JP6786095B2 - Sialic acid analog - Google Patents

Description

The present invention relates to novel sialic acid analogs useful as sialidase inhibitors, and their uses and production methods.

Sialic acid exists at the terminal of glycolipids and glycolipids in the living body and is involved in the physiological activity of glycolipids and glycolipids. In order to elucidate the function of sialic acid at the molecular level, sialic acid derivatives have been actively synthesized.

Sialidase (sialic acid hydrolyzing enzyme), also called neuraminidase, is involved in the release of the virus by hydrolyzing the sialic acid present at the end of the sugar chain on the surface of virus-infected cells, so inhibiting this enzyme is not possible in the body. It leads to prevention of virus growth in. Sialidase inhibitors have been developed by mimicking the transition state structure of sialic acid in the hydrolysis reaction of sialidase, which is called the "transition state analog". Cialidase inhibitors are useful as medicines such as antiviral agents, immunomodulators, and anticancer agents.

The "transition state analog" has a structural development based on 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA), and by introducing a highly polar functional group at the 4-position of sialic acid, it becomes sialidase. It has been reported that the affinity between the two is improved (Non-Patent Documents 1 and 2). For example, as a sialic acid derivative in which a guanidino group is introduced at the 4-position of sialic acid, Relenza ^TM and Inavir ^TM having a structure having sp ² carbons at the ^2- and 3-positions of sialic acid, similar to DANA, have been put into practical use.
2-position sp ³ carbon of sialic acid, a structure having a sp ² carbon position 3 has not been reported so far.

Nature 1993, 363, 418. Glycoconj. J. 1993, 10, 40.

An object of the present invention is to provide a novel sialic acid analog useful as a sialidase inhibitor.

As a result of intensive research to solve the above-mentioned problems, the present inventors have placed the second position of sialic acid, which has a different basic skeleton from DANA, which was the basis of the structural development of the conventional "transition state analog". When a 3-position exomethylene-type sialic acid analog having a structure having sp ^3- carbon and sp ^2- carbon at the 3-position was newly synthesized and the sialidase inhibitory activity was examined, the activity was significantly higher than that of DANA. This has led to the completion of the present invention.

［式中、Ｘ^１は−Ｏ−Ｒ^１（式中、Ｒ^１は置換又は非置換の糖残基、置換又は非置換の芳香族基、又は置換又は非置換のＣ_１−６−脂肪族炭化水素基を表す。）又はフッ素原子を表し；Ｘ^２は−Ｏ−Ｒ^２（式中、Ｒ^２は水素原子、置換又は非置換の芳香族基、又は置換又は非置換のＣ_１−６−アルキル基を表す。）、Ｃ_１−６−アルキル基で置換されていてもよいアジド基、Ｃ_１−６−アルキル基で置換されていてもよいグアニジノ基又は−Ｎ（Ｒ^ａ）（Ｒ^ｂ）（式中、Ｒ^ａ及びＲ^ｂは同一又は異なり、水素原子又はＣ_１−６−アルキル基を表す。）を表し；Ｘ^３は置換又は非置換のＣ_１−６−アルキル基、又は置換又は非置換のＣ_１−６−アルコキシ基を表し；Ｘ^４は水素原子、メチル基又はハロゲン原子を表し、Ｘ^５は−ＮＨＣＯ−Ｒ^３（式中、Ｒ^３は水素原子、置換又は非置換のＣ_１−６−アルキル基又はヒドロキシメチル基を表す。）、水酸基、又は置換又は非置換のＣ_１−６−アルコキシ基を表し；Ｘ^６はカルボキシル基、リン酸基、ホスホノ基、スルホ基、スルフィノ基、アルコキシカルボニル基、リン酸アルキルエステル基、ホスホン酸アルキルエステル基、スルホン酸アルキルエステル基又はスルフィン酸アルキルエステル基を表す。］
で示される化合物又はその塩。
（２）Ｒ^１が置換又は非置換の糖残基である前記（１）に記載の化合物又はその塩。
（３）Ｒ^１が置換又は非置換のガラクトース残基である前記（１）に記載の化合物又はその塩。
（４）Ｒ^１が置換又は非置換のフェニル基で１位の水酸基が置換されたガラクトース残基である前記（１）に記載の化合物又はその塩。
（５）前記（１）〜（４）のいずれかに記載の化合物又はその塩を有効成分として含有するシアリダーゼ阻害剤。
（６）次式（II）：

［式中、Ｘ^２は−Ｏ−Ｒ^２（式中、Ｒ^２は水素原子、置換又は非置換の芳香族基、又は置換又は非置換のＣ_１−６−アルキル基を表す。）、Ｃ_１−６−アルキル基で置換されていてもよいアジド基、Ｃ_１−６−アルキル基で置換されていてもよいグアニジノ基又は−Ｎ（Ｒ^ａ）（Ｒ^ｂ）（式中、Ｒ^ａ及びＲ^ｂは同一又は異なり、水素原子又はＣ_１−６−アルキル基を表す。）を表し；Ｘ^３は置換又は非置換のＣ_１−６−アルキル基、又は置換又は非置換のＣ_１−６−アルコキシ基を表し；Ｘ^４は水素原子、メチル基又はハロゲン原子を表し、Ｘ^５は−ＮＨＣＯ−Ｒ^３（式中、Ｒ^３は水素原子、置換又は非置換のＣ_１−６−アルキル基又はヒドロキシメチル基を表す。）、水酸基、又は置換又は非置換のＣ_１−６−アルコキシ基を表し；Ｘ^６ａはアルコキシカルボニル基、リン酸アルキルエステル基、ホスホン酸アルキルエステル基、スルホン酸アルキルエステル基又はスルフィン酸アルキルエステル基を表し；Ｒ’は炭素原子を介して結合している有機基を表す。］
で示される化合物又はその塩を、１価の金の塩又は錯体の存在下、次式（III）：
Ｒ^１−ＯＨ （III）
（式中、Ｒ^１は置換又は非置換の糖残基、置換又は非置換の芳香族基、又は置換又は非置換のＣ_１−６−脂肪族炭化水素基を表す。）
で示される化合物と反応させることを含む次式（Ｉ’）：

（式中、Ｘ^２、Ｘ^３、Ｘ^４、Ｘ^５、Ｘ^６ａ及びＲ^１は前記と同義である。）
で示される化合物又はその塩の製造方法。 That is, the gist of the present invention is as follows.
(1) The following equation (I):

