Phthalazines with angiogenesis inhibiting activity

Details Phthalazines with angiogenesis inhibiting activity Phthalazines with angiogenesis inhibiting activity

2003-01-07

2004-03-23

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S248000, C544S224000, C544S233000, C544S235000, C544S237000, C544S238000, C544S239000

Reexamination Certificate

active

06710047

ABSTRACT:

The invention relates to the use of phthalazine derivatives—alone or in combination with one or more other pharmaceutically active compounds—for the treatment especially of a proliferative disease, such as a tumour disease, a method for the treatment of such disease in animals, especially in humans, and the use of such a compound—alone or in combination with one or more other pharmaceutically active compounds—for manufacture of a pharmaceutical preparation (medicament) for the treatment especially of a proliferative disease, such as a tumour; to certain of these compounds for use in the treatment of the animal or human body; to new phthalazine derivatives; and to processes for the preparation thereof.
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 growth of new capillary vessels from existing blood vessels (angiogenesis), are involved in the development of the vascular systems of animal organs and tissues. Transient phases of new vessel formation (neovascularization) also occur in the adult body, for example during the menstrual cycle, pregnancy, or wound healing.
On the other hand, a number of diseases are known to be associated with deregulated angiogenesis, for example retinopathies, psoriasis, haemangioblastoma, haemangioma, and neoplastic diseases (solid tumours).
The complex processes of vasculogenesis and angiogenesis have been found to involve a whole range of molecules, especially angiogenic growth factors and their endothelial receptors, as well as cell adhesion molecules.
Recent findings show that at the centre of the network regulating the growth and differentiation of the vascular system and its components, both during embryonic development and normal growth and in a wide number of pathological anomalies and diseases, lies the angiogenic factor known as “Vascular Endothelial Growth Factor” (=VGEF), along with its cellular receptors (see Breier, G., et al., Trends in Cell Biology 6, 454-6 [1996] and the references cited therein).
EP 0 722 936 discloses certain phthalazines where n is other than 0 in formula I given below, but doesn't disclose their utility against diseases associated with deregulated angiogenesis. DE 1 061 788 discloses a compound with X=oxa falling under formula I below, bit no medical use. None of the two discloses any compound of formula I given below wherein n=0 and X is imino or thia.
VEGF is a dimeric, disulfide-linked 46-kDa glycoprotein and is related to “Platelet-Derived Growth Factor” (PDGF). It is produced by normal cell lines and tumour cell lines, is an endothelial cell-specific mitogen, shows angiogenic activity in in vivo test systems (e.g. rabbit cornea), is chemotactic for endothelial cells and monocytes, and induces plasminogen activators in endothelial cells, which are then involved in the proteolytic degradation of extracellular matrix during the formation of capillaries. A number of isoforms of VEGF are known, which show comparable biological activity, but differ in the type of cells that secrete them and in their heparin-binding capacity. In addition, there are other members of the VEGF family, such as “Placenta Growth Factor” (PLGF) and VEGF-C.
VEGF receptors by contrast are transmembranous receptor tyrosine kinases. They are characterized by an extracellular domain with seven immunoglobulin-like domains and an intracellular tyrosine kinase domain. Various types of VEGF receptor are known, e.g. VEGFR-1, VEGFR-2, and VEGFR-3.
A large number of human tumours, especially gliomas and carcinomas, express high levels of VEGF and its receptors. This has led to the hypothesis that the VEGF released by tumour cells could stimulate the growth of blood capillaries and the proliferation of tumour endothelium in a paracrine manner and thus, through the improved blood supply, accelerate tumour growth. Increased VEGF expression could explain the occurrence of cerebral oedema in patients with glioma. Direct evidence of the role of VEGF as a tumour angiogenesis factor in vivo has been obtained from studies in which VEGF expression or VEGF activity was inhibited. This was achieved with antibodies which inhibit VEGF activity, with dominant-negative VEGFR-2 mutants which inhibited signal transduction, or with the use of antisense-VEGF RNA techniques. All approaches led to a reduction in the growth of glioma cell lines or other tumour cell lines in vivo as a result of inhibited tumour angiogenesis.
Hypoxia and also a large number of growth factors and cytokines, e.g. Epidermal Growth Factor, Transforming Growth Factor &agr;, Transforming Growth Factor &bgr;, Interleukin 1, and Interleukin 6, induce the expression of VEGF in cell experiments. Angiogenesis is regarded as an absolute prerequisite for those tumours which grow beyond a maximum diameter of about 1-2 mm; up to this limit, oxygen and nutrients may be supplied to the tumour cells by diffusion. Every tumour, regardless of its origin and its cause, is thus dependent on angiogenesis for its growth after it has reached a certain size.
Three principal mechanisms play an important part in the activity of angiogenesis inhibitors against tumours: 1) Inhibition of the growth of vessels, especially capillaries, into avascular resting tumours, with the result that there is no net tumour growth owing to the balance that is achieved between apoptosis and proliferation; 2) Prevention of the migration of tumour cells owing to the absence of bloodflow to and from tumours; and 3) Inhibition of endothelial cell proliferation, thus avoiding the paracrine growth-stimulating effect exerted on the surrounding tissue by the endothelial cells which normally line the vessels.
The German patent application DE 1 061 788 names generic intermediates for antihypertensives as belonging to the class of phthalazines. No pharmaceutical use for these intermediates has been declared.
SUMMARY OF THE INVENTION
Surprisingly, it has now been found that phthalazine derivatives of formula I, described below, have advantageous pharmacological properties and inhibit, for example, the activity of the VEGF receptor tyrosine kinase and the growth of tumours.
The compounds of formula I permit, for example, an unexpected new therapeutic approach, especially for diseases in the treatment of which, and also for the prevention of which, an inhibition of angiogenesis and/or of the VEGF receptor tyrosine kinase shows beneficial effects.
FULL DESCRIPTION OF THE INVENTION
The compounds comprised in a pharmaceutical formulation preparation or to be used in accordance with the invention are of formula I,
wherein
r is 0 to 2,
n is 0 to 2,
m is 0 to 4,
R
1
and R
2
(i) are lower alkyl, especially methyl, or
(ii) together form a bridge in subformula I*
 the binding being achieved via the two terminal carbon atoms, or
(iii) together form a bridge in subformula I**
 wherein one or two of the ring members T
1
, T
2
, T
3
and T
4
are nitrogen, and the others are in each case CH, and the binding is achieved via T
1
and T
4
A, B, D, and E are, independently of one another, N or CH, with the stipulation that not more than 2 of these radicals are N;
G is lower alkylene, lower alkylene substituted by acyloxy or hydroxy, —CH
2
—O—, —CH
2
—S—, —CH
2
—NH—, oxa (—O—), thia (—S—), or imino (—NH—);
Q is lower alkyl, especially methyl;
R is H or lower alkyl;
X is imino, oxa, or thia;
Y is aryl, pyridyl, or unsubstituted or substituted cycloalkyl; and
Z is mono- or disubstituted amino, halogen, alkyl, substituted alkyl, hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy, esterified carboxy, alkanoyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl, amidino, guanidino, mercapto, sulfo, phenylthio, phenyl lower alkylthio, alkylphenylthio, phenylsulfinyl, phenyl-lower alkylsulfinyl, alkylphenylsulfinyl, phenylsulfonyl, phenyl-lower alkylsulfonyl, or alkylphenylsulfonyl, wherein—if more than 1 radical Z (m=≧2) is present—the substituents Z are the same or dif

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