JPH11343295A - Sialic acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a sialic acid derivative useful as an antiviral, capable of showing strongly inhibitory actions on sialidase being a membrane protein of influenza virus and on hemagglutinin. SOLUTION: This compound is shown by formula I [R<1> is H or a 1-6C alkyl; R<2> is a (substituted) phenyl, a 1-20C alkyl or the like; R<3> is H or a (substituted) OH; R<4> is H, a halogen or the like; R<5> to R<8> are each a (substituted) OH; Ac is acetyl; with the proviso that R<3> and R<4> are not H at the same time] such as methyl(p-nitrophenyl 5-acetamide-4,7,8,9-tetra-O-acetamide-5-deoxy-α-D-erythro- L-gluco-2-nonulopyranosido)nate. The compound of formula I is obtained, in the case of the exemplified compound, by reacting a glucosyl bromide of formula II (Me is methyl) with sodium p-nitrophenoxide in a solvent such as N,N- dimethylformamide, for example, at a room temperature for 12 hours.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel sialic acid derivative which can be used as an active ingredient of a medicine.

[0002]

2. Description of the Related Art Since viruses, including influenza, multiply depending on the biosynthesis mechanism of the host, it is difficult to develop a drug capable of exhibiting a sufficient antiviral action specifically against the virus, and clinically. There are few known drugs that can exhibit high efficacy. For virus infection,
At present, treatment with vaccines is the most effective means, but if the virus in question is not identified, vaccines cannot be produced and used, and viruses with severe mutations However, there is a problem that the vaccine produced cannot be expected to be effective.

[0003] Influenza viruses include types A, B, and C. It is known that type A virus can pass through the human immune system as a host by drastically changing the structure of a protein as an antigen. Therefore, there is a problem that vaccine treatment cannot sufficiently cope. Recently, very effective antiviral agents have been developed based on the analysis of the crystal structure of sialidase, one of two viral membrane proteins of influenza virus (von Itzs
tein, M. et al., Nature, 363, 1883). However, since sialidase is not involved in the first stage of infection, there is a problem that this antiviral agent cannot prevent the establishment of infection itself. Therefore, two types of membrane proteins (sialidase and hemagglutinin)
It is necessary to develop an antiviral agent that can exert a strong inhibitory effect on both.

[0004]

An object of the present invention is to provide a compound capable of exhibiting excellent antiviral activity against influenza virus and the like. More specifically, it is an object of the present invention to provide a compound that can exert a strong inhibitory action on both of two types of membrane proteins (sialidase and hemagglutinin) of influenza virus. Another object of the present invention is to provide an antiviral agent comprising the above compound as an active ingredient.

As a result of intensive efforts to solve the above problems, the present inventors have found that a sialic acid derivative having a substituent on the 3-position carbon atom has the above-mentioned characteristics, and have completed the present invention. I came to.

That is, the present invention provides the following formula (I):

Embedded image (Wherein R ¹ represents a hydrogen atom or a C _1-6 alkyl group; R ² represents a phenyl group which may have a substituent,
_1-20 alkyl group, C _1-20 alkenyl group,-(C
H ₂ ) _k- [NH- (CH ₂ ) _m -NH] _n -Y (Y represents a phosphatidylethanolamine residue or a polyglutamic acid residue, and k and m each independently represent 2 to 1
Represents an integer of 0, n represents 0 or 1, provided that when n represents 1, Y represents a phosphatidylethyl group); R ³ represents a hydrogen atom or a hydroxyl group which may have a substituent; ⁴ is a hydrogen atom, a halogen atom, an azide group,
Represents an amino group which may have a substituent, or a hydroxyl group which may have a substituent; R ⁵ , R ⁶ , R ⁷ , and R
⁸ each independently represents a hydroxyl group which may have a substituent. Provided that R ³ and R ⁴ are not hydrogen atoms at the same time) or a salt thereof.

[0007] In another aspect, the present invention provides a medicament comprising a compound represented by the above formula (I) or a physiologically acceptable salt thereof as an active ingredient. This medicament is useful for preventing and / or treating viral diseases such as influenza virus infection. From still another viewpoint, use of the compound represented by the formula (I) or a salt thereof for the manufacture of the medicament; and a method for preventing and / or treating a viral disease such as influenza virus infection, There is provided a method comprising the step of administering to a mammal, including a human, an effective amount of a compound represented by the formula (I) or a physiologically acceptable salt thereof.

[0008]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The terms used in the present specification have the following meanings. The alkyl moiety in the alkyl group or the functional group containing the alkyl moiety may be linear, branched, cyclic, or a combination thereof. For example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, a cyclopropylmethyl group, a cyclobutyl group, and the like can be used.

