US 20090076174A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0076174 A1 BeZWada (43) Pub. Date: Mar. 19,9 2009

(54) CONTROL RELEASE OF BIOLOGICALLY Related U.S. Application Data St.SENSE (60) Provisional application No. 60/969,787, filed on Sep. 4, 2007. (75) Inventor: Rao S. Bezwada, Hillsborough, NJ Publication Classification (US) (51) Int. Cl. A6II 47/48 (2006.01) Correspondence Address: (52) U.S. Cl...... 514/772.3 FELDMANGALE, P.A. (57) ABSTRACT 1700 Market Street, Suite #3130 Philadelphia, PA 19103 (US) The present invention relates to the discovery of biodegrad able multi-armed oligomers wherein the end groups of these (73) Assignee: BEZWADA BIOMEDICAL oligomers have been functionalized with biologically active 9 molecules. The resultant multi-armed oligomers end-func LLC, Hillsborough, NJ (US) tionalized with biologically active molecules have a control lable degradation profile. The hydrolytic degradation of oli (21) Appl. No.: 12/203,761 gomers of the present invention releases the biologically active compound as such with no change in native chemical (22) Filed: Sep. 3, 2008 Structure. US 2009/0076174 A1 Mar. 19, 2009

CONTROL RELEASE OF BIOLOGICALLY 0009. The invention also provides processes of function ACTIVE COMPOUNDS FROM alizing biologically active compounds and preparation of bio MULT-ARMED OLIGOMERS logically active oligomer with controlled degradation pro files. CROSS REFERENCE TO RELATED APPLICATIONS DETAILED DESCRIPTION OF THE PRESENT INVENTION 0001. This application claims the benefit of U.S. Applica 0010. The present invention relates to the discovery of tion No. 60/969,787, filed Sep. 4, 2007, the entirety of which biodegradable multi-armed (two armed, three armed, four is incorporated herein by reference. armed, six armed) oligomers wherein the end groups of these oligomers have been functionalized with biologically active FIELD OF THE INVENTION molecules. The resultant multi-armed oligomers end-func tionalized with biologically active molecules have a control 0002 The present invention relates to the discovery of lable degradation profile. The hydrolytic degradation of oli biodegradable multi-armed oligomers wherein the end gomers of the present invention releases the biologically groups of these oligomers have been functionalized with bio active compound as such with no change in native chemical logically active molecules. The resultant multi-armed oligo Structure. mers end-functionalized with biologically active molecules 0011. As used herein, the term “biologically active com have a controllable degradation profile. The hydrolytic deg pound” refers to a naturally occurring, semi-synthetic, or radation of oligomers of the present invention releases the synthetic therapeutic agent that provides a therapeutically biologically active compound as such with no change in desirable effect when administered to a mammal (e.g., native chemical structure. human). Biologically active compounds capable of incorpo ration into polymers of the present invention possess at least BACKGROUND OF THE INVENTION two functional groups that can each be incorporated into an ester or amide linkage of a polymer of the present invention, 0003 Biologically active compounds are well known Such that, upon hydrolysis of the polymer, the therapeutic (e.g., and capsaicin) and have been beneficially agent is obtained. The biologically active compounds useful administered to patients in need thereof for more than a cen in the present invention have at least one aryl or heteroaryl tury. One problem that has been associated with many bio ring and at least one hydroxyl (OH), Substituted or unsubsti logically active compounds is that they can be difficult to tuted amino, or carboxylic acid Substituent on the aromatic or dissolve in water or the human body and can also be very heteroaromatic ring, or functional derivatives of Such Sub difficult to polymerize. Due to the availability and numerous stituents. Such as esters, amides, methyl ethers, and/or glyco uses of biologically active compounds, it is desirable to sides, or other derivatives that would be apparent to those enhance their native value by, for example, providing com skilled in the art. Additional examples of the number of aro pounds or combinations of compounds with a specific con matic groups present in the phenolic include (a) 1, 2, and 3 trolled degradation profile or range enabling controlled and (b) 1 and 2. Additional examples of the number of func release of the biologically active compound over an extended, tional (e.g., hydroxyl) groups present on the phenolic include controllable time range. The present invention is directed to (a) 1, 2, 3, 4, and 5 and (b) 1 and 2. these and other important ends. 0012. The biologically active compounds can also com prise other functional groups (e.g., hydroxyl groups, amine groups, and carboxylic acids) that can be used to modify the SUMMARY OF INVENTION properties of the polymer (e.g. for branching, for cross link 0004. The present invention relates to biodegradable ing, for appending other molecules (e.g. another biologically multi-armed (e.g. 2, 3, 4, 5, or 6 arms) oligomers wherein the active compound) to the polymer, for changing the solubility end groups of these oligomers have been functionalized with of the polymer, or for effecting the biodistribution of the biologically active molecules. polymer. Lists of therapeutic agents can be found, for 0005. The present invention also provides a method of example, in: Physicians’ Desk Reference, 61' Ed., 2007. preparing absorbable oligomer compositions comprising Thomson Healthcare Company: USPN Dictionary of USAN functionalized biologically active compounds and a pharma and International Drug Names, 2000. The United States Phar macopoeia Convention, Inc., Rockville, Md.; and The Merck ceutically acceptable carrier. Index, 14' Ed., 2007, John Wiley & Sons. One skilled in the 0006. The present invention also provides a therapeutic art can readily select therapeutic agents that possess the nec method for treating a disease in a mammal comprising admin essary functional groups for incorporation into the polymers istering to a mammal in need of Such therapy, an effective of the invention from these lists. amount of an oligomer of the present invention. 0013 Therapeutic agents that may be incorporated into 0007. The present invention also provides a method of the polymers of the invention include suitably functionalized delivering a biologically active compound to a mammal com analgesics or general or local anesthetics, anti-convulsants, prising administering to the mammal a biocompatible and anti-diabetic agents, anti-fibrotic agents, anti-infectives, anti biodegradable oligomer of the present invention, which bacterials, anti-fungals, anti-neoplastics, cardioprotective degrades into the biologically active compound. agents, cardiovascular agents, anti-thrombotics, central ner 0008. The present invention also provides an oligomer for Vous system , cholinesterase inhibitors, contracep use in medical therapy, as well as the use of an oligomer for tives, deodorants, receptor agonists, erectile dys the manufacture of a medicament useful for the treatment of function agents, fertility agents, gastrointestinal agents, gout a disease in a mammal. agents, hormones, immunomodulators, immunosuppressive, US 2009/0076174 A1 Mar. 19, 2009 migraine agents, non-steroidal anti-inflammatory drugs Vine, glibenclamide, glucametacin, guajacol, halquinol, (NSAIDs), motion sickness agents, muscle relaxants, nucleo hexachlorophene, hexestrol, hexobendine, hexoprenaline, side analogs, neurodegenerative agents (e.g., Parkinson's dis hexylresorcinol, hydroxyethyl salicylate, hydroxy stilbami ease), obesity agents, ophthalmic agents, osteoporosis dine isethionate, hymecromone, ifenprodil, indomethacin, agents, parasympatholytics, parasympathomimetics, anti-an ipriflavone, , , isoxSuprine, itopride esthetics, prostaglandins, psychotherapeutic agents, respira hydrochlor-ide, ketobemidone, khellin, labetalol, lactylphe tory agents, sedatives, hypnotics, skin and mucous membrane netidin, levodopa. levomepromazine, levorphanol, levothy agents, Smoking cessation agents, sympatholytics, urinary roXine, mebeverine, medrylamine, , mepacrine, tract agents, vaginal agents, and vasodilators, and the like (see mesalazine, mestranol, , methocarbamol, meth Physicians’ Desk Reference, 61' Ed., 2007, Thomson Health oxamine, methoXSalen, methyldopa, midodrine, mitox Care). antrone, morclofone, nabumetone, naproxen, nitroxo-line, 0014 Phenol is the simplest example of a phenolic com , normolaxol, , omeprazole, orci pound, but most phenolics have two or more hydroxyl groups prenaline, , oxitriptan, oxyfedrine, oxypertine, and are in many instances bioactive substances occurring oxyphenbutaZone, oxyphenisatin acetate, oxyquinoline, widely in food plants that are eaten regularly by Substantial papaverine, paracetanol, parethoxycaine, phenacaine, phen numbers of animals and people. These food-plant bioactive acetin, phenazocine, phenolphthalein, phenprocoumon, phenolic compounds have typically been found to be safe phentolamine, phloedrine, picotamide, pimobendan, prenal compounds. Included in the definition of biologically active terol, primaquine, progabide, propanidid, protokylol. phenolics are highly substituted poly-phenols whose struc proxymetacaine, raloxifene hydrochloride, repaglinide, tures include condensed rings. reproterol, rimiterol, ritodrine, salacetamide, Salazosulfapy 00.15 Examples of naturally occurring biologically active ridine, , salicylamide, , salmeterol, phenolics include bergaptol, caffeic acid, capsaicin, cou Salsalate, sildenafil. Silibinin, Sulmetozin, tamsulosin, tera marin, daidzein, 2.5-dihydroxy-benzoic acid, ferulic acid, Zosin, terbutaline, tetroXoprim, theo-drenaline, tioclomarol, flavonoids, glycitein (isoflavone), 4-hydroxycinnamic acid, tioxolone, C.