Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-10-02
2003-04-15
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S218000, C548S302100, C548S420000
Reexamination Certificate
active
06548530
ABSTRACT:
FIELD OF INVENTION
The invention relates to antitumor antibiotics. More particularly, the invention relates to analogs of CC-1065 and the duocarmycins having antitumor antibiotic activity.
BACKGROUND
(+)-CC-1065 (1) and the duocarmycins 2-3 represent the initial members of a class of exceptionally potent antitumor antibiotics. Members of this class of antitumor antibiotic derive their biological effects through the reversible, stereoelectronically-controlled sequence selective alkylation of duplex DNA. (H. Sugiyama, et al.,
Tetrahedron Lett.
1990, 31, 7197; C. H. Lin, et al.,
J. Am. Chem. Soc.
1992, 114, 10658; H. Sugiyama, et al.,
Tetrahedron Lett.
1993, 34, 2179; K. Yamamoto, et al.,
Biochemistry
1993, 32, 1059; A. Asai, et al.,
J. Am. Chem. Soc.
1994, 116, 4171; and D. L. Boger, et al.,
Tetrahedron
1991, 47, 2661.) (+)-CC-1065 (1) was first disclosed in 1981 by L. J. Hanka, et al.. (
J. Am. Chem. Soc.
1981, 103, 7629.) The duocarmycins 2-3 were first disclosed in 1988 and 1990. (Takahashi, et al..
J. Antibiot.
1988, 41, 1915; T. Yasuzawa, et al.,
Chem. Pharm. Bull.
1988, 36, 3728; M. Ichimura, et al.,
J. Antibiot.
1988, 41, 1285; M. Ichimura, et al.,
J. Antibiot.
1990, 43, 1037; M. H. Ichimura, et al.,
J. Antibiot.
1991, 44, 1045; K. Ohba, et al.,
J. Antibiot.
1988, 41, 1515; and S. Ishii,
J. Antibiot.
1989, 42, 1713.)
Subsequent to their disclosure, extensive efforts have been devoted to establish their duplex DNA alkylation selectivity and its structural origin. (D. L. Boger,
Acc. Chem. Res.
1995, 28, 20; D. L. Boger,
Proc. Nal. Sci. U.S.A.
in press; D. L. Boger,
Chemtracts: Org. Chem.
1991, 4, 329; D. L. Boger, In
Proceed R. A. Welch Found. Conf. on Chem. Res., XXXV. Chem. at the Frontiers of Medicine
1991, 35, 137; D. L. Boger, In
Advances in Heterocyclic Natural Products Synthesis,
Vol. 2, Pearson, W. H. Ed.; JAI Press: Greenwich, Conn., 1992, 1-188; D. L. Boger,
Pure Appl. Chem.
1993, 65, 1123; D. L. Boger,
Pure Appl. Chem.
1994, 66, 837; R. S. Coleman, In
Studies in Nat. Prod. Chem.,
Vol 3, Rahman, A.-u.-, Ed.; Elsevier: Amsterdam, 1989, 301; and D. L. Boger, In
Heterocycles in Bioorganic Chemistry;
J. Bergman, H. C. van der Plas, and M. Simonyl, Eds; Royal Society of Chemistry: Cambridge, 1991, 103.) Progress has also been made with respect to characterizing the link between DNA alkylation and the ensuing biological properties. (D. L. Boger, et al.,
Bioorg. Med. Chem. Lett.
1994, 4, 631.) Extensive efforts have also been devoted to define the fundamental principles underlying the relationships between structure, chemical reactivity, and biological properties. (W. Wierenga, et al.,
Adv. Enzyme Regul.
1986, 25, 141; M. A. Warpehoski, et al.,
J. Med. Chem.
1988, 31, 590; D. L. Boger, et al.,
J. Am. Chem. Soc.
1993, 115, 9025; D. L. Boger, et al.,
J. Am. Chem. Soc.
1992, 114, 10056; H. Muratake, et al.,
Tetrahedron Lett.
1994, 35, 2573; Y. Fukuda, et al.,
Tetrahedron
1994, 50, 2793; Y. Fukuda, et al.,
Tetrahedron
1994, 50, 2809; Y. Fukuda, et al.,
Bioorg. Med. Chem. Lett.
1992, 2, 755; Y. Fukuda, et al.,
Tetrahedron Lett.
1990, 31, 6699; W. Wierenga,
J. Am. Chem. Soc.
1981, 103, 5621; P. Magnus, et al.,
J. Am. Chem. Soc.
1987, 109, 2706; G. A. Kraus, et al.,
J. Org. Chem.
1985, 50, 283; D. L. Boger, et al.,
J. Am. Chem. Soc.
1988, 110, 1321, 4796; R. E. Bolton, et al.,
J. Chem. Soc., Perkin Trans.
1 1988, 2491; R. J. Sundberg, et al.,
J. Org. Chem.
1988, 53, 5097; R. J. Sundberg, et al.,
J. Org. Chem.
1991, 56, 3048; V. P. Martin,
Helv. Chim. Acta
1989, 72, 1554; M. Toyota, et al.,
J. Chem. Soc., Perkin Trans.
1 1992, 547; and L. F. Tietze, et al.,
J. Org. Chem.
1994, 59, 192.) The relationships between structure, chemical reactivity, and biological properties of CI-based analogs have also been characterized. (D. L. Boger, et al.,
Proc. Natl. Acad. Sci. U.S.A.
