Quinazoline derivatives as VEGF inhibitors

Details Quinazoline derivatives as VEGF inhibitors Quinazoline derivatives as VEGF inhibitors

1998-08-13

2001-02-06

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S259500, C544S245000, C544S287000, C544S293000

Reexamination Certificate

active

06184225

ABSTRACT:

The present invention relates to quinazoline derivatives, processes for their preparation, pharmaceutical compositions containing them as active ingredient, methods for the treatment of disease states associated with angiogenesis and/or increased vascular permeability, to their use as medicaments and to their use in the manufacture of medicaments for use in the production of antiangiogenic and/or vascular permeability reducing effects in warm-blooded animals such as humans.
Normal angiogenesis plays an important role in a variety of processes including embryonic development, wound healing and several components of female reproductive function. Undesirable or pathological angiogenesis has been associated with disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and haemangioma (Fan et al, 1995, Trends Pharmacol. Sci. 16: 57-66; Folkman, 1995, Nature Medicine 1: 27-31). Alteration of vascular permeability is thought to play a role in both normal and pathological physiological processes (Cullinan-Bove et al, 1993) Endocrinology 133: 829-837; Senger et al, 1993, Cancer and Metastasis Reviews. 12: 303-324). Several polypeptides with in vitro endothelial cell growth promoting activity have been identified including, acidic and basic fibroblast growth factors (aFGF & bFGF) and vascular endothelial growth factor (VEGF). By virtue of the restricted expression of its receptors, the growth factor activity of VEGF, in contrast to that of the FGFs, is relatively specific towards endothelial cells. Recent evidence indicates that VEGF is an important stimulator of both normal and pathological angiogenesis (Jakeman et al, 1993, Endocrinology, 133: 848-859; Kolch et al, 1995, Breast Cancer Research and Treatment, 36:139-155) and vascular permeability (Connolly et al, 1989, J. Biol. Chem. 264: 20017-20024). Antagonism of VEGF action by sequestration of VEGF with antibody can result in inhibition of tumour growth (Kim et al, 1993, Nature 362: 841-844).
Receptor tyrosine kinases (RTKs) are important in the transmission of biochemical signals across the plasma membrane of cells. These transmembrane molecules characteristically consist of an extracellular ligand-binding domain connected through a segment in the plasma membrane to an intracellular tyrosine kinase domain. Binding of ligand to the receptor results in stimulation of the receptor-associated tyrosine kinase activity which leads to phosphorylation of tyrosine residues on both the receptor and other intracellular molecules. These changes in tyrosine phosphorylation initiate a signalling cascade leading to a variety of cellular responses. To date, at least nineteen distinct RTK subfamilies, defined by amino acid sequence homology, have been identified. One of these subfamilies is presently comprised by the fms-like tyrosine kinase receptor, Flt or Flt1, the kinase insert domain-containing receptor, KDR (also referred to as Flk-1), and another fms-like tyrosine kinase receptor, Flt4. Two of these related RTKs, Flt and KDR, have been shown to bind VEGF with high affinity (De Vries et al, 1992, Science 255: 989-991; Terman et al, 1992, Biochem. Biophys. Res. Comm. 1992, 187: 1579-1586). Binding of VEGF to these receptors expressed in heterologous cells has been associated with changes in the tyrosine phosphorylation status of cellular proteins and calcium fluxes.
