US009937259B2 (12 ) United States Patent ( 10 ) Patent No. : US 9 ,937 ,259 B2 Sun (45 ) Date of Patent : Apr . 10 , 2018
(54 ) ABIRATERONE DERIVATIVES AND 8 ,927 ,694 B2 1 /2015 McDonagh et al . 8, 927 , 725 B2 1 / 2015 Greig et al. NON -COVALENT COMPLEXES WITH 9 ,150 ,585 B2 10 / 2015 Sun ALBUMIN 2009 /0253651 A1 10 / 2009 Norbedo et al. (71 ) Applicant: Zhuhai Beihai Biotech Co ., Ltd ., 2011/ 0021567 A1 1 / 2011 Devarakonda et al. 2012 /0177743 Al 7 /2012 Desai et al. Zhuhai (CN ) 2012 /0283292 AL 11 /2012 Milne et al . ( 72 ) Inventor: Qun Sun , Princeton , NJ (US ) 2014 /0024807 A1 1 / 2014 Salamone et al . 2014 /0135356 A1 5 / 2014 Sun ( 73 ) Assignee : Zhuhai Beihai Biotech Co. , Ltd . , 2015 / 0290332 A1 10 / 2015 Kim et al . Zhuhai (CN ) 2015 / 0291562 A1 10 / 2015 Crew et al. ( * ) Notice : Subject to any disclaimer , the term of this 2015 /0366984 Al 12 / 2015 Sun patent is extended or adjusted under 35 2016 /0145314 A15 /2016 Li et al . U . S . C . 154 ( b ) by 0 days . FOREIGN PATENT DOCUMENTS (21 ) Appl. No. : 15 /320 , 353 CN 1863790 11 / 2006 EP 2007386 8 / 2012 WO WO2003066595 8 / 2003 ( 22 ) PCT Filed : Jun . 26 , 2015 WO WO2005030753 4 / 2005 WO WO2008133973 11 / 2008 (86 ) PCT No .: PCT/ US2015 /038077 wo WO2009023539 2 / 2009 WO WO2009074678 6 / 2009 $ 371 (c ) ( 1 ) , WO WO2009126920 10 / 2009 ( 2 ) Date : Dec. 20 , 2016 WO WO2010092342 8 / 2010 WO WO2011085000 7 / 2011 (87 ) PCT Pub . No. : WO2015 / 200837 WO WO2014121033 8 / 2014 PCT Pub . Date : Dec . 30 , 2015 OTHER PUBLICATIONS Marbury et al, Chemical Abstract 162: 265369 , Abstract of Journal (65 ) Prior Publication Data of Clinical Pharmacology, 53 ( 7 ) , pp . 732 - 741 ( Year: 2013 ) * International Preliminary Report on Patentability for PCT/ US2015 / US 2017 / 0216443 A1 Aug. 3, 2017 056900 , dated May 4 , 2017 , 6 pages. International Search Report and Written Opinion for PCT/ US2015 / 056900 , dated Dec . 29, 2015, 13 pages . Related U .S . Application Data “ Multiple Myeloma: Treatment Options, ” Cancer. Net [ online ] Sep . 2014 ( retrieved on Sep . 23 , 2014 ] . Relieved from the Internet: (60 ) Provisional application No . 62 /046 ,616 , filed on Sep . < URL : http : // www .cancer . net /cancer -types /multiple -myeloma / 5 , 2014 , provisional application No. 62 /018 , 236 , filed treatment -options > , 7 pages . on Jun . 27 , 2014 . “ Myelodysplastic Syndromes Treatment ( PDQ® ) ,” Cancer .gov [ online ] Jun . 11, 2014 [retrieved on Sep . 24 , 2014 ] . Retrieved from (51 ) Int. Ci. the Internet : < URL : http :/ / www . cancer .gov /cancertopics /pdq / treat ment/ myelodysplastic /page1 / AllPages/ Print> , 17 pages . C07D 213/ 02 ( 2006 .01 ) “ POMALYST® (pomalidomide ) capsules, for oral use ,” (prescrib C07J 43/ 00 ( 2006 . 01 ) ing informations ], Feb . 2013 , 13 pages . A61K 31/ 44 ( 2006 .01 ) “ REVLIMID ?lenalidomide ) capsules , for oral use, ” (prescribing A61K 31/ 58 ( 2006 .01 ) information ], Jun . 2013 , 33 pages A61K 47/ 42 (2017 .01 ) “ Revlimid® (lenalidomide ) capsules Data sheet , " 22 pages , Apr. 2013 . ( 52 ) U .S . CI. “ ZYTIGA? ( abiraterone acetate ) Tablets, ” [prescribing informa CPC ...... A61K 47/ 42 (2013 .01 ) ; A61K 31/ 58 tion ] , Dec . 2012 , 9 pages . ( 2013 .01 ) ; C07J 43/ 003 ( 2013 . 01 ) Accession No . 158 : 253017 CA , 1 page , 2012 ( 58 ) Field of Classification Search Accession No . 158 :662530 CA , 1 page , 2012 . None Akhtar et al. , " Cytochrome b ( 5 ) modulation of 17 {alpha } See application file for complete search history. hydroxylase and 17 -20 lyase (CYP17 ) activities in steroidogenesis, ” J Endocrinol. , 187 ( 2 ) : 267 -274 , Nov . 2005 . Birder et al . , “ Altered urinary bladder function in mice lacking the ( 56 ) References Cited vanilloid receptor TRPV1, " Nat . Neurosci. , 5 ( 9 ) :856 - 360 , Sep . 2002 . U . S. PATENT DOCUMENTS (Continued ) 5 ,604 , 213 A 2 / 1997 Barrie et al. 5 ,635 ,517 A 6 / 1997 Muller et al . Primary Examiner — Zinna Northington Davis 7 , 445 , 764 B1 11/ 2008 Kratz (74 ) Attorney , Agent, or Firm — Fish & Richardson P .C . 7 , 452 , 900 B2 11 / 2008 Marzi 7 , 498 , 340 B2 3 / 2009 Marzi (57 ) ABSTRACT 7 , 576 , 104 B2 8 / 2009 Robarge et al. The present disclosure provides derivatives of abiraterone , 7 , 772 , 254 B2 8 / 2010 Sun non - covalently bound complexes of the abiraterone deriva 7 , 820 , 788 B2 10 / 2010 Desai et al. tives with serum albumin , pharmaceutical compositions of 7 . 923 , 536 B2 4 / 2011 Desai et al. the same, and methods of use thereof. The non -covalently 8 ,076 , 474 B2 12 / 2011 Hunt bound complexes are significantly more water - soluble than 8 , 138 , 229 B2 3 / 2012 Desai et al. abiraterone and are useful for the treatment of a disease or 8 , 338 , 588 B2 12 / 2012 Hunt condition that can benefit from CYP17 inhibition , such as 8 , 748, 610 B2 6 / 2014 Sun 8 , 853 , 260 B2 10 / 2014 Desai et al. prostate cancer. 8 , 911, 775 B2 12/ 2014 Lee et al . 19 Claims, 4 Drawing Sheets US 9 , 937 ,259 B2 Page 2
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Lin et al. , “ Stability of human serum albumin during bioprocessing : 24 , 2014 ] . Retrieved from the Internet: < URL : https: / /clinicaltrials . denaturation and aggregation during processing of albumin paste ," gov /ct2 / show /NCTO 1358734 ? term = lenalidomide & rank = 15 % , 4 Pharm Res ., 17 (4 ): 391 - 396 , Apr. 2000 . pages . Lipinski, “ Drug - like properties and the causes of poor solubility and ClinicalTrials .gov Identifier: NCT01460940 , “ A Phase II Trial of poor permeability , ” J Pharmacol Toxicol Methods, 44 ( 1 ) : 235 - 249, Panobinostat and Lenalidomide in Patients with Relapsed or Refrac Jul. - Aug. 2000 . tory Hodgkin ' s Lymphoma, " ClinicalTrials . gov [online ] Jul. 15 , Lopez -Gomez , “ Management of colorectal cancer patients after 2013 [ retrieved on Sep . 24 , 2014 ] . 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References Cited Trudeau et al ., “ Docetaxel in patients with metastatic breast cancer: ( 56 ) a phase II study of the National Cancer Institute of Canada -Clinical OTHER PUBLICATIONS Trials Group , ” J Clin Oncol. , 14 ( 2 ) :422 -428 , Feb . 1996 . Trynda -Lemiesz , “ Effect of cis - , trans - diam Rajkumar et al. , “ Combination therapy with lenalidomide plus minedichloroplatinum ( II ) and DBP on human serum albumin ,” J Inorg Biochem . , 77 ( 3 - 4 ) : 141 - 146 , Nov. -Dec . 1999 . dexamethasone (Rev / Dex ) for newly diagnosed myeloma, ” Blood , Tullis , “ Albumin . 1. Background and use, ” JAMA. , 237 (4 ) :355 - 360 , 106 ( 13 ): 4050 - 4053 , Epub Aug . 23, 2005. Jan . 24 , 1977 . Ratain , “ Flushing oral oncology drugs down the toilet, ” J Clin Vannucchi, “ Management of myelofibrosis , ” Hematology Am Soc Oncol. , 29 (30 ) :3958 -3959 , Epub Sep . 19 , 2011. Hematol Educ Program ., 2011: 222 - 230 , 2011. Ryan et al. , “ Structural basis of binding of fluorescent, site - specific Vorum , “ Reversible ligand binding to human serum albumin . Theo dansylated amino acids to human serum albumin , ” Journal of retical and clinical aspects, ” Dan Med Bull. , 46 ( 5 ) :379 - 399 , Nov . Structural Biology ., 174 : 84 - 91, 2011 . 1999 . Samor et al. , “ The role of polyamine architecture on the pharma Walker et al. , “ The VR1 antagonist capsazepine reverses mechani cological activity of open lactone camptothecin -polyamine conju cal hyperalgesia in models of inflammatory and neuropathic pain , " gates, ” Bioconjug Chem ., 19 ( 11) : 2270 - 2279 , Nov. 19 , 2008 . J . Pharm . Exp . Ther. , 304 ( 1 ) : 56 -62 , Jan . 2003 . Sartor et al. , “ Novel therapeutic strategies for metastatic prostate Yu et al. , “ Spectroscopic investigation of the interaction between cancer in the post -docetaxel setting, ” Oncologist. , 16 ( 11) : 1487 camptothecin and bovine serum albumin , ” Fenxi Shiyanshi, 31 ( 1 ) : 1497, Epub Nov. 2, 2011. 42 -46 , 2012 [ English abstract ] . Schmid et al ., “ Development of albumin -binding camptothecin Zhang , “ Methoxy poly ( ethylene glycol) conjugated denatured prodrugs using a Peptide positional scanning library ,” Bioconjug bovine serum albumin micelles for effective delivery of Chem ., 18 (6 ): 1786 - 1799 , Epub Oct. 5, 2007 . camptothecin , ” Polym Chem , 3 ( 8 ) : 1958 - 1961, Aug . 2012 . Semeraro et al. , “ Trial Watch : Lenalidomide -based Zsila , “ Evaluation of drug -human serum albumin binding interac immunochemotherapy, ” 2 ( 11) : e26494 . Epub Oct. 21, 2013 . tions with support vector machine aided online automated docking ," Silverman and Holladay, The Organic Chemistry of Drug Design Bioinformatics, 27 ( 13 ) : 1806 - 1813 , Epub May 18 , 2011 . and Drug Action , Elsevier, pp . 29 - 32 , 2004 . Zu et al ., “ Preparation of 10 -hydroxycamptothecin - loaded glycyr Sugio et al. , “ Crystal structure of human serum albumin at 2 . 5 A rhizic acid -conjugated bovine serum albumin nanoparticles for resolution , ” Protein Eng. , 12 ( 6 ) :439 -446 , Jun . 1999 . hepatocellular carcinoma- targeted drug delivery, ” Int J Todd et al. , “ Fast and flawed or scientifically sound : the argument Nanomedicine. , 8 : 1207 - 1222 , Epub Mar. 27 , 2013 . for administering oral oncology drugs during fasting, " J Clin Oncol. , 30 ( 8 ) :888 - 889 , Epub Feb . 13 , 2012 . * cited by examiner atent Apr . 10 , 2018 Sheet 1 of 4 US 9 ,937 , 259 B2
Individual and Mean Plasma Concentration -time Data of Comp B - 001 after an IV Dose of 1004 mg/ kg the B - 001 and HSA complex in SD Rats
Rat # 1 - 0 - Rat # 2 Rat # 3 PlasmaConcentration(ng/mL)
Time ( hr)
271111 111111 FIG . 1. atent Apr . 10 , 2018 Sheet 2 of 4 US 9 ,937 , 259 B2
Individual and Mean Plasma Concentration - time Data ofMetabolite (Abiraterone ) after an IV Dose of 1004 mg/ kg the B - 001 and HSA complex in SD Rats Rat # 1 -- 0 -- Rat # 2 + Rat # 3 PlasmaConcentration(ng/mL)
Time (hr )
FIG . 2 . atent Apr . 10 , 2018 Sheet 3 of 4 US 9 ,937 , 259 B2
Individual Plasma Concentration - time Data of Comp B -003 after an IV Dose of 932 mg/kg B - 003 and HSA complex in SD Rats
Rat # 1 - - - Rat # 2 + Rat # 3 vreerrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrr PlasmaConcentration(ng/mL) Time (hr )
wwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww FIG . 3 . atent Apr . 10 , 2018 Sheet 4 of 4 US 9 ,937 , 259 B2
Individual Plasma Concentration - time Data of Metabolite ( Abiraterone ) after an I Dose of 932 mg /kg B -003 and HSA complex in SD Rats
Rat # 1 - O - Rat # 2 + Rat # 3 PlasmaConcentration(ng/mL)
Time (hr )
FIG . 4 . US 9 ,937 , 259 B2 ABIRATERONE DERIVATIVES AND actions with other administered drugs that inhibit or induce NON -COVALENT COMPLEXES WITH CYP3A4 . See ZytigaTM Full Prescribing Information , 2012 , ALBUMIN Janssen Biotech Inc . , Section 7 . 2 . The development of soluble abiraterone derivatives 5 would allow for IV dosing, which bypasses the liver , and CROSS REFERENCE TO RELATED could alleviate some of the aforementioned problems. APPLICATIONS Accordingly , there is a clear and continuing need to create This application is a national stage application under 35 more soluble forms of abiraterone. U . S . C . $ 371 of International Application No. PCT/ US2015 / SUMMARY 038077 , filed on Jun . 26 , 2015 , which claims the benefit of 10 An aspect of the current disclosure provides a non U . S . Provisional Ser . No. 62 /018 , 236 filed Jun . 27 , 2014 and covalently bound complex of an abiraterone derivative and U . S . Provisional Ser. No . 62 /046 ,616 filed Sep . 5 , 2014 . The human serum albumin in a molar ratio from about 1 : 1 to entire contents of the above applications, including draw about 10 : 1 , wherein the non - covalently bound complex has ings , are incorporated by reference . 15 a solubility in aqueous solution of at least 5 mg/mL , and the abiraterone derivative comprises a compound of Formula TECHNICAL FIELD ( 1 ) : This disclosure relates to abiraterone derivatives , non covalent complexes of the derivatives with albumin , for example , human serum albumin , methods of preparation and 20 pharmaceutical uses thereof . BACKGROUND About 30 % of drugs that appear on the World Health 25 Organization (WHO ) Essential Drug List were reported to be poorly water -soluble , based on the Biopharmaceutics hu Classification System (BCS ). See , for example , Kasim , N . A ., et al. , Molecular properties of WHO essential drugs and provisional biopharmaceutical classification , Molecular 30 Pharmaceutics 2004 , 1 ( 1 ) : p . 85 - 96 . Over 40 % of newly developed pharmaceutically active substances have solubil ity issues. See Lipinski, C . A . , Drug - like properties and the causes of poor solubility and poor permeability , Journal of Pharmacological and Toxicological Methods 2000 , 44 ( 1 ) : p . 35 235 - 249 . The poor dissolution and / or permeability of these drugs often results in low , but highly variable , bioavailabil wherein ity . Further, a major obstacle of successfully commercializ A is a covalent bond , O , or NR ' ; ing these compounds is the difficulty of enhancing their R1 is H , lower alkyl, or alkaryl, wherein the alkyl or alkaryl is optionally substituted with 1 - 3 substituents inde dissolution rate and extent of dissolution . pendently selected from the group consisting of: halo , nitro , For example , abiraterone acetate is approved in the United amine , amide , hydroxyl, O - lower alkyl, and carboxy ; and States as an oral treatment for metastatic castration - resistant is a group that selectively binds to human serum prostate cancer . The product insert describes abiraterone albumin . acetate as a lipophilic compound that is practically insoluble The present disclosure further provides a compound , or a in water. See ZytigaTM Full Prescribing Information , 2012 , 45 pharmaceutically acceptable salt thereof, according to For Janssen Biotech Inc ., Section 11 . While the insolubility of mula ( II ) : abiraterone acetate allows for its preparation in capsule form for oral dosing, it precludes intravenous ( IV ) administration which is used for other treatments of prostate cancer , such as ( II) cabazitaxel. See Sartor, O . et al. The Oncologist 2011 , 16 : 50 1487 - 1497 . Due to its insolubility , abiraterone acetate suffers from low bioavailability that arises from poor absorption , as 77 % of the administered drug is excreted . See Ratain , M . J . Journal of Clinical Oncology 2011, 29 (30 ) : 3958 - 3959 ) . 55 Thus , most of the administered drug is not used for its intended treatment . The low water solubility of abiraterone acetate has led to funt a food -effect that is greater than any other marketed drug ( five - to ten - fold , depending on fat content of the meal) , and 60 significant interindividual pharmacokinetic variability . This food - effect can also afford a large intraindividual variability, resulting in underdosing or overdosing . Thus, strict patient compliance is required to achieve the dosing under labeled - conditions 65 Further, abiraterone acetate is a substrate of the CYP3A4 liver enzyme , which can lead to potential drug- drug inter US 9 , 937 , 259 B2 wherein each heteroatom replaces a CH , with the proviso that no 0 , A is a covalent bond , O , or NR '; S , or N atom in the C - alkyl , C2- 8 alkenyl or C2- 8 alkynyl L is alkyl, alkenyl, alkynyl , carbocyclyl , carbocyclylalkyl, is covalently bonded to another O , S , or N atom ; aryl, alkaryl , or R3 is independently in each instance H , alkyl , phenyl, or alkaryl , wherein the alkyl, phenyl, or alkaryl is optionally substituted with 1 - 3 substituents independently selected mi mm from the group consisting of : halo , - NO2, CF3, amido , 10 sulfonamide , aryl, OH , alkyl, O - lower alkyl, O alkaryl, and - O - aryl ; each of which is optionally substituted with 1 - 3 substituents R4 is independently in each instance H , OH , NO2, NH ,, independently selected from the group consisting of halo , NH3* , SH , or a branched or unbranched C1- 10 alkyl, C2- 10 - NO2, amine , amide, hydroxyl , O - lower alkyl, and 15 alkenyl or C2- 10 alkynyl, wherein the C1- 10 alkyl , C2- 10 - COOH , provided that there be no covalent bonds between alkenyl or C2- 10 alkynyl is optionally substituted with 1 -2 oxygen atoms; substituents independently selected from the group consist W is ing of halo , OH , NO2, NH , NH3 , SH , and = O , and wherein the C1- 10 alkyl , C2- 10 alkenyl or C2- 10 alkynyl 20 optionally has 1 -2 heteroatoms independently selected from ni 0 , S and NH wherein each heteroatom replaces a CH2, with the proviso that no 0 , S , or N atom in the C1 -10 alkyl, C2 -10 alkenyl, or C2- 10 alkenyl is covalently bonded to another O , 25 S , or N atom ; C COOHCOOL , ON C + COOH , R is H , alkyl, phenyl, or alkaryl, wherein the alkyl , P phenyl, or alkaryl is optionally substituted with 1 - 3 sub A LR3 , stituents independently selected from the group consisting 30 of: halo , — NO , , - CFz , amido , sulfonamide , aryl, — OH , alkyl, - O - lower alkyl, - O -alkaryl , and - O - aryl; R and R7 are each independently H or lower alkyl, optionally substituted with 1 - 3 substituents independently selected from the group consisting of halo , nitro , amine , 35 Selectamide , hydroxyl, O - lower alkyl and carboxy ; R3 - N B is a covalent bond , O or NRj; p is 1 , 2 , 3 , 4 , 5 , or 6 ; B n is 1 , 2 , 3 , 4 , 5 , or 6 ; and c + COOH , COOH , or 40 r is 1, 2 , 3 , 4 , 5, 6 , 7 , 8 , 9, or 10 . 3 ) The disclosure further provides a compound , or pharma ceutically acceptable salt thereof, according to Formula (III ) : 45
