Method of Treating Diseases and Conditions Associated with an Altered Level of Amyloid Beta Peptides and New Enolcarboxamide Compounds

Abstract

A method of treating or preventing of a disease or condition associated with an increased level of isoforms of amyloid β peptides (Aβ) and/or with a changed ratio of levels of Aβ isoforms and/or with the formation of plaques containing amyloid β peptide (Aβ) isoforms in a mammal comprising administering to said mammal an therapeutically effective amount of a compound selected from the formulas Ia, Ib wherein V, W, Y, R 2 , R 3 , R 5 , R 6 , L 1 and i are defined as in claim 1.

1 . A method of treating or preventing of a disease or condition associated with an increased level of one or more isoforms of amyloid β peptides (Aβ) and/or with a changed ratio of levels of Aβ isoforms and/or with the formation of plaques containing one or more amyloid β peptide (Aβ) isoforms in a mammal comprising administering to said mammal a therapeutically effective amount of at least one compound selected from the formulas Ia, Ib 
     
       
         
         
             
             
         
       
     
     wherein
    represents a single or a double bond, such that the ring containing the groups V and W is a phenyl, a furanyl or a thiophenyl ring; 
 V is defined as —CR 1 ═ or Q, and in case W is Q, then V is a single bond; 
 W is defined as ═CR 4 — or Q, and in case V is Q, then W is a single bond; 
 Q is O or S; 
 Y is —(C═O)— or —(SO 2 )—; 
 R 1 , R 4  are each independently selected from the group consisting of H, F, Cl, Br, CN, CF 3 , C 1-4 -alkyl and C 1-4 -alkoxy; and 
 R 2 , R 3  are each independently selected from the group consisting of H, F, Cl, Br, CN, CF 3 , C 1-4 -alkyl and C 1-4 -alkoxy; or 
 in case V is —CR 1 ═ and W is ═CR 4 —, the substituents R 2  and R 3  may be linked together forming with the C-atoms to which they are attached to a C 5-7 -cycloalkyl, C 5-7 -cycloalkenyl or a phenyl group, wherein the cycloalkyl, cycloalkenyl or phenyl ring may be substituted with one or more substituents L2; or 
 in case V is —CR 1 ═ and W is ═CR 4 —, the substituents R 1  and R 2  may be linked together forming with the C-atoms to which they are attached to a C 5-7 -cycloalkyl, C 5-7 -cycloalkenyl or a phenyl group, wherein the cycloalkyl, cycloalkenyl or phenyl ring may be substituted with one or more substituents L2; 
 R 5  is selected from the group consisting of H, C 1-4 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, phenyl and phenyl-C 1-3 -alkyl, wherein a cycloalkyl or phenyl ring may be substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, CN, CF 3 , C 1-4 -alkyl, C 1-4 -alkoxy, C 1-4 -alkylcarbonyl; 
 R 6  is H or C 1-4 -alkyl; 
 L1 is each independently selected from the group consisting of C 1-4 -alkyl, C 1-3 -alkoxy, F, Cl, Br, CN, NO 2  and CF 3 ; 
 L2 is each independently selected from the group consisting of C 1-4 -alkyl, F, Cl, Br, CN and CF 3 ; 
 i is 0, 1, 2, 3, 4 or 5; 
 
     or a pharmaceutically acceptable salt thereof. 
   
   
       2 . A method according to  claim 1  wherein the compound is selected from the formulas I.1a, I.1b 
     
       
         
         
             
             
         
       
       wherein the group Y, the substituents R 1 , R 4 , R 5 , R 6  and L1 and the index i are defined as in  claim 1 , and 
       R 2 , R 3  are each independently selected from the group consisting of H, F, Cl, Br, CN, CF 3 , C 1-4 -alkyl and C 1-4 -alkoxy; 
       or a pharmaceutically acceptable salt thereof. 
     
   
   
       3 . A method according to  claim 1  wherein the compound is selected from the formulas I.2a, I.2b 
     
       
         
         
             
             
         
       
       wherein the group Y, the substituents R 1 , R 4 , R 5 , R 6 , L1 and L2 and the index i are defined as in  claim 1 , 
       wherein j is 0, 1, 2, 3 or 4; 
       or a pharmaceutically acceptable salt thereof. 
     
   
   
       4 . A method according to  claim 1  wherein the compound is selected from the formulas I.3a, I.3b, I.4a, I.4b 
     
       
         
         
             
             
         
       
       wherein the group Y, the substituents R 1 , R 3 , R 4 , R 5 , R 6 , L1 and L2 and the index i are defined as in  claim 1 , 
       j is 0, 1, 2 or 3; and 
       m is 0, 1 or 2; 
       or a pharmaceutically acceptable salt thereof. 
     
   
   
       5 . A method according to  claim 1  wherein the compound is selected from the formulas I.5a, I.5b, I.6a, I.6b 
     
       
         
         
             
             
         
       
     
     wherein the groups Q and Y, the substituents R 5 , R 6  and L1 and the index i are defined as in  claim 1 ,
 R 2 , R 3  are each independently selected from the group consisting of H, F, Cl, Br, CN, CF 3 , C 1-4 -alkyl and C 1-4 -alkoxy; 
 
     or a pharmaceutically acceptable salt thereof. 
   
   
       6 . A method according to  claim 1  wherein R 5  is selected from the group consisting of H, methyl, ethyl, cyclopropyl, phenyl and phenylmethyl, wherein the phenyl ring in the phenyl group or phenylmethyl group may be substituted with one, two or more substituents selected from the group consisting of F, Cl, Br, CN, CF 3 , C 1-4 -alkyl, C 1-4 -alkoxy or C 1-4 -alkyl-carbonyl. 
   
