US 2010O286 107A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0286107 A1 Zhang et al. (43) Pub. Date: Nov. 11, 2010

(54) OLIGOMER-CORTICOSTEROID Related U.S. Application Data CONUGATES (60) Provisional application No. 60/997,835, filed on Oct. (75) Inventors: Wen Zhang, Madison, AL (US); 5, 2007. Jennifer Riggs-Sauthier, Publication Classification Huntsville, AL (US); J. Milton Harris, Huntsville, AL (US); (51) Int. Cl. Michael D. Bentley, Huntsville, AL A 6LX 3/573 (2006.01) (US) C07. 4I/00 (2006.01) C07J 5/00 (2006.01) Correspondence Address: A6IPI/08 (2006.01) NEKTAR THERAPEUTICS A6IP 25/08 (2006.01) 2O1 INDUSTRIAL ROAD A6IP 25/22 (2006.01) SAN CARLOS, CA 94070 (US) A6IP 25/24 (2006.01) A6IP 25/00 (2006.01) (73) Assignee: Nektar Therapeutics, San Carlos, (52) U.S. Cl...... 514/179; 552/518; 552/577;552/574 CA (US) (57) ABSTRACT (21) Appl. No.: 12/680,877 The invention provides corticosteroids that are chemically (22) PCT Filed: Oct. 3, 2008 modified by covalent attachment of a water soluble oligomer. A compound of the invention, when administered by any of a (86). PCT No.: PCT/US08/11523 number of administration routes, exhibits a reduced biologi cal membrane crossing rate as compared to the biological S371 (c)(1), membrane crossing rate of the corticosteroid not attached to (2), (4) Date: Jun. 18, 2010 the water soluble oligomer. US 2010/02861 07 A1 Nov. 11, 2010

OLGOMER-CORTICOSTEROID one or atoms) at a position other than through D-ring atom CONUGATES positions to a water-soluble, non-peptidic oligomer. 0011. In one or more embodiments of the invention, a CROSS REFERENCE TO RELATED compound is provided, the compound comprising a corticos APPLICATION teroid residue covalently attached (either directly or through 0001. This application claims the benefit of priority under one or more atoms) at a position selected from the consisting 35 U.S.C. S 119(e) to U.S. Provisional Patent Application No. of A-ring atom positions, B-ring atom positions, and C-ring 60/997.835, the disclosure of which is hereby incorporated by atom positions to a water-soluble, non-peptidic oligomer. 0012. In one or more embodiments of the invention, a reference. compound is provided, the compound comprising a corticos FIELD OF THE INVENTION teroid residue covalently attached (either directly or through one or more atoms) at A-ring atom positions to a water 0002 This invention comprises (among other things) soluble, non-peptidic oligomer. chemically modified corticosteroids that possess certain 0013. In one or more embodiments of the invention, a advantages over corticosteroids lacking the chemical modi compound is provided, the compound comprising a corticos fication. The chemically modified corticosteroids described teroid residue covalently attached at the 3 position to a water herein relate to and/or have application(s) in (among others) soluble, non-peptidic oligomer. the fields of drug discovery, pharmacotherapy, physiology, 0014 Exemplary compounds of the invention include organic chemistry and polymer chemistry. those having the following structure: BACKGROUND OF THE INVENTION

0003 Corticosteroids represent a broad class of agents (Formula I-C) employed in the treatment of individuals suffering from a variety of disorders. In the treatment of an individual suffer ing from arthritis, for example, administration of a corticos teroid may reduce inflammation. In addition, individuals Suf fering autoimmune disorders often benefit from the administration of a corticosteroid. Other applications in which corticosteroids have been used include the treatment of individuals Suffering from allergic reactions, ankylosing POLY-X spondylitis, asthma, Crohn's disease dermatological disor ders and psoriasis among others. As a class, corticosteroids represent an important and widely used tool in pharmaco therapy. wherein: 0004 Although corticosteroids serve an important role in 00.15 the dashed line independently represents an treating patients, their use is sometimes associated with optional double bond; (among other things) CNS side effects, such as insomnia, I0016) R' is selected from the group consisting of halo eurphoria, mood changes, nervousness, personality changes, (e.g., fluoro, chloro, bromo, iodo) and alkyl; depression, nausea, headaches and convulsions. 0017 either 0005. As a consequence, pharmacotherapy with corticos 10018 R is selected from the group consisting of hydroxy teroids would be improved if these and/or other side effects and alkyl and R is selected from the group consisting of associated with their use could be decreased. hydroxy, alkyl, —OC(O)-alkyl, and —OC(O)-cyclo, or 0006. The present invention seeks to address these and 0019 Rand R combine to form a moiety selected from other needs in the art. the group consisting of SUMMARY OF THE INVENTION 0007. In one or more embodiments of the invention, a CH3, and compound is provided, the compound comprising a corticos teroid residue covalently attached via a hydrazone linkage to ----vwrO X a water-soluble, non-peptidic oligomer. O CH3 0008. In one or more embodiments of the invention, a compound is provided, the compound comprising a corticos teroid residue covalently attached via a hydrazone linkage to a water-soluble, non-peptidic oligomer, wherein the weight average molecular weight of the water-soluble, non-peptidic I0020 R is selected from the group consisting of CH, oligomer is less than 400 Daltons. —CH2—OH, -CH2-halo. —S-CH-halo. —CH2— 0009. In one or more embodiments of the invention, a O-C(O)-CH, CH, O C(O)—CH, CH compound is provided, the compound comprising a corticos CH PO, —CH2—O C(O)—C(CH), —CH2—O— teroid residue covalently attached (either directly or through C(O)—CH2—CH2—CH, CH, CH, C(O) O one or more atoms) at a position other than through the 16 or CH, —CH, O C(O) CH-CH C(O)—OH: 17 positions to a water-soluble, non-peptidic oligomer. 0021 either 0010. In one or more embodiments of the invention, a (0022 R is HandR is selected from the group consist compound is provided, the compound comprising a corticos ing of —H and hydroxy, or teroid residue covalently attached (either directly or through 0023 R and R combine to form carbonyl: US 2010/02861 07 A1 Nov. 11, 2010

0024 R7 is halo: attached via a stable or degradable linkage to a water-soluble, 0025 X is a spacer moiety; and non-peptidic oligomer, wherein the compound is present in a 0026 POLY is a water-soluble, non-peptidic oligomer. dosage form. 0027. The “corticosteroid residue' is a compound having 0036. In one or more embodiments of the invention, a a structure of a corticosteroid that is altered by the presence of method is provided, the method comprising covalently one or more bonds, which bonds serve to attach (either attaching a water-soluble, non-peptidic oligomer to a corti directly or indirectly) one or more water-soluble, non-pep costeroid. tidic oligomers. In this regard, any compound having corti 0037. In one or more embodiments of the invention, a costeroid activity can be used. Exemplary corticosteroids method is provided, the method comprising administering a have a structure encompassed by the structure defined herein compound comprising a corticosteroid residue covalently as Formula I: attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer. 0038. These and other objects, aspects, embodiments and

(Formula I) features of the invention will become more fully apparent to one of ordinary skill in the art when read in conjunction with the following detailed description. DETAILED DESCRIPTION OF THE INVENTION 0039. As used in this specification, the singular forms “a, “an and “the include plural referents unless the context clearly dictates otherwise. 0040. In describing and claiming the present invention, the following terminology will be used in accordance with the definitions described below. 0041. “Water soluble, non-peptidic oligomer' indicates an wherein: oligomer that is at least 35% (by weight) soluble, preferably 0028 the dashed line independently represents an greater than 95% (by weight), in water at room temperature. optional double bond; An unfiltered aqueous preparation of a “water-soluble' oli 0029) R' is selected from the group consisting of halo gomer transmits at least 75%, more preferably at least 95%, of (e.g., fluoro, chloro, bromo, iodo) and alkyl, the amount of light transmitted by the same solution after I0030) either R is selected from the group consisting of filtering. On a weight basis, a “water soluble' oligomer is hydroxy and alkyl and R is selected from the group con preferably at least 35% (by weight) soluble in water, more sisting of hydroxy, alkyl, —OC(O)-alkyl, and —OC(O)- preferably at least 50% (by weight) soluble in water, still cyclo, or RandR combinetoformamoiety selected from more preferably at least 85% (by weight) soluble in water. It the group consisting of is preferred, however, that the water-soluble oligomer is at least 95% (by weight) soluble in water or completely soluble in water. 0042. The terms “monomer,”99 “monomeric&g subunit' and ris-N- - X: and “monomeric unit are used interchangeably herein and refer Vvv^O O CH3 to one of the basic structural units of a polymer or oligomer. In the case of a homo-oligomer, this is defined as a structural repeating unit of the oligomer. In the case of a co-oligomer, a monomeric unit is more usefully defined as the residue of a monomer which was oligomerized to form the oligomer, since the structural repeating unit may include more than one I0031) R' is selected from the group consisting of CHs. type of monomeric unit. Preferred oligomers are homo-oli —CH2—OH, -CH2-halo. —S-CH-halo. —CH2— gomers. O C(O)-CH, —CH, O C(O)—CH, CH, 0043. An "oligomer' is a molecule possessing from about CH PO, —CH2—O C(O)—C(CH), —CH2— 1 to about 30 monomers. Specific oligomers for use in the O—C(O)—CH, CH, CH, CH, CH-C(O) invention include those having a variety of geometries such as O CH, —CH2—O C(O)—CH2—CH2—C(O)—OH: linear, branched, or forked, to be described in greater detail 0032 either R is – H and R is selected from the group below. consisting of H and hydroxy, or R and R combine to 0044) “PEG' or “polyethylene glycol, as used herein, is form carbonyl; and meant to encompass any water-soluble poly(ethylene oxide). 0033 R7 is halo. Unless otherwise indicated, a “PEG oligomer' or an oligoet 0034. In one or more embodiments of the invention, a hylene glycol is one in which substantially all (preferably all) composition is provided, the composition comprising a com monomeric Subunits are ethylene oxide subunits, though the pound comprising a corticosteroid residue covalently oligomer may contain distinct end capping moieties or func attached via a stable or degradable linkage to a water-soluble tional groups, e.g., for conjugation. PEG oligomers for use in and non-peptidic oligomer, and optionally, a pharmaceuti the present invention may comprise the following structures: cally acceptable excipient. “—(CH2CH2O), or “ (CH2CH2O), CHCH 0035. In one or more embodiments of the invention, a depending upon whether or not the terminal oxygen(s) has dosage form is provided, the dosage form comprising a com been displaced, e.g., during a synthetic transformation. As pound comprising a corticosteroid residue covalently stated above, for the PEG oligomers, the variable (n) ranges US 2010/02861 07 A1 Nov. 11, 2010

