HRP930090A2 - Disaccharide derivatives - Google Patents

Description

The proposed invention relates to a new disaccharide derivative and its salt, which has excellent antitumor activity and low toxicity and is useful as an antitumor agent.

Natural lipid A has mitogenic activity, that is, the activity of stimulating lymphocytes, to cause the transformation of blastocytes, which promotes the increase of lymphatic cells and thereby increases immunity, the activity of deriving tumor necrosis factor, etc. and is therefore beneficial as a medicine and prophylactic agent for many diseases, that cause a decrease in immune function, such as various infectious diseases, or as an antitumor agent.

Known derivatives of natural lipid A are described in Japanese Patent Application (OPI) no. 48497/84, 53295/86 and 227586/86 (the term “OPI”, as used herein, means “unexamined published Japanese patent application”). Between them is for 2-deoxy-6-O-(2-deoxy-2-[(R)-3-dodecanoyloxy-tetradecanoylamino]-4-O-phosphono-3-O-[(R)-4-tetradecanoyloxy-

tetradecanoyl]-β-D-glucopyranosyl)-3-O-[(R)-3-hydroxytetradecanoyl]-2-[(R)-3-hydroxytetradecanoylamino]-1-O-phosphono-α-D-glucopyranose, described in Japanese Patent Application (OPI) no. 53295/86 (hereinafter referred to as compound A), known to have equal or much greater physiological activities than natural lipid A, as described in Eur. J. Biochem., Vol. 148, 1-5 (1985). Compound A is unfavorable for practical use due to high toxicity, which is consistent with the toxicity of natural lipid A. The known compounds described above, other than compound A, are also unsatisfactory for practical use, due to toxicity or antitumor activity. For this reason, it has become a very important task to develop a compound that will have useful physiological properties with reduced toxicity.

The inventors conducted extensive tests to find a compound with beneficial physiological activities and low toxicity and as a result found the proposed invention.

The proposed invention relates to the compound of formula (I):

[image]

[image] in which each of Z, Z1 and Z2 represents an alkylene group with 1 to 6 carbon atoms and R6 represents a carboxyl group or a phosphonooxy group; each of R1, R2, R3 and R4 represents -COR7

[image]

where R7 represents an alkyl group with 1 to 30 carbon atoms, which can be substituted with one or more hydroxyl groups, Z3 represents an alkylene group with 1 to 9 carbon atoms, R8 represents a cycloalkyl group with 3 to 12 carbon atoms, which can be substituted with one or more hydroxyl groups, Q represents a hydrogen atom, an acyl group with 1 to 6 carbon atoms, -CONH2, -COOH or -CH2OH, Q1 represents a hydrogen atom or an alkyl group with 1 to 20 carbon atoms, n1 represents 0 or an integer from 1 to 10 and each of n2 and n3 represents an integer from 1 to 20; and R5 represents a hydrogen atom, a phosphono group or -CO(CH2)mCOOH, where m represents 0 or an integer from 1 to 6; provided that the combination where R is a phosphono group is excluded; R5 is a hydrogen atom and each of R1, R2, R3 and R4 is -COR7, and to its salt.

The compound of formula (I) and its salt have excellent antitumor activity and low toxicity and are useful as antitumor agents.

The term "alkylene group", as used herein, means a methylene group, a polymethylene group, or a methylene or polymethylene group substituted with an alkyl group having 1 to 6 carbon atoms.

Specific examples of the alkylene group are methylene, ethylene, propylene, trimethylene, ethylethylene, tetramethylene, 2-methyl tetramethylene, 2,3-dimethyltetramethylene, 2-ethyl-3-methylpentamethylene and octamethylene groups and so on. In formula (I), it contains an alkylene group, represented by Z, Z1, Z2 and Z3, preferably from 1 to 4 carbon atoms.

The term "alkyl group", as used herein, means a straight or branched alkyl group and is, for example, methyl, ethyl, propyl, t-butyl, hexyl, nonyl, decyl, 3-ethylundecyl, 2-ethyl-4-methyltridecyl, tetradecyl , nonadecyl, tetraeicosyl, 2-ethyl-5-propyltetraeicosyl and octaeicosyl group. The alkyl group represented by R7 preferably contains 5 to 20 carbon atoms.

The term "cycloalkyl group" as used herein means, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclodecyl and cyclododecyl groups, and groups having 5 to 8 carbon atoms are preferred.

In formula (I), n1 preferably represents 0 or an integer from 1 to 5, each of n2 and n3 preferably represents an integer from 1 to 6.

The compound of formula (I) includes α- and β-isomers due to the substituent OR, where both isomers and their mixture fall within the scope of the proposed invention. Furthermore, the compound of formula (I) includes optical isomers due to different substituents, such optical isomers and their mixtures also fall within the scope of the proposed invention.

A salt of a compound of formula (I) includes a salt formed between its phosphono group or carboxyl group and an organic amine, e.g. triethylamine, pyridine, N-methylamine, N-methylglucamine, etc., or inorganic bases, e.g. ammonia, sodium, potassium, calcium, magnesium, etc.

Among the compounds of formula (I), those in which R represents IR6 or

[image]

each of R1, R2, R3, R4 represents -COR7, -COZ3R8,

[image]

-CO(CH2)n2COR7 or -CO(CH2)n2COZ3R8. More favorable are those in which R represents ZOPO(OH)2, where each of R1, R2, R3 and R4 represents -COR7 or

[image]

Compounds in terms of the proposed invention can be made by different reaction procedures. An example of one process is shown below.

[image]

where R9 represents a hydrogen atom or a hydroxyl-protecting group (i.e. a protecting group for a hydroxyl group), which can be removed by a catalytic reaction and the like; R10 represents

[image]

R51 represents a hydrogen atom, -CO(CH2)mCOOR16 or PO(OR15)2, where each of R12 and R13 represents a protective group for phosphono, which can be removed by catalytic reaction; R14 represents a protective group for carboxyl, which can be removed by catalytic reduction; R71 represents an alkyl group with 1 to 30 carbon atoms, which can be substituted with one or more hydroxyl groups, protected by a hydroxyl protecting group; R81 represents a cycloalkyl group with 3 to 12 carbon atoms, which can be substituted with one or more hydroxyl groups, protected by a hydroxyl protecting group; Q2 represents a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, -CONH2, -COOR16 or -CH2-O-R91, where R16 represents a carboxyl protecting group, which can be removed by catalytic reduction; R15 represents a protective group for phosphono, which can be removed by catalytic reduction; and R91 represents a protecting group for hydroxyl, which can be removed by catalytic reduction; and Z, Z1, Z2, Z3, Q1, n1, n2, n3 and m are the same as previously.

The carboxyl protecting group, which can be removed by catalytic reduction, is a benzyl group, etc., which can be substituted by a halogen atom, a nitro group, a lower alkoxy group, etc. The phosphono protecting group, which can be removed by catalytic reduction, is a phenyl group, benzyl group, etc. , each of which can be substituted by a halogen atom, a nitro group, a lower alkoxy group, etc. The protecting group for hydroxyl includes groups, which can be removed by catalytic reduction, such as a benzyl group, etc., which can be substituted by a halogen atom, a nitro group, a lower alkoxy group group, etc., trichloroethoxycarbonyl group, trichloro-t-butoxy-carbonyl group, etc.

According to the procedure described above, the compound of formula (II) is catalytically reduced in an inert solvent, e.g. tetrahydrofuran, methanol, ethanol, acetic acid, water, a mixture of these solvents, etc., in an atmosphere of hydrogen gas in the presence of a catalyst, such as palladium black, palladium on charcoal , paltin dioxide, etc., in order to remove the protective group. If desired, we can purify the product by silica gel chromatography or a suitable technique. The reduction reaction can usually be carried out at room temperature (0 to 30°C) to 60°C within 1 to 12 hours. The quantities of solvents and catalysts that we use are not particularly limited.

In examples of the use of the compound of formula (II), where R11, R21 or R31 contain a protecting group for hydroxyl, this protecting group is such that it can be advantageously removed by catalytic reduction.

The salt of the compound of formula (I) can be obtained by adding the necessary amount of the base of the compound, which is then sedimented, lyophilized and the like.

The procedure for preparing the starting compounds of formula (II) can be advantageously chosen in relation to the type of substituents R10 and R51, as shown below.

[image]

[image]

where R18 represents an allyl group, ZCOOR14, ZOPO(OR13)2,

[image]

R17 represents a protecting group for hydroxyl; R41 represents -COR71, -COZ3R81,

[image]

R 20 represents -CO(CH 2 )COOR 16 or PO(OR 15 ) 2 ; R92 represents a protective group for hydroxyl, which can be removed by catalytic reduction and are R11, R21, R31, R12, R13, R14, R15, R16, R71, R81, Z, Z1, Z2, Z3, n1, Q2, Q1, n2 , n3 and m the same as mentioned earlier.

Subsequently, the compound of the formula (IV) is dissolved in an inert solvent (e.g. methylene chloride, acetic acid, etc. either alone or in its combinations), which contain gaseous hydrogen bromide, and allowed to react for more than 10 minutes to 24 hours at 0°C to room temperature , that the acetyl group at position 1 of the sugar part is substituted with a bromine atom. The obtained bromine-substituted compound is dissolved in a dry solvent, preferably methylene chloride, chloroform, etc., and then condensed with the compound of formula (III) in the presence of any one or more of mercuric silver(II) cyanide, mercuric bromide, silver carbonate, silver oxide, silver perchlorate, mercury(II) nitrate, etc., and in the presence of a dehydrating agent, e.g., anhydrous calcium sulfate, etc., at a temperature from room temperature to the reflux temperature in a period of several hours to two days, in which case the compound of formula (V) is obtained.

The obtained compound is then partitioned with the compound of the formula X-R20, where X represents a halogen atom, in an organic solvent, e.g. methylene chloride, chloroform, acetonitrile, tetrahydrofuran, etc., in the presence of an organic base, e.g. pyridine, 4-dimethyl-aminopyridine, triethylamine, etc. ., or we divide the compound of the formula HO-R20 with a catalyst, such as dicyclohexylcarbodiimide in the presence of 4-dimethylaminopyridine, to obtain the compound of the formula (V').

Compounds of the formula (IIA) to (IID), i.e. the starting compounds of the formula (II), can then be synthesized from the thus obtained compounds of the formula (V) and (V') according to the following reaction paths (A) to (D).

Reaction path (A):

The compound of formula (V), where R18 or R19 are mentioned, dissolve or suspend in acetic acid and add zinc powder to start the reaction, during which we remove the protective group at position 2' and R17. The obtained compound without a protective group is then condensed with the compound of the formula R31-OH according to the procedure, which is usually used in the synthesis of peptides for the preparation of the compound of the formula (IIA).

The removal of the protective group is usually performed within 10 minutes to 24 hours at room temperature. The condensation reaction can be carried out according to the carbodiimide method, the method in one reaction vessel, the method of active esters and the like.

In the above-described deprotection reaction, as R17, i.e. the protecting group for the hydroxyl group, is preferably a trichloroethoxycarbonyl or trichloro-t-butoxy-carbonyl group. When R41 has a hydroxyl protecting group in its molecule, the same groups as the hydroxyl protecting groups are preferred.

Reaction path (B):

The compound of formula (V), where R18 is an allyl group, is processed in the same way as in reaction path (A), to remove R17 and then bind R31 to the amino group in the 2' position. After protection of the hydroxyl group in position 6' with a protecting group, which can be removed by catalytic reduction, the compound is blocked with an iridium complex, for example 1,5-cycloocta-dienbis(methyldiphenylphosphine)-iridium-hexafluorophosphate, etc., then it is hydrolyzed, to would remove the allyl group. The resulting compound is then partitioned with

[image]

to obtain the compound of formula (IIB).

The protection of the hydroxyl group in the 6' position can be carried out, for example, by partitioning for 1 to 2 days with benzyloxymethylchloride in an organic solvent, for example anhydrous chloroform, anhydrous methylene chloride, etc., in the presence of an organic base, e.g. pyridine, diisopropylethylamine, etc., at room temperature. Protection can be performed using benzyltrichloroacetimidate in the presence of trifluoromethanesulfonic acid at about 0°C.

The separation of the allyl group is usually carried out from 10 minutes to 3 hours by partitioning with the above-described iridium complex in an organic solvent, e.g. methylene chloride, chloroform, tetrahydrofuran, etc., at about 50°C, and then water and iodine are added to the reaction mixture, to perform hydrolysis at room temperature. temperature and time up to about 5 to 30 minutes.

[image] is performed after 10 minutes in an anhydrous aprotic solvent, for example anhydrous tetrahydrofuran, in the presence of butyl-lithium at a temperature of -70°C to 50°C.

Reaction path (C):

The compound of formula (IIC) can be prepared by subjecting the compound of formula (V') to the same reactions as in reaction path (A).

Reaction path (D):

The compound of formula (IID) can be prepared by subjecting the compound of formula (V') to the same reactions as in reaction path (B).

The compound of formula (IV), used as a starting material in the process shown above, can be synthesized by known procedures or according to the procedure described in Japanese patent application (OPI) no. 53295/86.

The compound of formula (III), the second starting substance in the process, can be prepared according to the reaction path (a) or (b), as shown earlier, by choosing the type of substituent R18.

Reaction path (a)

[image]

[image]

where X represents a halogen atom; Y represents a lower acyl group, a trichloroethoxycarbonyl group or a trichloro-t-butoxycarbonyl group;

[image]

Y1 represents a trichloroethoxycarbonyl group or a trichloro-t-butoxycarbonyl group; W2 represents an acetyl group, a benzoyl group, a benzyl group or a p-chlorobenzyl group; W3 represents an alkyl group with 1 to 6 carbon atoms or a carboxyl protecting group, removable with catalytic reduction, W4 represents a hydrogen atom, a benzyl group or a p-chlorobenzyl group; and R 11 , R 21 , R 13 , R 14 , Z , Z 1 and Z 2 are the same as those mentioned above.

The compound of the formula (VII) can be prepared by partitioning the compound of the formula (IVa) with the compound of the formula WOH in the presence of a Lewis acid or by condensing the compound of the formula (VIb) with the compound WOH in the presence of mercury(II) cyanide, silver carbonate, mercury bromide, silver perchlorate or mercury (II) nitrates or their mixture. The compound of formula (VII), where W is a ZO-acetyl group, can be obtained by partitioning the compound of formula (VIc) with the compound of formula HOZOH in the presence of p-toluenesulfonic acid hydrochloride, etc., followed by acetylation.

The compound of formula (VII), in which Y is a lower acyl group, is treated with Meerwein's reagent, or the compound of formula (VII), where Y is a trichloroethoxycarbonyl or trichloro-t-butoxy-carbonyl group, is treated with zinc powder in the presence of hydrochloric acid, acetic acid, etc., in order to remove the protective group for the amino group in position 2. The resulting compound is then condensed with the compound of the formula R11OH by the acid chloride method, the carbodiimide method, the one-reaction vessel method, or the active ester method, to obtain the compound of the formula (VIII ).

A compound of formula (VIII), where W is ZCOO-alkyl or

[image]

hydrolyze with sodium hydroxide, etc., to remove acyl or alkyl groups, and partition the resulting compound with a compound of formula X-R14 in the presence of an organic amine, eg triethylamine, to prepare a compound of formula (IX). A compound of formula (VIII), where W is otherwise specified, is hydrolyzed with aqueous ammonia, etc., to give a compound of formula (IX).

We protect the hydroxyl groups at positions 4 and 6 of the compound of formula (IX) using isopropylidene to obtain the compound of formula (X).

The compound of formula (X), where W1 is Z-O-benzyl or ZO-p-carboxylic group, is condensed with the compound of formula R21-OH and then the obtained compound is catalytically reduced to the compound where W1 is ZOH. The resulting compound is partitioned with the compound of formula X-PO(OR13)2 in the presence of an organic amine, eg triethylamine, 4-dimethylaminopyridine, pyridine, etc., to prepare the compound of formula (XI).

A compound of formula (X), wherein W 1 is ZCOOR 14 or

[image]

condense with the compound of the formula R21-OH, to prepare the compound of the formula (XI).

The compound of formula (IIIa) can be obtained by hydrolysis of the thus prepared compound of formula (XI) in acetic acid, which contains water, for example in a 50 to 90% by weight aqueous solution of acetic acid, or by treating the compound with p-toluenesulfonic acid in methanol, ethanol, water or their mixture.

A compound of formula (IIIa), where R 22 is ZOPO(OR 13 ) 2 or

[image]

i.e. the compound of formula (IIIa') can be prepared as follows.

A compound of formula (VII), where W is ZO-acetyl; ZO-benzoyl,

[image]

and Y is a trichloroethoxycarbonyl or trichloro-t-butoxyl-carbonyl group, treated with aqueous ammonia to obtain a compound of formula (XII), which is then protected with isopropylidene to obtain a compound of formula (XIII). The obtained compound is condensed with the compound of the formula XPO(OR13)2 and then with the compound of the formula R21OH, to prepare the compound of the formula (XIV). Isopropylidene is removed from the obtained compound in the same way as described above for the preparation of the compound of formula (XVa). Y' in the compound of formula (XVa) is removed in the same way, as described above, and the obtained compound is then condensed with the compound of formula R11OH, to obtain the compound of formula (IIIa'). The compound of formula (XVb) can be prepared by removing Y1 from the compound of formula (XIV) in the same way, as described above, and then condensing the resulting compound with the compound of formula R11OH. From it we then remove isopropylidene in the same way as described above to prepare the compound of formula (IIIa').

The compound of formula (IIIa'), where R11 and R21 are equal, can be obtained by removing Y1 from the compound of formula (XIII) and condensing the obtained compound with a fatty acid, and then removing isopropylidene.

Reaction path (b):

[image]

in which Y1, R21 and R11 are the same as above.

The compound of formula (XVI) is condensed with the compound of formula R21OH to prepare the compound of formula (XVII). After removing Y1 in the same manner as described above, the compound is condensed with a compound of formula R11OH to obtain a compound of formula (XVIII). Isopropylidene is then removed from the compound of formula (XVIII) in the same manner as described above to give the compound of formula (IIIb).

The compounds of the proposed invention have antitumor activity, which is equal to or even greater than the activity of compound A, and have significantly lower toxicity compared to compound A. Therefore, the compounds of the invention are applicable as antitumor agents.

We now explain the proposed invention in more detail with reference examples, examples and tests, although it is believed that the proposed invention is not limited thereby. In these examples, all percentages are by weight, unless otherwise stated.

Reference example 1

1) Preparation of 2-acetoxyethyl-3,4,6-tri-O-acetyl-2-deoxy-2-(2,2,2-trichloroethoxycarbonylamino)-α-D-glucopyranoside

To 5.00 g of 2-deoxy-2-(2,2,2-trichloroethoxycarbonylamino)-D-glucose, add 5.0 ml of ethylene glycol and 0.5 ml of gaseous hydrogen chloride, which contains dioxane, and stir the mixture for 4 hours while heating at 90°C. After cooling with ice water, add 75 ml of pyridine and then 30.6 g of acetonanhydride to the reaction mixture and mix. After 20 minutes of mixing, warm the reaction mixture to room temperature and stir for another 16 hours. Pour the reaction mixture into 350 ml of ice water and mix. The precipitated solid substance is collected by filtration and washed with water.

Dissolve the resulting solid in chloroform, wash in sequence with 1 N hydrochloric acid and saturated aqueous sodium chloride solution, and dry over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure, the residue is recrystallized from ethanol and 4.96 g of the title compound are obtained as colorless prisms. Melting point 138 to 140°C.

[α]D25 : +74.0° (c = 1.2, chloroform)

2) Preparation of 2-acetoxyethyl-3,4,6-tri-O-acetyl-2-deoxy-2-tetradecanoylamino-α-D-glucopyranoside

In 60 ml of acetic acid, dissolve 4.96 g of the compound obtained above in 1), and with stirring, add 7 g of zinc powder in small portions at room temperature. Stir for another hour and remove the rest of the insoluble matter by filtering. The solvent is removed from the filtrate by distillation under reduced pressure, toluene is added to the residue and the solvent is removed by distillation under reduced pressure. Dissolve the residue in dioxane and add gaseous hydrogen chloride, which contains dioxane, to the solution. Remove the solvent by distillation under reduced pressure and dry the rest.

The resulting oil product is dissolved in 70 ml of anhydrous methylene chloride and, after cooling with ice, 2.88 ml of N-methylmorpholine and 3.24 g of tetradecanoyl chloride are added to the solution, and then stirred for 1 hour. Add 10 ml of methanol to the reaction mixture. With stirring at room temperature for 10 minutes, dilute the reaction mixture with chloroform, and wash in sequence with 1 N hydrochloric acid and saturated aqueous sodium chloride solution and dry over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure and the residue is purified by chromatography on a silica gel column using as eluent a mixture of benzene and ethyl acetate in a ratio of 9:1 (v/v) and then 1:1 (v/v), whereby we obtain 4.77 g of the title compound as colorless oily product.

3) Preparation of 2-hydroxylethyl-2-deoxy-2-tetradecanoylamino-α-D-glucopyranoside

In 80 ml of absolute methanol, we dissolve 4.77 g of the compound, obtained above in 2), and add to the solution, while cooling with ice, a methanol solution containing 9 mmol of sodium methylate, then mix for another 30 minutes at room temperature. Add tetrahydrofuran to precipitate the solution, neutralize the solution with highly acidic ion exchanger resin, Dowex-50 (type H+) and remove the resin by filtration. Remove the solvent by distillation from the filtrate under reduced pressure. The residue is washed with diethyl ether, then filtered, and 3.02 g of the title compound are obtained as a white solid. Recrystallization from ethanol-water gives a purified product with a melting point of 158 to 160°C.

[α]D25 : +8.21° (c = 0.8, tetrahydrofuran : water = 4:1 (v/v))

4) Preparation of 2-hydroxyethyl-2-deoxy-4,6-O-isopropylidene-2-tetradecanoylamino-α-D-glucopyranoside

In 20 ml of dimethylformamide, dissolve 0.87 g of the compound, obtained above in 3), and add 062 g of 2,2-dimethoxypropane and 38 mg of p-toluenesulfonic acid monohydrate to the solution at room temperature, and stir for another 1.5 hours. After neutralization with a 5% aqueous solution of sodium hydrogencarbonate, the solvent is removed by distillation under reduced pressure. Dissolve the residue in ethyl acetate, wash in sequence with water and saturated aqueous sodium chloride solution, and dry over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure and the residue is purified by chromatography on a silica gel column using as eluent a mixture of chloroform:acetone 19:1 (v/v) and then chloroform:methanol 19:1 (v/v), whereby we obtain 0.78 g of the title compound as a colorless and viscous oil product.

5) Preparation of 2-(diphenylphosphonoxy)ethyl-2-deoxy-4,6-O-isopropylidene-2-tetradecanoylamino-α-glucopyranoside

In 15 ml of anhydrous methylene chloride, we dissolve 0.77 g of the compound obtained above in 4), and add 0.48 g of diphenyl-phosphorochloridate, 0.19 ml of pyridine and 0.30 g of dimethylamino-pyridine to the solution while cooling with ice. After mixing for 1 hour, the temperature of the mixture is raised to room temperature and mixed for another hour. Add 0.17 g of diphenylphosphorochloridate to the reaction mixture, then mix for 30 minutes. Add 3 ml of methanol to the reaction mixture. After stirring for some time, remove the solvent by distillation under reduced pressure. The residue was purified by chromatography on a silica gel column using a mixture of chloroform:acetone 19:1 (v/v) as eluent, whereby 0.81 g of the title compound was obtained as a colorless viscous oil.

6) Preparation of 2-(diphenylphosphonoxy)ethyl-2-deoxy-3-O-(N-dodecanoylglycyl)-2-tetradecanoylamino-A-D-glucopyranoside

In 5 ml of anhydrous methylene chloride, dissolve 0.51 g of the compound obtained above in 5) and add 0.22 g of N-dodecanoylglycine, 44 mg of dimethylaminopyridine and 0.18 g of dicyclohexylcarbodiimide to the solution while cooling with ice. The mixture is stirred for 30 minutes with ice cooling and then for 2 hours at room temperature. The insoluble substance is removed by filtration, the filtrate is successively washed with 1 N hydrochloric acid, water saturated with sodium chloride solution and dried over anhydrous sodium sulfate. Remove the solvent by distillation under reduced pressure and add 20 ml of 90% aqueous acetic acid solution to the residue, then mix for another 30 minutes while heating at 90°C. Remove the solvent by distillation, add toluene to the residue, then distill to remove the solvent. Once again, we repeat the addition of toluene and repeat the distillation. The residue was purified by chromatography on a silica gel column using as eluent a mixture of chloroform:acetone 19:1 (v/v), and then a mixture of chloroform:methanol 19:1 (v/v), whereby we obtained 0.51 g of the title compound as a colorless oily product.

[α]D25 : +46.2° (c = 1.1, chloroform)

NMR-(CDCl3), δ (ppm): 0.88 (6H, t), 1.26 (s), 2.07 (2H, t), 2.27 (2H, t), 4.84 (1H, d), 5.18 (1H, m) , 7.2-7.4 (10H, m).

Reference example 2

1) Preparation of 2-hydroxyethyl-2-deoxy-2-(2,2,2,-trichloro-ethoxycarbonylamino)-α-D-glucopyranoside

5.05 g of the compound prepared in reference example 1-1) is suspended in 6 ml of 28% aqueous ammonia and 120 ml of methanol, and the suspension is stirred for 8 hours at room temperature. The reaction mixture is evaporated under reduced pressure, whereupon we obtain 3.50 g of the title compound as a caramel-like substance.

NMR-(CDCl3-CD3OD, ca. 1:1), δ (ppm): 4.78 (2H, s), 4.90 (1H, d)

2) Preparation of 2-hydroxyethyl-2-deoxy-4,6-O-isopropylidene-2-(2,2,2-trichloroethoxycarbonylamino)-α-D-glucopyranoside

We process 3.58 g of the compound obtained above in 1) in the same way as in reference example 1-4). Add n-hexane to the resulting fraction and collect the resulting precipitate by filtration, whereupon we obtain 2.78 g of the compound as a white powder. Melting point 190 to 192°C.

3. Preparation of 2-(diphenylphosphonoxy)ethyl-2-deoxy-4,6-O-isopropylidene-2-(2,2,2-trichloroethoxycarbonylamino)-α-D-

glucopyranoside

1.12 g of the compound obtained above in 2), we process in the same way as in reference example 1-5), and add diethyl ether and n-hexane to the obtained fraction. The resulting precipitate is collected by filtration, where we obtain 1.23 g of the title compound. Melting point 121 to 124°C.

[α]D25 : +46.4° (c = 1.0, chloroform)

4) Preparation of 2-(diphenylphosphonoxy)ethyl-2-deoxy-4,6-O-isopropylidene-3-O-tetradecanoyl-2-(2,2,2-trichloroethoxy-carbonyl)

amino)-α-D-glucopyranoside

In 10 ml of anhydrous methylene chloride, dissolve 0.50 g of the compound obtained above in 3), and add 0.30 ml of pyridine, 0.22 g of tetradecanoyl chloride and 20 ml of dimethylaminopyridine to the solution, then continue mixing for 2 hours. add 2 ml of methanol to the reaction mixture. After stirring for some time at room temperature, the reaction mixture is evaporated under reduced pressure. The residue is purified by chromatography on a silica gel column using chloroform containing 2% acetone as eluent, and then chloroform containing 5% acetone, whereupon we obtain 0.49 g of the title compound as a colorless oily substance.

[α]D25 : +36.1° (c = 1.0, chloroform)

5) Preparation of 2-(diphenylphosphonoxy)ethyl-2-deoxy-2-(N-dodecanoylglycylamino)-4,6-O-isopropolydene-3-O-tetradecanoyl-α-

D-glucopyranoside

In 12 ml of acetic acid, dissolve 0.47 g of the compound, obtained above in 4), and suspend 0.5 g of zinc powder to it, then stir for about 1.5 hours at room temperature. If insoluble substances remain, remove it by filtration, wash the filtrate with chloroform and remove the solvent by distillation under reduced pressure. Dissolve the residue in chloroform, wash in sequence with a 5% sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, and dry over anhydrous sodium sulfate. The solvent is removed by distillation and the remaining solid substance is dissolved in 8 ml of anhydrous methylene chloride. Add 0.21 g of N-dodecanoylglycine to the solution. Add 0.17 g of dicyclohexylcarbodiimide and 32 mg of dimethylaminopyridine to the mixture while cooling with ice. After 20 minutes, the temperature of the mixture is raised to room temperature and the mixture is left to react for 15 hours with stirring. If there are insoluble substances, remove them by filtration and remove the solvent from the filtrate by distillation under reduced pressure. The residue is purified by chromatography on a silica gel column using chloroform containing 2 to 10% acetone as an eluent. The desired fraction was treated with n-hexane, whereupon we obtained 0.48 g of the title compound as a white powder. Melting point 79 to 80°C.

[α]D25 : +28.1° (c = 1.1, chloroform)

6) Preparation of 2-(diphenylphosphonoxy)ethyl-2-deoxy-2-(N-dodecanoylglycylamino)-3-O-tetradecanoyl-α-D-glucopyranoside

In 20 ml of 90% aqueous solution of acetic acid, dissolve 0.45 g of the compound obtained above 5), and mix the solution for 30 minutes, heated at 90°C. Remove the solvent by distillation under reduced pressure and add toluene to the residue, then distill under reduced pressure. We add toluene again and distill again, and the finally obtained residue is purified by chromatography on a silica gel column using as an eluent chloroform containing 5 to 10% acetone and then a mixture of chloroform:methanol 19:1 (v/v), where we obtain 0.39 g of the title compound as white waxy solids.

[α]D25 : +36.1° (c = 1.1, chloroform)

NMR-(CDCl3), δ (ppm): 0.90 (6H, t), 1.28 (s), 2.13 (2H, m), 2.36 (2H, t), 4.90 (1H, d), 7.2-7.5 (10H, m).

Reference example 3

1) Preparation of 2-(diphenylphosphonoxy)ethyl-2-deoxy-3-O-(N-dodecanoylglycyl)-4,6-O-isopropylidene-2-(2,2,2-trichloro-

ethoxycarbonylamino)-α-D-glucopyranoside

In 20 ml of anhydrous methylene chloride, dissolve 1.89 g of the compound obtained in reference example 2-3), and add 0.83 g of N-dodecanoylglycine, 0.17 g of dimethylaminopyridine and 0.67 g of dicyclohexylcarbodiimide while cooling with ice. After 30 minutes, let the mixture warm to room temperature and stir it for 1 hour at that temperature. If there are insoluble substances, remove them by filtration and evaporate the filtrate under reduced pressure. The residue was purified by chromatography on a silica gel column using a mixture of chloroform:acetone 10:1 (v/v) as eluent, whereupon we obtained 2.80 g of the title compound as a colorless oily substance.

[α]D25 : +32.2° (c = 0.8, chloroform).

2) Preparation of 2-(diphenylphosphonoxy)ethyl-2-deoxy-3-O-(N-dodecanoylglycyl)-2-[6-(octanoylamino)hexanoylamino]-α-D-

glucopyranoside

In 10 ml of acetic acid, dissolve 0.71 g of the compound obtained above in 1), and add 0.5 g of zinc powder while stirring at room temperature. After stirring for 2 hours, remove the insoluble matter by filtration, wash the filtrate with chloroform and double the solvent by distillation. Dissolve the residue in chloroform, wash sequentially with a 5% aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, and dry over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure, which gives an oily product.

Dissolve 0.26 g of separated 6-(octanoylamino)caproic acid in 7 ml of anhydrous tetrahydrofuran and add 0.16 g of 1-hydroxybenzotriazole and 0.21 g of dicyclohexylcarbodiimide to the solution while cooling with ice. The temperature of the liquid is slowly raised to room temperature and the mixture is stirred for 3 hours. The precipitate of insoluble matter is removed by filtering. Combine the filtrate with the oily product prepared above while cooling with ice, then warm it to room temperature, and stir the mixture for 4 hours. Remove the solvent by distillation and add 20 ml of 90% aqueous acetic acid solution to the residue. Mix the mixture for 20 minutes with heating at 90°C. The solvent is removed by distillation and the residue is purified by chromatography on a silica gel column using as eluent a mixture of chloroform and acetone 10:1 (v/v), a mixture of chloroform and methanol 20:1 (v/v) and a mixture of chloroform and methanol 10:1 (v/ v), where we reject 0.56 g of the title compound as a colorless waxy substance.

[α]D25 : +31.2° (c = 1.1, chloroform)

NMR-(CDCl3), δ (ppm): 0.88 (6H, t), 2.0-2.4 (6H, m), 4.85 (1H, d), 7.2-7.4 (10H, m).

Reference example 4

Preparation of 2-(diphenylphosphonoxy)ethyl-2-deoxy-3-O-(N-dodecanoyl-N-methylglycyl)-2-[(N-dodecanoyl-N-methylglycine)-amino]-α-D-glucopyranoside

In 10 ml of acetic acid, dissolve 1.00 g of the compound obtained in reference example 2-3), and add 0.5 g of zinc powder while stirring at room temperature. Stir for another 2.5 hours and remove the insoluble matter by filtration. The filtrate is washed with chloroform and the solvent is removed by distillation under reduced pressure. The residue is washed in chloroform, washed sequentially with a 5% aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure, and the remaining oily substance and 1.21 g of N-dodecanoyl-N-methylglycine are dissolved in 10 ml of anhydrous methylene chloride. Add 90 mg of dimethylaminopyridine and 0.92 g of dicyclohexylcarbodiimide to the solution while cooling with ice. After heating to room temperature, mix the mixture for 3 hours.

The precipitated insoluble substance is removed by filtration and the filtrate is evaporated under reduced pressure. The remaining oily substance is purified by chromatography on a silica gel column, in which we use a mixture of chloroform and acetone 9:1 (v/v) and a mixture of chloroform and methanol 19:1 (v/v) as the eluent, respectively, to obtain an oily substance. The resulting oily substance is dissolved in 40 ml of 90% aqueous acetic acid solution, and then stirred for 30 minutes while heating to 90°C. The solvent is removed by distillation under reduced pressure and the residue is purified by chromatography on a silica gel column using as an eluent a mixture of chloroform and methanol with a ratio of 50:1 (v/v) and then 20:1 (v/v), whereby we obtain 0.87 g of the title compound as an oily product.

[α]D25 : +34.9° (c = 1.0, chloroform)

NMR-(CDCl3), δ (ppm): 0.89 (6H, t), 1.28 (s), 2.36 (4H, m), 2.84 and 3.00 (total 3H, each s), 3.13 and 3.15 (total 3H, each s ), 4.45 (2H, m), 4.87 (1H, d), 7.2-7.4 (10H, m).

Reference example 5

1) Preparation of 2-(diphenylphosphonoxy)ethyl-2-deoxy-3-O-tetradecanoyl-2-(2,2,2-trichloroethoxycarbonylamino)-α-D-

glucopyranoside

In 15 ml of anhydrous methylene chloride, dissolve 0.50 g of the compound obtained in reference example 2-3), and 0.22 g of tetradecanoic acid, and add 0.12 g of dimethylaminopyridine and 0.20 g of dicyclohexylcarbodiimide to the solution while cooling with ice. Warm the mixture to room temperature and stir for 2 hours. The precipitated insoluble substance is removed by filtration and the filtrate is evaporated under reduced pressure. The remaining oily substance is purified by chromatography on a silica gel column, in which we use a mixture of chloroform and acetone 10:1 (v/v) as eluent, in order, to obtain an oily substance. The resulting oily substance is dissolved in 10 ml of 90% aqueous acetic acid solution, then stirred for 25 hours while heating at 90°C. The solvent is removed by distillation under reduced pressure and the residue is purified by chromatography on a silica gel column using as an eluent a mixture of chloroform and acetone 10:1 (v/v) and then a mixture of chloroform and methanol 10:1 (v/v), where we obtain 0.61 g of an oily products.

[α]D25 : +43.0° (c = 1.2, chloroform)

2) Preparation of 2-(diphenylphosphonoxy)ethyl-2-deoxy-2-[(N-dodecanoyl-D-isoglutaminyl)amino]-3-O-tetradecanoyl-α-D-

glucopyranoside

0.47 g of the compound obtained in 1) above, treated with zinc powder in an acetic acid solution, and then partitioned with N-dodecanoyl-D-isoglutamine in the same way as in reference example 3-2), where we obtain 0.36 g of the title compound as white waxy substance.

[α]D25 : +38.7° (c = 0.1, chloroform)

NMR-(CDCl3), δ (ppm): 0.88 (6H, t), 1.26 (s), 2.1-2.5 (6H, m), 4.96 (1H, d), 5.18 (1H, d), 7.2-7.5 ( 10H, m).

Reference example 6

1) Preparation of 1,3-(diethoxycarbonyl)isopropyl-2-deoxy-3,4,6-tri-O-acetyl-2-(2,2,2-trichloroethoxycarbonylamino)-α-D-

glucopyranoside

To 8.00 g of 1,3,4,6-tetra-O-acetyl-2-deoxy-2-(2,2,2-trichloroethoxycarbonylamino)-D-glucopyranose, add a cooled acetic acid solution containing 25% hydrogen bromide, at room temperature, and stir it for 1 hour. Dilute the reaction mixture with chloroform, wash it with a 5% aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, and dry it over anhydrous magnesium sulfate.

The solvent is removed by distillation under reduced pressure and the residue is dissolved in 72 ml of anhydrous methylene chloride. Add 8 g of anhydrous calcium sulfate, a suspension of 4.12 g of silver perchlorate in 40 ml of anhydrous benzene and 6.24 g of diethyl-3-hydroxyglutarate to the solution while cooling with ice. Let the mixture react for 3 hours at room temperature, then neutralize it with a 5% aqueous solution of sodium bicarbonate. The insoluble substance is removed by filtration, the filtrate is washed with water and dried over anhydrous magnesium sulfate. The solvent is separated by distillation and the residue is purified by chromatography on a silica gel column using a mixture of chloroform and acetone 30:1 (v/v) as eluent, whereby 7.36 g of the title compound are obtained as an oily substance.

[α]D25 : +42.8° (c = 0.7, chloroform)

2) Preparation of 1,3-(diethoxycarbonyl)isopropyl-2-deoxy-2-tetradecanoylamino-3,4,6-tri-O-acetyl-α-D-glucopyranoside

4.00 g of the compound obtained in 1) above is treated with zinc powder in an acetic acid solution and then partitioned with tetradecanoic acid in the same way as in reference example 3-2), whereby we obtain 3.78 g of the title compound as an oily substance.

[α]D25 : +46.9° (c = 0.16, chloroform).

3) Preparation of 1,3-(dibenzyloxycarbonyl)isopropyl-2-deoxy-2-tetradecanoylamino-α-D-glucopyranoside

Dissolve 1.80 g of the compound obtained in 2) above in 30 ml of dioxane, and add 10 ml of water. After cooling to 5°C, add 15 ml of 1 N aqueous potassium hydroxide solution to the solution. After stirring for 6 hours, add 1 N hydrochloric acid to adjust the pH to 7.5. The reaction mixture is evaporated to dryness under reduced pressure. The residue is suspended in 100 ml of dimethylformamide and 1 ml of benzyl bromide is added. After stirring for 3 hours at 40°C, remove excess dimethylformamide by distillation under reduced pressure. The residue is extracted with benzene, the benzene layer is washed sequentially with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium chloride, a 5% aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue is purified by chromatography on a silica gel column using as an eluent a mixture of chloroform, methanol and acetone in a volume ratio of 50:1:5 and then 50:1:15, whereby we obtain 0.65 g of the title compound as a white wax solid substances.

[α]D25 : +13.2° (c = 0.51, chloroform)

4) Preparation of 1,3-(dibenzyloxycarbonyl)isopropyl-2-deoxy-4,6-O-isopropylidene-2-tetradecanoylamino-α-D-

glucopyranoside

In 10 ml of acetone, we dissolve 0.64 g of the compound obtained in 3) above, and process in the same way as in reference example 1-4), where we obtain 0.54 g of the title compound as a solid substance.

[α]D25 : +3.3° (c = 0.7, chloroform)

5) Preparation of 1,3-(dibenzyloxycarbonyl)isopropyl-2-deoxy-3-O-tetradecanoyl-2-tetradecanoylamino-α-D-glucopyranoside

In the same way as in reference example 1-6) 0.48 g of the compound obtained in 4) above, we separated with tetradecanoic acid and the reaction product was poured into a 90% aqueous solution of acetic acid, where we obtained 0.53 g of the title compound as a white waxy solid substances.

[α]D25 : +32.8° (c = 0.9, methanol)

NMR-(CDCl3), δ (ppm): 0.88 (6H, t), 1.26 (s), 4.96 (1H), 5.20 (4H, s), 7.40 (10H, s).

Reference example 7

Preparation of 1,3-(dibenzyloxycarbonyl)isopropyl-2-deoxy-3-O-(N_dodecanoylglycyl)-2-tetradecanoylamino-α-D-

glucopyranoside

In the same way as in reference example 1-6) 0.60 g of the compound obtained in reference example 6-4) is partitioned with N-dodecanoylglycine and the reaction product is treated with a 90% aqueous solution of acetic acid, whereupon we obtain 0.63 g of the title compound as waxy solids.

[α]D25 : +36.9° (c = 1.3, chloroform)

NMR-(CDCl3), δ (ppm): 0.89 (6H, t), 1.26 (s), 2.1-2.3 (4H, m), 2.5-2.9 (4H, m), 4.50 (1H, m), 4.97 ( 1H, d), 5.07 (1H, m), 5.18 (4H), 7.4 (10H, s).

Reference example 8

1) Preparation of 2-acetoxyethyl-3,4,6-tri-O-acetyl-2-deoxy-2-[6-(octanoylamino)hexanoylamino]-α-D-glucopyranoside

In the same way as in reference example 2-5), 3.00 g of the compound obtained in reference example 1-1) are treated with zinc powder in an acetic acid solution and the reaction product is partitioned with 6-(octanoylamino)caproic acid, whereupon we obtain 2.84 g of the title compounds as waxy solids.

[α]D25 : +55.4° (c = 1.1, chloroform)

2) Preparation of 2-hydroxyethyl-2-deoxy-2-[6-(octanoylamino)-hexanoylamino]-α-D-glucopyranoside

In the same way as in reference example 1-3), we separate 2.82 g of the compound obtained in 1) above, where we obtain 1.66 g of the title compound as a white powder. Melting point 156 to 157ºC.

[α]D25 : +78.8° (c = 0.9, ethanol)

3) Preparation of 2-hydroxyethyl-2-deoxy-4,6-O-isopropylidene-2-[6-(octanoylamino)hexanoylamino]-α-D-glucopyranoside

In the same way as in reference example 1-4), we partition 1.60 g of the compound prepared in 2) above, where we obtain 1.48 g of the title compound as an oily substance.

[α]D25 : +35.2° (c = 1.0, chloroform)

4) Preparation of 2-(diphenylphosphonoxy)ethyl-2-deoxy-4,6-O-isopropylidene-2-[6-(octanoylamino)hexanoylamino]-α-D-

glucopyranoside

In the same way as in reference example 1-5), we partition 1.26 g of the compound obtained in 3) above, where we obtain 1.35 g of the title compound as an oily substance.

