US 20020071822A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2002/0071822 A1 Uhrich (43) Pub. Date: Jun. 13, 2002

(54) THERAPEUTIC POLYESTERS AND provisional application No. 60/261,337, filed on Jan. POLYAMIDES 12, 2001. (76) Inventor: Kathryn E. Uhrich, Hoboken, NJ (US) Publication Classification Correspondence Address: (51) Int. Cl." ...... A61K 31/785; A61K 31/765; SCHWEGMAN, LUNDBERG, WOESSNER & C08G 63/685; CO8G 63/688 KLUTH, PA. (52) U.S. Cl...... 424/78.37; 528/288; 528/293 P.O. BOX 2938 MINNEAPOLIS, MN 55402 (US) (57) ABSTRACT (21) Appl. No.: 09/917,194 Polymers (i.e. polyesters, polyamides, and polythioesters or (22) Filed: Jul. 27, 2001 a mixture thereof) which degrade hydrolytically into bio logically active compounds are provided. Methods of pro Related U.S. Application Data ducing these polymers, intermediates useful for preparing these polymers, and methods of using these polymers to (63) Non-provisional of provisional application No. deliver biologically active compounds to a host are also 60/220,707, filed on Jul. 27, 2000. Non-provisional of provided. US 2002/0071822 A1 Jun. 13, 2002

THERAPEUTIC POLYESTERS AND POLYAMDES 0012. The invention also provides processes and inter mediates disclosed herein that are useful for preparing a PRIORITY OF INVENTION polymer of the invention.

0001. This application claims priority from U.S. Provi DETAILED DESCRIPTION OF THE sional Application No. 60/220,707, filed Jul. 27, 2000 and INVENTION U.S. Provisional Application No. 60/261,337, filed Dec. 1, 2001, which are incorporated herein by reference. 0013 Definitions 0014. The following definitions are used, unless other BACKGROUND OF THE INVENTION wise described: halo is fluoro, chloro, bromo, or iodo. Alkyl, 0002 Polyesters are used routinely by those skilled in the alkoxy, etc. denote both Straight and branched groups, but art in various drug delivery Systems. reference to an individual radical Such as “propyl” embraces only the Straight chain radical, a branched chain isomer Such 0003) For example, U.S. Pat. No. 5,942,252 describes a as "isopropyl being Specifically referred to. Aryl denotes a microcapsule comprising as its biocompatible excipient a phenyl radical or an ortho-fused bicyclic carbocyclic radical poly(lactide-co-glycolide), poly(lactide), poly(glycolide), having about nine to ten ring atoms in which at least one ring copolyoxalate, polycaprolactone, poly(lactide-co-caprolac is aromatic. Heteroaryl encompasses a radical attached via a tone), poly(esteramide), polyorthoester, poly(p-hydroxybu ring carbon of a monocyclic aromatic ring containing five or tyric) acid and/or polyanhydride for use in delivering anti Six ring atoms consisting of carbon and one to four heteroa gens or vaccines into and through mucosally-associated toms each Selected from the group consisting of non lymphoid tissue. peroxide oxygen, Sulfur, and NCX) wherein X is absent or is 0004 WO 99/29885 describes a process for degrading H, O,(C-C)alkyl, phenyl or benzyl, as well as a radical of poly(ester-amides) and poly(ester-urethanes) encapsulating an Ortho-fused bicyclic heterocycle of about eight to ten ring chemicals, drugs, enzymes, microorganisms and Seeds by atoms derived therefrom, particularly a benz-derivative or introducing the polymer to an aqueous nutrient Solution and one derived by fusing a propylene, trimethylene, or tetram inoculating the Solution with a culture containing a Selected ethylene diradical thereto. bacteria. 0015 The term ester linkage means -OC(=O)- or 0005 WO 98/36013 describes aliphatic-aromatic dihy -C(=O)C)-; the term thioester linkage means droxy compounds for use as controlled drug delivery Sys -SC(=O)- or -C(=O)S-; and the term amide linkage temS. means-N(R)C(=O)- or-C(=O)N(R)-, wherein each R is a Suitable organic radical, Such as, for example, hydro 0006 WO 97/39738 describes preparation of micropar gen, (C-C)alkyl, (C-C)cycloalkyl, (C- ticles of a Sustained release ionic conjugate comprising a C.)cycloalkyl(C-C)alkyl, aryl, heteroaryl, aryl(C- free carboxyl group containing biodegradable polymers and C.)alkyl, or heteroaryl(C-C)alkyl. a free amino group-containing drug. 0016. The term “amino acid,” comprises the residues of SUMMARY OF THE INVENTION the natural amino acids (e.g. Ala, Arg, ASn, Asp, Cys, Glu, Gln, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, 0007 Polyesters, polythioesters, and polyamides which and Val) in D or L form, as well as unnatural amino acids degrade into useful biologically active compounds have now (e.g. phosphoSerine, phosphothreonine, phosphotyrosine, been developed. Accordingly, the invention provides a poly hydroxyproline, gamma-carboxyglutamate, hippuric acid, mer of the invention which is polymer comprising a back octahydroindole-2-carboxylic acid, Statine, 1,2,3,4-tetrahy bone, wherein the backbone comprises ester, thioester, or droisoquinoline-3-carboxylic acid, penicillamine, omithine, amide linkages, and wherein the backbone comprises one or citruline, a-methyl-alanine, para-benzoylphenylalanine, more groups that will yield a biologically active compound phenylglycine, propargylglycine, Sarcosine, and tert-butylg upon hydrolysis of the polymer. lycine). The term also comprises natural and unnatural amino acids bearing a conventional amino protecting group 0008. The invention also provides a pharmaceutical com (e.g. acetyl or benzyloxycarbonyl), as well as natural and position comprising a polymer of the invention and a unnatural amino acids protected at the carboxy terminus pharmaceutically acceptable carrier. (e.g. as a (C-C)alkyl, phenyl or benzyl ester or amide; or 0009. The invention also provides a therapeutic method as an O-methylbenzyl amide). Other Suitable amino and for treating a disease in an animal comprising administering carboxy protecting groups are known to those skilled in the to an animal in need of Such therapy, an effective amount of art (See for example, Greene, T. W.; Wutz, P. G. M. a polymer of the invention. “Protecting Groups. In Organic Synthesis” second edition, 0.010 The invention also provides a method of delivering 1991, New York, John Wiley & Sons, Inc., and references a biologically active compound to a host comprising admin cited therein). istering to the host a biocompatible and biodegradable 0017. The term “host” includes animals and plants. polymer of the invention, which degrades into the biologi 0018. The term “peptide' describes a sequence of 2 to 35 cally active compound. amino acids (e.g. as defined hereinabove) or peptidyl resi 0.011 The invention provides a polymer of the invention dues. The Sequence may be linear or cyclic. For example, a for use in medical therapy, as well as the use of a polymer cyclic peptide can be prepared or may result from the of the invention for the manufacture of a medicament useful formation of disulfide bridges between two cysteine residues for the treatment of a disease in a mammal, Such as a human. in a Sequence. Preferably a peptide comprises 3 to 20, or 5 US 2002/0071822 A1 Jun. 13, 2002

to 15 amino acids. Peptide derivatives can be prepared as controlled release Source for a biologically active com disclosed in U.S. Pat. Nos. 4,612,302; 4.853,371; and 4,684, pound, or as a medium for the localized delivery of a 620, or as described in the Examples hereinbelow. Peptide biologically active compound to a Selected Site. For Sequences Specifically recited herein are written with the example, the polymers of the invention can be used for the amino terminus on the left and the carboxy terminus on the localized delivery of a therapeutic agent to a Selected Site right. within the body of a human patient (i.e. within or near a 0019 Polymers of the Invention tumor), where the degradation of the polymer provides localized, controlled, release of the therapeutic agent. 0020. The biocompatible, biodegradable polyesters, polythioesters, and polyamides of the invention are useful in 0027 Biologically Active Compounds a variety of applications where delivery of a biologically active compound is desired. Examples of Such applications 0028. The term “biologically active compound” includes include, but are not limited to, medical, dental and cosmetic therapeutic agents that provide a therapeutically desirable SCS. effect when administered to an animal (e.g. a mammal, Such as a human). Biologically active compounds that can be 0021. The polymers of the invention may be prepared in incorporated into the polymers of the invention possess at accordance with methods commonly employed in the field of Synthetic polymers to produce a variety of useful products least two functional groups that can each be incorporated with valuable physical and chemical properties. The poly into an ester, thioester, or amide linkage of a polymer (as mers can be readily processed into pastes or Solvent cast to discussed in detail below), Such that, upon hydrolysis of the yield films, coatings, microSpheres and fibers with different polymer, the therapeutic agent is obtained. These groups can geometric shapes for design of various medical implants, independently be a hydroxy group (-OH), a mercapto and may also be processed by compression molding and group (-SH), an amine group (-NHR), or a carboxylic extrusion. acid (-COOH). 0022 Polyesters and polyamides prepared in accordance 0029. The biologically active compounds can also com with the present invention have average molecular weights prise other functional groups (including hydroxy groups, of about 1500 Daltons up to about 100,000 Daltons, calcu mercapto groups, amine groups, and carboxylic acids, as lated by Gel Permeation Chromatography (GPC) relative to well as others) that can be used to modify the properties of narrow molecular weight polystyrene Standards. Preferred the polymer (e.g. for branching, for cross linking, for polyesters and polyamides have average molecular weights appending other molecules (e.g. another biologically active of about 1500 Daltons, up to about 50,000 Daltons calcu compound) to the polymer, for changing the solubility of the lated by Gel Permeation Chromatography (GPC) relative to polymer, or for effecting the biodistribution of the polymer). narrow molecular weight polystyrene Standards. Preferred Lists of therapeutic agents can be found, for example, in: polyesters and polyamides have average molecular weights Physicians Desk Reference, 55 ed., 2001, Medical Eco of about 1500 Daltons, up to about 35,000 Daltons. nomics Company, Inc., Montvale, N.J.; USPN Dictionary of USAN and International Drug Names, 2000, The United 0023 Medical implant applications include the use of States Pharmacopeial Convention, Inc., Rockville, Md., and polyesters, polythioesters, or polyamides to form shaped The Merck Index, 12 ed., 1996, Merck & Co., Inc., White articles Such as vascular grafts and Stents, bone plates, house Station, N.J. One skilled in the art can readily select Sutures, implantable Sensors, implantable drug delivery therapeutic agents that possess the necessary functional devices, Stents for tissue regeneration, and other articles that groups for incorporation into the polymers of the invention decompose into non-toxic components within a known time from these lists. period. 0030 Therapeutic agents that can be incorporated into 0024 Polymers of the present invention can also be the polymers of the invention include suitably functionalized incorporated into oral formulations and into products Such as analgesics or general or local anesthetics, anti-convulsants, skin moisturizers, cleansers, pads, plasters, lotions, creams, anti-diabetic agents, anti-fibrotic agents, anti-infectives, gels, ointments, Solutions, shampoos, tanning products and anti-bacterials, anti-fungals, anti-neoplastics, cardioprotec lipsticks for topical application. tive agents, cardiovascular agents, anti-thrombotics, central 0.025 Although the invention provides homopolymers nervous System Stimulants, cholinesterase inhibitors, con that are prepared from Suitably functionalized biologically traceptives, deodorants, dopamine receptor agonists, erectile active compounds, Applicant has discovered that the dysfunction agents, fertility agents, gastrointestinal agents, mechanical and hydrolytic properties of polymers compris gout agents, hormones, immunomodulators, immunoSup ing one or more biologically active compounds can be pressives, migraine agents, non-Steriodal anti-inflammatory drugs (NSAIDs), motion sickness agents, muscle relaxants, controlled by incorporating a linking group (L) into the nucleoside analogs, neurodegenerative agents (e.g., Parkin polymer backbone. Son's disease), obesity agents, ophthalmic agents, 0.026 Preferably, the polymers of the invention comprise Osteoporosis agents, parasympatholytics, parasympathom backbones wherein biologically active compounds and metics, anti-anesthetics, prostaglandins, psychotherapeutic linker groups are bonded together through ester linkages, agents, respiratory agents, Sedatives, hypnotics, skin and thioester linkages, amide linkages, or a mixture thereof. Due mucous membrane agents, Smoking Sessation agents, Sym to the presence of the ester, thioester, and/or amide linkages, patholytics, urinary tract agents, vaginal agents, and vasodi the polymers can be hydrolyzed under physiological condi lators (see Physicians’ Desk Reference, 55 ed., 2001, Medi tions to provide the biologically active compounds. Thus, cal Economics Company, Inc., Montvale, N.J., pages 201 the polymers of the invention can be particularly useful as a 202). US 2002/0071822 A1 Jun. 13, 2002

