Polymeric molecular receptors as phosphate sequestrants

Abstract

Polymers and compositions utilizing such polymers are disclosed for treating hyperphosphatemia and other illnesses associated with elevated serum phosphate levels. Phosphate binding polymers, or a pharmaceutically acceptable salt of the polymers, comprise pendent groups extending from a backbone of the polymer. Each pendent group comprises at least two nitrogen-bearing functional groups which bind phosphate. Variations of such polymer and compositions are disclosed.

1 - 96 . (canceled) 
     
     
         97 . A method of removing phosphate from a subject in need thereof, comprising administering to the subject an effective amount of a phosphate binding polymer or a pharmaceutically acceptable salt of the polymer, wherein the polymer comprises pendent groups extending from a backbone, wherein each pendent group, referred to as a “multifunctional phosphate binding pendent group”, comprises at least two nitrogen bearing functional groups which bind phosphate,
 provided that if the polymer comprises a repeat unit represented by any one of Structural Formulas (A)-(G): 
 
       
         
           
           
               
               
           
         
         wherein
 A is either a covalent bond, C(O), or CH 2 ; 
 R 1  is an alkyl amine or alkyl ammonium group; 
 R 1A  is a polyalkyleneimine; 
 R 2  and R 3  are each independently hydrogen, an alkyl group, an alkyl amino group, or an aryl group; 
 R 4  is an alkyl ammonium group; and 
 R 5  is hydrogen, or an optionally substituted alkyl group, or an optionally substituted aryl group; 
 
       
       then the polymer comprises a second repeat unit with a multifunctional phosphate binding pendent group, wherein said second repeat unit is not represented by Structural Formulas (A)-(G). 
     
     
         98 . The method of  claim 97 , wherein the polymer is a copolymer and wherein each pendent group comprises at least three nitrogen bearing functional groups and is represented by Structural Formula (I): 
       
         
           
           
               
               
           
         
         wherein:
 each amine in Structural Formula (I) is independently optionally quatemarized with R; 
 each R is independently hydrogen or an optionally substituted alkyl group; 
 T 0  is a covalent bond, carbonyl, —Ar—, -T 1 -, -Ar-T 1 -, —O-T 2 -, —S-T 2 -, —C(O)-T 1 -, —C(O)O-T 2 -, —C(O)S-T 1 -, or —C(O)N(R T )-T 2 -, wherein R T  is hydrogen or an optionally substituted C1-C3 alkyl group; 
 Ar is an optionally substituted arylene group; 
 T 1  is an optionally substituted C1-C5 alkylene group optionally interrupted by an optionally substituted arylene group; 
 T 2  is an optionally substituted C2-C5 alkylene group; and 
 a) NR 6 R 7  taken together is
 1) a monocyclic non-aromatic ring substituted with two or more groups selected from amine, ammonium, amino alkyl, and ammonium alkyl, or 
 2) a bridged bicycle non-aromatic ring comprising at least two ring 
 amine or ammonium groups; or 
 
 b) R 6  is hydrogen, an optionally substituted alkyl group, or an optionally substituted aryl group, and 
 R 7  is 
 1) represented by Structural Formula (Ia): 
 
       
       
         
           
           
               
               
           
         
         
           wherein
 X is 
 (A) C—R x , where R x  is hydrogen, an optionally substituted alkyl group, or an optionally substituted aryl group, or 
 (B) N or N + (R), 
 Y is 
 (A) a covalent bond or an optionally substituted C1-C10 alkylene group optionally interrupted by an optionally substituted arylene group, if X is C—R x , and 
 (B) an optionally substituted C2-C10 alkylene group optionally interrupted by an optionally substituted arylene group, if X is N or N + (R), 
 R 9  is 
 (A) an alkyl group or an aryl group, the group substituted with at least one group selected from amine, ammonium, amino alkyl, and ammonium alkyl, if X is C—R x , and 
 (B) hydrogen, an optionally substituted alkyl group, or an optionally substituted aryl group, if X is N or N + (R), and R 10  is hydrogen, an optionally substituted alkyl group, or an optionally substituted aryl group, 
 provided that if T 0  is carbonyl, then R 10  is an alkyl or aryl group, the group substituted with at least one group selected from amine, ammonium, amino alkyl, and ammonium alkyl or 
 2) —Y 1 -Cy, 
 where Y 1  is a covalent bond or an optionally substituted C1-C5 alkylene group, and Cy is a monocyclic non-aromatic ring substituted with two or more groups selected from amine, ammonium, amino alkyl, and ammonium alkyl. 
 
         
       
     
     
         99 . The method of  claim 98 , wherein each pendent group is represented by Structural Formula (II), (V), (VI), (IX) or (X): 
       
         
           
           
               
               
           
         
         wherein:
 each amine in Structural Formulas (II), (V), (VI), (IX) and (X) is independently optionally quaternarized with R; 
 each R in Structural Formulas (II), (V), (VI), (IX) and (X) is independently hydrogen or an optionally substituted alkyl group; 
 each R 9  in Structural Formula (II) is an alkyl group substituted with amine or ammonium; 
 R 10  in Structural Formula (II) is 
 i. hydrogen or an optimality substituted alkyl group if X is N or N + (R); or 
 ii. an alkyl group substituted with amine or ammonium if is C-Rx; and
 each R 16  in Structural Formula (V) is independently a C1-C3 alkyl chain terminally substituted with amine or ammonium; 
 each R 18  in Structural Formula (IX) is independently a C1-C3 alkyl chain terminally substituted with amine or ammonium; 
 Z 3  and Z 4  in Structural Formula (VI) are each independently amine or ammonium; 
 Cy in Structural Formula (IX) is a non-aromatic ring with 3 to 7 carbon atoms optionally substituted with R; 
 Cy1 in Structural Formula (V) is a nitrogen-containing non-aromatic ring with 3 to 7 carbon atoms; 
 Cy2 and Cy3 in Structural Formula (VI) are each independently a 5, 6, or 7 member, non-aromatic ring with two ring nitrogen atoms; and 
 
 
         each j in Structural Formula (X) is independently 2 or 3. 
       
     
     
         100 . The method of  claim 99 , wherein each pendent group is represented by Structural Formula (IIa), (IIb) or (III): 
       
         
           
           
               
               
           
         
         wherein:
 each amine of Structural Formula (IIa), (IIb) or (III) is independently optionally quaternarized with R; 
 each R is independently hydrogen or an optionally substituted alkyl group; 
 R 10  is hydrogen, or X 3 —N(R 14 ) 2  or X 3 —N+(R 14 ) 3  with X 3  being an optionally substituted C2-C5 alkylene group; 
 each R 14  is independently hydrogen or an optionally substituted alkyl group; and 
 X 1  and X 2  are each independently an optionally substituted alkylene group. 
 
       
     
     
         101 . The method of  claim 99 , wherein the polymer comprises a repeat unit represented by
 i) a structural formula selected from:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein
 R 18  is hydrogen or a methyl group, each V is N or CH, 
 each amine is independently optionally quaternarized with hydrogen, 
 each j is independently 1, 2, 3, 4 or 5, and each k is independently 2, 3 or 4; 
 
         ii) a structural formula selected from: 
       
       
         
           
           
               
               
           
         
         wherein
 each amine in the structural formulas is Independently optionally quaternarized with hydrogen, k is 1,2,3,4 or 5, and each m is independently 2 or 3; 
 
         iii) a structural formula selected from: 
       
       
         
           
           
               
               
           
         
         wherein
 each amine in the structural formulas is independently optionally quaternarized with hydrogen, and each j is independently 2 or 3; 
 
         iv) a structural formula selected from: 
       
       
         
           
           
               
               
           
         
         wherein
 each amine is independently optionally quaternarized with hydrogen and j is 1, 2, 3 or4; 
 
         v) the following structural formula: 
       
       
         
           
           
               
               
           
         
         wherein
 each amine in the structural formula is independently optionally quaternarized with hydrogen and j is 1, 2, 3 or 4; or 
 
         vi) a structural formula selected from: 
       
       
         
           
           
               
               
           
         
         wherein
 each amine in the structural formula is independently optionally quaternarized with R, and each R and R* is independently C1-C3 alkyl or hydrogen. 
 
       
     
     
         102 . The method of  claim 97 , wherein the polymer repeat unit represented by one of Structural Formulas (VII) and (VIII): 
       
         
           
           
               
               
           
         
         wherein:
 each amine in Structural Formulas (VII) and (VIII) is independently optionally quaternarized with R; 
 each R is indecently hydrogen or an optionally substituted alkyl group; 
 R 8  is hydrogen or methyl; 
 each R 17  is independently hydrogen or an optionally substituted C1-C5 alkyl group 
 Ar is an optionally substituted arylene group; 
 each T 0  is independently a covalent bond, carbonyl, —Ar—, -Ar-T 1 -, -T 1 -, —O-T 2 -, —S-T 2 -, —C(O)-T 1 -, —C(O)O-T 2 -, —C(O)S-T 1 -, or —C(O)N(R T )-T 2 -, 
 wherein
 R T  is hydrogen or an optionally substituted C1-C3 alkyl group; 
 T 1  is an optionally substituted C1-C5 alkylene group optionally interrupted by an optionally substituted arylene group; 
 T 2  is an optionally substituted C2-C5 alkylene group; 
 X is C—R x , N, or N + (R), where R x  is hydrogen or an optionally substituted alkyl group; and 
 
 each Y 2  is independently 
 (i) optionally substituted C2-C5 alkylene when X is N or N + (R), and 
 (ii) optionally substituted CI-CS alkylene when X is C—R x .