[In the formula, X ¹ is -OR ¹ (in the formula, R ¹ is a substituted or unsubstituted sugar residue, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted C _1-6 -aliphatic group. Represents a hydrocarbon group) or a fluorine atom; X ² is -OR ² (in the formula, R ² is a hydrogen atom, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted C _1-6. -. represents an alkyl _{group), C 1-6} - alkyl optionally azido group optionally substituted with a _{group, C 1-6} - alkyl group optionally substituted guanidino group, or -N ^(R a) ^{(R b} ) (In the formula, ^Ra and R ^b are the same or different and represent a hydrogen atom or a C _1-6 -alkyl group); X ³ is a substituted or unsubstituted C _1-6 -alkyl group, or Substituted or unsubstituted C _1-6 -alkoxy group; X ⁴ represents a hydrogen atom, a methyl group or a halogen atom, X ⁵ represents a −NHCO-R ³ (in the formula, R ³ is a hydrogen atom, substituted or non-substituted Represents a substituted C _1-6 -alkyl group or hydroxymethyl group), a hydroxyl group, or a substituted or unsubstituted C _1-6 -alkoxy group; X ⁶ represents a carboxyl group, a phosphate group, a phosphono group, a sulfo. Represents a group, a sulfino group, an alkoxycarbonyl group, a phosphoric acid alkyl ester group, a phosphonic acid alkyl ester group, a sulfonic acid alkyl ester group or a sulfinic acid alkyl ester group. ]
A compound or a salt thereof.
(2) The compound or salt thereof according to (1) above, wherein R ¹ is a substituted or unsubstituted sugar residue.
(3) The compound according to (1) above or a salt thereof, wherein R ¹ is a substituted or unsubstituted galactose residue.
(4) The compound according to (1) above or a salt thereof, wherein R ¹ is a galactose residue in which the hydroxyl group at the 1-position is substituted with a substituted or unsubstituted phenyl group.
(5) A sialidase inhibitor containing the compound according to any one of (1) to (4) above or a salt thereof as an active ingredient.
(6) The following equation (II):

[In the formula, X ² is −O-R ² (in the formula, R ² represents a hydrogen atom, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted C _1-6 -alkyl group), C. _An azide group optionally substituted with a _1-6 -alkyl group, a guanidino group optionally substituted with a C _1-6 -alkyl group or -N ( ^Ra ) (R ^b ) (in the formula, ^Ra and R ^b is the same or different and represents a hydrogen atom or a C _1-6 -alkyl group); X ³ is a substituted or unsubstituted C _1-6 -alkyl group or a substituted or unsubstituted C _1-6. -Representing an alkoxy group; X ⁴ represents a hydrogen atom, a methyl group or a halogen atom, and X ⁵ is a -NHCO-R ³ (in the formula, R ³ is a hydrogen atom, substituted or unsubstituted C _1-6 -alkyl group. Or a hydroxymethyl group), a hydroxyl group, or a substituted or unsubstituted C _1-6 -alkoxy group; X ^6a is an alkoxycarbonyl group, a phosphate alkyl ester group, a phosphonic acid alkyl ester group, a sulfonic acid alkyl ester. Represents a group or sulfinate alkyl ester group; R'represents an organic group attached via a carbon atom. ]
In the presence of a monovalent gold salt or complex, the compound represented by (III):
R ^1- OH (III)
(In the formula, R ¹ represents a substituted or unsubstituted sugar residue, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted C _1-6 -aliphatic hydrocarbon group.)
The following formula (I'), which comprises reacting with the compound represented by

(In the formula, X ² , X ³ , X ⁴ , X ⁵ , X ^6a and R ¹ are synonymous with the above.)
A method for producing a compound or a salt thereof.

According to the present invention, the basic skeleton is different from DANA, which was the basis of the structural development of the "transition state analog" of the conventional sialic acid derivative, and the 3-position exo is expected to become a lead compound for a new sialidease inhibitor. Methylene-type sialic acid analogs can be provided.

It is a figure which shows an example of the compound which has the structure which imitated glycoprotein among the compound of this invention. It is a figure which shows an example of the compound which has the structure which imitated a glycolipid among the compound of this invention. It is a figure which shows the result of having measured the sialidase inhibitory activity of a test compound.

The present invention relates to a compound represented by the formula (I) or a salt thereof, a sialidase inhibitor containing the compound or a salt thereof as an active ingredient, and a method for producing the compound or a salt thereof.

In the present specification, examples of the aromatic group include aromatic hydrocarbon groups such as phenyl group, tolyl group and naphthyl group; frill group, thienyl group, pyrrolyl group, oxazolyl group, isooxazolyl group, thiazolyl group, isothiazolyl group and imidazolyl Aromatic heterocyclic groups such as a group, a triazolyl group (for example, 1H-1,2,4-triazol-1-yl group), a pyrazolyl group, a pyridyl group, a pyrimidinyl group, a pyridadinyl group, a pyrazinyl group, a quinolyl group, and an isoquinolyl group. Can be mentioned.

The aromatic group is C _1-6 such as a halogen atom (for example, fluorine atom, chlorine atom, bromine atom, iodine atom) and an acyl group (for example, formyl group, acetyl group, propanoyl group, butanoyl group, pentanoyl group, hexanoyl group and the like. -Adiphilic acyl group; Aroyl group such as benzoyl group and toluoil group), acyloxy group (for example, formyloxy group, acetoxy group, propanoyloxy group, butanoyloxy group, pentanoyloxy group, hexanoyloxy group and the like C _1-6 -aliphatic acyloxy group; alloyloxy group such as benzoyloxy group, toluoiloxy group), hydroxyl group, carboxyl group, C _1-6 -alkoxy group (for example, methoxy group, ethoxy group, propoxy group), acetamide group, It may be substituted with one or more substituents selected from a carbamoyl group, a cyano group, a nitro group, an aromatic group (for example, a phenyl group) and the like.

Examples of the C _1-6 -alkyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group (1-methylpropyl group), tert-butyl group, pentyl group and isopentyl. Examples thereof include a group, a 1-ethylpropyl group, a hexyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. The C _1-6 -alkyl group is a hydroxyl group, a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), an amino group, a mono or dialkylamino group, a C _1-6 -alkoxy group, an oxo group, and an aromatic group. It may be substituted with one or more substituents selected from a group group, a heterocyclic group and the like.

As the C _1-6 -aliphatic hydrocarbon group, in addition to the above C _1-6 -alkyl group, a vinyl group, a 1-propenyl group, an allyl group, a 1-butenyl group, a 2-butenyl (crotyl) group and a pentenyl group can be used. C _2-6 -alkenyl group such as group, 3-methyl-2-butenyl (prenyl) group, hexenyl group; ethynyl group, 1-propynyl group, 2-propynyl (propargyl) group, 3-butynyl group, pentynyl group, Examples thereof include a C _2-6 -alkynyl group such as a hexynyl group. The C _1-6 -aliphatic hydrocarbon group includes a hydroxyl group, a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), an amino group, a mono or dialkylamino group, a C _1-6 -alkoxy group, and an oxo. It may be substituted with one or more substituents selected from a group, an aromatic group, a heterocyclic group and the like.

Examples of the C _1-6 -alkoxy group include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group and hexyl. Examples thereof include an oxy group, a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group and a cyclohexyloxy group. The C _1-6 -alkoxy group may be substituted with one or more substituents selected from an aromatic group, an acyl group, a hydroxyl group, a carboxyl group, a halogen atom, a C _1-6 -alkoxy group and the like.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Examples of the alkoxycarbonyl group include a carbonyl group substituted with the C _1-6 -alkoxy group.

Examples thereof include a phosphoric acid alkyl ester group, for example, a phosphoric acid alkyl ester group in which the alkyl is the C _1-6 -alkyl group.

