Two cyclic oxomorphorin derivatives

Abstract

The present invention relates to a compound represented by formula (I): wherein R 1 represents a C1-3 alkyl group, R 2 represents a hydrogen atom or a C1-3 alkyl group, Ar represents a phenyl group or the like which may be substituted with 1 to 3 substituents, X represents an oxygen atom or the like, n and m are the same or different and integers of 0 to 2, or a pharmacologically acceptable salt, and use thereof as a medicament.

1 . A compound represented by formula (I): 
       
         
           
           
               
               
           
         
       
       wherein (1) R 1  represents a C1-3 alkyl group, R 2  represents a hydrogen atom or a C1-3 alkyl group, or (2) R 1  and R 2 , together with the carbon atom to which they are attached, form a C3-6 cycloalkyl group,
 Ar represents a phenyl group which may be substituted with 1 to 3 substituents that are the same or different and selected from substituent group A1 or a pyridinyl group which may be substituted with 1 to 3 substituents that are the same or different and selected from substituent group A1,
 X represents a methylene group which may be substituted with 1 or 2 substituents selected from substituent group A1 or a vinylene group which may be substituted with 1 or 2 substituents selected from substituent group A1, an oxygen atom, or an imino group which may be substituted with a C1-6 alkyl group or a C1-6 acyl group, and n and m are the same or different and integers of 0 to 2, or a pharmacologically acceptable salt thereof; 
 Substituent group A1: (1) a halogen atom, (2) a hydroxyl group, (3) a cyano group, (4) a C3-8 cycloalkyl group, (5) a C3-8 cycloalkoxy group, (6) a C1-6 alkyl group (the C1-6 alkyl group may be substituted with 1 to 5 halogen atoms or 1 to 3 C1-6 alkoxy groups), (7) an amino group which may be substituted with 1 or 2 C1-6 alkyl groups (the C1-6 alkyl group may be substituted with 1 to 5 halogen atoms), (8) a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with 1 to 5 halogen atoms), and (9) a carbamoyl group which may be substituted with 1 or 2 C1-6 alkyl groups (the C1-6 alkyl group may be substituted with 1 to 3 halogen atoms). 
 
 
     
     
         2 . The compound or a pharmacologically acceptable salt thereof according to  claim 1 , wherein X represents a methylene group (the methylene group may be substituted with 1 or 2 substituents that are the same or different and selected from the group consisting of C1-6 alkyl groups and hydroxyl group), and n and m are 1. 
     
     
         3 . The compound or a pharmacologically acceptable salt thereof according to  claim 1 , wherein X represents an oxygen atom, and n and m are 1. 
     
     
         4 . The compound or a pharmacologically acceptable salt thereof according to  claim 1 , wherein X represents a methylene group, n is 1, and m is 0. 
     
     
         5 . The compound or a pharmacologically acceptable salt thereof according to  claim 1 , wherein Ar is a phenyl group substituted with 1 to 3 halogen atoms. 
     
