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Ovarian Cancer I1111111111111111 1111111111 1111111111 111111111111111 IIIII lll111111111111111 US010874646B2 c12) United States Patent (IO) Patent No.: US 10,874,646 B2 Nicolaou et al. (45) Date of Patent: Dec. 29, 2020 (54) EPOTHILONE ANALOGS, METHODS OF (58) Field of Classification Search SYNTHESIS, METHODS OF TREATMENT, None AND DRUG CONJUGATES THEREOF See application file for complete search history. (71) Applicant: WILLIAM MARSH RICE UNIVERSITY, Houston, TX (US) (56) References Cited U.S. PATENT DOCUMENTS (72) Inventors: Kyriacos C Nicolaou, Houston, TX (US); Derek Rhoades, Houston, TX 2003/0203938 Al * 10/2003 Nicolaou C07D 313/00 (US); Yanping Wang, Houston, TX 514/338 (US); Sotirios Totokotsopoulos, 2010/0168179 Al 7/2010 Klar et al. Chicago, IL (US) 2011/0112149 Al 5/2011 Li et al. 2014/0323533 Al* 10/2014 Jure-Kunkel .......... A61K45/06 514/365 (73) Assignee: William Marsh Rice University, Houston, TX (US) FOREIGN PATENT DOCUMENTS ( * ) Notice: Subject to any disclaimer, the term ofthis EP 1930004 Al 6/2008 patent is extended or adjusted under 35 EP 2009114 Al 12/2008 U.S.C. 154(b) by O days. JP 2001-504856 4/2001 JP 2009-516753 4/2009 JP 2009-538350 11/2009 (21) Appl. No.: 15/768,800 WO WO 1998-025929 6/1998 WO WO 99/54319 10/1999 (22) PCT Filed: Oct. 14, 2016 (Continued) (86) PCT No.: PCT/US2016/057093 OTHER PUBLICATIONS § 371 (c)(l), Chemical Abstract Registry No. 1348540-91-9, indexed in the (2) Date: Apr. 16, 2018 Registry File on STN CAS Online Dec. 4, 2011.* (87) PCT Pub. No.: WO2017/066606 (Continued) PCT Pub. Date: Apr. 20, 2017 Primary Examiner - Kamal A Saeed (65) Prior Publication Data (74) Attorney, Agent, or Firm - Parker Highlander PLLC US 2019/0022069 Al Jan. 24, 2019 (57) ABSTRACT Related U.S. Application Data In one aspect, the present disclosure provides epothilone (60) Provisional application No. 62/242,702, filed on Oct. analogs of the formula (I) wherein the variables are as 16, 2015. defined herein. In another aspect, the present disclosure also provides methods of preparing the compounds disclosed (51) Int. Cl. herein. In another aspect, the present disclosure also pro­ A61K 311427 (2006.01) vides pharmaceutical compositions and methods of use of A61K 3114155 (2006.01) the compounds disclosed herein. Additionally, drug conju­ A61K 47168 (2017.01) gates with cell targeting moieties of the compounds are also A61P35/02 (2006.01) provided. A61K 311428 (2006.01) A61K 39/395 (2006.01) A61K 3114427 (2006.01) (I) C07D 407106 (2006.01) A61K 45106 (2006.01) C07D 405/06 (2006.01) C07D 491/08 (2006.01) C07D 493/08 (2006.01) (52) U.S. Cl. CPC ........ A61K 311427 (2013.01); A61K 3114155 (2013.01); A61K 311428 (2013.01); A61K 3114427 (2013.01); A61K 39/395 (2013.01); A61K 45106 (2013.01); A61K 4716869 (2017.08); A61P 35102 (2018.01); C07D 405/06 (2013.01); C07D 407106 (2013.01); C07D 491/08 (2013.01); C07D 493/08 (2013.01) 17 Claims, 45 Drawing Sheets US 10,874,646 B2 Page 2 (56) References Cited Nicolaou, K. C., et al. "Molecular design and chemical synthesis of a highly potent epothilone." ChemMedChem: Chemistry Enabling Drug Discovery 1.1 (2006): 41-44. FOREIGN PATENT DOCUMENTS Nicolaou, K. C., et al. "The olefin metathesis approach to epothilone WO WO 00/47584 8/2000 