CA2019315A1 - Anthracycline derivatives, a process for the preparation thereof and the use thereof as a pharmaceutical - Google Patents
Anthracycline derivatives, a process for the preparation thereof and the use thereof as a pharmaceuticalInfo
- Publication number
- CA2019315A1 CA2019315A1 CA002019315A CA2019315A CA2019315A1 CA 2019315 A1 CA2019315 A1 CA 2019315A1 CA 002019315 A CA002019315 A CA 002019315A CA 2019315 A CA2019315 A CA 2019315A CA 2019315 A1 CA2019315 A1 CA 2019315A1
- Authority
- CA
- Canada
- Prior art keywords
- roa
- compound
- rod
- formula
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/244—Anthraquinone radicals, e.g. sennosides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P19/00—Preparation of compounds containing saccharide radicals
- C12P19/44—Preparation of O-glycosides, e.g. glucosides
- C12P19/56—Preparation of O-glycosides, e.g. glucosides having an oxygen atom of the saccharide radical directly bound to a condensed ring system having three or more carbocyclic rings, e.g. daunomycin, adriamycin
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- Microbiology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Abstract of the disclosure:
Novel anthracycline derivatives, a process for the preparation thereof and the use thereof as a pharmaceutical The present invention relates to anthracycline deriv-atives of the formula I
(I) in which R1 is the sugar residue Roa or the combination of sugars Roa-Rod-Rod and R2 is the sugar residue Roa, Roa being rhodosamine of the formula II
(II) and Roa-Rod-Rod being rhodosamine-rhodinose-rhodinose of the formula III
(III) and the pharmacologically acceptable salts thereof, and a microbiological process for the preparation thereof.
The compounds have cytostatic activity and can therefore be used as pharmaceuticals.
Novel anthracycline derivatives, a process for the preparation thereof and the use thereof as a pharmaceutical The present invention relates to anthracycline deriv-atives of the formula I
(I) in which R1 is the sugar residue Roa or the combination of sugars Roa-Rod-Rod and R2 is the sugar residue Roa, Roa being rhodosamine of the formula II
(II) and Roa-Rod-Rod being rhodosamine-rhodinose-rhodinose of the formula III
(III) and the pharmacologically acceptable salts thereof, and a microbiological process for the preparation thereof.
The compounds have cytostatic activity and can therefore be used as pharmaceuticals.
Description
HOECHST AKTIENGESELLSCHAFT HOE 89/F 191 Dr. LA/rh Description Novel anthracycline derivatives, a process for the preparation thereof and the use thereof as a pharmaceutical The present invention relates to anthracycline deriv-atives of the formula I
O HO OR , (I) OH O HO
, :
in which R1 iB the sugar residue Roa or the combination of ~-sugars Roa-Rod-Rod:and R2 is the sugar residue Roa, Roa being rhodosamine of the formula II
~: ,N~CH~3)2 OH (II) ~ ' ~", ~
:~ .
and Roa-Rod-Rod being rhodosamine-rhodinose-rhodinose of the formula III
N ( CH 31 2 '; ~ '=" ~ "'~ (III) and the pharmacologically acceptable salts thereof.
O HO OR , (I) OH O HO
, :
in which R1 iB the sugar residue Roa or the combination of ~-sugars Roa-Rod-Rod:and R2 is the sugar residue Roa, Roa being rhodosamine of the formula II
~: ,N~CH~3)2 OH (II) ~ ' ~", ~
:~ .
and Roa-Rod-Rod being rhodosamine-rhodinose-rhodinose of the formula III
N ( CH 31 2 '; ~ '=" ~ "'~ (III) and the pharmacologically acceptable salts thereof.
2 ~
The invention also relates to a proces~ for the prepar-ation of compounds of the formula I, which comprises the cytorhodin crude mixture which is obtained as fraction B
according to Example 4 of the EP-A-0,131,181 by cultiva-tion of the microorganism strain Y-11,472 (DSM 2658) and extraction of the mycelium and of the culture filtrate using various organic solvents, a) being dissolved in aqueous buffer, preferably at pH 3.0-~.O, the resulting solution being extracted at pH values which are increased stepwise, preferably at pH 6.0, 7.0 and 8.0, with an organic solvent, preferably ethyl acetate, obtaining a com-pound of the formula I in which Rl is Roa-Rod-Rod and R2 is Roa by chromatographic purification from the extracts which have been concentrated, and b) the resulting compound being optionally converted into a compound of the formula I in which Rl and R2 are each Roa by hydrolysis with an inorganic acid.
