WO1998002412A1 - Propionanilide derivatives or salts thereof - Google Patents

Abstract

Propionanilide derivatives of general formula (I) or pharmaceutically acceptable salts thereof; and drug compositions useful as an ACAT inhibitor or the like and comprising the derivatives or salts and pharmaceutically acceptable carriers. In the said formula, the symbols have the following meanings: A: an aryl or 5- or 6-membered heterocyclic group, R?1 and R2¿: each lower alkyl, R3: hydrogen or lower alkyl, B: a bond, lower alkylene, lower alkenylene, lower alkynylene, or -S(O)¿n?- wherein n is 0, 1 or 2, and R?4¿: alkyl, aralkyl, carboxyl, lower alkoxycarbonyl, cycloalkyl, or aryl such as pyridyl.

Description

 Description Propionanilide derivative or salt thereof

 INDUSTRIAL APPLICABILITY The present invention relates to a pharmaceutical, in particular, an ACAT (acyl CoA cholesterol acyltransferase) inhibitory action, in particular, an action of inhibiting macrophage ACAT, an action of suppressing foaming in macrophage, and an action of lowering blood cholesterol. And a propionanilide derivative having the formula: Also, a pharmaceutical composition comprising the propionanilide derivative or a salt thereof and a pharmaceutically acceptable carrier, particularly an ACAT inhibitor, a macrophage ACAT inhibitor, a macrophage foaming inhibitor, a blood cholesterol inhibitor, The present invention relates to a pharmaceutical composition useful as a drug for reducing or reducing cholesterol, an activator of the reverse cholesterol transfer system, a drug for preventing or treating arteriosclerosis, or a drug for preventing or treating various diseases caused by arteriosclerosis. Background art

 In recent years, increases in ischemic heart disease and cerebrovascular disease have become a social problem. Atherosclerosis is the basis of this problem and is closely related to the pharmacokinetics of cholesterol.

 Cholesterol ingested from food is absorbed from the small intestine or is biosynthesized in the liver. These cholesterol circulates in the blood, is taken up by peripheral cells and is used as energy, and excess cholesterol is accumulated in the cells and causes arteriosclerosis.

Various factors are involved in the formation of atherosclerosis in a complex manner, and an increase in blood cholesterol is considered to be a major risk factor. Therefore, suppressing the increase in cholesterol in blood is considered to be extremely significant in preventing or treating arteriosclerosis. To date, inhibitors of enzymes at various stages of cholesterol biosynthesis have been found. Although these cholesterol synthase inhibitors inhibit cholesterol biosynthesis in the body and control cholesterol levels in the blood, they are effective in preventing or deteriorating arteriosclerosis. It had no effect on treating the established atherosclerotic lesions.

 At present, it has been reported that ACAT (Acinole CoA cholesterol acyltransferase) plays an important role in cholesterol absorption and cholesterol accumulation in blood vessel walls. ACAT is mainly present in organs such as the small intestine and liver, and macrophages, and is known to catalyze the esterification of cholesterol to cholesterol esters (J. Lipid Res. 26, 647). -670 (1985)).

 On the other hand, it is known that excess cholesterol accumulates in macrophages in blood vessels and causes foaming of macrophages. In other words, it has been found that the mechanism of macrophage foaming occurs because cholesterol taken up by macrophages entering the blood vessel wall is re-esterified by ACAT and accumulated as fat globules. (Proc. Natl. Acad. Sci. USA 82, 416-420 (1985)). Therefore, by inhibiting ACAT in macrophages, the accumulation of cholesterol esters can be suppressed, and thus foaming of vascular macrophages can be suppressed.

 Furthermore, ACAT in macrophages is thought to be involved in the reverse cholesterol transfer system. The reverse cholesterol transfer system is a mechanism in which excess cholesterol in peripheral cells is extracted by HDL, transferred to the liver, and excreted as bile acids.

The mechanism by which HDL extracts cholesterol from cells has not been elucidated at this stage, but it is thought that one of the mechanisms is due to the concentration gradient of free cholesterol. Inhibition is thought to increase free cholesterol, which activates the reverse cholesterol transfer system by HDL (FEBS Lett. 363, 29-32 (1995)). Until now, imidazole derivatives have been disclosed in Jpn. J. Pharmacol. 68, 191-199 (1995) (hereinafter abbreviated as Reference 1) as compounds inhibiting ACAT of macrophages. The thioacetamide derivative is described in WO92 / 09572 (hereinafter abbreviated as Document 2), the alkylperrea compound is a cyclopentyl compound in JP-A-5-208948, and the substituted pyridine derivative is described in JP-A-5-320143. Azaindole compounds are disclosed in Kaihei 6-1788, and pyrimidine and pyridine derivatives are disclosed in JP-A-7-101940. Japanese Patent Application Laid-Open No. 6-48942 discloses a benzimidazole derivative as a compound that suppresses macrophage foaming.

 JP-A-3-220164 discloses a lower alkanoanilide derivative substituted with a disubstituted carbamoyl group as a compound having an ACAT inhibitory action and suppressing intestinal absorption and reabsorption of cholesterol. It has been disclosed. However, these compounds have not been reported to inhibit macrophage ACAT. Nor to suppress the foaming of macula phage. Disclosure of the invention

 The present inventors have conducted intensive studies on a compound having a macrophage ACAT inhibitory action, which suppresses foaming of macrophages, and as a result, a novel disubstituted compound not described in any of the above prior art documents was found. It has been found that propionanilide derivatives substituted with an amino group are compounds having excellent macrophage ACAT inhibitory activity, macrophage foaming inhibitory activity and blood cholesterol lowering activity, and are highly useful as pharmaceuticals. The present invention has been completed based on these findings.

 That is, the present invention provides the following general formula (I)

(I) (However, the symbols in the formula have the following meanings.

 A ring group: A nitrogen atom, oxygen atom or sulfur atom which may be condensed with cyclopentane, dioxol or dioxane and which may be substituted or aryl group, or which may be substituted 5- or 6-membered heterocyclic group having 1 to 3 heteroatoms selected from

R ¹ and R ^{2 are the} same or different and are lower alkyl groups

 R °: hydrogen atom or lower alkyl group

 B: bond, optionally substituted lower alkylene group, lower alkenylene group or lower alkynylene group, or group represented by the formula —S (0) n—

 n: 0, 1 or 2

R ⁴ : Condensed with an alkyl group, an aralkyl group, a carboxyl group, a lower alkoxycarbonyl group, a cycloalkyl group, an optionally substituted pyridyl group, cyclopentane, thiadiazole, dioxol or dioxane. A substituted or unsubstituted aryl group, or a group represented by the formula OR ⁵ , — SR ⁶ or

R ^u : hydrogen atom or aryl group which may be substituted

R ⁶ : imidazolyl group which may be condensed with benzene 璟 and may be substituted

R ⁷ and R ^{8 are the} same or different and are a hydrogen atom, a lower alkyl group, an optionally substituted aryl group, an aralkyl group, or

R ⁷ and R are connected

(1) A 5- or 6-membered nitrogen-containing saturated or unsaturated heterocyclic group which may contain one heteroatom selected from nitrogen, oxygen or sulfur as another heteroatom And the nitrogen-containing saturated or unsaturated heterocyclic group may be substituted and is substituted with a substituted or unsubstituted benzene ring. May be combined.

 Young

 (2) a cyclic imide which may be condensed with a benzene ring) or a pharmaceutically acceptable salt thereof. The compound (I) of the present invention always has the formula at position 3 of the propionanilide skeleton.

It has a chemical structure in that it has a disubstituted amino group represented by.

 The present invention also relates to a pharmaceutical composition comprising the propionanilide derivative or a salt thereof and a pharmaceutically acceptable carrier. Specifically, ACAT inhibitor, macrophage ACAT inhibitor, macrophage foaming inhibitor, cholesterol lowering agent in blood, activator of cholesterol reverse transfer system, prophylactic or therapeutic agent for arteriosclerosis, or caused by arteriosclerosis The present invention relates to a pharmaceutical composition useful as an agent for preventing or treating various diseases.

 The compound (I) of the present invention is further described as follows.

 The ring A may have 1 to 3 substituents, and preferred substituents are a lower alkyl group, a lower alkoxy group, a halogen atom, a phenyl group, a lower alkylene group, and a lower alkylene dioxy group. Examples include a quin group, a nitro group, an amino group, and a mono- or di-lower alkylamino group.

The aryl group of R ⁴ , R ⁵ , R ⁷ and R ° may have 1 to 3 substituents, and preferred substituents are lower alkyl, lower alkenyl, lower alkoxy, lower alkoxy and lower alkoxy. Alkanoylamino group, halogen atom, lower alkoxycarbonyl group, arylalkyl group, lower alkylenedioxy group, aralkyloxy group, arylsulfonyloxy group, aryl group, aralkyl group, aralkenyl group, aralkynyl Group, hydroxyl group, cyano group, nitro group, amino group, mono- or di-lower alkylamino group, carboxyl group, aroyl group and imidazolyl group. The heterocyclic group in which R ⁷ and R ⁸ are in the form may have 1 to 3 substituents. Preferred substituents are a lower alkyl group, a lower alkoxycarbonyl group and a carboxyl group. Group, an optionally substituted aryl group (substituent: halogen atom, lower alkyl group or lower alkoxy group), an aralkyl group or a 5- or 6-membered heteroaryl group having 1 or 2 nitrogen atoms. Can be

 Unless otherwise specified in the definition of the general formula of the present specification, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms.

 The “lower alkyl group” is preferably a straight-chain or branched lower alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like.

 The “alkyl group” is preferably a straight-chain or branched one having 1 to 20 carbon atoms. Specifically, in addition to the specific examples of the above “lower alkyl group”, heptyl, octyl, nonyl Decyl, pendecyl, dodecyl, dodecyl, tridecyl, tetradecyl, pencil decyl, hexadecyl, hepcil decyl, octadecyl, nonadecyl, aicosyl and the like.

The “lower alkenyl group” is preferably a straight-chain or branched lower alkenyl group having 2 to 6 carbon atoms, for example, vinyl, aryl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3 —Butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, methallyl, 1,1-dimethylaryl And a lower alkenyl group having 2 to 4 carbon atoms is particularly preferable.

As the “lower alkylene group”, an alkylene group having 1 to 6 carbon atoms is preferable, and specific examples include methylene, ethylene, methylmethylene, trimethylene, propylene, tetramethylene, pentamethylene, and hexamethylene. No. Preferably, it is an alkylene group having 1 to 3 carbon atoms, and preferably cow, methylene and ethylene. The “lower alkenylene group” is preferably a straight-chain or branched lower alkenylene group having 2 to 6 carbon atoms, for example, vinylene, 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3 —Butenylene, and 111-methylpropenylene.

