Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-07-30
2001-09-18
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S257000, C514S252020, C514S307000, C514S414000, C514S424000
Reexamination Certificate
active
06291453
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 VLA-4.
References
The following publications, patents and patent applications are cited in this application as superscript numbers:
Hemler and Takada,
European Patent Application Publication
No. 330,506, published Aug. 30, 1989
2 Elices, et al.,
Cell
, 60:577-584 (1990)
3 Springer,
Nature
, 346:425-434 (1990)
4 Osborn,
Cell
, 62:3-6 (1990)
5 Vedder, et al.,
Surgery
, 106:509 (1989)
6 Pretolani, et al.,
J. Exp. Med
., 180:795 (1994)
7 Abraham, et al.,
J. Clin. Invest
. 93:776 (1994)
8 Mulligan, et al.,
J. Immunology
, 150:2407 (1993)
9 Cybulsky, et al.,
Science
, 251:788 (1991)
10 Li, et al.,
Arterioscler. Thromb
., 13:197 (1993)
11 Sasseville, et al.,
Am. J. Path
., 144:27 (1994)
12 Yang, et al.,
Proc. Nat. Acad. Science
(USA), 90:10494 (1993)
13 Burkly, et al.,
Diabetes
, 43:529 (1994)
14 Baron, et al.,
J. Clin. Invest
., 93:1700 (1994)
15 Hamann, et al.,
J. Immunology
, 152:3238 (1994)
16 Yednock, et al.,
Nature
, 356:63 (1992)
17 Baron, et al.,
J. Exp. Med
., 177:57 (1993)
18 van Dinther-Janssen, et al.,
J. Immunology
, 147:4207 (1991)
19 van Dinther-Janssen, et al.,
Annals. Rheumatic Dis
., 52:672 (1993)
20 Elices, et al.,
J. Clin. Invest
., 93:405 (1994)
21 Postigo, et al.,
J. Clin. Invest
., 89: 1445 (1991)
22 Paul, et al.,
Transpl. Proceed
., 25:813 (1993)
23 Okarhara, et al.,
Can. Res
., 54:3233 (1994)
24 Paavonen, et al.,
Int. J. Can
., 58:298 (1994)
25 Schadendorf, et al.,
J. Path
., 170:429 (1993)
26 Bao, et al.,
Diff
., 52:239 (1993)
27 Lauri, et al.,
British J. Cancer
, 68:862 (1993)
28 Kawaguchi, et al.,
Japanese J. Cancer Res
., 83:1304 (1992)
29 Kogan, et al., U.S. Pat. No. 5,510,332, issued Apr. 23, 1996
30 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.
2. State of the Art
VLA-4 (also referred to as &agr;4&bgr;1 integrin and CD49d/CD29), first identified by Hemler and Takada
1
, is a member of the &bgr;1 integrin family of cell surface receptors, each of which comprises two subunits, an &agr; chain and a &bgr; chain. VLA-4 contains an &agr;4 chain and a &bgr;1 chain. There are at least nine &bgr;1 integrins, all sharing the same &bgr;1 chain and each having a distinct &agr; chain. These nine receptors all bind a different complement of the various cell matrix molecules, such as fibronectin, laminin, and collagen. VLA-4, for example, binds to fibronectin. VLA-4 also binds non-matrix molecules that are expressed by endothelial and other cells. These non-matrix molecules include VCAM-1, which is expressed on cytokine-activated human umbilical vein endothelial cells in culture. Distinct epitopes of VLA-4 are responsible for the fibronectin and VCAM-1 binding activities and each activity has been shown to be inhibited independently.
2
Intercellular adhesion mediated by VLA-4 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
3
and Osborn
4
.
Inflammatory bra in 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.
5
). Other inflammatory conditions mediated by an adhesion mechanism include, by way of example, asthma
6-8
, Alzheimer's disease, atherosclerosis
9-10
, AIDS dementia
11
, diabetes
12-14
(including acute juvenile onset diabetis), inflammatory bowel disease
15
(including ulcerative colitis and Crohn's disease), multiple sclerosis
16-17
, rheumatoid arthritis
18-21
, tissue transplantation
22
, tumor metastas
23-28
, 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 level of VLA-4 in a biological sample containing VLA-4 would be useful, for example, to diagnosis VLA-4 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 in diseases and other inflammatory conditions
29,30
. The present invent ion addresses these and other needs.
SUMMARY OF THE INVENTION
This invention provides compounds which bind to VLA-4. Such compounds can be used, for example, to assay for the presence of VLA-4 in a sample and, in pharmaceutical compositions , to inhibit cellular adhesion mediated by VLA-4, for example, binding of VCAM-1 to VLA-4. The compounds of this invention have a binding affinity to VLA-4 as expressed by an IC
50
of about 15 &mgr;M or less (as measured by Example 98 below) which compounds are defined by formula I below:
where
R
1
is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
R
2
is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and R
1
and R
2
together with the nitrogen atom bound to Rand the SO
2
group bound to R
1
can form a heterocyclic or a substituted heterocyclic group;
R
3
is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and, when R
2
does not form a heterocyclic group with R
1
, R
2
and R
3
together with the nitrogen atom bound to R
2
and the carbon atom bound to R
3
can form a heterocyclic or a substituted heterocyclic group;
R
5
is —(CH
2
)
x
—Ar—R
5′
where R
5′
is selected from the group consisting of —NR
12
C(Z)NR
8
R
8
and —NR
12
C(Z)R
13
wherein R
12
is selected from the group consisting of hydrogen, alkyl and aryl, R
8
and R
8′
are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl provided that when Z is oxygen, at least one of R
8
and R
8
is substituted alkyl, cycloalkyl, substituted cycloalkyl, saturated heterocyclic other t
Ashwell Susan
Grant Francine S.
Konradi Andrei W.
Kreft Anthony
Lombardo Louis John
Athena Neurosciences, Inc.
Burns Doane , Swecker, Mathis LLP
Kifle Bruck
Patel Sudhaker B.
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