WO1993015043A1 - Arylalkananilide compound and pharmaceutical use thereof - Google Patents

Abstract

An arylalkananilide compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein X represents S, O, NR', CO, CH2 or a chemical bond; R1 represents C¿5?-C18 alkyl, optionally substituted phenyl, pyridyl, etc.; R?2 and R3¿ represent each hydrogen, halogen, alkyl, alkoxy, etc.; R?4 and R5¿ represent each hydrogen, alkyl, cycloalkyl, etc.; R?6, R7 and R8¿ represent each hydrogen, halogen, alkyl, etc.; and n represents 0, 1 or 2. The compound has an ACAT inhibitory effect and is useful for reducing lipid content and treating arteriosclerosis.

Description

 Incense

 Aryl alkanoic acid compounds and their pharmaceutical uses

 `` Technical field J

 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.

 `` Background technology J

 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.

 Dietary cholesterol is esterified by small intestinal mucosal microsomes, acyl-enzyme A cholesterol acyl transferase (hereinafter referred to as ACAT). After cholesterol esters are incorporated into chylomicrons, they are released into the blood via the lymph. ACAT inhibitors inhibit the esterification of free cholesterol in food bile. Therefore, ACAT inhibitors are expected to reduce blood cholesterol levels by suppressing cholesterol absorption.

 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.

As described above, ACAT inhibitors suppress cell foaming and promote atherosclerosis Is expected to be reduced.

 Until now, amide compounds having ACAT inhibitory activity have been disclosed in JP-A-59-231.

Compounds disclosed in, for example, JP-A Nos. 058 and 63-3253600 are known. Similarly, Japanese Patent Application Laid-Open Nos. Sho 60-41665, 63-3161661, and

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.

 "Disclosure of the invention"

 The present inventors have conducted intensive studies from this viewpoint. As a result, 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

1. —Crotch

[In the formula, 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

(Wherein, m is 0 or an integer of 1 to 3, R,, R ^ie the same or different and hydrogen, halogen, hydroxyl, Shiano may be straight鏆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.)

Represents a group represented by

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.

Bonded 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 represents 0, 1 or 2. 'An aryl alkanoic acid anilide compound represented by or a pharmaceutically acceptable salt thereof,

2. In the general formula (I), X represents an oxygen atom, NR ¹¹ (R ¹¹ represents hydrogen or alkyl having 1 to 4 carbon atoms), C0, CH ₂ or a chemical bond:

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

(In the formula, m is 0 or an integer of 1 to 3, and 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. Alkyl, C1-C12 alcohol or alkokiji which can be divided, haloalkyl having C1-C4, aryl optionally having ft-substituent, aryl optionally having tt-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 an alkoxy or aryl alkenyloxy which may have a substituent; Represents a group which may combine to form 5, 6, Ί, 8-tetrahydroquinoline with ring Q.)

Represents a group represented by; 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 ;

Bonded 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 represents 0, 1 or 2;

The compound according to claim 1 or a pharmaceutically acceptable salt thereof,

3. —In the formula (I), 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. Alkyl having 5 to 12 carbon atoms which may be substituted or may be divided, or a formula

(In the formula, m is 0 or an integer of 1 to 3, and R ′ and R ¹⁰ are the same or different and are hydrogen, halogen, hydroxyl, cyano, linear or branched with 1 to 2 carbon atoms. A good alkyl, an alkoxy having 1 to 12 carbon atoms which may be straight-chained or separated, an arylalkoxy optionally having a substituent, or an arylalkenyloxy optionally having a substituent. , Z represents CH, D and E represent hydrogen.) Shows a group represented by:

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;

Rs, R ^7, R 'represents hydrogen, halogen or number 1 to 40 alkyl carbons same or different:

 η indicates 0, 1 or 2:

The compound according to claim 1 or a pharmaceutically acceptable salt thereof,

4. — In the general formula (I), 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

(In the formula, m is 0 or an integer of 1 to 3, 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.)

Represents a group represented by;

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 represents 0, 1 or 2;

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, 5. Preferred compounds are N- (2,6-diisopropylphenyl) 141-octylphenylacetamide,

 N- (2,6-diisobrovirphenyl) -1-4-decyloxyphenylacetamide,

 N- (2,6—Jetylphenyl) 1-3— (5-Fluoro-2-Cetyloxysibenbuyl) phenylacetamide,

 N— (2, 6—Jetylphenyl) -1-3- (4-Fluorobenzyl) phenylacetamide,

 N- (2,6-diisoprovirphenyl) 14-year-old octyloxyphenyl acetate,

 N— (2,6—Jetylphenyl) 1-4-octyloxyphenylacetamide ',

 N— (2,6-Detylphenyl) -1-4-octylphenylacetamide, N— (2,6-Diisopropylphenyl) -13-year-old butyloxyphenylacetamide,

 N- (2,6-diisopropylphenyl) 1-2-chloro-4 year-old octyloxyphenylacetamide,

 N- (2,6-diisopropylphenyl) -1-4-decylphenylacetamide, N- (2,6-diisopropylphenyl) -12-year-old octyloxyphenylacetamide,

 N- (2,6-diisopropyl phenyl) 1-3- (2-benzyloxy 5-cyclobenzyl) phenylacetamide,

 N- (2,6-diisopropylphenyl) 1-3- (5-fluoro-2-octyloxybenzoyl) phenylacetamide,

 N- (2,6-diisopropylphenyl) 1-3- (5-fluoro-2-hexoxybenzoyl) phenylacetamide,

N- (2,6-diisopropylphenyl) -1-3- (4-hexylbenzyl) phenylacetamide, and -(2,6-diisopropylphenyl) 1-41-decyloxyphenylpropionamide

The compound according to claim 1 or a pharmaceutically acceptable salt thereof,

 6. 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,

 7. 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,

Is provided.

 The meaning of each definition in the above definition and in this specification is as follows.

 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. Well, for example, benzyl, 1-la-ruethyl, 2-phenyl-ethyl, 1-methyl-1-1-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenyl-2-propyl, 2-methyl-2-phenylpropyl, Examples thereof include 1-naphthylmethyl and 1- (1-1-naphthyl) ethyl, and the aryl group may have the same substituent as described above.

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.

In the compound of the formula (I), R ¹ is a group represented by the formula (II), and when X represents CO, a compound in which m is 0 is preferable.

 If the compounds of the present invention can form salts, these 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.

Among the compounds of the present invention, 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.

Method 1

 The compound of the general formula (I) has the general formula

(In the formula, each symbol is as defined in the general formula (I).)

A carboxylic acid or a reactive derivative thereof represented by the general formula:

(In the formula, each symbol is as defined above.)

It is produced by reacting a compound represented by

 — When the compound of the general formula (II) is a free carboxylic acid, 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.

When an acid halide such as acid chloride or acid bromide is used as the reactive derivative of the carboxylic acid of the general formula (III), 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. When an acid anhydride is used, 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.

 — When an ester such as methyl ester, ethyl ester, p-ditrophenyl ester or p-chlorophenyl ester is used as a reactive derivative of the compound of the general formula (III), the reaction is conducted in an inert solvent (compound (IV) Can be used as a solvent in excess) at room temperature or under heating, preferably under reflux with heating.

 Examples of the solvent used in the above reaction include 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 απ) or a reactive derivative thereof is

 Tetrahedron. 1967, Vol. 23, pp. 1735-1738; U.S. Pat. No. 3,641,127;

Chem. 1977, 17 (8). Pp. 293-294; French Patent No. 1,516,775; Journal of Medicinal Chemistry, 1976. Vol. 19. No. 7. pp. 941-946; It is manufactured by the methods described in Japanese Patent Application Laid-Open Nos. 0-5398, 50-36468 and 50-36469.

Method 2

 — Among the compounds of the general formula (I), those in which X is a sulfur atom or an oxygen atom are represented by the general formula

(In the formula, X ¹ represents a sulfur atom or an oxygen atom, and other symbols are as defined above.) And a compound represented by the general formula

R ¹ -J CVO

 (In the formula, 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 溶媒 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.

 In the same way,

(In the formula, each symbol is as defined above.)

(This is obtained by demethylating the corresponding methoxy compound by a method known per se) and a compound represented by the general formula

R ¹¹ -J CVD

(Wherein, 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. And J is as defined above.)

By reacting the compound represented by the formula (I), 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 -Among the compounds of formula (I), the compound wherein X is CH ₂ can also be produced by the following method. For example, 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 .

Method 4

—A compound of the general formula (I) wherein X is NR ¹¹ is a compound of the general formula (I)

(In the formula, each symbol is as defined above.)

And a compound represented by the general formula

R ¹ '-CHO (IX)

(In the formula, R ¹ ′ represents alkyl having one less carbon atom in R ^1. )

Is produced by reacting the compound represented by the formula with a reducing agent such as sodium borohydride or sodium cyanoborohydride in an inert solvent such as ethanol under ice cooling or at room temperature. Alternatively, using a compound of the general formula (VI II) and a compound of the general formula (VI) in an inert solvent at room temperature or under heating, tertiary amines such as triethylamine, pyridine and N, N-dimethylaniline It is produced by carrying out the reaction in the presence of a base or in an inert solvent at room temperature or under heating in the presence of an alkali such as sodium hydroxide or potassium carbonate.

 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.

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.

 The ability of the compound of the present invention to inhibit ACAT and lower lipids can be confirmed, for example, by the following pharmacological experiment examples.

Pharmacological experiment 1: A CAT inhibitory action

Heider. JG et al. (J. Lipid Res., 24, 1127 (1983) used the enzyme as a microsomal fraction of the small intestinal membrane of male rabbits bred for 2 months on a diet containing 2% cholesterol. ) was measured ACAT activity according. that, after Bok 5 minutes brain-incubated over the test compound ^[1-14 C] Oreoiru CoA to 37 'C, were incubated enzyme preparation was added pressure for 3 minutes. black port Holm After stopping the reaction by adding a mixture of methanol and methanol (2: 1), removing the form layer by centrifugation and performing thin-layer chromatography (TLC). The incorporation of radioactivity into the cholesterol ester fraction was measured by using the following method.The concentration ( _ICse ) that inhibited the incorporation of radioactivity by 50% was determined.

Table 1 Inhibition of test compound A CAT

 (Example number) I Cso (M

1 1 0. 00 7

 1 6 0. 004

 1 7 0. 00 7

 52 0.0 0 6

 5 5 0. 00 7

 60 0.00 7

Pharmacological experiment 2: Lipid-lowering effect

 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.

 As a result, the cholesterol level of serum and hepatic glare in the group to which the compound of the present invention was administered was significantly lower than that in the control group. Similar results were obtained in experiments using mice and egrets.

 From these pharmacological experiments, 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.

Pharmacological experiment 3: Inhibition of cholesterol esterification in cultured macrophages Denatured LDL-dependent cholesterol esterification in macrophages (M0) was measured according to the method of Brown et al., J. Biol. Chem., 255, 9344 (1980)]. That is, at 37, under conditions of 5% CO ₂ /95% air, male d dY mice The coming peritoneal cavity M0 was pre-cultured with the test compound for 2 hours, and then [〖C] oleic acid, bovine serum albumin and acetyl LDL were added and the culture was continued. After 5 hours, the reaction was stopped, and intracellular lipids were extracted with hexane Z-propanol (3: 2). The subsequent operation is the same as the method described in the section on pharmacological experiment 1. As a result, IC _{5 of the} compound was determined. Values 1 0 - indicates ⁷ to 1 M篋of it was found to have a strong cholesterol ester Kasomosomo for production.

Pharmacological Experiment 4: Toxicity ''

 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.

When the compound of the present invention is used as a medicament, it can be administered orally or parenterally. For that purpose, 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.

"Best mode for carrying out the invention"

 Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited thereto.

