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(12) United States Patent (10) Patent No.: US 8,907,101 B2 Beaudoin Et Al

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(12) United States Patent (10) Patent No.: US 8,907,101 B2 Beaudoin Et Al USOO8907101B2 (12) United States Patent (10) Patent No.: US 8,907,101 B2 Beaudoin et al. (45) Date of Patent: *Dec. 9, 2014 (54) SULFONAMIDE DERIVATIVES C07D 40/12 (2006.01) (71) Applicants: Pfizer Limited, Sandwich (GB); Icagen, C07D 417/12 (2006.01) Inc., Durham, NC (US) A613 L/496 (2006.01) (72) Inventors: Serge Beaudoin, Cary, NC (US); (52) U.S. Cl. Michael Christopher Laufersweiler, CPC ............ C07D 417/12 (2013.01); C07F 9/6539 Maineville, OH (US); Christopher John (2013.01); A61 K3I/675 (2013.01); A61 K Markworth, Bellingham, WA (US); 31/454 (2013.01); C07D 285/08 (2013.01); Brian Edward Marron, Durham, NC A6IK3I/433 (2013.01); C07D 263/50 (US); David Simon Millan, Sandwich (2013.01); A61K 45/06 (2013.01); A61 K (GB); David James Rawson, Sandwich 31/4439 (2013.01); COID 277/18 (2013.01); (GB); Steven Michael Reister, Cary, NC C07D 413/12 (2013.01); C07D 417/14 (US); Kosuke Sasaki, Osaka (JP); (2013.01); A61 K3I/501 (2013.01); A61 K Robert Ian Storer, Sandwich (GB); 31/427 (2013.01); C07D 275/03 (2013.01); Paul Anthony Stupple, Sandwich (GB); A6 IK3I/506 (2013.01); A61 K3I/4545 Nigel Alan Swain, Sandwich (GB); (2013.01); C07D 401/12 (2013.01); A61 K Christopher William West, Cary, NC 3 1/496 (2013.01) (US); Shulan Zhou, Chapel Hill, NC USPC ............ 546/290; 544/333; 514/345; 514/256 (US) (58) Field of Classification Search None (73) Assignees: Pfizer Limited, Sandwich (GB); Icagen, See application file for complete search history. Inc., Durham, NC (US) (*) Notice: Subject to any disclaimer, the term of this (56) References Cited patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. U.S. PATENT DOCUMENTS This patent is Subject to a terminal dis 3,905,971 A 9, 1975 Miller claimer. 4,782,056 A 11/1988 Rosner et al. (21) Appl. No.: 13/968,561 (Continued) (22) Filed: Aug. 16, 2013 FOREIGN PATENT DOCUMENTS (65) Prior Publication Data EP O532239 3, 1993 US 2013/0338111A1 Dec. 19, 2013 EP O569 193 11, 1993 (Continued) Related U.S. Application Data OTHER PUBLICATIONS (63) Continuation of application No. 13/400,356, filed on Feb. 20, 2012, now Pat. No. 8,541,588, which is a Hong, Guizhu, et al., PPARy activation enhances cell surface ENaCa continuation of application No. 12/685,913, filed on via up-regulation of SGK1 in human collecting duct cells, The Jan. 12, 2010, now Pat. No. 8,153,814. FASEB Journal, Oct. 2003, pp. 1966-1968, vol. 17. (60) Provisional application No. 61/258,760, filed on Nov. (Continued) 6, 2009, provisional application No. 61/245,726, filed on Sep. 25, 2009, provisional application No. Primary Examiner — Heidi Reese 61/143,920, filed on Jan. 12, 2009. (74) Attorney, Agent, or Firm — J. Michael Dixon (51) Int. Cl. (57) ABSTRACT A6 IK3I/44 (2006.01) C07D 21 1/72 (2006.01) The present invention relates to compounds of the formula CO7D 40/00 (2006.01) C07F 