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(12) Patent Application Publication (10) Pub. No.: US 2006/0211752 A1 Kohn Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2006/0211752 A1 Kohn Et Al US 20060211752A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0211752 A1 Kohn et al. (43) Pub. Date: Sep. 21, 2006 (54) USE OF PHENYLMETHIMAZOLES, Publication Classification METHIMAZOLE DERIVATIVES, AND TAUTOMERC CYCLC THONES FOR THE (51) Int. Cl. TREATMENT OF A61K 31/4166 (2006.01) AUTOIMMUNEANFLAMMATORY DISEASES (52) U.S. Cl. .............................................................. S14/389 ASSOCATED WITH TOLL-LIKE RECEPTOR OVEREXPRESSION (76) Inventors: Leonard D. Kohn, Athens, OH (US); (57) ABSTRACT Norikazu Harii, Yaminashi (JP); Uruguaysito Benavides-Peralta, The present invention relates to the treatment of autoim Montevideo (UY); Mariana mune and/or inflammatory diseases associated with overex Gonzalez-Murguiondo, Montevideo pression of Toll-like receptor 3 (TLR3) as well as Toll-like (UY); Christopher J. Lewis, Athens, receptor 4 (TLR4) and/or TLR3/TLR4 signaling in nonim OH (US); Giorgio Napolitano, Pescara mune cells, monocytes, macrophages, and/or dendritic cells (IT): Cesidio Giuliani, Roccamonce in association with related pathologies. This invention also (IT); Ramiro Malgor, Athens, OH relates to the use of phenylmethimazoles, methimazole (US); Douglas J. Goetz, Athens, OH derivatives, and tautomeric cyclic thiones for the treatment (US) of autoimmune and inflammatory diseases associated with Correspondence Address: Toll-like receptor 3 (TLR3) as well as Toll-like receptor 4 FROST BROWN TODD, LLC (TLR4) and/or TLR3/TLR4 signaling in nonimmune cells, 2200 PNC CENTER monocytes, macrophages, and/or dendritic cells in associa tion with related pathologies. This invention also relates to 201 E. FIFTH STREET treating a subject having a disease or condition associated CINCINNATI, OH 45202 (US) with abnormal Toll-like receptor 3 as well as Toll-like (21) Appl. No.: 11/130,922 receptor 4 and/or TLR3/TLR4 signaling in nonimmune cells, monocytes, macrophages, and/or dendritic cells in (22) Filed: May 17, 2005 association with related pathologies. The present invention also relates to the treatment of autoimmune-inflammatory Related U.S. Application Data pathologies and chemokine and cytokine-mediated diseases associated with TLR overexpression and signaling. This (63) Continuation-in-part of application No. 10/912.948, invention also relates to pharmaceutical formulations filed on Aug. 6, 2004. capable of inhibiting the IRF-3/Type 1 IFN/STAT/ISRE/ Continuation-in-part of application No. 10/801,986, IRF-1 pathway associated with Toll-like receptor overex filed on Mar. 16, 2004. pression or signaling. Patent Application Publication Sep. 21, 2006 Sheet 1 of 17 US 2006/0211752 A1 SNS C) C a f O h w Z O G O > s f 3 9. d na SSSSSSSSSSSN C V s s CD CCC L nz - c V d.O 1 C & CD S. S. S 9 C AA)ow eSejeon enlee SSC c 2 2 2. 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O. w V C O N C) E > wn al V w v 9. w & 3 H f OSNO O V O 5 H OO ?a H OSNO IWW O-O OSNO s Patent Application Publication Sep. 21, 2006 Sheet 7 of 17 US 2006/0211752 A1 Quêu?eÐI)00||W Patent Application Publication Sep. 21, 2006 Sheet 8 of 17 US 2006/0211752 A1 Patent Application Publication Sep. 21, 2006 Sheet 9 of 17 US 2006/0211752 A1 |Ou?uO3W/NYJuu Patent Application Publication Sep. 21, 2006 Sheet 10 of 17 US 2006/0211752 A1 Patent Application Publication Sep. 21, 2006 Sheet 11 of 17 US 2006/0211752 A1 Patent Application Publication Sep. 21, 2006 Sheet 12 of 17 US 2006/0211752 A1 Patent Application Publication Sep. 21, 2006 Sheet 13 of 17 US 2006/0211752 A1 C XHO0,0C10!,OCI sdnsdisan(-) Patent Application Publication Sep. 21, 2006 Sheet 14 of 17 US 2006/0211752 A1 Patent Application Publication Sep. 21, 2006 Sheet 15 of 17 US 2006/0211752 A1 Patent Application Publication Sep. 21, 2006 Sheet 16 of 17 US 2006/0211752 A1 Patent Application Publication Sep. 21, 2006 Sheet 17 of 17 US 2006/0211752 A1 ??egsZZZuesd ??egssoudun OSINCI0!,0,0OSINC]O0!, LVLSI,021A1d| V//,/,"$DIE US 2006/021. 