-tocopherol (vitamin E), tofisopam, tolcapone, 4-hydroxy-coumarin, isopimpinellin, resveratrol. Sinapic tolterodine, tranilast, tretoquinol, triclosan, trimaZosin, tri acid, , vanillin, and derivatives thereof. metazidine, trimethobenz-amide, trimethoprim, trimetozine, 0016 Capsaicin is a biologically active phenolic that is the trimetrexate glucuronate, troXipide, Verapamil, Vesnarinone, active component of cayenne pepper. The capsaicin is an Vetrabutine, , warfarin, Xamoterol. amide of Vanillylamine and Cs to C branched fatty acids. (0019. Other bioactive phenolics include acacetin, 4-aceta Topical application of capsaicin stimulates and blocks Small mido-2-methyl-1-naphthol, acetaminophen, albuterol, alle pain fibers by depleting them of the neurotransmitter sub nolic acid, aloe emodin, aloin, B-amino-4-hydroxy-3,5-di stance P that mediates pain impulses. A cream made from iodohydrocinnamic acid, N-(5-amino-2-hydroxyphenyl)- 0.025%-0.075% capsaicin applied 4 times daily reportedly benzeneacetamide, 4-amino-1-naphthol, 3-aminosalicylic may help peripheral neuropathic pain, post-herpetic neural acid, 4-aminosalicylic acid, anacardic acid, p-anol, gia, trigeminal neuralgia, psoriasis and fibromyalgia. It may anthragallol, anthralin, anthranol, anthrarobin, anthrarufin, also be useful for diabetic neuropathy, cluster headaches, apigenin, apin, apocynin, aspidinol, aspirin, baptigenin, ben earache, osteo- and rheumatoid arthritis. Capsaicin is a pow Zestrol, benzoresorcinol, bisphenola, bisphenolb, butylated erful pain reliever. hydroxylanisole, butylated hydroxytoluene, capobenic acid, 0017 Naproxen, paracetanol, acetaminophen and acetyl trans-1-(3'-carboxy-4-hydroxyphenyl)-2-(2".5"-dihydrox salicylic acid are biologically active phenolics that belong to yphenyl)ethane, catechin, chlorogenic acid, m-chlorophenol, the class of drugs called non-steroidal anti-inflammatory 5-chloro-8-quinolinol, chloroxylenol, chlorquinaldol. drugs or NSAIDs. It is generally believed that NSAIDs pro chromo-nar, chrysin, cinametic acid, clorophene, coniferyl vide reliefby blocking the action of prostaglandins, which are , p-coumaric acid, coumes-trol, coumetarol, daphne hormone-like Substances that contribute to pain, inflamma tin, datiscetin, , 3.5-diiodothyronine, 3.5- tion, fever and muscle cramps. di-iodotyrosine, dimethophrine, dioSmetin, diresorcinol, 0018 Phenolic moieties, synthetic and naturally occur disoprofol, dopa, dopamine, drosophilina, efloxate, ellagic ring, are part of many drugs. Examples of these medicinals acid, embelin, Equol. eriodictyol, esculetin, esculin, ethyl include acenocoumarol, acetarsol, actinoquinol, adrenalone, , ethyl Vanillin, eugenol, eupatorin, fenadiaz alibendol, amodiaquine, anethole, balsalazide, bamethan, ole, ferulic acid, fisetin, 3-fluoro-4-hydroxyphenylacetic benserazide, bentiromide, benzarone, benzquinamide, acid, fraxetin, fustin, galangin, gallacetophe-none, gallic bevantolol, bifluranol, buclosamide, bupheniode, chlorotria acid, gardenins, genistein, gentisyl alcohol, , gera nisene, chloroxylenol, cianidanol, cinepazide, cinitapride, nylhydroqui-none, 6-gingerol, gossypol, guaiacol, guaifen cinepazide, cinmetacin, clebopride, clemastine, clioquinol, esin, harmalol, hematoxylin, hinderin, homoeriodictyol. cyclovalone, cynarine, , dextroy thyroxine, homogentisic acid, homoVanillic acid, hydroxyamphet diacerein, dichlorophen, dienestrol, diethylstilbestrol, amine, 2-hyd-roxy-5-(2,5-dihydroxybenzylamino)-2-hy diflunisal, diiodohydroxyquinoline, dilaZep, dilevalol, droxybenzoic acid, 4-hydroxy-3-methoxy-mandelic acid, dimestrol, dimoxyline, dioSmin, dithranol, , n-(p-hydroxyphenyl)glycine, hydroxyprocaine, 8-hydrox donepezil, dopamine, , doxazosin, entacapone, ycuinoline, hypericin, irigenin, isoproterenol, isoquercitrin, epanolol, epimestrol, epinephrine, Valerate, estriol, isothebaine, kaempferol, liothyronine, luteolin, mangostin, estriol Succinate, estrone, etamivan, etamsylate, ethaverine, 5.5'-methylenedisalicylic acid, n-methylepinephrine, mety ethoXZolamide, ethyl biscoum-acetate, etillefrine, etiroXate, rosine, morin, mycophenolic acid, myricetin, naringenin, exalamide, exifone, fendosal, fenoldopam mesilate, fenot nylidrin, orcinol, osalmid, osthole, oxantel, paroxypropione, erol, fenoxedil, fenticlor, flopropione, floredil, fluorescein, pentachlorophenol, 3-pentadecylcatechol, p-pentyloxy-phe folescutol, formo-terol, gallopamil, gentistic acid, glazio nol, phloretin, phloroglucinol, pinosylvine, plumbagin, pyro US 2009/0076174 A1 Mar. 19, 2009 catechol, pyrogallol, quercetagetin, quercetin, resacetophe 0025. Further examples of biologically active compounds none, rhamnetin, rhein, Sakuranetin, Salicyl alcohol, with hydroxyl, carboxyl and/or amino groups useful in the salicylanilide, 4-Salicyloylmorpholine, Salsalate, Scopoletin, present invention may be found in the following texts, which Scutellarein, serotonin, (3,4,5-trihydroxyphenyl)methyl are hereby incorporated in their entireties herein by reference. enepropanedinitrile, thymol, thyropropic acid, thyroxine, 0026 a. Shahidi, Ferriodoon and Marian Naczk, Pheno tiratricol, , Vanillic acid, and Vanillin. lics in Food and Nutriceuticals, Boca Raton, Fla.: CRC 0020 Examples of biologically active amino compounds Press, 2003. include Aceclofenac, Acediasulfone, Alminoprofen, Amisul 0027 b. Kleemann, A. et al. Pharmaceutical Substances, pride, AmLexanox, Amodiaquine. Amosulalol. Amoxicillin, 4th Edition, Thieme (2000). Amsacrine, Anileridine, AZacyclonol, Baccofen, BalsalaZide 0028 c. Phenolic Compounds in Food and Their Effects on Sodium, Benzocaine, Bromopride, Bumetanide, Carprofen, Health II; Antioxidants and Cancer Prevention, ACS Sym Carvedilol, Carzenide, Cefprozil, Cinitapride, Clebopride, posium Series No. 507, Washington, D.C.: ACS, 1992. , Diclofenac, EthoXZolamide, Flufenamic acid, 0029 d. Food Phytochemicals for Cancer Prevention I. Furosemide, lobenzamic acid, locetamic acid, Mefenamic ACS Symposium Series N. 546, Washington, D.C.: ACS, acid, Nadoxolol, D-Nor- and paracetamol. 1994. 0021 Examples of biologically active carboxylic acid 0030) e. ROMPP Encyclopedia Natural Products, New compounds include Acemetacin, Aceclofenac, Acediasul York: Thieme, 2000. fone, Adipiodone, Alminoprofen, AmLexanox, Anileridine, 0031 f. The Merck Index, 14 edition, John Wiley & Sons, Baccofen, Balsalazide sodium, Bentiromide, Benzocaine, 2007. Bumetanide, Carprofen, Carzenide, Cinmetacin, Clometa 0032 g. A Single Source for Flavonoids and Coumarins cin, Cromoglicic acid, Diclofenac, Diflunisal, Eprosartan, (2005-2006), INDOFINE Chemical Company, Inc. 2006. Fendosal, Flufenamic acid, Furosemide, Indometacin, Ioben 0033. The present invention provides novel oligomers of Zamic acid, locarmic acid, locetamic acid, Iodoxamic acid, formulae I and/or II or a pharmaceutically acceptable salt loglycamic acid, lophenoic acid, lotroXic acid, Mefenamic thereof: acid, Naproxen, Nedocromil, Repaglinide, Salazosulfapyri dine, Salicylic Acid, Salsalate, and Sarpogrelate. 0022 Flavonoids, sometimes called bioflavonoids, are 3-ring phenolic compounds consisting of a double ring —R II attached by a single bond to a third ring. Examples include 0034 wherein: flavonoids, flavanones, flavones, flavanols, anthocyanidins, I0035) R'-O is a biologically active compound resi proanthocyanidins, procyanidolic oligomers (PCO), cat due; echins, biflavans, polyphenols, rutin, rutinosides, hydroxy I0036) R' C(=O)C)— is a biologically active com ethylrutosides (HER), hesperidin, quercetin, quercetrin, pound residue; polyphenols, catechin, epicatechin, epicatechin gallate, epi 0037 X is selected from: —OC(=O)CH (inverse gallocatechin gallate, and leucoanthocyanins. Flavonoids moiety), —OC(=O)CH(CH)— (inverse include the water-soluble pigments, such as anthocyanins, lactic acid moiety), —OC(=O)CHOCHCH (in that are found in cell vacuoles. Flavonols are colorless or verse dioxanone acid moiety), —OC(=O) yellow flavonoids found in leaves and many flowers. CHCHCHCHCH (inverse caprolactone acid 0023. A therapeutic dose of bioflavonoids is helpful for moiety), OC(=O) (CH), , or OC(=O)CH, conditions related to Chronic Venous Insufficiency (CVI). (OCH2CH)—. Some examples are: thrombophlebitis, thrombosis, varicose 0038 X is selected from: —CHC(=O)C)-(glycolic veins, leg ulcers, spider veins, hemorrhoids, chronic nose acid moiety), —CH(CH)C(=O)C)— (lactic acid moi bleeds, prolonged menstrual bleeding. Even eye problems ety), —CHCHOCHC(=O)C) (dioxanone acid like macular degeneration and diabetic retinopathy have been moiety), —CH2CH2CH2CHCHC(=O)C)— (capro helped with bioflavonoids. Along with the anti-inflammatory lactone acid moiety), -(CH2),C(=O)C , or effects, bioflavonoids can be very helpful for tendonitis, —(CHCHO). CHC(=O)C)–: arthritis, rheumatoid arthritis, joint injury, fibromyalgia, cel 0.039 Y is selected from: C(=O)CH-O-(glycolic lulite, and gout. Bioflavonoids, specifically proanthcyani ester moiety), —C(=O)CH(CH)O— (lacticester moi dins, are found in grape seed extract. The proanthcyanidins ety), —C(=O)CHOCH2CH2O (dioxanone ester appear to enhance the activity of vitiamin C. The biofla moiety), —C(=O)CHCH2CH2CHCHO— (capro vonoids in grape seed extract may also reduce the painful lactone ester moiety), —C(=O)(CH)O , or inflammation of swollen joints and prevent the oxidation of —C(=O)CH O—(CH2CH2O), ; cholesterol in arteries that leads to plaque in the arterial walls. 0040 Y is selected from: —OCHC(=O)– (inverse 0024. Isoflavones exert a broad spectrum of biological glycolic ester moiety), —OCH(CH)C(=O)— (inverse activities. Besides antioxidant and estrogenic activities, lactic ester moiety), —OCHCHOCHC(=O)— (in isoflavones protect against several chronic diseases. Results VeSe dioxanone ester moiety), of epidemiological studies indicate that consumption of soy —OCH2CH2CHCHCHC(=O)— (inverse caprolac bean isoflavones lowers the incidence of breast, prostate, tone ester moiety), —O(CH),C(=O)—, or urinary tract and colon cancers. They also provide protection - O(CHCHO), OCHC(=O)–: against coronary heart diseases and osteoporosis. Examples 0041 R is a di-, tri, tetra-, penta- or hexaradical derived of isoflavones include are glycitein (isoflavone), daidzein, from Cs alkyl, aryl, or aryl-(Calkyl)--, wherein prunetin, biochanin A, orobol, Santal, pratensein, formonon from 1-3 of the CH groups within the alkyl chain are etin, genistein, glycitein, and the glucosides, B-glycosides optionally independently replaced by O atoms, such that and other derivatives of the aforementioned isoflavones. each of said O atom is attached only to carbon atoms in US 2009/0076174 A1 Mar. 19, 2009

