Oxindolylquinazoline derivatives as angiogenesis inhibitors

Details Oxindolylquinazoline derivatives as angiogenesis inhibitors Oxindolylquinazoline derivatives as angiogenesis inhibitors

2000-05-03

2001-09-25

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S228500, C514S233800, C514S234200, C514S234500, C514S258100, C514S259500, C544S058200, C544S116000, C544S117000, C544S280000, C544S284000

Reexamination Certificate

active

06294532

ABSTRACT:

The present invention relates to heteroaromatic oxindole 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). Basic FGF (bFGF) is a potent stimulator of angiogenesis (e.g. Hayek et al, 1987, Biochem. Biophys. Res. Commun. 147: 876-880) and raised levels of FGFs have been found in the serum (Fujimoto et al, 1991, Biochem. Biophys. Res. Commun. 180: 386-392) and urine (Nguyen et al, 1993, J. Natl. Cancer. Inst. 85: 241-242) of patients with cancer.
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.
The present invention is based on the discovery of compounds that surprisingly inhibit the effects of VEGF and FGF, properties 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 and against FGF R1 receptor tyrosine kinase than against epidermal growth factor (EGF) receptor tyrosine kinase. Furthermore, compounds of the present invention, possess substantially higher potency against VEGF receptor tyrosine kinase and against FGF R1 receptor tyrosine kinase than against EGF receptor tyrosine kinase. Compounds of the invention which have been tested possess activity against VEGF receptor tyrosine kinase and against FGF R1 receptor tyrosine kinase such that they may be used in an amount sufficient to inhibit VEGF receptor tyrosine kinase and FGF R1 receptor tyrosine kinase whilst demonstrating no significant activity against EGF receptor tyrosine kinase. Thus compounds of the present invention possess good VEGF receptor tyrosine kinase activity and good FGF R1 receptor tyrosine kinase activity. Compounds with both VEGF receptor tyrosine kinase activity and FGF R1 receptor tyrosine kinase activity are believed to be of particular value in the treatment of disease states associated with angiogenesis and/or increased vascular permeability.
According to one aspect of the present invention there are provided compounds of the formula I:
[wherein:
ring Z is a 5 or 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected independently from O, N and S with the proviso that the group at the 4-position of the quinazoline ring is not a substituted or unsubstituted group selected from 4,5,7-triazaoxindol-3-yl and 4,6,7-triazaoxindol-3-yl;
R
1
represents hydrogen, C
1-4
alkyl, C
1-4
alkoxymethyl, di(C
1-4
alkoxy)methyl or C
1-4
alkanoyl;
R
2
represents hydroxy, halogeno, C
1-3
alkyl, C
1-3
alkoxy, C
1-3
alkanoyloxy, trifluoromethyl, 2,2,2-trifluoroethyl, cyano, amino, nitro, C
2-4
alkanoyl, C
1-4
alkanoylamino, C
1-4
alkoxycarbonyl, C
1-4
alkylthio, C
1-4
alkylsulphinyl, C
1-4
alkylsulphonyl, carbamoyl, N-C
1-4
alkylcarbarnoyl, N,N-di(C
1-4
alkyl)carbamoyl, aminosulphonyl, N-C
1-4
alkylaminosulphonyl, N,N-di(C
1-4
alkyl)aminosulphonyl or C
1-4
alkylsulphonylamino or R
2
is selected from one of the following four groups:
1) R
4
X
1
wherein X
1
represents a direct bond, —O—, —NR
5
—, C
1-3
alkyl, C
2-4
alkanoyl, —CONR
6
R
7
—, —SO
2
NR
8
R
9
— or —SO
2
R
10
— (wherein R
5
, R
6
and R
8
, each independently represents hydrogen or C
1-2
alkyl and R
7
, R
9
and R
10
each independently represents C
1-4
alkyl and wherein R
4
is linked to R
7
, R
9
or R
10
) and R
4
represents phenyl or a 5 or 6-membered heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may be saturated or unsaturated and which phenyl or heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C
1-3
alkyl, C
1-3
alkoxy, C
1-3
alkanoyloxy, trifluoromethyl, cyano, amino, nitro and C
1-4
alkoxycarbonyl;
2) X
2
C
2-4
alkylX
3
C
1-3
alkyl (wherein X
2
is —O— or —NR
11
— (wherein R
11
is hydrogen, C
1-3
alkyl or C
1-3
alkoxyC
2-3
alkyl) and X
3
is —O—, —NR
12
—, —S—, —SO— or —SO
2
— (wherein R
12
is hydrogen, C
1-3
alkyl or C
1-3
alkoxyC
2-3
alkyl);
3) C
1-2
alkylX
4
C
2-3
alkylX
5
C
1-3
alkyl (wherein X
4
and X
5
which may be the same or different are each —O—, —S—, —SO—, —SO
2
— or —NR
13
— (wherein R
13
is hydrogen, C
1-3
alkyl or C
1-3
alkoxyC
2-3
alkyl); and
4) C
1-3
alkylX
6
C
1-3
alkyl (wherein X
6
is —O—, —S—, —SO—, —SO
2
— or —NR
14
— (wherein R
14
is hydrogen, C
1-3
alkyl or C
1-3
alkoxyC
2-3
alkyl);
n is an integer from 0 to 3 when Z is a 6-membered heterocyclic ring and n is an integer from 0 to 2 when Z is a 5-membered heterocyclic ring;
m is an integer from 0 to 4; and
R
3
represents hydroxy, halogeno, nitro, trifluoromethyl, C
1-3
alkyl, cyano, amino or R
15
X
7
(wherein X
7
represents

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