Amino acid derivatives inhibiting extracellular matrix...

Details Amino acid derivatives inhibiting extracellular matrix... Amino acid derivatives inhibiting extracellular matrix...

1999-12-17

2002-02-05

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S575000, C544S162000, C544S168000, C558S445000, C562S621000, C562S623000

Reexamination Certificate

active

06344457

ABSTRACT:

This application is a 371 of PCT/FR98/00801 filed Apr. 21, 1998.
This invention relates to new amino acid derivatives possessing an inhibiting action on metalloproteinase of the extracellular matrix, and more particularly gelatinase, a process for the production of these derivatives and pharmaceutical compositions containing them. These derivatives also possess an inhibiting action on the release of &agr;TNF (Tumor Necrosis Factor) as well as on the production of &agr;TGF (Tumor Growth Factor).
The breakdown of the extracellular matrix is due principally to the enzymatic action of metalloproteinase (MMP).
The enzymatic activity of this metalloproteinase is regulated physiologically by natural inhibitors such as TIMP (Tissue Inhibitor of Metalloproteinase) or alpha-2-macroglobulin. An imbalance in the production of the enzymes and their inhibitors leads to a high protein activity observed in pathologies involving a process of breakdown of the extracellular matrix.
Compounds having the property of inhibiting the action of the metalloproteinase involved in the breakdown of the extracellular matrix, such as collagenase, gelatinase and stromelysine therefore may be used in the treatment of pathologies in which metalloproteinase is involved, such as rheumatoid arthritis, osteoarthritis, osteoporosis, corneal ulceration, periodontitis, gingivitis or tumorous invasion and metastatic proliferation, atherosclerosis, AIDS, chronic inflammatory diseases of the intestine, these examples not being restrictive.
&agr;TNF is a pro-inflammatory cytokin which is produced initially in the form of an inactive 28 kDa precursor. The cleavage of this precursor leads to the release of an active form of 17 kDa involved in numerous inflammatory, immunological, infectious or malignant pathologies. Compounds inhibiting the release of &agr;TNF therefore may be used in the treatment of numerous pathologies in which &agr;TNF is involved, such as rheumatoid arthritis, Crohn's disease, plaque sclerosis, septic shock, cancer or cachexia associated with an immunodeficiency, these examples not being restrictive.
&agr;TGF is a growth factor forming part of the EGF (Epidermal Growth Factor) family. It is produced by the embryonic tissues, keratinocytes, macrophages, eosinophiles, epitheliums (mammary gland and cornea), pancreas, gastric mucous membrane, pituitary and brain.
&agr;TGF interacts with the EGF receptor; a cascade of reactions, resulting in mitosis, ensues. &agr;TGF also is mitogenic for tumorous cells.
&agr;TGF induces the transformation and growth of cells in vitro.
An overproduction of &agr;TGF is observed in tumors as well as in cell stock derived from mammary tumors. &agr;TGF also is involved in angiogenesis. It likewise stimulates hypercalcemia and inhibits gastric acid secretion. Finally, it is involved in inflammatory reactions.
Compounds inhibiting the production of &agr;TGF therefore may be used in the treatment of pathologies in which &agr;TGF is involved, such as cancer, psoriasis, eczema, the formation of keloids, diabetic retinopathy, atherosclerosis, inflammatory diseases, these examples not being restrictive.
Numerous inhibitors of MMP and/or of TNF release already are known, the most active being the derivatives of hydroxamic acid with the general formula I:
wherein R
1
represents an alkyl chain, generally isobutyl, and AA an amino acid or an amino acid chain. Such compounds are described, for example, in patent applications EP 0214639, WO 93/20047, WO 94/02447, WO 94/21625, WO 94/10990, WO 95/06031. MMP inhibitors inhibiting the production of &agr;TGF are described in international application WO 96/25156.
Other compounds have been described as inhibitors of matrix metalloproteinase in which the hydroxamic function has been replaced by a thiol (general formula II) or phosphinic (general formula III) function.
