Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-08-17
1996-12-10
Berch, Mark L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514266, 544250, 544277, 544278, C07D47316, C07D49504, A61K 31505
Patent
active
055831370
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/US92/09554.
TECHNICAL FIELD
This invention relates to certain heterocyclic compounds and their use as sensitizers of tumor cells to anticancer agents.
BACKGROUND ART
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 cells cross-resistance to 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 phosphoglycoproteins (P-glycoprotein) which function 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.
2-Piperazino-4-morpholinothieno[3,2-d]pydmidines are reported in German Often. 2,055,085 [CA 77, 88539f (1972)].
Thienopyrimidines and pyridopyrimidines are claimed as gastric acid secretion inhibitors in European Patent Application 404,356 and 404,355, respectively.
DISCLOSURE OF THE INVENTION
The compounds of the present invention are of the formulae ##STR1##
and a pharmaceutically acceptable acid addition salt thereof where R is hydrogen, alkyl of one to three carbon atoms or phenylalkyl of seven to ten carbon atoms; R.sub.1 and R.sub.3 are each hydrogen or alkyl of one to three carbon atoms; R.sub.2 and R.sub.4 are each aralkyl of the formula ##STR2##
where X and X.sup.1 are each hydrogen, alkyl of one to three carbon atoms, alkoxy of one to three carbon atoms, hydroxy, fluoro, chloro, 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 or 1, W is S, 0 or a chemical bond and A is alkylene of two to four carbon atoms; and R.sub.1 and R.sub.2 or R.sub.3 and
R.sub.4 when taken together with the nitrogen to which they are attached each form a moiety of the formula ##STR3##
where R.sub.6 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 and 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.
A preferred group of compounds are those of formula I, where R is phenylalkyl of seven to ten carbon atoms; R.sub.1 and R.sub.2 taken together with the nitrogen to which they are attached form a moiety of the formula ##STR4##
where R.sub.6 is hydrogen and Y and Y.sup.1 are each alkoxy of one to three carbon atoms; R.sub.3 is hydrogen; and R.sub.4 is aralkyl of the formula ##STR5##
where X and X.sup.1 are each alkoxy of one to three carbon atoms, n is 0, W is a chemical bond and A is ethylene. Especially preferred within this group are the compounds where R is 1-phenylethyl; Y is 6-methoxy and Y.sup.1 is 7-methoxy; and X is 3-methoxy and X.sup.1 is 4-methoxy and where R is benzyl; Y is 6-methoxy and Y.sup.1 is 7-methoxy; and X is 3-methoxy and X.sup.1 is 4-methoxy.
A second group of preferred compounds are those of formula II where R is alkyl of one to three carbon atoms or phenylalkyl of seven to ten carbon atoms; R.sub.1 and R.sub.2 taken together with the nitrogen to which they are
REFERENCES:
Fojo, Cancer Res. 45, 3002-7 (1985).
Tsuruo in "Xenobiotics and Cancer", pp. 241-251 (1991).
Gottesman, J. Biol. Chem., 263, p. 12163 (1988).
Mmardanov, Chem. Abs., 84, 85431 (1975).
Bellamy, Cancer Inves., 8, 547 (1990).
Kaneko, Current Opinion in Therapeutic Patents, p. 1043 (Jul. 1991).
Hochhauser, Brit. Med. Bull. 47, pp. 178-196 (1991).
Coe Jotham W.
Fliri Anton F. J.
Kaneko Takushi
Larson Eric R.
Benson Gregg C.
Berch Mark L.
Conway John D.
Pfizer Inc.
Richardson Peter C.
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