JPS62281891A - Anthracycline compound and use thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I (R1 and R2 are H or OH; with a proviso that the case where R1 is H and R2 is OH is omitted). When both R1 and R2 are H, the compound has the following properties. appearance: yellow powder. Melting point: 140-143 deg.C or 142-145 deg.C depending upon isomers. Molecular weight: 578. Molecular formula: C31H34O9N2. Elemental analysis value (%): C 64.28, H 5.85, 24.92, N 4.83. Solubility: soluble in methanol, etc., and insoluble in water, hexane, etc. EXAMPLE:A 3'-deamino-3'-(3-cyano-4-morpholinyl) derivative of 13-deoxo-11- deoxycarminomycin shown by formula II. USE:An antitumor agent. PREPARATION:Actinomadura reseoviolacea R20 strain (FERM P-945) belonging to the genus Actinomadura is cultivated to give 13-deoxo-11-deoxycarminomycin, which is reacted with diglycolaldehyde shown by formula III in a solvent such as THF, etc., by the use of BaBH3CN as a reducing agent.

Description

DETAILED DESCRIPTION OF THE INVENTION [Background of the Invention] 13-deoxo-11-deoxycarminomycin (hereinafter referred to as R20Y5), an anthracycline compound having antitumor activity, minomycin (hereinafter referred to as R20x), and 13-deoxo-10-hydroxycarminomycin (hereinafter referred to as R20
3'-deamino-3'-(3-cyano-4-
morpholinyl) derivatives.

As an anthracycline compound, downmycin (U.S. Pat. Nos. 3 and 6
16.242) and adriamycin (see US Pat. No. 3,590,028), and these compounds are widely used clinically as antitumor agents. However, although these compounds exhibit strong antitumor effects, they also have strong side effects, so they are not necessarily satisfactory.

As a compound related to the anthracycline compound of the present invention (details will be described later), Giuseppe Catuccinelli et al.
5 to Streptomyces peucetius var canisillus (Streptomycespeucetius)
Streptomyces peucetius v.
ar, aurcus), and reported that it has antitumor activity (Japanese Patent Application Laid-Open No. 1986-7).
6896). Furthermore, Giuseppe Cassinelli et al.
0X as Streptomyces Peucetius Barr.
Streptomyces pet+ce
tiUsvar, caesius), namely, Streptomyces peucetius var carminatus (Streptomyccs peucetius).
It has been reported that it has antitumor activity (Journal of Natural Pro
ducts, Su(3), 435-439 (1985
)). On the other hand, Umezawa et al. tested R20X2 (D788-7>), which is a gluing compound of the present invention, using Streptomyces D 788.
Mutant strains of Streptomyces (Strepyo
Myces) was obtained from the culture solution of RM P-5, and it has been reported that it has antitumor activity (Japanese Patent Laid-Open No. 6
1-331.94). Furthermore, various derivatives of adriamycin and downmycin have been synthesized as cyanomorphorinyl derivatives of anthracycline compounds, and their anti-It! ! Tumor activity has been reported (Japanese Unexamined Patent Publication No. 6
No. 0-224696, JP-A-59-33278, JP-A-59-212484, JP-A-59-Sho.
-212499 Publication, Edward H, Acton
et, al, : J, Hed, Ch.
em, 27.638-645 (1984), B
rania+ir 1.5ikic et, at,:
5science, 228.1544-1546 (1
985)).

However, to the best of the inventors' knowledge, these compounds are not necessarily satisfactory in terms of antitumor activity or toxicity.

Since anthracycline compounds constitute a group of useful antitumor agents, there is a constant desire for better anthracycline compounds.

[Summary of the invention]

The present invention meets the above needs.

That is, the anthracycline compound according to the present invention is
It is represented by the following formula (I). The invention also relates to acid addition salts of this compound.

The invention also relates to the use of this compound.

That is, the antitumor agent according to the present invention contains an anthracycline compound represented by the following formula (I) or an acid addition salt thereof as an active ingredient.

In the formula, R and R2 are each a hydrogen atom or a hydroxyl group, and are selected from the following combinations.

