Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-08
2001-05-29
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S001000, C546S312000, C514S352000
Reexamination Certificate
active
06239138
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 herein 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 it 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 bone resportion 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 cylco-S,S-N
&agr;
-acetyl-cysteinyl-N
&agr;
-methyl-argininyl-glycyl-aspartyl-penicillamine inhibits osteoclast attachment to bone. EP 528 587 and 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 95104057, Egbertson, et al, EP 0 478 328, Sugihara, et al. EP 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. It has now been discovered that certain compounds are potent inhibitors of the vitronectin receptor. 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 (1) 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 (1) 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 benzocycloheptenyl core in which a nitrogen-containing substituent is present on the aromatic six-membered ring of the benzocycloheptene and an aliphatic substituent containing an acidic moiety is present on the seven-membered ring of the benzocycloheptene. The benzocycloheptene 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 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 benzocycloheptene and the nitrogen of the nitrogen-containing substituent on the aromatic six-membered ring of the benzocycloheptene.
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
;
X is O, C(O)NR′, or NR′C(O);
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
, —B(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), C(O)NR
1
, NR
1
C(O), C(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
, NR
g
CR
g
2
, 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
3-7
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
1-6
alkyl;
R
e
is H, C
1-6
alkyl, Ar-C
1-6
alkyl, Het-C
1-6
alkyl, C
3-7
cycloalkyl-C
1-6
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
,
Kinzig Charles M.
McCarthy Mary E.
Patel Sudhaker B.
Shah Mukund J.
SmithKline Beecham Corporation
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