Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-27
2003-08-05
Rao, Deepak (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S563000, C544S330000, C544S332000, C562S471000
Reexamination Certificate
active
06602878
ABSTRACT:
A subject of the present invention is new acylguanidine derivatives, their preparation process, their use as medicaments and the pharmaceutical compositions containing them.
A subject of the invention is the compounds of formula (I):
in which R
1
, R
2
, R
4
, R
5
, R
7
and R
8
have the meanings indicated below, their physiologically acceptable salts and their prodrugs. The compounds of formula (I) are compounds having a pharmacological activity and can therefore be used as medicaments. These are antagonists of the vitronectin receptor and inhibitors of cell adhesion and they inhibit bone resorption mediated by the osteoclasts. They are therefore useful for the therapeutic or prophylactic treatment of diseases which are caused at least in part by an undesirable increase in bone resorption, for example osteoporosis. A subject of the invention is also the preparation process for the compounds of formula (I), their use, in particular as medicaments and the pharmaceutical compositions containing them.
The bone is constantly subjected to a dynamic process which includes bone resorption and bone formation. These processes are mediated via specialized cells. Bone formation is the result of the deposit of a mineral matrix by the osteoblasts and bone resorption is the result of the dissolution of this bone matrix by the osteoclasts. The majority of bone disorders are caused by a disturbed equilibrium between bone formation and bone resorption. Osteoporosis is characterized by a dry loss of this bone matrix. An activated mature osteoclast resorbs the bone after adhesion to the bone matrix via the secretion of proteolytic enzyme, and protons inside the adhesion zone, resulting in depressions or hollows on the bone surface which appear when the osteoclast detaches itself from the bone.
Studies have shown that the fixation of the osteoclast on the bone is mediated by receptors: the integrins. Integrins are a superfamily of receptors mediating the cell/cell and more particularly cell/matrix adhesion process, including in particular &agr;
IIb
&bgr;
3
as a blood platelet receptor (fibrinogen) and &agr;
v
&bgr;
3
as vitronectin receptor. The peptides containing the RGD unit as well as the anti &agr;
v
&bgr;
3
antibodies are known for their ability to inhibit resorbtion of dentin and prevention of osteoclast adhesion on the mineralized matrices (Horton et al. Exp. Cell. Res. (1991), 195, 368). The peptide Echistatine, isolated from snake venom also contains an RGD unit and is described as an inhibitor of the adhesion of osteoclasts to the bone and is a powerful inhibitor of bone resorption in tissues cultured in vitro (Sato et al. J. Cell. Biol. (1990), 111, 1713) and in vivo in the rat (Fisher et al. Endocrinology (1993), 132, 1411).
The &agr;
v
&bgr;receptor is a transmembrane glycoprotein which is expressed in a large number of cells including endothelial cells, smooth muscle cells, osteoclast and cancerous cells which thus leads to a pluripotentiality of the compounds of formula (I) according to the invention.
In fact, the &agr;
v
&bgr;receptors expressed in the membrane of the osteoclasts are the basis of the adhesion/resorption process, contribute to the organization of the cell cytoskeleton, and are involved in osteoporosis. The &agr;
v
&bgr;receptors expressed in the smooth muscle cells of the aorta, stimulate their migration towards the neointima, which leads to the formation of arteriosclerosis and the occurrence of post-angioplastic recurrence of stenosis (Brown et al., cardiovascular Res. (1994), 28, 1815). The endothelial cells secrete growth factors which are mitogens for the endothelium and can contribute to the formation of new blood vessels (Angiogenesis).
The antagonists of &agr;
v
&bgr;integrin can therefore lead to a regression of cancerous tumors by inducing apoptosis of the angiogenic blood vessels. (Brook et al. Cell (1994) 79, 1157).
Cheresh et al (Science 1995, 270, 1500) have described anti-&agr;
v
&bgr;antibodies or antagonists of the &agr;
v
&bgr;receptor which inhibit the process of angiogenesis induced by bFGF in the rat eye, a property which can be used for the treatment of retinopathies, in particular in diabetics.
The patent application WO-A-94/12181 describes aromatic or non-aromatic substituted systems and WO-A-94/08577 describes substituted heterocycles as antagonists of the fibrinogen receptor and inhibitors of platelet aggregation. EP-A-528586 and EP-A-528587 describe phenylalanine derivatives substituted by an aminoalkyl or a heterocycle and WO-A-95/32710 describes aryl derivatives as inhibitors of bone resorption by the osteoclasts. WO-A-96/00574 describes benzodiazepines and WO-A-96/00730 describes compounds which inhibit the fibrinogen receptor, in particular benzodiazepines which are linked to a ring with 5 nitrogenous members as antagonists of the vitronectin receptor. DE-A-19654483 describes tyrosine derived antagonists of the vitronectin receptor. DE-A-19629816.4 claims cycloalkyl derivatives as antagonists of the vitronectin receptor. Other investigations have made it possible to show that the acylguanidine derivatives of formula (I) show marked activity as inhibitors of the vitronectin receptor and of bone resorption mediated via the osteoclasts.