the alkyl chain, with the proviso that multiple O atoms 0053 As used herein, the term “aryl-(C. alkyl)- that replace CH2 groups within the alkyl chain must be refers to a aryl ring, preferably a benzene ring, having 1 to 3 separated from each other by at least two carbon atoms pendant alkyl groups, wherein the aryl-(C. alkyl)--, pref and from the di-, tri, tetra-, penta- or hexaradical chain erably phenyl-(C. alkyl)-moiety, is attached to the ends by at least one carbonatom; or R is the backbone of remainder of the structure in a given formula through its a polymer or copolymer bearing carboxylic acid and/or pendant alkyl group(s). hydroxyl functional groups, where the average molecu 0054. In certain preferred embodiments of the present lar weight of the polymer or copolymer is between 500 invention, a is independently an integer from about 1 to about to 5000 and wherein w is an integer from about 6 to about 5. Alternatively preferred, eacha is independently an integer 50; from about 1 to about 6, preferably from 1 to about 3, with 0042 a is independently selected from 1,2,3,4,5,6,7, from 1 to about 2 being even more preferred. 8,9, and 10; 0055. In other preferred embodiments of the present 0043 b is independently selected from 1, 2, 3, 4, 5, 6, 7, invention, b is independently an integer from about 1 to about 8,9, and 10; 5. Alternatively preferred, each b is independently an integer 0044 each a and b is independently an integer from from about 1 to about 6, preferably from 1 to about 3, with about 1 to about 10; from 1 to about 2 being even more preferred. 004.5 each m, n, y, and Z is independently an integer 0056. In still other preferred embodiments of the present invention, w is the integer 2, 3, or 4. from about 2 to about 24; and 0057 The present invention also provides novel multi 0046) w is an integer from about 2 to about 6. armed oligomers of formulae I or II or a pharmaceutically 0047. The groups represented by X, X, Y, and Y are acceptable salt thereof, wherein the moiety R and the “w” attached as shown. Their left hand sides are attached to the number of attached oxygen atoms (R—IO) is O(CH2)2O, group shown in the corresponding formula to be on the left of wherein w is 2: O(CH)O, wherein w is 2: CH(CHO), the X, X, Y, or Y' group and on their right hand sides to the wherein w is 3: C(CH2O), wherein w is 4; and C(CH2CH) group shown in the corresponding formula to be on the right (CHO), wherein w is 3. of the X, X, Y, or Y' group. 0058. In other preferred embodiments of the present 0048. In some preferred embodiments of oligomers or invention, each X is independently —OC(=O)CH2—, —OC pharmaceutically acceptable salts thereof of formula I or II, (=O)CH(CH) , OC(=O)CHOCHCH , or - OC X' and Y are derived from different hydroxyacid or lactone (=O)CHCHCHCHCH ; more preferably —OC(=O) precursors. CH or - OC(=O)CH(CH)–. 0049. In some preferred embodiments of oligomers or 0059. In certain preferred embodiments of the present pharmaceutically acceptable salts thereof of formula I or II, X invention, each X* is independently —CHC(=O)C) , and Y are derived from different hydroxyacid or lactone pre —CH(CH)C(=O)C) , —CHCHOCHC(=O)C)—, or CUSOS. —CH2CH2CH2CHCHC(=O)C)—, more preferably 0050. In other preferred embodiments of oligomers or —CHC(=O)C)– or -CH(CH)C(=O)C) . pharmaceutically acceptable salts thereof of formulas I or II, 0060. In some preferred embodiments of the present R is a di-, tri, tetra-, penta- or hexaradical derived from C-2s invention, each Y is independently —C(=O)CHO , alkyl, aryl, preferably phenyl, or aryl-(Calkyl)--, prefer —C(=O)CH(CH)O-, -C(=O)CHOCHCH-O-, or ably phenyl-(C. alkyl)-. Whether R is a di-, tri, tetra-, —C(=O)CHCH2CH2CHCHO—; more preferably penta- or hexaradical is determined by W. For example, when - C(=O)CHO or - C(=O)CH(CH)O-. w is 2, R is a diradical; when W is 4, R is a tetraradical, and so 0061. In some other preferred embodiments of the present forth. In certain preferred embodiments wherein R is derived invention, each Y is independently —OCHC(=O) , from Cs alkyl or aryl-(C. alkyl)--, 1-3 of the CH –OCH(CH)C(=O)— —OCHCHOCHC(=O)—, or groups within the alkyl chain are optionally independently —OCH2CH2CHCHCHC(=O)—, more preferably replaced by O or Satoms, preferably by O atoms, such that –OCHC(=O)– or - OCH(CH)C(=O)-. each of said O or Satoms is attached only to carbon atoms in 0062) Examples of polymers or copolymers containing the alkyl chain, preferably with the proviso that the O or S carboxylic acid group and/or hydroxyl functional groups atoms are separated from the di-, tri, tetra-, penta- or hexaradi include poly(acrylic acid), poly(acrylic acid-co-maleic acid), cal chain ends by at least one carbonatom and that multiple O poly(ethylene glycol), branched poly(ethylene glycol), and or Satoms in the diradical chain must be separated from each poly(acrylic acid-graft-polyethylene glycol). other by at least two carbon atoms. Alternatively in some 0063 Examples of biologically active compounds include preferred embodiments, when R is alkyl, it is more preferably phenolic compounds including phenols, naphthols, indoles, (CH), (CH), CH(CH), C(CH), or C(CH2CH)(CH). acetophenones, benzophenones, coumarins, furanocou In still other preferred embodiments, R is (CH), and marins, alkaloids, catechins, chromones, chalcones, fla wherein the C-2 CH group within the (CH) chain is option vonoids or bioflavonoids, isoflavones, drugs containing phe ally replaced by an O atom. In yet other preferred embodi nolic groups, and natural products containing phenolic ments, R is (CH), (CH), (CH), (CHOCH), or groups. (CHCHOCH2CH). In still other preferred embodiments, 0064. Examples of biologically active dihydroxy com R is (CHCHCH) when w is 3, or (C(CH2)) when w is 4. pound that can be used to prepare a polymer of the present 0051. In certain other preferred embodiments, the present invention include Adrenalone, Alfuzosin, Alibendol, Amru invention provides novel multi-armed oligomers of formulae bicin, Apomorphine, Bamethan, BenZquinamide, Bevan I or II or a pharmaceutically acceptable salt thereof, wherein: tolol, Bifluranol, Bisacodyl, Brodimoprim, Bunazosin, 0052 R is a di-, tri, tetra-, penta- or hexaradical derived Bupheniode, Carbidopa, Carbuterol, Cyclofenil, Cyclova from a C-12 alkyl, phenyl, and phenyl-(C1-alkyl)--. lone, Daunorubicin, Dichlorophen, Dienestrol, Diethylstil US 2009/0076174 A1 Mar. 19, 2009 bestrol, Dimestrol, Dithranol, Donepezil, Doxefazepam, Doxorubicin, Entacapone, Epinepheine, Epirubicin, Esome -continued prazole, Etamivan, Etamsylate, , EZetimibe, Fenti O clor, Fluorescein, Folescutol, Formoterol, Gefitinib, Hex estrol, Hexylresorcinol, Hydroxyethyl salicylate, Ifenprodil, Isoetarine, IsoxSuprine, Itopride. HCl, Khellin, Labetalol, Mitoxantrone, Morclofone, Moxaverine, Normolaxol, Ome prazole, Oxilofrine, Oxepertine, Phenacaine, Phenolphtha O lein, PraZosin, Tolcapone, Vesnarinone, and Vetradutine. Benzarone 0065. Examples of biologically active hydroxy/amino OH compounds that can be used to prepare a polymer of the present invention include Amisulpride, Amodiaquine, Amo HO O O Sulalol. Amoxicillin, Amsacrine, AZacyclonol, Bromopride, Carvedilol, Cefprozil, Cinitapride, Clebopride, Clenbuterol, EthoXZolamide, Nadoxolol, D-Norpseudoephedrine, and paracetamol. oC CC 0066 Examples of biologically active dicarboxylic acid Chloroxylenol Hymercromone compounds that can be used to prepare a polymer of the present invention include Adipiodone, Cromoglicic acid, r Eprosartan, locarmic acid, Iodoxamic acid, loglycamic acid, S N lotroxic acid, Nedocromil. OH nu1 0067 Examples of biologically active hydroxy/carboxylic I N acid compounds that can be used to prepare a polymer of the 2 present invention include Acemetacin, Bentiromide, Cin N 1. metacin, Clometacin, Diflunisal, Fendosal, Indometacin, O lophenoic acid, Naproxen, Repaglinide, Salazosulfapyridine, Salicylic Acid, Salsalate, and Sarpogrelate. C OH 0068 Examples of biologically active hydroxyl-acids use Clioquinol Etamivan ful in the present invention include but not limited to 4-hy OH droxycinnamic acid, Caffeic acid, Chlorogenic acid, Ferulic acid, Sinapinic acid, Vanillic acid, Acemetacin, Bentiromide, OH Cinmetacin, Clometacin, Diflunisal, Fendosal, Indometacin, N lophenoic acid, Naproxen, Repaglinide, Salazosulfapyridine, n Salicylic Acid, Salsalate, and Sarpogrelate. H 2 N 0069. Examples of biologically active amino/carboxylic N acid compounds that can be used to prepare a polymer of the present invention include Aceclofenac, Acediasulfone, Almi NO noprofen, Amlexanox, Anileridine, Baccofen, BalsalaZide Nitroxoline OH Sodium, Benzocaine, Bumetanide, Carprofen, Carzenide, OH Diclofenac, Flufenamic acid, Furosemide, lobenzamic acid, N O locetamic acid, and Mefenamic acid. 0070. Some structures of Biologically Active Compounds ul N bearing hydroxyl functional groups useful in present inven 21 H tion are shown below. Oxyquinoline Paracetamol HO O

HO X- NH S H Ou ~s Tioxolone O 0071 Examples of Biologically Active Compounds bear Capsaicin ing carboxylic acid functional groups include but not limited C OH to Acemetacin, Aceclofenac, Acediasulfone, Adipiodone, Alminoprofen, Amlexanox, Anileridine, Baccofen, Bal Salazide sodium, Bentiromide, Benzocaine, Bumetanide, Carprofen, Carzenide, Cinmetacin, Clometacin, Cromoglicic acid, Diclofenac, Diflunisal, Eprosartan, Fendosal, Flufe C C C C namic acid, Furosemide, Indometacin, lobenzamic acid, Triclosan locarmic acid, locetamic acid, Iodoxamic acid, loglycamic acid, lophenoic acid, lotroxic cid, Mefenamic acid, US 2009/0076174 A1 Mar. 19, 2009

Naproxen, Nedocromil, Repaglinide, Salazosulfapyridine, Salicylic Acid, Salsalate, and Sarpogrelate. -continued 0072 Some structures of biologically active compounds bearing carboxyl functional groups useful in present inven tion are shown below. OH N O

o'7.Ketorolac CrOH Methyl Salicylate \ 9 O OH N H OH

Etodolac c. OH OH F F Diflunisal cror Ketoprofen OH F OH 3-O-() O Flurbiprofen

NH Cro OH Tiaprofenic Acid

1S OH r Diclofenac O O MeO OH Naproxen O O O N HO \ | Fenbufen

Tolimetin C OH O

O OH O N Loxoprofen Carprofen US 2009/0076174 A1 Mar. 19, 2009

-continued O S Step 1 HOOC COOH \ / O Functionalization with safe and biocompatible molecules OH ...OOK. Multiarmed acid Suprofen precursor H- o (X)a-H

H-(X)a-OOC COO-(X)a-H Formula A Funcionalized multiarmed r acid precursor with a = 1 to 6 Functionalization with safe Mefenamic acid and biocompatible molecules F GBC-OH -- Biologically active compound bearing hydroxyl group

HO CI GBac)-O-(Yb-co-CHQ Functionalized Biologically active compound with b = 0 to 6 and Q = F, Cl, Br, I O Formula B Step 2 H-(X)a-OOC COO-(X)a-H Lumiracoxib O H-(X)a-OOC DOCCOO-(X)a-H -- Formula A Funcionalized multiarmed N acid precursor with a = 1 to 6

