Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-07-20
2002-08-06
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S158000
Reexamination Certificate
active
06429214
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a series of tetrahydro- and dihydroquinoline, tetrahydronaphthalene and tetrahydro-5H-benzocycloheptene bicyclic compounds of Formulae (I) and (II) and non-toxic salts thereof, which selectively antagonize the &agr;
v
&bgr;
3
integrin while minimally inhibiting platelet aggregation mediated by &agr;
IIb
&bgr;
3
integrin and are useful as bone antiresorptive agents.
BACKGROUND OF THE INVENTION
The present invention relates to fused bicyclic derivatives which exhibit activity as bone antiresorptive agents by inhibition of the osteoclast vitronectin receptor(&agr;
v
&bgr;
3
). The integrin &agr;
v
&bgr;
3
has been shown to mediate the invasion of cancerous melanoma cells into healthy tissue (Seftor et al., Proc. Natl. Acad. Sci, USA, 1992, 89, 1557-1561) and to protect these cells against natural cell death cycle (apoptosis) (Montgomery et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 8856-8860). Vitronectin receptor (&agr;
v
&bgr;
3
) antagonists have been shown to inhibit the growth of various solid tumors of human origin (Brooks et al., Cell, 1994, 79, 1157-1164). More recently, &agr;
v
&bgr;
3
has been shown to be involved in liver metastasis (Yun et al., Cancer Res., 1996, 56, 3103-3111). Although angiogenesis is an important and natural process in growth and wound healing, it is now appreciated that a variety of clinically relevent conditions are pathologically related to these processes, and that the integrin &agr;
v
&bgr;
3
is involved. For example, &agr;
v
&bgr;
3
was shown to be expressed on human wound tissue but not on normal skin (Brooks, et al., Science, 1994, 264, 569-571) and is preferentially expressed on angiogenic blood vessels, such as those feeding a growing/invading tumor. It has also been shown that antagonists of &agr;
v
&bgr;
3
promote tumor regression by inducing apoptosis of the tumor cells (Brooks et al., Cell, 1994, 79, 1157-1164). The process of neovascularization (new blood vessel growth, angiogenesis), which is critical for tumor growth and metastasis, is also an important event in occular tissue, leading to diabetic retinopathy, glaucoma and blindness (Adamis et al., Am. J. Ophthal., 118, 445-450(1994); Hammes et al., Nature Med., 1996, 2,529-533; Friedlander, et al., Natl. Acad. Sci. U.S.A., 1996, 93, 9764-9769) and in joints, promoting rheumatoid arthritis (Peacock et al., J. Exp. Med., 1992, 175, 1135-1138). &agr;
v
&bgr;
3
has been shown to play a pivotal role in the proliferation and migration of smooth muscle and vascular endothetial cells, a pathological process leading to restenosis after balloon angioplasty (Choi et al., J. Vasc. Surgery, 1994, 19, 125-134; Matsuno et al., Circulation, 1994, 90, 2203-2206). At least one type of virus (adenovirus) has been shown to utilizeo &agr;
v
&bgr;
3
for entering host cells (White et al., Current Biology, 1993, 596-599).
Various bone diseases involve bone resorption, the dissolution of bone matter, which is mediated by only one known class of cells, the osteoclasts. When activated for resorption, these motile cells initially bind to bone, a process well known to be mediated by &agr;
v
&bgr;
3
(Davies et al., J. Cell. Biol., 1989 109, 1817-1826; Helfrich et al., J Bone Mineral Res., 1992, 7, 335-343). It is also well known that blockade of &agr;
v
&bgr;
3
with antibodies or peptides containing the sequence arginine-glycine-aspartic acid (RGD) blocks osteoclast cell adhesion and bone resorption in vitro (Horton et al., Exp. Cell Res. 1991, 195, 368-375) and that echistatin, an RGD containing protein, inhibits bone resorption in vivo (Fisher et al., Endocrinolog. y, 1993, 132, 1411-1413). More recently, an RGD peptidomimetic has likewise been shown to inhibit osteoclasts in vitro and, by iv administration prevents osteoporosis in vivo (Engleman et al., J. Clin. Invest., 1997, 99, 2284-2292).
