JPH07242684A - New glucuronic acid compound - Google Patents

Abstract

PURPOSE:To obtain a new glucuronic acid compound having beneficial activities, e.g. immunostimulating activity, anti-tumor activity and tumor necrosis factor- inducing activity and reduced toxicity and useful as an immunostimulating agent, an anti-tumor agent, etc. CONSTITUTION:This is a new glucuronic acid compound expressed by formula I [R<1> is OH, a lower alkoxy or an amino acid residue; A is 0 or NH; B is N or CH; (m) and (n) are each an integer of 5-17; (r) is an integer of 4-16], e.g. {1,2-deoxy-3-0-(2-dodecyltetradecanoyl)-2-[(3R)-3-hydroxytetradecanami do]-4-O- phosphono-D-glucuronyl}-glycine. The compound has beneficial activities, e.g. immunostimulating activity, anti-tumor activity and tumor necrosis factor- inducing activity and reduced toxicity and accordingly useful as an immunostimulating agent and an anti-tumor agent. The compound is synthesized by using a known compound of 2-amino-1,5-anhydro-2-deoxy-4,6-protecting group- D-glycitol expressed by formula II as a starting material.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel glucuronic acid compound useful as a drug such as an immunostimulant and an antitumor agent.

[0002]

2. Description of the Related Art The cell surface of Gram-negative bacteria consists of a cell membrane, a cell wall peptidoglycan that surrounds it, and an outer membrane. Lipopolysaccharide (hereinafter referred to as LPS) is present on the outer membrane.
It is included.

LPS consists of three parts, O-antigen polysaccharide, core polysaccharide and lipid A, and has harmful activities such as fever, bleeding, arthritis and encephalomyelitis.
It is called endotoxin or endotoxin.

However, LPS has an immunostimulating action (macrophage activating action, B cell blastogenic action, cellular immune activating action, etc.) and antitumor action [IFN (interferon) inducing action, TNF (tumor necrosis factor) inducing action). It is also known to have a beneficial activity such as "action and the like".

The active center of LPS is lipid A, which has the structure shown below in which a fatty acid residue and phosphoric acid are bound to the disaccharide of glucosamine, and the structure of the fatty acid residue differs depending on the type of bacterium. [Japanese Journal of Bacteriology 40 (1), 57
(1985) and Proc. Natl. Acad. Sc
i. USA 80 , 4624 (1983)].

[0006]

[Chemical 2]

[0007] Recent studies have revealed that the monosaccharide subunit shown in the above formula alone has lipid A-like activity, and various analogs have been synthesized.

For example, JP-A-60-501259 discloses a lipid-X analog close to the reducing subunit type and a method for producing the same, and JP-A-1-121295 discloses a similar type to the reducing subunit type. 3,4-triacylated glucosamine, a monophosphoryl lipid A derivative in JP-A-1-146891, a novel muramyl dipeptide derivative of lipid A type in JP-A-1-221397, and JP-A Japanese Patent Laid-Open No. 1-146892 and Japanese Patent Laid-Open No. 1-1
No. 80895, No. 1-180896, No. 1-213290, and No. 3-29129.
No. 2 discloses a phosphorylglucosamine derivative similar to the non-reducing subunit type.

The present inventors also tried various syntheses in order to obtain a lipid A analog having a stronger activity, and focused on the non-reducing subunit type, and synthesized many new analogs. As a result, it was found that these derivatives have a strong activity similar to that of natural lipid A, and many patent applications have been filed so far (for example, JP-A-3-264594, JP-A-5-59079, and Kaihei 5-2020
82, JP-A-5-202083).

[0010]

As described above, Lipid A
Active research has been carried out on analogues so far, and modification with various substituents and introduction sites thereof have been studied. However, none of them has been practically used as a pharmaceutical, and a compound having stronger activity and low toxicity is expected.

[0011]

[Means for Solving the Problems] Therefore, the inventors of the present invention have conducted intensive studies to find a lipid A analog having reduced toxicity while retaining strong activity.
The inventors have found a novel glucuronic acid compound useful as a drug such as an antitumor agent, and completed the present invention.

That is, the present invention relates to novel glucuronic acid compounds represented by the following (1) to (3).

(1) General formula [I]

(Wherein R ¹ represents a hydroxyl group, a lower alkoxy group or an amino acid residue; A represents an oxygen atom or an NH group;
B represents a nitrogen atom or a CH group; m and n may be the same or different and represent an integer of 5 to 17; r is 4 to 16
Represents the integer. ] The novel glucuronic acid compound shown by these, or its pharmacologically acceptable salt.

(2) The novel glucuronic acid compound according to (1) above, wherein R ¹ is a hydroxyl group, a lower alkoxy group, glutamic acid or glycine, or a pharmaceutically acceptable salt thereof.

(3) [1,2-Dideoxy-3- O-
(2-dodecyl-tetradecanoyl) -2 - {(3 R) -
3-Hydroxytetradecanamid} -4- O -phosphono- D -glucuronyl] -glycine; 1,2-dideoxy-3- O- (2-dodecyltetradecanoyl) -2-
[( 3R ) -3-Hydroxytetradecanamido] -4-
O -phosphono- D -glucuronic acid; [1,2-dideoxy-3- O- (2-dodecyltetradecanoyl) -2-
{( 3R ) -3-Hydroxytetradecanamid} -4-
O -phosphono- D -glucuronyl] -L -glutamic acid;
1,2-dideoxy-3- O- (2-didodecylaminocarbonyl) -2-[( 3R ) -3-hydroxytetradecanamido] -4- O -phosphono- D -glucuronic acid;
[1,2-dideoxy-3-O - (2-didodecyl-aminocarbonyl) -2 - {(3 R) -3- hydroxy-tetradecanoyl cyanamide}-4-O - phosphono - D - glucuronyl] - L - Glutamic acid 1,2,3-trideoxy-3
-(2-dodecyltetradecanamide) -2-[( 3R )
-3-Hydroxytetradecanamid] -4- O -phosphono- D -glucuronate methyl; 1,2,3-trideoxy-3- (2-dodecyltetradecanamid) -2-
[( 3R ) -3-Hydroxytetradecanamido] -4-
The novel glucuronic acid compound according to the above (2) selected from O -phosphono- D -glucuronic acid, or a pharmacologically acceptable salt thereof.

The meanings of the terms used in this specification are as follows. "Amino acid residue" means alanine, arginine, asparagine, aspartic acid, cysteine,
Amino acid such as glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine or valine, which forms an amide bond with glucuronic acid at the N-terminal and releases a carboxyl group. In this state, alanine, aspartic acid, glutamic acid, glycine, isoleucine, leucine, phenylalanine or valine is preferable, and glutamic acid or glycine is particularly preferable.

The "pharmacologically acceptable salt" may be any salt as long as it forms a non-toxic salt with the novel glucitol compound represented by the above general formula [I]. For example, sodium, potassium, Examples thereof include alkali metal salts such as lithium; alkaline earth metal salts such as magnesium and calcium; ammonium salts; organic amine salts such as triethanolamine, diethanolamine, monoethanolamine and triethylamine.

The "amino group-protecting group" or "primary alkylamino group-protecting group" may be any protective group commonly used, for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group,
Isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, tert
-Amyloxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, 1,1-dimethyl-2-chloroethoxycarbonyl group, 1,1-dimethyl-2,2-dibromoethoxycarbonyl group, 1,1-dimethyl -2
Carbamate such as 2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, 9- (2,7-dibromo) fluorenylmethoxycarbonyl group; formyl group, acetyl group, propionyl group , Butyroyl group, valeroyl group, pivaloyl group, chloroacetyl group, trichloroacetyl group, trifluoroacetyl group, benzoyl group and other acyl groups; methanesulfonyl group, ethanesulfonyl group, benzenesulfonyl group, p-bromobenzenesulfonyl group, p
-A sulfonyl group such as a toluenesulfonyl group; a methanesulfenyl group, an ethanesulfenyl group, a benzenesulfenyl group, a p-bromobenzenesulfenyl group, a sulfenyl group such as a p-toluenesulfenyl group, and the like. Is a tert-butoxycarbonyl group or a 2,2,2-trichloroethoxycarbonyl group, and particularly preferably a tert-butoxycarbonyl group.

The "substituted sulfonyl group" may be any one commonly used, for example, methanesulfonyl group, benzenesulfonyl group, p-bromobenzenesulfonyl group, p-toluenesulfonyl group, trifluoromethanesulfonyl group and the like. And preferably a methanesulfonyl group or a trifluoromethanesulfonyl group.

The "carboxyl-protecting group" may be any protective group which is usually used, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-
Alkyl group such as butyl group; halogen-substituted alkyl group such as 2,2,2-trichloroethyl group, 2,2,2-trifluoroethyl group; benzyl group, p-methoxybenzyl group, 3,4-dimethoxybenzyl group , O-nitrobenzyl group, p-nitrobenzyl group, p-bromobenzyl group,
Aralkyl groups such as diphenylmethyl group and trityl group; trimethylsilyl group, triethylsilyl group, isopropyldimethylsilyl group, tert-butyldimethylsilyl group, di-tert-butylmethylsilyl group, phenyldimethylsilyl group, tert-butyldiphenylsilyl group Examples of the silyl group include an allyloxycarbonyl group and the like, and a methyl group, an ethyl group, a benzyl group, a p-methoxybenzyl group and the like are preferable, and a methyl group and a benzyl group are particularly preferable.

The "hydroxyl-protecting group" may be any protective group commonly used, for example, formyl group, acetyl group, propionyl group, butyroyl group, valeryl group, pivaloyl group, chloroacetyl group, trichloroacetyl group. Group, acyl group such as trifluoroacetyl group; methyl group, ethyl group, propyl group, isopropyl group, n-
Alkyl or substituted alkyl groups such as butyl group, isobutyl group, tert-butyl group, methoxymethyl group, methoxyethoxymethyl group, tert-butoxymethyl group, tetrahydropyranyl (THP) group; benzyl group, p-
Methoxybenzyl group, 3,4-dimethoxybenzyl group,
Aralkyl groups such as benzyloxymethyl group and trityl group; trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, dimethylisopropylsilyl group,
Diethyl isopropylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group,
Diphenylmethylsilyl group, triphenylsilyl group, tribenzylsilyl group, tert-butylmethoxyphenylsilyl group, 2- (trimethylsilyl) ethyl group, 2-
A silyl group such as (trimethylsilyl) ethoxymethyl group;
Methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, n-
Butoxycarbonyl group, isobutoxycarbonyl group, s
ec-butoxycarbonyl group, tert-butoxycarbonyl group, tert-amyloxycarbonyl group, 2,
Carbonates such as 2,2-trichloroethoxycarbonyl group, 2- (trimethylsilyl) ethoxycarbonyl group, benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group and 2,4-dimethoxybenzyloxycarbonyl group; ethylidene group, isopropylidene group Group, a protecting group capable of simultaneously protecting two hydroxyl groups such as a benzylidene group, and the like, preferably an acetyl group, a benzoyl group, a trityl group, a tert-butyldimethylsilyl group, an isopropylidene group, a benzylidene group and the like, and particularly preferably An acetyl group, a trityl group, a tert-butyldimethylsilyl group, and an isopropylidene group.

The "lower alkoxy group" is a linear or branched lower alkoxy group having 1 to 6 carbon atoms, and includes, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, Isobutoxy group, sec-
A butoxy group, a tert-butoxy group, an n-pentoxy group, an isopentoxy group, a tert-pentoxy group, a neopentoxy group, an n-hexoxy group, an isohexoxy group and the like can be mentioned, but a methoxy group having 1 to 4 carbon atoms and an ethoxy group are preferable. , N-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group and the like, particularly preferably methoxy group and ethoxy group.

The compound of the present invention is a glucitol derivative 6
It is characterized by converting the position to a glucuronic acid type, which greatly improves water solubility and is particularly expected to be useful as a medicine.

The compounds of the present invention may have stereoisomers, all of which are included in the present invention.

The compound of the present invention can be produced, for example, by the following method. However, it goes without saying that the method for producing the compound of the present invention is not limited to these.

Scheme 1

[Chemical 3]

Scheme 2

[Chemical 4]

Scheme 3

[Chemical 5]

First Step This step is the known 2-amino-1,5-anhydro-
It is a step of protecting the amino group of 2-deoxy-4,6- O -isopropylidene- D -glucitol (i).

When the compound (i) is protected with, for example, a tert-butoxycarbonyl group, it is dissolved in chloroform, dichloromethane, dioxane, tetrahydrofuran, water or the like or a mixed solvent thereof, and di-tert-butyl dicarbonate is added. By the compound (ii) (R ²
Represents an amino-protecting group. ) Is obtained. When another protecting group is used, a commonly used method for introducing the protecting group may be used.

From the second step to the seventh step, an amino group is introduced at the 3-position. When a compound represented by the general formula [I] in which A is an oxygen atom is desired, the process may proceed to the eighth step immediately after the completion of the first step.

Step 2 Compound (ii) was added to dichloromethane, chloroform, 1,2
-In a solvent such as dichloroethane or pyridine in the presence of a base such as pyridine, triethylamine or N, N-diisopropylethylamine, methanesulfonyl chloride, benzenesulfonyl chloride, p-bromobenzenesulfonyl chloride, p-toluenesulfonyl chloride or anhydrous trifluoromethane. Compound (iii) is obtained by performing sulfonylation using a sulfonylating reagent such as sulfonic acid (R ³ represents a substituted sulfonyl group, and R ² represents the same meaning as described above).
Is obtained.

Third Step Compound (iii) is treated with sodium acetate, in a solvent such as N, N-dimethylformamide or dimethylsulfoxide.
The reaction is carried out using a metal acetate such as potassium acetate or cesium acetate at room temperature or under heating, preferably under heating.
The compound (iv) (R ² has the same meaning as described above) can be obtained by reversing the position.

Step 4 Compound (iv) is treated with sodium methoxide, sodium ethoxide, potassium ter in methanol, ethanol, n-propanol, water or a mixed solvent thereof.
Deacetylation is carried out in the presence of a base such as t-butoxide, sodium hydroxide, potassium hydroxide or barium hydroxide to give compound (v) (R ² has the same meaning as described above).

Step 5 In this step, compound (v) is used to carry out the same method as in step 2, to obtain compound (vi) (R ² and R ³ have the same meanings as described above). Is obtained.

Step 6 In this step, the compound (vi) was used, and the same method as in the third step was used except that sodium azide was used in place of the metal acetate in the third step. vii) (R ²
Represents the same meaning as described above. ) Is obtained.

Step 7 Reduction of compound (vii) with sodium borohydride, lithium borohydride or lithium aluminum hydride in a solvent such as methanol, ethanol, n-propanol, dioxane, tetrahydrofuran or diethyl ether. By carrying out a reduction reaction using an agent, or by carrying out catalytic hydrogenation using palladium carbon, palladium black or palladium hydroxide carbon as a catalyst, the compound (viii)
(R ² has the same meaning as described above).

Eighth step This step is a step of introducing a side chain into the 3-position of compound (ii) or compound (viii). Compound (ii) or compound (viii),
Dissolve in a solvent such as dichloromethane, 1-ethyl-3-
Compound (ix) (where B is CH is the ^{expressed;. R 2, a, m} , n are each the same meanings as defined above) is obtained. In this reaction, a catalytic amount of 4-
It may be preferred to add dimethylaminopyridine or the like.

Alternatively, a compound (ix) in which B is a nitrogen atom
When desired, compound (ii) or compound (viii) is dissolved in a solvent such as tetrahydrofuran or dichloromethane, and trichloromethyl chloroformate is added under cooling in the presence of a base such as triethylamine or N, N-diisopropylethylamine. React. It may be preferable to add activated carbon here. Next, after removing the insoluble matter from the reaction mixture, the compound (ix) is obtained by adding a dialkylamine in a solvent such as tetrahydrofuran or dichloromethane at 0 ° C. to room temperature in the presence of a base such as triethylamine.
(Wherein B represents a nitrogen atom; R ² , A, m, and n each have the same meaning as described above).

Step 9 This step is a step of deprotecting the isopropylidene group, which is a protecting group at the 4th and 6th positions. Compound (ix) is hydrolyzed with an aqueous acid solution such as an aqueous acetic acid solution at room temperature to under heating, preferably under heating to give compound (x) (B represents a nitrogen atom or a CH group; R ² , A,
m and n have the same meanings as described above. ) Is obtained.

Step 10 Steps 10 to 12 are a step of introducing a phosphoric acid group at the 4-position and a step of protection and deprotection accompanying it. Compound (x) is dissolved in dichloromethane, 1,2-dichloroethane, pyridine or the like or a mixed solvent thereof, and trityl chloride is added in the presence of a base such as triethylamine, N, N-diisopropylethylamine, pyridine or 4-dimethylaminopyridine. Alternatively, a compound (xi) in which a protecting group is introduced only at the 6-position by reacting with tert-butyldimethylchlorosilane or the like (R ⁴ represents a protecting group for a hydroxyl group; R ² , A, B, m and n are as described above) Has the same meaning).

Eleventh step The compound (xi) is dissolved in dichloromethane, 1,2-dichloroethane, pyridine or the like or a mixed solvent thereof,
By reacting diphenylphosphoric chloride in the presence of a base such as pyridine or 4-dimethylaminopyridine,
The compound (xii) (R ² , R ⁴ , A, B, m and n each have the same meaning as described above) can be obtained.

Step 12 Compound (xii) is hydrolyzed with an acid aqueous solution such as an acetic acid aqueous solution at room temperature to under heating, preferably under heating to give compound (xiii) (R ² , A, B, m,
Each n has the same meaning as described above. ) Is obtained.

Thirteenth step This step is a step of oxidizing the 6-position. Compound (xiii)
Is dissolved in carbon tetrachloride, acetonitrile, acetone, methyl ethyl ketone, acetic acid, water or the like or a mixed solvent thereof, and an oxidation reaction is performed using an oxidizing agent such as sodium periodate in the presence of a catalyst such as ruthenium trichloride. Thus, the compound (xiv) (R ² , A, B, m and n each have the same meaning as described above) is obtained. As the oxidizing agent used here, chromium trioxide, pyridinium chlorochromate (PCC), Jones reagent (a mixture of chromium trioxide and sulfuric acid), or the like can be used, but preferably it affects other substituents or protecting groups. It is better to use ruthenium trichloride and sodium periodate which are not present.

Step 14 This step is a step of protecting the 6-position carboxyl group or introducing an amino acid residue. Introduction of amino acid residues is the first
It may be carried out in 8 steps. The order of introducing amino acid residues is
It may be appropriately selected in consideration of easiness of production, stability of the compound, and the like.

When the group introduced here is a desired alkoxy group as R ¹ , it goes through the 15th and 16th steps, and if necessary the 19th step, and then proceeds to the final 20th step. Good. When protecting with an alkyl group as a protecting group for the carboxyl group used here, or when introducing a protected amino acid, the compound (xiv) is dissolved in a solvent such as dichloromethane, and 1-ethyl-3- (3-dimethyl Aminopropyl) -carbodiimide hydrochloride (WSC / HC
1) or a condensing agent such as dicyclohexylcarbodiimide (DCC) is reacted with an amino acid or a salt thereof in which a desired alcohol or carboxyl group is protected. At this time, it may be preferable to add 4-dimethylaminopyridine, triethylamine, or the like. In the case of protecting with a benzyl group, a compound (xv) [R ⁵ is O- ( A protecting group for a carboxyl group) or a protected amino acid residue; R ² , A,
B, m and n have the same meanings as described above. ] Is obtained. When another protecting group is used, a commonly used method for introducing the protecting group may be used.

Fifteenth step This step is a step of deprotecting the protecting group of the 2-position amino group. When this protecting group is, for example, a tert-butoxycarbonyl group, it can be deprotected by dissolving the compound (xv) in a solvent such as dichloromethane and using an acid such as trifluoroacetic acid. Further, for example, when protected with a 2,2,2-trichloroethoxycarbonyl group, the compound (xvi is deprotected by deprotecting in acetic acid in the presence of zinc powder at room temperature to under heating, preferably under heating. ) (R ⁵ ,
A, B, l, m, and n have the same meanings as described above. ) Is obtained. When another protecting group is used, a commonly used method for deprotecting the protecting group may be used.

Sixteenth Step This step is a step of introducing a side chain into the amino group at the 2-position. Compound (xvi) is dissolved in a solvent such as dichloromethane and reacted with 3-hydroxy fatty acid in the presence of a condensing agent such as WSC · HCl or DCC to give compound (xvii) (R ⁵ , A, B, m , N, and r each have the same meaning as described above).

Thereafter, among the compounds represented by the general formula [I], the compound represented by R ^{1 in the form} of an amino acid residue may be passed through the 19th step to the 20th step if desired.

Step 17 This step is a step of deprotecting the protecting group for the 6-position carboxyl group. When compound (xvii) is protected with, for example, a benzyl group, acetic acid, methanol, ethanol, n
-Catalytic reduction in a hydrogen stream using a catalyst such as palladium carbon, palladium hydroxide carbon or palladium black in a solvent such as propanol, tetrahydrofuran or dioxane gives compound (xviii). When protected with an alkyl group, for example, a solvent such as methanol, ethanol, n-propanol, tetrahydrofuran or dioxane and a base such as sodium hydroxide, potassium hydroxide or lithium hydroxide in a mixed solvent of water are used. The compound (xviii) (A, B, m, n,
Each r has the same meaning as described above. ) Is obtained.
When another protecting group is used, a commonly used method for deprotecting the protecting group may be used.

After this, among the compounds represented by the general formula [I], if R ¹ is a hydroxyl group, then
It suffices to proceed to the 20th step which is the final step.

Step 18 This step is a step of introducing a compound in which R ¹ is an amino acid residue when desired, and the compound (xviii) is used to protect the carboxyl group in place of 3-hydroxy fatty acid. A compound (xix) (R ^{1 ′} represents a lower alkoxy group or a protected amino acid residue) by the same method as in the 16th step except that the amino acid described above is used;
n and r each have the same meaning as described above. ) Is obtained.

Step 19 This step is a step of deprotecting the protecting group for the carboxyl group present in the amino acid residue. xx) (wherein R ¹ represents a lower alkoxy group or an amino acid residue;
Each of A, B, m, n and r has the same meaning as described above. ) Is obtained.

Step 20 This step is the final step of deprotecting the phenyl group, which is the protecting group for the phosphoric acid residue, to give the compound of the general formula [I]. When the compound (xx) is dissolved in acetic acid, methanol, ethanol, n-propanol, tetrahydrofuran, dioxane or the like or a mixed solvent thereof and catalytically reduced in a hydrogen stream using a catalyst such as platinum oxide, the target compound is obtained. [I] is obtained.

Step 21: Although not shown, this step is a step of converting the target compound [I] into a pharmacologically acceptable salt. Compound [I]
The salt can be formed by dissolving or suspending in water, methanol, ethanol, tetrahydrofuran or the like or a mixed solvent thereof and adding a desired base such as sodium hydroxide or potassium hydroxide or an aqueous solution thereof. At this time, if a compound in which R ¹ is an alkoxy group is used,
R ¹ may be a compound represented by a hydroxyl group.

[0056]

[Indication for Pharmaceuticals] The compound of the present invention represented by the general formula [I] thus obtained has a strong immunostimulating activity and antitumor activity. When the compound of the present invention is used as an immunostimulant or antitumor agent, it is usually administered systemically or locally, orally or parenterally.

The dose varies depending on the age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually in the range of 0.01 to 100 mg per adult, orally or non-orally once to several times a day. Orally administered.

When the compound of the present invention is made into a solid composition for oral administration, it may be in the form of tablets, pills, powders or granules. In such solid compositions, the one or more active substances are at least one inert diluent, dispersant or adsorbent, such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose. , Starch, polyvinylhydrin, magnesium aluminometasilicate or anhydrous silicic acid powder. Further, the composition may be mixed with an additive other than the diluent according to a conventional method.

When prepared into tablets or pills, it may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose or hydroxymethylcellulose phthalate, if necessary, or in two or more layers. You may coat. Further, it may be a capsule of a substance such as gelatin or ethyl cellulose.

When the composition is a liquid composition for oral administration, it may be in the form of a pharmaceutically acceptable emulsion, solubilizer, suspension, syrup or elixir. Examples of the diluent to be used include purified water, ethanol, vegetable oil or emulsifier. In addition to the diluent, this composition may be mixed with an auxiliary agent such as a wetting agent, a suspending agent, a sweetening agent, a flavoring agent, an aromatic agent or a preservative.

When preparing an injection for parenteral use,
Sterile aqueous or non-aqueous solutions, solubilizers, suspensions or emulsifiers are used. Examples of the water-soluble solution, solubilizer, and suspension include distilled water for injection, physiological saline cyclodextrin, and derivatives thereof, triethanolamine,
Examples include organic amines such as diethanolamine, monoethanolamine, and triethylamine, and inorganic alkaline solutions.

In the case of a water-soluble solution, for example, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohols such as ethanol, etc. may be used. As the solubilizer, for example, polyoxyethylene hydrogenated castor oil, surfactants such as sucrose fatty acid ester (mixed micelle formation), lecithin or hydrogenated lecithin (liposome formation) and the like are used. or,
It is also possible to prepare an emulsion preparation comprising a water-insoluble solubilizer such as vegetable oil and lecithin, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol or the like.

Other compositions for parenteral administration include external preparations, ointments such as ointments, suppositories or pessaries containing one or more active substances and prepared by a method known per se. Etc.

The method for producing the final object compound [I] according to the present invention will be specifically described below with reference to Examples.

[0065]

【Example】

Production Example 1 [1,2-dideoxy-3-O - (2-dodecyl-tetradecanoyl) -2 - {(3 R) -3- hydroxy-tetradecanoyl cyanamide}-4-O - phosphono - D - glucuronyl]
-Glycine synthesis.

Reference Example 1 (Step 1) 1,5-anhydro-2-tert-butoxycarboxamido-2-deoxy-4,6- O -isopropylidene- D -glucitol (Compound (ii); R ² = tert -Butoxycarbonyl group) 2-amino-1,5-anhydro-2-deoxy-4,
6- O -isopropylidene- D -glucitol (11.7 g) was dissolved in dichloromethane (120 ml), and the mixture was diluted with di-ter at room temperature.
t-Butyl dicarbonate (13.0 g) was added and the mixture was stirred for 3.5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was crystallized from diisopropyl ether. The crystals were recrystallized from a mixed solvent of diisopropyl ether and ethyl acetate to give the title compound (15.1 g). ¹ H NMR (300 MHz, δppm, in CDCl ₃ ): 1.43 (3H, s), 1.45 (9
H, s), 1.51 (3H, s), 2.80 (1H, broad s), 3.18 (1H, t, J = 1
1.1Hz), 3.09-3.22 (1H, m), 3.46-3.47 (2H, m), 3.61-3.7
6 (2H, m), 3.90 (1H, dd, J = 5.4 and 10.8Hz), 4.12 (1H, dd,
J = 5.4 and 11.1Hz), 4.60 (1H, d, J = 6.6Hz)

Reference Example 2 (8th Step) 1,5-Anhydro-2-tert-butoxycarboxamide-2-deoxy-3- O- (2-dodecyltetradecanoyl) -4,6- O -isopropylidene- D - glucitol (compound (ix); R ² = tert- butoxycarbonyl group, A = O, B = CH , m = 11, n = 11) obtained in reference example 1 1,5-anhydro -2-tert
-Butoxycarboxamide-2-deoxy-4,6- O
-Isopropylidene- D -glucitol (6.0 g) was dissolved in dry dichloromethane (60 ml), 2-dodecyltetradecanoic acid (8.24 g), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (WSC・ HCl)
(5.69 g) and 4-dimethylaminopyridine (1.21 g) were added, and the mixture was stirred at room temperature for 3 hours. After the completion of the reaction, dichloromethane was added to the reaction solution and washed with water. The dichloromethane layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained residue was subjected to silica gel flash column chromatography. The title compound (13.4 g) was obtained from n-hexane: ethyl acetate (5: 1) eluate. Got ¹ H NMR (300 MHz, δ ppm, in CDCl ₃ ) 0.88 (6 H, t, J = 6.6 Hz),
1.18-1.69 (44H, m), 1.35 (3H, s), 1.40 (9H, s), 1.44 (3H,
s), 2.31-2.47 (1H, m), 3.13 (1H, t, J = 11.0Hz), 3.19-3.52
(2H, m), 3.64-3.82 (1H, m), 4.12 (1H, dd, J = 5.4 and 11.0
Hz), 4.28 (1H, dd, J = 2.0 and 12.2Hz), 4.50 (1H, dd, J = 4.
1 and 12.2Hz), 4.67 (1H, broad s), 4.81 (1H, dd, J = 8.9
and 10,6Hz)

Reference Example 3 (Step 9) 1,5-anhydro-2-tert-butoxycarboxamide-2-deoxy-3- O- (2-dodecyltetradecanoyl) -D -glucitol (compound (x); R ² = tert-butoxycarbonyl group, A = O, B = CH , m = 11, n = 11) obtained in reference example 2 1,5-anhydro -2-tert
-Butoxycarboxamide-2-deoxy-3- O-
(2-Dodecyltetradecanoyl) -4,6- O -isopropylidene- D -glucitol (13.5 g) was dissolved in a 95% acetic acid aqueous solution and stirred at 70 ° C for 2 hours. After the reaction,
The residue obtained by concentration under reduced pressure was subjected to silica gel flash column chromatography, and the title compound (4) (9.90 g) was obtained from the eluate of n-hexane: ethyl acetate (1: 1). ¹ H NMR (300 MHz, δ ppm, in CDCl ₃ ) 0.88 (6 H, t, J = 6.3 Hz),
1.14-1.70 (44H, m), 1.41 (9H, s), 2.34-2.48 (1H, m), 3.1
8 (1H, t, J = 11.1Hz), 3.26-3.35 (1H, m), 3.65-3.84 (3H,
m), 3.90 (1H, dd, J = 3.6 and 12.0Hz), 4.13 (1H, dd, J = 4.9
and 11.1Hz), 4.74 (1H, d, J = 7.8Hz), 4.80 (1H, t, J = 9.9H
z)

Reference Example 4 (10th Step, 11th Step, 1st Step)
2 steps) 1,5-anhydro-2-tert-butoxycarboxamide-2-deoxy-4- O -diphenylphosphono-
3- O - (2-dodecyl-tetradecanoyl) - D - glucitol (compound (xiii); R ² = tert- butoxycarbonyl group, A = O, B = CH , m = 11, n = 11) Reference Example 3 1,5-anhydro-2-tert obtained in
-Butoxycarboxamide-2-deoxy-3- O-
(2-dodecyltetradecanoyl) -D -glucitol
Dissolve (2.00 g) in pyridine (8 ml) and add trityl chloride.
(1.3 g) and 4-dimethylaminopyridine (0.19 g) were added, and the mixture was stirred at 80 ° C for 3 hr. After the reaction was completed, the reaction solution was concentrated under reduced pressure. Water was added to this residue, and the mixture was extracted twice with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was washed with dichloromethane (9m
l) and pyridine (4.5 ml), 4-dimethylaminopyridine (762 mg) was added, and diphenylphosphoric acid chloride (1.3 ml) was added dropwise under ice cooling. After stirring for 3 hours, the reaction solution was diluted with chloroform and washed with water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was dissolved in 95% acetic acid aqueous solution (70 ml) and stirred at 60 ° C. for 1.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was subjected to silica gel flash column chromatography, and n-hexane: ethyl acetate (2:
1) The title compound (2.73 g) was obtained from the eluate. ¹ H NMR (300MHz, δppm, in CDCl ₃ ) 0.78-0.97 (6H, m), 0.9
7-1.75 (44H, m), 1.40 (9H, s), 2.28 (1H, quint., J = 6.0H
z), 3.19 (1H, t, J = 11.1Hz), 3.32 (1H, d, J = 9.3Hz), 3.53-
3.72 (3H, m), 3.77-3.92 (1H, m), 4.18 (1H, dd, J = 5.1 and
11.1Hz), 4.76 (1H, quint., J = 9.5Hz), 4.82 (1H, d, J = 6.0H
z), 5.19 (1H, t, J = 9.5Hz), 7.12-7.41 (10H, m)