9/6539 (2006.01) A6 IK3I/675 (2006.01) (I) A6 IK3 L/454 (2006.01) CO7D 285/08 (2006.01) A6 IK3I/433 (2006.01) CO7D 263/50 (2006.01) A6 IK 45/06 (2006.01) A6 IK3I/4439 (2006.01) CO7D 413/2 (2006.01) and pharmaceutically acceptable salts, Solvates or tautomers CO7D 417/4 (2006.01) thereof, to processes for the preparation of intermediates A6 IK3I/50 (2006.01) used in the preparation of, and compositions containing Such A6 IK3I/427 (2006.01) compounds, and the uses of such compounds, in particular for C07D 275/03 (2006.01) the treatment of pain. A6 IK3I/506 (2006.01) A6 IK3 L/4545 (2006.01) 8 Claims, No Drawings US 8,907.101 B2 Page 2 (56) References Cited WO 2005.007621 1, 2005 WO 2005O13914 2, 2005 U.S. PATENT DOCUMENTS WO 2005054176 6, 2005 WO 2005116O26 12/2005 4,945,090 A 7, 1990 Schmiechen et al. WO 2006O14012 A2 2/2006 5,389,635 A 2, 1995 Olson WO 2006030925 3, 2006 6,087,392 A 7/2000 Reiter WO 2006051270 5, 2006 6,110,964 A 8, 2000 Robinson WO 2006060762 6, 2006 6, 197,810 B1 3/2001 Reiter WO 2006076644 T 2006 6,214,870 B1 4/2001 McClure et al. WO 2007OO2584 A1 1/2007 6,342,521 B1 1/2002 Reiter WO 2007002635 A2 1/2007 2001/0046989 A1 11/2001 Levin et al. WO 2007039171 A1 4, 2007 2003. O1581.86 A1 8, 2003 Malik et al. WO 2007076.034 7/2007 2004/01 10743 A1 6/2004 Miyamato et al. WO 2007.118859 10/2007 2004/0214870 A1 10, 2004 Xin et al. WO 2007125351 11, 2007 2005.00098.71 A1 1/2005 Ramesh et al. WO 2008002490 1, 2008 2005/0107364 A1 5/2005 Hutchinson et al. WO 200804621.6 A1 4, 2008 2005/02828.18 A1 12/2005 Ramesh et al. WO 2008050200 5, 2008 2006, O183745 A1 8, 2006 Bo et al. WO 200805728O 5, 2008 2007. O135431 A1 6, 2007 Smith et al. WO 2008057280 A1 5, 2008 2007/0167497 A1 7, 2007 Nambu et al. WO 20080792.91 A2 7, 2008 2008/0103129 A1 5/2008 Zhang et al. WO 2008118758 10, 2008 2008/0242656 Al 10/2008 Fryer et al. WO 2008137027 11, 2008 2008/0293706 A1 11/2008 Chaudhari et al. WO 200901 1850 1, 2009 2010.0056528 A1 3/2010 Yacovan et al. W. 29:22, 58 2011/OO77269 A1 3/2011 Martinborough WO 2009065131 5, 2009 WO 2009 127822 A2 10, 2009 FOREIGN PATENT DOCUMENTS WO 2009 129267 A2 10, 2009 EP 1088.819 4/2001 OTHER PUBLICATIONS EP 1201.238 5, 2002 GB 2263635 8, 1993 Payne, J., et al., “Identification of KD5170: A novel mercaptoketone JP 2064538 3, 1990 based histone deacetylase inhibitor'. Bioorganic and Medicinal JP 2007 231005 9, 2007 Chemistry Letters, vol. 18, No. 23, 2008, pp. 6093-6096. JP 2008214.222 9, 2008 WO 94.27979 A1 12, 1994 RN 1031058-98-6 Chemical Abstracts Registry database, Jun. 26. WO 9746.556 12/1997 2008, Aurora Fine Chemicals. WO 9942462 8, 1999 Kharul, Rajendra K., et al. “Efficient Synthesis of Structurally Novel WO O156989 A2 8, 2001 Diaryl Ethers by Regioselective Functionalization'. Synthetic Com WO 02051831 A1 T 2002 munications (2008), 38(23), pp. 4282-4294. WO O3O22277 A1 3, 2003 Ohta, B., “Studies on Chemotherapeutics, XVII. Intramolecular WO O3O48159 6, 2003 Rearrangement of p-Hydroxy-benzenesulfonamide Derivatives'. WO 2004.002481 A1 1, 2004 Yakugaku Zasshi (Series) vol. 71, 1951, pp. 315-318. WO 2004.014370 2, 2004 Reiter, L., et al., “Pyran-containing Sulfonamide hydroxamic acids: WO 2004084898 A1 10, 2004 potent MMP inhibitors that spare MMP-1”, Journal Bioorganic and WO 2004 103.980 12, 2004 Medicinal Chemistry Letters, vol. 14, No. 13, 2004, pp. 3389-3395. WO 2005.000309 1, 2005 Vippagunta, Adv. Drug Deliv. Rev., 2001, vol. 14, pp. 15-18. US 8,907,101 B2 1. 