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WO2000076995A1 - Procede de preparation de derives de l'acide (-)-1,4-benzothiazine-2-acetique - Google Patents

Procede de preparation de derives de l'acide (-)-1,4-benzothiazine-2-acetique Download PDF

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Publication number
WO2000076995A1
WO2000076995A1 PCT/JP2000/003741 JP0003741W WO0076995A1 WO 2000076995 A1 WO2000076995 A1 WO 2000076995A1 JP 0003741 W JP0003741 W JP 0003741W WO 0076995 A1 WO0076995 A1 WO 0076995A1
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Prior art keywords
acetic acid
benzothiazine
group
salt
acid derivative
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP2000/003741
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English (en)
Japanese (ja)
Inventor
Yuji Ono
Fumihiko Akahoshi
Akihiko Moriguchi
Satoru Uemori
Tsuguo Ikebe
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Senju Pharmaceutical Co Ltd
Tanabe Pharma Corp
Original Assignee
Senju Pharmaceutical Co Ltd
Mitsubishi Pharma Corp
Welfide Corp
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Publication date
Application filed by Senju Pharmaceutical Co Ltd, Mitsubishi Pharma Corp, Welfide Corp filed Critical Senju Pharmaceutical Co Ltd
Priority to AU52464/00A priority Critical patent/AU5246400A/en
Publication of WO2000076995A1 publication Critical patent/WO2000076995A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to a method for producing (1) -1,4-benzothiazine-2-acetic acid derivative. More specifically, it is described that the (Sat) 1,1,4-benzothiazine-2-acetic acid derivative is subjected to optical resolution by forming a salt between the (I) monoenantiomer of the derivative and an optically active substance.
  • the present invention relates to a method for producing a monoacetic acid derivative.
  • R 1 and R 2 may be the same or different, show it it it hydrogen atom, C androgenic atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, triflate Ruoromechiru group or Torifuruorome butoxy group
  • R 3 Represents a carboxyl group which may be esterified
  • R 4 , R 5 , R 6 and R 7 may be the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or
  • X represents an oxygen atom or a sulfur atom, is capable of reducing aldoses such as glucose and galactose.
  • An object of the present invention is to provide a method for producing a (_)-11,4-benzothiazine-12-acetic acid derivative represented by the above general formula (I).
  • the present inventors have conducted various studies, and found that the 1,4-benzothiazine_2-acetic acid derivative represented by the above general formula (I) can be dissolved in an optically active substance and acetate nitrile.
  • the reaction is performed to racemize the (+)-enantiomer of the derivative and to form a salt between the (-) enantiomer of the derivative and the optically active substance, thereby performing optical resolution.
  • the present invention is as follows.
  • R 1 and R 2 may be the same or different, show it it it hydrogen atom, C androgenic atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, triflate Ruoromechiru group or Torifuruorome butoxy group,
  • R 3 Represents a carboxyl group which may be esterified;
  • R 4 , R 5 , R 6 and R 7 may be the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or Represents a trifluoromethyl group, and
  • X represents an oxygen atom or a sulfur atom.
  • the method further comprises heat-treating the salt of the (1) -enantiomer of the derivative and the optically active substance in a solvent.
  • a method for producing an nzothiazin-1-acetic acid derivative is
  • R 1 and R 2 may be the same or different and each represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a trifluoromethyl group or a trifluoromethoxy group, and R 3 represents Represents a carboxyl group which may be esterified; R 4 , R 5 , R 6 and R 7 may be the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or Represents a trifluoromethyl group, and X represents an oxygen atom or a sulfur atom.
  • the 1,4-benzothiazine-2-acetic acid derivative is reacted with an optically active substance in a solvent under heating conditions. Optical resolution is performed by forming a salt between the (1) one enantiomer of the derivative and the optically active substance.
  • the method further comprises heat-treating the salt of the (1) -enantiomer of the derivative and the optically active substance in a solvent.
  • (Sat) represented by the general formula (I) —1,4-benzothiazine—2-acetic acid derivative is (S) -1,3,4-Dihydro-1-3-oxo-14-1 ([4 , 5,7-Trifluoro-2-benzothiazolyl) methyl] — 2H—1,4-benzothiazine-12-acetic acid, (1) — according to any one of [1] to [4], A method for producing 1,4-benzothiazine-2-acetic acid derivatives.
  • R 1 and R 2 may be the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a trifluoromethyl group or a trifluoromethoxy group, 3 represents a carboxyl group which may be esterified; R 4 , R 5 , R 6 and R 7 may be the same or different, and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group; Or X represents an oxygen atom or a sulfur atom.), And its optical purity is higher than 98.5%.
