Soluble tachykinin antagonists, the preparation and use thereof

Details Soluble tachykinin antagonists, the preparation and use thereof Soluble tachykinin antagonists, the preparation and use thereof

1998-08-28

2000-06-13

Russel, Jeffrey E.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514 10, 530317, 530321, 530322, A61K 3812, A61K 3814, C07K 756, C07K 900

Patent

active

060750065

DESCRIPTION:

BRIEF SUMMARY
The present invention refers to soluble tachykinin antagonists, to their preparation and to pharmaceutical compositions containing them.
Many tachykinin antagonists are known in literature and among these the monocycle (A. T. McKnight et al., Br. J. Pharmacol. 1991, 41,376) and bicycle (V. Pavone et al., J. Chem. Soc. Perkin Trans 2, 1995, 987) compounds are particularly interesting. All the compounds developed up to now are characterized by a high hydrophobicity and therefore are all water insoluble. In fact patent WO 93/21227 discloses insoluble bicycle peptide tachykinin antagonists, wherein all the claimed structures are characterized by amino acids with hydrophobic side chains or if the chains are polar, they are functionalized so as to confer hydrophobicity to the functional group. The low water solubility (no more than 15 .mu.g/ml) which inevitably characterizes these extremely hydrophobic compounds, has effectively hampered any possible pharmacological applications of such molecules up to now, notwithstanding their in vitro interesting biological activity. It is likewise known from literature (L. Quartara et al., J. Med. Chem. 1994, 37, 3630) that an increase in the hydrophilicity of this class of molecules causes a progressive reduction in their biological activity. From this reference point, the pharmaceutical industry's interest comes out in the search for new classes of tachykinin-antagonists of the water soluble type, but with a highly specific activity.
The present invention discloses tachykinin-antagonists which at the same time present a high water solubility and a high biologic activity. The compounds of the invention have the following general formula (I): cyclo[X.sub.1.sup.1 --Z.sub.1.sup.2 --X.sub.2.sup.3 --X.sub.3.sup.4 --Z.sub.2.sup.5 --X.sub.4.sup.6 ]cyclo(2.beta.-5.beta.) wherein: X.sub.1 =(D or L)Cys(Y) or (D or L)SeCys(Y), Z.sub.1 =Asp and Z.sub.2 =Dap or Z.sub.1 =Dap and Z.sub.2 =Asp and X.sub.2, X.sub.3 and X.sub.4 =natural or synthetic hydrophobic amino acids, having Z.sub.1, Z.sub.2, X.sub.2, X.sub.3 and X.sub.4 the same D or L configuration; Y=is a glycosidic group selected from the aldo and keto hexoses in the furanose or pyranose form bound to the cysteine or to the selenocysteine with an .alpha. or .beta. thio- or seleno-acetal bond or a cyclithol or a polyvinyl alcohol or PEG, constituted of 5 to 10 monomeric unities, bound to the cysteine or to the seleno cysteine respectively with a thio- or seleno-ether bond.
The compounds with X.sub.2 =Trp or 1-Nal; X.sub.3 =Phe and X.sub.4 =Leu or Cha are particularly preferred.
The compounds of formula (I) have many chiral centres, and therefore the invention comprises all the possible enantiomers.
The compounds of formula (I) show unique structural characteristics, which differentiate them from the known products. In fact, the claimed compounds, contrary to those reported up to now (A. T. McKnight et al., Br. J. Pharmacol. 1991, 41, 376; C. A. Maggi et al., J. Pharmacol. and Expt. Therapeutics, 1994, 271, 1489), contain highly hydrophilic functional groups, which give them an at least 100 times higher water solubility. The high water solubility and the strong pharmacological activity, higher than that of the insoluble compounds previously developed, make this new class of molecules ideal for the development of a wide set of pharmaceutical formulations. As far as these applicative aspects are concerned, the compounds of the invention substantially differ from the insoluble derivatives previously studied in that the latter do not permit the development of pharmaceutical compositions which can be used therapeutically.
In particular, the compounds of formula I characterized by a residue of cysteine or of selenocysteine, whose respective --SH or --SeH group is involved in a thio- or seleno-glycosidic or thio- or seleno-ether bond with a galactose, glucose, inositol or PEG residue or low molecular weight polyalcohols, even though with high water solubility, they have an activity even a little higher than the activity of the best antagoni

REFERENCES:
By A.T. McKnight et al., "Pharmacological specificity of novel, synthetic, cyclic peptides as antagonists at tachykinin receptors", British Journal of Pharmacology, vol. 104, 1991, pp. 355-360.
By G. Holzemann et al., "Cyclic hexapeptide NK-2 antagonists", International Journal of Peptide and Protein Research, vol. 44, 1994, pp. 105-111.
By C.A. Maggi et al., "Men 10,627, a Novel Polycyclic Peptide Antagonist of Tachykinin NK2 Receptors", Journal of Pharmacology and Experimental Therapeutics, vol. 271, No. 3, 1994, pp. 1489-1500.
By V. Pavone et al., Design and structure of a novel Neurokinin A receptor antagonist cyclo(-Met.sup.1 -Asp.sup.2 -Trp.sup.3 -Phe.sup.4 -Dap.sup.5 -Leu.sup.6 -)cyclo (2.beta.-5.beta.), Journal of the Chemical Society Perkin Transactions 2, 1995, pp. 987-993.

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