Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-15
2004-04-20
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S198000, C544S207000, C544S209000, C544S264000, C544S265000, C544S266000, C544S267000, C544S268000, C544S269000, C544S270000, C544S271000, C544S272000, C544S276000, C544S277000, C514S263220
Reexamination Certificate
active
06723727
ABSTRACT:
The present invention relates to compounds of the formulae I and Ia
in which X, Y, W, W
a
, G and G
a
have the meanings indicated below, and to their physiologically tolerable salts and their prodrugs, their preparation, their use and pharmaceutical preparations comprising them.
The compounds of the formula I are valuable pharmaceutical active compounds. In particular, they are vitronectin receptor antagonists and are suitable for the therapy and prophylaxis of illnesses which are based on the interaction between vitronectin receptors and their ligands in cell-cell or cell-matrix interaction processes or which can be prevented, alleviated or cured by influencing this interaction. The invention relates, inter alia, to the use of compounds of the formula I and of their physiologically tolerable salts and of pharmaceutical preparations which contain such compounds, as therapeutics for the prevention, alleviation or cure of illnesses which are caused at least partially by an undesired extent of bone resorption, angiogenesis or proliferation of cells of the vascular smooth musculature, or for whose therapy or prophylaxis an influencing of these processes is intended. In particular, the compounds of the formula I are suitable, for example, as inhibitors of bone resorption, as inhibitors of tumor growth and tumor metastasis, as antiinflammatories, for the treatment or prophylaxis of cardiovascular disorders, such as, for example, arteriosclerosis or restenosis, or for the treatment or prophylaxis of nephropathies and retinopathies, such as, for example, diabetic retinopathy.
The compounds of the formulae I and Ia according to the invention inhibit bone resorption by osteoclasts. Bone diseases against which the compounds of the formula I can be employed are especially osteoporosis, hypercalcemia, osteopenia, for example caused by metastases, dental disorders, hyperparathyroidism, periarticular erosions in rheumatoid arthritis and Paget's disease. The compounds of the formula I can furthermore be employed for the alleviation, avoidance or therapy of bone disorders which are caused by glucocorticoid, steroid or corticosteroid therapy or by a lack of sex hormone(s). All these disorders are characterized by bone loss which is based on the inequilibrium between bone formation and bone destruction.
Human bones are subject to a constant dynamic renovation process comprising bone resorption and bone formation. These processes are controlled by types of cell specialized for these purposes. Bone formation is based on the deposition of bone matrix by osteoblasts, and bone resorption is based on the destruction of bone matrix by osteoclasts. The majority of bone disorders are based on a disturbed equilibrium between bone formation and bone resorption. Osteoporosis is characterized by a loss of bone matrix. Activated osteoclasts are polynuclear cells having a diameter of up to 400 &mgr;m, which remove bone matrix. Activated osteoclasts become attached 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 acidic environment and the proteases cause the destruction of the bone.
Studies have shown that the attachment of osteoclasts to the bones is controlled by integrin receptors on the cell surface of osteoclasts. Integrins are a superfamily of receptors which include, inter alia, the fibrinogen receptor a
IIb
&bgr;
3
on the blood platelets and the vitronectin receptor a
v
&bgr;
3
. The vitronectin receptor a
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 vascular smooth musculature, osteoclasts and tumor cells. The vitronectin receptor a
v
&bgr;
3
, which is expressed on the osteoclast membrane, controls the process of attachment to the bone and bone resorption and thus contributes to osteoporosis, a
v
&bgr;
3
in this case binds to bone matrix proteins such as osteopontin, bone sialoprotein and thrombospontin, which contain the tripeptide motif Arg-Gly-Asp (or RGD).
Horton and co-workers describe RGD peptides and an anti-vitronectin receptor. antibody (23C6) which inhibit tooth destruction by osteoclasts and the migration of osteoclasts (Horton et al., Exp. Cell. Res. 1991, 195, 368). In J. Cell Biol. 1990, 111, 1713, Sato et al. describe echistatin, an RGD peptide from snake venom, as a potent inhibitor of bone resorption in a tissue culture and as an inhibitor of osteoclast adhesion to the bone. Fischer et al. (Endocrinology 1993, 132, 1411) were able to show in the rat that echistatin also inhibits bone resorption in vivo. Wayne et al. (J. Clin. Invest. 1997, 99, 2284) were able to demonstrate in the rat the in vivo efficacy of the inhibition of bone resorption by a vitronectin receptor antagonist.
