Synthesis of Polyanhydrides

Abstract

The present invention provides a method for forming compounds of Formula HO—C(═O)R 1 —X—R 2 —X—R 1 —C(═O)—O—H wherein compound (I) can be polymerized to provide a polymer that contains therapeutically active compounds. In the compounds of the invention, each R 1 is group that will provide the therapeutically active compound upon hydrolysis of the polymer; each X is independently an ester linkage or an amide linkage; and R 2 is a linking group.

1 . A polymer comprising a backbone that has a plurality of anhydride bonds and a plurality of aryl containing groups, wherein the polymer has an average molecular weight of at least about 40,000 daltons. 
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . The polymer of  claim 1  that has an average molecular weight of at least about 100,000 daltons. 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . The polymer of  claim 1  wherein each aryl containing group is a group that will yield a therapeutic agent upon hydrolysis of the polymer. 
     
     
         12 . The polymer of  claim 11  wherein each therapeutic agent is independently an anti-inflammatory, analgesic, anesthetic, or antipyretic compound. 
     
     
         13 . The polymer of  claim 12  wherein each therapeutic agent is an anti-inflammatory compound. 
     
     
         14 . The polymer of  claim 12  wherein each therapeutic agent is salicylic acid, 4-aminosalicylic acid, 5-aminosalicylic acid, 4-(acetylamino)salicylic acid, 5-(acetylamino)salicylic acid, 5-chlorosalicylic acid, salicylsalicylic acid (salsalate), 4-thiosalicylic acid, 5-thiosalicylic acid, or 5-(2,4-difluorophenyl)salicylic acid (diflunisal), 4-trifluoromethylsalicylic acid sulfasalazine, dichlofenac, penicillamine, balsalazide, olsalazine, mefenamic acid, carbidopa, levodopa, etodolac, cefaclor, or captopril. 
     
     
         15 . A polymer comprising a backbone that comprises a plurality of groups of Formula (IV)
   -[(═Y)R 1 —X—R 2 —X—R 1 —C(═Y)—O]—  (IV)   wherein each R 1  is independently an aryl containing group; Each Y is independently O or S; each X is independently an amide linkage, an ester linkage, a thioamide linkage, a thioester linkage or a thioamide linkage; and R 2  is a linking group; wherein the polymer has an average molecular weight of at least about 40,000 daltons.   
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . The polymer of  claim 15  that has an average molecular weight of at least about 100,000 daltons. 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . The polymer of  claim 15  wherein each R 1  is derived from a compound having the formula: 
       
         
           
           
               
               
           
         
         wherein R 3  is an hydroxy, amine, thiol group; R 4  is hydrogen, halo, NHR 5 , or aryl optionally substituted with hydroxy, halo or haloC 1-4 alkyl; and R 5  is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, aryl, heteroaryl, aryl(C 1 -C 6 )alkyl, or heteroaryl(C 1 -C 6 )alkyl or —C(O)C 1-4 alkyl. 
       
     
     
         25 . The polymer of  claim 15  wherein each R 1  is an aryl containing group that will yield a therapeutic agent upon breakdown of the polymer. 
     
     
         26 . The polymer of any of  claim 27  wherein each therapeutic agent is independently an anti-inflammatory, analgesic, anesthetic, antipyretic, antiseptic or antimicrobial compound comprising a carboxylic acid group and at least one amine, thiol, or hydroxy group. 
     
     
         27 . The polymer of  claim 25  wherein each therapeutic agent is independently an anti-inflammatory compound. 
     
     
         28 . The polymer of  claim 26  wherein each therapeutic agent is independently salicylic acid, 4-aminosalicylic acid, 5-aminosalicylic acid, 4-(acetylamino)salicylic acid, 5-(acetylamino)salicylic acid, 5-chlorosalicylic acid, salicylsalicylic acid (salsalate), 4-thiosalicylic acid, 5-thiosalicylic acid, or 5-(2,4-difluorophenyl)salicylic acid (diflunisal), 4-trifluoromethylsalicylic acid sulfasalazine, dichlofenac, penicillamine, balsalazide, olsalazine, mefenamic acid, carbidopa, levodopa, etodolac, cefaclor, or captopril. 
     
