Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-07-11
2003-09-23
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S352000, C546S143000, C546S309000
Reexamination Certificate
active
06624174
ABSTRACT:
This application is a 371 of PCT/EP01/00835 filed Jan. 25, 2001.
The invention relates to the use of 2-amino-nicotinamide derivatives alone or in combination with one or more other pharmaceutically active compounds for the preparation of a pharmaceutical composition for use for therapy of a disease which responds to an inhibition of the VEGF-receptor tyrosine kinase activity, especially a neoplastic disease, retinopathy or age-related macular degeneration; a method for the treatment of such a disease in animals, especially in humans; new 2-amino-nicotinamide derivatives and processes for the preparation thereof.
Certain diseases are known to be associated with deregulated angiogenesis, for example diseases caused by ocular neovascularisation, such as retinopathies (including diabetic retinopathy), age-related macular degeneration, psoriasis, haemangioblastoma, haeman-gioma, endometriosis, and especially neoplastic diseases, for example so-called solid tumors and liquid tumors (such as leukemias).
According to recent findings, 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; originally termed “Vascular Permeability Factor”,=VPF), along with its cellular receptors (see Breler, G., et al., Trends in Cell Biology 6, 454-6 [1996] and references cited therein).
VEGF is a dimerc, disulfide-linked 46-kDa glycoprotein produced by normal cell lines and tumor cell lines. It 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 proteolytc 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 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 tumors, especially gliomas and carcinomas, express high levels of VEGF and its receptors. This has led to the hypothesis that the VEGF released by tumor cells could stimulate the growth of blood capillaries and the proliferation of tumor endothelium in a paracrine manner and thus, through the improved blood supply, accelerate tumor growth. Increased VEGF expression could explain the occurrence of cerebral oedema in patients with glioma. Direct evidence of the role of VEGF as a tumor 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 tumor cell lines in vivo as a result of inhibited tumor angiogenesis.
Angiogenesis is regarded as an absolute prerequisite for those tumors which grow beyond a maximum diameter of about 1-2 mm; up to this limit, oxygen and nutrients may be supplied to the tumor cells by diffusion. Every tumor, 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 tumors: 1) Inhibition of the growth of vessels, especially capillaries, into a vascular resting tumors, with the result that there is no net tumor growth owing to the balance that is achieved between apoptosis and proliferation; 2) Prevention of the migration of tumor cells owing to the absence of blood flow to and from tumors; 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.
Surprisingly, it has now been found that nicotinamide derivatives of formula I, described below, are a new class of compounds that have advantageous pharmacological properties and inhibit, for example, the activity of the VEGF receptor tyrosine kinase, the growth of tumors and VEGF-dependent cell proliferation, and the other diseases mentioned above and below.
The compounds of formula I open up, 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.
The invention relates to the use of a compound of formula I,
wherein
n is from 1 up to and including 6;
W is O or S;
R
1
and R
3
represent independently of each other hydrogen, lower alkyl or lower acyl;
R
2
represents an cycloalkyl group, an aryl group, or a mono- or bicyclic heteroaryl group comprising one or more ring nitrogen atoms and 0, 1 or 2 heteroatoms independently from each other selected from the group consisting of oxygen and sulfur, which groups in each case are unsubstituted or mono- or polysubstituted;
R and R′ are independently of each other hydrogen or lower alkyl;
X represents an aryl group, or a mono- or bicyclic heteroaryl group comprising one or more ring nitrogen atoms and 0, 1 or 2 heteroatoms independently from each other selected from the group consisting of oxygen and sulfur, which groups in each case are unsubstituted or mono- or polysubstituted;
and of a N-oxide or a possible tautomer thereof;
or of a pharmaceutically acceptable salt of such a compound for the preparation of a pharmaceutical composition for the treatment of a disease which responds to an inhibition of the VEGF receptor tyrosine kinase activity.
The general terms used hereinbefore and hereinafter preferably,have within the context of this disclosure the following meanings, unless otherwise indicated:
The prefix “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 either linear or branched with single or multiple branching.
Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like.
Any asymmetric carbon atoms (for example in compounds of formula I, wherein R or R′ is lower alkyl) may be present in the (R)-, (S)- or (R,S)-configuration, preferably in the. (R)- or (S)-configuration. The compounds may thus be present as mixtures of isomers or as pure isomers, preferably as enantiomer-pure diastereomers.
The invention relates also to possible tautomers of the compounds of formula I.
X is preferably pyridyl or phenyl, most preferred it is 3- or 4-pyridyl.
In a preferred embodiment of the invention X is substituted by lower alkoxy.
In further a very preferred embodiment of the invention X has the substructure X′
wherein Rx is hydrogen or lower alkyl.
R
2
is preferably phenyl which is mono- or disubstituted by lower alkyl, lower alkynyl, halogen, preferably fluoro, and trifluorbmethyl; or cycloalkyl, preferably cydohexyl substituted by lower alkyl, preferably tert-butyl.
R
3
is preferably hydrogen.
W is preferably O.
The integer n is preferably 1 or 2, very preferably 1.
Lower alkyl is preferably alkyl with from and including 1 up to and including 7, preferably from and including 1 to and including 5, and is linear or branched; preferably, lower alkyl is pentyl, such as n-pentyl, butyl, such as n-butyl, sec-butyl, isobutyl, tert-butyl, propyl,
Bold Guido
Manley Paul William
Davis Zinna Northington
Dohmann George R.
Novartis AG
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