JP2535048B2 - Novel disaccharide derivative and its salt - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Field of Application> The present invention relates to compounds represented by the following formulas (I) and (II) and salts thereof.

In the above formula, R is a phosphono group, -ZR ⁶ or Z, Z ¹ and Z ² are each an alkylene group having 1 to 6 carbon atoms, R ⁶ is a carboxyl group or a phosphonoxy group, R ¹ , R ² ,
R ³ and R ⁴ are -COR ⁷ , -COZ ³ R ⁸ , respectively. ^{_{-CO (CH 2) n2 -OCCR 7}} , -CO (CH 2) n2 OCOZ 3 R 8, -CO (CH
^{_{2) n2 -COR 7, -CO (}} CH 2) n2 -COZ 3 R 8, Or R ⁷ is a linear or branched alkyl group having 1 to 30 carbon atoms which may be substituted with one or more hydroxyl groups, Z ³ is an alkylene group having 1 to 9 carbon atoms, R ⁸ Is a cyclic alkyl group having 3 to 12 carbon atoms which may be substituted with one or more hydroxyl groups,
Q is hydrogen, an alkyl group having 1 to 6 carbon atoms, -CONH _2, -COOH
Or -CH ₂ OH, an alkyl group of Q ₁ is hydrogen or a C 1-20, n1 is an integer of 0, is n2, and n3, respectively 20
R ⁵ is hydrogen, a phosphono group or —CO (CH ₂ ) _m COOH
And m means an integer of 0 to 6. However, R is phosphono group or -ZR ^6, is R ⁵ is hydrogen or a phosphono group, and R
Excludes combinations in which ^{1 to} R ⁴ are each -COR ⁷ .

In the above formula, R ¹⁸ is an allyl group, -ZCOOR ¹⁴ , -ZOPO (O
R ¹³ ) ₂ , Or Z, Z ¹ and Z ² are each an alkylene group having 1 to 6 carbon atoms, R ¹⁴ is a protecting group for a carboxyl group which can be eliminated by catalytic reduction, and R ¹³ is a phosphono group which can be eliminated by catalytic reduction. R ¹¹ and R ²¹ are respectively -COR ⁷¹ , -COZ ³ R ⁸¹ , -CO (CH ₂ ) _n2 OCOR ⁷¹ , -CO (CH ₂ ) _n2 OCOZ ³ R ⁸¹ , -CO (CH
₂ ) _n2 COR ⁷¹ , -CO (CH ₂ ) _n2 COZ ³ R ⁸¹ , Or R ⁷¹ is an alkyl group having 1 to 30 carbon atoms, which may be substituted with one or more hydroxyl groups protected by a hydroxyl-protecting group, Z ³ is an alkylene group having 1 to 9 carbon atoms, and R ⁸¹ Is a cyclic alkyl group having 3 to 12 carbon atoms which may be substituted with one or more hydroxyl groups protected by a hydroxyl protecting group, Q ₁ is hydrogen or an alkyl group having 1 to 20 carbon atoms, Q ₂ Is hydrogen, carbon number 1
6 alkyl group, -CONH _2, -COOR ¹⁶ or -CH ₂ OR
⁹¹ , R ¹⁶ is a protective group for a carboxyl group that can be eliminated by catalytic reduction, R ⁹¹ is a protective group for a hydroxyl group that can be eliminated by catalytic reduction, n1 is an integer of 0 to 10, and n2 and n3 are respectively It means an integer of 1 to 20. However, a combination in which R ¹⁸ is an allyl group, —ZCOOR ¹⁴ or —ZOPO (OR ¹³ ) ₂ and R ¹¹ and R ²¹ are each —COR ⁷¹ is excluded.

The compound of formula (I) exhibits excellent antitumor activity and low toxicity, and is useful as an antitumor agent.

Further, the compound of formula (II) is important as an intermediate for the production of the compound of formula (I).

<Prior Art> Natural lipid A has a mitogenic activity, that is, a function of stimulating lymphocytes, stimulating lymphocytes to promote the increase of lymphoid cells and enhancing immune function, and a tumor necrosis factor-inducing effect. It is promising as a prophylactic / therapeutic agent and an antitumor agent for many diseases caused by reduced immune function, for example, various infectious diseases.

As a derivative of the above natural lipid A, JP-A-59-4849.
Those disclosed in Nos. 7, 61-53295 and 61-227586 are known. Among them, 2-deoxy-6-O- {2-
Deoxy-2-[(R) -3-dodecanoyloxytetradecanoylamino] -4-O-phosphono-3-O-
[(R) -3-Tetradecanoyloxytetradecanoyl] -β-D-glucopyranosyl} -3-O-[(R)
-3-Hydroxytetradecanoyl] -2-[(R)-
3-Hydroxytetradecanoylamino] -1-O-phosphono-α-D-glucopyranose (JP-A-61-53295)
It is known that the compound A) has an activity equal to or higher than the physiological activity of natural lipid A (Eur.
J. Biochem., 148 1-5, 1985) is as toxic as natural lipid A and is not practical. Also, compound A
The above-mentioned known compounds other than are also unsatisfactory in toxicity or antitumor activity and are not practical. Therefore, compounds having useful physiological activities and reduced toxicity are desired.

<Problems to be Solved by the Invention> The present inventors have completed the present invention as a result of extensive studies to find a compound having useful physiological activity and low toxicity.

<Structure of the Invention> The present invention relates to a compound of formula (I) and a salt thereof, and formula (II)
And the salts thereof.

Substituents in compounds of formula (I) are detailed below.

The alkylene group means methylene, polymethylene or methylene or polymethylene substituted with an alkyl group having 1 to 5 carbon atoms, and examples thereof include methylene, ethylene, propylene, trimethylene, ethylethylene, tetramethylene and 2-methyltetramethylene. Examples include methylene, 2,3-dimethyltetramethylene, 2-ethyl-3-methylpentamethylene, octamethylene and the like. The alkylene group in formula (I), Z, Z ¹ , Z ² and Z ³ has 1 to 1 carbon atoms.
No. 4 can be mentioned as a preferable one. Examples of the linear or branched alkyl group include methyl, ethyl,
Propyl, tertiary butyl, hexyl, nonyl, decyl,
Examples thereof include 3-ethylundecyl, 3-ethyl-4-methyl-tridecyl, tetradecyl, nonadecyl, tetraeicosyl, 2-ethyl-5-propyl-tetraeicosyl, octaeicosyl and the like. As the alkyl group R ⁷ in the formula (I), those having 5 to 20 carbon atoms can be mentioned as preferable ones. Examples of the cyclic alkyl group include cyclopropyl, cyclobutyl, cycloheptyl,
Cyclohexyl, cycloheptyl, cyclodecyl, cyclododecyl and the like, preferably those having 5 to 8 carbon atoms can be mentioned.

In the formula (I), n1 is an integer of 0 to 5, n2 is
For n3, an integer of 1 to 6 can be mentioned as a preferable one.

The compounds of formula (I) have α and β isomers derived from the substituent OR, and these isomers and mixtures thereof are also included in the present invention. The compound of formula (I) has optical isomers derived from various substituents, and these isomers and mixtures thereof are also included in the present invention.

The salt of the compound of formula (I) includes a phosphoric acid group or a carboxyl group and an organic amine such as triethylamine, pyridine, N-methylamine, N-methylglucamine or an inorganic base such as ammonia, sodium, potassium, calcium or magnesium. I can give you salt.

Preferred compounds of the formula (I) are R
Is ZR ⁶ or And R ^{1 to} R ⁴ are each represented by the formula −COR ⁷ , −COZ ³ R ⁸ , Examples thereof include a compound that is a group represented by —CO (CH ₂ ) _n2 —COR ⁷ or —CO (CH ₂ ) _n2 COZ ³ R ⁸ .

Further, in the compound of the formula (I), as a more preferable compound, R is —ZOPO (OH) ₂ and R ^{1 to} R ⁴ are respectively of the formula —CO.
R ⁷ or A compound that is

Next, the protecting group in formula (II) will be described. Examples of the protective group for the carboxyl group which can be eliminated by catalytic reduction include a benzyl group which may have a substituent such as a halogen atom, a nitro group and a lower alkoxy group. Examples of the phosphono group-protecting group which can be eliminated by catalytic reduction include a phenyl group and a benzyl group which may have a substituent such as a halogen atom, a nitro group and a lower alkoxy group. The protective group for the hydroxyl group may have a substituent such as a halogen atom, a nitro group, a lower alkoxy group, and the like, which can be eliminated by catalytic reduction such as benzyl group, trichloroethoxycarbonyl group, trichlorotertiary butoxycarbonyl group. Etc. can be given.

The compounds of the present invention can be prepared by various methods,
An example is shown below.

[In the formula, R ⁹ represents hydrogen or a protective group of a hydroxyl group which can be eliminated by catalytic reduction, and R ¹⁰ represents −ZCOOR ¹⁴ , −ZOPO (OR ¹³ ) ₂ , Or , R ³¹ is −COR ⁷¹ , −COZ ³ R ⁸¹ , -CO (CH ₂ ) _n2 OCOR ⁷¹ , -CO (CH ₂ ) _n2 OCOZ ³ R ⁸¹ , -CO (CH
₂ ) _n2 COR ⁷¹ , -CO (CH ₂ ) _n2 COZ ³ R ⁸¹ , Or R ⁵¹ is hydrogen, --CO (CH ₂ ) _m COOR ¹⁶ or --PO (OR ¹⁵ )
₂ , R ¹² is a protecting group for a phosphono group which can be eliminated by catalytic reduction, R ¹⁵ is a protecting group for a phosphono group which is capable of leaving by catalytic reduction, R ¹¹ , R ²¹ , R ¹³ R ¹⁶ , R ⁷¹ , R ⁸¹ , Z, Z ¹ , Z ² , Z ³ , Q
₁ , Q ₂ , n1, n2, n3, and m are the same as above. ] That is, the compound (III) is catalytically reduced with a catalyst such as palladium black, palladium carbon, platinum dioxide or the like in an inert solvent such as tetrahydrofuran, methanol, ethanol, acetic acid, water or a mixture thereof in a hydrogen gas atmosphere. Then, the protecting group is removed, and the compound of the formula (I) can be produced by purifying using silica gel chromatography or the like, if necessary. The reduction reaction is usually at room temperature (0 to 30 ° C)
It is carried out at 60 ° C for 1 to 12 hours. The amounts of the solvent and catalyst used are not particularly limited.

