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United States Patent (19) 11 Patent Number: 5,840,750 Longley Et Al

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United States Patent (19) 11 Patent Number: 5,840,750 Longley Et Al USOO584O750A United States Patent (19) 11 Patent Number: 5,840,750 LOngley et al. (45) Date of Patent: Nov. 24, 1998 54) DISCODERMOLIDE COMPOUNDS Fuchs, D.A., R.K. Johnson (1978) “Crtologic Evidence that Taxol, an Antineoplastic Agent from Taxus brevifolia, Acts 75 Inventors: Ross E. Longley; Sarath P. as a Mitotic Spindle” Cancer Treatment Reports Gunasekera, both of Vero Beach; 62(8):1219–1222. Shirley A. Pomponi, Fort Pierce, all of Schiff, P.B. et al. (1979) “Promotion of microtubule assem Fla. bly in vitro by taxol” Nature (London) 22:665–667. Rowinsky, E.K., R.C. Donehower (1995) “Paclitaxel 73 Assignee: Harbor Branch Oceanographic (Taxol)” The New England Journal of Medicine Institution, Inc., Fort Pierce, Fla. 332(15):1004–1014. Minale, L. et al. (1976) “Natural Products from Porifera” 21 Appl. No. 761,106 Fortschr. Chem. org. Naturst. 31:1-72. Kelly-Borges et al. (1994) “Species Differentiation in the 22 Filed: Dec. 5, 1996 Marine Sponge Genus DiscOdermia (DemoSpongiae: Lithis tida): the Utility of Ethanol Extract Profiles as Species-Spe Related U.S. Application Data cific Chemotaxonomic Markers’ Biochemical Systematics 63 Continuation-in-part of Ser. No. 567,442, Dec. 5, 1995. and Ecology 22(4):353–365. ter Haar, E., H.S. Rosenkranz, E. Hamel, B.W. Day (1996) 51) Int. Cl. ......................... A61K31/35; CO7D 309/30 “Computational and Molecular Modeling Evaluation of the 52 U.S. Cl. ............................................. 514/459; 549/292 Structural Basis for Tubulin Polymerization Inhibition by 58 Field of Search .............................. 549/292; 514/459 Colchicine Site Agents,” Bioorganic and Medicinal Chem istry 4(10): 1659–1671. 56) References Cited Hung, D.T., J. Chen. S.L. Schreiber (1996) “(+)-Discoder mollide binds in microtubules in Stoichiometric ratio to U.S. PATENT DOCUMENTS tubulin dimers, blockS binding and results in mitotic arrest,” 4,206,221 6/1980 Miller et al. ............................ 514/471 Chemistry & Biology 3(4):287–293. 4,939,168 7/1990 Gunasekera et al. ... 514/559 4,960,790 10/1990 Stella et al. ...... ... 514/449 Primary Examiner Amelia Owens Attorney, Agent, or Firm-Saliwanchik, Lloyd & 5,157,049 10/1992 Haugwitz et al. ...................... 514/449 Saliwanchik OTHER PUBLICATIONS 57 ABSTRACT Nerenberg, J.B. et al. (1993) “Total Synthesis of the Immu Novel lactone compounds from the marine Sponge DiscO noSuppressive Agent (-)-Discodermolide” J. Am. Chem. dermia dissoluta have been isolated. These compounds and Soc. 115:12621-12622. their analogs have been shown to have activity against Uemura, D. et al. (1985) “Norhalichondrin A: An Antitumor Polyether Macrollide from a Marine Sponge” J. Am. Chem. mammalian cancer cells, and can be used in treating human Soc. 107:4796-4798. patients which host cancer cells, including leukemia, Faulkner, D.J. (1987) “Marine Natural Products” Natural melanoma, and breast, colon, CNS, and lung tumors. Products Reports 4:539–576. 7 Claims, 21 Drawing Sheets U.S. Patent Nov. 24, 1998 Sheet 1 of 21 5,840,750 U.S. Patent 5,840,750 U.S. Patent 5,840,750 *130up3))seºig.-•’|* ºu?I[[30/?ºuba? U.S. Patent Nov. 24, 1998 Sheet S of 21 5,840,750 U.S. Patent Nov. 24, 1998 Sheet 7 of 21 5,840,750 *********•§-«-….….….. I,º*•+—- °°°°°*•4. **********•+-. CIIWTOWN B)[9CI 93ueYI U.S. Patent Nov. 24, 1998 Sheet 8 of 21 5,840,750 *•• *••- U.S. Patent Nov. 24, 1998 Sheet 10 of 21 5,840,750 J00ueOue?IBAO IAORIOI U.S. Patent Nov. 24, 1998 Sheet 12 of 21 5,840,750 VI0I-IÐ !Crº??UTCC)VNICI \/ 61-I JeCUN LeO U.S. Patent 5,840,750 O O t JeCUN II eC) U.S. Patent 5,840,750 VI0I-IÐ ?seo.IOEI ?Iu??u00I G10XeL []ºI DJiz JeCUN?DEI II eC) U.S. Patent Nov. 24, 1998 Sheet 15 of 21 5,840,750 ?untI 4trº?UTCC)VNICI W79 10.I?u0O[][]E ‘61-I JeCUN eO U.S. Patent 5,840,750 4TTº?UTCC)VNICI 09-6) 0DE JeCUN eO U.S. Patent Nov. 24, 1998 Sheet 18 of 21 5,840,750 DJEBED?ZEL PR?_..…95I___DEIDED+7[] 3-U?º?.UTCC)VNICI Dº Diz []izI [][]EI []I 008 [][]E JeCUN II eC) U.S. Patent Nov. 24, 1998 Sheet 20 of 21 5,840,750 QEEDËZË 9%šz|oxeI, 0585) DEE []BE DJETI <Ot'fil JeCUN II GO U.S. Patent Nov. 24, 1998 Sheet 21 of 21 5,840,750 w s P Po 5,840,750 1 2 DISCODERMOLIDE COMPOUNDS BRIEF SUMMARY OF THE INVENTION CROSS-REFERENCE TO ARELATED A principal object of this invention is the provision of APPLICATION novel compositions of biologically active, lactone com pounds which can advantageously be used for treating This is a continuation-in-part of co-pending application cancer. More specifically, the novel compositions and meth Ser. No. 08/567,442, filed Dec. 5, 1995. ods of use can advantageously be useful in the treatment of a patient hosting cancer cells, for example, inhibiting the FIELD OF THE INVENTION growth of tumor cells in a mammalian host. More This invention