JP3032058B2 - Homolid X analogs - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel homolipid X analog having an excellent protective effect against bacterial infection and a salt thereof.

[0002]

BACKGROUND OF THE INVENTION Most of the lipopolysaccharide (LPS) endotoxin activity, a component of the outermost membrane of Gram-negative bacteria, is present in lipid A, located at the end of LPS. This lipid A
Has a beneficial effect such as nonspecific bacterial infection protection effect, immunoadjuvant activity, tumor necrosis effect, macrophage activation effect in addition to toxicity and pyrogenicity.
Focusing on the fact that lipid A can be an interesting parent compound as one of M (Biological Response Modifier), synthesis of chemically modified compounds has been widely performed.

[0003]

DISCLOSURE OF THE INVENTION The inventors of the present invention have conducted intensive studies over many years on the synthesis of a derivative having a weak side effect and an excellent protective effect against bacterial infection and an immunostimulatory effect and its pharmacological activity. The present inventors have found that a novel homolipid X analog has an excellent macrophage activating action and is useful as an immunostimulator, and completed the present invention. The novel homolipid X analog of the present invention has the general formula:

[0004]

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[0005]

In the general formula (1), R ¹ and R ⁴ are a hydrogen atom, and —P (O) (OR ⁶ ) ₂ group (where R ⁶ is a hydrogen atom or a substituent selected from the following group A) Represents a phenyl group or a benzyl group which may be present on the aromatic ring.)
Or a hydroxyl-protecting group, wherein R ² and R ³ are the same or different and have the formula R ⁷ CH (OR ⁸ ) CαβCO (wherein R
⁷ represents an alkyl group having 7 to 17 carbon atoms, R ⁸ represents an aliphatic acyl group having 10 to 20 carbon atoms, α and β
Represents the same or different hydrogen atoms or halogen atoms. ) Represents a substituted aliphatic acyl group having 10 to 20 carbon atoms, and R ⁵ represents a hydrogen atom or a protecting group for a hydroxyl group. [Group A] an alkyl group having 1 to 4 carbon atoms and an alkoxy group having 1 to 4 carbon atoms.

In the general formula (1), R ¹ and R ⁴
Examples of the alkyl group having 1 to 4 carbon atoms in Group A according to R ⁶ of —P (O) (OR ⁶ ) ₂ include methyl, ethyl, propyl, butyl and the like. is there. In the general formula (1), -P of R ¹ and R ⁴
(O) (OR ⁶ ) Examples of the alkoxy group having 1 to 4 carbon atoms in Group A relating to _two R ⁶ groups include methoxy, ethoxy, propoxy and butoxy, and methoxy is preferred. In the general formula (1), examples of the hydroxyl-protecting group for R ¹ , R ⁴ and R ⁵ include those generally used as a hydroxyl-protecting group. In R ¹ , preferably, methyl, Lower alkyl groups such as ethyl,
Aryl groups such as allyl group, phenyl and naphthyl, aralkyl groups such as benzyl and naphthylmethyl, lower acyl groups such as acetyl and propionyl, aromatic acyl groups such as benzoyl and naphthoyl or trichloroacetimidoyl and tribromo A trihalogenimidoyl group such as acetimidoyl; R ⁴ and R ⁵ are preferably an aliphatic acyl group such as acetyl and propionyl; an aromatic acyl group such as benzoyl and naphthoyl; a benzyl group or trimethylsilyl; Tri-substituted silyl groups such as t-butyldimethylsilyl and t-butyldiphenylsilyl, or R ⁴ and R ^{5 taken} together are an alkylidene group such as isopropylidene or a benzylidene group.

In the general formula (1), R ² and R ³
Examples of the alkyl group having 7 to 17 carbon atoms of R ^{7 according} to heptyl, 5-methylheptyl, 6-methylheptyl,
1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl, octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylnonyl, 3-methyloctyl, 4-methyloctyl, 5-methyl Octyl, 6-methyloctyl, 1-propylhexyl, 2-ethylheptyl,
6,6-dimethylheptyl, decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3,7-
Dimethyloctyl, 7,7-dimethyloctyl, undecyl, 4,8-dimethylnonyl, dodecyl, tridecyl, tetradecyl, pentadecyl, 3,7,11-trimethyldodecyl, hexadecyl, 4,8,12-trimethyltridecyl, 1-
Methylpentadecyl, 14-methylpentadecyl, 13,13-
Examples thereof include dimethyltetradecyl, heptadecyl, and 15-methylhexadecyl, and preferably have 7 to 13 carbon atoms.
Individual.

In the general formula (1), R ² and R ³
Examples of the aliphatic acyl group having 10 to 20 carbon atoms for R ⁸ include nonylcarbonyl, decylcarbonyl,
3-methylnonylcarbonyl, 8-methylnonylcarbonyl, 3-ethyloctylcarbonyl, 3,7-dimethyloctylcarbonyl, undecylcarbonyl, dodecylcarbonyl, tridecylcarbonyl, tetradecylcarbonyl, pentadecylcarbonyl, hexadecylcarbonyl, 1 -Methylpentadecylcarbonyl, 14-methylpentadecylcarbonyl, 13,13-dimethyltetradecylcarbonyl, heptadecylcarbonyl, 15-methylhexadecylcarbonyl, octadecylcarbonyl, 1-methylheptadecylcarbonyl, nonadecylcarbonyl, It preferably has 10 to 16 carbon atoms.

In the general formula (1), R ² and R ³
Examples of the α and β halogen atoms according to the above include fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine. In the compound (1), as a suitable compound, ^one of R ¹ and R ⁴ is a group represented by the formula —P (O) (OH) ₂
A hydrogen atom or -P (O) (OH) ₂
In the compounds R ² is a group, R ⁷ is C 7 to 13 alkyl group carbon, R ⁸ is an aliphatic acyloxy group having 10 to 16 carbon atoms, alpha and β are in the compounds R ³ is hydrogen atom, R Compounds in which ⁷ is an alkyl group having 7 to 13 carbon atoms, R ⁸ is an aliphatic acyloxy group having 10 to 16 carbon atoms, and α and β are hydrogen atoms.

Representative compounds of the present invention include the compounds shown in Table 1, but the present invention is not limited to these compounds. In Table 1, R _(XX) represents a straight-chain alkyl group having XX carbon atoms.

[0012]

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[0013]