In the compound of the above formula (III), the substituent R ¹¹ ,
When R ²¹ or R ³¹ has a hydroxyl-protecting group in its molecule, it is desirable that the protecting group be removable by catalytic reduction.

To the resulting compound of formula (I) is added the required amount of base,
Then, a salt of the compound of formula (I) can be produced by using a precipitation method, a freeze-drying method or the like.

The method for producing the starting compound of the formula (III) shown above differs depending on the kinds of the substituents R ¹⁰ and R ⁵¹ , and they can be shown as follows.

[In the formula, R ¹⁷ represents a hydroxyl-protecting group, and R ⁴¹ represents -COR ⁷¹ , -COZ ³
R ⁸¹ , -CO (CH ₂ ) _n2 OCOR ⁷¹ , -CO (CH ₂ ) _n2 OCOZ ³ R ⁸¹ , -CO (CH
₂ ) _n2 COR ⁷¹ , -CO (CH ₂ ) _n2 COZ ³ R ⁸¹ , Or , R ¹⁹ is -ZCOOR ¹⁴ ,, -ZOPO (OR ¹³ ) ₂ , Or R ²⁰ is —CO (CH ₂ ) _m COOR ¹⁶ or —PO (OR ¹⁵ ) ₂
⁹² means a protective group for a hydroxyl group that can be eliminated by catalytic reduction, and R
¹¹ , R ²¹ , R ³¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁸ , R ⁷¹ , R ⁸¹ , Z, Z ¹ ,
Z ² , Z ³ , Q ₁ , Q ₂ , n1, n2, n3, and m are the same as above. ] The compound of the formula (IV) is dissolved in a solvent that does not participate in the reaction containing hydrogen bromide gas, for example, a single or mixed solvent such as methylene chloride, acetic acid, etc. By reacting, the sugar 1-position acetyl group of the present compound can be replaced with bromine. The obtained bromine substitution product is a dry solvent,
Preferably, it is dissolved in methylene chloride, chloroform, etc., and dehydrated with mercuric cyanide, mercuric bromide, silver carbonate, silver oxide, silver perchlorate, mercuric nitrate alone or a mixture thereof with anhydrous calcium sulfate, etc. The compound of formula (V) can be obtained by condensation with the compound of formula (II) in the presence of an agent for several hours to 2 days under reaction conditions such as room temperature to reflux.

The obtained compound of the formula (V) is added to an organic solvent such as methylene chloride, chloroform, acetonitrile, tetrahydrofuran or the like in the presence of an organic base such as pyridine, 4-dimethylaminopyridine or triethylamine, X—R ²⁰ (X represents a halogen atom). Or with a catalyst such as HO-R ²⁰ and dicyclohexylcarbodiimide in the presence of a catalyst such as 4-dimethylaminopyridine to give a compound of formula (V '). The compounds of the formulas (V) and (V ') thus produced are reacted according to the following production methods (A) to (D) to produce the compounds of the formulas (IIIA) to (III).
D), that is, the starting compound of formula (III) can be prepared.

Method for producing (A) In the formula (V), a compound in which R ¹⁸ is R ¹⁹ is dissolved or suspended in acetic acid, zinc powder is added, and the reaction is carried out to form a protecting group for the 2′-position amino group and R ¹⁷ . Can be detached. The compound of formula (IIIA) can be produced by using the obtained elimination product with R ³¹ —OH and a condensation method commonly used in the field of peptide chemistry.

The reaction for eliminating the protecting group is usually carried out at room temperature for several tens of minutes to 24 hours. Examples of condensation reaction include carbodiimide method, eintop method, active ester method and the like.

In the above elimination reaction, for R ¹⁷ , which is a hydroxyl-protecting group, trichloroethoxycarbonyl and trichlorotertiary butoxycarbonyl are desirable, and substituted R ⁴¹
There is the same as also R ¹⁷ when having a hydroxy-protecting group in the molecule.

(B) the preparation formula (V) R ¹⁸ not is in the same manner as the preparation of the compounds of the allyl group (A) desorbed R ^17, the next 2 'position amino group be bonded to R ³¹ You can The 6'-hydroxyl group of the obtained conjugate was protected with a protective group for the hydroxyl group which can be eliminated by catalytic reduction, and then with an iridium complex such as 1,5-cyclooctadienebis (methyldiphenylphosphine) -iridium hexafluorophosphate. The allyl group can be eliminated by reacting and then hydrolyzing. The obtained detached body A compound of formula (III B) can be prepared by reacting with.

The 6'-hydroxyl group is protected with benzyloxymethyl chloride in an organic solvent such as anhydrous chloroform or anhydrous methylene chloride in the presence of an organic base such as pyridine or diisopropylethylamine at room temperature for 1 to 2 days.
Further, the protection reaction may be carried out by reacting with benzyltrichloroacetimide in the presence of trifluoromethanesulfonic acid at around 0 ° C.

The elimination reaction of the allyl group is usually carried out with an iridium complex in an organic solvent such as methylene chloride, chloroform or tetrahydrofuran at about 50 ° C. for 10 minutes to 3 hours, then water and iodine are added, and the reaction is carried out at room temperature for about 5 to 30 minutes.

The elimination product obtained by the elimination reaction of the allyl group, The reaction with is usually carried out in the presence of butyllithium in an anhydrous aprotic solvent such as anhydrous tetrahydrofuran at -75 ° C to 50 ° C.
It is performed for several tens of minutes at the temperature of.

Production method of (C) By reacting the compound of formula (V ') in the same manner as in the production method of (A) above, the compound of formula (III C) can be produced.

Production method of (D) The compound of formula (IIID) can be produced by reacting the compound of formula (V ') in the same manner as in the production method of (B) above.

Next, a method for producing the raw material compounds of the above formulas (IV) and (II) will be described. The compound of formula (IV) can be produced by a known method or a method disclosed in JP-A-61-53295.

The method for producing the compound of the formula (II) differs depending on the kind of the substituent R ¹⁸ in the formula (II), and they are shown in the following production methods (a) and (b).

[In the above formula, X is a halogen atom, Y is a lower acyl group,
The trichloroethoxycarbonyl group or trichloromethyl tert-butoxycarbonyl, W is -ZOW ^2, -ZCOOW ^3, W ¹ is −ZOW ⁴ , R ²² is -ZOPO (OR ¹³ ) ₂ , -ZCOOR ¹⁴ , Or W ⁷ is -ZOPO (OR ¹³ ) ₂ or , Y ¹ means trichloroethoxycarbonyl or trichlorotertiary butoxycarbonyl, W ² is acetyl, benzoyl, benzyl or p-chlorobenzyl, W ³ is an alkyl group having 1 to 6 carbon atoms or is removed by catalytic reduction. W ⁴ represents hydrogen, benzyl or p-chlorobenzyl, and R ¹¹ , R ²¹ , R ¹³ , R ¹⁴ , Z, Z ¹ and Z ² are the same as the above]. The compound of formula (VII) may be prepared by reacting the compound of formula (IVa) with HOW in the presence of a Lewis acid, or by reacting the compound of formula (VIb) with HOW and mercuric cyanide, silver carbonate, mercury bromide, a peroxide. It can be produced by condensation in the presence of silver chlorate, mercuric nitrate or a mixture thereof. In addition, the formula (VI
In I), the compound in which W is -ZO-acetyl has the formula (VI c)
The compound can be produced by reacting HOZOH with HOZOH in the presence of hydrogen chloride, p-toluenesulfonic acid and the like, and then acetylating.

The compound in which Y is a lower acyl group in the formula (VII) is treated with a Meyerbain's reagent, or the compound in which Y is trichloroethoxycarbonyl or trichlorotertiary butoxycarbonyl in the formula (VII) is present in the presence of hydrochloric acid, acetic acid or the like. A compound of formula (VIII) is produced by treating with lower zinc dust to release the 2-position amino group and then condensing it with R ¹¹ OH using an acid chloride method, a carbodiimide method, an eintop method or an active ester method. be able to.

In formula (VIII), W is -ZCOO-alkyl or A compound of formula (III) is hydrolyzed with sodium hydroxide to eliminate acetyl and alkyl, and the product is then reacted with X--R ^{14 in} the presence of an organic amine such as triethylamine, and other than the above in formula (VIII). The compound of formula (IX) can be produced by a method of hydrolyzing the compound with aqueous ammonia.

The compound of formula (X) can be prepared by protecting the 4- and 6-positions of the compound of formula (IX) with isopropylidene according to a conventional method.

In the formula (X), W ¹ is -ZO-benzyl or -ZO-p.
A compound which is -chlorobenzyl is condensed with R ²¹ OH, then catalytically reduced and then in the presence of an organic amine such as triethylamine, 4-dimethylaminopyridine or pyridine, X-PO (OR ¹³ ).
_{In the} method of reacting with _2, and in the formula (X), W ¹ is —ZCOOR ¹⁴ or A compound of formula (XI) by condensation with R ²¹ OH
Can be produced.

A compound of formula (IIa) is obtained by hydrolyzing a compound of formula (XI) in hydrous acetic acid such as 50-90% aqueous acetic acid or by treating with p-toluenesulfonic acid in methanol, ethanol, water or a mixture thereof. Compounds of can be prepared.

In the formula (IIa), R ²² is -ZOPO (OR ¹³ ) ₂ or The compound (II a ′) which is can be produced as follows.

That is, in the formula (VII), W is -ZO-acetyl, A compound of formula (XII) can be prepared by treating a compound in which Y is trichloroethoxycarbonyl or trichlorotertiary butoxycarbonyl with aqueous ammonia. The compound of formula (XIII) can be obtained by protecting it with isopropylidene. This is condensed with XPO- (OR ¹³ ) _{2 in} the presence of an organic amine and then R ²¹
The compound of formula (XIV) can be prepared by condensation with OH. The compound of formula (XV a) can be produced by removing isopropylidene in the same manner as described above. Y ¹ is eliminated in the same manner as described above, and then condensed with the formula R ¹¹ OH to form the compound of formula (II
The compounds of a ') can be prepared. The compound of formula (XIV) is desorbed to Y ^{1 in the same} manner as described above, and then R ¹¹ OH
A compound of formula (XV b) can be prepared by condensation with The compound of formula (IIa ') can also be produced by removing isopropylidene in the same manner as above.

When R ¹¹ and R ²¹ in the compound of formula (II a ′) are the same substituents, X ¹ is eliminated from the compound of formula (XIII), then a fatty acid is bound, and then isopropylidene It may be detached.

Manufacturing method b (In the formula, Y ¹ , R ²¹ and R ¹¹ are the same as above) The compound of formula (XVII) can be produced by condensing the compound of formula (XVI) with R ²¹ OH in the same manner as above. From this, Y ¹ is desorbed in the same manner as described above, and then R ¹¹ O
The compound of formula (XVIII) can be prepared by condensation with H 2. The compound of formula (II b) can be produced by removing isopropylidene in the same manner as above.

<Effect of the Invention> The compound of formula (I) of the present invention has antitumor activity equivalent to or higher than that of the compound A, and its toxicity is much lower than that of the compound A.

Therefore, the compound of formula (I) of the present invention is excellent as an antitumor agent.

The compound of formula (II) is important as an intermediate for the production of the compound of formula (I).

Hereinafter, the present invention will be further described with reference to Reference Examples, Examples and Test Examples, but the present invention is not limited thereto.

Reference Example 1 Step 1 2-acetoxyethyl 3,4,6-tri-O-acetyl-2-deoxy-2- (2,2,2-trichloroethoxycarbonylamino) -α-D-glucopyranoside 5.00 g of 2- To deoxy-2- (2,2,2-tricrotoethoxycarbonylamino) -D-glucose, 5.0 ml of ethylene glycol and 0.5 ml of dioxane containing hydrogen chloride gas were added, heated to 90 ° C and stirred for 4 hours. To do. The reaction mixture is ice-cooled, 75 ml of pyridine is added, 30.6 g of acetic anhydride is added, and the mixture is stirred. After 20 minutes, return to room temperature and stir for another 16 hours. The reaction solution is poured into 350 ml of ice water and stirred, and the precipitated solid is filtered and washed with water.

The obtained solid was dissolved in chloroform, 1N hydrochloric acid was added,
It is washed successively with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was recrystallized from ethanol to obtain 4.96 g of the title compound as colorless prism-like crystals.

Melting point 138 to 140 ° C ▲ [α] ²⁵ _D ▼ + 74.0 ° C (C 1.2 chloroform) Step 2 2-acetoxyethyl 3,4,6-tri-O-acetyl-2-deoxy-2-tetradecanoylamino- α
-D-Glucopyranoside 9.46 g of the compound obtained in Step 1 is dissolved in 60 ml of acetic acid, 7 g of zinc powder is added little by little while stirring at room temperature, and the mixture is stirred for 1 hour or more. The insoluble matter is filtered off, the solvent is distilled off under reduced pressure, toluene is added to the obtained residue, and the solvent is distilled off under reduced pressure again. The obtained residue is dissolved in dioxane, dioxane containing hydrogen chloride gas is added, the solvent is distilled off under reduced pressure, and then dried.

Dissolve the resulting oil in 70 ml of anhydrous methylene chloride,
Under ice cooling, 2.88 ml of N-methylmorpholine and 3.24 g of tetradecanoic acid chloride were added and the mixture was stirred for 1 hour. After adding 10 ml of methanol and stirring at room temperature for 10 minutes, the mixture is diluted with chloroform and washed successively with 1N hydrochloric acid and saturated saline. After drying over anhydrous sodium sulfate, the solution was evaporated under reduced pressure, and the resulting residue was filtered through a silica gel column (eluting solvent; a mixture of benzene and ethyl acetate (initially 9/1 (v / v) ratio, then 1/1 (Change to (v / v))) to give 4.77 g of the title compound as a colorless oil.

Step 3 2-hydroxyethyl 2-deoxy-2-tetradecanoylamino-α-D-glucopyranoside 4.77 g of the compound obtained in Step 2 was dissolved in 80 ml of anhydrous methanol, and 9 mmol of sodium methylate methanol was added under ice cooling. Add the solution and stir at room temperature for 30 minutes. Tetrahydrofuran is added to dissolve the precipitated insoluble matter, which is then neutralized with a strongly acidic ion exchange resin Dowex-50 (H ⁺ ) and the resin is removed by filtration. The solvent of the filtrate was distilled off under reduced pressure, and the residue obtained was washed with ether and collected by filtration to give the title compound 3.02
g is obtained as a white solid. Recrystallized with ethanol-water.

Melting point 158-160 ° C ▲ [α] ²⁵ _D ▼ + 82.1 ° (C 0.8, tetrahydrofuran:
Water = 4/1 v / v) Step 4 2-hydroxyethyl 2-deoxy-4,6-
O-isopropylidene-2-tetradecanoylamino-
α-D-Glucopyranoside 0.87 g of the compound obtained in Step 3 was dissolved in 20 ml of dimethylformamide, and 0.62 g of 2,2-dimethoxypropane and 38 mg of p-toluenesulfonic acid monohydrate were added at room temperature, and 1.
Stir for 5 hours. Neutralize in a 5% aqueous sodium hydrogen carbonate solution and evaporate the solvent under reduced pressure. The residue is dissolved in ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was applied to a silica gel column (eluting solvent; first a mixed solution of chloroform and acetone 19/1 v / v and then changed to a mixed solution of chloroform and methanol 19/1 v / v). Purified, 0.78 g of the title compound
As a colorless viscous oil.

Step 5 2- (Diphenylphosphonoxy) ethyl 2-deoxy-4,6-O-isopropylidene-2-tetradecanoylamino-α-D-glucopyranoside 0.77 g of the compound obtained in Step 4 was dissolved in 15 ml of anhydrous methylene chloride. It is then dissolved in, and under ice cooling, 0.48 g of diphenylphosphorochloridate, 0.19 ml of pyridine and 0.30 g of dimethylaminopyridine are added, and the mixture is stirred for 1 hour. After returning to room temperature and stirring for 1 hour, 0.17 g of diphenylphosphorochloridate is added and stirred for 30 minutes. 3 ml of methanol was added to the reaction solution, the mixture was stirred for a while, and the solvent was distilled off under reduced pressure. The residue is a silica gel column (elution solvent; chloroform: acetone = 19/1, v
/ v) to give 0.81 g of the title compound as a colorless viscous oil.

Step 6 2- (diphenylphosphonoxy) ethyl 2-deoxy-3-O- (N-dodecanoylglycyl) -2-
Tetradecanoylamino-α-D-glucopyranoside 0.51 g of the compound obtained in Step 5 was dissolved in 5 ml of anhydrous methylene chloride, and 0.22 g of N-dodecanoylglycine, 44m under ice cooling.
Dimethylaminopyridine (g) and dicyclohexylcarbodiimide (0.18 g) were added, and the mixture was stirred under ice cooling for 30 minutes and then returned to room temperature and stirred for 2 hours. The insoluble matter is filtered off, the filtrate is washed successively with 1N hydrochloric acid, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and 20 ml of the residue was obtained.
Add 90% aqueous acetic acid and stir for 30 minutes while heating to 90 ° C. The solvent was distilled off under reduced pressure, toluene was added to the residue and the solvent was distilled off under reduced pressure twice. The residue obtained was a silica gel column (eluting solvent; first a mixture of chloroform and acetone (19/1, v / v ) And changed to a mixed solution of chloroform and methanol (19/1, v / v)) to purify the title compound.
51 g are obtained as a colorless oil.

▲ [α] ²⁵ _D ▼ + 46.2 ° (C 1.1, chloroform) NMR (CDCl ₃ ), δ (ppm): 0.88 (6H, t), 1.26 (S), 2.07 (2H.t), 2.27 (2H ,
t), 4.84 (1H, d), 5.18 (1H, m), 7.2 to 7.4 (10H, m) Reference Example 2 Step 1 2-hydroxyethyl 2-deoxy-2-
(2,2,2-Trichloroethoxycarbonylamino) -α
-D-glucopyranoside 5.05 g of the compound obtained in Step 1 of Reference Example 1 was added to 6 ml of 28%
Suspend in aqueous ammonia and 120 ml of methanol and stir at room temperature for 8 hours. The reaction solution is concentrated under reduced pressure to obtain 3.50 g of the title compound as a carmel-like substance.

NMR (CDCl ₃ -CD ₃ OD, about 1: 1), δ (ppm): 4.78 (2H, s), 4.90 (1H, d) Step 2 2-hydroxyethyl 2-deoxy-4,6-
O-isopropylidene-2- (2,2,2-trichloroethoxycarbonylamino) -α-D-glucopyranoside 3.58 g of the compound obtained in Step 1 was treated in the same manner as in Step 4 of Reference Example 1 to obtain N-Hexane was added to the target fraction, and the precipitated solid was collected by filtration to give the title compound (2.78 g) as a white powder.

Melting point 190-192 [deg.] C. Step 3 2- (Diphenylphosoxy) ethyl 2-deoxy-4,6-Oisopropylidene-2- (2,2,2-trichloroethoxycarbonylamide)-[alpha] -D-glucopyranoside Step 2 1.12 g of the compound obtained in 1. was treated in the same manner as in Step 5 of Reference Example 1, and the obtained target fraction was treated with ether and n-
Hexane was added and the precipitated solid was collected by filtration to give the title compound (1.23 g)
Get.

Melting point 121 to 124 ° C ▲ [α] ²⁵ _D ▼ + 46.4 ° (C 1.0, chloroform) Step 4 2- (diphenylphosphonoxy) ethyl 2-deoxy-4,6-O-isopropylidene-3-O- Tetradecanoyl-2- (2,2,2-trichloroethoxycarbonylamino) -α-D-glucopyranoside 0.50 g of the compound obtained in Step 3 was dissolved in 10 ml of anhydrous methylene chloride, and 0.30 ml of pyridine under ice cooling, Add 0.22 g of tetradecanoic acid chloride and 20 mg of dimethylaminopyridine and stir for 2 hours. Add 2 ml of methanol, stir at room temperature for a while, and concentrate under reduced pressure. The obtained residue is purified by silica gel column (eluent: chloroform containing 2% acetone, then chloroform containing 5% acetone) to obtain 0.49 g of the title compound as a colorless oil.