Example 1

 24 g of 3- (4-methoxybenzoyl) phenylacetic acid was dissolved in 250 ml of dichloroethane, 2 Oml of thionyl chloride was added, and the mixture was stirred at room temperature for 3 hours. After the solvent was concentrated under reduced pressure, 20 Oml of dichloroethane was added again, and at 0, a solution of 18 g of triethylamine and 13 Og of 2,6-diethylaniline in 5 g of dichloromethane was added dropwise and stirred at the same temperature for 1 hour. did. After stirring at room temperature for 1 hour, the reaction solution was washed with water, washed with a saturated aqueous solution, further washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give colorless crystals of N- (2,6-ethylphenyl) -13- (4-methoxybenzyl) phenylacetamide. Melting point 1

40 to 1 41. C

Example 2

 8.0 g of 3- (5-fluoro-2-methoxybenzoyl) phenylacetic acid was dissolved in 8 Oml of dichloromethane, and 2.Om1 of thionyl chloride was added, followed by observation at room temperature for 3 hours. After concentrating the solvent under reduced pressure, add 8 Oml of dichloroethane again, and add 3.3 g of N-methylmorpholine and 7 Oml of 4,6-diethylaniline 4.lg of dichloroethane at Ο'ς. The time was stirred. After further stirring at room temperature for 2 hours, the reaction solution was washed with water, washed with a saturated aqueous solution of sodium hydrogen carbonate, further washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate and isopropyl ether to give N- (2,6-methylthiophenyl) -13- (5-fluoro-2-methoxybenzoyl) phenylacetamide. Mp 180-181. C

Example 3

 3-((4-fluorobenzoyl)) Dissolve 5.0 g of phenylacetic acid in 5 Om 1 of ethyl acetate, add 2.7 g of triethylamine, and use O'C to obtain a viva-yield lid 2.

5 g was added dropwise, and the mixture was stirred at the same temperature for 15 minutes. Then 2, 6—Jetiraniline 2. 9 g of an ethyl acetate solution 2 Om1 was added dropwise with O'C, and the mixture was stirred at the same temperature for 30 minutes, and further stirred at room temperature for 3 hours. The reaction solution was washed with water, washed with a saturated aqueous solution of sodium hydrogencarbonate, further washed with water, and dried over magnesium triluate, and the solvent was distilled off. The residue was recrystallized from ethyl acetate and isopropyl ether to give colorless crystals of N- (2,6-methylphenyl) -13- (4-fluorobenzoyl) phenylacetamide. Melting point i 32〜 1 3 3 'C

Example 4

 (Earth) 2- (6-Methoxy-2-naphthyl) Dissolve 2.0 g of bromopionic acid in 40 ml of ethyl acetate, add 1.1 g of triethylamine, and stir under ice-cooling while stirring. Ride 1.04 g was added dropwise, and the mixture was stirred at the same temperature for 30 minutes. Then, 1.23 g of 2,6-diethylaniline was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with an aqueous potassium carbonate solution, dried and concentrated under reduced pressure. The solid residue was recrystallized from ethyl acetate-isopropyl ether to give colorless crystals of (earth) N- (2,6-getylphenyl) 1-2- (6-methoxy-2-naphthyl) propionamide. Melting point 182-184'C

Example 5

(Earth) 1.4 g of 2- (4-methoxy-3-nicotinoylphenyl) brobionic acid was dissolved in a mixed solvent of 10 ml of dimethylformamide and 40 ml of tetrahydrofuran, and 0.6 g of N-methylmorpholine was dissolved. It was added dropwise an 5 ^e C in Isopuchi Le chloroformate 0. 7 g from a 1 0 ° C, was攪捽30 minutes at the same temperature. Next, 10 ml of a tetrahydrofuran solution of 0.9 g of 2,6-diethylaniline was added dropwise at −10 ° C. at −5 ° C., and the mixture was stirred at the same temperature for 1.5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, washed with a saturated aqueous solution of sodium hydrogencarbonate, further washed with water and dried over magnesium sulfate, and the solvent was distilled off. The residue was recrystallized from ethyl acetate and isopropyl ether to give a colorless needle-like (soil) N- (2,6-diethylphenyl) 1-2- (4-methoxy-3-nicotinylphenyl) propionamide I got it. Melting point 1 24-125'C

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. The reaction solution was washed with water, washed with an aqueous solution of potassium carbonate, further washed with water and dried over magnesium sulfate, and the solvent was distilled off. The residue was recrystallized from acetic acid E chill and isopropyl ether, colorless crystals (Sat) N-(2, 6- Jechirufueniru) Single 2- (3-Benzo I Ruch enyl) _c mp 1 0 5 to give the Burobion'ami de ~ 106

Example 7

 Dissolve 2.0 g of 4-methoxy-3- (2-chloro-6-isopropylnicotinoyl) phenyl acetic acid in 4 Om 1 of ethyl acetate, and dicyclohexylcarposimid

1.1 g was added, and the mixture was stirred at room temperature for 1 hour. Then, 0.8 g of 2,6-diethylaniline was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The precipitated dicyclohexyl perea was removed by filtration, and the filtrate was washed with a saturated aqueous solution of sodium hydrogen carbonate and water, dried over magnesium sulfate, and the solvent was distilled off. The residue was recrystallized from toluene and isopropyl ether to give colorless crystals of N- (2,6-methylthiophenyl) -14-methoxy-3- (2-1-chloro-6-isopropylnicotinol) phenylacetamide. Was. Melting point

16 3 to 16 4. C

Example 8

Dissolve 3.5 g of 3- (5-chloro-2-methoxybenzoyl) phenidulic acid in 6 mL of dichloroethane, add 0.8 ml of thionyl chloride, 2-3 drops of dimethylformamide, and add at room temperature. Stir for 1 hour. At O'C, 3 Om1 of a dichloroethane solution of 1.3 g of N-methylmorpholine and 1.6 g of 2,6-diethylaniline was added dropwise, and the mixture was stirred at the same temperature for 1 hour. The mixture was further stirred at room temperature for 2 hours. Next, the reaction solution was washed with water, washed with a saturated aqueous solution of sodium hydrogen carbonate, further washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate to give colorless crystals of N- (2,6-getylphenyl) 13- (5-chloro-2-methoxybenzyl) phenyl. Obtained rasetamide. Melting point 1 86-1 8 7'C

