Substituted urea derivatives as cell adhesion inhibitors

Details Substituted urea derivatives as cell adhesion inhibitors Substituted urea derivatives as cell adhesion inhibitors

2000-07-11

2002-02-05

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S307000, C514S338000, C514S363000, C514S393000, C514S394000, C514S419000, C514S464000, C514S465000, C514S533000, C514S535000, C546S146000, C546S284100, C548S140000, C548S305100, C548S454000, C560S009000, C560S012000, C560S042000, C564S133000

Reexamination Certificate

active

06344570

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 &bgr; subunit can form a heterodimer with one or more &agr; 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 [Osbom, 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, in WO 96/00581, Publi. date Jan. 11, 1996, and WO96/20216, Publi. date Jul. 4, 1996, cyclic peptides containing the Leu-Asp-Val sequence have been reported to inhibit the binding of &agr;
4
&bgr;
1
integrin to VCAM-1 or fibronectin.
A few small non-peptidic Leu-Asp-Val surrogate compounds have been reported in WO 94/02445, Publ. date Feb. 3, 1994 to inhibit &agr;
4
&bgr;
1
-induced adhesion.
More recently, non-peptidic compounds of formula I which can be orally adminstered, and which inhibit VCAM/VLA4 binding have been reported in PCT application WO96/22966.
The preferred compounds are those in which in formula I, R
1′
is an urea derivative, R
2′
is hydrogen, R
3′
is an alkyl or substituted alkyl, R
4′
is dimethoxyl phenyl or benzo dioxol-5-yl and Y is CO.
There remains a continuing need for alternative compounds which inhibit the interaction between VCAM-1 and fibronectin with integrin VLA-4 and, in particular, for compounds which can be adminstered by an oral route.
We have now found a group of compounds containing a substituted phenoxy group which inhibit this interaction.
According to one aspect of the present invention there is provided a compound of formula (II)
wherein:
R
1
is in the para or meta position and is
where R
2
and R
3
are each independently selected from hydrogen, nitro, C
1-6
alkyl, C
3-6
cycloalkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
1-4
alkoxy, C
1-6
alkylamino, C
1-6
dialkylamino, C
1-6
alkylC
1-4
alkoxyl, C
1-6
alkylaminoC
1-6
alkyl, amino, cyano, halogeno, trifluoromethyl, —CO
2
R
12
, and —CONR
12
R
13
, where R
12
and R
13
are independently selected from hydrogen or C
1-6
alkyl, or R
2
and R
3
together with the phenyl to which they are attached form a 9 or 10 membered bicyclic ring system;
R
4
is C
1-4
alkyl;
R
5
is selected from hydrogen and C
1-4
alkyl;
R
6
is selected from C
1-6
alkyl, C
1-4
alkyl(C
4-6
)cycloalkyl, C
1-6
alkyl(C
1-6
)alkoxyl, C
1-6
alkylS(C
1-6
)alkyl, C
1-4
alkylsulphonyl(C
1-4
)alkyl,
where q is an integer from 1 to 6 and R
14
is halogeno;
R
7
is selected from C
1-6
alkyl, C
1-8
alkoxylcarbonyl, C
2-6
alkenyl, 1,3-benzodioxol-5-yl and aryl optionally substituted by one or more substituents selected from C
1-4
alkoxy, C
1-6
alkyl, cyano, halogeno, and trifluoromethyl;
R
8
is aryl, heteroaryl, a bicyclic heteroaryl ring system linked to the nitrogen via a ring carbon or a 9 or 10 membered bicyclic ring system linked to the nitrogen via a ring carbon and each ring is optionally substituted with up to two substituents, whi

Affiliated with

Also associated with

Rating

Substituted urea derivatives as cell adhesion inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Substituted urea derivatives as cell adhesion inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted urea derivatives as cell adhesion inhibitors will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2960004