(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 10 April 2008 (10.04.2008) WO 2008/043075 A2 (51) International Patent Classification: Not classified AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY,BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, (21) International Application Number: ES, FT, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, PCT/US2007/080600 IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY,MA, MD, ME, MG, MK, MN, MW, (22) International Filing Date: 5 October 2007 (05.10.2007) MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, (25) Filing Language: English PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, (26) Publication Language: English ZM, ZW (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 60/849,580 5 October 2006 (05.10.2006) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (71) Applicant (for all designated States except US): WYETH ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), [US/US] ; Five Giralda Farms, Madison, New Jersey 07940 European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, (US). FR, GB, GR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, (72) Inventors; and GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (75) Inventors/Applicants (for US only): BEDARD, Patricia, W. [US/US]; 30 Hill Street, Foxboro, Massachusetts 02035 Declarations under Rule 4.17: (US). SCHAUB, Robert, G. [US/US]; 118 Jeremy Hill — as to applicant's entitlement to applyfor and be granted a Road, Pelham, New Hampshire 03076 (US). patent (Rule 4.17(U)) (74) Agent: HERMAN, Michael; Wyeth, Patent Law Depart — as to the applicant's entitlement to claim the priority of the ment, Five Giralda Farms, Madison, New Jersey 07076 earlier application (Rule 4.17(Ui)) (US). Published: (81) Designated States (unless otherwise indicated, for every — without international search report and to be republished kind of national protection available): AE, AG, AL, AM, upon receipt of that report (54) Title: METHODS AND COMPOSITIONS FOR TREATMENT OF SCLERITIS AND RELATED DISORDERS (57) Abstract: The present teachings relate to the field of anti-inflammatory substances and more particularly to compounds that are useful for the treatment of scleritis, a scleritis symptom, or a scleritis-related disorder. In one aspect, methods of treating scleri- tis, a scleritis symptom, or a scleritis-related disorder generally include administering to a subject a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein W1, W2, Ri, L, X, Y, Z, and n are defined as described herein. METHODS AND COMPOSITIONS FOR TREATMENT OF SCLERITIS AND RELATED DISORDERS BACKGROUND OF THE INVENTION The present teachings relate to methods and compositions for treatment of scleritis, scleritis symptoms, or a scleritis-related disorder. During the initial phase of vascular inflammation, leukocytes and platelets in flowing blood decrease velocity by adhering to the vascular endothelium and by exhibiting rolling behavior. This molecular tethering event is mediated by specific binding of a family of calcium dependent or "C-type" lectins, known as selectins, to ligands on the surface of leukocytes. Three human selectin proteins have been identified, including P-selectin (formerly known as PADGEM or GMP-140), E-selectin (formerly known as ELAM-1), and L-selectin (formerly known as LAM-1). E-selectin expression is induced on endothelial cells by proinflammatory cytokines via its transcriptional activation. L- selectin is constitutively expressed on leukocytes and appears to play a key role in lymphocyte homing. P-selectin is stored in the alpha granules of platelets and the Weibel-Palade bodies of endothelial cells and therefore can be rapidly expressed on the surface of these cell types in response to proinflammatory stimuli. Several diseases and disorders can cause the deleterious triggering of selectin-mediated cellular adhesion. Scleritis is believed to be one such disorder. Scleritis is an inflammation of the sclera, which is the white outer wall of the eye that forms the white of an eye. Scleritis often causes red or pink eye, tears, pain and sensitivity of the eye, and blurred vision. Left untreated, scleritis is a vision- threatening condition that can lead to permanent visual impairment. Although the specific cause of scleritis is unknown, autoimmunity disorders are believed to be the most common cause. To treat the inflammation, patients suffering from scleritis often are given nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen or steroidal compounds, for example, cortisone-related drugs. These drugs have unwanted side effects particularly when multiple doses are administered over time. However, because the adhesion of leukocytes to the vascular endothelium is a step in developing an inflammatory response, interfering with the selectin-mediated cell adhesion process can provide a new type of treatment for conditions such as scleritis or scleπtis-related disorders (See Sangwan, V.S et al Arch Ophthalmol 116. 