JP2774429B2 - Branched-chain derivatives having a sugar skeleton - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a branched derivative having a novel sugar skeleton. This derivative is useful as a glycolipid derivative for use as a microparticle carrier in drug delivery technology.

[0002]

2. Description of the Related Art In the development of a drug delivery system, it is already well known that a fine particle carrier such as a liposome or a lipid microsphere is used as a drug carrier. However, it is also well known that when a particulate carrier is administered intravenously, it is likely to be trapped in the cell endothelial system such as the liver and spleen, which poses a challenge when applying the particulate carrier as a drug to a drug delivery system. It has become.

[0003] Conventionally, the microcirculation of liposomes has been improved,
That is, various attempts have been made to make the liposome easier to circulate in the peripheral capillaries. For example, as shown in the following documents 1) to 9).

[0004] 1) Biochem. Pharmacol., 32, 609 (1983) 2) Biochim. Biophys. Acta., 839, 1 (1985) 3) J. Pharmacol. Exp. Therap., 226, 539 (1983) 4) Biochim. Biophys. Acta., 981, 27 (1989) 5) “The 9th Symposium on Interaction between Drugs and Biological Membrane” p. 193 (Tokyo 1986) 6) Chem. Pharm. Bull., 36, 4187 ( 1988) 7) Chem. Lett., Pp. 1789 (1988) 8) J. Appl. Biochem., 121-125 (1982) 9) "Cranial nerve" 39 (8): 783-788 (1987) Reference 1) and 2) describes that cholesterol and a lipid having a high phase transition temperature are added to liposomes, and 3) describes an example in which microcirculation is increased by reducing the size of liposomes. It is shown. The literature 4), the ganglioside GM ₁ which is derived glycolipid cell membrane, In addition, the document 5), glycophorin is a glycoprotein derived from human erythrocytes, further literature 6)
Describe that a glycoprotein derived from fetuin, which is a serum protein, was reconstituted in a liposome membrane, and references 4) and 5) describe that microcirculation was improved. Reference 7) states that sialic acid was bound to a polysaccharide such as pullulan or amylopectin together with a cholesterol residue and used as a liposome membrane component. References 8) and 9) disclose that sulfatide is inserted into the liposome membrane to pass through the blood-brain barrier and human Glio, respectively.
It is stated that the uptake into ma cells was successful.

[0005] On the other hand, it is known that organs have a specific protein lectin. This protein has a site for binding to sugar, and the type of sugar to be bound varies from organ to organ. It is expected to function as a receptor for the ligand at the end. In other words, it is expected that the drug delivery technique will be a key for recognition of a specific organ.

The relationship between a receptor and a ligand having a sugar at the end thereof is described in, for example, the following literature 10)
12), and examples of technical applications include, for example,
There are the following references 13) to 14).

[0007] 10) Biochemistry, 23, 4255-4261 (1981) 11) 1989 Carbohydrate recognition in cellular ju
nction.Wiley, Chichester (Ciba Foundation Symposi
um 145) p.80-95 12) Carbohydrate Research, 198, 235-246 (1990) 13) JP-A-57-181095 14) JP-A-2-288891 A synthetic ligand in which a sugar is clustered at the terminal is prepared, and the existence of a so-called cluster effect has been recognized from the affinity between the ligand and the receptor. Reference 13) discloses a technique for binding a drug to a synthetic ligand, that is, a glycopeptide, and intended for selective delivery of the drug. Reference 14) discloses a similar technique, but is particularly characterized in that the sugar density is increased by binding the sugar to a tris group.

[0008]

According to the above-mentioned prior art, if a peptide is used as a skeleton and a saccharide is clustered on the skeleton, the effect of the clustering is recognized. However, the effect of using a substance other than the peptide as the skeleton has not been clarified, and remains as a problem in the conventional art. An object of the present invention is to provide a novel substance for this problem.

[0009]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, a synthetic ligand comprising a saccharide as a skeleton and a cluster of saccharides at the terminal thereof has been developed for organ targeting in drug delivery technology. They have found that they are useful as glycolipid derivatives, and have completed the present invention described in the claims based on this finding.

Hereinafter, the present invention will be described in detail.

The substance of the present invention is a branched derivative having a sugar skeleton represented by the following formula (I).

[0012]

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In the formula (I), n represents an integer of 4 or 3.

When n is 4, formula (I) represents a compound in which ^four bonding groups X ¹ , X ² , X ³ and X ⁴ are bonded to [S ⁴ ] having four bonding hands. . Here, [S ⁴ ] represents any of the following formulas (II), (III) and (IV).
As is clear from the respective formulas, formula (II) is the one in which the binding group Y is glycosyl-bound to mannose, formula (III) is the one in which the binding group Y is glycosyl-bound to galactose, and formula (IV) is the binding group to glucose. Y represents a glycosyl bond. Thus, ultimately, when n is 4, formula (I) represents a compound wherein the binding groups X ¹ , X ² , X ³ , X ⁴ and Y are bound to mannose, galactose or glucose, where mannose, galactose Or, glucose forms a skeleton portion in each compound, and is called a sugar skeleton.

Similarly, when n is 3, equation (I) is
Represents a compound in which ^three bonding groups X ¹ , X ² and X ³ are bonded to [S ³ ] having three bonding hands, provided that [S ³ ]
Represents any of the following formulas (V) and (VI). In this case, the sugar skeleton is fucose or xylose as shown by the formulas (V) and (VI).

X ¹ , X ² , X ³ and X ⁴ each independently represent H, a benzyl group, a trityl group, a benzylidene group, a carboxymethyl group or a group represented by the formula (VII) or (VII ').

[0017]

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Here, the benzyl group, the trityl group and the benzylidene group are protecting groups for the hydroxyl group of the skeleton sugar. Further, a carboxymethyl group and a compound of the formula (VII) or (VII ')
Are related to each other. First, a carboxymethyl group is introduced into the hydroxyl group of the skeletal sugar, and then a predetermined sugar chain amine is condensed to the carboxyl group of the formula (VII) or (VII '). It becomes the group shown by. The group represented by the formula (VII) or the formula (VII ′) may be respectively linked via a methylene chain as a spacer (the methylene chain has 2 to 8 carbon atoms) or via a different spacer from the (T) Is a group having a saccharide at the terminal, which is branched from a skeletal saccharide and has a saccharide at the terminal, so that it becomes a group forming a so-called branched-chain saccharide.

The sugar represented by (T) is specifically described as follows:
The following formulas (VIII) to (XIII). That is, the formula (VII
(I) is mannose, (IX) is mannosamine, (X) is galactose, (XI) is galactosamine, (XII) is glucose, and (XIII) is glucosamine. In these formulas, R represents H or an acetyl group as a protecting group.

(X ¹ ,..., X ⁿ ) in the formula (I) has a special meaning. In (), n bonding groups are described, and these groups are represented by [S ⁿ ]. And these groups may be the same or different from each other, provided that at least one of these groups is a carboxymethyl group or a group represented by the formula (VII) or ( VII '). Therefore, the compound of the formula (I) represents a derivative having a sugar as a skeleton and having a carboxymethyl group or a sugar at a terminal.

In the formulas (II) to (VI), Y represents a group — (CH ₂ )
_r N _3, group _{- (CH 2) r NH 2} , group - (CH _{2) r} N
HZ, group _{- (CH 2) r CH =} CH 2 or a group - (C
H ₂ ) _r COR ¹ , wherein r represents an integer from 2 to 10, Z represents a benzyloxycarbonyl group, a t-butoxycarbonyl group or a linear or branched alkylcarbonyl group, and R ¹ Represents a group —OH, a group —NHNH ₂ or an alkoxyl group having 1 to 3 carbon atoms or an alkylamino group. In other words, it is a group having an azide group, an amino group, a carbonylamino group, or the like at the terminal via a methylene chain (the methylene chain has 2 to 10 carbon atoms). Thus, the compounds of formula (I) are sugar-based, while having a carboxymethyl group or a branched sugar,
On the other hand, it shows a derivative having a fatty chain.

[0022]

Embedded image

Formulas (II) to (VI) and (VIII) to (XIII)
In, the bond shown by a wavy line represents an α bond or a β bond.

The final target substance of the present invention is a compound of the formula (I) wherein at least one of the bonding groups represented by (X ¹ ,..., X ⁿ ) is a group represented by the formula (VII) or (VII ′) Wherein the remaining linking group is H, where R in formula (VII) and (T) of formula (VII ') is H, and Y is a (CH ₂ ) _r NHZ group, wherein Z Is a substance representing a straight-chain or branched-chain alkylcarbonyl group (a branched sugar complex having a sugar skeleton). The other substance of the present invention is an intermediate for producing this final target substance.

The production of the substance of the present invention may be carried out by appropriately combining several kinds of reactions. The main three reactions constituting the production process are as follows. The first is a reaction of preparing an azide derivative or a phthalimide derivative in which an azide chain or a phthalimide chain is introduced at the 1-position of a sugar to be a skeleton, and introducing a protecting group into a predetermined hydroxyl group of the sugar, Is a series of reactions in which a carboxymethyl group is introduced into another predetermined hydroxyl group of the sugar, and then a sugar chain amine is condensed to the carboxyl group to introduce a branched chain sugar. This is a series of reactions in which the azide in the chain is hydrogen reduced to an amine and then a carbonyl group is introduced into the amine. Other reactions include preparing a sugar chain amine for a branched sugar in advance, removing the hydroxyl-protecting group of the skeletal sugar at an appropriate stage of the production process, or performing a branched chain reaction at the final stage. There is a reaction for removing the acetyl protecting group of the hydroxyl group of the sugar, and the like may be appropriately employed.

In the first main reaction, an azide chain is introduced into the 1-position of a sugar to be a skeleton by adding a bromoalkanol to a sugar whose hydroxyl group is protected in advance in the presence of a Lewis acid such as boron trifluoride ether. The reaction may be followed by the reaction with sodium azide. Examples of the protecting group to be introduced into the predetermined hydroxyl group of the sugar include a benzyl group, a trityl group, a benzylidene group, and the like, and benzyl chloride, trityl chloride, dimethoxybenzylidene, and the like may be reacted, respectively. May be removed by hydrogen reduction or the like.

In the second main reaction, a carboxymethyl group can be introduced into another predetermined hydroxyl group of the sugar by reacting, for example, tetrabutylammonium monochloroacetate in the presence of sodium hydride. Next, a sugar chain amine for a branched sugar may be condensed in the presence of, for example, dicyclohexylcarbodiimide and hydroxysuccinimide.

In the third main reaction, for example, an azido group is hydrogen-reduced to an amine group in the presence of a Lindlar catalyst, and then a predetermined carbonyl compound is reacted in the presence of, for example, dicyclohexylcarbodiimide.

