Aryl boronate functionalized polymers for treating obesity

Abstract

Disclosed are polymers comprising one or more phenyl boronate ester, boronamide or boronate thioester groups. The phenyl boronate ester, boronamide and boronate thioester groups are represented by one of the following structural formulas: Ar in Structural Formulas (I) and (II) is substituted or unsubstituted; and each Z is —O—, —NH— or —S— and is independently selected. Pharmaceutically acceptable salts of the polymer are also included. The aryl boronate ester, boronamide or boronate thioester can be cleaved to release the corresponding aryl boronic acid. Also disclosed are pharmaceutical compositions comprising the polymers of the present invention and a pharmaceutically acceptable carrier or diluent; and methods of treating a subject for obesity with the polymers of the present invention.

1 - 100 . (canceled)  
   
   
       101 . A method of treating a subject afflicted with a condition selected from Type II diabetes mellitus, impaired glucose tolerance, hypertension, coronary thrombosis, stroke, lipid syndromes, hyperglycemia, hypertriglyceridemia, hyperlipidemia, sleep apnea, hiatal hernia, reflux esophagisitis, osteoarthritis, gout, gallstones, kidney stones, pulmonary hypertension, infertility and cardiovascular disease, the method comprising the step of administering to the subject an effective amount of a polymer comprising one or more groups selected from pendent aryl boronate ester groups, pendent aryl boronamide groups and aryl boronate thioester groups, wherein the groups are represented by a structural formula selected from:  
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt of said polymer, wherein Ar is a substituted or unsubstituted aryl group; and each Z is —O—, —NH— or —S— and is independently selected.  
     
   
   
       102 . The method of  claim 101  wherein each Z is —O—.  
   
   
       103 . The method of  claim 102 , wherein the polymer comprises one or more pendent aryl boronate ester groups represented by a structural formula selected from:  
     
       
         
         
             
             
         
       
       wherein the Phenyl Ring is substituted or unsubstituted, or a pharmaceutically acceptable salt of said polymer.  
     
   
   
       104 . The method of  claim 103  wherein the Phenyl Ring is substituted with one or more electron withdrawing groups.  
   
   
       105 . The method of  claim 104  wherein the pendent phenyl boronate ester groups are represented by a structural formula selected from:  
     
       
         
         
             
             
         
       
       wherein:  
       X is an electron withdrawing group;  
       R is a substituted or unsubstituted straight chained hydrocarbyl group optionally containing one or more ether, thioether, phenylene, amine or ammonium linkage; and  
       the Phenyl Ring is substituted or unsubstituted.  
     
   
   
       106 . The method of  claim 105  wherein X is —CHD-, —CD 2 —, —CO—, —CONH—, —COO—, —S(O)—, —S(O 2 )O— or —SO 2 —; the Phenyl Ring is optionally substituted with one or more electron withdrawing groups; D is a halogen; and R is a straight chained hydrocarbyl group with an ether or thioether linkage and is substituted at the terminal position with an amine, halogen, —CF3, thiol, ammonium, alcohol, —COOH, —SO 3 H, —OSO 3 H or phosphonium group.  
   
   
       107 . The method of  claim 106  wherein X is —CHD-, —CD 2 —, —CO—, —CONH—, —COO— or —SO 2 —.  
   
   
       108 . The method of  claim 105  wherein X is —CHD-, —CD 2 —, —COO—, —CONH—, —CO— or —SO 2 —; the Phenyl Ring is optionally substituted with one or more electron withdrawing groups; D is a halogen; and R is a straight chained hydrocarbyl group with an ether or thioether linkage and is substituted at the terminal position with —[NH—(CH 2 ) q ] r —NH 2 ), wherein q is an integer from 2 to about 10 and r is an integer from 1 to about 5, provided that one or more of the secondary amines in —[NH—(CH 2 ) q ] r —NH 2 ) are optionally N-alkylated or N,N-dialkylated and the primary amine in —[NH—(CH 2 ) q ] r —NH 2 ) is optionally N-alkylated, N,N-dialkylated or N,N,N-trialkylated.  
   