Examples of the phosphonate alkyl ester group include a phosphonate alkyl ester group in which the alkyl is the C _1-6 -alkyl group.

Examples of the sulfonic acid alkyl ester group include a sulfonic acid alkyl ester group in which the alkyl is the C _1-6 -alkyl group.

Examples of the sulfinic acid alkyl ester group include a sulfinic acid alkyl ester group in which the alkyl is the C _1-6 -alkyl group.

As R ¹ in the -O-R ¹ represented by X ¹ in the formula (I) is, in terms of sialidase inhibitory activity, a substituted or unsubstituted sugar residue are preferred.

The sugar residue is not particularly limited, and is, for example, a galactose residue, a glucose residue, an N-acetylglucosamine residue, a glucuronic acid residue, a glucosamine residue, a mannose residue, a xylose residue, and an N-acetyl. A monosaccharide residue selected from a galactosamine residue, a galactosamine residue, an N-acetylmannosamine residue, a mannosamine residue, a sialic acid residue, etc., and an oligosaccharide or polysaccharide residue composed of the monosaccharide residue. Can be mentioned.

The substituted or unsubstituted sugar residue represented by R ^1, preferably a substituted or unsubstituted galactose residues, more preferably a substituted or unsubstituted phenyl group (e.g., p- nitrophenyl group) at the 1-position Examples thereof include galactose residues in which the hydroxyl groups of the above are substituted.

As the compound of the present invention, a compound having a 2,3-sialyllactose structure is particularly preferable from the viewpoint of sialidase inhibitory activity.

Examples of the substituted or unsubstituted sugar residue include a structure that mimics a glycolipid (for example, ganglioside (sialoglycolipid)) or a glycoprotein (FIGS. 1 and 2). In FIG. 1, R is not particularly limited, and examples thereof include sugar chains, peptides, and alkyl groups.

The substituted or unsubstituted aromatic group represented by R ¹ is preferably substituted with one or more substituents selected from a nitro group, a C _1-6 -alkoxy group, a halogen atom and an alkyl halide group. Examples include phenyl groups.

The substituted or unsubstituted C _1-6 -aliphatic hydrocarbon group represented by R ¹ preferably includes an allyl group, a 2-butenyl (crotyl) group, a 3-methyl-2-butenyl (prenyl) group and the like. Can be mentioned.

Examples of X ² include an azide group substituted with a hydroxyl group, a C _1-6 -alkoxy group, an azido group, an amino group, a guanidino group, or a C _1-6 -alkyl group, an amino group or a guanidino group.

Examples of X ³ include -CH (OH) -CH (OH) -CH ₂ OH and -O-CH (CH ₂ CH ₃ ) ₂ .

Preferred examples of X ⁴ include a hydrogen atom, a fluorine atom, and a chlorine atom.

Examples of X ⁵ include an acetamide group and -NHCOCH ₂ OH.

Examples of X ⁶ include a carboxyl group, a phosphoric acid group, a phosphono group, a sulfo (sulfonic acid) group, and a sulfino group.

The salt of the compound represented by the formula (I) is preferably a pharmaceutically acceptable salt, and when the compound represented by the formula (I) has an acidic substituent such as a carboxyl group or a phenolic hydroxyl group, it is preferable. For example, alkali metal salts such as sodium salt and potassium salt, lysine salt and arginine salt can be mentioned. When the compound represented by the formula (I) has a basic substituent such as an amino group or a guanidino group, for example, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, nitrate and pyro. Inorganic acids such as sulfuric acid and metaphosphoric acid, or citric acid, benzoic acid, acetic acid, propionic acid, fumaric acid, maleic acid, tartaric acid, succinic acid, sulfonic acid (eg, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid). ), Salts with organic acids such as amino acids (eg, glutamate).

The compound of the present invention has an asymmetric carbon and may exist as an optically active substance, but is a stereoisomer such as an optically active substance or a diastereoisomer, an arbitrary mixture of stereoisomers, or a racemate. Etc. are all included in the scope of the present invention.

The compound represented by the formula (I) can be produced, for example, as follows.

（式中、Ｘ^２、Ｘ^３、Ｘ^４、Ｘ^５、Ｘ^６ａ、Ｒ^１及びＲ’は前記と同義であり、Ａｕ^Ｉは１価の金の塩又は錯体を表す。）

(In the formula, X ² , X ³ , X ⁴ , X ⁵ , X ^6a , R ¹ and R'have the same meaning as above, and Au ^I represents a monovalent gold salt or complex.)

The organic group bonded via the carbon atom represented by R'is not particularly limited, and examples thereof include a C _1-6 -alkyl group, preferably a butyl group and a cyclopropyl group.

The monovalent gold salt or complex represented by Au ^I preferably includes Ph ₃ PAuNTf ₂ and Ph ₃ PAuOTf.

The above reaction is carried out in an atmosphere of an inert gas such as argon gas, for example, in an organic solvent (for example, a halogenated hydrocarbon system such as dichloromethane) of compound (II), compound (III) and a dehydrating agent (for example, molecular sieve). Solvent) A solution of a monovalent gold salt or a complex in an organic solvent (for example, a halogenated hydrocarbon solvent such as dichloromethane) can be added to the solution.

The reaction temperature of the reaction is usually −78 to 30 ° C., preferably 0 to 25 ° C., and the reaction time is usually within 24 hours, preferably 1 to 12 hours.

When the compound represented by the above formula (II) has a hydroxyl group, the hydroxyl group is an acyl group such as an acetyl group or a picoloyl group, or a trityl group, and the two hydroxyl groups are an alkylidene group of a methylidene group and a propan-2-iriden group. It is preferable to protect and carry out the above reaction, and then deprotect if necessary (see the formula below).

（式中、Ｘ^６ａ、Ｒ^１、Ｒ’及びＡｕ^Ｉは前記と同義である。）

(In the formula, X ^6a , R ¹ , R'and Au ^I are synonymous with the above.)

Azide group (X ² of the formula (I) and (I ^')) 4-position substituent of sialic acid, as a synthetic method of the derivative is an amino group or guanidino group, as shown below, a common synthetic intermediate A method of synthesizing a glycosyl donor into which an azido group has been introduced using a body and then sequentially converting a substituent at the 4-position can be mentioned.

