Beta-amyloid protein production/secretion inhibitors

Abstract

Provided are novel compounds having an inhibitory activity against production or secretion of β-amyloid protein. They embrace compounds represented by the following formula (1): and capable of being replaced with a variety of substituents; and salts thereof, and solvates of any one of them.

1 - 17 . (canceled)  
     
     
         18 . A compound represented by the following formula (3):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 15  represents a heterocyclic group which may have a substituent,  
 R 16  represents a cyclic hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent,  
 R 17  represents pyridyl group which may have at least one substituent,  
 R 18  represents a hydrogen atom or a C 1-6  alkyl group, and  
 X represents —S—, —SO— or —SO 2 —;  
 or N-oxide or S-oxide of the compound; salt thereof; or solvate of the above-described compound.  
 
     
     
         19 . The compound of  claim 18 , wherein X represents —SO— or —SO 2 —; or N-oxide or S-oxide of the compound; salt thereof; or solvate of the above-described compound.  
     
     
         20 . The compound of  claim 18 , wherein X represents —SO 2 —; or N-oxide or S-oxide of the compound; salt thereof; or solvate of the above-described compound.  
     
     
         21 . The compound of  claim 18 , wherein the heterocyclic group represented by R 15  or R 16  is a 3- to 7-membered saturated or 4- to 7-membered unsaturated monocyclic heterocyclic group having from 1 to 4 atoms selected from nitrogen atom, oxygen atom and sulfur atom, or a 7- to 14-membered polycyclic heterocyclic group having from 1 to 4 atoms selected from nitrogen atom, oxygen atom and sulfur atom; or N-oxide or S-oxide of the compound; salt thereof; or solvate of the above-described compound.  
     
     
         22 . The compound of  claim 18 , wherein the cyclic hydrocarbon group represented by R 16  is a cycloalkyl group having from 3 to 7 carbon atoms, cycloalkenyl group having from 4 to 7 carbon atoms, monocyclic or polycyclic aromatic hydrocarbon group having from 6 to 14 carbon atoms, spirohydrocarbon group having from 7 to 11 carbon atoms, crosslinked cyclic hydrocarbon group having from 7 to 10 carbon atoms or condensed polycyclic hydrocarbon group having from 8 to 14 carbon atoms; or N-oxide or S-oxide of the compound; salt thereof; or solvate of the above-described compound.  
     
