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WO1998048029A1 - Procede de preparation de derives d'acide cyclopentanecarboxylique - Google Patents

Procede de preparation de derives d'acide cyclopentanecarboxylique Download PDF

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Publication number
WO1998048029A1
WO1998048029A1 PCT/JP1998/001900 JP9801900W WO9848029A1 WO 1998048029 A1 WO1998048029 A1 WO 1998048029A1 JP 9801900 W JP9801900 W JP 9801900W WO 9848029 A1 WO9848029 A1 WO 9848029A1
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Prior art keywords
group
carbon atoms
cyclopentanecarboxylic acid
hydrocarbon residue
oxo
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English (en)
Japanese (ja)
Inventor
Seiichi Saito
Mitsuyuki Nishide
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Nippon Kayaku Co Ltd
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Nippon Kayaku Co Ltd
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    • 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
    • C12P11/00—Preparation of sulfur-containing organic compounds
    • 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
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/02—Amides, e.g. chloramphenicol or polyamides; Imides or polyimides; Urethanes, i.e. compounds comprising N-C=O structural element or polyurethanes

Definitions

  • the present invention relates to a method for producing a cyclopentanecarboxylic acid derivative. More specifically, the present invention relates to a process for producing cyclopentanecarboxylic acid derivatives such as cystacyclin and related compounds, which are expected to be used as therapeutic agents for peripheral neuropathy, using microorganisms.
  • Background art cyclopentanecarboxylic acid derivatives such as cystacyclin and related compounds, which are expected to be used as therapeutic agents for peripheral neuropathy, using microorganisms.
  • WO94 / Z565 / 79 discloses a physiologically active substance NK1752 / 203 (Stistamyces S. P. NK1752 / 203 strain (FERM BP—43372)) (Cyclin) is disclosed.
  • the present inventor has conducted repeated studies with the aim of finding an excellent method for producing cystacyclin and its related compounds.As a result, the inventors added various mercapto compounds to the culture solution of cystazycycline or sarcomycin-producing bacteria and cultured the cells. The present inventors have found that the mercapto compound is converted to cystazacycline or a related compound thereof, and a desired cyclopentanecarboxylic acid derivative such as cistacycline or a related compound thereof can be obtained with high productivity.
  • the present invention relates to the following (1) Force, (13).
  • Y is a substituted or unsubstituted hydrocarbon residue having 1 to 20 carbon atoms and having a total molecular weight of 15 or more and 400 or less, and the hydrocarbon residue When the group is cyclic, it may contain one or two heteroatoms in the ring.
  • a process for producing cyclopentanecarboxylic acid or a salt thereof comprising:
  • cystazycline or sarcomycin-producing bacterium is a strain belonging to the genus Streptomyces;
  • cystacycline or sarcomycin-producing bacterium is a strain belonging to Streptomyces endus or Streptomyces erythrum chromogenes;
  • cystazycline or sarcomycin-producing bacterium is a strain belonging to Streptomyces sp. 1) production method
  • the cystacyclin-producing bacterium belongs to the genus Streptomyces, and the spore-forming hypha belongs to the section Spirales, and the spore surface is smooth or rough, and the color of the mature hypha is It is a gray color-series, wettable (hygroscopic), does not produce melanin-like pigments, has a pale yellow or light brown base mycelium color, and has L-arabinose as a carbon source.
  • a method for producing the above (1) which is a strain utilizing D_glucose, D-fructose, sucrose, D-mannitol or D-xylose, or a mutant thereof;
  • the aliphatic hydrocarbon residue is represented by — COR! (R> is one OR 2 or —NR 3 R 4 as a substituent, and R 2 is a hydrogen atom or a hydrocarbon residue having 1 to 6 carbon atoms.
  • R> is one OR 2 or —NR 3 R 4 as a substituent
  • R 2 is a hydrogen atom or a hydrocarbon residue having 1 to 6 carbon atoms.
