Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2000-02-28
2002-06-25
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S132000, C514S227500, C514S357000, C514S478000, C514S548000, C544S059000, C546S333000
Reexamination Certificate
active
06410781
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to compounds which inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by &agr;
4
&bgr;
7
. Accordingly, compounds of this invention are useful in the treatment and prevention of diseases mediated by &agr;
4
&bgr;
7
binding and cell adhesion and activation such as multiple sclerosis, asthma, allergic rhinitis, rheumatoid arthritis, septic arthritis, restenosis, inflammatory bowel disease including ulcerative colitis and Crohn's disease, dermatitis, psoriasis, and the like.
2. State of the Art
References
The following publications, patents and patent applications are cited in this application as superscript numbers:
1
Tidswell, et al.,
J. of Immunology.,
1497-1505 (1997)
2
Springer,
Nature,
346:425-434 (1990)
3
Osborn,
Cell,
62:3-6 (1990)
4
Vedder, et al.,
Surgery,
106:509 (1989)
5
Pretolani, et al.,
J. Exp. Med.,
180:795 (1994)
6
Abraham, et al.,
J. Clin. Invest.,
93:776 (1994)
7
Mulligan, et al.,
J. Immunology,
150:2407 (1993)
8
Cybulsky, et al.,
Science,
251:788 (1991)
9
Li, et al.,
Arterioscler. Thromb.,
13:197 (1993)
10
Sasseville, et al.,
Am. J Path.,
144:27 (1994)
Yang, et al., Proc. Nat. Acad. Science (
USA
), 90:10494 (1993)
12
Burkly, et al.,
Diabetes,
43:529 (1994)
13
Baron, et al.,
J. Clin. Invest.,
93:1700 (1994)
14
Hamann, et al.,
J. Immunology,
152:3238 (1994)
15
Yednock, et al.,
Nature,
356:63 (1992)
16
Baron, et al.,
J. Exp. Med.,
177:57 (1993)
17
van Dinther-Janssen, et al.,
J. Immunology,
147:4207 (1991)
18
van Dinther-Janssen, et al.,
Annals. Rheumatic Dis.,
52:672 (1993)
19
Elices, et al.,
J. Clin. Invest.,
93:405 (1994)
20
Postigo, et al.,
J. Clin. Invest.,
89:1445 (1991)
21
Paul, et al.,
Transpl. Proceed.,
25:813 (1993)
22
Okarhara, et al.,
Can. Res.,
54:3233 (1994)
23
Paavonen, et al.,
Int. J. Can.,
58:298 (1994)
24
Schadendorf, et al.,
J. Path.,
170:429 (1993)
25
Bao, et al.,
Diff.,
52:239 (1993)
26
Lauri, et al.,
British J. Cancer,
68:862 (1993)
27
Kawaguchi, et al.,
Japanese J. Cancer Res.,
83:1304 (1992)
28
Kogan, et al., U.S. Pat. No. 5,510,332, issued Apr. 23, 1996
29
International Patent Appl. Publication No. WO 96/01644
All of the above publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
Integrins are heterodimeric adhesion receptors that mediate cell-cell and cell-extracellular matrix interactions. The &bgr;
7
integrin subfamily has two known members: &agr;
4
&bgr;
7
and &agr;
E
&bgr;
7
. These &bgr;
7
integrins are expressed primarily by leukocytes. &bgr;
7
integrins are unique among known integrins in their ability to recognize certain ligands expressed on the surface of endothelial and epithelial cells in mucosal organs.
1
&agr;
4
&bgr;
7
is a lymphocyte homing receptor and plays a crucial role in the migration of these cells to the intestine and associated lymphoid tissue, such as Peyer's patches in the intestine. &agr;
4
&bgr;
7
mediates adhesion to a ligand on Peyer's patch high endothelial venules (“HEV
4
”). The ligand on Peyer's patch HEV is MAdCAM-1, a glycoprotein in the Ig superfamily. MAdCAM-1 is expressed on Peyer's patch HEV, mesenteric lymph node HEV, and lamina propria venules within the gut. Antibodies against &agr;
4
or &bgr;
7
subunits inhibit attachment of circulating lymphocytes to Peyer's patch HEV in vivo.