 The "lower alkynylene group" is preferably a straight-chain or branched lower alkynylene group having 2 to 6 carbon atoms, such as ethynylene, 1-propynylene, and petinylene, and more preferably 2 to 4 carbon atoms. Is a lower alkynylene group.

 In each of the above “lower alkylene group”, “lower alkenylene group” and “lower alkynylene group”, a hydrogen atom at any position is an aryl group, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a halogen atom (each of which is preferable). Specific examples thereof include those described above and below.) And the like.

 The lower alkyl group of the “lower alkoxy group” is preferably the above lower alkyl group having 1 to 6 carbon atoms. Examples of the lower alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butyl. Examples thereof include butoxy, pentyloxy, and hexyloxy, and a lower alkoxy group having 1 to 3 carbon atoms is particularly preferable.

 The lower alkyl group of the “lower alkoxycarbonyl group” is preferably a lower alkyl group having 1 to 6 carbon atoms. Examples of the lower alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc., and more preferably a lower alkyloxy group having 1 to 3 carbon atoms.

The “lower alminylamino group” is preferably a lower alminolylamino group having 1 to 6 carbon atoms, specifically, formylamino, acetamino, propioamino, ptyrylamino, Valeryl amino, bivaloylamino, and the like, and more preferably a lower alkyl group having 1 to 4 carbon atoms. It is an amino group.

 “Mono or di-lower alkylamino group” means a group in which one or two hydrogen atoms of an amino group are substituted by the above-mentioned “lower alkyl group”. Specifically, examples of the “mono-lower alkylamino group” include methylamino, ethylamino, n-propylamino, n-butylamino, tert-butylamino, and n-pentylamino. , N-hexylamino and the like. Examples of the “di-lower alkylamino group” include dimethylamino, getylamino, methylethylamino, di- (n-propyl) amino, di- (n-butyl) amino and the like. A mono- or di-lower alkylamino group substituted with a lower alkyl group having 1 to 3 carbon atoms is preferred.

 The "cycloalkyl group" is preferably a 3- to 7-membered alicyclic hydrocarbon group having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. , Norbornyl, adamantyl and the like, and a cycloalkyl group having 5 to 7 carbon atoms is preferable.

 The “aryl group” is preferably an aromatic hydrocarbon group having 6 to 12 carbon atoms, for example, phenyl, mono-naphthyl, β-naphthyl, biphenyl and the like. Further, those having 6 to 10 carbon atoms are preferable, and phenyl and naphthyl are particularly preferable.

Therefore, the “ring group” indicates an “aryl group condensed with cyclopentane, dioxol or dioxane”, and R ⁴ indicates “an aryl group condensed with cyclopentene, thiadiazole, dioxol or dioxane. The “aryl group” constituting each group of the “condensed aryl group” is also preferably the above, and a preferred specific example of the “condensed aryl group” is indanyl 2,3—dihydro-1H—cyclopentanaphthyl, benzo-1,3—dioxolyl, naphthol 1,3—dioxolyl, 2,3—dihydrobenzo-1,4 Mono-dioxinyl group, 2,3-dihydronapto 1,4, -dioxinyl group, 2,1,3-benzothiadiazole group C

It is.

 The “aralkyl group” is preferably an aromatic-substituted lower alkyl group having 7 to 12 carbon atoms, such as benzyl, 1-phenylethyl, 2-phenylethyl, phenylpropyl, and naphthylmethyl. Benzyl is particularly preferable.

 Is the aralkyl group in the “aralkyl group” the above carbon number? Preferred are aralkyl groups of 16 to 16, and examples of the aralkyl groups include benzyloxy, 1-phenylethyloxy, 2-phenylethyloxy, naphthylmethyloxy, benzhydryloxy, and trityloxy. And more preferably an aralkyloxy group having 7 to 9 carbon atoms, particularly preferably benzyloxy.

 The aryl group of the "aralkenyl group" is preferably the above aryl group having 6 to 10 carbon atoms, and the alkenyl group is preferably the lower alkenyl group having 2 to 6 carbon atoms. For example, phenyletenyl, phenylpropenyl, naphthylethenyl, naphthylpropenyl and the like are preferable, and an aralkenyl group having 8 to 10 carbon atoms is particularly preferable.

 The aryl group of the “aralkynyl group” is preferably the above-mentioned aryl group having 6 to 10 carbon atoms, and the alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms. Examples thereof include phenylethynyl, phenylprovinyl, Naphthylethynyl, naphthylpropynyl and the like.

 The “aroyl group” specifically includes benzoyl, naphthoyl and the like, and is preferably benzoyl.

 The arylsulfonyl group of the "arylsulfonyloxy group" is preferably an arylsulfonyl group having 6 to 10 carbon atoms, for example, phenylsulfonyloxy, naphthylsulfonyloxy and the like.

As the aryl group of the "arylcarbamoyl group", the above aryl group having 6 to 10 carbon atoms is preferable, and as the arylcarbamoyl group, phenylcarbamoyl, naphthylcarbamoyl and the like can be mentioned.

"Lower alkylenedioxy group" refers to an alkylene chain having 1 to 3 carbon atoms. Oxygen atoms are bonded on both sides, and include methylenedioxy, ethylenedioxy, propylenedioxy and the like, preferably methylenedioxy and ethylenedioxy.

 Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

 "Cyclic imid which may be condensed with a benzene ring" specifically includes succinimide, glutalimide, phthalimid and the like, with phthalimido being preferred.

 The "5- or 6-membered heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom or a sulfur atom" is a nitrogen atom. A 5- or 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms selected from, oxygen and sulfur. Specifically, furan, thiophene, pyrrole, imidazole, thiazole, pyrazole, isothiazole, isoxazole, pyridine, pyrimidine, pyridazine, pyrazine, triazole, terazole Tolazole and the like. Among these groups, rings such as pyridine, pyrimidine, and isoxazole are preferred, and particularly preferred is pyridine.

"A 5- or 6-membered nitrogen-containing saturated or unsaturated heterocyclic group which may contain one nitrogen atom, oxygen atom or sulfur atom as another hetero atom" is a bond of 'and 1 ^ ⁸ Means a 5- or 6-membered saturated or unsaturated heterocyclic group which may contain one heteroatom consisting of a nitrogen atom, an oxygen atom or a sulfur atom as a heteroatom other than the nitrogen atom . Specifically, examples of the saturated heterocyclic group include pyrrolidinyl, piperidino, piperazinyl, morpholino, and the like, and preferably piperidino, piperazinyl, and morpholino. Unsaturated heterocyclic groups include, for example, pivalyl, imidazolyl, thiazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidyl, pyridazinyl, virazyl, pyridin-13-ene, and pyridin-12. —They are preferred _u

They are imidazolyl and pyridine.

 The term "5- or 6-membered heteroaryl group having 1 or 2 nitrogen atoms" means a 5- or 6-membered heteroaryl group having 1 or 2 nitrogen atoms. Imidazolyl, pyridyl, pyrimidyl and the like are preferred, and pyridyl and pyrimidyl are preferred.

Among the compounds (I) of the present invention, preferred compounds are an aryl group or a pyridyl group in which the ring A may be substituted, and B is a lower alkylene group or a group represented by the formula —S (0) n—. And R ⁴ is an alkyl group, an aryl group which may be substituted and may be condensed with dioxotool, or a group represented by the formula:

Particularly preferred compounds are

3— [N-[(1,3-benzodioxol-1-5-yl) sulfonyl] —N— (4.6-dimethyl-1-pyridyl) amino] -1-N— (2,6-diisopropyl Phenyl) propionamide or a salt thereof;

N- (2,6-diisopropylphenyl) -1- [N-pyronyl-N- (3,5-xylyl) amino] propionamide or a salt thereof; 3- [N-[(1,3 —Benzodioxo-5-yl) sulfonyl]--(3,5-xylyl) amino] — N— (2,6-diisopropylpropyl) propionamide or a salt thereof;

 N- (2,6-diisopropylphenyl) -1- [N- (4-ethylbenzyl) -1-N- (3,5-xylyl) amino] propionamide or a salt thereof;

N- (2,6-diisopropylphenyl) -1-3- [N-hexylyl N- (3,5-xylyl) amino] propionamide or a salt thereof; N- (2,6-diisopropylphenyl) I- [N-phenyl-N- [2- (4-phenyl-1-1-piperazinyl) ethyl] amino] propionamide or a salt thereof; N- (2,6-diisopropylpropenyl) -3- (N-hexyl-N-phenylamino) propionamide or a salt thereof;

It is.

 The compound (I) of the present invention has geometric isomers based on amide bonds. Further, depending on the type of substituent, it may have one or more asymmetric carbon atoms, and based on this, optical isomers such as (R) -form and (S) -form, racemic forms, diastereomers, etc. Exists. In addition, some types of substituents have a double bond, and there are geometrical isomers such as (Z) -form and (E) -form. The present invention includes all separated or mixtures of these isomers.

 The compound (I) of the present invention may form a salt with an acid. Such salts include mineral acids with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc., formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid Acid addition with organic acids such as acid, maleic acid, lactic acid, lingic acid, quinic acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, and glumic acid Salts may be mentioned.

 Further, in the present invention, compound (I) may be obtained as a hydrate, a solvate such as ethanol, or various substances forming a polymorph depending on the physicochemical properties or production conditions. . The present invention includes all of these hydrates, solvates with ethanol, and the like, and substances in various crystal forms.

(Manufacturing method)

The compounds of the present invention and salts thereof can be produced by applying various synthetic methods, utilizing characteristics based on the basic skeleton or types of substituents. Hereinafter, a typical production method will be described. First manufacturing method

(In the formula, A ring, B, Ri to R ⁴ represent the above-mentioned groups. The same applies hereinafter.)

