JPH0525115A - Amide compound and its synthetic intermediate - Google Patents

Abstract

PURPOSE:To obtain a new amide compound useful as an antilipi demic agent of an antiarteriosclerotic agent, inhibiting acyl-coenzyme A and cholesterol acryltransferase or a pharmaceutically permissible salt thereof. CONSTITUTION:An amide compound shown by formula I [R<1> and R<2> are H, halogen, nitro, amino, OH, alkyl, alkoxy, aryl, etc.; R<3> and R<4> are H, halogen, amino, alkyl, alkoxy, etc.; R<5> is aryl or arylalkyl; A is alkylene or alkenylene; X is single bond or N (R<7>) (R<7> is H, alkyl, cycloalkyl, etc.) ; Y is alkylene, thia-alkylene or single bond; Z is CH or N; D and E are H, R<1>, R<2>, H, etc.) or a salt thereof such as N-(2,6-diethylphenyl)-3-[4-[2(3,5-ditert-butyl-4- hydroxyphenylthio)ethoxy]cinnamoyl]phenylacetamide. A compound shown by formula I wherein X is single bond is obtained by reacting a compound shown by formula II with a compound shown by formula III.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel and pharmaceutically useful amide compound and a drug containing the same.
More specifically, the present invention relates to compounds that inhibit acyl-coenzyme A: cholesterol acyltransferase (ACAT) and are useful as hypolipidemic agents and anti-atherosclerotic agents.

[0002]

2. Description of the Related Art Elevated blood cholesterol is known as a risk factor for many cardiovascular diseases. An increase in blood cholesterol causes deposition of cholesterol in the vascular system and atherosclerosis, which are considered to cause circulatory diseases such as angina and myocardial infarction. Dietary cholesterol is esterified by the action of acyl-coenzyme A: cholesterol acyltransferase (ACAT) in the small intestinal mucosal microsome, then absorbed, and released into the blood in the form of lipoprotein called chylomicrons. Therefore AC
By inhibiting the AT enzyme, it is expected that the absorption of dietary cholesterol from the intestinal tract is suppressed, the reabsorption of cholesterol released in the intestine is also suppressed, and blood cholesterol is reduced. Atherosclerosis is also a form of arteriosclerosis characterized by the accumulation of lipids, especially cholesterol esters, on the arterial wall. The accumulation of cholesterol ester in the arterial wall is considered to be involved in the accumulation of cholesterol ester in macrophages derived from blood monocytes as a scratch. Recently, it has been known that the production of cholesterol ester in macrophages and vascular smooth muscle cells is catalyzed by ACAT. Therefore, inhibition of the ACAT enzyme is expected to reduce the esterification rate of cholesterol and suppress the onset and progression of atherosclerosis due to the large accumulation of cholesterol ester in the arterial wall. Heretofore, as amide compounds having an ACAT inhibitory action, JP-A-59-231058 and JP-A-63-253060.
Compounds disclosed in Japanese Patent Publications and the like are known. Similarly, urea compounds having an ACAT inhibitory action are disclosed in JP-A-60-41655, JP-A-63-316761, JP-A-1-93569, JP-A-2-6456, and JP-A-2-275848. Are known. Further, carboxylic acid compounds are disclosed in JP-A Nos. 53-116356, 58-105935, Bull. Chem. Soc. Jpn. 56 (1), 347-8 (1983) and the like.

[0003]

The present invention provides a useful medicine,
In particular, it is an object of the present invention to provide a highly safe lipid-lowering drug and anti-atherosclerotic drug having an ACAT inhibitory action.

[Means for Solving the Problems] The inventors of the present invention have made extensive studies from this point of view, and as a result, the novel amide compound has a strong ACAT inhibitory action and a cell-level cholesterol esterification inhibitory action, as well as hyperlipidemia. The present invention was completed by discovering that it has serum and hepatic cholesterol lowering effects in model animals. That is,
The present invention has the general formula

[Chemical 5] [In the formula, R ¹ and R ² are the same or different and each represents hydrogen, halogen, nitro, amino, hydroxyl group, acylamino, alkyl, alkoxy, cycloalkyl, haloalkyl, aminoalkyl, mono- or di-substituted amino, mono- or di-substituted amino. Alkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, arylthioalkyl, aryloxyalkyl or —O—R ⁶
(Wherein R ⁶ represents cycloalkyl, haloalkyl, aminoalkyl, mono- or di-substituted aminoalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, arylthioalkyl or aryloxyalkyl). And each of the above aryls and heteroaryls may have 1 to 3 substituents selected from lower alkyl, lower alkoxy, cycloalkyl, halogen, nitro, amino, mono- or di-substituted amino, hydroxyl group, and acylamino. Good.
R ³ and R ⁴ are the same or different and each represents hydrogen, halogen, nitro, amino, mono- or di-substituted amino, hydroxyl group, acylamino, lower alkyl or lower alkoxy.
R ⁵ represents aryl or arylalkyl, each aryl having 1 to 3 substituents selected from lower alkyl, lower alkoxy, cycloalkyl, halogen, nitro, amino, mono- or di-substituted amino, hydroxyl group and acylamino. May be. A is a carbon number which may be branched 1 to
5 represents an alkylene or an alkenylene having 2 to 5 carbon atoms which may be branched. X is a single bond or -N (R ⁷⁾ -
(In the formula, R ⁷ represents hydrogen, alkyl, cycloalkyl or arylalkyl, and arylalkyl is lower alkyl, lower alkoxy, cycloalkyl, halogen,
1 to 3 substituents selected from nitro, amino, mono- or di-substituted amino, hydroxyl group, and acylamino). Y represents an alkylene having 1 to 5 carbon atoms that may be branched, an oxaalkylene having 1 to 5 carbon atoms that may be branched, a thiaalkylene having 1 to 5 carbon atoms that may be branched, or a single bond. . Z represents CH or a nitrogen atom. D and E are the same or different and are hydrogen or a substituent R
^They may represent ¹ or R ² or may be linked to each other with ring Q to form naphthalene, 1,2,3,4-tetrahydronaphthalene or quinoline, 5,6,7,8-tetrahydroquinoline. ] The amide compound represented by these, or its pharmaceutically acceptable salt.

