JP2997768B2 - Sulfated galactose compound, intermediate thereof, and method for producing the sulfated galactose compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel sulfated galactose compound which is considered to be recognized by human influenza virus and the like in its infection, an intermediate thereof, and a method for producing the same.

[0002]

BACKGROUND OF THE INVENTION Human influenza virus infection
Neu5Acα2 → 3Galβ, a specific trisaccharide unit on the surface of human cells
1 → 4 (3) GlcNAcβ1 →, Neu5Acα2 → 6Galβ1 → 4 (3) Gl
cNAcβ1 →, Neu5Acα2 → 3Galβ1 → 3GalNAc β1 →,
Or Neu5Acα2 → 6Galβ1 → 3GalNAc β1 → (However, Ne
u5Ac indicates N-acetylneuraminic acid, Gal indicates galactose, and GlcNAc indicates N-acetylglucosamine. ) Is known to begin. If these trisaccharide units can be obtained in a sufficient amount and can be further polymerized, it is expected that a new material capable of capturing viruses can be provided. Conventional methods for obtaining these trisaccharide units include (1) removal from natural products, (2) synthesis using organic synthetic chemical means,
(3) synthesis using biochemical means such as enzymes,
(4) The methods (1) to (3) are appropriately combined. However, when isolated from natural products, only a very small amount is obtained, and when synthesized, there is a problem that the number of steps is large, and it has been difficult to obtain a sufficient amount of these trisaccharide units. Therefore, there has been a demand for the development of a novel compound which is easier to obtain than these trisaccharide units and has a virus recognizing property and a method for producing the same.

[0003]

DISCLOSURE OF THE INVENTION The present invention relates to a sulfated galactose compound and a high molecular weight compound thereof, which are capable of recognizing human influenza virus and AIDS virus (HIV) and can be used as a material for capturing a virus instead of the above-mentioned trisaccharide unit. The purpose is to provide.

[0004]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems, and as a result, have synthesized a sugar derivative having a sulfate ester group at a specific position of a molecule and a polymer compound containing the same. And succeeded in making the present invention based on this finding. That is, the above object has been achieved by the following inventions. (1) The following formula (I-1), formula (I-2) or formula (I-
A galactose compound represented by 3).

[0005]

Embedded image 06

[0006] (In the formula, R ₁ represents a hydrogen atom or an acetyl group and equal to or greater than the deacylation hard acyl group, R ₂ represents a deacylation easily acyl group than hydrogen atom or an acetyl group, R ₃ R ₄ represents an acyl group or a silyl group which is harder to deacylate than or equal to a hydrogen atom or an acetyl group, and R ₄ represents an acyl group or a silyl group which is more easily deacylated than a hydrogen atom or an acetyl group. Or three R _{1 s} may be the same or different, and the substituents at the 3- and 4-positions or the 4- and 6-positions may combine with each other to form an acetal or a hemiacetal. The substituents at the 3-, 3-, 4- and 6-positions are not all hydrogen atoms.
Enoxy group, aminophenoxy group, acrylamide
Nonoxy group, allylphenoxy group, allylalkyloxy
Represents an alkyloxy group or an allyloxy group. (2) A sulfated galactose compound represented by the following formula (II), formula (III) or formula (IV).

[0007]

Embedded image 07

Wherein R ₅ , R ₆ and R ₇ are a hydrogen atom,
Represents an acyl group or a silyl group. R _{5 to} R ₇ may be the same or different from each other. In the formula (II), R ₆
And R ₇ may combine with each other to form an acetal or hemiacetal. Y has the same meaning as described above. M represents a hydrogen atom, an alkali metal atom, an ammonium group or an organic amine. (3) A sulfated galactose compound represented by the following formula (VIII):

[0009]

Embedded image 08

(Wherein R ₅ , R ₆ , Y and M are as defined above). (4) The following formula (V), formula (VI), formula (VII) or formula (IX)
A sulfated galactose polymer compound represented by the formula:

[0011]

Embedded image 09

(Wherein R ₅ , R ₆ and R ₇ are as defined above. In the formula (V), R ₆ and R ₇ may be bonded to each other to form an acetal or a hemiacetal.

[0013]

Embedded image 10

(Wherein, * is bonded to the 1-position of the pyranose ring. L is alkylene, arylene, —O—, —CO—,
Represents a linking group consisting of one or more combinations selected from -NH-. B) represents a portion consisting of a repeating unit having no galactose residue. p and q are molar ratios (%), 0 <p ≦ 100, and the sum of p and q is 100. (5) The following formula (I) wherein a galactose compound represented by the formula (I-1), (I-2) or (I-3) described in the item (1) is reacted with a sulfate reagent. II), formula (I
II) or a method for producing a sulfated galactose compound represented by the formula (IV).

[0015]

Embedded image 11

(Wherein R ₅ , R ₆ , R ₇ , Y and M are as defined above) (6) One sulfate ester of the galactose compound represented by the formula (VIII) described in (3). Wherein only the group is hydrolyzed in the presence of a sulfatase,
A method for producing a sulfated galactose compound represented by I) or the formula (IV).

[0017]

Embedded image 12

(In the formula, R ₅ , R ₆ , R ₇ , Y and M have the same meanings as described above.) In the present invention, deacylation includes not only a hydrolysis reaction but also a reaction such as transesterification. It is a thing.

[0019]

BEST MODE FOR CARRYING OUT THE INVENTION The galactose compounds represented by the formulas (I-1), (I-2) and (I-3) are represented by the formulas (II), (III) and (IV), respectively. It is a synthetic intermediate of the compound represented.

In the formulas (I-1) to (I-3), R ₁
Represents a hydrogen atom or an acyl group. This acyl group can be used under normal transesterification (hydrolysis) reaction conditions (pH 9 to 12).
A benzene group (e.g., a benzoyl group, which may be substituted, e.g., a benzoyl group, etc.). 4-
Methoxybenzoyl group, 4-chlorobenzoyl group, etc.), pivaloyl group and the like, and preferably a benzoyl group or a pivaloyl group. Two or three R ₁ in the formula may be the same or different from each other.

R ₂ is a milder condition than a normal aliphatic group such as a hydrogen atom or an acetyl group (condition closer to neutral than R ₁ )
Represents an acyl group which can be eliminated, and examples of such an acyl group include a levulinoyl group and a monochloroacetic acid ester group, and a hydrogen atom or a levulinoyl group is preferable.

R ₃ represents a hydrogen atom, an acyl group as described above for R ₁ , or a silyl group (optionally substituted, for example, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, etc.). , R _1, and more preferably a benzoyl group. R ₄ represents a hydrogen atom, the same acyl group as described in R ₂ , or the same silyl group as described in R ₃ , and is preferably a silyl group. However, R1 to R4 are not all hydrogen atoms at the 2-, 3-, 4- and 6-positions.

