Phenylserine derivatives as integrin antagonists

Details Phenylserine derivatives as integrin antagonists Phenylserine derivatives as integrin antagonists

2001-06-12

2003-04-08

Richter, Johann (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C560S034000, C560S045000, C562S439000, C562S444000, C546S332000, C514S534000, C514S538000, C514S539000, C514S567000

Reexamination Certificate

active

06545029

ABSTRACT:

The present invention relates to new phenylserine derivatives 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.
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 present invention relates to new compounds of the general formula (I)
in which
R
1
represents a radical of the formula
in which
A represents a 5- to 7-membered saturated, partially unsaturated or aromatic heterocycle having up to three identical or different heteroatoms from the group consisting of N, O and/or S,
n denotes a number 0, 1, 2, 3 or 4,
R
6
represents hydrogen, (C
3
-C
8
)-cycloalkyl, or straight-chain or branched (C
1
-C
6
)-alkyl, which for its part is optionally substituted by (C
6
-C
10
)-aryl, by 5- to 6-membered heteroaryl having up to three identical or different heteroatoms from the group consisting of N, O and/or S, or up to several times by halogen,
and
X denotes O, NH or a radical of the formula ═N—CN or ═CH—NO
2
,
R
2
and R
3
are identical or different and denote hydrogen, halogen, (C
1
-C
4
)-alkyl or (C
1
-C
4
)-alkoxy,
R
4
represents (C
1
-C
6
)-alkoxycarbonyl, (C
6
-C
10
)-arylmethyloxycarbonyl, (C
1
-C
6
)-alkylsulfonyl or (C
3
-C
8
)-cycloalkylsulfonyl,
or
represents 5- to 6-membered heteroarylsulfonyl having up to three identical or different heteroatoms from the group consisting of N, O and/or S, or (C
6
-C
10
)-arylsulfonyl, each of which is optionally substituted up to several times identically or differently by halogen, (C
1
-C
4
)-alkyl or (C
1
-C
4
)-alkoxy,
and
R
5
denotes hydroxy, (C
1
-C
6
)-alkoxy or benzyloxy,
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 hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention. Those particularly preferred are, for example, sodium, potassium, magnesium or calcium salts, and also ammonium salts which are derived from ammonia, or organic amines, such as, for example, ethylamine, di- or triethylamine, ethanolamine, di- or triethanolamine, dicyclohexylamine, dimethyl-aminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
The present invention also includes ammonium compounds which can be prepared by conversion of the free amines by means of alkylation.
In the context of the present invention, the substituents in general have the following meaning:
(C
1
-C
6
)-alkyl in general represents, depending on the abovementioned substituents, a straight-chain or branched hydrocarbon radical having 1 to 6, preferably 1 to 4 carbon atoms. Examples which may be mentioned are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl.
(C
1
-C
6
)-alkoxycarbonyl can be represented, for example, by the formula
Alkyl here represents a straight-chain or branched hydrocarbon radical having 1 to 6 carbon atoms. Lower alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl moiety is preferred. Examples which may be mentioned are the following alkoxycarbonyl radicals: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert.-butoxycarbonyl or isobutoxycarbonyl.
(C
3
-C
8
)-cycloalkyl in general represents a cyclic hydrocarbon radical having 3 to 8 carbon atoms. Cyclopropyl, cyclopentyl and cyclohexyl are preferred. Examples which may be mentioned are cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
(C
6
-C
10
)-aryl in general represents an aromatic radical having 6 to 10 carbon atoms. Preferred ar

Affiliated with

Also associated with

Rating

Phenylserine derivatives as integrin antagonists does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Phenylserine derivatives as integrin antagonists, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Phenylserine derivatives as integrin antagonists will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3044951