 The compound (I) of the present invention can be produced by a condensation reaction of the amide represented by (Π) and the carboxylic acid represented by (ΠΙ). This reaction is carried out by using the commonly used condensation reagents (dicyclohexylcarbodiimide, diphenylphosphoryl azide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, 1, Γ-carbonyldiimidazo ), A mixed acid anhydride method using ethyl ethyl chloroformate or isobutyl chloroformate, or (1) using a halogenating reagent such as thionyl chloride, oxalyl chloride, or phosphorus chloride. It is also possible to react with (Π) after converting it into a compound. The reaction is usually carried out in a solvent such as tetrahydrofuran, dimethylformamide, dichloromethane or the like, if necessary, in the presence of a base such as triethylamine or potassium carbonate, and under cooling (preferably -15 to 0). It is appropriate to work at room temperature. Second manufacturing method

(IV) (V) (la) (In the formula, represents a halogen atom or an organic sulfonic acid residue.) In the compound of the present invention, (Ia) represents an amide represented by (IV) and a halide or sulfonate represented by (V). Can be produced by reacting Examples of the halogen atom include an iodine atom, a bromine atom and a chlorine atom. Organic sulfonic acid residues include alkanesulfonic acid residues such as methanesulfonic acid residues and ethanesulfonic acid residues, toluene sulfonic acid residues (for example, p-toluenesulfonyloxy group), and benzenesulfonic acid residues. An aromatic sulfonic acid residue such as a group is used. The reaction is carried out in an organic solvent that does not normally participate in the reaction, for example, compounds (IV) and (V) in an organic solvent such as tetrahydrofuran, dimethylformamide, and hexamethylphosphoric triamide. It is usually advantageous to carry out the reaction under normal heating with almost equimolar amounts of each, or a slight excess of one. This reaction is advantageously carried out in the presence of a base. Examples of such a base include bases such as potassium hydroxide, sodium hydroxide, sodium hydride, and potassium carbonate. It is suitable. When is a halogen atom other than iodine, the reaction may be accelerated by adding sodium iodide or iodium. Third manufacturing method

In the compound of the present invention, (Ia) can also be produced by reductive condensation in which an amide compound represented by (IV) and an aldehyde compound represented by (VI) are reacted in the presence of a reducing agent. The reaction is usually an organic solvent that is inert to the reaction. Compounds (IV) and (VI) in an organic solvent such as tetrahydrofuran, acetate nitrile, dichloromethane, methanol, ethanol, etc. in the presence of a reducing agent. The reaction is carried out under cooling or at room temperature using an excess amount of one or more moles or at room temperature, or using (IV) and (VI) in a solvent-free state or in benzene, toluene, etc., azeotropically or in the presence of a drying agent. After synthesizing a Schiff base by condensing while removing, it may be reduced in methanol, ethanol or the like. As the reducing agent, hydrides such as sodium triacetoxyborohydride, sodium borohydride, and sodium cyanoborohydride are used. Also, an acid catalyst such as acetic acid may be used. If there are other groups that are susceptible to reduction, the desired product can be selectively obtained by selecting the reaction conditions. Fourth manufacturing method

(In the formula, η is the same as above, and Υ ₂ is a halogen atom.)

In the compound of the present invention, (lb) can be produced by reacting the amide compound represented by (IV) with the halide represented by (ΥΠ). The reaction is usually carried out in an organic solvent which is inert to the reaction, such as dichloromethane, benzene, ether, chloroform, carbon tetrachloride, acetonitrile, etc., with equimolar amounts of (IV) and (W). It is advantageous to use either of them in an excessive amount and to carry out the reaction under cooling (preferably 0) or at room temperature. This reaction is advantageously carried out in the presence of a base. As such a base, an organic base such as triethylamine, pyridine, dimethylaminopyridine and the like is preferable. Fifth manufacturing method

 (Crane (IX)

(Wherein, R ^7, R ^u represents the aforementioned groups Y. halogen atom or a sulfo down acid residue, m:.. L~5 an integer of similar or less)

 In the compound of the present invention, (Ic) can be produced by reacting a halide or sulfonate represented by (\) with an amide derivative represented by (DO. The reaction is usually carried out in an organic solvent not involved in the reaction. For example, in methanol, ethanol, tetrahydrofuran, acetonitril, dimethylformamide, hexamethylphosphoric triamide, etc., (VB) and (K) are almost Usually, it is advantageous to carry out the reaction in an equimolar amount or one of them in a slightly excessive molar amount while heating, and in some cases, it is advantageous to carry out the reaction in the presence of a base. Bases such as sodium hydride and sodium hydroxide are preferred.

(In the formula, R ⁹ , R ^{1 ()} or R ¹¹ are the same or different and represent a hydrogen atom, a lower alkyl group, or an optionally substituted aryl group.)

In the compound of the present invention, (Id) represents a halide or sulfo represented by (Cor). The compound can be produced by reacting the Nate with an imidazole derivative represented by (X). The reaction is usually carried out in an organic solvent that does not participate in the reaction, for example, ethanol, tetrahydrofuran, acetonitril, dimethylformamide, etc., in which (Cor) and (X) are almost equimolar. It is advantageous to carry out the reaction, usually with heating, in a slightly molar amount, or one of them. In some cases, it is advantageous to carry out the reaction in the presence of a base. As such a base, a base such as potassium carbonate, sodium hydroxide or sodium hydroxide is preferred. Seventh manufacturing method

(In the formula, R ⁵ represents the aforementioned group.)

In the compound of the present invention, (Ie) can be produced by reacting with a halide or a sulfonate represented by (Week) or an alcohol derivative or a phenol derivative represented by (XI). The reaction is usually carried out by equimolarly adding (VDI) and () in an organic solvent that does not participate in the reaction, for example, tetrahydrofuran, acetonitrile, dimethylformamide, etc. Usually, it is advantageous to carry out the reaction from room temperature to heating, and in some cases, it is advantageous to carry out the reaction in the presence of ¾. Examples of such a base include potassium carbonate, cesium carbonate, and sodium hydride. Bases such as lime and sodium hydroxide are preferred. Eighth manufacturing method

(vm) (ΧΠ)

(In the formula, R ⁶ represents the aforementioned group.)

 In the compound of the present invention, (If) can be produced by reacting a halide or a sulfonate represented by () with a thiol form represented by (M).

 The reaction is almost the same as (VI) and () in organic solvents that are not normally involved in the reaction, such as methanol, ethanol, acetonitril, tetrahydrocran, dimethylformamide, and the like. It is usually advantageous to carry out the reaction in a molar amount, or one of them in a slightly excessive molar amount, usually under heating. In some cases, it is advantageous to carry out the reaction in the presence of a base group. As such a base, a base such as sodium carbonate, sodium hydride or sodium hydroxide is preferred. Ninth manufacturing method

(xm) (XIV) (I g) In the compound of the present invention, (I g) can be produced by a Mitsunobu reaction in which an alcohol compound represented by (xm) is reacted with a sulfonamide derivative represented by (XIV). The reaction is usually carried out in an organic solvent inert to the reaction, for example, tetrahydrofuran, dichloromethane, benzene, etc., in the presence of a trisubstituted phosphine compound and an azodicarboxylic acid derivative, with the compound (xm) and the compound (X). The reaction is carried out at room temperature or under heating using an equimolar amount of (IV) or an excess amount of (XIV) and an equimolar or excess amount of the trisubstituted phosphine compound and the azodicarboxylic acid derivative.

 As the trisubstituted phosphine compound, triphenylphosphine, tributylphosphine or the like is used. As the azodicarboxylic acid derivative, acetyl azodicarboxylate, diisopropyl azodicarboxylate or the like is preferably used. Can be Tenth production method (interconversion of substituents)

 (1) Reduction (source of aromatic nitro group)

 In the compound of the present invention, a compound having an amino group on an aromatic ring as a substituent can be produced by reducing the corresponding nitrogen compound. For the reduction, catalytic reduction using palladium carbon or the like as a catalyst is also possible, but chemical reduction using a metal such as zinc or iron and an acid such as hydrochloric acid is advantageously used.

(2) Deprotection of benzyl group

 In the compound of the present invention, a compound having a hydroxyl group on an aromatic ring as a substituent can be produced by treating the compound having a corresponding benzyloxy group as a raw material with an acid. In this case, trifluoroacetic acid is preferably used as the acid, and the reaction may be accelerated in the presence of thioazole or pentamethylbenzene. Alternatively, depending on the reaction conditions, it can be produced by catalytic reduction using palladium carbon as a usual method for deprotection of the benzyl group.

 (3) Alkylation of phenolic hydroxyl groups

In the compound of the present invention, a compound having an alkoxy group on an aromatic ring as a substituent can be produced by alkylating the compound having a corresponding hydroxyl group as a raw material. _{2 ()}

In this method, cesium carbonate, potassium carbonate, or sodium hydroxide is used in a mixed solvent of aceton and dimethylformamide or dimethylformamide, using the corresponding alkyl halide as a reaction reagent. It is preferable to carry out the reaction usually under heating using a base such as

 (4) Ester hydrolysis

 Among the compounds of the present invention, a compound having a carboxyl group in its structure can be produced by hydrolyzing the corresponding alkyl ester as a raw material. In this method, a conventional method of ester hydrolysis is used, and sodium hydroxide or the like is used as a base.

 (5) Amide bond formation

 In the compound of the present invention, when a compound having a corresponding carboxyl group as a raw material is used as a raw material, a compound having a substituting rubamoyl group as a substituent can be produced by condensing the compound with a corresponding amide. In this case, the reaction can be carried out by a conventional method using a commonly used condensing reagent such as hexylcarbodiimide. Alternatively, a mixed acid anhydride method using ethyl chloroformate or the like, or a method in which a raw carboxylic acid is converted into an acid halide using a halogenating reagent such as thionyl chloride or oxalyl chloride, and then reacted with the amide. It is possible.

 The compound of the present invention thus produced can be purified as a salt, hydrate, solvate, or polymorphic substance as it is in a free state. The salt of the compound (I) of the present invention can also be produced by subjecting the salt to a conventional salt formation reaction.

 Simple purification is performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, crystallization, recrystallization, and various types of mouth chromatography.

Various isomers can be separated by selecting appropriate starting compounds or by utilizing the difference in physical properties between the isomers. For example, the optical isomer can be obtained by selecting an appropriate raw material or by a method of resolving a racemic compound (for example, a method of optically resolving a diastereomer salt with a general optically active base). , Three-dimensional It can lead to chemically pure isomers. The mixture of diastereomers can be separated by a conventional method, for example, fractional crystallization or mouth chromatography. An optically active compound can also be produced by using an appropriate optically active raw material. Industrial applicability

 The compound of the present invention has an ACAT inhibitory action, particularly an excellent macrophage ACAT inhibitory action, and suppresses foaming of vascular macula phages, and is therefore expected to act directly on atherosclerotic lesions It is. Furthermore, it is expected to activate the reverse cholesterol transfer system, making it a useful compound as a preventive and therapeutic agent for arteriosclerosis. It also has an ACAT inhibitory effect that is present in the liver, etc., and shows a blood cholesterol lowering effect in in vivo.

 Therefore, the compound of the present invention is based on the above-mentioned actions, and is based on atherosclerosis or various diseases caused by atherosclerosis, that is, ischemic heart disease such as angina or myocardial infarction due to coronary atherosclerosis. Cerebrovascular disorders such as cerebral infarction and cerebral hemorrhage due to sclerosis, optic atrophy and hydrocephalus due to mechanical compression of sclerotic cerebral arteries, sclerosis due to renal arteriosclerosis, arterial obstruction due to stenosis of aorta and peripheral arteries It is a very useful compound for the prevention and treatment of arteriosclerosis, hyperlipidemia, hypercholesterolemia, and xanthomas. experimental method

 The ACAT inhibitory effect of the compound of the present invention on THP-1 cells, the ACAT inhibitory effect on HepG2 cells, the foaming inhibitory effect on macula phage, and the blood cholesterol lowering effect on normal diet hamsters were confirmed as follows. It is a thing.

(1) ACAT inhibitory activity in THP-1 cells

THP—1 cell (human monocyte) was added to 0.1 / z M PMA (Phorbol Pour the mixture into RPMI1640 + 10% FBS (Fetal Bovine Serum) medium supplemented with 12-Myristate 13-acetate) in a 12-well plate at 75 x 10 ⁴ cells / well, incubate for 4 days, and differentiate into a Mcguchi phage. Was. Then, the medium was replaced with RPMI1640 + 10% LPDS (Lipoprotein Deficient Serum) containing the same concentration of PMA, and the cells cultured for one day were used for measurement. To this, 0.2 mM sodium [ ¹⁴ C] oleate-albumin complex (25, OOOdpm / nmol), 50 / zg / ml oxidized LDL (Low Density Lipoproten) and a test compound (the compound of the present invention) were added, and cultured for 6 hours. After removing the medium and washing the cells twice with 0.1% BSA (Bovine Serum Albumine) / 50 mM NaCl (pH 7.4) and once with 50 mM Tris-HCl / 150 mM NaCl (pH 7.4), hexane-isopropanol (3: 2) The lipid was extracted twice with 1 ml. After extracting cholesteryl oleate from the extracted lipids by thin-layer chromatography, the radioactivity was measured.

 As a control, the compound described in Reference 1 (n-butyl N '-[2- [3- (5-ethyl-4-phenyl-1H) -imidazol-1-yl) propoxy] — 6-Methylphenyl] ゥ rare) (hereinafter abbreviated as Comparative Example 1) was used.

 As a result (see Table 1 below), it was confirmed that the compound of the present invention exhibited excellent human macrophage cell ACAT inhibitory activity. Table 1 ACAT inhibitory activity of the compounds of the present invention in THP-1 cells

*: Data described in Document 1 (2) ACAT inhibitory activity in HepG2 cells

Entrainment in 12-well plates so as to be ^{15 x 10, 4 ¾ cells /} ml HepG2 cells to 10% FCSZDMEM medium, were cultured for 3 days, test compounds (the compounds of the present invention and the N-(2, 6- diisopropyl off We .. yl) one 2- (te Toradeshiruchio) § Se Toami de (in the document 2, the compound described as example 1 hereinafter abbreviated as Comparative example 2)) and ^{0.2mM sodium [* 1 C] oleate} - Albumin complex (10,000 dpm / nmol) was added, and the cells were cultured for 6 hours. After removing the medium, wash the cells twice with 0.1% BSAZ 50 mM NaCl (pH 7.4) and once with 50 mM Tris-HCl / 150 mM NaCl (pH 7.4), and then wash twice with 1 ml of hexane-isopropanol (3: 2). The lipid was extracted. Of the extracted lipids, cholesteryl oleate was separated by thin-layer chromatography, and the radioactivity was measured.

 As a result (see Table 2 below), it was confirmed that the compound of the present invention exhibited excellent ACAT inhibitory activity in HepG2 cells. Table 2 ACAT inhibitory activity of the compounds of the present invention in HepG2 cells

 (3) Evaluation of foaming inhibitory effect on macrophages

 The inhibitory effect of foaming on macrophages was evaluated based on the inhibition rate of the increase of ester cholesterol (CE) in macrophage cells.

THP-1 cells were seeded on a 12-well plate (75 × 10 ⁴ cells / ml / well) in RPMI1640 medium containing 10% FBS and 0.1 / M PMA for 4 days to differentiate into macrophages. Then, the same concentration of PMA, 10 After culturing for 1 day after replacing with a medium containing% LPDS, acetylated LDL (prepared LDL prepared from human plasma by ultracentrifugation using acetic anhydride) 50 g / ml, and 10 ^_Q M A solution dissolved in DMSO (dimethylsulfoxide) was added to achieve a concentration of, and the cells were further cultured for 24 hours. After removing the medium, wash the cells twice with 0.1% BSA / 50 mM Tris-HCl / 150 mM NaCl (pH 7.4) and once with 50 mM Tris-HCl / 150 mM NaCl (pH 7.4), then wash with hexane-isopropanol (3 : 2) The lipid was extracted twice with 1 ml, dried under reduced pressure, and dissolved in ethanol to obtain a sample. Total cholesterol and free cholesterol were measured using the highly sensitive cholesterol measuring reagents “Detamina-I TC555J” and “Detamina-FC555J (Kyowa Medix), respectively, and the difference between the two values showed that CE accumulated in macrophage cells. (cholesteryl ester: ester-type cholesterol = accumulation-type cholesterol) From this value, the inhibition rate of increase in intracellular CE phage cells was calculated by the following formula: Increase in CE in the presence of the test compound

 100 • X

CE increase in the absence of test compound

The above test confirmed that the compound of the present invention had an inhibitory effect on foaming in macula phage (see Table 3 below). Table 3 Inhibitory effect of the compounds of the present invention on foaming in macula phage

 (4) Blood cholesterol lowering effect in normal diet hamsters

0.5% meth to 7-week-old male golden hamster reared on a normal diet The test compound suspended in a 5% cellulose solution was orally administered once a day for 5 days at a rate of 50 mg Zkg. The control group received only 0.5% methylcellulose solution. The animals were fasted overnight before the final administration, and blood was collected 2 hours after the final administration. The blood was centrifuged at 3, OOOrpm for 5 minutes to separate the serum. Serum total cholesterol was measured by "Data Mineral LTC J (Kyowa Medix)".

 The blood cholesterol lowering rate was calculated from the relative value of total cholesterol in serum between the control group and the test compound administration group.

 The above test confirmed that the compound of the present invention had an excellent blood cholesterol lowering effect (see Table 4 below). Table 4 Blood cholesterol lowering effect of the compound of the present invention

Formulations containing one or more of the compounds of the present invention or salts thereof as an active ingredient are prepared using carriers, excipients, and other additives that are commonly used for formulation. Administration may be oral, such as tablets, pills, capsules, granules, powders, or liquids, or parenteral, such as injections such as intravenous and intramuscular injections, suppositories, and transdermals. Good. The dosage is determined as appropriate for each individual case, taking into account the symptoms, age of the subject, gender, etc. Usually, about 0.01 to 50 mg per day per adult for oral administration and per adult per day for parenteral administration. The dose is about 0.001 to 5 mg, and should be administered once or in 2 to 4 divided doses.

Solid compositions for oral administration according to the present invention include tablets, powders, Granules and the like are used. In such a solid composition, the one or more active substances may include at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch. , Polyvinylpyrrolidone, metasilicate, and magnesium aluminate. The compositions may contain, in a conventional manner, additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, stabilizers such as lactose, A solubilizing agent such as glutamate or aspartate may be contained. If necessary, tablets or pills may be coated with a sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylpyrumethylcellulose phthalate, or a film of a gastric or enteric substance.

 Liquid compositions for oral administration include pharmaceutically acceptable emulsifiers, solutions, suspensions, syrups, elixirs, etc., and include commonly used inert diluents such as purified Contains water and ethanol. The composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, flavoring agents and preservatives.

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Examples of non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (trade name). Etc. Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, and stabilizing agents (eg, lactose) and solubilizing agents (eg, glutamate, aspartic acid). May be. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. In addition, these can be used as a sterile solid composition which is dissolved in sterile water or a sterile injection solvent before use. BEST MODE FOR CARRYING OUT THE INVENTION

 Examples are described below, and the production examples of the compound of the present invention are described in more detail. The present invention is not limited to these embodiments. The production examples of the main raw material compounds used in the examples are also described in reference examples. Reference example 1

 3-Promo N- (2,6-diisopropylpropyl) Propionamide (15.0 g) and aniline (12.0 g) were dissolved in hexanemethylphosphoric acid triamide (50 ml), and the mixture was stirred at 110 for 3 hours. After allowing the reaction solution to cool, 200 ml of ethyl acetate was added, and the mixture was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel gel ram chromatography. N- (2,6-diisopropylpropyl) 13- (N-phenylamino) is eluted with a mixed solvent of ethyl acetate and n-hexane (1: 5 → 1: 2). Propionamide (11.8 g) was obtained as a white solid.

 Mass spectrometry value (m / z): FAB325 The compounds of Reference Examples 2 to 21 were obtained in the same manner as in Reference Example 1.

Reference example 2

 N- (2,6-diisopropylpropyl) -3- (N- (3-methoxyphenyl) amino) propionamide

 Starting compounds: 3-bromo-N- (2,6-diisopropylpropyl) propionamide and 3_anisidine

 Mass spectrometry value (mZz): FAB 355, 354 Reference example 3

N- (2,6-diisopropylpropyl) -1-3- [N- (3-tri) amino] propionamide .

Starting compounds: 3-Promo N- (2,6-diisopropylpropyl) propionamide and 3-Toluidine

 Mass spectrometry value (mZz): FAB 339, 338 Reference example 4

 N- (2,6-diisopropylpyrphenyl) -1-3- [N- (3,4-xylyl) amino] propionamide

 Starting compounds: 3-bromo-N- (2,6-diisopropylpropyl) propionamide and 3,4-xylysine

 Mass spectrometry value (m / z): FAB 353, 352 Reference example 5

 N— (2,6-diisopropylphenyl) -1-3- [N— (3,5-xylyl) amino] propionamide

 Starting compounds: 3-bromo-N- (2,6-diisopropylpropyl) propionamide and 3,5-xylysine

 Mass spectrometry value (mZz): FAB 353, 352 Reference example 6

 N- (2,6-diisopropylphenyl) -1-3- [N— (3,5-dimethoxyphenyl) amino] propionamide

 Starting compounds: 3-Promo N- (2,6-diisopropylpropyl) propionamide and 3,5-Dimethoxyaniline

 Mass spectrometry value (m / z): FAB 385, 384 Reference example 7

 3— [N— (4-promo 3-methylphenyl) amino] 1 N— (2, 6-diisopropyl propyl) propionamide

Starting compound: 3-bromo-N- (2,6-diisopropylpropyl) Propionamide and 4-bromo-3-methylaniline

 Mass spectrometry value (mZz): FAB 420, 419, 418, 417, 416 Reference Example 8

 3— [N- (1,3-benzodioxol-4-yl) amino] —N— (2,6-diisopropylpropylphenyl) propionamide

 Starting compounds: 3-bromo-N- (2,6-diisopropylpropyl) propionamide and 4-amino-1,3-benzodioxole