The hydrolysis is carried out using a dilute inorganic acid, preferably hydrochloric acid, for example with stirring for several hours at room temperature. The desired compound is then obtained from the reaction medium by extraction, for example using chloroform.
I
The anthracyclinone glycoside class of substances has been known for a long time. The cytostatically active compounds daunorubicin and doxorubicin (cf. for example F. Arcamone, Doxorubicin, Academic Press, New York, 1981) which arè used in particular for the treatment of malig-nant tumors belong thereto. Many other representatives of this class of substances have now been prepared by a biological or semisynthetic route, amongst these also being the cytorhodins which are particularly interesting because of their superior cytostatic effect ~EP-A-0,131,181; EP-A-0,131,942).
Structural features of almost all the biosynthetically prepared anthracyclines are the variously substituted anthracyclinone framework, one or more sugars which are ~lycosidically bonded to secondary hydroxyl groups (usually C-7, C-10), and often a free, tertiary OH group on C-9 (D.G. Strauss, Pharmazie 42 (1987), 289~.
Surprisingly, it has now also been possible to prepare by a microbiological route anthracyclinone C-9 glycosides which are distinguished by their cytostatic activity and low acute toxicity.
The cytostatic activity was determined on L 1210 leukemia cells in the so-called proliferation test as follows:
L 1210 cells in the exponential growth phase (5 x 103/ml in RPMI 1640) are incubated in a micro~iter plate for 72 hours with various concent~ations of the test subs-tance (37C, 5 % CO2, 95 % relative humidity).
Controls are composed of cells which are incubated withfresh medium only. All determinations are carried out as quadruple determination~. After 65 hours 50 ~l of MTT ~3-(4-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, 2.5 mg~ml in PBS) are added. MTT is reduced to a red, insoluble formazan dye by live cells. After a further 7-hour incubation the supernatant medium i8 carefully aspirated off. The formazan dye is dissolved by the addition of 100 ~l of DMSO into each of the wells of the microtiter plate and careful shaking. The extinction of each solution is measured at 492 nm using a Multiscan 340 CC photometer, from Plow.
From the measurements thus obtained the dose effect plot is determined, and the IC50, i.e. the concentration which, under the test conditions, reduces the formation of the formazan dye by 50 % in comparison with the control, is determined graphically.
For the determination of the acute toxicity, BDF1 mice were injected intravenously on day 0, day 3 and day 6 with various doses of the teæt substance which had been dissolved in 0.4 ml of physiological saline. Control groups received only 0.4 ml of physiological saline. Two mice were used per concentration of the test substance.
On day 20, the number of surviving mice and, from this, the LDso was determined. The toxicity of the compound described here in comparison with adriamycin is sum-marized in Table 1.
Table 1 Compound Cytotoxicity Acute (Continuous toxicity incubation) LDso , . , ~ IC50 (~g/ml) (mg/kg) :
Cytorhodin Z 0.33 10-25 9-O,10-O-bis(~-L-rhodosaminyl)-~-rhodo-0.35 25-50 mycinone ~ Adriamycin 0.02-0.03 10 :;~ :' :
On the basis of the cystosta~ic activity sho~n, the com-pounds according to the invention are suitable for the treatment of malignant tumors of mammals, for example of human gastro-intestinal, mammary, ovarian and bronchial tumors.
