Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Utility Patent
1998-08-26
2001-01-02
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...
C544S279000
Utility Patent
active
06169091
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). Protein tyrosine kinases can be broadly classified as growth factor receptor (e.g. EGF-R, PDGF-R, FGF-R and c-erbB-2) or non-receptor (e.g. c-src, bcr-abl) kinases. Inappropriate or uncontrolled activation of many of these kinases 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, p561ck, EGF-R, PDGF-R, and zap70 has been implicated in human malignancies.
Aberrant EGF-R activity has, for example, been implicated in cancers of the head and neck, and aberrant c-erbB-2 activity in breast, ovarian, non-small cell lung, pancreatic, gastric and colon cancers. Inhibitors of protein tyrosine kinase 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; 1991, 113, 857-865), fibrosis, atherosclerosis, restenosis, (Buchdunger et al, Proc.Natl.Acad.Sci. U.S.A.; 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, 4034-4039). 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. P561ck and zap 70 are indicated in disease conditions in which T cells are hyperactive eg rheumatoid arthritis, autoimmune disease, allergy, asthma and graft rejection.
WO 9519774 discloses bicyclic derivatives of formula (I):
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; and R
2
includes optionally substituted alkyl, alkoxy, cycloalkoxy, cycloalkoxy, or 2 together form a carbocycle or heterocycle, and m is 0 to 3. 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.
EP0635507 discloses a class of tricyclic quinazoline derivatives of the formula (III):
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 in common human cancers such as breast cancer (Sainsbury et al Brit. J. Cancer 1988, 58, 458). This citation also states that tyrosine kinase activity is rarely detected in normal cells whereas it is frequently detectable in malignant cells (Hunter,
Cell,
1987, 50, 823) and 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.
The above compounds suffer the disadvantage that they are more difficult to synthesize than their quinoline and quinazoline counterparts on account of the additional structural complexity and accordingly there is a need for quinoline and quinazoline deriatives which are capable of inhibiting protein tyrosine kinase activity and yet are relatively simple to synthesize. There is no reference in the above citation to any such bicyclic heterocyclic system capable of inhibiting protein tyrosine kinase activity and the present invention seeks to fill this omission.
Selective inhibition of the EGF receptor is, however, disclosed by Fry et al (Science, 265, 1093 (1994)). This citation discloses that the compound:
is a highly selective inhibitor of the EGF receptor tyrosine kinase at picomolar concentrations while inhibiting other tyrosine kinases only at micromolar or higher concentrations. This compound does not however exhibit good in vivo activity in contrast to the compounds of the present invention.
WO 93/17682 and Bioorg Med Chem Lett (1993, 4 (1), 173-176) disclose compounds which block angiotensin II receptors and have the general formula (IV)
in which D is a bicyclic heterocyle comprising a 6-membered ring fused to another 6-membered ring, the bicyclic heterocycle comprising at least one heteroatom selected from N, O and S, and each fused ring independently containing 0 to 3 N atoms, 1 N atom and 1 O atom, 1 N atom or 1 S atom, 1 O atom and 1 S atom, 2 O atoms, 2 S atoms or 1 O atom or 1 S atom, with the remaining ring atoms being carbon atoms. Pendant R
1
and R′
1
groups include tetra zolyl, N substituted amino, N substituted amide, N substituted urea, carboxylate, amino sulphone, carbonyl, methylene alkoxy, sulphonate and phosphate.
WO 93/18035 and Bioorg Med Chem Lett (1993, 4 (1), 173-176) relate to further angiotension II receptor blocking compounds of formula (I) above, with the difference that D in formula (I) now represents a bicyclic heterocycle comprising a 6-membered ring fused to a 5-membered ring, the bicyclic heterocycle comprising at least one heteroatom selected from N, O and S. In this application, the 6-membered ring comprises 0 to 3 N atoms, 1 N atom and 1 O atom, 1 N atom and 1 S atom, 1 O atom and 1 S atom, 2 O atoms, 2 S atoms, 1 O atom, or 1 S atom; and the 5-membered ring comprises 0 to 3 N atoms, 1 N atom and 1 O atom, 1 N atom and 1 S atom, 1 O atom and 1 S atom, 1 O atom, or 1 S atom with the remaining atoms in the fused rings being carbon atoms.
WO 86/06718 relates to a class of mono- and di- Mannich bases, derived from 4-(7′-substituted-1′,5′-naphthyridin-4′-ylamino)phenols and 4-(7′-substituted-quinolin-4′-ylamino) -phenols of formula (V):
in which Y is N or CH, and R
1
and R
2
are independently hydrogen or specified substituted amino groups. The compounds of formula (II) exhibit antimalarial activity.
EP 0534341 relates to the preparation of 4-[(ar)alkoxy] pyrimidines for use as pesticides and agrochemical fungicides. This application discloses compounds of formula (VI):
in which R
2
and R
3
together form an unsaturated 5-membered ring, together with the C atoms to which they are attached, containing an O or S atom; or R
2
and R
3
together form a saturated 5, 6 or 7-membered ring which may contain an O or S atom.
EP 0452002 relates to 4-substituted thieno [2,3-d], [3,2-d] and [3,4-d] pyrimidines of formula (VII) below having fungicidal, insecticidal and miticidal utility:
in which
and X includes O, S or NR
4
where R
4
=H or C
1-4
alkyl; Y includes a carbocyclic ring which may contain a heteroatom; and Z is a C
3-8
cycloalky or phenyl.
Tetrahedron (1971, 27 487-499) concerns an academic study which discloses nucleophilic substitution reactions of 4-chlorothieno[3,2-d]pyrimidines to produce a number of compounds in which the 4-substituent is bound to the pyrimidine via a heteroatom,
Barraclough Paul
Cockerill George Stuart
Franzmann Karl Witold
Guntrip Stephen Barry
Hudson Alan Thomas
Glaxo Wellcome Inc.
Lemanowicz John L.
Rao Deepak R.
Shah Mukund J.
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