A series of bicyclic compounds having a nucleus formed of two fused six-membered rings which include isoquinoline, isoquinolone, tetrahydronaphthalene, dihydronaphthalene or tetralone substituted with both basic and acidic functionality and which are useful in inhibition of platelet aggregation are disclosed in EP 0635492, WO96/22288, U.S. Pat Nos. 5,618,843 and 5,731,324 and are described by Formula I
The current major bone diseases of public concern are osteoporosis, hypercalcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, immobilization-induced osteopenia and the result of glucocorticoid treatment.
All these conditions are characterized by bone loss, resulting from an imbalance between bone resorption (breakdown) and bone formation, which continues throughout life at the rate of about 14% per year on the average. However, the rate of bone turnover differs from site to site, for example, it is higher in the trabecular bone of the vertebrae and the alveolar bone in the jaws than in the cortices of the long bones. The potential for bone loss is directly related to turnover and can amount to over 5% per year in vertebrae immediately following menopause, a condition which leads to increased fracture risk.
There are currently 20 million people with detectable fractures of the vertebrae due to osteoporosis in the United States. In addition, there are 250,000 hip fractures per year attributed to osteoporosis. This clinical situation is associated with a 12% mortality rate within the first two years, while 30% of the patients require nursing home care after the fracture.
The minimal inhibition of platelet aggregation mediated by &agr;
IIb
&bgr;
3
integrin while selectively antagonizing the &agr;
v
&bgr;
3
integrin and thus being available as bone antiresorptive agents is an important benefit of compounds of the invention and is important in mammals, especially man.
BRIEF SUMMARY OF THE INVENTION
Accordingly, the present invention discloses bicyclic compounds represented by general Formula (I):
wherein:
— — — represents the presence of an optional double bond;
n is an integer of 2 to 5;
v is an integer of 0 or 1;
A—B is a diradical of the formulae:
m is an integer of 1 or 2;
Y is selected from the group consisting of —O—, —CH
2
—CH
2
—, —CH═CH—,
R
1
is hydrogen or straight chain alkyl of 1 to 6 carbon atoms; phenylalkyl wherein the alkyl moiety is a straight chain alkyl of 1 to 6 carbon atoms and the phenyl moiety is optionally substituted with one or more substituents which may be the same or different and are selected from hydroxy, amino, halogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cyano, nitro, alkylamino of 1 to 6 carbon atoms, and dialkylamino of 1 to 6 carbon atoms; heterocyclylalkyl, wherein the alkyl moiety is a straight chain alkyl of 1 to 6 carbon atoms and the heterocyclyl moiety is selected from a 5- or 6-membered heterocyclic ring which contains 1 to 3 heteroatoms which may be the same or different, selected from nitrogen, oxygen and sulfur optionally substituted with one or more substituents which may be the same or different, and are selected from hydroxy, amino, halogen, straight chain alkyl of 1 to 6 carbon atoms, cyano and nitro;
R
1a
is hydrogen or straight chain alkyl of 1 to 6 carbon atoms; phenylalkyl wherein the alkyl moiety is a straight chain alkyl of 1 to 6 carbon atoms and the phenyl moiety is optionally substituted with one or more substituents which may be the same or different and are selected from hydroxy, amino, halogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cyano, nitro, alkylamino of 1 to 6 carbon atoms, and dialkylamino of 1 to 6 carbon atoms;
R
2
is hydrogen, —NHR
1
, or —OR
1
; aryl of 6 to 12 carbon atoms optionally substituted with one or more substituents selected from straight chain alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, —S-alkyl of 1 to 6 carbon atoms, cyano, nitro, halogen and phenyl; the heterocyclyl moiety is selected from a 5- or 6-membered heterocyclic ring which
Coghlan Richard Dale
Hauze Diane Barbara
Kees Kenneth Lewis
Yardley John
Zask Arie
Milowsky Arnold S.
Robinson Binta
Rotman Alan L.
Wyeth
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