Chemistry of carbon compounds – Miscellaneous organic carbon compounds – C-metal
Patent
1980-12-12
1984-02-28
Phillips, Delbert R.
Chemistry of carbon compounds
Miscellaneous organic carbon compounds
C-metal
C07C10352
Patent
active
044340958
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to novel biologically active peptide-type compounds, namely to a novel cyclic analogue of a naturally-occurring phagocytosis-stimulant threonyl-cyclo-[-N.sup..epsilon. -lysyl-prolyl-arginyl] possessing a phagocytosis-stimulating activity which is useful in medicine as an immunostimulant possessing a wide range of action and resistance against carboxypeptidases.
BACKGROUND OF THE INVENTION
Tuftsin having threonyl-cyclo-[-N.sup..epsilon. -lysyl-prolyl-arginyl-] as its analogue comprises a fragment of a heavy chain of immunoglobulins, class IgG, of a human being (Thr-Lys-Pro-Aig). This tetrapeptide reveals a considerable stimulant effect with regard to various immunological responses in vivo and in vitro. It substantially increases phagocytic activity of leukocytes and macrophages, and activates immunogenesis of the latter, etc. (cf. Proc. Natl. Acad. Sci USA, vol. 75, No. 7, 1978; E. Tzehoval, S. Segal, Y. Stabinsky, M. Fridkin, Z. Spirer, M. Feldman "Tuftsin (an Ig-associated tetrapeptide) triggers the immunogenic function of macrophages: Application for activation of programmed cells", pp. 3400-3404).
It has been suggested that tuftsin is useful as a therapeutical remedy for the treatment of diseases associated with a lower activity of leukocytes, as well as splenectomy and certain spleen disturbances accompanied by a noticeably reduced resistance of the organism against infectious diseases. In such cases tuftsin can replace .gamma.-globulin (J. Pediat. vol. 80, No. 4, 1972, D. Constantopoulos, V. D. Najjar, J. W. Smith "Tuftsin deficiency: a new syndrome with defective phagocytosis", pp. 464-572).
A disadvantage of tuftsin as a medicated compound resides in its rapid splitting by enzymes such as carboxypeptidases thus defining its short-time effect under in vivo conditions.
The cyclic analogue of the naturally-occurring phagocytosis-stimulant peptide--threonyl-cyclo-[-N.sup..epsilon. -lysyl-prolyl-arginyl-] has not been hitherto described in the literature.
DISCLOSURE OF THE INVENTION
The present invention is directed to the provision of such a novel compound which would be resistant towards the enzymatic splitting agents such as carboxypeptidases.
This object is accomplished by a novel cyclic analogue of a naturally-occurring phagocytosis-stimulant peptide, viz. threonyl-cyclo-[-N.sup..epsilon. -lysyl-prolyl-arginyl-] of the formula: ##STR2## and by a method for preparing same by a step-wise building-up of the peptide chain from the C-terminal using activated ethers of benzyloxycarbonylproline, tert. butyloxycarbonyl-N.sup..epsilon. -benzyloxycarbonyl-lysine and tert.butyloxycarbonylthreonine, followed by cyclization of the resulting partly blocked tetrapeptide by means of the Woodward reagent and isolation of the desired product.
BEST MODE FOR CARRYING-OUT THE INVENTION
According to the present invention the novel compound, viz. threonyl-cyclo-[-N.sup..epsilon. -lysyl-prolyl-arginyl-] has the following formula: ##STR3##
Cyclo-[-N.sup..epsilon. -lysyl-prolyl-arginyl-] comprises an amorphous white powder decomposing above 100.degree. C.; specific rotation [Z].sub.D.sup.22 -63.degree. (c 0.2; 5% CH.sub.3 COOH).
Elemental analysis: Found, % by weight: C 40.18; H 7.47; N 14.68. Calculated, for C.sub.21 H.sub.38 N.sub.8 O.sub.5.2CH.sub.3 COOH.4H.sub.2 O, % by weight: C 44.50; H 8.06; N 16.60.
Aminoacid analysis: Thr-1.0; Lys-1.1; Pro-0.9; Arg-1.0.
Electrophoretic analysis: electrophoretic mobility is determined through the ratio to histidine in 1 N acetic acid on paper FN-15 (GDR) at the voltage difference of 900 V. For the novel compound according to the present invention E.sub.his =0.90 (pH 2.4).
Chromatographic analysis: chromatographic mobilities R.sub.f =0.07 (n.butanol-ethanol-water-acetic acid-80:10:30:5), R.sub.f =0.22 (n.butanol-pyridine-water-acetic acid 30:20:24:6) were determined on "Merck" plates.
Biological activity of threonyl-cyclo-[-N.sup..epsilon. -lysyl-prolyl-arginyl-] is studied in vitro experiments. The effect of this compoun
REFERENCES:
patent: 3778426 (1973-12-01), Najjar
Munsgard et al., Internat'l Journal of Peptid and Protein Research, pp. 130-138.
Chem. Abstr. vol. 94, 1981, p. 114883m.
Atare Zeltite A.
Chipens Gunar I.
Veretennikova Nadezhda I.
Institute Organicheskogo Sinteza
Phillips Delbert R.
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