JPS5843391B2 - New urea derivatives and their production method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel urea derivative and a method for producing the same, and more particularly to a novel urea derivative represented by the general formula [wherein R1 is an alkyl group having 1 to 2 carbon atoms,
Represents a hydroxyalkyl group having 1 to 6 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, or an alkynyl group having 3 to 5 carbon atoms, and R2 is a D-glucopyranosyl group, a D-galactopyranosyl group, a D-mannopyranosyl group, D-xylopyranosyl group, L-arabinopyranosyl group, 0-α-D-glucopyranosyl-(l→4)-D-glucopyranosyl group or formula % formula % (however, n is O or an integer from 1 to 4) represent.

represents a group represented by

The present invention relates to a 1-(2-chloroethyl)-3,3-disubstituted urea represented by the following formula and a method for producing the same.

The 1-(2-chloroethyl)-3,3-di)substituted urea (1) of the present invention has a general formula (wherein R1 and R2 in the above formula have the same meanings as above) having an excellent antitumor effect.

) is a compound useful as a synthetic intermediate for 1-(2-chloroethyl)-1-nitroso-3,3-disubstituted urea.

In the general formula [I], representative examples of the group represented by the symbol R1 include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s
ec, -butyl group, fert, -butyl group, n-pentyl group, isopentyl group, neopentyl group, 1-methylbutyl group, 1-ethylpropyl group, tert, -pentyl group, n-hexyl group, 2-methylpentyl group , isohexyl group, 3,3-dimethylbutyl group, n-heptyl group,
n-octyl group, n-nonyl group, n-decyl group, n-undecyl group, n-dodecyl group, n-tridecyl group, n-
Tetradecyl group, n-pentadecyl group, n-hexadecyl group, n-heptadecyl group, n-octadecyl group, n-
Straight chain or branched alkyl groups such as nonadecyl group, n-eicosyl group; hydroxyalkyl groups such as 2-hydroxyethyl group, 3-hydroxypropyl group; 2-n-propenyl group, 2-methyl-2-n-flobenyl group group, 2-
Straight chain or branched alkenyl groups such as n-phanyl group, 3-n-butenyl group; 2-n-propynyl group, 2-n
-butynyl group, 3-n-butynyl group, 2-methyl-3-
Examples include straight chain or branched alkynyl groups such as n-butynyl.

On the other hand, representative examples of the group represented by the symbol R2 are:

For example, D-glucopyranosyl group, D-galactopyranosyl group, D-mannopyranosyl group, D-xylopyranosyl group, L-arabinopyranosyl group, 〇-α-D-glucopyranosyl (1→4) -D - glucopyranosyl group;
2-hydroxyethyl group, 2,3-dihydroxy-n-
Propyl group, 2,34-trihydroxy-subbutyl group, 2,3.45-tetradroxy-n-pentyl group, 2
, 3°4.5.6-pentahydroxy-n-hexyl group, and the like groups represented by the formula -CH2(CHOH)nCH20H.

In the compounds CI, 1 of the present invention, a preferred group is that R1 is an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 3 to 4 carbon atoms, an alkynyl group having 3 carbon atoms, or a 2-hydroxyethyl group, and R2 is D-glucopyranosyl group, D-galactopyranosyl group, D-mannopyranosyl group, D-xylopyranosyl group, L-arabinopyranosyl group, 0-α-D-glucopyranosyl-(1→4)-D-
Glucopyranosyl group or formula -CH2(CHOH)nC
H20H (where n represents 0 or an integer from 1 to 4)
Examples include compounds that are groups represented by the following.

A more preferred group includes R in formula CI)
1 is an alkyl group having 1 to 5 carbon atoms or an alkenyl group having 3 to 4 carbon atoms, and R2 is a D-glucopyranosyl group, a D-galactopyranosyl group, an L-arabinopyranosyl group, or a D-xylopyranosyl group. group, O-α-D-glucopyranosyl-(1→4)-D-glucopyranosyl group or formula -CH2(CHOH)mcH20H (where m is 1,2
or 4).

A further preferred group includes formula CI) in which R1 is a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, n-pentyl group, impentyl group, neopentyl group, 2-n -propenyl group, 2-methyl-2-n-propenyl group, 2-n-
butenyl group or 3-n-butenyl group, and R2
is D-glucopyranosyl group, D-galactopyranosyl group, L-arabinopyranosyl group, D-xylopyranosyl group, 0-α-D-glucopyranosyl-(1→4)-D-glucopyranosyl group, 2,3 Mention may be made of compounds which are -dihydroxy-n-propyl or 2,3,4-trihydroxy-n-butyl groups.

Further, in compound CI), the most preferred group is that R1 is an n-butyl group, an isobutyl group or a 2-methyl-
2-n-furobenyl group, and R2 is D-galactopyranosyl group, L-arabinopyranosyl group, or O-α
-D-glucopyranosyl-(1→4)-D-glucopyranosyl group can be mentioned.

According to the invention, 1-(2-chloroethyl)-3,3-
Disubstituted urea [I] has the general formula (wherein R1 and R2 have the same meanings as above).

It can be produced by subjecting a secondary amine represented by the formula % to a condensation reaction with 2-chloroethyl isocyanate represented by the formula %.

The raw material of the present invention [hypolyte Cm] has, for example, the general formula (wherein R1 has the same meaning as above).

) is a primary amine represented by the general formula (where R2 has the same meaning as above, and X represents a hydroxyl group or a halogen atom).

) and a suitable solvent (for example, methanol, ethanol) at a temperature of 200 to 800 ℃.

The condensation reaction of the present invention, i.e., secondary amine (II) and 2
-Chloroethyl isocyanate CI) can be suitably carried out at 00 to 30°C in a suitable solvent.

Preferred examples of the reaction solvent include tetrahydrofuran, methanol, and ethanol.

The thus obtained 1-(2-chloroethyl)-3,3-
Disubstituted urea CI) is a new compound and the compound (1)
By nitrosating it, a 1-(2-chloroethyl)-1 nitroso-3,3-disubstituted urea (A) having excellent antitumor activity can be derived.

