JPH06256373A - Sulfated oligosaccharide glycoside acyl compound and antiviral agent containing the same - Google Patents

Abstract

(57) [Summary] [Structure] One of the reducing terminal sugars of oligosaccharides composed of the same or two kinds of monosaccharides as constituents and having glycosidic bonds between them.
Hydrogen of the hydroxyl group at the position is an alkyl group, an aromatic alkyl group,
Substituted with an aglycone selected from the group consisting of aromatic alkoxy groups, 12 to 80% of the remaining hydroxyl groups are acylated with an acyl group selected from the group consisting of aliphatic acyl groups and aromatic acyl groups, and 88 to 20% acylated sulfated oligosaccharide glycoside acylated product or a physiologically acceptable salt thereof (excluding compounds in which the aglycone is an alkyl group and the acyl group is an aliphatic acyl group). And an antiviral agent containing this as an active ingredient. [Effect] It is possible to provide a novel acylated product of a sulfated oligosaccharide glycoside, and a low toxicity orally administrable antiviral agent containing this as an active ingredient.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an acylated product of a sulfated oligosaccharide glycoside having antiviral activity, and an antiviral agent containing this compound as an antiviral component.

[0002]

2. Description of the Related Art Antiviral agents using glycosides of sulfated oligosaccharides are disclosed in JP-A-5-78382 and JP-A-5-279381 by the present inventors, and they are not effective as glycosides. It has been found that the virus activity is improved by one digit compared with glycoside compounds. However, these are compounds in which the sugar hydroxyl groups are not acylated, and when orally administered, the activity persistence in blood was poor.

Japanese Unexamined Patent Publication (Kokai) No. 3-43401 describes an antiviral agent of a sulfated polysaccharide alkyl ether or an alkyl ester compound, but completely describes an aromatic or tocopherol glycoside and an aromatic esterification. There is no.

As an esterified product of an alkyl glycoside composed of oligosaccharides, there is US Pat. No. 4,840,815, which is esterified but not sulfated. Furthermore, in JP-A-4-264102, a compound in which the sugar hydroxyl group of galactomannan is substituted with an aliphatic, araliphatic or aromatic ether or aromatic ester is also found, but it is not a glycoside and is different from the present invention. It was also not a sulfated compound.

US Pat. No. 4,597,770 describes a sulfuric acid ester of an alkyl glycoside alkyl ether compound of monosaccharide to decasaccharide as a slurry agent for coal, but its specific structure is not clear. The sugar hydroxyl group is not acylated and is a completely different idea from the compounds of the present invention.

[0006] US Pat. No. 4,761,401 describes a sulfated product of a disaccharide glycoside containing uronic acid for cosmetics. However, the sugar chain is a disaccharide and it contains uronic acid. It is a compound having a structure different from that of the compound of the present invention. U.S. Pat. No. 3,478,016 discloses a cellulose ester and a sulfated product of cellulose ether, but it is not an antiviral use and the structure is clear. It is a compound that is not compounded.

As outlined above, a compound in which the hydroxyl groups of oligosaccharide glycosides are acylated and sulfated has not been known so far. Recently, sulfated polysaccharides are antiviral agents,
Particularly effective as an anti-HIV agent, US Pat. No. 4,783,446, and reports by Baba et al. (Journal of Acquired Immun Deficitency
Syndrome (M. Baba, et al., Jour
nal of Acquired Immune De
fi-ciency Syndrome), 3 volumes, 49
3 to 499, 1990), etc., but none of these have a glycoside structure, and their high molecular weight of tens of thousands or more results in poor absorbability into the living body and oral administration. However, there are various problems such as difficulty in administration, large anticoagulant activity, especially poor continuous activity in blood, and decomposition within one hour after administration. For example, in the case of dextran sulfate, it has been reported by Kevin et al. That there is no effect when administered orally (Kevin J Lorentsen,
et al. , Annals of Internal
Medicine), Volume 111, 561-566, 19
1989).

Further, AZT (3'-azido-3'-deoxythymidine), which is widely used as an anti-AIDS agent, has strong side effects, and therefore, development of a new drug having low toxicity is desired.

[0009]

The problem to be solved by the present invention is to provide a drug having low toxicity, excellent activity persistence in blood, and excellent activity persistence even when orally administered. is there.

[0010]

[Means for Solving the Problems] The inventors of the present invention have conducted diligent research with the aim of providing an excellent antiviral agent.
A novel sulfated oligosaccharide glycoside acyl derivative and its physiologically acceptable salt have low toxicity, excellent blood persistence of antiviral activity even in oral administration, and the antiseptic activity found in sulfated polysaccharides. The present invention has been completed when it was found that the drug has low coagulation activity and high safety.

That is, according to the present invention, the hydrogen of the hydroxyl group at the 1-position of the reducing terminal sugar of an oligosaccharide composed of the same or two kinds of monosaccharides as constituent components and having glycosidic bonds between them is an alkyl group, an aromatic alkyl group or an aromatic group. Substituted with an aglycone selected from the group consisting of group-alkoxy groups, the remaining 12-
80 to 80% is acylated with an acyl group selected from the group consisting of an aliphatic acyl group and an aromatic acyl group, 88 to 20%
Is a sulfated sulfated oligosaccharide glycoside acyl compound or a physiologically acceptable salt thereof (excluding compounds in which aglycone is an alkyl group and an acyl group is an aliphatic acyl group), and The present invention relates to an antiviral agent as an active ingredient.

The above compounds of the present invention will be described below. The number of monosaccharides constituting the oligosaccharide in the compound of the present invention,
That is, the length of the sugar chain varies depending on the type of sugar used, the aglycone, etc., but a sugar chain longer than a trisaccharide is preferred for antiviral use, and from the viewpoint of anticoagulant action, biocompatibility, etc.
Usually, 20 sugars or less are preferable. That is, 3-20 sugars are preferable, and 3-12 sugars are more preferable.

The oligosaccharide moiety of the compound of the present invention comprises the same or two kinds of monosaccharides as constituent components. As the monosaccharide, various monosaccharides can be used, but a monosaccharide selected from glucose, galactose, mannose, talose, idose, altrose, allose, gulose, xylose, arabinose, rhamnose, fucose, fructose, ribose, deoxyribose is used. preferable. Further, a monosaccharide such as glucosamine or galactosamine having an amino group may be used.

The glycosidic bond between monosaccharides of the compound of the present invention is (1 → 2), (1 → 2) from the viewpoint of antiviral activity.
3), (1 → 4), (1 → 5), (1 → 6), and the binding mode may be either α-bond or β-bond. Also, branched sugar chains can be used. Above all, β (1 →
3), β (1 → 4), α (1 → 4) and α (1 → 6) linked sugars are preferred. In particular, β (1 → 3) sugars and β (1 → 4) sugars are easy to use for maintaining sustained activity when administered as a drug. For example, laminari oligosaccharides (oligosaccharides formed by β-bonding the 3-position of glucose to the 1-position of the next glucose), that is, oligosaccharides obtained by decomposing polysaccharides such as curdlan and laminaran,
Oligosaccharides formed by β-bonding to the 1-position of galactose at the 4-position of the galactose site of lactose, and β- (1 → 4) -bonding galactose at the 4-position of the oligosaccharide terminal galactose, and glucose such as malto-oligosaccharide (1 → 4) linked oligosaccharides and the like are preferable, and oligosaccharides such as isomalt oligosaccharides (α (1 → 6) linked oligosaccharides of glucose) can also be used. Others, mannose-based oligosaccharides, β
(1 → 6) Various oligosaccharides such as oligoglucose, xylan-based, schizophyllan-based, lentinan-based, galactan-based, and pullulan-based can also be used. Further, a part of the hydroxyl groups of the oligosaccharide may be replaced with an amino group or a substituted amino group.

The compound of the present invention is a reducing terminal sugar 1 of oligosaccharide.
The hydrogen of the hydroxyl group at the position must be replaced with an aglycone, and examples of the aglycone include an alkyl group, an aromatic alkyl group, and an aromatic alkoxy group.

Examples of the alkyl group include linear or branched alkyl groups having 1 to 24 carbon atoms, preferably 4 to 22 carbon atoms, and more preferably 8 to 12 carbon atoms. An unsaturated bond may be present in the alkyl group. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl,
Pentyl, isopentyl, 2-methylbutyl, hexyl, heptyl, octyl, 2-octyl, 2-ethylhexyl, 2,2,3,3-tetramethylbutyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl, eicosyl, Docosyl, tricosyl, etc. can be mentioned.

The aromatic alkyl group has 1 to 1 carbon atoms.
8, preferably a phenyl group substituted with 4 to 12 linear or branched alkyl groups. The alkyl group as a substituent may have an unsaturated bond. For example, o-methylphenyl, p-methylphenyl, m-methylphenyl, ethylphenyl, propylphenyl, butylphenyl, pentylphenyl, hexylphenyl, heptylphenyl, octylphenyl, nonylphenyl, decylphenyl, dodecylphenyl, tetradecylphenyl. , Hexadecylphenyl, octadecylphenyl, eicosylphenyl, tricosylphenyl and the like.

The aromatic alkoxy group has 1 to 1 carbon atoms.
18, preferably a phenyl group substituted with 4 to 12 linear or branched alkoxy groups. The alkoxy group as a substituent may have an unsaturated bond. For example, methoxyphenyl, ethoxyphenyl, propoxyphenyl, butoxyphenyl, pentyloxyphenyl, hexyloxyphenyl, heptyloxyphenyl, octyloxyphenyl, nonyloxyphenyl, decyloxyphenyl, dodecyloxyphenyl, tetradecyloxyphenyl, hexadecyloxy. Examples thereof include phenyl, octadecyloxyphenyl, eicosyloxyphenyl and tricosyloxyphenyl.

In the compound of the present invention, 12 to 80% of the sugar hydroxyl groups of the oligosaccharide glycoside compound having an aglycone is acylated with an aromatic acyl group when the aglycone is an alkyl group, and the aglycone is an aromatic alkyl group. In the case of a group or an aromatic alkoxy group, it is a compound acylated with an aliphatic acyl group or an aromatic acyl group. Regarding the position of the acylated hydroxyl group, any position other than the hydroxyl group at the 1-position of the reducing terminal sugar can be used.

The aliphatic acyl group has 2 to 2 carbon atoms.
4, preferably 3 to 22, more preferably 4 to 12 linear or branched alkanoyl groups. Examples thereof include acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, decanoyl, dodecanoyl, hexadecanoyl, eicosanoyl, docosanoyl, tricosanoyl and the like.

Examples of the aromatic acyl group include an unsubstituted benzoyl group, an alkyl group, an alkoxy group and a halogen-substituted benzoyl group. The alkyl group or alkoxy group has 1 to 18 carbon atoms, preferably 3 to 12 carbon atoms.
And the halogen includes fluorine, chlorine, bromine and iodine. The number of substitutions and the substitution position of these substituents are arbitrary. For example,
Benzoyl, fluorobenzoyl, 2,4-difluorobenzoyl, chlorobenzoyl, 4-methylbenzoyl, 4-butylbenzoyl, 4-pentylbenzoyl,
4-hexylbenzoyl, 4-octylbenzoyl, 4
-Propoxybenzoyl, 4-butoxybenzoyl, 4
-Pentoxybenzoyl, 4-dodecyloxybenzoyl and the like can be mentioned, but not limited thereto.

After acylation, the unreacted residual hydroxyl group is converted to a sulfuric acid ester to obtain the desired compound of the present invention. As the sulfate counter ion, any physiologically acceptable cation can be used,
For example, it can be finally taken out in the form of a commonly used salt such as sodium salt, potassium salt and magnesium salt. Further, at this time, even if hydrogen ions are mixed as a counter ion of the sulfuric ester, it can be used.

The ratio of sulfate esterification is 20% of that of the sugar hydroxyl group.
It is ˜88%, any position other than the reducing terminal 1-position and the acylated hydroxyl group can be used as the position of sulfate esterification, and the higher the ratio of sulfate esterification is, the more preferable.

The proportion of acylation and sulfate esterification of the acylated product of the sulfated oligosaccharide glycoside of the present invention can be calculated as follows. For example, in the case of an oligosaccharide glycoside consisting of 5 galactoses, there are 16 hydroxyl groups that can be acylated. When 4 of these are acylated, 4/16 × 100 = 25 (%), and 25% is acylated, that is, the degree of acylation is 25%. Then, when it is subsequently sulphated and eight hydroxyl groups are sulphated, 8/16 × 100 = 50 (%) and the degree of sulphation becomes 50%.

Regarding the degree of sulfuric acid esterification and the degree of acylation of the oligosaccharide glycoside hydroxyl group, it is preferable that the degree of sulfuric acid esterification of the hydroxyl group is high for antiviral action, and the degree of acylation is required for enhancing the oral absorbability. It is preferable that the
It is possible to change the degree of sulfation and the degree of acylation depending on the usage conditions. For example, when the compound of the present invention is used by intravenous administration, the acylation degree may be lowered and the sulfation degree may be increased. When used by oral administration, the acylation degree may be increased, but from the viewpoint of antiviral activity, the sulfation degree is preferably 20% or more of the oligosaccharide glycoside hydroxyl groups.

