WO1994012512A1 - Glucosylglucoside derivative - Google Patents

Abstract

An antitumor compound represented by general formula (1), wherein Q1 represents carboxy or phosphono; Q2 represents carboxy, phosphono or hydrogen; m represents an integer of 0 to 10; n represents an integer of 0 to 10; R1 represents acyl or substituted acyl; R2 represents acyl or substituted acyl; and R3 represents acyl or substituted acyl.

Description

 Specification

AAvid compound A '' Technical field

 The present invention relates to compounds having antitumor activity. Background art

 Natural lipid A has a tumor necrosis factor-inducing effect, an immunopotentiating effect, and the like, and is considered to be useful as an antitumor agent and a prophylactic / therapeutic agent for various infectious diseases. Lipid A is known to have various structures, and as an organically synthesized compound, 2-deoxy-6-0-dexoxy-1-[(R) — 3—dodecanoyloxytradeca [Nylamino] 1 3— 0— [(R) — 3—Tetradecanoyloxytide Tradecanol] 1-41 0—Phosphono 8— D—Glucopyranosil} 1 3— 0— [(R) 1 3— Hydroxytetradecanoyl] 1-2-[(R) 1-3-Hydroxytetradecanoylamino] 1 1 1-0-phosphono α-D-glucoviranose (hereinafter abbreviated as compound Α) is known. (See Japanese Unexamined Patent Publication No. Sho 61-53295)

 The above compound A has an activity equal to or greater than the physiological activity of natural lipid A, but is highly toxic similarly to natural lipid A and has not been put to practical use as a pharmaceutical. Therefore, a compound that has enhanced useful physiological activity and reduced toxicity has been desired. Disclosure of the invention

 The present inventors have conducted intensive studies to solve the above problems, and as a result, have found that 2,2 ', 3'-triacyl derivatives of glucosamine disaccharide derivatives have strong antitumor activity, and completed the present invention. .

That is, the present invention relates to a compound represented by the following general formula (1) and a salt thereof.

(H0) ₂ P0

 (1)

In the formula, Q ′ represents a carboxyl group or a phosphono group; Q ² represents a carboxyl group; a phosphono group or a hydrogen atom; m represents an integer of 0 to 10; n represents an integer of 0 to 10; R ¹ represents an acyl group or a substituted acryl group, R ² represents an acryl group or a substituted acetyl group, and R ³ represents an acryl group or an substituted acryl group.

In the above general formula (1), the acyl group can be represented by the formula of CO—Z ¹ , wherein the moiety represented by Z ¹ represents a linear or branched alkyl group, Examples thereof include methyl, ethyl, propyl, butyl, pentyl, heptyl, nonyl, pendecyl, tridecyl, pentadecyl and the like, preferably an alkyl group having 9 to 13 carbon atoms.

. Substituent Ashiru group as a ^{- C 0- Z 2 - NZ 3} - C 0 - is favored arbitrariness in the form of § Shiruami Noashiru represented by the formula Z. In the formula, the moiety represented by Z ⁴ represents the same alkyl group as Z ¹ , for example, a linear or branched alkyl group such as methyl, ethyl, propyl, butyl, pentyl, heptyl, nonyl, pentadecyl, tridecyl, pentadecyl, etc. It is a branched alkyl group, particularly preferably an alkyl group having 1 to 11 carbon atoms. Z ³ represents a hydrogen atom or an alkyl group. The alkyl group suitably has 1 to 4 carbon atoms, and may have a branched chain. Z ² represents an alkylene group, and examples thereof include methylene, ethylene, propylene, hexylene, and pentylene. The alkylene group may have a branched chain.

Specific examples of R ′, R ² and R ³ include a tetradecanoyl group, a dodecanoyl group, an N-decanoylglycyl group, an N-dodecanoylglycyl group, a 6-octaylylaminohexanoyl group, and an N-dodecanyl Lusarcosyl group, 8-hexano Nil-dodecanoyl group, 1 2—acetamino dodecanoyl group, N—dodecaneyl N—methyldalisil group, N—dodecanoyl—N—dodecylglycyl group. N—dodecyl-N—tetradecanoylglycyl group, etc. are preferred. . In particular, R ³ is N - Dodekanoiruguri sills group or N - Dekanoiruguri arbitrary preferable from the viewpoint of possible toxic reducing a Ashiru group having amino de coupling structure, such as a sill groups. Regarding the configuration at the 1-position of the sugar skeleton of the compound of the formula (1), isomers of α and; S are known, and any configuration may be used in the compound of the present invention. It may be a mixture, but the α-type is

For the 1 'position, the type is preferred.

 Examples of the salt of the compound of the formula (1) include a phosphono group (100 (Ο 2) 2) or a carbonyl group, triethylamine, pyridine, Ν-methyldalcamin, tris (hydroxymethyl). ) Salts with organic amines such as aminomethane or salts with inorganic bases such as ammonia, sodium, calcium, calcium and magnesium can be mentioned.

 Many known lipid Α derivatives have higher fatty acids or their derivatives bonded to the 2-, 3-, 2'-, and 3'-positions of the glucosamine disaccharide skeleton, many of which are bonded to each other. And has a structure in which a phosphoric acid group is bonded to the 1-position and the 4′-position. The compound of the formula (1) has a structure in which the 3-position is a hydroxyl group and the 2-, 2'- and 3'-positions are acylated, and a phosphono group or a carboxyl group is bonded to the 1-position via an alkylene group. Is a compound characterized in that

Examples of the method for producing the compound of the present invention will be described below.

(Q ³¹ 0) ₂ P0

 (2)

[Wherein, Q ¹¹ represents a carboxyl group having a protecting group or phosphono having a protecting group, Q ²¹ represents a carboxyl group having a protecting group, a phosphono group having a protecting group or a hydrogen atom, and Q ³¹ is a phosphono group. Represents a protecting group for a group, R ⁴¹ represents a protecting group for a hydroxyl group (for example, a benzyl group) or a hydrogen atom, R ⁵¹ represents a protecting group for a hydroxyl group (for example, a benzyloxycarbonyl group) or a hydrogen atom, and Q ¹ , Q ² , m, n, R ¹ , R ² and R ³ are the same as defined in the formula (1). The protecting group in the above formula (2) will be further described.

Examples of a protecting group for a carbonyl group include a benzyl group which may have a substituent, for example, a substituent such as a halogen atom, a nitrogen atom, and an alkoxy group having 1 to 6 carbon atoms. And a benzyl group which may have a group. Examples of the protecting group for the phosphono group include a phenyl group and a benzyl group which may have a substituent, for example, a halogen atom, a nitrogen atom, an alkoxy group having 1 to 6 carbon atoms. A phenyl group or a phenyl group which may have a substituent such as And the like.

 In the above method, the compound of the formula (2) is converted into a mixture of tetrahydrofuran, methanol, ethanol, acetic acid, water, etc., alone or in a mixed solvent under a hydrogen gas atmosphere using palladium carbon, palladium black, a platinum dioxide catalyst or the like. To remove the protecting group by catalytic reduction, and if necessary, isolate and purify the obtained compound by silica gel column chromatography, high performance liquid chromatography, etc., and then ion-exchange resin method, electrodialysis method, The compound (1) of the present invention can be obtained by desalting as appropriate by an acid precipitation method or the like.

