Tricyclic indole compounds having an affinity against serotonin receptors

Abstract

Having an affinity against serotonine receptors, compound (I) shown below is useful as a therapeutic agent against various kinds of diseases of central nervous systems. (wherein R 1 is hydrogen; R 2 is hydrogen or lower alkyl; R 3 is hydrogen, —COOR 12 and so on; R 4 is hydrogen, lower alkyl and so on, or R 3 and R 4 taken together may form ═O or ═S; R 5 is hydrogen, or R 3 and R 5 taken together may form a bond; R 6 is hydrogen, —COOR 24 and so on; R 7 is hydrogen, halogen, lower alkyl and so on; R 8 is hydrogen, lower alkyl, cycloalkyl and so on; R 9 , R 10 and R 11 are each independently hydrogen, halogen, lower alkyl and so on)

1 . A compound, prodrug, pharmaceutically acceptable salt or solvate thereof of the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is hydrogen;  
 R 2  is hydrogen or lower alkyl;  
 R 3  is hydrogen, —COOR 12  (R 12  is hydrogen or ester moiety), or —CN;  
 R 4  is hydrogen, lower alkyl, —COOR 13  (R 13  is hydrogen or ester moiety), —CONR 14 R 15  (R 14  and R 15  are each independently hydrogen, lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl or optionally substituted heteroaryl, or R 14  and R 15  taken together may form a 5- to 7-membered heterocycle ring with the neighboring nitrogen atom), —CN, —NO 2 , —NR 16 R 17  (R 16  and R 17  are each independently hydrogen, —CN, optionally substituted lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted amino or R 16  and R 17  taken together may form optionally substituted 5- to 7-membered heterocyclyl with the neighboring nitrogen atom), —NR 18 COR 19  (R 18  and R 19  are each independently hydrogen, optionally substituted lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, or optionally substituted heteroaryl), —NR 20 COOR 21  (R 20  is hydrogen, lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 21  is ester moiety), —NR 22 SO 2 R 23  (R 22  is hydrogen, lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 23  is lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl, or lower alkylamino), —OH, lower alkoxy, —SH or lower alkylthio or R 3  and R 4  taken together may form ═O, ═S, or lower alkylene dioxy;  
 R 5  is hydrogen, or R 3  and R 5  taken together may form a bond;  
 R 6  is hydrogen, —COOR 24  (R 24  is hydrogen or ester moiety), —CN, or —CH 2 NR 25 R 26  (R 25  and R 26  are each independently hydrogen, lower alkyl, cycloalkyl, or lower alkenyl);  
 R 7  is hydrogen, halogen, —CN, optionally substituted lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, optionally substituted lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amino, —COOR 34  (R 34  is hydrogen or ester moiety), —COR 35  (R 35  is hydrogen, lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted amino, optionally substituted aryl, or optionally substituted heteroaryl) or —CHNOH;  
 R 8  is hydrogen, optionally substituted lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl, —COR 27  (R 27  is hydrogen, lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, or optionally substituted heteroaryl), —COOR 28  (R 28  is ester moiety), or —SO 2 R 29  (R 29  is lower alkyl, cycloalkyl, optionally substituted lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl), or tri-lower alkyl silyl;  
 R 9 , R 10  and R 11  are each independently hydrogen, halogen, optionally substituted lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, optionally substituted lower alkenyl, lower alkoxy, —OH, —CN, —SR 30  (R 30  is hydrogen or lower alkyl), —CONH 2 , —CHO, —CHNOH, —COOR 31  (R 31  is hydrogen or ester moiety), —NR 32 R 33  (R 32  and R 33  is each independently hydrogen or lower alkyl), optionally substituted aryl or optionally substituted heteroaryl.  
 
     
     
         2 . A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to  claim 1 , wherein R 2  is hydrogen.  
     
     
         3 . A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to  claim 1 , wherein R 3  is hydrogen.  
     
     
         4 . A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to  claim 1 , wherein R 5  is hydrogen.  
     
     
         5 . A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to  claim 1 , wherein R 3  and R 5  taken together may form a bond.  
     
     
         6 . A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to  claim 1 , wherein R 3  and R 4  taken together may form ═O, ═S or lower alkylenedioxy.  
     
     
         7 . A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to  claim 1 , wherein R 4  represents —COOR 13  (R 13  is hydrogen or lower alkyl), —NR 16 R 17  (R 16  and R 17  are each independently hydrogen, optionally substituted lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted amino, or R 16  and R 17  taken together may form an optionally substituted 5- to 7-membered heterocyclyl ring with the neighboring nitrogen atom), —NR 18 COR 19  (R 18  and R 19  are each independently hydrogen, optionally substituted lower alkyl or optionally substituted aralkyl), —NR 20 COOR 21  (R 20  is hydrogen, or lower alkyl; R 21  is an ester moiety), —NR 22 SO 2 R 23  (R 22  is hydrogen; R 23  is lower alkyl or lower alkylamino), —OH, or lower alkoxy.  
     
