Polymer derivatives having particular atom arrangements

Abstract

Polymeric reagents are provided comprising a moiety of atoms arranged in a specific order, wherein the moiety is positioned between a water-soluble polymer and a reactive group. The polymeric reagents are useful for, among other things, forming polymer-active agent conjugates. Related methods, compositions, preparations, and so forth are also provided.

1 . A polymeric reagent comprising a 
       
         
           
           
               
               
           
         
       
       moiety positioned between a water-soluble polymer and a reactive group, wherein: (i) the nitrogen atom in the 
       
         
           
           
               
               
           
         
       
       moiety is proximal to the water-soluble polymer; (ii) the carbonyl carbon atom of the 
       
         
           
           
               
               
           
         
       
       moiety is proximal to the reactive group; and (iii) R 1  is H or an organic radical. 
     
     
         2 . The polymeric reagent of  claim 1 , wherein R 1  is H or is an organic radical selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl. 
     
     
         3 . (canceled) 
     
     
         4 . The polymeric reagent of  claim 2 , wherein R 1  is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and piperidonyl. 
     
     
         5 . The polymeric reagent of  claim 1 , wherein the water-soluble polymer portion is a polymer selected from the group consisting of a poly(alkylene oxide), poly(vinyl pyrrolidone), poly(vinyl alcohol), polyoxazoline, poly(acryloylmorpholine), and poly(oxyethylated polyols). 
     
     
         6 . (canceled) 
     
     
         7 . The polymeric reagent of  claim 5 , wherein the poly(alkylene oxide) is a poly(ethylene glycol). 
     
     
         8 . (canceled) 
     
     
         9 . The polymeric reagent of  claim 7 , wherein the poly(ethylene glycol) is terminally capped with methoxy. 
     
     
         10 . (canceled) 
     
     
         11 . The polymeric reagent of  claim 7 , wherein the poly(ethylene glycol) has a molecular weight of from about 1,000 Daltons to about 60,000 Daltons. 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . The polymeric reagent of  claim 1 , wherein the nitrogen atom of the 
       
         
           
           
               
               
           
         
       
       moiety is linked to the water-soluble polymer through a direct covalent bond or is linked to the water-soluble polymer through a first spacer moiety. 
     
     
         15 . (canceled) 
     
     
         16 . The polymeric reagent of  claim 1 , wherein the reactive group is selected from the group consisting of hydroxyl, ester, ester, orthoester, carbonate, carbonate, acetal, aldehyde, aldehyde hydrate, ketone, vinyl ketone, ketone hydrate, thione, monothiohydrate, dithiohydrate, hemiketal, monothioketal hemiketal, dithiohemiketal, ketal, dithioketal, alkenyl, acrylate, methacrylate, acrylamide, sulfone, sulfone, amine, hydrazide, thiol, disulfide, thiol hydrate, carboxylic acid, isocyanate, isothiocyanate, maleimide, succinimide, benzotriazole, vinylsulfone, chloroethylsulfone, dithiopyridine, vinylpyridine, iodoacetamide, epoxide, glyoxals, diones, mesylates, tosylates, thiosulfonate, tresylate, silane, —(CH 2 ) r CO 2 H, —(CH 2 ) r′ CO 2 NS, —(CH 2 ) r′ CO 2 Bt, —(CH 2 ) r —CH(OR) 2 , —(CH 2 ) r —CHO, —(CH 2 ) 2 —NH 2 , —(CH 2 ) r M, —(CH 2 ) r —S—SO 2 —R, where r is 1-5, r′ is 0-5, R is aryl or alkyl, NS is N-succinimidyl, Bt is 1-benzotriazolyl, and M is N-maleimidyl, and protected and activated forms of any of the foregoing. 
     
     
         17 . The polymeric reagent of  claim 1 , comprising a structure: 
       
         
           
           
               
               
           
         
         wherein:
 POLY 1  is a poly(ethylene glycol); 
 (a) is 0, 1, 2 or 3; 
 (b) is 0, 1, 2 or 3; 
 R 1  is H or an organic radical; 
 X 1 , when present, is a first spacer moiety; 
 X 2 , when present, is a second spacer moiety; and 
 Z is a reactive group. 
 
