Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-09-26
2004-02-03
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, C514S252030, C514S279000, C514S300000, C514S303000, C544S237000, C544S238000, C544S236000, C544S268000, C546S113000, C546S268100
Reexamination Certificate
active
06686347
ABSTRACT:
The invention relates to a new medical use for phthalazine derivatives, especially for the treatment of inflammatory rheumatic or rheumatoid diseases and/or pain, more especially for the treatment of rheumatoid arthritis and/or pain; as well as to new phthalazine derivatives, processes for the preparation thereof, the application thereof in a process for the treatment of the human or animal body, the use thereof—alone or in combination with one or more other pharmaceutically active compounds—for the treatment of a disease, especially as mentioned above, a disease caused by ocular neovascularisation, such as age-related macula degeneration or diabetic retinopathy, or other diseases that respond to the inhibition of tyrosine kinases, such as a proliferative disease, such as a tumour disease, a method for the treatment of such disease in mammals, especially in humans, and the use of such a compound—alone or in combination with one or more other pharmaceutically active compounds—for the manufacture of a pharmaceutical preparation (medicament) for the treatment especially a disease as mentioned above or 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 growth of new capillary vessels from existing blood vessels (angiogenesis), are involved in the development of the vascular systems of animal organs and tissues, as well as in transitory phases of angiogenesis, for example during the menstrual cycle, in pregnancy, or in wound healing. On the other hand, a number of diseases are known to be associated with deregulated angiogenesis, for example diseases caused by ocular neovascularisation, such as retinopathies (including diabetic retinopathy), age-related macula degeneration, psoriasis, haemangioblastoma, haemangioma, an inflammatory disease, such as a rheumatoid or rheumatic inflammatory disease, especially arthritis, such as rheumatoid arthritis, and especially neoplastic diseases, for example so-called solid tumours and liquid tumours (such as leucemias).
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).
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 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, however, are transmembranous receptor tyrosine kinases and have an extracellular domain with seven immunoglobulin-like domains and an intracellular tyrosine kinase domain. Various types 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 anti-tumour activity of angiogenesis inhibitors: 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.
SUMMARY OF THE INVENTION
Surprisingly, it has now been found that phthalazine derivatives of formula I, described hereinafter, have advantageous pharmacological properties and inhibit, for example, the activity of VEGF receptor tyrosine kinase and VEGF-dependent cell proliferation, or the treatment of especially inflammatory rheumatic or rheumatoid diseases, such as rheumatoid arthritis, and/or pain, or the other diseases mentioned above and below.
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
In accordance with the present invention it has now surprisingly been found that the compounds of the formula I defined below have use in the treatment of inflammatory rheumatic and rheumatoid diseases, especially of the inflammation, e.g. of inflammatory processes, conditions, events and disease, as well as their sequelae or symptoms, associated with a rheumatic or rheumatoid disease; and/or for the treatment of pain.
The invention relates to the treatment of an inflammatory disease, especially an inflammatory rheumatoid or rheumatic disease, more especially to the treatment of arthritis, preferably rheumatoid arthritis, and/or pain, or (especially in the case of new compounds of the formula I) any other disease mentioned hereinbefore and hereinafter, with a compound of the formula I,
wherein
r is 0 to 2,
n is 0 to 3
R
1
and R
2
a) are independently in each case a lower alkyl;
b) together form a bridge of subformula I*,
wherein
the bond is achieved via the two terminal C atoms and
m is 0 to 4, or
c) together form a bridge of 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 bond is achieved via atoms T
1
and T
4
;
G is —C(═O)—, —CHF—, —CF
2
—, lower alkylene, C
2
-C
6
alkenylene, lower alkylene or C
3
-C
6
alkenylene substituted by acyloxy or hydroxy, —CH
2
—O—, —CH
2
—S—, —CH
2
—NH—, —CH
2
—O—CH
2
—, —CH
2
—S—CH
2
—, —CH
2
—NH—CH
2
—, oxa (
Bold Guido
Frei Jörg
Heng Richard
King Janet Dawson
Manley Paul William
Brouillette D. Gabrielle
Loeschorn Carol A.
Novartis AG
Patel Sudhaker B.
Shah Mukund J.
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