The present invention also provides a compound of the general formula (I)

[Chemical 6] (In the formula, Ya represents an alkylene having 1 to 5 carbon atoms which may be branched or a thiaalkylene having 1 to 5 carbon atoms which may be branched, and the other symbols are as defined above. ) A carboxylic acid compound represented by) or a reactive derivative thereof, a general formula

[Chemical 7] (In the formula, Yb represents an optionally branched oxaalkylene having 1 to 5 carbon atoms or a single bond, and other symbols are as defined above.) Or a reaction thereof. Derivatives, and general formula

[Chemical 8] [Wherein R ¹ 'is nitro, amino, acylamino, cycloalkyl, haloalkyl, aminoalkyl, mono- or di-substituted amino, mono- or di-substituted aminoalkyl, aryl, arylalkyl, heteroarylalkyl,
Arylalkenyl, arylthioalkyl, in aryloxyalkyl or -O-R ⁶ (wherein, R ⁶ is cycloalkyl, haloalkyl, aminoalkyl, mono- or di-substituted aminoalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, shows a arylthioalkyl or aryloxyalkyl.) by a group represented, R ² 'is hydrogen, halogen, nitro, amino, hydroxyl, acylamino, alkyl, alkoxy, cycloalkyl, haloalkyl, aminoalkyl, mono- or di Substituted amino, mono- or di-substituted aminoalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, arylthioalkyl, aryloxyalkyl or -O-
R ⁶ ′ (wherein R ⁶ ′ represents cycloalkyl, haloalkyl, aminoalkyl, mono- or di-substituted aminoalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, arylthioalkyl or aryloxyalkyl). Each of the above aryls and heteroaryls has 1 to 3 substituents selected from lower alkyl, lower alkoxy, cycloalkyl, halogen, nitro, amino, mono- or di-substituted amino, hydroxyl group and acylamino. You may have. Yb represents an oxaalkylene having 1 to 5 carbon atoms which may be branched or a single bond. Each other symbol is as defined above. ] The carboxylic acid compound represented by these or its reactive derivative is also provided.

In the definition of the general formula, valogen means chlorine, fluorine, bromine and iodine. Acylamino is formylamino, acetylamino, propionylamino,
Butyrylamino, isobutyrylamino, benzoylamino and the like are shown. Alkyl is alkyl having 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, hexyl, heptyl, 1
-Ethylpropyl, 2,2-dimethylpropyl and the like can be mentioned. Alkoxy is alkyl having 1 to 7 carbon atoms and includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy, tertiary butoxy, pentyloxy, hexyloxy, heptyloxy, 1 -Ethyl propoxy, 2,
2-dimethylpropoxy and the like can be mentioned. Cycloalkyl has 3 to 8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Examples thereof include cycloheptyl and cyclooctyl. Haloalkyl is chloromethyl, chloroethyl, bromomethyl, difluoromethyl, trifluoromethyl, 2,
2,3,3-tetrafluoropropyl, 2,2,2-trifluoroethyl and the like are shown. Aminoalkyl refers to aminomethyl, aminoethyl, aminopropyl, aminobutyl and the like. Mono- or di-substituted amino is methylamino, dimethylamino, ethylamino, diethylamino,
Dipropylamino, pyrrolidinyl, piperidino, 1-piperazinyl, morpholino and the like are shown. Mono- or di-substituted aminoalkyl means mono- or dialkylaminoalkyl such as methylaminomethyl, dimethylaminomethyl, diethylaminomethyl, dipropylaminomethyl, methylaminoethyl, dimethylaminoethyl, or pyrrolidinylmethyl, piperidinomethyl, Peridinoethyl, piperidinopropyl, morpholinomethyl, thiomorpholinomethyl, 1-piperazinylmethyl, 4-methyl-
Examples thereof include cyclic aminoalkyl such as 1-piperazinylmethyl. Aryl represents phenyl, naphthyl and the like. Arylalkyl is benzyl, 1-phenylethyl, 2-phenylethyl, α, α-dimethylbenzyl,
1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 2-methyl-2-phenylpropyl,
1-naphthylmethyl, 1- (1-naphthyl) ethyl and the like are shown. Heteroarylalkyl represents tenyl, pyridylmethyl, furfuryl, pyrimidinylmethyl, 2-pyridylethyl and the like. Arylalkenyl means styryl, cinnamyl, 3-phenyl-1-propenyl, 4-
Phenyl-2-butenyl, 4-phenyl-1,3-butadienyl and the like are shown. Arylthioalkyl means phenylthiomethyl, 2-phenylthioethyl, 3-phenylthiopropyl and the like. Aryloxyalkyl means phenoxymethyl, 2-phenoxyethyl, 3-phenoxypropyl and the like. Lower alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Secondary butyl, tertiary butyl and the like are shown. Lower alkoxy refers to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy, tertiary butoxy and the like. The alkylene having 1 to 5 carbon atoms which may be branched includes methylene, ethylene, trimethylene, tetramethylene, pentamethylene, propylene, 1-ethylethylene, 1-propylethylene and the like. Alkenylene having 2 to 5 carbon atoms that may be branched is vinylene,
Propylene, 3-methylpropenylene, butadienylene, 2-pentenylene, 1-methylvinylene, 1-ethylvinylene, 1-propylvinylene and the like are shown. The oxaalkylene having 1 to 5 carbon atoms which may be branched is -OC.
_{H 2 -, - OCH 2 CH} 2 -, - OCH 2 CH 2 CH 2
_{-, - OCH 2 CH 2 CH} 2 CH 2 -, - OCH 2 CH
_{2 CH 2 CH 2 CH 2 -} , - OCH 2 CH (CH 3)
_{-, - OC (CH 3)} (CH 3) - shows the like. Thiaalkylene having 1 to 5 carbon atoms which may be branched is -SCH.
_{2 -, - SCH 2 CH 2} -, - SCH 2 CH 2 CH
_{2 -, - SCH 2 CH 2} CH 2 CH 2 CH 2 -, - SC
_{H 2 CH (CH 3) -} , - SCH (CH 3) -, - SC
(CH ₃ ) (CH ₃ )-and the like.

