Substituted purine derivatives as inhibitors of cell adhesion

Details Substituted purine derivatives as inhibitors of cell adhesion Substituted purine derivatives as inhibitors of cell adhesion

2002-03-06

2004-06-08

Berch, Mark L (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

C514S245000, C514S248000, C514S263200, C514S263210, C514S263220, C514S263300, C514S263380, C544S276000, C544S277000, C544S264000, C544S244000, C544S198000, C544S258000

Reexamination Certificate

active

06747016

ABSTRACT:

The present invention relates to compounds of the formula I,
in which B, D, E, G, X, Y, Z, R
1
, R
2
and s have the meanings indicated below, their physiologically tolerable salts and their prodrugs. The compounds of the formula I are valuable pharmacologically active compounds. They are vitronectin receptor antagonists and inhibitors of cell adhesion 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 such interactions. For example, they can be applied for inhibiting bone resorption by osteoclasts and thus for treating and preventing osteoporosis, or for inhibiting undesired angiogenesis or proliferation of cells of the vascular smooth musculature. The invention furthermore relates to processes for the preparation of compounds of the formula I, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical compositions 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 31 (1996) 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 adds 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;
v
&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 osteoclasts (Horton et al., Exp. Cell. Res. 195 (1991) 368). In J. Cell Biol. 111 (1990) 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. Fisher et al. (Endocrinology 132 (1993) 1411) and Yamamoto et al. (Endocrinology 139 (1998) 1411) were able to show in the rat that echistatin also inhibits bone resorption in vivo.
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. 28 (1994) 1815). Yue et al. (Pharmacology Reviews and Communications 10 (1998) 9) show the inhibition of neointima formation using an &agr;
v
&bgr;
3
antagonist.
Brooks et al. (Cell 79 (1994) 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 31 (1996) 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 91 (1996) 639). Carron et al. (Cancer Res. 58 (1998) 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 270 (1995) 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 and in the treatment of psoriasis. Storgard et al. (J. Clin. Invest. 103 (1999) 47) describe the use of avid antagonists in the treatment of arthritic diseases.
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.
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. In WO-A-95/28426 RGD peptides are described as inhibitors of bone resorption, angiogenesis and restenosis. International Patent Application PCT/EP98/08051 discloses carbamic ester derivatives, and International Patent Application PCT/EP99/00242 discloses sulfonamides which are vitronectin receptor antagonists. Further vitronectin receptor antagonists are disclosed in WO-A-98/08840 and WO-A-98/18461. Substituted purine derivatives as inhibitors of bone resorption are described in EP-A853084. Further investigations have shown that the compounds 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
B is (C
1
-C
18
)-alkyl, (C
3
-C
14
)-cycloalkyl, (C
3
-C
14
)-cycloalkyl-(C
1
-C
8
)-alkyl-, (C
5
-C
14
)-aryl, (C
5
-C
14
)-aryl-(C
1
-C
8
)-alkyl-, (C
5
-C
14
)-heteroaryl, (C
5
-C
14
)-heteroaryl-(C
1
-C
8
)-alkyl-, fluorine, chlorine, bromine, hydroxy, cyano, trifluoromethyl, nitro, hydroxycarbonyl-, (C
1
-C
6
)-alkoxy, (C
1
-C
6
)-alkoxy-(C
1
-C
6
)-alkyl-, (C
1
-C
6
)-alkoxycarbonyl-, (C
1
-C
6
)-alkylcarbonyl-, (C
5
-C
14
)-arylcarbonyl-, (C
1
-C
6
)-alkylaminocarbonyl-, (C
1
-C
6
)-alkoxy-(C
1
-C
6
)-alkoxy-, (C
5
-C
14
)-aryl-(C
1
-C
8
)-alkylcarbonyl-, (C
1
-C
6
)-alkanoylamino-, (C
1
-C
6
)-alkylsulfonylamino-, (C
5
-C
14
)-arylsulfonylamino-, (C
1
-C
6
)-alkylamino-, di-((C
1
-C
6
)-alkyl)-amino-, (C
1
-C
6
)-alkylsulfonyl-, aminosulfonyl-, (C
5
-C
14
)-arylsulfonyl-, (C
5
-C
14
)-aryl-(C
1
-C
6
)-alkylsulfonyl-, (C
5
-C
14
)-aryl or (C
5
-C
14
)-heteroaryl, where all residues B are independent of one another and can be identical or different, or B denotes an aromatic or non-aromatic ring system that is fused to the 6-membered ring containing the groups G and Z

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