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(12) Patent Application Publication (10) Pub. No.: US 2010/0056488 A1 Teicher Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2010/0056488 A1 Teicher Et Al US 2010.0056488A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0056488 A1 Teicher et al. (43) Pub. Date: Mar. 4, 2010 (54) CORTICOSTEROD CONUGATES AND USES Publication Classification THEREOF (51) Int. Cl. (75) Inventors: Martin H. Teicher, Rye, NH (US); A6II 3/56 (2006.01) Susan L. Andersen-Navalta, C073/00 (2006.01) C07J 53/00 (2006.01) Medfield, MA (US) C07K I4/00 (2006.01) Correspondence Address: C07. 4I/00 (2006.01) CLARK & ELBNG LLP C08F 290/4 (2006.01) 101 FEDERAL STREET C07K 2/00 (2006.01) BOSTON, MA 02110 (US) COSB 37/00 (2006.01) C08G 69/48 (2006.01) (73) Assignee: The McLean Hospital A6IP37/06 (2006.01) Corporation, Belmont, MA (US) A6IP 29/00 (2006.01) (52) U.S. Cl. ......... 514/177: 552/611; 552/514; 530/395; (21) Appl. No.: 12/612,273 536/5: 525/50, 530/300; 536/55.1: 525/419 (22) Filed: Nov. 4, 2009 (57) ABSTRACT The invention features corticosteroids conjugated to either a Related U.S. Application Data charged group or a bulky group in a manner that resists in vivo Continuation of application No. 10/646,063, filed on cleavage, the resulting conjugate is a peripherally acting Ste (63) roid with reduced activity in the central nervous system. The Aug. 22, 2003, now abandoned. invention provides a method for treating a patient having an (60) Provisional application No. 60/405,688, filed on Aug. inflammatory disease by administering to the patient a corti 23, 2002. costeroid conjugate. US 2010/0056488 A1 Mar. 4, 2010 CORTICOSTEROD CONUGATES AND USES 25:643-50 (1983)). Hydrocortisone sodium succinate is also THEREOF CNS active (see Kasperlik-Zaluska et al., Horm. Metab. Res., 12:676-9 (1980) and Posener et al., Psychoneuroendocrinol CROSS-REFERENCE TO RELATED ogy, 22:169-76 (1997)). Because these compounds are APPLICATIONS designed to be rapidly cleaved in Vivo, producing their par ents dexamethasone and hydrocortisone, respectively, no 0001. This application is a Continuation of U.S. Utility application Ser. No. 10/646,063, filed Aug. 22, 2003, which reduction in CNS activity is achieved. claims benefit of U.S. Provisional Application No. 60/405, 688, filed Aug. 23, 2002, each of which is incorporated herein SUMMARY OF THE INVENTION by reference. 0008 We have discovered that when a corticosteroid is conjugated to either a charged group or a bulky group in a BACKGROUND OF THE INVENTION manner that resists in vivo cleavage, the resulting conjugate is a peripherally acting steroid with reduced activity in the cen 0002. The invention relates to the field of corticosteroids. tral nervous system. The invention provides structurally 0003. The mineralocorticoid, aldosterone, and the gluco modified corticosteroids with altered biodistributions, corticoids, cortisol and corticosterone, are produced in the thereby reducing the occurrence of adverse reactions associ adrenal cortex. These steroids act by binding to receptors ated with this class of drug. which then act to modulate gene transcription in target tis 0009. The invention features a corticosteroid conjugate SUS. comprising a corticosteroid covalently attached via a linkerto 0004 Corticosteroids are used to treat swelling, redness, a bulky group of greater than 400 daltons or a charged group itching, allergic reactions, and a wide range of conditions of less than 400 daltons. The corticosteroid conjugate has including: allergic rhinitis, ankylosing spondylitis, asthma, anti-inflammatory activity in vivo and reduced activity in the atopic dermatitis, autoimmune disorders, bursitis, Crohn's central nervous system in comparison to the parent corticos disease, congenital adrenal hyperplasia, contact dermatitis, teroid. dermatological disorders, drug hypersensitivity reactions, endocrine disorders, hypercalcemia associated with cancer, 0010. The corticosteroid conjugate is further described by iritis and iridocyclitis, nonsuppurative thyroiditis; primary or formula I: secondary adrenocortical insufficiency, psoriatic and rheu matoid arthritis, tendinitis and non-specific tenosynovitis, and ulcerative colitis. 0005. The brain is well protected from outside influences by the blood-brain barrier, which prevents the free entry of many circulating molecules, cells or micro-organisms into the brain interstitial space. However, this is not true for cor ticosteroids, which penetrate the blood-brain barrier. Thus, in the treatment of peripheral disorders (e.g., asthma or arthri tis), the brain is exposed to the corticosteroid without any therapeutic benefit and with the possibility of severe adverse effects. These adverse effects, which are described in the PDR, include: insomnia, euphoria, mood changes, nervous ness, personality changes, depression, severe nausea, head aches, and convulsions. 0011 Informula I, the bond between C and C is a double 0006 Even topical and ocular administration of corticos or a single bond; X, represents H or a halogen atom: X teroids can enter the systemic circulation, cross the blood represents H, CH, or a halogen atom; X represents H or a brain-barrier, and effect the regulation of the hypothalamic halogen atom; R represents =O or OH: R represents CH, pituitary-adrenal axis (see, for example, Krupin et al., Arch SCHF, CHC1, CHG, CHOH, CHO P(O)(O), Opthalmol, 94:919-20 (1976) and Meredig et al., Klin CHO-acyl, CHNHG, CHSG', or CHOG'; R and R. MonatsblAugenheilkd, 176:907-10 (1980)). Thus, even topi each independently represent H. Co alkyl, -OH, -O- cal administration of corticosteroids for the treatment of acyl, —OR, or R and R combine to form a cyclic acetal chronic conditions can have untoward CNS effects. described by formula II: 0007 21-phosphate and 21-succinate esters of corticoster oids, which are clinically well known, are modified by inclu sion of a charged moiety to render them soluble in aqueous II Solutions for intravenous injection. Both 21-phosphate and O 21-succinate esters of corticosteroids are rapidly hydrolyzed X (CRR)-W1 in the bloodstream to produce the free steroid (see, for R example, Miyabo et al., Eur. Clin. Pharmacol. 20:277-82 O 5 (1981)). These modifications do not reduce CNS activity. For example, dexamethasone sodium phosphate is CNS active, producing Suppression of cortisol production or ACTH (see, where n is a whole integer from 0 to 6: Rs. R and R, each Abou Samra et al., J. Clin. Endocrinol. Metab., 6 1:116-9 independently represent H or Co alkyl; W represents H. (1985), Kemppainen R. J., and Sartin J. L., Am. J. Vet. Res., CH, G', NRG', OG, SG, NH NH-G', C(O)-G', or 45.742-6 (1984), Linquette et al., Pathol. Biol. (Paris), C(S)-G'; Rs is H. Clio alkyl or Cso aryl; and G' is a bond 28:85-9 (1980), and Petersen et al., Fur. J. Clin. Pharmacol., between the corticosteroid and the linker. US 2010/0056488 A1 Mar. 4, 2010 0012 Desirably, linker L is described by formula III: 0018. The invention features a pharmaceutical composi G'-(Z)-(Y), (Z), (Rio)—(Z), (Y)' (Z) tion that includes an effective amount of a corticosteroid P-G2 III conjugate described herein in any pharmaceutically accept 0013 Informula III, G' is a bond between the corticoster able form, along with a pharmaceutically acceptable carrier oid and the linker, G is a bond between the linker and the or diluent. bulky group or between the linker and the charged group, 0019. By “Clio alkyl is meant a branched or unbranched each of Z', Z, Z, and Z' is, independently, selected from O, saturated hydrocarbon group, having 1 to 10 carbon atoms, S, and NR; R is hydrogen or a Co alkyl group; each of inclusive. An alkyl may optionally include monocyclic, bicy Y' and Y is, independently, selected from carbonyl, thiocar clic, or tricyclic rings, in which each ring desirably has three bonyl, Sulphonyl, phosphoryl or similar acid-forming groups; to six members. The alkyl group may be substituted or unsub o, p, s, t, u, and V are each independently 0 or 1; and Ro is a stituted. Exemplary Substituents include alkoxy, aryloxy, Co alkyl, a linear or branched heteroalkyl of 1 to 10 atoms, Sulfhydryl, alkylthio, arylthio, halogen, hydroxyl, fluoro a Coalkene, a Co alkyne, a Cso aryl, a cyclic System of alkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, 3 to 10 atoms, -(CH2CH2O). CHCH in which q is an quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl integer of 1 to 4, or a chemical bond linking G'-(Z"). (Y') groups. —(Z)- tO —(Z), (Y), (Z)-G. 0020. By “Clio alkene' is meant a branched or 0014. The bulky group can be a naturally occurring poly unbranched hydrocarbon group containing one or more mer or a synthetic polymer. Examples of natural polymers double bonds, desirably having from 2 to 10 carbon atoms. A that can be used include, without limitation, glycoproteins, Coalkene may optionally include monocyclic, bicyclic, or polypeptides, or polysaccharides. Desirably, when the bulky tricyclic rings, in which each ring desirably has five or six group includes a natural polymer, the natural polymer is members. The Coalkene group may be substituted or selected from alpha-1-acid glycoprotein and hyaluronic acid. unsubstituted. Exemplary Substituents include alkoxy, ary Examples of synthetic polymers that can be used as bulky loxy, Sulfhydryl, alkylthio, arylthio, halogen, hydroxyl, fluo groups include, without limitation, polyethylene glycol, and roalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted the synthetic polypetide N-hxg. The bulky group may also amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and include another corticosteroid. carboxyl groups. 0015 The charged group can be a cation or an anion. Desirably, the charged group is a polyanion including at least 0021. By “Co alkyne” is meant a branched or three negatively charged moieties or a cation having at least unbranched hydrocarbon group containing one or more triple one positively charged moiety. bonds, desirably having from 2 to 10 carbon atoms. A Co 0016. The corticosteroid conjugates of the invention may alkyne may optionally include monocyclic, bicyclic, or tricy be used to treat inflammatory conditions, including condi clic rings, in which each ring desirably has five or six mem tions resulting from an immune response in a mammal.
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