Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-11-29
2001-03-20
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S234500, C544S139000, C548S305100, C548S309700
Reexamination Certificate
active
06204282
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to compounds which are vitronectin receptor antagonists and are useful for the treatment of cancer, retinopathy, cardiovascular disorders, such as atherosclerosis and restenosis, and diseases wherein bone resorption is a factor, such as osteoporosis.
BACKGROUND OF THE INVENTION
Integrins are a superfamily of cell adhesion receptors, which are transmembrane glycoproteins expressed on a variety of cells. These cell surface adhesion receptors include gpIIb/IIIa, also known as the “fibrinogen receptor,” and &agr;
v
&bgr;
3
, also known as the “vitronectin receptor.” The fibrinogen receptor gpIIb/IIIa is expressed on the platelet surface, and it mediates platelet aggregation and the formation of a hemostatic clot at the site of a bleeding wound. Philips, et al.,
Blood.,
1988, 71, 83 1. The vitronectin receptor &agr;
v
&bgr;
3
is expressed on a number of cells, including endothelial, smooth muscle, osteoclast, and tumor cells, and, thus, it has a variety of functions. The &agr;
v
&bgr;
3
receptor expressed on the membrane of osteoclast cells mediates the bone resorption process and contributes to the development of osteoporosis. Ross, et al.,
J. Biol, Chem.,
1987, 262, 7703. The &agr;
v
&bgr;
3
receptor expressed on human aortic smooth muscle cells stimulates their migration into neointima, which leads to the formation of atherosclerosis and restenosis after angioplasty. Brown et al.,
Cardiovascular Res.,
1994, 28, 1815. Additionally, a recent study has shown that a &agr;
v
&bgr;
3
antagonist is able to promote tumor regression by inducing apoptosis of angiogenic blood vessels. Brooks, et al.,
Cell,
1994, 79, 1157. Thus, agents that would block the vitronectin receptor would be useful in treating diseases mediated by this receptor, such as osteoporosis, atherosclerosis, restenosis and cancer.
The vitronectin receptor is known to bind to bone matrix proteins, such as osteopontin, bone sialoprotein and thrombospondin, which contain the tri-peptide Arg—Gly—Asp (or RGD) motif. Thus, Horton, et al.,
Exp. Cell Res.
1991, 195, 368, disclose that RGD-containing peptides and an anti-vitronectin receptor antibody (23C6) inhibit dentine resorption and cell spreading by osteoclasts. In addition, Sato, et al.,
J Cell Biol.
1990, 111, 1713 disclose that echistatin, a snake venom peptide which contains the RGD sequence, is a potent inhibitor of bone resorption in tissue culture, and inhibits attachment of osteoclasts to bone. Fisher, et al.,
Endocrinology
1993, 132, 1411, has further shown that echistatin inhibits bone resorption in vivo in the rat. Bertolini et al.,
J Bone Min. Res.,
6, Sup. 1, S146, 252 have shown that cyclo-S,S—N
&agr;
- acetyl-cysteinyl-N
&agr;
- methyl-argininyl-glycyl-aspartyl-penicillamine inhibits osteoclast attachment to bone. EP 0 528 587 and EP 0 528 586 report substituted phenyl derivatives which inhibit osteoclast mediated bone resorption.
Alig et al., EP 0 381 033, Hartman, et al., EP 0 540 334, Blackburn, et al., WO 93/08174, Bondinell, et al., WO 93/00095, Blackburn, et al., WO 95/04057, Egbertson, et al., EP 0 478 328, Sugihara, et al., EP 0 529 858, Porter, et al., EP 0 542 363, and Fisher, et al., EP 0 635 492 disclose certain compounds that are useful for inhibiting the fibrinogen receptor. WO 96/00730 discloses certain compounds that are vitronectin receptor antagonists.
