DK160879B - Anthracycline antibiotics - Google Patents

Description

DK 160879 B

The present invention relates to novel anthracycline antibiotics produced by microorganisms belonging to the genus Streptomyces.

It is known that antibiotics of the anthracycline type, daunomycin and adriamycin, can be isolated from a culture solution of actinomycetes, cf. respectively. U.S. Patent Nos. 3,616,242 and 3,590,028. These compounds have a broad anti-cancer spectrum against experimental tumors and have also been used clinically as chemotherapeutic agents for cancer. However, the anticancer effect of daunomycins and adriamycins is not necessarily satisfactory, although they have a significant potent effect. It has therefore been attempted to produce various compounds analogous to daunomycin and adriamycin in various ways, such as fermentation, semisynthesis and conversion using microorganisms, and some anthracycline antibiotics have been prepared, cf. eg. published Japanese Patent Application Laid-Open No. 34915/76, Aclacinomycins A and B, T. Oki et al., The Journal of Antibiotics, Volume 33, pages 20 1331-1340, P. Areamone, Topics in Antibiotic Chemistry, Volume 2, page 102 -279, published by Ellis Horwood Limited, published Unexamined Japanese Patent Application No. 56494/82 (4-demethoxy-11-deoxydaunomycin, etc.), Unexamined Japanese Patent Application No. 15299/81 (antibiotics of the 25 rhodomycin series) and others.

In "Journal of Medicinal Chemistry", 21, 280 (1978), "Canadian Journal of Chemistry, 5j), 1868-1874 (1980), and" Topics in Antibiotic Chemistry ", vol. 2, pp. 105-108 describe monosaccharides, analogous to the compounds of the invention as described later, however, the aglycone and / or sugar moieties of these known compounds belong to different categories, although, for example, rhodomycin B described in "Topics in Antibiotic Chemistry" is similar to compound D788-7. According to the invention, a major difference between the two compounds is that the sugar portion of the known compound 2

DK 160879B

either L-rhodosamine or daunosamine. This difference results in a clear difference in the antitumor effect of these compounds (see, for example, the right column on page 1869 in the Canadian Journal of Chemistry).

Furthermore, a number of compounds similar to the compounds of the invention have been investigated as anti-cancer agents.

However, none of the known compounds are satisfactory in terms of both toxicity and anticancer activity.

The object of the invention is therefore to provide new compounds with low toxicity and high anticancer effect.

The present invention provides novel anthracycline antibiotics of the formula

O OH

HO O OH q HO NH 2 wherein Y means a group of the formula

OH OH

r t CH300C o hooc oh euer ^ Sn® ·

3 DK 160879 B

These compounds have a potent inhibitory effect on the proliferation of cultured leukemia cells L 1210 and are useful as anticancer agents.

These compounds are novel antibiotics which are structurally characterized by ring A in the anthracyclinone skeleton. Among the compounds of formula (I), the antibiotic compound of formula O has OHCOOCH3

J * OH

(I a)

OH O OH O

-ΓΟΗ nh2 designation D788-6, the antibiotic compound of formula 10

0 OH. OH

YYyV d-b) OH 0 OH q Η3εΓ "0- OH NH2 designation D788-7, the antibiotic compound of formula

4 DK 160879 B

O OH OH

(I-C)

ISLAND

NH3αΤΝ ^ HO NH2 designation D788-8, the antibiotic compound of formula CCOCH3 O OH o (I-d) HO O OH 1

I nh2 HO

the term D788-9 and the antibiotic compound of the formula

0 OH CCOH OH

HO ° ° H O (I.e) HO NH2 designation D788-10.

. DK 160879B

5

These compounds have potent inhibitory action against the proliferation of cultured leukemia cells L 1210 and are per se useful as anticancer agents.

