JPH0383928A - Antitumor agent - Google Patents

Abstract

PURPOSE:To obtain an antitumor agent, containing a specific lipid A derivative or salt thereof as an active ingredient and excellent in antitumor activity with low toxicity. CONSTITUTION:An antitumor agent containing a compound expressed by formula I [R is Z-OPO(OH)2 or formula II (Z, Z<1> and Z<2> are 1-6C alkylene); R<1> and R<3> are COR<5> or formula III (R<5> is 5-20C alkyl; Q is 1-6C alkyl); R<2> and R<4> are formula IV; (n) is 1-6] or salt thereof, e.g. 2-phosphonoxyethyl 2-deoxy-6-O-{2- deoxy-3-O-(N-dodecanoylglycyl)-2-[(N-dodecanoyl-N-methylglycyl) amino]-4-O- phosphono-beta-D-glucopyranosyl}-3-O-(N-dodecanoylglycyl)-2-[(N-dodeca noyl-N- methylglycyl) amino]-alpha-D-glucopyranoside, as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention is an antitumor agent containing a compound represented by the following formula (I) or a salt thereof as an active ingredient.

In the above formula, R is -Z-OPO(O)l) 2 * Tah6 alkylene group, and R1 and R3 are each independently -
COR' or -Co (CH2) rl-N-COR
', R2 and R4 are each independently -CO(CH2)
nNH-COR', R5 is a linear or branched alkyl group having 5 to 20 carbon atoms, Q is an alkyl group having 1 to 6 carbon atoms, and n is an integer of 1 to 6.

The compound of formula (I) and its salts exhibit excellent antitumor activity and low toxicity, and are useful as anti-Ill tumor agents.

<Prior art> Natural Livid A has mitogen activity, that is, an effect that stimulates lymphocytes, makes them young, increases the number of lymphoid cells, enhances immune function, and induces tumor death factor. It is promising as a prophylactic and therapeutic agent for many diseases caused by a decline in immune function, such as various infectious diseases, and as an antitumor agent.

As a derivative of the above-mentioned natural Livid A, JP-A-59-48
Those disclosed in No. 497, No. 61-53295, No. 81-227586 and No. 63-183594 are known. These known compounds are still unsatisfactory in terms of toxicity or antitumor activity, and cannot be said to be sufficient from a practical standpoint.Therefore, compounds with useful antitumor activity and reduced toxicity are desired. ing.

<Problems to be Solved by the Invention> The present inventors completed the present invention as a result of intensive studies to find an antitumor agent with excellent antitumor activity and low toxicity.

<Configuration of the Invention> The present invention relates to an antitumor agent containing a compound of formula (1) or a salt thereof as an active ingredient.

The substituents in the compound of formula (RI) will be explained in detail below.

Alkylene group is methylene, polymethylene or carbon number 1
Means methylene or polymethylene substituted with ~6 alkyl groups, examples of which include methylene, ethylene, propylene, trimethylene, ethylethylene, tetramethylene, 2-methyltetramethylene, 2,3-dimethyltetramethylene, etc. For the alkylene group, z, z' and 22 companies in the formula 0 CI) mentioned above, the number of carbon atoms is 1 to 4
The following can be cited as preferable. Straight or branched alkyl groups include methyl, ethyl, propyl, tertiary butyl, hexyl, nonyl, decyl, 3
- Ethylundecyl, 3-ethyl-4-methyl-tridecyl, tetradecyl, nonadecyl, etc. As for the alkyl group R5 in formula (I), those having 8 to 14 carbon atoms are preferred. .

The compound of formula (1) has α and β isomers derived from the substituent OR, and the present invention also includes antitumor agents containing these isomers or a mixture thereof as an active ingredient.

Examples of the salt of the compound of formula (I) include a phosphoric acid group or a carboxyl group and an organic compound such as triethylamine, pyridine, N-methylamine, N-methylglucan, trisaminomethane, arginine, ethanolamine, ethylenediamine, jetanolamine, etc. Salts with inorganic bases such as ammonia or ammonia, sodium, potassium, calcium, magnesium and the like can be mentioned.

Compounds of formula (I) can be produced by various methods,
An example is shown below.

('I) [In the formula, R6 means -ZOPO(OR') or a protecting group for a phosphono group that can be removed by the radical, R9 means a protecting group for a carboxyl group that can be removed by catalytic reduction, R1, R2, R2 and R4 are the same as above.] The protecting groups in the above reaction formula will be explained.

Examples of protective groups for carboxyl groups that can be removed by catalytic reduction include benzyl groups that may have substituents such as halogen atoms, nitro groups, and lower alkoxy groups. Further, examples of the protective group for the phosphono group that can be removed by catalytic reduction include phenyl and benzyl groups, which may have substituents such as halogen atoms, nitro groups, and lower alkoxy groups.

The compound of formula (II) is catalytically reduced in an inert solvent such as tetrahydrofuran, methanol, ethanol, acetic acid, water, or a mixture thereof under a hydrogen gas atmosphere using a catalyst such as palladium black, palladium on carbon, or platinum dioxide. The compound of formula (1) can be produced by removing the protecting group and purifying, if necessary, using silica gel chromatography or the like. The reduction reaction is usually performed at room temperature (0 to 30°C) to BO
℃ for 1 to 12 hours. The amounts of the solvent and catalyst used are not particularly limited.

By adding a necessary amount of base to the obtained compound of formula (I) and then using a precipitation method, freeze-drying method, etc., formula (I) is obtained.
A salt of the compound can be prepared.

The raw material compound of the formula (!■) shown above can be produced as follows.

(N) Earth (■ → (III) [In the formula, RIG means a hydroxyl protecting group, R1゜R2
, R1, n4. u@ and R are the same as above.] In the above reaction formula, the protecting group for the hydroxyl group is a benzyl group that may have a substituent such as a halogen atom, a nitro group, or a lower alkoxy group, and can be removed by catalytic reduction. Protective groups, trichloroethoxycarbonyl group, trichloro tertiary butoxycarbonyl group, etc. can be mentioned.

Dissolving the compound of formula (rV) in a solvent that does not participate in the reaction and contains hydrogen bromide gas, such as a single or mixed solvent such as methylene chloride or acetic acid, and reacting at 0°C to room temperature for several tens of minutes to 24 hours. The acetyl group at the 1-position of the sugar in the present compound can be replaced with bromine.

The obtained brominated product is dissolved in a dry solvent, preferably methylene chloride, chloroform, etc., and mercuric cyanide, mercuric bromide, silver carbonate, silver oxide, silver perchlorate, mercuric nitrate, etc. alone or By condensing these mixtures with a compound of formula (Ill) in the presence of a dehydrating agent such as anhydrous calcium sulfate for several hours to two days under reaction conditions such as room temperature to reflux, formula (
The compound V) can be obtained.

By dissolving or suspending the compound of formula (V) in acetic acid, adding zinc powder, and allowing the reaction to occur, the protecting group of the amino group at the 2° position and RIG can be removed.

A compound of formula (■) can be produced by condensing the resulting eliminated product with R'-OH using a condensation method frequently used in the field of peptide chemistry.

The protective group elimination reaction is usually carried out at room temperature for several tens of minutes to 24 hours. Examples of the condensation reaction include the carbodiimide method, the Eintop method, and the active ester method.

In the above elimination reaction, RIG, which is a hydroxyl protecting group, is preferably trichloroethoxycarbonyl or trichlorotertiary-butoxycarbonyl.

Next, a method for producing the raw material compounds of formulas (mV) and (III) above will be explained.

The compound of formula (ff) can be prepared by known methods or by JP-A-61-53.
It can be manufactured according to the method disclosed in No. 295.

or, formula %formula%) The compound is prepared by the method shown below. can be manufactured.

[In the above formula, X is a halogen atom, Y is a lower Asian 1z
group, trichloroethoxycarbonyl group or trichloro tertiary-butoxycarbonyl group, W is -zow''.

W2 is acetyl, benzoyl, benzyl or p-chlorobenzyl W3 is an alkyl group having 1 to 6 carbon atoms or a carboxyl protecting group that can be removed by catalytic reduction W4 represents hydrogen, benzyl or p-chlorohensyl, R',
R", R", R", Z, Z' and z2 are the same as above].

The compound of formula (■) can be prepared by reacting the compound of formula (Vla) with 10W (in the presence of a Lewis acid) or by reacting the compound of formula (■b) with HOW and mercuric cyanide, silver carbonate, or mercuric bromide. ,
It can be produced by condensation in the presence of silver perchlorate, mercuric nitrate, or a mixture thereof. Also, the formula (
In (2), the compound in which W is -ZO-acatyl can be produced by reacting the compound of formula (Vie) with HOZOH in the presence of hydrogen chloride, p-toluenesulfonic acid, etc., and then acetylating it.

A compound in which Y is a lower acyl group in the formula (■) is treated with a Mayerpine reagent or a compound in which Y is a lower acyl group in the formula (■)
is trichloroethoxycarbonyl or trichlorotertiary-butoxycarbonyl, is treated with zinc powder in the presence of hydrochloric acid, acetic acid, etc. to liberate the amino group at the 2-position, and then R
A compound of formula (■) can be produced by condensation with 'O)I using an acid chloride method, a carboxyde method, an eintop method, or an active ester method.

In formula (■), W is hydrolyzed using sodium hydroxide etc. to eliminate acetyl groups and alkyl groups, and then the product is reacted with X-R' in the presence of an organic amine such as triethylamine. A compound of formula (fK) can be produced by the method of (2) in which a compound other than the above is hydrolyzed using aqueous ammonia.

A compound of formula (X) can be produced by protecting the 4- and 6-positions of the compound of formula (IX) with isopropylidene according to a conventional method.

In formula (X), Wl is -Z-0-benzyl or -
The compound that is ZO-p-chlorobenzyl is R
After condensation with 20H, catalytic reduction followed by triethylamine,
A compound of formula (XI) can be produced by reacting with X-PO(OR')* in the presence of an organic amine such as 4-dimethylaminopyridine or pyridine, or by a method in which w' in formula (X) is replaced.

Compounds of formula (m a ) can be prepared by hydrolyzing them in aqueous acetic acid, such as a 50-90% aqueous acetic acid solution, or by treating them with p-toluenesulfonic acid in methanol, ethanol, water or a mixture thereof. compounds can be manufactured.

Also, the formula (Illa) Niite R6 is -ZOPO(OR”
) 2 The compound (uta') can be produced as follows.

That is, by treating a compound of formula (■) in which W is -20-acetyl or -ZO-benzoyl and Y is trichloroethoxycarbonyl or trichlorotertiary-butoxycarbonyl with aqueous ammonia, formula (xn) is obtained.
Compounds of can be produced. By protecting this with isopropylidene, a compound of formula (Xlll) can be obtained. This was combined with XPO-(
A compound of formula (XIV) can be prepared by condensation with OR') 2 and then with iteR'OH. A compound of formula (XVa) can be produced by removing isopropylidene from this in the same manner as described above. In the same manner as above, Yl is eliminated, and then condensed with the formula R'OH, resulting in the formula Cl1la')
Compounds of can be produced. In addition, a compound of formula (1) was prepared in the same manner as above to eliminate Yl, and then R'0)
A compound of formula (xvb) can be produced by condensation with 1. The compound of formula (Ila') can also be produced by removing isopropylidene in the same manner as above.

The compound of formula (r) or a salt thereof is usually administered intravenously, subcutaneously or topically, and the dosage is usually 30 I per adult.
The dosage is in the range of 1 g to 0.1 mg for 7 days, and may be increased or decreased as appropriate depending on the patient's symptoms.

Further, the compound of formula (I) or a salt thereof can be formulated into an injection solution together with additives such as stabilizers and tonicity agents by known formulation techniques.

<Effects of the Invention> The compound of formula (I) and its salt are excellent anti-IN! It had tumor activity and its toxicity was very low.

Therefore, the present invention is excellent as an anti-111 tumor agent.

Hereinafter, the present invention will be further explained with reference to Reference Examples and Examples, but the present invention is not limited thereto.

Reference example! -1 Step 1 2-acetoxyethyl 3,4.6-tri〇-acetyl-2-deoxy-2-(2,2,2-trichloroethoxycarbonyl))-α-D-glucopyranoside 5.0Og of 2- 5 to deoxy-2-(2,2,2-trichloroethoxycarbonylamino)-D-glucose
．． Add 0ml of ethylene glycol and dioxane containing 0.5a+1 hydrogen chloride gas, heat to 90°C and
1. Stir for 1 hour. Cool the reaction solution with water, add 75 ml of pyridine, add 30.6 g of acetic anhydride, and stir.

After 20 minutes, the mixture was returned to room temperature and stirred for an additional 16 hours. The reaction solution was poured into 350 ml of ice water and stirred, and the precipitated solid was collected by filtration and washed with water.

The obtained solid was dissolved in chloroform, washed successively with 1N hydrochloric acid and saturated saline, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure is recrystallized from ethanol to obtain 4.96 g of the title compound as colorless prismatic crystals.

Melting point 138~! 40℃ 5 [α]. +74,0° (C1,2, chloroform) Step 22-acetoxyethyl 3,4.6-tri〇-acetyl-2-deoxy-2-tetradecanoylamino-
α-D-Glucopyranoside 4.96 g of the compound obtained in step 1 was dissolved in 60 ml of acetic acid, and 7 g of zinc powder was added little by little while stirring at room temperature.
Stir for an hour. Insoluble materials are filtered off, the solvent is distilled off under reduced pressure, toluene is added to the resulting residue, and the solvent is distilled off again under reduced pressure. The resulting residue is dissolved in dioxane, dioxane containing hydrogen chloride gas is added, the solvent is distilled off under reduced pressure, and the mixture is dried.

The resulting oil was dissolved in 70 ml of anhydrous methylene chloride, and mixed with 2.88 μl of N-methylmorpholine and 3.2 μl of N-methylmorpholine under ice cooling.
Add 4 g of tetradecanoic acid chloride and stir for 1 hour.

After adding 10 ml of methanol and stirring at room temperature for 10 minutes, the mixture was diluted with chloroform and washed successively with 1N hydrochloric acid and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was applied to a silica gel column (elution solvent: a mixture of benzene and ethyl acetate (initially 9/1 (v/v)).
After adjusting the ratio to 1/1 (v/v)), 4.77 g of the title compound is obtained as a colorless oil.

Step 3 2-Hydroxyethyl 2-deoxy-2-tetradecanoylamino-α-D-glucobyranoside 4.77 g of the compound obtained in Step 2 was dissolved in 80I1 of anhydrous methanol, and under water cooling, a methanol solution of 9 mmol of sodium methylate was prepared. and stir at room temperature for 30 minutes. After adding tetrahydrofuran to dissolve the precipitated insoluble matter, the strongly acidic ion exchange resin DOWEX-50 (
The resin is removed by filtration. The solvent of the filtrate is distilled off under reduced pressure. The residue obtained is washed with ether and collected by filtration to obtain 3.02 g of the title compound as a white solid. Ethanol. - Recrystallized in water.

Melting point 158-160°C 5 [α] ◆ 82.1” (CO, 8, tetrahydrofuran: water ← 4/1 v/v) Step 42-Hydroxyethyl 2-deoxy-4,6-
0-isopropylidene-2-tetradecanoylamino-
α-D-Glucopyranoside Compound obtained in Step 3 0.87
Dissolve g in 2011 dimethylformamide and add 0.62 g of 2,2-dimethoxypropane and 38+a at room temperature.
g of P-toluenesulfonic acid hydrate is added and stirred for 1.5 hours. Neutralize with 5% aqueous sodium hydrogen carbonate solution,
The solvent is removed under reduced pressure. Dissolve the residue in ethyl acetate, add water,
Wash sequentially with saturated saline and dry with anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was transferred to a silica gel column (elution solvent: initially a mixture of chloroform and acetone).
/l v/v) and then changed to a mixture of chloroform and methanol (19/1 v/v) to obtain 0.78 g of the title compound as a colorless viscous oil.

Step 5 2-(Diphenylphosphonoxy)ethyl 2-deoxy-4,6-0-isopropylidene-2-tetradecanoylacuno-α-D-glucobylanoside 0.77 g of the compound obtained in Step 4 was converted to anhydrous salt with IS+el. Dissolved in methylene and cooled with water, 0.48 g of diphenylphosphorochloridate, 0.19 ml of pyridine and 0.30
g of dimethylaminopyridine is added and stirred for 1 hour.

Further, the mixture was returned to room temperature, stirred for 1 hour, 0.17 g of diphenylphosphorochloridate was added, and the mixture was stirred for 30 minutes. 3 ml of methanol was added to the reaction mixture, and after stirring for a while, the solvent was distilled off under reduced pressure. The residue was purified using a silica gel column (elution solvent: chloroform: 7 setone-19/1, v/v) to obtain 0.81 g of the title compound as a colorless viscous oil.

Step 62-(diphenylphosphonoxy)ethyl 2-deoxy-3-0-(N-dodecanoylglycyl)-2-tetradecanoylamino-α-D-glucobylanoside 0.51 g of the compound obtained in Step 5 was added to 5 ml. of anhydrous methylene chloride, and cooled with water, 0.22 g of N-dodecanoylglycine, 44 mg of dimethylaminopyridine, and 0.22 g of N-dodecanoylglycine were dissolved in anhydrous methylene chloride.
Add 18 g of dicyclohexylcarbodiimide, cool with water for 30 minutes, then return to room temperature and stir for 2 hours. Insoluble materials are removed by filtration, and the filtrate is washed successively with 1N hydrochloric acid, water, and saturated brine, and dried over anhydrous sodium sulfate. 20 ml of 90% acetic acid aqueous solution is added to the residue obtained by distilling off the solvent under reduced pressure, and the mixture is stirred for 30 minutes while heating to 90°C. The solvent was distilled off under reduced pressure, toluene was added to the residue, and the solvent was distilled off under reduced pressure, which was repeated twice.
, v/v) and then purified with a mixture of chloroform and methanol (19/l, v/v) to obtain 0.51 g of the title compound as a colorless oil.

5 [α]0◆46.2° (C1,1, chloroform) N
MR (CDC13), δ (ppa+): 0.811
(6H,t), 1.28(S), 2.07(2)1. t
), 2.27 (2H, t), 4.84 (1) 1. d),
5.18 (IH, a+), 7.2-7.4 (IOH, ■
) Reference Example I-2 Step 1 1.3-(jethoxycarbonyl)isopropyl 2-deoxy-3,4,6-0-acetyl-2-(
2,2,2-trichloroethoxycarbonylamino)-
α-D-glucopyranoside 8, OOg of 1,3,4,6-tetra-0-acetyl-
A 25% hydrogen bromide-acetic acid solution cooled at room temperature is added to 2-deoxy-2-(2,2,2-trichloroethoxycarbonylamino)-D-glucobylanose and stirred for 1 hour. The mixture is diluted with chloroform, washed successively with 5% aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate.

The residue obtained by distilling off the solvent under reduced pressure was dissolved in 72a+1 anhydrous methylene chloride, and 8 g of anhydrous calcium sulfate was added under water cooling.
4, 12 g of silver perchlorate and 6.24 g of diethyl-3-hydroxyglutarate suspended in 4 hl of anhydrous benzene are added.

After reacting at room temperature for 3 hours, a 5% aqueous sodium hydrogen carbonate solution was added to neutralize. Insoluble materials are removed by filtration, and the filtrate is washed with water and dried over anhydrous magnesium sulfate.

The solvent was distilled off under reduced pressure, and the resulting residue was purified using a silica gel column (elution solvent: chloroform:acetone 30:1) to obtain 7.38 g of the title compound as an oil.

5 [α]D◆42.8″″ (CG, 7, chloroform) Step 2 L, 3-(jethoxycarbonyl)isopropyl 2-deoxy-2-tetradecanoylamino-
3,4,6-tri〇-acetyl-α-D-glucopyranoside process! Dissolve 4.0 Hg of the compound obtained in 20 ml of acetic acid, add 3 g of zinc powder, and stir at room temperature for 2 hours.

Insoluble matter is filtered off and the solvent is distilled off. The residue and distillate were dissolved in benzene, washed with a 5% aqueous sodium bicarbonate solution and saturated brine, and dried over magnesium sulfate. Distill the solvent,
The residue is dissolved in 30 ml of tetrahydrofuran.

Meanwhile, 1.64 g of tetradecanoic acid, 1.28 g of 1-hydroxybenzotriazole, and 1.48 g of dicyclohexylcarbodiimide were added to 20 m of tetrahydrofuran.
In addition to 1, the reacted insoluble matter was filtered off, and the mixture was added to the above tetrahydrofuran solution under water cooling, and stirred overnight at room temperature. After removing insoluble matter by filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: a mixture of chloroform and acetone (10/1)) to obtain 3.78 g of the title compound from the target fraction. An oil was obtained.

5 [α]D◆46.9° (CG, 16.Chloroform)
Step 3 1.3-(Dibenzyloxycarbonyl)isopropyl 2-deoxy-2-tetradecanoylamino-α-D-glucopyranoside Dissolve 1.80 g of the compound obtained in Step 2 in 30a+1 dioxysan and add 10 ml of water. . Cool to 5° C., add 15 ml of 1N aqueous potassium hydroxide solution, stir for 6 hours, and then add 1N hydrochloric acid to adjust the pH to 7.5.

Concentrate to dryness under reduced pressure, suspend the resulting residue in 100 ml of dimethylformamide, and add 1 ml of benzyl bromide. After stirring at 40° C. for 3 hours, most of the dimethylformamide was distilled off under reduced pressure and the resulting residue was extracted with benzene. The benzene layer was mixed with 5% citric acid aqueous solution, saturated saline, 5
After sequentially washing with % sodium bicarbonate aqueous solution and saturated saline, drying over anhydrous magnesium sulfate.

The solvent is distilled off under reduced pressure and the residue is purified by silica gel chromatography (elution solvent: chloroform:methanol:acetone=50:1:5 and then 50:1:15) to obtain 0.65 g of the title compound as a white waxy solid.

[α]25◆13.2' (G O, 51, Chloroform) Step 4 1.3-(Dibenzyloxycarbonyl)isopropyl 2-deoxy-4,8-0-isopropylidene-2-tetradecanoyl 0.64 g of the compound obtained in step 3 of non-alpha-reactive glucopyranoside was dissolved in 10+ al of acetone and reacted in the same manner as in step 4 of Reference Example I-1 to obtain 0.54 g of the title compound as an oil.

[α]25◆3.3@(CO,7,chloroform) Step 5 1.3-(dibenzyloxycarbonyl)isopropyl 2-deoxy-3-0-(N-dodecanoylglycyl)-2-tetradeca After reacting the compounds o and aog obtained in Noylamino-α-D-glucopyranoside Step 4 with N-dodecanoylglycine in the same manner as in Step 6 of Reference Example rt,
Treatment with 90% aqueous acetic acid gives 0.63 g of the title compound as a waxy solid.

[α]25◆36.9° (C1,3, chloroform)
NMR (CDCIs), δ (ppm): 0.89
(6B, t), 1.26(s), 2.1~2.3(4H
, ml.

2.5-2.9 (4H, m), 4.50 (IH, m),
4.97 (1)1. d), 5.70 (IH, m), 5
．． 18(4)1), 7.40 (IOH, s) Reference example! −
A reference example compound represented by the following formula (III^) was obtained in the same manner as in Methods 1 to I-2.

Reference Example TI-1 Step 12-(diphenylphosphonoxy)ethyl 2-deoxy-6-0-[2-deoxy-4-〇-diphenylphosphono3-0-(N-dodecanoylglycyl)-6
-0-(2,2,2-trichloroethoxycarbonyl)
-2-(2,2,2-trichloroethoxycarbonylamino)-β-D-glucopyranosyl] -3-0-(
370 mg of 1-0-acetyl-2-deoxy-4-
〇-Diphenylphosphono3-0- (N-dodecanoylglycyl) -e-o -(2,2,2-trichloroethoxycarbonyl) -2-(2,2,2-trichloroethoxycarbonylamino) -D - Dissolve glucobylanose in 211 IIL of anhydrous methylene chloride, add a cooled 25% hydrogen bromide-acetic acid solution of 611 IIL at room temperature, and stir for 1 hour. Diluted with chloroform, ice-water,
After sequentially washing with 5% sodium bicarbonate water and saturated saline, drying with anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure and 344 mg of 2-(diphenylphosphonoxy)ethyl 2-deoxy-3-0-(N-dodecanoylglycyl)-2-[(N-dodecanoyl-N -Methylglycyl〉Aho〕]-α-D-glucopyranoside 5
Dissolve in mJ2 of anhydrous methylene chloride, add 0.5 g of active calcium sulfate and 182 mg of mercuric cyanide, heat to 50-60°C and stir for 3 hours. Insoluble materials were removed by filtration through Celite, and the filtrate was washed successively with a 5% aqueous potassium iodide solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was transferred to a silica gel column (elution solvent, first chloroform:acetone-1).
Purification is then carried out using chloroform:methanol (20:1), then chloroform:methanol (20:1) to obtain the title compound 599 rsg as an oil.

5 [α] +20.0° (C1,0, chloroform)
Step 22-(diphenylphosphonoxy)ethyl 2-deoxy-6-0-(2-deoxy-4-0-(diphenylphosphono)-3-0-(N-dodecanoylglycyl)-
2-[(N-dodecanoyl-N-methylglycyl)amino]-β-D-glucopyranosyl)-3-0-(N-dodecanoylglycyl)-2-[(N-dodecanoyl-N
-Methylglycyl)amino]-α-D-glucopyranoside 587 mg of the compound obtained in Step 1 is dissolved in 8 liters of acetic acid, 0.6 g of zinc powder is suspended, and the mixture is stirred at room temperature for 2 hours. Remove insoluble matter by filtration, wash with chloroform,
The solvent is removed under reduced pressure. The operation of dissolving the residue in toluene and distilling off the solvent is repeated three times, and the resulting residue is dissolved in chloroform. The chloroform layer is washed successively with 1N hydrochloric acid, 5% aqueous sodium bicarbonate, and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain an oil.

Meanwhile, 122 mg of N-dodecanoyl-N-methylglycine was dissolved in 3 mft of anhydrous tetrahydrofuran.
77 mg of 1-hydroxybenzotriazole and 10
Add 3 mg of dicyclohexylcarbohydrate and stir. After 30 minutes, the mixture was returned to room temperature and stirred for 3 hours, and the precipitated crystals were removed by filtration. The oily substance was dissolved in 5IIJZ anhydrous methylene chloride, and the filtrate was added under ice cooling. The reaction solution was returned to room temperature and stirred for 1 hour and 30 minutes. The reaction solution was diluted with chloroform, washed with 1N hydrochloric acid, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was separated into a silica gel column (elution solvent; first chloroform:acetone-10:1).
Then, the product is purified with chloroform:methanol=50:1 and finally with chloroform:methanol=20:1) to obtain the title compound 445B as an oil.

5 [α] +19.2° (C1,0, chloroform)
Step 32-phosphonoxyethyl 2-deoxy-6-0
-(2-deoxy-3-0-(N-dodecanoylglycyl)-2-[(N-dodecanoyl-N-methylglycyl)amino] -4-0-phosphono-β-D-glucopyranosyl)-3-0 -(N-dodecanoylglycyl)-2
-[(N-dodecanoyl-N-methylglycyl)amino]-α-D-glucopyranoside 424 mg of the compound obtained in Step 2 was dissolved in a mixture of 50111 tetrahydrofuran and 2.5 tafL of water, and 0.2 g of platinum dioxide was added. and stirred for 2 hours under a hydrogen stream. The catalyst is filtered and the residue is washed with a mixture of chloroform and methanol (8:3:1 lower layer). The filtrate and washing liquid were combined, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to thin layer chromatography [elution solvent; developed with chloroform:methanol:water-6:4:0°7 (v/v)]. It is purified and treated with a strongly acidic ion exchange resin DOWEX 50 (H" type, manufactured by Dow Chemical Company).

The residue obtained by distilling off the solvent under reduced pressure is suspended in dioxane and then lyophilized to obtain 204 mg of the title compound as a white powder.

Melting point 165-170°C (gradually becomes colored candy-like) 5 [α] +4.6° ((: 0.7, chloroform:methanol = 3:1 (v/v)) IRν
ni"cm-';3400.2930.2850.1?
50,1675,1650a+aX NMR (CDCIs-CDsOD), δ(ppIll
) :0.90(12)1. t), 1.30(s)
, 2.29 (4H, m).

2.44 (4H, t), 2.94 and 3.11 (total 6
8. Each S).

4.84 (1)! ,d) ,5.18 (18,m)
, 5.34 (1)1. a+) A portion of the title compound was dissolved in a mixture of chloroform-methanol (3:1), adjusted to pH approximately 9 with triethylamine, and then concentrated under reduced pressure.

The resulting residue was dissolved in a 0.1% triethylamine aqueous solution, filtered through a Millipore filter, and then lyophilized to obtain the triethylamine salt of the title compound as a white powder.

Reference example! ! A reference example compound represented by the following formula (I^) was produced in the same manner as in -1.

Example I BALB/C mice were induced with methylcholanthrene and 2×10' fibrosarcoma cells (Meth^) were injected into syngeneic BAL cells.
B/C mice (7 mice/group) were implanted in the flank region. The triethylamine salt of the compound of Reference Example H was dissolved or suspended in a 0.1% triethylamine aqueous solution (v/v%>k: 500 μg/1 afl, and the solution was adjusted to 500 μg/1afl.
7 days, 12 days, and 21 days after transplantation to become mice.
It was administered into the tail vein on day 1, and the antitumor activity was examined 21 days later.

The results are shown in Table IC.

Table 1 *(Average tumor weight on day 21 of treatment group/average tumor weight of untreated control group) xlOO As is clear from the above table, the compound of formula CI) and its salt have excellent antitumor activity It was confirmed that it has.

Example 2 Three NZW male rabbits in one group were treated with the triethylamine salt of the compound of Reference Example II containing 0.1% triethyl acetate 5
% glucose solution or suspended in 1ooooμg/IIJ2
A solution prepared by Il was administered into the ear vein at a dose of 0, s + *t/kg (body weight) for 3 consecutive days. It was determined by the number of dead rabbits/number of rabbits used 24 hours after the final administration. The results are shown in Table 2.

As is clear from the above table, the compound of formula (RI) and its salts had very low toxicity.Furthermore, 24 hours after the completion of administration of the compound of Reference Example II, exsanguination was performed under bendoparbital anesthesia.
Reference Example 11 was slaughtered, the whole body was examined, and a histological search was performed on the liver, prefecture area, kidneys, heart, and lungs.
No changes that could be attributed to the compound were observed.

Therefore, it was confirmed that the compound of formula (I) and its salt have excellent safety.

Claims (1)

[Scope of Claims] An antitumor agent containing a compound represented by the formula ▲A mathematical formula, a chemical formula, a table, etc.▼ or a salt thereof as an active ingredient. In the above formula, R is -Z-OPO(OH)_2 or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, Z, Z^1 and Z^2
are each an alkylene group having 1 to 6 carbon atoms, R^1 and R^3 are each independently -COR^5 or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and R^2 and R^4 are each independently -CO(CH_2)_nNH-COR^5, R
^5 represents a linear or branched alkyl group having 5 to 20 carbon atoms, Q represents an alkyl group having 1 to 6 carbon atoms, and n represents an integer of 1 to 6.