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WO2007100027A1 - Optically active thiazolidinedione derivative - Google Patents

Optically active thiazolidinedione derivative Download PDF

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Publication number
WO2007100027A1
WO2007100027A1 PCT/JP2007/053869 JP2007053869W WO2007100027A1 WO 2007100027 A1 WO2007100027 A1 WO 2007100027A1 JP 2007053869 W JP2007053869 W JP 2007053869W WO 2007100027 A1 WO2007100027 A1 WO 2007100027A1
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WO
WIPO (PCT)
Prior art keywords
methoxy
benzyl
thiazolidine
methyl
dione
Prior art date
Application number
PCT/JP2007/053869
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French (fr)
Japanese (ja)
Inventor
Jun Ohsumi
Kunio Wada
Yumi Matsui
Tsuneaki Ogata
Original Assignee
Daiichi Sankyo Company, Limited
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Application filed by Daiichi Sankyo Company, Limited filed Critical Daiichi Sankyo Company, Limited
Publication of WO2007100027A1 publication Critical patent/WO2007100027A1/en

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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
    • C07D417/12—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 chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to an optically active thiazolidinedione derivative having excellent binding affinity with PPAR or a pharmacologically acceptable salt thereof, and diabetes, hyperglycemia, glucose intolerance, hypertension containing them
  • the present invention relates to a therapeutic or prophylactic agent for glucose metabolism diseases such as hyperlipidemia, diabetic complications, gestational diabetes, and polycystic ovary syndrome.
  • [0002] is a thiazolidinedione derivative (RS)-5- ⁇ 4- [(6 methoxy-1- 1-methyl-1- 1H-benzoimidazole-2-yl) methoxy] benzyl ⁇ -1, 3, thiazolidine 2, 4- Dione and its pharmacologically acceptable salts have excellent PPAR (peroxisome proliferator activated receptor) ⁇ activation action, insulin resistance improvement action, etc., diabetes, hyperglycemia, glucose intolerance, hypertension It is known as a compound that is useful for the prevention and treatment of glucose metabolism diseases such as infectious diseases, hyperlipidemia, diabetic complications, gestational diabetes, and polycystic ovary syndrome (for example, see Patent Document 1).
  • PPAR peroxisome proliferator activated receptor
  • Patent Document 1 Patent No. 2976885 (U.S. Pat. No. 5,886,014)
  • the active ingredient contained in the medicament of the present invention is: (5S) _5_ ⁇ 4 _ [(6-methoxy-1_methyl-1H-benzimidazole 1_yl) methoxy] benzyl ⁇ _1, 3_thiazolid 2,4-dione or a pharmacologically acceptable salt thereof (preferably, (5S) -5- ⁇ 4-[(6-methoxy-1- 1-methyl-1- 1H-benzimidazol-2-yl) methoxy ] Benzyl ⁇ _ 1, 3 —thiazolidine mono 2,4 dione monohydrochloride).
  • Such salts include mineral salts such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate or phosphate; methanesulfonate, Sulfonates such as trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate or p-toluenesulfonate; fumarate, succinate, succinate, tartrate, oxalate Or a carboxylate such as maleate; or an amino acid salt such as glutamate or aspartate, Preferred is hydrochloride.
  • the said formulation may contain a pharmaceutically acceptable additive suitably.
  • additives include, for example, excipients (eg sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbitol; corn starch, potato starch, pregelatinized starch, dextrin, carboxymethyl starch, carboxymethyl Starch derivatives such as starch sodium; pregelatinized starch; crystalline cellulose, methylcellulose, hydroxypropylcellulose, low substituted hydroxypropylcellulose, hydroxypropylmethylosenorellose, canolemellose, canolemellose canolecium, croscanolemellose, Cellulose derivatives such as cross-strength noromerose sodium; gum arabic; dextran; pullulan; Silicate derivatives such as magnesium aluminate; phosphate derivatives such as dicalcium phosphate; chloride derivatives such as sodium chloride
  • surfactants e.g., polysorbate, such as polysorbate 80; polyoxyethylene hydrogenated castor oils such as polyoxyethylene hydrogenated castor oil 60 Sorbitan fatty acid esters; sucrose fatty acid esters; polyoxyethylene polyoxypropylene glycols; polyoxyethylene fatty acid ethers; polyoxyl stearates; or mixtures thereof, preferably polysorbate 80, polyoxyethylene cured Castor oil 60 or a mixture thereof
  • coloring agent for example, yellow iron sesquioxide, iron trioxide, black iron oxide
  • flavoring agent for example, commonly used sweetener, acidulant
  • the type and amount of additives used will vary depending on the tablet, capsanolate or other dosage form drug, but are selected by well-known techniques in the field of formulation.
  • the content of the binder in the whole pharmaceutical composition is usually 1 to 10 parts by weight (preferably 2 to 5 parts by weight), and the content of the disintegrant is Usually, it is 1 to 40 parts by weight (preferably 5 to 30 parts by weight), and the content of the lubricant is usually 0.1 to 10 parts by weight (preferably 0.5 to 3 parts by weight).
  • the content of the fluidizing agent is 0.1 to 10 parts by weight (preferably 0.5 to 5 parts by weight).
  • the pharmaceutical composition of the present invention can be administered to warm-blooded animals (especially humans) and is an active ingredient (5S) -5- ⁇ 4- [(6 methoxy-1-1-methyl-1H-benzo Imidazole-2-yl) methoxy] benzyl ⁇ 1,3 thiazolidine 2,4 dione or its pharmacologically acceptable salt dosage may vary depending on various conditions such as patient symptoms, age, weight, etc.
  • 5S active ingredient
  • -5- ⁇ 4- [(6 methoxy-1-1-methyl-1H-benzo Imidazole-2-yl) methoxy] benzyl ⁇ 1,3 thiazolidine 2,4 dione or its pharmacologically acceptable salt dosage may vary depending on various conditions such as patient symptoms, age, weight, etc.
  • 0.1 mg / body to 20 mg / body (preferably 0.5 mg / body to 3 mg / body) per dose may be administered to humans 1 to 6 times daily depending on symptoms. it can.
  • Rosiglitazone maleate (hereinafter referred to as Compound A) is a compound described in US Pat. No. 5,741,803 and can be produced according to the method described in the publication.
  • N- (2-amino-5-methoxyphenyl) -N-methylol tert-butyl (54.72 kg) , 216.9 mol) and triethylamine (26.35 kg, 260.4 mol) in dichloromethane (562 L) were added dropwise over 1 hour and stirred at 0-5 ° C for 15 minutes.
  • the activated carbon was washed with dichloromethane (92 L), and the filtrate and the washing solution were combined and concentrated under reduced pressure at an internal temperature of 20 to 30 ° C. to about 300 L.
  • Methanol (305 L) was poured into this, and the mixture was concentrated to about 300 L under reduced pressure at an internal temperature of 20-30 ° C. Further, methanol (305 L) was poured here, and the mixture was concentrated to about 300 L under reduced pressure at an internal temperature of 20 to 30 ° C.
  • Methanol (201 L) was poured into this, and the mixture was stirred at 5 ° C for 1 hour.
  • LBD Ligand binding domain
  • His histidine
  • PCR polymerase chain reaction
  • restriction sequences Sa 11 and BamH I were added to both ends of the sequence encoding human PPAR y -LBD (amino acids 208-477), and His-tagged protein expression vector pQE30 (QIAGEN)
  • an oligonucleotide having the following nucleotide sequence was synthesized.
  • a human cDNA library (Clontech, catalog number: K-1420-1) is used as a cage, and the above ⁇ 1 and ⁇ 2 are Incubate for 2 minutes at 99 ° C as a primer, then 30 cycles at 99 ° C for 30 seconds, then 55 ° C for 30 seconds, then 72 ° C for 1 minute 30 times PCR was performed by repeating.
  • the amplified polynucleotide fragment was subcloned into pUC118 vector (TAKARA), and the nucleotide sequence of the insert was determined by a conventional method.
  • the obtained recombinant vector was treated with restriction enzymes Sal I and BamH I, and then the inserted portion was recovered and subcloned into pQE30 to construct a recombinant expression vector.
  • amino acid sequence at the amino terminal is the same as that reported in the X-ray crystal structure analysis (RT Nolte et al, Nature, 1998, No. 395, No. 10, ⁇ ⁇ 137_143).
  • RT Nolte et al Nature, 1998, No. 395, No. 10, ⁇ ⁇ 137_143.
  • an oligonucleotide having the following nucleotide sequence was synthesized.
  • the recombinant expression vector obtained above was made into a saddle type, and the above ⁇ 3 was used as a primer, followed by incubation at 95 ° C for 30 seconds, at 95 ° C for 30 seconds, and then at 55 ° C. PCR was performed by repeating a heat retention cycle consisting of C for 1 minute and then at 68 ° C for 6 minutes 12 times.
  • the nucleotide sequence (SEQ ID NO: 4) of the inserted portion was determined by a conventional method.
  • the recombinant expression vector PQE30-PP AR y -LBD was obtained by the above operation.
  • E. coli strain SG13009 (QIAGEN) was transformed.
  • L-broth medium containing 20 g of LB BR OTH BASE (Invitrogen) dissolved in 1 L of water containing 5 ⁇ g of this transformed strain containing ampicillin at a concentration of 100 / ig / mL and kanamycin at a concentration of 25 ⁇ g / mL Inoculated and cultured with shaking at 37 ° C for 4 hours.
  • the precipitate fraction was collected by centrifugation at 4000 X g for 30 minutes, suspended in a 25 mL suspension buffer (composition shown below), and the suspension was sonicated. .
  • the supernatant was collected by centrifugation at 14000 ⁇ g for 30 minutes, and added to a HiTrap Chelating HP column (Amersham Bioscience) supplemented with nickel sulfate.
  • the elution fraction containing His-PPAR y -LBD was collected by the gradient elution method using Nickel column A buffer (composition shown below) and Nickenole column B buffer (composition shown below), and the dialysis buffer was collected. Dialysis was carried out according to the composition shown below.
  • the dialyzed HiTrap Chelating HP column elution fraction is then applied to a HiTrap SP HP column (Amersham Bioscience), and ion-exchange column A buffer (composition is shown below) and ion-exchange column B buffer (combination).
  • the elution fraction containing His-PPAR-LBD was collected by the gradient elution method described below.
  • the HiTrap SP HP column elution fraction was added to HiLoad Superdex75 (Amersham Bioscience) equilibrated with gel filtration buffer (composition is shown below), and eluted with gel filtration buffer.
  • PPAR o / _LBD was recovered.
  • the resulting fusion protein had a molecular weight of about 32000 under reducing conditions.
  • the His-PPAR y -LBD protein purified in Test Example (1 _ 1) was bound to Binding Buffer (50 mM Tris-HCl, pH 8.0, 50 mM KCl, 2 mM EDTA, 5 mM CHAPS, 0.1 mg / mL) BSA, 5 mM DTT) was diluted to 75 nM and stored on ice until use.
  • Binding Buffer 50 mM Tris-HCl, pH 8.0, 50 mM KCl, 2 mM EDTA, 5 mM CHAPS, 0.1 mg / mL
  • BSA 5 mM DTT
  • Binding inhibition rate (%) 100 X [1- (C-BG) / (C-BG))] C: Radioactivity of each reaction
  • Binding inhibition rate (%) [ ⁇ (dose) 11 ] I [(IC
  • n sigmoidicity factor
  • the S form has an affinity about 20 times stronger than the racemate and about 50 times stronger affinity than the R form.
  • optically active thiazolidinedione derivative of the present invention or a pharmacologically acceptable salt thereof has an excellent PPAR y binding ability, diabetes, hyperglycemia, glucose intolerance, hypertension, hyperlipidemia, It is useful as a therapeutic or prophylactic agent for glucose metabolic diseases such as diabetic complications, gestational diabetes mellitus, and polycystic ovary syndrome.
  • SEQ ID NO: 1 Sense plasmid for amplifying a polynucleotide encoding human PPAR y Imama.
  • SEQ ID NO: 2 Antisense for amplifying a polynucleotide encoding human PPAR ⁇
  • SEQ ID NO: 3 Amino terminal amino acid configuration 1J is the same as that reported for X-ray crystal structure analysis
  • SEQ ID NO: 4 Polynucleotide inserted into pQE30_PPAR y -LBD.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

Disclosed are an optically active thiazolidinedione derivative, a pharmacologically acceptable salt thereof, and a pharmaceutical product containing any of them. The optically active thiazolidinedione derivative can be obtained by optical resolution of (RS)-5-{4-[(6-methoxy- 1-methyl-1H-benzoimidazol-2-yl)methoxy]benzyl}-1,3- thiazolidine-2,4-dione.

Description

明 細 書  Specification
光学活性なチアゾリジンジオン誘導体  Optically active thiazolidinedione derivative
技術分野  Technical field
[0001] 本発明は、優れた PPAR との結合親和性を有する光学活性なチアゾリジンジオン 誘導体又はその薬理上許容し得る塩、及び、それらを含有する糖尿病、高血糖症、 耐糖能不全、高血圧症、高脂血症、糖尿病合併症、妊娠糖尿病、多嚢胞卵巣症候 群等の糖代謝系疾患の治療薬又は予防薬に関する。  [0001] The present invention relates to an optically active thiazolidinedione derivative having excellent binding affinity with PPAR or a pharmacologically acceptable salt thereof, and diabetes, hyperglycemia, glucose intolerance, hypertension containing them The present invention relates to a therapeutic or prophylactic agent for glucose metabolism diseases such as hyperlipidemia, diabetic complications, gestational diabetes, and polycystic ovary syndrome.
背景技術  Background art
[0002] チアゾリジンジオン誘導体である（RS) - 5-{4- [ (6 メトキシ一 1—メチル一 1H 一べンゾイミダゾールー 2 ィル）メトキシ]ベンジル }ー1 , 3 チアゾリジン 2, 4— ジオン及びその薬理上許容される塩は、優れた PPAR (ペルォキシソーム増殖因子活 性化受容体） γ活性化作用、インスリン抵抗性改善作用等を有し、糖尿病、高血糖 症、耐糖能不全、高血圧症、高脂血症、糖尿病合併症、妊娠糖尿病、多嚢胞卵巣 症候群などの糖代謝系疾患の予防および治療に有用な化合物として知られている（ 例えば、特許文献 1を参照）。  [0002] is a thiazolidinedione derivative (RS)-5- {4- [(6 methoxy-1- 1-methyl-1- 1H-benzoimidazole-2-yl) methoxy] benzyl} -1, 3, thiazolidine 2, 4- Dione and its pharmacologically acceptable salts have excellent PPAR (peroxisome proliferator activated receptor) γ activation action, insulin resistance improvement action, etc., diabetes, hyperglycemia, glucose intolerance, hypertension It is known as a compound that is useful for the prevention and treatment of glucose metabolism diseases such as infectious diseases, hyperlipidemia, diabetic complications, gestational diabetes, and polycystic ovary syndrome (for example, see Patent Document 1).
特許文献 1 :特許第 2976885号 (米国特許第 5886014号明細書）  Patent Document 1: Patent No. 2976885 (U.S. Pat. No. 5,886,014)
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0003] 本発明者等は、優れた糖尿病の治療又は予防薬の開発を目指し、種々のチアゾリ ジンジオン誘導体の PPAR γ活性化作用について、長年に亘り鋭意研究を行った結 果、ラセミ体である（RS) _ 5 _{4_ [ (6—メトキシ一 1 _メチル一1H—ベンゾイミダゾ ール一 2 _ィル）メトキシ]ベンジル }_ 1， 3_チアゾリジン一2, 4—ジオンの、一方の 光学異性体である（5S) - 5-{4- [ (6—メトキシ一 1—メチル一 1H_ベンゾイミダゾ ール一 2 _ィル）メトキシ]ベンジル }_ 1， 3_チアゾリジン一2, 4—ジオン及びその薬 理上許容される塩が、特に優れた PPAR τ /との結合親和性を示すことを見出し、本発 明を完成するに至った。 [0003] The present inventors have conducted extensive research on the PPARγ activation activity of various thiazolidindione derivatives with the aim of developing an excellent therapeutic or preventive agent for diabetes. (RS) _ 5 _ {4_ [(6-Methoxy-1 1-methyl-1H-benzoimidazole 2- yl) methoxy] benzyl} _ 1,3_thiazolidine-1,2,4-dione The optical isomer (5S)-5- {4- [(6-Methoxy-1- 1-methyl-1- 1H_benzoimidazole 2- yl) methoxy] benzyl} _ 1, 3_thiazolidine 1, 2, 4 —The inventors have found that dione and its pharmaceutically acceptable salts exhibit particularly excellent binding affinity with PPAR τ / and have completed the present invention.
課題を解決するための手段 [0004] 本発明の（53)—5—{4 [(6—メトキシー1ーメチルー1^^ーべンゾィミダゾールー 2 ィル）メトキシ]ベンジル }ー1, 3 チアゾリジン—2, 4 ジオン又はその薬理上許 容される塩は、以下の構造式 Means for solving the problem [0004] (53) -5- {4 [(6-Methoxy-1-methyl-1 ^^-benzomidazol-2-yl) methoxy] benzyl} -1,3 thiazolidine-2,4 dione of the present invention Or a pharmacologically acceptable salt thereof has the following structural formula:
[0005] [化 1]
Figure imgf000003_0001
[0005] [Chemical 1]
Figure imgf000003_0001
[0006] を有する（RS ) _ 5 _ {4 _ [ ( 6—メトキシ一 1 _メチル _ 1 H—ベンゾイミダゾール - 2 —ィル)メトキシ]ベンジル }_1， 3_チアゾリジン—2, 4—ジオンの 5位に光学活性部 位を有する化合物又はその薬理上許容される塩である。  [0006] (RS) _5_ {4 _ [(6-Methoxy-1- 1-methyl_1H-benzimidazol-2-yl) methoxy] benzyl} _1,3_thiazolidine-2,4-dione Or a pharmacologically acceptable salt thereof.
[0007] また、本発明の医薬が含有する有効成分は、 （5S)_5_{4_[(6—メトキシ— 1_ メチル一1H—ベンゾイミダゾール一 2_ィル）メトキシ]ベンジル }_1， 3_チアゾリジ ン— 2, 4—ジオン又はその薬理上許容される塩 (好適には、 (5S)-5-{4-[(6- メトキシ一 1—メチル一 1H—ベンゾイミダゾール一 2 _ィル）メトキシ]ベンジル }_ 1 , 3 —チアゾリジン一 2, 4 ジオン 1塩酸塩）である。  [0007] The active ingredient contained in the medicament of the present invention is: (5S) _5_ {4 _ [(6-methoxy-1_methyl-1H-benzimidazole 1_yl) methoxy] benzyl} _1, 3_thiazolid 2,4-dione or a pharmacologically acceptable salt thereof (preferably, (5S) -5- {4-[(6-methoxy-1- 1-methyl-1- 1H-benzimidazol-2-yl) methoxy ] Benzyl} _ 1, 3 —thiazolidine mono 2,4 dione monohydrochloride).
[0008] (5S) 5—{4 [(6—メトキシ 1ーメチルー 1H—べンゾイミダゾールー 2 ィル） メトキシ]ベンジル }ー1, 3 チアゾリジン 2, 4 ジオンは、所望に応じて、常法に 従って塩にすることができる。例えば、そのような塩は、溶媒中（例えば、エーテル類 、エステル類又はアルコール類であり得、好適にはアルコール類）、 (5S) -5-{4- [(6—メトキシ 1ーメチルー 1H—べンゾイミダゾールー 2—ィル）メトキシ]ベンジル } 1, 3—チアゾリジン 2, 4—ジオンを相当する酸と室温乃至使用溶媒の還流する 温度下で 5分間乃至 5時間処理し、析出した結晶を濾取するか又は減圧下で溶媒を 留去することにより得ること力 Sできる。そのような塩としては弗化水素酸塩、塩酸塩、臭 化水素酸塩、沃化水素酸塩、硝酸塩、過塩素酸塩、硫酸塩又は燐酸塩等の鉱酸塩 ；メタンスルホン酸塩、トリフルォロメタンスルホン酸塩、エタンスルホン酸塩、ベンゼン スルホン酸塩又は p-トルエンスルホン酸塩のようなスルホン酸塩；フマ -ル酸塩、コハ ク酸塩、クェン酸塩、酒石酸塩、蓚酸塩又はマレイン酸塩のようなカルボン酸塩；又 は、グルタミン酸塩若しくはァスパラギン酸塩のようなアミノ酸塩を挙げることができ、 好適には、塩酸塩である。 [0008] (5S) 5- {4 [(6-Methoxy-1-methyl-1H-benzoimidazole-2-yl) methoxy] benzyl} -1,3 thiazolidine 2,4 dione can be prepared by conventional methods as desired. Therefore, it can be made into a salt. For example, such a salt can be obtained in a solvent (for example, ethers, esters or alcohols, preferably alcohols). Benzoimidazole-2-yl) methoxy] benzyl} 1,3-thiazolidine 2,4-dione was treated for 5 minutes to 5 hours at the reflux temperature of the corresponding acid and the solvent used. Can be obtained by filtering off or removing the solvent under reduced pressure. Such salts include mineral salts such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate or phosphate; methanesulfonate, Sulfonates such as trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate or p-toluenesulfonate; fumarate, succinate, succinate, tartrate, oxalate Or a carboxylate such as maleate; or an amino acid salt such as glutamate or aspartate, Preferred is hydrochloride.
[0009] 本発明の（5S)— 5—{4 [ (6—メトキシー 1ーメチルー 1H—べンゾイミダゾールー 2 ィル）メトキシ]ベンジル }ー1 , 3 チアゾリジン—2, 4 ジオン又はその薬理上許 容される塩は、各々水和物として存在することができる力 その各々或はそれらの混 合物のいずれも本発明に包含される。  [0009] (5S) -5- {4 [(6-Methoxy-1-methyl-1H-benzoimidazole-2-yl) methoxy] benzyl} -1,3 thiazolidine-2,4 dione of the present invention or pharmacologically Each of the permissible salts can be present as a hydrate, each of which is included in the present invention, or any mixture thereof.
[0010]  [0010]
発明の効果  The invention's effect
[0011] 本発明の（53)—5—{4 [ (6—メトキシー1ーメチルー：^ーべンゾィミダゾールー 2 ィル）メトキシ]ベンジル }ー1 , 3 チアゾリジン—2, 4 ジオン又はその薬理上許 容される塩は、優れた PPAR yとの親和性を示すため、糖尿病、高血糖症、耐糖能不 全、高血圧症、高脂血症、糖尿病合併症、妊娠糖尿病、多嚢胞卵巣症候群等の糖 代謝系疾患の治療薬又は予防薬として有用である。  [0011] (53) -5- {4 [(6-Methoxy-1-methyl-: ^-benzimidazole-2-yl) methoxy] benzyl} -1,3 thiazolidine-2,4 dione or Because its pharmacologically acceptable salt shows excellent affinity for PPAR y, diabetes, hyperglycemia, impaired glucose tolerance, hypertension, hyperlipidemia, diabetic complications, gestational diabetes, polycyst It is useful as a therapeutic or prophylactic agent for glucose metabolic diseases such as ovarian syndrome.
[0012]  [0012]
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0013] 本発明の（5S) _ 5_{4_ [ (6 メトキシ一 1—メチル一 1H—ベンゾイミダゾール一 2_ィル）メトキシ]ベンジル 3_チアゾリジン—2, 4—ジオン又はその薬理上許 容される塩は、特許第 2976885号、 EP第 0745600号、米国特許第 5,886,014号、国際 公開第 00/71540号パンフレット及び国際出願 PCT/JP2006/301058に記載の方法に 従い製造される（RS)— 5— {4— [ (6—メトキシ一 1—メチル 1H—ベンゾイミダゾー ルー 2 ィル）メトキシ]ベンジル }ー1, 3 チアゾリジン 2, 4 ジオン又はその薬理 上許容される塩を、光学分割することにより製造することができる。  [0013] The (5S) _5_ {4 _ [(6 methoxy-1- 1-methyl-1H-benzimidazol-1-yl) methoxy] benzyl 3_thiazolidine-2,4-dione of the present invention or a pharmacologically acceptable one thereof. The salt produced is produced according to the methods described in Patent No. 2976885, EP 0745600, US Pat. No. 5,886,014, pamphlet of International Publication No. 00/71540 and International Application PCT / JP2006 / 301058 (RS) — 5— {4— [(6-Methoxy-1-methyl 1H-benzimidazole 2-yl) methoxy] benzyl} -1, 3 thiazolidine 2, 4 dione or its pharmacologically acceptable salt by optical resolution Can be manufactured.
[0014] 本発明の（5S)— 5—{4一 [ (6—メトキシー 1ーメチルー 1H—べンゾイミダゾールー 2 ィル）メトキシ]ベンジル }ー1 , 3 チアゾリジン—2, 4 ジオン又はその薬理上許 容される塩を、上記疾患の予防薬又は治療薬として使用する場合には、それ自体或 いは適宜の薬理学的に許容される、賦形剤、滑沢剤、結合剤、崩壊剤、乳化剤、安 定剤、矯味矯臭剤、希釈剤等の添加剤を用いて周知の方法に従い製造される、錠 剤、カプセル剤、顆粒剤、散剤若しくはシロップ剤等による経口的又は注射剤若しく は坐剤等による非経口的に投与することができる。 上記製剤は、適宜、製薬学的に許容される添加物を含有してもよい。そのような添 加物は、例えば、賦形剤（例えば、乳糖、白糖、ブドウ糖、マンニトール、ソルビトール のような糖誘導体；トウモロコシデンプン、馬鈴薯デンプン、 α化デンプン、デキストリ ン、カルボキシメチルデンプン、カルボキシメチルデンプンナトリウムのようなデンプン 誘導体；予めゼラチン化したデンプン；結晶セルロース、メチルセルロース、ヒドロキシ プロピルセルロース、低置換度ヒドロキシプロピルセルロース、ヒドロキシプロピルメチ ノレセノレロース、カノレメロース、カノレメロースカノレシゥム、クロスカノレメロース、クロス力ノレ メロースナトリウムのようなセルロース誘導体；アラビアゴム；デキストラン；プルラン；軽 質無水ケィ酸、ケィ酸カルシウム、珪酸水和物、合成ケィ酸アルミニウム、メタケイ酸 アルミン酸マグネシウムのようなケィ酸塩誘導体；リン酸二カルシウムのようなリン酸塩 誘導体;塩化ナトリウムのような塩化塩誘導体;炭酸カルシウムのような炭酸塩誘導体 ；硫酸カルシウムのような硫酸塩誘導体;又はこれらの混合物）、結合剤（例えば、上 記の賦形剤で例示した化合物；ゼラチン；ポリビエルピロリドン；マクロゴール；又はこ れらの混合物）、崩壊剤（例えば、上記の賦形剤で例示した化合物;架橋ポリビュル ピロリドン；又はこれらの混合物）、滑沢剤（例えば、ステアリン酸;ステアリン酸カルシ ゥム、ステアリン酸マグネシウムのようなステアリン酸金属塩;安息香酸ナトリウムのよう な安息香酸金属塩；ビーガム、ゲイロウのようなワックス類；硼酸；グリコーノレ；フマル酸 、アジピン酸のようなカルボン酸類；硫酸ナトリウムのような硫酸金属塩；ロイシン；ラウ リル硫酸ナトリウム、ラウリル硫酸マグネシウムのようなラウリル硫酸金属塩；上記の賦 形剤で例示したケィ酸塩誘導体；上記の賦形剤で例示したデンプン誘導体；水素化 植物油；カルナパロウ；蔗糖脂肪酸エステル;又はこれらの混合物）、安定剤（例えば 、安息香酸;安息香酸ナトリウムのような安息香酸金属塩;メチルパラベン、プロピル パラベンのようなパラォキシ安息香酸エステル類；クロロブタノール、ベンジルアルコ ール、フヱニルエチルアルコールのようなアルコール類；塩化ベンザルコニゥム；フエ ノーノレ、タレゾールのようなフエノール類；チメロサール；無水酢酸；ソルビン酸；又はこ れらの混合物）、流動化剤（例えば、上記の賦形剤で例示したケィ酸塩誘導体;タル ク；又はこれらの混合物）、界面活性剤（例えば、ポリソルベート 80のようなポリソルべ ート類；ポリオキシエチレン硬化ヒマシ油 60のようなポリオキシエチレン硬化ヒマシ油 類；ソルビタン脂肪酸エステル類；蔗糖脂肪酸エステル類；ポリオキシエチレンポリオ キシプロピレングリコール類；ポリオキシエチレン脂肪酸エーテル類;ステアリン酸ポリ ォキシル類；又はこれらの混合物、好適には、ポリソルベート 80、ポリオキシエチレン 硬化ヒマシ油 60又はこれらの混合物）、着色剤（例えば、黄色三二酸化鉄、三二酸 化鉄、黒酸化鉄）、抗酸化剤、矯味矯臭剤 (例えば、通常使用される、甘味料、酸味 料、香料等）又は希釈剤であり得、使用される添加剤の種類及び量は、錠剤、カプセ ノレ剤又は他の投与形態薬剤により異なるが、製剤の分野の周知の技術に選択される [0014] (5S) -5- {4 [(6-Methoxy-1-methyl-1H-benzoimidazole-2-yl) methoxy] benzyl} -1,3 thiazolidine-2,4 dione of the present invention or its pharmacology When a topically acceptable salt is used as a prophylactic or therapeutic agent for the above-mentioned diseases, it is an appropriate pharmacologically acceptable excipient, lubricant, binder, disintegration. Oral or injection preparations such as tablets, capsules, granules, powders or syrups manufactured according to well-known methods using additives such as agents, emulsifiers, stabilizers, flavoring agents, and diluents. Alternatively, it can be administered parenterally, such as with a suppository. The said formulation may contain a pharmaceutically acceptable additive suitably. Such additives include, for example, excipients (eg sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbitol; corn starch, potato starch, pregelatinized starch, dextrin, carboxymethyl starch, carboxymethyl Starch derivatives such as starch sodium; pregelatinized starch; crystalline cellulose, methylcellulose, hydroxypropylcellulose, low substituted hydroxypropylcellulose, hydroxypropylmethylosenorellose, canolemellose, canolemellose canolecium, croscanolemellose, Cellulose derivatives such as cross-strength noromerose sodium; gum arabic; dextran; pullulan; Silicate derivatives such as magnesium aluminate; phosphate derivatives such as dicalcium phosphate; chloride derivatives such as sodium chloride; carbonate derivatives such as calcium carbonate; sulfates such as calcium sulfate Derivatives; or mixtures thereof), binders (eg, compounds exemplified in the above excipients; gelatin; polyvinyl pyrrolidone; macrogol; or mixtures thereof), disintegrants (eg, excipients as described above) Compounds exemplified by the agents; cross-linked polybutylpyrrolidone; or mixtures thereof), lubricants (eg, stearic acid; stearic acid metal salts such as calcium stearate, magnesium stearate; benzoic acid such as sodium benzoate) Metal salts; waxes such as veegum and geiro; boric acid; glyconole; fumaric acid and adipic acid Carboxylic acids; Metal sulfates such as sodium sulfate; Leucine; Metal lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; Kayate derivatives exemplified in the above-mentioned excipients; Starch derivatives; hydrogenated vegetable oils; carnapa wax; sucrose fatty acid esters; or mixtures thereof), stabilizers (for example, benzoic acid; benzoic acid metal salts such as sodium benzoate; paraoxybenzoic acid esters such as methylparaben and propylparaben) Alcohols such as chlorobutanol, benzyl alcohol, vinyl ethyl alcohol; benzalkonium chloride; phenols such as phenol, talesol, thimerosal; acetic anhydride; sorbic acid; or a mixture thereof) Fluidizing agents (e.g. exemplified by the above excipients) And Kei salt derivatives; Tal click; or mixtures thereof), surfactants (e.g., polysorbate, such as polysorbate 80; polyoxyethylene hydrogenated castor oils such as polyoxyethylene hydrogenated castor oil 60 Sorbitan fatty acid esters; sucrose fatty acid esters; polyoxyethylene polyoxypropylene glycols; polyoxyethylene fatty acid ethers; polyoxyl stearates; or mixtures thereof, preferably polysorbate 80, polyoxyethylene cured Castor oil 60 or a mixture thereof), coloring agent (for example, yellow iron sesquioxide, iron trioxide, black iron oxide), antioxidant, flavoring agent (for example, commonly used sweetener, acidulant) The type and amount of additives used will vary depending on the tablet, capsanolate or other dosage form drug, but are selected by well-known techniques in the field of formulation.
[0016] 例えば、錠剤の場合には、全薬剤組成物中、結合剤の含量は、通常、 1乃至 10重 量部 (好適には、 2乃至 5重量部)であり、崩壊剤の含量は、通常、 1乃至 40重量部 (好 適には、 5乃至 30重量部)であり、滑沢剤の含量は、通常、 0.1乃至 10重量部 (好適に は、 0.5乃至 3重量部)であり、流動化剤の含量は、 0.1乃至 10重量部 (好適には、 0.5乃 至 5重量部）である。 [0016] For example, in the case of tablets, the content of the binder in the whole pharmaceutical composition is usually 1 to 10 parts by weight (preferably 2 to 5 parts by weight), and the content of the disintegrant is Usually, it is 1 to 40 parts by weight (preferably 5 to 30 parts by weight), and the content of the lubricant is usually 0.1 to 10 parts by weight (preferably 0.5 to 3 parts by weight). The content of the fluidizing agent is 0.1 to 10 parts by weight (preferably 0.5 to 5 parts by weight).
[0017] 本発明の医薬組成物は、温血動物（特にヒト）に投与することができ、有効成分であ る（5S)— 5— {4— [ (6 メトキシ一 1—メチルー 1H—ベンゾイミダゾールー 2 ィル） メトキシ]ベンジル } 1 , 3 チアゾリジン 2, 4 ジオン又はその薬理上許容される 塩の投与量は、患者の症状、年齢、体重等の種々の条件により変化し得る力 例え ば経口投与の場合、 1回当たり 0.1mg/body〜20mg/body (好適には 0.5mg/body〜3m g/body)をヒトに対して、 1日当たり 1乃至 6回症状に応じて投与することができる。  [0017] The pharmaceutical composition of the present invention can be administered to warm-blooded animals (especially humans) and is an active ingredient (5S) -5- {4- [(6 methoxy-1-1-methyl-1H-benzo Imidazole-2-yl) methoxy] benzyl} 1,3 thiazolidine 2,4 dione or its pharmacologically acceptable salt dosage may vary depending on various conditions such as patient symptoms, age, weight, etc. In the case of oral administration, 0.1 mg / body to 20 mg / body (preferably 0.5 mg / body to 3 mg / body) per dose may be administered to humans 1 to 6 times daily depending on symptoms. it can.
[0018]  [0018]
実施例  Example
[0019] 以下に実施例等を示し本発明をさらに詳細に説明するが、本発明の範囲は、これ らに限定されるものではない。  Hereinafter, the present invention will be described in more detail with reference to examples and the like, but the scope of the present invention is not limited thereto.
ロジグリタゾン マレイン酸塩（以下、化合物 Aとする）は、米国特許第 5，741，803号 公報に記載された化合物であり、該公報に記載の方法に準じて製造することができ る。  Rosiglitazone maleate (hereinafter referred to as Compound A) is a compound described in US Pat. No. 5,741,803 and can be produced according to the method described in the publication.
(実施例 1)  (Example 1)
(5S) 5—{4 [ (6—メトキシ 1ーメチルー 1H—べンゾイミダゾールー 2—ィル） メトキシ]ベンジル }— 1 , 3 チアゾリジン— 2, 4 ジオン 塩酸塩の製造方法 (5S) 5— {4 [(6-Methoxy 1-methyl-1H-benzoimidazole-2-yl) Methoxy] benzyl} — 1,3 thiazolidine— 2,4 dione hydrochloride
(1 - 1) (1-1)
4 [ (2,4 ジォキソチアゾリジンー5 ィル）メチル]フエノキシ酢酸（61. Okg, 216.9 mol)のジクロロメタン（398L)懸濁液に、塩化チォニル（28.15kg, 236.6mol)、ジメチル ホルムアミド（6.1L)を注カ卩し、 6時間還流した。得られた溶液を 0〜5°Cまで冷却したの ち、内温 5°C以下を保ちながら、 N- (2—ァミノ _ 5—メトキシフヱニル）一N—メチノレ 力ルバミン酸 tert—ブチル（54.72kg， 216.9mol)及びトリェチルァミン（26.35kg, 260.4 mol)のジクロロメタン（562L)溶液を 1時間かけて滴下し、 0〜5°Cで 15分間撹拌した。 ここへ攪拌しながら水（488L)を注ぎ、炭酸水素ナトリウム（24.4kg)を加えたのち（内 温度は約 20°Cに上昇した）、ジクロロメタン (305L)を注ぎ、冷却しながら 20分間攪拌 し、 0〜3°Cとした。ここへ水（488L)を注ぎ、 10〜20°Cで 5分間攪拌した後、 30分間静 置し、水層を廃棄した。ここへ水 (488L)ついで 38%塩酸 (23.8kg)を注ぎ 5分間攪拌 した後、 10分間静置し、水層を廃棄した。ここへ水 (488L)注ぎ、 5分間攪拌した後、 1 2時間静置し、水層を廃棄した。ここへ活性炭（1.83kg)のジクロロメタン（18L)懸濁液 を加え、 30分間攪拌した後、活性炭をろ別した。活性炭をジクロロメタン (92L)で洗浄 し、ろ液と洗浄液を合わせ、内温 20〜30°Cで減圧下、約 300Lとなるまで濃縮した。こ こへメタノール（305L)を注ぎ、内温 20〜30°Cで減圧下、約 300Lとなるまで濃縮した。 さらにここへメタノール（305L)を注ぎ、内温 20〜30°Cで減圧下、約 300Lとなるまで濃 縮した。ここへメタノール (201L)を注ぎ、 5°Cで 1時間攪拌後、得られた結晶をろ別し、 メタノール（244L)で洗浄後、減圧下、 50°Cで乾燥し、 N— { 2— {4 [ (2,4 ジォキ ソチアゾリジン一 5—ィル）メチル]フエノキシァセチルァミノ } - 5—メトキシフエ二ル} —N—メチルカルバミン酸 tert—ブチル（103.9kg, 201.5mol)を得た（収率 93%)。  4 To a suspension of [(2,4 dioxothiazolidine-5-yl) methyl] phenoxyacetic acid (61. Okg, 216.9 mol) in dichloromethane (398 L), thionyl chloride (28.15 kg, 236.6 mol), dimethylformamide ( 6.1L) was poured and refluxed for 6 hours. After cooling the resulting solution to 0-5 ° C, N- (2-amino-5-methoxyphenyl) -N-methylol tert-butyl (54.72 kg) , 216.9 mol) and triethylamine (26.35 kg, 260.4 mol) in dichloromethane (562 L) were added dropwise over 1 hour and stirred at 0-5 ° C for 15 minutes. Pour water (488L) with stirring, add sodium bicarbonate (24.4kg) (internal temperature increased to about 20 ° C), pour dichloromethane (305L), and stir for 20 minutes with cooling. 0 to 3 ° C. Water (488 L) was poured here, and the mixture was stirred at 10 to 20 ° C. for 5 minutes, then allowed to stand for 30 minutes, and the aqueous layer was discarded. Water (488 L) and 38% hydrochloric acid (23.8 kg) were poured into this, and the mixture was stirred for 5 minutes and then allowed to stand for 10 minutes. The aqueous layer was discarded. Water (488 L) was poured into this, stirred for 5 minutes, and then allowed to stand for 12 hours, and the aqueous layer was discarded. To this was added a suspension of activated carbon (1.83 kg) in dichloromethane (18 L), stirred for 30 minutes, and then the activated carbon was filtered off. The activated carbon was washed with dichloromethane (92 L), and the filtrate and the washing solution were combined and concentrated under reduced pressure at an internal temperature of 20 to 30 ° C. to about 300 L. Methanol (305 L) was poured into this, and the mixture was concentrated to about 300 L under reduced pressure at an internal temperature of 20-30 ° C. Further, methanol (305 L) was poured here, and the mixture was concentrated to about 300 L under reduced pressure at an internal temperature of 20 to 30 ° C. Methanol (201 L) was poured into this, and the mixture was stirred at 5 ° C for 1 hour. The obtained crystals were filtered off, washed with methanol (244 L), dried at 50 ° C under reduced pressure, and N— {2— {4 [(2,4 dioxothiazolidine mono 5-yl) methyl] phenoxycetylamino} -5-methoxyphenyl} —N-methylcarbamate tert-butyl (103.9 kg, 201.5 mol) was obtained. (Yield 93%).
(1 - 2) (1-2)
(1 - 1)で得られた N - { 2 - {4- [ (2,4-ジォキソチアゾリジン一 5 _ィル）メチノレ] フエノキシァセチルァミノ } - 5—メトキシフエ二ノレ }— N—メチルカルバミン酸 tert -ブ チルを（97.0kg， 188. lmol)をメタノーノレ（2803L)、水（43L)および 38%塩酸（72.8kg) からなる溶液に懸濁後、 5時間攪拌しながら還流した。反応液を 0〜5°Cに冷却後、 1 時間攪拌し、同温度で 12時間静置した。得られた結晶をろ別し、メタノール (291L)で 洗浄後、減圧下 50°Cで乾燥し、（RS)— 5— {4— [ (6—メトキシ— 1—メチル 1H— ベンゾイミダゾールー 2 ィル）メトキシ]ベンジル }ー1 , 3 チアゾリジン 2, 4—ジ オン 1塩酸塩（74.9kg、 172.5mol)を得た（収率 92%)。 N-{2-{4- [(2,4-Dioxothiazolidine mono 5 _yl) methinole] phenoxyacetylamino}-5 -methoxypheninole}-obtained in (1-1) Tert-Butyl N-methylcarbamate (97.0 kg, 188. lmol) was suspended in a solution of methanol (2803 L), water (43 L) and 38% hydrochloric acid (72.8 kg), and then refluxed with stirring for 5 hours. . The reaction solution was cooled to 0-5 ° C, stirred for 1 hour, and allowed to stand at the same temperature for 12 hours. The obtained crystals were filtered off with methanol (291L) After washing and drying at 50 ° C under reduced pressure, (RS) — 5— {4— [(6-Methoxy-1-methyl 1H-benzimidazole-2-yl) methoxy] benzyl} -1,3 thiazolidine 2, 4-Dione monohydrochloride (74.9 kg, 172.5 mol) was obtained (yield 92%).
(1 - 3) (13)
(1 - 2)で得られた（RS) _ 5 _{4_ [ (6—メトキシ _ 1—メチル一 1H—ベンゾイミダ ゾール _ 2_ィル）メトキシ]ベンジル }_ 1， 3 _チアゾリジン一2, 4—ジオン 1塩酸 塩 (以下、ラセミ体と省略する）を、下記条件下で、高速液体クロマトグラフィー（HPL C)に付し、（5R)— 5— {4— [ (6—メトキシ一 1—メチル一 1H—ベンゾイミダゾール一 2—ィル）メトキシ]ベンジル }— 1 , 3—チアゾリジン— 2, 4—ジオン 塩酸塩（以下、 R 体と省略する。 )及び（5S) _ 5 _{4_ [ (6—メトキシ一 1—メチノレ一 1H_ベンゾイミダ ゾール _ 2_ィル）メトキシ]ベンジル }_ 1， 3 _チアゾリジン一2, 4—ジオン 1塩酸 塩 (以下、 S体と省略する。）を、各々分離した。また、分離した各々の光学異性体は 、下記分析条件で光学純度を測定した。 HPLCのカラムは、全てダイセル化学工業（ 株)製を使用した。 分取 HPLCの条件  (RS) _ 5 _ {4_ [(6-Methoxy _ 1-methyl 1H-benzoimidazole _ 2_ yl) methoxy] benzyl} _ 1, 3 _thiazolidine 1 2, obtained in (1-2) 4-Dione monohydrochloride (hereinafter abbreviated as racemate) was subjected to high performance liquid chromatography (HPL C) under the following conditions to give (5R) — 5— {4— [(6-methoxy- 1 —Methyl-1H-benzimidazole-2-yl) methoxy] benzyl} —1,3-Thiazolidine-2,4-dione hydrochloride (hereinafter abbreviated as R form) and (5S) _ 5 _ {4_ [(6-Methoxy-1- 1-methylol 1H_benzoimidazole_2_yl) methoxy] benzyl} _ 1,3 _thiazolidine-1,4-dione monohydrochloride (hereinafter abbreviated as S form) , Each separated. Further, the optical purity of each separated optical isomer was measured under the following analysis conditions. All HPLC columns used were manufactured by Daicel Chemical Industries. Preparative HPLC conditions
カラム： CHIRALCEL OJ (10 μ m pirticle), 10.0cm φ X 25cm  Column: CHIRALCEL OJ (10 μm pirticle), 10.0cm φ X 25cm
移動相：メタノール/酢酸（100/0. ιχν/ν)  Mobile phase: Methanol / acetic acid (100/0. Ιχν / ν)
流速： 140ml/min  Flow rate: 140ml / min
検出器： UV(254nm)  Detector: UV (254nm)
カラム温度： 40°C  Column temperature: 40 ° C
試料濃度：ラセミ体 4.5gZメタノーノレ 1.51  Sample concentration: Racemic 4.5gZ methanole 1.51
試料注入量： 38ml/ 1回  Sample injection volume: 38ml / time
分析 HPLCの条件  Analytical HPLC conditions
カラム： CHIRALCEL〇J-RH， 0.46cm φ X 15cm  Column: CHIRALCEL〇J-RH, 0.46cm φ X 15cm
移動相： ρΗ2·0 0.1Mリン酸緩衝液/メタノール （45/55XV/V)  Mobile phase: ρΗ2 · 0 0.1M phosphate buffer / methanol (45 / 55XV / V)
流速： 0.8ml/min  Flow rate: 0.8ml / min
検出器： UV(254nm) カラム温度： 40°C Detector: UV (254nm) Column temperature: 40 ° C
上記分析条件での保持時間： 14.2min  Retention time under the above analysis conditions: 14.2min
性状： 白色粉末  Properties: White powder
マススペクトル (FAB,m/z) : 398 (M+H)+. Mass spectrum (FAB, m / z): 398 (M + H) + .
'Η NMRスペクトル (DMSOd , δ ): 3.10 (1Η, dd， J=14Hz及び 9Hz)， 3.34 (1H， dd, J=  'Η NMR spectrum (DMSOd, δ): 3.10 (1Η, dd, J = 14Hz and 9Hz), 3.34 (1H, dd, J =
6  6
14Hz及び 4Hz), 3.89 ( 3H， s)， 3.98 (3H， s), 4.90 (1H, dd, J=9Hz及び 4Hz), 5.63 (2H ， s)， 7.13 (2H, d, J=9Hz), 7.15 (1H, dd, J=9Hz及び 2Hz)， 7.25 (2H, d, J=9Hz), 7.49 (1H， d, J=2Hz), 7.70(1H, d, J=9Hz), 12.04(1H, s;重水素添加により消失).  14Hz and 4Hz), 3.89 (3H, s), 3.98 (3H, s), 4.90 (1H, dd, J = 9Hz and 4Hz), 5.63 (2H, s), 7.13 (2H, d, J = 9Hz), 7.15 (1H, dd, J = 9Hz and 2Hz), 7.25 (2H, d, J = 9Hz), 7.49 (1H, d, J = 2Hz), 7.70 (1H, d, J = 9Hz), 12.04 (1H, s; disappeared by deuterium addition).
IRスペクトル (KBr，え maxcm— ： 1751, 1700.  IR spectrum (KBr, e maxcm—: 1751, 1700.
(51 ) _ 5 _{4_ [ (6 _メトキシ_ 1 _メチル_ 1^^_べンゾィミダゾール_ 2_ィル）メ トキシ]ベンジル 3 _チアゾリジン— 2， 4—ジオン 1塩酸塩 （R体） (51) _ 5 _ {4_ [(6 _Methoxy _ 1 _Methyl _ 1 ^^ _ Benzazomidazole _ 2_ yl) methoxy] benzyl 3 _thiazolidine-2,4-dione monohydrochloride (R)
上記分析条件での保持時間： 18.2min  Retention time under the above analysis conditions: 18.2min
性状： 白色粉末  Properties: White powder
マススペクトル (FAB,m/z) : 398 (M+H)+. Mass spectrum (FAB, m / z): 398 (M + H) + .
JH NMRスペクトル (DMSOd , δ ): 3.10 (1Η, dd, J=14Hz及び 9Hz)， 3.34 (1H， dd, J= J H NMR spectrum (DMSOd, δ): 3.10 (1Η, dd, J = 14Hz and 9Hz), 3.34 (1H, dd, J =
6  6
14Hz及び 4Hz), 3.89 ( 3H, s)， 3.98 (3H， s), 4.90 (1H, dd, J=9Hz及び 4Hz), 5.63 (2H ， s)， 7.13 (2H, d, J=9Hz), 7.15 (1H, dd, J=9Hz及び 2Hz)， 7.25 (2H， d, J=9Hz), 7.49 (1H， d, J=2Hz), 7.70(1H, d, J=9Hz), 12.04(1H, s;重水素添加により消失).  14Hz and 4Hz), 3.89 (3H, s), 3.98 (3H, s), 4.90 (1H, dd, J = 9Hz and 4Hz), 5.63 (2H, s), 7.13 (2H, d, J = 9Hz), 7.15 (1H, dd, J = 9Hz and 2Hz), 7.25 (2H, d, J = 9Hz), 7.49 (1H, d, J = 2Hz), 7.70 (1H, d, J = 9Hz), 12.04 (1H, s; disappeared by deuterium addition).
IRスペクトル (KBr maxcm— ： 1751, 1700.  IR spectrum (KBr maxcm—: 1751, 1700.
(試験例 1) (Test Example 1)
ヒト型 PPAR -LBDを用いた受容体結合試験 Receptor binding test using human PPAR-LBD
(1 _ 1)ヒト型 PPAR y -LBDの調製 (1 _ 1) Preparation of human PPAR y -LBD
ポリメラーゼ連鎖反応（polymerase chain reaction :以下、「PCR」とレヽう）法により、ヒ スチジン（以下、「His」という）タグ融合ヒト PPAR γのリガンド 'バインディング 'ドメイン（ ligand binding domain :以下、「LBD」という）の融合タンパク質（以下、「His_PPAR y - LBDJという）をコードした組換え発現ベクターを取得し、そのベクターで形質転換さ れた大腸菌を培養し、その培養物より His-PPAR y -LBDを回収した。 Ligand binding domain (hereinafter referred to as “LBD”) of histidine (hereinafter referred to as “His”)-tagged human PPAR γ by the polymerase chain reaction (hereinafter referred to as “PCR”) method. A recombinant expression vector encoding a fusion protein (hereinafter referred to as “His_PPAR y-LBDJ”) and transformed with that vector. The cultured Escherichia coli was cultured, and His-PPAR y -LBD was recovered from the culture.
[0021] まず、ヒト PPAR y -LBD (アミノ酸 208-477)をコードする配列の両末端に制限酵素 Sa 1 1および BamH Iの認識配列を付加し、 Hisタグ融合タンパク質発現ベクター pQE30 ( QIAGEN社）に組み込むために、下記ヌクレオチド配列を有するオリゴヌクレオチドを 合成した。 [0021] First, restriction sequences Sa 11 and BamH I were added to both ends of the sequence encoding human PPAR y -LBD (amino acids 208-477), and His-tagged protein expression vector pQE30 (QIAGEN) In order to incorporate into the oligonucleotide, an oligonucleotide having the following nucleotide sequence was synthesized.
[0022] 5， -TGGGATCCGAGTCCGCTGACCTCCGGGCCCTGG-3 '： γ 1 (酉己歹 lj表の酉己 列番号： 1)  [0022] 5, -TGGGATCCGAGTCCGCTGACCTCCGGGCCCTGG-3 ': γ 1 (酉 己 歹 lj column number: 1)
5 ' -ACAAGCTTCTAGTACAAGTCCTTGT-3 '： γ 2 (配列表の配列番号： 2) 次いで、ヒト cDNAライブラリー（Clontech社、カタログ番号： K-1420-1)を錡型とし、 上記 γ 1および γ 2をプライマーとして 99°Cにて 2分間からなる保温を行った後、 99 °Cにて 30秒間、次いで 55°Cにて 30秒間、次いで 72°Cにて 1分間からなる保温サイ クルを 30回繰り返すことにより PCRを行った。増幅されたポリヌクレオチド断片を pUC 118ベクター（TAKARA社）へサブクローニングし、常法により挿入部分のヌクレオチド 配列を決定した。次いで、得られた組換えベクターを制限酵素 Sal Iおよび BamH Iで 処理した後、挿入部分を回収して pQE30へサブクローユングし、組替え発現ベクター を構築した。  5′-ACAAGCTTCTAGTACAAGTCCTTGT-3 ′: γ 2 (SEQ ID NO: 2 in the sequence listing) Next, a human cDNA library (Clontech, catalog number: K-1420-1) is used as a cage, and the above γ 1 and γ 2 are Incubate for 2 minutes at 99 ° C as a primer, then 30 cycles at 99 ° C for 30 seconds, then 55 ° C for 30 seconds, then 72 ° C for 1 minute 30 times PCR was performed by repeating. The amplified polynucleotide fragment was subcloned into pUC118 vector (TAKARA), and the nucleotide sequence of the insert was determined by a conventional method. Next, the obtained recombinant vector was treated with restriction enzymes Sal I and BamH I, and then the inserted portion was recovered and subcloned into pQE30 to construct a recombinant expression vector.
[0023] 次レ、で、ァミノ末端のアミノ酸配列を X線結晶構造解析の報告（R. T. Nolte et al, N ature, 1998年,第 395卷， 第 10号， ρ·137_143)のあるものと同じ配列にするため、下 記ヌクレオチド配列を有するオリゴヌクレオチドを合成した。  [0023] Next, the amino acid sequence at the amino terminal is the same as that reported in the X-ray crystal structure analysis (RT Nolte et al, Nature, 1998, No. 395, No. 10, ρ · 137_143). In order to make a sequence, an oligonucleotide having the following nucleotide sequence was synthesized.
[0024] 5 ' -CACCATCACGGACCCGAGTCCGCTGACCTC-3，： γ 3 (配列表の配列番 号: 3)  [0024] 5'-CACCATCACGGACCCGAGTCCGCTGACCTC-3,: γ 3 (SEQ ID NO: 3 in the sequence listing)
次いで、先に得られた組換え発現ベクターを錡型とし、かつ、上記 γ 3をプライマー として 95°Cにて 30秒間からなる保温を行った後、 95°Cにて 30秒間、次いで 55°Cに て 1分間、次いで 68°Cにて 6分間からなる保温サイクルを 12回繰り返すことによる PC Rを行った。増幅されたポリヌクレオチド断片につき、常法により揷入部分のヌクレオ チド配列（配列番号 4)を決定した。以上の操作により組換え発現ベクター PQE30-PP AR y -LBDを得た。  Next, the recombinant expression vector obtained above was made into a saddle type, and the above γ3 was used as a primer, followed by incubation at 95 ° C for 30 seconds, at 95 ° C for 30 seconds, and then at 55 ° C. PCR was performed by repeating a heat retention cycle consisting of C for 1 minute and then at 68 ° C for 6 minutes 12 times. For the amplified polynucleotide fragment, the nucleotide sequence (SEQ ID NO: 4) of the inserted portion was determined by a conventional method. The recombinant expression vector PQE30-PP AR y -LBD was obtained by the above operation.
[0025] 次いで、得られた組換え発現ベクター pQE30-PPAR o/ -LBDで、電気穿孔法により 大腸菌株 SG13009株（QIAGEN社）を形質転換した。この形質転換株を、 100 /i g/mL 濃度のアンピシリンおよび 25 μ g/mL濃度のカナマイシンを含む L-broth培地 [LB BR OTH BASE (Invitrogen社） 20gを 1Lの水に溶解したもの] 5mlに接種し、 37°Cにて 4 時間振とう培養を行った。次いで、 100 μ g/mL濃度のアンピシリンおよび 25 μ g/mL 濃度のカナマイシンを含む L_broth培地 lOOmLに 2. 0% (容積 Z容積）接種し、 37 °Cにて 12時間振とう培養を行なった。次いで、 100 μ g/mL濃度のアンピシリンおよ び 25 μ g/mL濃度のカナマイシンを含む L_broth培地 1Lに 10% (容積/容積)接種 し、 37°Cにて 4時間振とう培養を行なった。次いで 0. ImMイソプロピル- /3 -D -チォ ガラクトシドを添加し、 30°Cにて 6時間振とう培養を行なった。 [0025] Next, the obtained recombinant expression vector pQE30-PPAR o / -LBD was electroporated. E. coli strain SG13009 (QIAGEN) was transformed. L-broth medium containing 20 g of LB BR OTH BASE (Invitrogen) dissolved in 1 L of water containing 5 μg of this transformed strain containing ampicillin at a concentration of 100 / ig / mL and kanamycin at a concentration of 25 μg / mL Inoculated and cultured with shaking at 37 ° C for 4 hours. Next, 2.0% (volume Z volume) was inoculated into lOOmL of L_broth medium containing ampicillin at a concentration of 100 μg / mL and kanamycin at a concentration of 25 μg / mL, followed by shaking culture at 37 ° C for 12 hours. . Next, 10% (volume / volume) was inoculated into 1 L of L_broth medium containing ampicillin at a concentration of 100 μg / mL and kanamycin at a concentration of 25 μg / mL, followed by shaking culture at 37 ° C for 4 hours. . Subsequently, 0. ImM isopropyl- / 3-D-thiogalactoside was added, and shaking culture was performed at 30 ° C for 6 hours.
[0026] 培養終了後、 4000 X g、 30分間の遠心分離で沈殿画分を回収し、 25mLの懸濁バ ッファー（組成は以下に示した）に懸濁し、懸濁液を超音波処理した。 14000 X g、 3 0分間の遠心分離を行い上清を回収し、ニッケル硫酸を付加した HiTrap Chelating H Pカラム (Amersham Bioscience社)に添加した。ニッケルカラム Aバッファー（組成は以 下に示した）およびニッケノレカラム Bバッファー（組成は以下に示した）によるグラジェ ント溶出法により、 His-PPAR y -LBDを含む溶出画分を回収し、透析バッファー（組 成は以下に示した）により透析を行った。次いで、透析を行った HiTrap Chelating HP カラム溶出画分を HiTrap SP HPカラム（Amersham Bioscience社）に添カロし、イオン交 換カラム Aバッファー（組成は以下に示した）およびイオン交換カラム Bバッファー（組 成は以下に示した）によるグラジェント溶出法により、 His-PPAR-LBDを含む溶出画 分を回収した。次いで、ゲル濾過バッファー（組成は以下に示した）で平衡ィ匕した HiL oad Superdex75 (Amersham Bioscience社）に HiTrap SP HPカラム溶出画分を添加し 、ゲル濾過バッファ一により溶出し、融合タンパク質 His-PPAR o/ _LBDを回収した。  [0026] After culturing, the precipitate fraction was collected by centrifugation at 4000 X g for 30 minutes, suspended in a 25 mL suspension buffer (composition shown below), and the suspension was sonicated. . The supernatant was collected by centrifugation at 14000 × g for 30 minutes, and added to a HiTrap Chelating HP column (Amersham Bioscience) supplemented with nickel sulfate. The elution fraction containing His-PPAR y -LBD was collected by the gradient elution method using Nickel column A buffer (composition shown below) and Nickenole column B buffer (composition shown below), and the dialysis buffer was collected. Dialysis was carried out according to the composition shown below. The dialyzed HiTrap Chelating HP column elution fraction is then applied to a HiTrap SP HP column (Amersham Bioscience), and ion-exchange column A buffer (composition is shown below) and ion-exchange column B buffer (combination). The elution fraction containing His-PPAR-LBD was collected by the gradient elution method described below. Next, the HiTrap SP HP column elution fraction was added to HiLoad Superdex75 (Amersham Bioscience) equilibrated with gel filtration buffer (composition is shown below), and eluted with gel filtration buffer. PPAR o / _LBD was recovered.
[0027] 10乃至 20%ポリアクリルアミド 'ドデシル硫酸ナトリウム ·ゲル電気泳動を行なった 結果、得られた融合タンパク質の還元条件下における分子量は約 32000であった。  [0027] As a result of 10 to 20% polyacrylamide sodium dodecyl sulfate gel electrophoresis, the resulting fusion protein had a molecular weight of about 32000 under reducing conditions.
[0028] 懸獨バッファー： [0028] Suspension buffer:
Tris-HCl (PH8. 0) Tris-HCl ( PH 8.0)
NaCl NaCl
ィミダゾ一ル Imidazol
Complete EDTA - free (Roche社) (プロテアーゼインヒビタ一） 二ッケノレ力ラム A ファ一： Complete EDTA-free (Roche) (Protease inhibitor)
Tris-HCl (pH8. 0) Tris-HCl (pH 8.0)
NaCl 二ッケノレ力ラム B ファ— NaCl Fickenole force ram B
Tris-HCl (pH8. 0) Tris-HCl (pH 8.0)
NaCl  NaCl
ィミダゾール 透析バッファ一： Imidazole dialysis buffer:
HEPES (PH7. 5) HEPES ( P H7. 5)
(±) -ジチォトレイ トール (DTT) エチレンジァミン四齚酸 (EDTA) ィォン交換力ラム Aバッファ一 HEPES (pH7. 5)  (±) -dithiothreitol (DTT) ethylenediamin tetrasuccinic acid (EDTA) ion exchange ram A buffer one HEPES (pH 7.5)
(土）-ジチォトレイ トール (DTT) エチレンジァミン四酢酸 (EDTA) イオン交換カラム Bバッファ一 (Sat) -dithiothreitol (DTT) ethylenediamine tetraacetic acid (EDTA) ion exchange column B buffer
HEPES (PH7. 5) HEPES ( P H7. 5)
NaCl  NaCl
( ±) -ジチオトレイ トール (DTT) エチレンジァミン四齚酸 (EDTA) ゲル濾過バッファ— ：  (±) -Dithiothreitol (DTT) Ethylenediamine tetrasuccinic acid (EDTA) gel filtration buffer:
Tris-HCl (pH8. 0) Tris-HCl (pH 8.0)
NaCl NaCl
(土）-ジチオトレイ トール (DTT) エチレンジァミン四齚酸 (EDTA) 受容体結合試験 (Sat) -Dithiothreitol (DTT) Ethylenediamine tetrasuccinic acid (EDTA) Receptor binding test
Sephadex G-25 (アマシャムフアルマシアバイオテク株式会社）を Blocking Buffer (50 mM Tris-HCl, pH 8.0， 50 mM KCl, 2 mM EDTA, 5 mM CHAPS, 1 mg/mL BSA ， 5 mM DTT)に 0.18 g/mLの濃度で懸濁し、 MultiScreen (MAHVN4510, Millipore C o.)へ 300 μ L/well分注し、 4°Cにて静置保存し、 PPAR yリガンドの B/F分離に使用 した。  Sephadex G-25 (Amersham Pharmacia Biotech) 0.18 in Blocking Buffer (50 mM Tris-HCl, pH 8.0, 50 mM KCl, 2 mM EDTA, 5 mM CHAPS, 1 mg / mL BSA, 5 mM DTT) Suspended at a concentration of g / mL, dispensed into MultiScreen (MAHVN4510, Millipore Co.) at 300 μL / well, stored at 4 ° C, and used for B / F separation of PPARy ligand.
[0029] 試験例（1 _ 1)で精製した His- PPAR y -LBD蛋白質を Binding Buffer (50 mM Tris- HCl, pH8.0, 50 mM KCl, 2 mM EDTA, 5 mM CHAPS, 0.1 mg/mL BSA, 5 mM DTT )で 75 nMに希釈し、使用まで氷上にて保存した。 S体、 R体、ラセミ体、化合物 Aの粉 末を氷冷した DMSO:MeOH (7:3)混合液にそれぞれ溶解した。更に DMSO:MeOH (7: 3)混合液を用いて、アツセィ終濃度の 60倍濃度まで希釈した。  [0029] The His-PPAR y -LBD protein purified in Test Example (1 _ 1) was bound to Binding Buffer (50 mM Tris-HCl, pH 8.0, 50 mM KCl, 2 mM EDTA, 5 mM CHAPS, 0.1 mg / mL) BSA, 5 mM DTT) was diluted to 75 nM and stored on ice until use. The powders of S-form, R-form, racemate, and compound A were dissolved in an ice-cooled DMSO: MeOH (7: 3) mixture. Further, the mixture was diluted with a DMSO: MeOH (7: 3) mixture to a concentration 60 times the final concentration of Atsy.
[0030] 氷上にて保冷しながら、 R体、 S体、ラセミ体、化合物 Aの希釈溶液、若しくは最大結 合測定用として DMSO:MeOH (7:3)混合液、非特異結合測定用として 9 mM化合物 A 溶液を、 Binding Bufferで 20倍希釈し、結合反応用 96穴プレートへ 72 μ L/well分注し た。 100 nM化合物 A， [ring-3H] (6 nCi/ μ L、 ARC社）溶液を 72 μ L/well、添加し、攪 拌混合した後、更に 75 nM His-PPAR y蛋白質を 72 μ L/well,添加、攪拌し、結合 反応を開始させ、氷上にて 30分静置した。 [0030] While cooling on ice, R-form, S-form, racemate, dilute solution of Compound A, or DMSO: MeOH (7: 3) mixture for maximum binding measurement, 9 for non-specific binding measurement The mM compound A solution was diluted 20-fold with Binding Buffer and dispensed into a 96-well plate for binding reaction at 72 μL / well. Add 72 μL / well of 100 nM Compound A, [ring- 3 H] (6 nCi / μL, ARC) solution, mix by stirring, and then add 72 μL of 75 nM His-PPAR y protein. / well, added and stirred to initiate the binding reaction and left on ice for 30 minutes.
[0031] 結合反応終了直前に、 Sephadex G-25入り MultiScreenプレートをバキュームマニホ 一ルド（Millipore Co.)を用いて Sephadex G-25懸濁液の溶液を吸引で除去し、氷冷 した Binding Bufferを 150 μ L/well添加して、同様に吸引にて除去した。 2回繰り返し た後、予め 4°Cに冷却した遠心機にて 410gで 2分間遠心分離し、残留 Binding Buffer を除去した。結合反応開始 30分後に、結合反応用 96穴プレートの各 wellの反応液を S印 hadex G-25入り MultiScreenプレートへ 45 μ L/well, 4 wellずつ分注添加し、 410g にて 10分間（4°C)遠心分離した。ろ過液を回収し、全量を液体シンチレーシヨン測 定用バイアルに移し、放射活性を測定した。  [0031] Immediately before the end of the binding reaction, remove the Sephadex G-25 suspension from the MultiScreen plate containing Sephadex G-25 using a vacuum manifold (Millipore Co.), and remove the ice-cooled Binding Buffer. 150 μL / well was added and similarly removed by aspiration. After repeating twice, the remaining binding buffer was removed by centrifugation at 410 g for 2 minutes in a centrifuge previously cooled to 4 ° C. 30 minutes after the start of the binding reaction, add each well of the 96-well plate for binding reaction to a MultiScreen plate containing S-labeled hadex G-25 at 45 μL / well, 4 wells, and add 410 g for 10 minutes ( (4 ° C) was centrifuged. The filtrate was recovered, and the entire amount was transferred to a liquid scintillation measurement vial and the radioactivity was measured.
[0032] 各反応の結合阻害率を以下の式にて算出した。  [0032] The binding inhibition rate of each reaction was calculated by the following formula.
[0033] 結合阻害率（％) = 100 X [1- (C-BG)/(C - BG) )] C:各反応の放射活性 [0033] Binding inhibition rate (%) = 100 X [1- (C-BG) / (C-BG))] C: Radioactivity of each reaction
c：最大結合測定用バイアルの放射活性平均値  c: Average radioactivity of vial for maximum binding measurement
0  0
BG：非特異結合測定用バイアルの放射活性平均値  BG: Average radioactivity of vials for nonspecific binding measurement
各被験化合物それぞれに対して、結合阻害率と測定検体用量を用い、以下の Sigm oid E モデルに適用して、 IC 値を算出し表 1に示した。  For each test compound, the binding inhibition rate and measured sample dose were applied to the following Sigmoid E model, and the IC values were calculated and shown in Table 1.
max 50  max 50
結合阻害率 (%) = [ιοοχ(用量)11] I [(IC Binding inhibition rate (%) = [ιοοχ (dose) 11 ] I [(IC
50 Γ + (用量) 11] 50 Γ + (dose) 11 ]
IC ： 50%結合阻害率  IC: 50% binding inhibition rate
50  50
n : sigmoidicity factor  n: sigmoidicity factor
(表 1)  (table 1)
Figure imgf000014_0001
Figure imgf000014_0001
上記より、 S体は、ラセミ体に比べ約 20倍強力な、また R体に比べて約 50倍強力な 親和性を示すことが見出された。 From the above, it was found that the S form has an affinity about 20 times stronger than the racemate and about 50 times stronger affinity than the R form.
[0035]  [0035]
産業上の利用可能性  Industrial applicability
[0036] 本発明の光学活性なチアゾリジンジオン誘導体またはその薬理上許容される塩は 、優れた PPAR y結合能を有するため、糖尿病、高血糖症、耐糖能不全、高血圧症、 高脂血症、糖尿病合併症、妊娠糖尿病、多嚢胞卵巣症候群等の糖代謝系疾患の治 療薬又は予防薬として、有用である。 [0036] Since the optically active thiazolidinedione derivative of the present invention or a pharmacologically acceptable salt thereof has an excellent PPAR y binding ability, diabetes, hyperglycemia, glucose intolerance, hypertension, hyperlipidemia, It is useful as a therapeutic or prophylactic agent for glucose metabolic diseases such as diabetic complications, gestational diabetes mellitus, and polycystic ovary syndrome.
[0037]  [0037]
配列表フリーテキスト  Sequence listing free text
[0038] 配列番号 1：ヒト PPAR yをコードしたポリヌクレオチドを増幅するためのセンス.プラ イマ一。 [0038] SEQ ID NO: 1: Sense plasmid for amplifying a polynucleotide encoding human PPAR y Imama.
[0039] 配列番号 2 :ヒト PPAR γをコードしたポリヌクレオチドを増幅するためのアンチセンス  [0039] SEQ ID NO: 2: Antisense for amplifying a polynucleotide encoding human PPARγ
'プライマー。  'Primer.
[0040] 配列番号 3：ァミノ末端のアミノ酸配歹 1Jを X線結晶構造解析の報告のあるものと同じ 配  [0040] SEQ ID NO: 3: Amino terminal amino acid configuration 1J is the same as that reported for X-ray crystal structure analysis
列にするためのセンス'プライマー。  Sense 'primer to line up.
[0041] 配列番号 4 : pQE30_PPAR y -LBDに揷入されたポリヌクレオチド。 [0041] SEQ ID NO: 4: Polynucleotide inserted into pQE30_PPAR y -LBD.

Claims

請求の範囲 The scope of the claims
(5S) _5_{4_[(6—メトキシ _1_メチル _1H—ベンゾイミダゾール一 2_ィル） メトキシ]ベンジル 3_チアゾリジン _2， 4—ジオン又はその薬理上許容し得る 塩。  (5S) _5_ {4 _ [(6-Methoxy_1_methyl_1H-benzimidazole-2-yl) methoxy] benzyl 3_thiazolidine_2,4-dione or a pharmacologically acceptable salt thereof.
(5S) _5_{4_[(6—メトキシ _1_メチル一1H—ベンゾイミダゾール一 2_ィル） メトキシ]ベンジル }— 1, 3—チアゾリジン一 2, 4—ジオン 1塩酸塩。 (5S) _5_ {4 _ [(6-Methoxy_1_methyl-1H-benzimidazole-2-yl) methoxy] benzyl} —1,3-thiazolidine mono-2,4-dione monohydrochloride.
(RS)— 5— {4— [(6—メトキシ一 1—メチル 1 H ベンゾイミダゾール 2 ィル） メトキシ]ベンジル }ー1, 3 チアゾリジン 2, 4 ジオン 1塩酸塩を光学分割するこ とにより得られうる、 CHIRALCEL OJ-RH (0.46cm X 15cm,移動相： ρΗ2·00·1Μリ ン酸緩衝液/メタノール（45/55)(V/V)、流速： 0.8mL/min、検出器： UV(254nm)、力 ラム温度： 40°C)による分析で保持時間が 14.2分である、光学活性なチアゾリジンジ オン誘導体。 請求項 1乃至 3に記載の光学活性化合物を有効成分として含有する医薬。 (RS) — 5— {4— [(6-Methoxy-1- 1-methyl 1 H benzimidazole 2-yl) methoxy] benzyl} -1, 3 thiazolidine 2, 4 dione monohydrochloride obtained by optical resolution CHIRALCEL OJ-RH (0.46 cm X 15 cm, mobile phase: ρΗ2.0 · 1Μ phosphate buffer / methanol (45/55) (V / V), flow rate: 0.8 mL / min, detector: UV (254 nm), force ram temperature: 40 ° C), an optically active thiazolidinedione derivative having a retention time of 14.2 minutes. A pharmaceutical comprising the optically active compound according to claim 1 as an active ingredient.
PCT/JP2007/053869 2006-03-02 2007-03-01 Optically active thiazolidinedione derivative WO2007100027A1 (en)

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US9925175B2 (en) 2007-09-26 2018-03-27 Deuterx, Llc Deuterium-enriched pioglitazone
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