JPH069675A - Branched chain-type derivative having glucoskeleton - Google Patents

Abstract

PURPOSE:To provide a new branched chain-type derivative capable of imparting fine particle carriers with high organotropism. CONSTITUTION:The derivative of formula I {n is 4 or 3; when n is 4, S<4> being of formula II or III (wavy bond is alpha or beta bond), etc.; when n is 3, S<3> being of formula IV, etc. [Y is (CH2)rN3, COR1 (r is 2-10; R1 is OH, NHNH2, etc.), etc.]; X is H, benzyl, carboxymethyl, of formula V, formula VI [T is of formula VII (R is H or acetyl), etc.; m is 2-8], etc.}, e.g. a compound of formula NIII. The compound of the formula I can be obtained, for example, by the following process: a bromoalkanol is made to react with an OH-protected saccharide in the presence of a Lewis acid such as boron trifluoride ether followed by reaction with sodium azide to introduce an azide chain into the 1-site of the saccharide to represent skeleton to form an azide derivative, which is, in turn, reduced by hydrogen in the presence of Lindlar catalyst into an amine modification, which is then made to react with a carbonyl compound in the presence of dicyclohexylcarbodiimide followed by deacetylation.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a branched chain derivative having a novel sugar skeleton. This derivative is useful as a glycolipid derivative for use as a particulate carrier in drug delivery technology.

[0002]

2. Description of the Related Art When developing a drug delivery system, it is already well known to use fine particle carriers such as liposomes and lipid microspheres as drug carriers. However, it is well known that when a fine particle carrier is administered intravenously, it is easily trapped in the cell endothelium system such as the liver and spleen, which is a problem in applying the fine particle carrier as a formulation to a drug delivery system. Has become.

Conventionally, improvement of liposome microcirculation,
That is, various attempts have been made to improve the circulation of liposomes into peripheral capillaries. For example, as shown in the following documents 1) to 9).

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) “Proceedings of the 9th Symposium on Interactions between Biomembranes and Drugs” 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 In 2), it is described that cholesterol and a lipid having a high phase transition temperature are respectively added to liposomes, and in Reference 3), there is an example in which microcirculation is increased by reducing the size of liposomes. It is shown. Reference 4) describes ganglioside GM ₁ which is a glycolipid derived from cell membrane, reference 5) describes glycophorin which is a glycoprotein derived from human red blood cell, and reference 6).
Describes that glycoproteins derived from serum proteins, fetuin, were reconstituted in the liposome membrane, respectively, and it is described in References 4) and 5) that microcirculation was improved. Reference 7) describes 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. In References 8) and 9), sulfatide was inserted into the liposome membrane to cross the blood-brain barrier and human Glio, respectively.
It has been described that the uptake into ma cells was successful.

[0005] On the other hand, it is known that a unique protein lectin exists in organs, and this protein has a binding site for sugar, and the type of sugar that binds differs from organ to organ. It is expected to function as a receptor for the ligand at the end. That is, it is expected to be a clue for the recognition of a specific organ in drug delivery technology.

Regarding the relationship between a receptor and a ligand having a sugar at its end, for example, the following Reference 10)-
12), and examples of technical applications include, for example,
There are the following documents 13) to 14).

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 In References 10) to 12), a peptide is used as a backbone. We prepared a synthetic ligand that clusters sugars at the ends, and confirmed the existence of the so-called cluster effect from the affinity of this with the receptor. Reference 13) shows a technique for binding a drug to a synthetic ligand, that is, a glycopeptide, and intending the selective delivery of the drug. Reference 14) also discloses a similar technique, but is characterized in that the sugar density is increased by binding the sugar to the tris group.

[0008]

According to the above-mentioned prior art, if a peptide is used as a skeleton and sugars are clustered to this, the effect by that is recognized. However, the effect of using a substance other than a peptide as a skeleton has not been clarified, and it remains as a problem in the prior art. The present invention aims to provide a novel substance for this problem.

[0009]

Means for Solving the Problems As a result of earnest research to solve the above-mentioned problems, the present inventor has found that a synthetic ligand having a sugar as a skeleton and having the sugar clustered at the end thereof is useful for organ orientation in drug delivery technology. They have found that they are useful as glycolipid derivatives, and have completed the invention described in the claims based on this finding.

The present invention will be described in detail below.

