Tricyclic compound

Abstract

The invention provides a method of activating PPAR γ and a method of treating or preventing a disease associated with PPAR γ by administering a tricyclic compound having a PPAR γ agonist activity, which is represented by the formula (I) wherein Z represents a single bond or the like, Y represents a hydrogen atom, lower alkyl optionally having substituent(s) or the like, X represents a hydrogen atom or the like, A represents aryl or the like, B and C are the same or different and each represents an aromatic carbocycle or the like, R 4 -R 9 are the same or different and each represents hydrogen or the like, V represents a single bond or the like, R 10 and R 11 are the same or different and each represents hydrogen or the like, or a pharmaceutically acceptable salt thereof or the like:

1 . A method of activating PPAR γ comprising administering a tricyclic compound represented by the formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 Z represents CH 2 O, OCH 2 , CH 2 S(O) n  or S(O) n CH 2  wherein n is an integer of 0 to 2, 
 Y represents a hydrogen atom, lower alkyl optionally having substituent(s), lower alkoxy optionally having substituent(s), cycloalkyl optionally having substituent(s) or halogen, 
 X represents a hydrogen atom, lower alkyl, cyano, halogen, hydroxymethyl, aminomethyl, carboxy, lower alkoxycarbonyl optionally having substituent(s), carbamoyl, lower alkylcarbamoyl optionally having substituent(s), di-lower alkylcarbamoyl optionally having substituent(s), arylcarbamoyl optionally having substituent(s), lower alkylsulfonylcarbamoyl optionally having substituent(s), arylsulfonylcarbamoyl optionally having substituent(s), cycloalkylsulfonylcarbamoyl optionally having substituent(s), lower alkylaminosulfonylcarbamoyl optionally having substituent(s), aliphatic heterocyclyl carbonyl optionally having substituent(s), lower alkanoylaminomethyl optionally having substituent(s), lower alkylsulfonylaminomethyl optionally having substituent(s), an aliphatic heterocyclic group optionally having substituent(s) or an aromatic heterocyclic group optionally having substituent(s), 
 A represents aryl optionally having substituent(s) or an aromatic heterocyclic group optionally having substituent(s), 
 B and C are the same or different and each represents an aromatic carbocycle or aromatic heterocycle, 
 R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are the same or different and each represents a hydrogen atom, halogen, hydroxy, lower alkoxy or lower alkyl, 
 V represents a single bond, O, NR A  wherein R A  represents a hydrogen atom, lower alkyl optionally having substituent(s), lower alkanoyl optionally having substituent(s), lower alkoxycarbonyl optionally having substituent(s), lower alkylcarbamoyl optionally having substituent(s) or lower alkylsulfonyl optionally having substituent(s), or S, and 
 R 10  and R 11  are the same or different and each represents a hydrogen atom or lower alkyl, 
 
       or a pharmaceutically acceptable salt thereof, thereby activating activating PPAR γ. 
     