Example 9

 (±) 2-[4-Methoxy-3- (2-chloro-6-isobentylnicotinol) phenyl] Dissolve 2.0 g of bromoponic acid in 4 Oml of dichloroethane and add 0.4 ml of thionyl chloride. In addition, the mixture was stirred at room temperature for 2 hours. After distilling off the solvent under reduced pressure, add 40 ml of dichloromethane again, and at 0 ° C, a solution of 0.6 g of N-methylmorpholine and 0.8 g of 2,6-diethylaniline 0.8 g 20 mi was added dropwise, and the mixture was stirred at the same temperature for 1 hour. The mixture was further stirred at room temperature for 2 hours. Next, the 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 subjected to silica gel column chromatography, distilled with chloroform-form methanol (99: 1), recrystallized from isopropyl ether, and (Sat) N- (2,6-Jetylphenyl) 1-2- [ 4-Methoxy-3- (2-chloro-6-T-soventilnicotinol) phenyl] propionamide was obtained. Melting point 147 ~ 1 48 'C

Example 10

3.3 g of 4-cyclohexylphenyl acid was dissolved in 60 ml of dichloroethane, 1.1 ml of thionyl chloride and 2-3 ml of dimethylformamide were added, and the mixture was stirred at room temperature for 1 hour. After distilling off the solvent under pressure, add 60 ml of dichloroethane again. At 0, add 30 ml of a solution of 1.5 g of N-methylmorpholine and 1.9 g of 2,6-getylaniline in dichloromethane at the same temperature. For 1 hour. The mixture was further stirred at room temperature for 2 hours. The 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 ethyl acetate and isopropyl ether to obtain N- (2,6-getylphenyl) -14-cyclohexylphenylacetoamide. Melting point 152-153 ^e C

Example 1 1

2.0 g of 4-octylphenylacetic acid was dissolved in 40 ml of dichloromethane, 0.7 ml of thionyl chloride was added, 2-3 drops of dimethylformamide were added, and the mixture was stirred at room temperature for 2 hours. After the solvent was concentrated under reduced pressure, 40 ml of dichloroethane was added again, and N-methyl A solution of 1.O g of rumorpholine and 1.4 g of 2,6-diisobroviraniline in 2 Om1 of dichloroethane was added dropwise, and the mixture was stirred at the same temperature for 1 hour. The mixture was further stirred at room temperature for 2 hours. The 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

Example 1 2

 Dissolve 2.0 g of N- (2,6-diisopropylpyrphenyl) 1-4-hydroxydiphenylacetamide in 4 Om1 of dimethylformamide, add 1.3 g of potassium carbonate, and add 40 g of potassium carbonate. For 10 minutes. After allowing to cool, 1.4 g of decyl bromide was added at room temperature, and the mixture was stirred for 6 hours with 6 (TC. The reaction solution was poured into water, extracted with dichloromethane, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from isopropyl ether and hexane to give N- (2,6-diisopropylphenyl) 141-decyloxyphenylacetamide as colorless crystals, mp 122-12. 3. C

Example 13

 Dissolve 5.8 g of N- (2,6-getylphenyl) 1-3- (4-methoxybenzoyl) phenylacetamide in 6 mL of dichloroethane and add 6.7 g of aluminum chloride with stirring at room temperature. The mixture was added little by little and stirred at reflux temperature for 2 hours. The reaction solution was poured into ice water, 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, and distilled with chloroform-methanol (98: 2) to give an oily N- (2,6-ethylphenyl) -13- (4-hydroxybenzoyl) phenylacetamide I got

 ^ -NMRCCDCh) ά: 1.10 (t.6H). 2.40 (q, 4H), 3.80 (s, 2H), 6.65 (d, 2H), 6.80 -7.20 (m.4H), 7.30-7.70 (m.6H )

Example 14

N- (2,6-Jetylphenyl) -3- (5-Fluoro-2-methoxybenzyl) Dissolve 10.6 g of phenylacetamide in 100 ml of dichloroethane, Under stirring at room temperature, 6.3 g of aluminum chloride was added little by little, and the mixture was concentrated at reflux temperature for 2 hours. The reaction solution was poured into water, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, distilled with chloroform-methanol (98: 2), and the solvent was distilled off. The residue was recrystallized from ethyl acetate and butyl ether to give N- (2,6-getylphenyl) -3- (5-monofluoro-2-hydroxybenzoyl) phenylacetamide as pale yellow crystals. With a melting point of 15 5 to 15 6 "

Example 15

 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

Example 16

 Dissolve 3.0 g of N- (2,6-getylphenyl) -13- (5-fluoro-2-hydroxybenzoyl) phenylacetamide in 60 ml of dimethylformamide, and add potassium carbonate 1.5 g was added and shaken with 4 O'C for 10 minutes. Next, 1.6 g of octyl promide was added, and the mixture was stirred at 6 O'C for 3 hours. The reaction solution was poured into water, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate and isopropyl ether to give colorless crystals of N- (2,6-getylphenyl) -13- (5-fluoro-2-octyloxybenzoyl) phenylacetamide. With a melting point of 77-78

Example 17

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.

Distillation was performed at (99: 1), and the solvent was distilled off. The residue was recrystallized from isopropyl ether to give N- (2,6-getylphenyl) -13- (4-fluorobenzyl) phenyl cetamide as colorless crystals. Melting point 105 ~ 106 ° C

 The following compounds were obtained in the same manner as in Examples 1 to 17 above.