0031 Linking Group “L” midine, podophyllinic acid 2-ethylhydrazine; acriflavine; 0.032 The nature of the linking group “L” in a polymer of chloroaZOdin, arsphenamine, amicarbilide, aminoquinuride; the invention is not critical provided the polymer of the quinapril, Oxymorphone, buprenorphine, butorphanol, nal invention possesses acceptable mechanical properties and buphine. Streptozocin, doxorubicin; daunorubicin; plicamy release kinetics for the Selected therapeutic application. The cin, idarubicin, mitomycin C, pentostatin, mitoxantrone; linking group L is typically a divalent organic radical having cytarabine; fludarabine phosphate, floXuridine, cladribine; a molecular weight of from about 25 daltons to about 400 6-mercaptopurine; thioguanine; capecitabine, docetaxel, daltons. More preferably, L has a molecular weight of from etoposide, gemcitabine; topotecan; Vinorelbine, Vincristine; about 40 daltons to about 200 daltons. Vinblastine, teniposide, melphalan; methotrexate, 2-p -Sul 0033. The linking group L typically has a length of from fanilyanilinoethanol; 4,4'-Sulfinyldianiline, 4-Sulfanilami about 5 angStroms to about 100 angStroms using Standard dosalicylic acid; acediasulfone, acetosulfone, amikacin; bond lengths and angles. More preferably, the linking group amphotericin B, amplicillin, apalcillin, apicycline, apramy L has a length of from about 10 angstroms to about 50 cin; arbekacin; aspoxicillin; azidamfenicol; aztreonam, baci angStroms. tracin; bambermycin(s); biapenem; brodimoprim; butirosin; capreomycin; carbenicillin; carbomycin; carumonam, 0034. The linking group may be biologically inactive, or cefadroxil, cefamandole, cefatrizine, cefbuperaZone, cefcli may itself possess biological activity. The linking group can din, cefdinir, cefditoren, cefepime, cefetamet, cefixime; also comprise other functional groups (including hydroxy cefinenoXime, cefminox, cefodizime, cefonicid, cefopera groups, mercapto groups, amine groups, carboxylic acids, as Zone, ceforanide, cefotaxime, cefotetan, cefotiam, cefoZo well as others) that can be used to modify the properties of pran, cefpimizole, cefpiramide, cefpirome, cefprozil; the polymer (e.g. for branching, for cross linking, for cefroXadine, cefteram, ceftibuten, cefuZonam, cephalexin; appending other molecules (e.g. another biologically active cephaloglycin; cephalosporin C, cephradine, chlorampheni compound) to the polymer, for changing the Solubility of the col, chlortetracycline; clinafloxacin; clindamycin; clomocy polymer, or for effecting the biodistribution of the polymer). cline, colistin; cyclacillin; dapSone; demeclocycline; diathy 0035) Specific And Preferred Values moSulfone, dibekacin; dihydroStreptomycin; dirithromycin; 0.036 Specific and preferred values listed herein for radi doxycycline; enoxacin; enviomycin; epicillin, erythromy cin; flomoxef; fortimicin(s); gentamicin(s); glucosulfone cals, Substituents, groups, and ranges, are for illustration Solasulfone, gramicidin S; gramicidin(s); grepafloxacin; only; they do not exclude other defined values or other guamecycline; hetacillin, isepamicin; joSamycin; kanamy values within defined ranges for the radicals and Substitu cin(s), leucomycin(s), lincomycin; lomefloxacin; lucenSo entS. mycin; lymecycline, meclocycline, meropenem; methacy 0037 Specifically, (C-C)alkyl can be methyl, ethyl, cline; micronomicin; midecamycin(s); minocycline; propyl, isopropyl, butyl, iso-butyl, Sec-butyl, pentyl, 3-pen moxalactam, mupirocin, nadifloxacin; natamycin; neomy tyl, or hexyl, (C-C)cycloalkyl can be cyclopropyl, cin, netilmicin; norfloxacin, oleandomycin; oxytetracycline; cyclobutyl, cyclopentyl, O cyclohexyl, (C- p-Sulfanilylbenzylamine; panipenem; paromomycin; paZu C)cycloalkyl(C-C)alkyl can be cyclopropylmethyl, floxacin; penicillin N, pipacycline, pipemidic acid; poly cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, myxin; primycin, quinacillin, ribostamycin, rifamide; 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, rifampin; rifamycin SV, rifapentine, rifaximin, ristocetin; or 2-cyclohexylethyl, (C-C)alkoxy can be methoxy, ritipenem; rokitamycin; rollitetracycline, rosaramycin; ethoxy, propoxy, iSopropoxy, butoxy, iSo-butoxy, Sec-bu roXithromycin; SalazOSulfadimidine, Sancycline, Sisomicin; toxy, pentoxy, 3-pentoxy, or hexyloxy, (C-C)alkanoyl can Sparfloxacin; Spectinomycin; Spiramycin; Streptomycin; Suc be acetyl, propanoyl or butanoyl, (C-C)alkoxycarbonyl cisulfone, Sulfachrysoidine, Sulfaloxic acid; Sulfamidoch can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, rySoidine, Sulfanilic acid, Sulfoxone, teicoplanin; temafloxa isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, or cin; temocillin, tetroXoprim; thiamphenicol; thiazolsulfone, hexyloxycarbonyl, (C-C)alkylthio can be methylthio, eth thiostrepton, ticarcillin, tigemonam, tobramycin; toSufloxa ylthio, propylthio, isopropylthio, butylthio, isobutylthio, cin; trimethoprim; trospectomycin; trovafloxacin; tuberacti pentylthio, or hexylthio; (C-C)alkanoyloxy can be nomycin; Vancomycin; azaserine; candicidin(s); chlorphen acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pen esin; dermostatin(S); filipin; fungichromin; mepartricin; tanoyloxy, or hexanoyloxy, aryl can be phenyl, indenyl, or nyStatin; oligomycin(S); perimycin A; tubercidin;6-azauri naphthyl, and heteroaryl can be furyl, imidazolyl, triazolyl, dine, 6-diazo-5-oxo-L-norleucine, aclacinomycin(S); ancit triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyra abine; anthramycin; azacitadine, azaserine; bleomycin(s); Zolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-ox carubicin; carZinophillin A; chlorozotocin, chromomycin(s); ide), thienyl, pyrimidinyl (or its N-oxide), indolyl, iso denopterin, doxifluridine, edatrexate, eflomithine; ellip quinolyl (or its N-oxide) or quinolyl (or its N-oxide). tinium; enocitabine; epirubicin; mannomustine; menogaril; 0.038 Aspecific biologically active compound that can be mitobronitol; mitolactol, mopidamol, mycophenolic acid; incorporated into the polymers of the invention is atorvas nogalamycin; olivomycin(S); peplomycin; pirarubicin; piri tatin; enalapril, ranitidine, ciprofloxacin, pravastatin; trexim; prednimustine; procarbazine, pteropterin; puromy clarithromycin; cycloSporin; famotidine; leuprolide, acyclo cin; ranimustine; Streptonigrin; thiamiprine; Tomudex(E) (N- Vir, paclitaxel, azithromycin; lamivudine, budeSonide; 5-(1,4-Dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl albuterol; indinavir, metformin; alendronate, nizatidine, methylamino-2-thienylcarbonyl-L-glutamic acid), Zidovudine, carboplatin; metoprolol, amoxicillin; trimetrexate, tubercidin, ubenimex, Vindesline, Zorubicin; diclofenac, lisinopril, ceftriaxone, captopril; Salmeterol, Xin argatroban; coumetarol; dicoumarol, ethyl biscoumacetate; afoate, imipenem; cilastatin; benazepril, cefaclor, ceftazi ethylidene dicoumarol, iloprost, lamifiban; taprostene, tio dime; morphine, dopamine; bialamicol; fluvastatin; phena clomarol; tirofiban; amiprilose, bucillamine; gusperimus, US 2002/0071822 A1 Jun. 13, 2002 mycophenolic acid; procodazole, romurtide; Sirolimus cephradine, chloramphenicol, chlortetracycline, ciprofloxa (rapamycin); tacrolimus, butethamine; fenalcomine; cin, clarithromycin, clinafloxacin, clindamycin, clomocy hydroxytetracaine; naepaine; Orthocaine, piridocaine; Sali cline, colistin, cyclacillin, dapSone, demeclocycline, diathy cyl alcohol, 3-amino-4-hydroxybutyric acid; aceclofenac, moSulfone, dibekacin, dihydroStreptomycin, dirithromycin, alminoprofen; amfenac, bromfenac, bromosaligenin, doxycycline, enoxacin, enviomycin, epicillin, erythromycin, bumadizon; carprofen;diclofenac; diflunisal; ditazol; enfe flomoxef, fortimicin(s), gentamicin(s), glucosulfone Solas namic acid; etodolac, etofenamate; fendosal; fepradinol; ulfone, gramicidin S, gramicidin(s), grepafloxacin, guame flufenamic acid; gentisic acid; glucamethacin; glycol Sali cycline, he tacillin, imipenem, iSepamicin, josamycin, kana cylate; meclofenamic acid, mefenamic acid; meSalamine; mycin(s), leucomycin(s), lincomycin, lomefloxacin, niflumic acid; olSalazine; oxaceprol; S-adenosylmethionine; lucensomycin, lymecycline, meclocycline, meropenem, Salicylic acid; Salsalate, SulfaSalazine, or tolfenamic acid. methacycline, micronomicin, midecamycin(s), minocycline, moxalactam, mupirocin, nadifloxacin, natamycin, neomy 0039. A preferred biologically active compound suitable cin, netilmicin, norfloxacin, oleandomycin, oxytetracycline, for incorporation into polyesters of the invention is mor p-Sulfanilylbenzylamine, panipenem, paromomycin, paZu phine, dopamine, bialamicol, or tetracycline. floxacin, penicillin N, pipacycline, pipemidic acid, poly 0040. A preferred biologically active compound suitable myxin, primycin, quinacillin, ribostamycin, rifamide, for incorporation into polyamides of the present invention is rifampin, rifamycin SV, rifapentine, rifaximin, ristocetin, phenamidine, acriflavine, chloroaZOdin, arsphenamine, ami ritipenem, rokitamycin, rollitetracycline, rosaramycin, carbilide or aminoquinuride. roXithromycin, SalazOSulfadimidine, Sancycline, Sisomicin, Sparfloxacin, Spectinomycin, Spiramycin, Streptomycin, Suc 0041 Another preferred biologically active compound cisulfone, Sulfachrysoidine, Sulfaloxic acid, Sulfamidoch that can be incorporated into a polymer of the invention is rySoidine, Sulfanilic acid, Sulfoxone, teicoplanin, temafloxa Oxymorphone, buprenorphine, butorphanol, or nalbuphine. cin, temocillin, tetracycline, tetroXoprim, thiamphenicol, 0.042 Another preferred biologically active compound thiazolsulfone, thiostrepton, ticarcillin, tigemonam, tobra that can be incorporated into a polymer of the invention is mycin, toSufloxacin, trimethoprim, trospectomycin, trova methotrexate, doxorubicin, or daunorubicin. floxacin, tuberactinomycin, Vancomycin and the like. 0.043 Another preferred biologically active compound 0046) Anther preferred biologically active compound that that can be incorporated into a polymer of the invention is can be incorporated into a polymer of the invention is an atorvastatin, enalapril, ranitidine, pravastatin, cycloSporin, anti-fungal, for example, azaserine, candicidin(S), chlor famotidine, leuprolide, acyclovir, lamivudine, budesonide, phenesin, dermostatin(s), filipin, fungichromin, mepartricin, albuterol, indinavir, metformin, alendronate, nizatidine, nyStatin, oligomycin(s), perimycin A, tubercidin and the Zidovudine, carboplatin, metoprolol, lisinpril, captopril, Sal like. meterol, cilastatin, benazepril, cefaclor, fluvastatin, 0047 Anther preferred biologically active compound that quinapril, gemcitabine or Vincristine. can be incorporated into a polymer of the invention is an 0044 Another preferred biologically active compound anti-cancer (e.g., carcinomas, Sarcomas, leukemias and can that can be incorporated into a polymer of the invention is cers derived from cells of the nervous System), including a nonsteroidal anti-inflammatory drug, for example, a non anti-neoplastic, for example, 6-azauridine, 6-diazo-5-oxo-L- Steroidal anti-inflammatory drug as described in U.S. patent norleucine, 6-mercaptopurine, aclacinomycin(s), ancitabine, application (Ser. No. 09/732,516, filed Dec. 7, 2000), anthramycin, azacitadine, azaserine, bleomycin(s), capecit 3-amino-4-hydroxybutyric acid, aceclofenac, alminoprofen, abine, carubicin, carZinophillin A, chlorozotocin, chromo amfenac, bromfenac, bromosaligenin, bumadizon, carpro mycin(s), cladribine, cytarabine, daunorubicin, denopterin, fen, diclofenac, diflunisal, ditazol, enfenamic acid, etodolac, docetaxel, doxifluridine, doxorubicin, edatrexate, eflorni etofenamate, fendosal, fepradinol, flufenamic acid, gentisic thine, elliptinium, enocitabine, epirubicin, etoposide, floXu acid, glucamethacin, glycol Salicylate, meclofenamic acid, ridine, fludarabine, gemcitabine, idarubicin, mannomustine, mefenamic acid, meSalamine, niflumic acid, olSalazine, melphalan, menogaril, methotrexate, mitobronitol, mitolac Oxaceprol, S-adenosylmethionine, Salicylic acid, Salsalate, tol, mitomycin C, mitoxantrone, mopidamol, mycophenolic acid, nogalamycin, olivomycin(s), paclitaxel, pentostatin, SulfaSalazine, tolfenamic acid and the like. peplomycin, pirarubicin, piritrexim, plicamycin, podophyl 0.045 Anther preferred biologically active compound that linic acid 2-ethylhydrazine, prednimustine, procarbazine, can be incorporated into a polymer of the invention is an pteropterin, puromycin, ranimustine, Streptonigrin, Strepto anti-bacterial, for example, 2-p-Sulfanilyanilinoethanol, Zocin, teniposide, thiamiprine, thioguanine, TomudeXOR (N- 4,4'-Sulfinyldianiline, 4-Sulfanilamidosalicylic acid, acedia 5-(1,4-Dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl Sulfone, acetoSulfone, amikacin, amoxicillin, amphotericin methylamino-2-thienylcarbonyl-L-glutamic acid), B, amplicillin, apalcillin, apicycline, apramycin, arbekacin, toptecan, trimetrexate, tubercidin, ubenimex, vinblastine, aspoxicillin, azidamfenicol, azithromycin, aztreonam, baci Vindesline, Vinorelbine, Zorubicin and the like. tracin, bambermycin(s), biapenem, brodimoprim, butirosin, capreomycin, carbenicillin, carbomycin, carumonam, 0048 Anther preferred biologically active compound that cefadroxil, cefamandole, cefatrizine, cefbuperaZone, cefcli can be incorporated into a polymer of the invention is an din, cefdinir, cefditoren, cefepime, cefetamet, cefixime, anti-thrombotic, for example, argatroban, coumetarol, cefinenoXime, cefminox, cefodizime, cefonicid, cefopera dicOumarol, ethyl biscoumacetate, ethylidene dicoumarol, Zone, ceforanide, cefotaXime, cefotetan, cefotiam, cefoZop iloprost, lamifiban, taprostene, tioclomarol, tirofiban and the ran, cefpimizole, cefpiramide, cefpirome, cefprozil, cefroXa like. dine, ceftazidime, cefteram, ceftibuten, ceftriaxone, 0049 Anther preferred biologically active compound that cefuZonam, cephalexin, cephaloglycin, cephalosporin C, can be incorporated into a polymer of the invention is an US 2002/0071822 A1 Jun. 13, 2002 immunosuppressive, for example, 6-mercaptopurine, ami 0060 A preferred value for L is a divalent, branched or prilose, bucillamine, gusperimus, mycophenolic acid, pro unbranched, hydrocarbon chain, having from 6 to 10 carbon codazole, romurtide, Sirolimus (rapamycin), tacrolimus, atOmS. ubenimex and the like. 0061. A more preferred value for L is a divalent hydro 0050 Anther preferred biologically active compound that carbon chain having 7, 8, or 9 carbon atoms. can be incorporated into a polymer of the invention is a general or local anesthetic, for example, butethamine, fenal 0062. A most preferred value for L is a divalent hydro comine, hydroxytetracaine, naepaine, orthocaine, piri carbon chain having 8 carbon atoms. docaine, Salicyl alcohol and the like. 0063 Aspecific polymer of the invention comprises one 0051. A specific value for L is a divalent, branched or or more units of formula (I): unbranched, Saturated or unsaturated, hydrocarbon chain, -R-A-L-A- (I) 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 0064 wherein R is group that will provide a biologically (-O-) or (-NR-), and wherein the chain is optionally active compound upon hydrolysis of the polymer; each A is Substituted on carbon with one or more (e.g. 1, 2, 3, or 4) independently an amide linkage, a thioester linkage, or an Substituents selected from the group consisting of (C- ester linkage; and L is a linking group. C.)alkoxy, (C-C)cycloalkyl, (C-C)alkanoyl, (C- C.)alkanoyloxy, (C-C)alkoxycarbonyl, (C-C)alkylthio, 0065. Another specific polymer of the invention is a azido, cyano, nitro, halo, hydroxy, OXO (=O), carboxy, aryl, polymer which comprises one or more units of formula (II) aryloxy, heteroaryl, and heteroaryloxy. in the backbone: 0.052 Another specific value for L is a divalent, branched -R-A-L-A-R-A-L-A- (II) or unbranched, Saturated or unsaturated, hydrocarbon chain, 0066 wherein: RandR are each independently a group having from 1 to 25 carbon atoms, wherein the chain is that will yield a biologically active compound upon hydroly optionally Substituted on carbon with one or more (e.g. 1, 2, sis of the polymer; each A is independently an amide, 3, or 4) Substituents selected from the group consisting of thioester, or ester linkage; and each L is independently a (C-C)alkoxy, (C-C)cycloalkyl, (C-C)alkanoyl, (C- linking group. Such a polymer, wherein R and R are C.)alkanoyloxy, (C-C)alkoxycarbonyl, (C-C)alkylthio, groups that will yield differing biologically active com azido, cyano, nitro, halo, hydroxy, OXO, carboxy, aryl, ary pounds upon hydrolysis of the polymer, are particularly loxy, heteroaryl, and heteroaryloxy. useful for the administration of a combination of two therapeutic agents to an animal. 0.053 Another specific value for L is an amino acid. 0067. A preferred group of polyesters and polyamides 0.054 Another specific value for L is a peptide. includes polymers that are comprised of compounds con 0.055 Another specific value for L is a divalent, branched taining at least two free alcohol or phenol groups or two at or unbranched, Saturated or unsaturated, hydrocarbon chain, least two free amine groups available for reactions which having from 1 to 25 carbon atoms, wherein one or more (e.g. co-polymerize with carboxylic acid groups or bis(acyl) 1, 2, 3, or 4) of the carbon atoms is optionally replaced by chlorides. 0068 Formulations 0056. A more specific value for L is a divalent, branched 0069. The polymers of the invention can be formulated as or unbranched, Saturated or unsaturated, hydrocarbon chain, pharmaceutical compositions and administered to a mam having from 3 to 15 carbon atoms, wherein one or more (e.g. malian host, Such as a human patient in a variety of forms 1, 2, 3, or 4) of the carbon atoms is optionally replaced by adapted to the chosen route of administration, i.e., orally (-O-) or (-NR-), and wherein the chain is optionally rectally, or parenterally, by intravenous, intrarnuscular, Substituted on carbon with one or more (e.g. 1, 2, 3, or 4) intraperitoneal, intraspinal, intracranial, topical or Subcuta Substituents selected from the group consisting of (C- C.)alkoxy, (C-C)cycloalkyl, (C-C)alkanoyl, (C- neous routes. For Some routes of administration, the polymer C.)alkanoyloxy, (C-C)alkoxycarbonyl, (C-C)alkylthio, can conveniently be formulated as micronized particles. azido, cyano, nitro, halo, hydroxy, OXO, carboxy, aryl, ary 0070 Thus, the present compounds may be systemically loxy, heteroaryl, and heteroaryloxy. administered, e.g., orally, in combination with a pharmaceu tically acceptable vehicle Such as an inert diluent or an 0057 Another more specific value for L is a divalent, assimilable edible carrier. They may be enclosed in hard or branched or unbranched, Saturated or unsaturated, hydrocar Soft shell gelatin capsules, may be compressed into tablets, bon chain, having from 3 to 15 carbon atoms, wherein one or may be incorporated directly with the food of the patient's or more (e.g. 1, 2, 3, or 4) of the carbon atoms is optionally diet. For oral therapeutic administration, the active com replaced by (-O-) or (-NR-). pound may be combined with one or more excipients and 0.058 Another more specific value for L is a divalent, used in the form of ingestible tablets, buccal tablets, troches, branched or unbranched, Saturated or unsaturated, hydrocar capsules, elixirs, Suspensions, Syrups, wafers, and the like. bon chain, having from 3 to 15 carbon atoms. Such compositions and preparations preferably contain at least 0.1% of polymer by weight. The percentage of the 0059 Another more specific value for L is a divalent, compositions and preparations may, of course, be varied and branched or unbranched, hydrocarbon chain, having from 3 may conveniently be between about 2 to about 80% of the to 15 carbon atoms. weight and preferably 2 to about 60% of a given unit dosage US 2002/0071822 A1 Jun. 13, 2002 form. The amount of polymer in Such therapeutically useful able Solutions, the preferred methods of preparation are compositions is Such that an effective dosage level will be Vacuum drying and freeze drying techniques, which yield a obtained. powder of the active ingredient plus any additional desired ingredient present in the previously Sterile-filtered Solutions. 0071. The tablets, troches, pills, capsules, and the like may also contain the following: binderS Such as gum traga 0075 For topical administration, the present polymers canth, acacia, corn Starch or gelatin; excipients Such as can be applied in pure form. However, it will generally be dicalcium phosphate, a disintegrating agent Such as corn desirable to administer them as compositions or formula Starch, potato Starch, alginic acid and the like; a lubricant tions, in combination with a dermatologically acceptable Such as magnesium Stearate; and a Sweetening agent Such as carrier, which may be a Solid or a liquid. Sucrose, fructose, lactose or aspartame or a flavoring agent 0076 Useful solid carriers include finely divided solids Such as peppermint, oil of wintergreen, or cherry flavoring Such as talc, clay, microcrystalline cellulose, Silica, alumina may be added. When the unit dosage form is a capsule, it and the like. Useful liquid carriers include water, alcohols or may contain, in addition to materials of the above type, a glycols or water-alcohol/glycol blends, in which the present liquid carrier, Such as a vegetable oil or a polyethylene compounds can be dissolved or dispersed at effective levels, glycol. Various other materials may be present as coatings or optionally with the aid of non-toxic Surfactants. Adjuvants to otherwise modify the physical form of the solid unit Such as fragrances and additional antimicrobial agents can dosage form. For instance, tablets, pills, or capsules may be be added to optimize the properties for a given use. The coated with gelatin, wax, shellac or Sugar and the like. A resultant liquid compositions can be applied from absorbent Syrup or elixir may contain the active compound, Sucrose or pads, used to impregnate bandages and other dressings, or fructose as a Sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring Such as cherry or Sprayed onto the affected area using pump-type or aeroSol orange flavor. Of course, any material used in preparing any SprayerS. unit dosage form should be pharmaceutically acceptable and 0077. Thickeners such as synthetic polymers, fatty acids, Substantially non-toxic in the amounts employed. In addi fatty acid Salts and esters, fatty alcohols, modified celluloses tion, the active compound may be incorporated into SuS or modified mineral materials can also be employed with tained-release preparations and devices. liquid carriers to form spreadable pastes, gels, ointments, Soaps, and the like, for application directly to the skin of the 0.072 The polymer may also be administered intrave nously, intraspinally, intracranially, or intraperitoneally by USC. infusion or injection. Solutions of the polymer can be 0078 Dosages prepared a Suitable Solvent Such as an alcohol, optionally 0079 Useful dosages of the polymers can be determined mixed with a nontoxic Surfactant. Dispersions can also be by comparing their in vitro activity, and in Vivo activity of prepared in glycerol, liquid polyethylene glycols, triacetin, the therapeutic agent in animal models. Methods for the and mixtures thereof and in oils. Under ordinary conditions extrapolation of effective dosages in mice, and other ani of Storage and use, these preparations contain a preservative mals, to humans are known to the art; for example, See U.S. to prevent the growth of microorganisms. Pat. No. 4,938,949. Additionally, useful dosages can be 0073. The pharmaceutical dosage forms suitable for determined by measuring the rate of hydrolysis for a given injection or infusion can include Sterile Solutions or disper polymer under various physiological conditions. The Sions or Sterile powders comprising the polymer containing amount of a polymer required for use in treatment will vary the active ingredient which are adapted for the extempora not only with the particular polymer selected but also with neous preparation of Sterile injectable or infusible Solutions the route of administration, the nature of the condition being or dispersions, optionally encapsulated in liposomes. In all treated and the age and condition of the patient and will be cases, the ultimate dosage form should be Sterile, fluid and ultimately at the discretion of the attendant physician or Stable under the conditions of manufacture and Storage. The clinician. liquid carrier or vehicle can be a Solvent or liquid dispersion medium comprising, for example, ethanol, a polyol (for 0080. The desired dose may conveniently be presented in example, glycerol, propylene glycol, liquid polyethylene a single dose or as divided doses administered at appropriate glycols, and the like), vegetable oils, nontoxic glyceryl intervals, for example, as two, three, four or more Sub-doses esters, and Suitable mixtures thereof. The proper fluidity can per day. The Sub-dose itself may be further divided, e.g., into be maintained, for example, by the formation of liposomes, a number of discrete loosely spaced administrations. by the maintenance of the required particle Size in the case 0081) Combination Therapies of dispersions or by the use of Surfactants. The prevention of the action of microorganisms can be brought about by 0082 The polymers of the invention are also useful for various antibacterial and antifungal agents, for example, administering a combination of therapeutic agents to an parabens, chlorobutanol, phenol, Sorbic acid, thimerosal, animal. Such a combination therapy can be carried out in the and the like. In many cases, it will be preferable to include following ways: 1) a second therapeutic agent can be isotonic agents, for example, Sugars, buffers or Sodium dispersed within the polymer matrix of a polymer of the chloride. Prolonged absorption of the injectable composi invention, and can be released upon degradation of the tions can be brought about by the use in the compositions of polymer; 2) a Second therapeutic agent can be appended to agents delaying absorption, for example, aluminum a polymer of the invention (i.e. not in the backbone of the polymer) with bonds that hydrolyze to release the second monoStearate and gelatin. therapeutic agent under physiological conditions; 3) the 0.074 Sterile injectable solutions are prepared by incor polymer of the invention can incorporate two therapeutic porating the polymer in the required amount in the appro agents into the polymer backbone (e.g. a polymer compris priate Solvent with various of the other ingredients enumer ing one or more units of formula (II)) or 4) two polymers of ated above, as required, followed by filtersterilization. In the the invention, each with a different therapeutic agent can be case of Sterile powders for the preparation of Sterile inject administered together (or within a short period of time). US 2002/0071822 A1 Jun. 13, 2002

