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WO1996022996A1 - Derives de dihydrophenazine - Google Patents

Derives de dihydrophenazine Download PDF

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Publication number
WO1996022996A1
WO1996022996A1 PCT/JP1996/000128 JP9600128W WO9622996A1 WO 1996022996 A1 WO1996022996 A1 WO 1996022996A1 JP 9600128 W JP9600128 W JP 9600128W WO 9622996 A1 WO9622996 A1 WO 9622996A1
Authority
WO
WIPO (PCT)
Prior art keywords
dihydrophenazine
strain
derivative
streptomyces
derivatives
Prior art date
Application number
PCT/JP1996/000128
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English (en)
Japanese (ja)
Inventor
Haruo Seto
Kazuo Shin-Ya
Original Assignee
Nippon Chemiphar 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
Priority claimed from JP3015295A external-priority patent/JPH08198888A/ja
Priority claimed from JP3148295A external-priority patent/JPH08198889A/ja
Application filed by Nippon Chemiphar Co., Ltd. filed Critical Nippon Chemiphar Co., Ltd.
Priority to AU44959/96A priority Critical patent/AU4495996A/en
Publication of WO1996022996A1 publication Critical patent/WO1996022996A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/10—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K15/00—Anti-oxidant compositions; Compositions inhibiting chemical change
    • C09K15/04—Anti-oxidant compositions; Compositions inhibiting chemical change containing organic compounds
    • C09K15/30—Anti-oxidant compositions; Compositions inhibiting chemical change containing organic compounds containing heterocyclic ring with at least one nitrogen atom as ring member
    • 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
    • C12P19/58—Preparation of O-glycosides, e.g. glucosides having an oxygen atom of the saccharide radical directly bound through only acyclic carbon atoms to a non-saccharide heterocyclic ring, e.g. bleomycin, phleomycin

