Substituted pyridoxine-lactam carboxylate salts

Abstract

The present invention provides salt adducts comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5- to 7-membered lactam ring, optionally additionally substituted, methods of their preparation, and pharmaceutical compositions and medicaments comprising them. Salt adducts of the invention and compositions comprising them may be used to in the treatment of diseases or disorders associated with or inflicted by alcohol consumption.

1 . A salt adduct comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5- to 7-membered lactam ring, optionally additionally substituted; provided that when said carboxylated lactam ring is an L-2-pyroglutamate, said positively charged moiety is other than pyridoxine. 
     
     
         2 . A salt adduct according to  claim 1 , wherein said positively charged moiety is a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is straight or branched C 1 -C 6  alkyl; 
         R 2  is selected from —OH, straight or branched C 1 -C 6  alkoxy, and straight or branched C 1 -C 6  alkoxycarbonyl; 
         R 3  and R 4  are each independently selected from formyl, straight or branched C 1 -C 6  alkyl optionally substituted by at least one halogen, amine, hydroxyl, C 1 -C 6  alkoxy, thiol, C 1 -C 6  alkoxycarbonyl. 
       
     
     
         3 . A salt adduct according to  claim 1 , wherein said carboxylated lactam ring is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein 
         R 6  is selected from H, straight or branched C 1 -C 6  alkyl optionally substituted by at least one halogen, straight or branched C 2 -C 6  alkenyl, straight or branched C 2 -C 6  alkynyl, cycloalkyl, aryl and heteroaryl optionally substituted by a C 1 -C 6  alkyl; 
         R 7 , R 8 , R 9 , R 10  R 11 , R 12 , R 13  and R 14  are each independently selected from H, straight or branched C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, cycloalkyl, aryl and heteroaryl optionally substituted by at least one group selected from C 1 -C 6  alkyl, halogen, amino, cyano, nitro, thiol, C 1 -C 6  alkoxy, aminocarbonyl, C 1 -C 6  alkoxycarbonyl, C 1 -C 6  carboxyalkyl, C 1 -C 6  alkoxycarbonylalkyl and amidino. 
       
     
     
         4 . A salt adduct according to  claim 1 , wherein said carboxylated lactam ring is a compound of formula (II): 
       
         
           
           
               
               
           
         
       
       and
 said positively charged moiety is compound (2): 
 
       
         
           
           
               
               
           
         
         R 6  is selected from H, straight or branched C 1 -C 6  alkyl substituted by at least one halogen, straight or branched C 2 -C 6 alkenyl, straight or branched C 2 -C 6  alkynyl, cycloalkyl, aryl and heteroaryl optionally substituted by a C 1 -C 6  alkyl; 
         R 7 , R 8 , R 9 , R 10  are each independently selected from H, straight or branched C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, cycloalkyl, aryl and heteroaryl optionally substituted by at least one group selected from C 1 -C 6  alkyl, halogen, amino, cyano, nitro, thiol, C 1 -C 6  alkoxy, aminocarbonyl, C 1 -C 6  alkoxy carbonyl, C 1 -C 6  carboxyalkyl, C 1 -C 6  alkoxycarbonylalkyl and amidino. 
       
     
     
         5 . A salt adduct according to  claim 1 , wherein said carboxylated lactam ring is compound (1): 
       
         
           
           
               
               
           
         
       
       and
 said positively charged moiety is a compound of formula (I): 
 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is straight or branched C 1 -C 6  alkyl; 
         R 2  is selected from —OH, straight or branched C 1 -C 6  alkoxy, and straight or branched C 1 -C 6  alkoxycarbonyl; 
         R 3  and R 4  are each independently selected from formyl, straight or branched C 1 -C 6  alkyl optionally substituted by at least one halogen, amine, hydroxyl, C 1 -C 6  alkoxy, thiol, C 1 -C 6  alkoxycarbonyl. 
       
     
     
         6 . A salt adduct according to  claim 1 , wherein said carboxylated lactam ring is compound (1): 
       
         
           
           
               
               
           
         
       
       and
 said positively charged moiety is a compound of formula (I): 
 
       
         
           
           
               
               
           
         
         wherein R 1  is a C 1 -C 6  alkyl; 
         R 2  is selected from —OH, straight or branched C 1 -C 6  alkoxy, and straight or branched C 1 -C 6  alkoxycarbonyl; 
         R 3  and R 4  are each independently selected from formyl, straight or branched C 1 -C 6  alkyl optionally by at least one halogen, amine, hydroxyl, C 1 -C 6  alkoxy, thiol, C 1 -C 6  alkoxycarbonyl. 
       
