Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-01-14
2003-07-01
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S225000, C544S059000, C514S227500, C514S300000, C514S365000, C514S423000
Reexamination Certificate
active
06586602
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.
2. References
The following publications, patents and patent applications are cited in this application as superscript numbers:
1
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.
3. 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 is unique among &bgr;
1
integrins in that it 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 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.
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 diabetes), inflammatory bowel disease
15
(including ulcerative colitis and Crohn's disease), multiple sclerosis
16-17
, rheumatoid arthritis
18-21
, tissue transplantation
22
, tumor metastasis
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 VLA-4 level 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 diseases and other inflammatory conditions
29,30
. The present invention 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 95 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
and R
3
together with the nitrogen atom bound to R
2
and the carbon atom bound to R
3
form a saturated heterocyclic group or a saturated substituted heterocyclic group with the proviso that when monosubstituted, the substituent on said saturated heterocyclic group is not carboxyl;
R
5
is selected from the group consisting of —(CH
2
)
n
-aryl and —(CH
2
)
n
-heteroaryl, where n is an integer equal to 1 to 4;
Q is —C(X)NR
7
— wherein R
7
is selected from the group consisting of hydrogen and alkyl, and X is selected from the group consisting of oxygen and sulfur;
and pharmaceutically acceptable salts thereof,
with the proviso that when R
1
is 2,4,6-trimethylphenyl, R
2
and R
3
together with the pendent nitrogen and carbon atoms form a pyrrolidinyl ring and Q is —C(O)NH—, then R
5
is not benzyl; and
with the further proviso that when R
1
is p-methylphenyl, R
2
and R
3
together with the pendent nitrogen and carbon atoms form a pyrrolidinyl ring derived from D-proline and Q is —C(O)NH—, then R
5
is not benzyl derived from D-phenylalanine.
In another embodiment, the compounds of this invention can also be provided as prodrugs which convert (e.g., hydrolyze, metabolize, etc.) in vivo to a compound of formula I above. In a preferred example of such an embodiment, the carboxylic acid of the compound of formula I is modified into a group which, in vivo, will c
Dappen Michael S.
Dressen Darren B.
Grant Francine S.
Konradi Andrei W.
Lombardo Louis John
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