Terminally-branched polymeric linkers and polymeric conjugates containing the same

Abstract

The present invention is directed to polymeric-prodrug transport forms of the formula: E 1-4 are independently selected from the group consisting of hydrogen, C 1-6 alkyls, C 3-12 branched alkyls, C 3-8 cycloalkyls, C 1-6 substituted alkyls, C 3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C 1-6 heteroalkyls, substituted C 1-6 heteroalkyls, C 1-6 alkoxy, phenoxy C 1-6 heteroalkoxy, and at least one of E 1-4 includes a B moiety, wherein B is a leaving group, OH, a residue of a hydroxyl- or amino-containing moiety or wherein J 1 is the same as J, or another member of the group defining J and E 5 is the same as E 1-4 , or another member of the group defining E 1-4 , Y 1-2 are independently O, S or NR 9 ; M is a heteroatom selected from either X or Q; wherein X is an electron withdrawing group and Q is a moiety containing a free electron pair positioned three to six atoms from C(═Y 2 ); R 2-5 and R 7-9 are independently selected from the group consisting of hydrogen, C 1-6 alkyls, C 3-12 branched alkyls, C 3-8 cycloalkyls, C 1-6 substituted alkyls, C 3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C 1-6 heteroalkyls, substituted C 1-6 heteroalkyls, C 1-6 alkoxy, phenoxy and C 1-6 heteroalkoxy; (m1) and (m2) are independently zero or one; (n1), (n2), (p1), (p2) and (q) are independently zero or a positive integer; Z is an electron withdrawing group; and R 1 is a polymeric residue. which is optionally capped with a moiety of the formula:

We claim:  
     
         1 . A compound comprising the formula:  
       
         
           
           
               
               
           
         
         E 1-4  are independently selected from the group consisting of hydrogen, C 1-6  alkyls, C 3-12  branched alkyls, C 3-8  cycloalkyls, C 1-6  substituted alkyls, C 3-8  substituted cycloalkyls, aryls, substituted aryls, aralkyls, C 1-6  heteroalkyls, substituted C 1-6  heteroalkyls, C 1-6  alkoxy, phenoxy, C 1-6  heteroalkoxy,  
         
           
             
             
                 
                 
             
           
         
         and at least one E 1-4  includes a B moiety, wherein B is a leaving group, OH, a residue of a hydroxyl-containing moiety, a residue of an amine-containing moiety or  
         
           
             
             
                 
                 
             
           
         
         wherein J 1  is the same as J, or another member of the group defining J and E 5  is the same as E 1-4 , or another member of the group defining E 1-4 ;  
         Y 1-2  are independently O, S or NR 9 ,  
         M is a heteroatom selected from either X or Q; wherein X is an electron withdrawing group and Q is a moiety containing a free electron pair positioned three to six atoms from C(═Y 2 );  
         R 2-5  and R 7-9  are independently selected from the group consisting of hydrogen, C 1-6  alkyls, C 3-12  branched alkyls, C 3-8  cycloalkyls, C 1-6  substituted alkyls, C 3-8  substituted cycloalkyls, aryls, substituted aryls, aralkyls, C 1-6  heteroalkyls, substituted C 1-6  heteroalkyls, C 1-6  alkoxy, phenoxy and C 1-6  heteroalkoxy;  
         (m1) and (m2) are independently zero or one;  
         (n1), (n2), (p1), (p2) and (q) are independently zero or a positive integer;  
         Z is an electron withdrawing group; and  
         R 1  is a polymeric residue.  
       
     
     
         2 . The compound of  claim 1 , wherein R 1  further comprises a capping group A selected from the group consisting of hydrogen, CO 2 H, C 1-6  alkyl moieties, dialkyl acyl urea alkyls and  
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , wherein Y 1  and Y 2  are oxygen.  
     
     
         4 . The compound of  claim 1 , wherein R 2-5 , R 7  and R 8  are hydrogen.  
     