[Table 1] No. R ¹ R ² R ³ R ⁴ R ⁵ １ 1 H -COCH ₂ CH (OH) R ₍₇₎ -COCH ₂ CH (OH) R ₍₇₎ -P (O) (OH) ₂ H 2 H -COCH ₂ CH (OH) R ₍₈₎ -COCH ₂ CH (OH) R ₍₈₎ -P (O) (OH) ₂ H 3 H -COCH ₂ CH (OH) R ₍₉₎ -COCH ₂ CH (OH) R ₍₉₎ -P (O) (OH) ₂ H 4 H -COCH ₂ CH (OH) R _{( 11)} -COCH ₂ CH (OH) R ₍₁₁₎ -P (O) (OH) ₂ H 5 H -COCH ₂ CH (OH) R ₍₁₂₎ -COCH ₂ CH (OH) R ₍₁₂₎ -P ( O) (OH) ₂ H 6 H -COCH ₂ CH (OH) R ₍₁₃₎ -COCH ₂ CH (OH) R ₍₁₃₎ -P (O) (OH) ₂ H 7 H -COCH ₂ CH (OH) R ₍₁₄₎ -COCH ₂ CH (OH) R ₍₁₄₎ -P (O) (OH) ₂ H 8 H -COCH ₂ CH (OH) R ₍₁₅₎ -COCH ₂ CH (OH) R ₍₁₅₎ - P (O) (OH) ₂ H 9 H -COCH ₂ CH (OH) R ₍₁₇₎ -COCH ₂ CH (OH) R ₍₁₇₎ -P (O) (OH) ₂ H 10 H -COCH ₂ CH ( OH) R ₍₁₉₎ -COCH ₂ CH (OH) R ₍₁₉₎ -P (O) (OH) ₂ H 11 H -COCH ₂ CH (OH) R ₍₁₁₎ -COCH ₂ CH (OH) R _{(13 )} -P (O) (OH) ₂ H 12 H -COCH ₂ CH (OH) R ₍₁₃₎ -COCH ₂ CH (OH) R ₍₁₁₎ -P (O) (OH) ₂ H 13 H -COCH ₂ CH (OOCR ₍₉₎ ) R ₍₇₎ -COCH ₂ CH (OH) R ₍₇₎ -P (O) (OH) ₂ H 14 H -COCH ₂ CH (OOCR ₍₁₀₎ ) R ₍₈₎ -COCH ₂ CH (OH) R ₍₈₎ -P (O) (OH) ₂ H 15 H -COCH ₂ CH (OOCR ₍₁₁₎ ) R ₍₉₎ -COCH ₂ CH (OH) R _{( 9)} -P (O) (OH) ₂ H 16 H -COCH ₂ CH (OOCR ₍₁₄₎ ) R ₍₁₀₎ -COCH ₂ CH (OH) R ₍₁₁₎ -P (O) (OH) ₂ H 17 H -COCH ₂ CH (OOCR ₍₁₃₎ ) R ₍₁₁₎ -COCH ₂ CH (OH) R ₍₁₁₎ -P (O) (OH) ₂ H 18 H -COCH ₂ CH (OOCR ₍₁₄₎ ) R _{( 11)} -COCH ₂ CH (OH) R ₍₁₁₎ -P (O) (OH) ₂ H 19 H -COCH ₂ CH (OOCR ₍₁₅₎ ) R ₍₁₁₎ -COCH ₂ CH (OH) R ₍₁₁₎ -P (O) (OH) ₂ H 20 H -COCH ₂ CH (OOCR ₍₁₇₎ ) R ₍₁₁₎ -COCH ₂ CH (OH) R ₍₁₃₎ -P (O) (OH) ₂ H 21 H- COCH ₂ CH (OOCR ₍₁₉₎ ) R ₍₁₁₎ -COCH ₂ CH (OH) R ₍₁₃₎ -P (O) (OH) ₂ H 22 H -COCH ₂ CH (OOCR ₍₁₃₎ ) R ₍₁₃₎ -COCH ₂ CH (OH) R ₍₁₃₎ -P (O) (OH) ₂ H 23 H -COCH ₂ CH (OOCR ₍₁₅₎ ) R ₍₁₃₎ -COCH ₂ CH (OH) R ₍₁₃₎ -P (O) (OH) ₂ H 24 H -COCH ₂ CH (OH) R ₍₁₁₎ -COCH ₂ CH (OOCR ₍₁₃₎ ) R ₍₁₁₎ -P (O) (OH) ₂ H 25 H -COCH ₂ CH (OH) R ₍₁₁₎ -COCH ₂ CH (OOCR ₍₁₄₎ ) R ₍₁₁₎ -P (O) (OH) ₂ H 26 H -COCH ₂ CH (OH) R ₍₁₁₎ -COCH ₂ CH ( OOCR ₍₁₅₎ ) R ₍₁₁₎ -P (O) (OH) ₂ H 27 H -COCH ₂ CH (OH) R ₍₁₃₎ -COCH ₂ CH (O OCR ₍₁₇₎ ) R ₍₁₁₎ -P (O) (OH) ₂ H 28 H -COCH ₂ CH (OH) R ₍₁₃₎ -COCH ₂ CH (OOCR ₍₁₉₎ ) R ₍₁₁₎ -P (O ) (OH) ₂ H 29 H -COCH ₂ CH (OH) R ₍₁₃₎ -COCH ₂ CH (OOCR ₍₁₃₎ ) R ₍₁₃₎ -P (O) (OH) ₂ H 30 H -COCH ₂ CH ( OH) R ₍₁₃₎ -COCH ₂ CH (OOCR ₍₁₅₎ ) R ₍₁₃₎ -P (O) (OH) ₂ H 31 H -COCH ₂ CH (OOCR ₍₁₃₎ ) R ₍₁₁₎ -COCH ₂ CH (OOCR ₍₁₃₎ ) R ₍₁₁₎ -P (O) (OH) ₂ H 32 H -COCH ₂ CH (OOCR ₍₁₃₎ ) R ₍₁₁₎ -COCH ₂ CH (OOCR ₍₁₁₎ ) R ₍₁₁₎ -P (O) (OH) ₂ H 33 H -COCH ₂ CH (OOCR ₍₁₁₎ ) R ₍₁₁₎ -COCH ₂ CH (OOCR ₍₁₁₎ ) R ₍₁₁₎ -P (O) (OH) ₂ H 34 H -COCH ₂ CH (OOCR ₍₁₁₎ ) R ₍₁₁₎ -COCH ₂ CH (OOCR ₍₁₃₎ ) R ₍₁₁₎ -P (O) (OH) ₂ H 35 H -COCF ₂ CH (OOCR _{(13 )} ) R ₍₁₁₎ -COCH ₂ CH (OOCR ₍₁₃₎ ) R ₍₁₁₎ -P (O) (OH) ₂ H 36 H -COCHFCH (OOCR ₍₁₃₎ ) R ₍₁₁₎ -COCH ₂ CH (OOCR ₍₁₃₎ ) R ₍₁₁₎ -P (O) (OH) ₂ H 37 H -COCHFCH (OOCR ₍₁₃₎ ) R ₍₁₁₎ -COCH ₂ CH (OH) R ₍₁₁₎ -P (O) (OH ) ₂ H 38 H -COCF ₂ CH (OOCR ₍₁₃₎ ) R ₍₁₁₎ -COCH ₂ CH (OH) R ₍₁₁₎ -P (O) (OH) ₂ H 39 H -COCCl ₂ CH (OH) R ₍₁₁₎ -COCH ₂ CH (OH) R ₍₁₁₎ -P (O) (OH) ₂ H 40 H -COCH ₂ CH (OH) R ₍₁₁₎ -COCH ₂ CH (OOCR ₍₁₃₎ ) R _{(11 )} -P (O) (OH) ₂ H 41 H -COCHClCH (OH) R ₍₁₁₎ -COCH ₂ CH (OOCR ₍₁₃₎ ) R ₍₁₁₎ -P (O) (OH) ₂ H ────────────────────────────── ────── 番号 Number R ¹ R ² R ³ R ⁴ R ⁵ ──────────────────────────────────── 42 -P (O) (OH) _2- COCH ₂ CH (OH) R ₍₇₎ -COCH ₂ CH (OH) R ₍₇₎ HH 43 -P (O) (OH) ₂ -COCH ₂ CH (OH) R ₍₈₎ -COCH ₂ CH (OH) R ₍₈₎ HH 44 -P (O) (OH) ₂ -COCH ₂ CH (OH) R ₍₉₎ -COCH ₂ CH (OH) R ₍₉₎ HH 45 -P (O) (OH) ₂ -COCH ₂ CH (OH) R ₍₁₀₎ -COCH ₂ CH (OH) R ₍₁₀₎ HH 46 -P (O) (OH) ₂ -COCH ₂ CH (OH) R ₍₁₁₎ -COCH ₂ CH (OH) R ₍₁₁₎ HH 47 -P (O) (OH) ₂ -COCH ₂ CH (OH) R ₍₁₃₎ -COCH ₂ CH (OH) R ₍₁₃₎ HH 48 -P (O) (OH) ₂ -COCH ₂ CH (OH) R ₍₁₅₎ -COCH ₂ CH (OH) R ₍₁₅₎ HH 49 -P (O) (OH) ₂ -COCH ₂ CH (OH) R ₍₁₇₎ -COCH ₂ CH (OH) R _{( 17)} HH 50 -P (O) (OH) ₂ -COCH ₂ CH (OOCR ₍₁₃₎ ) R ₍₁₁₎ -COCH ₂ CH (OH) R ₍₁₁₎ HH 51 -P (O) (OH) _2- COCH ₂ CH (OOCR ₍₁₅₎ ) R ₍₁₁₎ -COCH ₂ CH (OH) R _{( 13)} HH 52 -P (O) (OH) ₂ -COCH ₂ CH (OH) R ₍₁₁₎ -COCH ₂ CH (OOCR ₍₁₁₎ ) R ₍₁₃₎ HH 53 -P (O) (OH) _2- COCH ₂ CH (OH) R ₍₁₁₎ -COCH ₂ CH (OOCR ₍₁₃₎ ) R ₍₁₅₎ HH 54 -P (O) (OH) ₂ -COCH ₂ CH (OOCR ₍₁₁₎ ) R ₍₁₁₎ - COCH ₂ CH (OOCR ₍₁₁₎ ) R ₍₁₁₎ HH 55 -P (O) (OH) ₂ -COCH ₂ CH (OOCR ₍₁₃₎ ) R ₍₁₁₎ -COCH ₂ CH (OOCR ₍₁₃₎ ) R _{( 11)} HH 56 -P (O) (OH) ₂ -COCH ₂ CH (OOCR ₍₁₅₎ ) R ₍₁₁₎ -COCH ₂ CH (OOCR ₍₁₃₎ ) R ₍₁₁₎ HH ────────の う ち Among the above exemplified compounds, preferred compounds are 3,
4, 5, 6, 15, 16, 17, 24, 25, 31, 3
2, 33, 34, 46, 47, 50, 51, 53 and 55, and more preferably 4, 6, 17, 3
1, 32, 33, 34, 46 and 47.

The compound of the present invention can be produced by the method described below. In addition, process charts 1, 2, 3, 4
And 5, R ^{1 ′} represents an allyl group, R ^{5 ′} represents a hydroxyl-protecting group (benzyl group or trialkylsilyl group), and R ⁷ and R ^{7 ′} are the same or different and have 7 to 1 carbon atoms.
7 represents an alkyl group, R ^8a and R ^8b are the same or different and represent an aliphatic acyl group having 10 to 20 carbon atoms or a hydroxyl-protecting group, and α, α ', β and β' are the same or different Represents a hydrogen atom or a halogen atom, Ph represents a phenyl group, and DMB represents a dimethoxybenzyl group.

[0015]

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[0016]

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[0017]

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[0018]

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[0019]

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(First Step) In this step, the known compound (1) (Bull. Chem. Soc. Jpn. 62, 3) is prepared in an inert solvent in the presence of a silver salt.
950 (1989); Shiozaki, N.M. Isida, S.M. In this step, the compound (2) is produced by reacting (Sato) with an allyl halide R ^{1 ′} X.

The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent, but is preferably a nitrile such as acetonitrile or isobutyronitrile, formamide, Examples include amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphorotriamide, and sulfoxides such as dimethylsulfoxide and sulfolane, and are preferably amides. Examples of the silver salt to be used include silver salts such as silver carbonate, silver oxide, silver perchlorate, and silver cyanide, and silver oxide is preferable. The allyl halide used includes allyl chloride, allyl bromide, allyl iodide and the like, and preferably allyl iodide.

The reaction is carried out at a temperature of 0 ° C. to 150 ° C., preferably around room temperature.

The reaction time mainly depends on the reaction temperature, the starting compound,
Depending on the type of reaction reagent or solvent used,
Usually 5 hours to 2 days. After completion of the reaction, it is collected from the reaction mixture according to a conventional method.

For example, if insolubles are present, they are removed by filtration, an immiscible organic solvent such as water and ethyl acetate are added, and after washing with water, the organic layer containing the target compound is separated and dried over anhydrous magnesium sulfate. And then the solvent is distilled off. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

(Second Step) This step is a step of producing compound (3) by reacting compound (2) with a reducing agent in an inert solvent.

The solvents used include aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether. Examples thereof include ethers, and preferred are ethers. As the reducing agent used, sodium borohydride, alkali metal borohydride such as lithium borohydride,
Examples thereof include an aluminum hydride compound such as lithium aluminum hydride and lithium triethoxide aluminum, and a hydride reagent such as sodium tellurium hydride, and lithium aluminum hydride is preferable.

The reaction is carried out at a temperature of -50 ° C to 100 ° C, preferably -10 ° C to 50 ° C.

The reaction time mainly depends on the reaction temperature, the starting compound,
Depending on the type of reaction reagent or solvent used,
Usually 10 minutes to 5 hours.

After completion of the reaction, it is collected from the reaction mixture according to a conventional method.

For example, an alcohol such as methanol or ethanol or an organic fatty acid such as acetic acid or propionic acid is added to the reaction mixture to decompose excess reducing agent and not to mix with slightly acidic water and ethyl acetate. Add an organic solvent,
After washing with water, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off.

If necessary, the obtained target compound can be obtained by a conventional method,
For example, it can be further purified by recrystallization, reprecipitation or chromatography.

(Third Step) In this step, the carboxylic acid R ⁷ CH (OR ^8a ) is prepared in an inert solvent in the presence of a condensing agent and a base.
In this step, compound (4) is produced by reacting CαβCOOH (R ⁷ , R ^8a , α and β have the same meanings as described above) with compound (3).

The solvents used include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, chloroform, carbon tetrachloride, Halogenated hydrocarbons such as dichloroethane, chlorobenzene and dichlorobenzene, esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate, diethyl ether and diisopropyl ether
Ethers such as ter, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, ketones such as cyclohexanone, acetonitrile, nitriles such as isobutyronitrile, formamide, Dimethylformamide, dimethylacetamide, amides such as hexamethylphosphorotriamide, dimethylsulfoxide, sulfoxides such as sulfolane, preferably,
Ethers and halogenated hydrocarbons.

Examples of the condensing agent to be used include di-lower alkyl-triphenylphosphines of azodicarboxylate such as diethyl-triphenylphosphine azodicarboxylate, and N-ethyl-5-phenylisoxazolium-
N-lower alkyl-5-arylisoxazolium-3'-sulfonates, such as 3'-sulfonate, N ', N'-, such as N', N'-dicyclohexylcarbodiimide (DCC) Dicycloalkylcarbodiimides, diheteroaryldiselenides such as di-2-pyridyldiselenide, triarylphosphines such as triphenylphosphine, arylsulfonyltriazolyl such as p-nitrobenzenesulfonyltriazolide And 2-halo-1-lower alkylpyridinium halides such as 2-chloro-1-methylpyridinium iodide and diphenylphosphorylazide (D
Diarylphosphoryl azides such as PPA), imidazole derivatives such as N, N'-carbodiimidazole (CDI), benzotriazole derivatives such as 1-hydroxybenzotriazole (HOBT), N-hydroxy-5-norbornene- Examples include dicarboxyimide derivatives such as 2,3-dicarboximide (HONB) and carbodiimide derivatives such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDAPC). , N'-Dicycloalkylcarbodiimides and imidazole derivatives.