 The salt of the compound of the present invention with a base can be obtained by adding a required amount of the base to the compound of the formula (1) by a conventional method, and then by an appropriate method such as a precipitation method and a lyophilization method.

 The compound of the present invention is useful as an antitumor agent, and can be expected to have an excellent effect on treatment and prevention of various solid tumors, for example, colon cancer, stomach cancer and liver cancer. For adults-the usual dosage is 0.1 to 30 mg / day intravenously, but the dose may be adjusted according to the patient's condition. Subcutaneous administration or local (intratumoral) administration is also possible. The compound of the present invention can be made into various preparations, for example, injections by a usual preparation technique using an isotonic agent, a stabilizer and other additives.

The compound of the formula (2) can be produced by the following method.

(Q ^S1 0) [Wherein, R ¹ , R ² , R ³ , R ⁴¹ , R ⁵¹ , ¹¹ , Q ²¹ , Q ³¹ , m and n are the same as defined above, and R ⁸² is a benzyloxycarbonyl group or 2, 2, 2 represents a trichloroethoxycarbonyl group, and R ⁷² and R ⁸² each independently represent a lower alkyl group, a fuunyl group or hydrogen. ]

 The starting compound of the formula (3) and the starting compound of the formula (5) can be prepared by the methods described in the literature (for example, Kusamaeta 1., Chem. Pharm. Bui 1., 38, 33, 66). (1990), Kusamaeta 1., Chem.Pharm.Bull., 39, 1994 (1991), Kusamaeta \., Chem.Pharm. , 39, 324 4 (1991) or a method analogous thereto The starting compound of the formula (7) can be produced, for example, by the method described in Japanese Patent Application Laid-Open No. The method can be produced by a known method described in JP-A No. 4-294974 and JP-A-4-132696 or a method analogous thereto.

That is, a compound of formula (3) is treated with benzyloxycarbonyl chloride or 2,2,2-trichloromouth ethoxycarbonyl chloride in the presence of a suitable base, for example, pyridine, to give a hydroxyl group at the 3-position of the sugar. introducing a protecting group (R ⁶²⁾ in the compounds of formula (4) by the following Ide sugar 4 and 6-positions of the protecting group (R ⁷² and R ⁸²⁾ is hydrolyzed under acidic conditions to divided I can guide you.

 On the other hand, by dissolving the compound of the formula (5) in a solvent containing hydrogen bromide gas and reacting the compound, the acetyl group at the 1-position of the sugar can be converted to bromine. Then, this odor-substituted product is dissolved in a dry organic solvent, and mercuric cyanide, mercury bromide, silver carbonate, silver oxide, silver perchlorate, zinc bromide, zinc chloride or zinc trifluoromethanesulfonate is dissolved. The compound of formula (6) can be produced by condensing the compound of formula (4) with the compound of formula (4) for several hours to several days at room temperature or under reflux conditions.

By treating the compound of the formula (6) with zinc powder in a solvent such as acetic acid, the 2,2,2—trichloro mouth ethoxycarbonyl group at the 2′- and 6′-positions can be removed. To a compound having a free amino group at the 2′-position, a carboxylic acid corresponding to the formula R ² COOH is condensed by a method commonly used in the field of peptide chemistry, The compound of the formula (2) can be produced by condensation using an imid method, a topping method, an active ester method or the like.

Alternatively, the compound of formula (7) is reacted with so-called Vilsmeier reagents such as (dichloromethylene) dimethylammonium chloride to convert the hydroxyl group at position 1 of the sugar to chlorine, The chlorine-substituted product is dried in an organic solvent in the presence of zinc chloride-zinc trifluoromethanesulfonate, mercuric cyanide, mercury bromide, silver carbonate, silver oxide, silver perchlorate, etc., and the formula (4) The compound of formula (2) in which R ⁴¹ represents a protecting group (benzyl group) can be produced by condensation with the compound of formula (1) for several hours to several days at room temperature or under heating and reflux. At this time, in the compound of the formula (4), when the protecting group R ⁶² of the 3-position hydroxyl group is a 2,2,2-trichloromouth ethoxycarbonyl group, the zinc powder in acetic acid is added following the above condensation reaction. The compound of the formula (2) can be produced by removing this protecting group by treatment. BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be further described with reference examples, examples, and test examples, but the present invention is not limited thereto. Temperatures such as melting points are in degrees Celsius. In the following Reference Examples and Examples,% is ^ unless otherwise specified.

 Example

Reference example 1

Step 1: 2-benzyloxycarbonyl 1- (benzyloxycarbonylmethyl) ethyl 2-deoxy-1 2-tetradecanoylamino 3-0- (2,2,2-trichloro Methoxyethoxycarbonyl) D-Dalco pyranoside (Formula (4))

780 mg of 2-benzyloxycarbonyl 1- (benzyloxycarboxy) ethyl 2-deoxy-2-tetradecanoylamino-1-α-D-darcopyranoside Dissolve in dry methylene chloride, add 0.68 ml of 2,2-dimethoxypropane and about 10 mg of camphorsulfonic acid at room temperature. The mixture was stirred at room temperature for 5 hours. Anhydrous potassium carbonate was added to the reaction solution, and the mixture was stirred. After neutralization, a 5% (W / V) aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting yellow oil was dissolved in 6 ml of dry pyridine, and to this solution was added 0,33 ml of 2,2,2-trichloromouth ethoxycarbonyl chloride under ice-cooling. It returned to room temperature and stirred for 3 hours. After adding 1 ml of water to the reaction solution and stirring, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and washed successively with 1N hydrochloric acid, water, and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained pale brown oil was dissolved in 30 ml of a 90% aqueous acetic acid solution, and the mixture was heated with stirring at 90 ° C. for 20 minutes. After cooling, the solvent was distilled off under reduced pressure, and the procedure of adding toluene to the residue and distilling off the solvent under reduced pressure was repeated. The obtained residue was purified by silica gel gel (eluting solvent; chromate form containing 5% acetone, then changed to chromate form containing 2% methanol) to give the title compound 75 1 mg was obtained as a pale orange viscous oil.

[a] ₂₅ + 37.9 ° (c1.0, black mouth form)

^{J H - NMR (CDC 1 a} / TM S): <5 = 0. 8 8 (3 H, t, J = 7 H z), 1. 2 4 (2 0 H, m), 1. 5 7 ( 2 H, m), 2.25 (2 H, m), 2.6-2.8 (4 H, m), 3.7-3.9 (4 H, m), 4.32 ( 1 H, td, J = 10 Hz, 3 Hz), 4.47 (1 H, m), 4.76 (2 H, s), 4.88 (1 H, t J = 10 Hz), 4.94 (1H, d, J = 3Hz), 5.14 (4H, m). Step 2: 2-Venzyloxycarbone-1-1 (benzyl 2-Carboxymethyl) ethyl 2-Doxy 6-0— [2-Doxy-1 410—diphenylphosphono 3—0— (N—Dodecanylglycyl) 1 6—0— (2,2,2 1- 2- (2,2,2-trichloroethoxycarbonylamino) 1; 5-D-Darcopyranosyl] 1-2-Tetradecanoylamino 3-0- (2,2, 2-trichloroethoxycarbonyl) α-D-g Rucoviranoside (Formula (6))

4 4 O mg of 10-Acetyl-2-Doxy 4--0-Diphenylphosphono 3--0- (N-Dodecanylglycyl) -6-0- (2,2,2-Trichloroethoxycarbonyl) 1 2— (2,2,2—trichloro mouth ethoxycarbamine) 1-D-Darcoviranose is dissolved in 3 ml of dry methylene chloride. 8 ml of cooled 25% at room temperature A hydrogen bromide acetic acid solution was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into iced water and extracted with black-mouthed form. The organic layer was washed successively with a 5% (W / V) aqueous solution of sodium hydrogen carbonate and a saturated saline solution, dried over sodium sulfate anhydride, and then the solvent was distilled off under reduced pressure to obtain a yellow color. A caramel oil was obtained. ₍ This oil and 357 mg of the compound of Step 1 were dissolved in 6 ml of dry methylene chloride, and 0.4 g of anhydrous calcium sulfate and 207 mg of cyanide were added thereto. The suspension was stirred for 18 hours while heating and refluxing at 50 to 60 ° C. The mixture was returned to room temperature, the insolubles were removed by celite filtration, and the mixture was diluted with chloroform. % (W / V) aqueous sodium iodide solution and saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was evaporated on a silica gel column (developing solvent; 5%). (Formerly changed to 10% by the same method) containing the title compound (605 mg) in pale yellow viscous form. It was obtained as Jo products.

_{^{[a] D 25 + 2 2.}} 3 ° (c 1. 2, CHC 1 3)

^{! H - NMR (CDC 1 3} / TM S): <5 = 0. 8 8 (6 H, t), 1. 2 4 (3 6 H, m), 1. 5 - 1. 6 (4 H, m), 2.05-2.25 (2 H, m), 2.6-2.75 (3 H, m), 2.87 (1 H, dd,

J = 16 Hz, 6 Hz), 3.35 (1H, m), 3.67 (1H, t,

J = 10 Hz), 3.95 (1 H, d d, J = 18 Hz, 5 Hz), 4.

4 1 (1H, m), 4.83 (1H, dd, J = 11Hz, 9Hz), 4.90 (1H, d, J = 3Hz), 5. 0 6 (1 H, d, J = 8 H z), 5.

1 3 (4 H, m), 5.68 (1 H, t, J = 10 Hz), 6.13 (1

H, br), 6.21 (1H, br), 6.27 (1H, d, J = 9Hz), 7.05-7.4 (20H, m). Step 3: 2-benzyloxycarbonyl-1- (benzyloxycarbonylmethyl) ethyl 2-deoxy 6-0- [2-deoxy-1 4--0-diphenylphosphonol 3-0- (N-dodecanylglycyl) 1—2—Tradecanylamino 3 / 3—D—Darcopyranosyl] — 2—Tradecanylamino 1 a—D 1Darcodylanoside (Formula (2))

 58.5 mg of the compound of Step 2 was dissolved in 10 ml of acetic acid, 0.5 g of zinc powder was added, and the mixture was vigorously stirred at room temperature for 3 hours. Further, 0.5 g of zinc powder was added and the mixture was stirred for 2 hours. The insoluble material was removed by filtration, and the residue was washed with a chloroform form, and the solvent in the filtrate was distilled off under reduced pressure. After repeating the procedure of adding toluene to the residue and distilling under reduced pressure, dissolve in chloroform and then dissolve this solution in 1N hydrochloric acid, water, 5% (W / V) aqueous sodium hydrogencarbonate, and saturated Washing was sequentially performed with saline. The solution was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain an oil. On the other hand, 108 mg of myristic acid and 68 mg of 1-hydroxybenzotriazole were dissolved in 2 ml of dry tetrahydrofuran, and 104 mg of dicyclohexylcarpoimide was added thereto under ice-cooling. In addition, the mixture was returned to room temperature and stirred for 3 hours to prepare an active ester solution. The above oily substance was dissolved in 8 ml of dry methylene chloride, and under ice-cooling, the above-mentioned activated ester reaction solution was added while filtering out the insoluble matter precipitated, and the mixture was returned to room temperature and stirred for 15 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column (developing solvent; chloroform containing 5% acetone and later changed to chloroform containing 3% methanol) to give the title compound 30. 3 mg was obtained as a colorless caramel oil.

[a] ^D 25 + 3.1 ° (c 1.2, Holm in mouth)

'H-NMR CCDC / TMS): <5 = 0.88 (9H, t, J-7Hz), 1.25 (56Η, m), 1.5-1.7 (6 M, m), 2.0 5—2.3 (6 Η, m), 2.6-2.7 (3 Η, m), 2.94 (1 Η, dd, J = 17 Hz , 5 Hz), 3.35 (1 H, m), 3.48 (1 H, t, J = 9 Hz), 3.94 (1 H, m), 4.06 ( 1 H, AB t yped, J = 10 Hz), 4.34 (1 H, m), 4.68 (1 H, q, J = 9 Hz), 4.91 (1 H, d, J = 4 Hz), 5.1 (4H, m), 5.28 (1H, d, J = 8Hz), 5.73 (1H, t, J = 10Hz), 6.17 (1H, br), 6.53 (1H, br), 6.97 (1H, br), 7.15-7.4 (20H, m). Example 2

 Step 1: 2-benzyloxycarbonyl 2- (benzyloxycarbonylmethyl) ethyl 3-benzyloxycarbonyl 2-deoxy-2-tetradecanolamine α-D-darcopyranoside (Formula (7) ))

2.3 Add 2 g of 2-benzyloxycarbonyl 1- (benzyloxycarbonylmethyl) ethyl 2-deoxy-2-tetradecanoylamino a-D-dalcoviranoside to 15 ml After dissolving in dry methylene chloride, 2.0 ml of 2,2-dimethoxypropane and 38 mg of camphorsulfonic acid were added at room temperature, and the mixture was stirred at room temperature for 15 hours. 2 O mg of camphorsulfonic acid and 2.04 ml of 2,2-dimethoxypropane were added to the reaction mixture, and the mixture was further stirred for 8 hours. Anhydrous calcium carbonate was added to the reaction solution, and the mixture was stirred and neutralized. The reaction solution was washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. . The resulting yellow oil was dissolved in 20 ml of dry methylene chloride and, at room temperature, 0.4 ml of pyridine, 0.61 g 0N, N-dimethylamino pyridine and 0.1 ml 1 Benzyloxycarbonyl chloride was sequentially added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was washed sequentially with 1N hydrochloric acid, water, and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained yellow oil was dissolved in 50 ml of a 90% aqueous acetic acid solution, followed by heating and stirring at 90 ° C for 30 minutes. After cooling, the solvent was distilled off under reduced pressure, and the operation of adding toluene to the residue and distilling off the solvent under reduced pressure was repeated. The obtained residue was purified by a silica gel column (developing solvent; changed to a chromate form containing 5% acetate and later to a chromate form containing 2% methanol) to give a pale yellow oil. I got Add hexane to this After crystallizing, 2.42 g of the title compound was obtained as a white solid. This solid was recrystallized from hexane. Melting point: 80-82 ° C

[α] ^D ₂₅ + 46.5 ° (c 0.8, black mouth form)

 I R (K B r): 3350, 1750, 1730, 16501502 75, 1260cm- 1.

 ^-NMR CCDC la / TM S): 6 = 0.88 (3 H, t, J = 7 Hz), 1.22 (20 H, s), 1.52 (2 H, m ), 20-2.1 (2H, m), 2.64 (3H, m), 2.77 (1H, dd, J = l6Hz, 6Hz), 3. 7 5 (4H, m), 4.26 (1H, td, J = 10Hz, 3Hz), 4.46 (1H, m), 4.82 (1H, dd, J = 11 Hz, 8 Hz), 4.92 (1H, d, J = 4Hz), 5.10 (1H, AB typed, J = 12Hz), 5.1 3 (4 H, s),

5.14 (1H, AB typed, J = 12Hz), 6.31 (1H, d, J = 9Hz), 73-7.4 (15H, m). Step 2: 2-benzyloxycarbonyl 2- 1- (benzyloxycarbonylmethyl) ethyl 6-0-[6-0-benzyl-2-dexoxy 4 1 0-diphenylphosphono 3-0-(N-dodecanolyl) Syl) 1 2 — tetradecanoylamino / 3— D-darcovirano syl] 1 3 — 0—benzyloxycarbonyl 2 — dexoxy 2 — tetradecanoylamino α—D—dalcoviranoside ( Expression (2 "

Under a nitrogen atmosphere, 1.54 g of phosgene imidium chloride was dried in 8 ml of methylene chloride, suspended in methylene chloride, and 3.012 of 6—0—benzyloxy 2 _deoxy 4—10—gif was added. Enylphosphono-1 3-0-(N-dodecanoylglycyl)-2-tetradecanoylamino-D-glucose in 3 O ml of dry methylene chloride solution was added at room temperature. After stirring the mixture at room temperature for 3 hours, the mixture was cooled with ice and water was added. After stirring at room temperature for about 30 minutes, the mixture was extracted with methylene chloride. The extract was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. This gave an orange caramel oil. This oily substance and the compound obtained in 2.402 were dissolved in 20 ml of dry methylene chloride, and 1.2 g of anhydrous calcium sulfate was suspended in this solution. After stirring at room temperature for 10 minutes, 0.43 g of dried zinc chloride was added to the suspension, and the mixture was heated to an external temperature of 50 ° C and stirred for 3 hours. Then, the mixture was diluted with ethyl acetate and washed with a 5% (W / V) aqueous sodium hydrogen carbonate solution and a saturated saline solution in that order. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to a silica gel column (developing solvent: a chromatographic form containing 5% acetate, followed by a chromatographic liquid containing 1% methanol). And then 2%) to obtain about 3.6 g of a crude product. This was purified by high-performance liquid chromatography (used column: 0 DS reverse-phase column, developing solvent: aceto nitrile: tetrahydrofuran = 4: 1), and treated with hexane to give the title compound 2.0. 3 g was obtained as a white solid. This solid was recrystallized from isopropyl ether.

 Melting point: 1 1 2—1 13 ° C

[a] ^D ₂₅ + 32.4 ° (c 0.7, black-holm)

^{! H - NMR (CDC 1 3} / TMS): 5 = 0. 8 8 (9 H, t, J = 6 H z), 1. 2 5 (5 6 H, m), 1. 5 2 (6 H , m), 1.9-2.2 (6 H, m), 2.61 (3 H, m), 2.8 1 (1 H, dd, J = 16 Hz, 5 Hz) , 3.24 (1 H, m), 3.5—3.9 (8 H, m), 4.05 (1 H, dd), 4.27 (1 H, td, J = 1 0 Hz, 4 Hz), 4.38 (1 H, m), 4.41 (2 H, s), 4.70 (1 H, q, J = 9 Hz), 4. 8 5 (1 H, t, J = 10 Hz), 4.91 (1 H, d, J = 4 Hz), 5.1 (6 H, m), 5.38 (1 H , d, J = 8 Hz), 5.61 (1 H, t, J = 10 Hz), 6.12 (1 H, d, J = 10 Hz), 6.19 (1 H, t, J = 5 Hz), 6.33 (1 H, d, J = 6 Hz), 7.1-7.4 (30 H, m). Reference example 3 Step 1: 2-benzyloxycarbonyl 1- (benzyloxycarbonylmethyl) ethyl 3-0-benzyloxycarbonyl 2-dexoxy 6-0-[2- dexoxy 4-0-diphenyl Nilphosphono 1 3 — 0—Tetradecanol — 6 — 0— (2,2,2—Ethoxycarbone) 1 2— (2,2,2—Ethoxycarbonylamide No) 1 / 3—D—Darcopyranosyl] 1—2—Tetradecanoylamino No a—D—Darcovyranoside (Formula (6))

 1 1-acetyl- 2 -doxy-4 1 0-diphenylphosphono 6-0- (2,2,2-trichloroethoxycarbonyl) 1-2-(2,2,2 -trichloroethoxycarbonyl) Mino) 1 3 — 0—tetradecanoyl D-Darcovyranoose was reacted with the compound obtained in Step 1 of Reference Example 2 in the same manner as in Step 2 of Reference Example 1 to give the title compound as a colorless viscous oil. Obtained.

[a] ^D 25 + 18.2 ° (c 1.1, black mouth form)

'H-NMR CCDC / TM S): 5 = 0.88 (6 H, t' x 2, J = 7 Hz), 1.22 (40 H, m), 1.3-1. 6 (4 H, m), 1.9-2.2 (4 H, m), 2.65 (3 H, m), 2.86 (1 H, dd, J = 16 H z, 6 Hz), 3.45 (1 H, m), 3.59 (1 H, t, J = 10 Hz), 3.70 (1 H, dd, J = 11 Hz) , 4 H z), 3.79 (1 H, m), 3.85 (1 H, m), 4.07 (1 H, dd), 4.24 (1 H, td, J = 10 Hz, 3 Hz), 4.78 (1H, t, J = 10Hz), 4.89 (1H, d, J = 4Hz), 4.89 (1 H, d, J = 7 Hz), 5.13 (6 H, m), 5.59 (1 H, t, J = 10 Hz), 5.67 (1 H, d, J = 8 Hz), 6.16 (1 H, d, J = 9 Hz), 7.1 — 7.4 (25 H, m). Step 2: 2 — benzyloxy Carbonyl 1- (benzyloxycarbonylmethyl) ethyl 3 — 0—benzyloxycarbonyl—2 —deoxy 6 — 0 — (2 —dexoxy 4 1 0—diphenylphosphono-1 3 — 0—tetradecanoyl One two—te tradecanoyl ami no ^ ー D—Darcopyrano sill) 1 2—Te Torade A-D-Darco villanoside (Formula (2))

 The compound of Step 1 was reacted with myristic acid in the same manner as in Step 3 of Reference Example 1 to give the title compound as a colorless caramel oil.

[a] ^D ₂₅ + 10.5 ° (c 1.1, black mouth form)

 -NMR (CDC13 / TMS): 5 = 0.88 (9Η, m), 1.2

3 (60 H, m), 1.3 — 1.7 (6 H, m), 1.9 — 2.2 (6 H m), 2.64 (3 H, m), 2.8 2 (1H, dd, J = 16Hz, 6Hz), 3.50 (1H, m), 3.58 (1H, m), 3.98 (1H, d , J = 9 Hz), 4.25 (1 H, m), 4.38 (1 H, m, 4.69 (1 H, q, J = 9 Hz), 4.82 (1H, t, J = 10Hz), 4.90 (1H, d, J = 4Hz), 4.97 (1H, d, J = 8Hz), 5. 1 (6 H, m), 5.5 3 (1 H, t, J = 10 Hz), 5.80 (1 H, br), 6.16 (1 H, d, J = 9 H z), 7.1-7.

4 (25 H, m). Reference example 4

Step 1: 2—Benzyloxycarbonyl 1 1— (Benzyloxycarbonylmethyl) ethyl 3 — 0—Benzyloxycarbonyl 2-deoxy-1 2 —

(8—Hexanoylaminooctanoylamino) a—D—Darco villanoside

(Equation (4))

7 9 2 mg of 2-benzyloxycarbonyl 1-(benzyloxycarbonylmethyl) ethyl 2-Deoxy (8-hexadecanoylaminooctanoylamino) 1-D-Glucoviranoside Reference Example The reaction was carried out in the same manner as in Step 1 of 2 to give the title compound as a colorless oil.

[a] ^D 25 + 39.9 ° (c 1.6, black-holm)

Ή-NMR (CDC 13 / TMS): <5 = 0.88 (3H, t, J = 6Hz), 1.26 (10H, m), 1.42 (2 H, m), 1.5 3 (2 H, m), 1.61 (2H, m), 2.06 (2H, m), 2.12 (2H, t, J = 8Hz), 2.64 (2 H, m), 2.70 (1 H, dd, J = 16 Hz, 8 Hz), 2.77 (1 H, dd, J = 16 Hz, 6 Hz), 3 . 18 (2 H, q, J = 7 Hz), 3.75 (4 H, m), 4.26 (1 H, ddd, J = 11 Hz, J = 10 Hz , 4 Hz), 4.46 (1 H, m), 4.82 (1 H, dd, J = 11 Hz, 8 Hz), 4.92 (1 H, d, J = 3 Hz), 5.10 (1 H, AB tyed, J = 12 Hz), 5.14 (4 H, s), 5.14 (1 H, AB tyed, J = 1 2 Hz), 5.48 (1 H, br), 6.33 (1 H, d, J = 9 Hz), 7.3-7.4 (15 H, m). : 2-benzyloxycarbonyl-1-(benzyloxycarbonylmethyl) ethyl 3-0-benzyloxycarbonyl 2-dexoxy 6-0 [2-dexoxy 4-0-diphenylphosphono 3 — 0— (N—dodecanoylglycyl) 1 6 — 0— (2,2,2—trichloromouth ethoxycarbonyl) 1 2-(2, 2, 2 — Trichloromouth ethoxycarbonylamino) 1 3 — D-Darcopyranosyl] 1 2 — (8-Hexanoylaminooctanoylamino) 1 α-D—Darcovyranoside (Formula ( 6))

 1 1 0—Acetyl-2—Doxy 1 4 1 0—Diphenylphosphono 3 — 0— (N—Dodecanylglycyl) 1 6 — 0— (2,2,2—Tricyclomouth ethoxycarbonyl) 1 2 — (2,2,2—Trichloromouth ethoxycarbonylamino) 1-D-Dalcoviranose is reacted with the compound obtained in the above Step 1 in the same manner as in Step 2 of Reference Example 1 to give the title compound. Obtained as a pale yellow viscous oil.

[a] ^D ₂₅ + 25.0 ° (c 1.1, black-hole form)

Ή-NMR (CDC 13 / TMS): 6 = 0.88 (3H, t, J = 7Hz), 0.89 (3H, t, J = 7Hz), 1. 2 5 (28 H, s), 1.4 — 1.7 (8 H, m), 1.9-2.2 (6 H, m), 2.65 (3 H, m), 2 8 7 (1 H, dd, J = 16 H z, 7 H z), 3.18 (2 H, m), 3.32 (1 H, m), 3.59 (1 H, t J = 10 Hz), 3.69 (1 H, dd, J = 11 Hz, 5 H z), 3 7 8 (1 H, dd

J = 18 Hz, 5 Hz), 3.83 (2 H, m), 3.94 (1 H, dd, J = I 8 Hz, 5 Hz), 4.10 ( 1 H, d, J = 1 1 H z), 4 2 4 (1 H, td, J = 10 H z, 3 H z), 4.32 (1 H, dd, J = 1 2 H z , 4 Hz), 4.41 (1 H, m), 4.48 (1 H, dd, J = 12 Hz, 2 Hz), 4.5 3 (1 H, d, J = 1 2 Hz), 4.6-4.75 (4 H, m), 4.79 (1 H, dd, J = 10 Hz, 9 Hz), 4.89 (1 H, d, J = 3 Hz), 5.06 (1H, d, J = 8Hz), 5.13 (6H, m), 5.49 (1H, br), 5.70 (1 H, t, J = 10 Hz), 6.20 (3 H, m), 7.1-7.4 (25 H, m).

Process 3: 2-benzyloxycarbonyl 1- (benzyloxycarbonylmethyl) ethyl 3-0-benzyloxycarbonyl-2-dexoxy-6-0-1 [2-dexoxy-4-0-diphenyl Phosphonol 3 — 0— (N—dodecanoylglycyl) 1 2 —Tetradecanoylamino / 3 / D—Glupyranosyl] 1 2 — (8—Hexanoylaminoctanoylamino) 1 a— D —Darcopyranoside (Formula (2))

 The compound obtained in the above Step 2 was reacted with myristic acid in the same manner as in Step 3 of Reference Example 1 to obtain the title compound as a colorless viscous oil.

_{^{[a] D 25 + 2 8.}} 8 ° (c 1. 1, click b port Holm)

! H-NMR (CDC 1 a / TM S): 5 = 0.88 (9 Η, m), 1.26 (46 H, m), 1.4-1.7 (10 H, m), 1.9-2.2 (8 H, m), 2.64 (3 H, m), 2.81 (1 H, dd, J = 16 Hz, 6 Hz), 3.18 (3 H, m), 3.67 (1 H, t, J = 10 Hz), 4.26 (1 H, td, J = 10 Hz, 3 Hz) , 4.39 (1 H, m), 4.66 (1 H, q, J = 9 Hz), 4.83 (1 H, t, J = 10 H z), 4.91 (1H, d, J = 4Hz), 5.11 (6H, m), 545 (1H, d, J = 8Hz) 5.65 (1H, t, J = 10Hz), 6.12 (1H, br), 617 (1H, d, J = 9Hz), 6.55 (1H, br) ), 7.1-7 4 (25 H, m). Reference example 5

 Process 1 2-Benzyloxycarbone 1-1 (benzyloxycarbonylmethyl) ethyl 3-0-Benzyloxycarbonyl 2-Deoxy 6-0-

[2-Doxy 4-1 0-diphenylphosphono 3--0- (N-dodecanol glycyl) 1-6-0— (2,2,2-Triethoxy mouth ethoxycarponyl) 1 2—

(2,2,2-Triethoxy ethoxycarbonylamino) 1 ^ -1 D-Darcovyranosyl] — 2 —Tetradecanoylamino 1 α-D-Darcoviranoside (Formula (6)

 1 1 0-Acetyl- 2-Doxy 4--0-Diphenylphosphono-1 3-0-Ν-Dodecanylglycyl-1-6- 0— (2,2,2-Triethoxy mouth ethoxylponyl) 1 2— ( 2,2,2-Trichloromouth ethoxycarbonylamino) 1D 1-Darcoviranose is reacted with the compound of Step 1 of Reference Example 2 in the same manner as Step 2 of Reference Example 1, and the title compound is pale yellow. As a viscous oil.

[a] ^D ₂₅ + 25.5 ° (c 1.1, black mouth form)

'H-NMR CCD C / TMS): <5 = 0.88 (6H, m), 1.24 (36H, m), 1.54 (4H, m), 2.0 -2.1 (4 H, m),

2.65 (3H, m), 2.86 (1H, dd, J = 16Hz, 5Hz),

3.31 (1H, m), 3.58 (1H, t, J = 10Hz), 4.89 (1H, d, J = 3Hz), 5.07 (1 H, d, J = 8 Hz), 5.13 (6 H, m), 5.70 (1 H, t, J = 10 Hz), 6.07 (1 H, d, J = 7 Hz), 6.18 (2 H, m), 7.1-7.4 (25 H, m). Step 2: 2-benzyloxycarbonyl 1 (benzyloxycarbonylmethyl) ethyl 3—0—benzyloxycarbonyl 2-deoxy-1 6—0—1—2-dexoxy 4—0— Diphenylphosphono-1- 3— 0— (N—dodecanoylglycyl) 1-2— (N-dodecanoyl N—methyldalicylamino) — β—D—dalcopyranosyl] 1-2—tetradecanoylamino α—D —Darco Villanoside (Equation (2))

 The compound of the above-mentioned step 1 was reacted with p-radioyl sarcosine in the same manner as in step 3 of reference example 1 to obtain the title compound as a colorless viscous oil.

[a] ^D ₂₅ + 22.6 ° (c 1.0, black mouth form)

 Ή-NMR (CDC 13 / TMS): <5 = 0.88 (9H, t, J = 6Hz), 1.25 (52H, m), 1.4-1.7 (6 H, m), 1.9-2.4 (2 H, m), 2.63 (3 H, m), 2.78 (1 H, dd, J = 16 Hz, 6 H z), 3.06 and 3.20 (3 H, eachs, 1 1: 1), 3.37 (1 H, m), 4.27 (1 H, td, J = 10 H z, 4 H z), 4.40 (1 H, m), 4.66 (1 H, q, J = 9 H z), 4.86 (1 H, dd, J = 1 1 H z, 9 H z), 4.92 (1 H, d, J = 3 H z), 5.1 1 (6 H, m), 5.17 (1 H, d, J = 8 H z), 5.77 (1H, t, J-10Hz), 6.18 (1H, d, J = 9Hz), 6.41 (1H, t, J = 5 H z), 6.45 (1 H, d, J = 6 H z), 7.1 — 7.4 (25 H, m). Reference example 6

Step 1: 2- (diphenylphosphonoxy) ethyl 3--0-benzyloxy 2-dioxy-1-tetradecanoylamino α-D-glucopyranoside (Formula (4))

2- (Diphenylphosphonoxy) ethyl 2-Doxy 4,6-0-Isopropylidene-1 2-Tetradecanoylamino D α-D-Darcovyranoside is dissolved in 5 ml of methylene chloride and ice-cooled Bottom 9 0 1 pyridine and 1 3 71 112 1 ^, N-Dimethylaminopyridine was added, and further, 199〃1 benzyloxycarbonylcarbonyl chloride was added, followed by stirring at the same temperature for 30 minutes. Here, 13 volumes of each of the above three reagents were added, and the mixture was further stirred for 50 minutes. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, extracted with chloroform, washed with water and 1N hydrochloric acid sequentially, and then the solvent was distilled off under reduced pressure. The residue was dissolved in 10 ml of a 90% aqueous acetic acid solution, heated to 90 ° C., and stirred for 45 minutes. The solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, and the solution was washed with a saturated aqueous solution of sodium hydrogen carbonate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent; chloroform containing 3% methanol) to give the title compound. Was obtained as an oil.

[a] ^D 25 + 49.0 ° (c 1.1, black mouth form)

 ^-NMR CC DC ls / TMS) δ = 0.88 (3 Η, t J = 7 Η z), 1.25 (22 Η, m), 1.47 (2 Η, m), 1 9 8 (2Η, m), 3.78 (3Η, m), 3.92 (1Η, m), 4.30 (1Η, m), 4.4 (2Η, m) m), 4.82 (1 Η, d, J = 3 Hz), 4.92 (1 Η, dd, J = 1 1 ζ Η 8 Η ζ), 5.15 (2 Η, s ), 6.36 (1 1, d, J = 9Η), 7.1-7.4 (15 5, m).

Step 2: 2- (diphenylphosphonoxy) ethyl 3-—benzyloxycarbonyl 2-deoxy 6—0— [2-deoxy 4—0—diphenylphosphono—3—0— (Ν—dodecanylglycyl) 1) 6-0— (2,2,2-trichloroethoxycarbonyl) 1-2 (2,2,2-trichloromouth ethoxycarbonylamino) 1—S—D—Darcopyranosyl] 1-2—Tetra Decanoylamino — α—D—Darcovyranoside (Formula (6))

1-0-acetyl-2-dexoxy 4-1 0-diphenylphosphono-3-0-(Ν-dodecanoylglycyl) 1-6-0-(2,2,2-trichloroethoxycarbonyl) 1 2-(2 , 2,2-Trichloro mouth ethoxycarbonylamino) 1-D-Dalcoviranose was reacted with the compound obtained in the above Step 1 in the same manner as in Step 2 of Reference Example 1 to convert the title compound to an oil. I got it. [a] ^D ₂₅ + 2 7.2 ° (c 1.6, black mouth holm)

'H -. NMR (CDC 1 3 / TM S) δ = 0 8 8 (6 Η, t, J = 7 Η ζ), 1. 2 5 (3 6 Η, m), 1. 4 5 (2 Η , m), 1.55 (2 H, m), 1.94 (2 Η, m), 2.09 (2 Η, m), 3.29 (1 Η, m), 3. 6 2 (1 Η, t, J = 9 Η ζ), 4.10 (1 Η, d _; J = 10 Η ζ), 4.88 (1 Η, t, 3 = 10 Η ζ) , 5.05 (1 d, J = 8 Η ζ), 5.15 (2 Η, s), 5.66 (1 Η, t, J = 1 Ο Η), 6.16 ( 1Η, d, J = 7ΗΗ), 6.19 (1Η, d, J = 9Η), 7.1-7.4 (25 5, m). Step 3: 2-( Diphenylphosphonoxy) ethyl 3 — 0—benzyloxycarbonyl 2 —deoxy 1 6 — 0— [2 —doxy 4 — 0—diphenylphosphono 3 — 0— (N—dodecanylglycyl) 1 2 — tetradeca Nylamino—D—Darcopyranosyl] 1—2—Tetradecanoylamino—α—D—Glucovyranoside (Formula (2))

 The compound of Step 2 described above was reacted with myristic acid in the same manner as in Step 3 of Reference Example 1 to obtain the title compound as an oil.

_{^{[a] D 2S + 2 9.}} 2. (C1.2, Holm Cloth)

'Η-NMR CCDC "TMS): 5 = 0.88 (9 9, t, J = 6Hz), 1.23 (56 6, m), 1.4 — 1.6 (6 H, m), 1.93 (2Η, m), 2.13 (4Η, m), 3.26 (1Η, m), 4.08 (1Η, d, J = 1 0 Η ζ), 4.33 (1 Η, td, J = 8 Hz, 4 Hz), 4.37 (4 Η, m), 4.65 (1 Η, q, J = 9 Η), 1.80 (1 Η, d, J = 3 Η Η), 4.93 (1 Η, t, J = 10 Η ζ), 5.12 (1 Η, A Β typed, J = 1 2 Η ζ), 5.16 (1 Η, A ty tyed, J = 1 2 Η ζ), 5.38 (1 H, d, J-8 Η ζ), 5.6 1 (1 Η, t, J = 10 Η ζ), 6.11 (1 Η, t, J = 6 Hz), 6.2 2 (1 Η, d, J = 9 Η ζ), 6 . 5 7 (1 Η, d, J = 7 Hz), 7.1-7.4 (25H, m) .Example 1

 2-Carboxymethyl 1- (carboxymethyl) ethyl 2-Doxy 6- 0- [2-Doxy 3--0- (N-Dodecanylglycyl) -4-1-0-Phosphonone 2-Tetradecanoylami No β-Ό-Darco viranosyl] 1-Tetradecanoylamino No α-D-Darcoviranosyl

 Dissolve 2 72 mg of the compound of Step 3 of Reference Example 1 in a mixture of 3 O ml of tetrahydrofuran and 1.5 ml of water, and add 0.3 g of 10% (W / W) palladium carbon. Was added and the mixture was stirred vigorously under a hydrogen gas atmosphere for 1 hour. To this reaction solution, 150 mg of platinum dioxide was added, and the mixture was vigorously stirred for 2 hours under a hydrogen gas atmosphere. The catalyst was filtered off from the mixture and the solvent was distilled off under reduced pressure. The residue was purified by silica gel thin-layer chromatography (developing solvent; liquid form: methanol: water = 6: 4: 1). The obtained white solid is suspended in a mixed solvent of tetrahydrofuran and water (approximately 3: 1), and a strongly acidic ion exchange resin (manufactured by Dowex, 50W—X2 type) is added to dissolve the solid. Of the same resin. The solvent of the eluate was distilled off under reduced pressure, and the residue was suspended in dioxane and freeze-dried to obtain 120 mg of the title compound as a white powder.

 [a + 11.8 ° (c 0.6, black form-methanol (3: 1))

 I R (K B r): 3400, 1715, 1650, 1550, 1285, 1252, 1250cm-1.

'Η-NMR (CDC 1 -C Ds 0 D (1: 1) / TMS): δ = 0.89 (9H, t, J = 7Hz), 1.27 (56H, s), 1.5-1.7 (6 H, m), 2.16 (2 H, t, J = 7 Hz), 2.26 (4 H, m), 2.65 ( 3 H, m), 2.80 (1 H, dd, J = 17 Hz, 6 Hz), 3.36 (1 H, t, J = 9 Hz), 3.5 3 ( 2 H, m), 4.09 (1 H, AB typed, J = 1 1 H z), 4.28 (1 H, q, J = 9 Hz), 4.37 (1 H, m), 4.83 (1 H, d, J =

8Hz), 494 (1H, d, J = 4Hz) 5.39 (1H, t, J = 9Hz) Example 2

 2 1-carboxy-1 1- (carboxymethyl) ethyl 2 -Doxy 6-0-[2 -Doxy 3-0-(N-dodecanoylglycyl) 1 4 1 0 -Phosphono 2 -Tetradecanoylamino / S — D—Glucopyrano syl] 1 2 — Tetra decanoylamino no α — D—Darcovyranoside

 A catalytic reduction reaction was carried out in the same manner as in Example 1 using the compound obtained in Step 2 of Reference Example 2 to obtain the same title compound as in Example 1. Example 3

 2-carboxy-1-(carboxymethyl) ethyl 2-dexoxy 6-0-1 (2-dexoxy 4-1-phosphono 3-0-tetradecanoyl-2-tetradecanoylamino-3-D-darcoviranosyl) 2-te Tradecanoylamino α-D-Darcovyranoside

 A catalytic reduction reaction was carried out in the same manner as in Example 1 using the compound obtained in Step 2 of Reference Example 3 to obtain the title compound as a white powder.

[a] ^D 25 + 12.3 ° (c 0.6: chlorophonorem-metano-norre (3: 1))

 I R (KBr): 350 0, 1 7 4 5 1 7 2 0, 1 660, 1 550 m-1.

^{! H - NMR (CDC 1 3} - CD a 0 D (1: 1) ZTM S):. 6 = 0 8 9 (9 H, t, J = 7 H z), 1 2 7 (6 0 H, s ), 1.5 — 16 (6 H, m), 2.16 (2 H, m), 2.27 (2 H, m), 2 3

5 (2 H, m), 2.65 (3 H, m), 2.75 (1 H, d d, J 1

6 Hz, 6 Hz), 3.36, (1 H, J = 10 Hz), 3.50 (1H, m), 3.55 (1H, t, J = 10Hz), 3.78 (2H, m), 3.89 (4H, m), 4.0 6 (1 H, d, J = 10 H z),

4.26 (1H, q, J = 10Hz), 4.37 (1H, m), 4.66 (1H, d, J = 9Hz), 4.94 (1 H, d, J = 3 H z), 5.2

5 (1 H, t, J = 10 Hz).

 2 —Carboxy 1 — (carboxymethyl) ethyl 2 —Doxy 6 — 0 — [2 —Doxy 3 — 0— (N—Dodecanylglycyl) 1-4 — 0—Phosphono 2 —Tetradecanoylamino One D—Darcopyranosyl] — 2 — (8-Hexanoylaminooctanoylamino) One α—D—Darcoviranoside

 Reference Example 4 A catalytic reduction reaction was carried out using the compound of Step 3 in the same manner as in Example 1 to obtain the title compound as a white powder. ―

[a] ^D ₂₅ + 10.1 ° (c 0.6, black mouth form-metal (3: 1)) IR (KBr): 3 3 2 0, 1 7 5 5, 1 7 3 0, 1 65 0, 1 5 5 0, 1 0 4 5 cm-1.

^ - NMR (CDC 1 3 - CD 3 0 D (1: 1) Bruno TM S):. 6 = 0 8 9 (9 H, t, J = 7 H z), 1. 2 5 - 1. 3 5 (46 H, m), 1.4 — 1.7 (10 Η, m), 2.17 (4 Η, m), 2.27 (4 Η, m), 2.65 ( 3Η, m), 2.80 (1Η, dd, J = 16 Hz, 6 Hz), 3.17 (2H, t, J = 7 Hz), 3.35 ( 1 H), 3.52 (1 H, m), 3.55 (1 H, t, J = 10 Hz), 4.28 (1 H, q, J = 10 Hz) , 4.36 (1H, m), 4.83 (1H, d, J = 8Hz), 4.94 (1H, d, J = 3Hz), 5.39 (1 H, t, J = 10 Hz). Example 5

2—Carboxy 1- (carboxymethyl) ethyl 2—Doxy—6—0 -[2—Doxy-1 3—O— (N—Dodecanylglycyl) —2— (N—Dodecanyl-1-N-methyldalicylamino) 1-4—0—Phosphono-1-D—Glucopyranosyl] 1-2—Te Tradecanoylamino-α-D-dalcoviranoside Reference example 5 A catalytic reduction reaction was carried out using the compound of step 2 in the same manner as in Example 1 to obtain the title compound as a white powder.

 [a + 10.3. (C0.6, Chloroform-meta-nore (3: 1)) IR (KBr): 3390, 1730, 1635, 12000, 1400cm -1.

 »H-NMR (CDC 1 -CD a0D (1: 1) / TMS): 6 = 0.89 (9H, t, J = 6Hz), 1.27 (52Η, m), 1.62 (6H, m), 2.27 (4H, t, J = 8Hz), 2.43 (2H, t, J = 8Hz), 2. 6 4 (3 H, m), 2.7 1 (1 H, dd, J = 16 Hz, 7 Hz), 2.92 and 3.1 1 (3 H, eachs, — 1: 7 ), 3.52 (3H, m), 4.29 (1H, q, J = 9Hz), 4.39 (1H, m), 4.95 (1H, d , J = 3 Hz), 5.33 (1 H, t, J = 10 Hz).

 2 —phosphonoxicetyl 2 —doxy 6 — 0— [2—doxy 1 3 — 0 1 (N—dodecanylglycyl) 1 4 1 0—phosphono 2 —tetradecanoyl amino 1 D—darcopyranosyl] — 2 —Tetradecanoylamino a—D-Dalcoviranoside

 The compound of Step 3 of Reference Example 6 was subjected to catalytic reduction in the same manner as in Example 1 to obtain the title compound as a white solid. Melting point: 1 61-1 65 ° C (decomposition)

[a] ^D ₂₅ + 9.9 ° (c 0.5, pyridine)

 I R (K B r): 3390, 1755, 1660, 1555, 1205, 1085 cm-1.

. 'H - NM R (C 5 D 5 N / TMS): <5 = 0 8 7 (9 H, t, J = 7 H z), 1 2 2 (56 H, m), 1.81 (6 H, m), 2.45 (4 H, m), 2.57 (2 H, m), 3.7 1 (1 H, m), 5.09

(1H, q, J = 10Hz), 5.36 (1H, d, J = 9Hz), 538 (1H, d, J = 4Hz), 6.2 5 (1 H, t, J = 10 Hz).

Industrial applicability

 As shown in the test examples below, the compound of the present invention had low toxicity and exhibited an antitumor effect superior to that of natural lipid A (compound A) from E.co.sub.i. Therefore, the compound of the present invention is useful for prevention and treatment of tumor.

 Test example

 BAL BZc mice were transplanted intracellularly into the right flank of BAL BZc mice of the same type, with 5105 fibrosarcoma cells (MethA) induced by methylcholanthrene. On days 7, 12 and 17 after the transplantation, the compound of the present invention or compound A (manufactured by Daiichi Pure Chemicals Co., Ltd.) was dissolved in a 0.1% aqueous solution of triethylamine (vZ v%). The solution was administered intravenously and tumor weight was measured on day 21. Toxicity was determined by the number of dead mice on day 21 of the above test. Table 1 shows the results. The tumor growth inhibitory effect is a value (%) calculated by the following formula.

 (Average tumor weight on day 2 of treatment group Average weight of untreated control group) X 100 1

 Amount administered Tumor growth inhibition Number of dead mice Z fee (ng / mouse) Effect (%) Number of mice used Compounds of Example 1 190 0/6 Compounds of Example 1 80/6 Compounds of Example 5 70 / 6 Compound of Example 5 20/6

 Compound A34 / 6 Compound A25480 / 06 As is clear from Table 1, the compound of the present invention exhibited excellent antitumor effect and low toxicity.

Claims

The scope of the claims

 1. General formula (1)

 (1)

(In the formula, Q ¹ represents a carboxyl group or a phosphono group, Q ² represents a carboxy group. Represents a phosphono group or a hydrogen atom, m represents an integer of 0 to 10, n represents an integer of 0 to 10 R ¹ represents an acryl group or a substituted acryl group, R ² represents an acryl group or a substituted acryl group, and R ³ represents an acryl group or a substituted acryl group.

2. In the general formula (1), Q ¹ and Q ² are carboxyl groups, m and n are 1, R ¹ is tetradecanoyl group, dodecanoyl group, 6-octanoylamino hexanoyl group, 8 — Hexanoylaminooctanoyl group or 1 2 —acetamido dodecanoyl group, R ² is tetradecanoyl group, dodecanoyl group, 6 —year-old octanoylamino hexanoyl group or 12 —acetamidododecanol group, ^{3. The method according} to claim 1, wherein ³ is an N-decanoylglycyl group, an N-dodecanoylglycyl group, an N-dodecanoyl N-methyldaricyl group, an N-dodecanoyl N-one dodecyldaricyl group or an N-dodecyl-N-tetradecanoylglycyl group. And its salts

3.2—Carboxy 1- (carboxymethyl) ethyl 2—Doxy 1 6 1 0— [2—Doxy 3—0— (N—Dodecanylglycyl) 1 4 0—Hoshonor 2—Tetradecanoylami No 1; 3—D-Darco pyranosyl] 1 2—Tetradecanoylamino No 1 D—Darcoviranoside or its salt

4.2—Carboxy-1- (carboxymethyl) ethyl 2-Doxy-6 1 0— [2 —Doxy 3 — 0— (N—dodecanoylglycyl) 1 2 — (N— dodecanoyl N—methylglycylamino) 1 4 — 0 — Phosphono D—Glucopyranosyl] 1 2 — Tetra Decanoylamino α-D—Darcovyranoside or its salt