Y is a nitrophenoxy group (for example, p-nitrophenoxy, o-nitrophenoxy, m-nitrophenoxy), an aminophenoxy group (for example, p-aminophenoxy), an acrylamidophenoxy group (for example, p-nitrophenoxy group).
Acrylamide phenoxy), allyl phenoxy group (e.g. 2-allylphenoxy), -O (CH ₂ having a double bond in the allyl-alkyl group (preferably terminal) _n CH ₂ CH = CH
_2, n an integer) preferably of 1-5, an alkyl group (preferably having from 1 to 4 carbon atoms, such as methoxy, ethoxy, etc.), represents an allyloxy group. Y is preferably a nitrophenoxy group.

In the formula (I-1), the substituents at the 3- and 4-positions may combine with each other to form an acetal structure. Examples of the acetal structure include an isopropylidene group and a cyclohexylidene group.
A stannylene acetal structure (for example, dibutylstannylene acetal) formed by an organotin is also included. Formula (I-
In 2) and (I-3), the substituents at the 4- and 6-positions may be bonded to each other to form an acetal or hemiacetal structure. Examples of the acetal structure include an isopropylidene group and a cyclohexylidene group, and examples of the hemiacetal structure include a benzylidene group and a methoxybenzylidene group.

In the compound of the formula (I-1), the 3-position is a hydrogen atom or an acyl group which is more easily deacylated than an acetyl group, and the 2- and 4-positions are dehydrogenated to a degree equal to or greater than that of a hydrogen atom or an acetyl group. An acyl group that is difficult to acylate, 6
The position is the same acyl group or silyl group as in the 2-position and 4-position. Since the compound represented by the formula (I-1) has such a substituent, only the 3-position can be selectively deprotected and sulfated while protecting the 2-, 4- and 6-positions. Is possible. Similarly, the compounds of the formulas (I-2) and (I-3) are compounds having a combination of substituents capable of selectively deprotecting and sulfating only the 4-position or 6-position.

As the compound of the formula (I-1), the substituents at the 3- and 4-positions are combined to form a stannylene acetal, and the substituents at the 2- and 6-positions are a hydrogen atom or a benzoyl group. It is particularly preferable that the 2- and 6-positions are hydrogen atoms. As the compound of the formula (I-2), those in which R ₁ and R ₃ are benzoyl groups and R 2 is a hydrogen atom, or those in which R ₁ is a benzoyl group, R ₂ is a hydrogen atom and R ₃ is a silyl group, are preferred. The compound (I-3) is preferably a compound wherein R ₁ is a benzoyl group and R ₄ is a silyl group.

In the formulas (II), (III) and (IV), R ₅ , R ₆ and R ₇ represent a hydrogen atom or an acyl group or a silyl group as a protecting group. It may be different. Examples of the acyl group and the silyl group include, but are not particularly limited to, the above-described R.
Include those mentioned in ₁ to R _4. In the formula (II), R ₆ and R ₇ may form the same acetal or hemiacetal as mentioned in the formulas (I-1) to (I-3). Y has the same meaning as in formulas (I-1) to (I-3). M represents a hydrogen atom, an alkali metal atom (eg, a sodium atom, a potassium atom, a lithium atom, etc.), an organic amine (eg, a substituted or unsubstituted amino group such as trimethylamino, triethylamino, etc.), and an ammonium group, preferably a sodium atom It is. Among the compounds of the formula (II), those in which R ₅ and R ₇ are hydrogen atoms or benzoyl groups and R ₆ is hydrogen atoms are preferred, and those in which R _{5 to} R ₇ are hydrogen atoms are particularly preferred. Among the compounds of the formulas (III) and (IV), those in which R _{5 to} R ₇ are hydrogen atoms or benzoyl groups are preferred, and those in which R _{5 to} R ₇ are hydrogen atoms are particularly preferred.

A synthetic route for producing a compound of the formula (II) from a compound of the formula (I-1) is shown in the following scheme 1.

[0029]

Embedded image 13

[0030] (wherein, R ₁₁ represents an acetyl group and equal to or greater than the deacylation hard acyl group, R ₁₂
Represents an acyl group which is more easily deacylated than an acetyl group, and R ₁₃ represents an acyl group or a silyl group which is harder to be deacylated than or equal to the acetyl group. 2 in the formula
R ₁₁ may be the same or different from each other. Y and M
Has the same meaning as defined in the above formulas (I-1) and (II). To explain an example of this synthesis method, first, a compound 2 is obtained by acetalizing two hydroxyl groups at the 3- and 4-positions of a commercially available compound 1 (for example, nitrophenylgalactose). The reaction first involves acetone (anhydrous),
Along with acetal sources such as dimethoxypropane,
The reaction is performed in the presence of an acidic catalyst. Examples of the acid catalyst include camphorsulfonic acid (CSA), p-toluenesulfonic acid (pT
sOH), pyridinium p-toluenesulfonic acid (PP
TS), trimethylsilyl chloride (TMSCl), ion exchange resin (H ⁺ type) and the like are used. As the solvent,
Solvent-free (ie acetone as an acetal source,
Dimethoxypropane and a mixed solvent of both) or dimethylformamide, and the reaction temperature is usually 0 ° C to
At 130 ° C., the reaction time is usually about 5 minutes to 5 days.

The compound 2 thus obtained is acylated to give a compound 3. This reaction can be carried out by first reacting in the presence of a carbodiimide compound such as dicyclohexylcarbodiimide or diisopropylcarbodiimide with a carboxylic acid capable of introducing an acyl group which can be eliminated by a reaction with, for example, benzoic acid or acetic acid. Alternatively, as an alternative, by reacting with the anhydride of the carboxylic acid or the corresponding acid chloride, acid bromide, usually in the presence of pyridine as a solvent, if necessary, in the presence of a base such as dimethylaminopyridine or triethylamine. It can be carried out. As the solvent, in the case of the former, dimethylformamide, benzene, toluene, methylene chloride, dichloroethane or a mixed solution thereof is used, and in the latter case, besides pyridine, methylene chloride, dichloroethane, chloroform and a mixed solution thereof are usually used. The reaction temperature is usually 0 ° C. to 50 ° C., and the reaction time is usually about 5 minutes to 5 days.

When R ₁₃ is a silyl group, for example, a halogenated silane compound or a silane compound of trifluoromethanesulfonic acid is added and reacted with an amine such as pyridine, lutidine, triethylamine, dimethylaminopyridine, imidazole and the like. As the solvent, pyridine, dimethylformamide, acetonitrile, methylene chloride, dichloroethane, chloroform and a mixture thereof are usually used, and the reaction temperature is usually -20.
The reaction time is usually from about 5 minutes to 7 days. Compound 3 is obtained by treating compound 3 with an acid. The acid treatment includes camphorsulfonic acid (CSA), p-toluenesulfonic acid, pyridinium p-toluenesulfonic acid (PPTS), acetic acid, sulfuric acid, hydrochloric acid, and ion exchange resin (H
⁺ ), Trifluoroacetic acid (TFA) and the like. As the solvent, methanol, ethanol, methanol-methylene chloride, water and the like are usually used,
The reaction temperature is −20 ° C. to 80 ° C., and the reaction time is usually 5 minutes to
It is about three days.

