US008O26285B2

(12) United States Patent (10) Patent No.: US 8,026,285 B2 BeZWada (45) Date of Patent: Sep. 27, 2011

(54) CONTROL RELEASE OF BIOLOGICALLY 6,955,827 B2 10/2005 Barabolak ACTIVE COMPOUNDS FROM 2002/0028229 A1 3/2002 Lezdey 2002fO169275 A1 11/2002 Matsuda MULT-ARMED OLGOMERS 2003/O158598 A1 8, 2003 Ashton et al. 2003/0216307 A1 11/2003 Kohn (75) Inventor: Rao S. Bezwada, Hillsborough, NJ (US) 2003/0232091 A1 12/2003 Shefer 2004/0096476 A1 5, 2004 Uhrich (73) Assignee: Bezwada Biomedical, LLC, 2004/01 17007 A1 6/2004 Whitbourne 2004/O185250 A1 9, 2004 John Hillsborough, NJ (US) 2005/0048121 A1 3, 2005 East 2005/OO74493 A1 4/2005 Mehta (*) Notice: Subject to any disclaimer, the term of this 2005/OO953OO A1 5/2005 Wynn patent is extended or adjusted under 35 2005, 0112171 A1 5/2005 Tang U.S.C. 154(b) by 423 days. 2005/O152958 A1 7/2005 Cordes 2005/0238689 A1 10/2005 Carpenter 2006, OO13851 A1 1/2006 Giroux (21) Appl. No.: 12/203,761 2006/0091034 A1 5, 2006 Scalzo 2006/0172983 A1 8, 2006 Bezwada (22) Filed: Sep. 3, 2008 2006,0188547 A1 8, 2006 Bezwada 2007,025 1831 A1 11/2007 Kaczur (65) Prior Publication Data FOREIGN PATENT DOCUMENTS US 2009/0076174 A1 Mar. 19, 2009 EP OO99.177 1, 1984 EP 146.0089 9, 2004 Related U.S. Application Data WO WO9638528 12/1996 WO WO 2004/008101 1, 2004 (60) Provisional application No. 60/969,787, filed on Sep. WO WO 2006/052790 5, 2006 4, 2007. OTHER PUBLICATIONS (51) Int. Cl. J. Org. Chem, 1959, 24, 523-526. A6 IK 47/48 (2006.01) Gutowska et al. J. Biomater, Res., 29, 811-21 (1995). Hoffman, J. Controlled Release, 6, 297-305 (1987). (52) U.S. Cl...... 514/772.3; 424/426 Mikos et al. Biomaterials, 14, 323-329 (1993). (58) Field of Classification Search ...... None Shugens et al. J. Biomed. Mater. Res., 30, 449-462 (1996). Bulletin of the Material Research Society, Special Issue on Tissue See application file for complete search history. Engineering (Guest Editor: Joachim Kohn), 21 (11), 22-26 (1996). Remington's Pharmaceutical Sciences, 18' ed., Mack Publishing (56) References Cited Company, Eason, PA, 1990, p. 1445. van Dijk-Wolthuis, W.N.W.; Hoogeboom, J.; van Steenbergen, M.; U.S. PATENT DOCUMENTS Tsang, S.; and Hennick, W. "Degradation and Release Behavior of Dextran-Based Hydrogels', Macromolecules, 30; (1997) 4639 3,903,007 A 9, 1975 Ernst 4645. 3,987,797 A 10/1976 Stephenson van Dijk-Wolthuis, W.N.E., Tsang, S.; Kettenes-van den Bosch, J.; 4,020, 100 A 4, 1977 Evans and Hennick, W. "A new class of polymerizable dextrans with 4,024,871 A 5/1977 Stephenson hydrolysable groups: hydroxyethyl methacrylated dextran with and 4,130,639 A 12/1978 Shalaby without oligolactate spacer', Polymer, 38 (25); (1997) 6235-6242. 4,532,928 A 8, 1985 Bezwada Kurisawa et al. Macromol. Chem. Phys. 199,705-709 (1998). 4,605,730 A 8/1986 Shalaby Heller, J.; Helwing, R.F.; Baker, R.W.; and Tuttle, M.E. "Controlled 4,653,497 A 3, 1987 Bezwada release of water-soluble macromolecules from bioerodible 4,689,424 A 8/1987 Shalaby hydrogels' Biomaterials, 4; (1983) 262-266. 4,829,099 A 5, 1989 Fuller Brondsted (Brondsted, H.; and Kopccek, J. “Hydrogels for site 4,886,870 A 12/1989 D'Amore specific oral drug deliver: Synthesis and characterization' Biomateri 5,082,925 A 1/1992 Shalaby als, 12; (1991) 584-592. 5,378,540 A 1, 1995 Olson Ulbrich, K.; Subr, V.; Seymour, L.W.; and Duncan, R. “Novel biode 5,521,431 A 5, 1996 Tahara gradable hydrogels prepared using the divinylic crosslinking agent 5,759,830 A 6, 1998 Vacanti N, O-dimethacryloylhydroxylamine 1. Synthesis and characteriza 5,801,033. A 9, 1998 Hubbell tion of rates of gel degradation, and rate of release of model drugs, in 5,834,274 A 11, 1998 Hubbell vitro and in vivo” Journal of Controlled Release, 24; (1993) 181-190. 5,834,513 A 11/1998 Ptchelintsev 5,843,743 A 12, 1998 Hubbell Primary Examiner — Robert A Wax 5,895,150 A 4, 1999 Watabe Assistant Examiner — Danah Al-Awadi 5,932,229 A 8, 1999 Ptchelintsev (74) Attorney, Agent, or Firm — Vance Intellectual Property, 5,951,997 A 9, 1999 Bezwada PC 6,045,813 A 4/2000 Ferguson 6,083,208 A 7, 2000 Modak (57) ABSTRACT 6,106,505 A 8, 2000 Modak The present invention relates to the discovery of biodegrad 6,207,139 B1 3, 2001 Lee 6,224,579 B1 5, 2001 Modak able multi-armed oligomers wherein the end groups of these 6,468,519 B1 10/2002 Uhrich oligomers have been functionalized with biologically active 6,596,657 B1 7/2003 Shalaby molecules. The resultant multi-armed oligomers end-func 6,689,350 B2 2/2004 Uhrich tionalized with biologically active molecules have a control 6,773,721 B1 8/2004 Wong lable degradation profile. The hydrolytic degradation of oli 6,780,799 B2 8/2004 Shalaby gomers of the present invention releases the biologically 6,861,068 B2 3/2005 Ng active compound as such with no change in native chemical 6,869,615 B2 3, 2005 Chen Structure. 6,887,974 B2 5, 2005 Pathak 6,890,561 B1 5, 2005 Blatt 38 Claims, No Drawings US 8,026,285 B2 1. 2 CONTROL RELEASE OF BIOLOGICALLY DETAILED DESCRIPTION OF THE PRESENT ACTIVE COMPOUNDS FROM INVENTION MULT-ARMED OLIGOMERS The present invention relates to the discovery of biodegrad CROSS REFERENCE TO RELATED 5 able multi-armed (two armed, three armed, four armed, six APPLICATIONS armed) oligomers wherein the end groups of these oligomers have been functionalized with biologically active molecules. This application claims the benefit of U.S. Application No. The resultant multi-armed oligomers end-functionalized with 60/969,787, filed Sep. 4, 2007, the entirety of which is incor biologically active molecules have a controllable degradation 10 profile. The hydrolytic degradation of oligomers of the porated herein by reference. present invention releases the biologically active compound as such with no change in native chemical structure. FIELD OF THE INVENTION As used herein, the term “biologically active compound The present invention relates to the discovery of biodegrad refers to a naturally occurring, semi-synthetic, or synthetic 15 therapeutic agent that provides a therapeutically desirable able multi-armed oligomers wherein the end groups of these effect when administered to a mammal (e.g., human). Bio oligomers have been functionalized with biologically active logically active compounds capable of incorporation into molecules. The resultant multi-armed oligomers end-func polymers of the present invention possess at least two func tionalized with biologically active molecules have a control tional groups that can each be incorporated into an ester or lable degradation profile. The hydrolytic degradation of oli amide linkage of a polymer of the present invention, such that, gomers of the present invention releases the biologically upon hydrolysis of the polymer, the therapeutic agent is active compound as Such with no change in native chemical obtained. The biologically active compounds useful in the Structure. present invention have at least one aryl or heteroaryl ring and at least one hydroxyl (OH), substituted or unsubstituted BACKGROUND OF THE INVENTION 25 amino, or carboxylic acid substituent on the aromatic or het eroaromatic ring, or functional derivatives of Such substitu Biologically active compounds are well known (e.g., aspi ents, such as esters, amides, methyl ethers, and/or glycosides, rin and capsaicin) and have been beneficially administered to or other derivatives that would be apparent to those skilled in patients in need thereof for more than a century. One problem the art. Additional examples of the number of aromatic that has been associated with many biologically active com 30 groups present in the phenolic include (a) 1, 2, and 3 and (b) pounds is that they can be difficult to dissolve in water or the 1 and 2. Additional examples of the number of functional human body and can also be very difficult to polymerize. Due (e.g., hydroxyl) groups present on the phenolic include (a) 1, to the availability and numerous uses of biologically active 2, 3, 4, and 5 and (b) 1 and 2. compounds, it is desirable to enhance their native value by, for The biologically active compounds can also comprise example, providing compounds or combinations of com 35 other functional groups (e.g., hydroxyl groups, amine groups, pounds with a specific controlled degradation profile or range and carboxylic acids) that can be used to modify the proper ties of the polymer (e.g. for branching, for cross linking, for enabling controlled release of the biologically active com appending other molecules (e.g. another biologically active pound over an extended, controllable time range. The present compound) to the polymer, for changing the solubility of the invention is directed to these and other important ends. 40 polymer, or for effecting the biodistribution of the polymer. Lists of therapeutic agents can be found, for example, in: SUMMARY OF INVENTION Physicians’ Desk Reference, 61 Ed., 2007, Thomson Healthcare Company: USPN Dictionary of USAN and Inter The present invention relates to biodegradable multi national Drug Names, 2000, The United States Pharmaco armed (e.g., 2, 3, 4, 5, or 6 arms) oligomers wherein the end 45 poeia Convention, Inc., Rockville, Md.; and The Merck groups of these oligomers have been functionalized with bio Index, 14" Ed., 2007, John Wiley & Sons. One skilled in the logically active molecules. art can readily select therapeutic agents that possess the nec The present invention also provides a method of preparing essary functional groups for incorporation into the polymers absorbable oligomer compositions comprising functional of the invention from these lists. ized biologically active compounds and a pharmaceutically 50 Therapeutic agents that may be incorporated into the poly acceptable carrier. mers of the invention include Suitably functionalized analge The present invention also provides a therapeutic method sics or general or local anesthetics, anti-convulsants, anti for treating a disease in a mammal comprising administering diabetic agents, anti-fibrotic agents, anti-infectives, anti to a mammal in need of such therapy, an effective amount of bacterials, anti-fungals, anti-neoplastics, cardioprotective an oligomer of the present invention. 55 agents, cardiovascular agents, anti-thrombotics, central ner The present invention also provides a method of delivering Vous system stimulants, cholinesterase inhibitors, contracep a biologically active compound to a mammal comprising tives, deodorants, dopamine receptor agonists, erectile dys administering to the mammalabiocompatible and biodegrad function agents, fertility agents, gastrointestinal agents, gout able oligomer of the present invention, which degrades into agents, hormones, immunomodulators, immunosuppressive, the biologically active compound. 