Inhibitory action against proliferation of mouse L 1210 leukemia cells and against the synthesis of nucleic acid L 1210 cells in an amount of 5 x 10 5 / ml is inoculated on e.g. RPM 11640 medium (Rosewellberg Research Laboratories) containing 20% bovine serum and the test compound is added at a concentration of 0.02-0.25 µg / ml 10 in a similar manner. The culture is carried out at 37 ° C in a carbon dioxide culture flask. Then, 50% of the inhibitory effect against proliferation is determined based on a control fraction. In addition, the above L 1210 cell culture is suspended in 10% bovine serum-containing RPM 11640 medium at a concentration of 5 x 10 6 / ml. After growing at 37 ° C for 1-2 hours in a carbon dioxide culture flask, the substance is added at various concentrations, and 15 minutes later, C-uridine (0.05 µCi / ml) or ^ C-thymidine (0.05 µCi / ml) is added. , and then the culture is continued for 20 60 minutes at 37 ° C. The reaction is quenched by adding cold 10% trichloroacetic acid to the reaction solution, and at the same time, material which is insoluble in the acidic medium is precipitated. After further washing twice with cold 5% trichloroacetic acid, the insoluble material is dissolved in formic acid and radioactivity is measured. 50% of the uptake inhibition concentration is determined from the uptake rate of the radioactivity based on the control fraction to which no substance has been added. The results are shown in Table 1 below.

DK 160879B

6

Table 1

Inhibitory action against proliferation of mouse leukemia L 1210 culture cells and against synthesis of nucleic acid 50% inhibition concentration (IC, q) 5 (µg / ml)

Inhibition of Inhibition of Inhibition of cell proliferation DNA synthesis RNA synthesis D 788-6 0.25 2.6 1.30 D 788-7 0.0003 0.29 0.68 10 D 788-8 0.22 3.4 1.58 D 788-9 0.22 4.2 2.59 D 788-10 0.083 10 10

The antitumor effect against mouse L 1210 leukemia is shown in Table 2 below.

Table 2

In vivo anti-tumor activity of D788-7 against mouse L 1210 leukemia

Anti-tumor activity in vivo

Dose Antitumor effect T / c (%) 20 (uq / kg / day) __ 250 100 125 172 62.5 204 32 187 25 16 133 8 104 4 102 mice: CDF1 n = 6 inoculation: 1 x 10 6 cells / mouse ( ip) 30 treatment: day 1 to day 10 (ip)

7 DK 160879B

The above-mentioned anthracycline antibiotics may be prepared by culturing in a medium containing suitable nutritional sources a strain / forming the compounds of the invention, which are readily isolated by a conventional variation treatment of a strain belonging to the genus Actinomyces, capable of producing daunomycin and thus analogous compounds, which are isolated from soil or known, using a variant, e.g. N-methyl-N'-nitro-N-nitrosoguanidine (NTG). Among these 10 producing strains, a specific example is the strain RPM-5, a variant obtained by a variation treatment of Streptomyces strain D 788, which forms daunomycin and paumycin and has recently been isolated from soil, with NTG.

15 This strain was deposited in the Fermentation Research Institute, Agency of Industrial Sciences and Technology on July 2, 1984 under International Deposit No. 811 (FERM BP-811).

The bacteriological properties of strain RPM-5 are described below.

(A) Morphology

Linear aerial mycelium develops from branched substrate mycelium, but no spirals are formed. Mature spores in a chain of 10 or more have a diameter of approx. 0.6-0.8 x 25 0.9-2.5 µm. The spores have smooth surfaces. Neither ascospores nor flagella spores are formed.

(B) Growth conditions in different media

With respect to the color statement, standards are specified in parentheses based on the "System of Color Wheels for Strepto-30 mycete Taxonomy" by Tresner & E.J. Backus (J. Appl. Microbiol., Vol. 11, pages 335-338, 1963), supplemented by the "Color Standard" published by Nippon Color Research Laboratories.

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(C) Physiological properties (1). Growth temperature range: (tested at temperatures 20 ° C, 28 ° C, 30 ° C, 37 ° C and 42 ° C at pH 6.0 using yeast maltose agar medium). Growth at temperatures of 20-37 ° C; but no growth at 42 ° C.

(2) Melting of gelatin: positive (growing at 20 ° C using glucose-peptone-gelatin medium) (3) Hydrolysis of starch: 10 positive (starch-inorganic salt-agar medium).

(4) Coagulation of skimmed milk and peptonization: the result negative in the initial phase, but after 15 days of cultivation, peptonization occurs.

(5) Melanin-like pigment formation: (using tryptone yeast culture liquid, peptone yeast iron agar and tyrosine agar media) positive in all media.

(D) Utilization of various carbon sources: (Pridham-Gottlieb agar medium) 1. L-Arabinose positive 20 2. D-Xylose positive 3. D-Glucose positive 4. D-Fructose positive 5. Sucrose positive 6. Inositol positive 25 7 .L-Rhamnose negative 8. Raffinose negative 9. D-Mannitol positive

The compounds of the invention can be prepared by cultivating producing bacteria in media of known composition, usually used for culture, of actinomycetes. For example, carbon sources may be used glucose, glycerol, sucrose, starch, maltose, animal and vegetable oils, etc.

9 DK 160879B

organic substances such as e.g. soybean powder, meat extract, yeast extract, peptone, maize cast water, cotton seed residues, fish powders, etc., and inorganic nitrogen sources such as ammonium sulphate, ammonium chloride, sodium nitrate, ammonium phosphate, etc. If necessary or if desired, sodium chloride, sodium chloride, of divalent metals, 4 * 4 * -t-4- 4 »4 * 4 * 4 * 4 * 4 · 4 * 4 * I“ I · e.g. of Mg, Ca +, Zn, Pe, Cu, Mn or Ni, etc. and amino acids or vitamins. In addition, to avoid foam formation during the fermentation, anti-foaming agents, e.g. silicone "KM75" (Shin-Etsu Kagaku K.K.).

Fermentation conditions such as temperature, pH, air stirring and fermentation time and the like can be selected in such a way that the bacteria used accumulate the maximum amount of the desired compound. For example, it is advantageous to carry out the fermentation at temperatures of 20-40 ° C, preferably 28 ° C, at pH 5-9, preferably 6-7, at a fermentation time of 1-10 days, preferably 6 days.

For isolation of compounds D788-6 to -10 from the fermentation solution, it may be separated after centrifugation or filtration in the presence of a suitable filter aid, such as diatomaceous earth, whereby the fermentation liquid is separated into bacteria and supernatant or filtrate. The compounds are extracted from the supernatant with organic solvents such as chloroform, toluene, ethyl acetate, etc. at pH 7-9.

The bacteria are extracted from the bacteria if necessary or, if desired, using organic solvents such as acetone, methanol, ethanol, butanol, etc. The individual extracts are concentrated to dryness to give a red, raw powder. The powder is subjected to chromatography using adsorbent carriers, e.g.

35 synthetic adsorbent resins or silica gel or they are treated with anion exchange resins and cation exchange resins individually or in appropriate combination to recover the compounds D788-6 to -10 in pure form.

DK 160879B

10

The invention is further illustrated in the following examples. The compound designated as D-788-6 is known from the above-mentioned literature site in Canadian J. Chem. and 5 are not included in the invention.

Example 1

From a YS (0.3% yeast extract, 1% soluble starch, 1.5% agar, pH 7.2) swab culture solution of Streptomyces D788, strain RPM-5 (deposited in Fermentation Re-10 search Institute, Agency of Industrial Science and Technology, Landfill No. 7703) is taken out by means of a platinum-needle needle which is inoculated into a 500 ml Erlenmeyer flask containing 100 ml of the seed culture medium described below in sterile form. Shake at 20 ° C for 2 days on a rotary shaker table (220 rpm) to make seed culture.

Seed culture medium:

Soluble starch 0.5%

Glucose 0.5% 20 Esus meat (soybean powder from Ajinomoto Limited). 1.0% Yeast extract 0.1%

Sodium chloride 0.1%

Secondary potassium phosphate 0.1% Magnesium sulfate (containing 7 50) 0.1%

Tap water pH 7.4 (before sterilization).

15 liters of production medium of the composition described below is added to a 30-liter fermentation vessel, then sterilized, then 750 ml (corresponding to 5%) of the above-described seed culture solution is then inoculated.