The base to be used is not particularly limited as long as it is used as a base in a usual reaction, but preferably, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, -(N, N-dimethylamino) pyridine, N,
N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo
[2.2.2] Octane (DABCO), 1,8-diazabicyclo [5.4.0]
Organic bases such as undec-7-ene (DBU) are preferable, and pyridines such as pyridine and dimethylaminopyridine are preferable.

The reaction is carried out at a temperature of 0 ° C. to 150 ° C., preferably around room temperature.

The reaction time mainly depends on the reaction temperature, the starting compound,
Depending on the type of reaction reagent or solvent used,
Usually 2 hours to 24 hours.

After completion of the reaction, the reaction mixture is collected from the reaction mixture according to a conventional method.

For example, the reaction mixture is appropriately neutralized, and if there is any insoluble matter, it is removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added.
An organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and then obtained by distilling off the solvent.

If necessary, the obtained target compound can be obtained by a conventional method,
For example, it can be further purified by recrystallization, reprecipitation or chromatography.

(Fourth Step) In this step, the compound (4) is reacted with an oxidizing agent at the benzyl position in an inert solvent to give DMB.
This is a step of producing compounds (5) and (6) by removing the group.

Examples of the solvent to be used include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, chloroform, carbon tetrachloride, Halogenated hydrocarbons such as dichloroethane, chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; diethyl ether, diisopropyl ether
Ethers such as ter, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propano-
, Isopropanol, n-butanol, isobutanol
Alcohols such as toluene, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone;
Nitro compounds such as nitroethane and nitrobenzene; nitriles such as acetonitrile and isobutyronitrile; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide; sulfoxides such as dimethylsulfoxide and sulfolane And a mixed solvent of these and water, and preferably a mixed solvent of halogenated hydrocarbons and water.

The deprotecting agent used is preferably
An oxidizing agent such as DDQ.

The reaction is carried out at a temperature of from -20 ° C to 100 ° C, preferably from 20 ° C to 50 ° C.

The reaction time mainly depends on the reaction temperature, starting compound,
Depending on the type of reaction reagent or solvent used,
Usually 30 minutes to 20 hours.

After completion of the reaction, the reaction mixture is collected from the reaction mixture according to a conventional method.

For example, the reaction mixture is appropriately neutralized, and if an insoluble substance is present, it is removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added. It is obtained by separating an organic layer containing the organic layer, drying the organic layer with anhydrous magnesium sulfate or the like, and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

(Fifth Step) In this step, the carboxylic acid R ^{7 ′} CH (OR ^8b ) Cα ′ is prepared in an inert solvent in the presence of a condensing agent.
β′COOH (R ^{7 ′} , R ^8b , α ′ and β ′ have the same meanings as R ⁷ , R ⁸ , α and β, respectively) and compound (5) or (6), This is a step of producing the compound (7), and is carried out in the same manner as in the third step.

(Sixth Step) In this step, the compound (7) is isomerized with a double bond of an allyl group with an isomerizing agent in an inert solvent and then reacted with a deprotecting agent to give a compound (8). This is the step of manufacturing.

Solvents used include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol. Alcohols such as glycerin, octanol, cyclohexanol and methyl cellosolve; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; nitro compounds such as nitroethane and nitrobenzene; acetonitrile and isobutyro Nitriles such as nitriles; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide, dimethylsulfoxide;
Sulfoxides such as sulfolane or a mixed solvent of these organic solvents and water can be mentioned, and preferred are alcohols and ethers.

The isomerizing agent used is preferably
[Bis (diphenylmethylphosphine) cyclooctadieneiridium] An iridium complex such as hexafluorophosphate and a rhodium complex such as triphenylrhodium chloride.

The deprotecting agent used here is a mixed reagent of iodine, pyridine and water, and potassium t-butoxide.

The reaction is carried out at a temperature from -20 ° C to 80 ° C, preferably around room temperature. The reaction time mainly depends on the reaction temperature, the starting compound, the reaction reagent or the type of the solvent used, but is usually 1 hour to 10 hours in the isomerization reaction, and 10 minutes to 3 hours in the deprotection reaction. Time.

After completion of the reaction, the reaction mixture is collected from the reaction mixture according to a conventional method.

For example, the reaction mixture is appropriately neutralized, and if there is any insoluble matter, it is removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added. It is obtained by separating an organic layer containing the organic layer, drying the organic layer with anhydrous magnesium sulfate or the like, and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

(Step 7a) This step is carried out in an inert solvent
This is a step of removing the isopropylidene group by reacting with an isopropylidene group removing agent.

Examples of the solvent used include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, methanol, ethanol, n-propanol, and the like. Alcohols such as isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve or their organic solvents and water And a mixed solvent of water and ethers.

Examples of the isopropylidene group removing agent include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as acetic acid and p-toluenesulfonic acid.
20% aqueous acetic acid.

The reaction is carried out at a temperature from 0 ° C. to around the boiling point of the solvent used, preferably around room temperature.

The reaction time mainly depends on the reaction temperature, starting compound,
Depending on the type of reaction reagent or solvent used,
Usually 30 minutes to 24 hours.

After completion of the reaction, the reaction mixture is collected from the reaction mixture according to a conventional method.

For example, the reaction mixture is appropriately neutralized, and if there is any insoluble matter, it is removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added. It is obtained by separating an organic layer containing the organic layer, drying the organic layer with anhydrous magnesium sulfate or the like, and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Step 7b) This step is carried out in an inert solvent in the presence of an acid.
In this step, the compound (9) is produced by reacting the isopropylidene group-introducing agent obtained in Step 7a.

Examples of the solvent used include halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene; nitriles such as acetonitrile and isobutyronitrile; formamide, dimethylformamide; Dimethylacetamide, amides such as hexamethyl phosphorotriamide or acetone, preferably,
Halogenated hydrocarbons and amides.

The reagent used includes acetone, monomethoxypropene, dimethoxypropane and the like, and preferably dimethoxypropane.

Examples of the acid used include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as acetic acid and p-toluenesulfonic acid. P-toluenesulfonic acid is preferred.

The reaction is carried out at a temperature of from 0 ° C. to 100 ° C., preferably from 20 ° C. to 70 ° C. The reaction time is
Although it depends mainly on the reaction temperature, the starting compound, the reaction reagent or the type of the solvent used, it is usually 30 minutes to 24 hours. After completion of the reaction, it is collected from the reaction mixture according to a conventional method.

For example, the reaction mixture is appropriately neutralized, and if there is any insoluble matter, it is removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added. It is obtained by separating an organic layer containing the organic layer, drying the organic layer with anhydrous magnesium sulfate or the like, and distilling off the solvent.

If necessary, the obtained target compound can be obtained by a conventional method.
For example, it can be further purified by recrystallization, reprecipitation or chromatography.

(Eighth Step) This step is a step of reacting compound (9) with allyl bromide in an inert solvent in the presence of a silver salt to produce compound (10). The same is done. (Ninth Step) This step is to prepare a compound (10) in an inert solvent.
This is a step of producing a compound (11) by reacting the compound with a deprotecting agent, and is carried out in the same manner as in the sixth step.

(Tenth Step) This step is a step of producing a compound (12) by reacting the compound (11) with a hydroxyl-protecting agent in an inert solvent in the presence of a base.

