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C12) United States Patent (IO) Patent No.: US 10,065,924 B2 Nicolaou Et Al

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C12) United States Patent (IO) Patent No.: US 10,065,924 B2 Nicolaou Et Al I 1111111111111111 1111111111 11111 lllll 111111111111111 111111111111111 IIII IIII US010065924B2 c12) United States Patent (IO) Patent No.: US 10,065,924 B2 Nicolaou et al. (45) Date of Patent: Sep.4,2018 (54) PREPARATION AND BIOLOGICAL FOREIGN PATENT DOCUMENTS EVALUATION OF VIRIDICATUMTOXIN ANALOGS WO WO 2009/008906 1/2009 (71) Applicant: WILLIAM MARSH RICE OTHER PUBLICATIONS UNIVERSITY, Houston, TX (US) Breinholt, et al., "Hypomycetin-an Antifungal, tetracyclic (72) Inventors: Kyriacos C Nicolaou, Houston, TX Metabolite from Hypomyces aurantius: Production, Structure and (US); Christopher R. H. Hale, Biosynthesis," Acta Chem. Scand., 51:855-860, 1997. Houston, TX (US); Christian Nilewski, Brubaker and Myers, "A practical, enantioselective synthetic route Houston, TX (US); Heraklidia to a key precursor to the tetracycline antibiotics." Org. Lett., Ioannidou, Houston, TX (US); 9:3523-3525, 2007. Abdellatif El Marrouni, Houston, TX Charest, et al., "Synthesis of(-)-Tetracycline," J Am. Chem. Soc., (US) 127:8292-8293, 2005. Charest, et al., "A Convergent Enantioselective Route to Structur­ (73) Assignee: WILLIAM MARSH RICE ally Diverse 6-Deoxytetracycline Antibiotics," Science, 308, 395­ UNIVERSITY, Houston, TX (US) 398, 2005. Chooi, et al., "Identification of the Viridicatumtoxin and Griseoful­ ( *) Notice: Subject to any disclaimer, the term ofthis vin Gene Clusters from Penicillium aethiopicum," Chem. Biol., patent is extended or adjusted under 35 17:483-494, 2010. U.S.C. 154(b) by O days. Chooi, et al., "Discovery and Characterization of a Group of Fungal Polycyclic Polyketide Prenyltransferases," J Am. Chem. Soc., (21) Appl. No.: 15/327,912 134:9428-9437, 2012. Chooi, et al., J. Am. Chem. Soc., 135:16805-16808, 2013. (22) PCT Filed: Jul. 22, 2015 Chopra and Roberts, "Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial (86) PCT No.: PCT/US2015/041494 resistance," Microbial. Mo!. Biol. R., 65:232-260, 2001. De Jesus, A.E., et al., "Biosynthesis of viridicatumtoxin, a § 371 (c)(l), mycotoxin from Penicillin expansum," J Chem. Soc., Chem. (2) Date: Jan.20, 2017 Comm., 902-904, 1982. Hutchison, et al., "Viridicatumtoxin, a new mycotoxin from Penicil­ (87) PCT Pub. No.: WO2016/014643 lium viridicatum Westling," Toxicol. Appl. Pharmacol., 24:507-509, 1973. PCT Pub. Date: Jan. 28, 2016 (Continued) (65) Prior Publication Data US 2017/0210699 Al Jul. 27, 2017 Primary Examiner - Barbara P Badia (74) Attorney, Agent, or Firm - Parker Highlander PLLC Related U.S. Application Data (60) Provisional application No. 62/027,500, filed on Jul. 22, 2014. (57) ABSTRACT In one aspect, the present invention provides novel deriva­ (51) Int. Cl. A61K 31/65 (2006.01) tives of viridicatumtoxin of the formula wherein the vari­ C07C 237126 (2006.01) ables are as defined herein. The application also provides C07C 235182 (2006.01) compositions, methods of treatment, and methods of syn­ C07D 261/20 (2006.01) thesis thereof. A61K 45106 (2006.01) (52) U.S. Cl. CPC ............ C07C 235182 (2013.01); A61K 31/65 (I) (2013.01); A61K 45106 (2013.01); C07C 237126 (2013.01); C07D 261/20 (2013.01); C07C 2603/94 (2017 .05) R2 ( 58) Field of Classification Search /0 CPC . C07C 235/82; C07C 237/26; C07C 2603/94; R10 C07D 261/20; A61K 31/65 USPC ........................................... 