WO1997047616A1 - 6,7-dihydroxy-8-methyl-4-oxo-4h-1-benzopyran-5-carboxylic acid with antibacterial activity - Google Patents
6,7-dihydroxy-8-methyl-4-oxo-4h-1-benzopyran-5-carboxylic acid with antibacterial activity Download PDFInfo
- Publication number
- WO1997047616A1 WO1997047616A1 PCT/EP1997/002899 EP9702899W WO9747616A1 WO 1997047616 A1 WO1997047616 A1 WO 1997047616A1 EP 9702899 W EP9702899 W EP 9702899W WO 9747616 A1 WO9747616 A1 WO 9747616A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- pharmaceutically acceptable
- oxo
- methyl
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
-
- 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
Definitions
- R is a hydrogen atom or an acetyl group, and their pharmaceutically acceptable salt, having antibacterial activity.
- the compound of the formula (I) of the invention wherein R is hydrogen is prepared by fermentation of the microorganism Streptomyces sp. identified in our strain bank by the number 17040 and registered on 20.3.1996 with the DSMZ (DEUTSCHE).
- the macroscopic characteristics of the strain 17040 were recorded after 14 days of incubation at 28°C and are given in table 1. Growth is generally satisfactory both on organic as well as synthetic media. TABLE 1. Cultural characteristics of the strain 17040.
- strain 17040 All the characteristics shown by the strain 17040 clearly correspond to those reported for the genus Streptomyces by Waksman and Henrici (BERGEY'S MANUAL OF DETERMINATIVE BACTERIOLOGY 6 th Ed, THE WILLIAMS AND WILKINS BALTLMORA - 1948).
- the medium used for this test was Yeast nitrogen base (Difco) with the addition of
- the medium used for growth of the strain 17040 was ISP3 (Difco). An aqueous suspension of the mycelium was used to determine the enzymatic activity.
- the fermentation in liquid phase can be carried out in two phases: vegetative and productive, at a temperature ranging from 23 to 31°C.
- the first phase can be carried out for periods varying from 28 to 72 hours; the second for periods varying from 96 to 200 hours.
- the culture media consist of sources of carbon, nitrogen and mineral salts.
- the sources of carbon can be starch, dextrine and sucrose; the sources of nitrogen can be cornsteep liquor, soy flour, corn flour, caseine and yeast extract; the sources of mineral salts can be calcium carbonate, potassium phosphate, iron sulphate, zinc sulphate, manganese sulphate, copper sulphate and sodium chloride.
- the fermentation can be carried out either in a flask or in fermenters of different volumes.
- the compound according to the invention Upon completion of the fermentation, the compound according to the invention is present in the liquid culture broth, which is separated from the mycelium by centrifuging at neutral pH.
- the supernatant liquor, with the addition of sodium chloride can be loaded onto LRA 450 Amberlite® resin, from which the new compound is eluted with solutions of phosphate buffer of increasing molarity.
- the fractions selected by HPLC analysis are loaded onto a XAD-4 Amberlite® resin column from which the active principle is eluted with a mixture of water and miscible organic solvent such as for example acetone, methanol, acetonitrile. Acetonitrile is preferably used.
- the fractions with a high concentration of active compound (HPLC analysis) are combined and concentrated at reduced pressure.
- the raw compound can be treated with an absolute ethanol-methanol mixture and the suspension brought to boil. After removal of the insoluble residue by filtering, the solution is concentrated at reduced pressure to eliminate the more volatile solvent. After the residual ethanolic solution is left to stand at +4°C for 24 hours, the compound according to the invention crystallizes and is filtered off and dried at reduced pressure at +45°C.
- the compound of the formula (I) wherein R is hydrogen can be converted into a compound of the formula (I) wherein R is acetyl by acetylation.
- the acetylation is preferably carried out by dissolving the starting compound wherein R is H in pyridine, and treating it with acetic anhydride. The resulting acetylated compound is then isolated and characterized by known methods. BIOLOGICAL ACTIVITY Antibacterial activity
- the Streptomyces sp. 17040 culture was allowed to grow for 14 days at 28°C on a CZY agarized culture medium (sucrose 30 g/1; NaNO 3 3 g/1; K 2 HPO 4 1 g/1;
- MgS0 4 .7H 2 O 0.5 g/1; KC1 0.5 g/1; yeast extract 4 g/1; FeSO 4 .7H 2 O 0.01 g/1; agar 20 g/1; deionized H 2 O to 1000 ml; pH uncorrected; sterilization 1 15°C x 20 minutes).
- the mycelial growth on the agarized culture medium was used as inoculum for the vegetative phase which occurred in the following culture medium: casein 8 g/1; cornsteep liquor 8 g/1; dextrine 16 g/1; (NH 4 ) 2 S0 4 0.8 g/1; K 2 HP0 4 0.2 g/1; CaC0 3 4 g/1; deionized H 2 O to 1000 ml; pH uncorrected; sterilization 120°C x 20 minutes.
- the flask containing 30 ml of the aforementioned medium was inoculated with 1/5 of the mycelial growth of the strain on agarized culture medium.
- the fractions in HPLC with a peak with a retention time of 8.1 minutes, were combined, sodium chloride (1% w/v) was added and the resulting solution was loaded on top of a 8x20 cm column (IL approx.) of XAD-4 Amberlite® resin.
- the column was eluted with gradient from 0 to 50% of acetonitrile in water.
- the fractions containing the active compound were concentrated under vacuum until the organic solvent was completely eliminated.
- the residual aqueous solution (approx.
- FCE 22325 was obtained as fine yellowish crystals; it is soluble in dimethylsulfoxide, dimethylformamide and alkaline water, poorly soluble in alcohols, and insoluble in water. Moreover, it is unstable in alkaline water with a pH higher than 8.
- the pharmaceutically acceptable salt, e.g. the alkali metals salts, of FCE 22325 can be prepared by methods per se known in the art.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19781792A DE19781792B4 (de) | 1996-06-07 | 1997-06-04 | 6,7-Disubstituierte 8-Methyl-4-oxo-4H-1-benzopyran-5-carbonsäuren, Fermentationsverfahren zu deren Herstellung und diese Verbindungen enthaltende therapeutische Zusammensetzung |
GB9825857A GB2328945B (en) | 1996-06-07 | 1997-06-04 | 6,7-Dihydroxy-8-Methyl-4-Oxo-4H-1-Benzopyran-5-Carboxylic Acid with antibacterial activity |
JP10501152A JP2000512144A (ja) | 1996-06-07 | 1997-06-04 | 抗菌活性を有する6,7―ジヒドロキシ―8―メチル―4―オキソ―4h―1―ベンゾピラン―5―カルボン酸 |
DE19781792T DE19781792T1 (de) | 1996-06-07 | 1997-06-04 | 6,7-Dihydroxy-8-methyl-4-oxo-4H-1-benzopyran-5-carbonsäure mit antibakterieller Wirkung |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT96MI001174A IT1283115B1 (it) | 1996-06-07 | 1996-06-07 | Acido 6,7-didrossi-8-metil-4-oxo-1-benzopiran carbossilico con attivita' antibatterica. |
ITMI96A001174 | 1996-06-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997047616A1 true WO1997047616A1 (en) | 1997-12-18 |
Family
ID=11374399
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1997/002899 WO1997047616A1 (en) | 1996-06-07 | 1997-06-04 | 6,7-dihydroxy-8-methyl-4-oxo-4h-1-benzopyran-5-carboxylic acid with antibacterial activity |
Country Status (5)
Country | Link |
---|---|
JP (1) | JP2000512144A (de) |
DE (2) | DE19781792B4 (de) |
GB (1) | GB2328945B (de) |
IT (1) | IT1283115B1 (de) |
WO (1) | WO1997047616A1 (de) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2132260A1 (de) * | 1970-07-01 | 1972-02-03 | Takeda Chemical Industries Ltd | Chromoncarbonsaeurederivate und Verfahren zu ihrer Herstellung |
EP0114899A1 (de) * | 1982-12-28 | 1984-08-08 | Eisai Co., Ltd. | 2-Methylchromon-Derivate und Verfahren zu ihrer Herstellung |
-
1996
- 1996-06-07 IT IT96MI001174A patent/IT1283115B1/it active IP Right Grant
-
1997
- 1997-06-04 GB GB9825857A patent/GB2328945B/en not_active Expired - Lifetime
- 1997-06-04 DE DE19781792A patent/DE19781792B4/de not_active Expired - Lifetime
- 1997-06-04 WO PCT/EP1997/002899 patent/WO1997047616A1/en active Application Filing
- 1997-06-04 JP JP10501152A patent/JP2000512144A/ja not_active Ceased
- 1997-06-04 DE DE19781792T patent/DE19781792T1/de active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2132260A1 (de) * | 1970-07-01 | 1972-02-03 | Takeda Chemical Industries Ltd | Chromoncarbonsaeurederivate und Verfahren zu ihrer Herstellung |
EP0114899A1 (de) * | 1982-12-28 | 1984-08-08 | Eisai Co., Ltd. | 2-Methylchromon-Derivate und Verfahren zu ihrer Herstellung |
Non-Patent Citations (2)
Title |
---|
CHEMICAL ABSTRACTS, vol. 88, no. 17, 24 April 1978, Columbus, Ohio, US; abstract no. 117779u, page 270; XP002039093 * |
CHEMICAL ABSTRACTS, vol. 99, no. 25, 19 December 1983, Columbus, Ohio, US; abstract no. 209832m, page 407; XP002039094 * |
Also Published As
Publication number | Publication date |
---|---|
DE19781792B4 (de) | 2006-06-08 |
DE19781792T1 (de) | 1999-05-27 |
GB2328945B (en) | 2000-01-12 |
ITMI961174A1 (it) | 1997-12-07 |
GB9825857D0 (en) | 1999-01-20 |
GB2328945A (en) | 1999-03-10 |
IT1283115B1 (it) | 1998-04-07 |
JP2000512144A (ja) | 2000-09-19 |
ITMI961174A0 (it) | 1996-06-07 |
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