When the phenyl group represented by R ² has a substituent, the number and position of the substituent are not particularly limited. For example, a substituted or unsubstituted C _1-6 alkyl group such as a methyl group, a trifluoromethyl group, and a hydroxyethyl group; a C _1-6 alkoxy group such as a methoxy group and an ethoxy group; a halogen atom (in the present specification, a halogen atom In this case, any of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom may be used); a substituted or unsubstituted C _1-6 alkanoyl group such as an acetyl group and a trifluoroacetyl group; a benzyl group and a p-methoxy group A substituted or unsubstituted aralkyl group such as a benzyl group or a p-chlorobenzyl group; a nitro group; a cyano group; a substituted or unsubstituted aryl group such as a phenyl group or a chlorophenyl group; Substituted aroyl group; carboxyl group; ethoxycarbonyl group, te
a C _1-6 alkoxycarbonyl group such as an rt-butoxycarbonyl group; a substituted or unsubstituted amino group such as an amino group, a monomethylamino group, and an acetylamino group; and the like, but is not limited thereto. .
Of these, a nitro group is preferred, and the substitution position is p-
Position is preferred.

A C _1-20 alkyl group represented by R ² or C
_{The 1-20} alkenyl group may be linear, branched, cyclic, or a combination thereof. The number of unsaturated bonds in the alkenyl group is not particularly limited, but is, for example, one to three, and preferably one. -(CH ₂ ) _k- [N
H- In the group represented by _{(CH 2) m -NH] n} -Y, Y is showing a phosphatidylethanolamine residue or polyglutamic acid residue, k is 2, n is preferably zero. In this case, Y is a nitrogen atom of phosphatidylethanolamine - (CH ₂₎ k _- is preferably bound to. Polyglutamic acid residues include N
It is preferable to use a residue of terminally acetylated polyglutamic acid, and it is preferable that k is 2 and n is 1.

R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , or R ⁸
When represents a hydroxyl group having a substituent, the substituent on the hydroxyl group is not particularly limited, for example, a substituent commonly used as a protecting group for a hydroxyl group, or a substituent used for removing a hydroxyl group may be used. Can be. Examples of such a substituent include a substituted or unsubstituted C _1-6 alkanoyl group such as an acetyl group and a trifluoroacetyl group; and a substituted or unsubstituted group such as a benzyl group, a p-methoxybenzyl group, and a p-chlorobenzyl group. An alkylsilyl group such as a trimethylsilyl group; a substituted or unsubstituted C _1-6 alkyl group such as a methyl group, a trifluoromethyl group, or a hydroxyethyl group; a substituted or unsubstituted aryl group such as a phenyl group or a chlorophenyl group; Group;
A substituted or unsubstituted aroyl group such as a benzoyl group and a chlorobenzoyl group; a C _1-6 alkoxycarbonyl group such as an ethoxycarbonyl group and a tert-butoxycarbonyl group; a p-toluenesulfonyl group, a methanesulfonyl group;
Examples thereof include a substituted sulfonyl group such as a trifluoromethanesulfonyl group, but are not limited thereto.

When R ⁴ represents an amino group having a substituent, one or two substituents on the amino group may be the same or different, and the type thereof is not particularly limited. It is preferable to use a commonly used substituent or the like as the protecting group. Examples of such a substituent include a substituted or unsubstituted C _1-6 alkanoyl group such as an acetyl group and a trifluoroacetyl group; a benzyl group;
substituted or unsubstituted aralkyl groups such as p-methoxybenzyl group and p-chlorobenzyl group; substituted or unsubstituted C _1-6 alkyl groups such as methyl group, trifluoromethyl group and hydroxyethyl group; phenyl group, chlorophenyl A substituted or unsubstituted aryl group such as a group; a substituted or unsubstituted aroyl group such as a benzoyl group or a chlorobenzoyl group; a C _1-6 alkoxycarbonyl group such as an ethoxycarbonyl group or a tert-butoxycarbonyl group. It is possible, but not limited to these.

The compound of the present invention may form a salt depending on the type of the substituent. As the salt, for example, hydrochloride,
Mineral salts such as sulfates; or organic acid salts such as p-toluenesulfonate; metal salts such as sodium, potassium and calcium salts; ammonium salts; organic ammonium salts such as methylammonium salts; Examples include, but are not limited to, amino acid salts. The compounds in free form or salts thereof, as well as any hydrates or solvates thereof, are included in the scope of the present invention.

The compound of the present invention has an asymmetric carbon,
Although it may be present as an optically active substance, stereoisomers such as optically active substances or diastereoisomers, arbitrary mixtures of stereoisomers, and racemic forms are all included in the scope of the present invention. Note that R ⁶ and R ⁷ in the formula (I)
The steric notation for represents the relative configuration thereof, and should not be interpreted as indicating the absolute configuration of the compound represented by the formula (I).