Definitions

  • the present invention relates to a novel dihydrophenazine derivative, a strain capable of producing the same, and a drug using the same.
  • L one Glutamate is a kind of Amino acid Natural constituting the evening protein, known to be force s' has a toxicity to neurons. If a substance having the effect of suppressing glutamate toxicity is obtained, it is expected that the substance can be used as a drug to activate and improve brain metabolism.
  • Diseases that may be related to reactive oxygen species include inflammation, rheumatoid arthritis, autoimmune diseases, radiation-induced skin disease, Parkinson's disease, and ischemic heart and brain disorders. If an antioxidant capable of appropriately removing active oxygen can be obtained, it is expected that the antioxidant can be used as a therapeutic agent for these diseases.
  • JP-A-64-22861 discloses the following compound produced from a strain shown as Streptomyces ⁇ .
  • Tetrahedron Letters, No. 7, 943-946 (1991) discloses the following compounds produced from a strain belonging to Streptomyces ⁇ .
  • Said R is H or CH 3.
  • the above compound exhibits a function as a radical avenger of radicals such as vitamin E.
  • the present inventors have discovered a new actinomycete strain belonging to the genus Streptomyces from soil. This strain has been deposited on December 22, 1994 at the Institute of Biotechnology and Industrial Technology, 1-3-1 Higashi, Tsukuba, Ibaraki, Japan (Accession number: F ERM P-14717). Based on the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for Patent Procedures, it was internationally deposited on January 27, 1995 with the Institute of Biotechnology and the Institute of Biotechnology. The accession number is FERM BP-5303
  • the present inventors have conducted research on this strain and found that this strain is capable of producing a novel dihydrophenazine derivative represented by the following formula I or II.
  • FIG. 1 is a graph showing the UV-visible absorption ⁇ spectrum of dihydrophenazine derivative I.
  • FIG. 2 is a graph showing an infrared absorption spectrum of the dihydrophenazine derivative I.
  • FIG. 3 is a graph showing the 'H-NMR spectrum of the dihydrophenazine derivative I.
  • FIG. 4 is a graph showing a 13 C-NMR spectrum of the dihydrophenazine derivative I.
  • FIG. 5 is a graph showing an ultraviolet-visible absorption spectrum of a dihydrophenazine derivative.
  • FIG. 6 is a graph showing an infrared absorption spectrum of the dihydrophenazine derivative.
  • FIG. 7 is a graph showing a ⁇ -NMR spectrum of the dihydrophenazine derivative ⁇ .
  • FIG. 8 is a graph showing a 13 C-NMR spectrum of a dihydrophenazine derivative.
  • FIG. 9 is a micrograph ( ⁇ 100) of the strain.
  • FIG. 10 is a micrograph (approximately 120 ⁇ 0 ⁇ ) of the strain.
  • FIG. 11 is a graph showing the results of measuring the glutamate toxicity inhibitory action of dihydrophenazine derivative I.
  • FIG. 12 is a graph showing the results of measuring the glutamate toxicity inhibitory action of a dihydrophenazine derivative.
  • a hydroxyl group at the 1-position of ⁇ -L-rhamnose having a viranose structure is bonded to the carboxyl group of the carboxydihydrophenazine derivative by an s-ester bond.
  • This ester bond can be hydrolyzed and recombined. Accordingly, this compound is decomposed into ⁇ -L-rhamnose and a carboxyl dihydrophenazine derivative, and the carboxyl dihydrophenazine derivative, which is a decomposition product, is ester-bonded to another sugar to form another type of dihydrophenazine.
  • a nadine derivative can also be synthesized.
  • dihydrophenazine derivative I The physicochemical properties of dihydrophenazine derivative I are as follows.
  • Shape orange powder Melting point: 63. 0-64. O
  • Solubility soluble in methanol, chloroform, dimethyl sulfoxide, and acetone, insoluble in hexane
  • FIG. 1 shows an ultraviolet-visible absorption spectrum of the dihydrophenazine derivative I.
  • the measurement was performed in methanol and the scanning speed was 120. OnmZ min.
  • the band pass is 2. OOnm.
  • FIG. 2 shows an infrared absorption spectrum of the dihydrophenazine derivative I.
  • the measurement was performed by the KBr tablet method.
  • absorption powers derived from a hydroxyl group (3450 cm- 1 ), a secondary amine (3330 cm- 1 ), a ketone (1680 crrr) and an ester (1680 cm- ', 1260 cm-') were observed.
  • the figure shows the 'H-NMR spectrum of the dihydrophenazine derivative I. The measurement was performed at 500 MHz in deuterated acetone.
  • FIG. 4 shows a 13 C-NMR spectrum of the dihydrophenazine derivative I. The measurements were performed at 500 MHz in heavy acetone.
  • the Rf value of the dihydrophenazine derivative I by thin-layer chromatography (cloform form Z methanol-10-1) was 0.42.
  • the physicochemical properties of the dihydrophenazine compound are as follows.
  • Solubility soluble in methanol, chloroform, dimethyl sulfoxide, and acetone, insoluble in hexane
  • FIG. 5 shows an ultraviolet-visible absorption spectrum of the dihydrophenazine compound. The measurement was performed in methanol and the scanning speed was 120. Onm / min. The band pass is 2.00 nm. As shown in FIG. 5, there are absorption peaks at 229 nm (28 900), 245 nm (27400), 296 nm (26000), 367 nm (4000) and 490 nm (1 1700). No change in the absorption beak due to acid and alkali was observed.