That is, the degree of acylation is 12% of the glycoside hydroxyl groups.
It is preferably 80% or more, and more preferably 30% to 60%. The degree of sulfation is preferably about 88% to 20% of the glycoside hydroxyl group, more preferably about 70% to 40%.

The acylation degree and the sulfation degree of the sulfated oligosaccharide glycoside acylated product which can be produced in this manner are the values of the synthetic product by one reaction, and naturally show the average value of each molecule synthesized. It is a thing.

Next, a general method for producing the compound of the present invention will be omitted, but this method is not the only synthetic method. (1) Production of oligosaccharide glycosides In the presence of sodium acetate, oligosaccharides are acetylated with all the hydroxyl groups of the target sugar by a conventional method with acetic anhydride to obtain peracetate. Then a Lewis acid (eg, zinc chloride,
An acid catalyst such as boron trifluoride ether, tin tetrachloride, titanium tetrachloride, iron chloride, trimethylsilyl triflate, etc., and a protic acid (eg, sulfuric acid, paratoluene sulfonic acid, etc.) with respect to peracetate of 0.1 ~ 1,5 mol, in the presence of this acid catalyst, in an aprotic solvent such as methylene chloride, toluene, xylene, dimethoxyethane, the aglycone alcohol, phenols and the above peracetate from -30 ℃ The reaction is carried out at a temperature in the range of the boiling point of the solvent for 0.5 to 10 hours. After the reaction, the glycoside can be obtained by post-treatment by a conventional method and purification by a silica gel column chromatography method. Although the anomeric ratio of glycosides varies depending on the reaction conditions, β-form is mainly obtained. Depending on the production method and the selection of the catalyst or the operation of the purification step,
The anomer ratio of α and β can be adjusted. Of course, there is no problem in carrying out the following reaction even with α-form. The glycoside peracetylated product thus obtained can be deacetylated with sodium ethoxide in methanol at a reaction temperature of room temperature to 50 ° C to obtain the desired glycoside.

(2) Production of oligosaccharide glycoside acylated product The glycoside obtained in (1) is acylated by a conventional method.
For example, in the presence of amines, acylation (esterification) with an acyl halide at 0 ° C. to room temperature, or in the presence of a dehydrating agent,
It is carried out by dehydration esterification with a carboxylic acid. The acylating agent may be used in approximately the same amount as the equivalent amount of the hydroxyl group of the raw material according to the desired degree of acylation. The acylation degree of the obtained acylated product can be easily determined by analyzing the reaction product by nuclear magnetic resonance spectroscopy.

(3) Production of Sulfated Oligosaccharide Glycosyl Acylate The acylated product produced in (2) is subjected to sulfate esterification by a method usually used in the esterification of sugar hydroxyl groups. For example, the reaction is carried out in a polar aprotic solvent such as dimethylformamide, pyridine or dimethylsulfoxide using a sulfating agent suitable for the desired degree of sulfation. The sulfating agent used here is 1.0 to 3.0 equivalents, preferably 1.2 to 3.0 equivalents to the equivalents of the hydroxyl group of the raw material.
It is better to use 2.0 equivalents. As the sulfating agent, a sulfur trioxide amine complex or the like, for example, a sulfur trioxide pyridine complex or a sulfur trioxide triethylamine complex is used, and the temperature is in the range of room temperature to 90 ° C., preferably 40 to 90 ° C., and 1 to 24.
Sulfate esterification is carried out by stirring reaction in an inert gas for a time. After completion of the reaction, it can be taken out as a metal salt with a metal hydroxide, an ion exchange resin or the like. The obtained target product can be purified by an ion exchange membrane method, an ion exchange column method, a reverse osmosis method, an ultrafiltration method, a reprecipitation method or the like.

Typical examples of the sulfated oligosaccharide glycoside acylated product which is the compound of the present invention are shown below, but the compound of the present invention is not limited thereto. In the compounds, only the name of the acyl group is mentioned as the acyl group, but these mean compounds having an acylation degree of 12% to 80%. Sulfuric acid ester is simply described as sulfation, but the degree of sulfation is 20% to 88%.
% Means compound. Although the counter cation is omitted, physiologically acceptable salt forms are included. Regarding sugar chains, β (1 → 3) -linked oligosaccharides of glucose are conventionally referred to as laminari-oligosaccharides, and laminaripentaoside refers to laminari-oligosaccharides having pentasaccharide chains. Further, the α (1 → 4) -linked oligosaccharide of glucose is conventionally referred to as maltooligosaccharide, and maltopentaoside represents a maltooligosaccharide having a pentasaccharide chain. Α of glucose (1 → 6)
The linked oligosaccharide is called isomaltooligosaccharide, and isomaltopenoside represents an isomaltooligosaccharide having a pentasaccharide chain.

Sulfated dodecyl O-benzoyl-laminaripentaoside Sulfated dodecyl O-p-fluorobenzoyl-laminaripentaoside Sulfated dodecyl O-2,4-difluorobenzoyl-laminaripentaoside Sulfated dodecyl O-methylbenzoyl-laminaripentaoside sulfated dodecyl O-methylbenzoyl-laminaripentaoside sulfated dodecyl O-pentylbenzoyl-laminaripentaoside sulfated dodecyl O-octylbenzoyl-laminaripentaoside sulfate Dodecyl O-dodecyl benzoyl-laminaripentaoside

Sulfated butylphenyl O-benzoyl-laminaripentaoside Sulfated butylphenyl O-p-fluorobenzoyl-laminaripentaoside Sulfated butylphenyl O-2,4-difluorobenzoyl-laminaripentaoside Sulfated butylphenyl O-methylbenzoyl-laminaripentaoside Sulfated butylphenyl O-methylbenzoyl-laminaripentaoside Sulfated butylphenyl O-pentylbenzoyl-laminaripentaoside Sulfated butylphenyl O-octylbenzoyl -Laminaripentaoside Sulfated butylphenyl O-dodecylbenzoyl-Laminaripentaoside

Sulfated butylphenyl O-acetyl-
Laminaripentaoside Sulfated Butylphenyl O-Propionyl-Laminaripentaoside Sulfated Butylphenyl O-Butyryl-Laminaripentaoside Sulfated Butylphenyl O-Pentanoyl-Laminaripentaoside Sulfated Butylphenyl O- Hexanoyl-laminaripentaoside Sulfated butylphenyl O-octanoyl-laminaripentaoside Sulfated butylphenyl O-hexadecanoyl-laminaripentaoside Sulfated butylphenyl O-docosanoyl-laminaripentaoside

Sulfated heptylphenyl O-benzoyl-laminaripentaoside Sulfated heptylphenyl O-p-fluorobenzoyl-laminaripentaoside Sulfated heptylphenyl O-2,4-difluorobenzoyl-laminaripentaoside Sulfated heptylphenyl O-methylbenzoyl-laminaripentaoside Sulfated heptylphenyl O-methylbenzoyl-laminaripentaoside Sulfated heptylphenyl O-pentylbenzoyl-
Laminaripentaoside Sulfated heptylphenyl O-octylbenzoyl-
Laminaripentaoside Sulfated heptylphenyl O-dodecylbenzoyl-
Laminaripentaoside Sulfated heptylphenyl O-acetyl-laminaripentaoside

Sulfated heptylphenyl O-propionyl-laminaripentaoside Sulfated heptylphenyl O-butyryl-laminaripentaoside Sulfated heptylphenyl O-pentanoyl-laminaripentaoside Sulfated heptylphenyl O-hexanoyl- Laminaripentaoside Sulfated Heptylphenyl O-Octanoyl-Laminaripentaoside Sulfated Heptylphenyl O-Hexadecanoyl-Laminaripentaoside Sulfated Heptylphenyl O-Docosanoyl-Laminaripentaoside

Sulfated octylphenyl O-benzoyl-laminaripentaoside Sulfated octylphenyl O-p-fluorobenzoyl-laminaripentaside Sulfated octylphenyl O-2,4-difluorobenzoyl-laminaripentaside Sulfated octylphenyl O-methylbenzoyl-laminaripentaside Sulfated octylphenyl O-methylbenzoyl-laminaripentaside Sulfated octylphenyl O-pentylbenzoyl-
Laminaripentaoside Sulfated octylphenyl O-octylbenzoyl-
Laminaripentaoside Sulfated octylphenyl O-dodecylbenzoyl-
Laminari pentaoside

Sulfated octylphenyl O-acetyl-laminaripentaoside Sulfated octylphenyl O-propionyl-laminaripentaside Sulfated octylphenyl O-butyryl-laminaripentaside Sulfated octylphenyl O-pentanoyl- Laminaripentaoside Sulfated Octylphenyl O-Hexanoyl-Laminaripentaoside Sulfated Octylphenyl O-Octanoyl-Laminaripentaoside Sulfated Octylphenyl O-Hexadecanoyl-Laminaripentaoside Sulfated Octylphenyl O-docosanoyl-laminaripentaoside

Sulfated methoxyphenyl O-benzoyl-laminaripentaoside Sulfated methoxyphenyl O-p-fluorobenzoyl-laminaripentaoside Sulfated methoxyphenyl O-2,4-difluorobenzoyl-laminaripentaoside Sulfated methoxyphenyl O-methylbenzoyl-laminaripentaoside Sulfated methoxyphenyl O-methylbenzoyl-laminaripentaoside Sulfated methoxyphenyl O-pentylbenzoyl-
Laminaripentaoside Sulfated methoxyphenyl O-octylbenzoyl-
Laminaripentaoside Sulfated methoxyphenyl O-dodecylbenzoyl-
Laminari pentaoside

Sulfated methoxyphenyl O-acetyl-laminaripentaoside Sulfated methoxyphenyl O-propionyl-laminaripentaoside Sulfated methoxyphenyl O-butyryl-laminaripentaoside Sulfated methoxyphenyl O-pentanoyl- Laminaripentaoside Sulfated methoxyphenyl O-hexanoyl-laminaripentaoside Sulfated methoxyphenyl O-octanoyl-laminaripentaoside Sulfated methoxyphenyl O-hexadecanoyl-laminaripentaoside Sulfated methoxyphenyl O-docosanoyl-laminaripentaoside

Sulfated butoxyphenyl O-benzoyl-laminaripentaoside Sulfated butoxyphenyl O-p-fluorobenzoyl-laminaripentaoside Sulfated butoxyphenyl O-2,4-difluorobenzoyl-laminaripentaoside Sulfated butoxyphenyl O-methylbenzoyl-laminaripentaoside Sulfated butoxyphenyl O-methylbenzoyl-laminaripentaoside Sulfated butoxyphenyl O-pentylbenzoyl-
Laminaripentaoside Sulfated butoxyphenyl O-octylbenzoyl-
Laminaripentaoside Sulfated butoxyphenyl O-dodecylbenzoyl-
Laminari pentaoside

Sulfated Butoxyphenyl O-Acetyl-Laminaripentaoside Sulfated Butoxyphenyl O-Propionyl-Laminaripentaoside Sulfated Butoxyphenyl O-Butyryl-Laminaripentaoside Sulfated Butoxyphenyl O-Pentanoyl- Laminaripentaoside Sulfated Butoxyphenyl O-Hexanoyl-Laminaripentaoside Sulfated Butoxyphenyl O-Octanoyl-Laminaripentaoside Sulfated Butoxyphenyl O-Hexadecanoyl-Laminaripentaoside Sulfated Butoxyphenyl O-docosanoyl-laminaripentaoside

Sulfated octyloxyphenyl O-benzoyl-laminaripentaoside Sulfated octyloxyphenyl O-p-fluorobenzoyl-laminaripentaside Sulfated octyloxyphenyl O-2,4-difluorobenzoyl-laminari Pentaoside Sulfated Octyloxyphenyl O-Methylbenzoyl-Laminaripentaoside Sulfated Octyloxyphenyl O-Methylbenzoyl-Laminaripentaoside Sulfated Octyloxyphenyl O-Pentylbenzoyl-Laminaripentaoside Sulfated Octyloxyphenyl O-octylbenzoyl-laminaripentaoside Sulfated octyloxyphenyl O-dodecylbenzoyl-laminaripentaside

Sulfated octyloxyphenyl O-acetyl-laminaripentaoside Sulfated octyloxyphenyl O-propionyl-
Laminaripentaoside Sulfated octyloxyphenyl O-butyryl-Laminaripentaoside Sulfated octyloxyphenyl O-pentanoyl-
Laminaripentaoside Sulfated octyloxyphenyl O-hexanoyl-
Laminari pentaoside Sulfated octyloxyphenyl O-octanoyl-
Laminaripentaside Sulfated Octyloxyphenyl O-Hexadecanoyl-Laminaripentaoside Sulfated Octyloxyphenyl O-Docosanoyl-
Laminari pentaoside

Sulfated dodecyl O-benzoyl-maltopentaoside Sulfated dodecyl O-p-fluorobenzoyl-maltopentaoside Sulfated dodecyl O-2,4-difluorobenzoyl-maltopentaoside Sulfated dodecyl O-methyl Benzoyl-maltopentaoside sulfated dodecyl O-methylbenzoyl-maltopentaoside sulfated dodecyl O-pentylbenzoyl-maltopentaoside sulfated dodecyl O-octylbenzoyl-maltopentaoside sulfated dodecyl O-dodecylbenzoyl- Maltopentaoside