0.083 Thus, the invention also provides a pharmaceutical composition comprising a polymer of the invention and a -continued Second therapeutic agent that is dispersed within the poly mer matrix of a polymer of the invention. The invention also Functional Group On provides a pharmaceutical composition comprising a poly Biologically active Functional Group On mer of the invention having a Second therapeutic agent compound Linker Precursor Resulting Linkage. In appended to the polymer (e.g. with bonds that will hydrolyze (X or X) (Z or Z) Polymer to release the Second therapeutic agent under physiological -SH -COOH Thioester -NHR -COOH Amide conditions). -SOH -OH Sulfate Ester 0084. The polymers of the invention can also be admin -OH -SOH Sulfate Ester istered in combination with other therapeutic agents that are effective to treat a given condition to provide a combination therapy. Thus, the invention also provides a method for 0091 AS will be clear to one skilled in the art, suitable treating a disease in a mammal comprising administering an protecting groups can be used during the reaction illustrated effective amount of a combination of a polymer of the in Scheme I (and in the reactions illustrated in Schemes invention and another therapeutic agent. The invention also II-XV below). For example, other functional groups present provides a pharmaceutical composition comprising a poly in the biologically active compound or the linker precursor mer of the invention, another therapeutic agent, and a can be protected during polymerization, and the protecting pharmaceutically acceptable carrier. groups can Subsequently be removed to provide the polymer of the invention. Suitable protecting groups and methods for 0085 Preferred drug combinations for incorporation into their incorporation and removal are well known in the art the polymers or the compositions of the invention include (see for example Greene, T. W.; Wutz, P. G. M. “Protecting the following: amoxicillin/clavulanic acid; and imipenem/ Groups. In Organic Synthesis” second edition, 1991, New cilastatin. York, John Wiley & Sons, Inc.). 0.086 Preparation Of Polymers Of The Invention 0092 Additionally, when a carboxylic acid is reacted 0.087 Processes for preparing polymers of the invention With a hydroxy group, a mercapto group, or an amine group are provided as further embodiments of the invention and to provide an ester linkage, thioester linkage, or an amide are illustrated by the following procedures in which the linkage, the carboxylic acid can be activated prior to the meanings of the generic radicals are as given above unless reaction, for example, by formation of the corresponding otherwise qualified. acid chloride. Numerous methods for activating carboxylic 0088 For example, a polymer of the invention can be acids, and for preparing ester linkages, thioester linlages, prepared, as illustrated in Scheme I, from a biologically and amide linkages, are known in the art (see for example active compound of formula (X-R-X) and a linker pre Advanced Organic Chemistry: Reaction Mechanisms and cursor of formula Z-L-Z, wherein X, X, Z, and Z are Structure, 4 ed., Jerry March, John Wiley & Sons, pages Selected from the values in the table below. 419–437 and 1281). 0093. A polyester of the invention can be formed from a biologically active compound of formula (HO-R-OH) Scheme I and from a linker precursor of formula HOOC-L-COOH as illustrated in Scheme II. X-R-X + Z-L-Z -- -(-R-A-L-A-I- (Ia) SCHEME II

