University of Kentucky UKnowledge Markey Cancer Center Faculty Patents Cancer 6-20-2006 Highly Lipophilic Camptothecin Intermediates and Prodrugs and Methods of Preparation Thereof Thomas G. Burke University of Kentucky Dennis P. Curran Wu Du Right click to open a feedback form in a new tab to let us know how this document benefits oy u. Follow this and additional works at: https://uknowledge.uky.edu/markey_patents Part of the Oncology Commons Recommended Citation Burke, Thomas G.; Curran, Dennis P.; and Du, Wu, "Highly Lipophilic Camptothecin Intermediates and Prodrugs and Methods of Preparation Thereof" (2006). Markey Cancer Center Faculty Patents. 2. https://uknowledge.uky.edu/markey_patents/2 This Patent is brought to you for free and open access by the Cancer at UKnowledge. It has been accepted for inclusion in Markey Cancer Center Faculty Patents by an authorized administrator of UKnowledge. For more information, please contact [email protected]. US007064206B1 (12) United States Patent (10) Patent N0.: US 7,064,206 B1 Burke et al. (45) Date of Patent: *Jun. 20, 2006 (54) HIGHLY LIPOPHILIC CAMPTOTHECIN Liu, X. A Versatile Prodrug Approach for Liposomal Core INTERMEDIATES AND PRODRUGS AND Loading of Water-Insoluble Camptothecin Anticancer METHODS OF PREPARATION THEREOF Drugs, J. Amer. Chem. Soc., 124, pp. 7650-7651 (2002).* Josien, H., et al., Bioorganic & Medicinal Chemistry Letters, (75) Inventors: Thomas G. Burke, deceased, late of vol. 7, pp. 3189-3194 (1997).* Lexington, KY (US); by Lori Latus, Liu, Xinli et al., A Versatile Prodrug Approach for legal representative, Lexington, KY Liposomal Core-Loading of Water-Insoluble Camptothecin (US); Dennis P. Curran, Pittsburgh, PA Anticancer Drugs; J. Am. Chem. Soc.; Jan. 16, 2002, 124, (US); Wu Du, San Diego, CA (US) 7650-7651. Curran, D.P. Liu, H.; Josien, H; Ko, S.B., Tandem Radical (73) Assignees: University of Kentucky Research Reactions of Isonitriles With 2-Pyridonyl and other aryl Foundation, Lexington, KY (US); radicals: Scope and Limitations, and a First Generation University of Pittsburg, Pittsburgh, PA Synthesis of (+/—)-Camptothecin, Tetrahedron, 52, 11385 (Us) 11404 (1996). Published Aug. 1996. Palmisano, F. et al., Determination of Methotrexate in ( * ) Notice: Subject to any disclaimer, the term of this Untreated Body Fluids by Micellar Liquid Chromatography, patent is extended or adjusted under 35 Anal. Chem., May 1989, (61) 946-950. U.S.C. 154(b) by 0 days. PinnaduWage, P. et al. Stable Target-Sensitive Immunoliposomes, Biochemistry, 32, pp. 2850-2855 1992. This patent is subject to a terminal dis Mi, Z. and Burke, T.G., Di?cerential Interactions of claimer. Camptothecin Lactone and Carboxylate Forms With Human Blood Components, Biochemistry, 33, 10325-10336 (1994). (21) Appl. No.: 10/843,822 Mi, Z. and Burke, T.G., Marked Interspecies Variations (22) Filed: May 12, 2004 Concerning the Interactions of Camptothecin With Serum Albumins: A Frequency-Domain Fluorescence Spectro Related US. Application Data scopic Study, Biochemistry, 33, 12540-12545 (1994). Mi, Z. et al., Reduced Albumin Binding Promotes the (60) Provisional application No. 60/469,805, ?led on May Stability and Activity of Topotecan in Human Blood, Bio 12, 2003. chemistry, 34, 13722-13727 (1995). Josien, H. et al., 7-Silylcamptothecins (Silatecans): A New (51) Int. Cl. Family of Camptothecin Antitumor Agents, Bioorg. Med. C07F 7/10 (2006.01) Chem. Lett. vol. 7, No. 24, 3189-3295 (1997). (52) US. Cl. ...................................................... .. 