(a) R:H, R2:H (b) R:0)-1, R2: H (c) R:OH, R2:OH [Detailed description of the invention] (1 Ri Bunri 1 1) Compound Kind: Compounds according to the invention are represented by formula (I) above, but R
Since there are three types of combinations of R2 and R2, this compound can be roughly classified into three types, and each has two types of isomers regarding the configuration of the cyano group.

These six types of compounds are listed below together with their names.

HHCNM-R20Y5-A B OHHCNM-R20X-A B OHOHCNM-R20X2-A B That is, CNM-R20Y5-A and -B are 3' of the anthracycline compound R20Y5, that is, 13-deoxo-11-deoxycarminomamycin. −
It is a deamino-3'-(3-cyano-4-morpholinyl) derivative and has the chemical structure shown by the following formula (II>. Two types of isomers exist depending on the stereochemistry of the cyano group, and WjFA chromatography Based on the behavior, one is designated as CNM-R20Y5-A and the other is designated as -B.

(n) CNM-R20X-AJ5J: Bi-B1. t, 3'-deamino-3'- of the anthracycline compound R20X, i.e., 13-deoxo-carminomycin.
(3-cyano-4-morpholinyl) derivative, which has a chemical structure represented by the following formula (III). Two types of isomers exist due to the stereochemistry of the cyano group, and one is CNM-R20X-A,
Let the other be -B.

(厘) CNM-R20X2-A and -B are anthracycline compounds R20X2, namely 10-hydroxy-1
3'-deamino-3 of 3-deoxocarminomycin
'-(3-cyano-4-morpholinyl) derivative having a chemical structure represented by the following formula (IV). Two types of isomers exist due to the stereochemistry of the cyano group, and one is called CNM-R20X2- due to the behavior of 8-layer chromatography.
A, the other one is -B.

() Since these compounds have a tertiary amine nitrogen atom derived from a morpholinyl group, acid addition salts exist.

The acid in this case may be any suitable acid, for example, unmineralized acids such as hydrochloric acid, fit acid, phosphoric acid, and acetic acid, propionic acid, maleic acid, oleic acid, palmitic acid, citric acid, succinic acid. , organic acids such as tartaric acid, fumaric acid, glutamic acid, pantothenic acid, and lauryl sulfonic acid.

2) Physicochemical properties Anthracycline compound (CNNI?-) according to the present invention
The physicochemical properties of R20 substance) are as shown in Tables 1 and 2.

Table 2 Ultraviolet/Visible Absorption Spectrum Table 2 Continued Rom's Complaint 1) Overview The 3'-deamino-3'-(3-cyano-4-morpholinyl) derivative of the present invention is produced by culturing microorganisms. The crude compounds R20Y5, R20X and R2
It can be produced by chemical modification of 0X2 (reductive alkylation of Edward H, Acjon, etc.).

2JR20Y5, R20X and R20X2R20Y5
, R20x and R20X2 can be obtained from a culture of Actinomadura roseoviolacea R20 strain isolated by the present inventors or a mutant strain thereof. Note that R2
0Y5, R20X and R20X2 are all known substances, R20Y5 can also be produced by the method described in JP-A-55-76896, and R20X is
Natural or Natural Product
s, 48 (3), 435-439 (1985)
It can also be produced by the method described in R20X
As mentioned above, No. 2 can also be produced by the method described in JP-A-61-33194.

(1) Strain R20 The R20 strain, which the present inventors have discovered as a strain of the genus Actinomadura that has the ability to produce anthracycline compounds R20Y5, R20x, and R20X2, has the following content.

■ Origin and deposit number Strain R20 was isolated from soil collected from a vegetable field in Oaza Onodani, Kaho-machi, Kaho-gun, Fukuoka Prefecture, and was deposited at the Institute of Microbial Technology, Agency of Industrial Science and Technology on July 5, 1981. hand"
It has a number of ``Feikoken Jokyo No. 945''.

■ Mycological properties and physiological properties The characterization of this bacterial strain according to the method manual of the International Committee on Streptomyces Nomenclature (ISP) is as follows.

A) Morphology The basal hyphae spread radially on the agar medium surface while branching, and the hyphae are divided into li! Not noticed. Aerial hyphae extend their main axis long, branch their short branches at right angles (with respect to the main axis) (uniaxial branching), and at their tips produce dense small spiral spores vA ( 1 to 3 turns, diameter 2.
0-2.5μ), t; and pseudosporangium (diameter 2.5-3
．． 5μ) and form spore masses.

The spore chain is covered with a cylindrical sheath with a width of 0.5 to 0.8 μ, the surface of which is rough, and the individual spores are connected in a phalanx shape. The spore mass is irregularly shaped, and the spore surface is covered with a sticky substance. i Synthespores are rarely observed, cylindrical or oblong, 0.5-0.8μ wide, 0.7-1.1μ long.
, exhibits a smooth surface. No true sporangia, flagellated spores, or sclerotia are observed or suspected. Since the whole cell hydrolyzate contains meso-type dianopimelic acid and madulose, the cell wall type is determined to be ■B.

B) Culture properties Observation results of culture properties in various media (27°C medium M) are as shown in Table 3.

C) Physiological properties Physiological properties (including carbon source assimilability) are as shown in Table 4.

D) Discussion and Identification This strain has a cell wall type of I[[B and (
2) A spore chain consists of 10 or more spores, (
3) It forms pseudospore sacs and spore masses, and (4) true sporangia and flagellated spores are not observed, so it is judged that it belongs to the genus Acti nomadura. According to Nonomura's search table [Rikou, Vol. 52, pp. 71-77, 1974] and the description [Rikou, Vol. 49, pp. 904-912, 1971], this strain is A.
It is judged to be most closely related to A. roseoviolacea.

Therefore, this strain A, a standard strain of Roseoviolaceae (KC
CA-145 (Nonomura A-5>) was cultured under the same conditions,
The main properties of both strains were compared. As shown in Table 5, the results are very similar taxonomically, although there are slight differences in bacterial flora color, underside color, and optimal growth temperature.

Therefore, this strain is Actinomadura roseoviola (actinomadura roseoviola).
ceaNonomura et 0hara 1971
) was identified.

(2) Culture/R20Y5, R20X and R20X
2 production anthracycline compounds R20Y5, R20x and R20X2 are R20Y5 belonging to Actino Majura notification.
, R20X and R20x2 producing bacteria can be cultured aerobically in an appropriate medium, and the desired product can be produced from the culture hX.

The medium can contain any nutrient source that can be utilized by the R20Y5, R20X and R20X2 producing bacteria.

Specifically, for example, glucose, sucrose, maltose, starch, and fats and oils can be used as carbon sources, and soybean flour, cottonseed meal, meat extract, peptone, dried yeast, yeast extract, and corn starch can be used as nitrogen sources. Organic materials such as cheap liquor and inorganic materials such as ammonium salts or nitrates such as ammonium sulfate, sodium nitrate, and ammonium chloride can be used.

In addition, if necessary, add salt, potassium chloride, phosphorus
! Non-isolated salts such as di-salts and heavy metal salts can be added. In order to suppress foaming during fermentation, suitable antifoaming agents such as silicones can also be added according to conventional methods.

The most suitable culture method is the aerobic liquid deep culture method, which is the same as the commonly used method for producing antibiotics. The appropriate culture temperature is 25°C to 45°C, but 27°C
~30°C is preferred. In this method, R20Y5, R20X
Oyohi R20X 2+7) The production amount reaches its maximum in 6 to 7 days for both shaking culture and aerated agitation culture.

In this way R20Y5, R20X and R20X2
An accumulated culture of . In culture, R20
Some of Y5, R20X and R20X2 exist in the bacterial cells, but most of them exist in the culture solution.

From such cultures R20Y5, R20X and R2
Any suitable method for harvesting 0X2 can be used. One method is based on the principle of extraction, for example, for R20Y5, R20X and R20X2 in the culture solution, the water immiscible (7) R20Y5, R20Xe ,,l'
Extraction methods using solvents for R20X2, such as ethyl acetate, chloroform, butanol, etc. (extraction efficiency is good if the medium Ht tear fluid is neutral or slightly basic), or for R20Y5, R20X and R20X2 inside the bacterial cells. A bacterial mass obtained by filtration, centrifugation, etc. can be recovered by treatment with chloroform, ethyl acetate, butanol, methanol, ethanol, acetone, a hydrochloric acid solution, an acetic acid solution, or the like. The culture can be used as is without separating the bacterial cells.
can also be subjected to the above extraction operation. Countercurrent distribution methods using suitable solvents can also be included in the scope of extraction.