（式中、Ｒ^１、Ｒ’及びＡｕ^Ｉは前記と同義であり、ＴＭＳＯＴｆはトリメチルシリルトリフラートを表し、ＴＭＳＮ_３はトリメチルシリルアジドを表し、２，２−ＤＭＰは２，２−ジメトキシプロパンを表し、ＣＳＡは１０−カンファースルホン酸を表し、ＣＯＭＵはウロニウム系縮合剤ＣＯＭＵを表し、ｏ−substituted ＢｚＣｌはｏ−位がＲ’−Ｃ≡Ｃ−（例えば、ヘキシニル基）で置換されたベンゾイルクロリドを表し、ＴＦＡはトリフルオロ酢酸を表し、ｂｉｓＢｏｃＰＣＨはＮ，Ｎ’−ビス（ｔｅｒｔ−ブトキシカルボニル）−１Ｈ−ピラゾール−１−カルボキサミジンを表す。）

(In the formula, R ¹ , R'and Au ^I are synonymous with the above, TMSOTf stands for trimethylsilyl triflate, TMSN ₃ stands for trimethylsilyl azide, 2,2-DMP stands for 2,2-dimethoxypropane, and CSA. Represents 10-camphorsulfonic acid, COMU represents the uronium-based condensing agent COMU, and o-substituted BzCl represents the benzoyl chloride in which the o-position is substituted with R'-C≡C- (eg, hexynyl group). TFA stands for trifluoroacetic acid and bisBocPCH stands for N, N'-bis (tert-butoxycarbonyl) -1H-pyrazol-1-carboxamidin.)

The compound represented by the formula (I) can be formulated as a sialidase inhibitor, more specifically, an antiviral agent, an immunomodulator, an anticancer agent, etc. in combination with a conventional preparation carrier. The administration form is not particularly limited and is appropriately selected and used as necessary. Tablets, capsules, granules, fine granules, powders, sustained-release preparations, liquids, suspensions, emulsions, syrups. , Oral preparations such as elixirs, parenteral preparations such as injections, inhalants and suppositories.

The oral preparation is produced by a conventional method using, for example, starch, lactose, sucrose, mannitol, carboxymethyl cellulose, inorganic salts and the like. In addition to these, binders, disintegrants, surfactants, lubricants, fluidity promoters, flavoring agents, colorants, fragrances and the like can be appropriately added.

Examples of the binder include starch, dextrin, gum arabic, gelatin, hydroxypropyl starch, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, ethyl cellulose, polyvinylpyrrolidone, macrogol and the like.

Examples of the disintegrant include starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and the like.

Examples of the surfactant include sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 80 and the like.

Examples of the lubricant include talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol and the like.

Examples of the fluidity accelerator include light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate and the like.

The injection is produced according to a conventional method, and generally distilled water for injection, physiological saline, aqueous glucose solution, olive oil, sesame oil, lacquer oil, soybean oil, corn oil, propylene glycol, polyethylene glycol and the like can be used as the diluent. .. Further, if necessary, a bactericidal agent, a preservative, a stabilizer, an isotonic agent, a painless agent and the like may be added. Further, from the viewpoint of stability, the injection can be filled in a vial or the like and then frozen, water is removed by a usual freeze-drying technique, and the liquid preparation can be re-prepared from the freeze-dried product immediately before use.

Examples of other parenteral preparations include inhalants, suppositories for rectal administration, and the like, which are manufactured according to a conventional method.

The formulated sialidase inhibitor varies depending on the dosage form, administration route, etc., but for example, it is possible to administer 1 to 4 times a day for a period of 1 week to 3 months.

In order to exert the desired effect as an oral preparation, it depends on the age, body weight, and degree of disease of the patient, but in the case of an adult, the weight of the compound represented by the above formula (I) is, for example, 5 to 500 mg. It is appropriate to take once a day or in several divided doses.

In order to exert the desired effect as a parenteral agent, it depends on the age, body weight, and degree of disease of the patient, but in the case of an adult, the weight of the compound represented by the above formula (I) is, for example, 1 to 1. It is appropriate to administer 500 mg by intravenous injection, intravenous drip infusion, subcutaneous injection, intramuscular injection, or inhalation.

In addition, the compound represented by the formula (I) may be used in combination with another drug that can be used in combination with a sialidase inhibitor. They are administered separately during the course of treatment or combined with the compounds of formula (I) above in a single dosage form such as tablets, intravenous solutions, or capsules.

Examples will be shown below and the present invention will be described in more detail, but the scope of the present invention is not limited to the scope of the following examples.

(Example 1)
(1) Synthesis of compound 2

Sodium methoxide in a methanol solution (30 ml) of Compound 1 (von Itzstein, M .; Dyason, JC; Thomson, R .; Rudrawar, S .; Pascolutti. M. US2012202877A1) (0.79 g, 1.5 mmol). Do (83 mg, 1.5 mmol) was added. The reaction solution was stirred at room temperature for 17 hours and then neutralized with Amberlite IR120 (H ⁺ type). The solid of the reaction mixture was filtered off and the solution was evaporated under reduced pressure to give compound 2 (0.50 g, 97%) as a pale yellow non-crystalline solid.
¹ H-NMR (401 MHz, CD ₃ OD) δ 1.79 (dd, J = 6.9, 1.4 Hz, 3H), 2.01 (s, 3H), 3.55 (dd, J = 8.7, 1.4 Hz, 1H), 3.63 ( dd, J = 11.5, 5.5 Hz, 1H), 3.76 (s, 3H), 3.82-3.84 (m, 2H), 4.03 (dd, J = 9.7, 1.4 Hz, 1H), 4.13 (dd, J = 9.7, 6.9 Hz, 1H), 4.52 (d, J = 6.9 Hz, 1H), 6.05 (dq, J = 16.1, 6.9 Hz, 1H), 6.82 (dd, J = 16.1, 1.4 Hz, 1H).

(2) Synthesis of compound 3

2,2-Dimethoxypropane (0.21 ml, 1.7 mmol) and 10-camphorsulfonic acid (32 mg, 32 mg,) in an N, N-dimethylformamide solution (14 ml) of compound 2 (0.50 g, 1.4 mmol) under an argon atmosphere. 0.14 mmol) was added. The reaction solution was stirred at room temperature for 24 hours and then neutralized by adding triethylamine. The reaction mixture was azeotroped with toluene (3 times), N, N-dimethylformamide was distilled off under reduced pressure, and the residue was crudely purified by silica gel chromatography (eluent: hexane / acetone = 1/4).

The resulting crude pyridine solution (12 ml) was cooled to -40 ° C and acetic anhydride (6.0 ml) was added. After stirring the reaction solution at -40 ° C for 44 hours, methanol was added to stop the reaction. The reaction mixture is azeotroped with toluene (3 times), the residue is purified by silica gel chromatography (eluent: hexane / acetone = 1/1), and compound 3 (0.26 g, 2-step yield 48%) is colorless and non-free. Obtained as a crystalline solid.
¹ H-NMR (401 MHz, CDCl ₃ ) δ 1.34 (s, 3H), 1.38 (s, 3H), 1.78 (dd, J = 6.9, 1.8 Hz, 3H), 2.05 (s, 3H), 2.08 (s , 3H), 3.46 (brd, J = 8.3 Hz, 1H), 3.79 (s, 3H), 3.86 (dd, J = 11.0, 0.9 Hz, 1H), 4.06 (dd, J = 8.7, 5.1 Hz, 1H) , 4.14 (dd, J = 8.7, 6.4 Hz, 1H), 4.25-4.36 (m, 2H), 4.82 (br, 1H), 5.42 (dq, J = 16.1, 6.4 Hz, 1H), 5.92 (d, J = 8.7 Hz, 1H), 6.03 (d, J = 7.4 Hz, 1H), 6.92 (dd, J = 16.1, 1.8 Hz, 1H).