from 1 to 30, and the terminal groups and architecture of the example, in T. W. Greene and G. M. Wuts, Protecting Groups overall PEG can vary. When PEG further comprises a func in Organic Synthesis, Third Edition, Wiley, New York, 1999, tional group, A, for linking to, e.g., a small molecule drug, the and references cited therein. functional group when covalently attached to a PEG oligomer 0.052 A functional group in “protected form” refers to a does not result in formation of (i) an oxygen-oxygen bond functional group bearing a protecting group. As used herein, (—O-O-, a peroxide linkage), or (ii) a nitrogen-oxygen the term “functional group' or any synonym thereof encom bond (N-O, O N). passes protected forms thereof. 0045. The terms "end-capped' or “terminally capped are 0053 A “physiologically cleavable' or “hydrolyzable” or interchangeably used herein to refer to a terminal or endpoint “degradable bond is a relatively labile bond that reacts with of a polymer having an end-capping moiety. Typically, water (i.e., is hydrolyzed) under physiological conditions. although not necessarily, the end-capping moiety comprises a The tendency of a bond to hydrolyze in water may depend not hydroxy or Coalkoxy group. Thus, examples of end-cap only on the general type of linkage connecting two central ping moieties include alkoxy (e.g., methoxy, ethoxy and ben atoms but also on the substituents attached to these central Zyloxy), as well as aryl, heteroaryl, cyclo, heterocyclo, and atoms. Appropriate hydrolytically unstable or weak linkages the like. In addition, Saturated, unsaturated, Substituted and include but are not limited to carboxylate ester, phosphate unsubstituted forms of each of the foregoing are envisioned. ester, anhydrides, acetals, ketals, acyloxyalkyl ether, imines, Moreover, the end-capping group can also be a silane. The orthoesters, peptides, oligonucleotides, thioesters, thiolest end-capping group can also advantageously comprise a ers, and carbonates. detectable label. When the polymer has an end-capping group 0054 An “enzymatically degradable linkage” means a comprising a detectable label, the amount or location of the linkage that is Subject to degradation by one or more polymer and/or the moiety (e.g., active agent) of interest to enzymes. which the polymer is coupled, can be determined by using a 0055 A“stable' linkage or bond refers to a chemical bond suitable detector. Such labels include, without limitation, that is substantially stable in water, that is to say, does not fluorescers, chemiluminescers, moieties used in enzyme undergo hydrolysis under physiological conditions to any labeling, colorimetric moieties (e.g., dyes), metalions, radio appreciable extent overan extended period of time. Examples active moieties, and the like. Suitable detectors include pho of hydrolytically stable linkages includebut are not limited to tometers, films, spectrometers, and the like. the following: carbon-carbonbonds (e.g., in aliphatic chains), 0046) “Branched, in reference to the geometry or overall ethers, amides, urethanes, amines, and the like. Generally, a structure of an oligomer, refers to an oligomer having two or stable linkage is one that exhibits a rate of hydrolysis of less more polymer 'arms' extending from a branch point. than about 1-2% per day under physiological conditions. 0047. “Forked” in reference to the geometry or overall Hydrolysis rates of representative chemical bonds can be structure of an oligomer, refers to an oligomer having two or found in most standard chemistry textbooks. more functional groups (through one or more atoms) extend 0056 “Substantially” or “essentially” means nearly ing from a branch point. totally or completely, for instance, 95% or greater, more 0048. A “branch point” refers to a bifurcation point com preferably 97% or greater, still more preferably 98% or prising one or more atoms at which an oligomer branches or greater, even more preferably 99% or greater, yet still more forks from a linear structure into one or more additional arms. preferably 99.9% or greater, with 99.99% or greater being 0049. The terms “reactive' and “activated refer to a func most preferred of some given quantity. tional group that reacts readily or at a practical rate under 0057. “Monodisperse' refers to an oligomer composition conventional conditions of organic synthesis. This is in con wherein Substantially all of the oligomers in the composition trast to those groups that either do not react or require strong have a well-defined, single (i.e., the same) molecular weight catalysts or impractical reaction conditions in order to react and defined number of monomers, as determined by chroma (i.e., a “nonreactive' or “inert' group). tography or mass spectrometry. Monodisperse oligomer 0050 “Not readily reactive,” with reference to a functional compositions are in one sense pure, that is, Substantially group present on a molecule in a reaction mixture, indicates having a single and definable number (as a whole number) of that the group remains largely intact under conditions that are monomers rather than a large distribution. A monodisperse effective to produce a desired reaction in the reaction mixture. oligomer composition possesses a MW/Mn value of 1.0005 0051. A "protecting group' is a moiety that prevents or or less, and more preferably, a MW/Mn value of 1.0000. By blocks reaction of a particular chemically reactive functional extension, a composition comprised of monodisperse conju group in a molecule under certain reaction conditions. The gates means that Substantially all oligomers of all conjugates protecting group may vary depending upon the type of chemi in the composition have a single and definable number (as a cally reactive group being protected as well as the reaction whole number) of monomers rather than a large distribution conditions to be employed and the presence of additional and would possess a MW/Mn value of 1.0005, and more reactive or protecting groups in the molecule. Functional preferably, a MW/Mn value of 1.0000 if the oligomer were groups which may be protected include, by way of example, not attached to the corticosteroid residue. A composition carboxylic acid groups, amino groups, hydroxyl groups, thiol comprised of monodisperse conjugates may, however, groups, carbonyl groups and the like. Representative protect include one or more nonconjugate Substances such as Sol ing groups for carboxylic acids include esters (such as a vents, reagents, excipients, and so forth. p-methoxybenzyl ester), amides and hydrazides; for amino 0.058 “Bimodal” in reference to an oligomer composi groups, carbamates (such as tert-butoxycarbonyl) and tion, refers to an oligomer composition wherein Substantially amides; for hydroxyl groups, ethers and esters; for thiol all oligomers in the composition have one of two definable groups, thioethers and thioesters; for carbonyl groups, acetals and different numbers (as whole numbers) of monomers and ketals; and the like. Such protecting groups are well rather than a large distribution, and whose distribution of known to those skilled in the art and are described, for molecular weights, when plotted as a number fraction versus US 2010/02861 07 A1 Nov. 11, 2010 molecular weight, appears as two separate identifiable peaks. conjugate are administered orally. Orally administered drugs Preferably, for a bimodal oligomer composition as described are absorbed from the gastro-intestinal tract into the portal herein, each peak is generally symmetric about its mean, circulation and may pass through the liver prior to reaching although the size of the two peaks may differ. Ideally, the the systemic circulation. Because the liver is the primary site polydispersity index of each peak in the bimodal distribution, of drug metabolism or biotransformation, a substantial Mw/Mn, is 1.01 or less, more preferably 1.001 or less, and amount of drug may be metabolized before it reaches the even more preferably 1.0005 or less, and most preferably a systemic circulation. The degree of first pass metabolism, and MW/Mn value of 1.0000. By extension, a composition com thus, any reduction thereof, may be measured by a number of prised of bimodal conjugates means that Substantially all different approaches. For instance, animal blood samples oligomers of all conjugates in the composition have one of may be collected at timed intervals and the plasma or serum two definable and different numbers (as whole numbers) of analyzed by liquid chromatography/mass spectrometry for monomers rather than a large distribution and would possess metabolite levels. Other techniques for measuring a “reduced a MW/Mnvalue of 1.01 or less, more preferably 1.001 or less rate of metabolism' associated with the first pass metabolism and even more preferably 1.0005 or less, and most preferably and other metabolic processes are known, described herein a MW/Mn value of 1.0000 if the oligomer were not attached and/or in the relevant literature, and/or can be determined by to the corticosteroid residue. A composition comprised of one of ordinary skill in the art. Preferably, a conjugate of the bimodal conjugates may, however, include one or more non invention can provide a reduced rate of metabolism reduction conjugate Substances such as solvents, reagents, excipients, satisfying at least one of the following values: at least about and so forth 5%; at least about 15%; at least about 20%; at least about 0059 A“corticosteroid’ refers to an organic, inorganic, or 25%; at least about 30%; at least about 40%; at least about organometallic compound having a molecular weight of less 60%, at least about 70%, at least about 80%, and at least about than about 1000 Daltons and having some degree of corticos 90%. teroid activity. Corticosteroid activity can be measured by 0063 “Alkyl refers to a hydrocarbon chain, ranging from art-known methods. For example, corticosteroid activity can about 1 to 20 atoms in length. Such hydrocarbon chains are be measured by testing male Sprague-Dawley rats by inject preferably but not necessarily saturated and may be branched ing a relatively large amount (e.g., 5-20 mg/kg) of the com or straight chain. Exemplary alkyl groups include methyl, pound of interest into an animal. After three days, the thymus ethyl, propyl, butyl, pentyl, 2-methylbutyl, 2-ethylpropyl. glands can be removed and weighed using the procedure 3-methylpentyl, and the like. As used herein, “alkyl includes described in Vicent et al. (1997) Mol. Pharmacol. 52:749 cycloalkyl when three or more carbon atoms are referenced. 753. 0064 “Lower alkyl refers to an alkyl group containing 0060 A“biological membrane' is any membrane made of from 1 to 6 carbon atoms, and may be straight chain or cells or tissues that serves as a barrier to at least Some foreign branched, as exemplified by methyl, ethyl, n-butyl, i-butyl, entities or otherwise undesirable materials. As used herein a t-butyl. “biological membrane' includes those membranes that are 0065 “Non-interfering substituents’ are those groups associated with physiological protective barriers including, that, when present in a molecule, are non-reactive with other for example: the blood-brain barrier (BBB); the blood-cere functional groups contained within the molecule. brospinal fluid barrier; the blood-placental barrier; the blood 0.066 “Alkoxy' refers to an —O R group, wherein R is milk barrier; the blood-testes barrier; and mucosal barriers alkyl or Substituted alkyl, preferably C-Coalkyl (e.g., meth including the vaginal mucosa, urethral mucosa, anal mucosa, oxy, ethoxy, propyloxy, benzyl, etc.), preferably C-C7. buccal mucosa, Sublingual mucosa, and rectal mucosa. 0067 “Electrophile' refers to an ion, atom, or an ionic or Unless the context clearly dictates otherwise, the term “bio neutral collection of atoms having an electrophilic center, i.e., logical membrane' does not include those membranes asso a center that is electron seeking, capable of reacting with a ciated with the middle gastro-intestinal tract (e.g., stomach nucleophile. and Small intestines). 0068 “Nucleophile' refers to an ion or atom or an ionic or 0061. A “biological membrane crossing rate.” provides a neutral collection of atoms having a nucleophilic center, i.e., measure of a compound's ability to cross a biological mem a center that is seeking an electrophilic center, and capable of brane, such as the blood-brain barrier (“BBB). A variety of reacting with an electrophile. methods may be used to assess transport of a molecule across 0069. “Pharmaceutically acceptable excipient’ or “phar any given biological membrane. Methods to assess the bio maceutically acceptable carrier refers to component that logical membrane crossing rate associated with any given may be included in the compositions of the invention and that biological barrier (e.g., the blood-cerebrospinal fluid barrier, causes no significant adverse toxicological effects to a the blood-placental barrier, the blood-milk barrier, the intes patient. tinal barrier, and so forth), are known, described herein and/or 0070 The term “aryl' means an aromatic group having up in the relevant literature, and/or may be determined by one of to 14 carbon atoms. Aryl groups include phenyl, naphthyl, ordinary skill in the art. biphenyl, phenanthrenyl, naphthacenyl, and the like. “Substi 0062. A “reduced rate of metabolism” refers to a measur tuted phenyl' and “substituted aryl' denote a phenyl group able reduction in the rate of metabolism of a water-soluble and aryl group, respectively, Substituted with one, two, three, oligomer-Small molecule drug conjugate as compared to the four or five (e.g. 1-2, 1-3 or 1-4 substituents) chosen from halo rate of metabolism of the small molecule drug not attached to (F, Cl, Br, I), hydroxy, hydroxy, cyano, nitro, alkyl (e.g., C the water-soluble oligomer (i.e., the Small molecule drug alkyl), alkoxy (e.g., C alkoxy), benzyloxy, carboxy, aryl, itself) or a reference standard material. In the special case of and so forth. “reduced first pass rate of metabolism,” the same “reduced 0071 "Pharmacologically effective amount,” “physi rate of metabolism' is required except that the small molecule ologically effective amount, and “therapeutically effective drug (or reference standard material) and the corresponding amount are used interchangeably herein to mean the amount US 2010/02861 07 A1 Nov. 11, 2010 of a water-soluble oligomer-Small molecule drug conjugate I0082 R and R combine to form a moiety selected from present in a composition that is needed to provide a desired the group consisting of level of active agent and/or conjugate in the bloodstream or in the target tissue. The precise amount may depend upon numerous factors, e.g., the particular active agent, the com CH3, and ponents and physical characteristics of the composition, ----- intended patient population, patient considerations, and may vvurO OX CH3 readily be determined by one skilled in the art, based upon the information provided herein and available in the relevant literature. 0072 A “difunctional oligomer is an oligomer having two functional groups contained therein, typically at its ter I0083) R' is selected from the group consisting of CH, mini. When the functional groups are the same, the oligomer —CH2—OH, -CH2-halo. —S-CH-halo. —CH2— is said to be homodifunctional. When the functional groups O-C(O)-CH, —CH O—C(O)—CH, CH, are different, the oligomer is said to be heterobifunctional. 0073. A basic reactant or an acidic reactant described herein include neutral, charged, and any corresponding salt forms thereof. either 0074 The term “patient,” refers to a living organism suf I0085) R is HandR is selected from the group consist fering from or prone to a condition that can be prevented or ing of —H and hydroxy, or treated by administration of a conjugate as described herein, I0086 RandR combine to form carbonyl; and and includes both humans and animals. 0087 R7 is halo. 0075 “Optional” or “optionally” means that the subse I0088. Examples of specific corticosteroids include those quently described circumstance may but need not necessarily selected from the group consisting of desoxycorticosone, occur, so that the description includes instances where the hydrocortisone, cortisone, methylprednisolone, prednisone, circumstance occurs and instances where it does not. prednisolone, triamcinolone, dexamethasone, betametha 0076. As indicated above, the present invention is directed Sone, beclomethasone, beclomethasone-17,21-dipropionate, to (among other things) a compound comprising a corticos budesonide, flunisolide, fludrocortisone, mometaSone, fluti teroid residue covalently attached via a stable or degradable casone, alclometaSone, clocortolone, flurandrenolide, fluoci linkage to a water-soluble, non-peptidic oligomer. nonide, hydrocortisone acetate, fluorometholone, fluocino 0077. In one or more embodiments of the invention, a lone acetonide, diflucortolone Valerate, paramethasone compound is provided, the compound comprising a corticos acetate, halcinonide, hydrocortisone phosphate, clobetaSone teroid residue covalently attached via a stable or degradable butyrate, amcinonide, and prednisolone Succinate. linkage to a water-soluble, non-peptidic oligomer, wherein I0089. As used herein, the conventional ring atom number the corticosteroid has a structure encompassed by the follow ing system for identifying positions of atoms and rings within ing formula: a corticosteroid will be used, as follows:

