Isoquinoline derivatives with angiogenesis inhibiting activity

Details Isoquinoline derivatives with angiogenesis inhibiting activity Isoquinoline derivatives with angiogenesis inhibiting activity

2001-02-09

2003-08-19

Seaman, D. Margaret (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S255050, C514S252040, C514S307000, C514S309000, C514S310000, C544S238000, C544S299000, C544S326000, C544S333000, C546S141000, C546S143000, C546S148000

Reexamination Certificate

active

06608071

ABSTRACT:

The invention relates to novel isoquinoline derivatives, to a process for their preparation, to their use in a method of treating the human or animal body, to their use, alone or in combination with one or more other compounds having pharmaceutical activity, in the treatment of a disease (especially a proliferative disease), such as a tumour disease, to a method of treating such a disease in an animal, especially a human being, and to the use of such a compound, alone or in combination with one or more other compounds having pharmaceutical activity, in the preparation of a pharmaceutical composition (medicament) for the treatment especially of a proliferative disease, such as a tumour disease.
BACKGROUND TO THE INVENTION
Two processes, the de novo formation of vessels from differentiating endothelial cells or angioblasts in the developing embryo (vasculogenesis) and the budding of new capillary vessels from existing finished blood vessels (angiogenesis), are involved in the development of the vascular system of animal organs and tissues, as well as in transient phases of new vessel formation, for example in the female cycle, in pregnancy or in the healing of wounds. On the other hand, a number of diseases are known which are associated with deregulated angiogenesis, for example diseases caused by ocular neovascularisation, especially retinopathies (diabetic retinopathy, age-related macular degeneration); psoriasis; haemangioblastomas, such as “strawberry-marks” (=haemangioma); various inflammatory diseases, such as arthritis, especially rheumatoid arthritis, arterial atherosclerosis and atherosclerosis occurring after transplants, endometriosis or chronic asthma; and, especially, tumour diseases (solid tumours, but also leukaemias and other liquid tumours, since many primitive blood cells and leukaemia cells express c-kit, KDR and flt-1).
According to more recent experience, the angiogenic factor known as vascular endothelial growth factor=VEGF, and its cellular receptors, lies at the centre of the regulatory network which controls the growth and the differentiation of the blood vessel system and its parts, both during development of the embryo and during normal growth, and also in a large number of pathological abnormalities and diseases (see Breier, G., et al., Trends in Cell Biology 6, 454-456 (1996) and references cited therein).
VEGF is a dimeric, disulfide-linked 46 kDa glycoprotein and is related to platelet-derived growth factor (PDGF). It is secreted by normal cell lines and tumour cell lines, is an endothelial-cell-specific mitogen, has angiogenic activity in in vivo test systems (e.g. rabbit cornea), has chemotactic activity on endothelial cells and monocytes, and induces plasminogen activators in endothelial cells, which are then involved in the proteolytic degradation of the extracellular matrix during the budding of capillaries. A number of isoforms of VEGF are known, which have comparable biological activities but can be differentiated in respect of the secreting cell types and the heparin bond. In addition, there are other members of the VEGF family, for example placenta growth factor (PIGF) and VEGF-C.
VEGF receptors, by contrast, are transmembrane receptor tyrosine kinases and have an extracellular domain with seven immunoglobulin-like domains and an intracellular tyrosine kinase domain. Various types are known, for example VEGFR-1, VEGFR-2 and VEGFR-3.
