Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Patent
1993-10-14
1996-02-13
Tsang, Cecilia
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
544298, 544324, C07D23902, C07D40104, A61K 31505
Patent
active
054912342
DESCRIPTION:
BRIEF SUMMARY
This application is the 371 of PCT/US92/02434, filed Mar. 30, 1992.
BACKGROUND OF THE INVENTION
This invention relates to 2,4-diaminopyrimidines 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 structurally unrelated drugs. The drugs which are the target of resistance include adriamycin, daunomycin, vinblastine, vincristine, actinomycin D and etoposide. The resistance cells are often associated with over-expression of the mdr1 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 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.
Fukazawa, et al. describes a series of heterocyclic compounds (EP Application No. 89310235.0) useful as anticancer-drug reinforcing agents. This same utility is also claimed for a series of pteridine derivatives (EP Application No. 89117610.9).
Tomino, et al. (EP Application No. 89313595.4) claims a series of pyrimidines, including 2,4-diaminopyrimidines, useful in the treatment of neurological diseases.
A series of 2,4,6-triaminopyrimidine-N-oxides (U.S. Pat. No. 4,945,093) are described as being useful for promoting hair growth.
SUMMARY OF THE INVENTION
The compounds of the present invention are of the formula ##STR1## and the pharmaceutically acceptable salts thereof wherein M is hydrogen, alkoxy of one to three carbon atoms, alkyl of one to three carbon atoms or benzyl optionally substituted by one or two alkoxy substituents each having one to three carbon atoms, chloro, fluoro, amino, alkylamino of one to three carbon atoms, dialkylamino of two to six carbon atoms or trifluoromethyl; M.sup.1 is hydrogen, amino, alkylamino of one to three carbon atoms, dialkylamino of two to six carbon atoms, alkyl of one to three carbon atoms, fluoro or chloro; R.sub.1 is aralkyl of the formula ##STR2## wherein n is an integer of 0 or 1, W is O, S or a chemical bond, A is alkylene of one to four carbon atoms, Y and Y.sup.1 are each hydrogen, alkyl of one to three carbon atoms, alkoxy of one to three carbon atoms, fluoro, chloro, trifluoromethyl, amino, alkylamino of one to three carbon atoms or dialkylamino of two to six carbon atoms and Y and Y.sup.1 when taken together are ethylenedioxy or methylenedioxy; R.sub.2 is hydrogen or alkyl of one to eight carbon atoms; R.sub.1 and R.sub.2 when taken together with the nitrogen atom to which they are attached form a moiety of the formula ##STR3## where R.sub.5 is hydrogen, alkyl of one to three carbon atoms or dialkoxyphenylalkyl said alkoxy having one to three carbon atoms and said alkyl having from 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, chloro, trifluoromethyl, amino, alkylamino of one to three carbon atoms or dialkylamino of two to six carbon atoms and Q and Q.sup.1 taken together are methylenedioxy or ethylenedioxy; R.sub.3 is aralkyl of the formula ##STR4## where m is an integer of 0 or 1, Z is 0, S or a chemical bond, B is alkylene of one to four carbon atoms, X and X.sup.1 are each hydrogen, alkyl of one to three carbon atoms, alkoxy of one to three carbon atoms, fluor
REFERENCES:
patent: 3670077 (1972-06-01), Freeman et al.
patent: 3974162 (1976-08-01), Santilli et al.
patent: 4003699 (1977-01-01), Rose et al.
patent: 4945093 (1990-07-01), Maignan et al.
M. Naito et al., Cancer Chemother. Pharmacol., (1992) 29:195-200.
D. Boesch et al., Cancer Research, 51, 4226-4233, Aug. 15, 1991.
P. R. Twentyman, Eur. J. Cancer, vol. 27, No. 12, pp. 1639-1642, 1991.
T. Kaneko, Current Opinion in Therapeutic Patents, Jul. 1991.
D. Hochhauser et al., Brit. Med. Bull., 47, 178-190, 1991.
W. T. Bellamy et al., Cancer Invest., 8, 547-562, 1990.
Gottesman et al., J. Biol. Chem., vol. 263, No. 25, pp. 12163-12166, 1988.
Fojo et al., Cancer Research, 45, 3002-3007, Jun. 1985.
Sonneveld et al., The Lancet, vol. 340, No. 8814, pp. 255-259 (1992).
T. Tsuruo, Xenobiotics and Cancer, L. Ernster et al., (Eds.), Japan Sci. Soc. Press Tokyo/Taylor and Francis Ltd., London, pp. 241-251, 1991.
W. S. Dalton et al., Cancer Invest., 8, 547-562 (1990).
Coe Jotham W.
Fliri Anton F. J.
Kaneko Takushi
Larson Eric R.
Benson Gregg C.
Conway John D.
Pfizer Inc.
Richardson Peter C.
Tsang Cecilia
LandOfFree
Pyrimidine 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 Pyrimidine derivatives for enhancing antitumor activity, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pyrimidine derivatives for enhancing antitumor activity will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-241586