(Formula I) (Formula I)

fy C a l N1N19 14 N15 A R 2 3 na 5 NB 7 R1

(0090. One of ordinary skill in the art will readily deter mine the positions of atoms and rings of the corresponding wherein: corticosteroid residue. When referring to positions of attach 0078 the dashed line independently represents an ment, it will be understood that when a given moiety is stated optional double bond; to be attached at a certain numbered position or a position within a ring it can be either direct (i.e., directly to one of the 0079) R' is selected from the group consisting of halo ring atoms numbered 1 through 17) or indirect (i.e., one or (e.g., fluoro, chloro, bromo, iodo) and alkyl, more atoms linking the moiety to one of the ring atoms 0080 either numbered one 1 through 17). As used herein, the first num I0081) R' is selected from the group consisting of hydroxy bered ring atom to which a given moiety is attached deter and alkyl and R is selected from the group consisting of mines that moiety's attachment site. Thus, a corticosteroid hydroxy, alkyl, —OC(O)-alkyl, and —OC(O)-cyclo, or residue attached in accordance with Formula I-C is only US 2010/02861 07 A1 Nov. 11, 2010

considered attached to an oligomer at the 3-position, and not tions of: at least about 5%; at least about 10%; at least about (for example) attached to the 2 position by way of the ring 25%; at least about 30%; at least about 40%; at least about atom at the 3-position. 50%; at least about 60%; at least about 70%; at least about 0091 Use of discrete oligomers (e.g., from a monodis 80%; or at least about 90%, when compared to the blood perse or bimodal composition of oligomers, in contrast to brain barrier crossing rate of the Small molecule drug not relatively impure compositions) to form oligomer-containing attached to the water-soluble oligomer. A preferred reduction compounds can advantageously alter certain properties asso in blood-brain barrier crossing rate for a conjugate of the ciated with the corresponding Small molecule drug. For invention is at least about 20%. instance, a compound of the invention, when administered by 0.095 As indicated above, the compounds of the invention any of a number of Suitable administration routes, such as include a corticosteroid residue. Assays for determining parenteral, oral, transdermal, buccal, pulmonary, or nasal, whether a given compound (regardless of whether the com exhibits reduced penetration across the blood-brain barrier. It pound includes a water-soluble, non-peptidic oligomer or is preferred that the compounds of the invention exhibit not) act as a corticosteroid are described herein. slowed, minimal or effectively no crossing of the blood-brain barrier, while still crossing the gastro-intestinal (GI) walls 0096. In one or more embodiments, the corticosteroid is and into the systemic circulation if oral delivery is intended. one of the following corticosteroids: Moreover, the compounds of the invention maintain a degree of bioactivity as well as bioavailability in comparison to the bioactivity and bioavailability of the compound free of all OH oligomers. 0092. With respect to the blood-brain barrier (“BBB), CH3 O this barrier restricts the transport of drugs from the blood to O OH the brain. This barrier consists of a continuous layer of unique endothelial cells joined by tight junctions. The cerebral cap CH3 illaries, which comprise more than 95% of the total surface area of the BBB, represent the principal route for the entry of most solutes and drugs into the central nervous system. 0093. For compounds whose degree of blood-brain barrier O crossing ability is not readily known, such ability can be (cortisone); determined using a suitable animal model Such as an in situ rat OH brain perfusion (“RBP) model as described herein. Briefly, the RBP technique involves cannulation of the carotid artery CH O followed by perfusion with a compound solution under con O trolled conditions, followed by a wash out phase to remove compound remaining in the vascular space. (Such analyses CH can be conducted, for example, by contract research organi Zations such as Absorption Systems, Exton, Pa.). In one example of the RBP model, a cannula is placed in the left carotidartery and the side branches are tied off. A physiologic O buffer containing the analyte (typically but not necessarily at (desoxycortisone); a 5 micromolar concentration level) is perfused at a flow rate OH of about 10 mL/minute in a single pass perfusion experiment. After 30 seconds, the perfusion is stopped and the brain vascular contents are washed out with compound-free buffer CH O for an additional 30 seconds. The brain tissue is then removed HO OH and analyzed for compound concentrations via liquid chro matograph with tandem mass spectrometry detection (LC/ CH MS/MS). Alternatively, blood-brain barrier permeability can be estimated based upon a calculation of the compound's molecular polar surface area (“PSA), which is defined as the Sum of surface contributions of polar atoms (usually oxygens, O nitrogens and attached hydrogens) in a molecule. The PSA (hydrocortisone); has been shown to correlate with compound transport prop OH erties such as blood-brain barrier transport. Methods for determining a compound's PSA can be found, e.g., in, Ertl, P. CH O et al., J. Med. Chem. 2000, 43, 3714-3717; and Kelder, J., et al., Pharm. Res. 1999, 16, 1514-1519. O OH 0094. With respect to the blood-brain barrier, the water CH soluble, non-peptidic oligomer-Small molecule drug conju gate exhibits a blood-brain barrier crossing rate that is reduced as compared to the crossing rate of the Small mol ecule drug not attached to the water-soluble, non-peptidic O oligomer. Exemplary reductions in blood-brain barrier cross (prednisone); ing rates for the compounds described herein include reduc US 2010/02861 07 A1 Nov. 11, 2010

-continued -continued OH OH

CH3 O CH O HO OH HO OH CH3 CH CH

O O (prednisolone); (betamethasone); OH OH

CH O CH3 O HO OH HO OH CH3 o CH O O (beclomethasone); CH (methylprednisolone); O OH

O CH O CH3 HO OH HO -N-" CH OH CH3 O) CH3 O CD O (beclomethasone-17,21-dipropionate); (triamcinolone); OH OH CH3 CH O CH3 O HO O HO \ CH O CH3 O

O O (budesonide); (triamcinolone acetonide); OH

OH

CH O HO O CH O

O

F (dexamethasone); (flunisolide); US 2010/02861 07 A1 Nov. 11, 2010

-continued -continued

OH

CH3 O HO OH HO CH3 C H3 C H3

O O (fluidrocortisone); (clocortolone);FO OH C

O CH O CH3 CH3 O | O "N-N-("ACH O CH3 CH3 O) CH3

O O F (mometasone); (flurandrenolide); ) o1 C YCH, S CH O CH3 CH O O CH HO O-C HO SA CH CH O 3 CH CH

