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Bom, David

Burke, Thomas

Curran, Dennis P.

English

University of Kentucky

University of KentuckyUKnowledgePharmaceutical Sciences Faculty Patents Pharmaceutical Sciences7-19-2011Camptothecin Analogs and Methods ofPreparation ThereofDennis P. CurranDavid BomThomas BurkeUniversity of KentuckyRight click to open a feedback form in a new tab to let us know how this document benefits you.Follow this and additional works at: https://uknowledge.uky.edu/ps_patentsPart of the Pharmacy and Pharmaceutical Sciences CommonsThis Patent is brought to you for free and open access by the Pharmaceutical Sciences at UKnowledge. It has been accepted for inclusion inPharmaceutical Sciences Faculty Patents by an authorized administrator of UKnowledge. For more information, please contactUKnowledge@lsv.uky.edu.Recommended CitationCurran, Dennis P.; Bom, David; and Burke, Thomas, "Camptothecin Analogs and Methods of Preparation Thereof " (2011).Pharmaceutical Sciences Faculty Patents. 34.https://uknowledge.uky.edu/ps_patents/34(12) United States Patent Curran et a1. US007982041B2 US 7,982,041 B2 *Jul. 19, 2011 (10) Patent N0.: (45) Date of Patent: (54) (75) (73) (*) (21) (22) (65) (60) (51) (52) (58) (56) CAMPTOTHECIN ANALOGS AND METHODS OF PREPARATION THEREOF Inventors: Dennis P. Curran, Pittsburgh, PA (US); David Bom, Pittsburgh, PA (US); Thomas G. Burke, Lexington, KY (US) Assignees: University of Pittsburgh-of the Commonwealth System of Higher Education, Pittsburgh, PA (US); University of Kentucky Research Foundation, Lexington, KY (US) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. This patent is subject to a terminal dis claimer. Appl. N0.: 12/425,364 Filed: Apr. 16, 2009 Prior Publication Data US 2009/0198061 A1 Aug. 6, 2009 Related US. Application Data Division of application No. 11/805,169, ?led on May 22, 2007, noW Pat. No. 7,538,220, Which is a division ofapplication No. 10/919,068, ?led onAug. 16, 2004, noW Pat. No. 7,220,860, Which is a division of application No. 10/164,326, ?led on Jun. 6, 2002, noW Pat. No. 6,809,103, Which is a division of application No. 09/728,031, ?led on Nov. 30, 2000, noW Pat. No. 6,410,731, Which is a continuation of application No. 09/290,019, ?led on Apr. 9, 1999, noW Pat. No. 6,207,832. Int. Cl. C07D 405/04 (2006.01) US. Cl. ..................................................... .. 546/115 Field of Classi?cation Search ................. .. 546/115 See application ?le for complete search history. References Cited U.S. PATENT DOCUMENTS * 6/1995 Comins ....................... .. 546/116 11/1995 Fortunak 12/1997 Fortunak 4/1998 Curran 6/ 1999 Hausheer 8/1999 Hausheer 11/1999 Bigg 5/2000 Haridas 10/2000 Curran 6,150,343 A 11/2000 Curran 7,220,860 B2 * 5/2007 Curran et al. ............... .. 546/115 FOREIGN PATENT DOCUMENTS 5,428,166 A 5,468,859 A 5,700,939 A 5,744,605 A 5,910,491 A 5,935,967 A 5,981,542 A 6,057,303 A 6,136,978 A 9529917 * 9/1995 97/00876 1/1997 98/07727 2/1998 98/28304 7/1998 98/28305 7/1998 WO 98/35940 8/1998 WO 99/11646 3/1999 WO 00/50427 8/2000 WO 00/61146 10/2000 OTHER PUBLICATIONS Curran et al , 1995, Cascade Radical reactions of Isonitriles.