( 12 ) United States Patent
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US010233174B2 (12 ) United States Patent ( 10 ) Patent No. : US 10 ,233 , 174 B2 Long ( 45) Date of Patent : Mar. 19 , 2019 ( 54 ) THIOCARBAMATE PRODRUGS OF FOREIGN PATENT DOCUMENTS TOFACITINIB CN 106496233 A 3 /2017 WO 93 /22334 Al 11/ 1993 (71 ) Applicant : THERAVANCE BIOPHARMA R & D wo 2011 /097987 A1 8 / 2011 IP , LLC , South San Francisco , CA WO 2011097087 AL 8 / 2011 (US ) OTHER PUBLICATIONS ( 72 ) Inventor: Daniel D . Long , San Francisco , CA Amidon et al ., " Colon - targeted oral drug delivery systems: Design (US ) trends and approaches ” , AAPS PharmSciTech , 16 ( 4 ) : 731 - 741 ( 2015 ) . (73 ) Assignee : THERAVANCE BIOPHARMA R & D Azad Khan et al. , “ Tissue and bacterial splitting of sulphasalazine ” , IP , LLC , South San Francisco , CA Clinical Science, 64 : 349 - 354 ( 1983 ) . Bouvier et al. , “ First enzymatically activated Taxotere prodrugs (US ) designed for ADEPT and PMT” , Bioorganic & Medicinal Chem istry , 12 : 969 -977 (2004 ) . ( * ) Notice: Subject to any disclaimer, the term of this Bunnelle , “ Reagents for stereoselective preparation of N - carbamyl patent is extended or adjusted under 35 beta - D - glucuronides ” , The Journal of Organic Chemistry , 76 : 5429 5432 ( 2011 ) . U . S . C . 154 ( b ) by 0 days . Burke et al. , “ Development of novel quaternary ammonium linkers for antibody -drug conjugates ” , Molecular Cancer Therapeutics, (21 ) Appl. No. : 15 / 986 ,018 15 ( 5 ) : 938 - 945 (May 2016 ) . Chourasia et al. , “ Pharmaceutical approaches to colon targeted drug delivery systems” , J Pharm Pharmaceut Sci, 6 ( 1 ) : 33 -66 (2003 ) . ( 22) Filed : May 22 , 2018 Clark et al. , “ Discovery and development of Janus Kinase (JAK ) inhibitors for inflammatory diseases ” , Journal of Medicinal Chem istry , 57 : 5023 - 5038 ( 2014 ) . Prior Publication Data Danese, " New therapies for inflammatory bowel disease: from the US 2018 /0339980 A1 Nov. 29, 2018 bench to the bedside” , Gut, 61: 918 - 932 ( 2012 ) . Friend et al . , “ A colon - specific drug -delivery system based on drug glycosides and the glycosidases of colonic bacteria ” , J Med Chem , 27 : 261 - 266 ( 1984 ) . Related U . S . Application Data (Continued ) (60 ) Provisional application No . 62 /509 , 852 , filed on May Primary Examiner — Venkataraman Balasubramanian 23 , 2017 , provisional application No . 62/ 544, 318 , ( 74 ) Attorney, Agent, or Firm — Jeffrey A . Hagenah ; filed on Aug . 11 , 2017 . Florence Jovic (51 ) Int. CI. (57 ) ABSTRACT C07D 405 / 14 ( 2006 . 01 ) The invention relates to thiocarbamate prodrug compounds C07D 487 /04 ( 2006 .01 ) of the Janus kinase ( JAK ) inhibitor tofacitinib having for CO7H 15 / 26 ( 2006 . 01 ) mula 1: C12P 17 / 16 ( 2006 . 01 ) A61P 1 /00 ( 2006 . 01 ) A61K 31 / 7028 ( 2006 . 01 ) (52 ) U .S . CI. CPC . .. .. .. C07D 405 / 14 ( 2013 .01 ) ; A61K 31 / 7028 ( 2013 .01 ) ; A61P 1 /00 (2018 .01 ) ; C07D 487/ 04 -z ( 2013 .01 ) ; C07H 15 / 26 ( 2013 .01 ) ; C12P 17 / 165 ( 2013. 01 ) ( 58 ) Field of Classification Search CH3 CPC . .. CO7D 405 / 14 ; CO7D 487 /04 ; CO7H 15 / 26 ; N CH3 C12P 17 / 165 ; A61K 31 /7028 (( R2 ) ) :n 1 USPC .. .. 544 /280 ; 514 / 265. 