He 0089. The biologically active compound and the linker precursor can be polymerized using well known Synthetic (III) techniques (e.g. by condensation) to provide a polymer of the invention (Ia) wherein each A is independently an ester linkage, a thioester linkage, or an amide linkage. 0094) Reaction of the hydroxy groups of the biologically 0090 Depending on the reactive functional group (X or active compound with the carboxylic acids of the linker X) of the biologically active compound, a corresponding precursor provides a polymer of formula (III), which is a functional group (Z or Z) can be selected from the fol polymer of the invention. lowing table, to provide an ester linkage, thioester linkage, 0095) A preferred biologically active dihydroxy com or amide linkage in the polymer backbone. pound that can be used to prepare a polyester of the invention is: amikacin; amphotericin B, apicycline, apramy cin; arbekacin; azidamfenicol; bambermycin(s); butirosin, Functional Group On carbomycin, cefpiramide; chloramphenicol, chlortetracy Biologically active Functional Group On cline; clindamycin; clomocycline, demeclocycline; diathy compound Linker Precursor Resulting Linkage. In moSulfone, dibekacin, dihydroStreptomycin; dirithromycin; (X or X) (Z or Z) Polymer doxycycline, erythromycin; fortimicin(s); gentamicin(s); -COOH -OH Ester glucosulfone Solasulfone, guamecycline, isepamicin; josa -COOH -NHR Amide mycin; kanamycin(s); leucomycin(s); lincomycin; lucenso -COOH -SH Thioester mycin; lymecycline, meclocycline, methacycline; microno -OH -COOH Ester micin; midecamycin(s); minocycline; mupirocin, natamycin; neomycin, netilmicin, oleandomycin; oxytetra US 2002/0071822 A1 Jun. 13, 2002 cycline, paromomycin; pipacycline, podophyllinic acid 2-ethylhydrazine; primycin, ribostamycin; rifamide; rifampin; rifamycin SV, rifapentine, rifaximin, ristocetin; SCHEME III rokitamycin; rollitetracycline, rosaramycin; roXithromycin; He Sancycline, Sisomicin; Spectinomycin; Spiramycin; Strepto mycin, teicoplanin, tetracycline; thiamphenicol; thiostrep ton; tobramycin; trospectomycin; tuberactinomycin; Vanco (IV) mycin; candicidin(S); chlorphenesin; dermostatin(S); filipin; fungichromin; mepartricin; nyStatin, oligomycin(s); perimy 0099 Reaction of the hydroxy group and the amino cin A; tubercidin; 6-azauridine, aclacinomycin(S); ancitab group of the biologically active compound with the carboxy ine; anthramycin; azacitadine, bleomycin(s); carubicin; lic acids of the linker precursor provides a polymer of carzinophillin A; chlorozotocin, chromomycin(s), doxiflu formula (IV), which is a polymer of the invention. ridine, enocitabine, epirubicin, gemcitabine, mannomustine; 0100 A preferred biologically active hydroxy/amino menogaril; atorvastatin; pravastatin, clarithromycin; leupro compound that can be used to prepare a polyester/polyamide lide, paclitaxel, mitobronitol, mitolactol, mopidamol; of the invention is: 2-p-Sulfanilyanilinoethanol, 4-Sulfanil nogalamycin; olivomycin(s); peplomycin; pirarubicin; pred amidosalicylic acid; amikacin; amphotericin B, apramycin; nimustine; puromycin; ranimustine; tubercidin; Vindesine; arbekacin; aspoxicillin, butirosin; capreomycin, cefadroxil, Zorubicin; coumetarol; dicoumarol; ethyl biscoumacetate; cefatrizine, cefdinir, cefprozil, dibekacin, dihydroStrepto ethylidene dicoumarol, iloprost, taprostene, tioclomarol; mycin; dirithromycin; enviomycin; gramicidin(S); teicopla amiprilose; romurtide; Sirolimus (rapamycin), tacrolimus, nin; fortimicin(s); gentamicin(s); glucosulfone Solasulfone, Salicyl alcohol, bromosaligenin; ditaZol, fepradinol, gentisic isepamicin; kanamycin(s); lucensomycin; lymecycline; acid; glucamethacin; olSalazine, S-adenosylmethionine; meropenem; micronomicin; natamycin; neomycin, netilmi cin; paromomycin; ribostamycin; ristocetin, Sisomicin; azithromycin; Salmeterol; budeSonide, albuterol; indinavir, Spectinomycin; Streptomycin; thiostrepton; tobramycin; tro fluvastatin; Streptozocin, doxorubicin; daunorubicin; plica spectomycin; tuberactinomycin; Vancomycin; candicidin(S); mycin, idarubicin; pentostatin, mitoxantrone, cytarabine; mepartricin; nyStatin; perimycin A, tubercidin; anthramycin; fludarabine phosphate; floxuridine, cladribine, capecitabine; azacitadine, bleomycin(s); carubicin; carZinophillin A; cyt docetaxel, etopoSide; topotecan; vinblastine, or teniposide. arabine; denopterin; elliptinium, epirubicin, gemcitabine; 0.096] A polyamide of the invention can be prepared using mannomustine, peplomycin; pirarubicin; pteropterin; puro a procedure similar to that illustrated in Scheme II by mycin; Streptonigrin, tubercidin, ubenimex, Vindesline; Zoru replacing the biologically active dihydroxy compound in bicin; gusperimus; ubenimex, fenalcomine; hydroxytetra caine; Orthocaine, 3-amino-4-hydroxybutyric acid; Scheme II with a suitable biologically active diamino com etofenamate; fepradinol; meSalamine, S-adenosylmethion pound. A preferred biologically active diamino compound ine; leuprolide, acyclovir, paclitaxel, lamivudine, albuterol; that can be used to prepare a polymer of the invention is: indinavir, alendronate, Zidovudine, metoprolol, amoxicillin; 2-p-Sulfanilyanilinoethanol; 4,4'-Sulfinyldianiline; acedia Salmeterol, imipenem, doxorubicin; daunorubicin, idarubi Sulfone, acetoSulfone, amikacin, apramycin; arbekacin; cin; pentostatin, mitoxantrone; fludarabine phosphate; bacitracin; brodimorprim; butirosin; colistin, capreomycin; floxuridine, cladribine; vinorelbine; Vincristine; or vinblas dapSone; dibekacin; enviomycin; gramicidin S, polymyxin; tine. teicoplanin; fortimicin(s); gentamicin(s); glucosulfone Sola Sulfone, grepafloxacin, imipenem, isepamicin; kanamy 0101 A polythioester/polyamide of the invention can be cin(s); lymecycline; micronomicin; neomycin; netilmicin; prepared using a procedure Similar to that illustrated in p-Sulfanilylbenzylamine; paromomycin, ribostamycin; ris Scheme II by replacing the hydroxy/amino biologically tocetin; Sisomicin; Sparfloxacin; Spectinomycin; Sulfach active compound in Scheme II with a Suitable mercapto/ rySoidine, Sulfamidochrysoidine, Sulfoxone, tetroXoprim; amino biologically active compound. thiazolsulfone, tobramycin; trimethoprim; edatrexate, eflo 0102) A polyamide of the invention can be formed from mithine, mannomustine, mitoxantrone; peplomycin; piritr exim; procarbazine, pteropterin; trimetrexate, gusperimus, a biologically active compound of formula (HOOC-R- butethamine; naepaine, piridocaine; trospectomycin; tuber COOH) and from a linker precursor of formula HRN-L- actinomycin; Vancomycin; candicidin(s); mepartricin; peri NRH as illustrated in Scheme IV. mycin A, ranitidine, famotidine, metformin; nizatidine, car boplatin; lisinopril; methotrexate, mitomycin bleomycin(s) SCHEME IV or thioguanine. --- 0097. A polythioester of the invention can be prepared using a procedure Similar to that illustrated in Scheme II by replacing the biologically active dihydroxy compound in Scheme II with a suitable biologically active dimercapto compound. 0.103 Reaction of the carboxylic acid groups of the 0098. A polysulfate ester of the invention can be formed biologically active compound with the amino groups of the by replacing the dicarboxylic acid linker compound with a linker precursor provides a polymer of formula (V), which disulfo acid compound A polyester/polyamide of the inven is a polymer of the invention. tion can be formed from a biologically active compound of 0104. A preferred biologically active dicarboxylic acid formula (HRN-RI -OH) and from a linker precursor of compound that can be used to prepare a polyamide of the formula HOOC-L-COOH as illustrated in Scheme III. invention is: bambermycin(s); carbenicillin; carZinophillin US 2002/0071822 A1 Jun. 13, 2002