     
         2 . A method of treating or preventing a disease associated with PPAR γ, which method comprises administering a tricyclic compound represented by the formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 Z represents CH 2 O, OCH 2 , CH 2 S(O) n  or S(O) n CH 2  wherein n is an integer of 0 to 2, 
 Y represents a hydrogen atom, lower alkyl optionally having substituent(s), lower alkoxy optionally having substituent(s), cycloalkyl optionally having substituent(s) or halogen, 
 X represents a hydrogen atom, lower alkyl, cyano, halogen, hydroxymethyl, aminomethyl, carboxy, lower alkoxycarbonyl optionally having substituent(s), carbamoyl, lower alkylcarbamoyl optionally having substituent(s), di-lower alkylcarbamoyl optionally having substituent(s), arylcarbamoyl optionally having substituent(s), lower alkylsulfonylcarbamoyl optionally having substituent(s), arylsulfonylcarbamoyl optionally having substituent(s), cycloalkylsulfonylcarbamoyl optionally having substituent(s), lower alkylaminosulfonylcarbamoyl optionally having substituent(s), aliphatic heterocyclyl carbonyl optionally having substituent(s), lower alkanoylaminomethyl optionally having substituent(s), lower alkylsulfonylaminomethyl optionally having substituent(s), an aliphatic heterocyclic group optionally having substituent(s) or an aromatic heterocyclic group optionally having substituent(s), 
 A represents aryl optionally having substituent(s) or an aromatic heterocyclic group optionally having substituent(s), 
 B and C are the same or different and each represents an aromatic carbocycle or aromatic heterocycle, 
 R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are the same or different and each represents a hydrogen atom, halogen, hydroxy, lower alkoxy or lower alkyl, 
 V represents a single bond, O, NR A  wherein R A  represents a hydrogen atom, lower alkyl optionally having substituent(s), lower alkanoyl optionally having substituent(s), lower alkoxycarbonyl optionally having substituent(s), lower alkylcarbamoyl optionally having substituent(s) or lower alkylsulfonyl optionally having substituent(s), or S, and 
 R 10  and R 11  are the same or different and each represents a hydrogen atom or lower alkyl, 
 
       or a pharmaceutically acceptable salt thereof, to a subject in need thereof, thereby treating or preventing a disease associated with PPAR γ. 
     
     
         3 . The method of  claim 2 , wherein the disease associated with PPAR γ is type 2 diabetes, impaired glucose tolerance, insulin resistance syndrome, hypertension, hyperlipidemia, metabolic syndrome, visceral obesity, obesity, hypertriglyceridemia, or tumor. 
     
     
         4 . The method of  claim 3 , wherein the subject has the disease associated with PPAR γ, and administering the tricyclic compound, or the pharmaceutically salt thereof, to the subject treats the disease associated with PPAR γ in the subject. 
     
     
         5 . The method of  claim 2 , wherein 
       
         
           
           
               
               
           
         
       
       represents the following formula c21 or c22 
       
         
           
           
               
               
           
         
       
       wherein R 4 , R 5 , R 6 , R 7 , R 8 , and R 9  are each as defined above, Y A  represents lower alkyl or cycloalkyl optionally having substituent(s),
 X B  represents the following group (b19)-(b24) 
 
       
         
           
           
               
               
           
         
       
       wherein R B-3  represents lower alkyl optionally having substituent(s) or aryl optionally having substituent(s),
 A represents the following group (a38) or (a39) 
 
       
         
           
           
               
               
           
         
       
       wherein R 1A  represents lower alkyl optionally having substituent(s), aryl optionally having substituent(s) or cycloalkyl optionally having substituent(s), R L  and R M  are the same or different and each represents a hydrogen atom, halogen, carbamoyl, lower alkylcarbamoyl optionally having substituent(s), lower alkyl optionally having substituent(s) or lower alkylsulfonylamino optionally having substituent(s),
 V represents a single bond, and 
 R 10  and R 11  are the same or different and each is a hydrogen atom or lower alkyl. 
 
     
     
         6 . The method of  claim 5 , wherein 
       
         
           
           
               
               
           
         
       
       represents the following formula c24 
       
         
           
           
               
               
           
         
       
       wherein R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and Y A  are each as defined above, X C  is represented by the following group (b20) 
       
         
           
           
               
               
           
         
       
       R 1A  represents lower alkyl optionally having substituent(s) other than hydroxy, aryl optionally having substituent(s) or cycloalkyl optionally having substituent(s), and
 R L  and R M  are the same or different and each represents a hydrogen atom, lower alkyl, halogen, carbamoyl or lower alkylcarbamoyl optionally having substituent(s). 
 