▲ [α] ²⁵ _D ▼ + 36.1 ° (C 1.0, chloroform) Step 5 2- (diphenylphosphonoxy) ethyl 2-deoxy-2- (N-dodecanoylglycylamino) -4,
6-O-isopropylidene-3-O-tetradecanoyl-α-D-glucopyranoside 0.47 g of the compound obtained in step 4 is dissolved in 12 mln of acetic acid, 0.5 g of zinc powder is suspended, and at room temperature for about 1.5 hours. Stir. The insoluble matter is removed by filtration, washed with chloroform, and the solvent is evaporated under reduced pressure. The residue was dissolved in chloroform, washed successively with 5% aqueous sodium hydrogen carbonate solution and saturated brine,
Dry over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure,
The obtained oily substance was dissolved in 8 ml of anhydrous methylene chloride to give 0.2
Add 1 g of N-dodecanoylglycine. 0.17 g under ice cooling
Dicyclohexylcarbodiimide of (3) and 32 mg of dimethylaminopyridine are added, and after 20 minutes, the mixture is returned to room temperature and reacted with stirring for 15 hours.

The insoluble material was removed by filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by a silica gel column (eluent: chloroform containing 2 to 10% acetone). The target fraction was treated with n-hexane to give the title. 0.48 g of compound is obtained as a white powder.

Melting point 79-80 ° C. [α] ²⁵ _D ▼ + 28.1 ° (C 1.1, chloroform) Step 6 2- (diphenylphosphonoxy) ethyl 2-deoxy-2- (N-dodecanoylglycylamino) -3
-O-Tetradecanoyl-α-D-glucopyranoside 0.45 g of the compound obtained in Step 5 is dissolved in 20 ml of 90% acetic acid aqueous solution, heated to 90 ° C and stirred for 30 minutes. The solvent was distilled off under reduced pressure, toluene was added to the residue, and the procedure of distilling off under reduced pressure was repeated to obtain a residue.
Purification with chloroform containing% acetone and then with a mixed solution of chloroform: methanol = 19: 1) gives 0.39 g of the title compound as a white waxy solid.

▲ [α] ²⁵ _D ▼ + 36.1 ° (C 1.1, chloroform) NMR (CDCl ₃ ), δ (ppm): 0.90 (6H, t), 1.28 (S), 2.13 (2H.m), 2.36 (2H ,
t), 4.90 (1H, d), 7.2 to 7.5 (10H, m) Reference Example 3 Step 1 2- (diphenylphosphonoxy) ethyl 2-deoxy-4,6-O-isopropylidene-3-O- ( N-
Dodecanoylglycyl) -2- (2,2,2-trichloroethoxycarbonylamino) -α-D-glucopyranoside 1.89 g of the compound obtained in Step 3 of Reference Example 2 was dissolved in 20 ml of anhydrous methylene chloride and cooled under ice-cooling. 0.83 g of N-dodecanoylglycine, 0.17 g of dimethylaminopyridine and 0.6
After adding 7 g of dicyclohexylcarbodiimide, after 30 minutes, the mixture was returned to room temperature and stirred for 1 hour. The insoluble material was removed by filtration, and the residue obtained by concentrating the filtrate under reduced pressure was used as a silica gel column (elution solvent:
Purification with chloroform: acetone = 10: 1) gives 2.80 g of the title compound as a colorless oil.

▲ [α] ²⁵ _D ▼ + 32.2 ° (C 0.8, chloroform) Step 2 2- (diphenylphosphonoxy) ethyl 2-deoxy-3-O- (N-dodecanoylglycyl) -2-
[6- (Octanoylamino) hexanoylamino]-
α-D-Glucopyranoside 0.71 g of the compound obtained in Step 1 is dissolved in 10 ml of acetic acid, 0.5 g of zinc powder is added with stirring at room temperature, and the mixture is stirred for 2 hours. Insoluble matter is removed by filtration, washed with chloroform,
The solvent is distilled off under reduced pressure. The obtained residue is dissolved in chloroform, washed successively with a 5% aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure to obtain an oily substance.

On the other hand, 0.26 g of 6- (octanoylamino) caproic acid was dissolved in 7 ml of anhydrous tetrahydrofuran, and the solution was cooled to 0.1 under ice-cooling.
6 g of 1-hydroxybenzotriazole and 0.21 g of dicyclohexylcarbodiimide were added, and the mixture was gradually warmed to room temperature and stirred for 3 hours. The precipitated insoluble matter is removed by filtration, the filtrate and the oily substance obtained above are mixed under ice-cooling, then returned to room temperature and stirred for 4 hours. The solvent is evaporated, 20 ml of 90% acetic acid aqueous solution is added to the obtained residue, the mixture is heated to 90 ° C. and stirred for 20 minutes. The solvent was distilled off under reduced pressure and the obtained residue was a silica gel column (elution solvent; first chloroform: acetone = 1).
Purification with 0: 1, then chloroform: methanol = 20: 1, and finally chloroform: methanol = 10: 1) gives 0.56 g of the title compound as a colorless wax.

▲ [α] ²⁵ _D ▼ + 31.2 ° (C 1.1, chloroform) NMR (CDCl ₃ ), δ (ppm): 0.88 (6H, t), 2.0 to 2.4 (6H, m), 4.85 (1H, d) , 7.2
-7.4 (10H, m) Reference Example 4 2- (diphenylphosphonoxy) ethyl 2-deoxy-3-O- (N-dodecanoyl-6-methylglycyl)
2-[(N-dodecanoyl-N-methylglycyl) amino] -α-D-glucopyranoside 1.00 g of the compound obtained in Step 3 of Reference Example 2 was dissolved in 10 ml of acetic acid, and 0.5 g of zinc powder was stirred with stirring at room temperature. Add 2.
Stir for 5 hours. The insoluble matter is removed by filtration, washed with chloroform, and the solvent is evaporated under reduced pressure. The obtained residue is dissolved in chloroform, washed successively with a 5% aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate.
The oily substance obtained by distilling off the solvent under reduced pressure and 1.21 g of N-dodecanoyl-N-methylglycine were dissolved in 10 ml of anhydrous methylene chloride, and 90 mg of dimethylaminopyridine and
0.92 g of dicyclohexylcarbodiimide is added, and the mixture is returned to room temperature and stirred for 3 hours. The precipitated insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the oily substance obtained was purified by silica gel column (elution solvent; chloroform: acetone = 9: 1, then chloroform: methanol = 19: 1) to give an oily substance. obtain. The oil obtained is then dissolved in 40 ml of 90% aqueous acetic acid, heated to 90 ° C. and stirred for 30 minutes. The solvent is distilled off under reduced pressure and the obtained residue is purified by a silica gel column (elution solvent; chloroform: methanol = 50: 1 and then 20: 1) to obtain 0.87 g of the title compound as an oily substance.

▲ [α] ²⁵ _D ▼ + 34.9 (C 1.0, chloroform) NMR (CDCl ₃ ), δ (ppm): 0.89 (6H, t), 1.28 (s), 2.36 (4H.m), 2.84 and 3.00
(Total 3H, each s), 3.13 and 3.15 (total 3H, each s) 4.45 (2H,
m), 4.87 (1H, d), 7.2 to 7.4 (10H, m) Reference Example 5 Step 1 2- (diphenylphosphonoxy) ethyl 2-deoxy-3-O-tetradecanoyl-2- (2,2) , 2-Trichloroethoxycarbonylamino) -α-D-glucopyranoside 0.50 g of the compound obtained in Step 3 of Reference Example 2 and 0.22 g of tetradecanoic acid were dissolved in 15 ml of anhydrous methylene chloride, and 0.12 g of dimethylaminopyridine under ice cooling. And 0.20 g of dicyclohexylcarbodiimide are added, and the mixture is returned to room temperature and stirred for 2 hours.

The precipitated insoluble matter is filtered off, the filtrate is concentrated under reduced pressure, and the resulting oily substance is purified by a silica gel column (elution solvent; chloroform: acetone = 10: 1) to give an oily substance. The oil obtained is then added to 10 ml of 90% aqueous acetic acid, heated to 90 ° C. and stirred for 25 minutes. The solvent was distilled off under reduced pressure and the resulting residue was subjected to silica gel chromatography (elution solvent; chloroform: acetone = 10: 1, then chloroform: methanol = 10:
Purification in 1) gives 0.61 g of the title compound as an oil.

▲ [α] ²⁵ _D ▼ + 43.0 ° (C 1.2, chloroform) Step 2 2- (diphenylphosphonoxy) ethyl 2-deoxy-2 [(N-decanoyl-D-isoglutaminyl) amino] -3-O- Tetradecanoyl-α-D-glycopyranoside 0.47 g of the compound obtained in Step 1 was treated with zinc powder in an acetic acid solution in the same manner as in Step 2 of Reference Example 3, and then N was similarly added.
The reaction with dodecanoyl-D-isoglutamine gives 0.36 g of the title compound as a white waxy substance.

▲ [α] ²⁵ _D ▼ + 38.7 ° (C 0.1, chloroform) NMR (CDCl ₃ ), δ (ppm): 0.88 (6H, t), 1.26 (s), 2.1 to 2.5 (6H, m), 4.96
(1H, d), 5.18 (1H, d), 7.2 to 7.5 (10H, m) Reference Example 6 Step 1 1,3- (diethoxycarbonyl) isopropyl 2-deoxy-3,4,6-O-acetyl- 2- (2,2,2-
Trichloroethoxycarbonylamino) α-D-glucopyranoside 8.00 g of 1,3,4,6-tetra-O-acetyl-2-deoxy-2- (2,2,2-trichloroethoxycarbonylamino) -D-glucopyranose 25% hydrogen bromide-acetic acid solution cooled at room temperature is added to and stirred for 1 hour. The mixture is diluted with chloroform, washed with a 5% aqueous sodium hydrogen carbonate solution and a saturated saline solution in that order, and dried over anhydrous magnesium sulfate.

The residue obtained by distilling off the solvent under reduced pressure was dissolved in 72 ml of anhydrous methylene chloride, and under ice cooling, 8 g of anhydrous calcium sulfate, 4.12 g of silver perchlorate suspended in 40 ml of anhydrous benzene, and 6.24 g of diethyl- Add 3-hydroxyglutarate.