When the compounds of the present invention are capable of forming salts, those salts are also included in the present invention. Examples of the pharmaceutically acceptable salt include hydrochloride, hydrobromide, sulfate,
Examples thereof include acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate and benzenesulfonate. Among the compounds of the present invention, there are compounds having cis and trans configurations when A is alkenylene and when R ¹ and R ² represent arylalkenyl (oxy). The present invention includes these cis isomers, trans isomers, and mixtures thereof. The compound of the present invention is preferably a trans compound. Further, in the group having a chiral carbon in the molecule, various optical isomers exist. The present invention also includes optical isomers and racemates thereof. General formula (II-
a), (II-b), (II-c) and the general formula (I
Examples of the reactive derivative of the carboxylic acid compound of I) include acid halides such as acid chloride and acid bromide; symmetrical acid anhydrides;
Mixed acid anhydrides such as alkyl carbonic acid mixed acid anhydride, alkyl phosphoric acid mixed acid anhydride, alkyl phosphorous acid mixed acid anhydride, and sulfuric acid mixed acid anhydride; methyl ester, ethyl ester, p-nitrophenyl ester, p- Chlorophenyl ester and the like are included.

The compound of the general formula (I) can be produced by the following method. Method 1 In the compound of the general formula (I), X is a single bond,

[Chemical 9] (In the formula, each symbol is as defined in the above general formula (I).) And a carboxylic acid or a reactive derivative thereof and a general formula R ⁵ —NH ₂ (III) (wherein R ⁵ is It has the same meaning as described above.) And is produced. General formula (I
When the compound of I) is a free carboxylic acid, the reaction is dicyclohexylcarbodiimide, titanium tetrachloride, phosphorus halide (phosphorus trichloride, phosphorus oxychloride, etc.), diethylchlorophosphite, o-phenylenechlorophosphite, ethyldichloro. It is carried out in an inert solvent in the presence of a condensing agent such as phosphite, 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 (II), the reaction is carried out in an inert solvent with a tertiary base such as triethylamine, pyridine or N, N-dimethylamine. It is carried out in the presence of cooling or at room temperature, or in the presence of an alkali such as sodium hydroxide or potassium hydroxide, in water under cooling or at room temperature. Symmetric acid anhydrides or mixed acid anhydrides such as alkyl carbonic acid mixed acid anhydrides, alkyl phosphoric acid mixed acid anhydrides, alkyl phosphorous acid mixed acid anhydrides, and sulfuric acid mixed acid anhydrides as the reactive derivative of the compound (II) Is used, the reaction is carried out in an inert solvent in the presence of a tertiary base such as triethylamine, pyridine, N, N-dimethylaniline, under cooling, at room temperature or under heating.
Methyl ester as a reactive derivative of compound (II),
When an ester such as ethyl ester, p-nitrophenyl ester or p-chlorophenyl ester is used, the reaction is performed in an inert solvent (compound (III) can be used in excess to serve as a solvent) at room temperature or under heating. To
The heating is preferably carried out under reflux. Examples of the solvent used in the above reaction include solvents inert to the reaction such as ethyl acetate, dimethylformamide, and acetone.

Method 2 In the compound of the general formula (I), the compound in which X is NR ⁷ is produced by the following method.

[Chemical 10] Hereinafter, these manufacturing methods will be described in more detail. (Method a) A compound (I) is produced by reacting an amino compound (IV) or a salt thereof with an isocyanate (V). This reaction can usually be performed by diluting with a suitable solvent. The solvent used may be any inert solvent such as ethyl ether,
Ethers such as isopropyl ether, dimethoxyethane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as methyl acetate and ethyl acetate, ketones such as acetone and methyl ethyl ketone, dichloromethane, chloroform and dichloroethane. Halogenated hydrocarbons, dimethylformamide, acetamide, acetonitrile, dimethylsulfoxide, pyridine and the like can be used. The reaction temperature is −20 ° C. to 150 ° C., preferably room temperature to 100 ° C. If necessary, a substance that accelerates the reaction (for example, triethylamine, N-methylmorpholine, diisopropylethylamine, 1,4-diazabicyclo [2.2.
2] Octane, pyridine, picoline, 4-dimethylaminopyridine, 4- (1-pyrrolidinyl) pyridine, N,
Bases such as N-dimethylaniline) can be added. (Method b) Isocyanic acid ester (VI) and amine (II
By reacting I) under the same conditions as in method a, R ⁷
Compound (I) can be produced in which is hydrogen. (Method c) Carbamoyl halide (VII) and amine (I
The compound (I) in which R ⁷ is a group other than hydrogen can be produced by reacting II) with the same conditions as in method a.

