Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-01-23
2002-08-27
Chang, Ceila (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S367000, C548S161000, C548S222000
Reexamination Certificate
active
06441012
ABSTRACT:
This invention relates to compounds which are inhibitors of the interaction between the integrin &agr;
4
&bgr;
1
, also known as Very Late Antigen-4 (VLA-4) or CD49d/CD29, and its protein ligands, for example Vascular Cell Adhesion Molecule-1 (VCAM-1) and fibronectin. This invention further relates to processes for preparing such compounds, to pharmaceutical compositions containing them and to their use in methods of therapeutic application.
&agr;
4
&bgr;
1
is a member of the integrin family of heterodimeric cell surface receptors that are composed of noncovalently associated glycoprotein subunits (&agr; and &bgr;) and are involved in cell adhesion to other cells or to extracellular matrix. There are at least 14 different human integrin &agr; subunits and at least 8 different &bgr; subunits and each , subunit can form a heterodimer with one or more a subunits. Integrins can be subdivided based on their &bgr; subunit composition. &agr;
4
&bgr;
1
is one of several &bgr;
1
integrins, also known as Very Late Antigens (VLA).
The interactions between integrins and their protein ligands are fundamental for maintaining cell function, for example by tethering cells at a particular location, facilitating cell migration, or providing survival signals to cells from their environment. Ligands recognised by integrins include extracellular matrix proteins, such as collagen and fibronectin; plasma proteins, such as fibrinogen; and cell surface molecules, such as transmembrane proteins of the immunoglobulin superfamily and cell-bound complement. The specificity of the interaction between integrin and ligand is governed by the &agr; and &bgr; subunit composition
Integrin &agr;
4
&bgr;
1
is expressed on numerous hematopoietic cells and established cell lines, including hematopoietic precursors, peripheral and cytotoxic T lymphocytes, B lymphocytes, monocytes, thymocytes and eosinophils [Hemler, M. E. et al (1987), J. Biol. Chem., 262, 11478-11485; Bochner, B. S. et al (1991), J. Exp. Med., 173, 1553-1556]. Unlike other &bgr;
1
, integrins that bind only to cell-extracellular matrix proteins, &agr;
4
&bgr;
1
binds to VCAM-1, an immunoglobulin superfamily member expressed on the cell surface, for example on vascular endothelial cells, and to fibronectin containing the alternatively spliced type III connecting segment (CS-1 fibronectin) [Elices, M. J. et al (1990), Cell, 60, 577-584; Wayner, E. A. et al (1989). J. Cell Biol., 109, 1321-1330].
The activation and extravasation of blood leukocytes plays a major role in the development and progression of inflammatory diseases. Cell adhesion to the vascular endothelium is required before cells migrate from the blood into inflamed tissue and is mediated by specific interactions between cell adhesion molecules on the surface of vascular endothelial cells and circulating leukocytes [Sharar, S. R. et al (1995). Springer Semin. Immunopathol., 16, 359-378]. &agr;
4
&bgr;
1
is believed to have an important role in the recruitment of lymphocytes, monocytes and eosinophils during inflammation. &agr;
4
&bgr;
1
/ligand binding has also been implicated in T-cell proliferation, B-cell localisation to germinal centres, haemopoeitic progenitor cell localisation in the bone marrow, placental development, muscle development and tumour cell metastasis.
The affinity of &agr;
4
&bgr;
1
for its ligands is normally low but chemokines expressed by inflamed vascular endothelium act via receptors on the leukocyte surface to upregulate &agr;
4
&bgr;
1
function [Weber, C. et al (1996), J. Cell Biol., 134, 1063-1073]. VCAM-1 expression is upregulated on endothelial cells in vitro by inflammatory cytokines [Osborn, L. et al (1989) Cell, 59, 1203-1211] and in human inflammatory diseases such as rheumatoid arthritis [Morales-Ducret, J. et al (1992). J. Immunol., 149, 1424-1431], multiple sclerosis [Cannella, B. et al., (1995). Ann. Neurol., 37, 424-435), allergic asthma [Fukuda, T. et al (1996), Am. J. Respir. Cell Mol. Biol., 14, 84-94] and atherosclerosis [O'Brien, K. D. et al (1993). J. Clin. Invest., 92, 945-951].
Monoclonal antibodies directed against the &agr;
4
integrin subunit have been shown to be effective in a number of animal models of human inflammatory diseases including multiple sclerosis, rheumatoid arthritis, allergic asthma, contact dermatitis, transplant rejection, insulin-dependent diabetes, inflammatory bowel disease, and glomerulonephritis.
