Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-15
2002-07-16
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S312000
Reexamination Certificate
active
06420396
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to new biphenyl and biphenyl-analogous compounds, their preparation and use as pharmaceutical compositions, as integrin antagonists and in particular for the production of pharmaceutical compositions for the treatment and prophylaxis of cancer, arteriosclerosis, restenosis, osteolytic disorders such as osteoporosis, rheumatoid arthritis and ophthalmic diseases.
BACKGROUND OF THE INVENTION
Integrins are heterodimeric transmembrane proteins found on the surface of cells, which play an important part in the adhesion of the cells to an extracellular matrix. They recognize extracellular glycoproteins such as fibronectin or vitronectin on the extracellular matrix by means of the RGD sequence occurring in these proteins (RGD is the single letter code for the amino acid sequence arginine-glycine-aspartate).
In general, integrins such as, for example, the vitronectin receptor, which is also called the &agr;
v
&bgr;
3
receptor, or alternatively the &agr;
v
&bgr;
5
receptor or the GpIIb/IIIa receptor play an important part in biological processes such as cell migration and cell-matrix adhesion and thus in diseases in which these processes are crucial steps. Cancer, osteoporosis, arteriosclerosis, restenosis (reoccurrence of stenosis after percutaneous transluminal angioplasty) and opthalmia may be mentioned by way of example.
The &agr;
v
&bgr;
3
receptor occurs, for example, in large amounts on growing endothelial cells and makes possible their adhesion to an extracellular matrix. Thus the &agr;
v
&bgr;
3
receptor plays an important part in angiogenesis, i.e. the formation of new blood vessels, which is a crucial prerequisite for tumor growth and metastasis formation in carcinoses. Furthermore, it is also responsible for the interaction between osteoclasts, i.e. cells resorbing mineralized tissue, and the bone structure. The first step in the degradation of bone tissue consists in the adhesion of osteoclasts to the bone. This cell-matrix interaction takes place via the &agr;
v
&bgr;
3
receptor, which is why the corresponding integrin plays an important part in this process. Osteolytic diseases such as osteoporosis are induced by an inequilibrium between bone formation and bone destruction, i.e. the resorption of bone material caused by accumulation of osteoclasts predominates.
It was possible to show that the blockage of the abovementioned receptors is an important starting point for the treatment of disorders of this type. If the adhesion of growing endothelial cells to an extracellular matrix is suppressed by blocking their appropriate integrin receptors, for example, by a cyclic peptide or a monoclonal antibody, the endothelial cells die. Therefore angiogenesis does not occur, which leads to a cessation or resolution of the tumor growth (cf., for example, Brooks et al., Cell, Volume 79, 1157-1164, 1994).
Moreover, the invasive properties of tumor cells and thus their capability for metastasis formation are markedly decreased if their &agr;
v
&bgr;
3
receptor is blocked by an antibody (Brooks et al., J. Clin. Invest., Volume 96, 1815, 1995).
The degradation of bone tissue can be suppressed by blockage of the &agr;
v
&bgr;
3
receptors of the osteoclasts, since these are then unable to accumulate on the bone in order to absorb its substance (WO 98/18461, p. 1, 1.24 to p. 2,1.13).
By means of the blockage of the &agr;
v
&bgr;
3
receptor on cells of the smooth aorta vascular musculature with the aid of integrin receptor antagonists, the migration of these cells into the neointima and thus angioplasty leading to arteriosclerosis and restenosis can be suppress ed (Brown et al., Cardiovascular Res., Volume 28, 1815, 1994).
In recent years, compounds have therefore been sought which act as a ntagonists of integrin receptors. For example, WO 98/00395 discloses the para-substituted phenylalanine derivative (I), which shows an IC
50
value of 0.13 nM in an &agr;
v
&bgr;
3
receptor assay and an IC
50
value of 0.16 nM in an &agr;
v
&bgr;
5
receptor assay:
The abovementioned compound (I) has a guanidine unit, by means of which the oral availability is limited on account of the relatively rapid clearance rate of the compound in the digestive tract. Thus the compound (II), for example, is preferably administered parenterally (cf. WO 98/00395, p. 25, 1.31-32).
Furthermore, WO 98/18461, for example, discloses naphthyl compounds such as (II), which have an IC
50
value in the range from 0.4 to 110 nM against the &agr;
v
&bgr;
3
receptor in an SPA assay:
Biphenyl nuclei are present in numerous pharmaceutical compositions. Experiments carried out until now to establish integrin antagonists having a biphenyl nucleus only led, however, to compounds having relatively poor activity. Thus, in addition to numerous substances included by a general formula, WO 94/12181 actually describes the biphenyl compounds (III) as antagonists of the GpIIb/IIIa receptor. The use of these compounds as &agr;
v
&bgr;
3
or &agr;
v
&bgr;
5
receptor antagonists is not described:
The biphenyl compounds such as (IV) prepared by B. R. Neustadt et al. exhibit activity as &agr;
v
&bgr;
3
receptor antagonists which is far below that of known integrin antagonists, which is why they are not suitable lead structures according to this document (Bioorg. Med. Chem. Lett. 8, 2395, 1998, in particular p. 2398, second paragraph):
It was the object of the present invention to develop compounds which exhibit a high activity as integrin antagonists and in particular against the &agr;
v
&bgr;
3
and/or the &agr;
v
&bgr;
5
receptor.
SUMMARY OF THE INVENTION
The present object is achieved according to the invention by the substituted biphenyl compounds defined below. In particular, it has emerged that the biphenyl compounds according to the invention have a very high activity as integrin antagonists, especially against the &agr;
v
&bgr;
3
and/or the &agr;
v
&bgr;
3
receptor.
The present invention relates to compounds of the general formula (1)
wherein
R
1
is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue;
R
2
is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue, a saturated or unsaturated, optionally substituted heterocyclic residue, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue, —NR
2′
SO
2
R
2″
, —NR
2′
COOR
2′
, —NR
2′
COR
2′
, —NR
2′
CONR
2′
2
or —NR
2′
CSNR
2′
2
;
R
2′
is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue;
R
2″
is a substituted or unsubstituted alkyl, alkenyl or cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue;
U is a direct bond or a substituted or unsubstituted alkylene group;
V is a substituted or unsubstituted alkylene group, —NR
2′
CO— or —NR
2′
SO
2
—;
A and B are each independently of one another a 1,3- or 1,4-bridging phenylene group or a 2,4- or 2,5-bridging thienylene group each of which may optionally have additional substituents,
W is a direct bond or a substituted or unsubstituted alkylene group;
C is a direct bond or
R
3
is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue, a saturated or unsaturated, optionally substituted heterocyclic residue, an alkylamine residue, an alkylamide residue or is connected to one of R
4
, Y, R
5
or R
6
, if present, with formation of an optionally substituted heterocyclic ring system which includes the nitrogen atom to which R
3
is bonded, and can be saturated or unsaturated and/or can contain further heteroatoms;
R
4
is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a
Albers Markus
Brueggemeier Ulf
Gerdes Christoph
Härter Michael
Keldenich Jörg
Beiersdorf AG
McKenzie Thomas
Norris & McLaughlin & Marcus
Raymond Richard L.
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