1
Memory T cells that circulate preferentially to intestinal tissues express high levels of &agr;
4
&bgr;
7
, whereas those that circulate to other organs are mostly &agr;
4
&bgr;
7
. These &agr;
4
&bgr;
7
memory T cells express a related integrin, &agr;
4
&bgr;
1
, which is not able to mediate cell adhesion to MAdCAM-1. However, both &agr;
4
&bgr;
7
and &agr;
4
&bgr;
1
can mediate adhesion to VCAM-1 and to fibronectin.
1
Intercellular adhesion mediated by &agr;
4
&bgr;
7
and other cell surface receptors is associated with a number of inflammatory responses. At the site of an injury or other inflammatory stimulus, activated vascular endothelial cells express molecules that are adhesive for leukocytes. The mechanics of leukocyte adhesion to endothelial cells involves, in part, the recognition and binding of cell surface receptors on leukocytes to the corresponding cell surface molecules on endothelial cells. Once bound, the leukocytes migrate across the blood vessel wall to enter the injured site and release chemical mediators to combat infection. For reviews of adhesion receptors of the immune system, see, for example, Springer
2
and Osborn
3
.
Inflammatory brain disorders, such as experimental autoimmune encephalomyelitis (EAE), multiple sclerosis (MS) and meningitis, are examples of central nervous system disorders in which the endothelium/leukocyte adhesion mechanism results in destruction to otherwise healthy brain tissue. Large numbers of leukocytes migrate across the blood brain barrier (BBB) in subjects with these inflammatory diseases. The leukocytes release toxic mediators that cause extensive tissue damage resulting in impaired nerve conduction and paralysis.
In other organ systems, tissue damage also occurs via an adhesion mechanism resulting in migration or activation of leukocytes. For example, it has been shown that the initial insult following myocardial ischemia to heart tissue can be further complicated by leukocyte entry to the injured tissue causing still further insult (Vedder et al.
4
). Other inflammatory conditions mediated by an adhesion mechanism include, by way of example, asthma
5-7
, Alzheimer's disease, atherosclerosis
8-9
, AIDS dementia
10
, diabetes
11-13
(including acute juvenile onset diabetes), inflammatory bowel disease
14
, (including ulcerative colitis and Crohn's disease), multiple sclerosis
15-16
, rheumatoid arthritis
17-20
, tissue transplantation
21
, tumor metastasis
22-27
, meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in adult respiratory distress syndrome.
In view of the above, assays for determining the &agr;
4
&bgr;
7
level in a biological sample containing &agr;
4
&bgr;
7
would be useful, for example, to diagnosis &agr;
4
&bgr;
7
mediated conditions. Additionally, despite these advances in the understanding of leukocyte adhesion, the art has only recently addressed the use of inhibitors of adhesion in the treatment of inflammatory brain diseases and other inflammatory conditions
28,29
. The present invention addresses these and other needs.
SUMMARY OF THE INVENTION
In one aspect, this invention provides compounds of Formula I:
wherein:
A together with —CH— and W forms a cyclic group selected from the group consisting of heterocyclic, substituted heterocyclic, cycloalkyl, and substituted cycloalkyl;
Q is selected from the group consisting of alkylene, substituted alkylene, —CO—, —NR
5
— (where R
5
is hydrogen, alkyl, or acyl), —O—, or —S(O)
q
where q is an integer from 0 to 2;
W is —CH— or —N—;
Z is —O— or —S—;
R
1
is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, and substituted cycloalkyl;
R
2
is selected from the group consisting of hydrogen, alkyl which is optionally substituted with one to four substituents independently selected from R
a
and Cy which is optionally substituted with one to four substituents independently selected from R
b
wherein R
a
and R
b
are as defined below;
R
3
is selected from the group consisting of:
(a) -(alkylene)-Ar—R
6
, -(alkenylene)-Ar—R
6
, or -(alkynylene)-Ar—R
6
where:
Ar is selected from the group consisting of aryl, heteroaryl, or heterocyclic wherein said aryl, heteroaryl, and heterocyclic rings are optionally
Konradi Andrei W.
Pleiss Michael A.
Thorsett Eugene D.
Burns Doane , Swecker, Mathis LLP
Elan Pharmaceuticals Inc.
Kumar Shailendra
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