     
         23 . The compound of  claim 18 , wherein the substituent for the group represented by R 15 , R 16 , or R 17  is a group -Q 201 -Q 202 -Q 203 -Q 204 , Q 205 -Q 206 -Q 207 , in which represents a single bond, an alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 2 to 6 carbon atoms or a heterocyclic group; Q 202  represents a single bond, —O—, —NH—, —CH═—N—, —C(alkyl)═N—, —N(alkyl)- or —S—; Q 203  represents a single bond, —CO—, —CS—, —SO—, —SO 2 — or —CONH—; Q 204  represents a single bond, an alkyl group from 1 to 6 carbon atoms, an alkenyl group having from 2 to 6 carbon atoms, a cycloalkyl group, a cycloalkenyl group, an aromatic hydrocarbon group or a heterocyclic group; Q 205  represents a single bond, —NH— or —N(alkyl)-; Q 206  represents a single bond, —O—, —CO—, —CS—, —SO 2 —, —SO— or —S—; and Q 207  represents a hydrogen atom, a halogen atom, a hydroxy group, an oxo group, a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 3-8  cycloalkyl group, a C 1-6  alkoxy group, a C 2-6  alkenyloxy group, an azide group, a cyano group, an amino group, a C 1-6  alkylamino group, a di(C 1-6  alkyl)amino group, a C 2-6  alkanoylamino group, a di(C 2-6  alkanoyl)amino group, a carboxyamino group, a C 1-6  alkoxycarbonylamino group, a di(C 1-6  alkoxy)carbonylamino group, a heterocyclic group, an aromatic hydrocarbon group, a cycloalkenyl group, a heterocyclic oxy group, or an aromatic hydrocarbon-oxy group (wherein, the alkyl group having from 1 to 6 carbon atoms, alkenyl group having from 2 to 6 carbon atoms, cycloalkyl group, cycloalkenyl group, heterocyclic group, heterocyclic-oxy group, aromatic hydrocarbon group or aromatic hydrocarbon-oxy group may be substituted with 1 to 3 substituents selected from halogen atoms, C 1-6  alkyl groups, C 1-6  alkoxy groups, C 2-6  alkenyl groups, carboxyamino C 1-6  alkyl groups, C 1-6  alkoxycarbonylamino C 1-6  alkyl groups, formyl group, C 2-6  alkanoyl groups, oxo group, nitro group, cyano group, azide group, amidino group, C 2-6  alkenyloxy groups, hydroxy group, carboxyl group, C 7-16  aralkyl groups, thioxo group, C 2-7  alkanoyl groups, C 2-7  thioalkanoyl groups, thioformyl group, amino group, C 1-6  alkylamino groups, di(C 1-6  alkyl)amino groups, C 1-6  alkoxycarbonyl groups, carbamoyl group, C 1-6  alkylcarbamoyl groups, di(C 1-6  alkyl)carbamoyl groups, thiocarbamoyl group, C 1-6  alkylthiocarbamoyl groups, di(C 1-6  alkyl)thiocarbamoyl groups, C 1-6  alkoxycarbamoylamino groups, 
 C 1-6  alkoxycarbamoyl(C 1-6  alkyl)amino groups, C 2-7  alkanoylamino groups, C 2-7  alkanoyl (C 1-6  alkyl)amino groups, thio C 2-7  alkanoylamino groups, thio C 2-7  alkanoyl (C 1-6  alkyl)amino groups, formylamino group, formyl(C 1-6  alkyl)amino groups, thioformylamino group, thioformyl(C 1-6  alkyl)amino groups, C 2-7  alkanoyloxy groups, formyloxy group, C 1-6  alkoxycarbonyloxy groups, carbamoyloxy group, C 1-6  alkylcarbamoyloxy groups, di(C 1-6  alkyl)carbamoyloxy groups, aminocarbonylamino group, (C 1-6  alkyl)aminocarbonylamino groups, di(C 1-6  alkyl)aminocarbonylamino groups, aminocarbonyl(C 1-6  alkyl)amino groups, (C 1-6  alkyl)aminocarbonyl(C 1-6  alkyl)amino groups, di(C 1-6  alkyl)aminocarbonyl(C 1-6  alkyl)amino groups, mercapto group, C 1-6  alkylthio groups, C 1-6  alkylsulfinyl groups, C 1-6  alkylsulfonyl groups, aminosulfonyl group, C 1-6  alkylaminosulfonyl groups, di(C 1-6  alkyl)aminosulfonyl groups, C 1-6  alkylsulfonylamino groups, C 1-6  alkylsulfonyl(C 1-6  alkyl)amino groups, aminosulfonylamino group, C 1-6  alkylaminosulfonylamino groups, di(C 1-6  alkyl)aminosulfonylamino groups, aminosulfonyl(C 1-6  alkyl)amino groups, C 1-6  alkylaminosulfonyl(C 1-6  alkyl)amino groups, and di(C 1-6  alkyl)aminosulfonyl(C 1-6  alkyl)amino groups; or N-oxide or S-oxide of the compound; salt thereof; or solvate of the above-described compound.    
     
