Sulfonamide derivatives as inhibitors of bone resorption and...

Details Sulfonamide derivatives as inhibitors of bone resorption and... Sulfonamide derivatives as inhibitors of bone resorption and...

2000-05-05

2001-11-06

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S237800, C514S275000, C514S327000, C514S510000, C514S542000, C514S562000, C544S122000, C544S159000, C544S331000, C544S332000, C546S222000, C560S010000, C560S013000, C562S427000, C562S430000

Reexamination Certificate

active

06313119

ABSTRACT:

BACKGROUND OF THE INVENTION
Human bones are subject to a constant, dynamic renovation process comprising bone resorption and bone formation. These processes are controlled by types of cells 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: 211 (1996)).
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.
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;
llb
&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: 368( 1991)). In
J. Cell Biol.
111: 1713 (1990), 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
132: 1411 (1993)) 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: 1815 (1994)).
Brooks et al.,
Cell
79: 1157 (1994), 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: 191 (1996)). 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: 639 (1996)). Carron et al.,
Cancer Res.
58: 1930 (1998), describe the inhibition of tumor growth and the inhibition of hypercalcemia of malignancy using an &agr;
v
&bgr;
3
antagonist.
Cheresh et al.,
Science
270: 1500 (1995), 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.
Thus, vitronectin receptors, and the interactions in which they are involved, are involved in a number of diseases. Influencing of the vitronectin receptor or of the interactions in which it is involved thus offers the possibility of influencing numerous disease states for whose therapy and prophylaxis there continues to be a need for suitable pharmaceutical active ingredients.
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. WO-A-98/00395 (DE-A-19654483) describes vitronectin receptor antagonists derived from a tyrosine scaffold. EP-A-820991 (German patent application 19629816.4) describes cycloalkyl derivatives and European patent application 97122520.6 describes carbamic ester derivatives which are vitronectin receptor antagonists. There remains, however, the need for additional compounds that influence the vitronectin receptor and/or the interactions in which it is involved.
In accordance with this need, the present inventors have discovered that certain sulfonamide derivatives are particularly strong inhibitors of the vitronectin receptor and of bone resorption by osteoclasts.
SUMMARY OF THE INVENTION
The present invention relates to sulfonamide derivatives, their physiologically tolerable salts and their prodrugs. In accordance with one aspect of the invention, there are provided compounds having the general formula I:
wherein:
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
, or in which the radicals R
1
— and R
2
— together are a saturated or unsaturated bivalent (C
2
-C
9
)-alkylene radical 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
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
and which is a carbocyclic ring or a heterocyclic ring containing one or two ring nitrogen atoms, can be fused to a carbon-carbon bond in the (C
2
-C
9
)-alkylene radical;
R
3
is (C
1
-C
10
)-alkyl, (C
3
-C
20
)-monocycloalkyl, (C
5
-C
20
)-bicycloalkyl, (C
5
-C
20
)-tricycloalkyl, (C
1
-C
8
)-alkoxy, (C
6
-C
14
)-aryl, (C
6
-C
14
)-aryl-(C
1
-C
4
)-alkyl-, (C
5
-C
14
)-heteroaryl, (C
5
-C
14
)-heteroaryl-(C
1
-C
4
)-alkyl-, halogen, trifluoromethyl, cyano, hydroxyl, oxo, nitro, amino, —NH—(C
1
-C
4
)-alkyl, —N((C
1
-C
4
)-alkyl)
2
, —NH—CO—(C
1
-C
4
)-alkyl, or —CO—(C
1
-C
4
)-alkyl;
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 selected from the group consisting of hydroxyl, (C
1
-C
4
)-alkoxy, (C
1
-C
4
)-alkyl-S(O)
2
—, —NR
7
R
7′
and —N
+
R
7
R
7′
R
7″
Q
31
, where R
7
, R
7′
and R
7″
independently of one another are hydrogen, (C
1
-C
6
)-alkyl, (C
5
-C
14
)-aryl or (C
5
-C
14
)-aryl-(C
1
-C
6
)-alkyl- and Q
−
is a physiologically tolerable anion, o

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