Quinolizinones as integrin inhibitors

Details Quinolizinones as integrin inhibitors Quinolizinones as integrin inhibitors

2001-03-20

2003-10-07

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...

C544S331000, C544S333000, C544S405000, C546S138000

Reexamination Certificate

active

06630488

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compounds that inhibit certain integrins, particularly to compounds that inhibit &agr;
v
&bgr;
3
and &agr;
IIb
&bgr;
3
integrins, their synthesis and their use as integrin inhibitors.
BACKGROUND OF THE INVENTION
Integrins are a family of cell adhesion receptors. The integrin family of proteins are expressed on the surface of a cell and contain a binding site that binds the cell to certain glycoproteins and therefore mediate cell-cell and cell-extracellular matrix (ECM)interactions.
They are heterodimer transmembrane proteins that consist of an alpha unit and a beta unit. The integrin family has been designated a standard nomenclature system based upon the structure of the alpha unit and the beta unit of the receptor. Therefore, all compounds that have the designation &agr;
v
each share the same alpha unit. All compounds that have the &bgr;
3
designation have the same beta subunit. The various combinations of those subunits give a wide array of heterodimers with distinct cellular and adhesive specificities.
The family includes cell adhesion receptors such as &agr;
IIb
&bgr;
3
(previously called GpIIb/IIIa, generally known as the fibrinogen receptor), &agr;
v
&bgr;
3
(generally known as the vitronectin receptor), and &agr;
v&bgr;
5
(generally known as the osteopontin receptor)
Some integrins (including &agr;
IIb
&bgr;
3
, &agr;
v
&bgr;
3
and &agr;
v
&bgr;
5
) bind to a group of glycoproteins that contain the tripeptide moiety, Arg-Gly-Asp (RGD). While several members of the integrin family members may bind to RGD containing proteins, the physical configuration of the binding site on each protein affects binding affinity between the integrin and the RGD containing glycoprotein. Nonetheless, each integrin may be capable of binding to more than one molecule containing the RGD moiety with differing degrees of effectiveness.
The integrin, &agr;
v
&bgr;
3
, is a particularly important integrin family member that has a wide range of reactivity. It is expressed on a variety of cells, including endothelial cells, osteoclasts, platelets, and smooth muscle cells, and binds to vitronectin and plays an important role in bone resporption, angiogenesis, and neovascularization. The binding of &agr;
v
&bgr;
3
to vitronectin is an important step in the process of angiogenesis or neovascularization.
Angiogenesis is described as the formation of new blood vessels into a tissue. Angiogenesis is an important process in neonatal growth, but is also important in wound healing and in.the pathogenesis of a large variety of clinically important diseases including tissue inflammation, arthritis, psoriasis, cancer, diabetic retinopathy, macular degeneration and other neovascular eye diseases. These clinical entities associated with angiogenesis are referred to as angiogenic diseases. See Folkman et al.,
Science
, 235:442-447 (1987) and Folkman et al., J. B. C., 267: 10931-10934 (1992).
It has been postulated that the growth of tumors depends on an adequate blood supply, which in turn is dependent on the growth of new vessels into the tumor; thus inhibition of angiogenesis can cause tumor regression in animal models. Integrin antagonists, such as &agr;v&bgr;3 antagonists which inhibit angiogenesis are therefore useful in the treatment of cancer for inhibiting tumor growth.
Inhibiting angiogenesis will slow or halt the growth of tumors. Inhibition of &agr;
v
&bgr;
3
is believed to cause tumor regression and induce apoptosis. The &agr;
v
&bgr;
3
integrin also binds to bone matrix proteins that contain the RGD moiety such as osteopontin, bone sialoprotein and thrombospondin. Inhibition of &agr;
v
&bgr;
3
is believed to have potential therapeutic value in the prevention of osteoporosis. &agr;
v
&bgr;
3
is implicated in bone resorption at the level of osteoclasts and in osteoporosis such as described in WO 98/31359, WO 98/08840 and WO 98/18461.
