JPS6222794A - 6-alkylellipticine derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is H, OH, etc.; R<2> is (deoxy)aldose residue, etc.; R<3> is 1-5C alkyl; X<-> is anion; the bond N<+>-R<2> is glycoside bond of the N atom at the 2-position of ellipticine to the C atom at the 1-position of the sugar]. EXAMPLE:2-(2,3,5-Tri-O-benzoyl-beta-D-xylofuranosyl)-9-acetoxy-6-methy lellipticinium chloride. USE:A carcinostatic agent capable of exhibiting powerful antimalignant tumor activity. PREPARATION:Ellipticine (derivative) expressed by formula II which is a starting raw material is reacted with a halogenated sugar expressed by the formula R<4>-Y (R<4> is acylated or alkylated aldose residue, etc.; Y is halogen) are heated in an organic solvent, e.g. DMF, in the presence of a base, CaCO3, while heating to afford the aimed compound expressed by formula I (R<2> is R<4>; X is Y).

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to the general formula (wherein R1 represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 4 carbon atoms, or an acyloxy group having 2 to 7 carbon atoms, and R2 represents an aldose residue, acylated aldose residue in which the hydrogen atom of the hydroxyl group of a sugar is substituted with an acyl group having 2 to 9 carbon atoms, and the hydrogen atom of the hydroxyl group of sugar is substituted with an aralkyl group having 7 to 8 carbon atoms Aralkylated aldose residue, deoxyaldose residue, acylated deoxyaldose residue in which the hydrogen atom of the hydroxyl group of a sugar is substituted with an acyl group having 2 to 9 carbon atoms, the hydrogen atom of the hydroxyl group of a sugar is substituted with an acyl group having 7 carbon atoms Aralkylated deoxyaldose residue substituted with ~8 aralkyl groups, "nitrogen atom of amino group" where the second hydrogen atom is carbon vi, 2-4
N-acylaminoaldose residue substituted with an acyl group, the hydrogen atom on the nitrogen atom of the amine group is substituted with an acyl group having 2 to 4 carbon atoms, and the hydrogen atom of the hydroxyl group of the sugar is substituted with an acyl group having 2 to 4 carbon atoms. Acylated N-acylaminoaldose residue substituted with one acyl group, two hydrogen atoms of the amino group are substituted with an acyl group having 2 to 4 carbon atoms, and the hydrogen atom of the hydroxyl group of the sugar is Aralkylated N-acylaminoaldose residue substituted with 7-8 aralgyl groups, aldohexouronic acid amide residue, hydrogen atom of hydroxyl group of sugar substituted with acyl group having 2-9 carbon atoms Acylated aldohexouronic acid amide residue, aralkylated aldohexouronic acid amide residue in which the hydrogen atom of the hydroxyl group of a sugar is substituted with an aralkyl group having 7 to 8 carbon atoms, a hydrogen atom of the hydroxyl group of a sugar is substituted with an acyl group having 2 to 9 carbon atoms, an acylated aldohexouronic acid lower alkyl ester residue, and an aralkyl group in which the hydrogen atom of the hydroxyl group of the sugar is substituted with an aralkyl group having 7 to 8 carbon atoms. acylated aldohexouronic acid lower alkyl ester residue, aldohexouronic acid residue, acylated aldohexouronic acid residue in which the hydrogen atom of the hydroxyl group of a sugar is substituted with an acyl group having 2 to 9 carbon atoms, or Represents an aralkylated aldohexouronic acid residue in which the hydrogen atom of the hydroxyl group of the sugar is substituted with an aralkyl group having 7 to 8 carbon atoms, and R3 is a linear, branched, or cyclic group having 1 to 5 carbon atoms. or a cyclic-straight alkyl group, Xo represents an anion of a pharmaceutically acceptable inorganic or organic acid, and in the formula, N
The 6-alkyl ellipticine derivative having the bond represented by Φ-R2 represents a glycosidic bond between the 2nd-position nitrogen atom of ellipticine and the 1st-position carbon atom of a sugar, and a method for producing the same, Since the derivative has strong anti-cancer activity, it is a compound that is expected to be used as an anti-cancer agent.

Conventional technology Ellipticine (5,1
1-dimethyl-(4,3-b)(6H)pyridocarbazole, R=H in the following general formula (A)), 9-methoxyellipticine (R=QCH3 in the general formula (A))
and pyridocarbazole alkaloids such as 9-hydroxyellipticine (R=OH in general formula (A)).
ds) is contained in spidospermina and Ochrosia leaves, and is a type of alkaloid that has been well known since ancient times.

In recent years, it has been reported that formula (B) 1-N-methyl-9-hydroxyelibutidinium acetate (Celiptium) is effective against breast cancer (J,
Rouesse' et al., Bull, Cancer
(Paris) Volume 68.

pp. 437-441, 1981].

In addition, ellipticine and 9-methoxyellipticine are effective against mouse leukemia L-1210 and Sarcoma 180 (solid), which are experimental animal tumors (R,W', Guthrie et al., J, Med.
icinal Chemistry + Volume 18 (7), 7
55-760, 1975], 9-hydroxyellipticine is 9-methoxyellipticine, 9100-10
It has been reported to have 00 times higher activity against murine leukemia L-1210 (Japanese Patent Publication No. 5835196, British Patent No. 1436080).

As mentioned above, compounds having a pilicarbazole pathway are useful as compounds having antitumor activity,
For example, 1st, J. Ch.
em, vol. +20, pp. 2715-2727 (1967); ^, 11. Jackson et al.

J, Chem, Soc, r'erkin L 16
pp. 98-1704 (1977); J, Y, Lall
emand et al., Tetrahedron Letter
's+ No, 15+1261-1264 (1978
A number of synthetic methods have been studied, as shown in European Patent No. 9445 (2010) and European Patent No. 9445.

Compounds with substituents introduced into the pyridocarbazole skeleton have also been found to have activity against murine leukemia L-1210 (US Pat. No. 4,434,290).

However, ellipticine, 9-methoxy ellipticine, and 9-hydroxy ellipticine have not yet been put into practical use as anticancer agents, and one reason for this is that these compounds have very poor solubility in water.

JP-A-58-222087 discloses 2-N-alkyl-
It has been proposed to introduce an amino acid, oligopeptide, nucleotide, or nucleoside into the 10th position of the backbone by oxidizing 9-hydroxyeributidinium salt, and these compounds have shown a positive survival effect on murine leukemia L-1210. have not yet been given.

Problems to be Solved by the Invention The present inventors have discovered the properties of ellipticine in the process of conducting research to develop useful, especially medicinally active, derivatives from naturally occurring skeletons. We focused on the antitumor properties of ellipticine, and in particular, focused on the fact that it is expected that a useful compound could be obtained by improving the fact that ellipticine is extremely sparingly soluble in water, as predicted from its skeleton. did.

However, until now, only an example is known in which an alkyl group, hydroxyalkyl group, aminoalkyl group, etc. is introduced into the 2-position nitrogen atom of ellipticine (US Pat. No. 4,310,667).

Means for Solving the Problems The present inventors attempted to make ellipticine water-soluble by introducing, for example, a sugar or a nucleic acid into its backbone. It has been found that the 6-alkyl ellipticine derivative of the general formula (I) into which is introduced is a useful compound having desired properties.

The introduction of a sugar into the nitrogen atom at the 2-position of ellipticine can be easily carried out in the same manner as the well-known reaction in which a sugar forms a covalent bond with the nitrogen of the pyridine ring to form a quaternary salt during the synthesis of nicotinamide nucleotides. I can do it. For example, L, J
J, Chem, Soc, of l1aynes et al.

pp. 303-308 (1950) and Hay, J.
J, Chem, Soc, 3727-3 of n+s et al.
As described on page 732 (1957).

Furthermore, S. C. Jain et al., J. Moj. Biol.
As described in Vol. 135, pp. 813-840 (1979), the affinity with nucleobases can be further increased by introducing a group with an appropriate size and hydrophilicity into the 2-position nitrogen atom of ellipticine. There is expected.

The 6-alkyl ellipticine derivative represented by the general formula (1) according to the present invention starts from an ellipticine derivative R' of the following general formula (TI) (wherein R1 and R3 are as defined above). It can be easily synthesized as a raw material as follows. These compounds include, for example, K.

Au5t, J, Chem, + 2 of Dalton et al.
0, pp. 2715-2727 (1967), etc., it can be derived from pyridocarbazole.

For example, in general formula (II), the group R3 has 1 carbon atom
The 6-alkyl ellipticine derivative, which is an alkyl group of ~5, is a compound in which R3 is a hydrogen atom, in an organic solvent such as an amide type, an ether type, preferably dimethylformamide, sodium hydride, potassium hydride, potassium t-butoxy. , treated with a base such as triphenylmethylsodium/lium to form an alkali metal salt, and then converted to the corresponding alkyl halide, such as methyl iodide, ethyl iodide, propyl iodide, isopropyl iodide, butyl iodide, 5ec iodide.
-Butyl/isobutyl iodide, pentyl iodide, cyclopropylmethyl iodide, cyclobutylmethyl iodide, cyclopropylethyl iodide, methyl bromide, ethyl bromide,
Propyl bromide, isopropyl bromide, butyl bromide, 5 bromide
It can be obtained by adding ec-butyl, isobutyl bromide, pentyl bromide, cyclopropylmethyl bromide, cyclobutylmethyl bromide, cyclopropylethyl bromide, cyclopropyl bromide F, and the like.

The most important synthetic step of the present invention is the addition reaction of the 6-alkyl ellipticine derivative having the general formula (formula) and the sugar derivative.