       
     
     
         18 . The polymeric reagent of  claim 1 , comprising a structure: 
       
         
           
           
               
               
           
         
         wherein:
 POLY 1  is a poly(ethylene glycol); 
 POLY 2  is a poly(ethylene glycol); 
 (a) is 0, 1, 2 or 3; 
 (b) is 0, 1, 2 or 3; 
 (e) is 0, 1, 2 or 3; 
 (f) is 0, 1, 2 or 3; 
 (g) is 0, 1, 2 or 3; 
 (h) is 0, 1, 2 or 3; 
 (j) is 0 to 20; 
 each R 1  is independently H or an organic radical selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl; 
 X 1 , when present, is a first spacer moiety; 
 X 2 , when present, is a second spacer moiety; 
 X 5 , when present, is a fifth spacer moiety; 
 X 6 , when present, is a sixth spacer moiety; 
 X 7 , when present, is a seventh spacer moiety; 
 X 8 , when present, is an eighth spacer moiety; 
 R 5  is a branching moiety; and 
 Z is a reactive group. 
 
       
     
     
         19 . The polymeric reagent of  claim 18 , wherein R 5  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein (p) is 1-8 and (q) is 1-8. 
       
       wherein POLY 1 , X, (a), (c), Q, and Z are as previously defined. 
     
     
         20 .- 25 . (canceled) 
     
     
         26 . A method of preparing a polymeric reagent comprising the steps of
 (i) providing a precursor molecule optionally comprised of a protected reactive group and one or more hydroxyl groups;   (ii) activating at least one of the one or more hydroxyl groups of the precursor molecule for reaction with an amino group to form an activated precursor molecule;   (iii) contacting under covalent coupling conditions at least one of the one or more activated hydroxyl groups with a water-soluble polymer having an amino group, thereby forming a polymer comprised of the water-soluble polymer portion and the protected reactive group; and   (iv) deprotecting the protected reactive group, when present, thereby forming the polymeric reagent.   
     
     
         27 . The method of  claim 26 , further comprising the step of isolating the polymeric reagent. 
     
     
         28 . The method of  claim 27 , wherein the polymeric reagent is isolated by chromatography. 
     
     
         29 .- 34 . (canceled) 
     
     
         35 . The method of  claim 26 , wherein the water-soluble polymer having an amino group is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein:
 (m) is 2 to 4000. 
 
       
     
     
         36 . The method of  claim 26 , wherein the deprotecting step comprises the methods selected from the group consisting of base-promoted hydrolysis, acid-catalyzed hydrolysis and reduction. 
     
     
         37 .- 38 . (canceled) 
     
     
         39 . A conjugate comprising a water-soluble polymer, a 
       
         
           
           
               
               
           
         
       
       moiety, and a pharmacologically active agent, wherein: (i) the water-soluble polymer is linked to the nitrogen atom of the 
       
         
           
           
               
               
           
         
       
       moiety through either a direct covalent bond or through a first spacer moiety; (ii) the pharmacologically active agent is linked to the carbonyl carbon atom of the 
       
         
           
           
               
               
           
         
       
       moiety through either a direct covalent bond or a second spacer moiety; and (iii) R 1  is H or an organic radical. 
     
     
         40 . A method of preparing a conjugate comprising a step of contacting a polymeric reagent according to  claim 1  with an active agent under conditions suitable to thereby form the active agent-polymer conjugate. 
     
     
         41 . A pharmaceutical preparation comprising the conjugate prepared according to  claim 40  in combination with a pharmaceutical excipient. 
     
     
         42 .- 47 . (canceled) 
     
     
         48 . A method of delivering a conjugate comprising a step of administering to a patient a therapeutically effective amount of a conjugate according to  claim 39 . 
     
     
         50 . (canceled)