(3) Synthesis of compound 4

Condensing agent COMU (340 mg, 0.794 mmol) and N, N-diisopropylethylamine (0.32) in a dichloromethane solution (15 ml) of compound 3 (261 mg, 0.611 mmol) and picolinic acid (90.3 mg, 0.733 mmol) under an argon atmosphere. ml, 1.8 mmol), and N, N-dimethyl-4-aminopyridine (7.5 mg, 0.061 mmol) were added. After stirring at room temperature for 3 hours, a saturated aqueous sodium hydrogen carbonate solution was added to terminate the reaction. Then, ethyl acetate was added, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was separated by filtration, and the residue obtained by distilling off the solvent under reduced pressure was subjected to medium pressure preparative liquid chromatography (column: Yamazen ULTRAPACK Silica-40B, eluent: hexane / ethyl acetate = 1/1) and gel permeation chromatography. Purification by chromatography (eluent: chloroform) gave compound 4 (167 mg, 51%) as a colorless non-crystalline solid.
¹ H-NMR (401 MHz, CDCl ₃ ) δ 1.21 (s, 3H), 1.32 (s, 3H), 1.75 (dd, J = 6.4, 1.4 Hz, 3H), 1.92 (s, 3H), 1.98 (s , 3H), 3.77 (s, 3H), 4.07 (ddd, J = 9.7, 8.3, 6.9 Hz, 1H), 4.13 (dd, J = 9.2, 6.4 Hz, 1H), 4.19 (dd, J = 9.2, 6.4 Hz, 1H), 4.46 (td, J = 6.4, 4.1 Hz, 1H), 4.67 (dd, J = 9.7, 2.8 Hz, 1H), 5.61 (dq, J = 16.1, 6.4 Hz, 1H), 5.78 (dd , J = 4.1, 2.8 Hz, 1H), 6.19 (d, J = 6.9 Hz, 1H), 6.37 (d, J = 8.3 Hz, 1H), 6.88 (dd, J = 16.1, 1.4 Hz, 1H), 7.42 (ddd, J = 7.8, 4.6, 0.9 Hz, 1H), 7.79 (td, J = 7.8, 1.8 Hz, 1H), 8.04 (brd, J = 7.8 Hz, 1H), 8.72 (brd, J = 4.6 Hz, 1H).

(4) Synthesis of compound 5

2,6-Lutidine (0.072 ml, 0.63 mmol) and sodium periodate (268 mg, 1.25) in a dioxane / water (3/1, v / v, 8.0 ml) solution of compound 4 (261 mg, 0.611 mmol). mmol) and 50 mM OsO ₄ aqueous solution (0.26 ml, 13 μmol) were added. After stirring at room temperature for 30 minutes, ethyl acetate was added. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (eluent: chloroform / methanol = 98/2) to obtain compound 5 (167 mg, 51%) as colorless non-crystal. Obtained as a quality solid.
¹ H-NMR (401 MHz, CDCl ₃ ) δ 1.31 (s, 3H), 1.35 (s, 3H), 1.94 (s, 3H), 1.95 (s, 3H), 3.90 (s, 3H), 4.08 (dd , J = 9.2, 6.0 Hz, 1H), 4.16 (dd, J = 9.2, 6.0 Hz, 1H), 4.25 (ddd, J = 8.3, 6.9, 6.0 Hz, 1H), 4.51 (q, J = 6.0 Hz, 1H), 4.83 (dd, J = 6.0, 3.2 Hz, 1H), 5.73 (dd, J = 6.0, 3.2 Hz, 1H), 6.12 (d, J = 6.9 Hz, 1H), 6.30 (d, J = 8.3) Hz, 1H), 7.48 (ddd, J = 7.8, 5.1, 1.4 Hz, 1H), 7.84 (td, J = 7.8, 1.8 Hz, 1H), 8.08 (brd, J = 7.8 Hz, 1H), 8.75 (brd) , J = 5.1 Hz, 1H), 10.0 (s, 1H).

(5) Synthesis of compound 6

A solution of compound 5 (15.6 mg, 30.0 μmol) and cerium (22 mg, 60 μmol) in tetrahydrofuran / methanol (1/1, v / v, 1.0 ml) was cooled to -78 ° C and borohydrided. Sodium borohydride (1.4 mg, 36 μmol) was added. After stirring at -78 ° C for 30 minutes, the reaction was stopped with phosphate buffer (pH 7). Ethyl acetate was added to the reaction mixture, the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off and the solvent was evaporated under reduced pressure to give a crude product.

O-Hexinyl benzoate acid chloride (ca.33 mg / ml dichloromethane solution, 1.0 ml), N, N-dimethyl-4-aminopyridine in an argon atmosphere in the above crude product in dichloromethane (1.0 ml). (One grain), pyridine (24 μl, 0.30 mmol) was added. After stirring at room temperature for 4 hours, a saturated aqueous sodium hydrogen carbonate solution was added under ice-cooling to stop the reaction. Ethyl acetate was added and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The desiccant was separated by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (eluent: hexane / acetone = 1/1) and gel permeation chromatography (eluent: chloroform). (12.2 mg, 2-step yield 58%) was obtained as a colorless oily substance.
¹ H-NMR (401 MHz, CDCl ₃ ) δ 0.93 (t, J = 7.4 Hz, 3H), 1.27 (s, 3H), 1.34 (s, 3H), 1.43-1.53 (m, 2H), 1.55-1.63 (m, 2H), 1.92 (s, 3H), 1.96 (s, 3H), 2.45 (t, J = 6.9 Hz, 2H), 3.84 (s, 3H), 4.10-4.20 (m, 3H), 4.51 ( td, J = 6.4, 5.1 Hz, 1H), 4.72 (dd, J = 10.6, 1.8 Hz, 1H), 5.00 (dd, J = 12.9, 0.9 Hz, 1H), 5.47 (d, J = 12.9 Hz, 1H) ), 5.71 (dd, J = 5.1, 1.8 Hz, 1H), 5.88 (brd, J = 8.7 Hz, 1H), 6.06 (brd, J = 8.7 Hz, 1H), 7.28 (td, J = 7.4, 0.9 Hz) , 1H), 7.40 (td, J = 7.4, 1.4 Hz, 1H), 7.44-7.49 (m, 2H), 7.81 (dd, J = 7.4, 0.9 Hz, 1H), 7.83 (td, J = 7.8, 1.8 Hz, 1H), 8.09 (brd, J = 7.8 Hz, 1H), 8.77 (m, 1H).

（式中、ＰＮＰはｐ−ニトロフェニル基を表す。） (6) Synthesis of compound 8

(In the formula, PNP represents a p-nitrophenyl group.)

Triisopropylsilyl chloride (0.34 ml, 1.6 mmol) in N, N-dimethylformamide solution (10 ml) of compound 7 (409 mg, 1.36 mmol) and imidazole (120 mg, 1.76 mmol) under an argon atmosphere under ice-cooling. ) Was added. After stirring for 13 hours and 30 minutes, imidazole (65 mg, 0.95 mmol) and triisopropylsilyl chloride (0.17 ml, 0.82 mmol) were added, and the mixture was further stirred for 4 hours. Chloroform was added to the reaction mixture, and the organic layer was washed with water, 1M aqueous hydrochloric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off and the solvent was evaporated under reduced pressure to give a crude product.

