Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-08
2002-03-26
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S510000, C549S511000
Reexamination Certificate
active
06362217
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention concerns antitumor compounds. More particularly, the invention provides novel paclitaxel derivatives, pharmaceutical formulations thereof, and their use as antitumor agents.
2. Background Art
Paclitaxel is a natural product extracted from the bark of Pacific yew trees, Taxus brevifolia and the active constituent of the anticancer agent TAXOL®. It has been shown to have excellent antitumor activity in in vivo animal models, and recent studies have elucidated its unique mode of action, which involves abnormal polymerization of tubulin and disruption of mitosis. It is used clinically against a number of human cancers. It is an important cancer agent both therapeutically and commercially. Numerous clinical trials are in progress to expand the increase the utility of this agent for the treatment of human proliferative diseases. The results of TAXOL® clinical studies have been reviewed by numerous authors. A very recent compilation of articles by a number of different authors is contained in the entire issue of Seminars in Oncology 1999, 26 (1, Suppl 2). Other examples are such as by Rowinsky et al. in TAXOL®: A Novel Investigational Antimicrotubule Agent, J. Natl. Cancer Inst., 82: pp 1247-1259, 1990; by Rowinsky and Donehower in “The Clinical Pharmacology and Use of Antimicrotubule Agents in Cancer Chemotherapeutics,” Pharmac. Ther., 52:35-84,1991; by Spencer and Faulds in “Paclitaxel, A Review of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Potential in the Treatment of Cancer,” Drugs, 48 (5) 794-847,1994; by K. C. Nicolaou et al. in “Chemistry and Biology of TAXOL®,” Angew. Chem., Int. Ed. Engl., 33: 15-44, 1994: by F. A. Holmes, A. P. Kudelka, J. J. Kavanaugh, M. H. Huber. J. A. Ajani, V. Valero in the book “Taxane Anticancer Agents Basic Science and Current Status” edited by Gunda 1. Georg, Thomas T. Chen, lwao Ojima, and Dolotrai M. Vyas, 1995, American Chemical Society, Washington, D.C., 31-57; by Susan G. Arbuck and Barbara Blaylock in the book “TAXOL® Science and Applications” edited by Mathew Suffness, 1995, CRC Press Inc., Boca Raton, Fla., 379-416; and also in the references cited therein.
A semi-synthetic analog of paclitaxel named docetaxel has also been found to have good antitumor activity and is the active ingredient of the commercially available cancer agent TAXOTERE®. See, Biologically Active Taxol Analogues with Deleted A-Ring Side Chain Substitutents and Variable C-2′ Configurations, J. Med. Chem., 34, pp 1176-1184 (1991); Relationships between the Structure of Taxol Analogues and Their Antimitotic Activity, J. Med. Chem., 34. pp 992-998 (1991). A review of the clinical activity of TAXOTERE® by Jorge E. Cortes and Richard Pazdur has appeared in Journal of Clinical Oncology 1995, 13(10), 2643 to 2655. The structures of paclitaxel and docetaxel are shown below along with the conventional numbering system for molecules belonging to the class; such numbering system is also employed in this application.
paclitaxel (TAXOL®): R=Ph; R′=acetyl
docetaxel (TAXOTERE®): R=t-butoxy; R′=hydrogen
The intention of this invention is to provide new 7-deoxy taxane analogs with useful anticancer properties. Some of the background art pertaining to this invention are shown below.
Several Publications have described the synthesis or attempted synthesis of the 7-deoxy analog of paclitaxel. These are:
Chen, Shu Hui; Huang, Stella; Kant, Joydeep; Fairchild, Craig Wei, Jianmei; Farina, Vittorio. “Synthesis of 7-deoxy- and 7,10-dideoxytaxol via radical intermediates”. J. Org. Chem., 58(19). 5028-9, 1993.
Chaudhary, Ashok G.; Rimoldi, John M.; Kingston, David G. I. “Modified taxols. 10. Preparation of 7-deoxytaxol, a highly bioactive taxol derivative, and interconversion of taxol and 7-epi-taxol”. J. Org. Chem., 58(15), 3798-9, 1993.
Matovic, Radomir; Saicic, Radomir N. “An efficient semisynthesis of 7-deoxypaclitaxel from taxine”. Chem. Commun. (Cambridge). (16), 1745-1746, 1998.
A U.S. patent (U.S. Pat. No. 5,478,854) covering certain deoxy taxanes issued on Dec 26th 1995 by Farina et. al.