After reacting for 3 hours at room temperature, a 5% aqueous sodium hydrogen carbonate solution is added to neutralize. The insoluble matter is filtered off, the filtrate is washed with water and then dried over anhydrous magnesium sulfate.

The solvent was distilled off under reduced pressure, and the obtained residue was purified by a silica gel column (elution solvent; chloroform: acetone = 30: 1) to obtain 7.36 g of the title compound as an oil.

▲ [α] ²⁵ _D ▼ + 42.8 ° (C 0.7, chloroform) Step 2 1,3- (diethoxycarbonyl) isopropyl 2-deoxy-2-tetradecanoylamino-3,4,6
-Tri-O-acetyl-α-D-glucopyranoside The compound (4.00 g) obtained in Step 1 was treated with zinc powder in an acetic acid solution in the same manner as in Step 2 of Reference Example 3 and then reacted with tetradecanoic acid to give the title compound. An oil of 3.78 g of compound is obtained.

▲ [α] ²⁵ _D ▼ + 46.9 ° (C 0.16, chloroform) Step 3 1,3- (dibedyloxycarbonyl) isopropyl 2-deoxy-2-tetradecanoylamino-α
-D-Glucopyranoside 1.80 g of the compound obtained in step 2 is dissolved in 30 ml of dioxisan and 10 ml of water is added. The mixture is cooled to 5 ° C, 15 ml of 1N potassium hydroxide aqueous solution is added, and the mixture is stirred for 6 hours.

The residue obtained by concentration to dryness under reduced pressure is suspended in 100 ml of dimethylformamide, and 1 ml of benzyl bromide is added. After stirring for 3 hours at 40 ° C., most of the dimethylformamide is distilled off under reduced pressure and the resulting residue is extracted with benzene.
The benzene layer is washed successively with 5% aqueous citric acid solution, saturated saline solution, 5% aqueous sodium hydrogen carbonate solution and saturated saline solution, and dried over anhydrous magnesium sulfate.

The solvent was distilled off under reduced pressure and silica gel chromatography (eluting solvent: chloroform: methanol: acetone = 50: 1: 5 and then 50:
1:15) to give 0.65 g of the title compound as a white waxy solid.

▲ [α] ²⁵ _D ▼ + 13.2 ° (C 0.51, chloroform) Step 4 1,3- (dibenzyloxycarbonyl) isopropyl 2-deoxy-4,6-O-isopropylidene-
2-Tetradecanoylamino-α-D-glucopyranoside 0.64 g of the compound obtained in step 3 was dissolved in 10 ml of acetone and treated in the same manner as in step 4 of Reference Example 1 to give the title compound.
54 g are obtained as an oil.

▲ [α] ²⁵ _D ▼ + 3.3 ° (C 0.7, chloroform) Step 5 1,3- (dibenzyloxycarbonyl) isopropyl 2-deoxy-3-O-tetradecanoyl-2
-Tetradecanoylamino-α-D-glucopyranoside 0.48 g of the compound obtained in Step 4 was reacted with tetradecanoic acid in the same manner as in Step 6 of Reference Example 1 and treated with a 90% aqueous acetic acid solution to give 0.53 g of the title compound in white. As a waxy solid.

▲ [α] ²⁵ _D ▼ + 32.8 ° (C 0.9, chloroform) NMR (CDCl ₃ ), δ (ppm): 0.88 (6H, t), 1.26 (s), 4.94 (1H), 5.20 (4H,
s), 7.40 (10H, s) Reference Example 7 1,3- (Dibenzyloxycarbonyl) isopropyl 2-deoxy-3-O- (N-dodecanoylglycyl) -2-tetradecanoylamino-α-D -Glucopyranoside 0.60 g of the compound obtained in Step 4 of Reference Example 6 was used in Reference Example 1
After reacting with N-dodecanoylglycine in the same manner as in step 6 above, the mixture was treated with a 90% aqueous acetic acid solution to obtain 0.63 g of the title compound as a waxy solid.

▲ [α] ²⁵ _D ▼ + 36.9 ° (C 1.3, chloroform) NMR (CDCl ₃ ), δ (ppm): 0.89 (6H, t), 1.26 (s), 2.1 to 2.3 (4H, m), 2.5 ~
2.9 (4H, m), 4,50 (1H, m), 4.97 (1H, d), 5.70 (1H, m)
m), 5.18 (4H), 7.40 (10H, s) Reference Example 8 Step 1 2-acetoxyethyl 3,4,6-tri-O-acetyl-2-deoxy-2- [6- (octanoylamino) hexa Noylamino] -α-D-glucopyranoside 3.00 g of the compound obtained in Step 1 of Reference Example 1 is used in Reference Example 2
After treatment with zinc powder in acetic acid solution as in step 5 of
By reacting with-(octanoylamino) caproic acid, 2.84 g of the title compound is obtained as a waxy solid.

▲ [α] ²⁵ _D ▼ + 55.4 ° (C 1.1, chloroform) Step 2 2-Hydroxyethyl 2-deoxy-2-
[6- (Octanoylamino) hexanoylamino]-
α-D-Glucopyranoside 2.82 g of the compound obtained in Step 1 is treated in the same manner as in Step 3 of Reference Example 1 to obtain 1.66 g of the title compound as a white powder.

Melting point 156-157 ° C ▲ [α] ²⁵ _D ▼ + 78.8 ° (C 0.9, ethanol) Step 3 2-hydroxyethyl 2-deoxy-4,6-
O-isopropylidene-2- [6- (octanoylamino) hexanoylamino] -α-D-glucopyranoside 1.60 g of the compound obtained in Step 2 was treated in the same manner as in Step 4 of Reference Example 1 to give the title compound. 1.48 g of oil are obtained.

▲ [α] ²⁵ _D ▼ + 35.2 ° (C 1.0, chloroform) Step 4 2- (diphenylphosphonoxy) ethyl 2-deoxy-4,6-O-isopropylidene-2- [6- (octanoylamino) ) Hexanoylamino] -α-D-glucopyranoside 1.26 g of the compound obtained in Step 3 is treated in the same manner as in Step 5 of Reference Example 1 to obtain 1.35 g of the title compound as an oil.

▲ [a] ²⁵ _D ▼ + 26.7 ° (C 1.2, chloroform) Step 5 2- (diphenylphosphonoxy) ethyl 2-deoxy-3-O-dodecanoyl-2- [6- (octanoylamino) hexanoyl Amino] -α-D-glucopyranoside 0.65 g of the compound obtained in Step 4 was reacted with dodecanoic acid in the same manner as in Step 6 of Reference Example 1 and then heat-treated with a 90% aqueous acetic acid solution to obtain 0.73 g of the title compound as an oily substance. obtain.

▲ [α] ²⁵ _D ▼ + 37.3 (C 1.1, chloroform) NMR (CDCl ₃ ), δ (ppm): 0.89 (6H, m), 2.10 (4H.m), 2.33 (2H, m), 3.20 ( 2
H, m), 4.30 (1H, m), 4.46 (2H, m) 4.85 (1H, d), 5.1
0 (1H, m) In the same manner as in the methods of Reference Examples 1 to 8, the following formula (IIIa)
A compound of Reference Example represented by

Example 1 Step 1 2- (Diphenylphosphonoxy) ethyl 2-deoxy-6-O- [2-deoxy-4-O-diphenylphosphono-3-O- (N-dodecanoylglycyl) -6- O- (2,2,2-trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) -β-D-glucopyranosyl] -3-O- (N-
Dodecanoylglycyl) -2-[(N-dodecanoyl-
N-methylglycyl) amino] -α-D-glucopyranoside 370 mg of 1-O-acetyl-2-deoxy-4-O-
Diphenylphosphono-3-O- (N-dodecanoylglycyl) -6-O- (2,2,2-trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) -D- Glucopyranose was dissolved in 2 ml of anhydrous methylene chloride and cooled to room temperature in 6 ml of cooled 25% hydrogen bromide.
Add acetic acid solution and stir for 1 hour. The mixture is diluted with chloroform, washed successively with ice-water, 5% aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure and 344 mg of 2- (diphenylphosphonoxy) ethyl 2-deoxy-3-O- (N-dodecanoylglycyl) -2-[(N-dotecanoyl-N
-Methylglycyl) amino] -α-D-glucopyranoside was dissolved in 5 ml of anhydrous methylene chloride, 0.5 g of activated calcium sulfate and 182 mg of mercuric cyanide were added, and the mixture was added to 50-60%.
Heat to ℃ and stir for 3 hours. The insoluble matter is removed by filtration through Celite, and the filtrate is washed successively with a 5% aqueous potassium iodide solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was applied to a silica gel column (elution solvent, first chloroform: acetone = 10: 1, then chloroform: methanol = 50: 1, finally chloroform: methanol = 20: 1). Purification gives 599 mg of the title compound as an oil.

▲ [α] ²⁵ _D ▼ + 20.0 ° (C 1.0, chloroform) Step 2 2- (diphenylphosphonoxy) ethyl 2-deoxy-6-O- {2-deoxy-4-O-
(Diphenylphosphono) -3-O- (N-dodecanoylglycyl) -2-[(N-dodecanoyl-N-methylglycyl) amino] -β-D-glucopyranosyl} -3-
O- (N-dodecanoylglycyl) -2-[(N-dodecanoyl-N-methylglycyl) amino] -α-D-glucopyranoside The compound (587 mg) obtained in Step 1 was dissolved in 8 ml of acetic acid to give 0.6 g.
The zinc powder of 1. is suspended and stirred at room temperature for 2 hours. The insoluble matter is removed by filtration, washed with chloroform, and the solvent is distilled off under reduced pressure. The residue is dissolved in toluene and the solvent is distilled off three times. The residue obtained is dissolved in chloroform. The chloroform layer is washed successively with 1N hydrochloric acid, 5% aqueous sodium hydrogen carbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure to obtain an oily substance.