Integrins recognise short peptide motifs in their ligands The minimal &agr;
4
&bgr;
1
binding epitope in CS-1 is the tripeptide leucine-aspartic acid-valine (Leu-Asp-Val) [Komoriya, A., et al (1991). J. Biol. Chem., 266, 15075-15079] while VCAM-1 contains the similar sequence isoleucine-aspartic acid-serine [Clements, J. M., et al (1994). J. Cell Sci., 107, 2127-2135]. The 25-amino acid fibronectin fragment, CS-1 peptide, which contains the Leu Asp-Val motif, is a competitive inhibitor of &agr;
4
&bgr;
1
binding to VCAM-1 [Makarem, R., et al (1994). J. Biol. Chem., 269, 4005-4011]. Small molecule &agr;
4
&bgr;
1
inhibitors based on the Leu-Asp-Val sequence in CS-1 have been described, for example the linear molecule phenylacetic acid-Leu-Asp-Phe-D-Pro-amide [Molossi, S. et al (1995). J. Clin. Invest., 95, 2601-2610] and the disulphide cyclic peptide Cys-Trp-Leu-Asp-Val-Cys [Vanderslice, P., et al (1997). J. Immunol., 158, 1710-1718].
More recently, non- and semi-peptidic compounds which inhibit &agr;
4
&bgr;
1
/VCAM binding and which can be orally administered have been reported in for example, WO96/22966 and WO98/04247.
There remains a continuing need for alternative compounds which inhibit the interaction between VCAM-1 and fibronectin with integrin &agr;
4
&bgr;
1
and, in particular, for compounds which can be administered by an oral route.
We have now found a group of compounds which contain a bicyclic heteroaryl ring system which inhibit this interaction.
Accordingly the present invention provides a compound of formula (I)
wherein:
A is a bicyclic heteroaryl, optionally substituted with one or more substituents independently selected from C
1-6
alkyl, C
1-6
alkanoyl, C
2-6
alkenyl, C
2-6
alkynyl, C
1-6
alkoxy, C
1-6
alkylamino, C
1-6
alkylthio, C
1-4
alkylsulphonyl, C
1-4
alkoxylC
1-6
alkyl, C
1-6
alkylamino-C
1-6
alkyl, carboxy, carbamoyl, C
2-6
alkenyloxy, C
2-6
alkynyloxy, di-[(C
1-6
)alkyl]amino, C
2-6
alkanoylamino, N—C
1-6
alkylcarbamoyl, C
1-6
alkoxylcarbonyl, halogeno, nitro, cyano, amino trifluoromethyl, trifluoromethoxy, hydroxy, (CH
2
)
p
OH where p is 1 or 2, —CO
2
R
a
and —CONR
a
R
b
, where R
a
and R
b
are independently hydrogen or C
1-6
alkyl, linked to the nitrogen via a ring carbon atom in one ring and to the group B by a ring carbon atom in the second ring;
B is linker group connecting group A to group D and comprising a 3 or 4 atom linker where each atom is independently selected from carbon, oxygen, nitrogen and sulphur and is optionally substituted with one or more C
1-6
alkyl groups or two of such adjacent alkyl substituents may form a ring;
C is aryl or a mono or bicyclic heteroaryl, each of which can be optionally substituted with one or more substituents independently selected from C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
1-6
alkoxy, C
1-4
alkanoyl, C
1-6
alkylamino, C
1-6
alkylthio, C
1-4
alkylsulphonyl, C
1-4
alkoxyl-C
1-6
alkyl, C
1-6
alkylaminoC
1-6
alkyl, carboxy, carbamoyl, C
2-6
alkenyloxy, C
2-6
alkynyloxy, di-[(C
1-6
)alkyl]amino, C
2-6
alkanoylamino, N—C
1-6
alkylcarbamoyl, C
1-6
alkoxylcarbonyl, phenoxy, cyano, nitro, amino, halogeno, trifluoromethyl, trifluoromethoxy, hydroxy, (CH
2
)
p
OH where p is 1 or 2, —CO
2
R
a
and —CONR
a
R
b
, where R
a
and R
b
are independently hydrogen or C
1-6
alkyl, linked to NR
1
through a ring carbon atom;
D is an aryl or heteroaryl, both of which are optionally substituted with one or more substituents independently selected from C
1-6
alkyl, C
2-6
alk
Brittain David R
Davies Gareth M
Johnstone Craig
Large Michael S
AstraZeneca AB
Chang Ceila
Granahan Patricia
Halstead David P.
Ropes & Gray
LandOfFree
Chemical compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Chemical compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Chemical compounds will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2955962