Oxadiazolones and derivatives thereof as ppar delta agonists

Abstract

The invention relates to oxadiazolones and to their physiologically acceptable salts and physiologically functional derivatives showing PPARdelta agonist activity. What is described are compounds of the formula I, in which the radicals are as defined, and their physiologically acceptable salts and processes for their preparations. The compounds are suitable for the treatment and/or prevention of disorders of fatty acid metabolism and glucose utilization disorders as well as of disorders in which insulin resistance is involved; neurodegenerative diseases and/or demyelinating disorders of the central and peripheral nervous systems and/or neurological diseases involving neuroinflammatory processes and/or other peripheral neuropathies.

1 . PPAR agonist compounds according to formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 X is CH 2  or a bond;  
 R 1 , R 2 , R 3  and R 4  are independently H, F, Cl, Br, CF 3 , (C 1 -C 4 ) alkyl, (C0-C4) alkylene-O—(C 0 -C 4 ) alkylene-H, SCH 3 , S(O)CH 3 , S(O) 2 CH 3 , CN, OCF 3 , OCHF 2 , OCH 2 F;  
 Z is a bond or CH 2 ;  
 Y is O, S, S(O) or S(O) 2 ;  
 W is CH 2  or CH 2 CH 2 ;  
 one of U and V is N and the other is S or O;  
 R 5  and R 6  are selected from the group consisting of (C 1 -C 8 ) alkyl, (C 1 -C 6 ) alkylene-O—(C 0 — is (C 1 -C 6 ) alkyl or (C 2 -C 6 ) alkenyl, where (C 1 -C 6 ) alkyl can be substituted 1-2 times by Ch 2 OHF 3 , SF 5 , OCH 3 , phenyl phenyl, (C 3 -C 6 ) cycloalkyl, (C 2 -C 8 ) alkenyl, and where (C 1 -C 8 ) alkyl or alkylenee can be substituted 1-2 times by OH or O—(C 1 -C 4 ) alkyl; alkyl, (C 0 -C 4 ) alkylene-O—(C 0 -C 4 ) alkylenee-H, SCF 3 , SF 5 , OCF 2 —CHF 2 , OCHF 2 , OCH 2 F, O-phenyl, phenyl, or NO 2  as well as their physiologically acceptable salts, tautomeric forms and mixtures thereof.  
 
     
     
         2 . The compounds of formula I as recited in  claim 1  in which 
 X is a bond    
     
     
         3 . Compounds of formula I as recited in  claim 1  in which 
 X is a bond or CH 2 ;    R 1  is H, F, Cl, Br, CF 3 , (C 1 -C 4 ) alkyl, O—(C 1 -C 4 ) alkyl, SCH 3 , S(O)CH 3 , S(O) 2 CH 3 , CN;    R 2  is H, F;    R 3  is H, Br, O—(C 1 -C 4 ) alkyl;    R 4  is H;    Z is a bond or CH 2 ;    Y is O, S, S(O) or S(O) 2 ;    W is CH 2  or CH 2 CH 2 ;    U is Sand V is N or U is N and V is S or U is N and V is O;    R 5  is (C 1 -C 6 ) alkyl or (C 2 -C 6 ) alkenyl, where (C 1 -C 6 ) alkyl can be substituted 1-2 times by OH;    R 6  is in para position and is CF 3 , SF 5 , OCH 3 , phenyl;    R 7  is H or F.    
     
     
         4 . The compounds of formula I as recited in  claim 1  in wherein: 
 X is a bond;    R 1  is C 1  or CH 3 ;    R 2 , R 3  and R 4  are H;    Z is a bond;    W is CH 2 ;    U is S and    V is N or    U is N and    V is O or    U is O and    V is N; —(C 1 -C 4 ) alkylene-H or (C 1 -C 4 ) alkylene-O—(C 1 -C 4 ) alkylene-phenyl, where alkylene can be substituted by O—(C 1 -C 4 ) alkyl;    R6 is in para position and CF 3  or OCH 3 ;    R7 is H.    
     
     
         5 . The compounds of formula I as recited in  claim 1  wherein: 
 X is a bond;    R 2 , R 3 , R 4  are H;    Z is a bond;    Y is O or S;    W is CH 2  or CH 2 CH 2 ;    U is S and    V is N or    U is N and    V is S or    U is O and    V is N or    U is N and    V is O;    R 5  is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkylene-O—(C 1 -C 4 ) alkylene-H or (C 1 -C 4 ) alkylene-O—(C 1 -C 4 ) alkylene-phenyl, where alkylene can be substituted by O—(C 1 -C 4 ) alkyl;    R 6  is in the para position and is CF 3  or OCH 3 ; and,    R 7  is H.    
     
     
         6 . The compounds of formula I as recited in  claim 1  wherein 
 X is a bond or CH 2 ;    R 1  is H, F, Cl, Br, —OCH 3 , —SCH 3 , —CF 3 , —CH 3 , CN, —S(O)CH 3 , —S(O) 2 CH 3 ;    R 2  is H or F;    R 3  is H, —OCH 3 , Br;    R 4  is H;    Z is a bond or CH 2 ;    Y is O, S, —S(O) or —S(O) 2 ;    W is CH 2  or CH 2 CH 2 ;    U is S, and    V is N or    U is N, and    V is S;    R 5  is (C 1 -C 4 ) alkyl or (C 2 -C 4 ) alkenyl, where (C 1 -C 4 ) alkyl can be substituted 1-2 times by OH, or    R 5  is (C 1 -C 4 ) alkylene-O—(C 1 -C 4 ) alkylene-H or (C 1 -C 4 ) alkylene-O—(C 1 -C 4 ) alkylene-phenyl, where alkylene can be substituted by O—(C 1 -C 4 ) alkyl;    R 6  is p-CF3 or p-SF5; and    R 7  is H.    
     
