Posaconazole polymer conjugates and methods of treatment using posaconazole and polymer conjugates thereof

Abstract

Improved posaconazole-based compositions and methods of treating and preventing fungal infections, cancer or metastatic diseases are disclosed. In preferred aspects, the conjugates are PEG-posaconazole conjugates in which the PEG has a molecular weight of about 20,000 daltons.

1 . A polymeric conjugate comprising posaconazole and a substantially non-antigenic polymer. 
   
   
       2 . The polymeric conjugate of  claim 1 , wherein the substantially non-antigenic polymer is a polyalkylene oxide. 
   
   
       3 . The polymeric conjugate of  claim 2 , wherein the polyalkylene oxide is a polyethylene glycol. 
   
   
       4 . The polymeric conjugate of  claim 2 , wherein the polyalkylene oxide has a weight average molecular weight of from about 1,000 to about 100,000 daltons. 
   
   
       5 . The polymeric conjugate of  claim 2 , wherein the polyalkylene oxide has a weight average molecular weight of from about 5,000 to about 60,000 daltons. 
   
   
       6 . The polymeric conjugate of  claim 2 , wherein the polyalkylene oxide has a weight average molecular weight of from about 12,000 to about 24,000 daltons. 
   
   
       7 . A polymeric conjugate of  claim 1  having Formula (I): 
     
       
         
         
             
             
         
       
       wherein 
       A is a capping group or 
     
     
       
         
         
             
             
         
       
       X is 
     
     
       
         
         
             
             
         
       
       Z 1 , Z 1′ , Z 2  and Z 2′  are independently selected from the group consisting of O, S and NR 1 ; 
       R is a polyalkylene oxide; 
       Y 1  and Y 1′  are independently O, S, SO, SO 2 , CR 2 R 3  or NR 4 ; and 
       R 1 , R 2 , R 3  and R 4  are independently selected from the group consisting of hydrogen, C 1-6  alkyls, C 3-19  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. 
     
   
   
       8 . The polymeric conjugate of  claim 7  having Formula (II): 
     
       
         
         
             
             
         
       
     
   
   
       9 . The polymeric conjugate of  claim 7 , wherein the capping group is selected from the group consisting of H, NH 2 , OH, CO 2 H, C 1-6  alkoxy and C 1-6  alkyl. 
   
   
       10 . The polymeric conjugate of  claim 7 , wherein R comprises a linear, branched or multi-armed polyalkylene oxide. 
   
   
       11 . The compound of  claim 7 , wherein R is selected from the group consisting of polyethylene glycol, polypropylene glycol, and copolymers thereof. 
   
   
       12 . The polymeric conjugate of  claim 7 , wherein R is
   —Y 1 1-(CH 2 CH 2 O) n —CH 2 CH 2 Y 11 —,   wherein:   Y 11  and Y 11′  are independently O, S, or NR 11 ;   R 11  is selected from the group consisting of hydrogen, C 1-6  alkyls, C 3-19  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;   (n) is an integer from about 20 to about 2300.   
   
   
       13 . The polymeric conjugate of  claim 7  having Formula (III): 
     
       
         
         
             
             
         
       
       wherein (n) is an integer from about 20 to about 2300. 
     
   
   
       14 . The polymeric conjugate of  claim 13 , wherein Y 1 , Y 1′ , Z 1 , Z 1′ , Z 2  and Z 2′  are each O. 
   
   
       15 . A method of preparing a polymeric conjugate, comprising
 a) reacting a compound of the structure   
     
       
         
         
             
             
         
       
     
     in the presence of a base
 wherein 
 Z 21  and Z 22  are independently selected from the group consisting of O, S and NR 21 ; 
 Y 21  is O, S, SO, SO 2 , CR 22 R 23  or NR 24 ; 
 R 21 , R 22 , R 23  and R 24  are independently selected from the group consisting of hydrogen, C 1-6  alkyls, C 3-19  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  hetero-alkyls, C 1-6  alkoxy, phenoxy and C 1-6  heteroalkoxy; and 
 b) reacting the resulting product of step a) with an amine-terminated polyalkylene oxide in the presence of a base and a coupling agent under conditions sufficient to form a polymeric conjugate. 
 
   
   
       16 . The method of  claim 15 , wherein the base is 4-dimethylaminopyridine (DMAP) and the coupling agent is 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (EDC). 
   
   
       17 . A pharmaceutical composition comprising an effective amount of the polymeric conjugate of  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
   
   
       18 . A method of treating and/or preventing fungal infections in a mammal, comprising administering an anti-fungally effective amount of a polymeric conjugate of  claim 1  to a mammal in need thereof. 
   
   
       19 . The method of  claim 18 , wherein the polymeric conjugate is administered parenterally. 
   
   
       20 . The method of  claim 18 , wherein the amount of posaconazole administered to the mammal is from about 10 to about 2,000 mg per day. 
   
   
       21 . The method of  claim 18 , wherein the amount of posaconazole administered to the mammal is from about 50 to about 800 mg per day. 
   
   
       22 . The method of  claim 18 , wherein the amount of posaconazole administered to the mammal is from about 5 to about 50 mg/kg/day. 
   
   
       23 . The method of  claim 18 , wherein the amount of posaconazole administered is an amount effective to produce an arithmetic mean steady state average maximum plasma concentration of posaconazole that exceeds the majority of the Minimum Inhibitory Concentrations needed to kill 90% (“MICs 90 ”) of the clinically relevant pathogenic fungi. 
   
   
       24 . A method of treating and/or preventing cancer or metastatic diseases in a mammal, comprising administering an effective amount of a polymeric conjugate of  claim 1  to a mammal in need thereof. 
   
   
       25 . The method of  claim 24 , wherein the polymeric conjugate is administered parenterally. 
   
   
       26 . The method of  claim 24 , wherein the amount of posaconazole administered to the mammal is from about 10 to about 2,000 mg per day. 
   
   
       27 . The method of  claim 24 , wherein the amount of posaconazole administered to the mammal is from about 50 to about 800 mg per day. 
   
   
       28 . The method of  claim 24 , wherein the amount of posaconazole administered to the mammal is from about 5 to about 50 mg/kg/day.