This compound 4 is esterified to give compound 5. This reaction involves dicyclohexylcarbodiimide,
The reaction can be carried out by reacting with a carboxylic acid such as levulinic acid or monochloroacetic acid or an acid anhydride thereof in the presence of a carbodiimide compound such as diisopropylcarbodiimide. Alternatively, as an alternative, by reacting with the anhydride of the carboxylic acid or the corresponding acid chloride, acid bromide, usually in the presence of pyridine as a solvent, if necessary, in the presence of a base such as dimethylaminopyridine or triethylamine. It can be carried out. As the solvent, in the former case, usually dimethylformamide, benzene, toluene,
Methylene chloride, dichloroethane or a mixture thereof is used, and in the latter case, pyridine, methylene chloride,
Dichloroethane, chloroform and a mixture thereof are used, and the reaction temperature is usually 0 ° C.
To 50 ° C., and the reaction time is usually about 5 minutes to 5 days.

Then, the compound 5 is further esterified to obtain a compound 6. This reaction can be carried out in the presence of a carbodiimide compound such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, or the like, by reacting with a carboxylic acid capable of introducing an acyl group capable of being eliminated by reaction with, for example, benzoic acid, acetic acid, or the like. Alternatively, as an alternative, by reacting with the anhydride of the carboxylic acid or the corresponding acid chloride, acid bromide, usually in the presence of pyridine as a solvent, if necessary, in the presence of a base such as dimethylaminopyridine or triethylamine. It can be carried out. As the solvent, in the former case, dimethylformamide, benzene, toluene, methylene chloride, dichloroethane or a mixture thereof is used, and in the latter case,
Usually, pyridine, methylene chloride, dichloroethane, chloroform and a mixture thereof are used. The reaction temperature is usually 0 to 50 ° C. for the former and the latter is usually 5 to 50 ° C.
Minutes to 5 days.

The compound 6 thus obtained is subjected to selective deprotection to obtain a compound 7. This reaction can be performed by treating with hydrazineacetic acid, hydrazine-piperidine, lithium hydroxide-hydrogen peroxide, or the like.
As the solvent, methanol, ethanol, isopropanol, toluene, pyridine, THF and the like are usually used. The reaction temperature is usually -78 ° C to 50 ° C, and the reaction time is usually 5 minutes to 3 days.

Then, the compound 7 is sulfated to introduce a sulfate group to obtain a compound 8. This reaction can be performed by reacting with a sulfating reagent such as a trimethylamine sulfur trioxide complex, a triethylamine sulfur trioxide complex, a dimethylformamide sulfur trioxide complex, a pyridine sulfur trioxide complex, and chlorosulfonic acid. As the solvent,
Usually, dimethylformamide, pyridine, hexamethylphosphonamide (also referred to as HMPA or hexamethylphosphorous triamide (HMPT)), dimethylsulfoxide (DMSO) and the like are used, and the reaction temperature is 0 ° C to 80 ° C. The reaction time is usually 5 minutes to 1 week. If necessary, M can be converted to a sodium atom or the like by treating the obtained compound with an ion exchange resin (Na ⁺ type or the like).

The compound 8 is then deacylated by treating it with a base such as sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like. In the formula (II) of the present invention, R ₅ , Compound 9 in which R ₆ and R ₇ are all hydrogen atoms can be obtained. As the solvent, methanol, ethanol, tetrahydrofuran (THF), methanol-THF, ethanol-THF and the like are usually used, and the reaction temperature is usually -30.
The reaction time is usually 5 minutes to 5 days. When R ₁₃ (R ₃ of the compound of the formula (I-1)) is a silyl group, the removal of the silyl group is performed as follows. Tetrabutylammonium fluoride, potassium fluoride,
In the presence of hydrofluoric acid, hydrogen fluoride-pyridine, trifluoroacetic acid, boron trifluoride ether complex, etc., acetic acid is added as necessary. As the solvent, tetrahydrofuran, dioxane, diethyl ether, methylene chloride, chloroform, toluene, acetonitrile, ethanol, water and a mixture thereof are usually used. The reaction temperature is usually 0 ° C to 100 ° C, and the reaction time is usually 5 minutes. ~ 1
It is about 0 days.

As an alternative to obtaining compound 8 from compound 4,
There are also the following methods. While heating and refluxing with dibutyltin oxide, compound 4 and benzene or toluene (if necessary, in the presence of a hydrophilic solvent such as methanol, ethanol, tetrahydrofuran and dimethylformamide), water generated in the reaction is removed. afterwards,
After distilling off the solvent, the residue is treated with the above-mentioned sulfating reagent to give compound 8. As a solvent for performing the sulfating reagent, dimethylformamide, pyridine, hexamethylphosphoramide (HMPA or hexamethylphosphorustriamide (HMPA)
T)), dimethyl sulfoxide (DMSO)
The reaction temperature is 0 ° C. to 80 ° C., and the reaction time is usually 5 minutes to 1 week. The galactose has 6 hydroxyl groups.
Since the reactivity is higher in the order of position>3> 4, when the compound 4 is sulfated as described above, a sulfate group is introduced at the position 3.

In order to obtain compound 9 from compound 1 in one step, compound 1 may be used in place of compound 4, and a method similar to the above-mentioned sulfation method using dibutyltin oxide may be used. Alternatively, as shown at the bottom of Scheme 1, only the primary hydroxyl group of Compound 1 can be acylated or silylated (Compound 20), and then sulfated using an organotin (Compound 21) as described above. The selective acylation and silylation of the primary hydroxyl group of Compound 1 is the same as the method of synthesizing Compound 3. Then, the compound 21 is deprotected to obtain a sulfated saccharide derivative 9. This deprotection can be carried out in the same manner as for compound 8 → compound 9.

When Y has an allyloxy group, a benzyloxy group, or the like, any of the compounds 2 to 9 can be appropriately removed in any step.
Further, after converting Y into an imidate group or a halogen atom, it can be converted into a p-nitrophenoxy group, an allylphenoxy group or the like. Removal of the allyloxy group can be performed by (cyclooctadiene) bis (methyldiphenylphosphine) iridium hexafluorophosphate, palladium acetate,
Isomerization of the double bond in tetrahydrofuran in the presence of palladium chloride, etc. or, alternatively, heating with a strongly basic reagent such as potassium t-butoxy, followed by isomerization in the presence of iodine and, if necessary, sodium hydrogen carbonate, The double bond which has been converted is removed. Alternatively, the reaction may be carried out in the presence of mercury chloride and silver oxide after isomerization. The reaction time is usually about 5 minutes to 5 days, and the reaction temperature is 0 ° C to 120 ° C.
It is. When Y has a benzyl group (including a substituted one), it can be removed by catalytic reduction in the presence of hydrogen together with palladium, palladium-carbon, palladium hydroxide and the like. As the solvent, usually, methanol, ethanol, t-butyl alcohol, water,
Tetrahydrofuran, diethyl ether, methylene chloride, chloroform, toluene, acetate, dioxane, dimethylformamide, acetic acid and a mixture thereof are used. The reaction temperature is usually 0 ° C to 100 ° C, and the reaction time is usually 5 minutes to 10 days. It is about.

