Ureido substituted pyrrolidines

Details Ureido substituted pyrrolidines Ureido substituted pyrrolidines

2001-11-02

2003-04-15

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S423000, C514S428000, C548S530000, C548S567000

Reexamination Certificate

active

06548533

ABSTRACT:

This invention is directed to substituted pyrrolidines, 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, 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, inflanimation, atherosclerosis and autoimniune 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 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 upregulated by proinflammatory cytokines such as INF-&ggr;, TNF-&agr;, IL-1⊕ 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 inflanimation (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 pyrrolidines 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:
one of A
1
, A
2
and A
3
represents NR
2
and the others represent C(R
3
)(R
4
);
R
1
represents R
5
Z
1
—Het— or R
6
N(R
7
)—C(═O)—NH—Ar
2
—
R
2
represents —C(═O)—R
8
, —C(═O)—OR
8a
or R
8b
;
R
3
and R
4
each represent hydrogen or R
8
;
R
5
represents aryl; heteroaryl; alkyl, alkenyl or alkynyl, each optionally substituted by R
9
, —Z
2
R
10
, —Z
3
H, —C(═O)—R
10
, —NR
11
—C(═Z
3
)—R
11
, —NR
11
—C(═O)—OR
10
, —NR
11
—SO
2
—R
10
, —SO
2
—NY
1
Y
2
, —NY
1
Y
2
or —C(═Z
3
)—NY
1
Y
2
; or cycloalkyl or heterocycloalkyl, each optionally substituted by R
10
, —Z
2
R
10
, —Z
3
H, —C(═O)—R
10
, —NR
11
—C(═Z
3
)—R
10
, —NR
11
—C(═O)—OR
10
, —NR
11
—SO
2
—R
10
, —SO
2
-NY
1
Y
2
, —NY
1
Y
2
or —C(═Z
3
)—NY
1
Y
2
;
R
6
represents hydrogen or lower alkyl and R
7
represents aryl, arylalkyl, heteroaryl or heteroarylalkyl; or
R
6
and R
7
together with the nitrogen atom to which they are attached form a cyclic amine;
R
8
represents alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl, or alkyl substituted by an acidic functional group or corresponding protected derivative, or by —Z
3
H, —Z
2
R
10
, —C(═O)—NY
1
Y
2
or —NY
1
Y
2
;
R
8a
represents alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
R
8b
represents alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or alkyl substituted by an acidic functional group or corresponding protected derivative;
R
9
represents aryl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocycloalkyl;
R
10
represents alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocycloalkyl or heterocycloalkylalkyl;
R
11
represents hydrogen or lower alkyl;
R
12
is a direct bond or an alkylene chain, an alkenylene chain or an alkynylene chain;
R
13
is a direct bond, cycloalkylene, heterocycloalkylene, aryldiyl, heteroaryldiyl, —C(═Z
3
)—NR
11
—, —NR
11
—C(═Z
3
)—, —Z
3
—, —C(═O)—, —C(═NOR
11
), —NR
11
—, —NR
11
—C(═Z
3
)—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
—;
Ar
1
represents aryldiyl or heteroaryldiyl;
Ar
2
represents aryldiyl or heteroaryldiyl;
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;
L
1

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