A sugar chain amine for a branched sugar is prepared by protecting a hydroxyl group of a sugar to be a branched sugar with an acetyl group in advance, and then adding bromoalkanol to the sugar in the presence of boron trifluoride ether or the like. Glycosylation,
Next, sodium azide is reacted to form a sugar chain azide,
Finally, it can be prepared by, for example, hydrogen-reducing the azide group in the presence of a Lindlar catalyst to form an amine group.

The removal of the acetyl protecting group for the hydroxyl group of the branched sugar in the final stage of the production process may be carried out by adding sodium methylate in methanol according to a conventional method.

[0031]

As shown in Experimental Example 1 below, the substance of the present invention is useful as a glycolipid derivative for organ orientation in drug delivery technology using fine particle carriers.

[0032]

The present invention will be specifically described below with reference to examples.

EXAMPLE 1 The chemical reactions involved in this example are shown in FIGS. 1A and 1B.

Synthesis of Compound (25 ) 100 g of β-D-Galactose pentaacetate (Compound (23))
38.4 g of -bromoethanol was dissolved in 900 ml of dry methylene chloride, and 160 ml of boron trifluoride etherate was added dropwise under ice cooling. After stirring at room temperature for 2.5 hours, the mixture was poured into sodium bicarbonate water, washed twice with water, and then the solvent was distilled off. Crystallization with isopropyl ether gave 63 g of a glycoside (54% yield). R
_F = 0.49 (PhCH ₃ -AcOEt 2: 1).

60 g of the bromoethyl glycoside compound was added to N, N-
The residue was dissolved in 200 ml of dimethylformamide, added with 32 g of sodium azide, and stirred at room temperature overnight. Then at 80 ℃ 2
After stirring for an hour, 200 ml of ethyl acetate was added, and the solid matter was removed by filtration. After distilling out dimethylformamide and ethyl acetate, the solution was made into an ethyl acetate solution again, and washed four times with water to quantitatively obtain an azidoethyl glycoside compound (compound (24)). R _F = 0.40
(PhCH ₃ -AcOEt 2: 1).

Azide 4.17 g and P-toluenesulfonic acid
Hydrogen reduction (45 psi, 1.5 h) of 2.28 g of the ethanol solution in the presence of 4.0 g of Lindlar catalyst gave an amine compound (compound (25)). R _F = 0.18 (CHCl ₃ -MeOH 20: 1).

Synthesis of compound (2) and compound (3 ) 16.4 g of L-fucose (compound (1)) and resin "Dowe
x 50WX8 "5.0 g to 50 ml of 2-bromoethanol,
The reaction was carried out at 60 ° C. for 3 hours and then at room temperature overnight. After removing the resin, ethanol was added and the mixture was crystallized to obtain 20.2 g of a glycosyl compound. R _F = 0.51 (CHCl ₃ -MeOH 5: 1).

[Α] _D -142.9 ° (C 0.45, MeOH).

NMR: ¹ H, δ (CD ₃ OD) 4.81 (d, 1 H, J = 3.2
Hz), 4.10 (q, 1H, J = 6.6 Hz), 1.21 (d, 1H, J = 6.6 Hz).

Then, the glycosyl compound was dissolved in dimethylformamide (50 ml), 1.2 M equivalent of sodium azide was added, and the mixture was stirred and reacted at room temperature overnight to obtain a compound (2).

Then, 1.3 M equivalent of sodium hydride, 10 ml of dimethylformamide and tetrabutylammonium monochloroacetate ClCH ₂ CO ₂ NBu ₄ 1.2
M equivalent was added and stirred at room temperature overnight. The mixture was poured into water to adjust the pH to 3, and then dried. Ethyl acetate was added, and the insoluble matter was collected by filtration. Then, it was dissolved in methanol and water to adjust the pH to 0.4, and further dried to obtain a compound (3).

NMR: ¹ H, δ (DMSO-d ₆ ) 4.99 (d, 1 H, J =
3.4Hz), 1.19 (d, 3H, J = 6.6Hz).

Synthesis of compound (4) 1.84 g of compound (3) and compound (25) (from 5.64 g of azide form) were condensed by a DCC method and subjected to silica gel column chromatography (50: 1 CHCl ₃ -MeOH). Purify compound (4)
Was obtained in an amount of 0.28 g. R _F = 0.44 (CHCl ₃ -MeOH 10: 1).

[Α] _D -29.2 ° (C 0.5, CHCl ₃ ).

NMR: ¹ H, δ (CDCl ₃ ) 5.40 (m, 3H), 5.1
5 (m, 3H), 5.03 (m, 4H), 4.52 (d, 1H, J = 7.8Hz), 4.51 (d, 1
H, J = 7.8Hz), 4.47 (d, 1H, J = 7.8Hz), 2.18, 2.17, 2.166
, 2.06, 2.05, 2.048, 1.999, 1.988, 1.984, 1.5
85, 1.32 (d, 3H, J = 5.5Hz).

Synthesis of Compound (5) Compound (4) was deacetylated using sodium methoxide in methanol to give an aqueous solution, which was subjected to gel column chromatography ("Sephadex G-10", H ₂ O). Purification gave compound (5). R _F = 0.47 (CHCl ₃ -MeOH-H ₂
O 10: 10: 3).

[Α] _D -50.2 ° (C 0.25, H ₂ O).

NMR: ¹ H, δ (DMSO-d ₆ ) 5.04 (d, 1H, J =
3.4Hz), 1.18 (d, 3H, J = 6.6Hz).

Synthesis of Compound (6 ) 100 mg of Compound (4) was dissolved in ethanol, and
100 mg was added and the mixture was reduced with hydrogen (48 psi, 1.5 hours), and then reacted with N-hydroxysuccinimide palmitate in acetonitrile at room temperature overnight. Purification by silica gel column chromatography (50: 1 CHCl ₃ -MeOH) gave 68 mg of a condensate. Then, compound (6) was obtained by deacetylation using sodium methoxide in methanol. R _F = 0.19 (CHCl ₃ -MeOH-H ₂ O 60: 35: 4).

[Α] _D -26.7 ° (C 0.42, MeOH).

NMR: ¹ H, δ (CD ₃ OD) 5.07 (d, 1 H, J = 2.2
Hz), 4.26 (d, 3H, J = 7.6 Hz), 1.25 (d, 3H, J = 6.6 Hz), 0.90
(t, 3H, J = 7.1Hz).

Example 2 FIG. 2 shows the chemical reactions involved in this example.

Synthesis of Compound (8) α-D-mannose pentaacetate (100 g of Compound (7)
38.4 g of -bromoethanol was dissolved in 900 ml of dry methylene chloride, and 160 ml of boron trifluoride etherate was added dropwise under ice cooling. After stirring at room temperature for 2.5 hours, pour into sodium bicarbonate water and wash with water.
After that, the solvent was distilled off. Crystallization with isopropyl ether gave a glycoside form (68.5% yield). R _F =
_{0.47 (PhCH 3 -AcOEt 2: 1} ).

Dissolve 60 g of 2-bromoethyl glycoside in 200 ml of dimethylformamide and add sodium azide
g was added and stirred at room temperature overnight. Then, the mixture was stirred at 80 ° C. for 2 hours, 200 ml of ethyl acetate was added, and the solid matter was removed by filtration. After dimethylformamide was distilled off, an ethyl acetate solution was obtained. After washing with water four times, ethyl acetate was distilled off to quantitatively obtain a 2-azidoethylglycoside. R _F = 0.40 (PcCH ₃
-AcOEt 2: 1).

Further, deacetylation was carried out using sodium methoxide in methanol to obtain 28 g of compound (8).

Synthesis of Compound (9) 4.98 g of Compound (8), 250 mg of p-toluenesulfonic acid and 8.2 ml of benzaldehyde dimethyl acetal were added to N, N
-Dissolved in 50 ml of dimethylformamide and stirred at room temperature overnight. After adding 0.5 ml of triethylamine, the mixture is concentrated, and then subjected to silica gel column chromatography (5: 1 CHCl ₃ -AcOE
Through t), 2.62 g of a benzylidene compound was obtained. R _F = 0.63 (C
HCl ₃ -MeOH 10: 1).

Then, carboxymethylation was carried out in the same manner as before using ClCH ₂ CO ₂ NBu ₄ to give 2.5 g of compound (9).
Obtained. R _F = 0.30 (CHCl ₃ -MeOH-H ₂ O 60: 35: 4).

Synthesis of Compound (10) 1.97 g of Compound (9) and Compound (25) (from 3.76 g of azide) were condensed in acetonitrile by the DCC method, followed by silica gel column chromatography (50: 1 CHCl ₃ -MeOH). And purified. 3.51 g of a condensate was obtained. R _F = 0.46 (CHCl ₃ -MeOH 2
0: 1).

[Α] _D −5.8 ° (C 0.66, CHC ₃ ).

NMR: ¹ H, δ (CDCl ₃ ) 5.74 (s, 1 H), 5.3
9 (m, 2H), 5.18 (m, 2H), 5.01 (d, 2H), 4.98 (bs, 1H), 4.4
8 (d, 1H, J = 8.1Hz), 4.37 (d, 1H, J = 7.8Hz), 2.16, 2.13,
2.07, 2.05, 2.00, 1.99.

Then, 1.71 g of the above condensate was taken, and the azide group was reduced using a Lindlar catalyst and palmitoylation was performed in the same manner as above to obtain a compound (10). Proceeded to the next step without silica gel column chromatography purification. R
_{F = 0.43 (CHCl 3 -MeOH 20} : 1).

NMR: ¹ H, δ (CDCl ₃ ) 4.48 (d, 1 H, J = 8.1
Hz), 4.44 (d, 1H, J = 7.8Hz).

Synthesis of Compound (11) 1.3 mmol of Compound (10) was dissolved in a mixture of 100 ml of ethanol and 0.1 ml of acetic acid, and reduced with hydrogen (45 psi) with 10% Pd / C (1.5 g). Silica gel column chromatography
(50: 1 and 30: 1 CHCl ₃ -MeOH) to obtain 1.04 g of a debenzylidene derivative. R _F = 0.68 (CHCl ₃ -MeOH 10: 1)
.

[Α] _D −18.1 ° (C 0.74, CHCl ₃ ).

NMR: ¹ H, δ (CDCl ₃ ) 5.40 (m, 2H), 5.1
7 (m, 2H), 5.03 (m, 2H), 4.89 (bs, 1H), 4.47 (d, 1H, J = 8.1H
z), 4.46 (d, 1H, J = 8.1 Hz), 0.88 (t, 3H, J = 6.8).

Subsequently, the compound (11) was quantitatively obtained by deacetylation using sodium methoxide in methanol.
R _F = 0.26 (CHCl ₃ -MeOH-H ₂ O 65: 30: 4).

NMR: ¹ H, δ (CD ₃ OD) 4.96 (d, 1 H, J = 1.5
Hz), 4.30 & 4.11 (ABq, J = 15.9Hz), 4.28 (d, 1H, J = 7.3H
z), 4.24 (d, 1H, J = 7.6 Hz), 0.90 (t, 3H, J = 7.0).