  • R 3 and R 4 are each a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an acyl group having 1 to 20 carbon atoms; — NR 5 R 6 (where R 5 and R 6 are each hydrogen atom, a group represented by from 1 alkyl group carbon atoms or 1 to 6 carbon atoms 2 0 of Ashiru group); and single ⁇ _R 7 (R 7 is a hydrogen atom, a hydrocarbon of 1 to 6 carbon atoms (6)
  • the aromatic hydrocarbon residue is, as a substituent, — COR, (R> is one OR 2 or —NR 3 R 4 , and R 2 is a hydrogen atom or a hydrocarbon residue having 1 to 6 carbon atoms.
  • R 3 and R 4 are each a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an acyl group having 1 to 20 carbon atoms); one NR 5 R 6 (R 5 and R 6 Is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an acyl group having 1 to 20 carbon atoms, respectively;
  • OR 7 (R 7 is a hydrogen atom, a carbon atom having 1 to 6 carbon atoms) (6) having at least one group selected from the group consisting of a hydrogen residue and an alkyl group having 1 to 20 carbon atoms; and an alkyl group having 1 to 6 carbon atoms. Manufacturing method;
  • the aliphatic hydrocarbon residue is, as a substituent, a carboxyl group, an alkoxycarbonyl group having 2 to 6 carbon atoms, an alkenyloxycarbonyl group having 3 to 6 carbon atoms, an amino group, a mono- or diacylamino group (asyl group).
  • the group has 2 to 6 carbon atoms, a hydroxy group, an alkoxy group having 2 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and a group selected from the group consisting of alkenyloxy groups having 2 to 6 carbon atoms.
  • substituents When at least one substituent is present, and when there are two or more substituents selected therefrom, they may be the same or different groups;
  • Y in the general formula (I) is 2-carboxy one 2- Amino (or C Bok 2. Ashirua Amino) Echiru group, 2-d-alkoxycarbonyl, or C 2 - Arukeniruoki Shikarubo two Lu 2 Aminoechinore group, 2 -d alkoxycarbonyl (or C 2 - 6 alkenyl O alkoxycarbonyl) one 2 - 2.
  • the process for producing (1) above which is an acetylaminoethyl group, a 2,3-dihydroxypropyl group, a 2-hydroxyethynole group or a 2-amino or acetylaminoethyl group;
  • Novel cyclopentanecarboxylic acid derivative selected from the group consisting of A biologically acceptable salt.
  • hydrocarbon residue in the present invention refers to a group obtained by removing one hydrogen atom from a hydrocarbon (which may contain a hetero atom in the case of a ring).
  • groups of a general concept used in the present invention for example, hydrocarbon residues, aliphatic hydrocarbon residues, alkyl groups, alkenyl groups, aromatic ring groups, acyl groups, amino groups, alkylamino groups, acylamino groups, alkoxy groups Unless otherwise specified, groups such as a group, an acyloxy group, and an alkoxycarbonyl group are used to mean both unsubstituted and substituted groups.
  • Y is a substituted or unsubstituted hydrocarbon residue having 1 to 20 carbon atoms and having a total molecular weight of 15 or more and 400 or less.
  • a hydrocarbon residue may be linear, cyclic, saturated, or unsaturated.
  • the number of carbon atoms is preferably 15 or less, more preferably 10 or less, and most preferably about 1 to 6.
  • Y is a "cyclic group” or a "cyclic group substituted with a cyclic group"
  • the ring may contain one or two hetero atoms such as oxygen, nitrogen, sulfur, etc. .
  • the hydrocarbon residue preferably has a substituent in terms of physiological activity.
  • the hydrocarbon residue is an aliphatic hydrocarbon residue, it may be linear, branched, saturated, unsaturated or cyclic.
  • Preferred examples of the unsubstituted aliphatic hydrocarbon residue include an alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, 2-methylbutyl and hexyl; A C 2 -C 6 alkenyl group such as phenyl, aryl and the like; a C 3 -C 6 cyclic group such as cyclopentyl and cyclohexyl and piperidinyl; and a C 1 -C 6 chain or carbon number Examples thereof include a cyclic aliphatic hydrocarbon residue having 3 to 6 carbon atoms, and a chain aliphatic hydrocarbon residue having 2 to 4 carbon atoms is usually preferred.