Sulfated butylphenyl O-benzoyl-maltopentaoside Sulfated butylphenyl O-p-fluorobenzoyl-maltopentaoside Sulfated butylphenyl O-2,4-difluorobenzoyl-maltopentaoside Sulfated butyl Phenyl O-methylbenzoyl-maltopentaoside sulfated butylphenyl O-methylbenzoyl-maltopentaoside sulfated butylphenyl O-pentylbenzoyl-maltopentaoside sulfated butylphenyl O-octylbenzoyl-maltopentaoside sulfate Butylphenyl O-dodecylbenzoyl-maltopentaoside

Sulfated butylphenyl O-acetyl-
Maltopentaoside Sulfated butylphenyl O-propionyl-maltopentaoside Sulfated butylphenyl O-butyryl-maltopentaoside Sulfated butylphenyl O-pentanoyl-maltopentaoside Sulfated butylphenyl O-hexanoyl-maltopentaoside Osid sulfated butylphenyl O-octanoyl-maltopentaoside Sulfated butylphenyl O-hexadecanoyl-maltopentaoside Sulfated butylphenyl O-docosanoyl-maltopentaoside

Sulfated heptylphenyl O-benzoyl-maltopentaoside Sulfated heptylphenyl O-p-fluorobenzoyl-maltopentaoside Sulfated heptylphenyl O-2,4-difluorobenzoyl-maltopentaoside Sulfated heptyl Phenyl O-methylbenzoyl-maltopentaoside sulfated heptylphenyl O-methylbenzoyl-maltopentaoside sulfated heptylphenyl O-pentylbenzoyl-
Maltopentaoside Sulfated heptylphenyl O-octylbenzoyl-
Maltopentaoside Sulfated heptylphenyl O-dodecylbenzoyl-
Maltopentaoside

Sulfated heptylphenyl O-acetyl-maltopentaoside Sulfated heptylphenyl O-propionyl-maltopentaoside Sulfated heptylphenyl O-butyryl-maltopentaoside Sulfated heptylphenyl O-pentanoyl-maltopentaoside Sid sulfated heptylphenyl O-hexanoyl-maltopentaoside Sulfated heptylphenyl O-octanoyl-maltopentaoside Sulfated heptylphenyl O-hexadecanoyl-maltopentaoside Sulfated heptylphenyl O-docosanoyl-maltopentaoside Sid

Sulfated octylphenyl O-benzoyl-maltopentaoside Sulfated octylphenyl O-p-fluorobenzoyl-maltopentaoside Sulfated octylphenyl O-2,4-difluorobenzoyl-maltopentaoside Sulfated octyl Phenyl O-methylbenzoyl-maltopentaoside sulfated octylphenyl O-methylbenzoyl-maltopentaoside sulfated octylphenyl O-pentylbenzoyl-
Maltopentaoside Sulfated octylphenyl O-octylbenzoyl-
Maltopentaside Sulfated octylphenyl O-dodecylbenzoyl-
Maltopentaoside

Sulfated octylphenyl O-acetyl-maltopentaoside Sulfated octylphenyl O-propionyl-maltopentaoside Sulfated octylphenyl O-butyryl-maltopentaoside Sulfated octylphenyl O-pentanoyl-maltopentaoside Sid sulfated octylphenyl O-hexanoyl-maltopentaoside Sulfated octylphenyl O-octanoyl-maltopentaoside Sulfated octylphenyl O-hexadecanoyl-maltopentaoside Sulfated octylphenyl O-docosanoyl-maltopentaoside Sid

Sulfated methoxyphenyl O-benzoyl-maltopentaoside Sulfated methoxyphenyl O-p-fluorobenzoyl-maltopentaoside Sulfated methoxyphenyl O-2,4-difluorobenzoyl-maltopentaoside Sulfated methoxy Phenyl O-methylbenzoyl-maltopentaoside sulfated methoxyphenyl O-methylbenzoyl-maltopentaoside sulfated methoxyphenyl O-pentylbenzoyl-
Maltopentaoside Sulfated methoxyphenyl O-octylbenzoyl-
Maltopentaoside Sulfated methoxyphenyl O-dodecylbenzoyl-
Maltopentaoside

Sulfated methoxyphenyl O-acetyl-maltopentaoside Sulfated methoxyphenyl O-propionyl-maltopentaoside Sulfated methoxyphenyl O-butyryl-maltopentaoside Sulfated methoxyphenyl O-pentanoyl-maltopentaoside Sid sulfated methoxyphenyl O-hexanoyl-maltopentaoside Sulfated methoxyphenyl O-octanoyl-maltopentaoside Sulfated methoxyphenyl O-hexadecanoyl-maltopentaoside Sulfated methoxyphenyl O-docosanoyl-maltopentaoside Sid

Sulfated butoxyphenyl O-benzoyl-maltopentaoside Sulfated butoxyphenyl O-p-fluorobenzoyl-maltopentaoside Sulfated butoxyphenyl O-2,4-difluorobenzoyl-maltopentaoside Sulfated butoxy Phenyl O-methylbenzoyl-maltopentaoside sulfated butoxyphenyl O-methylbenzoyl-maltopentaoside sulfated butoxyphenyl O-pentylbenzoyl-
Maltopentaoside Sulfated butoxyphenyl O-octylbenzoyl-
Maltopentaoside Sulfated butoxyphenyl O-dodecylbenzoyl-
Maltopentaoside

Sulfated butoxyphenyl O-acetyl-maltopentaoside Sulfated butoxyphenyl O-propionyl-maltopentaoside Sulfated butoxyphenyl O-butyryl-maltopentaoside Sulfated butoxyphenyl O-pentanoyl-maltopentaoside Sid sulfated butoxyphenyl O-hexanoyl-maltopentaoside Sulfated butoxyphenyl O-octanoyl-maltopentaoside Sulfated butoxyphenyl O-hexadecanoyl-maltopentaoside Sulfated butoxyphenyl O-docosanoyl-maltopentaoside Sid

Sulfated octyloxyphenyl O-benzoyl-maltopentaoside Sulfated octyloxyphenyl O-p-fluorobenzoyl-maltopentaoside Sulfated octyloxyphenyl O-2,4-difluorobenzoyl-maltopentaoside Sulfated octyloxyphenyl O-methylbenzoyl-maltopentaoside Sulfated octyloxyphenyl O-methylbenzoyl-maltopentaoside Sulfated octyloxyphenyl O-pentylbenzoyl-maltopentaoside Sulfated octyloxyphenyl O-octyl Benzoyl-maltopentaoside Sulfated octyloxyphenyl O-dodecylbenzoyl-maltopentaoside

Sulfated octyloxyphenyl O-acetyl-maltopentaoside Sulfated octyloxyphenyl O-propionyl-
Maltopentaoside Sulfated octyloxyphenyl O-butyryl-maltopentaoside Sulfated octyloxyphenyl O-pentanoyl-
Maltopentaoside Sulfated octyloxyphenyl O-hexanoyl-
Maltopentaoside Sulfated octyloxyphenyl O-octanoyl-
Maltopentaoside Sulfated octyloxyphenyl O-hexadecanoyl-maltopentaoside Sulfated octyloxyphenyl O-docosanoyl-
Maltopentaoside

Sulfated dodecyl O-benzoyl-isomaltopentaoside Sulfated dodecyl O-p-fluorobenzoyl-isomaltopentaoside Sulfated dodecyl O-2,4-difluorobenzoyl-isomaltopentaoside Sulfated dodecyl O-methylbenzoyl-isomaltopentaoside sulfated dodecyl O-methylbenzoyl-isomaltopentaoside sulfated dodecyl O-pentylbenzoyl-isomaltopentaoside sulfated dodecyl O-octylbenzoyl-isomaltopentaoside sulfate Dodecyl O-dodecyl benzoyl-isomaltopentaoside

Sulfated butylphenyl O-benzoyl-isomaltopentaoside Sulfated butylphenyl O-p-fluorobenzoyl-isomaltopentaoside Sulfated butylphenyl O-2,4-difluorobenzoyl-isomaltopentaoside Sulfated butylphenyl O-methylbenzoyl-isomaltopentaoside Sulfated butylphenyl O-methylbenzoyl-isomaltopentaoside Sulfated butylphenyl O-pentylbenzoyl-isomaltopentaoside Sulfated butylphenyl O-octylbenzoyl -Isomaltopentaoside sulfated butylphenyl O-dodecylbenzoyl-isomaltopentaoside

Sulfated butylphenyl O-acetyl-
Isomaltopentaoside sulfated butylphenyl O-propionyl-isomaltopentaoside sulfated butylphenyl O-butyryl-isomaltopentaoside sulfated butylphenyl O-pentanoyl-isomaltopentaoside sulfated butylphenyl O- Hexanoyl-isomaltopentaoside Sulfated butylphenyl O-octanoyl-isomaltopentaoside Sulfated butylphenyl O-hexadecanoyl-isomaltopentaoside Sulfated butylphenyl O-docosanoyl-isomaltopentaoside

Sulfated heptylphenyl O-benzoyl-isomaltopentaoside Sulfated heptylphenyl O-p-fluorobenzoyl-isomaltopentaoside Sulfated heptylphenyl O-2,4-difluorobenzoyl-isomaltopentaoside Sulfated heptylphenyl O-methylbenzoyl-isomaltopentaoside Sulfated heptylphenyl O-methylbenzoyl-isomaltopentaoside Sulfated heptylphenyl O-pentylbenzoyl-
Isomaltopentaoside Sulfated heptylphenyl O-octylbenzoyl-
Isomaltopentaoside Sulfated heptylphenyl O-dodecylbenzoyl-
Isomaltopentaoside

Sulfated heptylphenyl O-acetyl-isomaltopentaoside Sulfated heptylphenyl O-propionyl-isomaltopentaoside Sulfated heptylphenyl O-butyryl-isomaltopentaoside Sulfated heptylphenyl O-pentanoyl- Isomaltopentaoside Sulfated heptylphenyl O-hexanoyl-isomaltopentaoside Sulfated heptylphenyl O-octanoyl-isomaltopentaoside Sulfated heptylphenyl O-hexadecanoyl-isomaltopentaoside Sulfated heptylphenyl O-docosanoyl-isomaltopentaoside

Sulfated octylphenyl O-benzoyl-isomaltopentaoside Sulfated octylphenyl O-p-fluorobenzoyl-isomaltopentaoside Sulfated octylphenyl O-2,4-difluorobenzoyl-isomaltopentaoside Sulfated octylphenyl O-methylbenzoyl-isomaltopentaoside Sulfated octylphenyl O-methylbenzoyl-isomaltopentaoside Sulfated octylphenyl O-pentylbenzoyl-
Isomaltopentaoside Sulfated octylphenyl O-octylbenzoyl-
Isomaltopentaoside Sulfated octylphenyl O-dodecylbenzoyl-
Isomaltopentaoside

Sulfated octylphenyl O-acetyl-isomaltopentaoside Sulfated octylphenyl O-propionyl-isomaltopentaoside Sulfated octylphenyl O-butyryl-isomaltopentaoside Sulfated octylphenyl O-pentanoyl- Isomaltopentaoside Sulfated octylphenyl O-hexanoyl-isomaltopentaoside Sulfated octylphenyl O-octanoyl-isomaltopentaoside Sulfated octylphenyl O-hexadecanoyl-isomaltopentaoside Sulfated octylphenyl O-docosanoyl-isomaltopentaoside

Sulfated methoxyphenyl O-benzoyl-isomaltopentaoside Sulfated methoxyphenyl O-p-fluorobenzoyl-isomaltopentaoside Sulfated methoxyphenyl O-2,4-difluorobenzoyl-isomaltopentaoside Sulfated methoxyphenyl O-methylbenzoyl-isomaltopentaoside Sulfated methoxyphenyl O-methylbenzoyl-isomaltopentaoside Sulfated methoxyphenyl O-pentylbenzoyl-
Isomaltopentaoside Sulfated methoxyphenyl O-octylbenzoyl-
Isomaltopentaoside Sulfated methoxyphenyl O-dodecylbenzoyl-
Isomaltopentaoside

Sulfated methoxyphenyl O-acetyl-isomaltopentaoside Sulfated methoxyphenyl O-propionyl-isomaltopentaoside Sulfated methoxyphenyl O-butyryl-isomaltopentaoside Sulfated methoxyphenyl O-pentanoyl- Isomaltopentaoside Sulfated methoxyphenyl O-hexanoyl-isomaltopentaoside Sulfated methoxyphenyl O-octanoyl-isomaltopentaoside Sulfated methoxyphenyl O-hexadecanoyl-isomaltopentaoside Sulfated methoxyphenyl O-docosanoyl-isomaltopentaoside

Sulfated butoxyphenyl O-benzoyl-isomaltopentaoside Sulfated butoxyphenyl O-p-fluorobenzoyl-isomaltopentaoside Sulfated butoxyphenyl O-2,4-difluorobenzoyl-isomaltopentaoside Sulfated butoxyphenyl O-methylbenzoyl-isomaltopentaoside Sulfated butoxyphenyl O-methylbenzoyl-isomaltopentaoside Sulfated butoxyphenyl O-pentylbenzoyl-
Isomaltopentaoside Sulfated butoxyphenyl O-octylbenzoyl-
Isomaltopentaoside Sulfated butoxyphenyl O-dodecylbenzoyl-
Isomaltopentaoside

