|HAO WAKAT I MARIAUS009937186B2 DEL CON AT MALAMAN NAT (12 ) United States Patent (10 ) Patent No. : US 9 , 937 , 186 B2 Ohlmeyer et al. (45 ) Date of Patent: Apr. 10 , 2018 ( 54 ) SULFONAMIDES DERIVED FROM USPC .. .. .. .. .. 514 / 217 TRICYCLYL - 2 - AMINOCYCLOALKANOLS See application file for complete search history . AS ANTICANCER AGENTS ( 71 ) Applicant: ICAHN SCHOOL OF MEDICINE ( 56 ) References Cited AT MOUNT SINAI, New York , NY U . S . PATENT DOCUMENTS (US ) 4 ,634 ,766 A 1 / 1987 Atkinson et al. (72 ) Inventors : Michael Ohlmeyer , Plainsboro , NJ 4 ,668 ,671 A 5 / 1987 Gribble et al . (US ) ; David Kastrinsky , Fair Lawn, NJ 4 , 882 , 351A 11/ 1989 Oshima et al . 6 ,583 , 138 B1 6 /2003 Miyamoto et al . (US ) 9 , 540 , 358 B2 1 / 2017 Ohlmeyer et al. 2002/ 0103189 A18 / 2002 Miyamoto et al. @(73 ) Assignee : ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI, New York , NY 2008/ 0275023 Al 11/ 2008 Guidi et al . (US ) (Continued ) ( * ) Notice : Subject to any disclaimer , the term of this FOREIGN PATENT DOCUMENTS patent is extended or adjusted under 35 CN 102942562 A 2 /2013 U . S . C . 154 (b ) by 0 days . EP 0679641 A1 11 / 1995 (21 ) Appl. No. : 15 /124 , 891 (Continued ) ( 22 ) PCT Filed : Mar. 10 , 2015 OTHER PUBLICATIONS Zhang et al, “ Akt, FoxO and regulation of apoptosis, ” Biochimica ( 86 ) PCT No .: PCT/ US2015 /019770 et Biophysica Acta , 2011 , vol. 1813 , pp . 1978 -1986 . * $ 371 (c ) ( 1 ) , (Continued ) ( 2 ) Date : Sep . 9 , 2016 (87 ) PCT Pub . No. : WO2015 / 138500 Primary Examiner — Kathrien A Cruz Assistant Examiner — Janet L . Coppins PCT Pub . Date : Sep . 17 , 2015 (74 ) Attorney, Agent, or Firm — Heslin Rothenberg (65 ) Prior Publication Data Farley & Mesiti P . C . US 2017 /0015625 A1 Jan . 19 , 2017 ( 57 ) ABSTRACT Related U . S . Application Data A genus of arylsulfonamide derivatives of aminocycloal ( 60 ) Provisional application No . 61/ 951 , 237 , filed on Mar . kanols is disclosed . The compounds are of the following 11 , 2014 . genus : ( 51 ) Int. Ci. A61K 31/ 517 ( 2006 .01 ) R 3 A61K 31 /55 ( 2006 .01 ) A61K 31 / 18 ( 2006 .01 ) UR4 C07C 311 /29 ( 2006 .01 ) CO7D 243 / 38 ( 2006 .01 ) OH 025 C070 471/ 04 ( 2006 .01 ) CO7D 265 / 38 ( 2006 . 01 ) NH CO7D 267 / 18 ( 2006 .01 ) CO7D 495 / 04 ( 2006 .01 ) R2 - + IT C07D 209 /86 ( 2006 .01 ) ( CH2) CO7D 487/ 04 ( 2006 .01 ) (52 ) U . S . CI. CPC . .. .. A61K 31 /55 ( 2013 .01 ) ; A61K 31/ 18 (2013 . 01 ) ; A61K 31/ 517 ( 2013 . 01) ; C07C 311/ 29 ( 2013 .01 ) ; C07D 209 /86 (2013 .01 ) ; The compounds induce FOXO1 transcription factor trans C07D 243 /38 (2013 . 01 ) ; C07D 265 / 38 location to the nucleus by modulating PP2A and , as a ( 2013 .01 ) ; C07D 267 / 18 (2013 . 01 ) ; C07D consequence , exhibit anti- proliferative effects . They are 471/ 04 (2013 . 01 ) ; C07D 487 /04 ( 2013 .01 ) ; useful in the treatment of a variety of disorders , including as C07D 495 /04 (2013 .01 ) ; C07C 2601/ 08 a monotherapy in cancer treatment, or used in combination ( 2017 .05 ) ; C07C 2601/ 14 ( 2017. 05 ) ; C07C with other drugs to restore sensitivity to chemotherapy 2603 / 18 ( 2017 .05 ) where resistance has developed . (58 ) Field of Classification Search CPC .. .. A61K 31/ 18 ; A61K 31/ 517 ; A61K 31/ 55 19 Claims, No Drawings US 9 ,937 , 186 B2 Page 2 ( 56 ) References Cited carbon bonds, " Chemical Communications, 2011 ( published on Web : Jun . 22, 2011) , vol. 47 , No . 29 , pp . 8343 - 8345 . U . S . 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In addition , PP2A directly regu TRICYCLYL - 2 - AMINOCYCLOALKANOLS lates FOXO3 a subcellular localization and transcriptional AS ANTICANCER AGENTS activation . Without wishing to be held to any particular theory , it may be that the compounds described herein CROSS REFERENCE TO RELATED 5 promote apoptosis by acting on FOXO transcription factors APPLICATIONS via activation of PP2A . This application is a U . S . National Phase filing under 35 Prostate cancer is the second leading cause of cancer U . S . C . $ 371 of International Application PCT/ US2015 / death in men in America , behind lung cancer. According to 019770 , filed Mar . 10 , 2015 , and published as WO 2015 / 10 the American Cancer Society , approximately 1 man in 36 138500 on Sep . 17 , 2015 . PCT/ US2015 /019770 claims will die of prostate cancer. Male hormones, specifically priority of U . S . provisional application 61 / 951 ,237 , filed testosterone , fuel the growth of prostate cancer. By reducing Mar. 11 , 2014 . The entire contents of each of the prior the amount and activity of testosterone, the growth of applications are incorporated herein by reference . advanced prostate cancer is slowed . Endocrine therapy , 15 known as androgen ablation , is the first line of treatment for