WO1995004041A1 - Compose de carbazole - Google Patents

Compose de carbazole Download PDF

Info

Publication number
WO1995004041A1
WO1995004041A1 PCT/JP1993/001077 JP9301077W WO9504041A1 WO 1995004041 A1 WO1995004041 A1 WO 1995004041A1 JP 9301077 W JP9301077 W JP 9301077W WO 9504041 A1 WO9504041 A1 WO 9504041A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
culture
strain
present
minutes
Prior art date
Application number
PCT/JP1993/001077
Other languages
English (en)
Japanese (ja)
Inventor
Haruo Seto
Yoichi Hayakawa
Original Assignee
Taisho 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 Taisho Pharmaceutical Co., Ltd. filed Critical Taisho Pharmaceutical Co., Ltd.
Priority to PCT/JP1993/001077 priority Critical patent/WO1995004041A1/fr
Priority to AU45863/93A priority patent/AU4586393A/en
Publication of WO1995004041A1 publication Critical patent/WO1995004041A1/fr

Links

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
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/10—Nitrogen as only ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system

Definitions

  • the present invention relates to a compound having an antioxidant action and a cell death inhibitory action.
  • JP-A-3-227971 As a related compound having the same action as the compound of the present invention, a compound described in JP-A-3-227971 is known, but it is structurally unstable. Disclosure of the invention
  • the present inventors have isolated a large number of strains from soil and conducted various studies on cultures of the strains.As a result, the inventors have found that compounds produced by certain strains have strong antioxidant activity and cell death inhibitory activity. They have found and completed the present invention. That is, the present invention provides a formula
  • the strain that produces CS-79 is a strain newly isolated from the soil collected by the present inventors in Matsumoto City, Nagano Prefecture, and has the microorganism name “Streptomyces ex fo l iatus 24 19—S VT 2J and deposited under Microorganisms Deposit No. “Micro-organism Deposit No. 12707 (FERM P-12707)” with the National Institute of Advanced Industrial Science and Technology.
  • the aerial hyphae form the main axis, thereby forming a curved or looped sporangium consisting of 10 to 50 or more at the irregularly branched tip.
  • the spores are non-motile, cylindrical or oblong in shape, 0.6-0.8 m wide, 0.8-1.0 m long, and the spore surface is smooth.
  • the cell wall chemical type is type I.
  • Table 27 shows the results of visual observation when cultured for 14 days at 27 on various media.
  • the flora color on the colony surface is a gray series, and the reverse color is unclear, slightly changing at pH.
  • the diffusible dye was light brown.
  • the strain was grown in a range of 2 0 4 5 ° C, the optimum temperature for growth because in 2 0 3 7 0
  • S. species of the genus Streptomyces (hereinafter abbreviated as S.) described in the “List of Approved Bacteria Names 1980” and the list of valid names thereafter. , And two closely related species were selected. Comparison of the diagnostic properties of S. nash virensis (S. nash V i 11 e_ns_is—) and _S. Only the assimilation of carbon sources is different.
  • S. soft skulls have morphology, surface color, pH sensitivity of diffusible dyes, carbon Source assimilation is different. Therefore, this strain is most similar to S. nasivirensis, but is described in “Bergey's Manual of Systematic B acteriology Vol. According to Williams et al. (Williams, et. A 1.), S. nasibirensis is a synonym of S. exfoliatus. Therefore, the present strain 24 19— SVT 2 was identified as one strain contained in S. ixhorietus, and S. tomvcesexfo 1 iatus (Stre. Tomvcesexfo 1 iatus) was identified. Called SVT 2 shares
  • Production of CS-79 is carried out by culturing the strain under aerobic conditions in a medium containing various nutrients, in a manner similar to the production of general fermentation products.
  • a carbon source glucose, lactose, starch, etc. are used alone or in combination.
  • a nitrogen source meat extract, automeal, yeast extract, soybean powder, polybebutone, etc. are used alone or in combination.
  • organic and inorganic salts that promote the growth of the strain and promote the production of CS-79 can be added as necessary.
  • Adekinol, silicon, or the like can be used as the defoaming agent.
  • Aerobic culture such as shaking culture and aeration / agitation culture is suitable for the culture method, and is performed at pH 4 to 8, 24 to 30 for 2 to 6 days, preferably at pH 6 to 7, 24 to 27. Incubate in C for 2-3 days.
  • the CS-79 produced by this culture can be isolated according to a general method for collecting S-produced products. Since C S _ 79 is accumulated in the satellite, for example, the following method is effective.
  • the S-isomer is eluted with an organic solvent such as acetate by centrifugation or filtration.
  • the compound of the present invention can be purified and isolated by dissolving it in an organic solvent such as n-port form and subjecting it to silica gel column chromatography, gel filtration power chromatography, and high-performance liquid power chromatography.
  • Figure 1 shows the results determined in the KBr lock.
  • FIG. 2 shows the results measured at 500 MHz in els—DMSO.
  • FIG. 3 shows the results of measurement at 125 MHz in ds-DMS O.
  • Solubility in solvents :
  • FIG. 1 shows the infrared absorption spectrum of CS-79 measured in KBr tablets.
  • FIG. 2 shows the 1 H-NMR spectrum of CS-79 measured at 500 MHz in d 6 -DMSO.
  • FIG. 3 shows the 13 C-NMR spectrum of CS-79 measured at 125 MHz in cls-DMS0.
  • a 50 L jar fermenter containing 30 L of a sterile medium having the same composition as the seed medium was inoculated with 500 ml of the above-described seed culture, which had been precultured, and aerated for 27, 48 hours. Agitation culture was performed. After completion of the culture, 30 L of the culture solution was separated into a supernatant and cells, and then 15 L of acetone was added to the cells and extracted. The acetone extract was extracted twice with 3 L of ethyl acetate after the acetone was distilled off. The ethyl acetate fraction was dehydrated with anhydrous sodium sulfate, concentrated, and then added to the concentrated solution with 100 ml of n-butyl ether to obtain 5.5 g of a yellow precipitate.
  • the compound of the present invention Since the compound of the present invention has an antioxidant effect and a cell death inhibitory effect, it is useful for brain diseases, heart diseases, liver diseases and arteriosclerosis diseases.
  • the compound of the present invention is orally or parenterally administered in the form of tablets, pills, capsules, granules, injections, etc., manufactured according to conventional formulation techniques. be able to.
  • usual additives such as efficacious agents, tying agents, pH adjusters, dissolving agents, emulsifying agents, and suspending agents are used.
  • the administration of the compound of the present invention to a subject can vary depending on the age of ⁇ , the type and condition of the disease, and the like. 100 to 500 mg can be administered in 1 to several divided doses o
  • Test example 1 antioxidant action
  • the liver of a 10-week-old male male rat was taken, homogenized, centrifuged at 3 ° C. and 30000 rpm for 10 minutes, and the supernatant was taken. The supernatant was collected, centrifuged at 100,000 rpm for 10 minutes, and the supernatant was collected. This was further centrifuged at 4 ° C and 300,000 rpm for 60 minutes, and the sedimented fraction was collected.
  • the buffer (0. OSS mol Zl tris-hydrochloric acid, 0.174m0 It was composed of 1/1 Shirayidari potassium ⁇ ml 7.4) 70 ml was added to obtain a microsome solution.
  • L-ascorbic acid (0.05 ml) was added. 0 1 511 0 1/1) was allowed to react for 0.5 hour with 0.5 calories. The reaction was stopped by the addition of 0.5 ml of 20% trifluoroacetic acid, and the mixture was centrifuged at 300 rpm for 10 minutes, and the supernatant was collected. To this was added 0.5 ml of 0.67% thiobarbituric acid.
  • Control 1 A group in which the cervical vein was exposed and the skin was sewn without being tied for 3 minutes
  • Control 2 A group in which the carotid artery was exposed and ligated for 3 minutes, and then the skin was sutured.
  • MK 80, an NMDA (N-methyl D-aparlarate) antagonist with a reported cytoprotective effect The result of 1 is described. The test was performed according to the same method as described above. MK-801 was dissolved in physiological saline and administered intraperitoneally immediately after ischemia for 3 minutes.
  • MK—801 (+) — 5—methyl 1 0, 11—dihid 5H—dibenzo [a, d] cycloheptene 1-5, 10—imin CS-79, which is a pedestal of the present invention, exhibited MK-80 action.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biotechnology (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composé de formule (I) doté de vertus antioxydantes et inhibitrices de la dégénérescence cellulaire, et s'avérant utile dans le traitement de troubles d'ordre cérébral, cardiaque et hépatique, de l'artériosclérose, etc.
PCT/JP1993/001077 1993-08-02 1993-08-02 Compose de carbazole WO1995004041A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/JP1993/001077 WO1995004041A1 (fr) 1993-08-02 1993-08-02 Compose de carbazole
AU45863/93A AU4586393A (en) 1993-08-02 1993-08-02 Carbazole compound

