Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-12-31
2001-01-16
Raymond, Richard L. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S252020, C514S255050, C544S238000, C544S279000
Reexamination Certificate
active
06174889
ABSTRACT:
The present invention relates to a series of substituted heteroaromatic compounds, methods for their preparation, pharmaceutical compositions containing them and their use in medicine. In particular, the invention relates to bioisosteres of quinoline and quinazoline derivatives which exhibit protein tyrosine kinase inhibition.
Protein tyrosine kinases catalyse the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth and differentiation (A. F. Wilks, Progress in Growth Factor Research, 1990, 2, 97-111; S. A. Courtneidge, Dev. Supp.l, 1993, 57-64; J. A. Cooper, Semin. Cell Biol., 1994, 5(6), 377-387; R. F. Paulson, Semin. Immunol., 1995, 7(4), 267-277; A. C. Chan, Curr. Opin. Immunol., 1996, 8(3), 394-401). Protein tyrosine kinases can be broadly classified as receptor (e.g. EGFr, c-erbB-2, c-met, tie-2, PDGFr, FGFr) or non-receptor (e.g. c-src, lck, Zap70) kinases. Inappropriate or uncontrolled activation of many of these kinase, i.e. aberrant protein tyrosine kinase activity, for example by over-expression or mutation, has been shown to result in uncontrolled cell growth.
Aberrant activity of protein tyrosine kinases, such as c-erbB-2, c-src, c-met, EGFr and PDGFr have been implicated in human malignancies. Elevated EGFr activity has, for example, been implicated in non-small cell lung, bladder and head and neck cancers, and increased c-erbB-2 activity in breast, ovarian, gastric and pancreatic cancers. Inhibition of protein tyrosine kinases should therefore provide a treatment for tumours such as those outlined above.
Aberrant protein tyrosine kinase activity has also been implicated in a variety of other disorders: psoriasis, (Dvir et al, J. Cell. Biol; 991, 113, 857-865), fibrosis, atherosclerosis, restenosis, (Buchdunger et al, Proc. Natl. Acad. Sci. USA; 1991, 92, 2258-2262), auto-immune disease, allergy, asthma, transplantation rejection (Klausner and Samelson, Cell; 1991, 64, 875-878), inflammation (Berkois, Blood; 1992, 79(9), 2446-2454), thrombosis (Salari et al, FEBS; 1990, 263(1), 104-108) and nervous system diseases (Ohmichi et al, Biochemistry, 1992, 31, 4034-4939). Inhibitors of the specific protein tyrosine kinases involved in these diseases eg PDGF-R in restenosis and EGF-R in psoriasis, should lead to novel therapies for such disorders. P56lck and zap 70 are indicated in disease conditions in which T cells are hyperactive e.g. rheumatoid arthritis, autoimmune disease, allergy, asthma and graft rejection. The process of angiogenesis has been associated with a number of disease states (e.g. tumourogenesis, psoriasis, rheumatoid arthritis) and this has been shown to be controlled through the action of a number of receptor tyrosine kinases (L. K. Shawver, DDT, 1997, 2(2), 50-63).
EP0635507 discloses a class of tricyclic quinazoline derivatives of the formula:
wherein R
1
and R
2
together form specified optionally substituted groups containing at least one heteroatom so as to form a 5 or 6-membered ring, in which there is a N atom at the 6 position of the quinazoline ring; R
3
includes independently hydrogen, hydroxy, halogeno, (1-4C)alkyl, (1-4C) alkoxy di-[(1-4C)alkyl]amino, or (2-4C)alkanoylamino. The above citation notes that receptor tyrosine kinases in general, which are important in the transmission of biochemical signals initiating cell replication, are frequently present at increased levels or with higher activities in common human cancers such as breast cancer (Sainsbury et al, Brit, J. Cancer, 1988, 58, 458). It is suggested that inhibitors of receptor tyrosine kinase should be of value as inhibitors of the growth of mammalian cancer cells (Yaish et al. Science, 1988, 242, 933). This citation therefore has the aim of providing quinazoline derivatives which inhibit receptor tyrosine kinases involved in controlling the tumourigenic phenotype.
WO 95/15758 discloses aryl and heteroaryl quinazoline derivatives of formula
wherein X includes a bond, O, S, SO, SO
2
, C≡C, C═C, CH
2
and NH; Ar includes phenyl, naphthyl, naphthalenyl, indolyl, pyridyl, piperidinyl, piperazinyl, dinydroquinolinyl, tetrahydroquinolinyl, thienyl, indanyl, pyrazolyl and 1,4-benzodioxanyl; and R
5
, R
6
and R
7
independently include hydrogen, alkyl, alkylthio, cycloalkyl, hydroxy, alkoxy, aralkoxy, aryl, halo, haloalkyl, carboxy or carbalkoxy; as inhibitors of CSF-1R and/or p56lck receptor tyrosine kinase activity.
