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WO1993015043A1 - Compose arylalkananilide et utilisation pharmaceutique - Google Patents

Compose arylalkananilide et utilisation pharmaceutique Download PDF

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Publication number
WO1993015043A1
WO1993015043A1 PCT/JP1993/000035 JP9300035W WO9315043A1 WO 1993015043 A1 WO1993015043 A1 WO 1993015043A1 JP 9300035 W JP9300035 W JP 9300035W WO 9315043 A1 WO9315043 A1 WO 9315043A1
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Prior art keywords
carbon atoms
alkyl
substituent
hydrogen
substituted
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PCT/JP1993/000035
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English (en)
Japanese (ja)
Inventor
Takanori Oe
Mitsuharu Sano
Ryuhei Ikezawa
Noriyoshi Izumi
Hidenobu Kusuhara
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Mitsubishi Tanabe Pharma Corp
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Yoshitomi Pharmaceutical Industries Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/76—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C235/78—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/11—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
    • C07C233/15—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/29—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/80—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton

Definitions

  • the present invention relates to a novel and pharmaceutically useful aryl alkanoic acid anilide compound or a pharmaceutically acceptable salt thereof and a pharmaceutical use thereof. More specifically, the present invention relates to an aryl alkanoic acid compound or an aryl alkanoic acid compound which inhibits acetyl cholesteryltransferase (ACAT), which is useful as a lipid-lowering drug or anti-atherosclerosis drug. It relates to a pharmaceutically acceptable salt and its pharmaceutical use.
  • ACAT acetyl cholesteryltransferase
  • Hypercholesterolemia is known as a risk factor for many cardiovascular diseases. Elevated blood cholesterol can cause accumulation of foam cells that have taken up lipids in the blood vessel wall, which has been attributed to the development of atherosclerosis. Atherosclerosis may cause many cardiovascular diseases such as angina and myocardial infarction.
  • ACAT acyl-enzyme A cholesterol acyl transferase
  • Atherosclerosis has a pathological feature in which the arterial wall is associated with accumulation of lipids, especially cholesterol esters. This cholesterol ester accumulation is rich in lipids! : It has been proved that the formation of foam cells derived from the macrophages taken up into the cells is deeply involved. Since the esterification of intracellular free cholesterol in macrophages is also effected by the action of ACAT, it is believed that ACAT inhibitors reduce the accumulation of intracellular cholesterol esters.
  • ACAT inhibitors suppress cell foaming and promote atherosclerosis Is expected to be reduced.
  • a urea compound having an ACAT inhibitory action is known from JP-A Nos. 1-93359, 2-6456, and 2-275584.
  • An object of the present invention is to provide a useful drug, particularly a highly lipid-lowering drug having an ACAT inhibitory action and high safety, and an anti-atherosclerotic drug.
  • the present inventors have conducted intensive studies from this viewpoint.
  • the novel arylyl alkanoate compound has a strong ACAT inhibitory action and a cholesterol esterification inhibitory action at a cell level, and has a high lipemic model animal.
  • the present invention was found to have a serum and hepatic cholesterol lowering effect in the present invention. That is, the present invention
  • X represents a sulfur atom, an oxygen atom, NR 11 (R u represents hydrogen or alkyl having 1 to 4 carbon atoms), CO, CH 2 or a chemical bond.
  • R 1 is a linear or branched alkyl having 5 to 18 carbon atoms, an alkenyl having a linear or branched carbon having 2 to 18 carbon atoms, or a linear or branched alkyl having 2 to 18 carbon atoms.
  • Alkynyl which may be substituted with alkyl having 1 to 4 carbons, cycloalkyl having 3 to 8 carbons, cycloalkyl having 3 to 8 carbons substituted with cycloalkyl having 3 to 8 carbons C1-C4 alkyl substituted by C3-C8 cycloalkyl, C1-C2 alkyl substituted by mono- or di-alkyl-substituted amino, i-i2 straight chain or Is an alkyl that may be divided, or a formula
  • R,, R ie the same or different and hydrogen, halogen, hydroxyl, Shiano may be straight ⁇ or technique from 1 1 2 carbon atoms Alkyl, alkoxy having 1 to 12 carbon atoms, which may be straight or divided, cycloalkyl having 3 to 8 carbon atoms which may be substituted by alkyl having 14 carbon atoms, haloalkyl having 1 to 4 carbon atoms, An aryl which may have a substituent, an arylalkyl which may have a substituent, an arylalkoxy which may have a substituent, an arylalkenyl or a substituent which may have a substituent.
