Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-25
2003-10-07
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...
C548S414000, C548S491000, C564S015000, C514S007600
Reexamination Certificate
active
06630501
ABSTRACT:
This application is a 371 of PCT/FR00/00093 Jan. 18, 2000.
FIELD OF THE INVENTION
The present invention relates to phosphinic pseudo-peptides that may particularly be used as very powerful and specific inhibitors for matrix zinc metalloproteases MMP, particularly MMP-11, MMP-2, MMP-9 and MMP-8. However, these pseudo-peptides appear to show a low activity with respect to MMP-1 and MMP-7. In this way, these inhibitors offer the possibility to only inhibit one MMP sub-family in vivo, and could therefore prove to be less toxic than MMP inhibitors with a very broad spectrum of activity.
Said pseudo-peptides may have applications in the treatment of diseases characterised by the over-expression of matrix proteases, such as connective and joint tissue degeneration, rheumatoid arthritis, osteoarthritis, aortic aneurysm and cancer.
On the basis of the studies conducted in vivo on animals, these phosphinic inhibitors appear to allow use in pharmaceutical formulations to inhibit primary or secondary tumour growth.
STATE OF THE RELATED ART
Matrix zinc metalloproteases MMP represent a family of enzymes collectively capable of splitting all the proteins of the extracellular matrix. Due to their role on extracellular matrix proteins, these enzymes play a very important role during the development and the course of various tissue remodelling processes, such as involution of the mammary gland, cicatrisation and extravasion of specialised immune response cells.
Around fifteen enzymes in humans belonging to the MMP family are known to date:
Matrixins
MMP-1
Interstitial collagenase
MMP-8
Neutrophil collagenase
MMP-13
Collagenase 3
MMP-18
Collagenase 4
MMP-3
Stromelysin 1
MMP-10
Stromelysin-2
MMP-11
Stromelysin-3
MMP-2
Gelatinase-A
MMP-9
Gelatinase-B
MMP-12
Metalloelastase
MMP-14
MT-1 MMP
MMP-15
MT-2 MMP
MMP-16
MT-3 MMP
MMP-17
MT-4 MMP
MMP-7
Matrilysin
Collagenases appear to be the only MMPs to be capable of splitting collagen in fibrillary form. Gelatinases A and B are characterised by their ability to split type IV collagen, which is very abundant in the basal membranes and collagen in denatured form. Stromelysins 1 and 2 appear to be responsible for the breakdown of other proteins of the extracellular matrix, such as fibronectin and various proteoglycans. MT-MMPs appear to be above all involved in the activation of gelatinase A, and due to their membrane location, these matrixins appear to play a role as a membrane receptor of gelatinase A. It is important to note that the physiological substrate of stromelysin-3 is not known to date. However, several studies on this protease, which was initially characterised in breast tumours, suggest that stromelysin-3 is an important factor in the development and survival of tumours.
MMPs appear to be over-expressed in various human diseases, particularly cancer. In this disease, for a long time, the role of MMPs was associated with the invasion of tumour cells and their ability to pass through various barriers to form secondary tumours. More recently, various studies have established that said proteases certainly play a more fundamental role in carcinogenesis, particularly by taking part in primary tumour growth. Of different theories to explain this function of MMPs, the most studied relate to their role in:
their ability, by means of extracellular matrix protein proteolysis, to release from said matrix the growth factors essential for the development and survival of tumours, and
angiogenesis, required for tumour growth.
The apparent involvement of MMPs in tumour growth has led numerous teams world-wide to focus on the role of compounds capable of inhibiting these enzymes.