     
         7 . The compounds of formula I as recited in  claim 1  wherein 
 X is a bond;    R 1  is Cl, —CH3;    R 2  is H;    R 3  is H;    R 4  is H;    Z is a bond;    Y is O;    W is CH 2 ;    U is N, and    V is O, or    U is O, and    V is N;    R 5  is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkylene-O—(C 1 -C 4 ) alkylene-H or (C 1 -C 4 ) alkylene-O—(C 1 -C 4 ) alkylene-phenyl, where alkylene can be substituted by 0-(C 1 -C 4 ) alkyl;    R 6  is para-OCH3 or p-phenyl, and;    R 7  is H.    
     
     
         8 . The compounds of formula I as recited claim in  claim 1  wherein 
 U is S, and    V is N or    U is N, and    V is S, or    U is O, and    V is N, or    U is N, and;    V is O.    
     
     
         9 . The compounds of formula I as recited in  claim 8  wherein; 
 U is S,    V is N, and;    Z is a bond.    
     
     
         10 . The compounds of the formula I as recited in  claim 8  wherein 
 U is N,    V is O,    Z is a bond,    X is a bond.    
     
     
         11 . The compounds of formula I as recited in  claim 10  wherein 
 X is a bond, and    Z is a bond.    
     
     
         12 . The compounds of formula I as recited in  claim 11  wherein; 
 R 6  is in the para-position.    
     
     
         13 . The compounds of formula I as recited in  claim 12  wherein; 
 R 7  is H or F.    
     
     
         14 . The compounds of formula I as recited in  claim 13  wherein; 
 R 2 , R 3 , and R 4  are H,    R 1  is H, F, Cl, Br, CF 3 , (C 1 -C 4 ) alkyl, (C 0 -C 4 ) alkylene-O—(C 0 -C 4 ) alkylene-H , —SCH 3 , S(O)CH 3 , S(O) 2 CH 3 , CN.    
     
     
         15 . The compounds of formula I as recited in  claim 14  in which 
 Y is O or S.    
     
     
         16 . The compounds of formula I as recited in  claim 15  wherein; 
 W is —CH 2 .    
     
     
         17 . The compounds of formula I as recited in  claim 16  wherein; 
 R 5  is (C 1 -C 4 ) alkyl or (C 1 -C 4 ) alkylene-O—(C 0 -C 4 ) alkylene-H, where alkylene can be substituted by O—(C 0 -C 4 ) alkylene-H or phenyl.    
     
     
         18 . The compounds of formula I as recited  claim 17  in which 
 R 1  is F, Cl, —CH 3 , —OCH 3 .    
     
     
         19 . The compounds of formula I as recited in  claim 18  wherein 
 R 5  is (C 1 -C 4 ) alkyl.    
     
     
         20 . The compounds of formula I as recited in  claim 19  wherein 
 R 6  is CF 3 , SF 5 , phenyl, —OCH3.    
     
     
         21 . A pharmaceutical composition comprising one or more compounds of formula I as recited in  claim 1 .  
     
     
         22 . A pharmaceutical composition comprising one or more compounds of formula I as recited in  claim 1  in combination with at least one anti-diabetic for the treatment of metabolic disorders.  
     
     
         23 . A pharmaceutical composition comprising one or more compounds of formula I as recited in  claim 6  in combination with at least one anti-diabetic for the treatment of metabolic and central nervous system disorders.  
     
     
         24 . A pharmaceutical composition comprising one or more compounds of formula I as recited in  claim 1  in combination with one or more lipid modulators for the treatment and/or prevention of fatty acid metabolism and glucose utilization disorders.  
     
     
         25 . A method for the treatment of fatty acid metabolism and glucose utilization disorders comprising the administration of one or more compounds of formula I as recited in  claim 1  in combination with other pharmaceutically acceptable excipients.  
     
     
         26 . A method for the treatment of fatty acid metabolism and glucose utilization disorders as well as for the treatment and/or prevention of diabetes mellitus including the prevention of the squelae associated therewith comprising the administration of one or more compounds of formula I as recited in  claim 6  in combination with other pharmaceutically acceptable excipients.  
     
     
         27 . The use of the compounds of the formula I as claimed in one or more of  claim 20  for the treatment and/or prevention of dyslipidemias and their squelae.  
     
     
         28 . The use of the compounds of the formula I as claimed in one or more of  claim 20  for the treatment and/or prevention of conditions which may be associated with the metabolic syndrome.  
     
     
         29 . A method for the treatment and/or prevention of neurodegenerative diseases and/or demyelinating disorders of the central and peripheral nervous systems and/or neurological diseases involving neuroinflammatory processes and/or other peripheral neuropathies comprising the administration of one or more compounds of formula 1 as recited in  claim 1  in combination with one or more pharmaceutically acceptable excipients.  
     
     
         30 . A method for the treatment and/or prevention of neurodegenerative diseases and/or demyelinating disorders of the central and peripheral nervous systems and/or neurological diseases involving neuroinflammatory processes and/or other peripheral neuropathies comprising the administration of one or more compounds of formula 1 as recited in  claim 6  in combination with one or more pharmaceutically acceptable excipients.  
     
     
         31 . A process for preparing a pharmaceutical composition comprising one or more of the compounds of formula 1 as recited in  claim 1  which comprises mixing the active compound with a pharmaceutically suitable carrier and bringing this mixture into a form suitable for administration.