  • Z represents CH or a nitrogen atom
  • D and E are the same or different and represent hydrogen or alkyl having 1 to 4 carbon atoms, or are bonded to each other to form a ring
  • Q With naphthalene, 1, 2, 3, 4-tetrahydronaphthale Shows a quinoline or 5, 6, 7, 8-tetra Hidorokino phosphorus formed group which may be.
  • R 2 and R 3 may be the same or different and may be hydrogen, halogen, hydroxyl, cyano, alkyl having 1 to 12 carbons, which may be straight or branched, linear or having 1 to 12 carbons, Alkoxy, cycloalkyl having 3 to 8 carbon atoms which may be substituted with alkyl having 1 to 4 carbon atoms, haloalkyl having 1 to 4 carbon atoms, aryl which may have a substituent, Arylalkyl which may have a substituent, arylalkyl which may have a substituent, alkenyl which may have a substituent or arylalkenyl which may have a substituent. Show.
  • R 1 one X and R 3 are each, substituents together with the benzene ring which may have a (halogen, water group, ShiRyono, alkoxy of 1-8 alkyl carbon atoms or 1 to 8 carbon atoms) The group which may form a good naphthalene is shown.
  • R 4 and R 5 are the same or different and are hydrogen, alkyl having 1 to 4 carbons, 1 to carbon C3-C8 cycloalkyl optionally substituted with 4 alkyls, C1-C4 alkyl substituted with C3-C8 cycloalkyls or arylalkyl optionally having substituents Or! ⁇ And R 5 represent a group which binds to each other to form a hydrocarbon ring having 3 to 1 carbon atoms together with adjacent carbon atoms.
  • R 8 , R 7 , and R 8 are the same or different and represent hydrogen, halogen, hydroxyl,
  • 4 represents alkyl or alkoxy having 1 to 4 carbon atoms.
  • n 0, 1 or 2.
  • X represents an oxygen atom
  • NR 11 represents hydrogen or alkyl having 1 to 4 carbon atoms
  • R 1 is a straight or branched alkyl having 5 to 18 carbon atoms, may be substituted with an alkyl having 1 to 4 carbon atoms, a cycloalkyl having 3 to 8 carbon atoms, mono- or dialkyl-substituted C1-C12 straight-chain or alkyl-substituted alkyl substituted by amino, or formula
  • m is 0 or an integer of 1 to 3
  • R e and R lfl are the same or different and may be hydrogen, halogen, hydroxyl, cyano, or a straight chain having 1 to 12 carbon atoms or a technique.
  • R 2 and R 3 are the same or different and each represents hydrogen, halogen, a straight or branched alkoxy having 1 to 12 carbon atoms or an aryl group which may have a group ;
  • R 1 one X and R s are each a substituted group with a benzene ring which may have a (halogen, water group, Shiano, alkoxy of 1-8 alkyl carbon atoms or 1 to 8 carbon atoms) naphthalene Represents a group that may form
  • R ′ and R 6 are the same or different and represent hydrogen or alkyl having 1 to 4 carbons, or R 6 is a group which is bonded to each other to form a hydrocarbon ring having 3 to 7 carbons together with adjacent carbon atoms. Shows:
  • R e , R 7 , R are the same or different and represent hydrogen, halogen, or alkyl having 1 to 4 carbons;
  • n 0, 1 or 2;
  • X represents an oxygen atom, NR 11 (R 11 represents hydrogen or alkyl having 1 to 4 carbon atoms), CO, CH 2 or a chemical bond;
  • R 1 is a straight or branched alkyl having 5 to 18 carbon atoms, a cycloalkyl having 3 to 8 carbon atoms which may be substituted by an alkyl having 1 to 4 carbon atoms, or a mono- or dialkyl-substituted amino.
  • m is 0 or an integer of 1 to 3
  • R ′ and R 10 are the same or different and are hydrogen, halogen, hydroxyl, cyano, linear or branched with 1 to 2 carbon atoms.
