Vitronectin receptor antagonists

Details Vitronectin receptor antagonists Vitronectin receptor antagonists

2003-10-22

2004-11-30

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S531000

Reexamination Certificate

active

06825188

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to pharmaceutically active compounds which inhibit the vitronectin receptor and are useful for the treatment of inflammation, cancer and 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 (the fibrinogen receptor) and &agr;
v
&bgr;
3
(the vitronectin receptor). The fibrinogen receptor gpIIb/IIIa is expressed on the platelet surface, and mediates platelet aggregation and the formation of a hemostatic clot at the site of a bleeding wound. Philips, et al.,
Blood
., 1988, 71, 831. 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 adhesion of osteoclasts to the bone matrix, a key step in the bone resorption process. Ross, et al.,
J. Biol. Chem
., 1987, 262, 7703. A disease characterized by excessive bone resorption is osteoporosis. The &agr;
v
&bgr;
3
receptor expressed on human aortic smooth muscle cells mediates their migration into neointima, a process which can lead to restenosis after percutaneous coronary angioplasty. Brown, et al.,
Cardiovascular Res
., 1994, 28, 1815. Additionally, Brooks, et al.,
Cell
, 1994, 79, 1157 has shown that an &agr;
v
&bgr;
3
antagonist is able to promote tumor regression by inducing apoptosis of angiogenic blood vessels. Thus, agents that block the vitronectin receptor would be useful in treating diseases, such as osteoporosis, restenosis and cancer.
The vitronectin receptor is now known to refer to three different integrins, designated &agr;
v
&bgr;
1
, &agr;
v
&bgr;
3
and &agr;
v
&bgr;
5
. Horton, et al.,
Int. J. Exp. Pathol
., 1990, 71, 741. &agr;
v
&bgr;
1
binds fibronectin and vitronectin. &agr;
v
&bgr;
3
binds a large variety of ligands, including fibrin, fibrinogen, laminin, thrombospondin, vitronectin, von Willebrand's factor, osteopontin and bone sialoprotein I. &agr;
v
&bgr;
5
binds vitronectin. The vitronectin receptor &agr;
v
&bgr;
5
has been shown to be involved in cell adhesion of a variety of cell types, including microvascular endothelial cells, (Davis, et al.,
J. Cell. Biol
., 1993, 51, 206), and its role in angiogenesis has been confirmed. Brooks, et al.,
Science
, 1994, 264, 569. This integrin is expressed on blood vessels in human wound granulation tissue, but not in normal skin.
The vitronectin receptor is known to bind to bone matrix proteins 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 discloses 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.
It has now been discovered that certain compounds are potent inhibitors of the &agr;
v
&bgr;
3
and &agr;
v
&bgr;
5
receptors. In particular, it has been discovered that such compounds are more potent inhibitors of the vitronectin receptor than the fibrinogen receptor.
SUMMARY OF THE INVENTION
This invention comprises compounds of the formula (I) as described hereinafter, which have pharmacological activity for the inhibition of the vitronection receptor and are useful in the treatment of inflammation, cancer and cardiovascular disorders, such as atherosclerosis and restenosis, and diseases wherein bone resorption is a factor, such as osteoporosis.
This invention is also a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically carrier.
This invention is also a method of treating diseases which are mediated by the vitronectin receptor. In a particular aspect, the compounds of this invention are useful for treating atherosclerosis, restenosis, inflammation, cancer and diseases wherein bone resorption is a factor, such as osteoporosis.