ni o R2 ] (III ) 2 + c + 0 + 0 + COOH ; 50 M R ? ] , RÓ R3 ]
R ! is H , lower alkyl, or alkaryl, wherein the alkyl or 55 alkaryl is optionally substituted with 1 - 3 substituents inde .11 pendently selected from the group consisting of: halo , NO2, amine , amide , hydroxyl , O - lower alkyl, and — COOH ; R ? is independently in each instance H , OH , NO2, NH2, 60 NH3 * , SH , or a branched or unbranched C1- 8 alkyl, C2- 8 alkenyl, or C2- 3 alkynyl , wherein the C1- 3 alkyl, C2- 8 alkenyl, or C2- 3 alkynyl is optionally substituted with 1 - 2 substituents - independently selected from the group consisting of halo , OH , NO2, NH , NH3 * , SH and = 0 , and wherein the C1- 8 65 - alkyl, C2- alkenyl or C2- 8 alkynyl optionally has 1 - 2 het eroatoms independently selected from 0 , S , and NH wherein US 9 ,937 ,259 B2 wherein eroatom replaces a CH , with the proviso that no 0 , S A is a covalent bond , O , or NR '; or N atom in the C1- 10 alkyl, C2- 10 alkenyl or C2- 10 L " is a linker including a — s — S — moiety ; alkynyl is covalently bonded to another O , S or N atom ; W is RS is H , alkyl, phenyl, or alkaryl, wherein the alkyl, 5 phenyl , or alkaryl is optionally substituted with 1 -3 substituents independently selected from the group consisting of: halo , - NO2, – CF3, amido , sulfona man mide , aryl, - OH , alkyl, O -lower alkyl, O -alkaryl , - 10 and O -aryl ; min R and R7 are each independently H or lower alkyl, AT optionally substituted with 1 - 3 substituents indepen 0? dently selected from the group consisting of halo , nitro , - COOH , C COOH , amine , amide, hydroxyl, O - lower alkyl and carboxy ; 1 LR' n 15 B is a covalent bond , O or NRj; B?R p is 1 , 2 , 3 , 4 , 5 , or 6 ; and n is 1 , 2 , 3 , 4 , 5 , or 6 . mon The application also describes a non - covalently bound R - N 20 complex of the compound of Formula (I ), Formula ( II ), and /or Formula ( III) , or pharmaceutically acceptable salt thereof, and human serum albumin in a molar ratio from about 1 : 1 to about 10 : 1 , wherein the non - covalently bound + COOH , COOH , or complex has solubility in aqueous solution of at least 5 25 mg/ mL . Jn Additionally provided is a pharmaceutical composition including a non - covalently bound complex as described wins herein , and a pharmaceutically acceptable carrier . 20o R7 [ R27 [ R4 An aspect of the application is a method of treating - N + c + 0 + 0 + COOH ; 30 prostate cancer, the method including the step of adminis tering to the subject in need thereof a therapeutically effec - R2 ] , R6 [ R3 ] tive amount of a pharmaceutical composition as described herein . 35 Unless otherwise defined , all technical and scientific R ! is H , lower alkyl, or alkaryl, wherein the alkyl or terms used herein have the same meaning as commonly alkaryl is optionally substituted with 1 - 3 substituents understood by one of ordinary skill in the art to which this independently selected from the group consisting of: disclosure belongs. Methods and materials are described halo , NO , , amine , amide, hydroxyl , O - lower alkyl, and herein for use in the present disclosure; other , suitable _ COOH ; 40 methods and materials known in the art can also be used . R is independently in each instance H , OH , NO , , NH , , The materials , methods, and examples are illustrative only NH + , SH , or a branched or unbranched C . , alkyl, C , and not intended to be limiting . All publications, patent alkenyl, or Cz. , alkynyl, wherein the Cys, alkyl, Cze applications, patents , and other references mentioned herein alkenyl or C2- 8 alkynyl is optionally substituted with are incorporated by reference in their entirety . In case of 1 - 2 substituents independently selected from the group 45 conflict , the present specification , including definitions , will consisting of halo , OH , NO2, NH , NHZ , SH and = O , control. and wherein the C1- 3 alkyl, C2- 3 alkenyl or C2- 8 alkynyl Other features and advantages of the disclosure will be optionally has 1 - 2 heteroatoms independently selected apparent from the following detailed description , and from from O , S and NH wherein each heteroatom replaces a the claims. CH , , with the proviso that no 0 , S or N atom in the C1- 8 50 alkyl, C2- 3 alkenyl, or C2- 8 alkynyl is covalently bonded to another O , S or N atom ; DESCRIPTION OF DRAWINGS R * is independently in each instance H , alkyl, phenyl, or alkaryl, wherein the alkyl, phenyl, or alkaryl is option FIG . 1 shows individual and mean plasma concentration ally substituted with 1 - 3 substituents independently 55 time data for Compound B - 001 after an IV dose of 1004 selected from the group consisting of: halo , — NO2, mg/ kg of the Compound B - 001- Human Serum Albumin CF3, amido, sulfonamide , aryl, — OH , alkyl, - O - (HSA ) complex in Sprague Dawley® (SD ) rats . lower alkyl, - O - alkaryl, and — O - aryl; R * is independently in each instance H , OH , NO2, NH2, FIG . 2 shows individual and mean plasma concentration NH3 * , SH , or a branched or unbranched1 : C1-02 10 . alkylNAZ, 60 time data for abiraterone after an IV dose of 1004 mg/ kg of C2- 10 alkenyl, or C2- 10 alkynyl, wherein the C1- 10 alkyl, the Compound B - 001- HSA complex in SD rats . C2- 10 alkenyl or C2- 10 alkynyl is optionally substituted FIG . 3 shows individual plasma concentration - time data with 1 - 2 substituents independently selected from the for Compound B -003 after an IV dose of 932 mg/ kg of the group consisting of halo , OH , NO2, NH2, NH3* , SH , Compound B -003 -HSA complex in SD rats . and = 0 , and wherein the C1- 10 alkyl, C2- 10 alkenyl, or 65 FIG . 4 shows the individual plasma concentration -time C2- 10 alkynyl optionally has 1 - 2 heteroatoms indepen - data for the B -003 metabolite ( abiraterone ) after an IV dose dently selected from O , S and NH wherein each het - of 932 mg/kg of the B -003 -HSA complex in SD rats US 9 ,937 ,259 B2 DETAILED DESCRIPTION octadecyl, 16 -methylheptadecyl , 5 -propylpentadecyl , non adecyl, 17 -methyloctadecyl , 4 -ethylheptadecyl , icosyl, Definitions 18 -methylnonadecyl , 3 -ethyloctadecyl , henicosyl, docosi For the terms “ for example ” and “ such as” and grammati - nyl, tricosinyl, tetracosinyl and pentacosinyl groups . cal equivalences thereof, the phrase " and without limitation ” 5 The term “ Cx - v alkyl” refers to an alkyl group between x is understood to follow unless explicitly stated otherwise . As and y carbon atoms in size . For example , C1- 8 alkyl refers to used herein , the term “ about" is meant to account for an alkyl of 1 to 8 carbon atoms. variations due to experimental error . All measurements The term “ alkaryl” represents an alkyl group substituted reported herein are understood to be modified by the term with an aryl group . Examples of alkaryl groups include " about" . whether or not the term is explicitly used , unless 10 benzyl, phenethyl, and 2 - ( naphthalen - 1 - yl) ethyl . explicitly stated otherwise . As used herein , the singular The term “ (Cx - y alkyl) aryl ” is an alkaryl group containing forms “ a ," " an ,” and “ the ” include plural referents unless the an alkyl group between x and y carbon atoms in size . For context clearly dictates otherwise . example , (C1 - 3 alkyl) aryl refers to an alkyl of 1 to 3 carbon ein , chemical structures which contain one or atoms attached to an aryl group . As usedreocenters herein , chemicaldepicted structureswith dashed which and contain hold onebonds or 15 a torThe term “ alkenyl” represents a straight or branched chain more stereocenters depicted with dashed and bold bonds 15 alkenyl group , having from 2 to 20 carbon atoms. It may ( i .e . , and I are meant to indicate absolute stereochemistry have 1 or more double bonds . In some embodiments, the of the stereocenter ( s ) present in the chemical structure . As alkenyl group may have 2 - 6 double bonds. Examples of such used herein , bonds symbolized by a simple line do not groups include the vinyl, alkyl, 1 - propenyl , isopropenyl, indicate a stereo -preference . Unless otherwise indicated to 20 2 -methyl - 1 -propenyl , 1 -butenyl , 2 -butenyl , 3 - butenyl, the contrary , chemical structures, which include one or more 1 - pentenyl, 2 -pentenyl , 3 - pentenyl , 4 - pentenyl, 1- hexenyl , stereocenters , illustrated herein without indicating absolute 2 - hexenyl, 3 -hexenyl , 4 -hexenyl , 5 - hexenyl, 1 -heptenyl , or relative stereochemistry encompass all possible stereoi 2 -heptenyl , 3 -heptenyl , 1- octenyl, 8 -nonenyl , 1 -nonenyl , someric forms of the compound ( e . g ., diastereomers , 1 -decenyl , 9 -decenyl , 8 - tridecenyl, cis - 8 -pentadecenyl , enantiomers ) and mixtures thereof. Structures with a single 25 trans -8 - pentadecenyl , 8 - heptadecenyl , 8 - heptadecenyl, 8 , 11 bold or dashed line , and at least one additional simple line , heptadecadienyl, 8 , 11, 14 -heptadecatrienyl , 4 , 7 , 11, 14 - non encompass a single enantiomeric series of all possible adecatetraenyl and 2 , 6 -dimethyl - 8 - ( 2 , 6 , 6 - trimethyl- 1 - cyclo diastereomers . hexen - 1 - yl) - 1 , 3 , 5 , 7 -nonatetraen - 1 - yl, cis - 10 - nonadecaenyl, Compounds provided herein can also include all isotopes 10 , 13 - nonadecadienyl, cis - 7 , 10 , 13 - nonadecatrienyl, 5 , 8 , 11 , of atoms occurring in the intermediates or final compounds . 30 14 - nonadecatetraenyl, nonadecapentaenyl , henecosatetra Isotopes include those atoms having the same atomic num - enyl, henecosapentaenyl , henecosahexaenyl, myristyl, and ber but different mass numbers . For example , isotopes of eicosyl groups . hydrogen include hydrogen , tritium , and deuterium . The term " Cx- v alkenyl” refers to an alkenyl group The term , “ compound ” , as used herein is meant to include between x and y carbon atoms in size. For example , C2- 8 all stereoisomers , geometric isomers , tautomers , and iso - 35 alkenyl refers to an alkenyl of 2 to 8 carbon atoms. topes of the structures depicted . Compounds herein identi - The term “ alkynyl” represents an alkynyl group having fied by name or structure as one particular tautomeric form from 2 to 20 carbon atoms, and may be a straight or are intended to include other tautomeric forms unless oth - branched chain group . In addition to one or more triple erwise specified . bonds, the alkynyl group may have one or more double All compounds , and pharmaceutically acceptable salts 40 bonds . thereof, can be found together with other substances such as The term “ Cr- v alkynyl” refers to an alkynyl group water and solvents ( e . g . , hydrates and solvates ) . between x and y carbon atoms in size . For example , C , 8 The term “ halo ” refers to fluoro , chloro , bromo or iodo . alkynyl refers to an alkynyl of 2 to 8 carbon atoms . The term “ alkyl” refers to a straight or branched chain When specifically stated , alkyl, alkenyl, or alkynyl groups alkyl group , having from 1 - 20 carbon atoms. Illustrative of 45 may include ring structures of 3 to 8 carbon atoms. the alkyl group include the methyl, ethyl, propyl, isopropyl, When an alkyl, alkenyl or alkynyl group is described as butyl, isobutyl, sec -butyl , t- butyl , pentyl, 3 -methylbutyl , a " lower ” alkyl, alkenyl or alkynyl group , it has a maximum 2 ,2 -dimethylpropyl , 1 ,1 -dimethylpropyl , hexyl, 1 -methyl - of 6 carbon atoms. pentyl, 4 -methylpentyl , heptyl, 1 -methylhexyl , 2 -methyl When specifically stated , alkyl, alkenyl or alkynyl groups hexyl, 5 -methylhexyl , 3 - ethylpentyl, octyl, 2 -methylheptyl , 50 may include heteroatoms of oxygen , sulfur, nitrogen and /or 6 -methylheptyl , 2 -ethylhexyl , 2 - ethyl- 3 -methylpentyl , silicon . Where specifically stated , alkyl , alkenyl or alkynyl 3 - ethyl- 2 -methylpentyl , nonyl, 2 -methyloctyl , 7 -methyloc groups may be substituted with halo , hydroxyl, nitro (NO2 ) , tyl, 4 - ethylheptyl, 3 - ethyl - 2 -methylhexyl , 2 - ethyl- 1 -methyl amine , amide , sulfhydryl (SH ) , O - lower alkyl and carboxy hexyl, decyl, 2 -methylnonyl , 8 -methylnonyl , 5 -ethyloctyl , (COOH ) groups . Illustrative examples of the alkyl group 3 - ethyl - 2 -methylheptyl , 3 , 3 - diethylhexyl, undecyl, 2 -meth - 55 substituted with oxygen or including a heteroatom of oxygen yldecyl, 9 -methyldecyl , 4 - ethylnonyl, 3 , 5 - dimethylnonyl, include methoxymethyl, ethoxymethyl, propoxymethyl , 3 - propyloctyl, 5 - ethyl- 4 - methyloctyl, 1 -pentylhexyl , dode - n -butoxymethyl , 2 -methoxyethyl , 2 -ethoxyethyl , cyl, 1 -methylundecyl , 10 -methylundecyl , 3 - ethyldecyl, 2 - propoxyethyl, 3 -methoxypropyl , 3 - ethoxypropyl, 5 - propylnonyl, 3 , 5 - diethyloctyl, tridecyl, 11 -methyldodecyl , 3 -propoxypropyl , 4 -methoxybutyl , 4 -propoxybutyl , dime 7 - ethylundecyl, 4 -propyldecyl , 5 -ethyl - 3 -methyldecyl , 60 thoxymethyl, 2, 2 -dimethoxyethyl , diethoxymethyl, 2, 2 -di 3 -pentyloctyl , tetradecyl , 12 -methyltridecyl , 8 - ethyldode ethoxyethyl, dipropoxymethyl and 2 , 2 - dipropoxyethyl cyl , 6 -propylundecyl , 4 - butyldecyl, 2 -pentylnonyl , pentade groups. Illustrative examples of the alkyl group substituted cyl, 13 - methyltetradecyl, 10 -ethyltridecyl , 7 -propyldodecyl , with sulfur are methylthiomethyl , ethylthiomethyl, propyl 5 -ethyl - 3 -methyldodecyl , 4 -pentyldecyl , 1 -hexylnonyl , thiomethyl, n -butylthiomethyl , 2 -methylthiolethyl , 2 -ethyl hexadecyl, 14 -methylpentadecyl , 6 - ethyltetradecyl, 4 - pro - 65 thiolethyl, 2 -propylthiolethyl , 3 -methylthiopropyl , 3 - ethyl pyltridecyl, 2 - butyldodecyl , heptadecyl, 15 -methylhexade - thiopropyl, 3 - propylthiopropyl, 4 -methylthiobutyl , and cyl, 7 - ethylpentadecyl, 3 - propyltetradecyl, 5 -pentyldodecyl , 4 -propylthiobutyl groups. Illustrative examples of the alkyl US 9 ,937 ,259 B2 10 group substituted with nitrogen are aminomethyl, dimeth The term “ carbocyclylalkyl” refers to a carbocyclyl group ylaminomethyl, (N -acetyl )methylaminomethyl , diethylam - substituted with an alkyl group . inomethyl, dipropylaminomethyl, dibutylaminomethyl, The terms “ sulfonamide” and “ sulfonamido ” are art dimethylaminoethyl, diethylaminoethyl, dipropylamino - recognized as an amino - substituted sulfonyl and include a ethyl, and dibutylaminoethyl groups. Illustrative examples 5 moiety that can be represented by the general formula : of the alkyl group substituted with silicon are trimethylsilyl, triethylsilyl, tributylsilyl , t - butyldimethylsilyl , t -butyldieth ylsilyl and t -butyldiphenylsilyl . The terms " amine” and “ amino ” are art -recognized and Rio refer to both unsubstituted and substituted amines and salts thereof, e. g ., a moiety that can be represented by the general R9 formulae: wherein Rº and R10 are as defined above . 15 The term “ linker” as used herein refers to a group of atoms, e . g ., 0 - 500 atoms, and may be comprised of the oror - N - R10 atoms or groups such as , but not limited to , carbon , amino , Odk ?