O O F F (fluocinonide); (fluticaSone); OH

OH CH O CH3

HO SA CH CH O 3 CH O HO OH CH CH O

O C (fluocinonide acetonide); (alclometsaone); US 2010/02861 07 A1 Nov. 11, 2010

-continued -continued

C o1 YCH, C

CH3 O HO OH HO O CH3 CH

O (hydrocortisone acetate); (halcinonide); HC

HO (H, to CH3

CH O O HO OH CH3 CH (fluorometholone);

H3CN-1-N-1C No (hydrocortisone phosphate);

CH O HO CH3 CH

O

F (diflucortolone valerate);

(clobestaSone butyrate); HC1 C No

CH3 O HO CH3 CH3

CH3 O HO O O O CH3 F (paramethasone acetate);

(amcinonide); and US 2010/02861 07 A1 Nov. 11, 2010 10

ric isomer or a mixture of two or more geometric isomers. A -continued Small molecule drug for use in the present invention can be in its customary active form, or may possess some degree of f modification. For example, a small molecule drug may have a O-C targeting agent, tag, or transporter attached thereto, prior to or after covalent attachment of an oligomer. Alternatively, the Small molecule drug may possess a lipophilic moiety attached CH O O thereto. Such as a phospholipid (e.g., distearoylphosphati HO OH O dylethanolamine or "DSPE. dipalmitoylphosphatidyletha CH nolamine or “DPPE.” and so forth) or a small fatty acid. In Some instances, however, it is preferred that the Small mol ecule drug moiety does not include attachment to a lipophilic moiety. 0101 The corticosteroid for coupling to a water-soluble, (prednisolone Succinate). non-peptidic oligomer possesses a free hydroxyl, carboxyl, thio, amino group, or the like (i.e., “handle') suitable for covalent attachment to the oligomer. In addition, the corticos 0097. In some instances, corticosteroids can be obtained teroid can be modified by introduction of a reactive group, from commercial Sources. In addition, corticosteroids can be preferably by conversion of one of its existing functional obtained through chemical synthesis. Examples of corticos groups to a functional group Suitable for formation of a stable teroids as well as synthetic approaches for preparing corti covalent linkage between the oligomer and the drug. costeroids are described in the literature and in, for example, 0102 Accordingly, each oligomer is composed of up to U.S. Pat. No. 2,403,683 (cortisone and others); U.S. Pat. No. three different monomer types selected from the group con 2,602,769 (hydrocortisone and others); U.S. Pat. No. 2,897, sisting of alkylene oxide. Such as ethylene oxide or propy 216 (prednisone and others); U.S. Pat. No. 2,837,464 (pred lene oxide; olefinic alcohol, such as vinyl alcohol. 1-propenol nisolone and others); U.S. Pat. No. 2,897.218 (methylpred or 2-propenol; vinyl pyrrolidone; hydroxyalkyl methacryla nisolone and others); U.S. Pat. No. 2,789,118 and U.S. Pat. mide or hydroxyalkyl methacrylate, where alkyl is preferably No. 3,031,347 (triamcinolone and others); U.S. Pat. No. methyl, C.-hydroxy acid, such as lactic acid or glycolic acid; 2.990,401 (triamcinolone acetonide and others); U.S. Pat. phosphaZene, oxazoline, amino acids, carbohydrates such as No. 3,007,923 (dexamethasone and others); U.S. Pat. No. monosaccharides, saccharide or mannitol; and N-acryloyl 3,053,865 and U.S. Pat. No. 3,104.246 (betamethasone and morpholine. Preferred monomer types include alkylene others); U.S. Pat. No. 3.312,590 (beclomethasone and oth oxide, olefinic alcohol, hydroxyalkyl methacrylamide or ers); U.S. Pat. No. 3,929,768 (budesonide and others); U.S. methacrylate, N-acryloylmorpholine, and C-hydroxy acid. Pat. No. 2,852,511 (fludrocortisone and others); U.S. Pat. No. Preferably, each oligomeris, independently, a co-oligomer of 4,472.393 (mometasone and others); U.S. Pat. No. 4,335,121 two monomer types selected from this group, or, more pref (fluticasone and others); U.S. Pat. No. 4,076,708 and U.S. erably, is a homo-oligomer of one monomer type selected Pat. No. 4,124,707 (alclometasone and others); U.S. Pat. No. from this group. 3,729,495 (clocortolone and others); U.S. Pat. No. 3,126.375 0103) The two monomer types in a co-oligomer may be of (flurandrenolide and others); U.S. Pat. No. 3,124,571 (fluo the same monomer type, for example, two alkylene oxides, cinonide and others); U.S. Pat. No. 3,014.938 (fluocinonide such as ethylene oxide and propylene oxide. Preferably, the acetonide and others); U.S. Pat. No. 2,602.769 (hydrocorti oligomer is a homo-oligomer of ethylene oxide. Usually, sone and others); U.S. Pat. No. 3,038,914 (fluorometholone although not necessarily, the terminus (or termini) of the and others); U.S. Pat. No. 3,426,128 (diflucortolone and oth oligomer that is not covalently attached to a small molecule is ers); U.S. Pat. No. 3,892,857 (halcinonide and others); and capped to render it unreactive. Alternatively, the terminus U.S. Pat. No. 3,721,687 (clobetasone and others). In addition, may include a reactive group. When the terminus is a reactive salts and esters of a corticorsteroid can also be used so long as group, the reactive group is either selected Such that it is the oligomer-containing compound retains at least some unreactive under the conditions of formation of the final oli degree of corticosteroid activity. gomer or during covalent attachment of the oligomer to a 0098. Each of these (and other) corticosteroids can be Small molecule drug, or it is protected as necessary. One covalently attached (either directly or through one or more common end-functional group is hydroxyl or —OH, particu atoms) to a water-soluble and non-peptidic oligomer. larly for oligoethylene oxides. 0099 Exemplary molecular weights of small molecule 0104. The water-soluble, non-peptidic oligomer (e.g., drugs include molecular weights of less than about 950; less “POLY” in various structures provided herein) can have any than about 900; less than about 850; less than about 800; less of a number of different geometries. For example, the water than about 750; less than about 700; less than about 650; less soluble, non-peptidic oligomer can be linear, branched, or than about 600; less than about 550; less than about 500; and forked. Most typically, the water-soluble, non-peptidic oligo less than about 450. mer is linear or is branched, for example, having one branch 0100. The small molecule drug used in the invention, if point. Although much of the discussion herein is focused chiral, may be obtained from a racemic mixture, or an opti upon poly(ethylene oxide) as an illustrative oligomer, the cally active form, for example, a single optically active enan discussion and structures presented herein can be readily tiomer, or any combination or ratio ofenantiomers (i.e., scale extended to encompass any of the water-soluble, non-pep mic mixture). In addition, the Small molecule drug may tidic oligomers described above. possess one or more geometric isomers. With respect to geo 0105. The molecular weight of the water-soluble, non metric isomers, a composition can comprise a single geomet peptidic oligomer, excluding the linker portion, is generally US 2010/02861 07 A1 Nov. 11, 2010

relatively low. Exemplary values of the molecular weight of so forth: 5-6, 5–7, 5-8, 5 9, 5-10, and so forth; 6-7, 6-8, 6-9, the water-soluble polymer include: below about 1500; below 6-10, and so forth; 7-8, 7 9, 7-10, and so forth; and 8-9, 8-10, about 1450; below about 1400; below about 1350; below and so forth. about 1300; below about 1250; below about 1200; below 0110. In some instances, the composition containing an about 1150; below about 1100; below about 1050; below activated form of the water-soluble, non-peptidic oligomer about 1000; below about 950; below about 900; below about will be trimodal or even tetramodal, possessing a range of 850; below about 800; below about 750; below about 700; monomers units as previously described. Oligomer compo below about 650; below about 600; below about 550; below sitions possessing a well-defined mixture of oligomers (i.e., about 500; below about 450; below about 400; below about being bimodal, trimodal, tetramodal, and so forth) can be 350; below about 300; below about 250; below about 200; and prepared by mixing purified monodisperse oligomers to below about 100 Daltons. obtain a desired profile of oligomers (a mixture of two oligo mers differing only in the number of monomers is bimodal; a 0106 Exemplary ranges of molecular weights of the mixture of three oligomers differing only in the number of water-soluble, non-peptidic oligomer (excluding the linker) monomers is trimodal; a mixture of four oligomers differing include: from about 100 to about 1400 Daltons; from about only in the number of monomers is tetramodal), or alterna 100 to about 1200 Daltons; from about 100 to about 800 tively, can be obtained from column chromatography of a Daltons; from about 100 to about 500 Daltons; from about polydisperse oligomer by recovering the “center cut’, to 100 to about 400. Daltons; from about 200 to about 500 obtain a mixture of oligomers in a desired and defined Daltons; from about 200 to about 400 Daltons; from about 75 molecular weight range. to 1000 Daltons; and from about 75 to about 750 Daltons. 0111. It is preferred that the water-soluble, non-peptidic 0107 Preferably, the number of monomers in the water oligomer is obtained from a composition that is preferably soluble, non-peptidic oligomer falls within one or more of the unimolecular or monodisperse. That is, the oligomers in the following ranges: between about 1 and about 30 (inclusive); composition possess the same discrete molecular weight between about 1 and about 25; between about 1 and about 20: value rather than a distribution of molecular weights. Some between about 1 and about 15; between about 1 and about 12; monodisperse oligomers can be purchased from commercial between about 1 and about 10. In certain instances, the num Sources such as those available from Sigma-Aldrich, or alter ber of monomers in series in the oligomer (and the corre natively, can be prepared directly from commercially avail sponding conjugate) is one of 1, 2, 3, 4, 5, 6, 7, or 8. In able starting materials such as Sigma-Aldrich. Water-soluble, additional embodiments, the oligomer (and the correspond non-peptidic oligomers can be prepared as described in Chen ing conjugate) contains 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, Y., Baker, G. L., J. Org. Chem. 6870-6873 (1999), WO 19, or 20 monomers. In yet further embodiments, the oligo 02/098.949, and U.S. Patent Application Publication 2005/ mer (and the corresponding conjugate) possesses 21, 22, 23. O136O31. 24, 25, 26, 27, 28, 29 or 30 monomers in series. Thus, for 0112. When present, the spacer moiety (through which the example, when the water-soluble and non-peptidic polymer water-soluble, non-peptidic polymer is attached to the corti includes CH (OCHCH) “n” is an integer that can be costeroid) may be a single bond, a single atom, Such as an 1,2,3,4,5,6,7,8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, oxygen atom or a Sulfur atom, two atoms, or a number of 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30, and can fall within one atoms. A spacer moiety is typically but is not necessarily or more of the following ranges: between about 1 and about linear in nature. The spacer moiety, “X” is hydrolytically 25; between about 1 and about 20; between about 1 and about stable, and is preferably also enzymatically stable. Preferably, 15; between about 1 and about 12; between about 1 and about the spacer moiety “X” is one having a chain length of less than 10. about 12 atoms, and preferably less than about 10 atoms, and 0108. When the water-soluble, non-peptidic oligomer has even more preferably less than about 8 atoms and even more 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 monomers, these values corre preferably less than about 5 atoms, whereby length is meant spond to a methoxy end-capped oligo(ethylene oxide) having the number of atoms in a single chain, not counting Substitu a molecular weights of about 75, 119, 163, 207, 251, 295, ents. For instance, a urea linkage such as this, R 339, 383, 427, and 471 Daltons, respectively. When the oli NH-(C=O) NH-R is considered to have a chain gomer has 11, 12, 13, 14, or 15 monomers, these values length of 3 atoms ( NH CO) NH ). In selected correspond to methoxy end-capped oligo(ethylene oxide) embodiments, the linkage does not comprise further spacer having molecular weights corresponding to about 515, 559, groups. 603, 647, and 691 Daltons, respectively. 0113. In some instances, the spacer moiety “X” comprises 0109 When the water-soluble, non-peptidic oligomer is an ether, amide, urethane, amine, thioether, urea, or a carbon attached to the corticosteroid (in contrast to the step-wise carbon bond. Functional groups such as those discussed addition of one or more monomers to effectively “grow’ the below, and illustrated in the examples, are typically used for oligomer onto the corticosteroid), it is preferred that the com forming the linkages. The spacer moiety may less preferably position containing an activated form of the water-soluble, also comprise (or be adjacent to or flanked by) other atoms, as non-peptidic oligomer be monodisperse. In those instances, described further below. however, where a bimodal composition is employed, the 0114 More specifically, in selected embodiments, a composition will possess a bimodal distribution centering spacer moiety of the invention, X, may be any of the follow around any two of the above numbers of monomers. For ing: ' ' (i.e., a covalent bond, that may be stable or degrad instance, a bimodal oligomer may have any one of the fol able, between the corticosteroid residue and the water lowing exemplary combinations of monomer Subunits: 1-2, soluble, non-peptidic oligomer), —O— —NH-, —S , 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, and so forth: 2-3, 2-4, C(O) C(O) NH, NH C(O) NH, O C(O) NH, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, and so forth: 3-4, 3-5, 3-6, 3-7, –OC(O) NH N— —N. NH C(O)O-, -C(O)– 3-8, 3-9, 3-10, and so forth: 4-5, 4-6, 4-7 4-8, 4-9, 4-10, and NH N=, —N. NH C(O) , C(S)—, CH2—, US 2010/02861 07 A1 Nov. 11, 2010