Method 3 In the compound of the general formula (I), the compound in which A is alkenylene having 2 to 5 carbon atoms has the general formula

[Chemical 11] (Wherein each symbol has the same meaning as defined above) and the general formula

[Chemical 12] (In the formula, n represents an integer of 0 to 3, and other symbols have the same meanings as described above.) The reaction is carried out in the presence of a suitable base (eg, alkali hydroxide such as sodium hydroxide or potassium hydroxide or alcoholic alkali such as sodium ethylate or sodium methylate), a suitable solvent such as ethanol, methanol, dioxane, water or the like. -20 ° C to 100 in an inert solvent such as a mixture of
C., preferably 0.degree. C. to room temperature. Alternatively, the reaction is carried out in the presence of a suitable acid (eg p-toluenesulfonic acid) in a suitable solvent such as an inert solvent such as benzene, toluene and xylene at 0 ° C. to 150 ° C., preferably under reflux.

General formulas (II), (IV), (VI),
Of the compounds of (VII), for example, R ¹ is —O—R ⁶
The compound which is the group of can be produced, for example, according to the following reaction route.

[Chemical 13] Compound (I) is reacted with R ⁶ -Cl in an inert solvent such as dimethylformamide in the presence of a suitable deoxidizing agent such as potassium carbonate to give compound (2).
Compound (II-1) is obtained by dehydration condensation of compound (2) with an acetophenone derivative in an alcoholic solvent in the presence of sodium hydroxide or a metal alkali. When compound (II-1) is reduced with zinc dust in acetic acid, compound (II-2) is obtained. Compound (II-2) is reacted with an alkyl carbonate halide such as isobutyl chlorocarbonate in the presence of a suitable deoxidizing agent such as triethylamine in an inert solvent such as chloroform, acetone or ethyl acetate to produce a mixed acid anhydride. After that, the acid azide obtained by reacting with an aqueous solution of sodium azide is heated in an inert solvent such as benzene to obtain the compound (VI). Compound (VI) can also be obtained by directly reacting compound (II-1) with compound (II-2) under the same conditions. Compound (VI) is hydrolyzed to give compound (IV
After obtaining -1), the compound (IV-2) is obtained by reacting with R _b ⁷ -Cl. Compound (IV-2) is reacted with phosgene in an inert solvent such as toluene to give compound (VII). Compound (VII) can also be obtained by directly reacting compound (IV-1) with phosgene. General formula (I) obtained as described above
The compound (1) 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 obtained as a mixture of cis isomers and trans isomers, it can be separated into cis isomers and trans isomers by treatment by a conventional method such as recrystallization or chromatography. When the compound of the present invention has an asymmetric center, it is usually produced as a racemate, which can be optically resolved into optical isomers by a conventional method such as fractional recrystallization or chromatography. Further, an optical isomer can be produced using an optically active raw material compound.

[0011]

The action of the compounds of the present invention having an ACAT inhibitory action and a lipid lowering action will be shown below by pharmacological experimental examples. Pharmacological Experiment Example 1: ACAT Inhibitory Action A small intestinal mucosal microsome fraction of a male rabbit fed with a feed containing 2% cholesterol for 2 months was used as an enzyme sample.
JG et al. Method (J.Lipid Res., 24,1127 (according 1983) was measured ACAT activity. That is, a test compound ^[1-14 C] After the oleoyl CoA and 5 minutes pre-incubation at 37 ° C., The enzyme preparation was added and incubated for 3 minutes, mixed with chloroform-methanol (2:
1) was added to stop the reaction, and after centrifugation, the chloroform layer was removed and subjected to thin layer chromatography (TLC). After the completion of the development, the radioactivity uptake into the cholesterol ester fraction was measured using a Radio-TLC analyzer. The concentration at which the uptake of radioactivity was inhibited by 50% (IC ₅₀ ) was determined, and the results are shown in Table 1. Table 1 ────────────────────────────── Test compound ACAT inhibitory action (Example number) (IC ₅₀ , μM) ─ ───────────────────────────── 2 0.02 3 0.02 5 0.07 6 0.02 9 0.07 10 0.05 11 0.06 24 0.04 25 0.05 26 26 0.04 27 0.03 ──────────────────────────── ───

Pharmacological Experiment 2: Lipid-lowering action A certain amount of a test compound was added to a feed containing 1.5% cholesterol, 0.5% cholic acid and 10% coconut oil, and Lewis rats (6 rats per group) ) Was ingested for 3 days.
After slaughter, serum and liver cholesterol were measured by an enzymatic method. The respective reduction rates were determined and the results are shown in Table 2. Table 2 ─────────────────────────────────── Test compound Dose Serum cholesterol Liver cholesterol (Example number) ) (%) ^* Decrease rate (%) Decrease rate (%) ──────────────────────────────────── 2 0.01 25 37 3 0.01 12 35 〃 0.03 18 51 〃 0.1 25 61 ────────────────────────── ──────── * Additional concentration of compound in feed When the compound of the present invention is used as a medicine, it can be administered orally or parenterally, and therefore, a pharmaceutically acceptable carrier or excipient. , Mixed with diluents, powders, tablets,
It can be administered in the form of capsules, granules, suppositories, injections and the like. The dose may vary depending on the patient's symptoms, body weight, age, etc., but usually 10 to 500 mg per day for an adult is suitable, and this can be administered once or in several divided doses.