Example 3 FIG. 3 shows the chemical reactions involved in this example.

Synthesis of Compound (12) 2-azidoethyl α-D-mannopyranoside (Compound (8))
49 g and 2.99 g of trityl chloride were dissolved in 30 ml of pyridine, and reacted by stirring at room temperature overnight. After distilling off pyridine,
Silica gel column chromatography (40: 1 CHCl ₃ -MeO
H) to give 3.60 g of 6-0-trityl form (compound (12))
Obtained. R _F = 0.67 (CHCl ₃ -MeOH 10: 1).

[Α] _D −8.4 ° (C 1.03, CHCl ₃ ).

NMR: ¹ H, δ (CD ₃ OD) 7.35 (m, 5H,),
4.88 (d, 1H, J = 1.5Hz).

Synthesis of compound (13) 693-trityl form (compound (12)) (993 mg) was treated in the same manner as described above for C1
Carboxymethylation was performed using CH ₂ COONBu ₄ to obtain a tricarboxylic acid compound. R _F = 0.12 (CHCl ₃ -MeOH-H ₂ O 60:35:
Four).

Then, the amine compound (compound (25)) was condensed in acetonitrile using DDC method to convert compound (13) to 610.
mg was obtained. R _F = 0.38 (CHCl ₃ -MeOH 30: 1).

[Α] _D -10.6 ° (C 0.99, CHCl ₃ ).

NMR: ¹ H, δ (CDCl ₃ ) 4.55 (d, 1 H, J = 7.8
Hz), 4.44 (d, 1H, J = 8.1 Hz), 4.37 (d, 1H, J = 7.8 Hz).

Synthesis of Compound (14) 200 mg of Compound (13) and 14 mg of P-toluenesulfonic acid were dissolved in 3.5 ml of methanol and stirred at room temperature for 7.5 hours. After distilling off methanol, silica gel column chromatography
(30: 1 CHCl ₃ -MeOH) to give 89 mg of the detrityl product. R _F = 0.38 (CHCl ₃ -MeOH 20: 1).

NMR: ¹ H, δ (CDCl ₃ ) 5.40 (m, 3H), 5.15
(m, 3H), 5.04 (m, 3H), 4.93 (bs, 1H), 4.57 (d, 1H, J = 8.1H
z), 4.50 (d, 1H, J = 8.1 Hz), 4.45 (d, 1H, J = 7.8 Hz).

Then, the compound was dissolved in 2 ml of methanol, 0.2 M equivalent of sodium methoxide was added, and the mixture was stirred at room temperature for 3 hours to deacetylate to obtain a compound (14). R _F = 0.3
_{8 (CHCl 3 -MeOH- H 2 O} 10: 10: 3).

NMR: ¹ H, δ (D ₂ O) 5.03 (d, 1H, J = 1.7 Hz), 4.
34 (d, 1H, J = 7.8Hz), 4.33 (d, 1H, J = 7.8Hz), 4.328 (d, 1H, J
= 7.8Hz).

Example 4 FIG. 4 shows the chemical reactions involved in this example.

Synthesis of Compound (15) 2.11 g of the 6-0-trityl compound (Compound (12)) and 1.61 g of di-n-butyltin oxide (n-Bu) ₂ SnO were suspended in anhydrous methanol, and the mixture was heated under reflux for 2 hours. did. After distilling off the methanol, toluene was added and further distilled off. Then PhCH ₂ Br6ml
And tetrabutylammonium iodide NBu ₄ I (1.48
g) was added and reacted at 70 ° C. for 5 hours and at room temperature for 4 days.
Toluene was added to the reaction solution, and after washing with water, the solvent was distilled off to obtain an oil. Silica gel column chromatography ((i) CHCl
₃ only, (ii) purified by PhCH ₃ -AcOEt 5: 1) to give compound (15)
0.93 g was obtained. R _F = 0.63 (CHCl ₃ -MeOH 12: 1).

[Α] _D + 10.3 ° (C 0.64, CHCl ₃ ).

NMR: ¹ H, δ (CDCl ₃ ) 4.93 (d, 1 H, J = 1.5
Hz), 4.70 & 4.67 (ABq, J = 4.7 Hz), 4.03 (m, 1H), 3.71 (d
d, 1H, J = 3.4,9.0Hz).

Synthesis of Compound (16) Compound (15) was carboxymethylated in the same manner as above,
Extraction with ethyl acetate at 2.0 yielded a dicarboxylic acid partially containing the detrityl form. R _F = 0.77 (CHCl ₃ -MeOH-H
₂ O 65: 30: 4).

Dicarboxylic acid mixture and amine (compound
(25)) was condensed by a DDC method, and purified by silica gel column chromatography (1: 1 to 1: 3 CHCl ₃ -AcOEt) to obtain a compound (16). R _F = 0.70 (CHCl ₃ -MeOH 20: 1).

[Α] _D −9.7 ° (C 0.72, CHCl ₃ ).

NMR: ¹ H, δ (CDCl ₃ ) 5.36 (m, 2H), 5.1
5 (m, 2H), 4.98 (m, 2H), 4.97 (d, 1H, J = 1.7 Hz), 4.71 & 4.
63 (ABq, J = 11.7Hz), 4.40 (d, 1H, J = 8.6Hz), 4.34 (d, 1H, J
= 7.8Hz).

Synthesis of Compound (18) 580 mg of Compound (16) and 38 mg of P-toluenesulfonic acid were dissolved in 6 ml of methanol, reacted at room temperature for 1 hour, added with ethyl acetate and washed with aqueous sodium hydrogen carbonate. After drying the ethyl acetate layer, ethyl acetate was distilled off to obtain an oil, which was purified by silica gel column chromatography (50: 1 CHCl ₃ -MeOH) to obtain 336 mg of a detrityl form (compound (17)). R _F = 0.53 (CHCl
₃ -MeOH 20: 1).

[Α] _D + 4.1 ° (C 1.0, CHCl ₃ ).

NMR: ¹ H, δ (CDCl ₃ ) 7.36 (m, 5H), 5.3
8 (m, 2H), 5.17 (m, 2H), 5.02 (M, 2H,), 4.86 (d, 1H, J = 1.5H
z), 4.72 & 4.65 (ABq, J = 11.5Hz), 4.47 (d, 1H, J = 8.1H
z), 4.43 (d, 1H, J = 8.1Hz), 2.14, 2.13, 2.06, 2.056,
2.049, 2.046, 1.99, 1.986.

Further, the resultant was dissolved in 5 ml of methanol, 0.2 M equivalent of sodium methoxide was added, and the mixture was stirred at room temperature overnight. Then, "Amberlyst 15" was added for neutralization, and then methanol was distilled off to obtain Compound (18). R _F = 0.43 (CHCl ₃ -M
_{eOH- H 2 O 65: 30:} 4).

[Α] _D + 15.3 ° (C 1.5, MeOH).

NMR: ¹ H, δ (CD ₃ OD) 7.30 (m, 5H), 4.9
8 (d, 1H, J = 1.7Hz), 4.22 (d, 1H, J = 7.6Hz), 4.21 (d, 1H, J =
7.6Hz).

Example 5 The chemical reactions involved in this example are shown in FIGS. 5A and 5B.

Synthesis of Compound (19) The 6-0-trityl form (Compound (12)) was carboxymethylated in the same manner as above to obtain a tricarboxylic acid form (Compound (16a)). Subsequently, an amine compound (compound (7b) obtained from compound (7a) in the same manner as in the synthesis of compound (25)) was condensed with DDC to obtain a trimannose compound (compound (19)). R _{F
= 0.49 (CHCl 3 -MeOH 20:} 1).

[Α] _D + 24.4 ° (C 0.43, CHCl ₃ ).

¹ H-NMR (CDCl ₃ ) δ: 7.10 (t, 1H, J = 5.9H
z), 6.77 (bt, 1H, J = 6.1 Hz), 5.04 (bs, 1H), 4.85 (bs, 1
H), 4.78 (bs, 1H), 4.69 (bs, 1H).

Synthesis of Compound (20) Compound (19) was dissolved in acetic acid and heated and stirred at 60 ° C. for 3 hours. After acetic acid was distilled off, the residue was purified by silica gel column chromatography (CHCl ₃ -MeOH 50: 1) to obtain a detrityl product (compound (20)). R _F = 0.19 (CHCl ₃ -MeOH 20:
1)

[Α] _D + 30.5 ° (C 2.0, CHCl ₃ ).

¹ H-NMR (CDCl ₃ ) δ: 7.42 (t, 1H, J = 5.9H
z), 7.24 (t, 1H, J = 5.6Hz), 7.15 (t, 1H, J = 5.9Hz), 4.95 (b
s, 1H), 4.87 (bs, 1H), 4.85 (bs, 1H).

Synthesis of Compound (22) Compound (20) was reduced with hydrogen using a Lindlar catalyst in the same manner as before to form an amine compound, and then palmitoylated in the same manner as compound (10) to give compound (21) I got Further, by deacetylation, the mannose terminal compound (22)
I got R _F = 0.45 (CHCl ₃ -MeOH-H ₂ O 20: 20: 3).

[Α] _D + 43.3 ° (C 0.67, MeOH).

¹ H-NMR (CD ₃ OD) δ: 4.96 (bs, 1H), 4.78
(bs, 1H), 4.32 & 4.26 (ABq, 2H, J = 15.1Hz), 4.23 & 4.1
6 (ABq, 2H, J = 14.9Hz), 4.23 & 4.13 (ABq, 2H, J = 15.4Hz),
2.19 (t, 2H, J = 7.6Hz), 0.90 (t, 3H, J = 7.0Hz).

Example 6 FIG. 6 shows the chemical reactions involved in this example.

Synthesis of compound (26) 2'-azitoethyl α-D-mannopyranoside (compound
(8)) (2.99g) and di-n-butyltin oxide
(3.30 g) in methanol (150 ml) was heated under reflux for 1.5 hours. After the solvent was distilled off, benzene (100 ml) was added and the solvent was distilled off, and this was repeated four times. Benzene obtained residue
(150 ml) To the solution were added benzyl bromide (2.9 ml) and tetrabutylammonium iodide (4.88 g). After heating under reflux for 6 hours, the mixture was left at room temperature overnight, and benzyl bromide (1.45 ml) was added. Heated to reflux. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform: methanol 100: 0.5-2%, ethyl acetate: hexane 8: 2, ethyl acetate) to give the monobenzyl compound (compound (26)). (1.84 g, 45%).

R _F 0.45 (chloroform-methanol).

[Α] _D + 27.0 ° (c 0.8, chloroform).

¹ H-NMR (deuterated chloroform) δ (ppm) in 500 M
Hz: 3.39 (t like 2H), 3.68 (m, 1H), 4.09 (m, 1H), 4.3
0 (dd, 1H), 4.33 (m, 1H), 4.40 (dt, 1H), 4.56 (ddd, 1H)
H), 4.66 (brs, 1H), 4.79 (dt, 1H), 4.96 (d, 1H), 4.97
(d, 1H), 4.98 (s, 2H), 5.39 (d, 1H).

IR (KBr): 3430, 2150 cm ^-1 .

Synthesis of Compound (27) (i) Monobutylacetic acid (1.24 g) in tetrabutylammonium hydroxide (1M methanol solution 13.1 ml) was added to methanol (2
(0 ml) solution, and the solvent was distilled off. Toluene in residue
(20 ml) was added and the solvent was distilled off. This was repeated three times, and the obtained residue was dissolved in dimethylformamide (6 ml).

(Ii) sodium hydride under an argon atmosphere
(60% oil suspension 0.39g) in dimethylformamide (15ml) suspension under ice-cooled monobenzyl form (compound (26))
(1.00 g) in dimethylformamide (10 ml) was added.
Stir for 5 minutes. The dimethylformamide solution of tetrabutylammonium monochloroacetate obtained in (i) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 16 hours.

The reaction mixture was poured into water, diluted aqueous sodium bicarbonate and a small amount of sodium iodide were added to the aqueous layer, and the mixture was extracted with chloroform. The aqueous layer was acidified with citric acid, and the desired product was extracted with ethyl acetate. The extract was washed with water and saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a crude product (0.83 g). A part (0.43 g) of this was dissolved in water, and the solution was purified with "Diaon HP-20" (manufactured by Mitsubishi Kasei Kogyo Co., Ltd.) (50 ml) (acetonitrile-water 20:
80-80: 20) Among them, the fractions eluted with acetol-water 40:60 were collected, the solvent was distilled off, the mixture was acidified with citric acid, and the target product was extracted with ethyl acetate, and the extract was saturated with water. After washing with brine, the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the dicarboxymethyl derivative (compound (27)) (2
30 mg) as a crude product.

Synthesis of compound (25) 2'-azidoethyl 2,3,4,6-tetraacetyl-β-D
-To a solution of galactopyranoside (compound (24)) (1.50 g) and paratoluenesulfonic acid (682 mg) in ethanol (40 ml) was added Lindlar's catalyst (1.80 g), and the mixture was added with hydrogen (50 p.
si) The mixture was shaken and stirred at room temperature for 1 hour. Lindlar catalyst (0.
48g), and the mixture was shaken and stirred for 30 minutes.
Toluene was added to the residue, and the solvent was again distilled off to obtain an amino compound (compound (25)) (2.14 g) as a crude product.

Synthesis of Compound (28) The crude product (4) of a dicarboxymethyl derivative (Compound (27))
00 mg), N-hydroxysuccinimide (322 mg), triethylamine (0.51 ml) and the amino compound (compound (25)) (2.14 g) obtained above in dimethylformamide (15 ml) were added to a solution of N, N'-dicyclohexyl under ice-cooling. Carbodiimide (5
30 mg) in dimethylformamide (3 ml) and stirred at room temperature overnight.

Ethyl acetate (20 ml) was added to the reaction solution, insolubles were removed by filtration, the filtrate was poured into water, and the desired product was extracted with ethyl acetate. The extract was washed with water and saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (chloroform-methanol 100: 0.5 to 100: 4) to obtain compound (28) from a chloroform-2% methanol fraction.
(360 mg, 20%).

R _F 0.33 (chloroform-methanol 9
5: 5).

[Α] _D + 1.6 ° (c 1.0, chloroform).

¹ H-NMR (deuterated chloroform) δ (ppm) in 500M
Hz: 1.99 (s, 6H), 2.045 (s, 3H), 2.051 (s, 3H), 2.065
(s, 3H), 2.071 (s, 3H), 2.11 (s, 3H), 2.15 (s, 3H), 4.4
5 (d, 1H), 4.47 (d, 1H), 4.72 (d, 1H), 4.87 (m, 1H), 4.88
(brs, 1H), 5.00 (dd, 1H), 5.02 (dd, 1H), 5.17 (dd, 1H)
, 5.21 (dd, 1H), 7.17 (brt, 1H), 7.2-7.4 (m, 5H), 7.7
4 (brt, 1H).

MS (FAB): 1201 (MH ⁺ ).

IR (KBr): 3400, 1750, 1670, 1540 cm ^-1 .

Synthesis of compound (29a) (i) To a solution of the azide form (compound (28)) (800 mg, 0.67 mmol) and paratoluenesulfonic acid (139 mg) in ethanol (60 ml) was added a Lindlar catalyst (600 mg). Under pressure (50psi)
Shake for 2.5 hours.

The catalyst was removed by filtration, the solvent was distilled off, and the amino compound (9
36 mg) was obtained as a crude product. Used for the next reaction without purification.

(Ii) To a solution of the amino compound (345 mg) obtained above in dimethylformamide (3 ml) was added di-tert-butyl dicarbonate (BocO) ₂ O (98 mg) and triethylamine (110 μm).
l) was added and the mixture was stirred at room temperature overnight.

The reaction solution was poured into a half-saturated saline solution, and the desired product was extracted with ethyl acetate. The extract was washed with water and a saturated saline solution and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (chloroform-methanol 95: 5) to obtain a Boc form (compound (29a)) (326 mg, quantitative).

R _F 0.26 (chloroform-methanol 96: 4
).

[Α] _D + 3.8 ° (c 0.81, chloroform).

¹ H-NMR (deuterated chloroform) δ (ppm) in 50
0MHz: 1.45 (s, 9H), 1.992 (s, 3H), 1.993 (s, 3H), 2.0
47 (s, 3H), 2.05 (s, 3H), 2.064 (s, 3H), 2.069 (s, 3H)
, 2.11 (s, 3H), 2.15 (s, 3H), 4.44 (d, 1H), 4.48 (d, 1
H), 4.73 (d, 1H), 4.83 (brs, 1H), 4.90 (d, 1H), 5.00 (dd,
1H), 5.02 (dd, 1H), 5.18 (dd, 1H), 5.21 (dd, 1H), 5.
39 (m, 2H), 7.1 (brs, 1H), 7.3-7.5 (m, 5H), 7.7 (brt, 1H)
H).

IR (KBr): 3530, 1750, 1670, 1440 cm ^-1 .

Synthesis of Compound (29b) N-palmitoyloxysuccinimide (176 mg) in toluene (2 ml) and triethylamine (0.15 mg) were added to a methylene chloride (4 ml) solution of the amino compound (591 mg) obtained by reducing compound (28). ml) and stirred at room temperature overnight.

The reaction mixture was poured into water, and the desired product was extracted with ethyl acetate. The extract was washed with water and a saturated saline solution.
It was dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (chloroform-methanol 100: 3) to obtain a palmitoyl compound (compound (29b)) (386 mg, 62%).

R _F 0.24 (chloroform-methanol 95:
Five).

[Α] _D + 3.5 ° (c 1.0, chloroform).

¹ H-NMR (deuterated chloroform) δ (ppm) in 50
0MHz: 0.88 (t, 3H), 1.990 (s, 3H), 1.994 (s, 3H), 2.0
46 (s, 3H), 2.049 (s, 3H), 2.066 (s, 3H), 2.070 (s, 3H)
, 2.105 (s, 3H), 2.149 (s, 3H), 4.44 (d, 1H), 4.48 (d,
1H), 4.74 (d, 1H), 4.85 (brs, 1H), 4.89 (d, 1H), 5.00 (d
d, 1H), 5.02 (dd, 1H), 5.17 (dd, 1H), 5.21 (dd, 1H),
5.39 (brs, 2H), 5.86 (brt, 1H), 7.11 (brt, 1H), 7.2-7.4
(m, 5H), 7.72 (brt, 1H).

IR (KBr): 3400, 1750, 1660, 1540 cm ^-1 .

Synthesis of compound (30a) (i) Boc form (compound (29a)) (45 mg) in ethanol (7 ml)
10% Pd carbon powder (22 mg) was added to the solution, and hydrogen pressure was applied (50p
sha) for 3 hours.

The catalyst was removed by filtration, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (chloroform-methanol 97: 3) to give the diol compound (44 mg,
Quantitative).

R _F 0.13 (chloroform-methanol 96:
Four).

[Α] _D -11.9 ° (c 1.0, chloroform).

¹ H-NMR (deuterated chloroform) δ (ppm) in 50
0MHz: 1.44 (s, 9H), 1.992 (s, 6H), 2.052 (s, 3H), 2.0
66 (s, 3H), 2.073 (s, 3H), 2.090 (s, 3H), 2.171 (s, 3H)
, 2.192 (s, 3H), 4.49 (d, 1H), 4.51 (d, 1H), 4.87 (brs,
1H), 5.03 (dd, 2H), 5.18 (dd, 2H), 5.40 (brd, 2H).

IR (KBr): 3350, 1750, 1680, 1540 cm ^-1 .

(Ii) To a solution of the diol (34 mg) obtained above in methanol (1 ml) was added sodium methoxide (5 μl of a 28% methanol solution) under ice-cooling, and the mixture was stirred for 4 hours.

A strongly acidic cation exchange resin for non-aqueous solution “Amberlyst 15E” was added to the reaction solution until the solution became almost neutral, and the resin was filtered off. The solvent was distilled off to remove the Boc form (compound (30)
a)) was obtained (14 mg, 57%).

R _F 0.23 (n-butanol-acetic acid-water 4: 1: 1
).

[Α] _D + 7.0 ° (c 0.9, methanol).

¹ H-NMR (deuterated methanol) δ (ppm) in 500M
Hz: 1.43 (s, 9H), 4.25 (d, 1H), 4.26 (d, 1H).

IR (KBr): 3470, 1680, 1660, 1550 cm ^-1 Synthesis of compound (30b) (i) A solution of palmitoyl compound (compound (29b)) (97 mg) in ethanol (30 ml) was dissolved in 10% Pd carbon powder ( 52 mg), and the mixture was shaken and stirred under hydrogen pressure (50 psi) for 1.5 hours. Add catalyst (5
(0 mg).

The catalyst was removed by filtration, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (chloroform-methanol 97: 3) to obtain a diol form (82 mg, 90%).

R _F 0.12 (chloroform-methanol 95:
Five).

[Α] _D -0.8 ° (c 0.5, methanol).

¹ H-NMR (deuterated chloroform) δ (ppm) in 50
0MHz: 1.992 (s, 6H), 2.052 (s, 3H), 2.070 (s, 3H), 2.
075 (s, 3H), 2.092 (s, 3H), 2.172 (s, 3H), 2.190 (s, 3
H), 4.50 (d, 1H), 4.51 (d, 1H), 4.87 (m, 1H), 5.0-5.06
(m, 2H), 5.15-5.2 (2H), 5.41 (m, 2H), 6.07 (brt, 1H), 7.
12 (brt, 1H), 8.26 (brt, 1H).

IR (KBr): 3400, 1750, 1670, 1540 cm ^-1 .

(Ii) The diol obtained above (125 mg, 94 μm
To a solution of l) in methanol (2 ml) was added sodium methoxide (10 μl of a 28% methanol solution) under ice-cooling, followed by stirring at room temperature for 3 hours.

After adding "Amberlyst 15E" to the reaction solution until the solution became almost neutral, the resin was filtered off and the solvent was distilled off to obtain a palmitoyl compound (compound (30b)) (79 mg, 85 mg).
%).

R _F 0.3 (n-butanol-acetic acid-water 4: 1:
1).

[Α] _D + 0.6 ° (c 1.0, methanol).

¹ H-NMR (deuterated methanol) δ (ppm) in 500M
Hz: 0.90 (t, 3H), 4.25 (d, 1H), 4.26 (d, 1H).

IR (KBr): 3450, 1660, 1560, 1540 cm ^-1 .

Synthesis of Compound (31a) The Boc compound (compound (29a)) (97 mg) obtained above in methanol
(3 ml) To the solution was added sodium methoxide (15 μl of a 28% methanol solution) under ice cooling, and the mixture was stirred at room temperature for 3 hours.

After adding "Amberlyst 15E" to the reaction mixture until the solution became almost neutral, the resin was removed by filtration, and the crude product (60 mg) obtained by distilling off the solvent was added to Sephadex LH-20. "
The product was purified by (Pharmacia) (methanol) to obtain a Boc form (compound (31a)) (40 mg, 56%).

R _F 0.22 (ethyl acetate-pyridine-acetic acid-water 10: 5: 1: 1).

[Α] _D + 12.1 ° (c 1.0, methanol).

¹ H-NMR (deuterated chloroform) δ (ppm) in 50
0MHz: 1.44 (s, 9H), 4.17 (d, 1H), 4.24 (d, 1H), 7.3-7.5
(m, 5H).

IR (KBr): 3400, 1695 (sh), 1660, 1550 cm
^-1 .

Synthesis of Compound (31b) The palmitoyl compound (Compound (29b)) obtained above (80 mg, 56 μm)
mol) in methanol (3 ml) was added with sodium methoxide (10 μl of a 28% methanol solution) and stirred at room temperature for 3 hours.

After adding "Amberlyst 15E" to the reaction solution until the solution became almost neutral, the resin was filtered off and the solvent was distilled off to obtain a crude product (62 mg). This was purified with "LH-20" (methanol) to obtain a palmitoyl compound (compound (31b)) (60 mg, 98%).

R _F 0.29 (acetic acid ethyl ester-pyridine-acetic acid-water 5: 5: 1: 1).

[Α] _D + 15.6 ° (c 0.5, methanol).

¹ H-NMR (deuterated methanol) δ (ppm) in 500M
Hz: 0.90 (t, 3H), 4.18 (d, 1H), 4.24 (d, 1H), 7.2-7.5
(m, 5H).

IR (KBr): 3500, 1650, 1560, 1550 cm ^-1 .

Example 7 FIG. 7 shows the chemical reactions involved in this example.

Synthesis of Compound (32) Under an argon atmosphere, sodium hydride (60% oil suspe
nsion (132 mg) in dimethylformamide (3 ml) was added to a solution of the monobenzyl compound (compound (26)) (340 mg) in dimethylformamide (2 ml), and the mixture was stirred at room temperature for 30 minutes and further at 60 ° C. for 15 minutes. did. Example 6 (Compound
A dimethylformamide solution of tetrabutylammonium monochloroacetate (425 mg of monochloroacetic acid / 4.5 ml of 1 M methanol solution of tetrabutylammonium hydroxide) obtained in the same manner as in (27) was added dropwise, and the mixture was stirred at room temperature for 15 hours.

The reaction mixture was stirred at 60 to 70 ° C. for 3 hours, cooled to room temperature, poured into water, diluted aqueous sodium bicarbonate and a small amount of sodium iodide were added to the aqueous layer, and the mixture was extracted with chloroform. The mixture was acidified with citric acid and the desired product was extracted with ethyl acetate. The extract was washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain a crude product (0.4 g). Dissolve this in water and transfer the solution to HP-2
0 "(50 ml) (acetonitrile-water 20: 80-8
0:20), of which acetonitrile-water 70: 30-60: 40
The eluted fractions were collected, the solvent was distilled off, the mixture was acidified with citric acid, the desired product was extracted with ethyl acetate, the extract was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate.
Evaporation of the solvent gave a mixture of di and tricarboxymethyl derivatives (327 mg).

Synthesis of Compound (33) A mixture of the di- and tricarboxymethyl derivatives obtained above (300 mg), N-hydroxysuccinimide (242 mg),
Triethylamine (0.33 ml) and 2'-aminoethyl 2,3,4,6-tetraacetyl-β-D- obtained above
Crude product of galactopyranoside (compound (25)) (1.22
g) in dimethylformamide (10 ml) solution under ice-cooling.
A solution of N'-dicyclohexylcarbodiimide (404 mg) in dimethylformamide (3 ml) was added, and the mixture was stirred at room temperature overnight.

Ethyl acetate (20 ml) was added to the reaction solution, insolubles were removed by filtration, the filtrate was poured into water, and the desired product was extracted with ethyl acetate. The extract was washed with water and saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (chloroform-methanol 99: 1 to 98.5: 1.5), and the diamide derivative (compound (28)) (104 mg, 9%, Then, a triamide compound (compound (33)) was obtained (119 mg, 7%, 2 steps).

R _F 0.36 (chloroform-methanol 96:
Four).

[Α] _D -1.7 ° (c 1.7, methanol).

¹ H-NMR (deuterated chloroform) δ (ppm) in 50
0MHz: 1.988 (s, 3H), 1.991 (s, 3H), 1.992 (s, 3H), 2.
030 (s, 3H), 2.037 (s, 3H), 2.048 (s, 6H), 2.054 (s, 6
H), 2.111 (s, 3H), 2.128 (s, 3H), 2.159 (s, 3H), 4.4
1 (d, 1H), 4.47 (d, 1H), 4.48 (d, 1H), 4.65 (d, 1H), 4.73
(d, 1H), 4.93 (d, 1H), 4.99 (dd, 1H), 5.01 (dd, 2H), 5.
12-5.19 (m, 3H), 5.40 (m, 3H), 6.96 (t, 1H), 7.08 (t, 1
H), 7.3-7.4 (m, 5H).

MS (FAB): 1633 (MH ⁺ ).

IR (KBr): 3400, 1750, 1680, 1540 cm ^-1 .

Synthesis of compound (34a) (i) To a solution of the triamide derivative (compound (33)) (122 mg) and paratoluenesulfonic acid (16 mg) in methanol (6 ml) was added a Lindlar catalyst (150 mg). 50psi)
The mixture was shaken and stirred for 2.5 hours.

The catalyst was removed by filtration, the solvent was distilled off, and the amino compound (1) was removed.
26 mg) was obtained as a crude product. Used for the next reaction without purification.

(Ii) (BocO) ₂ O (35 mg) and triethylamine (38 μl) were added to a solution of the amino compound (126 mg) obtained above in dimethylformamide (3 ml), and the mixture was stirred at room temperature overnight.

The reaction solution was poured into half-saturated saline, and the desired product was extracted with ethyl acetate. The extract was washed with water and saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (chloroform-methanol 95: 5) to obtain a Boc form (compound (34a)) (82 mg, 64%, 2 steps).

R _F 0.39 (chloroform-methanol 96:
Four).

[Α] _D + 1.9 ° (c 1.2, methanol).

¹ H-NMR (deuterated chloroform) δ (ppm) in 50
0MHz: 1.45 (s, 9H), 1.99 (s, 9H), 2.028 (s, 3H), 2.038
(s, 3H), 2.048 (s, 6H), 2.054 (s, 3H), 2.06 (s, 3H),
2.09 (s, 3H), 2.13 (s, 3H), 2.16 (s, 3H), 4.41 (d, 1H), 4.
47 (d, 1H), 4.49 (d, 1H), 4.67 (d, 1H), 4.75 (d, 1H), 4.89
(m, 1H), 4.99 (dd, 1H), 5.017 (dd, 1H), 5.021 (dd, 1H),
5.13-5.19 (m, 3H), 5.39 (brs, 3H), 6.99 (brt, 1H), 7.11
(brs, 1H), 7.3-7.4 (m, 5H).

IR (KBr): 1735, 1679 cm ^-1 .

Synthesis of Compound (34b) (i) To a solution of the triamide (compound (33)) (244 mg) and paratoluenesulfonic acid (31 mg) in ethanol was added a Lindlar catalyst (346 mg), and the mixture was subjected to hydrogen pressure (50 psi). For 2.5 hours.

The catalyst was removed by filtration, the solvent was distilled off, and the amino compound (1) was removed.
77 mg) as a crude product. Used for the next reaction without purification.

(Ii) To a solution of the amino compound (177 mg) obtained above in methylene chloride (4 ml) was added a solution of N-palmitoyloxysuccinimide (47 mg) in toluene (2 ml) and triethylamine (37 μl), and the mixture was stirred at room temperature overnight. did.

The reaction solution was poured into water, and the desired product was extracted with ethyl acetate. The extract was washed with water and a saturated saline solution.
It was dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by column chromatography (chloroform-methanol 98: 2) to obtain a palmitoyl compound (compound (34)
b)) was obtained (101 mg, 48%, 2 steps).

R _F 0.3 (chloroform-methanol 96:
Four).

[Α] _D + 2.1 ° (c 1.05, methanol).

¹ H-NMR (deuterated chloroform) δ (ppm) in 50
0MHz: 0.88 (t, 3H), 1.990 (s, 6H), 1.993 (s, 3H), 2.0
29 (s, 3H), 2.039 (s, 3H), 2.047 (s, 6H), 2.057 (s, 3H)
, 2.061 (s, 3H), 2.097 (s, 3H), 2.129 (s, 3H), 2.157
(s, 3H), 4.41 (d, 1H), 4.47 (d, 1H), 4.49 (d, 1H), 4.67
(d, 1H), 4.74 (d, 1H), 4.91 (m, 1H), 4.99 (d, 1H), 5.017
(d, 1H), 5.020 (d, 1H), 5.12-5.19 (m, 3H), 5.39 (m, 3
H), 6.07 (t, 1H), 6.98 (t, 1H), 7.14 (t, 1H), 7.3-7.4 (m,
5H).

IR (KBr): 1753, 1677, 1540 cm ^-1 .

Synthesis of Compound (35a) (i) A 10% Pd-carbon powder (60 mg) was added to a solution of the Boc compound (compound (34a)) (80 mg) in methanol (5 ml), and the mixture was added under hydrogen pressure (5%).
(0 psi) with shaking for 3 hours.

The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (chloroform-methanol).
97: 3) to give an alcohol form (60 mg, 79
%).

R _F 0.59 (chloroform-methanol 92:
8).

¹ H-NMR (deuterated chloroform) δ (ppm) in 50
0MHz: 1.433 (s, 9H), 1.991 (s, 6H), 1.997 (s, 3H), 2.0
52 (s, 6H), 2.058 (s, 3H), 2.064 (s, 3H), 2.066 (s, 3H)
, 2.08 (s, 3H), 2.16 (s, 6H), 2.17 (s, 3H), 4.49 (d, 1
H), 4.50 (d, 2H), 4.88 (m, 1H), 5.01-5.05 (m, 3H), 5.12
-5.16 (m, 3H), 5.40 (m, 3H), 7.10 (brs, 1H), 7.38 (brt, 1
H), 7.96 (brt, 1H).

IR (KBr): 3435, 1751, 1540 cm ^-1 .

(Ii) Sodium methoxide (28%) was added to a solution of the alcohol (58 mg) obtained above in methanol (2 ml) under ice-cooling.
Methanol solution (10 μl) and stirred for 3 hours.

[0202] "Amberlyst 15E" was added to the reaction solution until the solution became almost neutral, and the resin was filtered off.
(35a)) was obtained (35 mg, 88%).

R _F 0.68 (ethyl acetate-pyridine-acetic acid-water 5: 5: 1: 3).

[Α] _D + 3.4 ° (c 1.1, methanol).

¹ H-NMR (deuterated methanol): 1.44 (s, 9H),
4.2-4.3 (m, 3H).

IR (KBr): 3450, 1660, 1550, 1450, 1430
cm ^-1 .

Synthesis of Compound (35b) (i) 10% Pd carbon powder (100 mg) was added to a solution of palmitoyl compound (compound (34b)) (109 mg) in methanol (6 ml), and the mixture was shaken under hydrogen pressure (50 psi) for 1.5 hours. Stirred.

The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (chloroform-methanol).
98: 2 to 97: 3) to give an alcohol form (47 mg,
43%).

R _F 0.5 (chloroform-methanol 92:
8).

[Α] _D -3.1 ° (c 0.96, methanol).

¹ H-NMR (deuterated methanol) δ (ppm) in 500M
Hz: 0.88 (t, 3H), 1.99 (s, 6H), 2.00 (s, 3H), 2.052 (s, 3H)
H), 2.054 (s, 3H), 2.06 (s, 3H), 2.07 (s, 6H), 2.08 (s,
3H), 2.13 (s, 3H), 2.16 (s, 3H), 2.17 (s, 3H), 4.495 (d, 1
H), 4.497 (d, 1H), 4.503 (d, 1H), 4.88 (m, 1H), 5.01-
5.05 (m, 3H), 5.13-5.17 (m, 3H), 5.40 (m, 3H), 6.11 (br
s, 1H), 7.11 (brt, 1H), 7.33 (brt, 1H), 7.96 (brt, 1H).

IR (KBr): 3410, 1753, 1670, 1541 cm ^-1 .

(Ii) To a solution of the alcohol (47 mg) obtained above in methanol (2 ml) was added sodium methoxide (28%
Methanol solution (5 μl) was added and the mixture was stirred for 3 hours.

After adding "Amberlyst 15E" to the reaction solution until the solution became almost neutral, the resin was filtered off to obtain a palmitoyl compound (compound (35b)) (29 mg, 86%).

R _F 0.8 (ethyl acetate-pyridine-acetic acid-water 5: 5: 1: 3).

[Α] _D + 3.1 ° (c 0.81, methanol).

¹ H-NMR (deuterated methanol) δ (ppm) in 500M
Hz: 0.90 (s, 9H), 4.27 (d, 3H).

IR (KBr): 3430, 1650, 1560 cm ^-1 .

Example 8 FIG. 8 shows the chemical reactions involved in this example.

Synthesis of Compound (38) (i) To a solution of the azide form (compound (36)) (242 mg) and paratoluenesulfonic acid (102 mg) in ethanol (20 ml) was added a Lindlar catalyst (180 mg), and the mixture was added with hydrogen under pressure ( (50 psi) with shaking for 1.5 hours. After adding Lindlar's catalyst (60 mg) and shaking for 1.5 hours, further adding Lindlar's catalyst (90 mg) and shaking and stirring for 1 hour.

The Lindlar catalyst was removed by filtration, the filtrate was concentrated, and triethylamine (0.18 ml) was added to a solution of the residue amino compound (compound (37)) in acetonitrile (4 ml).

(Ii) Tricarboxylic acid (compound (16)) (100 m
g) and N-hydroxysuccinimide (62 mg) in acetonitrile (5 ml) were added with N, N'-diclohexylcarbodiimide (111 mg) and stirred at room temperature for 1.5 hours. The insolubles were filtered with cotton, and an acetonitrile solution of the amino compound (compound (37)) obtained in (i) was added dropwise to the filtrate, followed by stirring at room temperature overnight.

The solvent was distilled off, and the methylene chloride solution of the residue was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was subjected to silica gel column chromatography (chloroform-methanol 98: 2 to 95:
Purification in 5) gave a triamide form (compound (38)) (197m).
g).

R _F 0.61 (chloroform-methanol 9:
1).

[Α] _D -19.3 ° (c 1.0, chloroform).

¹ H-NMR (deuterated methanol) δ (ppm) in 500M
Hz: 1.90 (s, 3H), 1.91 (s, 3H), 1.92 (s, 3H), 1.95 (s, 9
H), 2.014 (s, 3H), 2.021 (s, 6H), 2.13 (s, 6H), 2.14
(s, 3H), 4.52 (d, 1H), 4.56 (d, 2H), 5.04-5.09 (m, 3H),
5.15 (brs, 1H), 5.33 (m, 3H), 7.2-7.5 (m, 15H).

IR (KBr): 3430, 1750, 1660, 1550 cm ^-1 .

Synthesis of Compound (39) A triamide compound (Compound (38)) (24 mg) was dissolved in acetic acid (1.5 ml), and the mixture was heated with stirring at 60 ° C. for 7 hours.

The reaction solution was poured into water, neutralized with sodium hydroxide, the desired product was extracted with ethyl acetate, the extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue (20 mg) was purified by silica gel column chromatography (chloroform-methanol 95: 5).
-92: 8) to give an alcohol (compound (39)) (13 mg, 62%).

R _F 0.56 (chloroform-methanol 9:
1).

[Α] _D -16.8 ° (c 0.5, chloroform).

¹ H-NMR (deuterated methanol) δ (ppm) in 500M
Hz: 1.93 (s, 9H), 1.95 (s, 9H), 2.03 (s, 9H), 2.15 (s, 9H)
H), 4.558 (d, 1H), 4.563 (d, 1H), 4.568 (d, 1H), 5.00
(brs, ManC1-H), 5.05-5.1 (m, 3H), 5.34 (d, 3H).

IR (KBr): 3450, 1750, 1660, 1560 cm ^-1 .

Synthetic alcohol (compound (39)) of compound (40 ) (13 mg) in methanol (1 ml)
Add sodium methoxide (28% methanol solution 2μ)
l) was added and the mixture was stirred at room temperature for 2 hours.

The solvent was distilled off, and the residue was purified with "LH-20" (methanol) to obtain a deacetylated compound (compound (40)) (5 mg, 50%).

R _F 0.62 (acetic acid ethyl ester-pyridine-acetic acid-water 5: 5: 1: 3).

[Α] _D -0.7 ° (c 0.5, methanol).

¹ H-NMR (deuterated methanol) δ (ppm) in 500M
Hz: 1.98 (s, 9H), 4.369 (d, 1H), 4.373 (d, 1H), 4.376
(d, 1H), 5.00 (brs, 1H).

IR (KBr): 3420, 1660, 1570, 1550 cm ^-1 .

Example 9 FIG. 9 shows the chemical reactions involved in this example.

To a solution of the azide form (compound (38)) (86 mg) and paratoluenesulfonic acid (9 mg) in ethanol (10 ml) was added a Lindlar catalyst (120 mg), and the mixture was pressurized with hydrogen (50 psi).
Shake and stir for hours. Add Lindlar catalyst (120mg),
The mixture was further shaken and stirred for 2 hours.

The Lindlar catalyst was removed by filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (chloroform-methanol 9: 1 to 7: 3) to give the amino compound (compound (41)) (43 mg) and the starting material. (Compound (38)) (40 mg) was obtained. Triethylamine (5 drops) was added to a solution of the obtained compound (41) in methylene chloride (4 ml), and a solution of N-palmitoyloxysuccinimide (12 mg) in toluene (2 ml) was added dropwise thereto, followed by stirring at room temperature overnight.

Methylene chloride was added to the reaction solution, and the extract was washed with water and saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by column chromatography (chloroform-methanol 97: 3 to 95: 5) to obtain a palmitoyl compound (compound (42)) (43 mg, 89).
%).

R _F 0.6 (chloroform-methanol 93: 7
).

[Α] _D -13.8 ° (c 1.0, chloroform).

¹ H-NMR (deuterated methanol) δ (ppm) in 500M
Hz: 0.89 (t, 3H), 1.90 (s, 3H), 1.91 (s, 3H), 1.92 (s, 3H)
H), 1.94 (s, 3H), 1.95 (s, 6H), 2.01 (s, 3H), 2.017 (s, 3H)
H), 2.018 (s, 3H), 2.124 (s, 3H), 2.127 (s, 3H), 2.1
39 (s, 3H), 4.52 (d, 1H), 4.56 (d, 2H), 5.04-5.09 (m, 3H)
, 5.15 (brs, 1H), 5.33 (m, 3H), 7.2-7.5 (m, 15H).

IR (KBr): 3450, 1750, 1670, 1560 cm ^-1 .

Synthesis of Compound (43) A palmitoyl compound (compound (42)) (42 mg) was dissolved in acetic acid (2 ml), and the mixture was heated and stirred at 60 ° C. for 6 hours.

The reaction solution was poured into water, neutralized with sodium hydroxide, and the desired product was extracted with ethyl acetate. The extract was washed with water and saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue (20 mg) was purified by silica gel column chromatography (chloroform-methanol 95: 5).
To 93: 7) to give an alcohol form (compound (43)) (23 mg, 62%).

R _F 0.5 (chloroform-methanol 92: 8
).

¹ H-NMR (deuterated methanol) δ (ppm) in 500M
Hz: 0.90 (t, 3H), 1.926 (s, 9H), 1.950 (s, 9H), 2.026
(s, 9H), 2.144 (s, 9H), 4.559 (d, 1H), 4.565 (d, 1H)
, 4.569 (d, 1H), 4.94 (brs, 1H), 5.06-5.09 (m, 3H),
5.34 (brd, 3H).

