Compounds that inhibit the binding of integrins to their...

Details Compounds that inhibit the binding of integrins to their... Compounds that inhibit the binding of integrins to their...

1999-10-14

2001-07-17

Solola, Taofiq A. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S444000, C514S512000, C546S283700, C548S267800, C549S060000, C549S452000, C562S431000

Reexamination Certificate

active

06262084

ABSTRACT:

FIELD OF THE INVENTION
This invention is directed generally to the inhibition of the binding of &agr;
4
&bgr;
1
integrin to its receptors, for example VCAM-1 (vascular cell adhesion molecule-1) and fibronectin. The invention also relates to compounds that inhibit this binding; to pharmaceutically active compositions comprising such compounds; and the use of such compounds either as above, or in formulations for the control or prevention of disease states in which &agr;
4
&bgr;
1
is involved.
BACKGROUND OF THE INVENTION
When a tissue has been invaded by a microorganism or has been damaged, white blood cells, also called leukocytes, play a major role in the inflammatory response. One of the most important aspects of the inflammatory response involves the cell adhesion event. Generally, white blood cells are found circulating through the bloodstream. However, when a tissue is infected or becomes damaged, the white blood cells recognize the invaded or damaged tissue, bind to the wall of the capillary and migrate through the capillary into the affected tissue. These events are mediated by a family of proteins called cell adhesion molecules.
There are three main types of white blood cells: granulocytes, monocytes and lymphocytes. The integrin &agr;
4
&bgr;
1
(also called VLA-4 for very late antigen-4) is a heterodimeric protein expressed on the surface of monocytes, lymphocytes and two subclasses of granulocytes: eosinophils and basophils. This protein plays a key role in cell adhesion through its ability to recognize and bind VCAM-1 and fibronectin, proteins associated with the endothelial cells that line the interior wall of capillaries.
Following infection or damage of tissue surrounding a capillary, endothelial cells express a series of adhesion molecules, including VCAM-1, that are critical for binding the white blood cells that are necessary for fighting infection. Prior to binding to VCAM-1 or fibronectin, the white blood cells initially bind to certain adhesion molecules to slow their flow and allow the cells to “roll” along the activated endothelium. Monocytes, lymphocytes, basophils and cosinophils are then able to firmly bind to VCAM-1 or fibronectin on the blood vessel wall via the &agr;
4
&bgr;
1
integrin. There is evidence that such interactions are also involved in transmigration of these white blood cells into the damaged tissue, as well as the initial rolling event itself.
Although white blood cell migration to the site of injury helps fight infection and destroy foreign material, in many instances this migration can become uncontrolled, with white blood cells flooding to the scene, causing widespread tissue damage. Compounds capable of blocking this process, therefore, may be beneficial as therapeutic agents. Thus, it would be useful to develop inhibitors that would prevent the binding of white blood cells to VCAM-1 and fibronectin.
Some of the diseases that might be treated by the inhibition of &agr;
4
&bgr;
1
binding include, but are not limited to, atherosclerosis, rheumatoid arthritis, asthma, allergy, multiple sclerosis, lupus, inflammatory bowel disease, graft rejection, contact hypersensitivity, sickle cell disease and type I diabetes. In addition to being found on some white blood cells and some reticulocytes, &agr;
4
&bgr;
1
is also found on various cancer cells, including leukemia, melanoma, lymphoma and sarcoma cells. It has been suggested that cell adhesion involving &agr;
4
&bgr;
1
may be involved in the metastasis of certain cancers. Inhibitors of &agr;
4
&bgr;
1
binding may, therefore, also be useful in the treatment of some forms of cancer.
The isolation and purification of a peptide which inhibits the binding of &agr;
4
&bgr;
1