514/152; 552/203 0 R., See application file for complete search history. /0 /0 0 0 N (56) References Cited Rs R1 Rs/......_~ U.S. PATENT DOCUMENTS 2010/0291622 Al 11/2010 Tomoda et al. 2013/0338117 Al 12/2013 Ricciardi 20 Claims, 4 Drawing Sheets US 10,065,924 B2 Page 2 (56) References Cited PCT International Search Report and Written Opinion issued in International Application No. PCT/US2015/041494; dated Oct. 19, 2015. OTHER PUBLICATIONS Sun, et al., "A Robust Platform for the Synthesis of New Tetracy­ cline Antibiotics" J Am. Chem. Soc., 130:17913-17927, 2008. Inokoshi, et al., "Spirohexalines, new inhibitors of bacterial Sutcliffe, et al., "Antibacterial activity of eravacycline (TP-434), a undecaprenyl pyrophosphate synthase, produced by Penicilliurn novel fluorocycline, against hospital and community pathogens." brasilianurn FKI-3368," J Antibiot., 66:37-41, 2013. Antimicrob. Agents Chemother., 57:5548-5558, 2013. Koyama, et al., "Anti-infectious agents against MRSA." Molecules, 18:204-224, 2013. Tally, et al., "Glycylcyclines: a new generation of tetracyclines" J Kummer, et al., "A practical, convergent route to the key precursor Antimicrob. Chemother., 35:449-452, 1995. to the tetracycline antibiotics." Chem. Sci., 2:1710-1718, 2011. Wright and Myers, "Methodological Advances Permit the Nicolaou, et al., "Total synthesis and structural revision of Stereocontrolled Construction of Diverse Fully Synthetic Tetracy­ viridicatumtoxin B." Angew. Chem. Int. Ed., (52) 8736-8741, 2013. clines Containing an All-Carbon Quaternary Center at Position Nicolaou, et al., "Total synthesis of viridicatumtoxin B and ana­ C5a." Tetrahedron, 67:9853-9869, 2011. logues thereof: strategy evolution, structural revision, and biologi­ Wzorek, et al., "A macrocyclic approach to tetracycline natural cal evaluation." J Am. Chem. Soc., 136(34):12137-12160, 2014. products. Investigation of transannular alkylations and Michael National Center for Biotechnology Information. PubChem Com­ additions." Org. Lett., 14:5840-5843, 2012. pound Database; CID~72203888, https://pubchem.ncbi.nlm.nih. Zheng, et al., "Viridicatnmtoxin B, a new anti-MRSA agent from gov/compound/72203888. Penicilliurn sp. FRll." J Antibiot. 61:633-637, 2008. U.S. Patent Sep.4,2018 Sheet 1 of 4 US 10,065,924 B2 a) 4: chiortetracycline (Aureomycin-:I~,1 5: R = OH, oxytetracyciine {Terramycin@) 6: R = H, tetracycBrie {,A,chromycin(~°'.'.l Nfv1e2 H H 7Me2 +=· 'H~i JlQ f~J,,..~---,,J~~/~,,_l~.,.,.--<.,,(,OH..., ,._,ti, n '- ).! ,/ ,.___ ,.. A ,.<._, -"'___ ·~ ~ 'y-- 'lf ,r·h'r( ---~r OH O HOH O NH2 7: minocycllne (t,11inocini®) 9: Ugscyc!ine {Tygact!@) 8: doxycycline (Vlbramycin:E·l 10: eravacycHne (TP-434) 11: hypomycetin ? --..,.--­ ____~ _ 14: BMS-192548 FIGS. lA& B U.S. Patent Sep.4,2018 Sheet 2 of 4 US 10,065,924 B2 ? -----­•----­ 3: spirohexaline FIG.2 U.S. Patent Sep.4,2018 Sheet 3 of 4 US 10,065,924 B2 [Friede!