The process according to the invention is illustrated by the following examples:
~xample 1 21 g of cytorhodin crude mixture are dissolved in 5.0 1 of sodium acetate buffer pH 3.0, the pH subsequently l~ 30 being adjusted to 6.0 using 2 N sodium hydroxide solu-¦ tion. The aqueous phase is extracted with 1 1 of ethyl ¦ acetate, adjusted to pH 7.0 using 2 N NaOH and extracted twice with 2 1 of ethyl acetate each time. For the complete extraction of the cytorhodins, the pH of the aqueous phase is increased to 8.0 and it is extracted with 2 1 of chloroform. The organic phases are dried over sodium sulfate and concentrated in vacuo. The following products are obtained:
Fraction I (pH 6.0): 11.4 g of mainly nonpolar cyto-rhodins ; Fraction II (pH 7.0): 8.3 g of cytorhodins of medium ~o polarity Fraction III (pH 8.0~: 1.7 g of polar cytorhodins 4.8 g of the drisd extract from fraction II (pH 7.0) are dissolved in 30 ml of methanol/l % triethylammonium phosphate buffer pH 7.0 = 93:7 (system A) and applied to a steel column containing 1.9 1 of RP-18 silica gel (LiChroprep RP-18, 25-40 ~m, Merck) which has been equilibrated with system A, and are eluted with system A
~;~ at a flow rate of 20 ml/min. After a fore-run of 1000 ml, fractions of 20 ml are collected and analyzed by thin-layer chromatography (silica gel 60 F254 Merck, system B:
chloroform/ methanol/glacial acetic acid/water = 75:16:10:4). The fractions containing cytorhodin Z
(Fr. 55-95) are combined, an equal volume of water i8 added and they are extracted with 1/5 of the volume of chloroform. The organic phase is washed with water, dried over sodium sulfate, concentrated in vacuo and precipita-ted using hexane.
Yield: 1.9 g of~enriched cytorhodin Z.
~xample 2 1.5 g of cytorhodin Z obtained as in Example 1 are dissolved in 6 ml of chloroform/methanol/glacial acetic acid/water = 50:25:7:4 (system C) and applied to a column containing 205 ml of silica gel 60 Merck 15-40 ~m, equilibrated with system C, and are eluted with system C.
After a fore-run of 600 ml, fractions of 10 ml are col-lected and analyzed by thin-layer chromatography (silica gel 60 F254 Merck, system B). Fractions containing cytorhodin Z (Fr. 10-60) are combined, and a 5 % strength aqueous NaaHPO4 solution is added until the chloroform phase separates~out. The organic phase is washed with Na2HPO4 solution and with water, dried over sodium 8ul-fate, concentrated in vacuo and precipitated using hexane.
Yield: 660 mg of pure cytorhodin Z.
Red, amorphous substance, readily soluble in methanol, ethyl acetate, chloroform, insoluble in water and hexane.
Thin-layer chromatography: Silica gel 60 F~54 Merck System: CHCl3/MeOH/glacial acetic acid/H2O
75:16:10:4; Rf = 0.50 W Maxima: 236, 256, 296, 466 (sh.), 493, 512 (sh.) in methanol/10 % HCl NMR spectrum: Figure 1 -H6gN2Ol5/ Mca1C. 912 (FAB NS confirmed) Cytorhodin Z has the formula I in which R1 is Roa-Rod-Rod ~ and R2 is Roa.
: ~
~xample 3 0.2 g of cytorhodin Z prepared according to Example 2 are stirred in 20 ml of dilute hydrochloric acid (pH 1.3) for 2 hours at room temperature. The solution is extracted with one volume of chloroform, and the aqueous phase is ad~usted to pH 8.0 using 1 N NaOH and is extracted twice with one volume of chloroform each time. The organic phases are combined, dried over sodium sulfate, con-centrated in vacuo and precipitated using hexane.
Yields 135 mg of hydrolysis product = 9-O,10-O-bis(~-L-rhodosaminyl)-~-rhodomycinone.
Red, amorphous substance, readily soluble in methanol, ethyl acetate, chloroform, insoluble in water and hexane.
Thin-layer chromatography: Silica gel 60 F254 Merck System B: Chloroform/methanol/glacial acetic acid/water 75:16:10:4; R~ = 0.27 W Maxima: 236, 255, 295, 465 (sh.), 493, 513 (sh.), in methanol/10 % HC1 NMR spectrum: Figure 2 N2O1l~ Mc~1c. 684 (FAB MS confirmed).
The identification of the compounds from the above examples is carried out using the measuring conditions described hereinafter The lH-NNR spectra were recorded on a HX-270 BRUKER Fourier Transform nuclear magnetic reson-ance spectrometer at 270 MHz. The concentrations were 2-4 mg/0.5 ml of 99.8 % pure CDC13; the solutions were shaken with 0.1 ml of 5 % ~trength Na2CO3 in 99.5 ~ D2O
immediately of preparation.