 Mass spectrometry value (m / z): FAB 369, 368 Reference Example 9

 N- (2,6-diisopropylphenyl) -1-3- [N- (2-methoxyphenyl) amino] propionamide

 Mass spectrometry value (m / z): FAB 355, 354 Reference example 10

 N- (2,6-diisopropylpyrphenyl) -1-3- [N— (2-trilyl) amino] propionamide

 Mass spectrometry value (mZz): 339, 338 Reference Example 11

 3— (N—biphenylamino) N— (2,6-diisopropylphenyl) propionamide

 Mass spectrometry value (m / z): FAB 401 Reference Example 12

 N- (2,6-diisopropylpyrphenyl) -1-3- [N- (5-indanyl) amino] propionamide

Mass spectrometry value (m / z): FAB 365 g _Q

Reference Example 13

 3-[N— (1,3-benzodioxol-5-yl) amino] 1 N- (2,6-diisopropirpanyl) propionamide

 Mass spectrometry value (mZz): FAB 369, 368 Reference example 14

 3— [N— (2,3-dihidro 1, 4-benzodioxin-1 6-yl) amino] —N— (2,6-diisopropyiphenyl) propionamide

 Quality i Analysis value (mZz): APCI 383 Reference example 15

 N— (2,6-diisopropylpyrudinyl) -1-3- [N— (4-tril) amino] propionamide

 Mass spectrometry value (m_z): FAB 339, 338 Reference example 16

 N- (2,6-diisopropropirnyl) -1-3- [N- (2,3-xylyl) amino] propionamide

 Mass spectrometry value (m / z): FAB 353, 352 Reference example 17

 3-[N— (4-chlorophenyl) amino] — N— (2,6-diisopropylpropionyl) propionamide

 Mass spectrometry value (mZz): FAB 360, 359, 358 Reference Example 18

N— (2,6-diisopropylpropenyl) -1- [N— (2,4-xylyl) amino] propionamide Mass spectrometry value (mZz) _: FAB 353, 352 Reference example 19

 3-[N— (3,4-dichlorophenyl) amino] — N— (2,6—diisopropylpyridinyl) propionamide

 Mass spectrometry (m / z): FAB 395, 394, 393 Reference Example 20

 3-[N- (3,5-dichlorophenyl) amino] — N— (2,6—diisopropylpyridinyl) propionamide

 Mass spectrometry value (m / z): FAB 395, 394, 393 Reference example 21

 N- (2,6-diisopropylpropyl) -1-3- (3,4-difluorobenzoylamino) propionamide

Nuclear magnetic resonance spectrum (DMSO - d _6, TMS internal standard)

 δ 1.08 (12H, m), 2.60 (2H, m), 3.01 (2H, m),

 3.33 (2H, m), 5.7-6.6 (3Η, m),

 7.1-7.3 (3H, m), 9.19 (0.8H, s),

 9.40 (0.2H, s). Reference Examples 22 and 23 were obtained in the same manner as in the production method of Example 25 described later. Reference Example 22

 3— [N- (2-promoethyl) -N-phenylamino] —N— (2,6-diisopropyrupanyl) propionamide

 Starting compounds: N- (2,6-diisopropylpropyl) 13- (N-phenylamino) propionamide and 1,2-dibromoethane

Mass spectrometry value (mZz): FAB 433, 432, 431 Reference Example 23

 3- [N- (3-bromopropyl) 1-N-phenylamino] 1-N- (2,6-diisopropylpropyl) propionamide

 Mass spectrometry (mZz): FAB 366, 365 Reference example 24

 370 mg of 3-[(N-hexyl-N-phenyl) amino] propionate was dissolved in 5 ml of ethanol, 2 ml of a 1N aqueous solution of sodium hydroxide was added, and the mixture was stirred at room temperature for 3 hours. After adding 2 ml of 1N hydrochloric acid to the reaction solution, 50 ml of ethyl acetate was added, and the organic layer was washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 320 mg of 3-[(N-hexyl-N-phenyl) amino] propionic acid as a colorless oil.

Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard)

 δ: 0.88 (3Η, t), 1.0—1.7 (8H, brm),

 2.59 (2H, t), 3.25 (2Η, t), 3.59 (2H, t), 6.70-1 7.35 (5H, m). Reference Example 25

 3-[(N, N-diphenyl) amino] propionic acid

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 <5: 2.71 (2H, t), 4.06 (2H, t),

 6.87-1 7.37 (10H, m). Reference Example 26

 3- [N-Hexyl-N- (3-methoxyphenyl) amino] propionic acid

Nuclear magnetic resonance scan Bae-vector (CDC1 _9, TMS internal standard)

δ: 0.86 (3Η, t), 1.1-1.6 (8H, brm), 2.44 (2H, t), 3.07 (2H, t), 3.35 (2H, t), 3.79 (3H, s), 6.77-7.28 (4H, m). Reference Example 27

 600 mg of methyl acrylate and l-Og of N- (2-isopropoxicetyl) -aniline were dissolved in 10 ml of acetic acid, and the mixture was refluxed for 3 hours. 30 ml of toluene was added, and the solvent was distilled off under reduced pressure. The residue was dissolved in 50 ml of ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of ethyl acetate and n-hexane (1: 10 → 1: 5) to give 3— [N— (2-I Sopropboxyl) [1-N-phenylamino] methyl propionate (480 mg) was obtained as a yellow oil.

Nuclear magnetic resonance scan Bae-vector (CDC1 _0, TMS internal standard)

 δ: 1.14 (6Η, d), 2.64 (2H, t),

 3.48-3.58 (5H, m), 3.68 (3H, s),

 3.70 (2Η, t), 6.65-6.70 (3Η, m),

 7.17-1 7.25 (2Η, m). Reference example 28

200 mL of ethanol was added to 5.45 g of sodium borohydride, and 3- [N- (2,6-diisopropylpropylamino) amino] — 3-year-old Kip mouth ethyl pionate 21.0 g of ethanol 100 mL The solution was added at room temperature. After heating to 60 for 2 hours, the mixture was allowed to cool to room temperature, and 50 ml of water was added. After evaporating the solvent under reduced pressure, 200 ml of ethyl acetate was added to the residue, washed with 300 ml of water and 200 ml of saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 16.7 _g of a pale yellow solid, which was crystallized from diisopropyl ether to give N- (2,6-diisopropylpropyl) -1-hydroxypropionamide 15.0 g. g White crystals were obtained.

 Mass spectrometry value (m / z): FAB 250

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 6: 1.10 (12H, d), 2.48 (2H, t), 3.07 (2H, m),

 3.72 (2H, dt), 4.65 (1H, t), 7.12 (2H, d),

7.23 (1H, t), 9.12 (1H, s).

 Dissolve 500 mg of 2-amino-4,6-dimethylpyridine in 10 ml of chloroform and add 900 mg of (1,3-benzodioxol-5-yl) sulfonyl chloride and 350 mg of pyridine. The mixture was stirred overnight at room temperature. To the reaction mixture was added 50 ml of chloroform, washed successively with 50 ml of water and 50 ml of saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel gel chromatography, and eluted with a mixed solvent of methanol and chloroform (1:20) to give a pale yellow foam. By crystallizing the substance from isopropanol, 680 mg of (1,3-benzodioxol-5-yl) -N- (4,6-dimethyl-2-pyridyl) sulfonamide was converted to pale yellow crystals. I got it.

 Mass spectrometry value (mZz): FAB 307

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 2.25 (3Η, s), 2.44 (3Η, s), 6.03 (2H, s),

 6.38 (1H, s), 6.83 (1H, d), 6.89 (1Η, s), 7.37 (1H, d), 7.52 (1H, dd).

1.6 g of N- (2,6-diisopropylpyrphenyl) 1-3- [N- (3,5-xylyl) amino] propionamide was dissolved in 30 ml of N, N-dimethylformamide, and at room temperature, Anhydrous potassium carbonate 1.25g, iodine After adding 680 mg of sodium bromide and 850 mg of 4-ethylbenzyl chloride in sequence, the mixture was heated to 80 and stirred at the same temperature for 2 hours. 150 ml of ethyl acetate was added to the reaction solution, and the mixture was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and water. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and 2.0 g of a white solid obtained by eluting with a mixed solvent of ethyl acetate and n-hexane (1: 10-1: 6) was added to acetone and n-hexane. By crystallization from a mixed solvent of hexane (1: 4), N- (2,6-diisopropylpropyl) -l- [N- (4-ethylbenzyl) -N- (3,5-xy Lil) amino] Propionamide 1.05 g was obtained as white crystals.

 Melting point: 127-128. C

Elemental analysis _{(C 32 H 42 N 2 0} )

 C (%) H (%) N (%)

 Theoretical 81.66 8.99 5.95

 Experimental value 81.68 9.12 5.97 The following compounds of Examples 2 to 7 were obtained in the same manner as in Example 1.

Example 2

 N- (2,6-Diisopropylpropyl) -1-3- [N- (4-ethylbenzyl) -1-N— (3,4-xylyl) amino] propionamide Starting compound: N— (2, 6-Diisopropylpropyl) — 3—CN- (3,4-xylyl) amino] propionamide and 4-ethylbenzyl chloride

 Melting point: 139-141ΐ

Elemental analysis value (C ₃ QH ₄₂ N ₂ O)

 C (%) H (%) N (%)

 Theoretical 81.66 8.99 5.95

Experimental value 81.89 9.04 5.99 Example 3

 N — (2, 6 — diisopropylpropyl) 1 3 — [N — (4 — methylbenzyl) 1 N — (3,5-xylyl) amino] propionamide Raw material compound: N — (2,6-diisopropylphenyl) — 3— [N- (3,5-xylyl) amino] propionamide and 4-methylbenzyl chloride

 Melting point: 155-157 ° C

Elemental analysis _{(C 31 H 4 () N} 2 0)

 C (%) H (%) N (%)

 Theoretical 81.53 8.83 6.13

 Experimental value 81.51 9.16 6.00 Example 4

 3 — [N— (1,3—benzodioxo-l-l-ylmethyl) -l-N-phenylamino] — N— (2,6-di-isopropylpropyl) propionamide

 Starting compounds: N — (2, 6 — diisopropyl phenyl) — 3 — (N-phenylamino) propionamide and 2, 3 — methylenedioxybenzyl chloride

 Melting point: 155-156

 Elemental analysis value (C ^ H ^ NOOQ)

 C (%) H (%) N (%)

 Theory 75.95 7.47 6.11

 Experimental value 75.63 7.45 5.89 Example 5

3 — [N- (1,3—benzodioxo-l-4-methyl) -1-N- (3,5-xylyl) amino] — N— (2,6-di-isopropylphenyl) propionamide Starting compounds: N- (2,6-diisopropylpropyl) -1-3- [3- (3-, 5-xylyl) amino] propionamide and 1,3-benzodioxolu-one 4 One carbaldehyde

 Melting point: 161-163 ° C

Elemental analysis value (C ₃₁ H ₃ .N

 C (%) H (%) N (%)

 Theory 76.51 7.87 5.76

 Experimental value 76.48 8.07 5.81 Example 6

 N— (2,6-diisopropylpropenyl) —3— [N-hexyl—N- (3,5-xylyl) amino] propionamide

 Starting compounds: N— (2,6-diisopropylpropyl) -3 -— [N- (3,5-xylyl) amino] propionamide and hexylpromy K

 Melting point: 117-118

Elemental analysis value (C ₂₉ H _{4 / l} N ₀ 0)

 C (%) H (%) N (%)

 Theory 79.77 10.16 6.42

 Experimental value 79.83 10.22 6.37 Example 7

 3-[N- (3-benzyloxybenzyl) 1N-phenylamino]-N- (2,6-diisopropylpropyl) propionamide

 Starting compounds: N— (2,6-diisopropylpropyl) —3— (N-phenylamino) propionamide and methanesulfonic acid 3-benzyloxybenzyl ester

Melting point: 150-152 ° C Elemental analysis _{(C 35 H 4 () N} 2 0 2)

 C (%) H (%) N (%)

 Theoretical 80.73 7.74 5.38

 Experimental value 80.64 7.89 5.37 Example 8

 N- (2,6-diisopropylpropyl) -13- [N-phenyl-N- (2-promoethyl) amino] propionamide 480 mg and N-phenylpiperazine 540 mg hexamethyl phosphate It was dissolved in 10 ml of amide and stirred at 100 ° C for 5.5 hours. After allowing the reaction solution to cool, 200 ml of ethyl sulphate was added, and the mixture was washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was applied to silica gel column chromatography, and eluted with a mixed solvent of ethyl acetate and n-hexane (1: 1) to obtain N- ( 340 mg of 2,6-diisopropylpropylphenyl-3- [N-phenyl-N- [2- (4-phenyl-1-piperazinyl) ethyl] amino] propionamide were obtained as white crystals.

 Melting point: 167-1169

Infrared absorption spectrum max (KBr) cm- ¹ : 3256, 2974, 1653, 1602, 1509, 1233, 750, 693 Example 9

Ν- (2,6-diisopropylpropenyl) 1-3- [Ν-phenyl- (2-promoethyl) amino] propionamide 500 mg and 1,2,3,4-tetrahydrosokinolin 320 mg The mixture was refluxed for 30 minutes in 20 ml of acetonitrile. After allowing the reaction mixture to cool, 60 ml of ethyl acetate was added. After washing with an aqueous solution of sodium hydroxide, the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography, and a mixed solvent of ethyl acetate and n-hexane (1: The crude product obtained by elution in 2) is crystallized from hexane to give N- (2,6-diisopropylpropyl) -1-3- [N-phenyl—N— [2- (1, 2,3,4-Tetrahydro-2-isoquinolyl) ethyl] amino] propionamide 402 mg was obtained as white crystals. Melting point: 119-122

Nuclear magnetic resonance spectrum (DMSO- d _6, TMS internal standard)

 δ: 1.08 (12H, d), 2.65 (4H, t), 2.74 (2H, m), 2.82 (2Η, m), 3.02 (2H, m), 3.57 (2H, t), 3.63 (2H, s) , 3.68 (2H, t), 6.61 (1H, t), 6.77 (2H, d), 7.0-7.3 (9H, m), 9.24 (1H, s).

 N— (2,6-diisopropylpropenyl) —3— (4-ethylphenylamino) 1350 mg of propionamide and 1.4 ml of 1,2-dibromopentane in 20 ml of hexamyl trilinamide triamide for 12 hours Heated to 110. After allowing the reaction solution to cool, 150 ml of ethyl acetate was added, and the mixture was washed with water and saturated saline in this order. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a brown oil. This was heated to -120 in 1080 mg of N-propylaniline and 10 ml of hexamethylphosphoric triamide. After allowing the reaction solution to cool, 150 ml of ethyl acetate was added, and the mixture was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and the oil obtained by eluting with a mixed solvent of ethyl acetate and n-hexane (1: 4) was converted to η-1. Crystallization from a mixed solvent of xan and chloroform affords Ν— (2,6-diisopropylpropyl) 1-3— [Ν— (4-ethylphenyl) 1Ν— [2— (Ν-Ν 250 mg of roupyl-propylamino) ethylaminopropionamide were obtained as white crystals.

Melting point: 105-107 V Elemental analysis _{(C 34 H 47 N 3 0} )

 C (%) H (%) N (%)

 Theory 79.49 9.22 8.18

 Experimental value 79.59 9.32 8.13 Example 11

 N- (2,6-diisopropylpropenyl) 1-3- [N- (2-bromoethyl) -1-N- (3,5-dimethylphenyl) amino] propionamide 1500mg, N-phenylbiperazine 970mg , And 410 mg of potassium carbonate were refluxed in 30 ml of acetone-linole for 5.5 hours. After allowing the reaction solution to cool, the solvent was distilled off, and the residue was subjected to silica gel column chromatography. The oil obtained by elution with a mixed solvent of ethyl acetate and n-hexane (1: 3) was crystallized from hexane to give N- (2,6-diisopropylpropylphenyl) 1- [N — [21- (4-Phenyl-1-piperazinyl) ethyl] amino] 573 mg of propionamide was obtained as white crystals.

 Melting point: 136-138

Nuclear magnetic resonance scan Bae-vector (DMSO- d _6, TMS internal standard)

 δ: 1.08 (12H m) 2.21 (6H, s), 2.50 (2H, m), 2.60 (4H, t), 2.64 (2H, t), 3.03 (2H, m), 3.13 (4H, t), 3.47 (2H, t), 3.63 (2Η, t), 6.27 (1H, s), 6.36 (2H, s), 6.76 (1Η, t), 6.92 (2H, d), 7.12 (2H, d), 7.21 ( 3H, m), 9.24 (1H, s).

N- (2,6-diisopropylpropenyl) -1-3- [N- (2-promoethyl) -1-N- (3,5-xylyl) amino] Propionamide 460 mg and 1,2,3,4-te Trahidroy Sokinolin 330 mg Acetonito Ril was dissolved in 20 ml, and the mixture was heated under reflux overnight. After allowing the reaction solution to cool, 150 ml of ethyl acetate was added, and the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate and water in that order, and the organic layer was dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, the residue is subjected to silica gel column chromatography, and eluted with a mixed solvent of ethyl acetate and n-hexane (1: 2). By crystallizing the oily substance from hexane, N- (2,6-diisopropylpropyl) -3- (N- [2-(1,2,3,4-tetrahydroquinoline) 2- (yl) ethyl] —N— (3,5-xylyl) amino] propionamide (209 mg) was obtained as white crystals.

 Melting point ： 118-120 V

Nuclear magnetic resonance scan Bae-vector (DMSO - d _6, TMS internal standard)

 δ: 1.08 (12H, m), 2.20 (6H, s), 2.63 (4Η, t),

 2.74 (2Η, t), 2.81 (2H, t), 3.02 (2H, m), 3.53 (2Η, t), 3.63 (4H, t) '6.27 (1H, s), 6.37 (2H, s), 7.0 -7.3 (7H, m), 9.24 (1H, s). Example 13

Dissolve 400 mg of N- (2,6-diisopropylpyrphenyl) 1-3- [N- (3,5-xylyl) amino] propionamide in 20 ml of Cloguchi form and add pyridine lOOmg, (4— 330 mg of promophenyl) sulfonyl chloride were added in sequence, and the mixture was stirred overnight at the same temperature. 30 ml of toluene was added to the reaction solution, and the solvent was distilled off under reduced pressure. After adding 50 ml of ethyl acetate, washing with water, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to gel chromatography on a silica gel gel column, and eluted with chloroform. 272 mg of the obtained colorless solid was crystallized from a mixed solvent of acetone and n-hexane (1: 4). Is converted to white crystals of 220 mg of 3- [N-[(4-bromophenyl) sulfonyl] -N- (3,5-xylyl) amino] -N- (2,6-diisopropylphenyl) propionamide. As obtained. Melting point: 195-197Ό

Elemental analysis _{(C. 9 H. 5 N 2 0} 3 SBr)

 C (%) H (%) N (%) S (%) Br (%) Theoretical 60.94 6.17 4.90 5.61 13.98 Experimental 60.90 6.04 4.81 5.57 13.82 The following compounds of Examples 14 to 24 in the same manner as in Example 13. I got Example 14

 3— [N — [(4-bromophenyl) sulfonyl] -1-N— (3,4-xylyl) amino] —N— (2,6-diisopropylpropyl) propionamide

 Starting compounds: N— (2,6-diisopropylpropyl) -3— [N— (3,4-xylyl) amino] propionamide and (4-bromophenyl) sulfonyl chloride

 Melting point: 249-250

Elemental analysis _{(C 29 H 35 N 2 0} 3 SBr)

 C (%) H (%) N (%) S (%) Br (%) Theoretical 60.94 6.17 4.90 5.61 13.98 Experimental 60.78 6.20 4.88 5.61 14.24 Example 15

 N— (2,6-diisopropylpropyl) 1-3— [N-[(4-ethylphenyl) sulfonyl] —N— (3-tolyl) amino] propionamide '

 Starting compounds: N— (2,6-diisopropylpropyl) —3— [N- (3-tri) amino] propionamide and (4-ethylphenyl) sulfonyl chloride

Melting point: 199-200 ° C Elemental analysis (C _{3 ()} H ₃₈ N. 0 ゥ S)

 C (%) H (%) N (%) S (%) Theoretical 71.11 7.56 5.53 6.33 Experimental 71.00 7.66 5.46 6.30 Example 16

 N- (2,6-diisopropylpropenyl) 1-3- [N-[(4-ethylfurunyl) sulfonyl] —N-phenylamino] propionamide Raw material: N— (2,6-diisopropylpropyl) (Dienyl) — 3— (N-phenylamino) propionamide and 4-ethylfurnil sulfonyl chloride

 Melting point: 104- 105

Elemental analysis _{(C 29 H Q6 N 2 0} 3 S)

 C (%) H (%) N (%) S (%) Theoretical 70.70 7.36 5.69 6.51 Experimental 70.66 7.46 5.57 6.52 Example 17

 N- (2,6-diisopropylpropyl) -1-3- [N-[(4-ethylphenyl) sulfonyl] —N— (3,4-xylyl) amino] propionamide

 Starting compounds: N— (2,6-diisopropylpropyl) —3— [N- (3,4-xylyl) amino] propionamide and (4-ethylphenyl) sulfonyl chloride

 Melting point: 215-216V

Elemental analysis value (C _Q1 H _{4 ()} N ₂ 0 ₃ S)

C (%) H (%) N (%) S (%) Theoretical 71.50 7.74 5.38 6.16 Experimental 71.50 7.72 5.38 6.10 Example 18

 3-[N— (4-promo 3-methyl phenyl) 1 N— [(4-ethyl phenyl) sulfonyl] amino] 1 N— (2, 6-diisopropyl phenyl) propionamide

 Starting compounds: 3- [N- (4-promo-3-methylphenyl) amino] -N- (2,6-diisopropylpropyl) propionamide and (4-ethylphenyl) snolephonyl chloride

 Melting point: 205-206 V

Elemental analysis _{(C 3 () H 37 N} 9 0 3 SBr)

 C (%) H (%) N (%) S (%) Br (%) Theoretical 61.53 6.37 4.78 5.48 13.64

 Experimental value 61.36 6.38 4.73 5.56 13.58 Example 19

 N- (2,6-diisopropylpyrphenyl) 1-3- [N-[(4-ethylphenyl) sulfonyl] —N— (3,5-xylyl) amino] propionamide

 Starting compounds: N— (2,6-diisopropylpropyl) — 3— [N- (3,5-xylyl) amino] propionamide and (4-ethylphenyl) sulfonyl chloride

 Melting point: 196-198

 Elemental analysis (C ^ H ^ N OgS)

 C (%) H (%) N (%) S (%) Theoretical 71.50 7.74 5.38 6.16 Experimental 71.34 7.73 5.36 6.07 Example 20

N- (2,6-diisopropylpropenyl) 1 3— [N-[(4-ethylphenyl) sulfonyl] -1-N— (3-methoxyphenyl) amino 1 Pro Piona Mid

 Starting compounds: N- (2,6-diisopropylphenyl) -1-3- [N- (3-methoxyphenyl) amino] propionamide and (4-ethylphenyl) sulfoninolechlori Do

 Melting point: 178-179

Elemental analysis value (C. ₀ H ₃₈ N ₂ O ₄ S)

 C (%) H (%) N (%) S (%) Theoretical 68.94 7.33 5.36 6.13 Experimental 69.05 7.41 5.19 6.02 Example 21

 N- (2,6-diisopropylpropenyl) 1-3- [N- (3,5-dimethoxyphenyl) -1-N-[(4-ethylphenyl) sulfonyl] amino] propionamide

 Starting compounds: N— (2,6-diisopropylpropenyl) —3— [N- (3,5-dimethoxyphenyl) amino] propionamide and (41-ethynolef)

 Melting point: 213—215

Elemental analysis _{(C 31 H 4 () N} 2 0 5 S)

 C (%) H (%) N (%) S (%) Theoretical 67.36 7.29 5.07 5.80 Experimental 67.25 7.36 5.03 5.85 Example 22

3— [N — [(3-benzyloxyphenyl) sulfonyl] —N— (3,5-xylyl) amino] —N— (2,6-diisopropylpropylphenyl) propionamide Starting compounds: N- (2,6-diisopropylpropylphenyl) -1- [N- (3,5-xylyl) amino] propionamide and (3-benzyloxyphenyl) sulfonyl chloride Do Melting point: 155-157V

 Elemental analysis value (C ^ H ^ NoO ^ S)

 C (%) H (%) N (%) S (%) Theoretical 72.21 7.07 4.68 5.35 Experimental 72.37 7.08 4.62 5.34 Example 23

 3— [N — [(2,1,3-benzothiadiazole-41-yl) sulfonyl] —N— (3,5-xylyl) amino] -1-N— (2,6-di-sopro Pirphanil) Pro Piona Mid

 Raw material compounds: N- (2,6-diisopropylpropyl) -1-3- [N- (3,5-xylyl) amino] propionamide and (2,1,3-benzothiadiazoazo) Lou 41 yl) Sulfonyl chloride

 Melting point: 177-179

 Mass spectrometry value (mZz): FAB 551 Example 24

 3— [N — [(2,1,3-benzothiadiazole-4-yl) sulfonyl] -1-N— (3,5-dimethoxyphenyl) amino] 1-N— (2,6-diyl Sopro-Pyrufnil) Pro-Piona Mid

 Starting compounds: N— (2,6-diisopropylpropyl) —3— [N- (3,5-dimethoxyphenyl) amino] propionamide and (2,1,3-benzothiadiazole-4-1) B) Sulfonyl chloride Melting point: 204-206 ° C

Elemental analysis _{(C 29 H 34 N 4 0} 5 S 2)

C (%) H (%) N () S (%) Theoretical 59.77 5.88 9.61 11.01 Experimental 59.66 5.91 9.64 11.04 Example 25

 Dissolve 320 mg of N- (2, 6-diisopropylpyrfanil) 13- (N-phenylamino) propionamide and 200 mg of iodide thiol in 10 ml of hexamyltrilinic acid triamide, Stir for 3 hours. After allowing the reaction solution to cool, 50 ml of ethyl acetate was added, and the mixture was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and water, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was applied to silica gel column chromatography, and the white solid obtained by elution with a mixed solvent of ethyl acetate and n-hexane (1:10) was obtained. By crystallization in a mixed solvent of getyl ether and n-hexane, N- (2,6-diisopropylphenyl) 13- (N-ethyl-N-fuunilamine) porionamide (140 mg) as white crystals. Example 26

 430 mg of thionyl chloride was added dropwise to 10 ml of a dichloromethane solution of 300 mg of 3- (N-hexylyl N-phenylamino) propionic acid under ice-cooling, and the temperature was gradually returned to room temperature. After stirring at the same temperature for 1 hour, the solvent was distilled off under reduced pressure. The residue was dissolved in 10 ml of methylene chloride, and under ice-cooling, 2 ml of a 2,6-diisopropylamine solution (220 mg) in methylene chloride and triethylamine (130 mg) were added sequentially, and the temperature was gradually returned to room temperature. Stir for 3 hours. The reaction solution was washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel gel chromatography. Attached.溶出 By eluting with a mixed solvent of ethyl acetate and n-hexane (1: 20 → 1: 8), N— (2,6-diisopropylphenyl) 13- (N-hexyl-N— (Phenylamino) propionamide (320 mg) was obtained as a white solid.

Melting point: 138-140 Elemental analysis _{(C 27 H 4 () N} 2 0)

 C (%) H (%) N (%)

 Theory 79.36 9.87 6.86

 Experimental value 79.24 10.10 6.79 Example 27

 N- (2,6-diisopropylpropyl) -13- (N-phenylamino) propionamide 320 mg and 980 mg of bromomethylcyclohexane were dissolved in 10 ml of hexanemethylphosphoric acid triamide. To this were added 280 mg of carbon dioxide and 300 mg of sodium iodide sequentially, and the mixture was stirred at 120 for 2 hours. After allowing the reaction mixture to cool, 50 ml of ethyl acetate was added, and the mixture was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and water, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of ethyl acetate and n-hexane (1:10). 150 mg) was crystallized in a mixed solvent of acetone and n-hexane (1: 3) to give 3- (N-cyclohexylmethyl-N-phenylamino) N- (2,6- 70 mg of diisopropipirnil) propionamide were obtained as white crystals. Example 28

500 mg of N— (2,6-diisopropylpropyl) -13- (N-phenylamino) propionamide was dissolved in 15 ml of N, N-dimethylformamide. To this solution, 430 mg of anhydrous potassium carbonate, 230 mg of sodium iodide and 260 mg of 4-methylbenzyl chloride were sequentially added at room temperature, followed by heating to 80 and stirring at the same temperature for 1 hour. The reaction mixture was added with 50 ml of ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. Acetate A white solid (580 mg) was obtained by elution with a mixed solvent of chill and n-hexane (1: 10 → 1: 5). This was dissolved in acetone, and 0.35 ml of a 4N solution of hydrogen chloride in ethyl acetate was added to precipitate crystals. This was collected by filtration and dried to give N- (2,6-diisopropylpropyl) -13- [N- (4-methylbenzyl) -1-N-phenylamino] propionamide monohydrochloride (217 mg). ) Was obtained as white crystals. Example 29

 3— [N— (4-Benzyloxybenzyl) -1-N-phenylamino]--(2,6-Diisopropylpyrdanyl) Dissolve 400 mg of propionamide in 10 ml of trifluoroacetic acid and add pentamethyl Benzene (I. lg) was added, and the mixture was stirred at room temperature for 2 hours. 30 ml of toluene was added to the reaction solution, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and a colorless oil (270 mg) obtained by elution with a mixed solvent of ethyl acetate and n-hexane (1: 10-1: 5) was dissolved in ethyl acetate. Then, 0.15 ml of a 4N hydrogen chloride acetate solution was added, and the solvent was distilled off. The residue was crystallized from a mixed solvent of acetone and n-hexane (1: 3), collected by filtration and dried to give N- (2,6-diisop-piruphenyl) 13- [N- (4-H [Droxybenzyl) [1-N-phenylamino] propionamide monohydrochloride (170 mg) was obtained as white crystals. Example 30

Dissolve 500 mg of N- (2,6-diisopropylpropyl) -13- (N-phenylamino) propionamide in 15 ml of hexamethylphosphoric acid triamide and add 480 mg of 4-methoxybenzyl chloride. The mixture was stirred at 120 for 3 hours. Add 50 ml of ethyl acetate to the reaction mixture, and add saturated carbonated water. After washing with an aqueous sodium phosphate solution, the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue is subjected to silica gel column chromatography, and eluted with a mixed solvent of ethyl acetate and n-hexane (1:10 to 1: 5). The pale yellow oil (410 mg) was dissolved in ethyl acetate, and 0.23 ml of a 4N hydrogen chloride / ethyl acetate solution was added. The precipitated crystals are collected by filtration and dried to give N- (2,6-diisopropylpropyl) -13- [N- (4-methoxybenzyl) -1-N-phenylamino] propionamide monohydrochloride (270 mg) Was obtained as white crystals. Example 31

 4-[[N- [2- [N- (2,6-diisopropylpropyl) carbamoyl] ethyl] -1-N-phenylamino] methyl] Benzoic acid methyl ester 600 mg in 10 ml of tetrahydrofuran And 3 ml of a 1N aqueous sodium hydroxide solution was added at room temperature, followed by stirring at the same temperature overnight. 50 ml of ethyl acetate was added to the reaction solution, and 3 ml of 1N hydrochloric acid was added dropwise, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is subjected to silica gel column chromatography, and eluted with a mixed solvent of methanol and chloroform (1:20) to give a colorless amorphous (595 mg). Of these, 200 mg was dissolved in sodium chloride, and 0.11 ml of 4N hydrogen chloride in ethyl acetate was added to precipitate crystals. This is collected by filtration and dried to give 4-[[N- [2- [N- (2,6-diisopropylpropyl) phenyl] -lvamoyl] ethyl] -1-N-phenylamino] methyl] benzoic acid 1 The hydrochloride (150 mg) was obtained as a white solid. Example 32