1 R1 See application file for complete search history. HOCO O ( 56 ) References Cited HO Y " OH NC U . S . PATENT DOCUMENTS OH 5 ,811 , 388 A 9 / 1998 Friend et al. RE41 ,783 E 9 / 2010 Blumenkopf et al. wherein R1, R², RS, R4 and n are as defined . The invention 2011 /0086810 A1 4 / 2011 Rodgers et al. also relates to pharmaceutical compositions comprising such 2011 /0152207 AL 6 / 2011 Goff et al . compounds ; methods of using such compounds to treat 2012 / 0289571 AL 11/ 2012 Zhao et al . gastrointestinal inflammatory diseases, and processes and 2014 / 0357557 Al 12/ 2014 Cole et al. 2017 /0145044 A1 * 5 / 2017 Hudson .. C07H 15 / 26 intermediates for preparing such compounds . 2018 / 0258094 AL 9 / 2018 Long et al. 27 Claims, No Drawings US 10 , 233 , 174 B2 Page 2 References Cited Heller et al. , “ Oxazolone coatis , a Th2 colitis model resembling ( 56 ) ulcerative colitis , is mediated by IL - 13 - producing NK - T cells ” , Immunity , 17 : 629 -638 (Nov . 2002 ) . OTHER PUBLICATIONS Kodela et al. , “ NOSH -aspirin : a novel nitric oxide - hydrogen sulfide Friend et al. , “ Drug glycosides: Potential prodrugs for colon releasing hybrid : a new class of anti - inflammatory pharmaceuti cals ” , ACS Med Chem Lett, 3 : 257 - 262 ( 2012 ) . specific drug delivery ” , J Med Chem , 28: 51 - 57 (1985 ) . Lonnerholm et al. , “ Amount and distribution of carbonic anhydrases Friend , “ Glycosides in colonic drug delivery ” , Oral colon -specific CAI and CA II in the gatrointestinal tract" , Gastroenterology , 88 : drug delivery , pp . 153 - 187 ( 1992 ) . 1151 - 1161 ( 1985 ) . Goff et al. , “ Targeted delivery of vitamin D to the colon using Schmidt et al. , “ Prodrug mono therapy : synthesis and biological beta - glucuronides of vitamin D : therapeutic effects in a murine evaluation of an etoposide glucuronide - prodrug” , Bioorganic & model of inflammatory bowel disease” , Am J Physiol Gastrointest Medicinal Chemistry , 11 : 2277 -2283 (2003 ) . Liver Physiol , 302 : G460 -G469 ( 2012 ) . Schmidt et al. , “ Cancer chemotherapy : a paclitaxel prodrug for Jeffrey et al. , “ Expanded utility of the beta - glucuronide linker : ADEPT ( antibody -directed enzyme prodrug therapy ) ” , Eur J Org Chem , pp . 2129 -2134 (2001 ) . ADCs that deliver phenolic cytotoxic agents ” , ACS Medicinal Steiger et al. , “ Bio - orthogonal “ click -and - release ” donation of caged Chemisty Letters , 1 : 277 - 280 ( 2010 ) . carbonyl sulfide (COS ) and hydrogen sulfide (H2S ) ” , Chem Com Kagan et al. , “ Systems for region selective drug delivery in the mun , 53 : 1378 -1380 (2017 ) . gastrointestinal tract : biopharmaceutical considerations ” , Expert Steiger et al. , “ Self - immolative thiocarbamates provide access to Opin Drug Deliv , 5 ( 6 ) : 681 -692 ( 2008 ) . triggered H2S donors and analyte replacement fluorescent probes” , Kolakowski et al . , “ The methylene alkoxy carbamate self J Am Chem Soc, 138 : 7256 -7259 (2016 ) . immolative unit : utilization for the targeted delivery of alcohol Tan et al. , “ New method for quantification of gasotransmitter containing payloads with antibody - drug conjugates” , Angew Chem hydrogen sulfide in biologicalmatrices by LC -MS / MS ” , Nature , pp . Int Ed , 55 : 1 - 5 ( 2016 ) . 