1752 A1 Sep. 21, 2006 USE OF PHENYLMETHIMAZOLES, 0005 Recent studies demonstrate a formidable link METHIMAZOLE DERIVATIVES, AND between the Toll-like receptor (TLR) signaling pathway of TAUTOMERC CYCLC THONES FOR THE innate immunity and the slower, more deliberate adaptive TREATMENT OF immune system that characterizes humoral and cellular AUTOMMUNEANFLAMMATORY DISEASES autoimmunity (K. S. Michelsen, et al., Proc Natl Acad Sci ASSOCATED WITH TOLL-LIKE RECEPTOR USA, 101: 10679-84 (2004); G. Pasterkamp, et al., EurJ Clin OVEREXPRESSION Invest, 34:328-34 (2004); K. Takeda, et al., Annu Rev Immunol, 21:335-76 (2003); K. Takeda, et al., Cell Micro 0001. The present application is a continuation-in-part of biol. 5:143-53 (2003); R. J. Ulevitch, J Infect Dis, 187 Suppl U.S. patent application Ser. No. 10/912,948, filed Aug. 6, 2:S351-5 (2003); L. Steinman, Science, 305:212-6 (2004); 2004, and U.S. patent application Ser. No. 10/801,986, filed L. D. Kohn, et al., Research Ohio, In press, (2005); N. Hari, Mar. 16, 2004, both of which are incorporated by reference et al., Mol Endocrinol, 19:1231-50 (2005); D. Devendra, et in their entirety. al., Clin Immunol, 111:225-33 (2004); L. Wen, et al., J Immunol, 172:3173-80 (2004); H. Oshiumi, et al., Nat TECHNICAL FIELD Immunol. 4:161-7 (2003); M. Yamamoto, et al., J Immunol, 0002 The present invention relates to the treatment of 169:6668-72 (2002); M. Miettinen, et al., Genes Immun, autoimmune and/or inflammatory diseases associated with 2:349-55 (2001): L. Alexopoulou, et al., Nature, 413:732-8 overexpression of Toll-like receptor 3 (TLR3) as well as (2001); G. Andonegui, et al., J. Clin Invest, 111:1011 - 1020 Toll-like receptor 4 (TLR4) and/or TLR3/TLR4 signaling in (2003); C. Fiocchi, Gastroenterology, 115:182-205 (1998); nonimmune cells, monocytes, macrophages, and/or den E. Cario, et al., Infect Immun, 68:7010-7 (2000)). Innate dritic cells in association with related pathologies. This immunity is a protective immune cell response that func invention also relates to the use of phenylmethimazoles, tions rapidly to fight environmental insults including, but not methimazole (MMI) derivatives, and tautomeric cyclic limited to, bacterial or viral agents. Adaptive immunity is a thiones for the treatment of autoimmune and inflammatory slower response, which involves differentiation and activa diseases associated with Toll-like receptor 3 (TLR3) as well tion of naive T lymphocytes into Thelper 1 (Th1) or Thelper as Toll-like receptor 4 (TLR4) and/or TLR3/TLR4 signaling 2 (Th2) cell types (I. Roitt, Essential Immunology, 7th ed., in nonimmune cells, monocytes, macrophages, and/or den 312-346. (1991)). Th1 cells mainly promote cellular immu dritic cells in association with related pathologies. This nity, whereas Th2 cells mainly promote humoral immunity. invention also relates to treating a subject having a disease Though primarily a host protective system, pathologic or condition associated with abnormal Toll-like receptor 3 expression of the innate immunity signals emanating from (TLR3) as well as Toll-like receptor 4 (TLR4) and/or the TLR pathway are now implicated in initiating autoim TLR3/TLR4 signaling in nonimmune cells, monocytes, mune-inflammatory diseases. macrophages, and/or dendritic cells in association with 0006 Therapies for autoimmune-inflammatory endo related pathologies. This invention also relates to treating a crine or non-endocrine diseases are largely aimed at treating Subject having a disease or condition associated with abnor the symptoms of the disease. For the most part, the under mal Toll-like receptor expression or signaling involving lying genetic Susceptibilities are poorly defined, are mul activation of Type I interferons in nonimmune cells, mono tiple, are often not disease specific, and are largely not cytes, macrophages, and/or dendritic cells in association readily amenable to therapy. Immunosuppressive agents that with related pathologies. are used to treat autoimmune-inflammatory diseases largely target the immune cell response or the cytokines they BACKGROUND OF THE INVENTION produce. They are only partially effective in inducing remis sion (methimazole in Graves), toxic (cyclosporin for Type 0003 A. Innate and Adaptive Immunity 1 diabetes), or simply palliative (anti-inflammatory corti 0004 Autoimmune diseases, are currently clinically costeroids for colitis or systemic lupus). The involvement of defined by (i) humoral or autoantibody response to a self TLR in autoimmune-inflammatory diseases raises the pos antigen, e.g. Graves’ primary hyperthyroidism with antibod sibility that diagnosis and treatment must undergo a re ies to the TSH receptor, or (ii) cellular response wherein alignment (K.
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