60 migraine agents, non-steroidal anti-inflammatory drugs The present invention also provides an oligomer for use in (NSAIDs), motion sickness agents, muscle relaxants, nucleo medical therapy, as well as the use of an oligomer for the side analogs, neurodegenerative agents (e.g., Parkinson's dis manufacture of a medicament useful for the treatment of a ease), obesity agents, ophthalmic agents, osteoporosis disease in a mammal. agents, parasympatholytics, parasympathomimetics, anti-an The invention also provides processes of functionalizing 65 esthetics, prostaglandins, psychotherapeutic agents, respira biologically active compounds and preparation of biologi tory agents, sedatives, hypnotics, skin and mucous membrane cally active oligomer with controlled degradation profiles. agents, Smoking cessation agents, sympatholytics, urinary US 8,026,285 B2 3 4 tract agents, vaginal agents, and vasodilators, and the like (see norfenefrine, normolaxol, octopamine, omeprazole, orci Physicians’ Desk Reference, 61 Ed., 2007, Thomson Health prenaline, OXilofrine, oxitriptan, oxyfedrine, oxypertine, Care). oxyphenbutaZone, oxyphenisatin acetate, oxyquinoline, Phenol is the simplest example of a phenolic compound, papaverine, paracetanol, parethoxycaine, phenacaine, phen but most phenolics have two or more hydroxyl groups and are 5 acetin, phenazocine, phenolphthalein, phenprocoumon, in many instances bioactive Substances occurring widely in phentolamine, phloedrine, picotamide, pimobendan, prenal food plants that are eaten regularly by Substantial numbers of terol, primaquine, progabide, propanidid, protokylol. animals and people. These food-plant bioactive phenolic proxymetacaine, raloxifene hydrochloride, repaglinide, compounds have typically been found to be safe compounds. reproterol, rimiterol, ritodrine, salacetamide, Salazosulfapy Included in the definition of biologically active phenolics are 10 highly Substituted poly-phenols whose structures include ridine, Salbutamol, salicylamide, Salicylic acid, salmeterol, condensed rings. Salsalate, sildenafil. Silibinin, Sulmetozin, tamsulosin, tera Examples of naturally occurring biologically active phe Zosin, terbutaline, tetroXoprim, theo-drenaline, tioclomarol, nolics include bergaptol, caffeic acid, capsaicin, coumarin, tioxolone, C.-tocopherol (vitamin E), tofisopam, tolcapone, daidzein, 2.5-dihydroxy-benzoic acid, ferulic acid, fla 15 tolterodine, tranilast, tretoquinol, triclosan, trimaZosin, tri vonoids, glycitein (isoflavone), 4-hydroxycinnamic acid, metazidine, trimethobenz-amide, trimethoprim, trimetozine, 4-hydroxy-coumarin, isopimpinellin, resveratrol. Sinapic trimetrexate glucuronate, troXipide, Verapamil, Vesnarinone, acid, vanillic acid, vanillin, and derivatives thereof. Vetrabutine, Viloxazine, warfarin, Xamoterol. Capsaicin is a biologically active phenolic that is the active Other bioactive phenolics include acacetin, 4-acetamido component of cayenne pepper. The capsaicin is an amide of 2-methyl-1-naphthol, acetaminophen, albuterol, allenolic Vanillylamine and Cs to C branched fatty acids. Topical acid, aloe emodin, aloin, B-amino-4-hydroxy-3,5-di-iodohy application of capsaicin Stimulates and blocks Small pain drocinnamic acid, N-(5-amino-2-hydroxyphenyl)-benzene fibers by depleting them of the neurotransmitter substance P acetamide, 4-amino-1-naphthol, 3-aminosalicylic acid, that mediates pain impulses. A cream made from 0.025%- 4-aminosalicylic acid, anacardic acid, p-anol, anthragallol, 0.075% capsaicin applied 4 times daily reportedly may help 25 anthralin, anthranol, anthrarobin, anthrarufin, apigenin, peripheral neuropathic pain, post-herpetic neuralgia, trigemi apiin, apocynin, aspidinol, aspirin, baptigenin, benzestrol, nal neuralgia, psoriasis and fibromyalgia. It may also be use benzoresorcinol, bisphenol a, bisphenol b, butylated ful for diabetic neuropathy, clusterheadaches, earache, osteo hydroxylanisole, butylated hydroxytoluene, capobenic acid, and rheumatoid arthritis. Capsaicin is a powerful pain trans-1-(3'-carboxy-4-hydroxyphenyl)-2-(2".5"-dihydrox reliever. 30 yphenyl)ethane, catechin, chlorogenic acid, m-chlorophenol, Naproxen, paracetanol, acetaminophen and acetylsalicylic 5-chloro-8-quinolinol, chloroxylenol, chlorquinaldol. acid are biologically active phenolics that belong to the class chromo-nar, chrysin, cinametic acid, clorophene, coniferyl of drugs called non-steroidal anti-inflammatory drugs or alcohol, p-coumaric acid, coumes-trol, coumetarol, daphne NSAIDs. It is generally believed that NSAIDs provide relief tin, datiscetin, deoxyepinephrine, 3.5-diiodothyronine, 3.5- by blocking the action of prostaglandins, which are hormone 35 di-iodotyrosine, dimethophrine, dioSmetin, diresorcinol, like Substances that contribute to pain, inflammation, fever disoprofol, dopa, dopamine, drosophilina, efloxate, ellagic and muscle cramps. acid, embelin, Equol. eriodictyol, esculetin, esculin, ethyl Phenolic moieties, synthetic and naturally occurring, are norepinephrine, ethyl Vanillin, eugenol, eupatorin, fenadiaz part of many drugs. Examples of these medicinals include ole, ferulic acid, fisetin, 3-fluoro-4-hydroxyphenylacetic acenocoumarol, acetarsol, actinoquinol, adrenalone, aliben 40 acid, fraxetin, fustin, galangin, gallacetophe-none, gallic dol, amodiaquine, anethole, balsalazide, bamethan, benser acid, gardenins, genistein, gentisyl alcohol, gepefrine, gera azide, bentiromide, benzarone, benzquinamide, bevantolol. nylhydroqui-none, 6-gingerol, gossypol, guaiacol, guaifen bifluranol, buclosamide, bupheniode, chlorotrianisene, esin, harmalol, hematoxylin, hinderin, homoeriodictyol. chloroxylenol, cianidanol, cinepazide, cinitapride, homogentisic acid, homoVanillic acid, hydroxyamphet cinepazide, cinmetacin, clebopride, clemastine, clioquinol, 45 amine, 2-hyd-roxy-5-(2,5-dihydroxybenzylamino)-2-hy cyclovalone, cynarine, denopamine, dextroy thyroxine, droxybenzoic acid, 4-hydroxy-3-methoxy-mandelic acid, diacerein, dichlorophen, dienestrol, diethylstilbestrol, n-(p-hydroxyphenyl)glycine, hydroxyprocaine, 8-hydrox diflunisal, diiodohydroxyquinoline, dilaZep, dilevalol, ycuinoline, hypericin, irigenin, isoproterenol, isoquercitrin, dimestrol, dimoxyline, dioSmin, dithranol, dobutamine, isothebaine, kaempferol, liothyronine, luteolin, mangostin, donepezil, dopamine, dopexamine, doxazosin, entacapone, 50 5.5'-methylenedisalicylic acid, n-methylepinephrine, mety epanolol, epimestrol, epinephrine, estradiol Valerate, estriol, rosine, morin, mycophenolic acid, myricetin, naringenin, estriol Succinate, estrone, etamivan, etamsylate, ethaverine, nylidrin, orcinol, osalmid, osthole, oxantel, paroxypropione, ethoXZolamide, ethyl biscoum-acetate, etillefrine, etiroXate, pentachlorophenol, 3-pentadecylcatechol, p-pentyloxy-phe exalamide, exifone, fendosal, fenoldopam mesilate, fenot nol, phloretin, phloroglucinol, pinosylvine, plumbagin, pyro erol, fenoxedil, fenticlor, flopropione, floredil, fluorescein, 55 catechol, pyrogallol, quercetagetin, quercetin, resacetophe folescutol, formo-terol, gallopamil, gentistic acid, glazio none, rhamnetin, rhein, Sakuranetin, salicyl alcohol, Vine, glibenclamide, glucametacin, guajacol, halquinol, salicylanilide, 4-salicyloylmorpholine, Salsalate, Scopoletin, hexachlorophene, hexestrol, hexobendine, hexoprenaline, Scutellarein, serotonin, (3,4,5-trihydroxyphenyl)methyl hexylresorcinol, hydroxyethyl salicylate, hydroxyStilbami enepropanedinitrile, thymol, thyropropic acid, thyroxine, dine isethionate, hymecromone, ifenprodil, indomethacin, 60 tiratricol, tyrosine, Vanillic acid, and Vanillin. ipriflavone, isoetarine, isoprenaline, isoxSuprine, itopride Examples of biologically active amino compounds include hydrochlor-ide, ketobemidone, khellin, labetalol, lactylphe Aceclofenac, Acediasulfone, Alminoprofen, Amisulpride, netidin, levodopa, levomepromazine, levorphanol, levothy AmLexanox, Amodiaquine, Amosulalol. Amoxicillin, Amsa roXine, mebeverine, medrylamine, mefexamide, mepacrine, crine, Anileridine, AZacyclonol, Baccofen, BalsalaZide mesalazine, mestranol, metaraminol, methocarbamol, meth 65 Sodium, Benzocaine, Bromopride, Bumetanide, Carprofen, oxamine, methoXSalen, methyldopa, midodrine, mitox Carvedilol, Carzenide, Cefprozil, Cinitapride, Clebopride, antrone, morclofone, nabumetone, naproxen, nitroxo-line, Clenbuterol, Diclofenac, EthoXZolamide, Flufenamic acid, US 8,026,285 B2 5 6 Furosemide, lobenzamic acid, locetamic acid, Mefenamic g. A Single Source for Flavonoids and Coumarins (2005 acid, Nadoxolol, D-Nor-pseudoephedrine and paracetamol. 2006), INDOFINE Chemical Company, Inc. 2006. Examples of biologically active carboxylic acid com The present invention provides novel oligomers of formu pounds include Acemetacin, Aceclofenac, Acediasulfone, lae I and/or II or a pharmaceutically acceptable salt thereof: Adipiodone, Alminoprofen, AmLexanox, Anileridine, Bac cofen, Balsalazide Sodium, Bentiromide, Benzocaine, Bumetanide, Carprofen, Carzenide, Cinmetacin, Clometa cin, Cromoglicic acid, Diclofenac, Diflunisal, Eprosartan, Fendosal, Flufenamic acid, Furosemide, Indometacin, Ioben Zamic acid, locarmic acid, locetamic acid, Iodoxamic acid, 10 R'-O- is a biologically active compound residue; loglycamic acid, lophenoic acid, lotroXic acid, Mefenamic R’ C(=O)C)— is a biologically active compound resi acid, Naproxen, Nedocromil, Repaglinide, Salazosulfapyri due; dine, Salicylic Acid, Salsalate, and Sarpogrelate. X is selected from: —OC(=O)CH (inverse glycolic Flavonoids, sometimes called bioflavonoids, are 3-ring acid moiety), —OC(=O)CH(CH)— (inverse lactic phenolic compounds consisting of a double ring attached by 15 acid moiety), —OC(=O)CHOCH2CH2— (inverse a single bond to a third ring. Examples include flavonoids, dioxanone acid moiety), OC(=O) flavanones, flavones, flavanols, anthocyanidins, proanthocya CHCHCHCH-CH (inverse caprolactone acid nidins, procyanidolic oligomers (PCO), catechins, biflavans, moiety), OC(=O) (CH), , or OC(=O)CH, polyphenols, rutin, rutinosides, hydroxyethylrutosides (OCH2CH)—. (HER), hesperidin, quercetin, quercetrin, polyphenols, cat X' is selected from: —CHC(=O)C)—(glycolic acid moi echin, epicatechin, epicatechin gallate, epigallocatechingal ety), —CH(CH)C(=O)C)— (lactic acid moiety), late, and leucoanthocyanins. Flavonoids include the water —CH2CH2OCHC(=O)C)— (dioxanone acid moiety), soluble pigments, such as anthocyanins, that are found in cell —CHCHCHCHCHC(=O)C)— (caprolactone vacuoles. Flavonols are colorless or yellow flavonoids found acid moiety), -(CH2),C(=O)C , or -(CH2CH2O). in leaves and many flowers. 25 CHC(=O)C)–: A therapeutic dose of bioflavonoids is helpful for condi Y is selected from: —C(=O)CHO— (glycolic ester moi tions related to Chronic Venous Insufficiency (CVI). Some ety), —C(=O)CH(CH)O— (lactic ester moiety), examples are: thrombophlebitis, thrombosis, varicose veins, —C(=O)CHOCH2CH2O (dioxanone ester moi leg ulcers, spider veins, hemorrhoids, chronic nosebleeds, ety), —C(=O)CHCH2CH2CH2CH2O (caprolac prolonged menstrual bleeding. Even eye problems like macu 30 tone ester moiety), —C(=O)(CH)O , or—C(=O) lar degeneration and diabetic retinopathy have been helped CH-O-(CH2CH2O) ; with bioflavonoids. Along with the anti-inflammatory effects, Y' is selected from: —OCHC(=O)– (inverse glycolic bioflavonoids can be very helpful for tendonitis, arthritis, ester moiety), —OCH(CH)C(=O)— (inverse lactic rheumatoid arthritis, joint injury, fibromyalgia, cellulite, and ester moiety), —OCHCHOCHC(=O)— (inverse gout. Bioflavonoids, specifically proanthcyanidins, are found 35 dioxanone ester moiety), —OCHCHCHCHCHC in grape seed extract. The proanthcyanidins appear to (=O)— (inverse caprolactone ester moiety), —O(C enhance the activity of vitiamin C. The bioflavonoids in grape H),C(=O)—, or —O(CH2CH2O), OCHC(=O)—: seed extract may also reduce the painful inflammation of R is a di-, tri, tetra-, penta- or hexaradical derived from swollen joints and prevent the oxidation of cholesterol in C-2s alkyl, aryl, or aryl-(Calkyl)--, wherein from arteries that leads to plaque in the arterial walls. 