Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-14
2003-10-07
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S537000, C548S307400, C548S467000, C514S388000, C514S414000
Reexamination Certificate
active
06630503
ABSTRACT:
BACKGROUND
Cell adhesion is a process by which cells associate with each other, migrate towards a specific target or localize within the extra-cellular matrix. As such, cell adhesion constitutes one of the fundamental mechanisms underlying numerous biological phenomena. For example, cell adhesion is responsible for the adhesion of hematopoietic cells to endothelial cells and the subsequent migration of those hemopoietic cells out of blood vessels and to the site of injury. As such, cell adhesion plays a role in pathologies such as inflammation and immune reactions in mammals.
Investigations into the molecular basis for cell adhesion have revealed that various cell-surface macromolecules—collectively known as cell adhesion molecules or receptors—mediate cell-cell and cell-matrix interactions. For example, proteins of the superfamily called “integrins” are key mediators in adhesive interactions between hematopoietic cells and their microenvironment (M. E. Hemler, “VLA Proteins in the Integrin Family: Structures, Functions, and Their Role on Leukocytes.”,
Ann. Rev. Immunol
., 8, p. 365 (1990)). Integrins are non-covalent heterodimeric complexes consisting of two subunits called &agr; and &bgr;. There are at least 12 different a subunits (&agr;-&agr;6, &agr;-L, &agr;-M, &agr;-X, &agr;-IIB, &agr;-V and &agr;-E) and at least 9 different &bgr;(&bgr;1-&bgr;9) subunits. Based on the type of its &agr; and &bgr; subunit components, each integrin molecule is categorized into a subfamily.
&agr;4&bgr;1 integrin, also known as very late antigen-4 (“VLA-4”), CD49d/CD29, is a leukocyte cell surface receptor that participates in a wide variety of both cell-cell and cell-matrix adhesive interactions (M. E. Hemler,
Ann. Rev. Immunol
., 8, p. 365 (1990)). It serves as a receptor for the cytokine-inducible endothelial cell surface protein, vascular cell adhesion molecule-1 (“VCAM-1”), as well as to the extracellular matrix protein fibronectin (“FN”) (Ruegg et al.,
J. Cell Biol
., 177, p. 179 (1991); Wayner et al.,
J. Cell Biol
., 105, p. 1873 (1987); Kramer et al.,
J. Biol. Chem
., 264, p. 4684 (1989); Gehlsen et al.
Science
, 24, p. 1228 (1988)). Anti-VLA4 monoclonal antibodies (“mAb's”) have been shown to inhibit VLA4-dependent adhesive interactions both in vitro and in vivo (Ferguson et al.
Proc. Natl. Acad. Sci
., 88, p. 8072 (1991); Ferguson et al.,
J. Immunol
., 150, p. 1172 (1993)). Results of in vivo experiments suggest that this inhibition of VLA-4-dependent cell adhesion may prevent or inhibit several inflammatory and autoimmune pathologies (R. L. Lobb et al., “The Pathophysiologic Role of &agr;4 Integrins In Vivo”,
J. Clin. Invest
., 94, pp. 1722-28 (1994)).
Despite these advances, there remains a need for small, specific inhibitors of VLA-4-dependent cell adhesion. Ideally, such inhibitors may be orally administered. Such compounds would provide useful agents for treatment, prevention or suppression of various pathologies mediated by cell adhesion and VLA-4 binding.
SUMMARY
The present invention relates to novel non-peptidic compounds that specifically inhibit the binding of ligands to VLA-4. These compounds are useful for inhibition, prevention and suppression of VLA-4-mediated cell adhesion and pathologies associated with that adhesion, such as inflammation and immune reactions. The compounds of this invention may be used alone or in combination with other therapeutic or prophylactic agents to inhibit, prevent or suppress cell adhesion. This invention also provides pharmaceutical compositions containing the compounds of this invention and methods of using the compounds and compositions of the invention for inhibition of cell adhesion.
According to one embodiment of this invention, these novel compounds, compositions and methods are advantageously used to treat inflammatory and immune diseases. The present invention also provides methods for preparing the compounds of this invention and intermediates therefor.
An aspect of this invention relates to cell adhesion inhibitors of formula (I):
R
3
—L—L′—R
1
(I)
R
1
is H, C
1-10
alkyl, C
2-10
alkenyl, C
2-10
alkynyl, Cy, Cy—C
1-10
alkyl, Cy—C
1-10
alkenyl, or Cy—C
1-10
alkynyl.
