Thienyl substituted acylguanidines as inhibitors of bone...

Details Thienyl substituted acylguanidines as inhibitors of bone... Thienyl substituted acylguanidines as inhibitors of bone...

2001-03-06

2003-05-20

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S438000, C514S448000, C514S449000, C514S218000, C544S297000, C544S330000, C544S331000, C544S332000, C549S065000, C549S066000, C549S070000, C549S072000, C549S074000, C549S075000, C549S076000, C549S079000

Reexamination Certificate

active

06566366

ABSTRACT:

This application is a 371 of PCT/EP99/03064 filed May 5, 1999.
The present invention relates to thienyl substituted acylguanidine derivatives, such as compounds of the formula I
in which R
1
, R
2
, R
4
, R
6
, A, B and D have the meanings indicated below, their physiologically tolerable salts and their prodrugs. The compounds of the present invention are valuable pharmaceutical active compounds. They are vitronectin receptor antagonists and inhibitors of bone resorption by osteoclasts. They are suitable, for example, for the therapy and prophylaxis of diseases which are caused at least partially by an undesired extent of bone resorption, for example of osteoporosis. The invention furthermore relates to processes for the preparation of thienyl substituted acylguanidines, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.
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 resorption is based on the destruction of bone matriy by osteoclasts. The majority of bone disorders are based on a disturbed equilibrium between bone formation and bone resorption. Osteoporosis is a disease characterized by low bone mass and enhanced bone fragility resulting in an increased risk of fractures. It results from a deficit in new bone formation versus bone resorption during the ongoing remodelling process. Conventional osteoporosis treatment includes, for example, the administration of bisphosphonates, estrogens, estrogen/progesterone (hormone replacement therapy or HRT), estrogen agonists/antagonists (selective estrogen receptor modulators or SERMs), calcitonin, vitamin D analogues, parathyroid hormone, growth hormone secretagogues, or sodium fluoride (Jardine et al., Annual Reports in Medicinal Chemistry 1996, 31, 211).
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. The compounds of the present invention inhibit bone resorption by osteoclasts.
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 &agr;
IIb
&bgr;
3
on 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 osteoclast attachment to the bones 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 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 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 containing peptide from snake venom, as a potent inhibitor of bone resorption in a tissue culture and as an inhibitor of osteoclast adhesion to the bones. Fisher et al. (Endocrinology 1993, 132, 1411) were able to show in the rat that echistatin also inhibits bone resorption in vivo. Yamamoto et al. (Endocrinology 1998, 139, 1411) show that echistatin prevents bone loss in ovarectomized mice and rats.
It was furthermore shown that the vitronectin &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). Yue et al. (Pharmacology Reviews and Communications 1998, 10, 9) show the inhibition of neointima formation using an &agr;
v
&bgr;
3
antagonist.
Brooks et al. (Cell 1994, 79, 1157) showed that antibodies against &agr;
v
&bgr;
3
or &agr;
v
&bgr;
3
antagonists can cause a shrinkage of tumors by inducing the apoptosis of blood vessel cells during angiogenesis. The vitronectin receptor &agr;
v
&bgr;
3
is also involved in the progression of a variety of other types of cancer, and is overexpressed in malignant melanoma cells (Engleman et al., Annual Reports in Medicinal Chemistry 1996, 31, 191). The melanoma invasiveness correlated with this overexpression (Stracke et al., Encylopedia of Cancer, volume III, 1855, Academic Press, 1997; Hillis et al., Clinical Science 1996, 91, 639). Carron et al. (Cancer Res. 1998, 58, 1930) describe the inhibition of tumor growth and the inhibition of hypercalcemia of malignancy using an &agr;
v
&bgr;
3
antagonist.
Friedlander et al. (Science 1995, 270, 1500) describe anti-&agr;
v
&bgr;
3
antibodies or &agr;
v
&bgr;
3
antagonists which inhibit the bFGF-induced angiogenesis processes in the rat eye, a property which can be used therapeutically in the treatment of retinopathies. Storgard et al. (J. Clin. Invest 1999, 103, 47) describe the use of &agr;
v
&bgr;
3
antagonists in the treatment of arthritic diseases. Hammes et al. showed that cyclic peptidic &agr;
v
&bgr;
3
antagonists inhibit angiogenesis in an ischemic model of retinopathy (Nature Medicine 1996, 2, 529). Influencing of the vitronectin receptor or of the interactions in which it is involved thus offers the possibility of influencing different disease states for whose therapy and prophylaxis there continues to be a need for suitable pharmaceutical active ingredients.
Patent application WO-A-94/12181 describes substituted aromatic or nonaromatic ring systems, and WO-A-94/08577 describes substituted heterocycles as fibrinogen receptor antagonists and inhibitors of platelet aggregation. EP-A-528586 and EP-A-528587 disclose aminoalkyl-substituted or heterocyclyl-substituted phenylalanine derivatives, and WO-A-95/32710 discloses aryl derivatives as inhibitors of bone resorption by osteoclasts. WO-A-96/00574 describes benzodiazepines, and WO-A-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-A-820991 discloses cycloalkyl derivatives, international patent application PCT/EP98/08051 discloses carbamic ester derivatives and international patent application PCT/EP99/00242 discloses sulfonamides which are vitronectin receptor antagonists. Certain thiophene derivatives which are potent and selectively acting fibrinogen receptor antagonists are disclosed in WO-A-94/08577. Further investigations have shown that the thienyl substituted acylguanidines of the present invention are particularly strong inhibitors of the vitronectin receptor and of bone resorption by osteoclasts.
Thus, a subject of the present invention are compounds of the formula I,
in which
A is a saturated or unsaturated bivalent (C
1
-C
9
)-alkylene residue or a bivalent (C
3
-C
7
)-cycloalkylene residue, wherein the alkylene residue and the cycloalkylene residue each is unsubstituted or is substituted by one or more residues from the series consisting of 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;
B is hydrogen, —NH—CO—OR
5
, —NH—SO
2
—R
5
, —NH—SO
2
—(C
6
-C
14
)-aryl, —NH—SO
2
—(C
5
-C
14
)-heteroaryl, —NH—CO—R
5
, —NH—

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