On the other hand, 122 mg of N-dodecanoyl-N-methylglycine was dissolved in 3 ml of anhydrous tetrahydrofuran, and 77 mg of 1-
Add hydroxybenzotriazole and 103 mg dicyclohexylcarbodiimide and stir. After 30 minutes, the mixture was returned to room temperature and stirred for 3 hours, and the precipitated crystals were removed by filtration.
The above oily substance is dissolved in 5 ml of anhydrous methylene chloride, and the filtrate is added under ice cooling. Return to room temperature and stir for 1 hour 30 minutes. The reaction solution is diluted with chloroform, washed with 1N hydrochloric acid, dried over anhydrous sodium sulfate, and the solvent is evaporated. The obtained residue was purified by a silica gel column (eluent: first chloroform: acetone = 10: 1, then chloroform: methanol = 50: 1, finally chloroform: methanol = 20: 1) to obtain 445 mg of the title compound. Obtained as an oil.

▲ [α] ²⁵ _D ▼ + 19.2 ° (C 1.0, chloroform) Step 3 2-phosphonoxyethyl 2-deoxy-6-
O- {2-deoxy-3-O- (N-dodecanoylglycyl) -2-[(N-dodecanoyl-N-methylglycyl) amino] -4-O-phosphono-β-D-glucopyranosyl} -3- O- (N-dodecanoylglycyl) -2
[(N-dodecanoyl-N-methylglycyl) amino]
-Α-D-Glucopyranoside 424 mg of the compound obtained in Step 2 is dissolved in a mixture of 50 ml of tetrahydrofuran and 2.5 ml of water, 0.2 g of platinum dioxide is added, and the mixture is stirred for 2 hours with a steam flow. The catalyst is filtered off and the residue is washed with a mixture of chloroform: methanol: water (8: 3: 1 lower layer). The filtrate and washings are combined, the solvent is removed under reduced pressure, and the resulting residue is purified by thin-layer chromatography [eluting solvent: chloroform: methanol: water = 6: 4: 0.7 (v / v)]. , Strongly acidic ion exchange resin Dowex 50 (H
⁺ Type, manufactured by Dow Chemical Co., Ltd.).

The solvent was distilled off under reduced pressure and the obtained residue was suspended in dioxane and freeze-dried to obtain 204 mg of the title compound as a white powder.

Melting point 165-170 ° C (gradually becomes a colored candy-like) ▲ [α] ²⁵ _D ▼ + 4.6 ° (C 0.7, chloroform: methanol = 3: 1 (v / v)) NMR (CDCl ₃ −CD ₃ OD), δ (ppm): 0.90 (12H, t), 1.30 (s), 2.29 (4H.m), 2.44 (4H, t)
t), 2.94 and 3.11 (total 6H, each s), 4.84 (1H, d), 5.18 (1
H, m), 5.34 (1H, m) Part of the title compound was chloroform-methanol (3:
Dissolve in the mixture of 1), adjust to about pH 9 with triethylamine, and concentrate under reduced pressure. The obtained residue is dissolved in 0.1% triethylamine aqueous solution, filtered through a Millipore filter, and then freeze-dried to obtain the triethylamine salt of the title compound as a white powder.

Example 2 Step 1 2- (Diphenylphosphonoxy) ethyl 2-deoxy-6-O- [2-deoxy-4-O-diphenylphosphono-3-O- (N-dodecanoylglycyl) -6- O- (2,2,2-trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) -β-D-glucopyranosyl] -2- [6- (octanoylamino) hexanoylamino] -3-O-Tetraganoyl-α-D-glucopyranoside 445 mg 1-O-acetyl-2-deoxy-4-O-
Diphenylphosphono-3-O- (N-dodecanoylglycyl) -6-O- (2,2,2-trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) -D- Glucopyranose and 385 mg of 2- (diphenylphosphonoxy) ethyl 2-deoxy-2- [6
-(Octanoylamino) hexanoylamino] -3-
O-tetradecanoyl-α-D-glucopyranoside was treated in the same manner as in Step 1 of Example 1 to give the title compound 65.
0 mg of oil is obtained.

▲ [α] ²⁵ _D ▼ + 22.2 ° (C 1.0, chloroform) Step 2 2- (diphenylphosphonoxy) ethyl 2-deoxy-6-O- [2-deoxy-4-O-diphenylphosphono-3 -O- (N-dodecanoylglycyl) -2-tetradecanoylamino-β-D-glucopyranosyl] -2- [6- (octanoylamino) hexanoylamino] -3-O-tetradecanoyl-α -D-
Glucopyranoside 620 mg of the compound obtained in step 1 was dissolved in 10 ml of acetic acid to give 1.5
g zinc powder is suspended and stirred at room temperature for 3 hours. The insoluble matter is removed by filtration, the solvent is evaporated under reduced pressure, and the obtained residue is dissolved in chloroform. It is washed successively with 1N hydrochloric acid, water, 5% aqueous sodium hydrogen carbonate and water, and dried over anhydrous magnesium sulfate. The residue obtained by concentrating the solvent under reduced pressure was dissolved in 10 ml of anhydrous tetrahydrofuran, and under ice cooling, 98 mg of tetradecanoic acid, 58 mg of 1-hydroxybenzotriazole and
Add 90 mg of dicyclohexylcarbodiimide, gradually warm to room temperature and stir overnight. The precipitated insoluble matter is removed by filtration, and the residue obtained by concentration under reduced pressure is purified by silica gel chromatography (elution solvent; chloroform: acetone = 10: 1, then chloroform: methanol = 30: 1) and powdered from acetonitrile. This gives 428 mg of the title compound as a white powder.

Melting point 105-107 ° C. [α] ²⁵ _D ▼ + 24.7 (C 1.0, chloroform) Step 3 2-phosphonoxyethyl 2-deoxy-6-
O- [2-deoxy-4-O-phosphono-3-O- (N
-Dodecanoylglycyl) -2-tetradecanoylamino-β-D-glucopyranosyl] -2- [6- (octanoylamino) hexanoylamino] -3-O-tetradecanoyl-α-D-glucopyranoside step 350 mg of the compound obtained in 2 is treated in the same manner as in Step 3 of Example 1 to obtain 162 mg of the title as a white powder.

Melting point 169-172 ° C (colors to form a candy). ▲ [α] ²⁵ _D ▼ + 19.5 ° (C 0.6, chloroform: methanol = 3: 1 (v / v)) NMR (CDCl ₃ ), δ (ppm): 0.90 (12H, t), 1.30 (s), 2.1 to 2.4 (10H, m), 3.19 (2
H, t), 5.17 (1H, t), 5.38 (1H, t) The title compound is treated as in Step 3 of Example 1 to give the triethylamine salt of the title compound as a white powder.

Example 3 Step 1 2- (Diphenylphosphonoxy) ethyl 2-deoxy-6-O- [2-deoxy-4-O-diphenylphosphono-3-O- (4-oxotetradecanoyl) -6- O- (2,2,2-trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) -β-D-glucopyranosyl] -3-O- (4
-Oxotetradecanoyl) -2-tetradecanoylamino-α-D-glucopyranoside 435 mg of 1-O-acetyl-2-deoxy-4-O-
Diphenylphosphono-3-O- (4-oxotetradecanoyl) -6-O- (2,2,2-trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) D-gluco Pyranose and 380 mg of 2- (diphenylphosphonoxy) ethyl 2-deoxy-3-O-
(4-Oxotetradecanoyl) -2-tetradecanoylamino-α-D-glucopyranoside was treated in the same manner as in Step 1 of Example 1 to obtain 516 mg of the title compound as an oil.

▲ [α] ²⁵ _D ▼ + 14.7 ° (C 0.3, chloroform) Step 2 2- (diphenylphosphonoxy) ethyl 2-deoxy-6-O- [2-deoxy-4-O-diphenylphosphono-3 -O- (4-oxotetradecanoyl) -2-tetradecanoylamino-β-D-glucopyranosyl] -3-O- (4-oxotetradecanoyl) -2-tetradecanoylamino-α-D- Glucopyranoside 510 mg of the compound obtained in step 1 was dissolved in 5 ml of acetic acid to give 0.5 g.
The zinc powder of 1. is suspended and stirred at room temperature for 1 hour and 30 minutes. The insoluble matter is removed by filtration, the filtration is evaporated under reduced pressure, and the obtained residue is diluted with chloroform. It is washed successively with 1N hydrochloric acid, 5% aqueous sodium hydrogen carbonate and water, and dried over anhydrous sodium sulfate. The oily substance obtained by distilling off the solvent under reduced pressure was dissolved in 2 ml of anhydrous methylene chloride, 88 mg of tetradecanoic acid chloride and 2 ml of N-methylmorpholine were added under ice cooling,
Stir for 30 minutes at the same temperature.

It is diluted with chloroform, washed with 1N hydrochloric acid and water, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under pressure is purified by a silica gel column (elution solvent; chloroform, then chloroform: methanol = 20: 1) to obtain an oily substance of 229 mg of the standard compound.

▲ [α] ²⁵ _D ▼ + 17.3 ° (C 0.2, chloroform) Step 3 2-phosphonoxyethyl 2-deoxy-6-
O- [2-deoxy-4-O-phosphono-3-O- (4
-Oxotetradecanoyl) -2-tetradecanoylamino-β-D-glucopyranosyl] -3-O- (4-oxotetradecanoyl) -2-tetradecanoylamino-α-D-glucopyranoside Obtained in Step 2 The compound 225 mg was treated in the same manner as in Step 3 of Example 1 to obtain 91 mg of the title compound as a white powder.

Melting point 166-170 ° C (colors to form a candy) ▲ [α] ²⁵ _D ▼ + 11.0 ° (C 0.3, chloroform: methanol = 3: 1 (v / v)) NMR (CDCl ₃ −CD ₃ OD), δ (ppm): 0.88 (12H, t), 1.26 (s), 2.22 (4H.m), 2.54 (4H, t)
t), 2.64 (4H, m), 2.76 (4H, m), 5.16 (1H, t), 5.30 (1
H, t) The title compound is treated as in Step 3 of Example 1 to give the triethylamine salt of the title compound as a white powder.

Example 4 Step 1 Benzyloxycarbonylmethyl 2-deoxy-6-O- [2-deoxy-4-O-diphenylphosphono-3-O- (N-dodecanoylglycyl) -6-O
-(2,2,2-Trichloroethoxycarbonyl) -2-
(2,2,2-trichloroethoxycarbonylamino) -β
-D-glucopyranosyl] -3-O-tetradecanoyl-2-tetradecanoylamino-α-D-glucopyranoside 303 mg of 1-O-acetyl-2-deoxy-4-O-
Diphenylphosphono-3-O- (N-dodecanoylglycyl) -6-O- (2,2,2-trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) -D- Glucopyranose and 217 mg of benzyloxycarbonylmethyl 2-deoxy-3-O-tetradecanoyl-2-tetradecanoylamino-α-D-glucopyranoside were treated in the same manner as in Step 1 of Example 1 to give 408 mg of the title compound. Obtained as an oil.