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DK 160879 B

Production medium:

Taiwanese yeast 5.00%

Soluble starch 7.50% Yeast extract 0.20% 5 Sodium chloride 0.20%

Calcium carbonate 0.30%

Mineral mixture * 0.06%

Tap water pH-value 8.2 (prior to sterilization) 10 * A solution of 2.8 g CuSO4 .5H2O, 0.4 g FeSO4. 71 µl, 3.2 g MnCl 2, 4H 2 O, and 0.8 g ZnSO 4 O 2 O in 500 ml distilled water.

The cultivation is carried out at 28 ° C for 130 hours with an aeration of 15 l / min. with stirring at 45 rpm and the culture solution assumes a deep reddish-brown color due to the product formed. The culture liquid is taken from the fermentation vessel and the culture solution is set to pH 1.7 with the wife. sulfuric acid, which is stirred at room temperature for approx. 1 hour. To the culture liquid is added 2% 20 filtration aid and the bacteria are isolated by filtration to give 13.5 liters of filtrate. The bacterial fraction is suspended in 6 liters of acetone, then the suspension is stirred for 20 minutes and extracted. After filtration, the acetone extract is concentrated to a volume of approx. 1.5 liters under reduced pressure. The concentrate is combined with the filtrate formed above to a total volume of 15 liters.

The filtrate (pH adjusted to 2.0-2.5 with 4N sodium hydroxide solution) is passed through a column packed with 750 ml of 30 "Dia Ion HP-20" (synthetic absorption resin from Mitsubishi Chemical Co., Ltd.) at SV of 4.5 for absorption of the product. Washing is then carried out with 1.5 liters of water of pH 1.7 (dilute sulfuric acid), after which the absorbed material is eluted with 1.4 liters of 50% aqueous acetone (pH 1.7). The eluate is concentrated under reduced pressure to a volume of approx. 800 ml. then

12 DK 160879 B

the concentrate is adjusted to pH 8.5 with 4N sodium hydroxide solution and extracted with a total of 2 liters of chloroform. The chloroform extract thus obtained is washed with water and then with saturated aqueous sodium chloride solution and dried over sodium sulfate. The sodium sulfate is filtered off and the filtrate is concentrated to a small volume under reduced pressure. Excess n-hexane is added to precipitate. Filter and dry in vacuo to give 1.84 g of crude powder containing D788-6, D788-7, D788-8 and D788-9.

The extraction residue from the chloroform extraction is adjusted to pH 2.5 'with 6N hydrochloric acid and extracted with a total of 1.5 liters of n-butanol. The butanol extracts formed are shaken with water having a pH of 2.5. The butanol is removed by concentration under reduced pressure and the residue is dissolved in a small amount of methanol.

To the solution is added excess toluene to precipitate the product. The solvent is removed by distillation to give 5.0 g of raw powder containing D788-10.

Example 2

A column is packed with 30 g of Wako Silica Gel C-200 (Wako Junya-ku Kogyo Co., Ltd.) using a mixture of chloroform and methanol (20: 1). The crude powder, 600 mg, obtained in Example 1 by extraction with chloroform 25 is dissolved in a small amount of a mixture of chloroform and methanol (20: 1) and the solution is absorbed on the top layer of the silica gel column, which is developed with the same solvent system . First, aglycone is eluted, then developed with 160 ml of a mixture of chloroform and methanol (15: 1), 140 ml of a mixture of chloroform and methanol (13: 1) and then with 260 ml of a mixture of chloroform and methanol (12: 1) to elute a D788-6 fraction. Further, a fraction containing D788-9 is eluted with 200 ml of a mixture of chloroform and methanol (10: 1). Then, elute with 200 ml of a mixture of chloroform, methanol and. water (200: 20: 0.5) and then with 200 ml of a mixture of chloro-

13 DK 160879 B

form, methanol and water (180: 20: 1) to give a fraction containing D788-7 and D788-8. The amount of the raw powder in the individual fractions after concentration to dryness is as follows: 5 D788-6 ** fraction 21 mg D788-7 * “fraction 45 mg D788-8 * fraction 79 mg D788-9 fraction 85 mg

The crude powders described above are purified and fractionated by thin layer chromatography as described below.

D788-6: The above-described D788-6 fraction is purified using a thin layer of silica gel (20 x 20 cm) (PF 254 Silica Gel, Merck Inc.) for fractionation. The fraction is deposited in the form of a horizontal line at a distance of 15 by 15 mm from the lower end of the thin layer, which is developed with a mixture of chloroform, methanol and water (25: 10: 1). D788-6 bands are extracted, which is extracted with a mixture of chloroform and methanol (8: 1). The extract is concentrated to dryness, the resulting powder 20 is dissolved in 0.1 M acetic acid buffer solution (pH 3.0) and the solution extracted and washed with chloroform. The aqueous phase remaining after the extraction is adjusted to pH 8.5 with 4 N sodium hydroxide solution and then extracted with chloroform. The resulting extract 25 is washed with water and then with a saturated aqueous sodium chloride solution, and the extract is dried over sodium sulfate. The chloroform extract is filtered and the filtrate is concentrated under reduced pressure. To the concentrate is added excess n-hexane to induce precipitation. The 30 precipitated product is filtered off and dried in vacuo to give 10 mg of D788-6 in pure form.

D788-7: The above-mentioned D788-7 fraction is subjected to thin layer chromatography on silica gel (see above) for fractionation using a mixture of chloroform, methanol, water and acetic acid (120: 25: 6: 14). Ribbons are taken correspondingly

DK 160879B

14 D788-7 and the extracted material is extracted with a mixture of chloroform, methanol and water (4: 1: 0.5). After concentrating the extract to dryness, the residue is dissolved in 0.1 M acetic acid buffer (pH 3.0) and the solution 5 is washed with chloroform and extracted with chloroform at pH 8.5 in the same manner as described above for the purification of D788-6 to give 21 mg of D788-7 in pure form.

D788-8: The above-mentioned D788-8 fraction obtained by column chromatography on silica gel is purified by thin layer chromatography for fractionation in the manner described above using a developer solvent consisting of a mixture of chloroform, methanol, water, acetic acid and 28% ammonia water (125: 55: 5.5: 0.9: 1.1).

I5 Bands corresponding to D788-8 are extracted and extracted with a mixture of chloroform, methanol and water (4: 1: 0.5). Then, the extract is treated analogously to the above-described procedure for purifying the D788-6 fraction and 28 mg of pure D788-8 is obtained.

D788-9: The D788-9 fraction (80 mg) obtained by chromatography on silica gel as described above is loaded onto a column filled with a suspension of 4 g of Wako Silica Gel C-200 (see above) in a mixture of chloroform and methanol (20: 1), which is then chromatographed again, using the same solvent system as 25 to give D788-9 with a purity of approx. 50%. This substance is fractionated by thin layer chromatography (see above) using a developer solvent consisting of a mixture of chloroform, methanol, water and acetic acid (120: 25: 6: 14) to purify and separate the mixture. Strips similar to D788-9 are taken and the material is extracted with a mixture of chloroform, methanol and water (4: 1: 0.5). The extract is then worked up in the same way as described above for D788-6 to give 35 22 mg of pure D788-9.

DK 160879 B

15

Example 3

The crude powder (5 g) prepared in Example 1 containing D788-10 extracted with butanol is placed on a column filled with a suspension of 35 g Wako Silica Gel C-200 5 (see above) in a mixture of chloroform, methanol and water (100: 10: 0.5), then developed with 200 ml of a mixture of chloroform, methanol and water (90: 10: 1), then with 360 ml of a mixture of chloroform, methanol and water (80). : 10: 1), 240 ml of a mixture of chloroform, meth-10 anole and water (70: 10: 1) and finally with 210 ml of a mixture of chloroform, methanol and water in a ratio of 60: 10: 1, to obtain fractions of D788-10 which are further purified. The D788-10 fractions are taken out and concentrated under reduced pressure to give partially purified D788-10 15 in powder form. The powdered product is dissolved in a dilute aqueous sodium hydrogen carbonate solution. The solution is washed with chloroform and the residual aqueous phase is adjusted to pH 2.5 with 6N hydrochloric acid and the aqueous phase is extracted with n-butanol. The extract is evaporated under reduced pressure to give 80 mg of powdered product. The product is further purified by thin layer chromatography for fractionation using a mixture of chloroform, methanol, water, acetic acid and 28% ammonia water (125: 55: 5.5: 0.9: 1.1).

25 Fractions corresponding to D788-10 are extracted and extracted with a mixture of chloroform, methanol and water (4: 1: 0.5) to which is added 1 drop of acetic acid. After concentrating the extract under reduced pressure, the residue is dissolved in a dilute aqueous sodium hydrogen carbonate solution. The solution is washed with chloroform and adjusted to pH 2.5 with 6N hydrochloric acid and extracted with n-butanol. The extract is concentrated to dryness to give 32 mg of purified D788-10.

The physicochemical properties of each of the compounds prepared above are listed below.

D788-6 16

DK 160879B

A) Melting point 138-140 ° C (decomposition) B) [α] β5 + 165 ° (° = methanol) C) Absorption spectra in the UV region and visible region 5 (methanol) nm ·): 206 1311) max 1 cm 235 (647) 255 (403) 290 (141) 10 492 (229) 511sh (177) 527sh (153) D) IR absorption spectrum (KBr) γ cm -1 1720, 1590, 1450, 1420, 1390, 1280, 1270 , 1190, 1160, 1000, 980 E) 1 H NMR Spectrum (CDCl3) δ ppm 1.1 (3H, t, J = 7.5 H-14) 1.33 (3H, d, J = 6 5 H-6 ') 1.51 (1H, dd, J = 12.4 H-2'a) 1.6-2.1 (3H, m, H-13, H-2'b) 2 , 1-2.4 (2H, m, H-8) 3.05 (1H, dd, J = 11, 4H-3 ') 3.41 (1H, bs, H-4') 3.69 ( 3H, s, COOCH 3) 4.1 (1H, g, J = 6.5 H 2) 4.26 (1H, s, H-10) 5.22 (1H, bs, H-7)

5.43 (1H, bs, H-1M)

7.22 (1H, dd, J = 8.2H-3) 7.62 (1H, t, J = 8H-2) 7.71 (1H, dd, J = 8.2H-1) D788-7

17 DK160S79B

A) Melting point 165-167 ° C

B) [α] + + 16 ° (c- = 0.0125, methanol) C) Absorption spectra in the UV range and the visible range 5 (methanol) λ ^ 30Η nm (e}%): 207 (332) max 1 cm 235 (702) 254 (424) 292 (139) 10 492 (254) 512sh (187) 528 (169) D) IR absorption spectrum (KBr) γ 0¾-1 1595, 1450, 1430, 1400, 1290, 1230, 1190, 1160, 1110, 1005, 980 E) 1 H + NMR spectrum (CDCl3 + CD30D) δ ppm 1.09 (3H, t, J = 7.5 H-14) 1.32 (3H, d, J = 6.5 H-6 ') 1.6-1.9 (4H, m, H-2 \ H-13) 2.2 (2H, bs, H-8) 2.7-3.2 ( IH, m, H-3 ') 3.46 (1H, bs, H-4') 4.12 (1H, g, J = 6.5 H-5 ') 4.81 (1H, s, H- 10) 5.1 (1H, bs, H-7) 5.4 (1H, bs, H-1 ') 7.23 (1H, dd, J = 8, 1.5 H-3) 7.64 (1H, t, J = 8H-2) 7.79 (1H, dd, J = 8, 1.5 H1) D788-8

18 DK 160879B

A) Melting point 126-128 ° C (decomposition) B) [α] + 309 ° (c = 0.0175, methanol) C) Absorption spectra in the UV range and visible range 5 (in methanol) XCH30H nm (E? -%): 206 (609) max 1 cm 227 (429) 269 (619) 494 (283) 10 515 (300) 550sh (183) D) IR absorption spectrum (KBr) γ cm 2 1600, 1460, 1400, 1370 , 1285, 1250, 1200, 1170, 1110, 1015, 980 E) HH-NMR spectrum (CDCl - - CDgOD) δ ppm 1.3 (1H, d, J = 6.5 H-61) 1.4 (3H , d, J = 6.5 H-14) 1.5-1.9 (2H, m, H-2 ') 2.5 (1H, dd, J = 18, 4.5 H-8a) 2.8 (1H, d, J = 18H-8b) 2.8-3.2 (1H, m, H-3 ') 3.38 (1H, bs, H-41) 3.98 (1H, q, J = 6.5 H-5 ') 4.49 (1H, q, J = 6.5 H-13) 5.2 (1H, bs, H-1') 6.97 (1H, bs, H- 10): 7.18 · (1H, dd, J = 8, 1.5H-3)! 7.59 (1H, t, J = 8H-2) 7.75 (1H, dd, J = 8, 1.5H-1)

19 DK 160879B

D788-9

A) Melting point 175-180 ° C

B) [α] + 62 ° (c + = 0.0145, methanol) C) UV and visible range spectra (in methanol) ACH30H nm (E?%): 206 (307) max 1 cm 235 (671) 255 (428) 291 (153) 10 481sh (212) 493 (226) 512sh (171) 526 (148) D) IR absorption spectrum (KBr) γ cm 2 1725, 1710sh, 1600, 1450 , 1430, 1400, 1290, 1240, 1190, 1165, 1110, 1005, 980 E) 1 H-NMR spectrum (CDCl3): <5 ppm 1.36 (3H, d, J = 6.5 H-6 ') 1.5-2.0 (2H; m, H-21) 2.2 (1H, dd, J = 16, 4.5H-8a) 2.27 (3H, s, H-14) 2.6 ( 1H, d, J = 16H-8b) 2.9-3.3 (1H, m, H-3 ') 3.46 (1H, bs, H-41) 3.69 (3H, s, C 4.13 (1H, q, J = 6.5 H-5 ·) 4.37 (1H, s, H-10) 5.12 (1H, d, J = 4.5 H-7) 5.42 ( IH, bs, H1 *) 7.23 (1H, dd, J = 8, 1.5H-3) 7.6 (1H, t, J = 8H-2) 7.77 (1H, dd, J = 8 , 1.5 Hl) D-788-10 20

DK 160879B

A) Melting point 174-176 ° C

B) [a] p5 + 200 ° (C = 0.0185, methanol) C) Absorption spectra in the UV region and the visible region 5 (in methanol) XCH 30 H nm (eJ%): 209 (362) max 1 cm '226 (371) 257 (329) 497 (169) D 514sh (155) D) IR absorption spectrum (KBr) γ cm -1 1710, 1600, 1450, 1390, 1280, 1230, 1190, 1160, 1115, 1010, 980 E) 1 H-NMR Spectrum (CDCl3 -CD3 OD) δ ppm 1.3 (3H, d, J = 6.5 H-6 ') 1.4 (3H, d, J = 6.5 H-14) 1.5-1.9 (2H, m, H-21) 2.1-2.8 (2H, m, H-8) 3.7 (1H, bs, H-41) 4.0 (1H , g, J = 6.5 H-13) 4.1 (1H, s, H-10) 4.2 (1H, q, J = 6.5 H-5 ') 5.1 (1H, bs, H-7) 5.5 (1H, bs, H1) 7.2 (1H, dd, J = 8 1.5 H-3) 7.6 (1H, t, J = 8 H-2) 7.7 (1H, dd, J = 8, 1.5 Η, Ι)

Claims (5)

21 DK 160879 B Anthracycline antibiotics, characterized in that they have the general formula O OH HO O OH 0 »“ piV HO NH2 5 wherein Y means a group of the formula OH OH ′ OH, I CH °° CO HOOC OH ΛΛ I ′ OH or | ΌΗ * Anthracycline antibiotic according to claim 1, characterized in that it has the formula O OH OH ^ || 'I I' OH YyYV HO O OH O OH NH2 22 DK 160879 B Anthracycline antibiotic according to claim 1, characterized in that it has the formula OH O OH q 'NH, OH 1 Anthracycline antibiotic according to claim 1, characterized in that it has the formula cocch-3 O OH r, OH 0 ° H g * 3Cpd U CS2 An anthracycline antibiotic according to claim 1, characterized in that it has the formula O OH “(° H OH 0 0H ° h3 cpp Γ NH, OH 1