40 1-3 of the CH groups within the alkyl chain are option Isoflavones exert abroad spectrum of biological activities. ally independently replaced by O atoms, such that each Besides antioxidant and estrogenic activities, isoflavones of said O atom is attached only to carbon atoms in the protect against several chronic diseases. Results of epidemio alkyl chain, with the proviso that multiple O atoms that logical studies indicate that consumption of soybean isofla replace CH groups within the alkyl chain must be sepa Vones lowers the incidence of breast, prostate, urinary tract 45 rated from each other by at least two carbon atoms and and colon cancers. They also provide protection against coro from the di-, tri, tetra-, penta- or hexaradical chain ends nary heart diseases and osteoporosis. Examples of isofla by at least one carbon atom; or R is the backbone of a Vones include are glycitein (isoflavone), daidzein, prunetin, polymer or copolymer bearing carboxylic acid and/or biochanin A, orobol, Santal, pratensein, formononetin, hydroxyl functional groups, where the average molecu genistein, glycitein, and the glucosides, B-glycosides and 50 lar weight of the polymer or copolymer is between 500 other derivatives of the aforementioned isoflavones. to 5000 and wherein w is an integer from about 6 to about Further examples of biologically active compounds with 50; hydroxyl, carboxyl and/or amino groups useful in the present a is independently selected from 1, 2, 3, 4, 5, 6, 7,8,9, and invention may be found in the following texts, which are 10: hereby incorporated in their entireties herein by reference. 55 b is independently selected from 1, 2, 3, 4, 5, 6,7,8,9, and a. Shahidi, Ferriodoon and Marian Naczk, Phenolics in Food 10: and Nutriceuticals, Boca Raton, Fla.: CRC Press, 2003. each a and b is independently an integer from about 1 to b. Kleemann, A. et al., Pharmaceutical Substances, 4th Edi about 10: tion, Thieme (2000). each m, n, y, and Z is independently an integer from about c. Phenolic Compounds in Food and Their Effects on Health 60 2 to about 24; and II; Antioxidants and Cancer Prevention, ACS Symposium w is an integer from about 2 to about 6. Series No. 507, Washington, D.C.: ACS, 1992. The groups represented by X, X,Y', and Y are attached as d. Food Phytochemicals for Cancer Prevention I, ACS Sym shown. Their left hand sides are attached to the group shown posium Series N. 546, Washington, D.C.: ACS, 1994. in the corresponding formula to be on the left of the X, X, Y, e. ROMPP Encyclopedia Natural Products, New York: Thi 65 orY' group and on their right hand sides to the group shown eme, 2000. in the corresponding formula to be on the right of the X, X', f. The Merck Index, 14" edition, John Wiley & Sons, 2007. Y, or Y' group. US 8,026,285 B2 7 8 In some preferred embodiments of oligomers or pharma In certain preferred embodiments of the present invention, ceutically acceptable salts thereofofformula I or II, X" andY' each X* is independently —CHC(=O)C) , —CH(CH)C are derived from different hydroxyacid or lactone precursors. (=O)C) , - CHCHOCHC(=O)C) , O In some preferred embodiments of oligomers or pharma —CH2CH2CH2CHCHC(=O)C)—, more preferably ceutically acceptable salts thereof of formula I or II, X and Y 5 —CHC(=O)C)– or -CH(CH)C(=O)C-. are derived from different hydroxyacid or lactone precursors. In some preferred embodiments of the present invention, In other preferred embodiments of oligomers or pharma each Y is independently —C(=O)CHO , —C(=O)CH ceutically acceptable salts thereof of formulas I or II, R is a (CH)O-, -C(=O)CHOCHCH-O-, or -C(=O) di-, tri, tetra-, penta- or hexaradical derived from C-2s alkyl, CHCHCHCHCHO ; more preferably —C(=O) aryl, preferably phenyl, or aryl-(Calkyl)--, preferably 10 CHO or - C(=O)CH(CH)O-. phenyl-(Calkyl)-. Whether R is a di-, tri, tetra-, penta- or In some other preferred embodiments of the present inven hexaradical is determined by w. For example, when w is 2, R tion, each Y is independently —OCHC(=O)— —OCH is a diradical; when W is 4, R is a tetraradical, and so forth. In (CH)C(=O)—, –OCHCHOCHC(=O) , O certain preferred embodiments wherein R is derived from 15 —OCHCHCHCHCHC(=O) , more preferably C-2s alkyl or aryl-(C. alkyl). , 1-3 of the CH groups –OCHC(=O)– or - OCH(CH)C(=O)-. within the alkyl chain are optionally independently replaced Examples of polymers or copolymers containing carboxy by O or Satoms, preferably by Oatoms, such that each of said lic acid group and/or hydroxyl functional groups include O or S atoms is attached only to carbon atoms in the alkyl poly(acrylic acid), poly(acrylic acid-co-maleic acid), poly chain, preferably with the proviso that the O or S atoms are 20 (ethylene glycol), branched poly(ethylene glycol), and poly separated from the di-, tri, tetra-, penta- or hexaradical chain (acrylic acid-graft-polyethylene glycol). ends by at least one carbon atom and that multiple O or S Examples of biologically active compounds include phe atoms in the diradical chain must be separated from each nolic compounds including phenols, naphthols, indoles, other by at least two carbon atoms. Alternatively in some acetophenones, benzophenones, coumarins, furanocou preferred embodiments, when R is alkyl, it is more preferably 25 marins, alkaloids, catechins, chromones, chalcones, fla (CH), (CH), CH(CH), C(CH), or C(CH2CH)(CH). vonoids or bioflavonoids, isoflavones, drugs containing phe In still other preferred embodiments, R is (CH), and nolic groups, and natural products containing phenolic wherein the C-2CH group within the (CH), chain is option groups. ally replaced by an O atom. In yet other preferred embodi Examples of biologically active dihydroxy compound that ments, R is (CH), (CH), (CH), (CHOCH), or 30 can be used to prepare a polymer of the present invention (CHCHOCH2CH). In still other preferred embodiments, include Adrenalone, AlfuZosin, Alibendol, Amrubicin, Apo R is (CHCHCH) when w is 3, or (C(CH2)) when w is 4. morphine, Bamethan, Benzquinamide, Bevantolol, Biflura In certain other preferred embodiments, the present inven nol, Bisacodyl, Brodimoprim, Bunazosin, Bupheniode, Car tion provides novel multi-armed oligomers of formulae I or II bidopa, Carbuterol, Cyclofenil, Cyclovalone, Daunorubicin, or a pharmaceutically acceptable salt thereof, wherein: 35 Dichlorophen, Dienestrol, Diethylstilbestrol, Dimestrol, R is a di-, tri, tetra-, penta- or hexaradical derived from a Dithranol, Donepezil, Doxefazepam, Doxorubicin, Entaca C2-12 alkyl, phenyl, and phenyl-(C1-alkyl)--. pone, Epinepheine, Epirubicin, Esomeprazole, Etamivan, As used herein, the term “aryl-(C. alkyl)-- refers to a Etamsylate, Etilefrine, EZetimibe, Fenticlor, Fluorescein, aryl ring, preferably a benzene ring, having 1 to 3 pendant Folescutol. Formoterol, Gefitinib, Hexestrol, Hexylresorci alkyl groups, wherein the aryl-(C. alkyl)--, preferably 40 nol, Hydroxyethyl salicylate, Ifenprodil, Isoetarine, ISOXSu phenyl-(C. alkyl)-moiety, is attached to the remainder of prine, Itopride. HCl, Khellin, Labetalol, Mitoxantrone, Mor the structure in a given formula through its pendant alkyl clofone, Moxaverine, Normolaxol. Omeprazole, Oxilofrine, group(s). Oxepertine, Phenacaine, Phenolphthalein, Prazosin, Tolca In certain preferred embodiments of the present invention, pone, Vesnarinone, and Vetradutine. a is independently an integer from about 1 to about 5. Alter- 45 Examples of biologically active hydroxy/amino com natively preferred, each a is independently an integer from pounds that can be used to prepare a polymer of the present about 1 to about 6, preferably from 1 to about 3, with from 1 invention include Amisulpride, Amodiaquine, Amosulalol, to about 2 being even more preferred. Amoxicillin, Amsacrine, AZacyclonol, Bromopride, In other preferred embodiments of the present invention, b Carvedilol, Cefprozil, Cinitapride, Clebopride, Clenbuterol, is independently an integer from about 1 to about 5. Alterna- 50 EthoXZolamide, Nadoxolol, D-Norpseudoephedrine, and tively preferred, each b is independently an integer from paracetamol. about 1 to about 6, preferably from 1 to about 3, with from 1 Examples of biologically active dicarboxylic acid com to about 2 being even more preferred. pounds that can be used to prepare a polymer of the present In still other preferred embodiments of the present inven invention include Adipiodone, Cromoglicic acid, Eprosartan, tion, w is the integer 2, 3, or 4. 55 locarmic acid, Iodoxamic acid, loglycamic acid, lotroXic The present invention also provides novel multi-armed acid, Nedocromil. oligomers of formulae Ior II or a pharmaceutically acceptable Examples of biologically active hydroxy/carboxylic acid salt thereof, wherein the moiety R and the “w” number of compounds that can be used to prepare a polymer of the attached oxygenatoms (R—IO) is O(CH2)2O, wherein w is present invention include Acemetacin, Bentiromide, Cin 2: O(CH)O, wherein w is 2: CH(CHO), wherein w is 3: 60 metacin, Clometacin, Diflunisal, Fendosal, Indometacin, C(CHO), wherein w is 4; and C(CHCH)(CHO), lophenoic acid, Naproxen, Repaglinide, Salazosulfapyridine, wherein w is 3. Salicylic Acid, Salsalate, and Sarpogrelate. In other preferred embodiments of the present invention, Examples of biologically active hydroxyl-acids useful in each X is independently —OC(=O)CH2—, —OC(=O)CH the present invention include but not limited to 4-hydroxy (CH) , OC(=O)CHOCHCH , or - OC(=O) 65 cinnamic acid, Caffeic acid, Chlorogenic acid, Ferulic acid, CHCH2CH2CH2CH2—, more preferably —OC(=O) Sinapinic acid, Vanillic acid, Acemetacin, Bentiromide, Cin CH or - OC(=O)CH(CH) . metacin, Clometacin, Diflunisal, Fendosal, Indometacin, US 8,026,285 B2 lophenoic acid, Naproxen, Repaglinide, Salazosulfapyridine, -continued Salicylic Acid, Salsalate, and Sarpogrelate. OH Examples of biologically active amino/carboxylic acid compounds that can be used to prepare a polymer of the OH present invention include Aceclofenac, Acediasulfone, Almi N noprofen, Amlexanox, Anileridine, Baccofen, BalsalaZide n Sodium, Benzocaine, Bumetanide, Carprofen, Carzenide, H 21 N Diclofenac, Flufenamic acid, Furosemide, lobenzamic acid, N locetamic acid, and Mefenamic acid. 10 Some structures of Biologically Active Compounds bear NO ing hydroxyl functional groups useful in present invention are Nitroxoline Pholedrine shown below. OH OH N O 15 HO 21 ul NH Oxyquinoline Paracetamol N O N HO O O X= NH Capsaicin S Tioxolone 25 C OH Examples of Biologically Active Compounds bearing car O boxylic acid functional groups include but not limited to Acemetacin, Aceclofenac, Acediasulfone, Adipiodone, 30 Alminoprofen, Amlexanox, Anileridine, Baccofen, Bal C C Salazide sodium, Bentiromide, Benzocaine, Bumetanide, Carprofen, Carzenide, Cinmetacin, Clometacin, Cromoglicic Triclosan acid, Diclofenac, Diflunisal, Eprosartan, Fendosal, Flufe namic acid, Furosemide, Indometacin, lobenzamic acid, locarmic acid, locetamic acid, Iodoxamic acid, loglycamic O 35 acid, lophenoic acid, lotroxic cid, Mefenamic acid, Naproxen, Nedocromil, Repaglinide, Salazosulfapyridine, Salicylic Acid, Salsalate, and Sarpogrelate. Some structures of biologically active compounds bearing carboxyl functional groups useful in present invention are 40 O shown below. Benzarone

