Pyrimidine compounds and derivatives thereof

Details Pyrimidine compounds and derivatives thereof Pyrimidine compounds and derivatives thereof

1998-12-18

2004-12-14

Qazi, Sabiha (Department: 1616)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S322000

Reexamination Certificate

active

06831199

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to pharmaceutical agents (compounds) which are useful as &agr;
v
&bgr;
3
integrin antagonists and as such are useful in pharmaceutical compositions and in methods for treating conditions mediated by &agr;
v
&bgr;
3
by inhibiting or antagonizing &agr;
v
&bgr;
3
integrins.
BACKGROUND OF THE INVENTION
Integrins are a group of cell surface glycoproteins which mediate cell adhesion and therefore are useful mediators of cell adhesion interactions which occur during various biological processes. Integrins are heterodimers composed of noncovalently linked &agr; and &bgr; polypeptide subunits. Currently eleven different a subunits have been identified and six different &bgr; subunits have been identified. The various a subunits can combine with various &bgr; subunits to form distinct integrins.
The integrin identified as &agr;
v
&bgr;
3
(also known as the vitronectin receptor) has been identified as an integrin which plays a role in various conditions or disease states including tumor metastasis, solid tumor growth (neoplasia), osteoporosis, Paget's disease, humoral hypercalcemia of malignancy, angiogenesis, including tumor angiogenesis, retinopathy, arthritis, including rheumatoid arthritis, periodontal disease, psoriasis and smooth muscle cell migration (e.g. restenosis). Additionally, it has been found that such agents would be useful as antivirals, antifungals and antimicrobials. Thus, compounds which selectively inhibit or antagonize &agr;
v
&bgr;
3
would be beneficial for treating such conditions.
It has been shown that the &agr;
v
&bgr;
3
integrin and other &agr;
v
containing integrins bind to a number of Arg-Gly-Asp (RGD) containing matrix macromolecules. Compounds containing the RGD sequence mimic extracellular matrix ligands so as to bind to cell surface receptors. However, it is also known that RGD peptides in general are non-selective for RGD dependent integrins. For example, most RGD peptides which bind to &agr;
v
&bgr;
3
also bind to &agr;
v
&bgr;
5
, &agr;
v
&bgr;
1
and &agr;
IIb
&bgr;
3
. Antagonism of platelet &agr;
IIb
&bgr;
3
(also known as the fibrinogen receptor) is known to block platelet aggregation in humans. In order to avoid bleeding side-effects when treating the conditions or disease states associated with the integrin &agr;
v
&bgr;
3
, it would be beneficial to develop compounds which are selective antagonists of &agr;
v
&bgr;
3
as opposed to &agr;
IIb
&bgr;
3
.
Tumor cell invasion occurs by a three step process: 1) tumor cell attachment to extracellular matrix; 2) proteolytic dissolution of the matrix; and 3) movement of the cells through the dissolved barrier. This process can occur repeatedly and can result in metastases at sites distant from the original tumor.
Seftor et al. (Proc. Natl. Acad. Sci. USA, Vol. 89 (1992) 1557-1561) have shown that the &agr;
v
&bgr;
3
integrin has a biological function in melanoma cell invasion. Montgomery et al., (Proc. Natl. Acad. Sci. USA, Vol. 91 (1994) 8856-60) have demonstrated that the integrin &agr;
v
&bgr;
3
expressed on human melanoma cells promotes a survival signal, protecting the cells from apoptosis. Mediation of the tumor cell metastatic pathway by interference with the &agr;
v
&bgr;
3
integrin cell adhesion receptor to impede tumor metastasis would be beneficial.
Brooks et al. (Cell, Vol. 79 (1994) 1157-1164) have demonstrated that antagonists of &agr;
v
&bgr;
3
provide a therapeutic approach for the treatment of neoplasia (inhibition of solid tumor growth) since systemic administration of &agr;
v
&bgr;
3
antagonists causes dramatic regression of various histologically distinct human tumors.
The adhesion receptor integrin &agr;
v
&bgr;
3
was identified as a marker of angiogenic blood vessels in chick and man and therefore such receptor plays a critical role in angiogenesis or neovascularization. Angiogenesis is characterized by the invasion, migration and proliferation of smooth muscle and endothelial cells. Antagonists of &agr;
v
&bgr;
3
inhibit this process by selectively promoting apoptosis of cells in neovasculature. The growth of new blood vessels, or angiogenesis, also contributes to pathological conditions such as diabetic retinopathy (Adonis et al., Amer. J. Ophthal., Vol. 118, (1994) 445-450) and rheumatoid arthritis (Peacock et al., J. Exp. Med., Vol. 175, (1992), 1135-1138). Therefore, &agr;
v
&bgr;
3
antagonists would be useful therapeutic targets for treating such conditions associated with neovascularization (Brooks et al., Science, Vol. 264, (1994), 569-571).
It has been reported that the cell surface receptor &agr;
v
&bgr;
3
is the major integrin on osteoclasts responsible for attachment to bone. Osteoclasts cause bone resorption and when such bone resorbing activity exceeds bone forming activity it results in osteoporosis (a loss of bone), which leads to an increased number of bone fractures, incapacitation and increased mortality. Antagonists of &agr;
v
&bgr;
3
have been shown to be potent inhibitors of osteoclastic activity both in vitro [Sato et al., J. Cell. Biol., Vol. 111 (1990) 1713-1723] and in vivo [Fisher et al., Endocrinology, Vol. 132 (1993) 1411-1413]. Antagonism of &agr;
v
&bgr;
3
leads to decreased bone resorption and therefore restores a normal balance of bone forming and resorbing activity. Thus it would be beneficial to provide antagonists of osteoclast &agr;
v
&bgr;
3
which are effective inhibitors of bone resorption and therefore are useful in the treatment or prevention of osteoporosis. The role of the &agr;
v
&bgr;
3
integrin in smooth muscle cell migration also makes it a therapeutic target for prevention or inhibition of neointimal hyperplasia which is a leading cause of restenosis after vascular procedures (Choi et al., J. Vasc. Surg. Vol. 19(1) (1994) 125-34). Prevention or inhibition of neointimal hyperplasia by pharmaceutical agents to prevent or inhibit restenosis would be beneficial.
White (Current Biology, Vol. 3(9)(1993) 596-599) has reported that adenovirus uses &agr;
v
&bgr;
3
for entering host cells. The integrin appears to be required for endocytosis of the virus particle and may be required for penetration of the viral genome into the host cell cytoplasm. Thus compounds which inhibit &agr;
v
&bgr;
3
would find usefulness as antiviral agents.
SUMMARY OF THE INVENTION
The present invention relates to a class of compounds represented by the Formula I
or a pharmaceutically acceptable salt thereof, wherein
A is
 
