1,4-benzodiazepinone derivatives and their use as integrin...

Details 1,4-benzodiazepinone derivatives and their use as integrin... 1,4-benzodiazepinone derivatives and their use as integrin...

2001-06-12

2002-12-17

Kifle, Bruck (Department: 1609)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S504000, C540S512000, C540S513000, C540S516000

Reexamination Certificate

active

06495545

ABSTRACT:

The present invention relates to new multiheterocyclic compounds as integrin antagonists with a broad spectrum of action having, inter alia, antiosteoporotic, antirestenotic, anticarcinogenic and antiatherosclerotic activity. The present invention moreover relates to the preparation of these compounds and their use for the production of medicaments, and also medicaments comprising them.
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 suppressed (Brown et al., Cardiovascular Res., Volume 28, 1815, 1994).
In recent years, compounds have therefore been sought which act as antagonists of integrin receptors. For example WO 97/24119 discloses victronectin (&agr;
v
&bgr;
3
) receptor antagonist as antiosteoporosis agents which are structurally related to the compounds described here, but do not have a broad spectrum of action of this type.
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.
The compounds on which the present invention is based can be described by the following general formula (I):
where
R1 and R2 together with the formal double bond bridging them form a phenyl ring or a six-membered aromatic heterocycle having 1 or 2 nitrogen atoms, which is optionally substituted by halogen, nitro, cyano, trifluoromethyl, hydroxyl, (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy, (C
1
-C
6
)-alkoxycarbonyl, amino, carboxyl, phenoxy, (C
6
-C
10
)-aryl, (C
1
-C
6
)-alkylamino, (C
1
-C
6
)-alkylsulfone or a group of the formula —SO
2
NR
a
R
b
wherein R
a
and R
b
may independently represent hydrogen or (C
1
-C
6
)-alkyl, and
R3=H or (C
1
-C
4
)-alkyl, and
A=O, S, (CH
2
)
n
where n=1,2,3 or 4 or N—R7 where R7=H or (C
1
-C
4
)-alkyl, or is absent and
X, Y, Z=O, S, N, N—R8 where R8=H, (C
1
-C
6
)-alkyl or (C
6
-C
10
)-aryl, or C—(R9)(R10) where R9, R10=H, (C
1
-C
6
)-alkyl or (C
1
-C
10
)-aryl, or C—(R11) if the X, Y or Z in question is participating in a formal double bond, where R11=H, (C
1
-C
6
)-alkyl or (C
6
-C
10
)-aryl, and
D=O, S, (CH
2
)
n
where n=1,2,3 or 4, or N—R7 where R7=H or (C
1
-C
4
)-alkyl, or is absent and
E, G, L=H, halogen, nitro, cyano, trifluoromethyl, hydroxyl, carboxyl, (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy or (C
1
-C
6
)-alkoxycarbonyl, where E, G and L can be identical or different and
R4=H, (C
3
-C
8
)-cycloalkyl, (C
1
-C
6
)-alkyl, which is optionally substituted by hydroxyl, (C
1
-C
6
)-alkoxy or phenyl, where the latter is optionally in turn substituted on the phenyl ring by halogen, (C
1
-C
4
)-alkyl, (C
1
-C
4
)-alkoxy, hydroxyl, trifluoromethoxy or trifluoromethyl, and
R5=H or (C
1
-C
4
)-alkyl and
R6=H, (C
1
-C
6
)-alkyl or benzyl
and their salts.
Preferred compounds according to the general formula (I) are those where
R1 and R2 together with the formal double bond bridging them form a phenyl ring or a six-membered aromatic heterocycle having 1 or 2 nitrogen atoms, which is optionally substituted by (C
1
-C
6
)-alkoxy, nitro or amino, and
R3=H, and
A=O, S, (CH
2
)
n
where n=1,2,3 or 4 or N—H, or is absent and
X, Y, Z=O, S, N, N—R8 where R8=H, (C
1
-C
6
)-alkyl or (C
6
-C
10
)-aryl, or C—(R9)(R10) where R9, R10=H, (C
1
-C
6
)-alkyl or (C
6
-C
10
)-aryl, or C—(R11) if the X, Y or Z in question is participating in a formal double bond, where R11=H, (C
1
-C
6
)-alkyl or (C
6
-C
10
)-aryl, and
D=O, S, (CH
2
)
n
where n=1, 2, 3 or 4, or N—H, or is absent and
E, G, L=H, and
R4=H, benzyl, cyclopropyl, cyclopentyl, cyclohexyl, phenylethyl or (C
1
-C
4
)-alkyl, which is optionally substituted by hydroxyl or methoxy, and
R5=H, and
R6=H or methyl.
and their salts.
Particularly preferred compounds according to the general formula (I) are those where
R1 and R2 together with the formal double bond bridging them form a phenyl ring, which is optionally substituted by nitro. and
R3=H and
A=is absent and
X=N, Y=O and Z=N or X=N, Y=N and Z=O, S or X=CH
2
, Y=O, Z=N and
D=is absent and
E, G, L=H, and
R4=methyl, cyclopropyl or (C
1
-C
4
)-alkyl substituted by methoxy and
R5=H, and
R6=H or methyl
and their salts.
The compounds according to the invention can also be present in the form of their salts. In general, salts with organic or inorganic bases or acids may be mentioned here.
In the context of the present invention, physiologically acceptable salts are preferred. Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are, for example, those with hydro

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