[0013]

EXAMPLES The present invention will be described below with reference to reference examples and examples, but the present invention is not limited thereto. Reference Example 1 0.48 g of metallic sodium was dissolved in 50 ml of ethanol, 1.24 g of 3-acetylphenylacetic acid and 1.66 g of 2-cinnamyloxybenzaldehyde were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was acidified with hydrochloric acid, and the precipitated crystals were collected by filtration and recrystallized from ethyl acetate to give pale yellow crystals of 3- (2-cinnamyloxycinnamoyl) phenyl. Acetic acid was obtained. Melting point 125-1
The compounds of Reference Examples 2 to 27 were obtained in the same manner as 27 ° C. Reference Example 2 4- (2-Cinnamyloxycinnamoyl) phenylacetic acid, melting point 120-123 ° C Reference Example 3 3- (4-Cinnamyloxycinnamoyl) phenylacetic acid, melting point 168-171 ° C Reference Example 4 2- ( 4-Cinnamyloxycinnamoyl) phenylacetic acid, melting point 204-206 ° C Reference Example 5 3- (3-Cinnamyloxycinnamoyl) phenylacetic acid, melting point 147-149 ° C Reference Example 6 4- (3-Cinnamyloxycinna) Moyl) phenylacetic acid, melting point 165-168 ° C Reference Example 7 4- (4-cinnamyloxycinnamoyl) phenylacetic acid, melting point 188-191 ° C Reference Example 8 3- (2-benzyloxycinnamoyl) phenylacetic acid, melting point 159 ˜161 ° C. Reference Example 9 3- (4- (2-phenylethoxy) cinnamoyl) phenylacetic acid, melting point 122-1 4 ° C. Reference Example 10 3- (4- (3-phenylpropoxy) cinnamoyl)
Phenylacetic acid, melting point 155-159 ° C Reference Example 11 3- (4- (2-pyridyl) methoxycinnamoyl) Phenylacetic acid, melting point 147-149 ° C Reference Example 12 4- (4- (2-pyridyl) methoxycinnamoyl) Phenylacetic acid / hydrochloride, melting point 180-182 ° C Reference Example 13 3- (4- (2-phenylthioethoxy) cinnamoyl) phenylacetic acid, melting point 141-144 ° C Reference Example 14 3- (2- (2-phenylthioethoxy) ) Cinnamoyl) phenylacetic acid, melting point 150-152 [deg.] C Reference Example 15 3- (4- (2- (3,5-ditertiarybutyl-4-hydroxyphenylthio) ethoxy) cinnamoyl) phenylacetic acid, melting point 124-127 C. Reference Example 16 4-methoxy-3- (2-cinnamyloxycinnamoyl) phenylacetic acid, melting point 171-173 [deg.] C Reference Example 17 4-Methoxy-3- (4-cinnamyloxycinnamoyl) phenylacetic acid, melting point 192-195 ° C Reference Example 18 3- (4- (3-phenoxypropoxy) cinnamoyl) phenylacetic acid, melting point 107-110 ° C Reference Example 19 3- (2-Cinnamyloxycinnamoyl) phenoxyacetic acid, melting point 156-158 ° C Reference Example 20 2-Methyl-2- (4- (4-cinnamyloxycinnamoyl) phenoxy) propionic acid, melting point 194- 19
6 ° C. Reference Example 21 4- (4-hydroxy-3-methoxycinnamoyl) phenylacetic acid, melting point 156-158 ° C. Reference Example 22 4- (3,4-dihydroxycinnamoyl) phenylacetic acid, melting point 210-212 ° C. Reference Example 23 Methyl 4- (3,4-dihydroxycinnamoyl) phenylacetate, melting point 162-165 ° C Reference Example 24 3- (3,4-Dihydroxycinnamoyl) phenylacetic acid, melting point 207-210 ° C Reference Example 25 4- (4 -Pentyloxycinnamoyl) phenylacetic acid, melting point 139-141 ° C Reference Example 26 3- (4-pentyloxycinnamoyl) phenylacetic acid, melting point 93-100 ° C Reference Example 27 2- (4-pentyloxycinnamoyl) phenylacetic acid , Melting point 118 to 120 ° C.

Thereafter, the following intermediates are obtained in the same manner. ◎ 3- (3- (2-pyridyl) acryloyl) phenylacetic acid ◎ 3- (3- (3-pyridyl) acryloyl) phenylacetic acid ◎ 3- (3- (4-pyridyl) acryloyl) phenylacetic acid ◎ 3- (3 -(2-phenoxy-3-pyridyl) acryloyl) phenylacetic acid ◎ 3- (3- (2-cinnamyloxy-3-pyridyl) acryloyl) phenylacetic acid ◎ 3- (3- (2-benzyloxy-3-pyridyl) )
Acryloyl) phenylacetic acid ◎ 3- (3- (2-phenoxy-3-quinolyl) acryloyl) phenylacetic acid ◎ 3- (3- (3-phenoxy-2-naphthyl) acryloyl) phenylacetic acid ◎ 3- (3- (3 -Pyridyl) acryloyl) phenoxyacetic acid 2-methyl-2- (3- (3- (3-pyridyl) acryloyl) phenoxy) propionic acid