to a protein is disclosed in U.S. Pat. No. 5,510,332. Peptides which inhibit binding are disclosed in WO 95/15973, EP 0 341 916, EP 0 422 938 A1, U.S. Pat. No. 5,192,746 and WO 96/06108. Novel compounds which are useful for inhibition and prevention of cell adhesion and cell adhesion-mediated pathologies are disclosed in WO 96/22966, WO 98/04247 and WO 98/04913.
It is therefore an object of the invention to provide novel compounds which are inhibitors of &agr;
4
&bgr;
1
binding, and pharmaceutical compositions including such novel compounds.
The present invention also relates to pharmaceutical compositions comprising a physiologically acceptable diluent and at least one compound of the present invention.
The present invention further relates to a process of inhibiting the binding of &agr;
4
&bgr;
1
integrin to VCAM-1 comprising exposure of a cell expressing &agr;
4
&bgr;1 integrin to a cell expressing VCAM-1 in the presence of an effective inhibiting amount of a compound of the present invention. The VCAM-1 may be on the surface of a vascular endothelial cell, an antigen presenting cell, or other cell type. The &agr;
4
&bgr;1 may be on a white blood cell such as a monocyte, lymphocyte, granulocyte; a stem cell; or any other cell that naturally expresses &agr;
4
&bgr;
1
.
The invention also provides a method for treating disease states mediated by &agr;
4
&bgr;
1
binding which comprises administration of an effective amount of a compound of the present invention, either alone or in formulation, to an afflicted patient.
BRIEF SUMMARY OF THE INVENTION
The invention is directed to novel compounds of Formula I as follows:
wherein A is selected from the group consisting of —O—, —S—, and —NR
5
—;
E is selected from the group consisting of —CH
2
—, —O—, —S—, and —NR
6
;
Q is selected from the group consisting of —C(O)— and —(CH
2
)
k
— wherein k is an integer of 0 or 1;
J is selected from the group consisting of —O—, —S— and NR
8
—;
G is selected from the group consisting of —O—, —NH—, —S—, and —(CH
2
)
p
— wherein p is an integer of 0 or 1;
T is selected from the group consisting of —C(O)— and —(CH
2
)
b
— wherein b is an integer of from 0 to 3;
L is selected from the group consisting of —O—, —NR
7
—, —S—, and —(CH
2
)
n
— wherein n is an integer of 0 or 1;
M is selected from the group consisting of —C(R
9
)(R
10
)— and —(CH
2
)
u
—, wherein u is an integer of from 0 to 3;
X is selected from the group consisting of —CO
2
B, —PO
3
H
2
, —SO
3
H, —OPO
3
H
2
, —C(O)NHC(O)R
11
, —C(O)NHSO
2
R
12
, oxazolyl, tetrazolyl and hydrogen;
B, R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, and R
12
are independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, aliphatic acyl, —CF
3
, nitro, amino, cyano, —N(C
1
-C
3
alkyl)—C(O)(C
1
-C
3
alkyl), —C
1
-C
3
alkylamino, alkenylamino, alkynylamino, di(C
1
-C
3
alkyl)amino, —C(O)O—(C
1
-C
3
alkyl), —C(O)NH—(C
1
-C
3
alkyl), —CH═NOH, —PO
3
H
2
, —OPO
3
H
2
, —C(O)N(C
1
-C
3
alkyl)
2
, haloalkyl, alkoxylcarbonyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, heterocyclyl, heterocycloyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, sulfonamido, carbamate, aryloxyalkyl, carboxyl and —C(O)NH(benzyl);
wherein B, X, R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, and R
12
are unsubstituted or substituted with at least one electron donating or electron withdrawing group;
and wherein R
2
and R
3
taken together may form a first ring;
R
4
and R
7
taken together may form a second ring;
R
9
and R
10
taken together may form a third ring;
and pharmaceutically acceptable salts thereof.
For Formula I, presently preferred compounds may have R
1
, R
2
and R
3
as hydrogen, alkoxy, alkoxyalkoxy, aryl, alkylaryl, arylalkyl, heterocyclyl, heterocyclylalkyl, alkylheterocyclyl or alkyl; R
4
as aryl, alkylaryl, arylalkyl, heterocyclyl, alkylheterocyclyl or heterocyclylalkyl; X as —CO
2
B; and M as —C(R
9
)(R
10
)— wherein R
9
and R
10
are hydrogen or lower alkyl.
More specifically, the compounds of the present invention may be described by Formula II below.
wherein X is selected from the group consisting of —CO
2
B, —PO
3
H
2
, —SO
3
H, —OPO

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