     
     
         7 . The method of  claim 6 , wherein A is represented by the following group (a38-2) 
       
         
           
           
               
               
           
         
       
       wherein R 1A-2  represents lower alkyl optionally having substituent(s) other than hydroxy, aryl optionally having substituent(s), or cycloalkyl optionally having substituent(s), R L-2  and R M-2  are the same or different and each represents a hydrogen atom, lower alkyl, halogen, carbamoyl or lower alkylcarbamoyl optionally having substituent(s). 
     
     
         8 . The method of  claim 2 , wherein 
       
         
           
           
               
               
           
         
       
       represents the following formula c8 or c9 
       
         
           
           
               
               
           
         
       
       wherein R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and X B  are each as defined above,
 A represents the following formula 
 
       
         
           
           
               
               
           
         
       
       wherein R C  represents a hydrogen atom, halogen, nitro, cyano, formyl, oxo, hydroxy, lower alkoxy optionally having substituent(s), lower alkanoyloxy optionally having substituent(s), lower alkyl optionally having substituent(s), lower alkenyl optionally having substituent(s), lower alkanoyl optionally having substituent(s), lower alkoxycarbonyl optionally having substituent(s), lower alkylsulfonylamino optionally having substituent(s), —NR F R G  wherein R F  and R G  are the same or different and each represents a hydrogen atom, lower alkyl optionally having substituent(s), lower alkanoyl optionally having substituent(s) or lower alkoxycarbonyl optionally having substituent(s), or R F  and R G  form, each together with the adjacent nitrogen atom, a nitrogen-containing heterocyclic group optionally having substituent(s), —CONR H R I  wherein R H  and R I  are the same or different and each represents a hydrogen atom, lower alkyl optionally having substituent(s), lower alkanoyl optionally having substituent(s) or lower alkoxycarbonyl optionally having substituent(s), or R H  and R I , form, together with the adjacent nitrogen atom, a nitrogen-containing heterocyclic group optionally having substituent(s), aryl optionally having substituent(s), cycloalkyl optionally having substituent(s), an aromatic heterocyclic group optionally having substituent(s) or an aliphatic heterocyclic group optionally having substituent(s), R 1-2  represents lower alkyl optionally having substituent(s), cycloalkyl optionally having substituent(s) or lower alkoxy optionally having substituent(s), R J  represents aryl optionally having substituent(s), an aromatic heterocyclic group optionally having substituent(s) (except benzimidazolyl group) or an aliphatic heterocyclic group optionally having substituent(s), and
 V represents a single bond. 
 
     
     
         9 . The method of  claim 8 , wherein X B  is the following formula (b20) 
       
         
           
           
               
               
           
         
       
       and 
       R 1-2  is lower alkyl. 
     
     
         10 . The method of  claim 2 , wherein X represents a hydrogen atom, lower alkyl, cyano, halogen, hydroxymethyl, aminomethyl, lower alkoxycarbonyl optionally having substituent(s), carbamoyl, lower alkylcarbamoyl optionally having substituent(s), di-lower alkylcarbamoyl optionally having substituent(s), arylcarbamoyl optionally having substituent(s), lower alkylaminosulfonylcarbamoyl optionally having substituent(s), aliphatic heterocyclyl carbonyl optionally having substituent(s), lower alkanoylaminomethyl optionally having substituent(s), lower alkylsulfonylaminomethyl optionally having substituent(s) or any of the following formulas (b1)-(b16) 
       
         
           
           
               
               
           
         
       
       wherein R B-1  represents lower alkyl optionally having substituent(s) or cycloalkyl optionally having substituent(s), R B-2  represents cycloalkyl optionally having substituent(s), R B  represents a hydrogen atom, lower alkyl optionally having substituent(s) or cycloalkyl optionally having substituent(s), and the broken line is absent or a single bond. 
     
