WO1997040057A1 - Antitumoral anthracycline disaccharides - Google Patents
Antitumoral anthracycline disaccharides Download PDFInfo
- Publication number
- WO1997040057A1 WO1997040057A1 PCT/EP1997/001818 EP9701818W WO9740057A1 WO 1997040057 A1 WO1997040057 A1 WO 1997040057A1 EP 9701818 W EP9701818 W EP 9701818W WO 9740057 A1 WO9740057 A1 WO 9740057A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- coch
- fermentation
- vancosaminyl
- compound
- pharmaceutically acceptable
- Prior art date
Links
- 0 CC(CC(OC(C(C1)N)C(C(*)*)OC1O[C@@](C[C@](C)(Cc1c(c(C(c2cccc(C=O)c22)=O)c3C2=O)O)O)c1c3[O+])OC1C=C)(C1O)N Chemical compound CC(CC(OC(C(C1)N)C(C(*)*)OC1O[C@@](C[C@](C)(Cc1c(c(C(c2cccc(C=O)c22)=O)c3C2=O)O)O)c1c3[O+])OC1C=C)(C1O)N 0.000 description 1
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
- C07H15/252—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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
Definitions
- the present invention relates to new antitumoral anthracycline disaccharides, to their production and to pharmaceutical preparations containing them. These anthracyclines are useful as antitumoral agents and are active against gram positive and gram negative bacteria.
- the compounds object ofthe present invention have the formula reported below:
- R represents:
- the vegetative mycelium is formed of branched hyphae of varying length and 0.5-0.9 micron in diameter; the aerial mycelium which derives from the former is formed of long and flexuous hyphae often collapsed and tortuous of 0.9-1.2 micron in diameter.
- Sporulation is very poor, in short chains terminating in the form of hooks.
- the spores are oval and measure: 0.8-1.1 x 1.9-2.2 micron. On scanning electron microscopic examination the spores appear with a smooth surface.
- the cultural characteristics of the 15105 strain are reported in Table 1. Growth is generally good on organic and synthetic media. The course of growth was evaluated after 14 days of incubation at 28°C.
- the medium used for the test was Yeast nitrogen base (Difco) supplemented with 1% K 2 HPO 4 . TABLE 3 Biochemical characteristics of strain 15105
- the medium used for the growth ofthe strain was ISP3 (Difco).
- ISP3 ISP3 (Difco).
- a suspension of mycelium in water was used.
- Fermentation can be carried out in the liquid phase stirred at a temperature ranging between 25°C and 33°C for times varying between 4 and 7 days.
- the culture medium can consist of sources of carbon, nitrogen and mineral salts.
- the sources of carbon can be starch, dextrin, glucose, glycerine, mannitol and maltose; the nitrogen sources can be cornsteep liquor, soya flour, dry yeast, peptone and casein. Good results are also obtained using ammonium salts such as ammonium nitrate and ammonium sulphate
- the mineral salts used for the production can vary in function of the culture medium. In a complex culture medium, containing different types of flour or residues of fermentation, the addition of calcium carbonate or calcium phosphate may be useful. Fermentation can be carried out in a beaker and in fermenters of different capacity Analytical methods
- the new compound (I) is mainly contained in the broth filtrate which can be extracted in an alkaline ambient with a solvent immiscible in water, such as n-butanol From the organic phase, it can be re-extracted in acidified water from which, after concentration in the presence of alcohols, for example n- propanol, by addition of a poorly polar solvent, for example n-hexane, a crude red precipitate is obtained containing the compound (I) together with the other glycosidated anthracyclines.
- a solvent immiscible in water such as n-butanol
- a poorly polar solvent for example n-hexane
- Purification processes The purification of the crude product following fermentation, containing the compound (I) and compounds (II) and (III) obtained by subsequent chemical transformations of (I), can take place by using reversed-phase chromatographic columns, for example Lichroprep RP-(8) (Merck). Aqueous solutions containing the products to be purified can be chromatographed using as eluent mixtures of water and organic solvents such as acetonitrile acidified with acids such as trifluoroacetic acid. The fractions collected from the column, pooled and concentrated can be lyophilized.
- Red-phase chromatographic columns for example Lichroprep RP-(8) (Merck).
- Aqueous solutions containing the products to be purified can be chromatographed using as eluent mixtures of water and organic solvents such as acetonitrile acidified with acids such as trifluoroacetic acid.
- the fractions collected from the column, pooled and concentrated can be lyophilized.
- the new compounds (I), (II) and (III) obtained as freeze-dried products red in the form of trifluoroacetate salts are soluble in water, dioxane and alcohols, but insoluble in chloroform, ethyl ether and n-hexane.
- the minimal inhibitory concentration MIC of 4'-O-vancosaminyl daunomycin (I) was determined for some microorganisms using the method of scaled dilutions in agar and is reported in Table 6.
- IC50 concentration inhibiting 50% of the formation of the colony ⁇ S.E.
- the culture of Streptomyces sp. 15105 was allowed to grow for 12 days at 28°C on CZY agar medium (3% sucrose; 0.4% yeast extract; 0.3% NaNO 3 ; 0.1% K 2 HPO 4 ; 0.05% MgSO 4 .7H 2 O; 0.05% KCl; 0.001% FeSO 4 .7H 2 O; 2% agar, 100 ml of deionized water; pH 6.7; sterilisation at 120°C for 20 minutes).
- CZY agar medium 3% sucrose; 0.4% yeast extract; 0.3% NaNO 3 ; 0.1% K 2 HPO 4 ; 0.05% MgSO 4 .7H 2 O; 0.05% KCl; 0.001% FeSO 4 .7H 2 O; 2% agar, 100 ml of deionized water; pH 6.7; sterilisation at 120°C for 20 minutes).
- the spores of the culture thus obtained were collected and suspended in a 300 ml flask containing 30 ml ofthe following culture medium: 1% casein; 2% dextrin; 1% cornsteep liquor; 0.1% (NH ⁇ SO. * ; 0.01% K 2 HPO 4 ; 0.5% CaCO 3 ; 100 ml deionized water. Sterilisation at 120°C for 20 minutes. The pH after sterilisation varies between 6.8 and 7.0. The inoculated flasks were then stirred for 2 days at 28°C on a rotary shaker at 280 ⁇ m with 7 cm eccentricity.
- a quantity equivalent to 2 ml of the above described culture was inoculated into the 300 ml flask containing 30 ml of the following culture medium: 6% starch; 1.8% cornsteep liquor; 0.1% yeast extract; 0.25% NaCl; 0.3% CaCO 3 ; 0.001% FeSO 4 .7H 2 O; 0.001% ZnSO 4 .7H 2 O; 0.001% CuSO 4 .5H 2 O; 100 ml deionized water. Sterilisation at 120°C for 20 minutes. The flasks were incubated for 7 days at
- aqueous phase was separated and concentrated under vacuum with n- propanol up to a small volume, spectrophotometrically titrated, supplemented with 2 equivalents of methanolic HCl and an excess of n-hexane to induce the formation of a crude red precipitate.
- the precipitate was collected by filtration and dried under vacuum
- the red precipitate collected by filtration, washed with water, dried (2 mg) was examined by TLC and identified as daunomycinone (VIII) by direct comparison with an authentic sample.
- the aqueous residue examined by TLC contained two amino sugars identified as daunosamine (XI) and vancosamine (VII) by direct comparison with two authentic samples.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Oncology (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Communicable Diseases (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Microbiology (AREA)
- General Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP53767897A JP3971801B2 (ja) | 1996-04-24 | 1997-04-11 | 抗腫瘍性アントラサイクリン二糖類 |
DE19781703A DE19781703B4 (de) | 1996-04-24 | 1997-04-11 | Gegen Tumoren wirksame Anthracyclindisaccharide, Fermentationsverfahren zu deren Herstellung und diese enthaltende therapeutische Zusammensetzung |
DE19781703T DE19781703T1 (de) | 1996-04-24 | 1997-04-11 | Gegen Tumoren wirksame Anthracyclindisaccharide |
GB9823306A GB2328688B (en) | 1996-04-24 | 1997-04-11 | Antitumoral Anthracycline Disaccharides |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITMI96A000819 | 1996-04-24 | ||
IT96MI000819A IT1282379B1 (it) | 1996-04-24 | 1996-04-24 | Disaccaridi di antracicline antitumorali. |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997040057A1 true WO1997040057A1 (en) | 1997-10-30 |
Family
ID=11374120
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1997/001818 WO1997040057A1 (en) | 1996-04-24 | 1997-04-11 | Antitumoral anthracycline disaccharides |
Country Status (5)
Country | Link |
---|---|
JP (1) | JP3971801B2 (de) |
DE (2) | DE19781703B4 (de) |
GB (1) | GB2328688B (de) |
IT (1) | IT1282379B1 (de) |
WO (1) | WO1997040057A1 (de) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0014853A1 (de) * | 1979-02-03 | 1980-09-03 | Zaidanhojin Biseibutsu Kagaku Kenkyukai | Anthracyclin-Derivate, Verfahren zu ihrer Herstellung und sie enthaltende pharmazeutische Zusammensetzungen |
US4418192A (en) * | 1981-04-23 | 1983-11-29 | Sanraku-Ocean Co., Ltd. | Anthracyclinone trisaccharide compounds |
EP0131232A1 (de) * | 1983-07-07 | 1985-01-16 | Microbial Chemistry Research Foundation | Stereoselektives Verfahren zur Herstellung von Anthracyclin-Derivaten |
EP0311054A2 (de) * | 1987-10-06 | 1989-04-12 | Mercian Corporation | Anthracyclin-Antibiotika |
-
1996
- 1996-04-24 IT IT96MI000819A patent/IT1282379B1/it active IP Right Grant
-
1997
- 1997-04-11 WO PCT/EP1997/001818 patent/WO1997040057A1/en active Application Filing
- 1997-04-11 DE DE19781703A patent/DE19781703B4/de not_active Expired - Lifetime
- 1997-04-11 DE DE19781703T patent/DE19781703T1/de active Pending
- 1997-04-11 JP JP53767897A patent/JP3971801B2/ja not_active Expired - Lifetime
- 1997-04-11 GB GB9823306A patent/GB2328688B/en not_active Expired - Lifetime
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0014853A1 (de) * | 1979-02-03 | 1980-09-03 | Zaidanhojin Biseibutsu Kagaku Kenkyukai | Anthracyclin-Derivate, Verfahren zu ihrer Herstellung und sie enthaltende pharmazeutische Zusammensetzungen |
US4418192A (en) * | 1981-04-23 | 1983-11-29 | Sanraku-Ocean Co., Ltd. | Anthracyclinone trisaccharide compounds |
EP0131232A1 (de) * | 1983-07-07 | 1985-01-16 | Microbial Chemistry Research Foundation | Stereoselektives Verfahren zur Herstellung von Anthracyclin-Derivaten |
EP0311054A2 (de) * | 1987-10-06 | 1989-04-12 | Mercian Corporation | Anthracyclin-Antibiotika |
Also Published As
Publication number | Publication date |
---|---|
JP3971801B2 (ja) | 2007-09-05 |
ITMI960819A0 (de) | 1996-04-24 |
GB2328688B (en) | 1999-10-27 |
IT1282379B1 (it) | 1998-03-20 |
GB2328688A (en) | 1999-03-03 |
DE19781703B4 (de) | 2006-11-30 |
ITMI960819A1 (it) | 1997-10-24 |
DE19781703T1 (de) | 1999-03-25 |
JP2000508546A (ja) | 2000-07-11 |
GB9823306D0 (en) | 1998-12-23 |
GB2328688A8 (en) | 1999-03-12 |
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