KR840000679B1 - Method for preparing anthracycline derivatives - Google Patents

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Description

Method for preparing anthracycline derivatives

The present invention relates to a method for producing a novel anthracycline derivative represented by the following general formula (I).

Wherein R ¹ represents a hydrogen atom, an alkanoyloxy group having 2 to 7 carbon atoms or a phenylacetyloxy group, and R ² is an alkyloxyethyl, tetrahydrofuran-2-yl tetra having 3 to 10 carbon atoms Hydropyran-2-yl, 6-methoxytetrahydropyran-2-yl, 6-carbomethoxytetrahydropyran-2-yl, or 6-acetoxymethyltetrahydropyran-2-yl, provided that R ₁ is Except that at the same time a hydrogen atom and R ₂ is a tetrahydropyran-2- group.

In more detail, the present invention relates to a method for preparing an anthracycline derivative represented by Formula (I) through etherification of a C-4 ′ hydroxyl group of an anthracycline derivative represented by Formula (III) below. .

Wherein R ¹ represents a hydrogen atom or an alkanoyloxy group or phenylacetyloxy group having 2 to 7 carbon atoms or an acid addition salt containing dihydrofuran and its derivatives, dihydropyrans, derivatives thereof or reactive dihydropyranyl By reacting with an alkylvinyl ether or an alkylvinylether group to be introduced, the hydroxyl group can be reacted, and the aforementioned group is introduced into the hydroxyl group on the C-4 'of the anthracycline derivative represented by the general formula (III). A method for preparing anthracycline derivatives of formula (I).

Daunomycin (UK Patent Nos. 1, 003, 383, US Patent Nos. 3, 616, 242) and Adriamycin (US Pat. Nos. 3, 590, 028 and 3, 803, 124) obtained from a culture of actinomycetes Has been widely used clinically as a cancer chemotherapeutic agent as well as having a broad spectrum of cancers in experimental tumors. However, it is known that adriamycin is associated with severe side effects such as white blood cell sensitization, hair loss, and cardiomyopathy.

The present inventors have conducted studies to provide useful derivatives which further reduce the toxicity (side effects) by enhancing the anticancer activity of daunomycin and adriamycin, and thus, on the C-4 ′ of daunomycin and adriamycin. It has been found that derivatives in which hydroxyl groups are substituted with alkyloxyethyl, tetrahydropyranyl, tetrahydrofuranyl or 6-substituted-tetrahydropyranyl groups have low toxicity and strong anticancer activity.

Among the derivatives of the present invention represented by the general formula (I), pharmacologically useful derivatives are as follows.

In particular, examples of novel 14-0-acylated derivatives of adriamycin are as follows.

14-0-acetyl-4'-0-tetrahydropyranyl adriamycin a and b

14-0-isobutyloil-4'-0-tetrahydropyranyladriamycin a and b

14-0-phenylacetyl-4'-0-tetrahydropyranyl adriamycin a and b

14-0-phenylacetyl-4'-0- (6-methoxytetrahydropyranyl) adriamycin a and b

14-0-phenylacetyl-4'-0- (6-carbomethoxytetrahydropyranyl) adriamycin a and b

14-0-isobutyloil-4'-0- (6-acetoxytetrahydropyranyl) adriamycin a and b

14-0-acetyl-4'-tetrahydrofuranyl adriamycin a and b

14-0-isobutyloil-4'-0-tetrahydrofuranyl adriamycin a and b

14-0-phenylacetyl-4'-tetrahydrofuranyl adriamycin a and b

14-0-phenylacetylethyl-4'-0- (1-oxymethyl) adriamycin a and b

14-0-acetyl-4'-0- (1-butyloxymethyl) adriamycin a and b

14-0-acetyl-4'-0- (1-isobutyloxyethylene) adriamycin a and b

14-0-isobutyloil-4'-0- (1-isobutyloxyethyl) adriamycin a and b

14-0-phenylacetyl-4'-0- (1-isobutyloxymethyl) adriamycin a and b

14-0-acetyl-4'-0- (1- (6-methylheptyloxy) ethyl) adriamycin a and b

14-0-acetyl-4'-0-cyclohexyloxyethyl adriamycin a and b

The following are mentioned as an example of a novel derivative of daunomycin.

4'-0-tetrahydrofuranyl daunomycin a and b

4'-0- (1-ethyloxyethyl) daunomycin a and b

4'-0- (1-butyloxyethyl) daunomycin a and b

4'-0- (1-isobutyloxyethyl) daunomycin a and b

4'-0- (1- (6-methylheptyloxy) ethyl) daunomycin a and b

4'-0-cyclohexyloxyethyl daunomycin a and b

4'-0- (6-methoxytetrahydropyranylda) unomycin a and b

4'-0- (6-carbomethoxytetrahydropyranyl) daunomycin a and b

4'-0- (6-acetoxytetrahydropyranyl) daunomycin a and b

The method for producing a novel anthracycline derivative of general formula (I) in the present invention can be divided into two types as described in the following description.

