JPH06183965A - Suppressor for immunological function - Google Patents

Abstract

PURPOSE:To obtain the subject suppressor, comprising a specific enopyranose derivative (salt) as an active ingredient, excellent in therapeutic effects with hardly any side effects and useful for treating, e.g. chronic articular rheumatism, etc. CONSTITUTION:This suppressor for immunological function comprises an enopyranose derivative (salt) expressed by the formula [R<1> is H, (substituted) alkyl, alkenyl, etc.; R<2> is H or alkyl; R<3> is H or halogen; R<4> is H, (substituted) silyl, (substituted)alkyl, etc.; either of R<5> and R<6> is OH, (substituted)alkoxy, saccharide derivative residue, etc., and the other is H or (substituted)alkyl; X is H, (substituted)alkyl, (substituted)alkenyl, etc.; Y is H, (substituted)alkyl, etc.] as an active ingredient. Furthermore, the daily dose of the active ingredient for an adult is preferably 50-5000mg.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an immune function inhibitor containing an enopyranose derivative represented by formula (I) as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION In general, immunosuppressants are so-called diseases such as rheumatoid arthritis, systemic lupus erythematosus, chronic nephritis, chronic thyroiditis and autoimmune hemolytic anemia. It is used for the treatment of autoimmune diseases and the treatment for suppressing rejection during organ transplantation. As a conventional immune function suppressant,
Steroid hormones, azathioprine, cyclophosphamide, etc. are used.

[0003]

However, conventional immunosuppressive agents act not only on immune cells but also on a wide range of cells in a non-selective manner, affecting their function / proliferation. Serious side effects such as granulocytopenia and renal dysfunction are regarded as problems. Therefore, the emergence of a drug that has a strong inhibitory activity on immune functions and has minimal side effects is desired.

[0004]

DISCLOSURE OF THE INVENTION The present inventors have found that an enopyranose derivative having a chemical structure completely different from the active ingredient of the conventional immune function-suppressing agents exhibits an immune function-suppressing action, and have proposed the present invention. That is, the present invention has the general formula (I)

[0005]

[Chemical 3]

(In the formula, R ¹ is a hydrogen atom, an optionally substituted alkyl group, an alkenyl group, an alkynyl group or —OSO.
₂ R ⁷ group, halogen atom, -OCOR ⁷ group, -NHCO
R ⁸ group, alkoxy group, optionally substituted phenyl group or sugar derivative residue, R ² is hydrogen atom or alkyl group, R ³ is hydrogen atom or halogen atom, R ⁴
Is a hydrogen atom, a -COR ⁹ group, an optionally substituted silyl group or an optionally substituted alkyl group, and R ⁵ and R ⁶
Is a hydroxyl group, an optionally substituted alkoxy group, a sugar derivative residue, an optionally substituted cycloalkyloxy group or a -OCOR ¹⁰ group, and the other is a hydrogen atom or an optionally substituted alkyl group. Yes, R ⁴ and R ⁵
May together form a single bond, in which case R ⁶
Is a hydrogen atom or an optionally substituted alkyl group, and R
⁷ , R ⁹ and R ¹⁰ are each an alkyl group or an optionally substituted phenyl group, R ⁸ is an alkyl group, an optionally substituted phenyl group or a benzyloxy group, X
Is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group,
Optionally substituted cycloalkyl group, optionally substituted phenyl group, optionally substituted pyridyl group, optionally substituted furanyl group or optionally substituted thienyl group, formyl group, -COR ¹¹ group,- It is a C (W ¹ ) W ² R ¹¹ group or a —SO ₂ R ¹¹ group, and R ¹¹ is a chain hydrocarbon group which may be substituted, a monocyclic hydrocarbon group which may be substituted, or a substituent. A good polycyclic hydrocarbon group, an optionally substituted monocyclic heterocyclic group or an optionally substituted polycyclic heterocyclic group, W ¹ is an oxygen atom or a sulfur atom, and W ² is an oxygen atom. , A sulfur atom or a —NH— group, and Y is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group or an optionally substituted alkynyl group)
The present invention relates to an immunosuppressive agent or an anti-inflammatory agent, which comprises the enopyranose derivative represented by or a salt thereof as an active ingredient.

R ¹ , R ² , R ⁴ in the general formula (I)
^{5 As} an alkyl group represented by R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , X and Y or an alkyl moiety constituting a functional group, methyl, ethyl, propyl, butyl, pentyl,
Hexyl, heptyl, octyl, nonyl, decyl, tetradecyl, pentadecyl, octadecyl, nonadecyl and the like C _{1 to} C ₂₀ are included, and they also include structural isomers of straight chain or branched fatty chain. R ¹ , X
And the alkenyl group represented by Y is ethenyl,
Examples thereof include C _{2 to} C ₂₀ ones such as propenyl and butenyl, which include structural isomers of linear or branched fatty chains. The alkynyl group represented by R ¹ , X and Y includes C ₂ -C such as ethynyl, propynyl and butynyl.
₂₀ are mentioned, and these also include structural isomers of linear or branched fatty chains.

Examples of the halogen atom represented by R ¹ and R ³ in the general formula (I) include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. R ¹ and R ⁵ of the general formula (I)
And the sugar derivative residue represented by R ⁶ ,

[0009]

[Chemical 4]

And the like. R ⁵ in the general formula (I),
The cycloalkyl group of the cycloalkyl group or the cycloalkyloxy group represented by R ⁶ and X includes C ₃ -C such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
There are _eight .

R ¹ , R ⁷ , R ⁸ , R ^{9 of} the general formula (I)
Examples of the substituent of the optionally substituted phenyl group represented by R ¹⁰ include a halogen atom such as fluorine, chlorine, bromine and iodine, an alkyl group such as methyl and ethyl, and a nitro group.

The substituent of the optionally substituted silyl group represented by R ⁴ in the general formula (I) is methyl, ethyl,
Examples include alkyl groups such as propyl and butyl, and phenyl groups.

R ¹ , R ⁴ , R ⁵ and R of the general formula (I)
Examples of the substituent of the optionally substituted alkyl group, the optionally substituted alkoxy group or the optionally substituted cycloalkyloxy group represented by ⁶ include an alkoxy group such as methoxy and ethoxy, a phenyl group and a hydroxyl group. To be

These substituents may be substituted by 1 or 2 or more, and when 2 or more are substituted, they may be the same or different. In addition, X and Y of the general formula (I)
In the definition of, an alkyl group which may be substituted, an alkenyl group which may be substituted and a substituent of an alkynyl group which may be substituted are halogen atoms such as fluorine, chlorine, bromine and iodine, a hydroxyl group, a phenyl group, Examples thereof include alkyl-substituted phenyl groups such as toluyl and xylyl, pyridyl groups, furanyl groups, thienyl groups, acyloxy groups such as acetoxy and valeroxy, azido groups and amino groups, and cycloalkyl groups which may be substituted in the definition of X. , A phenyl group which may be substituted, a pyridyl group which may be substituted, a furanyl group which may be substituted or a thienyl group which may be substituted may be a halogen atom such as fluorine, chlorine, bromine or iodine, or hydroxyl. Groups, alkyl groups such as methyl and ethyl, acyloxy groups such as acetoxy and valeroxy, nitro groups An amino group be mentioned. These substituents may be substituted by 1 or 2 or more, and when they are 2 or more, they may be the same or different from each other.

In the general formula (I), examples of the chain hydrocarbon group contained in R ¹¹ include an alkyl group, an alkenyl group and an alkynyl group, and examples of the monocyclic hydrocarbon group include a cycloalkyl group and a cycloalkyl group. Examples of the polycyclic hydrocarbon group include an alkenyl group and a phenyl group, and examples of the polycyclic hydrocarbon group include naphthyl group, tetrahydronaphthyl group, condensed polycyclic hydrocarbon group such as indanyl group or adamantyl group, noradamantyl group, norbornanyl group. A crosslinked polycyclic hydrocarbon group such as a norbornanonyl group, and the monocyclic heterocyclic group includes a pyrrolyl group, a furanyl group, a thienyl group, a pyrazolyl group, an imidazolyl group, an oxazolyl group,
Isoxazolyl group, thiazolyl group, isothiazolyl group, thiadiazolyl group, pyrrolinyl group, pyrrolidinyl group, dihydrofuranyl group, tetrahydrofuranyl group, dihydrothienyl group, tetrahydrothienyl group, pyrazolinyl group, hydantoinyl group, oxazolinyl group, isoxazolinyl group, Isoxazolidinyl group, thiazolinyl group, thiazolidinyl group, dioxolanyl group, dithialanyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, dihydropyridyl group, tetrahydropyridyl group, piperidinyl group, dihydrooxopyridazinyl group, Tetrahydrooxopyridazinyl group, dihydrooxopyrimidinyl group, tetrahydrooxopyrimidinyl group, piperazinyl group, dihydropyranyl group, tetrahydropyranyl group, dioxy Examples of the polycyclic heterocyclic group include a thienothienyl group, a dihydrocyclopentathienyl group, an indolyl group, a benzofuranyl group, a benzothienyl group, and a benzoxa group. Zolyl group, benzisoxazolyl group, benzothiazolyl group, benzimidazolyl group, tetrahydrobenzothienyl group, dihydrobenzofuranyl group, tetrahydrobenzisoxazolyl group, benzodioxolyl group, quinolinyl group, isoquinolinyl group, benzo Examples thereof include fused polycyclic heterocyclic groups such as dioxanyl group and quinoxalinyl group, and bridged polycyclic heterocyclic groups such as quinuclidinyl group.

The substituent of the optionally substituted chain hydrocarbon group contained in R ¹¹ is a halogen atom, an alkoxy group, a haloalkoxy group, an alkylthio group, a cycloalkyl group, a cycloalkoxy group, a cycloalkenyl group, a cycloalkenyl group. Examples include oxy group, alkoxycarbonyl group, carboxyl group, alkylcarbonyl group, alkylcarbonyloxy group, aryl group, aryloxy group, arylthio group, amino group, and amino group substituted with an alkyl group. The number of substituents attached to these substituents may be one or two or more, and in the case of two or more, the substituents may be the same or different.

Further, the optionally substituted monocyclic hydrocarbon group contained in R ¹¹ , the optionally substituted polycyclic hydrocarbon group, the optionally substituted monocyclic heterocyclic group and the optionally substituted group. Examples of the substituent of the good polycyclic heterocyclic group include a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkylthio group, a cycloalkyl group, a cycloalkoxy group, a cycloalkenyl group, a cycloalkenyloxy group and an alkoxycarbonyl. Group, an alkylcarbonyl group, an alkylcarbonyloxy group, an aryl group, an aryloxy group, an arylthio group, an amino group, an amino group substituted with an alkyl group, a cyano group, a nitro group, a hydroxyl group, and the like. The number of substituents attached to these substituents may be one or more, and may be two or more. In the case of, those substituents may be the same or different.

In the general formula (I), the alkyl group and alkyl moiety contained in R ¹¹ have 1 to 18 carbon atoms, for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, Examples thereof include a heptyl group, an octyl group, a decyl group, a nonadecyl group, and the like, which also include structural isomers of straight or branched fatty chains. R ¹¹
The alkenyl group contained in includes those having 2 to 18 carbon atoms, for example, vinyl group, propenyl group, butenyl group, pentenyl group, hexenyl group, decenyl group, nonadecenyl group, etc. It also includes structural isomers of branched fatty chains. Examples of the alkynyl group contained in R ¹¹ include those having 2 to 18 carbon atoms, such as an ethynyl group, a propynyl group, a butynyl group, a pentynyl group, a hexynyl group, a decynyl group, and a nonadecynyl group.
They also include structural isomers of straight or branched fatty chains. The cycloalkyl group and the cycloalkyl moiety contained in R ¹¹ have 3 to 8 carbon atoms, for example,
Examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cyclooctyl group. Examples of the cycloalkenyl group and the cycloalkenyl moiety contained in R ¹¹ include those having 5 to 8 carbon atoms, for example, a cyclopentenyl group, a cyclohexenyl group, a cyclooctenyl group and the like. Further, the halogen atom contained in R ¹¹ is a fluorine atom, a chlorine atom, a bromine atom,
Iodine atom is mentioned. The aryl group and aryl moiety contained in R ¹¹ include a phenyl group, a thienyl group,
A furanyl group, a pyridyl group, a naphthyl group, a benzothienyl group, a benzofuranyl group, a quinolinyl group and the like can be mentioned.

The enopyranose derivative represented by the general formula (I) has stereoisomers based on the asymmetric carbon atoms at the 1-, 2- and 5-positions of the pyranose ring. The present invention also covers them. Further, examples of the salt of the enopyranose derivative represented by the general formula (I) include acid addition salts with mineral acids such as hydrochloric acid and sulfuric acid.

The enopyranose derivative represented by the general formula (I) is preferably the following. (1) The enopyranose derivative has the following general formula (I-1)
Alternatively, a stereoisomer represented by (I-2).

[0021]

[Chemical 5]

(In the formula, R ^{1 to} R ⁶ , X and Y are as described above. However, in the case of the formula (I-2), Y is a hydrogen atom.) (2) General formula (I-1) Or in (I-2), R ¹
Is a hydrogen atom, an optionally substituted alkyl group, an alkenyl group or an alkynyl group, R ² is a hydrogen atom or an alkyl group, and R ³ and R ⁶ are each a hydrogen atom,
R ⁴ and R ⁵ together form a single bond, and X
And Y are enopyranose derivatives as described above.

