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 .. 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