WO1991019496A1 - Agent hypolipidemique - Google Patents

Agent hypolipidemique Download PDF

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Publication number
WO1991019496A1
WO1991019496A1 PCT/JP1990/000791 JP9000791W WO9119496A1 WO 1991019496 A1 WO1991019496 A1 WO 1991019496A1 JP 9000791 W JP9000791 W JP 9000791W WO 9119496 A1 WO9119496 A1 WO 9119496A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
methyl
benzoxazole
production example
antilipidemic
Prior art date
Application number
PCT/JP1990/000791
Other languages
English (en)
Japanese (ja)
Inventor
Ikuo Iijima
Masakatsu Ozeki
Kunihito Okumura
Tetsuji Mori
Masanori Inamasu
Original Assignee
Tanabe Seiyaku 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 Tanabe Seiyaku Co., Ltd. filed Critical Tanabe Seiyaku Co., Ltd.
Publication of WO1991019496A1 publication Critical patent/WO1991019496A1/fr

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Classifications

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

Definitions

  • the present invention relates to an antilipidemic agent.
  • Hyperlipidemia is a condition in which the amount of blood lipids such as serum total cholesterol and serum triglyceride is increased, and is considered to be one of the main causes of various adult diseases such as arteriosclerosis.
  • anti-lipidemic agents such as kuguchi fibrate and blobcol have been used as therapeutic and prophylactic agents for hyperlipidemia.
  • V and DL very low specific lipoprotein
  • LDL low density lipoprotein
  • HDL high density lipoprotein
  • an antilipidemic agent capable of reducing the amount of blood lipids such as serum total cholesterol and serum triglyceride and simultaneously increasing the amount of HD monocholesterol.
  • the present invention has the general formula ( ⁇ )
  • R is a fur group, naphthyl group, cycloalkyl group or heterocyclic group which may have a substituent
  • Alk is a single bond, a lower alkylene group, a lower alkyne group or a substituent.
  • a lower alkylene group which may have a dashed line indicates that the bond at the site may be a double bond.
  • Benzoxazole derivative represented by the formula or its physiologically acceptable The present invention relates to an antilipidemic agent comprising a salt as an evening active ingredient.
  • the benzoxazole conductor ( ⁇ ) and the salt thereof, which are the active ingredients of the antilipidemic agent of the present invention, are both novel compounds and have an effect of decreasing serum cholesterol level, increasing HDL-cholesterol level and ⁇ . Or it has an excellent antilipidemic effect based on its serum triglyceride lowering effect. Furthermore, this compound (I) has low toxicity, for example, 5-[(2,4-dioxothiazolidin-15-yl) methyl] -12-[(2-naphthyl) methyl] benzoxazole Although the CMC virtual cloudy solution was observed orally administered to mice (throw Azukaryou 300 Omg / kg) after Ma 2 hours, deaths observed forces, seven ": 0
  • compound (I) or a pharmaceutically acceptable salt thereof is a compound useful as an antilipidemic agent, for example, hypolipidemia (eg, hypercholesterolemia), arteriosclerosis (eg, Treatment of atherosclerosis, Menkelberg's arteriosclerosis, etc. * Can be used for prevention. In addition, it has a special feature that raises HDL-cholesterol level while lowering serum total cholesterol level. Can be used for prevention.
  • hypolipidemia eg, hypercholesterolemia
  • arteriosclerosis eg, Treatment of atherosclerosis, Menkelberg's arteriosclerosis, etc. * Can be used for prevention.
  • it has a special feature that raises HDL-cholesterol level while lowering serum total cholesterol level. Can be used for prevention.
  • R represents a phenyl group, a naphthyl group, a cyclohexyl group, a 1,3-thiazole- 4-yl, 1,3-oxazolyl 4-yl, pyridine, benzoyl, benzoyl, chelyl, quinolyl, or benzofururyl, or these groups are (lower alkyne) Carbyl group, lower alkoxy group, lower alkyl group, trihalogeno lower alkyl group, lower alkylthio group, lower alkylsulfur group, lower alkylsulfonyl group, furyl group, fusoxy group, lower-substituted lower alcohol group Di-, hydroxyl, halogen, nitro, amino, lower alkylamino, di (lower alkyl) amino, cyclo Kill group, Biro Li Jinomoto
  • Alk is a single bond, a linear or branched lower alkylene group, a lower alkylene group or a lower alkylene group. And a lower alkylene group substituted with an oxo group, a fuunyl group or a cycloalkyl group.
  • Compounds which exhibit particularly excellent therapeutic effects include those represented by the formula (I) wherein R is a lower alkoxy group, a lower alkyl group, a trihalogeno lower alkyl group, a fuunyl group, a halogen atom, a nitro group or a di (lower alkyl) group.
  • a phenyl group, a naphthyl group, a pyridyl group, a 1,3-thiazole-4-yl group or a 1,3-oxazole-4 group which may be substituted with one or two groups selected from an amino group
  • the compound include a compound having a -yl group, and in particular, a compound in which R is a di (lower alkyl) aminofurinyl group or a naphthyl group.
  • Al k is a single bond or a lower alkylene group
  • 2,4-dioxothiazolidin, 5-yl (or ylidene) methyl group is a benzoxazole. It is a compound bonded to the 5-position of the ring.
  • Benzoxazole derivatives (I), which are the active ingredients of the present invention include lower alkoxy groups, lower alkyl groups, lower alkanoyl groups,
  • the alkylene group includes a alkylene group, a lower alkylene group and a lower alkulene group having 6 or less carbon atoms, particularly preferably having 4 or less carbon atoms, and a cycloalkyl group having 3 to 9 carbon atoms. And especially those having 4 to 7 are preferred.
  • benzoxazole derivatives (I) can be used for the purpose of the present invention either in a free form or in the form of a pharmaceutically acceptable salt thereof.
  • the salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and acid addition salts such as hydrochloride and sulfate.
  • the antilipidemic agent of the present invention can be administered orally or parenterally, and is used in a usual manner as a suitable pharmaceutical preparation such as a tablet, granule, capsule, powder, or injection. .
  • the dose of the active ingredient compound of the present invention varies depending on the administration method, the age, body weight and condition of the patient, but is usually about 5 to 20 OmgZkg per day, especially about 10 to 2 OmgZkg per day. Is preferred.
  • Benzoxazole derivatives (I) can be used as geometric isomers, optically active isomers, And mixtures thereof can be used as the active ingredient of the present invention.
  • the benzoxazole derivative (I), which is an active ingredient of the present invention, has the following general formula (1):
  • R 1 represents a hydroxyl group, a lower alkoxy group or a reactive residue
  • Y represents an oxygen atom or an imino group
  • R and Alk have the same meaning as described above.
  • a dehydrogenating agent for example, lead tetraacetate
  • the compound may be an alkylsulfonylphenyl group, or the compound (I) in which R is a benzyloxy group may be debenzylated to give a compound in which R is a hydroxyphenyl group.
  • SD male rats (weight: 120-140 g, 5 animals per group) were fed a diet containing 2 W / W% cholesterol and 0.5 W / W% sodium cholate for 4 days. They were allowed free intake. Thereafter, the control group the fodder, the specimen-administered group libitum by TsugiMitsuru feed plus sample to the feed at 1 0 O m g% 0 ratio. 3 After that, the rat was anesthetized with ether, and body weight was measured and blood was collected from the abdominal aorta. The blood was released for 1 hour at room temperature and then arrested and separated to obtain serum, from which serum cholesterol and serum triglyceride contents were measured by an enzyme method.
  • HDL Choesterol L—Cholesterol level Increase rate of control average HD L—
  • IR * Represents IR v max (cm " 1 )
  • Lin pentoxide 4 Og and hexamethyldisilium beef sun 10 ml, 1

Abstract

Agent hypolipidémique utile à la prévention ou au traitement de l'hypolipidémie, de l'athérosclérose ou analogue et renfermant à titre d'ingrédient actif un dérivé de benzoxazole correspondant à la formule générale (I), ou ses sels pharmacologiquement acceptables. Dans ladite formule (I), R représente un groupe phényle, naphtyle, cycloalkyle ou hétérocyclique éventuellement substitué; Alk représente une liaison simple, un groupe alcénylène ou alcynylène inférieur, ou un groupe alkylène inférieur éventuellement substitué; et une ligne interrompue signifie que la liaison en question peut être double.
PCT/JP1990/000791 1988-09-13 1990-06-18 Agent hypolipidemique WO1991019496A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP22908888 1988-09-13
JP1216742A JPH02167224A (ja) 1988-09-13 1989-08-22 抗脂血剤

Publications (1)

Publication Number Publication Date
WO1991019496A1 true WO1991019496A1 (fr) 1991-12-26

Family

ID=26521597

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1990/000791 WO1991019496A1 (fr) 1988-09-13 1990-06-18 Agent hypolipidemique

Country Status (2)

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JP (1) JPH02167224A (fr)
WO (1) WO1991019496A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6452014B1 (en) * 2000-12-22 2002-09-17 Geron Corporation Telomerase inhibitors and methods of their use
EP3178810A4 (fr) * 2014-08-08 2018-07-04 Kasuma Partners Inc. Composé hétérocyclique condensé

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0283035A1 (fr) * 1987-03-18 1988-09-21 Tanabe Seiyaku Co., Ltd. Dérivés de benzoxazole et leur préparation
JPS649979A (en) * 1987-06-10 1989-01-13 Pfizer Hypoglycemiant oxazolidine-2-one derivative
JPS649989A (en) * 1987-06-30 1989-01-13 Taiho Pharmaceutical Co Ltd Isoxazole compound
EP0299620A1 (fr) * 1987-06-13 1989-01-18 Beecham Group Plc Dérivés de thiazolidinedione

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0283035A1 (fr) * 1987-03-18 1988-09-21 Tanabe Seiyaku Co., Ltd. Dérivés de benzoxazole et leur préparation
JPS649979A (en) * 1987-06-10 1989-01-13 Pfizer Hypoglycemiant oxazolidine-2-one derivative
EP0299620A1 (fr) * 1987-06-13 1989-01-18 Beecham Group Plc Dérivés de thiazolidinedione
JPS649989A (en) * 1987-06-30 1989-01-13 Taiho Pharmaceutical Co Ltd Isoxazole compound

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Abstract No. 86:50481d; & J. MED. CHEM., Vol. 21(1), 169-71, (1977), EVANS, DELME; SMITH, CHRISTINE E., WILLLIAMSON, W.R. NIGEL. *

Also Published As

Publication number Publication date
JPH02167224A (ja) 1990-06-27

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