The enopyranose derivative represented by the general formula (I) includes a novel compound. The invention also relates to those compounds mentioned below. In formula (I-1) or (I-2), R ¹ represents a hydrogen atom,
Optionally substituted alkyl group, alkenyl group, alkynyl group, -OSO ₂ R ⁷ group, halogen atom, -OCOR ⁷
Group, -NHCOR ⁸ group, alkoxy group, optionally substituted phenyl group or sugar derivative residue, R ² is a hydrogen atom or an alkyl group, R ³ is a hydrogen atom or a halogen atom, R ⁴ and R ⁵ together forms a single bond, R ⁶ is a hydrogen atom or an optionally substituted alkyl group, R ⁷ is an alkyl group or an optionally substituted phenyl group, and R ⁸ is an alkyl group. Is an optionally substituted phenyl group or a benzyloxy group, and X is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, or an optionally substituted cyclo. Alkyl group, optionally substituted phenyl group, optionally substituted pyridyl group, optionally substituted furanyl group, optionally substituted thienyl group, formyl group, -CO
R ¹¹ group, —C (W ¹ ) W ² R ¹¹ group or —SO ₂ R
^And R ¹¹ is a chain hydrocarbon group which may be substituted, a monocyclic hydrocarbon group which may be substituted, a polycyclic hydrocarbon group which may be substituted, a monocyclic ring which may be substituted. Formula is a heterocyclic group or an optionally substituted polycyclic heterocyclic group, W ¹ is an oxygen atom or a sulfur atom, W ² is an oxygen atom, a sulfur atom or a —NH— group, and Y is a hydrogen atom. A compound which is an optionally substituted alkyl group, an optionally substituted alkenyl group or an optionally substituted alkynyl group. However, the following cases are excluded. In (I-1), R ¹ , R ² , R ³ , R ⁶ and X
Is a hydrogen atom and Y is a hydrogen atom or an optionally substituted alkyl group, in (I-1), R ¹ , R ² , R ³ , R ⁶ and Y
Is a hydrogen atom, X is acetyl, 3,5-dinitrobenzoyl or p-toluenesulfonyl, in (I-1), R ¹ , R ² , R ³ and Y are hydrogen atoms and R ⁶ Is an optionally substituted alkyl group, and when X is a hydrogen atom or acetyl, in (I-2), R ¹ , R ² , R ³ , R ⁶ and Y
Is a hydrogen atom, X is a hydrogen atom, methyl, benzyl,
Formyl, acetyl, benzoyl, 4-chlorobenzoyl, 3,5-dichlorobenzoyl, 4-nitrobenzoyl, 3,5-dinitrobenzoyl, 4-methoxybenzoyl, 3,5-dimethoxybenzoyl, methylsulfonyl or p-toluenesulfonyl. In some cases, and in (I-2), R ¹ is p-toluenesulfonyloxy, R ² , R ³ , R ⁶ and Y are hydrogen atoms, and X is a hydrogen atom, acetyl or p-toluenesulfonyl. If there is.

The following compounds are desirable as the compound of the present invention. (1) In the general formula (I-1), R ¹ is a hydrogen atom, an optionally substituted alkyl group, an alkenyl group or an alkynyl group, R ² is a hydrogen atom or an alkyl group, and R
^At least one of ¹ and R ² is a substituent other than a hydrogen atom, R ³ and R ⁶ are each a hydrogen atom, and R ⁴ and R ⁵ are taken together to form a single bond. (2) A compound represented by the formula (I-1), wherein X is furancarbonyl or furfuryl. (3) A compound represented by the formula (I-1), wherein Y is an alkynyl group which may be substituted.

The enopyranose derivative represented by the general formula (I) or a salt thereof can be produced by various methods. For example, 1,6-anhydro-3,4-dideoxy-β-D-glycero-hexo-3-enopyranose-2-ulose is reduced to give 1,6-anhydro-3,4.
-Dideoxy-β-D-threo-hex-3-enopyranose is once produced, and then acylated, carbonated, carbamide esterified, etherified or sulfonylated by a conventional method to produce the desired compound. In addition, 1,6-anhydro-3,4-dideoxy-β-D
-The 2-position of glycero-hex-3-enopyranose-2-ulose is alkylated, alkenylated or alkynylated by conventional methods to produce the desired compound. Further, the 2-position reaction product is acylated, carbonated, carbamide esterified, etherified or sulfonylated to produce the desired compound. On the other hand, 1,6-anhydro-3,4-
Dideoxy-β-D-erythro-hexo-3-enopyranose can be obtained by the above-mentioned reduction reaction, but can also be produced by isomerization of the threo body. Further, this compound can be acylated, carbonated, carbamide esterified, etherified or sulfonylated by a conventional method to produce a desired compound.

Further, instead of 1,6-anhydro-3,4-dideoxy-β-D-glycero-hexo-3-enopyranose-2-ulose, the following compound represented by the general formula (II) is used. be able to. General formula (I
I)

[0027]

[Chemical 6]

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as described above) The compound represented by the general formula (II) is reduced or alkylated by a conventional method. The desired compound is purified by alkenylation or alkynylation, and acylation, carbonation, carbamide esterification, etherification or sulfonylation by a conventional method. Further, the compound represented by the general formula (II) is reduced and then isomerized,
It can be acylated, carbonated, carbamide esterified, etherified or sulfonylated by a conventional method to produce the desired compound.

The compound represented by the general formula (II) has an enantiomer (L-form), which can be used for the same reaction as described above. In carrying out these reactions, by carrying out the reaction in an inert atmosphere such as nitrogen gas, helium gas or argon gas, side reactions and a decrease in yield can be prevented. The general production method using these reactions is described below.

A. Reduction 1,6-anhydro-3,4-dideoxy-β-D-glycero-hexo-3-enopyranose-2-ulose-containing dry ether solution or water containing it or alcohol solution such as methanol, ethanol, isopropanol, etc. Is gradually added to 0.3 equivalent or more, preferably 0.4 to 0.5 equivalent of lithium aluminum hydride or sodium borohydride. The reaction mixture is stirred at room temperature or lower, preferably at -10 to 0 ° C for 0.5 to 2 hours to carry out the reaction. After adding a small amount of water to the reaction product, the product is post-treated by a conventional method for purification and separation.

B. Acylated 1,6-anhydro-3,4-dideoxy-β-D-glycero-hexo-3-enopyranose-2-ulose reduced product or a suitable solution of acyl halide to a dry pyridine solution containing a 2-position reaction product thereof. 1 equivalent or more, preferably 1.5 to
Add 2 equivalents slowly. The reaction mixture is stirred at room temperature or lower, preferably at -10 to 0 ° C for 0.5 to 2 hours to carry out the reaction. After adding a small amount of water to the reaction product, it is concentrated under reduced pressure to obtain a crude product, which is purified and separated by a conventional method.

When the direct acylation is carried out using a carboxylic acid instead of an acyl halide, 1,6-anhydro-
1.5 to 2 equivalents of dicyclohexylcarbodiimide, diethylcarbodiimide, etc., and appropriate carboxylic acid 1.5 to 2 equivalents based on a dry methylene chloride solution containing 3,4-dideoxy-β-D-threo-hex-3-enopyranose Then, 0.1 to 0.2 equivalents of N, N-dimethylaminopyridine, diisopropylethylamine and the like as a catalyst are added, and the reaction is carried out at 0 to 30 ° C., preferably 10 to 20 ° C. for 6 to 12 hours with stirring. Post-treatment and purification and separation are carried out by a conventional method.

C. Carbonated 1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranose-2-ulose reduced product or a dry pyridine solution containing a 2-position reaction product thereof,
Suitable chlorocarbonate is 2 equivalents or more, desirably 2
The reaction mixture is stirred at 0 to 30 ° C, preferably 10 to 20 ° C for 6 to 12 hours, and the reaction is carried out. After adding a small amount of water to the reaction product, the product is post-treated by a conventional method for purification and separation.

D. Carbamic acid esterification Suitable for a dry toluene solution containing a reduced product of 1,6-anhydro-3,4-dideoxy-β-D-glycero-hexo-3-enopyranose-2-ulose or its 2-position reaction product. Isocyanate or isothiocyanate is added in an amount of 1.3 equivalents or more, preferably 1.5 to 2 equivalents, and the mixture is stirred for 10 to 15 minutes. 0.8 to 1.2 equivalents of sodium, potassium hydride and the like are added, and the mixture is further stirred and reacted. The reaction when triethylamine or the like is added requires reflux under heating.

When phenyl isocyanate is used, diisopropylethylamine, triethylamine and the like are preferable, and in other cases, potassium hydride, sodium hydride and the like are preferable. After completion of the reaction, the reaction product is post-treated by a conventional method for purification and separation.

E. Etherification 1,6-anhydro-3,4-dideoxy-β-D-glycero-hexo-3-enopyranose-2-ulose reduced product or its 2-position reaction product is treated with sodium hydride or potassium hydride. 1.0-1.5 equivalents of base, preferably 1.3 equivalents, are slowly added to a suspension in dry tetrahydrofuran. The reaction mixture is 0 to 20 ° C., preferably 0 to 10
After stirring at 10 ° C for 10 to 15 minutes, an appropriate organic halide is added in an amount of 1 equivalent or more, preferably 1.3 to 1.5 equivalents, and 10
The reaction is carried out by stirring at -30 ° C, preferably 20-30 ° C for 6-12 hours. The above-mentioned organic halide is selected according to the desired target substance, and for example, methyl iodide, butyl iodide, benzyl bromide and the like can be used. After adding a small amount of water to the reaction product, it is concentrated under reduced pressure to obtain a crude product, which is purified and separated by a conventional method.

F. Sulfonylated 1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranose-2-ulose reduced product or a dry pyridine solution containing the 2-position reaction product thereof
Equivalent or more, preferably 1.5 to 2 equivalents of a suitable sulfonyl halide is gradually added, and the reaction mixture is heated to 10 to 30 ° C.
Desirably, the reaction is performed by stirring at 20 to 30 ° C. for 6 to 12 hours. The above-mentioned sulfonyl halide is selected according to the desired target product, and for example, tosyl chloride, mesyl chloride, etc. can be used. After adding a small amount of water to the reaction product, extraction with a solvent such as toluene, the solvent is concentrated under reduced pressure to obtain a crude product, which is purified and separated by a conventional method.

G. Alkylated, alkenylated or alkynylated 1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranose-2-ulose suitable alkyl, alkenyl or alkynyl lithium in dry tetrahydrofuran solution Alternatively, 1.2 to 1.5 equivalents of each alkylated, alkenylated or alkynylated organometallic reagent such as alkyl, alkenyl or alkynyl magnesium bromide is gradually added. The reaction mixture is -7
The reaction is carried out by stirring at 8 to 0 ° C, preferably -10 to 0 ° C for 0.5 to 1 hour. A small amount of water is added to the reaction mixture and concentrated under reduced pressure to obtain a crude product, which is purified and separated by a conventional method.

H. Isomerization A solution of 1,6-anhydro-3,4-dideoxy-β-D-glycero-hexo-3-enopyranose-2-ulose reduced product or tosyl ester of its 2-position reactant in a dry dimethylformamide solution was mixed with benzoic acid. A metal salt of carboxylic acid such as sodium acid is added in an amount of 1 to 2 equivalents, preferably 2 equivalents, and the reaction is carried out by stirring at 100 to 150 ° C., preferably at reflux temperature for 30 minutes. The reaction mixture was post-treated by a conventional method, the solvent was removed, the residue was dissolved in dry methanol, and 1 to 2 equivalents, preferably 1.5 equivalents of a base was added,
The reaction is carried out at 30 ° C., preferably at 20-30 ° C. for 30 minutes with stirring. As the above-mentioned base, sodium hydroxide, potassium hydroxide, sodium methoxide and the like can be used. After completion of the reaction, post-treatment is carried out by a conventional method for purification and separation.

The compound represented by the general formula (II) can be produced by various methods. For example, 1,
The 3-position of 6-anhydro-3,4-dideoxy-β-D-glycero-hexo-3-enopyranose-2-ulose is halogenated to form a desired compound, and the reaction product of the 3-position is subjected to a coupling reaction. Can be alkylated, alkenylated, alkynylated, arylated to give the desired compounds. Also, 1,6-anhydro-3,
4-dideoxy-β-D-glycero-hexo-3-enopyranose-2-ulose or its 3-, 4- or 5-position-substituted derivative is treated with an acid condition to simultaneously open the acetal and ether at the 1-position. , Or acylation of the 1- and 6-positions to produce the desired compound. Further, the 6-position of the compound in which the 1-position is etherified can be etherified, acylated or silylated to form a desired compound. The resulting compound can be deacylated at the 1-position or the 1- and 6-positions by hydrolysis. On the other hand, a natural type sugar such as glucose, galactose, mannose or the like can be used as a raw material to be converted into a 2-ketone derivative to produce a desired enone derivative having an oxygen or nitrogen functional group at the 3-position.

In carrying out these reactions, by carrying out the reaction in an inert atmosphere such as nitrogen gas, helium gas, or argon gas, side reactions and reduction in yield can be prevented. The general manufacturing method using these reactions is described below.

A. Halogenation reaction (A-1) Bromination 1,6-Anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranose-2-ulose-containing halogenated dry carbon tetrachloride, chloroform, etc. 0.9 equivalents or more, preferably 1.5 to 2 equivalents of bromine are slowly added to the carbon solution at 0 ° C or less, preferably -10 to -15 ° C. The reaction mixture is kept at 0 ° C or lower, preferably -10 to -1.
The reaction is carried out by stirring at 5 ° C for 10 to 30 minutes. A base such as pyridine, triethylamine or diisopropylethylamine is added at 5 equivalents or more, preferably 8 to 10 equivalents.
The reaction is carried out by stirring for a time. After adding water to the reaction solution, the product is purified by a conventional method for purification and separation.

(A-2) Iodination In a dry pyridine-carbon tetrachloride solution containing 1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranose-2-ulose, 5 An equivalent or more, preferably 8 to 10 equivalents of a dry pyridine-carbon tetrachloride solution of iodine is gradually added at 5 ° C or less, preferably 0 to 5 ° C.
The reaction is carried out by stirring the reaction mixture at room temperature, preferably 15-25 ° C for 2 hours. After adding ethyl acetate, the product is post-treated by a conventional method for purification and separation. Car for this method
I. R. Synthesized according to the method of Johnson et al. [T
etrahedron Lett. 33.917-91
8. (1992)]. For the synthesis of α-iodine derivatives directly from enones, see John M. et al. McIntosh
Method [Can. J. Chem. 49,3045-30
47, (1971)] or T.W. H. Kim's method [C
hem. Express 5, 221, (1990)]
There is.

B. Coupling reaction 1,6-anhydro-3,4-dideoxy-3-iodo-β-D-glycero-hexo-3-enopyranose-2
-In a dry N-methylpyrrolidinone solution containing ulose,
0.01 to 0.3 equivalent, preferably 0.05 to 0.15 equivalent of cuprous iodide, 0.01 to 0.3 equivalent, preferably 0.
05-0.15 equivalents of triphenylarsenic, 0.01-
The reaction is carried out using a palladium-based catalyst such as 0.1 equivalent, preferably 0.03 to 0.07 equivalent of bis (benzonitrile) palladium (II) chloride. An organic tin compound or an organic zinc compound is added to the reaction mixture, and the reaction is carried out at 0 to 100 ° C., preferably 25 to 80 ° C. for 1 to 10 hours, preferably 2 to 6 hours. After adding ethyl acetate, the product is post-treated by a conventional method for purification and separation. This method is described in C.I. R. Jo
The method of Hunson et al. [Tetrahedron Let
t. 33, 919-922, (1992)].