Example 1 370 mg of 3- (4- (2- (3,5-ditertiarybutyl-4-hydroxyphenylthio) ethoxy) cinnamoyl) phenylacetic acid was dissolved in 20 ml of ethyl acetate, and 96 mg of triethylamine was added. While cooling with ice, 82 mg of pivaloyl chloride was added dropwise at 0 to 5 ° C. 1 at the same temperature
After stirring for 5 minutes, 121 mg of 2,6-diethylaniline was added dropwise at 0 to 5 ° C, and the mixture was stirred at room temperature for 1.5 hours.
Next, the reaction solution was washed with water, dried, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give N- (2,2) of pale yellow crystals.
6-diethylphenyl) -3- (4- (2- (3,5-
Ditertiary butyl-4-hydroxyphenylthio) ethoxy) cinnamoyl) phenylacetamide was obtained. Melting point 1
68 to 170 ° C. Similarly, the corresponding phenylacetic acid derivative was reacted with an amine to give amide compounds of Examples 2 to 11 below. Example 2 N- (2,6-diethylphenyl) -3- (2-cinnamyloxycinnamoyl) phenylacetamide, colorless crystals, melting point 185-186 ° C Example 3 N- (2,6-diisopropylphenyl) ) -3- (2-
Cinnamyloxycinnamoyl) phenylacetamide,
Colorless crystals, melting point 137-138 [deg.] C. Example 4 N- (2,4-difluorophenyl) -3- (2-cinnamyloxycinnamoyl) phenylacetamide, melting point 191 [deg.] C. (decomposition) Example 5 N- ( 2,6-Diethylphenyl) -4- (2-cinnamyloxycinnamoyl) phenylacetamide, colorless crystals, melting point 209-210 ° C (decomposition) Example 6 N- (2,6-diethylphenyl) -3 -(2-Benzyloxycinnamoyl) phenylacetamide, pale yellow crystals, melting point 199-201 ° C Example 7 N- (2,6-diethylphenyl) -3- (4-cinnamyloxycinnamoyl) phenyla Cetamide, pale yellow crystal, melting point 210 to 211 ° C. Example 8 N- (2,6-diethylphenyl) -4- (4-cinnamyloxycinnamoyl) phenylacetamide , Light brown crystal, melting point 188-190 ° C Example 9 N- (2,6-diethylphenyl) -4- (3-cinnamyloxycinnamoyl) phenylacetamide, colorless crystal, melting point 180-182 ° C Example 10 N- (2,6-diethylphenyl) -3- (2- (2-
Phenylthioethoxy) cinnamoyl) phenylacetamide, colorless crystals, melting point 133-135 ° C Example 11 N- (2,6-diethylphenyl) -3- (2-cinnamyloxycinnamoyl) phenoxyacetamide, colorless Crystal, melting point 166-168 ° C

Example 12 1.6 g of 3- (3-cinnamyloxycinnamoyl) phenylacetic acid was dissolved in 30 ml of dimethylformamide,
0.6 g of N-hydroxysuccinimide and 1.1 g of dicyclohexylcarbodiimide were added, and the mixture was stirred at 45 ° C. for 2 hours, then (±) α-phenethylamine 0.58 g was added while cooling with ice, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water, extracted with ethyl acetate, washed with water, dried,
The solvent was distilled off. The residue was recrystallized from ethyl acetate to give colorless crystals of (±) N- (1-phenylethyl) -3- (3-
Cinnamyloxycinnamoyl) phenylacetamide was obtained. Melting point 163 to 165 ° C In the same manner as in Example 12, the following compounds of Examples 13 to 21 were obtained. Example 13 (±) N- (1-phenylethyl) -3- (4- (2-
Phenylethoxy) cinnamoyl) phenylacetamide, colorless crystals, melting point 129-130 ° C Example 14 (±) N- (1-phenylethyl) -3- (4-cinnamyloxycinnamoyl) phenylacetamide, pale Yellow crystals, melting point 163-165 ° C Example 15 (R)-(+)-N- (1-phenylethyl) -3-
(4-cinnamyl-oxy cinnamoyl) phenyl acetamide, pale yellow crystals, melting point one hundred eighty-eight to one hundred eighty-nine ° C., [α] _D ^22.5 + 6.3 ° (chloroform: c, 1%) Example 16 (S) - (- ) -N- (1-Phenylethyl) -3-
(4-cinnamyl-oxy cinnamoyl) phenyl acetamide, pale yellow crystals, melting point one hundred eighty-seven to one hundred eighty-eight ° C., [α] _D ^22.5 -5.53 ° (chloroform: c, 1%) Example 17 (±) N- (1-Phenylethyl) -3- (2-cinnamyloxycinnamoyl) phenylacetamide, colorless crystals, melting point 136-139 ° C., Example 18 N- (1-methyl-1-phenylethyl) -3- (2-
Cinnamyloxycinnamoyl) phenylacetamide,
Colorless crystals, melting point 164-165 ° C Example 19 (±) N- (1-phenylethyl) -4- (3-cinnamyloxycinnamoyl) phenylacetamide, colorless crystals, melting point 178-180 ° C Example 20 (±) N- (1-phenylethyl) -3- (4- (2-
Phenylthioethoxy) cinnamoyl) phenylacetamide, pale yellow crystals, melting point 127-129 ° C. Example 21 (±) N- (1-phenylethyl) -2-methyl-2-
(4- (4-Cinnamyloxycinnamoyl) phenoxy) propionamide, colorless crystals, melting point 148-150
C. Example 22 N- (2,6-diethylphenyl) -3- (2-cinnamyloxycinnamoyl) phenylacetamide 1.46
30 ml of acetic acid was added to g, 0.36 g of zinc dust was added little by little at 45 to 50 ° C. while heating, and then the mixture was stirred at 50 ° C. for 30 minutes. The reaction solution was filtered through Celite, the mother liquor was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give N-color crystals.
(2,6-Diethylphenyl) -3- (3- (2-cinnamyloxyphenyl) propionyl) phenylacetamide was obtained. The following compound was obtained in the same manner with a melting point of 153-155 ° C. or lower. Example 23 N- (2,6-diethylphenyl) -4- (3- (2-
Cinnamyloxyphenyl) propionyl) phenylacetamide, pale yellow crystals, melting point 141-142 ° C

