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Pharmaceutical Sciences Faculty Patents Pharmaceutical Sciences

7-19-2011

Camptothecin Analogs and Methods of Preparation Thereof Camptothecin Analogs and Methods of Preparation Thereof

Dennis P. Curran

David Bom

Thomas Burke University of Kentucky

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Recommended Citation Recommended Citation Curran, 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

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(12) United States Patent Curran et a1.

US007982041B2

US 7,982,041 B2 *Jul. 19, 2011

(10) Patent N0.: (45) Date of Patent:

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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

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