Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-01-26
1997-05-06
Richter, Johann
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
549417, 536 172, C07D30914, C07D30928, C07H 506, C07H 510
Patent
active
056272901
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT JP95/00820 filed Apr. 26, 1995.
TECHNICAL FIELD
The present invention relates to 2,7-dideoxy-7-fluoro-2,3-didehydrosialic acid, and a synthetic intermediate thereof.
RELATED ART
Sialic acid (a1) exists at the terminal end of glycoproteins and glycolipids in a living body, particularly an interior of animals, and plays an important role for a life sustainment, such as an adhesion between cells, a transmission of information, a delivery of hormone, etc. In order to elucidate the functions of sialic acid on the molecular level, various derivatives of sialic acid have been synthesized by chemical modifications.
Regarding derivatives of 2,3-didehydrosialic acid, a natural type (a2) [Haruo OGURA, Chem. Pharm. Bull., 36, 1872-1876 (1988)], 4-amino (a3) and 4-guanidino (a4) derivatives [M. von Itzstein et al., Carbohydr. Res., 259, 301-305 (1994)] have been synthesized, and their antiviral actions on influenza virus have been known. Regarding fluorine-containing derivatives of sialic acid, a 2-F derivative (a5) [(M. N. Sharma et al., Carbohydr. Res., 127, 201-210 (1984)], a 3-F derivative (a6) [Tatsuo IDO et al., Agric. Biol. Chem., 52, 1209-1215 (1988)] and a 9-F derivative (a7) [W. Korytnyk et al., J. Carbohydr. Chem., 1, 311-315 (1982-1983)] have been synthesized. Among them, the 3-F derivative exhibits a sialidase inhibition action and the 9-F derivative exhibits a carcinostatic action. ##STR1##
As described above, the didehydro derivatives and fluorine-containing derivatives of sialic acid have various physiological activities.
It is expected to enhance physiological activities and impart a selectivity by combining properties of didehydro derivatives with those of fluorine-containing sialic acid.
In the synthesis method of sialic acid, a large amount of sialic acid can be obtained from N-acetyl-D-mannosamine and pyruvic acid by using an enzyme method. Accordingly, the 7-position of sialic acid corresponds to the 4-position of N-acetyl-D-mannosamine. In order to introduce a fluorine atom at the 4-position of N-acetyl-D-mannosamine while maintaining the configuration, N-acetyl-D-talosamine is required. N-acetyltalosamine exits in the cartilage of the trachea of sheep, but is scarce. N-acetyltalosamine can be produced by the synthesis from lyxose (R. Kuhn et al., Ann, 1958, 612, 65) and by the epimerization of the 3-position of D-idosamine derivatives (R. W. Jeanioz et al., J. Org. Chem., 1961, 26, 532). However, these methods are not suitable because, for example, the synthetic process has many steps.
SUMMARY OF THE INVENTION
An object of the present invention is to provide 2,7-dideoxy-7-fluoro-2,3-didehydrosialic acid which is expected as drugs such as antiviral agents, carcinostatic agents, immunomodulation agents, etc., and synthetic intermediates thereof.
The present inventors have researched for the purpose of synthesizing an analogue obtained by chemically modifying a side chain moiety of sialic acid with fluorine, and succeeded in synthesizing the analogue. Thus, the present invention has been accomplished.
In the present invention, N-acetyl-D-galactosamine is available in the same degree of ease as that in case of N-acetyl-D-mannosamine. Therefore, 2,7-dideoxy-7-fluoro-2,3-didehydrosialic acid can be easily synthesized by using N-acetyl-D-galactosamine as the starting raw material. Namely, 2,7-dideoxy-7-fluoro-2,3-didehydrosialic acid can be synthesized by protecting hydroxyl groups other than the hydroxyl group at the 4-position of N-acetyl-D-galactosamine, subjecting the hydroxyl group at the 4-position to Walden inversion simultaneously with introducing a fluorine atom, to give N-acetyl-4-deoxy-4-fluoro-D-glucosamine, isomerizing and subjecting it to aldol reaction together with pyruvic acid through the use of an enzyme (N-acetylneuraminic acid aldolase) to construct a novel route for synthesizing the objective 7-deoxy-7-fluoro-sialic acid, and then forming an intermediate from the resulting 7-fluorosialic acid to give 2,7-dideoxy-7-fluoro-2,3-didehydrosialic
Iida Takao
Ohira Yutaka
Daikin Industries Ltd.
Richter Johann
Stockton Laura L.
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