Example 18

 N- (2.6-diisopropylphenyl) 1-3- (4.1-fluorobenbuyl) phenylacetamide, melting point 180-181

Example 19

 N— (2,6-diphenylpyrphenyl) 1-41 (4-fluorobenbuyl) phenylacetamide, melting point 207-209. C

Example 20

 N- (2,4-difluorophenyl) 1-3- (4-fluorobenbuyl) phenylacetamide, melting point 131-13-132'C

Example 2 1

 N- (2,6-Jetylphenyl) 1-3-Phenoxyphenylacetamide, melting point 130-30C

Example 22

 N- (2,6-Jetylphenyl) 1-3- (4-Fluorophenoxy) phenylacetamide, melting point 122-124 ° C

Example 23

 N— (2,6-diphenyl biphenyl) —3— (4-fluorophenoxy) phenylacetamide, melting point 144-145 ° C

Example 24

N— (2,6-getylphenyl) 1-41 (2-fluorophenoxy) phenylacetamide, melting point 155-16.5 ”C Example 2 5

 N— (2,6-Jetylphenyl) 1-41 (4-fluorophenoxy) phenylacetamide, melting point 15 t to l 52 ° C

Example 26

 N- (2, S-Jetylphenyl) 1-41- (4-fluorobenzyloxy) phenylacetamide, mp 1 S6-16-167

Example 2 7

 N- (2,6-Jetylphenyl) 1-41- (4-cyanophenoxy) phenylacetamide, melting point 169-17-170

Example 2 8

 (Earth) N— (2,6-Jetylphenyl) 1-2- (2-Fluoro-4-biphenylyl) Probionamide, mp 144-146

Example 2 9

 (Sat) N- (2,6-Jetylphenyl) 1-2- [4-Methoxy-3- (2-benzyloxynicotinyl) phenyl] propionamide, melting point 91-93C Example 30

 (Sat) N— (2,6-Jetylphenyl) 1-2— (4-benzyloquinone-3-Nicotinylphenyl) Bropionamide, melting point 121-122

Example 3 1

 (Sat) N- (2,6-Jetylphenyl) 1-2- [4-Methoxy-3- (2-cyclonicotinyl) phenyl] propionamide, melting point 160-162 ° C Example 32

 (Sat) N— (2,6-Jetylphenyl) 1 2— [4-Methoxy 3— (2-Cinnamyloxynicotinol) phenyl] Bropionamide, melting point 1 19 to 120 ° C

Example 3 3

N- (2,6-diisopropylphenyl) 1-3- (5-fluoro-2-methoxybenzoyl) phenylacetamide, mp 155-156. C Example 3 4

 N- (2,6-diisopropylpropyl) 1-41 (5-fluoro-2-methoxybenben) phenylacetamide, melting point 196-17-17'C

Example 3 5

 N- (2,6-Jetylphenyl) 1-41- (5-fluoro-2-methoxybenvyl) phenylacetamide, melting point 183-184. C

Example 3 6

 N- (2,6-Jetylphenyl) 1-2-methyl-2- [3- (4-fluorobenzoyl) phenyl] propionamide, melting point 123-124. C

Example 3 7

 (Earth) N— (2,6-Jetylphenyl) -12- [4-Methoxy-13- (2-chloro-6-isopropylnicotinol) phenyl] propionamide, melting point 144-144. C

Example 3 8

 N— (2,6-getylphenyl) 1-41 (3-cyano 6-isopentyl-2-pyridyloxy) phenylacetamide, melting point 160-162. C

Example 3 9

 N— (2,6-Jetylphenyl) 1-41 (3-Cyan-6-phenyl-2-pyridyloxy) phenylacetamide, melting point 23 37-239'C

Example 40

 N- (2,6—Jetylphenyl) 1-41 (3-Cyanol 5,6,7,8-Tetrahydro-2-quinolyloxy) phenylacetamide, melting point 202-205 ° C

Example 4 1

 N- (2,6-Jetylphenyl) 1-41 (3-Cyanol 6-methyl-2-pyridyloxy) phenylacetamide, melting point 2 17 ~ 2 18 ° C

Example 4 2

N— (2, 6—Jetylphenyl) 1-41 (3—Cianeau 6—tert-butyl) 2-pyridyloxy) funynylacetamide, mp 175-17. C

Example 4 3

 -(2,6-Jetylphenyl) 1-41 (3-Cyan-4, S-dimethyl-21-pyridyloxy) phenylacetamide, melting point 22-25-22 7 ° C

Example 4 4

 N— (2,6-Jetylphenyl) 1-41 (3-Cyanol 2-pyridyloxy) phenylacetamide, mp 206-207. C '

Example 4 5

 N- (2,6-Jetylphenyl) 1-3-Chloro-4-1 (3-Syno 6-isopropyl-12-pyridyloxy) phenylacetamide, melting point 159-16.0 V

Example 4 6

 N— (2,6-Jetylphenyl) 1-41 (3-Cyanol 6-Tsopropyl-12-pyridyloxy) phenylacetamide, melting point 160-i61. C

Example 47

N-(2, 6-Jechirufueniru) Single 3 Shiano 6-isopropyl one 2-Hoon Rijiruokishi) phenylalanine § Seto Ami de, mp 1 4 5~1 4 6 ^e C

Example 4 8

 (Sat) N— (2,6-Jetylphenyl) 1 2— [4-1 (3-Cyanol 6-sopropyryl 2-pyridyloxy) phenyl] Bropionamide, melting point 156-15-17'C

Example 4 9

 N— (2,6-Jetylphenyl) 1 3- (4-1 (3-Cyanol 6-isopropyl-12-pyridyloxy) phenyl) Bropionamide, melting point 152-i54 ° C

Example 5 0

-(2,6-Jetylphenyl) 1-41 (5-trifluoromethyl-2-pyridyloxy) phenylacetamide, mp 1779-i80. C Example 5 1

 N- (2,6-diisopropylphenyl) 1-4 octyloxyphenyl acetate, melting point 1 4 6

Example 5 2

 N— (2,6-Jetylphenyl) 14-year-old octyloxyphenylacetamide, mp 105-106

Example 5 3-

N- (2,6-Jetylphenyl) 1-3-Chloro-4-octyloxyphenyl acetoamide, melting point 1 16 to 1 18'C

Example 5 4

N-(2, 6- diisopropyl-phenylalanine) Single 3-chloro 4 Okuchiruokin phenylene Ruasetoami de, mp 1 0 9~1 1 0 ^e C

Example 5 5

N-(2, 6- Jechirufueniru) Single 4- Okuchirufue two Ruasetoami de, melting point 8 5~ 8 6 ^e C

她 Example 5 6

 N- (2,6-diisopropylphenyl) 1- 4-hexyloxyphenylacetamide, melting point 172-174'C

Example 5 7

 N- (2,6-diisopropylphenyl) 1-41-hexadecyloxyphenylacetamide, melting point 1 1 1 to 1 1 3

Example 5 8

 N- (2,6-diisopropylphenyl) -1-3-octyloxyphenyl acetate, melting point 98-99'C

Example 5 9

 N- (2,6-diisopropylpyrphenyl) 1-2-chloro-4-octyloxyphenylacetamide, melting point 1 1 1 to 1 1 3 ° C

Example 6 0 -(2,6-diisopropyl phenyl) 1-4-decylphenylacetamide, melting point 89-91 ° C

Example 6 1.

