WO2001000639A1 - Nouveau derive de sordarine utilise en tant qu'agent therapeutique antimicrobien - Google Patents

Nouveau derive de sordarine utilise en tant qu'agent therapeutique antimicrobien Download PDF

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Publication number
WO2001000639A1
WO2001000639A1 PCT/JP2000/004027 JP0004027W WO0100639A1 WO 2001000639 A1 WO2001000639 A1 WO 2001000639A1 JP 0004027 W JP0004027 W JP 0004027W WO 0100639 A1 WO0100639 A1 WO 0100639A1
Authority
WO
WIPO (PCT)
Prior art keywords
substance
salt
pharmaceutically acceptable
acceptable salt
liters
Prior art date
Application number
PCT/JP2000/004027
Other languages
English (en)
Inventor
Yasuhiro Hori
Kumiko Nitta
Motoo Kobayashi
Shigehiro Takase
Motohiro Hino
Original Assignee
Fujisawa Pharmaceutical Co., Ltd.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to JP2001507047A priority Critical patent/JP2003503416A/ja
Publication of WO2001000639A1 publication Critical patent/WO2001000639A1/fr

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Classifications

    • 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
    • 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
    • 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
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings

Definitions

  • the present invention relates to a new antimicrobial compound, hereinafter entitled FR231956 or its salt which is useful as a medicament.
  • the present invention relates to a new antimicrobial compound, FR231956 or its salt
  • one object of this invention is to provide the novel compound, FR231956 or its salt which is of use for treating infectious diseases caused by pathogenic microorganisms .
  • Another object of this invention is to provide a process for production of the FR231956 substance or its salt by fermentation of the FR231956-producing strain such as Sordax ⁇ a araneosa. ATCC36386 in a nutrient medium.
  • a further object of this invention is to provide a pharmaceutical composition containing, as an active ingredient, the FR231956 substance or its salt.
  • Still further object of this invention is to provide a use of the FR231956 substance or its salt for treating infectious diseases caused by pathogenic microorganisms .
  • the structure of the new compound, FR231956 substance consists of a skeleton of sordarin, which is an antifungal antibiotic (see Helvetica Chimica Acta, 1971, 54, 1178-1190) .
  • the FR231956 substance is produced by fermentation of the strain ATCC36386 of the fungus species Sordar ⁇ a araneosa which is known as a sordarin producing strain .
  • Japanese Kokai J62040292 discloses the compound zofimarin having the sordarin skeleton, which is reported to have antifungal activity.
  • Semi-synthetic sordarin derivatives are reported in PCT Applications WO96/14326, 096/14327 and 098/15178.
  • the new compound, FR231956 substance is represented by the following formula :
  • the FR231956 substance has the following physico-chemical properties : Molecular formula :
  • Soluble methanol, ethyl acetate, chloroform, di ethylsulfoxide
  • the FR231956 substance can be produced by fermentation of the FR231956-producing strain such as Sordaria araneosa ATCC36386 in a nutrient medium.
  • Sordaria araneosa ATCC36386 is preserved and can be distributed by the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Maryland 20852, USA. It is to be understood that the production of the FR231956 substance is not limited to the use of the particular organism described herein, which is given for the illustrative purpose only . This invention also includes the use of any mutants which are capable of producing the FR231956 substance including natural mutants as well as artificial mutants which can be produced from the described organism by conventional means such as irradiation of X-ray, ultra-violet radiation, treatment with N-methyl-N' -nitro-N-nitrosoguanidine, 2- aminopurine , and the like .
  • the FR231956 substance is produced when the FR231956 producing strain such as Sordar ⁇ a araneosa ATCC36386 is grown in a nutrient medium containing sources of assimilable carbon and nitrogen under aerobic conditions (e. g. shaking culture, submerged culture , etc . ) .
  • the preferred sources of carbon in the nutrient medium are carbohydrates such as glucose, sucrose, starch, fructose or glycerin , or the like .
  • the preferred sources of nitrogen are peanut powder , yeast extract , peptone , gluten meal , cotton seed flour , soybean powder, soybean meal, corn steep liquor, dried yeast, wheat germ, etc., as well as inorganic and organic nitrogen compounds such as ammonium salts (e. g. ammonium nitrate, ammonium sulfate , ammonium phosphate , etc . ) , urea or amino acid, or the like.
  • the carbon and nitrogen sources though advantageously employed in combination, need not to be used in their pure form because less pure materials , which contain traces of growth factors and considerable quantities of mineral nutrients , are also suitable for use .
  • medium mineral salts such as sodium or calcium carbonate , sodium or potassium phosphate, sodium or potassium chloride, sodium or potassium iodide, magnesium salts , copper salts, zinc salts, iron salts, or cobalt salts , or the like .
  • a defoaming agent such as liquid paraffin, fatty oil, plant oil , mineral oil, silicone or the like may be added.
  • Agitation and aeration of the culture mixture may be accomplished in a variety of ways , such as agitation by a propeller or similar mechanical agitation equipment, by revolving or shaking the fermenter, and the like .