   
       109 . The method of  claim 103 , wherein the polymer comprises one or more pendent phenyl boronate ester groups represented by a structural formula selected from:  
     
       
         
         
             
             
         
       
       R is a substituted or unsubstituted straight chained hydrocarbyl group optionally containing one or more ether, thioether, phenylene, amine or ammonium linkage; and  
       the Phenyl Ring is substituted or unsubstituted; or a pharmaceutically acceptable salt of said polymer.  
     
   
   
       110 . The method of  claim 109  wherein the Phenyl Ring is optionally substituted with one or more additional electron withdrawing groups; R is a straight chained hydrocarbyl group optionally comprising an ether or thioether linkage; and R is substituted at the terminal position with an amine, halogen, —CF3, thiol, ammonium group, alcohol, —COOH, —SO 3 H, —OSO 3 H or phosphonium group.  
   
   
       111 . The method of  claim 110  wherein R is a straight chained hydrocarbyl group comprising an ether or thioether linkage and substituted at the terminal position with an ammonium group.  
   
   
       112 . The method of  claim 110  wherein R is a straight chained hydrocarbyl group comprising an ether or thioether linkage and substituted at the terminal position with a trialkyl ammonium group.  
   
   
       113 . The method of  claim 110  wherein R is a straight chained hydrocarbyl group comprising an ether or thioether linkage and substituted at the terminal position with a trimethyl ammonium group.  
   
   
       114 . The method of  claim 109  wherein the Phenyl Ring is optionally substituted with one or more additional electron withdrawing groups; R is a straight chained hydrocarbyl group with an ammonium linkage and optionally substituted at the terminal position with an amine, halogen, —CF3, thiol, ammonium group, alcohol, —COOH, —SO 3 H, —OSO 3 H or phosphonium group.  
   
   
       115 . The method of  claim 109  wherein the Phenyl Ring is optionally substituted with one or more additional electron withdrawing groups; R is a straight chained hydrocarbyl group with an ammonium linkage.  
   
   
       116 . The method of  claim 109  wherein the Phenyl Ring is optionally substituted with one or more additional electron withdrawing groups; R is a straight chained hydrocarbyl group substituted at the terminal position with an amine, halogen, —CF3, thiol, ammonium group, alcohol, —COOH, —SO 3 H, —OSO 3 H or phosphonium group.  
   
   
       117 . The method of  claim 116  wherein R is a straight chained hydrocarbyl group substituted at the terminal position with an ammonium group.  
   
   
       118 . The method of  claim 116  wherein R is a straight chained hydrocarbyl group substituted at the terminal position with a trialkyl ammonium group.  
   
   
       119 . The method of  claim 105  wherein —XR is —C(O)CH 2 —O[—(CH 2 )pO]m-(CH 2 )p-Y or —C(O)CH 2 —S[—(CH 2 )pO]m-(CH 2 )p-Y, p is 2 or 3, m is an integer from 1-5 and Y is an ammonium group.  
   
   
       120 . A method of inhibiting the uptake of fat in the gastrointestinal tract of a subject in need of such treatment, wherein the subject is afflicted with a condition selected from Type II diabetes mellitus, impaired glucose tolerance, hypertension, coronary thrombosis, stroke, lipid syndromes, hyperglycemia, hypertriglyceridemia, hyperlipidemia, sleep apnea, hiatal hernia, reflux esophagisitis, osteoarthritis, gout, gallstones, kidney stones, pulmonary hypertension, infertility and cardiovascular disease, said method comprising the step of administering to the subject an effective amount of a polymer comprising one or more groups selected from pendent aryl boronate ester groups, pendent aryl boronamide groups and aryl boronate thioester groups, wherein the groups are represented by a structural formula selected from:  
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt of said polymer, wherein Ar is a substituted or unsubstituted aryl group; and each Z is —O—, —NH— or —S— and is independently selected.