0117. A particularly preferred water-soluble, non-peptidic oligomer is an oligomer bearing an aldehyde functional group. In this regard, the oligomer will have the following structure: CH,O (CH, CH, O), (CH), C(O)H, wherein (n) is one of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 and (p) is one of 1, 2, 3, 4, 5, 6 and 7. Preferred (n) values include 3, 5 and 7 and preferred (p) values 2, 3 and 4. 0118. The terminus of the water-soluble, non-peptidic oli O—, C(O) NH-CH , C(O) NH CH, gomer not bearing a functional group is capped to render it CH , —CH2—C(O) NH-CH , —CH2—CH2—C unreactive. When the oligomer includes a further functional (O) NH-, C(O)—NH CH, CH, CH , group at a terminus other than that intended for formation of CH, C(O) NH CH-CH , CH, CH, C a conjugate, that group is either selected Such that it is unre (O) NH-CH , —CH2—CH2—CH2—C(O) NH . active under the conditions of formation of the linkage “X” or C(O) NH CH, CH, CH, CH, , CH, C it is protected during the formation of the linkage “X” (O) NH-CH CH-CH , —CH2—CH2—C(O) 0119. As stated above, the water-soluble, non-peptidic oli NH-CH CH , —CH2—CH2—CH2—C(O)—NH gomer includes at least one functional group prior to conju gation. The functional group typically comprises an electro philic or nucleophilic group for covalent attachment to a Small molecule, depending upon the reactive group contained CH NH COO)—CH2—, NH CO)—CH2—CH2—, within or introduced into the small molecule. Examples of CH-NH C(O)-CH, CH, -CH-CH NH C nucleophilic groups that may be present in either the oligomer (O) CH, CH, C(O) NH-CH –C(O) NH or the Small molecule include hydroxyl, amine, hydrazine CH, CH2—, —O C(O) NH-CH —O—C(O) ( NHNH), hydrazide ( C(O)NHNH), and thiol. Pre NH-CH CH , NH-CH , NH CH, ferred nucleophiles includeamine, hydrazine, hydrazide, and CH , —CH2 NH-CH , —CH2—CH NH thiol, particularly amine. Most Small molecule drugs for CH , C(O)—CH2—, C(O)—CH, CH, , covalent attachment to an oligomer will possess a free hydroxyl, amino, thio, aldehyde, ketone, or carboxyl group. I0120 Examples of electrophilic functional groups that (O) , —CH, CH, CH, C(O) NH CH, CH, may be present in either the oligomer or the Small molecule NH , —CH2—CH2—CH2—C(O) NH CH-CH include carboxylic acid, carboxylic ester, particularly imide NH-C(O) , —CH, CH, CH, C(O) NH-CH esters, orthoester, carbonate, isocyanate, isothiocyanate, CH NH COO)—CH2—, bivalent cycloalkyl group, aldehyde, ketone, thione, alkenyl, acrylate, methacrylate, —N(R)—, R is H or an organic radical selected from the acrylamide, Sulfone, maleimide, disulfide, iodo, epoxy, Sul group consisting of alkyl, Substituted alkyl, alkenyl, Substi fonate, thiosulfonate, silane, alkoxysilane, and halosilane. tuted alkenyl, alkynyl, Substituted alkynyl, aryl and Substi More specific examples of these groups include Succinimidyl tuted aryl. ester or carbonate, imidazoyl ester or carbonate, benzotriaz 0115 For purposes of the present invention, however, a ole ester or carbonate, vinyl sulfone, chloroethylsulfone, group of atoms is not considered a linkage when it is imme vinylpyridine, pyridyl disulfide, iodoacetamide, glyoxal, diately adjacent to an oligomer segment, and the group of dione, mesylate, tosylate, and tresylate (2.2.2-trifluoroet atoms is the same as a monomer of the oligomer Such that the hanesulfonate). group would represent a mere extension of the oligomer I0121. Also included are sulfur analogs of several of these chain. groups, such as thione, thione hydrate, thioketal, is 2-thiazo 0116. The linkage “X” between the water-soluble, non lidine thione, etc., as well as hydrates or protected derivatives peptidic oligomer and the Small molecule is typically formed of any of the above moieties (e.g. aldehyde hydrate, hemiac by reaction of a functional group on a terminus of the oligo etal, acetal, ketone hydrate, hemiketal, ketal, thioketal, thio mer (or nascent oligomer when it is desired to “grow’ the acetal). oligomer onto the corticosteroid) with a corresponding func I0122) An “activated derivative' of a carboxylic acid refers tional group within the corticosteroid. Illustrative reactions to a carboxylic acid derivative that reacts readily with nucleo are described briefly below. For example, an amino group on philes, generally much more readily than the underivatized an oligomer may be reacted with a carboxylic acid or an carboxylic acid. Activated carboxylic acids include, for activated carboxylic acid derivative on the small molecule, or example, acid halides (such as acid chlorides), anhydrides, Vice versa, to produce an amide linkage. Alternatively, reac carbonates, and esters. Suchesters include imide esters, of the tion of an amine on an oligomer with an activated carbonate general form —(CO)O N(CO)—; for example, N-hy (e.g. Succinimidyl or benzotriaZyl carbonate) on the drug, or droxysuccinimidyl (NHS) esters or N-hydroxyphthalimidyl Vice versa, forms a carbamate linkage. Reaction of an amine esters. Also preferred are imidazolyl esters and benzotriazole on an oligomer with an isocyanate (R-N=C=O) on a drug, esters. Particularly preferred are activated propionic acid or or vice versa, forms a urea linkage (R-NH (C=O)— butanoic acid esters, as described in co-owned U.S. Pat. No. NH-R). Further, reaction of an alcohol (alkoxide) group on 5,672,662. These include groups of the form —(CH2)C an oligomer with an alkyl halide, or halide group within a (=O)C-Q, where Q is preferably selected from N-succinim drug, or vice versa, forms an ether linkage. In yet another ide, N-sulfosuccinimide, N-phthalimide, N-glutarimide, coupling approach, a small molecule having an aldehyde N-tetrahydrophthalimide, N-norbornene-2,3-dicarboximide, function is coupled to an oligomeramino group by reductive benzotriazole, 7-azabenzotriazole, and imidazole. amination, resulting in formation of a secondary amine link I0123. Other preferred electrophilic groups include succin age between the oligomer and the Small molecule. imidyl carbonate, maleimide, benzotriazole carbonate, gly US 2010/02861 07 A1 Nov. 11, 2010 cidyl ether, imidazoyl carbonate, p-nitrophenyl carbonate, to deprotonate the hydroxyl group followed by reaction with acrylate, tresylate, aldehyde, and orthopyridyl disulfide. a halide-terminated oligomeric ethylene glycol. 0.124. These electrophilic groups are subject to reaction I0129. In another example, it is possible to prepare a con with nucleophiles, e.g., hydroxy, thio, or amino groups, to jugate of a small molecule corticosteroid bearing a ketone group by first reducing the ketone group to form the corre produce various bond types. Preferred for the present inven sponding hydroxyl group. Thereafter, the Small molecule cor tion are reactions which favor formation of a hydrolytically ticosteroid now bearing a hydroxyl group can be coupled as stable linkage. For example, carboxylic acids and activated described herein. derivatives thereof, which include orthoesters, succinimidyl 0.130. In still another example, it is possible to prepare a esters, imidazolyl esters, and benzotriazole esters, react with conjugate of a small molecule corticosteroid bearing a carbo the above types of nucleophiles to form esters, thioesters, and nyl group by using hydrazono-de-oxo-substitution. In one amides, respectively, of which amides are the most hydrolyti approach, a carbonyl group-bearing Small molecule corticos cally stable. Carbonates, including Succinimidyl, imidazolyl, teroid (Such as a ketone group-bearing corticosteroid) and a and benzotriazole carbonates, react with amino groups to hydrazine-bearing oligomer are dissolved in a suitable buffer form carbamates. Isocyanates (R-N=C=O) react with and allowed to react, thereby forming a hydrazone-containing hydroxyl or amino groups to form, respectively, carbamate linkage between the corticosteroid residue and the oligomer. (RNH C(O) OR") or urea (RNH C(O) NHR) link I0131. In still another instance, it is possible to prepare a ages. Aldehydes, ketones, glyoxals, diones and their hydrates conjugate of a small molecule corticosteroid bearing an or alcohol adducts (i.e., aldehyde hydrate, hemiacetal, acetal, amine group. In one approach, the amine group-bearing Small ketone hydrate, hemiketal, and ketal) are preferably reacted molecule corticosteroid and an aldehyde-bearing oligomer with amines, followed by reduction of the resulting imine, if are dissolved in a suitable buffer after which a suitable reduc desired, to provide an amine linkage (reductive amination). ing agent (e.g., NaCNBH) is added. Following reduction, the 0.125 Several of the electrophilic functional groups result is an amine linkage formed between the amine group of include electrophilic double bonds to which nucleophilic the amine group-containing Small molecule corticosteroid groups, such as thiols, can be added, to form, for example, and the carbonyl carbon of the aldehyde-bearing oligomer. thioether bonds. These groups include maleimides, vinyl Sul 0.132. In another approach for preparing a conjugate of a fones, vinyl pyridine, acrylates, methacrylates, and acryla Small molecule corticosteroid bearing an amine group, a car mides. Other groups comprise leaving groups that can be boxylic acid-bearing oligomer and the amine group-bearing displaced by a nucleophile; these include chloroethylsulfone, Small molecule corticosteroid are combined, typically in the pyridyl disulfides (which include a cleavable S–S bond), presence of a coupling reagent (e.g., DCC). The result is an iodoacetamide, mesylate, tosylate, thiosulfonate, and tresy amide linkage formed between the amine group of the amine late. Epoxides react by ring opening by a nucleophile, to group-containing Small molecule corticosteroid and the car form, for example, an ether or amine bond. Reactions involv bonyl of the carboxylic acid-bearing oligomer. ing complementary reactive groups such as those noted above 0.133 An exemplary conjugate of the invention is provided on the oligomer and the Small molecule are utilized to prepare below having the following structure: the conjugates of the invention. 0126. In some instances the corticosteroid may not have a functional group Suited for conjugation. In this instance, it is (Formula I-C) possible to modify (or “functionalize’) the “original corti costeroid so that it does have a functional group Suited for conjugation. For example, if the corticosteroid has an amide group, but an amine group is desired, it is possible to modify the amide group to an amine group by way of a Hofmann rearrangement, Curtius rearrangement (once the amide is converted to an azide) or Lossen rearrangement (once amide is concerted to hydroxamide followed by treatment with toly POLY-X ene-2-sulfonyl chloride/base). 0127. It is possible to prepare a conjugate of small mol ecule corticosteroid bearing a carboxyl group wherein the carboxyl group-bearing Small molecule corticosteroid is wherein: coupled to an amino-terminated oligomeric ethylene glycol, 0.134 the dashed line represents an optional double bond; to provide a conjugate having an amide group covalently I0135) R' is selected from the group consisting of halo and linking the Small molecule corticosteroid to the oligomer. alkyl; either This can be performed, for example, by combining the car 10136 R is selected from the group consisting of hydroxy boxyl group-bearing Small molecule corticosteroid with the and alkyl and R is selected from the group consisting of amino-terminated oligomeric ethylene glycol in the presence hydroxy, alkyl, —OC(O)-alkyl, and —OC(O)-cyclo, or of a coupling reagent, (such as dicyclohexylcarbodiimide or I0137 R and R combine to form a moiety selected from “DCC) in an anhydrous organic solvent. the group consisting of 0128. Further, it is possible to prepare a conjugate of a Small molecule corticosteroid bearing a hydroxyl group wherein the hydroxyl group-bearing Small molecule corticos CH3, and teroid is coupled to an oligomeric ethylene glycol halide to ----- result in an ether (-O ) linked Small molecule conjugate. wrC) vrrOX CH This can be performed, for example, by using Sodium hydride US 2010/02861 07 A1 Nov. 11, 2010 14

