Use of (2r, 6r)-hydroxynorketamine, (s)-dehydronorketamine and other stereoisomeric dehydro and hydroxylated metabolites of (r,s)- ketamine in the treatment of depression and neuropathic pain

Abstract

The disclosure provides pharmaceutical preparations containing (2R,6R)-hydroxynorketamine, or (R)- or (S)-dehydronorketamine, or other stereoisomeric dehydro or hydroxylated ketamine metabolite. The disclosure also provides novel ketamine metabolite prodrugs. The disclosure provides methods of treating, bipolar depression, major depressive disorder, neuropathic and chronic pain, including complex regional pain synthetic pain disorder (CRPD) by administering a purified ketamine metabolite or a ketamine metabolite prodrug directly to patients in need of such treatment.

1 . A pharmaceutical composition comprising a compound of Formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient, where 
         R 1  is hydrogen, hydroxyl, or a group -A 1 B 1  where A 1  is —O—, —O(C═O)—, —(C═O)O—, —O(C═O)O, —O(C═O)NR6—, —OS(O) 2 —, —OS(O) 3 , or —OP(O) 3 —, and B i  is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (carbocycle)C 0 -C 4 alkyl, or (heterocycle)C 0 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 6 alkylester, mono- and di-(C 1 -C 4 alkyl)amino, (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl, (heterocycloalkyl)C 0 -C 2 alkyl, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy; 
         wherein the six-membered ring to which R 1  is bound contains a double bond when R 1  is hydrogen and is fully saturated when R 1  is hydroxyl or A 1 B 1 ; 
         R 2  is hydrogen or -A 2 B 2  where A 2  is a bond, —O(C═O)—, —(C═O)O—, —S(O) 2 —, —(S═O)NR 6 —, or —(C═O)NR 6 —, B 2  is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 2 -C 6 alkanoyl, (carbocycle)C 0 -C 4 alkyl, (heterocycle)C 0 -C 4 alkyl, or an amino acid or dipeptide covalently bound to A 2  by its C-terminus, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 6 alkylester, mono- and di-(C 1 -C 4 alkyl)amino, (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl, (heterocycloalkyl)C 0 -C 2 alkyl, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy; 
         R 3  is hydrogen or C 1 -C 6 alkyl; 
         R 4  and R 5  are 0 or 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- and di-C 1 -C 4 alkylamino, Ci-C2haloalkyl, and C 1 -C 2 haloalkoxy; and 
         R 6  is hydrogen or C 1 -C 6 alkyl. 
       
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the compound is a compound of the formula: 
       
         
           
           
               
               
           
         
         or a salt thereof, and R 1  is not hydrogen. 
       
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the compound is a compound of the formula: 
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the composition is formulated for oral administration, intravenous administration, or intramuscular injection. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the composition is a solution and contains from about 0.05 mg/ml to about 0.5 mg/ml. 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the composition is formulated as an oral dosage form containing about 0.2 mg to about 500 mg of the compound. 
     
     
         8 . A compound of the formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
       
       R 1  is hydrogen, hydroxyl or -A 1 B 1  where A 1  is —O—, —O(C═O)—, —(C═O)O—, —O(C═O)O—, —O(C═O)NR 6 —, —OS(O) 2 —, —OS(O) 3 , or —OP(O) 3 —, and B 1  is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (carbocycle)C 0 -C 4 alkyl or (heterocycle)C 0 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 6 alkylester, mono- and di-(C 1 -C 4 alkyl)amino, (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl, (heterocycloalkyl)C 0 -C 2 alkyl, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy; with the proviso that -A 1 B 1  is not (4-methylphenyl)-S(O)O—; 
       wherein the six-membered ring to which R 1  is bound is fully saturated when R 1  is hydroxyl or -A 1 B 1 ; 
       R 2  is hydrogen or -A 2 B 2  where A 2  is a bond, —O(C═O)—, —(C═O)O—, —S(O) 2 —, —(S═O)NR 6 —, or —(C═O)NR 6 —, B 2  is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 2 -C 6 alkanoyl, (carbocycle)C 0 -C 4 alkyl, (heterocycle)C 0 -C 4 alkyl, or an amino acid or dipeptide covalently bound to A 2  by its C-terminus, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 6 alkylester, mono- and di-(C 1 -C 4 alkyl)amino, (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl, (heterocycloalkyl)C 0 -C 2 alkyl, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy; with the proviso that B 2  is not methyl when A 2  is a bond or —(C═O)O—; 
       R 1  is not hydrogen or hydroxyl when R 2  is hydrogen; 
       R 3  is hydrogen or C 1 -C 6 alkyl; 
       R 4  and R 5  are 0 or 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- and di-C 1 -C 4 alkylamino, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy; and 
       R 6  is hydrogen or C 1 -C 6 alkyl. 
     
     
         9 . A compound or salt of  claim 8 , of the formula 
       
         
           
           
               
               
           
         
       
     
     
         10 . A compound or salt of  claim 8 , of the formula 
       
         
           
           
               
               
           
         
         where A 1  is —O—, —O(C═O)—, or —O(C═O )O—. 
       
     
     
         11 . A compound or salt of  claim 9 , wherein
 R 1  is hydrogen or hydroxyl;   R 3  is hydrogen or methyl;   R 4  and R 5  are each 0 to 2 substituents independently chosen from halogen, hydroxyl, amino, C 1 -C 2 alkyl, and C 1 -C 2 alkyl; and   R 6  is hydrogen or methyl.   
     
     
         12 . A compound or salt of  claim 11 , wherein
 R 2  is -A 2 B 2  where A 2  is a bond, —(C═O)O—, —S(O) 2 —, —(S═O)NR 6 —, or —(C═O)NR 6 —, B 2  is C 1 -C 6 alkyl, C 2 -C 4 alkanoyl, (phenyl)C 0 -C 2 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, (heterocycloalkyl)C 0 -C 2 alkyl, (5- or 6-membered heteroaryl)C 0 -C 2 alkyl, or an amino acid covalently bound to A 2  by its C-terminus, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 6 alkylester, mono- and di-(C 1 -C 4 alkyl)amino, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy.   
     
     
         13 . A compound or salt of  claim 12 , wherein
 A 2  is a bond and B 2  is an amino acid covalently bound to A 2  by its C-terminus.   
     
     
         14 . A compound or salt of  claim 13 , wherein
 B 2  is   
       
         
           
           
               
               
           
         
       
     
     
         15 . A compound or salt of  claim 11 , where
 A 2  is a bond or —(C═O)O— and B 2  is C 2 -C 6 alkyl, (phenyl)Co-C 2 alkyl, or (C 3 -C 7 alkyl)C 0 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and mono- and di-(C 1 -C 4 alkyl)amino.   
     
     
         16 . A compound or salt of  claim 8 , where
 R 2  is hydrogen;   R 3  is hydrogen or methyl;   R 4  and R 5  are each 0 to 2 substituents independently chosen from halogen, hydroxyl, amino, C 1 -C 2 alkyl, and C 1 -C 2 alkyl; and   R 6  is hydrogen or methyl.   
     
     
         17 . A compound or salt of  claim 16 , where
 R 1  is -A 1 B 1  where A 1  is —O(C═O)— or —O(C═O)O—, and B 1  is C 1 -C 6 alkyl, (phenyl)C 0 -C 4 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, (heterocycloalkyl)C 0 -C 2 alkyl, or (5- or 6-membered heteroaryl)C 0 -C 2 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxyl, amino, cyano, C 1 l-C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 6 alkylester, mono- and di-(C 1 -C 4 alkyl)amino, (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl, (heterocycloalkyl)C 0 -C 2 alkyl, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy.   
     
     
         18 . A compound or salt of  claim 16 , where
 B 1  is C 1 -C 6 alkyl, (phenyl)C 0 -C 2 alkyl, or (heterocycloalkyl)C 0 -C 2 alkyl, each of which is substituted with from 0 to 2 substituents independently chosen from halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- and di-(C 1 -C 4 alkyl)amino, (C 3 -C 7 cycloalkyl)Co-Czalkyl, and (heterocycloalkyl)Co-C 2 alkyl.   
     
     
         19 . A compound or salt of  claim 8 , of the formula 
       
         
           
           
               
               
           
         
       
     
     
         20 . A compound or salt of  claim 19 , wherein
 R 3  is hydrogen or methyl;   R 4  and R 5  are each 0 to 2 substituents independently chosen from halogen, hydroxyl, amino, C 1 -C 2 alkyl, and C 1 -C 2 alkyl; and   R 6  is hydrogen or methyl.   
     
     
         21 .- 36 . (canceled)