Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-25
2003-02-11
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S300000, C514S259500, C514S678000, C544S283000, C546S190000, C546S191000, C546S122000, C546S123000, C568S381000
Reexamination Certificate
active
06518283
ABSTRACT:
This invention relates to a series of squaric acid derivatives, 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.
Some integrin chains are capable of pairing with more than one partner. For example, the &agr;
v
chain has been reported to pair with the beta 1 chain, the beta 3 chain, the beta 5 chain, the beta 6 chain and the beta 8 chain to give molecules which bind to different sets of ligands and which are referred to respectively as the integrins aver &agr;
v
&bgr;
1
, &agr;
v
&bgr;
3
, &agr;
v
&bgr;
5
, &agr;
v
&bgr;
6
, and &agr;
v
&bgr;
8
. 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 integrin function in normal physiological responses is highlighted by two human deficiency diseases in which integrin function is defective. Thus in the disease termed Leukocyte Adhesion Deficiency (LAD) there is a defect in one of the families of integrins expressed [on leukocytes. Patients suffereing from this disease have a reduced ability to recruit leukocytes to inflammatory sites and suffer recurrent infections which in extreme cases may be fatal. In the case of patients suffering from the disease termed Glanzman's thrombasthenia (a defect in a member of the beta 3 integer famly) there is a defect in blood clotting.
The potential to modify integrin function in such a way as to beneficially modulate cell adhesion has been extensively investigated in animal models using specific monoclonal antibodies and peptides 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); Mitjans et al J. Cell Sci. 108, 2825 (1995), Brooks P. C. et al J. Clin. Invest. 96, 1815 (1995), Binns, R. M. et al J. Immunol. 157,4094, (1996), Hammes, H-P, et al Nature Medicine 2, 529 (1996), Srivata, S. et al Cardiovascular Res. 36, 408 (1997)]. A number of monoclonal antibodies which block integrin function are currently being investigated for their therapeutic potential in human disease.
Inhibition of integrin-mediated cell interaction can be expected to be beneficial in a number of disease states, and in addition to the monoclonal antibodies and peptides just mentioned there has been great interest in selective low molecular weight inhibitors of integrin function. Thus, for example selective &agr;
4
integrin inhibitors have been described in International patent Specifications Nos. WO96/22966, WO97/03094, WO 98/04247, WO98/04913, WO98/53814, WO98/53817, WO98/53818, WO98/54207, WO98/58902, WO99/06390, WO99/064310-6437, WO99/10312, WO99/10313, WO99/67230, WO 99/26922, WO99/60015, WO99/26921, WO9936393, WO99/52898 and WO99/64395. Numerous selective &agr;
v
integrin inhibitors have also been described, for example in International Patent Specifications Nos. WO97/08145, WO97/23480, WO97/36858, WO97136859, WO97/36861, WO97136862, WO97/44333, WO97/47618, WO98/31359, WO98/25892, WO98/18460, WO99/44994, WO99/30709, WO99/31061, WO 99/26945, WO99/52896, WO99/52879, WO99/32457, WO99/31099, WO00/07544, WO00/00486, WO00/06169, WO00/17197 and WO00/01383.
While it is clearly possible to obtain selective integrin inhibitors, their usefulnesses in medicine may be limited due to poor pharmacokinetic properties. Thus, for example, in our hands, integrin inhibitors falling within the general structural types featured in the above-mentioned patent specifications are not particularly attractive for development as medicines since they can be cleared rapidly from the body. In order to overcome this problem we have made use of a squaric acid framework which can be readily adapted to provide potent and selective integrin inhibitors using recognised integrin binding groups (for example as described herein and in the patent specifications listed above), which advantageously possess good pharmacokinetic properties, especially low plasma clearance.
Thus according to one aspect of the invention we provide a compound of formula (1)
wherein
R
1
is an integrin binding group;
R
2
is a hydrogen atom or a C
1-6
alkyl group;
L
1
is a covalent bond or a linker atom or group;
n is zero or the integer 1;
Alk
1
is an optionally substituted aliphatic chain;
R
3
is a hydrogen atom or an optionally substituted heteroaliphatic, cycloaliphatic, heterocycloaliphatic, polycycloaliphatic, polyheterocycloaliphatic, aromatic or heteroaromatic group: and the salts, solvates, hydrates and N-oxides thereof.
It will be appreciated that compounds of formula (1) may have one or more chiral centres, and exist as enantiomers or diastereomers. The invention is to be understood to extend to all such enantiomers, diastereomers and mixtures thereof, including racemates. Formula (1) and the formulae hereinafter are intended to represent all individual isomers and mixtures thereof, unless stated or shown otherwise.
In the compounds according to the invention, integrin-binding groups represented by R
1
include for example those which are able to bind &agr;
4
- or &agr;
v
-integrins. Particular examples of such integrins include &agr;
4
&bgr;
1
, &agr;
4
&bgr;
7
and &agr;
v
&bgr;
3
integrins.
In general, the term integrin-binding group is used herein in relation to R
1
to mean any group which when part of the compound of formula (1) is able to interact with an integrin to modulate cell adhesion in vivo and achieve a therapeutic response. Typically the R
1
group may bind to the integrin in such a way that it modulates the interaction of the integrin with its ligand. Thus for example the R
1
group may inhibit binding of the ligand and decrease cell adhesion. Such a response enables appropriate R
1
groups to be readily identified using small scale routine in vitro screening assays to determine the degree of inhibition of integrin-ligand binding in the presence of a compound of formula (1). Examples of such screening assays are widely reported in the literature, for example in the papers and International patent specifications described above, and in the Examples hereinafter.
Thus in general R
1
may be any group which when present in a compound of formula (1) is able to bind to an integrin such that the compound of formula (1) inhibits the binding of the integrin with its ligand with an IC
50
of 10 &mgr;M or below, particularly 1 &mgr;M or below, especially 500 nM or below, e.g. in the range 0.001-500 nM.
Particular R
1
groups in compounds of the invention include those of formula Ar
1
L
2
Ar
2
Alk- wherein Ar
1
is an optionally substituted aromatic or heteroaromatic group, L
2
is
Alexander Rikki Peter
Archibald Sarah Catherine
Head John Clifford
Langham Barry John
Linsley Janeen Marsha
Celltech R&D Limited
Shah Mukund J.
Truong Tamthom N.
Woodcock & Washburn LLP
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