O Formula I No GBAC-O-(Yb-Co-CHQ - - of present Functionalized Biologically active compound invention with b = 0 to 6 and Q = F, Cl, Br, I OH Formula B Indometacin 0074. In another embodiment of the present invention, 0073. Some of the biodegradable oligomers of the present oligomers of present invention can be prepared in two steps as invention can be prepared in two steps as shown in Scheme 1. In the first step, a multi-armed backbone for the oligomers is shown in Scheme 2. In the first step, a multi-armed biode derived by the functionalization of multi-armed acid mol gradable backbone can be derived by the functionalization of ecules (shown as a tetra-acid) with safe and biocompatible multi-armed hydroxyl (polyol) molecules with safe and bio monomers or oligomeric segments containing repeat units compatible monomers or oligomeric segments containing derived from them to form multi-armed hydrolysable linker repeat units derived from them to form multi-armed hydrolys of formula A. Similarly, Biologically Active Compounds able linkers of formula C. Similarly, Biologically Active bearing hydroxyl functional groups can also be functional Compounds bearing carboxyl functional groups can also be ized with safe and biocompatible monomers or oligomeric functionalized with safe and biocompatible monomers or segments containing repeat units derived from them to form oligomeric segments containing repeat units derived from functionalized Biologically Active Compounds of Formula them to form functionalized Biologically Active Compounds B. In the second step, multi-armed hydrolysable linker of of Formula D. In the second step, multi-armed hydrolysable formula A and functionalized Biologically Active Com linker of formula C and functionalized Biologically Active pounds of Formula B are reacted together in stoichiometric Compounds of Formula D are reacted together in stoichio amounts to form multi-armed, biodegradable end functional metric amounts to form multi-armed, biodegradable end ized therapeutic oligomers of Formula I of the present inven functionalized therapeutic oligomers of Formula II of the tion with controllable hydrolytic degradation profiles. The present invention with controllable hydrolytic degradation resulting multi-armed oligomers of the present invention can profile. The resulting multi-armed oligomers of the present provide site specific delivery of bioactive compounds upon invention can provide site specific delivery of bioactive com biodegradation by hydrolytic and/or enzymatic actions with pounds upon biodegradation by hydrolytic and/or enzymatic controlled release of biologically active compounds as such actions with controlled release of biologically active com with no change in native chemical structure. pounds as such with no change in native chemical structure. US 2009/0076174 A1 Mar. 19, 2009

-continued Scheme 2 Step 1 O O HO OH Functionalization with safe HO --- OH and biocompatible molecules He HO OH Multiarmed O O polyol precursor HO--- N---> OH ------O O HO N--- OH Formula C Functionalized multiarmed polyol precursor with b = 0 to 6 O Functionalization with safe and biocompatible molecules -as Biologically active compound bearing carboxyl group ---~~~~ O GAC-COO-Xa-H O O O O Formula D Functionalized Biologically HO OH HO OH active compound with a = 1 to 6 HO OH Step 2

O O O OH ------O OH Formula C Functionalized multiarmed polyol precursor with b = 0 to 6 Formula II of Ga)-coo- (X)a-H -- present invention HO OH Formula D O O Functionalized Biologically active compound with a = 1 to 6 HO 0075 Some examples of linear and multi-armed hydrolys O O O able linker precursors of present invention are shown below: (e.g., —OC(=O) R, wherein each carboxylic acid pro HO OH ton (H) present in the di- or poly acid shown below is absent in the linker): O OH OH O O O O O O OH O -N-N- HO R OH OH n = 10-50 --N-- O HO 1n-1'N-1a OH 0076 Examples of the number-average molecular weight r r of PEG (polyethylene glycol) include 400, 500, 600, 700, 800, 900, to 1000. 0077. Some examples of linear and multi-armed hydrolys --N- OH able linkers of the present invention are shown below (e.g., HO r —(X) OC(=O) R, wherein each carboxylic acid pro ton (H) shown is absent in the linker): US 2009/0076174 A1 Mar. 19, 2009 r---,r re-or-continued O O *N-so-N-os-~N-so

O 0078 For example, the first diacid derived linker in the list O shown directly above has R as a three carbon diradical, wherein one of the CH groups in the diradical is replaced by HO O OH an oxygen atom, X is —OC(=O)CH2—, a is the integer 1, O O and w is the integer 2. O O 0079. Some examples of linear and multi-armed hydrolys able precursors and linkers of the present invention are shown ~~~~---

cy is ------^ s------

----- A ------US 2009/0076174 A1 Mar. 19, 2009 10

-continued O O O O O or ouls r O O O rO -- r --- O O O O O X. O O O ------X ---

0080 wherein Q is a bond (when part of an oligomer) or F. I0083 wherein Q is a bond (when part of an oligomer) or F. Cl, Br, or I (when part of a precursor). Cl, Br, or I as a replacement for the O atom (when part of a 0081 For example, the first precursor in the list shown precursor). I0084. For example, the first precursor in the list shown directly above has Ras a two carbon diradical, whereinY' is directly above has Ras a two carbon diradical, whereinY' is —OCHC(=O)—, b is the integer 2, and w is the integer 2. —OCHC(=O)—, b is the integer 2, and w is the integer 2. 0082 Some examples of linear and multi-armed hydrolys I0085 “Alkyl includes both branched and straight-chain able precursors and linkers of the present invention are shown saturated aliphatic hydrocarbon groups having the specified below (e.g., -(Y), OR): number of carbonatoms. Calkyl, for example, includes C. C, CCCs, and Calkyl groups. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, O n-pentyl, S-pentyl, and n-hexyl. I0086) “Aryl refers to an optionally substituted, mono-, ON-1N Q di-, tri-, or other multicyclic aromatic ring system having from about 5 to about 50 carbon atoms (and all combinations r O O and Subcombinations of ranges and specific numbers of car bon atoms therein), with from about 6 to about 10 carbons being preferred. Non-limiting examples include, for example, r N-1N1 r phenyl, naphthyl, anthracenyl, and phenanthrenyl. I0087. The present invention also provides novel therapeu tic methods for producing effects or treating diseases by (~N- administering to a patient in need thereof a therapeutically O effective amount of at least one polymer of the present inven O n = 2 O tion. Examples of effects and diseases include an analgesic effect, cancer, an anti-inflammatory effect. an anti-bacterial effect, an anti-fungal effect, an immunosuppressive effect, an anti-thrombotic effect, psoriasis, inflammatory bowel dis ease, skin cancer, brain tumor, an anti-infective effect, and su. Xu - pa1n. O I0088. The rate of hydrolysis of Biologically Active Com pounds of formula Band Das shown in Scheme 1 and Scheme 2 respectively will depend upon a number of factors, includ ing the functionalization species used and the number of repeat units of functionalization species present on the func tionalized Biologically Active Compound (e.g., 1-6). Gly colic acid modified Biologically Active Compound should hydrolyze faster than dioxanone modifies ones, where as lactic acid and caprolactone modified Biologically Active Compound should take much longer to hydrolyze than gly colic acid and dioxanone modified Biologically Active Com pound. Furthermore, it is expected that the rate of hydrolysis US 2009/0076174 A1 Mar. 19, 2009

