Cyclic adhesion inhibitors

Details Cyclic adhesion inhibitors Cyclic adhesion inhibitors

1999-04-08

2000-10-03

Low, Christopher S. F.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514 11, 514 17, 530317, 530329, 530330, A61K 3812, C07K 512

Patent

active

06127335&

DESCRIPTION:

BRIEF SUMMARY
The invention relates to novel cyclopeptides of the formula I homo-Phe, Phg, Thi, Trp, Tyr or derivatives of Tyr, it being possible for the OH group to be etherified by alkyl radicals having 1-18 carbon atoms and also for the amino acid residues mentioned to be additionally derivatized, atoms, Ar, Ar--O or .sup.3 H, R.sup.2 and/or the .alpha. C atom to be substituted by R.sup.3 and/or R.sup.4, with the proviso that Gly is substituted at least once in the manner indicated, NO.sub.2, I, Br, Cl, F, alkyl having 1-6 carbon atoms or .sup.3 H, having 1-18 carbon atoms, otherwise a branched or unbranched alkylene chain having 3 to 18 carbon atoms, so that therein either the .alpha. N atom and the .alpha. C atom together with the alkylene chain, or the .alpha. C atom alone with the alkylene chain, forms a ring, derivatives are involved, both the D and the L forms are included, and to derivatives, especially aspartic acid .beta.-esters or N-guanidine-acyl derivatives of arginine, to prodrugs, and also to the physiologically acceptable salts thereof.
Similar compounds are known from, for example, EP 0 406 428 and FEBS Lett. 291, 50-54 (1991).
The object of the invention was to discover novel compounds having valuable properties, especially those which can be used for the production of medicaments.
It has surprisingly been found that the compounds of the formula I and their salts possess very valuable properties. In particular, they act as integrin inhibitors, in which context they inhibit in particular the interactions of .beta..sub.3 - or .beta..sub.5 -integrin receptors with ligands. The compounds are particularly active in the case of the integrins a.sub.V .beta..sub.3, a.sub.V .beta..sub.5 and a.sub.II .beta..sub.3, but also relative to a.sub.V .beta..sub.1 -, a.sub.V .beta..sub.6 - and a.sub.V .beta..sub.8 receptors. These actions can be demonstrated, for example, according to the method described by J. W. Smith et al. in J. Biol. Chem. 265, 12267-12271 (1990). In addition, there are anti-inflammatory effects.
The dependency of the development of angiogenesis on the interaction between vascular integrins and extra-cellular matrix proteins is described by P. C. Brooks, R. A. Clark and D. A. Cheresh in Science 264, 569-71 (1994).
The possibility of inhibiting this interaction and the associated initiation of apotosis (programmed cell death) of angiogenic vascular cells by a cyclic peptide is described by P. C. Brooks, A. M. Montgomery, M. Rosenfeld, R. A. Reisfeld, T.-Hu, G. Klier and D. A. Cheresh in Cell 79, 1157-64 (1994).
Compounds of the formula I which block the interaction of integrin receptors and ligands, for example of fibrinogen to the fibrinogen receptor (glycoprotein IIb/IIIa), act as GPIIb/IIIa antagonists in preventing the propagation of tumour cells by metastasis. This is demonstrated by the following observations:
The propagation of tumour cells from a local tumour into the vascular system takes place via the formation of microaggregates (microthrombi) by interaction of the tumour cells with blood platelets. The tumour cells are screened by the protection afforded in the microaggregates, and are not recognized by the cells of the immune system.
The microaggregates are able to settle on vessel walls, facilitating the further penetration of tumour cells into the tissue. Since the formation of the microthrombi is mediated by binding of fibrinogen to the fibrinogen receptors on activated blood platelets, the GPIIa/IIIb antagonists can be regarded as effective inhibitors of metastasis.
The compounds of the formula I can also be employed as antimicrobial substances in the case of operations where biomaterials, implants, catheters or pacemakers are employed. In this context they have an antiseptic action. The effectiveness of the antimicrobial activity can be demonstrated by the method described by P. Valentin-Weigund et al., in Infection and Immunity, 2851-2855 (1988).
Since the compounds of the formula I constitute inhibitors of fibrinogen binding and thus ligands of the fibrinogen receptors on blood

REFERENCES:
patent: 5849692 (1998-12-01), Jonczyk et al.
Pfaff et al. `Selective Recognition of Cyclic RGD Peptides of NMR Defined Conformation by Alpha.IIB.Beta 3, Alpha V Beta 3, and Alpha 5 Beta Integrins`, Journal of Biological Chemistry. 1994, vol. 269, No. 32, pp. 20233-20238, 1994.
Delforge et al., `Automated Solid Phase Synthesis of Cyclic Bearing a Side Chain Tail Designed for Subsequent Chemical Grafting`, Anal. Biochem. 1996, vol. 242, pp. 180-186, 1996.
Journal of Biological Chemistry, Bd. 269, No. 32, Aug. 12, 1994, pp. 20233-20238, Selective recognition of cyclic RGD peptides of NMR defined conformation by alphaIIb-beta3, alpha V-beta3, and alpha5-betaI integrines, M. Pfaff et al., XP002036951.
DE19534177-English Abstract.
EP578083-English Abstract.
EP632053-English Abstract.

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