A published PCT international application (WO 94/17050) from Holton et. al. discloses 7-deoxy taxane derivatives. Other than actual supporting examples already claimed in the above mentioned U.S. patent, this application discloses many multitudes of hypothetical 7-deoxy taxane analogs with no indication of which compounds would really be useful. This application also does not provide details of the preparation of any C-7 deoxy taxanes which are not covered by the above mentioned U.S. patent. Corresponding U.S. Pat. No. 5,271,268 to Holton et al was granted.
An issued U.S. patent (U.S. Pat. No. 5773461) by Wittman et. al. claims 7-deoxy taxane analogs with unique functional groups at the 6 position as antitumor agents.
A published PCT application (WO 9828288) by Staab et. al. published Jul. 2, 1998, corresponding to U.S. Pat. No. 5,977,386 granted Nov. 2, 1999, describes C-7 deoxy taxanes with thio substituents at the 6 position.
A published PCT application (WO 9838862) by Wittman et. al. published Sep. 11, 1998, corresponding to U.S. Pat. No. 5,912,264 granted Jun. 15, 1998, describes C-7 deoxy taxanes with halogen or nitro substituents on C-6.
Nondeoxy analogs with a 3′ furyl amide substituent on the sidechain have appeared in both the patent (U.S. Pat. No. 5227,400 and U.S. Pat. No. 5,283,253) and chemistry literature Georg, Gunda I.; Harriman, Geraldine C. B.; Hepperle, Michael; Clowers, Jamie S.; Vander Velde, David G.; Himes, Richard H. Synthesis, Conformational Analysis, and Biological Evaluation of Heteroaromatic Taxanes. J. Org. Chem. (1996), 61(8), 2664-76. Importantly, we are unaware of any reports describing the synthesis of a 7-deoxy analog with this 3′N furoylamide sidechain or any of their novel, useful anticancer properties such as those described by this invention.
Hydroxylation of the 3′ sidechain phenyl group of paclitaxel has been reported to lead to reduced potency and thus has been inferred to result in less activity as discussed in the following examples: Wright, M.; Monsarrat, B.; Royer, I.; Rowinsky, E. K.; Donehower, R. C.; Cresteil, T.; Guenard, D. Metabolism and pharmacology of taxoids. Pharmacochem. Libr. (1995), Volume Date 1995, 22 131-64; Sparreboom, Alexander; Huizing, Manon T.; Boesen, Jan J. B.; Nooijen, Willem J.; van Tellingen, Olaf; Beijnen, Jos H. Isolation, purification, and biological activity of mono- and dihydroxylated paclitaxel metabolites from human feces. Cancer Chemother. Pharmacol. (1995). 36(4), 299-304.
Monsarrat, Bernard; Mariel, Eric; Cros, Suzie; Gares, Michele, Guenard, Daniel; Gueritte-Voegelein, Francoise; Wright, Michel. Taxol metabolism. Isolation and identification of three major metabolites of taxol in rat bile. Drug Metab. Dispos. (1990), 18(6), 895-901.
The synthetic preparation of the parahydroxylated 3′phenyl metabolite has been described in the literature. Park, Haeil; Hepperle, Michael; Boge, Thomas C.; Himes, Richard H.; Georg, Gunda I. Preparation of Phenolic Paclitaxel Metabolites. J. Med. Chem. (1996), 39(14), 2705-2709. We are not aware of any published reports of synthetic analogs with phydroxy phenyl 3′ sidechains that are purported to have activity advantages.
However, one reference in the patent literature mentions in passing that the para hydroxy phenyl metabolite might have an improved therapeutic index despite reduced potency and thus it's formation in vivo may be fortuitous. Broder et.al. PCT Int. Appl. WO 9715269 published May 1, 1997.
However, this patent does not describe the synthesis or administration of para-hydroxyphenyl taxanes nor any actual efficacy results. Thus, the art clearly shows that the phydroxy phenyl sidechain analog of paclitaxel will be less potent than the parent drug. Most significantly, we are unaware of any prior art which describes the synthesis of novel 7-deoxy taxanes with a 3′parahydroxyphenyl containing sidecha
Kadow John F.
Schwartz Wendy S.
Scola Paul M.
Wittman Mark D.
Wu Mu-Jen
Bristol--Myers Squibb Company
DuBoff Samuel J.
Lambkin Deborah C.
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