     
         24 . The compound of  claim 18 , wherein R 16  represents a monocyclic or polycyclic aromatic hydrocarbon group having from 6 to 14 carbon atoms, or a heterocyclic group (in which, the hydrocarbon group or heterocyclic group may have 1 to 3 substituents selected from halogen atoms, C 1-6  alkyl groups, C 1-6  alkoxy groups, C 2-6  alkenyl groups, formyl group, C 2-6  alkanoyl groups, carboxyl group, carboxyamino C 1-6  alkyl groups, C 1-6  alkoxycarbonylamino C 1-6  alkyl groups, oxo group, nitro group, cyano group, amidino group, C 2-7  alkenyloxy groups, hydroxy group, thioxo group, amino group, C 1-6  alkylamino groups, di C 1-6  alkylamino groups, C 1-6  alkoxycarbonyl groups, carbamoyl group, C 1-6  alkylcarbamoyl groups, di C 1-6  alkylcarbamoyl groups, thiocarbamoyl group, C 1-6  alkylthiocarbamoyl groups, di C 1-6  alkylthiocarbamoyl groups, mercapto group, C 1-6  alkylthio groups, C 1-6  alkylsulfinyl groups and C 1-6  alkylsulfonyl groups); and 
 R 15  represents a heterocyclic group (in which, the heterocyclic group may be substituted with a halogen atom, C 1-6  alkyl group, C 1-6  alkoxy group, C 2-6  alkenyl group, C 2-6  alkenyloxy group, hydroxy group, carboxyl group, carboxy C 1-6  alkyl group, C 1-6  alkoxycarbonyl C 1-6  alkyl group, C 1-6  alkoxycarbonyl-C 2-6  alkenyl group, hydroxyl C 1-6  alkyl group, C 6-14  aromatic hydrocarbon-sulfonyl C 1-6  alkyl group, heterocyclic-C 1-6  alkylamino group, heterocyclic group, heterocyclic-C 1-6  alkyl group, C 6-14  aromatic hydrocarbon group, C 6-14  aromatic hydrocarbon C 1-6  alkyl group, C 6-14  aromatic hydrocarbon thio C 1-6  alkyl group, azido-(C 1-6  alkyl) group, amino C 1-6  alkyl group, C 1-6  alkylamino C 1-6  alkyl group, di C 1-6  alkylamino C 1-6  alkyl group, hydroxyl C 1-6  alkylamino C 1-8  alkyl group, C 1-6  alkoxy C 1-6  alkylamino C 1-6  alkyl group, (hydroxy C 1-6  alkyl)(C 1-6  alkoxy C 1-6  alkyl)amino C 1-6  alkyl group, C 2-6  alkanoylamino C 1-6  alkyl group, C 6-14  aromatic hydrocarbon sulfonylamino C 1-6  alkyl group, C 1-6  alkoxycarbonylamino C 1-6  alkyl group, carbamoylamino C 1-6  alkyl group, N-alkylcarbamoylamino C 1-6  alkyl group, N,N-dialkylcarbamoylamino C 1-6  alkyl group, aminosulfonylamino C 1-6  alkyl group, N-alkylsulfonylamino C 1-6  alkyl group, N,N-dialkylsulfonylamino C 1-6  alkyl group, C 6-14  aromatic hydrocarbon C 1-6  alkylamino group, heterocyclic C 1-6  alkylamino group, carbamoyloxy C 1-6  alkyl group, N-alkylcarbamoyloxy C 1-6  alkyl group, N,N-dialkylcarbamoyloxy C 1-6  alkyl group, C 6-14  aromatic hydrocarbon-C 1-6  alkylcarbamoyloxy C 1-6  alkyl group, C 1-6  alkoxycarbonyloxy-C 1-6  alkyl group, C 6-14  aromatic hydrocarbonoxycarbonyloxy C 1-6  alkyl group, C 6-14  aromatic hydrocarbonsulfonylamino-C 1-6  alkanoylamino C 1-6  alkyl group, C 1-6  alkoxycarbonylamino C 1-6  alkylamino group, amino C 1-6  alkylamino group, C 1-6  alkylamino C 1-6  alkylamino group, di(C 1-6  alkyl)amino C 1-6  alkylamino group, carboxyamino C 1-6  alkyl group, C 1-6  alkoxycarbonylamino C 1-6  alkyl group, C 1-6  alkylsulfonylamino C 1-6  alkyl group, amino C 1-6  alkylcarbonylamino C 1-6  alkyl group, N—C 1-6  alkylamino C 1-6  alkylcarbonylamino C 1-6  alkyl group, N,N-di C 1-6  alkylamino C 1-6  alkylcarbonylamino C 1-6  alkyl group, heterocyclic carbonyl group, heterocyclic carbonylamino group, C 6-14  aromatic hydrocarboncarbonyl group, C 6-14  aromatic carbonylamino group, heterocyclic C 1-6  alkylcarbonylamino C 1-6  alkyl group, heterocyclic C 2-6  alkenylcarbonylamino C 1-6  alkyl group, C 6-14  aromatic hydrocarbonalkenylcarbonylamino C 1-6  alkyl group, C 6-14  aromatic hydrocarboncarbonylamino C 1-6  alkyl group, heterocyclic carbonylamino C 1-6  alkyl group, C 1-6  alkoxyoxalylamino C 1-6  alkyl group, carbamoyl group, N—C 1-6  alkylcarbamoyl group, N,N-di C 1-6  alkylcarbamoyl group, C 1-6  alkyl-C 3-8  cycloalkylcarbamoyl group, C 3-8  cycloalkyl-C 1-6  alkylcarbamoyl group, heterocyclic carbamoyl group, C 1-6  aromatic carbamoyl group, heterocyclic carbonylhydrazonomethyl group, C 6-14  aromatic hydrocarboncarbonylhydrazonomethyl group, C 1-6  alkylthio C 1-6  alkylcarbamoyl group, C 1-6  alkylsulfinyl C 1-6  alkylcarbamoyl group, C 