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WO 2015/181797 Al 3 December 2015 (03.12.2015) P O P C T

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WO 2015/181797 Al 3 December 2015 (03.12.2015) P O P C T (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 2015/181797 Al 3 December 2015 (03.12.2015) P O P C T (51) International Patent Classification: (74) Agent: OLSON, A. Dean; Pfizer Worldwide Research & C07D 417/12 (2006.01) A61K 31/425 (2006.01) Development, Eastern Point Road MS8260-2141, Groton, C07D 417/14 (2006.01) A61P 29/00 (2006.01) CT 06340 (US). A61K 31/435 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/IB20 15/054072 AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (22) International Filing Date: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 29 May 2015 (29.05.2015) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (25) Filing Language: English KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (26) Publication Language: English PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (30) Priority Data: SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 62/004,935 30 May 2014 (30.05.2014) US TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 62/139,266 27 March 2015 (27.03.2015) US (84) Designated States (unless otherwise indicated, for every (71) Applicant: PFIZER INC. [US/US]; 235 East 42nd Street, kind of regional protection available): ARIPO (BW, GH, New York, New York 10017 (US). GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (72) Inventors: SWAIN, Nigel Alan; c/o Neusentis, Portway TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, Building, Granta Park, Great Abington Cambridge CB21 DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, 6GS (GB). BROWN, Alan Daniel; c/o Neusentis, Portway LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Building, Granta Park, Great Abington Cambridge CB21 SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, 6GS (GB). JONES, Lyn Howard; 8 Russett Lane, GW, KM, ML, MR, NE, SN, TD, TG). Winchester, Massachusetts 01890 (US). MARRON, Brian Edward; 4 North Poston Court, Durham, North Carolina Declarations under Rule 4.17 : 27705 (US). RAWSON, David James; c/o Pfizer Limited, — as to the identity of the inventor (Rule 4.1 7(Ϊ)) Ramsgate Road, Sandwich Kent CT13 9NJ (GB). RYCK- — as to applicant's entitlement to apply for and be granted a MANS, Thomas; c/o Pfizer Limited, Ramsgate Road, patent (Rule 4.1 7(H)) Sandwich Kent CT13 9NJ (GB). STORER, Robert Ian; c/o Neusentis, Portway Building, Granta Park, Great — as to the applicant's entitlement to claim the priority of the Abington Cambridge CB21 6GS (GB). WEST, Christoph¬ earlier application (Rule 4.1 7(in)) er William; 113 Ansley Walk Lane, Cary, North Carolina Published: 2751 8 (US). — with international search report (Art. 21(3)) (54) Title: BENZENESULFONAMIDES USEFUL AS SODIUM CHANNEL INHIBITORS Het (I) (57) Abstract: The invention relates to sulfonamide derivatives, to their use in medicine, to compositions containing them, to pro - cesses for their preparation and to intermediates used in such processes. More particularly the invention relates to a new sulfonamide Navl.7 inhibitors of formula (I), or a pharmaceutically acceptable salt thereof, wherein X, R 1, R2, R , R and R4 are as defined in the description. Nav 1.7 inhibitors are potentially useful in the treatment of a wide range of disorders, particularly pain. BENZENESULFONAMIDES USEFUL AS SODIUM CHANNEL INHIBITORS The invention relates to sulfonamide derivatives, to their use in medicine, to compositions containing them, to processes for their preparation and to intermediates used in such processes. Voltage-gated sodium channels are found in all excitable cells including myocytes of muscle and neurons of the central and peripheral nervous system. In neuronal cells, sodium channels are primarily responsible for generating the rapid upstroke of the action potential. In this manner sodium channels are essential to the initiation and propagation of electrical signals in the nervous system. Proper and appropriate function of sodium channels is therefore necessary for normal function of the neuron. Consequently, aberrant sodium channel function is thought to underlie a variety of medical disorders (see Hubner CA, Jentsch TJ , Hum. Mol. Genet, 11(20): 2435-45 (2002) for a general review of inherited ion channel disorders) including epilepsy (Yogeeswari et a/. , Curr. Drug Targets, 5(7): 589-602 (2004)), arrhythmia (Noble D., Proc. Natl. Acad. Sci. USA, 99(9): 5755-6 (2002)) myotonia (Cannon, SC, Kidney Int. 57(3): 772-9 (2000)), and pain (Wood, JN et ai, J. Neurobiol. , 6 