546/14 Josien, H. et al., A General Synthetic Approach to the (58) Field of Classi?cation Search ................. .. 546/ 14 (20S)-Camptothecin Family of Antitumor Agents by a See application ?le for complete search history. Regiocontrolled Cascade Radical CycliZation of Aryl Isonitrites, Chem. Eur. J. 4, 67-83 (1998). (56) References Cited Curran, D.P. et al., New 4+1 Radical Annulations: A Formal Total Synthesis of (+/—)-Camptothecin, J. Am. Chem. Soc., U.S. PATENT DOCUMENTS 114, 5863-5864 (1992). 5,552,156 A 9/1996 Burke (Continued) 5,736,156 A 4/1998 Burke 6,136,978 A 10/2000 Curran et a1. Primary ExamineriKamal A. Saeed 6,207,832 B1 3/2001 Curran et a1. Assistant ExamineriNyeemah GraZier 6,291,676 B1 9/2001 Burke et a1. (74) Attorney, Agent, or F irmiKing & Schickli, PLLC 6,376,676 B1 4/2002 Curran et a1. 6,410,731 B1 6/2002 Currant et al. (57) ABSTRACT 6,743,917 B1 6/2004 Curran et a1. The present invention relates to novel, highly lipophilic OTHER PUBLICATIONS silatecan intermediates and prodrugs of DB-67 and other Josien, H. 7-Silylcamptothecins (Silatecans): ANeW Family silatecans. of Camptothecin Antitumor Agents, Bioorg. Med. Chem. Lett. 7(24), pp. 3189-3194 (1997).* 2 Claims, No Drawings US 7,064,206 B1 Page 2 OTHER PUBLICATIONS SZoka, F. et al., Procedure for Preparation of Liposomes With Burke, T. et al., Liposomal Stabilization of Camptothecin’s Large Internal Aqueous Space and High Capture by Lactone Ring, J. Am. Chem. Soc., 114, 8318-8319 (1992). Reverse-Phase Evaporation, Proc. Nat. Acad. Sci., vol. 75, Margali, R. et al., Liposomal Drug Delivery: Thermody 4194-4198. (Sep. 1978). namic and Chemical Kinetic Considerations, J. Controlled GabiZon, A. et al., Liposome Formulations With Prolonged Release, vol. 17, 285-296 (1991). Circulation Time in Blood and Enhanced Uptake by Tumors, Akhtar, et al., Liposome delivery of Antisense Proc. Natl. Acad. Sci. 85, 6949-6953, Sep. 1988. Oligonucleotides: Adsorption and El?ux characteristics of Papahadjopoulos et al., Sterically StabiliZed Liposomes: Phosphorothioate Oligodeoxynucleotides, J. Controlled Improvements in Pharmacokinetics and Antitumor Thera Release 22 (1992) 47-56. peutic Ef?cacy, Proc. Natl. Acad. Sci. 88, 11460-11464, Dec. Hong, C. et al., Nucleoside Conjugates. 11. Synthesis and 1991. Antitumor Activity of 1- -D-Arabinofuranosylcytosine and Shelly, K. et al., Model Studies Directed ToWard the Boron Cytidine Conjugates of Thioether Lipids, J. Med. Chem., Neutron-Capture Therapy of Cancer: Boron Delivery to 1990, 33, 1380-1386. Murine Tumors With Liposomes, Proc. Natl. Acad. Sci. vol. Burke, T.G. et al., The Structural Basis of Camptothecin 89, 9039-9043, Oct. 1991. Interactions With Human Serum Albumin: Impact on Drug Giovanella, B. et al., DNA Topoisomerase I-Targeted Che Stability, J. Med. Chem., 37, 40-46 (1994). motherapy