Bioresorbable polymers synthesized from monomer analogs of natural metabolites

Abstract

New bioresorbable polymers are synthesized from monomer analogs of natural metabolites In particular, polymers are polymerized from analogs of amino acids that contribute advantageous synthesis, processing and material properties to the polymers prepared therefrom, including particularly advantageous degradation profiles

1 . A polymer comprising at least 10 mol % of a repeating unit having a structure selected from Formula I and Formula Ia 
       
         
           
           
               
               
           
         
         for which the variables are defined as follows:
 Ar is a phenyl ring optionally substituted with from one to four substituents independently selected from the group consisting of halogen, halomethyl, halomethoxy, methyl, methoxy, thiomethyl, nitro, sulfoxide and sulfonyl; 
 R 1  is selected from the group consisting of a bond and optionally substituted alkyl, heteroalkyl, alkenyl and heteroalkenyl groups containing from one to ten carbon atoms; 
 
         X 1 , X 2  and X 3  are independently selected from the group consisting of O, S and NR 3 ;
 R 2  is selected from the group consisting of hydrogen and alkyl groups contain-ing from one to thirty carbon atoms, or R 2a  is an alkylene group covalently bonded to both the NR 2  nitrogen atom and AA, so that —N—R 2a -AA- define a heterocyclic ring; 
 R 3  is selected from the group consisting of hydrogen and alkyl groups contain-ing from one to thirty carbon atoms; 
 AA has a pendant COOR 4  group in which R 4  is selected from the group consisting of hydrogen, alkyl, heteroalkyl and alkylaryl groups containing up to 30 carbon atoms and alkyl-terminated poly(alkylene oxide) groups of molecular weight 100 to 10,000; and 
 AA and X 3 H of Formula I are selected so that (R 2 —HN-)AA-X 3 H defines an —X 3 H substituted amino acid and AA and X 3 H of Formula Ia are selected so that 
 
       
       
         
           
           
               
               
           
         
         defines an X 3 H— substituted amino acid; 
       
       wherein said polymer has a glass transition temperature or crystalline melting temperature greater than 37° C. when fully hydrated in phosphate buffered saline (PBS) (0.1 M, pH 7.4) at 37° C. and said Formula I and Ia variables are selected so that monomers comprising said Formula I and Formula Ia repeating units have a solubility in said PBS solution at 37° C. of at least about 3 mg/mL. 
     
     
         2 . The polymer of  claim 1 , wherein AA and X 3  are selected so that 
       
         
           
           
               
               
           
         
       
       defines an amino acid selected from the group consisting of hydroxy-tryptophan, mercapto-tryptophan, hydroxy-proline and mercapto-proline. 
     
     
         3 . A polymer comprising at least 10 mol % of repeating units having a structure selected from Formula I and Formula Ia 
       
         
           
           
               
               
           
         
         for which the variables are defined as follows:
 Ar is a phenyl ring optionally substituted with from one to four substituents independently selected from the group consisting of halogen, halomethyl, halomethoxy, methyl, methoxy, thiomethyl, nitro, sulfoxide and sulfonyl; 
 R 1  is selected from the group consisting of a bond and optionally substituted alkyl, heteroalkyl, alkenyl and heteroalkenyl groups containing from one to ten carbon atoms; 
 
         X 1 , X 2  and X 3  are independently selected from the group consisting of O, S and NR 3 ;
 R 2  is selected from the group consisting of hydrogen and alkyl groups contain-ing from one to thirty carbon atoms, or R 2a  is an alkylene group covalently bonded to both the NR 2  nitrogen atom and AA, so that —N—R 2a -AA- define a heterocyclic ring; 
 R 3  is selected from the group consisting of hydrogen and alkyl groups containing from one to thirty carbon atoms; 
 AA has a pendant COOR 4  group in which R 4  is selected from the group consisting of hydrogen, alkyl, heteroalkyl and alkylaryl groups containing up to 30 carbon atoms and alkyl-terminated poly(alkylene oxide) groups of molecular weight 100 to 10,000; and 
 AA and X 3 H of Formula I are selected so (R 2 —HN-)AA-X 3 H defines an —X 3 H substituted amino acid and AA and X 3 H of Formula Ia are selected so 
 
       
       
         
           
           
               
               
           
         
         defines an X 3 H— substituted amino acid; 
       
       wherein and said polymer has a glass transition temperature or crystalline melting temperature greater than 37° C. when fully hydrated in phosphate buffered saline (PBS) (0.1M, pH 7.4) at 37° C. and said Formula I and Ia variables are selected so that monomers comprising said Formula I and Formula Ia repeating units have a solubility in said PBS solution at 37° C. of less than about 3 mg/mL. 
     