Synthesis programmes on MMP inhibitors were initiated a number of years ago. At this time, applications of MMP inhibitors particularly related to inflammatory diseases of the connective tissue. It was only more recently that multiple programmes on the application of MMP inhibitors in cancerology have developed, as described by Brown, Medical Oncology, 1997, 14, 1-10, [1]. Indeed, as mentioned above, the studies demonstrating that MMPs must be considered as priority targets in the development of new anticancer agents are relatively recent. As such, it may be noted that, in 1997, 67 patents relating to MMP inhibitors were registered world-wide, the majority of which relate to cancerology applications, as described by Beckett et al, 1998, Exp. Opin. Ther. Patents, 8, p.259-289 [2]. In most of these patents, the synthesised compounds belong to the family of pseudo-peptide derivatives comprising a hydroxamate function. Some patents relate to pseudo-peptide compounds comprising carboxyl-alkyl or thiol functions. In said compounds, the hydroxamate, thiol or carboxyl-alkyl functions interact with the zinc atom present in the active MMP site. The most advanced compounds in terms of anticancer activity have been developed by the firm British Biotechnology. Two compounds, Batimastat BB94 and Marimastat have been the subject of phase II and III clinical studies in humans. Since then, other firms (Roche, Bayer, Agouron, Novartis) appear to have conducted phase I and II clinical studies on MMP inhibitors in cancerology.
In this way, none of the compounds liable to inhibit MMPs known by means of references [1] and [2], are composed of a phosphinic pseudo-peptide.
However, the document: Goulet et al, Bioorg. Med. Chem. Lett. 4, 1994, p. 1221-1224 [3], describes phosphinic pseudo-peptides that can be used as a selective inhibitor of stromelysin-1 (MMP-3), which comprise the final sequence:
Caldwell et al, Bioorg. Med. Chem. Letter 6, 1996, p.323-328 [4], also describe a phosphinic pseudo-peptide which is a selective inhibitor of stromelysin-1 (MMP-3), which comprises the same terminal sequence as the pseudo-peptide of reference [3].
In these references [3] and [4], it is attempted to detect activity with respect to MMP-3, while in the invention, it is attempted to detect a selective activity with respect to MMP-11, MMP-2, MMP-9 and MMP-8. It is also important to note that, in the present invention, R
3
is not only a phenylethyl residue. In addition, the invention demonstrates that other substituents in this position give compounds with increased inhibitory power.
The documents FR-A-2 676 059 [5], FR-A-2 689 764 [6] and EP-A-0 725 075(7] illustrate phosphinic pseudo-peptides showing an inhibitory activity with respect to bacterial collagenases and zinc endopeptidases 24.15 and 24.16.
The present invention specifically relates to new phosphinic pseudo-peptides showing a powerful and specific inhibitory activity with respect to the matrix zinc metalloproteases MMP-11, MMP-2, MMP-9 and MMP-8.
DESCRIPTION OF THE INVENTION
According to the invention, the phosphinic pseudo-peptide complies with the formula:
wherein
R
1
is a group inhibiting an amine function, or an amino acid residue or peptide with an amino-terminal group protecting function,
R
2
represents the lateral chain of a natural or non-natural amino acid,
R
3
represents:
1) the lateral chain of a natural amino acid except for Gly and Ala, not substituted or substituted by an aryl group,
2) an aralkyl group, or
3) an alkyl group comprising at least 3 carbon atoms, and
R
4
represents a lateral chain of natural or non-natural amino acid, or a dinitrobenzyl group.
Said pseudo-peptide according to formula I is a pseudo-tripeptide comprising a phosphinic type chemical group, the function of which is to chelate the zinc atom in MMPs. In said pseudo-tripeptide, the choice of the R
2
, R
3
and R
4
groups makes it possible to ensure the interaction of the tripeptide with the MMP sub-sites S1, S1′ and S2′, respectively. The R
1
group is assumed to interact at the junction of the sub-sites S3/S2.
In the above definition of the pseudo-peptides according to the invention, the terms “amino acid” used for R
1
, R
2
, R
3
and R
4
in [5] refer to the twenty &agr;-amino acids commonly found in proteins which are also kno
Basset Geneviéve
Basset Paul
Beau Fabrice
Cuniasse Philippe
Dive Vincent
Basset Geneviéve
Commissariat A L'Energie Atomique
McKane Joseph K.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Shameem Golam M. M.
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