SUMMARY OF THE INVENTION
We have invented novel compounds that are antagonists at the vitronectin receptor, i.e., they have a high affinity for the vitronectin receptor, thereby making them useful for treating disorders or diseases mediated by the vitronectin receptor, e.g., cancer, retinopathy, artherosclerosis, vascular restenosis and osteoporosis. The compounds of our invention have the formula:
wherein n, p, q and r are each independently selected from 0 or 1;
a, b, c, and d each independently represents a carbon or nitrogen atom, with the proviso that no more than two of a, b, c, and d are nitrogen atoms;
Y and Y
1
each independently represents 1-4 optional substituents selected from alkyl, alkoxy, halo, —CF
3
, and —C(O)OH;
R
1
is H, alkyl, aryl, aralkyl, arylcycloalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, heteroaralkyl, cycloalkylalkyl, heterocycloalkylalkyl, —NHR
A
, —NHC(O)R
A
, —NHSO
2
R
A
, NHC(O)NHR
A
or —NHC(O)OR
A
, R
1
being optionally substituted by 1-3 groups selected from halo, alkyl, —CF
3
, —CN, —OR
B
, —SR
B
, —CO
2
R
B
, —C(O)R
B
, —OC(O)R
B
, —OC(O)OR
B
and —SO
2
R
B
, and R
A
and R
B
are independently selected from H, alkyl, aryl, aralkyl, arylcycloalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, heteroaralkyl, cycloalkylalkyl or heterocycloalkylalkyl, with the proviso that when R
1
is alkyl, R
1
is not substituted with halo, the proviso that when R
1
is —NHSO
2
R
A
or —NHC(O)OR
A
, R
A
is not H, and the proviso that for —SO
2
R
B
or —OC(O)OR
B
, R
B
is not H;
R
2
is H, alkyl, aryl, aralkyl, arylcycloalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, heteroaralkyl, cycloalkylalkyl, or heterocycloalkylalkyl, R
2
being optionally substituted by 1-3 groups selected from halo, alkyl, —CF
3
, —CN, —OR
C
, —SR
C
, —CO
2
R
C
, —C(O)R
C
, —OC(O)R
C
, —OC(O)OR
C
and —SO
2
R
C
, wherein R
C
is selected from H, alkyl, aryl, aralkyl, arylcycloalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, heteroaralkyl, cycloalkylalkyl or heterocycloalkylalkyl, with the proviso that when R
2
is alkyl, R
2
is not substituted with halo, and the proviso that for —SO
2
R
C
or —OC(O)OR
C
, R
C
is not H;
R
3
is H, alkyl, aralkyl, arylcycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, heteroaralkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, —C(O)R
D
, —C(O)OR
D
, —SO
2
R
E
, —C(O)NR
F
R
G
, —C(O)NR
F
SO
2
R
E
, or —C(═S)NR
F
R
G
, wherein R
D
, R
E
, R
F
and R
G
are independently selected from H, alkyl, aryl, aralkyl, arylcycloalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl or heterocycloalkylalkyl, or R
F
and R
G
taken together complete a 5-7 member ring containing 0 to 1 oxygen or sulfur atoms, and 1 to 2 nitrogen atoms, R
3
being optionally substituted by 1-3 groups selected from halo, alkyl, aryl, —CF
3
, —CN, —OR
H
, —SR
H
, —CO
2
R
H
, —C(O)R
H
, —OC(O)R
H
, —OC(O)OR
H
, —SO
2
R
H
and —NR
H
R
H
, wherein R
H
is selected from H, alkyl, aryl, aralkyl, arylcycloalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, heteroaralkyl, cycloalkylalkyl or heterocycloalkylalkyl, with the proviso that when R
3
is alkyl, R
3
is not substituted with halo, the proviso that when R
3
is —SO
2
R
E
, —C(O)NR
F
SO
2
R
E
, or —CO(O)R
D
, R
D
and R
E
are not H, and the proviso that for —SO
2
R
H
or —OC(O)OR
H
, R
H
is not H;
R
4
is H, alkyl, aralkyl, arylcycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, heteroaralkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, R
4
being optionally substituted by 1-3 groups selected from halo, alkyl, —CF
3
, —CN, —OR
J
, —SR
J
, —CO
2
R
J
, —C(O)R
J
, —OC(O)R
J
, —OC(O)OR
J
and —SO
2
R
J
, wherein R
J
is selected from H, alkyl, aryl, aralkyl, arylcycloalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, heteroaralkyl, cycloalkylalkyl or heterocycloalkylalkyl, with the proviso that when R
4
is alkyl, R
4
is not substituted with halo, and the proviso that for —SO
2
R
J
or —OC(O)OR
J
, R
J
is not H;
R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
and R
12
are independently selected from H or C
1
-C
3
alkyl;
and wherein
are positioned meta or para relative to each other; or a biolabile ester thereof, or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
R
1
is preferably H, —NHR
A
, —NHC(O)R
A
, —NHC(O)OR
A
, —NHC(O)NHR
A
, or —NHSO
2
R
A
. R
1
ismorepreferably —NHC(O)OR
A
. R
1
is most preferably,
R
2
is preferably H.
R
3
is preferably selected from H, alkyl, —C(O)R
D
, —C(O)OR
D
, —C(O)NR
F
R
G
, and —C(═S)NR
F
R
G
. R
D
is preferably selected from phenyl, alkyl, aralkyl, arylcycloalkyl, cycloalkyl, and
wherein R
D
is optionally substituted by 1-3 substituents selected from alkoxy, halo, cycoalkyl, —S—
Neustadt Bernard R.
Smith Elizabeth M.
Lee William
Mann Arthur
Schering Corporation
Stockton Laura L.
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