Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1995-08-31
1997-04-15
Kunz, Gary L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 281, 536 284, 536 285, 536 2853, 536 2854, 536 2855, 536 286, 536 271, 536 276, 536 2781, 536 53, 536 553, 536 261, 536 267, 536 2671, 536 2672, C07H 1300, C07H 1500, A61K 3170
Patent
active
056210868
DESCRIPTION:
BRIEF SUMMARY
This application is the U.S. national stage of international application PCT/JP 95/00418, filed Mar. 14, 1995.
1. Technical Field
The present invention relates to a method of manufacturing a sialic acid derivative and a novel sialic acid derivative.
2. Prior Art
A sialic acid is a sugar residue binding to ends of various sugar-chain present on a cellular surface layer. Intercellular interaction is mediated with the sialic acid and a substance capable of binding to the sialic acid. For example, it is known that, when an influenza virus invades into a living body, a protein (called hemaglutinine) present on the surface layer of the influenza virus binds to a sialic acid on the surface layer of a erthrocyte, and then the virus invades to the erthrocyte.
To prevent infection with influenza viruses, the following prevention method has been proposed. In the method, a sialic-acid analogue is allowed to bind to a carrier such as a cell or an artificial cell. The carrier is placed in a living body, and viruses are allowed to bind to the sialic acid analogue on the carrier. Therefore, the binding of the viruses to original cells of the living body in vivo, thereby preventing the infection with the viruses. Furthermore, the viruses also may be removed by taking the carrier out of the living body after the viruses bind thereto. At present, a wide variety of therapeutic methods are being studied, using a sialic acid.
Cytidine-5'-monophosphosialic acid (hereinafter referred to as "CMP-sialic acid") represented by the following formula, is known to serve as a sialic-acid donor when a sialic acid transferase (sialyltransferase) acts. The sialic acid transferase transfers the sialic acid from CMP-sialic acid (12) to the sugar chain of a sialic acid acceptor, thereby synthesizing sialoside.
Sialoside described above is known to have various physiological activities. For example, sialoside, known as a ganglioside, having a sialic acid polymer bonded thereto, has a neural growth activity. From the foregoing, it may be understood that the CMP-sialic acid can be used in the synthesis of an anti-virus agent and an anti-dementia agent. ##STR2##
Hence, it is extremely useful to develop a chemical synthetic method for synthesizing a sialic acid derivative represented by CMP-sialic acid in a large amount. Hitherto, the following manufacturing methods of CMP-sialic acid have been reported.
A sialic acid or a modified sialic acid, namely a sialic acid analogue, is condensed with cytidine-5'-triphosphate using cytidine-5'-monophosphosialic acid synthetase as an enzyme.
After an leaving group is introduced into the 2-position of a sialic acid and a protecting group is introduced into each of hydroxyl groups of the sialic acid, the 2-position of the sialic acid is nucleophilically displaced with a phosphoric acid portion of cytidine-5'-monophosphate and subsequently the protecting group is removed to obtain CMP-sialic acid (12).
After individual hydroxyl groups of cytidine are protected with allyloxycarbamate, allyl N,N,N',N'-tetraisopropylphosphorodiamidite is reacted with the protected cytidine. An allyl N,N-1-diisopropyl phosphoroamidite group is thereby introduced into the 5'-position of cytidine. As a result, a cytidine derivative is obtained. Subsequently, the cytidine derivative is condensed with a sialic acid whose hydroxyl group at the 2-position is protected and whose other hydroxyl groups are protected with allyloxycarbamate, thereby obtaining an intermediate. The phosphoric acid portion of the intermediate is oxidized and the protecting group is removed, thereby obtaining CMP-sialic acid (12).
However, in the aforementioned Method (i), the condensation reaction of some kinds of sialic acid analogues with cytidine-5'-triphosphate mediated by cytidine-5'-monophosphosialic acid synthetase is not carried out due to the substrate-specificity of the synthetase. In addition, cytidine-5'-monophosphosialic acid synthetase is expensive, resulting in high manufacturing cost. Hence, Method (i) is not suitable for the industrial large-sca
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E. Simon et al., J. Am. Chem. Soc., 110:7159-7163 (1988).
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Yasuhiro Kajihara et al "Carbohydrate Research" (1994) vol. 264, pp. C1-C5.
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Ebata Takashi
Kajihara Yasuhiro
Kodama Hisashi
Fonda Kathleen Kahler
Japan Tobacco Inc.
Kunz Gary L.
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