Sulfated butoxyphenyl O-acetyl-isomaltopentaoside Sulfated butoxyphenyl O-propionyl-isomaltopentaoside Sulfated butoxyphenyl O-butyryl-isomaltopentaoside Sulfated butoxyphenyl O-pentanoyl- Isomaltopentaoside Sulfated butoxyphenyl O-hexanoyl-isomaltopentaoside Sulfated butoxyphenyl O-octanoyl-isomaltopentaoside Sulfated butoxyphenyl O-hexadecanoyl-isomaltopentaoside Sulfated butoxyphenyl O-docosanoyl-isomaltopentaoside

Sulfated octyloxyphenyl O-benzoyl-isomaltopentaoside Sulfated octyloxyphenyl O-p-fluorobenzoyl-isomaltopentaoside Sulfated octyloxyphenyl O-2,4-difluorobenzoyl-isomalto Pentaoside Sulfated Octyloxyphenyl O-methylbenzoyl-isomaltopentaoside Sulfated Octyloxyphenyl O-methylbenzoyl-isomaltopentaoside Sulfated Octyloxyphenyl O-pentylbenzoyl-isomaltopentaoside Sulfated Octyloxyphenyl O-octylbenzoyl-isomaltopentaoside Sulfated octyloxyphenyl O-dodecylbenzoyl-isomaltopentaoside

Sulfated octyloxyphenyl O-acetyl-isomaltopentaoside Sulfated octyloxyphenyl O-propionyl-
Isomaltopentaoside sulfated octyloxyphenyl O-butyryl-isomaltopentaoside sulfated octyloxyphenyl O-pentanoyl-
Isomaltopentaoside Sulfated octyloxyphenyl O-hexanoyl-
Isomaltopentaoside Sulfated octyloxyphenyl O-octanoyl-
Isomaltopentaoside sulfated octyloxyphenyl O-hexadecanoyl-isomaltopentaoside sulfated octyloxyphenyl O-docosanoyl-
Isomaltopentaoside

Sulfated dodecyl O-benzoyl-β-D
-Galactopyranosyl (1 → 4) -β-D-galactopyranosyl
(1 → 4) -β-D-Glucopyranoside Sulfated dodecyl Op-fluorobenzoyl-β-D
-Galactopyranosyl (1 → 4) -β-D-galactopyranosyl
(1 → 4) -β-D-Glucopyranoside Sulfated dodecyl O-2,4-difluorobenzoyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-Glucopyranoside Sulfated dodecyl O-methylbenzoyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4)
-β-D-Glucopyranoside Sulfated dodecyl O-pentylbenzoyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 →
4) -β-D-Glucopyranoside Sulfated dodecyl O-octylbenzoyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 →
4) -β-D-Glucopyranoside Sulfated dodecyl O-dodecylbenzoyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 →
4) -β-D-glucopyranoside

Sulfated butylphenyl O-benzoyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated butylphenyl O- p-Fluorobenzoyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated butylphenyl O-2,4-difluorobenzoyl -Β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated butylphenyl O-methylbenzoyl-β-D
-Galactopyranosyl (1 → 4) -β-D-galactopyranosyl
(1 → 4) -β-D-Glucopyranoside Sulfated butylphenyl O-pentylbenzoyl-β
-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated butylphenyl O-octylbenzoyl-β
-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside sulfated butylphenyl O-dodecylbenzoyl-β
-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside

Sulfated butylphenyl O-acetyl-
β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated butylphenyl O-propionyl-β-D-galactopyranosyl ( 1 → 4) -β-D-galactopyranosyl (1 →
4) -β-D-Glucopyranoside Sulfated butylphenyl O-butyryl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4)-
β-D-glucopyranoside Sulfated butylphenyl O-pentanoyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 →
4) -β-D-Glucopyranoside Sulfated butylphenyl O-hexanoyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 →
4) -β-D-Glucopyranoside Sulfated butylphenyl O-octanoyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 →
4) -β-D-Glucopyranoside Sulfated butylphenyl O-hexadecanoyl-β-D
-Galactopyranosyl (1 → 4) -β-D-galactopyranosyl
(1 → 4) -β-D-Glucopyranoside Sulfated butylphenyl O-docosanoyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 →
4) -β-D-glucopyranoside

Sulfated heptylphenyl O-benzoyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated heptylphenyl O- p-Fluorobenzoyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated heptylphenyl O-2,4-difluorobenzoyl -Β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated heptylphenyl O-methylbenzoyl-β
-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated heptylphenyl O-pentylbenzoyl-
β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated heptylphenyl O-octylbenzoyl-
β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated heptylphenyl O-dodecylbenzoyl-
β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside

Sulfated heptylphenyl O-acetyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated heptylphenyl O- Propionyl-β-D-
Galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1
→ 4) -β-D-Glucopyranoside Sulfated heptylphenyl O-butyryl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4)
-β-D-Glucopyranoside Sulfated heptylphenyl O-pentanoyl-β-D-
Galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1
→ 4) -β-D-Glucopyranoside Sulfated heptylphenyl O-hexanoyl-β-D-
Galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1
→ 4) -β-D-Glucopyranoside Sulfated heptylphenyl O-octanoyl-β-D-
Galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1
→ 4) -β-D-Glucopyranoside Sulfated heptylphenyl O-hexadecanoyl-β
-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated heptylphenyl O-docosanoyl-β-D-
Galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1
→ 4) -β-D-glucopyranoside

Sulfated octylphenyl O-benzoyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated octylphenyl O- p-Fluorobenzoyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated octylphenyl O-2,4-difluorobenzoyl -Β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated octylphenyl O-methylbenzoyl-β
-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated octylphenyl O-pentylbenzoyl-
β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated octylphenyl O-octylbenzoyl-
β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated octylphenyl O-dodecylbenzoyl-
β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside

Sulfated octylphenyl O-acetyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated octylphenyl O- Propionyl-β-D-
Galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1
→ 4) -β-D-Glucopyranoside Sulfated octylphenyl O-butyryl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4)
-β-D-Glucopyranoside Sulfated octylphenyl O-pentanoyl-β-D-
Galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1
→ 4) -β-D-Glucopyranoside Sulfated octylphenyl O-hexanoyl-β-D-
Galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1
→ 4) -β-D-Glucopyranoside Sulfated octylphenyl O-octanoyl-β-D-
Galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1
→ 4) -β-D-Glucopyranoside Sulfated octylphenyl O-hexadecanoyl-β
-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated octylphenyl O-docosanoyl-β-D-
Galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1
→ 4) -β-D-glucopyranoside

Sulfated methoxyphenyl O-benzoyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated methoxyphenyl O- p-Fluorobenzoyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated methoxyphenyl O-2,4-difluorobenzoyl -Β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated methoxyphenyl O-methylbenzoyl-β
-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated methoxyphenyl O-pentylbenzoyl-
β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated methoxyphenyl O-octylbenzoyl-
β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated methoxyphenyl O-dodecylbenzoyl-
β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside

Sulfated methoxyphenyl O-acetyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated methoxyphenyl O- Propionyl-β-D-
Galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1
→ 4) -β-D-Glucopyranoside Sulfated methoxyphenyl O-butyryl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4)
-β-D-Glucopyranoside Sulfated methoxyphenyl O-pentanoyl-β-D-
Galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1
→ 4) -β-D-Glucopyranoside Sulfated methoxyphenyl O-hexanoyl-β-D-
Galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1
→ 4) -β-D-Glucopyranoside Sulfated methoxyphenyl O-octanoyl-β-D-
Galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1
→ 4) -β-D-Glucopyranoside Sulfated methoxyphenyl O-hexadecanoyl-β
-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated methoxyphenyl O-docosanoyl-β-D-
Galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1
→ 4) -β-D-glucopyranoside

Sulfated butoxyphenyl O-benzoyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated butoxyphenyl O- p-Fluorobenzoyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated butoxyphenyl O-2,4-difluorobenzoyl -Β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated butoxyphenyl O-methylbenzoyl-β
-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated butoxyphenyl O-pentylbenzoyl-
β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated butoxyphenyl O-octylbenzoyl-
β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated butoxyphenyl O-dodecylbenzoyl-
β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside

Sulfated butoxyphenyl O-acetyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated butoxyphenyl O- Propionyl-β-D-
Galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1
→ 4) -β-D-Glucopyranoside Sulfated butoxyphenyl O-butyryl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4)
-β-D-Glucopyranoside Sulfated butoxyphenyl O-pentanoyl-β-D-
Galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1
→ 4) -β-D-glucopyranoside Sulfated butoxyphenyl O-hexanoyl-β-D-
Galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1
→ 4) -β-D-Glucopyranoside Sulfated butoxyphenyl O-octanoyl-β-D-
Galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1
→ 4) -β-D-Glucopyranoside Sulfated butoxyphenyl O-hexadecanoyl-β
-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated butoxyphenyl O-docosanoyl-β-D-
Galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1
→ 4) -β-D-glucopyranoside

Sulfated octyloxyphenyl O-benzoyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated octyloxyphenyl O-p-fluorobenzoyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated octyloxyphenyl O-2,4 -Difluorobenzoyl-β-D-galactopyranosyl (1 → 4) -β-D
-Galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated octyloxyphenyl O-methylbenzoyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-Glucopyranoside Sulfated octyloxyphenyl O-pentylbenzoyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D -Glucopyranoside sulfated octyloxyphenyl O-octylbenzoyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside sulfated octyloxyphenyl O-dodecylbenzoyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside

Sulfated octyloxyphenyl O-acetyl-β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated octyloxyphenyl O-propionyl-
β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated octyloxyphenyl O-butyryl-β-D
-Galactopyranosyl (1 → 4) -β-D-galactopyranosyl
(1 → 4) -β-D-Glucopyranoside Sulfated octyloxyphenyl O-pentanoyl-
β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated octyloxyphenyl O-hexanoyl-
β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated octyloxyphenyl O-octanoyl-
β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated octyloxyphenyl O-hexadecanoyl-β-D-galactopyra Nosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside Sulfated octyloxyphenyl O-docosanoyl-
β-D-galactopyranosyl (1 → 4) -β-D-galactopyranosyl (1 → 4) -β-D-glucopyranoside

The antiviral agent according to the present invention exhibits antiviral activity against various viruses, and is useful for treating diseases caused by the virus as a pathogenic virus or complex infections thereof. The antiviral agent according to the present invention includes, for example, influenza viruses such as influenza A virus,
It exhibits antiviral activity against herpesviruses such as HSV-1 and retroviruses such as HIV, and particularly has excellent antiviral activity against HIV.

Although the mechanism of action of the antiviral agent according to the present invention has not been clarified yet, it is presumed that it has an inhibitory effect on the adsorption to the virus target cells like the conventionally known sulfated polysaccharides. In addition, the glycoside structure makes the antiviral long-lasting effect much better than that of the non-glycoside structure, and the introduction of an acyl group improves the oral absorbability of sulfated polysaccharides and sulfated oligosaccharides. It is a feature of the compound of the present invention that it is a compound that is remarkably superior to glycosides and the like.

The compounds of the present invention are effective in controlling diseases caused by viruses, and in particular HI
It is a compound having an excellent antiviral activity against V and is useful as an antiviral agent. Therefore, it is useful for suppressing, preventing, and treating diseases caused by these viruses, and can be administered by various methods such as intravenous administration, oral administration, intramuscular administration, intraperitoneal administration, and rectal administration. .

The antiviral agent according to the present invention is a conventional formulation,
For example, the form of the preparation varies depending on the method of administration, but it is usually formulated into tablets, capsules, granules, microspheres, pills, solutions, injections, syrups, suppositories, etc., It can be administered orally and parenterally. In order to produce a preparation, the present compound as an active ingredient is preferably contained in an amount of 0.1 to 100%. As a means for this purpose, conventional excipients and additives used for producing pharmaceuticals can be used. Examples of conventional excipients include distilled water, physiological saline, alcohol, polyethylene glycol, glycerol ester, gelatin, carbohydrate magnesium stearate, talc and the like. In addition, conventional additives include preservatives, sterilizers, lubricants, coating agents, wetting agents, emulsifiers, colorants, masking flavors, and fragrances.

The dose of the antiviral agent according to the present invention varies depending on the dosage form of the agent, the number of administrations, the condition of the patient, the weight of the patient, and the severity of the disease.
It is preferable to administer 0.1 mg to 500 mg, more preferably 0.5 mg to 100 mg, 1 to 3 times a day. The frequency of administration is also determined by the form of the drug, the condition of the patient, the body weight, and the severity of the disease. It can also be administered by intravenous infusion.

Furthermore, this compound has a low toxicity in vivo and is a safe compound without dying even when administered to mice at 1 g / kg. In addition, the compound of the present invention has a smaller anticoagulant activity than dextran sulfate, which is one of sulfated polysaccharides, and the antiviral effect of the compound in blood is not found in conventional sulfated polysaccharides, It was confirmed that the compound of the present invention has extremely high efficacy, because a long-lasting effect was observed, and particularly in the case of oral administration as well.

