Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-08-16
2004-02-24
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S529000, C514S546000, C540S519000, C560S139000, C568S376000, C568S719000
Reexamination Certificate
active
06696436
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the general field of steroid chemistry, particularly to estrone derivatives, and more particularly to B-ring expanded estra-1,3,5(10)-triene compounds. The invention also relates to the field of anti-mitotic, anti-tumor, and anti-angiogenic therapeutics, particularly to the field of therapeutics that function by modulation of the polymerization of tubulin and/or the depolymerization of microtubules.
BACKGROUND OF THE INVENTION
1 Tubulin polymerization and Microtubule Assembly and Disassembly.
Cell mitosis is a multi-step process that includes chromosome replication and cell division. It is characterized by the intracellular movement and segregation of organelles, including mitotic spindles and the replicated chromosomes. Organelle movement and segregation are dependent upon the polymerization of the heterodimeric cell protein tubulin into structures called microtubules. Successful cell division is therefore dependent upon the proper polymerization of tubulin, and also upon the proper functioning and subsequent disassembly of the resulting microtubules.
Tubulin and microtubules are sensitive to a variety of antimitotic drugs. For example, colchicine and nocadazole are anti-mitotic drugs that bind tubulin and inhibit tubulin polymerization, preventing microtubule formation. As such they have anti-tumor activity. In contrast, the anti-cancer drug TAXOL™ binds to and stabilizes the microtubules, inhibiting depolymerization and thereby interfering with the later stages of mitosis. Thus, compounds that inhibit either the polymerization or depolymerization of tubulin are potential antitumor agents. For reviews, see E. Hamel,
Med. Res. Rev.
16:207-231 (1996) and L. Wang et al.,
Cancer Chemother Pharmacol,
44:355-361 (1999).
Three major pharmacological sites are present on tubulin: the colchicine site, the vinca alkaloid domain, and the “taxoid” site. The latter site is fully developed only in tubulin polymers with a well-defined protofilament substructure. Parness and Horwitz,
J Cell. Biol.
91:479-487 (1981); Takoudju et al.,
FEBS Lett
227:96-98 (1988).
2. Non-steroidal Modulators of Tubulin Polyimerization.
Colchicine and nocadazole are anti-mitotic drugs that bind tubulin and inhibit tubulin polymerization. When used alone or in combination with other therapeutic drugs, colchicine in particular may be used to treat cancer. See for example PCT application WO 93/03729, and Japanese patent 03240726 (1991). Allocolchicines, with a 7-membered B ring but 6-membered C ring, have been reported, some of which are more active than the corresponding colchicines. Ionio,
Heterocycles
22:2207-2211 (1984); Kang et al.
J Biol. Chem.
265:10255-10259(1990)).
There are several cytotoxic vinca alkaloids that operate by the mechanism of inhibition of tubulin polymerization. P. Verdier-Pinard et al.,
Biochem. Pharmacol.
58:959-971 (1999). In particular, the vinca alkaloid vinorelbine (NAVELBINE™) is a potent inhibitor of tubulin polymerization that is currently approved for certain solid tumors. (Piccart,
Cancer Treat. Rev.,
23:S59 (1997). Cryptophycin is an even more potent inhibitor that is currently under investigation. D. Panda, Biochemistry, 36:12948 (1997).
Paclitaxel (TAXOL™) and docetaxel (TAXOTERE™) are examples of the taxane class of antimitotics, which bind to microtubules much more strongly than they do to individual tubulin molecules. They have the effect of accelerating tubulin polymerization, and stabilizing the microtubules against disassembly, which prevents successful completion of the mitotic process. For reviews, see Rowinsky,
Ann. Rev. Med.,
48:353 (1997), deFurla,
Phytomedicine
4:273 (1997), and Balasubramanian et al.,
Ann. Reports Med. Chem.,
33:151-162. These compounds are moderately effective against certain solid tumors. A combination of paclitaxel with vinorelbine has recently been approved by the F.D.A.
Compounds with similar biological effects to those of paclitaxel and docetaxel include discodermolide, eleutherobin, sarcodictyin, and the epothilones. These compounds are in various stages of study and/or development as anti-tumor agents.