Acetic anhydride (4.0 ml) was added to the pyridine solution (6.0 ml) of the crude product. After stirring at room temperature for 11 hours and 30 minutes, methanol was added to stop the reaction. The reaction mixture was azeotroped with toluene (3 times), pyridine and acetic anhydride were distilled off under reduced pressure, and then the residue was subjected to medium pressure preparative liquid chromatography (column: Yamazen, ULTRAPACK Silica-40B, eluent: hexane / ethyl acetate). Purification with = 3: 1) gave compound 8 (706 mg, 2-step yield 89%).
¹ H-NMR (401 MHz, CDCl ₃ ) δ 0.99-1.06 (m, 21H), 2.02 (s, 3H), 2.07 (s, 3H), 2.16 (s, 3H), 3.76 (dd, J = 9.9, 6.0 Hz, 1H), 3.83 (dd, J = 9.9, 6.7 Hz, 1H), 3.95 (dd, J = 6.7, 6.0 Hz, 1H), 5.15 (dd, J = 10.1, 3.7 Hz, 1H), 5.17 ( d, 8.3 Hz, 1H), 5.49-5.55 (m, 2H), 7.10 (d, J = 9.2 Hz, 2H), 8.19 (d, J = 9.2 Hz, 2H).

(7) Synthesis of compound 9

To a solution of compound 8 (348 mg, 0.597 mmol) in tetrahydrofuran (2.0 ml) under an argon atmosphere, tetra-n-butylammonium fluoride / acetic acid (1/1, v / v, 2.0 ml) was added under ice-cooling. It was. The reaction solution was stirred at room temperature for 5 hours and 30 minutes, and then a saturated aqueous solution of ammonium chloride was added under ice-cooling to stop the reaction. Ethyl acetate was added to the reaction mixture, the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was separated by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 1/1) to make compound 9 (230 mg, 90%) a colorless oil. Obtained as a substance.
¹ H-NMR (401 MHz, CDCl ₃ ) δ 2.02 (s, 3H), 2.05 (s, 3H), 2.18 (s, 3H), 2.58 (br, 1H), 3.58 (dd, J = 11.5, 6.0 Hz , 1H), 3.76 (dd, J = 11.5, 6.0 Hz, 1H), 3.98 (brt, J = 6.0 Hz, 1H), 5.16 (dd, J = 10.3, 3.2 Hz, 1H), 5.22 (d, J = 7.8 Hz, 1H), 5.47 (brd, J = 3.2 Hz, 1H), 5.52 (dd, J = 10.3, 7.8 Hz, 1H), 7.08 (d, J = 9.2 Hz, 2H), 8.18 (d, J = 9.2 Hz, 2H).

(8) Synthesis of compound 11

Under an argon atmosphere, compound 6 (29.1 mg, 41.2 μmol), galactose 9 (35.2 mg, 82.4 μmol) and a molecular sieve 4 Å in a dichloromethane solution (4.0 ml) under ice-cooling, gold complex Ph ₃ PAuNTf ₂ (65 mg / ml dichloromethane solution, 0.10 ml) was added. After 4 hours and 30 minutes, Ph ₃ PAuNTf ₂ (65 mg / ml dichloromethane solution, 0.10 ml) was added. After further stirring for 9 hours, chloroform was added, and the solid matter was filtered off by Celite filtration. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (eluent: hexane / acetone = 1/1) and high performance liquid chromatography (eluent: chloroform / methanol = 98/2), and compound 11 (eluent: chloroform / methanol = 98/2) was purified. 12.2 mg, 32%) was obtained as a colorless oily substance.
¹ H-NMR (401 MHz, CDCl ₃ ) δ 1.30 (s, 3H), 1.36 (s, 3H), 1.94 (s, 3H), 2.02 (s, 3H), 2.09 (s, 6H), 2.19 (s , 3H), 3.77-3.82 (m, 2H), 3.86 (s, 3H), 3.94 (dd, J = 10.6, 7.4 Hz, 1H), 4.13-4.21 (m, 2H), 4.24 (m, 1H), 4.50 (m, 1H), 4.57 (dd, J = 10.6, 1.4 Hz, 1H), 5.19 (dd, J = 10.3, 3.4 Hz, 1H), 5.25 (d, J = 7.8 Hz, 1H), 5.34 (d , J = 2.3 Hz, 1H), 5.52-5.58 (m, 4H), 5.63 (dd, J = 4.6, 1.4 Hz, 1H), 5.78 (dt, J = 10.6, 2.3 Hz, 1H), 7.14 (d, J = 9.2 Hz, 2H), 7.46 (brdd, J = 7.6, 4.8 Hz, 1H), 7.85 (td, J = 7.8, 1.4 Hz, 1H), 8.07 (brd, J = 7.8 Hz, 1H), 8.19 ( d, J = 9.2 Hz, 2H), 8.75 (d, J = 4.8 Hz, 1H).

（式中、ＰＮＰはｐ−ニトロフェニル基を表し、Ｔｒはトリチル基を表す。） (9) Synthesis of compound 12

(In the formula, PNP represents a p-nitrophenyl group and Tr represents a trityl group.)

In an argon atmosphere, compound 6 (5.6 mg, 7.9 μmol), compound 10 (Ekborg, G .; Vranesic, B .; Bhattacharjee, AK; Kovac, P .; Glaudemans, CPJ Carbohydrate Research, 1985, 142, 203-211 The gold complex Ph ₃ PAuNTf ₂ (12 mg / ml dichloromethane solution, 0.10 ml) was added to (8.6 mg, 16 μmol) (the compound described) and a dichloromethane solution (0.59 ml) of molecular sieve 4 Å under ice-cooling. After 1 hour, Ph ₃ PAuNTf ₂ (12 mg / ml dichloromethane solution, 0.10 ml) was added. After further stirring for 1 hour, chloroform was added, and the solid matter was filtered off by Celite filtration. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (eluent: chloroform / methanol = 99/1 to 97/3) and high performance liquid chromatography (eluent: chloroform / methanol = 97/3). , Compound 12 (1.0 mg, 12%) was obtained as a colorless oily substance.
¹ H-NMR (401 MHz, CDCl ₃ ) δ 1.33 (s, 3H), 1.37 (s, 3H), 1.95 (s, 3H), 2.08 (s, 3H), 3.31 (dd, J = 9.9, 3.9 Hz , 1H), 3.62 (dd, J = 9.9, 7.5, 1H), 3.75 (dd, J = 7.5, 3.9, 1H), 3.84 (s, 3H), 3.88 (m, 1H), 4.01-4.05 (m, 3H), 4.14 (dd, J = 9.0, 7.4 Hz, 1H), 4.21 (dd, J = 9.0, 3.0 Hz, 1H), 4.43 (m, 1H), 4.67 (dd, J = 11.9, 1.4 Hz, 1H) ), 5.00 (d, J = 7.4 Hz, 1H), 5.46-5.48 (m, 2H), 5.63 (d, J = 8.7 Hz, 1H), 5.75 (d, J = 1.8 Hz, 1H), 5.86 (dt) , J = 9.7, 1.8 Hz, 1H), 7.20-7.26 (m, 11H), 7.38-7.41 (m, 7H), 7.80 (td, J = 7.8, 1.8 Hz, 1H), 8.12 (brd, J = 7.8 Hz, 1H), 8.17 (d, J = 9.2 Hz, 2H), 8.68 (brd, J = 4.6 Hz, 1H).

