JPS6055077B2 - Nitrosourea derivatives and their production method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel nitrosourea derivatives and methods for their production.

For more details, general formula>N-C0--N-CH2CH2C
1C1] [However, R1 represents a lower alkoxy group, a lower alkoxy-methoxy group, or a 2-hydroxyethoxy group, and R2 represents an aldopentopyranosyl group, an aldohexopyranosyl group, or a 0-aldohexopyranosyl group (
1→4)-Aldohexopyranosyl group, A has 1 to 4 carbon atoms and may be substituted with a lower alkoxy group.
represents a straight-chain or branched alkylene group.

].

It is known that (N''-chloroethyl-N''-nitrosocarbamoyl)-amino derivatives of monosaccharides can be obtained by nitrosation of (N'-chloroethylcarbamoyl)-amino monosaccharides with an alkali metal nitrite salt such as sodium nitrite. (Japanese Patent Application Laid-open No. 108043/1983, Japanese Patent Application Laid-Open No. 1983-
No. 26876, JP-A No. 51-52128).

In addition, these patent publications include 1-(2-chloroethyl)-1-nitroso-3-(D-mannopyranosyl)urea and 1-(2-chloroethyl)-1-nitroso-3-(
It has been revealed that D-glucopyranosyl) urea (hereinafter abbreviated as "GANU") has a survival effect on mice intraperitoneally transplanted with lymphocytic leukemia cells L-1210.In addition, 1-(2-chloroethyl) urea -(N″-chloroethyl-N-nitrosocarbamoyl)amino derivatives of disaccharides such as 1-nitroso-3-(D-lactosyl)urea and 1-(2-chloroethyl)-1-nitroso-3-(D-maltosyl)urea can be synthesized from the corresponding (N'-chloroethylcarbamoyl)aminoni-saccharide by the same method as above, and it is also known that it exhibits antitumor activity against leukemia cells (Japanese Unexamined Patent Publication No. 14181-1981).
No. 5). On the other hand, as a result of various studies, the present inventors found that the novel nitrosourea compound [1] exhibits excellent antitumor and antileukemia effects. For example, when each compound was continuously administered intraperitoneally for 5 days to mice transplanted with leukemia cells L-1210,
1-(2-chloroethyl)-1-nitroso 3-(2-
Methoxyn-propyl)-3-(L-arabinopyranosyl)urea was also administered at 0.5 m9/K9/Day to 1-(2-chloroethyl)-1-nitroso-3-(1-
Methyl-2-methoxyethyl)-3-(L-arabinopyranosyl)urea can increase the average survival days of the aforementioned mice by approximately 30% compared to the non-administered group by administering 0.45Tn9/K9/Day. can.

Furthermore, the nitrosourea compound [1] of the present invention exhibits excellent safety when used as an antitumor agent.

For example, the therapeutic index for leukemia cells L-1210 is set to 0.
D (optimal dose = daily dose showing the maximum survival effect on mice transplanted with the tumor cells)/1. L.
S3.

(The daily dose required to increase the average survival days of mice transplanted with the tumor cells by 30% compared to the non-administered group), 1-(2-chloroethyl)-
1-nitroso-3-(1-methyl-2-methoxyethyl)-3-[0-α-D-glucopyranosyl(1→4)
-D-glucopyranosyl]urea, 1-(2-chloroethyl)-1-nitroso3-(3-methoxy n-propyl)-3-(L-arabinobyranosyl)urea and 1-(
2-chloroethyl)-1-nitroso-3-(3-methoxyn-propyl)-3-(D-arabinopyranosyl)
Urea exhibits a therapeutic index approximately 7 to 12 times greater than GANU. In addition, the therapeutic index for Ehrlichi's ascites cancer was determined by M. T. D. (Maximum tolerated dose=maximum dose that inhibits the growth of Ehrlichi's ascites carcinoma by 100% without causing the death of the transplanted mouse)/M. E. Calculated from the ratio of D (minimum effective dose = minimum dose that inhibits the growth of the ascites cancer by 100%), 1-(2-chloroethyl)-
1-nitroso3(1-methyl-2-methoxyethyl)-3-[0-α-D-glucopyranosyl(1→4)
-D-glucopyranosyl]urea, 1-(2-chloroethyl)-1 nitroso-3-(3-methoxy n-propyl)-3-(L-arabinopyranosyl)urea and 1-(2-chloroethyl)-1
The therapeutic index of -chloroethyl)-1-nitroso-3-(3-methoxy n-propyl)-3-(D-arabinopyranosyl) urea is four times greater than that of GANU. The above general formula [
1], examples of R1 include lower alkoxy groups such as methoxy, ethoxy and propoxy groups; lower alkoxy-methoxy groups such as methoxymethoxy and ethoxymethoxy groups; and 2-hydroxyethoxy groups; Examples include D-ribopyranosyl; L-
Aldopentopyranosyl groups such as arabinopyranosyl group, D-arabinopyranosyl group and D-xylopyranosyl group; D-glucopyranosyl group, D-galactopyranosyl group, D-mannopyranosyl group, L-rhamnopyranosyl group aldohexopyranosyl group such as D-fucopyranosyl group and D-talopyranosyl group; O-α-D-glucopyranosyl (1→4)-D-glucopyranosyl group (=
D-maltosyl group) and O-aldohexopyranosyl group (1→4)-D-glucopyranosyl group (=D-lactosyl group)
→4)-Aldohexopyranosyl group is mentioned.

Examples of A include linear or branched groups such as methylene group, ethylene group, propylene group, butylene group, 1-methylethylene group, 1-ethylethylene group, 2-methylethylene group, and 2-ethylethylene group. Arekylene group; 2
-methoxyethylene group, 2-ethoxyethylene group, 2-
Included are lower alkoxy-substituted alkylene groups such as methoxypropylene and 2-ethoxypropylene. Among the compounds of the present invention, as a preferable group of compounds of general formula [1], R2 is a D-ribopyranosyl group, a L-arabinopyranosyl group, a D-arabinopyranosyl group, a D-xylopyranosyl group, a D- -glucopyranosyl group, D-galactopyranosyl group, D-mannopyranosyl group or O-α
-D-glucopyranosyl-(1→4)-D-glucopyranosyl group is mentioned.

A more preferable group of compounds [1] is R1
is an alkoxy group having 1 to 2 carbon atoms, R2 is a D-ribopyranosyl group, an L-arabinopyranosyl group, a D-arabinopyranosyl group, a D-xylopyranosyl group, a D-galactopyranosyl group, D-mannopyranosyl group or O-α-
D-glucopyranosyl (1→4)-D-glucopyranosyl group, and compounds in which A is a linear or branched alkylene group having 2 to 3 carbon atoms are mentioned. In a still more preferable group of compounds [1], R1 has 1 carbon number.
~2 alkoxy group, R2 is L-arabinopyranosyl group, D-arabinopyranosyl group, or 0-α-D-glucopyranosyl(1→4)-D-glucopyranosyl and A is an ethylene group, a propylene group, a 1-methylethylene group or a 2-methylethylene group. According to the present invention, the nitrosourea compound [1] can be produced by nitrosating a compound represented by the general formula [■].