-2 alkylamino , oxygen , sulfur , sulfoxide , sulfonyl, carbonyl, RIO and imine . The linker chain may also include part of a 20 saturated , unsaturated or aromatic ring, including polycyclic where R9, R10 and R10 ' each independently represent a and heteroaromatic rings wherein the heteroaromatic ring is hydrogen , an alkyl, an alkenyl, — ( CH2) m - R®, or R9 and an aryl group containing from one to four heteroatoms, N , O R10 taken together with the N atom to which they are or S . Specific examples include , but are not limited to , attached complete a heterocycle having from 4 to 8 atoms in unsaturated alkanes, polyethylene glycols , and dextran poly 1 25 mers . The linker must not interfere with binding of the the ring structure ; R8 represents an aryl , a cycloalkyl, a ligand to the target . cycloalkenyl, a heterocyclyl or a polycyclyl; and m is zero In its simplest form , a linker can be a covalent chemical or an integer from 1 to 8 . In some embodiments , only one of bond . In other embodiments , the linker can be a chemical R9 or R10 is a carbonyl, e . g ., Rº, R10 , and the nitrogen group . Since the function of the linking group is merely to together do not form an imide . In some embodiments , R andM 2030 provide a physical connection , a wide variety of chemical R1° ( and optionally R10' ) each independently represent a groups can serve as linking groups . A linker is typically a hydrogen , an alkyl, an alkenyl, or — ( CH2) m771 - Rº . In certain divalent organic linking group where one valency represents embodiments , an amino group is basic , meaning its proto the point of attachment to ligand or payload molecule and nated form has a pK , above 7 . 00 . one valency represents the attachment to the compound . The The terms " amide ” and “ amido ” are art -recognized as an 35 only requirement for the linker is to provide a stable physical amino -substituted carbonyl and include a moiety that can be linkage that is compatible with maintaining the function of represented by the general formula : the ligand or payload molecule and is compatible with the chemistry . In some embodiments , the linking group includes a — S - S — moiety . 40 Examples of suitable linking groups include, e . g .: 0 - , S - , - S ( O ) - , - S ( O ) 2 - , S - S — , - C ( O ) N RIO – NH , ZN( C - Clalkyl, _ NHC( O ) - , C ( O ) NH , - LO( CO ) , C ( O ) O , O ( CO ) NH , NHCUOÀO , O( CODO , NHC( O ) NH , OOC - C6Jalkylene- , 45 - S ( C - C . ) alkylene - , - S ( O ) (C1 - C . ) alkylene - , - S ( O ) 2 wherein Rº and R10 are as defined above. In some embodi (C1 - C . ) alkylene - , - C ( O ) ( C . - C . ) alkylene- , NH ( ( C / - C . ) alkylene ) C ( O ) - , - C ( O ) ( ( C / - C ) alkylene ) C ( O ) - , - C ( O ) ments , the amide will not include imides , which may be (( C /- C . )alkylene )NH , O ( CO ) , C ( O ) O - , unstable . LO( CO) NH , NHCUOÀO , O ( CO) O , NHC( 0 ) The term “ aryl” as used herein includes 5 ., 6 - , and 50 NH — , unsubstituted - (C , -C10 )alkylene -, unsubstituted - (C ) 7 -membered substituted or unsubstituted single -ring aro C10 )heteroalkylene , or — (C1 -C1o ) alkylene or — (C1 - C10 ) matic groups in which each atom of the ring is carbon . The heteroalkylene substituted with one or more ( e . g ., 1 , 2 , 3 , 4 term “ aryl” also includes polycyclic ring systemshaving two or 5 substituents ) independently selected from the group cyclic rings in which two or more carbons are common to consisting of (C2 - C ) alkyl, (C2 - C .) alkenyl , (C2 - C .) alkynyl , two adjoining rings wherein at least one of the rings 155is halogen , ( C . - C . )haloalkyl , CN , NO2, C ( O ) R , aromatic , e . g ., the other cyclic rings can be cycloalkyls , OCCO) Ar , CEO )OR , CEO) NR2 , CENR ) cycloalkenyls , cycloalkynyls , aryls , heteroaryls , and / or het NR2, OR , - Ar, OAr, ( (C - C ) alkylene )Ar , erocyclyls . Aryl groups include benzene , naphthalene , phe ( (C1 - C . ) alkylene )Ar , OCEO ) ( C . - C . ) alkyl, OC nol, aniline , and the like. GOO ( C , - C . ) alkyl, _ OCCO) NR2, NR2, — NRAr, The terms “ carbocycle ” and “ carbocyclyl” as used herein 60 — NR ( ( C . - C . Jalkylene Ar, NRC ( = O ) R . — NRC ( = O ) refer to a 3 - to 6 -membered non - aromatic substituted or Ar, NRC O ) O (C7 - C ) alkyl, NRCEO )NR2 , unsubstituted ring in which each atom of the ring is carbon . — NRSOR, SR , S ( O ) R , SOR , OSO2 ( C , - C . ) The ring may be completely saturated or may have one or alkyl, SO2NR2, (C ,- C ) perfluoroalkyl, — (C2 - C )alky more unsaturated bonds such that the ring remains non - lene -OR , (C2 -C6 ) alkylene - N ( (C / -C .) alkyl) 2, — P (= O ) aromatic . Examples of carbocyclyls include cyclopropyl, 65 (OR )2 , - OP (= O ) (OR )2 , oxo and sulfido , wherein each R cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, group is hydrogen or ( C2- C6 alkyl) , e . g . ,methyl and wherein cyclohexylmethyl, and 4 -methylcyclohexyl . each Ar is independently unsubstituted aryl or heteroaryl or US 9 ,937 ,259 B2 12 aryl or heteroaryl substituted with one or more of ( C . - C . ) tryptophan ; thyroxine ; 3 , 5 , 3 '- L - triiodothyronine ; indole pro alkyl , (C2 - C . )alkenyl , (C2 - C . ) alkynyl, halogen , ( C , - C . )ha pionate ; kynurenine ; ethacrynate ; panproxen ; chlorophe loalkyl, CN , — NO2, CEO) R , C O )OR noxyisobutyrate ; 3 ' azido - 3 '- deoxythymidine ; non - steroidal CEO )NR2 , C NR )NR2 , OR , OC ( = O ) ( C , - C ) anti - inflammatory agents containing ionized carboxyl alkyl, — OCO O ( C , - Cm ) alkyl, — OCCO )NR2 , — NR2, 5 groups ; gossypol; meso - 2 , 3 - dimercaptosuccinic acid ; cap - NRCTOR , - NRC ( = O ) O ( C . - C . ) alkyl , - NRCEO topril ; N2- mercaptoethyl - 1, 2 - diaminopropane ; disulfurama NR2, — NRSO R , SR , S ( O ) R , SO , R , OSO2( C1 cetaminophen , dis -dichlorodiamineplatinum 9II ; pyridoxal C . )alkyl , SO2NR2, ( C , - C ) perfluoroalkyl, (C2 - C6) alkylene- OR , (C2 - C .) alkylene -N (( C / - C . )alkyl ) 2 , 5 '- phosphate ; aquocobalamin form of vitamin B12 ; folate ; - P ( O ) (OR ) 2, OP ( = O ) (OR ) 2 wherein each R group is 10 ascorbate (and its oxidation product dehydroascorbate ) ; hydrogen or (C . - C . alkyl ). In addition , (C -C10 )alkylene melatonin ; a -melanotropin ; gastrin ; corticotropin and and (C1 - C10 )heteroalkylene can be substituted by one or methotrexate . The group that selectively binds to serum more oxo groups (CFO ) and the nitrogen and sulfur atoms albumin may bind to serum albumin at specific , defined of a heteroalkylene group can optionally be oxidized ( e . g . , sites, as detailed by crystallographic and displacement stud to form S (O ), S (0 )2 - , or N -oxide ). Suitable heteroalky - 15 ies, and may also bind serum albumin at non - specific sites lene groups can include one or more 1 , 2 - dioxyethylene units that have yet to be clearly defined . Binding between the - O CH , CH , 0 , where n is an integer, e . g ., 1 . 2 . 3 . 4 group that selectively binds serum albumin and serum or 5 ). The (C , -C10 )alkylene - and (C , -C10 ) heteroalky albumin occurs by non - covalent mechanisms. These groups lene also include — (C -C6 ) alkylene - and (C - C . )het selectively bind serum albumin in that when added to eroalkylene ; and — ( C , -C3 ) alkylene - and — (C2 - C3 ) het - 20 mammalian blood , they bind in greatest quantity to serum ereroalkylene . albumin over other blood proteins. One of skill in the art of The term “ group of natural amino acid side chains ” pharmacology is well able to envision and use a wide variety represents the set of chemical groups attached to the alpha of groups that selectively bind serum albumin due to their carbon for each of the twenty naturally occurring amino familiarity with the literature showing many pharmaceutical acids: Cysteine , Histidine , Isoleucine , Methionine , Serine , 25 compounds which preferentially bind serum albumin in Valine, Alanine, Glycine , Leucine , Proline, Threonine , Phe mammals . See , for example , F . Kratz , et al, Journal of nylalanine , Arginineinine , Tyrosine, Tryptophan , Aspartic AcidAcid , Controlled Release 2008 , 132 : 171 - 183 . Asparagine, Glutamic Acid , Glutamine and Lysine . As used herein , “ solubility in aqueous solution of at least The phrase “ pharmaceutically acceptable ” is employed X mg/ mL ” refers to a composition that forms an optically 30 herein to refer to those ligands , materials , compositions, clear solution at room temperature in water, without addi- and /or dosage forms which are , within the scope of sound tional, non -water , solvents . medical judgment, suitable for use in contact with the tissues As used herein , “ substantially free of solvent” , in refer - of human beings and animals without excessive toxicity , ence to an aqueous solution , refers to an aqueous solution irritation , allergic response, or other problem or complica that contains less than 0. 5 % , by weight, of any non -water 35 tion , commensurate with a reasonable benefit/ risk ratio . solvent. “ pharmaceutically acceptable salt ” includes a salt with As used herein , “ a group that selectively binds to serum an inorganic base , organic base , inorganic acid , organic acid , albumin ” refers to a chemical group suitable for adminis tration to a mammal, for example, a human , which exhibits or basic or acidic amino acid . Salts of inorganic bases binding affinity for serum albumin . Examples of such groups 40 include , for example , alkali metals such as sodium or that selectively bind to serum albumin include , but are not potassium ; alkaline earth metals such as calcium and mag limited to , long chain fatty acids (C16 - C20 ; including oleic , nesium or aluminum ; and ammonia . Salts of organic bases palmitic , linoleic , stearic , arachidonic , and palmitoleic ) ; include, for example , trimethylamine , triethylamine , pyri medium chain fatty acids (Co -C14 ; including caprylate or dine , picoline , ethanolamine , diethanolamine , and trietha octanoate ); phospholipids ( lysolecithins, oleoyllysophosophosa - 45 nolamineno . Salts of inorganic acids include for example , phatidic acid , phosphatidylcholine, phosphatidyletha hydrochloric acid , hydroboric acid , nitric acid , sulfuric acid , nolamine ) ; eicosanoid derivatives (leukotrienes , thrombox - and phosphoric acid . Salts of organic acids include for anes , prostaglandins A , E , F , and I) ; steroid hormones example , formic acid , acetic acid , trifluoroacetic acid , ( cholesterol, testosterone , pregnenolone , cortisol, androster fumaric acid , oxalic acid , tartaric acid , maleic acid , citric one, indol, progesterone, estrogen ); vitamin D (both mono - 50 acid , succinic acid , malic acid , methanesulfonic acid , ben hydroxyvitamin D and dihydroxyvitamin D ) ; bile salts zenesulfonic acid , and p - toluenesulfonic acid . Salts of basic (lithocholate , chenodeoxycholate , deoxycholate , ursodeoxy amino acids include , for example , arginine , lysine and cholate , cholate , glycolitocholate , glycochenodeoxycholate , ornithine. Acidic amino acids include , for example , aspartic taurochenodoxycholate , glycodeoxycholate , glycocholate , acid and glutamic acid . taurocholate ); bilirubins (bilirubin , biliverdin , xanthobiliru - 55 1 bin , EZ - cyclobilirubin , d -bilirubin ) ; porphyrins ( hematin , The phrase " pharmaceutically acceptable carrier” as used protoporphyrin ); warfarin ; salicylates, ibuprofen ; pred herein means a pharmaceutically acceptable material, com nisone ; iophenoxate ; sulfisoxazole ; phenylbutazone ; oxphe position , or vehicle , such as a liquid or solid filler, diluent, nylbutazone ; digitoxin ; indomethacin ; tolbutamide ; furo excipient, solvent or encapsulating material . As used herein semide : phenyloin : chlorpropamide : chlorthiazide: the 60the language “ pharmaceutically acceptable carrier” includes penicillins ( including oxacillin , benzylpenicillin ); aceto buffer, sterile water for injection , solvents , dispersion media , trizoate ; isulfobromophthalein ; deacetylcolchicine ; dansyl coatings , antibacterial and antifungal agents , isotonic and amide ; dansylglutamine ; dansylsarcosine ; indomethacin ; absorption delaying agents , and the like , compatible with phenylpropazone ; azobenzene derivatives ; sulfobro pharmaceutical administration . Each carrier must be mophthalein ; triiodobenzoate ; benzodiazepine (including 65 “ acceptable ” in the sense ofbeing compatible with the other diazepam ) ; flufenamate ; iopanoate ; ethacrynate ; panproxen ; ingredients of the formulation and not injurious to the clofibrate ; L - tryptophan ; N - acetyl- L -tryptophan ; 6 -methyl - patient. US 9 ,937 ,259 B2 13 1414 As used herein , the term “ cancer” refers to all known forms of cancer including , solid forms of cancer ( e . g ., tumors ), lymphomas , and leukemias. As used herein , an " effective amount or a “ pharmaceu tically - effective amount” in reference to the compounds or compositions of the present disclosure refers to the amount sufficient to induce a desired biological , pharmacological, or therapeutic outcome in a subject. That result can be reduc tion , prevention , mitigation , delay , shortening the time to 10 resolution of, alleviation of the signs or symptoms of, or exert a medically -beneficial effect upon the underlying pathophysiology or pathogenesis of an expected or observed side- effect, toxicity , disorder or condition , or any other 15 desired alteration of a biological system . In cancer treat - ment, the result will generally include the reduction , pre vention , mitigation , limitation , and /or , delay of the delete - rious physiological manifestations, growth or metastases of 20 neoplasms. wherein A is a covalent bond , O or NR ' ; Compounds L is alkyl, alkyl- O -alkyl , alkenyl, alkynyl, carbocyclyl, Provided herein are compounds having a structure of carbocyclylalkyl, aryl, alkaryl , or Formula ( I ) : 25
man mer 7 (1) 30 each of which is optionally substituted with 1 -3 substituents independently selected from the group consisting of halo , — NO , , amine , amide , hydroxyl, O - lower alkyl, and - COOH , provided that there be no covalent bonds between oxygen atoms; W is II.) pullit $
min B COOH À N + c + COOH , B LR ,
R? [ 21] wherein Son mi RS - N A is a covalent bond , O , or NR '; Py > COOH R is H , lower alkyl, or alkaryl, wherein the alkyl or alkaryl is optionally substituted with 1 - 3 substituents BH+ c + COOH , , or independently selected from the group consisting of: halo , nitro , amine , amide , hydroxyl, O - lower alkyl, and carboxy; and Q is a group that selectively binds to human serum mu albumin . R ? [ R21 | R41 In some embodiments , Riis H or lower alkyl. For - N + c + – c + c + – COOH ; example , R ' can be H . [ R ] , R6 [ R ] , In some embodiments , Q includes — COOH . In some embodiments , Q includes a -S - S — moiety . 65 ME In some embodiments , the compound of Formula (I ) has Rl is H , lower alkyl, or alkaryl, wherein the alkyl or the structure of Formula ( II ) : alkaryl is optionally substituted with 1 -3 substituents US 9 ,937 ,259 B2 15 16 independently selected from the group consisting of: wherein halo , NO2, amine , amide , hydroxyl, O - lower alkyl and COOH ; A is a covalent bond , O or NR ' ; R2 is independently in each instance H , OH , NO2, NH , Lº is a linker including a S - S — moiety ; NHZ* , SH , or a branched or unbranched C1- alkyl, C2- 8 5 W is alkenyl or C2- 3 alkynyl, wherein the C1- 3 alkyl, C2- 8 alkenyl or C2- 3 alkynyl is optionally substituted with 1 - 2 substituents independently selected from the group consisting of halo , OH , NO2, NH , NHZ , SH , and = 0 , and wherein the C1- 3 alkyl , C2- 3 alkenyl or C2- alkynyl mun optionally has 1 - 2 heteroatoms independentlyly selected 10 from O , S and NH wherein each heteroatom replaces a CH , , with the proviso that no 0 , S or N atom in the C1- 8 N - + - + COOH alkyl, C2- 3 alkenyl or C2- 3 alkynyl is covalently bonded N + c + COOH , B LR to another O , S or N atom ; - R * is independently in each instance H , alkyl , phenyl, or 15 POR R ] alkaryl, wherein the alkyl, phenyl , or alkaryl is option ally substituted with 1 - 3 substituents independently selected from the group consisting of: halo , - NO2, CFz, amido , sulfonamide, aryl, OH , alkyl, O lower alkyl, — O -alkaryl , and — O - aryl; 20 R4 is independently in each instance H , OH , NO2, NH ,, NH3 * , SH , or a branched or unbranched C1- 10 alkyl, win C2- 10 alkenyl, or C2- 10 alkynyl, wherein the C1- 10 alkyl, C2- 10 alkenyl or C2- 10 alkynyl is optionally substituted R3 — N with 1 - 2 substituents independently selected from the 25 COOH group consisting of halo , OH , NO2, NH2, NH3* , SH , o and = 0 , and wherein the C1- 10 alkyl, C2- 10 alkenyl or B - + + COOH , , or C2- 10 alkynyl optionally has 1- 2 heteroatoms indepen dently selected from O , S , and NH wherein each R ? n heteroatom replaces a CH ,, with the proviso that no 0 , S , or N atom in the Ch. 10 alkyl, C . . 10 alkenyl or C2. 