     
         8 . A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to  claim 1 , wherein R 4  is —COOR 13  (R 13  is hydrogen or methyl), —NR 16 R 17  (R 16  is hydrogen or lower alkyl, R 17  is hydrogen, optionally substituted lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted amino or R 16  and R 17  are taken together may form a optionally substituted 5- to 7-membered heterocyclyl ring with the neighboring nitrogen atom), —NR 18 COR 19  (R 18  is hydrogen, R 19  is hydrogen, optionally substituted lower alkyl or optionally substituted aralkyl), —NR 20 COOR 21  (R 20  is hydrogen or methyl; R 21  is methyl), —NR 22 SO 2 R 23  (R 22  is hydrogen; R 23  is methyl or methylamino), —OH, or lower alkoxy.  
     
     
         9 . A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, described in  claim 1 , wherein R 4  is —NH 2 , —NHCH 3  or N(CH 3 ) 2 .  
     
     
         10 . A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, described in  claim 1 , wherein R 6  is hydrogen, COOCH 3 , COOCH 2 CH 3 , CN, or CH 2 NH 2 .  
     
     
         11 . A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, described in  claim 1 , wherein R 6  is hydrogen.  
     
     
         12 . A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, described in  claim 1 , wherein R 7  is hydrogen, lower alkyl, halogen, phenyl, —COOR 34  (R 34  is mentioned before), —CHO or —CHNOH.  
     
     
         13 . A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, described in  claim 1 , wherein R 7  is hydrogen, methyl, ethyl, halogen, or phenyl.  
     
     
         14 . A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to  claim 1 , wherein R 8  is hydrogen, optionally substituted lower alkyl, —COR 27  (R 27  is hydrogen, lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, or optionally substituted heteroaryl), —COOR 28  (R 28  is ester moiety), or —SO 2 R 29  (R 29  is lower alkyl, cycloalkyl, optionally substituted lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl), or tri-lower alkyl silyl.  
     
     
         15 . A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to  claim 1 , wherein R 8  is hydrogen or —SO 2 R 29  (R 20  is mentioned before).  
     
     
         16 . A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to  claim 1 , wherein all of R 9 , R 10  and R 11  are hydrogen.  
     
     
         17 . A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to  claim 1 , wherein R 2  is hydrogen; R 3  and R 5  are hydrogen or taken together may form a bond.  
     
     
         18 . A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to  claim 1 , wherein R 6  is hydrogen, COOCH 3 , COOCH 2 CH 3 , CN, or CH 2 NH 2 ; R 7  is hydrogen, lower alkyl, halogen or phenyl; R 8  is hydrogen, lower alkyl, COPh, or SO 2 Ph (Ph represents phenyl).  
     
     
         19 . A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to  claim 1 , wherein R 9  is hydrogen or halogen.  
     
     
         20 . A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to  claim 1 , wherein R 9  is hydrogen.  
     
     
         21 . A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, described in to  claim 1 , wherein R 10  is hydrogen.  
     
     
         22 . A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to  claim 1 , wherein R 11  is hydrogen, halogen, lower alkyl, optionally substituted lower alkenyl, —CN, —SR 30  (R 30  is hydrogen or lower alkyl), —CONH 2 , —CHO, —CHNOH, —NR 32 R 33  (R 32  and R 33  are each independently hydrogen or lower alkyl) or aryl.  
     
     
         23 . A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to  claim 1 , wherein Rid is hydrogen, halogen, methyl, —CN, or —CONH 2 .  
     
     
         24 . A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to  claim 1 , wherein R 1 , R 2 , R 3 , R 5 , R 6 , R 9 , and R 10  is hydrogen; R 4  is —NH 2 , —NHCH 3 , or —N(CH 3 ) 2 ; R 7  is hydrogen, halogen, lower alkyl, or phenyl; R 8  is hydrogen or —SO 2 R 29  (R 29  is mentioned before); R 11  is hydrogen, halogen, lower alkyl, —CN, or —CONH 2 .  
     
     
         25 . A pharmaceutical composition comprising a compound, prodrug, pharmaceutically acceptable salt or solvate thereof according to  claim 1 , together with a pharmaceutically acceptable additive thereof.  
     
     
         26 . A therapeutic or prophylactic medicament against the serotonin receptors mediated diseases, comprising a compound, prodrug, pharmaceutically acceptable salt or solvate thereof according to  claim 1 .  
     
     
         27 . A therapeutic or prophylactic medicament according to  claim 26 , wherein the serotonin receptor is a 5-HT 6  receptor.  
     
     
         28 . A therapeutic or prophylactic medicament according to  claim 26 , wherein the disease is that of central nervous system.  
     
     
         29 . A therapeutic or prophylactic medicament according to  claim 28 , wherein the disease of the central nervous system is schizophrenia, Alzheimer's disease, Parkinson's disease, depression, anxiety, pain, or migraine.  
     
     
         30 . A method for treating or preventing a serotonin receptor mediated disease, which comprises administrating to a mammal in need thereof an effective amount of a compound, prodrug, pharmaceutically acceptable salt or solvate thereof according  claim 1 .  
     
     
         31 . A method for preparing a therapeutic or prophylactic medicament for a serotonin receptor mediated disease, which comprises mixing a compound, prodrug, pharmaceutically acceptable salt or solvate thereof according to  claim 1 , together with a pharmaceutically acceptable additive thereof.