will increase with the increase in the value of a and b. Thus, applications, flavors, coatings, drug intermediates, solvents the desired time range may be obtained by altering the num for drugs, new monomers for polymerization, and when poly ber of repeat units and type of functionalization species used merized, as polymers for biomedical applications, drugs, to functionalize the Biologically Active Compound. nutrition Supplements, nutraceuticals, drug delivery, cos 0089. The definitions and examples provided in this appli metic applications, flavors, and coatings. cation are not intended to be limiting, unless specifically 0097. The array of functionalized phenolic compounds stated. developed as an aspect of the invention, have a wide range of 0090 The starting material for the compounds of the hydrolysis rates that are controllable. The specific moiety or present invention may be a phenolic compound or may be a combination of moieties used for functionalization yields a precursor of a phenolic, such as a methoxyphenol, benzylox compound or mixture with specific hydrolysis ranges. yphenol or acetoxyphenol. 0098. The new functionalized biologically active com 0091. The present invention also provides a blend com pounds have more controllable hydrolysis profiles, improved prising one or more of the functionalization species with one bioavailability, improved efficacy and enhanced functional or more species of phenolic compounds. ity. The difunctional compounds polymerize into biodegrad 0092. The compositions of the present invention may be able polymers, for example, useful for applications, including suitable for administration via a route selected from oral, biomedical applications, foodstuffs, cosmetics, medica enteral, parenteral, topical, transdermal, ocular, vitreal, rec ments, coatings and other uses readily apparent to one skilled tal, nasal, pulmonary, and Vaginal. in the art. 0093. “Pharmaceutically acceptable salts' refer to deriva tives of the disclosed compounds wherein the parent com Bioactive Formulations pound is modified by making acid or base salts thereof. 0099. In other aspects of the present invention some func Examples of pharmaceutically acceptable salts include, but tionalized biologically active compounds of the present are not limited to, mineral or organic acid salts of basic invention are further manufactured into formulations suitable residues such as amines; alkali or organic salts of acidic for oral, rectal, parenteral (for example, Subcutaneous, intra residues such as carboxylic acids; and the like. The pharma muscular, intradermal, or intravenous), transdermal, vitreal ceutically acceptable salts include the conventional non-toxic or topical administration. The most Suitable route in any given salts or the quaternary ammonium salts of the parent com case will depend on the nature and severity of the condition pound formed, for example, from non-toxic inorganic or being treated and on the nature of the particular active com organic acids. For example, Such conventional non-toxic salts pound that is being used. The formulations of a pharmaceu include, but are not limited to, those derived from inorganic tical composition are typically admixed with one or more and organic acids selected from 1.2-ethanedisulfonic, 2-ac pharmaceutically or veterinarially acceptable carriers and/or etoxybenzoic, 2-hydroxyethanesulfonic, acetic, ascorbic, excipients as are well known in the art. benzenesulfonic, benzoic, bicarbonic, carbonic, citric, edetic, 0100 Formulations suitable for oral administration may ethane disulfonic, ethane Sulfonic, fumaric, glucoheptonic, be presented in discrete units. Such as capsules, cachets, loZ gluconic, glutamic, glycolic, glycolyarsanilic, hexylresor enges, or tablets, each containing a predetermined amount of cinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, the active compound; as a powder or granules; as a solution or hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lacto a Suspension in an aqueous or non-aqueous liquid; or as an bionic, lauryl Sulfonic, maleic, malic, mandelic, methane oil-in-water or water-in-oil emulsion. Sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, pheny 0101 Compositions of the present invention suitable for lacetic, phosphoric, polygalacturonic, propionic, salicyclic, parenteral administration conveniently comprise sterile aque Stearic, Subacetic, succinic, Sulfamic, Sulfanilic, Sulfuric, tan ous preparations of the active compounds, where prepara nic, tartaric, and toluenesulfonic. tions are preferably isotonic with the blood of the intended 0094. The pharmaceutically acceptable salts of the present recipient. invention can be synthesized from the parent compound that 0102 Formulations suitable for rectal administration are contains a basic or acidic moiety by conventional chemical preferably presented as unit dose Suppositories. methods. Generally, such salts can be prepared by reacting the (0103 Formulations suitable for ocular or vitreal adminis free acid or base forms of these compounds with a stoichio tration may be presented as bioabsorbable coatings for metric amount of the appropriate base or acid in water or in an implantable medical devices, injectables, liquids, gels or Sus organic solvent, or in a mixture of the two: generally, non pensions. aqueous media like ether, ethyl acetate, ethanol, isopropanol, 0104 Formulations or compositions suitable for topical oracetonitrile are preferred. Lists of suitable salts are found in administration to the skin preferably take the form of an Remington's Pharmaceutical Sciences, 18th ed., Mack Pub ointment, cream, lotion, paste, gel, spray, aerosol, or oil. lishing Company, Easton, Pa., 1990, p 1445, the disclosure of Examples of carriers that conventionally used include Vase which is hereby incorporated by reference. line, lanoline, polyethylene glycols, alcohols, and combina 0095 “Therapeutically effective amount” includes an tion of two or more thereof. amount of a compound of the present invention that is effec 0105 Formulations suitable for transdermal administra tive when administered alone or in combination to treat the tion may be presented as discrete patches adapted to remain in desired indication. intimate contact with the epidermis of the recipient for a 0096. One aspect of the present invention combines the prolonged period of time. phenolic compound with one or more of the selected group of 0106 The active compounds may be provided in the form compounds to form a functionalized phenolic compound with of foodstuffs or nutrition Supplements, such as being added uses in medicine, as enhanced drugs, drug intermediates, to, admixed into, coated, combined or otherwise added to a cancer preventing agents, nutrition Supplements, nutraceuti foodstuff. The term foodstuff is used in its widest possible cals, antioxidants, controlled release preparations, cosmetic sense and includes liquid formulations such as drinks includ US 2009/0076174 A1 Mar. 19, 2009 ing dairy products, biodegradable chewing gums, and other 0113. A solution ethylene glycol (5 grams, 80.55 foods, such as health bars, desserts, etc. Food formulations mmoles), 6-bromo hexanoic acid (47 grams, 240.96 mmoles) containing compounds of the invention can be readily pre and paratoluene sulphonic acid (0.5 gram) in toluene (150 ml) pared according to standard practices. in a 500 ml 4 neck round bottom flask equipped with a 0107 Compounds of the formula used as medicaments or mechanical stirrer, Dean-stark apparatus was refluxed for 4 pharmaceuticals are typically administered in a manner and hours, cooled to room temperature. The toluene layer was amount as is conventionally practiced. See, for example, washed with water (2x100 ml), 5% sodium bicarbonate solu Goodman and Gilman, The Pharmaceutical Basis of Thera tion (3x50 ml), water (2x100 ml), dried over sodium sulphate peutics, current edition. and distilled to get example 2 (30 grams, 91%) as a light 0108 Compounds of the present invention have potent yellow syrup. m.p: 44° C., H NMR (CDC1): 8 1.45 (m. 2H, antioxidant activity and increased acidity of their phenolic CH), 1.59 (m. 2H, CH), 1.82 (m. 2H, CH), 2.26 (t, 2H, component, as well as the improved biodegradation provided CH), 3.34 (t, 2H, CH), 4.18 (s. 2H, CH). by the functionalization, and thus find wide application in pharmaceutical and veterinary uses, in cosmetics such as Example 3 more effective skin creams to prevent skin ageing, in Sun Chloro-acetic Acid 3-(2-chloro-acetoxy)-2.2-bis-(2- screens, in foods, health drinks, nutritional Supplements, chloro-acetoxymethyl)-propyl Ester shampoos, and the like. 0109 Examples of functionalized biologically active 0114 compounds of the present invention are provided for some embodiments of the current invention. It can be extended to other species. This selection is not meant to limit the scope of O O the invention in any way. Other variations in the procedure may be readily apparent to those skilled in the art. sus -- EXAMPLES O O Example 1 C ~ ^a Chloro-acetic acid 2-(2-chloro-acetoxy)-ethyl Ester O O 0110 0.115. A solution pentaerythritol (25 grams, 183.62 mmoles), chloroacetic acid (105.2 grams, 1.10 moles) and paratoluene Sulphonic acid (2 gram) in toluene (500 ml) in a 2 lit 4 neck round bottom flask equipped with a mechanical stirrer, Dean-stark apparatus was refluxed for 8 hours, cooled to room temperature. The toluene layer was washed with ------O water (2x300 ml), 5% sodium bicarbonate solution (3x500 ml), water (2x300 ml), dried over sodium sulphate and dis 0111. A solution ethylene glycol (100 grams, 1.611 tilled to get crude 3, which was purified by recrystallisation moles), chloroacetic acid (385 grams, 4.031 moles) and para from chloroform: Hexane (1:7) to get pure 3 (77 grams, toluene sulphonic acid (1 gram) in toluene (750 ml) in a 2 lit 94.8%), as a white powder. m.p. 94-96° C., IH NMR 4 neck round bottom flask equipped with a mechanical stirrer, (CDC1): 84.16 (s. 2H, CH), 4.28 (s. 2H, CH). Dean-stark apparatus was refluxed for 8 hours, cooled to room temperature. The toluene layer was washed with water Example 4 (2x300 ml), 5% sodium bicarbonate solution (3x500 ml), Chloro-acetic Acid 2.2-bis-(2-chloro-acetoxym water (2x300 ml), dried over sodium sulphate and distilled to ethyl)-butyl Ester get crude 1, which was purified by high vacuum distillation to get pure 1 (242 grams, 69.8%), which slowly crystallized to 0116 white crystals m.p: 44° C., H NMR (CDC1): 84.16 (s. 2H, CH), 4.85 (s. 2H, CH). Example 2 6-Bromo-hexanoic Acid 2-(6-bromo-hexanoyloxy)- ethyl Ester 0112

0117. A solution Trimethylolpropane (100 grams, 745.82 -n-n-n N---~~ Br mmoles), chloro acetic acid (422 grams, 4.465 moles) and O Para toluene sulphonic acid (5 grams) in Toluene (500 ml) in a 2 liter 4 neck round bottom flask equipped with a mechani cal stirrer, Dean-stark apparatus was refluxed for 8 hours, US 2009/0076174 A1 Mar. 19, 2009

cooled to room temperature. The toluene layer was washed 0.122 To a solution of Aspirin (20.37 grams, 113.07 with water (2x300 ml), 5% sodium bicarbonate solution mmoles), triethylamine (18.29 grams, 180.74 mmoles) in dry (3x500 ml), water (2x300 ml), dried over sodium sulphate acetone (100 ml) was added tetra chloro linker (10 grams, and distilled to get the linker as light yellow syrup. 22.62 mmoles), example 3 and stirred at room temperature for 0118. IH NMR (CDC13) & 0.9 (t, 3H, CH3), 1.6 (q, 2H, 20 hours. The solid triethylamine hydrochloride is filtered, CH2), 4.07 (s, 6H, CH2x3), 4.15 (s, 6H, CH2x3) acetone distilled off. Crude mass was dissolved in ethyl acetate, washed with 5% sodium bicarbonate solution, dried Example 5 over sodium sulphate and distilled. The crude 6 was recrys tallised from chloroform:hexane (1:6) to get pure 6 (10 Aspirin Dimer grams, 44%) as white powder. m.p. 85-88° C., HNMR 0119) (CDC1): 82.31 (s.3H, OAc), 4.16 (s.2H, CH2), 4.78 (s. 2H, CH2), 7.12 (d. 1H, Ar), 7.32 (t, 1H, Ar), 7.60 (t, 1H, Ar), 8.08 (d. 1H, Ar).

O Example 7 Aspirin Trimer O s' ric (0123 -NO 0120 To a solution of Aspirin (25.13 grams, 139.49 mmoles), triethylamine (23.52 grams, 232.43 mmoles) in dry H3C Oluo acetone (100 ml) was added chloro-acetic acid 2-(2-chloro O acetoxy)-ethyl ester 1 (10 grams, 46.50 mmoles) and stirred at room temperature for 20 hours. The solid triethylamine O O hydrochloride is filtered and to the filtrate, cold water (300 O O ml) was added. The precipitated polymer 5 was filtered, dried or ^O and recrystallised from chloroform:hexane (1:6) to get pure O O dimer 5 (16 grams, 68.4%) as white powder. m.p. 91-92.5°C., OAc AcO HNMR (CDC1): 8 2.30 (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, 0.124. To a solution of Aspirin (124.5 grams, 91.09 1H, Ar), 8.10 (d. 1H, Ar). mmoles), triethylamine (111.8 grams, 1.104 moles) in dry acetone (500 ml) at reflux temperature was added a solution Example 6 of Trichloro linker (50 grams, 137.89 mmoles), example 4, in acetone (100 ml) drop wise. Later further refluxed for 16 Aspirin Tetramer hours, cooled to room temperature, the Solid triethylamine 0121 hydrochloride is filtered, acetone distilled off. Crude mass was dissolved in ethyl acetate, washed with 5% sodium bicar bonate solution, dried over sodium sulphate and distilled. The OAc AcO crude 7 was purified by column chromatography on silica gel O O using chloroform as eluant to get pure 7 (25 grams, 23.2%) as ousO O -N-o 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, O O 6H, CH), 4.80 (s, 6H, CH), 7.14 (d,3H, Ar), 7.34 (t,3H, Ar), O O 7.60 (t, 3H, Ar), 8.10 (d. 3H, Ar). O O or ^O Example 8 O O OAc ACO Naproxen Dimer 0.125

MeO US 2009/0076174 A1 Mar. 19, 2009

0126 To a solution of Naproxen (56 grams, 243.20 eluant to get pure 8 (32 grams, 76.1%) as white powder. m.p.: mmoles), triethylamine (36.3 grams, 358.73 mmoles) in dry 69-71°C., HNMR (CDC1): 81.61 (d. 6H, CH), 3.90 (s, 6H, acetone (150 ml) was added dichloro linker (15 grams, 69.75 OCH3), 3.97 (q, 2H, CH), 4.26 (s, 4H, CH2), 4.58 (q, 4H, mmoles), example 1 and stirred at room temperature for 20 CH2), 7.10 (m, 4H, Ar), 7.41 (d. 2H, Ar), 7.70 (m, 6H, Ar). hours. The solid triethylamine hydrochloride is filtered, acetone distilled off. Crude mass was dissolved in ethyl Example 9 acetate, washed with 5% sodium bicarbonate solution, dried over sodium sulphate and distilled. The crude 8 was purified Naproxen Tetramer by column chromatography on silica gel using benzene as O127

O E

O--- O

O MeO OMe

MeO OMe O O O O r O E

0128. To a solution of Naproxen (13 grams, 56.45 mmoles), triethylamine (9.14 grams, 90.32 mmoles) in dry acetone (50 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 distilled off. Crude mass was dissolved in ethyl acetate, washed with 5% sodium bicarbonate solution, dried over sodium sulphate and distilled. The crude 9 was purified by recrystallisation from chloroform:hexane (1:6) to get pure 9 (3 grams, 21.8%) as white powder. m.p: 128-130° C., HNMR (CDC1): 81.58 (d. 12H, CH3), 3.84 (m, 8H, CH), 3.88 (s, 12H, OCH), 3.94 (q, 4H, CH), 4.52 (q, 8H, CH), 7.10 (m, 8H, Ar), 7.41 (d. 4-H, Ar), 7.70 (m, 12H, Ar). Example 10 Naproxen Trimer 0129

O O OMe

OMe O O US 2009/0076174 A1 Mar. 19, 2009 15

0130. To a solution of Naproxen (127 grams, 551.15 eluant to get pure 10 (30 grams, 23%) as light green thick mmoles), triethylamine (83.5 grams, 825.18 mmoles) in dry syrup. HNMR (CDC1): 8 0.66 (t, 3H, CH), 1.15 (q, 2H, acetone (500 ml) was added trichloro linker (50 grams, 137. CH), 1.61 (d. 9H, CH), 3.96 (m, 15H, OCH, CH), 4.56 (q, 89 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 Example 11 acetate, washed with 5% Sodium bicarbonate solution, dried over sodium sulphate and distilled. The crude 10 was purified Sulindac by column chromatography on silica gel using benzene as 0131)