­ CraftsJ 21 FIG.3 U.S. Patent Sep.4,2018 Sheet 4 of 4 US 10,065,924 B2 0 0 OH OH OH OH (+)-1: viridicatumtoxin B (+)-2: viridicatumtoxin A Me Me Meo Meo 0 0 OH OH OR OH (±)-V2 R = H: (±)-V3 R = Me: (±)-V4 Me Me Meo Meo 0 0 OH OH OH OH (±)-VS (±)-V6 FIG.4 US 10,065,924 B2 1 2 PREPARATION AND BIOLOGICAL of the commercial importance of these molecules for the EVALUATION OF VIRIDICATUMTOXIN biological activity, many efforts have been undertaken to ANALOGS synthesize tetracycline derivatives including recent efforts by the Myers (Charest, et al., 2005; Charest, et al., 2005; This invention was made with government support under 5 Brubaker and Myers, 2007; Sun, et al., 2008; Kummer, et al., Grant Number AI055475 awarded by the National Institutes 2011; Wright and Myers, 2011) and Evans groups (Wzorek, of Health. The government has certain rights in the inven­ et al., 2012). tion. In 2008, Kim, et al., isolated viridicatumtoxin B (1) from This application claims the benefit of priority to U.S. Penicillium sp. FRl 1 along with viridicatumtoxinA (2). This Provisional Application Ser. No. 62/027,500, filed on Jul. 10 compound was investigated through NMR spectroscopy and 22, 2014, the entire contents of which are hereby incorpo­ assigned the structure 1'. These compounds have been rated by reference. shown to have potent antibacterial properties in a number of bacterial strains including both gram positive and gram BACKGROUND OF THE INVENTION negative bacteria (Kim, et al., 2008). Without being bound 15 by theory, further study and analysis suggests that the 1. Field of the Invention viridicatumtoxin's antibacterial properties arise not by bind­ ing to the 30S subunit ofthe ribosome like many tetracycline This disclosure relates to the fields of medicine, pharma­ compounds (e.g., 4-10, FIG. lA) but by inhibiting UPP cology, chemistry, antimicrobial activity, and oncology. In synthase, an enzyme associated with bacterial peptidoglycan particular, new compounds, compositions, methods of treat­ 20 biosynthesis (Inokoshi, et al., 2013; Koyama, et al., 2013). ment, and methods of synthesis relating to viridicatumtoxin Furthermore, viridicatumtoxin A (2) shows promising anti­ and derivatives thereof are disclosed. cancer activity against a selection of cancer cell lines (NIH Results of Viridicatumtoxin A NCI 60 Cell line assay) as 2. Related Art well as shows antiviral activity (WO 2009/008906). 25 As such, new analogs of viridicatumtoxin could provide Since the discovery of chlortetracycline ( 4; FIG. lA) in access to a more efficacious antimicrobial or cancer drug and the late 1940's, tetracycline antibiotics such as chlortetra­ new methods of synthesis could allow cost effective clinical cycline (4), oxytetracycline (5), and tetracycline (6) have access to these compound for use in the treatment of been commonly prescribed to treat bacterial infections microbial infections and as chemotherapeutic agents. (Duggar, 1948). Throughout the years, as bacterial resis­ 30 tance grew or improved therapeutic properties were needed, SUMMARY OF THE INVENTION additional therapeutic agents including second generation tetracycline derivatives such as minocycline (7) and doxy­ Thus, in accordance with the present invention, there is cycline (8) and third generation tetracycline derivatives such provided a compound of the formula: as tigecycline (9) and eravacycline (TP-434, 10) have been 35 developed (FIG. lA) (Tally, et al, 1995; Sutcliffe, et al., 2013; Chopra and Roberts, 2001). (I) Penicillium is a genus of ascomycetous fungi of major importance in the natural environment as well as food and drug production. Members of the genus may be best known 40 for producing penicillin, a molecule that is used as an antibiotic, which kills or stops the growth ofcertain kinds of bacteria inside the body. According to the Dictionary ofthe Fungi (l 0th edition, 2008), the widespread genus contains over 300 species.
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