In addition, the results of the acute toxicity test of the antiviral agent of the present invention in mice by single oral administration showed that all the compounds described in the Examples described later survived at the dose of 1.0 g / kg. Was there. Thus, the LD ₅₀ (50% lethal dose) for oral administration of the compounds according to the invention is
Both are 1 g / Kg or more. The LD ₅₀ of the representative compound 6 of the present invention administered intravenously to mice was 300 mg / Kg or more, and as a result, it was revealed that the antiviral agent according to the present invention is a compound with extremely low toxicity.

[0091]

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited thereto. (Reference Synthesis Example 1) Synthesis of dodecyl β-D-laminaripentaoside In a flask, 0.55 g of sodium acetate and 10 ml were added.
Of acetic anhydride was heated, and 1.003 g of laminaripentaose was added thereto little by little. And under reflux 2
Reacted for hours. The reaction product was poured into 100 g of ice,
Then, it was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and concentrated to obtain a syrupy peracetyllaminaripentaose (yield 90% or more). The α / β ratio of the product is approximately 25/75 from nuclear magnetic resonance resonance spectroscopy. Specific rotation: [α] _D = -43.5 ° (c = 1.0 / chloroform) (25 ° C) Next, this peracetetyl laminaripentaose 500
mg and n-dodecanol 60 mg were dissolved in 20 ml of methylene chloride in a 50 ml three-necked flask, 1 mmol of tin tetrachloride was added under nitrogen flow, and the mixture was reacted at room temperature for 20 hours. The reaction mixture was poured into a sodium bicarbonate aqueous solution, filtered through a Celite-coated funnel, and extracted with methylene chloride. The methylene chloride layer was dried with sodium sulfate and concentrated. The residue after concentration was purified by a column chromatography method (silica gel: ethyl acetate / hexane), and main components having a thin layer chromatography Rf value of 0.72 were collected and concentrated. The product was n-dodecyl peracetyl-β-D-laminaripentaoside (yield 0.265 g; 49% yield), determined by nuclear magnetic resonance resonance spectroscopy. Specific rotation: [α] _D = −42.8 ° (c = 1.0 / chloroform) (28 ° C.) Next, 238 mg of the peracetate glycoside synthesized above was dissolved in 10 ml of methanol, , 0.1 N sodium methoxide methanol solution (4.3 ml) was added, and the mixture was stirred at room temperature for 2.5 hours. Then, it was treated with an ion exchange resin to remove sodium ions. After removing the ion exchange resin by filtration, the methanol solution was concentrated,
138 mg of the desired product was obtained. Specific rotation: [α] _D = -16.4 ° (c = 0.50 / methanol) (30 ° C)

Example 1 Sulfated n-dodecyl O
Synthesis of -benzoyl-β-D-laminaripentaoside:
(Compound 1) n-dodecyl synthesized in the same manner as in Reference Synthesis Example 1
600 mg of β-D-laminaripentaoside was dissolved in 30 ml of dry pyridine, and 460 ml of benzoyl chloride was added dropwise under a nitrogen stream while keeping the temperature at 0 to 3 ° C.
After the dropping, the temperature was kept at the same temperature for 20 minutes, and then the reaction was performed at room temperature for 19.5 hours. The mixture was then poured into 150 g of ice water and this was extracted 3 times with 100 ml of ethyl acetate. The extract was washed several times with water, dried over Glauber's salt, and concentrated to 840 m.
g of n-dodecyl O-benzoyl-β-D-laminaripentaoside was obtained. The results of the proton nuclear magnetic resonance resonance spectrum (ppm) (CDCl ₃ , TMS) are as follows: 0.85 (3H), 1.15 to 1.33 (18)
H), 1.40-1.55 (2H), 3.1-3.9.
(32H), 4.1-5.7 (including hydroxyl protons and anomeric protons), 7.45-7.55 (1
1.2H), 7.6 (5.6H), 7.9-8.1 (1
1.2H) As a result, 37% of the glycoside is acylated by the benzoyl group.

Next, 10% of 406 mg of this benzoyl compound was added.
It was added to ml of dry pyridine and concentrated once under reduced pressure. To this residue was added 10 ml of dry pyridine, and the mixture was heated to 85 ° C. under an argon stream, and sulfur trioxide pyridine complex 480 was added thereto.
mg was added, and the mixture was reacted at the same temperature for 2 hours. After cooling to room temperature, the precipitated oily substance was separated, 15 ml of water was added and dissolved in this oily substance, and the hydrogen ion concentration was adjusted to 7.2 with an aqueous barium hydroxide solution. The precipitate generated there was removed by centrifugation, and this precipitate was washed with water. The supernatant after centrifugation and the washed solution were combined, passed through a sodium type ion exchange resin column, and the effluent was concentrated to 5 ml.
Then, it was poured into 200 ml of acetone, and the resulting precipitate was collected by centrifugation. This precipitate was dissolved in 20 ml of water, adjusted to a hydrogen ion concentration of 7.11 with a 0.2 N hydrochloric acid aqueous solution, then frozen and dried, and 440
Obtained mg of the desired compound.

Target specific optical rotation: [α] _D = -19.9 °
(C = 0.4 / H2O) (27 ° C) Infrared absorption spectrum wave number (cm ^-1 ) 3430, 3050, 2930, 2850, 1720,
1630, 1450, 1240, 1120, 800, 7
20 proton nuclear magnetic resonance resonance spectrum (PMR) spectrum (D2O) (ppm) 0.84
Alkylmethyl (3H) 1.1-1.8 Alkylmethylene (1
8H) 1.45-1.55 (2H) 3.4-5.5 7.35-7.70 (16.8H) 7.85-8.1 (11.2H) Percentage of acylation of this compound (Degree of acylation) was 35% from PMR data. The rate of sulfation of this compound (degree of sulfation) was calculated to be 51% by elemental analysis.

Example 2 Sulfated n-dodecyl O
Synthesis of -benzoyl-β-D-laminaripentaoside (2): (Compound 2) By the same reaction as in Example 1, 0.16 ml of benzoyl chloride and 600 mg of n-dodecyl β-D-laminaripentaside were prepared. 760 mg of benzoyl compound was synthesized from oside, and further reacted with 1.0 g of sulfur trioxide pyridine complex to obtain 760 mg of the target compound. Target specific optical rotation: [α] _D = -14.4 ° (c = 0.
4 / H2O) (30 ° C.) infrared absorption spectrum wave number (cm ⁻¹ ) 3400, 2900, 2850, 1710, 1630,
1450, 1240, 980, 800, 720 (PMR) spectrum (D2O) (ppm) 0.86 (3H) 1.1-1.3 (18H) 1.5-1.6 (2H) 3.4-5 .3 7.40-7.70 (6.9H) 7.85-8.1 (4.6H) The acylation degree of this compound was 14% from PMR data. The degree of sulfation of this compound is 66% by elemental analysis.
Was calculated.

Example 3 Sulfated n-dodecyl O
Synthesis of 4-fluorobenzoyl-β-D-laminaripentaoside: (Compound 3) By the same reaction as in Example 1, 280 mg of 4-fluorobenzoyl chloride and 600 mg of n-dodecyl β-D-laminari were obtained. 720 mg 4-from pentaoside
A fluorobenzoyl compound was synthesized and further reacted with 0.54 g of sulfur trioxide pyridine complex to obtain 430 mg of the target compound.

Target specific optical rotation: [α] _D = −9.2 ° (c
= 0.4 / H 2 O) (30 ° C.) Infrared absorption spectrum wave number (cm ⁻¹ ) 3450, 2930, 2850, 1720, 1600,
1510, 1240, 1160, 800, 770 (PMR) spectrum (D2O) (ppm) 0.85 (3H) 1.15-1.35 (18H) 1.5-1.6 (2H) 3.4-5 .3 7.15-7.35 (6H) 8.00-8.2 (6H) The acylation degree of this compound was 19% from PMR data. The degree of sulfation of this compound is 59% by elemental analysis.
Was calculated.

Example 4 Sulfated n-dodecyl O
Synthesis of 4-fluorobenzoyl-β-D-laminaripentaoside (2): (Compound 4) By the same reaction as in Example 1, 370 mg of 4-fluorobenzoyl chloride and 600 mg of n-dodecyl β-D were used. -From laminaripentaoside to 620 mg of 4-
Fluorobenzoyl compound was synthesized, and 400 mg of this was reacted with 0.47 g of sulfur trioxide pyridine complex 430
Obtained mg of the desired compound.

Target specific optical rotation: [α] _D = -20.1 °
(C = 0.4 / H2O) (30 ° C.) infrared absorption spectrum wave number (cm ⁻¹ ) 3400, 2930, 2850, 1720, 1630,
1600, 1410, 1240, 1160, 990, 8
00,770 (PMR) spectrum (D2O) (ppm) 0.86 (3H) 1.15-1.30 (18H) 1.5-1.6 (2H) 3.4-5.5 7.00- 7.40 (8.2H) 8.00-8.15 (8.2H) The degree of acylation of this compound was 26% from PMR data. The degree of sulfation of this compound is 56% by elemental analysis.
Was calculated.

Example 5 Sulfated n-dodecyl O
Synthesis of 4-fluorobenzoyl-β-D-laminaripentaoside (3): (Compound 5) By the same reaction as in Example 1, 220 mg of 4-fluorobenzoyl chloride and 600 mg of n-dodecyl β-D were used. -From laminaripentaoside to 720 mg of 4-
A fluorobenzoyl compound was synthesized, and 400 mg of this was reacted with 0.54 g of sulfur trioxide pyridine complex.
80 mg of the desired compound was obtained.

Target specific optical rotation: [α] _D = -12.0 °
(C = 0.4 / H2O) (30 ° C.) infrared absorption spectrum wave number (cm ⁻¹ ) 3400, 2900, 2850, 1700, 1630,
1510, 1220, 990, 800, (PMR) spectrum (D2O) (ppm) 0.86 (3H) 1.15-1.30 (18H) 1.5-1.6 (2H) 3.4-5. 5 7.10-7.35 (4.8H) 8.00-8.20 (4.8H) The acylation degree of this compound was 15% from PMR data. The degree of sulfation of this compound is 63% by elemental analysis.
Was calculated.

Example 6 Sulfated n-dodecyl O
Synthesis of 2,4-difluorobenzoyl-β-D-laminaripentaoside: (Compound 6) By the same reaction as in Example 1, 330 mg of 2,4-difluorobenzoyl chloride and 600 mg of n-dodecyl β- 830mg from D-laminaripentaoside
2,4-difluorobenzoyl compound was synthesized and 400 mg of this was reacted with 550 mg of sulfur trioxide pyridine complex to obtain 502 mg of the target compound.

Target specific optical rotation: [α] _D = -14.5 °
(C = 0.4 / H2O) (30 ° C.) Infrared absorption spectrum wave number (cm ⁻¹ ) 3400, 2930, 2850, 1720, 1610,
1500, 1260, 1120, 1080, 990, 8
00, (PMR) spectrum (D2O) (ppm) 0.82 (3H) 1.10-1.30 (18H) 1.45-1.55 (2H) 3.4-5.5 6.9-7 .2 (6.2H) 7.9-8.15 (3.1H) The acylation degree of this compound was 19% from the PMR data. The sulfation degree of this compound is 64% by elemental analysis.
Was calculated.

Example 7 Sulfated n-dodecyl O
Synthesis of 2,4-difluorobenzoyl-β-D-laminaripentaoside (2): (Compound 7) By the same reaction as in Example 1, 170 mg of 2,4-difluorobenzoyl chloride and 600 mg of n- were used. 680mg from dodecyl β-D-laminaripentaoside
2,4-difluorobenzoyl compound was synthesized and 400 mg of this was reacted with 570 mg of sulfur trioxide pyridine complex to obtain 602 mg of the target compound.

Target specific optical rotation: [α] _D = −6.4 ° (c
= 0.45 / H2O) (30 ° C) infrared absorption spectrum wave number (cm ^-1 ) 3400, 3050, 2930, 2850, 1710,
1610, 1510, 1260, 1120, 1070,
800, (PMR) spectrum (D2O) (ppm) 0.85 (3H) 1.15-1.30 (18H) 1.50-1.60 (2H) 3.4-5.5 7.1-7 0.25 (4.6H) 8.0-8.2 (2.3H) The acylation degree of this compound was 14% from PMR data. The degree of sulfation of this compound is 62% by elemental analysis.
Was calculated.

Example 8 Synthesis of Sulfated 4-n-octylphenyl O-benzoyl-β-D-laminaripentaoside: (Compound 8) 4-n-octylphenyl β-D-laminaripentaoside Sid was synthesized in the same manner as in the reference synthesis example. Specific rotation: [α] _D = + 0.74 ° (c = 0.4 / methanol) (30 ° C) By the same reaction as in Example 1, 500 mg of benzoyl chloride and 1.01 g of 4-n-octylphenyl were prepared. 1.72 g of benzoyl compound was synthesized from β-D-laminaripentaoside, and 520 mg of this was further converted to 980 m.
This was reacted with g of sulfur trioxide pyridine complex to obtain 682 mg of the target compound.

Target specific optical rotation: [α] _D = -14.1 ° (c
= 0.41 / H2O) (30 ° C) (PMR) spectrum (D2O) (ppm) 0.8-0.9 1.0-2.5 3.5-5.5 7.07 (2H) 7. 18 (2H) 7.4-7.7 (14.9H) 7.9-8.2 (9.9H) The acylation degree of this compound was 31% from the PMR data. The degree of sulfation of this compound is 61% by elemental analysis.
Was calculated.