     
         6 . The compound or a pharmacologically acceptable salt thereof according to  claim 1 , which is selected from the following group:
 1) (Z)-(1R,6R,9aR)-3-[3-Methoxy-4-(4-methylimidazol-1-yl)benzylidene]-1-methyl-6-(3,4,5-trifluorophenyl)tetrahydro-[1,4]oxazino[3,4-c][1,4]oxazin-4-one,   2) (Z)-(1S,6R,9aR)-3-[3-Methoxy-4-(4-methylimidazol-1-yl)benzylidene]-1-methyl-6-(3,4,5-trifluorophenyl)tetrahydro-[1,4]oxazino[3,4-c][1,4]oxazin-4-one,   3) (Z)-(1S,6R,9aR)-6-(3,4-Difluoro-phenyl)-3-[-3-methoxy-4-(4-methylimidazol-1-yl)benzylidene]-1-methyltetrahydro-[1,4]oxazino[3,4-c][1,4]oxazin-4-one,   4) (Z)-(6S,8aR)-6-(4-Fluorophenyl)-3-[3-methoxy-4-(4-methylimidazol-1-yl)benzylidene]-1,1-dimethyltetrahydropyrrolo[2,1-c][1,4]oxazin-4-one,   5) (Z)-(1S,6R,9aR)-3-[3-Methoxy-4-(4-methylimidazol-1-yl)benzylidene]-1-methyl-6-(4-chlorophenyl)hexahydropyrido[2,1-cl [1,4]oxazin-4-one,   6) (Z)-(1S,6S,8aR)-6-(4-Fluorophenyl)-3-[3-methoxy-4-(4-methylimidazol-1-yl)benzylidene]-1-methyltetrahydropyrrolo[2,1-c][1,4]oxazin-4-one,   7) (Z)-(1R,6S,8aR)-6-(4-Fluorophenyl)-3-[3-methoxy-4-(4-methylimidazol-1-yl)benzylidene]-1-methyltetrahydropyrrolo[2,1-c][1,4]oxazin-4-one,   8) (Z)-(6S,8aR)-6-(4-Chlorophenyl)-3-[3-methytoxy-4-(4-methylimidazol-1-yl)benzylidene]-1,1-dimethyltetrahydropyrrolo[2,1-c][1,4]oxazin-4-one,   9) (Z)-(1S,6S,8aR)-6-(4-Chlorophenyl)-3-[3-methoxy-4-(4-methylimidazol-1-yl)benzylidene]-1-methyltetrahydropyrrolo[2,1-c][1,4]oxazin-4-one,   10) (Z)-(1R,6S,8aR)-6-(4-Chlorophenyl)-3-[3-methoxy-4-(4-methylimidazol-1-yl)benzylidene]-1-methyltetrahydropyrrolo[2,1-c][1,4]oxazin-4-one,   11) (Z)-(6S,8aR)-3-[3-Methoxy-4-(4-methylimidazol-1-yl)benzylidene]-1,1-dimethyl-6-(3,4,5-trifluorophenyl)tetrahydropyrrolo[2,1-c][1,4]oxazin-4-one,   12) (Z)-(1S,6S,8aR)-3-[3-Methoxy-4-(4-methylimidazol-1-yl)benzylidene]-1-methyl-6-(3,4,5-trifluorophenyl)tetrahydropyrrolo[2,1-c]l[1,4]oxazin-4-one,   13) (Z)-(1R,6S,8aR)-3-[3-Methoxy-4-(4-methylimidazol-1-yl)benzylidene]-1-methyl-6-(3,4,5-trifluorophenyl)tetrahydropyrrolo[2,1-c][1,4]oxazin-4-one,   14) (Z)-(6S,8aR)-6-(3,4-Difluoro-phenyl)-3-[3-methoxy-4-(4-methylimidazol-1-yl)benzylidene]-1,1-dimethyltetrahydropyrrolo[2,1-c][1,4]oxazin-4-one,   15) (Z)-(1S,6S,8aR)-6-(3,4-Difluoro-phenyl)-3-[3-methoxy-4-(4-methylimidazol-1-yl)benzylidene]-1-methyltetrahydropyrrolo[2,1-c][1,4]oxazin-4-one,   16) (Z)-(1R,6S,9aR)-3-[3-Methoxy-4-(4-methylimidazol-1-yl)benzylidene]-1-methyl-6-(3,4,5-trifluorophenyl)hexahydropyrido[2,1-c][1,4]oxazin-4-one,   17) (Z)-(1S,6S,9aR)-3-[3-Methoxy-4-(4-methylimidazol-1-yl)benzylidene]-1-methyl-6-(3,4,5-trifluorophenyl)hexahydropyrido[2,1-c][1,4]oxazin-4-one,   18) (Z)-(6S,8aR)-3-[3-Methoxy-4-(4-methylimidazol-1-yl)benzylidene]-1,1-cyclopropyl-6-(3,4,5-trifluorophenyl)tetrahydropyrrolo[2,1-c][1,4]oxazin-4-one, and   19) (6a,9aR)-3-[1-[3-methoxy-4-(methyl-1H-imidazol-1-yl) phenyl-(Z)-methylidene]-1,1-dimethyl-6-(3,4,5-trifluorophenyl)tetrahydro[1,4]oxazino[3,4-c][1,4]oxazin-4-one.   
     
     
         7 . A drug containing the compound or a pharmacologically acceptable salt thereof according to any one of  claims 1  to  6  as an active ingredient. 
     
     
         8 . The drug according to  claim 7  for prophylactic or therapeutic treatment of a disease attributable to amyloid beta. 
     
     
         9 . The drug according to  claim 8 , the disease attributable to amyloid beta is Alzheimer's disease, senile dementia, Down's syndrome, or amyloidosis.