Immunomodulatory agent-polymeric compounds

Abstract

This invention relates to compositions, and related compounds and methods, of conjugates of immunomodulatory agents and polymers or unit(s) thereof. The conjugates may be contained within synthetic nanocarriers, and the immunomodulatory agents may be released from the synthetic nanocarriers in a pH sensitive manner.

1 .- 122 . (canceled) 
     
     
         123 . A compound that comprises a structure as in formula (I): 
       
         
           
           
               
               
           
         
         wherein R 1 ═H, OH, SH, NH 2 , (C1-C4)alkyl, (C1-C4)alkyl comprising a substituent of (C1-C3)alkoxy, or (C1-C3)alkoxy; 
         R 2 ═H, (C1-C4)alkyl, or (C1-C4)alkyl comprising a substituent selected from the group consisting of: methyl, hydroxyl, phenyl, and —NHSO 2 CH 3 ; 
         Y═N or C; 
         R 3  is absent if Y═N; or if Y is C, then R 3  is H or R 3  is combined with R 4  to form a 6-membered carbocycle with the carbon atoms of the pyridine ring to which they are; 
         R 4  is H, (C1-C5)alkyl, (C1-C4)alkoxy, or (C1-C4)alkylamino, or (C1-C4)alkylamino comprising a substituent of a phenyl when not combined with R 3  to form the 6-membered carbocycle with the carbon atoms of the pyridine ring to which they are connected; or R 4  is combined with R 3  to form the 6-membered carbocycle with the carbon atoms of the pyridine ring to which they are connected; and 
         R 8  is a biodegradable polymer. 
       
     
     
         124 . The compound of  claim 123 , wherein:
 R 1 ═H, OH, ethoxymethyl;   R 2 =isobutyl, hydroxyisobutyl, methanesulfonamidoisobutyl, or benzyl;   R 3  is absent if Y═N; or is combined with R 4  to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected if Y═C;   
       R 4  is pentyl, butoxy, benzylamino, or butylamino when not combined with R 3  to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected; or is combined with R 3  to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected. 
     
     
         125 . A compound that comprises a structure as in formula (II): 
       
         
           
           
               
               
           
         
         wherein R 1 ═H, OH, SH, NH 2 , (C1-C4)alkyl, (C1-C4)alkyl comprising a substituent of (C1-C3)alkoxy, or (C1-C3)alkoxy; 
         R 2 ═H, (C1-C4)alkyl, or (C1-C4)alkyl comprising a substituent selected from the group consisting of: methyl, hydroxyl, phenyl, and —NHSO 2 CH 3 ; 
         Y═N or C; 
         R 3  is absent if Y═N; or if Y is C, then R 3  is H or R 3  is combined with R 4  to form a 6-membered carbocycle with the carbon atoms of the pyridine ring to which they are; 
         R 4  is H, (C1-C5)alkyl, (C1-C4)alkoxy, or (C1-C4)alkylamino, or (C1-C4)alkylamino comprising a substituent of a phenyl when not combined with R 3  to form the 6-membered carbocycle with the carbon atoms of the pyridine ring to which they are connected; or R 4  is combined with R 3  to form the 6-membered carbocycle with the carbon atoms of the pyridine ring to which they are connected; 
         R 5  is a polymer; 
         X═C, N, O, or S; 
         R 6  and R 7  are each independently absent, H, or substituted; and 
         R 9 , R 10 , R 11 , and R 12  are each independently H, a halogen, OH, thio, NH 2 , or substituted or unsubstituted alkyl, aryl, heterocyclic, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, or arylamino. 
       
     
     
         126 . The compound of  claim 125 , wherein:
 R 1 ═H, OH, ethoxymethyl;   R 2 =isobutyl, hydroxyisobutyl, methanesulfonamidoisobutyl, or benzyl;   R 3  is absent if Y═N; or is combined with R 4  to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected if Y═C;   R 4  is pentyl, butoxy, benzylamino, or butylamino when not combined with R 3  to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected; or is combined with R 3  to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected.   
     
     
         127 . A composition comprising the compound of  claim 123 . 
     
     
         128 . A synthetic nanocarrier that comprises the compound of  claim 123 . 
     
     
         129 . A composition comprising the synthetic nanocarrier of  claim 128 . 
     
     
         130 . A composition comprising a vaccine comprising the compound of  claim 123 . 
     
