JPS6026120B2 - Production method of nitrosourea derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention describes the general formula (where RI is a linear alkyl group having 1 to 20 carbon atoms, R2
is D-glucopyranosyl group, 0-galactopyranosyl group, D-mannopyranosyl group, D-xylopyranosyl group,
The present invention relates to a method for producing a novel nitrosourea derivative represented by L-arapinopyranosyl group or ○1Q-○-glucopyranosyl-(1→4)-D-glucopyranosyl group.

Accordingly, a large number of nitrosourea compounds with antitumor effects have been synthesized, but most of these compounds have a hydrogen atom on the nitrogen atom at the 3-position in the substructure [m] below [ For example, Internal Medicine; Madamaki, pp. 911-916 (1976); Area of Chemistry; 29 Lid, pp. 765-775 (1975)].

An exception to this is 1-(2-chloroethyl)
A methyl group is further introduced onto the nitrogen atom at the 3-position of a nitrosourea compound such as -1 nitroso-31n-bropylurea, 1-(2-chloroethyl)-11-nitroso-31-(2-chloroethyl)-11-nitroso-3-cyclohexylurea. These compounds have recently been reported [Brundretz et al., Bulletin of the American Association for Cancer Research, Vol. 17, Meeting 67, p. 102 (1976)]. Also, no improvement in the antitumor effect was observed due to the introduction of a substituent to the 3-position nitrogen atom. However, as a result of various studies, the present inventors unexpectedly found that three of the nitrosourea derivatives reported in Tokkan Sho 51-2 Kayu No. 76, Sho 51-52128, and Sho 51-141815, etc. The new parent Nigelosourea compound [1], which corresponds to a compound in which the hydrogen atom on the nitrogen atom is replaced with a group represented by the symbol RI, exhibits excellent anti-tumor effects and has unexpectedly demonstrated safety. It was found that the drug showed remarkable improvement and had excellent properties as an anti-tumor agent.

The present invention is a method for producing an anti-tumor agent that has excellent safety.

In the compound obtained by the present invention, for example, in the general formula [1], the group represented by the symbol RI is a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-bentyl group, an n-hexyl group, etc. 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-bentadecyl group, n-hexadecyl group base, n
- Heptadecyl group, n-octadecyl group, n-nonadecyl group, or n-eicosyl group, and the group represented by the symbol R2 is D-glucopyranosyl group, D-galactopyranosyl group, D-mannopyranosyl group, D-xylopyranosyl group , L-arabinopyranosyl group, or -Q-D-glucopyranosyl-(1→4)-D-glucopyranosyl group.

According to the present invention, the target compound [1] has the general formula (where RI and R2 have the same meanings as above).

) It can be produced by reacting the urea derivative shown in ) with nitrogen tetroxide.

This reaction can be carried out, for example, by dissolving the raw material compound [B] in an appropriate solvent and introducing nitrogen tetroxide gas in the presence or absence of a deoxidizing agent, or by adding nitrogen tetroxide gas to the solution and an appropriate solvent. It is preferable to carry out this by mixing with a solution in which a substance is introduced and dissolved.

Examples of the starting compound [b] include compounds in which the groups represented by the symbols RI and R2 are as described above, respectively. As the deoxidizing agent, for example, sodium bicarbonate, soda carbonate, potassium bicarbonate, potassium carbonate, sodium acetate, potassium acetate, etc. can be advantageously used. In either case, the reaction proceeds smoothly at room temperature or under cooling, particularly preferably at 0 to 5°C, and the target compound [1] can be obtained in high yield. The objective compound of the present invention thus obtained [1
) are all new compounds, and are useful pharmaceutical compounds that have excellent anti-leukemia and anti-tumor effects and have extremely low plexus.

For example, in its antitumor action against Ehrlich's ascites tumor, the object compound of the present invention, 1-(2-chloroethyl)11nitroso-31n-butyl-31D-galactopyranosylurea (RI= n・C4 day 9) is the known compound 1-(2-chloroethyl)-1 nitroso 3-(8
-D-glucopyranosyl) urea (abbreviation: GANU, RI
Although the minimum effective concentration is slightly inferior to that of =H), the maximum effective concentration at which no toxicity occurs is one needle sound louder. When the target compound of the present invention is used as a medicine, it can be administered orally or parenterally.

When administered orally, it can be used in the form of tablets, tablets, capsules, granules, liquids, etc. When administered parenterally, it can be used as injection preparations, suppositories, etc. can do. Incidentally, all of the raw material compounds [b] of the method of the present invention are also new compounds, and can be produced, for example, by the method shown in the following reaction formula. (However, RI and R2 have the same meanings as above.) (See Reference Examples below) Example 1 1-(2-chloroethyl)-13-methyl-3-D-glucopyranosyl urea 3.0 units (10 mmol) was dissolved in a solution of 80 parts of tetrahydrofuran and 80 parts of methylene chloride, 15 minutes of anhydrous sodium carbonate was added, and the solution was heated with ice-cooled stirring and nitrogen tetroxide gas was added for 10 minutes. Introduce.

Stir for another minute at the same temperature to complete the reaction. Add 10 parts of methanol and then 3 parts of water to the reaction solution and stir for 10 minutes. After drying this liquid, the solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent: ethyl acetate: chloroform: methanol = 5:2:1). 2.4 ml of nitroso-3-methyl-3-D-glucopyranosyl urea was obtained as a pale yellow powder. mp. 6930 (decomposition),
Yield 73.5%. IR Re obi ink ol (Ken-1): Spot 50
, 1690, 1070 NMR (D20) 6:3.15 (
s, is, N-C Mochido), [Q] Yoichi 22.9o (C=1
．． 0, methanol) Examples 2 to 17 In the same manner as in Example 1, the following compounds were prepared from the corresponding urea derivatives.

Example 18 4.6 mmol (10 mmol) of 1-(2-chloroethyl)-3-methyl-D-maltosyl urea was dissolved in a mixture of 170 mmol of tetrahydrofuran and 30 mmol of acetic acid, and 20 mmol of hot sodium carbonate was added. Add evening.

Nitrogen tetroxide gas was introduced into this solution over 6 minutes under ice-cooling and stirring, followed by stirring at the same temperature for 20 minutes. Add 200 parts of n-hexane to the reaction solution, filter off the precipitate, remove the solvent from the filtrate, and add 200 parts of methanol/ether (1:20) solution to the residue. 1-(2
-chloroethyl)-1-nitroso-3-methyl-3-○
-Maltosyl urea was obtained as a pale yellow powder at 3.359 g.
mp. 66-70qo (decomposition), yield Iso. 3% Urushi Tomb ol (Ken-1): 3300, 1700, 1050NM
R (D20) 6:3.12 (s, thin, N-C93) [Q
] Volume +42.9o (C=1.0, methanol) Example
19-22 In the same manner as in Example 18, the following compounds were prepared from the corresponding urea derivatives.

Reference Example A mixture of 2.7 parts of glycose, 4.5 parts of n-nonadecylamine and 6 parts of methanol is stirred at 65°C for 25 minutes.

After wrapping, the precipitated N-n./nadecyl glycosylamine is collected by filtration, washed with hexane, and dried. This product was mixed with 100% of tetrahydrofuran and 100% of methanol.
The mixture was heated to a boil, and after cooling to room temperature, a 20M solution of 2-chloroethyl isocyanate and 1.7 g of 2-chloroethyl isocyanate in 20M tetrahydrofuran was added dropwise while stirring.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (However, R^1 is a linear alkyl group having 1 to 20 carbon atoms, R
^2 is D-glucopyranosyl group, D-galactopyranosyl group, D-mannopyranosyl group, D-xylopyranosyl group, L-arabinopyranosyl group or O-α-D-glucopyranosyl-(1→4)-D A general formula characterized by reacting a urea derivative represented by -glucopyranosyl group with nitrogen tetroxide ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, R^1 and R^2 are the same as above) have meaning)
A method for producing a nitrosourea derivative shown in