Preparation of Polymer Conjugates of Therapeutic, Agricultural, and Food Additive Compounds

Abstract

Disclosed is a process for preparing polymer conjugates of agricultural, therapeutic, and food additive compounds using Mitsunobu conditions.

1 . A process for the preparation of conjugates of active compounds comprising:
 a) reacting a polymeric alcohol with a nucleophilic active compound having an acidic hydrogen under Mitsunobu conditions; and   b) isolating the conjugate.   
     
     
         2 . (canceled) 
     
     
         3 . A process for the preparing a conjugate of the formula I: 
       
         
           
           
               
               
           
         
         B is a bio-compatible polymer moiety optionally covalently attached to a branched-arm hub molecule; 
         q is from about 1 to about 100; 
         A at each occurrence is independently a compound of formula II 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         J is selected from:
 a) a group of formula (a): 
 
       
       
         
           
           
               
               
           
         
         
           wherein R 31  is a covalent bond to the polymer moiety which optionally comprises a linker, or R 31  is —H, R 31′ , —NH 2 , —NHR 31′  or —N(R 31′ ) 2 , —NC 3 -C 6 cyclic, —OR 31′ , —SR 31′ , wherein each R 31′  is independently an optionally substituted straight or branched C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, 
           and R 32  is a covalent bond to the polymer moiety which optionally comprises a linker, or R 32  is —H, —NO 2 , haloalkyl or the group —N(MR 41 )R 42  wherein M is a covalent bond, —C(O)— or —SO 2 —, R 41  is R 41′ , N(R 41′ ) 2 , or —OR 41′ , 
           wherein each R 41′  is independently hydrogen, an optionally substituted straight or branched C 1 -C 6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic or an optionally substituted heteroaryl, wherein optional substitutions are halide, C 1 -C- 6 alkyl, or —OC 1 -C 6 alkyl, 
           and R 42  is hydrogen or R 41′ ; and 
           b) a group of formula (b): 
         
       
       
         
           
           
               
               
           
         
         
           wherein R is selected from the group consisting of a covalent bond to the polymer moiety, amino, hydroxyl, substituted amino, alkyl, alkyloxy, aryloxy, heteroaryloxy, heterocyclyloxy, thiol, arylthio, heteroarylthio, heterocyclylthio and substituted alkyl wherein each amino, substituted amino, alkyl and substituted alkyl is optionally covalently bound to the polymer moiety wherein, in each case, the polymer moiety optionally comprises a linker which covalently links the polymer moiety; 
           Ar 1  is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl wherein each of aryl, substituted aryl, heteroaryl and substituted heteroaryl is optionally covalently bound to the polymer moiety wherein the polymer moiety optionally comprises a linker which covalently links the polymer moiety to Ar 1 ; 
           Ar 2  is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl wherein each of aryl, substituted aryl, heteroaryl and substituted heteroaryl is optionally covalently bound to the polymer moiety wherein the polymer moiety optionally comprises a linker which covalently links the polymer moiety to Ar 2 ; 
           X is selected from the group consisting of —NR 1 —, —O—, —S—, —SO—, —SO 2  and optionally substituted —CH 2 — where R 1  is selected from the group consisting of hydrogen and alkyl; 
         
         T is selected from:
 a) a group of formula (c) 
 
       
       
         
           
           
               
               
           
         
         
           wherein Y is selected from the group consisting of —O— and —NR 1 — wherein R 1  is selected from the group consisting of hydrogen and alkyl; 
           W is selected from the group consisting of a covalent bond to a polymer moiety which optionally comprises a linker and —NR 2 R 3  wherein R 2  and R 3  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, and where R 2  and R 3 , together with the nitrogen atom bound thereto, form a heterocyclic ring or a substituted heterocyclic ring wherein each of alkyl, substituted alkyl, heterocyclic and substituted heterocyclic is optionally covalently bound to a polymer moiety which further optionally comprises a linker; 
           m is an integer equal to 0, 1 or 2; 
           n is an integer equal to 0, 1 or 2; and 
           b) a group of formula (d) 
         
       
       
         
           
           
               
               
           
         
         
           wherein G is an optionally substituted aryl or optionally substituted heteroaryl 5 or 6 membered ring containing 0 to 3 nitrogens, wherein said aryl or heteroary optionally further comprises a covalent bond to a polymer moiety which optionally comprises a linker; 
           R 6  is a covalent bond to a polymer moiety which optionally comprises a linker, or R 6  is —H, alkyl, substituted alkyl, or —CH 2 C(O)R 17 , wherein R 17  is —OH, —OR 18 , or —NHR 18 , wherein R 18  is alkyl, substituted alkyl, aryl or substituted aryl; 
         
         R 55  is selected from the group consisting of amino, substituted amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, aryloxy and substituted aryloxy, and —OH; 
         provided that:
 A. at least one of R, Ar 1 , Ar 2 , and T contains a covalent bond to the polymer moiety; 
 B. when R is covalently bound to the polymer moiety, n is one and X is not —O—, —S—, —SO—, or —SO 2 —; 
 C. when X is —O— or —NR 1 —, then m is two; and 
 D. the conjugate of formula I has a molecular weight of no more than 100,000; 
 
         comprising the steps of:
 a) adding a polymeric alcohol of formula Ia 
 
       
       
         
           
           
               
               
           
         
         
            wherein B is as described above, to a nucleophile of formula H-Nu in the presence of a trivalentphosphine of the formula PR 3  and a dialkyl azodicarboxylate to form the compound of formula I, wherein Nu is a radical of formula A described above; and 
         
         isolating the compound of formula I. 
       