     
         131 . A method comprising:
 administering the compound of  claim 123  to a subject.   
     
     
         132 . A method for making a conjugate that comprises a structure as in formula (I): 
       
         
           
           
               
               
           
         
       
       Method (A):
 (a) activating a biodegradable polymer or unit thereof, and 
 (b) exposing the activated biodegradable polymer or unit thereof and a compound comprising a structure as in formula (III) to a base and/or solvent; or 
 
       
         
           
           
               
               
           
         
       
       Method (B)
 (a) exposing a composition comprising a polymer or unit thereof and a compound comprising a structure as in formula (III) to a coupling agent and base and/or solvent; 
 
       wherein in formula (I) and formula (III):
 R 1 ═H, OH, SH, NH 2 , (C1-C4)alkyl, (C1-C4)alkyl comprising a substituent of (C1-C3)alkoxy, or (C1-C3)alkoxy; 
 R 2 ═H, (C1-C4)alkyl, or (C1-C4)alkyl comprising a substituent selected from the group consisting of: methyl, hydroxyl, phenyl, and —NHSO 2 CH 3 ; 
 Y═N or C; 
 R 3  is absent if Y═N; or if Y is C, then R 3  is H or R 3  is combined with R 4  to form a 6-membered carbocycle with the carbon atoms of the pyridine ring to which they are; 
 R 4  is H, (C1-C5)alkyl, (C1-C4)alkoxy, or (C1-C4)alkylamino, or (C1-C4)alkylamino comprising a substituent of a phenyl when not combined with R 3  to form the 6-membered carbocycle with the carbon atoms of the pyridine ring to which they are connected; or R 4  is combined with R 3  to form the 6-membered carbocycle with the carbon atoms of the pyridine ring to which they are connected; and 
 R 8  is a biodegradable polymer. 
 
     
     
         133 . The method of  claim 132 , wherein:
 R 1 ═H, OH, ethoxymethyl;   R 2 =isobutyl, hydroxyisobutyl, methanesulfonamidoisobutyl, or benzyl;   R 3  is absent if Y═N; or is combined with R 4  to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected if Y═C;   R 4  is pentyl, butoxy, benzylamino, or butylamino when not combined with R 3  to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected; or is combined with R 3  to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected.   
     
     
         134 . A method for making a conjugate that comprises a structure as in formula (II): 
       comprising: 
       
         
           
           
               
               
           
         
       
       Method (A):
 (a) combining an alcohol, a catalyst, and a compound comprising a structure as in formula (IV): 
 
       
         
           
           
               
               
           
         
         (b) heating the alcohol, catalyst, and compound; or 
       
       Method (B):
 (a) combining an alcohol and a compound comprising a structure as in formula (IV); 
 (b) heating the alcohol and compound; and 
 (c) adding a catalyst; or 
 
       Method (C):
 (a) combining an alcohol, a catalyst, and a compound comprising a structure as in formula (IV); 
 
       wherein in formula (II) and formula (IV):
 R 1 ═H, OH, SH, NH 2 , (C1-C4)alkyl, (C1-C4)alkyl comprising a substituent of (C1-C3)alkoxy, or (C1-C3)alkoxy; 
 R 2 ═H, (C1-C4)alkyl, or (C1-C4)alkyl comprising a substituent selected from the group consisting of: methyl, hydroxyl, phenyl, and —NHSO 2 CH 3 ; 
 Y═N or C; 
 R 3  is absent if Y═N; or if Y is C, then R 3  is H or R 3  is combined with R 4  to form a 6-membered carbocycle with the carbon atoms of the pyridine ring to which they are; 
 R 4  is H, (C1-C5)alkyl, (C1-C4)alkoxy, or (C1-C4)alkylamino, or (C1-C4)alkylamino comprising a substituent of a phenyl when not combined with R 3  to form the 6-membered carbocycle with the carbon atoms of the pyridine ring to which they are connected; or R 4  is combined with R 3  to form the 6-membered carbocycle with the carbon atoms of the pyridine ring to which they are connected; 
 R 5  is a polymer; 
 X is C, N, O, or S; 
 R 6  and R 7  are each independently H or substituted; and 
 R 9 , R 10 , R 11 , and R 12  are each independently H, a halogen, OH, thio, NH 2 , or substituted or unsubstituted alkyl, aryl, heterocyclic, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, or arylamino. 
 