* Josein Hubert et al , A general synthetic approarch to (20$) Camptothecin Family of Antitumor agents, 1998* Curran, DP. and Liu, H., “New 4+1 Radical AnnulationsiA Formal Total Synthesis of (+/—)-Camptothecin,” J. Am. Chem Soc., 114, 5863-5864 (1992). Published Jul. 1, 1992. Curran, D.P., “The CamptothecinsiA reborn Family of Antitumor Agents”, J. Chin. Chem. Soc., 40, 1-6 (1993). Published Feb. 1993. Curran, D.P. et al., “Recent Applications of Radical Reactions in Natural Product Synthesis,” Pure Appl. Chem., 65, 1153-1159 (1993). Published Jun. 1993. Curran, D.P. et al., “Cascade Radical Reactions of Isonitriles: A Second-Generation Synthesis of (20S)-Camptothecin, Topotecan, Irinotecan, and GI-147211C,” Angew. Chem. Int. Ed, 34, 2683-2684 (1995). Published Jan. 5, 1996. Curran, D.P., Liu, H.; Josien, H; Ko, S.B., “Tandem Radical Reac tions of Isonitriles with 2-pyrdonyl and other aryl radicals: Scope and Limitations, and a First Generation Sunthesis of (+/—) Camptothecin,” Tetrahedron, 52, 11385-11404 (1996). Published Aug. 1996. Josien, H. et al., “Synthesis of (S)-mappicine and Mappicine Ketone Via Radical Cascade Reaction of Isonitirles,” Tetrahedron, 53, 8881 8886 (1997). Published Jun. 30, 1997. Josien, H. et al., “7-Silylcamptothecins (Silatecans): A New Family of Camptothecin Antitumor Agents,” Bioorg. Med. Chem. Lett. 7, 3189-3295 (1997). Josien, H. et al., “A General Synthetic Approach to the (20S) Camptothecin Family of Antitumor Agents by a Regiocontrolled Cascade Radical CycliZation of Aryl Isonitriles,” Chem. Eur. J. 4, 67-83 (1998). Published Jan. 1998. (Continued) Primary Examiner * Rita J Desai (74) Attorney, Agent, orFirm * Bartony & Associates, LLC (57) ABSTRACT A compound having the formula in racemic form, enantiomerically enriched form or enantio merically pure form, and pharmaceutically acceptable salts thereof. 5 Claims, 18 Drawing Sheets US 7,982,041 B2 Page 2 OTHER PUBLICATIONS Zihou, M. et al., “Reduced Albumin Binding Promotes the Stability and Activity of Topotecan in Human Blood,” Biochemistry, 34, 13722-13727 (1995). Burke, T.G. and Zihou, M., “The Structural Basis of Camptothecin Interaction With Human Serum Albumin: Impact on Drug Stability,” J. Med. Chemistry, 37, 40-46 (1994). Zihou, M. and Burke, T.G., “Marked Interspecies Variations Con cerning the Interactions of Camptothecin With Serum Albumins: A Frequency-Domain ?uorescence Spectroscopic Study,” Biochemis try, 33, 12540-12545 (1994). Zihou, M. and Burke, T.G., “Differential Interactions of Camptothecin Lactone and CarboXylate Forms With Human Blood Components,” Biochemistry, 33, 10325-10336 (1994). Burke, T.G., and Zihou, M., “Ethyl Substitution at the 7 Position Extends the Half-Life of 10-HydroXycamptothecin in the Presence of Human Serum Albumin,” J. Med. Chemistry, 37:17, 2580-2582 (1993). Burke, T.G. et al., “Lipid Bilayer Partitioning and Stability of Camptothecin Drugs,” Biochemistry, 32:20, 5352-5364 (1993). Zihou, M. and Burke, T.G., Preferential Binding of the CarboXylate Form of Camptothecin by Human Serum Albumin, Anal. Biochem., 212, 285-287 (1993). Burke, T.G. and Tritton, T.R., “Structural Basis of Anthracycline Selectivity for Unilamellar Phosphatidylcholine Vesicles: An Equi librium Binding Study,” Biochemistry, 24, 1768-1776 (1985). Burke, T.G. and Tritton, T.R., “Location and Dynamics of Anthracycline Bound to Unilamellar Phosphatidylcholine Vesicles,” Biochemistry, 24, 5972-5980 (1985). Burke, T.G. et al., “The Important Role of Albumin in Determining the Relative Human Blood Stabilities of the Camptothecin Antican cer Drugs,” J. Parm. Sciences, 84:4 (1995). Born et al.; Novel A,B,E-ring Modi?ed Camptothecins Displaying High Lipophilicity and Markedly Improved Human Blood Stabili ties; Med. Chem.; Aug. 1999; vol. 42; No. 16; pp. 3018-3022. Lavergne, Olivier et al.; Homocamptothecins: Synthesis and Antitu mor Activity of Novel E-Ring-Modi?ed Camptothecin