  • Aliphatic hydrocarbon residues having a substituent may be present on these unsubstituted linear or cyclic alkyl or alkenyl groups, for example, with 1 to 4, preferably 1 to 3, more preferably 1 to 3, Examples include those having two substituents, and the substituent is not particularly limited as long as it does not impair the physiological activity of the compound of the present invention.
  • Y including the substituent The molecular weight of the entire group is about 400 or less, preferably about 300 or less, and more preferably about 150 or less.
  • Examples of the type of the substituent include a carboxyl group, an aldehyde group, a group in which the carboxyl group is esterified or amidated, a nitrinole group, an amino group, a mono- or dialkyl- or acyl-substituted amino group, a hydroxy group, an alkoxy group, an alkenyl group.
  • Examples include a oxy group, an acyloxy group, a nitro group, and a halogen atom.
  • Examples of the acyl group in the present invention include an acyl group having 1 to 20 carbon atoms.
  • the hydrocarbon residue portion in these acyl groups may be any of a chain, a branch, and a ring, and may have the above-described substituent. Preferred among these acyl groups are those having usually about 2 to 6 carbon atoms.
  • Examples of the halogen atom in the present invention include chlorine, fluorine, and bromine.
  • One of the preferable substituents on the aliphatic hydrocarbon residue is a carboxyl group or a group in which the carboxyl group is esterified or amidated, for example, a group represented by —COR !.
  • a hydroxy group or an alkoxy group represented by one OR 2 (wherein R 2 is a hydrogen atom or a hydrocarbon residue having 1 to 6 carbon atoms); or one NR 3 R 4 (wherein R 3 and R 4 is a hydrogen atom, an aliphatic hydrocarbon residue having 1 to 6 carbon atoms or an acyl group having 1 to 20 carbon atoms, respectively.
  • Examples of the hydrocarbon residue having 1 to 6 carbon atoms in R 2 include the same as those exemplified for Y having 1 to 6 carbon atoms.
  • Examples of the aliphatic hydrocarbon residue having 1 to 6 carbon atoms for R 3 and R 4 include the same groups as those exemplified for the aliphatic hydrocarbon residue for Y.
  • the acetyl group having 1 to 20 carbon atoms including R 3 and R 4 in the present invention includes acetyl, mono, di or trihalogenoacetyl, propionyl, butanol, pentanoyl, heptanoyl, heptadecanol, benzoyl, halogenobenzoyl And so on.
  • the hydrocarbon residue portion in these acyl groups may be any of a chain, a branch, and a ring, and they may have a substituent.
  • acyl groups are those having 1 to 6 carbon atoms, and more preferred are carbon groups. It is an acyl group having a prime number of 2 to 3, and an acetyl group is most preferred.
  • substituent include the same as those exemplified for the aliphatic hydrocarbon.
  • substituents on the aliphatic hydrocarbon residue include -NR 5 Re (wherein R 5 and R 6 are each a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a carbon atom An unsubstituted amino group, a mono- or di-substituted amino group represented by the formula (1), wherein R 5 and R 6 may be the same or different. Specific examples of R 5 and R 6 are the same ones listed et al are as exemplified for R 3 and R 4.
  • Preferred substituents on the aliphatic hydrocarbon residue other than those described above include, for example, a group obtained by a hydroxy group and a hydroxy group by etherification or asinoleich.
  • a group represented by one OR 7 (wherein R 7 is a hydrogen atom, a C 1-6 hydrocarbon residue or a C 1-20 acyl group), and the hydrocarbon represented by R 7 As the residue or acyl group, the same as those exemplified for Y can be mentioned.
  • substituent in the aliphatic hydrocarbon residue having 1 to 6 carbon atoms in the present invention include carboxyl, alkoxycarbonyl having 2 to 4 carbon atoms, amino, and halogenyl substitution having 1 to 4 carbon atoms.
