Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-06-11
1998-05-19
Gupta, Yogendra N.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544321, A61K 31505, C07D23942
Patent
active
057536686
ABSTRACT:
The present invention provides certain novel nitro or nitroso substituted benzyloxy pyrimidines useful as AGT inactivators. An example of such a pyrimidine is a compound of the formula ##STR1## wherein R.sub.1, is NO.sub.2 or NO, and R.sub.2 is hydrogen, halo, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 hydroxyalkyl, thiol, C.sub.1 -C.sub.4 alkythio, trifluoromethoxy, oxymethanesulfonyl, oxytrifluoromethanesulfonyl, or C.sub.1 -C.sub.4 oxyacyl. The present invention further provides pharmaceutical compositions comprising these compounds, and a method of enhancing the chemotherapeutic treatment of tumor cells in a mammal with an antineoplastic alkylating agent which causes cytotoxic lesions at the O.sup.6 -position of guanine.
REFERENCES:
patent: 4199574 (1980-04-01), Schaeffer
patent: 4495190 (1985-01-01), Hagberg et al.
patent: 4751221 (1988-06-01), Watanabe et al.
patent: 4801710 (1989-01-01), MacCoss et al.
patent: 4965270 (1990-10-01), Harnden et al.
patent: 5075445 (1991-12-01), Jarvest et al.
patent: 5091430 (1992-02-01), Moshel et al.
patent: 5352669 (1994-10-01), Moshel et al.
patent: 5358952 (1994-10-01), Moshel et al.
patent: 5364904 (1994-11-01), Farmer et al.
patent: 5525606 (1996-06-01), Moschel et al.
Harnden et al., "Synthesis and Antiviral Activity of 1636-1642 (1987).
Beaman et al., in Zorbach and Tipson, Synthetic Procedures in Nucleic Acid Chemistry, vol. 1, pp. 41-43 (John Wiley & Sons, New York, NY, 1968).
Boon et al., J. Chem. Soc., pp. 96-102 (1951).
Chae et al., J. Med. Chem., 37, 342-347 (1994).
Chae et al., J. Med. Chem., 38, 359-365 (1995).
Crone et al., Cancer Res., 53, 4750-4753 (1993).
Daves, Jr., et al., J. Am. Chem. Soc., 82, 2633-2640 (1960).
Delia et al., Heterocycles, 20, 1805-1809 (1983).
Dolan et al., Proc. Natl. Acad. Sci. U.S.A., 87, 5368-5372 (1990).
Dolan et al., Cancer Commun.,2, 371-377 (1990).
Dolan et al., Cancer Res., 51, 3367-3372 (1991).
Dolan et al., Biochem. Pharmacol., 46, 285-290 (1993).
Dolan et al., Cancer Chem. Pharmacol., 32, 221-225 (1993).
Felker et al., Cancer Chem. Pharmacol., 32, 471-476 (1993).
Friedman et al., J. Natl. Cancer Inst., 84, 1926-1931 (1992).
Gerster et al., J. Am. Chem. Soc., 87, 3752-3759 (1965).
Jones et al., J. Am. Chem. Soc., 82, 3773-3779 (1960).
Kosary et al., Acta Pharm. Hung., 49, 241-247 (1989).
Mitchell et al., Cancer Res., 52, 1171-1175 (1992).
Moschel et al., J. Med. Chem., 35, 4486-4491 (1992).
Moschel et al., J. Org. Chem., 51, 4180-4185 (1986).
O'Brien et al., J. Med. Chem., 9, pp. 573-575 (1966).
Pfleiderer et al., Chem. Ber., 94, 12-18 (1961).
Pfleiderer et al., Liebigs Ann. Chem., 726, 201-215 (1969).
Philips et al., J. Org. Chem., 28, 1488-1490 (1963).
Ram et al., Chem. Abstr., 101, 230466q (1984).
Robins et al., J. Org. Chem., 34, 2160-2163 (1969).
Shealey et al., J. Org. Chem., 27, 4518-4523 (1962).
Wakabayashi et al., Nippon Dojo-Hiryyogaku Zasshi, 41, 193-200 (1970) (Abstract CA73: 108869m).
Wasserman et al., Cancer, 36, 1258-1268 (1975).
Beecham Group, "Preparation of Guaninie Derivatives and Their Use in Antiviral Preparations," 28-Heterocyles, 103:123509a (1985).
Biasacchi et al., Preparation of clobutyl!-6H-purin-6-one, Chem. Abs., 115:159683q.
Biasacchi et al., Synthesis and Antiviral Activity of Enantiomeric Forms of Cyclobutyl Nucleoside Analogues, J. Med. Chem., 34, 1415-1421 (1991).
Bowles et al., "Synthesis and Antitumor Activity of 9-(Tetrahydro-2-furyl)purine Analogs of Biologically Important Deoxynucleosides," . Med. Chem., 6, 471-480 (1963).
Brix et al., "Androgen-linked Alkylating Agents: Biological Activity in Methylnitrosourea-induced Rat Mammary Carcinoma," J. Cancer Res. Clinical Oncology, 116, 538-549 (1990).
Carbon et al., "Synthesis and Reactions of 5-Bromomethyl-and 5-Chloromethyluracil," J. Org. Chem., 25, 1731-1734 (1960).
Dolan et al., "Depletion of O.sup.6 -alkylguanine-DNA Alkyltransferase Activity in Mammalian Tissues and Human Tumor Xenografts in Nude Mice by Treatment with O.sup.6 -methylguanine," Cancer Chemother. Pharmacol., 25, 103-108 (1989).