The vitronectin receptor a
v
&bgr;
3
on human cells of the vascular smooth musculature of the aorta stimulates the migration of these cells into the neointima, which finally leads to arteriosclerosis and restenosis after angioplasty (Brown et al., Cardiovascular Res. 1994, 28, 1815).
Brooks et al. (Cell 1994, 79, 1157; J. Clin. Invest. 96 (1995) 1815) and Mitjans et al., J. Cell Science 1995, 108, 2825) showed that antibodies against a
v
&bgr;
3
or a
v
&bgr;
3
antagonists can cause a shrinkage of tumors by inducing the apoptosis of blood vessel cells during angiogenesis. Cheresh et al. (Science 1995, 270, 1500) describe anti-a
v
&bgr;
3
antibodies or a
v
&bgr;
3
antagonists which inhibit the bFGF-induced angiogenesis process in the rat eye, a property which can be used therapeutically in the treatment of retinopathies.
EP-A-0 528 586 and EP-A-0 528 587 disclose aminoalkyl- or heterocyclyl-substituted phenylalanine derivatives, and WO 95/32710 discloses aryl derivatives as inhibitors of bone resorption by osteoclasts. WO 95/28426 describes RGD peptides as inhibitors of bone resorption, angiogenesis and restenosis. WO 96/00574 and WO 96/26190 describe benzodiazepines, inter alia, as vitronectin receptor antagonists or integrin receptor antagonists. WO 96/00730 describes fibrinogen receptor antagonist templates, in particular benzodiazepines, which are linked to a nitrogen-bearing 5-membered ring, as vitronectin receptor antagonists. EP-A0 531 883 describes fused 5-membered heterocycles which inhibit fibrinogen binding to platelets.
The present invention relates to compounds of the formulae I and Ia
in which:
X is hydrogen, NR
6
R
6′
, fluorine, chlorine, bromine, OR
6
, SR
6
, hydroxy-(C
1
-C
6
)-alkyl-NH, (hydroxy-(C
1
-C
6
)-alkyl)
2
N, amino-(C
1
-C
6
)-alkyl-NH, (amino-(C
1
-C
6
)-alkyl)
2
N, hydroxy-(C
1
-C
6
)-alkyl-O, hydroxy-(C
1
-C
6
)-alkyl-S or NH—CO—R
6
;
Y is R
6
, fluorine, chlorine, bromine, cyano, NR
6
R
6′
, OR
6
, SR
6
or hydroxy-(C
1
-C
6
)-alkyl-NH;
G is a radical of the formula II
—(CR
1
R
2
)
n
—A—(CR
1
R
2
)
m
—(CR
1
R
3
)
i
—(CR
1
R
2
)
g
—R
4
(II);
W is a radical of the formula III
—B—(CR
1
R
2
)
r
—A′—(CR
1
R
2
)
s
—(CR
1
R
3
)
k
—(CR
1
R
2
)
t
—D—E (III);
G
a
is a radical of the formula IIa
—(CR
1
R
2
)
r
—A′—(CR
1
R
2
)
s
—(CR
1
R
3
)
k
—(CR
1
R
2
)
t
—D—E (IIa);
W
a
is a radical of the formula IIIa
—B—(CR
1
R
2
)
n
—A—(CR
1
R
2
)
m
—(CR
1
R
3
)
i
—(CR
1
R
2
)
q
—R
4
(IIIa);
A, A′ independently of one another are a direct bond, —C(O)NR
5
—, —NR
5
C(O)—, —C(O)—, —NR
5
—, —O—, —S—, —SO—, —SO
2
—, (C
5
-C
14
)-arylene, where in the aryl radical one to five carbon atoms can be replaced by one to five heteroatoms, (C
2
-C
4
)-alkynylene, (C
2
-C
4
)-alkenylene, or a divalent radical of a 3- to 7-membered saturated or unsaturated ring which can contain one or two heteroatoms, such as, for example, nitrogen, sulfur or oxygen, and which can be monosubstituted or disubstituted by radicals from the group consisting of ═O, ═S and R
3
;
R
1
, R
2
independently of one another are hydrogen, flurine, chlorine, cyano, nitro, (C
1
-C
10
)-alkyl, (C
3
-C
14
)-cycloalkyl, (C
3
Breipohl Gerhard
Carniato Denis
Gadek Thomas Richard
Gourvest Jean-Francois
Knolle Jochen
Berch Mark L.
Foley & Lardner
Hoechst Aktiengesellschaft
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