  • acetylamino, acetylamino, trifluoroacetylamino and the like are preferable.
  • alkoxycarbonyl methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, aryl (allyl) oxycarbonyl and the like are preferable.
  • the aromatic hydrocarbon residue usually has 4 to 6 carbon atoms, for example, phenyl, pyridyl, pyrazinyl, Examples include pyrrolyl and piperidinyl. These may be substituted with an alkyl group having 1 to 6 carbon atoms or the same substituent as the above-mentioned substituent in the aliphatic hydrocarbon residue.
  • Preferred as the group represented by Y are an alkyl group having 1 to 4 carbon atoms having 1 or 2 substituents or an aromatic hydrocarbon residue having 4 to 6 carbon atoms (1 And may contain two heteroatoms. ) Wherein the substituents are selected from carboxy or alkoxycarbonyl, amino or acylamino, and hydroxy or alkoxy, and when there are two substituents, they are the same. Alternatively, they may be different. Further, these functional groups may be protected if necessary. As the “alkyl group” and “acyl group” appearing in these groups, those described above can be exemplified as they are.
  • alkoxy group examples include a saturated or unsaturated alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and allyloxy, and preferably 1 to 6 carbon atoms. And 4 alkoxy groups.
  • 2-carboxyethyl 2-hydroxyethyl, 2-aminoethyl, 2-acetylaminoethyl, 3-hydroxypropyl, 3-carboxypropyl, 3-methoxycarbonylpropyl, 2-carboxy-1-acetyl Aminoethyl, 2-carboquinone 2-aminoethyl, 2-carboxy-12-trifluoroacetylaminoethyl, 2-carboxy-2-pentadecanoylaminoethyl, 2-carboxy 2-benzoylaminoethyl, 2 —Methoxycarbonyl-1-2-acetylaminominethyl, 2-ethoxyquincarbonyl-2-acetylaminoethyl, 2-propoxycarbonyl 2-acetylaminoethyl, 2-aryloxycarbonyl-2-acetyl Aminoethyl and 2,3-dihydroxypropyl and the like.
  • Representative compounds represented by the above general formula (I) in the present invention include, for example, the following compounds.
  • the method for producing a (1R, 2S) 1-2-substituted-1,3-oxo-1-cyclopentanecarboxylic acid derivative represented by the general formula ( ⁇ ) or a salt thereof using a microorganism according to the present invention is as follows. It can be carried out.
  • the mercapto compound represented by the general formula (I) to be added to the nutrient medium may be free or may be added in a salt form.
  • the medium may be added to the medium in advance of the culture, or may be added in portions during the culture. They may be used in combination.
  • a mercapto compound may be dissolved in methanol, ethanol, dimethyl sulfoxide or the like at a concentration that does not affect the growth of the microorganism, and the resulting solution may be added.
  • the addition amount may be within a range that does not show toxicity such as growth inhibition to bacteria due to the mercapto compound, and is preferably 0.01 mg / ml to 5 mgZm with respect to the normal medium, preferably 0.1 mg / ml. 0 5 mg gZm 1—The optimal range may be determined in advance by a simple preliminary test within the range of 3 mg gZm 1. For example, when the mercapto compound was N-acetyl-L-cysteine, a concentration of 0.1 mgZm1 to 11 mg / m1 showed good results.
  • the nutrient medium to be used is not particularly limited as long as it is a nutrient medium that can be used for cultivation of actinomycetes and the like, and a nutrient medium containing ordinary carbon sources, nitrogen sources and inorganic substance sources is used.
  • the carbon source is not particularly limited as long as it can be used for actinomycetes, and usually dalcose, fructose, glycerin, sucrose, dextrin, galactose, and organic acids are used alone or in combination. You.
  • Sources of inorganic and organic nitrogen include ammonium chloride, ammonium sulfate, urea, ammonium nitrate, sodium nitrate, peptone, meat extract, yeast extract, dried yeast, corn strep, soy flour, cottonseed meal, casamino acid, pactosoton. , One-to-meal and the like are used alone or in combination.