     
         29 . The polymer of  claim 15  wherein R 2  is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 25 carbon atoms, wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms is optionally replaced by (—O—) or (—NR—), or an amino acid derivative or a peptide, and wherein the chain is optionally substituted on carbon with one or more (e.g. 1, 2, 3, or 4) substituents selected from the group consisting of (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy. 
     
     
         30 . The polymer of  claim 15  wherein R 2  is a divalent, branched or unbranched, hydrocarbon chain, having from 1 to 25 carbon atoms, wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms is optionally replaced by (—O—) or (—NR—), or an amino acid derivative or a peptide, and wherein the chain is optionally substituted on carbon with one or more (e.g. 1, 2, 3, or 4) substituents selected from the group consisting of (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy. 
     
     
         31 . The polymer of  claim 15  wherein R 2  is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 3 to 20 carbon atoms, wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms is optionally replaced by (—O—) or (—NR—), or an amino acid derivative or a peptide, and wherein the chain is optionally substituted on carbon with one or more (e.g. 1, 2, 3, or 4) substituents selected from the group consisting of (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy. 
     
     
         32 . The polymer of  claim 15  wherein R 2  is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 4 to 15 carbon atoms, wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms is optionally replaced by (—O—) or (—NR—), or an amino acid derivative or a peptide. 
     
     
         33 . The polymer of  claim 15  wherein R 2  is a divalent, branched or unbranched, hydrocarbon chain, having from 3 to 20 carbon atoms. 
     
     
         34 . The polymer of  claim 15  wherein R 2  is a divalent, branched or unbranched, hydrocarbon chain, having from 4 to 15 carbon atoms. 
     
     
         35 . The polymer of  claim 15  wherein R 2  is an amino acid derivative. 
     
     
         36 . The polymer of  claim 15  wherein R 2  is a peptide. 
     
     
         37 . The polymer of  claim 15  wherein each X is an amide linkage. 
     
     
         38 . The polymer of  claim 15  wherein each X is an ester linkage. 
     
     
         39 . The polymer of  claim 15  that comprises a plurality of repeating units of Formula (IV). 
     
     
         40 . The polymer of  claim 15  wherein each R 1  is a group that will yield a salicylate upon breakdown of the polymer; each X is independently an amide linkage or an ester linkage; and R 2  is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 15 carbon atoms. 
     
     
         41 . The polymer of  claim 40  wherein the salicylate is salicylic acid, 4-amino-salicylic acid, 5-aminosalicylic acid, 4-(acetylamino)salicylic acid, 5-(acetylamino)-salicylic acid, 5-chlorosalicylic acid, salicylsalicylic acid (salsalate), 4-thiosalicylic acid, 5-thiosalicylic acid, or 5-(2,4-difluorophenyl)salicylic acid (diflunisal), 4-trifluoromethylsalicylic acid sulfasalazine, dichlofenac, penicillamine,balsalazide, olsalazine, mefenamic acid, carbidopa, levodopa, etodolac, cefaclor, or captopril. 
     
     
         42 . The polymer of  claim 41  wherein the salicylate is salicylic acid. 
     
     
         43 . The polymer of  claim 42  wherein each X is an ester linkage; and R 2  is a divalent, branched or unbranched hydrocarbon chain, having from 1 to 10 carbon atoms. 
     
     
         44 . The polymer of  claim 41  wherein the salicylate is -(2,4-difluorophenyl)-salicylic acid acid. 
     
     
         45 . The polymer of  claim 44  wherein each X is an ester linkage, R 2  is a divalent branched or unbranched hydrocarbon chain having from 1 to 15 carbon atoms.