10 30 alkynyl is covalently bonded to another O , S , or N atom ; R $ is H , alkyl, phenyl, or alkaryl, wherein the alkyl, phenyl, or alkaryl is optionally substituted with 1 - 3 substituents independently selected from the group 35 nnnn consisting of: halo , — NO , , CFz, amido, sulfona mide, aryl, OH , alkyl, O - lower alkyl, O -alkaryl , § [ R ] | * and — O - aryl; HC + c + COOHDOH ; R? and RP are each independently H or lower alkyl, - [ R ] , RO ( R3 optionally substituted with 1 - 3 substituents indepen - 40 LIFTE dently selected from the group consisting of halo , nitro , amine , amide, hydroxyl , O - lower alkyl, and carboxy ; B is a covalent bond , O or NR '; R1 is H , lower alkyl, or alkaryl, wherein the alkyl or the wavy line indicates the point of W to L ; alkaryl is optionally substituted with 1 - 3 substituents p is 1 , 2 , 3 , 4 , 5 , or 6 ; 45 n is 1 , 2 , 3 , 4 , 5 , or 6 ; and 45 independently selected from the group consisting of : ris 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , or 10 . halo , NO ,, amine , amide, hydroxyl, O - lower alkyl , and In some embodiments , a compound of Formula (I ) has the - COOH ; structure of Formula (III ) : R2 is independently in each instance H , OH , NO2, NH , ( III ) 50 NH3* , SH , or a branched or unbranched C1- 8 alkyl, C2- 8 alkenyl or C2- 3 alkynyl , wherein the C1- 8 alkyl, C2- 8 alkenyl or C2- 3 alkynyl is optionally substituted with 1 - 2 substituents independently selected from the group consisting ofhalo , OH , NO2, NH , NH3 + , SH , and = O , 55 and wherein the C1- 8 alkyl, C2- 8 alkenyl , or C2- 8 alkynyl H optionally has 1 - 2 heteroatoms independently selected from O , S , and NH wherein each heteroatom replaces a CH2, with the proviso that no O , S , or N atom in the C1- 3 alkyl, C2- 8 alkenyl , or C2- 3 alkynyl is covalently 60 bonded to another O , S , or N atom ; R is independently in each instance H , alkyl, phenyl, or alkaryl, wherein the alkyl, phenyl, or alkaryl is option -> ally substituted with 1- 3 substituents independently 65 selected from the group consisting of: halo , - NO2, - CF3, amido , sulfonamide , aryl, — OH , alkyl, - O lower alkyl , O -alkaryl , and O - aryl; US 9 ,937 ,259 B2 17 18 R4 is independently in each instance H , OH , NO2, NH , NHZ , SH or a branched or unbranched C1- 10 alkyl , C2- 10 alkenyl, or C2- 10 alkynyl, wherein the C1- 10 alkyl, m C2- 10 alkenyl or C2- 10 alkynyl is optionally substituted mm with 1 - 2 substituents independently selected from the 5 wa group consisting of halo , OH , NO2, NH , NH3+ , SH , and = O , and wherein the C1- 10 alkyl, C2- 10 alkenyl or C2- 10 alkynyl optionally has 1- 2 heteroatoms indepen each of which is optionally substituted with 1 - 3 substituents dently selected from O , S , and NH wherein each independently selected from the group consisting of halo , heteroatom replaces a CH2, with the proviso that no O , 10 — NO2 , amine , amide , hydroxyl, O - lower alkyl , and S , or N atom in the C1- 10 alkyl, C2- 10 alkenyl , or C2- 10 COOH , provided that there be no covalent bonds between alkynyl is covalently bonded to another O , S , or N oxygen atoms; and atom ; L ’ is alkyl, alkyl- O - alkyl, alkenyl, alkynyl , carbocyclyl, R is H , alkyl, phenyl, or alkaryl, wherein the alkyl, carbocyclylalkyl, aryl, alkaryl, or phenyl , or alkaryl is optionally substituted with 1 -3 15 substituents independently selected from the group consisting of: halo , — NO2, CF3, amido , sulfona mide , aryl, - OH , alkyl, - O - lower alkyl, — O -alkaryl , m and — O - aryl; m R and R7is each independently H or lower alkyl, option 20 ally substituted with 1- 3 substituents independently each of which is optionally substituted with 1- 3 substituents selected from the group consisting of halo , nitro , independently selected from the group consisting of halo , amine , amide , hydroxyl, O - lower alkyl, and carboxy ; — NO2, amine , amide, hydroxyl , O - lower alkyl, and B is a covalent bond , O or NR , ; 25 - COOH ; and the wavy line indicates the point of W to L " ; ris 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , or 10 , p is 1 , 2 , 3 , 4 , 5 , or 6 ; and provided that there be no covalent bonds between oxygen atoms. n is 1 , 2 , 3 , 4 , 5 , or 6 . In some embodiments , Ll is an alkyl, alkyl- O - alkyl, In some embodiments , A is a covalent bond . In some 30 alkaryl, or aryl , wherein the alkyl, alkyl- O -alkyl , alkaryl , or embodiments , A is O . In some embodiments , A is NR !. aryl is optionally substituted with 1 - 3 substituents indepen In some embodiments , L is alkyl, alkenyl, alkynyl, car dently selected from the group consisting of halo , - NO2, bocyclyl, carbocyclylalkyl, aryl, alkaryl, or amine , amide, hydroxyl, O - lower alkyl, and — COOH . In some embodiments , L ' is an alkyl , optionally substituted 3 with 1 - 3 substituents independently selected from the group consisting of halo , amine , amide , hydroxyl, O - lower alkyl, im and – COOH . In some embodiments , L ' is an alkyl, option ally substituted with 1 - 3 substituents independently selected 40 from the group consisting of halo and O - lower alkyl. In some embodiments , L ' is a C - , alkyl. For example , L ' can each ofwhich is optionally substituted with 1- 3 substituents be independently selected from the group consisting of halo , be CH2CH2 - . - NO2, amine , amide, hydroxyl, O - lower alkyl and In some embodiments , L2 is an alkyl, alkyl- O -alkyl , - COOH , provided that there be no covalent bonds between alkaryl, or aryl, wherein the alkyl, alkaryl, or aryl is option oxygen atoms. In some embodiments , L is an alkyl, an 45 ally substituted with 1 - 3 substituents independently selected alkenyl, or alkynyl, wherein the alkyl, alkenyl, or alkynyl is from the group consisting of halo , - NO2, amine, amide , optionally substituted with 1- 3 substituents independently hydroxyl, O - lower alkyl and — COOH . In some embodi selected from the group consisting of halo , — NO , , amine , ments , L² is an alkyl, optionally substituted with 1 -3 sub amide, hydroxyl, O -lower alkyl, and COOH . In some stituents independently selected from the group consisting of embodiments , L is an alkyl, optionally substituted with 1 - 3 30 halo , amine, amide, hydroxyl, O - lower alkyl and — COOH . substituents independently selected from the group consist. In some embodiments , L - is an alkyl, optionally substituted ing of halo , - NO , , amine, amide , hydroxyl, O - lower alkyl with 1 - 3 substituents independently selected from the group and – COOH . In some embodiments, L is an alkyl, option consisting of halo and O -lower alkyl. In some embodiments , ally substituted with 1 - 3 substituents independently selected L ’ is a C1- 6 alkyl. For example , L ’ can be - CH2 - CH2— . from the group consisting of halo , amine , amide, hydroxyl, In some embodiments , L ' is an alkyl or aryl, wherein the O -lower alkyl and — COOH . alkyl or aryl is optionally substituted with 1 - 3 substituents In some embodiments , Lºis independently selected from the group consisting of halo , - NO2, amine , amide , hydroxyl, O - lower alkyl , and - COOH ; and L2 is an alkyl or aryl , wherein the alkyl or aryl is optionally substituted with 1 - 3 substituents independently 11 - 5 - 5 - 12 selected from the group consisting of halo , - NO2, amine , amide , hydroxyl, O - lower alkyl and COOH . min In some embodiments , L ' is an alkyl, optionally substi 65 tuted with 1 - 3 substituents independently selected from the wherein L ' is alkyl, alkyl- O - alkyl, alkenyl, alkynyl, car group consisting of halo , amine , amide, hydroxyl, O - lower bocyclyl, carbocyclylalkyl, aryl, alkaryl, or alkyl and COOH ; and L ’ is an alkyl, optionally substituted US 9 ,937 ,259 B2 19 20 with 1 - 3 substituents independently selected from the group In some embodiments , W is consisting of halo , amine , amide , hydroxyl, O - lower alkyl and – COOH . In some embodiments , W is 5 mimin mi
N - + 0 + COOH or N + c + COOH . 7 LH . 10 H [ R} ] , [ R* In some embodiments , W is COOH . N + 0 + COOH . In some embodiments , R is H or lower alkyl, optionally R3 substituted with 1 - 3 substituents independently selected from the group consisting of: halo , NO2, amine , amide , hydroxyl, O - lower alkyl , and — COOH . In some embodi In some embodiments , W is ments , R is alkaryl, optionally substituted with 1 -3 sub stituents independently selected from the group consisting 20 of: halo , NO2, amine, amide, hydroxyl , O - lower alkyl and COOH . In some embodiments , R ' is benzyl. In some embodiments , Rl is H or lower alkyl. N + 0 + COOH . In some embodiments , Rl is H . 25 In some embodiments , R2 is independently in each LR ,1 - instance H , OH , NO2, NH , NH3+ , SH , or a branched or unbranched C1- 8 alkyl, C2- 8 alkenyl, or C2- 3 alkynyl, wherein the C1- 8 alkyl , C2- 8 alkenyl, or C2- 8 alkynyl is optionally substituted with 1 - 2 substituents independently selected In some embodiments , W is 30 from the group consisting of halo , OH , NO2, NH , NH3* , SH , and — O . In some embodiments , R2 is H . In some embodiments , R is independently in each instance H , alkyl, phenyl, or alkaryl, wherein the alkyl, 35 phenyl, or alkaryl is optionally substituted with 1 - 3 sub R5 - N stituents independently selected from the group consisting 0 = R41 of: halo , — NO , , - CFz, amido , sulfonamide , aryl, — OH , | Blº? – COOH . alkyl, O - lower alkyl, O -alkaryl , and — O -aryl . In some embodiments , Rºis independently in each 40 instance H , C1-8 alkyl, or ( C1- 3 alkyl) aryl, wherein the C1- 8 alkyl or (C1 -3 alkyl) aryl is optionally substituted with 1 - 3 substituents independently selected from the group consist In some embodiments , W is ing of: halo , CF3, amido , sulfonamide , aryl, OH , alkyl, - O -lower alkyl, — O - alkaryl, and O - aryl. 45 In some embodiments , R3 is independently in each instance C1- 6 alkyl or (C1 - 3 alkyl) aryl optionally substituted with 1 - 3 substituents independently selected from the group R7 R2 consisting of: halo , CF3, aryl, OH , alkyl, O - lower alkyl , O - alkaryl , and O - aryl . - +O- + 0 + COOHOH . 50 In some embodiments , R * is (C1 - 3 alkyl) aryl. T Up RO R3 In some embodiments , R is benzyl. In some embodiments , R4 is independently in each instance H , OH , NO2, NH , NH3 , SH or a branched or unbranched C1- 8 alkyl, C2- 3 alkenyl or C2- 3 alkynyl, wherein In some embodiments , W is 55 the C1- 8 alkyl, C2- 8 alkenyl or C2- 3 alkynyl is optionally substituted with 1 - 2 substituents independently selected from the group consisting of halo , OH , NO2, NH , NH +, SH , and = O . For example , R + can be H . min mm In some embodiments , R4 is H or lower alkyl. 60 In some embodiments , R is H , alkyl , phenyl, or alkaryl , wherein the alkyl , phenyl, or alkaryl is optionally substituted with 1 - 3 substituents independently selected from the group consisting of: halo , — NO2, CF3, amido , sulfonamide, + + COOH or N + c + ????COOH . aryl, OH , alkyl, O - lower alkyl, O -alkaryl , and — O H 65 aryl. 101|Hun R?In, In some embodiments , R5 is H , C1- 8 alkyl, or (C1 -3 alkyl )aryl , wherein the C1- 8 alkyl or (C1 - 3 alkyl ) aryl is US 9 , 937 ,259 B2 21 22 optionally substituted with 1 - 3 substituents independently wherein selected from the group consisting of: halo , CF3, amido , m is 1 , 2 , 3 , 4 , 5 , 6 , 7 , or 8 . sulfonamide , aryl, OH , alkyl, - O - lower alkyl, - O In some embodiments , m is 1 , 2 , 3 , or 4 . In some alkaryl, and — O - aryl. 5 embodiments , m is 2 . In some embodiments , m is 3 . In some embodiments , the compound of Formula (1 ) and / or Formula ( II ) has the structure : In some embodiments, R is C1- 6 alkyl or (C1 - 3 alkyl) aryl optionally substituted with 1- 3 substituents independently 10 selected from the group consisting of: halo , CF3, aryl, alkyl, O - lower alkyl, O - alkaryl, and O - aryl. À
1515 In some embodiments , RS is (C1 - 3 alkyl) aryl. In some embodiments , R is benzyl . IND) 20 In some embodiments , R is H or lower alkyl. For example , R can be H . In some embodiments , R ’ is H or lower alkyl. For 25 example , R ' can be H . (CH2 )m
In some embodiments , B is a covalent bond . In some embodiments , B is O . In some embodiments , B is NR ! . . RINIToCOOH COOH 30 In some embodiments , n is 1 , 2 , 3 , 4 , 5 , or 6 . In some an embodiments , n is 1 , 2 , 3 , or 4 . In some embodiments , n is 1 , or 2 . In some embodiments , n is 1 . In some embodiments , n is 2 . 35 wherein m is 1, 2, 3 , 4 , 5 , 6 , 7, or 8 . In some embodiments , r is 1, 2 , 3, 4 , 5 , 6 , 7 , 8 , 9 , or 10 . In some embodiments , the compound of Formula ( I ) In some embodiments , the compound of Formula ( I ) 40 anyand /or Formula ( II ) has the structure : and / or Formula ( II ) has the structure :
H – C – CH3 (CH2 ) m (CH2 ) m -1 RS- Ñ / R47 COOH ro + COOH R3 LR3an ] n US 9 ,937 , 259 B2 23 24 wherein m is 1 , 2 , 3 , 4 , 5 , 6 , 7 , or 8 . -continued In some embodiments , m is 1 , 2 , 3 , or 4 . In some embodiments , m is 2 . In some embodiments , m is 3 . In some embodiments , the compound of Formula ( I ) and / or Formula ( II ) has the structure :
11111T
H porill
0 = .til (CH2 ) m 0 =
- COOH LR3 ] , wherein m is 1 , 2 , 3 , 4 , 5 , 6 , 7 , or 8 . In some embodiments, m is 1, 2 , 3 , or 4 . In some 30 embodiments, m is 2 . In some embodiments , m is 3 . In some embodiments , m is 2 or 3 . For example , m can be 2 . In some embodiments , n is 1 , 2 , 3 , 4 , 5 , or 6 . In some embodiments , n is 2 or 3 . For example , n can be 2 . In some embodiments , n is 1 . In some embodiments, m is 2 or 3 ; and n is 1 , 2 , or 3 . In 33 217 some embodiments , m is 2 or 3 ; and n is 2 or 3 . In some embodiments , m is 2 or 3 ; and n is 1 or 2 . In some embodiments , m is 2 ; and n is 1 . In some embodiments, the compound of Formula (1 ) and / or Formula ( II ) , or a pharmaceutically acceptable salt 40 thereof, has a structure selected from :
ut funt US 9 , 937 ,259 B2 25 26 -continued -continued
u
ö
HO
11 = 1
H3C( HAC )
HO
nult INT.)
OS
NH CH3 H3C( HAC) 15 65 HO ?? US 9 ,937 ,259 B2 27 28 - continued -continued
2 III. LU 11117 Il
HN
HOO H00C
. ý I II III found
HN
COOH DrogurttaHO
)
1 II IND
111111 HO Dorthe. g HO en US 9 , 937 ,259 B2 29 30 -continued - continued and
11111 po
03 N - ( CH2) 7CH3 20 HOOC COOH
11111
1111 vi HOOC 40 In some embodiments , the compound of Formula ( 1 ) and /or Formula ( II ) , or a pharmaceutically acceptable salt thereof, has a structure selected from :
COOH 8
8
.T1 8
Br
8 NH
8 COOH US 9 ,937 ,259 B2 31 32 -continued -continued vraag .11 begonHO ' . ou H fossible
OH L 17 ly
CH3
HO US 9 , 937 ,259 B2 33 34 -continued -continued
NH 20 H3C ( H2O )15
HO
25 In some embodiments , the compound of Formula ( I ) and / or Formula ( III ) has the structure :
30
35
40
; and 45 ( R8 — © — R8) ' S
50 (R8 — C — R8) , 0 /RS R5- N NCHCOOHCOOH 55 n
wherein 60 ragaNH R® is each independently H or lower alkyl; HC( HAC) - - x is 1 , 2 , 3 , 4 , 5 , 6 , 7 , or 8 ; and HO 65 y is 1, 2 , 3, 4 , 5, 6 , 7 , or 8 . US 9 ,937 , 259 B2 35 36 In some embodiments , the compound of Formula ( 1) In some embodiments , x is 1 , 2 , 3 , 4 , or 5 . In some and /or Formula ( III ) has the structure : embodiments , x is 1 , 2 , or 3 . In some embodiments , x is 2 . In some embodiments , y is 1 , 2 , 3 , 4 , or 5 . In some embodiments , y is 1 , 2 , or 3 . In some embodiments , y is 2 . 5 In some embodiments , n is 1 or 2 . For example , n can be In some embodiments , x is 1 , 2, or 3; y is 1, 2 , or 3 ; and n is 1 or 2 . In some embodiments , the compound of Formula (I ) " and / or Formula ( III) , or pharmaceutically acceptable salt thereof, has a structure selected from :
(R8 — -0C — RS)
11 (R8 — C — R8) ,
in RS- N HICH COOH 30 wherein x is 1, 2 , 3 , 4 , 5 , 6 , 7 , or 8 ; and y is 1, 2 , 3, 4 , 5, 6 , 7, or 8 . In some embodiments , the compound of Formula ( I ) 35 and / or Formula ( III ) has the structure :
.1111
(RS - 0- - RS)
V
( R8 — C — R $) ©
COOH
NH wherein x is 1 , 2 , 3 , 4 , 5 , 6 , 7 , or 8 ; and HO y is 1 , 2 , 3 , 4 , 5 , 6 , 7 , or 8 . US 9 , 937, 259 B2 37 38 - continued -continued
{
{H h F1117 H
HO H70
Hr III iiiH ?III iiH
OH HO US 9 , 937, 259 B2 39 40 -continued -continued
"
LIII: 115 =
????| ??
??
?? H ( ??
|
; and
IIII '} LIIII) ??/
H ( US 9 , 937 ,259 B2 41 42 - continued -continued
a
111111 .u11 IND TI
?
30 In some embodiments , the compound of Formula ( 1) and / or Formula ( III ) , or pharmaceutically acceptable salt thereof, has a structure selected from :
8
8
8
8 bago
8
8 NH
8 HO US 9, 937 , 259 B2 43 44 - continued -continued N?
. IIIII iH SII H , ?