Preferred examples of the compound of the present invention include R
²Is a p-nitrophenyl group, and R³Is hydrogen atom, hydroxyl
Or a substituted sulfonyloxy group,⁴Is a hydrogen source
Atom, halogen atom, azide group, amino group, or C_1-6
An alkanoyloxy group; R⁵, R⁶, R⁷,as well as
R⁸Are each independently a hydroxyl group or C_1-6Alkanoyl
Compounds that are oxy groups can be mentioned. More preferred
As a new compound, R ²Is a p-nitrophenyl group
R³Is a hydrogen atom, a hydroxyl group, or trifluoromethane
A sulfonyloxy group,⁴Is hydrogen atom, fluorine atom
R, azide, amino, or acetoxy;
⁵, R⁶, R⁷, And R⁸Are each independently a hydroxyl group or
Compounds that are acetoxy groups can be mentioned. Ma
In these compounds, R¹Is a hydrogen atom or methyl
It is preferred that it is a hydroxyl group.

Among the compounds of the present invention, compounds in which R ² is a phenyl group which may have a substituent include, for example, known bromohydrin compounds (Okamoto, K., et al., Bull.
l. Chem. Soc. Jpn., 60, pp. 631-636, 1987) according to the following scheme. In the scheme, Ac represents an acetyl group, Me represents a methyl group,
Tf indicates a trifluoromethanesulfonyl group, Py indicates pyridine, DMF indicates dimethylformamide, THF indicates tetrahydrofuran, and TASF indicates tris (dimethylamino) -sulfonium difluorotrimethylsilicate.

[0017]

Embedded image

In the examples of the present specification, the methods for preparing the representative compounds of the present invention described in the schemes are described specifically and in detail. It is understood that any compound included in the general formula (I) can be easily produced by appropriately selecting a reaction raw material, a reaction reagent, a reaction condition and the like according to the above, and adding an appropriate modification or modification as necessary. Let's do it. However, the method for producing the compound of the present invention is not particularly limited, and it goes without saying that compounds produced by any method are included in the scope of the present invention. Compounds 2 to 13 shown in the above schemes are particularly preferred compounds of the present invention, but the compounds of the present invention are not limited to these specific compounds.

R ² is a C _1-20 alkyl group;
Compounds that are _1-20 alkenyl groups are described in Okamoto et al.
kamoto, K., et al., Bull. Chem. Soc. Jpn., 60, pp.
637-643, 1987), an alkyl group or an alkenyl group may be introduced into the epoxy compound described above, and deprotection may be performed if necessary. The compound having an alkenyl group (for example, an allyl group) introduced therein is subjected to ozonolysis, and the obtained ketone is reacted with phosphatidylethanolamine to obtain-(C
A compound having H ₂ ) _k -Y (Y is a phosphatidylethanolamine residue) can be produced. Further, the above ketone body is reacted with a diamine compound represented by H ₂ N— (CH ₂ ) _m —NH ₂ as a linker, and further, a reactive acetylated polyglutamic acid derivative is reacted with the terminal amino group of the reaction product. This makes it possible to produce a compound into which a polyglutamic acid residue has been introduced. As a method for introducing polyglutamic acid, for example, a method described in Japanese Patent Application No. 10-194 can be employed.

The compound of the present invention is expected to have an inhibitory action on both influenza virus membrane-bound proteins, hemagglutinin and sialidase, and can also be expected to have a similar inhibitory action on membrane-bound proteins of other viruses. . Therefore, the compound of the present invention or a salt thereof is useful as an active ingredient of a medicament for preventing and / or treating viral infections such as influenza virus infection. The active ingredient of the medicament provided by the present invention includes a compound in free form represented by the formula (I) and a physiologically acceptable salt thereof, and a hydrate and a solvate thereof. The substance of choice can be used. The medicament of the present invention is generally, as a pharmaceutical composition comprising the above-mentioned substance as an active ingredient and a pharmaceutical additive,
It can be used orally or parenterally. Those skilled in the art can appropriately select the form of the medicament of the present invention, the additives for preparations to be used, and the method for producing the preparations.

[0021]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples. In the following examples, the compound numbers correspond to the compound numbers in the above scheme. In the examples,
TLC was performed on silica gel 60-F254 (Merck) and detected by fluorescence quenching and sulfuric acid coloration. Column chromatography was performed on silica gel (Merck, Kieselgel 60). Optical rotation was measured using a HORIBA SEPA-200 polarimeter. IR spectra were recorded using a HORIBA FT-200 spectrometer. ^{The 1} H NMR spectrum was measured at 270 MHz (JEOL EX-270) using CDCl ₃ or CD ₃ OD (internal standard: tetramethylsilane, δ = 0), or D ₂ O (internal standard: 3-trimethylsilyl-2,2). , 3,3-d ₄ - sodium propionate was measured with a solution of [delta] = 0). HRFAB-MS is measured with JEOL JMS-HX-110,
SI-MS was measured on a Finigan MAT TSQ 700 mass spectrometer.

