Cycloalkyl derivatives as inhibitors of bone resporption and...

Details Cycloalkyl derivatives as inhibitors of bone resporption and... Cycloalkyl derivatives as inhibitors of bone resporption and...

2000-06-29

2002-06-04

Coleman, Brenda (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S086000, C514S183000, C514S241000, C514S242000, C514S245000, C514S269000, C514S272000, C514S274000, C514S275000, C544S179000, C544S182000, C544S198000, C544S209000, C544S212000, C544S215000, C544S216000, C544S217000, C544S218000, C544S219000, C544S238000, C544S243000, C544S294000, C544S295000, C544S296000, C544S297000, C544S310000, C544S312000, C544S315000, C544S316000, C544S318000, C544S321000, C544S330000, C544S331000, C544S332000, C544S319000, C544S333000, C544S335000

Reexamination Certificate

active

06399620

ABSTRACT:

BACKGROUND OF THE INVENTION
1) Field of the Invention
The present invention relates to compounds of the formula I and their physiologically tolerable salts. The present invention also relates to pharmaceutical preparations comprising such compounds, their preparation and use as medicaments, in particular as inhibitors of bone resorption by osteoclasts, as inhibitors of tumor growth and tumor metastasis, as antiinflammatories, for the treatment or prophylaxis of cardiovascular disorders such as arteriosclerosis or restenosis, for the treatment or prophylaxis of nephropathies and retinopathies, such as, for example, diabetic retinopathy, and as vitronectin receptor antagonists for the treatment and prophylaxis of illnesses 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 tolerable salts and pharmaceutical preparations comprising such compounds as medicaments for the 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.
2) Description of Related Art
Human bones undergo a continuous dynamic renovation process which involves bone resorption and bone formation. These processes are controlled by types of cell specialized for this. Bone formation is based on the deposition of bone matrix by osteoblasts, bone resorption is based on the degradation 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 accumulate on 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 degradation of the bone.
Studies have shown that the accumulation of osteoclasts on the bone is controlled by integrin receptors on the cell surface of osteoclasts.
Integrins are a superfamily of receptors which include, 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 vascular smooth musculature, osteoclasts and tumor cells. The vitronectin receptor &agr;
V
&bgr;
3
which is expressed on the osteoclast membrane controls the process of accumulation on the bone and bone resorption and thus contributes to osteoporosis.
&agr;
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 attachment 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.
The vitronectin receptor &agr;
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) show that antibodies against &agr;
V
&bgr;
3
or &agr;
V
&bgr;
3
antagonists can bring about a shrinkage of 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, which could be useful therapeutically in the treatment of retinopathies.
The Patent Application WO 94/12181 describes substituted aromatic or nonaromatic ring systems and WO 94/08577 describes substituted heterocycles as fibrinogen receptor antagonists and inhibitors of platelet aggregation. EP-A-518 586 and EP-A-528 587 disclose aminoalkyl- or heterocyclyl-substituted phenylalanine derivatives, and WO 95/32710 discloses aryl derivatives as inhibitors of bone resorption by osteoclasts. WO 96/100574 describes benzodiazepines, and WO 96/100730 describes fibrinogen receptor antagonist templates, in particular benzodiazepines which are linked to a nitrogen-bearing 5-membered ring, as vitronectin receptor antagonists.
SUMMARY OF THE INVENTION
One object of the present invention is to provide compounds and their pharmacologically tolerable salts capable of being used as inhibitors of bone resorption by osteoclast, as inhibitors of tumor growth and tumor metastasis, as antiinflammatories, for the treatment or prophylaxis of cardiovascular disorders such as arteriosclerosis or restenosis, for the treatment or prophylaxis of nephropathies and retinopathies and as vitronectin receptor antagonists for the treatment and prophylaxis of illnesses which are based on the interaction between vitronectin receptors and their ligands in cell-cell or cell-matrix interaction processes. Another object of the invention is to provide compounds which can be used as carriers for active compounds in order to transfer the active compounds specifically to the site of action.
Another object of the invention is to provide a pharmaceutical preparation which includes the compound of the present invention. Still another object of the invention is to provide methods for the production of the compound of the present invention. Still another object of the present invention is to provide methods for the treatment of the conditions described above.
In accomplishing the foregoing objects, there has been provided according to one aspect of the present invention, cycloalkyl derivatives of the formula I
R
1
—Y—A—B—D—E—F—G  I
in which:
A is a direct bond, (C
1
-C
8
)-alkanediyl, —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, —CEC≡C—, —NR
2
—C(O)—, —C(O)—NR
2
—, —(C
5
-C
14
)—arylene-C(O)—NR
2
—, —O—, —S(O)
n
—, —(C
5
-C
14
)-arylene-, —CO—, —(C
5
-C
14
)-arylene-CO—, —NR
2
—, —SO
2
—NR
2
—, —CO
2
—, —CR
2
═CR
3
—, —(C
5
-C
14
)—arylene-S(O)
n
—, which in each case can be mono- or disubstituted by (C
1
-C
8
)-alkanediyl, such as, for example, —(C
1
-C
8
)—alkanediyl —CO—NR
2
—(C
1
-C
8
)—alkanediyl, —(C
1
-C
8
)-alkanediyl-CO—NR
2
—(C
1
-C
8
)-alkanediyl;
B is a direct bond, (C
1
-C
10
)-alkanediyl, —CR
2
═CR
3
— or —C≡C—, which in each case can be mono- or disubstituted by (C
1
-C
8
)-alkanediyl, such as, for example, —CH
2
—CR
2
═CR
3
—;
D is a direct bond, (C
1
-C
8
)-alkanediyl, —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—, —CO—, —CS—, —S(O)—, —S(O)
2
—, —S(O)
2
—NR
2
—S(O)—, —NR
2
—S(O)
2
—, —S—, —CR
2
═CR
3
—, —C≡C—, or —CH(OH)—, which in each case can be mono- or disubstituted by (C
1
-C
8
)-alkanediyl;
E is a 6-membered aromatic ring system, which optionally contains up to 4 nitrogen atoms and is optionally substituted by 14 identical or different radicals from the group consisting of R
2
, R
3
, fluorine, Cl, Br, I, NO
2
, and OH;
F is defined as D;
G is
Y is a direct bond or —NR
2
—;
R
1
is R
2
—C(═NR
2
)—NR
2
—, R
2
R
3
N—C(═NR
2
)—, R
2
R
3
N—C(═NR
2
)—NR
2
—, or a 4-10—membered mo

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