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WO 2017/060488 Al 13 April 2017 (13.04.2017) P O PCT

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WO 2017/060488 Al 13 April 2017 (13.04.2017) P O PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/060488 Al 13 April 2017 (13.04.2017) P O PCT (51) International Patent Classification: (74) Agent: SRINIVASAN, Ravi Chandran; 14 South Square, A61K 31/522 (2006.01) A61P 17/00 (2006.01) Gray's Inn, London Greater London WC1R 5JJ (GB). A61P 13/00 (2006.01) A61P 29/00 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/EP20 16/074094 AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, (22) Date: International Filing DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 7 October 2016 (07. 10.2016) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (25) Filing Language: English KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (26) Publication Language: English OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (30) Priority Data: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, 15382492.5 >October 201 5 (09. 10.2015) EP TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, zw. (71) Applicant: ALMIRALL, S.A. [ES/ES]; Ronda del Gener al Mitre 15 1, 08022 Barcelona (ES). (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (72) Inventors: AIGUADE BOSCH, Jose; c/o Laurea Miro GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 408-410, Sant Feliu de Llobregat, 08980 Barcelona (ES). TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, CONNOLLY, Stephen; 23 The Square, Tadcaster Road, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, York Yorkshire Y024 1UR (GB). EASTWOOD, Paul DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Robert; c/o Laurea Miro 408-410, Sant Feliu de Llobregat, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, 08980 Barcelona (ES). GOMEZ CASTILLO, Elena; c/o SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Laurea Miro 408-410, Sant Feliu de Llobregat, 08980 Bar GW, KM, ML, MR, NE, SN, TD, TG). celona (ES). MORENO MOLLO, Immaculada Montser- rat; c/o Laurea Miro 408-410, Sant Feliu de Llobregat, Published: 08980 Barcelona (ES). ROBERTS, Richard Spurring; — with international search report (Art. 21(3)) c/o Laurea Miro 408-410, Sant Feliu de Llobregat, 08980 Barcelona (ES). SEVILLA GOMEZ, Sara; Avda. 11 de Septiembre 12, 3°, 3a, Coloma de CervelkS, 08690 Bar celona (ES). (54) Title: NEW TRPAl ANTAGONISTS 00 00 o Formula (I) o (57) Abstract: The present invention relates to compounds of Formula (I), to the process for preparing such compounds and to their © use in the treatment of a pathological condition or disease susceptible to amelioration by TRPAl channel inhibition or antagonism. New TRPA1 antagonists FIELD OF THE INVENTION The present invention relates to novel compounds having TRPA1 activity. This invention also relates to pharmaceutical compositions containing them, processes for their preparation and their use in the treatment of several disorders. BACKGROUND OF THE INVENTION TRPA1 is a non-cation selective channel that belongs to the Transient Receptor Potential (TRP) superfamily. TRPA1 was first identified from cultured lung fibroblasts (Jaquemar ef a/. , 1999), and further studies indicated that TRPAI was highly expressed in sensory neurons of the dorsal root, trigeminal and nodose ganglia. In sensory neurons, TRPA1 expression is most prevalent in small diameter neurons where it colocalizes with markers of peptidergic nociceptors such as TRPV1 , calcitonin gene-related peptide (CGRP) and substance P (Kaneko e t al. , 201 3). Moreover, TRPA1 has been identified in the small intestine, colon, pancreas, skeletal muscle, heart, brain, and T and B-lymphocytes (Stokes e t al. , 2006). TRPA1 is activated by a variety of noxious stimuli, including cold temperatures and pungent natural compounds (e.g. , mustard, cinnamon and garlic). TRPA1 is also activated by environmental irritants, including isocyanates and heavy metals produced during the manufacturing of polymers, fertilizers and pesticides. Vehicle exhaust, burning vegetation and electrophilic tear gases used as incapacitating agents, are potent activators of TRPA1 . TRPA1 antagonists or inhibitors could also have applications in defence against such agents. TRPA1 is not only sensitive to electrophiles, but is also activated by oxidizing agents. Reactive oxygen species (ROS) are released by cells in response to tissue damage and can cause lipid peroxidation. Reactive carbonyl species like 4- hydroxynonenal (4-H NE) and 4-oxononenal (4-ON E), resulting from lipid peroxidation act directly on TRPA1 . ROS generated during inflammation excites airway sensory nerve fibres, and this response is largely reduced in TRPA1 -deficient mice. Another mechanism of TRPA1 activation is modulation by G protein-coupled receptors (GPCRs) through