Example 24 0.32 g of triethylamine was added to a solution of 1.0 g of 3- (4- (2-phenylethoxy) cinnamoyl) phenylacetic acid in 20 ml of acetone, and pivaloyl chloride 0 was added at 0 to 5 ° C. while cooling with ice. 0.343 g was added dropwise and 3 at the same temperature.
Stir for 0 minutes. Then add sodium azide 0.
5 ml of an aqueous solution of 5 g was added dropwise, and the mixture was stirred for 2 hours. The reaction solution was poured into ice water, extracted with ether, washed with water, and dried. This ether solution was added dropwise to 40 ml of toluene which had been heated to 80 ° C. in advance, and stirred at the same temperature for 1 hour to prepare a toluene solution of isocyanate. To this toluene solution, 0.45 g of 2,6-diethylaniline was added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and the residue was distilled off with chloroform-ethyl acetate-methanol (100: 1: 1) and then recrystallized from ethanol to give 1 of colorless crystals.
-(2,6-Diethylphenyl) -3- (3- (4-
(2-Phenylethoxy) cinnamoyl) benzyl) urea was obtained. Melting point 177 to 179 [deg.] C. In the same manner as in Example 24, the following compounds of Examples 25 to 27 were obtained. Example 25 1- (2,6-diethylphenyl) -3- (3- (2-
(2-Phenylthioethoxy) cinnamoyl) benzyl) urea, colorless crystals, melting point 162-163 ° C. Example 26 1- (2,6-diisopropylphenyl) -3- (4-
(2-Cinnamyloxycinnamoyl) benzyl) urea, colorless crystals, melting point 205-206 ° C. Example 27 1- (2,6-diethylphenyl) -3- (3- (2-
Cinnamyloxycinnamoyl) benzyl) urea, pale yellow crystals, melting point 201-203 ° C Example 28 0.142 g of sodium metal was dissolved in 30 ml of ethanol, and 1- (2,6-diethylphenyl) -3- (4-
(Acetylbenzyl) urea (1.0 g) was added at room temperature.
After stirring for 1 minute, 0.734 g of 2-cinnamyloxybenzaldehyde was added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction solution, and the crystals were collected by filtration and then recrystallized from chloroform-methanol to give colorless crystals of 1- (2,6-diethylphenyl) -3- (4- (2-cinnamyloxycinnamoyl). (Benzyl) urea was obtained. Colorless crystals, melting point 224-225 ° C

Thereafter, the following compounds are obtained in the same manner as in these examples. ◎ 1- (2,6-diethylphenyl) -3- (3-
(2-Cinnamyloxycinnamoyl) phenoxymethyl) urea ◎ N- (2,6-diethylphenyl) -3- (3-
(2-Pyridyl) acryloyl) phenylacetamide ◎ N- (2,6-diethylphenyl) -3- (3-
(3-Pyridyl) acryloyl) phenylacetamide ◎ N- (2,6-diethylphenyl) -3- (3-
(4-Pyridyl) acryloyl) phenylacetamide ◎ N- (2,6-diethylphenyl) -3- (3-
(2-phenoxy-3-pyridyl) acryloyl) phenylacetamide ◎ N- (2,6-diethylphenyl) -3- (3-
(2-Cinnamyloxy-3-pyridyl) acryloyl) phenylacetamide ◎ N- (2,6-diethylphenyl) -3- (3-
(2-benzyloxy-3-pyridyl) acryloyl)
Phenylacetamide ◎ N- (2,6-diethylphenyl) -3- (3-
(2-phenoxy-3-quinolyl) acryloyl) phenylacetamide ◎ N- (2,6-diethylphenyl) -3- (3-
(3-phenoxy-2-naphthyl) acryloyl) phenylacetamide ◎ N- (2,6-diisopropylphenyl) -3-
(3- (2-Cinnamyloxy-3-pyridyl) acryloyl) phenylacetamide ◎ 1- (2,6-diisopropylphenyl) -3-
(3- (3- (2-pyridyl) acryloyl) benzyl) urea ◎ 1- (2,6-diethylphenyl) -3- (3-
(3- (3-Pyridyl) acryloyl) benzyl) urea ◎ 1- (2,6-diethylphenyl) -3- (3-
(3- (4-Pyridyl) acryloyl) benzyl) urea ◎ 1- (2,6-diisopropylphenyl) -3-
(3- (3- (2-phenoxy-3-pyridyl) acryloyl) benzyl) urea ◎ 1- (2,6-diisopropylphenyl) -3-
(3- (3- (2-cinnamyloxy-3-pyridyl))
Acryloyl) benzyl) urea ◎ 1- (2,6-diisopropylphenyl) -3-
(3- (3- (2-benzyloxy-3-pyridyl) acryloyl) benzyl) urea 1- (2,6-diisopropylphenyl) -3-
(3- (3- (2-phenoxy-3-quinolyl) acryloyl) benzyl) urea 1- (2,6-diisopropylphenyl) -3-
(3- (3- (3-cinnamyloxy-2-naphthyl))
Acryloyl) benzyl) urea ◎ 1- (2,6-diethylphenyl) -3- (3-
(3- (2-Cinnamyloxy-3-pyridyl) acryloyl) benzyl) urea ◎ N- (2,6-diethylphenyl) -3- (3-
(3-Pyridyl) acryloyl) phenoxyacetamide ◎ N- (2,6-diethylphenyl) -2-methyl-
2- (3- (3- (3- (3-pyridyl) acryloyl) phenoxy) propionamide

Pharmaceutical Formulation Example A tablet containing the compound (I) of the present invention can be prepared by the following formulation. Compound (I) 100 mg Lactose 76 mg Corn starch 10 mg Carboxymethylcellulose calcium 5 mg Methylcellulose 3 mg Magnesium stearate 2 mg Polyvinylpyrrolidone 4 mg ─────────────────────────── ———————————————————————−−−−−−−−————————————————————————————————————————————————————— Full-200-mg compound (I) are pulverized using an atomizer to obtain fine powder having an average particle size of 10 μm or less. After thoroughly mixing the compound (I), lactose, corn starch, carboxymethyl cellulose calcium and methyl cellulose in a kneader, a polyvinylpyrrolidone paste solution is added and kneaded. The kneaded product is granulated through a 200 mesh sieve, dried in a hot air dryer at 50 ° C. until the water content becomes 3 to 4%, passed through a 24 mesh sieve, mixed with magnesium stearate, and then rotary type. Tablets are made with a tableting machine using a flat punch having a diameter of 8 mm.