O OH 45 1n-1 HO O O OH 21 Methyl Salicylate 50 O OH C Chloroxylenol Hymercromone OH

55

S N OH n1 F F

I N Diflunisal 21 60 OH N O 1. O C OH 65 Clioquinol Etamivan Ibuprofen US 8,026,285 B2 11 12 -continued -continued

NH Cro C OH Tiaprofenic Acid O

10 Diclofenac 1S OH O OH O MeO 15 Naproxen O

O O N Fenbufen C O HO \ /

Tolimetin 25 N H Carprofen OH O O 30 S O \ / O Loxoprofen OH

35 O Suprofen

O OH N 40 O r

Ketorolac Mefenamic acid F 45 \ o HO C N H 50 OH O Etodolac O

OH 55 Lumiracoxib

O Ketoprofen C 60 OH F O S-C O R OH 65 Flurbiprofen Indometacin US 8,026,285 B2 13 14 Some of the biodegradable oligomers of the present inven Scheme 2. In the first step, a multi-armed biodegradable tion can be prepared in two steps as shown in Scheme 1. In the backbone can be derived by the functionalization of multi first step, a multi-armed backbone for the oligomers is derived armed hydroxyl (polyol) molecules with safe and biocompat ible monomers or oligomeric segments containing repeat by the functionalization of multi-armed acid molecules units derived from them to form multi-armed hydrolysable (shown as a tetra-acid) with safe and biocompatible mono linkers of formula C. Similarly, Biologically Active Com mers or oligomeric segments containing repeat units derived pounds bearing carboxyl functional groups can also be func from them to form multi-armed hydrolysable linker of for tionalized with safe and biocompatible monomers or oligo mula A. Similarly, Biologically Active Compounds bearing meric segments containing repeat units derived from them to hydroxyl functional groups can also be functionalized with form functionalized Biologically Active Compounds of For safe and biocompatible monomers or oligomeric segments 10 mula D. In the second step, multi-armed hydrolysable linker containing repeat units derived from them to form function of formula C and functionalized Biologically Active Com alized Biologically Active Compounds of Formula B. In the pounds of Formula D are reacted together in stoichiometric second step, multi-armed hydrolysable linker of formula A amounts to form multi-armed, biodegradable end functional and functionalized Biologically Active Compounds of For ized therapeutic oligomers of Formula II of the present inven 15 tion with controllable hydrolytic degradation profile. The mula B are reacted together in Stoichiometric amounts to resulting multi-armed oligomers of the present invention can form multi-armed, biodegradable end functionalized thera provide site specific delivery of bioactive compounds upon peutic oligomers of Formula I of the present invention with biodegradation by hydrolytic and/or enzymatic actions with controllable hydrolytic degradation profiles. The resulting controlled release of biologically active compounds as Such multi-armed oligomers of the present invention can provide site specific delivery of bioactive compounds upon biodegra with no change in native chemical structure. dation by hydrolytic and/or enzymatic actions with controlled release of biologically active compounds as Such with no Scheme 2 change in native chemical structure. Step 1 25 HO OH Scheme 1 Functionalization with safe and biocompatible molecules Step 1 HO OH HOOC COOH Functionalization with safe 30 Multiarmed and biocompatible molecules polyol HOOC DOC. H-e- precursor Multiarmed acid precursor 35 ------Formula C Functionalized multiarmed --- polyol precursor with b = 0 to 6 Formula A Functionalization with safe Funcionalized multiarmed 40 and biocompatible molecules acid precursor with a = 1 to 6 --- Functionalization with safe Biologically active compound and biocompatible molecules bearing carboxyl group GBAO-OH H-r Grad-COO-Xa-H Biologically active compound 45 bearing hydroxyl group Formula D Functionalized Biologically active compound with a = 1 to 6 Giac)-O-(Yb-CO-CHQ Step 2 Functionalized Biologically active compound with b = 0 to 6 and Q = F, Cl, Br, I 50 Formula B Step 2 ------Formula C -- Functionalized multiarmed --- polyol precursor with b = 0 to 6 Formula II of Formula A Functionalized multiarmed Grad-COO- (X)a-H -> present invention acid precursor with a = 1 to 6 Formula D Formula I 60 Functionalized Biologically Hoss of present active compound with a = 1 to 6 Functionalized Biologically active compound invention with b = 0 to 6 and Q = F, Cl, Br, I Formula B Some examples of linear and multi-armed hydrolysable linker precursors of present invention are shown below: (e.g., 65 —OC(=O) R, wherein each carboxylic acid proton (H) In another embodiment of the present invention, oligomers present in the di- or poly acid shown below is absent in the of present invention can be prepared in two steps as shown in linker): US 8,026,285 B2 15 16 -continued O O HO O HO 1- NullsOH 5 O O HO OH O O OH 10 OH O O O O O OH O HO 1N1 O N-1No OH HO R OH 15 OH O O n = 10-50

O -- OH 20 Examples of the number-average molecular weight of PEG HO N-n}^ (polyethylene glycol) include 400, 500, 600, 700, 800,900, to 1OOO. O Some examples of linear and multi-armed hydrolysable O O linkers of the present invention are shown below (e.g., —CX), 25 —OC(=O) R, wherein each carboxylic acid proton (H) -- shown is absent in the linker): HO OH

O O ro r O O

35 O O O O N--- HO -- OH HO OH r r 40 O O

O --- O OH O O HO N-1\o 45 HO 1. ------~. or OH O O

O O 50 HO --~~ OH HO OH HO OH ^o or HO OH O O O O HO -N-O ouls O OH O O 55 Yno n-or-n-n OH. O O

For example, the first diacid derived linker in the list shown directly above has R as a three carbon diradical, wherein one of the CH groups in the diradical is replaced by an oxygen atom, X is —OC(=O)CH2—, a is the integer 1, and w is the HO OH integer 2. 65 Some examples of linear and multi-armed hydrolysable O O precursors and linkers of the present invention are shown below (e.g., —CHC(=O)–(Y), OR): US 8,026,285 B2 17 18 ~~~~~~~ cy s.r.t----- ~~~~ ------r s------

----- A -ss r -- y rr.

------US 8,026,285 B2 19 20 wherein Q is a bond (when part of an oligomer) or F, Cl, Br, respectively will depend upon a number of factors, including or I (when part of a precursor). the functionalization species used and the number of repeat For example, the first precursor in the list shown directly units of functionalization species present on the functional above has R as a two carbon diradical, wherein Y is ized Biologically Active Compound (e.g., 1-6). Glycolic acid —OCHC(=O)—, b is the integer 2, and w is the integer 2. modified Biologically Active Compound should hydrolyze Some examples of linear and multi-armed hydrolysable faster than dioxanone modifies ones, where as lactic acid and precursors and linkers of the present invention are shown caprolactone modified Biologically Active Compound below (e.g., -(Y), OR): should take much longer to hydrolyze than glycolic acid and dioxanone modified Biologically Active Compound. Further 10 more, it is expected that the rate of hydrolysis will increase with the increase in the value of a and b. Thus, the desired time range may be obtained by altering the number of repeat units --- and type of functionalization species used to functionalize the Biologically Active Compound. The definitions and examples provided in this application are not intended to be limiting, unless specifically stated. The starting material for the compounds of the present r S-r invention may be a phenolic compound or may be a precursor of a phenolic, such as a methoxyphenol, benzyloxyphenol or acetoxyphenol. (~~~ N The present invention also provides a blend comprising n = 2 one or more of the functionalization species with one or more O O species of phenolic compounds. The compositions of the present invention may be suitable for administration via a route selected from oral, enteral, NullsO O O.-- O. 25 parenteral, topical, transdermal, ocular, vitreal, rectal, nasal, pulmonary, and vaginal. "Pharmaceutically acceptable salts' refer to derivatives of Q O O-- the disclosed compounds wherein the parent compound is O modified by making acid or base salts thereof. Examples of 30 pharmaceutically acceptable salts include, but are not limited O --- to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically accept able salts include the conventional non-toxic salts or the qua O O ternary ammonium salts of the parent compound formed, for 35 example, from non-toxic inorganic or organic acids. For r s example, such conventional non-toxic salts include, but are O O not limited to, those derived from inorganic and organic acids selected from 1.2-ethanedisulfonic, 2-acetoxybenzoic, 2-hy wherein Q is a bond (when part of an oligomer) or F, Cl, Br, droxyethanesulfonic, acetic, ascorbic, benzenesulfonic, ben or I as a replacement for the O atom (when part of a precur 40 Zoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, sor). ethane Sulfonic, fumaric, glucoheptonic, gluconic, glutamic, For example, the first precursor in the list shown directly glycolic, glycolyarsanilic, hexylresorcinic, hydrabamic, above has R as a two carbon diradical, wherein Y is hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, —OCHC(=O)—, b is the integer 2, and w is the integer 2. hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl Sul Alkyl includes both branched and straight-chain satu 45 fonic, maleic, malic, mandelic, methanesulfonic, napsylic, rated aliphatic hydrocarbon groups having the specified num nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, ber of carbon atoms. Calkyl, for example, includes C. C. polygalacturonic, propionic, Salicyclic, Stearic, Subacetic, C, C, Cs, and C alkyl groups. Examples of alkyl include Succinic, Sulfamic, Sulfanilic, Sulfuric, tannic, tartaric, and methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, toluenesulfonic. n-pentyl, S-pentyl, and n-hexyl. 50 The pharmaceutically acceptable salts of the present inven Aryl refers to an optionally substituted, mono-, di-, tri-, tion can be synthesized from the parent compound that con or other multicyclic aromatic ring system having from about tains a basic or acidic moiety by conventional chemical meth 5 to about 50 carbon atoms (and all combinations and sub ods. Generally, such salts can be prepared by reacting the free combinations of ranges and specific numbers of carbonatoms acid or base forms of these compounds with a stoichiometric therein), with from about 6 to about 10 carbons being pre amount of the appropriate base or acid in water or in an ferred. Non-limiting examples include, for example, phenyl, 55 organic solvent, or in a mixture of the two: generally, non naphthyl, anthracenyl, and phenanthrenyl. aqueous media like ether, ethyl acetate, ethanol, isopropanol, The present invention also provides novel therapeutic oracetonitrile are preferred. Lists of suitable salts are found in methods for producing effects or treating diseases by admin Remington's Pharmaceutical Sciences, 18th ed., Mack Pub istering to a patient in need thereofatherapeutically effective lishing Company, Easton, Pa., 1990, p 1445, the disclosure of amount of at least one polymer of the present invention. 60 which is hereby incorporated by reference. Examples of effects and diseases include an analgesic effect, “Therapeutically effective amount” includes an amount of cancer, an anti-inflammatory effect, an anti-bacterial effect, a compound of the present invention that is effective when an anti-fungal effect, an immunosuppressive effect, an anti administered alone or in combination to treat the desired thrombotic effect, psoriasis, inflammatory bowel disease, indication. skin cancer, brain tumor, an anti-infective effect, and pain. 65 One aspect of the present invention combines the phenolic The rate of hydrolysis of Biologically Active Compounds compound with one or more of the selected group of com of formula B and D as shown in Scheme 1 and Scheme 2 pounds to form a functionalized phenolic compound with US 8,026,285 B2 21 22 uses in medicine, as enhanced drugs, drug intermediates, Compounds of the formula used as medicaments or phar cancer preventing agents, nutrition Supplements, nutraceuti maceuticals are typically administered in a manner and cals, antioxidants, controlled release preparations, cosmetic amount as is conventionally practiced. See, for example, applications, flavors, coatings, drug intermediates, solvents Goodman and Gilman, The Pharmaceutical Basis of Thera for drugs, new monomers for polymerization, and when poly 5 peutics, current edition. merized, as polymers for biomedical applications, drugs, Compounds of the present invention have potent antioxi nutrition Supplements, nutraceuticals, drug delivery, cos dant activity and increased acidity of their phenolic compo metic applications, flavors, and coatings. nent, as well as the improved biodegradation provided by the The array of functionalized phenolic compounds devel functionalization, and thus find wide application in pharma oped as an aspect of the invention, have a wide range of 10 ceutical and veterinary uses, in cosmetics such as more effec hydrolysis rates that are controllable. The specific moiety or tive skin creams to prevent skin ageing, in Sun screens, in combination of moieties used for functionalization yields a foods, health drinks, nutritional Supplements, shampoos, and compound or mixture with specific hydrolysis ranges. the like. The new functionalized biologically active compounds Examples of functionalized biologically active compounds have more controllable hydrolysis profiles, improved bio 15 of the present invention are provided for some embodiments availability, improved efficacy and enhanced functionality. of the current invention. It can be extended to other species. The difunctional compounds polymerize into biodegradable This selection is not meant to limit the scope of the invention polymers, for example, useful for applications, including bio in any way. Other variations in the procedure may be readily medical applications, foodstuffs, cosmetics, medicaments, apparent to those skilled in the art. coatings and other uses readily apparent to one skilled in the art. EXAMPLES Bioactive Formulations In other aspects of the present invention some functional Example 1 ized biologically active compounds of the present invention are further manufactured into formulations suitable for oral, 25 rectal, parenteral (for example, Subcutaneous, intramuscular, Chloro-acetic acid 2-(2-chloro-acetoxy)-ethyl Ester intradermal, or intravenous), transdermal, vitreal or topical administration. The most Suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular active compound 30 On 1 --- that is being used. The formulations of a pharmaceutical composition are typically admixed with one or more pharma r O ceutically or veterinarially acceptable carriers and/or excipi ents as are well known in the art. A solution ethylene glycol (100 grams, 1.611 moles), chlo Formulations suitable for oral administration may be pre roacetic acid (385 grams, 4.031 moles) and paratoluene Sul sented in discrete units, such as capsules, cachets, lozenges, 35 phonic acid (1 gram) in toluene (750 ml) in a 2 lit 4 neck round or tablets, each containing a predetermined amount of the bottom flask equipped with a mechanical stirrer, Dean-stark active compound; as a powder or granules; as a solution or a apparatus was refluxed for 8 hours, cooled to room tempera Suspension in an aqueous or non-aqueous liquid; or as an ture. The toluene layer was washed with water (2x300 ml), oil-in-water or water-in-oil emulsion. 5% sodium bicarbonate solution (3x500 ml), water (2x300 Compositions of the present invention suitable for 40 ml), dried over sodium Sulphate and distilled to get crude 1. parenteral administration conveniently comprise sterile aque which was purified by high vacuum distillation to get pure 1 ous preparations of the active compounds, where prepara (242 grams, 69.8%), which slowly crystallized to white crys tions are preferably isotonic with the blood of the intended tals m.p: 44° C., H NMR (CDC1): 84.16 (s. 2H, CH), 4.85 recipient. (s. 2H, CH). Formulations suitable for rectal administration are prefer 45 ably presented as unit dose Suppositories. Example 2 Formulations suitable for ocular or vitreal administration may be presented as bioabsorbable coatings for implantable medical devices, injectables, liquids, gels or Suspensions. 6-Bromo-hexanoic Acid Formulations or compositions Suitable for topical admin 50 2-(6-bromo-hexanoyloxy)-ethyl Ester istration to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Examples of carriers that conventionally used include Vaseline, lanoline, polyethylene glycols, alcohols, and combination of two or 1-n-r N---~~ Br more thereof. O Formulations suitable for transdermal administration may 55 be presented as discrete patches adapted to remain in intimate A solution ethylene glycol (5 grams, 80.55 mmoles), contact with the epidermis of the recipient for a prolonged 6-bromo hexanoic acid (47 grams, 240.96 mmoles) and para period of time. toluene sulphonic acid (0.5 gram) in toluene (150 ml) in a 500 The active compounds may be provided in the form of ml 4 neck round bottom flask equipped with a mechanical foodstuffs or nutrition Supplements, such as being added to, 60 stirrer, Dean-stark apparatus was refluxed for 4 hours, cooled admixed into, coated, combined or otherwise added to a food to room temperature. The toluene layer was washed with stuff. The term foodstuff is used in its widest possible sense water (2x100 ml), 5% sodium bicarbonate solution (3x50 and includes liquid formulations such as drinks including ml), water (2x100 ml), dried over sodium sulphate and dis dairy products, biodegradable chewing gums, and other tilled to get example 2 (30 grams, 91%) as a light yellow foods, such as health bars, desserts, etc. Food formulations 65 syrup. m.p: 44° C., H NMR (CDC1): 8 1.45 (m, 2H, CH), containing compounds of the invention can be readily pre 1.59 (m,2H, CH), 1.82 (m,2H, CH), 2.26 (t, 2H, CH), 3.34 pared according to standard practices. (t, 2H, CH), 4.18 (s. 2H, CH). US 8,026,285 B2 23 24 Example 3 To a solution of Aspirin (25.13 grams, 139.49 mmoles), triethylamine (23.52 grams, 232.43 mmoles) in dry acetone Chloro-acetic Acid 3-(2-chloro-acetoxy)-2.2-bis-(2- (100 ml) was added chloro-acetic acid 2-(2-chloro-acetoxy)- chloro-acetoxymethyl)-propyl Ester ethyl ester 1 (10 grams, 46.50 mmoles) and stirred at room temperature for 20 hours. The solid triethylamine hydrochlo ride is filtered and to the filtrate, cold water (300 ml) was O O added. The precipitated polymer 5 was filtered, dried and recrystallised from chloroform:hexane (1:6) to get pure dimer cus --- 5 (16 grams, 68.4%) as white powder. m.p. 91-92.5° 10 C., HNMR (CDC1): 82.30 (s.3H, OAc), 4.40 (s. 2H, CH), 4.76 (s. 2H, CH), 7.10 (d. 1H, Ar), 7.32 (t, 1H, Ar), 7.58 (t, O O C ~ ^a 1H, Ar), 8.10 (d. 1H, Ar). O O Example 6 A solution pentaerythritol (25 grams, 183.62 mmoles), 15 chloroacetic acid (105.2 grams, 1.10 moles) and paratoluene Aspirin Tetramer sulphonic acid (2 gram) in toluene (500 ml) in a 2 lit 4 neck OAc AcO round bottom flask equipped with a mechanical stirrer, Dean O O Stark apparatus was refluxed for 8 hours, cooled to room temperature. The toluene layer was washed with water oulsO O1-0 (2x300 ml), 5% sodium bicarbonate solution (3x500 ml), water (2x300 ml), dried over sodium sulphate and distilled to O O get crude 3, which was purified by recrystallisation from O O chloroform: Hexane (1:7) to get pure 3 (77 grams, 94.8%), as a white powder. m.p. 94-96°C.H NMR (CDC1): 84.16 (s, O O 25 or ^O 2H, CH), 4.28 (s. 2H, CH). O O Example 4 OAc ACO To a solution of Aspirin (20.37 grams, 113.07 mmoles), Chloro-acetic Acid triethylamine (18.29 grams, 180.74 mmoles) in dry acetone 2.2-bis-(2-chloro-acetoxymethyl)-butyl Ester 30 (100 ml) was added tetra chloro linker (10 grams, 22.62 mmoles), example 3 and stirred at room temperature for 20 hours. The solid triethylamine hydrochloride is filtered, acetone distilled off. Crude mass was dissolved in ethyl C 35 acetate, washed with 5% sodium bicarbonate solution, dried over sodium sulphate and distilled. The crude 6 was recrys tallised from chloroform:hexane (1:6) to get pure 6 (10 grams, 44%) as white powder. m.p. 85-88° C., HNMR C (CDC1): 82.31 (s.3H, OAc), 4.16 (s. 2H, CH4), 4.78 (s. 2H, 40 CH2), 7.12 (d. 1H, Ar), 7.32 (t, 1H, Ar), 7.60 (t, 1H, Ar), 8.08 (d. 1H, Ar). A solution Trimethylolpropaner-- (100 grams, 745.82 mmoles), chloro acetic acid (422 grams, 4.465 moles) and Example 7 Para toluene sulphonic acid (5 grams) in Toluene (500 ml) in a 2 liter 4 neck round bottom flask equipped with a mechani 45 Aspirin Trimer cal stirrer, Dean-stark apparatus was refluxed for 8 hours, cooled to room temperature. The toluene layer was washed AcO with water (2x300 ml), 5% sodium bicarbonate solution O (3x500 ml), water (2x300 ml), dried over sodium sulphate and distilled to get the linker as light yellow syrup. HC O1-0 50 IH NMR (CDC13) & 0.9 (t, 3H, CH3), 1.6 (q, 2H, CH2), O 4.07 (s, 6H, CH2x3), 4.15 (s, 6H, CH2x3) O O Example 5 or O O ^O Aspirin Dimer O O OAc AcO

To a solution of Aspirin (124.5 grams, 91.09 mmoles), triethylamine (111.8 grams, 1.104 moles) in dry acetone (500 ml) at reflux temperature was added a solution of Trichloro linker (50 grams, 137.89 mmoles), example 4, in acetone (100 ml) drop wise. Later further refluxed for 16 hours, cooled to room temperature, the solid triethylamine hydrochloride is filtered, acetone distilled off. Crude mass was dissolved in ethyl acetate, washed with 5% sodium bicarbonate solution, dried over sodium sulphate and distilled. The crude 7 was purified by column chromatography on silica gel using chlo US 8,026,285 B2 25 26 roform as eluant to get pure 7 (25 grams, 23.2%) as light yellow syrup: m.p:85-88°C., HNMR (CDC1): 8 0.82 (t,3H, CH), 1.38 (q, 2H, CH), 2.32 (s, 9H, OAc), 4.10 (s, 6H, CH), 4.80 (s, 6H, CH), 7.14 (d. 3H, Ar), 7.34 (t, 3H, Ar), 7.60 (t, 3H, Ar), 8.10 (d. 3H, Ar). 5 Example 8

Naproxen Dimer

O Me E O O - 1N1 Nr. O O MeO

To a solution of Naproxen (56 grams, 243.20 mmoles), 2O triethylamine (36.3 grams, 358.73 mmoles) in dry acetone (150 ml) was added dichloro linker (15 grams, 69.75 mmoles), example 1 and stirred at room temperature for 20 hours. The solid triethylamine hydrochloride is filtered, acetone distilled off. Crude mass was dissolved in ethyl 25 acetate, washed with 5% sodium bicarbonate solution, dried over sodium sulphate and distilled. The crude 8 was purified by column chromatography on silica gel using benzene as eluant to get pure 8 (32 grams, 76.1%) as white powder. m.p.: 69-71 C, HNMR (CDC1): 81.61 (d. 6H, CH), 3.90 (s, 6H, OCH3), 3.97 (q, 2H, CH), 4.26 (s, 4H, CH2), 4.58 (q, 4H, CH), 7.10 (m, 4H, Ar), 7.41 (d. 2H, Ar), 7.70 (m, 6H, Ar).

Example 9 35

Naproxen Tetramer

O O

O O MeO OMe

MeO OMe O O O~ O O rO

To a solution of Naproxen (13 grams, 56.45 mmoles), triethylamine (9.14 grams, 90.32 mmoles) in dry acetone (50 55 ml) was added tetrachlorolinker (5 grams, 11.31 mmoles), example 3 and stirred at room temperature for 20 hours. The solid Triethylamine hydrochloride is filtered, acetone dis tilled off. Crude mass was dissolved in ethyl acetate, washed 60 with 5% sodium bi carbonate solution, dried over sodium sulphate and distilled. The crude 9 was purified by recrystal lisation from chloroform:hexane (1:6) to get pure 9 (3 grams, 21.8%) as white powder. m.p. 128-130° C., HNMR (CDC1): & 1.58 (d. 12H, CH3), 3.84 (m, 8H, CH), 3.88 (s, 12H, 65 OCH), 3.94 (q, 4H, CH), 4.52(q, 8H, CH), 7.10 (m, 8H, Ar), 7.41 (d, 4H, Ar), 7.70 (m, 12H, Ar). US 8,026,285 B2 27 28 Example 10 Naproxen Trimer

O

H3C O -N-

OMe

OMe O

O

O O To a solution of Naproxen (127 grams, 551.15 mmoles), eluant to get pure 10 (30 grams, 23%) as light green thick triethylamine (83.5 grams, 825.18 mmoles) in dry acetone syrup. HNMR (CDC1): 8 0.66 (t, 3H, CHA), 1.15 (q, 2H, (500 ml) was added trichloro linker (50 grams, 137.89 CH), 1.61 (d. 9H, CH), 3.96 (m, 15H, OCH, CH), 4.56 (q, mmoles), example 4 and stirred at room temperature for 20 6H, CH), 7.08 (m, 6H, Ar), 7.40 (d. 3H, Ar), 7.67 (m,9H. Ar). hours. The solid triethylamine hydrochloride is filtered, acetone distilled off. Crude mass was dissolved in ethyl E le 11 acetate, washed with 5% Sodium bicarbonate solution, dried 25 Xample over sodium sulphate and distilled. The crude 10 was purified by column chromatography on silica gel using benzene as Sulindac

O HC1 t CH O O F OH Sulindac

O C ~ O N-1 no --- O O Acetone, Triethylamine

CH F r O n-1\o --- F O Sulu US 8,026,285 B2 29 30 Example 12 wherein: R'-O- is a biologically active compound residue. R’ C(=O)C)— is a biologically active compound resi Exisulind due;

O leo HC1

CH3

F OH Exisulind

Acetone, Triethylamine O le HC1 1)"CH3 F

-CH Saso O 45 When ranges are used herein for physical properties, such X is selected from: —OC(=O)CH (inverse glycolic as molecular weight, or chemical properties, such as chemical acid moiety), —OC(=O)CH(CH)— (inverse lactic formulae, all combinations and Subcombinations of ranges acid moiety), —OC(=O)CHOCH2CH2— (inverse and specific embodiments therein are intended to be included. dioxanone acid moiety), OC(=O) The disclosures of each patent, patent application and pub 50 CHCHCHCH-CH (inverse caprolactone acid lication cited or described in this document are hereby incor moiety), OC(=O)(CH), , or OC(=O)CH, porated herein by reference, in their entireties. (OCHCH)—. Those skilled in the art will appreciate that numerous X' is selected from: —CHC(=O)C)—(glycolic acid moi changes and modifications can be made to the preferred ety), —CH(CH)C(=O)C)— (lactic acid moiety), embodiments of the invention and that such changes and 55 —CH2CH2OCHC(=O)C)— (dioxanone acid moiety), modifications can be made without departing from the spirit —CHCHCHCHCHC(=O)C)— (caprolactone of the invention. It is, therefore, intended that the appended acid moiety), -(CH2),C(=O)C , or -(CH2CH2O). CHC(=O)C)–: claims cover all such equivalent variations as fall within the Y is selected from: —C(=O)CHO— (glycolic ester moi true spirit and scope of the invention. ety), —C(=O)CH(CH)O (lactic ester moiety), Embodiment 1 60 —C(=O)CHOCH2CH2O (dioxanone ester moi ety), —C(=O)CHCHCHCHCHO (caprolac An oligomer orpharmaceutically acceptable salt thereof of tone ester moiety), —C(=O)(CH)O—, or—C(=O) CH-O-(CHCHO) ; formula I or II: Y' is selected from: —OCHC(=O)– (inverse glycolic 65 ester moiety), —OCH(CH)C(=O)— (inverse lactic ester moiety), —OCHCHOCHC(=O)— (inverse —R II dioxanone ester moiety), —OCH2CH2CH2CH2CH2C US 8,026,285 B2 31 32 (=O)— (inverse caprolactone ester moiety), each Y is independently —COCHO and COCH —O(CH),C(=O)—, or —O(CHCHO), OCHC (CH)O—; and, (=O)—: eachY' is independently—OCHCO-and-OCH(CH) R is a di-, tri, tetra-, penta- or hexaradical derived from CO . Cs alkyl, aryl, or aryl-(Calkyl)--, wherein from 1-3 of the CH groups within the alkyl chain are option Embodiment 6 ally independently replaced by O atoms, such that each of said O atom is attached only to carbon atoms in the An oligomer of Embodiment 1, 2, 3, 4, or 5, wherein alkyl chain, with the proviso that multiple O atoms that R'-O-is selected from acenocoumarol, acetarsol, actino replace CH groups within the alkyl chain must be sepa 10 quinol, adrenalone, alibendol, amodiaquine, anethole, bal rated from each other by at least two carbon atoms and Salazide, bamethan, benserazide, bentiromide, benzarone, from the di-, tri, tetra-, penta- or hexaradical chain ends benzquinamide, bevantolol, bifluranol, buclosamide, buphe by at least one carbon atom; or R is the backbone of a polymer or copolymer bearing carboxylic acid and/or niode, chlorotrianisene, chloroxylenol, cianidanol, hydroxyl functional groups, where the average molecu cinepazide, cinitapride, cinepazide, cinmetacin, clebopride, lar weight of the polymer or copolymer is between 500 15 clemastine, clioquinol, cyclovalone, cynarine, denopamine, to 5000 and wherein w is an integer from about 6 to about dextroythyroXine, diacerein, dichlorophen, dienestrol, dieth 50; ylstilbestrol, diflunisal, diiodohydroxyquinoline, dilazep, dil each a and b is independently an integer from about 1 to evalol, dimestrol, dimoxyline, dioSmin, dithranol, dob about 10: utamine, donepezil, dopamine, dopexamine, doxazosin, each m, n, y, and Z is independently an integer from about entacapone, epanolol, epimestrol, epinephrine, estradiol val 2 to about 24; and erate, estriol, estriol Succinate, estrone, etamivan, etamsylate, w is an integer from about 2 to about 6. ethaverine, ethoXZolamide, ethyl biscoum-acetate, etillefrine, etiroXate, exalamide, exifone, fendosal, fenoldopam mesi Embodiment 2 late, fenoterol, fenoxedil, fenticlor, flopropione, floredil, 25 fluorescein, folescutol, formo-terol, gallopamil, gentistic An oligomer of Embodiment 1, wherein: acid, glaziovine, glibenclamide, glucametacin, guajacol, R is a di-, tri, tetra-, penta- or hexaradical derived from halquinol, hexachlorophene, hexestrol, hexobendine, hexo C-alkyl, phenyl, or phenyl-(Calkyl)--, wherein prenaline, hexylresorcinol, hydroxyethyl salicylate, hydrox from 1-3 of the CH groups within the alkyl chain are yStilbamidine isethionate, hymecromone, ifenprodil, optionally independently replaced by Oatoms, such that 30 indomethacin, ipriflavone, isoetarine, isoprenaline, isoxSu each of said O atom is attached only to carbonatoms in prine, itopride hydrochlor-ide, ketobemidone, khellin, labe the alkyl chain, with the proviso that multiple O atoms talol, lactylphenetidin, levodopa, levomepromazine, levor that replace CH2 groups within the alkyl chain must be phanol, levothyroXine, mebeverine, medrylamine, separated from each other by at least two carbon atoms mefexamide, mepacrine, mesalazine, mestranol, metarami and from the di-, tri, tetra-, penta- or hexaradical chain nol, methocarbamol, methoxamine, methoXSalen, methyl 35 dopa, midodrine, mitoxantrone, morclofone, nabumetone, ends by at least one carbon atom; naproxen, nitroxo-line, norfenefrine, normolaxol, octopam each a and b is independently an integer from about 1 to ine, omeprazole, orciprenaline, oxillofrine, oxitriptan, oxy about 5; and fedrine, oxypertine, oxyphenbutaZone, oxyphenisatin w is an integer from about 2 to about 4. acetate, oxyquin-oline, papaverine, paracetanol, parethox 40 ycaine, phenacaine, phenacetin, phenazocine, phenolphtha Embodiment 3 lein, phenprocoumon, phentolamine, phloedrine, picota An oligomer of Embodiment 1 or 2, wherein: mide, pimoben-dan, prenalterol, primaquine, progabide, R—IO is O(CH)O, O(CH)O, CH(CHO), propanidid, protokylol, proxymetacaine, raloxifene hydro C(CHO), or C(CHCH)(CHOH). chloride, repaglinide, reproterol, rimiterol, ritodrine, salac 45 etamide, Salazosulfapyridine, salbutamol, Salicylamide, Sali Embodiment 4 cylic acid, Salmeterol, Salsalate, sildenafil, silibinin, Sulmetozin, tamsulosin, teraZosin, terbutaline, tetroXoprim, theo-drenaline, tioclomarol, tioXolone, C-tocopherol (vita An oligomer of Embodiment 1, 2, or 3, wherein: min E), tofisopam, tolcapone, tolterodine, tranilast, treto each X is independently —OC(=O)CH , —OC(=O) quinol, triclosan, trimaZosin, trimetazidine, trimethobenz CH(CH) , —OC(=O)CHOCHCH , or - OC 50 (=O)CHCHCHCHCH-. amide, trimethoprim, trimetozine, trimetrexate glucuronate, each X* is independently --CHCOO ... —CH(CH) troXipide, Verapamil, Vesnarinone, Vetrabutine, Viloxazine, COO : —CHCHOCHCOO : O warfarin, and Xamoterol. - CHCHCHCH-CHCOO–. Embodiment 7 each Y is independently —COCHO : —COCH(CH) 55 O—; - COCHOCHCHO : O - COCHCHCHCHCH-O-, and An oligomer of Embodiment 1, 2, 3, 4, or 5, wherein each Y is independently —OCH2CO ; –OCH(CH) R'-O-is: CO : –OCHCHOCHCO : O –OCHCHCHCH-CHCO-. 60 HO Embodiment 5 N An oligomer of Embodiment 1, 2, 3, or 4, wherein: N X is independently —OCOCH and —OCOCH (CH)—; 65 O each X is independently —CHCOO and —CH(CH) Capsaicin COO : US 8,026,285 B2 34 -continued Benzocaine, Bumetanide, Carprofen, Carzenide, Cinmeta C OH cin, Clometacin, Cromoglicic acid, Diclofenac, Diflunisal, Eprosartan, Fendosal, Flufenamic acid, Furosemide, Indometacin, Iobenzamic acid, Iocarmic acid, Iocetamic acid, Iodoxamic acid, Ioglycamic acid, Iophenoic acid, Iotroxic cid, Mefenamic acid, Naproxen, Nedocromil, Repa C C C Cl; glinide, Salazosulfapyridine, Salicylic Acid, Salsalate, and Triclosan Sarpogrelate.

O 10 Embodiment 9

An oligomer of claim Embodiment 1, 2, 3, 4, or 5, wherein OH: R° C(=O)C is: O 15 Benzarone O OH

s HO O O;

2 CrOH Methyl Salicylate O OH C

Chloroxylenol Hymercromone 25

S N OH n-1 I N 30 c. OH: 21 F F Diflunisal N 1. O

C OH 35 OH: Clioquinol Etamivan OH O Ibuprofen OH 40 N n O O) - OH: H 21 N N 45 NO Tiaprofenic Acid Nitroxoline Pholedrine OH -a -OH: OH, or N O 50 O MeO 2 NH Naproxen O Oxyquinoline Paracetamol HO O 55 HO N

X=NH. O S Tioxolone Tolimetin 60 OH Embodiment 8 O O; An oligomer of Embodiment 1, 2, 3, 4, or 5, wherein R’ C(=O)C)— is selected from Acemetacin, Aceclofenac, 65 Acediasulfone, Adipiodone, Alminoprofen, Amlexanox, Loxoprofen Anileridine, Baccofen, Balsalazide sodium, Bentiromide, US 8,026,285 B2 36 -continued -continued O O S O OH: O N \ | OH:

Suprofen Ketorolac 10

O O

15 OH: r N H Mefenamic acid F

; or Etodolac

HO C OH: Cor 25 O Ketoprofen Lumiracoxib

30 l. OH F

3 )-() 35 Flurbiprofen O. Indometacin C

40 Embodiment 10 An oligomer of Embodiment 1, 2, 3, 4, 5, 6, or 7, wherein C OH: R'-O- is selected from capsaicin, coumarins, furanocou 45 marins, alkaloids, catechins, chromones, chalcones, fla vonoids or bioflavonoids, isoflavones, resveratrol, and Sinapic acid. Diclofenac Embodiment 11 50 OH: An oligomer of Embodiment 1, 2, 3, 4, 5, 6, or 7, wherein R"—O— is selected from 4-hydroxycinnamic acid, caffeic acid, chlorogenic acid, ferulic acid, capsaicin, 4-hydroxycou marin, psoralen, bergapten, bergaptol, Xanthotoxin, isopimp 55 inellin.

Embodiment 12 orFenbufen O 60 An oligomer of Embodiment 1, 2, 3, 4, 5, 6, 7, 10, or 11, OH: wherein—OC(=O), R is:

O O N 65 Carprofen HO 1- sus OH: US 8,026,285 B2 37 38 -continued Embodiment 13 O An oligomer of Embodiment 1, 2, 3, 4, 5, 8, or 9, wherein O OH: —(Y'), OR is: O H--- n1nr 5 O HO O OH: r 1S-1 n1nr ------O O O O 10 rN-n-r -- OH: O O HO N-n}^ O O O 15 (~~~"N-O *: n = 2 HO -- OH: O O Nulls -- O O N--- O O O O. O. -- OH: NusO O -- O O O 25 --- . N--- OH: O O

O r s O O O O O O wherein each Q is a bond. 35 HO OH: HO OH: Embodiment 14 HO OH An oligomer of Embodiment 1,2,3,4,5,6,7, 10, 11, or 12, O O O OH wherein—CX), OC(=O), R is: O OH 40

HO OH: 45 O O O O O O HO HO -- OH: O O O r O~ 50 O O O O HO OH: HO ------~. OH: O ^O or OH 55 O O O O OH O O O HO os--- OH, or O OH, or HO ullsR OH N->O or O O O O O 60 HO 1-0 ouls OH N->O n1Nor-n-r OH: n = 10-50 O O

65 wherein each carboxylic acid proton (H) present in the wherein each carboxylic acid proton (H) present in the di di-acid shown is absent in the moiety. —(X), OC(=O)— or poly-acid shown is absent in the moiety —OC(=O) R. R. US 8,026,285 B2 39 40 Embodiment 15 benzoic acid, dihydroxy-benzoic acid, indoles, acetophe nones, benzophenones, catechins, flavonoids, coumarins, An oligomer of Embodiment 1, 2, 3, 4, 5, 8, 9, or 13, hydroquinone, naproxen, acetaminophen, and acetylsalicylic wherein—CHC(=O)—(Y), OR) is: acid. ------~~~~~~~~~~~ ------or r-rror or r Arror

wherein Q is a bond. Embodiment 17 Embodiment 16 65 A cosmetic composition, comprising at least one com An oligomer of Embodiment 1, 2, 3, 4, 5, 6, 7, 10, 11, 12, pound of Embodiment 1,2,3,4,5,6,7,8,9, 10, 11, 12, 13, 14. or 14, wherein R'—O—is selected from chalcones, hydroxy- 15, or 16, and a cosmetic ingredient. US 8,026,285 B2 41 42 Embodiment 18 Embodiment 29 A pharmaceutical composition, comprising at least one A pharmaceutical composition of Embodiment 28, further compound of Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, comprising: an antioxidant agent. 13, 14, 15, or 16, and a pharmaceutically acceptable excipi ent. Embodiment 30

Embodiment 19 A suture coating, comprising: at least one oligomer of Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or A pharmaceutical composition of Embodiment 18, 10 16. wherein the composition is suitable for administration via a Embodiment 31 route selected from oral, enteral, parenteral, topical, transder mal, ocular, vitreal, rectal, nasal, pulmonary, and vaginal. An antimicrobial agent, comprising: at least one oligomer 15 of Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, Embodiment 20 or 16. A pharmaceutical composition of Embodiment 18, Embodiment 32 wherein the phenolic residue in the compound of formula I was derived from a cancer preventing phenolic. A therapeutic method for treating a disease in a patient, comprising: administering to a patient in need of Such Embodiment 21 therapy, an effective amount of at least one oligomer of Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or A pharmaceutical composition of Embodiment 20, further 16. comprising: an anti-cancer agent. 25 Embodiment 33 Embodiment 22 A therapeutic method for producing an analgesic effect in a patient, comprising: administering to a patient in need of A pharmaceutical composition of Embodiment 18, Such therapy, an effective amount of at least one oligomer of wherein the phenolic residue of formula I or II is derived from 30 Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or a phenolic compound with antimicrobial properties. 16.

Embodiment 23 Embodiment 34 A pharmaceutical composition of Embodiment 22, further 35 A therapeutic method for treating cancer in a patient, com comprising: an antimicrobial agent. prising: administering to a patient in need of such therapy, an effective amount of at least one oligomer of Embodiment 1, 2, Embodiment 24 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16. A pharmaceutical composition of Embodiment 18, 40 Embodiment 35 wherein the phenolic residue in the compound of formula I was derived from a phenolic with anti-inflammatory proper A therapeutic method for producing an anti-inflammatory ties. effect in a patient, comprising: administering to a patient in need of Such therapy, an effective amount of at least one 45 Embodiment 25 oligomer of Embodiment 1,2,3,4,5,6,7,8,9, 10, 11, 12, 13, 14, 15, or 16. A pharmaceutical composition of Embodiment 24, further Embodiment 36 comprising: anti-inflammatory agent. 50 Atherapeutic method for producing an anti-bacterial effect Embodiment 26 in a patient, comprising: administering to a patient in need of Such therapy, an effective amount of at least one oligomer of A pharmaceutical composition of Embodiment 18, Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or wherein the phenolic residue in the compound of formula I 16. was derived from a phenolic with pain-reducing properties. 55 Embodiment 37 Embodiment 27 Atherapeutic method for producing an anti-fungal effect in a patient, comprising: administering to a patient in need of A pharmaceutical composition of Embodiment 26, further 60 Such therapy, an effective amount of at least one oligomer of comprising: a pain reducing agent. Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16. Embodiment 28 Embodiment 38 A pharmaceutical composition of Embodiment 18, 65 wherein the phenolic residue in the compound of formula I A therapeutic method for producing an immunosuppres was derived from a phenolic with antioxidant properties. sive effect in a patient, comprising: administering to a patient US 8,026,285 B2 43 44 in need of Such therapy, an effective amount of at least one ester moiety), —OCHCHOCHC(=O)— (inverse oligomer of Embodiment 1,2,3,4,5,6,7,8,9, 10, 11, 12, 13, dioxanone ester moiety), —OCHCHCHCHCHC 14, 15, or 16. (=O)— (inverse caprolactone ester moiety), —O(CH),C(=O)—, or —O(CHCHO), OCHC Embodiment 39 (=O)—: R is a di-, tri, tetra-, penta- or hexaradical derived from A therapeutic method for producing an anti-thrombotic C-2s alkyl, aryl, or aryl-(Calkyl)--, wherein from effect in a patient, comprising: administering to a patient in 1-3 of the CH groups within the alkyl chain are option need of Such therapy, an effective amount of at least one ally independently replaced by O atoms, such that each of said O atom is attached only to carbon atoms in the oligomer of Embodiment 1,2,3,4,5,6,7,8,9, 10, 11, 12, 13, 10 alkyl chain, with the proviso that multiple O atoms that 14, 15, or 16. replace CH groups within the alkyl chain must be sepa Embodiment 40 rated from each other by at least two carbon atoms and from the di-, tri, tetra-, penta- or hexaradical chain ends by at least one carbon atom; or R is the backbone of a A therapeutic method for treating psoriasis, inflammatory 15 polymer or copolymer bearing carboxylic acid and/or bowel disease, skin cancer, or a brain tumor in a patient, hydroxyl functional groups, where the average molecu comprising: administering to a patient in need of Such lar weight of the polymer or copolymer is between 500 therapy, an effective amount of at least one oligomer of to 5000 and wherein w is an integer from about 6 to about Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 50; 16. each a and b is independently an integer from about 1 to about 10: Embodiment 41 each m, n, y, and Z is independently an integer from about 2 to about 24; and Atherapeutic method for producing an anti-infective effect w is an integer from about 2 to about 6. in a patient, comprising: administering to a patient in need of 25 2. An oligomer of claim 1, wherein: Such therapy, an effective amount of at least one oligomer of R is a di-, tri, tetra-, penta- or hexaradical derived from Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or C-alkyl, phenyl, or phenyl-(Calkyl)--, wherein 16. from 1-3 of the CH groups within the alkyl chain are optionally independently replaced by O atoms, such that Embodiment 42 30 each of said O atom is attached only to carbon atoms in the alkyl chain, with the proviso that multiple O atoms A therapeutic method for treating pain in a patient, com that replace CH groups within the alkyl chain must be prising: administering to a patient in need of such therapy, an separated from each other by at least two carbon atoms effective amount of at least one oligomer of Embodiment 1, 2, and from the di-, tri, tetra-, penta- or hexaradical chain 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16. 35 ends by at least one carbon atom; What is claimed is: each a and b is independently an integer from about 1 to 1. An oligomer or pharmaceutically acceptable salt thereof about 5; and of formula I or II: w is an integer from about 2 to about 4. 3. An oligomer of claim 1, wherein: 40 R—IO is O(CH)O, O(CH)O, CH(CHO), C(CHO), or C(CH2CH)(CHOH). 4. An oligomer of claim 1, wherein: each X is independently —OC(=O)CH —OC(=O) R'-O- is a biologically active compound residue. CH(CH) , —OC(=O)CHOCHCH , or - OC R’ C(=O)C)— is a biologically active compound resi 45 (=O)CHCHCHCHCH-; due; each X is independently —CHCOO ... —CH(CH) X is selected from: —OC(=O)CH (inverse glycolic COO : —CHCHOCHCOO : O acid moiety), —OC(=O)CH(CH)— (inverse lactic - CHCHCHCH-CHCOO : acid moiety), —OC(=O)CHOCHCH (inverse each Y is independently —COCHO : —COCH(CH) dioxanone acid moiety), OC(=O) 50 O—; - COCHOCHCHO : O CHCHCHCH-CH (inverse caprolactone acid - COCHCHCHCHCHO ; and moiety), OC(=O)(CH), , or OC(=O)CH, each Y is independently OCHCO ; –OCH(CH) (OCH2CH)—: CO : –OCHCHOCH2CO : O X' is selected from: —CHC(=O)C)—(glycolic acid moi –OCHCHCHCH-CHCO-. ety), —CH(CH)C(=O)C)— (lactic acid moiety), 55 5. An oligomer of claim 4, wherein: —CHCHOCHC(=O)C)— (dioxanone acid moiety), X is independently —OCOCH and —OCOCH - CHCHCHCHCHC(=O)C)– (caprolactone (CH)—; acid moiety), (CH),C(=O)C , or -(CH2CH2O), each X* is independently —CHCOO and —CH(CH) CHC(=O)C)–: COO : Y is selected from: —C(=O)CHO— (glycolic ester moi 60 each Y is independently —COCHO and COCH ety), —C(=O)CH(CH)O (lactic ester moiety), (CH)O—; and, —C(=O)CHOCH2CH2O (dioxanone ester moi eachY' is independently—OCHCO-and-OCH(CH) ety), —C(=O)CHCHCHCHCHO (caprolac CO . tone ester moiety), —C(=O)(CH)O—, or—C(=O) 6. An oligomer of claim 1 wherein R'-O is selected CH-O-(CH2CH2O) ; 65 from acenocoumarol, acetarSol, actinoquinol, adrenalone, Y' is selected from: —OCHC(=O)— (inverse glycolic alibendol, amodiaquine, anethole, balsalazide, bamethan, ester moiety), —OCH(CH)C(=O)— (inverse lactic benserazide, bentiromide, benzarone, benzquinamide, US 8,026,285 B2 45 46 bevantolol, bifluranol, buclosamide, buphcniodc, capsaicin, 11. An oligomer of claim 1, wherein R'-O is selected chlorotrimliscnc, chloroxylenol, cianidanol, cinepazide, cini from 4-hydroxycinnamic acid, caffeic acid, chlorogenic acid, tapride, cinepazide, cinmetacin, clebopride, clemastine, clio ferulic acid, capsaicin, 4-hydroxycoumarin, psoralen, ber quinol, cyclovalone, cynarine, denopamine, dextroythyroX gapten, bergaptol, Xanthotoxin, isopimpinellin. ine, diacerein, dichlorophen, dienestrol, diethyistibestroi. 5 diflunisal, diiodohydroxyquinoiine, dilaZep, dilevalol, 12. An oligomer of claim 1, wherein—OC(=O), R is: dimestrol, dimoxyline, dioSmin, dithranol, dobutamine, donepezil, dopamine, dopexamine, doxazosin, entacapone, epanolol, epimestrol, epinephrine, estradiol Valerate, estriol, O O estriol Succinate, estrone, etamivan, etamsylate, ethaverine, 10 ethoXZolamide, ethyl biscoum-acetate, etillefrine, etiroXate, HO --N- OH: exalamide, exifone, fendosal, fenodolpham mesilate, fenot O erol, fenoxedil, fenticlor, flopropione, floredil, fluorescein, folescutol, formo-terol, gallopamil, gentistic acid, glazio O OH: Vine, glibenclamide, glucametacin, guajacol, halquinol, 15 -- n-r hexachlorophene, hexestrol, hexobendine, hexoprenaline, O hexylresorcinol, hydroxyethyl salicylate, hydroxyStilbami HO O OH: dine isethionate, hymecromone, ifenprodil, indomethacin, ipritlavone, isoetarine, isoprenaline, isoxSuprine, itopride -> 1N1 n-r hydrochioride, ketobemidone, khellin, labetalol, lactyiphe O O netidin, levodopa, levomepromazine, levorphanol, levothy O roXine, mebeverine, medrylamine, mefexamide, mepacrine, -- OH: mesalazine, mestranol, metaraminol, methocarbamol, meth HO N-sh oxamine, methoXSalen, methyldopa, midodrine, mitox O antrone, morclofone, nabumetone, naproxen, nitroxoline, 25 norfenefrine, normolaxol, octopamine, omeprazole, orci O O prenaline, oxilofrine, oxitriptan, oxyfedrine, oxypertine, oxyphenbutaZone, oxyphenisatin acetate, oxyquinoline, HO --- OH: papaverine, paracetamol, parethoxycaine, phenacaine, phen acetin, phenazocine, phenolphthalein, phenprocoumon, 30 phentolamine, pholedrine, picotamide, pimoben-dan, prenal O O terol, primaquine, progabide, propanidid, protokylol, proxymetacaine, raloxifene hydrochloride; repaglinide, HO 1- N--- OH: reproterol, rimiterol, ritodrine, salacetamide, Salazosulfapy O O ridine, Salbutamol, salicylamide, Salicylic acid, salmeterol, 35 Salsalate, sildenafil. Silibinin, Sulmetozin, tamsulosin, tera HO N--- OH: Zosin, terbutaline, tetroXoprim, theo-drenaline, tioclomarol, tioXolone, a-tocopherol (vitamin E), tofisopam, tolcapone, tolterodine, tranilast, tretoquinol, triclosan, trimaZosin, tri O metazidine, trimethobenz-amide, trimethoprim, trimetozine, 40 trimetrexate glucuronate, troXipide, Verapamil, Vesnarinone, Vetrabutine, Viloxazine, warfarin, and Xamoterol. 7. An oligomer of claim 6, wherein R'-O is selected from benzarone, chloroxylenol, clioquinol, etamivan, hyme cromone, nitroxoline, oxyquinoline, paracetamol, 45 pholedrine, tioxolone, and tricolsan. 8. An oligomer of claim 1, wherein R C(=O)C)— is HO O H; t g selected from Acemetacin, Aceclofenac, Acediasulfone, Adipiodone, Alminoprofen, Amlexanox, Anileridine, Bac O O cofen, Balsalazide Sodium, Bentiromide, Benzocaine, 50 O O H Bumetanide, Carprofen, Carzenide, Cinmetacin, Clometa cin, Cromoglicic acid, Diclofenac, Diflunisal, Eprosartan, O O H Fendosal, Flufenamic acid, Furosemide, Indometacin, Ioben Zamic acid, Iocarmic acid, Iocetamic acid, Iodoxamic acid, Ioglycamic acid, Iophenoic acid, IotroXic cid, Mefenamic 55 acid, Naproxen, Nedocromil, Repaglinide, Salazosulfapyri HO OH: dine, Salicylic Acid, Salsalate, and Sarpogrelate. 9. An oligomer of claim 1, wherein R C(=O)C)— is selected from methyl salicylate, diflusinal, ibuprofen, tiapro O O HO fenic acid, naproxen, tolmetin, losoprofen, ketorolac, etod 60 olac, ketoprofen, fluribprofen, diclofenac, fenbufen, carpro O O O fen, Suprofen, mefenamic acid, lumiracoxib, and indomethacin. HO OH: 10. An oligomer of claim 1, wherein R'-O is selected O from capsaicin, coumarins, furanocoumarins, alkaloids, cat 65 echins, chromones, chalcones, flavonoids or bioflavonoids, OH isoflavones, resveratrol, and Sinapic acid. US 8,026,285 B2 47 48 -continued -continued OH O O O O

O O OH, or HO lusR OH. ---

OH

10 n = 10-50

wherein each Q is a bond. wherein each carboxylic acid proton (H) present in the di 14. An oligomer of claim 1, wherein—CX), OC(=O) or poly-acid shown is absent in the moiety —OC 15 —R is: (=O) R. 13. An oligomer of claim 1, wherein—(Y), OR is: O O HO --N- OH: O ro r O O ON-1a -- O O r O HO -- OH: 25 rO O~ O O ^^-n-r O O O O HO ------~. OH: 30 ^o or O O O O (~~~N- HO Yo os--- or OH, or 35 O O O O HO 1-0 ouls O O Yno n-or-n-r OH: O O Nulls -- O 40 o O O o wherein each carboxylic acid proton (H) present in the di-acid shown is absent in the moiety, —(X), OC Q O O -- (=O) R. 15. An oligomer of claim 1, wherein —CHC(=O)— (Y), OR) is: ------

------US 8,026,285 B2 49 50 -continued ----~~~~------O ------

------O O r O ------O O or r ------

wherein Q is a bond. 24. A pharmaceutical composition of claim 18, wherein the 16. An oligomer of claim 1, wherein R'-O is selected phenolic residue in the compound of formula I was derived from chalcones, hydroxy-benzoic acid, dihydroxy-benzoic 45 from a phenolic with pain-reducing properties. acid, indoles, acetophenones, benzophenones, catechins, fla 25. A pharmaceutical composition of claim 24, further vonoids, coumarins, hydroquinone, naproxen, acetami comprising: a pain reducing agent. nophen, and acetylsalicylic acid. 26. A pharmaceutical composition of claim 18, wherein the 17. A cosmetic composition, comprising at least one com phenolic residue in the compound of formula I was derived pound SA 1 and ENT ingredient. 1 from a phenolic with antioxidant properties. 18. Ap armaceutical composition, comprising at least one 27. A pharmaceutical composition of claim 26, further compound of claim 1 and a pharmaceutically acceptable comprising:- - - - an antioxidant agent. excipient. 28. A Suture coating, comprising: at least one oligomer of 19. A pharmaceutical composition of claim 18, wherein the v. 9. p 9. 9. composition is suitable for administration via a route selected 55 claim 1. from oral, enteral, parenteral, topical, transdermal, ocular, 29. An antimicrobial agent, comprising: at least one oligo vitreal, rectal, nasal, pulmonary, and vaginal. mer of claim 1, wherein the biologically active compound has 20. A pharmaceutical composition of claim 18, wherein the an antimicrobial effect. phenolic residue of formula I or II is derived from a phenolic 30. A therapeutic method for treating a disease in a patient, compound with antimicrobial properties. 60 comprising: administering to a patient in need of Such 21. A pharmaceutical composition of claim 20, further therapy, an effective amount of at least one oligomer of claim comprising: an antimicrobial agent. 1. 22. A pharmaceutical composition of claim 18, wherein the 31. A therapeutic method for producing an analgesic effect phenolic residue in the compound of formula I was derived in a patient, comprising: administering to a patient in need of from a phenolic with anti-inflammatory properties. 65 Such therapy, an effective amount of at least one oligomer of 23. A pharmaceutical composition of claim 22, further claim 1, wherein the biologically active compound has an comprising: anti-inflammatory agent. analgesic effect. US 8,026,285 B2 51 52 32. A therapeutic method for treating cancer in a patient, 36. A therapeutic method for producing an immunosup comprising: administering to a patient in need of Such pressive effect in a patient, comprising: administering to a therapy, an effective amount of at least one oligomer of claim patient in need of such therapy, an effective amount of at least 1, wherein the biologically active compound has an anti one oligomer of claim 1, wherein the biologically active cancer effect. compound has an immunosuppressive effect. 33. A therapeutic method for producing an anti-inflamma 37. A therapeutic method for producing an anti-thrombotic tory effect in a patient, comprising: administering to a patient effect in a patient, comprising: administering to a patient in in need of Such therapy, an effective amount of at least one oligomer of claim 1, wherein the biologically active com need of Such therapy, an effective amount of at least one pound has anti-inflammatory effect. oligomer of claim 1, wherein the biologically active com 34. A therapeutic method for producing an anti-bacterial 10 pound has anti-thrombotic effect. effect in a patient, comprising: administering to a patient in 38. A therapeutic method for treating psoriasis, or inflam need of Such therapy, an effective amount of at least one matory bowel disease in a patient, comprising: administering oligomer of claim 1, wherein the biologically active com to a patient in need of Such therapy, an effective mount of at pound has anti-bacterial effect. least one oligomer of claim 1, wherein the biologically active 35. A therapeutic method for producing an anti-fungal 15 compound has an anti-psoriasis or anti-inflammatory bowel effect in a patient, comprising: administering to a patient in disease effect. need of Such therapy an effective amount of at least one oligomer of claim 1 wherein the biologically active com pound has an anti-fungal effect.