Vitronectin receptor antagonists, their preparation and...

Details Vitronectin receptor antagonists, their preparation and... Vitronectin receptor antagonists, their preparation and...

2001-02-08

2002-11-19

Shah, Mukund (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S494000, C540S497000, C514S221000

Reexamination Certificate

active

06482821

ABSTRACT:

The present invention relates to compounds of the formula I
A—B—D—E—F—G   (I)
in which A, B, D, E, F and G have the meanings given below, their physiologically tolerated salts and pharmaceutical preparations comprising these compounds, and to their preparation and use 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, for example inflammations, cancer, tumor metastasis, cardiovascular disorders such as arteriosclerosis or restenosis, retinopathies and nephropathies, and diseases which are based on an undesirable degree of bone resorption, for example osteoporosis.
Human bones are subject to a continuous, dynamic process of reconstruction involving bone resorption and bone synthesis. These processes are regulated by cell types which are specialized for these purposes. While bone synthesis is based on the deposition of bone matrix by osteoblasts, bone resorption is based on the degradation of bone matrix by osteoclasts. Most bone disorders are based on an imbalance in the equilibrium between bone formation and bone resorption. Osteoporosis is characterized by a loss of bone matrix. Activated osteoclasts are multinuclear cells which have a diameter of up to 400 &mgr;m and which demolish 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, i.e. the region between their cell membrane and the bone matrix. The acid environment and the proteases degrade the bone.
Studies have shown that the attachment of osteoclasts to bone is regulated by integrin receptors on the surface of the osteoclast cells. 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 surface of a number of cells such as endothelial cells, cells of the smooth musculature of the blood vessels, osteoclasts and tumor cells. The vitronectin receptor &agr;
V
&bgr;
3
which is expressed on the osteoclast membrane regulates the process of attachment to bone and bone resorption and consequently contributes to osteoporosis. In this connection, &agr;
V
&bgr;
3
binds to bone matrix proteins, such as osteopontin, bone sialoprotein and thrombospontin, which contain the tripeptide motif Arg-Gly-Asp (or RGD).
As vitronectin receptor antagonists, the novel compounds of the formula I inhibit bone resorption by osteoclasts. Bone disorders for which the novel compounds can be employed are, in particular, osteoporosis, hypercalcaemia, osteopenia, e.g. caused by metastases, dental disorders, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, and Paget's disease. In addition, the compounds of the formula I may 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 a loss of bone, due to an imbalance between bone synthesis and bone degradation.
Horton and coworkers describe RGD peptides and an anti-vitronectin receptor antibody (23C6) which inhibit tooth breakdown 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. report that echistatin, an RGD peptide from snake venom, is a potent inhibitor of bone resorption in a tissue culture and an inhibitor of the attachment of osteoclasts to the bone. Fischer et al. (Endocrinology, 1993, 132, 1411) showed that echistatin also inhibits bone resorption in vivo in the rat.
The vitronectin receptor &agr;
V
&bgr;
3