     
     
         7 . A salt adduct according to  claim 1 , wherein said carboxylated lactam ring is compound (1): 
       
         
           
           
               
               
           
         
       
       and
 said positively charged moiety is a compound of formula (I): 
 
       
         
           
           
               
               
           
         
         wherein R 2  is selected from —OH and C 1 -C 6  alkoxy; and 
         R 1  is straight or branched C 1 -C 6  alkyl; 
         R 3  and R 4  are each independently selected from formyl, straight or branched C 1 -C 6  alkyl optionally substituted by at least one halogen, amine, hydroxyl, C 1 -C 6  alkoxy, thiol, C 1 -C 6  alkoxycarbonyl. 
       
     
     
         8 . A salt adduct according to  claim 1 , wherein said carboxylated lactam ring is compound (1): 
       
         
           
           
               
               
           
         
       
       and
 said positively charged moiety is a compound of formula (I): 
 
       
         
           
           
               
               
           
         
         wherein R 3  is —CH 2 R 15 , wherein R 15  is selected from —C 1 -C 6  alkoxy, —OH and —NH 3   + ; and 
         R 1  is straight or branched C 1 -C 6  alkyl; 
         R 2  is selected from —OH, straight or branched C 1 -C 6  alkoxy, and straight or branched C 1 -C 6  alkoxycarbonyl; 
         R 4  is selected from formyl, straight or branched C 1 -C 6  alkyl optionally substituted by at least one halogen, amine, hydroxyl, C 1 -C 6  alkoxy, thiol, C 1 -C 6  alkoxycarbonyl. 
       
     
     
         9 . A salt adduct according to  claim 1 , wherein said carboxylated lactam ring is compound (1): 
       
         
           
           
               
               
           
         
       
       and
 said positively charged moiety is a compound of formula (I): 
 
       
         
           
           
               
               
           
         
         wherein R 4  is selected from formyl and —CH 2 R 16 , wherein R 16  is selected from —C 1 -C 6  alkoxy and —OH; and 
         R 1  is straight or branched C 1 -C 6  alkyl; 
         R 2  is selected from —OH, straight or branched C 1 -C 6  alkoxy, and straight or branched C 1 -C 6  alkoxycarbonyl; 
         R 3  is selected from formyl, straight or branched C 1 -C 6  alkyl optionally substituted by at least one halogen, amine, hydroxyl, C 1 -C 6  alkoxy, thiol, C 1 -C 6  alkoxycarbonyl. 
       
     
     
         10 . A salt adduct according to  claim 1 , wherein said carboxylated lactam ring is a compound of formula (II): 
       
         
           
           
               
               
           
         
         wherein 
         R 6  is selected from H, straight or branched C 1 -C 6  alkyl optionally substituted by at least one halogen, straight or branched C 2 -C 6  alkenyl, straight or branched C 2 -C 6  alkenyl, cycloalkyl, aryl and heteroaryl optionally substituted by a C 1 -C 6  alkyl; 
         R 7 , R 8 , R 9 , R 10  are each independently selected from H, straight or branched C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, cycloalkyl, aryl and heteroaryl optionally substituted by at least one group selected from C 1 -C 6  alkyl, halogen, amino, cyano, nitro, thiol, C 1 -C 6  alkoxy, aminocarbonyl, C 1 -C 6  alkoxycarbonyl, C 1 -C 6  carboxyalkyl, C 1 -C 6  alkoxycarbonylalkyl and amidino. 
       
     
     
         11 . A salt adduct according to  claim 1 , wherein said carboxylated lactam ring is a compound of formula (II): 
       
         
           
           
               
               
           
         
         wherein R 6  is C 1 -C 6  alkyl and R 7 , R 8 , R 9 , R 10  are each independently selected from H, straight or branched C 1 -C 6  allyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, cycloalkyl, aryl and heteroaryl optionally substituted by at least one group selected from C 1 -C 6  alkyl, halogen, amino, cyano, nitro, thiol, C 1 -C 6  alkoxy, aminocarbonyl, C 1 -C 6  alkoxycarbonyl, C 1 -C 6  carboxyalkyl, C 1 -C 6  alkoxycarbonylalkyl and amidino. 
       
     
     
         12 . A salt adduct according to  claim 1 , wherein said carboxylated lactam ring is a compound of formula (II): 
       
         
           
           
               
               
           
         
         wherein R 9  is C 1 -C 6  alkyl, 
         R 6  is selected from H, straight or branched C 1 -C 6  alkyl optionally substituted by at least one halogen, straight or branched C 2 -C 6  alkenyl, straight or branched C 2 -C 6  alkenyl, cycloalkyl, aryl and heteroaryl optionally substituted by a C 1 -C 6  alkyl; 
         R 7 , R 8 , R 9 , R 10  are each independently selected from H, straight or branched C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, cycloalkyl, aryl and heteroaryl optionally substituted by at least one group selected from C 1 -C 6  alkyl, halogen, amino, cyano, nitro, thiol, C 1 -C 6  alkoxy, aminocarbonyl, C 1 -C 6  alkoxycarbonyl, C 1 -C 6  carboxyalkyl, C 1 -C 6  alkoxycarbonylalkyl and amidino. 
       
     
     
         13 . A salt adduct according to  claim 1 , wherein said carboxylated lactam ring is a compound of formula (III): 
       
         
           
           
               
               
           
         
       
       and
 said positively charged moiety is a compound of formula (I): 
 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is straight or branched C 1 -C 6  alkyl; 
         R 2  is selected from —OH, straight or branched C 1 -C 6  alkoxy, and straight or branched C 1 -C 6  alkoxycarbonyl; 
         R 3  and R 4  are each independently selected from formyl, straight or branched C 1 -C 6  alkyl optionally substituted by at least one halogen, amine, hydroxyl, C 1 -C 6  alkoxy, thiol, C 1 -C 6  alkoxycarbonyl 
         R 6  is selected from H, straight or branched C 1 -C 6  alkyl optionally substituted by at least one halogen, straight or branched C 2 -C 6  alkenyl, straight or branched C 2 -C 6  alkynyl, cycloalkyl, aryl and heteroaryl optionally substituted by a C 1 -C 6  alkyl; 
         R 7 , R 8 , R 9 , R 10  R 11 , R 12 , R 13  and R 14  are each independently selected from H, straight or branched C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, cycloalkyl, aryl and heteroaryl optionally substituted by at least one group selected from C 1 -C 6  alkyl, halogen, amino, cyano, nitro, thiol, C 1 -C 6  alkoxy, aminocarbonyl, C 1 -C 6  alkoxycarbonyl, C 1 -C 6  carboxyalkyl, C 1 -C 6  alkoxycarbonylalkyl and amidino. 
       
     
     
         14 . A salt adduct according to  claim 1 , wherein said carboxylated lactam ring is a compound of formula (IV): 
       
         
           
           
               
               
           
         
       
       and
 said positively charged moiety is a compound of formula (I): 
 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is straight or branched C 1 -C 6  alkyl; 
         R 2  is selected from —OH, straight or branched C 1 -C 6  alkoxy, and straight or branched C 1 -C 6  alkoxycarbonyl; 
         R 3  and R 4  are each independently selected from formyl, straight or branched C 1 -C 6  alkyl optionally substituted by at least one halogen, amine, hydroxyl, C 1 -C 6  alkoxy, thiol, C 1 -C 6  alkoxycarbonyl 
         R 6  is selected from H, straight or branched C 1 -C 6  alkyl optionally substituted by at least one halogen, straight or branched C 2 -C 6  alkenyl, straight or branched C 2 -C 6  alkynyl, cycloalkyl, aryl and heteroaryl optionally substituted by a C 1 -C 6  alkyl; 
         R 7 , R 8 , R 9 , R 10  R 11 , R 12 , R 13  and R 14  are each independently selected from H, straight or branched C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, cycloalkyl, aryl and heteroaryl optionally substituted by at least one group selected from C 1 -C 6  alkyl, halogen, amino, cyano, nitro, thiol, C 1 -C 6  alkoxy, aminocarbonyl, C 1 -C 6  alkoxycarbonyl, C 1 -C 6  carboxyalkyl, C 1 -C 6  alkoxycarbonylalkyl and amidino. 
       
     
     
         15 . (canceled) 
     
     
         16 . A salt adduct according to  claim 1 , selected from the following group: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         17 . A pharmaceutical composition comprising a salt adduct of  claim 1 . 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . (canceled) 
     
     
         23 . A method for treating or preventing a disease or disorder associated with or inflicted by alcohol consumption, comprising administering to a subject in need thereof an effective amount of a salt adduct of  claim 1 . 
     
     
         24 . A method according to  claim 23 , wherein said disease or disorder is selected from alcohol intoxication, alcoholism, cardiovascular disease, hypertension, coronary heart disease, ischemic stroke, malabsorption, pancreatitis, liver diseases, cancer, CNS damage, neuropsychiatric or neurological impairment, neoplasms, psychiatric disorders or any combination thereof. 
     
     
         25 . A method of shortening the half-life of ethanol in the blood of a subject, comprising administering to a subject in need thereof an effective amount of a salt adduct of  claim 1 . 
     
     
         26 . A kit for reducing the effect of alcohol intoxication, comprising at least one container comprising a salt adduct according to  claim 1 , and instructions for use thereof. 
     
     
         27 . (canceled)