Example 1: Methyl (p-nitrophenyl 5-acetamido-4,7,8,9-tetra-O-acetyl-5-deoxy-α-D-
Erythro-L-gluco-2-nonulopyranoside) nate (Compound 2) Glycosyl bromide (Compound 1,500 mg,
0.90 mmol) and sodium p-nitrophenoxide (52
(0 mg, 2.7 mmol, 3 eq) of a dry N, N-dimethylformamide (DMF) solution (50 ml) was stirred at room temperature for 12 hours. At this time, the disappearance of Compound 1 was confirmed by TLC. The solution was concentrated and the residue was repeatedly distilled with xylene to leave traces of DMF
Was removed. The residue was purified by a silica gel column (n-hexane-acetone 4: 3) to obtain Compound 2 (430 mg, 76%).

[Α] _D ²⁵ + 51.5 ° (c 0.63, CHCl ₃ ). ¹ H NMR (CDCl ₃ ) δ: 1.94, 2.05, 2.07, 2.11, 2.16 (e
ach s, 3 H, OAc × 4, NHAc), 3.20 (d, 1 H, J _{3OH, 3} 4.
9 Hz, OH-3), 3.70 (s, 3 H, COOMe), 4.06 (dd, 1 H, J
_{9 ', 9} 12.3, J _{9', 8} 5.8 Hz, H-9 '), 4.12 (dd, 1 H, J
_3,4 8.9 Hz, H-3), 4.24 (dd, 1 H, J _9,8 2.5 Hz, H-9),
4.25 (ddd, 1 H, J _5,4 8.9, J _{5, NH} 10.0, J _5,6 10.0 H
z, H-5), 4.88 (dd, 1 H, J _6,7 1.3 Hz, H-6), 5.23
(t, 1 H, H-4), 5.27 (dd, 1 H, J _7,8 8.9 Hz, H-7),
5.34 (ddd, 1 H, H-8), 5.70 (d, 1 H, NH), 7.16, 8.21
(AX, each 2 H, J 9.2 Hz, nitrophenyl), Anal.Calcd. For C ₂₆ H ₃₂ N ₂ O ₁₆ : C, 49.68; H, 5.13;
N, 4.46. Found: C, 49.63; H, 5.09; N, 4.42.

Example 2: p-Nitrophenyl 5-acetamido-
5-Deoxy-β-D-erythro-L-gluco-2-nonulopyranoside acid (Compound 3). LiOH.H ₂ O (12 mg, 0.288 mg, 6 eq) dissolved in water (1 ml)
In a methanol solution containing compound 2 (30 mg, 0.048 mmol) (5
ml). After stirring at room temperature for 1 hour, the reaction mixture was adjusted to pH 4 by adding the cation exchange resin Dowex-50 (H ⁺ ),
The resin was filtered off and the filtrate was evaporated to dryness. Sephadex G
After subjecting to -25 chromatography (eluent: water) and freeze-drying, compound 3 (20 mg, 93%) was obtained as an amorphous solid.

[Α] _D ²⁵ + 40.0 ° (c 0.23, H ₂ O). ¹ H NMR (D ₂ O) δ: 2.04 (s, 3 H, NHAc), 3.55 (d, 1
H, J _7,8 8.6 Hz, H-7), 3.61 (dd, 1 H, J _{9 ', 9} 12.3, J
_{9 ', 8} 6.4 Hz, H-9'), 3.77-3.87 (m, 4 H), 4.11 (t, 1
H, J _5,4 = J _5,6 8.6 Hz, H-5), 4.32 (d, 1 H, J _3,4 10.
8 Hz, H-3), 7.28, 8.21 (AX, each 2 H, J 9.2 Hz, nitrophenyl). ESIMS m / z: 445.0 [M-1] ^- (in H ₂ O-MeOH, 1: 1) .

EXAMPLE 3 Methyl (p-nitrophenyl 5-acetamido-4,7,8,9-tetra-O-acetyl-5-deoxy-3-O-trifluoromethylsulfonyl-α-D-erythro-L -Gluco-
2-Nonunopyranoside) nate (Compound 4) Compound 2 (200 mg, 0.32 mmol) was added to dichloromethane (6 ml).
And pyridine (0.152 ml, 1.91 mmol, 6 eq), and cooled (salt bath) to give trifluoromethanesulfonic anhydride (Tf ₂
O) (0.206 ml, 1.28 mmol, 4 eq) was added dropwise over 2 minutes. The ice bath was removed and the reaction was followed by TLC (n-hexane-acetone 2: 1). After 20 minutes, the reaction solution was cooled on ice 0.1
After washing sequentially with M HCl and water, it was dried over anhydrous Na ₂ SO _{4 and} concentrated under reduced pressure. The residue was purified on a silica gel column (n-hexane-
Purification with acetone (2: 1) gave compound 4 (163 mg, 67%).