The signals which are marked with an asterisk * in the figures are due to residual solvent. The mass spectra were recorded after on MS-902 S mass spectrometer, EAI
u~ing a FAB ioA s~orce.
~:; ,, .
,~
....
The invention also relates to a proces~ for the prepar-ation of compounds of the formula I, which comprises the cytorhodin crude mixture which is obtained as fraction B
according to Example 4 of the EP-A-0,131,181 by cultiva-tion of the microorganism strain Y-11,472 (DSM 2658) and extraction of the mycelium and of the culture filtrate using various organic solvents, a) being dissolved in aqueous buffer, preferably at pH 3.0-~.O, the resulting solution being extracted at pH values which are increased stepwise, preferably at pH 6.0, 7.0 and 8.0, with an organic solvent, preferably ethyl acetate, obtaining a com-pound of the formula I in which Rl is Roa-Rod-Rod and R2 is Roa by chromatographic purification from the extracts which have been concentrated, and b) the resulting compound being optionally converted into a compound of the formula I in which Rl and R2 are each Roa by hydrolysis with an inorganic acid.
The hydrolysis is carried out using a dilute inorganic acid, preferably hydrochloric acid, for example with stirring for several hours at room temperature. The desired compound is then obtained from the reaction medium by extraction, for example using chloroform.
I
The anthracyclinone glycoside class of substances has been known for a long time. The cytostatically active compounds daunorubicin and doxorubicin (cf. for example F. Arcamone, Doxorubicin, Academic Press, New York, 1981) which arè used in particular for the treatment of malig-nant tumors belong thereto. Many other representatives of this class of substances have now been prepared by a biological or semisynthetic route, amongst these also being the cytorhodins which are particularly interesting because of their superior cytostatic effect ~EP-A-0,131,181; EP-A-0,131,942).
Structural features of almost all the biosynthetically prepared anthracyclines are the variously substituted anthracyclinone framework, one or more sugars which are ~lycosidically bonded to secondary hydroxyl groups (usually C-7, C-10), and often a free, tertiary OH group on C-9 (D.G. Strauss, Pharmazie 42 (1987), 289~.
Surprisingly, it has now also been possible to prepare by a microbiological route anthracyclinone C-9 glycosides which are distinguished by their cytostatic activity and low acute toxicity.
The cytostatic activity was determined on L 1210 leukemia cells in the so-called proliferation test as follows:
L 1210 cells in the exponential growth phase (5 x 103/ml in RPMI 1640) are incubated in a micro~iter plate for 72 hours with various concent~ations of the test subs-tance (37C, 5 % CO2, 95 % relative humidity).
Controls are composed of cells which are incubated withfresh medium only. All determinations are carried out as quadruple determination~. After 65 hours 50 ~l of MTT ~3-(4-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, 2.5 mg~ml in PBS) are added. MTT is reduced to a red, insoluble formazan dye by live cells. After a further 7-hour incubation the supernatant medium i8 carefully aspirated off. The formazan dye is dissolved by the addition of 100 ~l of DMSO into each of the wells of the microtiter plate and careful shaking. The extinction of each solution is measured at 492 nm using a Multiscan 340 CC photometer, from Plow.
From the measurements thus obtained the dose effect plot is determined, and the IC50, i.e. the concentration which, under the test conditions, reduces the formation of the formazan dye by 50 % in comparison with the control, is determined graphically.
For the determination of the acute toxicity, BDF1 mice were injected intravenously on day 0, day 3 and day 6 with various doses of the teæt substance which had been dissolved in 0.4 ml of physiological saline. Control groups received only 0.4 ml of physiological saline. Two mice were used per concentration of the test substance.
On day 20, the number of surviving mice and, from this, the LDso was determined. The toxicity of the compound described here in comparison with adriamycin is sum-marized in Table 1.
Table 1 Compound Cytotoxicity Acute (Continuous toxicity incubation) LDso , . , ~ IC50 (~g/ml) (mg/kg) :
Cytorhodin Z 0.33 10-25 9-O,10-O-bis(~-L-rhodosaminyl)-~-rhodo-0.35 25-50 mycinone ~ Adriamycin 0.02-0.03 10 :;~ :' :
On the basis of the cystosta~ic activity sho~n, the com-pounds according to the invention are suitable for the treatment of malignant tumors of mammals, for example of human gastro-intestinal, mammary, ovarian and bronchial tumors.
The process according to the invention is illustrated by the following examples:
~xample 1 21 g of cytorhodin crude mixture are dissolved in 5.0 1 of sodium acetate buffer pH 3.0, the pH subsequently l~ 30 being adjusted to 6.0 using 2 N sodium hydroxide solu-¦ tion. The aqueous phase is extracted with 1 1 of ethyl ¦ acetate, adjusted to pH 7.0 using 2 N NaOH and extracted twice with 2 1 of ethyl acetate each time. For the complete extraction of the cytorhodins, the pH of the aqueous phase is increased to 8.0 and it is extracted with 2 1 of chloroform. The organic phases are dried over sodium sulfate and concentrated in vacuo. The following products are obtained:
Fraction I (pH 6.0): 11.4 g of mainly nonpolar cyto-rhodins ; Fraction II (pH 7.0): 8.3 g of cytorhodins of medium ~o polarity Fraction III (pH 8.0~: 1.7 g of polar cytorhodins 4.8 g of the drisd extract from fraction II (pH 7.0) are dissolved in 30 ml of methanol/l % triethylammonium phosphate buffer pH 7.0 = 93:7 (system A) and applied to a steel column containing 1.9 1 of RP-18 silica gel (LiChroprep RP-18, 25-40 ~m, Merck) which has been equilibrated with system A, and are eluted with system A
~;~ at a flow rate of 20 ml/min. After a fore-run of 1000 ml, fractions of 20 ml are collected and analyzed by thin-layer chromatography (silica gel 60 F254 Merck, system B:
chloroform/ methanol/glacial acetic acid/water = 75:16:10:4). The fractions containing cytorhodin Z
(Fr. 55-95) are combined, an equal volume of water i8 added and they are extracted with 1/5 of the volume of chloroform. The organic phase is washed with water, dried over sodium sulfate, concentrated in vacuo and precipita-ted using hexane.
Yield: 1.9 g of~enriched cytorhodin Z.
~xample 2 1.5 g of cytorhodin Z obtained as in Example 1 are dissolved in 6 ml of chloroform/methanol/glacial acetic acid/water = 50:25:7:4 (system C) and applied to a column containing 205 ml of silica gel 60 Merck 15-40 ~m, equilibrated with system C, and are eluted with system C.
After a fore-run of 600 ml, fractions of 10 ml are col-lected and analyzed by thin-layer chromatography (silica gel 60 F254 Merck, system B). Fractions containing cytorhodin Z (Fr. 10-60) are combined, and a 5 % strength aqueous NaaHPO4 solution is added until the chloroform phase separates~out. The organic phase is washed with Na2HPO4 solution and with water, dried over sodium 8ul-fate, concentrated in vacuo and precipitated using hexane.
Yield: 660 mg of pure cytorhodin Z.
Red, amorphous substance, readily soluble in methanol, ethyl acetate, chloroform, insoluble in water and hexane.
Thin-layer chromatography: Silica gel 60 F~54 Merck System: CHCl3/MeOH/glacial acetic acid/H2O
75:16:10:4; Rf = 0.50 W Maxima: 236, 256, 296, 466 (sh.), 493, 512 (sh.) in methanol/10 % HCl NMR spectrum: Figure 1 -H6gN2Ol5/ Mca1C. 912 (FAB NS confirmed) Cytorhodin Z has the formula I in which R1 is Roa-Rod-Rod ~ and R2 is Roa.
: ~
~xample 3 0.2 g of cytorhodin Z prepared according to Example 2 are stirred in 20 ml of dilute hydrochloric acid (pH 1.3) for 2 hours at room temperature. The solution is extracted with one volume of chloroform, and the aqueous phase is ad~usted to pH 8.0 using 1 N NaOH and is extracted twice with one volume of chloroform each time. The organic phases are combined, dried over sodium sulfate, con-centrated in vacuo and precipitated using hexane.
Yields 135 mg of hydrolysis product = 9-O,10-O-bis(~-L-rhodosaminyl)-~-rhodomycinone.
Red, amorphous substance, readily soluble in methanol, ethyl acetate, chloroform, insoluble in water and hexane.