O HC1 O t CH3 O O F OH Sulindac

O O ---

Acetone, Triethylamine US 2009/0076174 A1 Mar. 19, 2009 16

Example 12 Exisulind (0132

O e HC1 t CH3 O O F OH Exisulind

Acetone, Triethylamine O e HC1

O

O F

DuluH3C

S -CH3 So O

0.133 When ranges are used herein for physical proper EMBODIMENT 1 ties, such as molecular weight, or chemical properties, such as 0.136 An oligomer or pharmaceutically acceptable salt chemical formulae, all combinations and Subcombinations of ranges and specific embodiments therein are intended to be thereof of formula I or II: included. 0134. The disclosures of each patent, patent application and publication cited or described in this document are hereby incorporated herein by reference, in their entireties. —R II 0135 Those skilled in the art will appreciate that numer 0.137 wherein: ous changes and modifications can be made to the preferred I0138) R'-O is a biologically active compound resi embodiments of the invention and that such changes and due; modifications can be made without departing from the spirit I0139) R' C(=O)C)— is a biologically active com of the invention. It is, therefore, intended that the appended pound residue; claims cover all such equivalent variations as fall within the 0140 X is selected from: – OC(=O)CH (inverse true spirit and scope of the invention. glycolic acid moiety), —OC(=O)CH(CH)— (inverse US 2009/0076174 A1 Mar. 19, 2009 17

lactic acid moiety), —OC(=O)CHOCH2CH2— (in EMBODIMENT 4 verse dioxanone acid moiety), —OC(=O) CHCHCHCH-CH (inverse caprolactone acid 0154 An oligomer of Embodiment 1, 2, or 3, wherein: moiety), OC(=O)(CH), , or OC(=O)CH, O155 each X is independently —OC(=O)CH , (OCH2CH)—. –OC(=O)CH(CH) , OC(=O) I0141 X" is selected from: —CHC(=O)C)—(glycolic CHOCHCH- O OC(=O) acid moiety), —CH(CH)C(=O)C)— (lactic acid moi CHCHCHCHCH-. ety), —CHCHOCHC(=O)C)— (dioxanone acid 0156 each X is independently -CHCOO. : CH moiety), —CHCHCHCHCHC(=O)C)— (capro (CH)COO–: - CHCHOCHCOO : O lactone acid moiety), -(CH2),C(=O)C , or - CHCHCHCH-CHCOO–. —(CHCHO). CHC(=O)C)–: (O157 each Y is independently – COCHO : 0.142 Y is selected from: —C(=O)CHO— (glycolic - COCH(CH)O ; –COCHOCHCHO-; or ester moiety), —C(=O)CH(CH)O— (lacticester moi - COCHCHCHCHCH-O-, and ety), —C(=O)CHOCH2CH2O (dioxanone ester moiety), —C(=O)CHCH2CH2CHCHO— (capro 0158 each Y is independently —OCHCO-; OCH lactone ester moiety), —C(=O)(CH)O—, or (CH)CO : –OCHCHOCHCO : O —C(=O)CH O—(CH2CH2O), ; –OCHCHCHCH-CHCO-. 0.143 Y is selected from: —OCHC(=O)– (inverse glycolic ester moiety), —OCH(CH)C(=O)— (inverse EMBODIMENT 5 lactic ester moiety), —OCHCHOCHC(=O)— (in VeSe dioxanone ester moiety), 0159. An oligomer of Embodiment 1, 2, 3, or 4, wherein: —OCH2CH2CHCHCHC(=O)— (inverse caprolac (0160 X is independently —OCOCH and tone ester moiety), —O(CH),C(=O)—, or OCOCH(CH.) : - O(CHCHO), OCHC(=O)–: (0161 each X* is independently —CHCOO and 0144 R is a di-, tri, tetra-, penta- or hexaradical derived -CH(CH,)COO : from C-2s alkyl, aryl, or aryl-(Calkyl)--, wherein from (0162 each Y is independently —COCHO and 1-3 of the CH groups within the alkyl chain are optionally - COCH(CH)O ; and, independently replaced by O atoms, such that each of said O (0163 each Y is independently —OCHCO- and atom is attached only to carbon atoms in the alkyl chain, with the proviso that multiple O atoms that replace CH groups –OCH(CH)CO-. within the alkyl chain must be separated from each other by at least two carbon atoms and from the di-, tri, tetra-, penta- or EMBODIMENT 6 hexaradical chain ends by at least one carbonatom; or R is the backbone of a polymer or copolymer bearing carboxylic acid 0164. An oligomer of Embodiment 1, 2, 3, 4, or 5, wherein and/or hydroxyl functional groups, where the average R'-O-is selected from acenocoumarol, acetarsol, actino molecular weight of the polymer or copolymer is between quinol, adrenalone, alibendol, amodiaquine, anethole, bal Salazide, bamethan, benserazide, bentiromide, benzarone, 500 to 5000 and wherein w is an integer from about 6 to about benzquinamide, bevantolol, bifluranol, buclosamide, buphe 50; niode, chlorotrianisene, chloroxylenol, cianidanol, 0145 each a and b is independently an integer from cinepazide, cinitapride, cinepazide, cinmetacin, clebopride, about 1 to about 10; clemastine, clioquinol, cyclovalone, cynarine, denopamine, 0146 each m, n, y, and Z is independently an integer dextroythyroXine, diacerein, dichlorophen, dienestrol, dieth from about 2 to about 24; and ylstilbestrol, diflunisal, diiodohydroxyquinoline, dilazep, dil 0147 w is an integer from about 2 to about 6. evalol, dimestrol, dimoxyline, dioSmin, dithranol, dob EMBODIMENT 2 utamine, donepezil, dopamine, dopexamine, doxazosin, entacapone, epanolol, epimestrol, epinephrine, estradiol val 0148. An oligomer of Embodiment 1, wherein: erate, estriol, estriol Succinate, estrone, etamivan, etamsylate, 0149 R is a di-, tri, tetra-, penta- or hexaradical derived ethaverine, ethoXZolamide, ethyl biscoum-acetate, etillefrine, from C2-alkyl, phenyl, or phenyl-(Coalkyl)-3-, etiroXate, exalamide, exifone, fendosal, fenoldopam mesi wherein from 1-3 of the CH groups within the alkyl late, fenoterol, fenoxedil, fenticlor, flopropione, floredil, chain are optionally independently replaced by O atoms, fluorescein, folescutol, formo-terol, gallopamil, gentistic such that each of said O atom is attached only to carbon acid, glaziovine, glibenclamide, glucametacin, guajacol, atoms in the alkyl chain, with the proviso that multiple O halquinol, hexachlorophene, hexestrol, hexobendine, hexo atoms that replace CH2 groups within the alkyl chain prenaline, hexylresorcinol, hydroxyethyl salicylate, hydrox must be separated from each other by at least two carbon yStilbamidine isethionate, hymecromone, ifenprodil, atoms and from the di-, tri, tetra-, penta- or hexaradical indomethacin, ipriflavone, isoetarine, isoprenaline, isoxSu chain ends by at least one carbon atom; prine, itopride hydrochlor-ide, ketobemidone, khellin, labe 0150 each a and b is independently an integer from talol, lactylphenetidin, levodopa. levomepromazine, levor about 1 to about 5; and phanol, levothyroXine, mebeverine, medrylamine, 0151 w is an integer from about 2 to about 4. mefexamide, mepacrine, mesalazine, mestranol, metarami nol, methocarbamol, , methoXSalen, methyl EMBODIMENT 3 dopa, midodrine, mitoxantrone, morclofone, nabumetone, 0152. An oligomer of Embodiment 1 or 2, wherein: naproxen, nitroxo-line, norfenefrine, normolaxol, octopam (O153 R-O is O(CH)O, O(CH)O, CH(CHO), ine, omeprazole, , oxillofrine, oxitriptan, oxy C(CHO), or C(CHCH)(CHOH). fedrine, oxypertine, oxyphenbutaZone, oxyphenisatin US 2009/0076174 A1 Mar. 19, 2009 acetate, oxyquin-oline, papaverine, paracetanol, parethox ycaine, phenacaine, phenacetin, phenazocine, phenolphtha -continued lein, phenprocoumon, phentolamine, phloedrine, picota OH mide, pimoben-dan, prenalterol, primaquine, progabide, propanidid, protokylol, proxymetacaine, raloxifene hydro OH chloride, repaglinide, reproterol, rimiterol, ritodrine, salac N etamide, Salazosulfapyridine, salbutamol, Salicylamide, Sali n cylic acid, Salmeterol, Salsalate, sildenafil, silibinin, H Sulmetozin, tamsulosin, teraZosin, terbutaline, tetroxoprim, 21 N theo-drenaline, tioclomarol, tioXolone, C-tocopherol (vita N min E), tofisopam, tolcapone, tolterodine, tranilast, treto NO quinol, triclosan, trimaZosin, trimetazidine, trimethobenz amide, trimethoprim, trimetozine, trimetrexate glucuronate, Nitroxoline Pholedrine OH troXipide, Verapamil, Vesnarinone, Vetrabutine, Viloxazine, OH, or warfarin, and Xamoterol. N O EMBODIMENT 7 ul N 0.165 An oligomer of Embodiment 1, 2, 3, 4, or 5, wherein 2 H R'-O-is: Oxyquinoline Paracetamol HO O HO X=NH S No N Tioxolone O EMBODIMENT 8 Capsaicin 0166 An oligomer of Embodiment 1, 2, 3, 4, or 5, wherein Cl OH R° C(=O)C)— is selected from Acemetacin, Aceclofenac, Acediasulfone, Adipiodone, Alminoprofen, Amlexanox, Anileridine, Baccofen, Balsalazide sodium, Bentiromide, Benzocaine, Bumetanide, Carprofen, Carzenide, Cinmeta C r Cl; cin, Clometacin, Cromoglicic acid, Diclofenac, Diflunisal, Eprosartan, Fendosal, Flufenamic acid, Furosemide, Triclosan Indometacin, lobenzamic acid, locarmic acid, locetamic acid, O Iodoxamic acid, loglycamic acid, lophenoic acid, lotroXic cid, Mefenamic acid, Naproxen, Nedocromil, Repaglinide, Salazosulfapyridine, Salicylic Acid, Salsalate, and Sarpogre ( ) OH: late. O EMBODIMENT 9 Benzarone 0167. An oligomer of claim Embodiment 1, 2, 3, 4, or 5, OH wherein R C(=O)C) is: HO O O O

1N-1 s -ClC Chloroxylenol Hymercromone OH Methyl Salicylate O OH S N OH n-1 OH: I N 21 N 1. O

C OH F F Clioquinol Etamivan Diflunisal US 2009/0076174 A1 Mar. 19, 2009 19

-continued -continued OH F OH: 3 ) ( ) uor Flurbiprofen Ibuprofen C O O OH: O) C OH: Tiaprofenic Acid O

s OH: Diclofenac O

O OH: MeO Naproxen O O

HO N \ f Fenbufen O

Tolimetin OH:

OH O N H O; C airprO fe l O Loxoprofen S O \ f O

O OH: OH: N \ f Suprofen O OH

Ketorolac

O O

Mefenamic acid N H F

Etodolac

Ketoprofen Lumiracoxib US 2009/0076174 A1 Mar. 19, 2009 20

-continued -continued O C.