3. Steroidal Modulators of Tubulin Polymerization.
Among antimitotic agents that appear to bind at the colchicine site are synthetic analogs of estradiol, such as diethylstilbestrol and estramustine, and the major endogenous metabolite of estradiol, 2-methoxyestradiol (“2ME”). See for example R. D'Amato et al.,
Proc Natl Acad Sci USA,
91:3964-3968 (1994); M. Lottering et al.,
Cancer Res.
52:5926-5923 (1992); L. Spicer and J. Hammond,
Mol. and Cell. Endo.
64:119-126 (1989); S. Rao and Engelberg,
J Exp. Cell Res.
48:71-81 (1967).
2-Methoxyestradiol (2ME) is a naturally occurring mammalian metabolite of estradiol; it has very low affinity for the estrogen receptor. H. Breuer and R. Knuppen,
Naturwissenschafte
12:280-281 (1960); H. Gelbke and R. Knuppen,
Steroid Biochem.,
7:457-463 (1976). Interest in 2ME has been stimulated by its cytotoxicity in cancer cell cultures, which is characterized by uneven chromosome distribution, faulty spindle formation, inhibition of DNA synthesis and mitosis, and an increase in the number of abnormal metaphases. J. Seegers et al.,
J Steroid Biochem.
32:797-809 (1989); M. Cushman et al,.
J Med. Chem.
38:2041-2049 (1995).
2ME has been shown to bind to the colchicine binding site of tubulin, resulting in inhibition of tubulin polymerization and/or formation of polymer with altered stability properties and morphology. Hamel et al.,
Biochemistry
35:1304-1310 (1996). Recent in vitro and in vivo results have shown that 2ME inhibits angiogenesis and tumor growth. Fotsis et al.,
Nature
368:237-239 (1994); Klauber et al.,
Cancer Res.
57:81-86 (1997).
Efforts have been made to investigate the structure-activity relationships of 2ME and its analogues, in an effort to design more potent anticancer agents. Most work has been directed at modifications in the steroid A ring, which is presumed to be analogous to the colchicine tropolonic C ring. Among the compounds reported, 2-ethoxyestradiol (2EE) has greater inhibitory effects on tubulin polymerization and is 10-fold more cytotoxic than 2ME. Some 6-substituted 2-ethoxyestradiols were synthesized and also demonstrated promising biological activities. Estradiol analogs bearing acetyl groups at positions C-2 and/or C-17 have also been evaluated for their effects on tubulin polymerization, but had minimal or no effect on tubulin polymerization. H.-M. He and M. Cushman,
Bioorg. Med. Chem. Lett.
4:1725-1728 1994); M. Cushman et al.,
J. Med. Chem.
38:2041-2049 (1995); M. Cushman et al.,
J. Med. Chem.
40:2323-2334 (1997).
Miller et al.,
J Med. Chem.
40:3836-3841 (1997) disclosed 7-membered tropolonic A ring analogs of 2ME, which were designed to enhance the similarity of the steroid A ring to the C ring of colchicine. They found several of these A-homoestranes to be highly active inhibitors of tubulin assembly.
4. B-Homoestra-1 .3.5(10)-trienes.
B-Homoestra-1,3,5(10)-trienes are a little-known and very little-studied class of compounds. There have been few reported syntheses of such compounds, and even fewer biochemical or pharmaceutical studies. To the best of the present inventors' knowledge, the five references discussed below constitute the known prior art in this area.
L. W. Rampy, in a thesis entitled “Total Synthesis of B-homoestrone and Approaches to Azaestrones” (1967, University of Michigan, Ann Arbor Mich.;
Chemical Abstracts
68:96028;
Diss. Abstr.
B 1967, 28(6):2364) described the first total synthesis of racemic “B-homoestrone” (3-hydroxy-B-homoestra-1,3,5(10)-trien-17-one). Eleven intermediates and derivatives having 3-hydroxy and 3-methoxy groups were described. None of the compounds disclosed had more than a single hydroxy or methoxy group on the A ring, and this group was always at the 3-position. No biological or biochemical activity of the compounds was disclosed, although “B-homoestrone” was prepared for the stated purpose of investigating its po
Cushman Mark S.
Hamel Ernest
Badio Barbara P.
Leydig , Voit & Mayer, Ltd.
The United States of America as represented by the Department of
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