WO1985004171A1 - Derives de thiazolidinedione, leur procede de preparation et compositions medicinales les contenant - Google Patents

Derives de thiazolidinedione, leur procede de preparation et compositions medicinales les contenant Download PDF

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Publication number
WO1985004171A1
WO1985004171A1 PCT/JP1984/000445 JP8400445W WO8504171A1 WO 1985004171 A1 WO1985004171 A1 WO 1985004171A1 JP 8400445 W JP8400445 W JP 8400445W WO 8504171 A1 WO8504171 A1 WO 8504171A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
thiazolidinedione
acid
ethoxy
hydrogen
Prior art date
Application number
PCT/JP1984/000445
Other languages
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 US06/711,536 priority Critical patent/US4582839A/en
Priority to EP85301895A priority patent/EP0155845A1/fr
Priority to CA000476976A priority patent/CA1263961A/fr
Publication of WO1985004171A1 publication Critical patent/WO1985004171A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—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
    • 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
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • 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

Definitions

  • the present invention relates to a novel thiazolidinedione derivative which has an excellent blood glucose and blood lipid lowering effect, a process for producing the same, and a pharmaceutical composition containing the same.
  • the present invention is a.
  • R 1 , R 2 and n are as defined above!
  • R 4 each represent hydrogen or an acetyl group
  • R 5 represents hydrogen or a lower phenol group
  • X represents a halogen atom.
  • the lower quinolyl group represented by R 1 or R 2 includes, for example, methinole, ethyl and f. Examples thereof include those having 1 to 4 carbon atoms such as mouth pinole, isopropi, and butyral, but those having 1 to 3 carbon atoms are preferable, and they may be substituted at any position of the pyridine ring.
  • the acyl group represented by R 3 include holmi, for example, Chill, hu.
  • Alkyl carbonyls having 2 to 6 carbon atoms such as pionyl, dibutylyl, isobutylyl, pentanoyl, isobutanol, and hexanol, and carbon such as phenylacetyl and phenylpropionyl
  • Aralkylcarbonyl of the formulas 8 to 9 include, for example, arylcarbonyl groups having 1 to 8 carbon atoms such as benzoinole and paratoluene, and aralkylcarbonyl and arylcarbonyl at any position on the ring such as halogen (Fluorine, chlorine, bromine, etc.), alkoxy (methkin, etokine, etc.). Trifluoromethyl, etc. may be substituted.
  • the ⁇ Le group represented by R4 those similar to the Ashiru group represented by R 3 are exemplified.
  • the lower alkyl / alkyl group represented by R 5 the same as the lower alkyl group represented by R 1 and R 2 can be mentioned.
  • the halogen atom represented by X include chlorine, bromine, and iodine.
  • the thiazolidinedione derivative represented by the general formula (I) is an amphoteric compound having an acidic nitrogen in the thiazoline ring and a basic nitrogen in the pyridine ring, and includes diacid salts and basic salts.
  • the salts of the thiazoli ⁇ dione derivative (I) include, for example, inorganic salts such as hydrochloride, hydrobromide, sulfate, phosphate, and methanesulfonate, such as toluene sulfonic acid Salts, oxalates, malonates, maleates, fumarates, succinates, tartrates, lactates, and other organic acid salts, such as sodium salts Metal salts such as iron salts, aluminum salts, aluminum salts, magnesium salts, and calcium salts.
  • thiazolidinedione derivative represented by the general formula (I) and a salt thereof according to the present invention include the following compounds.
  • the reaction between the compound represented by the formula ( ⁇ ) and the urea is usually carried out with alcohols (eg, methanol, ethanol, propanol, 2-propanol, butanol, isobutanol, 2-methanol). It is carried out in a solvent such as toxic ethanol, dimethyl sulfoxide, and snoreholane.
  • the reaction temperature is usually 20 to 180, preferably 60 to 150 t.
  • the amount of urea used is 1 to 2 moles per 1 mole of compound (I).
  • hydrogen halide is produced as a by-product as the reaction progresses.
  • a deoxidizing agent such as sodium acetate or potassium sulphate is added, the reaction is performed.
  • Yo The deoxidizing agent is usually used in a ratio of 1 to 1: 1.5 per compound (E).
  • the hydrolysis of the compound (dish) is usually performed in a suitable solvent in the presence of water and a mineral acid.
  • the solvent include a solvent used for a reaction between the compound (H) and a urea.
  • the mineral acid include hydrochloric acid, hydrobromic acid, sulfuric acid and the like.
  • the amount of the mineral acid to be used is 0.1 to 10 ', preferably 0.2 to 3 per mole of the compound (K). is there.
  • the amount of water to be added is usually a large excess with respect to 1 mol of the compound (I). This reaction is usually carried out under heating or heating, and the reaction temperature is usually 60 to 150. Heated orchids usually last several hours to over a dozen hours.
  • the above hydroxyl group (I ') may be subjected to the following acylation reaction.
  • the acylation reaction of the hydroxy; compound (I ') is usually carried out by reacting an acylating agent in a suitable solvent in the presence of a base! Is done.
  • the solvent include esters of ethyl acetate, for example, aromatic hydrocarbons such as benzene, toluene, xylene, etc.