     
     
         4 . The process according to  claim 1 , wherein only one of J, Ar 2 , and T contains a covalent bond to a polymer moiety. 
     
     
         5 - 9 . (canceled) 
     
     
         10 . The process of  claim 1 , wherein the nucleophilic active compound is a compound of the formula 
       
         
           
           
               
               
           
         
         wherein 
         J is selected from:
 a) a group of formula (a): 
 
       
       
         
           
           
               
               
           
         
         
           wherein R 31  is a covalent bond to the polymer moiety which optionally comprises a linker, or R 31  is —H, R 31′ , —NH 2 , —NHR 31′  or —N(R 31′ ) 2 , —NC 3 -C 6 cyclic, —OR 31′ , —SR 31′ , wherein each R 31′  is independently an optionally substituted straight or branched C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, 
           and R 32  is a covalent bond to the polymer moiety which optionally comprises a linker, or R 32  is —H, —NO 2 , haloalkyl or the group —N(MR 41 )R 42  wherein M is a covalent bond, —C(O)— or —SO 2 —, R 41  is R 41′ , N(R 41′ ) 2 , or —OR 41′ , 
           wherein each R 41′  is independently hydrogen, an optionally substituted straight or branched C 1 -C 6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic or an optionally substituted heteroaryl, wherein optional substitutions are halide, C 1 -C- 6 alkyl, or —OC 1 -C 6 alkyl, 
           and R 42  is hydrogen or R 41′ ; and 
           b) a group of formula (b): 
         
       
       
         
           
           
               
               
           
         
         
           wherein R is selected from the group consisting of a covalent bond to the polymer moiety, amino, hydroxyl, substituted amino, alkyl, alkyloxy, aryloxy, heteroaryloxy, heterocyclyloxy, thiol, arylthio, heteroarylthio, heterocyclylthio and substituted alkyl wherein each amino, substituted amino, alkyl and substituted alkyl is optionally covalently bound to the polymer moiety wherein, in each case, the polymer moiety optionally comprises a linker which covalently links the polymer moiety; 
           Ar 1  is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl wherein each of aryl, substituted aryl, heteroaryl and substituted heteroaryl is optionally covalently bound to the polymer moiety wherein the polymer moiety optionally comprises a linker which covalently links the polymer moiety to Ar 1 ; 
           Ar 2  is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl wherein each of aryl, substituted aryl, heteroaryl and substituted heteroaryl is optionally covalently bound to the polymer moiety wherein the polymer moiety optionally comprises a linker which covalently links the polymer moiety to Ar 2 ; 
           X is selected from the group consisting of —NR 1 —, —O—, —S—, —SO—, —SO 2  and optionally substituted —CH 2 — where R 1  is selected from the group consisting of hydrogen and alkyl; 
         
         T is a group carrying an acidic hydrogen; and 
         R 55  is a acid protecting group. 
       
     
     
         11 . The of  claim 10 , the nucleophilic active compound has the formula: 
       
         
           
           
               
               
           
         
         where R 55  is an acid protecting group. 
       
     
     
         12 . A process according to  claim 11 , where R 55  is C 1 -C 6  alkoxy. 
     
     
         13 . The process according to  claim 11  wherein m is 1, X is S, and R at each occurrence is independently selected from hydroxyl, alkyloxy, alkyl, or a covalent bond to the polymer moiety. 
     
     
         14 . The process according to  claim 12  wherein n is 2, and R at both occurrences is methyl. 
     
     
         15 . The process of  claim 1 , wherein the nucleophilic active compound has the formula: 
       
         
           
           
               
               
           
         
         where R 55  is an acid protecting group. 
       
     
     
         16 . A process according to  claim 15 , where R 55  is C 1 -C 6  alkoxy. 
     
     
         17 . The process according to  claim 15  wherein G is pyridinyl, R 31  is hydrogen or dialkylamino, and R 32  is sulfonamide, amide, or urea. 
     
     
         18 . A process according to  claim 1 , wherein the nucleophilic active compound is: 
       
         
           
           
               
               
           
         
       
     
     
         19 . A process according to  claim 1 , wherein the polymer alcohol is 
       
         
           
           
               
               
           
         
       
     
     
         20 . A process according to  claim 1 , wherein the polymer alcohol is selected from the group in column A and the nucleophilic active compound is selected from the group in column B: 
       
         
           
                 
                 
               
                     
                 
                   A 
                   B 
                 
                     
                 
                                     
   (total Mw of conjugate is about 41,500) 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                                     
   (total Mw of conjugate is about 42,000) 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                                     
   (total Mw of conjugate is about 41,500) 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
               
            
           
         
       
     
     
         21 . The process according to  claim 1  wherein the polymeric alcohol is added to the nucleophile of formula H-Nu in the presence of the trivalentphosphine and the dialkyl azodicarboxylate in at least one solvent. 
     
     
         22 - 27 . (canceled) 
     
     
         28 . A process according to  claim 1 , wherein the conjugate is prepared using polymer alcohol/nucleophilic active compound combination 1, 2, or 3: 
       
         
           
                 
                 
                 
               
                     
                 
                   Combination 
                   Polymer Alcohol 
                   Nucleophilic Active Compound 
                 
                     
                 
                   1 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   2 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   3