When R ¹ in the general formula (II) is an optionally substituted alkyl group, the following method can be used. That is, 1,6-anhydro-3-bromo-
3,4-dideoxy-β-D-glycero-hex-3-
Enopyranose-2-ulose was reacted with 1 equivalent or more of ethylene glycol and a catalytic amount of paratoluenesulfonic acid at a reflux temperature of a solvent such as benzene or toluene to protect the carbonyl group at the 2-position of the pyranose ring.
6-anhydro-3-bromo-3,4-dideoxy-β
-D, glycero-hexo-3-enopyranose-2-ulose ethylene acetal, which is then added to a solvent such as tetrahydrofuran with 1 equivalent or more of n-butyllithium and 1 equivalent or more of alkyl iodide and -60 ~
The reaction is carried out at a reaction temperature of -80 ° C. After the reaction, the protecting group at the 2-position of the pyranose ring is eliminated together with a catalytic amount of paratoluenesulfonic acid at the reflux temperature of tetrahydrofuran and water. Various ketones or aldehydes can be used in place of the alkyl iodide described above. In that case, a compound having an alkyl group substituted with a hydroxyl group as R ¹ is obtained. Furthermore, in the reaction for eliminating the protecting group, if an alcohol such as methanol is used as a solvent, the hydroxy moiety of the alkyl group substituted with a hydroxyl group can be converted into an alkoxy group such as methoxy. Also,
The hydroxy moiety of the alkyl group substituted with a hydroxyl group can also be aminated by a known method.

C. Ring-Opening Reaction of Acetal 1,6-Anhydro-3,4-dideoxy-β-D-glycero-hexo-3-enopyranose-2-ulose or its 1-, 3-, 4- or 5-position-substituted derivative A solution of a suitable acid anhydride or a corresponding acid anhydride in dry chloroform is stored at -20 ° C to 15 ° C, preferably at -10 ° C to 0 ° C, with sulfuric acid or a Lewis acid such as boron trifluoride / ethylate. 0.05 to 0.5 equivalent, preferably 0.08 to 0.15 equivalent is gradually added. The reaction mixture is stirred for 10 minutes to 2 hours, preferably 15 to 30 minutes, and then the reaction solution is added to ice-saturated aqueous sodium hydrogencarbonate and then treated by a conventional method for purification and separation. [Carbohydr, Res. 7
1, 169-191 (1979)]

On the other hand, in the case of synthesizing a 1-alkoxy derivative, 1-5% of concentrated sulfuric acid, preferably 3-4% is added to a corresponding alcohol solution of dry methanol, ethanol, propanol or the like, and the temperature is preferably 10-30 ° C. 15-25
Stir at 5 ° C. for 5 to 48 hours, preferably 12 to 36 hours.
The reaction solution is neutralized with a base such as sodium hydrogencarbonate and then treated and purified and separated by a conventional method. The alcohol at the 6-position generated at this time can be converted to the corresponding derivative by etherification, acylation, etc. by a conventional method.

D. Hydrolysis 1,6-di-O-acyl-3,4-dideoxy-α-D
Lithium hydroxide, sodium hydroxide, in water or an alcohol solution containing methanol, ethanol, isopropanol or the like containing glycero-hexo-3-enopyranose-2-ulose or its 1-, 3-, 4- or 5-position-substituted derivative Add a base such as potassium hydroxide in an amount of 0.05 to 0.3 equivalent, preferably 0.1 to 0.15 equivalent, and add 10 to 30 ° C.
Desirably 10 to 45 minutes at 15 to 25 ° C. Desirably 20
Stir for ~ 30 minutes. After adding ethyl acetate to the reaction product, the precipitate is filtered off and concentrated under reduced pressure to obtain the product, which is purified and separated by a conventional method.

E. Oxidation reaction To a dry methylene chloride solution containing 3,4-dideoxy-hex-3-enopyranose or a derivative thereof, 1 to 10 equivalents, preferably 2 to 5 equivalents of pyridinium chlorochromate is added, and 0 to 40 ° C, preferably 10 1-2 at -20 ° C
Stir for 0 hours, preferably 2 to 12 hours to react. After adding diethyl ether and filtering through silica gel, the filtrate is concentrated to obtain a crude product, which is purified and separated by a conventional method.
The compounds represented by the general formula (II) include compounds not described in the literature. For example, the general formula (II ′)

[0050]

[Chemical 7]

(In the formula, R ¹ ′ is an optionally substituted alkyl group, alkenyl group, alkynyl group, —OSO ₂ R
⁷ groups, a halogen atom, an optionally substituted phenyl group or a sugar derivative residue, and R ⁴ , R ⁵ , R ⁶ and R ⁷ are as described above. However, the case where R ¹ ′ is a bromine atom, R ⁴ and R ⁵ form a single bond, and R ⁶ is a hydrogen atom is excluded. The compound represented by) or a salt thereof is a novel compound.

Further, the compound represented by the general formula (II) also has an immunosuppressive effect. Next, the enone derivatives represented by the general formula (II) are shown in Tables 1 and 2.
For example.

[0053]

[Table 1]

[0054]

[Table 2]

Intermediate Synthesis Example 1 1,6-anhydro-
3,4-dideoxy-3-iodo-β-D-glycero-
Hexo-3-enopyranose-2-ulose (intermediate N
o. Synthesis of 5) 1,6-anhydro-3, under an inert atmosphere of nitrogen gas,
4-dideoxy-β-D-glycero-hexo-3-enopyranose-2-ulose (US Pat. No. 3,926,9)
No. 47) (5 g) to a solution of 5 g of dry pyridine-carbon tetrachloride (1: 1) in 150 ml, a solution of 40 g of iodine in 150 ml of dry pyridine-carbon tetrachloride (1: 1) was slowly added at 0 ° C. After stirring at room temperature for 2 hours, disappearance of the raw material was confirmed by thin layer chromatography, and 200 ml of ethyl acetate was added. 2 times with 200 ml of saturated saline
It was washed once with 200 ml of 0% sodium thiosulfate. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting syrupy crude product was subjected to silica gel column chromatography (ethyl acetate: hexane =
Purification by 1: 3) yielded 6.1 g of the desired product (Intermediate No. 5) as pale yellow crystals. The NMR analysis values and physical properties of this product are as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 3.81
(1H, d, J = 6.8Hz); 3,87 (1H, d
d, J = 6.8, 5.0 Hz); 4.93 (1H, t,
J = 5.0 Hz); 5.57 (1H, s); 7.96
(1H, d, J = 5.0 Hz) m. p. 66-67 ° C

Intermediate Synthesis Example 2 1,6-anhydro-
3,4-dideoxy-3-methyl-β-D-glycero-
Hexo-3-enopyranose-2-ulose (intermediate N
o. Synthesis of 2) 1,6-anhydro-3, under an inert atmosphere of nitrogen gas
4-dideoxy-3-iodo-β-D-glycero-hex-3-enopyranose-2-ulose 5 g, cuprous iodide 0.4 g, triphenylarsenic 0.6 g and bis (benzonitrile) palladium chloride ( II) To 20 ml of a dry N-methylpyrrolidinone solution containing 0.4 g of the mixture, 5.3 g of tetramethyltin was added, and the mixture was stirred at 80 ° C. for 4 hours. 200 ml of ethyl acetate was added, and the mixture was washed 3 times with 100 ml of 10% aqueous potassium fluoride solution. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained syrupy product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3), and then distilled under reduced pressure to give the desired product (intermediate No. 2) as a colorless transparent liquid. 0.61 g was obtained. NM of this thing
The analysis value of R is as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 1.79
(3H, s); 3.68 (1H, d, J = 6.8H
z); 3.83 (1H, dd, J = 6.8, 4.8H
z); 4.95 (1H, t, J = 4.8Hz); 5.3.
6 (1H, s); 6.96 (1H, dq, J = 4.8,
1.6 Hz) b. p. 150-170 ° C. (40 mmHg) The following compounds were synthesized according to the case of the above Intermediate Synthesis Example 2, and the physical properties thereof are described.

Intermediate No. 42 ¹ H NMR (CDCl ₃ , 400 MHz): 2.36
(3H, s); 3.85 (1H, d, J = 6.8H
z); 3.95 (1H, dd, J = 6.6, 4.8H
z); 5.15 (1H, t, J = 4.8Hz); 5.5
0 (1H, s); 719 (2H, br, d, J = 8.1
7.23 (1 H, d, J = 4.8 Hz);
32 (2H, br, d, J = 8.1 Hz) m. p. 117-119 ° C

Intermediate No. 9 ¹ H NMR (CDCl ₃ , 400 MHz): 1.82
(1H, dt, J = 11.5, 4.8Hz); 1.90
(1H, m); 1.98 (1H, dt, J = 11.5,
3.3 Hz); 2.22 (1 H, m); 2.64 (1
H, dddd, J = 20.0, 3.5, 3.5, 3.5
Hz); 3.15 (1H, m); 3.62 (1H, d,
J = 6.9 Hz); 3.88 (1H, d, J = 7.3H)
z); 3.79 (1H, dd, J = 7.3, 4.7H
z); 3.87 (1H, dd, J = 6.9, 4.3H
z); 4.40 (1H, d, J = 4.7Hz); 5.0
1 (1H, t, J = 4.7Hz); 5.17 (1H,
s); 5.35 (1H, s); 6.80 (1H, dd,
J = 4.7, 1.2 Hz); 6,93 (1H, q, J =
3.5Hz)

Intermediate Synthesis Example 3 Synthesis of methyl 3,4-dideoxy-3-methyl-α-D-glycero-hexo-3-enopyranose-2-ulose (Intermediate No. 20) 1,6-anhydro- 3,4-Dideoxy-3-methyl-β-D-glycero-hex-3-enopyranose-2
-To 50 ml of a dry methanol solution containing 500 mg of ulose (intermediate No. 2), 0.1 ml of concentrated sulfuric acid was added, and
Stir for 8 hours. 30 ml of saturated sodium hydrogen carbonate solution was added, and the mixture was stirred at room temperature for 15 minutes and then concentrated under reduced pressure. 200 ml of ethyl acetate was added to this, and 200 ml of saturated saline solution was added.
It was washed 3 times. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting syrupy crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 3) to obtain 350 mg of the desired compound (Intermediate No. 20) as a colorless liquid. The NMR analysis values of this product are as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 1.86
(3H, m); 1.95 (1H, t, J = 6.0H
z); 3.54 (3H, s); 3.76 (1H, dd
d, J = 11.2, 6.8, 6.0 Hz); 3.84
(1H, ddd, J = 11.2, 6.0, 3.6H
z); 4.83 (1H, m,); 4.80 (1H,
s); 6.68 (1H, m)

Intermediate Synthesis Example 4 1,6-di-O-propionyl-3,4-dideoxy-α-D-glycero-hex-3-enopyranose-2-ulose (Intermediate No.
Synthesis of 19) 1,6-anhydro-3,4-dideoxy-β-D-glycerohexo-3-enopyranose-2-ulose 1
Dissolve 00 mg in 3 ml of propionic anhydride, -20 ℃
Cooled down to. Add 0.06 ml of concentrated sulfuric acid to this, and add 30
After stirring for a minute, the reaction mixture was added to 100 ml of ice-saturated aqueous sodium hydrogen carbonate. After stirring for 30 minutes, the mixture was extracted with 100 ml of ethyl acetate and washed 3 times with 100 ml of saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting syrupy crude product was subjected to silica gel chromatography (ethyl acetate: hexane =
1: 2) to obtain the desired product (intermediate No. 1).
100 mg of 9) was obtained as a colorless transparent liquid. The NMR analysis values of this product are as follows.

Intermediate No. 19 ¹ H NMR (CDCl ₃ , 400 MHz): 1.14
(3H, t, J = 5.2Hz); 1.16 (3H.t,
J = 5.2 Hz); 2.38 (4H, m); 4.22
(1H, dd, J = 11.4, 4.6 Hz); 4.41
(1H, dd, J = 11.4, 4.7 Hz); 4.81
(1H, m,); 6.20 (1H, s); 6.28 (1
H, dd, J = 10.6, 2.4 Hz); 7.05 (1
H, dd, J = 10.6, 1.9 Hz) The following compounds were synthesized according to the case of Synthesis Example 4, and the physical properties thereof will be described.

Intermediate No. 16 ¹ H NMR (CDCl ₃ , 400 MHz): 2.10.
(3H, s); 2.13 (3H, s); 4.20 (1
H, dd, J = 11.4, 5.0 Hz); 4.38 (1
H, dd, J = 11.4, 5.0 Hz); 4.88 (1
H, td, J = 5.0, 1.9 Hz); 6.34 (1
H, s); 7.43 (1H, d, J = 1.9 Hz)

Intermediate Synthesis Example 5 6-O-acetyl-3-
Bromo-3,4-dideoxy-D-glycero-hexo-
3-enopyranose-2-ulose (Intermediate No. 1
8) Synthesis of Carbohydrate Research 198
1, 6-anhydro-3-bromo-3,4-dideoxy-β-D-glycero-hexo-3-enopyranose-2-ulose obtained by the method described in Vol. 93, pp. 284-287. 1,6-di-O-acetyl-3- synthesized from (Intermediate No. 4) according to Synthesis Example 4 above.
Bromo-3,4-dideoxy-α-D-glycero-hexo-3-enopyranose-2-ulose 200 mg was dissolved in tetrahydrofuran-water (5: 1) 6 ml, and lithium hydroxide monohydrate 70 mg was added at room temperature. And stirred for 30 minutes. 100 ml of ethyl acetate was added to the reaction solution, and the mixture was washed 3 times with 100 ml of saturated saline. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained syrupy crude product was subjected to preparative thin layer chromatography (Merck, NO-5744, ethyl acetate: hexane =
1: 1) to obtain the desired product (intermediate No. 1).
40 mg of 8) was obtained as a pale yellow liquid. N of this thing
The analysis value of MR is as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 2.12
(0.9H, s); 2.13 (0.1H, s); 4.2
4 (0.1H, dd, J = 11.2, 5.0Hz);
4.26 (0.9H, dd, J = 11.5, 5.0H
z); 4.35 (0.9H, dd, J = 11.5, 5.
0Hz); 4.47 (0.1H, dd, J = 11.2,
6,5 Hz); 4.78 (0.1H, dddd, J =
6.5, 5.0, 1.9, 1.0 Hz); 5.00
(0.9 H.td, J = 5.0, 2.2 Hz); 5.3
1 (0.1H, br, s); 5.46 (0.9H, b
r, s); 7.38 (0.9H, d, J = 2.2H)
z); 7.44 (0.1 H, d, J = 1.9 Hz) The following compounds were synthesized according to Synthesis Example 5 above, and the physical properties thereof will be described.

Intermediate No. 17 ¹ H NMR (CDCl ₃ , 400 MHz): 2.09
(2.25, s); 2.10 (0.75H, s); 4.
26 (0.25H, dd, J = 11.5, 5.0H
z); 4.27 (0.75H, dd, J = 11.5,
4.3 Hz); 4.34 (0.75H, dd, J = 1)
1.5, 5.3 Hz); 4.42 (0.25H, dd,
J = 11.5, 6.2 Hz); 4.79 (0.25H,
m); 4.93 (0.75H, m); 5.19 (0.2
5H, br, d, J = 5.7 Hz); 5.26 (0.7
5H, br, d, J = 3.3 Hz); 6.19 (0.7
5H, dd, J = 10.4, 2.5Hz); 627
(0.25H, dd, J = 10.0, 2.8Hz) =
6.99 (0.75H, dd, J = 10.4, 1.7H
z); 6.99 (0.25H, dd, J = 10.0,
1.9 Hz)

Intermediate Synthesis Example 6 1,6-anhydro-3
-Op-toluenesulfonyl-4-deoxy-β-D
-Synthesis of glycero-hexo-3-enopyranose-2-ulose (intermediate No. 3) 1,6-anhydro-3-Op-toluenesulfonyl-4-deoxy-β-D-erythro-hexo-3 20 ml of a dry methylene chloride solution of 50 mg of enopyranose
To the above, 360 mg of pyridinium chlorochromate was added,
Stir at room temperature for 48 hours. After disappearance of the starting material was confirmed by thin layer chromatography, 60 ml of ethyl ether was added. After stirring for a further 15 minutes at room temperature, the reaction mixture was filtered through silica gel and washed with 200 ml diethyl ether. The washing solution was concentrated under reduced pressure together with the filtrate. The obtained syrupy crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to obtain 34 mg of the desired product (Intermediate No. 3) as a colorless transparent liquid. The NMR analysis values of this product are as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 2.45
(3H, s); 3.83 (1H, d, J = 7.2H
z); 3.92 (1H, dd, J = 7.2, 4.8H
z); 5.14 (1H, t, J = 4.8Hz); 5.3
6 (1H, s); 7.17 (1H, d, J = 4.8H
z); 7.35 (2H, br, d, J = 80 Hz);
7.82 (2H, dt, J = 8.8, 2.0Hz) m. p. 81-86 ° C

Intermediate Synthesis Example 7 1,6-anhydro-
3,4-dideoxy-4-methyl-β-D-glycero-
Hexo-3-enopyranose-2-ulose (intermediate N
o. 43) Synthesis of diisopropylamine in an inert atmosphere of nitrogen gas.
45 ml (mmol) and 1.75 ml of butyllithium were added to a lithium amide solution prepared by a conventional method in 25 ml of anhydrous tetrahydrofuran to prepare 1,6-anhydro-3,
4-dideoxy-4-C-methyl-β-D-erythro-
Hexopyranose-2-ulose (Carbohydr
ate Res. 71, (1979) 169) 3
A solution of 00 mg of 1 ml tetrahydrofuran was added at -78 ° C. After stirring for 1 hour, 3 mg of a tetrahydrofuran solution containing 500 mg (mmol) of phenylselenyl chloride and 0.75 ml of phosphoric acid hexamethyltriamide was added, and the mixture was stirred at -78 ° C for 30 minutes. A saturated aqueous ammonium chloride solution was added, the solvent was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate. After washing twice with saturated saline, it was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a syrupy crude product. This was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 10) to obtain 106 mg of a selenium derivative.

The selenium derivative obtained by the above reaction was dissolved in 20 ml of dry methylene chloride under an inert atmosphere of nitrogen gas, and 60 mg of m-chloroperbenzoic acid was added at -78 ° C. After stirring for 20 minutes, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted twice with methylene chloride. The organic layers were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting syrup-like crude product was purified by silica gel thin layer chromatography (methylene chloride) to give the desired 1,6-anhydro-
3,4-dideoxy-4-methyl-β-D-glycero-
Hexo-3-enopyranose-2-ulose (intermediate N
o. 43) 1.7 mg was obtained as a colorless transparent liquid. The NMR analysis values of this product are as follows. ¹ H NMR (CDCl _{3 ′} 400 MHz): 2.08
(3H, d, J = 1.2Hz); 3.71 (1H, d,
J = 6.8 Hz); 3.91 (1H, dd, J = 6.
8, 4.8 Hz); 4.80 (1H, d, J = 4.8H
z); 5.32 (1H, d, J = 1.2 Hz): 5.8
7 (1H, m)

Intermediate Synthesis Example 8 1,6-anhydro-
3,4-Dideoxy-3-ethyl-β-D-glycero-
Hexo-3-enopyranose-2-ulose (intermediate N
o. Synthesis of 46) [1] 22 g of 1,6-anhydro-3-bromo-3,4-dideoxy-β-D-glycero-hex-3-enopyranose-2-ulose was dissolved in 500 ml of dry benzene, and ethylene glycol was added. 66 g and p-toluenesulfonic acid monohydrate 3 g were added, and the mixture was heated under reflux while removing the produced water. After 19 hours, the disappearance of the starting materials was confirmed by TLC, and the reaction mixture was cooled to room temperature. To this, 500 ml of ethyl acetate was added, and the mixture was washed 3 times with 200 ml of saturated saline. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The crude crystals obtained were subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 1).
Purified in 1), 1,6-anhydro-3-promo-3,
4-dideoxy-β-D-glycero-hexo-3-enopyranose-2-ulose ethylene acetal 20
g was obtained as white crystals. The NMR analysis values of this product are as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 3.71
(1H, dd, J = 6.8, 4.4 Hz); 3.79
(1H, d, J = 6.8 Hz); 4.04 (1H,
m); 4.17 (1H, m); 4.28 (2H, m);
4.75 (1H, t, J = 4.4Hz); 5.28 (1
H, s); 6.60 (1H, d, J = 4.4 Hz) m. p. 111-112 ° C

[2] 1,6-Anhydro-3-promo-3,4-dideoxy-β-D-obtained in the above [1]
3 g of glycero-hexo-3-enopyranose-2-ulose ethylene acetal was dissolved in 200 ml of dry tetrahydrofuran, and 1.2 equivalents of n-butyllithium was added with stirring at -78 degrees under a nitrogen atmosphere. After stirring for 20 minutes, 1.9 ml of ethyl iodide was added to the resulting mixture.
And 10 ml of an anhydrous tetrahydrofuran solution containing 5.2 ml of hexamethylphosphoamide. After stirring for 30 minutes, the temperature was gradually raised to room temperature. After confirming the completion of the reaction by TLC, a small amount of water was added and the solvent was distilled off under reduced pressure.
300 ml of ethyl acetate was added to the residue and the mixture was washed 3 times with 100 ml of saturated saline, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting syrupy crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give 1,6-anhydro-3,4-dideoxy. -3-Ethyl-β-D-glycero-hexo-3-enopyranose-2
-Ulose 1.48 g of ethylene acetal was obtained as white crystals. The NMR analysis values of this product are as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 1.03
(3H, t, J = 7.2 Hz); 2.03 (1H,
m); 2.11 (1H, dqd, J = 16.6, 7.
2, 2.0 Hz); 3.70 (2H, m); 4.00-
4.10 (3H, m); 4.16 (1H, m); 4.7
4 (1H, m); 5.19 (1H, s); 5.94 (1
H, dt, J = 4.4, 2.0 Hz)

[3] 1,6-anhydro-3,4-dideoxy-3-ethyl-β-D-obtained in the above [2]
1.47 g of glycero-hexo-3-enopyranose-2-ulose ethylene acetal was dissolved in 150 ml of dry tetrahydrofuran-water (2: 1), and 2 g of p-toluenesulfonic acid monohydrate was added. The resulting mixture was heated under reflux for 2 hours, and then the solvent was distilled off under reduced pressure. The obtained syrup-like crude product was dissolved in 200 ml of ethyl acetate, washed 3 times with 100 ml of saturated saline, and then the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to obtain 1.1 g of the desired product (intermediate No. 46). N of this thing
The MR analysis values are as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 1.16
(3H, t, J = 7.6 Hz); 2.35 (2H, q
d, J = 7.6, 1.5 Hz); 3.81 (1H, d,
J = 6.6 Hz); 3.95 (1H, dd, J = 6.
6, 4.6 Hz); 5.12 (1H, t, J = 4.6H
z); 5.48 (1H, s); 7.03 (1H, dt,
J = 4.6, 1.5 Hz) The following compounds were synthesized according to the above-mentioned intermediate synthesis example 8, and the physical property values thereof are described.

Intermediate No. 47 1H NMR (CDCl ₃ , 400 MHz): 0.90
(3H, t, J = 7.2 Hz); 1.30-150 (4
H, m); 2.17 (1 Hddd, J = 14.4, 6.
8, 1.6 Hz); 2.23 (1H, dd, J = 14.
4,6.8 Hz); 3.69 (1H, d, J = 6.8H)
z); 3.86 (1H, dd, J = 6.8, 4.4H
z); 4.98 (1H, t, J = 4.4Hz); 5.3
6 (1H, s); 6.92 (1H, dt, J = 4.4
1.6 Hz)

Intermediate Synthesis Example 9 1,6-anhydro-
Synthesis of 3,4-dideoxy-3-methoxymethyl-β-D-glycero-hexo-3-enopyranose-2-ulose (Intermediate No. 48) [1] Obtained in Intermediate Synthesis Example 8 [1] above 1,6-
Anhydro-3-bromo-3,4-dideoxy-β-D
-Glycero-hex-3-enopyranose-2-ulose 1.65 g of ethylene acetal was dissolved in 200 ml of dry tetrahydrofuran and cooled to -78 ° C.
5 ml (1.6 N) of n-butyllithium was gradually added to this, and the mixture was further stirred for 20 minutes. A large excess of formaldehyde was added to the obtained reaction mixture, and then the temperature was raised to room temperature.
After confirming the completion of the reaction by TLC, the precipitate was removed by filtration through Celite. The filtrate was concentrated under reduced pressure, and the resulting syrupy composition product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give 1,6-anhydro-3,4-dideoxy-3. 0.7 g of -hydroxymethyl-β-D-glycero-hexo-3-enopyranose-2-ulose ethylene acetal was obtained. The NMR analysis values of this product are as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 2.04
(1H, br.s); 3.73 (2H, m); 4.00
-4.20 (5H, m); 4.17 (1H, dd, J =
12.0, 1.2 Hz); 4.79 (1 H, m);
19 (1H, s); 6.32 (1H, dt, J = 4.
8, 1.2Hz)

1,6-anhydro-3,4-dideoxy-3-hydroxymethyl-β-D obtained in the above [1]
2 g of p-toluenesulfonic acid monohydrate was added to 150 ml of a methanol solution of 2.8 g of glycero-hex-3-enopyranose-2-ulose, and the mixture was heated under reflux for 1 hour. TL
After confirming the disappearance of the raw materials by C, the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to obtain 0.8 g of the desired product (intermediate No. 48). The NMR analysis values of this product are as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 3.40
(3H, s); 3.73 (1H, d, J = 6.8H
z); 3.89 (1H, dd, J = 6.8, 4.4H
z); 4.07 (1H, br, d, J = 15 Hz);
4.11 (1H, dd, J = 14.4, 1.6Hz);
5.06 (1H, t, J = 4.4Hz); 5.36 (1
H, s); 7.20 (1H, dt, J = 4.4, 1.
6) Next, specific synthesis examples of the compound represented by formula (I) will be described.

Synthesis Example 1 1,6-anhydro-3,4-
Synthesis of dideoxy-β-D-threo-hex-3-enopyranose (Compound No. 1) At 0 ° C. under an inert atmosphere of nitrogen gas, lithium aluminum hydride (3.0 g) was added to 500 ml of a dry diethyl ether suspension (500 ml). 6-Anhydro-3,4-dideoxy-β-D-glycero-hexo-3-enopyranose-2
50 ml of a dry diethyl ether solution of 20 g of ulose
Was gradually added dropwise. Immediately after completion of dropping, return to room temperature 30
Stirring was continued for a minute. It was confirmed by thin layer chromatography that the raw material had disappeared, and a small amount of water was added to inactivate the excess lithium aluminum hydride. After stirring for another 30 minutes, the reaction mixture was filtered through Celite to remove the precipitate. The precipitate was washed several times with diethyl ether, and the washing solution was concentrated under reduced pressure together with the filtrate. The crude crystals that have precipitated are recrystallized from diethyl ether to give the desired product (Compound No. 1)
14.5 g was obtained. The NMR analysis values and physical properties of this product are as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 3.73
(1H, dd, J = 6.4, 4.0 Hz); 3.82
(1H, d, J = 6.4 Hz); 4.32 (1H, b
r. s); 4.65 (1H, t, J = 4.0Hz);
5.51 (1H, t, J = 2.2Hz); 5.69 (1
H, dt, J = 10.0, 2.2 Hz); 6.09 (1
H, dd, J = 10.0, 4.0 Hz) m. p. 69-71 ° C

Synthesis Example 2 1,6-anhydro-3,4-
Dideoxy-2-O-isovaleryl-β-D-threo-
Synthesis of Hexo-3-enopyranose (Compound No. 2; isovaleric acid ester of Compound No. 1) 1,6-anhydro-3, obtained in Synthesis Example 1 at 0 ° C. under an inert atmosphere of nitrogen gas. 4-dideoxy-β-D
-To 0.5 ml of threo-hex-3-enopyranose in 30 ml of a dry pyridine solution, 0.7 of isovaleryl chloride was added.
g was added slowly. After stirring for about 10 minutes, the ice bath was removed and the mixture was further stirred at room temperature for 2 hours. A small amount of water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained crude product was dissolved in 200 ml of ethyl acetate, and 200 ml of saturated saline solution was added.
It was washed 3 times. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting syrup-like crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5) to obtain the desired product (compound N
o. 0.85 g of 2) was obtained as a colorless liquid. The NMR analysis values of this product are as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 0.97
(6H, d, J = 6.9 Hz); 2.12 (1H, qq
t J = 6.9, 6.9, 6.9 Hz); 2.27 (2
H, d, J = 6.9 Hz); 3.79 (1H, dd, J
= 6.6, 4.0 Hz); 3.97 (1H, d, J =
6.6 Hz); 4.68 (1H, t, J = 4.0H
z); 5.53 (1H, br.s); 5.61 (1H,
dt, J = 9.6, 2.0 Hz); 5.63 (1H,
m); 6.19 (1H, ddd, J = 9.6, 4.0,
1.2 Hz) The following compounds were synthesized according to the case of the above Synthesis Example 2, and the physical properties thereof are described.

Compound No. 3 (Crotonic acid ester of compound No. ¹ ) ¹ H NMR (CDCl ₃ , 400 MHz): 1.95
(3H, dd, J = 6.8, 1.6Hz); 3.80
(1H, ddd, J = 6.5, 4.2, 1.2Hz);
3.98 (1H, d, J = 6.5 Hz); 4.69 (1
H, t, J = 4.2 Hz); 5.55 (1 H, m);
5.65 (1H, dt, J = 9.2, 2.3Hz);
5.66 (1H, m); 5.92 (1H, dq, J = 1
5.5, 1.6 Hz); 6.19 (1H, ddt, J =
9.2, 4.2, 1.2 Hz); 7.04 (1H, d
q, J = 15.5, 6.8Hz)

Compound No. 4 (Cyclohexanoic acid ester of Compound No. ¹ ) ¹ H NMR (CDCl ₃ , 400 MHz): 1.15
-1.30 (3H, m); 1.43 (2H, m);
61 (1H, m); 1.73 (2H, m); 1.90.
(2H, m); 2.37 (1H, tt, J = 11.4,
3.3 Hz); 3.76 (1H, ddd, J = 6.5)
4.1, 1.2 Hz); 3.94 (1H, d, J = 6.
5 Hz); 4.66 (1H, t, J = 4.1 Hz);
5.47 (1H, m); 5.58 (1H, dt, J =
9.7, 2.2 Hz); 5.60 (1 H, m); 6.1
7 (1H, ddd, J = 9.7, 3.7, 1.2Hz)

Compound No. 5 (benzoic acid ester of compound No. ¹ ) ¹ H NMR (CDCl ₃ , 400 MHz): 3.84
(1H, ddd, J = 6.5, 4.2, 1.1 Hz);
4.03 (1H, d, J = 6.5Hz); 4.74 (1
H, t, J = 4.2 Hz); 5.74 (2H, m);
5.78 (1H, m); 6.26 (1H, dd, J =
9.2, 4.2 Hz); 7.44 (2H, t, J = 7.
5Hz); 7.57 (1H, tt, J = 7.5, 1.5)
Hz); 8.09 (2H, m) m.p. p. 116-117
℃

Compound No. 6 (n-hexanoic acid ester of compound No. 1) ¹ H NMR (CDCl ₃ , 400 MHz): 0.88
(3H, t, J = 6.6Hz); 1.32 (4H,
m); 1.64 (2H, m); 2.38 (2H, t, J
= 7.7 Hz); 3.80 (1H, m); 3.98 (1
H, d, J = 7.1 Hz); 4.68 (1 H, t, J =
4.8 Hz); 5.52 (1 H, br.s); 5.61
(1H, m); 5.64 (1H, br.s); 6.19
(1H, dd, J = 11.1, 4.8Hz)

Compound No. 7 (Palmitic acid ester of compound No. ¹ ) ¹ H NMR (CDCl ₃ , 400 MHz): 0.88
(3H, t, J = 6.8Hz); 1.25 (24H, b
r. s); 1.60-1.70 (2H, m); 2.38
(2H, dd, J = 7.6, 6.8Hz); 3.80
(1H, ddd, J = 6.4, 4.0, 1.0 Hz);
3.98 (1H, d, J = 6.4 Hz); 4.69 (1
H, t, J = 4.0 Hz); 5.52 (1 H, m);
5.62 (1H, dt, J = 10.0, 2.2Hz);
5.64 (1H, m); 6.20 (1H, m) m.p. p. 39-41 ° C. [α] ²⁰ _D = -17.4 (c = 0.402, chloroform)

Compound No. 109 (Compound No. 103
Palmitate ester) ¹ H NMR (CDCl ₃ , 400 MHz): 0.88
(3H, t, J = 6.8Hz); 1.25 (24H, b
r. s); 1.63 (2H, quin, J = 7.2H)
z); 2.35 (2H, t, J = 7.2Hz); 3.7.
2 (2H, m); 4.76 (1H, t, J = 4.4H
z); 4.78 (1H, br.d, J = 4.0 Hz);
5.53 (1H, m); 5.78 (1H, ddd, J =
9.6, 4.0, 2.0 Hz); 6.31 (1H, dd
d, J = 9.6, 4.4, 0.8 Hz)

Compound No. 8 (oleic acid ester of compound No. ¹ ) ¹ H NMR (CDCl ₃ , 400 MHz): 0.90
(3H, t, J = 7.6Hz); 1.35-1.23
(20H, m); 1.64 (2H, m); 1.98 (4
H, m); 2.38 (2H, t, J = 7.7 Hz);
3.79 (1H, ddd, J = 6.5, 4.2, 1.5
3.97 (1H, d, J = 6.5 Hz);
68 (1H, t, J = 4.2Hz); 5.85 (2H,
m); 5.52 (1H, br.s); 5.62 (1H,
dt, J = 9.9, 1.6 Hz); 5.63 (1H,
m); 6.29 (1H, dd, J = 9.9, 4.2H
z)

Compound No. 9 (acetic acid ester of compound No. 1) ¹ H NMR (CDCl ₃ 400 MHz): 2.14
(3H, s); 3.80 (1H, ddd, J = 6.8,
4.4, 0.8 Hz); 3.98 (1H, d, J = 6.
8Hz); 4.69 (1H, t, J = 4.4Hz);
5.52 (1H, m); 5.63 (1H, m); 5.6
5 (1H, d, J = 2.8HZ); 6.20 (1H, d
dt, J = 9.2, 4.4, 0.8 Hz)

Compound No. 10 (Compound No. 1 α-
Chloroacetic acid ester) ¹ H NMR (CDCl ₃ , 400 MHz): 3.81
(1H, ddd, 6.8, 4.0, 1.0Hz); 3.
97 (1H, d, J = 6.8 Hz); 4.13 (1H,
d, J = 15.2 Hz); 4.17 (1H, d, J = 1
5.2 Hz); 4.71 (1H, t, J = 4.0H
z); 5.59 (1H, m); 5.64 (1H, dt,
J = 10.0, 2.2 Hz); 5.67 (1H, t, J
= 2.2 Hz); 6.25 (1H, ddd, J = 10.
0, 4.0, 1.0HZ) [α] ²⁰ _D = -43.1 (c = 0.627, chloroform)

Compound No. 11 (Compound No. 1 O-
Acetylsalicylic acid ester) ¹ H NMR (CDCl ₃ , 400 MHz): 2.36
(3H, s); 3.83 (1H, ddd, J = 6.8,
4.4, 1.6 Hz); 3.98 (1H, d, J = 6.
8 Hz); 4.72 (1H, t, J = 4.4 Hz);
5.72 (3H, m); 6.24 (1H, ddd, J =
10.8, 4.4, 1.6 Hz); 7.10 (1H, d
d, J = 7.6, 1.2 Hz); 7.31 (1H, t
d, J = 7.6, 1.2 Hz); 7.56 (1H, t
d, J = 7.6, 12 Hz); 8.08 (1H, dd,
J = 7.6, 1.2Hz)

Synthesis Example 3 1,6-anhydro-2-O-
Synthesis of decanoyl-3,4-dideoxy-β-D-threo-hex-3-enopyranose (compound No. 12; decanoic acid ester of compound No. 1) The above synthesis with stirring under an inert atmosphere of nitrogen gas. Example 1
1,6-anhydro-3,4-dideoxy-obtained in
β-D-threo-hexo-3-enopyranose 0.3 g
0.6 g of decanoic acid in 50 ml of dry methylene chloride solution of
Dicyclohexylcarbodiimide 0.97 g and N, N
28 mg of dimethylaminopyridine was added. The reaction mixture was stirred for 12 hours at room temperature, the resulting precipitate was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained syrup-like crude product was purified by column chromatography on silica gel (ethyl acetate: hexane = 1: 3) to obtain 0.38 g of the desired product (Compound No. 12). The NMR analysis values of this product are as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 0.87
(3H, t, J = 68Hz); 1.26 (12H,
m); 1.64 (2H, quin, J = 7.5 Hz);
2.36 (1H, dt, J = 16.8, 7.5Hz);
2.40 (1H, dt, J = 16.8, 7.5Hz);
3.97 (1H, ddd, J = 6.4, 4.0, 1.0
3.98 (1H, d, J = 6.4Hz);
69 (1H, t, J = 4.0Hz); 5.52 (1H,
m); 5.63 (1H, dt, J = 9.6, 2.2H
z); 5.65 (1H, m); 6.19 (1H, dd
d, J = 9.6, 4.0, 1.0 Hz) The following compounds were synthesized according to the case of the above Synthesis Example 3, and the physical properties thereof are described.

Compound No. 13 (Compound No. 1 6-
Bromohexanoic acid ester) ¹ H NMR (CDCl ₃ , 400 MHz): 1.49
(2H, tt, J = 8.0,6.8Hz); 1.68
(2H, quin.J = 8.0 Hz); 1.88 (2
H, quin. J = 6.8 Hz); 2.41 (2H, t
d, J = 8.0, 1.6 Hz); 3.40 (2H, t,
J = 6.8 Hz); 3.79 (1H, ddd, J = 6.
8.4.4, 1.6 Hz); 3.97 (1H, d, J =
6.8 Hz); 4.69 (1H, t, J = 4.4H
z); 5.52 (1H, m); 5.62 (1H, dt,
J = 10.0, 2.0 Hz); 5.64 (1H, m);
6.20 (1H, ddd, J = 10.0, 4.4, 1.
6Hz)

Compound No. 14 (2- of compound No. 1
Thiophenecarboxylic acid ester) ¹ H NMR (CDCl ₃ , 400 MHz): 3.83
(1H, ddd, J = 6.8, 4.5, 1.0 Hz);
4.02 (1H, d, J = 6.8 Hz); 4.73 (1
H, t, J = 4.5 Hz); 5.69 (1 H, m);
5.75 (1H, dt, J = 9.9, 2.3Hz);
5.77 (1H, m); 6.25 (1H, ddd, J =
9.9, 4.5, 1.0 Hz); 7.11 (1H, d
d, J = 4.8, 3.8 Hz); 7.59 (1H, d
d, J = 4.8, 0.9 Hz); 7.86 (1H, d
d, J = 3.8, 0.9 Hz) m. p. 69-71 ° C

Compound No. 15 (nicotinic acid ester of compound No. ¹ ) ¹ H NMR (CDCl ₃ , 400 MHz): 3.84
(1H, ddd, J = 6.4, 4.4, 1.2Hz);
4.02 (1H, d, J = 6.4 Hz); 4.75 (1
H, t, J = 4.4 Hz); 5.74 (2H, m);
5.77 (1H, dt, J = 9.6, 2.4Hz);
6.29 (1H, ddd, J = 9.6, 4.4, 1.2
Hz); 7.40 (1H, ddd, J = 8.0, 5.
0, 1.2 Hz); 8.35 (1H, dt, J = 8.
0, 1.2 Hz); 8.79 (1H, dd, J = 5.
0, 1.2 Hz); 9.27 (1H, br.d, J =
1.2 Hz) m. p. 76-81 ° C

Compound No. 16 (p- of compound No. 1
Chlorobenzoic acid ester) ¹ H NMR (CDCl ₃ 400 MHz): 3.83
(1H, ddd, J = 6.4, 4.0, 1.2Hz);
4.02 (1H, d, J = 6.4 Hz); 4.74 (1
H, t, J = 4.0 Hz); 5.72 (1 H, m);
5.74 (1H, dt, J = 9.2, 2.4Hz);
5.76 (1H, m); 6.26 (1H, ddd, J =
9.2, 4.0, 1.2 Hz); 7.41 (2H, d
t, J = 8.8, 2.0 Hz); 8.02 (2H, d
t, J = 8.8, 2.0 Hz) m. p. 57-59 ° C

Compound No. 17 (Compound No. 1 2-
Furancarboxylic acid ester) ¹ H NMR (CDCl ₃ , 400 MHz): 3.82
(1H, dd, J = 6.4, 4.4 Hz)) 4.02
(1H, d, J = 6.4 Hz); 4.72 (1H, t,
J = 4.4 Hz); 5.71 (1H, m); 5.72
(1H, m); 5.75 (1H, m); 6.25 (1
H, dd, J = 9.6, 4.4 Hz); 6.51 (1
H, dd, J = 3.4, 2.0 Hz); 7.26 (1
H, dd, J = 3.4, 1.0 Hz); 7.59 (1
H, m) m. p. 86-88 ° C

Compound No. 18 (cinnamic acid ester of compound No. ¹ ) ¹ H NMR (CDCl ₃ , 400 MHz): 3.83
(1H, ddd, J = 6.8, 4.2, 1.6Hz);
4.02 (1H, d, J = 6.8 Hz); 4.73 (1
H, t, J = 4.2 Hz); 5.66 (1 H, m);
5.71 (1H, dt, J = 10.0, 2.2Hz);
5.73 (1H, m); 6.24 (1H, ddd, J =
10.0, 4.4, 1.6 Hz); 6.54 (1H,
d, J = 16.0 Hz); 7.39 (3H, m);
53 (2H, m); 7.25 (1H, d, J = 16.0)
Hz) m. p. 147-153 ° C

Compound No. 19 (Anthranilic acid ester of compound No. ¹ ) ¹ H NMR (CDCl ₃ , 400 MHz): 3.83
(1H, ddd, J = 6.8, 4.2, 0.8 Hz);
4.02 (1H, d, J = 6.8 Hz); 4.73 (1
H, t, J = 4.2 Hz); 5.71 (1 H, m);
5.75 (2H, m); 6.25 (1H, ddd, J =
10.2, 4.2, 0.8 Hz); 6.66 (1H, d
dd, J = 8.4, 6.8, 1.6 Hz); 6.67
(1H, br, d, J = 8.4 Hz); 7.28 (1
H, ddd, J = 8.4, 6.8, 1.6 Hz);
94 (1H, dd, J = 8.4, 1.6 Hz) m. p. 95-100 ° C

Compound No. 20 (Aratidylic acid ester of compound No. ¹ ) ¹ H NMR (CDCl ₃ , 400 MHz): 0.88
(3H, t, J = 7.2 Hz); 1.26 (32H, b
r. s); 1.65 (2H, m); 2.38 (2H,
t, J = 7.8 Hz); 3.80 (1H, ddd, J =
6.4, 4.3, 1.0 Hz); 3.98 (1H, d,
J = 6.4 Hz); 4.69 (1H, t, J = 4.3H)
z); 5.52 (1H, m); 5.62 (1H, dt,
J = 9.6, 2.2 Hz); 5.64 (1H, m);
6.19 (1H, dddd, J = 9.6, 4.3, 1.
2, 1.0 Hz)

Compound No. 50 (Compound No. 1 o-
Methylbenzoic acid ester) ¹ H NMR (CDCl ₃ , 400 MHz): 2.61
(3H, s); 3.83 (1H, m); 4.01 (1
H, d, J = 6.4 Hz); 4.73 (1H, t, J =
4.1 Hz); 5.72 (1 H, m); 5.76 (1
H, dt, J = 9.5, 2.2 Hz); 5.79 (1
H, m); 6.25 (1H, dd, J = 9.5, 4.1)
Hz); 7.24 (2H, m); 7.40 (1H, t
d, J = 7.4, 1.4 Hz); 7.97 (1H, d
d, J = 8.3, 1.4 Hz)

Synthesis Example 4 1,6-anhydro-3,4-
Dideoxy-2-O-methoxycarbonyl-β-D-threo-hex-3-enopyranose (Compound No. 2
1; Compound No. 1, methyl carbonate ester) 1,6-anhydro-3, under an inert atmosphere of nitrogen gas,
0.33 g of methylchlorocarbonate was gradually added to 30 ml of a dry pyridine solution of 0.3 g of 4-dideoxy-β-D-threo-hex-3-enopyranose. The reaction mixture was stirred at room temperature for 12 hours, 0.33 g of methylchlorocarbonate was added, and the mixture was stirred for 30 minutes. After a small amount of water was added to inactivate the excess methyl chlorocarbonate, the solvent was distilled off under reduced pressure. 200m ethyl acetate on the residue
1 was added thereto, washed with 200 ml of a saturated saline solution three times, and the organic layer was dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting syrupy crude product was subjected to silica gel column chromatography (ethyl acetate-hexane =
1: 3) and the desired product (Compound No. 21) was purified to 0.
33 g was obtained. The NMR analysis values of this product are as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 3.80
(1H, m); 3.81 (3H, s); 3.96 (1
H, d, J = 6.8 Hz); 4.70 (1H, t, J =
4.4 Hz); 5.37 (1 H, m); 5.68 (1
H, dt, J = 10.0, 2.0 Hz); 5.71 (1
H, t, J = 2.2 Hz); 6.23 (1H, ddd,
J = 10.0, 4.4, 0.2 Hz) The following compounds were synthesized according to the case of Synthesis Example 4, and the physical properties thereof are described.

