Substituted benzoxazole compounds

Details Substituted benzoxazole compounds Substituted benzoxazole compounds

2001-08-09

2003-07-15

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S222000

Reexamination Certificate

active

06593354

ABSTRACT:

This invention is directed to substituted bicyclic compounds, their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states capable of being modulated by the inhibition of cell adhesion.
Cell adhesion is a process by which cells associate with each other, migrate towards a specific target or localise within the extra-cellular matrix. Many of the cell-cell and cell-extra-cellular matrix interactions are mediated by protein ligands (e.g. fibronectin, VCAM-1 and vitronectin) and their integrin receptors [e.g. &agr;5&bgr;1 (VLA-5), &agr;4&bgr;1 (VLA-4) and &agr;V&bgr;3]. Recent studies have shown these interactions to play an important part in many physiological (e.g. embryonic development and wound healing) and pathological conditions (e.g. tumour-cell invasion and metastasis, inflammation, atherosclerosis and autoimmune disease).
A wide variety of proteins serve as ligands for integrin receptors. In general, the proteins recognised by integrins fall into one of three classes: extracellular matrix proteins, plasma proteins and cell surface proteins. Extracellular matrix proteins such as collagen fibronectin, fibrinogen, laminin, thrombospondin and vitronectin bind to a number of integrins. Many of the adhesive proteins also circulate in plasma and bind to activated blood cells. Additional components in plasma that are ligands for integrins include fibrinogen and factor X. Cell bound complement C3bi and several transmembrane proteins, such as Ig-like cell adhesion molecule (ICAM-1,2,3) and vascular cell adhesion molecule (VCAM-1), which are members of the Ig superfamily, also serve as cell-surface ligands for some integrins.
Integrins are heterodimeric cell surface receptors consisting of two subunits called &agr; and &bgr;. There are at least fifteen different &agr;-subunits (&agr;1-&agr;9, &agr;-L, &agr;-M, &agr;-X, &agr;-IIb, &agr;-V and &agr;-E) and at least least seven different &bgr; (&bgr;1-&bgr;7) subunits. The integrin family can be subdivided into classes based on the &bgr; subunits, which can be associated with one or more &agr;-subunits. The most widely distributed integrins belong to the &bgr;1 class, also known as the very late antigens (VLA). The second class of integrins are leukocyte specific receptors and consist of one of three &agr;-subunits (&agr;-L, &agr;-M or &agr;-X) complexed with the &bgr;2 protein. The cytoadhesins &agr;-IIb&bgr;3 and &agr;-V&bgr;3, constitute the third class of integrins.
The present invention principally relates to agents which modulate the interaction of the ligand VCAM-1 with its integrin receptor &agr;4&bgr;1 (VLA-4), which is expressed on numerous hematopoietic cells and established cell lines, including hematopoietic precursors, peripheral and cytotoxic T lymphocytes, B lymphocytes, monocytes, thymocytes and eosinophils.
The integrin &agr;4&bgr;1 mediates both cell-cell and cell-matrix interactions. Cells expressing &agr;4&bgr;1 bind to the carboxy-terminal cell binding domain (CS-1) of the extracellular matrix protein fibronectin, to the cytokine-inducible endothelial cell surface protein VCAM-1, and to each other to promote homotypic aggregation. The expression of VCAM-1 by endothelial cells is up-regulated by proinflammatory cytokines such as INF-&ggr;, TNF-&agr;, IL-1&bgr; and IL-4.
Regulation of &agr;4&bgr;1 mediated cell adhesion is important in numerous physiological processes, including T-cell proliferation, B-cell localisation to germinal centres, and adhesion of activated T-cells and eosinophils to endothelial cells. Evidence for the involvement of VLA-4/VCAM-1 interaction in various disease processes such as melanoma cell division in metastasis, T-cell infiltration of synovial membranes in rheumatoid arthritis, autoimmune diabetes, collitis and leukocyte penetration of the blood-brain barrier in experimental autoimmune encephalomyelitis, atherosclerosis, peripheral vascular disease, cardiovascular disease and multiple sclerosis, has been accumulated by investigating the role of the peptide CS-1 (the variable region of fibronectin to which &agr;4&bgr;1 binds via the sequence Leu-Asp-Val) and antibodies specific for VLA-4 or VCAM-1 in various in vitro and in vivo experimental models of inflammation. For example, in a Streptococcal cell wall-induced experimental model of arthritis in rats, intravenous administration of CS-1 at the initiation of arthritis suppresses both acute and chronic inflammation (S. M. Wahl et al., J. Clin. Invest., 1994, 94, pages 655-662). In the oxazalone-sensitised model of inflammation (contact hypersensitivity response) in mice, intravenous administration of anti-&agr;4 specific monoclonal antibodies significantly inhibited (50-60% reduction in the ear swelling response) the efferent response (P. L. Chisholm et al. J. Immunol., 1993, 23, pages 682-688). In a sheep model of allergic bronchoconstriction, HP1/2, an anti-&agr;4 monoclonal antibody given intravenously or by aerosol, blocked the late response and the development of airway hyperresponsiveness (W. M. Abraham et al. J. Clin. Invest., 1994, 93 pages 776-787).
We have now found a novel group of substituted bicyclic compounds which have valuable pharmaceutical properties, in particular the ability to regulate the interaction of VCAM-1 and fibronectin with the integrin VLA-4 (&agr;4&bgr;1).
Thus, in one aspect, the present invention is directed to compounds of general formula (I):
wherein
Het represents a saturated, partially saturated or fully unsaturated 8 to 10 membered bicyclic ring system containing at least one heteroatom selected from O, S or N, optionally substituted by one or more aryl group substituents;
R
1
represents optionally substituted aryl or optionally substituted heteroaryl;
R
2
represents hydrogen, halogen, lower alkyl or lower alkoxy;
R
3
is an alkylene chain, an alkenylene chain or an alkynylene chain;
R
4
is a direct bond, cycloalkylene, heterocycloalkylene, arylene, heteroaryldiyl, —C(═Z
2
)—NR
5
—, —NR
5
—C(═Z
2
)—, —Z
2
—, —C(═O)—, —C(═NOR
5
)—, —NR
5
—, —NR
5
—C(═Z
2
)—NR
5
—, —SO
2
—NR
5
—, —NR
5
—SO
2
—, —O—C(═O)—, —C(═O)—O—, —NR
5
—C(═O)—O— or —O—C(═O)—NR
5
—;
R
5
represents hydrogen or lower alkyl;
R
6
represents alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocycloalkyl or heterocycloalkylalkyl;
L
1
represents a —R
3
—R
4
— linkage;
L
2
represents an alkylene or alkenylene linkage each optionally substituted by R
6
or by alkyl substituted by hydroxy, —OR
6
, —O—C(═O)—R
6
or —NY
1
Y
2
;
Y is carboxy or an acid bioisostere;
Y
1
and Y
2
are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group —NY
1
Y
2
may form a cyclic amine;
Z
1
represents NR
5
; and
Z
2
is O or S;
and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs, but excluding compounds where an oxygen, nitrogen or sulphur atom is attached directly to a carbon-carbon multiple bond of an alkenyl, alkenylene, alkynyl, alkynylene or cycloalkenyl residue.
In the present specification, the term “compounds of the invention”, and equivalent expressions, are meant to embrace compounds of general formula (I) as hereinbefore described, which expression includes the prodrugs, the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so

Affiliated with

Also associated with

Rating

Substituted benzoxazole 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 Substituted benzoxazole compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted benzoxazole compounds will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3019748