on human cells of the smooth blood vessel musculature of the aorta stimulates the migration of these cells into the neointima, thereby leading finally to arteriosclerosis and restenosis following angioplasty (Brown et al., Cardiovascular Res. 1994, 28, 1815). Brooks et al. (Cell 1994, 79, 1157) show 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. Cheresh 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, a property which could be therapeutically useful in the treatment of retinopathies.
Patent application WO 94/12181 describes substituted aromatic or nonaromatic ring systems, and WO 94/08577 describes substituted heterocycles, which are fibrinogen receptor antagonists and inhibitors of platelet aggregation. EP-A0 528 586 and EP-A0 528 587 disclose aminoalkyl-substituted or heterocyclyl-substituted phenylalanine derivatives, and WO 95/32710 discloses aryl derivatives, which are inhibitors of bone resorption due to osteoclasts. WO 96/00574 and WO 96/26190 describe benzodiazepines which are vitronectin receptor antagonists and integrin receptor antagonists, respectively. WO 96/00730 describes fibrinogen receptor antagonist templates, in particular benzodiazepines which are linked to a nitrogen-carrying 5-membered ring, which are vitronectin receptor antagonists. German patent applications P 19629816.4, P 19629817.2 and P 19610919.1 and also EP-A0 796 855 describe substituted aromatic ring systems or 5-membered ring heterocycles which are vitronectin receptor antagonists.
The present invention relates to compounds of the formula I,
A—B—D—E—F—G   (I)
in which:
A is
is a 5-membered to 10-membered monocyclic or polycyclic, aromatic or nonaromatic ring system which can contain from 1 to 4 heteroatoms from the group N, O and S and can optionally be substituted, once or more than once, by R
12
, R
13
R
14
and R
15
;
B is a direct linkage, (C
1
-C
8
)-alkanediyl, (C
5
-C
10
)-arylene, (C
3
-C
8
)-cycloalkylene, —C═C—, —NR
2
—, —NR
2
—C(O)—, —NR
2
—C(O)—NR
2
—, —NR
2
—C(S)—NR
2
—, —O—C(O)—, —NR
2
—S(O)—, —NR
2
—S(O)
2
—, —O—, —S— or —CR
2
═CR
3
—, which can in each case be substituted, once or twice, by (C
1
-C
8
)-alkyl, for example -methyl-phenyl-methyl-, -ethyl-NR
2
—C(O)— etc.;
D is a direct linkage, (C
1
-C
8
)-alkanediyl, (C
5
-C
10
)-arylene, —O—, —NR
2
—, —CO—NR
2
—, —NR
2
—CO—, —NR
2
—C(O)—NR
2
—, —NR
2
—C(S)—NR
2
—,—OC(O)—,—C(O)O—,—S(O)—, —S(O)
2
—, —S(O)
2
—NR
2
—, —S(O)—NR
2
—, —NR
2
—S(O)—, —NR
2
—S(O)
2
—, —S—, —CR
2
═CR
3
— or —C═C— which can in each case be substituted, once or twice, by (C
1
-C
8
)-alkyl, —CR
2
═CR
3
— or (C
5
-C
6
)-aryl, for example methyl-phenyl-CH═CH—, ethyl-O- etc., with it not being possible for D to be —CO—NR
2
—, —C(O)O—, —S(O)—, —S(O)
2
—, —S(O)—NR
2
— or —S(O)
2
—NR
2
— when B is a direct linkage;
E a) is a template which is selected from the series of fibrinogen receptor antagonists and which is taken from the following patent applications, patent documents or literature references:
Adir et Compagnie
FR 928004, Jun. 30, 1992, Fauchere, J. L., et al..
EP 0578535, Jun. 29, 1993, Fauchere, J. L., et al..
CA 212850, Jan. 24, 1995, Godfroid, J. J., et al..
Asahi Breweries, Ltd.
JP 05239030, Sep. 17, 1993.
Asahi Glass
WO 90/02751, Ohba, M. et al., Sep. 8, 1989.
WO 90/115950, Mar. 22, 1990, Ohba, M., et al..
EP 0406428,1/9/91.
WO 92/09627, Isoai, A. et al., Nov. 29,1991.
Chiron
WO 93/07169, (Der 93-134382/16), Mar. 15,1993, Devlin, J. J., et al..
Ciba Geigy
EP 0452210, (Der 91-305246/42) Apr. 5, 1990.
EP 0452257, Mar. 26,1991, Allen, M. C., et al..
COR Therapeutics
WO 90115620, Jun. 15, 1990.
EP 0477295, Apr. 1, 1992: Scarborough, R. M., et al..
WO 92108472, May 29, 1992, Scarborough, R. M., et al..
WO 93/223356, Apr. 27, 1993, Swift, R. L., et al..
EP 0557442, Sep. 1, 1993, Scarborough, R. M., et al..
Scarborough, R. M.; Rose, J. W.; Hsu, M. A.; Phillips, D. R.; Fried, V. A; Campbell, A. M.; Nunnizzi, L.; Charo, I. F.,

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