(10) Synthesis of compound 13

3-Phenyl-1-propanol (19 mg / ml) at room temperature in a solution of compound 6 (4.9 mg, 6.9 μmol) and molecular sieves 4 Å in dichloromethane / ether (3/7, v / v, 0.50 ml) under an argon atmosphere. Dichloromethane solution) was added in an amount of 0.10 ml (equivalent to 14 μmol). This was ice-cooled, and the gold complex Ph ₃ PAuNTf ₂ (11 mg / ml dichloromethane solution, 0.10 ml) was added. After 2 hours, Ph ₃ PAuNTf ₂ (11 mg / ml dichloromethane solution, 0.10 ml) was added. After further stirring for 4 hours, chloroform was added, and the solid matter was filtered off by Celite filtration. Silica gel chromatography (eluent: hexane / ethyl acetate = 9/1 to hexane / acetone = 7/3) and high performance liquid chromatography (eluent: chloroform / methanol = 99 /) were obtained by distilling off the solvent under reduced pressure. Purification in 1) gave compound 13 (2.1 mg, 52%, α / β = ca.12: 1) as a colorless oily substance.
¹ H-NMR (401 MHz, CDCl ₃ ) δ 1.26 (s, 3H), 1.34 (s, 3H), 1.93 (s, 3H), 1.93-2.03 (m, 2H), 2.09 (s, 3H), 2.68 -2.80 (m, 2H), 3.53 (dt, J = 9.2, 6.4 Hz, 1H), 3.77-3.85 (m, 2H), 3.80 (s, 3H), 4.12 (dd, J = 8.3, 6.9 Hz, 1H ), 4.19 (dd, J = 8.3, 6.4 Hz, 1H), 4.52 (ddd, J = 6.9, 6.4, 4.1 Hz, 1H), 4.58 (dd, J = 11.0, 1.8 Hz, 1H), 5.33 (d, J = 1.8 Hz, 1H), 5.60 (brd, J = 9.2 Hz, 1H), 5.64 (d, J = 1.8 Hz, 1H), 5.69 (dd, J = 4.1, 1.8 Hz, 1H), 5.74 (dt, dt, J = 10.1, 1.8 Hz, 1H), 7.16-7.22 (m, 3H), 7.26-7.29 (m, 2H), 7.47 (brdd, J = 7.8, 4.6 Hz, 1H), 7.81 (td, J = 7.8, 1.4 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 8.76 (brd, J = 4.6 Hz, 1H).

(11) Synthesis of compound 14

A solution of compound 11 (12.2 mg, 13.1 μmol) in dichloromethane (2.0 ml) was cooled to -20 ° C and trifluoroacetic acid (100 μl) was added. The reaction solution was stirred for 1 hour and 30 minutes under cooling at -20 ° C, and then triethylamine was added to neutralize the reaction solution. The residue obtained by distilling off the solvent under reduced pressure was crudely purified with Sep-Pak ^(R) (eluent: water / methanol = 100/0 to 0/100).

Sodium methoxide (3.5 mg, 0.065 mmol) was added to a solution of the crude product in methanol (2.0 ml). The reaction solution was stirred at room temperature for 3 hours and then neutralized with Amberlite IRC50 (H ⁺ type). The solid of the reaction mixture was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by high performance liquid chromatography (eluent: chloroform / methanol = 80/20) to obtain heptaol.

1 M sodium hydroxide (23 μl) was added to the methanol solution (1.0 ml) of heptaol. After 5 hours and 50 minutes and after 7 hours and 15 minutes, 1 M sodium hydroxide (23 μl) was added, respectively. Nine hours after the start, the cells were neutralized with Amberlite IRC50 (H ⁺ type). The solid of the reaction mixture was filtered off, and the solvent was evaporated under reduced pressure. This was dissolved in methanol (1.0 ml), treated with Chelex ^(R) 100 for 15 minutes, and the solid was filtered off. The residue obtained by distilling off the solvent under reduced pressure was purified by Sep-Pak ^(R) (eluent: water) to obtain Compound 14 (2.6 mg, 3-step yield 78%) as a colorless non-crystalline solid.
¹ H-NMR (401 MHz, D ₂ O) δ 2.02 (s, 3H), 3.55 (dd, J = 9.2, 1.8 Hz, 1H), 3.60 (dd, J = 12.2, 6.2 Hz, 1H), 3.74- 3.90 (m, 7H), 3.98 (dd, J = 10.1, 8.3 Hz, 1H), 4.06 (d, J = 3.2 Hz, 1H), 4.10-4.14 (m, 2H), 5.22 (d, J = 7.4 Hz) , 1H), 5.50 (m, 1H), 5.61 (m, 1H), 7.27 (d, J = 9.2 Hz, 2H), 8.26 (d, J = 9.2 Hz, 2H).

(12) Synthesis of compound 15

A solution of compound 12 (3.4 mg, 3.2 μmol) in dichloromethane (1.0 ml) was cooled to -20 ° C and trifluoroacetic acid (10 μl) was added. After stirring for 1 hour and 30 minutes, triethylamine was added for neutralization. The residue obtained by distilling off the solvent under reduced pressure was crudely purified with Sep-Pak ^(R) (eluent: water / methanol = 100/0 to 0/100).

Sodium methoxide (1.8 mg, 32 μmol) was added to a methanol solution (0.8 ml) of the crude product. The reaction solution was stirred at room temperature for 1.5 hours and then neutralized with Amberlite IRC50 (H ⁺ type). The solid of the reaction mixture was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by high performance liquid chromatography (eluent: chloroform / methanol = 80/20) to obtain pure heptaol.

1 M sodium hydroxide (28 μl) was added to the methanol solution (0.4 ml) of heptaol. After stirring for 2 hours and 30 minutes, the mixture was neutralized with Amberlite IRC50 (H ⁺ type). The solid of the reaction mixture was filtered off, and the solvent was evaporated under reduced pressure. This was dissolved in methanol (0.4 ml), treated with Chelex ^(R) 100 for 15 minutes, and the solid was filtered off. The residue obtained by distilling off the solvent under reduced pressure was purified by Sep-Pak ^(R) (eluent: water) to obtain Compound 15 (1.1 mg, 3-step yield 56%) as a colorless non-crystalline solid.
^{1 1} H-NMR (401 MHz, D ₂ O) δ 2.03 (s, 3H), 3.59-3.63 (m, 2H), 3.76-3.78 (m, 2H), 3.84 (dd, J = 11.5, 1.8 Hz, 1H ), 3.87-3.94 (m, 4H), 3.99 (dd, J = 9.7, 7.8 Hz, 1H), 4.10 (d, J = 2.8 Hz, 1H), 4.14 (m, 1H), 4.32 (m, 1H) , 5.32 (d, J = 7.8 Hz, 1H), 5.51 (s, 1H), 5.80 (s, 1H), 7.26 (d, J = 9.2 Hz, 2H), 8.27 (d, J = 9.2 Hz, 2H) ..