1-6  alkylsulfonyl C 1-6  alkylcarbamoyl group, hydroxyaminocarbonyl group, hydrazinocarbonyl group or N—C 1-6  alkylhydrazinocarbonyl group, thioformylamino-C 6-14  aromatic hydrocarbon-thiocarbonylamino C 1-6  alkyl group, thioformyl-(C 1-6  alkylamino-C 6-14  aromatic hydrocarbon-thiocarbonylamino C 1-6  alkyl group, formylamino-C 6-14  aromatic hydrocarbon-carbonylamino C 1-6  alkyl group,    formyl-C 1-6  alkylamino-C 6-14  aromatic hydrocarbon-carbonylamino C 1-6  alkyl group, C 1-6  alkanoyl-heterocycle-carbonylamino C 1-6  alkyl group, di(C 2-6  alkanoyl)amino(C 1-6  alkyl) group, di(C 1-6  alkoxycarbonyl)amino C 1-6  alkyl group, C 1-6  alkyl-heterocycle-carbonyl group, C 3-7  cycloalkyl C 1-6  alkylaminocarbonyl group, C 1-6  alkoxyaminocarbonyl group, (hydroxy)(C 1-6  alkyl)aminocarbonyl group, (C 1-6  alkoxy)(C 1-6  alkyl)aminocarbonyl group, N′—C 1-6  alkylhydrazinocarbonyl group, N′,N′-di C 1-6  alkylhydrazinocarbonyl group, N,N′-di C 1-6  alkylhydrazinocarbonyl group, N,N′,N′-tri C 1-6  alkylhydrazinocarbonyl group, N′-(heterocycle-carbonyl)-hydrazinocarbonyl group, formyl group, hydroxyimino group, C 1-6  alkoxyimino group, bis(C 1-6  alkoxy C 1-6  alkyl)amino C 1-6  alkyl group, hydroxy-C 1-6  alkyl-heterocyclic group, C 1-6  alkoxy-C 1-6  alkyl-heterocyclic group, C 1-6  alkoxycarbonylamino C 1-6  alkyl-heterocyclic group, amino C 1-6  alkyl-heterocyclic group, N—C 1-6  alkylamino C 1-6  alkyl-heterocyclic group, N,N-di C 1-6  alkylamino C 1-6  alkyl-heterocyclic group, hydroxy-heterocyclic group, C 1-6  alkoxy-heterocyclic group, carboxy-C 2-5  alkenyl group, or oxo group (wherein, the above-described C 6-14  aromatic hydrocarbon group or heterocyclic group may be substituted with a halogen atom, C 1-6  alkyl group, C 1-6  alkoxy group, C 2-6  alkenyl group, formyl group, C 2-6  alkanoyl group, carboxyl group, carboxyamino C 1-6  alkyl group, C 1-6  alkoxycarbonylamino C 1-6  alkyl group, oxo group, nitro group, cyano group, amidino group, C 2-6  alkenyloxy group, hydroxy group, thioxo group, amino group, C 1-6  alkylamino group, di C 1-6  alkylamino group, amino C 1-6  alkyl group, C 1-6  alkoxycarbonyl group, carbamoyl group, C 1-6  alkylcarbamoyl group, di C 1-6  alkylcarbamoyl group, thiocarbamoyl group, C 1-6  alkylthiocarbamoyl group, di(C 1-6  alkyl)thiocarbamoyl group, C 2-7  alkanoylamino group, C 2-7  alkanoyl(C 1-6  alkyl)amino group, thio(C 2-7  alkanoyl)amino group, thio(C 2-7  alkanoyl)(C 1-6  alkyl)amino group, formylamino group, formyl(C 1-6  alkyl)amino group, thioformylamino group, thioformyl(C 1-6  alkyl)amino group, C 2-7  alkanoyloxy group, formyloxy group, mercapto group, C 1-6  alkylthio group, C 1-6  alkylsulfinyl group, C 1-6  alkylsulfonyl group, aminosulfonyl group, C 1-6  alkylaminosulfonyl group, di(C 1-6  alkyl)aminosulfonyl group, C 1-6  alkylsulfonylamino group or C 1-6  alkylsulfonyl(C 1-6  alkyl)amino group); or N-oxide or S-oxide of the compound; salt thereof, or solvate of the above-described compound.    
     
     
         25 . A medicament comprising, as an active ingredient, a compound of  claim 18 , or N-oxide or S-oxide of the compound, salt thereof, or solvate of the above-described compound.  
     
     
         26 . The medicament of  claim 25 , which is used for prevention or treatment of a disease resulting from abnormal production or secretion of β-amyloid.  
     
     
         27 . The medicament of  claim 25 , which is used for prevention or treatment of Alzheimer disease or Down syndrome.  
     
     
         28 . A pharmaceutical composition comprising a compound of  claim 18 , or N-oxide or S-oxide of the compound, salt thereof, or solvate of the above-described compound; and a pharmaceutically acceptable carrier.  
     
     
         29 . A method to treat a disease resulting from abnormal production or secretion of β-amyloid, which comprises administering to a subject an effective amount of a compound of  claim 18 , or N-oxide or S-oxide of the compound, salt thereof, or solvate of the above-described compound.  
     
     
         30 . The method of  claim 29 , wherein the disease resulting from abnormal production or secretion of β-amyloid protein is Alzheimer disease or Down syndrome.