[Α] _D ²⁵ + 35.3 ° (c 0.39, CHCl ₃ ). ¹ H NMR (CDCl ₃ ) δ: 1.95, 2.06, 2.12, 2.13, 2.18 (e
ach s, 3 H, OAc × 4, NHAc), 3.67 (s, 3 H, COOMe),
4.05 (dd, 1 H, J _{9 ', 9} 12.3, J _{9', 8} 3.9 Hz, H-9 '), 4.
18 (dd, 1 H, J _9,8 2.3 Hz, H-9), 4.39 (ddd, 1 H, J
_5,4 10.4, J _{5, NH} 8.5, J _5,6 10.8 Hz, H-5), 5.08 (d,
1 H, H-6), 5.15 (d, 1 H, J _3,4 10.4 Hz, H-3), 5.32
(m, 2 H, H-7, 8), 5.35 (t, 1 H, H-4), 5.64 (d, 1
H, NH), 7.14, 8.23 (AX, each 2 H, J 9.2 Hz, nitrophenyl).

Example 4: Methyl (p-nitrophenyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-3-
Fluoro-α-D-erythro-L-manno-2-nonulopyranoside) nate (compound 5) Tris (dimethylamino) -sulfonium difluorotrimethyl silicate (TASF) (86 mg, 0.31 mmol) capped with a rubber septum Placed in flask. Compound 4 (8
(0 mg, 0.105 mmol) in anhydrous tetrafuran (5 ml) was added via syringe. Then, the reaction solution was placed in an argon
After heating under reflux for an hour, pour into water and add ethyl acetate (20
(ml × 3). The extract was washed with saturated saline and dried
Dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column (n-hexane-acetone 2: 1) to give compound 5 (40
mg, 60%).

[Α] _D ²⁵ + 20.7 ° (c 0.34, CHCl ₃ ). ¹ H NMR (CDCl ₃ ) δ: 1.97, 2.06, 2.14, 2.16, 2.20 (e
ach s, 3 H, OAc × 4, NHAc), 3.74 (s, 3 H, COOMe),
4.11 (ddd, 1 H, J _5,4 9.5, J _{5, NH} 8.7, J _5,6 11.1 H
z, H-5), 4.17 (dd, 1 H, J _{9 ', 9} 12.1, J _{9', 8} 4.5 Hz,
H-9 '), 4.25 (dd, 1H, J _9,8 2.4 Hz, H-9), 4.75 (dd,
1 H, J _6,7 1.2 Hz, H-6), 5.22 (dd, 1 H, J _3,4 2.7, J
_{3, F} 49.2 Hz, H-3), 5.33 (dd, 1 H, H-4), 5.34 (dd,
1 H, J _7,8 7.9 Hz, H-7), 5.41 (ddd, 1 H, H-8), 5.43
(d, 1 H, NH), 7.22, 8.19 (AX, each 2 H, J 9.2 Hz,
HRMS (FAB) cacld. For C ₂₆ H ₃₂ FN ₂ O ₁₅ [M + H] ⁺ : 631.181
9; found: 631.1790.

Example 5: p-Nitrophenyl 5-acetamido-
3,5-dideoxy-3-fluoro-α-D-erythro-L-manno-2
-Nonulopyranoside acid (Compound 6) A methanol solution containing Compound 5 (14 mg. 0.02 mmol) (5 m
LiOH · H ₂ O (6 mg dissolved in water (1 ml) to l), 0.13 mg, 6 e
q) was added. After stirring at room temperature for 1 hour, the reaction mixture was treated in the same manner as in the preparation of compound 3, and after freeze-drying,
(9 mg, 90%) was obtained as an amorphous solid.

[Α] _D ²⁵ + 13.7 ° (c 0.18, H ₂ O). ¹ H NMR (D ₂ O) δ: 2.04 (s, 3 H, NHAc), 3.62 (d, 1
H, J _7,8 8.7 Hz, H-7), 3.64 (dd, 1 H, J _{9 ', 9} 11.2, J
_{9 ', 8} 6.2 Hz, H-9'), 3.86 (m, 2 H, H-8, 9), 3.97 (d
d, 1 H, J _4,3 2.2, J _4,5 10.2 Hz, H-4), 4.18 (d, 1
H, J _6,5 10.2 Hz, H-6), 4.26 (t, 1 H, H-5), 5.33 (d
d, 1 H, J _{3, F} 49.5 Hz, H-3), 7.35, 8.24 (AX, each 2
H, J 9.2 Hz, nitrophenyl). ESIMS m / z: 447.0 [M-1] ^- (in H ₂ O-MeOH, 1: 1).

Example 6: Methyl (p-nitrophenyl 5-acetamido-3,4,7,8,9-penta-O-acetyl-5-deoxy-α-D
-Erythro-L-manno-2-nonulopyranoside) nate (Compound 7). Compound 4 (65 mg, 0.086 mmol) was dissolved in dry benzene (10 ml) containing 18-crown-6 (11 mg, 0.043 mmol), Cesium acetate (50 ml, 0.256 mmol, 3 eq) was added. The reaction mixture was then heated at reflux for 36 hours under an argon atmosphere. The reaction mixture is concentrated under reduced pressure, and the residue is
(n-hexane-acetone 4: 3) to purify compound 7 (40 m
g, 70%).

[Α]_D ^{twenty five} + 21.8 ° (c 0.41, CHCl_Three).¹ H NMR (CDCl_Three) δ: 1.95, 2.04, 2.06, 2.17, 2.20,
2.26 (each s, 3 H, OAc × 5, NHAc), 3.70 (s, 3 H, CO
OMe), 4.13 (dd, 1 H, J_{9 ', 9} 12.6, J_{9 ', 8} 5.4 Hz, H-
9 '), 4.24 (dd, 1 H, J_9,8 3.4 Hz, H-9), 4.36 (ddd,
1 H, J_5,4 10.8, J _{5, NH} 9.9, J_5,6 10.8 Hz, H-5), 4.
64 (dd, 1 H, J_6,7 1.6 Hz, H-6), 5.13 (dd, 1 H, J
_4,3 3.2 Hz, H-4), 5.22 (d, 1 H, NH), 5.33 (dd, 1
H, J_7,8 8.9 Hz, H-7), 5.44 (ddd, 1 H, H-8), 5.88
(d, 1 H, H-3), 7.13, 8.17 (AX, each 2H, J 9.2 Hz,
HRMS (FAB) cacld. For C₂₈H₃₅N_TwoO₁₇ [M + H]⁺: 671.193
6; found: 671.1943.

Example 7: p-Nitrophenyl 5-acetamido-
5-deoxy-α-D-erythro-L-manno-2-nonulopyranoside acid (Compound 8) A methanol solution containing Compound 7 (20 mg. 0.03 mmol) (5 m
LiOH · H ₂ O (9 mg dissolved in water (1 ml) to l), 0.19 mg, 6 e
q) was added. After stirring at room temperature for 1 hour, the reaction mixture was treated in the same manner as in the preparation of compound 3, and after lyophilization, compound 8 (12 mg, 91%) was obtained as an amorphous solid.

[Α] _D ²⁵ + 9.2 ° (c 0.13, H ₂ O). ¹ H NMR (D ₂ O) δ: 2.04 (s, 3 H, NHAc), 3.55 (d, 1
H, J _7,8 8.7 Hz, H-7), 3.67 (dd, 1 H, J _{9 ', 9} 12.4, J
_{9 ', 8} 6.8 Hz, H-9'), 3.89 (dd, 1 H, J _9,8 2.2 Hz, H-
9), 3.92 (ddd, 1 H, J _8,7 8.7 Hz, H-8), 4.09 (d, 1
H, J _6,5 9.5 Hz, H-6), 4.32 (dd, 1 H, J _4,3 2.4, J
_4,5 9.5 Hz, H-4), 4.41 (t, 1 H, H-5), 5.02 (d, 1
H, H-3), 7.20, 8.21 (AX, each 2 H, J 9.2 Hz, nitrophenyl). ESIMS m / z: 445.0 [M-1] ^- (in H ₂ O-MeOH, 1: 1).

Example 8: Methyl (p-nitrophenyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3-azido-3,5-dideoxy-α-D-erythro-L-manno- 2-Nonulopyranoside) nate (compound 9) Compound 4 (50 mg, 0.066 mmol) and sodium azide (43 mg, 0.66 mmol) were added to anhydrous DMF (5 ml), and the mixture was stirred at 70 ° C for 30 minutes. The reaction mixture was poured into water (10 ml) and extracted with ethyl acetate (20 ml × 3). The extract was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column (n-hexane-acetone 3: 2) to obtain compound 9 (36 mg, 85%).

[Α] _D ²⁵ + 20.7 ° (c 0.67, CHCl ₃ ). IR (CCl ₄ ) 2120 cm ^-1 (N ₃ ). ¹ H NMR (CDCl ₃ ) δ: 1.95, 2.06, 2.14, 2.17, 2.20 (e
ach s, 3 H, OAc × 4, NHAc), 3.74 (s, 3 H, COOMe),
4.07 (ddd, 1 H, J _5,4 10.8, J _{5, NH} 9.6, J _5,6 10.8 H
z, H-5), 4.16 (dd, 1 H, J _{9 ', 9} 12.2, J _{9', 8} 4.3 Hz,
H-9 '), 4.23 (dd, 1 H, J _9,8 2.7 Hz, H-9), 4.57 (d, 1
H, J _3,4 2.8 Hz, H-3), 4.70 (dd, 1 H, J _6,7 1.0 Hz,
H-6), 5.22 (dd, 1 H, H-4), 5.31 (dd, 1 H, J _7,8 9.2
Hz, H-7), 5.34 (d, 1 H, NH), 5.41 (ddd, 1 H, H-
8), 7.20, 8.21 (AX, each 2 H, J 9.2 Hz, nitrophenyl). HRMS (FAB) cacld. For C ₂₆ H ₃₂ FN ₅ O ₁₅ [M + H] ⁺ : 654.189
5; found: 654.1892.

Example 9: p-Nitrophenyl 5-acetamido-
3-azido-3,5-dideoxy-α-D-erythro-L-manno-2-
Nonulopyranoside acid (Compound 10) Compound 9 (20 mg. 0.03 mmol) was dissolved in methanol (5 ml), and LiOH.H ₂ O (9 mg, 0.19 mg, 6 e) dissolved in water (1 ml) was dissolved.
q) was added. After stirring at room temperature for 1 hour, the reaction mixture was treated in the same manner as in the preparation of compound 3, and after lyophilization, compound 10 (9 mg, 90%) was obtained as an amorphous solid.

[Α] _D ²⁵ + 31.0 ° (c 0.12, H ₂ O). ¹ H NMR (D ₂ O) δ: 2.03 (s, 3 H, NHAc), 3.56 (dd, 1
H, J _7,8 9.2, J _7,6 1.2Hz, H-7), 3.63 (dd, 1 H, J
_{9 ', 9} 12.3, J _{9', 8} 6.7 Hz, H-9 '), 3.82 (ddd, 1 H, J
_8,9 2.4 Hz, H-8), 3.84 (dd, 1 H, H-9), 3.92 (dd, 1
H, J _4,3 3.4, J _4,5 10.3 Hz, H-4), 4.15 (dd, 1 H, J
_6,5 10.5 Hz, H-6), 4.26 (t, 1 H, H-5), 4.64 (d, 1
H, H-3), 7.23, 8.24 (AX, each 2 H, J 9.2 Hz, nitrophenyl). ESIMS m / z: 469.9 [M-1] ^- (in H ₂ O-MeOH, 1: 1).

Example 10: Methyl (p-nitrophenyl 5-acetamido-3-azido-3,5-dideoxy-α-D-erythro-L-manno-2-nonulopyranoside) nate (Compound 11) Compound 9 (20 mg) 0.03 mmol) in methanol (5 ml) and methanolic sodium methoxide (28%) (0.1 ml).
Was added. After the mixture was stirred at room temperature for 1 hour, the pH was adjusted to 7 by adding a cation exchange resin Dowex-50 (H ⁺ ).
The resin was removed by filtration, the filtrate was evaporated to dryness, and the residue was subjected to silica gel column chromatography (CHCl ₃ -MeOH 7: 1) to obtain compound 11 (14 mg, 94%) as an amorphous solid.

[Α] _D ²⁵ + 29.0 ° (c 0.53, CHCl ₃ ). ¹ H NMR (CD ₃ OD) δ: 2.00 (s, 3 H, NHAc), 3.49 (d, 1
H, J _7,8 8.6 Hz, H-7), 3.62 (dd, 1 H, J _{9 ', 9} 11.0, J
_{9 ', 8} 6.1 Hz, H-9'), 3.74 (s, 3 H, COOMe), 3.75 (dd
d, 1 H, J _8,9 3.4 Hz, H-8), 3.78 (dd, 1 H, H-9), 3.
85 (dd, 1 H, J _{4 , 3} 3.0, J _4,5 9.8 Hz, H-4), 4.18 (d
d, 1 H, J _6,5 9.8 Hz, H-6), 4.23 (t, 1H, H-5), 4.54
(d, 1 H, H-3), 7.37, 8.22 (AX, each 2 H, J 9.2 H
z, nitrophenyl). ESIMS m / z: 486.2 [M + 1] ⁺ (in H ₂ O-MeOH, 1: 1).

Example 11: Methyl (p-nitrophenyl 5-acetamido-3-amino-3,5-dideoxy-α-D-erythro-L-manno-2-nonulopyranoside) nate (Compound 12) 80% pyridine water ( Compound 11 (10 mg, 0.021 mmol)
Was dissolved and hydrogen sulfide was bubbled with stirring at room temperature for 36 hours. The reaction solution was concentrated to dryness, and the residue was purified by a silica gel column (CHCl ₃ -MeOH 6: 1) to obtain Compound 12 (7 mg, 70%).