N No / O OH Indometacin

EMBODIMENT 10 0168 An oligomer of Embodiment 1, 2, 3, 4, 5, 6, or 7. wherein R-O- is selected from capsaicin, coumarins, furanocoumarins, alkaloids, catechins, chromones, chal cones, flavonoids or bioflavonoids, isoflavones, resveratrol, and Sinapic acid. HO OH:

EMBODIMENT 11 HO 0169. 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-hy droxycoumarin, psoralen, bergapten, bergaptol, Xanthotoxin, HO isopimpinellin.

EMBODIMENT 12 OH OH 0170 An oligomer of Embodiment 1, 2, 3, 4, 5, 6, 7, 10, or 11, wherein—OC(=O), R is:

O O OH n = 10-50 HO--- Nulls OH: O 0171 wherein each carboxylic acid proton (H) present in the di- or poly-acid shown is absent in the moiety —OC --N-- O (=O) R. HO O OH: r1N1 n-rr EMBODIMENT 13 O O O 0172 An oligomer of Embodiment 1, 2, 3, 4, 5, 8, or 9. wherein—(Y), OR is: HO -- O OH:

O O O

O --- OH:

O O --- N--- OH: O O

HO N--- OH: US 2009/0076174 A1 Mar. 19, 2009 21

-continued -continued O oulNulls, X.1--- Q; or HO ---O O O OH: --- "--~~~~ O O HO os--- OH: Q~ “s. Yno1.O O~ O O O O O O (0173 wherein each Q is a bond. "-----~~~N-so O O EMBODIMENT 14 0.174. An oligomer of Embodiment 1, 2, 3, 4, 5, 6, 7, 10, 11, or 12, wherein—(X) OC(=O), R is: 0.175 wherein each carboxylic acid proton (H) present in the di-acid shown is absent in the moiety. —CX), OC(=O) —R. O O HO --N- OH: EMBODIMENT 15 ro r 0176 An oligomer of Embodiment 1,2,3,4,5,8,9, or 13, O O wherein —CHC(=O)—(Y'), OR) is: r s------

(r s' ------r -r-r-- r --- Nulls, ------US 2009/0076174 A1 Mar. 19, 2009 22

-continued

re-r's ------O O O X O re-r O ------1.-1.-1. ----- X 1.-1.-1.

(0177 wherein Q is a bond. EMBODIMENT 20 0182. A pharmaceutical composition of Embodiment 18, EMBODIMENT 16 wherein the phenolic residue in the compound of formula I was derived from a cancer preventing phenolic. 0.178 An oligomer of Embodiment 1, 2, 3, 4, 5, 6, 7, 10, 11, 12, or 14, wherein R-O is selected from chalcones, hydroxy-benzoic acid, dihydroxy-benzoic acid, indoles, EMBODIMENT 21 acetophenones, benzophenones, catechins, flavonoids, cou 0183) A pharmaceutical composition of Embodiment 20, marins, hydroquinone, naproxen, acetaminophen, and acetyl further comprising: an anti-cancer agent. salicylic acid. EMBODIMENT 22 EMBODIMENT 17 0184. A pharmaceutical composition of Embodiment 18, wherein the phenolic residue of formula I or II is derived from 0179 A cosmetic composition, comprising at least one a phenolic compound with antimicrobial properties. compound of Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, and a cosmetic ingredient. EMBODIMENT 23

EMBODIMENT 18 0185. A pharmaceutical composition of Embodiment 22, further comprising: an antimicrobial agent. 0180 A pharmaceutical composition, comprising at least one compound of Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, EMBODIMENT 24 12, 13, 14, 15, or 16, and a pharmaceutically acceptable excipient. 0186 A pharmaceutical composition of Embodiment 18, wherein the phenolic residue in the compound of formula I was derived from a phenolic with anti-inflammatory proper EMBODIMENT 19 ties.

0181 A pharmaceutical composition of Embodiment 18, EMBODIMENT 25 wherein the composition is suitable for administration via a route selected from oral, enteral, parenteral, topical, transder 0187. A pharmaceutical composition of Embodiment 24, mal, ocular, vitreal, rectal, nasal, pulmonary, and vaginal. further comprising: anti-inflammatory agent. US 2009/0076174 A1 Mar. 19, 2009

EMBODIMENT 26 in need of Such therapy, an effective amount of at least one 0188 A pharmaceutical composition of Embodiment 18, oligomer of Embodiment 1,2,3,4,5,6,7,8,9, 10, 11, 12, 13, wherein the phenolic residue in the compound of formula I 14, 15, or 16. was derived from a phenolic with pain-reducing properties. EMBODIMENT 37 EMBODIMENT 27 0199 Atherapeutic method for producing an anti-fungal effect in a patient, comprising: administering to a patient in 0189 A pharmaceutical composition of Embodiment 26, need of Such therapy, an effective amount of at least one further comprising: a pain reducing agent. oligomer of Embodiment 1,2,3,4,5,6,7,8,9, 10, 11, 12, 13, EMBODIMENT 28 14, 15, or 16. 0190. A pharmaceutical composition of Embodiment 18, EMBODIMENT 38 wherein the phenolic residue in the compound of formula I 0200 Atherapeutic method for producing an immunosup was derived from a phenolic with antioxidant properties. pressive effect in a patient, comprising: administering to a patient in need of such therapy, an effective amount of at least EMBODIMENT 29 one oligomer of Embodiment 1,2,3,4,5,6,7,8,9, 10, 11, 12, 0191) A pharmaceutical composition of Embodiment 28, 13, 14, 15, or 16. further comprising: an antioxidant agent. EMBODIMENT 39 EMBODIMENT 30 0201 Atherapeutic method for producing an anti-throm 0192 A Suture coating, comprising: at least one oligomer botic effect in a patient, comprising: administering to a of Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, patient in need of such therapy, an effective amount of at least or 16. one oligomer of Embodiment 1,2,3,4,5,6,7,8,9, 10, 11, 12, 13, 14, 15, or 16. EMBODIMENT 31 0193 An antimicrobial agent, comprising: at least one EMBODIMENT 40 oligomer of Embodiment 1,2,3,4,5,6,7,8,9, 10, 11, 12, 13, (0202 Atherapeutic method for treating psoriasis, inflam 14, 15, or 16. matory bowel disease, skin cancer, or a brain tumor in a patient, comprising: administering to a patient in need of such EMBODIMENT 32 therapy, an effective amount of at least one oligomer of 0.194. A therapeutic method for treating a disease in a Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or patient, comprising: administering to a patient in need of such 16. 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 EMBODIMENT 41 16. 0203 A therapeutic method for producing an anti-infec tive effect in a patient, comprising: administering to a patient EMBODIMENT 33 in need of Such therapy, an effective amount of at least one 0.195 A therapeutic method for producing an analgesic oligomer of Embodiment 1,2,3,4,5,6,7,8,9, 10, 11, 12, 13, effect in a patient, comprising: administering to a patient in 14, 15, or 16. need of Such therapy, an effective amount of at least one oligomer of Embodiment 1,2,3,4,5,6,7,8,9, 10, 11, 12, 13, EMBODIMENT 42 14, 15, or 16. 0204 Atherapeutic method for treating pain in a patient, comprising: administering to a patient in need of Such EMBODIMENT 34 therapy, an effective amount of at least one oligomer of 0196. A therapeutic method for treating cancer in a Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or patient, comprising: administering to a patient in need of such 16. therapy, an effective amount of at least one oligomer of What is Claimed: Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 1. An oligomer or pharmaceutically acceptable salt thereof 16. of formula I or II: EMBODIMENT 3.5 0.197 Atherapeutic method for producing an anti-inflam matory effect in a patient, comprising: administering to a patient in need of such therapy, an effective amount of at least R'-O- is a biologically active compound residue. one oligomer of Embodiment 1,2,3,4,5,6,7,8,9, 10, 11, 12, R’ C(=O)C) is a biologically active compound resi 13, 14, 15, or 16. due; EMBODIMENT 36 X is selected from: —OC(=O)CH (inverse glycolic acid moiety), —OC(=O)CH(CH)— (inverse lactic 0198 Atherapeutic method for producing an anti-bacte acid moiety), —OC(=O)CHOCH2CH2— (inverse rial effect in a patient, comprising: administering to a patient dioxanone acid moiety), OC(=O) US 2009/0076174 A1 Mar. 19, 2009 24