Dolan et al., "Effect of O.sup.6 -Alkylguanine Pretreatment on the Sensitivity of Human Colon Tumor Cells to the Cytotoxic Effects of Chloethylating Agents," Cancer Research, 46, 4500-4505 (1986).
Dolan et al., "Comparison of the Inctivation of Mammalian and Bacterial O.sup.6 -Alkylguanine-DNA Alkyltransferases by O.sup.6 -Benzylguanine and O.sup.6 -Methylguanine," Carcinogenesis, 12 (12), 2305-2309 (1991).
Dorr et al. in Cancer Chemotherapy Handbook, 715-742 (Elsevier Science Publishing, New York, NY 1980).
Fischer et al. in Cancer Chemotherapy Handbook, 3rd ed., 4-9, 60-61, 164-165, 171 (Year Book Medical Publishers, Inc., Chicago, IL 1989).
Folkman et al., "A New One-Step Method for the Preparation of 3',5'-Bisphosphates of Acid-Labile Deoxynucleosides," Chem. Res. Toxicol., 3, 536-539 (1990).
Fondy et al., "Haloacetamido Analogues of 2-Amino-2-deoxy-D-glucose and 2-Amino-2-deoxy-D-galactose. Syntheses and Effects on the Friend Murine Erythroleukemia," J. Med. Chem., 21 (12), 1222-1225 (1978).
Ford et al., "A Simple Method for Predicting Hydration Energies of Organic Cations Derived from Protonation of Alkylation of Neutral Oxygen and Nitrogen Bases," J. Org. Chem., 48 (13), 2226-2233 (1983).
Frihart et al., "Allylic Rearrangement from O.sup.6 to C-8 in the Guanine Series," J. Am. Chem. Soc., 95 (21), 7174-7175 (1973).
Gerson et al., "Synergistic Efficacy of O.sup.6 -Benxzylguanine and 1,3-Bis(2-Chloroethyl=-Nitrosourea (BCNU) in a Human Colon Cancer Xenograft Completely Resistant to BCNU Alone," Biochem. Pharmacol., 45 (2), 483-491 (1993).
Green et al., "Preparation of Purine Acyclonucleoside Intermediates," Chem. Abs., 115:28993t (1991).
Hagberg et al., "Guanine Derivatives," Chem. Abs., 97:182809d (1982).
Hannah et al., "Substituted Butylguanines and Their Utilization in Antiviral Compositions," 26-Biomolecules, 104:68682 (1986).
Hannah et al., "Carba-acylonucleoside Antiherpetic Agents," J. Heterocyclic Chem., 26, 1261-1271 (1989).
Harnden et al., "Prodrugs of the Selective Antiherpesvirus Agent Gastrointestinal Absorption Properties," J. Med. Chem., 32, 1738-1743 (1989).
Harrison's Principles of Internal Medicine, 10th ed., 751, 758, 766-775 (1983).
Himmelsback et al., "The p-Nitrophenylethyl (NPE) Group. A Versatile New Blocking Group for Phosphate and Aglycone Protection in Nucleosides and Nucleotides," Tet., 40 (1), 59-72 (1984).
Holmes et al., "Rearrangement of Cinnamyl Groups from O.sup.6 to C-8 in the Guanine Series," J. Org. Chem., 43 (3), 516-518 (1978).
House in Modern Synthetic Reactions, 2nd ed., 536-541, 602-603 (1972).
Jacobs et al., "Synthesis of SQ-32,829, A New Nucleoside Antiviral Agent," Tet. Letters, 30 (50), 6955-6958 (1989).
Karkas et al., "Enzymatic Phosphorylation of the Antiherpetic Agent 842-848 (1986).
Kim et al., "Acyclic Purine Phosphonate Analogues as Antiviral Agents. Syntheisis and Structure-Activity Relationships," J. Med. Chem., 33, 1207-1213 (1990).
Kjellberg et al., "Regioselective Alkylation of 6-(8-Methoxyethoxy) Guanine to Give the 9-Alkylguanine Derivative," Tet. Letters, 27 (7), 877-880 (1986).
Kusmiesek et al., "Synthesis of N.sup.2,3-Ethenodeoxyguanosine, N.sup.2,3-Ethenodeoxyguanosine 5'-Phosphate, and N.sup.2,3-Ethenodeoxyguanosine 5'-Triphosphate. Stability of the Glycosyl Bond in the Monomer and in Poyl(dG,.epsilon.dG-dC)," Chem. Res. Toxicol., 2, 230-233 (1989).
Leonard et al., "Intramolecular Mechanism of the Allylic Rearrangement from O.sup.6 to C-8 in the Guanine Series Double Labeling Experiments," J. Am. Chem. Soc., 96, 5894-5903 (1974).
March in Advanced Organic Chemistry, 3rd ed., 358-359, 574-575, 802-803, 982-985 (John Wiley & Sons 1985).
MacCoss et al., "Regioselective Synthesis of 9-Substituted Purine Acyclonucleoside Derivatives," Chem. Abs., 105:115383f (1986).
MacCoss et al., "Synthesis of the Chiral Acyclonucleoside Antiherpetic Agent (S)-9-(2,3-Dihydroxy-1-Propoxymethyl)guanine," Tet. Letters, 26 (15), 1815-1818 (1985).
Mansuri et al., "Preparation of 4-phosphoromethoxycyclopent=(en)-1-ylpurines and -pyrimidines as Virucides, Bactericides,
Chae Mi-Young
Dolan M. Eileen
Moschel Robert C.
Pegg Anthony E.
ARCH Development Corporation
Gupta Yogendra N.
Penn State Research Foundation
The United States of America as represented by the Department of
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