  • ketones such as acetone and methethyl ketone, such as dichloromethane, chloromethane, chlorinated hydrocarbons such as carbon tetrachloride, and dimethylformamide.
  • the acylating agent include acid anhydrides or acid halides of formic acid, aliphatic, araliphatic or aromatic carboxylic acids.
  • aliphatic carboxylic acid examples include those having 2 to 6 carbon atoms such as drunkic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid and hexanoic acid. Ferulic acid,
  • OMPI Those having 8 to 9 carbon atoms, such as enoleprobionic acid, and those having 7 to 8 carbon atoms, such as benzoic acid and pademethinole benzoic acid, are examples of the aromatic olevonic acid.
  • Halogen eg, fluorine, chlorine, bromine, etc.
  • anorecoxy eg, methoxy, ethoxy, etc.
  • trichloroemethyi groups may be substituted.
  • the amount of the acylating agent to be used is generally 1 to 10 moles, preferably 1 to 2 moles, per 1 monol of the hydroxy form (I ').
  • the base include amines such as pyridin and triethynoleamine, and carbonates such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, hydrogencarbonate lime, and bicarbonate.
  • the base is usually used in the same amount as the asinolelating agent or in an excess amount. When pyridine is used as the base, a large excess amount of pyridine can be used.]
  • This reaction is usually performed at 120 to 40 t, and the reaction time is usually 10 minutes to 24 hours. Due to this reaction! ) It is possible to obtain a compound of the formula (I) wherein R 3 is an acyl group (also referred to as “3 ⁇ 4” below).
  • the thiazolidinedione derivative (I) can be reacted with an acid or a base according to a conventional method to lead to a salt.
  • the thiazolidinedione derivative and its salt obtained in this manner can be separated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatobuoy pulp, etc. ) It can be isolated and purified.
  • the compound (I) of the present invention and a salt thereof exhibit an excellent blood sugar and lipid lowering effect on mammals (for example, mice, dogs, cats, sa; 1, horses, and humans).
  • the toxicity is low in both acute and subacute toxicity.
  • 0.01 ⁇ ⁇ 1 OWZ ⁇ is given parenterally, and when used as a therapeutic agent for hyperlipidemia, 0.05 « ⁇ ⁇ 10 ZA3 ⁇ 4f is usually given orally per adult per day. 0.01 ⁇ to 1 OW / ⁇ can be administered parenterally, and this amount is preferably administered once a day or intermittently 2 to 4 times a week.
  • the starting compound (H) of the present invention can be produced, for example, by the following method. i) —Preparation of compound of formula () where n is 0
  • R 1 , R 2 and X are as defined above] is the same as the acyl group represented by H 3 or R 4 , and R is a lower anoalkylene group represented by R 5 It is equivalent. ]
  • the oxidation reaction from compound ( ⁇ ) to compound (V) can be easily carried out by reacting compound IV) with hydrogen peroxide or an organic peracid]).
  • compound IV hydrogen peroxide or an organic peracid
  • Formic acid, peracid, pertrifluoroacid, perbenzoic acid, m-peroxybenzoic acid and the like can be mentioned.
  • This oxidation reaction can be carried out according to a general method known per se.
  • the acylation reaction from (V) to the compound ( ⁇ ) is carried out by reacting the compound (V) with a compound (3 ⁇ 4), and usually reacts with an acid anhydride or an acid halide.
  • the hydrolysis reaction from the compound (IT) to the compound (IT) can be carried out by a usual method using sodium hydroxide or potassium hydroxide.
  • the reaction from the compound ( ⁇ ) to the compound (a) is carried out by condensing the compound (' ⁇ ) with the compound (by condensing 3 ⁇ 40 in the presence of sodium hydride)). This reaction was carried out in a solvent such as dimethinolehonoremamide or tetrahydrophenone.
  • test compound was mixed with powdered feed (CE-2, Nippon Crea) at 0.005 and fed to ⁇ - mice (male, 8 to 10 weeks old, 5 mice per group) for 4 days. Water was provided ad libitum during this time. Blood is collected from the orbital vein, blood glucose is measured by the glucose oxidase method, and plasma triglyceride is measured by the enzymatic method using glycerol produced by the Cleantech TG-S kit. Each was measured by quantification using Each value was shown as a reduction rate () with respect to the group not administered with the drug. .-
  • novel thiazolidinedione derivative (I) according to the present invention has excellent blood glucose and blood lipid lowering effects, and is useful as a drug for treating diabetes and hyperlipidemia.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Dérivés de thiazolidinedione représentés par la formule générale (I), où R1 et R2 peuvent être identiques ou différents et chacun représente de l'hydrogène ou un alkyle inférieur, R3 représente de l'hydrogène ou un acyle et n vaut 0 ou 1. Ces composés ainsi que leur sels sont efficaces dans la réduction du niveau des sucres et des lipides dans le sang, et sont utiles comme agents de traitement du diabète et de l'hyperlipémie.
PCT/JP1984/000445 1984-03-21 1984-09-14 Derives de thiazolidinedione, leur procede de preparation et compositions medicinales les contenant WO1985004171A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US06/711,536 US4582839A (en) 1984-03-21 1984-09-21 2,4-thiazolidinediones
EP85301895A EP0155845A1 (fr) 1984-03-21 1985-03-19 Dérivés de la thiazolidinedione, leur préparation et leur utilisation
CA000476976A CA1263961A (fr) 1984-03-21 1985-03-20 Composes de 5-¬4-(2 pyridylalkoxy|-2,4- thiazolidinedione

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
USPCT/JP84/00117 1984-03-21
PCT/JP1984/000117 WO1985004170A1 (fr) 1984-03-21 1984-03-21 Derives de thiazolidinedione, leur procede de preparation et compositions medicinales les contenant

Publications (1)

Publication Number Publication Date
WO1985004171A1 true WO1985004171A1 (fr) 1985-09-26

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Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/JP1984/000117 WO1985004170A1 (fr) 1984-03-21 1984-03-21 Derives de thiazolidinedione, leur procede de preparation et compositions medicinales les contenant
PCT/JP1984/000445 WO1985004171A1 (fr) 1984-03-21 1984-09-14 Derives de thiazolidinedione, leur procede de preparation et compositions medicinales les contenant

Family Applications Before (1)

Application Number Title Priority Date Filing Date
PCT/JP1984/000117 WO1985004170A1 (fr) 1984-03-21 1984-03-21 Derives de thiazolidinedione, leur procede de preparation et compositions medicinales les contenant

Country Status (2)

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JP (1) JPS60208980A (fr)
WO (2) WO1985004170A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4891216A (en) * 1987-04-14 1990-01-02 Alcide Corporation Disinfecting compositions and methods therefor
US5266582A (en) * 1991-08-20 1993-11-30 Adir Et Compagnie 2,4-thiazolidinedione compounds

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5183823A (en) 1991-04-11 1993-02-02 Takeda Chemical Industries, Ltd. Pyridine n-oxide compounds which are useful as hypoglycemic and hypolipidemic agents
JP2009530293A (ja) * 2006-03-16 2009-08-27 メタボリック ソリューションズ ディベロップメント カンパニー チアゾリジンジオン類似体およびグルココルチコイドアゴニストの併用療法
ES2397944T3 (es) * 2006-03-16 2013-03-12 Metabolic Solutions Development Company Llc Análogos de tiazolidindiona
ES2388555T3 (es) * 2006-03-16 2012-10-16 Metabolic Solutions Development Company Llc Análogos de tiazolidindiona
WO2010105048A1 (fr) * 2009-03-12 2010-09-16 Metabolic Solutions Development Company Analogues de thiazolidinedione
KR102029611B1 (ko) 2009-12-15 2019-10-07 씨리우스 테라퓨틱스, 엘엘씨 대사성 질환의 치료를 위한 ｐｐａｒ 절약형 티아졸리딘디온염

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5522636A (en) * 1978-08-04 1980-02-18 Takeda Chem Ind Ltd Thiazoliding derivative

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5522636A (en) * 1978-08-04 1980-02-18 Takeda Chem Ind Ltd Thiazoliding derivative

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Chemical Abstracts, Vol. 98, No. 15, (1983-4-11) Abstract No. 98 : 125945s; & Chem. Pharm. Bull. 1982, 30 (10), 3580-600 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4891216A (en) * 1987-04-14 1990-01-02 Alcide Corporation Disinfecting compositions and methods therefor
US5266582A (en) * 1991-08-20 1993-11-30 Adir Et Compagnie 2,4-thiazolidinedione compounds
US5330999A (en) * 1991-08-20 1994-07-19 Adir Et Compagnie 2,4-thiazolidinedione compounds

Also Published As

Publication number Publication date
JPS60208980A (ja) 1985-10-21
JPH0570633B2 (fr) 1993-10-05
WO1985004170A1 (fr) 1985-09-26

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