  • [8] The (1) — 1,4-benzothiazine — 2-acetic acid derivative represented by the general formula (I) is (1) 1, 3, 4-dihydro-13-oxo-1 4-— ((4, 5,7-Trifluoro-2-benzothiazolyl) methyl] —2H—1,4-benzothiazine-monoacetic acid (1) described in [7] —1,4-benzothiazine-2-acetic acid derivative or Its pharmacologically acceptable salts.
  • R 1 and R 2 may be the same or different and each represents a hydrogen atom, A hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a trifluoromethyl group or a trifluoromethoxy group;
  • R 3 represents a carboxyl group which may be esterified;
  • R 4 , R 5 , R 6 and R 7 may be the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a trifluoromethyl group, and
  • X represents an oxygen atom or a sulfur atom.
  • the general formula (I) is a racemic form of a 1,4-benzothiazine-2-acetic acid derivative ((P) -11,4-benzothiazine-12-acetic acid derivative), Includes (—) — enantiomer ((—) — 1,4-benzthiazine-12-acetic acid derivative) and (+) — enantiomer ((+) — 1,4-benzothiazine-2-acetic acid derivative) It shall be.
  • carbon atoms marked with * indicate asymmetric carbon atoms.
  • the definition of each substituent in the general formula (I) is as follows. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.
  • a linear or branched alkyl group having 1 to 6 carbon atoms is preferable.
  • methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butyl, tert-butyl, pentyl examples include isopentyl, hexyl, and isohexyl.
  • a linear or branched alkoxy group having 1 to 6 carbon atoms Preferred are, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, isohexyloxy and the like.
  • the lower alkylthio group a straight-chain or branched alkylthio group having 1 to 6 carbon atoms is preferable. Examples include isopentylthio, hexylthio, and isohexylthio.
  • the carboxyl group which may be esterified means a carboxyl group or an esterified carboxyl group.
  • esterified carboxyl group examples include lower alkoxy groups having 1 to 6 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, and tert-butoxycarbonyl.
  • the pharmacologically acceptable salt of the compound represented by the general formula (I) is not particularly limited as long as it is a pharmacologically acceptable non-toxic salt.
  • a pharmacologically acceptable non-toxic salt for example, lithium salt, sodium salt, potassium Alkali metal salts such as salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts; salts with organic bases such as triethylamine salts, pyridine salts; and basic amino acids such as lysine salts and arginine salts. Salt etc.
  • R 4 , RR 6 and R 7 may be the same or different, and a compound each of which is a hydrogen atom, a fluorine atom or a chlorine atom is a compound of the present invention. Preferred as a compound.
  • preferred specific examples of the compound represented by the general formula (I) include, for example, the compounds described in JP-A-5-92961 (EP 0 492 667 A1). Typical examples thereof include, for example, 3,4-dihydro-3-oxo-4-[(4,5,7-trifluoro-2-benzothiazolyl) methyl] —2H—1,4-benzothiazine 2-Acetic acid can be mentioned.
  • the process for producing the (-)-1,4-benzothiazine-12-acetic acid derivative of the present invention comprises preparing the ( ⁇ )-1,4, -benzothiazine-12-acetic acid derivative represented by the above general formula (I). Reacting the optically active substance with acetonitrile to racemize the (+)-enantiomer of the derivative and to form a salt between the (-) enantiomer of the derivative and the optically active substance It is characterized by performing optical division.
  • optically active substance used in the production method of the present invention is not particularly limited as long as it forms a salt with the compound represented by the above general formula (I).
  • ) Brucine (anhydrous or dihydrate), cinchonine, dehydroabiethylamine, D — (—) _ 2—amino-1- (p-ditrophenyl) -1,3-propanediol, S — (-) — 1-phenylethylamine, R-(+) — 1-phenylethylamine, (+) —norephedrine, (1) 1-norphedrine, etc.)
  • Preferred are optically active amines, and particularly preferred is (1) -brucine (anhydride or dihydrate).
  • the addition amount is 0.5 to 1.0 equivalent, preferably 1.0 equivalent, per the above-mentioned (P) -1,4-benzothiazine-2-acetic acid derivative.
  • the optical resolution in the production method of the present invention is preferably performed in acetonitrile.
  • (1) -mirror of compound represented by the above general formula (I) with respect to acetonitrile The salt of the enantiomer and the optically active substance has much lower solubility than the salt of the (+)-enantiomer of the compound and the optically active substance.
  • Acetonitrile also has the effect of racemizing the enantiomer of the compound due to its solvent effect.
  • the above-mentioned optical resolution is carried out under conditions where the enantiomer of the compound represented by the above general formula (I) is racemized.
  • the conditions are not particularly limited as long as the enantiomer of the compound is racemized, and include, for example, room temperature to heating conditions, and preferably heating conditions.
  • As the reaction temperature under heating conditions include, for example, room temperature to heating conditions, and preferably heating conditions.
  • reaction time is not particularly limited, but may be, for example, 1 to 100 hours, preferably 40 to 50 hours.
  • the optical resolution is preferably carried out in the presence of a reaction accelerator.
  • the reaction time can be shortened by coexisting the reaction accelerator.
  • the reaction accelerator include organic bases (eg, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] —7-indene, N-methylmorpholine, etc.), inorganic bases (eg, sodium hydroxide) , Hydroxide hydroxide, sodium hydrogen carbonate, potassium carbonate, etc.).
  • organic bases particularly preferred.
  • Preferable is triethylamine.
  • the amount of addition is 0.1 to 1.0 equivalent, preferably 0.2 to 0.5 equivalent, per the above-mentioned (soil) 1,4-benzothiazine_2-acetic acid derivative.
  • the salt of the (1) —1,4-benzothiazine-12-acetic acid derivative represented by the above general formula (I) and the optically active substance obtained by the above optical resolution can be obtained by a conventional separation method, for example, filtration, centrifugation It can be separated from the reaction solution by distillation (eg, distillation under reduced pressure, distillation under normal pressure, etc.), decantation and the like.
  • the optical resolution can be performed while evaporating acetonitrile (for example, distillation under reduced pressure, atmospheric pressure, etc.) while concentrating.
  • This concentration is preferably carried out intermittently, whereby the optical resolution efficiency is increased, and the (1) 1, 4-benzothiazine 1-2-represented by the above general formula (I) obtained after the completion of the reaction is obtained. Separation of the salt between the acetic acid derivative and the optically active substance can be facilitated.
  • the yield of the salt of the ( ⁇ ) — 1,4-benzothiazine-2-acetic acid derivative represented by the above general formula (I) and the optically active substance obtained by the above optical resolution is 50% or more (preferably Is 80% or more).
  • the yield referred to here was obtained based on the total amount of the starting materials used ((P) _1,4-benzothiazine-12-acetic acid derivative represented by the general formula (I)) and the optically active material used. It is the ratio (%) of the amount of salt formed between the (1) enantiomer of the compound and the optically active substance (the amount of formation is the difference between the (+)-enantiomer of the compound and the optically active substance). Includes salt production).
  • the optical purity of (1) -enantiomer in this salt is 70% or more (preferably 80% or more).
  • the optical purity here is a value measured by the method described later (the optical purity in the following description of the present specification is also a value measured by the method described later). Such high yield and high optical purity cannot be obtained by ordinary optical resolution.
  • Another method for producing (-)-1,4-benzothiazine-12-acetic acid derivative according to the present invention is a method for producing a (Sat) -1,4-benzothiazine-12-acetic acid derivative represented by the general formula (I) by photoirradiation. Reaction with a biologically active substance in a solvent under heating conditions to obtain the (1) -enantiomer of the derivative And optically resolving the optically active substance by forming a salt thereof.
  • optically active substance examples include those defined above, but are preferably
  • the solvent used in the optical resolution in the above-mentioned production method is appropriately selected depending on the optically active substance used. Examples thereof include ethyl acetate, water, methanol, ethanol, isopropyl alcohol, acetone, dimethylformamide and these. Mixed solvents, etc., preferably ethyl acetate, methanol, ethyl acetate containing 0.1 to 5% (v / v) (preferably 0.2 to 2% (v / v)) water
  • the optical resolution is performed under heating conditions.
  • the reaction temperature is from room temperature to 100 ° C, preferably 70 to 100 ° C, particularly preferably the temperature at which the solvent used is refluxed.
  • reaction time is not particularly limited, but may be, for example, 0.1 to 5 hours, and preferably 0.5 to 2 hours.
  • the salt of the (-) — 1,4-benzothiazine-2-acetic acid derivative represented by the above general formula (I) and the optically active substance obtained by the above optical resolution can be obtained by the usual separation method as described above. It can be separated from the reaction solution. In addition, the optical resolution can be performed while concentrating as described above.
  • the salt of (1) an 1,1,4-benzothiazine-2-acetic acid derivative represented by the general formula (I) obtained by the optical resolution in the production method of the present invention and a specific optically active amine is a novel salt.
  • the salt with propanediol is It is a salt not known until.
  • the salt of the (1) —1,4-benzothiazine-12-acetic acid derivative represented by (I) and the optically active substance can be further purified by a conventional purification method such as recrystallization, chromatography, decantation and the like. It can be purified.
  • the production method of the present invention preferably comprises the above-mentioned general formula generated by the optical resolution.
  • the method includes heat-treating a salt of an (-)-1,4-benzothiazine-12-acetic acid derivative represented by (I) with an optically active substance in a solvent.
  • a solvent used here can be appropriately selected depending on the (1) 1,4-benzothiazine-12-acetic acid derivative used and the optically active substance. Examples of the solvent include ethyl acetate, water, methanol, ethanol, and the like.
  • Examples include isopropyl alcohol, acetone, dimethylformamide and a mixture thereof, preferably ethyl acetate, 0.1 to 5% (v / v) (preferably 0.2 to 2% (v / v) ) Aqueous ethyl acetate or a mixed solvent of ethyl acetate and methanol [10: 1 to 1: 1 (preferably 5: 1 to 2: 1) (volume ratio)].
  • the treatment temperature in the heat treatment is from room temperature to 100 ° C., preferably 70 to 100 ° C., and particularly preferably the temperature at which the solvent is refluxed (in this case, the treatment is performed in a reflux state).
  • the processing time is not particularly limited, but is, for example, 0.5 to 10 hours, and preferably 1 to 5 hours.
  • this treatment can be applied to the residue obtained after concentrating to dryness by distilling off the used solvent after completion of the optical resolution.
  • an acid is used according to a usual method.
  • (-) It can be obtained by liberating a 1,4-benzothiazine-12-acetic acid derivative.
  • the free form of the (—) — 1,4-benzothiazine-2-acetic acid derivative represented by the general formula (I) is a derivative of the (—) — 1,4-benzothiazine-12-acetic acid derivative and an optical derivative. It is obtained by treating a salt with an active substance in a mixed solvent of an organic solvent and water under acidic conditions.
  • Examples of the acid used here include mineral acids such as hydrochloric acid, sulfuric acid and nitric acid, and organic acids such as citric acid and maleic acid, and preferably hydrochloric acid.
  • the concentration of the acid in the mixed solvent is not particularly limited as long as the mixed solvent becomes acidic.
  • Examples of the organic solvent in the mixed solvent of the organic solvent and water include toluene, acetone, and methanol, and preferably toluene.
  • the mixing ratio of the organic solvent to water is 1: 1 to 1: 2 (preferably 1: 1) (volume ratio).
  • the processing conditions are not particularly limited.
  • the processing temperature may be room temperature to 50 ° C. (preferably room temperature)
  • the processing time may be 0.1 to 2 hours (preferably 0.5. ⁇ 1 hour).
  • the organic solvent layer in which the free form of (-) 1-1,4-benzothiazine_2-acetic acid derivative is present is separated, the solvent is dried and evaporated, and the residue is evaporated with a solvent (eg, ethyl acetate, Hexane) or by filtering, washing, and drying the crystals precipitated from the mixed solvent to obtain the free (-)-1,4-benzothiazine-12-acetic acid derivative Can be.
  • a solvent eg, ethyl acetate, Hexane
  • the thus obtained free form of the free form represented by the above general formula (I) (-) 1-1: 4-benzothiazine-12-acetic acid derivative can be purified by ordinary purification such as recrystallization, chromatography, decantation and the like.
  • the method can be used for further purification.
  • the recrystallization is preferably carried out by using a solvent such as ethyl acetate, hexane, heptane, ethanol, water, acetic acid, isopropyl alcohol or a mixed solvent thereof, particularly preferably a mixed solvent of ethyl acetate and hexane (for example, : 1 to 1:20, preferably 1: 2 to 1:10 (volume ratio)).
  • optical purity of —benzothiazine—2-acetic acid derivatives is preferably higher than 98.5%, especially It is preferably higher than 99.0%, and more preferably 99.8% or more.
  • the upper limit is not particularly limited, but is substantially (+) — optical purity substantially free of enantiomer (for example, 99.99%, which is the measurement limit of the method for measuring optical purity in the present specification). be able to.
  • Such high optical purity (-)-1,4-benzothiazine-12-acetic acid derivatives have not been known so far. Therefore, it is preferable that the (+) — 1,4, -benzothiazine-2-acetic acid derivative is present in the (—) — 1,4-benzothiazine-2-acetic acid derivative represented by the general formula (I) even in a trace amount.
  • the optical purity obtained by the production method of the present invention is higher than 98.5% in the use of (1,1) -1,4-benzothiazine-12-acetic acid derivative.
  • the acetic acid derivative is much more useful than the one with an optical purity of 98.5% obtained so far.
  • the (—) — 1,4-benzothiazine-12-acetic acid derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof obtained by the production method of the present invention includes, for example, cataract, neurosis, It can be used as an active ingredient of preventive and therapeutic agents for diabetic complications such as nephropathy and retinopathy.
  • optical purity was determined by separating the two enantiomers by high performance liquid chromatography (HPLC) using an optically active column under the following conditions and determining the area percentage.
  • Example 5 (Earth) —Compound A (2.12 g; 5.0 mmol) dissolved in acetonitrile (50 mL) by heating, and then (-) 1 brucine 2H 2 ⁇ (2.15 g; 5.0 mmol) 1) Add triethylamine (0.14 mL; 1. Ommo 1), reflux for 18 hours, stir at room temperature for 1 hour and under ice-cooling for 1 hour, filter the crystals, and (1) one compound A (-) — Brucin salt (3.70 g; optical purity 86.9% de, yield 90%) was obtained.
  • Residual solvent 0.096% of ethyl acetate, 0.011% of hexane (measured by gas chromatography)
  • the (I) -one enantiomer of the (P)-(1,4) -benzothiazin-2-acetic acid derivative represented by the above general formula (I) in high yield and high optical purity is obtained.
  • a method of obtaining the body can be provided.
  • a (1) _1,4-benzothiazine-2-acetic acid derivative represented by the general formula (I) having an optical purity higher than 98.5%, which has not been obtained so far, and a drug therefor A physically acceptable salt can be provided.
  • This application is based on a patent application No. 167447 filed in Japan, filed in Japan, the contents of which are incorporated in full herein.

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  • Health & Medical Sciences (AREA)
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  • Organic Chemistry (AREA)
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  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

Abstract

Ce procédé de préparation de dérivés de l'acide (-)-1,4-benzothiazine-2-acétique est caractérisé en ce qu'on exécute une résolution optique d'une modification racémique d'un dérivé de l'acide 1,4-benzothiazine-2-acétique, représenté par la formule générale (I), en formant un sel du (-)-énantiomère du dérivé à l'aide d'une substance active sur le plan optique. Dans cette formule, R1 et R2 représentent chacun hydrogène ou analogue, R3 représente carboxyle ou analogue, R?4, R5, R6 et R7¿ représentent chacun hydrogène, halogéno ou analogue, et X représente oxygène ou analogue. Grâce à ce procédé, on peut séparer des dérivés de l'acide (-)-1,4-benzothiazine-2-acétique, respectivement à partir des dérivés correspondants de l'acide (±)-1,4-benzothiazine-2-acétique, en obtenant un rendement et une pureté optique élevés.
PCT/JP2000/003741 1999-06-14 2000-06-08 Procede de preparation de derives de l'acide (-)-1,4-benzothiazine-2-acetique Ceased WO2000076995A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU52464/00A AU5246400A (en) 1999-06-14 2000-06-08 Process for the preparation of (-)-1,4-benzothiazine-2-acetic acid derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP16744799 1999-06-14
JP11/167447 1999-06-14

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WO2000076995A1 true WO2000076995A1 (fr) 2000-12-21

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0492667A1 (fr) * 1990-12-27 1992-07-01 The Green Cross Corporation Dérivés de l'acide 1,4-benzothiazine-2-acétique, procédés pour leur préparation et leur utilisation
JPH06100490A (ja) * 1992-09-17 1994-04-12 Fuji Yakuhin Kogyo Kk 光学活性α−メチルコハク酸の製造方法
EP0602814A1 (fr) * 1992-12-18 1994-06-22 Takeda Chemical Industries, Ltd. Formes de cristaux d'isoindolines optiquement actifs et leur utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0492667A1 (fr) * 1990-12-27 1992-07-01 The Green Cross Corporation Dérivés de l'acide 1,4-benzothiazine-2-acétique, procédés pour leur préparation et leur utilisation
JPH06100490A (ja) * 1992-09-17 1994-04-12 Fuji Yakuhin Kogyo Kk 光学活性α−メチルコハク酸の製造方法
EP0602814A1 (fr) * 1992-12-18 1994-06-22 Takeda Chemical Industries, Ltd. Formes de cristaux d'isoindolines optiquement actifs et leur utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
AOTSUKA TOMOJI ET AL.: "Novel and potent aldose reductase inhibitors:4-benzyl- and 4-(benzothiazol-2-ylmethyl)-3,4-dihydro-3-oxo-2H-1,4-benzothiazine-2-acetic acid derivatives", CHEM. PHARM. BULL., vol. 42, no. 6, 1994, pages 1264 - 1271, XP002930701 *

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