IR (KBr): 3350, 1750, 1660, 1550 cm ^-1 .

Synthetic alcohol (compound (43)) (23 mg) of compound (44 ) in methanol (2 ml)
Add sodium methoxide (28% methanol solution 2μ)
l) was added and the mixture was stirred at room temperature for 7 hours.

The solvent was distilled off, and the residue was purified with "LH-20" (methanol) to obtain a deacetylated compound (compound (44)) (13 mg, 71%).

R _F 0.89 (ethyl acetate-pyridine-acetic acid-water 5: 5: 1: 3).

[Α] _D + 18.5 ° (c 1.3, methanol).

¹ H-NMR (deuterated methanol) δ (ppm) in 500M
Hz: 0.90 (t, 3H), 1.98 (s, 9H), 4.36 (d, 3H), 4.93 (brs,
1H).

IR (KBr): 3420, 1650, 1550 cm ^-1 .

Example 10 The chemical reactions involved in the example are shown in FIGS. 10A-C.

(A) 9-decenyl 2,3,4,6-O-
Synthesis of tetraacetyl-α-D-mannopyranoside (compound 1) Pentaacetyl β-D-galactranoside (20.85
g) and a solution of 9-decene-1-ol (21.7 g) in methylene chloride (400 ml) were added with a boron fluoride ether complex (27 ml) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction solution was poured into ice-saturated aqueous sodium bicarbonate, and the organic layer was washed with half-saturated saline and dried over magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (SiO ₂ 2
00g, chloroform) to give a crude product (3
4.84 g). Acetic anhydride (80 ml) and pyridine (70 ml) were added to the obtained crude product, and the mixture was stirred overnight. The solvent was distilled off, the residue was dissolved in ethyl acetate, and the residue was diluted with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and saturated saline in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (S
iO ₂ 200 g, toluene: acetone = 99: 1 to 99:
2) to obtain a glycoside compound (compound 1) (14.86 g, 58)
%).

[Α] _D ²⁶ + 0.5 ° (c 1.21, chloroform).

IR (CHCl ₃ ): 1747 cm ⁻¹ .

¹ H-NMR (CDCl ₃ ): 1.25-1.42 (10H, m),
1.55-1.66 (4H, m), 1.993 (3H, s), 2.04 (3H, s), 2.10 (3
H, s), 3.45 (1H, dt, J = 6.5,9.5), 3.68 (1H, dt, J = 6.5,9.
5), 3.98 (1H, ddd, J = 2.5,5.5,10Hz), 4.11 (1H, dd, J = 2.
5,12.5Hz), 4.28 (1H, dd, J = 5.5,12.5Hz), 4.80 (1H, d, J = 2
Hz), 4.93 (1h, brd, J = 10.5Hz), 5.00 (1H, brd, J = 17Hz)
, 5.23 (1H, dd, J = 2,3.5Hz), 5.27 (1H, t, J = 10Hz), 5.3
5 (1H, 5.81 (1H, ddt, J = 10.5, 17Hz).

Rf = 0.33 (toluene: acetone = 9:
1).

(B) Synthesis of 9-decenyl α-D-mannopyranoside (compound 2) The glycoside (14.86 g) obtained above was treated with methanol (10.86 g).
Sodium methoxide (28% methanol solution)
1.5 ml) and stirred at room temperature for 2.5 hours. “Dowex 50W 1 × 8” was added to the reaction solution until the solution became neutral, the resin was removed by filtration, and the filtrate was concentrated to obtain a tetraol compound (compound 2) (9.88 g quant).

IR (neat): 3450 cm ^-1 .

¹ H-NMR (CDCl ₃ ): 1.25-1.35 (8H, m),
1.35-1.42 (2H, m), 1.5-1.6 (2H, m), 2.04 (2H, brq, J = 7H
z), 3.38 (1H, dt, J = 7.9.5Hz), 3.51 (1H, brd, J = 9.5Hz),
3.62 (1H, dt, J-7,9.5Hz), 3.76 (1H, dd, J = 2.5,12.5Hz,)
, 3.81 (1H, dd, J = 3.5,9.5Hz), 3.87 (1H, t, J = 9.5Hz),
3.90 (1H, m), 3.92 (1H, dd, J = 2.5,12.5Hz,), 4.79 (1H, br
s), 4.92-4.98 (1H, m), 5.00-5.02 (1H, m), 5.81 (1H, dd
t, J = 10,17.6Hz).

Rf = 0.40 (chloroform: methanol =
9: 1).

(C) Synthesis of 9-decenyl 6-O-triphenylmethyl-α-D-mannopyranoside (compound 3) The tetraol compound (9.88 g) obtained above in pyridine (60 m
l) Trityl chloride (10.2 g) was added to the solution, and the mixture was stirred overnight at 50 ° C while heating. The solvent was distilled off, the residue was dissolved in ethyl acetate, washed with diluted hydrochloric acid, water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (SiO ₂ 100 g, chloroform: methanol = 99:
1-98: 2) to give a trityl form (compound 3) (11.52).
g).

[Α] _D ²⁹ + 15.9 ° (c 1.25, chloroform).

IR (CHCl ₃ ): 3700, 3600, 1520, 1480,
1420cm ^-1 .

¹ H-NMR (CDCl ₃ ): 1.25-1.40 (10H, m),
1.54-1.62 (2H, m), 2.03 (2H, brq, J = 7Hz), 3.37-3.48 (3
H, m), 3.68 (1H, dd, J = 7,9.5H,), 3.70-3.72 (2H, m),
3.78-3.83 (1H, m), 3.90 (1H, dd, J = 1.5,3.5Hz), 4.81 (1
H, brd, J = 1.5Hz,), 4.91-4.94 (1H, m), 4.96-5.01 (1H,
m), 5.81 (1H, ddt, J = 10,17,6.5Hz,), 7.2-7.5 (15H,
m).

Rf = 0.63 (chloroform: methanol =
9: 1).

(D) 9-decenyl-2,3,4-0-tricarboxymethyl-6-0-triphenylmethyl α-
Synthesis of D-mannopyranoside (compound 4) A solution of the trityl compound (0.99 g) obtained in a DMF (10 ml) suspension of sodium hydride (0.26 g) in DMF (10 ml) was added under ice-cooling, and the mixture was cooled to room temperature. And stirred for 2 hours. Another 30 minutes
The mixture was stirred at 50 ° C. To this, a solution of tetrabutylammonium monochloroacetic acid in DMF (15 ml) (previously, monochloroacetic acid (0.76 g) and tetrabutylammonium hydroxide (8 ml of a 1 M methanol solution) was mixed, and water was repeatedly azeotroped with toluene. After removal, the mixture was dried under reduced pressure.) Under ice-cooling. The mixture was stirred at room temperature for 2.5 days. The solvent was evaporated and the residue was purified by reverse phase chromatography (Cosmosil 75C ₂₀ -OPN 40g, acetonitrile: water = 1: 1) to give tri carboxymethyl body (Compound 4) (206 mg, 15%) .

Rf = 0.37 (n-butanol: acetic acid: H ₂ O
= 4: 1: 1).

(E) Synthesis of triamide (compound 6) Tricarboxymethyl (200 mg) obtained above and N-
N, N-Cyclohexylcarbodiimide (189 mg) was added to a solution of hydroxysuccinimide (105 mg) in acetonitrile (40 ml), and the mixture was stirred at room temperature for 3 hours. 2-
(2- (2-aminoethoxy) ethoxy) ethyl 2,
Paratoluenesulfonic acid salt of 3,4,6-0-tetraacetyl-β-D-galactopyranoside (compound 5) (60
Triethylamine (0.27 ml) was added to a solution of 9 mg) in acetonitrile (40 ml), and the solution was added dropwise to the above reaction mixture at room temperature and stirred overnight. The insoluble material was removed by filtration, the filtrate was concentrated, and the methylene chloride solution of the residue was washed with water and half-saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (SiO ₂ 40 g, chloroform: methanol = 99: 1 to 98: 2) to obtain a triamide compound (compound 6) (346 mg, 65%). .

[Α] _D ²⁶ + 1.2 ° (c 1.14, chloroform).

IR (CHCl ₃ ): 3700, 3600, 3450, 1750,
1680, 1520cm ^-1 .

¹ H-NMR (CDCl ₃ ): 1.25-1.4 (8H, m), 1.5
5-1.65 (4H, m), 1.99 (9H, s), 2.02 (3H, s), 2.04-2.05 (1
5H, s), 2.141 (3H, s), 2.145 (3H, s), 2.15 (3H, s), 4.5
25,4.534,4.54 (each 1H, d, J = 8Hz), 4.93 (1H, brs), 5.0
-5.06 (3H, m), 5.17-5.23 (3H, m), 5.39 (3H, m), 5.80 (1
H, ddt, J = 10,17.6.5Hz), 6.75 (1H, t, J = 5.5Hz), 7.2-7.5
(15H, m).

Rf = 0.43 (chloroform: methanol = 9
5: 5).

(F) Synthesis of aldehyde compound (compound 7) The triamide compound (340 mg) was dissolved in a mixed solvent of methanol (30 ml) and methylene chloride (5 ml), and ozone was passed at -78 ° C for about 30 minutes. Dimethyl sulfide (15 ml) was added, the mixture was stirred at room temperature for 1.5 hours, the solvent was distilled off, and the residue was purified by silica gel column chromatography (Si
O ₂ 40 g, chloroform: methanol = 98: 2) and an aldehyde compound (compound 7) were obtained (307 mg).

IR (KBr): 3450, 3360, 1740, 1690, 1530
cm ^-1 .

¹ H-NMR (CDCl ₃ ): 1.28-1.36 (8H, m),
1.55-1.65 (4H, m), 1.984 (9H, s), 2.021 (3H, s), 2.04
(15H, s), 2.143 (3H, s), 2.148 (3H, s), 2.152 (3H, s)
, 2.41 (2H, dt, J = 1.5,7Hz), 4.526 (1H, d, J-8Hz), 4.5
37 (1H, d, J = 8H), 4.541 (1H, d, J = 8Hz), 4.93 (1H, brs),
5.00-5.05 (3H, m), 5.17-5.23 (3H, m), 5.38-5.41 (3H, m
m), 7.2-7.5 (15H, m), 9.75 (1H, t, J = 1.5Hz).

(G) Synthesis of carboxylic acid (compound 8) The aldehyde (307 mg) obtained above was treated with tert-butanol (5.5 ml) and 2-methyl-2-butene (1.5 ml).
In a mixed solvent of NaClO ₂ (227 mg) and N
An aqueous solution (3 ml) of aHPO ₄ (294 mg) was added dropwise at room temperature, and the mixture was stirred for 1.5 hours. Ethyl acetate was added to the reaction mixture, which was washed with a 2.5% sodium thiosulfate solution, water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (SiO ₂ 10 g, chloroform: methanol = 98: 2 to 9: 1), and the recovered material (100 m
g) and a carboxylic acid (compound 8) were obtained (180 mg).