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

[0012]

[Chemical 4]

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

When n is 4, the 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 bonds. . However, [S ⁴ ] represents one of the following formulas (II), (III) and (IV).
As is clear from the respective formulas, the formula (II) is a mannose in which the linking group Y is glycosylated, the formula (III) is a galactose in which the linking group Y is glycosylated, and the formula (IV) is a glucose-bonding group. Y represents a glycosyl bond. Therefore, when n is 4, the formula (I) represents a compound in which the linking groups X ¹ , X ² , X ³ , X ⁴ and Y are bonded to mannose, galactose or glucose, where mannose and galactose are used. Or, since glucose forms a skeleton portion in each compound, it is called a sugar skeleton.

Similarly, when n is 3, the formula (I) becomes 3
It represents a compound in which ^three bonding groups X ¹ , X ² and X ³ are bonded to [S ³ ] having one bond, provided that [S ³ ]
Represents one of the following formulas (V) and (VI). The sugar skeleton in this case is fucose or xylose as shown in formula (V) and formula (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]

[Chemical 5]

Here, the benzyl group, the trityl group and the benzylidene group are protective groups for the hydroxyl groups of the skeletal sugar. In addition, a carboxymethyl group and the formula (VII) or the formula (VII ')
It has a mutual relationship with the group represented by, and first, a carboxymethyl group is introduced into the hydroxyl group of the skeletal sugar, and then a predetermined sugar chain amine is condensed with this carboxyl group to form the formula (VII) or the formula (VII ′). It becomes the group shown by. The group represented by the formula (VII) or the formula (VII ′) is (T) via a methylene chain (the number of carbon atoms of the methylene chain is 2 to 8) as a spacer or a spacer different from this, respectively. Is a group having a sugar at the terminal, and since these are branched from the skeletal sugar and have a sugar at the terminal, they are groups that form a so-called branched chain sugar.

The sugar represented by (T) is specifically shown as follows.
Formulas (VIII) to (XIII) below. 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, and n bonding groups are described in (), 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 formula (VII) or a formula (VII). VII ') is meant. 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 the terminal.

Y in the formulas (II) to (VI) is 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 of 2 to 10, Z represents a benzyloxycarbonyl group, t-butoxycarbonyl group or a linear or branched alkylcarbonyl group, and R ¹ Represents a group —OH, a group —NHNH _2, 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 carbon number of the methylene chain is 2 to 10). Thus, the compounds of formula (I) have a sugar skeleton on the one hand, while having a carboxymethyl group or a branched sugar,
On the other hand, it shows a derivative having a fatty chain.

[0022]

[Chemical 6]

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

The final target substance of the present invention is a group in which at least one of the linking groups represented by (X ¹ , ..., X ⁿ ) in formula (I) is represented by formula (VII) or formula (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, where Z Is a substance that represents a straight-chain or branched-chain alkylcarbonyl group (a branched-chain sugar complex having a sugar skeleton). The other substances of the present invention are intermediates 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, and the following three main reactions constitute the manufacturing process. The first is a reaction in which an azido derivative or a phthalimide derivative in which an azido chain or a phthalimide chain is introduced at the 1-position of a sugar to be a skeleton is prepared, and a protecting group is introduced 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 into the carboxyl group to introduce a branched chain sugar. It is a series of reactions in which the azide of the chain is hydrogenated to an amine and then a carbonyl group is introduced into the amine. Other reactions include a reaction in which a sugar chain amine for a branched sugar is prepared in advance, a reaction in which a protecting group for a hydroxyl group of a skeletal sugar is removed at an appropriate stage of the production process, or a branched chain in the final step. There is a reaction for removing the acetyl protecting group of the hydroxyl group of sugar, and it may be appropriately adopted.

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

In the second main reaction, for example, tetrabutylammonium monochloroacetate may be reacted in the presence of sodium hydride to introduce a carboxymethyl group into another predetermined hydroxyl group of the sugar. Then, a sugar chain amine for the branched chain sugar may be condensed in the presence of, for example, dicyclohexylcarbodiimide and hydroxysuccinimide.

In the third main reaction, for example, the 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.

The sugar chain amine for the branched chain sugar is prepared by previously protecting the hydroxyl group of the sugar to be the branched chain sugar with an acetyl group and then adding bromoalkanol to the sugar in the presence of boron trifluoride ether or the like. Glycosylation by reacting with
Then, reacting with sodium azide to give sugar chain azide,
Finally, it can be prepared, for example, by reducing the azido group with hydrogen in the presence of a Lindlar catalyst to give an amine group.