   
       7 . A method according to  claim 1  wherein the compound is selected from the formulas I.1.1a, I.1.1b 
     
       
         
         
             
             
         
       
     
     wherein the substituents R 1 , R 4  and L1 and the index i are defined as in  claim 1 ,
 R 2 , R 3  are each independently selected from the group consisting of H, F, Cl, Br, CN, CF 3 , C 1-4 -alkyl and C 1-4 -alkoxy; 
 
     or a pharmaceutically acceptable salt thereof. 
   
   
       8 . A method according to  claim 1  wherein the compound is selected from the formulas I.2.1a, I.2.1b 
     
       
         
         
             
             
         
       
       wherein the substituents R 1 , R 4 , L1 and L2 and the index i are defined as in  claim 1 , 
       wherein j is 0, 1, 2, 3 or 4; 
       or a pharmaceutically acceptable salt thereof. 
     
   
   
       9 . A method according to  claim 1  wherein the compound is selected from the formulas I.3.1a, I.3.1b 
     
       
         
         
             
             
         
       
       wherein the substituents R 1 , R 4 , L1, L2 and the index i are defined as in  claim 1 , 
       j is 0, 1, 2 or 3 
       or a pharmaceutically acceptable salt thereof. 
     
   
   
       10 . A method according to  claim 1  wherein the disease or condition is associated with an increased level of a pathogenic isoform of Aβ or with a changed ratio of levels of Aβ isoforms or with the formation of plaques containing one or more isoforms of Aβ. 
   
   
       11 . A method according to  claim 1  wherein the disease or condition is associated with an increased level of Aβ 42  and/or with the formation of plaques containing Aβ 42 . 
   
   
       12 . A method according to  claim 1  wherein the disease or condition is selected from the group consisting of diseases associated with the formation of diffuse and senile plaques, amyloidosis associated with the formation of Aβ isoforms, brain amyloidosis, vascular amyloidosis, age related amyloidosis, and central or peripheral amyloid diseases. 
   
   
       13 . A method according to  claim 1  wherein the disease or condition is selected from the group consisting of Alzheimer's disease, Down's syndrome, MCI (“Mild Cognitive Impairment”), Heriditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, Cerebral Amyloid Angiopathy, Traumatic Brain Injury, Stroke, Dementia, Dementia of Alzheimer type (DAT), age associated memory impairment (AAMI), Parkinson's Disease and Parkinson's Syndrome, and diffuse Lewy body type AD. 
   
   
       14 . A compound selected from the group of formulas I.3a, I.3b, I.4a, I.4b 
     
       
         
         
             
             
         
       
       Y is —(C═O)— or —(SO 2 )—; 
       R 1 , R 3 , R 4  are each independently selected from the group consisting of H, F, Cl, Br, CN, CF 3 , C 1-4 -alkyl and C 1-4 -alkoxy; and 
       R 5  is selected from the group consisting of H, C 1-4 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, phenyl and phenyl-C 1-3 -alkyl, wherein the phenyl ring of the phenyl or the phenyl-alkyl group may be substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, CN, CF 3 , C 1-4 -alkyl, C 1-4 -alkylcarbonyl; 
       R 6  is H or C 1-4 -alkyl; 
       L1 is each independently selected from the group consisting of C 1-4 -alkyl, C 1-3 -alkoxy, F, Cl, Br, CN, NO 2  and CF 3 ; 
       L2 is each independently selected from the group consisting of C 1-4 -alkyl, F, Cl, Br, CN and CF 3 ; 
       i is 0, 1, 2, 3, 4 or 5; 
       j is 0, 1, 2 or 3; 
       m is 0, 1 or 2; 
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       15 . A compound according to  claim 14  wherein R 5  is selected from the group consisting of H, methyl, ethyl, cyclopropyl, phenyl and phenylmethyl, wherein the phenyl ring in the phenyl group or phenylmethyl group may be substituted with F, Cl, Br, C 1-4 -alkyl or C 1-4 -alkyl-carbonyl. 
   
   
       16 . A compound according to  claim 14  wherein the compound is selected from the formulas I.3.1a, I.3.1b 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof. 
     
   
   
       17 . A compound according to  claim 14  wherein the compound is selected from the group consisting of 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof. 
     
   
   
       18 . A compound selected from the formulas I.5.1a, I.5.1 b, I.6.1a, I.6.1b 
     
       
         
         
             
             
         
       
     
     wherein
 Q is O or S; 
 R 2 ,R 3  are independently selected from the group consisting of F, Br, CN, CF 3 , C 1-4 -alkyl and C 1-4 -alkoxy; 
 R 5  is selected from the group consisting of H, C 1-4 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, phenyl and phenyl-C 1-3 -alkyl, wherein the phenyl ring of the phenyl or the phenyl-alkyl group may be substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, CN, CF 3 , C 1-4 -alkyl, C 1-4 -alkoxy, C 1-4 -alkylcarbonyl; 
 R 6  is H or C 1-4 -alkyl; 
 L1 is each independently selected from the group consisting of C 1-4 -alkyl, C 1-3 -alkoxy, F, Cl, Br, CN, NO 2  and CF 3 , with the proviso that L1 is not Cl in para-position if index i is 1 and R 5  is methyl; 
 i is 0, 1, 2, 3, 4 or 5; 
 
     or a pharmaceutically acceptable salt thereof. 
   
   
       19 . A compound according to  claim 18  wherein R 5  is selected from the group consisting of H, C 1-4 -alkyl, phenyl and phenyl-C 1-3 -alkyl, wherein the phenyl ring of the phenyl or the phenyl-alkyl group may be substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, CN, CF 3 , C 1-4 -alkyl, C 1-4 -alkoxy, C 1-4 -alkylcarbonyl. 
   
   
       20 . A compound according to  claim 19  of the formula 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof.