Substituted &bgr;-alanines

Details Substituted &bgr;-alanines Substituted &bgr;-alanines

2000-06-08

2002-03-05

Russel, Jeffrey E. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S019300, C514S183000, C514S247000, C514S332000, C514S343000, C514S352000, C514S563000, C514S597000, C514S245000, C530S331000, C546S309000, C562S450000, C564S051000

Reexamination Certificate

active

06352977

ABSTRACT:

This invention is directed to substituted &bgr;-alanines, 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-extracellular matrix interactions are mediated by protein ligands (e.g. fibronectin, vitronectin and VCAM-1) and their integrin receptors [e.g. VLA-4 (&agr;
4
&bgr;
1
)]. 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 twelve different &agr;-subunits (&agr;1-&agr;6, &agr;-L, &agr;-M, &agr;-X, &agr;-IIb, &agr;-V and &agr;-E) and at least nine different &bgr; (&bgr;1-&bgr;9) 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, preipheral 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 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 upregulated by proinflammatory cytokines such as INF-&ggr;, TNF-&agr; and LI-1&bgr;.
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 VLA4/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, 24, 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).
We have now found a novel group of substituted &bgr;-alanines 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:
R
1
is hydrogen, halogen, lower alkyl or lower alkoxy;
X
1
, X
2
and X
6
independently represent N or CR
2
; and
one of X
3
, X
4
and X
5
represents CR
3
and the others independently represents N or CR
2
[where R
2
is hydrogen, halogen, lower alkyl or lower alkoxy; and R
3
represents a group —L
1
—(CH
2
)
n
—C(═O)—N(R
4
)—CH
2
—CH
2
—Y in which:
R
4
is aryl or heteroaryl, or R
4
is alkyl, alkenyl, alkynyl each optionally substituted by one or more groups chosen from halo, oxo, R
5
, —C(═O)—R
7
, —NH—C(═O)—R
7
or —C(═O)NY
1
Y
2
, or R
4
is cycloalkenyl, cycloalkyl or heterocycloalkyl each optionally substituted by one or more groups chosen from oxo, R
6
or —L
2
—R
6
{where R
5
is an acidic functional group (or corresponding protected derivative), aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, —ZR
7
or —NY
1
Y
2
; R
6
is an acidic functional group (or corresponding protected derivative), aryl, heteroaryl, heterocycloalkyl, —ZH, —Z
1
R
7
or —NY
1
Y
2
; R
7
is alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; L
2
is alkylene; Y
1
and Y
2
are independently hydrogen, acyl, alkyl [optionally substituted by hydroxy, heterocycloalkyl, or one or more carboxy or —C(═O)—NHR
8
groups (where R
8
is hydrogen or lower alkyl)], alkylsulphonyl, aryl, arylalkyloxycarbonyl, arylsulphonyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; or the group —NY
1
Y
2
may form a 5-7 membered cyclic amine which (i) may be optionally substituted with one or more substituents selected from carboxamido, carboxy, hydroxy, oxo, hydroxyalkyl, HOCH
2
CH
2
—(OCH
2
CH
2
)
m
— (where m is zero, or an integer one or two), or alkyl optionally substituted by carboxy or carboxamido (ii) may also contain a further heteroatom selected from O, N, S or SO
2
and (iii) may also be fused to additional aromatic, licteroaromatic, heterocycloalkyl or cycloalkyl rings to form a bicyclic or tricyclic ring system; Z is O or S; and Z
1
is O or S(O)
m
};
L
1
represents a —R
9
—R
10
— linkage, in which R
9
is a straight or branched C
1-6
alkylene chain, a straight or branched C
2-6
alkenylene chain or a straight or branched C
2-6
alkynylene chain, and R
10
is a direct bond, cycloalkylene, heterocycloalkylene, arylene, heteroaryidiyl, —C(═Z)—NR
11
—, —NR
11
—C(═Z)—, —Z
1
, —NR
11
—, —C(═O)—, —C(═NOR
11
)—, —NR
11
—C(═Z)—NR
11
—, —SO
2
—NR
11
—, —NR
11
—SO
2
—, —O—C(═O)—, —C(═O)—O—, —NR
11
—C(═O)—O— or —O—C(═O)—NR
11
— (where R
11
is a hydrogen atom or R
4
); but excluding compounds where an oxygen, nitrogen or sulphur atom is attached directly to a carbon carbon multiple bond;
Y is carboxy (or an acid bioisostere) or —C(═O)—NY
1
Y
2
; and n is an integer from 1 to 6];
and their prodrugs, and pharmaceut

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