Finally, derivatives of N-carboxymethyl peptides also have been claimed (general formula IV).
In these different families, the R
1
residue interacts with the subsite S′
1
of the various enzymes. The stereochemistry of the carbon bearing this residue is essential for activity and must be of precise configuration, R, in the case of hydroxamic (J. Enzyme Inhibition, (1987), 2, 1-22) and phosphinic derivatives. None of the existing patents describing the MMP inhibitors makes reference to disubstitution on the R
1
-bearing carbon.
The substitution of this carbon therefore is of extreme importance for activity, and it has been shown in particular that substitution of the hydrogen in this carbon with a methyl remainder brings about a loss of activity of a factor of 300 between compound V and compound VI (J. Am. Chem. Soc. (1995), 117, 4671-4682).
R. P. ROBINSON et al. (Bioorg. Med. Chem. Letters (1996), 6, 1719-1724) also have studied the substitution of this carbon. The gem disubstitution leads systematically to a significant loss of activity (compound VII versus compounds VIII and IX).
This invention is derived from the discovery made by the Inventors that, in a completely unexpected manner considering the state of the art set forth above, the compounds of the following general formula X:
characterized by a gem disubstitution of this carbon with an R
1
residue and an alcohol function are powerful inhibitors of metalloproteinase of the extracellular matrix, and more particularly of gelatinase (inhibiting concentration at 50%: C150<200 nM). These compounds also inhibit the release of &agr;TNF from macrophages in mice stimulated by LPS (lipopolysaccharides) (C150: 10 to 0.01 &mgr;M) as well as the production of &agr;TGF.
This invention has as its purpose to provide new compounds inhibiting metalloproteinase, and/or the release of &agr;TNF and/or the production of &agr;TGF, the different inhibition activities of
R
6
represents —H, or a C
1
to C
6
alkoxy group, or a benzyloxy group,
R
7
represents —H, or a halogen atom such as —Cl or —Br,
R
1
represents:
a C
3
to C
16
linear or branched, or C
3
to C
6
cyclized alkyl chain, said chain comprising, as the case may be, a heteroatom such as O, S or N,
a phenoxyalkyl or phenylalkyl group, substituted or unsubstituted, or a heteroarylalkyl group, the alkyl group being C
2
to C
5
,
R
2
represents:
a hydrogen atom, or,
a C
1
to C
5
alkyl or C
2
to C
5
alkylidene group, or
a hydroxyl, a C
1
to C
6
alkoxy or a benzyloxy, provided that Y represents —CONHOH when R
2
represents a hydroxyl, or
a hydroxymethyl, or C
1
to C
6
alkoxymethyl group, or
an arylalkyl group in which the alkyl portion is C
1
to C
6
, an aryloxymethyl group, an arylthiomethyl group, a heteroarylthiomethyl group, in which aryl designates a phenyl remainder, possibly substituted, in particular by —OH, —OCH
3
, a linear or branched C
1
to C
3
alkyl group, a halogen such as —Cl or —Br, an amine group such as —NH
2
, —NHCOCH
3
, —NHCOOR
10
, R
10
representing a linear or branched C
1
to C
3
alkyl group, or
A phthalimide alkyl group in which the alkyl portion is C
1
to C
6
, or
an alkoxycarbonylmethyl group (alkoxy designating methoxy, ethoxy), a benzyloxycarbonylmethyl, an acetylmethyl, provided that Y represents —SH in these three cases.
AA represents an amino acid, or an amino acid chain, these amino acids being natural or otherwise, and advantageously with an absolute S configuration, in particular an amino acid with the formula these compounds being comparable or even superior to those of compounds of the state of the art described above.
This invention further has as its purpose to provide new medicines containing the aforementioned new compounds as active principle, and offering the advantage of possessing a better bioavailability than the compounds of the state of the art described above.
This invention likewise has as its purpose the use of the aforementioned new compounds for the preparation of new medicines described above, capable of being used in the context of treatment of pathologies in which the metalloproteinase of the extracellular matrix and/or &agr;TNF are involved, as well as pathologies in which an overproduction of

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