WO2006103995A1 - PROCEDE DE PRODUCTION D'UN DERIVE D'ACIDE α-AMINE OPTIQUEMENT ACTIF - Google Patents

PROCEDE DE PRODUCTION D'UN DERIVE D'ACIDE α-AMINE OPTIQUEMENT ACTIF Download PDF

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Publication number
WO2006103995A1
WO2006103995A1 PCT/JP2006/305737 JP2006305737W WO2006103995A1 WO 2006103995 A1 WO2006103995 A1 WO 2006103995A1 JP 2006305737 W JP2006305737 W JP 2006305737W WO 2006103995 A1 WO2006103995 A1 WO 2006103995A1
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Prior art keywords
optically active
amino acid
acid derivative
hydantoinase
rubamyl
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PCT/JP2006/305737
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English (en)
Japanese (ja)
Inventor
Makoto Ueda
Hirokazu Nanba
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Kaneka Corporation
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Publication of WO2006103995A1 publication Critical patent/WO2006103995A1/fr

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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
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/006—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • C12N1/205—Bacterial isolates
    • 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
    • C12P13/04—Alpha- or beta- amino acids
    • 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
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/07—Bacillus

Definitions

  • the present invention relates to a method for producing an optically active ⁇ -amino acid derivative that is useful as an intermediate for pharmaceuticals and the like. More specifically, in the presence of a divalent metal ion, the racemic ⁇ -strength rubamylamino acid derivative is allowed to produce a hydantoinase whose hydrolysis activity is inhibited by the metal ion.
  • the present invention relates to a method for obtaining a hydantoin derivative and an optically active ⁇ ⁇ carbamyl amino acid derivative.
  • an extraction method requires large-scale purification equipment from protein hydrolysates.
  • the amino acid to be produced is usually a racemate, so that an expensive resolving agent, an asymmetric catalyst, etc. are required to produce an optically active substance.
  • Fermentation methods have low product concentrations and require large-scale purification equipment, as with extraction methods.
  • Non-patent Documents 1 and 2 As a method for synthesizing D-a amino acid by enzymatic synthesis, for example, a microorganism or enzyme having hydantoinase activity is used to selectively hydrolyze racemic 5-substituted hydantoin derivatives to form D Lubamil D—a Methods for producing amino acid derivatives are known (Patent Documents 1 and 2). In addition, it is generally known that there are examples in which divalent metal ions such as manganese and cobalt contribute to the improvement of enzyme activity in a hydrolysis reaction in which a hydantoinase is allowed to act on a 5-substituted hydantoin derivative to open the ring. (Non-patent documents 2 and 3).
  • Patent Documents 3 and 4 There are also known examples of adding manganese, which is a divalent metal ion, to carry out a cyclization reaction (Patent Document 5).
  • Patent Document 1 JP-A 53-44690
  • Patent Document 2 JP-A-53-91189
  • Patent Document 3 JP-A-60-180596
  • Patent Document 4 JP-A-1-124398
  • Patent Document 5 WO03Zl06689
  • Non-patent literature 1 Advances Biochemical EngmeermgZBiotechnoiogy, 41 ⁇ , 29, 1990
  • Patent Document 2 Bioscience Biotechnology Biochemistry ⁇ 58 ⁇ , 1621, 19 94
  • Non-Patent Document 3 Journal of Molecular Catalysis B: Enzymatic, 2 ⁇ , 163, 1997
  • the reaction of hydantoinase is a reversible reaction, and in the method of adding a divalent metal ion, the reverse reaction is not only the target hydrolysis reaction (or cyclization reaction). Is easily expected to be promoted.
  • a method of promoting only the target hydrolysis reaction or cyclization reaction more preferably a method of promoting the target reaction and inhibiting the reverse reaction Is desired.
  • an object of the present invention is to provide a practical method for industrial production, for example, an optically active ⁇ -amino acid derivative useful as an intermediate of a pharmaceutical can be easily produced from a predetermined raw material. There is.
  • optically active 5-substituted hydantoin derivatives can be obtained by stereoselectively cyclizing racemic and strong rubamyl amino acid derivatives using hydantoinase.
  • the divalent metal ion inhibits the hydrolysis activity, which is the reverse reaction of the above cyclization reaction.