Compound No. 22 (phenyl carbonate ester of compound No. ¹ ) ¹ H NMR (CDCl ₃ , 400 MHz): 3.85
(1H, ddd, J = 6.8, 4.3, 1.3 Hz);
4.02 (1H, d, J = 6.8Hz); 4.74 (1
H, t, J = 4.3 Hz); 5.47 (1H, m);
5.77 (1H, dt, J = 9.3, 2.4Hz);
5.79 (1H, m); 6.29 (1H, ddt, J =
9.3, 4.3, 1.3 Hz); 7.20 (2H,
m); 7.26 (1H, m); 7.39 (2H, m) m. p. 98-99 ° C

Compound No. 26 (phenylthiocarbonate ester of compound No. 1) ¹ H NMR (CDCl ₃ , 400 MHz): 3.86
(1H, ddd, J = 6.8, 4.0, 1.0 Hz);
4.05 (1H, d, J = 6.8 Hz); 4.76 (1
H, t, J = 4.0 Hz); 5.84 (1H, dt, J
= 10.0, 2.4 Hz); 5.86 (1H, m);
6.05 (1H, m); 6.31 (1H, ddd, J =
10.0, 4.0, 1.0Hz); 7.31 (2H
m ,; 7.30 (1H, tt, J = 7.6, 1.1H
z); 7.42 (2H, tt, J = 7.6, 2.2H
z)

Synthesis Example 5 1,6-anhydro-3,4-
Dideoxy-2-O-phenylcarbamoyl-β-D-
Threo-hex-3-enopyranose (Compound No. 2
3; Compound No. 1 phenylcarbamic acid ester)
Synthesis of 1,6-anhydro-3, under an inert atmosphere of nitrogen gas
0.56 g of phenyl isocyanate was added to 30 ml of a dry toluene solution of 0.3 g of 4-dideoxy-β-D-threo-hex-3-enopyranose at room temperature. Further 0.1 ml of triethylamine was added and the reaction mixture was refluxed with heating for 2 hours. After the completion of the reaction was confirmed by thin layer chromatography, the solvent was distilled off immediately under reduced pressure to obtain a crude syrup product. This was chromatographed on silica gel (ethyl acetate: hexane = 1: 3) to obtain 0.5 g of the desired product (Compound No. 23). The NMR analysis values of this product are as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 3.83
(1H, ddd, J = 7.6, 5.2, 1.9 Hz);
3.99 (1H, d, J = 7.6 Hz); 4.73 (1
H, t, J = 5.2, Hz); 5.57 (1H, m);
5.71 (1H, m); 5.73 (1H, dt, J = 1
0.0, 2.7 Hz); 6.23 (1H, ddd, J =
10.0, 5.2, 1.9 Hz); 6.83 (1H, b
r. s) = 7.08 (1H, tt, J = 7.6,1.0
7.32 (2H, t, J = 7.6Hz); 7.
37 (2H, d, J = 7.6 Hz) m. p. 107-109 ° C

Synthesis Example 6 1,6-anhydro-3,4
Dideoxy-2-O-methylthiocarbamoyl-β-D
-Threo-hex-3-enopyranose (Compound No.
24; Compound No. 1, methylthiocarbonate ester) 1,6-anhydro-3, under an inert atmosphere of nitrogen gas,
0.4 g of methylthioisocyanate was added to 30 ml of a dry toluene solution of 0.35 g of 4-dideoxy-β-D-threo-hex-3-enopyranose, and then sodium hydride (60% dispersion in mineral oil, 1. 3 eq.) Was added slowly. After confirming that the generation of hydrogen was completed (5-10 minutes), stirring was continued for another hour. After confirming the completion of the reaction by thin layer chromatography, a small amount of water was added to inactivate excess sodium hydride, and the formed precipitate was removed by filtration through Celite-anhydrous sodium sulfate. The syrup-like crude product obtained by concentrating the filtrate under reduced pressure was purified by column chromatography (ethyl acetate: hexane = 2: 3) on silica gel to obtain 0.45 g of the desired product (Compound No. 24). It was The NMR analysis values of this product are as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 2.92
(0.9H, d, J = 4.6Hz); 3.07 (2.1
H, d, J = 4.6 Hz); 3.79 (1 H, m);
3.94 (0.7H, d, J = 6.5Hz); 3.97
(0.3H, d, J = 6.5Hz); 4.70 (0.7
H, t, J = 3.7 Hz); 4.71 (0.3 H, t,
J = 3.7 Hz); 5.72 (2H, m); 6.19
(2H, m); 6.61 (0.7H, br.s);
79 (0.3 H, br.s) The following compounds were synthesized according to the case of Synthesis Example 6 above, and the physical properties thereof are described.

Compound No. 25 (N- of compound No. 1
tert-Butylcarbamate) ¹ H NMR (CDCl ₃ , 400 MHz): 1.31
(9H, s); 3.79 (1H, ddd, J = 6.4,
4.4, 1.5 Hz); 3.95 (1H, d, J = 6.
4Hz); 4.68 (1H, t, J = 4.4Hz);
4.87 (1H, br.s); 5.41 (1H, br.s).
s); 5.65 (1H, m); 5.66 (1H, dt,
J = 9.6, 2.2 Hz); 6.16 (1H, ddd,
J = 9.6, 4.4, 1.5 Hz) m. p. 113-115 ° C

Synthesis Example 7 1,6-Anhydro-3,4-
Dideoxy-2-vinyl-β-D-threo-hexo-3
-Synthesis of enopyranose (Compound No. 27) 1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranose-2 stirred at 0 ° C under an inert atmosphere of nitrogen gas. -To 50 ml of a dry tetrahydrofuran solution containing 1 g of ulose, 9.5 ml (1 mol) of vinylmagnesium bromide was gradually added. After 30 minutes, the ice bath was removed and stirring was continued at room temperature for another 30 minutes. After confirming the completion of the reaction by thin layer chromatography, a small amount of water was added to inactivate the excess Grignard reagent, and the solvent was distilled off under reduced pressure. The obtained crude product was dissolved in 200 ml of ethyl acetate, and saturated saline solution was added to 200 m.
It was washed 3 times with 1 and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained syrupy product was purified by column chromatography (ethyl acetate: hexane = 1: 2) on silica gel to give the desired product (Compound No. 27) as 0.2. 9 g were obtained. NM of this thing
The analysis value of R is as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 3.73
(1H, dd, J = 6.4, 3.9 Hz); 3.82
(1H, d, J = 6.4 Hz); 4.68 (1H, t,
J = 3.9 Hz); 5.19 (1H, br.s);
26 (1H, dt, J = 10.5, 1.3Hz); 5.
36 (1H, dt, J = 17.7, 1.3Hz);
53 (1H, dt, J = 9.4, 1.3 Hz); 5.9
2 (1H, ddd, J = 17.7, 10.5, 1.0H
z); 6.09 (1H, dd, J = 9.4, 3.9H
z) The following compounds were synthesized in the same manner as in Synthesis Example 7, and the physical properties are described below.

Compound No. 28 ¹ H NMR (CDCl ₃ , 400 MHz): 1.26
(3H, s): 3.69 (1H, dd, J = 7.0,
4.6 Hz); 3.76 (1H, d, J = 7.0H)
z); 4.62 (1H, t, J = 4.6Hz); 5.1
7 (1H, d, J = 2.2 Hz); 5.67 (1H, d
d, J = 10.0, 2.2 Hz): 5.94 (1H, d
d, J = 10.0, 4.6 Hz)

Compound No. 29 ¹ H NMR (CDCl ₃ , 400 MHz): 2.69
(1H, s); 3.76 (1H, dd, J = 6.8,
4.4 Hz); 3.82 (1H, d, J = 6.8H)
z); 4.73 (1H, t, J = 4.4Hz); 5.4.
9 (1H, d, J = 2.0 Hz); 5.75 (1H, d
d, J = 9.8, 2.0 Hz); 6.12 (1H, d
d, J = 9.8, 4.4 Hz) m. p. 64-67 ° C. [α] ²⁰ _D = -214.8 (c = 0.433, chloroform)

Compound No. 30 ¹ H NMR (CDCl ₃ , 400 MHz): 0.90
(3H, t, J = 7.0Hz); 1.35-1.50
(4H, m); 1.60-1.75 (2H, m);
70 (1H, dd, J = 6.8, 4.4 Hz); 3.7
7 (1H, d, J = 68Hz); 4.64 (1H, t,
J = 4.4 Hz); 5.22 (1H, d, J = 2.0H
z); 5.61 (1H, dd, J = 10.0, 2.0H
z); 6.00 (1H, dd, J = 10.0, 4.4H
z) m. p. 31-33 ° C

Compound No. 31 ¹ H NMR (CDCl ₃ , 400 MHz): 0.97
(3H, t, J = 7.2 Hz); 1.55 (2H, si
x, J = 7.2 Hz); 2.23 (2H, t, J = 7.
2Hz); 2.26 (1H, br.s); 3.74 (1
H, dd, J = 6.8, 4.4 Hz); 3.80 (1
H, d, J = 6.8 Hz); 4.71 (1H, t, J =
4.4 Hz); 5.44 (1H, d, J = 2.4H
z); 5.74 (1H, dd, 10.0, 2.4H
z); 6.05 (1H, dd, J = 10.0, 4.4H
z) m. p. 43-46 ° C

Synthesis Example 8 2-O-acetyl-1,6-anhydro-3,4-dideoxy-2-methyl-β-D-
Threo-hex-3-enopyranose (Compound No. 3
Synthesis of 2) Drying of 0.3 g of 1,6-anhydro-3,4-dideoxy-β-D-glycero-hexo-3-enopyranose-2-ulose stirred at 0 ° C under an inert atmosphere of nitrogen gas. 2.4 ml (1.5 mol) of methyllithium was gradually added to 30 ml of a tetrahydrofuran solution, and after confirming the completion of the reaction by thin layer chromatography, 0.25 ml of acetyl chloride was added. The ice bath was removed, the reaction solution was returned to room temperature, and stirring was continued for 1 hour. The solvent was distilled off under reduced pressure, and 200 ml of ethyl acetate was added to the residue. After washing with 200 ml of saturated saline three times, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by column chromatography (ethyl acetate-hexane = 1: 5) on silica gel to obtain 0.29 g of the desired product (Compound No. 32). It was The NMR analysis values of this product are as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 1.59
(3H, s); 2.05 (3H, s); 3.76 (1
H, dd, J = 6.8, 4.4 Hz); 3.89 (1
H, d, J = 6.8 Hz); 4.63 (1H, t, J =
4.4 Hz); 5.78 (1H, dd, J = 9.6,
1.6Hz); 5.89 (1H, d, J = 1.6H
z); 6.06 (1H, dd, J = 9.6, 4.4H
z) [α] ²⁰ _D = -114.7 (c = 0.654, chloroform) The following compounds were synthesized according to the case of Synthesis Example 8, and the physical properties thereof are described.

Compound No. 33 ¹ H NMR (CDCl ₃ , 400 MHz): 0.88
(3H, t, J = 7.2 Hz); 1.25 (24H, b
r. s); 1.57 (2H, m); 1.59 (3H,
s); 2.29 (2H, td, J = 8.0, 1.0H
z); 3.76 (1H, dd, J = 6.4, 4.4H
z); 3.87 (1H, d, J = 6.4 Hz); 4.6.
2 (1H, t, J = 4.4 Hz); 5.77 (1H, d
d, J = 9.6, 2.0 Hz); 5.90 (1H, d,
J = 2.0 Hz); 6.06 (1H, dd, J = 9.
6, 4.4 Hz)

Synthesis Example 9 1,6-anhydro-3,4-
Synthesis of dideoxy-β-D-erythro-hexo-3-enopyranose (Compound No. 103) (1) The above Synthesis Example 1 at room temperature under an inert atmosphere of nitrogen gas.
1,6-anhydro-3,4-dideoxy-obtained in
To 50 ml of a dry pyridine solution of 5 g of β-D-threo-hexo-3-enopyranose was added 15 g of tosyl chloride. After stirring for 12 hours, add a small amount of water to 300 m
It was extracted with 1 l of toluene. After washed once with 200 ml of 1N hydrochloric acid, washed three times with 200 ml of saturated saline, and the organic layer was dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting syrupy crude product was purified by column chromatography on silica gel (ethyl acetate: hexane = 1: 1) to give 1,6-anhydro-3,4-.
Dideoxy-2-O- (p-toluene) sulfonyl-β
-D-threo-hexo-3-enopyranose (compound N
o. 46) was obtained. The NMR analysis values of this product are as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 2.45
(3H, s); 3.76 (1H, ddd, J = 6.8,
4.0, 12 Hz); 3.94 (1H, d, J = 6.8)
Hz); 4,65 (1H, t, J = 4.0Hz);
22 (1H, m); 5.45 (1H, t, J = 2.4H
z); 5.52 (1H, dt, J = 10.4, 2.4H
z); 6.19 (1H, ddd, J = 10.4, 4.
0, 1.2 Hz) = 7.35 (2H, br.d, J =
8.4 Hz); 7.83 (2H, dt, J = 8.4,
2.0 Hz) m. p. 81-83 ° C

(2) 10.5 g of 1,6-anhydro-3,4-dideoxy-2-O- obtained in the above reaction
(P-Toluene) sulfonyl-β-D-threo-hex-3-enopyranose was dissolved in 100 ml of dry dimethylformamide and 6 g of sodium benzoate was added,
The mixture was heated under reflux for 30 minutes. The solvent was distilled off under reduced pressure, 20
0 ml of water was added and the mixture was extracted with 300 ml of chloroform. The organic layer was washed once with 200 ml of saturated aqueous sodium hydrogen carbonate solution, twice with 200 ml of saturated saline, and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, 100 ml of the obtained syrupy crude product was obtained.
Was dissolved in dry methanol, and 2 ml of a sodium methoxide methanol solution (28 wt.%) Was added, and the mixture was stirred at room temperature for 25 minutes. The reaction solution was neutralized with a 20% aqueous citric acid solution and then filtered through Celite to remove the precipitate. The filtrate was concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 1).
Purified in 2), the target product (Compound No. 103) was 1.1.
g was obtained. The NMR analysis values of this product are as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 3.50
(1H, br.d, J = 3.6Hz); 3.64 (2
H, m); 4.69 (1H, ddd, J = 5.0, 4.
0,1.8Hz); 5.53 (1H, t, J = 1.8H
z); 5.82 (1H, ddd, J = 9.6, 4.0,
1.8 Hz); 6.19 (1H, ddd, J = 9.6,
5.0, 0.8 Hz) m. p. 50-54 ° C

Synthesis Example 10 1,6-Anhydro-3,4
-Synthesis of dideoxy-2-O-methyl-β-D-threo-hex-3-enopyranose (Compound No. 41) Sodium hydride (60% dispersion in mineral oil, under an inert atmosphere of nitrogen gas) 1,6-anhydro-3, in 30 ml of dry tetrahydrofuran solution (1.3 eq)
0.3 g of 4-dideoxy-β-D-threo-hex-3-enopyranose was gradually added. After continuing stirring for 15 minutes, 0.45 ml of methyl iodide was added, and the reaction solution was stirred at room temperature for 12 hours. Excess sodium hydride was inactivated by the addition of a small amount of water and concentrated under reduced pressure. 200 ml of ethyl acetate was added to the obtained syrupy crude product, washed with 200 ml of a saturated saline solution three times, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained syrupy product was purified by column chromatography (ethyl acetate: hexane = 2: 3) on silica gel to give the desired product (Compound No. 41) of 0. 25 g was obtained. The NMR analysis values of this product are as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 3.44
(3H, s); 3.74 (1H, ddd, J = 6.7,
4.1, 1.3 Hz); 3.91 (1H, d, J = 6.
7Hz); 4.07 (1H, m); 4.62 (1H,
t, J = 4.1 Hz); 5.61 (1H, t, J = 2.
2 Hz); 5.72 (1H, dt, J = 9.8, 2.2)
Hz) = 6.09 (1H, ddd, J = 9.8, 4.
1, 1.3 Hz) The following compounds were synthesized according to the case of Synthesis Example 10, and the physical properties thereof will be described.

Compound No. 40 (Compound No. 1 n-
Butyl ether) ¹ H NMR (CDCl ₃ , 400 MHz): 0.92
(3H, t, J = 7.2 Hz); 1.39 (2H,
m); 1.60 (2H, m); 3.57 (1H, dtJ
= 9.2, 6.8 Hz); 3.60 (1H, dt, J =
9.2, 6.8 Hz) = 3.77 (1H, ddd, J =
6.8, 4.0, 1.2 Hz); 3.97 (1H, d,
J = 6.8 Hz); 4.17 (1H, m); 4.63
(1H, t, J = 4.0 Hz); 5.62 (1H, t,
J = 2.2 Hz); 5.72 (1H, dt, J = 9.
6, 2.2 Hz); 6.08 (1H, ddd, J = 9.
6, 4.0, 1.2 Hz) Compound No. 48 (benzyl ether of compound No. 1) ¹ H NMR (CDCl ₃ , 400 MHz): 3.78
(1H, ddd, J = 6.4, 4.0, 1.2Hz);
3.98 (1H, d, J = 6.4 Hz); 4.28 (1
H, m); 4.63 (1H, t, J = 4.0 Hz);
4.66 (1H, d, J = 12.0Hz); 4.70
(1H, d, J = 12.0 Hz); 5.56 (1H,
t, J = 2.4 Hz); 5.71 (1H, dt, J = 1)
0.0, 2.4 Hz); 6.10 (1H, ddd, J =
10.0, 4.0, 1.2 Hz); 7.29 (1H, t
t, J = 6.8, 2.0 Hz); 7.34 (2H,
m); 7.38 (2H, m)

Synthesis Example 11 1,6-anhydro-3,4
-Synthesis of dideoxy-2-O- (16-hydroxy) hexadecanoyl-β-D-threo-hexo-3-enopyranose (Compound No. 49) Under an inert atmosphere of nitrogen gas, 1 g of 16-hydroxyhexadecane 50 ml of a dry tetrahydrofuran solution of the acid, 1.1 g of tert-butyldimethylsilyl chloride and 0.75 g of imidazole was stirred at room temperature for 12 hours. After the solvent was distilled off under reduced pressure, 200 ml of ethyl acetate was added, and this was washed 3 times with 200 ml of saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a syrupy product. 40m here
1 diethyl ether, 30 ml methanol and 30
ml of 1N hydrochloric acid was added, and the mixture was stirred at room temperature for 15 minutes. After evaporating the solvent under reduced pressure, 200 ml of ethyl acetate was added, and this was washed once with 200 ml of saturated sodium hydrogen carbonate and twice with 200 ml of saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a syrupy product. This was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 1).
Purification in 1) yielded 1.4 g of 16-tert-butyldimethylsilyloxyhexadecanoic acid.

16-tert-Butyldimethylsilyloxyhexadecanoic acid obtained in the above reaction and compound No.
The condensation reaction with 1 was carried out according to Synthesis Example 3 above. After post-treatment by a conventional method, it was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 7). Dissolve this in 50 ml of dry tetrahydrofuran and
3 ml of a tetrahydrofuran solution of tetra-normal-butylammonium fluoride of was added at room temperature and stirred for 12 hours. After distilling off the solvent under reduced pressure, 200 ml of ethyl acetate was added and washed twice with 200 ml of saturated saline,
It was dried over anhydrous sodium sulfate. The solvent was again distilled off under reduced pressure to obtain a syrupy product. This is subjected to silica gel column chromatography (ethyl acetate: hexane =
2: 3) to give the desired product (Compound No. 49) at 0.
Obtained 59 g. The NMR analysis values of this product are as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 1.20
−1.37 (22H, m); 1.57 (2H, qui
n, J = 7.0 Hz); 1.64 (2H, quin.,
J = 7.0 Hz); 2.38 (2H, t, J = 7.4H)
z); 2.64 (2H, td, J = 5.6, 5.6H
z); 3.80 (1H, ddd, J = 6.6, 4.1,
1.1 Hz); 3.98 (1H, d, J = 6.6H
z); 4.69 (1H, t, J = 4.1Hz); 5.5
2 (1H, m); 5.62 (1H, dt, J = 9.5,
2.1 Hz); 5.64 (1 H, m); 6.20 (1
H, ddt, J = 9.5, 4.1, 1.1 Hz) The following compounds were synthesized according to Synthesis Example 1 or 2 above, and the physical properties thereof are described below.

1,6-Anhydro-3,4-dideoxy-3-methyl-β-D-threo-hex-3-enopyranose (Compound No. 51) ¹ H NMR (CDCl ₃ , 400 MHz): 1.72
(3H, m); 2.03 (1H, d, J = 12.0H
z); 3.71 (1H, dd, J = 6.4, 4.4H
z); 3.78 (1H, d, J = 6.4 Hz); 4.1
1 (1H, m); 4.60 (1H, t, J = 4.4H
z); 5.51 (1H, d, J = 2.8 Hz); 5.8
0 (1H, dd, 4.4, 1.6Hz) m. p. 62.5-64 ° C

1,6-Anhydro-3,4-dideoxy-3-ethyl-β-D-threo-hex-3-enopyranose (Compound No. 95) ¹ H NMR (CDCl ₃ , 400 MHz): 1.02
(3H, t, J = 7.2 Hz); 1.57 (1H, b
r. s); 2.12 (2H, m); 3.73 (1H, d
d, J = 6.0, 4.4 Hz); 3.78 (1H, d,
J = 6.0 Hz); 4.21 (1H, d, J = 3.2H)
z); 4.65 (1H, t, J = 4.4Hz); 5.5
3 (1H, d, J = 3.2Hz); 5.80 (1H,
m) m. p. 75-76 ° C

1,6-anhydro-3-butyl-3,4
-Dideoxy-β-D-threo-hex-3-enopyranose (Compound No. 97) ¹ H NMR (CDCl ₃ , 400 MHz): 0.94
(3H, t, J = 7.2 Hz); 1.41 (4H,
m); 165 (1H, br.s); 2.06 (1H, d
dd, J = 15.0, 9.6, 6.0 Hz); 2.18
(1H, ddd, J = 15.0, 8.8, 5.6H
z); 3.72 (1H, dd, J = 6.8, 4.0H
z); 3.78 (1H, d, J = 6.8 Hz); 4.1
9 (1H, d, J = 2.8 Hz); 4.63 (1H,
t, J = 4.0 Hz); 5.52 (1H, d, J = 2.
8 Hz); 5.79 (1 H, br.d, J = 5 Hz) m. p. 43-44 ° C

1,6-Anhydro-3,4-dideoxy-3-methoxymethyl-β-D-threo-hex-3-
Enopyranose (Compound No. 96) ¹ H NMR (CDCl ₃ , 400 MHz): 3.35
(3H, s); 3.75 (1H, dd, J = 6.8,
4.4 Hz); 3.83 (1H, d, J = 6.8H)
z); 3.91 (1H, br.d, J = 13 Hz);
4.01 (1H, br.d, J = 13Hz); 4.32
(1H, br, d, J = 2Hz); 4.70 (1H,
t, J = 4.4 Hz); 5.53 (1H, d, J = 2.
8 Hz); 6.09 (1H, m) m.p. p. 53-56 ° C

Compound No. 98 ¹ H NMR (CDCl ₃ , 400 MHz): 1.63
(3H, s); 3.72 (1H, dd, J = 5.6,
4.4 Hz); 3.92 (1H, d, J = 5.6H)
z); 4.61 (1H, t, J = 4.4Hz); 5.6.
0 (1H, br.s); 5.68 (1H, d, J = 2.
4Hz); 5.90 (1H, m); 6.46 (1H, d
d, J = 3.6, 2.0 Hz); 7.21 (1H, d,
J = 3.6 Hz); 7.54 (1H, s)

Compound No. 99 ¹ H NMR (CDCl ₃ , 400 MHz): 2.85
(1H, s); 3.82 (1H, dd, J = 6.8,
4.3 Hz); 3.94 (1H, d, J = 6.8H)
z); 4.76 (1H, t, J = 4.3Hz); 6.0
1 (1H, dd, J = 9.7, 2.0 Hz); 6.18
(1H, d, J = 2.0 Hz); 6.27 (1H, d
d, J = 9.7, 4.3 Hz); 6.51 (1H, d
d, J = 3.3, 1.3 Hz); 7.23 (1H, d,
J = 3.3 Hz); 7.58 (1H, br.s)

Compound No. 100 ¹ H NMR (CDCl ₃ , 400 MHz): 1.57
(3H, s); 3.66 (1H, dd, J = 5.6,
4.4 Hz); 3.83 (1H, d, J = 5.6H)
z); 4.06 (1H, br.s); 4.50 (1H,
t, J = 4.4 Hz); 4.54 (1H, d, J = 1)
3.09Hz); 4.59 (1H, d, J = 13.0H
z); 5.40 (1H, d, J = 2.4 Hz); 5.7.
2 (1H, m); 6.28 (1H, dd, J = 3.0,
2.0 Hz); 6.30 (1H, d, J = 3.0H
z); 7.36 (1H, s)

Compound No. 101 ¹ H NMR (CDCl ₃ , 400 MHz): 3,77
(1H, ddd, J = 7.2, 4.4, 1.2Hz);
3.96 (1H, d, J = 7.2 Hz); 4.31 (1
H, m); 4.60 (1H, d, J = 13.2Hz);
4.63 (1H, m); 4.64 (1H, d, J = 1
3.2 Hz); 5.50 (1H, t, J = 2.4H
z); 5.64 (1H, dt, J = 9.6, 2.4H
z); 6.09 (1H, ddd, J = 9.6, 4.4,
1.2 Hz); 6.36 (2H, m); 7.41 (1
H, dd, J = 1.6,0.8Hz)

Compound No. 102 ¹ H NMR (CDCl ₃ , 400 MHz): 2.92
(1H, s); 3.78 (1H, dd, J = 6.8,
4.4Hz); 3.95 (1H, d, J = 6.8H)
z); 4.17 (1H, dt, J = 4.4Hz);
73 (1H, d, J = 12.6 Hz); 4.80 (1
H, d, J = 12.6 Hz); 5.57 (1H, d, J
= 2.0 Hz); 5.70 (1H, dd, J = 9.6,
2.0 Hz); 6.12 (1H, dd, J = 9.6,
4,4 Hz); 6.33 (2H, m); 7.41 (1
H, m) Next, the enopyranose derivatives represented by the general formula (I-1) or (I-2) are shown in Tables 3 to 11.

[0124]

[Table 3]

[0125]

[Table 4]

[0126]

[Table 5]

[0127]

[Table 6]

[0128]

[Table 7]

[0129]

[Table 8]

[0130]

[Table 9]

[0131]

[Table 10]

[0132]

[Table 11]

Next, it will be shown that the enopyranose derivative represented by the above general formula (I) or a salt thereof is useful as an active ingredient of an immunosuppressive agent. (Pharmacological test) (1) Collagen-induced arthritis inhibitory effect 4 to 6-week-old male DBA / 1JNCrj mice in 1 group 4
Used in animals, bovine collagen type II (Collagen Technology Workshop, product No. K41) (3 mg / ml) was suspended in an equal volume of complete Freund's adjuvant (ICN Immunobiologicals, product No. 642851). The product was injected intradermally at the ridge of the mouse (150 μg /
0.1 ml / mouse), collagen arthritis was induced.
The strength of arthritis was scored as follows (0 to 3 points per limb, a maximum of 12 points in total of four limbs) and evaluated. 0 points No change 1 point Weak finger swelling and weak erythema 2 points Weak swelling and erythema 3 points Strong swelling and erythema, or bone deformity The basic operation of the above test is The Journal of Immunology (The Journal of Immun
140), pp. 1477-1484, (19).
1988).

(A) Effect of suppressing the onset of collagen arthritis Administration of the compound of the general formula (I) (50 mg / kg) was started 18 days after the inoculation of the antigen, and the intraperitoneal or oral administration was carried out once a day for 4 days. The drug was administered daily for a week and the condition of joint inflammation was observed. The same test was performed using physiological saline as a control. The result is shown in FIG.

(2) Effects on various cultured cells (a) Effects on blastogenic reaction using mouse thymocytes Using BALB / c mouse thymocytes, concanavalin A (abbreviated as ConA hereinafter, Vector Laboratories). Manufactured by Product No. L-1000) was investigated for the action of the compound of the general formula (I) on the lymphocyte blastogenic reaction. That is, 4 × 10 ⁵ thymocytes were converted to ConA (5 μg /
ml) and a compound of the general formula (I) and 10% fetal calf serum in RPMI 1640 solution (hereinafter 10% FCS-R).
48 in a 96-well microplate with PMI solution)
Incubated for 5 hours (5% CO ₂ , 37 in incubator)
C). After that, 0.5 μCi of ³ H-thymidine (hereinafter referred to as ³
(H-TdR) was added, and after further culturing for 4 hours, cells were collected by a cell harvester, and the radioactivity (dpm) of ³ H-TdR incorporated into the cells was measured. The measured uptake of ³ H-TdR into cells was used as an index for the blastogenic response of thymocytes, and the radiation of the compound of general formula (I) at each concentration (0.001 to 1000 μg / ml) was measured. The activity value was compared with the control value of ConA alone treatment, and IC5
The 0 value was calculated, and the results are shown in Tables 6 and 7. In Tables 6 and 7, the results of thymocytes are shown as (a). Regarding these basic operations, cell immunoassay experimental operation method, pp. 144-146 (Katsuyuki Imai et al., Published by Rikagakusha,
1982) was used as a reference.

(B) Effect on mixed culture reaction of mouse lymphocytes: Effect of the compound of the general formula (I) on bidirectional mixed culture reaction of lymphocytes using spleen cells of BALB / c and C57BL / 6 mice. It was investigated. That is, spleen cells of both strains of mice were mixed at 5 × 10 ⁵ cells and cultured with a compound of the general formula (I) in a 96-well microplate for 48 hours in a 10% FCS-RPMI solution (5 % CO ₂ , 37 ° C.). Then 0.5 μCi of ³
H-TdR was added, and after further culturing for 16 to 18 hours, cells were collected by a cell harvester and incorporated into cells.
The radioactivity (dpm) of ³ H-TdR was measured. The measured uptake amount of ³ H-TdR into cells was used as an index of the mixed lymphocyte culture reaction, and the radioactivity value at each concentration (0.001 to 1000 μg / ml) of the compound of the general formula (I) was obtained. Was compared with untreated control values to calculate IC50 values and the results are shown in Tables 6 and 7. In Tables 6 and 7, the results of the mixed lymphocyte culture reaction are shown as (b). For these basic operations, reference was made to the Cell Immunity Experiment Operation Method, pages 147 to 149 (Katsuyuki Imai et al., Published by Rigaku Kogyo Publishing, 1982).

(C) Effect on mouse bone marrow cells Bone marrow cells were excised from the femur of BALB / c mice, and 1
The cells suspended in 0% FCS-RPMI solution were suspended on a 10 cm plastic petri dish and left standing (5% CO ₂ , 37 ° C. in an incubator). After 2 hours, only floating cells were collected and adhered cells were removed. Suspension cells 1x
10 ⁵ cells were combined with 20% culture supernatant of L929 fibroblastoma cells and the compound of general formula (I) in 10% FCS-RPM.
The solution I was cultured in a 96-well microplate for 48 hours (5% CO _{2 in} an incubator, 37 ° C.). Then, 0.5 μCi of ³ H-TdR was added, and after further culturing for 4 hours, the cells were collected by a cell harvester, and the radioactivity (dpm) of ³ H-TdR incorporated into the cells was measured. The measured uptake of ³ H-TdR into cells was used as an index of the proliferative response of bone marrow cells, and the concentration of each compound of general formula (I) (0.001 to 1000 μg /
(ml) radioactivity value was compared with the control value of L929 culture supernatant added alone to calculate the IC50 value, and the results are shown in Table 1.
2 and Table 13. In Tables 12 and 13, the results of bone marrow cells are shown as (c). For these basic operations, see the Biochemical Society of Japan sequel biochemistry experiment course No. 5
Volume 266-270 (Tokyo Kagaku Doujin Shuppan, 1986)
Year) was used as a reference.

[0138]

[Table 12]

[0139]

[Table 13]

(D) Effect on mouse spleen cell antibody production Induced by LPS (lipopolysaccharide; Wako Pharmaceutical, product No. 520.02051) and IL4 (interleukin 4) stimulation using mouse spleen B cells. I
The effect of compounds of general formula (I) on the production of gG1, IgE and IgM antibodies was investigated. That is, BALB / c
Spleen B cells 3 × 10 ⁵ after T cell removal by treating mouse spleen cells with mouse anti-Thy-1 antibody (obtained from Chiba University School of Medicine) and rabbit complement (Sedalene, product No. 3051) LPS 10 μg / ml, mouse-
Recombinant IL4 (manufactured by The Dienzyme, product No.
MIL-4C) 100 U / ml and each concentration (0.001 to 1000 μg / ml) of the compound of the general formula (I) were cultured in a 96-well microplate in a 10% FCS-RPMI solution for 7 days (in an incubator, 5% CO ₂ ,
37 ° C).

For these basic operations, The Journal of Immunology, Vol. 136, p. 4538,
(1986) was used as a reference. The amount of each antibody in the cell culture supernatant obtained here was measured by the enzyme immunoassay as shown below. First, a rabbit anti-mouse IgG1 antibody (manufactured by Kappel, product no.
36243) 1 μg / ml or goat anti-mouse IgM antibody (Kappel, product No. 0611-0201) 1
μg / ml, rat anti-IgE monoclonal antibody (manufactured by Experimental Immunology, product No. LO-
ME-2) 10 μg / ml (50 μl / hole, room temperature, 60
For 10 minutes, and then 10 mM sodium phosphate buffered saline containing 0.1% bovine serum albumin (pH 7.
2) blocked non-specific binding (room temperature, 60
Minutes). Then, the above cell culture supernatant or its diluted solution 50 μm
1 / well, react at room temperature for 60 minutes, then add 100
Alkaline phosphatase-labeled rabbit anti-mouse IgG1 antibody diluted 0-fold (Zymet, product No. 61-0
122), a 2000-fold diluted alkaline phosphatase-labeled rabbit anti-mouse IgM antibody (Zymet, product No. 61-6822) or a 500-fold diluted alkaline phosphatase-labeled sheep anti-mouse IgE antibody (manufactured by Binding Site, product No. PA). -284) was added to each in an amount of 50 μl / well and reacted at room temperature for 60 minutes. 10% diethanolamine buffer (pH 9.8) containing para-nitrophenyl phosphate as enzyme substrate 10
0 μl / well was reacted and the absorbance at 405 nm was measured. The amount of each antibody was calculated from the calibration curve of each standard antibody, and the value in the absence of the compound of general formula (I) was used as a control value.
The IC50 value of the effect of the compound of general formula (I) on antibody production in the presence of each concentration was calculated, and the results are shown in Tables 14 and 15 together with the results of the effect on the mouse bone marrow cells. In Table 14 and Table 15, the IC50 value of the effect on antibody production is shown for each antibody, namely IgG1, IgM.
, And IgE, and the results of the aforementioned mouse bone marrow cells are shown as (c).

[0144]

[Table 14]

[0145]

[Table 15]

(Toxicity Test) A compound of the general formula (I) (5) was prepared by grouping DBA1 / J mice, 6 weeks old, 4 males, 1 group.
(0 mg / kg) was intraperitoneally or orally administered once a day for four consecutive days, and the change in body weight and the number of deaths were examined. As a result, there were no significant changes in body weight and no deaths. Therefore,
The compound of formula (I) has an LD ₅₀ value of at least 50.
mg / kg.

The enopyranose derivative represented by the general formula (I) or a salt thereof also has an anti-inflammatory action, and the test examples thereof will be described below. (Anti-inflammatory action test) The anti-inflammatory action was tested using the carrageenin-induced paw edema method, which is widely used for evaluating the efficacy of general anti-inflammatory agents (NSAIDs). 0.1 ml of 1% λ-carrageenan solution was injected into the sole of the right foot of SD male rat (6 weeks old), and 3 hours later, the volume of the sole of both feet was measured and the difference in volume between the right side and the left side was edema. And the degree. The test compound was 1 ml / 100 g 1 hour before carrageenin administration.
Oral administration was performed in the (body weight) volume. The control group was given the same amount of physiological saline only. The results are shown in Table 16. As is clear from Table 16, the test compound showed a statistically significant inhibitory effect on carrageenin-induced paw edema, and its effectiveness as an anti-inflammatory agent was confirmed.

[0148]

[Table 16]

When the enopyranose derivative represented by the general formula (I) or a salt thereof is used as an active ingredient of an immune function-suppressing agent, it cannot be generally specified due to the difference in administration conditions, but it is usually about 50 mg / day for an adult. It is 5000 mg and is administered orally or parenterally. Drug administration can be carried out by oral, intravenous, intramuscular, dermal, mucosal routes and the like. Dosage forms include powders, fine granules, granules, tablets, capsules, injections, nasal drops, suspensions, drops, ointments, syrups, sustained release preparations and the like. These can be produced by an ordinary method using an ordinary pharmaceutically acceptable pharmaceutical carrier as in the case of ordinary pharmaceuticals.

[0150]

INDUSTRIAL APPLICABILITY The present invention provides an immune function inhibitor containing the compound represented by the general formula (I) as an active ingredient, and specifically, it is caused by abnormally enhanced immune function. Diseases such as rheumatoid arthritis, systemic lupus erythematosus, chronic nephritis, chronic thyroiditis, treatment of so-called autoimmune diseases such as autoimmune hemolytic anemia, and treatment for inhibition of rejection during organ transplantation, and further allergic diseases, It is effective for treating inflammatory diseases, particularly autoimmune diseases such as rheumatoid arthritis.

[0149]

[Brief description of drawings]

FIG. 1 is a graph showing the effect of suppressing the onset of collagen arthritis by the compound of general formula (I).

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location C07D 309/32 7252-4C 493/04 106 A 9165-4C

Claims (3)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R ¹ is a hydrogen atom, an optionally substituted alkyl group, an alkenyl group, an alkynyl group, an —OSO ₂ R ⁷ group,
Halogen atom, -OCOR ⁷ group, -NHCOR ⁸ group, alkoxy group, optionally substituted phenyl group or sugar derivative residue, R ² is hydrogen atom or alkyl group, R ^2
3 is a hydrogen atom or a halogen atom, R ⁴ is a hydrogen atom, a —COR ⁹ group, an optionally substituted silyl group or an optionally substituted alkyl group, and one of R ⁵ and R ⁶ is a hydroxyl group. , An optionally substituted alkoxy group, a sugar derivative residue, an optionally substituted cycloalkyloxy group or an —OCOR ¹⁰ group, and the other is a hydrogen atom or an optionally substituted alkyl group, and R ⁴ and R ⁵ may together form a single bond, in which case R ⁶ is a hydrogen atom or an optionally substituted alkyl group, and R ⁷ , R ⁹
And R ¹⁰ are each an alkyl group or an optionally substituted phenyl group, R ⁸ is an alkyl group, an optionally substituted phenyl group or a benzyloxy group, X is a hydrogen atom, an optionally substituted alkyl group An optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted phenyl group, an optionally substituted pyridyl group, an optionally substituted furanyl group, An optionally substituted thienyl group, a formyl group,
—COR ¹¹ group, —C (W ¹ ) W ² R ¹¹ group or —SO
₂ R ¹¹ group, R ¹¹ is an optionally substituted chain hydrocarbon group, an optionally substituted monocyclic hydrocarbon group, an optionally substituted polycyclic hydrocarbon group, or an optionally substituted A monocyclic heterocyclic group or an optionally substituted polycyclic heterocyclic group, W
¹ is an oxygen atom or a sulfur atom, W ² is an oxygen atom, a sulfur atom or an —NH— group, Y is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group or a substituted Is an alkynyl group) or an enopyranose derivative represented by the formula) or a salt thereof as an active ingredient. 2. An anti-inflammatory agent, which comprises the enopyranose derivative represented by the general formula (I) or a salt thereof as an active ingredient. 3. A compound represented by the general formula (I-1) or (I-2): (In the formula, R ¹ is a hydrogen atom, an optionally substituted alkyl group, an alkenyl group, an alkynyl group, an —OSO ₂ R ⁷ group,
Halogen atom, -OCOR ⁷ group, -NHCOR ⁸ group, alkoxy group, optionally substituted phenyl group or sugar derivative residue, R ² is hydrogen atom or alkyl group, R ^2
3 is a hydrogen atom or a halogen atom, R ⁴ and R ⁵ are taken together to form a single bond, R ⁶ is a hydrogen atom or an optionally substituted alkyl group, and R ⁷ is an alkyl group or a substituted group. Optionally a phenyl group, R ⁸ is an alkyl group, an optionally substituted phenyl group or a benzyloxy group, X is a hydrogen atom, an optionally substituted alkyl group,
An optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted phenyl group, an optionally substituted pyridyl group,
A furanyl group which may be substituted, a thienyl group which may be substituted, a formyl group, a -COR ¹¹ group, -C (W ¹ ) W ²
R ¹¹ group or —SO ₂ R ¹¹ group, R ¹¹ is a chain hydrocarbon group which may be substituted, a monocyclic hydrocarbon group which may be substituted, or a polycyclic hydrocarbon group which may be substituted. A monocyclic heterocyclic group which may be substituted or a polycyclic heterocyclic group which may be substituted, W ¹ is an oxygen atom or a sulfur atom,
W ² is an oxygen atom, a sulfur atom or an —NH— group, and Y is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group or an optionally substituted alkynyl group, provided that Excluding cases. In (I-1), R ¹ , R ² , R ³ , R ⁶ and X
Is a hydrogen atom and Y is a hydrogen atom or an optionally substituted alkyl group, in (I-1), R ¹ , R ² , R ³ , R ⁶ and Y
Is a hydrogen atom, X is acetyl, 3,5-dinitrobenzoyl or p-toluenesulfonyl, in (I-1), R ¹ , R ² , R ³ and Y are hydrogen atoms, and R is ^{When 6} is an optionally substituted alkyl group and X is a hydrogen atom or acetyl, in (I-2), R ¹ , R ² , R ³ , R ⁶ and Y
Is a hydrogen atom, X is a hydrogen atom, methyl, benzyl,
Formyl, acetyl, benzoyl, 4-chlorobenzoyl, 3,5-dichlorobenzoyl, 4-nitrobenzoyl, 3,5-dinitrobenzoyl, 4-methoxybenzoyl, 3,5-dimethoxybenzoyl, methylsulfonyl or p-toluenesulfonyl. In some cases, and in (I-2), R ¹ is p-toluenesulfonyloxy, R ² , R ³ , R ⁶ and Y are hydrogen atoms, X is a hydrogen atom, acetyl or p-toluenesulfonyl. If there is. )