     
         11 . The method of  claim 2 , wherein A is represented by any of the formulas (a1)-(a34) 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and R 3  are the same or different and each represents a hydrogen atom, lower alkyl optionally having substituent(s), cycloalkyl optionally having substituent(s), halogen, lower alkoxy optionally having substituent(s), lower alkylsulfanyl optionally having substituent(s), lower alkenyl optionally having substituent(s), lower alkanoyl optionally having substituent(s), lower alkoxycarbonyl optionally having substituent(s), carbamoyl, lower alkylcarbamoyl optionally having substituent(s), di-lower alkylcarbamoyl optionally having substituent(s), aliphatic heterocyclyl carbonyl optionally having substituent(s), aryloxy optionally having substituent(s), aryl optionally having substituent(s), an aromatic heterocyclic group optionally having substituent(s), or an aliphatic heterocyclic group optionally having substituent(s), R 1-1  represents a hydrogen atom, lower alkenyl optionally having substituent(s), lower alkanoyl optionally having substituent(s), lower alkoxycarbonyl optionally having substituent(s), carbamoyl, lower alkylcarbamoyl optionally having substituent(s), di-lower alkylcarbamoyl optionally having substituent(s), aliphatic heterocyclyl carbonyl optionally having substituent(s), aryloxy optionally having substituent(s), aryl optionally having substituent(s), an aromatic heterocyclic group optionally having substituent(s), an aliphatic heterocyclic group optionally having substituent(s) or aralkyloxy optionally having substituent(s), R C , R D  and R E  are the same or different and each is as defined for the aforementioned R C , R K  represents cycloalkyl optionally having substituent(s), halogen, lower alkoxy optionally having substituent(s), lower alkylsulfanyl optionally having substituent(s), carbamoyl, aryloxy optionally having substituent(s), aryl optionally having substituent(s), an aromatic heterocyclic group optionally having substituent(s), aralkyl optionally having substituent(s), or an aliphatic heterocyclic group optionally having substituent(s), R D-1  represents cycloalkyl optionally having substituent(s). 
     
     
         12 . The method of  claim 2 , wherein V is O, NR A  wherein R A  is as defined above, or S. 
     
     
         13 . The method of  claim 2 , wherein at least one of R 10  and R 11  is lower alkyl. 
     
     
         14 . The method of  claim 2 , wherein 
       
         
           
           
               
               
           
         
       
       is represented by any of the following formulas c10-c13 
       
         
           
           
               
               
           
         
       
       wherein R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , X and Y are each as defined above. 
     
     
         15 . The method of  claim 2 , wherein X is the following formula (b17) or (b18) 
       
         
           
           
               
               
           
         
       
     
     
         16 . The method of  claim 2 , wherein
 A is a group selected from the group consisting of the following formulas (a1)-(a14) and (a23)-(a34)   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3 , R 1-1 , R D-1 , R C , R D , R E  and R K  are each as defined above, and
 V is a single bond. 
 
     
     
         17 . The method of  claim 10 , wherein V is O, NR A  wherein R A  is as defined above, or S. 
     
     
         18 . The method of  claim 2 , wherein
 A represents a group selected from the group consisting of the following formulas (a15)-(a22),   
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and R 3  are each as defined above, and
 V is O or NR A  wherein R A  is as defined above. 
 
     
     
         19 . The method of  claim 2 , wherein A is the following formula 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R C  and R D-1  are each as defined above. 
     
     
         20 . The method of  claim 2 , wherein 
       
         
           
           
               
               
           
         
       
       is a group selected from the group consisting of the following formula c2 or c3 
       
         
           
           
               
               
           
         
       
       wherein Y, R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are each as defined above and X A  represents any of the following formulas (b1)-(b16) 
       
         
           
           
               
               
           
         
       
       wherein R B-1 , R B-2  and R B  are each as defined above, and the broken line is absent or a single bond. 
     
     
         21 . The method of  claim 2 , wherein 
       
         
           
           
               
               
           
         
       
       is a group selected from the group consisting of the following formula c5 or c6 
       
         
           
           
               
               
           
         
       
       wherein X A , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are each as defined above. 
     
     
         22 . The method of  claim 10 , wherein at least one of R 10  and R 11  is lower alkyl.