N- (2.6-diisopropylpropenyl) -1-2-octyloxyphenylacetamide, melting point 114-115'C

Example 6 2

 N- (2,6-diisopropylpyrphenyl) 1-4-dodecylphenylacetamide, melting point 103-105'C

Example 6 3

 N- (2,6-Getylphenyl) 1-3- (5-Chloro-2-hydroquinbene butyl) phenylacetamide, mp 203-204. C

Example 6 4

 N- (2,6-diisopropylpropyl) 1-3- (5-fluoro-2-hydrokizibenzyl) phenylacetamide, melting point 179-180 ° C

Example 6 5

 N- (2,6-diisopropyl phenyl) 1-41 (5-fluoro-2-hydroxybenzoyl) phenyl cetamide, melting point 1669-i72

Example 6 6

 N— (2,6-getylphenyl) 1-41 (5-fluoro-2-hydroxybenzoyl) phenylacetamide, melting point 186-187′C

Example 6 7

 N- (2,6-diisopropylphenyl) 1-3- (5-chloro-2-hydroxybenzoyl) phenylacetamide, melting point 184-185'C

Example 6 8

 N- (2,6-diisopropylphenyl) -13- (5-chloro-2-hydroxybenzyl) phenylacetamide, melting point 135-137

Example 6 9

N- (2.6-Jetylphenyl) 1 3- (4-Isopropyloxybenzoy F) Fenilacetamide, melting point 13 6-13

Example 7 0

 N— (2, 6-Jetylphenyl) — 3— (2-Benzyloxy 5-cyclobenzoyl) phenylacetamide, melting point 151-15-152

Example 1 1

 N- (2,6-Jetylphenyl) -1-3- (5-Chloro-2-cinnamyloxysibenvyl) phenylacetamide, melting point 160-16C-Example 72

 N- (2,6-Jetylphenyl) 1-3- (5-Chloro-2-isopropyloxybenzoyl) phenylacetamide, melting point 170-172 ° C

Example 7 3

 N- (2,6-getylphenyl) 1-3- (5-chloro-2-octyloxybenzoyl) phenylacetamide, mp 93-94. C

Example 74

 N- (2,6-diisopropylpropyl) 1-3- (2-benzyloxy-5-chloro benzyl) phenylacetamide, melting point 130-132

Example 75

 N— (2,6-Jetylphenyl) 1-3— (2-Benzyroxy-5-fluoro-benbuyl) Phenylacetamide, melting point 124-125. C

Example 76

 N- (2,6-diisopropylphenyl) -4-1 (5-fluoro-2-octyloxybenzoyl) phenylacetamide, melting point 156-17-17 ° C

Example 77

 N- (2,6-diisopropylphenyl) 1-3- (5-fluoro-2-octyloxybenzoyl) phenylacetamide, melting point 109-110 ° C

Example 7 8

N- (2,6-diisopropylphenyl) -1-3- (2-benzyloxy-5-fluorobenzoyl) phenylacetamide, melting point 144-149 ° C Example 7 9

 -(2,6-diisopropylphenyl) 1-3- (5-fluoro-2-hexoxybenbuyl) funinyl acetate, melting point 1 I 4 to 115 ° C

Example 8 0

 N- (2,6-diphenylpyruphenyl) 1-3- (4-fluorobenzyl) phenylinacetamide, mp 142-134

Example 8 1.

 N- (2,6-Jetylphenyl) 1-3- (5-Fluoro-2-octyloxybenzyl) phenylacetamide, melting point 95-96Ό

Example 8 2

 N- (2,6-Jetylphenyl) -1-3- (2-benzyloquin-5-chlorobenzyl) phenylacetamide, mp 133-136. C

Example 8 3

 N- (2,6-Jetylphenyl) 1-3- (5-Chloro-2-octyloxybenzyl) phenylacetamide, mp 99-100. C

Example 8 4

 N- (2,6-Jetylphenyl) -1- (5-fluoro-2-methoxybenzyl) phenyl phenylacetamide, mp 103-104

Example 8 5

 (Earth) N- (2,6-diisopropylphenyl) 1-2- (4-octylphenyl) brobionamide, melting point 146-148. C

Example 8 6

 N— (2.6-diisopropylphenyl) 111 (4-octylphenyl) cyclopentanecarboxyamide, melting point 73-75. C

Example 8 7

 N- (2,6-diisopropylphenyl) 1-2-methyl-2- (4-octylphenyl) propionamide, melting point 82-84. C

Example 8 8 -(2,6-diisopropylphenyl) 1-41 (8-dimethylaminooctyloxy) phenylacetamide, melting point 105-107'C

Example 8 9

 (Sat) N— (2,6-diisopropylphenyl) -2- (4-decyloxyphenyl) probionamide, mp 124-125. C

Example 9 0

 N- (2,6-diphenyl biphenyl) 1-2-methyl-2 (3- (2-benzyloxy-5-cyclobenzyl) phenyl) propionamide, melting point 88-90 ° C

Example 9 1

 N— (2,6-dipyrrophenyl) 1-3— (2,4-difluorobenzoyl) phenylacetamide, melting point 14 1 to 14 3 * C

Example 9 2

 N- (2,6-diisopropylphenyl) 1-3- (2,4-difluorobenzyl) phenylacetamide, mp 108-109. C

Example 9 3

 N- (2,6-diisopropylphenyl) -1- (4-hexylbenzoyl) phenylacetamide, mp 92-94

Example 94

 N- (2,6-diisopropylphenyl) 1-3- (4-hexylbenzyl) phenylacetamide, melting point 101-103 * C

Example 9 5

 N- (2,6-diisopropylphenyl) 1-3- (4-decyloxyphenyl) propionamide, mp 96-99. C

Example 9 6

N- (2,6-diisopropylphenyl) -1-5- (1,1,3,3-tetramethylbutyl) -12-methoxyphenylacetamide, melting point 133-134 ° C Example 97 ' 4 N- (2.6-diisobu π-pyrphenyl) obtained by reacting in the same manner as in Example 11 using 12-port phenylacetic acid and 2,6-diisopropylaniline, and reducing with iron powder monohydrochloric acid Dissolve 6.0 g of 4-aminophenylacetamide (melting point: 133 to 135 ° C) in 10 Om1 of ethanol, add 2.47 g of octylaldehyde under ice-cooling, and press at 0. After stirring for 1 hour, 1.65 g of sodium borohydride was added at the same temperature, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under pressure, added with ice water, extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and distilled off with chloroform-methanol (99.5: 0.5). The residue was recrystallized from ethanol to give colorless crystals of N- ( 2,6-Diisopropylphenyl) 1-41 (octylamino) phenylacetamide was obtained. With melting point 1 2 3 to 1 24

 Hereinafter, the following compounds were obtained in the same manner.

Example 9 8

 N— (2,6-diisopropylphenyl) 1-41 (dodecylamino) phenylacetamide, melting point 110 to 11 rc

Example 9 9

 N- (2,6-diisopropylphenyl) 1-41 (decylamino) phenylacetamide, melting point 115-116

Similarly, the compounds shown in Table 2 below are obtained.

(Continued from Table 2)

No.R ¹ X position SR ¹ n

111 CH ₂ 3 HHOHH

112 CH; 3 H H 0 CH:-^> H

116 ^ "CH: 3 HH 0 HH

Formulation example

锭剤containing the present invention compound (I), _c compounds which can be prepared by the following formulation (I) 1 00 mg Lactose 76 mg Corn starch 1 Omg carboxymethylcellulose calcium 5mg cellulose 3mg magnesium stearate 2mg Boribinirubi port Li Don: 4 mg Total 20 Omg Compound (I) is pulverized by an atomizer into fine powder with an average particle size of 1 Ozm or less. Compound (I), lactose, corn starch, carboxymethylcellulose calcium and methylcellulose are thoroughly mixed in a multi-purpose machine, and a polyvinyl pyrrolidone paste solution is added and kneaded. Granulate the mixture through a 200 mesh sieve, 50. After drying in a hot air drier of C to a moisture content of 3 to 4%, passing through a 24-mesh sieve, mixing with magnesium stearate, and using a rotary punch, a flat punch having a diameter of 8 mm. Hit it.

 Although the present invention has been adequately and fully described in the foregoing specification and the examples contained therein, they can be changed or modified without departing from the spirit and scope of the invention.

Claims

The scope of the claims  General formula (I)

[In the formula, X represents a sulfur atom, an oxygen atom, NR ¹¹ (R ¹¹ represents hydrogen or alkyl having 1 to 4 carbon atoms.), C 0, CH i, or a chemical bond. R ¹ is a straight or branched alkyl having 5 to 18 carbon atoms, an alkenyl having 2 to 18 carbon atoms or a straight chain, a straight or branched chain having 2 to 18 carbon atoms. May be substituted with alkynyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, or cycloalkyl having 3 to 8 carbon atoms substituted with cycloalkyl having 3 to 8 carbon atoms. Cycloalkyl, C1-C4 alkyl substituted with C3-C8 alkyl, C1-C12 straight or branched substituted with mono- or dialkyl-substituted amino Good alkyl, or formula ([I)

(In the formula, m is 0 or an integer of 1 to 3, and R and are the same or different and each may be hydrogen, halogen, hydroxyl, cyano, or a straight-chain or subdivision having 1 to 12 carbon atoms. Alkyl, linear or branched alkoxy having 1 to 12 carbon atoms, 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 An aryl which may have a substituent, an arylalkyl which may have a substituent, an arylalkoxy which may have a substituent, an arylalkenyl which may have a substituent or which has a substituent. Represents aryl alkenyloxy, Z represents CH or a nitrogen atom, and D and E are the same or different and have a hydrogen or carbon number Represents an alkyl of 1 to 4 or binds together to form naphthylene, 1,2,3,4-tetrahydronaphthalene, quinoline or 5,6,7,8-tetrahydroquinoline with ring Q Show good groups. ) Represents a group represented by R ² and R ^s are the same or different and are hydrogen, halogen, hydroxyl group, cyano, alkyl having 1 to 12 carbon atoms, which may be straight-chain or capable of being separated, linear or branched having 1 to 12 carbon atoms. 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, And arylalkyl which may have a substituent, aryloxy which may have a substituent, arylalkenyl which may have a substituent and arylalkenyloxy which may have a substituent. Bonded R ¹ one X and R ³ are each, substituents together with the benzene ring may be 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 ⁴ and R ⁶ may be the same or different and may be substituted by hydrogen, alkyl having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms. Represents alkyl having 1 to 4 carbon atoms substituted with alkyl or arylalkyl which may have a substituent, or R ⁶ is bonded to each other to form a carbon atom having 3 to 7 carbon atoms together with an adjacent carbon atom. Shows a group forming a hydrogen ring. , R ^7, R 'represents hydrogen, halogen, hydroxyl, alkyl or alkoxy of 1 to 4 carbon atoms 1 to 4 carbon atoms the same or different.  n represents 0, 1 or 2. ] Or a pharmaceutically acceptable aryl alkanoic acid compound represented by 2. In the general formula (I), X is an oxygen atom, NR ^U (. R ¹¹ is showing an alkyl having 1 to 4 carbon hydrogen or carbon), indicating CO, CH ₂ or a chemical bond; R ¹ is a linear or branched alkyl having 5 to 18 carbon atoms, a cycloalkyl having 3 to 8 carbon atoms which may be substituted with alkyl having 1 to 4 carbon atoms, mono or dial Alkyl having 1 or 2 carbon atoms substituted by amino substituted with amino,