The removal of the acetyl-protecting group for the hydroxyl group of the branched chain sugar, which is carried out 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 a drug delivery technique using a fine particle carrier.

[0032]

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

60 g of bromoethyl glycoside compound was added to N, N-
It was dissolved in 200 ml of dimethylformamide, 32 g of sodium azide was added, and the mixture was stirred at room temperature overnight. Then 2 at 80 ℃
After stirring for 200 hours, 200 ml of ethyl acetate was added, and the solid matter was filtered off. After distilling off dimethylformamide and ethyl acetate, the solution was again made into an ethyl acetate solution and washed with water 4 times to quantitatively obtain an azidoethyl glycoside compound (compound (24)). R _F = 0.40
(PhCH ₃ -AcOEt 2: 1).

4.17 g of azide and P-toluenesulfonic acid
An amine compound (compound (25)) was obtained by hydrogen reduction (45 psi, 1.5 h) of 2.28 g of ethanol solution in the presence of 4.0 g of Lindlar catalyst. 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 was added 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 product 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 = 6.6Hz), 1.21 (d, 1H, J = 6.6Hz).

Then, the glycosyl compound was made into a 50 ml dimethylformamide solution, 1.2 M equivalent of sodium azide was added, and the mixture was reacted with stirring 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 were added to the solution as it was.
M equivalent was added and stirred at room temperature overnight. The mixture was poured into water, adjusted to pH 3, and 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 then dried to obtain 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) were condensed by DCC method and subjected to silica gel column chromatography (50: 1 CHCl ₃ -MeOH). Purified compound (4)
0.28 g was obtained. 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) The compound (4) was deacetylated with sodium methoxide in methanol to give an aqueous solution, which was then subjected to gel column chromatography (“Sephadex G-10”, H ₂ O). Purification yielded 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 to prepare a Lindlar catalyst.
100 mg was added for hydrogen reduction (48 psi, 1.5 hours) and then reacted with N-hydroxysuccinimide palmitate ester in acetonitrile overnight at room temperature. Purification by silica gel column chromatography (50: 1 CHCl ₃ -MeOH) gave 68 mg of a condensate. Then, the 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 = 7.6Hz), 1.25 (d, 3H, J = 6.6Hz), 0.90
(t, 3H, J = 7.1Hz).

Example 2 The chemical reactions involved in this example are shown in FIG.

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

60 g of 2-bromoethyl glycoside was dissolved in 200 ml of dimethylformamide, and sodium azide 32
g, and the mixture was 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 filtered off. Dimethylformamide was distilled off to obtain an ethyl acetate solution, which was washed with water 4 times and then ethyl acetate was distilled off to quantitatively obtain a 2-azidoethyl glycoside. R _F = 0.40 (PcCH ₃
-AcOEt 2: 1).

Furthermore, 28 g of compound (8) was obtained by deacetylation with sodium methoxide in methanol.

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 overnight at room temperature. After adding 0.5 ml of triethylamine, concentrate and concentrate on silica gel column chromatography (5: 1 CHCl ₃ -AcOE
2.62 g of a benzylidene compound was obtained through t). R _F = 0.63 (C
HCl ₃ -MeOH 10: 1).

Then, using ClCH ₂ CO ₂ NBu ₄ , carboxymethylation was carried out in the same manner as the previous time, and 2.5 g of compound (9) was obtained.
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 DCC method and then subjected to silica gel column chromatography (50: 1 CHCl ₃ -MeOH). Refined. 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, the azido group was reduced using a Lindlar catalyst in the same manner as above, and palmitoylation was carried out to obtain a compound (10). Silica gel column chromatography It was recommended to proceed to the next step without 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 mixed solution of 100 ml of ethanol and 0.1 ml of acetic acid, and reduced with hydrogen (45 psi) together with 10% Pd / C (1.5 g). Silica gel column chromatography
Purification with (50: 1 and 30: 1 CHCl ₃ -MeOH) gave 1.04 g of 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 = 8.1Hz), 0.88 (t, 3H, J = 6.8).

Then, the compound (11) was quantitatively obtained by deacetylation with 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 = 7.6Hz), 0.90 (t, 3H, J = 7.0).

Example 3 The chemical reactions involved in this example are shown in FIG.

Synthesis of Compound (12) 2-azidoethyl α-D-mannopyranoside (Compound (8)) 2.
49 g and trityl chloride 2.99 g were dissolved in 30 ml of pyridine and reacted with stirring at room temperature overnight. After distilling off pyridine,
Silica gel column chromatography (40: 1 CHCl ₃ -MeO
3.60 g of 6-0-trityl compound (compound (12)) after purification with H)
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) 993 mg of 6-0-trityl compound (compound (12)) was treated with C1 in the same manner as above.
Carboxymethylation was performed using CH ₂ COONBu ₄ to obtain a tricarboxylic acid body. R _F = 0.12 (CHCl ₃ -MeOH- H ₂ O 60:35:
Four).

Then, the amine compound (compound (25)) was condensed with acetonitrile by the DDC method to give compound (13) 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 = 8.1Hz), 4.37 (d, 1H, J = 7.8Hz).

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
Purification with (30: 1 CHCl ₃ -MeOH) yielded 89 mg of detritylated 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 = 8.1Hz), 4.45 (d, 1H, J = 7.8Hz).

Then, the compound (14) was obtained by dissolving in 2 ml of methanol, adding 0.2 M equivalent of sodium methoxide, and stirring for 3 hours at room temperature to deacetylate. R _F = 0.3
_{8 (CHCl 3 -MeOH- H 2 O} 10: 10: 3).

NMR: ¹ H, δ (D ₂ O) 5.03 (d, 1 H, 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 The chemical reactions involved in this example are shown in FIG.

Synthesis of Compound (15) 2.11 g of 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 heated under reflux for 2 hours. did. After distilling off methanol, toluene was added and further distilled off. Then PhCH ₂ Br 6ml
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, washed with water and the solvent was distilled off to obtain an oil. Silica gel column chromatography ((i) CHCl
₃ only, (ii) PhCH ₃ -AcOEt 5: 1) purified 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 = 4.7Hz), 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, pH was adjusted.
When it was extracted with ethyl acetate at 2.0, a dicarboxylic acid compound including a partially detrityl compound was obtained. R _F = 0.77 (CHCl ₃ -MeOH- H
₂ O 65: 30: 4).

Mixture of dicarboxylic acid compound and amine compound (compound
(25)) was condensed by the DDC method and purified by silica gel column chromatography (1: 1 to 1: 3 CHCl ₃ -AcOEt) to obtain the 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 = 1.7Hz), 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. The ethyl acetate layer was dried and then 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 detritylated product (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, it 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 a 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 =
7.6 Hz).

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

Synthesis of Compound (19) The 6-0-trityl compound (Compound (12)) was carboxymethylated in the same manner as above to obtain a tricarboxylic acid compound (Compound (16a)). Then, the 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 = 6.1Hz), 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 the mixture was heated with stirring 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 detritylated 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) Using a Lindlar catalyst, the compound (20) was reduced with hydrogen to an amine form in the same manner as the previous time, and then palmitoylated in the same manner as the compound (10) to give the compound (21). Got Furthermore, by deacetylating the mannose terminal compound (22)
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 The chemical reactions involved in this example are shown in FIG.

Synthesis of compound (26) 2'-azitoethyl α-D-mannopyranoside (compound
(8)) (2.99 g) and di-n-butyltin oxide
A solution of (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, which was repeated 4 times. Benzene of the obtained residue
(150 ml) Benzyl bromide (2.9 ml) and tetrabutylammonium iodide (4.88 g) were added to the solution, heated under reflux for 6 hours, then left overnight at room temperature, and benzyl bromide (1.45 ml) was added, and further 7 hours. Heated to reflux. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform: methanol 100: 0.5 to 2%, acetic acid ethyl ester: hexane 8: 2, acetic acid ethyl ester) to give a monobenzyl compound (compound (26)). Obtained (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 500M
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, 1
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) Tetrabutylammonium hydroxide (1M solution in methanol 13.1 ml) was mixed with monochloroacetic acid (1.24 g) in methanol (2
(0 ml) solution was added and the solvent was evaporated. Toluene in the residue
(20 ml) was added and the solvent was distilled off. This was repeated 3 times, and the obtained residue was dissolved in dimethylformamide (6 ml).

(Ii) Sodium hydride under argon atmosphere
(60% oil suspension 0.39g) in dimethylformamide (15ml) suspension under ice-cooling monobenzyl form (compound (26))
Add (1.00 g) dimethylformamide (10 ml) solution,
Stir for 5 minutes. A solution of tetrabutylammonium monochloroacetate obtained in (i) in dimethylformamide 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 hydrogen carbonate and a small amount of sodium iodide were added to the aqueous layer, and the mixture was extracted with chloroform. Then, 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 brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give a crude product (0.83 g). A part of this (0.43 g) was dissolved in water, and the solution was purified with "Diaon HP-20" (manufactured by Mitsubishi Kasei Co., Ltd.) (50 ml) (acetonitrile-water 20:
80 to 80:20), of which the elution fraction of acetryl-water 40:60 was collected, the solvent was distilled off, the residue was acidified with citric acid, and the desired product was extracted with ethyl acetate, and the extract was saturated with water. After washing with brine, it was dried over anhydrous magnesium sulfate. The solvent was distilled off to dicarboxymethyl derivative (compound (27)) (2
30 mg) was obtained 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 catalyst (1.80 g) under hydrogen pressure (50 p).
si) Shaking and stirring at room temperature for 1 hour. Lindlar catalyst (0.
48 g) was added, the solvent was distilled off after shaking and stirring for another 30 minutes,
Toluene was added to the residue and the solvent was evaporated again to give an amino compound (compound (25)) (2.14 g) as a crude product.

Synthesis of compound (28) Crude product of dicarboxymethyl derivative (compound (27)) (4
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) under ice-cooling N, N'-dicyclohexyl. Carbodiimide (5
30 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, the insoluble matter was filtered off, the filtrate was poured into water, and the desired product was extracted with ethyl acetate. The extract was washed with water and saturated brine 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 the 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 azide (compound (28)) (800 mg, 0.67 mmol) and paratoluenesulfonic acid (139 mg) in ethanol (60 ml) was added Lindlar catalyst (600 mg), and hydrogen was added. Under pressure (50 psi)
Shake for 2.5 hours.

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

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

The reaction mixture 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 compound (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, 1
H).

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

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

The reaction mixture was poured into water, the desired product was extracted with ethyl acetate, the extract was washed with water and saturated saline,
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)
Add 10% Pd carbon powder (22mg) to the solution and pressurize under hydrogen (50p
si) and shaken and stirred for 3 hours.

The catalyst was filtered off, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol 97: 3) to obtain a diol (44 mg,
Quantitative) was obtained.

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

The strongly acidic cation exchange resin for non-aqueous solution "Amberlyst 15E" was added to the reaction solution until the solution became almost neutral, the resin was filtered off, and the solvent was distilled off to remove the Boc compound (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) Palmitoyl Form (Compound (29b)) (97 mg) in Ethanol (30 ml) in 10% Pd Carbon Powder ( 52 mg) was added, and the mixture was shaken and stirred under hydrogen pressure (50 psi) for 1.5 hours. Add catalyst (5
(0 mg), and the mixture was further shaken and stirred for 1 hour.

The catalyst was filtered off, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol 97: 3) to obtain a diol (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 compound obtained above (125 mg, 94 μmo
After adding sodium methoxide (10 μl of 28% methanol solution) to a solution of l) in methanol (2 ml) under ice cooling, the mixture was stirred at room temperature for 3 hours.

"Amberlyst 15E" was added 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).
%).

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) Boc Form (Compound (29a)) (97 mg) Methanol Obtained Above
(3 ml) Sodium methoxide (15% of 28% methanol solution) was added to the solution under ice cooling, and the mixture was stirred at room temperature for 3 hours.

"Amberlyst 15E" was added 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 (60 mg), which was used as "Sephadex LH-20". "
The product was purified by (Pharmacia) (methanol) to obtain a Boc body (compound (31a)) (40 mg, 56%).

R _F 0.22 (Acetic acid ethyl ester-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 derivative (Compound (29b)) obtained above (80 mg, 56 μm
Sodium methoxide (10 μl of 28% methanol solution) was added to a methanol (3 ml) solution of (mol) and stirred at room temperature for 3 hours.

“Amberlyst 15E” was added 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 The chemical reactions involved in this example are shown in FIG.

