Integrin antagonists

Details Integrin antagonists Integrin antagonists

1999-06-08

2001-06-12

Lee, Howard C. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S538000, C514S562000, C560S013000, C562S430000, C562S439000

Reexamination Certificate

active

06245809

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel &agr;-sulfonamido and &agr;-sulfinamido containing carboxylic acid compounds which are potent inhibitors of Arginyl-Glycyl-Aspartyl-(RGD)-dependent integrins. In another aspect, the present invention relates to these &agr;-sulfonamido and &agr;-sulfinamido containing carboxylic acids, their pharmaceutically-acceptable salts, and pharmaceutically-acceptable compositions thereof which are useful as potent inhibitors of integrin adhesive functions in mammals. In yet another aspect, the invention relates to methods for using these inhibitors as therapeutic agents for disease states in mammals characterized by aberrant cellular adhesive disorders that occur during thrombosis and restenosis.
BACKGROUND OF THE INVENTION
Cellular adhesion is believed to play an important role in both thrombus formation and cellular responses to vascular injury, as well as for normal hemostasis. Vascular injury and thrombosis are prevalent during the development and progression of vascular disease states. These include conditions such as atherosclerosis, acute myocardial infarction, chronic stable angina, unstable angina, transient ischemic attacks, stroke, peripheral vascular disease, arterial thrombosis, and conditions induced by interventional procedures such as restenosis following angioplasty.
Cellular adhesions can be characterized as either cell-cell adhesions or cell-matrix adhesions. Cells utilize a variety of cell surface adhesion receptors and adhesive proteins to facilitate these adhesive interactions. For cell-cell type adhesions, platelets play a major role in this type of adhesive interaction that occurs during acute thrombosis. Platelet aggregation, thrombus formation and consolidation of clots mediated by platelets are principally achieved by adhesive protein crosslinking of the platelet glycoprotein (GPIIb-IIIa) also referred to as &agr;
II&bgr;
&bgr;
3
which is found on the platelet surface. This heterodimeric adhesion receptor is one member of a large family of heterodimeric transmembrane glycoprotein receptors, called integrins (Hynes, R. O., “Integrins: Versatility, Modulation and Signaling in Cell Adhesion”,
Cell
69:11 (1992)).
Other integrins which may have important cell adhesion functions in thrombosis, hemostasis or in disease states characterized by vascular injury are the vitronectin receptors (&agr;
v
&bgr;
3
and &agr;
v
&bgr;
5
) and the fibronectin receptor (&agr;
5
&bgr;
1
). In particular, the vitronectin receptor, &agr;
v
&bgr;
3
has been postulated to play roles in cellular migration of smooth muscle cells following vascular injury that can ultimately lead to restenosis of the vessel (Yue, T. L., et al., “Osteopontin-Stimulated Vascular Smooth Muscle Cell Migration is Mediated by &bgr;
3
Integrin”,
Exp. Cell. Res
. 214:459-464 (1994); Choi, E. T., et al., “Inhibition of Neointimal Hyperplasia by Blocking &agr;
v
&bgr;
3
Integrin with a Small Peptide Antagonist GpenGRGDSPCA”,
J. Vasc. Sur
. 19:125-134 (1994); Matsuno, H., “Inhibition of Integrin Function by A Cyclic RGD-Containing Peptide Prevents Neointima Formation”, Circulation 90:2203-2206 (1994)). A number of the natural ligands of these integrins (e.g. &agr;
II&bgr;
&bgr;
3
,&agr;
v
&bgr;
3
, &agr;
v
&bgr;
5
, and &agr;
5
&bgr;
1
) such as fibrinogen, fibronectin, von Willebrand factor, thrombospondin, osteopontin, vitronectin and others, contain and utilize the tripeptide sequence, Arg-Gly-Asp (RGD) to bind to their respective integrins. Small synthetic peptides containing the RGD sequence have been shown to bind to these integrins and to compete for the binding of natural adhesive ligands (Rouslahti, E. and Pierschbacher, M. D., “New Perspectives in Cell Adhesion: RGD and Integrins”,
Science
238:491-497 (1987)). Peptides containing the RGD sequence or mimetic compounds have thus been the basis for the discovery of several potent and highly specific inhibitors of platelet &agr;
