Heterocyclic ring-fused pyrimidine derivatives

Details Heterocyclic ring-fused pyrimidine derivatives Heterocyclic ring-fused pyrimidine derivatives

1999-11-09

2002-05-28

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S234500, C514S258100, C544S117000, C544S280000

Reexamination Certificate

active

06395733

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to heterocyclic ring-fused pyrimidine derivatives and methods of using the same in the treatment of hyperproliferative diseases, such as cancers and acnes, 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. Alterative approaches to anti-cancer agents which act by mechanisms other than the 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 tyrosine 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 heteroaryl-fused pyrimidine 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.
European patent publication EP 0 496 617 A1 discloses certain pyrazolo[3,4-d]pyrimidines and pyrrolo[2,3-d]pyrimidines which possess adenosine kinase inhibitory properties.
European patent publication EP 0 475 413 A2 discloses certain carbocyclic nucleoside analogs as useful immunosuppressants.
European patent publication EP 0 414 386 A1 discloses certain pyrido[2,3-d]pyrimidines as fungicides, insecticides and miticides. The synthesis and antiallergic activity of 9-aryl-8-azaadenine derivatives is described in
II Farmco—Ed. Sc
., vol 35, fasc. 4 p308-323 (1980).
Co-pending U.S. patent applications (U.S. Ser. Nos. 08/200,359 and 08/413,800) and PCT application docket no. PC8836A, assigned to the Assignee of this application, describe optionally substituted indolyl- and phenylamino quinazolines, respectively, which are useful in the treatment of hyperproliferative diseases involving receptor tyrosine kinases. 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 compounds of the Formula
and stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Y together with the carbons to which it is attached form a 5 or 6 membered, optionally unsaturated or aromatic ring wherein said ring is optionally substituted with (R
3
)
p
and/or R
4
groups and comprises one to three heteroatoms selected from S, O and N with the proviso that at least one of said hetero atoms is N;
Z is NR
1
R
2
wherein R
1
is H and R
2
is phenyl substituted by (R
5
)
m
or Q or R
1
R
2
N is a group of the formula
wherein the dotted line represents an optional double bond;
each R
3
is attached to a carbon atom in Y and is independently selected from
a. hydrogen, trifluoromethyl, halo, nitro, hydroxy, amino, cyano, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, (C
1
-C
4
)alkoxycarbonyl, (C
1
-C
4
)alkanoyloxy, (C
1
-C
4
)alkanoylamino, carboxy, phenoxy, benzoyloxy, carbamoyl, mono-N- or di-N-N-di-(C
1
-C
4
)alkylcarbamoyl, mono-N- or di-N,N-(C
1
-C
4
)alkylamino, mono-N or di-N,N-(hydroxy(C
2
-C
4
)alkyl)amino, mono-N or di-N,N-((C
1
-C
4
)alkoxy(C
2
-C
4
)alkyl)amino, anilino, pyrrolidin-1-yl, piperidin-1-yl, morpholino, piperazin-1-yl, 4(C
1
-C
4
)alkylpiperazin-1-yl, pyridyl, pyrrolo, imidazolo, thiazolo, benzimidazolo, pyridonyl, (C
1
-
4
)alkylthio, phenylthio, or such groups substituted on (C
1
-C
4
)alkyl;
b. hydroxy(C
2
-C
4
)alkoxy(C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy-(C
2
-C
4
)alkoxy-(C
1
-C
4
)alkyl, hydroxy(C
2
-C
4
)alkylthio(C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy(C
2
-C
4
)alkylthio(C
1
-C
4
)alkyl, hydroxyamino, benzoylamino, mono-N or di- N,N-(C
1
-C
4
)alkylcarbamoylmethylamino, carbamoylmethylamino, (C
1
-C
4
)alkoxycarbonylamino, (C
1
-C
4
)alkanoylamino, carboxymethylamino, (C
1
-C
4
)alkoxycarbonylmethylamino, (C
1
-C
4
)alkoxyamino, (C
2
-C
4
)alkanoyloxyamino, phenyl(C
1
-C
4
)alkylamino, (C
1
-C
4
)alkylsulphonylamino, benzenesulphonamido, 3phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, ureido,(C
1
-C
4
)alkoxy(C
1
-C
4
)alkylcarbonylamino,(C
1
-C
4
)alkylsulfinyl,(C
1
-C
4
)alkylsulfonyl, (C
1
-C
4
)alkoxy(C
2
-C
4
)alkylthio, mono-, di- or trifluoromethyloxy, (C
1
-C
4
)alkylenedioxy, benzyloxy, guanidino, aminocarbonyl, mono-N- or di-N,N-(C
1
-C
4
)alkylaminocarbonyl, phenyl(C
1
-C
4
)alkoxy, carboxymethoxy, (C
1
-C
4
)alkoxycarbonylmethoxy, carbamoylmethoxy, mono-N or di-N,N-(C
1
-C
4
)alkyl carbamoylmethoxy, mono-N- or di-N,N-(hydroxy(C
2
-C
4
)alkyl)carboxamido, mono-N- or di-N,N-((C
1
-C
4
)alkoxy (C
2
-C
4
)alkyl)carboxamido or bis((C
1
-C
4
)alkanesulfonyl)amido; or
c. (C
2
-C
4
)alkoxy, (C
2
-C
4
)alkylthio, (C
2
-C
4
)alkanoyloxy, (C
2
-C
4
)alkylamino, (C
1
-C
4
)alkyl(C
1
-C
4
)alkylenedioxy, (C
2
-C
4
)alkanoylamino, (C
2
-C
4
)alkenyl, or (C
2
-C
4
)alkynyl; each such group substituted with amino, halo, hydroxy, (C
2
-C
4
)alkanoyloxy, (C
1
-C
4
)alkoxy, mono-N- or di-N,N-(C
1
-C
4
)alkylamino, mono-N or di-N,N-(hydroxy(C
2
-C
4
)alkyl)amino, mono-N or di-N,N-((C
1
-C
4
)alkoxy(C
2
-C
4
)alkyl)amino, (C
1
-C
4
)alkanoylamino, phenoxy, anilino, imidazol-1-yl, phenylthio, piperidino, pyridyl, carboxy(C
1
-C
4
)alkylthio(C
1
-C
4
)alkoxy, morpholino, piperazin-1-yl-, 4-(C
1
-C
4
)alkylpiperazin-1-yl-, carboxy, (C
1
-C
4
)alkoxycarbonyl, carbamoyl, mono-N- or di-N,N-(C
1
-C
4
)alkylcarbamoyl, carboxamido, mono-N- or di-N,N-(C
1
-C
4
)alkylcarboxamido or mono-N- or di-N,N-(hydroxy(C
2
-C
4
)alkyl)carboxamido; and any phenyl in an R
3
substituent is optionally mono- or di- substituted with halo, nitro, trifluoromethyl, hydroxy, (C
1
-C
4
)alkoxy, (C
1
-C
4
)alkyl, amino, mono-N-alkylamino, or N,N-dialkylamino;
R
4
is attached to a N-atom in Y and is independently selected from:
hydrogen, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxycarbonyl, (C
1
-C
4
)alk

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