A, cefixime, cefminox, cefpimizole, cefodizime, cefonicid; amphotericin B; amplicillin, argatroban; aspoxicillin, azaser ceforanide, cefotetan, ceftibuten; cephalosporin C, denop ine; aztreonam, bromfenac, bumadizon; candicidin(s); car terin, edatrexate, moxalactam, olSalazine; penicillin N; profen, carumonam, carZinophillin A, cefadroxil, cefatriz quinacillin; temocillin; ticarcillin; TomudeX(R) (N-5-(1,4- Dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl)methy ine, cefclidin, cefdinir, cefditoren, cefepime, cefetamet; lamino-2-thienylcarbonyl-L-glutamic acid), lisinopril; cefixime, cefinenoXime, cefininox, cefodizime, ceforanide; cilastatin, ceftazidime; or methotrexate. cefotaxime, cefotiam, cefoZopran, cefpirome, cefprozil; cefroXadine, ceftazidime, cefteram, ceftibuten, ceftriaxone; 0105. A polyester of the invention can be prepared using cefuZonam, cephalexin; cephaloglycin; cephalosporin C, a procedure similar to that illustrated in Scheme IV by cephradine, clinafloxacin; cyclacillin; denopterin, edatrex replacing the diamino linker precursor with a dihydroxy linker precursor. Similarly, a polyester/polyamide of the ate, eflomithine; enfenamic acid; enoxacin; epicillin, etod invention can be prepared using a procedure Similar to that olac, enviomycin, teicoplanin; flufenamic acid, grepafloxa illustrated in Scheme IV by replacing the diamino linker cin, hetacillin, imipenem, lomefloxacin; lucensomycin; precursor with an hydroxy/amino linker precursor, and a lymecycline; meclofenamic acid, mefenamic acid; mero polythioester/polyamide of the invention can be prepared penem; meSalamine; natamycin; niflumic acid; norfloxacin; using a procedure similar to that illustrated in Scheme IV by nyStatin; paZufloxacin; penicillin N, pipemidic acid; pro replacing the diamino linker precursor with an mercapto/ codazole, pteropterin; S-adenosylmethionine, Sparfloxacin; amino linker precursor. Streptonigrin, Succisulfone, Sulfachrysoidine, temafloxacin; 0106 A polyester of the invention can be formed from a tigemonam, tirofiban; tolfenamic acid; toSufloxacin; trova biologically active compound of formula (HO-R- floxacin, ubenimex, Vancomycin; enalapril; amoxicillin; COOH) and from a linker precursor of formula HO-L- ciprofloxacin; diclofenac, lisinopril, ceftriaxone; cilastatin; COOH as illustrated in Scheme V. benazepril, cefaclor, ceftazidime; quinapril; melphalan; or 01.07 Scheme V methotrexate. 0108 Reaction of the hydroxy group and the carboxylic 0112 A polythioester/polyester of the invention can be acid of the biologically active prepared using a procedure Similar to that illustrated in Scheme V by replacing biologically active hydroxy/car boxylic compound with a biologically active mercapto/ HO-R-COOH + HO-L-COOH -> carboxylic acid compound. A preferred biologically active mercapto/carboxylic acid compound that can be used to prepare a polymer of the invention is bucillamine or capto pril. 0109 compound, with the carboxylic acid and the 0113 A polysulfonamide of the invention can be pre hydroxy group of the linker precursor provides a polymer of pared using a procedure Similar that illustrated in Scheme V formula (VI), which is a polymer of the invention. by replacing the biologically active hydroxy/carboxylic 0110. A preferred biologically active hydroxy/carboxylic compound with a biologically active amine/sulfo acid com acid compound that can be used to prepare a polymer of the pound. A preferred biologically active amine/Sulfo acid invention is: 4-Sulfanilamidosalicylic acid; amphotericin B; compound that can be used to prepare a polymer of the apalcillin, apicycline; aspoxicillin; bambermycin(s); biap invention is: Sulfanilic acid or Sulfoxone. enem, cefadroxil, cefamandole, cefatrizine, cefbuperaZone; cefdinir, cefonicid, cefoperaZone, cefpiramide, cefprozil; 0114. In the polymers of formulae (I, and III-VI) illus enviomycin, teicoplanin; flomoxef, glycol Salicylate; lucen trated in Schemes I-V above, R, A, L, and R can have any Somycin; lymecycline; meropenem; moxalactam, mupiro of the values, Specific values, or preferred values described cin; nadifloxacin; natamycin; panipenem; podophyllinic herein. acid 2-ethylhydrazine; ritipenem; SalazOSulfadimidine, Sul faloxic acid; Vancomycin; 3-amino-4-hydroxybutyric acid; 0115 The co-polymerization of morphine with a diacid candicidin(s); carZinophillin A; denopterin; diflunisal; fen chloride to provide a polyester of the invention is depicted dosal; gentisic acid, iloprost, lamifiban; meSalamine, nysta in Scheme VI. tin, olSalazine, oxaceprol, pteropterin; romurtide, Salicylic acid; Salsalate, Streptonigrin, SulfaSalazine, taprostene, ube nimex, amoxicillin, pravastatin, imipenem; mycophenolic Scheme VI acid; or fluvastatin. 0111 A polyester/polyamide of the invention can be prepared using a procedure Similar to that illustrated in Scheme V by replacing biologically active hydroxy/car boxylic compound with a biologically active amino?car boxylic acid compound. A preferred biologically active amino/carboxylic acid compound that can be used to prepare a polymer of the invention is: 3-amino-4-hydroxybutyric acid, 4-Sulfanilamidosalicylic acid; 6-diazo-5-oxo-L-norleu cine; aceclofenac; acediasulfone, alminoprofen, amfenac, US 2002/0071822 A1 Jun. 13, 2002 10

any of the values, specific values, or preferred values -continued described herein is a preferred polymer of the invention. For

a polymer of formula (8), m is an integer that is greater than or equal to 2. Prior to the polymerization illustrated in Scheme VII, the amino group of dopamine can be protected with a Suitable protecting group, which can Subsequently be removed, to provide the polymer of the invention. 0119) It should be noted that dopamine can also be incorporated into a polyester/polyamide of the invention by reacting the amino group and either hydroxy group of dopamine with a compound of formula HOOC-L- (7) COOH, or an activated derivative thereof to provide a compound of formula (21) or (22):

0116. In the reaction illustrated in Scheme VI, the linking (21) group L is preferably -(CH2)-, and more preferably, L is -(CH-)-. A polymer of formula (7) wherein Lhas any of the values, Specific values, or preferred values described herein is a preferred polymer of the invention. For a polymer of formula (7), m is an integer that is greater than or equal to 2. 0117 The co-polymerization of dopamine with bis(acyl) chloride to provide a polyester of the invention is depicted in Scheme VII.

Scheme VII (22) HO NH2

HO

OC(=O)-L-C(=O)C

NH2 0120 Prior to the polymerization, the hydroxy group (8) which will not be polymerized can be protected with a Suitable protecting group, which can Subsequently be removed to provide the polymer of the invention. 0118. In the reaction illustrated in Scheme VII, the link ing group L is preferably -(CH-)-, and more preferably, 0121 The co-polymerization of acriflavine to provide a L is -(CH-)-. A polymer of formula (8) wherein L has polyamide of the invention is depicted in Scheme VIII.

Scheme VIII HN NH2 OOC -- co-or US 2002/0071822 A1 Jun. 13, 2002 11

-continued

HN NH2 OOC - HOOC-L-COOH

H H HN N NH2 MeSi-N N N-SiMes n n He 21 2

0122) The diamino groups of acriflavine are copolymer erably, L is -(CH) . A polymer of formula (9) wherein ized in Solution (preferably high-boiling point organic Sol L has any of the values, Specific values, or preferred values vent Such as dimethylformamide) with an activated dicar described herein is a preferred polymer of the invention. For boxylic acid (e.g. Sebacoyl chloride). The polyamide is a polymer of formula (9), m is an integer that is greater than isolated by methods well known in the art. Alternatively, the or equal to 2. amino groups can be reacted with a dicarboxylic acid by 0.124. The preparation of a polymer of the invention employing high temperatures (e.g. in the melting range), or comprising methotrexate is illustrated in Scheme IX.

