Modulators for amyloid beta

Abstract

The invention relates to compounds of formula wherein R 1 , R 2 , R3, R 4 , and Ar are as defined in the specification and claims, or to pharmaceutically active acid addition salts of such compounds. Compounds of formula I are modulators for amyloid beta and may be useful for the treatment or prevention of a disease associated with the deposition of β-amyloid in the brain, in particular Alzheimer's disease, and other diseases such as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.

1 . A compound of formula I 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is hydrogen, lower alkyl or is lower alkyl substituted by hydroxy; 
         R 2  is hydrogen, lower alkoxy or lower alkyl; 
         R 3  and R 4  are each independently hydrogen, halogen, lower alkyl, C(O)O-lower alkyl, OR′, NR″R′″, lower alkyl substituted by halogen or hydroxy, or is phenyl or benzyl, each of which is optionally substituted by one or two halogen atoms; 
         R′ is lower alkyl, or is phenyl, benzyl or pyridinyl, whereine phenyl, benzyl or pyridinyl are each optionally substituted by one or more halogen, lower alkyl or lower alkyl substituted by fluoro; 
         R″ is hydrogen or lower alkyl; 
         R′″ is lower alkyl, lower alkyl substituted by one or two hydroxy groups, CH(CH 2 OH)-phenyl, —(CH 2 ) 2 O-lower alkyl, or phenyl substituted by halogen, or 
         R″ and R′″ together with the N-atom to which they are attached form a heterocyclic ring, optionally substituted by one or more lower alkyl, CH 2 C(O)O-lower alkyl, or CH 2 C(O)OH; 
         Ar is a five-membered heteroaryl group; 
         or a pharmaceutically active acid addition salt thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein Ar is imidazol-1-yl. 
     
     
         3 . The compound of  claim 2 , wherein one of R 3  or R 4  is NR″R′″ and R″ and R′″ together with the N-atom to which they are attached form a heterocyclic ring, optionally substituted by one or more lower alkyl, CH 2 C(O)O-lower alkyl or CH 2 C(O)OH. 
     
     
         4 . The compound of  claim 2 , wherein one of R 3  or R 4  is OR′. 
     
     
         5 . The compound of  claim 2 , wherein one of R 3  or R 4  is NR″R′″ and R″ is H or lower alkyl and R′″ is lower alkyl, lower alkyl substituted by one or two hydroxy groups, —(CH 2 ) 2 OCH 3 , or phenyl substituted by halogen. 
     
     
         6 . The compound of  claim 1 , wherein one of R 3  and R 4  is halogen. 
     
     
         7 . The compound of  claim 1 , wherein one of R 3  and R 4  is lower alkyl. 
     
     
         8 . The compound of  claim 1 , wherein one of R 3  and R 4  is C(O)O-lower alkyl. 
     
     
         9 . The compound of  claim 1 , wherein one of R 3  and R 4  is OR′. 
     
     
         10 . The compound of  claim 1 , wherein one of R 3  and R 4  is NR″R′″. 
     
     
         11 . The compound of  claim 1 , wherein one of R 3  and R 4  is lower alkyl substituted by halogen or hydroxyl. 
     
     
         12 . The compound of  claim 1 , wherein one of R 3  and R 4  is phenyl optionally substituted by one or two halogen atoms. 
     
     
         13 . The compound of  claim 1 , wherein one of R 3  and R 4  is benzyl optionally substituted by one or two halogen atoms. 
     
     
         14 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is hydrogen, lower alkyl or is lower alkyl substituted by hydroxy; 
         R 2  is hydrogen, lower alkoxy or lower alkyl; 
         R 3  and R 4  are each independently hydrogen, halogen, lower alkyl, C(O)O-lower alkyl, OR′, NR″R′″, lower alkyl substituted by halogen or hydroxy, or is phenyl or benzyl, each of which is optionally substituted by one or two halogen atoms; 
         R′ is lower alkyl, or is phenyl, benzyl or pyridinyl, whereine phenyl, benzyl or pyridinyl are each optionally substituted by one or more halogen, lower alkyl or lower alkyl substituted by fluoro; 
         R″ is hydrogen or lower alkyl; 
         R′″ is lower alkyl, lower alkyl substituted by one or two hydroxy groups, CH(CH 2 OH)-phenyl, —(CH 2 ) 2 O-lower alkyl, or phenyl substituted by halogen, or 
         R″ and R′″ together with the N-atom to which they are attached form a heterocyclic ring, optionally substituted by one or more lower alkyl, CH 2 C(O)O-lower alkyl, or CH 2 C(O)OH; 
         Ar is a five-membered heteroaryl group; 
         or a pharmaceutically active acid addition salt thereof and a pharmaceutically acceptable carrier.