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Ep 1919867 B1 (19) & (11) EP 1 919 867 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 209/08 (2006.01) C07D 209/80 (2006.01) 17.08.2011 Bulletin 2011/33 C07D 221/08 (2006.01) C07D 223/22 (2006.01) (21) Application number: 06813923.7 (86) International application number: PCT/US2006/033777 (22) Date of filing: 29.08.2006 (87) International publication number: WO 2007/027719 (08.03.2007 Gazette 2007/10) (54) LISOFYLLINE ANALOGUES AND THEIR PHARMEACUETICAL USES LISOFYLLIN-ANALOGIKA UND IHRE PHARMAZEUTISCHEN VERWENDUNGEN ANALOGUES D’UNE LISOFYLLINE ET PROCEDES D’UTILISATION DE CEUX-CI (84) Designated Contracting States: (56) References cited: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR WO-A-99/36073 WO-A2-02/068421 HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI US-B1- 6 316 458 SK TR • CUI ET AL: "Synthesis and biological evaluation (30) Priority: 29.08.2005 US 712114 P of lisofylline (LSF) analogs as a potential treatment for Type 1 diabetes" BIOORGANIC & (43) Date of publication of application: MEDICINAL CHEMISTRY LETTERS, OXFORD, 14.05.2008 Bulletin 2008/20 GB,vol. 16, no. 13, 1 July 2006 (2006-07-01), pages 3401-3405, XP005461933 ISSN: 0960-894X (60) Divisional application: • YANG Z ET AL: "Lisofylline: a potential lead for 10012734.9 / 2 325 169 the treatment of diabetes" BIOCHEMICAL PHARMACOLOGY, PERGAMON, OXFORD, GB, (73) Proprietor: UNIVERSITY OF VIRGINIA PATENT vol. 69, no. 1, 1 January 2005 (2005-01-01), pages FOUNDATION 1-5, XP004664587 ISSN: 0006-2952 Charlottesville, VA 22902 (US) • RYBCZYNSKI,PHILIP J. ET AL: "Benzoxazinones as PPAR.gamma. Agonists. 2. SAR of the Amide (72) Inventors: Substituent and In Vivo Results in a Type 2 • MACDONALD, Timothy, L. Diabetes Model" JOURNAL OF MEDICINAL Charlottesville, VA 22902 (US) CHEMISTRY , 47(1), 196-209 CODEN: JMCMAR; • NADLER, Jerry, L. ISSN: 0022-2623, 2004, XP002414296 Charlottesville, VA 22911 (US) • KEINAN E ET AL: "Natural ozone scavenger • CUI, Peng prevents asthma in sensitized rats" Los Angeles,CA 90034 (US) BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER SCIENCE LTD, GB, vol. 13, no. 2, 17 (74) Representative: McNab, Donald C. January 2005 (2005-01-17), pages 557-562, Marks & Clerk LLP XP004681539 ISSN: 0968-0896 Aurora 120 Bothwell Street Glasgow G2 7JS (GB) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 919 867 B1 Printed by Jouve, 75001 PARIS (FR) EP 1 919 867 B1 Description Government Funding 5 [0001] The invention described herein was made with government support under Grant Numbers DK 63521 and R21DK 063521 awarded by the National Institute of Health. The United States Government has certain rights in the invention. Background of the Invention 10 [0002] Type 1 diabetes is an autoimmune disorder which results from the immune- mediated inflammatory destruction of insulin-producing β-cells in pancreatic islets. Although the specific pathogenic mechanisms in Type 1 diabetes are not known, it is believed that activated T cells and macrophages are required for the initiation. Once activated, macro- phages secrete several inflammatory cytokines, such as interleukin 1 β(IL-1β), interleukin 12 (IL-12) and tumor necrosis 15 factor α (TNF-α), and trigger interferon-γ (IFN-γ) production from activated T cells (see Z. D. Yang, M. Chen, R. Wu, M. McDuffie, J. L. Nadler, Diabetologia, 2002, 45, 1307-1314). These cytokines are reported to be cytotoxic to β cells and enhance Th1-mediated inflammatory responses, which are believed to be responsible for the β cell destruction (see M. Chen, Z. D. Yang, R. Wu, J. L. Nadler, Endocrinology, 2002, 143(6), 2341-2348). [0003] The anti-inflammatory compound Lisofylline (LSF; 1-(5-R-hydroxyhexyl)-3,7-dimethylxanthine)) has been 20 shown to be able to protect β-cells from multiple inflammatory cytokine- mediated injuries by its ability to maintain insulin secretory capability and cell viability. [0004] Agents such as Lisofylline may have clinical utility in preventing β-cell damage during the development of Type 1 diabetes. This hypothesis is supported by the studies that showed Lisofylline could significantly reduce spontaneous Type 1 diabetes development in the non-obese diabetic (NOD) mouse (see Yang). However, the disadvantages of 25 Lisofylline may limit its clinical development because it is not orally bioavailable and has relatively weak potency. The structure of LSF is Formula I. [0005] Currently, there is a need for novel, potent, and selective agents which There is a long felt need in the art for small molecules based on the Lisofylline backbone which have enhanced potency, selectivity, and oral bioavailability. The present invention satisfies this need. 30 Summary of the Intention [0006] The present invention