Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-05-11
1996-07-16
Ford, John M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544198, C07D25170, C07D40304, A61K 3153
Patent
active
055367224
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to 2,4,6 triaminotriazines and their use as sensitizers of tumor cells to anticancer agents.
In cancer chemotherapy the effectiveness of anticancer drugs is often limited by the resistance of tumor cells. Some tumors such as of the colon, pancreas, kidney and liver are generally innately resistant, and other responding tumors often develop resistance during the course of chemotherapy. The phenomena of multidrug resistance (MDR) is characterized by the tumor cell's cross-resistance to target of resistance include adriamycin, daunomycin, vinblastine, vincristine, daxol, actinomycin D and etoposide. The resistance cells are often associated with overexpression of the mdrl gene. This gene product is a family of 140-220 kd trans-membrane phosphoglycoprotein (P-glycoprotein) which functions as an ATP-dependent efflux pump. Thus, it has been postulated that this efflux mechanism keeps the intracellular level of the anticancer drug low, allowing the tumor cells to survive.
In recent years various substances such as verapamil, nifedipine and diltiazem have been used in vitro experimental systems to reverse the MDR phenomena. More recently some of these agents have been tested clinically as MDR reversing agents. Little efficacy has been observed with verapamil or trifluoroperazine. Thus, there is a need for an effective MDR reversing agent.
2,4,6-Triamino-1,3,5-triazines are reported to be useful in the treatment of tissue hypoxia in European Patent Application 90733A.
SUMMARY OF THE INVENTION
The compounds of the present invention are of the formula ##STR1## and the pharmaceutically acceptable acid addition salts thereof wherein R.sub.1 and R.sub.2 are taken with the nitrogen atom to which they are attached and form a moiety of the formula ##STR2## where R.sub.7 is hydrogen, alkyl of one to three carbon atoms or dialkoxyphenylalkyl said alkoxy each of one to three carbon atoms and said alkyl of one to three carbon atoms, Q and Q.sup.1 are each hydrogen, alkyl of one to three carbon atoms, alkoxy of one to three carbon atoms, fluoro, bromo, iodo, chloro, trifluoromethyl, amino, alkylamino having one to three carbon atoms or dialkylamino having two to six carbon atoms and Q and Q.sup.1 taken together are methylenedioxy or ethylenedioxy; R.sub.3 is hydrogen, or alkyl of one to three carbon atoms, R.sub.4 is (a) hydrogen, (b) alkyl of one to three carbon atoms, (c) aralkyl of the formula ##STR3## where X and X.sup.1 are each hydrogen, alkyl of one to three carbon atoms, hydroxy, alkoxy of one to three carbon atoms, fluoro, chloro, bromo, iodo, trifluoromethyl, amino, alkylamino of one to three carbon atoms or dialkylamino of two to six carbon atoms, X and X.sup.1 taken together are methylenedioxy or ethylenedioxy, n is an integer of 0 to 1 and X.sup.2 is hydrogen, alkoxy of one to three carbon atoms or hydroxy or (d) aralkyl of the formula ##STR4## where Z and Z.sup.1 are each hydrogen, alkyl of one to three carbon atoms, hydroxy, alkoxy of one to three carbon atoms, fluoro, chloro, bromo, iodo, trifluoromethyl, amino, alkylamino of one to three carbon atoms or dialkylamino of two to six carbon atoms, Z and Z.sup.1 taken together are methylenedioxy or ethylenedioxy, m is an integer of 0 or 1, W is O,S or a chemical bond and A is alkylene of two to four carbon atoms and R.sub.3 and R.sub.4 when taken together with the nitrogen to which they are attached to form a moiety of the formula ##STR5## where P and P.sup.1 are each hydrogen, alkyl of one to three carbon atoms, alkoxy of one to three carbon atoms, fluoro, bromo, iodo, chloro, amino, alkylamino of one to three carbon atoms or dialkylamino of two to six carbon atoms, P and P.sup.1 taken together are methylenedioxy or ethylenedioxy and R.sub.8 is hydrogen, alkyl of one to three carbon atoms or dialkoxyphenylalkyl said alkoxy each of one to three carbon atoms and said alkyl of one to three carbon atoms; R.sub.5 is (a) hydrogen, (b) alkyl of one to three carbon atoms, (c) benzodioxan-2-ylmethyl, (d) aralkyl of the
REFERENCES:
patent: 4514398 (1985-04-01), Regnier et al.
D. Boesch et al., Cancer Research, 51, 4226-4233, Aug. 15, 1991.
Twentyman et al., Cancer Chemotherapy and Pharmacology (1991) 29: 24-28.
Sato et al., Cancer Research 51, 2420-2424, May 1, 1991.
T. Tsuruo, Xenobiotics and Cancer, L. Ernster et al. (Eds.), Japan Sci. Soc. Press, Tokyo/Taylor & Francis Ltd., London, pp. 241-251, 1991.
Fojo et al., Cancer Research, 45, 3002-3007, Jun. 1985.
T. Kaneko, Current Opinion in Therapeutic Patents, Jul. 1991.
D. Hochhauser and A. L. Harris, Brit. Med. Bull., 47, 178-190 (1991).
W. T. Bellamy, W. S. Dalton and R. T. Dorr, Cancer Invest., 8, 547-562 (1990).
Gottesman et al., J. Biol. Chem., vol. 263, No. 25, pp. 12163-12166, 1988.
Coe Jotham W.
Fliri Anton F. J.
Kaneko Takushi
Larson Eric R.
Benson Gregg C.
Conway John D.
Ford John M.
Pfizer Inc.
Richardson Peter C.
LandOfFree
Triazine derivatives for enhancing antitumor activity does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Triazine derivatives for enhancing antitumor activity, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Triazine derivatives for enhancing antitumor activity will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1784456