?
? HO HO
?C HIII) ni HIII: T11
HO US 9 ,937 ,259 B2 45 46 - continued -continued
1113 "
IIIIIIII
IIIIIIII
?? BuguHO
ý
TIL rogoII. Im
iley g
en HO US 9 ,937 ,259 B2 47 48 - continued -continued
a
!111 LIT
IIIIIIII IIIIIII E
IIIIIIII
?
?? ?k
; and
TTTTTTTT
HO ?? US 9 , 937 , 259 B2 49 50 -continued from about 7 : 1 to about 10 : 1 , from about 8 : 1 to about 10 : 1 , or from about 9 : 1 to about 10 : 1 . In some embodiments, the molar ratio is greater than about 2 : 1 , 3 : 1 , 4 : 1 , 5 : 1 , 6 : 1 , 7 : 1 , 8 : 1 , or 9 : 1 . 5 In some embodiments , the non -covalently bound complex of a compound as described herein and serum albumin has a molar ratio of compound to serum albumin of from about 2 : 1 to about 7 : 1 . "1111 11111 In some embodiments , the non -covalently bound complex 10 of a compound as described herein and serum albumin has a molar ratio of compound to serum albumin of from about 3 : 1 to about 7 : 1 . In some embodiments , the non - covalently bound complex of a compound as described herein and serum albumin has 15 a molar ratio of compound to serum albumin of from about 4 : 1 to about 6 : 1. In some embodiments , the non -covalently bound complex of a compound described herein and serum albumin is in a solid formulation . The solid formulation typically has been 20 produced in a uniform manner by lyophilization . A skilled artisan would recognize other methods , such as rotary evaporation , that can also produce solid formulations. In some embodiments , the non - covalently bound complex of a compound described herein and serum albumin is in an HÓ 25 aqueous formulation . In some embodiments , the non -cova lently bound complex of the compound and serum albumin is in an aqueous formulation substantially free of solvents Non - Covalent Complexes other than water. In some embodiments , the non - covalently An aspect of the present disclosure is directed toward bound complex of the compound and serum albumin is in an non - covalently bound complexes of a compound as 30 aqueous solution that contains less than about 0 .5 % , 0 . 3 % , described herein , or a pharmaceutically acceptable salt 0 . 2 % , 0 . 1 % , 0 .075 % , 0 .05 % , 0 .03 % , 0 .02 % , 0 .01 % , thereof, and serum albumin . In some embodiments , a non - 0 .0075 % , 0 . 005 % , 0 . 003 % , 0 . 002 % , or 0 .001 % by weight, covalently bound complex can dissociate upon administra - of any non -water solvent. In some embodiments, the non tion to reveal an abiraterone derivative as described herein , covalently bound complex of the compound and serum which in turn can be cleaved by in vivo enzymes to produce 35 albumin is in an aqueous formulation free of solvents other the pharmaceutically active substance abiraterone. In some than water . embodiments , the compound has a structure according to The non -covalently bound complex of a compound Formula ( I ) as described anywhere herein . In some embodi- described herein and serum albumin has greatly enhanced ments , the compound has a structure according to Formula solubility compared with abiraterone . The non - covalently ( II ) as described anywhere herein . In some embodiments , 40 bound complex can have solubility in aqueous solution of the compound has a structure according to Formula ( III ) as about 5 , 8 , 10 , 12 , 14 , 16 , 18, 20 , 22 , 24 , 26 , 28 , 30 , 32 , 34 , described anywhere herein . 36 , 38 , 40 , 42 , 44 , 46 , 48 , or greater than about 50 mg/ mL . In some embodiments , the serum albumin is human serum In some embodiments , the non - covalently bound complex albumin (HSA ). has solubility in aqueous solution of at least 5 mg/ mL . In In some embodiments , the non - covalently bound complex 45 some embodiments , the non -covalently bound complex has of a compound as described herein and serum albumin has solubility in aqueous solution of at least 10 mg/ mL . In some a molar ratio of compound to serum albumin of from about embodiments , the non -covalently bound complex has solu 1 : 1 to about 10 : 1 . In some embodiments , the molar ratio has b ility in aqueous solution of at least 20 mg/ mL . In some a range of from about 1 : 1 to about 4 : 1 , from about 2 : 1 to embodiments, the non - covalently bound complex has solu about 4 : 1 , from about 3 : 1 to about 4 : 1 , about 1 : 1 to about 50 bility in aqueous solution of at least 30 mg/mL . In some 5 : 1 , from about 2 : 1 to about 5 : 1 , from about 3 : 1 to about 5 : 1 , embodiments , the non - covalently bound complex has solu from about 4 : 1 to about 5 : 1 , from about 1 : 1 to about 6 : 1 , bility in aqueous solution of greater than about 50 mg/ mL . from about 2 : 1 to about 6 : 1 , from about 3 : 1 to about 6 : 1 , In some embodiments , the non - covalently bound complex from about 4 : 1 to about 6 : 1 , from about 5 : 1 to about 6 : 1 , is a non - covalently bound complex of an abiraterone deriva from about 1 : 1 to about 7 : 1 , from about 2 : 1 to about 7 : 1 , 55 tive and human serum albumin in a molar ratio from about from about 3 : 1 to about 7 : 1 , from about 4 : 1 to about 7 : 1 , 1 : 1 to about 10 : 1 , wherein the non - covalently bound com from about 5 : 1 to about 7 : 1 , from about 6 : 1 to about 7 : 1 , plex has a solubility in aqueous solution of at least 5 mg/ mL , from about 1 : 1 to about 8 : 1 , from about 2 : 1 to about 8 : 1 , and the abiraterone derivative includes a compound of from about 3 : 1 to about 8 : 1 , from about 4 : 1 to about 8 : 1 , Formula ( I ), Formula (II ) , and / or Formula ( III ) . In some from about 5 : 1 to about 8 : 1 , from about 6 : 1 to about 8 : 1 , 60 embodiments , the non - covalently bound complex is a non from about 7 : 1 to about 8 : 1 , from about 1 : 1 to about 9 : 1 , covalently bound complex of an abiraterone derivative and from about 2 : 1 to about 9 : 1 , from about 3 : 1 to about 9 : 1 , human serum albumin in a molar ratio from about 1 : 1 to from about 4 : 1 to about 9 : 1 , from about 5 : 1 to about 9 : 1 , about 10 : 1 , wherein the non -covalently bound complex has from about 6 : 1 to about 9 : 1 , from about 7 : 1 to about 9 : 1 , a solubility in aqueous solution of at least 5 mg /mL , and the from about 8 : 1 to about 9 : 1 , from about 2 : 1 to about 10 : 1 , 65 abiraterone derivative consists essentially of a compound of from about 3 : 1 to about 10 : 1 , from about 4 : 1 to about 10 : 1 , Formula ( I ) , Formula ( II ) , and /or Formula (III ) . In some from about 5 : 1 to about 10 : 1 , from about 6 : 1 to about 10 : 1 , embodiments , the non - covalently bound complex is a non US 9 ,937 , 259 B2 51 52 covalently bound complex of an abiraterone derivative and Step 3 : A defined amount of serum albumin is then added human serum albumin in a molar ratio from about 1 : 1 to to the solution . about 10 : 1, wherein the non -covalently bound complex has In some embodiments , the serum albumin is human serum a solubility in aqueous solution of at least 5 mg /mL , and the albumin . The resulting non -covalently bound complex can abiraterone derivative consists of a compound of Formula 5 have any molar ratio of the abiraterone derivative to serum ( I) , Formula ( II ), and /or Formula ( III ) , or a pharmaceutically albumin as defined herein . acceptable salt thereof. In some embodiments , the serum albumin is added to the General Method for Preparing a Non - Covalently Bound water solution in step 2 first , and then the water solution of Complex of the Abiraterone Derivative with HSA the serum albumin is added to the polar organic solution Step 1 : The abiraterone derivative is dissolved in a polar " from step 1 . organic solvent, such as an alcohol, THF, CH , CN , etc . , or Step 4 : The mixture is agitated at a temperature and time mixtures thereof. until reaction is deemed complete . In some embodiments , the polar organic solvent is an In some embodiments , the mixture is stirred . In some alcohol. In some embodiments , the polar organic solvent is 1 embodiments , the mixture is shaken . ethanol or methanol , or mixtures thereof . For example , the In some embodiments , the temperature is from about 0° polar organic solvent can be methanol. In some embodi- C . to about 40° C . In some embodiments , the temperature is ments , the polar organic solvent is ethanol. at about room temperature . In some embodiments , the In some embodiments , the amount of polar organic sol- temperature is at about 25° C . vent is from about 0 .005 mL to about 10 mL per mg 20 In some embodiments , the time is from about 0 . 1 min to abiraterone derivative. In some embodiments , the amount of about 24 hours. In some embodiments , the time is from polar organic solvent is from about 0 .05 mL to about 5 mL about 0 . 5 min to about 1 hour. In some embodiments , the per mg abiraterone derivative . In some embodiments , the time is from about 1 min to about 10 min . amount of polar organic solvent is from about 0 . 1 mL to Step 5 : The polar organic solvent is removed . about 2 . 0 mL per mg abiraterone derivative . In some 25 In some embodiments , the polar organic solvent is embodiments , the amount of polar organic solvent is about removed under reduced pressure . In some embodiments , the 0 . 1 mL per mg abiraterone derivative. In some embodi- polar organic solvent is removed using rotary evaporation . ments , the amount of polar organic solvent is about 0 . 2 mL In some embodiments, the polar organic solvent is removed per mg abiraterone derivative . In some embodiments , the under a vacuum . amount of polar organic solvent is about 0 . 3 mL per mg 30 In some embodiments , the removal of the polar organic abiraterone derivative . In some embodiments , the amount of solvent yields a clear solution . polar organic solvent is about 0 . 4 mL per mg abiraterone Step 6 : The water from themixture is removed to provide derivative . In some embodiments , the amount of polar a solid . organic solvent is about 0 .5 mL per mg abiraterone deriva - In some embodiments , the water is removed under a tive . 35 vacuum . In some embodiments , the water is removed using Step 2 : An amount of water is added to the solution . rotary evaporation . In some embodiments , the water is In some embodiments , the amount of water is from about removed by lyophilization . 0 .010 mL to about 30 mL per mg abiraterone derivative . In Step 7 : Optionally , the solid is reconstituted by adding some embodiments , the amount of water is from about 0 . 10 water. mL to about 15 mL per mg abiraterone derivative . In some 40 In some embodiments , the addition of water for reconsti embodiments , the amount of water is from about 0 . 2 mL to tution yields a clear solution . about 6 mL per mg abiraterone derivative . In some embodi - Pharmaceutical Compositions and Administration ments , the amount of water is from about 0 . 3 mL to about The methods provided herein include the manufacture and 2 . 0 mL per mg abiraterone derivative. In some embodi - use of pharmaceutical compositions , which include one or ments , the amount of water is about 0 . 3 mL per mg abi- 45 more of the compounds provided herein . Also included are raterone derivative . In some embodiments , the amount of the pharmaceutical compositions themselves. water is about 0 . 4 mL per mg abiraterone derivative . In some Pharmaceutical compositions typically include a pharma embodiments , the amount of water is about 0 . 5 mL per mg c eutically acceptable carrier . Some examples of materials abiraterone derivative . In some embodiments , the amount of which can serve as pharmaceutically acceptable carriers water is about 1 . 0 mL per mg abiraterone derivative . In some 50 include : (1 ) sugars , such as lactose , glucose , and sucrose ; ( 2 ) embodiments , the amount of water is about 1 . 5 mL per mg starches, such as corn starch , potato starch , and substituted abiraterone derivative. or unsubstituted ß -cyclodextrin ; ( 3 ) cellulose , and its deriva In some embodiments , the water has pH of from about 1 tives, such as sodium carboxymethyl cellulose , ethyl cellu to about 7 . In some embodiments , the water has pH of from lose , and cellulose acetate ; ( 4 ) powdered tragacanth ; ( 5 ) about 2 to about 7. In some embodiments , the water has pH 55 malt ; (6 ) gelatin ; ( 7) talc ; (8 ) excipients , such as cocoa butter of from about 3 to about 7 . In some embodiments , the water and suppository waxes ; ( 9 ) oils , such as peanut oil , cotton has pH from about 4 to about 6 . seed oil , safflower oil, sesame oil , olive oil , corn oil, and In some embodiments , the water has pH of about 5 . soybean oil ; ( 10 ) glycols , such as propylene glycol; ( 11 ) In some embodiments , the water having pH of from about polyols, such as glycerin , sorbitol, mannitol, and polyeth 1 to about 7 is prepared by adding an acid into water. In 60 ylene glycol ; ( 12 ) esters , such as ethyl oleate and ethyl some embodiments , the water having pH of from about 1 to laurate ; ( 13 ) agar ; ( 14 ) buffering agents , such as magnesium about 7 is prepared by adding hydrochloric acid into water. hydroxide and aluminum hydroxide ; ( 15 ) alginic acid ; ( 16 ) In some embodiments , the water having pH of from about 1 pyrogen - free water; ( 17 ) isotonic saline ; ( 18 ) Ringer ' s solu to about 7 is prepared by adding 2 N aqueous hydrochloric tion ; ( 19 ) ethyl alcohol; ( 20 ) phosphate buffer solutions , and acid (HCl (aq ) ] into water. In some embodiments , the water 65 (21 ) other non - toxic compatible substances employed in having pH of from about 1 to about 7 is prepared by adding pharmaceutical formulations . In certain embodiments , phar a 1 N HC1 (aq ) into water. maceutical compositions provided herein are non -pyro US 9 , 937 , 259 B2 53 54 genic , i. e . , do not induce significant temperature elevations Methods of Use when administered to a patient. The endoplasmic reticular cytochrome P450 , 17a Examples of pharmaceutically acceptable antioxidants hydroxylase , 17 -20 lyase in humans (CYP17 ) plays a key include : ( 1 ) water soluble antioxidants , such as ascorbic role in the biosynthesis of steroid hormones ( Akhtar, M . K . acid , cysteine hydrochloride, sodium bisulfate , sodium 5 et al. Journal of Endocrinology 2005 , 187 , 267 - 274 ). Accordingly , its dysfunction has been correlated with a metabisulfiteantioxidants, ,such sodium as ascorbylsulfite , palmitateand the ,like butylated; ( 2 ) oil hydroxy - soluble - number of diseases , including polycystic ovary syndrome, Cushing ' s syndrome, congenital adrenal hyperplasia , and anisole (BHA ) , butylated hydroxytoluene (BHT ) , lecithin , prostate cancer. propyl gallate , alpha- tocopherol, and the like ; and ( 3 ) metal An aspect of the current application is directed to a chelating agents , such as citric acid , ethylenediamine tet - 10 compound provided herein , a non - covalent complex of raacetic acid ( EDTA ), sorbitol, tartaric acid , phosphoric serum albumin with the compound , or a pharmaceutical acid , and the like . A pharmaceutical composition may also contain adju composition including the same, that can be administered to vants such as preservatives , wetting agents , emulsifying treattion ofa diseaseCYP17 .or condition that would benefit from inhibi agents , and dispersing agents . Prevention of the action of 15 Also provided in the present disclosure is a method of microorganisms may be ensured by the inclusion of various treating a disease associaassociated with the activity of CYP17 , the antibacterial and antifungal agents , for example , paraben , method including administering to a mammalian patient a chlorobutanol, phenol sorbic acid , and the like . It may also pharmaceutical composition as described herein . In some be desirable to include tonicity - adjusting agents , such as embodiments, the disease is cancer . In some embodiments , sugars and the like into the compositions . In addition , 20 the cancer is breast cancer, ovarian cancer, or prostate prolonged absorption of the injectable pharmaceutical form cancer. may be brought about by the inclusion of agents which delay Also provided in the present disclosure is a compound as absorption such as aluminum monostearate and gelatin . described herein , a non -covalent complex of serum albumin In some cases, in order to prolong the effect of one or with the compound , or a pharmaceutical composition more compounds provided herein , it is desirable to slow the 25 including the same, which can be administered to treat cancer in a patient. Cancer refers to disease of blood , bone , absorption of the compound from subcutaneous or intra organs , skin tissue , and the vascular system , including, but muscular injection . For example , delayed absorption of a not limited to , cancers of the bladder , blood , bone, brain , parenterally administered compound can be accomplished breast, cervix , chest , colon , endometrium , esophagus, eye, by dissolving or suspending the compound in an oil vehicle . head , kidney , liver, lung , lymph nodes, mouth , neck , ovaries , Pharmaceutical compositions suitable for parenteral 30 pancreas , prostate , rectum , renal, skin , stomach , testis , administration can include one or more compounds provided throat, and uterus . In some embodiments, the cancer is herein in combination with one or more pharmaceutically selected from a breast cancer, a colon cancer , a leukemia , a acceptable sterile aqueous or nonaqueous solutions, disper bone cancer, a lung cancer, a bladder cancer, a brain cancer, sions , suspensions or emulsions , or sterile powders which a bronchial cancer, a cervical cancer, a colorectal cancer , an may be reconstituted into sterile injectable solutions or 35 endometrial cancer, an ependymoma cancer, a retinoblas dispersions just prior to use , which may contain antioxi toma cancer, a gallbladder cancer , a gastric cancer, a gas dants , buffers , bacteriostats , solutes which render the for - trointestinal cancer , a glioma cancer , a head and neck cancer , mulation isotonic with the blood of the intended recipient or a heart cancer , a liver cancer, a pancreatic cancer, a mela suspending or thickening agents . noma cancer, a kidney cancer, a laryngeal cancer , a lip or Examples of suitable aqueous and nonaqueous carriers 40 oral cancer , a lymphoma cancer, a mesothioma cancer , a which may be employed in the pharmaceutical compositions mouth cancer , a myeloma cancer, a nasopharyngeal cancer, provided herein include water for injection (e . g ., sterile a neuroblastoma cancer , an oropharyngeal cancer, an ovar water for injection ), bacteriostatic water , ethanol, polyols ian cancer , a thyroid cancer, a penile cancer, a pituitary ( such as glycerol, propylene glycol, polyethylene glycol cancer, a prostate cancer , a rectal cancer , a renal cancer , a such as liquid polvethylene glycol, and the like ), sterile 45 salivary gland cancer, a sarcoma cancer, a skin cancer, a stomach cancer, a testicular cancer , a throat cancer, a uterine buffer ( such as citrate buffer ) , and suitable mixtures thereof, cancer, a vaginal cancer, and a vulvar cancer. vegetable oils , such as olive oil, injectable organic esters , In some embodiments , the cancer is breast cancer. such as ethyl oleate , and Cremophor ELTM (BASF , Parsip In some embodiments , the cancer is prostate cancer. In pany , N . J . ) . In some embodiments , the composition is sterile some embodiments , prostate cancer is selected from hor and is fluid to the extent that easy syringability exists . Proper 50 mone refractory prostate cancer; prostate cancer with a fluidity can be maintained , for example , by the use of rising PSA ( prostate - specific antigen ); prostate cancer with coating materials , such as lecithin , by the maintenance of the a rising PSA and nodal disease following definitive radical required particle size in the case of dispersions , and by the prostatectomy; progressive chemotherapy -naïve castration use of surfactants . resistant prostate cancer; prostate cancer in patients who Sterile injectable solutions can be prepared by incorpo - 55 have failed hormone therapy ; prostate cancer in patients who rating the active compound in the required amount in an have failed androgen deprivation and docetaxel- based che appropriate solvent with one or a combination of ingredients motherapy ; metastatic hormone - resistant prostate cancer ; enumerated above , as required , followed by filtered steril - high - risk , metastatic hormone- naïve prostate cancer; and ization . Generally , dispersions are prepared by incorporating metastatic castration - resistant prostate cancer . For example , the active compound into a sterile vehicle , which contains a 60 prostate cancer can include metastatic castration - resistant basic dispersion medium and the required other ingredients prostate cancer. In some embodiments , the prostate cancer is from those enumerated above . In the case of sterile powders responsive to androgen -deprivation therapy . for the preparation of sterile injectable solutions, the pre ferred methods of preparation is freeze -drying ( lyophiliza EXAMPLES tion ), which yields a powder of the active ingredient plus 65 any additional desired ingredient from a previously sterile Syntheses of abiraterone and related compounds have filtered solution thereof. been reported by others . For example , U . S . Pat . Nos. 8 , 338 , US 9 ,937 ,259 B2 55 56 588 ; 8 ,076 ,474 ; and 5, 604 , 213 describe methods for the -continued synthesis of abiraterone and are hereby incorporated by reference in its entirety . Synthesis: A compound of Formula (I ) is an ester , a carbonate , or a 5 carbamate analog , when A is a covalent bond , O or NR respectively . The methods to prepare an ester , a carbonate , or a carbamate analog are well documented in the field of organic chemistry. It is well within the ability of a skilled -51113 organic chemist to prepare these compounds. 10 The following Schemes 1 - 4 are general synthetic methods for making compounds of Formula ( II ) from abiraterone . For conciseness, the Schemes are depicted for compounds of Formula ( II ) , wherein A is a covalent bond . It is well within the ability of a skilled artisan to adapt these Schemes for 15 synthesis of compounds of Formula ( II ) wherein A is O or NR1. N + c + COOH R5 | R R ? Scheme 1 an 1 . 4
II HO 1 . 1 Scheme 2
OH
EDCI DMAP T1 z Io + COOtBu COOtBu CH2Cl2* HO 1 . 1
!
L TFA OH CHÚC
H
- EDCI, DMAP Z COOtBu 0? CH2Cl2 z COOtBu n To R3 B?R 1 . 3 2 . 2 US 9 , 937 ,259 B2 57 58 - continued -continued o =OH 4 EDCI, DMAP RS — N CH2Cl2 OS COOtBu 10
TFA CHÚC , R 5 0 NoCoOtBu
- 20
2 . 3
25 111T TFA /CH2Cl2
830
R41 H 35 0 MaxB -to + - COOtBu COOtBu 1111111 [ R ]- 1n 3 . 3
840 ? , R41 N - COOH
845 Runn B?2 2 . 4
50
Scheme 3
55
-
60 -Z > P F11111 T11 - B + COOH HO 65 Rºn 3 . 4 US 9 ,937 ,259 B2 59 60 -continued Scheme 4 N a
-111
) ? 11 11
HO 1 . 1 o o RTR27 - TR4 ] iI N + 0 + 0 + o + COOH - [ R ] , R6 [ R ]12
? 4 . 4
Oy OH O R ? [ R27 EDCI, DMAP CH2Cl2 30 - N + 0 + 0 +-Ó o + CoOtBu Example 1 : Synthesis of A -001 RO | Rijn 5 R2 ,n
4 . 2 35
40
45 HO
50
55 111) TFA CH2Cl2
EDCI DMAP R [ R2 OH CH2Cl2 - N + c + CG COOtBu 09 [ R ] , NH
4 . 3 2 US 9 ,937 ,259 B2 61 62 -continued -continued on OH + NH
TFA CH2Cl2 10
EDCI 15 DMAP
HOV ?? 20 che Ti
!" 30
HO TO TFA A - 001 DCM 35 To a solution of Compound 1 ( 200 mg, 0 .573 mmol) in dichloromethane (DCM ) (10 mL ) was added Compound 2 ( 370 mg, 1 . 15 mmol) . 4 - (Dimethylamino ) pyridine ( DMAP ) NH ( 35 mg, 0 . 287 mmol) and 1 -ethyl - 3 - ( 3 -dimethylaminopro pyl) carbodiimide (EDCI ) ( 25 . 0 mg, 1. 26 mmol) were added 40 at 0° C . The mixture was stirred at room temperature (RT ) for 2 hours . Water was added and the solution was extracted with DCM . The organic layer was washed by brine, dried by Na S04, and concentrated to give a crude product, which was purified by column chromatography to give 300 mg of 45 Compound 3 . 11111I To a solution of Compound 3 ( 100 mg) in DCM ( 10 mL ) was added trifluoroacetic acid ( “ TFA " ) ( 2 mL ) dropwise at 0° C . The mixture was stirred at RT for overnight. The mixture was concentrated and crystallized from Et , to give so 60 mg of A - 001. Liquid chromatography -mass spectrometry (LC -MS ) : 597 .5 (m + 1 )+ Example 2 : Synthesis of A - 002 55 NH
NH2 A - 002 O Pyridine 60 X = 0 To a solution of Compound 4 ( 2 g , 10 . 7 mmol) in pyridine (20 mL ) was added dihydrofuran - 2 ,5 -dione ( 1. 4 g , 14 mmol) , and the mixture was stirred at RT overnight. The 65 mixture was concentrated , then treated with water and 4 extracted with ethyl acetate (“ EA " ) . The organic layer was washed with brine , dried over anhydrous Na2SO4, filtered , US 9 ,937 ,259 B2 63 64 and concentrated . The crude product was purified by recrys - continued tallization to give Compound 5 ( 2 g , 66 . 7 % ) . To a solution of Compound 1 (200 mg, 0 . 573 mmol) in DCM ( 10 mL ) was added Compound 5 ( 330 mg, 1 . 15 mmol) . Then DMAP (35 mg, 0 .287 mmol) and EDO (250 5 mg , 1 . 26 mmol) were added at 0° C . The mixture was stirred at RT overnight. The residue was treated with water and NH 1 ) DIEA , THF extracted with DCM . The organic layer was washed with 2 ) TFA brine , dried over anhydrous Na ,SO4 , filtered and concen trated to give 350 mg crude product. Then it was purified by column to afford Compound 6 ( 100 mg, 28 . 2 % ) . To a solution of Compound 6 ( 100 mg, 0 . 16 mmol ) in DCM ( 10 mL ) was added TFA ( 5 mL ) dropwise at 0° C . The mixture was stirred at RT for overnight. The mixture was concentrated and purified by column to give A -002 ( 10 mg, 11 % ). 15 LC -MS : 563. 5 ( m + 1) + Example 3 : Synthesis of A -003
20
25 TI
0 = 30
OH
Z A -003 35 To a solution of Compound 1 ( 200 mg, 0 .573 mmol) in tetrahydrofuran (THF ) (5 mL ) was added Compound 7 (150 THF mg, 0 . 744 mmol) dropwise at 0° C . The mixture was stirred 40 at reflux for 3 hours . After cooling to RT, petroleum ether (PE ) ( 10 mL ) was added . The precipitate was filtered | washed with PE and dried in vacuo to afford Compound 8 ( 200 mg, 69 % ) . HO To a solution of Compound 8 (200 mg, 0 .39 mmol) in 45 THF ( 2 mL ) was added Compound 9 (344 mg, 1 .56 mmol) and NN -diisopropylethylamine (DIEA ) (550 UL , 3. 11 mmol ). The mixture was stirred at reflux for overnight. The mixture was concentrated and purified by column to give 40 50 mg the intermediate . A mixture of the intermediate (40 mg) in DCM / TFA ( 3 mL , 2 : 1 ) was stirred at RT overnight. The residue was concentrated and purified by column to afford A - 003 ( 20 mg) . TU LC -MS : 541. 5 ( m + 1 ) * 55 Example 4 : Synthesis of A - 004
60 60 NH2NH
+ NO2 YtBr US 9 ,937 ,259 B2 65 66 - continued -continued
NH
- H111
9
OH HO + A -004
25 11 To a solution of phenylmethanamine ( 10 g , 94 mmol) in 100 mL of THF was added tert -butyl 2 -bromoacetate (6 .25 g , 32 mmol) . The mixture was refluxed for 1 hour. The solid 30 was filtered and the organic layer was concentrated and purified by silica gel column to give 7 . 35 g of Compound 10 . H NMR : (CDC12 MHz) 8 : 7 . 2 - 7 . 4 ( m , 5H ) , 3 . 8 ( s , 2H ), 3 . 3 (s , 2H ) , 1 . 5 ( s , 9H ) . EDC1, DMAP 3535 CH2Cl2 To a solution of Compound 10 ( 2 g , 9 . 0 mmol) in pyridine (17 mL ) was added dihydrofuran - 2, 5 -dione (1 . 36 g, 13 .6 mmol) , and the mixture was stirred at RT for overnight . The 40 mixture was concentrated , then treated with water and HO extracted with EA . The organic layer was washed with brine Saya and concentrated to give a crude product , which was recrys tallized to give 2 g of Compound 11. 'H NMR : (CDC13 , 300 45 MHz) 8 : 7 . 1 - 7 .5 ( m , 5H ) , 4 . 6 ( s , 2H ), 3 . 8 - 4 . 0 ( d , 2H ) , 2 . 6 - 2 . 9 ( m , 4H ) , 1 . 5 ( s , 9H ) . I To a solution of Compound 1 (200 mg, 0 .573 mmol) in 117 50 DCM ( 10 mL ) was added Compound 11 ( 370 mg, 1 . 15 mmol) . DMAP (35 mg , 0 . 287 mmol) was added and EDCI ( 250 mg, 1 .26 mmol) was added at 0° C . The mixture was TFA /CH2Cl2 stirred at RT for 2 hours . Water was added and the solution was extracted with DCM . The organic layer was washed by 55 brine dried by Na2SO4. The layers were concentrated to give 350 mg crude product of Compound 12 . To a solution of Compound 12 ( 350 mg, crude ) in DCM 60 ( 10 mL ) was added TFA (5 mL) dropwise at 0° C . The mixture was stirred at RT for overnight. The mixture was concentrated and purified by column chromatography to give 54 mg of A - 004 . ' H NMR (300 MHz, CDC12 ) 8 : 8 . 6 ( s , 1H ) , 8 . 4 ( s , 1H ) , 7 . 8 ( m , 1H ) , 7 . 1 - 7 . 4 ( m , 6H ) , 6 . 0 ( s , 1H ) , 65 5 . 3 (s , 1H ) , 3 . 9 -4 . 7 (m , 9H ) , 2 .6 - 2 . 9 ( m , 4H ), 2 .2 - 2 . 4 ( m , 12 3H ) , 1. 9 -2 . 1 ( m , 3H ), 1. 8 -1 . 9 ( m , 2H ), 1. 5 - 1 .8 (m , 7H ) , 1 .0 ( m , 8H ) . LC -MS : 597 . 5 ( m + 1 ) * US 9 ,937 , 259 B2 67 68 Example 5 : Synthesis of A - 005 -continued
NH2
* uit Br TFA / CH2Cl2
NH 15
13 H 11111
?? ??HO TO A -005 To a solution of phenylmethanamine ( 10 g, 82 mmol) in 50 100 mL THF was added tert- butyl 2 -bromoacetate (6 .25 g , 27 mmol) . The mixture was refluxed for 1 hour. The solid was filtered and the organic layer was concentrated . The crude product was purified by silica gel column to give 5 . 4 14 g of Compound 13 . To a solution of Compound 13 ( 1 g , 4 . 2 mmol) in pyridine ( 9 mL ) was added dihydrofuran - 2 , 5 -dione ( 1 . 28 g , 12 . 8 mmol ) , and the mixture was stirred at RT for overnight. The mixture was concentrated , then treated with water and EDCI, DMAP extracted with EA . The organic layer was washed with brine CH2Cl2 60 and concentrated . The crude product was recrystallized to give 1. 2 g of Compound 14 . To a solution of Compound 1 ( 200 mg, 0 .573 mmol) in 11 DCM ( 10 mL ) was added Compound 14 ( 384 mg, 1. 14 mmol) . DMAP (35 mg, 0 . 287 mmol) was added and EDCI HO 65 ( 391 mg, 2 . 0 mmol) was added at 0° C . The mixture was stirred at RT for 2 hours. Water was added and the solution was extracted with DCM . The organic layer was washed by US 9 ,937 ,259 B2 69 70 brine dried by Na2SO4 and concentrated to give 350 mg -continued crude product of Compound 15 . To a solution of Compound 15 (350 mg, crude ) in DCM ( 10 mL ) was added TFA (5 mL ) dropwise at 0° C . The mixture was stirred at RT for overnight. The mixture was 5 concentrated and purified by column chromatography to give 180 mg of A - 005 . LC -MS : 611. 6 (m + 1) * INT> .111 10 Example 6 : Synthesis of A -006 TFA /CH2Cl2
NH
. Sä 17
?111
HO
0
OH A -006 50 To a solution of Compound 10 ( 2 g , 9 . 0 mmol) in pyridine 16. ( 17 mL ) was added dihydro - 2H -pyran - 2, 6 (3H )- dione (1 . 54 g , 13 .5 mmol) , and the mixture was stirred at RT for overnight. The mixture was concentrated , then treated with 55 water and extracted with EA . The organic layer was washed with brine and dried by Na , SO and concentrated to give a crude product , which was purified by silica gel column to give 2 g of Compound 16 . EDCI, DMAP To a solution of compound 1 (200 mg, 0 .573 mmol) in CH2Cl2 60 DCM ( 10 mL ) was added Compound 16 ( 370 mg, 1 . 15 mmol) . DMAP ( 35 mg, 0 .287 mmol) and EDCI (250 mg, .-2017 1 . 26 mmol ) were added at 0° C . The mixture was stirred at RT for overnight. Water was added and the solution was extracted with DCM . The organic layer was dried by 65 Na2SO4 and concentrated to give a crude product , which was purified by silica gel column to give 150 mg of Compound 17. US 9 , 937 ,259 B2 71 To a solution of Compound 17 ( 150 mg, 0 .225 mol) in -continued DCM (10 mL ) was added TFA (5 mL ) drop -wise at 0° C . The mixture was stirred at RT for overnight. The mixture was concentrated and extracted with DCM . The organic layer was dried by Na SO , and concentrated to give a crude product , which was purified by silica gel column to give 80 mg of A -006 .
LC -MS : 611. 5 (m + 1 ) * "111 Example 7 : Synthesis of A - 007 TFA / CH2Cl2
Br og 20 HH O= = -O ?
HO $
# HO A - 007
To a solution of phenylmethanamine (5 g , 25 mmol) in 50 100 mL THF was added tert- butyl 2 - bromoacetate ( 2. 07 g , 17 mmol) . The mixture was stirred refluxed for 1 hour. The solid was filtered and the organic layer was concentrated to give a crude product, which was purified by silica gel 19 column to give 2 .5 g of Compound 18 . 55 To a solution of Compound 18 ( 1 g , 4 .2 mmol ) in pyridine ( 9 mL ) was added dihydrofuran - 2 , 5 -dione ( 1 . 28 g , 12 . 8 mmol) , DMAP ( 0 . 4 g ) and the mixture was heated to 50° C . EDCI, DMAP overnight. The mixture was concentrated , then treated with water and extracted with EA . The organic layer was washed CH2Cl2 with brine and concentrated to give a crude product, which was recrystallized to give 600 mg of Compound 19 . 2011 To a solution of Compound 1 ( 200 mg, 0 .573 mmol) in DCM ( 10 mL ) was added Compound 19 ( 384 mg, 1 . 14 ?? 65 mmol) . DMAP (35 mg, 0 . 287 mmol) was added and EDCI (391 mg, 1 . 3 mmol) was added at 0° C . The mixture was stirred at RT for 2 hours . Water was added and the solution US 9 , 937 ,259 B2 73 74 was extracted with DCM . The organic layer was washed by - continued brine dried by Na2SO4 and concentrated to give 40 mg crude product of Compound 20 . To a solution of Compound 20 (40 mg , crude ) in DCM ( 10 mL) was added TFA (5 mL ) dropwise at 0° C . The mixture was stirred at RT for overnight . The mixture was concen trated and purified by column chromatography to give 18mg H of A -007 . LC -MS : 611. 6 ( m + 1 ) * Example 8 : Synthesis of A -008 TFA /CH2Cl2
Z ?t? .tr H2N ,
2323
( .1111 ulNH |
21
OH HO HU A - 008 To a solution of ( S )- tert -butyl 2- aminopropanoate ( 1. 7 g , 50 11. 8 mmol) in 30 mL MeOH was added benzaldehyde ( 1 . 4 g , 12 . 4 mmol) portionwise at RT . After 1 h , the mixture was added NaCNBHZ ( 0 .75 g , 11 . 8 mmol) and acetic acid (“ AcOH ” ) (1 .42 g , 23 .6 mmol) . The mixture was stirred at RT for overnight. The mixture was concentrated , then added 55 water and pH was adjusted to between 8 - 9 with NaHCO , . The mixture was then extracted with EA . The organic layer was washed with water , brine and dried by Na, SO2, and then concentrated to give 2 . 4 g of Compound 21 . EDCI, DMAP To a solution of Compound 21 (500 mg, 2 . 2 mmol) in CH2Cl2 pyridine ( 5 mL ) was added dihydrofuran - 2 , 5 -dione (330 mg, " 3 . 3 mmol) , and the mixture was stirred at RT for overnight. E The mixture was concentrated , then treated with water and IT extracted with EA . The organic layer was washed with brine ?? 65 and dried by Na2SO4 and concentrated to give a crude product , which was purified by silica gel column to give 400 mg of Compound 22 . US 9 , 937 ,259 B2 75 76 To a solution of Compound 1 ( 94 mg, 0 . 27 mmol) in -continued DCM (6 mL ) was added Compound 22 ( 180 mg, 0 .54 mmol) . DMAP ( 17 mg, 0 . 14 mmol) was added and EDCI ( 186 mg, 0 . 945 mmol) was added at 0° C . The mixture was stirred at RT for overnight. Water was added and the solution 5 was extracted with DCM . The organic layer was dried by Na2SO4 and concentrated to give a crude product, which was purified by silica gel column to give 150 mg of Compound !I 23 . To a solution of Compound 23 ( 150 mg, 0 .225 mol) in DCM ( 8 mL ) was added TFA ( 4 mL ) dropwise at 0° C . The mixture was stirred at RT for overnight. The mixture was TFA / CH2Cl2 concentrated and extracted with DCM . The organic layer 0 was dried by Na , SO , and concentrated to give a crude product, which was purified by silica gel column to give 30 NH mg of A - 008 . 15 AYNA LC -MS : 611. 6 (m + 1) * Example 9 : Synthesis of A -009
20
25 25
NH
%11
24
NH
A - 009 To a solution of Compound 1 (200 mg, 0 . 573 mmol ) in 55 DCM ( 10 mL ) was added Compound 24 ( 390 mg, 1 . 15 mmol ). DMAP ( 35 mg, 0 .287 mmol) was added and EDCI ( 260 mg, 1 .26 mmol) was added at 0° C . The mixture was stirred at RT for 2 hours . Water was added and the solution EDC1, DMAP was extracted with DCM . The organic layer was washed by CH2Cl2 60 brine dried by Na , SO , and concentrated to give a crude product, which was purified by column chromatography to give 200 mg of Compound 25 . To a solution of Compound 25 ( 200 mg) in DCM ( 10 mL ) was added TFA ( 2 mL ) dropwise at 0° C . The mixture was 65 stirred at RT for overnight. The mixture was concentrated and crystallized from Et20 to give 105 mg of A -009 . LC -MS : 619 . 6 ( m + 1 ) + US 9 , 937 ,259 B2 77 78 Example 10 : Synthesis of A -010 -continued Box30 10 OH + NH
26
20
EDC1, DMAP CH2Cl2 25 T12 A -010 HO 30 To a solution of Compound 1 (200 mg, 0 .573 mmol ) in DCM ( 10 mL ) was added Compound 26 ( 520 mg, 1 . 15 mmol) . DMAP (35 mg, 0 .287 mmol) was added and EDCI ( 250 mg, 1 .26 mmol) was added at 0° C . The mixture was 35 stirred at RT for 2 hours . Water was added and the solution was extracted with DCM . The organic layer was washed by ergeço brine dried by Na2SO4 and concentrated to give a crude product, which was purified by column chromatography to NH 40 give 260 mg of Compound 27 .