     
     
         135 . The method of  claim 134 , wherein:
 R 1 ═H, OH, ethoxymethyl;   R 2 =isobutyl, hydroxyisobutyl, methanesulfonamidoisobutyl, or benzyl;   R 3  is absent if Y═N; or is combined with R 4  to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected if Y═C;   R 4  is pentyl, butoxy, benzylamino, or butylamino when not combined with R 3  to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected; or is combined with R 3  to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected.   
     
     
         136 . A compound that comprises a structure as in formula (IV): 
       
         
           
           
               
               
           
         
         wherein R 1 ═H, OH, SH, NH 2 , (C1-C4)alkyl, (C1-C4)alkyl comprising a substituent of (C1-C3)alkoxy, or (C1-C3)alkoxy; 
         R 2 ═H, (C1-C4)alkyl, or (C1-C4)alkyl comprising a substituent selected from the group consisting of: methyl, hydroxyl, phenyl, and —NHSO 2 CH 3 ; 
         Y═N or C; 
         R 3  is absent if Y═N; or if Y is C, then R 3  is H or R 3  is combined with R 4  to form a 6-membered carbocycle with the carbon atoms of the pyridine ring to which they are; 
         R 4  is H, (C1-C5)alkyl, (C1-C4)alkoxy, or (C1-C4)alkylamino, or (C1-C4)alkylamino comprising a substituent of a phenyl when not combined with R 3  to form the 6-membered carbocycle with the carbon atoms of the pyridine ring to which they are connected; or R 4  is combined with R 3  to form the 6-membered carbocycle with the carbon atoms of the pyridine ring to which they are connected; 
         X is C, N, O, or S; 
         R 6  and R 7  are each independently H or substituted; and 
         R 9 , R 10 , R 11 , and R 12  are each independently H, a halogen, OH, thio, NH 2 , or substituted or unsubstituted alkyl, aryl, heterocyclic, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, or arylamino. 
       
     
     
         137 . The compound of  claim 136 , wherein
 R 1 ═H, OH, ethoxymethyl;   R 2 =isobutyl, hydroxyisobutyl, methanesulfonamidoisobutyl, or benzyl;   R 3  is absent if Y═N; or is combined with R 4  to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected if Y═C;   R 4  is pentyl, butoxy, benzylamino, or butylamino when not combined with R 3  to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected; or is combined with R 3  to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected.   
     
     
         138 . A method for making a compound that comprises a structure as in formula (IV): 
       
         
           
           
               
               
           
         
       
       comprising:
 combining, in the presence of a solvent and/or heat, a compound that comprises a structure as in formula 
 
       
         
           
           
               
               
           
         
       
       and
 a compound comprising a structure as in formula (V): 
 
       
         
           
           
               
               
           
         
         wherein R 1 ═H, OH, SH, NH 2 , (C1-C4)alkyl, (C1-C4)alkyl comprising a substituent of (C1-C3)alkoxy, or (C1-C3)alkoxy; 
         R 2 ═H, (C1-C4)alkyl, or (C1-C4)alkyl comprising a substituent selected from the group consisting of: methyl, hydroxyl, phenyl, and —NHSO 2 CH 3 ; 
         Y═N or C; 
         R 3  is absent if Y═N; or if Y is C, then R 3  is H or R 3  is combined with R 4  to form a 6-membered carbocycle with the carbon atoms of the pyridine ring to which they are; 
         R 4  is H, (C1-C5)alkyl, (C1-C4)alkoxy, or (C1-C4)alkylamino, or (C1-C4)alkylamino comprising a substituent of a phenyl when not combined with R 3  to form the 6-membered carbocycle with the carbon atoms of the pyridine ring to which they are connected; or R 4  is combined with R 3  to form the 6-membered carbocycle with the carbon atoms of the pyridine ring to which they are connected; 
         X is C, N, O, or S; 
         R 6  and R 7  are each independently H or substituted; and 
         R 9 , R 10 , R 11 , and R 12  are each independently H, a halogen, OH, thio, NH 2 , or substituted or unsubstituted alkyl, aryl, heterocyclic, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, or arylamino. 
       
     
     
         139 . A method for making a conjugate that comprises a structure as in formula (VI): 
       
         
           
           
               
               
           
         
       
       comprising: 
       Method (A):
 (a) combining a catalyst, a diol having the formula (VII):
   HO-polymer-OH  (VII),
 
 
 and a compound comprising a structure as in formula (IV): 
 
       
         
           
           
               
               
           
         
       
       and
 (b) heating the alcohol, catalyst, and compound; or 
 
       Method (B):
 (a) combining a diol having the formula (VII):
   HO-polymer-OH  (VII),
 
 
 and a compound comprising a structure as in formula (IV); 
 (b) heating the alcohol and compound; and 
 (c) adding a catalyst; or 
 
       Method (C):
 (a) combining a catalyst, a diol having the formula (VII):
   HO-polymer-OH  (VII),
 
 
 and a compound comprising a structure as in formula (IV), 
 
       wherein in formula (IV) and formula (VI):
 R 1 ═H, OH, SH, NH 2 , (C1-C4)alkyl, (C1-C4)alkyl comprising a substituent of (C1-C3)alkoxy, or (C1-C3)alkoxy; 
 R 2 ═H, (C1-C4)alkyl, or (C1-C4)alkyl comprising a substituent selected from the group consisting of: methyl, hydroxyl, phenyl, and —NHSO 2 CH 3 ; 
 Y═N or C; 
 R 3  is absent if Y═N; or if Y is C, then R 3  is H or R 3  is combined with R 4  to form a 6-membered carbocycle with the carbon atoms of the pyridine ring to which they are; 
 R 4  is H, (C1-C5)alkyl, (C1-C4)alkoxy, or (C1-C4)alkylamino, or (C1-C4)alkylamino comprising a substituent of a phenyl when not combined with R 3  to form the 6-membered carbocycle with the carbon atoms of the pyridine ring to which they are connected; or R 4  is combined with R 3  to form the 6-membered carbocycle with the carbon atoms of the pyridine ring to which they are connected; 
 X is C, N, O, or S; 
 R 6  and R 7  are each independently H or substituted; and 
 R 9 , R 10 , R 11 , and R 12  are each independently H, a halogen, OH, thio, NH 2 , or substituted or unsubstituted alkyl, aryl, heterocyclic, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, or arylamino. 
 
     
     
         140 . The method of  claim 139 , wherein:
 R 1 ═H, OH, ethoxymethyl;   R 2 =isobutyl, hydroxyisobutyl, methanesulfonamidoisobutyl, or benzyl;   R 3  is absent if Y═N; or is combined with R 4  to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected if Y═C;   R 4  is pentyl, butoxy, benzylamino, or butylamino when not combined with R 3  to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected; or is combined with R 3  to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected.   
     
     
         141 . A compound that comprises a structure as in formula (VI): 
       
         
           
           
               
               
           
         
         wherein R 1 ═H, OH, SH, NH 2 , (C1-C4)alkyl, (C1-C4)alkyl comprising a substituent of (C1-C3)alkoxy, or (C1-C3)alkoxy; 
         R 2 ═H, (C1-C4)alkyl, or (C1-C4)alkyl comprising a substituent selected from the group consisting of: methyl, hydroxyl, phenyl, and —NHSO 2 CH 3 ; 
         Y═N or C; 
         R 3  is absent if Y═N; or if Y is C, then R 3  is H or R 3  is combined with R 4  to form a 6-membered carbocycle with the carbon atoms of the pyridine ring to which they are; 
         R 4  is H, (C1-C5)alkyl, (C1-C4)alkoxy, or (C1-C4)alkylamino, or (C1-C4)alkylamino comprising a substituent of a phenyl when not combined with R 3  to form the 6-membered carbocycle with the carbon atoms of the pyridine ring to which they are connected; or R 4  is combined with R 3  to form the 6-membered carbocycle with the carbon atoms of the pyridine ring to which they are connected; 
         X is C, N, O, or S; 
         R 6  and R 7  are each independently H or substituted; and 
         R 9 , R 10 , R 11 , and R 12  are each independently H, a halogen, OH, thio, NH 2 , or substituted or unsubstituted alkyl, aryl, heterocyclic, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, or arylamino. 
       
     
     
         142 . The compound of  claim 141 , wherein:
 R 1 ═H, OH, ethoxymethyl;   R 2 =isobutyl, hydroxyisobutyl, methanesulfonamidoisobutyl, or benzyl;   R 3  is absent if Y═N; or is combined with R 4  to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected if Y═C;   R 4  is pentyl, butoxy, benzylamino, or butylamino when not combined with R 3  to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected; or is combined with R 3  to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected.