Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-02-21
2003-09-16
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S016000, C546S020000
Reexamination Certificate
active
06620820
ABSTRACT:
BACKGROUND OF THE INVENTION
Human bones are subject to a continuous dynamic process of reconstruction which involves bone reabsorption and bone synthesis. These processes are controlled by cell types which are specialised for this purpose. Bone synthesis is based on the deposition of bone matrix by osteoblasts, while bone reabsorption is based on the breakdown of bone matrix by osteoclasts. The majority of bone diseases are due to the balance between bone formation and bone reabsorption being disturbed. Osteoporosis is characterised by a loss of bone matrix. Activated osteoclasts are multinuclear cells, having a diameter of up to 400 &mgr;m which demolish bone matrix. Activated osteoclasts attach themselves to the surface of the bone matrix and secrete proteolytic enzymes and acids into the so-called sealing zone, the region between their cell membrane and the bone matrix. The acid environment and the proteases bring about the breakdown of the bone.
Studies have demonstrated that the attachment of osteoclasts to the bones is regulated by integrin receptors on the cell surface of osteoclasts.
Integrins are a superfamily of receptors which includes, inter alia, the fibrinogen receptor &agr;
IIb
&bgr;
3
on the blood platelets and the vitronectin receptor &agr;
V
&bgr;
3
. The vitronectin receptor, &agr;
V
&bgr;
3
, is a membrane glycoprotein which is expressed on the cell surface of a number of cells such as endothelial cells, cells of the smooth blood vessel musculature, osteoclasts and tumor cells. The &agr;
V
&bgr;
3
vitronectin receptor which is expressed on the osteoclast membrane regulates the process of attachment to the bones and of bone reabsorption and consequently contributes to osteoporosis.
In this context, &agr;
V
&bgr;
3
binds to bone matrix proteins, such as osteopontin, bone sialoprotein and thrombospondin, which contain the tripeptide motif Arg-Gly-Asp (or RGD).
Horton and coworkers describe RGD peptides and an anti-vitronectin receptor antibody (23C6) which inhibit tooth breakdown by osteociasts and the migration of osteoclasts (Horton et al., Exp. Cell. Res. 1991, 195, 368). In J. Cell Biol. 1990, 111, 1713, Sato et al. report that echistatin, an RGD peptide from snake venom, is a potent inhibitor of bone reabsorption in a tissue culture and an inhibitor of the attachment of osteoclasts to bones. Fischer et al. (Endocrinology, 1993, 132, 1411) were able to demonstrate that, in the rat, echistatin also inhibits bone reabsorption in vivo.
The &agr;
V
&bgr;
3
vitronectin receptor on human cells of the smooth blood vessel musculature of the aorta stimulates migration of these cells into the neointima, a process which finally leads to arteriosclerosis and restenosis following angioplasty (Brown et al., Cardiovascular Res. 1994, 28, 1815).
Brooks et al. (Cell 1994, 79, 1157) have demonstrated that antibodies against &agr;
V
&bgr;
3
or &agr;
V
&bgr;
3
antagonists are able to shrink tumors by inducing the apoptosis of blood vessel cells during angiogenesis. Chersh et al. (Science 1995, 270, 1500) describe anti-&agr;
V
&bgr;
3
antibodies or &agr;
V
&bgr;
3
antagonists which inhibit bFGF-induced angiogenesis processes in the rat eye, something which might be of therapeutic value in the treatment of retinopathies.
EP-A 449 079, EP-A 530 505, EP-A 566 919 and WO 93/18057 describe hydantoin derivatives, and WO 95/14008 describes substituted 5-membered ring heterocycles, both of which sets of compounds exhibit thrombocyte aggregation-inhibiting effects. Patent Application WO 94/12181 describes substituted aromatic or non-aromatic ring systems, and WO 94/08577 describes substituted heterocycles, both of which sets of compounds act as fibrinogen receptor antagonists and inhibitors of platelet aggregation. EP-A-528 586 and EP-A-528 587 disclose aminoalkyl-substituted or heterocyclyl-substituted phenylalanine derivatives, and WO 95/32710 describes aryl derivatives, all of which sets of compounds act as inhibitors of bone reabsorption by osteoclasts. WO 95/28426 describes RGD peptides which act as inhibitors of bone reabsorption, angiogenesis and restenosis. WO 96/00574 describes benzodiazepines, and WO 96/00730 describes fibrinogen receptor antagonist templates, in particular benzodiazepines which are linked to a 5-membered ring carrying a nitrogen, both of which sets of compounds act as vitronectin receptor antagonists.
SUMMARY OF THE INVENTION
It is therefore an object of the instant invention to provide the compounds of formula I. It is a further object to provide pharmaceutical compositions of the compounds of formula I, and methods of treating with these compositions diseases associated with vitronectin receptor binding. It is a further object to provide methods for preparing the compounds of formula I. It is a further object to provide an in vitro method of inhibiting the activation of vitronectin receptor using the compounds of formula I.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The present invention relates to compounds of the formula I and their physiologically tolerated salts, to pharmaceutical preparations comprising these compounds and to their preparation and use as medicaments, in particular as inhibitors of bone reabsorption by osteoclasts, as inhibitors of tumor growth and tumor metastasis, as inflammation inhibitors, for the treatment or prophylaxis of cardiovascular diseases such as arteriosclerosis or restenosis, for the treatment or prophylaxis of nephropathies and retinopathies, for example diabetic retinopathy, and also as vitronectin receptor antagonists for the treatment and prophylaxis of diseases which are based on the interaction between vitronectin receptors and their ligands in cell—cell or cell-matrix interaction processes. The invention furthermore relates to the use of the compounds of the formula I, and their physiologically tolerated salts and pharmaceutical preparations comprising these compounds, as medicaments for alleviating or curing diseases which are associated, at least in part, with an undesirable degree of bone reabsorption, angiogenesis or proliferation of cells of the smooth blood vessel musculature.
The novel compounds of the formula I inhibit bone reabsorption by osteoclasts. Bone diseases against which the novel compounds can be employed are, in particular, osteoporosis, hypercalcemia, osteopenia, e.g. elicited by metastases, dental diseases, hyperparathyroidism, periarticular erosions in rheumatoid arthritis and Paget's disease.
In addition, the compounds of the formula I can be employed for the alleviation, avoidance or therapy of bone diseases which are provoked by glucocorticoid therapy, steroid therapy or corticosteroid therapy, or by a lack of sexual hormone(s). All these diseases are characterized by bone loss which is due to the imbalance between bone synthesis and bone breakdown.
Moreover, the compounds of formula I can be used as carrier of agents which are effective in the treatment of the afore-mentioned diseases thus allowing the specific transfer of said agents to the desired target (=Drug Targeting, see e.g. Targeted Drug Delivery, R. C. Juliano, Handbook of Experimental Pharmacology, Vol. 100, Ed. Born, G. V. R. et al, Springer Verlag), herein incorporated by reference.
The present invention relates to 5-membered ring heterocycles of the formula I,
in which:
W is R
1
—A—B—D—C(R
16
), R
1
—A—B—D—C(R
16
)═C,
or
with it being possible for the ring systems
to contain 1 or 2 heteroatoms from the group N, O and S, to be saturated or unsaturated, once or more than once, and be substituted by 1-3 substituents from R
16
or substituted, once or twice, by doubly bonded O or S;
Y is C═O, C═S or —CH
2
—;
Z is N(R
O
), O, S or —CH
2
—;
A is a direct linkage, (C
1
-C
8
)-alkanediyl, —NR
2
—N═CR
2
—, —NR
2
—C(O)—NR
2
—, —NR
2
—C(O)O—, —NR
2
—C(O)S—, —NR
2
—C(S)—NR
2
—, —NR
2
—C(S)—O—, —NR
2
—C(S)—S—, —NR
2
—S(O)
n
—NR
2
—, —NR
2
—S(O)
n
—O—, —NR
2
—S(O)
n
—, (C
3
-C
12
)-cycloalkanediyl, —C≡C—, —NR
2
—C(O)—, —C(O)—NR
2
—, —(C
5
-C
14
)-arylene-C(O)—NR
2
—,
Carniato Denis
Gadek Tom
Gourvest Jean-Francois
Knolle Jochen
McDowell Robert
Foley & Lardner
Hoechst Aktiengesellschaft
McKane Joseph K.
Sackey Ebenezer
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