Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-10-16
2000-02-01
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546 47, A61K 3147, C07D22118
Patent
active
060203412
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to enediyne quinone imines, compounds useful for the treatment of cancer, conjugates thereof with peptides, enzymes, carbohydrates, and monoclonal antibodies, and to methods of preparing and using them.
The novel enediyne antibiotic dynemicin A (1) (Konishi, M.; Ohkuma, H.; Matsumoto, K.; Tsuno, T.; Kamei, H.; Miyaki, T.; Oki, T.; Kawaguchi, H.; Van Duyne, G. D.; Clardy, J. J. Antibiot., 1989, 42, 1449. Konishi, M.; Ohkuma, H.; Tsuno, T.; Oki, T.; VanDuyne, G. D.; Clardy, J. J. Am. Chem. Soc., 1990, 112, 3715) has stimulated the pursuit of DNA cleavage studies (Sugiura, Y.; Shiraki, T.; Konishi, M.; Oki, T. Proc. Nat. Acad. Sci. U.S.A., 1990, 87, 3831), the design of new pro-drug constructs and the development of novel methodology directed at total synthesis. Nicolaou, K. C.; Dai, W.-M. Angew. Chem. Int. Ed. Enql., 1991, 30 1387; Taunton, J.; Wood, J. L.; Schreiber, S. L. J. Am. Chem. Soc., 1993, 115, 10378. The prevailing assumption (Semmelhack, M. F.; Gallagher, J.; Cohen, D. Tetrahedron Lett., 1990, 31, 1521; Sugiura, Y.; Shiraki, T.; Konishi, M.; Oki, T. Proc. Nat. Acad. Sci. U.S.A., 1990, 87, 3831) concerning the ignition mechanism for the drug to operate as a diyl precursor presupposes reduction of the quinone ring to the hydroquinone state. In this way the "lone pair" on nitrogen is unleashed to participate in mediating solvent attack on the epoxide (Scheme 1, see arrows). The opening of this epoxide is a critical prophase in fostering the Bergman (enediyne .fwdarw.1,4-diyl) transformation. Jones, R. R.; Bergman, R. G. J. Am. Chem. Soc., 1972, 94, 660. Bergman, R. G.; Acc. Chem. Res., 1973, 6, 25. The cytotoxicity of enediyne antibiotics is thought to arise from the DNA cutting tendency of diyl 2 or its quinone counterpart. Sugiura, Y.; Shiraki, T.; Konishi, M.; Oki, T. Proc. Nat. Acad. Sci. U.S.A., 1990, 87, 3831. The dihydroxy naphthaquinone sector presumably provides noncovalent intercalative contacts for directing the drug to its oligonucleotide target. Sugiura, Y.; Shiraki, T.; Konishi, M.; Oki, T. Proc. Nat. Acad. Sci. U.S.A., 1990, 87, 3831; Arcamone, F. in Doxorubicin Anticancer Antibiotics, Academic, New York, 1981; Neidle, S.; Pearl, L. H.; Skelly, J. V. Biochem. J., 1987, 243, 1-13; Wang, A.; Ughetto, G.; Quigley, G.; Rich, A. Biochemistry, 1987, 26, 1152. The present invention provides new analogues of enediyne antibiotics and methods of preparing and using them, and offers a potentially important advance for cancer chemotherapy.
SUMMARY OF THE INVENTION
The subject invention provides a compound having the structure: ##STR2## wherein R.sub.1, R.sub.2 and R.sub.3 are independently the same or different and are H, Br, Cl, F, NH.sub.2, CO.sub.2 H, or OH or a linear or branched alkyl, linear or branched acylamino, linear or branched acyloxy, linear or branched alkoxy-carbonyl, linear or branched alkoxy, aryloxy, linear or branched alkylaryl, linear or branched hydroxyalkyl, linear or branched aminoalkyl or aryl group; wherein R.sub.4 is H, OH or a linear or branched alkoxy, linear or branched alkoxycarbonyl, linear or branched acyloxy or aryloxy group; wherein R.sub.5 is H, Br, Cl, F, O.dbd., OH or S--SR, or a linear or branched alkyl, aryl, linear or branched alkylaryl, linear or branched alkoxy, linear or branched acyloxy or linear or branched hydroxyalkyl group; wherein R.sub.6 is H, Br, Cl, F, CO.sub.2 H, OH or S--SR', or a linear or branched alkyl, aryl, linear or branched alkylaryl, linear or branched alkoxycarbonyl, linear or branched alkoxy or linear or branched hydroxyalkyl group; wherein R.sub.7 is H, OH or S--SR", or a linear or branched alkyl, linear or branched alkoxycarbonyl, linear or branched alkoxy or linear or branched hydroxyalkyl group; and wherein R, R' and R" are independently the same or different and are a linear or branched alkyl, linear or branched acyl or linear or branched alkoxyalkyl group.
The subject invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the co
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Chou Ting-Chao
Danishefsky Samuel J.
Mosny Karoline K.
Shair Matthew D.
Yoon Taeyoung
Coleman Brenda
Shah Mukund J.
Sloan-Kettering Institute for Cancer Research
White John P.
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