of Human Colon Cancer in Xenografts, Science Born, D. et al., Novel A,B,E-Ring-Modi?ed Camptothecins Displaying High Lipophilicity and Marked Improved 246, 1046-1048, Nov. 24, 1989. Human Blood Stabilities, J. Med. Chem. 42, 3018-3022, Josien, H. et al, Synthesis of (S)-Mappicine and Mappicine 1999. Ketone Via Radical Cascade Reaction of Isonitriles, Tetra Killion, J. et al., Augmentation of Antiproliferative Activity hedron, 53, 8881-8886 (1997). of Interferon Alfa Against Human Bladder Tumor Cell Lines JeW et al., Synthesis and Antitumor Activity of 7-Substituted by Encapsulation of Interferon Alfa Within Liposomes, J. 20(RS)-Camptothecin Analogues, Bioorg. Med. Chem. Let Natl. Cancer Inst. 81, 1387-1392 (1989). ters 6, 845-848. Rahman, A. et al., Anti-Laminin Receptor Antibody Target Wang et al., Synthesis of Novel Water-Soluble ing of Liposomes With Encapsulated Doxorubicin to Human 7-(aminoacylhydraZono) -formyl Camptothecins With Breast Cancer Cells in Vitro, J. Natl. Cancer Inst. 81, Potent Inhibition of DNA Topo. I, Bioorg. Med. Chem. 1794-1800 (1989). 2(12), 1397-1402 (1994). Burris, H. et a1. Activity of Topotecan, a NeW Topoisinerase Wang et al., Novel Water-Soluble 7-(acylhydraZono) I Inhibitor, Against Human Tumor Colony-Forming Units In -formyl Camptothecins as Potent Inhibitors of DNA Topo, I, Vitro, J. Natl. Cancer Inst. 84, 1816-1820 (1992). Bioorg. Med. Chem. Lett. 4(4), 579-582 (1994). Jett, M. et al., Tumoricidal Effects of Liposomes Containing SaWada et al., Chem. Mod. of an Antitumor Alkaloid Phosphatidylinositol or Phosphatidylcholine, Methods in Camptothecin: Synthesis and Antitumor Activity of 7-C EnZymology, vol. 141, pp. 459-466 (1987). Sub. Camptothecs; Chem. Pharm. Bull. 39(10), 2574 Woodle, M. et al., Liposome Preparation and SiZe Charac teriZation, Methods in EnZymology, vol. 171, pp. 193-217 80(1991). (1989). * cited by examiner US 7,064,206 B1 1 2 HIGHLY LIPOPHILIC CAMPTOTHECIN nicks are converted to irreversible and lethal double strand INTERMEDIATES AND PRODRUGS AND DNA breaks during replication. METHODS OF PREPARATION THEREOF The camptothecin class of anticancer agents have exhib ited unusual reactivity in vivo, both With respect to drug This application claims the bene?t of Us. Provisional 5 hydrolysis and blood protein interactions. These factors Patent Application Ser. No. 60/469,805 ?led on May 12, 2003. have hindered the pharmaceutical development and clinical This invention Was made With Government support under implementation of camptothecins. In terms of hydrolysis, NIH Grant Number lR0lCA63653. The Government may each of the camptothecins shoWn in Table 1 contains an have certain rights in this invention. ot-hydroxy-o-lactone pharmacophore. TABLE 1 Clinical candidates and FDA-approved analogs in the camptothecin family of antiturnor agents Aqueous Solubility Compound R10 R1 R2 R3 Soluble Topotecan/TPT H CH2NH(CH3)2 OH H " CDK602 H C2H5NHCH(CH3)2 H H Irinotecan/CPT- ll C2H5 H O H GI-l472llC/GG-2ll H O \ — CH2 — N N — CH3 0/ Insoluble Camptothecin H H H H " 9-AC H NH2 H H 9-NC/Rubitecan H N02 H H SN-3 8 C2H5 H OH H DB-67 Si(CH3)2C(CH3)3 H OH H MDCPT H H <O— O— TECHNICAL FIELD At physiological