Acylguanidine derivatives as inhibitors of bone resorption...

Details Acylguanidine derivatives as inhibitors of bone resorption... Acylguanidine derivatives as inhibitors of bone resorption...

2000-11-02

2002-12-10

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S275000, C514S398000, C514S399000, C540S470000, C544S297000, C544S330000, C544S335000, C548S331500, C548S347100, C548S348100

Reexamination Certificate

active

06492356

ABSTRACT:

The present invention relates to acylguanidine derivatives of the formula I,
in which R
1
, R
2
, R
4
, R
5
, R
6
, A, m and n have the meanings indicated below, their physiologically tolerable salts and their prodrugs. The compounds of the formula I are valuable pharmaceutical active compounds. They are vitronectin receptor antagonists and inhibitors of bone resorption by osteoclasts and 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 compounds of the formula I, their use, in particular as pharmaceutical active ingredients, 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 matrix 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 formula I 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 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;
IIb
&bgr;
3
, which is expressed on the osteoclast membrane, controls the process of 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 thrombospontin, 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 osteociasts (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 bones. Fischer et al. (Endocrinology 1993, 132, 1411) were able to show in the rat that echistatin also inhibits bone resorption in vivo.
It was furthermore shown that 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). Yue et al. (Pharmacology Reviews and Communications 1998, 10, 9-18) showed 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.
Cheresh 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.
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.
The patent application WO-A-94/12181 describes substituted aromatic ring systems and WO-A-94/08577 describes substituted heterocycles 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. 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. WO-A-97/21726 describes agents for promoting bone formation which belong to various classes of compounds, among them tyrosine derivatives containing an unsubstituted guanidino group. Further investigations have shown that the acylguanidines of the formula I are particularly strong inhibitors of the vitronectin receptor and of bone resorption by osteoclasts.
The present invention relates to compounds of the formula I,
in which
R
1
and R
2
independently of one another are hydrogen or (C
1
-C
6
)-alkyl which is unsubstituted or substituted by R
3
, with the proviso that R
1
and R
2
are not both hydrogen at the same time,
or in which the radicals R
1
- and R
2
-together are a saturated or unsaturated bivalent (C
2
-C
9
)-alkylene radical, for example the group —(CH
2
)
p
—, in which p is 2, 3, 4, 5, 6, 7, 8 or 9, which is unsubstituted or is substituted by one or more groups from the group 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, where a 5-membered to 7-membered saturated or unsaturated ring which is unsubstituted or is substituted by R
3
, in particular by one or two radicals R
3
, and which is a carbocyclic ring or a heterocyclic ring containing one or two ring nitrogen atoms, can be fused to a carboncarbon bond in the (C
2
-C
9
)-alkylene radical;
R
3
is (C
1
-C
8
)-alkyl, (C
1
-C
8
)-alkoxy, (C
5
-C
14
)-aryl, (C
5
-C
14
)-aryl-(C
1
-C
4
)-alkyl- halogen, trifluoromethyl, hydroxyl, nitro or amino;
R
4
is hydrogen, (C
1
-C
6
)-alkyl-CO—O—(C
1
-C
4
)-alkyl- or (C
1
-C
6
)-alkyl, which is unsubstituted or is substituted by a radical from the group consisting of hydroxyl, (C
1
-C
4
)-alkoxy, (C
1
-C
4
)-alkyl-S(O)
2
—, NR
7
R
7&

Affiliated with

Also associated with

Rating

Acylguanidine derivatives as inhibitors of bone resorption... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Acylguanidine derivatives as inhibitors of bone resorption..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Acylguanidine derivatives as inhibitors of bone resorption... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2953449