Isotopically Enriched N-Substituted Piperazine Acetic Acids And Methods For The Preparation Thereof

Abstract

In some embodiments, this invention pertains to isotopically enriched N-substituted piperazine acetic acids. In some embodiments, this invention pertains to methods for the preparation of isotopically enriched N-substituted piperazine acetic acids.

1 . An isotopically enriched N-substituted piperazine acetic acid compound of the formula: 
       
         
           
           
               
               
           
         
         , or a salt thereof, wherein;
 X is O or S; 
 Y is a straight chain or branched C1-C6 alkyl group or a straight chain or branched C1-C6 alkyl ether group wherein the carbon atoms of the alkyl group or alkyl ether group each independently are optionally substituted with linked deuterium or fluorine atoms; 
 each Z is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, an amino acid side chain, a straight chain or branched C1-C6 alkyl group that may optionally contain a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups each independently are optionally substituted with linked deuterium or fluorine atoms, a straight chain or branched C1-C6 alkyl ether group that may optionally contain a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups each independently are optionally substituted with linked deuterium or fluorine atoms or a straight chain or branched C1-C6 alkoxy group that may optionally contain a substituted or unsubstituted aryl group wherein the carbon atoms of the alkoxy and aryl groups each independently are optionally substituted with linked deuterium or fluorine atoms. 
 
       
     
     
         2 . The compound of  claim 1 , wherein the N-substituted piperazine acetic acid is isotopically enriched with two or more heavy atom isotopes. 
     
     
         3 . The compound of  claim 1 , wherein the N-substituted piperazine acetic acid is isotopically enriched with three or more heavy atom isotopes. 
     
     
         4 . The compound of  claim 1 , wherein the N-substituted piperazine acetic acid is isotopically enriched with four or more heavy atom isotopes. 
     
     
         5 . The compound of  claim 2 , wherein the heavy atom isotopes are each independently  18 O,  15 N or  13 C, but not deuterium. 
     
     
         6 . The compound of  claim 1 , wherein each Z is independently hydrogen, fluorine, chlorine, bromine or iodine. 
     
     
         7 . The compound of  claim 1 , wherein each Z is independently hydrogen, methyl or methoxy. 
     
     
         8 . The compound of  claim 1 , wherein Y is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl. 
     
     
         9 . The compound of  claim 1 , wherein X is  16 O or  18 O. 
     
     
         10 . The compound of  claim 1 , wherein each nitrogen atom of the piperazine ring is independently  14 N or  15 N. 
     
     
         11 . The compound of  claim 1  of the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 each C* is independently  12 C or  13 C; 
 X is O or S; 
 Y is a straight chain or branched C1-C6 alkyl group or a straight chain or branched C1-C6 alkyl ether group wherein the carbon atoms of the alkyl group or alkyl ether group each independently are optionally substituted with linked deuterium or fluorine atoms; 
 each Z is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, an amino acid side chain, a straight chain or branched C1-C6 alkyl group that may optionally contain a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups each independently are optionally substituted with linked deuterium or fluorine atoms, a straight chain or branched C1-C6 alkyl ether group that may optionally contain a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups each independently are optionally substituted with linked hydrogen, deuterium or fluorine atoms or a straight chain or branched C1-C6 alkoxy group that may optionally contain a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups each independently are optionally substituted with linked hydrogen, deuterium or fluorine atoms. 
 
     
     
         12 . The compound of  claim 1  of the formula: 
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
         13 . The compound of  claim 12 , wherein the compound is a zwitterion, mono-TFA salt, a mono-HCl salt, a bis-TFA salt or a bis-HCl salt. 
     
     
         14 . The compound of  claim 12 , wherein each incorporated heavy atom isotope is present in at least 80 percent isotopic purity. 
     
     
         15 . The compound of  claim 12 , wherein each incorporated heavy atom isotope is present in at least 93 percent isotopic purity. 
     
     
         16 . The compound of  claim 12 , wherein each incorporated heavy atom isotope is present in at least 96 percent isotopic purity. 
     
     
         17 . The compound of  claim 1 , wherein the N-substituted piperazine acetic acid is a mono-TFA salt, a mono-HCl salt, a bis-HCl salt or a bis-TFA salt. 
     
     
         18 . The compound of  claim 1 , wherein each incorporated heavy atom isotope is present in at least 80 percent isotopic purity. 
     
     
         19 . The compound of  claim 1 , wherein each incorporated heavy atom isotope is present in at least 93 percent isotopic purity. 
     
     
         20 . The compound of  claim 1 , wherein each incorporated heavy atom isotope is present in at least 96 percent isotopic purity. 
     
     
         21 . The compound of  claim 12 , wherein the compound is a carboxylate anion. 
     
     
         22 . The compound of  claim 1 , wherein the compound is a carboxylate anion. 
     
     
         23 . An isotopically enriched N-substituted piperazine acetic acid compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein
 each X is O or S; 
 Y is a straight chain or branched C1-C6 alkyl group or a straight chain or branched C1-C6 alkyl ether group wherein the carbon atoms of the alkyl group or alkyl ether group each independently are optionally substituted with linked deuterium or fluorine atoms; and 
 each Z is independently hydrogen, fluorine, chlorine, bromine, iodine, an amino acid side chain or a straight chain or branched C1-C6 alkyl group that may optionally contain a substituted or unsubstituted aryl group wherein the carbon atom of the alkyl and aryl groups each independently are optionally substituted with linked fluorine atoms; 
 wherein the N-substituted piperazine acetic acid is isotopically enriched with one or more  13 C atoms and/or  15 N atoms. 
 
     
     
         24 . The compound of  claim 23 , wherein Y is a straight chain or branched C1-C6 alkyl group and each Z is independently hydrogen, fluorine, chlorine, bromine, iodine, an amino acid side chain or straight chain or branched C1-C6 alkyl group. 
     
     
         25 . An isotopically enriched N-substituted piperazine acetic acid compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein;
 X is O or S; 
 Y is a straight chain or branched C1-C6 alkyl group or a straight chain or branched C1-C6 alkyl ether group; and 
 each Z is independently hydrogen, fluorine, chlorine, bromine, iodine, an amino acid side chain or a straight chain or branched C1-C6 alkyl group; and 
 wherein the N-substituted piperazine is isotopically enriched with one or more  13 C atoms,  15 N atoms and/or  18 O atoms. 
 
     
     
         26 . An isotopically enriched N-substituted piperazine acetic acid compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein the N-substituted piperazine is isotopically enriched with one or more  13 C atoms,  15 N atoms and/or  18 O atoms.