DETAILED DESCRIPTION
This invention comprises novel compounds which are more potent inhibitors of the vitronectin receptor than the fibrinogen receptor. The novel compounds comprise a benzazepine core in which a nitrogen-containing substituent is present on the aromatic six-membered ring of the benzazepine and an aliphatic substituent containing an acidic moiety is present on the seven-membered ring of the benzazepine. The benzazepine ring system is believed to interact favorably with the vitronectin receptor and to orient the substituent sidechains on the six and seven membered rings so that they may also interact favorably with the receptor. It is preferred that about twelve to fourteen intervening covalent bonds via the shortest intramolecular path will exist between the acidic group on the aliphatic substituent of the seven-membered ring of the benzazepine and the nitrogen of the nitrogen-containing substituent on the aromatic six-membered ring of the benzazepine.
This invention comprises compounds of formula (I):
wherein:
R
1
is R
7
, or A-C
0-4
alkyl, A-C
2-4
alkenyl, A-C
2-4
alkynyl, A-C
3-4
oxoalkenyl, A-C
3-4
oxoalkynyl, A-C
1-4
aminoalkyl, A-C
3-4
aminoalkenyl, A-C
3-4
aminoalkynyl, optionally substituted by any accessible combination of one or more of R
10
or R
7
;
A is H, C
3-6
cycloalkyl, Het or Ar;
R
7
is —COR
8
, —COCR′
2
R
9
, —C(S)R
8
, —S(O)
m
OR′, —S(O)
m
NR′R″, —PO(OR′), —PO(OR′)
2
, —NO
2
, or tetrazolyl;
each R
8
independently is —OR′, —NR′R″, —NR′SO
2
R′, —NR′OR′, or —OCR′
2
CO(O)R′;
R
9
is —OR′, —CN, —S(O)
r
R′, —S(O)
m
NR′
2
, —C(O)R′, C(O)NR′
2
, or —CO
2
R′;
R
10
is H, halo, —OR
11
, —CN, —NR′R
11
, —NO
2
, —CF
3
, CF
3
S(O)
r
—, —CO
2
R′, —CONR′
2
, A-C
0-6
alkyl-, A-C
1-6
oxoalkyl-, A-C
2-6
alkenyl-, A-C
2-6
alkynyl-, A-C
0-6
alkyloxy-, A-C
0-6
alkylamino- or A-C
0-6
alkyl-S(O)
r
—;
R
11
is R′, —C(O)R′, —C(O)NR′
2
, —C(O)OR′, —S(O)
m
R′, or —S(O)
m
NR′
2
;
R
2
is
W is —(CHR
g
)
a
—U—(CHR
g
)
b
—;
U is absent or CO, CR
g
2
, C(═CR
g
2
), S(O)
k
, O, NR
g
, CR
g
OR
g
, CR
g
(OR
k
)CR
g
2
, CR
g
2
CR
g
(OR
k
), C(O)CR
g
2
, CR
g
2
C(O), CONR
i
, NR
i
CO, OC(O), C(O)O, C(S)O, OC(S), C(S)NR
g
, NR
g
C(S), S(O)
2
NR
g
, NR
g
S(O)
2
N═N, NR
g
NR
g
, NR
g
CR
g
2
, CR
g
2
NR
g
, CR
g
2
O, OCR
g
2
, C≡C or CR
g
═CR
g
;
G is NR
e
, S or O;
R
g
is H, C
1-6
alkyl, Het-C
0-6
alkyl, C
1-7
cycloalkyl-C
0-6
alkyl or Ar—C
0-6
alkyl;
R
k
is R
g
, —C(O)R
g
, or —C(O)OR
f
;
R
i
is is H, C
1-6
alkyl, Het-C
0-6
alkyl, C
3-7
cycloalkyl-C
0-6
alkyl, Ar—C
0-6
alkyl, or C
1-6
alkyl substituted by one to three groups chosen from halogen, CN, NR
g
2
, OR
g
, SR
g
, CO
2
R
g
, and CON(R
g
)
2
;
R
f
is H, C
1-6
alkyl or Ar—C
0-6
alkyl;
R
e
is H, C
1-6
alkyl, Ar—C
0-6
alkyl, Het-C
0-6
alkyl, C
3-7
cycloalkyl-C
0-6
alkyl, or (CH
2
)
k
CO
2
R
g
;
R
b
and R
c
are independently selected from H, C
1-6
alkyl, Ar—C
0-6
alkyl, Het-C
0-6
alkyl, or C
3-6
cycloalkyl-C
0-6
alkyl, halogen, CF
3
, OR
f
, S(O)
k
R
f
, COR
f
, NO
2
, N(R
f
)
2
, CO(NR
f
)
2
, CH
2
N(R
f
)
2
, or R
b
and R
c
are joined together to form a five or six membered aromatic or non-aromatic carbocyclic or heterocyclic ring, optionally substituted by up to three substituents chosen from halogen, CF
3
, C
1-4
alkyl, OR
f
, S(O)
k
R
f
, COR
f
, CO
2
R
f
, OH, NO
2
, N(R
f
)
2
, CO(NR
f
)
2
, and CH
2
N(R
f
)
2
; or methylenedioxy;
Q
1
, Q
2
, Q
3
and Q
4
are independently N or C—R
y
, provided that no more than one of Q
1
, Q
2
, Q
3
and Q
4
is N;
R′ is H,

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