A and its analogues," Journal of the American Chemical Society WO WO 2007-062288 5/2007 119.34 (1997): 7960-7973. WO WO 2007-140298 12/2007 Nicolaou, K. C., et al. "Total syntheses of epothilones A and B via WO W02014096551 * 6/2014 a macrolactonization-based strategy." Journal of the American Chemical Society 119.34 (1997): 7974-7991. OTHER PUBLICATIONS Nicolaou, K. C., et al. "Total syntheses of epothilones E and related Side-chain Modified Analogues via a Stille Coupling Based Strat­ Alhamadsheh, Mamoun M., et al. "Total synthesis and selective egy." Bioorganic & Medicinal Chemistry, vol. 7, No. 5 (1999), activity of a new class of conformationally restrained epothilones." 665-697. Chemistry-A European Journal 14.2 (2008): 570-581. Nicolaou, K. C., et al. "Total Synthesis of 16-Desmethylepothilone Bode, Jeffrey W., and Erick M. Carreira. "Stereo selective syntheses B, Epothilone BlO, Epothilone F, and Related Side Chain Modified of epothilones A and B via directed nitrile oxide cycloadditionl ." Epothilone B Analogues," Chemistry-A European Journal 6.15 Journal of the American Chemical Society 123.15 (2001): 3611- (2000): 2783-2800. 3612. Partial European Search Report dated May 2, 2019, issued in Carlomagno, Teresa, et al. "The High-Resolution Solution Structure European Application No. 16856299 filed May 15, 2018. of Epothilone A Bound to Tubulin: An Understanding of the PCT Search Report and Written Opinion dated Feb. 1, 2017 issued Structure-Activity Relationships for a Powerful Class of Antitumor in PCT/US2016/057093 filed Oct. 14, 2016. Agents." Angewandte Chemie International Edition 42.22 (2003): Reese, Marcel, et al. "Structural basis ofthe activity ofthe microtubule­ 2511-2515. stabilizing agent epothilone A studied by NMR spectroscopy in Ermolenko, Mikhail S., and Pierre Potier. "Synthesis of epothilones solution." Angewandte Chemie International Edition 46.11 (2007): B and D from D-glucose." Tetrahedron letters 43.16 (2002): 2895- 1864-1868. 2898. Sawada, Daisuke, Motomu Kanai, and Masakatsu Shibasaki. Heinz, Dirk W., Wolf-Dieter Schubert, and Gerhard Hoefle. "Much "Enantioselective total synthesis of epothilones A and B using anticipated-the bioactive conformation of epothilone and its bind­ ing to tubulin." Angewandte Chemie International Edition 44.9 multifunctional asynunetric catalysis." Journal of the American (2005): 1298-1301. Chemical Society 122.43 (2000): 10521-10532. Hofle, G., et al., "EpothiloneAandB-Novel 16-Mem-beredMacrolides Schinzer, et al., Synlett, 861-863, 1998. with Cytotoxic Activity: Isolation, Crystal Structure, and Confor­ Shoemaker, Robert H. "The NCI60 human tumour cell line anti­ mation in Solution", Angew. Chem. Int. Ed., vol. 35, 1567-1569, cancer drug screen." Nature Reviews Cancer 6.10 (2006): 813. 1996. Sinha, Subhash C., Carlos F. Barbas, and Richard A. Lerner, "The Keck, Gary E., et al. "Total synthesis of epothilones B and D: antibody catalysis route to the total synthesis of epothilones." Stannane equivalents for 13-keto ester dianions." The Journal of Proceedings of the National Academy of Sciences 95.25 (1998): organic chemistry 73 .24 (2008): 967 5-9691. 14603-14608. Manallack, David T. "The p K a distribution of drugs: application Taylor, Richard E., and Yue Chen. "Total synthesis of epothilones B to drug discovery." Perspectives in medicinal chemistry 1 (2007): and D." Organic letters 3.14 (2001): 2221-2224. 