According to the present invention, the general formula (IT) R' (wherein R1 represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 4 carbon atoms, or an acyloxy group having 2 to 7 carbon atoms, and R3 has 1 to 7 carbon atoms) (representing a linear, branched, cyclic, or cyclic-straight alkyl group of III) R”-Y (III) (In the formula, R4 is the hydrogen atom of the hydroxyl group of the sugar having 2 to 9 carbon atoms.
Acylated Al F-s residue substituted with an acyl group, hydrogen atom of sugar hydroxyl group has 7 to 8 carbon atoms (7) 771
/7 Aralkylated aldose residue substituted with R/L4, Acylated deoxyaldose residue in which the hydrogen atom of the hydroxyl group of the sugar is substituted with an acyl group having 2 to 9 carbon atoms, The hydrogen atom of the hydroxyl group of the sugar is Aralkylated deoxyaldose residue substituted with an aralkyl group having 7 to 8 carbon atoms, a hydrogen atom on the nitrogen atom of an amino group being substituted with an acyl group having 2 to 4 carbon atoms, and a hydrogen atom of a hydroxyl group of a sugar. is an acylated N-acylaminoaldose residue substituted with an acyl group having 2 to 9 carbon atoms, the hydrogen atom on the nitrogen atom of the amino group is substituted with an acyl group having 2 to 4 carbon atoms, and the hydroxyl group of the sugar is Aralkylated N-acylaminoaldose residue in which the hydrogen atom is substituted with an aralkyl group having 7 to 8 carbon atoms; Acylated N-acylaminoaldose residue in which the hydrogen atom of the hydroxyl group of a sugar is substituted with an acyl group having 2 to 9 carbon atoms Aldohexouronic acid amide residue, Arua Jl in which the hydrogen atom of the sugar hydroxyl group has 7 to 8 carbon atoms
/alkylated aldohexouronic acid amide residue substituted with a kill group.

Acylated aldohexouronic acid lower alkyl ester residue in which the hydrogen atom of the hydroxyl group of the sugar is substituted with an acyl group having 2 to 9 carbon atoms, or an aralkyl ester residue in which the hydrogen atom of the hydroxyl group of the sugar is substituted with an acyl group having 7 to 8 carbon atoms. (Y represents a halogen atom) is heated in an organic solvent or in the presence of a weak base. By reacting with the general formula (Ia) (wherein R1, R'', R'
and Y are as defined above, and in the formula, the bond represented by N - R4 represents a glycosidic bond between the nitrogen atom at the 2nd position and the carbon atom at the 1st position of the sugar.

In the above formula (I a), "11yo represents a halogen anion, but it generally depends on the ease of producing the sugar represented by the raw material R' -Y (Trl). For example, chlor and bromo sugars are generally easy to synthesize. This reaction is carried out by heating in an organic refrigerant, such as nitromethane, acetonitrile, propionitrile, henzene, toluene, xylene, dimethylbormamide, dimethylsulfoxide, aniline, etc., to produce the general formula ( The 6-alkyl ellipticine derivative of Ia) is obtained. This reaction can also be carried out in the organic solvent in the presence of a weakly basic metal compound with or without heating. Examples of weakly basic metal compounds include calcium carbonate, cadmium carbonate, basic zinc carbonate, silver carbonate, copper carbonate, and the use of these metal compounds can increase the yield of the reaction. .

The compound represented by the general formula (Ia) thus obtained can be purified by column chromatography, preparative thin layer chromatography or recrystallization after the reaction is completed. For example, when using cadmium carbonate as a base, by purifying it using column chromatography, it is possible to
The mium content was found to be below 0.1 ppm.

The 6-alkyl ellipticine derivative of the general formula (I a) can be further ion-exchanged using, for example, an anion exchange resin to obtain a compound of the general formula (I b) CH3 (wherein R1, R3 and R4 are as defined above). street,
Ellipticine derivatives can be synthesized (Zo represents an anion of a pharmaceutically acceptable inorganic or organic acid).

The anions of inorganic or organic acids that are acceptable as pharmaceuticals include, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, citric acid, tartaric acid, formic acid, maleic acid, butyric acid, Grass acid, caproic acid, heptanoic acid, capric acid, salicylic acid, methanesulfonic acid, Fit acid, propionic acid, oxalic acid, malic acid, fumaric acid, succinic acid, aspartic acid, glutamic acid, lactic acid, benzoic acid and cinnamic acid. Represents an anion. In addition, as an ion exchange resin, for example, Amberlite (manufactured by Organo OL)
Anion exchange resins commercially available under the names of Bioland (manufactured by Bioland Laboratories) and the like can be used.

The ellipticine derivative of the general formula (Ib) is further hydrolyzed to form a compound of the general formula Nc)R'J (wherein R3 and Zo are as defined above, and R5 is a hydrogen atom, a hydroxyl group, and a carbon atom having 1 to 1 carbon atoms). 4 represents an alkoxy group, R6 represents an aldose residue, an aralkylated aldose residue in which the hydrogen atom of the hydroxyl group of a sugar is substituted with an aralkyl group having 7 to 8 carbon atoms, a deoxyaldose residue, a hydroxyl group of a sugar Aralkylated deoxyaldose residue in which the hydrogen atom is substituted with an aralkyl group having 7 to 8 carbon atoms; N-acyl in which the hydrogen atom on the nitrogen atom of an amino group is substituted with an acyl group having 2 to 4 carbon atoms; Aminoaldose residue, aralkyl in which the hydrogen atom on the nitrogen atom of the amino group is substituted with an acyl group having 2 to 4 carbon atoms, and the hydrogen atom of the hydroxyl group of the sugar is further substituted with an aralkyl group having 7 to 8 carbon atoms. N-acylaminoaldose residue, aldohexouronic acid amide residue, aralkylated aldohexouronic acid amide residue in which the hydrogen atom of the hydroxyl group of a sugar is substituted with an aralkyl group having 7 to 8 carbon atoms , represents an aldohexouronic acid residue or an aralgylated aldohexouronic acid residue in which the hydrogen atom of the hydroxyl group of a sugar is substituted with an aralkyl group having 7 to 8 carbon atoms) is a 6-alkyl ellipticine derivative of It can be done.

The base used here is preferably a weak base, such as aqueous ammonia, sodium hydrogen carbonate, potassium hydrogen carbonate,
Distrium phosphate, dipotassium phosphate, sodium tetraborate (Na2B407), potassium tetraborate (R2B407), lithium carbonate, monolithium carbonate, potassium carbonate, calcium carbonate, trialkylamine Examples include dilute solutions of calcium hydroxide, sulfur and lithium hydroxide, and potassium hydroxide. This is best done using the .

On the other hand, the 6-alkyl ellipticine derivative of the general formula (Ia) can be hydrolyzed to give the general formula (in the formula R3, R
5, R6 and Y are as defined above). Then, this ellipticine derivative can be converted into a 6-alkyl ellipticine derivative of the general formula (Ic) by ion exchange as described above.

By using the above synthesis method, the above general formulas (Ia) to (Id) in which a sugar, an acylated sugar, or an aralkyl moiety is bound to the 2-position nitrogen atom of a 6-alkyl ellipticine derivative can be obtained.
The compound is obtained.

The 6-alkyl ellipticine derivative of the general formula (Ib) is further treated with a dealkylating agent to obtain a compound of the general formula (Ie) (wherein R3 and ZO are as defined above, and R7 is hydrogen). represents an atom, a hydroxyl group, or an acyloxy group having 2 to 7 carbon atoms, R8 is an aldose residue, an acylated aldose residue in which the hydrogen atom of the hydroxyl group of a sugar is substituted with an acyl group having 2 to 9 carbon atoms, or a deoxyaldose residue. group, an acylated deoxyaldose residue in which the hydrogen atom of the hydroxyl group of a sugar is substituted with an acyl group having 2 to 9 carbon atoms, and an acylated deoxyaldose residue in which the hydrogen atom on the nitrogen atom of an amino group is substituted with an acyl group having 2 to 4 carbon atoms. N-acylaminoaldose residue, ``The hydrogen atom on the nitrogen atom of the amino group is substituted with an acyl group having 2 to 4 carbon atoms, and the hydrogen atom of the hydroxyl group of the sugar is further substituted with an acyl group having 2 to 9 carbon atoms. acylated N-acylaminoaldose residues, aldohexouronic acid amide residues, and acylated aldohexouronic acid amide residues in which the hydrogen atom of the hydroxyl group of the sugar is substituted with an acyl group having 2 to 9 carbon atoms. , represents an aldohexouronic acid residue, or an acylated aldohexouronic acid residue in which the hydrogen atom of the hydroxyl group of a sugar is substituted with an acyl group having 2 to 9 carbon atoms). can do. The dealkylating agent used is preferably trialkylsilyl iodine, most preferably trimethylsilyl iodine. Further, the solvent may be any solvent as long as it does not participate in the reaction, but chlorine-based or aromatic hydrocarbon-based solvents are preferred. After the reaction is complete,
It can be purified by recrystallization, column chromatography, or preparative thin layer chromatography.

When the above general formula (Ia) is similarly dealkylated, the general formula (
A 6-alkyl ellipticine derivative of Ig) is obtained.

(In the formula, R3, R7, Rn and Y are as defined above.) Then, this ellipticine derivative (I g) is converted to the general formula <T e by ion exchange as described above.
6-alkyl ellipticine derivatives.

By further hydrolyzing the 6-alkyl ellipticine derivative of the general formula (re), a compound of the general formula (where R3 and Z are as defined above, R9 represents a hydrogen atom or a hydroxyl group, and RID represents an aldose residue) , deoxyaldose residue, the hydrogen atom on the nitrogen atom of the amino group has 2 or more carbon atoms
(representing an N-acylaminoaldose residue, an aldohexouronic acid amide residue, or an aldohexouronic acid residue) substituted with an acyl group of 4) can be produced. . The base used in this reaction is the same as described above.

When the above general formula Ng) is hydrolyzed in a similar manner, a 6-alkyl ellipticine derivative of the general formula (Ih) (wherein R3, R9, R10 and Y are as defined above) is obtained, and This 6-alkyl ellipticine derivative (I h) can be converted into the general formula (r f) by ion exchange as described above.

In addition, by using the dealkylation reaction described above,
The general formula (Ic) can be converted into the 6-alkyl ellipticine derivative of the general formula (If), and the general formula (Td) can be converted into the 6-alkyl ellipticine derivative of the general formula (Ih). It can be a syn derivative.

In this way, the ellipticine derivative (IT) and the general formula (
Using the general formula (Ia), which can be synthesized by reacting an aldose derivative having III), many derivatives can be obtained by combining hydrolysis, dealkylation, and ion exchange.

It was confirmed by nuclear magnetic resonance spectrum (NMR spectrum), mass spectrum, and elemental analysis that the 2-position nitrogen atom of each of the ellipticine derivatives and the 1-position carbon atom of the sugar have a glycosidic bond. When irradiated with the signal of the hydrogen atom at the 1st position of a sugar (anomeric hydrogen) in a nuclear magnetic resonance spectrum, the signal intensity of the hydrogen atoms at the 1st and 3rd positions of the 6-alkyl ellipticine derivative increases (NOE). NI recognizes that sugar is bound to the nitrogen atom at the 2-position of the puticine derivative.

Examples of the group R2 in each of the above general formulas include D-erythrose, D-threose, L-erythrose, L-threose, di-O-acetyl-D-erythrose, di-O-acetyl-D-threose, di-0 -acetyl-erythrose, di-acetyl-L-threose, di-O-benzoyl-D-erythrose, di-
0-benzoyl-D-threose, di-0-benzoyl-d-erythrose, di-0-benzoyl-d-threose, di-O-benzyl-D-erythrose, di-0-
Residues of aldotetroses such as benzyl-D-threose, di-0-benzyl-cy-erythrose, di-0-benzyl-threose, D-ribose, D-xylose, L-ribose, L-xylose, D -arabinose, D-lyxose, ■, -arabinose, ■, -lyxose, tree〇-acetyl-D-ribose, tree〇-
Acetyl-D-xylose, tri0-7 cetyl-1-ribose, tri-0-acetyl-1-xylose, tri-0-acetyl-D-arabinose, tri-0-acetyl-D-lyxose, tri-0-acetyl-1-arabinose, tri-0 -acetyl-benzoyl-D-ribose, tri-benzoyl-D-xylose, tri-benzoyl-I, -ribose, tri-benzoyl-L-xylose, tri-benzoyl-D-arabinose, Tory〇-Hensyru〇-Lyquisose, Tory〇-Hensyru〇-L-Arabinose, Tory〇-Benzyru■, -Lyxose, Tory〇-Benzyru D-ribose, Tory〇-Benzyru D-xylose, Tory〇-Benzyru■, -ribose, Aldopentose residues such as tri-0-benzyl-d-xylose, tri-0-benzyl-D-arabinose, tri-0-benzyl-D-IJ xylose, tri-0-benzyl-d-arabinose, tri-0-benzyl-L-lyxose, etc. Group; D-glucose, D-mannose, L-glucose, L-mannose, D-fucose, D-aldulose, L-fucose, L-aldulose, D-gulose, D-idose, L-gulose,
L-Idose, D-Galactose, D-Crose, L-
Galactose, D-Crose, Tetra-0-acetyl-
D-glucose, Tetra 0-acetyl D-
Mannose, tetra-0-acetyl-glucose,
Tetra-0-acetyl-monomannose, Tetra-0-
Acetyl-D-fucose, Tetra-O-acetyl-D-
aldrose, tetra-O-acetyl-fucose,
Tetra-0-acetyl-L-aldrose, Tetra-0
-acetyl-D-gulose, tetra-O-acetyl-
D-idose, tetra-0-acetyl-gulose, tetra-0-acetyl-cy-idose, tetra-0-
Acetyl-D-galactose, Tetra-0-acetyl-
D-Crose, Tetra-O-acetyl-shi-galactose, Tetra-0-acetyl-shi-Crose, Tetrabenzoyl-D-glucose, Tetra-0-Henseyl-D
-mannose, tetra-O-benzoyl-L-curcose, tetra-0-benzoyl-d-mannose, tetra-0-benzoyl-D-fucose, tetra-0-benzoyl-D-aldrose, tetra-0-benzoyl-d-allose , tetra-0-benzoyl-d-aldrose, tetra-0-benzoyl-D-gulose, tetra-0-benzoyl-D-idose, tetra-0-benzoyl-d-gulose, tetra-O-benzoyl-d-idose, Tetra-0-benzoyl-D-galactose, Tetra-○-benzoyl-D-Crose, Tetra-
0-benzoyl-cyclogalactose, tetra-0-benzoyl-cycloglucose, tetra-0-benzyl-D-glucose, tetra-0-benzyl-D-mannose, tetra-〇-benzyl-monoglucose, tetra-〇 -Hensyl-L-mannose, Tetra-0-hensyl-D-
fucose, tetra-0-benzyl-D-aldrose,
Tetra-O-benzyl-fucose, Tetra-0-benzyl-aldrose, Tetra-0-hensyl-D
- Gulose, Tetra-O-benzyl-D-idose,
Tetra-0-benzyl-gulose, Tetra-0-
Benzyl-cy-idose, tetra-O-benzyl-D-
Galactose, Tetra-O-benzyl-D-Crose,
Tetra-0-benzyl-galactose, Tetra-0
Residues of aldohexoses such as -benzyl-cyclohexose; -galactose), D-fucose (i.e. 6-zooxy-D-galactose), 6-zooxy-D-allose, 6-zooxy-D-aldrose, 6-zooxy-D-gulose,
6-dioxy-monocrose, tri-acetyl-D
-quinovose, tri-acetyl-rhamnose,
Tri-0-acetyl-1-fucose, tri-0-acetyl-D-fucose, 6-zooxy-tri-0-acetyl-D-fucose, 6-dioxy-tri-0-acetyl-
D-aldrose, 6-zooxytri-O-acetyl-D-gulose, 6-zooxytri-O-acetyl-
Shiichikrose, Tory O-henshiiru D-kinobose, l.two 0-henshiiru 1 fulumnose, Tory O-henshiiru L-fucose, Tory 0-henshiiru D-fucose, 6-zooxytree〇~henshiiru D-fucose, 6-dioxy-tri-0-henzoyl-D-aldrose, 6-dioxy-tri-0-henzoyl-D-gulose, 6-dioxy-tri-0-henzoyl-D-gulose, l-IJ-0-henzoyl-D-
Quinobose, tri-0-benzyl-rhamnose, tri-0-benzyl-d-fucose, tri-0-benzyl-D-fucose, 6-zooxytri-0-hensyl-
D-fucose, 6-zooxytri-O-benzyl-D
-Aldrose, 6-zooxytri-O-hensyl-
D-gulose, 6-zooxytri-0-hensyl-talose, 2-deoxy-glucose, 2-deoxy-D-gulose, 2-deoxy-D-galactose, 2-deoxy-tri-0-acetyl- D-glucose, 2-deoxy-tri-0-acetyl-D-gulose,
2-deoxy-tri〇-acetyl-D-galactose, 2-deoxy-1-tri〇-henshiyl-D-glucose, 2-deoxy-tri〇-henshiyl-D-gulose, 2-deoxy-tri〇-henshiyl-D-galactose 2- or 6-dioxyaldohexoses such as Residue; 2-deoxy-D-ribose, 5-deoxy-L
-arabinose, 5-deoxy-D-xylose, 5-
Deoxy-D-lyxose, 5-deoxy-D-ribose, 2-deoxy-di-0-acetyl-D-ribose,
2-deoxy-di-acetyl-D-arabinose,
5-deoxy-di〇-acetyl-I, -arabinose, 5-deoxy-di〇-acetyl-D-xylose,
5-deoxy-di-acetyl-D-lyxose, 5
-deoxy-di-0-acetyl-L-ribose, 2-deoxy-di-benzoyl-D-ribose, 2-deoxy-di-0-benzoyl-D-arabinose, 5-deoxy-di-0-benzoyl-dis-arabinose, 5-
Deoxy-D-0-henshiyl-D-xylose, 5-
Deoxy-di-0-benzoyl-D-lyxose, 5-
Deoxy-di-benzoyl-mono-ribose, 2-deoxy-di-benzyl-D-ribose, 2-deoxy-di-benzyl-D-arabinose, 5-deoxy-di-benzyl-bi-arabinose, 5- Deoxy-di-benzy-D-xylose, 5-deoxy-di-benzy-D-lyxose, 5-deoxy-
Residues of 2 or 5 deoxyaldopentose such as di-O-benzyl-L-ribose; N-acetyl-D-galactosamine, N-acetyl-D-glucosamine, N-acetyl-D-talosamine, N-acetyl-D-talosamine, N-acetyl-D-mannosamine, N-acetylcassamine, N-acetyl-D-fucosamine, N-acetyl-L-fucosamine, N-acetylmicosamine, N-acetylcassamine, N-acetyl-tri-acetyl D-galactosamine, N-acetyl-tri-0-acetyl-D-glucosamine, N-acetyl-tri-0-acetyl-D-talosamine, N-acetyl-tri-0-acetyl-D-talosamine, N-acetyl-tri-0-acetyl -D-Mannosamine, N-acetyl-tri-0-acetylcassamine, N-acetyl-di-acetyl-D-fucosamine, N-acetyl-di-acetyl-thi-fucosamine, N-acetyl-di-acetylmicho Samin, N-acetyl-di-acetylneumosamine,
N-acetyl-tri-O-benzoyl-D-galactosamine, N-acetyl-tri-O-benzoyl-D-glucosamine, N-acetyl-tri-O-benzoyl-D-
Glossamine, N-acetyl-tri-benzoyl-D
-Talosamine, N-acetyl-tri-O-henzoyl-D-mannozamine, N-acetyl-tri-O-henzoyl-canozamine, N-acetyl-di-O-henzoyl-D-fucosamine, N-acetyl-di-O-benzoyl, -fucosamine , N-acylaminoaldose residues such as N-acetyl-diO-henzoylmicosamine, N-acetyl-di0-henzoylneumosamine, L-iduronic acid, D-galacturonic acid, D-glucuronic acid, ■
, -glucuronic acid, D-mannuronic acid, L-iduronic acid methyl ester, D-galacturonic acid methyl ester,
D-glucuronic acid methyl ester, D-mansuronic acid methyl ester, )IJ-0-acetyl-d-iduronic acid methyl ester, tri-0-acetyl-D-galacturonic acid methyl ester, tri-0-acetyl-D-glucuronic acid methyl ester , l-so-0-acetyl-L-glucuronic acid methyl ester, tri-0-acetyl-D-
Residues of aldohexouronic acid derivatives such as mansuronic acid methyl ester; as well as L-iduronic acid amide, D-
Galacturonic acid amide, D-glucuronic acid amide, L-
Guluronic acid amide, D-mansuronic acid amide, tri-0-acetyl-mono-iduronic acid amide, tri-0-acetyl-D-galacturonic acid amide, tri-0-acetyl-D-glucuronic acid amide, tri-0-acetyl-mono-iduronic acid amide acid amide, tri0-acetyl-D-mansuronic acid amide, tri0-benzoyl-monoiduronic acid amide, tri0-benzoyl-D-galacturonic acid amide, tri0-benzoyl-D-glucuronic acid amide,
Tri-0-benzoyl-L-guluronic acid amide, tri-0-bezoyl-D-mansuronic acid amide, tri-0-benzylu-L-iduronic acid amide, tri-0-benzyru-D-galacturonic acid amide, tri-0-benzyru-D-
Examples include residues of aldohexouronic acid amide such as glucuronic acid amide, tri0-benzyl-L-glucuronic acid amide, and tri0-benzyl-D-mansuronic acid amide.

The compounds of the invention thus obtained are generally colored during the measurement of their melting points and decompose over a wide temperature range, so that no clear melting point can be obtained.

The compounds of the general formula (I) [and the general formulas ○a) to (Ih), which are included therein] according to the present invention can be used for murine leukemia L-, 121, as explained in the Examples.
It has a remarkable antitumor effect against 0.

Considering that seliptium, which was used as a control, is actually used for breast cancer, etc., it is thought that the compound of the present invention can be an excellent anticancer agent.

When the compound of the present invention is used as an anticancer agent, it may be used in the form of an injection for intravenous, intramuscular or subcutaneous injection, or in the form of a tablet,
It can be used in the form of orally administered preparations such as granules, powders or troches, or in the form of transdermal absorption preparations such as vaginal and anal herbal medicines and ointments.

In preparing these formulations, diluents, carriers, excipients, binders, vehicles, etc. commonly used in formulation technology are used.

Non-toxic vehicles such as liquid oils can be used to serve as suspending agents.

The appropriate dosage for this product is 0.1-30 kg/da.
y, but it goes without saying that it varies considerably depending on the administration method and dosage form.

EXAMPLES The present invention will be described in detail below with reference to Examples, but it goes without saying that the technical scope of the present invention is not limited to these Examples. In addition, in the following examples,
Ac represents an acetyl group, Bz represents a benzoyl group, Bn represents a benzyl group, and ph represents a phenyl group. In addition, the ion exchange resin BIO-RAD AG 1-X8 is manufactured by Bioland Chemical Distillation (BIO-RA
D Chemical Division) “Resin A, Sephadex (5ephadex) in gel filtration resin
L H-20 is manufactured by Pharmacia Fine Chemical (Ph
armacia Fine Chemicals AG
), and the silica gel used was Kieselgel 60 manufactured by Merck & Co., Ltd.

Example 1 2-(2,3,5-tri-benzoyl-β-D-
Synthesis of (xylofuranosyl)-9-acetoxy-6-methylnylipticinium chloride 2.3.5-tri〇-benzoyl-α-D-xylofuranosyl chloride 809■
was dissolved in 30 mQ of nitromethane to give 9-acetoxy-
6-methylniripticin 223 mg and cadmium carbonate 2
20 ml was added and heated under reflux for 10 minutes. Insoluble material was removed by filtration and the filtrate was concentrated. The residue was soaked in silica gel (10
The product was subjected to column chromatography using 0 mQ, Kieselgel 6 (manufactured by Merck & Co., Ltd.) and eluted with methylene chloride-methanol (94:6 to 92:8) to obtain 170 ml of a compound. This was then subjected to gel filtration column chromatography (Sephadex Lll-20, φ4.6c
mX32(2)) and eluted with methanol to give 149■(
The title compound was obtained with a yield of 27%.

Similarly, using 2.3.5-tri〇-benzoyl-L-xylofuranosyl chloride, 2-(2,3,5-tri〇-benzoyl-β-■,-xylofuranosyl)-9-acetoxy-6-methylnily Ptycinium chloride was obtained.

The following compounds were obtained in the same manner as in Example 1.

Example 2: 2-(2,3,5-)-O-benzoyl-β-D-ribofuranosyl)-9-acetoxy-6
-Methylniripticinium bromide 2- (2,3,5
-) So0-Hensyl-β-L-ribofuranosyl)-
9-acetoxy-6-methylnilipticinium bromide Example 3: l-(2,3,'5-tri0-hencyyl-α-D-arabinofuranosyl)-9-acetoxy-6-methylnilipticinium nium bromide 2- (2,3
, 5-) 2-(2,3-di-0-benzoyl-5-deoxy-)-9-acetoxy-6-methylnylipticinium bromide α-L-arabinofuranosyl)-9-acetoxy-6-methylnibuticinium chloride Example 5: 1-(2,3-di○-penduyl-β-ri-erythrofuranosyl)-9-acetoxy= 6-Methylnylipticinium chloride 2-(2,3-di0-benzoyl-β-■,-erythrofuranosyl)-9-acetoxy-6-methylnylipticinium chloride Example 6: 2-(2 ,3-di-0-hendiyl-5-deoxy-β-D-ribofuranosyl)-9-acetoxy-
6-Methylnylipticinium chloride Example 7: 2-(2,3,5-tri〇-hensylu β
-D-arabinofuranosyl)-9-acetoxy-6-methylnilipticinium bromide 2- (2,3,5-1
-So0-benzylu β-L-arabinofuranosyl)-
For 9-acetoxy-6-methylnylipticinium bromide Example 7, 2.3.5-tri-〇-henjiru-D-arabinofuranosyl bromide or 2゜3.5-1
-R-O-benzy-L-arabino was added using furanosyl bromide to obtain IZ 2' Gis form.

Example 8 2-(β-D-xylofuranosyl)-9-hydroxy-
Synthesis of 6-methylnylipticinium chloride 2-(2,3,5-tri〇-hencyyl-β-D-xylofuranosyl)-9-acetoxy-6-methylnylipticinium chloride 126■ in ammonia-saturated methanol 3BITIQ Comb and leave at room temperature overnight.

The residue obtained by concentration under reduced pressure was dissolved in 10 methanol of hot water and crystallized by adding ethyl acetate. Filter and wash the powder with ethyl acetate/methanol (4:1) to remove the title compound (63μ).
Yield: 90%).

2-(β-L-xylofuranosyl)-9-hydroxy-6-methylnylipticinium chloride was obtained in the same manner.

The following compound was obtained in the same manner as in Example 8.

Example 9: 2-'(β-D-ribofuranosyl)-9=hydroxy-6-methylnibuticinium bromide 2-(β-L-ribofuranosyl)-9-hydroxy-6
-Methylniripticinium bromide Example 10:2-(
α-L-arabinofuranosyl)-9-hydroxy-6-
Methylnilipticinium -bromide 2-(α-D-arabinofuranosyl)-9-hydroxy-6-methylnilipticinium bromide! ■Work 1-
(5deoxy-α-L-arabinofuranosyl)-9-hydroxyl 6-methylniliptycinium chloride ldL Example 12: 2-(β~D~erythrofuranosyl)-9-hydroxy-6-methylnilptycinium Cinium chloride 2-(β-17-nyrisulfuranosyl)-9-hydroxy-6-methylnibuticinium chloride fM]
3: 2-(5-deoxy-β-D-ribofuranosyl)-9-hy1:roxy6-methylellipticinium chloriF Major axis example 14. :2-(β-D-arabinofuranosyl)-
9-Hydroxy-6-methylnylipticinium chloride 2-(β-L-arabinofuranosyl)-9-hydroxy-6-methylnylipticinium chloride Example 15 2-(2,3,5-tri Synthesis of 9-acetoxy-6-methylnilipticinium chloride 9-acetoxy-6-methylnilipticin 150 m, 2
, 3.54 ly O-benzoyl-D-lyxofuranosyl chloride 424■ The title compound 224■ (yield 60%) was obtained in the same manner as in Example 1. In this (1,-compound, two stereoisomers existed at the 1-position of the sugar, and the ratio was α-form/β-form - 5/1.The physical data are shown in the table, but the NMR spectrum is Data for each α-form and β-form are shown.

The following compound was obtained in the same manner as in Example 15.

Example 16: l-(2,3,5-)so0-benzoyl-L-lyxofuranosyl)-9-acetoxy-6-methylniriputicinium chloride This compound is also α-form/β-form.
It was 5/1. The notation of physical data is also shown in the same manner as in the examples.

Example 17 2-(D-lyxofuranosyl)-9-hydroxy-6-
Synthesis of Methylniriputicinium Chloride 84 mg (yield 74%) of the title compound was obtained in the same manner as in Example 8 using Compound 203■ of Example 15. This compound is also tl! i
Regarding α-form/β-form, it was a 5/1 mixture. Regarding physical properties, NMR spectra show data for α-form and β-form.

The following compound was obtained in the same manner as in Example 17.

Example 18: 2-(L-lyxofuranosyl)-9-hydroxy-6-methylellipticinium chloride This compound is also α-form/β-form-5/1, and the data are expressed in the same manner as in Example 17. Ta.

Can Example 19 2-(2,3,4-)so0-acetyl-β-L-ribopyranosyl)-9-acetoxy-6-methylnilipticinium bromide 9-acetoxy-6-methylnilipticin 100■, 2
, 3.4-tri〇-acetyl-β-L-riboviranosyl bromide 288 ■, cadmium carbonate 150 nw, and nitromethane 10 mg were reacted to give the title compound 206 ■
Obtained.

The following compounds were obtained in the same manner.

Example 20: 2-(2,3,4-tri〇-acetyl-β-D-ribopyranosyl)-9-acetoxy-6
-Methylniripticinium bromide was obtained.

Example 21 2-(2,3,4,-)so0-acetyl-β-L-
Synthesis of (fucopyranosyl)-9-acetoxy-6-methylnilibuticinium bromide 9-acetoxy-6-methylnilibuticin 100■, 2
．． '3. Using 220 μ of 4-tri-acetyl-fucopyranosyl bromide, 120 μ of cadmium carbonate, and 10 mQ of nitromethane, 176 μ of the title compound (yield 84%) was obtained.
) was obtained.

The following compound was obtained in the same manner as in Example 21.

J Case Study 22: 2-(2,3,4-tri〇-acetyl-β-D-fucopyranosyl)-9-acetoxy-6-methylniripticinium bromide The following compound was prepared in the same manner as in Example 19.21. Obtained.

1+Example 23: 2- (2,3,4-tree 0-7'
cetyl-α-D-arabinopyranosyl)-9-acetoxy-6-methylnilipticinium bromide'U) ff
i (state ζ4: 2- (2,3,4-)-O-acetyl-α-L-arabinopyranosyl)-9-acetoxy-
6-Methylnylipticinium bromide Example 25:2-
(2,3,4-)Goo-O-acetyl-α-D-lyxopyranosyl)-9-acetoxy-6-methylnibuticinium chloride Example 26: 2-(2,3,4-)Le-O-acetyl-α -L-lyxopyranosyl)-9-acetoxy-6-methylnylipticinium chloride side example 271- 6-
Methyl niriputicinium, bromide 1- (2,3,4,6-tetra-0-acetyl-β-
L-galactopyranosyl)-9-acetoxy-6-methylnilipticinium, bromide Example 28: 2-
(2,3,4,6-tetra-0-acetyl-β-D-glucopyranosyl)-9-acetoxy-6-methylniripticinium bromide 2- (2,3,4,6-tetra-0-acetyl-β −
L-glucopyranosyl)-9-acetoxy-6-methylniriputicinium bromide Example 29: 2-(2-acetamido-3,4゜6-tri〇-acetyl-2-deoxy-β-D-glucopyranosyl)-9 -acetoxy-6-methylnylipticinium chloride Example 30: 2-(methyl 2,3.4-tri〇-acetyl-β-D-glucuronopyranosyl)-9-acetoxy-6-methylnylipticinium Example 31 Synthesis of 2-(2,3,4-tri0-7-t!thyl-D-xylopyranosyl)-9-acetoxy-6-methylnylipticinium bromide 9-acetoxy-6-methylnyli Petit Shin 100■, 2
, 3.4-1-10-acetyl-α-ly-xylopyranosyl bromide (210 μl), cadmium carbonate (120 μl), and nitromethane (10 ff IC) were used to obtain the title compound 107 μl (yield: 52%).

This compound was a mixture of two types of isomerization of sugar, α-form and β-form, and the ratio was α-form/β-form - 1/3.

The following compound was obtained in the same manner as in Example 3I.

Example 32: 1-(2,3,4-)di-0-acetyl-mono-xylopyranosyl)-9-acetoxy-6-methylnibuticinium bromide This compound is also α-/β-
It was 1/3. The NMR spectra of the α-form and β-form and the physical properties of the mixture are shown in the table.

Side Can Example 33 Synthesis of 2-β-L-ribopyranosyl-9-hydroxy=6-methylniriputicinium bromide Compound 122■ of Example 19 was dissolved in 10+++R ammonia-saturated methanol and hydrolyzed to yield the title compound 53■ (
A yield of 59% was obtained.

The following compounds were obtained in the same manner.

Example 34: 2-β-D-ribopyranosyl-9-hydroxy-6-methylniributicinium bromide Example 35 Synthesis of 2-β-L-fucopyranosyl-9-hydroxy-6-methylnilibuticinium bromide Example 2I Using 153 mg of the compound and 15 mg of ammonia-saturated methanol, 82 mg of the title compound (yield 72%) was obtained.

The following compounds were obtained in the same manner.

Example 36: 2-β-D-fucopyranosyl-9-hydroxy-6-methylniripticinium bromide The following compound was obtained in the same manner as in Example 33.35.

Example 37: 2-α-D-arabinopyranosyl-9-hydroxy-6-methylnilipticinium bromide Example 38: 2-α-L-arabinopyranosyl-9-hydroxy-6-methylnili (h-1+lI 39: 2-α-D-lyxopyranosyl-9-hydroxy-6-methylniripticinium chloride'fphIf; (1+I 40: 2-α-■,-lyxopyranosyl) Lanosyl-9-hydroxy-6-methylellipticinium chloride Example 41; 2-β-D-galactopyranosyl 9-hydroxy-6-methylnylipticinium bromide 2-β-L-galac I. Pyranosyl-9-hydroxy-
6-Methylniriputicinium bromide (i?Jl+
42: 2-β-D-glucopyranosyl-9-hydroxy-6-methylnibuticinium bromito' 2-β-L-glucopyranosyl-9-hydroxy-6-
Methylnylipticinium bromide Example 43: 2-(2
-acetamido-2-deoxy-β-D-glucopyranosyl)-9-hydroxy-6-methylnibuticinium chloride Example 44 2-β-D-glucuronamidopyranosyl-9-hydroxy-6-methylellipti Synthesis of Cinium Bromide The compound of Example 30 was mixed with ammonia-saturated methanol lr;
The title compound was obtained by standing at 0° to 5° C. for 15 hours.

Example 45 Synthesis of 2-D-xylopyranosyl-9-hydroxy-6-methylniripticinium bromide Compound 84 of Example 31, 10 ml of ammonia-saturated methanol! Using this method, the title compound 41 (yield 66%) was obtained. This product had α-form/β-form −1/3 regarding sugar.

The following compound was obtained in the same manner as in Example 45.

Example 46: 2-L-xylopyranosyl-9-hydroxy-6-methylniripticinium bromide This compound was also in the α-form/β-form-1/3. α-form, β-form N
The MR spectrum and physical properties of the mixture are shown in the table.

Example 47 2-(2,3,4-1-so0-acetyl-α-L-
Synthesis of (rhamnoviranosyl)-9-hydroxy-6-methylnilibuticinium bromide 9-hydroxy-6-methylnilibuticin 190m+r
190ff1g of cadmium carbonate and 399mg of α-bromoacetramnose were suspended in 19-nitromethane and heated under reflux for 10 minutes. Insoluble materials were removed and the resulting residue was purified with 200-g silica gel (elution: methylene chloride-methanol - 95:5 to 92:8) and 5 ep
hadex LH-20 (φ4.OcmX23cms
The mixture was subjected to column chromatography using methanol) to obtain the title compound 214 (yield: 49%).

The following compound was obtained in the same manner as in Example 47.

1 can example 48: l-(2,3,4,,6-chitler○-
Acetyl-α-D-mannopyranosyl)-9-hydroxy-6-methylnibuticinium bromide 2,- (2,3,4,6-Citler 0-acetyl-α
-L-mannopyranosyl)-9-hydroxy-6-methylniripticinium bromide Example 49 2-α-L-rhamnopyranosyl-9-hydroxy-6-
Synthesis of Methylniriputicinium Bromide Compound 194■ of Example 47 was diluted with 32 mff of ammonia-saturated methanol and left in a refrigerator for 15 hours to obtain 98 mg (yield 79%) of the title compound.

The following compound was obtained in the same manner as in Example 49.

Example 50: 2-α-D-mannopyranosyl-9-hydroxy-6-methylnibutiunium furomide 2-α-L-mannopyranosyl-9-hydroxy-6-
Methylnyliputinium bromide Example 51 Synthesis of 2-(2,3,4-)so0-acetyl-α-L-rhamnopyranosyl)-9-acetoxy-6-nitylelipticinium bromide 9-acetoxy-6- Nityle ellipticine 190■, cadmium carbonate 170■2, 3, 4. -) Lee〇-acetyl-α-L-rhamnopyranosyl bromide 292mg (
1.6 eg) was suspended in 17 J of nitromethane and heated under reflux for 10 minutes. Insoluble matters were filtered and the resulting residue was subjected to column chromatography on 100 m (+ silica gel (elution solvent, methylene chloride/methanol-96; 4-93 nia), then 5 ephadex Lit-20
(φ4cm x 30cm, methanol) column chromatography to obtain the title compound 262■ (yield 75%)
I got it.

Example 52 2-α-L-rhamnopyranosyl-9-hydroxy-6-
Synthesis of Nithylelipticinium Bromide Compound 240IIW of Example 51 was added to 40 mQ of ammonia-saturated methanol.
I left it in the refrigerator overnight.

The residue was pulverized with methanol/ethyl acetate to obtain the title compound 131 (yield 72%).

Example 53 2-(2,3,4-)lyO-acetyl-α-■,-
Synthesis of (rhamnopyranosyl)-9-acetoxy-6-ituprobil ellipticinium bromide 9-acetoxy-6
- ituprovir ellipticine 142■, cadmium carbonate 100■, 2.3.4-tri〇-acetyl-alpha-L-
Rhamnopyranosyl bromide to 12-nitromethane!
! ! The mixture was made cloudy and heated under reflux for 10 minutes. After removing insoluble materials, the resulting residue was mixed with 80 g of silica gel (solvent, 5%
methanol/chloroform) column chromatography, then 5ephadex LH-20 (φ4.8
The product was subjected to column chromatography (cm×27.5 cm, methanol) to obtain the title compound 152 cm (yield: 53%).

Example 54 2-α-L-rhamnopyranosyl-9-hydroxy-6-
Synthesis of ituprobil ellipticinium bromide Compound 130 of Example 53 was dissolved in 10-ammonium saturated methanol and left in a refrigerator for 21 hours. The residue obtained by concentration was powdered with methanol/ethyl acetate to obtain 70 mg (yield 71%) of the title compound.

Example 55 2-(2,3,41-so0-acetyl-α-L-rhamnopyranosyl)-9-acetoxy-6-cyclobrobylmethylellipticinium bromide 9-acetoxy-6
- 172 ■ of cyclopropyl methyl ellipticine, 170 ■ of cadmium carbonate, and 275 ■ of 2゜3.4-tri〇-acetyl-α-L-rhamnopyranosyl bromide were suspended in 17-nitromethane and heated under reflux for 7 minutes. did. After removing insoluble matter, the residue obtained by concentration was subjected to column chromatography on 100 J silica gel (elution solvent, methylene chloride: methanol - 95:5) and then 5 eph-adex.
The product was subjected to column chromatography on LH-20 (φ2.5c+nX53c+n, methanol) to obtain the title compound 259 (yield 76%).

Example 56 2-α-L-rhamnopyranosyl-9-hydroxy-6-
Synthesis of cyclobrobyl methyl ellipticinium bromide Compound 184 of Example 55 was dissolved in 32 mQ of ammonia-saturated methanol and left overnight in a refrigerator. The residue obtained by concentration was crystallized from methanol/ethyl acetate to obtain the title compound 122 (yield: 87%).

The following example compounds were synthesized in the same manner as described above.

Example 57: 2-(2,3,4-)so0-acetyl-α-L-rhamnopyranosyl)-6-methylniripticinium bromide Example 58: 2-α-L-rhamnopyranosyl-6-
Methyl ellipticinium bromide Example 59: 2-(2,3,4-)so0-acetyl-α-L-rhamnopyranosyl)-9-methoxy-6
-Methylnibuticinium bromide Example 60: 2-α
-L-rhamnopyranosyl-9-methoxy-6-methylniripticinium bromide Table 1 shows the physical properties of each compound obtained as described above.

Note that the compounds in the table have the following general formula.

UG2-22794 (24) Publication date UG2-22794 (24) Publication date 1986-2
2794 (27) JP 82-22794 (2B) HG2-22794 (29)'41 JP 1987-22794
-22794 (34) 11 1986-22794 (d6) Special Opening RG2-22794 (37) Test Examples The antitumor effects of the various ellipticine derivatives produced above were confirmed on mouse experimental tumor L1210 as follows. .

i) Animals used: BDF, female mice, 6 weeks old (average weight 17-18 g), 6 animals per group ii) Separation plates used: L1210 (mouse leukemia cells) 105 cells/mouse, intraperitoneal inoculation (ip) iii) Sample administration method: L12 to BDFI mice
10, and 24 hours later, intraperitoneal administration was administered once a day for 5 consecutive days.

iv) Evaluation method: Efficacy is indicated by the increase in mean survival time (ILS%) compared to the control group.

The results obtained are shown in Table 2, and it is clear from the results that the compound of the present invention has a significant anti-lIt tumor effect against murine leukemia L1210 (10B).

In addition, the 80-day survival increase was due to mouse leukemia L4210 administration 80B.
Represents the number of strokes of the surviving mouse.

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-X womb 1+l', Ip,
＼Sa IJ - し 褌 key jl + to small ko 1'1-to's I to 1 to 1 ω1 0- to the - mouth of - Reference Example 1 Synthesis of 9-hydroxy-6-itsuprobil ellipticine To 9-acetoxyellipticine (1.0 g) dissolved in 40-g of anhydrous dimethylformamide were added 160 ml of sodium hydride (50% in oil) and IOJ of anhydrous dimethylformamide at O'C, and the mixture was stirred for 30 minutes. Add 0.33 mQ of isopropyl iodine (1
sopropyl 1odide) and incubate at room temperature for 43 minutes.
Stir for hours. Ice-water was added to the reaction solution, and the mixture was extracted with chloroform (four times). The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The resulting residue was subjected to silica gel column chromatography, eluted with 1% methanol-chloroform, and purified with 9-acetoxy-6-iprobil elliptidine. Syn 268■ (yield 24%) was obtained.

This compound was mixed with ammonia-saturated methanol at 0°~
The title compound was obtained in a yield of 2 by treatment at 5°C for 15 hours.
Obtained at 2%.

Physical properties Nibrism group (yellowish brown) Melting point: 210-285°C (sublimation with decomposition) IR spectrum (KBr, cm'): 1600.1590.1
580.150 (1,1465,1390,1380,
1370, 1280, 1270, 1260, 1210,
1170, 1145, 1135, 1125, 1100,
1025 days boH UV spectrum (λ, nm): 212 (εm
αX 26000), 250 (ε30000) 277 (ε4
0000), 29B (ε55000) mass spectrum (El, m/z: 304 (M), 288
．． 261.247.233.217.77, NMR spectrum (DMSO-d6, δin ppm) 21.
57 (6H, d, J-1 (z7), 2.'91
(3H,s), 3.18 (3'H,s), 5.
27 (IH, dg, J=711z), 7.01
(IH,'dd.

J-2, 5, 8, 5Hz), 7. f32 (IH, d'
.

J=8. 5tlz), 7. 79 (“IH, d,
J-2°5Hz), 7. 94 (I H, d,
J=6. 5Hz), 8.42 (IH, d, J-6,
511z), 9.19(IH,s), 9. 65
(IH,s) Elemental analysis (C20H211N20) C (%) H (%) N (%) Calculated value: 78.92 6.62 9.20 Actual value:
78.80 6.4.2 9.10 Reference Example 2 Synthesis of 9-acetoxy-6-cyclopropylmethyl ellipticine 1.0 g of 9-acetoxy ellipticine was dissolved in 40 J of anhydrous dimethylformamide, and then hydrogenated. 131 mg of sodium was added. After stirring at room temperature for 10 minutes, bromomethylcyclopropane
yclo-propane) 44.2 mg of anhydrous dimethylformamide solution (IJ) was added. After stirring at room temperature for 6 hours, water was added to precipitate a powder.

The powder was filtered and subjected to column chromatography using silica gel (200d, 1% methanol/chloroform) to obtain the title compound 577 (yield 49%).

Physical properties: Yellow needle crystals, melting point: 200-205°C (114
,) IR spectrum (KB r, cm-'): 3000°2920, 1740, 1595, 1480, 1370.
1300, 1220.1200, 1140. Hishi0H UV spectrum (λ, nm): 205 (εmα
X 16000), 220 (ε 16000)
, 250 (ε23000), 278 (8380
00), 290 (ε53000), 298
(ε60000) Mass spectrum (ET, m
/z): 358 (M”), 316.232.20
4 NMR spectrum (DMSO-d6. δin 99
+11): 33-0. 47 (4H, m)
, 1. 22 (IH.

m), 2. 34 (3H,s), 3. 0
4 (3H.

s), 3. 19 (3H,s), 4-,
62 (2H.

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, R^1 is a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 4 carbon atoms, or a C 2 to 7 alkoxy group) represents an acyloxy group, R^2 is an aldose residue, an acylated aldose residue in which the hydrogen atom of the hydroxyl group of a sugar is substituted with an acyl group having 2 to 9 carbon atoms, and the hydrogen atom of the hydroxyl group of a sugar is a carbon atom of 7 Aralkylated aldose residues substituted with ~8 aralkyl groups, deoxyaldose residues, acylated deoxyaldose residues in which the hydrogen atom of the hydroxyl group of sugar is substituted with an acyl group having 2 to 9 carbon atoms, sugar an aralkylated deoxyaldose residue in which the hydrogen atom of the hydroxyl group is substituted with an aralkyl group having 7 to 8 carbon atoms, and the hydrogen atom on the nitrogen atom of the amino group is substituted with an acyl group having 2 to 4 carbon atoms. N-acylaminoaldose residue, the hydrogen atom on the nitrogen atom of the amino group is substituted with an acyl group having 2 to 4 carbon atoms, and the hydrogen atom of the hydroxyl group of the sugar is further substituted with an acyl group having 2 to 9 carbon atoms. Acylated N-acylaminoaldose residue, the hydrogen atom on the nitrogen atom of the amino group is substituted with an acyl group having 2 to 4 carbon atoms, and the hydrogen atom of the hydroxyl group of the sugar is replaced with an aralkyl group having 7 to 8 carbon atoms. Substituted aralkylated N-acylaminoaldose residue, aldohexouronic acid amide residue, acylated aldohexol in which the hydrogen atom of the hydroxyl group of the sugar is substituted with an acyl group having 2 to 9 carbon atoms. rononic acid amide residue, aralkylated aldohexouronic acid amide residue in which the hydrogen atom of the hydroxyl group of the sugar is substituted with an aralkyl group having 7 to 8 carbon atoms, the hydrogen atom of the hydroxyl group of the sugar having 2 carbon atoms Acylated aldohexouronic acid lower alkyl ester residue substituted with ~9 acyl groups, aralkylated aldohexouron in which the hydrogen atom of the hydroxyl group of the sugar is substituted with an aralkyl group having 7 to 8 carbon atoms. Acid lower alkyl ester residues, aldohexouronic acid residues, acylated aldohexouronic acid residues in which the hydrogen atom of the hydroxyl group of a sugar is substituted with an acyl group having 2 to 9 carbon atoms, or a hydroxyl group of a sugar. Represents an aralkylated aldohexouronic acid residue in which the hydrogen atom is substituted with an aralkyl group having 7 to 8 carbon atoms, and R^3 is a linear, branched, cyclic, or cyclic group having 1 to 5 carbon atoms. -represents a linear alkyl group, X^■ represents an anion of an inorganic or organic acid acceptable as a drug, and in the formula, the bond represented by N^■-R^2 is the 2 of ellipticine.
A 6-alkyl ellipticine derivative having the following formula (representing a glycosidic bond between the nitrogen atom at position 1 and the carbon atom at position 1 of a sugar). 2. In the general formula (I), the group R^2 is an aldotetrose residue, and the hydrogen atom of the hydroxyl group of the sugar has 2 to 4 carbon atoms.
The compound according to claim 1, which is an acylated aldotetrose residue substituted with an alkylacyl group or an arylacyl group having 7 to 9 carbon atoms. 3. In the general formula (I), the group R^2 is an aldopentose residue, and the hydrogen atom of the hydroxyl group of the sugar has 2 to 4 carbon atoms.
The compound according to claim 1, which is an acylated aldopentose residue substituted with an alkylacyl group or an arylacyl group having 7 to 9 carbon atoms. 4. In the general formula (I), the group R^2 is an aldohexose residue, and the hydrogen atom of the hydroxyl group of the sugar has 2 to 4 carbon atoms.
The compound according to claim 1, which is an acylated aldohexose residue substituted with an alkylacyl group or an arylacyl group having 7 to 9 carbon atoms. 5. In the general formula (I), the group R^2 is a 2-deoxyaldopentose residue, and the hydrogen atom of the hydroxyl group of the sugar is an alkylacyl group having 2 to 4 carbon atoms, or an alkylacyl group having 7 to 4 carbon atoms.
9. The compound according to claim 1, which is an acylated 2-deoxyaldopentose residue substituted with an arylacyl group of 9. 6. In the general formula (I), the group R^2 is a 2-deoxyaldohexose residue, and the hydrogen atom of the hydroxyl group of the sugar is an alkylacyl group having 2 to 4 carbon atoms, or an alkylacyl group having 7 to 4 carbon atoms.
The compound according to claim 1, which is an acylated 2-deoxyaldohexose residue substituted with an arylacyl group of 9. 7. In the general formula (I), the group R^2 is a 5-deoxyaldopentose residue, and the hydrogen atom of the hydroxyl group of the sugar is an alkylacyl group having 2 to 4 carbon atoms, or an alkylacyl group having 7 to 4 carbon atoms.
9. The compound according to claim 1, which is an acylated 5-deoxyaldopentose residue substituted with an arylacyl group of 9. 8. In the general formula (I), the group R^2 is a 6-deoxyaldohexose residue, and the hydrogen atom of the hydroxyl group of the sugar is an alkylacyl group having 2 to 4 carbon atoms, or an alkylacyl group having 7 to 4 carbon atoms.
The compound according to claim 1, which is an acylated 6-deoxyaldohexose residue substituted with an arylacyl group of 9. 9. N-acylaminoaldohexose residue in the general formula (I) in which the group R^2 has an amino group substituted with an acyl group having 2 to 4 carbon atoms, the amino group having 2 to 4 carbon atoms; An N-acylaminoacylated aldohexose residue in which the hydrogen atom of the hydroxyl group of the sugar is further substituted with an alkylacyl group having 2 to 4 carbon atoms or an arylacyl group having 7 to 9 carbon atoms. A compound according to claim 1. 10. In the general formula (I), the group R^2 is an aldohexouronic acid residue, an aldohexouronic acid amide residue,
Claims in which the hydrogen atom of the hydroxyl group of the sugar is an acylated aldohexouronic acid lower alkyl ester residue substituted with an alkylacyl group having 2 to 4 carbon atoms or an arylacyl group having 7 to 9 carbon atoms. A compound according to item 1. 11. The compound according to claim 1, wherein in the general formula (I), the hydrogen atom of the hydroxyl group of the sugar is an aralkylated aldotetrose residue substituted with an aralkyl group having 7 to 8 carbon atoms. . 12. Claim 1, wherein the hydrogen atom of the hydroxyl group of the sugar in the general formula (I) is an aralkylated pentose residue substituted with an aralkyl group having 7 to 8 carbon atoms.
Compounds described in Section. 13. The compound according to claim 1, wherein the hydrogen atom of the hydroxyl group of the sugar in the general formula (I) is an aralkylated aldohexose residue substituted with an aralkyl group having 7 to 8 carbon atoms. 14. Claim 1, wherein the hydrogen atom of the hydroxyl group of the sugar in the general formula (I) is an aralkylated 2-deoxyaldopentose residue substituted with an aralkyl group having 7 to 8 carbon atoms. compound. 15. Claim 1, wherein the hydrogen atom of the hydroxyl group of the sugar in the general formula (I) is an aralkylated 2-deoxyaldohexose residue substituted with an aralkyl group having 7 to 8 carbon atoms. compound. 16. Claim 1, wherein the hydrogen atom of the hydroxyl group of the sugar in the general formula (I) is an aralkylated 5-deoxyaldopentose residue substituted with an aralkyl group having 7 to 8 carbon atoms. compound. 17. Claim 1, wherein the hydrogen atom of the hydroxyl group of the sugar in the general formula (I) is an aralkylated 6-deoxyaldohexose residue substituted with an aralkyl group having 7 to 8 carbon atoms. compound. 18. In the general formula (I), the group R^2 has an amino group substituted with an acyl group having 2 to 4 carbon atoms, and the hydrogen atom of the hydroxyl group of the sugar is an aralkyl group having 7 to 8 carbon atoms. The compound according to claim 1, which is an aralkylated N-acylaminoaldohexose residue substituted with . 19. In the general formula (I), X^■ is an anion of an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, hydroiodic acid, hydrobromic acid and perchloric acid, or acetic acid, propionic acid, oxalic acid, tartaric acid, Claim 1 which is an anion of an organic acid such as lactic acid, malic acid, formic acid, fumaric acid, maleic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, capric acid, etc.
Compounds described in Section. 20. In the general formula (I), the group R^3 is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group,
The compound according to claim 1, which is an isobutyl group, a sec-butyl group, a pentyl group, a cyclopropylmethyl group, or a cyclopropylethyl group. 21, (i) General formula (II) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, R^1 is a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 4 carbon atoms, or a C 2 to 7 alkoxy group) ellipticine, 9-hydroxyellipticine, 9-alkoxy (represents an acyloxy group, and R^3 represents a linear, branched, cyclic, or cyclic-linear alkyl group having 1 to 5 carbon atoms) Ellipticine or 9-acyloxyellipticine and the general formula (III) R^4-Y(III) (In the formula, R^4 is the hydrogen atom of the hydroxyl group of the sugar having 2 to 2 carbon atoms.
Acylated aldose residue substituted with 9 acyl group, aralkylated aldose residue in which the hydrogen atom of the hydroxyl group of the sugar is substituted with an aralkyl group having 7 to 8 carbon atoms, the hydrogen atom of the hydroxyl group of the sugar is carbon Acylated deoxyaldose residue substituted with an acyl group having 2 to 9 atoms, aralkylated deoxyaldose residue in which the hydrogen atom of the hydroxyl group of a sugar is substituted with an aralkyl group having 7 to 8 carbon atoms, an amino group an acylated N-acylaminoaldose residue in which the hydrogen atom on the nitrogen atom of is substituted with an acyl group having 2 to 4 carbon atoms, and the hydrogen atom of the hydroxyl group of the sugar is further substituted with an acyl group having 2 to 9 carbon atoms; Aralkylated N-acylamino in which the hydrogen atom on the nitrogen atom of the amino group is substituted with an acyl group having 2 to 4 carbon atoms, and the hydrogen atom of the hydroxyl group of the sugar is further substituted with an aralkyl group having 7 to 8 carbon atoms. aldose residue, acylated aldohexouronic acid amide residue in which the hydrogen atom of the hydroxyl group of the sugar is substituted with an acyl group having 2 to 9 carbon atoms, and the hydrogen atom of the hydroxyl group of the sugar is substituted with an acyl group having 7 to 8 carbon atoms. Aralkylated aldohexouronic acid amide residue substituted with an alkyl group, acylated aldohexouronic acid lower alkyl ester residue in which the hydrogen atom of the hydroxyl group of a sugar is substituted with an acyl group having 2 to 9 carbon atoms. , or represents an aralkylated aldohexouronic acid lower alkyl ester residue in which the hydrogen atom of the hydroxyl group of a sugar is substituted with an aralkyl group having 7 to 8 carbon atoms, and Y represents a halogen atom). By reacting a high-fructose sugar derivative in the presence or absence of a base, the general formula (Ia) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(Ia) (In the formula, R^1, R^3, R ^4 and Y are as defined above, and the bond represented by N^■-R^4 in the formula represents a glycosidic bond between the nitrogen atom at the 2nd position and the carbon atom at the 1st position of the sugar). to generate syn derivatives, or
Or (ii) By further ion-exchanging the ellipticine derivative of the above general formula (I a), the general formula (I b) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I b) (In the formula, R^1, R ^3 and R^4 are as defined above, and Z^ represents an anion of a pharmaceutically acceptable inorganic or organic acid); or (iii) the above-mentioned By further hydrolyzing the ellipticine derivative of the general formula (I b), the general formula (I c) ▲ Numerical formula, chemical formula, table, etc. ▼ (I c) (In the formula, R^3 and Z^■ are as defined above. It's the street R^
5 represents a hydrogen atom, a hydroxyl group, or an alkoxy group having 1 to 4 carbon atoms, R^6 is an aldose residue, and aralkylation in which the hydrogen atom of the hydroxyl group of the sugar is substituted with an aralkyl group having 7 to 8 carbon atoms Aldose residue, deoxyaldose residue, aralkylated deoxyaldose residue in which the hydrogen atom of the hydroxyl group of a sugar is substituted with an aralkyl group having 7 to 8 carbon atoms, the hydrogen atom on the nitrogen atom of the amino group has a carbon number N-acylaminoaldose residue substituted with 2 to 4 acyl groups, the hydrogen atom on the nitrogen atom of the amino group is substituted with an acyl group having 2 to 4 carbon atoms, and the hydrogen atom of the hydroxyl group of the sugar has a carbon atom number Aralkylated N-acylaminoaldose residue substituted with 7 to 8 aralkyl groups, aldohexouronic acid amide residue, hydrogen atom of hydroxyl group of sugar substituted with aralkyl group having 7 to 8 carbon atoms aralkylated aldohexouronic acid amide residue, an aralkylated aldohexouron in which the hydrogen atom of the hydroxyl group of the aldohexouronic acid residue or sugar is substituted with an aralkyl group having 7 to 8 carbon atoms. (representing an acid residue) to produce a 6-alkyl ellipticine derivative,
Alternatively, (iv) the 6-alkyl ellipticine derivative of the general formula (Ia) is further hydrolyzed to obtain a compound of the general formula (I
d) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I d) Produces a 6-alkyl ellipticine derivative (in the formula, R^3, R^5, R^6 and Y are as defined above) or (v) further ion-exchange the 6-alkyl ellipticine derivative of the general formula (Id) to obtain the 6-alkyl ellipticine derivative of the general formula (Id).
By producing the 6-alkyl ellipticine derivative of I c), or (vi) further subjecting the 6-alkyl ellipticine derivative of the general formula (I b) to a dealkylation reaction, the general formula ▲ Numerical formula, There are chemical formulas, tables, etc.▼(Ie) (In the formula, R^3 and Z are as defined above, R^7 represents a hydrogen atom, a hydroxyl group, or an acyloxy group having 2 to 7 carbon atoms, and R^8 is Aldose residue, acylated aldose residue in which the hydrogen atom of the hydroxyl group of sugar is substituted with an acyl group having 2 to 9 carbon atoms, deoxyaldose residue, acyl group in which the hydrogen atom of the hydroxyl group of sugar is substituted with an acyl group having 2 to 9 carbon atoms Acylated deoxyaldose residue substituted with a group, N-acylaminoaldose residue in which the hydrogen atom on the nitrogen atom of an amino group is substituted with an acyl group having 2 to 4 carbon atoms, hydrogen on the nitrogen atom of an amino group Acylated N-acylaminoaldose residue, aldohexouronic acid amide, in which the atom is substituted with an acyl group having 2 to 4 carbon atoms, and the hydrogen atom of the hydroxyl group of the sugar is substituted with an acyl group having 2 to 9 carbon atoms. residue, an acylated aldohexouronic acid amide residue in which the hydrogen atom of the hydroxyl group of the sugar is substituted with an acyl group having 2 to 9 carbon atoms, an aldohexouronic acid residue or a hydrogen atom of the hydroxyl group of the sugar is (representing an acylated aldohexouronic acid residue substituted with an acyl group having 2 to 9 atoms) or a 6-alkyl ellipticine derivative of
Or (vii) further hydrolyzing the 6-alkyl ellipticine derivative of the general formula (Ie) to obtain the general formula (Ie)
If) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(If) (In the formula, R^3 and Z are as defined above, R^9 represents a hydrogen atom or a hydroxyl group, and R^1^0 represents aldose. residue, deoxyaldose residue, N in which the hydrogen atom on the nitrogen atom of the amino group is substituted with an acyl group having 2 to 4 carbon atoms
- representing an acylaminoaldose residue, an aldohexouronic acid amide residue, or an aldohexouronic acid residue), or
Or (viii) By further subjecting the 6-alkyl ellipticine derivative of the general formula (Ia) to a dealkylation reaction, the general formula (Ig) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(Ig) ( (wherein R^3, R^7, R^8 and Y are as defined above)
Alternatively, (ix) further hydrolyzing the 6-alkyl ellipticine derivative of the general formula (Ig) gives the general formula (I
h) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I h) 6-alkyl ellipticine derivative (in the formula, R^3, R^9, R^1^0 and Y are as defined above) (x) further ion exchange the 6-alkyl ellipticine derivative of the general formula (Ih) to produce the general formula (Ih);
(xi) further subjecting the 6-alkyl ellipticine derivative of the general formula (Ic) to a dealkylation reaction to produce the 6-alkyl ellipticine derivative of the general formula (I f); ), or (xii) further subjecting the 6-alkyl ellipticine derivative of the general formula (I d) to a dealkylation reaction to produce the 6-alkyl ellipticine derivative of the general formula (I h). General formula (I) which is characterized by producing a 6-alkyl ellipticine derivative of 4 represents an alkoxy group or an acyloxy group having 2 to 7 carbon atoms, R^2 is an aldose residue, an acylated aldose residue in which the hydrogen atom of the hydroxyl group of a sugar is substituted with an acyl group having 2 to 9 carbon atoms, Aralkylated aldose residues in which the hydrogen atom of the hydroxyl group of sugar is substituted with an aralkyl group having 7 to 8 carbon atoms, deoxyaldose residue, and acyl group having 2 to 9 carbon atoms as the hydrogen atom of the hydroxyl group of sugar. Substituted acylated deoxyaldose residues, aralkylated deoxyaldose residues in which the hydrogen atom of the hydroxyl group of the sugar is substituted with an aralkyl group having 7 to 8 carbon atoms, hydrogen atom on the nitrogen atom of the amino group is substituted with carbon N-acylaminoaldose residue substituted with an acyl group having 2 to 4 carbon atoms, the hydrogen atom on the nitrogen atom of the amino group is substituted with an acyl group having 2 to 4 carbon atoms, and the hydrogen atom of the hydroxyl group of the sugar is a carbon atom. Acylated N-acylaminoaldose residue substituted with an acyl group having 2 to 9 carbon atoms, in which the hydrogen atom on the nitrogen atom of the amino group is substituted with an acyl group having 2 to 4 carbon atoms, and the hydrogen atom of the hydroxyl group of the sugar is Aralkylated N-acylaminoaldose residue substituted with an aralkyl group having 7 to 8 carbon atoms, an aldohexouronic acid amide residue, an acyl group in which the hydrogen atom of the hydroxyl group of a sugar has 2 to 9 carbon atoms Acylated aldohexouronic acid amide residue substituted with , aralkylated aldohexouronic acid amide residue in which the hydrogen atom of the hydroxyl group of the sugar is substituted with an aralkyl group having 7 to 8 carbon atoms, Acylated aldohexouronic acid lower alkyl ester residue in which the hydrogen atom of the hydroxyl group is substituted with an acyl group having 2 to 9 carbon atoms, and the hydrogen atom of the hydroxyl group of sugar is substituted with an aralkyl group having 7 to 8 carbon atoms. aralkylated aldohexouronic acid lower alkyl ester residue, aldohexouronic acid residue, acylated aldohexouron in which the hydrogen atom of the hydroxyl group of the sugar is substituted with an acyl group having 2 to 9 carbon atoms. Represents an aralkylated aldohexouronic acid residue in which the hydrogen atom of the hydroxyl group of an acid residue or sugar is substituted with an aralkyl group having 7 to 8 carbon atoms, and R^3 is a straight aralkyl group having 1 to 5 carbon atoms. It represents a chain, branched chain, cyclic or cyclic linear alkyl group, X^■ represents an anion of a pharmaceutically acceptable inorganic or organic acid, and in the formula, the bond represented by N^■-R^2 is ellipticine. 2
a glycosidic bond between the nitrogen atom at position 1 and the carbon atom at position 1 of a sugar). 22. In the general formula (I), the group R^2 is an aldotetrose residue, and the hydrogen atom of the hydroxyl group of the sugar has 2 to 2 carbon atoms.
22. The method according to claim 21, wherein the acylated aldotetrose residue is substituted with an alkylacyl group having 4 carbon atoms or an arylacyl group having 7 to 9 carbon atoms. 23. In the general formula (I), the group R^2 is an aldopentose residue, and the hydrogen atom of the hydroxyl group of the sugar has 2 to 2 carbon atoms.
22. The production method according to claim 21, wherein the acylated aldopentose residue is substituted with an alkylacyl group having 4 carbon atoms or an arylacyl group having 7 to 9 carbon atoms. 24. In the general formula (I), the group R^2 is an aldohexose residue, and the hydrogen atom of the hydroxyl group of the sugar has 2 to 2 carbon atoms.
22. The production method according to claim 21, wherein the acylated aldohexose residue is substituted with an alkylacyl group having 4 carbon atoms or an arylacyl group having 7 to 9 carbon atoms. 25. In the general formula (I), the group R^2 is a 2-deoxyaldopentose residue, and the hydrogen atom of the hydroxyl group of the sugar is an alkylacyl group having 2 to 4 carbon atoms or an alkylacyl group having 7 carbon atoms.
Claim 21, which is an acylated 2-deoxyaldopentose residue substituted with ~9 arylacyl groups
Manufacturing method described in section. 26. In the general formula (I), the group R^2 is a 2-deoxyaldohexose residue, and the hydrogen atom of the hydroxyl group of the sugar is an alkylacyl group having 2 to 4 carbon atoms or an alkylacyl group having 7 carbon atoms.
Claim 21, which is an acylated 2-deoxyaldohexose residue substituted with ~9 arylacyl groups
Manufacturing method described in section. 27. In the general formula (I), the group R^2 is a 5-deoxyaldopentose residue, and the hydrogen atom of the hydroxyl group of the sugar is an alkylacyl group having 2 to 4 carbon atoms or an alkylacyl group having 7 carbon atoms.
Claim 21, which is an acylated 5-deoxyaldopentose residue substituted with ~9 arylacyl groups
Manufacturing method described in section. 28. In the general formula (I), the group R^2 is a 6-deoxyaldohexose residue, and the hydrogen atom of the hydroxyl group of the sugar is an alkylacyl group having 2 to 4 carbon atoms or an alkylacyl group having 7 carbon atoms.
Claim 21, which is an acylated 6-deoxyaldohexose residue substituted with ~9 arylacyl groups
Manufacturing method described in section. 29, an N-acylaminoaldohexose residue in which the group R^2 in the general formula (I) has an amino group substituted with an acyl group having 2 to 4 carbon atoms, the amino group having 2 to 4 carbon atoms; Acylated N in which the hydrogen atom of the hydroxyl group of the sugar is further substituted with an alkylacyl group having 2 to 4 carbon atoms or an arylacyl group having 7 to 9 carbon atoms
-acylaminoaldohexose residue. 30, in the general formula (I), the group R^2 is an aldohexouronic acid residue, an aldohexouronic acid amide residue,
Claims in which the hydrogen atom of the hydroxyl group of the sugar is an acylated aldohexouronic acid lower alkyl ester residue substituted with an alkylacyl group having 2 to 4 carbon atoms or an arylacyl group having 7 to 9 carbon atoms. The manufacturing method according to item 21. 31. The production according to claim 21, wherein the hydrogen atom of the hydroxyl group of the sugar in the general formula (I) is an aralkylated aldotetrose residue substituted with an aralkyl group having 7 to 8 carbon atoms. Law. 32. The production method according to claim 21, wherein the hydrogen atom of the hydroxyl group of the sugar in the general formula (I) is an aralkylated aldopentose residue substituted with an aralkyl group having 7 to 8 carbon atoms. . 33. The production method according to claim 21, wherein the hydrogen atom of the hydroxyl group of the sugar in the general formula (I) is an aralkylated aldohexose residue substituted with an aralkyl group having 7 to 8 carbon atoms. . 34. Claim 21, wherein the hydrogen atom of the hydroxyl group of the sugar in the general formula (I) is an aralkylated 2-deoxyaldopentose residue substituted with an aralkyl group having 7 to 8 carbon atoms. manufacturing method. 35. Claim 21, wherein the hydrogen atom of the hydroxyl group of the sugar in the general formula (I) is an aralkylated 2-deoxyaldohexose residue substituted with an aralkyl group having 7 to 8 carbon atoms. manufacturing method. 36. Claim 21, wherein the hydrogen atom of the hydroxyl group of the sugar in the general formula (I) is an aralkylated 5-deoxyaldopentose residue substituted with an aralkyl group having 7 to 8 carbon atoms. manufacturing method. 37. Claim 21, wherein the hydrogen atom of the hydroxyl group of the sugar in the general formula (I) is an aralkylated 6-deoxyaldohexose residue substituted with an aralkyl group having 7 to 8 carbon atoms. manufacturing method. 38. In the general formula (I), the group R^2 has an amino group substituted with an acyl group having 2 to 4 carbon atoms, and the hydrogen atom of the hydroxyl group of the sugar is an aralkyl group having 7 to 8 carbon atoms. 22. The production method according to claim 21, which is an aralkylated N-acylaminoaldohexose residue substituted with . 39. In the above general formula (I), Claim 2, which is an anion of an organic acid such as lactic acid, malic acid, formic acid, fumaric acid, maleic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, capric acid, etc.
The manufacturing method described in item 1. 40. In the general formula (I), the group R^3 is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group,
22. The production method according to claim 21, wherein the group is an isobutyl group, a sec-butyl group, a pentyl group, a cyclopropylmethyl group, or a cyclopropylethyl group. 41. In the general formula (I), the reagent used for hydrolysis is aqueous ammonia, sodium hydrogen carbonate, basic sodium phosphate, potassium hydrogen carbonate, basic potassium phosphate, lithium carbonate, sodium carbonate, potassium carbonate,
22. The method according to claim 21, wherein the base is selected from the group consisting of calcium carbonate. 42. The production method according to claim 21, wherein the reagent used for glycosylation in the general formula (I) is cadmium carbonate, basic zinc carbonate, basic copper carbonate, silver carbonate or calcium carbonate.