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(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.
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  • Characteristic List (PDF)

    Characteristic List (PDF)

    State of Alaska, Environmental Conservation Water Info Mgt 907-465-5153 Substance/Characteristic Name EPA Substance Registry ID (-)-cis-Permethrin 963314 (-)-trans-Permethrin 963322 (3-Bromopropyl)benzene 65862 2-Chloro-1-phenylethanol 961524 .alpha.,.alpha.-Dimethylphenethylamine 32128 .alpha.-Chlordene 694141 .alpha.-Endosulfan 75333 .alpha.-Hexachlorocyclohexane 42184 .alpha.-Methylstyrene 18317 .alpha.-Nitrotoluene 961201 .alpha.-Terpineol 18127 .beta.-Chlordene 694158 .beta.-Endosulfan 263996 .beta.-Hexachlorocyclohexane 42192 .delta.-Hexachlorocyclohexane 42200 .gamma.-Butyrolactone 16873 .gamma.-Chlordene 694174 Acetovanillone 48074 1,1,1,2-Tetrachloroethane 65102 1,1,1-Trichloro-2-propanone 650242 1,1,1-Trichloroethane 4796 CFC-113a 43570 1,1,2,2-Tetrabromoethane 7716 1,1,2,2-Tetrachloroethane 7773 1,1,2-Trichloroethane 7518 1,1'-Binaphthalene 58701 1,1-Dichloroethane 5520 1,1-Dichloroethylene 5538 1,1-Dichloropropane 7500 1,1-Dichloropropanone 650184 1,1-Dichloropropene 54676 1,1-Dimethylcyclopropane 961516 1,1'-Oxybis[3-chloropropane] 64733 1,2,3,4,5,6-Hexachlorocyclohexane 59220 1,2,3,4,6,7,8,9-Octachlorodibenzofuran 278218 1,2,3,4,6,7,8,9-Octachlorodibenzo-p-dioxin 113837 1,2,3,4,6,7,8-Heptachlorodibenzofuran 358382 1,2,3,4,6,7,8-Heptachlorodibenzo-p-dioxin 270140 1,2,3,4,7,8,9-Heptachlorodibenzofuran 304782 1,2,3,4,7,8-Hexachlorodibenzofuran 525212 1,2,3,4,7,8-Hexachlorodibenzo-p-dioxin 711986 1,2,3,4-Tetrachlorobenzene 65441 1,2,3,4-Tetrahydronaphthalene 30783 1,2,3,4-Tetramethylbenzene 47365 1,2,3,5-Tetrachlorobenzene 65458
  • Synthesis, Characterisation and Biological Evaluation Of

    Synthesis, Characterisation and Biological Evaluation Of

    ry: C ist urr m en e t Prabhakar et al., Organic Chem Curr Res 2016, 5:4 h R C e c s i e n DOI: 10.4172/2161-0401.1000174 a a r Organic Chemistry c g r h O ISSN: 2161-0401 Current Research ResearchResearch Article Article Open Accesss Synthesis, Characterisation and Biological Evaluation of Quinazoline Derivatives as Novel Anti-Microbial Agents Prabhakar V1*, Sudhakar BK2, Ravindranath LK2, Latha J3 and Venkateswarlu B4 1Faculty of Engineering Chemistry, SVR Engineering College, Jawaharlal Nehru Technological University - Ananthapuramu (JNTU-A), Nandyal, Kurnool District, Andhra Pradesh, India 2Department of Chemistry, Sri Krishnadevaraya University, Anantapuramu, Andhra Pradesh, India 3Department of Environmental Science, Sri Krishnadevaraya University College of Engineering and Technology, Ananthapuramu, Andhra Pradesh, India 4Jawaharlal Nehru Technological University (JNTU-A), Kavali, Nellore District, Andhra Pradesh, India Abstract A novel series of Quinazolines were synthesised by cyclisation reaction of Anthranilic acid with urea to get 2,4 di hydroxy quinazoline (2) intermediate, which were further treated with POCl3 to get 2,4 di chloro quinazoline (3), which was treated with Thio-morpholine (4) for 3 hrs to get compounds (5), which are reacted with aqueous ammonia to get compound(6), which was further reacts with different boronic acids 7(a-j) by using Chan-Lam coupling reaction conditions to get Target Novel Quinazoline derivatives (8a-8j). The structures of new compounds were confirmed by IR and 1H NMR and 13C NMR spectral data. Anti-bacterial and anti-fungal activities were evaluated and compared with the standard drugs, compounds 8i, 8d, 8h, 8g exhibited promising anti-microbial and anti-fungal activity compared to standard drugs.
  • Table of Contents

    Table of Contents

    World Journal of Pharmaceutical Research Pankaj et al. World Journal of Pharmaceutical SJIF ImpactResearch Factor 6.805 Volume 5, Issue 8, 737-743. Research Article ISSN 2277– 7105 SYNTHESIS AND EVALUATION OF ANTHELMINTIC ACTIVITY OF SOME SUBSTITUTED CINNOLOTHIOPHENE DERIVATIVES Pankaj Shankhdhar*1 and Vikas Saxena1 1Rakshpal Bahadur College of Pharmacy, Near ITBP campus, Bareilly, (U.P.) PIN-243001. ABSTRACT Article Received on 24 May 2016, Cinnoline are the six membered heterocyclic compound found to elicit Revised on 14 June 2016, Accepted on 04 July 2016 many pharmacological actions like anti-hypertensive, antithrombotic, DOI: 10.20959/wjpr20168-6706 antihistamine, antileukemic, CNS activity, anti tumor, antibacterial and antisecretory activity. Similarly thiophene moiety is well known for *Corresponding Author their therapeutic values. Study was aimed to synthesize some cinnoline Pankaj Shankhdhar derivatives from substituted anilines and these substituted cinnolines Rakshpal Bahadur College are further condensed with thiophene moiety and further evaluated of Pharmacy, Near ITBP these substituted cinnolothiophene derivatives for biological activity. campus, Bareilly, (U.P.) PIN-243001. KEY WORDS: Cinnoline, Aniline, Anthelmintic activity. INTRODUCTION The approach to the practice of medicinal chemistry has developed extensively involving synthesis of new organic compounds based on modification of naturally available compounds of biological interest. Cinnolines are the six-membered heterocyclic compounds having two hetero atoms in the ring. They are also called as 1,2- benzodiazines or benzopyridazine or 1,2- diazanaphthalene or phenodiazine[1]. V. Von. Richter (1883) prepared cinnoline derivatives by the diazotization of o-aminoaryl propiolic acids(1) or o-amino aryl acetylenes followed by hydration and cyclization. Thiophene is a heterocyclic compound with the formula C4H4S.