second-messenger signalling cascades. Prostaglandin PGE2 and bradykinin (BK) are indirect activators of TRPA1 (Bessac, 2008). TRPA1 has emerged as a key regulator of neuropeptide release and neurogenic inflammation . In mammals TRPA1 is expressed in a subset of C-fibres that express TrkA and TRPV1 . These afferent nerves have cell bodies in nodose, dorsal root ganglia (DRG) and trigeminal neurons (TG), and project to a variety of peripheral targets, including skin, airways, and gastrointestinal (Gl ) tract. TRP channels are present in both neuronal and non-neuronal cells in the skin where they are thought to play a key role in itch, regulation of barrier function , keratinocyte differentiation , hair growth , inflammation , and wound healing (reviewed in Moran e t al., 201 1). TRPA1 is an essential component of the pathways that promote histamine- independent itch and may act as a downstream transduction channel onto which multiple pathways converge. Among these, Mas-related GPCR from human (MrgprXI ) and mice (MrgprA3, MrgprCH ), receptors of chloroquine (A3, X 1) and BAM8-22 (C1 1, X 1) (Wilson 2011), TSLP-evoked scratching (Wilson e t al. , Cell 2013), dry skin-evoked chronic itch (Wilson e t al. 201 3), haptens-induced inflammation and itch in contact dermatitis (Liu e t al. , 2013), IL-1 3-induced itch in atopic dermatitis by IL-1 3 (Oh e t al. 201 3), IL-31 -induced Th cell-dependent itch (Cevikbas e t al., 201 3), and PGE2, bradykinin, PAR-2 ligands, etc. Overall, these studies suggest that TRPA1 would be key in the non-histaminergic itch . TRPA1 role as a pain sensor is well-established. A gain-of-function point mutation in TRPA1 was identified as the cause of Familial Episodic Pain Syndrome, a rare human pain disorder characterized by severe upper body pain triggered by fasting and physical stress (Kremeyer e t al. , 201 0). Taming these hyperactive TRP channels by antagonists may prove clinically beneficial. TRPA1 is required for the hypersensitivity that occurs in inflammatory pain models (Bautista e t al. 2013 , Julius 201 3). TRPA1 expression is increased by inflammatory mediators such as nerve growth factor (NGF) and following nerve injury or inflammation . Activation of TRPA1 has been shown to cause pain and neurogenic inflammation . Intrathecal TRPA1 antisense oligonucleotides administration suppressed inflammation and nerve injury-induced cold allodynia. TRPA1 gene knock-out studies showed impaired sensory function to noxious cold , chemical and mechanical stimuli, suggesting that TRPA1 represents an important target for development of therapeutics for inflammatory and neuropathic pain conditions (Obata e t al. 2003, McNamara e t al. 2007, Petrus e t al. 2007, Koivisto 2012). Disease models of diabetes strongly implicate TRPA1 in the inflammatory pain states associated with this metabolic disorder. Diabetic neuropathy affects more than 80% of all diabetes patients and can cause severe pain, tingling and numbing sensations, and disability. TRPA1 is a promising target for the treatment of this chronic diabetic neuropathy associated with peripheral demyelination and the degeneration of nerve fibres. In cancer research , there is an increasing appreciation of the role that chronic inflammation plays in tumorigenesis and of the presence of inflammation in the tumour microenvironment (Lorusso e t al. , 2008; reviewed in Bautista e t al. 2013). Neurogenic components of inflammation may contribute to pain and other debilitating consequences of cancer. TRPA1 may have a role in the pathogenesis of cancer and other inflammatory diseases. TRPA1 antagonists have been reported to revert oxaliplatin-induced neuropathic pain (Nativi, 2005). Some anaesthetics, such as isoflurane or lidocaine, also activate TRPA1 , suggesting a possible role for TRPAI antagonists in post-surgical pain . A number of studies suggest that TRPA1 is implicated in migraine (Edelmayer e t al., 201 2), and dental pain (Haas e t al., 201 1), as a result from neurogenic inflammation. The activation of trigeminal TG neurons through nasal application of TRPA1 activators causes a CGRP-dependent increase in meningeal blood flow, that has been clinically shown to correlate with migraine headache. TRPA1 could be considered a target for such conditions. There is growing evidence, generated using TRPA1 blockers and also TRPA1 -/- mice to support a role for TRPA1 in the pathogenesis of different airway diseases including chronic cough , asthma, and COPD (Nassini et al. , 201 2b). Several publications implicate TRPA1 in the generation of irritant-induced cough reflexes. Inhalation of a variety of TRPA1 agonists (acrolein , cinnamaldehyde, allyl isothiocyanate, crotonaldehyde) has been shown to produce a dose-dependent robust cough response in conscious guinea pigs and in humans (Andre e t al.
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