyl, cycloalkyl, alkenyl, alkynyl, aryl or aralkyl groups are each optionally substituted; R2 represents one or more groups chosen from hydrogen, halogen, alkyl, cycloalkyl, alkenyl, alkynyl or alkyl-Z-alkyl group, or else R2 represents a haloalkyl, alkoxy, haloalkoxy, hydroxy, nitro, cyano, amino, NR7R8, COOR, CONR7R8, OCOalkyl, S(O)m-NR7R8, or an optionally substituted aryl group; R3 represents a trifluoromethyl group; R4 and R5 represent hydrogen, or else R4 and R5 form with the carbon atom that bears them, a saturated ring and which may also optionally contain one heteroatom chosen from O, N or S; R6 represents hydrogen, halogen, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, nitro, amino, NR7R8, COOR, NR7(SO2)R8, CONR7R8, or an optionally substituted aryl or heterocycle group; X represents a (C1-C2)alkylene group, optionally substituted with one or more alkyl groups; and wherein the remaining substituents are as defined herein. Important representative compounds include N-[(1S,2R)-1-benzyl-2-hydroxy-3-{ [3-(trifluoromethyl)benzyl]amino} propyl]-1-oxo-2-(1-propylbutyl)isoindoline-4-carboxamide and its hydrochloride (1:1); N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({ 1-[3-(trifluoromethyl)phenyl]cyclopropyl} amino)propyl]-7-[methyl(methylsulfonyl)amino]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride (1:1); N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({ 1-[3-(trifluoromethyl)phenyl]cyclopropyl} amino)propyl]-7-(3-cyanophenyl)-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride (1:1) and N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({ 1-[3-(trifluoromethyl)phenyl]cyclopropyl} amino)propyl]-7-(2-cyanophenyl)-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride (1:1). Further disclosed is a medicament which comprises a compound of formula (I) as defined above, or an addition salt of the compound with a pharmaceutically acceptable acid, or a hydrate or solvate of the compound of formula (I), for treating and for preventing Alzheimer's disease, Parkinson's disease, Huntington's disease, Creutzfeldt-Jakob disease, Down's syndrome, dementia with Lewy bodies, senile dementia, frontotemporal dementia, cerebral and systemic amyloidosis, mild cognitive impairments, cerebral amyloid angiopathy, primary and secondary memory disorders, amyotrophic lateral sclerosis, multiple sclerosis, peripheral neuropathies, diabetic neuropathies, migraine, mood disorders, depression, anxiety, vascular disorders, and cell proliferation disorders.
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