Inorganic salts of nicotinic acid mononucleotide as anti-aging agents

Abstract

The present invention relates to inorganic salts of nicotinic acid mononucleotides and compositions of Formula I, useful in the treatment of disorders and diseases associated with deficiencies in NAD+:wherein A, M1, M2, k, R1, R2, and R3 are as described herein.

What is claimed is: 
     
         1 . A salt of Formula (I): 
       
         
           
           
               
               
           
         
         or enantiomer, stereoisomer, or tautomer thereof, 
         wherein
 A is O − ; 
 M 1  and M 2  are independently an inorganic cation; 
 R 1  and R 2  are independently H, C 1 -C 6 haloalkyl, (C 0 -C 3 alkylene)C(O)C 1 -C 6 alkyl, —C(O)OR a , —C(O)NR a R b , or —[CH 2 —CH 2 —O] n —R a ; 
 R 3  is a negative charge, H, or C 1 -C 6  alkyl; 
 R a  and R b  are independently, at each occurrence, H, or C 1 -C 6 alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from (C 0 -C 3 alkylene)C 3 -C 8 cycloakyl, (C 0 -C 3 alkylene)heterocycloakyl, (C 0 -C 3 alkylene)C 6 -C 14 aryl, and (C 0 -C 3 alkylene)heteroaryl; 
 k is 1 or 2; and 
 n is an integer from 1 to 8, 
 
         provided that when R 3  is H or C 1 -C 6 alkyl, then M 1  is absent. 
       
     
     
         2 . The salt of  claim 1 , wherein M 2  is a cation selected from the group consisting of Li + , Na + , K + , R b+ , Cs + , Be 2+ , Mg 2+ , Ca 2+ , Sr 2+ , Zn 2+ , and Ba 2+ . 
     
     
         3 . The salt of  claim 1 , wherein M 2  is Na + . 
     
     
         4 . The salt of  claim 1 , wherein M 2  is K + . 
     
     
         5 . The salt of  claim 1 , wherein M 2  is Li + . 
     
     
         6 . The salt of  claim 1 , wherein M 2  is R b+ . 
     
     
         7 . The salt of  claim 1 , wherein R 3  is H or methyl. 
     
     
         8 . The salt of  claim 1 , wherein M 1  is selected from the group consisting of Li + , Na + , K + , R b+ , Cs + , Be 2+ , Mg 2+ , Ca 2+ , Sr 2+ , Zn 2+ , and Ba 2+ . 
     
     
         9 . The salt of  claim 8 , wherein M 1  is Na + . 
     
     
         10 . The salt of  claim 8 , wherein M 1  is K + . 
     
     
         11 . The salt of  claim 8 , wherein M 1  is Li + . 
     
     
         12 . The salt of  claim 1 , wherein R 1  is H. 
     
     
         13 . The salt of  claim 1 , wherein R 2  is H. 
     
     
         14 . The salt of  claim 1  selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The salt of  claim 1  having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The salt of  claim 1  having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The salt of  claim 1  having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         18 . The salt of  claim 1  having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         19 . The salt of  claim 1  having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         20 . A pharmaceutical composition comprising a salt  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         21 . A method of treating or preventing an age-related infertility comprising administering to a subject in need thereof, an effective amount of a salt of  claim 1 . 
     
     
         22 . A method of treating or preventing infertility comprising administering to a subject in need thereof, an effective amount of a salt of  claim 1 . 
     
     
         23 . A method of improving oocyte quality and maturation comprising contacting the oocyte with an effective amount of a salt of  claim 1  prior to implantation into a subject in need of treatment of age-related infertility. 
     
     
         24 . The method of  claim 23 , wherein the oocyte is cultured in an IVF media containing the salt. 
     
     
         25 . A method of improving blastocyst quality and maturation comprising contacting the blastocyst with an effective amount of a salt of  claim 1  prior to implantation into a subject in need of treatment of age-related infertility. 
     
     
         26 . The method of  claim 25 , wherein the blastocyst is cultured in an IVF media containing the salt. 
     
     
         27 . A process for the preparation of a salt of Formula I: 
       
         
           
           
               
               
           
         
         or enantiomer, stereoisomer, or tautomer thereof 
         comprising contacting the compound of Formula II 
       
       
         
           
           
               
               
           
         
         or enantiomer, stereoisomer, or tautomer thereof 
         with a metal-alkali hydroxide under conditions effective to produce the product salt of Formula I, 
         wherein
 A is O − ; 
 M 1  and M 2  are independently an inorganic cation; 
 R 1  and R 2  are independently H, C 1 -C 6 haloalkyl, (C 0 -C 3 alkylene)C(O)C 1 -C 6 alkyl, —C(O)OR a , —C(O)NR a R b , or —[CH 2 —CH 2 —O] n —R a ; 
 R 3  is a negative charge, H, or C 1 -C 6  alkyl; 
 R a  and R b  are independently, at each occurrence, H, or C 1 -C 6 alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from (C 0 -C 3 alkylene)C 3 -C 8 cycloakyl, (C 0 -C 3 alkylene)heterocycloakyl, (C 0 -C 3 alkylene)C 6 -C 14 aryl, and (C 0 -C 3 alkylene)heteroaryl; 
 k is 1 or 2; and 
 n is an integer from 1 to 8, 
 
         provided that when R 3  is H or C 1 -C 6 alkyl, then M 1  is absent. 
       
     
     
         28 . The process of  claim 27 , wherein the metal-alkali hydroxide is added dropwise into a solution of the compound of Formula II. 
     
     
         29 . A cell culture medium for in vitro fertilization comprising:
 a salt of  claim 1 ; and   culturing agents.   
     
     
         30 . The cell culture medium of  claim 29 , wherein the culturing agent is an inorganic salt, an energy substrate, an amino acid, a chelator, a pH indicator, an antibiotic, a serum, a vitamin, a growth factor, or any combination thereof.