The method for producing the C-4'etherylated derivative of the 14-0-acylanthracycline derivative of the general formula (I) or an acid addition salt thereof is an anthracycline derivative represented by the following general formula (II-a) or its acid moiety. The salt is reacted with dihydrofuran, dihydrofuran, derivative dihydropyrandihydropyran derivative, or alkylvinyl ether in the presence of an inert solvent in the presence of an inert solvent and capable of reacting with a hydroxyl group. 1-methoxyethyl, 1-ethyloxyethyl, 1-butyloxyethyl, 1-isobutyloxyethyl, 1- (6- Alkoxyethyl, such as 6-methylheptyloxy) ethyl or cyclohexyloxyethyl, tetrahydrofuranyl, tetrahydropyranyl, 6-methoxyterhydropyranyl, 6-carbomethoxyterrahydropyranyl or 6-ace Methoxymethyltetrahydro The introduction of a raniyl group yields an etherified derivative or an acid addition salt thereof on C-4 'of the following general formula (II), or, if necessary, again on C-4' of a derivative of the general formula (II) Deacylation of a cannoyl group or a phenylacetyl group to prepare an anthracycline derivative of the general formula or an acid addition salt thereof.

Wherein R ³ is an alkanoyloxy group, such as an acetyloxy or isobutyl oiloxy or phenylacetyloxy group.

Wherein R ³ is an alkanoyloxy group or phenylacetyloxy group having 2 to 7 carbon atoms, R ² is alkyloxyethyl, tetrahydropranyl, tetrahydropranyl, 6-methoxytetrahydropyranyl, 6-carbomethoxy terrahydro pyranyl or 6-acetoxymethyltetrahydropyranyl group.

In the present invention, compounds derived from daunomycin by the method as described in Compt Rend. Acad. De Sciencent. 286, Serie D-443, 1978 used as starting materials (General Formula II- compound), and a compound having the general formula (IV).

Wherein R ⁴ is an alkyl or benzyl group having 1 to 6 carbon atoms.

The 14-0-acyl derivatives and 14-0-phenylacetyl derivatives are obtained by acylating hydroxyl groups on the C-14 of adriamycin with a structural formula, alkyl acid with R ⁴ COOH or phenylacetic acid. A novel derivative having the general formula (VII) (the same compound as the general formula II) is obtained as follows.

That is, the reactive group is introduced into a hydroxyl group on the C-4 ′ of the compound VI by reacting with dihydrofuran or dihydrodopyran or its derivative or alkylvinyl ether derivative having 3 to 10 carbon atoms. Obtained.

Wherein R ⁴ is the same group as above, R ² is tetrahydropyran-2-yl, 6-methoxyterahydropyran-2-yl, 6-carbomethoxytetrahydropyran-2-yl, 6 -Acetoxytetrahydropyran-2-yl, tetrahydrofuran-2-yl or 1-methoxyethyl, 1-ethyloxyethyl, 1-butyloxyethyl, 1-isobutyloxyethyl, 1- (6-methyl Alkyloxyethyl such as heptyloxy) ethyl or cyclohexyloxyethyl group.

In this case, the free base of the raw compound (VI) or the acid addition salt of the hydrochloride is dissolved or suspended in an organic solvent and dihydropyran, dihydropyran derivative, dihydrofuran derivative or C ³ -C10 alkyl in the presence of an acidic catalyst. When reacted with a vinyl ether derivative, the reactive hydroxyl group on the 4 'of compound (VI) is tetrahydrofuran-2-yl, terahydrofuran-2-yl, 6-substituted tetrahydropyran-2-yl, and It is substituted with the alkyloxyethyl group or cyclohexyloxyethyl group of 1-methoxyethyl, 1-ethoxyethyl, 1-butyloxyethyl, 1-isobutyloxyethyl, 1- (6-methylheptyloxy) ethyl.

2-acetoxyethyl-3,4-dihydro-2H-pyran, 2-methoxy-3,4-dihydro-H-pyran, 2-carbomethoxy-3, 4-dihydro-2H-pyran and Such dihydropyran derivatives can be preferably used in the present invention. Dihydrofuran itself and vinyl ether derivatives such as methyl vinyl ether, ethyl vinyl ether, butyl vinyl ether, isobutyl vinyl ether 6-methylheptyl vinyl ether or cyclohexyl vinyl ether are preferred for the present invention. Can be used.

As the reaction solvent, anhydrous organic solvents such as benzene, toluene, dimethylformamide (hereinafter referred to as DMF), tetrahydrofuran (hereinafter referred to as THF), dimethyl sulfoxide (hereinafter referred to as DMSO), dioxane and acetonitrile Is used alone or in combination.

Free sulfonic acids are used as the acidic catalyst, and aromatic sulfonic acids such as P-toluenesulfonic acid and benzenesulfonic acid are particularly preferable. It is a method of reacting for 20 minutes to 50 hours at room temperature using anhydrous DMF as a solvent and P-toluenesulfonic acid as an acidic catalyst. In another method, a mixture of anhydrous DMSO and anhydrous THF, or a mixture of anhydrous DMSO and dioxane anhydride is used as a solvent, and reacted for 20 minutes to 50 hours at room temperature using P-toluenesulfonic acid as an acid catalyst.

Next, the manufacturing method of the 2nd type of anthracycline glycoside of the following general formula (V) or its acid addition salt by this invention is as follows. That is, daunamacin represented by the following general formula (IV) or its acid addition salt and dihydropyran derivatives, for example, 2-acetoxyethyl-3,4-dihydro-2H-pyran and 2-methoxy- React with dihydropyran derivatives, dihydrofuran derivatives or hydroxyl groups such as 3,4-dihydro-2H-pyran, 2-carbomethoxy-3,4-dihydro-2H-pyran, etc. 10 alkylvinyl ethers, for example methylvinylether, ethylvinylether, butylvinylether, butylvinylether, isobutylvinylether, 6-methylheptylvinylether, or cyclovinyl Tetrahydrofuranyl, 6-methoxytetrahydrofuran-2-yl, 6-carbomethoxytetra as a hydroxyl group on C-4 ′ of daunomycin of the general formula (IV) or its acid addition salt by reacting with an ether or the like Hydropyran-2-yl, 6-acetoxymethyltetrahydropyranyl or 1-methoxyethyl, 1-ethyljade It is a manufacturing method of the said anthracycline or its acid addition salt formed by introduce | transducing alkyloxyethyl or cyclohexyloxyethyl groups, such as cyethyl, 1-butyloxyethyl, 1-isobutyloxyethyl, and 1- (6-methyloxy) ethyl. ,

(Wherein R ² is tetrahydrofuranyl, 6-methoxytetrahydropyran-2-yl, 6-carbomethyltetrahydropyran-2-yl, 6-acetoxytetrahydropyran-2yl-group or 1 An alkoxyethyl group such as -ethyloxyethyl, butyloxyethyl, 1-isobutyloxyethyl, 1- (6-methylheptyloxy) -ethyl or cycloheptyloxy group.

In this method, an acid addition salt of an organic base or hydrochloride of general formula (IV) (daunomycin) as a starting material is dissolved or suspended in an organic solvent, and according to the above-described method, a suitable dehydrochloride is present in the presence of an acidic catalyst. Reacted with pyran derivatives (except for hydropyrans themselves), dihydrofuran or alkylvinylethers having 3 to 10 carbon atoms. The derivative of formula (V) is thus obtained by substitution of the reactive hydroxyl group of C-4 'on the starting material with a 6-substituted tetrahydropyranyl, tetra hydrofuranyl, alkyloxyethyl group. In this case, as the reaction solvent, organic solvents such as benzene, toluene, dimethylformamide (DMF), tetrahydrofuran (THF) dioxane or acetonitrile are used alone or in combination. As the acidic catalyst, organic technical acid is used, and aromatic sulfonic acids such as P-toluenesulfonic acid and benzenesulfonic acid are particularly preferable. As a preferable example, the method of making it react for 20 minutes-50 hours at room temperature using anhydrous DMF as a solvent and P-toluenesulfonic acid as an acidic catalyst is mentioned. As another method, it is preferable to use a mixture of anhydrous DMSO and anhydrous THF or a mixture of anhydrous DMSO and dioxane anhydride, such as an acid group, at room temperature for 20 minutes to 3 hours. In order to more easily understand the preparation method of the anthracycline derivatives according to the present invention, as described above separately divided into the production method of the first type and the second type, but the manufacturing method of the two types of manufacturing in one The method is as follows.

Method for preparing anthracycline derivative of general formula (I) or acid addition salt thereof (method of combining general formula (II) and (V)) is as follows.

Wherein R ₁ is a hydrogen atom, an alkanoyloxy group or a phenylacetyloxy group having 2 to 7 carbon atoms, R ² is alkyloxyethyl, tetrahydrofuran-2-yl, tetrahydropyran-2-yl, 6-methoxytetrahydropyran-2-yl, 6-carbomethoxytetrahydropyran-2-yl, or 6-acetoxymethyltetrahydropyran-2-yl, provided that R ¹ is a hydrogen atom and at the same time R ² Is the case where is a tetrahydropyranyl group.

That is, to prepare anthracycline derivatives of formula (I) or acid addition salts thereof (methods of combining formula (II) and (V)), dihydrofuran, in the presence of an acidic catalyst and in an inert organic medium, The hydroxyl group on C-4 'of the anthracycline derivative of the general formula (III) by reacting the derivative, dihydropyran, the derivative or the derivative of alkylvinyl ether containing the corresponding group to be derived and a derivative capable of reacting with a hydroxyl group Rhoalkyloxyethyl, tetrahydrofuran-2-yl, tetrahydropyran-2-yl, 6-methoxytetrahydropyran-2-yl, 6-carbomethoxytetrahydropyran-2-yl, or 6-ace A oxymethyltetrahydropyran-2-yl group is introduced (method of combining (II-a) and (IV)).

In formula, R <^1> is an alkanoyloxy group which has a hydrogen atom or 2-7 carbon atoms.

Wherein R ¹ is a hydrogen atom or an alkanoyloxy group or phenylacetyloxy group having 2 to 7 carbon atoms, R ² is alkyloxyethyl, tetrahydrofuran-2-yl, tetrahydropyran-2-yl, 6-methoxytetrahydropyran-2-yl, 6-carbomethoxytetrahydropyran-2-yl, or 6-acetoxymethyltetrahydropyran-2-yl, provided that R ³ is a hydrogen atom and simultaneously R ^The case where bivalent is a tetrahydropyranyl group is excluded.

As described above, the method for producing an anthracycline derivative according to the present invention includes the production of one known compound, 4-tetrahydropyranyl adriamycin, but it is a novel method for producing this compound. It is manufactured by.