  • the fermentation is usually conducted at a temperature between about 10°C and 40 °C, preferably 20°C to 35°C, for a period of about 24 hours to 120 hours, which may be varied according to fermentation conditions and scales .
  • the culture broth is then subjected for recovery of the FR231956 substance to various procedures conventionally used for recovery and purification of biological active substance, for instance, solvent extraction with an appropriate solvent or a mixture of some solvents , chromatography or recrystallization from an appropriate solvent or a mixture thereof .
  • the FR231956 substance in its free form may also be converted to its salts by treating with an inorganic or organic base such as sodium or potassium hydroxide , ammonium hydroxide , ethanola ine and the like and with an amino acid such as glycine, lysine, glutamic acid and the like.
  • an inorganic or organic base such as sodium or potassium hydroxide , ammonium hydroxide , ethanola ine and the like and with an amino acid such as glycine, lysine, glutamic acid and the like.
  • the FR231956 substance has a strong antimicrobial activity against pathogenic microorganisms , especially pathogenic fungi such as pathogenic yeast (e.g. Candi a alb ⁇ cans etc.) and the like. Accordingly, the FR231956 substance or its pharmaceutically acceptable salt is useful as an antimicrobial agent , especially antifungal agent which is used for the treatment of infectious diseases in human beings and animals .
  • infections include superficial , cutaneous , subcutaneous and systemic mycotic infections such as respiratory tract infections , gastrointestinal tract infections , cardiovascular infections , urinary tract infections, candidiasis and chronic mucocandidiasis (e.g.
  • thrush and vaginal candidiasis skin infections caused by fungi , cutaneous and mucocutaneous candidiasis , dermatophytoses (e.g. ringworm and tinea infections, athletes foot, paronychia, pityriasis , intertrigo, Candi a vulvitis, Candidabalanitis and otitis externa) .
  • dermatophytoses e.g. ringworm and tinea infections, athletes foot, paronychia, pityriasis , intertrigo, Candi a vulvitis, Candidabalanitis and otitis externa
  • They may also be used as prophylactic agents to prevent systemic and topical ungal infections for immunocompromised patients (e.g. AIDS patients , patients receiving cancer therapy or transplant patients) .
  • Antimicrobial activities of the FR231956 substance were determined by a serial broth dilution method using 96-well microtiter plate in 100 ⁇ 1 of yeast nitrogen base dextrose medium. The inoculum was adjusted to 1 x 10 5 colony forming units/ml.
  • Candida alb ⁇ cans was cultured at 37°C for 24 hours and Cryptococcus neoformans was cultured at 37°C for 48 hours in 5% C0 2 incubator. After incubation, the growth inhibition of microorganism in each well was determined by microscopic observation . The results were shown as MEC (minimum ef ective concentration: ⁇ g/ml) value (Table 1).
  • Microorganisms MEC ( ⁇ g/ml)
  • the FR231956 substance of the present invention has an antimicrobial activity (especially, antifungal activity) .
  • composition of this invention can be used in the form of pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the FR231956 substance or a pharmaceutically acceptable salt thereof, as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable or external , enteral or parenteral applications .
  • the active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets , pellets , capsules , suppositories , solutions , emulsions, suspensions, injections, ointments, liniments, eye drops, lotion, gel, cream, and any other form suitable for use .
  • the carriers which can be used are water, glucose , lactose , gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening, solubilizing and coloring agents and perfumes .
  • the object compound or a pharmaceutically acceptable salt thereof is included in the pharmaceutical composition in an amount sufficient to produce the desired antimicrobial ef ect upon the process or condition of diseases .
  • the composition for applying the composition to a human being, it is preferable to apply itby intravenous , intramuscular, topical , percutaneous, pulmonary or oral administration, or insufflation .
  • the dosage or therapeutically e fective amount of the FR231956 substance or a pharmaceutically acceptable salt thereof varies depending on the age and conditions of each individual patient to be treated, in the case of intravenous administration, a daily dose of 0.01 - 20 mg of the FR231956 substance per kg weight of human being, in the case of intramuscular administration, a daily dose of
  • 0.5 - 50 mg of the FR231956 substance per kg weight of human being is generally given for treating or preventing infectious diseases .
  • aqueous seed medium 160 ml containing corn starch 2%, sucrose 1%, glycerol 1%, pharmamedia 1%, gluten meal 1%, and Tween 800.2% was placed in each of three 500-ml Erlenmeyer flasks and was sterilized at 120°C for 30 minutes.
  • the inoculated flasks were shaken on a rotary shaker (220 rpm, 5.1 cm-throw) at 25°C for 4 days, and 480ml (three flasks) of the seed culture were inoculated to 20 liters of sterile production medium consisting of modified starch 3%, pharmamedia 2%, oat meal 0.5%, (NH 4 ) 2 S0 4 0.3%, KH 2 P0 4 2 %, Na 2 HP0 4 - 12H 2 01.5%, Adekanol

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  • 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)
  • Genetics & Genomics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biotechnology (AREA)
  • Wood Science & Technology (AREA)
  • Biochemistry (AREA)
  • Zoology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Microbiology (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Veterinary Medicine (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Bioinformatics & Cheminformatics (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)

Abstract

La présente invention concerne un nouveau composé antimicrobien, la substance FR231956 et un procédé de production de la substance FR231956 consistant à faire croître un micro-organisme producteur de substance FR231956 dans un milieu d'agents nutritifs et à récupérer la substance FR231956 du bouillon de culture résultant. L'invention se rapporte également à un agent antimicrobien comportant la substance FR231956 et un ou plusieurs excipients, à une composition pharmaceutique comportant une quantité efficace de cette substance FR231956 et un ou plusieurs excipients pharmaceutiquement acceptables, à un procédé de destruction de micro-organismes consistant à appliquer la substance FR231956 sur lesdits micro-organismes et à l'utilisation de cette substance FR231956 pur le traitement de maladies infectieuses provoquées par des micro-organismes pathogènes.
PCT/JP2000/004027 1999-06-25 2000-06-21 Nouveau derive de sordarine utilise en tant qu'agent therapeutique antimicrobien WO2001000639A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2001507047A JP2003503416A (ja) 1999-06-25 2000-06-21 新規化合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPQ1208 1999-06-25
AUPQ1208A AUPQ120899A0 (en) 1999-06-25 1999-06-25 Novel compound

Publications (1)

Publication Number Publication Date
WO2001000639A1 true WO2001000639A1 (fr) 2001-01-04

Family

ID=3815398

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2000/004027 WO2001000639A1 (fr) 1999-06-25 2000-06-21 Nouveau derive de sordarine utilise en tant qu'agent therapeutique antimicrobien

Country Status (3)

Country Link
JP (1) JP2003503416A (fr)
AU (1) AUPQ120899A0 (fr)
WO (1) WO2001000639A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996014327A1 (fr) * 1994-11-08 1996-05-17 Glaxo Wellcome S.A. Derives de sordaridine a action antifongique
WO1998011891A1 (fr) * 1996-09-18 1998-03-26 Merck & Co., Inc. Sordarine et derives de sordarine a utiliser comme agents antifongiques dans les cultures vegetales
WO1998015178A1 (fr) * 1996-10-07 1998-04-16 Merck & Co., Inc. Derives de sordarine
WO1999009974A1 (fr) * 1997-08-22 1999-03-04 Merck & Co., Inc. Derives de 4-cyano-4-deformylsordarine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996014327A1 (fr) * 1994-11-08 1996-05-17 Glaxo Wellcome S.A. Derives de sordaridine a action antifongique
WO1998011891A1 (fr) * 1996-09-18 1998-03-26 Merck & Co., Inc. Sordarine et derives de sordarine a utiliser comme agents antifongiques dans les cultures vegetales
WO1998015178A1 (fr) * 1996-10-07 1998-04-16 Merck & Co., Inc. Derives de sordarine
WO1999009974A1 (fr) * 1997-08-22 1999-03-04 Merck & Co., Inc. Derives de 4-cyano-4-deformylsordarine

Also Published As

Publication number Publication date
JP2003503416A (ja) 2003-01-28
AUPQ120899A0 (en) 1999-07-22

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