TFA / CH2Cl2 45 To a solution of Compound 27 ( 260 mg) in DCM ( 10 mL ) was added TFA ( 2 mL ) dropwise at 0° C . The mixture was stirred at RT for overnight. The mixture was concentrated and crystallized from Et O to give 100 mg of A - 010 . 50 LC -MS : 731 (m + 1 )+ 7 Example 11 : Synthesis of B - 001 29 Ph NH
?? s EDCI DMAP trwy DMFgyny 28 US 9 ,937 ,259 B2 1979 - continued
HO EDCI DMAP DCM 30
TFA 1117 DCM 111T
Ph .
www. OH
31 B - 001
To a solution of compound 28 ( 5 . 7 g , 27 . 15 mmol) and Example 11 : Synthesis of B - 002 compound 29 ( 3 g , 13 . 6 mmol) in 50 mL of dimethylfor mamide (DMF ) at 0° C . , EDCI ( 5 . 2 g , 27 . 15 mmol) and 40 DMAP (828 mg, 6 . 8 mmol) were added . Then the reaction was stirred at RT for overnight. Water was added and extracted with EA . The organic layer was washed with water and brine , dried over Na2SO4, and concentrated to give a crude product, which was purified by column chromatogra - 45 phy to give 3 g of compound 30 . ' H NMR (CDC13 , 300 MHz) 8 : 1. 4 (s , 9H ), 2 . 7 - 3 . 1 (m , 8H ) , 3. 9 -4 .2 (s , 2H ), 4 .6 -4 .7 H ( s, 2H ), 7 .2 -7 . 5 ( m , 5H ) )II LC -MS : m /z = 436 ( M + 23 ) * To a solution of compound 30 (533 mg, 1 .29 mmol) , 50 EDCI (247 mg, 1 . 29 mmol) and DMAP ( 42 mg, 0 .344 mmol) in 30 mL of DCM at 0° C . , compound 1 ( 300 mg, 0 . 86 mmol) was added into the solution . Then the reaction was stirred at RT for overnight. Water was added and extracted with DCM . The organic layer was washed with brine , dried over Na , SO4, concentrated to give a crude product, which was purified by column chromatography to give 250 mg of compound 31 . 151117 LC -MS : m /z = 745 ( M + 1 ) To a solution of compound 31 (250 mg) in 15 mL ofDCM at 0° C . , TFA ( 2 mL ) was added . Then the reaction was 60 stirred at RT for 1 . 5 h . The mixture was concentrated and purified by column chromatography to give 100 mg of B - 001. HNMR (CDC12 , 300 MHz ) 8 : 1 . 0 - 1 . 1 ( d , 6H ) , 1 .5 - 2 . 4 ( m , 16H ) , 2. 7 - 3 .1 (m , 8H ), 4 .0 - 4 . 2 ( m , 2H ), 4 .6 -4 . 8 ( m , 3H ) , 5 . 4 - 5 . 5 ( d , 1H ) , 6 . 0 - 6 . 1 ( d , 1H ) , 7 . 2 - 7 . 4 ( m , 6H ) , 65 10 7 . 7 - 7 . 8 ( m , 1H ) , 8 . 4 - 8 . 5 ( d , 1H ) , 8 . 7 ( s , 1H ) . LC -MS : m / z = 689 ( M + 1 ) B - 002 US 9 ,937 ,259 B2 81 82 To a solution of abiraterone ( 500 mg, 1 .43 mmol) in crude product was purified by silica gel column to give 217 DMF / 1, 4 -dioxane ( 7 .5 mL /7 . 5 mL ) was added succinicm g of B -002 . anhydride ( 700 mg, 7 mmol) . DMAP (525 mg, 4 . 3 mmol ) was added and the mixture was stirred at RT for overnight. LC -MS : m / z = 450 .5 (M + 1) * Water was added and the mixture was extracted with EA 5 twice . The organic layer was dried and concentrated . The Example 12 : Synthesis of B -003
S HS HAN NH2 = O NaOH - OH 0 33
H2N 35
- OH
34
HO
SMS SH
33
NH US 9 , 937 ,259 B2 8383 84 - continued
11117 HO
HO
nilil - NH
37
N
TFA
HN . HN COOH
38 B -003
To a solution of compound 32 (21 g , 210 mmol ) in HBr 50 mixture was extracted with ethyl acetate , washed with water ( 86 .13 g , 425 . 8 mmol, 40 % ) was added thiourea (30 . 4 g , and brine , dried over anhydrous Na2SO4, and concentrated 399. 5 mmol) under 70° C . The mixture was stirred at 100° to give a crude product, which purified by a column chro C . overnight. Then the mixture was cooled and the pH was matography to give compound 34 ( 5 . 5 g , 60 . 7 % ) . "HNMR adjusted to 10 , and stirred at 100° C . overnight. Then the (CDC13 , 300 MHz) 8 : 1. 3 - 1. 4 (d , 2H ), 1. 8 -2 .05 (m , 2H ), reaction mixture was cooled and the pH was adjusted to 4 - 5 . – 2 .5 - 2 . 6 ( m , 2H ), 3 . 0 - 3 . 1 ( m , 1H ), 7 . 0 - 7 . 2 ( m , 1H ) , 7 .6 - 7 . 7 The mixture was extracted with ethyl acetate , washed with ( m , 1H ) , 7 . 7 - 7 . 8 ( d , 1H ) , 8 . 4 - 8 . 5 ( d , 1H ) . water and brine, dried over anhydrous Na, SO4, and con - To a solution of compound 34 ( 5 . 5 g , 22 . 6 mmol) and centrated to give a crude product , which was purified by a compound 35 ( 5 . 8 g , 22 .6 mmol) in 50 mL of DMF at 0° C . , column chromatography to give compound 33 ( 7 g , 24 . 9 % ) . 60 EDCI ( 6 . 8 g , 35 . 3 mmol) and DMAP (828 mg, 6 . 8 mmol) HNMR ( CDC13 , 300 MHz ) d : 1 . 3 - 1 . 4 ( d , 2H ) , 1 . 4 - 1 . 5 ( d , were added . Then the reaction was stirred at room tempera 2H ) , 1. 7 - 1. 8 (m , 1H ), 1 . 9 - 2 .0 ( m , 1H ), 2 . 4 -2 .6 (m , 2H ), ture overnight. Water was added and extracted with ethyl 2 . 9 - 3 . 1 ( m , 1H ). acetate . The organic layer was washed with water and brine, To a solution of compound 33 ( 5 g , 37. 3 mmol) in MeOH dried over anhydrous Na2SO4, and concentrated to give a ( 70 mL ) was added 1 ,2 -di ( pyridin - 2 - yl) disulfane ( 12 .3 g, 56 65 crude product, which was purified by column chromatogra mmol) . The mixture was stirred at room temperature over phy to give 2 . 8 g of compound 36 . 'HNMR (CDC12 , 300 night. The pH of the mixture was adjusted to 4 - 5 . The MHz) 8 : 1. 3 - 1 .4 (m , 3H ) , 1 .4 - 1. 6 (s , 9H ) , 1 .9 - 2. 1 (m , 2H ), US 9 , 937 , 259 B2 85 86 2 . 3 - 2 .5 ( m , 2H ), 3 . 1 - 3 .2 . 2 ( m , 2H ) , 4 .7 - 4 . 9 ( m , 1H ) , 6 . 0 - 6 . 1 Example B : Non - Covalently Bound Complex of ( m , 1H ), 7 . 0 - 7 . 1 (m , 1H ) , 7 .1 - 7 .2 (m , 2H ), 7 .3 - 7. 5 ( m , 3H ), A - 004 and HSA 7 . 6 - 7 . 8 ( m , 2H ) , 8 . 5 ( m , 1H ) . To a solution of compound 36 ( 1 g , 2 . 4 mmol) in In each of 3 vials , 1 mg of A - 004 was dissolved in 0 . 5 mL dimethylformamide (“ DMF” ) ( 5 mL ), was added compound 5 of0 methanol. Then 1 . 5 mL of water with a pH about 5 was added into the vials . The water with a pH of about 5 was 33 ( 0 .647 g , 4 .8 mmol) . The mixture was stirred at room prepared by adding 2 N HCl ( aq .) into water. After shaking temperature overnight. The mixture was extracted with EA . gently , a clear solution was obtained for all 3 vials. 22 . 3 mg, The organic layer was washed with water and brine, dried 18 . 6 mg, and 15 . 9 mg of HSA were added , respectively , into over anhydrous Na2SO4, and concentrated to give a crude 10 the vials . After shaking gently , a cloudy solution was product, which was purified by a column chromatography to obtained for the vials with 18 . 6 mg and 15 . 9 mg ofHSA , and give compound 37 ( 350 mg, 31 % ) . a clear solution was obtained for the vial with 22 . 3 mg of LC -MS : mlz = 470 ( M + 1 ) . HSA . Then methanol was removed under vacuum until the To a solution of compound 37 ( 350 mg , 0 .74 mmol) , volume of the solution was about 1 mL . A clear water EDCI (286 mg, 1. 48 mmol) and DMAP (42 mg , 0 .344 15 solution was obtained for the vials with 22 . 3 mg and 18 .6 mg mmol) in 30 mL of DCM at 0° C ., compound 1 ( 258 mg, of HSA , and a cloudy solution was obtained for the vial with 0 .74 mmol) was added in the solution . Then the reaction 15 .9 mg of HSA . The water solutions of the 3 vials were mixture was stirred at room temperature for overnight. lyophilized overnight to give the white solids, which were Water was added and extracted with ethyl acetate . The reconstituted by adding 0 . 5 mL of water into the vials . A organic layer was washed with water and brine , dried over 20 clear water solution was obtained for the vials with 22 . 3 mg anhydrous Na SO4, and concentrated to give a crude prod and 18 . 6 mg of HSA , and a cloudy solution was obtained for uct, which was purified by column chromatography to give the vial with 15 . 9 mg of HSA . 300 mg of compound 38 . LC -MS : m / z = 824 ( M + 23 ) + . TABLE 2 To a solution of compound 38 ( 300 mg) in 12 mL of 25 HSA (mg ) CH , C1, at 0° C ., TFA ( 2 mL ) was added . Then the reaction mixture was stirred at room temperature for 2 hours . The 22 .3 18. 6 15 . 9 mixture was concentrated and purified by column chroma tography to give 66 mg of B - 003. " HNMR (CDC12 , 300 Ratio of drug: HSA 5 6 7 MHz) 8 : 1 . 1 - 1 . 2 ( s , 6H ), 1 . 3 - 1 . 4 ( m , 6H ) , 1 . 6 - 1 . 8 ( m , 4H ) , 30 1 .8 - 1. 9 ( m , 4H ), 2 .0 -2 . 2 ( m , 2H ), 2 . 3 -2 .5 (m , 10H ), 2 .8 - 3. 0 Example C : Non - Covalently Bound Complex of ( m , 4H ) , 3 . 1 - 3 . 3 ( m , 4H ) , 4 .6 - 4 . 7 ( m , 2H ) , 4 . 8 - 5 . 0 ( m , 2H ) , 5 . 4 - 5 . 5 ( m , 1H ) , 6 . 2 -6 . 3 ( m , 1H ) , 6 . 3 - 6 . 4 ( m , 1H ) , 7 . 2 - 7 . 3 A -005 and HSA ( m , 3H ), 7 .7 - 7 .9 m , 1H ), 8 . 2 - 8 .4 (m , 1H ), 8. 6 - 8 . 8 ( m , 1H ), 35 . In each of 3 vials , 1 mg of A -005 was dissolved in 0 .5 mL 8 . 9 - 9 . 0 ( m , 1H ) . of methanol. Then 1 . 5 mL of water with a pH about 5 was LC -MS : m / z = 744 ( M + 1 ) * . added into each vial. The water with a pH of about 5 was prepared by adding 2 N HCl ( aq . ) into water. After shaking Example A : Non -Covalently Bound Complex of gently , a clear solution was obtained for all 3 vials . 27 . 2 mg, A -003 and HSA 40 21. 8 mg and 18. 1 mg of HSA were added , respectively , into the vials . After shaking gently , a clear water solution was In 2 vials , 1 mg of A - 003 was dissolved in 0 . 5 mL obtained for the vial with 27 . 2 mg of HSA , and a cloudy methanol. Then 1 . 5 mL water at a pH of about 5 was added solution was obtained for the vials with 21 . 8 mg and 18 . 1 mg into each vial. The water with a pH of about 5 was prepared of HSA . Then methanol was removed under vacuum until by adding 2 N HCl (aq .) into water . After shaking gently , a 45 the volume of the solution was about 1 mL. A clear water cloudy solution was obtained for both vials . 30 . 8 mg and solution was obtained for the vial with 27 . 2 mg of HSA , and 24 . 6 mg of HSA were then added , respectively , into the a cloudy solution was obtained for the vials with 21 . 8 mg vials . After shaking gently , a slightly cloudy solution was and 18 . 1 mg of HSA . The water solutions of the 3 vials were obtained for both vials . Then methanol was removed under lyophilized overnight to give the white solids , which were vacuum until the volume of the solution was about 1 mL . A 50 reconstituted by adding 0 . 5 mL water into the vials . A clear clear water solution was obtained for the vial with 30 . 8 mg water solution was obtained for the vial with 27 . 2 mg of of HSA , and a slightly cloudy solution was obtained for the HSA , and a cloudy solution was obtained for the vials with vial with 24 .6 mg of HSA . The water solutions of the 2 vials 21. 8 mg and 18 . 1 mg of HSA . were lyophilized overnight to give the white solids , which were reconstituted by adding 0 .5 mL water into the vials . A TABLE 3 clear water solution was obtained for the vial with 30 . 8 mg HSA (mg ) of HSA , and slightly cloudy solution was obtained for the vial with 24 .6 mg of HSA . 27. 2 21. 8 18 .1 TABLE 1 60 Ratio of drug : HSA 4 5 6 HSA (mg ) g ) Example D : Non - Covalently Bound Complex of 30 .. 8 8 2424 . 6 A - 006 and HSA Ratio of drug: HSA 4 5 65 In each of 3 vials , 1 mg of A -006 was dissolved in 0. 5 mL of methanol . Then 1 . 5 mL ofwater with a pH of about 5 was US 9 ,937 ,259 B2 87 88 added into each vial . The water with a pH of about 5 was respectively , into the vials. After shaking gently , then metha prepared by adding 2 N HC1 ( aq ) into water. After shaking nol was removed under vacuum until the volume of the gently , a clear solution was obtained for all 3 vials . 27 . 2 mg, solution was about 1 mL . A clear water solution was 21 .8 mg and 18 . 1 mg of HSA were added , respectively , into obtained for the vial with 24 . 1 mg of HSA , and a cloudy the vials . After shaking gently , a clear solution was obtained 5 solution was obtained for the vialwith 19 . 3 mg of HSA . The for vials with 27 . 2 mg and 21. 8 mg of HSA , a cloudy water solutions of the 2 vials were lyophilized overnight to solution was obtained for the vial with 18. 1 mg of HSA . give the white solids, which were reconstituted by adding Then methanol was removed under vacuum until the volume 0 . 5 mL water into the vials. A clear water solution was of the solution was about 1 mL . A clear water solution was obtained for the vial with 24 . 1 mg of HSA , and a cloudy obtained for the vials with 27 . 2 mg and 21 . 8 mg ofHSA , and 10 solution was obtained for the vial with 19 . 3 mg of HSA . a cloudy solution was obtained for the vial with 18 . 1 mg of HSA . The water solutions of the 3 vials were lyophilized TABLE 6 overnight to give the white solids, which were reconstituted by adding 0 . 5 mL water into the vials . A clear water solution 15 . HSA was obtained for the vials with 27 .2 mg and 21 .8 mg of 24 . 1 mg 19. 3 mg HSA , and a cloudy solution was obtained for the vial with 18 . 1 mg of HSA . Ratio of drug :HSA 4 5
TABLE 4 20 Example G : Non -Covalently Bound Complex of HSA (mg ) B - 002 and HSA 27 .2 21. 8 18 . 1 In each of 2 vials , 3 mg of B - 002 was dissolved in 3 mL Ratio of drug :HSA 4 5 6 25 methanol/DMF ( 4 : 1 ) . In another 2 vials , 111 mg and 148 mg of HSA were dissolved in 6 mL water, respectively . Then methanol solution of B -002 was added slowly into the vials Example E : Non -Covalently Bound Complex of of HSA with shaking , respectively . A clear solution was A -008 and HSA obtained in both vials . Then methanol was removed under 30 vacuum until the volume of the solution was about 3 - 4 mL . In each of 3 vials , 1 mg of A -008 was dissolved in 0 . 5 mL A clear water solution was obtained for both vials . The water methanol. Then 1 . 5 mL of water with a pH of about 5 was solutions of the 2 vials were lyophilized overnight to give added into each of 3 vials . The water with a pH of about 5 was prepared by adding 2 N HCl ( aq. ) into water . After white solids . 50 mg of the solids were reconstituted by shaking gently , a clear solution was obtained for all 3 vials . 35 addingW 0 .5 mL of water into the vials . A clear water solution 27 . 2 mg, 21. 8 mg and 18 . 1 mg of HSA were added , 35 was obtained for both vials . respectively , into the vials . After shaking gently , a clear solution was obtained for vials with 27 . 2 mg and 21 . 8 mg of TABLE 7 HSA , a cloudy solution was obtained for the vial with 18 . 1 HSA mg of HSA . Then methanol was removed under vacuum 40 until the volume of the solution was about 1 ml. A clear | 148 mg 111 mg water solution was obtained for the vials with 27 . 2 mg and Ratio of drug: HSA 3 4 21 . 8 mg of HSA , and a cloudy solution was obtained for the vial with 18 . 1 mg of HSA . The water solutions of the 3 vials were lyophilized overnight to give the white solids , which 45 were reconstituted by adding 0 . 5 mL water into the vials . A Example H : Non - Covalently Bound Complex of clear water solution was obtained for the vials with 27 . 2 mg B - 003 and HSA and 21 . 8 mg of HSA , and a cloudy solution was obtained for the vial with 18 . 1 mg of HSA . 25 mg of B - 003 was dissolved in 12 .5 mL ethanol/ DMF 50 ( 4 : 1 ) in a flask . Then 557 . 