provides analogs of a Lisofylline (LSF), and synthetic methods for the preparation of such analogs. The analogs can have greater potency and oral bioavailability than LSF. The analogs have the active 35 side chain moiety (5-R-hydroxyhexyl) of LSF. The invention also includes derivatives of LSF. LSF has formula I: 40 45 [0007] The analogs of the invention can be substituted with a variety of nitrogen-contained heterocyclic compounds or on the hydroxyl group of the side chain. Accordingly, the invention provides 1-substituted 5-hexanol compounds 50 having additional substitution on the hydroxyl group. [0008] Viewed from one aspect, therefore, the invention provides a compound of formula (II) as defined in claim 1, or a pharmaceutically acceptable salt thereof. [0009] The present invention provides analogs of LSF having the ability to protect cell viability, particularly the ability to protect pancreatic β-cells. Thus, the analogs of the invention can allow the pancreas to maintain its insulin secretory 55 capability. [0010] The present invention provides analogs of LSF which are effective in treating Type 1 diabetes. The present invention provides analogs of LSF which can inhibit the development of Type 1 diabetes. [0011] The present invention provides analogs of LSF which are effective in treating Type I diabetes. In another 2 EP 1 919 867 B1 embodiment, the present invention provides analogs of LSF which can lead to reversal of type I diabetes by allowing the body to regenerate beta cells. [0012] In another aspect, the present invention also provides: 5 a pharmaceutical composition comprising a compound of formula (II) as defined in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient (the composition preferably comprises an effective amount of the compound or salt); use of a compound of formula (II) as defined in claim 1, or a pharmaceutically acceptable salt thereof, to prepare a 10 medicament for use in the prevention or treatment of a pathological condition or symptom in a mammal, wherein the pathological condition or symptom is an inflammatory or autoimmune condition; use of a compound of formula (II) as defined in claim 1, or a pharmaceutically acceptable salt thereof, to prepare a medicament for us in the prevention or treatment of a pathological condition or symptom in a mammal, wherein the 15 pathological condition or symptom is Type 1 diabetes; and a compound of formula (II) as defined in claim 1, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a pathological condition or symptom in a mammal, wherein the pathological condition or symptom is an inflammatory or autoimmune condition or is Type 1 diabetes. 20 [0013] The analogs of the invention can be useful in the treatment of inflammatory and autoimmune diseases. Non- limiting examples of such diseases include atherosclerosis, type 2 diabetes, disorders associated with visceral obesity such as non-alcoholic *steatohepatitis (NASH), multiple sclerosis, inflammatory bowel disease, psoriasis, rheumatoid arthritis, Alzheimer’s disease and the like. 25 Brief Description of the Drawings [0014] 30 Figure 1 depicts specific examples of compounds of the invention, which are CPW5, CPW6, CPW8, CPW9, CPW10, CPW11, CPW12, CPW13, CPW20, CPW21 and CPW22. Figure 2 illustrates a scheme for preparing compound CPW11. Figures 5A-5P illustrate the β-cell protective effect of LSF and additional analogs of the invention for mouse-origin β-TC6 cells and mouse islet cells. 35 Figure 6 illustrates the release of insulin from mouse islet cells. Figures 7A-7D illustrate the release of insulin from mouse islet cells. Figure 7A illustrates the basal- stimulated Insulin Release. Figure 7B illustrates the glucose- stimulated Insulin Release. Figure 7C illustrates the ATP concentrations and Figure 7D illustrates the β-cell viability. Figures 8a-8c illustrate the ability of the analogs of the invention to stimulate insulin release from β-cells. 40 Figures 9A-9P illustrate the ability of LSF and additional analogs to effect insulin release in mouse-origin β-TC6 cells. Figure 10 illustrates the ability of compounds (analogs) of the invention to reduce STAT4 phosphorylation in murine splenocytes (Immuno-dot-blot). Detailed Description 45 Abbreviations [0015] In describing and claiming the invention, the following terminology will be used in accordance with the definitions set forth below. 50 [0016] For purposes of the description of this invention, the articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element [0017] A disease or disorder is "alleviated" if the severity of a symptom of the disease, condition, or disorder, or the frequency with which such a symptom is experienced by a subject, or both, are reduced.
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