     
         5 . The compound of  claim 1 , wherein X is selected from the group consisting of O, S, SO, SO 2 , C(Y 3 ) and NR 6 , wherein Y 3  is selected from the group consisting of O, S and R 9 , and R 6  is selected from the group consisting of hydrogen, C 1-6  alkyls, C 3-12  branched alkyls, C 3-8  cycloalkyls, C 1-6  substituted alkyls, C 3-8  substituted cycloalkyls, aryls, substituted aryls, aralkyls, C 1-6  heteroalkyls and substituted C 1-6  heteroalkyls.  
     
     
         6 . The compound of  claim 1 , wherein Q is selected from the group consisting of C 2-4  alkyls, cycloalkyls, aryls, aralkyl groups substituted with a member of the group consisting of NH, O, S, —CH 2 —C(O)—NH—, and ortho-substituted phenyls.  
     
     
         7 . The compound of  claim 1 , wherein (p1) and (p2) are 1.  
     
     
         8 . The compound of  claim 1 , wherein (n1) and (n2) are individually 1 or 2.  
     
     
         9 . The compound of  claim 8 , wherein (n1) is 1 and (n2) is 2.  
     
     
         10 . The compound of  claim 1 , wherein (m1) and (m2) are 1.  
     
     
         11 . The compound of  claim 1 , wherein (q) is 1.  
     
     
         12 . The compound of  claim 1 , wherein R 1  comprises a polyalkylene oxide residue.  
     
     
         13 . The compound of  claim 12 , wherein said polyalkylene oxide residue comprises polyethylene glycol.  
     
     
         14 . The compound of  claim 1  wherein said polymeric residue has a molecular weight of from about 2,000 to about 100,000.  
     
     
         15 . The compound of  claim 14 , wherein said polymeric residue has a molecular weight of from about 20,000 to about 40,000.  
     
     
         16 . The compound of  claim 1  wherein B is a residue of a member of the group consisting of Ara-C, camptothecin, camptothecin analogs, paclitaxel, taxoteres, gemcitabine, podophyllotoxin, fluconazole, ciclopirox, amphoteracin B, nystatin, doxorubicin, daunorubicin, maytansine, vancomycin and erythromycin.  
     
     
         17 . The compound of  claim 1  wherein B is a residue of a member of the group consisting of anti-tumor agents; cardiovascular agents, anti-neoplastics anti-infectives, anti-fungals, anti-anxiety agents, gastrointestinal agents, central nervous system-activating agents, analgesics, fertility or contraceptive agents, anti-inflammatory agents, steroidal agents, anti-urecemic agents, cardiovascular agents, vasodilating agents and vasoconstricting agents.  
     
     
         18 . A compound of  claim 1 , having a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         19 . A compound of  claim 1 , having a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein (x) represents the degree of polymerization and “Drug” represents a residue of a hydroxyl- or amine-containing biologically active compound which has undergone a substitution reaction which results in the attachment of the biologically active moiety to the branched polymer.  
     
     
         20 . A method of preparing a polymeric transport system, comprising 
 a) reacting a compound of formula:                        E 1-4  are independently selected from the group consisting of hydrogen, C 1-6  alkyls, C 3-12  branched alkyls, C 3-8  cycloalkyls, C 1-6  substituted alkyls, C 3-8  substituted cycloalkyls, aryls, substituted aryls, aralkyls, C 1-6  heteroalkyls, substituted C 1-6  heteroalkyls, substituted C 1-6  heteroalkyls, C 1-6  alkoxy, phenoxy, C 1-6  heteroalkoxy,                          and at least one of E 1-4  includes a B moiety, wherein B is a leaving group, OH or                            wherein J 1  is the same as J, or another member of the group defining J and E 5  is the same as E 1-4  or another member of the group defining E 1-4 ;    Y 1  is O, S, or NR 9 ;    R 4-5  and R 7-9  are independently selected from the group consisting of hydrogen, C 1-6  alkyls, C 3-12  branched alkyls, C 3-8  cycloalkyls, C 1-6  substituted alkyls, C 3-8  substituted cycloalkyls, aryls, substituted aryls, aralkyls, C 1-5  heteroalkyls, substituted C 1-6  heteroalkyls, substituted C 1-6  heteroalkyls, C 1-6  alkoxy, phenoxy, and C 1-6  heteroalkoxy;    (m1) and (m2) are independently zero or one;    (n1), (n2), (p1), and (p2) are independently zero or a positive integer; and    (Z) is an electron withdrawing group;    with a compound of the formula:                          wherein 
 B 2  is a leaving group which is capable of reacting with an unprotected amine;  
 Y 2  is O, S, or NR 9 ; 
 q is independently zero or a positive integer;  
 R 2-3  are selected from the group consisting of hydrogen, C 1-6  alkyls, C 3-12  branched alkyls, C 3-8  cycloalkyls, C 1-6  substituted alkyls, C 3-8  substituted cycloalkyls, aryls, substituted aryls, aralkyls, C 1-6  heteroalkyls, substituted C 1-6  heteroalkyls, substituted C 1-6  heteroalkyls, C 1-6  alkoxy, phenoxy, and C 1-6  heteroalkoxy,  
 M is a heteroatom selected from either X or Q; wherein X is an electron withdrawing group and Q is a moiety containing a free electron pair positioned three to six atoms from C(═Y 2 ); and  
 (R 1 ) is a polymeric residue; and  
 