Scheme DX

N CH 21 N N N l to- N NH2 CO2H O

N N CH 21 s i. H N N l --- l CO2H O (10) a coupling agent. This process of making polyamides is also 0.125. In the reaction illustrated in Scheme IX, the linking well known to those skilled in the art. In yet another group L is preferably -(CH2)-, and more preferably, L is embodiment, the diamino groups can be activated in the -(CH) . A polymer of formula (10) wherein L has any presence of hexamethylsilazine to form Sillylated amines. of the values, Specific values, or preferred values described The silylated amines can then be allowed to react with an herein is a preferred polymer of the invention. For a polymer activated dicarboxylic acid (e.g. Sebacyl chloride) to provide of formula (10), m is an integer that is greater than or equal to 2. Prior to the polymerization illustrated in Scheme IX, a polymer of the invention the carboxylic acids of methotrexate can be protected with 0123. In the reaction illustrated in Scheme VIII, the Suitable protecting groups, which can Subsequently be linking group L is preferably -(CH-)-, and more pref. removed, to provide the polymer of the invention. US 2002/0071822 A1 Jun. 13, 2002 12

0126. It will be appreciated by one skilled in the art that 0129. In the reaction illustrated in Scheme X, the linking a polymer of the invention of the following formula (20): group L is preferably -(CH2)-, and more preferably, L is

(20) N N NH2 CH N 2N

A-L-A NH2

0127 wherein each A is independently an ester linkage, -(CH-)-. A polymer of formula (11) wherein L has any a thioester linkage, or an amide linkage can be prepared as of the values, Specific values, or preferred values described illustrated in Scheme X by Selecting a linker precursor with the appropriate functionality. For a compound of formula herein is a preferred polymer of the invention. For a polymer (20) the linking group L is preferably -(CH2)-, and more of formula (11), m is an integer that is greater than or equal preferably, L is -(CH) . A polymer of formula (20) to 2. Prior to the polymerization illustrated in Scheme X, the wherein Land each A has any of the values, Specific values, amino groups of methotrexate can be protected with Suitable or preferred values described herein is a preferred polymer protecting groups, which can Subsequently be removed, to of the invention. For a polymer of formula (20), m is an integer that is greater than or equal to 2. provide the polymer of the invention. 0128. The preparation of another polymer of the inven 0.130. The preparation of another polymer of the inven tion comprising methotrexate is illustrated in Scheme X. tion comprising methotrexate is illustrated in Scheme XI.

Scheme X N N NH2 CH 21 s H N N 2N --- l NH2 CO2H O

N N NH2 CH 2 s N S 2 N H NH2

O O (11) US 2002/0071822 A1 Jun. 13, 2002 13

Scheme XI N CH 21 N | N S l --- N NH2 CO2H O

N CH 21 N-ur-o-o- H N N l

N NH2

COH O (12)

0131. In the reaction illustrated in Scheme XI, the linking group L is preferably -(CH2)-, and more preferably, L is -continued -(CH-)-. A polymer of formula (12) wherein L has any of the values, specific values, or preferred values described

herein is a preferred polymer of the invention. For a polymer of formula (12), m is an integer that is greater than or equal to 2. Prior to the polymerization illustrated in Scheme XI, the carboxylic acid and amino group of methotrexate that are not reacted to form the polymer can be protected with Suitable protecting groups, which can Subsequently be removed, to provide the polymer of the invention. 0132 A polymer of the invention that comprises meth otrexate is particularly useful for treating psoriasis, inflam matory bowel disease, skin cancer, or brain tumors. Such a polymer is also particularly useful as an anti-neoplastic agent anti-infective agent, and for local administration of an anti-tumor agent following a lumpectomy or mastectomy. HC 0133. The preparation of a polymer of the invention OH NH comprising doxorubicin is illustrated in Scheme XII. (13) Scheme XII 0.134. In the reaction illustrated in Scheme XII, the link ing group L is preferably -(CH2)-, and more preferably, L is -(CH) . A polymer of formula (13) wherein Lhas any of the values, specific values, or preferred values described herein is a preferred polymer of the invention. For a polymer of formula (13), m is an integer that is greater than or equal to 2. Prior to the polymerization illustrated in Scheme XII, the functional groups of doxorubicin that are not reacted to form the polymer can be protected with HC Suitable protecting groups, which can Subsequently be OH NH removed, to provide the polymer of the invention. 0.135 A polymer of the invention that comprises doxo rubicin is particularly useful for local administration as an anti-tumor (e.g. brain tumor) agent or anti-neoplastic agent. US 2002/0071822 A1 Jun. 13, 2002 15

0.136 The preparation of a polymer of the invention comprising daunorubicin is illustrated in Scheme XIII. -continued COOH Scheme XIII

(15)

0140. In the reaction illustrated in Scheme XIV, the linking group L is preferably -(CH2)-, and more pref erably, Lis-(CH2): . A polymer of formula (15) wherein L has any of the values, Specific values, or preferred values described herein is a preferred polymer of the invention. For HC a polymer of formula (15), m is an integer that is greater than or equal to 2. Prior to the polymerization illustrated in OH NH2 Scheme XIV, the carboxylic acid can be protected with a Suitable protecting group, which can Subsequently be removed, to provide the polymer of the invention. 0141 5-Aminosalicilic acid can also be incorporated into a polymer of the invention which is a polymer of formula (23) or (24):

t co-o-o: (23) HN (24)

HC OH NH2 C(F on-on (14) 0137 In the reaction illustrated in Scheme XIII, the xc OH linking group L is preferably -(CH2)-, and more pref erably, Lis-(CH) . A polymer of formula (14) wherein L has any of the values, Specific values, or preferred values 0142. The preparation of a polymer of the invention described herein is a preferred polymer of the invention. For comprising mycophenolic acid is illustrated in Scheme XV. a polymer of formula (14), m is an integer that is greater than Scheme XV or equal to 2. Prior to the polymerization illustrated in Scheme XIII, the functional groups of daunorubicin that are CH not reacted to form the polymer can be protected with Suitable protecting groups, which can Subsequently be HCO removed, to provide the polymer of the invention. O 0138 A polymer of the invention that comprises dauno HOOC 21 rubicin is particularly useful for local administration as an O anti-tumor (e.g. brain tumor) agent or an anti-neoplastic CH OH agent. 0.139. The preparation of a polymer of the invention comprising 5-aminosalicylic acid is illustrated in Scheme XIV. CH Scheme XIV H3CO COOH OH -- O(O=)C-L-O(O=)C 21 CH O HN (16) US 2002/0071822 A1 Jun. 13, 2002

0143. In the reaction illustrated in Scheme XV, the link carbomycin; carumonam, cefadroxil, cefamandole, cefatriz ing group L is preferably -(CH2)-, and more preferably, ine, cefbuperaZone, cefclidin, cefdinir, cefditoren; L is -(CH) . A polymer of formula (16) wherein Lhas cefepime, cefetamet, cefixime, cefinenoXime, cefininox; any of the values, specific values, or preferred values cefodizime, cefonicid, cefoperaZone, ceforanide, cefo described herein is a preferred polymer of the invention. For taxime, cefotetan, cefotiam, cefoZopran, cefpimizole, cef a polymer of formula (16), m is an integer that is greater than piramide, cefpirome, cefprozil, cefroXadine, cefteram, cef or equal to 2. tibuten; cefuZonam, cephalexin; cephaloglycin; 0144) Activity cephalosporin C; cephradine, chloramphenicol, chlortetra cycline; clinafloxacin; clindamycin; clomocycline, colistin; 0145 The ability of a polymer of the invention to pro cyclacillin; dapsone; demeclocycline, diathymoSulfone, duce a given therapeutic effect can be determined using in dibekacin, dihydroStreptomycin; dirithromycin; doxycy Vitro and in Vivo pharmacological models which are well cline; enoxacin, enviomycin; epicillin; erythromycin; flo known to the art. moxef; fortimicin(s); gentamicin(s); glucosulfone Solasul 0146 All publications, patents, and patent documents fone, gramicidin S; gramicidin(s); grepafloxacin; (including the entire contents of U.S. Provisional Patent guamecycline; hetacillin, isepamicin; joSamycin; kanamy Application No. 60/220,707, filed Jul. 27, 2000) are incor cin(s); leucomycin(s); lincomycin, lomefloxacin; lucenso porated by reference herein, as though individually incor mycin; lymecycline, meclocycline, meropenem; methacy porated by reference. The invention has been described with cline; micronomicin; midecamycin(s); minocycline; reference to various Specific and preferred embodiments and moxalactam, mupirocin, nadifloxacin; natamycin; neomy techniques. However, it should be understood that many cin, netilmicin; norfloxacin, oleandomycin; oxytetracycline; variations and modifications may be made while remaining p-Sulfanilylbenzylamine; panipenem; paromomycin; paZu within the Spirit and Scope of the invention. floxacin; penicillin N, pipacycline, pipemidic acid; poly What is claimed is: myxin; primycin, quinacillin, ribostamycin, rifamide; 1. A polymer comprising a backbone, wherein the back rifampin; rifamycin SV, rifapentine, rifaximin, ristocetin; bone comprises ester, thioester, or amide linkages, and ritipenem; rokitamycin; rollitetracycline, rosaramycin; wherein the backbone comprises one or more groups that roXithromycin; SalazOSulfadimidine, Sancycline, Sisomicin; will yield a biologically active compound upon hydrolysis of Sparfloxacin; Spectinomycin; Spiramycin; Streptomycin; Suc the polymer. cisulfone, Sulfachrysoidine, Sulfaloxic acid; Sulfamidoch 2. The polymer of claim 1 which comprises one or more rysoidine, Sulfanilic acid, Sulfoxone, teicoplanin; temafloxa units of formula (I) in the backbone: cin; temocillin, tetroXoprim; thiamphenicol; thiazolsulfone, -R-A-L-A- (I) thiostrepton, ticarcillin, tigemonam, tobramycin; toSufloxa wherein cin; trimethoprim; trospectomycin; trovafloxacin; tuberacti nomycin; Vancomycin; azaserine; candicidin(s); chlorphen R is group that will yield a biologically active compound esin; dermostatin(S); filipin; fungichromin; mepartricin; upon hydrolysis of the polymer; nyStatin; oligomycin(S); perimycin A; tubercidin;6-azauri each A is independently an ester linkage, a thioester dine, 6-diazo-5-oxo-L-norleucine, aclacinomycin(S); ancit linkage, or an amide linkage; and abine; anthramycin; azacitadine, azaserine; bleomycin(s); carubicin; carZinophillin A; chlorozotocin, chromomycin(s); L is a linking group. denopterin, doxifluridine, edatrexate, eflornithine, ellip 3. The polymer of claim 1 or 2 wherein the biologically active compound is a non-Steriodal ant-inflammatory drug, tinium; enocitabine; epirubicin; mannomustine; menogaril; anti-bacterial, anti-fungal, anti-cancer, anti-thrombotic, mitobronitol; mitolactol, mopidamol; nogalamycin, olivo immunosuppressive, or analgesic. mycin(s); peplomycin; pirarubicin; piritrexim; prednimus 4. The polymer of claim 1 or 2 wherein the biologically tine; procarbazine, pteropterin; puromycin; ranimustine; active compound is atorvastatin; enalapril, ranitidine, cipro streptonigrin; thiamiprine; N-5-(1,4-Dihydro-2-methyl floxacin; pravastatin, clarithromycin; cycloSporin; famoti 4-oxo-6-quinazolinyl)methylmethylamino-2-thienylcar dine; leuprolide, acyclovir, paclitaxel, azithromycin; lami bonyl-L-glutamic acid; trimetrexate, tubercidin, ubenimex, Vudine; budeSonide; albuterol; indinavir; metformin; Vindesline, Zorubicin, argatroban; coumetarol, dicoumarol; alendronate, nizatidine, Zidovudine, carboplatin; meto ethyl biscoumacetate; ethylidene dicoumarol, iloprost, lami prolol, amoxicillin; diclofenac, lisinopril, ceftriaxone, cap fiban; taprostene, tioclomarol; tirofiban; amiprilose; bucil topril; Salmeterol, imipenem; cilastatin; benazepril, cefaclor, lamine; gusperimus, oxymorphone; buprenorphine; butor ceftazidime; fluvastatin, quinapril; Streptozocin, doxorubi phanol, nalbuphine, mycophenolic acid; procodazole; cin; daunorubicin; plicamycin, idarubicin, mitomycin C, romurtide; Sirolimus (rapamycin); tacrolimus, butethamine; pentostatin, mitoxantrone, cytarabine; fludarabine phoS fenalcomine; hydroxytetracaine; naepaine; Orthocaine, piri phate, floxuridine, cladribine, 6-mercaptopurine; thiogua docaine, Salicyl alcohol, 3-amino-4-hydroxybutyric acid; nine; capecitabine, paclitaxel, docetaxel, etoposide; gemcit aceclofenac; alminoprofen, amfenac, bromfenac, bromo abine; topotecan; Vinorelbine, Vincristine, vinblastine; Saligenin; bumadizon; carprofen;diclofenac; diflunisal; dita teniposide; melphalan; 2-p-Sulfanilyanilinoethanol; 4,4'- Zol; enfenamic acid; etodolac, etofenamate, morphine; Sulfinyldianiline, 4-Sulfanilamidosalicylic acid; acediaSul dopamine; bialamicol; fendosal; fepradinol; flufenamic acid; fone, acetoSulfone, amikacin; amphotericin B; amplicillin; gentisic acid; glucamethacin, glycol Salicylate, meclofe apalcillin, apicycline, apramycin; arbekacin; aspoxicillin; namic acid, mefenamic acid; meSalamine, niflumic acid; azidamfenicol; aztreonam, bacitracin; bambermycin(s); bia olsalazine; oxaceprol; S-adenosylmethionine, Salicylic acid; penem; brodimoprim; butirosin; capreomycin; carbenicillin; Salsalate, SulfaSalazine, tolfenamic acid, or methotrexate. US 2002/0071822 A1 Jun. 13, 2002

