JP2018016579A - Sialic acid analog - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel sialic acid analog that is useful as a sialidase inhibitor.SOLUTION: Provided are: a compound represented by the following formula (I) or a salt thereof; a sialidase inhibitor containing said compound or a salt thereof as an active ingredient; and a process for producing said compound or a salt thereof. [Xis -O-Ror F; Xis -O-R, an azido group, a guanidino group or -N(R)(R); Xis an alkyl group or an alkoxy group; Xis H, a methyl group or a halogen; Xis -NHCO-R, a hydroxyl group or an alkoxy group; Xis a carboxyl group, a phosphoric acid group, a phosphono group, a sulfo group or the like; Ris a sugar residue, an aromatic group or an aliphatic group; Ris H, an aromatic group or an alkyl; Rand Rare each independently H, alkyl or alkoxy; and Ris H, alkyl or hydroxymethyl.].SELECTED DRAWING: None

Description

  The present invention relates to a novel sialic acid analog useful as a sialidase inhibitor, and its use and production method.

  Sialic acid is present at the end of glycoproteins and glycolipids in vivo and is involved in the physiological activities of glycoproteins and glycolipids. In order to elucidate the function of sialic acid at the molecular level, synthesis of sialic acid derivatives has been actively carried out.

  Sialidase (sialic acid hydrolase), also called neuraminidase, is involved in virus release by hydrolyzing sialic acid present at the sugar chain end of the virus-infected cell surface. Will help prevent virus growth in Sialidase inhibitors have been developed by mimicking the transition state structure of sialic acid in sialidase hydrolysis reactions, which are called “transition state analogs”. Sialidase inhibitors are useful as pharmaceuticals such as antiviral agents, immunomodulators, and anticancer agents.

“Transition state analogs” are based on 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA), and are introduced with a sialidase by introducing a highly polar functional group at the 4-position of sialic acid. It has been reported that the affinity of is improved (Non-patent Documents 1 and 2). For example, the sialic acid derivative obtained by introducing a guanidino group at the 4-position of sialic acid, Relenza ^TM having a structure having a sp ² carbon in position 2 and 3 of the same sialic acid and ^DANA, Inabiru ^TM has 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 studies to solve the above-mentioned problems, the inventors of the present invention are in the second position of sialic acid, which has a basic skeleton different from DANA, which has been the basis of the structural development of the conventional “transition state analog”. Sp ³ carbon, 3 position exomethylene type sialic acid analog having a structure with sp ² carbon at 3 position was newly synthesized and examined for sialidase inhibitory activity, it was significantly higher than DANA As a result, the present invention has been completed.

［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 formula (I):

[Wherein, X ¹ represents —O—R ¹ , wherein R ¹ represents a substituted or unsubstituted sugar residue, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted C _1-6 -aliphatic. Represents a hydrocarbon group.) Or a fluorine atom; X ² represents —O—R ² (wherein R ² represents 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} ) (wherein R ^a and R ^b are the same or different and each represents a hydrogen atom or a C _1-6 -alkyl group); X ³ represents a substituted or unsubstituted C _1-6 -alkyl group, or Represents a substituted or unsubstituted C _1-6 -alkoxy group; X ⁴ represents a hydrogen atom, a methyl group or a halogen atom; ⁵ represents —NHCO—R ³ (wherein R ³ represents a hydrogen atom, a substituted or unsubstituted C _1-6 -alkyl group or a hydroxymethyl group), a hydroxyl group, or a substituted or unsubstituted C _1-6. -Represents an alkoxy group; X ⁶ represents a carboxyl group, a phosphate group, a phosphono group, a sulfo 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 group. Represents an ester group. ]
Or a salt thereof.
(2) The compound or salt thereof according to (1), wherein R ¹ is a substituted or unsubstituted sugar residue.
(3) The compound or salt thereof according to (1), wherein R ¹ is a substituted or unsubstituted galactose residue.
(4) The compound or salt thereof according to (1), wherein R ¹ is a galactose residue in which the hydroxyl group at position ¹ is substituted with a substituted or unsubstituted phenyl group.
(5) A sialidase inhibitor containing the compound or salt thereof according to any one of (1) to (4) as an active ingredient.
(6) The following formula (II):

[Wherein, X ² represents —O—R ² (wherein R ² represents a hydrogen atom, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted C _1-6 -alkyl group), C _An azido group optionally substituted with a _1-6 -alkyl group, a guanidino group optionally substituted with a C _1-6 -alkyl group, or —N (R ^a ) (R ^b ) (wherein R ^a 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 -Represents an alkoxy group; X ⁴ represents a hydrogen atom, a methyl group or a halogen atom; X ⁵ represents -NHCO-R ³ (wherein R ³ represents a hydrogen atom, a substituted or unsubstituted C _1-6 -alkyl group; or represents a hydroxymethyl group), a hydroxyl group, or a substituted or unsubstituted C _{1-6 -.} al It represents a carboxymethyl group; X ^6a alkoxycarbonyl group, phosphoric acid alkyl ester group, a phosphonic acid alkyl ester group, a sulfonic acid alkyl ester group or a sulfinic acid alkyl ester group; R 'is bonded via a carbon atom Represents an organic group. ]
In the presence of a monovalent gold salt or complex, the compound represented by the following formula (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.)
Comprising reacting with a compound of formula (I ′):

(In the formula, X ² , X ³ , X ⁴ , X ⁵ , X ^6a and R ¹ are as defined above.)
Or a salt thereof.

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

It is a figure which shows an example of the compound which has a structure which imitated glycoprotein among the compounds of this invention. It is a figure which shows an example of the compound which has a structure imitating glycolipid among the compounds of this invention. It is a figure which shows the result of having measured the sialidase inhibitory activity of the 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 an aromatic hydrocarbon group such as phenyl group, tolyl group, and naphthyl group; furyl group, thienyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl. An aromatic heterocyclic group such as a group, triazolyl group (for example, 1H-1,2,4-triazol-1-yl group), pyrazolyl group, pyridyl group, pyrimidinyl group, pyridazinyl group, pyrazinyl group, quinolyl group, and isoquinolyl group. Can be mentioned.

The aromatic group is a C _1-6 such as a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), acyl group (eg, formyl group, acetyl group, propanoyl group, butanoyl group, pentanoyl group, hexanoyl group). -Aliphatic acyl group; aroyl group such as benzoyl group and toluoyl group), acyloxy group (for example, formyloxy group, acetoxy group, propanoyloxy group, butanoyloxy group, pentanoyloxy group, hexanoyloxy group, etc.) _1-6 -aliphatic acyloxy group; aroyloxy groups such as benzoyloxy group and toluoyloxy group), hydroxyl group, carboxyl group, C _1-6 -alkoxy group (for example, methoxy group, ethoxy group, propoxy group), acetamide group, Carbamoyl group, cyano group, nitro group, aromatic group (eg phenyl ) May be substituted with one or more substituents selected from the like.

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

As the C _1-6 -aliphatic hydrocarbon group, in addition to the C _1-6 -alkyl group, a vinyl group, 1-propenyl group, allyl group, 1-butenyl group, 2-butenyl (crotyl) group, pentenyl Group, C _2-6 -alkenyl group such as 3-methyl-2-butenyl (prenyl) group, hexenyl group; ethynyl group, 1-propynyl group, 2-propynyl (propargyl) group, 3-butynyl group, pentynyl group, C _2-6 -alkynyl groups such as a hexynyl group can be mentioned. 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, 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, 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 above C _1-6 -alkoxy group.

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

Examples of the phosphonic acid alkyl ester group include a phosphonic acid alkyl ester group in which 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 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 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 for example, galactose residue, glucose residue, N-acetylglucosamine residue, glucuronic acid residue, glucosamine residue, mannose residue, xylose residue, N-acetyl Monosaccharide residues selected from galactosamine residues, galactosamine residues, N-acetyl mannosamine residues, mannosamine residues, sialic acid residues and the like, and oligosaccharides or polysaccharide residues composed of the monosaccharide residues Is mentioned.

The substituted or unsubstituted sugar residue represented by R ¹ is preferably a substituted or unsubstituted galactose residue, more preferably a substituted or unsubstituted phenyl group (eg, p-nitrophenyl group) at the 1-position. A galactose residue substituted with a hydroxyl group.

