Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2001-07-31
2003-10-07
Cook, Rebecca (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Reexamination Certificate
active
06630511
ABSTRACT:
BACKGROUND
1. Field of the Invention
The present invention relates to new salts of 2-difluoromethyl-2,5-diaminopentanoic acid (DFMO).
2. Technical Field
This patent relates to new salts of 2-difluoromethyl-2,5-diaminopentanoic acid (DFMO) with polycations such as polycationic carbohydrates (chitosan, water-soluble chitosan derivative, or a salt thereof) or a polyaminoacid, a polyamine, a polypeptide, a basic polymer, a quartinary ammonium compound or a mixture thereof, the processes for obtaining them and to therapeutic uses of these new salts. DFMO, in vitro and in vivo, is an inhibitor of ornithine decarboxylase, an enzyme that is involved in polyamine formation in organisms.
BACKGROUND OF THE INVENTION
In both eukaryotic and prokaryotic cells, the decarboxylation of ornithine to putrescine, a reaction catalyzed by ornithine decarboxylase (ODC), is the first step in the biosynthesis of the polyamines known as spermidine and spermine. The polyamines, which are found in animal tissues and microorganisms, are known to play an important role in cell growth and proliferation. The onset of cell growth and proliferation is associated with a marked increase in ODC activity and an increase in the levels of putrescine and the polyamines. Although the exact mechanism of the role of the polyamines in cell growth and proliferation is not known, it appears that the polyamines may facilitate macromolecular processes such as DNA, RNA, or protein synthesis. (Tabor H, Tabor C W, Cohn M S, Hafner E W. Streptomycin resistance produces an absolute requirement for polyamines for growth on an
Escherichia coli
strain unable to synthesize spermidine. J Bacteriolol 1981; 147: 702-4; Mamont P S, Bohelen, P, McCann P P, Bey P, Schuber R, Tardif C. Alpha-methyl ornithine, a potent competitive inhibitor of ornithine decarboxylase, blocks proliferation of rat hepatoma cells in culture. Proc Natl Acad Sci USA
1976; 73: 1626-30.)
The association between high levels of the polyamines and rapid proliferation was discovered more than a quarter of a century ago. (Bachrach U and Weinstein A. Effect of aliphatic polyamines on growth and macromolecular syntheses in bacteria. J. Gen. Microbiol., 60: 159-165 1970.) Subsequent studies showed that activation of the enzyme ODC was important for carcinogenesis and subsequent tumor development in animal and tumor models. (Weeks C E, Hrrmann A L, Nelson F R, Slaga T J. Alpha difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase, inhibits tumor promoter-induced polyamine accumulation and carcinogenesis in mouse skin. Proc Natl Acad Sci USA 1982; 79:6028-32.)
It is currently known that increased intracellular polyamine concentrations are related to human neoplastic conditions. (Verma, A K Inhibition of tumor promotion by DL-alphadifluoromethylornithine, specific irreversible inhibitor of ornithine decarboxylase. Basic Life Sci., 52:195-204, 1990). A further example of this relationship between high polyamine concentrations and neoplasms involves colonic polyps and cancers compared to surrounding normal colon mucosa. (Hixson, L J, Garewal, H S, McGee D., Sloan D, Fennerty, M B, Sampliner R E and Gemer E W. Omithine decarboxylase and polyamines in colorectal neoplasia and adjacent mucosa. Cancer Epidemiol. Biomark. Prev. 2;369-374, 1993; Rozhin J, Wilson P S, Bull A W, and Nigro, N D. Ornithine decarboxylase activity in the rat and human colon. Cancer Res. 44: 3226-3230, 1984.)
Other groups have reported that polyamine metabolism was necessary for carcinogenesis, especially in epithelial tissues. ODC inhibitors have been found to inhibit or suppress tumor formation in models of bladder, breast, colon and skin carcinogenesis. (Verma, A K Inhibition of tumor promotion by DL-alpha-difluoromethylornithine, specific irreversible inhibitor of ornithine decarboxylase. Basic Life Sci., 52:195-204, 1990; Nigro N D, Bull A W and Boyd, M E. Inhibition of intestinal carcinogenesis in rats: effect of difluoromethylornithine for colon cancer prevention. J. Natl Cancer Inst. 77: 1309-1313, 1986; Thompson H J, and Ronan Am. Effect of DL-2-difluoromethylornithine and endocrine manipulation on the induction of mammary carcinogenesis by 1-methyl-1-nitrosourea. Carcinogenesis (Lond.), 7: 20032006, 1986.)