1476-1480 (1998)) Accordingly, there is a continuing need for new compounds that can be used to treat scleritis, scleritis symptoms, and/or scleπtis-related disorders SUMMARY OF THE INVENTION The present teachings provide compounds and methods for treating scleritis scleritis symptoms, and/or scleritis-related disorders In one aspect, the present teachings provide compounds useful in the methods, where the compounds have the Formula I I or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein R1, L X Y, Z, W1, W2, and n are as defined herein In various embodiments, the compounds have the Formula II, III or IV, including their pharmaceutically acceptable salts, hydrates and esters Also provided in accordance with the present teachings are pharmaceutical compositions for treating scleritis, scleritis symptoms, and/or scleπtis- related disorders, the pharmaceutical composition comprising a therapeutically effective amount of a compound of the present teachings, and a pharmaceutically acceptable carrier or excipient The present teachings also provide methods for using the compounds disclosed herein In some embodiments, the present teachings provide methods of treating scleritis, a scleritis symptom or a scleritis-related disorder, where the method generally comprises administering to a subject a therapeutically effective amount of a compound of the present teachings. In certain embodiments, the subject is a mammal, for example, a human. Additionally, the present teachings provide for a method for reducing and/or preventing leukocyte adhesion to the vascular endothelium. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph depicting leukocyte rolling flux (measured in rolling cells per minute) in cremaster postcapillary venules in C57 black/6J mice after oral dosing with vehicle, neutralizing anti-mouse P-selectin (CD62P) antibody or Compound 1 at dosages of 10 and 50 mg/kg. Figure 2 is a graph depicting leukocyte rolling flux (measured in rolling cells per minute) in cremaster postcapillary venules in Sprague-Dawley rats after oral dosing with vehicle, neutralizing anti-rat PSGL-1 antibody or Compound 1 at dosages of 30 and 50 mg/kg. DETAILED DESCRIPTION The present teachings provide methods and compounds for treating scleritis, a scleritis symptom, and/or a scleritis-related disorder. Without wishing to be bound to any particular theory, it is believed that interfering or preventing selectin- mediated intercellular adhesion can be useful both in the treatment of scleritis or a scleritis-related disorder, as well as for ameliorating one or more symptoms of such disease or disorder. In various embodiments, the methods include administering to a mammal a compound of Formula I, Formula II, Formula III, Formula IV, or a pharmaceutically acceptable salt, hydrate or ester thereof; or a pharmaceutical composition comprising a compound of Formula I, Formula II, Formula III or Formula IV, or a pharmaceutically acceptable salt, hydrate or ester thereof, and a pharmaceutically acceptable carrier or excipient. In some embodiments, methods of the present teachings comprise a method for treating scleritis, a symptom of scleritis, or a scleritis-related disorder comprising administering to a subject a therapeutically effective amount of one or more compounds having the Formula I: wherein: W i and W 2 taken together with the atoms to which they are attached form a 5 member carbocyclic o r heterocyclic ring or a 6 member carbocyclic or heterocyclic ring, any of which can be saturated, partially saturated or aromatic, and that can be substituted with up to three groups independently selected from hydrogen, C 1 alkyl, C 6 perhaloalkyl, OC 1.6 alkyl, OC 1 perhaloalkyl, halogen, C 1-6thioa!kyl, CN, OH, SH, (CH 2)nOSO 3H , (CH 2)nSO3H, (CH 2 nCO 2R6, OSO 3R6, SO3R6, SO 2R6, PO3R6R7, (CH 2)nS0 2N R8Ro, (CH 2)nC(=O)NR 8R9 , N R8R9, C(=0)R 12l C6. aryl, 3 to 14 membered heterocyclo, C(=O)C 6.i aryl, 3 to 14 membered C(=O)heterocyclo, OC(=O)C 6. 1 aryl, 3 to 14 membered OC(=0)heterocyclo, OC -I ! aryl, 3 to 14 membered Oheterocyclo, C7.24 arylalkyl, C(=O)C 7.24 arylalkyl, OC(=O)C 7.24 arylalkyl, OC7. 24 arylalkyl, C2-20 alkenyl, C2.2o alkynyl, and NHCORe, wherein any of said C1.6 alkyl, OCi. β alkyl, C6- aryl, 3 to 14 membered heterocyclo, C(=O)C 6-i 4 aryl, 3 to 14 membered C(=O)heterocyclo, O-C(=O)C 6-i4aryl, 3 to 14 membered O- C(=O)heterocyclo, OC6.14 aryl, 3 to 14 membered O-heterocyclo, C7.24 arylalkyl, C(=O)C 7.24 arylalkyl, O-C(=O)C 7.2 arylalkyl, 0-C 7-24 arylalkyl, C2-20 alkenyl o r C2-2oalkynyl can optionally be substituted with up to three substituents independently selected from halogen, C 1-6 alkyl, OC 1 alkyl and CN; L is CO 2H, an ester thereof, or a pharmaceutically acceptable acid mimetic; Y is O , (CR 3R ) or NR5; n' is O or 1; p is 1, 2 , or 3 X is hydrogen, OH, OR3, OC1.;; alkyl, OC(O)C 6.-,,, aryl, OC(=O)Ci.