Compounds which have good activity against epidermal growth factor (EGF) receptor tyrosine kinase are disclosed in the European Patent Publication No 0566226, but there is no disclosure or suggestion that the compounds inhibit the effects of VEGF. European Patent Publication No. 0326330 discloses certain quinoline, quinazoline and cinnoline plant fungicides. Certain of these plant fungicides are also stated to possess insecticidal and miticidal activity. There is however no disclosure or any suggestion that any of the compounds disclosed may be used for any purpose in animals such as humans. In particular, the European Patent Publication contains no teaching whatsoever concerning angiogenesis and/or increased vascular permeability mediated by growth factors such as VEGF.
The present invention is based on the discovery of compounds that surprisingly inhibit the effects of VEGF, a property of value in the treatment of disease states associated with angiogenesis and/or increased vascular permeability such as cancer, diabetes, psoriasis. rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation and ocular diseases with retinal vessel proliferation. Compounds of the present invention possess higher potency against VEGF receptor tyrosine kinase whilst possessing some activity against EGF receptor tyrosine kinase. Furthermore, compounds of the present invention, possess substantially higher potency against VEGF receptor tyrosine kinase than against EGF receptor tyrosine kinase or FGF R1 receptor tyrosine kinase. Thus compounds of the invention which have been tested possess activity against VEGF receptor tyrosine kinase such that they may be used in an amount sufficient to inhibit VEGF receptor tyrosine kinase whilst demonstrating no significant activity against EGF receptor tyrosine kinase or FGF R1 receptor tyrosine kinase.
According to one aspect of the present invention there is provided a quinazoline derivative of the formula I:
[wherein:
Z represents —O—, —NH— or —S—;
m is an integer from 1 to 5 with the proviso that where Z is —NH— m is an integer from 3 to 5;
R
1
represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C
1-3
alkyl, C
1-3
alkoxy, C
1-3
alkylthio, or —NR
5
R
6
(wherein R
5
and R
6
, which may be the same or different, each represents hydrogen or C
1-3
alkyl);
R
2
represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro;
R
3
represents hydroxy, halogeno, C
1-3
alkyl, C
1-3
alkoxy, C
1-3
alkanoyloxy, trifluoromethyl, cyano, amino or nitro;
X
1
represents —O—, —CH
2
—, —S—, —SO—, —SO
2
—, —NR
7
—, —NR
8
CO—, —CONR
9
-, —SO
2
NR
10
— or —NR
11
SO
2
—, (wherein R
7
, R
8
, R
9
, R
10
and R
11
each represents hydrogen, C
1-3
alkyl or C
1-3
alkoxyC
2-3
alkyl);
R
4
is selected from one of the following seven groups:
1) hydrogen, C
1-5
alkyl, C
1-5
hydroxyalkyl, (preferably C
2-3
hydroxyalkyl), C
1-5
fluoroalkyl, C
1-5
aminoalkyl;
2) C
1-5
alkylX
2
COR
12
(wherein X
2
represents —O— or —NR
13
— (in which R
13
represents hydrogen, C
1-3
alkyl or C
1-3
alkoxyC
2-3
alkyl) and R
12
represents C
1-3
alkyl, —NR
14
R
15
or —OR
16
(wherein R
14
, R
15
and R
16
which may be the same or different each represents hydrogen, C
1-3
alkyl or C
1-3
alkoxyC
2-3
alkyl));
3) C
1-5
alkylX
3
R
17
(wherein X
3
represents —O—, —S—, —SO—, —SO
2
—, —OCO—, —NR
18
CO—, —CONR
19
—, —SO
2
NR
20
—, —NR
21
SO
2
— or —NR
22
— (wherein R
18
, R
19
, R
20
, R
21
and R
22
each independently represents hydrogen, C
1-3
alkyl or C
1-3
alkoxyC
2-3
alkyl) and R
17
represents hydrogen, C
1-3
alkyl, cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which C
1-3
alkyl group may bear one or two substituents selected from oxo, hydroxy, halogeno and C
1-4
alkoxy and which cyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C
1-4
alkyl, C
1-4
hydroxyalkyl and C
1-4
alkoxy);
4) C
1-5
alkylR
23
(wherein R
23
is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C
1-4
alkyl, C
1-4
hydroxyalkyl and C
1-4
alkoxy);
5) C
2-5
alkenylR
23
(wherein R
23
is as defined hereinbefore);
6) C
2-5
alkynylR
23
(wherein R
23
is as defined hereinbefore); and
7) C
1-5
alkylX
4
C
1-5
alkylX
5
R
24
(wherein X
4
and X
5
which may be the same or different are each —O—, —S—, —SO—, —SO
2
—, —NR
25
CO—, —CONR
26
—, —SO
2
NR
27
—, —NR
28
SO
2
— or

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