5 mg of HSA was dissolved in 25 TABLE 5 mL of water with a pH of about 5 in another flask . The water with a pH of about 5 was prepared by adding 2 N HCl (aq . ) HSA into water . The solution of B -003 was added slowly into the HSA water solution with stirring . After addition , a clear 27. 2 mg 21. 8 mg 18. 1 mg — 55 solution was obtained . Then ethanol was removed under Ratio of drug :HSA 4 5 6 vacuum until the volume of the solution was about 25 - 26 mL . A clear aqueous solution was obtained . The aqueous solution was lyophilized overnight to give a white solid , Example F : Non -Covalently Bound Complex of which was reconstituted by adding 0 . 5 mL water into the B - 001 and HSA 60 vial. A clear water solution was obtained . In each of 2 vials , 1 mg of B -001 was dissolved in 0 . 5 mL Example AA : Persistence in Plasma methanol /DMF ( 4 : 1 ) . Then 1 . 0 mL of water with a pH of about 5 was added into each vial . The water with a pH of Test compounds and control ( procaine ) were incubated at about 5 was prepared by adding 2 N HCl ( aq. ) into water . 65 a concentration of 10 uM with human plasma. The duplicate After shaking gently , a slightly cloudy solution was obtained incubations, conducted in 96 -well plates in a shaking water for all 2 vials . 24 . 1 mg and 19 . 3 mg of HSA were added , bath maintained at 37° C ., were performed for 0 and 60 US 9 ,937 ,259 B2 89 90 minutes and quenched by addition of acetonitrile. Ingredi TABLE 10 ents for different incubations were added as shown in Table Percent Remaining of Procaine and Test Compounds after 24 - hr Incubation TABLE 8 % Remaining after 24 -hr Incubation at 37° C . Human Plasma PBS buffer Plasma Data Repli - RepliPII Repli- Repli Compound cate 1 cate 2 Average cate 1 cate 2 Average Add (UL ) 10 Procaine 0 . 0 0 . 0 0 . 0 20 . 65 80 . 5 51 Components A - 004 and 100 . 0 97 . 0 98 . 5 87 . 3 95 . 2 91 . 3 0 min 24 hr 24 hr in PBS HSA Complex Plasma 100 100 o0 B001 and 92 . 0 89 . 0 90 . 5 94 . 5 96 . 7 95 . 6 on on 16 HSA Phosphate -buffered saline (PBS ) Buffer 90 90 90 1 155 Complex (pH 7 .4 ) 20 uM Test Compound or Control in 0 10 Dimethyl sulfoxide (DMSO ): PBS buffer ( 1 : 1 ) Example AB : Pharmacokinetics Study of 20 Non - Covalently Bound Complex of B - 001 -HSA Vortex No Yes Yes 20 Incubated at 37° C . for 24 hr Yes Yes Yes A group of 3 Sprague Dawley® ( “ SD ” ) male rats were Vortex Yes No No used in pharmacokinetics study . The dosing route of the ACN ( UL ) 500 500 500 study was IV . The dose for the PK study of non - covalently 20 um Test Compound or Control in 10 o 25 bound complex of B - 001 and HSA was 1004 mg/ kg ( an DMSO :PBS buffer ( 1 : 1 ) equivalent of a dose of 40 mg/kg of B -001 ) . The 10 time Plasma 0 0 100100 points for the study were 0 .05 , 0 . 167 , 0 . 5 , 1 , 2 , 4 , 8 , 24 , 36 IS Solution ( 25 ug /mL ) (UL ) 20 20 20 and 72 hr post dose . All blood samples were collected from Vortex YesYes Yes YesYes cannula on the jugular vein . Blood samples were transferred Centrifuge at 3500 rpm for 10 min Yes Yes YesYes 30 into EDTA -K2 anti- coagulant tube and immediately placed on ice . After mixing on a rotator for 1 minute , the blood samples were centrifuged for 5 min at 3000x gravity ( “ g ” ) After quenching by acetonitrile , the plates were capped , and plasma was transferred to a microcentrifuge tube and vortexed , and centrifuged at 3000 rpm for 10 minutes . The kept in - 80° C . freezer until processed for bio - analysis . An supernatant was injected into LC -MS / MS . 35 LC -MS / MS method was developed for compound B - 001 and abiraterone in male SD rat plasma. Abiraterone can be Peak area ratios of procaine and test compounds in formed in vivo after compound B -001 dissociates from HSA incubation samples are listed in Table 9 . Percent remaining and is metabolized at the ester bond ( e . g . , undergoes hydro values are calculated from peak area ratios from the equation lysis ) . FIG . 1 shows individual and mean plasma concen shown below and are listed in Table 10 . 40 tration -time data for Compound B -001 after an IV dose of 1004 mg/ kg of the Compound B -001 - HSA complex in SD rats . FIG . 2 shows individual and mean plasma concentra % Remaining = tion - time data for abiraterone after an IV dose of 1004 PeakArea 1 hr mg/ kg of the Compound B - 001 -HSA complex in SD rats . 100 * (PeakArea 0 h - Replicate 1 + PeakArea 0 h - Replicate 2 ) /2 ? TABLE 11 Area Under Clearance Volume of the Curve TABLE 9 (" CL " ) distribution Terminal (" AUC ) Procaine and Test Compound Peak 50 comCompound (mL /min /kg ) ( Vss ” ) (L /kg ) T1/ 2 (hr ) ( hr * ng/mL ) Area Ratio in Incubation Samples B - 001 32 . 8 0 . 203 1 .09 28145 Peak Area Ratio ( Analyte / IS ) abiraterone 61. 1 2 . 92 1 . 93 5514 Human Plasma PBS Buffer 55 Example AC : Pharmacokinetics Study of 0 hr 24 hr 24 hr Non -Covalently Bound Complex of B - 003 and Repli - Repli - Repli - Repli - Repli - Repli HSA Compound cate 1 cate 2 cate 1 cate 2 cate 1 cate 2 Procaine 0 .443 0 . 444 0 . 0 0 . 0 0 .0916 0 . 357 60 A group of 3 SD male rats was used in pharmacokinetics A004 and 1 . 16 1 . 13 1 . 14 1. 11 1. 0 1 .09 study. The dosing route of the study was IV . The dose for the HSA PK study of Non - covalently bound complex of B - 003 and Complex B001 and 0 .753 0 .741 0 .689 0 .664 0 .706 0 .722 HSA was 1004 mg/ kg (an equivalent of a dose of 40 mg/ kg HSA of B - 003 ) . The 10 time points for the study were 0 . 05 , 0 . 167 , complex 65 0 . 5 , 1 , 2 , 4 , 8 , 24 , 36 and 72 hr post dose . All blood samples were collected from the cannula on the jugular vein . Blood samples were transferred into an EDTA -K2 anti - coagulant US 9 , 937 ,259 B2 92 tube and immediately placed on ice . After mixing on rotator for 1 min , the blood sample was centrifuged for 5 min at ( II ) 3000xg and plasma was transferred to a microcentrifuge tube and kept in - 80° C . freezer until processed for bio analysis . An LC -MS /MS method was developed for com - 5 pound B -003 and abiraterone in male SD rat plasma. Abi raterone can be formed in vivo after compound B - 003 dissociates from HSA and is metabolized at the ester bond ( e . g ., undergoes hydrolysis ) . FIG . 3 shows individual plasma concentration -time data for Compound B -003 after 10 an IV dose of 932 mg/ kg of the Compound B - 003 -HSA IM complex in SD rats . FIG . 4 shows the individual plasma concentration -time data abiraterone after an IV dose of 932 mg /kg of the B - 003 -HSA complex in SD rats . 15 TABLE 12
CL V ss Terminal $- Compound (mL /min / kg ) ( L /kg ) T12 ( hr ) AUCjast ( hr * ng/ mL ) B - 003 79 . 1 2 . 86 10 . 7 10174 20 abiraterone 50 . 8 0 . 598 1 . 79 5998 wherein A is a covalent bond , O or NR ' ; A number of embodiments have been described . Never L is alkyl, alkyl- O -alkyl , alkenyl, alkynyl, carbocyclyl, theless , it will be understood that various modifications may carbocyclylalkyl, aryl , alkaryl , or be made without departing from the spirit and scope of the 25 disclosure . Accordingly , other embodiments are within the scope of the following claims. What is claimed is : mi 1 . A non - covalently bound complex of an abiraterone 30 mv derivative and human serum albumin in a molar ratio from about 1 : 1 to about 10 : 1 , wherein : each of which is optionally substituted with 1 - 3 sub the non -covalently bound complex has a solubility in stituents independently selected from the group con aqueous solution of at least 5 mg/ mL , and the abirater sisting of halo , - NO , , amine , amide , hydroxyl, one derivative comprises a compound of Formula (1 ) : 35 O -lower alkyl and COOH , provided that there be no covalent bonds between oxygen atoms; W is
w min
O N - COOH
R ] M IND "1111 + COOH , B R ” ) , -2
winan
- R - N
O B + c + COOH , COOH , or wherein A is a covalent bond , O or NR ' ; |Run In R ! is H , lower alkyl, or alkaryl, wherein the alkyl or alkaryl is optionally substituted with 1 - 3 substituents mwen N independently selected from the group consisting of: o halo , nitro , amine , amide , hydroxyl, O - lower alkyl and 60 carboxy ; and N + 0 + 0 + 0 + COOH ; Q is a group that selectively binds to human serum M LR ) , RO R3 albumin . 2 . The non -covalently bound complex of claim 1, wherein 5 Q comprises - COOH . 65 3 . A compound , or a pharmaceutically acceptable salt Rl is H , lower alkyl, or alkaryl, wherein the alkyl or thereof, according to Formula ( II) : alkaryl is optionally substituted with 1 -3 substituents US 9 ,937 ,259 B2 93 94 independently selected from the group consisting of: 6 . The compound of claim 3 , or pharmaceutically accept halo , NO2, amine , amide, hydroxyl, 0 -lower alkyl and able salt thereof, wherein the compound has the structure : - COOH ; R is independently in each instance H , OH , NO , , NH , NH3 *, SH or a branched or unbranched C - alkyl, C2- 8 5 alkenyl or C2- 8 alkynyl, wherein the C1- 8 alkyl, C2- 8 alkenyl or C2- 8 alkynyl is optionally substituted with 1 - 2 substituents independently selected from the group consisting of halo , OH , NO2, NH , NHZ , SH and = O , and wherein the C1- 3 alkyl, C2- 3 alkenyl or C2- 3 alkynyl 10 optionally has 1 - 2 heteroatoms independently selected from O , S and NH wherein each heteroatom replaces a II. CH ,, with the proviso that no 0 , S or N atom in the C1- 8 11T alkyl , C2- 8 alkenyl or C2- 3 alkynyl is covalently bonded to another O , S or N atom ; 15 R * is independently in each instance H , alkyl, phenyl, or alkaryl, wherein the alkyl, phenyl, or alkaryl is option ally substituted with 1 - 3 substituents independently (CH2 ) m selected from the group consisting of: halo , - NO2, OS CFz, amido , sulfonamide, aryl, OH , alkyl, 0 - 20 TR47 lower alkyl , — O - alkaryl, and — O - aryl; R4 is independently in each instance H , OH , NO2, NH ,, RENR5 NO + COOH NH3* , SH or a branched or unbranched C1- 10 alkyl, RunJn C2- 10 alkenyl or C2- 10 alkynyl, wherein the C1- 10 alkyl, C2- 10 alkenyl or C2- 10 alkynyl is optionally substituted 25 with 1- 2 substituents independently selected from the wherein group consisting of halo , OH , NO2, NH , NH3 , SH m is 0 , 1, 2 , 3 , 4 , 5 , 6 , 7 , or 8 . and = O , and wherein the C1- 10 alkyl, C2- 10 alkenyl or 7 . The compound of claim 3 , or pharmaceutically accept C2- 10 alkynyl optionally has 1- 2 heteroatoms indepen able salt thereof, wherein the compound has the structure: dently selected from O , S and NH wherein each het - 30 eroatom replaces a CH2, with the proviso that no O , S or N atom in the C1- 10 alkyl, C2- 10 alkenyl or C2- 10 alkynyl is covalently bonded to another O , S or N atom ; R is H , alkyl, phenyl, or alkaryl, wherein the alkyl, phenyl , or alkaryl is optionally substituted with 1 -3 35 substituents independently selected from the group consisting of: halo , - NO2, CF3, amido , sulfona H mide, aryl, — OH , alkyl, - O -lower alkyl, - O - alkaryl, .
and — O -aryl ; I R and R ’ is each independently H or lower alkyl, option - 40 ally substituted with 1 - 3 substituents independently selected from the group consisting of halo , nitro , amine, amide , hydroxyl, O - lower alkyl and carboxy ; B is a covalent bond , O or NR ; (CH2 ) m p is 1 , 2 , 3 , 4 , 5 , or 6 ; 45 n is 1, 2 , 3 , 4 , 5 , or 6 ; and 04 r is 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , or 10 . 4 . The compound of claim 3 , or pharmaceutically accept ro + COOH able salt thereof, wherein W is 50 [ R ]
wherein mi m is 0 , 1 , 2 , 3 , 4 , 5 , 6 , 7 , or 8 . 8 . The compound of claim 3 , or pharmaceutically accept 55 able salt thereof, wherein R is independently in each R4 instance H , alkyl, phenyl, or alkaryl, wherein the alkyl, N + c + COOH . phenyl , or alkaryl is optionally substituted with 1 - 3 sub stituents independently selected from the group consisting R } ],n of: halo , — NO , — CFz, amido , sulfonamide, aryl, — OH , 60 alkyl. _ O - lower alkyl, O -alkaryl , 40 -aryl . 9 . The compound of claim 3 , or pharmaceutically accept 5 . The compound of claim 3 , or pharmaceutically accept able salt thereof, wherein R? is H , alkyl, phenyl, or alkaryl, able salt thereof, wherein : L is an alkyl, an alkenyl or wherein the alkyl, phenyl, or alkaryl is optionally substituted alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally with 1 - 3 substituents independently selected from the group substituted with 1- 3 substituents independently selected 65 consisting of: halo , - NO2, CF3 , amido , sulfonamide, from the group consisting of halo , - NO2, amine, amide, aryl , OH , alkyl , O - lower alkyl, O - alkaryl, and O hydroxyl, O - lower alkyl and COOH . aryl. US 9 , 937 ,259 B2 95 96 10 . The compound of claim 3 , or pharmaceutically -continued acceptable salt thereof, wherein the compound is selected from the group consisting of:
.IT
?? ?? Ooo ooontle.. LIDIR. .
**111
HO US 9 , 937 , 259 B2 97 98 -continued -continued
.1111
NH å H3C( HAC) - -
?? HO
H T11111 RIIT
NH H3CH2C ) 15 –
HO
.
?H T 1117
Hun
HO HOOC US 9 ,937 ,259 B2 66 100 -continued - continued
II. "
HN
COOH
H ý sulle
COOH
.11
111111** I g OH
?? enShows US 9 , 937 ,259 B2 101 102 -continued - continued ; and
u
1 TMM ö III
ö
N - ( CH2) 7CH : 20 HOOC - / . COOH
Bio H
1111T
HOOC 40 11 . The compound ofclaim 3 , or pharmaceutically accept able salt thereof, wherein the compound is selected from the group consisting of: 45 COOH
.
I UIT
Bing NH
COOH US 9 ,937 ,259 B2 103 104 - continued -continued
. 11111 I It
111
OH
*1111 H II.)
HO obsOH :Tiin |
O CH3
HO US 9 ,937 ,259 B2 105 106 -continued - continued N
T117 TI
NH 21111 20 HC( HAC) 15
HO HO 25 12 . A non - covalently bound complex of the compound of claim 3 , or pharmaceutically acceptable salt thereof, and human serum albumin in a molar ratio from about 1 : 1 to about 10 : 1, wherein the non -covalently bound complex has solubility in aqueous solution of at least 5 mg /mL . 30 13 . The non -covalently bound complex of claim 12 , wherein the non - covalently bound complex has solubility in ; and aqueous solution of at least 20 mg /mL . 14 . The non -covalently bound complex of claim 12 , in a solid formulation . 35 15 . The non -covalently bound complex of claim 12 , in an aqueous formulation . 16 . The non - covalently bound complex of claim 15 , ** wherein the aqueous formulation is free of solvents other than water. 40 17 . A pharmaceutical composition comprising a non covalently bound complex of claim 1 , and a pharmaceuti cally acceptable carrier. 18 . A method of treating prostate cancer, the method comprising the step of administering to the subject in need 45 thereof a therapeutically effective amount of a pharmaceu tical composition of claim 17 . 19 . A method of treating a disease associated with dys NH regulated activity of CYP17 , the method comprising admin H?C( HC) – istering to a mammalian patient a pharmaceutical composi 50 tion according to claim 17 wherein the disease is prostate cancer . * * * * *