  • metal halide salts such as salt and manganese chloride
  • metal carbonate salts such as calcium carbonate
  • metal sulfate salts such as magnesium sulfate, copper sulfate, iron sulfate, and zinc sulfate
  • inorganic salts such as phosphate salts.
  • Inorganic salts need not be added if the carbon source or nitrogen source used originally contains a sufficient amount, but usually the amount of the inorganic salt is also included in the medium. A concentration of about 0.001% to 1% is sufficient.
  • organic substances such as inorganic substances, amino acids, vitamins, nucleic acids, and salts thereof (inorganic salts or organic salts) other than those described above can be appropriately added.
  • carbohydrates such as glycerin, glucose, dextrin, starch, soybean flour, corn steep liquor, etc. are mainly used, and small amounts of inorganic substances such as potassium phosphate, copper sulfate, zinc sulfate, cobalt chloride, salt, etc. It is preferable to use the added medium.
  • the microorganism used in the present invention is not particularly limited as long as it is a cystazycline-producing bacterium or a sarcomycin-producing orchid.
  • Streptomyces sp. NK1752203 strain (FERM BP—43372)
  • a stastacyclin-producing bacterium and Streptomyces erythrochromosome, a sarcomycin-producing bacterium.
  • the mutant strain may be mutated by an artificial mutating means using ultraviolet rays, X-rays, drugs, or the like, or may be mutated in nature as long as it has cystazycline-producing ability or zarcomicin-producing ability. Can be used.
  • Streptomyces sp. NK1753 strain (FERMBP-434372), which is a typical example of a bacterium that produces the bioactive substance NK1752203, has the following mycological properties. Yo And physiological properties.
  • Tables A and B below show the growth state of each medium at 27 C for 2 weeks.
  • Glucose 'asparagine agar medium Abundant, brown-white to light brown-black-black
  • Glycerin ⁇ Asparagine agar medium Abundant, brown white to bright brown to black (ISP-5 medium) (wettable)
  • Tyrosine agar medium good moderate, brown to bright brown to black (ISP-7 medium) (wettable)
  • Yeast 'malt agar medium Good Abundant, Brown-white to bright brown-black to black (ISP-2 medium) (wettable)
  • Suitable growth range 24 to 37 degrees
  • Starch hydrolysis (starch 'inorganic salt agar): positive
  • this strain has a cell wall of LL diaminopimelic acid, and according to the method of International Streptomyces' Project (abbreviated as ISP), the spore-forming hypha has a morphology of section spirals (Spirales ), The spore surface is smooth or rough, and the color of the mature hyphae is gray color-series and wettable (hygroscopic). It does not produce melanin-like pigments. The color of the underlying mycelium is pale yellow, and pale brown. L-arabinose, D-glucose, D-fractose, sucrose, D-mannitol, and D-xylose are used as carbon sources.
  • ISP International Streptomyces' Project
  • Streptomyces endus (S trept omy cese ndu s), Streptomyces neyagawaen cis (S trept omy cesneyag awa e nn sis) and Streptomyces digroscopicus (S trept omy ces hyg roscopicus) .
  • the Streptomyces sp. NK 1 75203 strain used in the present invention has some differences from these similar strains, and it is difficult to determine the species.
  • Streptomyces it differs from this strain in the availability of sucrose and L-rhamnose, but is very similar in other properties. Therefore In the following, this strain will be named Streptomyces endus NK 1 75203 strain.
  • Table 1 compares the growth of the type strains Streptomyces' Endus ISP 5 187 (IF012859) and NK 1752 03 in the main medium, and Table 2 compares the carbon source availability. It was shown to.
  • Glycerin ⁇ ⁇ Paragine agar medium Moderate, brown-white, ruby-brown to black Moderate, brown-white, rua-brown to black
  • the culture method in the present invention is not particularly limited as long as it produces the target compound, but aerobic culture is usually preferred.