[α]D25 : +26.7° (c = 1.2, chloroform)

5) Preparation of 2-(diphenylphosphonoxy)ethyl-2-deoxy-3-O-dodecano-yl-2-[6-(octanoylamino)hexanoylamino]-α-D-

glucopyranoside

In the same way as in reference example 1-6) 0.65 g of the compound obtained in 4) above, partition with dodecanoic acid and pour the reaction product into a 90% aqueous solution of acetic acid, whereby we obtain 0.73 g of the title compound as an oily substance.

[α]D25 : +37.3° (c = 1.1, chloroform)

NMR-(CDCl3), δ (ppm): 0.89 (6H, m), 2.10 (4H, m), 2.33 (2H, m), 3.20 (2H, m), 4.30 (1H, m), 4.46 (2H, m), 4.85 (1H, d), 5.10 (1H, m).

Reference example 9

1) Preparation of 2-acetoxyethyl-3,4-6-tri-O-acetyl-2-[(R)-3-benzyloxytetradecanoylamino]-2-deoxy-α-D-glucopyranoside

In the same way as in reference example 2-5), 3.00 g of the compound obtained in reference example 1-1) above, is treated with zinc powder in an acetic acid solution and the reaction product is partitioned with 1.95 g of (R)-3-benzyloxytetradecanoic acid, at from which we get 3.70 g of the title compound as an oily substance.

NMR-(CDCl3), δ (ppm): 0.87 (3H, t, J=6 Hz), 2.00 (3H, s), 2.02 (3H, s), 2.04 (3H, s), 2.08 (3H, s) , 2.18 (2H, m), 4.54 (2H, ABq, J=12 Hz), 4.76 (1H, d, J=4 Hz), 7.36 (5H, s).

2) Preparation of 2-hydroxyethyl-2-[(R)-3-benzyloxytetradecanoyl-amino]-2-deoxy-α-D-glucopyranoside

In the same way as in reference example 1-3), we separate 3.68 g of the compound prepared in 1) above, where we obtain 2.49 g of the title compound as a pale red powder, recrystallized from water-ethanol. Melting point 125 to 127ºC.

[α]D25 : +73.3° (c = 0.9, methanol)

3) Preparation of 2-hydroxyethyl-2-[(R)-3-benzyloxytetradecanoyl-amino]-2-deoxy-4,6-O-isopropylidene-α-D-glucopyranoside

In the same way as in reference example 1-4), we obtain 0.98 g of the title compound as a colorless oily substance from 1.20 g of the compound, prepared in 2) above.

[α]D25 : +31.4° (c = 0.9, chloroform)

4) Preparation of 2-(diphenylphosphonoxy)ethyl-2-[(R)-3-benzyloxy-tetradecanoylamino]-2-deoxy-4,6-O-isopropylidene-α-D-

glucopyranoside

In the same way as in reference example 1-5), we obtain 0.98 g of the title compound as a colorless oily substance from 0.83 g of the compound, prepared in 3) above.

NMR-(CDCl3), δ (ppm): 0.88 (3H, t, J=7 Hz), 1.46 (3H, s), 1.53 (3H, s), 2.47 (2H, d, J=6 Hz), 4.2 (3H, m), 4.53 (2H, ABq, J=12 Hz), 4.64 (1H, d, J=4 Hz), 7.2-7.4 (15H, m).

5) Preparation of 2-(diphenylphosphonoxy)ethyl-3-O-[(R)-3-benzyloxy-tetradecanoyl]-2-[(R)-3-benzyloxytetradecanoylamino)]-2-

deoxy-α-D-glucopyranoside

In the same way as in the reference example 1-6), 0.96 g of the compound obtained in 4) above is partitioned with 0.59 g of (R)-3-benzyloxytetradecanoic acid, and the reaction product is poured into a 90% acetic acid solution, whereupon we obtain 1.23 g of the title compound as a colorless oily substance.

[α]D25 : +31.4° (c = 1.2, chloroform)

NMR-(CDCl3), δ (ppm): 0.88 (6H, t, J=7 Hz), 2.34 (2H, d, J=6 Hz), 2.6 (2H, m), 4.51 (2H, ABq, J= 12 Hz), 4.56 (2H, s), 4.71 (1H, d, J=4 Hz), 5.13 (1H, m), 7.2-7.4 (20H, m).

Reference example 10

Preparation of 2-(diphenylphosphonoxy)ethyl-3-O-[(R)-3-benzyloxy-tetradecanoyl]-2-deoxy-2-tetradecanoylamino-α-D-

glucopyranoside

In the same way as in reference example 1-6), the compound obtained in reference example 1-5) is partitioned with (R)-3-benzyloxytetradecanoic acid and the reaction product is poured into a 90% acetic acid solution, whereupon the title compound is obtained as oily substance.

NMR-(CDCl3), δ (ppm): 0.89 (6H, t), 2.06 (2H, t), 2.1-2.8 (2H, m), 4.85 (1H, d), 5.14 (1H, t), 7.1- 7.3 (15H, m).

Reference example 11

Preparation of 2-(diphenylphosphonoxy)ethyl-2-[(R)-3-benzyloxytetradecanoylamino]-2-deoxy-3-O-tetradecanoyl-α-D-

glucopyranoside

In the same way as in reference example 1-6), the compound obtained in reference example 9-4) is partitioned with tetradecanoic acid and the reaction product is poured into a 90% acetic acid solution, whereupon the title compound is obtained as a colorless oily substance.

NMR-(CDCl3), δ (ppm): 0.88 (6H, t), 2.3-2.4 (4H, m), 4.52 (2H, d), 4.72 (1H, d), 5.10 (1H, m), 7.2- 7.5 (15H, m).

Reference examples 12 of 52

In the same way, as described in reference examples from 1 to 11, we prepare the following compounds of formula (IIIa).

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In the same way, as described in Reference Examples 1 to 11, prepare the following compounds of formula (IIIa).

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Example 1

1) Preparation of 2-(diphenylphosphonoxy)ethyl-2-deoxy-6-O-[2-deoxy-4-O-diphenylphosphono-3-O-(N-dodecanoylglycyl)-6-O-(2,2,2- trichloroethoxycarbonyl)-2-(2,2,2-trichloroethoxycarbonyl-amino)-β-D-glucopyranosyl]-3-O-(N-dodecanoylglycyl)-2-[(N-dodecanoyl-N-methylglycyl)amino]-α -D-glucopyranoside

In 2 ml of anhydrous methylene chloride, dissolve 370 mg of 1-O-acetyl-2-deoxy-4_O-diphenylphosphono-3-O-(N-dodecanoylglycyl)-6-O-(2,2,2-trichloroethoxycarbonyl)-2-(trichloroethoxycarbonyl) -amino)-D-glucopyranose and add 6 ml of cooled acetic acid solution containing 25% hydrogen bromide to the solution at room temperature, and stir it for 1 hour. Dilute the reaction mixture with chloroform, wash with ice water, 5% aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, and dry over anhydrous sodium sulfate. Remove the solvent by distillation under reduced pressure. Dissolve the residue and 344 mg of 2-(diphenylphosphonoxy)ethyl-2-deoxy-3-O-(N-dodecanoylglycyl)-2-[(N-dodecanoyl-N-methylglycyl)amino]-α-D-glucopyranoside in 5 ml of anhydrous methylene chloride. Add 0.5 g of active calcium sulfate and 182 mg of mercury(II) cyanide to the solution and heat the mixture to 50 to 60°C and stir for 3 hours. The insoluble substance is removed by filtration through celite, the filtrate is washed sequentially with a 5% aqueous solution of potassium iodide and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent is removed by distillation and the residue is purified by chromatography on a silica gel column using as eluent a mixture of chloroform and acetone 10:1 (v/v), then a mixture of chloroform and methanol 50:1 (v/v), then a mixture of chloroform and methanol 20:1 (v/v), whereby we obtain 599 mg of the title compound as an oily substance.

[α]D25 : +20.0° (c = 1.0, chloroform)

2) Preparation of 2-(diphenylphosphonoxy)ethyl-2-deoxy-6-O-(2-deoxy-4-O-diphenylphosphono-3-O-(N-dodecanoylglycyl)-2-[(N-

dodecanoyl-N-methylglycyl)amino]-β-D-glucopyranoxy-3-O-(N-dodecanoylglycyl)-2-[(N-dodecanoyl-N-methylglycyl)amino]-

of α-D-glucopyranoside

Dissolve 587 mg of the compound prepared in 1) above in 8 ml of acetic acid, suspend 0.6 g of zinc powder in the solution, and stir for 2 hours at room temperature. The insoluble substance is removed by filtration and the filtrate is washed with chloroform. The solvent is removed by distillation under reduced pressure, toluene is added to the residue and then distilled to separate the solvent. We repeat the addition of toluene and the subsequent distillation in its entirety three times and dissolve the remainder in chloroform. The chloroform compound is sequentially washed with 1 N hydrochloric acid, 5% aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure, which gives an oily product.

Separately dissolve 122 mg of N-dodecanoyl-N-methylglycine in 3 ml of anhydrous tetrahydrofuran and add 77 mg of 1-hydroxybenzotriazole and 103 mg of dicyclohexylcarbodiimide to the solution, then mix in an ice bath. After 30 minutes, the temperature of the liquid is raised to room temperature and stirred for another 3 hours. Remove the precipitated crystals by filtering.

The oily substance prepared above is dissolved in 5 ml of anhydrous methylene chloride and the filtrate is added to it while cooling with ice. The temperature of the mixture is raised to room temperature and the mixture is stirred for 1.5 hours at that temperature. The reaction mixture is diluted with chloroform, washed with 1 N hydrochloric acid, dried over anhydrous sodium sulfate and then distilled to remove the solvent. The residue is purified by chromatography on a silica gel column using as eluent a mixture of chloroform and acetone 10:1 (v/v), then a mixture of chloroform and methanol 50:1 (v/v) and finally a mixture of chloroform and methanol 20:1 (v/ v), whereby we obtain 445 mg of the title compound as an oily substance.

[α]D25 : +19.2° (c = 1.0, chloroform)

3) Preparation of 2-phosphonooxyethyl-2-deoxy-6-O-(2-deoxy-3-O-(N-dodecanoylglycyl)-2-[(N-dodecanoyl-N-methylglycyl)amino]-

4-O-phosphono-β-D-glucopyranosyl)-3-O-(N-dodecanoylglycyl)-2-[(N-dodecanoyl-N-methylglycyl)amino]-α-D-glucopyranoside

In a mixture of 50 ml of tetrahydrofuran and 2.5 ml of water, dissolve 424 mg of the compound prepared in 2) above, and add 0.2 g of platinum dioxide to it, then mix under hydrogen gas for 2 hours. Remove the catalyst by filtering and wash the filter cake with a mixture (lower layer) of chloroform, methanol and water 8:3:1 (v/v). We combine the filtrate and the washing liquid and remove the solvent from it by distillation under reduced pressure. The residue is purified by thin-layer chromatography using a mixture of chloroform, methanol and water 6:4:0.7 (v/v) as a solvent and then treated with a highly acidic ionic resin, Dowex 50 (type H+), manufactured by Dow Chemical Co., Ltd. The solvent is removed by distillation under reduced pressure and the residue is suspended in dixane. With lyophilization of the suspension, we obtain 204 mg of the title compound as a white powder. Melting point 165 to 170°C (gradually colored and turned into a gel).

[α]D25 : +4.6° (c = 0.7, chloroform : methanol = 3:1 (v/v))

IR νmax KBr cm-1: 3400, 2930, 2850, 1750, 1675, 1650

NMR-(CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 1.30 (s), 2.29 (4H, m), 2.44 (4H, t), 2.94 and 3.11 (together 6H, each s) , 4.84 (1H, d), 5.18 (1H, m), 5.34 (1H, m).

Part of the obtained product is dissolved in a mixture of chloroform and methanol 3:1 (v/v) and the solution is adjusted with triethylamine to a pH value of about 9, and evaporated under reduced pressure. Dissolve the residue in a 0.1% aqueous solution of triethylamine, then filter through a millipore filter. The filtrate is lyophilized and the triethylamine salt of the title compound is obtained as a white powder.

Example 2

1) Preparation of 2-(diphenylphosphonoxy)ethyl-2-deoxy-6-O-[2-deoxy-4-O-diphenylphosphono-3-O-(N-dodecanoylglycyl)-6-O-(2,2,2- trichloroethoxycarbonyl)-2-(2,2,2-trichloroethoxycarbonylamino)-β-D-glucopyranosyl]-2-[6-(octanoylamino)hexanoylamino]-3-O-tetradecanoyl-α-D-glucopyranoside

In the same way as in example 1-1), we separate 445 mg of 1-O-acetyl-2-deoxy-4-O-diphenylphosphono-3-O-(N-dodecanoyl glycyl)-6-O-(2,2,2 -trichloroethoxycarbonyl)-2-(2,2,2-trichloroethoxy-carbonylamino)-D-glycopyranose and 385 mg of 2-(diphenyl-phosphonoxy)ethyl-2-deoxy-2-[6-(octanoylamino)hexanoylamino]-3- O-tetradecanoyl-α-D-glucopyranoside, where

we obtain 650 mg of the title compound as an oily substance.

[α]D25 : +22.2° (c = 1.0, chloroform)

2) Preparation of 2-(diphenylphosphonoxy)ethyl-2-deoxy-6-O-[2-deoxy-4-O-diphenylphosphono-3-O-(N-dodecanoylglycyl)-2-

tetradecanoyl-amino-β-D-glucopyranosyl]-2-[6-(octanoylamino)hexanoylamino]-3-O-tetradecanoyl-α-D-glucopyranoside

Dissolve 620 mg of the compound prepared in 1) above in 10 ml of acetic acid, suspend 1.5 g of zinc powder in it, and stir for 3 hours at room temperature. If there are insoluble substances, separate them by filtration, remove the solvent by distillation under reduced pressure and dissolve the rest in chloroform. The solution is washed sequentially with 1 N hydrochloric acid, 5% aqueous sodium hydrogencarbonate solution and water and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure and the residue is dissolved in 10 ml of anhydrous tetrahydrofuran. 98 mg of tetradecanoic acid, 58 mg of 1-hydroxybenzotriazole and 90 mg of dicyclohexylcarbodiimide are added to the solution while cooling with ice, and the temperature of the liquid is slowly raised to room temperature, and stirred overnight. The precipitated insoluble substance is removed by filtration and the filtrate is evaporated under reduced pressure. The remaining solid substance is purified by chromatography on a silica gel column using as an eluent a mixture of chloroform and acetone 10:1 (v/v) and then a mixture of chloroform and methanol 30:1 (v/v) and then removing acetonitrile, whereby we obtain 428 mg of the title compound as a white powder. Melting point 105 to 107°C.

[α]D25 : +24.7° (c = 1.0, chloroform)

3) Preparation of 2-phosphonooxyethyl-2-deoxy-6-O-[2-deoxy-4-O-phosphono-3-O-(N-dodecanoylglycyl)-2-tetradecanoylamino-β-D-glucopyranosyl]-2-[ 6-(octanoylamino)hexanoylamino]-3-O-tetradecanoyl-α-D-glucopyranoside

In the same way as in example 1-3), we separate 350 mg of the compound, prepared in 2) above, where we obtain 162 mg of the title compound as a white powder. Melting point 169 to 172ºC (colors and turns into a gel).

[α]D25 : +19.5° (c = 0.6, chloroform : methanol = 3:1 (v/v))

IR νmax KBr cm-1: 3405, 2925, 2855, 1740, 1645, 1560, 1460

NMR-(CDCl3), δ (ppm): 0.90 (12H, t), 1.30 (s), 2.1-2.4 (10H, m), 3.19 (2H, t), 5.17 (1H, t), 5.38 (1H, t).

We process the resulting compound in the same way as in example 1-3), where we obtain the triethylamine salt of the title compound as a white powder.

Example 3

1) Preparation of 2-(diphenylphosphonoxy)ethyl-2-deoxy-6-O-[2-deoxy-4-O-diphenylphosphono-3-O-(4-oxotetradecanoyl) 6-O-(2,2,2-tri -chloroethoxycarbonyl)-2-(2,2,2-trichloroethoxycarbonyl-amino)-β-D-glucopyranosyl]-3-O-(4-oxotetradecanoyl)-2-tetra-decanoylamino-α-D-glucopyranoside

In the same way as in example 1-1), we separate 435 mg of 1-O-acetyl-2-deoxy-4-O-diphenylphosphono-3-O-(4-oxotetradecanoyl)-6-O-(2,2, 2-trichloroethoxycarbonyl)-2-(2,2,2-trichloroethoxycarbonylamino)-D-glucopyranose and 380 mg of 2-(diphenylphosphonoxy)ethyl-2-deoxy-3-O-(4-oxotetradecanoyl)-2-tetradecanoylamino-α -D-glucopyranoside, whereby we obtain 516 mg of the title compound as an oily substance.

[α]D25 : +14.7° (c = 0.03, chloroform)

2) Preparation of 2-(diphenylphosphonoxy)ethyl-2-deoxy-6-O-[2-deoxy-4-O-diphenylphosphono-3-O-(4-oxotetradecanoyl)-2-tetra-

decanoylamino-β-D-glucopyranosyl]-3-O-(4-oxotetradecanoyl)-2-tetra-decanoylamino-α-D-glucopyranoside

Dissolve 510 mg of the compound prepared in 1) above in 5 ml of acetic acid, suspend 0.5 g of zinc powder in the solution, and stir for 1.5 hours at room temperature. The insoluble substance is removed by filtration and the filtrate is distilled under reduced pressure. The resulting residue is diluted with chloroform, washed sequentially with 1 N hydrochloric acid, 5% aqueous sodium hydrogencarbonate solution and water, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The obtained oily substance is dissolved in 2 ml of anhydrous methylene chloride and 88 mg of tetradecanoyl chloride and 2 ml of N-methylmorpholine are added to the solution while cooling with ice. Stir the mixture for 30 minutes at the same temperature. Dilute the reaction mixture with chloroform, wash with 1 N hydrochloric acid and water, and dry over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure and the residue is purified by chromatography on a silica gel column using chloroform as an eluent and then a mixture of chloroform and methanol 20:1 (v/v), whereby we obtain 229 mg of the title compound as an oily substance.

[α]D25 : +17.3° (c = 0.2, chloroform)

3) Preparation of 2-phosphonooxyethyl-2-deoxy-6-O-[2-deoxy-4-O-phosphono-3-O-(4-oxotetradecanoyl)-2-tetradecanoylamino-β-

D-glucopyranosyl]-3-O-(4-oxotetradecanoyl)-2-tetradecanoyl-amino-α-D-glucopyranoside

In the same way as in example 1-3), we partition and process 225 mg of the compound, prepared in 2) above, where we obtain 91 mg of the title compound as a white powder. Melting point 166 to 170ºC (colors and becomes a gel).

IR νmax KBr cm-1: 3406, 2926, 2854, 1710, 1662, 1557, 1470

NMR-(CDCl3-CD3OD), δ (ppm): 0.88 (12H, t), 1.26 (s), 2.2 (4H, m), 2.54 (4H, t), 2.64 (4H, m), 2.76 (4H, m), 5.16 (1H, t), 5.30 (1H, t).

We process the resulting compound in the same way as in example 1-3), where we get the triethylamine salt as a white powder.

Example 4

1) Preparation of benzyloxycarbonylmethyl-2-deoxy-6-O-[2-deoxy-4-O-diphenylphosphono-3-O-(N-dodecanoylglycyl)-6-O-(2,2,2-tri-chloroethoxycarbonyl)- 2-(2,2,2-trichloroethoxycarbonylamino)-β-D-glucopyranosyl]-3-O-tetradecanoyl-2-tetradecanoylamino-α-D-glucopyranoside

In the same way as in example 1-1), we partition 303 mg of 1-O-acetyl-2-deoxy-4-O-diphenylphosphono-3-O-(N-dodecane oilglycyl)-6-O-(2,2,2 -trichloroethoxycarbonyl)-2-(2,2,2-trichloroethoxy-carbonylamino)-D-glucopyranose and 217 mg of benzyl oxycarbonyl-methyl-2-deoxy-3-O-tetradecanoyl-2-tetradecanoylamino-α-D-glucopyranoside, at from which we obtain 408 mg of the title compound as an oily substance.

[α]D25 : +25.8° (c = 1.0, chloroform)

2) Preparation of benzyloxycarbonylmethyl-2-deoxy-6-O-[2-deoxy-4-O-diphenylphosphono-3-O-(N-dodecanoylglycyl)-2-

tetradecanoyl-amino-β-D-glucopyranosyl]-3-O-tetradecanoyl-2-tetradecanoyl-amino-α-D-glucopyranoside

In the same way as in example 1-2), 389 mg of the compound, prepared in 1) above, is partitioned with tetradecanoic acid, whereby we obtain 293 mg of the title compound as an oily substance.

[α]D25 : +28.4° (c = 1.1, chloroform)

3) Preparation of carbonylmethyl-2-deoxy-6-O-[2-deoxy-3-O-(N-dodecanoylglycyl)-4-O-phosphono--2-tetradecanoylamino-β-D-

glucopyranosyl]-3-O-tetradecanoyl-2-tetradecanoylamino-α-D-glucopyranoside

In a mixture of 40 ml of tetrahydrofuran and 1 ml of water, dissolve 278 mg of the compound prepared in 2) above, add 0.3 g of 5% palladium on charcoal, and mix under gaseous hydrogen for 1 hour. Then we add 150 mg of platinum dioxide and mix under hydrogen gas for another 2.5 hours. Filter off the catalyst and distill the filtrate to remove the solvent. The residue was purified by thin-layer chromatography using as the lower layer chloroform, methanol and water 8:3:1 (v/v) as solvents and then treated with a strongly acidic ion resin, Dowex 50 (type H+). The active fraction is distilled to remove the solvent and the residue is suspended in dioxane. The suspension is lyophilized, whereupon we obtain 68 mg of the title compound as a white powder. Melting point 150 to 155°C (colors and becomes a gel).

IR νmax KBr cm-1: 3400, 2925, 2855, 1745, 1650, 1470

NMR-(CDCl3), δ (ppm): 0.90 (12H, t), 1.30 (s), 2.1-2.4 (8H, m), 4.82 (2H, m), 5.22 (1H, t), 5.37 (1H, t).

Example 5

1) Preparation of allyl-2-deoxy-6-O-[2-deoxy-4-O-diphenylphosphono-3-O-(N-dodecanoylglycyl)-6-O-(2,2,2-trichloroethoxy

carbonyl)-2-(2,2,2-trichloroethoxycarbonylamino)-β-D-glucopyranosyl]-3-O-tetradecanoyl-2-tetradecanoylamino-α-D-glucopyranoside

In the same way as in example 1-1), we separate 2.00 g of 1-O-acetyl-2-deoxy-4-O-diphenylphosphono-3-O-(N-dodecanoylglycine)-6-O-(2,2,2- trichloroethoxycarbonyl)-2-(2,2,2-trichloroethoxy-carbonylamino)-D-glucopyranose and 1.23 g of allyl-2-deoxy-3-O-tetradecanoyl-2-tetradecanoylamino-α-D-glucopyranoside, which gives 2.65 g of the title compound as a caramel-like substance.

[α]D25 : +27.2° (c = 1.4, chloroform).

2) Preparation of allyl-2-deoxy-6-O-[2-deoxy-4-O-diphenylphosphono-3-O-(N-dodecanoylglycyl)-2-tetradecanoylamino-β-D-

glucopyranosyl]-3-O-tetradecanoyl-2-tetradecanoylamino-α-D-gluco-pyranoside

In the same way as in example 1-2), 2.65 g of the compound, prepared in 1) above, is partitioned with tetradecanoic acid, whereby we obtain 2.25 g of the title compound as a caramel-like substance.

[α]D25 : +21.8° (c = 0.9, chloroform).

3) Preparation of allyl-6-O-[6-O-benzyloxymethyl-2-deoxy-4-O-diphenylphosphono-3-O-(N-dodecanoylglycyl)-2-tetradecanoyl-

amino-β-D-glucopyranosyl]-2-deoxy-3-O-tetradecanoyl-2-tetradecanoylamino-α-D-glucopyranoside

In 25 ml of anhydrous methylene chloride, dissolve 870 mg of the compound prepared in 2) above, and add 0.82 ml of benzyloxymethylene chloride and 1.00 ml of diisopropylethylamine, then mix for 1 night at room temperature. Add 0.16 ml of benzyloxymethyl chloride and 0.20 ml of diisopropylethylamine to the mixture and stir the mixture for another 3 hours. The reaction mixture was washed sequentially with 1 N hydrochloric acid, 5% aqueous sodium hydrogen carbonate solution and water. The organic layer is dried over anhydrous magnesium sulfate. We remove the solvent by distillation under reduced pressure and add acetone to the residue. The precipitated white powder is collected by filtration. Dissolve the powder in chloroform, purify it by chromatography on a silica gel column using as an eluent a mixture of chloroform and ethyl acetate 10:1 (v/v), then a mixture of chloroform and ethyl acetate 5:1 (v/v) and finally chloroform and acetone 20:1 (v/v) and then remove the acetonitrile, whereupon we obtain 505 mg of the title compound as a white powder. Melting point 155 to 157°C.

[α]D25 : +32.4° (c = 1.2, chloroform).

4) Preparation of 6-O-benzyloxymethyl-2-deoxy-4-O-diphenylphosphono-3-O-(N-dodecanoylglycyl)-2-tetradecanoylamino-β-D-

gluco-pyranosyl-2-deoxy-3-O-tetradecanoyl-2-tetradecanoylamino-α-D-glucopyranoside

In 15 ml of anhydrous tetrahydrofuran, dissolve 480 mg of the compound prepared in 3) above. After replacing the air with gaseous nitrogen, add 10 mg of 1,5-cyclooctadienebis-(methyldiphenylphosphine)iridium hexafluorophosphate to the solution. We evacuate the system again, replace air instead of gaseous nitrogen and then air with gaseous hydrogen. When the red color of the iridium complex disappears, replace the air again with nitrogen and stir the mixture for 2.5 hours while maintaining the temperature at 50°C. After that, when we allowed the reaction mixture to cool, we added 5 ml of water and then 180 mg of iodine, then stirred for 20 minutes at room temperature. Add a 5% aqueous solution of sodium trisulfate to the reaction mixture until the iodine color disappears. The reaction mixture is extracted with chloroform, the organic layer is separated, washed with water and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure, the residue is purified by chromatography on a silica gel column using as eluent a mixture of chloroform and acetone 10:1 (v/v) and chloroform and methanol 50:1 (v/v), and then acetonitrile is removed, at of which we obtain 320 mg of the title compound as a white powder. Melting point 155 to 156°C.

[α]D25 : +17.1° (c = 0.7, chloroform).

5) Preparation of 2-deoxy-6-O-[2-deoxy-3-O-(N-dodecanoylglycyl)-4-O-phosphono-2-tetradecanoylamino-β-D-glucopyranosyl]-

1-O-phosphono-3-O-tetradecanoyl-2-tetradecanoylamino-α-D-gluco-pyranoside

Dissolve 170 mg of the compound prepared in 4) above in 15 ml of anhydrous tetrahydrofuran. After replacing the air with gaseous nitrogen and cooling to about -70°C, add a hexane solution containing 0.16 mmol of n-butyllithium. After 5 minutes, add a benzene solution containing 0.16 mmol of dibenzylphosphono-chloridate, then stir for another 30 minutes at -50°C. Add 100 mg of palladium black and 85 mg of 5% palladium on charcoal to the reaction mixture, then mix overnight under a stream of hydrogen. The catalyst is separated by filtration and the filtrate is distilled under reduced pressure. The obtained residue is dissolved in 150 ml of tetrahydrofuran and 0.27 g of platinum oxide is added to the solution. The mixture is stirred for 4 hours under a stream of hydrogen, then filtered to extract the catalyst. The filtrate is distilled under reduced pressure to remove the solvent, the residue is purified by thin-layer chromatography using a mixture of chloroform, methanol and water 6:4:0.7 (v/v) as solvents and then treated with a highly acidic ionic resin, Dowex 50 (type H+). Add 40 μl of triethylamine to the resulting fraction and distill under reduced pressure. The residue is suspended in dioxane and the suspension is lyophilized, which gives 38 mg of the triethylamine salt of the title compound as a white powder. Melting point 148 to 150°C (colors and becomes a gel).

[α]D25 : +10.1° (c = 0.6, chloroform : methanol = 3:1 (v/v))

IR νmax KBr cm-1: 3400, 2925, 2855, 2680, 2500, 1745, 1645, 1550, 1470, 1385, 1040

NMR(CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 1.28 (s), 2.1-2.5 (8H, m), 3.1-3.3 (12H, ext.).

Example 6

1) Preparation of 2-(diphenylphosphonoxy)ethyl-2-deoxy-6-[2-deoxy-4-O-diphenylphosphono-3-O-(N-dodecanoylglycyl)-6-O-(2,2,2-tri- chloroethoxycarbonyl)-2-(2,2,2-trichloroethoxycarbonylamino)-β-D-glucopyranosyl]-4-O-diphenylphosphono-3-O-(N-dodecanoyl-glycyl)-2-[(N-dodecanoyl-N- methylglycyl)amino]-α-D-gluco-pyranoside

In 5 ml of anhydrous methylene chloride, dissolve 500 mg of the compound prepared in example 1-1), and add at room temperature 0.04 ml of pyridine, 139 mg of diphenylphosphorochloridate and 64 mg of 4-dimethylaminopyridine in that order, then mix overnight. Dilute the reaction mixture with methylene chloride, wash in order with 10% aqueous hydrochloric acid solution, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution and dry over anhydrous magnesium sulfate. The solvent is removed from the mixture by distillation under reduced pressure and the residue is purified on a silica gel column using a mixture of chloroform and methanol 40:1 (v/v) as eluent, whereby 368 g of the title compound are obtained as an oily substance.

[α]D25 : +21.9° (c = 0.8, chloroform).

2) Preparation of 2-(diphenylphosphonoxy)ethyl-2-deoxy-6-O-(2-deoxy-4-O-diphenylphosphono)-3-O-(N-dodecanoylglycyl)-2-[N-

dodecanoyl-N-methylglycyl)amino]-β-D-glucopyranosyl-4-O-diphenylphosphono-3-O-(N-dodecanoylglycyl)-2-[(N-dodecanoyl-N-methylglycyl)amino]-α-D- glucopyranoside

In the same way as in example 1-2) 350 mg of the compound obtained in 1) above is treated with zinc powder in an acetic acid solution and then partitioned with N-dodecanoyl-N-methylglycine, whereupon we obtain 244 mg of the title compound as an oily substance .

[α]D25 : +3.5° (c = 0.6, chloroform).

d) Preparation of 2-phosphonooxyethyl)-2-deoxy-6-O-(2-deoxy-3-O-(N-dodecanoylglycyl)-2-[N-dodecanoyl-N-methylglycyl)amino]-4-O-phosphono -β-glucopyranosyl)-3-O-(N-dodecanoylglycyl)-2-[(N-dodecanoyl-N-methylglycyl)amino]-4-O-phosphono-α-D-gluco-pyranoside

In the same way as in example 1-3), 238 mg of the compound obtained in 2) above are subjected to catalytic reduction, whereupon we obtain 101 mg of the title compound as a white powder. Melting point 184 to 189°C (colors and becomes a gel).

[α]D25 : -4.3° (c = 0.6, chloroform : methanol = 3:1 (v/v))

IR νmax KBr cm-1: 3280, 2900, 1740, 1660, 1540

NMR(CDCl3-CD3OD), δ (ppm): 0.89 (12H, t, J=7.0 Hz), 1.28 (bt. s), 1.62 (8H, bt.), 2.24-2.31 (4H, m), 2.40- 2.42 (4H, m), 2.91-2.96, 3.09, 3.12 (together 6H, each s), 4.84 (1H, d), 5.19 (1H, t), 5.31 (1H, t).

Example 7

1) Preparation of 2-(diphenylphosphonoxy)ethyl-3-O-[(R)-benzyloxy-tetradecanoyl]-2-[(R)-3-benzyloxytetradecanoylamino]-2-

deoxy-6-O-(2-deoxy-4-O-diphenylphosphono-6-O-(2,2,2-tri-chloroethoxycarbonyl)-2-(2,2,2-trichloroethoxycarbonylamino)-3-O-[ (R)-3-(2,2,2-trichloroethoxycarbonyloxy)tetradecanoyl]-β-glucopyranosyl)-α-D-glucopyranoside

In the same way as in example 1-1) 409 mg of 1-O-acetyl-2-deoxy-4-O-diphenylphosphono-6-O-(2,2,2-trichloroethoxy-carbonyl)-2-(2,2 ,2-trichloroethoxycarbonylamino)3-O-[(R)-3-(2,2,2-trichloroethoxycarbonyloxy)tetradecanoyl]-D-glucopyranose is partitioned with hydrogen bromide, whereby an oily substance is obtained, and the obtained oily substance is partitioned with 370 mg 2-(diphenylphosphonoxy)ethyl-3-O-[(R)-benzyloxytetradecanoyl]-2-[(R)-3-benzyloxytetradecanoylamino]-2-deoxy-α-gluco-pyranoside in the presence of mercury(II) cyanide, where 577 mg of the title compound are obtained as a pale red viscous oily substance.

[α]D25 : +20.2° (c = 0.2, chloroform)

2) Preparation of 2-(diphenylphosphonoxy)ethyl-3-O-[(R)-3-benzyloxy-tetradecanoyl]-2-[(R)-3-benzyloxytetradecanoylamino]-2-

deoxy-6-O-(2-deoxy-4-O-diphenylphosphono-3-O-[(R)-3-hydroxy-tetradecanoyl]-2-[(R)-3-3-hydroxytetradecanoylamino]-β-D -glucopyranosyl)-α-D-glucopyranoside

In the same way as in example 1-2), 555 mg of the compound, prepared in 1) above, is treated with zinc powder in an acetic acid solution and the reaction product is partitioned with 93 mg of (R)-3-hydroxytetradecanoic acid, whereupon we obtain 312 mg of the title compound as a colorless oily substance.

[α]D25 : +6.3° (c = 0.7, chloroform).

3) Preparation of 2-phosphonoxyethyl-2-deoxy-6-O-(2-deoxy-3-O-[(R)-3-hydroxytetradecanoyl]-2-[(R)-3-hydroxytetradecanoyl]

decanoylamino]-4-O-phosphono-β-D-glucopyranosyl)-3-O-[(R)-3-hydroxytetradecanoyl]-2-[(R)-3-3-hydroxytetradecanoylamino]-α-D- glucopyranoside

In the same way as in example 4-3), 294 mg of the compound, prepared in 2) above, is catalytically reduced in the presence of a 5% palladium catalyst on charcoal, whereupon the title compound is obtained. The compound is treated with a 0.1% aqueous solution of triethylamine, whereupon we obtain 76 mg of the triethylamine salt of the title compound as a white powder. We treat part of the product with a strongly acidic ion resin, where we get the title compound in simple form as a white powder.

The following information applies to a simple connection.

[α]D25 : -1.8° (c = 0.5, chloroform : methanol = 3:1 (v/v))

Melting point 155 to 158°C (colors and becomes a gel)

IR νmax KBr cm-1: 3440, 2930, 2860, 1740, 1660

NMR(CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 2.3-2.5 (8H, m), 5.2 (2H, t).

Example 8

1) Preparation of 2-(diphenylphosphonoxy)ethyl-4-O-[3-(benzyloxy-carbonyl)propionyl]-2-deoxy-6-O-[2-deoxy-4-O-diphenyl-

phosphono-3-O-(N-dodecanoylglycyl)-6-O-(2,2,2-trichloroethoxy-carbonyl)-2-(2,2,2-trichloroethoxycarbonylamino)-β-D-gluco-pyranosyl]-3 -O-(N-dodecanoylglycyl)-2-tetradecanoylamino-α-D-glucopyranoside

In 6 ml of anhydrous methylene chloride, dissolve 483 mg of 2-(diphenylphosphonoxy)ethyl-2-deoxy-6-O-[2-deoxy-4-O-diphenyl-phosphono-3-O-(N-dodecanoylglycyl)-6-O- (2,2,2-trichloroethoxy-carbonyl)-2-(2,2,2-trichloroethoxycarbonylamino)-β-D-gluco-pyranosyl]-3-O-(N-dodecanoylglycyl)-2-tetradecanoylamino-α-D -glucopyranoside and add 108 mg of monobenzyl succinate and 16 mg of dimethylaminopyridine to the solution. Add 107 mg of dicyclohexylcarbodiimide to the solution while cooling with ice. The temperature of the liquid is raised to room temperature and the mixture is stirred for 1 hour. The insoluble substance is removed by filtration, the filtrate is washed with 1 N hydrochloric acid and dried over anhydrous sodium sulfate. The solvent is separated by distillation under reduced pressure and the residue is purified by chromatography on a silica gel column using chloroform containing 10% acetone and then chloroform containing 3% methanol as eluent, whereupon we obtain 113 mg of the title compound as an oily substance.

[α]D25 : +35.6° (c = 1.1, chloroform)

2) Preparation of 2-(diphenylphosphonoxy)ethyl-4-O-[3-(benzyloxy-carbonyl)propionyl]-2-deoxy-6-O-[2-deoxy-4-O-diphenyl-

phosphono-3-O-(N-dodecanoylglycyl)-2-tetradecanoylamino)-β-D-glucopyranosyl]-3-O-(N-dodecanoylglycyl)-2-tetradecanoyl-amino-α-D-glucopyranoside

In the same way as in example 1-2), 327 mg of the compound, prepared in 1) above, is treated with zinc powder in an acetic acid solution and the product is partitioned with tetradecanoic acid, whereupon we obtain 226 mg of the title compound as an oily substance.

[α]D25 : +29.6° (c = 1.2, chloroform)

3) Preparation of 2-phosphonooxyethyl-4-O-(3-carboxypropionyl)-2-deoxy-6-O-[2-deoxy-3-O-(N-dodecanoylglycyl)-4-O-phosphono-

2-tetradecanoylamino)-β-D-glucopyranosyl]-3-O-(N-dodecanoyl-glycyl)-2-tetradecanoylamino-α-D-glucopyranoside

In the same way as in example 4-3) we separate 204 mg of the compound prepared in 2) above, with chaga we get 97 mg of the title compound as a white powder. Melting point 150 to 155°C (colors and becomes a gel).

[α]20 : +24.4° (c = 0.5, chloroform : methanol = 3:1 (v/v))

IR νmax KBr cm-1: 3300, 2925, 2855, 1755, 1660, 1555

NMR(CDCl3-CD3OD), δ (ppm): 0.89 (12H, t), 1.27 (s), 2.2-2.3 (8H, m), 2.6-2.7 (4H, m), 4.18 (2H, m), 4.27 (2H, m), 4.61 (1H, d), 4.82 (1H, d), 5.06 (1H, t), 5.24 (1H, t), 5.30 (1H, t).

Examples 9 to 81

In the same way as described in examples 1 to 8, let's prepare the fatty compounds of formula (Ia).

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The physical properties of the compounds of examples 9 to 81 are as follows:

Example no. Physical properties

9 melting point: 140-150°C (colored and similar to gel)

[α]D25: +13.3° (c=0.6, chloroform:methanol =3:1 (v/v))

IR υKBrmax cm-1: 3400, 2930, 2855, 1750, 1660, 1560

NMR 9CDCl3-CD3OD), δ(ppm): 0.90 (12H, t), 1.32 (s),

2.1-2.3 (8H, m), 5.10 (1H, t), 5.38 (1H, t)

10 melting point: 174-180°C (colored and gel-like)

[α]D25: +11.8° (c=0.7, chloroform:methanol = 1:1 (v/v))

IR υKBrmax cm-1: 3425, 2930, 2854, 1745, 1675, 1470

NMR (CDCl3-CD3OD), δ (ppm): 0.89 (12H, t), 1.28 (s)

2.27 (2H, t), 2.4-2.8 (12H, m), 2.93 (2H, m), 4.81 (1H, m)

5.14 (1H, t), 5.32 (1H, m)

11 mp: 159-167°C (colored and gel-like)

[α]D25: +10.2° (c=0.6, chloroform:methanol = 1:1 (v/v))

IR υKBrmax cm-1: 3330, 2925, 2855, 1745, 1655, 1560, 1470, 1025

NMR (CDCl3-CD3OD), δ (ppm): 0.89 (12H, t), 1.27 (s),

2.20 (6H, m), 2.46 (2H, t), 2.6-2.8 (4H, m), 3.25 (2H, m),

3.63 (1H, m), 3.71 (1H, m), 3.90 (8H, m), 4.18 (4H, m),

4.76 (1H, d), 5.13 (1H, t), 5.24 (5H, t)

12 melting point: 165-171°C (colored and gel-like)

[α]D25: +9.0° (c=0.6, chloroform:methanol = 1:1 (v/v))

IR υKBrmax cm-1: 3320, 2925, 2855, 1710, 1645, 1555, 1470

NMR (CDCl3-CD3OD), δ (ppm): 0.89 (12H, t), 1.27 (s),

2.17 (6H, m), 2.47 (4H, m), 2.60 (4H, m), 2.73 (4H, m),

4.25 (1H, q), 4.75 (1H, d), 5.12 (1H, t), 5.25 (1H, t)

13 melting point: 169-173°C (colored and gel-like)

[α]D25: +9.0° (c=0.7, chloroform:methanol = 1:1 (v/v))

IR υKBrmax cm-1: 3425, 2925, 2855, 1735, 1645, 1555

NMR (CDCl3-CD3OD), δ (ppm): 0.9. (12H, t), 2.2-2.4 (10H, m),

3.18 (2H, t), 5.16 (1H, t), 5.36 (1H, t)

14 melting point: 161-165°C (colored and gel-like)

[α]D25: +9.2° (c=0.6, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3405, 2930, 2855, 1760, 1660, 1550

NMR (CDCl3-CD3OD), δ (ppm): 0.9. (12H, t), 2.2-2.5 (8H, m),

2.96 and 3.04 (total 6H, each s), 5.18 (1H, t), 5.34 (1H, t)

15 melting point: 144-147°C (colored and gel-like)

[α]D25: -2.4° (c=0.8, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3405, 2925, 2855, 1745, 1655, 1555

NMR (CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 2.1-2.5 (8H, m),

2.82 and 3.02 and 3.04 together 6H, each (s), 4.88 (1H, d),

5.16 (1H, t), 5.29 (1H, t)

16 melting point: 150-154°C (colored and gel-like)

[α]D25: +16.8° (c=0.6, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3450, 2930, 2860, 1745, 1675, 1470

NMR (CDCl3-CD3OD), δ (ppm): 0.88 (12H, t), 1.26 (width),

2.3-2.8 ((18H, m), 2.96 and 3.10 and 3.18 (together 6H, each s),

5.16 (1H, m), 5.34 (1H, m)

17 melting point: 190-193°C (colored and gel-like)

[α]D25: +16.8° (c=0.7, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3305, 2925, 2855, 1750, 1650

NMR (CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 2.1-2.4 (8H, m),

5.16 (1H, t), 5.38 (1H, t)

18 melting point: 175-177°C (colored and gel-like)

[α]D25: -2.2° (c=0.8, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3310, 2925, 2855, 1745, 1660, 1555

NMR (CDCl3-CD3OD), δ (ppm): 0.89 (12H, t), 2.1-2.4 (8H, m),

5.18 (1H, t), 5.32 (1H, t)

19 melting point: 145-150°C (colored and gel-like)

[α]D25: +1.7° (c=0.6, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3300, 2925, 2855, 1755, 1685, 1645, 1555

NMR (CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 1.30 (s),

2.29 (4H, t), 2.48 (4H, t), 4.73 (1H, d), 4.84 (1H, d),

5.19 (1H, t), 5.32 (1H, t)

20 melting point: 165-168°C (colored and gel-like)

[α]D25: +10.2° (c=0.5, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3310, 2930, 2865, 1735, 1645, 1555

NMR (CDCl3-CD3OD), δ (ppm): 0.90 (t-width), 1.30 (s),

2.20 (12H, t), 2.36 (4H, m), 3.19 (8H, t), 4.68 (1H, d),

4.79 (1H, d), 5.16 (1H, t), 5.24 (1H, t)

21 melting point: 178-183°C (colored and gel-like)

[α]D25: +10.2° (c=0.5, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3315, 2925, 2855, 1735, 1660, 1570

NMR (CDCl3-CD3OD), δ (ppm): 0.88 (12H, t), 1.26 (s),

2.20 (8H, m), 5.18, 2.56 (4H, m)(1H, t), 5.30 (1H, t)

22 melting point: 151-160°C (colored and gel-like)

[α]D25: +2.4° (c=0.3, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3350, 2925, 2855, 1750, 1647, 1555

NMR (CDCl3-CD3OD), δ (ppm): 0.88 (12H, t), 1.26 (s),

2.2-2.7 (16H, m), 5.18 (1H, t), 5.30 (1H, t)

23 melting point: 160-164°C (colored and gel-like)

[α]D25: +14.5° (c=0.7, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3330, 2930, 2860, 1755, 1660, 1565

NMR (CDCl3-CD3OD), δ (ppm): 0.90 912H, t), 1.32 (s),

2.1-2.3 (8H, m), 5.10 (1H, t), 5.38 (1H, t)

24 melting point: 168-174°C (colored and gel-like)

[α]D25: +6.6° (c=0.3, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3315, 2930, 2860, 1760, 1660, 1555

NMR (CDCl3-CD3OD), δ (ppm): 0.88 (12H, t), 1.26 (s),

2.1-2.8 (20H, m), 5.20 (1H, t), 5.34 (1H, t)

25 melting point: 160-170°C (gradually colored and gel-like)

[α]D25: +21.7° (c=0.6, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3450, 2930, 2860, 1760, 1675, 1470

NMR (CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 1.32 (s),

2.43 (8H, m), 2.96 and 3.08 and 3.16 (together 12H each m, s, s),

4.87 (2H, m), 5.20 (1H, m), 5.47 (1H, m)

26 melting point: 166-170°C (colored and gel-like)

[α]D25: +10.6° (c=1.0, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3330, 2925, 2855, 1745, 1660, 1560

NMR (CDCl3-CD3OD), δ (ppm): 0.88 (12H, t), 1.26 (s),

2.1-2.4 (8H, m), 3.5-3.8 (4H, m), 3.94 (6H, m), 4.20 (4H, m),

4.79 (1H, d), 5.19 (1H, t), 5.25 (1H, t)

27 melting point: 160-162°C (colored and gel-like)

[α]D25: +12.9° (c=0.7, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3320, 2925, 2855, 1730, 1655, 1565

NMR (CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 2.18 (8H, m),

2.36 (4H, m), 3.20 (4H, m), 4.78 (1H, d), 5.2 (2H, m)

28 melting point: 162-165°C (colored and gel-like)

[α]D25: +10.7° (c=0.6, chloroform:methanol:water = 8:3:1 (v/v)

bottom layer)

IR υKBrmax cm-1: 3315, 2925, 2860, 1760, 1645, 1555

NMR (CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 2.1-2.4 (12H, m),

3.1-3.3 (4H, t), 5.20 (1H, t), 5.37 (1H, t)

29 melting point: 160-164°C (colored and gel-like)

[α]D25: +14.1° (c=0.7, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 341, 2925, 2855, 1750, 1645, 1560

NMR (CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 2.1-2.4 (8H, m),

5.18 (1H, t), 5.38 (1H, t)

30 melting point: 165-168°C (colored and gel-like)

[α]D25: +8.1° (c=0.7, chloroform:methanol:water = 6:4:1 (v/v))

IR υKBrmax cm-1: 3315, 3100, 2925, 2855, 1745, 1660, 1565

NMR (CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 2.2-2.5 (12H, m),

4.81 (1H, d), 5.19 (1H, t), 5.35 (1H, t)

31 mp: 177-185°C (gradually colored and gel-like)

[α]D25: +3.7° (c=0.6, chloroform:methanol:water = 6:4:1 (v/v))

IR υKBrmax cm-1: 3315, 2930, 2855, 1750, 1660, 1560

NMR (CDCl3-CD3OD), δ (ppm): 0.88 (12H, t), 1.26 (s),

2.1-2.5 (10H, m), 5.18 (1H, t), 5.34 (1H, t)

32 [α]D25:+2.4° (chloroform:methanol:water:triethylamino = 8:3:0.5:0.01 (v/v))

NMR (CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 1.28 (s), 2.1-2.4

(8H, m), 5.16 (1H, t), 5.32 (1H, t)

33 melting point: 170-175°C (colored and gel-like)

[α]D25: +5.2° (c=0.6, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3315, 2925, 2855, 1735, 1645, 1560

NMR (CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 1.30 (s), 2.2-2.5

(8H, m), 5.20 (1H, m), 5.37 (1H, m)

34 melting point: 182-185°C (colored and gel-like)

[α]D25: +11.5° (c=0.7, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3315, 2925, 2855, 1735, 1645, 1560

NMR (CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 2.1-2.4 (12H, m),

3.1-3.3 (4H, m), 5.1-5.4 (2H, m)

35 mp.: 157-162°C (colored and gel-like)

[α]D25: +13.8° (c=0.5, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3330, 2930, 2860, 1755, 1660, 1565

NMR (CDCl3-CD3OD), δ (ppm): 0.91 (12H, t), 1.32 (s),

2.1-2.3 (8H, m), 5.10 (1H, t), 5.38 (1H, t)

36 melting point: 168-172°C (colored and gel-like)

[α]D25: +14.6° (c=1.0, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3320, 2930, 2860, 1755, 1660, 1565

NMR (CDCl3-CD3OD), δ (ppm): 0.91 (12H, t), 1.32 (width),

2.12-2.32 (8H, m), 5.18 (1H, m), 5.36 (1H, m)

37 melting point: 175-180°C (colored and similar to gel)

[α]D25: +9.9° (c=0.7, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3300, 2930, 2860, 1750, 1675, 1580, 1560

NMR (CDCl3-CD3OD), δ (ppm): 0.89 (12H, t), 1.30 (s)

2.2-2.5 (8H, m), 2.95 and 3.12 (together 9H, each m), 4.85 (1H, d),

5.18 (1H, t), 5.35 (1H, m)

38 melting point: 170-175°C (colored and similar to gel)

[α]D25: +14.9° (c=0.6, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3450, 3300, 2930, 2860, 1755, 1675, 1575

NMR (CDCl3-CD3OD), δ (ppm): 0.91 (12H, t), 1.32 (s)

2.29 (2H, m), 2.43 (6H, m), 2.94 and 3.12 (together 9H, each m),

4.83 (1H, m), 5.18 (1H, m), 5.44 (1H, m)

39 melting point: 166-174°C (colored and gel-like)

[α]D25: +9.2° (c=0.6, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3310, 2930, 2860, 1760, 1660, 1565

NMR (CDCl3-CD3OD), δ (ppm): 0.88 (12H, t), 1.26 (s), 2.1-2.4

(20H, m), 2.94 (3H, s), 3.04 (3H, s), 5.18 (1H, t), 5.36 (1H, t)

40 melting point: 170-186°C (gradually colored and gel-like)

[α]D25: +7.8° (c=1.1, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3310, 2930, 2860, 1750, 1660, 1565

NMR (CDCl3-CD3OD), δ (ppm): 0.88 (12H, t), 1.26 (s), 2.20

(8H, t), 2.43 (4H, t), 2.94 (1H, m), 3.11 (6H, s), 3.19 (4H, m),

4.81 (1H, m), 5.19 (1H, t), 5.38 (1H, t)

41 mp.: 184-186°C (colored and gel-like)

[α]D25: +6.0° (c=0.5, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3460, 1758, 1662

NMR (CDCl3-CD3OD), δ (ppm): 0.88 (12H, t), 1.26 (s), 2.1-2.5

(8H, m), 2.94, 3.12 (together 6H, s), 4.80 (1H, m), 5.18 (1H, m),

5.38 (1H, m)

42 melting point: 155-165°C (gradually colored and gel-like)

[α]D25: +8.2° (c=0.7, chloroform:methanol:water = 6:4:1 (v/v))

IR υKBrmax cm-1: 3320, 2930, 2850, 1760, 1645, 1565

NMR (CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 1.30 (s), 2.2

(12H, m), 3.18 (4H, t-width), 5.19 (1H, t), 5.36 (1H, t)

43 melting point: 165-168°C (colored and gel-like)

[α]D25: +23.6° (c=0.6, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3450, 2925, 2855, 1735, 1675, 1635

NMR (CDCl3-CD3OD), � (ppm): 0.90 (12H, t), 1.30 (s), 2.3-2.5

(8H, m), 2.92 and 2.94 and 3.07 and 3.09 (together 6H, s), 4.74 (1H, m),

4.87 (1H, d), 5.14 (1H, t), 5.38 (1H, t)

44 mp: 177-179°C (colored and similar to gel)

[α]D25: +11.7° (c=0.7, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3310, 2860, 1734, 1659, 1560

NMR (CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 2.1-2.4 (12H, m),

3.10 (4H, t), 5.1-5.3 (2H, m)

45 melting point: 145-150°C (colored and similar to gel)

[α]D25: +11.7° (c=0.8, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3300, 1760, 1665, 1555

NMR (CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 1.30 (s), 2.30

(8H, m), 4.84 (1H, d), 5.19 (1H, t), 5.33 (1H, t)

46 m.p.: 148-153°C (colored and gel-like)

[α]D25: +18.4° (c=0.9, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3300, 1745, 1645, 1555

NMR (CDCl3-CD3OD), � (ppm): 0.90 (12H, t), 1.30 (s), 2.30

(8H, m), 4.86 (1H, d), 5.16 (1H, t), 5.34 (1H, t)

47 mp.: 155-158°C (colored and gel-like)

[α]D25: +11.6° (c=1.0, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3320, 1745, 1645, 1555

NMR (CDCl3-CD3OD), δ (ppm): 0.89 (12H, t), 1.30 (s), 2.1-2.4

(12H, m), 3.18 (4H, width), 4.67 (1H, d), 5.2 (2H, m)

48 NMR (CDCl3-CD3OD), δ (ppm): 0.88 (12H, t), 1.26 (s), 1.9-2.1

(4H, m), 2.2-2.4 (8H, m), 5.16 (1H, t), 5.30 (1H, t)

49 [α]D25: +4.3° (c=0.8, chloroform:methanol = 3:1 (v/v))

NMR (CDCl3-CD3OD), δ (ppm): 0.88 (12h, t), 1.26 (s), 1.9-2.2

(4H, m), 2.2-2.4 (8H, m), 4.80 (1H, d), 5.14 (1H, t), 5.30 (1H, t)

50 [α]D25: +14.1° (c=0.7, chloroform:methanol:water = 8:3:0.5 (v/v))

NMR (CDCl3-CD3OD), δ (ppm): 0.88 (6H, t), 1.26 (s), 1.4-1.8

(m), 2.08 (4H, m), 2.34 (4H, m), 4.63 (1H, d), 4.78 (1H, d),

5.20 (2H, m)

51 [α]D25: +16.6° (c=1.0, chloroform:methanol:water = 8:3:0.5 (v/v))

NMR (CDCl3-CD3OD), δ (ppm): 0.88 (6H, t), 1.26 (s), 1.4-1.8

(m), 2.20 (4H, m), 2.36 (4H, m), 4.86 (1H, d), 5.14 (1H, t),

5.30 (1H, t)

52 mp.: 148-153°C (colored and gel-like)

[α]D25: +10.0° (c=0.7, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3320, 2925, 2855, 1745, 1645, 1565

NMR (CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 1.30 (s), 2.2-2.3

(8H, m), 4.70 (1H, d), 4.81 (1H, d), 5.16 (1H, t), 5.31 (1H, t)

53 mp.: 148-153°C (colored and gel-like)

[α]D25: +13.3° (c=0.1, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3405, 2925, 2855, 1720, 1660, 1555

NMR (CDCl3-CD3OD), δ (ppm): 0.88 (12H, t), 1.26 (width), 2.3-2.8

(24H, m), 5.16 (1H, m), 5.30 (1H, m)

54 mp.: 168-173°C (colored and gel-like)

[α]D25: +9.4° (c=0.5, chloroform:methanol:water = 6:4:1 (v/v))

IR υKBrmax cm-1: 3350, 2930, 1745, 1660, 1570

NMR (CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 1.30 (s), 2.1-2.3

(10H, m), 3.18 (2H, t), 4.78 (2H, m), 5.18 (1H, t), 5.35 (1H, t)

55 mp.: 182-188°C (colored and gel-like)

[α]D25: +11.8° (c=0.7, chloroform:methanol = 1:1 (v/v))

IR υKBrmax cm-1: 3310, 2926, 2854, 1749, 1677, 1563

NMR (CDCl3-CD3OD), δ (ppm): 0.89 (12H, t), 1.28 (s), 2.28

(4H, m), 2.4-2.8 (8H, m), 3.09, 3.13 (together 6H, each s), 3.6-4.3

(m), 4.82 (1H, d), 5.12 (1H, t), 5.34 (1H, t)

56 melting point: 160-165°C (colored and gel-like)

[α]D25: +16.8° (c=0.5, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3330, 2925, 2855, 1735, 1645, 1550

NMR (CDCl3-CD3OD), δ (ppm): 0.89 (12H, t), 1.27 (s), 2.1-2.4

(10H, m), 3.16 (12H, t), 4.27 (1H, q), 4.76 (1H, d), 4.79 (1H, d)

5.12 (1H, dd), 5.33 (1H, t)

57 mp.: 158-162°C (colored and gel-like)

[α]D25: +13.0° (c=0.4, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3328, 2926, 2854, 1749, 1659, 1563

NMR (CDCl3-CD3OD), δ (ppm): 0.89 (12H, t), 1.27 (s), 1.5-1.6

(8H, m), 2.1-2.3 (8H, m), 5.14 (1H, t), 5.32 (1H, t)

58 mp.: 168-172°C (colored and gel-like)

[α]D25: +14.2° (c=0.6, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3320, 2925, 2855, 1750, 1660, 1565

NMR (CDCl3-CD3OD), δ (ppm): 0.81 (12H, t), 1.18 (s)

1.5-1.6 (8H, m), 2.0-2.2 (8H, m), 5.05 (1H, t), 5.23 (1H, t)

59 mp.: 184-187°C (colored and gel-like)

[α]D25: +15.4° (c=0.6, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3430, 2930, 2855, 1755, 1660, 1565, 1470, 1385

60 melting point: 178-182°C (colored and gel-like)

[α]D25: +9.5° (c=0.6, chloroform:methanol = 1:1 (v/v))

IR υKBrmax cm-1: 3405, 2930, 2855, 1760, 1660, 1555, 1470, 1205,

1025

NMR (CDCl3-CD3OD), δ (ppm): 0.89 (12H, t), 1.27 (s), 1.61 (m),

2.12-2.36 (10H, m), 2.91, 3.03 (together 3H, each s), 4.77 (1H, d),

5.14 (1H, t), 5.32 (1H, t)

61 mp.: 192-198°C (colored and gel-like)

[α]D25: +7.8° (c=0.5, chloroform:methanol = 1:1 (v/v))

IR υKBrmax cm-1: 3355, 2930, 2855, 1745, 1660, 1565, 1470, 1385,

1210

NMR (CDCl3-CD3OD), δ (ppm): 0.89 (12H, t), 1.28 (s), 1.60 (m),

2.12-2.38 (10H, m), 3.16 (2H, t), 3.53 (2H, m), 3.62 (1H, m), 3.72

(1H, m), 3.90 (8H, m), 4.16 (6H, m), 4.23 (1H, q), 4.59 (1H, d),

5.15 (1H, t), 5.21 (1H, t)

62 mp.: 194-195°C (colored and gel-like)

[α]D25: +7.2° (c=0.8, chloroform:methanol = 1:1 (v/v))

IR υKBrmax cm-1: 3320, 2930, 2855, 1745, 1660, 1555, 1025

NMR (CDCl3-CD3OD), δ (ppm): 0.89 (12H, t), 1.27 (s), 1.60 (m),

2.03-2.35 (12H, m), 3.16 (5H, m), 3.50 (2H, m), 3.54 (1H, m),

3.72 (1H, m), 3.88 (2H, m), 4.15 (5H, m), 4.27 (1H, q), 4.77

(1H, d), 5.15 (1H, t), 5.23 (1H, t)

63 mp.: 177-182°C (colored and gel-like)

[α]D25: +11.6° (c=0.5, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3330, 2925, 2855, 1755, 1650, 1555, 1470

NMR (CDCl3-CD3OD), δ (ppm): 0.89 (12H, t), 1.27 (s), 2.13-2.27

(10H, m), 3.16 (2H, t), 4.74-4.77 (2H, t), 5.15 (1H, t),

5.32 (1H, t)

64 mp.: 173-177°C (colored and gel-like)

[α]D25: +9.5° (c=0.5, chloroform:methanol:water = 6:4:1 (v/v))

IR υKBrmax cm-1: 3330, 2925, 2855, 1755, 1660, 1565

NMR (CDCl3-CD3OD), δ (ppm): 0.89 (12H, t), 1.27 (s), 2.1-2.3

(10H m), 3.17 (2H, m), 4.29 (1H, q), 4.75 (1H, d), 4.77 (1H, d),

5.14 (1H, dd), 5.33 (1H, dd)

65 NMR (CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 1.26 (s), 2.1-2.5

(8H, m), 4.83 (1H, d), 5.1-5.4 (2H, m)

66 mp.: 148-151°C (colored and gel-like)

NMR (CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 1.26 (s), 2.10-2.50

(8H, m), 4.82 (1H, d), 5.1-5.3 (2H, m)

67 mp.: 166.5-168.5°C (gradually colored and gel-like)

NMR (CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 1.26 (s), 2.16

(2H, t), 2.32 (4H, m), 2.50 (2H, d), 4.82 (1H, d), 5.16 (1H, t)

5.32 (1H, t)

68 mp.: 155-158°C (colored and gel-like)

[α]D25: +1.5° (c=0.5, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3400, 2930, 2860, 1740, 1660

NMR (CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 2.3-2.5 (8H, m),

5.2 (2H, m)

69 mp: 153.5-155°C (gradually colored red and gel-like)

[α]D25: +13.3ş (c=0.6, chloroform:methanol = 9:1 (v/v))

IR υKBrmax cm-1: 3445, 2530, 1740, 1660, 1560

NMR (CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 2.1-2.26 (4H, m),

2.26-2.46 (4H, m)

70 mp.: 156-158.5°C (gradually colored red and similar to gel)

[α]D25: +16.5° (c=0.9, chloroform:methanol = 9:1 (v/v))

IR υKBrmax cm-1: 3450, 2930, 1735, 1660, 1560

NMR (CDCl3-CD3OD), δ (ppm): 0.89 (12H, t), 1.30 (s), 2.1-2.45

(8H, m), 5.20 (m)

71 mp: 148-152°C (gradually colored red and gel-like)

[α]D25: +14.5° (c=0.9, chloroform:methanol = 9:1 (v/v))

IR υKBrmax cm-1: 3450, 2930, 1745, 1650, 1560

NMR (CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 1.30 (s), 2.10-2.50

(8H, m), 5.10-5.35 (2H, m)

72 mp: 156-158.5°C (gradually colored red and similar to gel)

[α]D25: +14.1° (c=0.9, chloroform:methanol = 9:1 (v/v))

IR υKBrmax cm-1: 3350, 2930, 1730, 1660, 1560

NMR (CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 1.30 (s), 2.1-2.5

(8H, m), 5.1-5.3 (2H, m)

73 mp.: 184-188°C (gradually colored red and gel-like)

[α]D25: +8.3° (c=0.7, chloroform)

IR υKBrmax cm-1: 3455, 2925, 1745, 1665, 1555

NMR (CDCl3-CD3OD), δ (ppm): 0.89 (12H, t), 2.1-2.5 (8H, m),

5.1-5.4 (2H, m)

74 mp.: 169-171°C (colored and gel-like)

[α]D25: +6.2° (c=1.22, chloroform:methanol = 3:1 (v/v))

NMR (CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 1.26 (s), 2.1-2.6

(8H, m), 4.80 (1H, d), 5.16 (1H, t), 5.34 (1H, t)

75 melting point: 140-145°C (colored and gel-like)

[α]D25: +10.3° (c=0.6, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3330, 2925, 2855, 1755, 1645, 1550

NMR (CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 1.30 (s),

2.1-2.3 (8H, m), 2.6-3.0 (4H, m), 4.89 (1H, d), 4.99 (1H, d),

5.09 (1H, t), 5.45 (1H, t)

76 mp.: 142-147°C (colored and gel-like)

[α]D25: +11.7° (c=0.7, chloroform:methanol = 3:1 (v/v))

NMR (CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 1.30 (s),

2.1-2.4 (8H, m), 5.10 (1H, t), 5.30 (1H, t)

77 mp.: 145-148°C (colored and gel-like)

[α]D25: +14.2° (c=0.5, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3450, 2925, 2855, 1740, 1640

NMR (CDCl3-CD3OD), δ (ppm): 0.90 (12H, t, J=6 Hz),

2.1-2.4 (8H, m), 4.80 (1H, d, J=4 Hz), 5.24 (2H, m)

78 mp.: 149-153°C (colored and gel-like)

[α]D25: +20.6° (c=0.31, chloroform:methanol = 1:1 (v/v))

IR υKBrmax cm-1: 3406, 2926, 2854, 1746, 1662, 1557

NMR (CDCl3-CD3OD), δ (ppm): 0.89 (12H, t), 1.27 (s), 2.23

(4H, m), 2.46 (6H, m), 2.59 (3H, m), 2.68 (3H, m), 4.89 (1H, d),

5.16 (1H, t), 5.25 (1H, t), 5.38 (1H, t)

79 melting point: 170-175°C (colored and gel-like)

[α]D25: +12.6° (c=0.5, chloroform:methanol:water = 6:4:1 (v/v))

IR υKBrmax cm-1: 3320, 2925, 2855, 1755, 1660, 1560

NMR (CDCl3-CD3OD), δ (ppm): 0.89 (12H, t), 1.27 (s),

2.1-2.3 (8H, m), 3.18 (4H, m), 4.72 (1H, d), 5.23 (1H, t),

5.33 (1H, dd)

80 melting point: 172-175°C (colored and gel-like)

[α]D25: +12.6° (c=0.5, chloroform:methanol:water = 6:4:1 (v/v))

IR υKBrmax cm-1: 3320, 2920, 2850, 1755, 1655, 1550

NMR (CDCl3-CD3OD), δ (ppm): 0.89 (12H, t), 1.27 (s),

2.1-2.3 (10H, m), 3.16 (2H, m), 4.28 (1H, q), 4.35 (1H, q), 4.69

(1H, d), 4.80 (1H, d), 5.21 (1H, t), 5.32 (1H, t)

81 melting point: 170-175°C (colored and gel-like)

[α]D25: +20.2° (c=0.5, chloroform:methanol = 3:1 (v/v))

IR υKBrmax cm-1: 3330, 2930, 2855, 1755, 1655, 1555, 1470

NMR (CDCl3-CD3OD), δ (ppm): 0.89 (12H, t), 2.15-2.3

(10H, m), 2.6-2.7 ((4H, m), 3.17 (2H, m), 4.58 (1H, d),

4.83 (1H, d), 5.07 (1H, t), 5.23 (1H, t), 5.30 (1H, t)

An example of a test

Fibrosarcoma cells (Meth A) (2 x 105), induced in BALB/c mice with methyl-clolanthrene, were intracutaneously implanted on the flanks of a total of seven BALB/c mice. The triethylamine salt of each of the compounds of the present invention, as shown in Table 1 below, is dissolved or suspended in a 0.1% (v/v) triethylamine aqueous solution to prepare a 500 μm/ml solution or suspension. The solution or suspension is given to mice at a dose level of 100 μg/mouse through the tail vein on the 7th, 12th and 21st days after implantation.

The antitumor effect (%) on the growth of fibrosarcoma is determined by dividing the cross-sectional mass of the tumor of the test group on day 21 by the cross-sectional mass of the tumor of the control group (untreated group) and multiplying the quotient by 100.

For the experiments, we did the same evaluation using compound A as a comparison compound. The obtained results are shown in table 1.

TABLE 1

[image]

From table 1 we can see that the compounds in terms of the proposed invention have equal or greater antitumor activity than compound A.

Example of test 2

The triethylamine salt of each compound of the present invention, as shown in Table 2 below, is dissolved or suspended in a 5% (w/w) glucose aqueous solution, containing 0.1% (v/v) triethylamine, to prepare 100 μm/ml solution or suspension. The solution or suspension is administered to three single NZW rabbits at a dose level of 50 μg/kg of body weight through a vein in the ear regularly for 3 days. We evaluate the toxicity with the number of dead animals after 24 hours of the final administration/number of tested animals. For comparison, we give compound A at the level of 5 μg/kg of body weight. The obtained results are shown in table 2.

TABLE 2

[image]

As can be seen from Table 2, the compounds of the proposed invention have a toxicity below 1/10 of the toxicity of compound A and this is excellently shown in safety.

However, although we have described the invention in detail and in reference to its specific implementations, it is obvious to an expert that we can perform the invention with various changes and modifications, without departing from its essence and scope.

Claims (4)

1. Compound of formula (I) [image] indicated that R represents a phosphono group, ZR6 or [image] wherein each of Z, Z1 and Z2 represents an alkylene group having 1 to 6 carbon atoms and R6 represents a carboxyl group or a phosphonooxy group; each of R1, R2, R3 and R4 represents -COR7, -COZ3R8, [image] where R7 represents an alkyl group with 1 to 30 carbon atoms, which can be substituted with one or more hydroxyl groups, Z3 represents an alkylene group with 1 to 9 carbon atoms, R8 represents a cycloalkyl group with 3 to 12 carbon atoms, which can be substituted with one or more hydroxyl groups, Q represents a hydrogen atom, an acyl group with 1 to 6 carbon atoms, -CONH2, -COOH or -CH2OH, Q1 represents a hydrogen atom or an alkyl group with 1 to 20 carbon atoms, n1 represents 0 or an integer from 1 to 10 and each of n2 and n3 represents an integer from 1 to 20; and R5 represents a hydrogen atom, a phosphono group or -CO(CH2)mCOOH, where m represents 0 or an integer from 1 to 6; provided that the combination where R is a phosphono group is excluded; R5 is a hydrogen atom and each of R1, R2, R3 and R4 is -COR7, and to its salt. 2. Compound according to claim 1, characterized in that R represents [image] [image] 3. Compound according to claim 2, characterized in that R represents ZOPO(OH)2 and each of R1, R2, R3 and R4 represents [image] 4. Process for preparing the compound of formula (I) according to claim 1, characterized in that the compound of formula (II) [image] where R9 represents a hydrogen atom or a hydroxyl-protecting group (that is, a protecting group for a hydroxyl group), which can be removed by catalytic reduction and the like; R10 represents [image] where each of R12 and R13 represents a protective group for phosphono, which can be removed by catalytic reduction; R14 represents a protective group for carboxyl, which can be removed by catalytic reduction; R71 represents an alkyl group with 1 to 30 carbon atoms, which can be substituted with one or more hydroxyl groups, protected by a hydroxyl protecting group; R81 represents a cycloalkyl group with 3 to 12 carbon atoms, which can be substituted with one or more hydroxyl groups, protected by a hydroxyl protecting group; Q2 represents a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, -CONH2, -COOR16 or -CH2-O-R91, where R16 represents a carboxyl protecting group, which can be removed by catalytic reduction; R15 represents a protective group for phosphono, which can be removed by catalytic reduction; and R91 represents a protecting group for hydroxyl, which can be removed by catalytic reduction; and Z, Z1, Z2, Z3, Q1, n1, n2, n3 and m are the same as mentioned earlier, we reduce catalytically in a hydrogen atmosphere in the presence of a catalyst in an inert solvent.