The hemiacetal sugar derivative obtained by removing an allyloxy group or a benzyl group in this manner is a compound having Y as an imidate group or a brominated or fluorinated sugar having Y as a halogen atom as follows. And so on. The conversion to an imidate group is carried out in the presence of a hemiacetal compound and trichloroacetonitrile and diazabicycloundecene or potassium t-butoxide or sodium hydride. Conversion to a halogen atom can be performed by the above-mentioned R ₁₁
After acylating the position Y by the same method as the introduction of
Bromination in hydrogen bromide-acetic acid solution. This brominated form may be treated with silver fluoride in acetonitrile to lead to a fluorinated sugar. Alternatively, it may be directly fluorinated with a hemiacetal compound and diethylaminosulfur trifluoride. The reaction solvent and temperature are the same as in the case of removal of the benzyl group.

The thus obtained imidate sugar derivative and halogenated sugar can be converted into a compound having a nitrophenoxy group in Y as follows. When an imidate compound is used, p-nitrophenol (or o-nitrophenol) is used in the presence of a boron trifluoride ether complex, trimethylsilyl triflate, t-butyldimethylsilyl triflate, triethoxysilyl triflate, or the like as an acid catalyst. , M-nitrophenol). When bromide is used among the halogenated sugars, the reaction may be carried out with silver carbonate, silver oxide or the like. Alternatively, there is a method of heating in a solvent such as acetone together with an alkali metal salt of nitrophenol. In the case of a fluorinated sugar, silver perchlorate, biscyclopentadienyl hafnocene (or zirconium) chloride, silver triflate and a mixture thereof can be reacted with nitrophenol. In addition to the above, a compound obtained by acylating the position of Y shown above:
A p-nitrophenoxy group or the like can be directly introduced. For example, a p-nitrophenoxy group or the like can be directly introduced into a compound having an acetyl group at the Y position in the presence of an acid catalyst such as trimethylsilyl triflate.
In each case, the reaction temperature is -78 ° C to 100 ° C, and the reaction time is 5 minutes to 1 week. In this way, when the reaction step has progressed to some extent, the protecting group for Y can be freely and freely converted.

In Scheme 1, R ₁₁ and R ₁₃ are preferably a benzoyl group, and R ₁₂ is preferably a levulinoyl group. It is particularly preferable that the acetal structure of compound 2 is stannylene acetal. The hydroxyl group of Compound 9 synthesized by the synthesis route shown in Scheme 1 can be substituted or modified with groups represented by R _{5 to} R ₇ by a conventional method. The acylation and silylation can be performed in the same manner as described in the description of Scheme 1.

Next, a synthetic route for producing the compound of the formula (IV) from the compound of the formula (I-3) is shown in the following scheme 2.

[0045]

Embedded image 14

[0046] (wherein, R ₁₁ represents an acetyl group and equal to or greater than the deacylation hard acyl group, R ₁₄
Represents an acyl group or a silyl group which is more easily deacylated than an acetyl group. A plurality of R ₁₁ in the formula may be the same or different from each other. Y and M are represented by the formulas (I-3) and (I
It is the same as defined in V). First, Scheme 1
In the same compound 1 used in the above, an acetal group is introduced into the 4- and 6-positions to lead to the compound 10. This acetalization can be performed in the same manner as in the conversion of compound 1 → compound 2 in Scheme 1. At this time, a hemiacetal group may be introduced at the 4- and 6-positions, and the hemiacetalization can be carried out in the presence of an acid catalyst together with benzaldehyde, benzaldehyde dimethyl acetal and the like.
As the acid catalyst, zinc chloride or the like is usually used in addition to the acid catalyst used for acetalization. The solvent is the same as that used when performing acetalization, but sometimes the solvent is not added. The reaction time and temperature are the same as the conditions for acetalization. Next, an acyl group can be introduced into the 2-position and 3-position to lead to compound 11.
This acylation is carried out by compound 2 → compound 3 of Scheme 1 with R
It can be performed in the same manner as the method in which ₁₁ is introduced. The same applies to the reaction conditions.

Next, the acetal (or hemiacetal) at the 4- and 6-positions of the compound 11 can be converted to the compound 12 by removing it under acidic conditions. This reaction can be carried out in the same manner as in the reaction of compound 3 → compound 4 in Scheme 1. Removal of hemiacetal is similar to that of acetal. A substituent capable of being selectively removed under a milder condition than an acetyl group such as a levulinoyl group or a monochloroacetic acid ester group is introduced into the primary hydroxyl group of the compound 12, or a t-butyldimethylsilyl group or a t-butyldiphenyl group is introduced. The compound 13 can be introduced by introducing a silyl group such as a silyl group. The introduction of a levulinoyl group, a monochloroacetic ester group, etc. is the same as the introduction of R ₁₂ of compound 4 → compound 5 in scheme 1. The introduction of the silyl group is the same as the case where a silyl group is introduced into R _{13 of} compound 2 → compound 3 in scheme 1. An acyl group (R ₁₁ ) can be introduced into the 4-position of compound 13 to lead to compound 14. This acylation reaction is the same as the introduction of an acyl group at the 2-position and 3-position of compound 11 in Scheme 2.

Next, compound 14 can be converted to compound 15 by removing R ₁₄ (an acyl group or a silyl group which is more easily deacylated than an acetyl group). Removal of R ₁₄ can be accomplished by reacting compound 6 → compound 7 in scheme 1 or compound 8 → compound 9 (R
₍ Corresponding to the case where a silyl group is used for ₁₃ )). Thereafter, Compound 15 can be subjected to sulfation using a sulfation reagent to lead to Compound 16. The conditions for sulfation are the same as in the conversion of compound 7 → compound 8 in Scheme 1. After deprotection of compound 16, compound 17
Can be obtained. This deprotection can be performed in the same manner as in the compound 8 → the compound 9 in the scheme 1.

There is also a method of leading compound 14 from compound 1 via compound 18. That is, a silyl group is selectively introduced into the primary hydroxyl group of Compound 1 to convert it into Compound 18. The conditions for this silylation are the same as in the case where a silyl group is introduced into R _{13 of} compound 2 → compound 3 in scheme 1.
Next, the remaining three hydroxyl groups are acylated to lead to compound 14. The conditions for this acylation are as follows:
This is the same as the introduction of an acyl group at the position.

Further, there is a method of leading compound 17 from compound 12 via compound 19. The primary hydroxyl group of compound 12 is selectively sulfated to lead to compound 19 first. This selective sulfation can be performed using the sulfation reagent shown in Scheme 1 and reaction conditions. As in the case of compound 4 → compound 8 in scheme 1, the 6-position hydroxyl group has higher reactivity than the 4-position, so that the 6-position is selectively sulfated. Compound 19 can be deprotected leading to compound 17. The conditions for this deprotection are the same as those for compound 16 → compound 17.