clearance profiles have been obtained for each tested conju -continued gate, a Suitable conjugate can be identified. 0149 Animal models (rodents and dogs) can also be used to study oral drug transport. In addition, non-in vivo methods include rodent everted gut excised tissue and Caco-2 cell monolayer tissue-culture models. These models are useful in I0138) R' is selected from the group consisting of CHs. predicting oral drug bioavailability. —CH2—OH, -CH2-halo. —S CH-halo. —CH2— 0150. To determine whether the corticosteroid or the con O C(O)-CH, —CH2—O C(O)—CH2—CH, jugate of a corticosteroid and a water-soluble non-peptidic CH PO, —CH2—O C(O)—C(CH), —CH2— polymer has activity as a corticosteroid, it is possible to test O C(O)—CH2—CH2—CH2—CH, CH C(O) Such a compound. Such methods are known to those of ordi O CH, —CH2—O C(O)—CH2—CH2—C(O)—OH: nary skill in the art and described herein. 0139 either 0151. The present invention also includes pharmaceutical 0140 Ris—Hand R is selected from the group consist preparations comprising a conjugate as provided herein in ing of —H and hydroxy, or combination with a pharmaceutical excipient. Generally, the 0141 Rand R combine to form carbonyl: conjugate itself will be in a solid form (e.g., a precipitate), 0142 R is halo: which can be combined with a suitable pharmaceutical 0143 X is a spacer moiety; and excipient that can be in either solid or liquid form. 0152 Exemplary excipients include, without limitation, 0144 POLY is a water-soluble, non-peptidic oligomer. those selected from the group consisting of carbohydrates, 0145 First, an oligomer obtained from a monodisperse or bimodal water Soluble oligomer is conjugated to the Small inorganic salts, antimicrobial agents, antioxidants, Surfac molecule drug. Preferably, the drug is orally bioavailable, and tants, buffers, acids, bases, and combinations thereof. on its own, exhibits a non-negligible blood-brain barrier 0153. A carbohydrate such as a sugar, a derivatized sugar crossing rate. Next, the ability of the conjugate to cross the Such as an alditol, aldonic acid, an esterified Sugar, and/or a blood-brain barrier is determined using an appropriate model Sugar polymer may be present as an excipient. Specific car and compared to that of the unmodified parent drug. If the bohydrate excipients include, for example: monosaccharides, results are favorable, that is to say, if, for example, the rate of Such as fructose, maltose, galactose, glucose, D-mannose, crossing is significantly reduced, then the bioactivity of con Sorbose, and the like; disaccharides, such as lactose. Sucrose, jugate is further evaluated. Preferably, the compounds trehalose, cellobiose, and the like; polysaccharides, such as according to the invention maintain a significant degree of raffinose, melezitose, maltodextrins, dextrans, starches, and bioactivity relative to the parent drug, i.e., greater than about the like; and alditols, such as mannitol, Xylitol, maltitol, lac 30% of the bioactivity of the parent drug, or even more titol, Xylitol, Sorbitol (glucitol), pyranosyl Sorbitol, myoinosi preferably, greater than about 50% of the bioactivity of the tol, and the like. parent drug. 0154 The excipient can also include an inorganic salt or 0146 The above steps are repeated one or more times buffer Such as citric acid, Sodium chloride, potassium chlo using oligomers of the same monomer type but having a ride, Sodium Sulfate, potassium nitrate, Sodium phosphate different number of subunits and the results compared. monobasic, sodium phosphate dibasic, and combinations 0147 For each conjugate whose ability to cross the blood thereof. brain barrier is reduced in comparison to the non-conjugated 0155 The preparation may also include an antimicrobial Small molecule drug, its oral bioavailability is then assessed. agent for preventing or deterring microbial growth. Nonlim Based upon these results, that is to say, based upon the com iting examples of antimicrobial agents suitable for the present parison of conjugates of oligomers of varying size to a given invention include benzalkonium chloride, benzethonium Small moleculeata given position or location within the Small chloride, benzyl alcohol, cetylpyridinium chloride, chlorobu molecule, it is possible to determine the size of the oligomer tanol, phenol, phenylethyl alcohol, phenylmercuric nitrate, most effective in providing a conjugate having an optimal thimersol, and combinations thereof. balance between reduction in biological membrane crossing, 0156 An antioxidant can be present in the preparation as oral bioavailability, and bioactivity. The small size of the well. Antioxidants are used to prevent oxidation, thereby oligomers makes such screenings feasible and allows one to preventing the deterioration of the conjugate or other compo effectively tailor the properties of the resulting conjugate. By nents of the preparation. Suitable antioxidants for use in the making Small, incremental changes in oligomer size and ulti present invention include, for example, ascorbyl palmitate, lizing an experimental design approach, one can effectively butylated hydroxyanisole, butylated hydroxytoluene, hypo identify a conjugate having a favorable balance of reduction phosphorous acid, monothioglycerol, propyl gallate, Sodium in biological membrane crossing rate, bioactivity, and oral bisulfite, sodium formaldehyde sulfoxylate, sodium met bioavailability. In some instances, attachment of an oligomer abisulfite, and combinations thereof. as described herein is effective to actually increase oral bio 0157. A surfactant may be present as an excipient. Exem availability of the drug. plary surfactants include: polysorbates, such as “Tween 20 0148 For example, one of ordinary skill in the art, using and “Tween 80, and pluronics such as F68 and F88 (both of routine experimentation, can determine a best Suited molecu which are available from BASF, Mount Olive, N.J.); sorbitan lar size and linkage for improving oral bioavailability by first esters; lipids, such as phospholipids such as lecithin and other preparing a series of oligomers with different weights and phosphatidylcholines, phosphatidylethanolamines (although functional groups and then obtaining the necessary clearance preferably not in liposomal form), fatty acids and fatty esters; profiles by administering the conjugates to a patient and tak steroids, such as cholesterol; and chelating agents, such as ing periodic blood and/or urine sampling. Once a series of EDTA, Zinc and other such suitable cations. US 2010/02861 07 A1 Nov. 11, 2010

0158 Pharmaceutically acceptable acids or bases may be conjugates described herein. In addition to the conjugate, the present as an excipient in the preparation. Nonlimiting tablets and caplets will generally contain inactive, pharma examples of acids that can be used include those acids ceutically acceptable carrier materials such as binders, lubri selected from the group consisting of hydrochloric acid, ace cants, disintegrants, fillers, stabilizers, Surfactants, coloring tic acid, phosphoric acid, citric acid, malic acid, lactic acid, agents, flow agents, and the like. Binders are used to impart formic acid, trichloroacetic acid, nitric acid, perchloric acid, cohesive qualities to a tablet, and thus ensure that the tablet phosphoric acid, Sulfuric acid, fumaric acid, and combina remains intact. Suitable binder materials include, but are not tions thereof. Examples of suitable bases include, without limited to, starch (including corn starch and pregelatinized limitation, bases selected from the group consisting of starch), gelatin, Sugars (including Sucrose, glucose, dextrose Sodium hydroxide, Sodium acetate, ammonium hydroxide, and lactose), polyethylene glycol, waxes, and natural and potassium hydroxide, ammonium acetate, potassium acetate, Synthetic gums, e.g., acacia Sodium alginate, polyvinylpyr Sodium phosphate, potassium phosphate, sodium citrate, rolidone, cellulosic polymers (including hydroxypropyl cel Sodium formate, sodium Sulfate, potassium Sulfate, potas lulose, hydroxypropyl methylcellulose, methyl cellulose, sium fumerate, and combinations thereof. microcrystalline cellulose, ethyl cellulose, hydroxyethyl cel 0159. The amount of the conjugate in the composition will lulose, and the like), and Veegum. Lubricants are used to vary depending on a number of factors, but will optimally be facilitate tablet manufacture, promoting powderflow and pre a therapeutically effective dose when the composition is venting particle capping (i.e., particle breakage) when pres stored in a unit dose container. A therapeutically effective Sure is relieved. Useful lubricants are magnesium Stearate, dose can be determined experimentally by repeated adminis calcium Stearate, and Stearic acid. Disintegrants are used to tration of increasing amounts of the conjugate in order to facilitate disintegration of the tablet, and are generally determine which amount produces a clinically desired end starches, clays, celluloses, algins, gums, or crosslinked poly point. mers. Fillers include, for example, materials such as silicon 0160 The amount of any individual excipient in the com dioxide, titanium dioxide, alumina, talc, kaolin, powdered position will vary depending on the activity of the excipient cellulose, and microcrystalline cellulose, as well as soluble and particular needs of the composition. Typically, the opti materials such as mannitol, urea, Sucrose, lactose, dextrose, mal amount of any individual excipient is determined through sodium chloride, and sorbitol. Stabilizers, as well known in routine experimentation, i.e., by preparing compositions con the art, are used to inhibit or retard drug decomposition reac taining varying amounts of the excipient (ranging from low to tions that include, by way of example, oxidative reactions. high), examining the stability and other parameters, and then (0166 Capsules are also preferred oral dosage forms, in determining the range at which optimal performance is which case the conjugate-containing composition can be attained with no significant adverse effects. encapsulated in the form of a liquid or gel (e.g., in the case of 0161 Generally, however, excipients will be present in the a gel cap) or Solid (including particulates Such as granules, composition in an amount of about 1% to about 99% by beads, powders or pellets). Suitable capsules include hard and weight, preferably from about 5%-98% by weight, more pref Soft capsules, and are generally made of gelatin, starch, or a erably from about 15-95% by weight of the excipient, with cellulosic material. Two-piece hard gelatin capsules are pref concentrations less than 30% by weight most preferred. erably sealed, such as with gelatin bands or the like. 0162 These foregoing pharmaceutical excipients along 0.167 Included are parenteral formulations in the substan with other excipients and general teachings regarding phar tially dry form (typically as a lyophilizate or precipitate, maceutical compositions are described in "Remington: The which can be in the form of a powder or cake), as well as Science & Practice of Pharmacy”, 19' ed., Williams & Wil formulations prepared for injection, which are typically liq liams, (1995), the “Physician's Desk Reference', 52" ed., uid and requires the step of reconstituting the dry form of Medical Economics, Montvale, N.J. (1998), and Kibbe, A. parenteral formulation. Examples of suitable diluents for H., Handbook of Pharmaceutical Excipients, 3" Edition, reconstituting Solid compositions prior to injection include American Pharmaceutical Association, Washington, D.C., bacteriostatic water for injection, dextrose 5% in water, phos 2OOO. phate-buffered saline, Ringer's Solution, Saline, Sterile water, 0163 The pharmaceutical compositions can take any deionized water, and combinations thereof. number of forms and the invention is not limited in this 0.168. In some cases, compositions intended for parenteral regard. Exemplary preparations are most preferably in a form administration can take the form of nonaqueous Solutions, Suitable for oral administration Such as a tablet, caplet, cap Suspensions, or emulsions, each typically being sterile. Sule, gel cap, troche, dispersion, Suspension, Solution, elixir, Examples of nonaqueous solvents or vehicles are propylene syrup, lozenge, transdermal patch, spray, Suppository, and glycol, polyethylene glycol, vegetable oils, such as olive oil powder. and corn oil, gelatin, and injectable organic esters such as 0164 Oral dosage forms are preferred for those conju ethyl oleate. gates that are orally active, and include tablets, caplets, cap 0169. The parenteral formulations described herein can Sules, gel caps, Suspensions, Solutions, elixirs, and syrups, also contain adjuvants such as preserving, wetting, emulsify and can also comprise a plurality of granules, beads, powders ing, and dispersing agents. The formulations are rendered orpellets that are optionally encapsulated. Such dosage forms sterile by incorporation of a sterilizing agent, filtration are prepared using conventional methods known to those in through a bacteria-retaining filter, irradiation, or heat. the field of pharmaceutical formulation and described in the 0170 The conjugate can also be administered through the pertinent texts. skin using conventional transdermal patch or other transder 0.165 Tablets and caplets, for example, can be manufac mal delivery system, wherein the conjugate is contained tured using standard tablet processing procedures and equip within a laminated structure that serves as a drug delivery ment. Direct compression and granulation techniques are pre device to be affixed to the skin. In such a structure, the con ferred when preparing tablets or caplets containing the jugate is contained in a layer, or “reservoir, underlying an US 2010/02861 07 A1 Nov. 11, 2010

upper backing layer. The laminated structure can contain a lism may beachieved relative to the parent drug. Such a result single reservoir, or it can contain multiple reservoirs. is advantageous for many orally administered drugs that are 0171 The conjugate can also be formulated into a Sup Substantially metabolized by passage through the gut. In this pository for rectal administration. With respect to supposito way, clearance of the conjugate can be modulated by select ries, the conjugate is mixed with a Suppository base material ing the oligomer molecular size, linkage, and position of which is (e.g., an excipient that remains solid at room tem covalent attachment providing the desired clearance proper perature but softens, melts or dissolves at body temperature) ties. One of ordinary skill in the art can determine the ideal Such as coca butter (theobroma oil), polyethylene glycols, molecular size of the oligomer based upon the teachings glycerinated gelatin, fatty acids, and combinations thereof. herein. Preferred reductions in first pass metabolism for a Suppositories can be prepared by, for example, performing conjugate as compared to the corresponding nonconjugated the following steps (not necessarily in the order presented): small drug molecule include : at least about 10%, at least melting the Suppository base material to form a melt, incor about 20%, at least about 30; at least about 40; at least about porating the conjugate (either before or after melting of the 50%; at least about 60%, at least about 70%, at least about Suppository base material); pouring the melt into a mold; 80% and at least about 90%. cooling the melt (e.g., placing the melt-containing mold in a 0177 Thus, the invention provides a method for reducing room temperature environment) to thereby form Supposito the metabolism of an active agent. The method comprises the ries; and removing the Suppositories from the mold. steps of providing monodisperse or bimodal conjugates, 0172. The invention also provides a method for adminis each conjugate comprised of a moiety derived from a small tering a conjugate as provided herein to a patient Suffering molecule drug covalently attached by a stable linkage to a from a condition that is responsive to treatment with the water-soluble oligomer, wherein said conjugate exhibits a conjugate. The method comprises administering, generally reduced rate of metabolism as compared to the rate of orally, a therapeutically effective amount of the conjugate metabolism of the small molecule drug not attached to the (preferably provided as part of a pharmaceutical preparation). water-soluble oligomer, and administering the conjugate to a Other modes of administration are also contemplated, such as patient. Typically, administration is carried out via one type of pulmonary, nasal, buccal, rectal, Sublingual, transdermal, and administration selected from the group consisting of oral parenteral. As used herein, the term “parenteral' includes administration, transdermal administration, buccal adminis Subcutaneous, intravenous, intra-arterial, intraperitoneal, int tration, transmucosal administration, vaginal administration, racardiac, intrathecal, and intramuscular injection, as well as rectal administration, parenteral administration, and pulmo infusion injections. nary administration. 0173. In instances where parenteral administration is uti 0.178 Although useful in reducing many types of metabo lized, it may be necessary to employ somewhat bigger oligo lism (including both Phase I and Phase II metabolism) can be mers than those described previously, with molecular weights reduced, the conjugates are particularly useful when the Small ranging from about 500 to 30K Daltons (e.g., having molecu molecule drug is metabolized by a hepatic enzyme (e.g., one lar weights of about 500, 1000, 2000, 2500,3000, 5000, 7500, or more of the cytochrome P450 isoforms) and/or by one or 10000, 15000, 20000, 25000, 30000 or even more). more intestinal enzymes. 0.174. The method of administering may be used to treat 0179 All articles, books, patents, patent publications and any condition that can be remedied or prevented by adminis other publications referenced herein are incorporated by ref tration of the particular conjugate. Those of ordinary skill in erence in their entireties. the art appreciate which conditions a specific conjugate can effectively treat. The actual dose to be administered will vary EXPERIMENTAL depend upon the age, weight, and general condition of the subject as well as the severity of the condition being treated, 0180. It is to be understood that while the invention has the judgment of the health care professional, and conjugate been described in conjunction with certain preferred and spe being administered. Therapeutically effective amounts are cific embodiments, the foregoing description as well as the known to those skilled in the art and/or are described in the examples that follow are intended to illustrate and not limit pertinent reference texts and literature. Generally, a therapeu the scope of the invention. Other aspects, advantages and tically effective amount will range from about 0.001 mg to modifications within the scope of the invention will be appar 1000 mg, preferably in doses from 0.01 mg/day to 750 ent to those skilled in the art to which the invention pertains. mg/day, and more preferably in doses from 0.10 mg/day to 0181 All chemical reagents referred to in the appended 500 mg/day. examples are commercially available unless otherwise indi 0175. The unit dosage of any given conjugate (again, pref cated. The preparation of PEG-mers is described in, for erably provided as part of a pharmaceutical preparation) can example, U.S. Patent Application Publication No. 2005/ be administered in a variety of dosing schedules depending on O136O31. the judgment of the clinician, needs of the patient, and so (0182 All'HNMR (nuclear magnetic resonance) data was forth. The specific dosing schedule will be known by those of generated by an NMR spectrometer manufactured by Bruker. ordinary skill in the art or can be determined experimentally A list of certain compounds as well as the source of the using routine methods. Exemplary dosing schedules include, compounds is provided below. without limitation, administration five times a day, four times a day, three times a day, twice daily, once daily, three times EXAMPLE 1. weekly, twice weekly, once weekly, twice monthly, once Preparation of Hydrazine-Bearing Oligomers monthly, and any combination thereof. Once the clinical end point has been achieved, dosing of the composition is halted. 0183 Hydrazine-bearing oligomers (a type of oligomeric 0176 One advantage of administering the conjugates of reagent) were prepared following the schematic provided the present invention is that a reduction in first pass metabo below. US 2010/02861 07 A1 Nov. 11, 2010 17