     
         4 . The polymer of  claim 3 , wherein AA and X 3  are selected so that 
       
         
           
           
               
               
           
         
       
       defines an amino acid selected from the group consisting of hydroxy-tryptophan, mercapto-tryptophan, mercapto-phenylalanine, thryronine and thyroxine. 
     
     
         5 . A polymer comprising at least 10 mol % of repeating units having a structure selected from Formula I and Formula Ia 
       
         
           
           
               
               
           
         
         for which the variables are defined as follows:
 Ar is a phenyl ring optionally substituted with from one to four substituents independently selected from the group consisting of halogen, halomethyl, halomethoxy, methyl, methoxy, thiomethyl, nitro, sulfoxide and sulfonyl; 
 R 1  is selected from the group consisting of a bond and optionally substituted alkyl, heteroalkyl, alkenyl and heteroalkenyl groups containing from one to ten carbon atoms; 
 
         X 1 , X 2  and X 3  are independently selected from the group consisting of O, S and NR 3 ;
 R 2  is selected from the group consisting of hydrogen and alkyl groups containing from one to thirty carbon atoms, or R 2a  is an alkylene group covalently bonded to both the NR 2  nitrogen atom and AA, so that —N—R 2a -AA- define a heterocyclic ring; 
 R 3  is selected from the group consisting of hydrogen and alkyl groups containing from one to thirty carbon atoms; 
 AA has a pendant COOR 4  group in which R 4  is selected from the group consisting of hydrogen, alkyl, heteroalkyl and alkylaryl groups containing up to 30 carbon atoms and alkyl-terminated poly(alkylene oxide) groups of molecular weight 100 to 10,000; and 
 AA and X 3 H of Formula I are selected so that (R 2 —HN-)AA-X 3 H defines an —X 3 H substituted amino acid and AA and X 3 H of Formula Ia are selected so that 
 
       
       
         
           
           
               
               
           
         
         defines an X 3 H— substituted amino acid; 
       
       wherein said polymer has a glass transition temperature or crystalline melting temperature less than about 37° C. when fully hydrated in phosphate buffered saline (PBS) (0.1 M, pH 7.4) at 37° C. and said Formula I and Ia variables are selected so that monomers comprising said Formula I and Formula Ia repeating units have a solubility in said PBS solution at 37° C. greater than about 3 mg/mL. 
     
     
         6 . The polymer of  claim 5 , wherein (R 2 —HN-)AA-X 3 H defines an amino acid selected from the group consisting of hydroxy-leucine, mercapto-leucine, hydroxy-isoleucine, mercapto-isoleucine and mercapto-valine. 
     
     
         7 . A polymer comprising at least 10 mol % of repeating units having a structure selected from Formula I and Formula Ia 
       
         
           
           
               
               
           
         
         for which the variables are defined as follows:
 Ar is a phenyl ring optionally substituted with from one to four substituents independently selected from the group consisting of halogen, halomethyl, halomethoxy, methyl, methoxy, thiomethyl, nitro, sulfoxide and sulfonyl; 
 R 1  is selected from the group consisting of a bond and optionally substituted alkyl, heteroalkyl, alkenyl and heteroalkenyl groups containing from one to ten carbon atoms; 
 
         X 1 , X 2  and X 3  are independently selected from the group consisting of O, S and NR 3 ;
 R 2  is selected from the group consisting of hydrogen and alkyl groups containing from one to thirty carbon atoms, or R 2a  is an alkylene group covalently bonded to both the NR 2  nitrogen atom and AA, so that —N—R 2a -AA- define a heterocyclic ring; 
 R 3  is selected from the group consisting of hydrogen and alkyl groups containing from one to thirty carbon atoms; 
 AA has a pendant COOR 4  group in which R 4  is selected from the group consisting of hydrogen, alkyl, heteroalkyl and alkylaryl groups containing up to 30 carbon atoms and alkyl-terminated poly(alkylene oxide) groups of molecular weight 100 to 10,000; and 
 AA and X 3 H of Formula I are selected so that (R 2 —HN-)AA-X 3 H defines an —X 3 H substituted amino acid and AA and X 3 H of Formula Ia are selected so that 
 
       
       
         
           
           
               
               
           
         
         defines an X 3 H— substituted amino acid; 
       
       wherein said polymers have a glass transition temperature or crystalline melting temperature less than about 37° C. when fully hydrated in phosphate buffered saline (PBS) (0.1 M, pH 7.4) at 37° C. and said Formula I and Ia variables are selected so that monomers comprising said Formula I and Formula Ia repeating units have a solubility in said PBS solution at 37° C. of less than about 3 mg/mL. 
     
     
         8 . The polymer of  claim 7 , wherein AA and X 3 H of Formula I are selected so that (R 2 —HN-)AA-X 3 H defines an amino acid selected from the group consisting of cysteine, threonine, serine, lysine and mercapto-alanine. 
     
     
         9 . The polymer of  claim 3 , wherein said Formula I and Formula Ia variables are selected to provide a polymer with an equilibrium water content in said PBS solution at 37° C. of less than about 20 wt %. 
     
     
         10 . (canceled) 
     
     
         11 . The polymer of  claim 3 , wherein AA and X 3 H of Formula I are selected so that (R 2 —HN-)AA-X 3 H defines an alpha amino acid, and wherein AA and X 3 H of Formula Ia are selected so that 
       
         
           
           
               
               
           
         
       
       defines an alpha-amino acid. 
     
     
         12 . The polymer of  claim 11 , wherein said alpha amino acid is a naturally-occurring amino acid. 
     
     
         13 . The polymer of  claim 11 , wherein said alpha amino acid is an essential amino acid. 
     
     
         14 . The polymer of  claim 3 , comprising two different repeating units having the structures of Formula I or Formula Ia, wherein said polymer comprises a first repeating unit in which R 4  is hydrogen, so that COOR 4  is a pendant free carboxylic acid group, and a second repeating unit in which R 4  is an alkyl group containing up to 30 carbon atoms so that COOR 4  is a pendant carboxylate group. 
     
     
         15 . The polymer of  claim 14 , wherein between about 1 and about 50% of the AA groups have pendant free carboxylic acid groups. 
     
     
         16 . The polymer of  claim 3 , wherein at least 50% of the Ar groups are substituted with two to four atoms selected from the group consisting of iodine atoms and bromine atoms. 
     
     
         17 . The polymer of  claim 3 , wherein R 1  is —CH 2 —CH 2 —. 
     
     
         18 . The polymer of  claim 3 , wherein X 1 , X 2  and X 3  are all oxygen. 
     
     
         19 . The polymer of  claim 3 , characterized by being a polycarbonate, polyester, poly(phosphazine), poly(phosphoester), poly(iminocarbonate), polyether, polyurethane, poly(carbamate), poly(thiocarbonate), poly(carbonodithionate) or poly(thiocarbamate). 
     
     
         20 . The polymer of  claim 3 , characterized by being a polyalkylene oxide block copolymer. 
     
     
         21 . The polymer of  claim 3 , wherein R 1  is —CH 2 —CH 2 — or —CH═CH—, X 1 , X 2  and X 3  are O and Ar is a phenyl group optionally substituted with two to four atoms selected from the group consisting of iodine atoms and bromine atoms. 
     
     
         22 . A polymer according to  claim 3  comprising a repeating unit having a structure selected from Formula II and Formula IIa: 
       
         
           
           
               
               
           
         
       
       wherein A is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein R 10  is selected from the group consisting of H, and optionally substituted alkyl, heteroalkyl, alkenyl and heteroalkenyl groups containing from one to 30 carbon atoms, and R 12  is selected from the group consisting of optionally substituted alkyl, heteroalkyl, alkenyl and heteroalkenyl groups containing from one to 18 carbon atoms and alkylaryl, heteroalkylaryl, alkenylaryl and heteroalkenylary groups containing from three to 12 carbon atoms. 
       
     
     
         23 . A polymer according to  claim 3 , further comprising polyalkylene oxide block repeating unit having a structure according to Formula III:
   B-A 2   (III)
   
       wherein B is —O—((CHR 6 ) p —O) q —; each R 6  is independently H or C 1  to C 3  alkyl; p is an integer in the range of one to about 4; q is an integer in the range of one to about 100; and A 2  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein R 10  is selected from the group consisting of H and optionally substituted alkyl, heteroalkyl, alkenyl and heteroalkenyl groups containing from one to 30 carbon atoms, and R 12  is selected from the group consisting of optionally substituted alkyl, heteroalkyl, alkenyl and heteroalkenyl groups containing from one to 18 carbon atoms and alkylaryl, heteroalkylaryl, alkenylaryl and heteroalkenylary groups containing from three to 12 carbon atoms. 
       