Example 9 Synthesis of Sulfated 4-n-octylphenyl O-4-fluorobenzoyl-β-D-laminaripentaoside: (Compound 9) By the same reaction as in Example 1, 570 mg of 1. From 4-fluorobenzoyl chloride and 1.00 g of 4-n-octylphenyl β-D-laminaripentaoside.
75 g of 4-fluorobenzoyl compound was synthesized. Specific rotation of 4-n-octylphenyl O-4-fluorobenzoyl-β-D-laminaripentaoside: [α] _D =
+ 6.2 ° (c = 0.46 / pyridine) (30 ° C.) 500 mg of this was further reacted with 864 mg of sulfur trioxide pyridine complex to obtain 663 mg of the target compound.

Target specific optical rotation: [α] _D = −9.9 ° (c
= 0.42 / H2O) (29 ° C) (PMR) spectrum (D2O) (ppm) 0.8-0.9 (3H) 1.0-2.5 3.5-5.5 7.0-7 .4 (16.5H) 7.8-8.3 (12.5H) The acylation degree of this compound was 39% from the PMR data. The degree of sulfation of this compound is 41% by elemental analysis.
Was calculated.

Example 10 Sulfated 4-n-octylphenyl O-2,4-difluorobenzoyl-β-
Synthesis of D-laminaripentaoside: (Compound 10) By the same reaction as in Example 1, 270 mg of 2,4-difluorobenzoyl chloride and 600 mg of 4-n were prepared.
785 mg of 2,4-difluorobenzoyl compound was synthesized from -octylphenyl β-D-laminaripentaoside. 400 mg of this 4-n-octylphenyl O-2,4-difluorobenzoyl-β-D-laminaripentaoside was reacted with 970 mg of sulfur trioxide pyridine complex to obtain 602 mg of the target compound.

Target specific optical rotation: [α] _D = −9.2 ° (c
= 0.63 / H2O) (33 ° C) (PMR) spectrum (D2O) (ppm) 0.8-0.9 (3H) 1.0-2.5 3.5-5.5 6.8-7 .4 7.8-8.3 (4.6H) The degree of acylation of this compound was 29% from PMR data. The degree of sulfation of this compound is 46% by elemental analysis.
Was calculated.

Example 11 Sulfated 4-n-octyloxyphenyl O-benzoyl-β-D-laminaripentaside Synthesis: (Compound 11) 4-n-octyloxyphenyl β-D-laminari Pentaoside was synthesized in the same manner as in Reference Synthesis Example 1. Specific rotation: [α] _D = −4.1 ° (c = 0.42 / methanol) (30 ° C.) By the same reaction as in Example 1, 560 mg of benzoyl chloride and 1.00 g of 4-n-octyl were used. 1.03 g from oxyphenyl β-D-laminaripentaoside
Was synthesized. 4-n-octyloxyphenyl O-benzoyl-β
Specific rotation of -D-laminaripentaoside: [α] _D = ＋
3.6 ° (c = 0.40 / pyridine) (27 ° C.) 600 mg of this was reacted with 1.58 g of sulfur trioxide pyridine complex to obtain 744 mg of the target compound.

Target specific optical rotation: [α] _D = -19.5 °
(C = 0.48 / H2O) (30 ° C) (PMR) spectrum (D2O) (ppm) 0.8-0.9 (3H) 1.0-2.5 3.5-5.5 7.0 -7.7 7.8-8.3 (9.6H) The acylation degree of this compound was 30% from PMR data. The degree of sulfation of this compound is 51% by elemental analysis.
Was calculated.

Example 12 Sulfated 4-n-octyloxyphenyl O-4-fluorobenzoyl-β-
Synthesis of D-Laminaripentaoside: (Compound 12) By the same reaction as in Example 1, 760 mg of 4-fluorobenzoyl chloride and 1.00 g of 4-n-octyloxyphenyl β-D-laminaripentaoside were prepared. 1.20 g of 4-fluorobenzoyl compound was synthesized from Cid. Specific optical rotation of 4-n-octyloxyphenyl O-4-fluorobenzoyl-β-D-laminaripentaoside:
[α] _D = −22.6 ° (c = 0.67 / pyridine) (3
(0 ° C.) Of this, 700 mg was reacted with 2.07 g of sulfur trioxide pyridine complex to obtain 460 mg of the target compound.

Target specific optical rotation: [α] _D = -19.2 °
(C = 0.51 / H2O) (33 ° C) (PMR) spectrum (D2O) (ppm) 0.8-0.9 (3H) 1.0-2.5 3.5-5.5 7.0 -7.4 (12H) 7.8-8.3 (8H) The acylation degree of this compound was 25% from PMR data. The degree of sulfation of this compound is 59% by elemental analysis.
Was calculated.

Example 13 Synthesis of Sulfated 4-n-octyloxyphenyl O-2,4-difluorobenzoyl-β-D-laminaripentaoside: (Compound 1
3) By the same reaction as in Example 1, 170 mg of 2,4-difluorobenzoyl chloride and 600 mg of 4-n were used.
680 mg of 2,4-difluorobenzoyl compound was synthesized from -octyloxyphenyl β-D-laminaripentaoside. 400 mg of this was reacted with 570 mg of sulfur trioxide pyridine complex to obtain 602 mg of the target compound.

Specific rotation: [α] _D = -10.3 ° (c =
0.69 / H2O) (33 ° C) (PMR) spectrum (D2O) (ppm) 0.8-0.9 (3H) 1.0-2.5 3.5-5.5 7.0-7. 4 (14.8H) 7.8-8.3 (5.4H) The degree of acylation of this compound was 34% from PMR data. The degree of sulfation of this compound is 47% by elemental analysis.
Was calculated.

Example 14 Synthesis of Sulfated 4-t-octylphenyl O-benzoyl-β-D-laminaripentaoside: (Compound 14) 4-t-octylphenyl β-D-laminaripentaoside Sid was synthesized by the same method as in Reference Synthesis Example 1. Specific rotation: [α] _D = −0.1 ° (c = 0.35 / methanol)
(30 ° C.) By the same reaction as in Example 1, 570 mg of benzoyl chloride was reacted with 1.50 g of 4-t-octylphenyl β-D-laminaripentaoside, and then 4.74 g of trioxide was added. Reacting with a sulfur-pyridine complex, 1.
36 g of the desired compound are obtained. Intermediate 4-t-octylphenyl O-benzoyl-β
Specific rotation of −D-laminaripentaoside: [α] _D = −0.
32 ° (c = 0.41 / pyridine) (25 ° C.) Target specific optical rotation: [α] _D = −13.2 ° (c = 0.41)
/ H2O) (30 ° C) (PMR) spectrum (D2O) (ppm) 0.8-0.9 1.2-2.5 3.9-5.4 6.96 (2H) 7.13 7.3 -7.7 7.8-8.3 (14.1H) The acylation degree of this compound was 44% from PMR data. The degree of sulfation of this compound is 42% by elemental analysis.
Was calculated.

Example 15 Synthesis of Sulfated 4-t-octylphenyl O-4-fluorobenzoyl-β-D-laminaripentaoside: (Compound 15) By the same reaction as in Example 1, 580 mg of 4-fluorobenzoyl chloride is reacted with 1.00 g of 4-t-octylphenyl β-D-laminaripentaoside, and further reacted with 5.53 g of sulfur trioxide pyridine complex to obtain 1.16 g of the target compound. It was Specific rotation of the intermediate 4-t-octylphenyl O-4-fluorobenzoyl-β-D-laminaripentaoside:
[α] _D = + 6.2 ° (c = 0.46 / pyridine) (30
Target optical rotation: [α] _D = −23.3 ° (c = 0.42)
/ H2O) (30 ° C) (PMR) spectrum (D2O) (ppm) 0.8-0.9 (9H) 1.1-2.5 3.9-5.4 6.9-7.4 7. 8-8.3 (10.9H) The degree of acylation of this compound was 34% from PMR data. The degree of sulfation of this compound is 49% by elemental analysis
Was calculated.

Example 16 Sulfated 4-t-octylphenyl O-2,4-difluorobenzoyl-β-
Synthesis of D-Laminaripentaoside: (Compound 16) By the same reaction as in Example 1, 600 mg of 2,4-difluorobenzoyl chloride and 1.00 g of 4-t were used.
-Octylphenyl β-D-laminaripentaoside was reacted and further reacted with 2.50 g of sulfur trioxide pyridine complex to obtain 2.39 g of the target compound. Specific rotation of the intermediate 4-t-octylphenyl O-2,4-difluorobenzoyl-β-D-laminaripentaoside: [α] _D = -1.2 ° (c = 0.66 / pyridine)
(30 ° C) Target specific optical rotation: [α] _D = -7.6 ° (c = 0.62 /
H2O) (33 ℃) (PMR ) spectrum _{(DMSO-d 6 / D2O)} (pp
m) 0.8-0.9 (9H) 1.1-2.5 3.9-5.4 6.8-7.4 7.8-8.3 (13.8H) Acylation of this compound The degree was 43% from the PMR data. The degree of sulfation of this compound is 44% by elemental analysis
Was calculated.

Example 17 Sulfated 4-t-octylphenyl O-benzoyl-β-D-galactosyl-
(1 → 4) -β-D-galactosyl- (1 → 4) -β-D
-Synthesis of glucoside: (Compound 17) 4-t-octylphenyl β-D-galactosyl-
(1 → 4) -β-D-galactosyl- (1 → 4) -β-D
-Glucoside was synthesized in the same manner as in Reference Synthesis Example 1.
Specific rotation: [α] _D = −3.6 ° (c = 0.55 / methanol) (29 ° C.) By the same reaction as in Example 1,
150 mg benzoyl chloride and 300 mg 4
-T-octylphenyl β-D-galactosyl- (1
→ 4) -β-D-galactosyl- (1 → 4) -β-D-glucoside was reacted and further reacted with 1.09 g of sulfur trioxide pyridine complex to obtain 914 mg of the target compound. Intermediate 4-t-octylphenyl O-benzoyl-β
Specific rotation of -D-galactosyl- (1 → 4) -β-D-galactosyl- (1 → 4) -β-D-glucoside: [α] _D =
+ 49.6 ° (c = 0.41 / pyridine) (27 ° C) Target specific optical rotation: [α] _D = + 17.0 ° (c = 0.50)
/ H2O) (28 ° C.) (PMR) spectrum (D2O) (ppm) 0.8-0.9 (9H) 1.1-2.5 3.9-5.4 6.8 6.8-7.6 7. 8-8.3 (6.2H) The acylation degree of this compound was 31% from PMR data. The degree of sulfation of this compound is 40% by elemental analysis
Was calculated.

Example 18 Sulfated 4-n-heptylphenyl O-benzoyl-β-D-galactosyl-
(1 → 4) -β-D-galactosyl- (1 → 4) -β-D
-Synthesis of glucoside: (Compound 18) 4-n-heptylphenyl β-D-galactosyl-
(1 → 4) -β-D-galactosyl- (1 → 4) -β-D
-Glucoside was synthesized in the same manner as in Reference Synthesis Example 1.
Specific rotation: [α] _D = −2.0 ° (c = 0.53 / methanol) (29 ° C.) By the same reaction as in Example 1,
150 mg benzoyl chloride and 300 mg 4
-N-heptylphenyl β-D-galactosyl- (1
→ 4) -β-D-galactosyl- (1 → 4) -β-D-glucoside was reacted and further reacted with 571 mg of sulfur trioxide pyridine complex to obtain 554 mg of the target compound. Intermediate 4-n-heptylphenyl O-benzoyl-β
Specific rotation of -D-galactosyl- (1 → 4) -β-D-galactosyl- (1 → 4) -β-D-glucoside: [α] _D =
+ 40.6 ° (c = 0.43 / pyridine) (28 ° C) Target specific optical rotation: [α] _D = + 15.9 ° (c = 0.38)
/ H2O) (28 ℃) (PMR) spectrum (D2O)
(Ppm) 0.8-0.9 (3H) 1.1-2.5 3.9-5.5 6.9-7.6 7.8-8.3 (6H) Degree of acylation of this compound Was 30% from the PMR data. The degree of sulfation of this compound is 52% by elemental analysis.
Was calculated.

Example 19 Sulfated 4-n-butoxyphenyl O-hexadecanoyl-β-D-galactosyl- (1 → 4) -β-D-galactosyl- (1 → 4)
Synthesis of -β-D-glucoside: (Compound 19) 4-n-butoxyphenyl β-D-galactosyl-
(1 → 4) -β-D-galactosyl- (1 → 4) -β-D
-Glucoside was synthesized in the same manner as in Reference Synthesis Example 1.
Specific rotation: [α] _D = −3.5 ° (c = 0.51 / methanol) (29 ° C.) By the same reaction as in Example 1, 165 mg of hexadecanoyl chloride and 350 mg of 4-n-butoxy were prepared. Phenyl β-D-galactosyl- (1 → 4) -β-D-galactosyl- (1 → 4) -β-D-glucoside was reacted and further reacted with 690 mg of sulfur trioxide pyridine complex to give 495 mg of the target compound. Obtained.

Target specific optical rotation: [α] _D = + 10.4 °
(C = 0.25 / H2O) (28 ° C) (PMR) spectrum (D2O) (ppm) 0.8-0.9 (7.5H) 1.1-2.5 3.9-5.5 6 .9-7.3 (4H) The acylation degree of this compound was 15% based on PMR data. The degree of sulfation of this compound is 60% by elemental analysis.
Was calculated.

Example 20 Sulfated n-docosyl O
Synthesis of -benzoyl-β-D-laminaripentaoside:
(Compound 20) n-docosyl β-D-laminaripentaoside was synthesized in the same manner as in Reference Synthesis Example 1. Specific rotation: [α] _D = −11.3 ° (c = 0.53 / methanol) (28 ° C.) By the same reaction as in Example 1, 350 mg of benzoyl chloride and 680 mg of n-docosyl β-D- Laminaripentaoside was reacted to obtain 585 mg of a benzoyl compound. 477 mg of this was further reacted with 1.45 g of sulfur trioxide pyridine complex to obtain 811 mg of the target compound.

Target specific optical rotation: [α] _D = −4.6 ° (c
= 0.60 / H2O) (30 ° C) (PMR) spectrum (D2O) (ppm) 0.8-0.9 (3H) 1.1-2.5 3.6-5.4 7.3-7 .7 7.8-8.3 (8.3H) The degree of acylation of this compound was 26% from PMR data. The degree of sulfation of this compound is 44% by elemental analysis
Was calculated.

(Example 21) Synthesis of sulfated n-hexadecyl O-4-fluorobenzoyl-β-D-laminaripentaside: (Compound 21) n-hexadecyl β-D-laminaripentaoside is a reference. It was synthesized in the same manner as in Synthesis Example 1. Specific rotation: [α] _D = −13.3 ° (c = 0.50 / methanol) (28 ° C.) By the same reaction as in Example 1, 370 mg of 4-fluorobenzoyl chloride and 490 mg of n-hexadecyl β Reacting with -D-laminaripentaoside 570
Thus, mg of fluorobenzoyl compound was obtained. 400m of this
g, and further reacted with 1.57 g of sulfur trioxide pyridine complex to obtain 602 mg of the target compound.

Target specific optical rotation: [α] _D = −3.6 ° (c
= 0.52 / H2O) (30 ℃ ) (PMR) spectrum _{(DMSO-d 6 / D2O)} (pp
m) 0.8-0.9 (3H) 1.1-1.8 3.7-5.4 7.0-7.7 7.8-8.3 (6.4H) Acylation of this compound The degree was 20% based on the PMR data. The degree of sulfation of this compound is 61% by elemental analysis.
Was calculated.

Example 22 Synthesis of Sulfated n-hexadecyl O-4-n-pentylbenzoyl-β-D-laminaripentaoside: (Compound 22) By the same reaction as in Example 1, 340 mg of 4 -N-pentylbenzoyl chloride was reacted with 510 mg of n-hexadecyl β-D-laminaripentaoside 6
05 mg of the target, n-pentylbenzoyl compound was obtained. 400 mg of this was used and further reacted with 570 mg of sulfur trioxide pyridine complex to obtain 602 mg of the target compound.

Target specific optical rotation: [α] _D = -4.4 ° (c
= 0.35 / H2O) (30 ° C) (PMR) spectrum (D2O) (ppm) 0.8-0.9 (13.6H) 1.1-2.5 3.6-5.4 7.0 -8.3 (14.1H) The acylation degree of this compound was 22% from PMR data. The degree of sulfation of this compound is 41% by elemental analysis.
Was calculated.

Example 23 Sulfated n-dodecyl
O-4-n-butoxybenzoyl-β-D-laminaripentaoside: (Compound 23) By the same reaction as in Example 1, 440 mg of 4-n-butoxybenzoyl chloride and 620 mg of n-dodecyl β-D. -React with laminaripentaoside 740
mg of benzoyl compound was obtained. 700 mg of this was used to react with 2.25 g of sulfur trioxide pyridine complex 9
10 mg of the desired compound was obtained.

Target specific optical rotation: [α] _D = −6.8 ° (c
= 0.32 / H2O) (30 ° C) (PMR) spectrum (D2O) (ppm) 0.8-0.9 (3.6H) 1.1-2.0 3.6-5.4 6.9 -7.2 (2H) 7.8-8.3 (2H) The acylation degree of this compound was 32% from PMR data. The degree of sulfation of this compound is 53% by elemental analysis.
Was calculated.

Example 24 Synthesis of Sulfated 4-n-octylphenyl O-butyryl-β-D-laminaritrioside: (Compound 24) Peracetyl 4-n-octylphenyl β-D-laminaritrioside Sid was synthesized as in Reference Synthesis Example 1. Specific rotation: [α] _D = −53.1 ° (c = 1.0 / chloroform) (31 ° C.) Similarly deacetylated 4-n-octylphenyl β-D
-Laminaritrioside was synthesized. Specific rotation: [α] _D =
-7.1 ° (c = 1.1 / methanol) (32 ° C)
By a reaction similar to Example 1, using 97 mg of butyryl chloride and 697 mg of sulfur trioxide pyridine complex,
From 217 mg of 4-n-octylphenyl β-D-laminaritrioside, 680 mg of the desired compound was obtained.

Target specific optical rotation: [α] _D = -11.6 °
(C = 0.48 / H2O) (28 ° C) (PMR) spectrum (D2O) (ppm) 0.8-0.9 (12.6H) 1.2-1.3 1.5-1.62 3.3-2.6 3.3-5.5 7.07 (2H) 7.18 (2H) The acylation degree of this compound was 32% from PMR data. The degree of sulfation of this compound is 53% by elemental analysis.
Was calculated.

Example 25 Sulfated 3,5,5-Trimethylhexyl O-benzoyl-β-D-Laminarihexaside Synthesis: (Compound 25) 3,5,5-Trimethylhexyl β-D- Laminari hexaoside was synthesized in the same manner as in Reference Synthesis Example 1. Peracetyl 3,5,5-trimethylhexyl β-
_D -Laminarihexaside Specific rotation: [α] _D = -53.7
° (c = 1.95 / chloroform) (28 ° C) 3,5,5-Trimethylhexyl β-D-laminarihexaside Specific optical rotation: [α] _D = + 14.9 ° (c =
0.40 / pyridine) (26 ° C.) By the same reaction as in Example 1, using 63 mg of benzoyl chloride and 481 mg of sulfur trioxide pyridine complex, 121 mg of 3,5,5-trimethylhexyl was used.
254 mg of the target compound was obtained from β-D-laminarihexaside.

Target specific optical rotation: [α] _D = −24.1 °
(C = 0.36 / H2O) (30 ° C) (PMR) spectrum (D2O) (ppm) 0.75-0.93 (12H) 1.0-1.7 3.6-5.4 7.3 -8.2 (23.7H) The degree of acylation of this compound was 25% according to PMR data. The degree of sulfation of this compound is 60% by elemental analysis.
Was calculated.

Example 26 Synthesis of Sulfated 4-n-octyloxyphenyl On-n-octanoyl-β-D-laminaripentaoside: (Compound 26) By the same reaction as in Example 1, 390 mg of Using n-octanoyl chloride and 1.68 g of sulfur trioxide pyridine complex, 0.53 g of 4-n-octyloxyphenyl β-D-laminaripentaoside was obtained to give 0.53 g of the target compound. Target specific rotation: [α] _D = -1
6.9 ° (c = 0.63 / H2O) (31 ° C) (PM
R) spectrum (D2O) (ppm) 0.76 (6.2H) 0.91 (3H) 1.2-2.5 3.5-5.5 7.08 (2H) 7.43 (2H) The acylation degree of the compound was 13% based on the PMR data. The degree of sulfation of this compound is 77% by elemental analysis.
Was calculated.

Example 27 Synthesis of Sulfated 4-t-octylphenyl On-n-octanoyl-β-D-laminaripentaoside: (Compound 27) By the same reaction as in Example 1, 399 mg of n was obtained. Using octanoyl chloride and 1.72 sulfur trioxide pyridine complex, 0.79 g of the desired compound was obtained from 0.50 g of 4-n-octyloxyphenyl β-D-laminaripentaoside.

Target specific optical rotation: [α] _D = -16.3 °
(C = 0.72 / H2O) (31 ° C) (PMR) spectrum (D2O) (ppm) 0.8-0.9 (22.4H) 1.2-2.5 3.9-5.46 0.95 (2H) 7.13 (2H) The acylation degree of this compound was 28% based on PMR data. The degree of sulfation of this compound is 59% by elemental analysis.
Was calculated.

Example 28 Synthesis of Sulfated 4-n-hexylphenyl On-n-octanoyl-β-D-laminari-undecaoside: (Compound 28) 4-n-hexylphenyl β-D-laminari-undecaoside is It was synthesized in the same manner as in Reference Synthesis Example 1. Specific rotation of peracetyl 4-n-hexylphenyl β-D-laminari-undecaoside: [α] _D = −27.
7 ° (c = 1.1 / chloroform) (31 ° C.) Specific rotation of 4-n-hexylphenyl β-D-laminari-undecaoside: [α] _D = −2.1 ° (c = 1.27)
/ DMF) (32 ° C.) In the same reaction as in Example 1, 121 mg of n-octanoyl chloride and 473 mg of sulfur trioxide pyridine complex were used, and 127 mg of 4-n-hexylphenyl was used.
257 mg of the target compound was obtained from β-D-laminaripentaoside.

Target specific optical rotation: [α] _D = -11.3 °
(C = 0.49 / H2O) (31 ° C.) (PMR) spectrum (D2O) (ppm) 0.8-0.9 (17.3H) 1.2-2.5 3.4-5.5 7 0.0-7.3 (4H)% acylation of this compound was 14% from PMR data. The sulfation% of this compound is 72% by elemental analysis
Was calculated.

Example 29 Synthesis of Sulfated 4-n-hexylphenyl On-n-octanoyl-β-D-maltohexaoside: (Compound 29) 4-n-hexylphenyl β-D-maltohexaoo Sid was synthesized by the same method as in Reference Synthesis Example 1. Peracetyl 4-n-hexylphenyl β-D-maltohexaoside Specific optical rotation: [α] _D = + 110.8 ° (c
= 0.49 / chloroform) (30 ° C) 4-n-hexylphenyl β-D-maltohexaside Specific optical rotation: [α] _D = + 112.0 ° (c = 0.55 /
Methanol) (30 ° C.) By the same reaction as in Example 1, 710 mg of n-octanoyl chloride and 231 mg of sulfur trioxide pyridine complex were used, and 790 mg of 4-n-hexylphenyl was used.
850 mg of the target compound was obtained from β-D-maltohexaside.

Target specific optical rotation: [α] _D = + 38.6 ° (c
= 0.54 / H2O) (29 ° C) (PMR) spectrum (D2O) (ppm) 0.87-0.90 (16H) 1.1-1.8 2.2-2.7 3.8-5 .6 7.0-7.3 (4H) The degree of acylation of this compound was 27% from PMR data. The sulfation degree of this compound is 58% by elemental analysis.
Was calculated.

(Example 30) Evaluation of anti-AIDS virus activity of the compound of the present invention <Method and results> Various concentrations of test compounds were tested for HIV-
1 (HTLVIIIB) immediately after infection with MT-4 cells (2.5
X 10 ⁴ / well, MOI: 0.01) in a 96-well microtiter plate. To assess the cytotoxicity of the test compounds on MT-4 cells, uninfected cells were similarly cultured with various concentrations of the test compounds. After culturing in carbon dioxide at 37 ° C for 5 days,
The number of viable cells was determined by the MTT method. The anti-AIDS virus activity is determined by the method of Powell et al. (R. Pauwels, et.
al. J. Virol. Methods, 20 (1
988) 309-321). This anti-AIDS virus activity is caused by HIV-induced MT
It is expressed as the concentration of the test compound at the time of 50% inhibition of cytotoxicity of -4 cells (EC ₅₀ : 50% effective concentration).
Cytotoxicity is then expressed as the concentration of compound (CC ₅₀ ) when uninfected cells are reduced to 50%. Selection index (S.
I. ) Is expressed as a ratio of CC ₅₀ and EC ₅₀ (CC ₅₀ / EC ₅₀ ). The results are shown in Table 1.

[0145]

[Table 1]

(Example 31) (Intravenous administration test to mice) A compound 6 and dextran sulfate (control drug) were subjected to in vivo blood activity sustainability test using mice. 1 Test substance Compound 6 was dissolved in physiological saline at a ratio of 32 mg / 10 ml. As a control, dextran sulfate (molecular weight 8,000: manufactured by Sigma) was similarly dissolved in physiological saline at a ratio of 80 mg / 10 ml. 2 Animals used Mouse (Crj: CD-1 (ICR)) (Charles
Six weeks old from River Japan, Inc. was used. 3 Method and Results Using a mouse (3 mice per group) divided into 4 groups (for 1, 4, 6 and 12 hours), 32 mg / kg of compound 6 was administered through the tail vein, and an intravenous administration test was conducted. did.
On the other hand, 3 groups (20, 40 and 60 minutes) (1 group: 2 animals) were used to administer dextran sulfate in the same manner as compound 6 (dosage 80 mg / kg). Blood was collected from each group at a determined time and serum was collected by low speed centrifugation. Serum samples were stored at −80 ° C. until activity evaluation. To assess the effective serum concentration, each serum was diluted with medium (maximum serum concentration was set to 10%). This anti-HIV activity was performed as in Example 30,
The serum concentration at which the 50% effective concentration was obtained was determined, and the residual blood concentration was judged from the relationship with the dilution ratio of serum to physiological saline.
The test results are shown in Tables 2 and 3 by the reciprocal of the serum concentration when the EC50 value is shown. From this test, even 12 hours after administration,
Compound 6 was detected in serum at a high concentration and was found to have high activity persistence. On the other hand, dextran sulfate could not be detected in a shorter time than that of Compound 6 despite the high dose.