Analogues; J. Med. Chem, 1998; 41; pp. 5410-5419. * cited by examiner US. Patent Jul. 19, 2011 Sheet 2 0f 18 US 7,982,041 B2 Q 1%, R6 = $511113, $323 b, R5 : 3mg“, aw R3 R2 ‘Hair: 13 aemeg‘m 1:11am 15%;] 1h $115311 N82 3% 11:: Silva, NHEac 53% ‘ m swag NH; 15% 5 "5a amefsa ms 211% 11 simian 0H " 2 ‘- ' 1g 321115311 H 221% ii‘: $iMe3 H am US. Patent Jul. 19, 2011 Sheet 3 0f 18 US 7,982,041 B2 Genera! Rama in A“, 5",, and 14/8 Substifuiea’ Hamacampfaiheains >§ 11., <1, subs?iutaci m i madame aiiyi aicmhai swam as a we RM 1"“ R ?naiegenaiivsv 6 Rs -— “Refomawky f I, diasiiyiatim 1 1,: m \Z HM ‘ Wzyamuy R5 ‘3 gmmemygmn e “ _‘ R913 2; cascade radiaxalreactim Y _ _ . $513 13 2 R R E \ R3 / we R4 US. Patent Jul. 19, 2011 Sheet 6 0f 18 US 7,982,041 B2 Fuorescenm Emiasian Spectra m‘ DB~Q1 in Ethanmi Semi-Em": and PBS Szziutinn and Mixtures thereof Thex 394 nm, EX msoiution 4mm, EM ieaaiutim dram, withaut EM poEia?zga", HV 500 EMISSKZN WAVELENGTH {11m} 4511 51,10 EMRSSiCJN WAVELENGTH (am) 6626 600 US. Patent Jul. 19, 2011 Sheet 7 0f 18 US 7,982,041 B2 Fuorescance Emission Spectra of [35-91 in red cells (a) and nmmalized ?uoreacence emission spactra of 10 QM 9&8? in red cze?s and in PB& (b). Spactra was nbtained by using fmnt {ace method. hex 379 nm, EX resaé. Bnm, EM mes-0i. 4mm, without EM poiiarizer, HV : 1259 V -- M in red sails ~~~~ in PBS 456 EMISSION WAVELENGTH mm"; 11) 5 / f \ \. x“. x 50 9M 1113-91 -- - 10 “M DEE-91 2 1., 05450 55s EM§$S30N WAVELENGTH (mm; 408 569 US. Patent Jul. 19, 2011 Sheet 8 0f 18 US 7,982,041 B2 Fuorescence ?misgian Spectra of SW38 in red ceiis (a) and normaiized ?uorescence emission speestra 01‘ 19 11M Ski-38 in red cekis and in PBS (13). Spectra wag obtained by using from face methed. my; : 370 ram, EX E’Q80i. 8mm, EM resai. 1mm, wiihuui EM pniiar‘tzer, mm 1250 v 450 M w s d ?u. MWW \1\F0-5 L!. FM .m ,1W m wx111 1, 5 n21. GEmzm»; wozmuwmmon?mmm ?a z \ \ \ \  // 2,.,2. /f / 7E1 / , m as /f SM \VUM .\mm a\ - m W a,m _m2,, Gnu 2 4! RVs51: EMSSQON WAVELENGTH {mm} 6% 590 5513C EMZSSiON WAVELENGTH (ram) 666 450 US. Patent Jul. 19, 2011 Sheet 9 0f 18 US 7,982,041 B2 9H Denendencs a? the ?abiiity a‘? the 56H Lac'mne M13591}; a“? £3E~38 US. Patent Jul. 19, 2011 Sheet 10 0f 18 US 7,982,041 B2 pH ?agendencs m‘ the Stabiiity a? 151% §$~GH Lacmne Msiety m"? {SE81 , a z i I 1 I 1 f: 25 5i} ?5 ma “£25 15$ 1% 289 225 TE US. Patent Jul. 19, 2011 Sheet 12 0118 US 7,982,041 B2 pH ?épendeme :11‘ the Siabiiity sf the Lacmne Maiaty (2f D~9i {1Q . 1 , I I . a 25 50 1% ms 12:5 150 W5 2% US. Patent Jul. 19, 2011 Sheet 14 0118 US 7,982,041 B2 Gnmparissn a? tha Stab?ities m‘ a~Laatane Siiatecans wiih ?hair cerresponding Homcsiiatecans in PBSJSA at 3"?“6 A 3.3 ~ 1 as - {3.2 - G 66 125}. m m E“ “ H 6 0.8 ~ l5.‘ LL! % 135-264 C) DBQG 8.1%- - {12 ~ 0.2 ~ (3.11} US. Patent Jul. 19, 2011 Sheet 16 0f 18 US 7,982,041 B2 Stabiiity a? Hammséiatacans in Red Siam Caiis m ?mw? , BEBE“ QUDDM u @GVVM u “v8 A2aQ G3155 1% US. Patent Jul. 19, 2011 Sheet 17 0f 18 US 7,982,041 B2 Cumpwiss? a? the 8iabi§§?e$ of wLacmne Siiaiesans with their mwespanding HamQsiiatesans in Whséa ma 3113"?"6 Q53 , l G 6U 12% a0 12:: was US. Patent FMCTEGM 6FLA QNEJul. 19, 2011 Sheet 18 0f 18 US 7,982,041 B2 Gamparisan 0f the Stabiiity m‘ ?gmaaéiateaa?s with Ciiniaa?y eiévant Campnthecins in Whméa Emd at 3?"C 1.0 (5.53“ 9.4 0.2~ 

Camptothecin Analogs and Methods of Preparation Thereof

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Camptothecin Analogs and Methods of Preparation Thereof

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