5. The polymer of claim 4 wherein the biologically active momycin, paZufloxacin, penicillin N, pipacycline, pipemidic compound is morphine, dopamine, bialamicol, or tetracy acid, polymyxin, primycin, quinacillin, ribostamycin, rifa cline. mide, rifampin, rifamycin SV, rifapentine, rifaximin, risto 6. The polymer of claim 3 wherein the analgesic is cetin, ritipenem, rokitamycin, rollitetracycline, rosaramycin, Oxymorphone, buprenorphine, butorphanol, nalbuphine, roXithromycin, SalazOSulfadimidine, Sancycline, Sisomicin, butethamine, fenalcomine, hydroxytetracaine, naepaine, Sparfloxacin, Spectinomycin, Spiramycin, Streptomycin, Suc orthocaine, piridocaine or Salicyl alcohol. cisulfone, Sulfachrysoidine, Sulfaloxic acid, Sulfamidoch 7. The polymer of claim 3 wherein the anti-cancer com rySoidine, Sulfanilic acid, Sulfoxone, teicoplanin, temafloxa pound is 6-azauridine, 6-diazo-5-oxo-L-norleucine, 6-mer cin, temocillin, tetracycline, tetroXoprim, thiamphenicol, captopurine, aclacinomycin(s), ancitabine, anthramycin, thiazolsulfone, thiostrepton, ticarcillin, tigemonam, tobra azacitadine, azaserine, bleomycin(s), capecitabine, carubi mycin, toSufloxacin, trimethoprim, trospectomycin, trova cin, carZinophillin A, chlorozotocin, chromomycin(s), floxacin, tuberactinomycin or Vancomycin. cladribine, cytarabine, daunorubicin, denopterin, docetaxel, doxifluridine, doxorubicin, edatrexate, eflomithine, ellip 10. The polymer of claim 3 wherein the anti-fungal is tinium, enocitabine, epirubicin, etoposide, floXuridine, flu aZaSerine, candicidin(s), chlorphenesin, dermostatin(s), fil darabine, gemcitabine, idarubicin, mannomustine, mel ipin, fungichromin, mepartricin, nystatin, oligomycin(s), phalan, menogaril, methotrexate, mitobronitol, mitolactol, perimycin A or tubercidin. mitomycin C, mitoxantrone, mopidamol, mycophenolic 11. The polymer of claim 3 wherein the anti-thrombotic is acid, nogalamycin, olivomycin(s), paclitaxel, pentostatin, argatroban, coumetarol, dicoumarol, ethyl biscoumacetate, peplomycin, pirarubicin, piritrexim, plicamycin, podophyl ethylidene dicoumarol, iloprost, lamifiban, taprostene, tio linic acid 2-ethylhydrazine, prednimustine, procarbazine, clomarol or tirofiban. pteropterin, puromycin, ranimustine, Streptonigrin, Strepto 12. The polymer of claim 3 wherein the immunosuppres Zocin, teniposide, thiamiprine, thioguanine, N-5-(1,4- Sive is 6-mercaptopurine, amiprilose, bucillamine, gusperi Dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl)methy mus, mycophenolic acid, procodazole, romurtide, Sirolimus lamino-2-thienylcarbonyl-L-glutamic acid, toptecan, (rapamycin), tacrolimus or ubenimex trimetrexate, tubercidin, ubenimex, vinblastine, Vindesine, 13. The polymer of claim 4 wherein the biologically vinorelbine or Zorubicin. active compound is amikacin; amphotericin B, apicycline; 8. The polymer of claim 3 wherein the nonsteroidal apramycin; arbekacin; azidamfenicol; bambermycin(s); anti-inflammatory drug is 3-amino-4-hydroxybutyric acid, butirosin, carbomycin, cefpiramide; chloramphenicol, chlo aceclofenac, alminoprofen, amfenac, bromfenac, bromosali rtetracycline; clindamycin, clomocycline; demeclocycline; genin, bumadizon, carprofen, diclofenac, diflunisal, ditaZol, diathymoSulfone, dibekacin, dihydroStreptomycin; dirithro enfenamic acid, etodolac, etofenamate, fendosal, fepradinol, mycin, doxycycline, erythromycin; fortimicin(s); gentam flufenamic acid, gentisic acid, glucamethacin, glycol Salicy icin(s); glucosulfone Solasulfone, guamecycline, isepami late, meclofenamic acid, mefenamic acid, meSalamine, cin; josamycin; kanamycin(s); leucomycin(s); lincomycin; niflumic acid, olSalazine, oxaceprol, S-adenosylmethionine, lucensomycin; lymecycline, meclocycline; methacycline; Salicylic acid, Salsalate, SulfaSalazine or tolfenamic acid. micronomicin; midecamycin(s); minocycline; mupirocin, 9. The polymer of claim 3 wherein the anti-bacterial is natamycin; neomycin, netilmicin, oleandomycin; oxytetra 2-p-Sulfanilyanilinoethanol, 4,4'-Sulfinyldianiline, 4-Sulfa cycline; paromomycin; pipacycline, podophyllinic acid nilamidosalicylic acid, acediaSulfone, acetosulfone, amika 2-ethylhydrazine, primycin, ribostamycin; rifamide; cin, amoxicillin, amphotericin B, amplicillin, apalcillin, api rifampin; rifamycin SV, rifapentine, rifaximin, ristocetin; cycline, apramycin, arbekacin, aspoxicillin, azidamfenicol, rokitamycin; rollitetracycline, rosaramycin; roXithromycin; azithromycin, aztreonam, bacitracin, bambermycin(s), bia Sancycline, Sisomicin; Spectinomycin; Spiramycin; Strepto penem, brodimoprim, butirosin, capreomycin, carbenicillin, mycin, teicoplanin, tetracycline; thiamphenicol; thiostrep carbomycin, carumonam, cefadroxil, cefamandole, cefatriz ton; tobramycin; trospectomycin; tuberactinomycin; Vanco ine, cefbuperaZone, cefclidin, cefdinir, cefditoren, cefepime, mycin; candicidin(S); chlorphenesin; dermostatin(S); filipin; cefetamet, cefixime, cefinenoXime, cefminox, cefodizime, fungichromin; mepartricin, nystatin, oligomycin(s); perimy cefonicid, cefoperaZone, ceforanide, cefotaXime, cefotetan, cin A; tubercidin; 6-azauridine, aclacinomycin(s); ancitab cefotiam, cefoZopran, cefpimizole, cefpiramide, cefpirome, ine; anthramycin; azacitadine, bleomycin(s); carubicin; cefprozil, cefroXadine, ceftazidime, cefteram, ceftibuten, carzinophillin A; chlorozotocin, chromomycin(s), doxiflu ceftriaXOne, cefuZonam, cephalexin, cephaloglycin, cepha ridine, enocitabine; epirubicin, gemcitabine, mannomustine; losporin C, cephradine, chloramphenicol, chlortetracycline, menogaril; atorvastatin; pravastatin, clarithromycin; leupro ciprofloxacin, clarithromycin, clinafloxacin, clindamycin, lide, paclitaxel, mitobronitol, mitolactol, mopidamol; clomocycline, colistin, cyclacillin, dapsone, demeclocy nogalamycin; olivomycin(s); peplomycin; pirarubicin; pred cline, diathymoSulfone, dibekacin, dihydroStreptomycin, nimustine; puromycin; ranimustine; tubercidin; Vindesine; dirithromycin, doxycycline, enoxacin, enviomycin, epicil Zorubicin; coumetarol, dicoumarol; ethyl biscoumacetate; lin, erythromycin, flomoxef, fortimicin(s), gentamicin(s), ethylidene dicoumarol, iloprost, taprostene, tioclomarol; glucosulfone Solasulfone, gramicidin S, gramicidin(s), gre amiprilose; romurtide; Sirolimus (rapamycin), tacrolimus, pafloxacin, guamecycline, hetacillin, imipenem, isepamicin, Salicyl alcohol, bromosaligenin; ditaZol, fepradinol, gentisic josamycin, kanamycin(s), leucomycin(s), lincomycin, lom acid; glucamethacin; olSalazine, S-adenosylmethionine; efloxacin, lucensomycin, lymecycline, meclocycline, mero azithromycin; Salmeterol; budesonide, albuterol; indinavir, penem, methacycline, micronomicin, midecamycin(s), fluvastatin; Streptozocin, doxorubicin; daunorubicin; plica minocycline, moxalactam, mupirocin, nadifloxacin, natamy mycin, idarubicin; pentostatin, mitoxantrone, cytarabine; cin, neomycin, netilmicin, norfloxacin, oleandomycin, fludarabine phosphate; floxuridine, cladribine, capecitabine; Oxytetracycline, p-Sulfanilylbenzylamine, panipenem, paro docetaxel, etopoSide; topotecan; vinblastine; or teniposide. US 2002/0071822 A1 Jun. 13, 2002

