Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Silicon containing doai
Patent
1996-07-29
1998-04-07
Grumbling, Matthew V.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Silicon containing doai
514213, 5142345, 514259, 514260, 540594, 544116, 544284, 544293, C07D40302, C07D40214, A61K 31535, A61K 3154
Patent
active
057365342
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to quinazoline derivatives and methods of using the same, particularly as anti-cancer agents, in mammals.
Many of the current treatment regimes for cancer utilize compounds which inhibit DNA synthesis. Such compounds are toxic to cells generally but their toxic effect on the rapidly dividing tumor cells can be beneficial. Alternative approaches to anti-cancer agents which act by mechanisms other than the direct inhibition of DNA synthesis have been explored in order to enhance the selectivity of action against cancer cells.
It is known that a cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene (i.e. a gene which, on activation, leads to the formation of malignant tumor cells). Many oncogenes encode proteins which are aberrant tyrosine kinases capable of causing cell transformation. Alternatively, the overexpression of a normal proto-oncogenic tyrosine kinase may also result in proliferative disorders, sometimes resulting in a malignant phenotype.
Receptor tyrosine kinases are large enzymes which span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor, a transmembrane domain, and an intracellular portion which functions as a kinase to phosphorylate specific tyrosine residues in proteins and hence to influence cell proliferation. It is known that such kinases are frequently aberrantly expressed in common human cancers such as breast cancer, gastrointestinal cancer such as colon, rectal or stomach cancer, leukemia, and ovarian, bronchial or pancreatic cancer. It has also been shown that epidermal growth factor receptor (EGFR) which possesses tyrosins kinase activity is mutated and/or overexpressed in many human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynecological and thyroid tumors.
Accordingly, it has been recognized that inhibitors of receptor tyrosine kinases are useful as a selective inhibitors of the growth of mammalian cancer cells, For example, erbstatin, a tyrosine kinase inhibitor selectively attenuates the growth in athymic nude mice of a transplanted human mammary carcinoma which expresses epidermal growth factor receptor tyrosine kinase (EGFR) but is without effect on the growth of another carcinoma which does not express the EGF receptor.
Various other compounds, such as styrene derivatives, have also been shown to possess tyrosine kinase inhibitory properties. More recently three European patent publications, namely EP 0 566 226 A1, EP 0 602 851 A1 and EP 0 520 722 A1 have disclosed that certain quinazoline derivatives possess anti-cancer properties which result from their tyrosine kinase inhibitory properties. Also PCT publication WO 92/20642 discloses bis-mono and bicyclic aryl and heteroaryl compounds as tyrosine kinase inhibitors.
In addition U.S. Pat. No. 4,012,513 discloses certain 1-(heterocyclic)-indol-3-yl-acetic acid derivatives that have anti-inflammatory, analgesic and antipyretic activity.
Although the anti-cancer compounds described above make a significant contribution to the art there is a continuing search in this field of art for improved anti-cancer pharmaceuticals.
SUMMARY OF THE INVENTION
This invention is directed to quinazoline derivatives, particularly 4-aminoquinazolines, that are useful as anti-cancer agents. The compounds of this invention have the Formula I ##STR1## and the pharmaceutically acceptable salts and stereoisomers thereof wherein either A, B or C ##STR2## wherein X is methylene, thio, --N(H)-- or oxy; may incorporate an oxygen or sulfur atom; ##STR3## wherein D may be saturated carbon, oxy or thio; or Z is ##STR4## wherein A completes a 7 to 9 membered mono-unsaturated mono-aza ring; R.sup.1 for each occurrence is independently -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, (C.sub.1 -C.sub.4)alkoxycarbonyl, (C.sub.1 -C.sub.4)alkanoyloxy, (C.sub.1 -C.sub.4)alkanoylamino, carboxy, phenoxy, benzoyloxy, carbamoyl, mono-N- or di-N-N-di-(C.sub.1 -C.
REFERENCES:
patent: 3884919 (1975-05-01), Birchall et al.
patent: 4012513 (1977-03-01), Birchall et al.
patent: 5475001 (1995-12-01), Barker
patent: 5576322 (1996-11-01), Takase et al.
patent: 5580870 (1996-12-01), Barker et al.
Goodale et al., Journal of the American Chemical Society, vol. 71, 1893 (May 1949).
Benson Gregg C.
Grumbling Matthew V.
Olson A. Dean
Pfizer Inc.
Richardson Peter C.
LandOfFree
4-heterocyclyl-substituted quinazoline derivatives, processes fo does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 4-heterocyclyl-substituted quinazoline derivatives, processes fo, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 4-heterocyclyl-substituted quinazoline derivatives, processes fo will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-13703