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

  Examples of the substituted or unsubstituted sugar residue include structures mimicking glycolipids (eg, ganglioside (sialoglycolipid)) or glycoproteins (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 a halogenated alkyl group. A phenyl group is mentioned.

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

X ² is preferably a hydroxyl group, a C _1-6 -alkoxy group, an azide group, an amino group, a guanidino group, or an azide group, amino group or guanidino group substituted with a C _1-6 -alkyl group.

X ³ is preferably —CH (OH) —CH (OH) —CH ₂ OH or —O—CH (CH ₂ CH ₃ ) ₂ .

X ⁴ is preferably a hydrogen atom, a fluorine atom, or a chlorine atom.

X ⁵ is preferably an acetamide group or —NHCOCH ₂ OH.

X ⁶ is preferably a carboxyl group, a phosphoric acid group, a phosphono group, a sulfo (sulfonic acid) group, or a sulfino group.

  As the salt of the compound represented by the formula (I), a pharmaceutically acceptable salt is preferable, and when the compound represented by the formula (I) has an acidic substituent such as a carboxyl group or a phenolic hydroxyl group. Examples thereof include alkali metal salts such as sodium salt and potassium salt, lysine salt, and arginine salt. 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, nitric acid, 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 (for example, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid) ) And salts with organic acids such as amino acids (for example, glutamic acid).

  The compound of the present invention has an asymmetric carbon and may exist as an optically active substance, but may be 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。）

(Wherein X ² , X ³ , X ⁴ , X ⁵ , X ^6a , R ¹ and R ′ are as defined above, and Au ^I represents a monovalent gold salt or complex.)

The organic group bonded through 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.

Preferred examples of the monovalent gold salt or complex represented by Au ^I include Ph ₃ PAuNTf ₂ and Ph ₃ PAuOTf.

  For example, the reaction is performed under an atmosphere of an inert gas such as argon gas, and an organic solvent (for example, a halogenated hydrocarbon such as dichloromethane) of the compound (II), the compound (III), and a dehydrating agent (for example, molecular sieve). Solvent) solution can be carried out by adding a monovalent gold salt or complex organic solvent (for example, halogenated hydrocarbon solvent such as dichloromethane) 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 formula (II) has a hydroxyl group, the hydroxyl group is an acyl group such as an acetyl group or a picoyl group, or a trityl group, and the two hydroxyl groups are a methylidene group or an alkylidene group of a propane-2-ylidene group. After carrying out the above reaction with protection, it is preferable to deprotect as necessary (see the following formula).

（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 as defined above.)

As a synthesis method of a derivative in which the substituent at the 4-position of sialic acid (X ^{2 in the} above formulas (I) and (I ′)) is an azide group, an amino group or a guanidino group, An example is a method of synthesizing a glycosyl donor into which an azide group has been introduced using the body, and then sequentially converting the substituent at the 4-position.

（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。）

Wherein R ¹ , R ′ and Au ^I are as defined above, TMSOTf represents trimethylsilyl triflate, TMSN ₃ represents trimethylsilyl azide, 2,2-DMP represents 2,2-dimethoxypropane, CSA Represents 10-camphorsulfonic acid, COMU represents uronium-based condensing agent COMU, o-substituted BzCl represents benzoyl chloride substituted at the o-position with R′—C≡C— (for example, hexynyl group), TFA represents trifluoroacetic acid, bisBocPCH represents N, N′-bis (tert-butoxycarbonyl) -1H-pyrazole-1-carboxamidine)

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

  Oral preparations are produced in a conventional manner using, for example, starch, lactose, sucrose, mannitol, carboxymethylcellulose, inorganic salts and the like. In addition to these, a binder, a disintegrant, a surfactant, a lubricant, a fluidity promoter, a corrigent, a colorant, a fragrance, and the like can be appropriately added.

  Examples of the binder include starch, dextrin, gum arabic, gelatin, hydroxypropyl starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol and the like.

  Examples of the disintegrant include starch, hydroxypropyl starch, carboxymethylcellulose sodium, carboxymethylcellulose calcium, carboxymethylcellulose, and low-substituted hydroxypropylcellulose.

  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 promoter include light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate and the like.

  Injectables are produced according to conventional methods. In general, distilled water for injection, physiological saline, aqueous glucose solution, olive oil, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol and the like can be used as diluents. . Further, if necessary, bactericides, preservatives, stabilizers, isotonic agents, soothing agents and the like may be added. In addition, from the viewpoint of stability, the injection can be frozen after filling into a vial or the like, the water can be removed by a normal freeze-drying technique, and the solution can be re-prepared from the freeze-dried product immediately before use.

  Other parenteral agents include inhalants, suppositories for rectal administration, and the like, and are produced according to conventional methods.

  The formulated sialidase inhibitor varies depending on the dosage form, administration route and the like, but can be administered, for example, 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, although it varies depending on the age, body weight, and degree of disease of the patient, the weight of the compound represented by the formula (I) is usually 5 to 500 mg in the case of an adult Is suitably taken once a day or divided into several times a day.

  In order to exert the desired effect as a parenteral agent, it varies depending on the age, body weight, and degree of disease of the patient. It is appropriate to administer 500 mg by intravenous injection, intravenous infusion, subcutaneous injection, intramuscular injection, or inhalation.

  In addition, the compound represented by the formula (I) may be used in combination with other drugs that can be used in combination with sialidase inhibitors. These are administered separately during the course of therapy or combined with a compound of formula (I) above in a single dosage form, such as a tablet, intravenous solution, or capsule.

  The present invention will be described in more detail with reference to the following examples. However, the scope of the present invention is not limited to the scope of the following examples.

Example 1
(1) Synthesis of compound 2

Compound 1 (von Itzstein, M .; Dyason, JC; Thomson, R .; Rudrawar, S .; Pascolutti. M. Compound described in US2012202877A1) (0.79 g, 1.5 mmol) in methanol solution (30 ml) with sodium methoxy (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 ⁺ form). The solid in 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 amorphous 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

  Under an argon atmosphere, a solution of compound 2 (0.50 g, 1.4 mmol) in N, N-dimethylformamide (14 ml) was added to 2,2-dimethoxypropane (0.21 ml, 1.7 mmol) and 10-camphorsulfonic acid (32 mg, 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 roughly purified by silica gel chromatography (eluent: hexane / acetone = 1/4).

A pyridine solution (12 ml) of the obtained crude product was cooled to −40 ° C., and acetic anhydride (6.0 ml) was added. The reaction solution was stirred at −40 ° C. for 44 hours, and methanol was added to stop the reaction. The reaction mixture was azeotroped with toluene (3 times), and the residue was purified by silica gel chromatography (eluent: hexane / acetone = 1/1) to give compound 3 (0.26 g, 2-step yield 48%) as colorless 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

Under an argon atmosphere, compound 3 (261 mg, 0.611 mmol) and picolinic acid (90.3 mg, 0.733 mmol) in dichloromethane (15 ml) were mixed with condensing agent COMU (340 mg, 0.794 mmol) and N, N-diisopropylethylamine (0.32). 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 stop the reaction. Thereafter, ethyl acetate was added, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Filter off the desiccant and evaporate the solvent under reduced pressure. The residue is 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 amorphous 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

To a solution of compound 4 (261 mg, 0.611 mmol) in dioxane / water (3/1, v / v, 8.0 ml), 2,6-lutidine (0.072 ml, 0.63 mmol) and sodium periodate (268 mg, 1.25 mmol), and 50 mM OsO ₄ aqueous solution (0.26 ml, 13 μmol). 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 and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: chloroform / methanol = 98/2) to give Compound 5 (167 mg, 51%) as colorless and amorphous. Obtained as a fine 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 chloride heptahydrate (22 mg, 60 μmol) in tetrahydrofuran / methanol (1/1, v / v, 1.0 ml) is cooled to -78 ° C and hydrogenated Sodium boron (1.4 mg, 36 μmol) was added. After stirring at -78 ° C for 30 minutes, the reaction was stopped with a phosphate buffer (pH 7). Ethyl acetate was added to the reaction mixture, 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 distilled off under reduced pressure to obtain a crude product.

To a solution of the above crude product in dichloromethane (1.0 ml) under an argon atmosphere, o-hexynylbenzoic acid chloride (ca. 33 mg / ml in dichloromethane, 1.0 ml), N, N-dimethyl-4-aminopyridine (One grain) and pyridine (24 μl, 0.30 mmol) were added. After stirring at room temperature for 4 hours, the reaction was stopped by adding a saturated aqueous solution of sodium bicarbonate under ice cooling. 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 distilled off under reduced pressure. The residue obtained was purified by silica gel chromatography (eluent: hexane / acetone = 1/1) and gel permeation chromatography (eluent: chloroform) to give compound 6 (12.2 mg, 2-step yield 58%) was obtained as a colorless oil.
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.)

  Under an argon atmosphere, triisopropylsilyl chloride (0.34 ml, 1.6 mmol) was added to an N, N-dimethylformamide solution (10 ml) of compound 7 (409 mg, 1.36 mmol) and imidazole (120 mg, 1.76 mmol) 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 distilled off under reduced pressure to obtain a crude product.

Acetic anhydride (4.0 ml) was added to a 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 the residue was subjected to medium pressure preparative liquid chromatography (column: Yamazen, ULTRAPACK Silica-40B, eluent: hexane / ethyl acetate) = 3: 1) to give 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

Under argon atmosphere, tetra-n-butylammonium fluoride / acetic acid (1/1, v / v, 2.0 ml) was added to a tetrahydrofuran solution (2.0 ml) of compound 8 (348 mg, 0.597 mmol) under ice cooling. It was. The reaction solution was stirred at room temperature for 5 hours and 30 minutes, and then the reaction was stopped by adding a saturated aqueous solution of ammonium chloride under ice cooling. Ethyl acetate was added to the reaction mixture, 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 distilled off under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 1/1) to give Compound 9 (230 mg, 90%) as a colorless oil Obtained as material.
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

In an argon atmosphere, compound 6 (29.1 mg, 41.2 μmol), galactose 9 (35.2 mg, 82.4 μmol) and molecular sieve 4Å in dichloromethane solution (4.0 ml) were mixed with 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 in dichloromethane, 0.10 ml) was added. After further stirring for 9 hours, chloroform was added, and the solid matter was separated by filtration through celite. 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) to give compound 11 ( 12.2 mg, 32%) was obtained as a colorless oil.
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.)

Under 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 a dichloromethane solution (0.59 ml) of the described compound) (8.6 mg, 16 μmol) and molecular sieve 4Å 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 separated by filtration through celite. 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 oil.
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 dichloromethane / ether (3/7, v / v, 0.50 ml) solution of compound 6 (4.9 mg, 6.9 μmol) and molecular sieve 4Å in an argon atmosphere 0.10 ml (equivalent to 14 μmol) of dichloromethane solution was added. This was ice-cooled, and gold complex Ph ₃ PAuNTf ₂ (11 mg / ml in dichloromethane, 0.10 ml) was added. Two hours later, Ph ₃ PAuNTf ₂ (11 mg / ml in dichloromethane, 0.10 ml) was added. After further stirring for 4 hours, chloroform was added, and the solid was filtered off through Celite filtration. The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel chromatography (eluent: hexane / ethyl acetate = 9/1 to hexane / acetone = 7/3) and high performance liquid chromatography (eluent: chloroform / methanol = 99 / Purification by 1) gave Compound 13 (2.1 mg, 52%, α / β = ca. 12: 1) as a colorless oil.
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, 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 dichloromethane solution (2.0 ml) of compound 11 (12.2 mg, 13.1 μmol) 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 neutralized by adding triethylamine. The residue obtained by evaporating the solvent under reduced pressure was roughly purified by Sep-Pak ^(R) (eluent: water / methanol = 100/0 to 0/100).

Sodium methoxide (3.5 mg, 0.065 mmol) was added to a methanol solution (2.0 ml) of the crude product. The reaction solution was stirred at room temperature for 3 hours, and then neutralized with Amberlite IRC50 (H ⁺ form). The solid of the reaction mixture was filtered off and the solvent was distilled off 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 of heptaol (1.0 ml). After 5 hours 50 minutes and 7 hours 15 minutes, 1 M sodium hydroxide (23 μl) was added, respectively. Nine hours after the start, the mixture was neutralized with Amberlite IRC50 (H ⁺ type). The solid of the reaction mixture was filtered off and the solvent was distilled off 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 evaporating 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 amorphous 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 dichloromethane solution (1.0 ml) of compound 12 (3.4 mg, 3.2 μmol) was cooled to −20 ° C., and trifluoroacetic acid (10 μl) was added. After stirring for 1 hour and 30 minutes, triethylamine was added to neutralize. The residue obtained by evaporating the solvent under reduced pressure was roughly purified by 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 ⁺ form). The solid of the reaction mixture was filtered off and the solvent was distilled off 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 methanolic solution of heptaol (0.4 ml). 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 distilled off 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 evaporating 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 amorphous solid.
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 added with saturated aqueous sodium hydrogen carbonate solution. It was summed up. Thereafter, 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 distilled off under reduced pressure to obtain a crude product.

Sodium methoxide (0.3 mg, 5.6 μmol) was added to a methanol solution (100 μl) of the crude product. The reaction solution was stirred at room temperature for 1 hour and then neutralized with Amberlite IR120 (H ⁺ form). 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 distilled off under reduced pressure, and the resulting residue was purified by Sep-Pak ^(R) (eluent: water) to obtain Compound 16 (2.6 mg, 64%) as a colorless amorphous solid. It was.
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 C. perfringens sialidase, the sialidase inhibitory activity of the test compound was measured as follows.

  (Performed 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 15 (0.5 μl) mixed solution 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 based on the fluorescence value at 7 minutes 30 seconds (Reference: Chen, X. ChemBioChem 2007, 8, 194 − 201.).

The results are shown in FIG.
Compound 15 having a 2,3-sialylgalactose structure exhibited a sialidase inhibitory activity 100 times or more that of DANA, which was the basis of the structural development of the conventional “transition state analog”.

Claims (6)

Formula (I):

[Wherein, X ¹ represents —O—R ¹ , wherein R ¹ represents a substituted or unsubstituted sugar residue, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted C _1-6 -aliphatic. Represents a hydrocarbon group.) Or a fluorine atom; X ² represents —O—R ² (wherein R ² represents 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} ) (wherein R ^a and R ^b are the same or different and each represents a hydrogen atom or a C _1-6 -alkyl group); X ³ represents a substituted or unsubstituted C _1-6 -alkyl group, or Represents a substituted or unsubstituted C _1-6 -alkoxy group; X ⁴ represents a hydrogen atom, a methyl group or a halogen atom; ⁵ represents —NHCO—R ³ (wherein R ³ represents a hydrogen atom, a substituted or unsubstituted C _1-6 -alkyl group or a hydroxymethyl group), a hydroxyl group, or a substituted or unsubstituted C _1-6. -Represents an alkoxy group; X ⁶ represents a carboxyl group, a phosphate group, a phosphono group, a sulfo 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 group. Represents an ester group. ]
Or a salt thereof. The compound or a salt thereof according to claim 1, 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 residue. The compound or a salt thereof according to claim 1, wherein R ¹ is a galactose residue in which the hydroxyl group at position ¹ is substituted with a substituted or unsubstituted phenyl group.   The sialidase inhibitor which contains the compound or its salt of any one of Claims 1-4 as an active ingredient. Formula (II):

[Wherein, X ² represents —O—R ² (wherein R ² represents a hydrogen atom, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted C _1-6 -alkyl group), C _An azido group optionally substituted with a _1-6 -alkyl group, a guanidino group optionally substituted with a C _1-6 -alkyl group, or —N (R ^a ) (R ^b ) (wherein R ^a 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 -Represents an alkoxy group; X ⁴ represents a hydrogen atom, a methyl group or a halogen atom; X ⁵ represents -NHCO-R ³ (wherein R ³ represents a hydrogen atom, a substituted or unsubstituted C _1-6 -alkyl group; or represents a hydroxymethyl group), a hydroxyl group, or a substituted or unsubstituted C _{1-6 -.} al It represents a carboxymethyl group; X ^6a alkoxycarbonyl group, phosphoric acid alkyl ester group, a phosphonic acid alkyl ester group, a sulfonic acid alkyl ester group or a sulfinic acid alkyl ester group; R 'is bonded via a carbon atom Represents an organic group. ]
In the presence of a monovalent gold salt or complex, the compound represented by the following formula (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.)
Comprising reacting with a compound of formula (I ′):

(In the formula, X ² , X ³ , X ⁴ , X ⁵ , X ^6a and R ¹ are as defined above.)
Or a salt thereof.

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