The compound obtained in the above method is present as a mixture of stereoisomers a and b in the reaction mixture, and isomers a and b can be isolated and purified according to various known anthracycline glycoside purification methods. For example, the crude powder obtained by filtering off the solid material from the reaction mixture and drying the filtrate can be purified by column chromatography or thin layer chromatography using silica gel alumina or the like. The relationship in the structure of the a and b compounds is that the two compounds have different chemical changes in methine protons at different Chiral Centers, so the absolute configuration R of the Chiral Center of the 4'-0-substituted ether group and It is thought that there is a difference of S.

The compound according to the present invention has a remarkable anti-tumor action against tumors of various experimental animals, in particular, an anthracycline derivative represented by the following general formula (I) (where R 'is a hydrogen atom or a hydroxyl group) has a strong anticancer action. It is a compound with less toxicity (adverse reaction) than adriamycin and is useful as an anticancer agent. In addition, the anthracycline derivative of general formula (I) (wherein R ¹ is an alkanoyl oxy group having 2 to 7 carbon atoms such as acetyloxy, isobutyloxy or phenylacetyloxy group) is R ¹ in compound (I). It is preferably used as an intermediate of an anthracycline derivative having a hydroxyl group.

Among these derivatives according to the present invention, pharmaceutically useful compounds represented by general formula (I) are as follows.

TABLE 1

The pharmacological utility of the compounds according to the invention is as follows.

(1) Anti-tumor against various experimental animal tumors

L1210 leukemia cells of 1 × 10 ⁵ cells / mouse were transplanted intraperitoneally (ip) of CDF and mice, and the compound of the present invention was administered intraperitoneally for 10 days and then observed for 45 days after 24 hours.

Anti-tumor activity was expressed as the survival rate (T / C%) of survival days compared to the survival days of control mice treated with saline. Experimental results on the antitumor activity of the compounds having the numbers listed in Table 1 are shown in Table 2 below.

TABLE 2

Antitumor Activity of Derivatives of the Invention

Note: DAM-Daunomycin, ADM = Adriamycin

*: Toxicity

As a result of the reduction in weight and toxicity of the mice described in Tables 2 and 3, the derivatives according to the present invention had a toxicity of 1/2 to 1/3 compared to the raw materials of the present invention and the starting materials of adriamycin and daunomycin. It is thought to be reduced.

(2) Inhibitory effect on the proliferation and hexane biosynthesis of leukemia cultured cells (L1210)

Inoculating 5 × 10 ⁴ // ml of L1210 culture cells into RPM 1640 medium (Rosewell Park Memorial nstitute 1640) containing 20% calf serum and simultaneously adding 0.1-0.5 μg / ml of the compound of the present invention, 37 Cell numbers were periodically calculated by culturing in a carbon dioxide gas incubator at a temperature of ℃, and 50% growth inhibition concentration of the control was determined as shown in Table 8.

In addition, the 50% inhibitory concentration of the compound according to the present invention on hexane biosynthesis was tested as follows.

That is, the L1210 cells were suspended in an RPMI medium containing 10% calf serum to 1 × 10 ⁵ cells / ml, and pre-incubated for 1 to 2 hours in a carbon dioxide incubator at 37 ° C. Compound was added to the medium at various concentrations. After incubation for 15 minutes, C ¹⁴ -uridine (0.05μci / ml) or C ¹⁴ -thymidine (0.05μci / ml) was added and incubated at 37 ° C for 60 minutes. 10% trichloroacetic acid (TCA) was added to the medium to stop the reaction and at the same time an acid insoluble substance was precipitated and the precipitate was washed three times with 5-10% TCA, which can be dissolved in formic acid. Radioactive activity in acid-insoluble material was measured and expressed as 50% inhibitory concentration of the mixture. The results are shown in Table 3.

TABLE 3

Inhibitory Effects on Leukemia Cultured Cells (L1210) Proliferation and Hexane Biosynthesis

Note: DAM = daunomycin, APM = adriamycin

(3) inhibitory effect on the growth of various microorganisms

Compounds of formula (1) and non-toxic acid addition salts have significant bacterial growth inhibitory effects, for example Staph. aureus. The action of adriamycin on microorganisms such as Bacillus Subtilis, B. Cereus, B. Megaterium, Sarcina lutea, Micrococcus flavus Corynebacterium bovis, Pseudomonas aeruginosa, Escherichia Coli, Mycobacterium Smegmatis and Candia albicans.

Therapeutic uses

As described above, the compound of formula (I) and its nontoxic acid addition salts are novel antibiotics useful for both human and livestock drugs, and also have a distinct inhibitory effect on tumors of mammals containing solid and ascites. Indicates.

The present invention provides a method for the therapeutic treatment of a mammalian host infected with a bacterial infection (especially infection with Gram-positive bacterial pathogens) or a malignant tumor (ie, solid or plural tumors such as L1210 leukemia). This treatment may be achieved by administering to the host an effective antimicrobial or tumor-inhibitory amount of a compound of formula (I) or a nontoxic acid addition salt or mixture thereof.

According to another aspect of the present invention, a pharmaceutical composition is obtained, which composition is effective for the treatment of a compound of formula (I) or a compound thereof or its nontoxic acid addition salt, with an effective antibacterial or tumor-inhibiting amount and drug carrier or dilution. It is made by mixing. Such compositions may be prepared in any drug form suitable for parenteral administration.

Pharmaceuticals for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions, which can be prepared in the form of sterile solid compositions which can be dissolved immediately prior to use as sterile water, physiological saline or other sterile injections.

Actually preferred dosages will depend upon the particular composition formed with the particular compound employed, the method of application and the particular place, host and type of disease to be treated. In general, the compound is administered locally by subcutaneous injection in the human body, and is injected locally or by intravenous or subcutaneous injection for non-human mammals. Many factors that alter drug action are considered by those skilled in the art, including age, weight, sex, feeding, time of administration, route of administration, excreta, patient's condition, drug formulation, and response. Sensitivity and symptoms should be considered moderate. Dosages may be taken continuously or at regular intervals in amounts within the maximum acceptable dosage range. The optimum application rate in a particular case may be determined by those skilled in the art that perform routine usage determination tests in light of the above guidelines.

Prior to the description of the examples of the present invention, 14-14-acylated adriamycin used as starting material for the preparation of 14-0-acyl-4′-0-ethered adriamycin, Experimental Examples for the Preparation of 0-Acetyl-Adriamycin are described as follows, by which the other 14-0-acylated adriamycin used as starting material of the present invention can be prepared.

Experimental Example 1

(1) 14 bromodaunomycin-dimethyl ketal hydrochloride

230 mg (0.41 mmol) of daunomycin hydrochloride are dissolved in 10 ml of anhydrous methanol and 20 ml of dioxane is added. While stirring, 0.88 ml (0.55 mmol) of a clear 10% chloroform solution was added dropwise, followed by reacting for 2 to 3 hours at a temperature of 22 to 23 ° C. The reaction mixture is concentrated to about 5 ml under reduced pressure, and 15 ml of dry ether is added to odor the reddish precipitate. Washed three times with 3 ml of ether and dried to give 277 mg of 14-0-bromodaomycin-dimethylketal hydrochloride (yield 98%, m.p. 175-178 ° C.).

(2) 207 mg (0.3 mmol) of P-toluenesulfonic acid salt or hydrochloride 14-bromodaunomycin dimethyl ketal hydrochloride of 14-0-acetyl adriamycin are suspended in 100 ml of anhydrous acetone, dried and stirred by adding 0.4 g of sodium acetate. Heat and reflux for 1 hour while mixing. The reaction mixture is filtered to remove insoluble materials and the filtrate is condensed under reduced pressure. The residue is partitioned into a mixture containing 30 ml of chloroform and 20 ml of 0.05 mL hydrochloric acid. The acidic aqueous layer thus obtained is neutralized by adding sodium bicarbonate and then re-extracted with chloroform. The red chloroform layer was dried over anhydrous sodium sulfate, concentrated to 5 ml under reduced pressure, and 40 mg of P-toluenesulfonic acid or the corresponding amount of hydrochloric acid was added to produce an orange precipitate. The precipitate was filtered and washed with ether to give 160 mg of 14-0-acetyladriamycin P-toluenesulfonate (m.p. 165 to 168 ° C). In the case of hydrochloride, the same equivalent amount can be obtained.

The examples described below are provided for illustrative purposes only and should not be construed as limiting the scope of the invention. In this example, the ratio of solvent in the mixture is represented by the ratio of volume to volume, the ratio of liquid to liquid is V, V and the ratio of liquid to solid is expressed as W, V. To make it easier to read and find the properties of NMR, the composition of adriamycin along with the indication of the position of the carbon atom is shown below.

Example 1

155 mg of P-toluenesulfonate (or equivalent amount of hydrochloride) of 14-0-acetyl-4'-0-tetrahydropyranyl adriamycin a and b 14-0-acetyl adriamycin are dissolved in 2.0 ml of dry DMF. 2.0 ml of 3,4-dihydro-2-pyran is added, and a small amount of P-toluenesulfonic acid is added and it is left to stand at room temperature. When the reaction results were observed by silica gel thin layer chromatography (solvent-based chloroform-methanol = 7: 1 (volume ratio), the production of new material (Rf = 0.24 and 0.36) was observed with the consumption of the starting material (Rf = 0.04). 20 ml of chloroform and water are added to the reaction acid, and sodium hydrogen carbonate is added, and the aqueous layer is adjusted to pH 7-8, followed by extraction with chloroform The residue obtained by drying the chloroform solution and concentrated under reduced pressure is subjected to preparative silica gel plate. When separated and purified (solvent-based chloroform: methanol = 7: 1 (in phase), 14-0-acetyl-4'-tetrahydropyranyl adriamycin a and b are obtained as follows.

Compound a (Rf: 0.24) yield 24 mg

Molecular Weight: 669.68

Melting Point (℃): 185 ~ 195

Non-luminescence

(C = 0.2 chloroform): + 183 °

Ultraviolet Visible Absorption Spectrum (Methanol): 222S (335), 234 (515), 253 (360), 289 (130)

: 480(145), 496(145), 532(90), 576(20)λmaxnm

480 (145), 496 (145), 532 (90), 576 (20)

PMR (CDCl ₃ , ppm): 1.28 (6'-up), 1.50-1.85, (Pyran 3rd-5th), 2.21 (OAC), 4.05 (4'-OMe) 4.42 (Pyran, Anomatic), 5.18 ( 140), 5.26 (1'-up), 5.54 (7-up), 7.24-8.03, (1-up-3-up)

Compound b (Rf: 0.36) yield 34 mg

Molecular Weight: 669.68

Melting Point (℃): 180 ~ 190

Specific light intensity (C = 0.2 chloroform): +154.

Ultraviolet. Visible light absorption spectrum (ethanol): 222S (335), 234 (510), 253 (350), 289 (130)

480(140), 496(140), 532(85), 576(20)λmaxnm

480 (140), 496 (140), 532 (85), 576 (20)

PMR (CDCI ₃ , ppm): 1.37 (6'-up), 1.40-2.00 (pyran), 2.21 (OAC), 4.08 (4-OMe), 4.75 (pyran, anomeric), 5.18 (14-up), 5.25 (1'-up), 5.53 (7-up), 7.30-8.06 (1-up-3-up)

Example 2

Preparation of 14-0-isobutyl-4'-0-tetrahydropyranyl adriamycin a and b

104 mg (0.13 mmol) of P-toluenesulfonic acid salt of 14-0-isobutyl adriamycin are dissolved in 2.0 mg of dry methylformamide, 2.0 ml of dihydropyran and P-toluenesulfonic acid are added as a catalytic amount and left to stand at room temperature for 15 hours. Thin layer chromatography (solvent chloroform-methanol = 9: 1) shows products with Rf values of 0.38 and 0.45. The reaction solution is poured into 20 ml of water, neutralized by addition of sodium bicarbonate and extracted with 30 ml of chloroform. The chloroform layer is dried over anhydrous sodium sulfate, and then the residue obtained by concentration under reduced pressure is developed and separated on thin layer chromatography. 22.5 mg of red powder a was obtained from a fraction of Rf value 0.38.

Yield 24%, Melting Point (℃): 155 ~ 161

PMR (CDCl ₃ , ppm): 1.24 (up-6 '), 1.29 (isobutyl), 4.06 (4'-OMe), 4.40 (pyran, anomeric), 5.10 (up-14), 5.25 (1'- Above), 5.51 (7th place), 7.30-8.07 (1st place-3-place)

Then, a red powder of Compound b 22.7 mg was obtained from a fraction of Rf 0.45.

Yield 24%, Melting Point (℃): 169 ~ 174

PMR (CDCl ₃ , ppm): 1.25 (isobutyl), 1.37 (6'-up), 1.40-2.00 (THP), 4.08 (4-OMe), 4.75 (pyran, anomeric), 5.22 (14-up) , 5.25 (1'-up), 5.55 (67-up), 7.29-8.10 (1-up-3-up)

Example 3

Preparation of 14-0-phenylacetyl-4'-0-tetrahydropyranyl adriamycin a and b

80 mg (0.096 mmol) of P-toluenesulfonic acid salt of 14-0-phenylacetyl adriamycin are dissolved in 2.5 mg of dry dimethylformamide, and 0.5 ml of dihydropyran and a small amount of P-toluenesulfonic acid are added and left at room temperature. Observation of the reaction solution by thin layer chromatography using solvent-based chloroform-methanol (9: 1) showed the formation of a new material having Rf values of 0.93 and 0.48, and the starting material disappeared after 4 hours. The reaction solution is poured into 20 ml of an aqueous 1% sodium carbonate solution and extracted with 30 ml and 10 ml of chloroform. The combined chloroform layers were washed with water four times, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue obtained by silica gel plate (2 mm thickness 20 cm x 20 cm) and a solvent-based chloroform-methanol = 9: 1 were extracted. Developed by layer chromatography. A fraction of the Rf value of 0.39 was scraped off like a silica gel powder, and extracted with a mixture of chloroform-methanol (1: 1) to obtain 27.0 mg of a red powder a.

Yield 37%, Melting Point (℃): 156 ~ 163

, 4.02(4-OMe), 4.34(피란, 아노메릭), 5.21(위-14), 5.25(1'-위), 5.50(7-위), 7.30-8.02(1-위-3-위)PMR (CDCℓ ₃ , ppm): 1.25 (up-6 '), 1.40-2.00 (tetrahydropyran), 3.80 and 7.36

, 4.02 (4-OMe), 4.34 (Pyran, Anomeric), 5.21 (Up-14), 5.25 (1'-Up), 5.50 (7-Up), 7.30-8.02 (1-Up-3-Up)

According to the compound a method, 20.2 mg of a red powder of a compound was obtained in a fraction of Rf 0.48.

Yield 28%, Melting Point (℃): 159 ~ 165

4.05(4-OMe), 4.73(피란, 아노메릭), 5.25(14-위, 1'-위), 5.50(7-위), 7.30-8.06(1-위-3-위)PMR (CDCℓ ₃ , ppm): 1.37 (6'-up), 1.45-2.00 (Pyran), 3.80 and 7.32

4.05 (4-OMe), 4.73 (Pyran, Anomeric), 5.25 (14-up, 1'-up), 5.50 (7-up), 7.30-8.06 (1-up-3-up)

Example 4

Preparation of 4-0- (tetrahydrofuranyl) daunomycin

56 mg (0.1 mmol) of daunomycin hydrochloride are dissolved in 2.0 ml of dry dimethylformamide, 0.1 ml of dihydrofuran and P-toluenesulfonic acid as a catalyst are added and left at room temperature for 8 hours (4'-0- (tetrahydrofura). Nilation).

The reaction solution is poured into 20 ml of water, neutralized by addition of sodium bicarbonate, and extracted 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 (solvent chloroform-methanol = 9: 1), the targets of the fractions showing Rf values 0.29 and 0.31 were separated, but not completely separated. The fractions were scraped off and eluted with a mixture of chloroform-methanol (1: 1) to give 12.4 mg of 4'-0- (tetrahydrofuranyl) daunomycin in red powder.

Yield 21%

Melting Point (℃): 201 ~ 204 (Decomposition)

PMR (CDCI ₃ , ppm): 1.29 (6'-up '), 1.70-2.30 (furan 3,4-up), 2.44 (14-up), 4.11 (4-up), 5.28 (1'-up) , 5.43 (Furan, Anomeric), 5.54 (7th place), 7.33-8.11 (1st-3rd place)

Example 5

Preparation of 4'-0- (6-acetoxymethyltetrahydropyranyl) daunomycin 112 mg (0.2 mmol) of daunmycin hydrochloride were dissolved in 2.0 ml of dry dimethylformamide, and 15 mg of P-toluenesulfonic acid and 2- 3,3 ml of acetoxymethyl-3,4-dihydro-2H-pyran are added and allowed to stand overnight at room temperature. (4'-0- (6-acetoxymethyltetrahydropyranylation). The reaction solution is poured into 20 ml of 1% sodium hydrogen carbonate, 30 ml of chloroform is added and extracted. The aqueous layer is extracted twice with 10 ml of chloroform and the preceding chloroform layer. Wash the chloroform four times with 10 ml of water four times, dehydrate with anhydrous sodium sulfate, and then concentrate under reduced pressure to obtain a crude reaction product by preparative thin layer chromatography using silica gel and solvent-based chloroform-methanol (1). 2 mm thick 20 × 20 cm, 1 sheet), and the fraction having an Rf value of 0.47 is scraped together with the silica gel powder, and the red solution obtained by extracting with a mixture of chloroformmethanol (1: 1) is concentrated to dryness 55.3 mg was obtained.

Yield 40%

Melting Point (℃): 198 ~ 201

(CDCI ₃ , ppm): 1.21-1.42 (6'-up), 2.07-2.11 (OAC), 2.43 (14-up), 4.10 (4-OMe), 5.53 (7-up), 7.29-8.06 (1 -3-3)

Example 6

Preparation of 4'-0- (6-methoxytetrahydropyranyl) daunomycin a and b

112 mg (0.2 mmol) of daunomycin hydrochloride were dissolved in 3.0 ml of dry dimethylformamide, 0,15 ml of 2-methoxy-3,4-dihydro-2H-pyran and 10 ml of P-toluenesulfonic acid were added and left at room temperature overnight. do. (4'-0- (6-methoxytetrahydropyranylation). The reaction solution is poured into 20 ml of water, added with sodium bicarbonate to pH 8 and extracted four times with 10 ml of chloroform. The chloroform layers are combined, The red residue obtained by drying with anhydrous sodium sulfate and then concentrated to dryness is separated and separated by preparative thin layer chromatography using silica gel (2 mm thick, 20 × 20 cm) manufactured by Merck Co., Ltd. and solvent-based chloroform-methanol (9: 1). The fractions were scraped off with silica gel powder and reextracted with a mixture of chloroform-methanol (1: 1) When the resulting red solution was concentrated under reduced pressure, 23.1 mg of a red powder a substance was obtained.

Yield 18%

Melting Point (℃): 189 ~ 191

PMR (CDCl ₃ , ppm): 1.29 (6'-up), 2.40 (3-up), 3.46 (5'-OMe), 4.09 (4-OMe), 4.83 (1-top) 5.30 (1'-up) ), 5.58 (7th place), 7.28-8.08 (1st place-3-place)

According to the same method as the compound a, 19.4 mg of the compound b in red powder was obtained.

Yield 15%

Melting Point (℃): 198 ~ 199

PMR (CDCℓ ₃ , ppm): 1.39 (6'-up), 2.44 (14-up), 3.46 (pyran-OMe), 4.11 (4-top), 4.89 (pyran, anomeric), 5.22 (1'- Above), 5.53 (7th place), 7.28-8.14 (1st place-3-place)

Example 7

Preparation of 4'-0- (6-carbomethoxytetrahydropyranyl) daunomycin

112 mg (0.2 mmol) of daunomycin hydrochloride was dissolved in 3.0 ml of dry dimethylformamide, 0,1 ml of 2-carbomethoxy-3,4-dihydro-2H-pyran and 34 mg (0.2 mmol) of P-toluenesulfonic acid. Was added and left at room temperature for 10 hours in a dark place (4'-0- (6-carbomethoxytetrahydrofinylation). The reaction solution was poured into 20 ml of water, added with sodium bicarbonate to pH 8, and diluted to 10 ml of chloroform. Extraction was performed four times, the chloroform layers were combined, washed twice, and then dried over anhydrous sodium sulfate, and the residue obtained by concentrating the chloroform solution under reduced pressure was subjected to preparative thin layer chromatography using a silica gel plate manufactured by Merck (solvent-based chloroform). -Methanol = 9: 1) Separation was carried out with a mixture of four components with an Rf value of 0.35 0.37, whereby the formation of new materials was observed, which were not completely separated off. The solution obtained by extraction with a mixture of form-methanol (1: 1) was concentrated to dryness to give 25.9 mg of a red powder.

Yield 19%

Melting Point (℃): 190 ~ 193

PMR (CDCℓ ₃ , ppm): 1.23-1.40 (6'-up), 2.43 (14-up), 3.78 (COOCH3), 4.09 (4-OMe), 4.74, 5.07 (pyran, anomeric), 5.31 (1 '-Up), 5.54 (7-up), 7.30-8.06 (1-up-3-up)

Example 8

Preparation of 4'-0- (1-ethyloxyethyl) daunomycin a and b

112 mg (0.2 mmol) of daunomycin hydrochloride are dissolved in a mixture of 0.1 ml of dry dimethylformamide 3 ml of ethyl vinyl ether and P-toluenesulfonic acid, and left to stand at room temperature for 10 hours (1-ethyloxyethylation). In the silica gel thin layer chromatography (solvent-based chloroform-methanol = 9: 1), spots of new products having Rf values of 0.31 to 0.34 can be seen. Extract the reaction mixture with 20 ml of chloroform. The extract is dried and the red residue obtained by concentration under reduced pressure is purified by preparative thin layer chromatography using a solvent of silica gel (manufactured by Merck, 2 mm thick, 20 × 20 cm) and chloroform-methanol (15: 1). The target substance was scraped off at an Rf value of 0.31, chloroform-methanol was extracted with the mixture (1: 1), and the red extract was dried and concentrated to give 33.0 mg of red compound a.

Yield 27%

Melting Point (℃): 208 ~ 210

PMR (CDCℓ ₃ , ppm): 1.76, 3.59 (1'-CEt), 1.39 (2'-up), 1.79 (8-up), 2.41 (14-up), 4.07 (4-OMe), 4.64 (1 -Up), 5.25 (1'-up), 5.51 (7-up), 7.25-8.07 (1-up-3-up)

According to the same method as described above, the corresponding substance was also treated with Rf 0.34, and 31.8 mg of the compound in red powder was obtained.

Yield 26%

Melting Point (℃): 200 to 214

PMR (CDCℓ ₃ , ppm): 1.20, 3.64 (1'-OEt), 1.40 (2'-top), 2.41 (14-top), 4.09 (4-top), 4.94 (1-top), 5.26 (1 '-Up), 5.50 (7-up), 7.26-8.07 (1-up-3-up)

Example 9

4'-0- (1-isobutyloxyethyl) daunomycin a and b

60 mg (0.106 mmol) of daunomycin hydrochloride are dissolved in a mixture of 12 ml of anhydrous THP and 1.5 ml of anhydrous DMSO and 1.2 ml of 2-isobutylvinylether and 0.21 ml of 0.1 P-toluenesulfonic acid-THF solution Add and stir for 3 hours at room temperature containing 0.1 N sodium hydrogen carbonate. The reaction mixture is washed with 100 ml of 5% sodium chloride solution and then again with 5% sodium chloride solution (100 ml × 2). The oily substance obtained by drying the solvent layer with anhydrous sodium sulfate and concentrating under reduced pressure was treated by the same method as described in Example 8, to obtain 4'-0- (1-isobutyloxyethyl) daunomycin a 16.0 mg and b. 19.1 mg were obtained.

Compound a

Melting Point (℃): 143 ~ 148

Non-luminescence

(C = 0.1 chloroform): + 190 °

PMR (CDCℓ ₃ , ppm):

Compound b

Melting Point (℃): 141 ~ 146

Non-luminescence

(C = 0.1 chloroform): + 135 °

Example 10

Preparation of 4'-0- (1-butyloxyethyl) daunomycin a and b

100 mg (10.177 rimol) of daunomycin hydrochloride are dissolved in a mixture of 10 ml of anhydrous THF and 2 ml of anhydrous DMSO, and 3 ml of n-butylvinylether and 0.88 ml (0.88 mmol) of 0.1 P-toluenesulfonic acid-THF solution Add and stir for 2 hours at room temperature. Treatment in the same manner as described in Example 9 gave 27.1 mg and 34.8 mg of 4'-0- (1-butyloxymethyl) daunomycin a, respectively.

Compound a

Melting Point (℃): 141 ~ 145

Non-luminescence

(C = 0.1 chloroform): + 167 °

PMR (CDCI ₃ , ppm)

Compound b

Melting Point (℃): 138 ~ 142

Non-luminescence

(C = 0.1 chloroform): + 207 °

PMR (CDCl ₃ , ppm)

Claims (1)

The anthracycline derivative represented by the following general formula (II) or an acid addition salt thereof is reacted with a compound represented by the following general formula (IV) for 20 minutes to 50 hours at room temperature in the presence of an acidic catalyst in an inert solvent. An anthracycline derivative represented by I) or the manufacturing method of acid addition salt thereof.

Wherein R 'represents an alkanoyl oxy group or a phenylacetyloxy group having 2 to 7 hydrogen atoms or carbon atoms. HR ² Wherein R ² represents alkyloxyethyl having 3 to 10 carbon atoms, tetrahydrofuran-2-yl, tetrahydropyran-2-yl, 6-methoxy tetrahydropyran-2-yl, 6-carbomethoxytetra Hydropyran-2-yl group or 6-acetoxymethyltetrahydropyran-2-yl group.

In formula, R <^1> , R <^2> has the same meaning as the above. Provided that R ¹ is a hydrogen atom and R ² is a tetrahydropyran-2-yl group.