WO1996035688A1 - Derives de 2,4-thiazolidinedione ou d'oxazolidinedione et agent hypoglycemique - Google Patents

Derives de 2,4-thiazolidinedione ou d'oxazolidinedione et agent hypoglycemique Download PDF

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Publication number
WO1996035688A1
WO1996035688A1 PCT/JP1996/000829 JP9600829W WO9635688A1 WO 1996035688 A1 WO1996035688 A1 WO 1996035688A1 JP 9600829 W JP9600829 W JP 9600829W WO 9635688 A1 WO9635688 A1 WO 9635688A1
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WO
WIPO (PCT)
Prior art keywords
thiazolidinedione
methyl
indolyl
phenyl
benzo
Prior art date
Application number
PCT/JP1996/000829
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English (en)
Japanese (ja)
Inventor
Yutaka Nomura
Seiichiro Masui
Shogo Sakuma
Original Assignee
Nippon Chemiphar Co., 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 Nippon Chemiphar Co., Ltd. filed Critical Nippon Chemiphar Co., Ltd.
Priority to AU51217/96A priority Critical patent/AU5121796A/en
Publication of WO1996035688A1 publication Critical patent/WO1996035688A1/fr

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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

Definitions

  • the present invention relates to novel 2,4-thiazolidinedione or oxazolidinedione derivatives and compounds having a hypoglycemic action.
  • an insulin preparation as an injection or a sulfonyl urine such as a biguanide such as metformin hydrochloride and tolutamide as an oral preparation have been used.
  • a biguanide such as metformin hydrochloride and tolutamide
  • insulin preparations are cumbersome to use with injections, while biguanides, which are orally administered, cause lactic acidosis, and sulfonylureas have the side effect of hypoglycemia, which is MM.
  • troglitazone (tro gli taz one: European Patent No.
  • Troglisunzone has a hypoglycemic effect and a triglyceride-lowering effect, improves impaired insulin receptor function, and also acts on glucose transporters and glucokinase, resulting in insulin dysfunction. It is said to improve.
  • the present inventors have conducted research on novel 2,4-thiazolidinedione derivatives and 2,4-oxazolidinedion derivatives having no benzyl group at the 5-position, and as a result, the following general formula (I) The present inventors have found that the compound represented by the formula has an excellent hypoglycemic effect and completed the present invention.
  • R 1 is a phenyl group which may have a substituent selected from alkyl, alkoxy, halogen, hydroxy, halogenoalkyl, halogenoalkoxy, nitro, amino, phenyl, phenyl, phenyl, thienyl, furyl, thiazolyl and pyridyl, naphthyl group, a cycloalkyl group or a heterocyclic ⁇
  • V is, Table eagle CH or CH 2
  • W is 0 or S
  • Y represents CH or N
  • Z is 0, S
  • S0 represents S0 2 or NR 2
  • R 2 represents H, alkyl group, Araruki Le group or Ashiru group
  • X is, 0, S, C0, CH 2, NR 3, NR 4 C0 or, It represents CONR 5, wherein, R 3, R 4, R 5 each independently represent H or an alkyl group, m, n an integer from 0 each independently 4 Table eagle and
  • R 1 is preferably alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl, and isopropyl, and halogen such as alkoxy, chlorine and fluorine having 1 to 6 carbon atoms such as methoxy and ethoxy. , Hydroxy, 2-chloroethyl, trifluoromethyl, etc.
  • 1-3 halogen-substituted carbon atoms 1-3 halogenoalkyl, 2-chloro ethoxy, etc., 1-3 halogen-substituted carbon atoms, 1-3 6, amino, phenyl, substituted phenyl, such as halogenoalkoxy, nitro, amino (NH 2 ), methylamino, ethylamino, dimethylamino, and getylamino
  • Substituents include alkyl, alkoxyl, hydroxy, halogen, etc.), phenyl, substituted phenyl (substituents are alkyl, alkoxyl, hydroxy, halogen, etc.), furyl, substituted furyl (substituents: alkyl, alkoxy, etc.) Sil, hydroxy, halogen, etc.), thiazolyl, substituted thiazolyl (substituent May have 1 to 3 substituents selected from alkyl, alkoxyl, hydroxy, halogen, etc., pyridyl, and substituted pyridyl (substituents such as alkyl, alkoxyl, hydroxy, halogen, etc.) Phenyl, naphthyl, cycloalkyl having 3 to 8 carbon atoms constituting ⁇ (for example, cyclohexyl, cyclopentyl), pyridyl, thiazolyl
  • V represents CH or CH 2
  • W represents 0 or S.
  • Y represents CH or N
  • Z represents 0, S, S0, S0 2 or NR 2.
  • R 2 represents H, an alkyl group, an aralkyl group, or an acyl group, and is preferably H or an alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, and isopropyl.
  • the complex represented by the following formula (II) represented by the general formula (I) is preferably an indole ring, a benzothiophene ring (including a 1-oxide or a 1,1-dioxide), benzofuran. ⁇ , a benzimidazole ring and a benzothiazole ring, more preferably an indole ⁇ and a benzothiophene ring.
  • X represents 0, S, C0, CH 2 , NR 3, NR 4 C0, CONR 5.
  • R 3 , FT and R 5 each independently represent H or an alkylyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl and isopropyl, and preferably X is 0, S, C 0, CH 2 It is.
  • n represents an integer of 0 to 4, preferably 0 or 1, and more preferably 0.
  • a double line consisting of a broken line and a solid line represents a single bond or a double bond, and is preferably a single bond.
  • the heterocyclic ring of the above formula (II) includes alkyl having 1 to 6 carbon atoms such as methyl, ethyl and propyl, and alkoxy having 1 to 6 carbon atoms such as methoxy and ethoxy, and halogen such as chlorine and fluorine. It may be replaced.
  • the compounds of the present invention may exist as pharmacologically acceptable salts, such as acid salts with acids such as hydrochloric acid and acetic acid, and salts such as alkali metals (sodium and potassium). And a basic salt with a base.
  • the compound represented by the general formula (I) of the present invention can be obtained, for example, by the production method shown below.
  • ⁇ represents a leaving group such as chlorine, bromine, iodine, mesyloxy, tosyloxy, and R 1 , R 2 , and m each have the same meaning as described above.
  • the compound (e) is obtained by reacting the alcohol derivative (d) with thionyl chloride, hydrogen chloride, mesylate chloride, etc., and the tert-butyllithium, n-butyllithium, etc.
  • the compound (c) of the present invention can be obtained by reacting 2,4-thiazolidinedione in the presence of alkyllithium. (Synthesis method 3)
  • B represents a halogen such as chlorine, bromine or iodine, and R 1 and m have the same meaning as described above.
  • the above-mentioned compound (c) of the present invention can be obtained by reacting the 5-hydroxyindole derivative (f) with the halide (h) in the presence of a base such as sodium hydride or carbon dioxide.
  • KKA y mice a model animal of non-insulin-dependent diabetes.
  • KKA y mice (9-11 weeks old) were divided into homogeneous groups according to plasma glucose concentration, and then suspended in a 1% methylcellulose solution.
  • the compound of the present invention (compound synthesized in each Example described later) and bioglitazone (Comparative compound) was orally administered once a day for 3 days.
  • a 1% methylcellulose solution was also orally administered to the control mouth (drug non-administration group). Blood was collected 18 hours after the last administration, and the plasma glucose concentration was measured.
  • the measurement was performed by an automatic analyzer (Model 705, manufactured by Hitachi, Ltd.) by an enzyme method using Autocera GLU (Daiichi Pure Chemicals Co., Ltd.).
  • the plasma glucose concentration of each compound administration group was determined, and the ratio (percent) of the value to the control was calculated. The results are shown in Table 1.
  • Example 9 30 60 Table 1 It was revealed that the compound of the present invention significantly reduced the blood glucose level as compared with the control and had an excellent hypoglycemic effect.
  • the compound of the present invention has an excellent hypoglycemic effect and is useful as a therapeutic agent for diabetes.
  • Oral dosage forms include tablets, capsules, powders, granules and syrups.
  • Parenteral administration methods include mucosal administration such as eye drops, inhalants, sprays, suppositories, and ointments.
  • intravascular administration of injections and the like are produced using ordinary excipients, disintegrants, binders, lubricants, pigments, diluents and the like.
  • Excipients include glucose and lactose; disintegrating agents include starch and carboxymethylcellulose calcium; lubricating agents include magnesium stearate and talc; binders include hydroxypropylcellulose , Gelatin, polyvinylpyrrolidone, etc. are used.
  • injections for parenteral administration they are prepared using distilled water for injection, physiological saline, and Ringer's solution.
  • the dose of the compound of the present invention is usually about 0.1 mg to 200 mg per day for injection and about 111 to 200 mg per day for parenteral administration in adults. It can be increased or decreased depending on the race, symptoms, etc.
  • 6-Hydroxy-2-benzo [b] thiophencarbaldehyde (2.10 g, 1.1.8 mmol) is dissolved in 9 mL of dry N, N-dimethylformamide and hydrogenated under ice-cooling for 60%. Sodium (570 mg, 14.3 mmol) was added. Twenty minutes later, benzyl bromide (1.7 mL, 14.3 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 2.73 g of the title compound as pale yellow crystals (yield 86%).
  • 6-benzyloxy 2-benzo [b] thiophenecarbaldehyde (2.68 g, 10 mmol) and 90% 2,4-thiazolidinedione (1.30 g, 10 mmol) are suspended in 10 mL of ethanol.
  • the mixture was made cloudy, 0.8 ml of piperidine was added, and the mixture was heated under reflux overnight.
  • the reaction mixture was added to a 1N aqueous hydrochloric acid solution, and the precipitated crystals were collected by filtration.
  • the crystals were redissolved in tetrahydrofuran, dried over anhydrous sodium sulfate, and the solvent was distilled off to give 3.7 O g of the title compound quantitatively as pale yellow crystals.
  • Example 3 5-[(6-Benzyloxy-2-benzo [b] thenyl) methylene] obtained in Example 3 was converted to 1,2-dimethylimidazolidine with 1,2,4-thiazolidinedione (1.0 g, 2.7 mmol). After suspending in 35 mL of 2-one, the reaction temperature is set to 80 ° C, sodium borohydride (615 mg, 16.2 mmol) is added over 3 hours, and further 2 hours under the same conditions Reacted. After confirming the completion of the reaction, 2N aqueous hydrochloric acid It was added to the solution and extracted with ethyl acetate.
  • Example 6 5-[[5- (4-Trifluoromethyl) benzyloxy-21-indolyl] methylene] obtained in Example 6 was treated with 1,2,4-thiazolidinedione in the same manner as in Example 2 to give the title compound. Obtained.
  • Example 8 5-[[6- (4-Trifluoromethyl) benzyloxy-l-l-benzo [b] thenyl] methylene ⁇ -l, 4-l-thiazolidinedione obtained in Example 8 was treated in the same manner as in Example 12. This gave the title compound.
  • Example 10 The 5-[(5-benzyloxy-2-benzo [b] chenyl) methylene] -12,4-thiazolidinedione obtained in Example 10 was treated in the same manner as in Example 4 to obtain the title compound.
  • Example 12 5-[[6- (4-Trifluoromethyl) benzyloxy-2-indolyl] methylene] -12,4-thiazolidinedione obtained in Example 12 was treated in the same manner as in Example 2 to obtain the title compound.
  • Example 12 5-[[6- (4-Trifluoromethyl) benzyloxy-2-indolyl] methylene] -12,4-thiazolidinedione obtained in Example 12 was treated in the same manner as in Example 2 to obtain the title compound.
  • the 2,4-thiazolidinedione derivative or 2,4-oxazolidinedione derivative of the present invention has an excellent hypoglycemic effect.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne de nouveaux dérivés de 2,4-thiazolidinedione ou d'oxazolidinedione représentés par la formule générale (I) et présentant une grande efficacité en tant qu'agent hypoglycémique. Dans la formule (I), R1 représente phényle, naphtyle, cycloalkyle ou un hétérocycle comportant éventuellement des substituants sélectionnés parmi alkyle, alcoxy, halogéno, hydroxy, halogénoalkyle, halogénoalcoxy, nitro, amino, phényle, thiényle, furyle, thiazolyle et pyridyle; V représente CH ou CH¿2?; W représente O ou S; Y représente CH ou N; Z représente O, S, SO, SO2 ou NR?2 (R2¿ représentant H, alkyle, aralkyle ou acyle); X représente O, S, CO, CH¿2?, NR?3, NR4¿CO ou CONR?5 (R3, R4 et R5¿ représentant indépendamment l'un de l'autre H ou alkyle); m et n représentent indépendamment l'un de l'autre un entier de 0 à 4; et le symbole - - - représente une liaison simple ou double.
PCT/JP1996/000829 1995-05-08 1996-03-28 Derives de 2,4-thiazolidinedione ou d'oxazolidinedione et agent hypoglycemique WO1996035688A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU51217/96A AU5121796A (en) 1995-05-08 1996-03-28 2,4-thiazolidinedione or oxazolidinedione derivatives and hy poglycemic agent

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP7/134798 1995-05-08
JP13479895 1995-05-08
JP30356295 1995-10-27
JP7/303562 1995-10-27

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WO1996035688A1 true WO1996035688A1 (fr) 1996-11-14

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998057971A1 (fr) * 1995-02-27 1998-12-23 Senga Pharmaceutical Laboratory Inc. Derives thiazolidinedione, procede de production, et compositions pharmaceutiques en contenant
WO2005058842A1 (fr) 2003-12-15 2005-06-30 Laboratoire Theramex Derives de 1-n-phenyl-amino-1h-imidazole et compositions pharmaceutiques les contenant
US7119104B2 (en) 2001-10-12 2006-10-10 Nippon Chemiphar, Co., Ltd. Activator of peroxisome proliferator-activated receptor delta
US7648999B2 (en) 2001-08-10 2010-01-19 Nippon Chemiphar Co., Ltd. Activator for peroxisome proliferator-activated receptor δ
US8404726B2 (en) 2006-04-18 2013-03-26 Nippon Chemiphar Co. Ltd. Activating agent for peroxisome proliferator activated receptor δ
US8648208B2 (en) 2008-04-15 2014-02-11 Nippon Chemiphar Co. Ltd. Activating agent for peroxisome proliferator activated receptor

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0193256A1 (fr) * 1985-01-19 1986-09-03 Takeda Chemical Industries, Ltd. Dérivés de thiazolidinediones, leur préparation et utilisation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0193256A1 (fr) * 1985-01-19 1986-09-03 Takeda Chemical Industries, Ltd. Dérivés de thiazolidinediones, leur préparation et utilisation

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998057971A1 (fr) * 1995-02-27 1998-12-23 Senga Pharmaceutical Laboratory Inc. Derives thiazolidinedione, procede de production, et compositions pharmaceutiques en contenant
US7648999B2 (en) 2001-08-10 2010-01-19 Nippon Chemiphar Co., Ltd. Activator for peroxisome proliferator-activated receptor δ
US7652045B2 (en) 2001-08-10 2010-01-26 Nippon Chemiphar, Co., Ltd. Activator of peroxisome proliferator-activated receptor δ
US7119104B2 (en) 2001-10-12 2006-10-10 Nippon Chemiphar, Co., Ltd. Activator of peroxisome proliferator-activated receptor delta
US7402597B2 (en) 2001-10-12 2008-07-22 Nippon Chemiphar Co., Ltd Activator of peroxisome proliferator-activated receptor δ
WO2005058842A1 (fr) 2003-12-15 2005-06-30 Laboratoire Theramex Derives de 1-n-phenyl-amino-1h-imidazole et compositions pharmaceutiques les contenant
US8404726B2 (en) 2006-04-18 2013-03-26 Nippon Chemiphar Co. Ltd. Activating agent for peroxisome proliferator activated receptor δ
US8648208B2 (en) 2008-04-15 2014-02-11 Nippon Chemiphar Co. Ltd. Activating agent for peroxisome proliferator activated receptor

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