L′ is a hydrocarbon linker moiety having 1-5 carbon chain atoms and is (i) optionally interrupted by, or terminally attached to, one or more (e.g., 1, 2, or 3) of the following groups: —C(O)—, —O—C(O)—, —C(O)—O—, —C(O)—NR
c
, —NR
c
—C(O)—, —NR
c
—C(O)—NR
d
—, —NR
c
—(O)—O—, —O—C(O)—NR
c
—, —S(O)
m
—, —SO
2
—NR
c
—, —NR
c
—SO
2
—, —NR
c
—C(NR
m
)—, —O—, —NR
c
—, and —Cy; or (ii) optionally substituted with one or more substituents independently selected from R
b
.
L is a hydrocarbon linker moiety having 1-14 carbon chain atoms and is (i) optionally interrupted by, or terminally attached to, one or more (e.g., 1-5, 1-4, or 1-3) of the following groups: —C(O)—, —O—C(O)—, —C(O)—O—, —C(O)—NR
c
—, —NR
c
—C(O)—, —NR
c
—C(O)—NR
d
—, —NR
c
—C(O)—O—, —O—C(O)—NR
c
, —S(O)
m
—, —SO
2
—NR
c
—, —NR
c
—SO
2
—, —O—, —NR
c
—, and Cy; or (ii) optionally substituted with one or more substituents independently selected from R
b
.
R
3
is alkyl, alkenyl, alkynyl, cycloalkyl, aryl-fused cycloalkyl, cycloalkenyl, aryl, aralkyl, aryl-substituted alkenyl or alkynyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted cycloalkyl, biaryl, alkenoxy, alkynoxy, aralkoxy, aryl-substituted alkenoxy, aryl-substituted alkynoxy, alkylamino, alkenylamino, alkynylamino, aryl-substituted alkylamino, aryl-substituted alkenylamino, aryl-substituted alkynylamino, aryloxy, arylamino, heterocyclyl, heterocyclyl-substituted alkyl, heterocyclyl-substituted amino, carboxyalkyl substituted aralkyl, or oxocarbocyclyl-fused aryl; or R
3
is a moiety of formula (i):
Y
5
is —CO—, —O—CO—, —SO
2
— or —PO
2
—.
Each of R
4
and R
6
, independently, is alkyl, alkenyl, alkynyl, cycloalkyl, aryl-fused cycloalkyl, cycloalkenyl, aryl, aralkyl, aryl-substituted alkenyl or alkynyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted cycloalkyl, biaryl, alkenoxy, alkynoxy, aralkoxy, aryl-substituted alkenoxy, aryl-substituted alkynoxy, alkylamino, alkenylamino, alkynylamino, aryl-substituted alkylamino, aryl-substituted alkenylamino, aryl-substituted alkynylamino, aryloxy, arylamino, heterocyclyl, heterocyclyl-substituted alkyl, heterocyclyl-substituted amino, carboxyalkyl substituted aralkyl, oxocarbocyclyl-fused aryl, or an amino acid side chain selected from the group consisting of arginine, asparagine, glutarmine, S-methyl cysteine, methionine and corresponding sulfoxide and sulfone derivatives thereof, cyclohexylalanine, leucine, isoleucine, allo-isoleucine, tert-leucine, norleucine, phenylalanine, phenylglycine, tyrosine, tryptophan, proline, alanine, omithine, histidine, glutamine, norvaline, valine, threonine, serine, beta-cyanoalanine, 2-aminobutyric acid and allothreonine.
R
5
is hydrogen, aryl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or aryl-substituted alkyl. Note that R
5
and R
6
may be taken together with the atoms to which they are attached to form a heterocycle of 5 to 7 members.
Each of the above-stated Cy represents cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl. Each of the above-stated alkyl, alkenyl and alkynyl is optionally substituted with one to four substituents independently selected from R
a
. Further, each of the above-stated cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one to four substituents independently selected from R
b
.
R
a
is selected from the group consisting of: Cy (which is optionally substituted with one to four substituents independently selected from R
b
), —OR
c
, —NO
2
, -halogen, —S(O)
m
R
c
, —SR
c
, —S(O)
2
OR
c
, —S(O)
2
NR
c
R
d
, —NR
c
R
d
, —O(CR
e
R
f
)
n
NR
c
R
d
, —C(O)R
d
, —CO
2
R
c
, —P(O)(OR
c
)(OR
d
), —P(O)(R
c
)(OR
d
), —S(O)
m
OR
c
, —C(O)NR
c
R
j
, —CO
2
(CR
e
R
f
)
n
CONR
c
R
d
, —OC(O)R
c
, —CN, —NR
c
C(O)R
d
, —OC(O)NR
c
R
d
, —NR
c
C(O)OR
d
, —NR
c
C(O)NR
d
R
e
, —CR
c
(NOR
d
), —CF
3
, —OCF
3
, and oxo.
R
b
is a group selected from R
Cornebise Mark
Lee Wen-Cherng
Petter Russell C.
Scott Daniel
Biogen Inc.
Fish & Richardson P.C.
Stockton Laura L.
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