Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-04-28
1999-09-28
Gupta, Yogendra N.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514 45, 514263, 544265, 544266, 544267, A61K 3152, C07D47304, C07D47318
Patent
active
059589329
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD OF THE INVENTION
The present invention relates to substituted O.sup.6 -benzylguanines, O.sup.6 -benzyl-8-azaguanines, and 6(4)-benzyloxypyrimidines, pharmaceutical compositions comprising such compounds, and methods of using such compounds. The subject compounds are particularly useful in inactivating the human DNA repair protein O.sup.6 -alkylguanine-DNA alkyltransferase.
BACKGROUND OF THE INVENTION
The inactivation of the human DNA repair protein O.sup.6 -alkylguanine-DNA alkyltransferase (AGT) by O.sup.6 -benzylguanine leads to a dramatic enhancement in the cytotoxic response of human tumor cells and tumor xenografts to chemotherapeutic drugs whose mechanism of action involves modification of DNA guanine residues at the O.sup.6 -position (Dolan et al., Proc. Natl. Acad. Sci. U.S.A., 87, 5368-5372 (1990); Dolan et al., Cancer Res., 51, 3367-3372 (1991); Dolan et al., Cancer Commun., 2, 371-377 (1990); Mitchell et al., Cancer Res., 52, 1171-1175 (1992); Friedman et al., J. Natl. Cancer Inst., 84, 1926-1931 (1992); Felker et al., Cancer Chem. Pharmacol., 32, 471-476 (1993); Dolan et al., Cancer Chem. Pharmacol., 32, 221-225 (1993); Dolan et al., Biochem. Pharmacol., 46, 285-290 (1993)). The AGT inactivating activity of a large number of O.sup.6 -benzylguanine analogs have been compared with the aim of obtaining information about the types of substituent groups and the sites at which they could be attached to O.sup.6 -benzylguanine without significantly lowering its AGT-inactivating activity (Moschel et al., J. Med. Chem., 35, 4486-4491 (1992); Chae et al., J. Med. Chem., 37, 342-347 (1994)). While these studies led to the production of a variety of analogs that were as potent or somewhat less potent than O.sup.6 -benzylguanine, none of the analogs were better than O.sup.6 -benzylguanine.
Thus, there remains a need for additional compounds which are capable 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. The present invention provides such compounds and associated pharmaceutical compositions and treatment methods. These and other objects and advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.
BRIEF SUMMARY OF THE INVENTION
The present invention provides 7- and 8-substituted O.sup.6 -benzylguanine derivatives, 7,8-disubstituted O.sup.6 -benzylguanine derivatives, 7,9-disubstituted O.sup.6 -benzylguanine derivatives, 8-aza-O.sup.6 -benzylguanine derivatives, and 4(6)-substituted 2-amino-5-nitro-6(4)-benzyloxypyrimidine and 2-amino-5-nitroso-6(4)-benzyloxypyrimidine derivatives which have been found to be effective AGT inactivators, as well as pharmaceutical compositions comprising such derivatives along with a pharmaceutically acceptable carrier. The present invention further provides 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, by administering to a mammal an effective amount of one of the aforesaid derivatives, 2,4-diamino-6-benzyloxy-s-triazine, 5-substituted 2,4-diamino-6-benzyloxypyrimidines, or 8-aza-O.sup.6 -benzylguanine, and administering to the mammal an effective amount of an antineoplastic alkylating agent which causes cytotoxic lesions at the O.sup.6 -position of guanine.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention provides a compound of the formula I ##STR2## wherein R.sub.1 is a substituent selected from the group consisting of amino, hydroxy, C.sub.1 -C.sub.4 alkylamino, C.sub.3 -C.sub.4 dialkylamino, and C.sub.1 -C.sub.4 acylamino (although, as explained in further detail below, other substituents can be placed at this 2-position), R.sub.2 is a substituent selected from the group consisting of hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 aminoalkyl, C.sub.1 -C.sub.4 hydroxyalk
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: 5352669 (1994-10-01), Moschel et al.
patent: 5358952 (1994-10-01), Moschel et al.
patent: 5364904 (1994-11-01), Farmer et al.
patent: 5547932 (1996-08-01), Curiel et al.
patent: 5691307 (1997-11-01), Moschel et al.
patent: 5731304 (1998-03-01), Baer et al.
patent: 5753668 (1998-05-01), Moschel et al.
American Chemical Society, Chemical Abstracts Service Registry Handbook, No. Section 1965-1971 11267R, col. 3, Registry No. 30360-74-8 (published mid 1970's).
Beecham Group, "Preparation of Guaninie Derivatives and Their Use in Antiviral Preparations," 28-Heterocyles, 103:123509a (1985).
Biasacchi et al., Preparation of lobutyl!-6H-purin-6-one, Chem. Abs., 115-159683q , 1991.
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," J. 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).
Chemical Abstract 72: 100650 (1970).
Chemical Abstract 107: 194511 (1987).
Chemical Abstract 112:216531 (1989).
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., "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).
Gerster et al., J. Am. Chem. Soc., 87, 3752-3759 (1965).
Gerson et al., "Synergistic Efficacy of O.sup.6 -Benxzylguanine and 1,3-Bis(2-Chloroethyl.sub.-- -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," 33-Carbohydrates, 97:182809d (1982).
Hannah et al., "Substituted Butylguanines and Their Utilization in Antiviral Compositions," 26-B
Chae Mi-Young
Dolan M. Eileen
Moschel Robert C.
Pegg Anthony E.
ARCH Development Corporation
Gupta Yogendra N.
Penn State Research Foundation
Rao Deepak
The United States of America as represented by the Secretary of
LandOfFree
Substitutes O.sup.6 -benzylguanines, compositions, and methods o does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Substitutes O.sup.6 -benzylguanines, compositions, and methods o, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substitutes O.sup.6 -benzylguanines, compositions, and methods o will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-703558