[0147]

[Table 2]

[0148]

[Table 3]

(Example 32) (Oral administration mouse test) As an IN VIVO test, the test of Compound 1 by oral administration was examined from the blood activity persistence using mice. 1 Test substance Compound 1 500 mg / 10 ml and 1000 mg / 10
It was dissolved in distilled water at a concentration of ml. 2 Animals used Mouse (Crj: CD-1 (ICR)) (Charles
Six weeks old from River Japan, Inc. was used. 3 Methods and Results 3 groups (for 1, 2 and 3 hours) (1 group 3
Mice) were used for the test. Compound 9 was orally administered to these 9 mice at 500 mg / kg or 1000 mg / kg.
It was administered in an amount of kg. Blood was collected at each time after administration and serum was collected by low speed centrifugation. Serum samples were stored at −80 ° C. until activity evaluation. To assess the effective serum concentration, each serum was diluted with medium (maximum serum concentration was set to 10%). The obtained serum was evaluated in the same manner as in Example 31. The results are shown in Table 4.
From this test, Compound 12 was detected in the serum at a high concentration even 12 hours after the administration, and it was proved that the compound 1 is effective even if it is orally administered.

[0150]

[Table 4]

(Example 33) (Blood coagulation effect) A test of whole blood coagulation time was carried out using rabbit blood of Compound 1, Compound 6 and dextran sulfate. 1 Test substance Compound 1, compound 6, dextran sulfate 1, 0.1,
It was diluted with saline to a concentration of 0.01%. 120 U / m using heparin sodium (Kodama Corp.) as a positive control
It was diluted with physiological saline so as to be l. Tissue thromboplastin and calcium mixed solution (Rioplastin (registered trademark), Mochida Pharmaceutical Co., Ltd.) and physiological saline ((Co))
Otsuka Pharmaceutical) was used as a reagent. 2. Animals used Four-month-old Japanese white rabbits (Kitayama Labes Co., Ltd.) were used. 3 Methods and Results First, 100 μl of various concentrations of Compound 1 and Compound 6 and dextran sulfate, heparin sodium (positive control) and physiological saline (negative control) were used, each having an inner diameter of 10 mm for 2 times.
Put it in a double-glass test tube and incubator at 37 ℃
Kept at. Blood is taken from the rabbit heart with a needle, and the timer is activated at the moment the blood flows into the syringe. All blood drawn is carefully poured into double tubes and incubated. After standing for 3 minutes, the first test tube is gently tilted every 30 seconds to observe the blood flow. When the blood in the first test tube has solidified, the operation of the second test tube is started in the same manner. The timer is stopped when the blood in the second tube solidifies and this endpoint is recorded as the whole blood clotting time. The results are shown in Tables 5-7. Comparing the effects of compound 1, compound 6 and dextran sulfate at a concentration of 0.1% or more, the order is: dextran sulfate> compound 1> compound 6.

[0152]

[Table 5]

[0153]

[Table 6]

[0154]

[Table 7]

Example of Drug Production Example of drug production of the antiviral agent of the present invention is described below. Grind compound 1 and mix it with lactose and starch.
10% starch paste is added thereto and stirred to form granules. The granules were dried, sieved, talc and magnesium stearate were added and mixed, and tableted by a usual method to produce 200 mg tablets.

[0156] Using compound 2, 200 mg tablets were produced in the same manner as in antiviral agent production example 1.

[0157] Using compound 3, 200 mg tablets were produced in the same manner as in antiviral agent production example 1.

[0158] Using compound 4, a 200 mg tablet was produced in the same manner as in antiviral agent production example 1.

[0159] A 200 mg tablet was produced using compound 5 in the same manner as in antiviral agent production example 1.

[0160] A 200 mg tablet was produced using compound 6 in the same manner as in Production Example 1 of antiviral agent.

[0161] Compound 7 is ground and mixed with lactose and starch.
10% starch paste is added thereto and stirred to form granules. The granules were dried, sieved, magnesium stearate was added and mixed, and the mixture was compressed into tablets to give 100 mg tablets.

[0162] Using compound 27, a 200 mg tablet was produced in the same manner as in antiviral agent production example 1.

(Production Example 9 of antiviral agent) To 500 mg of Compound 1 was added physiological saline to bring the total volume to 10 ml, which was then sealed in an ampoule which had been sterilized by dry heat in an autoclave and placed in 10
A ml solution was prepared.

(Production Example 10 of antiviral agent) To 500 mg of Compound 2 was added physiological saline to make a total volume of 10 ml, and this was enclosed in an ampoule similar to Production Example 13 of antiviral agent,
10 ml of solution was prepared.

(Production Example 11 of antiviral agent) To 600 mg of Compound 3 was added physiological saline to bring the total volume to 10 ml, and this was sealed in an ampoule similar to Production Example 13 of antiviral agent,
10 ml of solution was prepared.

(Production Example 12 of antiviral agent) To 600 mg of compound 4, physiological saline was added to bring the total volume to 10 ml, and this was enclosed in an ampoule similar to Production Example 13 of antiviral agent,
10 ml of solution was prepared.

(Production Example 13 of antiviral agent) To 600 mg of Compound 5 was added physiological saline to bring the total volume to 10 ml, and this was enclosed in an ampoule similar to Production Example 13 of antiviral agent,
10 ml of solution was prepared.

(Production Example 14 of antiviral agent) To 500 mg of compound 6 was added physiological saline to make a total volume of 10 ml, and this was enclosed in an ampoule similar to Production example 13 of antiviral agent,
10 ml of solution was prepared.

(Production Example 15 of antiviral agent) To 500 mg of compound 7, physiological saline was added to bring the total volume to 10 ml, and this was enclosed in the same ampoule as in Production example 13 of antiviral agent,
10 ml of solution was prepared.

(Production Example 16 of antiviral agent) 500 mg of compound 24 was added with physiological saline to make a total volume of 10 ml, and this was enclosed in the same ampoule as in Production Example 13 of antiviral agent to prepare 10 ml of a liquid preparation.

(Antiviral Preparation Example 17) 500 mg of Compound 1 was pulverized, 1000 mg of mannitol and 400 mg of disodium phosphate were added and mixed well, and the mixture was sealed in an ampoule dry-heat sterilized in an autoclave to give a drug. .

(Antiviral Preparation Example 18) 500 mg of compound 2 was pulverized, 1000 mg of mannitol and 400 mg of disodium phosphate were added and mixed well, and the mixture was sealed in an ampoule dry-heat sterilized in an autoclave to give a drug. .

(Production Example 19 of antiviral agent) 500 mg of compound 3 was crushed, 1000 mg of mannitol and 400 mg of disodium phosphate were added thereto and mixed well, and the mixture was sealed in an ampoule sterilized by dry heat in an autoclave to give a drug. .

(Production Example 20 of antiviral agent) 500 mg of compound 4 was crushed, 1000 mg of mannitol and 400 mg of disodium phosphate were added and mixed well, and the mixture was sealed in an ampoule sterilized by dry heat in an autoclave to give a drug. .

(Production Example 21 of antiviral agent) 500 mg of compound 5 was crushed, 1000 mg of mannitol and 400 mg of disodium phosphate were added and mixed well, and the mixture was sealed in an ampoule sterilized by dry heat in an autoclave to give a drug. .

(Production Example 22 of antiviral agent) 500 mg of the compound 20 was pulverized, 1000 mg of mannitol and 400 mg of disodium phosphate were added thereto and mixed well, and the mixture was sealed in an ampoule sterilized by dry heat in an autoclave to give a drug. .

[0177]

INDUSTRIAL APPLICABILITY According to the present invention, a novel acetylated sulfated oligosaccharide glycoside or a physiologically acceptable salt thereof can be provided, which is an active ingredient with low toxicity and orally administrable. Can be provided.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Naoya Ikushima 3-13-1-802 Osakidai, Sakura City, Chiba Prefecture (72) Nahoko Takahashi 4-3-2-203 Takahama, Mihama-ku, Chiba Prefecture (72) ) Inventor Naoki Yamamoto 3-11-17-501, Ebisu-minami, Shibuya-ku, Tokyo (72) Inventor Hideki Nakajima 1559-1-E- 103 Narishima, Tamabo-cho, Nakakoma-gun, Yamanashi Prefecture

Claims (18)

[Claims] 1. The hydrogen of the hydroxyl group at the 1-position of the reducing terminal sugar of an oligosaccharide in which the same or two kinds of monosaccharides are composed as glycoside bonds, is an alkyl group, an aromatic alkyl group or an aromatic alkoxy. Substituted by an aglycone selected from the group consisting of groups, 12 to 80% of the remaining hydroxyl groups are acylated by an acyl group selected from the group consisting of aliphatic acyl group and aromatic acyl group, and 88 to 20%. A sulfated esterified sulfated oligosaccharide glycoside acyl compound or a physiologically acceptable salt thereof (excluding compounds in which the aglycone is an alkyl group and the acyl group is an aliphatic acyl group). 2. The sulfated oligosaccharide glycoside acyl compound or physiologically acceptable salt thereof according to claim 1, wherein the oligosaccharide moiety is an oligosaccharide composed of 3 to 20 identical monosaccharides. 3. An oligosaccharide constituting monosaccharide is glucose, galactose, mannose, talose, idose, altrose, allose, gulose, xylose, arabinose, rhamnose, fucose, fructose, ribose,
The sulfated oligosaccharide glycoside acyl compound or physiologically acceptable salt thereof according to claim 2, which is a monosaccharide selected from the group consisting of deoxyribose. 4. The sulfated oligosaccharide glycoside acyl compound or a physiologically acceptable salt thereof according to claim 3, wherein the oligosaccharide is an oligosaccharide having a β (1 → 3) bond. 5. The sulfated oligosaccharide glycoside acyl compound or the physiologically acceptable salt thereof according to claim 3, wherein the oligosaccharide is an oligosaccharide having an α (1 → 4) bond. 6. The sulfated oligosaccharide glycoside acyl compound or a physiologically acceptable salt thereof according to claim 1, wherein the oligosaccharide portion is an oligosaccharide composed of two types of monosaccharides of 3 to 20. 7. The oligosaccharide constituting monosaccharide is glucose, galactose, mannose, talose, idose, altrose, allose, gulose, xylose, arabinose, rhamnose, fucose, fructose, ribose,
The sulfated oligosaccharide glycoside acyl compound or a physiologically acceptable salt thereof according to claim 6, which is a monosaccharide selected from the group consisting of deoxyribose. 8. The sulfated oligosaccharide glycoside acyl compound or the physiologically acceptable salt thereof according to claim 7, wherein the oligosaccharide is an oligosaccharide having a β (1 → 4) bond. 9. The sulfated oligosaccharide compound according to claim 1, wherein the aglycone is a linear or branched alkyl group having 1 to 24 carbon atoms, and the acyl group is an aromatic acyl group. A sugar acylated product or a physiologically acceptable salt thereof. 10. The acylated product of sulfated oligosaccharide glycoside or the physiologically acceptable salt thereof according to claim 9, wherein the acyl group is a benzoyl group which is unsubstituted or substituted with an alkyl group, an alkoxy group or a halogen. . 11. An aglycone is a phenyl group substituted with a linear or branched alkyl group having 1 to 18 carbon atoms,
The sulfated oligosaccharide glycoside acylated product according to any one of claims 1 to 8 or a physiologically acceptable salt thereof, wherein the acyl group is an aliphatic acyl group or an aromatic acyl group. 12. The acylated product of sulfated oligosaccharide glycoside or the physiologically acceptable salt thereof according to claim 11, wherein the acyl group is a linear or branched alkanoyl group having 2 to 24 carbon atoms. 13. The acylated product of sulfated oligosaccharide glycoside or the physiologically acceptable salt thereof according to claim 11, wherein the acyl group is a benzoyl group which is unsubstituted or substituted with an alkyl group, an alkoxy group or a halogen. . 14. The aglycone is a phenyl group substituted with a linear or branched alkoxy group having 1 to 18 carbon atoms, and the acyl group is an aliphatic acyl group or an aromatic acyl group. 2. An acylated product of sulfated oligosaccharide glycoside or a physiologically acceptable salt thereof according to item 1. 15. The sulfated oligosaccharide glycoside acylated product according to claim 14, or a physiologically acceptable salt thereof, wherein the acyl group is a linear or branched alkanoyl group having 2 to 24 carbon atoms. 16. The acylated product of sulfated oligosaccharide glycoside or the physiologically acceptable salt thereof according to claim 14, wherein the acyl group is a benzoyl group which is unsubstituted or substituted with an alkyl group, an alkoxy group or a halogen. . 17. An antiviral agent comprising the sulfated oligosaccharide glycoside acylated product according to any one of claims 1 to 17 or a physiologically acceptable salt thereof as an active ingredient. 18. The antiviral agent according to claim 17, wherein the virus is HIV.