Ketamine Derivatives

Abstract

pa The present invention relates to ketamine derivatives of the formula (I), pharmaceutical compositions comprising them, and methods for treating pain comprising administering them, and their use in the manufacture of medicaments for treating pain. The present invention also relates to methods for anaesthetizing and methods for sedating a subject comprising administering ketamine derivatives of the formula (II).

1 . A method for anaesthetizing or sedating a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof to the subject, wherein: 
       
         
           
           
               
               
           
         
       
       wherein
 Y 1  is −C 2-6 aliphaticC(O)OR 1 , —C 2-6 aliphaticOC(O)R 1 , —C 1-6 aliphaticC(O)OC 1-6 aliphaticC(O)OR 1 , or —C 1-6 aliphaticC(O)OC 1-6 aliphaticOR 3 , wherein each aliphatic is optionally substituted with one or more R 2 ; 
 R 1  is C 1-6 aliphatic, optionally substituted with one or more halo, CN, NO 2 , NH 2 , NHR 11 , NR 11 -R 12 , C 1-6 haloalkyl, C 1-6 haloalkoxy, C(O)NH 2 , C(O)NHR 11 , C(O)NR 11 R 12 , SO 2 R 11 , OR 11 , C(O)R 11 , and C 1-6 aliphatic; 
 R 2  is C 1-6 aliphatic, optionally substituted with one or more halo, OR 11 , or CN; 
 R 3  is hydrogen or R 1 ; 
 R 11  and R 12  are each independently C 1-6 aliphatic; or R 11  and R 12  together with the nitrogen atom to which they are attached are a heteroaryl or heterocyclyl ring; 
 Y 2  is hydrogen or R 2 ; 
 X 1  and X 2  are each independently hydrogen, R 2 , halo, NO 2 , NH 2 , NHR 11 , NR 11 R 12 , C 1-6 haloalkyl, C 1-6 haloalkoxy, C(O)NH 2 , C(O)NHR 11 , C(O)NR 11 R 12 , SO 2 R 11 , OR 11 , C(O)R 11 , C 1-6 aliphaticY 1 , OY 1 , C(O)Y 1 , SO 2 Y 1 , or C(O)NHY 1  at any of the available 2-5 positions; 
 or a pharmaceutically acceptable salt or solvate thereof. 
 
     
     
         2 . The method of  claim 1 , wherein:
 Y 1  is −C 2-6 alkylC(O)OR 1 , —C 2-6 alkylOC(O)R 1 , —C 1-6 alkylC(O)OC 1-6 alkylC(O)OR 1 , or —C 1-6 alkylC(O)OC 1-6 alkylOR 3 , wherein each alkyl is optionally substituted with one or more R 2 ;   R 1  is C 1-6 aliphatic, optionally substituted with one or more halo, CN, NO 2 , NH 2 , NHR 11 , NR 11 -R 12 , C 1-6 haloalkyl, C 1-6 haloalkoxy, C(O)NH 2 , C(O)NHR 11 , C(O)NR 11 R 12 , SO 2 R 11 , OR 11 , C(O)R 11 , and C 1-6 aliphatic;   R 2  is C 1-6 aliphatic, optionally substituted with one or more halo, OR 11 , or CN;   R 3  is hydrogen or R 1 ;   R 11  and R 12  are each independently C 1-6 aliphatic; or R 11  and R 12  together with the nitrogen atom to which they are attached are a heteroaryl or heterocyclyl ring;   Y 2  is hydrogen or R 2 ;   X 1  and X 2  are each independently hydrogen, R 2 , halo, NO 2 , NH 2 , NHR 11 , NR 11 R 12 , C 1-6 haloalkyl, C 1-6 haloalkoxy, C(O)NH 2 , C(O)NHR 11 , C(O)NR 11 R 12 , SO 2 R 11 , OR 11 , C(O)R 11 , C 1-6 aliphaticY 1 , OY 1 , C(O)Y 1 , SO 2 Y 1 , or C(O)NHY 1  at any of the available 2-5 positions;   or a pharmaceutically acceptable salt or solvate thereof.   
     
     
         3 . The method of  claim 2 , wherein Y 1  is —C 2-6 alkylC(O)OR 1  or —C 2-6 alkylOC(O)R 1 , wherein each alkyl is optionally substituted. 
     
     
         4 . The method of  claim 2 , wherein Y 1  is —C 2-6 alkylC(O)OR 1 , wherein the alkyl is optionally substituted. 
     
     
         5 . The method of  claim 2 , wherein R 1  is C 1-6 alkyl, C 2-6 alkenyl, cycloalkyl, or cycloalkenyl, wherein each alkyl and cycloalkyl are optionally substituted with one or more halo, CN, NO 2 , NH 2 , NHR 11 , NR 11 R 12 , C 1-6 haloalkyl, C 1-6 haloalkoxy, C(O)NH 2 , C(O)NHR 11 , C(O)NR 11 R 12 , SO 2 R 11 , OR 11 , and C(O)R 11 ; and each alkyl is optionally substituted with cycloalkyl or cycloalkenyl; and each cycloalkyl is optionally substituted with C 1-6 alkyl or C 2-6 alkenyl. 
     
     
         6 . The method of  claim 5 , wherein R 1  is C 1-6 alkyl or cycloalkyl, wherein each alkyl and cycloalkyl is optionally substituted. 
     
     
         7 . The method of  claim 6 , wherein R 1  is C 1-6 alkyl, wherein each alkyl is optionally substituted. 
     
     
         8 . The method of  claim 2 , wherein R 2  is C 1-6 alkyl or cycloalkyl, optionally substituted with one or more halo, OR 11 , or CN. 
     