  • FIG. 6 shows the infrared absorption spectrum of the dihydrophenazine compound. The measurement was performed by the KBr tablet method. In the infrared absorption spectrum, a hydroxyl group (3450 cm- single, secondary Amin (3330Cm- absorption derived was observed in '), a ketone (1680Cnr one and esters (1680crtT l, 1260 cnr') .
  • FIG. 7 Shows the 'H-NMR spectrum of dihydrophenazine compound ⁇ . Was performed in heavy acetone at 500 MHz.
  • FIG. 8 shows a ' 3 C-NMR spectrum of the dihydrophenazine compound. The measurement was performed at 500 MHz in deuterated acetone.
  • the Rf value of the dihydrophenazine compound ⁇ by thin-layer chromatography was 0.42.
  • Aerial hyphae form a short main axis, and irregularly long branches, straight or curved, to form 10 to 50 or more spore chains.
  • the spores are non-motile, cylindrical or oblong and have a width of 0.5 to 0.8 "m.
  • the spore surface is smooth.
  • Spores, spores, and other special forms No cell wall chemical type is type I.
  • FIGS. 9 100 ⁇
  • 10 about 12000 ⁇
  • the length of the white bar seen in Fig. 10 is 500nm.
  • the strains were (1) sucrose-nitrate agar, (2) glucose-asparagine agar, (3) glycerin-asparagine agar, (4) inorganic salt-starch agar, (5) tyrosine agar.
  • the results of culturing on a medium, (6) nutrient agar medium, (7) yeast 'malt agar medium, and (8) oatmeal agar medium are shown.
  • Table 1 shows the culture characteristics on the above various media.
  • Table 1 Medium Color of the flora on the colony surface Color of the lining of the colony Diffusible dye
  • the flora color on the colony surface is a gray series.
  • the back color is dark reddish brown and dark brown.
  • Diffusible dyes are pale orange to pale red or dark orange. The hues of these dyes did not change with changes in PH.
  • Table 2 below shows the physiological properties and the assimilation of carbon sources.
  • this strain is mesophilic, and uses glucose, arabinose, xylose, and mannitol as carbon sources assimilating ability. Based on the morphological characteristics and cell wall chemical type of this strain, this strain is located in Streptomyces II.
  • Streptomyces purophofuscus Str-marked tomyces purpeofuscus
  • Table 3 the properties of this strain and Streptomyces * parvofuscus are based on the assimilation ability of the carbon source ( Except for the mannits).
  • Perovskus spore chain form straight or curved + +
  • the dihydrophenazine derivatives I and ⁇ of the present invention can be produced by aerobically culturing a production bacterium such as the present strain in a suitable medium and collecting the target substance from the culture.
  • the culture medium is composed of nutrient sources available for the dihydrophenazine derivative producing bacteria. Glycerol is preferred as the carbon source.
  • Glycerol is preferred as the carbon source.
  • molasses, casein and polypeptone force can be preferably used.
  • inorganic salts can be added according to the amount of water.
  • An appropriate antifoaming agent eg, silicone may be added to suppress foaming during acidification.
  • dihydrophenazine derivatives I and II it is preferable to employ aerobic submerged culture conditions. These conditions are the same as the culture conditions for mass production of other ⁇ 3 ⁇ 4 ⁇ -like bioactive substances. For small-scale production, shaking culture in a flask can be employed.
  • the cells may be cultured using a jar fermenter.
  • vegetative cells of the microorganism for inoculation in the acid fermentation tank in order to avoid growth delay in the production process.
  • the culture medium for producing vegetative cells may be different from the culture medium for producing the dihydrophenazine derivatives I and II.
  • Agitation and aeration of the culture mixture can be performed in a conventional manner.
  • a blower or a similar mechanical stirring device can be used. You may search by rotating or shaking the acid fermentation tank.
  • Various bomb devices can be used for ventilation.
  • aeration may be performed by passing sterilized air through the medium.
  • the acid fermentation temperature is generally from 10 to 40 ° C, preferably from 20 to 30 ° C.
  • the fermentation time is generally 50 to 200 hours. The acid fermentation time varies depending on the acid fermentation conditions and scale.
  • dihydric phenazine derivatives I and ⁇ ⁇ can be recovered from the culture solution by various conventional recovery and purification methods.
  • recovery method solvent extraction, chromatography, or recrystallization can be employed.
  • solvent extraction and recrystallization an appropriate solvent is used for each of the dihydrophenazine derivatives I and ⁇ . Two or more solvents may be used in combination.
  • the dihydrophenazine derivatives I and ⁇ are generally found in cultured bacterial cell components. Thus, extracts and whether we microbial cells obtained by the culture solution was centrifuged or ⁇ a suitable solvent, it forces s preferred to implement the purification treatment dihydro Hue phenazine derivatives.
  • the solvent acetone or methanol can be used.
  • Purification of the dihydrophenazine derivatives I and II can be performed by treating the extract in accordance with a conventional method. For example, removing the solvent from the extract by evaporation or distillation, re-extracting with an appropriate solvent (eg, ethyl acetate), and repeatedly drying to obtain a residue containing the dihydrophenazine derivatives I and ⁇ Can be.