(However, Rl, R2, and A have the same meanings as above.

) The raw material [■] can be easily produced. For example, the formula R1-A-NH2 (wherein R1 and A have the same meanings as above).

) and the formula R2-0H (However, R2 has the same meaning as above.

) in an inert solvent (e.g. methanol, ethanol) at 20°C to 80°C to form a compound represented by the formula (
However, Rl, R2 and A have the same meanings as above.

) and then combine the secondary amine with 2-chloroethyl isocyanate and an inert solvent (e.g., tetrahydrofuran, methanol, ethanol).
It can be produced by condensation at medium temperature of 0°C to 30°C.

The nitrosation reaction of the present invention can be carried out by bringing the compound [■] into contact with nitrous acid, nitrogen trioxide or nitrogen tetroxide in an inert solvent.

The reaction is carried out between -20°C and 20°C, particularly between about 0°C and about 5°C.
It is preferable to carry out. Inert solvents include water, lower alkanols (e.g. methanol, ethanol),
Tetrahydrofuran, methylene chloride, ethyl acetate, acetic acid, formic acid, etc. can be used as appropriate. Nitrous acid is a combination of an alkali metal salt of nitrite (e.g., sodium nitrite, potassium nitrite) or a lower alkyl ester of nitrite (e.g., butyl nitrite, amyl nitrite) and an inorganic or organic acid (e.g., hydrochloric acid). , sulfuric acid, formic acid, acetic acid) and is preferably used in the nitrosation reaction immediately after preparation. On the other hand, when using nitrogen trioxide or nitrogen tetroxide in the present invention, the raw material compound [■] is dissolved or suspended in an inert solvent, and the gaseous nitrogen trioxide is released in the presence or absence of an acid acceptor. Preferably, the nitrosation reaction is carried out by communicating nitrogen oxide or nitrogen tetroxide. Acid receptors include sodium bicarbonate, sodium carbonate, potassium carbonate,
Titrium acetate, potassium acetate, etc. can be used as appropriate. After the nitrosation reaction is completed, the compound [1] of the present invention can be easily recovered from the reaction mixture and, if necessary, purified by silica gel chromatography.

The thus obtained nitrosourea compound [1] can be used for Ehrlichigan, Sarcoma 180, Leukemia L-121C)
It exhibits strong antitumor effects against various tumor cells such as Lewis lung cancer, Yoshida sarcoma, and rat ascites liver cancer, prolongs the survival period of warm-blooded animals affected by these tumors, and/or It can inhibit the growth of tumor cells in animals. The compound [1] of the present invention can also be used for malignant lymphoma, leukemia,
It can also be used to treat stomach cancer, liver cancer, and other malignant tumors. When the nitrosourea compound [1] is used for pharmaceutical purposes, it may be used in any dosage form suitable for oral or parenteral administration, and it can also be used in combination with excipients.

As the excipient, a compound [one that does not chemically react with IL] is selected. Suitable excipients include, for example, gelatin, lactose, glucose, common salt, starch, magnesium stearate, talc, vegetable oils and other pharmaceutical excipients. The preparation may be a solid preparation such as a tablet, pill, or capsule, or a liquid preparation such as a solution, suspension, or emulsion. Furthermore, the compound [
1] can also be used as an injection or a suppository when administered parenterally. The formulation may also be sterilized and/or contain adjuvants such as preservatives and stabilizers. The pharmaceutical dosage of compound [1] varies depending on the administration method, patient's age, weight, condition, and disease to be treated, but the preferred daily dosage is usually about 0.1 to
about 30 mg/K9, especially about 0.2 to about 10 m9/K
There is z in g. Experimental Examples The therapeutic effects of the nitrosourea compounds of the present invention were tested using the following methods and compounds using mice transplanted with various cancer cells.

Test method ~ Effect of suppressing the growth of Ehrlichi's ascites carcinoma in female mice (I
CR mice, body weight: 19-23') 5 mice per group,
Ehrlichi ascites cancer cells (1×1 (1P cells)) are intraperitoneally transplanted into this.

Each test compound was dissolved in physiological saline (CCNU was 0
．． 24 hours after transplantation, this is administered intraperitoneally once a day for 5 consecutive days to mice. The effect was measured by measuring the amount of ascites cancer 7 days after the first administration. t) Effect of prolonging the survival days of leukemia L-12 cells transplanted mice Male mice (BDF1 mouse, body weight: 19-23y)
) Leukemia L-12W cells (1 x 1σ cells) are intraperitoneally transplanted into groups of 4 or 6 animals.

Each test compound was dissolved in physiological saline, and this was added to the
After a period of time, the drug is intraperitoneally administered to mice once a day for 5 consecutive days. Efficacy was determined by comparing the average survival days between the administered and non-administered groups. (Test compound 1 Compound name (Compound of the invention 1-(2-chloroethyl)-1-nitroso-3-(2-
methoxyn-propyl)-3-[0-α-D-glucopyranosyl(1→4)-D-glucopyranosyl]urea! 1-(2-chloroethyl)-1-nitroso3-(1
-methyl-2-methoxyethyl)-3-[0-α-D
-Glucopyranosyl(1→4)-D-glucopyranosyl]urea: 1-(2-chloroethyl)-1-nitroso3-(2-methoxyethyl)-3-(L-arabinopyranosyl)urea 1 -(2-chloroethyl)-1-nitroso3-(4-methoxyn-propyl)-3-(L-arabinopyranosyl)urea 1-(2-chloroethyl)-1
-Nitroso3-(2-methoxyn-propyl)-3
-(L-arabinopyranosyl)urea 1-(2-chloroethyl)-1-nitroso-3-(1-methyl-2-methoxyethyl)-3-(L-arabinopyranosyl)urea 1
-(2-chloroethyl)-1-nitroso3-(3-(
methoxyn-propyl)-3-(D-arabinopyranosyl)urea 1-(2-chloroethyl)-1-nitroso-3-(1-methyl-2-methoxyethyl)-3-(D
-galactopyranosyl)urea 1-(2-chloroethyl)
-1-nitroso-3-(2-methoxyethyl)-3-(
D-ribopyranosyl)urea 1-(2-chloroethyl)-
1-nitroso-3-(2-methoxyethyl)-3-(D
-xylopyranosyl)urea 1-(2-chloroethyl)-
1-nitroso-3-(2-methoxyethyl)-3-(D
-mannopyranosyl) urea 121-(2-chloroethyl)-1-nitroso 3-(3-methoxy n-propyl)-3-(D-glucopyranosyl) urea Known compounds CCNU: 1-(2-chloroethyl)-1-nitroso 3-Cyclohexylurea GANU: 1-(2-chloroethyl)-1-nitroso-3-(D-glucopyranosyl)urea Results The experimental results are shown in Tables 1 and 2, respectively.