When compound 17 is obtained in one step from compound 1, the reaction is carried out in the same manner as in the reaction of compound 4 → compound 8 in scheme 1 except that bisdibutyltin oxide is used instead of dibutyltin oxide used in scheme 1. . Conversion of Y can be appropriately performed in the same manner as described in Scheme 1. Further, similarly to the compound 9 in the scheme 1, the hydroxyl group of the compound 17 can be substituted or modified by the groups represented by R _{5 to} R ₇ . In Scheme 2, R ₁₁ is preferably a benzoyl group, and R ₁₄ is preferably a silyl group.

Next, a synthetic route for producing the compound of the formula (III) from the compound of the formula (I-2) is shown in the following scheme 3.

[0053]

Embedded image Fifteen

[0054] (wherein, R ₁₁ represents an acetyl group and equal to or greater than the deacylation hard acyl group, R ₁₃
Represents an acyl group or a silyl group which is hard to be deacylated more than or equal to an acetyl group. A plurality of R ₁₁ in the formula
May be the same or different from each other. Y and M have the same meanings as defined in the above formulas (I-2) and (III). First, the hydroxyl group at the 3-position of compound 4 synthesized in scheme 1 can be selectively acylated to give compound 28. This selective acylation reaction can be carried out in the same manner as the acylation reaction described in Scheme 1 and Scheme 2, but usually, the carboxylic acid used, its acid anhydride, and the corresponding acid halide (more The molar ratio of (preferably chloride) is usually 0.8 to 1.5 mol per 1 mol of compound 41. Reaction times are generally short,
Reaction temperatures are often low, but there are exceptions. Usually, the temperature is from -10C to 80C for about 1 minute to 5 days. In addition, this compound 4 can also be synthesized from the compound 20 of scheme 1 via the compounds 22 and 23. Compound 22 and Compound 2
The synthesis method of Compound 3 is the same as Compound 1 → Compound 2 → Compound 3 in Scheme 1. Compound 28 can be converted to compound 24 by introducing a sulfate group using the sulfating reagent described above. Compound 24 can be further deprotected to lead to compound 25. This deprotection method is also the same as described in Scheme 1 and Scheme 2.

As an alternative to obtaining compound 25, compound 1
There is a method of synthesizing Compound 26 and Compound 27 from Compound 2. That is, the protecting group R ₁₃ can be introduced into the primary hydroxyl group of the compound 12 to convert it into the compound 26 in the same manner as in the compound 2 → the compound 3 in the scheme 1. Thereafter, a sulfate group was introduced into the 4-position by the sulfation method described above to give Compound 2
After that, the compound is deprotected to give compound 25. All of these synthesizing methods can be carried out using the methods described above. Conversion of Y can be appropriately performed in the same manner as described in Scheme 1. Further, similarly to the compound 9 in the scheme 1, the hydroxyl group of the compound 25 can be substituted or modified by groups represented by R _{5 to} R ₇ . In Scheme 3, R ₁₁ and R ₁₃ are preferably a benzoyl group.

The compound represented by the formula (II) or (IV) can also be produced from a galactose compound having two sulfate groups at the 3- and 6-positions represented by the formula (VIII). First, the compound represented by the formula (VIII) will be described. In the formula (VIII), R ₅ and R ₆ are the same hydrogen atom, acyl group or silyl group as in the formula (II) or (IV), and a compound in which R ₅ and R ₆ are hydrogen atoms is preferable. The compound of the formula (VIII) in which R ₅ and R ₆ are hydrogen atoms can be synthesized by the method shown in Scheme 4 below.

[0057]

Embedded image 16

(In the formula, Y and M have the same meanings as defined in the above formulas (II) and (IV).) In the same compound 1 used in the scheme 1 and the scheme 2, the 3-position and the 6-position At the same time, a sulfate group can be introduced. In the case of sulfation at two places, first, compound 1 is subjected to reflux dehydration in dry benzene-tetrahydrofuran (THF) together with bistributyltin oxide and reacted with a sulfation reagent. As the sulfating reagent, those similar to those described in the description of Scheme 1 can be used (trimethylamine sulfur trioxide complex is shown as an example in Scheme 4). The amount of bistributyltin oxide used is preferably 1 to 3 mol per 1 mol of compound 11. The sulfating reagent is used in an amount of usually at least 2 mol, preferably 3 to 4 mol, per 1 mol of compound 11. The reaction time is usually 30 minutes to 5 minutes.
Time and reaction temperature are usually 0 to 80 ° C. Scheme 4
In the above, compound 29 in which M is a trimethylamino group is obtained, and if necessary, M can be converted by a conventional treatment. For example, a compound having M as an alkali metal atom can be obtained by treatment with a Na ⁺ type ion exchange resin. The hydroxyl group of the obtained compound 29 is represented by Scheme 1
In the same manner as described for compound 9 by conventional methods R _5,
The group represented by R ₆ can be substituted or modified.

Next, a method for synthesizing the compounds of the formulas (II) and (IV) from the compound of the formula (VIII) will be described.
The compound having two sulfate groups represented by the formula (VIII) can selectively hydrolyze only one sulfate group using an enzyme (sulfatase). Usually, this enzymatic reaction is carried out at pH 3-8, preferably 6-7.5.
In a buffer such as acetic acid-sodium acetate buffer, phosphate buffer, Tris buffer, etc., at 10 to 50 ° C, preferably 35 ° C.
~ 38 ° C. The reaction time is usually from 5 minutes to
One week. The selectivity of the sulfate group to be hydrolyzed differs depending on the origin of the enzyme (for example, whether it is derived from a mollusk or a microorganism), the reaction time, and the like. The enzyme has the formula (VI
Preferably 1 to 30 wt.
%use. Compound 9 of Scheme 1 from Compound 29 above
And the route to obtain compound 17 of Scheme 2 is shown in Scheme 5 below.

[0060]

Embedded image 17

(Wherein Y and M have the same meanings as defined in formulas (II) and (IV) above). When compound 29 is treated with sulfatase at about 37 ° C. in the above-mentioned buffer, sulfatase Compound 17 or Compound 9 can be obtained selectively or as a mixture depending on the type, reaction time, etc.

Next, the galactose polymer compound of the present invention represented by the formula (V), (VI), (VII) or (IX) will be described. The compound represented by the formula (V), the formula (VI), the formula (VII) or the formula (IX) is a compound represented by the formula (II) or the formula (I) in which the main chain represented by A is a pendant (modified residue).
II), a polymer compound having a compound of the formula (IV) or the formula (VIII). A is

[0063]

Embedded image 18

(Wherein, * is bonded to the 1-position of the pyranose ring. L is alkylene, arylene, —O—, —CO—,
Represents a linking group consisting of one or more combinations selected from -NH-. ). The alkylene of L preferably has 1 to 20 carbon atoms, and the arylene preferably has 6 to 30 carbon atoms, and may be substituted. Examples of the linking group include

[0065]

Embedded image 19

(Wherein, n represents an integer of 1 to 5). A is particularly preferably

[0067]

Embedded image 20

One or more selected from the above are homopolymerized or copolymerized. B is a repeating unit having no galactose residue, and is a portion for adjusting the content of the galactose residue of A as a pendant in the polymer compound, and is provided at a predetermined ratio if necessary.
B is, for example, a repeating unit derived from an ethylenically unsaturated monomer, for example, a repeating unit derived from acrylamides, methacrylamides, acrylates, methacrylates, olefins or the like; And a repeating unit derived from acrylamide or methacrylamide. Particularly preferred combinations of A and B are as follows.

