4-aminoquinazolone derivatives

Details 4-aminoquinazolone derivatives 4-aminoquinazolone derivatives

1999-11-26

2001-05-01

Shah, Mukund J. (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C544S284000

Reexamination Certificate

active

06225318

ABSTRACT:

BACKGROUND OF THE INVENTORS
This invention relates to 4-aminoquinazoline derivatives that are useful in the treatment of hyperproliferative diseases such as cancers 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 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 that 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, five European patent publications, namely EP 0 566 266 A1, published Oct. 20, 1993, EP 0 602 851 A1, published Jun. 22, 1994, EP 0 635 507 A1, published Jan. 25, 1995, EP 0 635 498 A1, published Jan. 25, 1995, and EP 0 520 722 A1, published Dec. 30, 1992, have referred to certain quinazoline derivatives as possessing anti-cancer properties that result from their tyrosine kinase inhibitory properties. Also, World Patent Application WO 92/20642, published Nov. 26, 1992, refers to certain bis-mono and bicyclic aryl and heteroaryl compounds as tyrosine kinase inhibitors that are useful in inhibiting abnormal cell proliferation. World Patent Application WO96/16960, published Jun. 6, 1996, and World Patent Application WO 95/23141, published Aug. 31, 1995, refer to certain phenylamino substituted quinazolines as tyrosine kinase inhibitors that are useful for the same purpose.
European patent publication EP 0 414 386 A1, published Feb. 27, 1991, refers to certain pyrido[2,3-d]pyrimidines as fungicides, insecticides and miticides.
Co-pending patent applications PCT/IB95/00436 and PCT/IB95/07881, which designate the United States and which were filed on Jun. 6, 1995 and Jun. 7, 1995, respectively, describe optionally substituted indolyl- and phenylamino-quinazolines, respectively, which are useful in the treatment of hyperproliferative diseases involving receptor tyrosine kinases.
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 relates to heterocyclic substituted aniline derivatives of the formula
wherein Z is NR
3
R
4
, wherein R
3
is hydrogen and R
4
is either Q
2
or phenyl substituted with (R
5
)
q
, or NR
3
R
4
is a group of the formula
wherein the dotted line represents an optional double bond;
each R
5
is independently selected from mono-, di- and tri-fluoromethyl, halo, nitro, hydroxy, amino, azido, isothiocyano, (C
1
-C
4
)alkyl, phenyl, thienyl, (C
1
-C
4
)alkoxy, benzyloxy, phenoxy, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, (C
1
-C
4
)alkylenedioxy, cyano, benzoylamino, trifluoromethylcarbonylamino, (C
1
-C
4
)alkanoylamino, (C
1
-C
4
)alkanoyl, N-mono- and N,N-di-(C
1
-C
4
)alkylamino, (C
1
-C
4
)alkylsulfonylamino, trifluoromethylsulfonylamino, (C
1
-C
4
)alkylthio, (C
1
-C
4
)alkylsulfinyl and (C
1
-C
4
)alkylsulfonyl, pyrrol-1-yl, piperidin-1-yl and pyrrolidin-1-yl, wherein said phenyl, benzyloxy, phenoxy and benzoylamino may optionally be mono-substituted with halo, nitro, trifluoromethyl, hydroxy or (C
1
-C
4
)alkyl, and wherein said (C
1
-C
4
)alkylenedioxy is linked at both ends to adjacent carbons on the benzene moiety;
or two R
5
's, together with the carbons atoms to which they are attached, form a group selected from imidazolyl, pyrrolo and pyrazolyl;
each R
6
is independently selected from hydroxy, amino, N-mono- and N,N-di-(C
1
-C
4
)alkylamino, sulfo and (C
1
-C
4
)alkoxy (provided that such groups are not attached to a ring carbon which is directly adjacent to the ring nitrogen), or each R
6
is independently selected from carboxy, hydroxy(C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy(C
1
-C
4
)alkyl, amino(C
1
-C
4
)alkyl, mono-N- and di-N,N-(C
1
-C
4
)alkylamino(C
1
-C
4
)alkyl, morpholino (C
1
-C
4
)alkyl, 4-(C
1
-C
4
)alkyl-piperazin-1-yl(C
1
-C
4
)alkyl, carboxy(C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxycarbonyl, sulfo(C
1
-C
4
)alkyl, pyridyl(C
1
-C
4
)alkyl and (C
1
-C
4
)alkyl;
q is an integer from 0 to 3;
o is 0, 1 or 2;
Q
2
is a 9- or 10-membered bicyclic heteroaryl cyclic moiety, or a hydrogenated derivative thereof, containing one or two nitrogen heteroatoms and optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur, and Q
2
may optionally bear one or two substituents independently selected from halogeno, hydroxy, oxo, amino, nitro, carbamoyl, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, (C
1
-C
4
)alkylamino, di-[(C
1
-C
4
)alkyl]amino, (C
2
-C
4
)alkanoylamino, (C
2
-C
4
)alkenyl and (C
2
-C
4
)alkynyl;
Q
1
is Ar-Y—X;
each Ar is a monocyclic or bicyclic aryl or heteroaryl ring (e.g., phenyl, naphthyl, pyridyl, pyrimidyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazelyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, pyranyl, pyrazinyl, thiazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, quinazolinyl, pterinyl, quinolinyl or isoquinolinyl), and wherein each Ar group may optionally be substituted with from one to three substituents R
2
;
each X is, independently, C
2
alkene (i.e., —C═C—), C
2
alkyne (i.e., —C≡C—) or absent;
m is one or two;
n is zero, one, two or three;
Y is (CH
2
)
p
wherein p is 0-5 and wherein one or two of the CH
2
groups may optionally and independently be replaced by either oxygen, sulfur, SO
2
, C═O, NH, or NCH
3
;
each R
1
is selected, independently, from:
(a) trifluoromethyl, halo, nitro, hydroxy, amino, cyano, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, (C
1
-C
4
)alkoxycarbonyl, thio, (C
1
-C
4
)alkanoyloxy, (C
1
-C
4
)alkanoylamino, carboxy, phenoxy, benzoyloxy, carbamoyl, mono-N- and di-N-N-di-(C
1
-C
4
)alkylcarbamoyl, mono-N- and di-N,N-(C
1
-C
4
)alkylamino, mono-N and di-N,N-(hydroxy(C
2
-C
4
)alkyl)amino, mono-N and 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, (C
1
-C
4
)alkylthio and phenylthio, and any of the foregoing R
1
groups substituted on (C
1
-C
4
)alky

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