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| Hao Wakat I Maria Del Con at Malaman |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 . PATENT DOCUMENTS Azuine et al ., “ Cancer chemopreventive effect of phenothiazines and related tri- heterocyclic analogues in the 12 - 0 2015 /0376191 Al 12 / 2015 Ohlmeyer et al . tetradecanoylphorbol - 13 -acetate promoted Epstein - Barr virus early 2017 /0015630 A11 / 2017 Ohlmeyer et al . antigen activation and the mouse skin two - stage carcinogenes is models ,” Pharmacological Research , 2004 , vol. 49 , No . 2 , pp . FOREIGN PATENT DOCUMENTS 161 - 169 . EP 0881220 A112 / 1998 Ohshima, et al ., “ Non - Prostanoid Thromboxane A , Receptor WO 2004052847 A2 6 / 2004 Antagonists with a Dibenzoxepin Ring System . 2 " J . Med . Chem , wo 2006116157 A2 11 /2006 1992 , 35 , 3402 - 3413 . WO 2006117183 A1 11/ 2006 Morak -Mlodawska et al. , “ Acyl and Sulfonyl Derivatives of WO 2013025882 A2 2 / 2013 10 - Aminoalkyl- 2 , 7 - Diazaphenothiazines # , Hetrocycles ” , vol . 78 , WO WO2013025882 A2 * 2 / 2013 . C07D 417 /04 No . 5 , 2009 . WO 2014031986 Al 2 / 2014 WO 2014130534 Al 8 / 2014 Alfonso et al. , “ Synthesis of a Cu Spiropiperdino derivative of WO 2015138496 A1 9 / 2015 8 - Chloro - 6 , 11 -dihydro 5H - Benzo [ 5 , 6 ] cyclohepta [ 1 , 2 WO 2017 /024229 A1 2 / 2017 b ]pyridine ” , Tetrahedron Letters 39 , 1998 , 7661 -7664 . WO 2017 /044567 A1 3 /2017 Kau et al ., A chemical genetic screen identifies inhibitors of regu WO 2017 /044569 A1 3 / 2017 lated nuclear export of a Forkhead transcription factor in PTEN WO 2017 / 044571 AL 3 / 2017 deficient tumor cells , Cancer Cell, XP008037524 , Dec . 2003 . WO 2017 /044572 Al 3 / 2017 Jelen et al ., “ Synthesis of 6 - Aminoalkyldiquino - 1 , 4 - Thiazines and WO 2017 /044575 A1 3 / 2017 Their Acyl and Sulfonyl Derivatives, Heterocycles ” , vol . 4 , No. 4 , XP055279565 , 2008 . OTHER PUBLICATIONS Pluta et al. , “ Anticancer activity of newly synthesized azaphenothiazines from NCI ' s anticancer screening bank # ” , Phar Extended EP Search Report for EP 12823881. 3 dated Mar . 3 , 2015 . maceutical Reports , 2010 , 62 , 319 -332 . International Search Report for PCT/ US2012 /051097 dated Feb . 20 , Motohashi et al . , “ Synthesis and Biological Activity of 2013 . N - acylphenothiazines” International Journal of Antimicrobial International Search Report for PCT/ US2014 /017127 dated May Agents, 2000 , pp . 203 - 207 , vol. 14 . 20 , 2014 Database PubChemCompound , “ N - [ 4 -methoxy - 3 - ( 3 - phenothiazin Alfredsson et al. , “ Mass Fragmentographic Analysis of Clomip 10 - ylpropylsulfamoyl) phenyl ]acetamide ," URL : http : / /pubchem . ramine and Its Mono - Demethylated Metabolite in Human Plasma” ncbi. nlm . nih . gov / search . cgi, 2005 - 2009 . Psychopharmacology , 52 , 25 -30 ( 1977) . International Search Report for PCT/ US2015 /019764 dated May 8 , Midgley et al. , " Synthesis of [ 13C2] - Amitriptyline , Nortriptyline 2015 . and Desmethynortriptyline” Journal of Labelled Compounds and International Search Report for PCT/ US2016 /050685 dated Oct. 18 , Radiopharmaceuticals , vol . XV , pp . 511 -521 ( 1978 ) . 2016 . Hadrich et al ., “ Synthesis and Characterization of Fluorescent International Search Report for PCT/ US2016 /050688 dated Oct . 18 , Ligands for the Norepinephrine Transporter : Potential 2016 . Neuroblastoma Imaging Agents ” , J . Med . Chem . , 1999, (published International Search Report for PCT/ US2016 /045779 dated Sep . 30 , on web Jul. 16 , 1999 ) . 2016 . Runyon et al . , “ Influence of Chain Length and N - Alkylation on the International Search Report for PCT/ US2016 / 050690 dated Oct. 18 , Selective Serotonin Receptor Ligand 9 - (Aminomethyl ) - 9 , 10 2016 . dihydroanthracene” , Bioorganic & Medicinal Chemistry Letters 11 International Search Report for PCT /US2016 /050696 dated Oct. 18 , (2001 ) , 655 -658 . 2016 . Van Dort et al. , Synthesis of 11 C - Labeled Desipramine and its International Search Report for PCT /US2016 /050692 dated Oct. 18 , Metabolite 2 -Hydroxydesipramine : Potential Radiotracers for PET 2016 . Studies of the Norepinephrine Transporter , Nuclear Medicine & O ' Brien et al ., “ cis - and trans -Stereoselective Epoxidation of N -pro Biology, vol. 24 , pp . 707 - 711 , 1997 . tected 2 - Cyclohexen - 1 -ylamines , ” Organic Letters , 2003 , 14 ( 23 ) , Ilies et al. , “ Protease Inhibitors : Synthesis of Bacterial Collagenase 6012 -6015 . and Matrix Metalloproteinase Inhibitors Incorporating International Search Report & Written Opinion issued in PCT/ Arylsulfonylureido and 5 -Dibenzo - suberenyl / suberyl Moieties" , US2015 /019770 , dated May 8 , 2015 . Bioorganic & Medicinal Chemistry , 11 (2003 ) 2227 -2239 . RN 1350122 - 38 - 1 CAS Registry , entered STN : Dec. 7 , 2011 . Yang et al. , “ Catalytic decarboxylative alkylationof B -keto acids with sulfonamides via the cleavage of carbon - nitrogen and carbon * cited by examiner US 9 , 937 , 186 B2 SULFONAMIDES DERIVED FROM proapoptotic protein BIM . 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
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