     
     
         24 .- 25 . (canceled) 
     
     
         26 . A load-bearing medical implant comprising the polymer of  claim 3 . 
     
     
         27 . A drug delivery implant, embolotherapy product, hernia repair mesh, envelope of the implantation of a cardiac device, bridging material, tissue sealant, adhesion prevention material, graft for nerve regeneration, implantable organ support or tissue engineering scaffold comprising the polymer of  claim 5 . 
     
     
         28 .- 33 . (canceled) 
     
     
         34 . A compound having the structure of formula IV or formula IVa: 
       
         
           
           
               
               
           
         
         for which the variables are defined as follows:
 Ar is a phenyl ring that optionally substituted with from one to four substituents independently selected from the group consisting of halogen, halomethyl, halomethoxy, methyl, methoxy, thiomethyl, nitro, sulfoxide and sulfonyl; 
 R 1  is selected from the group consisting of optionally substituted alkyl, heteroalkyl, alkenyl and heteroalkenyl groups containing from one to ten carbon atoms; 
 
         X 1 , X 2  and X 3  are independently selected from the group consisting of O, S and NR 3 ;
 R 2  is selected from the group consisting of hydrogen and alkyl groups containing from one to thirty carbon atoms bonded only to N, or R 2a  is an alkylene group covalently bonded to both the NR 2  nitrogen atom and AA, so that —N—R 2a -AA- define a heterocyclic ring; 
 R 3  is selected from the group consisting of hydrogen and alkyl groups containing from one to thirty carbon atoms; 
 AA has a pendant COOR 4  group in which R 4  is selected from the group consisting of hydrogen, alkyl, heteroalkyl and alkylaryl groups containing up to 30 carbon atoms and alkyl-terminated poly(alkylene oxide) groups of molecular weight 100 to 10,000; and 
 
       
       AA and X 3 H of Formula I are selected so that (R 2 —HN-)AA-X 3 H defines an —X 3 H substituted amino acid and AA and X 3 H of Formula Ia are selected so 
       
         
           
           
               
               
           
         
       
       defines an X 3 H— substituted amino acid; 
       wherein said Formula IV and Formula IVa variables are selected so that said compound has a solubility in phosphate buffered saline (PBS) (0.1 M, pH 7.4) at 37° C. greater than about 3 mg/mL. 
     
     
         35 . A compound having the structure of formula IV or formula IVa: 
       
         
           
           
               
               
           
         
         for which the variables are defined as follows:
 Ar is a phenyl ring that is optionally substituted with from one to four substituents independently selected from the group consisting of halogen, halomethyl, halomethoxy, methyl, methoxy, thiomethyl, nitro, sulfoxide and sulfonyl; 
 R 1  is selected from the group consisting of optionally substituted alkyl, heteroalkyl, alkenyl and heteroalkenyl groups containing from one to ten carbon atoms; 
 
         X 1 , X 2  and X 3  are independently selected from the group consisting of O, S and NR 3 ;
 R 2  is selected from the group consisting of hydrogen and alkyl groups containing from one to thirty carbon atoms bonded only to N, or R 2a  is an alkylene group covalently bonded to both the NR 2  nitrogen atom and AA, so that —N—R 2a -AA- define a heterocyclic ring; 
 R 3  is selected from the group consisting of hydrogen and alkyl groups containing from one to thirty carbon atoms; 
 AA has a pendant COOR 4  group in which R 4  is selected from the group consisting of hydrogen, alkyl, heteroalkyl and alkylaryl groups containing up to 30 carbon atoms and alkyl-terminated poly(alkylene oxide) groups of molecular weight 100 to 10,000; and 
 AA and X 3 H of Formula I are selected so that (R 2 —HN-)AA-X 3 H defines an —X 3 H substituted amino acid and AA and X 3 H of Formula Ia are selected so 
 
       
       
         
           
           
               
               
           
         
         defines an X 3 H— substituted amino acid; 
       
       wherein said Formula IV and Formula IVa variables are selected so that said compound has a solubility in phosphate buffered saline (PBS) (0.1 M, pH 7.4) at 37° C. less than about 3 mg/mL. 
     
     
         36 .- 40 . (canceled)