  • Z represents CH, D and E represent hydrogen.
  • R 2 and R 3 are the same or different and represent hydrogen, halogen, or a linear or branched alkoxy having 1 to 2 carbon atoms;
  • R 4 and R 5 are the same or different and represent hydrogen or alkyl having 1 to 4 carbons, or R ⁇ and R 5 are bonded to each other to form a hydrocarbon ring having 3 to 4 carbons together with adjacent carbon atoms. Represents a group;
  • R 7 represents hydrogen, halogen or number 1 to 40 alkyl carbons same or different:
  • ⁇ 0, 1 or 2:
  • X represents an oxygen atom, CO, CH 2 or a chemical bond.
  • R 1 is a straight or branched alkyl having 5 to 18 carbon atoms, or a formula
  • R e and R le are the same or different and are hydrogen, halogen, linear or branched alkyl having 1 to 12 carbons, 1 to 12 alkoxy or aryl alkoxy which may be substituted or aryl alkoxy which may have a substituent, Z represents CH, and D and E represent hydrogen.
  • R 2 and R 3 are the same or different and represent hydrogen or halogen
  • R 5 represents hydrogen
  • R 6 , R 7 and R 1 are the same or different and represent hydrogen or alkyl having 1 to 4 carbons;
  • n 0, 1 or 2;
  • Preferred compounds are N- (2,6-diisopropylphenyl) 141-octylphenylacetamide,
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of the above 1 to 5 and a pharmaceutically acceptable additive,
  • a lipid-lowering drug or an anti-arteriosclerosis drug characterized by containing the compound according to any one of the above items 1 to 5 as an active ingredient,
  • Halogen refers to chlorine, bromine, fluorine and iodine.
  • Alkyl having 1 to 4 carbon atoms may be straight or branched, and represents methyl, ethyl, propyl, ibguchi, butyl, isoptyl, tert-butyl, and tert-butyl.
  • Alkoxy having 1 to 4 carbon atoms may be either straight or branched, and represents methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, second-butoxy, and third-butoxy.
  • Alkyl having 1 to 8 carbon atoms may be linear or branched, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second-class butyl, tertiary-butyl, pentyl, Indicates hexyl, 1-methylhexyl, heptyl, octyl, etc.
  • Alkoxys having 1 to 8 carbon atoms may be linear or fractional, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, 2-butoxy, 3-butoxy, pentyloxy, Hexyloxy, 1,1-dimethylhexyloxy, heptyloxy, octyloxy, etc.
  • Alkyl having 5 to 18 carbon atoms which may be straight or divided may be, for example, 1'3,3-tetramethylbutyl, pentyl, neopentyl, isopentyl, tertiary pentyl, hexyl, isohexyl, Heptyl, octyl, nonyl, decyl, pendecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, Hebea decyl, octadecyl and the like may be included, and may have a branching chain as appropriate.
  • Alkenyl having 2 to 8 carbon atoms which may be straight-chain or may be divided into, for example, vinyl, bronyl, butenyl, pentenyl, hexenyl, hebutenyl, octenyl, nonenyl, decenyl, ndenyl, dodecenyl, tridecenyl, Examples thereof include tetradecenyl, pentadecenyl, hexadecenyl, heptane decenyl, octane decenyl and the like, and may have a branching chain as appropriate.
  • Alkynyl having 2 to 18 carbon atoms which may be straight or divided may be, for example, ethininole, provinyl, butynyl, benchinyl, hexynyl, hebutynyl, octynyl, noninyl, decynyl, pendecinyl, dodecynyl, tri.decinyl, Examples thereof include tetradecinole, pentadecinyl, hexadecynyl, heptane decynyl, octadecynyl, and the like, and may have an appropriate technique.
  • C3-8 cycloalkyl which may be substituted by C1-4 alkyl includes, for example, cyclobutyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-butylcyclohexyl, cycloheptyl, cyclooctyl and the like.
  • Can be Examples of the cycloalkyl having 3 to 8 carbon atoms substituted with the cycloalkyl having 3 to 8 carbon atoms include 4-cyclobutyrylcyclohexyl, 4-cyclohexylcyclohexyl, 4-cyclohexylcyclohexyl and the like.
  • Alkyl having 1 to 4 carbon atoms substituted with cycloalkyl having 3 to 8 carbon atoms means that the alkyl portion may be either linear or branched, for example, cyclopentylmethyl, cyclohexylmethyl, 2 — Cyclohexylethyl, 3-cyclohexylpropyl, 4-cyclohexylbutyl
  • Mono- or dialkyl-substituted amino-substituted straight-chain C 1 -C 12 alkyl which may be used is, for example, methylaminomethyl, dimethylaminomethyl, 4-dimethylaminobutyl, 6-dimethylaminohexyl, 8-methylaminooctyl, 8-dimethylaminooctyl, 10-dimethylaminodecyl and the like, and a straight or branched chain having 5 to 12 carbon atoms substituted by mono- or dialkyl-substituted amino.
  • Alkyl which may be used is preferred.
  • Alkyl having 1 to 12 carbon atoms which may be straight chain or divided may be, for example, methyl, Dityl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2,2-dimethylpropyl, isopentyl, 1-ethylpropyl, hexyl, heptyl, octyl, decyl, dodecyl, etc. And may have a branching chain as appropriate.
  • Alcoquins having 1 to 12 carbon atoms which may be straight or divided may be, for example, methoxy, nitroxy, propoxy, isopropoxy, butoxy, isobutoxy, second butoxy, tertiary butoxy, pentyloxy, 2 , 2-dimethylbroboxy, isopentyloxy, 1-ethylbroboxy, hexyloxy, heptyloxy, octyloxy, decyloxy, dodecyloxy, etc., and may have a suitable technique.
  • Haloalkyl having 1 to 4 carbon atoms may be straight-chain or branched, for example, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2, 2,3,3-Tetrafluorov mouth pill.
  • the aryl which may have a substituent includes phenyl, naphthyl and the like, and these include halogen, nitro, amino, hydroxyl, trifluoromethyl, alkyl having 1 to 4 carbons, alkyl having 1 to 4 carbons. May have from 1 to 3 substituents selected from alkoxy.
  • the arylalkyl which may have a substituent includes the same aryl moiety as described above, and the alkyl moiety preferably has 1 to 4 carbon atoms and may be either linear or branched.
  • the aryl alkoxy which may have a substituent includes the same aryl moiety as described above, and the alkoxy moiety preferably has 1 to 4 carbon atoms and has a straight-chain form or a partial form. Any of them may be used, for example, benzyloquine, 1-phenylethoxy, 2-Phenylethoxy, 1-methyl-1 1-phenylethoxy, 1-phenylpropoxy, 2-funylbroboxy, 3-phenylbroboxy, 2-methyl-2-phenylbroboxine, 1-naphthylmethoxy, And the like, and an aryl group may have the same S-substituent as described above.
  • the arylalkenyl which may have a substituent includes the same aryl moiety as described above, and the alkenyl moiety preferably has 2 to 4 carbon atoms and has a straight chain substituent. Or any of the divisional techniques, such as styryl, cinnamyl,, 3-phenylenyl 1-1-probenyl, 4-phenyl-2-butenyl, 4-phenyl-1,3-butadienyl, etc.
  • the aryl group may have the same substituent as described above.
  • the arylalkenyloxy which may have a substituent includes the same aryl moiety as described above, and the alkenyloxy moiety preferably has 2 to 4 carbon atoms. It can be either a stirrup or a diploma, for example, styryloxy, cinnamyloxy, 3-phenyloxyl, 4-broenyloxy, 4-phenyl-2-butenyloxy, 4-phenyl-1,3-butenyloxy And the aryl group may have the same substituent as described above.
  • R * and a hydrocarbon ring carbon number 3-7 to form together with the carbon atom to which R 5 is adjacent bonded to each other means cyclopropane, cyclobutane, butane cyclohexane, cyclohexane, butane cyclohexane.
  • R 1 is a group represented by the formula (II), and when X represents CO, a compound in which m is 0 is preferable.
  • salts are also included in the present invention.
  • Pharmaceutically acceptable salts include, for example, hydrochloride, hydrobromide, sulfate, acetate, fumarate, maleate, benzoate, qualate, malate, methanesulfonate, Benzene sulfonate and the like can be mentioned.
  • the group having a chiral carbon in the molecule has various optical isomers.
  • the present invention also includes those optical isomers and racemates.
  • the group in which geometric isomers are present also includes cis- and trans-forms thereof, and mixtures thereof.
  • the compound of formula (I) can be produced by the following method.
  • the compound of the general formula (I) has the general formula
  • the reaction is performed with dicyclohexylcarbodiimide, phosphorus halide (phosphorus trichloride, phosphorous oxychloride, etc.), methyl chlorophosphite, ethyl chlorophosphite, The reaction is carried out in an inert solvent in the presence of a condensing agent such as 0-phenylene chlorophosphate, under cooling, at room temperature or under heating.
  • a condensing agent such as 0-phenylene chlorophosphate
  • the reaction is carried out in an inert solvent using triethylamine, pyridin, N, N-dimethylamine or the like.
  • the reaction is performed under cooling or at room temperature in the presence of a handling base, or under cooling or at room temperature in water in the presence of an alkali such as sodium hydroxide or potassium hydroxide.
  • -As a reactive derivative of the compound of formula (III), a mixture of a symmetrical acid anhydride or an alkyl carbonate mixed anhydride, an alkyl phosphoric acid mixed anhydride, an alkyl phosphorous acid mixed anhydride, a sulfuric acid mixed anhydride, etc.
  • an acid anhydride the reaction is carried out in an inert solvent in the presence of a tertiary base such as triethylamine, pyridine or N, N-dimethylaniline under cooling, at room temperature or under heating.
  • solvents inert to the reaction such as ethyl acetate, dimethylformamide, toluene, toluene, tetrahydrofuran, pyridine, chloroform, dichloromethane, and the like.
  • the carboxylic acid represented by the general formula ⁇ ) or a reactive derivative thereof is
  • J represents a deprotecting group such as halogen or p-toluenesulfonylokidi, and has the same meaning as described above.
  • Reaction in an inert solvent at room temperature or under heating in the presence of a 3 ⁇ base such as triethylamine, pyridine, N, N-dimethylaniline, or It is produced by carrying out the reaction in a solvent at room temperature or under heating in the presence of sodium hydroxide such as sodium hydroxide and carbon dioxide.
  • R 12 is a straight or branched alkyl having 1 to 12 carbons, an arylalkyl which may have a substituent, or an aryl which may have a substituent.
  • J is as defined above.
  • R 1 D is a straight-chain (I) compound having 1 to 12 carbon atoms, which may be a straight-chain or capable of being separated, Further, a compound which is arylalkoxy or arylalkenyloxy which may have a substituent can be produced.
  • Method 3 the compound wherein X is CH 2 can also be produced by the following method.
  • a compound in which X is CO in the general formula (I) may be subjected to a weekly reduction under conditions of sodium borohydride or trifluoroacetic acid, or a selective reduction such as Clementen reduction, Meerwein-Bondloff reduction, etc. Can be converted to a compound in which X is CH 2 .
  • R 1 ′ represents alkyl having one less carbon atom in R 1.
  • the compound of the general formula (I) obtained as described above can be converted into the above-mentioned pharmaceutically acceptable salt by treating it with an inorganic acid or an organic acid by a conventional method.
  • the compound of the present invention When the compound of the present invention thus obtained has an asymmetric center, It is produced as an isomer, which can be optically resolved into optical isomers by conventional methods such as fractional recrystallization and chromatography. In addition, optical isomers can also be produced using optically active starting compounds. Furthermore, compounds having at least two asymmetric centers can be obtained as individual diastereomers or mixtures thereof, but individual diastereomers can be separated by means such as fractional recrystallization, chromatography and the like. In addition, the compound of the general formula (I) may have a cis-trans isomer, but these compounds can be prepared using a cis- or trans-form starting compound. Alternatively, if they are mixed, they can be separated into cis- and trans-forms by processing by conventional methods such as recrystallization and chromatography.
  • test compound A fixed amount of the test compound was added to a diet containing 1.5% cholesterol, 0.5 cholic acid, and 10% coconut oil, and fed to Lewis rats (6 per group) for 3 days. After sacrifice, serum and liver cholesterol were measured by enzymatic method. The respective reduction rates were determined.
  • the compound of the present invention has a strong ACAT inhibitory effect, and also shows a strong serum and hepatic cholesterol-lowering effect in experiments using hyperlipidemia model animals such as rats, mice, and egrets. It became clear.
  • the compound of Example 12 When the compound of Example 12 was repeatedly orally administered to a male rat for 10 days, no death occurred at a dose of 300 mgZKG.
  • the compound of the present invention has a strong ACAT inhibitory effect, and exhibits a cell-level cholesterol esterification inhibitory effect and a serum and liver cholesterol lowering effect in a model animal of hyperlipidemia. More specifically, the compound of the present invention suppresses the absorption of cholesterol from the intestinal tract and thereby has a serum cholesterol-lowering effect. Prevent lipid deposition at It is also excellent in oral absorption, bioavailability and gun-holding properties, and has low toxicity. Therefore, the present invention provides a safer and more convenient lipid-lowering drug and anti-atherosclerosis drug.
  • the compound of the present invention When used as a medicament, it can be administered orally or parenterally.
  • it is mixed with pharmaceutically acceptable carriers, excipients, diluents, etc. to give powders, tablets, capsules , Suppositories, suppositories, injections and the like.
  • the dose may vary depending on the condition, weight, age, etc. of the patient, but it is usually appropriate to be in the range of 10 to 500 per day for an adult, and it may be administered once or in several divided doses.
  • Example 6 ( ⁇ ) 2-(3-Benzoylphenyl) propionic acid 2.Og was dissolved in 4Oml of ethyl acetate, 1.1g of triethylamine was added, and OgC was added to 1.Og of pivaloyl chloride. The mixture was added dropwise, and the mixture was stirred at the same temperature for 15 minutes. Next, a solution of 1.2 g of 2,6-diethylaniline (2 g) in ethyl acetate (2 Om1) was added dropwise thereto, and the mixture was stirred at the same temperature for 30 minutes and further stirred at room temperature for 2 hours.
  • reaction solution was washed with water, washed with a saturated aqueous solution of sodium hydrogen carbonate, further washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the residue was recrystallized from isopropyl ether and hexane to obtain colorless crystals of N- (2,6-diphenylpyrphenyl) -141-year-old octylphenylacetamide. Melting point 1 3 4 to 1 3 5'C
  • N- (2,6-Jetylphenyl) 1-3- (4-hydroxyloxybenzoyl) phenyl cetamide 1.0 g was dissolved in dimethylform amide 2 Om 1 to obtain a carbon dioxide sorbent 0.7. g was added and shaken at 40 for 10 minutes. Next, 0.4 g of benzyl chloride was added, and the mixture was stirred at 60 for 3 hours. The reaction solution was poured into water, and the precipitated crystals were collected. The crystals were recrystallized from chloroform and methanol to give colorless crystals of N- (2,6-diethylphenyl) 13- (4-benzyloxybenzoyl) phenylacetamide. Melting point 19-9-20 O'C
  • N- (2,6-Jetylphenyl) 1-3- (4-fluorobenzoyl) phenylacetamide 4.1 g was dissolved in 50 ml of dichloroethane, and 2.5 g of sodium borohydride was added. With C, 54 ml of trifluoroacetic acid was added dropwise. At room temperature After stirring for 2 hours, the mixture was stirred at 40 to 45'C for 1 hour. Ice water was added to the reaction solution, extracted with dichloromethane, washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography.
  • Example 8 8 -(2,6-diisopropylphenyl) 1-41 (8-dimethylaminooctyloxy) phenylacetamide, melting point 105-107'C

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  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

On décrit un composé arylalkananilide représenté par la formule générale (I), ou un sel qui en est pharmaceutiquement acceptable, où X représente S, O, NR', CO, CH2 ou une liaison chimique; R1 représente C¿5?-C18 alkyle, phényle éventuellement substitué, pyridyle, etc.; R?2 et R3¿ représentent chacun hydrogène, halogène, alkyle, alkoxy, etc.; R4 et R5 représentent chacun hydrogène, alkyle, cycloalkyle, etc.; R?6, R7 et R8¿ représentent chacun hydrogène, halogène, alkyle, etc.; et n vaut 0, 1 ou 2. Ce composé présente un effet inhibiteur de l'ACAT acyle-coenzyme A cholestérol acyle transférase et se revèle utile pour abaisser le taux de lipides et traiter l'artériosclérose.
PCT/JP1993/000035 1992-01-24 1993-01-13 Compose arylalkananilide et utilisation pharmaceutique Ceased WO1993015043A1 (fr)

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JP3427092 1992-01-24

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3117466B2 (ja) 1995-11-27 2000-12-11 帝人株式会社 ベンゼン誘導体
WO2003099771A3 (fr) * 2002-05-29 2004-04-01 Novartis Ag Derives de diaryle-uree utilises pour le traitement des maladies dependant des proteines kinases
US7166738B2 (en) 2004-04-23 2007-01-23 Roche Palo Alto Llc Non-nucleoside reverse transcriptase inhibitors
US7273863B1 (en) 1999-09-04 2007-09-25 Smithkline Beecham Corporation Benzophenones as inhibitors of reverse transcriptase
US7388111B2 (en) 2005-10-19 2008-06-17 Roche Palo Alto Llc Non-nucleoside reverse transcriptase inhibitors
US7625949B2 (en) 2004-04-23 2009-12-01 Roche Palo Alto Llc Methods for treating retroviral infections
US7652041B2 (en) 2005-01-14 2010-01-26 Millennium Pharmaceuticals, Inc. Cinnamide and hydrocinnamide derivatives with kinase inhibitory activity
JP2014527043A (ja) * 2011-08-03 2014-10-09 ナショナル タイワン ユニバーシティ Ｓｒｃホモロジー２プロテインチロシンホスファターゼ−１を含むアゴニスト及びその治療方法
NO20161397A1 (no) * 2004-04-23 2016-09-02 Hoffmann La Roche Ikke-nukleosidbaserte revers-transkriptase-inhibitorer

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59231058A (ja) * 1983-05-06 1984-12-25 アメリカン・サイアナミド・カンパニ− アラルカンアミドフエニル化合物、その製法および薬としての用途

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59231058A (ja) * 1983-05-06 1984-12-25 アメリカン・サイアナミド・カンパニ− アラルカンアミドフエニル化合物、その製法および薬としての用途

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3117466B2 (ja) 1995-11-27 2000-12-11 帝人株式会社 ベンゼン誘導体
CN1081623C (zh) * 1995-11-27 2002-03-27 帝人株式会社 苯衍生物
US7273863B1 (en) 1999-09-04 2007-09-25 Smithkline Beecham Corporation Benzophenones as inhibitors of reverse transcriptase
WO2003099771A3 (fr) * 2002-05-29 2004-04-01 Novartis Ag Derives de diaryle-uree utilises pour le traitement des maladies dependant des proteines kinases
JP2005527622A (ja) * 2002-05-29 2005-09-15 ノバルティス アクチエンゲゼルシャフト プロテインキナーゼ依存性疾患の処置に有用なジアリールウレア誘導体
US7166738B2 (en) 2004-04-23 2007-01-23 Roche Palo Alto Llc Non-nucleoside reverse transcriptase inhibitors
US7625949B2 (en) 2004-04-23 2009-12-01 Roche Palo Alto Llc Methods for treating retroviral infections
US8329755B2 (en) 2004-04-23 2012-12-11 Roche Palo Alto Llc Methods for treating retroviral infections
NO20161397A1 (no) * 2004-04-23 2016-09-02 Hoffmann La Roche Ikke-nukleosidbaserte revers-transkriptase-inhibitorer
US7652041B2 (en) 2005-01-14 2010-01-26 Millennium Pharmaceuticals, Inc. Cinnamide and hydrocinnamide derivatives with kinase inhibitory activity
US7388111B2 (en) 2005-10-19 2008-06-17 Roche Palo Alto Llc Non-nucleoside reverse transcriptase inhibitors
JP2014527043A (ja) * 2011-08-03 2014-10-09 ナショナル タイワン ユニバーシティ Ｓｒｃホモロジー２プロテインチロシンホスファターゼ−１を含むアゴニスト及びその治療方法

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