 b) reacting the resultant compound with a sufficient amount of a biologically active moiety having a substitutable hydroxyl or amino group.  
   
     
     
         21 . A method of preparing a polymeric transport systems comprising 
 a) reacting a sufficient amount of a biologically active moiety having a substitutable hydroxyl or amino group with a compound of the formula:                          wherein B 3  is a cleavable protecting group;                        E 1-4  are independently selected from the group consisting of hydrogen, C 1-6  alkyls, C 3-12  branched alkyls, C 3-8  cycloalkyls, C 1-6  substituted alkyls, C 3-8  substituted cycloalkyls, aryls, substituted aryls, aralkyls, C 1-6  heteroalkyls, substituted C 1-6  heteroalkyls, substituted C 1-6  heteroalkyls, C 1-6  alkoxy, phenoxy, C 1-6  heteroalkoxy,                          and at least one of E 1-4  includes a B moiety, wherein B is a leaving group, OH, or                          wherein J 1  is the same as J, or another member of the group defining J and E 5  is the same as E 1-4  or another member of the group defining E 1-4 ;    Y 1  is O, S, or NR 9 ;    R 4-5  and R 7-9  are independently selected from the group consisting of hydrogen, C 1-6  alkyls, C 3-12  branched alkyls, C 3-8  cycloalkyls, C 1-6  substituted alkyls, C 3-8  substituted cycloalkyls, aryls, substituted aryls, aralkyls, C 1-6  heteroalkyls, substituted C 1-6  heteroalkyls; substituted C 1-6  heteroalkyls, C 1-6  alkoxy, phenoxy, and C 1-6  heteroalkoxy;    (m1) and (m2) are independently zero or one;    (n1), (n2), (p1), and (p2) are independently zero or a positive integer; and    (Z) is an electron withdrawing group;      with a biologically active moiety having a hydroxyl or amine group;    b) deprotecting the resultant intermediate by removing B 3 ; and    c) reacting the deprotected intermediate compound with a compound of the formula                          wherein 
 B 2  is a leaving group which is capable of reacting with an unprotected amine;  
 Y 2  is O, S, or NR 9 ;  
 q is independently zero or a positive integer;  
 R 2-3  are selected from the group consisting of hydrogen, C 1-6  alkyls, C 3-12  branched alkyls, C 3-8  cycloalkyls, C 1-6  substituted alkyls, C 3-8  substituted cycloalkyls, aryls, substituted aryls, aralkyls, C 1-6  heteroalkyls, substituted C 1-6  heteroalkyls, substituted C 1-6  heteroalkyls, C 1-6  alkoxy, phenoxy, and C 1-6  heteroalkoxy;  
 M is a heteroatom selected from either X or Q; wherein X is an electron withdrawing group and Q is a moiety containing a free electron pair positioned three to six atoms from C(═Y 2 ); and  
 (R 1 ) is a polymeric residue.  
   
     
     
         22 . A method of treating a mammal with prodrugs, comprising: 
 administering to a mammal in need of such treatment an effective amount of a composition of  claim 1  where in B is a residue of a biologically active moiety.