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US 2016/0326102 A1 Kobayashi Et Al US 2016.03261 O2A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0326102 A1 Kobayashi et al. (43) Pub. Date: Nov. 10, 2016 (54) CYCLIC COMPOUNDS (52) U.S. Cl. CPC ........... C07C317/12 (2013.01); C07D 317/72 (71) Applicant: Takeda Pharmaceutical Company (2013.01); C07D 309/28 (2013.01); C07C Limited, Osaka (JP) 2102/08 (2013.01); C07C 2101/16 (2013.01) (72) Inventors: Toshitake Kobayashi, Kanagawa (JP); (57) ABSTRACT Morihisa SAITOH, Kanagawa (JP); Yasufumi WADA, Kanagawa (JP); The present invention provides compounds having a Toll Hiroshi NARA, Kanagawa (JP); like receptor 4 (TLR4) signaling inhibitory action useful as Nobuyuki NEGORO, Kanagawa (JP); preventive and therapeutic drugs of inflammatory disease and/or central nervous system disease or diseases such as Taisuke KATOH, Kanagawa (JP); chemotherapy-induced peripheral neuropathy (CIPN), che Masashi YAMASAKI, Kanagawa (JP): motherapy-induced neuropathic pain (CINP), liver injury, Takahiro TANAKA, Kanagawa (JP); ischemia-reperfusion injury (IRI) and the like. Naomi KITAMOTO, Kanagawa (JP) The present invention relates to a compound represented by (73) Assignee: Takeda Pharmaceutical Company formula (I) and a salt thereof: Limited, Osaka (JP) (21) Appl. No.: 15/148,210 (I) (22) Filed: May 6, 2016 (30) Foreign Application Priority Data May 8, 2015 (JP) ................................. 2015-095817 Publication Classification (51) Int. Cl. C07C 317/12 (2006.01) C07D 309/28 (2006.01) (wherein, each symbol is explained in greater detail in the C07D 31 7/72 (2006.01) specification). US 2016/0326102 A1 Nov. 10, 2016 CYCLIC COMPOUNDS 0007. In Patent Document 2 the following compound TECHNICAL FIELD (I) 0001. The present invention relates to novel cyclic com pounds having a Toll-like receptor 4 (TLR4) signal inhibi tory action useful as preventive and therapeutic drugs of C-R autoimmune disease and/or inflammatory disease or dis eases such as chemotherapy-induced peripheral neuropathy (CIPN), chemotherapy-induced neuropathic pain (CINP), SO-Y-Ar liver injury, ischemia-reperfusion injury (IRI) and the like, and use thereof. 0008 (wherein, each symbol is described in the descrip tion in the said literature) is reported as a TLR4 signaling BACKGROUND OF THE INVENTION inhibitor. 0002 TLR4 was initially discovered as a receptor which 0009. In Patent Documents 3 and 4 the following com recognizes lipopolysaccharide of Gram negative bacteria pound and activates the natural immunity system. However, in recent years, it has been elucidated that not only does TLR4 activate Such natural immunity reactions for preventing (I) infections, but also recognizes various endogenous ligands produced in said various diseases and activates various cells playing central roles in the said diseases. Moreover, it has been reported that expression of TLR4 is accentuated in lesions of various diseases and that onset and progression of diseases in disease model animals are markedly suppressed in TLR4 knockout mouse and mutant mouse. Accordingly, it is suggested that TLR4 plays an important role in auto immune disease and/or inflammatory disease, and diseases 0010 (wherein, each symbol is described in the descrip such as cardiac disease, renal disease, liver disease, central tion in the said literature) is reported as TLR4 signaling nervous system disease, infectious disease, malignant tumor, inhibitor. sepsis, septic shock and the like. DOCUMENT LIST 0003. In addition to such diseases, the relationship to ischemia-reperfusion injury (ischemia reperfusion injury: Patent Document IRI) caused by reperfusion of blood flow to organs and tissues in ischemic condition upon organ transplantation and 0011 Patent Document 1 WO99/46242 the like, is also reported. High Mobility Group Box 1 0012 Patent Document 2 WO 2001/010826 (HMGB-1), which is one of TLR4 endogenous ligands, 0013 Patent Document 3 WO 2007/032362 increases in transplanted organ. Moreover, the transplanted organ derived from donor with genetically impaired TLR4 0014 Patent Document 4 JP 2008-260760 function shows resistance to IRI-associated dysfunction. From Such publicly known knowledge, it is suggested that Non-Patent Document TLR4 signal due to HMGB-1 plays an important role in IRI (0015 Non-Patent Document 1 Liver Transpl. 2008 (Non-Patent Document 1, Non-Patent Document 2). October, 14(10), 1517-25 0004 As a result, TLR4 signaling inhibitors (may also be (0016 Non-Patent Document 2 J. Hepatol. 