The binding of integrins such as &agr;
v
&bgr;
3
, &agr;
v
&bgr;
1
and &agr;
v
&bgr;
5
to fibronectin has been linked to the specific internalization of
Neisseria gonorrhoeae
bacteria into epithelial cells. Additionally, the binding of RGD containing domain of exogenous HIV-1 Tat protein is believed to decrease the function of dendric cells, possibly impairing antigen presentation.
The integrin, &agr;
v
&bgr;
5
, known primarily as the osteopontin receptor binds to other RGD containing molecules including vitronectin. Inhibitors of &agr;
v
&bgr;
5
have potential therapeutic value in the treatment in osteoporosis and angiogenesis.
Because of the similarity of molecules in the integrin family, integrins exhibit a considerable degree of cross reactivity as is illustrated above with the discussion regarding the &agr;
v
&bgr;
3
and &agr;
v
&bgr;
5
integrins. However, the inhibition of &agr;
v
&bgr;
3
and &agr;
v
&bgr;
5
or other integrins are rather unpredictable. One effective inhibitor of &agr;
v
&bgr;
3
may be also effective inhibitor of &agr;
IIb
&bgr;
3
but not of &agr;
v&bgr;
5
. Other inhibitors may selectively inhibit one integrin but not inhibit other integrins. The use of a compound for a particular application may depend upon which integrins it inhibits and to what extent it inhibits other molecules.
There have been several publications which disclose potential inhibitors of &agr;
v
&bgr;
3
. Some of these publications include Haubner et al., “Structural and Functional Aspects of RGD-Containing Cyclic Pentapeptides as Highly Potent and Selective Integrin &agr;
v
&bgr;
3
Antagonists,” J. Am. Chem. Soc., Vol. 118, 7461-7472 (1996); Wong et al., “Studies on &agr;
v
b
3
/Ligand Interactions Using a [
3
H] SK&F-107260 Binding Assay,” Molec. Pharm, Vol. 50, pp. 529-537, (1996); Brooks, “Integrin &agr;
v
b
3
: A Therapeutic Target,” DN&P Vol. 8(10), pp. 456-460 (1997); Samanen et al., “Vascular Indications for Integrin &agr;v Antagonists,” Current Pharmaceutical Design, Vol. 3, pp. 545-584 (1997); PCT Pub. No. WO 97/24124 to Smithkline Beecham Corporation ; PCT WO 98/23608 to The Du Pont Merck Pharmaceutical Co; PCT WO 97/36862 to G. D. Searle & Co; PCT WO 97/36859 so G. D. Searle.
There are other publications which disclose inhibitors of other integrins. Some of these publications include PCT Pub. No. WO 94/08577 to Merck & Co.; U.S. Pat. No. 5,084,466 to Alig et al.; PCT Publ. No. WO 97/01540 to Smithkline Beecham Corporation; Kunicki et al., “Exchange of Arg-Gly-Asp (RGD) and Arg-Tyr-Asp (RYD) Binding Sequences in a Recombinant Murine Fab Fragment” J. Bio. Chem, Vol. 270, No. 28, pp. 16660-16665 (1995); PCT Publ. No. WO 98/05774 to Merck & Co. Inc; U.S. Pat. No. 5,227,490 to Hartman et al.; U.S. Pat. No. 5,082,942 to Mahuzier; PCT WO 97/26250 to Merck & Co.
However, despite all of the studies on integrin receptor antagonists, there is still a need for compounds that bind to particular integrins effectively and particularly can effectively bind to &agr;
v
integrins including &agr;
v
b
3
and/or &agr;
IIb
&bgr;
3
. This Invention satisfies these and other needs.
The therapeutic use of certain quinolizinone derivatives has been described previously. For example, Y. Kitaura et al., in U.S. Pat. No. 4,650,804 issued Mar. 17, 1987 have disclosed quinolizinone compounds having a tetrazolylcarbamoyl substitiuent which are useful for the treatment of allergic and ulcer diseases.
J. V. Heck and E. D. Thorsett, in U.S. Pat. No 4,921,857 issued May 1, 1990 have disclosed the use of certain 4-oxo-4H-quinolizine-3-carboxylic acids and derivatives thereof for treating bacterial infections.
Y. Kurashiva et Al. in U.S. Pat. No. 4,935,425 issued Jun. 19, 1990 have disclosed 4H-quinolizin-4-ones for treatment of diseases associated with immunoglobulin E-antibody formation. However, quinolizinone compounds have not been described for the use of angiogenesis inhibitors.
Presently, there is a need to identify compounds which bind to integrin receptors. There is a further need to identify compounds which bind to the (&agr;v&bgr;3 receptor as well as the &agr;IIb&bgr;3 receptor both individually and co

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