Benzodiazepines

Details Benzodiazepines Benzodiazepines

1999-09-29

2001-08-14

Raymond, Richard L. (Department: 1609)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S567000

Reexamination Certificate

active

06274577

ABSTRACT:

This invention relates to a series of benzodiazepines, to compositions containing them, to processes for their preparation, and to their use in medicine.
Over the last few years it has become increasingly clear that the physical interaction of inflammatory leukocytes with each other and other cells of the body plays an important role in regulating immune and inflammatory responses [Springer, T. A. Nature, 346, 425, (1990); Springer, T. A. Cell 76, 301, (1994)]. Many of these interactions are mediated by specific cell surface molecules collectively referred to as cell adhesion molecules.
The adhesion molecules have been sub-divided into different groups on the basis of their structure. One family of adhesion molecules which is believed to play a particularly important role in regulating immune and inflammatory responses is the integrin family. This family of cell surface glycoproteins has a typical non-covalently linked heterodimer structure. At least 14 different integrin alpha chains and 8 different integrin beta chains have been identified [Sonnenberg, A. Current Topics in Microbiology and Immunology, 184, 7, (1993)]. The members of the family are typically named according to their heterodimer composition although trivial nomenclature is widespread in this field. Thus the integrin termed &agr;4&bgr;1 consists of the integrin alpha 4 chain associated with the integrin beta 1 chain, but is also widely referred to as Very Late Antigen 4 or VLA4. Not all of the potential pairings of integrin alpha and beta chains have yet been observed in nature and the integrin family has been subdivided into a number of subgroups based on the pairings that have been recognised [Sonnenberg, A. ibid].
The importance of cell adhesion molecules in human leukocyte function has been further highlighted by a genetic deficiency disease called Leukocyte Adhesion Deficiency (LAD) in which one of the families of leukocyte integrins is not expressed [Marlin, S. D. et al J. Exp. Med. 164, 855 (1986)]. Patients with this disease have a reduced ability to recruit leukocytes to inflammatory sites and suffer recurrent infections which in extreme cases may be fatal.
The potential to modify adhesion molecule function in such a way as to beneficially modulate immune and inflammatory responses has been extensively investigated in animal models using specific monoclonal antibodies that block various functions of these molecules [e.g. Issekutz, T. B. J. Immunol. 3394, (1992); Li, Z. et al Am. J. Physiol. 263, L723, (1992); Binns, R. M. et al J. Immunol. 157, 4094, (1996)]. A number of monoclonal antibodies which block adhesion molecule function are currently being investigated for their therapeutic potential in human disease.
One particular integrin subgroup of interest involves the &agr;4 chain which can pair with two different beta chains &bgr;1 and &bgr;7 [Sonnenberg, A. ibid]. The &agr;4&bgr;1 pairing occurs on many circulating leukocytes (for example lymphocytes, monocytes and eosinophils) although it is absent or only present at low levels on circulating neutrophils. &agr;4&bgr;1 binds to an adhesion molecule (Vascular Cell Adhesion Molecule-1 also known as VCAM-1) frequently up-regulated on endothelial cells at sites of inflammation [Osborne, L. Cell, 62, 3, (1990)]. The molecule has also been shown to bind to at least three sites in the matrix molecule fibronectin [Humphries, M. J. et al. Ciba Foundation Symposium, 189, 177, (1995)]. Based on data obtained with monoclonal antibodies in animal models it is believed that the interaction between &agr;4&bgr;1 and ligands on other cells and the extracellular matrix plays an important role in leukocyte migration and activation [Yednock, T. A. et al, Nature, 356, 63, (1992); Podolsky, D. K. et al. J. Clin. Invest. 92, 373, (1993); Abraham, W. M. et al. J. Clin. Invest. 93, 776, (1994)].