[0020]

INDUSTRIAL APPLICABILITY The compound of the present invention has a strong ACAT inhibitory activity, and exhibits a cell level cholesterol esterification inhibitory activity and a serum and liver cholesterol lowering activity in a hyperlipidemic model animal. More specifically, the compound of the present invention suppresses the absorption of cholesterol from the intestinal tract and exhibits a serum cholesterol lowering action, and also inhibits the esterification of cholesterol in macrophages and vascular smooth muscle cells to prevent the deposition of lipids on the blood vessel wall. To prevent. Also,
It has excellent oral absorbability, bioavailability, and longevity, and has low toxicity. Therefore, the present invention provides a highly safe and superior lipid-lowering drug and anti-atherosclerotic drug.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI Technical display location C07C 237/22 7106-4H 323/12 7419-4H 323/18 7419-4H 323/31 7419-4H C07D 213/46 6701-4C 213/56 6701-4C 215/14 7019-4C (72) Inventor Hidenobu Kusuhara 3-17-4 Aobacho, Higashimurayama-shi, Tokyo Fuamidol Aoba 101 (72) Inventor Izumi Ritsu 2-538-3 Shimomiyanaga, Nakatsu City, Oita Prefecture

Claims (4)

[Claims] 1. A general formula: [In the formula, R ¹ and R ² are the same or different and each represents hydrogen, halogen, nitro, amino, hydroxyl group, acylamino, alkyl, alkoxy, cycloalkyl, haloalkyl, aminoalkyl, mono- or di-substituted amino, mono- or di-substituted amino. Alkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, arylthioalkyl, aryloxyalkyl or —O—R ⁶
(Wherein R ⁶ represents cycloalkyl, haloalkyl, aminoalkyl, mono- or di-substituted aminoalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, arylthioalkyl or aryloxyalkyl). And each of the above aryls and heteroaryls may have 1 to 3 substituents selected from lower alkyl, lower alkoxy, cycloalkyl, halogen, nitro, amino, mono- or di-substituted amino, hydroxyl group, and acylamino. Good.
R ³ and R ⁴ are the same or different and each represents hydrogen, halogen, nitro, amino, mono- or di-substituted amino, hydroxyl group, acylamino, lower alkyl or lower alkoxy.
R ⁵ represents aryl or arylalkyl, each aryl having 1 to 3 substituents selected from lower alkyl, lower alkoxy, cycloalkyl, halogen, nitro, amino, mono- or di-substituted amino, hydroxyl group and acylamino. May be. A is a carbon number which may be branched 1 to
5 represents an alkylene or an alkenylene having 2 to 5 carbon atoms which may be branched. X is a single bond or -N (R ⁷⁾ -
(In the formula, R ⁷ represents hydrogen, alkyl, cycloalkyl or arylalkyl, and arylalkyl is lower alkyl, lower alkoxy, cycloalkyl, halogen,
1 to 3 substituents selected from nitro, amino, mono- or di-substituted amino, hydroxyl group, and acylamino). Y represents an alkylene having 1 to 5 carbon atoms that may be branched, an oxaalkylene having 1 to 5 carbon atoms that may be branched, a thiaalkylene having 1 to 5 carbon atoms that may be branched, or a single bond. . Z represents CH or a nitrogen atom. D and E are the same or different and are hydrogen or a substituent R
^They may represent ¹ or R ² or may be linked to each other with ring Q to form naphthalene, 1,2,3,4-tetrahydronaphthalene or quinoline, 5,6,7,8-tetrahydroquinoline. ] The amide compound represented by these, or its pharmaceutically acceptable salt. 2. A general formula: (In the formula, Ya represents alkylene having 1 to 5 carbon atoms which may be branched or thiaalkylene having 1 to 5 carbon atoms which may be branched, and other symbols are as defined in claim 1. A) a carboxylic acid compound represented by the formula (1) or its reactive derivative. 3. A general formula: (In the formula, Yb represents an oxaalkylene having 1 to 5 carbon atoms which may be branched or a single bond, and each other symbol is the term of claim 1.
As described in. ) A carboxylic acid compound represented by or a reactive derivative thereof. 4. A general formula: [Wherein R ¹ 'is nitro, amino, acylamino, cycloalkyl, haloalkyl, aminoalkyl, mono- or di-substituted amino, mono- or di-substituted aminoalkyl, aryl, arylalkyl, heteroarylalkyl,
Arylalkenyl, arylthioalkyl, in aryloxyalkyl or -O-R ⁶ (wherein, R ⁶ is cycloalkyl, haloalkyl, aminoalkyl, mono- or di-substituted aminoalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, shows a arylthioalkyl or aryloxyalkyl.) by a group represented, R ² 'is hydrogen, halogen, nitro, amino, hydroxyl, acylamino, alkyl, alkoxy, cycloalkyl, haloalkyl, aminoalkyl, mono- or di Substituted amino, mono- or di-substituted aminoalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, arylthioalkyl, aryloxyalkyl or -O-
R ⁶ ′ (wherein R ⁶ ′ represents cycloalkyl, haloalkyl, aminoalkyl, mono- or di-substituted aminoalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, arylthioalkyl or aryloxyalkyl). Each of the above aryls and heteroaryls has 1 to 3 substituents selected from lower alkyl, lower alkoxy, cycloalkyl, halogen, nitro, amino, mono- or di-substituted amino, hydroxyl group and acylamino. You may have. Yb represents an oxaalkylene having 1 to 5 carbon atoms which may be branched or a single bond. The other symbols are as described in claim 1. ] The carboxylic acid compound represented by these, or its reactive derivative.