2010 July called “TLR4 inhibitors') are anticipated to be preventive 53(1), 67-72 and therapeutic drugs of autoimmune disease and/or inflam matory disease or diseases such as cardiac disease, renal SUMMARY OF THE INVENTION disease, liver disease, central nervous system disease, infec tious disease, malignant tumor, sepsis, septic shock, etc. Problems to be Solved by the Invention 0005. In Patent Document 1 the following compound 0017. The object of the present invention is to provide a compound having excellent TLR4 signaling inhibitory action, which is useful as a drug in the treatment and (Iaa) prevention autoimmune disease and/or inflammatory dis ease, and diseases such as chemotherapy-induced peripheral neuropathy (CIPN), chemotherapy-induced neuropathic pain (CINP), liver injury, ischemia-reperfusion injury (IRI) and the like. Means of Solving the Problems 0006 (wherein, each symbol is described in the descrip 0018. These inventors made assiduous investigations in tion in the said literature) is reported as a TLR4 signaling order to achieve a solution to said problem, and as a result, inhibitor. it was discovered that the compounds represented by the US 2016/0326102 A1 Nov. 10, 2016 following formula (I) have excellent TLR4 signaling inhibi group(s) optionally substituted by 1 to 3 substituent(s) tory action. The present invention was completed on the selected from a hydroxy group and a C- alkoxy group; basis of this discovery. 0036 W is CH or O; and 0019. In other words, the present invention is as follows. I0037 R is a C- alkoxy group optionally substituted by 0020 (1) A compound represented by the following for 1 to 3 Co cycloalkyl group(s) optionally substituted by 1 mula (I) or a salt thereof (hereinafter, abbreviated to com to 3 C alkyl group(s). pound (I): 0038 (8) Ethyl (2R,3R,8R)-8-(((1S)-7-chloro-2,3-di hydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1, 4-dioxaspiro4.5 dec-6-ene-7-carboxylate. (I) 0039 (9) Ethyl (2R,3R,8R)-8-(((1S)-7-chloro-5-fluoro 2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxym ethyl)-1,4-dioxaspiro4.5 dec-6-ene-7-carboxylate. 0040 (10) Ethyl (2R,3R,8R)-8-(((1S)-7-chloro-2,3-di hydro-1H-inden-1-yl)sulfonyl)-2,3-bis(methoxymethyl)-1, 4-dioxaspiro4.5 dec-6-ene-7-carboxylate. 0041 (11) A medicament comprising the compound or salt according to the above-mentioned (1). 0042 (12) The medicament according to the above mentioned (11), which is a toll-like receptor 4 inhibitor. 0043 (13) The medicament according to the above 0021 (wherein, mentioned (11), which is an agent for the prophylaxis or 0022 Ring A is an optionally substituted 5 or 6 mem treatment of autoimmune disease and/or inflammatory dis bered ring; CaSC. 0023 Ring B is an optionally substituted benzene ring: 0044 (14) The medicament according to the above 0024) R' and Rare independently a hydrogen atom or a mentioned (11), which is an agent for the prophylaxis or substituent, or R' and R may bond together to form an treatment of chemotherapy-induced peripheral neuropathy optionally Substituted ring; (CIPN), chemotherapy-induced neuropathic pain (CINP), (0.025 W is CH, NH or O; and liver injury and/or ischemia-reperfusion injury (IRI). 0026 R is a substituent). 0045 (15) The compound or salt according to the above 0027 (2) The compound or salt according to the above mentioned (1) for use in the prophylaxis or treatment of mentioned (1), wherein Ring A is cyclopentene or cyclo autoimmune disease and/or inflammatory disease. hexene. 0046 (16) The compound or salt according to the above 0028 (3) The compound or salt according to the above mentioned (1) for use in the prophylaxis or treatment of mentioned (1), wherein Ring B is a benzene ring optionally chemotherapy-induced peripheral neuropathy (CIPN), che substituted by 1 to 3 substituent(s) selected from a halogen motherapy-induced neuropathic pain (CINP), liver injury atom and a C alkyl group. and/or ischemia-reperfusion injury (IRI). 0029 (4) The compound or salt according to the above 0047 (17) A method of inhibiting toll-like receptor 4 in mentioned (1), wherein as to R' and R. (1) R' and R are a mammal, which comprises administering an effective both hydrogen atoms, or (2) one of R and R is a hydrogen amount of the compound or salt according to the above atom, and the other is a hydroxy group, or R' and R may mentioned (1) to the mammal. bond together to form a 3- to 8-membered monocyclic 0048 (18) A method for the prophylaxis or treatment of non-aromatic heterocycle optionally substituted by 1 to 3 autoimmune disease and/or inflammatory disease in a mam C. alkyl group(s) optionally substituted by 1 to 3 Substitu mal, which comprises administering an effective amount of ent(s) selected from a hydroxy group and a C- alkoxy the compound or salt according to the above-mentioned (1) group. to the mammal. 0030 (5) The compound or salt according to the above 0049 (19) A method for the prophylaxis or treatment of mentioned (1), wherein W is CH or O. chemotherapy-induced peripheral neuropathy (CIPN), che 0031 (6) The compound or salt according to the above motherapy-induced neuropathic pain (CINP), liver injury mentioned (1), wherein R is a Calkoxy group optionally and/or ischemia-reperfusion injury (IRI) in a mammal, Substituted by 1 to 3 Co cycloalkyl group(s) optionally which comprises administering an effective amount of the Substituted by 1 to 3 C alkyl group(s).
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