1( 1) : 55-71 (2004)). There are currently at least nine known members of the family of voltage-gated sodium channel (VGSC) alpha subunits. Names for this family include SCNx, SCNAx, and Navx.x. The VGSC family has been phylogenetically divided into two subfamilies Nav1.x (all but SCN6A) and Nav2.x (SCN6A). The Navlx subfamily can be functionally subdivided into two groups, those which are sensitive to blocking by tetrodotoxin (TTX- sensitive or TTX-s) and those which are resistant to blocking by tetrodotoxin (TTX- resistant or TTX-r) . The Nav1.7 (PN 1, SCN9A) VGSC is sensitive to blocking by tetrodotoxin and is preferentially expressed in peripheral sympathetic and sensory neurons. The SCN9A gene has been cloned from a number of species, including human, rat, and rabbit and shows -90 % amino acid identity between the human and rat genes (Toledo-Aral et ai , Proc. Natl. Acad. Sci. USA, 94(4): 1527-1 532 ( 997)). An increasing body of evidence suggests that Nav1.7 may play a key role in various pain states, including acute, inflammatory and/or neuropathic pain. Deletion of the SCN9A gene in nociceptive neurons of mice led to a reduction in mechanical and thermal pain thresholds and reduction or abolition of inflammatory pain responses (Nassar et al. , Proc Natl Acad Sci USA, 10 1(34): 12706-1 1 (2004)). In humans, Nav1.7 protein has been shown to accumulate in neuromas, particularly painful neuromas (Kretschmer et al. , Acta. Neurochir. (Wien), 144(8): 803- 10 (2002)). Gain of function mutations of Nav1.7, both familial and sporadic, have been linked to primary erythermalgia, a disease characterized by burning pain and inflammation of the extremities (Yang et al. , J. Med. Genet. , 4 1(3): 171-4 (2004) , and paroxysmal extreme pain disorder (Waxman, SG Neurology. 7;69(6): 505-7 (2007)). Congruent with this observation is the report that the non-selective sodium channel blockers lidocaine and mexiletine can provide symptomatic relief in cases of familial erythermalgia (Legroux- Crepel et al. , Ann. Dermatol Venereol., 130: 429-433) and carbamazepine is effective in reducing the number and severity of attacks in PEPD (Fertleman et al, Neuron. ;52(5): 767-74 (2006). Further evidence of the role of Nav1 .7 in pain is found in the phenotype of loss of function mutations of the SCN9A gene. Cox and colleagues (Nature, 444(71 2 1) :894-8 (2006)) were the first to report an association between loss- of-function mutations of SNC9A and congenital indifference to pain (CI P), a rare autosomal recessive disorder characterized by a complete indifference or insensitivity to painful stimuli. Subsequent studies have revealed a number of different mutations that result in a loss of function of the SCN9A gene and and the C IP phenotype (Goldberg et al, Clin Genef.;71 (4): 3 11-9 (2007) , Ahmad et al, Hum Mol Genet. 1;16(1 7): 2 114-21 (2007)). Nav 1.7 inhibitors are therefore potentially useful in the treatment of a wide range of disorders, particularly pain, including: acute pain; chronic pain; neuropathic pain; inflammatory pain; visceral pain; and nociceptive pain. Certain inhibitors of voltage gated sodium channels useful in the treatment of pain are known. WO 2008/1 18758, WO 2009/01 2242, WO 201 0/079443, WO 201 2/004706, WO201 2/00471 4 and WO201 2/004743 disclose sulphonamides. There is, however, an ongoing need to provide new Nav1.7 inhibitors that are good drug candidates. Prefererably compounds are selective Nav1 .7 channel inhibitors. That is , preferred compounds show an affinity for the Nav1 .7 channel over other Nav channels. In particular, they show an affinity for the Nav1 .7 channel which is greater than their affinity for the Nav1 .5 channel. Advantageously, compounds should show little or no affinity for the Nav1 .5 channel. Selectivity for the Nav1 .7 channel over Nav1 .5 may potentially lead to one or more improvements in side-effect profile, such as with regard to any cardiovascular side effects which may be associated with affinity for the Nav 1.5 channel. Preferably compounds demonstrate a selectivity of 10-fold, more preferably 30-fold, most preferably 50-fold, for the Nav 1.7 channel when compared to their selectivity for the Nav1 .5 channel whilst maintaining good potency for the Nav1 .7 channel . Furthermore, preferred compounds should have good aqueous solubility. They should preferably exist in a physical form that is stable, non-hygroscopic and easily formulated (e.g for parenteral administration) . Ideal drug candidates should be non-toxic and demonstrate few side-effects. We have now found new sulphonamide Nav 1.7 inhibitors.
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