2 SULFONAMIDE DERVATIVES by tetrodotoxin (TTX-sensitive or TTX-s) and those which are resistant to blocking by tetrodotoxin (TTX-resistant or CROSS REFERENCE TTX-r). There are three members of the subgroup of TTX-resistant This application is a continuation of U.S. patent applica sodium channels. The SCN5A gene product (Na, 1.5, H1) is tion Ser. No. 13/400,356 filed Feb. 20, 2012, which is a almost exclusively expressed in cardiac tissue, is thought to continuation of U.S. patent application Ser. No. 12/685.913 play a central role in the generation of the cardia action filed Jan. 12, 2010 now U.S. Pat. No. 8,153,814 issued Apr. 4, potential and propagation of electrical impulses in the heart, 2012, which claims benefit under 35 USC 119(e) of U.S. and has also been shown to underlie a variety of cardiac 10 arrhythmias and conduction disorders (Liu H. et al., Am. J. Provisional Application 61/143,920, filed Jan. 12, 2009; U.S. Pharmacogenomics, 3(3): 173-9 (2003)). Consequently, Provisional Application 61/245,726, filed Sep. 25, 2009; and blockers of Nav1.5 have found clinical utility in treatment of U.S. Provisional Application 61/258,760, filed Nov. 6, 2009. such disorders (Srivatsa U, et al., Curr: Cardiol. Rep., 4(5): This invention relates to sulfonamide derivatives. More 401-10 (2002)), but binding of drugs to Nav1.5 may also particularly, this invention relates to heteroaryl substituted 15 result in abnormal cardiac rhythms. The remaining TTX Sulphonamide derivatives and to processes for the preparation resistant sodium channels, Nav1.8 (SCN10A, PN3, SNS) and of intermediates used in the preparation of compositions Nav1.9 (SCN11A, NaN, SNS2) are expressed in the periph containing, and the uses of Such derivatives. eral nervous system and show preferential expression in pri The sulfonamide derivatives of the present invention are mary nociceptive neurons. Human genetic variants of these Sodium channel modulators and have a number of therapeutic channels have not been associated with any inherited clinical applications, particularly in the treatment of pain. disorder. However, aberrant expression of Nav1.8 has been Voltage-gated Sodium channels are found in all excitable found in the CNS of human multiple sclerosis (MS) patients cells including myocytes of muscle and neurons of the central and also in a rodent model of MS (Black, JA, et al., Proc. Natl. and peripheral nervous system. In neuronal cells, sodium Acad. Sci. USA, 97(21): 11598-602 (2000)). Evidence for channels are primarily responsible for generating the rapid 25 involvement in nociception is both associative (preferential upstroke of the action potential.
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