<Note> (a): T = treatment group C = non-treatment group C-T (b): Suppression rate (4) = o x 100 (c): M
．． T. D = Maximum tolerated dose (maximum dose that suppresses the growth of Ehrlichi's ascites carcinoma by 100C!i without causing the death of the transplanted mouse) (d): MED
= Minimum effective dose (1009
6) (e): Therapeutic index = M. T.
D/M. E. D(+): Number of dead mice/Number of mice used Example 1 (1) D-maltose monohydrate 7.2y12-Methoxyethylamine 2.3f and methanol 15ml were stirred at 60°C to 65°C for 4 hours. It's heating up! Ru.

The reaction mixture is concentrated to dryness under reduced pressure. By washing the residue with ether, 1-(2-methoxyethylamino)-1-deoxy-D-maltose is obtained as a crude product. This crude product was dissolved in methanol 507711,
Add 2.5y of 2-chloroethyl isocyanate to this solution.
A solution of 10 ml of tetrahydrofuran was added dropwise at 0°C to 5°C. The reaction mixture is stirred at room temperature for 1 hour. After the reaction is complete, the mixture is concentrated under reduced pressure. By washing the residue with ether, 1-(2-chloroethyl)-3
-(2-methoxyethyl)-3-[0-α-D-glucopyranosyl(1→4)-D-glucopyranosyl]urea (i.e., 21-(2-chloroethyl)-3-(2-methoxyethyl) )-3-(D-maltosyl)urea 8.5q is obtained as a colorless powder.
): 3350, 1630, 1540, 1070
, 1025NMR (D2O) δ: 3.35 (S, OC Dan.

)) 1-(2-chloroethyl)-3-(2-methoxyethyl)-3-[0-α-D-glucopyranosyl(1→
4) Dissolve 5.0f1 of -D-glucopyranosyl]urea in a mixture of 20ml of tetrahydrofuran and 20ml of acetic acid,
Add 20 f of anhydrous sodium acetate to this solution. One drop of nitrogen tetroxide is passed through this mixture while stirring and cooling with ice. The mixture is further stirred at the same temperature for two more times. Add 200ml of n-hexane to the reaction mixture,
Insoluble materials are removed by filtration, and the filtrate is concentrated under reduced pressure. Add 200ml of a mixture of ethernimethanol (40:1) to the residue.
1 and the resulting oil was purified by silica gel chromatography (solvent: ethyl acetate dichloroformimethanol 2:1:1) to obtain 1-(2-chloroethyl)-1-nitroso 3-( 2-methoxyethyl)
-3-[0-α-D-glucopyranosyl(1→4)-
D-glucopyranosyl]urea (i.e. 1-(2-chloroethyl)-1-nitroso-3-(2-methoxyethyl)
-3-(D-maltosyl)urea) 2.9y is obtained as a pale yellow powder. M. P. 57C (decomposition) IRpH? 01 (Cm-1): 3350, 169 length 10
7011025NMR(D2O)δ:3.38(S,O
CH3) [α]? +54.7 (C=1.2, methanol) Example 2 (1) D-maltose monohydrate 7.2y
, 2.7 g of 3-methoxy n-propylamine and 2-
2.5y of chloroethyl isocyanate was added to (1
), 1-(2-chloroethyl)-3-(3-methoxyn-propyl)-3-[0
-α-D-glucopyranosyl(1→4)-D-glucopyranosyl]urea (i.e. 1-(2-chloroethyl)-
9.0y of 3-(3-methoxyn-propyl)-3-(D-maltosyl)urea) is obtained as a colorless powder.

IRv child P1 (d-1): 3350, 1635, 15
40, -1030NMR to -107 (D2O)
δ: 1.75-2.15 (M, 2H, -
CH2CH2CH2-) 3.30 (S, (1) days.

) (2) 1-(2-chloroethyl)-3-(3-meth.
5.
By treating 2f and nitrogen tetroxide gas 8f in the same manner as in (2) of Example 1, 1-(2-chloroethyl)-1
-Nitroso-3-ζ (3-methoxy n-propyl)-
3-[0-α-D-glucopyranosyl(1→4)-D
3.0 g of -glucopyranosyl]urea (i.e. 1-(2-chloroethyl)-1-nitroso-3-(3-methoxyn-propyl)-3-(D-maltosyl)urea) are obtained as a pale yellow powder.

M. P. 7O゜C-74 Yellow C (decomposition) IRp:? 01(
(7!t-1): 335 to 170 to 107 to 1030N
MR (D2O) δ: 1.85-2.25 (M, 2H, -
CH2C ratio CH2-) 3.30 (S, 3
H, O.C. H3) [α]? +62.4 Example 3: 1) By treating D-maltose monohydrate 7.2V12-ethoxyethylamine 2.8y and 2-chloroethyl isocyanate 2.5y in the same manner as in Example 1 (1). , 1-(2-chloroethyl)-3-(2-ethoxyethyl)-3-[0-α-D-glucopyranosyl(1→4)-D-glucopyranosyl]urea (i.e., 1-
(2-chloroethyl)-3-(2-ethoxyethyl)-3-(D-maltosyl)urea) 8.9y is obtained as a colorless powder.

■Rv? Gate ↓01 (α-1): 3340, 1640, 1
555, 07011025NMR (D2O) δ: 1.2
0(T,OCH2C)2)1-(2-chloroethyl)
-3-(2-ethoxyethyl)-3-[0-α-D-glucopyranosyl(1→4)-D-glucopyranosyl]
5.2 f of urea and 8 f of nitrogen tetroxide gas were added to (2
), 1-(2-chloroethyl)-1-nitroso-3-(2-ethoxyethyl)-3
-[0-α-D-glucopyranosyl(1→4)-D-
glucopyranosyl]urea (i.e., 1-(2-chloroethyl)-1-nitroso-3-(2-ethoxyethyl)-3
-(D-maltosyl)urea 3.2y is obtained as a pale yellow powder.

M. P. 58℃ (decomposition) Nail ν = Snake 01 (Tsuichi Riniyooi to 171 to 107 to 103
0NMR (D2O) δ: 1.21 (T, OCH2C.U
3) [α]W+52.0: (C=1.methanol) Example 4 =) D-maltose monohydrate 7.2y13-ethoxy n-propylamine 3.0f and 2-chloroethyl isocyanate 2 By treating .5V in the same manner as in Example 1 (1), 1-(2-chloroethyl)-3
-(3-ethoxy n-propyl)-3-[0-α-D
-glucopyranosyl(1→4)-D-glucopyranosyl]urea (i.e. 1-(2-chloroethyl)-3-(3
-ethoxy n-propyl)-3-(D-maltosyl)
Urea) 8.5y is obtained as a colorless powder.

IRv:X↓01(Cln-1):3350, 1630
, 1540, 107011025NMR (D2O) δ:
1.20 (T, 3H, OCH2CU3) 1.65-2.
15 (M, 2H, one CH2CU2CH2
-) b(2) 1-(2-chloroethyl)-3
-(3-ethoxy n-propyl)-3-[0-α-D
-Glucopyranosyl(1→4)-D-glucopyranosyl] By treating 5.3y of urea and 8y of nitrogen tetroxide gas in the same manner as in (2) of Example 1, 11-(2-chloroethyl)-1 -Nitroso-3-(3-ethoxy n-
propyl)-3-[0-α-D-glucopyranosyl(
1→4)-D-glucopyranosyl]urea (i.e. 1-(
2-chloroethyl)-1-nitroso3-(3-ethyl)
xy-n-propyl)-3-(D-maltosyl)urea)
3.0f is obtained as a pale yellow powder.

M. P. 63℃ (decomposition) IRp: 01 (Crft-1
): 335 to 169 to 107 to 1020NMR (D2O
) δ: 1.17 (T, 3H, OCH2qdan 23) 1.8
0-2.30 (M, 2H, 1 CH2CJ
J2CH2-) [α]f+63.7 (C=1.1, methanol) Example 5 (1) D-maltose monohydrate 7
．． 2f12-meth2xy n-propylamine 3.0V
and 2-chloroethyl isocyanate 2.5f in the same manner as in Example 1 (1) to obtain 1-(2-chloroethyl)-3-(2-methoxy n-propyl)-
3-[0-α-D-glucopyranosiluni(1→4)-
D-glucopyranosyl]urea (i.e. 1-(2-chloroethyl)-3-(2-methoxyn-propyl)-3-
(D-maltosyl)urea) 8.1q is obtained as a colorless powder.

IRp! X spoon 01 (c!rl-1): 3a0, 1640
, 107 to 1030 NMR (D2O) δ: 2.20 (D
,3H,-CH(0CH3)Cdan. )3.42(S,3
H, OCJ] 3) (2) 1-(2-chloroethyl)-3-(2-methoxy n-propyl)-3-[0-α-D-glucopyranosyl(1→4)-D-glucopyranosyl ] Urea 5.2y
and nitrogen tetroxide gas 8y in the same manner as in (2) of Example 1 to obtain 1-(2-chloroethyl)-1-nitroso-3-(2-methoxy n-propyl)-3-[
0-α-D-glucopyranosyl(1→4)-D-glucopyranosyl]urea, 1-(already, 1-2-chloroethyl)-1-nitroso-3-(2-methoxy n-propyl )-3-(D-maltosyl)urea) 3.3y is obtained as a pale yellow powder.

M. P. 5l3C (decomposition) IRvshi01 (Cm-1):
3380. ,170011075ps1030NMR(
D2O) δ:2.20(D,3H,-CH(0CH3)
C-dan.

)3.36 (S, 3H, OCH3) [α]? +55.3) (C=1.1, methanol)j Example 6) Maltose monohydrate 7.2y1 (1-methyl-2-methoxyethyl)amine 3.6y and 2-chloroethyl isocyanate 3.5y By treating in the same manner as in Example 1 (1), 1-(2-chloroethyl)-
3-(1-methyl-2-methoxyethyl)-3-[0
-α-D-glucopyranosyl(1→4)-D-glucopyranosyl]urea (i.e. 1-(2-chloroethyl)-
3-(1-methyl-2-methoxyethyl)-3-(D
-maltosyl)urea) 8.5y is obtained as a colorless powder.

IRv child r1 (0-1): 3350, 1630, 15
30106\10202)1-(2-chloroethyl)-
3-(1-methyl-2-methoxyethyl)-3-[0
1-(
2-chloroethyl)-1-nitroso3-(1-methyl-2-methoxyethyl)-3-[0-α-D-glucopyranosyl(1→4)-D-glucopyranosyl]urea (i.e., 1- (2-chloroethyl)-1-nitroso3
-(1-methyl-2-methoxyethyl)-3-(D-
Maltosyl) urea) 2.2f is obtained as a pale yellow powder.

M. P. 69℃ (decomposition) More than IRv? 01 (Cm-1): 3350, 170011
070NMR(D2O)δ:1.4(D,3FI,]C
H-C. U3) 3.33 (S, 3H, Oqdan
3) [α]■+59.8, (C=1.7, methanol) Example 7 (1) D-maltose monohydrate 7.2g, 2,
3-Dimethoxy n-propylamine [This amine is 2
It is produced by hydrogenating 2,3-dimethoxy-n-propyl azide obtained by condensing ,3-dihydroxy-n-propyl azide and methyl iodide in the presence of palladium and carbon. P. 73℃-7
4℃, Mass (m/e) 120 (M++1)]
By treating 3V and 2.5y of 2-chloroethyl isocyanate in the same manner as in Example 1 (1), 1-(2
-chloroethyl)-3-(2,3-dimethoxyn-propyl)-3-[0-α-D-glucopyranosyl(1
→4)-D-glucopyranosyl]urea (i.e. 1-(2
-chloroethyl)-3-(2,3-dimethoxyn-propyl)-3-(D-maltosyl)urea) is obtained as a colorless powder.

IRV: Nir1 (C1-1): 3350, 1640,
1550,! 1080, 1030NMR (D2O) δ:
3.35 (S, 3H, OCH3) 3.4
2 (S, 3H, OC Dan.

) (2) 1-(2-chloroethyl)-3-(2,3-dimethoxy n-propyl)-3-[0-α-2D-glucopyranosyl(1→4)-D-glucopyranosyl]urea5. 5' and 8fI of nitrogen tetroxide gas in Example 1 (2
), 1-(2-chloroethyl)-1-nitroso-3-(2,3-dimethoxyn-
propyl)3-3-[0-α-D-glucopyranosyl(1→4)-D-glucopyranosyl]urea (i.e., 1-
(2-chloroethyl)-1-nitroso-3-(2,3-dimethoxy n-propyl)-3-(D-maltosyl)
Urea) 2.8y was obtained as a pale yellow powder. M. P. 5
4℃ (decomposition) IRv 01 (CwL-1): 3350, 17001
1070, 1020 NMR (D2O) δ: 3.38 (S
, OCH3) 3.43 (S, 3H, OCH.3) 4.1
84(S, 2H, -N(NO)CH2CH2Cl) [α]? +50.7N (C=1.1, methanol) Example 8 (1) D-maltose monohydrate 7.2y12-(
Methoxy-methoxy)ethylamine [This amine is 2-
2-(methoxy-methoxy) obtained by condensing hydroxy-ethyl azide and chloromethyl methyl ether
This product is produced by reducing ethyl azide with lithium aluminum hydride. P. 56℃ (30T
1-(2-chloroethyl)-3-[2-(methoxy-methoxy)- ethyl]-3-[0-α-D-glucopyranosyl(1→4)-D-glucopyranosyl]urea (i.e., 1-(2-chloroethyl)-3-[2-(methoxy-methoxy)monoethyl ]-3-(D-maltosyl)urea) 6.8y is obtained as a colorless powder.

IRv = tray r1 (C7l-1): feather 50, 1?0, 1 father 5, 07 to 1030NMR (D2O) δ: 3.32 (S
,OCHJ)2)1-(2-chloroethyl)-3-[2
-(methoxy-methoxy)monoethyl]-3-[0-α-
D-glucopyranosyl(1→4)-D-glucopyranosyl urea 5.3 fI was added to 200 ml of tetrahydrofuran.
and add 20 g of anhydrous sodium carbonate to this solution.

Add 8y of nitrogen tetroxide to this mixture while stirring and cooling on ice.
It takes a while to establish continuity. The mixture was further stirred at the same temperature for 3 more minutes. Add 200 ml of n-hexane to the reaction mixture and filter. 10 ml of methanol was added to the filtrate, the resulting oil was washed with ether, and purified by silica gel chromatography (solvent: ethyl acetate dichloroformimethanol 2:1:1) to obtain 1-(2-chloroethyl). -1 nitroso 3-[2-(methoxy-
methoxy)monoethyl]-3-[0-α-D-glucopyranosyl(1→4)-D-glucobyranosyl]urea (i.e. 1-(2-chloroethyl)-1-nitroso3-[
2.6y of 2-(methoxy-methoxy)monoethyl]-3-(D-maltosyl)urea is obtained as a pale yellow powder. M.
P. 6O℃ (decomposition) 1Rv or more 01 (Cm-1): 3360, 10 to 171
7011025NMR(D2O)δ:3.24(S,3
H, OCU3) 4.56 (S, 2H, -0
-CH 2-0-) [α]? +49.2-(
C=1.2, methanol) Example 9 (1) D-maltose monohydrate 7.2y1 A mixture t of 3.2y of diglycolamine and 15ml of methanol is heated at 60°C to 65°C for 1 hour. .

The deposited precipitate is collected by filtration and washed with methanol to obtain 1-[2-hydroxyethoxy)ethylamino]-1-deoxy-D-maltose. Add this product to water 2
0ml, and 2-chloroethyl isocyanate λ5q is added dropwise to this solution at 0°C to 5°C while stirring.
The reaction mixture is stirred at the same temperature for 1.5 hours. The reaction mixture was dried under reduced pressure at 40°C (from this, 1-(2
-Chloroethyl)-3-[2-(2-hydroxyethoxy)ethyl]-3-[0-α-D-glucopyranosyl(1→4)-D-glucopyranosyl]urea (i.e. 1
-(2-chloroethyl)-3-[2-(2-hydroxyethoxy)ethyl]-3-(D-maltosyl)urea) 1
0.2y is obtained as a colorless powder. IRv cow r] (C
! fl-1): 3340, 1 ke 0, 1 father 0,
107 to 1030 (2) 1-(2-chloroethyl)
-3-[2-(2-hydroxyethoxy)ethyl]-3
-[0-2α-D-glucopyranosyl(1→4)-D
1-(2-chloroethyl)-1-nitroso 3-
[2-(2-hydroxyethoxy!cy)ethyl]-3-[
0-α-D-glucopyranosyl(1→4)-D-glucopyranosyl]urea (i.e. 1-(2-chloroethyl)
-1 Nitroso-3-[2-(2-hydroxyethoxy)ethyl]-3-(D-maltosyl)urea)ζ3.2q
is obtained as a pale yellow powder.

M. P. 78℃ (decomposition) IRv? Snake 1 (Cm-1): 33501169 10
6011030 [α]? +53.6m (C=1.01 methanol) Example 10 (1) D-ribose 3.8y12
-Methoxyethylamine 3.8V and methanol 5ml
The mixture is heated at 50°C to 55°C with stirring.

The reaction mixture was concentrated to dryness under reduced pressure. By washing the residue with ether, 1-(2-methoxyethylamino)
-1-deoxy-D-ribose is obtained as a crude product. This crude product was dissolved in 40 ml of methanol, and 2
- A solution of 3.5y of chloroethyl isocyanate in 10ml of tetrahydrofuran is added dropwise at 0°C to 5°C. The reaction mixture was stirred at the same temperature for 1 hour. After the reaction is complete, the reaction mixture is concentrated under reduced pressure. By washing the residue with ether, 7.0 Da of 1-(2-chloroethyl)-3-(2-methoxyethyl)-3-(D-ribopyranosyl)urea is obtained as a colorless caramel. IRp: Snake 01 (Cm-1
): 332 to 163 to 1540, 1110NMR (D2
O) δ: 3.40 (S, OCH3))) Dissolve 3.1y of 1-(2-chloroethyl)-3-(2-methoxy3-(D-ribopyranosyl)urea in a mixture of 60ml of tetrahydrofuran and 60ml of methylene chloride. Then, 15 f of anhydrous sodium carbonate is added to this solution.

Add 1 5f of nitrogen tetroxide to the reaction mixture while stirring and cooling on ice.
Continuity is required. The reaction mixture is stirred at the same temperature for 1 C@. 107 methanol in the reaction mixture! 1 and 3 ml of water and stir vigorously for 10 minutes at 0°C to 5°C. The mixture is filtered after drying. Concentrate the filtrate under reduced pressure,
The resulting residue was subjected to silica gel chromatography (solvent;
Ethyl acetate dichloroformimethanol di 5:2:1)
1-(2-chloroethyl)-1
-Nitroso-3-(2-methoxyethyl)-3-(D-
Ribopyranosyl) urea 2.2y is obtained as a yellow powder.
IRP=Rrl(C7n-1):3425, 1710,
1080, 1050s1020NMR (D
2O) δ: 3.36 (S, OC Dan.

)4.24(T,2H,-N(NO)-CH2CH2C
l) [α]f-21.9N (C=1.1, methanol) Example 111) D-ribose 3.8y12-ethoxyethylamine 4.0' and 2-chloroethyl isocyanate 3
．． By treating 5y in the same manner as in Example 10 (1), 8.0f1 of 1-(2-chloroethyl)-3-(2-ethoxyethyl)-3-(D-ribopyranosyl)urea was obtained as a brown oil. obtain.

IRp! ! Spoon 01 (Cm-1): 3350, 16401
1560, 1110NMR (D2O) δ: 1.20 (T
, OCH2CU3) (2) 1-(2-chloroethyl)-
Example 10 3.3fI of 3-(2-ethoxyethyl)-3-(D-ribopyranosyl)urea and 5f of nitrogen tetroxide gas
By treating in the same manner as in (2) above, 2.7 f of 1-(2-chloroethyl)-1-nitroso-3-(2-ethoxyethyl)-3-(D-ribopyranosyl) urine is obtained as a yellow powder. IRp:χr1 (CTfi-1):3
4201170011110, 108
011050NMR(D2O)δ:1.16(T,3H
,OCH2CH3)4.20(T,2H,-N
(NO) C-dan.

-) [α]e-17.1N (C=2.5.methanol) Example 12 (1) L-arabinose 3.0y12-methoxyethylamine 2.3fI and methanol 10ml
The mixture is heated with stirring at 6CfC to 65C for 2053 hours.

The reaction mixture was concentrated to dryness under reduced pressure. By washing the residue with ether, 1-(2-methoxyethylamino)-1-deoxy-L-arabinose is obtained as a crude product. The obtained crude product is dissolved in 40 ml of methanol, and a solution of 2.5 dA of 2-chloroethyl isocyanate in 10 ml of tetrahydrofuran is added dropwise at 0°C to 5°C. The reaction mixture is stirred at the same temperature for 1 hour. After the reaction is complete, the mixture is concentrated under reduced pressure. The resulting residue was diluted with formic acid 2
This solution was left to stand at room temperature, and mixed with ether-n-hexane (3:1). Add 150ml of liquid. By washing the obtained crude product with ether, 5.5y of 1-(2-chloroethyl)-3-(2-methoxyethyl)-3-(L-arabinopyranosyl)urea was converted into a light brown caramel. get as. IRv 1 ([-Rini 3350, 16401154011090NMR(D
2O) δ: 3.35(S, 3l(, 0 days.

) 4.90 (D, lH, Cl-H) (2
) 1-(2-chloroethyl)-3-(2-methoxyethyl)-3-(L-arabinopyranosyl) urea 3.1y
and nitrogen tetroxide gas 5y in the same manner as in (2) of Example 10, 1-(2-chloroethyl)-1-nitroso-3-(2-methoxyethyl)-3-(L-arabinopyrano 2.4y of urea is obtained as a yellow caramel. IRp: Mushi01 (CTfl-1):3420116
95.1080NMR(D2O)δ:3.35(S,3
H, OCU3) 4.20(T,2H,-
N(NO) -C. U2CH2Cl)4
．． 90 (D, lH, Cl-H) [α]? +45.5C (
C=1.5. methanol) Example 131) L-arabinose 3.0f13-methoxy n-propylamine 3.
Stir a mixture of 6q and methanol 10ml 60
Heat the two batches at ℃ to 65℃.

The reaction mixture was concentrated to dryness under reduced pressure and the resulting residue was washed with ether to obtain 1-(3-methoxy-n-propylamino)-1-deoxy-L-arabinose 4.
3y is obtained as crude product. This crude product was mixed with methanol 40
To this solution, add a solution of 3.0y of 2-chloroethyl isocyanate in 10ml of tetrahydrofuran at 0°C.
Add dropwise at ~5°C. The reaction mixture is stirred at the same temperature for 1 hour. After the reaction is complete, the mixture is concentrated under reduced pressure. The resulting residue was dissolved in 20 ml of formic acid and left to stand at room temperature. To this solution is added 150 ml of a mixture of ether and n-hexane (3:1). The supernatant was removed and the resulting oil was purified by silica gel chromatography (solvent: 2:1:1 ethyl acetate dichloroformimethanol) to obtain 1-(2-chloroethyl)-3-(3 5.3 q of -methoxyn-propyl)-3-(L-arabinopyranosyl)urea are obtained as a colorless caramel. IRv: 01 (Cu-1): 337 to 1 trouble to 1 Seki 1090NM
R(D2O)δ: 1.6-2.1(M,?,
Cll2CIL2CH2OCH3) 3.35 (S93
H? 0C Dan3), 4.90 (D, lH, Cl-H) )) 1-(2-chloroethyl)-3-(3-methoxyn-propyl)-3-(L-arabinopyranosyl)urea By treating 3.3 g and 5f of nitrogen tetroxide gas in the same manner as in (2) of Example 10, 1-(2-chloroethyl)
-1-Nitroso 3-(3-methoxy n-propyl)
-3-(L-arabinopyranosyl)urea 2.2y is obtained as a pale yellow powder.

M. P. lOO℃-101℃ (decomposition) ■Rp: Spoon 01 (0-1): 340011700, 10
75NMR (D2O) δ: 1.75-2.20 (M, 2
H, - CH2CJJ2CH2OCH3)3
．． 35 (S93H9OCdan 3), 4.10 (T, 2H,
-N(0N)CH2-)4.90(D,lH,Cl-H) [α]? +50.0 Example 14 (1) L-arabinose 3.0 da, 2-methoxy n-
By treating 3.6V of propylamine and 3.5y of 2-chloroethyl isocyanate in the same manner as in (1) of Example 13, 1-(2-chloroethyl)-3-(2-methoxy n-propyl)-3 3.0y of -(L-arabinopyranosyl)urea is obtained as a colorless caramel.

From IRv: ↓01 (C1!i-1): 3350, 1?0
, 1M5, 105 to 108 1000N
MR (D2O) δ: 1.15 (D, 3H, C-CH3)
H 3.38(S,3H,OCH3) (2) 1-(2-chloroethyl)-3-(2-methoxy n-propyl)-3-(L-arabinopyranosyl) urea 3.3y and 4 Example 10 (2) 5g of nitrogen oxide gas
By treating in the same manner as above, 2.5q of 1-(2-chloroethyl)-1-nitroso-3-(2-methoxyn-propyl)-3-(L-arabinopyranosyl)urea is obtained as a yellow powder. .

M. P. 6O℃ (decomposition) IRv cow ξ゛1 (Crfl-1): 34001169
5, 1020NMR (D2O) δ to 10801105:
1.20 (D, 3H,'/CH-CU3) 3.34 (S
,3H,OCU3) [α]? +30.53 (C=0.gs methanol) Example 15 (1) L-arabinose 3.0f1 (1-methyl-2-methoxyethyl)amine 3.6V and 2-chloroethyl isocyanate 3.5y Example 13 of (1
), 1-(2-chloroethyl)-3-(1-methyl-2-methoxyethyl)-3
-(L-arabinopyranosyl)urea 3.11 is obtained as a colorless caramel.

1Rp! 4?01 (d-lini 3320, 152 to 163
0,1080)1-(2-chloroethyl)-3-(1
-Methyl-2-methoxyethyl)-3-(L-arabinopyranosyl)urea 3.3y and nitrogen tetroxide gas 5y were treated in the same manner as in Example 10 (2) to obtain 1-(
1.0f of 2-chloroethyl)-1-nitroso-3-(1-methyl-2-methoxyethyl)-3-(L-arabinopyranosyl)urea is obtained as a yellow caramel.

IRv Kajima 13 (C7n-1): 3400, 17001
1080NMR(D2O)δ: 1.40(D,3H,〉
CH-CH3) 3.30 (S, 3H, OCH3) [α]? +42.6, (C=1.\methanol) Example 16) D-arabinose 3.09, 3-methoxy n-
By treating 3.6y of propylamine and 3.0y of 2-chloroethyl isocyanate in the same manner as in Example 13 (1), 1-(2-chloroethyl)-3-(3-methoxyn-propyl)-3 -(D-Arabinopyranosyl)urea 5.0V is obtained as a colorless caramel.

IRp: Shima 13 (Cm-1): 1640 to 337, 15
1 part to 3 5 NMR (D2O) δ: 1.6-2.1 (M,
2H, CH2C. H2CH2OCH3) 3.35 (S9
3H9OCH3) 4.90 (D, lH, Cl-H) L) 1-(2-chloroethyl)-3-(3-methoxy n-propyl)-3-(D-arabino 1-pyranosyl) urea 3.3f and 4 (2) of Example 10 with 5 da of nitrogen oxide gas
By treating in the same manner as above, 2.09 of 1-(2-chloroethyl)-1-nitroso-3-(3-methoxy n-propyl)-3-(D-arabinopyranosyl)urea is obtained as a yellow powder. .

M. P. lO7C-103℃ (decomposition) More than IRv? 01 (Crfl-Rini 3400, 1700,
1075NMR (D2O+↓-DMSO) δ: 1.75
-2.20(M,2H, -CH2CH2CH2OCH3
) 3.33 (S3H, OCH3), 4.16 (T, 2H
,N(NO)Cdan2-)4.83(D,lH,Cl-
H) [α]P50.8. (C=1.Table methanol)
Example 17 (1) 1-(2-chloroethyl )-3-(2-methoxyethyl)-3-(D-xylopyranosyl)urea 6
．． 1y is obtained as a colorless caramel.

IRV:Xrl(Cffl-1):3350, 1640
11540, 1110s1040NMR (D2O) δ:
3.35(S, 3l(,0CH3) 5
．． 0(D,lH,Cl-H)(2)1-(2-chloroethyl)-3-(2-methoxyethyl)-3-(D-xylopyranosyl), urea 3.1f and nitrogen tetroxide gas 5y carried out By processing in the same manner as in Example 10 (2), 1-
(2-chloroethyl)-1-nitroso-3-(2-methoxyethyl)-3-(D-xylopyranosyl)urea2.
5y is obtained as a yellow caramel.

2IRv Pass Fl3 (Cm-1): 16 to 341
95.110 1 μSONMR (CDCI3) δ: 3.
35 (S, OCU3) [α]? +4.9) (C=1.
2. Methanol) Example 18 (1) D-mannose 3.
6V12-Methoxyethyl Σamine 2.6y and 2-chloroethyl isocyanate 2.5f were added to Example 10 (1
), 6.5y of 1-(2-chloroethyl)-3-(2-methoxyethyl)-3-(D-mannopyranosyl)urea is obtained as a colorless caramel.

IRv:X↓01(CrR-1):3320, 1630
, 1550, 1060 NMR (D2O) δ: 3 to 111
．． 40(S,OCH))(2) 3.4fI of 1-(2-chloroethyl)-3-(2-methoxyethyl)-3-(D-mannopyranosyl)urea in 40% of tetrahydrofuran
ml and 10 ml of acetic acid, and anhydrous sodium acetate 17' is added to this solution.

6 y of nitrogen tetroxide gas is passed through this mixture while stirring and cooling with ice for one infusion. Further, the reaction mixture is stirred once at the same temperature. 70% n-hexane to the reaction mixture
Add m1 and filter. The filtrate is concentrated under reduced pressure, and a mixture of 200 mt of n-hexane and 4 mt of methanol is added to the residue. The oil obtained is washed with ether and then dissolved in 50 ml of ethyl acetate. Add 10 ml of water to this solution and shake. Ethyl acetate After drying, the ethyl acetate solution was distilled off under reduced pressure to give 1.7y of 1-(2-chloroethyl)-1-nitroso-3-(2-methoxyethyl)-3-(D-mannopyranosyl)urea as a pale yellow caramel. get as. IR
v Internal 13 (Cffl-1): 33701169\10
9 to 1070 NMR (D2O) δ: 3.30 (S, OC
H3) [α]r+20.0: (C=1.5s methanol) Example 191) D-galactose 3.6y 12-methoxyethylamine 1.8y and 2-chloroethyl isocyanate 2.5f were added to Example 12 (1 ), 1-(2-chloroethyl)-3-(2-
6.5y of methoxyethyl)-3-(D-galactopyranosyl)urea is obtained as a light brown caramel.

IRp heart Xrl (d-1): 50, 1630, 1 father-in-law 5
, 110s1060NMR (D2O) δ: 3.35 (S
, OC Dan.

) 1-(2-chloroethyl)-3-(2-methoxyethyl)-3-(D-galactopyranosyl)urea 3.4y
By treating 5 g of nitrogen tetroxide gas in the same manner as in Example 10 (2), 1-(2-chloroethyl)-1-nitroso-3-(2-methoxyethyl)-3-(D-galactopyranosyl ) 2.7y of urea is obtained as a pale yellow caramel. IRp: Shima 13 (d-1): 3350, 1 part ONMR to 170 (D6-DMSO-D2O) δ: 3.26
(S, 3H, OC Dan.

), 4.82 (D, lH, Cl-H) [α]? +9.
7 (C=1.1, methanol) Example 20) D-galactose 3.6y13-methoxy n-propylamine 2
．． By treating 2.5y of 5' and 2-chloroethyl isocyanate in the same manner as in Example 13 (1), 1-
(2-chloroethyl)-3-(3-methoxyn-propyl)-3-(D-galactopyranosyl)urea 5.1f
is obtained as a colorless caramel.

IRv: Spoon 01 (C7R-1): 335 to 163 to 15
4 to 1050 NMR (D2O) δ: 1.75-2.15
(M, 2H, 1 CH2CJlJ, CH2
-) 3.35 (S, 3H, OC Dan.

)(2) 1-(2-chloroethyl)-3-(3-methoxyn-propyl)-3-(D-galactopyranosyl)
3.6y of urea and 5y of nitrogen tetroxide gas were added (2
), 2.8y of 1-(2-chloroethyl)-1-nitroso-3-(3-methoxyn-propyl)-3-(D-galactopyranosyl)urea was obtained as a pale yellow caramel. obtain.

IRp:! ? 13 (Cm-1): 1μ to 338 to 170
SONMR (D2O) δ: 1.80-2.25 (M, 2
H, 1 CH2C month-2CH2-)3.3
5(S3H,OCH3)4.20(T,2H,-N(N
O)-Cdan 2CH2C1) [α]? +15.52 (C=1.3s methanol) Example 21 (1) 3.6g of D-galactose, 3.5y of (1-methyl-2-methoxyethyl)amine and 3.5f of ethyl isocyanate Example 13 (
By treating in the same manner as in 1), 1-(2-chloroethyl)-3-(1-methyl-2-methoxyethyl)-
3.8y of 3-(D-galactopyranosyl)urea is obtained as a colorless caramel.

IRv or moreX↓01(C7l-1):336011635
, 1540, 108011040 (2
)1-(2-chloroethyl)-3-(1-methyl-2-
methoxyethyl)-3-(D-galactopyranosyl)
3.6f of urea and nitrogen tetroxide gas. 5y in Example 10 (
2), 1-(2-chloroethyl)-1-nitroso-3-(1-methyl-2-methoxyethyl)-3-(D-galactopyranosyl)urea 1
．． 3V is obtained as a yellow powder.

M. P. 56℃ (decomposition) IRp:?゛1 (C7I-1): 3400, 16901
109 to 1040 NMR (D2O) δ: 1.38 (D,
3H,S/CH-CH3)3.33(S,3H,OCdan
3) [α]kon+12.9 Example 22 (1) D-galactose 3.6y12,2-diethoxyethylamine 3.5y and 2-chloroethyl isocyanate 2.5y were added in the same manner as in Example 10 (1). By treatment, 1-(2-chloroethyl)-3-(2,2-
7.2y of (diethoxyethyl)-3(D-galactopyranosyl)urea is obtained as a colorless caramel.

IRv to Xrl (C7l-1): 3370, 1635,
1545, 11011070 NMR (D2O) δ: 1.
06(T,OCH2CH3)')1-(2-chloroethyl)-3-(2,2-diethoxyethyl)-3-(D-
Galactopyranosyl) urea 4.0y and nitrogen tetroxide gas 5
By processing y in the same manner as in Example 10 (2),
1-(2-chloroethyl)-1-nitroso-3-(2,
1.5y of 2-diethoxyethyl)-3-(D-galactopyranosyl)urea is obtained as a pale yellow caramel.

IRv=Shima 13 (Cln-1): 340 to 170 to 11
2 to 1070 NMR (D6-DMSO) δ: 1.08 (
T, 6H, OCH2CH3×2), 4.80(D, lH
, Cl-H) [α] f-3.42 (C = 1. methanol) Example 231) D-glucose 3.6 f13-methoxy n-propylamine 2.7y and 2-chloroethyl isocyanate 3.0 g By treating in the same manner as in Example 13 (1), 1-(2-chloroethyl)-3
6.5 fI of -(3-methoxyn-propyl)-3-(4)-glucopyranosyl)urea are obtained as a colorless caramel.

IRv child r1 (Crfl-1): 3350, 1640
11530, 111 to 107 to 1020
NMR (D2O) δ: 1.70-2.20 (M, 2H,
CH2CH2CH2-)3.30(S,3H,OCdan.

), 5.00 (D, lH, Cl-H) 2) 1-(2-chloroethyl)-3-(3-methoxy n-propyl)-3-(D-glucopyranosyl) urea 3
．． By treating 6y and nitrogen tetroxide gas 5y in the same manner as in (2) of Example 10, 1-(2-chloroethyl)
-1-nitroso-3-(3-methoxy n-propyl)
2.7y of -3-(D-glucopyranosyl)urea is obtained as yellow caramel.

IRp:313(Cm-1):34001169飄10
70NMR (D2O) δ: 1.75-2.30 (M, 2
H, CH, CU2CH2-) 3.35 (S, 3H, OC
Dan.

), 4.20 (T, 2H, -N(NO)-q CH2Cl) 5.0 (D, lH, Cl-
H) [α] A+9.8 Example 24 1-(2-chloroethyl)-3-(3-methoxy n-
Propyl)-3-(L-arabinopyranosyl)urea3.
Dissolve 3y in formic acid 15711, gradually add 1.5y of sodium nitrite to this solution, and stir at 0°C for 1 hour.

The mixture is further stirred at the same temperature for 1 hour. After the reaction is completed, 15 ml of ethanol is added to the reaction mixture, and the mixture is neutralized with potassium carbonate while cooling on ice. Add 15 ml of ethyl acetate to this mixture.
Add 0 ml and remove insoluble matter by filtration. The filtrate is washed with an aqueous sodium hydrogen carbonate solution, dried, and then the solvent is distilled off under reduced pressure. The residue was subjected to silica gel chromatography (solvent;
Ethyl acetate dichloroformimethanol di 5:2:1)
1-(2-chloroethyl)-1
-Nitroso3-(3-methoxyn-propyl)-3
1.2y of -(L-arabinopyranosyl)urea is obtained as a yellow caramel. [α]f+50.0y (C=1.methanol) Example 251-(2-chloroethyl)-3-
(1-Methyl-2-methoxyethyl)-3-(D-galactopyranosyl)urea 3.6y and sodium nitrite 1
．． By treating 5y in the same manner as in Example 24, 1-
0.9 f of (2-chloroethyl)-1-nitroso-3-(1-methyl-2-methoxyethyl)-3-(D-galactopyranosyl)urea is obtained as a yellow powder.

Claims (1)

[Claims] 1. General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] (However, R
^1 represents a lower alkoxy group, a lower alkoxy-methoxy group, or a 2-hydroxyethoxy group, and R^2 represents an aldo-pentopyranosyl group, an aldo-hexopyranosyl group, or an O-aldo-hexopyranosyl-(1→4)-aldo-hexopyranosyl group. A represents a straight chain or branched alkylene group having 1 to 4 carbon atoms which may be substituted with a lower alkoxy group. ) Nitrosourea derivatives. 2 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [II] (However, R^
1 represents a lower alkoxy group, a lower alkoxy-methoxy group, or a 2-hydroxyethoxy group, and R^2 represents an aldo-
Pentopyranosyl group, aldo-hexopyranosyl group or O-aldo-hexopyranosyl-(1→4)-aldo-
It represents a hexopyranosyl group, and A represents a straight chain or branched alkylene group having 1 to 4 carbon atoms which may be substituted with a lower alkoxy group. ) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼〔I〕
(However, R_1, R_2 and A have the same meanings as above.) A method for producing a nitrosourea derivative.