relates to organic compounds and compo particularly, the Subject compounds, herein referred to as the Sitions which have useful therapeutic properties. More discodermolides, and compositions comprising the disco particularly, the invention concerns novel lactone com dermolides can be used for inhibiting in a human the growth pounds having immunomodulatory and antitumor activities, of tumor cells, including cells of breast, colon, CNS, or lung pharmaceutical compositions comprising Such compounds, tumors, as well as human leukemia or melanoma cells. It is methods for the preparation of the novel compounds, and 15 understood that the mechanisms for achieving anticancer compositions and methods of their use for therapeutic pur activity exhibited by the subject compounds would lead a pOSes. perSon of ordinary skill in the art to recognize the applica bility of the Subject compounds, compositions, and methods BACKGROUND OF THE INVENTION to additional types of cancer as described herein. In the past, considerable research and resources have been In accordance with the invention, methods for inhibiting devoted to oncology and antitumor measures including tumors in a host comprise contacting tumor cells with an chemotherapy. While certain methods and chemical com effective amount of the new pharmaceutical compositions of positions have been developed which aid in inhibiting, the invention. The tumor cells inhibited by the invention are remitting, or controlling the growth of tumors, new methods those which are Susceptible to the Subject compounds and antitumor chemical compositions are needed. 25 described herein or compositions comprising those com In Searching for new biologically active compounds, it pounds. has been found that Some natural products and organisms are Additional objects of the invention are the provision of potential Sources for chemical molecules having useful methods for producing the new compounds and composi biological activity of great diversity. For example, the diter tions. pene commonly known as taxol, isolated from Several Other objects and further scope of applicability of the Species of yew trees, is a mitotic Spindle poison that Stabi present invention will become apparent from the detailed lizes microtubules and inhibits their depolymerization to descriptions given herein; it should be understood, however, free tubulin (Fuchs, D. A., R. K. Johnson 1978 Cancer that the detailed descriptions, while indicating preferred Treat. Rep. 62:1219–1222; Schiff, P. B., J. Fant, S. B. 35 embodiments of the invention, are given by way of illustra Horwitz 1979 Nature (London) 22:665–667). Taxol is also tion only, Since various changes and modifications within the known to have antitumor activity and has undergone a Spirit and Scope of the invention will become apparent from number of clinical trials which have shown it to be effective Such descriptions. in the treatment of a wide range of cancers (Rowinski, E. K. R. C. Donehower 1995 N. Engl. J. Med. 332:1004–1014). 40 See also, e.g., U.S. Pat. Nos. 5,157,049; 4,960,790; and BRIEF DESCRIPTION OF THE DRAWINGS 4,206,221. FIGS. 1A-1K show antiproliferative effects, measured by Marine Sponges have also proven to be a Source of GIso, TGI, and LCs of discodermolides against a plurality biologically active chemical molecules. A number of pub of human tumor cell lines. lications have been issued disclosing organic compounds 45 derived from marine Sponges including Scheuer, P. J. (ed.) FIGS. 2A-2C show the effect of discodermolides on Marine Natural Products, Chemical and Biological GI-101A human breast cells according to the Subject inven Perspectives, Academic Press, New York, 1978–1983, Vol. tion. I-V; Uemura, D., K. Takahashi, T. Yamamoto, C. Katayama, FIGS. 3A-3C show the effect of discodermolides on A549 J. Tanaka, Y. Okumura, Y. Hirata (1985) J. Am. Chem. Soc. 50 human lung cells according to the Subject invention. 107:4796–4798; Minale, L. et al. (1976) Fortschr. Chem. org. Naturst. 33:1-72; Faulkner, D.J. (1996) Natural Prod FIGS. 4A-4C show the effect of discodermolides on ucts Reports 13:75-125, and references cited therein. Jurkat human leukemia cells. The present invention has added to the arsenal of antitu FIG. 5 shows the effect of discodermolides (compared to mor compounds by the discovery of new classes of organic 55 taxol) on tubulin polymerization according to the Subject compounds possessing, inter alia, useful tubulin invention. polymerizing and antitumor activities. These compounds can be isolated from extracts of the marine Sponge, DiscO DETAILED DISCLOSURE OF THE INVENTION dermia dissoluta. See U.S. Pat. Nos. 4,939,168 and 5,010, 099. In addition, these compounds can be synthesized by 60 In one embodiment, the objects of the invention are known organic chemistry procedures that are readily under accomplished by the provision of the biologically active stood by persons of ordinary skill in the art.
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