1 - 12 ( 2017 ) . Kolakowski et al ., “ The methylene alkoxy carbamate self Wallace et al. , " Gastrointestinal safety and anti - inflammatory effects immolative unit : utilization for the targeted delivery of alcohol of a hydrogen sulfide - releasing diclofenac derivative in the rat ” , containing payloads with antibody - drug conjugates ” , Angew Chem Gastroenterology , 132 : 261- 271 ( 2007 ) . Int Ed , 55 : 1 - 5 Supporting Information (2016 ) . Wallace et al. , “ Hydrogen sulfide -based therapeutics : exploiting a Lam et al. , “ Vedolizumab for ulcerative colitis and Crohn ' s disease : unique but ubiquitous gasotransmitter” , Nature Reviews, 14 : 329 results and implications of GEMINI studies” , Immunotherapy , 6 ( 9 ) : 345 (May 2015 ) . 963 - 971 ( 2014 ) . Angenault et al ., " Cancer chemotherapy: A SN - 38 ( 7 -ethyl - 10 Lougerstay -Madec et al. , “ Synthesis of self- immolative glucuronide hydroxycamptothecin ) glucuronide prodrug for treatment by a based prodrugs of a phenol mustard ” , Anti - Cancer Drug Design , 13 : PMT (prodrug montherapy ) strategy ” , Bioorganic & Medicinal Chem 995 - 1007 ( 1998 ) . istry Letters, 13 : 947 - 950 (2003 ) . Mozaffari et al. , “ New biologic therapeutics for ulcerative colitis Desbene et al. , “ Application of the ADEPT strategy to the MDR and Crohn ' s disease” , Expert Opin Biol Ther, 14 ( 5 ) : 583 -600 resistance in cancer chemotherapy ” , Anti- cancer Drug Design , ( 2014 ) . 14 ( 2 ) : 93 - 106 ( 1999 ) . Panes et al. , “ Randomized trial of tofacitinib in active ulcerative Desbene et al. , “ Application of the ADEPT strategy to the MDR colitis : analysis of efficacy based on patient- reported outcomes ” , resistance in cancer chemotherapy ” , XP- 002780712 ( 1999 ). BMC Gastroenterology , 15 : 14 - 23 ( 2015 ) . Goto et al ., “ Synthesis and biological activity of the metabolites of Philip et al. , “ Colon targeted drug delivery systems: A review on diethyl 4 - [ ( 4 -bromo - 2 -cyanophenyl ) carbamoyl] benzylphosphonate primary and novel approaches ” , Oman Medical Journal, 25 ( 2 ) : (NO - 1886 ) ” , Chem Pharm Bull , 44 ( 3 ) : 547 -551 ( 1996 ) . 70 - 78 (2010 ) . Kiss et al. , “ Synthesis and O . R . D ./ C . D . spectra of the anomers of Sandborn et al. , “ Tofacitinib , an oral janus kinase inhibitor, in active 2 - amino - 5 - ethoxyphenyl d - glucopyranosiduronic acid and some ulcerative colitis ” , The New England Journal of Medicine , pp . derivatives thereof” , Carbohydrate Research , 12 : 115 - 129 ( 1970 ) . 616 -624 ( 2012 ) . Kreuzer et al. , “ Aufbau von oligosacchariden mit glycosylfluoriden Scheline, “ Drug metabolism by intestinal microorganisms” , Journal unter lewissaure -katalyse ” , Carbohydrate Research , 149 : 347 -361 of Pharmaceutical Sciences , 57 ( 12 ) : 2021- 2037 ( 1968 ) . ( 1986 ) . Schmidt et al. , " Glucuronide prodrugs of hydoxy compounds for Papot et al. , “ Design of selectively activated anticancer prodrugs : antibody directed enzyme prodrug therapy (ADEPT ) : a phenol Elimination and cyclization strategies ” , Current Medicinal Chem nitrogen mustard carbamate ” , Bioorganic & Medicinal Chemistry istry , 2 ( 2 ) : 155 -185 (2002