Synthesis of Compound (32) Sodium hydride (60% oil suspe
nsion 132mg) in dimethylformamide (3ml) suspension, add monobenzyl compound (compound (26)) (340mg) in dimethylformamide (2ml), stir at room temperature for 30 minutes, then stir 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 1M tetrabutylammonium hydroxide in methanol) obtained in the same manner as in (27) was added dropwise, and the mixture was stirred at room temperature for 15 hours.

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

Synthesis of compound (33) Mixture of di- and tricarboxymethyl derivatives (300 mg) obtained above, 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 a dimethylformamide (10 ml) solution under ice-cooling N,
A solution of N'-dicyclohexylcarbodiimide (404 mg) in dimethylformamide (3 ml) was added, and the mixture was stirred at room temperature overnight.

Acetic acid ethyl ester (20 ml) was added to the reaction solution, the insoluble material was filtered off, the filtrate was poured into water, and the intended product was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (chloroform-methanol 99: 1 to 98.5: 1.5), and the diamide form (compound (28)) (104 mg, 9%, from the chloroform-1.5% methanol fraction). 2 steps) and 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 a triamide compound (Compound (33)) (122 mg) and paratoluenesulfonic acid (16 mg) in methanol (6 ml) was added a Lindlar catalyst (150 mg) under hydrogen pressure ( 50psi)
The mixture was shaken and stirred for 2.5 hours.

The catalyst was filtered off, the solvent was distilled off, and the amino compound (1
26 mg) was obtained as a crude product. Used in 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 body (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) A Lindamide catalyst (346 mg) was added to an ethanol solution of a triamide compound (Compound (33)) (244 mg) and paratoluenesulfonic acid (31 mg), and the mixture was heated under hydrogen pressure (50 psi). And stirred for 2.5 hours.

The catalyst was filtered off, the solvent was distilled off, and the amino compound (1
77 mg) was obtained as a crude product. Used in 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 mixture was poured into water and the desired product was extracted with ethyl acetate. The extract was washed with water and saturated saline,
It was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (chloroform-methanol 98: 2), and the 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) To a solution of Boc compound (compound (34a)) (80 mg) in methanol (5 ml) was added 10% Pd-carbon powder (60 mg), and hydrogen was added under pressure (5
(0 psi) The mixture was shaken and stirred for 3 hours.

The residue obtained by evaporating the solvent was subjected to silica gel column chromatography (chloroform-methanol).
(97: 3) to obtain an alcohol compound (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) A solution of the alcohol derivative (58 mg) obtained above in methanol (2 ml) was added with sodium methoxide (28%) under ice cooling.
Methanol solution (10 μl) was added and stirred for 3 hours.

"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 (acetic acid ethyl ester-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) To a solution of palmitoyl compound (Compound (34b)) (109 mg) in methanol (6 ml) was added 10% Pd carbon powder (100 mg), and the mixture was shaken under hydrogen pressure (50 psi) for 1.5 hours. It was stirred.

The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (chloroform-methanol).
98: 2 to 97: 3) to obtain an alcohol (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, 3
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 derivative (47 mg) obtained above in methanol (2 ml) was added sodium methoxide (28%) under ice cooling.
Methanol solution (5 μl) was added and the mixture was stirred for 3 hours.

“Amberlyst 15E” was added to the reaction solution until the solution became almost neutral, and the resin was filtered off to obtain a palmitoyl compound (Compound (35b)) (29 mg, 86%).

R _F 0.8 (acetic acid ethyl ester-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 The chemical reactions involved in this example are shown in FIG.

Synthesis of Compound (38) (i) To a solution of azide (compound (36)) (242 mg) and paratoluenesulfonic acid (102 mg) in ethanol (20 ml) was added Lindlar's catalyst (180 mg), and under hydrogen pressure ( It was shaken and stirred for 1.5 hours. The Lindlar catalyst (60 mg) was added, the mixture was shaken and stirred for 1.5 hours, and the Lindlar catalyst (90 mg) was further added, and the mixture was stirred and stirred for 1 hour.

The Lindlar catalyst was filtered off, 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'-dichlorohexylcarbodiimide (111 mg), and the mixture was stirred at room temperature for 1.5 hours. The insoluble matter was filtered through cotton, a solution of the amino compound (compound (37)) obtained in (i) in acetonitrile was added dropwise to the filtrate, and the mixture was stirred at room temperature overnight.