The solvents used include aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Halogenated hydrocarbons such as chlorobenzene and dichlorobenzene; and ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether. Kind.

The protective agent used is preferably aralkylhalogenomethyl ethers such as benzylchloromethyl ether.

The base used is preferably tetramethylurea. The reaction is carried out at a temperature of 0 ° C. to 100 ° C., preferably around room temperature. The reaction time varies depending mainly on the reaction temperature, the starting compound, the reaction reagent or the type of the solvent used, but is usually 6 hours to 2 days. After completion of the reaction, it is collected from the reaction mixture according to a conventional method.

For example, the reaction mixture is appropriately neutralized, and if there is any insoluble matter, it is removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added. It is obtained by separating an organic layer containing the organic layer, drying the organic layer with anhydrous magnesium sulfate or the like, and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

(Eleventh Step) In this step, a compound (12) is reacted with a phosphorylating agent in an inert solvent in the presence of a base.
This is a step of producing a compound (13). Examples of the solvent used include aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; diethyl ether and diisopropyl. Ethers such as ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether can be mentioned, and preferred are halogenated hydrocarbons.

The phosphorylating agent used is preferably a diarylphosphoryl halide such as diphenylphosphoryl chloride, or a diaralkylphosphoryl halide such as dibenzylphosphoryl chloride.

The base used is not particularly limited as long as it is used as a base in a usual reaction. Preferably, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, -(N, N-dimethylamino) pyridine, N,
N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo
[2.2.2] Octane (DABCO), 1,8-diazabicyclo [5.4.0]
Organic bases such as undec-7-ene (DBU) are preferable, and pyridines such as pyridine and dimethylaminopyridine are preferable.

The reaction is carried out at a temperature between -20 ° C and 100 ° C, preferably around room temperature.

The reaction time mainly depends on the reaction temperature, starting compound,
Depending on the type of reaction reagent or solvent used,
Usually 10 minutes to 24 hours.

After completion of the reaction, it is collected from the reaction mixture according to a conventional method.

For example, the reaction mixture is appropriately neutralized, and if there is any insoluble matter, it is removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added. It is obtained by separating an organic layer containing the organic layer, drying the organic layer with anhydrous magnesium sulfate or the like, and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

(Twelfth Step) This step is a step of producing a compound (14) by reacting the compound (13) with an agent for removing the protective group at the 1-position in an inert solvent. The same is done. (Thirteenth Step) The present step is to carry out the compound (14) in an inert solvent.
This is a step of producing a compound (15) by reacting the compound with a hydroxyl group deprotecting agent.

Examples of the solvent used include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether, methanol, ethanol, n-propanol, isopropanol and n-butanol. , Isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol,
Examples thereof include alcohols such as methyl cellosolve, fatty acids such as acetic acid and propionic acid, and mixed solvents of these organic solvents and water. Preferred are alcohols and fatty acids. As the deprotecting agent to be used, those usually used can be used as they are, and there is no particular limitation. When the protecting group is a benzyl group, a combination of a reducing catalyst such as palladium-carbon or platinum and hydrogen is used. Trialkylsilyl halides such as trimethylsilyl halide, boron trihalides such as boron tribromide, and the like.Preferably, palladium-carbons, and when the protecting group is a trialkylsilyl group Preferably, tetra n
-It produces a fluorine anion such as -butylammonium fluoride, or is an acid such as diluted hydrochloric acid or diluted sulfuric acid. The reaction is carried out at a temperature of -20 ° C to 150 ° C, preferably 0 ° C to 60 ° C.

The reaction time mainly depends on the reaction temperature, the starting compound,
Depending on the type of reaction reagent or solvent used,
Usually 1 hour to 10 hours.

After completion of the reaction, the reaction mixture is collected from the reaction mixture according to a conventional method.

For example, the reaction mixture is appropriately neutralized, and if there is any insoluble matter, it is removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added. It is obtained by separating an organic layer containing the organic layer, drying the organic layer with anhydrous magnesium sulfate or the like, and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

(Step 14) This step is a step of reacting the compound obtained in Step 18 with a deprotecting agent for a hydroxyl group in an inert solvent to produce a compound (19).
This is performed in the same manner as in the five steps. This manufacturing process is performed only when necessary.

Examples of the solvent used include aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether, methanol, ethanol, n-propanol, isopropanol, and n-butanol. , Isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol,
Examples thereof include alcohols such as methyl cellosolve, fatty acids such as acetic acid and propionic acid, and mixed solvents of these organic solvents and water. Preferred are alcohols and fatty acids. Examples of the protective group remover to be used include a combination of hydrogen with a reducing catalyst such as palladium-carbon, platinum and platinum oxide, and preferably palladium-carbon.

The reaction is carried out at a temperature of 0 ° C. to 100 ° C., preferably around room temperature. The reaction time varies depending mainly on the reaction temperature, the starting compound, the reaction reagent or the type of the solvent used, but is usually 1 hour to 24 hours.

After completion of the reaction, the reaction mixture is collected from the reaction mixture according to a conventional method.

For example, after removing the catalyst by filtration, an immiscible organic solvent such as water and ethyl acetate is added. After washing with water, the organic layer containing the target compound is separated and dried over anhydrous magnesium sulfate or the like. By distillation. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The present manufacturing process is performed only when necessary.

(Fifteenth Step) This step is a step of reacting the compound (15) with an agent for removing the protecting group of the phosphoric acid moiety in an inert solvent to produce the desired compound. Examples of the solvent used include aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether, methanol, and ethanol.
, N-propanol, isopropanol, n-butanol
, Alcohols such as isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellosolve; fatty acids such as acetic acid and propionic acid; Examples thereof include a mixed solvent with water, and preferred are alcohols and fatty acids.

Examples of the protective group removing agent used include a combination of hydrogen with a reducing catalyst such as palladium-carbon, platinum and platinum oxide, and platinum oxide is preferred.

The reaction is carried out at a temperature of 0 ° C. to 100 ° C., preferably around room temperature. The reaction time varies depending mainly on the reaction temperature, the starting compound, the reaction reagent or the type of the solvent used, but is usually from 3 hours to 3 days. After completion of the reaction, it is collected from the reaction mixture according to a conventional method.

For example, after removing the catalyst by filtration, adding an immiscible organic solvent such as water and ethyl acetate, washing with water, separating the organic layer containing the target compound, drying over anhydrous magnesium sulfate or the like, and removing the solvent. Obtained by distillation. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

(Step 16) In this step, compound (14) is reacted with a phosphorylating agent in an inert solvent to give compound (17).
Is performed in the same manner as in the eleventh step.

(Step 17) This step is a step of reacting compound (17) with an agent for removing a protecting group in an inert solvent to produce compound (18). Done.

(Step 18) This step is a step of reacting compound (18) with a deprotecting agent for a hydroxyl group in an inert solvent to produce the desired compound, and is carried out in the same manner as step 14. . This manufacturing process is performed only when necessary. (Step 19) In this step, compound (18) is prepared in an inert solvent.
Alternatively, the target compound is produced by reacting the agent for removing the protecting group of the phosphoric acid portion of the compound obtained in the eighteenth step, to produce the target compound, which is carried out in the same manner as the fifteenth step.

(Step 20) This step is a step of reacting compound (9) with a phosphorylating agent in an inert solvent in the presence of a base to produce compound (20). The same is done.

(Step 21) In this step, compound (20) is reacted with a deprotecting agent in an inert solvent to give compound (21).
Is performed in the same manner as in the sixth step.

(Step 22) This step is a step of reacting compound (21) with a deprotecting agent for a hydroxyl group in an inert solvent to produce the desired compound, and is carried out in the same manner as step 14. . This manufacturing process is performed only when necessary. (Step 23) In this step, compound (21) is prepared in an inert solvent.
Alternatively, the target compound is produced by reacting the agent for removing the protecting group of the phosphoric acid portion of the compound obtained in the eighteenth step, to produce the target compound, which is carried out in the same manner as the fifteenth step.

[0103]

The novel homolipid X analog of the present invention is
It has an excellent protective effect against bacterial infection, an immunoadjuvant activity, a tumor necrosis effect, a macrophage activating effect, and has low toxicity, and thus is useful as an immunostimulant.

The administration form of the compound (I) of the present invention includes, for example, oral administration by tablets, capsules, granules, powders or syrups, and parenteral administration by injections or suppositories. . These preparations are manufactured by a known method using additives such as excipients, binders, disintegrants, lubricants, stabilizers, and flavoring agents. The amount used depends on symptoms, age, etc.
Usually, the body weight can be administered to an adult once or several times a day.

Hereinafter, the present invention will be described more specifically with reference to examples.

(Example 1) 1a) (1R, 2S, 4S, 5S) -4-allyloxy
-6- (2,4-dimethoxybenzyl) -2-[(1 ′
R)-(1 ', 2'-O-isopropylidene) ethyl]
-3-oxa-6-azabicyclo [3.2.0] hepta
N-7-one (1R, 2S, 4S, 5S) -6- (2,4-dimethoxybenzyl) -4-hydroxy-2-[(1R) -1,
2-isopropylidenedioxyethyl] -3-oxa-
To a solution of 6-azabicyclo- [3.2.0] heptan-7-one (2.17 g) in dimethylformamide (30 ml),
Allyl iodide (5 ml) and silver oxide (6 g) were added, and the mixture was stirred at room temperature for 15 hours. After the reaction was completed, insolubles were removed by filtration, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluted with cyclohexane-ethyl acetate 1: 1) to obtain 2.70 g of the desired product as a mixture. Infrared absorption spectrum ν _max (CDCl ₃ ): 1747,1608, 15
85 cm ^-1 mass spectrum m / z: 419 (M ⁺ ).

1b) Allyl 2,3-dideoxy-2-
(2,4-dimethoxybenzylamino) -3-C-hydrido
Roxymethyl-5,6-O-isopropylidene-α-D
Lithium aluminum hydride (50 ml) was added to a solution of the compound obtained in Mannofuranoside 1a (2.7 g) in tetrahydrofuran (70 ml).
0 mg) under ice-cooling.
Stirred for minutes. After the reaction was completed, acetic acid was added to decompose excess lithium aluminum hydride, and ethyl acetate was added.
This was washed with a 5% aqueous sodium bicarbonate solution and subsequently with a saturated saline solution, and then washed with Mg.
And dried over SO _4. The residue obtained by evaporating the solvent was purified by chromatography (eluted with cyclohexane-ethyl acetate 1: 1) to obtain 1.53 g of the desired product. ¹ H-NMR spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.34 (3H,
s), 1.40 (3H, s), 2.66 (1H, quintuplet, J = 6.5Hz), 2.66
(2H, wide, OH), 3.34 (1H, dd, J = 2.5, 6.5Hz), 3.7-4.4 (16
H, m), 6.3-6.5 (2H, m), 7.12 (1H, d, J = 9Hz), 5.0-6.3 (3H,
m), 6.3-6.5 (2H, m), 7.12 (1H, d, J = 9Hz) Infrared absorption spectrum ν _max (CDCl ₃ ): 3450,1613c
m ^-1 .

1c)Allyl 3-C-[(3'R)-
(3′-benzyloxy) tetradecanoyloxy] me
Tyl-2,3-dideoxy-2- (2,4-dimethoxy
Benzylamino) -5,6-O-isopropylidene-α
-D-Mannofuranoside 1b Methylene chloride (25 g) of the compound (1.50 g) obtained in
ml) solution, add (3R) -3-benzyloxytetradeca
Acid (1.30 g), dicyclohexylcarbodiimide (D
CC) (876 mg) and dimethylaminopyridine (DM
(AP) (476 mg) and stirred at room temperature for 10 hours.
After completion of the reaction, insolubles were removed by filtration, and the solvent was distilled off.
Was. The residue was subjected to silica gel column chromatography (six
Eluted with hexane-ethyl acetate (3: 1))
Thus, 2.09 g of the desired product was obtained.¹ H-NMR spectrum (60MHz, CDCl_Three) δ ppm: 0.8-1.0 (3
H, m), 1.1-1.6 (26H, m), 2.45 (2H, dd, J = 2,6Hz), 3.70 (2H,
s), 3.75 (6H, s), 3.8-4.45 (9H, m), 4.50 (2H, s), 4.87 (1
H, d, J = 2Hz), 5.0-6.2 (3H, m), 6.3-6.5 (2H, m), 7.14 (1H,
d, J = 9Hz), 7.30 (5H, s) Infrared absorption spectrum ν_max (CDCl_Three): 2930,2850, 173
0, 1610cm^-1.

1d)Allyl 2-amino-3-C-
[(3′R)-(3′-benzyloxy) tetradecano
Yloxy] methyl-2,3-dideoxy-5,6-O
-Isopropylidene-α-D-mannofuranoside You
AndAllyl 2-[(3′R)-(3′-benzyloxy)
B) Tetradecanoylamino] -2,3-dideoxy-
3-hydroxymethyl-5,6-O-isopropylidene
-Α-D-Mannofuranoside 1c Methylene chloride (45 g) of the compound (2.03 g) obtained in
ml) solution into water (2.25 ml) and 2,3-dichloro-5.
6-dicyano-1,4-benzoquinone (760 mg) was added.
Well, it was stirred vigorously. After 2 hours, remove insolubles by filtration
Then, the solvent was distilled off and concentrated. 99.5% ethanol in the residue
(100 ml) and dissolved, and Girard T (920 m
g) was added and stirred at room temperature for 3 hours. After the reaction is complete,
The solvent is distilled off, and the residue is dissolved by adding ethyl acetate.
After washing, it was dried over sodium sulfate. Filter insolubles
And removed and the solvent was distilled off. Residue is subjected to column chromatography
Raffy (dissolved in cyclohexane-ethyl acetate (2: 1)
Purification was performed under the same conditions as in Example 1 to obtain 962 mg of the desired product. Infrared absorption spectrum ν_max (Nujol): 3220, 2920, 2
860, 1630cm^{-1 1} H-NMR spectrum (60MHz, CDCl_Three) δ ppm: 0.7-1.0 (6H,
m), 1.1-1.7 (26H, m), 1.9-2.6 (3H, m), 3.6-4.2 (9H, m),
4.5 (2H, s), 4.80 (1H, s), 4.9-6.0 (3H, m), 6.71 (1H, d, J =
7Hz, NH), 7.33 (5H, s).

1e) Allyl 2-[(3'R)-(3 '
-Benzyloxytetradecanoyl) amino] -3-C
-[(3′R)-(3′-benzyloxytetradecano
Yloxy) methyl-2,3-dideoxy-5,6-O
Compound (892 mg) obtained from 1-d -isopropylidene-α-D- mannofuranoside in methylene chloride (2
(3 ml) of (3R) -3-benzyloxytetradecanoic acid (595 mg) in methylene chloride (5 ml).
l) The solution, dimethylaminopyridine (200 mg) and dicyclohexylcarbodiimide (590 mg) were added at room temperature. 45 minutes after completion of the addition, the precipitate was collected by filtration, and the filtrate was concentrated to give a residue. The precipitate and the residue are combined and purified by silica gel column chromatography (eluted with cyclohexane-ethyl acetate (3: 1)) to give 1.66 of the desired product.
g was obtained. Infrared absorption spectrum ν _max (neat): 3330, 2930, 2860,
1735, 1675, 1650 cm ^-1 mass spectrum m / z: 905 (M ⁺ ), 890.

1f)2-[(3′R)-(3′-benzyl)
Ruoxytetradecanoyl) amino] -3-C-
[(3′R)-(3′-benzyloxytetradecanoy)
Ruoxy) methyl] -2,3-dideoxy-4,6-O
-Isopropylidene-α-D-mannofuranoside 1e Of the compound obtained in the above (1.64 g) in tetrahydrofuran
(80 ml) solution, [bis (diphenylmethylphosphine)
In) cyclooctadiene iridium] hexafluoro
Phosphate (100 mg) was added. Empty in reaction vessel
Gas replaced with hydrogen gas, stirred for 2 minutes, and replaced with nitrogen gas
did. After the reaction solution was stirred at room temperature for 3 hours,_TwoO (1
0 ml), pyridine (1.0 g) and iodine (0.7 g).
And further stirred for 30 minutes at room temperature. Evaporate the solvent
Then, ethyl acetate was added to the residue. 5% ethyl acetate solution
Sequentially with sodium sulfite, 5% aqueous sodium bicarbonate and saturated saline
Washed. The ethyl acetate layer was dried over MgSO_Four After drying and filtering, the solvent
Was distilled off under reduced pressure. The residue obtained is purified by silica gel column chromatography.
Chromatography (cyclohexane-ethyl acetate (7:
Purification was carried out under 3) to obtain 1.0 g of the desired product.¹ H-NMR spectrum (270MHz, CDCl_Three) δ ppm: 0.88 (6H,
t, J = 6.6Hz), 1.2-1.8 (48H, m), 2.24-2.44 (2H, m), 3.42-
4.04 (11H, m), 4.42-4.59 (4H, m), 5.06 (1H, t, J = 1.0Hz),
6.39 (1H, d, J = 8.8Hz), 7.31 (5H, s), 7.35 (5H, s).

1 g)2-[(3′R)-(3′-benzyl)
Ruoxytetradecanoyl) amino] -3-C-
[(3′R)-(3′-benzyloxytetradecanoy)
Ruoxy) methyl] -2,3-dideoxy-4,6-O
-Isopropylidene-α-D-mannopyranoside 1f 90% aqueous acetic acid (500 mg)
5 ml) solution was warmed at 60 ° C. for 4 hours 30 minutes. reaction
After completion, the solvent is distilled off under reduced pressure, and the pump is
Dried. Here, dimethylformamide (7 ml), 2,
2-dimethoxypropane (0.7 ml) and p-toluene
Rufonic acid (7 mg) was added, and the mixture was stirred at room temperature for 15 hours.
Dimethylformamide was distilled off under reduced pressure of the pump, and
Chill added. Ethyl acetate layer was saturated with 5% aqueous sodium bicarbonate, then saturated
Washed with saline. This is_Four And dry insoluble matter
After removal by filtration, the solvent was distilled off. Residue on column chromatography
Tomography (cyclohexane-ethyl acetate (3: 2)
And eluted with) to obtain 450 mg of the desired product.¹ H-NMR spectrum (270MHz, CDCl_Three) δ ppm: 0.88 (6H,
t, J = 6.2-7.0Hz), 1.18-1.80 (46H, m), 2.30-2.68 (4H, m),
 2.74 (1H, d, J = 37Hz, OH), 3.15-4.67 (14H, m), 4.77 (1 / 4H,
m, Cl-H), 5.03 (3 / 4H, d, J = 2.6Hz, Cl-H), 6.34 (1 / 4H, d, J =
9.5Hz, NH), 6.79 (3 / 4H, d, J = 9.5Hz, NH), 7.2-7.4 (10H, m) Infrared absorption spectrum ν_max (neat): 3340, 2915, 284
0, 1734, 1652cm^-1.

1h) Allyl 2-[(3'R)-(3 '
-Benzyloxytetradecanoyl) amino] -3-C
-[(3′R)-(3′-benzyloxytetradecano
Yloxy) methyl] -2,3-dideoxy-4,6-
To a solution of the compound (379 mg) obtained with 1 g of O-isopropylidene-D- mannopyranoside in dimethylformamide (2 ml) was added allyl iodide (2 ml) and silver oxide (1 g), and the mixture was stirred at room temperature for 5 hours. Stirred. After completion of the reaction, insolubles were removed by filtration, the solvent was distilled off, and the mixture was concentrated. The residue was purified by silica gel column chromatography (eluted with cyclohexane-ethyl acetate = 3: 1) to obtain 357 mg of the desired product as an anomeric mixture. ¹ H-NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.88 (6H,
t, J = 6.6Hz), 1.0-1.8 (47H, m), 3.1-4.3 (11H, m), 4.4-4.
7 (5H, m), 5.1-5.4 (2H, m), 5.8-6.0 (1H, m), 6.76 (1H, d, J
= 9.9Hz), 7.2-7.5 (10Hz, m) Infrared absorption spectrum ν _max (film) 3350, 2920, 2850, 17
33, 1652 cm ^-1 mass spectrum m / z: 905 (M ⁺ ), 890, 848.

1i) Allyl 2-[(3'R)-(3 '
-Benzyloxytetradecanoyl) amino] -3-C
-[(3′R)-(3′-benzyloxytetradecano
Yloxy) methyl] -2,3-dideoxy-D-man
85% aqueous acetic acid (40 ml) obtained from nopyranoside 1h (357 mg)
The solution was warmed at 60 ° C. for 30 minutes. After completion of the reaction, the mixture was concentrated and dried under reduced pressure. Purified by silica gel column chromatography (eluted with cyclohexane-ethyl acetate = 1: 1),
228 mg of the target β-anomer and 68 mg of the target α-anomer were obtained. Infrared absorption spectrum ν _max (film) β-anomer: 3350, 2920, 2860, 1732, 1675, 1655c
m ^-1 α-anomer: 3350, 2920, 2850, 1732, 1673, 1650c
m ^{-1 1} H-NMR spectrum _{(270MHz, CDCl 3) δ ppm} β- anomer: 0.88 (6H, t, J = 6.6-7.0Hz), 1.20-1.40 (3
6H, m), 1.43-1.70 (4H, m), 1.74 (1H, t, J = 5.9Hz OH), 2.3
1-2.62 (6H, m), 3.13 (d 1H, m, upon addition of D ₂ O, d, J = 5.4,10.
Changes _{8Hz, C 4 -H), 3.49-3.60} (3H, m C 6 -H 2, C 5 -H), 3.77
-4.30 (6H, m), 4.35 (1H, dd, J = 2.7,9.9Hz, C 2 -H), 4.49 and
4.61 (2H, AB-q, J = 11.4Hz), 4.51 and4.55 (2H, AB-q, J = 11.
7Hz), 4.59 (1H, d, J _1a , _2e = 1Hz, C ₁ -H), 5.16-5.31 (2H, m),
5.80-5.95 (1H, m), 6.55 (1H, d, J = 9.9Hz, NH), 7.15-7.64
(10H, m) α-anomer: 0.88 (6H, t, J = 6.2-7.0Hz), 1.19-1.40 (3
6H, m), 1.43-1.70 (4H, m), 1.73 (1H, t, J = 6.8Hz OH), 2.3
1-2.64 (including 6H, m, the OH), 3.02-3.18 (1H, m , C 4 -H), 3.44
-4.65 (15H, m), 5.14-5.27 (2H, m), 5.78-5.92 (1H, m), 6.
45 (1H, d, J = 9.5 Hz, NH), 7.30-7.64 (10H, m).