14. The polymer of claim 4 wherein the biologically fendosal; gentisic acid; iloprost, lamifiban; meSalamine; active compound is 2-p-Sulfanilyanilinoethanol; 4,4'-Sulfi nyStatin; olSalazine, Oxaceprol; pteropterin; romurtide; Sali nyldianiline; acediaSulfone, acetoSulfone, amikacin, apra cylic acid; Salsalate; Streptonigrin, SulfaSalazine, taprostene; mycin; arbekacin; bacitracin; brodimoprim; butirosin; colis ubenimex, amoxicillin; pravastatin; Xinafoate, imipenem; tin, capreomycin; dapsone; dibekacin; enviomycin; mycophenolic acid, or fluvastatin. glucosulfone Solasulfone, gramicidin S, polymyxin, teico 18. The polymer of claim 4 wherein the biologically planin; fortimicin(s); gentamicin(s); grepafloxin; imipenem; active compound is 3-amino-4-hydroxybutyric acid, 4-Sul isepamicin; kanamycin(s); lymecycline; micronomicin; neo fanilamidosalicylic acid; 6-diaZO-5-oxo-L-norleucine; ace mycin; netilmicin; p-Sulfanilylbenzylamine, paromomycin; clofenac; acediaSulfone, alminoprofen, amfenac; amphoteri ribostamycin, ristocetin; Sisomicin; Sparfloxacin; Spectino cin B; amplicillin, argatroban; aspoxicillin; azaserine; mycin; Sulfachrysoidine, Sulfamidochrysoidine, Sulfoxone; aztreonam, bromfenac, bumadizon; candicidin(s); carpro tetroXoprim; thiazolsulfone, tobramycin; trimethoprim; fen, carumonam, carZinophillin A, cefadroxil, cefatrizine; edatrexate, eflomithine, mannomustine, mitoxantrone; pep cefclidin, cefdinir, cefditoren, cefepime, cefetamet; lomycin; piritrexim; procarbazine, pteropterin; trimetrexate, cefixime, cefimenoXime, cefminox, cefodizime, ceforanide; gusperimus, butethamine; naepaine, piridocaine; troSpecto cefotaxime, cefotiam, cefoZopran, cefpirome, cefprozil; mycin; tuberactinomycin; Vancomycin; candicidin(S); cefroXadine, ceftazidime, cefteram, ceftibuten, ceftriaxone; mepartricin; perimycin A, ranitidine, famotidine, met cefuZonam, cephalexin; cephaloglycin; cephalosporin C, formin; nizatidine, carboplatin; lisinopril; methotrexate, cephradine, clinafloxacin; cyclacillin; denopterin, edatrex mitomycin; bleomycin(s); or thioguanine. ate, eflornithine; enfenamic acid; enoxacin; epicillin, etod 15. The polymer of claim 4 wherein the biologically olac, enviomycin, teicoplanin; flufenamic acid, grepafloxa active compound is 2-p-Sulfanilyanilinoethanol, 4-Sulfanil cin, hetacillin, imipenem, lomefloxacin; lucensomycin; amidosalicylic acid; amikacin; amphotericin B, apramycin; lymecycline; meclofenamic acid, mefenamic acid; mero arbekacin; aspoxicillin, butirosin; capreomycin, cefadroxil, penem; meSalamine; natamycin; niflumic acid; norfloxacin; cefatrizine, cefdinir, cefprozil, dibekacin, dihydroStrepto nyStatin; paZufloxacin; penicillin N, pipemidic acid; pro mycin; dirithromycin; enviomycin; gramicidin(s); teicopla codazole, pteropterin; S-adenosylmethionine, Sparfloxacin; nin; fortimicin(s); gentamicin(s); glucosulfone Solasulfone, Streptonigrin, Succisulfone, Sulfachrysoidine, temafloxacin; isepamicin; kanamycin(s); lucensomycin; lymecycline; tigemonam, tirofiban; tolfenamic acid; toSufloxacin; trova meropenem; micronomicin; natamycin; neomycin, netilmi floxacin, ubenimex, Vancomycin; enalapril; amoxicillin; cin; paromomycin; ribostamycin; ristocetin, Sisomicin; ciprofloxacin; diclofenac, lisinopril, ceftriaxone; cilastatin; Spectinomycin; Streptomycin; thiostrepton; tobramycin; tro benazepril, cefaclor, ceftazidime; quinapril; melphalan; or spectomycin; tuberactinomycin; Vancomycin; candicidin(S); methotrexate. mepartricin; nyStatin; perimycin A, tubercidin; anthramycin; 19. The polymer of claim 4 wherein the biologically azacitadine, bleomycin(s); carubicin; carZinophillin A; cyt active compound is phenamidine, acriflavine, chloroaZOdin, arabine, denopterin; elliptinium, epirubicin; mannomustine; arSphenamine, amicarbilide or aminoquinuride. peplomycin; pirarubicin; pteropterin; puromycin; Streptoni 20. The polymer of claim 2 which is a polymer of formula grin, tubercidin, ubenimex, Vindesline; Zorubicin, gusperi (7), (8), (9), (10), (11), (12), (13), (14), (15), or (16), or a mus, ubenimex, fenalcomine; hydroxytetracaine; polymer of formula (III), (IV), (V), or (VI), as illustrated orthocaine; 3-amino-4-hydroxybutyric acid; etofenamate; herein above. fepradinol, meSalamine, S-adenosylmethionine; leuprolide; 21. The polymer of claim 1 which comprises one or more acyclovir, paclitaxel, lamivudine, albuterol; indinavir, allen units of formula (II) in the backbone: dronate, Zidovudine, metoprolol, amoxicillin; Salmeterol; imipenem, doxorubicin; daunorubicin, idarubicin; pentosta -R-A-L-A-R-A-L-A- (II) tin, mitoxantrone; fludarabine phosphate; floXuridine, wherein cladribine; vinorelbine; Vincristine; or vinblastine. R and R are each independently a group that will yield 16. The polymer of claim 4 wherein the biologically a biologically active compound upon hydrolysis of the active compound is bambennycin(s); carbenicillin; carZino polymer; phillin A, cefixime, cefininox, cefpimizole, cefodizime, cefonicid, ceforanide, cefotetan, ceftibuten; cephalosporin each A is independently an amide or ester linkage, and C; denopterin, edatrexate, moxalactam, olSalazine; penicil each L is independently a linking group. lin N; quinacillin; temocillin; ticarcillin; N-5-(1,4-Dihy 22. The polymer of claim 2 wherein L is a divalent, dro-2-methyl-4-OXO-6-quinazolinyl)methylmethylamino branched or unbranched, Saturated or unsaturated, hydrocar 2-thienylcarbonyl-L-glutamic acid, lisinopril; cilastatin; bon chain, having from 1 to 25 carbon atoms, wherein one ceftazidime; or methotrexate. or more (e.g. 1, 2, 3, or 4) of the carbon atoms is optionally 17. The polymer of claim 4 wherein the biologically replaced by (-O-) or (-NR-), and wherein the chain is active compound is 4-Sulfanilamidosalicylic acid; amphot optionally Substituted on carbon with one or more (e.g. 1, 2, ericin B; apalcillin, apicycline; aspoxicillin, bambermy 3, or 4) Substituents selected from the group consisting of cin(s); biapenem, cefadroxil, cefamandole, cefatrizine, cef (C-C)alkoxy, (C-C)cycloalkyl, (C-C)alkanoyl, (C- buperaZone, cefdinir, cefonicid, cefoperaZone, cefpiramide; C.)alkanoyloxy, (C-C)alkoxycarbonyl, (C-C)alkylthio, cefprozil; enviomycin, teicoplanin; flomoxef, glycol Salicy azido, cyano, nitro, halo, hydroxy, OXO, carboxy, aryl, ary late; lucensomycin; lymecycline; meropenem; moxalactam, loxy, heteroaryl, and heteroaryloxy. mupirocin, nadifloxacin; natamycin; panipenem; podophyl 23. The polymer of claim 2 wherein L is a divalent, linic acid 2-ethylhydrazine, ritipenem; SalazOSulfadimidine, branched or unbranched, Saturated or unsaturated, hydrocar Sulfaloxic acid; Vancomycin; 3-amino-4-hydroxybutyric bon chain, having from 1 to 25 carbon atoms, wherein the acid; candicidin(s); carZinophillin A; denopterin; diflunisal; chain is optionally Substituted on carbon with one or more US 2002/0071822 A1 Jun. 13, 2002

(e.g. 1, 2, 3, or 4) Substituents selected from the group 40. A therapeutic method for treating cancer comprising consisting of (C-C)alkoxy, (C-C)cycloalkyl, (C- administering to an animal in need of Such therapy, an C.)alkanoyl, (C-C)alkanoyloxy, (C-C)alkoxycarbonyl, effective amount of a polymer of claim 7. (C-C)alkylthio, azido, cyano, nitro, halo, hydroxy, Oxo, 41. A therapeutic method for producing an anti-inflam carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy. matory effect in an animal comprising administering to an 24. The polymer of claim 2 wherein L is a peptide. 25. The polymer of claim 2 wherein L is an amino acid. animal in need of Such therapy, an effective amount of a 26. The polymer of claim 2 wherein L is a divalent, polymer of claim 8. branched or unbranched, Saturated or unsaturated, hydrocar 42. A therapeutic method for producing an anti-bacterial bon chain, having from 1 to 25 carbon atoms, wherein one effect in an animal comprising administering to an animal in or more (e.g. 1, 2, 3, or 4) of the carbon atoms is optionally need of Such therapy, an effective amount of a polymer of replaced by (-O-) or (-NR-). claim 9. 27. The polymer of claim 2 wherein L is a divalent, 43. A therapeutic method for producing an anti-fungal branched or unbranched, Saturated or unsaturated, hydrocar effect in an animal comprising administering to an animal in bon chain, having from 3 to 15 carbon atoms, wherein one need of Such therapy, an effective amount of a polymer of or more (e.g. 1, 2, 3, or 4) of the carbon atoms is optionally claim 10. replaced by (-O-) or (-NR-), and wherein the chain is 44. A therapeutic method for producing an immunoSup optionally Substituted on carbon with one or more (e.g. 1, 2, pressive effect in an animal comprising administering to an 3, or 4) Substituents selected from the group consisting of animal in need of Such therapy, an effective amount of a (C-C)alkoxy, (C-C)cycloalkyl, (C-C)alkanoyl, (C- polymer of claim 12. C.)alkanoyloxy, (C-C)alkoxycarbonyl, (C-C)alkylthio, 45. A therapeutic method for producing an anti-throm azido, cyano, nitro, halo, hydroxy, OXO, carboxy, aryl, ary botic effect in an animal comprising administering to an loxy, heteroaryl, and heteroaryloxy. animal in need of Such therapy, an effective amount of a 28. The polymer of claim 2 wherein L is a divalent, polymer of claim 11. branched or unbranched, Saturated or unsaturated, hydrocar bon chain, having from 3 to 15 carbon atoms, wherein one 46. A method for producing a biocompatible and biode or more (e.g. 1, 2, 3, or 4) of the carbon atoms is optionally gradable polyester or polyamide which degrades into a replaced by (-O-) or (-NR-). biologically active compound comprising co-polymerizing a 29. The polymer of claim 2 wherein L is a divalent, biologically active compound containing at least two alcohol branched or unbranched, Saturated or unsaturated, hydrocar or phenol groups or at least two amine groups with carboxy bon chain, having from 3 to 15 carbon atoms. lic acid groups or bis(acyl) chlorides. 30. The polymer of claim 2 wherein L is a divalent, 47. A method of delivering a biologically active com branched or unbranched, hydrocarbon chain, having from 3 pound to a host comprising administering to the host a to 15 carbon atoms. biocompatible and biodegradable polyester or polyamide of 31. The polymer of claim 2 wherein L is a divalent, claim 1. branched or unbranched, hydrocarbon chain, having from 6 48. A therapeutic method for treating pSoriasis, inflam to 10 carbon atoms. matory bowel disease, skin cancer, or a brain tumor com 32. The polymer of claim 2 wherein L is a divalent prising administering to a mammal in need of Such therapy, hydrocarbon chain having 7, 8, or 9 carbon atoms. an effective amount of a polymer of any one of formulae 10, 33. The polymer of claim 2 wherein L is a divalent 11, 12 or 20 as described herein. hydrocarbon chain having 8 carbon atoms. 49. A therapeutic method for producing an anti-infective 34. A biocompatible and biodegradable polyester or effect in an animal comprising administering to an animal in polyamide comprising a biologically active compound con need of Such therapy, an effective amount of a polymer of taining at least two alcohol or phenol groups or at least two any one of formulae 10, 11, 12 or 20 as described herein. amine groups co-polymerized to bis(acyl) chlorides or car boxylic acids. 50. A therapeutic method for treating cancer comprising 35. The polymer of claim 1 further comprising another administering to an animal in need of Such therapy, an therapeutic agent dispersed in the matrix of the polymer. effective amount of a polymer of any one of formulae 10, 11, 36. The polymer of claim 1 further comprising another 12, 13, 14 or 20 as described herein. therapeutic agent appended to the polymer backbone. 51. A therapeutic method for treating pain comprising 37. A pharmaceutical composition comprising a polymer administering to an animal in need of Such therapy, an of claim 1 and a pharmaceutically acceptable carrier. effective amount of a polymer of formula 7 as described 38. A therapeutic method for treating a disease in an herein. animal comprising administering to an animal in need of 52. A therapeutic method for treating Parkinson's disease Such therapy, an effective amount of a polymer of claim 1. comprising administering to a mammal in need of Such 39. Atherapeutic method for producing an analgesic effect therapy, an effective amount of a polymer of formula 8 as in an animal comprising administering to an animal in need described herein. of Such therapy, an effective amount of a polymer of claim 6.