Reference Example 5 (13th and 14th steps) [2-tert-butoxycarbonylamino-1,2-
Dideoxy-4- O -diphenylphosphono-3- O-
(2-dodecyl-tetradecanoyl) - D - glucuronyl] - glycine benzyl ester (Compound (xv); R ² = tert- butoxycarbonyl group, R ⁵ = glycine benzyl ester residue, A = O, B
= CH, m = 11, n = 11) 1,5-anhydro-2-tert obtained in Reference Example 4
-Butoxycarboxamide-2-deoxy-4- O -diphenylphosphono-3- O- (2-dodecyltetradecanoyl) -D -glucitol (1.0 g) was added to carbon tetrachloride (6 ml),
Dissolved in a mixed solvent of acetonitrile (6 ml) and water (9 ml),
Sodium periodate (1.1 g) was added under ice-cooling, ruthenium trichloride (60 mg) was added subsequently, and the mixture was stirred under ice-cooling for 10 minutes, and further stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction solution, and 10% aqueous sodium sulfite solution was added with vigorous stirring. The ethyl acetate layer was extracted and washed successively with 10% aqueous sodium sulfite solution, water and aqueous sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate,
It was concentrated under reduced pressure. The residue obtained was dried with dichloromethane (10 m
It was dissolved in l), glycine benzyl ester p-toluenesulfonate (386 mg), WSC.HCl (329 mg) and triethylamine (0.16 ml) were added, and the mixture was stirred at room temperature for 12 hours. Chloroform was added to the reaction solution and washed with water. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained residue was subjected to silica gel flash column chromatography to obtain the title compound (538 mg) from an eluent of n-hexane: ethyl acetate (3: 2). . 1H NMR (300MHz, δppm, in CDCl3) 0.89 (6H, t, J = 6.5Hz),
0.99-1.69 (53H, m), 2.22-2.45 (1H, m), 3.78-3.90 (1H,
m), 3.98-4.07 (2H, m), 4.09-4.29 (2H, m), 4.90-5.24 (5
H, m), 6.79-6.88 (1H, m), 7.09-7.52 (15H, m)

Reference Example 6 (15th and 16th Steps) [1,2-Dideoxy-4- O -diphenylphosphono-
3- O- (2-dodecyltetradecanoyl) -2-
{(3 R) -3- hydroxy-tetradecanoyl cyanamide} - D -
Glucuronyl] -glycine benzyl ester (Compound (xvii); R ⁵ = glycine benzyl ester residue, A = O, B = CH, m = 11, n = 11, r = 1)
0) [2-tert-butoxycarbonylamino-1,2-dideoxy-4-O-diphenylphosphono-3-O- (2-dodecyltetradecanoyl) -obtained in Reference Example 5
D-Glucuronyl] -glycine benzyl ester (538mg)
Was dissolved in dichloromethane (5.3 ml), trifluoroacetic acid (5.3 ml) was added under ice cooling, the mixture was stirred for 30 minutes, and further stirred at room temperature for 1 hour. After completion of the reaction, chloroform was added to the reaction solution, and the mixture was washed successively with an aqueous sodium hydrogen carbonate solution and an aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a residue. This residue was dissolved in dichloromethane (5.3 ml), (3 R ) -3-hydroxytetradecanoic acid (127 mg) and WSC.HCl (149 m
g) was added and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, chloroform was added to the reaction solution, washed with water, and dried over anhydrous magnesium sulfate. The residue obtained by concentrating the organic layer under reduced pressure was subjected to silica gel flash column chromatography, and the title compound (351 mg) was obtained from an eluate of n-hexane: ethyl acetate (1: 1) to ethyl acetate. 1H NMR (300MHz, δppm, in CDCl3) 0.88 (9H, t, J = 6.4Hz),
0.98-1.61 (64H, m), 2.11-2.35 (3H, m), 3.34 (1H, d), 3.4
1-3.53 (1H, m), 3.85-4.31 (6H, m), 5.04-5.28 (4H, m), 6.
73 (1H, d, J = 7.8Hz), 6.94 (1H, t, J = 5.3Hz), 7.09-7.40 (15
H, m)

[0072] Example 1 (19 step, 20th step) [1,2-dideoxy-3-O - (2-dodecyl-tetradecanoyl) -2 - {(3 R) -3- hydroxy-tetradecanoyl cyanamide } -4- O -phosphono- D -glucuronyl]
-Glycine (Compound [I]; R ¹ = Glycine residue, A = O, B = C
H, m = 11, n = 11, r = 10) [1,2-dideoxy-4- O -diphenylphosphono-3- O- (2-dodecyltetradecanoyl) -2 obtained in Reference Example 6 - {(3 R) -3- hydroxy-tetradecanoyl cyanamide} - D - glucuronyl] - glycine benzyl ester (351 mg) was dissolved in acetic acid (7 ml), palladium black (35 mg)
Was added to carry out catalytic reduction for 30 minutes in 1 atm of hydrogen. After completion of the reaction, the catalyst was filtered off and concentrated under reduced pressure to obtain a residue. This residue was dissolved in acetic acid (8 ml), platinum oxide (60 mg) was added,
Catalytic reduction was carried out in 3 atm of hydrogen for 4 hours. After completion of the reaction, the catalyst was filtered off and the filtered solution was freeze-dried to obtain the title compound as a white powder. Melting point 203.6-207.9 ° C (decomposition) FAB MS (m / z) 919.5 (M + H) ⁺

[0073] Production Example 2 1,2-dideoxy-3-O - (2-dodecyl-tetradecanoyl) -2 - [(3 R) -3- hydroxy-tetradecanoyl cyanamide]-4-O - phosphono - D - Synthesis of glucuronic acid.

Reference Example 7 (13th step, 14th step) 2-tert-butoxycarboxamide-1,2-dideoxy-4- O -diphenylphosphono-3- O- (2-
Dodecyl-tetradecanoyl) - D - glucuronic acid benzyl (compound (xv); R ² = tert- butoxycarbonyl group, R ⁵ = benzyl group, A = O, B = CH , m =
11, n = 11) 1,5-anhydro-2-tert obtained in Reference Example 4
-Butoxycarboxamide-2-deoxy-4- O -diphenylphosphono-3- O- (2-dodecyltetradecanoyl) -D -glucitol (1.3 g) was added to carbon tetrachloride (9 ml),
Dissolve in a mixed solvent of acetonitrile (9 ml) and water (13 ml), add sodium periodate (1.43 g) under ice cooling, then add ruthenium trichloride (33 mg), and stir for 2 hours under ice cooling. After that, the mixture was further stirred at room temperature for 1.5 hours. After completion of the reaction, ice-cooled ethyl acetate was added to the reaction solution, and 10% sodium sulfite aqueous solution was added thereto while vigorously stirring. The ethyl acetate layer was extracted and washed successively with 10% aqueous sodium sulfite solution, water and aqueous sodium chloride solution.
The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
The obtained residue was dissolved in dry dimethylformamide (20 ml), benzyl bromide (0.462 ml) and sodium hydrogencarbonate (272 mg) were added, and the mixture was stirred overnight at 60 ° C. in a nitrogen stream. After completion of the reaction, the mixture was concentrated under reduced pressure, the residue was dissolved in chloroform and washed with water. The chloroform layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was subjected to silica gel flash column chromatography. The title compound was obtained from n-hexane: ethyl acetate (5: 1) eluate.
(896 mg) was obtained. ¹ H NMR (300MHz, δppm, in CDCl ₃ ), 0.80-0.99 (6H, m), 0.
99-1.70 (44H, m), 1.40 (9H, s), 2.24 (1H, quint., J = 6.0H
z), 3.40 (1H, dd, J = 7.7Hz), 3.77-3.89 (1H, m), 4.17-4.3
2 (2H, m), 4.91-5.07 (3H, m), 5.08-5.26 (2H, m), 7.08-7.
38 (15H, m),

Reference Example 8 (15th and 16th Steps) 1,2-Dideoxy-4- O -diphenylphosphono-3
- O - (2-dodecyl-tetradecanoyl) -2 - [(3
R ) -3-Hydroxytetradecanamido] -D- benzyl glucuronic acid (Compound (xvii); R ⁵ = benzyloxy group, A = O, B
= CH, m = 11, n = 11) According to the same method as in Reference Example 6, obtained in Reference Example 7
tert-Butoxycarboxamide-1,2-dideoxy-4- O -diphenylphosphono-3- O- (2-dodecyltetradecanoyl) -D- benzyl glucuronate (89
The title compound (736 mg) was obtained from (5 mg). ¹ H NMR (300MHz, δppm, in CDCl ₃ ) 0.80-0.95 (6H, m), 1.0
6-1.68 (64H, m), 2.07-2.28 (3H, m), 3.28 (1H, broad s),
3.47 (1H, dd, J = 6.4 and 12.0Hz), 3.84-3.95 (1H, m), 4.1
1-4.22 (1H, m), 4.32 (1H, dd, J = 3.9 and 12.0Hz), 4.37 (1
H, d, J = 5.7Hz), 5.00 (1H, d, J = 12.2Hz), 5.23 (1H, d, J = 12.2
Hz), 4.98-5.09 (1H, m), 5.16 (1H, t, J = 6.5Hz), 6.57 (1H,
d, J = 7.0Hz), 7.10-7.35 (15H, m)

Reference Example 9 (Step 17) 1,2-Dideoxy-4- O -diphenylphosphono-3
- O - (2-dodecyl-tetradecanoyl) -2 - [(3
R ) -3-Hydroxytetradecanamido] -D -glucuronic acid (Compound (xviii); A = O, B = CH, m = 11, n =
11, r = 10) 1,2- dideoxy-4-O obtained in Reference Example 8 - diphenylphosphono-3-O - (2-dodecyl-tetradecanoyl) -2 - [(3 R) -3- Hydroxytetradecanamid] -D- benzyl glucuronate (206 mg) was added to acetic acid (3 ml)
10% palladium-carbon (50 mg) was added, and the mixture was catalytically reduced at room temperature in 1 atm of hydrogen for 1 hour. After completion of the reaction, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (280 mg). ¹ H NMR (300MHz, δppm, in CDCl ₃ ) 0.78-0.97 (9H, m), 0.9
7-1.60 (64H, m), 2.00-2.35 (3H, m), 3.36 (1H, dd, J = 7.3 a
nd 10.9Hz), 3.82-3.97 (1H, m), 4.11-4.28 (3H, m), 4.90
-5.01 (1H, m), 5.19 (1H, t, J = 7.2Hz), 6.66 (1H, d, J = 7.6H
z), 7.05-7.40 (10H, m)

[0077] Example 2 (20th Step) 1,2-dideoxy-3-O - (2-dodecyl-tetradecanoyl) -2 - [(3 R) -3- hydroxy-tetradecanoyl cyanamide]-4-O - phosphono - D - glucuronic acid (compound ^{(I); R 1 = OH, A =} O, B = CH, m =
11, n = 11, r = 10) 1,2- dideoxy-4-O obtained in Reference Example 9 - diphenylphosphono-3-O - (2-dodecyl-tetradecanoyl) -2 - [(3 R ) -3-Hydroxytetradecanamido] -D -glucuronic acid (170 mg) was dissolved in acetic acid (4 ml), platinum oxide (122 mg) was added, and catalytic reduction was carried out at room temperature for 1 hour in 3 atm of hydrogen. After completion of the reaction, the catalyst was filtered off, water was added to the obtained residue, and the residue was freeze-dried to obtain the title compound (95 mg) as a white powder. Melting point 188.0-189.2 ° C (decomposition) ¹ H NMR (300MHz, δppm, in Pyridine-d ₅ ) 0.78-0.97 (9H,
m), 0.97-1.95 (64H, m), 2.55-2.78 (3H, m), 4.04 (1H, dd, J
= 3.6 and 11.9Hz), 4.36-4.46 (1H, m), 4.68-4.79 (1H,
m), 4.87 (1H, dd, J = 3.1 and 11.9Hz), 5.21 (1H, d, J = 3.5H
z), 5.57-5.66 (1H, m), 5.94-6.03 (1H, m), 8.98 (1H, d, J =
8.5Hz) FAB MS (m / z) 884.5 (M + Na) ⁺ , 860.0 (MH) ^-

[0078] Production Example 3 [1,2-dideoxy-3-O - (2-dodecyl-tetradecanoyl) -2 - {(3 R) -3- hydroxy-tetradecanoyl cyanamide}-4-O - phosphono - D -Glucuronyl]
-Synthesis of L -glutamic acid.

Reference Example 10 (Step 18) [1,2-Dideoxy-4- O -diphenylphosphono-]
3- O- (2-dodecyltetradecanoyl) -2-
{(3 R) -3- hydroxy-tetradecanoyl cyanamide} - D -
Glucuronyl] -L -glutamic acid dibenzyl (compound (xix); R1 ^' = glutamic acid dibenzyl ester residue, A = O, B = CH, m = 11, n = 11, r =
10) 1,2-dideoxy-4 obtained in Reference Example 9 O - diphenylphosphono-3-O - (2-dodecyl-tetradecanoyl) -2 - [(3 R) -3- hydroxy-tetradecanoyl Nami D ] -D -Glucuronic acid (547 mg) in dry dichloromethane
(6 ml), dibenzyl glutamate p-toluenesulfonate (269 mg), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (WSC
-HCl) (155 mg) and triethylamine (0.075 mg) were added, and the mixture was stirred at room temperature for 1.5 hours. After the completion of the reaction, dichloromethane was added to the reaction solution and washed with water. The dichloromethane layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the obtained residue was subjected to silica gel flash column chromatography, and n-hexane: ethyl acetate (5:
The title compound (514 mg) was obtained from 4). ¹ H NMR (300MHz, δppm, in CDCl ₃ ) 0.80-0.95 (9H, m), 0.9
5-1.58 (64H, m), 1.95-2.46 (7H, m), 3.29 (1H, d, J = 3.3H
z), 3.38 (1H, dd, J = 8.9 and 12.9Hz), 3.87-3.96 (1H, m),
4.12-4.23 (2H, m), 4.59 (1H, tt, J = 6.3 and 7.0Hz), 4.9
7-5.07 (1H, m), 5.07 (2H, s), 5.11 (2H, s), 5.20 (1H, t, J =
7.7Hz), 6.57 (1H, d, J = 9.0Hz), 7.07-7.40 (20H, m)

Reference Example 11 (Process 19) [1,2-Dideoxy-4- O -diphenylphosphono-
3- O- (2-dodecyltetradecanoyl) -2-
{(3 R) -3- hydroxy-tetradecanoyl cyanamide} - D -
Glucuronyl] -L -glutamic acid (compound (xx); R ¹ = glutamic acid residue, A = O, B =
CH, m = 11, n = 11, r = 10) According to the same method as in Reference Example 9, [1,2-dideoxy-4- O -diphenylphosphono-obtained in Reference Example 10 was obtained.
3- O- (2-dodecyltetradecanoyl) -2-
[(3 R) -3- hydroxy-tetradecanoyl cyanamide] - D -
The title compound (72.8 mg) was obtained from dibenzyl [glucuronyl] -L -glutamate (100 mg). However, hydrous ethanol was used instead of acetic acid. ¹ H NMR (300MHz, δppm, in CDCl ₃ ) 0.77-0.94 (9H, m), 0.9
4-1.58 (64H, m), 1.87-2.46 (7H, m), 3.36 (1H, t, J = 9.4H
z), 3.90-4.02 (1H, m), 4.06-4.15 (1H, m), 4.18 (1H, d, J =
9.0Hz), 4.19-4.49 (2H, m), 4.92 (1H, q, J = 9.4Hz), 5.36
(1H, t, J = 9.4Hz), 6.72-6.88 (1H, m), 7.00-7.31 (10H, m),
7.61-7.76 (1H, m)

[0081] Example 3 (No. 20 step) [1,2-dideoxy-3-O - (2-dodecyl-tetradecanoyl) -2 - {(3 R) -3- hydroxy-tetradecanoyl cyanamide} -4- O -phosphono- D -glucuronyl]
- L - glutamic acid (Compound (I); R ¹ = glutamic acid residues, A = O, B
= CH, m = 11, n = 11, r = 10) According to the same method as in Example 2, [1,2-dideoxy-4- O -diphenylphosphono-obtained in Reference Example 11 was obtained.
3- O- (2-dodecyltetradecanoyl) -2-
{(3 R) -3- hydroxy-tetradecanoyl cyanamide} - D -
The title compound (40 mg) as a white powder was obtained from glucuronyl] -L -glutamic acid (72 mg). ¹ H NMR (300MHz, δppm, in pyridine-d ₅ ) 0.70-0.99 (9H,
m), 1.00-1.90 (64H, m), 1.90-3.19 (7H, m), 3.47-3.60 (1
H, m), 4.12-4.31 (1H, m), 4.34-4.58 (2H, m), 4.70-4.87
(1H, m), 5.02-5.22 (1H, m), 5.27-5.48 (1H, m), 5.78-5.9
6 (1H, m), 8.81-8.99 (1H, m), 9.70-10.50 (6H, broad s) Melting point 187.8-190.1 ℃ (decomposition) FAB MS (m / z) 991.5 (M + H) ⁺

Production Example 4 1,2-dideoxy-3- O- (2-didodecylaminocarbonyl) -2-[( 3R ) -3-hydroxytetradecanamido] -4- O -phosphono- D- Synthesis of glucuronic acid.

Reference Example 12 (8th step) 1,5-anhydro-2-tert-butoxycarboxamido-2-deoxy-3- O- (2-didodecylaminocarbonyl) -4,6- O -isopropylidene- D −
Glucitol (Compound (ix); R ² = tert- butoxycarbonyl group, A = O, B = N , m = 11, n = 11) obtained in Reference Example 1 1,5-anhydro -2-tert
-Butoxycarboxamide-2-deoxy-4,6- O
-Isopropylidene- D -glucitol (4.0 g) was dissolved in dry tetrahydrofuran (40 ml) in a nitrogen stream, and activated carbon was added.
(200 mg) and triethylamine (3.04 ml) were added. Further, while cooling in a dry ice-methanol bath, trichloromethyl chloroformate (1.19 ml) was added dropwise. After completion of dropping, the mixture was stirred for 3 hours while returning to room temperature. After passing nitrogen through the reaction solution for 30 minutes, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in dry dichloromethane (20 ml) in a nitrogen stream, and a solution of di-n-dodecylamine (4.67 g) and triethylamine (1.84 ml) in dry dichloromethane (20 ml) was added under ice-cooling at room temperature. It was stirred for 1.5 hours. After completion of the reaction, dichloromethane was added to the reaction solution to dilute it, and the dichloromethane layer was washed successively with 0.01N hydrochloric acid, water, saturated sodium hydrogen carbonate aqueous solution, and saturated sodium chloride aqueous solution. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the obtained residue was subjected to silica gel flash column chromatography to obtain the title compound (3.16 g) from a chloroform: methanol (100: 1) eluate. ¹ H NMR (300 MHz, δ ppm, in CDCl ₃ ) 0.88 (6 H, t, J = 6.4 Hz),
1.15-1.61 (40H, m), 1.38 ((3H, s), 1.40 (9H, s), 1.47 (3
H, s), 2.91-3.10 (2H, m), 3.15 (1H, t, J = 11.2Hz), 3.24 (1
H, tt, J = 5.5 and 9.9Hz), 3.28-3.46 (2H, m), 3.62-3.83
(3H, m), 3.92 (1H, dd, J = 5.5 and 10.7Hz), 4.16 (1H, dd, J
= 5.3 and 11.2Hz), 4.71 (1H, t, J = 9.9Hz), 5.44 (1H, d, J =
6.6Hz) FAB MS (m / z) 683.7 (M + H) ⁺ , 681.5 (MH) ^-

Reference Example 13 (Step 9) 1,5-anhydro-2-tert-butoxycarboxamido-2-deoxy-3- O- (2-didodecylaminocarbonyl) -D -glucitol (compound (x); R ² = tert-butoxycarbonyl group, A = O, B = N, m = 11, n = 11) According to the same method as in Reference Example 3, 1,5-anhydro-2-tert obtained in Reference Example 12 -Butoxycarboxamide-2-deoxy-3- O- (2-didodecylaminocarbonyl) -4,6- O -isopropylidene- D-
The title compound (1.98 g) was obtained from glucitol (2.1 g). ¹ H NMR (300 MHz, δ ppm, in CDCl ₃ ) 0.88 (6 H, t, J = 6.2 Hz),
1.41 (9H, s), 1.14-1.61 (40H, m), 3.05-3.36 (6H, m), 3.6
2 (1H, t, J = 9.5Hz), 3.72-3.86 (2H, m), 3.90 (1H, dd, J = 2.8
and 11.8Hz), 4.09 (1H, dd, J = 5.1 and 11.2Hz), 4.61 (1
H, t, J = 9.5Hz), 4.91 (1H, broad s)

Reference Example 14 (10th step, 11th step, 12th step) 1,5-anhydro-2-tert-butoxycarboxamide-2-deoxy-3- O- (2-didodecylaminocarbonyl) -4 - O - diphenylphosphono - D - glucitol (compound (Xiii); R ² = tert- butoxycarbonyl group, a = O, B = n , m = 11, n = 11) Following the same manner as in reference example 4, From 1,5-anhydro-2-tert-butoxycarboxamido-2-deoxy-3- O- (2-didodecylaminocarbonyl) -D -glucitol (1.98 g) obtained in Reference Example 13, the title compound (2.11 g) was obtained. ¹ H NMR (300 MHz, δ ppm, in CDCl ₃ ) 0.88 (6 H, t, J = 6.7 Hz),
1.00-1.51 (40H, m), 1.39 (9H, s), 2.68 (1H, quint., J = 6.8
Hz), 2.86 (1H, broad s), 2.90-3.11 (2H, m), 3.14 (1H, t,
J = 11.1Hz), 3.19-3.70 (4H, m), 3.77-3.92 (1H, m), 4.14
(1H, dd, J = 5.3 and 11.1Hz), 4.75 (1H, q, J = 9.4Hz), 5.02
-5.11 (3H, m), 7.09-7.38 (10H, m)

Reference Example 15 (13th Step, 14th Step) 2-tert-butoxycarboxamide-1,2-dideoxy-3- O- (2-didodecylaminocarbonyl)
-4- O -Diphenylphosphono- D -glucuronic acid benzyl (compound (xix); R ⁵ = benzyloxy group, A = O, B =
N, m = 11, n = 11) According to the same method as in Reference Example 7, 1,5-anhydro-2-tert-butoxycarboxamide-2-deoxy-3- O- (2- The title compound (372 mg) was obtained from didodecylaminocarbonyl) -4- O -diphenylphosphono- D -glucitol (1.16 g). ¹ H NMR (300 MHz, δ ppm, in CDCl ₃ ) 0.88 (6 H, t, J = 6.7 Hz),
1.08-1.57 (40H, m), 1.39 (9H, s), 2.71 (1H, quint., J = 6.6
Hz), 2.78-3.11 (2H, m), 3.28 (1H, t, J = 10.0Hz), 3.46 (1H,
quint., J = 6.6Hz), 3.80-3.93 (1H, m), 4.16 (1H, d, J = 7.1H
z), 4.23 (1H, dd, J = 4.9 and 10.0Hz), 4.87-5.14 (4H, m),
5.21 (1H, d, J = 7.4Hz), 7.05-7.40 (15H, m)

Reference Example 16 (15th and 16th Steps) 1,2-dideoxy-3- O- (2-didodecylaminocarbonyl) -4- O -diphenylphosphono-2-
[(3 R) -3- hydroxy-tetradecanoyl cyanamide] - D -
Benzyl glucuronate (Compound (xvii); R ⁵ = benzyloxy group, A = O, B
= N, m = 11, n = 11, r = 10) 2 obtained in Reference Example 15 according to the same method as in Reference Example 6
-Tert-butoxycarboxamide-1,2-dideoxy-3- O- (2-didodecylaminocarbonyl)-
The title compound (1.07g) was obtained from benzyl 4- O -diphenylphosphono- D -glucuronate (1.16g). ¹ H NMR (300MHz, δppm, in CDCl ₃ ) 0.81-0.95 (9H, m), 1.0
9-1.50 (60H, m), 2.10-2.30 (2H, m), 2.72 (1H, quint., J =
7.2Hz), 3.01 (1H, quint., J = 7.2Hz), 3.12 (1H, quint., J =
7.2Hz), 3.33 (1H, dd, J = 8.6 and 11.6Hz), 3.51 (1H, quin
t., J = 7.2Hz), 3.82-3.93 (1H, m), 4.10-4.38 (1H, m), 4.2
1 (1H, d, J = 7.3Hz), 4.32 (1H, dd, J = 4.5 and 11.6Hz), 4.90
-5.18 (4H, m), 6.70 (1H, d, J = 7.9Hz), 7.09-7.34 (15H, m)

Reference Example 17 (17th step) 1,2-dideoxy-3-O-(2-didodecylamino
Carbonyl) -4-O-Diphenylphosphono-2-
[(3R) -3-Hydroxytetradecanamid]- D−
Glucuronic acid (Compound (xviii); A = O, B = N, m = 11, n = 1)
1, r = 10) Obtained in Reference Example 16 according to the same method as in Reference Example 9.
1,2-dideoxy-3-O-(2-didodecylamino
Carbonyl) -4-O-Diphenylphosphono-2-
[(3R) -3-Hydroxytetradecanamid]-D−
From benzyl glucuronate (800 mg), the title compound (620 mg)
Got¹ H NMR (300MHz, δppm, in CDCl₃) 0.80-0.94 (9H, m), 1.0
2-1.53 (60H, m), 2.07-2.30 (2H, m), 2.74 (1H, quint., J =
7.2Hz), 2.96 (1H, quint., J = 7.2Hz), 3.08 (1H, quint., J =
7.2Hz), 3.27 (1H, t, J = 10.7Hz), 3.42 (1H, quint., J = 7.2H
z), 3.77-3.89 (1H, m), 4.02-4.17 (2H, m), 4.17-4.31 (1
H, m), 4.97 (1H, quint., J = 8.8Hz), 5.16 (1H, t, J = 8.8Hz),
 6.46 (2H, broad s), 6.90 (1H, d, J = 7.9Hz), 7.03-7.31 (1
0H, m)

Example 4 (20th step) 1,2-dideoxy-3- O- (2-didodecylaminocarbonyl) -2-[( 3R ) -3-hydroxytetradecanamido] -4- O - phosphono - D - glucuronic acid (compound ^{(I); R 1 = OH, A =} O, B = N, m = 1
1, n = 11, r = 10) According to the same method as in Example 2, 1,2-dideoxy-3- O- (2-didodecylaminocarbonyl) -4- O -diphenyl obtained in Reference Example 17 was used. Phosphono-2-
[(3 R) -3- hydroxy-tetradecanoyl cyanamide] - D -
From glucuronic acid (315 mg), the title compound (243 m
g) was obtained. Melting point 165.0-166.5 ° C (decomposition) ¹ H NMR (300MHz, δppm, Pyridine-d ₅ ) 0.80-0.96 (9H, m),
1.13-1.80 (60H, m), 2.67 (2H, d, J = 5.7Hz), 2.88-3.06 (1
H, m), 3.13-3.32 (1H, m), 3.32-3.51 (1H, m), 3.69-3.87
(1H, m), 3.94-4.10 (1H, m), 4.31-4.46 (1H, m), 4.63-4.7
6 (1H, m), 4.76-4.90 (1H, m), 5.12-5.27 (1H, m), 5.66-5.
85 (2H, m), 7.14 (4H, broad s), 8.80 (1H, d, J = 7.9Hz) FAB MS (m / z) 863.5 (M + H) ⁺ , 885.5 (M + Na) ⁺

Production Example 5 [1,2-dideoxy-3- O- (2-didodecylaminocarbonyl) -2-{( 3R ) -3-hydroxytetradecanamido} -4- O -phosphono- D -Glucuronyl] -L -glutamic acid synthesis.

Reference Example 18 (Step 18) [1,2-Dideoxy-3- O- (2-didodecylaminocarbonyl) -4- O -diphenylphosphono-2-]
{(3 R) -3- hydroxy-tetradecanoyl cyanamide} - D -
Glucuronyl] -L -glutamate dibenzyl (compound (xix); R ^{1 ′} = glutamate dibenzyl ester residue, A = O, B = N, m = 11, n = 11, r = 1
0) According to the same method as in Reference Example 10, 1,2-dideoxy-3- O- (2-didodecylaminocarbonyl) -4- O -diphenylphosphono-2-obtained in Reference Example 17 was used.
[(3 R) -3- hydroxy-tetradecanoyl cyanamide] - D -
The title compound (316 mg) was obtained from glucuronic acid (310 mg). ¹ H NMR (300MHz, δppm, in CDCl ₃ ) 0.82-0.95 (9H, m), 1.0
2-1.75 (60H, m), 1.94-2.48 (6H, m), 2.66 (1H, quint., J =
7.4Hz), 2.93 (1H, quint., J = 7.4Hz), 3.09 (1H, quint., J =
7.4Hz), 3.25 (1H, t, J = 10.6Hz), 3.59 (1H, quint., J = 7.4H
z), 3.82-3.95 (1H, m), 4.02 (1H, d, J = 9.1Hz), 4.09-4.22
(1H, m), 4.27 (1H, dd, J = 5.1 and 10.6Hz), 4.59 (1H, tt, J =
5.5 and 7.6Hz), 4.91 (1H, q, J = 9.1Hz), 5.02-5.17 (5H,
m), 6.68 (1H, d, J = 7.9Hz), 6.98-7.39 (21H, m)

Reference Example 19 (Step 19) [1,2-Dideoxy-3- O- (2-didodecylaminocarbonyl) -4- O -diphenylphosphono-2-]
{(3 R) -3- hydroxy-tetradecanoyl cyanamide} - D -
Glucuronyl] -L -glutamic acid (compound (xx); R1 ^' = glutamic acid residue, A = O, B =
N, m = 11, n = 11, r = 10) [1,2-dideoxy-3- O- (2-didodecylaminocarbonyl) -obtained in Reference Example 18 according to the same method as Reference Example 11. 4- O -diphenylphosphono-2-
[(3 R) -3- hydroxy-tetradecanoyl cyanamide] - D -
The title compound (65.6 mg) was obtained from dibenzyl [glucuronyl] -L -glutamate (100 mg). ¹ H NMR (300MHz, δppm, in CDCl ₃ ) 0.78-0.99 (9H, m), 0.9
9-1.50 (60H, m), 2.00-2.45 (6H, m), 2.63-2.77 (1H, m),
2.83-3.11 (2H, m), 3.28-3.56 (2H, m), 3.84-3.98 (1H, m),
4.09-4.27 (2H, m), 4.30-4.58 (2H, m), 5.02 (1H, q, J = 9.3
Hz), 5.25 (1H, t, J = 9.3Hz), 6.95 (1H, d, J = 7.9Hz), 7.00-
7.30 (10H, m), 7.49 (1H, d, J = 7.9Hz)

Example 5 (20th Step) [1,2-Dideoxy-3- O- (2-didodecylaminocarbonyl) -2-{( 3R ) -3-hydroxytetradecanamido} -4- O -phosphono- D -glucuronyl] -L -glutamic acid (compound [I]; R ⁵ = glutamic acid residue, A = O, B
= N, m = 11, n = 11, r = 10) According to the same method as in Example 2, [1,2-dideoxy-3- O- (2-didodecylaminocarbonyl) obtained in Reference Example 19 was obtained. -4- O -diphenylphosphono-2-
[(3 R) -3- hydroxy-tetradecanoyl cyanamide] - D -
The title compound (211 mg) as a white powder was obtained from glucuronyl] -L -glutamic acid (266 mg). However, hydrous ethanol was used instead of acetic acid. Melting point 169.5-172.7 ° C (decomposition) FAB MS (m / z) 992.4 (M + H) ⁺

[0094] Production Example 6 1,2,3-trideoxy-3- (2-dodecyl-tetradecanoyl cyanamide) -2 - [(3 R) -3- hydroxy-tetradecanoyl cyanamide]-4-O - phosphono - D -Synthesis of methyl glucuronate.

Reference Example 20 (Second Step) 1,5-Anhydro-2-tert-butoxycarboxamido-2-deoxy-4,6- O -isopropylidene-3- O -trifluoromethanesulfonyl- D -glucitol (Compound (iii); R ² = tert-butoxycarbonyl group, R ³ = trifluoromethanesulfonyl group) 1,5-anhydro-2-tert obtained in Reference Example 1
-Butoxycarboxamide-2-deoxy-4,6- O
-Isopropylidene- D -glucitol (3.0 g) was dissolved in dichloromethane (40 ml) and pyridine (1.72 ml) under ice cooling.
And trifluoromethanesulfonic anhydride (3.3 ml) were added, and the mixture was stirred for 30 minutes. After completion of the reaction, water was added to the reaction solution and the mixture was extracted twice with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was subjected to silica gel flash column chromatography to obtain the title compound (3.53 g) from the n-hexane: ethyl acetate (3: 1) eluate. Obtained. ¹ H NMR (300MHz, δppm, in CDCl ₃ ) 1.40 (3H, s), 1.45 (9H,
s), 1.48 (3H, s), 3.26 (1H, tt, J = 5.3 and 10.9Hz), 3.40
(1H, t, J = 9.9Hz), 3.67-3.84 (2H, m), 3.70-4.12 (3H, m),
4.66-4.82 (2H, m)

Reference Example 21 (Third Step) 1,5-anhydro-2-tert-butoxycarboxamido-2-deoxy-4,6- O -isopropylidene-3- O -acetyl- D -alisitol (compound (iv ); R ² = tert-butoxycarbonyl group) 1,5-anhydro-2-ter obtained in Reference Example 20
t-Butoxycarboxamide-2-deoxy-4,6-
O -isopropylidene-3- O -trifluoromethanesulfonyl- D -glucitol (3.53 g) was dissolved in N, N-dimethylformamide (30 ml), potassium acetate (4.15 g) was added, and the mixture was stirred at room temperature for 1 hr. After the reaction was completed, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Water was added to the obtained residue,
Extracted twice with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was subjected to silica gel flash column chromatography. The title compound (2.04 g) was obtained from the eluent of n-hexane: ethyl acetate (3: 1). Obtained. ¹ H NMR (300MHz, δppm, in CDCl ₃ ) 1.35 (3H, s), 1.44 (9H,
s), 1.47 (3H, s), 2.17 (3H, s), 3.38 (1H, t, J = 10.8Hz),
3.50-3.74 (3H, m), 3.82-3.94 (2H, m), 3.98-4.11 (1H, m),
4.43-4.58 (1H, m), 5.42-5.49 (1H, m)

Reference Example 22 (Step 4) 1,5-anhydro-2-tert-butoxycarboxamido-2-deoxy-4,6- O -isopropylidene- D -alisitol (compound (v); R ² = tert) -Butoxycarbonyl group) 1,5-anhydro-2-ter obtained in Reference Example 21
t-Butoxycarboxamide-2-deoxy-4,6-
O -isopropylidene-3- O -acetyl- D -alicitol was dissolved in methanol (15 ml), 28% sodium methoxide methanol solution was added under ice cooling, and the mixture was stirred for 30 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure. Water was added to this residue, and the mixture was extracted twice with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the obtained residue was subjected to silica gel flash column chromatography, and n-hexane: ethyl acetate (3: 1).
The title compound (1.48 g) was obtained from the eluate. ¹ H NMR (300MHz, δppm, in CDCl ₃ ) 1.41 (3H, s), 1.45 (9H,
s), 1.49 (3H, s), 3.43 (1H, t, J = 11.0Hz), 3.57 (6H, m),
4.02-4.08 (1H, m), 5.08 (1H, d, J = 9.0Hz)

Reference Example 23 (Step 5) 1,5-anhydro-2-tert-butoxycarboxamide-2-deoxy-4,6- O -isopropylidene-3- O- methanesulfonyl- D -alisitol (Compound ( vi); R ² = tert-butoxycarbonyl group, R ³
= Methanesulfonyl group) 1,5-anhydro-2-ter obtained in Reference Example 22
t-Butoxycarboxamide-2-deoxy-4,6-
O -isopropylidene- D -allysitol (870 mg) was dissolved in pyridine (7 ml), and methanesulfonyl chloride (0.
573 ml) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, water was added to the reaction solution and extracted twice with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the obtained residue was subjected to silica gel flash column chromatography to obtain the title compound (744 mg) from an eluent of n-hexane: ethyl acetate (3: 1). . ¹ H NMR (300 MHz, δ ppm, in CDCl ₃ ) 1.40 (3 H, s), 1.44 (9 H,
s), 1.50 (3H, s), 3.15 (3H, s), 3.42 (1H, t, J = 11.1Hz),
3.53-3.98 (5H, m), 4.00-4.14 (1H, m), 3.76 (1H, d, J = 9.3H
z), 5.07 (1H, t, J = 2.2Hz)

Reference Example 24 (Sixth step) 1,5-anhydro-3-azido-2-tert-butoxycarboxamide-2,3-dideoxy-4,6- O
- isopropylidene - D - glucitol (compound (vii); R ² = tert- butoxycarbonyl group) obtained in Reference Example 23 1,5-anhydro -2-ter
t-Butoxycarboxamide-2-deoxy-4,6-
O -isopropylidene-3- O- methanesulfonyl- D
-Alicitol (744 mg) was dissolved in N, N-dimethylformamide (16 ml), sodium azide (634 mg) was added, and the mixture was stirred at 160 ° C for 1 hr. After completion of the reaction, the insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, water was added to the residue,
It was extracted twice with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the obtained residue was subjected to silica gel flash column chromatography. The eluate of n-hexane: ethyl acetate (3: 1)
The title compound (576 mg) was obtained. ¹ H NMR (300MHz, δppm, in CDCl ₃ ) 1.43 (3H, s), 1.46 (9H,
s), 1.52 (3H, s), 3.23 (1H, tt, J = 4.9 and 10.0Hz), 3.28
(1H, t, J = 10.0Hz), 3.52-3.66 (2H, m), 3.70 (1H, t, J = 10.0
Hz), 3.91 (1H, dd, J = 4.9 and 10.0Hz), 4.04 (1H, dd, J = 4.
8 and 10.0Hz), 4.55 (1H, d, J = 7.8Hz)

Reference Example 25 (7th Step, 8th Step) 1,5-anhydro-2-tert-butoxycarboxamide-2,3-dideoxy-3- (2-dodecyltetradecanamido) -4,6- O -isopropylidene- D-
Glucitol (Compound (ix); R ² = tert-butoxycarbonyl group, A = NH, B = CH, m = 11, n = 11) 1,5-anhydro-3-azido-2 obtained in Reference Example 24 -Tert-Butoxycarboxamide-2,3-dideoxy-4,6- O -isopropylidene- D -glucitol (960 mg) was dissolved in ethanol (7 ml), 10% palladium carbon (300 mg) was added, and hydrogen was added at 1 atm. , At room temperature 4
Stir for hours. After completion of the reaction, the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in dry dichloromethane (15 ml) to prepare dodecyltetradecanoic acid (1.19 g) and WSC · H.
Cl (820 mg) was added, and the mixture was stirred at room temperature overnight. After the completion of the reaction, dichloromethane was added to the reaction solution and washed with water. The dichloromethane layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained residue was subjected to silica gel flash column chromatography. The title compound (935 mg) was obtained from the eluent of n-hexane: ethyl acetate (3: 1). Got ¹ H NMR (300 MHz, δ ppm, in CDCl ₃ ) 0.88 (6 H, t, J = 6.7 Hz),
1.13-1.68 (44H, m), 1.36 (3H, s), 1.40 (9H, s), 1.45 (3H,
s), 1.95-2.08 (1H, m), 3.18 (1H, t, J- = 10.9Hz), 3.25 (1H,
tt, J = 5.2 and 10.0Hz), 3.45 (1H, t, J = 10.0Hz), 3.52-3.
63 (1H, m), 3.67 (1H, t, J = 10.0Hz), 3.90 (1H, dd, J = 5.2 an
d 10.0Hz), 4.00 (1H, q, J = 10.0Hz), 4.15 (1H.dd, J = 5.1 a
nd 10.9Hz), 5.31-5.42 (2H, m)

Reference Example 26 (Step 9) 1,5-anhydro-2-tert-butoxycarboxamide-2,3-dideoxy-3- (2-dodecyltetradecanamido) -D -glucitol (Compound (x) R ² = tert-butoxycarbonyl group, A = NH, B = CH, m = 11, n = 11) According to the same method as in Reference Example 3, 1,5-anhydro-2-obtained in Reference Example 25. tert-Butoxycarboxamide-2,3-dideoxy-3- (2-dodecyltetradecanamido) -4,6- O -isopropylidene- D-
The title compound (3.39g) was obtained from glucitol (3.6g). ¹ H NMR (300 MHz, δ ppm, in CDCl ₃ ) 0.88 (6 H, t, J = 6.7 Hz),
1.15-1.65 (44H, m), 1.41 (9H, s), 2.06-2.19 (1H, m), 3.1
1-3.44 (3H, m), 3.49-3.62 (1H, m), 3.68-3.81 (2H, m), 3.
85 (1H, dd, J = 2.9 and 11.9Hz), 4.02 (1H, dd, J = 5.0 and 1
1.1Hz), 5.80 (1H, d, J = 7.9Hz), 7.31 (1H, d, J = 6.1Hz)

Reference Example 27 (10th step, 11th step, 12th step) 1,5-anhydro-2-tert-butoxycarboxamide-2,3-dideoxy-4- O -diphenylphosphono-3- (2 - dodecyl tetradecanoyl cyanamide) - D - glucitol (compound (xiii); R ² = tert- butoxycarbonyl group, a = NH, B = CH , according to the same manner as m = 11, n = 11) reference example 4 From 1,5-anhydro-2-tert-butoxycarboxamide-2,3-dideoxy-3- (2-dodecyltetradecanamido) -D -glucitol (3.39 g) obtained in Reference Example 26, the title compound (3.45g) was obtained. 1H NMR (300MHz, δppm, in CDCl ₃ ) 0.88 (6H, t, J = 6.6Hz),
0.97-1.63 (44H, m), 1.40 (9H, s), 2.11 (1H, quint., J = 6.4
Hz), 2.54 (1H, broad s), 3.17 (1H, t, J = 10.8Hz), 3.35-
3.86 (4H, m), 4.16-4.33 (2H, m), 4.64 (1H, q, J = 9.6Hz),
5.82 (1H, d, J = 5.1Hz), 6.86 (1H, d, J = 6.9Hz), 7.08-7.39
(10H, m)

Reference Example 28 (13th step, 14th step) 2-tert-butoxycarboxamide-1,2,3-
Trideoxy-4- O -diphenylphosphono-3- (2
- dodecyl tetradecanoyl cyanamide) - D - methyl glucuronic acid (compound (xv); R ² = tert- butoxycarbonyl group, R ⁵ = methoxy group, A = NH, B = CH , m = 1
1, n = 11) According to the same method as in Reference Example 5, 1,5-anhydro-2-tert-butoxycarboxamide-2,3-dideoxy-4- O -diphenylphosphono-3 obtained in Reference Example 27 was used. -(2-dodecyltetradecanamid) -D -glucitol (2.0 g) was added to carbon tetrachloride (15 ml) and acetonitrile.
(15 ml) and water (22 ml) dissolved in a mixed solvent, and sodium periodate (2.2 g) was added under ice cooling, followed by ruthenium trichloride.
(51 mg) was added, and the mixture was stirred under ice-cooling for 2 hr, and further stirred at room temperature overnight. Ethyl acetate was added to the reaction solution, and 10% aqueous sodium sulfite solution was added with vigorous stirring.
The ethyl acetate layer was extracted and washed successively with 10% aqueous sodium sulfite solution, water and aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
The obtained residue was dissolved in dry dichloromethane (20 ml), methanol (2 ml), WSC.HCl (648 mg) and 4-dimethylaminopyridine (138 mg) were added, and the mixture was stirred at room temperature overnight. Chloroform was added to the reaction solution and washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the obtained residue was subjected to silica gel flash column chromatography to obtain the title compound (1.66 g) from an eluent of n-hexane: ethyl acetate (4: 1). It was ¹ H NMR (300 MHz, δ ppm, in CDCl ₃ ) 0.89 (6 H, t, J = 6.7 Hz),
1.00-1.66 (44H, m), 1.39 (9H, s), 2.06-2.20 (1H, m), 3.2
1 (1H, t, J = 10.8Hz), 3.55 (3H, s), 3.59-3.73 (1H, m), 4.0
2 (1H, d, J = 9.3Hz), 4.18-4.39 (2H, m), 4.68 (1H, q, J = 9.3H
z), 5.91 (1H, d, J = 4.1Hz), 6.81 (1H, d, J = 6.8Hz), 7.01-
7.40 (10H, m)

Reference Example 29 (15th and 16th Steps) 1,2,3-Trideoxy-4- O -diphenylphosphono-3- (2-dodecyltetradecanamido) -2-
[(3 R) -3- hydroxy-tetradecanoyl cyanamide] - D -
Methyl glucuronate (Compound (xvii); R ⁵ = methoxy group, A = NH, B = C
H, m = 11, n = 11, r = 10) 2 obtained in Reference Example 28 according to the same method as Reference Example 6
-Tert-butoxycarboxamide-1,2,3-trideoxy-4- O -diphenylphosphono-3- (2-
Dodecyl tetradecanamido) -D -methyl glucuronic acid
The title compound (796 mg) was obtained from (820 mg). ¹ H NMR (300 MHz, δ ppm, in CDCl ₃ ) 0.88 (9 H, t, J = 6.7 Hz),
1.01-1.60 (64H, m), 2.08-2.29 (3H, m), 3.18 (1H, t, J = 10.
8Hz), 3.56 (3H, s), 3.61 (1H, d, J = 3.4Hz), 3.85-4.01 (2
H, m), 4.03 (1H, d, J = 9.7Hz), 4.25 (1H, tt, J = 6.4 and 9.7
Hz), 4.39 (1H, dd, J = 4.9 and 10.8Hz), 4.72 (1H, q, J = 9.7
Hz), 7.00-7.38 (12H, m)

[0105] Example 6 (20th step) 1,2,3-trideoxy-3- (2-dodecyl-tetradecanoyl cyanamide) -2 - [(3 R) -3-hydroxy-tetradecanoyl cyanamide] -4- Methyl O -phosphono- D -glucuronate (Compound [I]; R ¹ = methoxy group, A = NH, B = C
H, m = 11, n = 11, r = 10) According to the same method as in Example 2, 1,2,3-trideoxy-4- O -diphenylphosphono-3- (2 obtained in Reference Example 29). -Dodecyl tetradecanamide) -2-
[(3 R) -3- hydroxy-tetradecanoyl cyanamide] - D -
The title compound (469 mg) as a white powder was obtained from methyl glucuronate (680 mg). Melting point 225.1-228.0 ° C (decomposition) ¹ H NMR (300MHz, δppm, in CDCl ₃ ) 0.74-0.99 (9H, m), 1.1
1-1.83 (64H, m), 2.59-2.79 (3H, m), 3.30-3.48 (1H, m),
3.77 (3H, s), 4.36 (1H, d, J = 9.0Hz), 4.40-4.68 (4H, m),
5.03 (1H, q, J = 9.0Hz), 8.51 (3H, broad s), 9.61 (1H, broa
ds)

[0106] Production Example 7 1,2,3-trideoxy-3- (2-dodecyl-tetradecanoyl cyanamide) -2 - [(3 R) -3- hydroxy-tetradecanoyl cyanamide]-4-O - phosphono - D -Glucuronic acid
Synthesis of dipotassium salt.

[0107] Example 7 (21 step) 1,2,3-trideoxy-3- (2-dodecyl-tetradecanoyl cyanamide) -2 - [(3 R) -3-hydroxy-tetradecanoyl cyanamide] -4- O -phosphono- D -glucuronic acid
Dipotassium salt 1,2,3-Trideoxy-3-obtained in Example 6
(2-dodecyltetradecanamido) -2-[( 3R )-
3-Hydroxytetradecanamid] -4- O -phosphono- D- methyl glucuronate (100 mg) was added to tetrahydrofuran.
(7.5 ml), suspended in water (2 ml) and potassium hydroxide solution
(0.5 ml) was added and stirred for 20 minutes. After completion of the reaction, the reaction solution was passed through an ion exchange resin (Amberlite IRC-50) column, and the eluate of tetrahydrofuran: water (2: 1) was concentrated under reduced pressure to give the title compound as a white powder (48 m
g) was obtained. Melting point 258.8-259.9 (decomposition) FAB MS (m / z) 936.7 (MH) ^-

Tables 1 and 2 show the compounds of Examples 1 to 7.

[Table 1]

[0109]

[Table 2]

Needless to say, the present invention is not limited to the above examples, and the following compounds, for example, also belong to the present invention.

3- O- (2-decyldodecanoyl)-
1,2-dideoxy -2 - [(3 R) -3- hydroxy-pentadecanoyl cyanamide]-4-O - phosphono - D - glucuronic acid

3- O- (2-decyldodecanoyl)-
1,2-dideoxy -2 - [(3 R) -3- hydroxy-dodeca cyanamide]-4-O - phosphono - D - ethyl glucuronic acid

[1,2-dideoxy-2-{(3 R )-
3-Hydroxyoctanamide} -3- O- (2-pentadecylheptadecanoyl) -4- O -phosphono- D -glucuronyl] -glycine

[0114] 3- O - (2-didecyl-aminocarbonyl) -1,2-dideoxy -2 - [(3 R) -3- hydroxy-dec cyanamide]-4-O - phosphono - D - glucuronic acid

1,2-dideoxy-2-[(3 R ) -3
-Hydroxypentadecanamide] -3- O- (2-dioctylaminocarbonyl) -4- O -phosphono- D- propyl glucuronic acid

[0116] [1,2-dideoxy-3-O - (2-ditridecyl aminocarbonyl) -2 - {(3 R) -3-
Hydroxynonamide} -4- O -phosphono- D -glucuronyl] -glycine

1,2,3-Trideoxy-2-[(3
R ) -3-Hydroxydecanamid] -4- O -phosphono-3- (2-tridecylpentadecanamide) -D -glucuronic acid

1,2,3-Trideoxy-2-[(3
R ) -3-Hydroxytridecanamid] -4- O -phosphono-3- (2-undecyltridecanamid) -D- ethyl glucuronate

[1,2,3-Trideoxy-2-{(3
R ) -3-Hydroxyheptadecanamid} -4- O -phosphono-3- (2-tetradecylhexadecanamide)-
D -glucuronyl] -L -glutamic acid

[1,2,3-Trideoxy-3- (3,3
3-didodecyl ureido) -2 - {(3 R) -3- hydroxy-tetradecanoyl cyanamide}-4-O - phosphono - D - glucuronyl] - L - glutamic acid

[0121]

INDUSTRIAL APPLICABILITY The novel glucuronic acid compound represented by the general formula [I] according to the present invention has beneficial activities such as immunostimulating action, antitumor action and tumor necrosis factor-inducing action, and has reduced toxicity. Therefore, it is useful as an immunostimulant or an antitumor agent.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Shinichi Uesato 1-1, Murasaki-cho, Takatsuki-shi, Osaka Inside the Pharmaceutical Research Institute, Japan Tobacco Industry Co., Ltd. (72) Inventor, Toyotsu Shichi, Murasaki, Takatsuki-shi, Osaka No. 1-cho, Japan Tobacco Inc. Pharmaceutical Research Institute

Claims (3)

[Claims] 1. A compound represented by the general formula [I]: (In the formula, R ¹ represents a hydroxyl group, a lower alkoxy group or an amino acid residue; A represents an oxygen atom or an NH group; B represents a nitrogen atom or a CH group; m and n may be the same or different. Represents an integer of 1 to 17; r represents an integer of 4 to 16), or a pharmaceutically acceptable salt thereof. 2. The novel glucuronic acid compound according to claim 1, wherein R ¹ is a hydroxyl group, a lower alkoxy group, a glutamic acid residue or a glycine residue, or a pharmaceutically acceptable salt thereof. 3. [1,2-Dideoxy-3- O- (2-
Dodecyl-tetradecanoyl) -2 - {(3 R) -3- hydroxy-tetradecanoyl cyanamide}-4-O - phosphono - D -
Glucuronyl] -glycine; 1,2-dideoxy-3-
O- (2-dodecyltetradecanoyl) -2-[(3
R ) -3-Hydroxytetradecanamido] -4- O -phosphono- D -glucuronic acid; [1,2-dideoxy-3
- O - (2-dodecyl-tetradecanoyl) -2 - {(3
R ) -3-Hydroxytetradecanamid} -4- O -phosphono- D -glucuronyl] -L -glutamic acid; 1,2
-Dideoxy-3- O- (2-didodecylaminocarbonyl) -2-[( 3R ) -3-hydroxytetradecanamid] -4- O -phosphono- D -glucuronic acid; [1,
2-dideoxy-3-O - (2-didodecyl-aminocarbonyl) -2 - {(3 R) -3- hydroxy-tetradecanoyl cyanamide}-4-O - phosphono - D - glucuronyl] - L -
Glutamate 1,2,3-trideoxy-3- (2-dodecyl-tetradecanoyl cyanamide) -2 - [(3 R) -3- hydroxy-tetradecanoyl cyanamide]-4-O - phosphono - D - methyl glucuronic acid; selected from glucuronic acid - 1,2,3-trideoxy-3- (2-dodecyl-tetradecanoyl cyanamide) -2 - [(3 R) -3- hydroxy-tetradecanoyl cyanamide]-4-O - phosphono - D The novel glucuronic acid compound according to claim 2, or a pharmacologically acceptable salt thereof.