  • the cyclization reaction was greatly accelerated.
  • the present invention relates to the general formula (2):
  • R is an optionally substituted alkyl group having 1 to 20 carbon atoms, has a substituent !, may be an aralkyl group having 7 to 20 carbon atoms, or is substituted.
  • a hydantoinase that inhibits the activity of hydrolyzing a 5-substituted hydantoin derivative into N-strength rubamyl amino acid by the divalent metal ion is represented by the general formula (1):
  • the present invention relates to a production method comprising stereoselectively cyclizing a high-strength rubamyl amino acid derivative represented by the formula (wherein R is as defined above).
  • the present invention also provides an optically active 5-substituted hydantoin derivative represented by the above formula (2), and
  • the present invention relates to a production method characterized by stereoselectively cyclizing a strong rubamyl amino acid derivative.
  • the present invention has the above-described configuration, and can efficiently produce an optically active 5-substituted hydantoin derivative and an optically active high-power rubamyl amino acid derivative.
  • a general hydantoinase has an activity of hydrolyzing a 5-substituted hydantoin derivative to produce a strong rubamyl amino acid derivative, and the reverse reaction of the hydrolysis reaction. It is known to have both the activity of cyclizing strong rubamyl amino acid derivatives to form 5-substituted hydantoin derivatives. In addition, it is known that the enzyme activity of the above hydrolytic reaction of hydantoinase is improved by divalent metal ions.
  • R has a substituent, and may have an alkyl group having 1 to 20 carbon atoms, a substituent! However, it also has an aralkyl group having 7 carbon atoms or a aralkyl group having 20 substituents! Or may represent an aryl group having 6 to 20 carbon atoms.
  • the alkyl group having 1 to 20 carbon atoms is not particularly limited, and for example, a straight chain alkyl group such as a methyl group, an ethyl group, or an n-propyl group, an isopropyl group, an isobutyl group, or a t-butyl group. And branched alkyl groups such as a neopentyl group or a t-pentyl group.
  • the aralkyl group having 7 to 20 carbon atoms which may have a substituent is not particularly limited, and examples thereof include a benzyl group, an indolylmethyl group, a 4-hydroxybenzyl group, and 3, 4-methylenedialkyl.
  • aryl group having 6 to 20 carbon atoms which may have a substituent examples include a phenol group and a 4-hydroxyphenol group.
  • the alkyl group, aryl group or aralkyl group may be unsubstituted or may have a substituent.
  • substituent examples include an amino group, a hydroxyl group, a phenol group, an aryl group, an alkanol group, an alkenyl group, an alkyl group, an alkoxyl group, and a halogen atom.
  • Hydantoinase is an enzyme having an activity of hydrolyzing a 5-substituted hydantoin derivative to produce an N-force rubamylamino acid derivative.
  • this enzyme is known to cyclize an N-strength rubamoyl amino acid derivative to produce a 5-substituted hydantoin derivative as the reverse reaction of the hydrolysis reaction.
  • conventional hydantoinases have improved enzyme activity in the presence of divalent metal ions such as manganese and conoleto. It has been.
  • the hydantoinase used in the present invention has a property that its hydrolysis activity is inhibited by a predetermined divalent metal ion. Therefore, as the hydantoinase of the present invention, for example, hydantoinase derived from animals, plants, or microorganisms and having hydrolytic activity inhibited by divalent metal ions can be used. For industrial use, hydantoinase derived from microorganisms is preferred.
  • microorganism from which hydantoinase is derived can be used as long as it is a microorganism having the ability to produce the enzyme.
  • bacteria include Aceto bacter, Achromobacter, Aerobacter, Agrobacterium, Alcaligenes, Arthrobacter, Bacillus ( Bacillus), Brevibacterium, Corynebacterium, Enterobacter, Erwinia, Escherichia, Klebsiella, Microbacteria (Microbacterium), Micrococcus, Protaminobacter (Protaminobacter, Proteus no., Proteus no, No.
  • Domonas for Pseudomonas (Sartina), Serratia, Serratia, Xanthomonas Genus (Xanthomonas), Aeromonas, Flavobataterium (Fla vobacterium), or a microorganism belonging to the genus Rhi zobium.
  • actinomycetes microorganisms belonging to the genus Actinomyces, Mycobacterium, Nocardia, Streptomyces, Actinoplanes or Rhodococcus Can be mentioned.
  • Examples of the fungi include microorganisms belonging to the genus Aspergillus, Paecilomyces, Penicillium, and the like.
  • yeast examples include microorganisms belonging to the genus Candida, the genus Phichia, the genus Rhodo torula or the genus Torulopsis.
  • enzymes derived from microorganisms belonging to the genus Agrobacterium, Bacillus, Pseudomonas or Rhizobium can be mentioned. More preferably, Agrobacterium sp. KNK712 (FERM BP—1900), Bacillus sp. KNK2 45 (FERM BP— 4863), Pseudomonas putida NBRC12 996, Pseudomonas sp. (Pseudomonas sp.) KNK003A (FERM BP— 3181) or Rhizobium sp. KNK1415 (FERM BP— 44) Is mentioned.
  • Agrobacterium sp. KNK712 (FERM BP— 1900), Bacillus sp. KNK245 (FERM BP— 486 3), Pseudomonas sp. KNK003A (FERM BP-3 181) and Rhizobium sp. KNK1415 (FERM BP-441 9) are registered with the Patent Product Deposit Center (IPOD: 305- 8566 Deposited at Tsukuba Sakai Higashi, 1-chome, 1-chome, 1-center, 6), Ibaraki, Japan.
  • Rhizobium sp. KNK1415 (FERM BP- 4419): September 22, 1993.
  • NBRC12996 The above-mentioned Pseudomonas putida NBRC12996 is an independent administrative agency, National Institute of Technology and Evaluation, Biotechnology Headquarters, Biogenetic Resource Division (NBRC: 292-0818, Chiba Prefecture Kisarazu Kazusa Kamashisa 2-5-8) It is stored and can be obtained from the same institution.
  • Any transformant obtained in this manner that produces a high yield of D-form selective hydantoinase can be used as long as the hydrolysis activity is inhibited by a divalent metal ion.
  • Escherichia coli HB 101 pTH 104
  • FERM BP— 4864 containing a hydantoinase gene derived from Bacillus sp. K NK245 (FERM BP-4863) described in WO96Z20275.
  • the production of hydantoinase by these transformants, or the production of hydantoinase by a strain exhibiting the above-mentioned hydantoinase activity, for example, can be performed by culturing using a normal nutrient medium described in WO96 / 20275.
  • treatment for enzyme induction can be performed.
  • Escherichia coli HB 101 (pTHl 04) (FERM BP—486 4) is a patent biological deposit center (IPOD: 305) -8566 Deposited at Tsukuba Sakai Higashi, 1-chome, 1-chome, 1st, Central 6), Ibaraki, Japan (Deposit date: November 2, 1994).
  • the hydantoinase produced by the above-mentioned microorganism can be used not only as the enzyme itself, but also as a form of a microorganism having the enzyme activity or a processed product thereof.
  • the treated product of microorganisms means, for example, a crude extract, cultured cells, freeze-dried cells, acetone-dried cells, or a crushed product of these cells.
  • the hydantoinase or a processed product thereof may be used as the enzyme itself or as a fixed enzyme obtained by fixing it with a known means in the form of cells.
  • the immobilization may be carried out by a cross-linking method, a covalent bonding method, a physical adsorption method, a comprehensive method, etc., which are well known to those skilled in the art.
  • racemic N-strength rubamyl amino acid derivative (1) is stereoselectively cyclized with hydantoinase to synthesize an optically active 5-substituted hydantoin derivative (2) and an optically active N-force rubamyl amino acid derivative (3). How to do will be described.
  • the enzyme reaction of the present invention can be carried out by the following method.
  • a racemic N-type rubamyl amino acid derivative represented by the general formula (1) is used as a substrate, and the reaction is carried out in an aqueous medium in the presence of the above-mentioned hydantoinase and a divalent metal ion.
  • the concentration of the divalent metal ion is 0. OlmM or more, 1M or less, preferably 0. ImM or more, 1OmM or less, and the substrate concentration is 0.1% or more, 90% (wZv) or less, preferably 1% or less.
  • the reaction is performed in a dissolved or suspended state at 60% (wZv) or less.
  • the reaction temperature is adjusted to an appropriate temperature of 10 ° C or higher and 80 ° C or lower, preferably 20 ° C or higher and 60 ° C or lower, and is kept at pH 4 or higher, 9 or lower, preferably pH 5 or higher, 8 or lower for a while. It may be left still or stirred. Further, the substrate may be added continuously.
  • the reaction can be carried out batchwise or continuously.
  • the reaction of the present invention may be performed using an immobilized enzyme, a membrane reactor, or the like.
  • divalent metal ion examples include, but are not limited to, ions such as vanadium, chromium, manganese, iron, conoleto, nickel, copper, zinc, molybdenum, magnesium, or calcium. Cobalt, zinc, manganese or nickel ions are preferable, and cobalt or zinc ions are more preferable. These metal ions can be used alone or in combination of two or more metal ions.
