WO1995006045A1 - COMPOSE α-PYRONE - Google Patents

COMPOSE α-PYRONE Download PDF

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Publication number
WO1995006045A1
WO1995006045A1 PCT/JP1994/001391 JP9401391W WO9506045A1 WO 1995006045 A1 WO1995006045 A1 WO 1995006045A1 JP 9401391 W JP9401391 W JP 9401391W WO 9506045 A1 WO9506045 A1 WO 9506045A1
Authority
WO
WIPO (PCT)
Prior art keywords
medium
compound
culture
present
hexane
Prior art date
Application number
PCT/JP1994/001391
Other languages
English (en)
Japanese (ja)
Inventor
Mikio Yamazaki
Haruhiro Fujimoto
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 AU75083/94A priority Critical patent/AU7508394A/en
Publication of WO1995006045A1 publication Critical patent/WO1995006045A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • C07D309/38—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms one oxygen atom in position 2 or 4, e.g. pyrones

Definitions

  • the present invention relates to a novel ⁇ -pyrone compound having an immunosuppressive action.
  • the compound of the present invention is a novel compound, and no compound having an immunosuppressive activity with a structure similar to that of the present compound is known. Disclosure of the invention
  • the present inventors have found that they have developed a novel compound having a certain kind of strain for production, and have completed the present invention.
  • multifolicin A (Hereinafter, referred to as multifolicin A).
  • Gelasinospora multiforis IFM 4498 a strain producing the novel physiologically active substance multiforicin A of the present invention, was owned by the University of Chiba New Nuclear Microorganisms Research Center, which is the predecessor of the Research Center for New Nuclear Microorganisms, and has a deposit number. Deposited as “FE RM BP—4 7 5 4” with the Institute of Biotechnology and Industrial Technology, National Institute of Advanced Industrial Science and Technology.
  • This strain grows well on potato'glucose agar, potato / carrot agar, automeal agar, etc. 25
  • C A colony with a diameter of 90 ⁇ ⁇ is formed after 5 days of culture.
  • 25 Potato on carrot agar medium.
  • C The formation of ascocarps as teleomorphs can be confirmed by culturing for 2-3 weeks. The ascocarps are superficial to partially latent, dark brown to olive black, and are scattered in large numbers around the colony. The morphology of this strain observed with an optical microscope is described in the Mycological Encyclopedia (top), pages 555-556.
  • the ascus is pear-shaped, 500-1,000 350-650 111 in size, and its base is covered with many hairs (colorless to light tan, wavy, shelled wall, smooth surface).
  • the shell wall is quite thick and is composed of many polygonal cells.
  • the ascos are eight spores, cylindrical, 300-360X38-45 m, round or slightly cut at the top, with a small thick apex at the tip, and narrow at the bottom, short and short.
  • the side thread is colorless and juicy.
  • Ascospores are single row, dark olive gray to dark brown, almost black when ripe, ovoid, 38-52X30-41 ⁇ ⁇ Many holes are formed in the wall, and the pores are about 0.5 ⁇ m in diameter. Germination holes are circular, 1 to 1.5 / m in diameter, and 3 to 4 at one end.
  • the culture was extended to 3 weeks and observation was continued, but no anamorphic morphology was observed.
  • Table 1 below shows the results of macroscopic observations when cultured on various media at 26 e C for 14 days.
  • This strain grows in a sub-mouth liquid medium of ⁇ 6.0 in the range of 1239 C, and the optimal temperature is 30-32 ° C.
  • this strain was identified as Gelasinospora mult if oris IFM 4498.
  • ⁇ ⁇ Of multiforicin A is obtained by inoculating Gelasinospora mult iforis IFM 4498 strain into polished rice medium and culturing it.
  • the culture method is static culture, and the culture is performed in the dark for 25 days.
  • the solid rice culture is extracted with an organic solvent such as ethyl acetate, and the extract is concentrated to obtain a crude extract.
  • the obtained extract is further partitioned with hexane, ethyl acetate, water, and the like, and the ethyl acetate fraction is distilled off if solvent to obtain a solid.
  • the compound of the present invention can be purified and isolated by subjecting this solid fraction to silica gel gel column chromatography and medium pressure liquid column chromatography.
  • Negative ninhydrin, anisaldehyde, ferric chloride
  • FIG. 1 shows the infrared absorption spectrum of multipholysin A measured by the KBr method.
  • FIG. 2, in CDC 1 3, shows the 1 H- NMR scan Bae spectrum of multi Folli Shin A measured at 500 MHz.
  • Figure 3 is in CDC 1 3, shows the 13 C one NMR scan Bae spectrum of multi Folli Shin A measured by 125MH z.
  • milled rice medium saturated with water 200 g of the polished rice was placed in a roux flask and sterilized by heating. 100 seeds were inoculated and cultured in a dark place at 25 ° C.
  • 100 seeds were inoculated and cultured in a dark place at 25 ° C.
  • about 4 ml of sterilized water was added per flask, and the cells were cultured for 22 days.
  • about 300 ml of ethyl acetate was added per flask, and the mixture was left standing for 1 minute and shaken for about 5 hours to perform extraction.
  • the extract was filtered, and the filtrate was evaporated under reduced pressure. This operation was repeated twice to obtain 167 g of a crude extract.
  • This extract was added little by little to 58 Om1 of hexane with stirring to obtain a hexane-insoluble portion (dark brown, oily, 112 g). This was dissolved in 2.3 L of ethyl acetate, 2.3 L of water was added for distribution, and the ethyl acetate layer was evaporated under reduced pressure to obtain 74 g of a crude extract.
  • the compound multiforicin A of the present invention can be selectively used at a concentration at which no cytotoxicity occurs. It has an immunosuppressive effect that specifically suppresses the function of lymphocytes stimulated by mitogen and immunologically activated. Therefore, collagen diseases (rheumatoid arthritis, systemic lupus erythematosus, scleroderma, dermatomyositis, polymyositis, nodular periarthritis, and related diseases) that develop with abnormal immune functions, and autoimmunity other than collagen diseases Diseases (Beetiet's disease, autoimmune hepatitis, glomerulonephritis, autoimmune hemolytic anemia, ulcerative colitis, Hashimoto's disease, thrombocytopenia, Takayasu disease, temporal arteritis, cryoglobulinemia, Zegener meat Blastomatosis), as an antiallergic agent, and asthma therapeutic agent.
  • collagen diseases rheumatoid arthritis, system
  • the compounds of the present invention are orally or parenterally administered in the form of tablets, pills, capsules, granules, injections, etc., manufactured according to conventional pharmaceutical techniques.
  • usual additives such as bulking agents, binders, pH adjusters, solubilizers, emulsifiers and suspending agents can be used.
  • the dose of the compound of the present invention to the treated patient may vary depending on the age of the patient, the type and condition of the disease, and the like, but is usually 10 to 1000 mg per day, preferably
  • Test example 1 lymphocyte blastogenesis test
  • KB cells passaged in MEM medium (Gibco) supplemented with fetal bovine serum (GS 10%) and gentamicin (Shearing) 80 ⁇ g / m1 as tumor cells Was ⁇ Tsu to (Hitoro cavity cancer cells) lX10 4 ce 1 1 sZm l prepared following methods.
  • Microplate was added cell suspension 100 1 (flat bottom 96-well, inter one Med Inc.), 37 ° (:., 5% C0 2 were cultured for 24 hours in incubator Better present 3 ⁇ 4 bright compound solution at each concentration 1 0 mu
  • the compound of the present invention was dissolved in dimethyl sulfoxide so that the final concentration of dimethyl sulfoxide was 0.05%, and diluted with a medium, and then added. ⁇
  • IC 50 values of the multi-Huo ricin A was calculated to be 1 O gZm 1, suppressing immunosuppressive effect the function of specific lymphocytes at concentrations that are not found cytotoxicity

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Ce composé, qui est représenté par la formule (I), est caractérisé par une activité immunosuppressive sélectivement stimulée par un mitogène. Le degré de concentration de ce mitogène est tel qu'il n'induit aucun effet cytotoxique lorsqu'il doit supprimer de façon spécifique la fonction d'un lymphocyte immunologiquement activé. Ce composé est utile dans le traitement des affections du collagène causées par l'anomalie de la fonction immune, et dans le traitement des autres affections auto-immunes.
PCT/JP1994/001391 1993-08-25 1994-08-24 COMPOSE α-PYRONE WO1995006045A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU75083/94A AU7508394A (en) 1993-08-25 1994-08-24 Alpha-pyrone compound

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP5/210441 1993-08-25
JP21044193 1993-08-25

Publications (1)

Publication Number Publication Date
WO1995006045A1 true WO1995006045A1 (fr) 1995-03-02

Family

ID=16589383

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1994/001391 WO1995006045A1 (fr) 1993-08-25 1994-08-24 COMPOSE α-PYRONE

Country Status (2)

Country Link
AU (1) AU7508394A (fr)
WO (1) WO1995006045A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05310726A (ja) * 1992-03-13 1993-11-22 Shionogi & Co Ltd 免疫抑制物質
JPH0680565A (ja) * 1992-09-03 1994-03-22 Ishihara Sangyo Kaisha Ltd 免疫機能抑制剤

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05310726A (ja) * 1992-03-13 1993-11-22 Shionogi & Co Ltd 免疫抑制物質
JPH0680565A (ja) * 1992-09-03 1994-03-22 Ishihara Sangyo Kaisha Ltd 免疫機能抑制剤

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PHYTOCHEMISTRY, Vol. 15, No. 6, 1976, pages 1090-1091. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection

Also Published As

Publication number Publication date
AU7508394A (en) 1995-03-21

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