The integrin generated by the pairing of &agr;4 and &bgr;7 has been termed LPAM-1 [Holzmann, B and Weissman, I. EMBO J. 8, 1735, (1989)] and like &agr;4&bgr;1, binds to VCAM-1 and fibronectin. In addition, &agr;4&bgr;7 binds to an adhesion molecule believed to be involved in the homing of leukocytes to mucosal tissue termed MAdCAM-1 [Berlin, C. et al, Cell, 74, 185, (1993)]. The interaction between &agr;4&bgr;7 and MAdCAM-1 may also be important at sites of inflammation outside of mucosal tissue [Yang, X-D. et al, PNAS, 91, 12604 (1994)].
Regions of the peptide sequence recognised by &agr;4&bgr;1 and &agr;4&bgr;7 when they bind to their ligands have been identified. &agr;4&bgr;1 seems to recognise LDV, IDA or REDV peptide sequences in fibronectin and a QIDSP sequence in VCAM-1 [Humphries, M. J. et al, ibid] whilst &agr;4&bgr;7 recognises a LDT sequence in MAdCAM-1 [Briskin, M. J. et al, J. Immunol. 156, 719, (1996)]. There have been several reports of inhibitors of these interactions being designed from modifications of these short peptide sequences [Cardarelli, P. M. et al J. Biol. Chem. 269, 18668, (1994); Shroff, H. N. Bioorganic. Med. Chem. Lett. 6, 2495, (1996); Vanderslice, P. J. Immunol. 158, 1710, (1997)]. It has also been reported that a short peptide sequence derived from the &agr;4&bgr;1 binding site in fibronectin can inhibit a contact hypersensitivity reaction in a trinitrochlorobenzene sensitised mouse [Ferguson, T. A. et al, PNAS 88, 8072, (1991)].
Since the alpha 4 subgroup of integrins are predominantly expressed on leukocytes their inhibition can be expected to be beneficial in a number of immune or inflammatory disease states. However, because of the ubiquitous distribution and wide range of functions performed by other members of the integrin family it is very important to be able to identify selective inhibitors of the alpha 4 subgroup.
We have now found a group of compounds which are potent and selective inhibitors of &agr;4 integrins. Members of the group are able to inhibit &agr;4 integrins such as &agr;4&bgr;1 and/or &agr;4&bgr;7 at concentrations at which they generally have no or minimal inhibitory action on &agr; integrins of other subgroups. The compounds are thus of use in medicine, for example in the prophylaxis and treatment of immune or inflammatory disorders as described hereinafter.
Thus according to one aspect of the invention we provide a compound of formula (1):
wherein Ar
1
is an aromatic or heteroaromatic group;
R
1
, R
2
, R
3
and R
4
which may be the same or different is each an atom or group —L
2
(Alk
3
)
t
L
3
(R
6
)
u
in which L
2
and L
3
which may be the same or different is each a covalent bond or a linker atom or group, t is zero or the integer 1, u is an integer 1, 2 or 3, Alk
3
is an aliphatic or heteroaliphatic chain and R
6
is a hydrogen or halogen atom or a group selected from alkyl, —OR
7
[where R
7
is a hydrogen atom or an optionally substituted alkyl group], —SR
7
, —NR
7
R
8
[where R
8
is as just defined for R
7
and may be the same or different], —NO
2
, —CN, —CO
2
R
7
, —SO
3
H, —SOR
7
, —SO
2
R
7
, —OCO
2
R
7
, —CONR
7
R
8
, —OCONR
7
R
8
, —CSNR
7
R
8
, —COR
7
, —OCOR
7
, —N(R
7
)COR
8
, —N(R
7
)CSR
8
, —SO
2
N(R
7
)(R
8
), —N(R
7
)SO
2
R
8
, —N(R
7
)CON(R
8
)(R
9
), [where R
9
is a hydrogen atom or an optionally substituted alkyl group]—N(R
7
)CSN(R
8
)(R
9
), —N(R
7
)SO
2
N(R
8
)(R
9
) or —C(=NOR
6
)R
7
;
Alk
1
is an optionally substituted aliphatic or heteroaliphatic chain;
r is zero or the integer 1;
s is zero or the integer 1;
Alk
2
is —CH
2
—, —(CH
2
)
2
— or —CH(CH
3
)—;
L
1
is a linker atom or group;
R
5
is a carboxylic acid (—CO
2
H) or a derivative thereof;
Ar
2
is an optionally substituted aromatic or heteroaromatic group;
and the salts, solvates, hydrates and N-oxides thereof.
In the compounds of formula (1), derivatives of the carboxylic acid group R
5
include carboxylic acid esters and amides. Particular esters and amides include —CO
2
Alk
5
and —CONR
7
R
8
groups as described herein.
In gener

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