II&bgr;
&bgr;
3
which are useful as antithrombotic agents. This literature has been extensively reviewed. See Coller, B. S., “Blockade of Platelet GPIIb/IIIa Receptors as an Antithrombotic Strategy”,
Circulation
92:2373-2380 (1995); Cook, N. S., et al., “Platelet Glycoprotein IIb/IIIa Antagonists”,
Drugs of the Future
19:135-159 (1994); T. Weller., et al., “Fibrinogen Receptor Antagonists—A Novel Class of Promising Antithrombotics”,
Drugs of the Future
19:461 (1994); and Zablocki, J. A., et al., “Fibrinogen Receptor Antagonists”,
Exp. Opin. Invest. Drugs
, 3:437-448 (1994).
Highly specific inhibitors of &agr;
v
&bgr;
3
based on the RGD recognition sequence have also been recently described. Specifically, the cyclic peptide, cyclo[Arg-Gly-Asp-D-Phe-Val] is a very potent and specific inhibitor of the vitronectin receptor &agr;
v
&bgr;
3
(Pfaff, M., et al., “Selective Recognition of Cyclic RGD Peptides of NMR Defined Conformation by &agr;
II&bgr;
&bgr;
3
, &agr;
v
&bgr;
3
, and &agr;
5
&bgr;
1
Integrins”,
J. Biol. Chem
. 269:20233-20238 (1994); Jonczyk, A., et al., European Patent Application 578083A2 (1994)).
The present invention describes the preparation of novel compounds which inhibit the adhesive function of various RGD-dependent integrins. More specifically, the novel compounds are non-specific inhibitors of the platelet integrin &agr;
II&bgr;
&bgr;
3
and the vitronectin receptor &agr;
v
&bgr;
3
.
SUMMARY OF THE INVENTION
The present invention relates to novel &agr;-sulfonamido and &agr;-sulfinamido containing carboxylic acids or carboxylic esters, their pharmaceutically-acceptable stereoisomers, salts, hydrates, solvates and prodrug derivatives, and pharmaceutically-acceptable compositions thereof which have particular biological properties and are useful as potent antithrombotics and/or antirestenotic agents in mammals.
The present invention provides a compound of the formula:
wherein:
Y is selected from the group consisting of —COOH, —PO
3
H
2
, —SO
3
H and —COOR
4
; where R
4
is selected from the group consisting of C
1-10
alkyl, C
1-8
alkylaryl, aryl-C
1-8
alkyl, C
1-8
alkyloxycarbonyloxy-C
1-8
alkyl, aryloxycarbonyloxy-C
1-8
alkyl, C
1-8
alkyloxycarbonyloxyaryl, C
1-8
alkylcarbonyloxy-C
1-8
alkyl, arylcarbonyloxy-C
1-8
alkyl and C
1-8
alkylcarbonyloxyaryl;
A is selected from the group consisting of C
6-12
alkyl, C
0-8
alkyl-NR
5
—CO-C
0-8
alkyl, C
0-8
alkyl-CO—NR
5
-CO
0-8
alkyl, C
0-8
alkyl-O-C
0-8
alkyl, C
0-8
alkyl-NR
5
—CO-C
1-8
alkyl-NR
5
—CO-C
0-8
alkyl, C
0-8
alkyl-NR
5
—CO-C
1-8
alkyl-CO—NR
5
-C
0-8
alkyl, C
0-8
alkyl-CO—NR
5
-C
1-8
alkyl-NR
5
—CO-C
0-8
alkyl, C
0-8
alkyl-CO—NR
5
-C
0-8
alkyl-CO—NR
5
-C
8
alkyl, C
0-8
alkyl-CO-C
1-8
alkyl-CO—NR
5
-C
0-8
alkyl, C
0-8
alkyl-CO-C
0-8
alkyl-NR
5
—CO-C
0-8
alkyl, C
0-8
alkyl-O-C
2-8
alkyl-NR
5
—CO-C
0-8
alkyl, C
0-8
alkyl-O-C
0-8
alkyl-CO—NR
5
-C
0-8
alkyl, C
0-8
alkyl-O-C
2-8
alkyl-O-C
0-8
alkyl-CO—NR
5
-C
0-8
alkyl, C
0-8
alkyl-S-C
0-8
alkyl, C
0-8
alkyl-S(O
n
)-C
0-8
alkyl, C
0-8
alkyl-S-C
2-8
alkyl-NR
5
—CO-C
0-8
alkyl, C
0-8
alkyl-S(O
n
)-C
2-8
alkyl-NR
5
—CO-C
0-8
alkyl, C
0-8
alkyl-S-C
0-8
alkyl-CO—NR
5
-C
0-8
alkyl, C
0-8
alkyl-S(O
n
)-C
1-8
alkyl-CO—NR
5
-C
0-8
alkyl, C
0-8
alkyl-NR
5
—CO-C
0-8
alkyl-S-C
0-8
alkyl, C
0-8
alkyl-NR
5
—CO-C
1-8
alkyl-S(O
n
)-C
0-8
alkyl, C
0-8
alkyl-CO—NR
5
-C
2-8
alkyl-S-C
0-8
alkyl, C
0-8
alkyl-CO—NR
5
-C
2-8
alkyl-S(O
n
)-C
0-8
alkyl, C
0-8
alkyl-NR
5
-C
0-8
alkyl-CO
2
-C
0-8
alkyl, C
0-8
alkyl-NR
5
-C
0-8
alkyl-CS—O-C
0-8
alkyl, C
0-8
alkyl-NR
5
-C
0-8
alkyl-CO—NR
5
-C
0-8
alkyl, C
0-8
alkyl-NR
5
-C
0-8
alkyl-CS—NR
5
-C
0-8
alkyl, C
0-8
alkyl-O-C
0-8
alkyl-CO
2
-C
0-8
alkyl, C
0-8
alkyl-O-C
0-8
alkyl-CS—O-C
0-8
alkyl; C
0-8
alkyl-SiR
7
R
8
-C
0-8
alkyl, C
0-8
alkyl-SiR
7
R
8
-C
0-8
alkyl-NR
6
—CO-C
0-8
alkyl, and C
0-8
alkyl-SiR
7
R
8
-C
0-8
alkyl-CO—NR
6
-C
0-8
alkyl; where R
5
, R
6
, R
7
and R
8
are independently selected from the group consisting of H and C
1-6
alkyl; and where n=1 or 2;
Z is selected from the group consisting of —NH—C(NR
9
R
10
)═NR
11
, —NH—C(R
9
)═NR
11
, —C(NR
9
R
10
)═NR
11
and piperidinyl;

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