Polymeric coupling agents and pharmaceutically-active polymers made therefrom

Abstract

A pharmaceutically-active polymeric compound of the general formula (I), Y-[Y n -LINK B-X] m -LINK B  (I) wherein (i) X is a coupled biological coupling agent of the general formula (II) Bio-LINK A-Bio  (II) wherein Bio is a biologically active agent fragment or precursor thereof linked to LINK A through a hydrolysable covalent bond; and LINK A is a coupled central flexible linear first segment of <2000 theoretical molecular weight linked to each of said Bio fragments; (ii) Y is LINK B-OLIGO; wherein (a) LINK B is a coupled second segment linking one OLIGO to another OLIGO and an OLIGO to X or precursor thereof; and (b) OLIGO is a short length of polymer segment having a molecular weight of less than 5,000 and comprising less than 100 monomeric repeating units; (iii) m is 1-40; and (iv) n is selected from 2-50. The compounds are useful as biomaterials, particularly, providing antibacterial activity in vivo. Also provided are biological coupling agents useful as intermediates in the preparation of the pharmaceutically-active polymeric compounds.

1 . A compound of the general formula (III)
   PBio-LINK A-PBio  (III)
   wherein   (i) each PBio (a) is a biologically active agent fragment or precursor thereof linked to LINK A through a hydrolysable covalent bond and (b) comprises a primary or secondary amine functional group to permit step growth polymerization; and   (ii) LINK A is a coupled central flexible linear segment having a molecular weight of 60 to 2000 Daltons, is formed from a diol or diamine, and is linked to each of said PBio fragments.   
     
     
         2 . A compound as defined in  claim 1 , wherein LINK A is linked to Bio by carboxylic ester, amide or sulfonamide links. 
     
     
         3 . A compound as defined in  claim 1 , wherein LINK A has a molecular weight selected from 60-700. 
     
     
         4 . A compound as defined in  claim 1 , wherein said biologically active agent is selected from an anti-coagulant, an anti-inflammatory agent, an anti-proliferative agent, an antimicrobial agent, an anti-thrombic agent and a hydrolysable precursor fragment thereof. 
     
     
         5 . A compound as defined in  claim 4 , wherein said biologically active agent is an anti-microbial agent selected from ciprofloxacin and norfloxacin. 
     
     
         6 . A compound as defined in  claim 4 , wherein said biologically active agent is an antiflammatory agent selected from amfenac, and aceclofenac. 
     
     
         7 . A compound as defined in  claim 4 , wherein said biologically active agent is an anti-thrombic agent selected from bromofenac, tirofiban and lotrafiban. 
     
     
         8 . A compound as defined in  claim 4 , wherein said biologically active agent is an anti-proliferation agent selected from acivicin and alkeren. 
     
     
         9 . A compound as defined in  claim 1 , wherein LINK A is formed from a diol or diamine selected from ethylene glycol; butane diol; hexane diol; hexamethylene diol; 1,5 pentanediol; 2,2-dimethyl-1,3 propanediol; 1,4-cyclohexane diol; 1,4-cyclohexanedimethanol; tri(ethylene glycol); poly(ethylene oxide)diamine; lysine esters; silicone diols; carbonate diols; hexamethylene diamine; 1,2-diamino-2 methylpropane; 3,3,-diamino-N-methyldipropylamine; 1,4 diaminobutane; 1,7 diaminoheptane; and 1,8 diaminooctane. 
     
     
         10 . A compound of the general formula (III)
   PBio-LINK A-PBio  (III)
   wherein   (i) PBio is a biologically active agent fragment or precursor thereof linked to LINK A through a hydrolysable covalent bond selected from carboxylic ester, amide, and sulfonamide links and PBio comprises a primary or secondary amine functional group to permit step growth polymerization; and   (ii) LINK A is a coupled central flexible linear segment formed from a diol or diamine selected from ethylene glycol; butane diol; hexane diol; hexamethylene diol; 1,5 pentanediol; 2,2-dimethyl-1,3 propanediol; 1,4-cyclohexane diol; 1,4-cyclohexanedimethanol; tri(ethylene glycol); poly(ethylene oxide)diamine; lysine esters; silicone diols; carbonate diols; ethylene diamine, hexamethylene diamine; 1,2-diamino-2 methylpropane; 3,3,-diamino-N-methyldipropylamine; 1,4 diaminobutane; 1,7 diaminoheptane; and 1,8 diaminooctane.   
     
     
         11 . A compound as defined in  claim 10 , wherein said biologically active agent is selected from ciprofloxacin, norfloxacin, amfenac, aceclofenac, bromofenac, tirofiban, lotrafiban, acivicin, and alkeren. 
     
     
         12 . A compound as defined in  claim 11 , wherein said biologically active agent is ciprofloxacin or norfloxacin. 
     
     
         13 . A compound of the general formula (III)
   PBio-LINK A-PBio  (III)
   wherein PBio is formed from a fluoroquinolone comprising at least two functional groups selected from hydroxyl, amine, carboxylic acid, and sulfonic acid and wherein one of said functional groups can be used to permit step growth polymerization- and where PBio is linked to LINK A through a hydrolysable covalent bond;   and LINK A is a coupled central flexible linear first segment of <2000 theoretical molecular weight linked to each of said PBio fragments, wherein LINK A contains within itself polyalkyl, polyethylene oxide, polyalkylene oxide, polyamides, polyester, polyvinyl, or polysiloxanes.   
     
     
         14 . A compound as defined in  claim 13 , wherein LINK A is linked to Bio by carboxylic ester, amide or sulfonamide links. 
     
     
         15 . A compound as defined in  claim 13 , wherein LINK A has a molecular weight selected from 60-700. 
     
     
         16 . A compound as defined in  claim 13 , wherein LINK A is formed from a dihydroxyl or diamine selected from ethylene glycol; butane diol; hexane diol; hexamethylene diol; 1,5 pentanediol; 2,2-dimethyl-1,3 propanediol; 1,4-cyclohexane diol; 1,4-cyclohexanedimethanol; tri(ethylene glycol); poly(ethylene oxide)diamine; lysine esters; silicone diols; carbonate diols; ethylene diamine, hexamethylene diamine; 1,2-diamino-2 methylpropane; 3,3,-diamino-N-methyldipropylamine; 1,4 diaminobutane; 1,7 diaminoheptane; and 1,8 diaminooctane. 
     
     
         17 . A compound as defined in  claim 13 , wherein said fluoroquinolone is selected from ciprofloxacin and norfloxacin. 
     
     
         18 . A compound as defined in  claim 17 , wherein LINK A is tri(ethylene glycol). 
     
     
         19 . A compound as defined in  claim 17 , wherein said compound is selected from the group consisting of:
 (a) NORF-TEG-NORF, wherein Bio is norfloxacin (NORF) and LINK A is tri(ethylene glycol) (TEG);   (b) CIPRO-TEG-CIPRO, wherein Bio is ciprofloxacin (CIPRO) and LINK A is tri(ethylene glycol) (TEG);   (c) CIPRO-HDL-CIPRO, wherein Bio is ciprofloxacin (CIPRO) and LINK A is hexane diol (HDL); and   (d) NORF-HDA-NORF, wherein Bio is norfloxacin (NORF) and LINK A is hexamethylene diamine.   
     
     
         20 . A compound as defined in  claim 19 , wherein said compound is CIPRO-TEG-CIPRO.