Example 2 Allyl 6-benzyloxymethyl-2-[(3′R)
-(3'-benzyloxytetradecanoyl) amino]
-3-C-[(3'R)-(3'-benzyloxytet
Ladecanoyloxy) methyl] -2,3-dideoxy-
D- Mannopyranoside An anomeric mixture obtained in 1i of Example 1 (β: α
= 10: 3) To a solution of (212 mg) in methylene chloride (2 ml) were added tetramethyl urea (700 mg) and benzyl chloromethyl ether (700 mg), and the mixture was stirred at 15 to 20 ° C overnight. The reaction mixture was purified by silica gel column chromatography (eluted with cyclohexane-ethyl acetate = 3: 1) to obtain 310 mg of a target anomeric mixture as a partially purified product. This partially purified product was used for the next step without further purification.

Example 3 Allyl 6-benzyloxymethyl-2-[(3′R)
-(3'-benzyloxytetradecanoyl) amino]
-3-C-[(3'R)-(3'-benzyloxytet
Ladecanoyloxy) methyl] -2,3-dideoxy-
4-O-diphenylphosphoryl-D-mannopyranocy
To a solution of the mixture obtained in Example 2 (310 mg) in methylene chloride was added diphenylphosphoryl chloride (500 mg).
And 4-dimethylaminopyridine (500 mg) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluted with cyclohexane-ethyl acetate = 3: 1) to obtain 580 mg of the desired anomeric mixture as a partially purified product. This partially purified product was used for the next step without further purification.

Example 4 6-benzyloxymethyl-2-[(3′R)-(3 ′)
-Benzyloxytetradecanoyl) amino] -3-C
-[(3′R)-(3′-benzyloxytetradecano
Yloxy) methyl] -2,3-dideoxy-4-O-
Diphenylphosphoryl-D-mannopyranose The mixture (370 mg) obtained in Example 3 was treated in the same manner as in Example 6 to obtain 87 mg of the desired product. Infrared absorption spectrum ν _max (film) 3330, 2920, 2860,
1735, 1670 ^{(shoulder), 1653, 1590cm -1 1 H} -NMR spectrum _{(270MHz, CDCl 3) δ ppm} : 0.88 (6H,
t, J = 6.6Hz), 1.16-1.59 (40H, m), 2.30-2.68 (4H, m), 2.8
4 (1H, m), 2.88 (1H, b, OH), 3.52-4.80 (17H, m), 5.03 (1H, b
s, C ₁ -H), 6.62 (1H, d, J = 9.5 Hz, NH), 7.10-7.38 (25H, m) Infrared absorption spectrum ν _max (film): 3330, 2920, 286
0, 1735, 1670 (shoulder), 1653, 1590cm ^-1 .

Example 5 2-[(3′R)-(3′-hydroxytetradecanoy)
Ru) amino] -3-C-[(3′R)-(3′-hydro
Xytetradecanoyloxy) methyl] -2,3-dide
Oxy-4-O-diphenylphosphoryl-D-mannopi
Lanose The compound (63 mg) obtained in Example 4 was dissolved in acetic acid (4 ml), and hydrogenated at room temperature for 5 hours under a catalyst of 10% palladium on carbon (150 mg). The catalyst was removed by filtration, the solvent was distilled off under reduced pressure, and the residue was dried to obtain 46 mg of the desired product as an anomeric mixture. ¹ H-NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.88 (6H,
t, J = 6.6-7.0Hz), 1.20-1.62 (40H, m), 2.20-2.48 (4H, m),
_{2.90 (1H, m, C 3} -H), 3.32-4.70 ( including 13H, m, the OH × 4)
5.08 (1H, b, changes the S ₁ upon addition of D _{2 O, C 1 -H) 6.63 (1H} , d, J
= 10.3Hz, NH), 7.15-7.39 (10H, m) Infrared absorption spectrum ν _max (film): 3330, 2920, 285
0, 1730, 1653, 1590cm ^-1 .

Example 6 2-[(3′R)-(3′-hydroxytetradecanoy)
Ru) amino] -3-C-[(3′R)-(3′-hydro
Xytetradecanoyloxy) methyl] -2,3-dide
Oxy-D-mannopyranose 4-phosphate The anomeric mixture (29 mg) obtained in Example 13 was dissolved in acetic acid (6 ml), and hydrogenated at room temperature for 6 hours under the catalyst of platinum oxide (10 mg). The catalyst was removed by filtration, the solvent was distilled off under reduced pressure, and the residue was dried.
24 mg was obtained as 1). Infrared absorption spectrum ν _max (Nujol): 3300 (broad), 17
20, 1655 cm ^{-1 1} H-NMR spectrum (270 MHz, CDCl ₃ + D ₂ O) δ ppm: 0.88 (6
H, t, J = 6.0-7.0Hz), 1.1-1.7 (40H, m), 2.2-2.8 (5H, m),
3.6-5.0 (10H, m).

Continuation of the front page (51) Int.Cl. ⁷ Identification code FI A61P 35/00 A61P 35/00 37/04 37/04 (72) Inventor Yoshiyuki Kobayashi 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo, Sankyo (72) Inventor Masahiro Nishijima 1-4-29-A-101, Miyamadaira, Miyamae-ku, Kawasaki-shi, Kanagawa Prefecture (72) Inventor Minoru Akamatsu 1-26-21, Shimizu, Suginami-ku, Tokyo (58) Int.Cl. ⁷ , DB name) C07H 13 / 04,15 / 04 A61K 31 / 7024,31 / 7028 A61P 31 / 04,35 / 00,37 / 04 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A compound of the general formula [Wherein, R ¹ and R ⁴ represent a hydrogen atom, —P (O) (OR
⁶ ) _two groups (wherein, R ⁶ represents a hydrogen atom or a phenyl or benzyl group which may have a substituent selected from the following group A on the aromatic ring) or a protecting group for a hydroxyl group. , R ² and R ³ are the same or different and have the formula R ⁷ CH
(OR ⁸ ) CαβCO (wherein, R ⁷ has 7 to 17 carbon atoms)
R ⁸ represents an aliphatic acyl group having 10 to 20 carbon atoms, and α and β are the same or different and represent a hydrogen atom or a halogen atom. ) Represents a substituted aliphatic acyl group having 10 to 20 carbon atoms, and R ⁵ represents a hydrogen atom or a protecting group for a hydroxyl group. ] The compound represented by these. [Group A] an alkyl group having 1 to 4 carbon atoms and an alkoxy group having 1 to 4 carbon atoms. 2. A compound of the general formula [Wherein, R ¹ and R ⁴ represent a hydrogen atom or —P (O) (O
H) ₂ groups, wherein R ² and R ³ are the same or different,
Formula R ⁷ CH (OR ⁸ ) CαβCO (wherein, R ⁷ represents an alkyl group having 7 to 17 carbon atoms, R ⁸ represents an aliphatic acyl group having 10 to 20 carbon atoms, and α and β are the same. Or differently represent a hydrogen atom or a halogen atom.) And a substituted aliphatic acyl group having 10 to 20 carbon atoms, and R ⁵ represents a hydrogen atom. ] The compound represented by these.