Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1993-12-03
1995-12-19
Warden, Jill
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530329, A61K 3800, C07K 500, C07K 700, C07K 1700
Patent
active
054768403
DESCRIPTION:
BRIEF SUMMARY
The present application relates to new hexapeptide derivatives, the preparation process and the use as medicaments of these new derivatives.
It is known that endothelin is a powerful vasoconstrictor extracted from porcine aortic endothelium. This peptide, which has been isolated recently, contains 21 amino acids, has 2 disulphide bridges and has the following formula: ##STR1## (--A novel potent vasoconstrictor peptide produced by vascular endothelial cells. M. Yanagisawa, H. Kurihara, S. Kimura, Y. Tomobe, M. Kobayashi, Y. Mitsui, Y. Yazaki, K. Goto & T. Masaki, Nature, (1988) 332, pp. 411-415). This peptide is designated in what follows under the name of ET1.
The nomenclature used is that of the IUPAC-IUB commission (1984) European J. Biochem 183, 9-37.
This peptide, which contains 21 amino acid residues, 2 disulphide bridges, is capable of contracting at very low doses the smooth muscle cells (arteries and veins) of various types of mammals (man, dog, cat, pig, guinea pig, rat, rabbit . . . ). By trying to shorten the chain and replace certain amino acid residues of endothelin by other amino acids, the Applicant prepared by synthesis new hexapeptide derivatives containing only five or six amino acids in which the vasoconstrictive activity has practically disappeared and which furthermore have the property of blocking and fixing themselves on the natural receptors of endothelin. The products therefore present an activity which will oppose any subsequent action for releasing endothelin.
In addition, these products are of interest because they can be prepared by total synthesis in large quantities.
Therefore a subject of the present Application is new hexapeptide derivatives corresponding to the general formula (I): acetyl-histidine, or D-histidine, as well as their D series equivalents, leucine and aspartic acid as well as their D series equivalents, and their D series equivalents.
Among the new hexapeptide derivatives, as defined above, there are particularly preferred those characterized in that: equivalents, equivalent, equivalent.
Among these, there are preferred the peptide derivatives in which:
Among the preferred new hexapeptide derivatives of the invention, there is more particularly preferred one of the following peptide derivatives: ##STR2##
Among the new hexapeptide derivatives as defined above, the following peptide derivative is quite particularly preferred: ##STR3##
Also a subject of the invention is a preparation process for the new hexapeptide derivatives as defined above, characterized in that a solid-phase synthesis is carried out by sequentially introducing the duly-protected amino acids on a support of cross-linked polystyrene type, using a coupling agent, the amino acids are deprotected, and the peptide chain thus formed is released from the resin, in order to obtain the peptide derivative of formula (I) thus sought.
In the preferred implementation conditions, the process described above is characterized in that: type or "Boc-D-Trp-CM" type in which Boc is a tertiobutyloxycarbonyl group, Trp is a tryptophyl group and D- Trp is a D-tryptophyl group and CM designates the cross-linked polystyrene support, phosphonium hexafluorophosphate or Bop, deprotection of the amino acids is carried out using hydrofluoric acid operating at low temperature, preferably at about 0.degree. C.
The new hexapeptide derivatives which are a subject of the present invention have very useful pharmacological properties; in particular a remarkable, practically pure antagonistic effect against hypertension caused by endothelin and an anti-ischemic effect, the vasoconstrictive activity of endothelin being abolished, are noted.
Some of these properties are illustrated further on in the experimental part.
These properties justify the use of the new hexapeptide derivatives corresponding to formula (I) above as medicaments.
Therefore a subject of the present invention is also the use as medicaments of the new hexapeptide derivatives as defined by general formula (I) above.
Among the medicaments which are a subject of th
REFERENCES:
patent: 5260276 (1993-11-01), Cody et al.
Barauy et al. Int. J. Pep. Pnt. Res. vol. 30 p. 705 (1987).
Masaki et al. Med Res. Rev. vol. 12, p. 391 (1992).
Doherty et al. J. Cardiovascular Pharm. vol. 17 pp. 559-561 (1991).
Greenlee et al. Pharm. Res. vol. 4, p. 364 (1987).
Broto Pierre
Hamon Giles
Le-Nguyen Dung
Mahe Eve
Huff Sheela J.
Roussel Uclaf
Warden Jill
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