(H) Synthesis of methyl ester (compound 9) A solution of the carboxylic acid obtained in THF (10 ml) was added with an ether solution of diazomethane under ice cooling until the solution became pale yellow, and the mixture was stirred for 10 minutes. Thereafter, the mixture was further stirred at room temperature for 30 minutes. The solvent was distilled off, and the residue was purified by silica gel column chromatography (SiO ₂ 10 g, chloroform:
Methanol = 99: 1 to 98: 2) to give the methyl ester (compound 9) (158 mg).

[Α] _D ²⁶ + 0.7 ° (c 1.0, chloroform).

IR (CHCl ₃ ): 3450, 1750, 1675, 1535 cm
^-1 .

¹ H-NMR (CDCl ₃ ): 1.28-1.36 (8H, m),
1.55-1.65 (4H, m), 1.98-1.99 (9H, s), 2.02 (3H, s), 2.0
3-2.05 (15H, m), 2.14 (3H, s), 2.144 (3H, s), 2.148 (3H,
s), 2.29 (2H, t, J = 7.5 Hz), 4.526, 4.537, 4.541 (each 1
(H, d, J = 7.5Hz), 4.93 (1H, brs), 5.0-5.1 (3H, m), 5.15-
5.25 (3H, m), 5.39 (3H, brs), 6.74 (1H, t, J = 5.5Hz), 7.2
-7.6 (15H, m).

M / z (FAB) 2173 (M + Na ⁺ ), 2151 (MH ⁺ ).

Rf = 0.45 (chloroform: methanol = 9
5: 5).

(I) Synthesis of monoalcohol (compound 10) The methyl ester (170 mg) obtained above was added with acetic acid (8 ml), and the mixture was stirred at 65 ° C. for 9 hours. The solvent was distilled off, and the residue was purified by silica gel column chromatography (SiO 2
₂ 20 g, chloroform; methanol = 98: 2-97:
3) A monoalcohol compound (compound 10) was obtained (125 mg)
).

[Α] _D ²⁶ + 5.0 ° (c 0.92, chloroform).

IR (CHCl ₃ ): 3450, 1750, 1670, 1535 cm
^-1 .

¹ H-NMR (CDCl ₃ ): 1.28-1.36 (8H, m),
1.99,2.05,2.06,2.15 (each 9H, s), 2.31 (2H, t, J = 7.5H
z), 4.55 (2H, d, J = 8Hz), 4.56 (1H, d, J = 8Hz), 4.80 (1H, br
s), 5.01-5.06 (3H, m), 5.15-5.23 (3H, m), 7.20 (1H,
m), 7.33 (1H, m).

Rf = 0.50 (chloroform: methanol = 9
5: 5).

(J) Synthesis of Deprotected Compound (Compound 11) The monoalcohol compound (155 mg) obtained above was treated with methanol (10
ml) 28% sodium methoxide in methanol solution
60 μl) and stirred at room temperature for 2 hours. "Dowe
x50W 1x8 "was added until the solution became neutral, the resin was removed by filtration, and the filtrate was concentrated to obtain a deprotected compound (compound 11) (111 mg).

[Α] _D ²⁶ + 9.7 ° (c 1.0, methanol).

IR (KBr): 3400, 1660, 1550 cm ^-1 .

¹ H-NMR (CD ₃ OD): 1.3-1.4 (8H, m), 1.5
5-1.65 (4H, m), 2.32 (2H, r, J = 7.5Hz).

Rf = 0.40 (chloroform: methanol: H
₂ O = 10: 6: 1).

(K) Synthesis of hydrazide (compound 12) To a solution of the deprotected compound (105 mg) obtained above in methanol (5 ml) was added hydrazine monohydrate (0.5 ml), and the mixture was stirred at room temperature for 2 days. . The solvent is distilled off, and the hydrazide form (compound 12)
I got

[Α] _D ²⁶ + 10.9 ° (c 1.05, methanol).

IR (KBr): 3400, 1660, 1550 cm ^-1 .

¹ H-NMR (CD ₃ OD): 1.25-1.42 (8H, m),
1.55-1.64 (4H, m), 2.15 (2H, t, J-7.5Hz).

Rf = 0.1 (chloroform: methanol: H
₂ O = 10: 6: 1).

Experimental Example 1 1. Sample N-acetylgalatosamine (GalNAc) was used as a control sample, and "41-003A" (compound (40) produced in Example 8) was used as a sample.

[0307] 2. Experimental Method Rat hepatocytes were prepared by the collagenase perfusion method, and the following experiment was performed to evaluate the affinity of the sample for the Gal / GalNAc receptor possessed by the cells.
That is, ¹²⁵ I-neoglycoprotein ((Gal-
C ₈ ) ₃₅ -HSA) was incubated with hepatocytes for 2 hours at 4 ° C. at 1 μg / ml in the absence of (a) sample and EDTA, (b) sample or (c) 5 mM EDTA.
A part of the reaction solution was separated into an unreacted substance and a cell fraction according to an oil tube centrifugation method. The cell fraction (sediment portion) was cut, and the radioactivity of neoglycoprotein bound to the cells was measured by a γ-counter.

The inhibitory activity of the sample was determined by the following equation.

[0309]

(Equation 1)

In the formula, A: radioactivity in the absence of the sample and 5 mM EDTA (total binding activity), B: radioactivity in the presence of the sample (binding activity of the sample), C: radioactivity in the presence of 5 mM EDTA ( Non-specific binding activity).

[0311] 3. Results The inhibitory activities of the control sample and the test sample are as shown in FIG.
When the concentration of the sample giving 50% inhibition activity and IC _50, respectively IC ₅₀ of the control sample and the test sample, 2mM and 2nM
It became.

[0312] The affinity for hepatocytes analyte sample from the above description has been increased by 10 ⁶ times the control sample. That is, the recognition of N-acetylgalactoxamine by hepatic parenchymal cells is markedly improved by using mannose as a skeleton. Therefore, the substance of the present invention can be used as a glycolipid derivative for organ targeting in drug delivery technology. It turns out to be useful.

[0313]

Industrial Applicability According to the present invention, in a drug delivery technique using a fine particle carrier, a branched sugar complex having a novel sugar skeleton and imparting an excellent organ directivity to the fine particle carrier, and a synthetic intermediate thereof Will be provided.

[Brief description of the drawings]

FIG. 1A shows the chemical reactions involved in Example 1.

FIG. 1B shows the chemical reactions involved in Example 1.

FIG. 2 shows the chemical reactions involved in Example 2.

FIG. 3 shows the chemical reactions involved in Example 3.

FIG. 4 shows the chemical reactions involved in Example 4.

FIG. 5A shows the chemical reactions involved in Example 5.

FIG. 5B shows the chemical reactions involved in Example 5.

FIG. 6 shows the chemical reactions involved in Example 6.

FIG. 7 shows the chemical reactions involved in Example 7.

FIG. 8 shows the chemical reactions involved in Example 8.

FIG. 9 shows the chemical reactions involved in Example 9.

FIG. 10A shows the chemical reactions involved in Example 10.

FIG. 10B shows the chemical reactions involved in Example 10.

FIG. 10C shows the chemical reactions involved in Example 10.

FIG. 11 shows the inhibitory activity in Experimental Example 1.

Continued on the front page (58) Fields investigated (Int.Cl. ⁶ , DB name) C07H 15/04 C07H 15/06 A61K 9/127 A61K 47/26 CA (STN) REGISTRY (STN) WPIDS (STN)

Claims (4)

(57) [Claims] 1. A branched derivative having a sugar skeleton represented by the following formula (I). Embedded image In the formula (I), n represents an integer of 4 or 3,
[S ⁴ ] represents the following formula (II), (III) or (IV), and [S ³ ] represents the following formula (V) or (VI), and X ¹ ,.
ⁿ independently represents H, a benzyl group, a trityl group, a benzylidene group, a carboxymethyl group, or a group represented by the following formula (VII) or (VII '). Embedded image In the formula (I), (X ¹ ,..., X ⁿ ) means that the group shown in () is bonded to [S ⁿ ], and these groups may be the same or different from each other. , () Is at least one of the groups represented by formula (VII) or (VI
It is a group represented by I ′). Note that the formulas (VII) and (VI
In I '), (T) represents the following formulas (VIII) to (XIII), m represents an integer of 2 to 8, and m' represents an integer of 1 or 2. In the formulas (VIII) to (XIII), R represents H or an acetyl group. Also, the following formula (II)
In (VI) to (VI), Y represents a group — (CH ₂ ) _r N ₃ ;
H ₂ ) _r NH ₂ , group — (CH ₂ ) _r NHZ, group — (CH ₂ ) _r
CH ＝ CH ₂ or a group — (CH ₂ ) _r COR ¹ , wherein r represents an integer of 2 to 10, Z represents a benzyloxycarbonyl group or a t-butoxycarbonyl group, and R ¹ represents group -OH, group -NHNH ₂ or 1 to 3 carbon atoms
Represents an alkoxyl group or an alkylamino group. Embedded image In Formulas (II) to (VI) and Formulas (VIII) to (XIII), a bond represented by a wavy line represents an α bond or a β bond. 2. A branched derivative having a sugar skeleton represented by the following formula (I). Embedded image In the formula (I), n represents an integer of 4 or 3,
[S ⁴ ] represents the following formula (II), (III) or (IV), and [S ³ ] represents the following formula (V) or (VI), and X ¹ ,.
ⁿ independently represents H, a benzyl group, a trityl group, a benzylidene group, a carboxymethyl group, or a group represented by the following formula (VII) or (VII '). Embedded image In the formula (I), (X ¹ ,..., X ⁿ ) means that the group shown in () is bonded to [S ⁿ ], and these groups may be the same or different from each other. , () Is at least one of the groups represented by formula (VII) or (VI
It is a group represented by I ′). Note that the formulas (VII) and (VI
In I '), (T) represents the following formulas (VIII) to (XIII), m represents an integer of 2 to 8, and m' represents an integer of 1 or 2. In the formulas (VIII) to (XIII), R represents H or an acetyl group. Also, the following formula (II)
In ~ (VI), Y is a group - represents a (CH _{2) r} NHZ,
Here, r represents an integer of 2 to 10, and Z represents a linear or branched alkylcarbonyl group. Embedded image In Formulas (II) to (VI) and Formulas (VIII) to (XIII), a bond represented by a wavy line represents an α bond or a β bond. 3. The branched type derivative having a sugar skeleton according to claim 2, wherein [S ⁿ ] is formula (II) or formula (V). 4. When (T) is the formula (VIII), the formula (X) or the (X)
The branched derivative having a sugar skeleton according to claim 3, which is I).