(Wherein, m is 0 or an integer of 1 to 3, R,, R ^ie the same or different and hydrogen, halogen, hydroxyl, Shiano, be straight鏆or partial work of carbon atoms 1 to 1 2 Good alkyl, linear or branched alkoxy having 1 to 12 carbons, haloalkyl having 1 to 4 carbons, aryl which may have a substituent, aryl which may have a substituent Z represents alkoxy or arylalkylenyloxy which may have a substituent, Z represents CH or a nitrogen atom, and D and E represent the same or different and represent hydrogen or alkyl having 1 to 4 carbon atoms. Or a group which may combine with each other to form 5,6,7,8-tetrahydroquinoline with ring Q.) Represents a group represented by; R ² and R ⁵ are the same or different and each represents hydrogen, halogen, a straight or branched alkoxy having 1 to 12 carbon atoms or an arylalkoxy optionally having a substituent: R ¹ -X and R ³ may be bonded to each other to have a benzene ring and a substituent (halogen, hydroxyl, cyano, alkyl having 1 to 8 carbons or alkoxy having 1 to 8 carbons) Represents a group that may form naphthalene; R ⁴ and R ⁶ are the same or different and each represent hydrogen or alkyl having 1 to 4 carbon atoms, or! ^ And R ⁵ are bonded to each other to form a hydrocarbon ring having 3 or more carbon atoms together with adjacent carbon atoms. Represents a group; R ^e , R ⁷ , R, are the same or different and represent hydrogen, halogen, or alkyl having 1 to 4 carbon atoms:  n represents 0, 1 or 2; 2. The compound according to claim 1, which is or a pharmaceutically acceptable salt thereof. 3. —In the formula (I), X represents an oxygen atom, MR 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. Substituted or branched or unsubstituted alkyl having 5 to 12 carbon atoms, or a formula

(Wherein, m is 0 or an integer of 1 to 3, R ^8, R ^ie the same or different and hydrogen, halogen, hydroxyl, Shiano, also was Shizuma straight carbon atoms 1 to 1 2 and then phase techniques Good alkyl, linear or branched alkoxy having 1 to 12 carbon atoms, arylalkoxy optionally having a substituent, or arylalkenyloxy optionally having a substituent. , Z represents CH, D and E represent hydrogen.) Represents a group represented by; And R ⁵ are the same or different and represent hydrogen, halogen or alkoxy having 1 to 12 carbon atoms which may be straight-chained or separated; R ⁴ and R ⁶ are the same or different and represent hydrogen or alkyl having 1 to 4 carbon atoms, or R <and R ⁵ are bonded to each other to form a hydrocarbon ring having 3 to 7 carbon atoms together with adjacent carbon atoms. Represents a group; R ′, R ⁷ and R «are the same or different and represent hydrogen, halogen or alkyl having 1 to 4 carbons;  n represents 0, 1 or 2; 2. The compound according to claim 1, which is or a pharmaceutically acceptable salt thereof. 4. —In the general formula (I), X represents an oxygen atom, CO, CH ₂ or a chemical bond; R ¹ is a linear or branched alkyl having 5 to 18 carbon atoms, or a formula

(In the formula, m is 0 or an integer of 1 to 3, R ^e and R ^ie are the same or different and are hydrogen, halogen, alkyl having 1 to 12 carbon atoms, or alkyl or carbon which may be separated. A few to twelve straight-chain or optionally alkoxy or arylalkoxy optionally substituted, Z represents CH, and D and E represent hydrogen.) Shows a group represented by: R ² and R ³ are the same or different and represent hydrogen or halogen; R * R ⁵ represents hydrogen; R ^e , R ⁷ and R ′ are the same or different and represent hydrogen or alkyl having 1 to 4 carbons;  n represents 0, 1 or 2; 2. The compound according to claim 1, which is or a pharmaceutically acceptable salt thereof. 5. N- (2,6-diisopropylphenyl) -1-octylphenylacetamide,  N- (2,6-diisopropylphenyl) 1-41-decyloxyphenylacetamide,  N- (2,6-getylphenyl) 1-3- (5-fluoro-2-octyloxybenzoyl) phenylacetamide,  N— (2,6-Jetylphenyl) 1-3— (4-Fluorobenzyl) phenyl Cetamide,  N- (2,6-diisopropylphenyl) 1-4-octyloxyphenyl acetate, N— (2,6-Jetylphenyl) 14-year-old octyloxyphenylacetamide ',' N— (2,6-Jetylphenyl) 14-octylphenylacetamide, N— (2,6-diisobrovirphenyl) 1-3-octyloxyphenylacetamide,  N- (2,6-diisopropylphenyl) -1-2-chloro-4-octyloxyphenylacetamide,  N- (2,6-disopropylpyrenyl) -1-4-decylphenylacetamide, N- (2,6-diisopropylphenyl) -12-octyloxyphenylacetamide, , ' N- (2,6-diisopropylphenyl) 1-3- (2-benzyloxy 5-cyclobenzyl) phenylacetamide,  N- (2,6-diisopropylphenyl) 1-3- (5-fluoro-2-octyloxybenzoyl) phenylacetamide,  N- (2,6-diisopropyl phenyl) 1-3- (5-fluoro-2-hexyloxybenzoyl) phenylacetamide,  N— (2,6-diisopropyl phenyl) 1-3— (4-hexylbenzyl) phenylacetamide, and  N— (2,6-diisopropirphanyl) 1-41-decyloxyphenylpropionamide 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 6. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 5 and a pharmaceutically acceptable additive.  7. A lipid-lowering drug or an anti-atherosclerotic drug, comprising the compound according to any one of claims 1 to 5 as an active ingredient.