Valency platform molecules comprising carbamate linkages

Abstract

This invention pertains generally to valency molecules, such as valency platform molecules which act as scaffolds to which one or more molecules may be covalently tethered to form a conjugate. More particularly, the present invention pertains to valency platform molecules which comprise a carbamate linkage (i.e., —O—C(═O)—N<). In one aspect, the present invention pertains to valency platforms comprising carbamate linkages, which molecules have the structure of any one of Formulae I, II, or III, shown in FIG. 1. In one aspect, the present invention pertains to valency platforms comprising carbamate linkages, which molecules have the structure of any one of Formulae IV, V, or VI, shown in FIG. 8. The present invention also pertains to methods of preparing such valency platform molecules, conjugates comprising such valency platform molecules, and methods of preparing such conjugates.

1 . A compound having the structure of one of the following formulae:  
       
         
           
           
               
               
           
         
       
       wherein: 
 n is a positive integer from 1 to 10;  
 y 1 ,y 2 , and y 3  are independently 1 or 2;  
 J independently denotes either an oxygen atom or a covalent bond;  
 R C  is selected from the group consisting of: 
 hydrocarbyl groups having from 1 to 20 carbon atoms;  
 organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms;  
 organic groups consisting only of carbon, oxygen, nitrogen, and hydrogen atoms, and having from 1 to 20 carbon atoms;  
 organic groups consisting only of carbon, oxygen, sulfur, and hydrogen atoms, and having from 1 to 20 carbon atoms;  
 
 each G 1 , G 2 , and G 3  is independently selected from the group consisting of: 
 hydrocarbyl groups having from 1 to 20 carbon atoms;  
 organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms;  
 organic groups consisting only of carbon, oxygen, nitrogen, and hydrogen atoms, and having from 1 to 20 carbon atoms;  
 
 each R N  is independently selected from the group consisting of: 
 hydrogen;  
 linear or branched alkyl groups having from 1 to 15 carbon atoms;  
 alkyl groups comprising an alicyclic structure and having from 1 to 15 carbon atoms;  
 aromatic groups having from 6 to 20 carbon atoms;  
 heteroaromatic groups having from 3 to 20 carbon atoms;  
 
 each Z is independently selected from the group consisting of: 
 —H  
 —C(═O)OR CARB    
 —C(═O)R ESTER    
 —C(═O)NR A R B    
 
 wherein:  
 each R CARB  is organic groups comprising from 1 to about 20 carbon atoms;  
 each R ESTER  is organic groups comprising from 1 to about 20 carbon atoms;  
 each group —NR A R B  is independently selected from the group consisting of: 
 —NH 2    
 —NHR A    
 —NR A R B    
 —NR AB    
 
 wherein each monovalent R A  and R B  and each divalent R AB  is independently an organic group comprising from 1 to 20 carbon atoms, and further comprising a reactive conjugating functional group.  
 
     
     
         2 . A compound according to  claim 1 , wherein said compound has the structure of Formula I.  
     
     
         3 . A compound according to  claim 1 , wherein said compound has the structure of Formula II.  
     
     
         4 . A compound according to  claim 1 , wherein said compound has the structure of Formula III.  
     
     
         5 . A compound according to  claim 1 , wherein n is a positive integer from 2 to 4.  
     
     
         6 . A compound according to  claim 1 , wherein y 1 , y 2 , and y 3  are each 2.  
     
     
         7 . A compound according to  claim 1 , wherein J is an oxygen atom.  
     
     
         8 . A compound according to  claim 1 , wherein J is a covalent bond.  
     
     
         9 . A compound according to  claim 1 , wherein R C  is selected from the group consisting of hydrocarbyl groups having from 1 to 20 carbon atoms.  
     
     
         10 . A compound according to  claim 1 , wherein R C  is selected from the group consisting of: 
 —CH 2 —;    —CH 2 CH 2 —;    —CH 2 CH 2 CH 2 —;                          
     
     
         11 . A compound according to  claim 1 , wherein R C  is selected from the group consisting of organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms.  
     
     
         12 . A compound according to  claim 1 , wherein R C  is:  
       
         
           
           
               
               
           
         
         wherein p is a positive integer from 2 to 20.  
       
     
     
         13 . A compound according to  claim 1 , wherein each G 1 , G 2 , and G 3  is independently selected from the group consisting of hydrocarbyl groups having from 1 to 20 carbon atoms.  
     
     
         14 . A compound according to  claim 1 , wherein each G 1 , G 2 , and G 3  is —(CH 2 ) q — wherein q is a positive integer from 1 to 20.  
     
     
         15 . A compound according to any one of claims  1 , wherein each G 1 , G 2 , and G 3  is independently selected from the group consisting of organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms.  
     
     
         16 . A compound according to  claim 1 , wherein each G 1 , G 2 , and G 3  is:  
       
         
           
           
               
               
           
         
         wherein p is a positive integer from 2 to 20.  
       
     
     
         17 . A compound according to  claim 1 , wherein each R N  is independently selected from the group consisting of —H, —CH 3 , and —CH 2 CH 3 .  
     
     
         18 . A compound according to  claim 1 , wherein each Z is —NR A R B  and is independently selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         19 . A compound having the structure of one of the following formulae:  
       
         
           
           
               
               
           
         
       
       wherein: 
 n is a positive integer from 1 to 10;  
 y 1 , y 2 , and y 3  are independently a positive integer from 1 to 10;  
 J independently denotes either an oxygen atom or a covalent bond;  
 R C  is selected from the group consisting of: 
 hydrocarbyl groups having from 1 to 20 carbon atoms;  
 organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms;  
 organic groups consisting only of carbon, oxygen, nitrogen, and hydrogen atoms, and having from 1 to 20 carbon atoms,  
 organic groups consisting only of carbon, oxygen, sulfur, and hydrogen atoms, and having from 1 to 20 carbon atoms;  
 
 each G 1 , G 2 , and G 3  is independently selected from the group consisting of: 
 hydrocarbyl groups having from 1 to 20 carbon atoms;  
 organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms;  
 organic groups consisting only of carbon, oxygen, nitrogen, and hydrogen atoms, and having from 1 to 20 carbon atoms;  
 
 each R N  is independently selected from the group consisting of: 
 hydrogen;  
 linear or branched alkyl groups having from 1 to 15 carbon atoms;  
 alkyl groups comprising an alicyclic structure and having from 1 to 15 carbon atoms;  
 aromatic groups having from 6 to 20 carbon atoms;  
 heteroaromatic groups having from 3 to 20 carbon atoms;  
 
 each Z is independently selected from the group consisting of: 
 —H  
 —C(═O)OR CARB    
 —C(═O)R ESTER    
 —C(═O)NR A R B    
 wherein:  
 
 each R CARB  is organic groups comprising from 1 to about 20 carbon atoms;  
 each R ESTER  is organic groups comprising from 1 to about 20 carbon atoms;  
 each group —NR A R B  is independently selected from the group consisting of: 
 —NH 2    
 —NHR A    
 —NR A R B    
 —NR AB    
 
 wherein each monovalent R A  and R B  and each divalent R AB  is independently an organic group comprising from 1 to 20 carbon atoms, and further comprising a reactive conjugating functional group.  
 
     
     
         20 . A compound according to  claim 19 , wherein said compound has the structure of Formula IV.  
     
     
         21 . A compound according to  claim 19 , wherein said compound has the structure of Formula V.  
     
     
         22 . A compound according to  claim 19 , wherein said compound has the structure of Formula VI.  
     
     
         23 . A compound according to  claim 19 , wherein n is a positive integer from 2 to 4.  
     
     
         24 . A compound according to  claim 19 , wherein y 1 , Y 2 , and y 3  are each 2.  
     
     
         25 . A compound according to  claim 19 , wherein J is an oxygen atom.  
     
     
         26 . A compound according to  claim 19 , wherein J is a covalent bond.  
     
     
         27 . A compound according to  claim 19 , wherein R C  is selected from the group consisting of hydrocarbyl groups having from 1 to 20 carbon atoms.  
     
     
         28 . A compound according to any  claim 19 , wherein R C  is selected from the group consisting of: 
 —CH 2 —;    —CH 2 CH 2 —;    —CH 2 CH 2 CH 2 —;                          
     
     
         29 . A compound according to  claim 19 , wherein R C  is selected from the group consisting of organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms.  
     
     
         30 . A compound according to  claim 19 , wherein R C  is:  
       
         
           
           
               
               
           
         
         wherein p is a positive integer from 2 to 20.  
       
     
     
         31 . A compound according to  claim 19 , wherein each G 1 , G 2 , and G 3  is independently selected from the group consisting of hydrocarbyl groups having from 1 to 20 carbon atoms.  
     
     
         32 . A compound according to  claim 19 , wherein each G 1 , G 2 , and G 3  is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         33 . A compound according to  claim 19 , wherein each G 1 , G 2 , and G 3  is independently selected from the group consisting of organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms.  
     
     
         34 . A compound according to  claim 19 , wherein each R N  is independently selected from the group consisting of —H, —CH 3 , and —CH 2 CH 3 .  
     
     
         35 . A compound according to  claim 19 , wherein each Z is —NR A R B  and is independently selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         36 . A conjugate comprising a compound according to  claim 1  covalently linked to one or more biologically active molecules.  
     
     
         37 . A conjugate according to  claim 36 , wherein said biologically active molecules are selected from the group consisting of: oligonucleotides, peptides, polypeptides, proteins, antibodies, saccharides, polysaccharides, epitopes, mimotopes, and drugs.  
     
     
         38 . A composition comprising valency platform molecules, wherein each said valency platform molecule comprises at least 2 carbamate linkages and at least 4 reactive conjugating functional groups; and 
 wherein said valency platform molecules have a polydispersity less than about 1.2.    
     
     
         39 . The composition of  claim 38 , wherein said valency platform molecules have a polydispersity less than about 1.07.  
     
     
         40 . The composition of  claim 38 , wherein each said valency platform molecules comprises at least 4 carbamate linkages and at least 8 reactive functional groups.  
     
     
         41 . The composition of  claim 38 , wherein each said valency platform molecule comprises at least 4 identical reactive conjugating functional groups.  
     
     
         42 . The composition of  claim 38 , wherein each said valency platform molecule comprises 2 to 32 carbamate linkages and 4 to 64 reactive functional groups.  
     
     
         43 . The composition of  claim 38 , wherein comprising said valency platform molecules linked via said reactive functional groups to one or more biologically active molecules.  
     
     
         44 . A composition comprising valency molecules, wherein each said valency molecule comprises at least two branches and at least four terminal groups; 
 wherein each said valency molecule comprises at least 2 carbamate linkages; and    wherein said valency molecules have a polydispersity less than about 1.2.    
     
     
         45 . The composition of  claim 44 , wherein said valency molecules have a polydispersity less than about 1.07.  
     
     
         46 . The composition of  claim 44 , wherein said valency molecules comprise at least 4 carbamate linkages, at least 4 branches and at least 8 terminal groups.