1991, 88, 1431; D. L. Boger, et al.,
J. Am. Chem. Soc.
1991, 113, 3980; D. L. Boger, et al.,
J. Org. Chem.
1989, 54, 1238; D. L. Boger, et al.,
J. Am. Chem. Soc.
1990, 112, 5230; K. J. Drost, et al.,
J. Org. Chem.
1989, 54, 5985; J. H. Tidwell, et al.,
J. Org. Chem.
1992, 57, 6380; J. Sundberg, et al.,
Tetrahedron Lett.
1986, 27, 2687; Y. Wang, et al.,
Heterocycles
1993, 36, 1399; Y. Wang, et al.,
J. Med. Chem.
1993, 36, 4172; L. F. Tietze, et al.,
Chem. Ber.
1993, 126, 2733; and T. Sakamoto, et al.,
J. Chem. Soc., Perkin Trans.
1 1993, 1941.) The relationships between structure, chemical reactivity, and biological properties of C
2
BI-based analogs have also been characterized. (D. L. Boger, et al.,
J. Am. Chem. Soc.
1992, 114, 9318; and D. L. Boger, et al.,
Bioorg. Med. Chem.
1993, 1, 27.) The relationships between structure, chemical reactivity, and biological properties of CBQ-based analogs have also been characterized. (D. L. Boger, et al.,
J. Am. Chem. Soc.
1994, 116, 6461; and D. L. Boger, et al.,
J. Am. Chem. Soc.
1994, 116, 11335.) F. Mohamadi et al. have characterized the relationships between structure, chemical reactivity, and biological properties of CFI-based analogs (
J. Med Chem.
1994, 37, 232.) A p-quinonemethide analog was characterized by D. L. Boger, et al.. (
J. Org. Chem.
1994, 59, 4943.)
Concurrent with the above structure/function studies, substantial efforts have been devoted to developing potential clinical candidates based on the natural product structures having enhanced in vivo efficacy. Compounds 4-8 are analogs of the natural product structures having enhanced in vivo efficacy with clinical potential. (D. L. Boger, et al.,
J. Org. Chem.
1984, 49, 2240; M. A. Warephoski, M. A.
Tetrahedron Lett.
1986, 27, 4103; Li, L. H.;
Invest New Drugs
1991, 9, 137; B. K. Bhuyan, et al.,
Cancer Res.
1992, 52, 5687; B. K. Bhuyan, et al.,
Cancer Res.
1993, 53, 1354; L. H. Li, et al.,
Cancer Res.
1992, 52, 4904; M. A. Mitchell, et al.,
J. Am. Chem. Soc.
1991, 113, 8994. Lee, C.-S.; Gibson, N. W.
Cancer Res.
1991, 51, 6586. Lee, C.-S.; Gibson, N. W.
Biochemistry
1993, 32, 9108; Wierenga, W.
Drugs Fut.
1991, 16, 741; K. Gomi, et al.,
Jpn. J. Cancer Res.
1992, 83, 113. Okamoto, A.; Okabe, M.; Gomi, K.
Jpn. J. Cancer Res.
1993, 84, 93; E. Kobayashi, et al.,
Cancer Res.
1994, 54, 2404; and H. Ogasawara,
Jpn. J. Cancer Res.
1994, 85, 418. ) A Phase I clinical trial one one drug candidate in this class is described by G. F. Fleming, et al., (
J. Natl. Cancer Inst.
1994, 86, 368.) Efforts have also focused on the development of analogs having decreased delayed toxicity as compared to the natural form of (+)-CC-1065. (J. P. McGovren, et al.,
Cancer Res.
1993, 53, 5690.) Importantly, this unusual property has not been observed with ent-(−)-CC-1065, although it is equally cytotoxic, and is not observed with the naturally-derived duocarmycins as well as simplified analogs of the natural products.
The first preparation and examination of agents containing the 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) alkylation subunit were described in connection with efforts to evaluate CC-1065 and duocarmycin analogs bearing deep-seated structural alterations in the alkylation subunit. (D. L. Boger, et al.,
J. Am. Chem. Soc.
1989, 111, 6461; and D. L. Boger, et al.,
J. Org. Chem.
1990, 55, 5823.) These agents were employed as tools to identify the structural features of compounds 1-3 associated with their sequence selective alkylation of duplex DNA and to define the fundamental relationships between structure, chemical or functional reactivity and biological properties.
Prior to the present invention, it had been assumed that the unique alkylating activity of the naturally occurring CPI subunit of CC-1065 would be degraded if this portion of the molecule were structurally altered. (L. H. Hurley, et al.,
Science
1984, 226, 843; V. L. Reynolds, et al.,
Biochemistry
1985, 24, 6228. L. H. Hurley, et al.,
Biochemistry
1988, 27, 3886; L. H. Hurley, et al.,
J. Am. Chem. Soc.
1990, 112, 4633; M. A. Warpehoski, et al.,
J. B
Lewis Donald G.
Stockton Laura L.
The Scripps Research Institute
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