A subject of the invention is the compounds of formula (I)
in which
either R
1
and R
2
, independently from one another represent a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms non-substituted or substituted by R
3
, or R
1
and R
2
together form a divalent alkylene radical containing 2 to 9 carbon atoms, saturated or unsaturated, such as —(CH
2
)
p
— in which p is 2, 3, 4, 5, 6, 7, 8 or 9, non-substituted or substituted by one or more radicals chosen from halogen, (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy, (C
6
-C
14
)-aryl, (C
6
-C
14
)-aryl-(C
1
-C
6
)-alkyl, (C
5
-C
14
)-heteroaryl, (C
5
-C
14
)-heteroaryl-(C
1
-C
6
)-alkyl, (C
3
-C
12
)-cycloalkyl, (C
3
-C
12
)-cycloalkyl-(C
1
-C
6
)-alkyl and oxo, the said divalent alkylene radical being able to be attached at the level of the carbon-carbon bond to a carbocycle or a heterocycle with 5 to 7 members, containing 1 or 2 nitrogen atoms, saturated or unsaturated, non-substituted or substituted by 1 or 2 R
3
radicals;
R
3
represents a (C
1
-C
8
)-alkyl, (C
1
-C
8
)-alkoxy, (C
5
-C
14
)-aryl, (C
5
-C
14
)-aryl-(C
1
-C
4
)-alkyl, halogen, trifluoromethyl, hydroxyl, nitro, amino, NH—((C
1
-C
4
)-alkyl),N((C
1
-C
4
)alkyl)
2
, NHCO—(C
1
-C
4
)-alkyl or CO—(C
1
-C
4
)alkyl group;
R
4
represents
either a hydrogen atom,
or a (C
1
-C
6
)-alkyl-CO—O—(C
1
-C
4
)-alkyl or (C
1
-C
6
)-alkyl group, non-substituted or substituted by a radical chosen from hydroxyl, (C
1
-C
4
)-alkoxy, (C
1
-C
4
)-alkyl-SO
2
, NR
9
R
9
′ and N
+
R
9
R
9
′R
9
″Q
−
, in which R
9
, R
9
′ and R
9
″ independently from one another, represent a hydrogen, a (C
1
-C
6
)-alkyl, (C
5
-C
14
)-aryl or
(C
5
-C
14
)-aryl-(C
1
-C
6
)-alkyl group and Q
−
is a physiologically acceptable anion,
or one of the following radicals:
the dotted lines representing the position of the bond;
R
5
represents a hydrogen atom or a group chosen from COR
6
, CO
2
R
6
, SO
2
R
6
, SO
2
NHR
6
, SO
2
NHCOR
6
, SO
2
NHCO
2
R
6
,CONH
2
and CONHR
6
in which R
6
represents (C
1
-C
8
)-alkyl, (C
6
-C
14
)-aryl, (C
6
-C
14
)-aryl-(C
1
-C
6
)-alkyl, (C
5
-C
14
)-heteroaryl or (C
5
-C
14
)-heteroaryl-(C
1
-C
6
)-alkyl, (C
3
-C
20
) (mono-, bi- or tri-)-cycloalkyl, (C
3
-C
20
) (mono-, bi- or tri-)-cycloalkyl-(C
1
-C
6
)alkyl, the aryl, heteroaryl, alkyl or cycloalkyl radicals being non-substituted or substituted by 1, 2 or 3 R
3
radicals;
R
7
represents a hydrogen atom, (C
1
-C
6
)-alkyl-O—CO—, hydroxyl, (C
1
-C
6
)-alkyl-O—CO—O or nitro;
R
8
represents a hydrogen atom, halogen atom or an alkyloxy radical containing 1 to 6 carbon atoms;
m is equal to 0, 1, 2 or 3;
n is an integer equal to 1, 2 or 3;
the said compounds of formula (I) being in all their possible isomer forms, alone or in a mixture of any ratio, the acylguanidine group adjacent to the p
Bodary Sarah C.
Carniato Denis
Gadek Thomas R.
Gourvest Jean-Francois
Knolle Jochen
Aventis Pharma S.A.
Muserlian Lucas and Mercanti
Rao Deepak
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