Another method for harvesting R20Y5, R20XJ5 and R20X2 from cultures is based on the principle of adsorption, in which the already liquid R20Y5, R20X and R20X2 content, e.g. A suitable absorbing agent such as activated carbon,
Alumina, silica gel, "Diaion HP20J"
(manufactured by Mitsubishi Kasei Corporation), column chromatography, liquid chromatography, etc.
R20Y5, R20X and R20X2 can be obtained by adsorption and subsequent elution of 20Y5, R20X and R20X2. If the R20Y5, R20x and R20X2 solutions obtained in this way are concentrated to dryness under reduced pressure, R20Y5, R20X and R20
2(7)I standard specimen is obtained.

R20Y5, R20X and R obtained in this way
In order to roughly separate and purify the purified products of R20Y5, R20X and R20X2 from the crude sample of 20X2, the above extraction methods and adsorption methods may be combined as necessary and used as many times as necessary. For example, column chromatography using an adsorbent or gel filtration agent such as silica gel, weakly acidic ion exchange resin, or activated carbon, liquid chromatography using an appropriate solvent, and countercurrent distribution method can be carried out in an appropriate combination. can. Specifically, for example, R20Y
5. Dissolve R20X and R20X2 crude samples in a small amount of chloroform, develop with a suitable solvent using a silica gel column to elute the active ingredient, and concentrate the eluate under reduced pressure.
Roughly TLC''C-developed, scraped off and eluted,
Since R20Y5, R20X and R20X2 are separated as a single substance, if this is concentrated to dryness, R20Y5
, R'20X and R20X2 can be obtained.

R20Y5, R20X and R obtained in this way
The physical and chemical properties of 20X2 are shown in Table 6 below. R
20Y5. These values for R20X and R20X2 are disclosed in Japanese Patent Application Laid-open No. 55-76896 and Jou.
rnal of NaturalProducts,
48(3), 435-439 (1985) and the physicochemical properties described in JP-A-61-33194.

3) Chemical modification of R20Y 5, R20X and R20X2 The anthracycline compound of the present invention can be modified to 1! ? It can be produced by reacting R20Y5, R20X and R20x2 or their acid addition salts with a compound (diglycolaldehyde) represented by the following formula (V). This compound (V) is converted from meso-erythritol to Carbohydrate Re5earc.
It can be produced by the method described in J. H., 35.195-202 (1974).

The reaction of CH3CHO R20Y5, R20X and R20X2 or their acid addition salts with the compound of formula (V) is usually carried out in a solvent. Solvents that can be used include acetonitrile, methanol, ethanol, water, chloroform, dichloromethane, carbon tetrachloride, benzene, dioxane, tetrahydrofuran, etc. alone or in mixtures.

This reaction can be carried out using sodium cyanoborhydride (NaBH30N) as the reducing agent, or sodium cyanide (NaCN) or potassium cyanide (KC
The reaction is carried out using sodium borohydride (NaBH4) or sodium cyanoborohydride<NaBH30N) as a reducing agent in the presence of cyanide ions such as N). The amount of reducing agent used is not critical, R20Y5, R2
It can be used in an amount of at least 1 mol, preferably 1 to 5 mol, per mol of 0x and R20X2.

Use of compound of formula (V) (7) fm Ha, R20Y5, R
Advantageously, the proportion is 1.5 mol or more, preferably 2 to 10 mol, per mol of 20X and R20X2.

The reaction temperature is generally within the range from the freezing point of the solvent used to 50°C, particularly around the v temperature.

Under the above reaction conditions, the reaction for converting amine groups into morpholinyl groups can be completed in about 10 minutes to 2 hours.

R20Y5, R20X, l15 and R2 in the method of the present invention
3'-deamino-3', which is the target compound of the present invention, is obtained from the reaction mixture obtained by the reaction of 0X2 and the compound of formula (■).
-(3-cyano-4-morpholinyl) derivatives can be isolated and purified using W N of anthracycline glycosides.
A known purification method used in the field of J-isomer production, such as chromatography using silica gel or the like, can be used.

The 3'-deamino-3'-(3-cyano-4-morpholinyl) derivative of formula (I) thus obtained can be prepared as an acid addition salt thereof, for example with hydrochloric acid, according to methods known per se, lii! Treatment with inorganic acids such as tPa, phosphoric acid, or organic acids such as acetic acid, propionic acid, maleic acid, oleic acid, balmitic acid, citric acid, succinic acid, tartaric acid, fumaric acid, glutamic acid, pantothenic acid, lauryl sulfonic acid, etc. It can be converted into its acid addition salt by

Uses of Compounds of the Present Invention The anthracycline compound of the present invention has a strong growth-inhibiting effect on leukemia cultured m-cells P388, as described below, and is a useful compound as an anticancer agent.

1) Physiological activity (1) The antitumor compound of the present invention has the effect of suppressing the proliferation of mouse leukemia cultured cells P388. For example, add P38811 5x to RPMI 1640Im containing 10% tallow serum.
10' pieces/1ttp connection+! 1, and 0.0% of this substance in it.
It was added at a concentration of 1 to 20 ng/- and cultured for 2 days in a carbon dioxide incubator at 37°C, and the 50% growth inhibition concentration (IC5o) relative to the control group was determined. Table 7 shows the results.

As shown in the above results, the compound of the present invention inhibits the proliferation of murine leukemia cell P388 at low concentrations, and is therefore expected to be used as an anticancer agent.

2) Antitumor agent It has thus been revealed that the anthracycline compound of the present invention exhibits antitumor properties against animal tumors, particularly damaging tumors.

Therefore, the compounds of the present invention can be used as antitumor agents or tumor therapeutic agents.

The compounds of the present invention as antitumor agents can be administered by any convenient route of administration and in a dosage form determined by the route of administration employed. The drug is usually in the form diluted with a carrier or diluent that is acceptable for sugar production.

When actually administering the compound of the present invention as an antitumor agent, one typical method is to dissolve the compound in distilled water for injection or physiological saline and inject it. Specifically, in the case of animals, injection methods such as intraperitoneal injection, subcutaneous injection, intravascular injection into a vein or artery, and local administration are used, and in the case of humans, injection methods include intravascular injection into a vein or artery or local administration. There is a method of injection.

The dosage of the compound of the present invention is determined in consideration of the results of animal tests and various circumstances so that the total dose does not exceed a certain amount when administered continuously or intermittently. The specific dosage a may vary depending on the method of administration, the condition of the patient or treated animal, such as age, weight, sex, sensitivity, diet, administration time, concomitant drugs, and the degree of the patient or disease. Needless to say, the appropriate age and frequency of administration under certain conditions must be determined by a specialist in an appropriate dosage determination test based on the above guidelines.

Experimental Example The manufacturing method of R20Y5, R20 The manufacturing method of R20X-A and B is illustrated in Example 4, and the manufacturing method of CNM-R20X2-A and B is illustrated in Example 5.

In the following, "%" is "w/■%".

Support i ■ Yu (R20Y 5, R2015J: and R20X2
(1) Preparation of seed medium The medium used was prepared by dissolving the components of the following composition in 1 liter of water and adjusting the pH to 7.2.

Glucose 0.4% M mother extract
0.4% malt extract i, o% The above medium (10C)te was dispensed into a 500D Erlenmeyer flask and sterilized, one platinum loop of Actinomadura roseoviolaceae R20 was inoculated from a slant, and the mixture was heated at 27℃ for 5 days using a rotary shaker (20Orpm). ) was used as the seed mother.

(2) Culture The medium used was prepared by dissolving the following components in 1 liter of water and adjusting the pH to 6.8.

Glucose 0.5% maltose
4.0% Fish meal 2.0%
lI? Mother extract 0.2% dry yeast
0.2% Calcium carbonate (sedimented) 0.4% 200 liters of the above medium was placed in a 300 liter jar fermenter and sterilized, and 20 of the above seed starters were inoculated. Culture was performed for 10 days at 27° C. with aeration of 11 v, v, m and a rotational speed of 200 times/min.

Example 2 (Production of R20Y5, R20X and R20X2) The culture solution obtained in Example 1 was filtered to separate bacterial cells and tear fluid. The furnace solution was adjusted to pH 9.0 with 5N* sodium oxide.
It was adsorbed on a 20×100on column of Diaion PA308j (manufactured by Mitsubishi Chemical Corporation). After washing with distilled water, it was eluted with a mixture of acetic acid and methanol (1:99). The eluate was made alkaline by adding concentrated aqueous ammonia, concentrated, and the concentrated solution was adjusted to pH 8.5 and extracted three times with a chloroform-methanol (9:1) mixture.

After concentrating this extract, 6 times the amount of hexane was added and the resulting precipitate was dried, yielding 1 q of 3200 q of black-red powder. This was further added to chloroform: methanol: water = 70:
Place it on a silica gel column (Merck [Silica gel 60J, 5x40 cm) equilibrated at 10:1, R20
Y5, R20X and R20X2 fractions were fractionated. After drying both of the obtained components under reduced pressure, they were developed with TLc (Merck's "Silica Gel 6O") using a one-component system of chloroform:methanol:acetic acid:water=40:8:1:1(7). Rof, value 0.50.0.48t-i nibio, 35
Each nearby band was cut out and eluted with chloroborum-methanol (10:1). In this way, R
145q of 20Y5, 220 mg of R20X and 25 mg of R20X were obtained.

Example 3 (Production of 3'-deamino-3'-(3-cyano-4-morpholinyl)-R20Y5-, A and B) R20Y5
5701119 (1,179 mmol) was dissolved in 50 d of a mixture of methanol/chloroform (1/1), and diglycolaldehyde 280+1!9 (2,358 mmol) and sodium cyanoborhydride 148R9 (
2,358 mmol) and allowed to react for 1 hour at room temperature. After the reaction was completed, the reaction solution was diluted with 70Id of water,
The chloroform layer was separated, and the aqueous layer was further diluted with chloroform.
Extract twice at 0 d and wash the chloroform layer several times with water from 5 (7).

After dehydrating the chloroform layer with anhydrous sodium sulfate, the concentrated dry product under reduced pressure was dissolved in 50 ml of ethyl acetate, and 50 #li of 0.2% phosphoric acid ice water was added. Wash several times. The ethyl acetate layer was dehydrated with anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and subjected to silica gel column chromatography (Merck [Silica Gel 60
J, 230-400 mesh) and chloroform:
Elution with a mixed solvent of methanol (200:3) yielded 3'-deamino-3'-(3-°cyanol).The mixture was dissolved in chloroform:methanol (10:3).
Developed by thin layer chromatography (Merck's "Silica Gel 60") using the solvent system of 1), the Rf value was approximately 0.51.
and a yellow fraction of approximately 0.54 was scraped off. Both fractions thus obtained were drained, concentrated, and crystallized from ROO form/hexane to give CNM-R20Y5-Δ1.
．． 0 and CNM-R20Y5-8 1.5η.

IA (Production of 3'-deamino-3'-(3-cyano-4-morpholinyl)-R20X-A and B) R20X 3
30+114F (0.673 mmol) was dissolved in 20 m of methanol, and diglycolaldehyde 404n+
g (3.364 mmol) of acetonitrile/water <1/
1) 100 d of solution and 84 d of sodium cyanoborhydride. 10rd solution of 5ffi9 (1.345 mmol) in acetonitrile/water (1/1)! was added and allowed to react at room temperature for 1 hour. After the reaction is completed, the reaction solution is concentrated under reduced pressure, extracted twice with 30 m of chloroform, and the chloroform layer is washed several times with 30 m of water. The chloroform layer was dehydrated with anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. Dissolve the concentrated dry product in 30ml of ethyl acetate and add 3ml of 0.2% phosphoric acid in ice water.
Wash 0ine several times. The ethyl acetate layer was dehydrated over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. Concentrate to dryness using a solvent system of chloroform:methanol (10:1).
The mixture was developed using chromatography (Silica Gel 60, manufactured by Meruri), and red fractions with Rf values of about 0.51 and about 0.54 were scraped off. Both parts obtained in this way were eluted,
Concentrate and crystallize from chloroform/hexane to give C
NM-R20X-A 2.119 and CNM-R2
0X-8 4.2*l! is.

Shimiokako (3'-deamino-3'- (3-amino-4-
Morpholinyl)-R20X2-Production of A and B) R2
0X2 650■ (1.263 mmol) was dissolved in 60d of a mixture of methanol/chloroform (1/1),
Diglycoaldehyde 300q (2.526 mmol) and thorium cyanoborohydride 159IRg<2
．． 526 mmol) and allowed to react at room temperature for 1 hour. After the reaction was completed, the reaction solution was diluted with 90 m of water, the chloroform layer was separated, and the aqueous layer was further diluted with chloroform 5 (7 in 2
Extract twice and wash the chloroform layer several times with 50ml of water. After dehydrating the chloroform layer with anhydrous sodium sulfate, it was concentrated to dryness under reduced pressure, and the dried product was dissolved in 50 parts of ethyl acetate.
Wash several times with 50 d of 0.2% phosphoric acid and ice water. The ethyl acetate layer was dehydrated with anhydrous sodium sulfate and then concentrated to dryness under reduced pressure.

The concentrated and dried product was developed using thin layer chromatography (Merck's "Silica Gel 60") using a solvent system of chloroform:methanol (10:1), and a red pattern with Rf values of about 10, 40 and about 0.43 was obtained. I scraped the minutes. Both fractions thus isolated were eluted, concentrated, and crystallized with chloroform/hexane to give CNM-R20X2-Δ1.
4ηL1-3 and CNM-R20X2-81.2rn
I got g.

[Brief explanation of the drawing]

FIG. 1 is a reproduction of the ultraviolet/visible absorption spectrum of CNM-R20Y5-A. 1. In methanol 2. In alkaline methanol In the same manner, Figure 2 shows CNM-R20Y5-8, Figure 3 shows CNM-R20X-A, and Figure 4 shows CNM-R20Y5-8.
R20X-B, Figure 5 shows CNM-R20X2-A,
FIG. 6 is a reproduction of the ultraviolet and visible absorption spectra of CNM-R20X2-B. FIG. 7 is a reproduction of an infrared absorption spectrum diagram of CNM-R20Y5-A. Similarly, FIG. 8 shows the 9th section of CNM-R20Y5-B.
The figure shows cNM-R20X-A (7), and Figure 10 shows CNM-
The infrared absorption spectra of R20X-B, Figure 11 is a reproduction of CNM-R20X2-A, and Figure 12 is of CNM-R20x2-8. FIG. 13 is a reproduction of the 1H-NMR spectrum of CNM-R20Y5-A in deuterated chloroform. Similarly, Fig. 14 shows CNM-R20Y5-B (7)
, FIG. 15 shows CNM-R20-X-A (7), No. 16 [
ICNM-R20X-8, Figure 17 is CNM-R20
X2-A, Figure 18 is CNM-R20X2-B (7)
This is a reproduction of the 1H-NMR spectrum Az diagram. FIG. 19 is a reproduction of the ultraviolet/visible absorption spectrum of R20Y5. 1, in methanol 2, in acidic methanol 3, in alkaline methanol in the same manner, Figure 20 shows R20X, Figure 21 shows R2
This is a copy of the ultraviolet/visible absorption spectrum of 0X2. FIG. 22 is a reproduction of the infrared absorption spectrum of R20Y5. Similarly, FIG. 23 shows R20X, and FIG. 24 shows R20X.
This is a reproduction of the infrared absorption spectra 1 to 1 of X2. Figure 25 shows the 1H-
This is a reproduction of an NMR spectrum diagram. Similarly, Fig. 26 shows R20X, Fig. 27 shows R20
This is a copy of the 'H-NMR spectrum of X2. To the applicant's agent Sato-Yu ε Figure 19 Wavelength (1m) S (Sir) Procedural amendment May 22, 1986

Claims (1)

[Claims] 1. An anthracycline compound represented by the following formula (I) or an acid addition salt thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) In the formula, R_1 and R_2 are each a hydrogen atom or a hydroxyl group, and are selected from the following combinations. (a) R_1:H, R_2:H (b) R_1:OH, R_2:H (c) R_1:OH, R_2:OH 2, the anthracycline compound represented by the following formula (I) or its acid addition salt is effective. Antitumor agent as an ingredient. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) In the formula, R_1 or R_2 is a hydrogen atom or a hydroxyl group, respectively, and is selected from the following combinations. (a) R_1:H, R_2:H (b) R_1:OH, R_2:H (c) R_1:OH, R_2:OH