A large number of human tumours express VEGF and bring about large-scale induction of its receptors, for example gliomas or carcinomas. This has led to the hypothesis that the VEGF released by tumour cells might stimulate the growth of blood capillaries and the proliferation of tumour endothelium in a paracrine manner and thus, as a result of the improved blood supply, might accelerate tumour growth. The occurrence of cerebral oedemas in glioma patients might also be explained by increased VEGF expression. Direct proof of the role of VEGF as a tumour angiogenesis factor in vivo has in fact been provided by studies in which VEGF expression or VEGF activity was inhibited. That was achieved by means of antibodies which inhibit VEGF activity, by means of dominant-negative VEGFR-2 mutants, which inhibited signal transmission, or by the use of antisense VEGF-RNA techniques. All methods of treatment led to reduced tumour growth of glioma cell lines or other tumour cell lines in vivo as a consequence of inhibited tumour angiogenesis.
Hypoxia, and also a large number of growth factors and cytokines, for example epidermal growth factor, transforming growth factor a, transforming growth factor &bgr;, interleukin 1 and interleukin 6, induce the expression of VEGF in cell tests. Angiogenesis is an essential prerequisite for tumours that grow beyond a maximum diameter of approximately from 1 to 2 mm, up to which size the supply of oxygen and nutrients to the tumour cells can still be effected by diffusion. Accordingly, above a certain size, every tumour, regardless of its origin and its cause, is dependent on angiogenesis for its growth.
Three principal mechanisms are of importance for the effectiveness of angiogenesis inhibitors against tumours: 1) inhibition of the growth of vessels, especially capillaries, into tumours having an avascular basis, so that, as a result of a balance between apoptosis and proliferation, no net tumour growth occurs; 2) prevention of the flushing out of metastasis-forming tumour cells as a consequence of a deficient blood supply to the tumours; and 3) inhibition of the growth of endothelial cells, which would normally line the vessels, with the absence of their paracrine growth-stimulating action on the surrounding tissue.
SUMMARY OF THE INVENTION
Surprisingly, it has now been found that isoquinoline derivatives of formula I shown below have advantageous pharmacological properties and, for example, inhibit the activity of VEGF receptor tyrosine kinase and VEGF-dependent cell proliferation. Details of further activities are described below.
The compounds of formula I permit, for example, an unexpected new method of treatment especially for diseases in the treatment of which, and also for the prophylaxis of which, inhibition of angiogenesis and/or of VEGF receptor tyrosine kinase exhibits advantageous effects.
Complete description of the invention
The invention relates to compounds of formula I
wherein
r is from 0 to 2;
n is from 0 to 2;
m is from 0 to 4;
A, B, D and E are each independently of the others N or CH, with the proviso that not more than two of those radicals are N;
G is lower alkylene, —CH
2
—O—, —CH
2
—S—, —CH
2
—NH—, oxa (—O—), thia (—S—) or imino (—NH—), or is lower alkylene substituted by acyloxy or by hydroxy;
Q is lower alkyl, especially methyl;
R is H or lower alkyl;
X is imino, oxa or thia;
Y is lower alkyl or, especially, aryl, heteroaryl or unsubstituted or substituted cycloalkyl; and
Z is amino, mono- or di-substituted amino, halogen, alkyl, substituted alkyl, hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy, esterified carboxy, alkanoyl, carbamoyl, N-mono- or N,N-di-substituted carbamoyl, amidino, guanidino, mercapto, sulfo, phenylthio, phenyl-lower alkylthio, alkylphenylthio, phenylsulfinyl, phenyl-lower alkylsulfinyl, alkyl-phenylsulfinyl, phenylsulfonyl, phenyl-lower alkanesulfonyl or alkylphenylsulfonyl, and where, if more than one radical Z is present (m≧2), the substituents Z are identical or different;
and wherein the bonds indicated by a wavy line are either single bonds or double bonds;
or an N-oxide of the mentioned compound, wherein one or more N atoms carry an oxygen atom;
or a salt thereof.
Within the context of the present disclosure, the general terms used hereinbefore and hereinafter preferably have the following meanings, unless indicated otherwise:
The term “lower” denotes a radical having up to and including a maximum of 7, especially up to and including a maximum of 4, carbon atoms, the radicals in question being unbranched or branched one or more times.
Any reference to compounds, salts and the like in the plural is

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