[0069]

Embedded image 21

(Where n represents an integer of 1 to 5) In the formulas (V), (VI) and (VII), p and q are molar ratios (%), and 0 <p ≦ 100, and the sum of p and q is 100, and p is preferably 5 or more. Although the molecular weight of the polymer compound is not particularly limited, it is preferably 10,000 or more, and the terminal is not particularly limited, such as a hydrogen atom or an alkyl group.

The method for synthesizing the compound of the formula (V) will be described by taking as an example the case where the compound 9 in Scheme 1 is polymerized. When polymerizing, Y is converted into a polymerizable group (for example, acrylamidophenoxy group, allylphenoxy group, vinylbenzyloxy group, allylalkyloxy group, etc.), and this is homopolymerized or copolymerized with another compound. .
For example, when compound 9 has a p-nitrophenoxy group as Y, this nitro group is reduced and converted to a p-aminophenoxy group. The reaction is palladium,
Catalytic reduction is performed in the presence of hydrogen together with palladium carbon, palladium hydroxide and the like. As the solvent, methanol, ethanol, water, tetrahydrofuran, diethyl ether, methylene chloride, chloroform, toluene, acetate, a mixture thereof and the like are usually used. The reaction temperature is usually 0 ° C to 100 ° C, and the reaction time is usually 5 ° C. Minutes to about 10 days. Alternatively, the reaction can be performed in the presence of lithium aluminum hydride and sodium borohydride. As the solvent, methanol, ethanol,
Tetrahydrofuran, diethyl ether and the like are usually used. The reaction temperature is usually 0 ° C to 100 ° C, and the reaction time is
It is usually about 30 minutes to 10 days.

The reduced p-aminophenoxy sugar derivative can be further reacted with acrylic acid or acrylic acid chloride to convert it into a p-acrylamidophenoxy derivative. This reaction is the same as the method of introducing R ₁₁ in Scheme 1. Next, the monomer of the p-acrylamidophenoxy derivative is homopolymerized or copolymerized with acrylamide, methacrylamide, acrylate or the like to obtain a polymer. This polymerization reaction can be carried out by reacting only the monomer in the case of homopolymerization or the monomer in the case of copolymerization with ammonium persulfate, tetraethylenediamine or the like in the presence of acrylamide or the like. Note that the above series of operations, ie, the reduction, amidation, and polymerization reactions were performed in the compounds 8 and 21 in Scheme 1 having a protecting group, and also in the compound 9 after deprotection was completed. It can be carried out. When deprotection is carried out after conducting a polymerization reaction using compound 8 or 21, it can be carried out in the same manner as in the case of the monomer. Further, the p-acrylamidophenoxy derivative has been described as an example, but the operation of polymerizing is the same when a monomer having another polymerizable group is used for Y. Further, a plurality of types of monomers having different Y can be copolymerized. The synthesis of the compound of the formula (VI) or the formula (VII) from the compound of the formula (III) or the formula (IV) can be carried out in the same manner as described above. Scheme 2
Can be polymerized from Compounds 16 and 19 having a protecting group or Compound 17 having been completely deprotected. In Scheme 3, Compound 2 having a protecting group can be used.
Polymerization can be carried out from Compounds 4 and 27 or from Compound 25 which has been completely deprotected. The same applies to the case where the compound of the formula (IX) is synthesized from the compound of the formula (VIII),
Compound 29 in Scheme 4 or a compound in which the hydroxyl group of compound 29 has been converted to a protecting group can also be polymerized in the same manner as described above.

[0073]

EXAMPLES The present invention will be described in more detail with reference to examples. In the scheme 1, synthesis was performed in the case where R ₁₁ and R ₁₃ were a benzoyl group, M was a sodium atom, and Y was a p-nitrophenoxy group. The numbers of each compound correspond to those shown in Scheme 1. Example 1 (Compound 1 → Compound 2) Compound 1 (3.0 g, 9.96 mmol) was added to anhydrous acetone 600 m
l Dowex H ⁺ (trade name, manufactured by Dow Chemical Company) 120
mg was added and the mixture was stirred at room temperature for 18 hours. 10 ml of triethylamine was added, Dowex was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography (Merck,
60F ₂₅₄ , 300ml, methylene chloride-methanol = 100: 1)
To give Compound 2 (2.21 g, 65%). [α] D
-58.7 (C = 1.7, methanol) mp 154
-157 ° C

Example 2 (Compound 2 → Compound 3) Compound 2 (104 mg, 0.305 mmol) and dimethylaminopyridine (5 mg) were dissolved in pyridine (10 ml), and benzoyl chloride (0.11 ml, 0.95 mmol) was added. Stirred. 1
After 7 hours, ice chips and a saturated aqueous solution of sodium hydrogen carbonate were added to the reaction solution, and the mixture was extracted three times with 50 ml of chloroform. The extracted organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and water, dried over magnesium sulfate, and evaporated under reduced pressure. The residue is subjected to silica gel chromatography (Merck, 60F
Purification with ₂₅₄ , 30 ml, toluene-ethyl acetate 4: 1) gave compound 3 (158 mg, 94%). [α] D + 4.6 (C = 1.6, chloroform) mp 177-178 ° C. Elemental analysis calcd. for C ₂₉ H ₂₇ NO ₁₀ C: 63.38, H: 4.95, N: 2.55 found C: 63.46, H: 4.94 , N: 2.49

Example 3 (Compound 3 → Compound 4) Compound 3 (4.03 g, 7.3 mmol), methylene chloride 30 ml, methanol 60 ml, camphorsulfonic acid (CSA) (682 m
g, 2.9 mmol) and stirred at room temperature. After 16.5 hours,
5 ml of triethylamine was added and the mixture was concentrated under reduced pressure. The residue was immediately subjected to silica gel chromatography (Merck, 60F
Purification with ₂₅₄ , 400 ml, methylene chloride-methanol = 10: 1) gave compound 4 (3.35 g, 90%). [α] D + 14.2 (C = 0.68, methanol) mp 192-194 ° C. Elemental analysis calcd. for C ₂₆ H ₂₃ NO ₁₀ C: 61.30, H: 4.55, N: 2.75 found C: 60.82, H: 4.63, N: 2.64

Example 4 (Compound 4 → Compound 8) Compound 4 (0.95 g, 1.87 mmol) was dissolved in benzene (60 ml), dibutyltin oxide (488 mg, 1.96 mmol) was added, and the mixture was used for 3 hours using a Dean-Stark apparatus. The generated water was removed over time while refluxing. The remaining benzene was distilled off under reduced pressure, dissolved in dimethylformamide (DMF) (20 ml), and sulfur trioxide trimethylamine complex (331 mg, 2.
43 mmol) and 1 ml of triethylamine, and the mixture was stirred at 40 ° C. After 3 hours, methanol was added to the reaction solution, and the mixture was stirred for a while and then distilled off under reduced pressure. The residue was purified by silica gel chromatography (Merck, 60F ₂₅₄ , 200 ml, methylene chloride-methanol 10: 1.5) to give sodium-type ion. After treatment with an exchange resin (DowexNa ⁺ ), crystallization from hot ethanol-ether-hexane gave compound 8 (1.0
g, 90%). [α] D + 22.9 (C = 0.8, methanol) mp 169-172 ° C

Example 5 (Compound 8 → Compound 9) Compound 8 (1.64 g, 2.68 mmol) was dissolved in methanol (40 ml), 28% sodium methylate (0.35 ml) was added, and the mixture was stirred at room temperature for 5 hours. Dowex H ⁺ type (product name,
After neutralization with Dow Chemical Co., Ltd.) to pH 7, Dowex was removed by filtration, and the filtrate was concentrated under reduced pressure. Silica gel residue
Purification with 60 RP-18 (Merck, using water as eluent) gave compound 9 (990 mg, 92%). [α] D -41.8 (C = 1.3, methanol), mp 194 ° C. FABMS m / z 426 (M + Na) Elemental analysis calcd. for C ₁₂ H ₁₄ NNaO ₁₁ S C: 35.74, H: 3.50, N : 3.47 S: 7.95 found C: 35.19, H: 3.58, N: 3.35 S: 7.34

Example 6 (Compound 1 → Compound 9) Compound 1 (60 mg, 0.20 mmol) was added to tetrahydrofuran (30
The mixture was dissolved in benzene (30 ml), dibutyltin oxide (54.5 mg, 0.22 mmol) was added, and the generated water was removed with time while refluxing for 2 hours using a Dean-Stark apparatus. The reaction solution was distilled off under reduced pressure, dissolved in dimethylformamide (DMF) (5 ml), and sulfur trioxide trimethylamine complex (30.5 mg, 0.22 mmol) and triethylamine 0.1% were added.
5 ml was added and the mixture was stirred at 40 ° C. After 18 hours, methanol was added to the reaction solution, and after stirring for a while, the reaction solution was distilled off under reduced pressure, and the residue was subjected to silica gel 60 RP-18 (Merck,
Compound 9 (62.2 mg, 77.4) was purified using water as an eluent).
%). Data such as the physical constants of Compound 9 are the same as in Example 4.

Next, in the above scheme 2, R ₁₁ is a benzoyl group, R ₁₄ is a tert-butyldimethylsilyl group, M
Was a sodium atom and Y was a p-nitrophenoxy group. The number of each compound is shown in Scheme 2.
Correspond to those shown in FIG.

Example 7 (Compound 1 → Compound 14) Compound 1 (100 mg, 0.33 mmol) was dissolved in 5 ml of pyridine, and tert-butyldimethylsilyl chloride (120 mg, 0.1 mg) was dissolved.
80 mmol), dimethylaminopyridine (5 mg) and 0.5 ml of triethylamine, and the mixture was stirred at room temperature for 18 hours. Subsequently, benzoyl chloride (0.173 ml, 1.5 mmol) was added, and the mixture was further reacted at room temperature for 18 hours. Ice chips and a saturated aqueous solution of sodium hydrogen carbonate were added to the reaction solution, and the mixture was extracted three times with 50 ml of chloroform. The extracted organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and water, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (Merck, 60F _254, 60ml, of toluene - ethyl acetate 1
0: 1) to give compound 14 (158 mg, 94%). [α] D + 121.6 (C = 2.0, chloroform) Elemental analysis calcd. for C ₃₉ H ₄₁ NO ₁₁ Si C: 64.36, H: 5.68, N: 1.92 found C: 64.23, H: 5.63, N: 1.82

Example 8 (Compound 14 → Compound 15) Compound 14 (50 mg, 0.069 mmol) was dissolved in 5 ml of tetrahydrofuran, and 0.04 ml of acetic acid and 0.275 ml of 1.0 M tetrabutylammonium fluoride were added thereto, followed by stirring for 18 hours. The mixture was diluted with 100 ml of chloroform, washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (10 ml, toluene-ethyl acetate 3:
Purification in 1) gave compound 15 (38.5 mg, 91.3%). [α] D +148.1 (C = 3.9, chloroform)

Example 9 (Compound 15 → Compound 16) Compound 15 (1.94 g, 3.16 mmol) was dissolved in 30 ml of dimethylformamide, and 1 ml of triethylamine and a trimethylamine complex of sulfur trioxide (3.8 g, 27.3 mmol) were added.
Stirred at 0 ° C. for 48 hours. Purification by silica gel column chromatography gave Compound 16 (1.87 g, 83%). [α] D + 106.2 (C = 1.8, methanol) Elemental analysis calcd. for C ₃₃ H ₂₆ NNaO ₁₄ S ・ H ₂ OC: 54.03, H: 3.85, S: 4.37, N: 1.91 found C: 53.83, H: 3.79, S: 4.15, N: 1.83

Example 10 (Compound 16 → Compound 17) Compound 16 (80 mg, 0.11 mmol) was dissolved in methanol (2 ml), 28% sodium methylate (0.048 ml) was added, and the mixture was stirred at room temperature for 1 hour. Dowex H ⁺ type (product name,
After neutralization with Dow Chemical Co., Ltd.) to pH 7, Dowex was removed by filtration, and the filtrate was concentrated under reduced pressure. Silica gel residue
Purification with 60 RP-18 (Merck, using water as eluent) gave compound 17 (31.6 mg, 70.1%). [α] D-64.2 (C = 3.1, water) FABMS m / z 426 (M + Na) Elemental analysis calcd. for C ₁₂ H ₁₄ NNaO ₁₁ S · 2H ₂ OC: 32.81, H: 4.13, N: 3.19 S : 7.30 found C: 32.42, H: 3.44, N: 2.95 S: 6.88

Next, in the above scheme 4, synthesis was performed in the case where M was a trimethylamino group and Y was a p-nitrophenoxy group, and using the obtained compound 29, a compound 17 was synthesized by the method of scheme 5. The numbers of each compound correspond to those shown in Schemes 4 and 5.

Reference Example 1 (Compound 1 → Compound 29) 78.7 mg of Compound 1 was dissolved in 15 ml of dry benzene and 15 ml of THF, and 0.203 ml of bistributyltin oxide and 333 mg of sulfur trioxide / trimethylamine complex were added.
Stirred at C for 3 days. Silica gel 60 RP-18
(Merck, using water as eluent) to give compound 29
(132 mg, quant.) Was obtained. ¹ H-NMR (D ₂ O, 300 MHz) Acetone was used as an internal standard (2.07 ppm). δ 8.1 and 7.1 ppm (aromatics), 5.18 (H1, d, 7.8 H
z), 4.36 (H3, dd, 3.3 and 9.9 Hz), 4.30 (H4, bd,
3.3 Hz), 4.20-4.08 (m, H5, H6 and H6 '), 3.88 (H3,
dd, 7.8 and 9.6 Hz).

REFERENCE EXAMPLE 2 (Compound 29 → Compound 17) 80 mg of Compound 29 was dissolved in 2 ml of acetic acid-sodium acetate (0.25 M, pH 6.8) at 37 ° C. for 3 days.
5w Sulfatase from snail (Helix pomatia)
It was left in the presence of t%. After completion of the reaction, gel filtration (LH-
20, eluent is water) and silica gel 60 RP-18
(Merck, water as eluent) to give compound 17
(60 mg, 94%). The result of elemental analysis and NMR confirmed that the obtained compound was Compound 17.

Example 11 700 mg (1.74 mmol) of compound 9 obtained in Example 6
l) was dissolved in methanol (200 ml), palladium-carbon (30 mg) was added, and the mixture was reduced under a hydrogen atmosphere to convert a nitro group into an amino group. After 3 hours, the palladium-carbon was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure to obtain 648 mg of p-aminophenyl-3-sulfated galactoside which was positive for the ninhydrin reaction. Subsequently, the compound was subjected to acryloylation without further purification. That is, the obtained p-aminophenyl-3-sulfated galactoside was dissolved in 20 ml of methanol, and 1.6 ml of triethylamine and 0.1 ml of acrylic acid chloride were dissolved.
267 ml (10 ml of methylene chloride solution) were added, and 5
Stirred for hours. After that, neutralize with ion exchange resin,
After adjusting the pH to 7, the mixture was filtered to remove the ion exchange resin, and the filtrate was concentrated under reduced pressure. The residue is silica gel 60 RP-18
(Eluent: water-methanol = 1: 1, manufactured by Merck & Co.), and further treated with Dowex (Na ⁺ type) to give p-acrylamidophenyl-3-sulfated galactoside (Y of compound 9 431 mg (58%) of a compound converted to a p-acrylamidophenoxy group was obtained. The ¹ H-NMR spectrum of this compound is shown in FIG.

Reference Example 3 p-acrylamidophenyl-3 obtained in Example 11
-37 mg (0.087 mmol) of sulfated galactoside
And 62 mg of acrylamide, 1 ml of degassed water in advance
Was added, followed by sufficient nitrogen substitution. 0.01 ml of tetramethylethylenediamine and 0.01 ml of ammonium persulfate (using a solution having a concentration of 100 mg / ml H ₂ O) were added, and the mixture was shaken at 30 ° C. for 2 hours. The reaction solution was added to methanol, the precipitate was centrifuged, and the supernatant was removed. Then, a small amount of water was added, and reprecipitation was performed again in methanol. Lyophilized, 3
-32 mg of a polymer compound of sulfated galactose was obtained.
The ¹ H-NMR spectrum of this compound is shown in FIG.
FIG. 2 shows that the signal of the acrylic portion of the monomer disappeared.

[0089]

Embedded image 22

Test Example Influenza virus (A / Memphis / 1/71 (H3) to sialyl paragloposide (2-6 conjugate)
The degree of inhibition of the binding of N2)) by the polymer compound of 3-sulfated galactose obtained in Reference Example 3 was evaluated by ELISA, and the ability of the polymer compound to recognize a virus was tested. IC _{50 of the} polymer compound obtained in Reference Example 3 (concentration when inhibiting 50%)
Was about 2 times less than that of fetuin (positive control). Therefore, it is understood that the compound of the present invention can capture viruses.

[0091]

According to the present invention, a galactose compound having a specific position which is recognizable with human influenza virus or AIDS virus and which is sulfated at a specific position can be synthesized using a commercially available raw material in a conventional trisaccharide unit synthesis. It can be synthesized in fewer steps and can supply a sufficient amount. In addition, a high molecular compound having the sulfated galactose compound as a pendant can be synthesized, and an excellent effect that a novel compound that can be expected to be used as a virus capturing material can be provided is provided.

[Brief description of the drawings]

FIG. 1 is a ¹ H-NMR spectrum of the compound obtained in Example 11 .

FIG. 2 is a ¹ H-NMR spectrum of the compound obtained in Reference Example 3 .

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI A61K 31/795 A61K 31/795 C08F 220/56 C08F 220/56 (C08F 220/56 220: 58) (72) Inventor: Kazu Kobayashi Kiyoshi 3-13-10, Wadagaoka, Togo-cho, Aichi-gun, Aichi Prefecture (72) Inventor Yasuo Suzuki 52-1 Yata, Shizuoka-shi, Shizuoka Pref. 7 (56) References Carbohybrate Research Arch, Vol. 93 (1981) p. 177 -190 (58) Fields surveyed (Int.Cl. ⁷ , DB name) C07H 11/00 C07H 13/02-13/08 C07H 15/02-15/26 C07H 23/00 CAPPLUS (STN) REGISTRY (STN )

Claims (5)

(57) [Claims] 1. A galactose compound represented by the following formula (I-1), formula (I-2) or formula (I-3). Embedded image 01 (in the formula, R ₁ represents a hydrogen atom or an acyl group which is hard to be deacylated by the same degree or more as an acetyl group;
R ₂ represents a hydrogen atom or an acyl group which is more easily deacylated than an acetyl group; R ₃ represents a hydrogen atom, an acyl group or a silyl group which is harder to be deacylated than or more than an acetyl group; R ₄ is a hydrogen atom; It represents an acyl group or a silyl group that is more easily deacylated than an acetyl group. Two or three R ₁ in the formula may be the same or different from each other. Further, the substituents at the 3- and 4-positions or the 4- and 6-positions may be bonded to each other to form an acetal or a hemiacetal. However, the substituents at the 2-, 3-, 4- and 6-positions are not all hydrogen atoms. Y is nitrophenoxy
Group, aminophenoxy group, acrylamide phenoxy
Group, allylphenoxy group, allylalkyloxy group,
Represents a alkyloxy group or an allyloxy group. ) 2. A sulfated galactose compound represented by the following formula (II), formula (III) or formula (IV). Embedded image 02 (wherein, R _5, R ₆ and R ₇ are a hydrogen atom, .R ₅ to R ₇ representing an acyl group or a silyl group may be the same or different from each other. Further, the R ₆ in the formula (II) R ₇ may combine with each other to form an acetal or a hemiacetal; Y has the same meaning as described above; and M represents a hydrogen atom, an alkali metal atom, an ammonium group, or an organic amine. 3. The compound represented by the formula (I-1) according to claim 1.
Reacting a galactose compound with a sulfating reagent
Sulfated galactose represented by the following formula (II):
A method for producing a compound. Embedded image 03 (wherein R ₅ , R ₆ , R ₇ , Y and M are as defined above)
It is. ) 4. A compound represented by the formula (I-2) according to claim 1.
Reacting a galactose compound with a sulfating reagent
Characterized sulfated galactose represented by the following formula (III)
A method for producing a compound. Embedded image 04 (wherein, R ₅ , R ₆ , R ₇ , Y and M are as defined above.
It is. ) 5. The compound represented by the formula (I-3) according to claim 1.
Reacting a galactose compound with a sulfating reagent
Sulfated galactose represented by the following formula (IV):
A method for producing a compound. Embedded image 05 (wherein R ₅ , R ₆ , R ₇ , Y and M are as defined above)
It is. )