It is thought, however, that the mechanism of cancer prevention by ODC inhibitors such as DFMO may involve more than just inhibition of cell proliferation. Animal studies show that DFMO may act at later stages in models of chemical carcinogenesis. These stages involve the transition of non-invasive tumors to invasive cancers. (Slaga, T J. Multistage skin carcinogenesis: a useful model for the study of the chemoprevention of cancer. Acta Pharmacol. Toxicol., 55 (Suppl. 2): 107-124, 1984.)
DFMO has been studied and continues to be studied as a cancer prevention agent, especially in skin, cervical and colon cancer. (Love R R, Carbone, P P Verma, A K, Gilmore D, Carey P, Tutsch K D. Pomplun M, and Wilding G. Randomized Phase I chemoprevention dose-seeking study of alpha-difluoromethylornithine. J. Natl. Cancer Inst., 85:732-736, 1993; Nishioka K, Melgarejo A B, Lyon R R and Mitchell M F. Polyamines as biomarkers of cervical intraepithelial neoplasia. J. Cell. Biochem., 23 (Suppl.): 87-95, 1995; Mitchell M F, Tortolero-Luna G, Lee J J, Hittelman W N, Lotan R, Wharton J T, Hong, W K and Nishioka, K. Phase I dose de-escalation trial of alpha-difluoromethylornithine in patients with grade 3 cervical intraepithelial neoplasia. Clin. Cancer Res., 4:303-310, 1998; Meyskens F I, Emerson S S, Pelot D, Meshkinpour H, Shassetz R, Einspahr J, Alberts D S, and Gerner, E W. Dose de-escalation chemoprevention trial of alpha-difluoromethylornithine in patients with colon polyps. J. Natl. Cancer Inst., 86:1122-1130, 1994.)
While high doses of DFMO in humans can cause some problems with hearing (reversible upon discontinuation of DFMO), at the doses used for chemoprevention of cancer (0.50 g/m2/day) such concerns have been found to be groundless. (Meyskens F L, Gerner E, Emerson S, Pelot D, Durbin T, Doyle K and Lagerber W. A randomized double-blind placebo controlled Phase IIb trial of difluoromethylornithine for colon cancer prevention. J. Natl. Cancer Inst., 90: 1212-1218, 1998).
DFMO has also been found useful in conditions unrelated to cancer. ODC inhibitors have been associated with control of hair growth. Studies in mice have suggested that the ODC gene is an important regulatory gene for the mouse hair follicle. (Soler A P, Gilliard G, Megosh L C, O'Brien T G.J Modulation of murine hair follicle function by alterations in ornithine decarboxylase activity. Invest Dermatol 1996 May;106(5):1108-13.) The FDA, to control facial hair growth in women, has recently approved DFMO. (Current DFMO salts, when used topically, cause burning, irritation and inflammation.) DFMO may have use in controlling male facial hair growth as well and may constitute a methodology to supplant or reduce the use of razors to remove facial hair in men. New DFMO salts, which are the subject of this invention, have been shown to be less irritating, do not cause burning and inflammation when applied topically.
REVIEW OF PRIOR ART
U.S. Pat. No. 4,330,559, May 18, 1982, Bey, et al. discloses the use of DFMO to treat benign prostatic hypertrophy. U.S. Pat. No. 4,399,151, Aug. 16, 1983, Sjoerdsma, et al. discloses the use of 2-(difluoromethyl)-2,5-diaminopentanoic acid (DFMO) for inhibiting the growth of protozoa. U.S. Pat. No. 4,405,530, Sep. 20, 1983, Gerhart, discloses the preparation of fluorinated amino-nitriles. These patents do not disclose the preparation or use of new DFMO salts of the present invention made with chitosan or polycations.
U.S. Pat. No. 4,413,141, Nov. 1, 1983 Bey, et al. discloses 2-(difluoromethyl)2,5-diaminopentanoic acid (DFMO) and the methods for the preparation and use thereof U.S. Pat. No. 4,499,072, Feb. 12, 1985, Sunkara, et al. discloses the use of DFMO as an ODC inhibitor along with interferon in treating diseases. U.S. Pat. No. 4,720,489, Jan. 19, 1988, Shander, discloses the u
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