▲ [α] ²⁵ _D ▼ + 25.8 ° (C 1.0, chloroform) Step 2 Benzyloxycarbonylmethyl 2-deoxy-6-O- [2-deoxy-4-O-diphenylphosphono-3-O- (N -Dodecanoylglycyl) -2-tetradecanoylamino-β-D-glucopyranosyl]-
3-O-tetradecanoyl-2-tetradecanoylamino-α-D-glucopyranoside 389 mg of the compound obtained in Step 1 was reacted with tetradecanoic acid in the same manner as in Step 2 of Example 1 to give 293 mg of the title compound as an oil. obtain.

▲ [α] ²⁵ _D ▼ + 28.4 ° (C 1.1, chloroform) Step 3 Carboxymethyl 2-deoxy-6-O-
[2-Deoxy-3-O- (N-dodecanoylglycyl) -4-O-phosphono-2-tetradecanoylamino-β-D-glucopyranosyl] -3-O-tetradecanoyl-2-tetradeca Noylamino-α-D-glucopyranoside 278 mg of the compound obtained in Step 2 is dissolved in a mixed liquid of 40 ml of tetrahydrofuran and 1 ml of water, 0.3 g of 5% palladium carbon is added, and the mixture is stirred under a hydrogen stream for 1 hour. Then 150m
After adding g of platinum dioxide and stirring for 2 hours and 30 minutes in a hydrogen stream,
The catalyst is filtered off and the solvent is distilled off under reduced pressure. The remaining residue was purified by thin layer chromatography (eluting solvent: chloroform: methanol: water = 8: 3: 1 (v / v) developed in the lower layer),
Then, it is treated with a strongly acidic ion exchange resin Dowex 50 (H ⁺ type). The solvent was distilled off under reduced pressure and the obtained residue was suspended in dioxane and freeze-dried to obtain 68 mg of the title compound as a white powder.

Melting point 150-155 ° C (colors and becomes a candy). ▲ [α] ²⁵ _D ▼ + 17.1 ° (C 0.6, chloroform: methanol = 3: 1 (v / v)) NMR (CDCl ₃ ), δ (ppm): 0.90 (12H, t), 1.30 (s), 2.1 to 2.4 (8H.m), 4.82 (2
H, m), 5.22 (1H, t), 5.37 (1H, t) Example 5 Step 1 Allyl 2-deoxy-6-O- [2-deoxy-4-O-diphenylphosphono-3-O- ( N-dodecanoylglycyl) -6-O- (2,2,2-trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) β-D-glucopyranosyl] -3
-O-tetradecanoyl-2-tetradecanoylamino-α-D-glucopyranoside 2.00 g of 1-O-acetyl-2-deoxy-4-O-
Diphenylphosphono-3-O- (N-dodecanoylglycyl) -6-O- (2,2,2-trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) -D- Glucopyranose and 1.23g of allyl 2
-Deoxy-3-O-tetradecanoyl-2-tetradecanoylamino-α-D-glucopyranoside was prepared in Example 1.
The reaction is carried out in the same manner as in Step 1 above to obtain 2.65 g of the title compound as a caramel-like substance.

▲ [α] ²⁵ _D ▼ + 27.2 ° (C 1.4, chloroform) Step 2 Allyl 2-deoxy-6-O- [2-deoxy-4-O-diphenylphosphono-3-O- (N-dodecanoyl) Glycyl) -2-tetradecanoylamino-β
-D-glucopyranosyl] -3-O-tetradecanoyl-2-tetradecanoylamino-α-D-glucopyranoside 2.65 g of the compound obtained in Step 1 was reacted with tetradecanoic acid in the same manner as in Step 2 of Example 1 to give the title. 2.25 g of compound are obtained as a caramel.

▲ [α] ²⁵ _D ▼ + 21.8 ° (C 0.9, chloroform) Step 3 Allyl 6-O- [6-O-benzyloxymethyl-2-deoxy-4-O-diphenylphosphono-3
-O- (N-dodecanoylglycyl) -2-tetradecanoylamino-β-D-glucopyranosyl] -2-deoxy-3-O-tetradecanoyl-2-tetradecanoylamino-α-D-glucopyranoside 870 mg of the compound obtained in Step 2 was dissolved in 25 ml of anhydrous methylene chloride, and 0.82 ml of benzyloxymethyl chloride and 1.00 ml were dissolved.
Diisopropylethylamine was added, and the mixture was stirred at room temperature overnight, and then 0.16 ml of benzyloxymethyl chloride and 0.20
Add ml of diisopropylethylamine and stir for 3 hours. The reaction solution is washed successively with 1N hydrochloric acid, water, 5% aqueous sodium hydrogen carbonate solution and water, and the organic layer is dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, acetone is added to the obtained residue, and the white powder that precipitates is collected by filtration. This powder was dissolved in chloroform and silica gel chromatography (elution solvent; first chloroform: ethyl acetate = 10: 1, then chloroform:
Ethyl acetate = 5: 1, finally chloroform: acetone = 2
Purify (0: 1) and powder with acetonitrile to give 505 mg of the title compound as a white powder.

Melting point 154-157 ° C ▲ [α] ²⁵ _D ▼ + 32.4 ° (C 1.2, chloroform) Step 4 6-O- [6-O-benzyloxymethyl-2
-Deoxy-4-O-diphenylphosphono-3-O-
(N-Dodecanoylglycyl) -2-tetradecanoylamino-β-D-glucopyranosyl] -2-deoxy-
3-O-tetradecanoyl-2-tetradecanoylamino-α-D-glucopyranose 480 mg of the compound obtained in step 3 was dissolved in 15 ml of anhydrous tetrahydrofuran, and the system was once degassed and replaced with nitrogen gas. Then, 10 mg of 1,5-cyclooctadiene bis (methyldiphenylphosphine) iridium hexafluorophosphate (hereinafter iridium complex) is added. The system is degassed again and replaced with nitrogen gas, and then the system is replaced with hydrogen gas. When the red color of the iridium complex disappeared, the atmosphere was replaced with nitrogen again, and the temperature was maintained at 50 ° C, followed by stirring for 2 hours and 30 minutes.

After allowing the reaction solution to cool, 5 ml of water and then 180 mg of iodine were added, and the mixture was stirred at room temperature for 20 minutes, and then a 5% sodium thiosulfate aqueous solution was added until the color of iodine disappeared.

Chloroform is added for extraction, the organic layer is separated, washed with water, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by a silica gel column (eluting solvent: chloroform: acetone = 10: 1, then chloroform: methanol = 50: 1) and pulverized with acetonitrile to give 320 mg of the title compound as a white powder. Get as.

Melting point 155 to 156 ° C ▲ [α] ²⁵ _D ▼ + 17.7 ° (C 0.7, chloroform) Step 5 2-deoxy-6-O- [2-deoxy-3-
O- (N-dodecanoylglycyl) -4-O-phosphono-2-tetranoylamino-β-D-glucopyranosyl] -1-O-phosphono-3-O-tetradecanoyl-
2-Tetradecanoylamino-α-D-glucopyranose 170 mg of the compound obtained in Step 4 was dissolved in 15 ml of anhydrous tetrahydrofuran, the system was replaced with nitrogen, and the solution was cooled to about -70 ° C under cooling with n-butyllithium-hexane solution. (0.16 mmol equivalent) is added. After 5 minutes, add dibenzylphosphorochloridate-benzene solution (equivalent to 0.16 mmol) at 30 ° C at 30 ° C.
Stir for minutes. 100 mg palladium-black and 85 mg 5%
Palladium carbon is added and the mixture is stirred under a hydrogen stream overnight, and the catalyst is filtered off. The filtrate was evaporated under reduced pressure, the obtained residue was dissolved in 150 ml of tetrahydrofuran, 0.27 g of platinum dioxide was added, and the mixture was stirred under a hydrogen stream for 4 hours. The catalyst was removed by filtration, the filtrate was evaporated under reduced pressure, and the resulting residue was purified by thin-layer chromatography [elution solvent: chloroform: methanol: water = 6: 4: 1 (v / v)] to give a strongly acidic ion. Exchange Resin Dowex 50 (H
⁺ Type). 40 μL of triethylamine is added to the treated solution and the solvent is distilled off under reduced pressure. The obtained residue is suspended in dioxane and then lyophilized to give 38 mg of the triethylamine salt of the title compound as a white powder.

Melting point 148-150 ° C (colored into a candy-like form) ▲ [α] ²⁵ _D ▼ + 10.1 (C 0.6, chloroform: methanol = 3: 1 (v / v)) NMR (CDCl ₃ −CD ₃ OD), δ (ppm): 0.90 (12H, t), 1.28 (s), 2.1 to 2.5 (8H, m), 3.1 to 3.3
(12H, br) Example 6 Step 1 2- (diphenylphosphonoxy) ethyl 2-deoxy-6-O- [2-deoxy-4-O-diphenylphosphono-3-O- (N-dodecanoylgly Syl) -6-O- (2,2,2-trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) -β-D-glucopyranosyl] -4-O-diphenylphosphono-3 -O- (N-dodecanoylglycyl)
-2-[(N-dodecanoyl-N-methylglycyl) amino] -α-D-glucopyranoside 500 mg of the compound obtained in Step 1 of Example 1 was dissolved in 5 ml of anhydrous methylene chloride, and 0.04 ml of pyridine was added at room temperature.
139 mg diphenyl phosphorochloridate and 64 mg 4
-Add dimethylaminopyridine sequentially and stir overnight. It is diluted with methylene chloride, washed successively with 10% aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was applied to a silica gel column [elution solvent; chloroform: methanol =
40: 1] to obtain 368 mg of the title compound as an oil.