WO 95/19774 discloses bicyclic derivatives of formula:
in which A to E are nitrogen or carbon and at least one of A to E is nitrogen; or two adjacent atoms together are N, O or S; R
1
is H or alkyl and n is 0, 1 or 2; m is 0 to 3 and R
2
includes optionally substituted alkyl, alkoxy, cycloalkoxy, cycloalkoxy, or two R
2
groups together form a carbocycle or heterocycle. The compounds are said to inhibit epidermal growth factor receptor tyrosine kinase and suggested uses include the treatment of cancer, psoriasis, kidney disease, pancreatitis and contraception.
WO 96/07657 discloses pyrimido[5,4-d]pyrimidine derivatives of formula
wherein Ra includes hydrogen or alkyl; Rb includes optionally substituted phenyl; and Rc includes hydrogen, halo, alkyl, cycloalyl, cycloalkylalkylanyl, aralkyl, OH, optionally substituted alkoxy, cycloalkoxy, aryloxy, aralkoxy, mercapto, optionally substituted alkyl- or arysulfenyl, -sulfinyl, or -sulfonyl and substituted alkyleneimino; as EGF-R inhibitors.
WO 96/09294 discloses quinoline and quinazoline derivatives of formula
wherein X is N or CH; Y includes O, S, CH
2
O and NH; R
6
includes phenoxy, benzylozy, benzylmercapto, benzylamino, benzyl, anilino, benzoyl, anilinocarbonyl, anilnomethyl, phenylethynyl, phenylethenyl, phenylethyl, phenylthio, phenylsulphonyl, benzylthio, benzylsulphonyl, phenylthiomethyl, phenylsulphonylmethyl, phenoxymethyl, thienylmethoxy, furanylmethoxy, cyclohexyl, and cyclohexylmethoxy; and R
1
, R
2
, R
3
and R
3′
include a range of possible substituents, predominantly not including heterocyclic ring systems; as protein receptor tyrosine kinase inhibitors, in particular as c-erbB-2 and/or p56lck inhibitors.
WO 96/15118 discloses quinazoline derivatives of formula
wherein X includes O, S, SO, SO
2
, CH
2, OCH
2
, CH
2
O and CO; Q includes a phenyl or naphthyl group and various 5- or 6-membered heteroaryl moieties; n is 0, 1, 2 or 3
and each R
2
is independently halogeno, trifluoromethyl, hydroxy, amino, nitro, cyano, C
1-4
alkyl, C
1-4
alkoxy, C
1-4
alkylamino, diC
1-4
alkyl amino or C
2-4
alkanoylamino; m is 1, 2 or 3 and R
1
includes a range of possible substituents, predominantly not including heterocyclic ring systems; as receptor tyrosine kinase inhibitors, in particular as EGF-R inhibitors.
WO 96/15128 discloses pyrido[2,3-d]pyrimidine and naphthyridine derivatives of formula
wherein X is CH or N; B is halo, hydroxy or NR
3
R
4
; Ar includes unsubstituted and substituted phenyl or pyridyl; and R
1
, R
2
, R
3
and R
4
independently include hydrogen, amino, C
1-8
alkylamino, di-C
1-8
alkylamino, unsubstituted and substituted aromatic or heteroaromatic groups, and unsubstituted and substituted C
1-8
alkyl, C
2-8
alkenyl or C
2-8
alkynyl groups.
WO 96/16960 discloses quinazoline derivatives of formula
wherein m is 1 or 2; each R
1
independently includes hydrogen and C
1-4
alkoxy; n is 1, 2 or 3; each R
2
independently includes hydrogen, halogeno and C
1-4
alkyl, or R
2
is an aryl- or heteroaryl-containing group, including pyridylmethoxy and benzoyl; and Ar includes a substituted or unsubstituted 5- or 9-membered nitrogen-linked heteroaryl moiety containing up to four nitrogen atoms, in particular imidazol-1-yl, imidazolin-1-yl, benzimidazol-1-yl, pyrazol-1-yl and 1,2,4-triazol-1-yl; as receptor tyrosine kinase inhibitors, in particular as EGF-R inhibitors.
It is therefore a general object of the present invention to provide compounds suitable for the treatment of disorders mediated by protein tyrosine kinase activity, and in particular treatment of the above mentioned disorders.
In addi
Carter Malcolm Clive
Cockerill George Stuart
Guntrip Stephen Barry
Smith Kathryn Jane
Glaxo Wellcome Inc.
Lemanowicz John L.
Raymond Richard L.
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