Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-05-05
1995-08-22
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514267, 544250, 544291, A61K 31505, C07D23995
Patent
active
054440629
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to 2,4-diaminoquinazolines and their use as sensitizers of tumor cells to anticancer cells.
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 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 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.
The 2,4-diaminoquinazolines are prepared by known methods utilizing 2,4-dichloroquinazolines [Postovskii and Goncharova, Zh. Obsch. Khim., 32, 3323 (1962)]. Curd et al. (J. Chem. Soc., 1947, 775) reported the synthesis of 2,4-dichloroquinazolines from the corresponding 2,4(1H, 3H)quinazolinedione. The Wellcome Foundation discloses 2,4-diaminoquinazolines of general structure D as antibacterials [GB patent 806772 (1958)]. Hess [U.S. Pat. No. 3,511,836 (1970)] patented compounds of structures E, F, and G as antihypertensive agents. Wijbe [GB patent 1,390,014 (1975)] patented a process for compounds of structure H and these compounds are claimed to be antibacterials. Lacefield [U.S. Pat. No. 3,956,495 (1976)] describes compounds of the general formula I as antithrombotic agents. Crenshaw [U.S. Pat. No. 4,098,788 (1978)] patented a process for the production of compounds of formula J. Hess [European Patent 0,028,473 (1981)] describes chloro- and alkoxy-substituted 2,4-diaminoquinazolines of formula K. Ife et al. describe compounds of general structur L as inhibitors of gastric acid secretion [WO 89/0527 (1989)]. Compounds of structures M and N were published as phosphodiesterase inhibitors [Miller, J. Med. Chem., 28, 12 (1985)]. Richter et al. published compounds of structur O as inhibitors of dihydrofolate reductase [J. Med. Chem., 17, 943 (1974)]. In search of compounds with herbicidal activity Miki et al. reported the synthesis of 2,4-dialkglaminoquinazolines (P) (Chem. Pharm. Bull. 30, 2313 (1982)]. Arylazidoprazosin (Q) has been shown to bind to P-glycoprotein [Safa et al., Biochem. Biophys. Res. Comm. 166, 259 (1990)]. ##STR1##
SUMMARY OF THE INVENTION
The compound of the present invention are of the formula ##STR2## or a pharmaceutically acceptable acid addition salt thereof where X and X.sup.1 are each hydrogen, alkyl of one to four carbon atoms, iodo, bromo, nitro, chloro, fluoro, methylthio, amino, alkylamino of one to three carbon atoms, methylsulfinyl, aminomethyl, (CH.sub.3).sub.2 S.sup..sym., dialkylaminomethyl of three to seven carbon atoms, hydroxymethyl, morpholino, thiomorpholino, benzoylamino, substituted benzoylamino wherein said substituent is azido, methoxy, methyl, fluoro, chloro, or trifluoromethyl, alkanoylamino having two to four carbon atoms, 4-methylpiperazino, piperazino, piperidino, pyrrolidino, dialkylamino of two to six carbon atoms or alkoxy of one to four carbon atoms; X.sup.2 is hydrogen, alkyl of one to four carbon atoms or alkoxy of one to four carbon atoms; X and X.sup.1 together are ethylenedioxy or methylenedioxy; R.sub.1 is alkyl having one
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Coe Jotham W.
Fliri Anton F. J.
Kaneko Takushi
Larson Eric R.
Grumbling Matthew V.
Pfizer Inc.
Richardson Peter C.
Shah Mukund J.
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