  • a liquid culture method particularly a submerged stirring culture method, is preferred.
  • the culture temperature is the microbe used
  • the force depending on the object is usually 10 degrees C to 40 degrees C, preferably about 15 degrees C to 35 degrees C. Since the pH varies depending on the microorganism used, it cannot be unconditionally determined, but is preferably neutral or slightly acidic.
  • the culture period is not particularly limited, but is usually 1 to 10 days, preferably about 3 to 5 days in liquid culture, and when the production amount of the target compound in the culture solution reaches the maximum. Stop the culture, filter the culture, and purify and isolate the target compound.
  • Purification and isolation from the filtrate generally follow the separation and purification methods used to isolate microbial metabolites from their cultures, including adsorption and elution on activated carbon and purification by silica gel chromatography. May be combined for purification and isolation.
  • the culture solution is adjusted to pH 2.5, filtered, the filtrate is adsorbed on activated carbon, eluted sequentially with water and 80% methanol, concentrated under reduced pressure, and the concentrated solution is adjusted to pH 6
  • the sodium salt of cystacyclin can be obtained by successively performing a chromatography step using Sephadex LH-20, QAE-Sephadex, and then Sephadex LH-20.
  • Other compounds can be similarly separated by chromatography according to the case of stacyclin.
  • Examples of the compound of the general formula ( ⁇ ) produced as described above include the following compounds.
  • All of the above compounds and pharmacologically acceptable salts thereof have a neuronal differentiation promoting action similar to that of cystacyclin and can be used as a neuronal differentiation promoting agent.
  • a nerve cell differentiation promoting agent When used as a nerve cell differentiation promoting agent, it may be administered as an injection, oral preparation, suppository, or the like, alone or as a mixture with a pharmaceutical additive such as an excipient or carrier.
  • a pharmaceutical additive such as an excipient or carrier.
  • Any commonly used pharmaceutical additives can be used as long as they are pharmaceutically acceptable, and may be appropriately selected depending on the administration route, administration method and the like.
  • water, alcohols, animal and vegetable oils, synthetic oils, and the like are used as the liquid carrier.
  • Monosaccharides, oligosaccharides, polysaccharides, etc. as solid carriers Sugars and the like are used.
  • physiological saline In the case of injections, physiological saline; various buffers; saccharide solutions such as glucose, inositol and mannitol; and glycols such as ethylene glycol, propylene glycol and polyethylene glycol are generally desirable.
  • saccharide solutions such as glucose, inositol and mannitol
  • glycols such as ethylene glycol, propylene glycol and polyethylene glycol
  • excipients such as saccharides such as inositol, mannitol, glucose, mannose, maltose and sucrose, and amino acids such as phenylalanine, etc.
  • a suitable solvent for injection for example, sterile water, physiological saline, It can also be administered after dissolving in a liquid for intravenous administration such as glucose solution, electrolyte solution, amino acid solution and the like.
  • the dosage is determined by the method of administration, age of the patient, body weight, symptoms, treatment purpose, etc., but the therapeutic dose is generally 1 to 20 Omg / kg for parenteral administration, and 2 to 5 for oral administration. 0 0 mg / kg ⁇ day.
  • the action of the cyclopentanecarboxylic acid derivative produced according to the present invention for inducing neuronal cell differentiation may be determined by examining the action of elongating neurites on PC12 cells as follows. Pharmacological test of neurite outgrowth effect of compounds on PC12 cells
  • Glycerin 2% glucose 1%, dextrin 4%, soy flour 2.5%, yeast extract 0.1%, salt 0.3%, calcium carbonate 0.5%, iron sulfate7-hydrate 0.000 1 1%, copper sulfate pentahydrate 0.00 0 6 4%, zinc sulfate heptahydrate 0.00 0 15%, manganese chloride 'tetrahydrate 0.00 0 7 9 %, Conochlort chloride ⁇ hexahydrate 0.01%
  • the medium containing 0.1% was adjusted to pH 7.0, dispensed to 100 ml in a 500 ml Erlenmeyer flask, sterilized, and sterilized.
