Novel melatonin ligands having antidepressant activity as well as sleep inducing properties

Abstract

Novel melatonin ligands of Formula I: or pharmaceutically acceptable salts thereof wherein: n is 1 or 2; m is 0, 1 or 2; p is 0, 1, 2, 3, 4, 5, 6, 7 or 8; v is 2 or 3; A is aryl or heteroaryl; Z is O, S or NR 8 ; Y is selected from the group consisting of hydrogen, aryl, heteroaryl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and R is selected from the group consisting of hydrogen, hydroxyl, —OCF 3 , CF 3 , C 1 -C 8 alkyl, C 1 -C 8 alkyloxy, C 1 -C 8 alkylthio, halogen and —Z—(CH 2 ) p -A; R 1 is selected from the group consisting of C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, CF 3 , hydroxy-substituted C 1 -C 4 alkyl, hydroxy-substituted C 3 -C 6 cycloalkyl, and NHR 5 , wherein R 5 is C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl; R 2 is selected from the group consisting of: hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkyloxy, OCF 3 , CF 3 , hydroxyl, and halogen; R 3 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkyloxy, OCF 3 , CF 3 , hydroxyl, and halogen; R and R 3 may be connected together to form an —O—(CH 2 ) v bridge representing with the carbon atoms to which they are attached a 5- or 6-membered heterocyclic ring system; R 4 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkyloxy, OCF 3 , CF 3 , hydroxyl, and halogen; R 6 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 7 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkyloxy, OCF 3 , CF 3 , hydroxyl, and halogen; and R 8 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 a) n is 1 or 2; 
 b) m is 0, 1 or 2; 
 c) p is 0, 1, 2, 3, 4, 5, 6, 7 or 8; 
 d) v is 2 or 3; 
 e) A is aryl or heteroaryl; 
 f) Z is O, S or NR 8;    
 g) Y is selected from the group consisting of hydrogen, aryl, heteroaryl, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, and 
 
       
       
         
           
           
               
               
           
         
         
           h) R is selected from the group consisting of hydrogen, hydroxyl, —OCF 3 , CF 3 , C 1 -C 8  alkyl, C 1 -C 8  alkyloxy, C 1 -C 8  alkylthio, halogen and —Z—(CH 2 ) p -A; 
           i) R 1  is selected from the group consisting of C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, CF 3 , hydroxy-substituted C 1 -C 4  alkyl, hydroxy-substituted C 3 -C 6  cycloalkyl, and NHR 5 , wherein R 5  is C 1 -C 3  alkyl or C 3 -C 6  cycloalkyl; 
           j) R 2  is selected from the group consisting of: hydrogen, C 1 -C 4  alkyl, C 1 -C 4  alkyloxy, OCF 3 , CF 3 , hydroxyl, and halogen; 
           k) R 3  is selected from the group consisting of hydrogen, C 1 -C 4  alkyl, C 1 -C 4  alkyloxy, OCF 3 , CF 3 , hydroxyl, and halogen; 
           l) R and R 3  may be connected together to form an —O—(CH 2 ), bridge representing with the carbon atoms to which they are attached a 5- or 6-membered heterocyclic ring system; 
           m) R 4  is selected from the group consisting of hydrogen, C 1 -C 4  alkyl, C 1 -C 4  alkyloxy, OCF 3 , CF 3 , hydroxyl, and halogen; 
           n) R 6  is selected from the group consisting of hydrogen and C 1 -C 6  alkyl; 
           o) R 7  is selected from the group consisting of hydrogen, C 1 -C 4  alkyl, C 1 -C 4  alkyloxy, OCF 3 , CF 3 , hydroxyl, and halogen; and 
           p) R 8  is selected from the group consisting of hydrogen and C 1 -C 4  alkyl. 
         
       
     
     
         2 . The compound of  claim 1  being a ligand to MLT receptor subtypes MT 1  and/or MT 2.   
     
     
         3 . The compound of  claim 2 , wherein:
 a) n is 1 or 2;   b) m is 0, or 1;   c) p is 0, 1, 2, 3, or 4;   d) A is phenyl;   e) Z is O;   f) Y is selected from the group consisting of hydrogen, methyl, β-naphthyl, thiophene-2-yl, and   
       
         
           
           
               
               
           
         
         g) R is selected from the group consisting of hydrogen, methoxy, Br and —Z—(CH 2 ) p -A; 
         h) R 1  is selected from the group consisting of methyl, propyl and cyclobutyl; 
         i) R 2  is hydrogen; 
         j) R 3  is selected from the group consisting of hydrogen and methoxy; 
         k) R 4  is hydrogen; 
         l) R 6  is hydrogen or methyl; and 
         m) R 7  is hydrogen or methoxy. 
       