The solvent was distilled off, the methylene chloride solution of the residue was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was subjected to silica gel column chromatography (chloroform-methanol 98: 2-95:
5) to obtain the triamide compound (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) The triamide derivative (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 mixture was poured into water and 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 distilling off the solvent, the residue (20 mg) was subjected to silica gel column chromatography (chloroform-methanol 95: 5
~ 92: 8) to obtain an alcohol compound (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, 9
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 of compound (40) (compound (39)) (13 mg) in methanol (1 ml)
Sodium methoxide solution (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 product (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 The chemical reactions involved in this example are shown in FIG.

A Lindlar catalyst (120 mg) was added to a solution of an azide compound (compound (38)) (86 mg) and paratoluenesulfonic acid (9 mg) in ethanol (10 ml), and hydrogen pressure was applied (50 psi) 2.
The mixture was shaken and stirred for a period of time. Add Lindlar catalyst (120mg),
The mixture was shaken and stirred for another 2 hours.

The Lindlar catalyst was filtered off, 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), to which a solution of N-palmitoyloxysuccinimide (12 mg) in toluene (2 ml) was added dropwise, and the mixture was stirred 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 distilling off 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, 3
H), 1.94 (s, 3H), 1.95 (s, 6H), 2.01 (s, 3H), 2.017 (s, 3
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) The palmitoyl derivative (Compound (42)) (42 mg) was dissolved in acetic acid (2 ml), and the mixture was heated with stirring at 60 ° C. for 6 hours.

The reaction mixture was poured into water and 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 distilling off the solvent, the residue (20 mg) was subjected to silica gel column chromatography (chloroform-methanol 95: 5
~ 93: 7) to obtain an alcohol compound (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 (44) (Compound (43)) (23 mg) in methanol (2 ml)
Sodium methoxide solution (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 product (compound (44)) (13 mg, 71%).

R _F 0.89 (acetic acid ethyl ester-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 Examples The chemical reactions involved in the examples are shown in FIGS.

(A) 9-decenyl 2,3,4,6-O-
Synthesis of tetraacetyl-α-D-mannopyranoside (Compound 1) Pentaacetyl β-D-galactoranoside (20.85
g) and 9-decen-1-ol (21.7 g) in methylene chloride (400 ml) were added with boron fluoride ether complex (27 ml) under ice-cooling and stirred at room temperature overnight. The reaction solution was poured into ice-saturated aqueous sodium hydrogen carbonate, the organic layer was washed with semi-saturated saline and then dried over magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (SiO ₂ 2
Purified with 00g, chloroform) to obtain 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 this was successively normalized with dilute hydrochloric acid, dilute aqueous sodium hydrogen carbonate, water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (S
200 g of iO ₂ , toluene: acetone = 99: 1 to 99:
2), a glycoside (Compound 1) was obtained (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 derivative (14.86 g) obtained above was treated with methanol (10
Sodium methoxide (28% methanol solution)
1.5 ml) was added, and the mixture was stirred at room temperature for 2.5 hours. “Dowex 50W 1 × 8” was added to the reaction solution until the liquid became neutral, the resin was filtered off, 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 derivative (9.88 g) obtained above was treated with pyridine (60 m).
l) Trityl chloride (10.2 g) was added to the solution, and the mixture was stirred overnight with heating at 50 ° C. The solvent was distilled off, the residue was dissolved in ethyl acetate, washed with diluted hydrochloric acid water, 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 ₂ 100 g, Curlform: methanol = 99:
1-98: 2) and a trityl compound (compound 3) was obtained (11.52)
g).