  • N-acetyl-L-cystine 25 mg / 2 ml is added one day and two days later (two times in total).
  • Seed mother and main culture are performed in the same manner as in Example 1, except that N-isobutyryl-L-cysteine (30 mg / 4 ml) (30 mg / 4 ml) is added after 1 day and 2 days (2 times in total) instead of N-acetyl-cysteine.
  • the filtrate (74 ml) was purified in the same manner as in the compound (2) to obtain 28 mg of the sodium salt of the compound (3).
  • Seed mother and main culture are performed in the same manner as in Example 1, except that N-benzoyl-L-cysteine (30 mg / 4 ml) (30 mg / 4 ml) is added after 1 day and 2 days (2 times in total) instead of N-acetyl-L-cysteine.
  • the filtrate (84 ml) was purified in the same manner as in the compound (2) to obtain 22 mg of the sodium salt of the compound (5).
  • the medium containing 0.0001% was adjusted to pH 7.0, 100 ml was dispensed into a 500 ml Erlenmeyer flask, sterilized, and then inoculated with 1 ml of the previous seed, at 27 ° C at 220 rpm. Incubate for 4 days. N-Acetyl-L-cystine (25mgZml) is added 3 days later. Four days after culturing, measurement was performed by high performance liquid chromatography, and compound (1) was produced at 0.98 mg / m 1.

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Abstract

Les dérivés d'acide cyclopentanecarboxylique optiquement actifs (tels que la cystacycline ou la sarcomycine) capables d'induire la différenciation des cellules nerveuses peuvent être préparés par un processus de fermentation à rendement élevé, qui consiste: à cultiver une bactérie produisant la cystacycline ou la sarcomycine sur un milieu nutritif renfermant un composé mercapto de formule générale (I) de manière à produire un dérivé d'acide cyclopentanecarboxylique de formule générale (II) présentant une chaîne latérale correspondant au composé mercapto; puis à isoler le dérivé d'acide cyclopentanecarboxylique ainsi obtenu du milieu de culture. HS-Y (I), dans laquelle Y est un reste hydrocarboné en C1-C20 éventuellement substitué d'un poids moléculaire de 15 à 400, étant entendu que lorsque le reste est cyclique, un ou deux hétéroatomes peuvent être contenus dans le cycle. Formule (II) dans laquelle Y est tel que défini ci-dessus.
PCT/JP1998/001900 1997-04-24 1998-04-24 Procede de preparation de derives d'acide cyclopentanecarboxylique Ceased WO1998048029A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994005679A1 (fr) * 1992-09-09 1994-03-17 Nippon Kayaku Kabushiki Kaisha Nouvelle substance physiologiquement active appelee nk175203, son procede de production et son utilisation pharmaceutique
WO1997028114A1 (fr) * 1996-01-31 1997-08-07 Nippon Kayaku Co., Ltd. Derives du cyclopentanone disubstitues en 2,3, leur procede d'obtention et leurs emplois medicaux

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994005679A1 (fr) * 1992-09-09 1994-03-17 Nippon Kayaku Kabushiki Kaisha Nouvelle substance physiologiquement active appelee nk175203, son procede de production et son utilisation pharmaceutique
WO1997028114A1 (fr) * 1996-01-31 1997-08-07 Nippon Kayaku Co., Ltd. Derives du cyclopentanone disubstitues en 2,3, leur procede d'obtention et leurs emplois medicaux

Non-Patent Citations (1)

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Title
FROISSANT J., ET AL.: "SYNTHESIS OF NITRILE AND METHYL ESTER CORRESPONDING TO (DL)- SARKOMYCIN AND OF RELATED COMPOUNDS.", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 43., no. 02., 1 January 1987 (1987-01-01), AMSTERDAM, NL, pages 317 - 322., XP002911999, ISSN: 0040-4020, DOI: 10.1016/S0040-4020(01)89959-2 *

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