Thin-layer chromatography: Silica gel 60 F254 Merck System B: Chloroform/methanol/glacial acetic acid/water 75:16:10:4; R~ = 0.27 W Maxima: 236, 255, 295, 465 (sh.), 493, 513 (sh.), in methanol/10 % HC1 NMR spectrum: Figure 2 N2O1l~ Mc~1c. 684 (FAB MS confirmed).
The identification of the compounds from the above examples is carried out using the measuring conditions described hereinafter The lH-NNR spectra were recorded on a HX-270 BRUKER Fourier Transform nuclear magnetic reson-ance spectrometer at 270 MHz. The concentrations were 2-4 mg/0.5 ml of 99.8 % pure CDC13; the solutions were shaken with 0.1 ml of 5 % ~trength Na2CO3 in 99.5 ~ D2O
immediately of preparation.
The signals which are marked with an asterisk * in the figures are due to residual solvent. The mass spectra were recorded after on MS-902 S mass spectrometer, EAI
u~ing a FAB ioA s~orce.
~:; ,, .
,~
....
Claims (6)
1. A compound of the formula I
(I) in which R1 is the sugar residue Roa or the combination of sugars Roa-Rod-Rod and R2 is the sugar residue Roa, and the pharmacoligically acceptable salts thereof.
(I) in which R1 is the sugar residue Roa or the combination of sugars Roa-Rod-Rod and R2 is the sugar residue Roa, and the pharmacoligically acceptable salts thereof.
2. A process for the preparation of a compound as claimed in claim 1, which comprises the cytorhodin crude mixture which is obtained according to EP-A-0,131,181 by culti-vation of the microorganism strain EP-11,472 (DSM 2658) and extraction of the mycelium and of the culture filtrate using organic solvents, a) being dissolved in an aqueous buffer at a pH of 3.0 to 4.0, the resulting solution being extracted at pH values, which are increased stepwise, with an organic solvent and isolating the compound of the formula I in which R1 is Roa-Rod-Rod and R2 is Roa by means of chromatographic purification from the extracts which have been concentrated, and b) the resulting compound being optionally hydrolyzed to the compound of the formula I in which R1 and R2 are each Rosa using an inorganic acid.
3. The process as claimed in claim 2, wherein the aqueous buffer solution is in step a) extracted stepwise at the pH values 6.0, 7.0 and 8.0 with ethyl acetate.
4. A pharmaceutical which contains a compound as claimed in claim 1.
5. The use of a compound as claimed in claim 1 for the preparation of a pharmaceutical with a cytostatic effect.
6. The compound as claimed in claim 1 and substantially as described herein.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3920062A DE3920062A1 (en) | 1989-06-20 | 1989-06-20 | NEW ANTHRACYCLINE DERIVATIVES, A METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
| DEP3920062.0 | 1989-06-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2019315A1 true CA2019315A1 (en) | 1990-12-20 |
Family
ID=6383094
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002019315A Abandoned CA2019315A1 (en) | 1989-06-20 | 1990-06-19 | Anthracycline derivatives, a process for the preparation thereof and the use thereof as a pharmaceutical |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0403963A3 (en) |
| JP (1) | JPH0343093A (en) |
| KR (1) | KR910000781A (en) |
| AU (1) | AU5761690A (en) |
| CA (1) | CA2019315A1 (en) |
| DE (1) | DE3920062A1 (en) |
| IE (1) | IE902215A1 (en) |
| PT (1) | PT94406A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10029433A1 (en) * | 2000-06-15 | 2001-12-20 | Bioleads Gmbh | New rhodomycinone compounds, e.g. ditrisarubicin I and cytorhodin Y, useful as anticancer agents, prepared by culturing new actinomycete strain |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3323025A1 (en) * | 1983-06-25 | 1985-01-10 | Hoechst Ag, 6230 Frankfurt | ANTHRACYCLINE DERIVATIVES, A MICROBIOLOGICAL METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS CYTOSTATICS |
| DE3446052A1 (en) * | 1984-12-18 | 1986-07-17 | Hoechst Ag, 6230 Frankfurt | ANTHRACYCLINE DERIVATIVES, A MICROBIOLOGICAL METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
| DE3712350A1 (en) * | 1987-04-11 | 1988-10-20 | Behringwerke Ag | SEMISYNTHETIC RHODOMYCINES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS CYTOSTATICS |
-
1989
- 1989-06-20 DE DE3920062A patent/DE3920062A1/en not_active Withdrawn
-
1990
- 1990-06-15 EP EP19900111287 patent/EP0403963A3/en not_active Withdrawn
- 1990-06-19 AU AU57616/90A patent/AU5761690A/en not_active Abandoned
- 1990-06-19 PT PT94406A patent/PT94406A/en not_active Application Discontinuation
- 1990-06-19 JP JP2158887A patent/JPH0343093A/en active Pending
- 1990-06-19 IE IE221590A patent/IE902215A1/en unknown
- 1990-06-19 CA CA002019315A patent/CA2019315A1/en not_active Abandoned
- 1990-06-19 KR KR1019900008988A patent/KR910000781A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| KR910000781A (en) | 1991-01-29 |
| IE902215A1 (en) | 1991-01-16 |
| AU5761690A (en) | 1991-01-03 |
| JPH0343093A (en) | 1991-02-25 |
| DE3920062A1 (en) | 1991-01-10 |
| EP0403963A3 (en) | 1991-09-18 |
| EP0403963A2 (en) | 1990-12-27 |
| PT94406A (en) | 1991-03-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4067969A (en) | Anthracycline glycosides, their preparation and use | |
| US4316011A (en) | Rhodomycin antibiotics | |
| ECKARDT et al. | Isolation and chemical structure of aklanonic acid, an early intermediate in the biosynthesis of anthracyclines | |
| CA1206472A (en) | Anthracyclinone glycosides and their preparation method | |
| Cassinelli et al. | Preparation and biological evaluation of 4-O-demethyldaunorubicin (carminomycin I) and of its 13-dihydro derivative | |
| Matsuzawa et al. | New anthracycline metabolites from mutant strains of Streptomyces galilaeus MA144-M1 II. Structure of 2-hydroxyaklavinone and new aklavinone glycosides | |
| US4219622A (en) | Process for producing antibiotics MA 144-M1 and MA 144-M2 | |
| US4303785A (en) | Antitumor anthracycline antibiotics | |
| CA1090788A (en) | Process for the preparation of antitumor glycosides | |
| US4198480A (en) | Process for producing antibiotic baumycin complex and components | |
| EP0045474B1 (en) | Anthracycline derivatives | |
| US4386198A (en) | 2-Hydroxyaclacinomycin A and 2-hydroxyaklavinone and process for preparing same | |
| PANDEY et al. | MAGGIEMYCIN AND ANHYDROMAGGIEMYCIN: TWO NOVEL ANTHRACYCLINONE ANTITUMOR ANTIBIOTICS ISOLATION, STRUCTURES, PARTIAL SYNTHESIS AND BIOLOGICAL PROPERTIES | |
| US4199571A (en) | Substituted anthracyclines, their preparation and use | |
| CA2019315A1 (en) | Anthracycline derivatives, a process for the preparation thereof and the use thereof as a pharmaceutical | |
| EP0014425B1 (en) | Anthracycline glycosides, methods for the production thereof and therapeutical compositions containing same | |
| ISHII et al. | The structure of decilorubicin | |
| US4265885A (en) | Anthracyclines containing branched-chain amino-deoxy sugars | |
| LI et al. | Structural studies on rhodilunancins A and B | |
| US4204038A (en) | Process for preparing antibiotics MA 144-M1 and MA 144-M2 | |
| Argoudelis et al. | PAULOMYCIN-RELATED ANTIBIOTICS: PALDIMYCINS AND ANTIBIOTICS 273a2 ISOLATION AND CHARACTERIZATION | |
| YOSHIMOTO et al. | New anthracycline antibiotics obtained by microbial glycosidation of β-isorhodomycinone and α2-rhodomycinone | |
| US4877870A (en) | Process for producing 10-hydroxyanthracyclines | |
| US4501699A (en) | Maggiemycin, anhydromaggiemycin and processes for making | |
| JOHDO et al. | ANTHRACYCLINE METABOLITES FROM Streptomyces violaceus A262 IV. NEW ANTHRACYCLINE YELLAMYCINS PRODUCED BY A VARIANT STRAIN SC-7 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |