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WO1986006069A1 - Derives de thiazolidinedione, leur procede de preparation et composition medicinale les contenant - Google Patents

Derives de thiazolidinedione, leur procede de preparation et composition medicinale les contenant Download PDF

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Publication number
WO1986006069A1
WO1986006069A1 PCT/JP1985/000179 JP8500179W WO8606069A1 WO 1986006069 A1 WO1986006069 A1 WO 1986006069A1 JP 8500179 W JP8500179 W JP 8500179W WO 8606069 A1 WO8606069 A1 WO 8606069A1
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Prior art keywords
hydrogen
compound
general formula
salt
substituted
Prior art date
Application number
PCT/JP1985/000179
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English (en)
Japanese (ja)
Inventor
Kanji Meguro
Takeshi Fujita
Original Assignee
Takeda Chemical Industries, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to PCT/JP1985/000179 priority Critical patent/WO1986006069A1/fr
Priority to AR30172685A priority patent/AR240673A1/es
Priority to CN85107870.2A priority patent/CN1003445B/zh
Priority to KR1019850007158A priority patent/KR920002131B1/ko
Priority to JP60216050A priority patent/JPS6185372A/ja
Priority to DK444685A priority patent/DK444685A/da
Priority to FI853796A priority patent/FI81097C/fi
Priority to AU48176/85A priority patent/AU583537B2/en
Priority to NO853902A priority patent/NO157896C/no
Priority to ES547507A priority patent/ES8706150A1/es
Priority to PT81235A priority patent/PT81235B/pt
Priority to CA000492072A priority patent/CA1263655A/fr
Priority to GR852389A priority patent/GR852389B/el
Priority to DE8585307084T priority patent/DE3577092D1/de
Priority to US06/783,628 priority patent/US4725610A/en
Priority to AT85307084T priority patent/ATE51869T1/de
Priority to EP85307084A priority patent/EP0177353B1/fr
Priority to ES554559A priority patent/ES8801256A1/es
Priority to SU864028176A priority patent/SU1436876A3/ru
Publication of WO1986006069A1 publication Critical patent/WO1986006069A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/34—Oxygen atoms
    • 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
    • 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
    • C07D417/14—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 three or more hetero rings

Definitions

  • the present invention relates to a novel thiazolidinedione conductor having a blood glucose and blood lipid lowering action, a method for producing the same, and a pharmaceutical composition comprising the same.
  • the present invention is a.
  • R 1 represents hydrogen or a hydrocarbon residue or a heterocyclic residue which may be substituted
  • R 2 represents a lower alkyl group which may be substituted with hydrogen or a hydroxyl group
  • X represents oxygen.
  • Z represents methylene hydroxide or carbonyl
  • m represents 0 or 1
  • n represents an integer of 1-3.
  • a pharmaceutical composition comprising a compound represented by the general formula (I) or a salt thereof,
  • a general formula comprising reacting a compound represented by the formula (wherein each symbol is as defined above) or a salt thereof and, if necessary, reducing the product.
  • the hydrocarbon residue represented by R 1 is an alicyclic hydrocarbon residue, an alicyclic hydrocarbon residue, an alicyclic-aliphatic hydrocarbon residue.
  • the aromatic hydrocarbon residue include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, and neopentyl.
  • T-pentyl hexyl, isohexyl, heptyl, octyl and the like, and saturated aliphatic hydrocarbon residues having 1 to 8 carbon atoms, such as ethenyl, 1-propyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,
  • Examples of the group include a saturated alicyclic hydrocarbon residue having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and 1-cyclopentenyl, 2-cyclopentenyl, and 3-cyclopentyl.
  • the unsaturated alicyclic hydrocarbon residue is an alicyclic monoaliphatic hydrocarbon residue, and the alicyclic hydrocarbon residue and the aliphatic hydrocarbon residue are preferably those having a carbon number of 4: To 9 such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopropylmethyl Octenylpentylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylp ⁇ -pill, cycl
  • aromatic-aromatic hydrocarbon residues examples include benzyl, phenyl, 1-phenylethyl, phenylpropyl, 2-phenylpropyl, and 1-phenylpropyl.
  • C1-C9 phenylalkyl such as phenylpropyl, a-naphthylmethyl, ⁇ -naphthylethyl, 3-naphthylmethyl, —naphthylethyl, etc.
  • Naphthylalkyl having 11 to 13 carbon atoms is considered as an aromatic hydrocarbon residue. Examples include phenyl and naphthyl (na-naphthyl, / 3-naphthyl).
  • the heterocyclic residue represented by R 1 is a 5- or 6-membered ring containing 1 or 3 selected from N, 0, and S in addition to carbon as a ring-constituting atom and is a group bonded via carbon. Specific examples include chenyl (2-phenyl. 3-phenyl) ..
  • furyl (2-furyl, 3-furyl
  • pyridyl (2-pyridyl, 3-pyridyl, 4-— Heteroaromatic groups such as pyridyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl) and oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl); Dinyl (2-piridinyl, 3-piridinyl, 4-piridinyl), pyrrolidinyl (2-pyrrolidinyl, 3-pyrrolidinyl), morpholinyl (2-perfluorolinyl, 3 — Examples include saturated heterocyclic groups such as morpholinyl) and tetrahydrofuryl (2-tetrahydrofuryl, 3-tetrahydrofuryl).
  • the hydrocarbon residue or heterocyclic residue represented by R 1 may have a substituent at any position.
  • R 1 contains an alicyclic group or when R 1 is a saturated heterocyclic group, a lower alkyl group having 1 to 3 carbon atoms (eg, methyl, ethyl, propyl) , Isopropyl).
  • R 1 contains an aromatic hydrocarbon group or R 1 is a heteroaromatic group, it has 1 to 4 identical or different substituents on the ring (excluding the hetero atom).
  • substituents examples include halogen (fluorine, chlorine, iodine), hydroxy, cyano-, trifluoromethyl, and lower alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.).
  • lower alkyl eg, having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl
  • lower alkoxycarbonyl eg, methoxycarbonyl, ethoxyquincarbonyl, propoxycarbonyl, etc.
  • lower alkylthio eg, those having 1 to 3 carbon atoms such as methylthio, ethylthio, propylthio, and isopropylthio.
  • Examples of the lower alkyl group represented by R 2 include those having 1 to 5 carbon atoms, such as methyl, ethyl, ⁇ -pill, isopapyl, butyl: isobutyl, sec-butyl, t-butyl, and pentyl. However, those having 1 to 4 carbon atoms are preferred, and those having 1 to 3 carbon atoms are most preferred.
  • the alkyl group may have a hydroxyl group at an arbitrary position, but is preferably in the ⁇ -position.
  • the halogen represented by Y in the general formula (II) includes chlorine, bromine and iodine.
  • the compound represented by the general formula (I) Since the compound represented by the general formula (I) has an acidic nitrogen in the thiazolidin ring, it forms a salt with a base.
  • a base salt examples include metal salts such as sodium salt, potassium salt, aluminum salt, magnesium salt and calcium salt.
  • the compound in which II is 1 or a salt thereof, that is, a compound represented by the general formula (I-11) or a salt thereof [hereinafter, both are collectively referred to as a compound (I11)] is represented by the general formula ( ⁇ ) Is reacted with a compound represented by the general formula ( ⁇ ⁇ ⁇ ) or a salt thereof (hereinafter, these are collectively referred to as compound ( ⁇ )), and if desired, reduced to obtain a product.
  • Examples of such a solvent include dimethylformamide, dimethylsulfoxide, sulfolane, tetrahydrofuran, and dimethoxetane.
  • Examples of the base include sodium hydride, lithium hydride, sodium amide, and sodium.
  • Alkoxides eg, sodium methoxide, sodium ethoxide
  • low-temperature alkoxides eg, low-temperature butyl oxide
  • BAD ORIGINAU It is preferred to react the base to form a dianion, and then add 1 mole of ( ⁇ ) for the reaction.
  • This condensation reaction is usually carried out at 0 (: up to 120, preferably at 20 ° C. to 100), and the reaction time is usually 0.5 to 5 hours.
  • the compound represented by the general formula ( ⁇ 1-2) or a salt thereof [hereinafter collectively referred to as compound (I-12)] is represented by the general formula (I-13 :) by reduction
  • the compound or a salt thereof [hereinafter, these are collectively referred to as compound (I-13)] can be obtained.
  • This reduction reaction is a mixed solution of alkanol (eg, methanol, ethanol, 'propanol, 2-propanol, 2-methoxyethanol, etc.) and, if necessary, ⁇ , ⁇ -dimethylformamide. It is easier to use sodium borohydride in the medium.
  • the amount of sodium borohydride used is 0.3 to 2 mol per 1 mol of the compound (1-2).
  • the reaction temperature is —10 ° (: up to 100, reaction time: 0.5 to 5 hours).
  • Compound (I-13) This can be oxidized to give Compound (I-2).
  • This oxidation reaction is performed using activated dimethyl sulfoxide (DMS 0) and an activated DMS 0 oxidation using an electrophilic reagent (eg, acetic anhydride, dicyclohexyl carpoimide (DCC), phosphorus pentoxide, etc.) or chromium oxide. Often proceeds by acid oxidation.
  • an electrophilic reagent eg, acetic anhydride, dicyclohexyl carpoimide (DCC), phosphorus pentoxide, etc.
  • Activated DMS 0 oxidation can be performed by using an electrophilic test such as acetic anhydride, DCC, and phosphorus pentoxide in a mixed solvent containing benzene, pyridine, ether, etc., if necessary. It progresses by adding drugs.
  • the amount of DMS 0 used is usually in a large excess, and the reaction temperature varies depending on the electrophilic reagent used, but is 10 ° C to 60 ° C, preferably 0 to 30 ° C, and the reaction time is 1 ⁇ 30 hours.
  • Couperic acid oxidation can be carried out in an acetate solvent, Joues reagent (chromium oxide monosulfate-aceton), anhydrous chromic acid in acetic acid, chromic anhydride in pyridine, or chromium oxide-pyridine prepared in advance.
  • the process proceeds using dichloromethane as the solvent.
  • the amount of chromium (VI) to be used is generally 0.5 to 2 equivalents relative to compound (I-3).
  • the reaction temperature is ⁇ 10 ° C. to 60 t; preferably 0 to 30 ° C., and the reaction time is 0.5 to 50 hours.
  • a compound wherein L and ⁇ ⁇ ⁇ are both hydrogen atoms or a salt thereof that is, a compound represented by the general formula (I-14) or a salt thereof (hereinafter collectively referred to as compound [I — 4)) can be produced by hydrolyzing a compound represented by the general formula (jy) or a salt thereof (hereinafter collectively referred to as a compound (DO)).
  • a compound represented by the general formula (jy) or a salt thereof hereinafter collectively referred to as a compound (DO)
  • the reaction is carried out in a suitable solvent in the presence of water and a mineral acid.
  • Solvents are usually alcohols (eg, methanol, ethanol, propanol, 2-propyl ⁇ -phenol, butanol).
  • Mineral acids include hydrochloric acid, hydrobromic acid, sulfuric acid, etc.
  • the amount of water to be added is usually a large excess with respect to 1 mol of the compound (I-14).
  • This reaction is usually carried out with heating or heating, and the reaction temperature is usually 60 to 150 ° C.
  • the heating time is usually between several B and several tens of hours.
  • the compound represented by the general formula (I-15) or a salt thereof is a compound represented by the general formula (V) and a compound represented by the formula (VI) or The salt [hereinafter collectively referred to as Compound (VI) And the above].
  • This reaction is usually performed in a solvent in the presence of a suitable base.
  • Examples of such a solvent-based system include alkanols (eg, methanol, ethanol, propanol, 2-propanol, butanol, isobutanol, 2-methoxyethanol, etc.), Solvents such as dimethylformamide, dimethylsulfoxide, sulfolane, acetonitrile, dioxane, dimethoxetane, and oxalic acid; , Diisopres-pyramine, triethylamine, etc.), sodium alkoxide (eg, sodium methoxide, sodium ethoxide), carbonated sodium, sodium carbonate, hydrogenated
  • bases such as sodium, sodium acetate, and sodium phosphate is used.
  • Compound (VI) is generally used in an amount of 1 to 5 mol, preferably 1.5 to 3.0 mol, per 1 mol of compound of general formula (V).
  • the amount of the base to be used is 0.1 (U to 3.0 mol, preferably: 0.1 to 1.0 mol) per 1 mol of compound CVI.
  • the condensation reaction is usually performed at 0 ° C to 1 ⁇ 0V.
  • the reaction is carried out at 20 ° (: 100 ° C.), and the reaction time is usually 0.5 to 50 hours.
  • a compound or a salt thereof in which R 2 in the general formula (I) is an alkyl group having a hydroxyl group at the ⁇ -position can also be produced, for example, by the following method. '
  • R 3 is hydrogen or a lower alkyl group (eg, methyl, ethyl, propyl, isopopentyl, butyl, isobutyl, etc.), and other symbols are as defined above.
  • compound (I_6) the compound (I-6) or a salt thereof in which R 2 is lower alkyl as represented by CH 2 —R 3 [hereinafter, these are collectively referred to as compound (I_6)] can be converted into a compound represented by the general formula ( VH) or a salt thereof [hereinafter also collectively referred to as compound (71)] and then hydrolyzing it to give the desired compound represented by the general formula (I-7) or a salt thereof [ Hereinafter, these will be collectively referred to as compound (I-17)].
  • halogenation of (VE) can be carried out with N-bromosuccinic acid imid or N-chlorosuccinic acid imid, preferably in the presence of a radical initiator such as benzoyl peroxide, ⁇ , ⁇ '-diazobisisobutyronitrile. Can be performed. This reaction proceeds easily by refluxing in a solvent such as carbon tetrachloride or chloroform, and the amount of the radical initiator used is usually 0.01 to 0.2 mol per 1 mol of the compound (I-6).
  • the produced —halogen [compound (VI)] may be isolated and purified, if necessary, or may be immediately hydrolyzed without isolation to obtain an ⁇ -hydroxy form [compound (I-17)].
  • the hydrolysis reaction advantageously proceeds by using a mineral acid in a suitable solvent.
  • Dioxane, tetrahydrofuran, dimethoxetane and the like are used as solvents, and hydrochloric acid and sulfuric acid are used as mineral acids.
  • the reaction temperature is 20 ° C to 100 ° C, and the reaction time is 0.5 to 1 ° C. 0 hours.
  • the thiazolidinedione derivative (I) and its salt thus obtained can be isolated and purified by a known separation and purification means such as concentration-concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. be able to.
  • the compound (I) of the present invention and a salt thereof exhibit excellent blood glucose and blood lipid lowering effects on mammals (eg, mice, rat dogs, cats, monkeys, horses, and humans), and have acute, Both acute and acute toxicity are low. Therefore, the thiazolidinedione derivative (I) and its salts are useful for treating hyperlipidemia, diabetes and their complications in humans.
  • the method of administration is usually oral, for example, as tablets, capsules, powders, granules, etc. In some cases, parenteral administration such as injections, suppositories, or pellets is also possible.
  • the starting compound (V) of the present invention is produced, for example, by the following method.
  • reaction from compound 01) to compound (X) is carried out by condensing compound (1) and compound (IX), for example, in the presence of sodium hydride.
  • This reaction can be carried out in a solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dimethoxetane, etc. at -10 (: up to 30).
  • the reaction is carried out by ripening with a Raney Nigel alloy in a formic acid aqueous solution.
  • reaction of condensing compound (II) with compound (S) to give (V-2) usually involves
  • Examples of the lower alkyl group represented by R + in the above general formulas (XVI) and (XIX) include those having 1 to 4 carbon atoms such as methyl, ethyl, propyl and butyl.
  • reaction from compound (VH) to compound (XYI) is carried out by condensing compound ( ⁇ ) and compound (XV), for example, in the presence of sodium hydride.
  • This reaction can be carried out in a solvent such as dimethylformamide or tetrahydrofuran at 110 ° C at 30 ° C.
  • the reaction from compound (XVI) to compound (XVII) can be carried out by catalytic reduction of compound (XVI) using, for example, palladium carbon as a catalyst, or by using zinc or iron and acetic acid in a conventional manner. This is easily carried out by reduction.
  • Compound (X) may be isolated as a pure product, or may be subjected to the next step reaction without isolation and purification.
  • compound (XVI) is diazotized in the presence of hydrohalic acid (HY), and acrylic acid or its ester (X) is further converted to a steel catalyst (eg, Reaction in the presence of first net oxide, cupric oxide, first net chloride, second steel chloride, cuprous bromide, cupric bromide, etc.). It is performed by a so-called Meerwein arylat iori reaction.
  • Compound (XDO can be purified by chromatography or the like, but can also be subjected to the reaction in the next step without isolation and purification.
  • the compound (1Y-1) can be produced by reacting a compound (XDO followed by thiourea. "
  • This reaction is usually carried out with alcohols (eg, methanol, ethanol,
  • reaction temperature is usually 20 to 180 ° C., preferably 60 ° C.-1 ⁇ 0.
  • the amount of thiourea to be used is 1-2 mol per 1 mol of compound (XIX).
  • hydrogen halide which does not progress is produced as a by-product, but the reaction may be carried out in the presence of sodium acetate, acetic acid steam or the like in order to capture this.
  • sodium acetate, acetic acid steam or the like are generally used in an amount of 1 to 1.5 mol per 1 mol of the compound (XIX).
  • the compound (XVI) having a 'hydroxy-substituted phenyl group as R 1 is produced by condensing a compound (X') having a benzyloxy-substituted phenyl group as R 1 with the compound (XV) (XVI )
  • XVI benzyloxy-substituted phenyl group
  • Compound (XVII) can also be synthesized by the following method
  • reaction of condensing compound ( ⁇ -2) with compound (XX) to give compound (Xa) is usually carried out in a base such as dimethylformamide, tetrahydrofuran, acetate, methylethyl ketone (eg, carbonate Natoriumu, can be carried out in the presence of such carbonate force Riumu) 'Te 0 ⁇ 1 5 0 P C.
  • XXI is then hydrolyzed to give compound (XVI).
  • the hydrolysis reaction can be carried out with a mineral acid (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, etc.) or a hydroxide (eg, sodium hydroxide, potassium hydroxide, etc.). It is desirable to use an alkali oxide in a solvent such as methanol, ethanol, propanol, 2-propanol, or 2-methoxypropanol, and to carry out the reaction under ripening reflux.
  • a base such as dimethylformamide, tetra
  • the condensation reaction of the compound (II-13) with the compound (XX) can be carried out in the same manner as in the reaction of the compound ( ⁇ -2) with the compound (XX), and then the obtained compound (XXI) Is reduced with sodium borohydride in methanol or ⁇ -ethanol to give compound (XXH), which is then hydrolyzed in the same manner as in the above (XXI) to give compound (XXR).
  • Compound (XXiy) can be led to (] y-2) via (XIX-1) in the same manner as in the method for producing (IV- ⁇ ) from (XVII). The best form to carry out ''
  • Example 1 Example 1
  • Example 6 5 ⁇ ! : 4 -— [2- ( ⁇ -methyl-2-phenyl-14-year-old xazolyl) -2-oxotoquine] benzylidene ⁇ -1,2,4-thiazolidinedione 5- ⁇ 4-1-1 [2-hydroxy-1-2- (5 —Methyl-2-phenylphenyloxazolyl) ethoxy] benzylidene ⁇ —2,4-thiazolidinedione (the same compound as in Example 60) was obtained. mp 2 52-2 5 3.5. Yield '98. 4%.
  • cuprous oxide powder (1 g) was added little by little. Stir until the generation of nitrogen gas is over, then mix The residue was basified with aqueous ammonia and extracted with ethyl acetate. The ethyl ethyl layer was washed with water and dried (MgS C), and then the solvent was distilled off. The solvent was distilled off, and the solvent was distilled off. A crude oil of methyl ⁇ propionate ⁇ (12.6 g, 88.7%) was obtained.
  • Wave test-mixed with powdered feed (CE-2, CLEA Japan) 0.001% and 0.005%, and given to KKA7 mice (male, 8-10 weeks old, 5 mice per group) for 4 days was. Water was provided ad libitum during this time. Blood is collected from the orbital vein, blood glucose is determined by the glucose oxidase method, and plasma triglyceride (TG) is quantified by enzymatic method using the glycerol produced by the enzymatic method using a Cleantech TG-S kit. Each was measured. Each value was calculated using the following equation. Table 13 shows the results. Data for known compounds with similar structures are also shown for comparison.
  • the compound of the present invention showed a statistically significant blood glucose or TG lowering effect, whereas the control compound did not show a significant effect at the dose of this experiment.
  • the total amount of (1), (2) and (3) and 3 Og of (4) are kneaded with water, dried in vacuo and granulated. 14 g of (4) and 1 g of (5) are mixed with the granulated powder and made into tablets with a tableting machine, whereby 100 tablets containing (1) 1 Omg per break are obtained. Produce.
  • the total amount of (1), (2) and (3) and 3 Og of (4) are kneaded with water, dried in vacuum and granulated. 14 g of (4) and 1 g of (5) are mixed with this abalone and made into tablets with a tableting machine, whereby tablets containing (1) 30 mg per tablet have a value of 1000. Is manufactured.
  • novel thiazolidinedione derivative (I) and a salt thereof according to the present invention have excellent blood sugar and blood lipid lowering effects, and are useful as pharmaceuticals such as therapeutic agents for diabetes and hyperlipidemia.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)

Abstract

Des dérivés de thiazolidinedione sont représentés par la formule générale (I), dans laquelle R1 représente H ou un résidu hétérocyclique ou hydrocarbone éventuellement substitué, R2 représente H ou un alcoyle éventuellement substitué par hydroxyle, X représente O ou S, Z représente du méthylène ou du carbonyle hydroxylés, m est égal à 0 ou 1, n est égal à un nombre entier compris entre 1 et 3, L et M représentent chacun H ou une liaison lorsqu'ils sont pris ensemble. Ces dérivés et leurs sels représentent une façon novatrice et efficace de réduire le taux de sucre et de lipides dans le sang de mammifères, et sont donc utiles comme agents thérapeutiques du diabète et de l'hyperlipémie.
PCT/JP1985/000179 1984-10-03 1985-04-09 Derives de thiazolidinedione, leur procede de preparation et composition medicinale les contenant WO1986006069A1 (fr)

Priority Applications (19)

Application Number Priority Date Filing Date Title
PCT/JP1985/000179 WO1986006069A1 (fr) 1985-04-09 1985-04-09 Derives de thiazolidinedione, leur procede de preparation et composition medicinale les contenant
AR30172685A AR240673A1 (es) 1984-10-03 1985-09-26 Procedimiento para preparar derivados de tiazolidin-2,4-diona y sus sales de acidos farmaceuticamente aceptables
CN85107870.2A CN1003445B (zh) 1984-10-03 1985-09-26 噻唑烷二酮衍生物，其制备方法和用途
KR1019850007158A KR920002131B1 (ko) 1984-10-03 1985-09-27 타아졸리딘디온 유도체의 제조방법
JP60216050A JPS6185372A (ja) 1984-10-03 1985-09-27 チアゾリジンジオン誘導体、その製造法およびそれを含んでなる糖尿病または高脂血症治療剤
DK444685A DK444685A (da) 1984-10-03 1985-10-01 Tiazolidindionderivater, farmaceutiske praeparater indeholdende dem ogfremgangsmaader til fremstilling deraf
FI853796A FI81097C (fi) 1984-10-03 1985-10-01 Foerfarande foer framstaellning av nya terapeutiskt verksamma tiazolidindionderivat.
AU48176/85A AU583537B2 (en) 1984-10-03 1985-10-01 Thiazolidinedione derivatives, their production and use
NO853902A NO157896C (no) 1984-10-03 1985-10-02 Analogifremgangsmaate for fremstilling av terapeutisk virksomme tiazolidindion-derivater.
ES547507A ES8706150A1 (es) 1984-10-03 1985-10-02 Un procedimiento para producir un derivado de tiazolidina- diona
PT81235A PT81235B (pt) 1984-10-03 1985-10-02 Processo para a preparacao de derivados de tiazolidinadiona e de composicoes farmaceuticas que os contem
CA000492072A CA1263655A (fr) 1984-10-03 1985-10-02 Derives de thiazolidinedione; preparation et utilisation
GR852389A GR852389B (fr) 1984-10-03 1985-10-02
DE8585307084T DE3577092D1 (de) 1984-10-03 1985-10-03 Thiazolidindionderivate, ihre herstellung und anwendung.
US06/783,628 US4725610A (en) 1984-10-03 1985-10-03 Thiazolidinedione derivatives, their production and use
AT85307084T ATE51869T1 (de) 1984-10-03 1985-10-03 Thiazolidindionderivate, ihre herstellung und anwendung.
EP85307084A EP0177353B1 (fr) 1984-10-03 1985-10-03 Dérivés de thiazolidinedione, leur préparation et leur utilisation
ES554559A ES8801256A1 (es) 1984-10-03 1986-04-30 Un procedimiento para producir derivados de tiazolidindiona
SU864028176A SU1436876A3 (ru) 1985-04-09 1986-09-29 Способ получени производных тиазолидиндиона

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP1985/000179 WO1986006069A1 (fr) 1985-04-09 1985-04-09 Derives de thiazolidinedione, leur procede de preparation et composition medicinale les contenant

Publications (1)

Publication Number Publication Date
WO1986006069A1 true WO1986006069A1 (fr) 1986-10-23

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1985/000179 WO1986006069A1 (fr) 1984-10-03 1985-04-09 Derives de thiazolidinedione, leur procede de preparation et composition medicinale les contenant

Country Status (3)

Country Link
AR (1) AR240673A1 (fr)
SU (1) SU1436876A3 (fr)
WO (1) WO1986006069A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW245716B (fr) * 1992-12-28 1995-04-21 Takeda Pharm Industry Co
SK14452003A3 (sk) * 2001-04-26 2004-04-06 Liva, A. S. Spôsob výroby pioglitazonu ako antidiabetika

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3897558A (en) * 1973-08-29 1975-07-29 Roussel Uclaf Hypolipemiant and vasodilatatory methods of use
JPS58118577A (ja) * 1982-01-07 1983-07-14 Takeda Chem Ind Ltd チアゾリジン誘導体
JPS5948471A (ja) * 1982-09-10 1984-03-19 Takeda Chem Ind Ltd チアゾリジン誘導体

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3897558A (en) * 1973-08-29 1975-07-29 Roussel Uclaf Hypolipemiant and vasodilatatory methods of use
JPS58118577A (ja) * 1982-01-07 1983-07-14 Takeda Chem Ind Ltd チアゾリジン誘導体
JPS5948471A (ja) * 1982-09-10 1984-03-19 Takeda Chem Ind Ltd チアゾリジン誘導体

Also Published As

Publication number Publication date
SU1436876A3 (ru) 1988-11-07
AR240673A1 (es) 1990-08-31

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