WO1991013871A1 - Derive de monouree et ses sels - Google Patents

Derive de monouree et ses sels Download PDF

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Publication number
WO1991013871A1
WO1991013871A1 PCT/JP1991/000320 JP9100320W WO9113871A1 WO 1991013871 A1 WO1991013871 A1 WO 1991013871A1 JP 9100320 W JP9100320 W JP 9100320W WO 9113871 A1 WO9113871 A1 WO 9113871A1
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WO
WIPO (PCT)
Prior art keywords
group
compound
methyl
lower alkyl
nmr
Prior art date
Application number
PCT/JP1991/000320
Other languages
English (en)
Japanese (ja)
Inventor
Noriki Ito
Koyo Matsuda
Kiyoshi Iwaoka
Yuichi Iizumi
Original Assignee
Yamanouchi Pharmaceutical 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 Yamanouchi Pharmaceutical Co., Ltd. filed Critical Yamanouchi Pharmaceutical Co., Ltd.
Publication of WO1991013871A1 publication Critical patent/WO1991013871A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/91—Dibenzofurans; Hydrogenated dibenzofurans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—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
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/58—Radicals substituted by nitrogen atoms

Definitions

  • the present invention relates to a monourea derivative represented by the following formula (I) and a salt thereof useful as a medicament, a pharmaceutical composition containing them, and a method for producing them.
  • R 1 is a fused heterocyclic group optionally substituted with a lower alkyl group
  • R 2 is a cycloalkyl group
  • R 3 is a phenyl optionally substituted with a halogen atom and Z or a lower alkyl group.
  • n is 0 or an integer of 1 to 6.
  • Atherosclerosis is a form of atherosclerosis characterized by the accumulation and thickening of lipids in the intermediate and aortic walls, especially cholesterol esters.
  • ACAT acyl-Coenzyme A cholesterol acyl-transf erase
  • GB-A-2 113 684 further c discloses certain substituted consists urea and Chio urea anti Atero one arm arteriosclerosis agent having ACAT inhibitory activity
  • EP-A-0 335 375 also disclose anti-hyperlipidemic and anti-atherosclerotic agents consisting of certain substituted ureas having ACAT enzyme inhibitory ability.
  • the present invention relates to the monourea derivative represented by the above-mentioned (I) or a salt thereof.
  • the compound (I) of the present invention is a novel compound having a different chemical structure from the compound disclosed above, and has a pharmacological activity superior to that of the compound of the prior art, as shown by the results of comparative pharmacological experiments.
  • the compound (I) of the present invention is a compound in which a urea derivative is directly bonded to a condensed heterocyclic group via an alkylene group or not.
  • the lower alkyl group of the "condensed heterocyclic group optionally substituted by a lower alkyl group” is a straight-chain or branched alkyl group having 1 to 6 carbon atoms.
  • a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group examples include a pentyl group, tert-pentyl group, neopentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, and isohexyl group.
  • the fused heterocyclic group is a fused heterocyclic group containing one or more oxygen atoms, sulfur atoms or nitrogen atoms, and the fused heterocyclic group in the fused heterocyclic group is For example, 1, 4 1 Ben
  • the condensed heterocyclic group which may be substituted with a lower alkyl group may or may not be substituted with the above-mentioned condensed heterocyclic group with a lower alkyl group. When it is substituted, it may be substituted with one lower alkyl group or plurally with the same or different lower alkyl groups.
  • Specific examples include 2-methylquinolyl, 3-methylindryl, 6-methyl (1,4-benzodioxanyl), and 3-methyl-1-N-ethylethylcarbazolyl.
  • 2-methylbenzofuryl group 3-methyl-1- (N-ethylcarbazolyl) group, 3-methylbenzochenyl group and the like.
  • the “cycloalkyl group” is a cyclic alkyl group having 3 to 18 carbon atoms, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group , Cyclononyl, cyclodecyl, cyclododecyl, cyclotridecyl, cyclopentadecyl, adamantyl, norbornyl and the like. Particularly preferred are cycloalkyl groups having 6 to 10 carbon atoms.
  • the halogen atom in the “halogen atom and the fuunyl group optionally substituted by Z or a lower alkyl group” means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • the lower alkyl group means the above-mentioned linear or branched alkyl group having 1 to 6 carbon atoms.
  • the phenyl group optionally substituted with a halogen atom and / or a lower alkyl group may or may not be substituted with a phenyl group with a halogen atom or a lower alkyl group.
  • any position of the phenyl group is substituted with the above-mentioned halogen atom and Z or a lower alkyl group, and in this case, the halogen atom and the no or lower alkyl group are the same or different.
  • One or more phenyl rings can be substituted. Examples of such groups include 2,4,6—trifluorophenyl group, 2,4,6—trimethylphenyl group, 4-ethylphenyl group, 2,6-diethylphenyl group, and 4—s— And a butylphenyl group.
  • the compound of the formula (I) can form a salt, and the present invention also includes a salt of the compound (I).
  • salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, acetic acid, oxalic acid, citric acid, succinic acid, fumaric acid, and maleic acid.
  • Acid addition salts with various organic acids such as acid, linoleic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid and the like.
  • Compound (I) provided by the present invention can be produced by various methods. The typical method is illustrated below.
  • the present compound (I) has the formula ( Ii) It can be obtained by reacting the compounds represented by (m) and (IV) simultaneously or in any order. However, particularly preferably, the compound (I) of the present invention is obtained by reacting an amino compound represented by the formula (IV) with a halogen carbonate compound represented by the formula (m) to obtain a carbamic acid ester, The compound can be obtained by reacting the compound represented by).
  • halogenated carbonate compound represented by the formula (m) examples include isoptyl chlorocarbonate, methyl chlorocarbonate, ethyl bromocarbonate, and phenyl chlorocarbonate. Potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, It may be advantageous to carry out the reaction in the presence of a base such as N, N-dimethylaniline.
  • the reaction solvent may be any inert solvent such as N, N-dimethylformamide, chloroform, benzene, toluene, xylene, dioxane, ether, tetrahydrofuran, dichloromethane, dichloroethane, and the like.
  • the reaction temperature is from under cooling to room temperature, and the obtained carbamic acid ester and the compound (II) In the above reaction, the temperature is set from room temperature to heating.
  • the compound (I) of the present invention can be obtained by reacting a compound represented by the formula (H) with an isocyanate compound represented by the formula (V).
  • the isocyanate compound represented by the formula (V) is usually used in an equimolar amount to the compound represented by the formula (E).
  • the reaction is carried out in a solvent inert to the same reaction as the solvent in the first production method, from room temperature to under heating.
  • the compound (I) of the present invention can also be obtained by reacting an amino compound represented by the formula (E) with a halogen compound represented by the formula (I).
  • the thus-produced compound (I) of the present invention can be isolated or purified by salt formation or desalting by a conventional method as a free form or as a salt thereof. Isolation and purification are performed by applying ordinary chemical operations such as extraction, crystallization, recrystallization, and various types of chromatography. Industrial applicability
  • the compound (I) of the present invention or a salt thereof suppresses the accumulation of cholesterol ester in arterial wall smooth muscle cells in blood vessels by inhibiting the ACAT enzyme.
  • it suppresses the absorption of cholesterol from the intestinal tract and promotes the catabolism and excretion of cholesterol in the liver. It reduces the accumulation and storage of esters and inhibits the formation or development of atherosclerotic lesions.
  • the compound (I) of the present invention or its salt has an excellent effect of lowering total cholesterol in blood vessels and low density lipoprotein (LDL). It is useful for the prevention and treatment of various diseases related to, such as cerebral infarction, transient ischemic attack, angina pectoris, peripheral thrombus and obstruction.
  • the drug containing the compound (I) of the present invention or a salt thereof as a main component can be prepared by a commonly used method using pharmaceutical carriers, excipients and the like usually used in this field. .
  • Administration may be in the form of oral administration such as tablets, pills, capsules, granules, powders, and liquids, or parenteral administration such as injections such as intravenous and intramuscular injections and suppositories.
  • the dosage is appropriately determined depending on the individual case in consideration of the symptoms, age of the administration subject, gender, etc., but in the case of oral administration, it is usually about 50 to 500 nig per day for a synthetic person, and this should be done once. , Or 2 ⁇
  • -NMR indicates a hydrogen nuclear magnetic resonance spectrum
  • Mass indicates a mass spectrometry value
  • IR indicates an infrared absorption spectrum
  • IR cm- 1 , KBr tablet

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

Abstract

Dérivé de monourée de la formule générale (I) et ses sels, dans laquelle R1 représente un groupe hétérocyclique condensé pouvant être substitué par un alkyle inférieur; R2 représente un cycloalkyle; R3 représente un groupe phénylique pouvant être substitué par un halogène et/ou un alkyle inférieur ou un groupe représenté par la formule (a); et dans laquelle n signifie 0 ou un nombre entier de 1 à 6. Ces composés sont extrêmement utiles pour réduire la cholestérolémie totale et des concentrations de lipoprotéines de faible densité.
PCT/JP1991/000320 1990-03-12 1991-03-08 Derive de monouree et ses sels WO1991013871A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2/60755 1990-03-12
JP6075590 1990-03-12

Publications (1)

Publication Number Publication Date
WO1991013871A1 true WO1991013871A1 (fr) 1991-09-19

Family

ID=13151408

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1991/000320 WO1991013871A1 (fr) 1990-03-12 1991-03-08 Derive de monouree et ses sels

Country Status (2)

Country Link
AU (1) AU7440691A (fr)
WO (1) WO1991013871A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0512570A1 (fr) * 1991-05-10 1992-11-11 Fujisawa Pharmaceutical Co., Ltd. Dérivés de l'urée, procédé pour leur préparation et compositions pharmaceutiques les contenant
WO1993024458A1 (fr) * 1992-05-28 1993-12-09 Pfizer Inc. Nouveau derives n-aryle et de n-heteroaryluree en tant qu'inhibiteurs de l'acylcoenzime a: cholesterol acyltransferase (acat)
US5420164A (en) * 1991-04-04 1995-05-30 Yoshitomi Pharmaceutical Industries, Ltd. Cycloalkylurea compounds
ES2076865A1 (es) * 1993-07-05 1995-11-01 Pfizer Nuevos derivados de n-aril- y n-heteroaril-urea como inhibidores de acil-coenzima a: colesterol acil transferasa (acat).
WO1997001539A1 (fr) * 1995-06-27 1997-01-16 Takeda Chemical Industries, Ltd. Derives de 4-acylamino(halogeno)alkyl-quinoline, leur preparation et leur utilisation comme agonistes de la melatonine
TWI827760B (zh) * 2018-12-12 2024-01-01 加拿大商愛彼特生物製藥公司 經取代之芳基甲基脲類及雜芳基甲基脲類、其類似物及其使用方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4623662A (en) * 1985-05-23 1986-11-18 American Cyanamid Company Antiatherosclerotic ureas and thioureas
EP0297610A1 (fr) * 1987-07-02 1989-01-04 Warner-Lambert Company N-[(phényl 2,6-substitué)urées]-carbamates inhibiteurs de l'acyl-co-enzyme A:cholestérol-acyltransférase

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4623662A (en) * 1985-05-23 1986-11-18 American Cyanamid Company Antiatherosclerotic ureas and thioureas
EP0297610A1 (fr) * 1987-07-02 1989-01-04 Warner-Lambert Company N-[(phényl 2,6-substitué)urées]-carbamates inhibiteurs de l'acyl-co-enzyme A:cholestérol-acyltransférase

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5420164A (en) * 1991-04-04 1995-05-30 Yoshitomi Pharmaceutical Industries, Ltd. Cycloalkylurea compounds
EP0512570A1 (fr) * 1991-05-10 1992-11-11 Fujisawa Pharmaceutical Co., Ltd. Dérivés de l'urée, procédé pour leur préparation et compositions pharmaceutiques les contenant
WO1993024458A1 (fr) * 1992-05-28 1993-12-09 Pfizer Inc. Nouveau derives n-aryle et de n-heteroaryluree en tant qu'inhibiteurs de l'acylcoenzime a: cholesterol acyltransferase (acat)
US6001860A (en) * 1992-05-28 1999-12-14 Pfizer Inc. N-aryl and N-heteroarylurea derivatives as inhibitors of acyl coenzyme A: Cholesterol acyl transferase (ACAT)
ES2076865A1 (es) * 1993-07-05 1995-11-01 Pfizer Nuevos derivados de n-aril- y n-heteroaril-urea como inhibidores de acil-coenzima a: colesterol acil transferasa (acat).
WO1997001539A1 (fr) * 1995-06-27 1997-01-16 Takeda Chemical Industries, Ltd. Derives de 4-acylamino(halogeno)alkyl-quinoline, leur preparation et leur utilisation comme agonistes de la melatonine
US5708005A (en) * 1995-06-27 1998-01-13 Takeda Chemical Industries, Ltd. Quinolines, their production and use
TWI827760B (zh) * 2018-12-12 2024-01-01 加拿大商愛彼特生物製藥公司 經取代之芳基甲基脲類及雜芳基甲基脲類、其類似物及其使用方法

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Publication number Publication date
AU7440691A (en) 1991-10-10

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