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP1993/001077 WO1995004041A1 (fr) 1993-08-02 1993-08-02 Compose de carbazole

Publications (1)

Publication Number Publication Date
WO1995004041A1 true WO1995004041A1 (fr) 1995-02-09

Family

ID=14070435

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1993/001077 WO1995004041A1 (fr) 1993-08-02 1993-08-02 Compose de carbazole

Country Status (2)

Country Link
AU (1) AU4586393A (fr)
WO (1) WO1995004041A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002064169A1 (fr) * 2001-02-16 2002-08-22 Daiichi Suntory Pharma Co., Ltd. Procedes de traitement de maladies en association avec la diminution de l'expression du gene aop-1 ou de aop-1 et remedes conçus pour ces maladies
WO2006002908A1 (fr) * 2004-06-29 2006-01-12 Jadolabs Gmbh Compositions pharmaceutiques derivees du carbazole

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0341069A (ja) * 1989-07-07 1991-02-21 Banyu Pharmaceut Co Ltd 抗腫瘍性物質ｂｅ―１３７９３類
JPH03227971A (ja) * 1990-02-02 1991-10-08 Taisho Pharmaceut Co Ltd カルバゾール化合物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0341069A (ja) * 1989-07-07 1991-02-21 Banyu Pharmaceut Co Ltd 抗腫瘍性物質ｂｅ―１３７９３類
JPH03227971A (ja) * 1990-02-02 1991-10-08 Taisho Pharmaceut Co Ltd カルバゾール化合物

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002064169A1 (fr) * 2001-02-16 2002-08-22 Daiichi Suntory Pharma Co., Ltd. Procedes de traitement de maladies en association avec la diminution de l'expression du gene aop-1 ou de aop-1 et remedes conçus pour ces maladies
US7598228B2 (en) 2001-02-16 2009-10-06 Asubio Pharma Co., Ltd. Therapeutic methods and agents for diseases associated with decreased expression of AOP-1 gene or AOP-1
WO2006002908A1 (fr) * 2004-06-29 2006-01-12 Jadolabs Gmbh Compositions pharmaceutiques derivees du carbazole

Also Published As

Publication number Publication date
AU4586393A (en) 1995-02-28

Similar Documents

Publication Publication Date Title
FI112503B (fi) Polysyklisiä antiparasiittisia aineita ja niiden käyttö
KR830002801B1 (ko) 고(高) 콜레스테롤혈증치료제, 모나콜린 k의 제조방법
WO1995004041A1 (fr) Compose de carbazole
JPH10130269A (ja) カルボリン誘導体
US3616237A (en) Method of preparing thiogriseofulvins
KR940004128B1 (ko) 혈소판 활성화 인자 길항 물질인 "포막틴(phomactins)", 그의 제조방법 및 용도
US4436750A (en) 12'-Hydroxyverrucarin J and iso-satratoxin H
JPH0256423A (ja) ナフトピラン誘導体およびその用途
JPH01131177A (ja) Ｎｆ−１６１６−９０４物質
JPS59170092A (ja) 新規抗生物質ｓｓ８２０１ｄ及びその製造法
JPH0272167A (ja) Ｂｕ―３８６２ｔ抗腫瘍性抗生物質
JPH05201977A (ja) カルバゾール系化合物
KR820001221B1 (ko) 하이드록시아미노 하이드로카르본포스폰산 유도체의 제조방법
JPH0632778A (ja) カルバゾール系化合物
JPS62186787A (ja) 新規な微生物
JPH03220196A (ja) ベンズアンスラキノン化合物
JPS623789A (ja) 抗生物質トキマイシンａおよびその製造法
JPS62228074A (ja) Ｓｓ５０４０８物質及びその製造法
JPS6265692A (ja) レプトマイシンａの製造法
JPH0359911B2 (fr)
JPH01265893A (ja) 新規物質ｋ３６１９、その使用およびその製造
JPH0632796A (ja) ベンズアントラセン誘導体、該誘導体を含有する抗腫瘍剤及びその製造方法
JPS60246399A (ja) 新生理活性物質ホルオキシミチン、その製造法および用途
JPS61115081A (ja) 新規な抗生物質ｓｓ２１０２０ｄ及びその製造法
JPS6293256A (ja) アントラキノン類及びその製造法

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA JP KR US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA