Non-peptide oxytocin receptor agonists

Abstract

Disclosed herein are compounds according to Formula I; a pharmaceutical composition including, consisting essentially of, or consisting of: a pharmaceutically acceptable compound of Formula I and a pharmaceutically acceptable carrier, diluent, or excipient; the use of compounds of Formula I in the preparation of a medicament; and a method including administering a pharmaceutical compositions comprising the compound of Formula I to a patient. The compounds, compositions, use, and methods are directed to the treatment of neurological, psychiatric disorders which are characterised by a fundamental disruption of social behaviour, and substance use disorders.

1 . A method of treating or preventing a condition selected from a social dysfunction, a substance abuse disorder, and a psychiatric disorder in a subject in need thereof, comprising administering to the subject in need thereof a pharmaceutically effective amount of a compound of Formula I, in a pharmaceutically acceptable form: 
       
         
           
           
               
               
           
         
         wherein R1, R3, R4, R5, and R6 are each independently selected from the group consisting of: H, F, Cl, Br, I, NH 2 , NO 2 , OH, ON═O, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 2 -C 4  alkenyl, substituted or unsubstituted C 2 -C 4  alkynyl, substituted or unsubstituted OC 1 -C 4  alkyl, substituted or unsubstituted OC 2 -C 4  alkenyl, substituted or unsubstituted OC 2 -C 4  alkynyl, substituted or unsubstituted NHC 1 -C 4  alkyl, substituted or unsubstituted NHC 2 -C 4  alkenyl, substituted or unsubstituted NHC 2 -C 4  alkynyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heterocyclyl; 
         wherein R2 is independently selected from the group consisting of: H, F, Br, I, NH 2 , NO 2 , OH, ON═O, substituted methyl, substituted or unsubstituted C 2 -C 4  alkyl, substituted or unsubstituted C 2 -C 4  alkenyl, substituted or unsubstituted C 2 -C 4  alkynyl, substituted or unsubstituted OC 1 -C 4  alkyl, substituted or unsubstituted OC 2 -C 4  alkenyl, substituted or unsubstituted OC 2 -C 4  alkynyl, substituted or unsubstituted NHC 1 -C 4  alkyl, substituted or unsubstituted NHC 2 -C 4  alkenyl, substituted or unsubstituted NHC 2 -C 4  alkynyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heterocyclyl; 
         wherein each R1, R2, R3, R4, R5, or R6 that is a substituted aryl or a substituted heterocyclyl includes one or more substituent(s) selected from the group consisting of F, Cl, Br, I, NH 2 , N═O, NO 2 , NHCH 3 , OH, OCH 3 , OC≡N, ON═O, SH, SCH 3 , S(═O) n OH, S(═O) n CH 3 , SC≡N, COOH, CH 3 , CH m F (3-m) , CH m Cl (3-m) , CH m Br (3-m) , OCH 3 , OCH m F (3-m) , OCH m Cl (3-m) , or OCH m Br (3-m) ; 
         wherein X is a cyclic structure selected from the group consisting of: a substituted or unsubstituted, fused or unfused aryl; a substituted or unsubstituted, fused or unfused heterocyclyl; and a substituted or unsubstituted, fused or unfused cycloalkyl; and 
         wherein X1 represents one or more atoms or moieties independently selected from the group consisting of: H, F, Cl, Br, I, NH 2 , NO 2 , OH, ON═O, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 2 -C 4  alkenyl, substituted or unsubstituted C 2 -C 4  alkynyl, substituted or unsubstituted OC 1 -C 4  alkyl, substituted or unsubstituted OC 2 -C 4  alkenyl, substituted or unsubstituted OC 2 -C 4  alkynyl, substituted or unsubstituted NHC 1 -C 4  alkyl, substituted or unsubstituted NHC 2 -C 4  alkenyl, substituted or unsubstituted NHC 2 -C 4  alkynyl, COOH, C 1  alkyl-COOH, COOC 1 -C 2  alkyl, COOC 1 -C 2  alkaryl, C 1  alkyl-COOC 1 -C 2  alkyl, C 1 -C 2  alkaryl, OC 1 -C 2  alkaryl, NC 1 -C 2  alkaryl, C 1 -C 2  alkyl-heterocyclyl, OC 1 -C 2  alkyl-heterocyclyl, and NC 1 -C 2  alkyl-heterocyclyl; 
         wherein each alkyl, alkenyl, alkynyl, alkaryl, or alkyl-heterocyclyl that is substituted includes one or more substituents selected from the group consisting of: F, Cl, Br, I, ≡N, ═NH, NH 2 , N═O, NO 2 , NHCH 3 , N═C═O, N═C═S, ═O, OH, OCH 3 , OC≡N, ON═O, ═S, SH, SCH 3 , S(═O) n OH, S(═O) n CH 3 , and SC≡N; 
         wherein each m is an integer selected from 0, 1, or 2; and 
         each n is an integer selected from 0, 1, or 2. 
       
     
     
         2 . The method of  claim 1 , wherein the social dysfunction is selected from social withdrawal, aggressiveness, and an anti-social disorder. 
     
     
         3 . The method of  claim 1 , wherein the condition is a substance abuse disorder. 
     
     
         4 . The method of  claim 3 , wherein the substance is selected from the group consisting of: alcohol, cocaine, opiates, amphetamines, heroin, and nicotine. 
     
     
         5 . The method of  claim 1 , wherein the psychiatric disorder is selected from an autistic spectrum disorder, a social anxiety disorder, a depressive disorder including major depressive disorder, and schizophrenia. 
     
     
         6 . The method of  claim 1 , wherein the subject suffers from, or is recovering from, a substance abuse disorder; or
 the subject is recovering from the substance abuse disorder and is seeking to maintain ongoing abstinence from the substance.   
     
     
         7 . The method of  claim 1 , wherein X is a substituted or unsubstituted, fused or unfused aryl. 
     
     
         8 . The method of  claim 1 , wherein X is a substituted or unsubstituted, fused or unfused heterocyclyl. 
     
     
         9 . The method of  claim 1 , wherein X is a substituted or unsubstituted, fused or unfused cycloalkyl. 
     
     
         10 . The method of  claim 1 , wherein the cyclic structure is selected from the group consisting of: fused or unfused aryl groups; fused or unfused 5-, 6-, 7-membered heterocyclic groups having one or more hetero ring atoms selected from N, O, and S; and a 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, or 16-membered mono-, bridged bi-, or bridged tri-cycloalkyl groups. 
     
     
         11 . The method of  claim 1 , wherein the aryl group is an unfused aryl group, the heterocyclic group is an unfused heterocyclic group having only a single hetero ring atom, and the cycloalkyl is a bridged bi- or tri-cyclic alkyl group. 
     
     
         12 . The method of  claim 1 , wherein R1, R3, R4, R5, and R6 are each independently selected from the group consisting of: H, F, Cl, Br, I, OH, CH 3 , CH m F (3-m) , CH m Cl (3-m) , CH m Br (3-m) , OCH 3 , OCH m F (3-m) , OCH m Cl (3-m) , and OCH m Br (3-m) ; and
 R2 is independently selected from the group consisting of: H, F, Cl, Br, I, OH, CH 3 , CH m F (3-m) , CH m Cl (3-m) , CH m Br (3-m) , OCH 3 , OCH m F (3-m) , OCH m Cl (3-m) , and OCH m Br (3-m) .   
     
     
         13 . The method of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         14 . A method of treating a subject that suffers from, or is recovering from, a substance abuse disorder; or a subject that is recovering from the substance abuse disorder and is seeking to maintain ongoing abstinence from the substance,
 comprising administering to the subject an effective amount of a compound of formula (I) in a pharmaceutically acceptable form   
       
         
           
           
               
               
           
         
         wherein R1, R3, R4, R5, and R6 are each independently selected from the group consisting of: H, F, Cl, Br, I, NH 2 , NO 2 , OH, ON═O, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 2 -C 4  alkenyl, substituted or unsubstituted C 2 -C 4  alkynyl, substituted or unsubstituted OC 1 -C 4  alkyl, substituted or unsubstituted OC 2 -C 4  alkenyl, substituted or unsubstituted OC 2 -C 4  alkynyl, substituted or unsubstituted NHC 1 -C 4  alkyl, substituted or unsubstituted NHC 2 -C 4  alkenyl, substituted or unsubstituted NHC 2 -C 4  alkynyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heterocyclyl; 
         wherein R2 is independently selected from the group consisting of: H, F, Br, I, NH 2 , NO 2 , OH, ON═O, substituted methyl, substituted or unsubstituted C 2 -C 4  alkyl, substituted or unsubstituted C 2 -C 4  alkenyl, substituted or unsubstituted C 2 -C 4  alkynyl, substituted or unsubstituted OC 1 -C 4  alkyl, substituted or unsubstituted OC 2 -C 4  alkenyl, substituted or unsubstituted OC 2 -C 4  alkynyl, substituted or unsubstituted NHC 1 -C 4  alkyl, substituted or unsubstituted NHC 2 -C 4  alkenyl, substituted or unsubstituted NHC 2 -C 4  alkynyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heterocyclyl; 
         wherein each R1, R2, R3, R4, R5, or R6 that is a substituted aryl or a substituted heterocyclyl includes one or more substituent(s) selected from the group consisting of F, Cl, Br, I, NH 2 , N═O, NO 2 , NHCH 3 , OH, OCH 3 , OC≡N, ON═O, SH, SCH 3 , S(═O) n OH, S(═O) n CH 3 , SC≡N, COOH, CH 3 , CH m F (3-m) , CH m Cl (3-m) , CH m Br (3-m) , OCH 3 , OCH m F (3-m) , OCH m Cl (3-m) , or OCH m Br (3-m) ; 
         wherein X is a cyclic structure selected from the group consisting of: a substituted or unsubstituted, fused or unfused aryl; a substituted or unsubstituted, fused or unfused heterocyclyl; and a substituted or unsubstituted, fused or unfused cycloalkyl; and 
         wherein X1 represents one or more atoms or moieties independently selected from the group consisting of: H, F, Cl, Br, I, NH 2 , NO 2 , OH, ON═O, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 2 -C 4  alkenyl, substituted or unsubstituted C 2 -C 4  alkynyl, substituted or unsubstituted OC 1 -C 4  alkyl, substituted or unsubstituted OC 2 -C 4  alkenyl, substituted or unsubstituted OC 2 -C 4  alkynyl, substituted or unsubstituted NHC 1 -C 4  alkyl, substituted or unsubstituted NHC 2 -C 4  alkenyl, substituted or unsubstituted NHC 2 -C 4  alkynyl, COOH, C 1  alkyl-COOH, COOC 1 -C 2  alkyl, COOC 1 -C 2  alkaryl, C 1  alkyl-COOC 1 -C 2  alkyl, C 1 -C 2  alkaryl, OC 1 -C 2  alkaryl, NC 1 -C 2  alkaryl, C 1 -C 2  alkyl-heterocyclyl, OC 1 -C 2  alkyl-heterocyclyl, and NC 1 -C 2  alkyl-heterocyclyl; 
         wherein each alkyl, alkenyl, alkynyl, alkaryl, or alkyl-heterocyclyl that is substituted includes one or more substituents selected from the group consisting of: F, Cl, Br, I, ≡N, ═NH, NH 2 , N═O, NO 2 , NHCH 3 , N═C═O, N═C═S, ═O, OH, OCH 3 , OC≡N, ON═O, ═S, SH, SCH 3 , S(═O) n OH, S(═O) n CH 3 , and SC≡N; 
         wherein each m is an integer selected from 0, 1, or 2; and 
         each n is an integer selected from 0, 1, or 2. 
       
     
     
         15 . The method of  claim 14 , wherein the substance is selected from the group consisting of: alcohol, cocaine, opiates, amphetamines, heroin, and nicotine. 
     
     
         16 . The method of  claim 14 , wherein X is a substituted or unsubstituted, fused or unfused aryl. 
     
     
         17 . The method of  claim 14 , wherein X is a substituted or unsubstituted, fused or unfused heterocyclyl. 
     
     
         18 . The method of  claim 14 , wherein X is a substituted or unsubstituted, fused or unfused cycloalkyl. 
     
     
         19 . The method of  claim 14 , wherein the cyclic structure is selected from the group consisting of: fused or unfused aryl groups; fused or unfused 5-, 6-, 7-membered heterocyclic groups having one or more hetero ring atoms selected from N, O, and S; and a 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, or 16-membered mono-, bridged bi-, or bridged tri-cycloalkyl groups. 
     
     
         20 . The method of  claim 14 , wherein the compound is selected from the group consisting of: