Inorganic salts of nicotinic acid mononucleotide as anti-aging agents

Abstract

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 + , Rb + , Cs + , Be 2+ , Mg 2+ , Ca 2+ , Sr2+, 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 Rb + . 
     
     
         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 + , Rb + , 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.