New tetrahydropyrrolo(1,2-a)(1,4)-diazepine-carboxamide compounds are beta secretase inhibitors useful to treat e.g. senile dementia, mild cognitive disorder, Huntington disease, Creutzfeldt-Jakob disease, migraine and anxiety

摘要

Tetrahydropyrrolo[1,2-a][1,4]-diazepine-carboxamide compounds (I) and their base or acid addition salts, hydrates or solvates are new. Tetrahydropyrrolo[1,2-a][1,4]-diazepine-carboxamide compounds of formula (I) and their base or acid addition salts, hydrates or solvates are new. R 1H, 1-10C alkyl, 3-7C cycloalkyl, (CH 2) n-(1-6C)alkenyl, (CH 2) n-(1-6C)alkynyl, 1-6C alkyl-Z-(1-6C alkyl), aryl or aralkyl (all optionally substituted by halo, 1-6C alkyl, 3-7C cycloalkyl, halo(1-6C)alkyl, 1-6C alkoxy, halo(1-6C)alkoxy, NR 7R 8, nitro, cyano, OR, COOR, CONR 7R 8or S(O) mNR 7R 8), COOR or S(O) mR; Z : Heteroatom comprising O, N or S(O) m; R 2halo(1-6C)alkyl, halo(1-6C)alkoxy, OH, 1-6C alkoxy, NO 2, CN, NH 2, NR 7R 8, COOR, CONR 7R 8, OCO(1-6C)alkyl, S(O) mNR 7R 8or aryl (all optionally substituted by one or more halo, 1-6C alkyl, 3-7C cycloalkyl, halo(1-6C)alkyl, (1-6C)alkoxy, halo(1-6C)alkoxy, NR 7R 8, NO 2, CN, OR, COOR, CONR 7R 8or S(O) mNR 7R 8), H (preferred), halo, 1-6C alkyl, 3-7C cycloalkyl, (1-6C)alkenyl, (1-6C)alkynyl or 1-6C alkyl-Z-(1-6C alkyl); R 3CF 3; either R 4, R 5H; or CR 4R 5ring containing 3-6 carbon atoms (optionally saturated and optionally containing 0 or 1 heteroatom comprising O, N or S); R 6H (preferred), halo, 1-6C alkyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-6C alkyl, NO 2, NH 2, NR 7R 8, COOR, NR 7(SO 2)R 8, CONR 7R 8or aryl; either R 7, R 8, R : H, 1-6C alkyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-6C alkyl, aryl, aryl(1-6C)alkylene or COR; or R 7R 8ring containing 5-7 carbon atoms (optionally saturated and substituted by heteroatom of O, N or S(O) m); m : 0-2; and n : 1-6. Where the carbon carrying the benzyl substituted by R2 is absolute configuration S, and the carbon carrying the hydroxyl is absolute configuration R. An independent claim is included for a substituted tetrahydro-1H-pyrrolo[1,4]diazepine-carboxylic acid compound of formula (III). [Image] [Image] ACTIVITY : Neuroprotective; Nootropic; Antiparkinsonian; Cerebroprotective; Vasotropic; Cardiovascular-gen.; Anticonvulsant; Antimigraine; Antidepressant; Tranquilizer; Antiarteriosclerotic; Cytostatic. MECHANISM OF ACTION : Beta-secretase inhibitor. The ability of (I) to inhibit beta-secretase was tested using fluorescence resonance energy transfer assay. The result showed that N-[(1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl]-1-oxo-2-(1-propylbutyl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-7-carboxamide exhibited an IC 5 0value of 1.40 mu M.