▲ [α] ²⁵ _D ▼ + 21.9 ° (C 0.8, chloroform) Step 2 2- (diphenylphosphonoxy) ethyl 2-deoxy-6-O- {2-deoxy-4-O-diphenylphosphono-3 -O- (N-dotecanoylglycyl) -2-[(N-dodecanoyl-N-methylglycyl) amino] -β-D-glycopyranosyl} -4-O-
Diphenylphosphono-3-O- (N-dodecanoylglycyl) -2-[(N-dodecanoyl-N-methylglycyl) amino] -α-D-glucopyranoside 350 mg of the compound obtained in Step 1 was used in the process of Example 1. It was treated with zinc powder in an acetic acid solution in the same manner as in 2, and then treated with N-dodecanoyl-N-methylglycine to obtain 244 mg of the title compound as an oil.

▲ [α] ²⁵ _D ▼ + 3.5 ° (C 0.6, chloroform) Step 3 2-phosphonoxyethyl 2-deoxy-6-
O- {2-deoxy-3-O- (N-dodecanoylglycyl) -2-[(N-dodecanoyl-N-methylglycyl) amino] -4-O-phosphono-β-D-gucopyranosyl} -3- O- (N-dodecanoylglycyl) -2
-[(N-dodecanoyl-N-methylglycyl) amino] -4-O-phosphono-α-D-glucopyranoside The compound 238 mg obtained in Step 2 was subjected to catalytic reduction reaction in the same manner as in Step 3 of Example 1 to give 101 mg of the title compound. Obtained as a white powder.

Melting point 184-189 ° C (colors to form a candy) ▲ [α] ²⁵ _D ▼ -4.3 ° (C 0.6, chloroform: methanol = 3: 1 (v / v)) NMR (CDCl ₃ −CD ₃ OD), δ (ppm): 0.89 (12H, t, J = 7.0Hz), 1.28 (brs), 1.62 (8H, br),
2.24 to 2.31 (4H, m), 2.40 to 2.42 (4H, m), 2.91,2.96, 3.
09,3.12 (total 6H, each s), 4.84 (1H, d), 5.19 (1H, t), 5.3
1 (1H, t) Example 7 Step 1 2- (Diphenylphosphonoxy) ethyl 4-O- [3- (benzyloxycarbonyl) propionyl] -2-deoxy-6-O- [2-deoxy-4.
-O-diphenylphosphono-3-O- (N-dodecanoylglycyl) -6-O- (2,2,2-trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) -Β-D-Glucopyranosyl] -3-O
-(N-Dodecanoylglycyl) -2-tetradecanoylamino-α-D-glucopyranoside 483 mg 2- (diphenylphosphonoxy) ethyl 2
-Deoxy-6-O- [2-deoxy-4-O-diphenylphosphono-3-O- (N-dodecanoylglycyl)
-6-O- (2,2,2-trichloroethoxycarbonyl)
-2- (2,2,2-Trichloroethoxycarbonylamino) -β-D-glucopyranosyl] -3-O- (N-dodecanoylglycyl) -2-tetradecanoylamino-
α-D-Glucopyranoside was dissolved in 6 ml of anhydrous methylene chloride, and 108 mg of succinic acid monobenzyl ester and 16 mg were dissolved.
After adding dimethylaminopyridine, add 107 mg of dicyclohexylcarbodiimide under ice-cooling and bring to room temperature.
Stir for hours. The insoluble matter is filtered off, the filtrate is washed with 1N hydrochloric acid, and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the obtained residue is purified by silica gel chromatography (elution solvent; chloroform containing 10% acetone, then chloroform containing 3% methanol) to obtain 440 mg of the title compound as an oily substance.

▲ [α] ²⁵ _D ▼ + 35.6 ° (C 1.1, chloroform) Step 2 2- (diphenylphosphonoxy) ethyl 4-O- [3- (benzyloxycarbonyl) pyropionyl] -2-deoxy-6-O -[2-deoxy-4
-O-diphenylphosphono-3-O- (N-dodecanoylglycyl) -2-tetradecanoylamino) -β-D
-Glucopyranosyl] -3-O- (N-dodecanoylglycyl) -2-tetradecanoylamino-α-D-glucopyranoside 327 mg of the compound obtained in Step 1 was treated with zinc in acetic acid in the same manner as in Step 2 of Example 1. After treatment with powder, react with tetradecanoic acid to give 226 mg of the title compound as an oil.

▲ [α] ²⁵ _D ▼ + 29.6 ° (C 1.2, chloroform) Step 3 2-phosphonoxyethyl 4-O- (3-carboxypropionyl) -2-deoxy-6-O- [2-
Deoxy-3-O- (N-dodecanoylglycyl) -4
-O-phosphono-2-tetradecanoylamino) -β-
D-glucopyranosyl] -3-O- (N-dodecanoylglycyl) -2-tetradecanoylamino-α-D-glucopyranoside 204 mg of the compound obtained in Step 2 was treated in the same manner as in Step 3 of Example 4. 97 mg of the title compound are obtained as a white powder.

Melting point 150-155 ° C (colored to become a candy) ▲ [α] ²⁰ _D ▼ + 24.4 ° (C 0.5, chloroform: methanol = 3: 1 (v / v)) NMR (CDCl ₃ −CD ₃ OD), δ (ppm): 0.89 (12H, t), 1.27 (s), 2.2 to 2.3 (8H.m), 2.6 to 2.7
(4H, m), 4.18 (2H, m), 4.27 (2H, m), 4.61 (1H, d), 4.
82 (1H, d), 5.06 (1H, t), 5.24 (1H, t), 5.30 (1H, t) Compounds of Examples represented by the following formula (I a) in the same manner as in Examples 1 to 8. Was manufactured.

Test Example 1 BALB / C mice were treated with 2 × 10 ⁵ fibrosarcoma cells (Meth A) induced by methylcholanthrene, which were syngeneic BALB / C mice (7
(Animals / group) were transplanted intradermally in the flank. The triethylamine salt of the compound of the present invention was added to a 0.1% triethylamine aqueous solution (v / v
%) Dissolved or suspended in 500 μg / ml to prepare 100
7 days, 12 days, and 17 days after transplantation to achieve μg / mouse
The antitumor activity was examined 21 days after the administration in the tail vein on the day.

Further, the compound A was used as a control compound, and the antitumor activity was examined in the same manner as the compound of the present invention.

 The results are shown in Table 1.

As is clear from the above table, it was confirmed that the compound of the present invention has the same or higher antitumor activity as the control compound A.

Test Example 2 50 μg of a solution prepared by dissolving or suspending the triethylamine salt of the compound of the present invention in 5% glucose solution containing 0.1% triethylamine to 100 μg / ml in 3 groups of 3 NZW male rabbits
/ kg (body weight) was intravenously administered for 3 days every day. It was determined by the number of dead rabbits / the number of used rabbits 24 hours after the final administration. Compound A was administered at 5 μg / kg. The results are shown in Table 2.

As is clear from the above table, it was confirmed that the compound of the present invention has far lower toxicity than the control compound A and is excellent in safety.

Claims (2)

(57) [Claims] 1. A formula And a salt thereof. In the above formula, R is a phosphono group, -ZR ⁶ or Z, Z ¹ and Z ² are each an alkylene group having 1 to 6 carbon atoms, R ⁶ is a carboxyl group or a phosphonoxy group, R ¹ , R ² ,
R ³ and R ⁴ are -COR ⁷ , -COZ ³ R ⁸ , respectively. ^{_{-CO (CH 2) n2 -OCOR 7}} , -CO (CH 2) n2 OCOZ 3 R 8, -CO (CH
^{_{2) n2 -COR 7, -CO (}} CH 2) n2 -COZ 3 R 8, Or R ⁷ is a linear or branched alkyl group having 1 to 30 carbon atoms which may be substituted with one or more hydroxyl groups, Z ³ is an alkylene group having 1 to 9 carbon atoms, R ⁸ Is a cyclic alkyl group having 3 to 12 carbon atoms which may be substituted with one or more hydroxyl groups,
Q is hydrogen, an alkyl group having 1 to 6 carbon atoms, -CONH _2, -COOH
Or -CH ₂ OH, an alkyl group of Q ₁ is hydrogen or a C 1-20, n1 is an integer of 0, is n2, and n3, respectively 20
R ⁵ is hydrogen, a phosphono group or —CO (CH ₂ ) _m COOH
And m means an integer of 0 to 6. However, R is phosphono group or -ZR ^6, is R ⁵ is hydrogen or a phosphono group, and R
Excludes combinations where ^{1 through} R ⁴ are each -COR ⁷ . 2. A formula And a salt thereof. In the above formula, R ¹⁸ is an allyl group, -ZCOOR ¹⁴ , -ZOPO (OR ¹³ ) ₂ , Or Z, Z ¹ and Z ² are each an alkylene group having 1 to 6 carbon atoms, R ¹⁴ is a protecting group for a carboxyl group which can be eliminated by catalytic reduction, and R ¹³ is a phosphono group which can be eliminated by catalytic reduction. R ¹¹ and R ²¹ are respectively -COR ⁷¹ , -COZ ³ R ⁸¹ , -CO (CH ₂ ) _n2 OCOR ⁷¹ , -CO (CH ₂ ) _n2 OCOZ ³ R ⁸¹ , -CO (CH
₂ ) _n2 COR ⁷¹ , -CO (CH ₂ ) _n2 COZ ³ R ⁸¹ , Or R ⁷¹ is an alkyl group having 1 to 30 carbon atoms, which may be substituted with one or more hydroxyl groups protected by a hydroxyl-protecting group, Z ³ is an alkylene group having 1 to 9 carbon atoms, and R ⁸¹ Is a cyclic alkyl group having 3 to 12 carbon atoms and optionally substituted by one or more hydroxyl groups protected by a hydroxyl protecting group, Q ₁ is hydrogen or an alkyl group having 1 to 20 carbon atoms, and Q ₂ is Hydrogen, carbon number 1
6 alkyl group, -CONH ₂ , -COOR ¹⁶ or -CH ₂ OR ^91
16 is a protective group for carboxyl group that can be eliminated by catalytic reduction,
R ⁹¹ is a protecting group for a hydroxyl group that can be eliminated by catalytic reduction, and n1 is 0
An integer of 1 to 10 and n2 and n3 each represent an integer of 1 to 20. However, R ¹⁸ is an allyl group, -ZCOOR ¹⁴ or -ZOPO (OR
¹³ ) Exclude the combination in _{2 in} which R ¹¹ and R ²¹ are each —COR ⁷¹ .