     
     
         4 . The compound of  claim 3 , wherein the compound is selected from the group consisting of N-[2-(diphenylamino)ethyl]acetamide, N-{2-[(3-Methoxyphenyl)-phenylamino]ethyl}acetamide, N-[2-(bis-3-methoxyphenylamino)ethyl]acetamide, N-{2-[(4-Methoxyphenyl)-3-methoxyphenylamino]ethyl}acetamide, N-{2-[(4-Methoxyphenyl)-phenylamino]ethyl}acetamide, N-{2-[(3-bromophenyl)-phenylamino]ethyl}acetamide, N-{2-[(3-Methoxyphenyl)-β-naphthylamino]ethyl}acetamide, N-{2-[(3-phenylbutoxyphenyl)-phenyl-amino]ethyl}acetamide, N-{2-[(3-Methoxyphenyl)-methylamino]ethyl}acetamide, N-{2-[(3-Methoxyphenyl)-benzylamino]ethyl}acetamide, N-{2-[(3-Methoxyphenyl)-amino]ethyl}acetamide, N-{3-[(3-Methoxyphenyl)-methylamino]propyl}acetamide, N-{2-[(3-Methoxyphenyl)-phenylamino]ethyl}butanamide, N-{2-[(3-Methoxyphenyl)-phenylamino]ethyl}cyclobutancarboxamide, N-Methyl-N-{2-[(3-methoxyphenyl)-phenylamino]ethyl}acetamide; N-{2-[(3-Butoxyphenyl)-methylamino]ethyl}acetamide; N-{2-[(3-Hexyloxyphenyl)-methylamino]ethyl}acetamide, and N-{2-{[3-(4-phenylbutoxy)phenyl)-methylamino]}ethyl}acetamide. 
     
     
         5 . The compound of  claim 4 , wherein the compound is N-{2-[(3-Methoxyphenyl)-phenylamino]ethyl}acetamide. 
     
     
         6 . A therapeutically effective composition for treating a condition mediated by the MT 1  and/or MT 2  receptor, comprising one or more pharmaceutically acceptable excipients and a compound of Formula I or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein:
 a) n is 1 or 2; 
 b) m is 0, 1 or 2; 
 c) p is 0, 1, 2, 3, 4, 5, 6, 7 or 8; 
 d) v is 2 or 3; 
 e) A is aryl or heteroaryl; 
 f) Z is O, S or NR 8;    
 g) Y is selected from the group consisting of hydrogen, aryl, heteroaryl, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, and 
 
       
       
         
           
           
               
               
           
         
         
           h) R is selected from the group consisting of hydrogen, hydroxyl, —OCF 3 , CF 3 , C 1 -C 8  alkyl, C 1 -C 8  alkyloxy, C 1 -C 8  alkylthio, halogen and —Z—(CH 2 ) p -A; 
           i) R 1  is selected from the group consisting of C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, CF 3 , hydroxy-substituted C 1 -C 4  alkyl, hydroxy-substituted C 3 -C 6  cycloalkyl, and NHR 5 , wherein R 5  is C 1 -C 3  alkyl or C 3 -C 6  cycloalkyl; 
           j) R 2  is selected from the group consisting of: hydrogen, C 1 -C 4  alkyl, C 1 -C 4  alkyloxy, OCF 3 , CF 3 , hydroxyl, and halogen; 
           k) R 3  is selected from the group consisting of hydrogen, C 1 -C 4  alkyl, C 1 -C 4  alkyloxy, OCF 3 , CF 3 , hydroxyl, and halogen; 
           l) R and R 3  may be connected together to form an —O—(CH 2 ) v  bridge representing with the carbon atoms to which they are attached a 5- or 6-membered heterocyclic ring system; 
           m) R 4  is selected from the group consisting of hydrogen, C 1 -C 4  alkyl, C 1 -C 4  alkyloxy, OCF 3 , CF 3 , hydroxyl, and halogen; 
           n) R 6  is selected from the group consisting of hydrogen and C 1 -C 6  alkyl; 
           o) R 7  is selected from the group consisting of hydrogen, C 1 -C 4  alkyl, C 1 -C 4  alkyloxy, OCF 3 , CF 3 , hydroxyl, and halogen; and 
           p) R 8  is selected from the group consisting of hydrogen and C 1 -C 4  alkyl. 
         
       
     
     
         7 . The composition of  claim 6 , wherein the compound of Formula I is selected from the group consisting of N-[2-(diphenylamino)ethyl]acetamide, N-{2-[(3-Methoxyphenyl)-phenylamino]ethyl}acetamide, N-[2-(bis-3-methoxyphenylamino)ethyl]acetamide, N-{2-[(4-Methoxyphenyl)-3-methoxyphenylamino]ethyl}acetamide, N-{2-[(4-Methoxyphenyl)-phenylamino]ethyl}acetamide, N-{2-[(3-bromophenyl)-phenylamino]ethyl}acetamide, N-{2-[(3-Methoxyphenyl)-β-naphthylamino]ethyl}acetamide, N-{2-[(3-phenylbutoxyphenyl)-phenyl-amino]ethyl}acetamide, N-{2-[(3-Methoxyphenyl)-methylamino]ethyl}acetamide, N-{2-[(3-Methoxyphenyl)-benzylamino]ethyl}acetamide, N-{2-[(3-Methoxyphenyl)-amino]ethyl}acetamide, N-{3[(3-Methoxyphenyl)-methylamino]propyl}acetamide, N-{2-[(3-Methoxyphenyl)-phenylamino]ethyl}butanamide, N-{2-[(3-Methoxyphenyl)-phenylamino]ethyl}cyclobutancarboxamide, N-Methyl-N-{2-[(3-methoxyphenyl)-phenylamino]ethyl}acetamide, N-{2-[(3-Butoxyphenyl)-methylamino]ethyl}acetamide; N-{2-[(3-Hexyloxyphenyl)-methylamino]ethyl}acetamide, and N-{2-{[3-(4-phenylbutoxyl)phenyl)-methylamino]}ethyl}acetamide. 
     
     
         8 . The composition of  claim 7 , wherein the compound is N-{2-[(3-Methoxyphenyl)-phenylamino]ethyl}acetamide. 
     
     
         9 . The composition of  claim 6 , wherein the condition is associated with MLT activity. 
     
     
         10 . The composition of  claim 9 , wherein the condition is selected from the group consisting of sleep disorders, anxiety, depression, and chronobiological disorders. 
     
     
         11 . The composition of  claim 10 , wherein the condition is sleep disorders. 
     
     
         12 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound according to  claim 1 . 
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein the compound is selected from the group consisting of N-[2-(diphenylamino)ethyl]acetamide, N-{2-[(3-Methoxyphenyl)-phenylamino]ethyl}acetamide, N-[2-(bis-3-methoxyphenylamino)ethyl]acetamide, N-{2-[(4-Methoxyphenyl)-3-methoxyphenylamino]ethyl}acetamide, N-{2-[(4-Methoxyphenyl)-phenylamino]ethyl}acetamide, N-{2-[(3-bromophenyl)-phenylamino]ethyl}acetamide, N-{2-[(3-Methoxyphenyl)-β-naphthylamino]ethyl}acetamide, N-{2-[(3-phenylbutoxyphenyl)-phenyl-amino]ethyl}acetamide, N-{2-[(3-Methoxyphenyl)-methylamino]ethyl}acetamide, N-{2-[(3-Methoxyphenyl)-benzylamino]ethyl}acetamide, N-{2-[(3-Methoxyphenyl)-amino]ethyl}acetamide, N-{3[(3-Methoxyphenyl)-methylamino]propyl}acetamide, N-{2-[(3-Methoxyphenyl)-phenylamino]ethyl}butanamide, N-{2-[(3-Methoxyphenyl)-phenylamino]ethyl}cyclobutancarboxamide, N-Methyl-N-{2-[(3-methoxyphenyl)-phenylamino]ethyl}acetamide, N-{2-[(3-Butoxyphenyl)-methylamino]ethyl}acetamide; N-{2-[(3-Hexyloxyphenyl)-methylamino]ethyl}acetamide, and N-{2-{[3-(4-phenylbutoxyl)phenyl)-methylamino]}ethyl}acetamide. 
     
     
         14 . The pharmaceutical composition of  claim 13 , wherein the compound is N-{2-[(3-Methoxyphenyl)-phenylamino]ethyl}acetamide. 
     
     
         15 . The pharmaceutical composition of  claim 12 , comprising from about 0.1% to about 99% by weight of the compound of Formula I. 
     
     
         16 . The pharmaceutical composition of  claim 15 , comprising from about 10% to about 60% by weight of the compound of Formula I. 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein the compound is selected from the group consisting of N-[2-(diphenylamino)ethyl]acetamide, N-{2-[(3-Methoxyphenyl)-phenylamino]ethyl}acetamide, N-[2-(bis-3-methoxyphenylamino)ethyl]acetamide, N-{2-[(4-Methoxyphenyl)-3-methoxyphenylamino]ethyl}acetamide, N-{2-[(4-Methoxyphenyl)-phenylamino]ethyl}acetamide, N-{2-[(3-bromophenyl)-phenylamino]ethyl}acetamide, N-{2-[(3-Methoxyphenyl)-β-naphthylamino]ethyl}acetamide, N-{2-[(3-phenylbutoxyphenyl)-phenyl-amino]ethyl}acetamide, N-{2-[(3-Methoxyphenyl)-methylamino]ethyl}acetamide, N-{2-[(3-Methoxyphenyl)-benzylamino]ethyl}acetamide, N-{2-[(3-Methoxyphenyl)-amino]ethyl}acetamide, N-{3-[(3-Methoxyphenyl)-methylamino]propyl}acetamide, N-{2-[(3-Methoxyphenyl)-phenylamino]ethyl}butanamide, N-{2-[(3-Methoxyphenyl)-phenylamino]ethyl}cyclobutancarboxamide, N-Methyl-N-{2[(3-methoxyphenyl)-phenylamino]ethyl}acetamide, N-{2-[(3-Butoxyphenyl)-methylamino]ethyl}acetamide; N-{2-[(3-Hexyloxyphenyl)-methylamino]ethyl}acetamide, and N-{2-{[3-(4-phenylbutoxyl)phenyl)-methylamino]}ethyl}acetamide. 
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein the compound is N-{2-[(3-Methoxyphenyl)-phenylamino]ethyl}acetamide. 
     
     
         19 . A method of interacting with the MT 1  and/or MT 2  MLT receptor subtypes comprising administering to a subject in need thereof an effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 a) n is 1 or 2; 
 b) m is 0, 1 or 2; 
 c) p is 0, 1, 2, 3, 4, 5, 6, 7 or 8; 
 d) v is 2 or 3; 
 e) A is aryl or heteroaryl; 
 f) Z is O, S or NR 8;    
 g) Y is selected from the group consisting of hydrogen, aryl, heteroaryl, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, and 
 
       
       
         
           
           
               
               
           
         
         
           h) R is selected from the group consisting of hydrogen, hydroxyl, —OCF 3 , CF 3 , C 1 -C 8  alkyl, C 1 -C 8  alkyloxy, C 1 -C 8  alkylthio, halogen and —Z—(CH 2 ) p -A; 
           i) R 1  is selected from the group consisting of C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, CF 3 , hydroxy-substituted C 1 -C 4  alkyl, hydroxy-substituted C 3 -C 6  cycloalkyl, and NHR 5 , wherein R 5  is C 1 -C 3  alkyl or C 3 -C 6  cycloalkyl; 
           j) R 2  is selected from the group consisting of: hydrogen, C 1 -C 4  alkyl, C 1 -C 4  alkyloxy, OCF 3 , CF 3 , hydroxyl, and halogen; 
           k) R 3  is selected from the group consisting of hydrogen, C 1 -C 4  alkyl, C 1 -C 4  alkyloxy, OCF 3 , CF 3 , hydroxyl, and halogen; 
           l) R and R 3  may be connected together to form an —O—(CH 2 ), bridge representing with the carbon atoms to which they are attached a 5- or 6-membered heterocyclic ring system; 
           m) R 4  is selected from the group consisting of hydrogen, C 1 -C 4  alkyl, C 1 -C 4  alkyloxy, OCF 3 , CF 3 , hydroxyl, and halogen; 
           n) R 6  is selected from the group consisting of hydrogen and C 1 -C 6  alkyl; 
           o) R 7  is selected from the group consisting of hydrogen, C 1 -C 4  alkyl, C 1 -C 4  alkyloxy, OCF 3 , CF 3 , hydroxyl, and halogen; and 
           p) R 8  is selected from the group consisting of hydrogen and C 1 -C 4  alkyl. 
         
       
     
     
         20 . The method of  claim 19 , wherein the compound of Formula I is a ligand to MLT receptor subtypes MT 1  and/or MT 2.   
     
     
         21 - 28 . (canceled)