  • an appropriate solvent eg, ethyl acetate
  • a distilling method such as silica gel chromatography or HPLC separation can be performed to purify the dihydrophenazine derivatives I and ⁇ ⁇ ⁇ , respectively.
  • the ability to isolate the dihydrophenazine derivative I and II producing strains from the natural world by the usual method is also important for nonproprietary products other than this strain. Specifically, it can be carried out in the same manner as the method for isolating antibiotic-producing bacteria.
  • the strain may be subjected to irradiation or other mutation-inducing treatment to improve the productivity of dihydrophenazine derivatives I and II.
  • the dihydrophenazine derivatives I and ⁇ obtained as described above exhibit an inhibitory effect on glutamate toxicity.
  • the dihydrophenazine derivatives I and ⁇ also have an antioxidant effect. Therefore, the dihydrophenazine derivatives I and ⁇ of the present invention are useful as inhibitors of glutamic acid toxicity or as antioxidants.
  • the inhibitory action of the dihydrophenazine derivative of the present invention on glutamate toxicity is stronger than any of the conventionally known compounds, and the dihydrophenazine derivative I can suppress glutamate toxicity by about 50% at several ⁇ . Glutamic acid toxicity can be suppressed by about 50% with dihydrophenazine derivative ⁇ with more than 10 ⁇ .
  • Known compounds having an inhibitory action on glutamate toxicity suppress nerve cell death due to mild cerebral ischemia and activate brain metabolism. Therefore, the dihydrofunadine derivatives I and II of the present invention are also effective as therapeutic agents for cerebral ischemic disorders such as cerebral infarction and cerebrovascular dementia.
  • Glutamic acid has been suggested to be toxic by various mechanisms, but it has been implicated in the expression of free radicals such as active oxygen in all systems. For this reason, it is known that antioxidants such as vitamin ⁇ ⁇ ⁇ suppress glutamate toxicity.
  • the dihydrophenazine derivative of the present invention also exhibits a similar antioxidant effect. Therefore, the dihydrophenazine derivative of the present invention is also effective as a therapeutic agent for diseases involving active oxygen, such as inflammation, rheumatoid arthritis, and autoimmune diseases.
  • the active fractions were collected, concentrated under reduced pressure, applied to a reversed-phase silica gel column (Senshu ODS-SS-1020-T, 50 OmL), and eluted with 90% methanol. The active fraction obtained is concentrated under reduced pressure, and then reverse-phase silica gel column.
  • the active fractions were collected and concentrated under reduced pressure, and then applied to a reverse phase silica gel column (Senshu 0DS-SS_1020-T, 50 OmL), and eluted with 90% methanol. After the obtained active fraction was reduced under reduced pressure, HPLC fractionation was performed using a reversed phase silica gel column (Senshu Pak. PEGASIL ODS, diameter 2 Omm ⁇ 25 Omm) in a solvent system of 85% methanol. The activated beak was concentrated under reduced pressure to obtain 3 Omg of the dihydrofunazine derivative of the present invention as a red powder. [Example 3]
  • a hybridoma (N18-RE-105 cells) of mouse neuroblast JfiM and rat retinal neurons was used.
  • Hybridoma cells were inoculated so that the number of cells became 3 . Twenty-four hours later, 1 OmM glutamic acid and the dihydrophenazine derivative of the present invention were added. After the addition of glutamic acid, the cells were further cultured for 24 hours, and then the lactate dehydrogen lactate (LDH) activity contained in the cells and the medium was measured. Glutamate toxicity was evaluated by calculating the LDH release rate according to the following equation.
  • FIGS. 11 and 12 The measurement results of dihydrophenazine derivatives I and ⁇ are shown in FIGS. 11 and 12, respectively. These figures are graphs obtained by blotting the measurement results, where the horizontal axis represents the concentration of the dihydrophenazine compound of the present invention and the vertical axis represents the LDH release rate.
  • Microsomes were prepared from male Wistar rat livers according to the method of Ernster, Shimi et al. (Above Cell Biol. 15, 541 (1962)).
  • Liver microsomes (protein amount 0.5 mg), 0.2 M Tris-HCl buffer (pH 7.4), 2 mg / mLADP, DMS0 (dimethyl) of test substance (dihydrophenazine derivative I of the present invention) Sulfoxide) solution, and 0.5 mL of the reaction solution containing N ADPH in SmgZmL were incubated at 37 ° C for 1 hour.
  • reaction Transfer the container to ice water, immediately add 0.05 mL of 0.5% butylhydroxytoluene-ethanol solution to stop the reaction, and further add 0.1% SDS (sodium dodecyl sulfate) 0.25 mL, 20% 1.75 mL of diacid and 1.5 mL of 0.8% thiobarbituric acid solution (pH 3.5) were added. Transfer the reaction vessel into boiling water,
  • the dihydrophenazine derivative of the present invention exhibits a glutamate toxicity inhibitory action and an antioxidant action. Therefore, the dihydrophenazine derivative of the present invention has an effect as a glutamate toxicity inhibitor or an antioxidant.

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Abstract

Dérivés de dihydrophénazine représentés par les formules structurales (I) et (II), obtenus à partir des souches d'actinomycètes du genre Streptomyces déposées auprès d'une autorité internationale de dépôt, et ayant un effet antioxydant et de suppression de la toxicité de l'acide L-glutamique pour les neurones de mammifères.
PCT/JP1996/000128 1995-01-25 1996-01-25 Derives de dihydrophenazine WO1996022996A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU44959/96A AU4495996A (en) 1995-01-25 1996-01-25 Dihydrophenazine derivatives

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP7/30152 1995-01-25
JP3015295A JPH08198888A (ja) 1995-01-25 1995-01-25 ジヒドロフェナジン誘導体
JP7/31482 1995-01-27
JP3148295A JPH08198889A (ja) 1995-01-27 1995-01-27 ジヒドロフェナジン化合物

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1159964A2 (fr) 2000-05-31 2001-12-05 Pfizer Products Inc. Compositions et methodes pour stimuler la motilité gastrointestinale
EP0945444A4 (fr) * 1996-12-03 2002-02-06 Nippon Chemiphar Co Derives d'acide dihydrophenazinecarboxylique
KR100412909B1 (ko) * 2000-08-25 2003-12-31 한국생명공학연구원 뇌신경세포 보호물질 및 그 제조방법
WO2007098716A1 (fr) 2006-02-28 2007-09-07 Centro De Ingeniería Genética Y Biotecnología Composés analogues aux sécrétagogues peptidiques de l'hormone de croissance et préparations contenant ceux-ci
EP2457893A1 (fr) 2004-06-18 2012-05-30 Tranzyme Pharma, Inc. Intermédiaires pour des modulateurs macrocycliques du récepteur de ghréline
EP2644618A1 (fr) 2007-02-09 2013-10-02 Tranzyme Pharma, Inc. Intermédaires dans la synthese de modulateurs macrocycliques du récepteur de la ghréline
KR20170042123A (ko) * 2015-10-08 2017-04-18 한국과학기술연구원 페나진 유도체를 포함하는 신경세포 보호용 조성물

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06135982A (ja) * 1992-07-27 1994-05-17 Kirin Brewery Co Ltd 新規生理活性物質ｈｒ０４

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06135982A (ja) * 1992-07-27 1994-05-17 Kirin Brewery Co Ltd 新規生理活性物質ｈｒ０４

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0945444A4 (fr) * 1996-12-03 2002-02-06 Nippon Chemiphar Co Derives d'acide dihydrophenazinecarboxylique
EP1159964A2 (fr) 2000-05-31 2001-12-05 Pfizer Products Inc. Compositions et methodes pour stimuler la motilité gastrointestinale
KR100412909B1 (ko) * 2000-08-25 2003-12-31 한국생명공학연구원 뇌신경세포 보호물질 및 그 제조방법
EP2457893A1 (fr) 2004-06-18 2012-05-30 Tranzyme Pharma, Inc. Intermédiaires pour des modulateurs macrocycliques du récepteur de ghréline
EP2457925A1 (fr) 2004-06-18 2012-05-30 Tranzyme Pharma, Inc. Procédé pour la préparation d'un modulateur macrocyclique du récepteur de ghréline et intermédiaires
WO2007098716A1 (fr) 2006-02-28 2007-09-07 Centro De Ingeniería Genética Y Biotecnología Composés analogues aux sécrétagogues peptidiques de l'hormone de croissance et préparations contenant ceux-ci
EP2644618A1 (fr) 2007-02-09 2013-10-02 Tranzyme Pharma, Inc. Intermédaires dans la synthese de modulateurs macrocycliques du récepteur de la ghréline
KR20170042123A (ko) * 2015-10-08 2017-04-18 한국과학기술연구원 페나진 유도체를 포함하는 신경세포 보호용 조성물
KR101908454B1 (ko) 2015-10-08 2018-10-17 한국과학기술연구원 페나진 유도체를 포함하는 신경세포 보호용 조성물

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