JPS6259716B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula () (In the formula, R ₁ represents a hydrogen atom or a hydroxyl group, and R ₂ represents a 1-ethoxyethyl group, a tetrahydrofuranyl group, a 6-methoxytetrahydropyranyl group, a 6-carbomethoxytetrahydropyranyl group, or a 6-acetoxymethyltetrahydropyranyl group. Anthracycline represented by
This invention relates to novel derivatives of glycosides or acid addition salts thereof and methods for producing them. More specifically, the first invention is based on the following formula (') The hydroxyl group at the 4' position of the anthracycline glycoside derivative represented by (R represents hydrogen, hydroxyl group, or acyloxy group) is ethoxyethylated, tetrahydrofuranylated, or tetrahydropyranylated, and if necessary, the acyl group at the 14th position is The second and third aspects of the present invention relate to the novel anthracycline glycoside derivatives represented by the general formula () obtained by eliminating the group, and particularly the novel anthracycline glycoside derivatives obtained by two methods using daunomycin as a raw material. - It relates to a method for producing glycoside derivatives. Daunomycin obtained from actinomycete culture (UK Patent No. 1003383, US Patent No. 3616242)
and Adriamycin (U.S. Patent No. 3590028
No. 3,803,124) not only has a broad anticancer spectrum against experimental tumors but also is widely used clinically as a cancer chemotherapeutic agent, but on the other hand, it often causes leukopenia, hair loss, and myocardial damage. It is known to be accompanied by serious side effects such as The present inventors have conducted extensive research to provide useful derivatives that further enhance the anticancer activity of daunomycin and adriamycin and reduce toxicity (side effects). The inventors of the present invention have completed the present invention by discovering that derivatives which have been converted into fluorine, tetrahydrofuranylated or 6-substituted tetrahydropyranylated have low toxicity and strong anticancer activity. The compounds obtained in the present invention are represented by the above general formula (), and examples of compounds with excellent medicinal efficacy are as follows. Namely: 4'-O-(tetrahydrofuran-2-yl)adriamycin 4'-O-(tetrahydrofuran-2-yl)adriamycin a and b 4'-O-(1-ethoxyethyl)adriamycin a and b 4'-O -(6-acetoxymethyltetrahydropyran-2-yl)adriamycin 4'-O-(tetrahydrofuran-2-yl)daunomycin a and b 4'-O-(1-ethoxyethyl)daunomycin a and b 4'-O- (6-acetoxymethyltetrahydropyran-2-yl)daunomycin 4'-O-(6-methoxytetrahydropyran-
2-yl)daunomycin a and b 4'-O-(6-carbomethoxytetrahydropyran-2-yl)daunomycin The method for producing the novel derivative () of the present invention can be roughly divided into two, one of which is the method. As, the second invention has the following general formula () [In the formula, R ₃ is the formula

Anthracycline glycoside or its acid addition salt represented by [Formula] (where R ₄ represents an alkyl group having 1 to 6 carbon atoms or a benzyl group) or an acid addition salt thereof is treated with a reaction reagent with a hydroxyl group. A certain dihydropyran derivative, dihydrofuran derivative, or vinyl ether derivative is reacted to form a 1-ethoxyethyl group, tetrahydrofuranyl group, 6-methoxytetrahydropyranyl group, 6-carbomethoxytetrahydropyranyl group, or -The following general formula () is characterized by introducing an acetoxymethyltetrahydropyranyl group and hydrolyzing the product to eliminate the acyl group at position 14. _{Anthracycline} represented by the following formula:・The gist is the method for producing glycosides or their acid addition salts. In this second method of the invention, the following general formula () derived from daunomycin is used: (In the formula, R ₄ is an alkyl group having 1 to 6 carbon atoms,
or a benzyl group) [Reference: Comte Langille Académie de Chiens t.286 Seri D-443, 1978 (CRAcad Sc
Paris, t. 286 Se'rie D-443, 1978)] (same as the compound of formula () above) is used as a starting material. This is the formula for the 14-position hydroxyl group of adriamycin.
Corresponds to R ₄ COOH acylated with alkanoic acid or phenyl acetic acid. This compound () or () is reacted with a dihydropyran derivative, dihydrofuran derivative, or vinyl ether derivative to introduce a group corresponding to the 4'-position hydroxyl group, resulting in the following general formula () (In the formula, R ₄ represents the same group as above, and R ₂ is 1
-ethoxyethyl group, tetrahydrofuranyl group,
6-methoxytetrahydropyranyl group, 6-carboxymethyltetrahydropyranyl group, or 6-
An intermediate (representing an acetoxymethyltetrahydropyranyl group) is obtained. In this case, the compound () or (), either as its free base or as an acid addition salt such as a hydrochloride, is dissolved or suspended in an organic solvent and converted into a suitable dihydropyran derivative, dihydropyran derivative, dihydropyran, etc. in the presence of an acid catalyst. When reacted with a furan derivative or a vinyl ether derivative, the hydroxyl group at the 4' position is 6-substituted-tetrahydropyranylated, tetrahydrofuranylated or ethoxyethylated. Dihydropyran derivatives used for this purpose include 2-acetoxymethyl-3,4-dihydro-2H-pyran, 2-methoxy-3,4-dihydro-2H-pyran, 2-carbomethoxy-3,
4-dihydro-2H-pyran, dihydrofuran itself as a dihydrofuran derivative, and ethyl vinyl ether as a vinyl ether derivative. As the reaction solvent at this time, anhydrous solvents such as benzene, toluene, dimethylformamide (hereinafter referred to as DMF), and acetonitrile can be used alone or in combination. In addition, organic sulfonic acids are used as acid catalysts, but p-toluenesulfonic acid, p-toluenesulfonic acid,
Advantageously, aromatic sulfonic acids are used, such as benzenesulfonic acid. A preferred example is a method in which the reaction is carried out at room temperature for 20 to 50 hours using anhydrous DMF as a solvent and p-toluenesulfonic acid as an acid catalyst. Next, this intermediate () is hydrolyzed and the 14-position is deacylated to obtain the target compound (). In this hydrolysis, the intermediate compound () is dissolved in an organic solvent miscible with water such as aqueous methanol, a lower alkanol such as ethanol, or aqueous acetone, and the mixture is dissolved at an appropriate concentration, for example, about 10%. This is achieved by hydrolyzing the R ₄ CO group at position 14 (deacylation) in the presence of an alkali such as an alkali metal carbonate, preferably potassium carbonate, at room temperature or under slightly heated conditions. Ru. Hydrolysis is confirmed by thin layer chromatography. As another method, the third invention provides the following general formula () Daunomycin or its acid addition salt represented by is reacted with a dihydropyran derivative, dihydrofuran derivative, or vinyl ether derivative, which is a reaction reagent with a hydroxyl group, to form a 1-ethoxyethyl group, a tetrahydrofuranyl group, or a 6-methoxytetrahydrogen group at the 4'-position hydroxyl group. The following general formula () characterized by introducing a pyranyl group, a 6-carbomethoxytetrahydropyranyl group, or a 6-acetoxymethyltetrahydropyranyl group (In the formula, R ₂ represents a 1-ethoxyethyl group, a tetrahydrofuranyl group, a 6-methoxytetrahydropyranyl group, a 6-carbomethoxytetrahydropyranyl group, or a 6-acetoxymethyltetrahydropyranyl group)・The gist is the method for producing glycosides or their acid addition salts. In this third method of the present invention, daunomycin is used as a starting material, and the free base of daunomycin as it is or an acid addition salt such as hydrochloride is dissolved or suspended in an organic solvent, and the method is similar to the second method of the present invention. When reacted with an appropriate dihydropyran derivative, dihydrofuran derivative, or vinyl ether derivative in the presence of an acid catalyst, the hydroxyl group at the 4' position is converted to 6
-Substituted-tetrahydropyranylated, tetrahydrofuranylated or ethoxyethylated new derivatives () of interest are obtained. The dihydropyran derivatives, dihydrofuran derivatives, and vinyl ether derivatives used for this purpose may be the same as those used in the second invention. At this time, benzene, toluene, dimethylformamide (hereinafter referred to as
Anhydrous solvents such as DMF) and acetonitrile can be used alone or in combination. Further, as the acid catalyst, organic sulfonic acids are used, but it is advantageous to use aromatic sulfonic acids such as p-toluenesulfonic acid and benzenesulfonic acid. A preferred example is a method in which anhydrous DMF is used as a solvent, p-toluenesulfonic acid is used as an acid catalyst, and the reaction is carried out at room temperature for 20 to 50 hours. Of the above two methods for producing the compound () of the present invention, the former method yields the compound represented by the general formula (), but both of these are new, and the main one is R ₁ and R ₂ are the following compounds.

【table】

[Table] The final target compound of the present invention obtained as described above has the pharmacological action described below. (1) Antitumor properties against experimental animal tumors 1×10 ⁵ mice/mouse L1210 leukemia cells
The mouse was implanted intraperitoneally (ip), and 24 hours later, the substance of the present invention () was intraperitoneally administered daily for 10 days, followed by observation for 45 days. Table 1 below shows the effect in terms of survival rate (T/C, %), where the number of survival days of mice in the control group to which physiological saline was administered is taken as 100.

[Table] (2) Inhibitory effect on proliferation and nucleic acid synthesis of leukemia cultured cells (L1210) RPMI1640 medium containing 20% calf serum (Rosewell
Park Memonial Institute 1640) was inoculated with 5 x ¹⁰⁴ L1210 cultured cells/ml, the substance of the present invention () was added at the same time, cultured in a carbon dioxide gas incubator at 37°C, and the growth inhibition rate IC ₅₀ was measured. The results obtained are shown in Table 2 below. In addition, the IC ₅₀ of DNA and RNA inhibition rate was measured as follows. i.e. above L1210 containing 10% calf serum
Suspend in RPMI1640 medium at 1 x 10 ⁵ cells/ml, pre-culture in a carbon dioxide incubator at 37°C for 1 to 2 hours, then add the substance of the present invention, and after 15 minutes further incubate at carbon dioxide. ¹⁴ -Uridine (0.05 μCi/ml) or C ¹⁴ -thymidine (0.05 μCi/ml) was added and cultured at 37° C. for 60 minutes. Add 10% trichloroacetic acid solution to the reaction solution to stop the reaction, and at the same time precipitate the acid insoluble matter.
After washing three times with ~10% trichloroacetic acid solution, it was dissolved in formic acid, and the radioactivity in the acid-insoluble matter was measured. IC ₅₀
I asked for The results are also shown in Table 2.

[Table] Examples of the present invention are shown below, but the present invention is not limited thereto. In addition, Examples 1 to 4
exemplifies the second invention, and Examples 5 to 9 illustrate the third invention. Example 1 Production of 4'-O-(tetrahydrofuran-2-yl)adriamycin (a) 190 mg (0.25 mmol) of 14-O-acetyladriamycin p-toluenesulfonate was dissolved in 10 ml of dry dimethylformamide, and dihydrofuran 0.4 ml and catalytic amount of p-toluenesulfonic acid and leave at room temperature for 3.5 hours (4'-
O-tetrahydrofuranylation). When the reaction solution was observed by silica gel thin layer chromatography using the solvent system chloroform-methanol (9:1), the starting material almost disappeared, and a new Rf value of 0.24 ~
A substance showing a value of 0.27 was produced. Add the reaction solution to 100% water.
After neutralizing with sodium bicarbonate, extract with 60 ml of chloroform. After dehydration with anhydrous sodium sulfate, the chloroform solution was concentrated under reduced pressure, and the residue was subjected to preparative thin layer chromatography using Merck's silica gel 60 and solvent chloroform-methanol (9:1). Expand. Rf value 0.24
The fraction showing ~0.27 was scraped off together with the silica gel powder and re-extracted with a mixed solvent of chloroform-methanol (1:1). The resulting solution was concentrated to dryness to give 14-O-acetyl-4'-O as a red solid.
66.8 mg of -(tetrahydrofuran-2-yl)adriamycin was obtained. Yield 40% PMR (CDCl ₃ ppm): 1.23-1.34
(6′ position), 1.70-2.12 (furan), 2.20, 2.22 (acetyl), 4.06 (4-OMe), 5.20 (14th position),
5.36 (Franc, Anomericsk), 5.51 (7th place),
7.27-8.06 (positions 1-3) (b) Add 10 ml of methanol and 3 ml of water to 41.0 mg of 14-O-acetyl-4'-O-(tetrahydrofuran-2-yl)adriamycin, and stir well to dissolve. While stirring, add 10% potassium carbonate aqueous solution until the reaction solution turns blue-purple (PH 10-11), and leave at room temperature for 30 minutes (hydrolysis). When examined by silica gel thin layer chromatography (solvent system: chloroform-methanol 1:1 ratio), a clear decrease in the Rf value is observed. After neutralizing the reaction solution by adding a small piece of dry ice, extraction with chloroform is performed. The chloroform layer was washed with water, dried and concentrated, and the resulting residue was subjected to preparative thin layer chromatography in the same manner as in the previous reaction.
16.3 mg of 4'-O-(tetrahydrofuran-2-yl)adriamycin was obtained as a red powder.
Yield 43%, mp. 189-194° (decomposition), PMR (CDCl ₃ ppm): 1.25-1.27 (6'-
), 1.67-2.30 (Franc), 4.07-4.08 (Franc)
), 5.17 and 5.38 (franc, anomeric),
5.30 (1'), 5.51 (7th), 7.30~8.07 (1~
3rd place) Example 2 Production of 4'-O-(tetrahydrofuran-2-yl)-adriamycin a and b 40 mg of 4'-O-(tetrahydrofuran-2-yl)-adriamycin obtained in Example 1 was prepared by Merck & Co. Preparative thin layer chromatography is performed again using silica gel 60 and the solvent system chloroform-methanol (15:1). A silica gel plate with a thickness of 0.25 mm was used, the amount of separation was 1.0 mg or less per 20 x 20 cm plate, and good separation was achieved when the plate was developed three times from the origin. A fraction corresponding to an Rf value of 0.20 was scraped off together with silica gel powder, and the resulting solution was eluted with chloroform-methanol (1:1) and concentrated to dryness to obtain 11.0 mg of substance a. mp.189-191℃, [α] _D +175゜(CHCl ₃ c=
0.2) PMR (CDCl ₃ ppm): 1.25 (6′ position) 1.67 ~
2.37 (Franc), 4.07 (4th place), 5.17 (Franc, Anomeric), 5.30 (1′ place), 5.51 (7th place), 7.30~
8.06 (1st to 3rd) From the fraction derived from the Rf value of 0.22, 12.1 mg of substance b was obtained. mp.190～192℃〔α〕 _D +150゜(CHCl ₃ c=
0.2) PMR (CDCl ₃ ppm): 1.27 (6′ position), 1.67-2.30
(Franc), 4.08 (4th place), 5.30 (1′-place), 5.38
(Fran, Anomericsk), 5.51 (7th place), 7.30~
8.07 (1st to 3rd positions) Example 3 Production of 4'-O-(1-ethoxyethyl)adriamycin a and b (a) 14-O-phenylacetyladriamycin. Dissolve 2.00 mg of p-toluenesulfonate in 4.0 ml of dry dimethylformamide, add 0.2 ml of ethyl vinyl ether and a catalytic amount of p-toluenesulfonic acid, and leave at room temperature for 1.5 hours (4'-O-ethoxyethyl ). When examining the reaction solution using silica gel thin layer chromatography (solvent system: chloroform-methanol 9:1),
The starting material disappeared and new substances showing Rf of 0.36 and 0.39 were produced. The reaction solution was poured into 0 ml of water, the pH was adjusted to 8 by adding sodium bicarbonate, and the mixture was extracted with 60 ml of chloroform. The chloroform extract is dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain a red residue. Silica gel 60 manufactured by Merck (2 mm thickness 20 x 20 cm2)
), solvent system chloroform-methanol (9:
1) was developed by preparative thin layer chromatography using
134 mg of 14-O-phenylacetyl-4'-O-(1-ethoxyethyl)adriamycin was obtained. Yield 76% PMR spectrum (CDCl ₃ ppm): 1.21,
3.62 (1″-O-ethyl), 1.40 (2″ position), 3.81,
7.38 (phenylacetyl), 4.02 (4-O-methyl), 5.64, 5.94 (1″-position), 5.24 (14th position),
5.50 (7th place), 7.25 to 8.02 (1st to 3rd place) (b) Next, dissolve this substance in 40 ml of acetone and add 20 ml of water.
ml and 150 mg of anhydrous potassium carbonate and stir well (hydrolysis). When examined using silica gel thin layer chromatography (solvent system: chloroform-methanol 9:1), substances with Rf values of 0.36 and 0.39 gradually decreased, and new Rf values of 0.21 and 0.39 were found.
The formation of a new substance showing a value of 0.28 was observed. The reaction is stopped after 20 minutes, a small piece of dry ice is added to the reaction solution to neutralize it, and then the acetone is distilled off. The remaining aqueous solution is extracted twice with 30 ml of chloroform, the extract is washed with water, dried and concentrated to give a red residue. Purify this substance using silica gel preparative thin layer chromatography in the same manner as in the previous procedure. Development was performed using chloroform-methanol (15:
1) once, chloroform-methanol (9:
Good separation was obtained when 1) was repeated two more times.
The fraction assigned an Rf value of 0.21 was scraped off with silica gel and re-extracted with an equal volume mixture of chloroform-methanol. The resulting solution was concentrated as a red powder, 13.0 mg of 4'-O-(1-ethoxyethyl)adriamycin a. was gotten. (yield 13
%), mp.205-215℃ PMR (CDCl ₃・ppm): 1.15, 3.58 (1st place
OEt), 1.40 (2″ position), 3.58 (2″ position), 4.06 (4-
OMe), 4.65 (1″), 4.76 (14th), 5.25 (1′−
5.51 (7th place), 7.25-8.07 (1st-3rd place)
(1-ethoxyethyl)adriamycin b11.2
mg was obtained. Yield 11%, mp.190-200℃ PMR (CDCl ₃ ppm): 1.22, 3.63 (1″-
OEt), 4.08 (4th place), 4.76 (14th place), 4.93
(1″ place), 5.27 (1′- place), 5.50 (7th place), 7.22～
8.88 (1st to 3rd positions) Example 4 Production of 4'-O-(6-acetoxymethyltetrahydropyran-2-yl)adriamycin (a) 150 mg of 14-O-phenylacetyladriamycin/p-toluenesulfonate ( Dissolve 0.18 mmol) in 2.0 ml of dry dimethylformamide, add 0.2 ml of 2-acetoxymethyl-3,4-dihydro-2H-pyran and 15 mg (0.09 mmol) of p-toluenesulfonic acid, and leave at room temperature for 24 hours [4 '-O-(6-acetoxymethyltetrahydropyranyl) conversion]. When the reaction solution was examined by silica gel thin layer chromatography (solvent system: chloroform-methanol 9:1), in addition to the starting material, a new substance with an Rf value of 0.51 was produced.
The reaction solution was poured into 20 ml of water, neutralized with sodium bicarbonate, and then extracted twice with 30 ml of chloroform. A chloroform solution dehydrated with anhydrous sodium sulfate is adsorbed through a 10 g silica gel column (Kiesel Gel #100 manufactured by Merck).
After washing with 100 ml of chloroform, sequential elution is performed with a mixed solvent of chloroform-methanol (10:1), and the eluate is examined by thin layer chromatography. A fraction corresponding to Rf0.51 was collected and concentrated to dryness, resulting in a red solid, 14-O-phenylacetyl-4'-O-(6-acetoxymethyltetrahydropyran-2-yl)adriamycin.
100.2 mg was obtained. Yield 68% PMR spectrum (CDCl ₃ ppm): 1.24-1.34
(6' position), 2.08 (acetyl), 3.83, 7.40 (ferlacetyl), 4.08 (4' position), 4.95 (pyran, anomeric), 5.25 (14th position), 5.54 (7th place), 7.30~
8.08 (1st to 3rd) (b) Next, stir well and dissolve this substance in 20ml of acetone, and add 10ml of water and 0.5ml of 10% potassium carbonate.
and perform hydrolysis for 30 minutes. Thin layer chromatography showed a product at an Rf value of 0.41. A small piece of dry ice is added to the reaction solution to neutralize it, and the acetone is distilled off under reduced pressure. The remaining aqueous solution is extracted three times with 10 ml of chloroform. The chloroform layers are combined, washed with water, dehydrated with anhydrous sodium sulfate, and concentrated to dryness, leaving a red solid. Silica gel 60 manufactured by Merck (2 mm thickness, 20 x 20
cm), preparative thin layer chromatography was performed using a solvent system of chloroform-methanol (9:1), and re-extraction was performed from the fraction corresponding to Rf0.41. 26.9 mg of 6-acetoxymethyltetrahydropyran-2-yl)adriamycin was obtained. Yield 31%,
mp.174-178℃ PMR (CDCl ₃・ppm): 1.19-1.40
(6′ position), 2.06, 2.10 (OAc), 4.11 (4-
OMe), 4.78 (14th place), 5.55 (7th place), 7.35-8.10
(1st to 3rd positions) Example 5 Production of 4-O-(tetrahydrofuran-2-yl)daunomycin 56 mg (0.1 mmol) of daunomycin hydrochloride was dissolved in 2.0 ml of dry dimethylformamide, 0.1 ml of dihydrofuran and a catalytic amount of p -Toluenesulfonic acid is added and left at room temperature for 8 hours (4'-O-tetrahydrofuranylation). Pour the reaction solution into 20 ml of water, add sodium hydrogen carbonate to neutralize it, and then extract with 30 ml of chloroform. After dehydration with anhydrous sodium sulfate, the chloroform extract was concentrated to dryness under reduced pressure to obtain a red substance. When developed by preparative thin layer chromatography using Merck silica gel 60 (solvent system chloroform-methanol, 9:1), the Rf value was 0.29 and
The target product was separated into fractions showing 0.31, but complete separation of each was difficult. The fraction was scraped off and eluted with a chloroform-methanol (1:1) mixed solution. The resulting solution was concentrated under reduced pressure to yield 4'-O-(tetrahydrofuran-2-yl) as a red powder.
12.4 mg (yield 21%) of daunomycin was obtained.
mp201～204゜(dec) PMR (CDCl ₃・ppm): 1.29 (6′ position), 1.70～
2.30 (3rd and 4th place), 2.44 (14th place), 4.11 (4th place)
Example 6 4'-O-(1-ethoxyethyl)-daunomycin a and Preparation of b: 112 mg (0.2 mmol) of daunomycin hydrochloride was dissolved in 3 ml of dry dimethylformamide, 0.1 ml of ethyl vinyl ether and 2 mg of p-toluenesulfonic acid were added, and the mixture was left at room temperature for 10 hours (1-ethoxyethylation). When the reaction solution was observed by silica gel thin layer chromatography (solvent system: chloroform-methanol 9:1), the formation of new substances was observed at Rf values of 0.31 and 0.34. Pour the reaction solution into 20 ml of water, adjust the pH to 8 by adding sodium bicarbonate, and extract with 30 ml of chloroform. The red residue obtained by drying the chloroform layer and concentrating it under reduced pressure was subjected to preparative thin layer chromatography using Merck's silica gel 60 (2 mm thick, 1 piece of 20 x 20 cm) and the solvent system chloroform-methanol (15:1). , expand twice, and separate. Rf value
The fraction assigned to 0.31 was scraped off and the red solution extracted with a mixed solvent of chloroform-methanol (1:1) was concentrated to dryness, resulting in a red substance A powder of 33.0
mg was obtained. Yield 27%, mp.208-210℃ PMR spectrum (CDCl ₃ , ppm): 1.76, 3.59
(1″-OEt), 1.39 (2″), 1.79 (8th), 2.41
(14th place), 4.07 (4th place-O-Me), 4.64 (1″ place),
5.25 (1'-position), 5.51 (7th place), 7.25~8.06 (1~
3rd place) The fraction assigned an Rf value of 0.34 was treated in the same manner to obtain 31.8 mg of substance b in the form of a red powder. Yield 26%
mp.200~204℃ PMR spectrum (CDCl ₃ ppm) 1.20, 3.64
(1″-OEt), 1.40 (2″), 2.41 (14th), 4.09
(4th place), 4.94 (1″-position), 5.26 (1′-position), 5.50
(7th position), 7.26 to 8.07 (1st to 3rd positions) Example 7 Production of 4'-O-(6-acetoxymethyltetrahydropyran-2-yl)-daunomycin 112 mg (0.2 mmol) of daunomycin hydrochloride was dissolved in dry dimethylformamide. Dissolve in 2.0ml, p-
Add 15 mg of toluenesulfonic acid and 0.3 ml of 2-acetoxymethyl-3,4 dihydro-2H-pyran.
Leave to stand overnight at room temperature [4'-O-(6-acetoxymethyltetrahydropyranyl) formation]. Pour the reaction solution into 20 ml of 1% sodium hydrogen carbonate, add 30 ml of chloroform, and extract. Chloroform the aqueous layer
Extract twice with 10ml and combine with the chloroform layer. The chloroform layer was washed four times with 10 ml of water, dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a crude reaction product. Merck silica gel 60,
Preparative thin layer chromatography using the solvent system chloroform-methanol (9:1) (2 mm thickness, 20×
Develop with a 20 cm sheet) and scrape off the fraction showing an Rf value of 0.47 together with the silica gel powder. The red solution obtained by re-extracting with a mixed solvent of chloroform-methanol (1:1) was concentrated to dryness to give 55.3 mg of red powder (yield: 40
%)was gotten. mp198~201℃ PMR (CDCl ₃ ppm): 1.21~1.42 (6′ position), 2.07
~2.11 (OAc), 2.43 (14th place), 4.10 (4th place -
Example 8 4′-O-(6-methoxytetrahydropyran-
2-yl)-Preparation of daunomycin a and b 112 mg (0.2 mmol) of daunomycin hydrochloride was dissolved in 3.0 ml of dry dimethylformamide.
Methoxy-3,4-dihydro-2H-pyran 0.15
ml and 10 mg of p-toluenesulfonic acid were added and left at room temperature overnight [4'-O-(6-methoxytetrahydropyranyl) formation]. Pour the reaction solution into 20 ml of water, add sodium hydrogen carbonate to adjust the pH to 8, and extract 4 times with 10 ml of chloroform. The chloroform layers were combined, dried over anhydrous sodium sulfate, and concentrated to dryness.
60, (one sheet of 2 mm thick 20 x 20 cm), developed and separated by preparative thin layer chromatography using the solvent system chloroform-methanol (9:1) ratio. The fraction showing an Rf value of 0.38 was scraped off together with the silica gel powder and re-extracted with a mixed solution of chloroform-methanol (1:1). The resulting red solution was concentrated under reduced pressure to obtain 23.1 mg of Substance A as a red powder. Ta. Yield 18%,
mp.189-191℃ PMR (CDCl ₃ .ppm): 1.29 (6′-position), 2.40
(3rd place), 3.45 (5″-OMe), 4.09 (4-OMe),
4.83 (1″ position), 5.30 (1′- position), 5.58 (7th place), 7.28
~8.08 (1st to 3rd positions) 19.4 mg (yield 15%) of red powder substance b was obtained in the same manner from the fraction showing an Rf value of 0.43. mp.198
~199℃ PMR (CDCl _3.ppm ): 1.39 (6′ position), 2.44 (14
), 3.46 (Piran OMe), 4.11 (4th place), 4.89
(Piran, Anomeric), 5.22 (1′ position), 5.53 (7
7.28 to 8.14 (positions 1 to 3) Example 9 Production of 4'-O-(6-carbomethoxytetrahydropyran-2-yl)daunomycin 112 mg (0.2 mmol) of daunomycin hydrochloride was dissolved in 3.0 ml of dry dimethylformamide. Dissolve, 2-
Add 0.1 ml of carbomethoxy-3,4-dihydro-2H-pyran and 34 mg (0.2 mmol) of p-toluenesulfonic acid and leave in the dark at room temperature for 10 hours [4'-O-(6-carbomethoxytetrahydro pyranyl) conversion]. Pour the reaction solution into 20ml of water, add sodium hydrogen carbonate to adjust the pH to 8, and then add chloroform.
Extract 4 times with 10 ml. Combine the chloroform layer,
After washing twice with water, dry with anhydrous sodium sulfate. The residue obtained by concentrating the chloroform solution under reduced pressure was subjected to preparative thin layer chromatography using a Merck silica gel plate (solvent system chloroform-
Develop and separate with methanol (9:1). Rf value
A new substance was observed to be produced as a mixture of four components between 0.35 and 0.37, and complete separation was difficult. The substance was scraped off along with the silica gel powder, and the resulting solution was extracted with a mixed solvent of chloroform-methanol (1:1) and concentrated to dryness to obtain 25.9 mg of red powder. Yield 19%, mp.190-193℃ PMR (CDCl ₃ ppm): 1.23-1.40 (6' position), 2.43
(14th place), 3.78 (COOMe), 4.09 (4-OMe),
4.74, 5.07 (Piran, Anomeric), 5.31 (1′−
H), 5.54 (7th position), 7.30-8.06 (1-3) The following synthesis examples were also carried out during the research process of the present invention, and are shown as reference examples. Reference Example 1 Production of 14-O-acetyl-4'-O-tetrahydropyranyladriamycin a and b 155 mg (0.2 mmol) of 14-O-acetyldriamycin-p-toluenesulfonate was dissolved in 2.0 ml of dry dimethylformamide. , add 2.0 ml of dihydropyran and leave at room temperature overnight. When the reaction solution was observed by thin layer chromatography using silica gel 60 manufactured by Merck and the solvent system chloroform-methanol (9:1), the starting material almost disappeared and new Rf values of 0.24 (a) and 0.39 (b) were observed. ) was observed to produce a new substance. Pour the reaction solution into 20ml of water, add sodium carbonate powder to adjust the pH to 8, and then
Extract with 30 ml of chloroform. The chloroform layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the red residue obtained was purified by silica gel 60 (2 mm
It was developed and separated by preparative thin layer chromatography using a solvent system of chloroform-methanol (7:1). The fraction showing an Rf value of 0.24 was scraped off together with the silica gel powder, and the red solution obtained by re-extracting with a mixed solvent of chloroform-methanol (1:1) was concentrated to form a red powder of Substance A 24.7
I got mg. Yield 18%, mp.185-195℃ PMR spectrum (ppm in CDCl ₃ ): 1.28
(6′ position), 1.50 to 1.85 (Piran 3rd to 5th place), 2.21
(OAc), 4.05 (4'-OMe), 4.42 (Piran, Anomeric) 5.18 (14th), 5.26 (1'-H), 5.54
(7th place) 7.27 to 8.03 (1st to 3rd place) The fraction showing Rf value 0.39 was treated in the same way and the red b
34.5 mg of material powder was obtained. Yield 25%, mp.180-190
゜ PMR spectrum (ppm in CDCl ₃ ): 1.37
(6′ position), 1.40-2.00 (Piran), 2.21 (OAc),
4.08 (4th place OMe), 4.75 (Piran, Anomericsk), 5.18 (14th place), 5.25 (1′ place), 5.53 (7th place),
7.30 to 8.06 (1st to 3rd positions) Reference example 2 Production of 14-O-isobutyryl-4'-O-tetrahydropyranyladriamycin a and b 14-O-isobutyryladriamycin-p-
104 mg (0.13 mmol) of toluenesulfonate are dissolved in 2.0 ml of dry dimethylformamide, 2.0 ml of dihydropyran and a catalytic amount of p-toluenesulfonic acid are added, and the mixture is left at room temperature for 15 hours. Thin layer chromatography (solvent system chloroform-methanol 9:1) reveals products at Rf values of 0.38 and 0.45. Pour the reaction solution into 20 ml of water, neutralize by adding sodium bicarbonate, and extract with 30 ml of chloroform. The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was developed and separated on thin layer chromatography. 22.5 mg of red substance a powder was obtained from the fraction with an Rf value of 0.38. Yield 24
%, mp.155-161℃ PMR (CDCl ₃ ppm): 1.24 (6' position), 1.29 (isobutyl), 4.06 (4'-OMe), 4.40 (pyran, anomeric), 5.10 (14th position), 5.25 ( 1′ position), 5.51
(7th place), 7.30 to 8.07 (1st to 3rd place) From the fraction with Rf value 0.45, 22.7 mg of red powder substance B
was gotten. Yield 24%, mp.169-174℃ PMR (CDCl ₃ .ppm): 1.28 (isobutyl),
1.37 (6'-position), 1.40-2.00 (THP), 4.08 (4-
OMe), 4.75 (Piran, Anomeric), 5.22 (14
), 5.25 (1'), 5.55 (7th), 7.29-8.10 (1'),
~3rd place) Reference Example 3 Production of 14-O-phenylacetyl-4'-O-tetrahydropyranyl-adriamycin a and b 14-O-phenylacetyldriamycin-
80 mg (0.096 mmol) of p-toluenesulfonate are dissolved in 2.5 ml of dry dimethylformamide, 0.5 ml of dihydropyran and a small amount of p-toluenesulfonic acid are added and left at room temperature. When the reaction solution was observed by thin layer chromatography using silica gel 60 manufactured by Merck and the solvent system chloroform-methanol (9:1), the formation of new substances with Rf values of 0.39 and 0.48 was observed, indicating that the starting material was 4
It almost disappeared over time. Pour the reaction solution into 20 ml of 1% aqueous sodium carbonate solution and add 30 ml and 10 ml of chloroform.
Extract with The chloroform layers were combined, washed with water four times, dried over anhydrous sodium sulfate, concentrated to dryness, and the resulting residue was purified with Merck Silica Gel 60,
(2 mm thick, 20 cm x 20 cm, 1 sheet) It was developed and separated by preparative thin layer chromatography using a solvent system of chloroform-methanol (9:1). Rf value 0.39
The fraction was scraped off together with the silica gel powder, and the red solution obtained by re-extracting with a mixed solvent of chloroform-methanol (1:1) was concentrated to dryness to obtain 27.0 mg of Substance A as a red powder. Yield 37%, mp.156~
163℃ PMR spectrum (ppm in CDCl ₃ ): 1.25
(6′ position), 1.40-2.00 (tetrahydropyran), 3.80
and 7.36

[Formula] 4.02 (4-OMe), 4.35 (pyran, anomeric), 5.21 (14
), 5.25 (1'), 5.50 (7th), 7.30~8.02 (1'),
~3rd place) 20.2 mg of substance b was obtained as a red powder in the same manner from the fraction of Rf0.48 (yield 28%). mp.159~165
°C PMR spectrum (CDCl ₃ , ppm): 1.37 (6'-
), 1.45-2.00 (Piran), 3.80 and 7.32

[Formula] 4.05 (4-OMe), 4.73 (pyran, anomeric), 5.25 (14 and 1′ positions),
5.50 (7th place), 7.30-8.06 (1st-3rd place)

Claims (1)

[Claims] First-order general formula () (In the formula, R ₁ represents a hydrogen atom or a hydroxyl group, and R ₂ represents a 1-ethoxyethyl group, a tetrahydrofuranyl group, a 6-methoxy-tetrahydropyranyl group, a 6-carbomethoxytetrahydropyranyl group, or a 6-acetoxymethyl A novel derivative of anthracycline glycoside (representing a tetrahydropyranyl group) or an acid addition salt thereof. 2 The compound represented by the formula () is
R ₁ is a hydroxyl group and R ₂ is a 1-ethoxyethyl group
Claim 1 which is 4'-O-ethoxyethyl adriamycin a or its diastereomer b
Anthracycline glycosides or acid addition salts thereof as described in . 3 The compound represented by the formula () is
Anthracycline glycoside or its acid according to claim ₁ , which is 4'-O-ethoxyethyldaunomycin a or its diastereomer b, in which R ₁ is a hydrogen atom and R 2 is a 1-ethoxyethyl group Added salt. 4 The compound represented by the formula () is
The anthracycline according to claim ₁ , which is 4'-O-tetrahydrofuranyl adriamycin, 4'-O-tetrahydrofuranyl adriamycin a, or its diastereomer b, in which R 1 is a hydroxyl group and R ₂ is a tetrahydrofuranyl group. - Glycosides or their acid addition salts. 5 The compound represented by the formula () is
Anthracycline glycoside or an acid addition salt thereof according to claim 1, which is 4'-O-tetrahydrofuranyldaunomycin, wherein R ₁ is a hydrogen atom and R ₂ is a tetrahydrofuranyl group. 6 The compound represented by the formula () is
_{4' -} O-(6-
The anthracycline glycoside or its acid addition salt according to claim 1, which is acetoxymethyl-tetrahydropyranyl) adriamycin. 7 The compound represented by the formula () is
_{4′ -} O-(6
The anthracycline glycoside or its acid addition salt according to claim 1, which is daunomycin (acetoxymethyl-tetrahydropyranyl). 8 The compound represented by the formula () is
The anthracycline according to claim ₁ , wherein R 1 is a hydrogen atom and R ₂ is 4'-O-methoxy-tetrahydropyranyl daunomycin a or its diastereomer b. - Glycosides or their acid addition salts. 9 The compound represented by the formula () is
Anthracycline glycoside or its acid according to claim ₁ , which is 4'-O-carbomethoxytetrahydropyranyldaunomycin, where R ₁ is a hydrogen atom and R 2 is a 6-carbomethoxytetrahydropyranyl group. Added salt. 10 General formula () [Wherein R ₃ represents an acyloxy group of the formula [Formula] (where R ₄ represents an alkyl group having 1 to 6 carbon atoms or a benzyl group)] or an acid addition salt thereof] 1-ethoxyethyl group, tetrahydrofuranyl group, 6-methoxytetrahydropyranyl group, 6-carboxylic acid group by reacting with a dihydropyran derivative, dihydrofuran derivative, or vinyl ether derivative, which is a reaction reagent with the hydroxyl group, to form a 1-ethoxyethyl group, a tetrahydrofuranyl group, a 6-methoxytetrahydropyranyl group, or a 6-carbohydrate group. The following general formula () is characterized by introducing a methoxytetrahydropyranyl group or a 6-acetoxymethyltetrahydropyranyl group, and hydrolyzing the product to eliminate the acyl group at the 14th position. _{Anthracycline} represented by the following formula:・Glycoside (() in claim 1)
(when R ₁ is a hydroxyl group in the formula) or a method for producing its acid addition salt. 11 The following general formula () Daunomycin or its acid addition salt represented by is reacted with a dihydropyran derivative, dihydrofuran derivative, or vinyl ether derivative, which is a reaction reagent with a hydroxyl group, to form a 1-ethoxyethyl group, a tetrahydrofuranyl group, or a 6-methoxytetrahydrogen group at the 4'-position hydroxyl group. It is characterized by introducing a pyranyl group, a 6-carbomethoxytetrahydropyranyl group, or a 6-acetoxymethyltetrahydropyranyl group. The following general formula () (In the formula, R ₂ represents a 1-ethoxyethyl group, a tetrahydrofuranyl group, a 6-methoxytetrahydropyranyl group, a 6-carbomethoxytetrahydropyranyl group, or a 6-acetoxymethyltetrahydropyranyl group)・Glycoside (() in claim 1)
(when R ₁ is hydrogen in the formula) or a method for producing its acid addition salt.