CHCHCHCH-CH (inverse caprolactone acid each X is independently —CHCOO ... —CH(CH) moiety), OC(=O)(CH), , or OC(=O)CH, COO : - CHCHOCHCOO : O (OCH2CH)—. - CHCHCHCH-CHCOO–. X' is selected from: —CHC(=O)C)— (glycolic acid each Y is independently —COCHO : —COCH(CH) moiety), —CH(CH)C(=O)C)— (lactic acid moi O—; - COCHOCHCHO : O ety), —CH2CH2OCHC(=O)C)— (dioxanone acid - COCHCHCHCHCH-O-, and moiety), —CHCHCHCHCHC(=O)C)— (ca each Y is independently OCH CO. : —OCH(CH) prolactone acid moiety), -(CH2),C(=O)C , or CO : –OCHCHOCH2CO : O -(CHCHO)CHC(=O)C)–: –OCHCHCHCH-CHCO-. Y is selected from: —C(=O)CHO— (glycolic ester 5. An oligomer of claim 4, wherein: moiety), —C(=O)CH(CH)O— (lactic ester moi X is independently —OCOCH and —OCOCH ety), —C(=O)CHOCH2CHO (dioxanone ester (CH)—: moiety), —C(=O)CHCH2CH2CH2CH2O (ca each X* is independently —CHCOO and —CH(CH) prolactone ester moiety), —C(=O)(CH)O—, or COO : —C(=O)CH O—(CH2CH2O), ; each Y is independently —COCHO and COCH Y' is selected from: —OCHC(=O)– (inverse gly (CH)O—; and, colic ester moiety), —OCH(CH)C(=O)— (inverse eachY' is independently—OCHCO-and-OCH(CH) lactic ester moiety), —OCHCHOCHC(=O)— CO . (inverse dioxanone ester moiety), 6. An oligomer of claim 1, wherein R'-O is selected —OCH2CH2CH2CHCHC(=O)— (inverse capro from acenocoumarol, acetarSol, actinoquinol, adrenalone, lactone ester moiety), —O(CH2)C(=O)—, or alibendol, amodiaquine, anethole, balsalazide, bamethan, –O(CHCHO), OCHC(=O)–: benserazide, bentiromide, benzarone, benzquinamide, R is a di-, tri, tetra-, penta- or hexaradical derived from bevantolol, bifluranol, buclosamide, bupheniode, chlorotria Cs alkyl, aryl, oraryl-(Calkyl)--, wherein from nisene, chloroxylenol, cianidanol, cinepazide, cinitapride, 1-3 of the CH groups within the alkyl chain are cinepazide, cinmetacin, clebopride, clemastine, clioquinol, optionally independently replaced by O atoms, such cyclovalone, cynarine, denopamine, dextroy thyroxine, that each of said O atom is attached only to carbon diacerein, dichlorophen, dienestrol, diethylstilbestrol, atoms in the alkyl chain, with the proviso that multiple diflunisal, diiodohydroxyquinoline, dilaZep, dilevalol, O atoms that replace CH groups within the alkyl dimestrol, dimoxyline, diosmin, dithranol, dobutamine, chain must be separated from each other by at least donepezil, dopamine, dopexamine, doxazosin, entacapone, two carbonatoms and from the di-, tri, tetra-, penta- or epanolol, epimestrol, epinephrine, estradiol Valerate, estriol, hexaradical chain ends by at least one carbonatom; or estriol Succinate, estrone, etamivan, etamsylate, ethaverine, R is the backbone of a polymer or copolymer bearing ethoXZolamide, ethyl biscoum-acetate, etillefrine, etiroXate, carboxylic acid and/or hydroxyl functional groups, exalamide, exifone, fendosal, fenoldopam mesilate, fenot where the average molecular weight of the polymer or erol, fenoxedil, fenticlor, flopropione, floredil, fluorescein, copolymer is between 500 to 5000 and wherein w is folescutol, formo-terol, gallopamil, gentistic acid, glazio an integer from about 6 to about 50: Vine, glibenclamide, glucametacin, guajacol, halquinol, eacha and b is independently an integer from about 1 to hexachlorophene, hexestrol, hexobendine, hexoprenaline, about 10; hexylresorcinol, hydroxyethyl salicylate, hydroxy stilbami each m, n, y, and Z is independently an integer from dine isethionate, hymecromone, ifenprodil, indomethacin, about 2 to about 24; and ipriflavone, isoetarine, isoprenaline, isoxSuprine, itopride w is an integer from about 2 to about 6. hydrochlor-ide, ketobemidone, khellin, labetalol, lactylphe 2. An oligomer of claim 1, wherein: netidin, levodopa. levomepromazine, levorphanol, levothy R is a di-, tri, tetra-, penta- or hexaradical derived from roXine, mebeverine, medrylamine, mefexamide, mepacrine, C-alkyl, phenyl, or phenyl-(Calkyl)--, wherein mesalazine, mestranol, metaraminol, methocarbamol, meth from 1-3 of the CH groups within the alkyl chain are oxamine, methoXSalen, methyldopa, midodrine, mitox optionally independently replaced by Oatoms, such that antrone, morclofone, nabumetone, naproxen, nitroxo-line, norfenefrine, normolaxol, octopamine, omeprazole, orci each of said O atom is attached only to carbonatoms in prenaline, OXilofrine, oxitriptan, oxyfedrine, oxypertine, the alkyl chain, with the proviso that multiple O atoms oxyphenbutaZone, oxyphenisatin acetate, oxyquin-oline, that replace CH2 groups within the alkyl chain must be papaverine, paracetanol, parethoxycaine, phenacaine, phen separated from each other by at least two carbon atoms acetin, phenazocine, phenolphthalein, phenprocoumon, and from the di-, tri, tetra-, penta- or hexaradical chain phentolamine, phloedrine, picotamide, pimoben-dan, prenal ends by at least one carbon atom; terol, primaquine, progabide, propanidid, protokylol. each a and b is independently an integer from about 1 to proxymetacaine, raloxifene hydrochloride, repaglinide, about 5; and reproterol, rimiterol, ritodrine, salacetamide, Salazosulfapy w is an integer from about 2 to about 4. ridine, Salbutamol, salicylamide, Salicylic acid, salmeterol, 3. An oligomer of claim 1, wherein: Salsalate, sildenafil. Silibinin, Sulmetozin, tamsulosin, tera R—IO is O(CH)O, O(CH)O, CH(CHO), Zosin, terbutaline, tetroXoprim, theo-drenaline, tioclomarol, C(CHO), or C(CHCH)(CHOH). tioxolone, C.-tocopherol (vitamin E), tofisopam, tolcapone, 4. An oligomer of claim 1, wherein: tolterodine, tranilast, tretoquinol, triclosan, trimaZosin, tri each X is independently —OC(=O)CH —OC(=O) metazidine, trimethobenz-amide, trimethoprim, trimetozine, CH(CH) , —OC(=O)CHOCHCH , or - OC trimetrexate glucuronate, troXipide, Verapamil, Vesnarinone, (=O)CHCHCHCHCH-. Vetrabutine, Viloxazine, warfarin, and Xamoterol. US 2009/0076174 A1 Mar. 19, 2009

7. An oligomer of claim 6, wherein R-O-is: -continued HO O HO X= NH. S No S1S Tioxolone O Capsaicin 8. An oligomer of claim 1, wherein R C(=O)C)— is C OH selected from Acemetacin, Aceclofenac, Acediasulfone, Adipiodone, Alminoprofen, Amlexanox, Anileridine, Bac cofen, Balsalazide Sodium, Bentiromide, Benzocaine, Bumetanide, Carprofen, Carzenide, Cinmetacin, Clometa C C Cro s cin, Cromoglicic acid, Diclofenac, Diflunisal, Eprosartan, Triclosan Fendosal, Flufenamic acid, Furosemide, Indometacin, loben Zamic acid, locarmic acid, locetamic acid, Iodoxamic acid, O loglycamic acid, lophenoic acid, lotroxic cid, Mefenamic acid, Naproxen, Nedocromil, Repaglinide, Salazosulfapyri / dine, Salicylic Acid, Salsalate, and Sarpogrelate. OH: 9. An oligomer of claim 1, wherein R C(=O)C)— is: O Benzarone O OH

HO O O; CrOH Methyl Salicylate C C O OH Chloroxylenol Hymercromone

S N OH N-1 I N c. OH: 21 F F N 1. Diflunisal C OH OH: Clioquinol Etamivan OH O Ibuprofen OH

N n s H 21 N N O O) - OH: NO Nitroxoline Pholedrine Tiaprofenic Acid OH OH, or N O -n -OH:

ul N O 2 H MeO Oxyquinoline Paracetamol Naproxen US 2009/0076174 A1 Mar. 19, 2009 26

-continued -continued O O OH: HO N \ | O O

Tolimetin Fenbufen OH O O O H; O Loxoprofen N

OH:

Ketorolac Suprofen OH

O O YOYa Ya Ya NN OH: Mefenamic acid F

Etodolac O

OH: HO C

O O Ketoprofen

Lumiracoxib O OH F C.

N 3 ) ( ) N 7. 9 Flurbiprofen O C OH Indometacin 10. An oligomer of claim 1, wherein R-O is selected C OH: from capsaicin, coumarins, furanocoumarins, alkaloids, cat s echins, chromones, chalcones, flavonoids or bioflavonoids, isoflavones, resveratrol, and Sinapic acid. O 11. An oligomer of claim 1, wherein R-O is selected from 4-hydroxycinnamic acid, caffeic acid, chlorogenic acid, Diclofenac ferulic acid, capsaicin, 4-hydroxycoumarin, psoralen, ber gapten, bergaptol, Xanthotoxin, isopimpinellin. US 2009/0076174 A1 Mar. 19, 2009 27

12. An oligomer of claim 1, wherein—OC(=O), R is: -continued OH O O O O O O ls us --- O sus o O OH, or HO1 R1 OH. HO OH: O --- O OH: n = 10-50 OH HO n-rr O HO O OH: wherein each carboxylic acid proton (H) present in the di

^^- n-r s or—R. poly-acid shown is absent in the moiety —OC(=O) O O 13. An oligomer of claim 1, wherein—(Y'), OR is: O --- OH:

O O O --- S. rN-n-r --O N-- O (~~~ O N-1 *: O O n = 2 N--- O O O O O -- O n-n-n- OH: O O O --- O O O O

HO OH: HO OH: HO OH O O

O OH O O O O O OH wherein each Q is a bond. 14. An oligomer of claim 1, wherein —(X), OC(=O) —R is: HO OH: O O O O HO rO r O O O O HO OH: HO O OH: O OH rO r --- O O US 2009/0076174 A1 Mar. 19, 2009 28

-continued -continued O O O O HO 1-0 ouls HO O--~~ O OH: O n1no OH: O O O O O O N--- wherein each carboxylic acid proton (H) present in the "N-so O ^* O di-acid(=O) shownR. is absent in the moiety. —CX), OC O O 15. An oligomer of claim 1, wherein—CHC(=O)–(Y) OR) is:

re-r --- N-1------

---- A ------

O US 2009/0076174 A1 Mar. 19, 2009 29

-continued ------res? X ------

wherein Q is a bond. 32. A therapeutic method for treating a disease in a patient, 16. An oligomer of claim 1, wherein R-O is selected comprising: administering to a patient in need of Such from chalcones, hydroxy-benzoic acid, dihydroxy-benzoic therapy, an effective amount of at least one oligomer of claim acid, indoles, acetophenones, benzophenones, catechins, fla 1. vonoids, coumarins, hydroquinone, naproxen, acetami 33. A therapeutic method for producing an analgesic effect nophen, and acetylsalicylic acid. in a patient, comprising: administering to a patient in need of Such therapy, an effective amount of at least one oligomer of 17. A cosmetic composition, comprising at least one com claim 1. pound of claim 1 and a cosmetic ingredient. 34. A therapeutic method for treating cancer in a patient, 18. A pharmaceutical composition, comprising at least one comprising: administering to a patient in need of Such compound of claim 1 and a pharmaceutically acceptable therapy, an effective amount of at least one oligomer of claim excipient. 1. 19. A pharmaceutical composition of claim 18, wherein the 35. A therapeutic method for producing an anti-inflamma composition is suitable for administration via a route selected tory effect in a patient, comprising: administering to a patient from oral, enteral, parenteral, topical, transdermal, ocular, in need of Such therapy, an effective amount of at least one Vitreal, rectal, nasal, pulmonary, and Vaginal. oligomer of claim 1. 20. A pharmaceutical composition of claim 18, wherein the 36. A therapeutic method for producing an anti-bacterial phenolic residue in the compound of formula I was derived effect in a patient, comprising: administering to a patient in from a cancer preventing phenolic. need of Such therapy, an effective amount of at least one oligomer of claim 1. 21. A pharmaceutical composition of claim 20, further 37. A therapeutic method for producing an anti-fungal comprising: an anti-cancer agent. effect in a patient, comprising: administering to a patient in 22. A pharmaceutical composition of claim 18, wherein the need of Such therapy, an effective amount of at least one phenolic residue of formula I or II is derived from a phenolic oligomer of claim 1. compound with antimicrobial properties. 38. A therapeutic method for producing an immunosup 23. A pharmaceutical composition of claim 22, further pressive effect in a patient, comprising: administering to a comprising: an antimicrobial agent. patient in need of such therapy, an effective amount of at least 24. A pharmaceutical composition of claim 18, wherein the one oligomer of claim 1. phenolic residue in the compound of formula I was derived 39. A therapeutic method for producing an anti-thrombotic from a phenolic with anti-inflammatory properties. effect in a patient, comprising: administering to a patient in 25. A pharmaceutical composition of claim 24, further need of Such therapy, an effective amount of at least one comprising: anti-inflammatory agent. oligomer of claim 1. 26. A pharmaceutical composition of claim 18, wherein the 40. A therapeutic method for treating psoriasis, inflamma phenolic residue in the compound of formula I was derived tory bowel disease, skin cancer, or a brain tumor in a patient, from a phenolic with pain-reducing properties. comprising: administering to a patient in need of Such therapy, an effective amount of at least one oligomer of claim 27. A pharmaceutical composition of claim 26, further 1. comprising: a pain reducing agent. 41. A therapeutic method for producing an anti-infective 28. A pharmaceutical composition of claim 18, wherein the effect in a patient, comprising: administering to a patient in phenolic residue in the compound of formula I was derived need of Such therapy, an effective amount of at least one from a phenolic with antioxidant properties. oligomer of claim 1. 29. A pharmaceutical composition of claim 28, further 43. A therapeutic method for treating pain in a patient, comprising: an antioxidant agent. comprising: administering to a patient in need of Such 30. A Suture coating, comprising: at least one oligomer of therapy, an effective amount of at least one oligomer of claim claim 1. 1. 31. An antimicrobial agent, comprising: at least one oligo mer of claim 1.