0187. The corticosteroid, cortisone, (1.0 mmol) and a hydrazine-bearing oligomer prepared in accordance with Example 1 (1.5 mmol) were dissolved in 10 ml CH-OH to form a solution. To the solution, 5 drops of acetic acid were os-()-ox added. The reaction mixture was stirred overnight at room CH-(OCH2CH)-OH O temperature. DCM (150 ml) was added into the mixture. The DCM phase was washed with 1% NaCO and then with water (150 mlx2). After dried and removing the solvent, the al-on-S-O- crude product was purified by silicon gel column (DCM: O MeOH, 20:1). The products were obtained as solid or sticky ls t-BocNHNH oil (yield: -70-90%, purity: 92-99%). CH3-(OCH2CH2)-O O NO —- 0188 To conjugate dexamethasone, the same process is generally followed except that dexamethasone is used in place of cortisone and the reaction is run at reflux in methanol for three days. CH-(OCH2CH)-O ul NHNH 0189 Using this approach, hydrazine-bearing oligomeric reagents wherein in was 3 was made for hydrocortisone 0184 CH (OCHCH), OH (1.0 mmol) and DMAP (“mPEG-Hydrocortisone') and dexamethasone (“mPEG (1.5 mmol) were dissolved in 20 ml DCM to form a solution. Dexamethasone’), wherein in was 7 was made for hydrocor To the solution, 4-nitrophenyl chloformate (1.0 mmol) was tisone (“mPEG7-Hydrocortisone'), cortisone (“mPEG-Cor added. The reaction mixture was stirred overnight at room tisone') and dexamethasone (“mPEG,-Dexamethasone’), temperature.t-Butyl carbazate (2.0 mmol) was added into the and whereinn was 8 was made for hydrocortisone (“mPEGs mixture which was then stirred for additional 24 hours at Hydrocortisone'), cortisone (“mPEGs-Cortisone') and dex room temperature. DCM (150 ml) was added into the mixture amethasone (“mPEGs-Dexamethasone'). and the DCM phase was washed with water (150 mlx2) and then dried. The crude product was deprotected by DCM/TFA (2:1). The solvent and TFA were removed, and the residue EXAMPLE 3 was dissolved in 200 ml DCM, which was washed with 5% Hydrolysis Testing Na2CO and water. After removing solvent and drying, the product (a hydrazine-bearing oligomer reagent) was obtained (0190 mPEG-Cortisone prepared in accordance with as an oil, which could be used in a coupling reaction. Example 2 (n in the oligomer equal to seven) were tested for 0185. Using this approach, hydrazine-bearing oligomeric hydrolysis at pH 5.5 and 7.4. The drug was stable and the reagents wherein n is 3, 7 and 8 were made. conjugate was able to release cortisone clearly at pH 5.5. The cortisone release from the compound at pH 7.4 is much EXAMPLE 2 slower than that at pH 5.5. However, many decomposed Coupling Reaction impurities from cortisone were observed with extended time 0186. Using hydrazine-bearing oligomers prepared in at pH 7.4. Hydrocortisone is much more stable than cortisone accordance with Example 1, conjugates were prepared fol in PBS buffer at pH 7.4. lowing the schematic below. 0191) A graph of the results is provided below.

HO O

OH ul NHNH CH-(OCH2CH)-O

Cortisone

CH-(OCH2CH)-O US 2010/0286 107 A1 Nov. 11, 2010 18 Drug release from mPEG-7-cortisone PBS buffer, pH 5.5 and 7.4, 37 C

0.7 0.6 0.5 0.4 0.3 0.2 0.1

O 100 200 300 400 Time (h) US 2010/02861 07 A1 Nov. 11, 2010

EXAMPLE 4 9. The compound of claim 8, wherein the corticosteroid residue is covalently attached at A-ring atom positions of the Glucocorticoid Binding Assay corticosteroid residue to the water-soluble, non-peptidic oli gomer. 0.192 The assay was used to determine whether the tested compounds bound to the glucocorticoid binding site and is 10. The compound of claim 1, wherein the corticosteroid based on procedures set forth in the literature. See, for residue is covalently attached at the 3 position of the corti example, Da Han et al. (1994) Neurochem. Int. 24:339-348. costeroid residue to the water-soluble, non-peptidic oligomer. Briefly, using competitive binding of with the radioligand 11. The compound of claim 1, having the following struc “I6,7-H1triamcinolone acetonide” (30-50 Cl/mmol), reac ture: tions were carried out in 50 mM. KHPO (pH 7.4) containing 10 mM sodium molybdate and 10 mM.C.-monothioglycerolat

0° C. for 16 hours. The glucocorticoid receptors were (Formula I-C) obtained from rat brains. The reactions were terminated by rapid vacuum filtration onto glass fiber filters. Radioactively trapped onto the filters is determined and compared to control values. The ICso value, or the half maximal inhibitory con centration, represents the concentration of a test compound that is required for 50% displacement of the radioligand from the receptor. A higher ICs value reflects a weaker binding affinity. The ICso values for several compounds prepared in POLY-X accordance with Example 3 as well as some oligomer-free corticosteroids are presented in Table 1.

TABLE 1. wherein: ICso Values for Tested Compounds the dashed line represents an optional double bond; Drug ICso (M) R" is selected from the group consisting of halo and alkyl; either Triamcinolone Acetonide 1.21 x 10' Cortisone 3.89 x 10 R is selected from the group consisting of hydroxy and mPEG7-Cortisone 3.44 x 10 alkyl and R is selected from the group consisting of Hydrocortisone 3.62 x 10 mPEG7-Hydrocortisone 3.93 x 10 hydroxy, alkyl, —OC(O)-alkyl, and—OC(O)-cyclo, Dexamethasone 150 x 109 O mPEG7-Dexamethasone 7.93 x 107 R° and R combine to fauna moiety selected from the group consisting of

1. A compound comprising a corticosteroid residue CH3, and covalently attached via a linkage to a water-soluble, non peptidic oligomer. -----vvvrO X 2. The compound of claim 1, wherein the linkage is a stable linkage. 3. The compound of claim 1, wherein the linkage is a degradable linkage. 4. The compound of claim 1, wherein the linkage is a R" is selected from the group consisting of —CHs. hydrazone linkage. —CH2—OH, -CH2-halo. —S-CH-halo. —CH2— 5. The compound of claim 1, wherein the weight average O C(O) CH, CH O—C(O)—CH2—CH, molecular weight of the water-soluble, non-peptidic oligomer —CH PO, —CH, O C(O)—C(CH), is less than 400 Daltons. 6. The compound of claim 1, wherein the corticosteroid residue is covalently attached at a position other than through the 16 or 17 positions of the corticosteroid residue to the either water-soluble, non-peptidic oligomer. Ris—Hand R is selected from the group consisting of 7. The compound of claim 1, wherein the corticosteroid —H and hydroxy, or residue is covalently attached at a position other than through Rand R' combine to form carbonyl: D-ring atom positions of the corticosteroid residue to the water-soluble, non-peptidic oligomer. R’ is halo: 8. The compound of claim 1, wherein the corticosteroid X is a spacer moiety; and residue is covalently attached at a position selected from the POLY is a water-soluble, non-peptidic oligomer. consisting of A-ring atom positions, B-ring atom positions, 12. The compound of claim 1, wherein the corticosteroid and C-ring atom positions of the corticosteroid residue to the residue is a residue of a corticosteroid having the following water-soluble, non-peptidic oligomer. Structure: US 2010/02861 07 A1 Nov. 11, 2010 20

13. The compound of claim 1, wherein the corticosteroid is (Formula I) a residue of a corticosteroid selected from the group consist ing of desoxycorticosone, hydrocortisone, cortisone, methyl prednisolone, prednisone, prednisolone, triamcinolone, dex amethasone, betamethasone, beclomethasone, beclomethasone-17,21-dipropionate, budesonide, flunisolide, fludrocortisone, mometasone, fluticaSone, alclometaSone, clocortolone, flurandrenolide, fluocinonide, hydrocortisone acetate, fluorometholone, fluocinolone acetonide, diflucortolone Valerate, paramethasone acetate, halcinonide, hydrocortisone phosphate, clobetaSone butyrate, amcinonide, and prednisolone Succinate. 14. The compound of claim 1, wherein the water-soluble, wherein: non-peptidic oligomer is a poly(alkylene oxide). the dashed line independently represents an optional 15. The compound of claim 14, wherein the poly(alkylene double bond; oxide) is a poly(ethylene oxide). R" is selected from the group consisting of halo and alkyl: 16. The compound of claim 14, wherein the water-soluble, either non-peptidic oligomer has a number of repeating monomers R is selected from the group consisting of hydroxy and in the range of from 1 to 30. alkyl and R is selected from the group consisting of 17. The compound of claim 14, wherein the water-soluble, hydroxy, alkyl, —OC(O)-alkyl, and —OC(O)-cyclo, non-peptidic oligomer has a number of repeating monomers O in the range of from 1 to 10. R° and R combine to form a moiety selected from the 18. The compound of claim 14, wherein the poly(alkylene group consisting of oxide) includes an alkoxy or hydroxy end-capping moiety. 19. The compound of claim 1, wherein the linkage is an ether linkage. ris-t and 20. The compound of claim 1, wherein the linkage is an vvurO CH ester linkage. 21. A composition comprising a compound comprising (1) a corticosteroid residue covalently attached via a linkage to a water-soluble, non-peptidic oligomer, and (ii) optionally, a pharmaceutically acceptable excipient. R" is selected from the group consisting of —CHs. 22. A composition of matter comprising a compound com —CH2—OH, -CH2-halo. —S-CH-halo. —CH2— prising a corticosteroid residue covalently attached via a link O C(O) CH, —CH2—O C(O)—CH2—CH, age to a water-soluble, non-peptidic oligomer, wherein the —CH2—PO, —CH2—O—C(O)—C(CH), compound is present in a dosage form. CH, O C(O)—CH, CH, CH, CH, 23. A method comprising covalently attaching a water —CH2—C(O)—O CH, —CH2—O—C(O)— soluble, non-peptidic oligomer to a corticosteroid. CH-CH C(O) OH: 24. A method comprising administering to a Subject a either compound comprising a corticosteroid residue covalently Ris-HandR is selected from the group consisting of attached via a linkage to a water-soluble, non-peptidic —H and hydroxy, or oligomer. RandR combine to form carbonyl; and R7 is halo.