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

IR (CHCl ₃ ): 3700, 3600, 1520, 1480,
1420 cm ^-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 DMF (10 ml) solution of the trityl compound (0.99 g) obtained on a suspension of sodium hydride (0.26 g) in DMF (10 ml) was added under ice-cooling and then the temperature was raised to room temperature. And stirred for 2 hours. Another 30 minutes
Stir at 50 ° C. DMF (15 ml) solution of tetrabutylammonium salt of monochloroacetic acid (monochloroacetic acid (0.76 g) and tetrabutylammonium hydroxide (1M methanol solution 8 ml) were mixed with this, and water was repeatedly azeotroped with toluene. After removing, dried under reduced pressure) was added 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 (Compound 6) Tricarboxymethyl compound (200 mg) and N-
To a solution of hydroxysuccinimide (105 mg) in acetonitrile) 40 ml) was added N, N-cyclohexylcarbodiimide (189 mg), 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 this solution was added dropwise to the above reaction mixture at room temperature and stirred overnight as it was. The insoluble material was filtered off, the filtrate was concentrated, and the methylene chloride solution of the residue was washed with water and semisaturated 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, 1520 cm ^-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, and the mixture was stirred at room temperature for 1.5 hours, the solvent was evaporated, and the residue was purified by silica gel column chromatography (Si
O ₂ 40 g, curlform: methanol = 98: 2) and an aldehyde derivative (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 compound (307 mg) obtained above was added to tert-butanol (5.5 ml) and 2-methyl-2-butene (1.5 ml).
Dissolved 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. Acetic acid ethyl ester was added to the reaction mixture, which was washed with a 2.5% sodium thiosulfate solution, water and saturated brine, and 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: 2-9: 1), and recovered raw material (100 m
g) and carboxylic acid (compound 8) were obtained (180 mg).

(H) Synthesis of methyl ester compound (compound 9) To a solution of the carboxylic acid obtained here in THF (10 ml) was added an ether solution of diazomethane under ice cooling until the solution became pale yellow, and the mixture was stirred for 10 minutes. Then, the mixture was stirred at room temperature for another 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) and a methyl ester compound (compound 9) were obtained (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 = 7.5Hz), 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 (Chemical Compound 10) The methyl ester (170 mg) acetic acid (8 ml) obtained above was added, 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 to 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 added to methanol (10
ml) solution with sodium methoxide 28% methanol solution
60 μl) was added and the mixture was stirred at room temperature for 2 hours. "Dowe
x50W 1x8 "was added until the liquid became neutral, the resin was filtered off, 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 (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 was distilled off, and the hydrazide compound (Compound 12)
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 sample.

[0307] 2. Experimental Method Rat liver parenchymal cells were prepared by the collagenase perfusion method, and the following experiment was performed in order 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) at 1 μg / ml was incubated with hepatocytes at 4 ° C. for 2 hours 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 material and a cell fraction by 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 formula.

[0309]

[Equation 1]

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

3. Results The inhibitory activities of the control sample and the specimen sample are shown in Fig. 11.
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
Became.

From the above, the affinity of the specimen sample for hepatic parenchymal cells was increased 10 ⁶ times that of the control sample. That is, the recognition of N-acetylgalactoxamine by hepatic parenchymal cells is remarkably improved by using mannose as a skeleton. Therefore, the substance of the present invention is used as a glycolipid derivative for organ orientation in drug delivery technology. 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 chain type sugar complex having a novel sugar skeleton, which imparts excellent organ orientation to the fine particle carrier, and synthetic intermediates thereof are provided. Is being offered.

[Brief description of drawings]

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

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

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

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

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

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

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.

Claims (3)

[Claims] 1. A branched chain derivative having a sugar skeleton represented by the following formula (I). [Chemical 1] 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 , ...,
X ⁿ are each independently H, benzyl group, trityl group, benzylidene group, carboxymethyl group or the following formula (VII)
Alternatively, it represents a group represented by (VII ′). [Chemical 2] 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. , () Means that at least one of the groups shown in () is a carboxymethyl group or a group represented by the formula (VII) or the formula (VII ′). In formulas (VII) and (VII '), (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 is H
Or represents an acetyl group. Further, in the following formula (II) ~ (VI), Y is a group _{- (CH 2) r N 3} , group - (CH _{2) r}
NH _2, group - (CH _{2) r} NHZ, group - (CH _{2) r} C
H = CH ₂ or a group - (CH ₂₎ represents an _r COR ^1, wherein, r denotes an integer of 2 to 10, Z is benzyloxycarbonyl group, t-butoxy carbonyl group or a linear or branched It represents an 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. [Chemical 3] In formulas (II) to (VI) and formulas (VIII) to (XIII), the bond indicated by the wavy line represents an α bond or a β bond. 2. A branched chain derivative having a sugar skeleton according to claim 1, wherein [S ⁿ ] is formula (II) or formula (V). 3. A branched chain derivative having a sugar skeleton according to claim 2, wherein (T) is of formula (VIII), formula (X) or formula (XI).