(13) Synthesis of compound 16

A solution of Compound 13 (0.4 mg, 0.6 μmol) in dichloromethane / trifluoroacetic acid / water (1/4 / 0.1, v / v, 244 μl) was stirred at room temperature for 20 minutes, and then a saturated aqueous sodium hydrogen carbonate solution was added. It was harmonized. Then, ethyl acetate was added, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off and the solvent was evaporated under reduced pressure to give a crude product.

Sodium methoxide (0.3 mg, 5.6 μmol) was added to a solution of the crude product in methanol (100 μl). The reaction solution was stirred at room temperature for 1 hour and then neutralized with Amberlite IR120 (H ⁺ type). The solid of the reaction mixture was filtered off, and the solvent was distilled off under reduced pressure to obtain a crude product.

1 M sodium hydroxide (20 μl) was added to a methanol solution (0.8 ml) of the crude product (4.1 mg, 9.0 μmol). After stirring for 37 hours, the solvent was evaporated under reduced pressure and the obtained residue was purified with Sep-Pak ^(R) (eluent: water) to give compound 16 (2.6 mg, 64%) as a colorless non-crystalline solid. It was.
^{1 1} H-NMR (401 MHz, D ₂ O) δ 1.85-1.98 (m, 2H), 2.01 (s, 3H), 2.64-2.78 (m, 2H), 3.51 (dt, J = 9.2, 6.9 Hz, 1H ), 3.58 (dd, J = 9.2, 1.8 Hz, 1H), 3.61 (dd, J = 12.0, 5.5 Hz, 1H), 3.75-3.87 (m, 5H), 4.07 (dt, J = 10.1, 2.3 Hz, 1H), 5.44 (m, 1H), 5.58 (m, 1H), 7.22-7.36 (m, 5H).

(Example 2)
Using Clostridium perfringens sialidase, the sialidase inhibitory activity of the test compound was measured as follows.

(Implemented using a 96-well plate) 50 mM sodium acetate buffer pH 5.0 (38.5 μl), sialidase (neuraminidase, Clostridium perfringens-derived N2133, Aldrich, 3.33 U / ml buffer solution, 1 μl), sialic acid analog 14 Alternatively, add 2'-(4-methylumbelliferyl) -α-DN-acetylneuraminic acid (Aldrich, M8639, 1.5 mM aqueous solution, 10 μl) to a mixed solution of 15 (0.5 μl) and incubate at 37 ° C. did. The fluorescence of the reaction solution (excitation wavelength 365 nm, fluorescence wavelength 450 nm) was measured, and the sialidase inhibitory activity was evaluated by the fluorescence value at 7 minutes and 30 seconds (Reference: Chen, X. ChemBioChem 2007, 8, 194 − 201.).

The results are shown in FIG.
Compound 15 having a 2,3-sialyl galactose structure exhibited 100-fold or more sialidase inhibitory activity than DANA, which was the basis for the structural development of conventional "transition state analogs".

Claims (6)

Equation (I):

[In the formula, X ¹ is -OR ¹ (in the formula, R ¹ is a substituted or unsubstituted sugar residue, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted C _1-6 -aliphatic group. Represents a hydrocarbon group ) ; X ² is -OR ² (in the formula, R ² is a hydrogen atom, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted C _1-6 -alkyl group. . a _{representative), C 1-6} - alkyl optionally azido group optionally substituted with a _{group, C 1-6} - alkyl group optionally substituted guanidino group, or ^{-N (R a) (R b} ) ( In the formula, ^Ra and R ^b are the same or different and represent a hydrogen atom or a C _1-6 -alkyl group); X ³ is a substituted or unsubstituted C _1-6 -alkyl group, or substituted or non-substituted. Substituted C _1-6 -alkoxy group; X ⁴ represents hydrogen atom, methyl group or halogen atom, X ⁵ is -NHCO-R ³ (in the formula, R ³ is hydrogen atom, substituted or unsubstituted C. Represents a _1-6 -alkyl group or hydroxymethyl group), a hydroxyl group, or a substituted or unsubstituted C _1-6 -alkoxy group; X ⁶ represents a carboxyl group, a phosphate group, a phosphono group, a sulfo group, a sulfino. Represents a group, an alkoxycarbonyl group, a phosphoric acid alkyl ester group, a phosphonic acid alkyl ester group, a sulfonic acid alkyl ester group, or a sulfinic acid alkyl ester group. ]
A compound or a salt thereof. The compound according to claim 1 or a salt thereof, wherein R ¹ is a substituted or unsubstituted sugar residue. The compound or a salt thereof according to claim 1, wherein R ¹ is a substituted or unsubstituted galactose residues. The compound or a salt thereof according to claim 1, wherein the 1-hydroxyl group at R ¹ is a substituted or unsubstituted phenyl group is galactose residue substituted. A sialidase inhibitor containing the compound according to any one of claims 1 to 4 or a salt thereof as an active ingredient. Equation (II):

[In the formula, X ² is −O-R ² (in the formula, R ² represents a hydrogen atom, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted C _1-6 -alkyl group), C. _An azide group optionally substituted with a _1-6 -alkyl group, a guanidino group optionally substituted with a C _1-6 -alkyl group or -N ( ^Ra ) (R ^b ) (in the formula, ^Ra and R ^b is the same or different and represents a hydrogen atom or a C _1-6 -alkyl group); X ³ is a substituted or unsubstituted C _1-6 -alkyl group or a substituted or unsubstituted C _1-6. -Representing an alkoxy group; X ⁴ represents a hydrogen atom, a methyl group or a halogen atom, and X ⁵ is a -NHCO-R ³ (in the formula, R ³ is a hydrogen atom, substituted or unsubstituted C _1-6 -alkyl group. Or a hydroxymethyl group), a hydroxyl group, or a substituted or unsubstituted C _1-6 -alkoxy group; X ^6a is an alkoxycarbonyl group, a phosphate alkyl ester group, a phosphonic acid alkyl ester group, a sulfonic acid alkyl ester. Represents a group or sulfinate alkyl ester group; R'represents an organic group attached via a carbon atom. ]
In the presence of a monovalent gold salt or complex, the compound represented by (III):
R ^1- OH (III)
(In the formula, R ¹ represents a substituted or unsubstituted sugar residue, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted C _1-6 -aliphatic hydrocarbon group.)
The following formula (I'), which comprises reacting with the compound represented by

(In the formula, X ² , X ³ , X ⁴ , X ⁵ , X ^6a and R ¹ are synonymous with the above.)
A method for producing a compound or a salt thereof.

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