The above nitrosation reaction can be carried out by contacting compound CI) with nitrous acid, nitrogen trioxide or nitrogen tetroxide in a suitable solvent.

This reaction is preferably carried out at -200 to 20°C, especially at 00 to 5°C.

Examples of the solvent include water, tetrahydrofuran, methylene chloride, ethyl acetate, acetic acid, and formic acid.

Nitrous acid is an alkali metal salt of nitrous acid (sodium nitrite,
Preferably, O is obtained by reacting potassium nitrite, etc.) or a lower alkyl ester thereof (butyl nitrite, aluminum nitrite, etc.) with an inorganic or organic acid, and is used immediately after preparation in the nitrification reaction.

On the other hand, when using nitrogen trioxide or nitrogen tetroxide, the compound CI) is dissolved in a suitable solvent in the presence or absence of a deoxidizing agent (e.g., sodium bicarbonate, sodium carbonate, potassium carbonate, sodium acetate, etc.). It is preferable to carry out the process by passing nitrogen trioxide or nitrogen tetroxide through the bottom.

The 1-(2-chloroethyl)-1-nitroso-3,3-disubstituted urea [A] obtained by this process has an excellent antitumor effect, as is clear from the experimental examples described later.

Therefore, the 1-(2-chloroethyl)-3,3-
Disubstituted urea CI) is an extremely useful compound as a synthetic intermediate for the compound (A).

Example I A mixture of 3.6 g of D-curcose and 107 rll of 10% methylamine-methanol solution is heated in a sealed tube at 60° C. for 20 minutes.

After the reaction is completed, the reaction solution is dried under reduced pressure to obtain 3.8 g of -methylamino-1-deoxy-D-glucose as a crude product.

Dissolve 3.8 g of this crude product in 40 ml of methanol, and add a solution of 2.5 g of 2-chloroethyl isocyanate in 107 IL of tetrahydrofuran at 0 to 5°C.
and stirred at the same temperature for 1.5 hours.

After the reaction is completed, the reaction solution is concentrated under reduced pressure, and the residue is added with ethyl acetate.
If an ether mixture is added, 1-(2-chloroethyl)-
4.5 g of 3-methyl-3-D-curcopyranosyl urea
is obtained as a colorless caramel.

IRvnuJol(cIrL'): 3300.16
30゜aX 1530.1070, 03O N, MR (D20) δ: 3.10 (51C
H3) Example 2 D-glucose 3.6.9 and ethylamine 1.1 g
was treated as in Example 1 to obtain 1-ethylamino-1-deoxy-D-glucose, and then the product and 2
- If 2.5 g of chloroethyl isocyanate is treated in the same manner as in Example 1, 5.5 g of -(2-chloroethyl)-3-ethyl-3-glucohyranosyl urea is obtained as a colorless caramel.

IRvnuJol(crIL-'): 3350.
16401aX 1535.1080, 04O NMR (D20) δ: 1.25 (t% CH2-C
Example 3 A mixture of 3.6 L of D-glucose, 1.3 g of n-propylamine and 15 TL of methanol is heated at 60° C. for 30 minutes.

After the reaction is completed, the reaction solution is dried under reduced pressure and the residue is washed with ether to obtain 1-n-propylamino-1-deoxy-D.
- 4.4 g of glucose are obtained as crude material.

4.4 g of this crude product was dissolved in 50 Trll of methanol, and a solution of 2.5 g of 2-chloroethyl isocyanate dissolved in 10 wL of tetrahydrofuran was added to the solution.
It was added dropwise at 5°C and stirred at the same temperature for 1.5 hours.

After the reaction is completed, the reaction solution is concentrated under reduced pressure, and the residual aroma is removed with 2 ml of formic acid.
．． and leave at room temperature for 20 minutes.

Add a mixture of ether and n-hexane (1:1) to this solution, and wash the resulting oil repeatedly with ether.
1-(2-chloroethyl)-3-n-propyl-3-D
-Glucopyranosyl urea5. O,! li' is obtained as a brown caramel.

Further silica gel chromatography [solvent: chloroform/ethyl acetate/methanol (1:2:1)]
When refined, it becomes colorless caramel.

I RJ/nuJ"(crfL-'): 330
0.1630°aX 153011080, 04O NMR (D20) δ: 0.93 (t, 3H,
CH,) 1.35-2.0 (42H.

-Ctan2-CH5) Example 4 3.6 g of D-glucose and 2.
0 g was treated in the same manner as in Example 3 to obtain 1-isopropylamino-1-deoxy-D-glucose, and then this product and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as in Example 3 to obtain 1-isopropylamino-1-deoxy-D-glucose. , 1-(2-chloroethyl)-3-isopropyl-3-D-glucopyranosylurea 4.89 g is obtained as a colorless caramel.

IRνnuJ01(cIrL-”): 3350.
16401aX 1535.1070゜03O NMR (D20) δ: 1.3 s (dl-C
H((Lotus Qρ Example 5 D-glucose 3.6g and n-butylamine 1.7
g was treated in the same manner as in Example 3 to obtain 1-n-butylamino-
If 1-deoxy-D-glucose is obtained and then the product and 2.5 g of 2-chloroethyl isocyanate are treated as in Example 3, 1-(2-chloroethyl)-3
-n-butyl-3-D-glucopyranosyl urea 5.0g
is obtained as a colorless caramel.

IRνnuJ01(crrL-”): 33001
16301aX 1530.1070, 03O NMR (D20) δ: 0.75-1.70 (
m.

-CH, CH2, CH,) Example 6 3.6 g of D-glucose and 2.5 g of isobutylamine
g was treated in the same manner as in Example 3 to obtain 1-inbutylamino-
If 1-deoxy-D-glyose is obtained and then the product and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as in Example 3, 1-(2-chloroethyl)-3
50 g of -inbutyl-3-D-glucopyranosyl urea are obtained as colorless caramel.

IRvnuJ"(clrL-"):3350,1635
, aX 1535.1070, 03O NMR (D20) δ: 0.90 (d, 6
H1-CH(CH,)2) 1.7-2.3 (m% IH,-CH(CH3)2) Example 7 3.6 g of D-glucose and n-pentylamine 2.
1 g was treated as in Example 3 to obtain 1-n-pentylamino-1-deoxy-D-glucose, and then this product and 2.59 g of 2-chloroethyl isocyanate were treated as in Example 3. 1-(2-chloroethyl)
-3-n-pentyl-3-D-glucopyranosyl urea 6
．． 5 g are obtained as brown caramel.

IRvCHCl3(cIrL-1): 3350
．． 1640, aX 1540.107O NMR107ONδ: 0.70-2.00 (
ml-(CH2)3CH3) Example 8 3.6 g of D-glucose and 2. ml of n-hexylamine.
5 g was treated in the same manner as in Example 3 to obtain 1-n-hexylamino-1-deoxy-D-gluace, and then this product and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as in Example 3. If treated, 1-(2-chloroethyl)
-3-n-hexyl-3-D-glucopyranosyl urea 6
．． 8 g are obtained as light brown caramel.

HCl lR1/3 (crIL-1): 335011
640°aX 1520.1080°040 Example 9 3.6 g of D-glucose and n-dodecylamine5.
6 g was treated as in Example 3 to obtain 1-n-dodecylamino-1-deoxy-D-glucose, and then this product and 2.59 g of 2-chloroethyl isocyanate were treated as in Example 3. 1-(2-chloroethyl)
-3-n-dodecyl-D-glucopyranosyl urea 6.0
g is obtained as a colorless caramel.

Example 10 2.7 g of D-glucose, 4.5 g of n-nonadecylamine
g and methanol 6M mixture is stirred at 65° C. for 25 minutes.

After cooling, the precipitate is collected by filtration, washed with n-hexane and dried to obtain 6.4 g of 1-n-nonadecylamino-1-deoxy-D-glucose.

The main island was dissolved in a mixture of 100rrLl of tetrahydrofuran and 100TrLl of methanol while hot, and after cooling to room temperature, 1.7g of 2-chloroethyl isocyanate was added.
A solution of 207711 in tetrahydrofuran is added dropwise.

After further extrusion at room temperature for 30 minutes, the solvent was distilled off, and the residue was purified by silica gel chromatography [solvent: chloroform, methanol (10:1)] to obtain 1-(2-chloroethyl)-3-n-nonadecyl. 6.0 g of -3-D-glucopyranosyl urea are obtained as a colorless powder.

Example 11 3.6 g of D-glucose and 6.2 g of n-hexadecylamine were treated in the same manner as in Example 10 to obtain 1-n-hexadecylamino-1-deoxy-D-glucose, and then the product and 2-chloroethyl isocyanate 2
．． 5. ! 9 is processed in the same manner as in Example 10, 1-(2
-chloroethyl)-3-n-hexadecyl-D-glucopyranosylurea 6.0 is obtained as a colorless caramel.

Example 12 3.6 g of D-glucose and 6.8 g of n-octadecylamine were treated as in Example 10 to obtain 1-n-, octadecyl-1-deoxy-D-glucose, and then the product and 2 -chloroethyl isocyanate 2.5
By treating g in the same manner as in Example 10, 5.8 g of 1-(2-chloroethyl)-3-n-octadecyl-D-glucopyranosylurea is obtained as a colorless caramel.

Example 13 3.6 g D-galactose and 1 n-propylamine
．． 5 g was treated as in Example 3 to obtain 1-n-propylamino-1-deoxy-D-galactose, then the product and 2.59 g of 2-chloroethyl isocyanate.
When treated in the same manner as in Example 3, 4.5 g of 1-(2-chloroethyl)-3-n-propyl-3-D-galactopyranosylurea is obtained as colorless caramel.

Example 14 D-galactose 3.6g and isopropylamine 2
．． 4 g was treated as in Example 3 to obtain 1-isopropylamino-1-deoxy-D-galactose, then the product and 2.59 g of 2-chloroethyl isocyanate.
When treated in the same manner as in Example 3, 5.09 g of 1-(2-chloroethyl)-3-isopropyl-3-D-galactopyranosylurea is obtained as a colorless caramel.

Example 15 3.6 g of D-galactose and n-butylamine 1.
8 g were treated as in Example 3 to obtain 1-n-butylamino-1-deoxy-D-galactose, and then the product and 2-chloroethyl isocyanate 2.5. ! 9
When treated in the same manner as in Example 3, 5.2 g of 1-(2-chloroethyl)-3-n-butyl-3-D-galactopyranosylurea is obtained as colorless caramel.

Example 16 3.6 g of D-galactose and 2. isobutylamine.
0 g was treated in the same manner as in Example 3 to obtain 1-isobutylamino-1-deoxy-D-galactose, and then this product and 2-chloroethyl isocyanate-1-2,5 g were treated in the same manner as in Example 3. On treatment, 5.5 g of 1-(2-chloroethyl)-3-isobutyl-3-D-galactopyranosylurea are obtained as colorless caramel.

Example 17 3.6 g of D-galactose and 5 g of sec,-butylamine were treated in the same manner as in Example 3 for i sec.

-butyl 1-deoxy-D-galactose, then the product and 2-chloroethyl isocyanate 3.0
By treating g in the same manner as in Example 3, 4.5 g of 1-(2-chloroethyl)''-3-SeC,-butyl-3-D-galactopyranosyl urea is obtained as a light brown caramel.

Example 18 D-galactose 3.6g and n-pentylamine 2
．． 3 g was treated in the same manner as in Example 3 to obtain 1-n-pentylamino-1-deoxy-D-galactose, followed by the product and 2.5 g of 2-chloroethyl isocyanate.
When treated in the same manner as in Example 3, 5.59 g of 1-(2-chloroethyl)-3-n-pentyl-3-D-galactopyranosylurea is obtained as a colorless caramel.

Example 19 D-galactose 3.6g and isopentylamine 2
．． 3 g was treated in the same manner as in Example 3 to obtain 1-isopentylamino-1-deoxy-D-galactose, and then the product and 2-chloroethyl isocyanate t-2,5
By treating g in the same manner as in Example 3, 5.5 g of ■-(2-chloroethyl)-3-isopentyl-3-D-galactopyranosylurea is obtained as a colorless caramel.

Example 20 D-galactose 3.6g and neopentylamine 3
．． 5 g was treated in the same manner as in Example 3 to obtain 1-neopentylamino-1-deoxy-D-galactose, followed by the product and 2.5 g of 2-chloroethyl isocyanate.
When treated in the same manner as in Example 3, 5.0 g of 1-(2-chloroethyl)-3-neopentyl-3-D-galactopyranosylurea is obtained as colorless caramel.

Example 21 3.6 g of D-galactose and 6.8 g of n-octadecylamine were treated in the same manner as in Example 10 to obtain 1-n-octadecylamino-1-deoxy-D-galactose, and then the product and 2 - If 2.5 g of chloroethyl isocyanate is treated in the same manner as in Example 10, 1-(2
6.0 g of -chloroethyl)-3-n-octadecyl-3-D-galactopyranosylurea are obtained as colorless caramel.

Example 22 3.6 g of D-galactose and 1.5 g of 2-propenylamine were treated in the same manner as in Example 3 to obtain 1-(2-propenylamine)-1-deoxy-D-galactose,
The product and 2.5 g of 2-chloroethyl isocyanate are then treated in the same manner as in Example 3 to yield 1-(2-chloroethyl)-3-(2-propenyl)-3-D-galactopyranosylurea 4 .3g is obtained.

3.6 g of D-galactose and 1.4 g of 2-propynylamine were treated in the same manner as in Example 3 to obtain 1-(2-propynyl)-1-deoxy-D-galactose, and then the product and 2-chloro Ethyl isocyanate 2.5
If g is treated in the same manner as in Example 3, 4.3 g of 1-(2-chloroethyl)-3-(2-propynyl)-3-D-galactopyranosylurea is obtained as a colorless caramel.

Example 24 D-mannose 3.69 and n-butylamine 1.8
g was treated in the same manner as in Example 3 to obtain 1-n-butylamino-
1-Deoxy-D-mannose is obtained and then the product and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as in Example 3 to obtain 1-(2-chloroethyl)-
3-n-butyl-3-D-manonepyranosylurea 5.3
g is obtained as a colorless caramel.

Example 25 D-xylose 3, Og and n-propylamine 1.
5 g was treated in the same manner as in Example 3 to obtain 1-n-propylamino-1-deoxy-D-xylose, and then this product and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as in Example 3. 1-(2-chloroethyl)
-3-n-propyl-3-D-xylopyranosyl urea 4
．． 0.1 is obtained as a colorless caramel.

Example 26 3.0 g of D-xylose and 2.0 g of isopropylamine.
5 g was treated in the same manner as in Example 3 to obtain 1-isopropylamino-1-deoxy-D-xylose, and then 2.5 g of this product and 2-chloroethyl isocyanate) were treated in the same manner as in Example 3. 1-(2-chloroethyl)
-3-isopropyl-3-D-xylopyranosyl urea 4
．． 0 g is obtained as colorless caramel.

Example 27 3.0 g L-arabinose and 1 n-propylamine
．． 5 g was treated in the same manner as in Example 3 to obtain 1-n-propylamino-1-deoxy-L-arabinose, followed by the product and 2.5 g of 2-chloroethyl isocyanate.
When treated in the same manner as in Example 3, 4.1 g of 1-(2-chloroethyl)-3-n-propyl-3-L-arapippyranosylurea is obtained as colorless caramel.

Example 28 L-arabinose 3.0 g and isopropylamine 2
．． 5 g was treated in the same manner as in Example 3 to obtain 1-isopropylamino-1-deoxy-L-arabinose, followed by the product and 2.5 g of 2-chloroethyl isocyanate.
By treating in the same manner as in Example 3, 4.2 g of 1-(2-chloroethyl)-3-isopropyl-3-L-arabinopyranosyl urea is obtained as colorless caramel.

Example 29 3.0 g L-arabinose and isobutylamine 1.
8 g was treated in the same manner as in Example 3 to obtain 1-inbutylamino-1-deoxy-L-arabinose, and then this product and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as in Example 3. , 1-(2-chloroethyl)
-3-isobutyl-3-L-arabinopyranosyl urea 4
．． 3 g are obtained as colorless caramel.

Example 30 4.5 g of L-arabinose and 2.5 g of 2-propenylamine were treated in the same manner as in Example 3 to obtain 1-(2-propenylamino)-1-deoxy-L-arabinose,
The product and 3.5 g of 2-chloroethyl isocyanate are then treated in the same manner as in Example 3 to give 1-(2-chloroethyl)-3-(2-propenyl)-3-L-arapippyranosyl urea 5 .5 g are obtained as a colorless powder.

Example 31 D-maltose monohydrate 7.2 g, methylamine 0,'
1 and 2 oml methanol is heated in a sealed tube at 60° C. for 1 hour.

After the reaction is completed, the reaction solution is dried under reduced pressure to obtain N-(0-α-
D-glucopyranosyl-(1→4)-D-glucopyranosyl iomethylamine (i.e. 1-methylamino-
1-deoxy-D-maltose) 7.19 is obtained as crude product.

7.1 g of this crude product was dissolved in 50 ml of methanol, and a solution of 2.5 g of 2-chloroethyl isocyanate dissolved in 101 rL of tetrahydrofuran was added to the solution at 0 to 5 mL of tetrahydrofuran.
C. and stirred at the same temperature for 1.5 hours.

After the reaction is completed, the reaction solution is concentrated under reduced pressure, and the residual aroma is mixed with ethyl acetate,
If an ether mixture is added, 1-(2-chloroethyl)-
3-Methyl-3-[0-α-D-glucopyranosyl-(
1→4)-D-glucopyranosyl]urea (i.e.
7.4 g of -(2-chloroethyl)-3-methyl-3-D-maltosylurea) are obtained as a colorless amorphous powder.

Example 32 7.2 g of D-maltose monohydrate and 1.5 g of n-propylamine were treated in the same manner as in Example 31 to obtain 1-n-propylamino-1-deoxy-D-maltose, and then the Product and 2-chloroethyl isocyanate 2
．． 5g was treated in the same manner as in Example 31, 1-(2-chloroethyl)-3-n-propyl-3-[〇-α-D-
Glucopyranosyl(1→4)-D-glucopyranosyl]urea (i.e. 1-(2-chloroethyl)-3-n
8.5 g of -propyl-3-D-maltosylurea) are obtained as a colorless amorphous powder.

Example 33 7.2 g of D-maltose monohydrate and 2.0 g of isopropylamine were treated in the same manner as in Example 31 to obtain 1-isopropylamino-1-deoxy-D-maltose, and then the product and 2. -Chloroethyl isocyanate h2
．． If i is treated as in Example 31, 1-(2-chloroethyl)-3-isopropyl-cyl-(1→4)-D-glucopyranosyl]urea (i.e. 1-(2-chloroethyl)-3- Isopropyl
7.2 g of 3-D-maltosylurea are obtained as a colorless amorphous powder.

Example 34 7.2 g of D-maltose monohydrate and 2.2 g of n-butylamine were treated in the same manner as in Example 31 to obtain 1-n-butylamino-1-deoxy-D-maltose, and then the product and 2-chloroethyl isocyanate 2.5
g as in Example 31, 1-(2-chloroethyl)-3-n-butyl-3-(0-α-D-glucopyranosyl-(1→4)-D-glucopyranosyl)urea (i.e. , 1-(2-chloroethyl)-3-n-butyl-3-D-maltosylurea) s.og is obtained as a colorless powder.

Example 35 7.2 g of D-maltose monohydrate and 2.9 g of isobutylamine were treated as in Example 31 to obtain 1-isobutylamino-1-deoxy-D-maltose, and then the product and 2. -chloroethyl isocyanate 2.5
g in the same manner as in Example 31, 1-(2-chloroethyl)-3-isobutyl-3-(0-α-D-glycopyranosyl-(1→4)-D-glucopyranosyl)urea (sunawachi) , 1-(2-chloroethyl)-3-inphthyl-3-D-maltosylurea) are obtained as a colorless powder.

Example 36 7.2 g of D-maltose 1 hydrate and 2.5 g of n-pentylamine were treated in the same manner as in Example 31 to obtain 1-n
1-(
2-chloroethyl)-3-n-pentyl-3-[O-α
-D-glucopyranosyl-(1→4)-D-glucopyranosyl]urea (i.e. 1-(2-chloroethyl)-
3-n-pentyl-3-D-maltosyl urea)8. ]J
is obtained as a colorless powder.

Example 37 7.2 g of D-maltose monohydrate and 3.1 g of n-hexylamine were treated in the same manner as in Example 31 to obtain 1-n-hexylamino-1-deoxy-D-maltose, and then the Product and 2-chloroethyl isocyanate2.
When 5g of 5g is treated in the same manner as in Example 31, 1-(2-chlorinyl)-3-n-hexyl-3-[0-α-
D-glucopyranosyl-(1→4)-D-glucopyranosyl]urea (i.e. 1-(2-chloroethyl)-3
8.3 g of -n-hexyl-3-D-maltosylurea) are obtained as a colorless powder.

Example 38 7.2 g of D-maltose l-hydrate and 1.59 g of 2-propenylamine were treated in the same manner as in Example 31 to obtain 1-(2
-propenylamino)-1-deoxy-D-maltose is obtained, and if the product and 2.5 g of 2-chloroethyl isocyanate are then treated in the same manner as in Example 31, 1-
(2-chloroethyl)-3-(2-propenyl)-3-
(0-α-D-glucopyranosyl-(1→4)-D-glucopyranosyl]urea (i.e. 1-(2-chloroethyl)-3-(2-propenyl)-3-D-maltosyl urea) s, og Obtained as a colorless powder.

Example 39 7.2 g of D-maltose monohydrate and 2-methyl-2
-2.8 g of propenylamine was treated in the same manner as in Example 31 to obtain 1-(2-methyl-2-propenylamino)-1-
Example 31
If treated in the same manner as 1-(2-chloroethyl)-3-
(2-methyl-2-propenyl)-3-(0-α-D-
Glucopyranosyl-(1→4)-D-glucopyranosyl]urea (i.e. 1-(2-chloroethyl)-3-(
7.8 g of 2-methyl-2-propenyl)-3-D-maltosylurea are obtained as a colorless powder.

Example 40 7.2 g of D-maltose monohydrate and 2.1 g of 2-butenylamine were treated in the same manner as in Example 31 to obtain 1-(2-
Butenylamino)-1-deoxy-D-maltose is obtained, and if the product and 2.5 g of 2-chloroethyl isocyanate are then treated in the same manner as in Example 31, 1-(2
-chloroethyl)-3-(2-butenyl)-3-(0-
α-D-glucopyranosyl-(1→4)-D-glucopyranosyl]urea (i.e. 1-(2-chloroethyl)
-3-(2-butenyl)-3-D-maltosylurea)8
．． 2 g are obtained as a colorless powder.

Example 41 7.2 g of D-maltose monohydrate and 2.0 g of 3-butenylamine were treated in the same manner as in Example 31 to obtain 1-(3-
Butenylamine)-1-deoxy-D-maltose is obtained, and then this compound and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as in Example 31.
-chloroethyl)-3-(3-butenyl)-3-(0-
α-D-glucopyranosyl-(1→4)-D-glucopyranosyl]urea (i.e. 1-(2-chloroethyl)
-3-(3-butenyl)-3-D-maltosylurea)s
, og is obtained as a colorless powder.

Example 42 1.5 g of N-methyl-ethanolamine is dissolved in 30 rnl of tetrahydrofuran, and 2.19 g of 2-chloroethyl isocyanate is added dropwise thereto at 00-5°C.

The mixture is stirred at room temperature for 1.5 hours. After the reaction is completed, the reaction solution is concentrated under reduced pressure to obtain 1-(2-chloroethyl).
-3-Methyl-3-(2-hydroxyethyl)urea3.
5 g are obtained as a colorless oil.

Example 43 2.1 g of jetanolamine was dissolved in 30 g of tetrahydrofuran.
rIII! 2-chloroethyl isocyanate 1-2.19 is added dropwise thereto at 00 to 5°C.

This mixture is stirred at room temperature for 2 hours.

After the reaction is completed, the reaction solution is concentrated under reduced pressure to obtain 4.2 g of 1-(2-chloroethyl)3.3-bis(2-hydroxyethyl)urea as a colorless oil.

Example 44 3-chloro-1,2-dihydroxy-n-furopane 3
．． 3g and 2orn of 30% methylamine-methanol solution
The mixture with l is left at room temperature for 3 days.

After the reaction is completed, the reaction solution is dried under reduced pressure to obtain N-methyl-2
, 3-dihydroxy-n-propylamine hydrochloride 4.2
9 is obtained as crude product.

Dissolve 4.2 g of this product and 3 g of triethylamine in methanol 307721.

3.2 g of 2-chloroethyl isocyanate is added dropwise to this solution at 00 to 5°C, and the mixture is stirred at room temperature for 2 hours.

Next, the reaction solution was concentrated under reduced pressure, and the residual aroma was purified by silica gel chromatography [solvent: chloroform/ethyl acetate/methanol (3:1:1)] to obtain 1-(2-
3.5 g of chloroethyl)-3-methyl-3-(2,3-dihydroxy-n-propyl)urea are obtained as a colorless oil.

Example 45 3-chloro-1,2-dihydroxy-n-furopane 3
．． 3 g of n-propylamine and 8 g of n-propylamine at room temperature.
Leave it for several days.

After the reaction is completed, the reaction solution is dried under reduced pressure to obtain 5.0 g of N-n-propyl-2,3-dihydroxy-n-propylamine hydrochloride as a crude product.

Dissolve 5.0 g of this product and 3 g of triethylamine in 407 rL of methanol.

3.2 g of 2-chloroethyl isocyanate is added dropwise to this solution at 0 to 5°C.

If the reaction mixture is treated as in Example 44, 1-(2
-chloroethyl)-3-n-propyl-3-(2,3-
3.0 g of dihydroxy-n-propyl)urea are obtained as a colorless oil.

Example 6 1-n-Butylamino-1-deoxy-2,40-ethylidene-D-erythritol (from 2,4-0-ethylidene-D-erythrose J, Org.

Chem., 31.223 (1966)) was dissolved in 10% hydrochloric acid 207721.
Heat for an hour.

After the reaction is completed, the reaction solution is concentrated under reduced pressure to obtain 1-n-butylamino-1-deoxy-D-erythritol hydrochloride6.
4 g are obtained as crude.

6.4 g of main island and 3 g of triethylamine are dissolved in 40M methanol.

3.29 g of 2-chloroethyl isocyanate is added dropwise to this solution at 00-5°C.

If the reaction mixture is treated as in Example 44, 1-(2
-chloroethyl)-3-n-butyl-3-(1-deoxy-D-erythritryl)urea 5, Og is obtained as a colorless oil.

Example 47 1.6 g of 2-chloroethyl isocyanate is dissolved in 5 vllcc of tetrahydrofuran.

This solution was added to 50 ml of a methanol solution containing 2.9 g of N-methylglucamine under water cooling, and stirred at room temperature for 1 hour.

After the reaction is completed, the reaction solution is concentrated under reduced pressure, and the residual aroma is removed with ethanol.
Recrystallization from an ethyl acetate mixture yields 3.5 g of 1-(2-chloroethyl)-3-methyl-3-(1-deoxy-D-gluditolyl)urea as colorless crystals.

Example 48 N-n-butylglucamine (1-n-butylamino-1
Prepared by hydrogenation of -deoxy-D-glucose: J. Am. Chem. Soo.
79.3541 (1957)) 2.4.9 and 2
- If 1.1 g of chloroethyl isocyanate is treated in the same manner as in Example 47, 1-(2-chloroethyl)-3-n
3.5 g of -butyl-3-(1-deoxy-D-gluditolyl)urea are obtained as colorless caramel.

[method person]

1.2 g of 1-(2-chloroethyl)-3-methyl-3-D-glucopyranosyl urea prepared in Example 1 was mixed with 1.2 g of formic acid.
01rLl, and add 0.56% of sodium nitrite to this.
g is added over a period of 1 hour at 00-5° C. with stirring.

The mixture is stirred for an additional 1.5 hours at the same temperature.

After the reaction is completed, the reaction solution is freeze-dried, and the residual aroma is removed by silica gel chromatography [solvent: chloroform, ethyl acetate,
If purified with methanol (2:1:1), 1-(2
-chloroethyl)-1-nitroso-3-methyl-3-D
- 0.69 glucopyranosyl urea is obtained.

[Method B]

3.0 g of 1-(2-chloroethyl)-3-methyl-3-D-glucopyranosylurea prepared in Example 1 was added to 8 ornl of tetrahydrofuran and 80wLl of methylene chloride.
Dissolve in a mixed solution of and add 15 g of anhydrous sodium carbonate to this.

Add 5 g of nitrogen tetroxide gas to this mixture while cooling with water for 10 minutes.
After the introduction took a few minutes, the solution was stirred for an additional 10 minutes at the same temperature.

After the reaction is completed, methanol 107711 and 3 ml of water are added to the reaction solution, and the mixture is stirred for 10 minutes.

After drying this solution, the solvent was distilled off, and the residual aroma was removed by silica gel chromatography [solvent: ethyl acetate, chloroform,
If purified with methanol (5:2:1), 1-(2
-chloroethyl)-1-nitriso-3-methyl-3-D
-2.4 g of glucopyranosyl urea are obtained as a pale yellow powder.

Reference Examples 2-48 1-(2-chloroethyl)- prepared in Examples 2-48
The following compound was synthesized by nitrosating 3,3-disubstituted urea according to Method A or B of Reference Example 1.

(2) 1-(2-chloroethyl)-1-nitrone-3-
Ethyl-3-D-glucopyranosyl urea, pale yellow caramel (3) 1-(2-chloroethyl)-1-nitroso-3-
n-propyl-3-D-glucopyranosyl urea, pale yellow caramel (4) 1-(2-chloroethyl)-1-nitroso-3-
Isopropyl-3-D-glucopyranosyl urea, pale yellow caramel (5) 1-(2-chloroethyl)-1-nitroso-3-
n-Butyl-3-D-glucopyranosyl urea, pale yellow caramel (6) 1-(2-chloroethyl)-1-nitroso-3-
Inbutyl-3-D-glucopyranosyl urea, yellow caramel (7) 1-(2-chloroethyl)-1-nitroso-3-
n-pentyl-3-D-glucopyranosyl urea, yellow caramel (8) 1-(2-chloroethyl)-1-nitroso-3-
n-hexyl-3-D-glucopyranosyl (9) 1-(
2-chloroethyl)-1-nitroso-3-n-dodecyl-3-D-glucopyranosyl urea, yellow caramel (10) 1-(2-chloroethyl)-1-nitroso-3
-n-nonadecyl-3-D-glucopyranosyl urea, yellow caramel αυ 1-(210 loethyl)-1-nitroso-3-n
-hexadecyl-3-D-glucopyranosyl urea, yellow caramel (12) 1-(2-chloroethyl)-1-nitroso-3
-n-octadecyl-3-D-glucopyranosyl urea,
Yellow caramel α3) 1-(2-chloroethyl)-1-nitroso 3-n
-Propyl-3-D-galactopyranosyl urea, pale yellow caramel (14) 1-(2-chloroethyl)-1-nitroso-3
-isopropyl-3-D-galactopyranosyl urea, pale yellow caramel (151 1-(2-chloroethyl)-1-nitroso-3-n-butyl-3-D-galactopyranosyl urea, yellow powder M, p, 44° to 46.5°C (decomposed) (16) 1-(2-chloroethyl)-1-nitroso-3
-Inbutyl-3-D-galactopyranosyl urea, pale yellow powder (17) 1-(2-chloroethyl)-1-nitroso3-
see, butyl-3-D-galactopyranosyl urea,
Pale yellow caramel (18) 1-(2-chloroethyl)-1-nitroso-3
-n-pentyl-3-D-galactopyranosyl urea, yellow caramel (19) 1-(2-chloroethyl)-1-nitroso-3
-isopentyl-3-D-galactopyranosyl urea, yellow caramel (20) 1-(2-chloroethyl)-1-nitroso-3
-Neopentyl-□-D-galactopyranosyl urea, yellow caramel (21) 1-(2-chloroethyl)-1-nitroso-3
-n-octadecyl-3-D-galactopyranosyl urea, yellow caramel (2 pieces 1-(2-chloroethyl)-1-nitroso-3
-(2-propenyl)-3-D-galactopyranosyl urea, yellow caramel (23) 1-(2-chloroethyl)-1-nitroso 3
-(2-propynyl)-3-D-galactopyranosyl urea, pale yellow powder (2) 1-(2-chloroethyl)-1-nitroso-3
-n-butyl-3-D-mannopyranosyl urea, yellow caramel (25) 1-(2-chloroethyl)-1-nitroso-3
-n-propyl-3-D-xylopyranosyl urea, pale yellow caramel (26) 17(2-chloroethyl)-1-nitroso-3
-isopropyl-3-D-xylopyranosyl urea, yellow powder (27) 1-(2-chloroethyl)-1-nitroso-3
-n-propyl-3-L-arabinopyranosyl urea, pale yellow caramel (28) 1-(2-chloroethyl)-1-nitroso-3
-isopropyl-3-L-arabinopyranosyl urea, yellow caramel (29) 1-(2-chloroethyl)-1-nitroso-3
-isobutyl-3-L-arabinopyranosyl urea, pale yellow caramel (30) 1-(2-chloroethyl)-1-nitroso-3
-(2-propenyl)-3-L-arabinopyranosyl urea, yellow caramel (31) 1-(2-chloroethyl)-1-nitroso-3
-Methyl-3-[〇-α-D-glucopyranosyl(1
→4)-D-glucopyranosyl]urea (i.e. 1-
(2-chloroethyl)-1nitroso-3-methyl-3-
D-maltosylurea), pale yellow powder M, p, 66°~70'C (decomposed) (3 desired 1-(2-chloroethyl)-1-nitroso-3
-n-propyl-3-[0-α-D-glucopyranosyl-(1→4)-D-glucopyranosyl]urea (i.e. 1-(2-chloroethyl)-1-nitroso-3-n-
(33) 1-(2-chloroethyl)-1-nitroso-3
-isopropyl-3-[〇-α-D-glucopyranosyl(1→4)-D-glucopyranosyl]urea (i.e. 1-(2-chloroethyl)-1-nitroso-3-isopropyl-3-D- maltosylurea), pale yellow powder M, p, 6-6° to 71°C (decomposition) (34) 1-
(2-chloroethyl)-1-nitroso-3-n-butyl-3-[O-α-D-glucopyranosyl-(1→4)-
D-glucopyranosyl]urea (i.e. 1-(2-chloroethyl)-1-nitroso-3-n-butyl-3-D
-maltosylurea), pale yellow powder M, p, 76° to 80°C (decomposition) C35) 1-(2-chloroethyl)-1-nitroso-3
-isobutyl-3-[〇-α-D-glucopyranosyl)
-(1→4)-D-glucopyranosyl]urea (i.e. 1-(2-chloroethyl)-1-nitroso-3-inbutyl-3-D-maltosyl urea), yellow powder (36) 1(2-chloroethyl) -1-nitroso-3-
n-pentyl-3-[〇-α-D-glucopyranosyl(1→4)-D-glucopyranosyl]urea (i.e.
1-(2-chloroethyl)-1-nitroso-3-n-pentyl-3-D-maltosylurea), pale yellow powder (37) 1-(2-chloroethyl)-1-nitrone-3
-n-hexyl-3-[O-α-D-glucopyranosyl-(1→4)-D-glucopyranosyl]urea, i.e.
1-(2-chloroethyl)-1-nitroso-3-n-hexyl-3-D-maltosylurea), pale yellow powder (38) 1-(2-chloroethyl)-1-nitroso-3
-(2-propenyl)-3-("0-α-ri-glucopyranosyl(1→4)-D-glucopyranosyl)urea (
That is, 1-(2-chloroethyl)-1-nitroso-
3-(2-jlopenyl)-3-D-maltosylurea),
Pale yellow powder M, p, 67°C (decomposed) (39) 1-(2-chloroethyl)-1-nitroso-3
-(2-methyl-2-propenyl)-3-[O-α-D
-Glucopyranosyl-(1→4)-Dglucopyranosyl]urea (i.e. ■-(2-chloroethyl)-1-nitroso-3-(2-methyl-2-propenyl)-3-D
-maltosylurea), pale yellow powder M, p, 76° to 800C (decomposed) (40) 1-(2-chloroethyl)-1-nitroso-3
-(2-Butenyl)-3-(0-α-D-glucopyranosyl-(1→4)-D-glucopyranosyl)urea (i.e. 1-(2-chloroethyl)-1-nitroso-3-
(2-butenyl)-3-D-maltosylurea), pale yellow powder M, p, 73° to 76°C (decomposition) (4]) 1-(2-chloroethyl)-1-nitroso-
3-(3-butenyl)-3-(0-α-D-glucopyranosyl-(1→4)-D-glucopyranosyl)urea (i.e. 1-(2-chloroethyl)-1-nitroso-3
-(3-butenyl)-3-D-maltosylurea), pale yellow powder M, p, 74°C (decomposed) (42) 1-(2-chloroethyl)-1-nitroso-3-methyl-3-(2 -hydroxyethyl)urea, pale yellow oil (43) 1-(2-chloroethyl)-1-nitroso-3,3-bis(2-hydroxyethyl)urea, yellow oil (44) 1-(2-chloroethyl) )-1-nitroso 3-methyl-3-(2,3-dihydroxy-n-propyl)urea, pale yellow oil (45) 1-(2-chloroethyl)-1-nitroso-
3-n-propyl-3-(2,3-dihydroxy-n-
propyl) urea, yellow oil (45) 1-(2-chloroethyl)-1-nitroso-3-n-butyl-3-(1-deoxy-D-erythritryl) urea, yellow oil (47) 1-( 2-chloroethyl)-1-nitroso-3-methyl-3-(1-deoxy-D-gluditolyl)urea, pale yellow caramel (48) 1-(2-chloroethyl)-1-nitroso-
3-n-butyl-3-(1-deoxy-D-gluditolyl) urea, pale yellow powder M, p, 65° to 67°C (decomposed) Experimental example [Experimental method] Leukemia L-1210 cells (1 x IO5 cells) ) into BDF1 mice or Ehrlich ascites carcinoma cells (IXI
O' pieces) are intraperitoneally transplanted into ICR mice.

24 hours after transplantation, the following compound is continuously administered intraperitoneally once a day for 5 days.

The effect on leukemia L-1210 was determined by comparing the average survival days of the administered group and the non-administered group.

Furthermore, the effect on Ehrlich ascites cancer was determined by measuring the amount of ascites cancer accumulated 7 days after the first administration.

[Test compound]

〔Experimental result〕 The results are shown in Table 2 below.

However, the abbreviations in the table have the following meanings.

■LS3o; Daily dose 0, D, required to increase the average survival days of mice transplanted with tumor cells by 30% compared to that of the non-administered group; Maximum survival prolonging effect on mice transplanted with tumor cells. Shown daily dosage T, R, (for anti-L-1210 action); C6D, /■
LS3゜M, E, D,: 1 increase in the proliferation of Ehrlichi ascites cancer cells
Minimum effective dose that inhibits 00% Mex, D-: Maximum dose that inhibits cancer cell proliferation by 100% without killing mice T, R, (for anti-Ehrlich action); Max, D/
M, E, D.

Claims (1)

[Claims] 1 General formula [where R1 is an alkyl group having 1 to 2 carbon atoms, 1 to 2 carbon atoms]
6 represents a hydroxyalkyl group, an alkenyl group having 3 to 5 carbon atoms, or an alkynyl group having 3 to 5 carbon atoms, and R2 is a D-glucopyranosyl group, a D-galactopyranosyl group,
D-mannopyranosyl group, D-xylopyranosyl group, L
-arabinopyranosyl group, 0-α-D-glucopyranosyl-(1→4)-D-glucopyranosyl group or represented by the formula % (where n represents O or an integer from 1 to 4) represents a group. ] A urea derivative represented by 2 General formula [However, R1 is an alkyl group having 1 to 2 carbon atoms, 1 carbon number
-6 hydroxyalkyl group, alkenyl group having 3 to 5 carbon atoms, or alkynyl group having 3 to 5 carbon atoms, R2 is a D-glucopyranosyl group, a D-galactopyranosyl group,
D-mannopyranosyl group, D-xylopyranosyl group, L
-Arabinopyranosyl group, O-α-D-glucopyranosyl-(1→4)-D-glucopyranosyl group or represented by the formula % (where n represents O or an integer from 1 to 4) represents a group. ] (wherein R1 and R2 have the same meanings as above), characterized in that a secondary amine represented by the formula % is subjected to a condensation reaction with 2-chloroethyl isocyanate represented by the formula %. Method for producing urea derivatives.