  • aqueous medium examples include water, a buffer solution, an aqueous medium containing a water-soluble organic solvent such as ethanol, or an organic solvent that is difficult to dissolve in water, such as ethyl acetate, butylacetate, toluene,
  • a suitable solvent such as a two-layer system with an aqueous medium containing an organic solvent such as black mouth form and n-xane can be used.
  • antioxidants, surfactants, coenzymes, metals, etc. can be added as necessary.
  • optically active form of the racemic N-force rubamyl amino acid derivative is cyclized by the stereoselective hydantoinase of the present invention to produce an optically active 5-substituted hydantoin derivative.
  • an optically active N-force rubamyl amino acid derivative having the opposite steric structure remains. Isolation of the obtained optically active 5-substituted hydantoin derivative and optically active N-force rubamyl amino acid derivative can be performed by a conventional separation method such as extraction, concentration, crystallization, or column chromatography. Or they can be separated and purified by their combination.
  • optically active 5-substituted hydantoin derivative and optically active N-carbamylamino acid derivative can be obtained by known chemical methods (for example, acid / alkali treatment) or enzymatic methods (for example, decarbamylase). Can be easily derived to the corresponding optically active amino acid by the weak ruby moisturizing treatment.
  • the racemic N-force rubamyl amino acid derivative is exemplified.
  • a conductor may be used.
  • an optically active N-force rubamyl amino acid derivative is used, the optical purity of, for example, the remaining optically active N-force rubamyl amino acid derivative or the optically active 5-substituted hydantoin derivative produced by the hydantoinase of the present invention. Can be improved.
  • Escherichia coli HB101 pTH104 (FERM BP-4864), a recombinant E. coli with D-selective hydantoinase activity, sterilized in a 500 ml Sakaguchi flask (tryptone 16 g, yeast extract 10 g, chloride) 5 g of sodium, 11 deionized water, 400 ppm of manganese chloride, pH 7.0 before sterilization, and filter sterilized ampicillin sodium added separately at a final concentration of lOO ppm) and shaken at 37 ° C for 24 hours. Cultured aerobically.
  • the resulting culture is collected by centrifuging from 1 ml of the culture broth, suspended in 5 ml of 10 mM Tris-HCl buffer (pH 8.5), disrupted by sonication, and centrifuged to centrifuge the cells. The insoluble matter was removed, and a crude enzyme solution of D-form selective hydantoinase was obtained.
  • 4 ml of 50 mM sodium carbonate Z sodium hydrogen carbonate buffer (pH 8.7) containing 30 mM D-5-isobutylhydantoin and various metal salts shown in Table 1 was mixed. After standing at 40 ° C for 15 minutes, the reaction was stopped by adding 1 ml of 5N sulfuric acid. Table 1 shows the results of analyzing the amount of D—N—force rubamoyl leucine produced using high performance liquid chromatography (HPLC).
  • Table 2 shows the results of analysis of the amount of D—N-force rubermoyl (4-hydroxyphenyl) glycine produced using HPLC.
  • the obtained crude enzyme solution 0.1 ml contains 30 mM D—N—forced rubermoyl leucine and cobalt chloride or zinc sulfate at the concentrations shown in Table 3 50 mM 2— [4 (2- Hydroxy et hyl) 1 -piperazinyllethanesulfonic acid ( 4 ml of HEPES) -NaOH buffer (pH 7.0) was added and mixed. After standing at 40 ° C for 15 minutes, 4 ml of acetonitrile was added to stop the reaction. Table 3 shows the results of analysis of the amount of D-5 isoptylhydantoin produced in the same manner as in Reference Example 1.
  • Example 2 D-5- (4-hydroxyphenyl) hydantoin using hydantoinase Culture medium used in Example 1 11. Bacteria were collected by centrifugation at 7 ml force, and 10 mM Tris —Suspend in 5 ml of hydrochloric acid buffer (pH 8.5) and crush the cells by ultrasound. Then, remove the insoluble matter derived from the cells by centrifugation and remove the crude enzyme solution of D-form selective hydantoinase. Got.
  • Example 2 The crude enzyme solution used in Example 1 was mixed with 0.05 ml of 1M HEPES-NaOH buffer (6.8) containing 10% (wZv) DL-N-strong rubermoyl leucine and ImM cobalt chloride (6.8). . After stirring at 40 ° C for 3 hours, the yield and optical purity of the produced D-5 isoptylhydantoin and the remaining LN strength rubermoyl leucine were analyzed using HPLC, and as a comparative example, Table 5 shows the results when no force was added.

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Abstract

La présente invention propose un procédé de production d'un dérivé de l'hydantoïne optiquement actif portant une substitution en 5 et un dérivé de l'acide N-carbamoyl aminé optiquement actif. Le procédé comprend la cyclisation d'un dérivé racémique de l'acide N-carbamoyl aminé par une hydantoïnase de manière stéréo-sélective. La cyclisation est effectuée en présence d'un ion métallique divalent en utilisant une hydantoïnase telle que l'hydrolyse du dérivé de l'hydantoïne portant une substitution en 5 en dérivé de l'acide N-carbamoyl aminé (réaction inverse) causée par l'hydantoïnase soit inhibée par l'ion métallique. Le procédé peut produire de manière simple un dérivé de l'hydantoïne optiquement actif portant une substitution en 5 et un dérivé de l'acide N-carbamoyl aminé optiquement actif. Ces composés peuvent être utilisés pour produire aisément un dérivé d'acide α-aminé optiquement actif qui sert d'intermédiaire pour un médicament ou un produit similaire.
PCT/JP2006/305737 2005-03-25 2006-03-22 PROCEDE DE PRODUCTION D'UN DERIVE D'ACIDE α-AMINE OPTIQUEMENT ACTIF WO2006103995A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9499521B2 (en) 2014-12-11 2016-11-22 President And Fellows Of Harvard College Inhibitors of cellular necrosis and related methods

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60180596A (ja) * 1984-02-02 1985-09-14 スクラーボ・エセ・ピ・ア Ｌ‐α‐アミノ酸の製法
WO1996020275A1 (fr) * 1994-12-28 1996-07-04 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha PROCEDE DE FABRICATION DE L'ACIDE D-N-CARBAMYLE-α-AMINE
JP2003061692A (ja) * 2001-06-22 2003-03-04 Degussa Ag 活性化されたｒｅｃ−ヒダントイナーゼの製造方法、該方法で得られるｒｅｃ−ヒダントイナーゼ、これをコードする核酸、それを有するプラスミド、ベクター及び微生物、ハイブリダイズする核酸、その製造のためのプライマー並びにｒｅｃ−ヒダントイナーゼ及び核酸の使用
JP2003277343A (ja) * 2002-03-20 2003-10-02 Kanegafuchi Chem Ind Co Ltd 新規Ｎ−カルバモイル−α−アミノ酸及びその製造方法
WO2003106689A1 (fr) * 2002-06-05 2003-12-24 鐘淵化学工業株式会社 Procede de production de derive d'$g(a)-methylcysteine optiquement actif
WO2004022766A1 (fr) * 2002-09-06 2004-03-18 Kaneka Corporation Procede pour produire un derive de l-$g(a)-methylcysteine

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60180596A (ja) * 1984-02-02 1985-09-14 スクラーボ・エセ・ピ・ア Ｌ‐α‐アミノ酸の製法
WO1996020275A1 (fr) * 1994-12-28 1996-07-04 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha PROCEDE DE FABRICATION DE L'ACIDE D-N-CARBAMYLE-α-AMINE
JP2003061692A (ja) * 2001-06-22 2003-03-04 Degussa Ag 活性化されたｒｅｃ−ヒダントイナーゼの製造方法、該方法で得られるｒｅｃ−ヒダントイナーゼ、これをコードする核酸、それを有するプラスミド、ベクター及び微生物、ハイブリダイズする核酸、その製造のためのプライマー並びにｒｅｃ−ヒダントイナーゼ及び核酸の使用
JP2003277343A (ja) * 2002-03-20 2003-10-02 Kanegafuchi Chem Ind Co Ltd 新規Ｎ−カルバモイル−α−アミノ酸及びその製造方法
WO2003106689A1 (fr) * 2002-06-05 2003-12-24 鐘淵化学工業株式会社 Procede de production de derive d'$g(a)-methylcysteine optiquement actif
WO2004022766A1 (fr) * 2002-09-06 2004-03-18 Kaneka Corporation Procede pour produire un derive de l-$g(a)-methylcysteine

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9499521B2 (en) 2014-12-11 2016-11-22 President And Fellows Of Harvard College Inhibitors of cellular necrosis and related methods
US9944628B2 (en) 2014-12-11 2018-04-17 President And Fellows Of Harvard College Inhibitors of cellular necrosis and related methods
US10508102B2 (en) 2014-12-11 2019-12-17 President And Fellows Of Harvard College Inhibitors of cellular necrosis and related methods

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