¹ H NMR (D ₂ O) δ: 2.04 (s, 3 H, NHAc),
3.52 (s, 3 H, COOMe), 3.63 (d, 1 H, J _7,8 8.3 Hz, H
-7), 3.68 (dd, 1 H, J _{9 ', 9} 13.2, J _{9', 8} 6.2 Hz, H-
9 '), 3.77 (dd, 1 H, J _9,8 4.3 Hz, H-9), 3.84 (ddd,
1 H, H-8), 4.15 (d, 1 H, J _6,5 9.6 Hz, H-6), 4.22
(t, 1 H, J _5,4 9.6 Hz, H-5), 4.30 (dd, 1 H, J _4,3 3.
7 Hz, H-4), 4.47 (d, 1 H, H-3), 6.86, 8.10 (AX, ea
ch 2 H, J 9.2 Hz, nitrophenyl). ESIMS m / z: 460.2 [M + 1] ⁺ (in H ₂ O-MeOH, 1: 1).

Example 12: p-Nitrophenyl 5-acetamido-
3-amino-3,5-dideoxy-α-D-erythro-L-manno-2-
Nonulopyranoside acid (Compound 13) Compound 12 (4 mg. 0.01 mmol) was dissolved in methanol (5 ml), and LiOH.H ₂ O (3 mg, 0.06 mg, 6 e) dissolved in water (1 ml) was dissolved.
q) was added. After stirring at room temperature for 1 hour, the reaction mixture was treated according to the method for preparing compound 3, and after lyophilization, compound 13 (3 mg, 92%) was obtained as an amorphous solid.

[Α] _D ²⁹ + 23.9 ° (c 0.19, H ₂ O). ¹ H NMR (D ₂ O) δ: 2.02 (s, 3 H, NHAc), 3.52 (d, 1
H, J _7,8 9.2 Hz, H-7), 3.61 (dd, 1 H, J _{9 ', 9} 11.5, J
_{9 ', 8} 5.8 Hz, H-9'), 3.73-3.83 (m, 2 H, H-8, 9), 3.
86 (d, 1 H, J _6,5 10.3 Hz, H-6), 4.21 (t, 1 H, J _5,4
10.3 Hz, H-5), 4.33 (dd, 1 H, J _4,3 3.8 Hz, H-4),
4.19 (d, 1 H, H-3), 6.79, 8.05 (AX, each 2 H, J 9.
ESIMS m / z: 444.2 [M-1] ^- (in H ₂ O-MeOH, 1: 1).

[0046]

The compound of the present invention is expected to have an inhibitory effect on both hemagglutinin and sialidase which are membrane-bound proteins of influenza virus, and is useful as an active ingredient of, for example, an antiviral agent.

Claims (5)

[Claims] (1) The following formula (I): [Wherein, R ¹ represents a hydrogen atom or a C _1-6 alkyl group; R ² represents a phenyl group which may have a substituent,
_1-20 alkyl group, C _1-20 alkenyl group,-(C
H ₂ ) _k- [NH- (CH ₂ ) _m -NH] _n -Y (Y represents a phosphatidylethanolamine residue or a polyglutamic acid residue, and k and m each independently represent 2 to 1
Represents an integer of 0, n represents 0 or 1, provided that when n represents 1, Y represents a phosphatidylethyl group); R ³ represents a hydrogen atom or a hydroxyl group which may have a substituent; ⁴ is a hydrogen atom, a halogen atom, an azide group,
Represents an amino group which may have a substituent, or a hydroxyl group which may have a substituent; R ⁵ , R ⁶ , R ⁷ , and R
⁸ each independently represents a hydroxyl group which may have a substituent. Provided that R ³ and R ⁴ are not both hydrogen atoms at the same time]. ^2. The compound according to claim 1, wherein R ² is a phenyl group which may have a substituent, or a salt thereof. Wherein R ³ is p- nitrophenyl group, ^{R 3}
There is a hydrogen atom, a hydroxyl group, or a substituted sulfonyloxy group, R ⁴ is a hydrogen atom, a halogen atom, an azido group, an amino group, or a C _1-6 alkanoyloxy group, R ^5,
R ⁶ , R ⁷ and R ⁸ each independently represent a hydroxyl group or C
The compound according to claim 1, which is a _1-6 alkanoyloxy group or a salt thereof. Wherein R ² is p- nitrophenyl group, ^{R 3}
There is a hydrogen atom, a hydroxyl group, or a trifluoromethanesulfonyloxy group, R ⁴ is a hydrogen atom, a fluorine atom, an azido group, an amino group, or an acetoxy group, R ^5,
The compound according to claim 1, wherein R ⁶ , R ⁷ , and R ⁸ are each independently a hydroxyl group or an acetoxy group, or a salt thereof. 5. The compound according to claim 1, wherein R ¹ is a hydrogen atom or a methyl group, or a salt thereof.