     
         9 . The method of  claim 8 , wherein R 2  is C 1-6 alkyl, optionally substituted with one or more halo, OR 11 , or CN. 
     
     
         10 . The method of  claim 2 , wherein Y 2  is hydrogen or C 1-6 alkyl, wherein the alkyl is optionally substituted. 
     
     
         11 . The method of  claim 2 , wherein X 1  and X 2  are each independently hydrogen, R 2 , halo, NO 2 , NH 2 , NHR 11 , NR 11 R 12 , C 1-6 haloalkyl, C 1-6 haloalkoxy, C(O)NH 2 , C(O)NHR 11 , C(O)NR 11 R 12 , SO 2 R 11 , OR 11 , or C(O)R 11 ; or X 2  is C 1-6 alkylY 1 , OY 1 , C(O)Y 1 , SO 2 Y 1 , or C(O)NHY 1  at any of the available 2-5 positions. 
     
     
         12 . The method of  claim 11 , wherein X 1  and X 2  are each independently hydrogen, R 2 , halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, SO 2 R 11 , or OR 11  at any of the available 2-5 positions. 
     
     
         13 . The method of  claim 12 , wherein X 1  is 2-chloro; and X 2  is hydrogen, R 2 , halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, SO 2 R 11 , or OR 11  at any of positions 3-5. 
     
     
         14 . The method of  claim 2 , wherein Y 1  is —(CR A R B ) m (CR C R D ) n C(O)OR 1 , —(CR A R B ) m (CR C R D ) n OC(O)R 1 , —(CR A R B ) m-1 (CR C R D ) n C(O)O(CR G R H ) p (CR E R F ) o C(O)OR 1 , or —(CR A R B ) m-1 (CR C R D ) n C(O)O(CR G R H ) p (CR E R F ) o OR 3 ; m is an integer from 2 to 6; o is an integer from 1 to 6; n and p are each independently 0 or 1; the sum of m and n and the sum of o and p is 6 or less; and R A , R B , R C , R D , R E , R F , R G , and R H  at each instance of m, n, o, and p are each independently hydrogen or R 2 . 
     
     
         15 . The method of  claim 14 , wherein Y 1  is (CR A R B ) m (CR C R D ) n C(O)OR 1 . 
     
     
         16 . The method of  claim 14 , wherein R A , R B , R E , and R F  at each instance of m and o are each independently hydrogen; and R C , R D , R G , and R H  at each instance of n and p are each independently hydrogen or R 2 . 
     
     
         17 . The method of  claim 2 , wherein the compound is
 3-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino)propyl acetate,   ethyl 3-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino) propanoate,   iso-propyl 3-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino) propanoate,   n-propyl 3-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino) propanoate,   ethyl 4-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino) butanoate,   isopropyl 4-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino) butanoate,   n-propyl 4-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino) butanoate,   methyl 5-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino) pentanoate,   ethyl 5-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino) pentanoate,   isopropyl 5-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino) pentanoate,   n-propyl 5-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino) pentanoate,   ethyl 3-((1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)amino) propanoate,   ethyl 4-((1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)amino) butanoate, or   methyl 5-((1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)amino) pentanoate, or   a pharmaceutically acceptable salt or solvate thereof.   
     
     
         18 . The method of  claim 2 , wherein X 1  is 2-halo and X 2  is hydrogen. 
     
     
         19 . The method of  claim 2 , wherein Y 2  is hydrogen or methyl. 
     
     
         20 . The method of  claim 2 , wherein R 1  is C 1-6 alkyl. 
     
     
         21 . The method of  claim 2 , wherein X 1 is 2-chloro and X 2  is hydrogen. 
     
     
         22 . The method of  claim 2 , wherein the compound is methyl 5-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino)pentanoate, or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         23 . The method of  claim 2 , wherein the compound is isopropyl 3-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino)propanoate, or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         24 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 Y 1  is —C 2-6 aliphaticC(O)OR 1 , —C 2-6 aliphaticOC(O)R 1 , —C 1-6 aliphaticC(O)OC 1-6 aliphaticC(O)OR 1 , or —C 1-6 aliphaticC(O)OC 1-6 aliphaticOR 3 , wherein each aliphatic is optionally substituted with one or more R 2 ; 
 R 1  is C 1-6 aliphatic, optionally substituted with one or more halo, CN, NO 2 , NH 2 , NHR 11 , 
 NR 11 -R 12 , C 1-6 halalkyl, C 1-6 haloalkoxy, C(O)NH 2 , C(O)NHR 11 , C(O)NR 11 R 12 , SO 2 R 11 , OR 11 , C(O)R 11 , and C 1-6 aliphatic; 
 R 2  is C 1-6 aliphatic, optionally substituted with one or more halo, OR 11 , or CN; 
 R 3  is hydrogen or R 1 ; 
 R 11  and R 12  are each independently C 1-6 aliphatic; or R 11  and R 12  together with the nitrogen atom to which they are attached are a heteroaryl or heterocyclyl ring; 
 Y 2  is hydrogen or R 2 ; 
 X 1  and X 2  are each independently hydrogen, R 2 , halo, NO 2 , NH 2 , NHR 11 , NR 11 R 12 , C 1-6 haloalkyl, C 1-6 haloalkoxy, C(O)NH 2 , C(O)NHR 11 , C(O)NR 11 , R 12 , SO 2 R 11 , OR 11 , C(O)R 11 , C 1-6 aliphaticY 1 , OY 1 , C(O)Y 1 , SO 2 Y 1 , or C(O)NHY 1  at any of the available 2-5 positions; 
 or a pharmaceutically acceptable salt or solvate thereof.