wherein Y
1
is selected from the group consisting of N—R
2
, O, and S;
R
2
is selected from the group consisting of H; alkyl; aryl; hydroxy; alkoxy; cyano; nitro; amino; alkenyl; alkynyl; amido; alkylcarbonyl; arylcarbonyl; alkoxycarbonyl; aryloxycarbonyl; haloalkylcarbonyl; haloalkoxycarbonyl; alkylthiocarbonyl; arylthiocarbonyl; acyloxymethoxycarbonyl; alkyl optionally substituted with one or more substituent selected from lower alkyl, halogen, hydroxyl, haloalkyl, cyano, nitro, carboxyl, amino, alkoxy, aryl or aryl optionally substituted with one or more halogen, haloalkyl, lower alkyl, alkoxy, cyano, alkylsulfonyl, alkylthio, nitro, carboxyl, amino, hydroxyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fused monocyclic heterocycles; aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, hydroxy, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, cyano, nitro, alkylthio, alkylsulfonyl, sulfonic acid, sulfonamide, carboxyl derivatives, amino, aryl, fused aryl, monocyclic heterocycles and fused monocyclic heterocycle; monocyclic heterocycles; and monocyclic heterocycles optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, sulfonic acid, sulfonamide, aryl or fused aryl; or
R
2
taken together with R
7
forms a 4-12 membered dinitrogen containing heterocycle optionally substituted with one or more substituent selected from the group consisting

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