25-38. Valluri, Muralikrishna, et al. "Total synthesis of epothilone B." Martin and Thomas, Tet. Lett., 42:8378-8377, 2001. Organic letters 3.23 (2001): 3607-3609. Nicolaou, K. C., et al. "Designed Epoihilones: Combinatorial Syn­ Wang, Jie, et al. "An Efficient Total Synthesis of( - )-Epothilone B." thesis, Tubulin Assembly Properties, and Cytotoxic Action against Organic letters 14.24 (2012): 6354-6357. Taxol-Resistant Tumor Cells." Angewandte Chemie International White, James D., Rich G. Carter, and Kurt F. Sundermann "Ahighly Edition in English 36.19 (1997): 2097-2103. stereoselective synthesis of epothilone B." The Journal oforganic Nicolaou, K. C., et al. "Synthesis and Biological Evaluation of chemistry 64.3 (1999): 684-685. Novel Epothilone B Side Chain Analogues," ChemMedChem 10.12 Office Action issued in Japanese Application No. 2018-519372, (2015): 1974-1979. dated Oct. 7, 2020, and English translation thereof. Nicolaou, K. C., et al. "Chemical synthesis and biological properties ofpyridine epothilones." Chemistry & biology 7.8 (2000): 593-599. * cited by examiner U.S. Patent Dec. 29, 2020 Sheet 1 of 45 US 10,874,646 B2 s I );- N 1 epothilone 8 (epoB) 2: ixat;epilone ~ 0 ~ I f"S\ HO~.!.<---- ~1r-sMe ,,, : I 0 OH 0 3: rnethylthio-N-methyi pyrazoie epoB 4: methylthio epoB FIG.1 R1 R1 'Bo,Se~R" B ~--->HO ~I OH Slil!e coupiing 0 O 0 R1 = C-substituent 15: vinyl iodide A R2 = N-substituent FIG. 2 U.S. Patent Dec. 29, 2020 Sheet 2 of 45 US 10,874,646 B2 HO HO CF3 ~,N-O-NH2 0 OH 0 8 HO ~ OH 0 10 HO 11 HO 12 HO 13 HO OH O 14 FIG.3 U.S. Patent Dec. 29, 2020 Sheet 3 of 45 US 10,874,646 B2 ~ NH ..--S HO :>-Me ,, o OH o 70 73 74 75 OH OH ,-I - ,I ) NH ,.-s ¥ t/ -S~NH2 8 HO rt>-sMe M I fl HO ; I ~/-sMe ,, HOY,> ,, \\·,•~ b (SH 0 o OH o 8 61-1 b 76 77 78 FIG.4 I: 12,13-aziridine 29: aziridine epothilone B analogue5 methyi ketone il '<O '(!~)--Me TESOY""/'~0r, ~ < ~ '" *).,;.,".,~"' l..A..,! - N' -,.....----' ••' 0 ,,,·· " 1(0 ' 6 ~ 0 0 6H b OTES 1: epothilone B 23: o!efin methyl ketone FIG.5 National Cancer Institute Development Therapeutics Program e• in-Vitro Testing Results 00 NSC : D - 781077 / 1 Experimental ID: 1408~JS31 Test Type : 08 Units : Molar • Report Date : August 28, 2014 Test Date: August 11, 2014 QNS: MC: ~ ~ COMI : KCDR_SA Stain Reagent: SRB Dual-Pass Related SSPL: 0ZAS ~ Log10 Concentration ~ Mean Optical Densities Percent Growth =~ Panel/Cell Line Time Zero Ctrl -8.3 -7.3 -6.3 -5.3 -4.3 -8.3 -7.3 -6.3 -5.3 -4.3 GIS0 TGI LCS0 Leukemia CCRF-CEM 0.532 2.315 2.326 1.243 0.889 0.876 0.731 101 40 20 19 11 3.41E-08 >5.00E-5 >5.00E-5 c HL--60(TB) 0.953 2.815 2.712 1.059 0.891 0.974 1,070 94 6 -7 1 6 l.S8E--08 >5.00E-5 ('D K-562 0.270 1.982 1.960 0.758 0.518 0.477 0.503 99 28 14 12 14 2.47E-08 >5.00E5-5 >5.00E-5 ~ N MOLT-4 0.789 2.789 2.761 1.671 1.360 1.354 1.392 99 44 29 28 30 3.891:-08 >S.00E--5 >5.00E-5 ~\,Ci RPMl-8226 0.955 2.649 2.739 1.250 1.258 1.220 1.144 105 17 18 16 11 2.BE-08 >5.00E-5 >5.00E-5 N 0 SR 0.632 2.556 2.411 1.366 1.283 1.401 1.211 92 38 34 40 30 3.03E--08 >5.00E-5 >5.00E-5 N 0 Non-Small Celi Lung Cancer A549/ATCC 0.482 2.243 2.1.82 1.239 1.002.
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