ANTHRACYCLINE DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abstract: Anthracycline derivatives of adriamycin and daumonycin of formula: wherein R¹ is a hydrogen atom, a hydroxyl group, an alkanoyloxy group having a carbon number of 2 to 7 or a phenylacetyl group, and R² ia an alkyloxyethyl, a tetrahydrofuranyl, a tetrahyd­ ropyranyl, a 6-methoxytetrahydropyranyl, a 6-­ carbomethoxytetrahydropyranyl or a 6-­ acetoxymethyltetrahydropyranyl group, excluding the case where R¹ is a hydrogen atom or a hydroxyl group and simul­ taneously R² is a tetrahydropyranyl group, are prepared by the reaction of I (R₂ = H) with R₂OH or a derivative; they are useful as antitumor agents.

Description: New anthracycline derivatives and a process for the preparation thereof Detailed Explanation of the Invention This invention relates to new derivatives of anthracycline having the general formula I: EMI1.1 wherein RÚ is a hydrogen atom, a hydroxyl group, an alkanoyloxy group having a carbon number of 2 to 7 or a phenylacetyloxy group, and R2 is an alkyloxyethyl, a tetrahydrofuranyl, a tetrahydropyranyl, a 6-methoxytetrahydropyranyl, a 6-carbomethoxytetrahydropyranyl or a 6-acetoxymethyltetrahydropyranyl group, excluding the case where R1 is a hydrogen atom or a hydroxy1 group and simultaneously is 18 a tetrahydropyranyl group, or acid addition salts tl3ereof, and to a process for producing and recovering the compound having the formula I and a pharmaceutical composition containing thereof. More particularly, this invention relates to new derivatives of anthracycline having the formula I which include two types of derivatives, 14-0-acylated-4'etherified derivative and 4'-etherified anthracycline derivative. The process for producing the compound according to the present invention which is basically the etherification at the C-4' hydroxyl group of the anthracycline derivative, can be performed by two types of processes according to the difference of the initial material. One comprises etherification with alkyl vinyl ether having a carbon number of 3 to 10, dihydrofuran, dihydropyran or their derivatives at the C-4' hydroxyl group position of formula II-a: EMI2.1 wherein R3 is an alkanoyloxy group such as acetyloxy or isobutyloyloxy, or phenylacetyloxy group, or if necessary, subsequent deacylation at the C-14 position, and the other comprises the same etherification at the C-4' hydroxyl group position of daunomycin having the general formula IV: EMI3.1 Daunomycin (U.K. Patent 1,003,383, U.S. Patent 3,616, 242) and adriamycin (U.S. Patent 3,590,028, U.S. Patent 3,803,124), which are obtained from Streptomyces cultures, have a broad antitumor spectrum against various experimental tumors, and have been used clinically as potent cancer chemotherapeutic agents. However, it is known that they have severe side efiects such as alopecia, leukopenia, cardiotoxicity etc.. The present inventors have extensively studied the chemical modification of daunomycin and adriamycin to prepare more useful derivatives having more active anticancer activity and low toxicity ( side effects ) than parent compounds, and found that the derivatives of are daunomycin and adriamycin which substituted their reactive hydroxyl group at the C-4' position with alkyloxyethyl, tetrahydropyranyl, tetrahydrofuranyl or 6-substituted tetrahydropyranyl group have strong anticancer activity as well as low toxicity. Among the derivative of the present invention, 14-0-acyl-derivatives of adriamycin are also useful as intermediates to preferably obtain the derivatives of the present invention and are included in the derivatives of formula I according to the invention. Among new derivatives in the present invention having the general formula I, pharmaceutically useful representative derivatives are as follows. Specifically, as examples of the new 14-0-acylated derivative of adriamycin, the following are mentioned. 14-0-acetyl-4 -0-tetrahydropyranyl adriamycin a and b 14-O-isobutyloyl-4'-O-tetrahydropyranyl adriamycin a and b 14-O-phenylacetyl-4'-O-tetrahydropyranyl adriamycin a and b 14-0-phenylacetyl-4'-0-(6-methoxytetrahydropyranyl) adriamycin a and b 14-0-phenylacetyl-4'-0-(6-carbomethoxytetrahydro pyranyl) adriamycin a and b 14-0-isobutyloyl-4'-0-(6-acetoxytetrahydropyranyl) adriamycin a and b 14-0-acetyl-4'-tetrahydrofuranyl adrianiycin a and b 14-0-isobutyloyl-4 '-0-tetrahydrofuranyl adriamycin a and b 14-O-phenylacetyl-4'-O-tetrahydropyranyl adriamycin a and b 14-O-phenylacetyl-4'-O-(1-ethyloxyethyl) adriamycin a and b 14-0-acetyl-4'-0-(1-butyloxyethyl) adriamycin a and b 14-O-acetyl-4'-O-(1-isobutyloxyethyl) adriamycin a and b 14-O-isobutyloyl-4'-O-(1-isobutyloxyethyl) adriamycin a and b 14-O-phenylacetyl-4'-O-(1-isobutyloxyethyl) adriamycin a and b 14-0-acetyl-4'-0-(1-(6-methylheptyloxy)ethyl) adriamycin a and b 14-0-acetyl-4'-O-cyclohexyloxyethyl adriamycin a and b Secondly, as examples of the new 4'-O-pyranylated, -furanylated and -alkoxyethylated derivatives of adriamycin the following are mentioned. 4'-0-tetrahydrofuranyl adriamycin 4'-O-tetrahydrofuranyl adriamycin a and b 4'-0-(1-ethyloxyethyl) adriamycin a and b 4'-O-(l-butyloxyethy1) adriamycin a and b 4'-O-(1-isobutyloxyethyl) adriamycin a and b 4'-O-(l-(6-methylheptyloxy)ethyl) adriamycin a and b 4'-0-cyclohexyloxyethyl adriamycin a and b 4'-O-(6-methoxytetrahydropyranyl) adriamycin a and b 4'-O-(6-carbomethoxytetrahydropyranyl) adriamycin a and b 4'-O-(6-acetoxytetrahydropyranyl) adriamycin a and b As examples of the new derivative of daunomycin, the following are set forth. 4'-O-tetrahydrofuranyl daunomycin a and b 4'-O-(1-ethyloxyethyl) daunomycin a and b 4'-O-(1-butyloxyethyl) daunomycin a and b 4'-O-(l-isobutyloxyethyl) daunomycin a and b 4'-0-(l-(6-methylheptyloxy)ethyl) daunomycin a and b 4'-O-cyclohexyloxyethyl daunomycin a and b 4'-O-(6-methoxytetrahydropyranyl) daunomycin a and b 4 '-O-(6-carbomethoxytetrahydropyranyl) daunomycin a and b 4 '-O-(6-acetoxytetrahydropyranyl) daunomycin a and b The process for producing new anthracycline derivatives of formula I in the present invetion can be divided into two types as described in the following explanation. The first type of process for producing the C-4' etherified derivative of the 14-0-acyl anthracycline derivatives of general formula I or acid addition salts thereof, comprises 1-ethvloxvethvl - introducing an alkyloxyethyl su > EMI8.1 (1-methoyxyethyl,) 1-butyloxyethyl, 1-isobutyloxyethyl, 1-(6-methlyheptyloxy) ethyl or cyclohexyloxyethyl, tetrahydrofuranyl, tetrahydropyranyl, 6-methoxytetrahydropyranyl, 6carbomethoxytetrahydropyranyl or a 6-acetoxymethyltetrahydropyranyl group into the hydroxyl group at the C-4' position of an anthracycline derivative of the aforementioned (page 2) formula II-a, or an acid addition salt thereof by reaction with a dihydrofuran, a derivative thereof, dihydropyran, a derivative thereof or an alkyl vinyl ether which contains said corresponding group to be introduced; and is capable of reacting with a hydroxyl groupSin an inert organic solvent and in the presence of acid catalyst to produce a C-4' etherified derivative of the general formula II: EMI9.1 wherein R3 is an alkanoyloxy group having a carbon number of 2 to 7 or a phenylacetyloxy group, and R2 is an alkyloxyethyl, a tetrahydrofuranyl, a tetrahydropyranyl, a 6-methoxytetrahydropyranyl, a 6-carbomethoxytetrahydropyranyl or a 6-acetoxy methyltetrahydropyranyl group or an acid addition salt thereof; and optionally further comprises eliminating the alkanoyl group or the phenylacetyl group at the C-14 position of said derivative of general formula II by hydrolytic deacylation to produce an anthracycline derivative of the general formula III: EMI10.1 wherein R2 has the same definition as mentioned above or an acid addition salt thereof. In the present invention, the compounds (the same compounds as formula II-a) derived from daunomycin by the method as described in Compt. Rend. Acad. de Science t.286, Serie D-443, 1978 and having the general formula VI: EMI11.1 wherein R4 is an alkyl group having a carbon number of 1 to 6 or a benzyl group are used as an initial material. The 14-0-acyl derivatives and 14-0-phenylacetyl derivatives cqrrespond to the compound obtained by acylation of a hydroxyl group at the C-14 position of adriamycin with alkanoic acid or phenylacetic acid having the formula R4COOH. New derivatives having the general formula VII (the same compounds as formula II): : EMI12.1 wherein R4 is the same group as mentioned above, and R2 is a tetrahydropyranyl, a 6-methoxytetrahydro pyranyl, a 6-carbomethoxytetrahydropyranyl, a 6-acetoxytetrahydropyranyl, a tetrahydrofuranyl or l-methoxyethyl,} an alkyloxyethyl such as 1-ethyloxyethyl, 1-butyl oxyethyl, 1-isobutyloxyethyl, l-(6-methylheptyloxy) ethyl or cyclohexyloxyethyl group can be obtained by introducing the corresponding group into the hydroxyl group at the C-4' position of the compound VI by reaction with dihydrofuran or dihydropyran or its derivatives or alkyl vinyl ether derivatives having, a carbon number of 3 to 10 which contains corresponding reactive group. In this case, when the free base of the compound VI or its acid addition salts such as hydrochloride are suspended or dissolved in hereinafter mentioned organic solvents and reacted with dihydropyran, dihydropyran derivatives, dihydrofuran derivatives or C3 - C10 alkyl vinyl ether derivatives in the presence of an acid catalyst, the reactive hydroxyl group at the C-4' position of the compound VI can be substituted with tetrahydrofuranyl, tetrahydropyranyl, 6-substituted tetrahydro l-methoxyethyl, pyranyl, alkyloxyethyl group such as 1- e thoxyethyl, 1-butyloxyethyl, l-isobutyloxyethyl, 1-(6-methylhepty- loxy) ethyl or cyclohexyloxyethyl group. Dihydropyran derivatives such as 2-acetoxyethyl3,4-dihydro-2H-pyran, 2-methoxy-3,4-dihydro-2H-pyran, 2-carbomethoxy-3 , 4-dihydro-2H-pyran can be preferably used in the present invention. Dihydrofuran itself methyl vinyl ether and vinyl ether derivatives such as ethyl vinyl ether, butyl vinyl ether, isobutyl vinyl ether, 6-methylheptyl vinyl ether or cyclohexyl vinyl ether can be preferably used. Anhydrous organic solvents such as benzene, toluene dimethylformamide (hereinafter abbreviated as DMF), tetrahydrofuran (hereinafter abbreviated as THF), dimethylsulfoxide (hereinafter abbreviated as DMSO), dioxane and acetonitrile etc. can be preferably used for the reaction as a single agent or their mixture thereof. As the acid catalyst, organic sulfonic acids can be used, especially aromatic sulfonic acids such as p toluenesulforjic acid, benzene sulfonic acid are preferred. As a preferable example, reaction was carried out with anhydrous DMF as a solvent and p-toluene sulfonic acid as an acid catalyst for 20 min. to 50 hours at room temperature. Alternatively, using such a solvent mixture as that of anhydrous DM50 and anhydrous THF, or anhydrous DMSO and anhydrous dioxane and p-toluenesulfonic acid as the acid catalyst, the reaction can be carried out for 20 min. to 50 hours at room temperature. To eliminate the acyl group or phenylacyl group at the C-14 position of the compound having the general formula VII (same as formula II), the known method of hydrolysis can be sued to obtain the compound having the general formula III. Hydrolysis to remove the R4CO-group at the C-14 position of the compound VII can be achieved by dissolving or suspending the compound VII in water-miscible organic solvent, for example, lower alcohols such as methanol, ethanol etc. and aqueous acetone and reacting at room temperature or under slightly warmer conditions in the presence of alkali, preferably potassium carbonate, at the proper concentration, for example, about 1O(W/V). The completion of hydrolysis can be confirmed by thin-layer chromatography. iexL, the second type in the present invention rate to < process for producing an anthracycline glycoside having the general formula V: EMI15.1 wherein R2 is a tetrahydrofuranyl, a 6-methoxytetrahydro pyranyl, a 6-carboxymethyltetrahydropyranyl, a 6-acetoxytetrahydropyranyl group, or an alkyloxy ethyl group such as l-ethyloxyethyl, l-butyloxy ethyl, l-isobutyloxyethyl, 1-(6-methylheptyloxy) ethyl or a cyclohexyloxy group or acid addition salts thereof which comprises introducing a tetrahydrofuranyl, a 6-methoxytetrahydropyranyl, a 6-carbomethoxytetrahydropyranyl, a 6-aceotxy methyltetrahydropyranyl group or an alkyloxyethyl such as 1-methoxyethyl, 1-ethyloxyethyl, 1-butyloxyethyl, 1-isobutyloxyethyl, 1-(6-methylheptyloxy) ethyl or: : a cyclohexyloxyethyl group by reaction with dihydropyran derivatives, such as 2-acetoxyethyl-3,4-dihydro-2H-pyran, 2-methoxy3,4-dihydro-2H-pyran, 2-carbomethoxy-3,4-dihydro-2Hpyran, dihydrofuran derivatives or alkyl vinyl ether methyl vinyl ether # having a carbon number of 3 to 10, such as ethyl vinyl ether, butyl vinyl ether, isobutyl vinyl ether, 6-methylheptyl vinyl ether or cyclohexyl vinyl ether capable of reacting with a hydroxyl group, to the hydroxyl group at C-4' position of daunomycin having the general formula IV: EMI16.1 or acid addition salts thereof. In the process, as an initial material the free base of fox ulna IV (daunomycin) or its acid addition salts such as hydrochloride are dissolved or suspended in an organic solvent and reacted with proper dihydropyran derivatives (excluding dihydropyran itself), dihydrofuran derivatives or alkyl vinyl ethers having a carbon number of 3 to 10, in the presence of an acid catalyst according to the same method as mentioned previously. Thus, the reactive hydroxyl group at the C-4' position of the initial material is substituted with a 6-substituted tetrahydropyranyl, a tetrahydrofuranyl, an alkyloxyethyl group, to obtain the above mentioned derivatives of the general formula V. In this case, organic solvents such as benzene, toluene, dimethylformamide (DMF), tetrahydrofuran (THF), dioxane or acetonitrile etc. can be used for the reaction solvent as a single agent or their mixture. Organic sulfonic acids can be used for the acid catalyst, especially aromatic sulfonic acids such as p-toluenesulfonic acid, benzene sulfonic acid are preferred. As a preferred example, reaction was carried out with anhydrous DMF as a solvent, p-toluene sulfonic acid as an acid catalyst for 20 min. to 50 hours at room temperature. Alternatively, such a mixture as that of anhydrous DSO and anhydrous THF or anhydrous DMSO and anhydrous dioxane can be preferably used for carrying out the reaction at room temperature for 20 min. - 3 hours as mentioned above. Although the process of the present invention is mentioned separately in the divided form of first and second types for better understanding, they can be unified as follows: A process for producing an anthracycline derivative of the general formula I': (combining II and III with V) EMI18.1 wherein R1 is a hydrogen atom, a hydroxyl group, an alkanoyloxy group having a carbon number of 2 to 7 or a phenylacetyloxy group, and R2 is an alkyloxyethyl, a tetrahydrofuranyl, a tetrahydropyranyl, a 6-methoxytetrahydropyranyl, a 6-carbomethoxytetrahydropyranyl or a 6-acetoxy methyltetrahydropyranyl group, excluding the case where R1 is a hydrogen atom and simultaneously R2 is a tetrahydropyranyl group or an acid addition salt thereof which comprises introducing an alkyloxyethyl, a tetrahydrofuranyl, a tetrahydropyranyl, a 6-methoxytetrahydropyranyl, a 6-carbomethoxytetrahydropyranyl or a 6-acetoxymethyltetrahydropyranyl group into the hydroxyl group at the C-4' position of an anthracycline derivative of the formula VIII: (combining formula II-a with IV) EMI20.1 wherein R is a hydrogen atom or an alkanoyloxy group having a carbon number of 2 to 7 or a phenylacetyloxy group or an acid addition salt thereof by reaction with a dihydrofuran, a derivative thereof, dihydropyran, a derivative thereof or a derivative of alkyl vinyl ether which contains said corresponding group to be introduced and is capable of reacting with a hydroxyl group, in an inert organic solvent and in the presence of an acid catalyst to produce the anthracycline derivative of the general formula IX: (combining formula II with V) EMI21.1 wherein R3 is a hydrogen atom or an alkanoyloxy group having a carbon number of 2 to 7 or a phenylacetyloxy group, and R2 is an alkyloxyethyl, a tetrahydrofuranyl, a tetra hydropyranyl, a 6-methoxytetrahydropyranyl, a 6-carbo methoxytetrahydropyranyl or a 6-acetoxymethyltetra hydropyranyl group, excluding the case where R3 2 is a hydrogen atom and simultaneously R is a te trahydropyranyl group or an acid addition salt thereof and optionally further comprises eliminating the alkanoyl group or the phenylacetyl group at the C-14 position of said derivative of the general formula IX by hydrolytic deacylation to produce an anthracycline derivative of the general formula III: : EMI22.1 wherein R2 has the same definition as that mentioned in the formula IX or an acid addition salt thereof. As shown in the above, the process for preparing an anthracycline derivative according to the present invention includes the preparation of one known compound, 4-tetrahydropyranyl adriamycin, which, however, is prepared by a new process which constitutes that the process for preparing thereof is a novel invention. The compounds obtained above exist as a mixture of diastereomer a and b in the reaction mixture. If necessary, the diastereomer a and b can be separated from each other by known methods, and purified from the reaction mixture by conventional methods used for the purification of various anthracycline glycosides. As an example, after'filtering the reaction mixture to remove solid materials, the filtrate can be concentrated to dryness and then the resulting crude powder can be purified by column or thin-layer chromatography using alumina, silica gel etc.. The relationship between the structure of the compounds a and b is considered to be the difference in absolute configuration R and S of the chiral center of the 4' -0-substituted ether groups since both compounds respectively have different chemical shifts of the methine proton of the chiral center. The compounds in the present invention possess marked anti tumor activity against various experimental animal tumors, particularly anthracycline derivatives having the general formula I, wherein R1 is a hydrogen atom or a hydroxyl group, possess potent anti tumor activity and less toxicity than adriamycin, and can be advantageously used as antitumor agents. Furthermore, the anthracycline derivatives having the general formula I, wherein R1 is such an alkanoyloxy group having a carbon number of 2 to 7 as an acetyloxy, isobutyloxy or phenylacetyloxy group, can be preferably used as an intermediate of the anthracycline derivatives having the hydroxyl group at R1 in the compound I. Among these derivatives in the present invention, pharmaceutically useful compounds having the general formula I are as follows. EMI24.1 Table 1 EMI25.1 <tb> <SEP> Compounds <SEP> No. <SEP> ·' <SEP> 2 <tb> 14-0-acetyl-4'-0- <SEP> 0 <tb> tetrahydropyranyl- <SEP> I-a <SEP> ¯ <SEP> II <tb> ADM <SEP> (a) <SEP> 3 <tb> <SEP> " <SEP> (b) <SEP> 1-b <SEP> .. <SEP> " <SEP> II <tb> '4'-0-(tetrahydro <tb> furanyl)-ADM <SEP> 2 <SEP> -OH <tb> 4'-O-(tetrahydro <tb> furanyl)-ADM <SEP> (a) <SEP> 2-a <SEP> ., <tb> <SEP> " <SEP> (b) <SEP> 2-b <SEP> .. <SEP> II <tb> 4'-O-(6acetoxy- <SEP> 0 <tb> methyltetrahydro- <SEP> 3 <SEP> il <SEP> CH2-O-C-CH <tb> 3 <tb> pyranyl)-ADM <SEP> < <tb> 4'-O-(1-ethoxy- <SEP> 4-a <SEP> II <SEP> -CH-O-CH2CR <tb> <SEP> 4-a <SEP> ., <SEP> -CH-O-CH2CH <tb> ethyl)-ADM <SEP> (a) <SEP> I <SEP> 3 <tb> <SEP> CH3 <tb> EMI26.1 <tb> 4'-O-(l-ethoxy- <SEP> 4-b <SEP> -OH <SEP> -CH-O-CH2C}I <tb> ethyl)-ADM <SEP> (b) <SEP> 23 <tb> <SEP> CH3 <tb> 4'-0-(1-butyloxy- <SEP> 5-a <SEP> " <SEP> -CH-O-CH(CH)CH <tb> ethyl)-ADM <SEP> (a) <SEP> 1 <SEP> r <SEP> CH3 <tb> <SEP> CH3 <tb> <SEP> " <SEP> (b) <SEP> 5-b <SEP> ,I <SEP> ,. <tb> 4' <SEP> -O-(1-lso- <SEP> CH <tb> butyloxyethyl)- <SEP> 6-a <SEP> " <SEP> -CH-O-CH <SEP> C <SEP> H3 <tb> <SEP> I <SEP> 2CH <tb> ADM <SEP> (a) <SEP> CM3 <SEP> 3 <tb> <SEP> " <SEP> (b) <SEP> 6-b <SEP> ., <SEP> II <tb> 4'-0-(1-(6-methyl- <SEP> CR <tb> heptyloxyjethyl)- <SEP> 7-a <SEP> ,. <SEP> -CH-o-CH2(CH2)4cHA <tb> ADM <SEP> (a) <SEP> CH3 <SEP> 3 <tb> <SEP> CH3 <tb> <SEP> (b) <SEP> 7-b <SEP> ., <SEP> ,I <tb> 4'-O-(l-cyclo <tb> hexyloxyethyl)- <SEP> 8-a <SEP> .. <SEP> -CH-O <tb> ADM <SEP> (a) <SEP> CH3 <tb> <SEP> " <SEP> (b) <SEP> 8-b <SEP> II <SEP> 'I <tb> EMI27.1 <tb> 4'-O-(tetra- <SEP> 0 <tb> hydrofuranyl) <SEP> 9 <SEP> -11 <tb> <SEP> DAM <tb> <SEP> 4'-0-(6-methoxy- <SEP> 0SOCH <tb> <SEP> tetrahydro- <SEP> 10-a <SEP> 1I <SEP> 3 <tb> pyranyl <SEP> ) <SEP> -DAM <tb> <SEP> (b) <SEP> 10-b <SEP> (( <SEP> (I <tb> <SEP> 4'-O-(6-acetoxy <SEP> 0 <tb> methyltetra- <SEP> 11 <SEP> H <SEP> f <SEP> O <SEP> > <SEP> CH2 <SEP> -O-C-CH <tb> <SEP> hydropyranyl <SEP> ) <SEP> -DAM <tb> <SEP> 4'-0-(6-carbo- <SEP> O <tb> methoxytetra- <SEP> 12 <SEP> .. <SEP> < <SEP> > <SEP> CH3 <tb> <SEP> hydropyranyl)-DAM <SEP> < <tb> <SEP> 4'-O-(l-ethoxy- <SEP> -CH-O-CH <SEP> CH <tb> <SEP> ethyl)-DAM <SEP> (a) <SEP> 13-a <SEP> ,I <SEP> 2 <SEP> 3 <tb> <SEP> CH3 <tb> <SEP> (b) <SEP> 13-b <SEP> I, <SEP> (I <tb> <SEP> 41 <SEP> -O-(1-butyloxy- <SEP> -CH-O <tb> <SEP> 4'-0-(1-butyloxy- <SEP> -CH-o-CH2(CH2) <tb> <SEP> ethyl)-DAM <SEP> (a) <SEP> 14-a <SEP> 11 <SEP> CH3 <tb> EMI28.1 <tb> 4'-0-(l-butyloxy- <SEP> -CH-O-CHZ(CH),CH, <tb> <SEP> I <SEP> H <SEP> I <tb> ethyl)-DAM <SEP> (b) <SEP> 14-b <SEP> H <SEP> CH3 <tb> 4 <SEP> 1-O-(1-iso- <SEP> CH <tb> butyloxyethyl)- <SEP> 15-a <SEP> .. <SEP> -CH-O-CH2CH3 <tb> <SEP> I <SEP> 15-a <SEP> I <SEP> L <SEP> CH <tb> DAM <SEP> (a) <SEP> : <SEP> CH3 <SEP> 3 <tb> <SEP> 3 <tb> <SEP> " <SEP> (b) <SEP> 15-b <SEP> (( <SEP> .. <tb> The following describe the pharmacological useful ness of the compounds in the present invention. (1) Antitumor activity against various experi mental animal tumors. CDF1 mice were inoculated intraperitoneally (i.p.) with 1 x 105 cells/mouse of L1210 cells. After 24 hours had elapsed since inoculation, the mice were administered the compounds of the present invention intraperitoneally once daily for 10 consecutive days and observed for a 45 day period. The anti tumor activity was shown by the prolongation rate of survival day (T/C, %) to the survival day of control mice injected with physiological saline. The results of the compounds which were numbered in Table 1 are shown in Table 2. Table 2 Antitumor activity (T/C, %) of derivatives in the present invention EMI30.1 <tb> Compounds <SEP> Nos. <SEP> Dose <SEP> (mg/kg/day) <tb> <SEP> 5 <SEP> 2.5 <SEP> 1.25 <SEP> 0.625 <SEP> 0.31 <SEP> 0.15 <tb> <SEP> DAM <SEP> Tox. <SEP> 138* <SEP> 191 <SEP> 145 <SEP> 132 <SEP> 118 <tb> (for <SEP> comparison) <tb> <SEP> ADM <SEP> <tb> (for <SEP> comparison) <SEP> 189* <SEP> 351 <SEP> # <SEP> 272 <SEP> 239 <SEP> # <SEP> 147 <SEP> 130 <tb> <SEP> 1-a <SEP> 225 <SEP> 239 <SEP> 228 <SEP> 195 <SEP> 203 <SEP> <tb> <SEP> l-b <SEP> 241 <SEP> 218 <SEP> # <SEP> 220 <SEP> 184 <SEP> 145 <SEP> <tb> <SEP> 2 <SEP> 314 <SEP> 360 <SEP> 179 <SEP> 136 <SEP> 111 <SEP> 105 <tb> <SEP> 2-a <SEP> 212 <SEP> 288 <SEP> 189 <SEP> 135 <SEP> 115 <SEP> 115 <tb> <SEP> 2-b <SEP> 256 <SEP> 230 <SEP> 154 <SEP> 141 <SEP> 128 <SEP> 122 <tb> <SEP> 3 <SEP> 141 <SEP> 118 <SEP> 118 <SEP> 106 <SEP> 88 <SEP> 100 <tb> <SEP> 4-a <SEP> 108 <SEP> 277 <SEP> 145 <SEP> 127 <SEP> 101 <SEP> 96 <tb> <SEP> 4-b <SEP> 211 <SEP> 151 <SEP> 157 <SEP> 127 <SEP> 108 <SEP> 108 <tb> <SEP> 5-a <SEP> 163 <SEP> 138 <SEP> 125 <SEP> 119 <SEP> 100 <SEP> 100 <tb> <SEP> 5-b <SEP> # <SEP> 288 <SEP> 138 <SEP> 119 <SEP> 106 <SEP> 100 <SEP> 100 <tb> <SEP> 6-a <SEP> 257 <SEP> 151 <SEP> 125 <SEP> 112 <SEP> 105 <SEP> 105 <tb> <SEP> 6-b <SEP> 303 <SEP> 158 <SEP> 118 <SEP> 105 <SEP> # <SEP> 118 <SEP> 99 <tb> EMI31.1 <tb> Compounds <SEP> Nos. <SEP> Dose <SEP> (mg/kg/day) <tb> <SEP> 5 <SEP> 2.5 <SEP> 1.25 <SEP> 0.625 <SEP> 0.31 <SEP> 0.15 <tb> <SEP> 7-a <SEP> 125 <SEP> 125 <SEP> 118 <SEP> 99 <SEP> 92 <SEP> 105 <tb> <SEP> 7-b <SEP> 118 <SEP> 105 <SEP> 112 <SEP> 112 <SEP> 105 <SEP> 105 <tb> <SEP> 8-a <SEP> 184 <SEP> 125 <SEP> 118 <SEP> 105 <SEP> 99 <SEP> 105 <tb> <SEP> 8-b <SEP> 145 <SEP> 125 <SEP> 105 <SEP> 105 <SEP> 105 <SEP> 105 <tb> <SEP> 9 <SEP> 9 <SEP> 346 <SEP> 160 <SEP> 111 <SEP> 111 <SEP> 105 <SEP> 99 <tb> <SEP> 10-a <SEP> 232 <SEP> 125 <SEP> 106 <SEP> 100 <SEP> 100 <SEP> 100 <tb> <SEP> 10-b <SEP> 463 <SEP> 131 <SEP> 113 <SEP> 106 <SEP> 00 <SEP> 94 <tb> <SEP> 12 <SEP> 131 <SEP> 106 <SEP> 100 <SEP> 100 <SEP> 100 <SEP> 100 <tb> <SEP> 13-a <SEP> 217 <SEP> 157 <SEP> 1b2 <SEP> # <SEP> 104 <SEP> 96 <SEP> 96 <tb> <SEP> 13-b <SEP> 247 <SEP> 133 <SEP> 112 <SEP> 108 <SEP> 96 <SEP> 90 <tb> <SEP> 14-a <SEP> 144 <SEP> 116 <SEP> 116 <SEP> 110 <SEP> 103 <SEP> 110 <tb> 14-b <SEP> 188 <SEP> 151 <SEP> 110 <SEP> 110 <SEP> 1 <SEP> 96 <SEP> 103 <tb> <SEP> 15-a <SEP> 156 <SEP> 119 <SEP> 100 <SEP> 100 <SEP> ! <SEP> 100 <SEP> 100 <SEP> <tb> <SEP> 15-b <SEP> 188 <SEP> 113 <SEP> 106 <SEP> 100 <SEP> 100 <SEP> 100 <tb> Note: DAI=daunomycin, ADLI=adriamycin *: toxic It is considered from the results of toxic death and body weight loss of mice in Tables 2 and 3 that the derivatives in the present invention are 1/2 to 1/3 lower in toxicity than adriamycin and daunomycin which are the parent compound and the initial material in the present invention. (2) Inhibitory effect on the growth and nucleic acid biosynthesis in cultured Ll210 leukemia cells. L1210 cells (5 x 104 cells/ml) were inoculated in RPMI 1640 medium (Rosewell Park Memorial Institute 1640) containing 20% calf serum and cultivated at 37 C in the presence of 0.1 and 0.5 g/ml of the compounds in the present invention in a C02 incubator. The number of cells were periodically counted and the 50 growth inhibition concentration of control was determined as shown in Table 3. Furthermore, the 50% inhibition concentration of the compounds in the present invention on nucleic acid biosynthesis was examined as follows: 1 x 105 cells/ml of L1210 cells were suspended in RPMI medium containing 10% calf serum, pre-cultivated at 370C for 1 to 2 hours in a CO2 incubator and then the compounds in the present invention were added to the medium at various concentrations. After 15 min. of incubation, 14C-uridine (0.05 Ci/ml) or 14C-thymidine (0.05 Ci/ml) was added and incubated at 370C for 60 min. 10 Trichloroacetic acid (TCA) was added to the incubation medium to stop reaction and precipitate the acid-insoluble materials, and then the precipitate was washed three times with 5 to 10 TCA, soluble in formic acid. The radioactivity in the acid-insoluble materials was measured and expressed as 50 inhibition concentration of incorporation. The results are also shown in Table 3. Table 3 Inhibitory effect on the growth and nucleic acid biosynthesis in cultured L1210 cells. EMI34.1 <tb> Compounds <SEP> Nos. <SEP> ID50 <SEP> (g/ml) <SEP> against <SEP> L1210 <SEP> cells <tb> <SEP> growth <SEP> DNA <SEP> RNA <tb> <SEP> (after <SEP> 2 <SEP> days) <tb> <SEP> DAM <SEP> 0.036 <SEP> 0.3 <SEP> 1.7 <tb> <SEP> ADM <SEP> 0.018 <SEP> 1.25 <SEP> 0.49 <tb> <SEP> 2-a <SEP> 0.015 <SEP> 0.5 <SEP> 0.19 <tb> <SEP> 2-b <SEP> 0.015 <SEP> 0.54 <SEP> 0.19 <tb> <SEP> 3 <SEP> 0.04 <SEP> 0.56 <SEP> 0.29 <tb> <SEP> 4-a <SEP> 0.015 <SEP> 0.36 <SEP> 0.13 <tb> <SEP> 4-b <SEP> 0.01 <SEP> 0.43 <SEP> 0.18 <tb> <SEP> 5-a <SEP> 0.04 <SEP> 1.9 <SEP> 0.52 <tb> <SEP> 5-b <SEP> 0.05 <SEP> 1.5 <SEP> 0.37 <tb> <SEP> 6-a <SEP> 0.025 <SEP> 0.85 <SEP> 0.32 <tb> <SEP> 6-b <SEP> 0.03 <SEP> 0.5 <SEP> 0.15 <tb> <SEP> 7-a <SEP> 0.38 <SEP> > 10.0 <SEP> 2.5 <tb> <SEP> 7-b <SEP> 0.52 <SEP> > 10.0 <SEP> 2.8 <tb> <SEP> 8-a <SEP> 0.04 <SEP> 1.3 <SEP> 0.43 <tb> <SEP> 8-b <SEP> 0.06 <SEP> 1.3 <SEP> 0.32 <tb> EMI35.1 <tb> <SEP> Compounds <SEP> Nos. <SEP> ID50 <SEP> (g/ml) <SEP> against <SEP> L1210 <SEP> cells <tb> <SEP> growth <SEP> DNA <SEP> RNA <tb> <SEP> (after <SEP> 2 <SEP> days) <tb> <SEP> 9 <SEP> 0.017 <SEP> 0.41 <SEP> 0.17 <tb> 10-a <SEP> 0.04 <SEP> 0.62 <SEP> 0.3 <tb> 10-b <SEP> 0.025 <SEP> 0.8 <SEP> 0.33 <tb> <SEP> 12 <SEP> 0.095 <SEP> 0.93 <SEP> 0.44 <tb> 13-a <SEP> 0.025 <SEP> 0.34 <SEP> 0.13 <tb> 13-b <SEP> 0.03 <SEP> 0.65 <SEP> 0.29 <tb> 14-a <SEP> 0.08 <SEP> 0.93 <SEP> 0.37 <tb> 14-b <SEP> 0.075 <SEP> 1.4 <SEP> 0.6 <tb> 15-a <SEP> 0.08 <SEP> 1.4 <SEP> 0.5 <tb> 15-b <SEP> 0.06 <SEP> 0.8 <SEP> 0.28 <tb> Note: DAM=daunomycin, ADN=adriamycin (3) Inhibitory effect on the growth of various microorganisms. The compounds of formula 1 and their nontoxic acid addition salts have a remarkable bacteriostatic activity which is similar to that of adriamycin against several microorganisms, such as Staph. aureus, Bacillus subtilis, B. cereus, B. megaterium, Sarcina lutea, Micrococcus flavus, Corynebacterium bovis, Pseudomonas aerugino sa, Escherichja coli, Mycobacterium smegmatis and Candida albicans. Therapentic Use As mentioned above, the compounds of formula I and their nontoxic acid addition salts are novel antibiotics, useful in both human and veterinary medicine, and also possess marked inhibitory action against malignant mammalian tumors, including both solid and ascitic types. According to one aspect of the invention, a method is provided for therapeutically treating a mammalian host affected by a microbial infection (particularly a gram-positive bacterial infection) or by a malignant tumor (i.e. a solid- or ascitic-type tumor such as L1210 leukemia) which comprises admiristering to said host an effective antimicrobial or tumor-inhibiting dose of the compounds df formula I or a nontoxic acid addition salt thereof I or a mixture thereof. According to another aspect of the invention, a pharmaceutical composition is provided which comprises a therapeutically effective antimicrobial or tumorinhibiting amount of the compounds of formula I or a mixture thereof, or a nontoxic acid addition salt thereof, in combination with a pharmaceutical carrier or diluent. Such compositions may be made up in any pharmaceutical form appropriate for parenteral administration. Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. They may also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, physiological saline or some other sterile injectable medium immediately before use. It will be appreciated that the actual preferred dosage amounts used will vary according to the particular compound being used, the particular composition formula lated, the mode of application and the particular situs, host and disease being treated. In general the compounds are injected itraperitoneally, intravenously, subcutaneously or locally into non-human mammals and intravenously or locally into humans. Many factors that modify the action of the drug will be taken into account by those skilled in the art, for example, age, body weight, sex, diet, time of administration, route of administration, rate of excretion, condition of the patient, drug combinations, reaction sensitivities and severity of the disease. Administration can be carried out continuously or periodically within the maximum tolerated dose. Optimal application rates for a given set of conditions can be ascertained by those skilled in the art using conventional dosage determination tests in view of the above guidelines. Prior to the description of the Examples, as an example for preparing 14-0-acylated adriamycin which is to be used as an initial material for the preparation of 14-0-acyl-4'-0-etherified adriamycin, the experimental embodiment of the preparation of 14-0-acetyl-adriamycin will be mentioned as follows. Other 14-0-acylated adriamycin to be used as an initial material of the present invention can be prepared according to this experiment. Experiment 1 (1) 14 Bromodaunomycin-dimethylketal hydrochloride 230 mg (0.41 mmoles) of daunomycin hydrochloride was dissolved in 10 ml of absolute methanol, adding 20 ml of dioxane. The mixture was allowed to stand for 2 to 3 hours at 22 to 230C, followed by adding drop-wisely 0.88 ml (0.55 mmoles) of 10% chloroform containing bromine aqueous solution while stirring. The reaction mixture was concentrated to about 5 ml under reduced pressure and thereafter adding 15 ml of dry ether to obtain an orange-red precipitate by filtration. The precipitate was washed three times with 3 ml of ether and dried. 277 mg of hydrochloride salt of 14-0-bromodaunomycin-dimethyl ketal having a melting point at 175 to 1780C was obtained with a yield of 98%. (2) p-toluenesulfonate or hydrochloride salt of 14-O-acetyl adriamycin 207 mg (0.3 mmoles) of 14-bromodaunomycin dimethylketal hydrochloride salt was suspended in 100 ml of dry acetone, thereafter adding 0.4 g of dry sodium acetate and ref fluxed for 1 hour with agitation. The reaction mixture was filtered to remove impurities, and the filtrate was concentrated under reduced pressure. The residue was distributed in a mixture containing 30 ml of chloroform and 20 ml of 0.05N hydrochloric acid. The acidic aqueous layer thus obtained was neutralized with sodium hydrogen carbonate and then re-extracted with chloroform. The reddish chloroform layer was dried over anhydrous sodium sulfate and concentrated to about 5 ml under reduced pressure, and an orange precipitate of salt form was formed by adding 40 mg of p-toluenesulfonic acid or an equivalent amount of hydrochloric acid, according to the salifi- cation method of the corresponding acid addition salt. The resulting precipitate was filtered and washed with ether, and 160 mg of p-toluenesulfonate salt of 14-0acetyl adriamycin having a melting point at 165 to 168 0C was obtained. In the case of hydrochloride salt, about the same amount of compound can be obtained. The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention. In this example, the ratio of solvent in a mixture is indicated in the ratio of volume to volume and the % of liquid to liquid is indicated as V/V and that of solid to liquid is indicated as W/V unless otherwise mentioned. For the convenience of reading and locating the attributes of NMR, the configuration of adriamycin with indications showing the position of the carbon atoms is indicated below. EMI41.1 <tb> <SEP> 0 <SEP> OH <SEP> 10 <SEP> 0 <SEP> 14 <tb> <SEP> 1 <SEP> 52 <SEP> 13C11-COH <tb> 2 <SEP> = <SEP> S <SEP> C"CXOH <tb> 3 <SEP> N <SEP> 8 <tb> <SEP> ocb <SEP> o <SEP> oR <tb> <SEP> 3 <tb> <SEP> 0 <tb> <SEP> Adriamycin <tb> <SEP> 0 <tb> <SEP> 4r <SEP> /CH <tb> <SEP> HO <tb> <SEP> 1 <SEP> 2 <tb> Example 1 Process for producing 14-O-acetyl-4'-O-tetrahydro- pyranyl adriamycin a and b 155 mg (or equivalent amount of hydrochloride salt) of p-toluenesulfonate salt of 14-O-acetyl adriamycin was dissolved in 2.0 ml of dried dimethylformamide, thereafter adding 2.0 ml of 3,4-dihydro-2H-pyran and a small amount of p-toluenesulfonic acid, and allowed to stand at room temperature overnight. By observing the product and the residual initial material on a silica gel thin-layer chromatography (solvent system; h.loroform-methanol = 7: the formation of two new compounds having Rf values at 0.24 and 0.36 can be detected by the disappearance of the initial material having a Rf value of 0.04. The reaction mixture was extracted with 20 ml of chloroform and water. To the aqueous layer was added an amount of sodium hydrogen carbonate to adjust the pH of the aqueous layer at 7 to 8, and extracted it with chloroform. After the chloroform extract was dried and concentrated under reduced pressure, the resulting residue was applied to a preparative silica gel thin-layer plate and developed by a chloroform-methanol mixture (7:1) to obtain 14-0acetyl-4'-O-tetrahydropyranyl adriamycin a and b respectively as follows: Compound a (Rf: 0.24) yield 24 mg Molecular weight: 669.68 Melting point ( C): 185-195 Specific rotation (C=0.2 in chloroform) : +1830 [&alpha;]D22 UV and visible absorption 222s(335), 234(515) spectra in methanol 253 (360), 289 (130) : 480 (145), 496 (145) #maxnm(E1cm1%) 532 (90), 576 (20) PMR (CDCl3, ppm): 1.28(6'-H), 1.50-1.85 (pyran at 3-H to 5-H), 2.21(OAc), 4.05(4'-OMe), 4.42(pyran, anomeric), 5.18 (14-H), 5.26 (1'-H), 5.54(7-H), 7.27-8.03 (1-H-3-H) Compound b (Rf: 0.36) yield 34 mg Molecular weight: 669.68 Melting point ( C): 180-190 Specific rotation (C=0.2 in chloroform): +154 [&alpha;]D22 C UV and visible absorption 222s(335), 234(510) spectra in methanol 253(350), 289(130) : 481 (140), 495 (140) maxnm(E1cm1%) 532 (85), 576 (20) PMR (CDCl3, ppm) 1.37(6'-H), 1.40-2.00 (pyran), 2.21(OAc), 4.08 (4-OMe), 4.75 (pyran, anomeric), 5.18 (14-H), 5.25(1'-H), 5.53(7-H), 7.30-8.06(1-H-3-H) Example 2 Process for producing 14-O-isobutyloyl-4'-Otetrahydropyranyl adriamycin a and b 104 mg (0.13 mmoles) of p-toluenesulfonate of 14-0-isobutyloyl adriamycin was dissolved in 2.0 ml of dried dimethylformamide, adding 2.0 ml of dihydropyran and p-toluenesulfonic acid as a catalyst, and allowed to stand for 15 hours at room temperature. The products were detected on a thin-layer chromatogram (solvent system, chloroform-methanol = 9:1) at Rf values of 0.38 and 0.45. The reaction mixture was poured into 20 ml of water, neutralized with sodium hydrogen carbonate and extracted with 30 ml of chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The resulting residue was developed and purified by thin-layer chromatography. 22.5 mg of red powder of compound a ;was obtained from the fraction of Rf 0.38. Yield 24%, Melting point (or): 155-161 PMR (CDCl3, ppm): 1.24(H-6'), 1.29(isobutyl), 4.06(4'-OMe), 4.40(pyran, anomeric), 5.10(H-14), 5.25(1' H), 5.51(7-H), 7.30-8.07(1-H 3-H) And, 22.7 mg of red powder of compound b was obtained from the fraction of Rf 0.45. Yield Yield 24%, Melting point ( C) 169-174 PMR (CDC13, ppm): 1.25(isobutyl), 1.37(6'-H), 1.40-2.00(THP), 4.08(4-ON(e), 4.75(pyran, anomeric), 5.22 (14-H), 5.25(1'-H), 5.55(7-H), 7.29 - 8.10(1-H - 3-H) Example 3 Process for producing 14-0-phenylacetyl-4'-0tetrahydropyranyl adriamycin a and b 80 mg (0.096 mmoles) of p-toluenesulfonate of 14-0phenylacetyl adriamycin was dissolved in 2.5 ml of dried dimethylformamide, adding 0.5 ml of dihydropyran and a small amount of p-toluenesulfonic acid and allowed to stand at room temperature. The formation of the products having Rf values of 0.39 and 0.48 was confirmed by thinlayer chromatography using solvent system of chloroformmethanol (9:1), and the initial material apparently disappeared after 4 hours. The reaction mixture was poured into 20 ml of 1% sodium hydrogen carbonate aqueous solution and extracted with 30ml and again 10 my of chloroform. The chloroform layers were combined, washed four times with water, dried over anhydrous sodium sulfate, and concentrated to dryness. The resulting solid was developed by preparative thin-layer chromatography using a silica gel plate (2 mm thickness, 20x20 cm) and a solvent system of chloroform-methanol (9:1) to purify. The band of Rf 0.39 was scratched out from the thin-layer, extracted with a chloroform-methanol mixture (1:1), and concentrated to dryness. 27.0 mg of compound a was obtained as red powder. Yield 37%, Melting point ( C): 156-163 PMR (CDCl3, ppm): 1.25(H-6'), 1.40-2.00(tetra hydropyran), 3.80 and 7.36 EMI46.1 4.02(4-OMe), 4.35(pyran, anomeric), 5.21 (H-14), 5.25(1'-H), 5.50(7-H), 7.30-8.02(1-H - 3-H) 20.2 mg of compound b was obtained as red powder from the fraction of Rf 0.48 according to the method for compound a. Yield 28%, Melting point (OC): 159-165 PAIR (CDC13-, ppm): 1.37(6'-H), 1.45-2.00(pyran), 3.80 and 7.32 EMI46.2 4.05(4-OMe), 4.73(pyran, anomeric), 5.25(14H, l'-H), 5.50(7-H), 7.30-8.06(1-H - 3-H) Example 4 Process for producing 4'-O-tetrahydrofuranyl adriamycin (a) 190 mg (0.25 mmoles) of 14-0-acetyl adriamycin p-toluenesulfonate was dissolved in 10 ml of dried dimethylformamide, adding 0.4 ml of dihydrofuran and p-toluenesulfonic acid as a catalyst, and allowed to stand for 3.5 hours at room temperature (4'-0-tetrahydrofuranylation). The formation of the reaction product having an Rf of 0.24 to 0.27 and the disappearance of the initial material were observed by silica gel thin-layer chromatography using a solvent system of chloroformmethanol (9:1). The reaction mixture was poured into 100 ml of water, neutralized with sodium hydrogen carbonate and extracted with 60 ml of chloroform. The chloroform layer was dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure and developed by preparative thin-layer chromatography using two silica gel plates (20x20 cm, 2 nim thickness) and a solvent system of chloroform-methanol (9:1). The band of Rf 0.24 to 0.27 was scratched out from the silica gel thin-layer, extracted with a chloroform-methanol mixture (1:1), and concentrated to dryness. 66.8 mg of 14-0-acetyl-4'-O-tetrahydrofuranyl adriamycin was obtained as a red solid. Yield 40% P.UR (CDCl3, ppm,): 1.23-1.45 (6'-H), 1.70-2.12 (furan), 2.20, 2.22(acetyl), 4.06(4-ONle), 5.20(14-X), 5.36 (furan, anomeri-c), 5.51(7-H), 7.27-8.06(1-H - 3-H) (b) 41.0 mg of 14-O-acetyl-4'-O-tetrahydrofuranyl adriamycin was dissolved in 10 ml of methanol and 3 ml of water while stirring, adding 10% potassium carbonate solution to change the solution to blue-violet color (pH 10-11) and allowed to stand for 30 min. (hydrolysis). Descending of the Rf value was obserbed by silica gel thin-layer chromatography using a solvent system of chloroform-methanol (1:1). The reaction mixture was neutralized by adding a small piece of dry-ice and extracted with chloroform. The chloroform layer was washed with water, dried and concentrated to dryness. The resulting residue was purified by preparative thinlayer chromatography according to the method of (a). 16.3 mg of 4'-O-tetrahydrofuranyl adriamycin was obtained as red powder. Yield 43%, Nelting point ( C): 189-194 (decomposition) PMR (CDCl3, ppm): 1.25-1.27(6'-H), 1.67-2.30 (furan), 4.07-4.08(4-H), 5.17 and 5.38(furan, anomeric), 5.30(1'-H), 5.51(7-H), 7.30 8.07(1-H - 3-H) Example 5 Process for producing 4'-O-tetrahydrofuranyl adriamycin a and b 40 mg of 4'-O-tetrahydrofuranyl adriamycin obtained in Example 4 was preparatively re-chromatographed using silica gel (Merck Co.) and a solvent system of chloro form-methanol (15:1). An amount less than 1 mg per plate was applied on a silica gel plate (0.25 mm thickness, 20x20 cm), and developed three times to achieve good separation. The band corresponding to Rf 0.20 was scratched out from the silica gel plate, eluted with chloroform-methanol (1 ±1) and concentrated to dryness. The resulting compound a weighed 11.0 mg and contains the following properties. smelting point ( C): 189-191, {]D+1750 (CHC13, C=0.2) PMR (CDCl3, ppm): 1.25(6'-H), 1.67-2.37(furan), 4.07(4-H), 5.17(furan, anomeric), 5.30(1'-H), 5.51(7-H), 7.30 8.06(1-H - 3-H) The fractions of Rf 0.22 weighed 12.1 mg of compound b, and its properties are as follows: Melting point ( C): 190-192, [&alpha;]D+150 (CHCl3, C=0.2) PMR (CDCl3, ppm): 1.27(6'-H), 1.67-2.30(furan), 4.08(4-H), 5.30(1'-H), 5.38 (furan, anomeric), 5.51(7-H), 7.30-8.07(1-H - 3-H) Example 6 Process for producing 4'-O-(6-acetoxymethyltetrahydropyranyl) adriamycin (a) 150 mg (0.18 mmoles) of p-toluenesulfonate of 14-0-phenylacetyl adriamycin was dissolved in 2.0 ml of dry dimethylformamide., adding 0.2 ml of.2-acetoxymethyl-3,4-dihydro-2H-pyran and 15 mg (0.09 mmoles) of p-toluenesulfonic. acid and allowed to stand for 24 hours at room temperature [41-o-(6-acetoxymethyltetra- hydropyranylatior,. The spots of the initial material and the product having a Rf 0 51 was detected in the reaction mixture by silica gel thin-layer chromatography using a solvent system of chloroforn-methanol (9:1). The reaction mixture was poured into 20 ml of water, neutralized with sodium hydrogen carbonate and extracted twice with 30 ml of chloroform. The chloroform layer was dried over anhydrous sodium sulfate and chromatographed on 10 g of silica gel column (Alerck Co. Kiesel gel &num;100), and the column was washed with 100 ml of chloroform. The/ product was successively eluted with a chloroform-methanol mixture (10:1) and detected by thin-layer chromatography. The fraction of Rf 0.51 was collected, concentrated to dryness, and 100.2 mg of 14-O-phenylacetyl-4 '-O-(6-acetoxymethyltetrahydro- pyranyl) adriamycin was obtained as red solid. Yield 68% PMR (CDCl3, ppm): 1.24-1.34(6'-H), 2.08(acetyl), 3.83, 7.40(phenylacetyl), 4.08 (4'-H), 4.95(pyran, anomeric), 5.25(14-H), 5.54(7-H), 7.30 8.08(1-H - 3-H) (b) Then, the substance obtained above was dissolved in 20 ml of acetone with agitation, adding 10 ml of water and 0.5 ml of 10 potassium carbonate, and hydrolyzed for 30 min. The product of Rf 0.41 was observed on a thin-layer chromatogram. A piece of dryice was added to the reaction mixture for neutralizing and distilled to remove the acetone under reduced pressure. The resulting aqueous layer was extracted three times with 10 ml of chloroform respectively. The chloroform layers were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a red solid. The solid was further purified by preparative thin-layer chromatography using silica gel (Merck Co. 2 mm thickness and 20x20 cm, one plate) and a solvent system of chloroform-methanol (9:1), and re-extracted from the fraction of Rf 0.41. 26.9 mg of 4 '-O-(6-acetoxymethyltetrahydropyranyl) adriamycin was obtained as red powder. Yield 31%, Melting point ( C): 174-178 PMR (CDCl3, ppm): 1.19-1.40(6'-H), 2.06, 2.10 (OAc), 4.11(4-OMe), 4.78(14-H), 5.55(7-H), 7.35-8.10(1-H 3-H) Example 7 Process for producing 4'-O-(l-ethyloxyethyl) adriamycin a and b (a) 200 mg of p-toluenesulfonate of 14-0-phenylacetyl adriamycin was dissolved in 4.0 ml of dry dimethyl formamide, adding 0.2 ml of ethyl vinyl ether and p-toluenesulfonic acid as a catalyst, and allowed to stand for 1.i hours at room temperature (4'-Oethyloxyethylation). By silica gel thin-layer chromatography (solvent system; chloroform-methanol = 9:1) of the reaction mixture, it was confirmed that the initial material disappeared and new products of Rf 0.36 and 0.39 were formed. The reaction mixture was poured into 20 ml of water, adding sodium hydrogen carbonate to adjust the Ph at 8, and extracted with 60 ml of chloroform. The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a red material. After purifying the material by preparative thin-layer chromatography using silica gel (2 mm thickness, 20x20 cm, 2 plates) and a solvent system of chloroform-methanol (9:1), 134 mg of 14-0-phenylacetyl-42-0-(1-ethyloxyethyl) adriamycin was obtained from the band of Rf 0.36 - 0.39 as red powder. Yield 76% PMR (CDCl3, ppm): 1.21, 3.62(11-O-ethyl), 1.40 (2'-H), 3.81, 7.38(phenyl acetyl), 4.02(4-0-methyl), 5.64, 5.94(1'-H), 5.24(14-H), 5.50(7-H), 7.25-8.02(1-H 3-H) (b) Then, the compound obtained above was dissolved in 40 ml of acetone, adding 20 ml of water and 150 mg of anhydrous potassium carbonate and agitated well (hydrolysis). It was confirmed by silica gel thin-layer chromatography (solvent system, chloroform-methanol = 9:1) that the substances of Rf 0.36 and 0.39'gradually disappeared and new products of Rf 0.28 and 0.21 were formed. After 20 min. of reaction, the reaction mixture was neutralized with a piece of dry-ice and distilled to remove the acetone. The resulting aqueous layer was extracted twice with 30 ml of chloroform respectively, and the chloroform layer was washed with water, dried over anhydrous sodium sulfate and concentrated to obtain a red residue. According to the same method as mentioned above, the residue was purified by preparative silica gel thin-layer chromatography using a chloroform-methanol mixture (once with 15:1 and twice 9:1 to achieve god separation). The band of Rf 0.21 was scratched out from silica gel thin-layer and extracted with a chloroform-methanol mixture (1:1), and the extract was concentrated to obtain 13.0 mg of red powder of 4'-O-(1-ethyloxyethyl) adriamycin a. Yield 13%, Melting point ( C): 205-215 PMR (CDC13, ppm): 1.15, 3.58(1-OEt), 1.40(2'-H), 3.58(2'-H), 4.06(4-ONle), 4.65(1'-H), 4.76(14-H), 5.25 (1'-H), 5.51(7-H), 7.25-8.07 (l-H - 3-H) 11.2 mg of 4'-O-(l-ethyloxyethyl) adriamycin b was obtained from the band of Rf 0.28. Yield 11%, Melting point (OC): 190-200 PMR (CDCl3, ppm): 1.22, 3.63(1'-OEt), 4.08(4-H), 4.76(14-H), 4.93(1'-H), 5.27 (1'-H), 5.50(7-H), 7,22-8.88 (l-H - 3-H) Example 8 Process for producing 4'-O-(1-butyloxyethyl) adriamycin a and b (a)145.6 mg of p-toluenesulfonate of 14-acetyl adriamycin was dissolved in a mixture of 2 ml of absolute DMSO and 4 ml of absolute dioxane, adding 1.6 ml of n-butyl vinyl ether and further adding 0.396 ml of 0.lN p-toluenesulfonic'acid-dioxane solution under ice-cold conditions. After agitation for 35 min. at room temperature, the reaction mixture was poured into 50 ml of ethylacetate and washed twice with 30 ml of 1% sodium hydrogen carbonate solution respectively and three times with 30 ml of 5% sodium chloride aqueous solution respectively. The aqueous layer was extracted with 50 ml of ethylacetate, and the solvent extracts were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an oily substance. The oily substance was chromatographed on the silica gel column (Merck Art.7734, 4g, solvent: (1) CHCl3 60 ml, (2) ClICl3 : methanol=i0:l 30 ml) to obtain 141 mg from the eluate of the chloroformmethanol mixture. This product was further purified by preperative thin-layer chromatography (Merck Art. 5744, solvent system: CHCl : methanol=10:1) to obtain 4'-O(1-butyloxyethyl) adriamycin a and b. Compound a: 40.5 mg Compound b: 33.5 mg (b)Deacetylation 40.5 mg of 4'-O-(1-butyloxyethyl) adriamycin b was dissolved in 4 ml of methanol and 1 ml of water, and adding 0.23 ml of 1N potassium carbonate aqueous solution to change the solution to blue-violet color. After 8 min. of reaction, the reaction mixture was neutralized with a piece of dry-ice, adding 60 ml of water, extracted with 30 ml and 20 ml x 3 of chloroform, dried over anhydrous sodium sulfate and concentrated under reduced pressure. By preparative thin-layer chromatography (Merck Art. 5744, solvent system: CHCl3 : methanol=10:1), 14.2 mg of 4|-O-(1-butyloxy- ethyl) adriamycin b and 10.7 mg of compound a were obtained. Compound a Melting point ( C); 168-175 Specific rotation (C=0.1 in chloroform) : +157 [&alpha;]D25 UV and visible absorption 234(585), 251(405) spectra in methanol 288 (155), 480 (187) #maxnm(E1cm1%) : 495 (190), 530 (116) 575 (19) PMR (CDCl3, ppm): 0.92 (t, 3H) -CH2CH3 1.31 (d, 3H) C5'-CH3 1.38 (d, 3H) C4'-OCHCH3 EMI57.1 <tb> 2.91 <SEP> (d, <SEP> lH) <SEP> <tb> <SEP> C10-CH <tb> 3.21 <SEP> (d, <SEP> 1H) <SEP> 2 <tb> 4.03 (s, 3H) C4-OCH3 4.74 (s, 2H) C14-CH2 4.89 (q, 1H), C4'-OCHCH3 5.22 (bs, 1H) C7-H 5.48 (bs, 1H) C1'-H 7.25-7.98 (m, 3H) aromatic proton Compound b Melting point ( C): 155-160 Specific rotation (C=0.1 in chloroform) : +1880 [&alpha;]D20 UV and visible absorption 234(533), 251(371) spectra in methanol 288 (140), 480 (168) #maxnm(E1cm1%) : 495 (172), 530 (106) 575 (19) PMR (CDCl3, ppm): 0.91 (t, 3H) -CH2CH3 1.27 (d, 3H) C5'-CH3 1.40 (d, 3H) C4'-OCHCH3 EMI58.1 <tb> 2.95 <SEP> (d, <SEP> 1H) <tb> <SEP> C10-CR <SEP> <tb> 3.26 <SEP> (d, <SEP> 1H), <SEP> 2 <tb> 4.06 (s, 3H) C4-OCH3 4.61 (q, 1H), C4'-OCHCH3 4.74 (s, 2H) C14-CH2 5.27 (bs, 1H) C7-H 5.50 (bs, 1H) Cl '-H 7.31-8.02 (m, 3H) aromatic proton Example 9 Process for producing 4' - O-(1-isobutyloxy) adriamycin a and b (a) 150 mg of p-toluenesulfonate of 14-0-acetyl adriamycin was dissolved in 3 ml of anhydrous dioxane and 1.5 ml of anhydrous dimethylsulfoxide, adding 0.7 ml of isobutyl vinyl ether and 0.3 ml of 0.1N ptoluenesulfonic acid-dioxane solution, and agitated for 40 min. at room temperature (230C). The reaction mixture was diluted with 50 ml of ethylacetate, washed subsequently with 1% sodium hydrogen carbonate aqueous solution (30 ml x 2) and water (30 ml x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oily substance was chromatographed on silica gel column (Alerck Art. 7734, 4g; CHC13 CHC13 : methanol=10:1), and the fractions containing the main product were collected and concentrated to dryness to obtain 125.5 mg of orange powder. The powder was subjected to preparative thin-layer chromatography (Merck Art. 5744, 12 plates, CRCl : methanol=10:1) to separate and purify, and 14-O-acetyl-4'-O-(l-isobutyloxyethyl) adriamycin a and b were obtained as follows: Compound a:40.4 mg Compound b:51.7 mg (b) Deacetylation at C-14 position 40.4 mg of 14-O-acetyl-4'-O-(1-isobutyloxyethyl) adriamycin a obtained in (a) was dissolved in 4 ml of methanol, adding 2 ml of water and 0.36 ml of 1N potassium carbonate aqueous solution and agitated for 20 min. at room temperature. The reaction mixture was neutralized with dry-ice, extracted with 60 ml of chloroform and then washed with 50 ml of 5% sodium chloride aqueous solution. The aqueous layer was further extracted twice with 20 ml of chloroform respectively, and the combined chloroform extracts were dried over anhydrous sodium sulfate and concentrated to dryness. 35.8 mg of the resulting residue was chromatographed by preparative thin-layer chromatography (Merck Art. 5744, 4 plates, CHCl : methanol=l0:l) to obtain 12.5 mg of 4'-O-(1-isobutyloxyethyl) adriamycin a. Melting point ( C): 180-185 (decomposition) Specific rotation (C=0.1 in chloroform) O [&alpha;]D25 PMR (CDCl3, ppm): 0.93 (d, 6H) CH(CH3)2 1.32 (d, 3H) CS'-CH3 1.38 (d, 3H) C4'-OCHCH3 EMI60.1 <tb> 2.86 <SEP> (d, <SEP> 1H) <SEP> <tb> <SEP> C10-CH <SEP> <tb> 3.16 <SEP> (d, <SEP> 1H) <SEP> <tb> 3.66 (bs, 1H), C4'-H 4.02 (s, 3H) C4-OCH3 4.74 (s, 2H) C14-CH2 4.88 (q, 1H) C4'-OCHCH3 5.18 (bs, 1H) C7-H 5.48 (bs, 1H) C1'-H 7.25-7.92 (m-3H) aromatic proton 51.7 mg of 14-0-acetyl-4'-0-(1-butyloxyethyl) adriamycin b obtained in (a) was dissolved in 5 ml of methanol, adding 1.5 mlof water and 0.39 ml of 1N potassium carbonate aqueous solution and agitated for 15 min. at room temperature. According to the method for compound a, 18.1 mg of 4'-0-(1-butyloxyethyl) adriamycin b was obtained. Melting point ( C): 175-180 (decomposition) Specific rotation (C=0.1 in chloroform) [&alpha;]D25 : +191 PMR (CDC13, ppm): 0.90 (d, 6H) CH(CH3)2 1.27 (d, 3H) CS'-CH3 1.40 (d, 3H) C4'-OCHCH3 EMI61.1 <tb> <SEP> 2.84 <SEP> (d, <SEP> 1H) <SEP> <tb> C10-CH <tb> <SEP> 3.16 <SEP> (d, <SEP> 1H) <SEP> 2 <SEP> <tb> 3.26 (t, 2H) OCH2cH 3.58 (bs, 1H) C4'-H 4.01 (s, 3H) C4-OCH3 4.60 (q, 1H) 4'-OCHCE13 4.74 (s, 2H) C14-CH2 5.18 (bs, 1H) C7-H 5.48 (bs, 1H) C1'-H 7.25-7.90 (m, 3H) aromatic proton Example 10 Process for producing 4'-O-(l-(6-methylheptyloxy) ethyl) adriamycin a and b (a) 150 mg of 14-O-acetyi adriamycin p-toluenesulfonate was dissolved in 2 ml of absolute DLiSO and 4 ml of absolute dioxane, adding 1.6 ml of 6-methylheptyl vinyl ether and 0.396 ml of 0.1N p-toluenesulfonic acid-dioxane solution under ice-cold conditions, and agitated for 45 min. at room temperature. According to the same method as that of (a) in Example 8, 14-O-acetyl-4'-O-(6-methylheptyloxyethyl) adriamycin a and b were obtained. Compound a: 32.7 mg Compound b: 57.4 mg (b) Deacetylation 44.2 mg of 14-O-acetyl-4'-O-(1-(6-methylhepthyloxy) ethyl) adriamycin b was dissolved in 5.8 ml of methanol and 1.3 ml of water, adding 0.39 ml of 1N potassium carbonate solution to obtain a blue-violet color, and allowed to stand for 6 min. at room temperature. According to the same method as that of (b) in Example 8, 20.1 mg of 4'-0-(6-methylheptyloxy)ethyl adriamycin b was obtained. 13 mg of compound a was obtained in the same manner as mentioned above. Compound a Melting point ( C): 143-147 Specific rotation (C=0.1 in chloroform). +1780 [&alpha;]D20 PMR (CDC13, ppm): 1.32 (d, 3H) C5'-CH3 1.38 (d, 3H) C4'-OCHCH3 EMI63.1 <tb> 2.96 <SEP> 8d, <SEP> 1H) <tb> <SEP> #C10-CH2 <tb> 3.26 <SEP> 8d, <SEP> 1H) <tb> 4.06 (s, 3H) C4-OCH3 4.75 (s, 2H) C14-2H 4.90(q, 1H) C4'-OCHCH3 5.28 (bs, 1H) C7-H 5.51 (bs, 1H) C1'-H 7.31-8.03 (m, 3H) aromatic proton compound b Melting point ( C): 145-150 Specific rotation (C=0.1 in chloroform) +1830 [&alpha;]D20 PMR (CDCl3, ppm): 1.27 (d, 3H) C5'-CH3 1.40 (d, 3H) C4'-OCHCH3 EMI64.1 <tb> 2.93 <SEP> (d, <SEP> 1H) <SEP> <tb> <SEP> C10-CH2 <tb> 3.25 <SEP> (d, <SEP> 1H) <tb> 4.06 (s, 3H) C4-OCH3 4.61 (q, 1H) C4'-OCHCH3 4.75 (s, 2H) C14-CH2 5.25 (bs, 1H) C7-H 5.52 (bs, 1H) C1'-H 7.30-8.00 (m, 3H) aromatic proton Example 1-1 Process for producing 4'-O-(l-cyclohexloxyethyl) adriamycin a and b (a) 210 mg of p-toluenesulfonate of 14 0-acetyl adriamycin was dissolved in 4.2 ml of anhydrous dioxane and 2.1 ml of anhydrous dimethyl sulfoxide, adding 0.84 ml of cyclohexyl vinyl ether and 0.417 ml of 0.1N ptoluenesulfonic acid-dioxane solution, and allowed to react while agitating for 20 min. at room temperature. Subsequently, the reaction mixture was followed by the same treatment as that mentioned in Example 8 (a) to obtain 56.9 mg of 14-0-acetyl-4'-O-cyclohexyloxyethyl adriamycin a and 60.7 mg of 14-0-acetyl-4'-0cyclohexyloxyethyl adriamycin : (b) Deacetylation at the C-14 position 56.9 mg of 14-O-acetyl-4'-O-cyclohexyloxyethyl adriamycin a and 60.7 mg of 14-O-acetyl-4'-O-cyclohexloxyethyl adriamycin b respectively obtained in (a) were treated in the same manner auk that mentioned in Example 8 (b) to obtain 20.7 mg of orange powder of 4'-O-cyclohexyloxyethyl adriamycin a and 24.2 mg of orange powder of 41-O-cyclohexyloxyethyl adriamycin b respectively. Compound a Melting point (OC): 175-182 (decomposition) Specific rotation (C=0.1 in chloroform) O [&alpha;]D20 PMR (CDCl3 ppm): 1.32 (d, 3H) C5'-CH 3 1.38 (d, 3H) C4'-OCHCH3 EMI66.1 <tb> 2.92 <SEP> (d,1H) <tb> <SEP> # <SEP> C10-CH2 <tb> 3.23 <SEP> (d, <SEP> 1H) <tb> 4.05 (s, 3H) 4-OCH3 4.76 (s, 2H) C14-CH2 4.97 (q, 1H) C4'-OCHCH3 5.23 (bs, 1H) C7-H 5.49 (bs, 1H) C1'-H 7.30-8.00 (m, 3H) aromatic proton Compound b Melting point ( C): 177-181 (decomposition) Specific rotation (C=0.1 in chloroform) +172 [&alpha;]D20 PMR (CDC13, ppm): 1.26 (d, 3H) C5'-CH3 1.40 (d, 3H) C4'-OCHCH3 EMI66.2 <tb> 2.87 <SEP> (d, <SEP> 1H) <tb> <SEP> #C10-CH2 <tb> 3.18 <SEP> (d, <SEP> 1H) <tb> 4.02 (s, 311) 4-OCR3 4.68 (q, 1H) C4'-OCHCH3 4.74 (s, 2H) C14-CH2 5.19 (bs, 1H) C7-H 5.49 (bs, 1H) C1'-H 7.26-7.94 (m, 3H) aromatic proton Example 12 Process for producing 4'-O-(tetrahydrofuranylY daunomycin 56 mg (0.1 mmoles) of daunomycin hydrochloride was dissolved in dry dimethylformamide, adding 0.1 ml of dihydrofuran and a small amount of p-toluenesulfonic acid as a catalyst, and allowed to stand for 8 hours at room temperature (4'-O-tetrahydrofuranylation). The reaction mixture was poured into 20 ml of water, adding sodium hydrogen carbonate to neutralize, and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and concentrated to dryness to obtain red materials. T'vo bands of the product having Rf 0.29 and 0.31 were detected by preparative thin-layer chromatography using silica gel (Merck Co.) and a solvent system of chloroform: methanol (9:1), but these bands could not be completely separated from each other. The bands corresponding to the product were scratched out from silica gel plate and eluted with a chloroform-methanol mixture (1:1), and the eluate was concen- trated under reduced pressure to obtain 12.4 mg of 4'-O-(tetrahydrofuranyl)daunomycin as red powder. Yield 215 Melting point ( C): 201-204 (decomposition) PMR (CDC13, ppm): 1.29(6'-H), 1.70-2.30(furan 3,4-H), 2.44(14-H), 4.11(4-H), 5.28(1'-H), 5.43(furan, anomeric), 5.54(7-H), 7.33-8.11 (1-H - 3-H) Example 13 Process for producing 4'-O-(6-acetoxymethyItetra- hydropyranyl) daunomycin 112 mg (0.2 mmoles) of daunomycin hydrochloride was dissolved in 2.0 ml of dry dimethylformamide, adding 15 mg of p-toluenesulfonic acid and 0.3 ml of 2-acetoxymethyl-3,4-dihydro-2H-pyran and allowed to stand over night at room temperature (4'-O-(6-acetoxymethyltetra- hydropyranylation). The reaction mixture was poured into 20 ml of 1% sodium hydrogen carbonate aqueous solution and extracted with 30 ml of chloroform. The aqueous layer was extracted twice with 10 ml of chloroform respectively. The combined chloroform layer was washed four times with 10 ml of water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The product was developed on a preparative thin-layer chromatogram (2 mm thickness, 20x20 cm, one plate) using a solvent system of chloroform-methanol (9:1), and the band corresponding to the product having Rf 0.47 was scratched out from silica gel thin-layer and re-extracted with a chloroform-methanol mixture (1:1). The resulted red extract was concentrated to dryness and 55.3 mg of 4'-0-(6-acetoxymethyltetrahydropyranyl) daunomycin was obtained as red powder. Yield 40% Melting point (OC): 198-201 PAIR (CDCl3, ppm): 1.21-1.42(6'-H), 2.07-2.11 (OAc), 2.43(14-H), 4.10(4-ONle), 5.53(7-H), 7.29-8.06(1-H - 3-H) Example 14 Process for producing 4'-O-(6-methoxytetrahydro- pyranyl) daunomycill a and b 112 mg (0.2 mmoles) of daunomycin hydrochloride was dissolved in 3.0 ml of dry dimethylformamide, adding 0.15 ml of 2-methoxy-3,4-dihydro-2H-pyran and 10 mg of p-toluenesulfonic acid and allowed to stand overnight at room temperature (4'-0-(6-methoxytetrahydropyrany- lation). The reaction mixture was poured into 20 ml of water, adjusting the pH at 8.0 with sodium hydrogen carbonate and extracted four times with 10 ml of chloroform respectively. The chloroform extracts were combined, dried over anhydrous sodium sulfate and concentrated to dryness to obtain red residue. The residue was further purified by preparative thin-layer chromatography using silica gel (Merck Co. 2 mm thickness, 20x20 cm, one plate) and a solvent system of chloroform-methanol (9:1). A band of Rf 0.38 was scratched out'from the silica gel plate, and re-extracted with a chloroformmethanol mixture (1:1). The resulting red extract was concentrated under reduced pressure to obtain 23.1 mg of compound a as red powder. Yield 18% Melting point ( C): 189-191 PhlR (CDCl3), ppm: 1.29(6'-H), 2.40(3-H), 3.45(5'-OMe), 4.09(4-OMe), 4.83(1'-H), 5.30(1l-H), 5.58(7-H), 7.28-8.08(1-H 3-H) 19.4 mg of compound b was obtained as red powder according to the same method as that of compound a. Yield 15% Melting point ( C): 198-199 PMR (CDCl3, ppm): 1.39(6'-H), 2.44(14-H), 3.46 (pyran-OMe), 4.11(4-H), 4.89 (pyran, anomeric), 5.22(1'-H), 5.53(7-H), 7.28-8.14(1-H - 3-H) Example 15 Process for producing 4'-0-(6-carbomethoxytetra- hydropyranyl) daunomycin 112 mg (0.2 mmoles) of daunomycin hydrochloride was dissolved in 3.0 ml of dry dimethylformamide, adding 0.1 ml of 2-carbomethoxy-3,4-dihydro-2H-pyran and 34 mg (0.2 mmoles) of p-toluenesulfonic acid, and allowed to stand for 10 hours at room temperature in the dark (4'-O-6-carbomethoxytetrahydropyranylation). The reaction mixture as poured into 20 ml of water, adjusting the pH at 8 with sodium hydrogen carbonate and extracted four times with 10 ml of chloroform respectively, The chloroform extracts were combined, washed twice with water and dried over anhydrous sodium sulfate. The chloroform extract was concentrated under reduced pressure, and the resulting residue was purified by preparative thin-layer chromatography using a silica gel plate (Merck Co.) and a solvent system of chloroformmethanol (9:1). New products were detected between 0.35 and 0.37 of Rf values on the TLC as a mixture of 4 components, and they could not be separated completely. The corresponding bands on the TLC were scratched out from the silica gel plate and extracted with a chloroformmethanol mixture (1:1). The extract was concentrated to dryness to obtain 25.9 mg of red powder. Yield 19% Melting point (0C): 190-193 PMR (CDCl3, ppm): 1.23-l.40(61-H), 2.43(14-H), 3.78(COOCH3), 4.09(4-ONle), 4.74, 5.0pyran, anomeric), 5.31(1'-H), 5.54(7-H), 7.30 8.06(1-H - 3-H) Example 16 Process for producing 4'-0-(1-ethyloxyethyl) daunomycin a and b 112 mg (0.2 mmoles) 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 and allowed to stand for 10 hours at room temperature (1-ethyloxyethylation). New spots of the product were observed at Rf 0.31 and 0.34 on the silica gel thin-layer chromatogram (solvent system, chloroformmethanol=9:1). The reaction mixture was poured into 20 ml of water, adjusting the pH at 8 with sodium hydrogen carbonate, and extracted with 30 ml of chloroform. The chloroform layer was dried and concentrated under reduced pressure. The resulting red residue was purified by preparative thin-layer chromatography using silica gel (Merck Co. thickness 2 mm, 20x20 cm, one plate) and a solvent system of chloroform-methanol (15:1). The band corresponding to Rf 0.31 was scratched out, and extracted with a chloroform-methanol mixture (1:1). The red extract was concentrated to dryness to obtain 33.0 mg of red compound a. Yield 27% Melting point ( C): 208-210 PMR (CDCl3, ppm): 1.76, 3.59(1'-OEt), 1.39(2'-H), 1.79(8-H), 2.41(14-H), 4.07 (4-OMe), 4.64(1'-H), 5.25(1'-H), 5.51(7-H), 7.25-8.07(1-H - 3-H) The band corresponding to Rf 0.34 was also treated according to the same method as that mentioned above, and 31.8 mg of compound b was obtained as red powder. Yield 26% Melting point ( C): 200-204 PMR (CDC13, ppm): 1.20, 3.64(1'-OEt), 1.40(2'-H), 2.41(14-H), 4.09(4-H), 4.94 (1'-H), 5.26(1'-H), 5.50(7-H), 7.26-8.07(1-H - 3-H) Example 17 Process for producing 41-O-(1-isobutyloxyethyl) daunomycin a and b 60 mg (0.106-mmoles) of daunomycin hydrochloride was dissolved in 12 ml of absolute THP and 1.5 ml of absolute DMSO, adding 1.2 ml of 2-isobutyl vinyl ether and 0.21 ml of 0.1N p-toluenesulfonic acid-THF solution, and agitated for three hours at room temperature. The reaction mixture was dissolved in 100 ml of ethylacetate, washed with 100 ml of 5% sodium chloride aqueous solution containing 0.1N sodium hydrogen carbonate, and further washed with 5% sodium chloride aqueous solution (100 ml x2). The solvent layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oily substance was treated in the same manner as that mentioned in Example 16 to obtain 16.0 mg of 4'-0-(l-isobutyloxyethyl) daunomycin a and 19.1 mg of 4'-0-(1-isobutyloxymethyl) daunomycin b. Compound a Melting point ( C): 143-148 Specific rotation (C=0.1 in chlororform) O [&alpha;]D25 : +190 PMR(CDCl3,ppm) : 0.92 (d,6H) CH(CH3)2 1.33 (d, 3H) C5'-CH3 1.37 (d, 3H) C4'-OCHCH3 2.41 (s, 3H) C13-CH3 EMI75.1 <tb> 2.90 <SEP> (d, <SEP> lH) <tb> <SEP> C10-CH <tb> 3.22 <SEP> (d, <SEP> 1H) <SEP> <tb> 3.27 (t, 2H) OCH2CH 3.62 (bs, 1H) C4'-H 4.07 (s, 3H) C4-OCH3 4.89 (q, 1H) C4'-OCHCH3 5.28 (bs, 1H) C7-H 5.52 (bs, 1H) C1'-H 7.31-8.06 (m, 3H) aromatic proton Compound b Melting point ( C): 141-146 Specific rotation (C=0.1 in chloroform) . +1850 [&alpha;]D25 PMR (CDC13, ppm): 0.90 (d, 6H) CH(CH3)2 1.25 (d, 3H) C5'-CH3 1.39 (d, 3H) C4'-OCHCH3 2.40 (s, 3H) C13-CH3 EMI76.1 <tb> 2.89 <SEP> (d, <SEP> 1H)# <tb> <SEP> C10-CH2 <tb> 3.22 <SEP> (d, <SEP> 1H)# <tb> 3.26 (t, 2H) OCH2CH 3.54 (bs, 1H) C4'-H 4.06 (s, 3H) C4-OCH3 4.61 (q, 1H) C4'-OCHCH3 5.27 (bs, 1H) C7-H 5.52 (bs, 1H) C1'-H 7.31- 8.04 (m, 3H) aromatic proton Example 18 Process for producing 4'-0-(1-butyloxyethyl) daunomycin a and b 100 mg (0.177 mmoles) of daunomycin hydrochloride was dissolved in a mixture of 10 ml of absolute THF and 2 ml of absolute DMSO, adding 3 ml of n-butyl vinyl ether and 0.88 ml (0.088 mmoles) of 0.1N p-toluenesulfonic acid-THF solution, and agitated for two hours at room temperature. According to the method of Example 17; 27.1 mg of 4'-0-(1-butyloxyethyl) daunomycin a and 34.8 mg of 4'-0-(1-butyloxyethyl) daunomycin b were separated. Compound a Melting point ( C): 141-145 Specific rotation (C=0.1 in chloroform) +167 [&alpha;]D25 PMR (CDC13, ppm): 0.91 (t, 3H) -CH2CH3 1.32 (d, 3H) C5'-CH3 1.37 (d, 3H) C4'-OCHCR3 2.41 (s,'3H) C13-CH3 EMI77.1 <tb> 2.92 <SEP> (d, <SEP> 1H)# <tb> <SEP> C10-CH2 <tb> 3.24 <SEP> (d, <SEP> 1H)# <tb> 3.54 (m, 3H) C4'-H, OCH2- 4.07 (s, 3H) C4-OCH3 4.91 (q, 1H) C4'-OCHCH3 5.27 (bs, 1H) C7-H 5.52 (bs, 1H) C1'-H 7.31-8.06 (m, 3H) aromatic proton Compound b Melting point ( C): 138-142 Specific rotation (C=0.1 in chloroform) +2070 [&alpha;]D25 PMR (CDCl3, ppm): 0.89 (t, 3H) -CH2CH3 1.27 (d, 3H) C5'-CH3 1.39 (d, 3H) C4'-OCHCH3 2.40 (s, 3H) C13-CH3 EMI78.1 <tb> 2.86 <SEP> (d, <SEP> 1H)# <tb> <SEP> C10-CH2 <tb> 3.20 <SEP> (d, <SEP> 1H) <SEP> <tb> 3.52 (m, 3H) C4'-H, OCH24.06 (s, 3H) C4-OCH3 4.61 (Q, 1H) C4'-OCHCH3 5.25 (bs, 1H) C7-H 5.51 (bs, 1H) C1'-H 7.30-8.01 (m, 3H) aromatic proton

Claims: WHAT IS CLAIMED: 1. An anthracycline derivative of the general formula I: EMI79.1 wherein R1 is a hydrogen atom, a hydroxyl group, an alkanoyloxy group having a carbon number of 2 to 7 or a phenylacetyl group, and R2 ia an alkyloxyethyl, a tetrahydrofuranyl, a tetrahydropyranyl, a 6-methoxytetrahydropyranyl, a 6-carbomethoxytetrahydropyranyl cr a 6-acetoxymethyltetrahydropyranyl group, excluding the case where R1 is a hydrogen atom or a hydroxyl group and simultaneously R2 is a tetrahydropyranyl group or an acid addition salt thereof. 2. An anthracycline derivative according to claim 1 having the formula I: wherein R1 is an acetyloxy, an isobutyloyloxy or a phenyl acetyloxy group, and R2 is an alkyloxyethyl, a tetrahydrofuranyl, a tetra hydropyranyl, a 6-methoxytetrahydropyranyl, a 6-carbo methoxytetrahydropyranyl or a 6-acetoxymethyltetra hydropyranyl group or an acid addition salt thereof. 3. An anthracycline derivative according to claim 1 having the formula I: wherein R1 is a hydrogen atom or a hydroxyl group, and R2 is an alkyloxyethyl, a tetrahydrofuranyl, a 6-methoxytetrahydropyranyl, a 6-carbomethoxytetra hydropyranyl or a 6-acetoxymethyltetrahydropyranyl group or an acid addition salt thereof. 4. A process for producing 14-0-acylated or -phenylacetylated anthracycline derivative of the general formula II: EMI81.1 wherein R3 is an alkanoyloxy group having a carbon number of 2 to 7 or a phenylacetyloxy group, and 2 is an alkyloxyethyl, a tetrahydrofuranyl, a tetra hydropyranyl, a 6-methoxytetrahydropyranyl, a 6-carbo methoxytetrahydropyranyl or a 6-acetoxymethyltetra hydropyranyl group or an acid addition salt thereof; or a 14-0-deacylated derivative thereof of the general formula III: EMI82.1 wherein R2 has the same definition as mentioned above or an acid addition salt thereof which comprises introducing an alkyloxyethyl, a tetrahydrofuranyl, a tetrahydropyranyl, a 6-methoxytetrahydropyranyl, a 6-carbomethcytetrahydropyranyl or a 6-acetoxymethyltetrahydropyranyl group into the hydroxyl group at C-4' position of an anthracycline derivative of the formula II-a: : EMI83.1 wherein R3 is an alkanoyloxy group having a carbon number of 2 to 7 or a phenylacetyloxy group or an acid addition salt thereof by reaction with a dihydrofuran, a derivative thereof, dihydropyran, a derivative thereof or an alkyl vinyl ether which contains said corresponding group to be introduced and is capable of reacting with a hydroxyl group, in an inert organic solvent and in the presence of an acid catalyst to form said anthracycline derivative of the general formula II and optionally further comprises eliminating the alkanoyl group or the phenylacetyl group at the C-14 position of said derivative of the general formula II by hydrolytic deacylation to form said anthracycline derivative of the general formula III. 5. A process for producing an anthracycline derivative of the general formula V: EMI84.1 wherein R2is an alkyloxyethyl, a tetrahydrofuranyl, a 6-methoxytetrahydropyranyl, a 6-carbomethoxytetra hydropyranyl or a 6-acetoxymethyltetrahydropyranyl group or an acid addition salt thereof which comprises introducing an alkyloxyethyl, a tetrahydrofuranyl, a 6-methoxytetrahydropyranyl, a 6-carbomethoxy tetrahydropyranyl or a 6-acetoxymethyltetrahydropyranyl group into the hydroxyl group at the C-4' position oi the anthracycline glycoside of the general formula IV: EMI85.1 or an acid addition salt thereof by reaction with dihydrofuran, a derivative thereof or an alkyl : vinyl ether which contains said corresponding group to be introduced and is capable of reaction with a hydroxyl group, in an inert orgainc solvent and in the presence oi an acid catalyst to form said anthracycline derivative. 6. A pharmaceutical composition comprising a therapeutically effective amount of a compound as claimed in claim land a pharmaceutical carrier or diluent.

Inventors: NAGANAWA, HIROSHI, TAKEUCHI, TOMIO, TATSUTA, KUNIAKI, UMEZAWA, HAMAO
Applicants: MICROBIAL CHEM RES FOUND
Application year: 1980
Main classification: C07H15
IPC codes: C07H15