4-[[N- [2— [N— (2,6-diisopropylpropyl) carbamoyl] ethyl] 1-N-phenylamino] methyl] benzoic acid 320 mg Was dissolved in methylene chloride (10 ml), and N-hydroxybenzotriazole (100 mg) and 1-ethyl-13- (3-dimethylaminopropyl) carbodiimide hydrochloride (140 mg) were sequentially added. Under ice cooling, 70 mg of aniline was added, and the mixture was gradually returned to room temperature and stirred for 4 hours. The reaction solution was washed with water, and the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is applied to silica gel column chromatography, and eluted with a mixed solvent of ethyl acetate and n-hexane (1: 10 → 1: 5) to obtain a colorless solid (350 mg). This was crystallized from a mixture of acetate and n-hexane (1: 3), filtered and dried to give 4 — [[N— [2-—N— (2,6-diisocyanate). Propylphenyl) lvamoyl] ethyl] -N-phenylamino] methyl] benzanilide (185 mg) was obtained as white crystals. Example 33

Dissolve 700 mg of N- (2,6-diisopropylpropenyl) -propionamide and 440 mg of 4-122-benzaldehyde in 20 ml of chloroform and add 650 mg of acetic acid at room temperature. In addition, the mixture was stirred at the same temperature for 1 hour. Under ice-cooling, sodium triacetoxyborohydride l.Og was added, and the mixture was stirred for 1 hour under ice-cooling, gradually returned to room temperature, and stirred for 6 hours. 30 ml of toluene was added to the reaction solution, and the solvent was distilled off under reduced pressure. The residue was dissolved in 60 ml of ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is subjected to silica gel column chromatography and eluted with a mixed solvent of ethyl acetate and n-hexane (1: 10 → 1: 5) to give a yellow powder (540 mg). This was crystallized in a mixed solvent of acetone and n-hexane (1: 3), collected by filtration and dried to give N- (2,6-diisopropylpropyl) 13- [N -(41-2 trobenzyl) 1 N-phenylamino] propionamide (155 mg) was obtained as yellow crystals. Example 34

 N- (2,6—diisopropylpyrudenyl) -1-3- [N— (3-hydroxybenzyl) -1-N-phenylamino] propionamide 430 mg in 20 ml of acetone and N, N—dimene It was dissolved in a mixed solvent of 5 ml of tilformamide, and 510 mg of isopropyl iodide was added. Next, 1.4 g of cesium carbonate was added under a stream of argon gas, and the mixture was heated under reflux for 7 hours. After evaporating the solvent under reduced pressure, 50 ml of ethyl acetate was added to the residue, and the mixture was washed with water. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. A white solid (372 mg) obtained by elution with a mixed solvent of ethyl acetate and n-hexane (1: 10-1: 5) was mixed with a mixed solvent of acetate and n-hexane (1: 1). : 3) Crystallization in N- (2,6-diisopropylphenyl) -1- [N- (3-isopropoxybenzyl) -N-phenylamino] Propionamide (206 mg) was obtained as white crystals. Example 35

N- (2,6-Diisopropylpyrenyl) 1-3- [N- (3-Hydroxybenzyl) -1-N-phenylamino] Propionamide 540 mg is dissolved in 20 ml of oral form, and triethylamine 160 mg. And benzenesulfonyl chloride (250 mg) were added sequentially, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water and a saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was subjected to silica gel gel chromatography and eluted with a black hole form to give a colorless amorphous (560 mg). This was dissolved in acetone, and the crystals formed by adding 0.25 ml of a 4N hydrogen chloride acetate solution were collected, dried, and dried in 3-[[N— [2-—N- (2,6-di-ethyl acetate). Sopropylphenyl) rubamoyl] ethyl] 1 N-phenylamino] methyl] phenylbenzenesulfonic acid monohydrochloride (375mg) Was obtained as white crystals. Example 36

 Dissolve 500 mg of N- (2,6-diisopropylpropyl) -3- (N-phenylamino) propionamide in 20 ml of methylene chloride, and add N, 0-bis (trimethylsilyl) aceta 350 mg of amide was added, and the mixture was stirred at room temperature for 1 hour. 330 mg of P-toluenesulfonyl chloride was added under ice-cooling, the temperature was gradually returned to room temperature, and the mixture was stirred at the same temperature overnight. The reaction solution was washed with water, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of methanol and black form (1:20) to give N- (2,6-diisopropylpropylphenyl). 3- [N-Phenyl-N-[(4-tolyl) sulfonyl] amino] propionamide (380 mg) was obtained as white crystals. Example 37

3— [N — [(4-arylfurnyl) sulfonyl] -1-N-phenylamino] 1-N— (2,6-diisopropylphenyl) propionamide 300 mg is dissolved in ethanol 20 ml and argon is added. Under zero atmosphere, 30 mg of 10% palladium carbon was added. Hydrogen gas was introduced into the reaction system, and the mixture was stirred at room temperature overnight. The insoluble material was removed, and the filtrate was concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography, and a white solid (290 mg) obtained by elution with a mixed solvent of ethyl acetate and n-hexane (1: 5) was added to acetane and n-hexane. Crystallization in a mixed solvent (1: 3) yields N- (2,6-diisopropylpropyl) -13- [N-phenyl-N-[(4-propylphenyl) sulfonyl] amino] propiona Mid (165 mg) was obtained as white crystals. _{C / 1}

 54

Example 38

 3- [N- (4-promophenyl) sulfonyl N-phenylamino] 1 N- (2,6-diisopropylpropyl) Propionamide 380mg and Arinolet Liptyltin 280mg dissolved in toluene 10ml Then, 10 mg of tetrakistriphenylphosphine was added under argon atmosphere, and the mixture was heated under reflux overnight. After filtering off the insoluble matter, the solvent was distilled off under reduced pressure, and the residue was applied to silica gel column chromatography. The pale yellow solid (410 mg) obtained by elution with a cross-sectional form was crystallized from a mixed solvent of acetone and n-hexane (1: 3) to give 3- [N- [(4-arylphenyl) sulfonyl] -1-N-phenylamino] -1-N- (2,6-diisopropylphenyl) propionamide (190 mg) was obtained as white crystals. Example 39

 A suspension of 1.9 g of N- (2,6-diisopropylphenyl) -1-3- [N-[(4-nitophenyl) sulfonyl] -1-N-phenylamino] propionamide in 120 ml of ethanol, Under an atmosphere of argon gas, 400 mg of 10% palladium carbon was added. Hydrogen gas was introduced into the reaction system, and the mixture was stirred overnight at room temperature. The insoluble material was removed, and the solution was concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography, and a colorless amorphous (1.55 g) obtained by eluting with a mixed solvent of methanol and chloroform (1: 50 → 1: 30) was obtained. [N-[(4-Aminophenyl) sulfonyl] -1-N-phenylamino] N- (2,6— by crystallization from a mixed solvent (1: 3) of ethylene and diisopropyl ether Diisopropyrphenyl) propionamide (1.17 g) was obtained as white crystals. Example 40

3— [N-[(4-amino phenyl) sulfonyl N-phenyl Mino] — N— (2,6-diisopropylphenyl) propionamide (610 mg) was dissolved in methanol (30 ml), and 35% aqueous formaldehyde solution (l.lg) and 10% palladium carbon (100 mg) were added under an argon atmosphere. And hydrogen gas were introduced into the reaction system. After stirring at room temperature overnight, the insoluble material was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure to obtain a white solid (350 mg). By crystallizing this from ethanol, N— (2,6-diisopropylpropyl) 13— [N — [[4- (N, N—dimethylamino) phenyl] sulfonyl] —N —Phenylamino] propionamide (146 mg) was obtained as white crystals. Example 41

 Dissolve 200 mg of N- (2,6-diisopropylpyrphanyl) 13- (N-hexylamino) propionamide in 5 ml of N, N-dimethylformamide and add 60 mg of triethylamine, 2-chloro- 200 mg of 5-nitropyridin was added sequentially, and the mixture was stirred at 70 g overnight. To the reaction mixture was added 50 ml of ethyl acetate, washed with water and saturated saline in that order, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of ethyl acetate and n-hexane (1: 10 → 1: 5) to give a yellow solid ( 270 mg). This was crystallized from a mixed solvent of acetone and n-hexane (1: 3) to give N- (2,6-diisopropylpropyl) 1- [N-hexyl-N- ( 5- (2-Tro-2-pyridyl) amino] propionamide (180 mg) was obtained as yellow crystals. Example 42

Dissolve 180 mg of N- (2,6-diisopropylpyrphenyl) -1- [N-hexyl-N- (5-nitro-2-pyridyl) amino] propionamide in 20 ml of ethanol and flow with argon. Underneath, 50 mg of 10% palladium carbon was added. Introduce hydrogen gas into the reaction system, 5 hours at room temperature Stirred. The insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. Elution with a mixed solvent of ethyl acetate and n-hexane (1: 10-1: 5) yielded a pale purple oil (130 mg). This was dissolved in acetone, and 85 mg of oxalic acid was added. The crystals precipitated by the dropwise addition of n-hexane were collected by filtration and dried to give 3- [N- (5-amino-2-pyridyl). 1) N-hexylamino] N- (2,6-diisopropylpropyl) propionamide dioxalate (160 mg) was obtained as pale brown crystals. Example 43

 To 970 mg of 3-[N-hexyl-1-N-(4-methoxyphenyl) amino] propionic acid was added 2 g of thionyl chloride at room temperature, and the mixture was stirred for 2 hours. After evaporating the solvent under reduced pressure, the residue was dissolved in 15 ml of methylene chloride, and under ice-cooling, 2 ml of a solution of 620 mg of 2,6-diisopropylamine in 2 ml of methylene chloride and 360 mg of triethylamine were sequentially added. After stirring overnight, the reaction solution was washed with water, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of ethyl acetate and n-hexane (1: 10-1: 5) to give N- (2,6-diisopropylpropyl) 13- [ N-Hekinlu N- (4-methoxyphenyl) amino] propionamide (370 mg) was obtained as a pale yellow oil. This was dissolved in ethyl acetate, 0.25 ml of 4N hydrogen chloride in ethyl acetate was added, and n-hexane was added dropwise to give N— (2,6-diisopropylpropylphenyl) 1-3— [N-hexyl acetate. N- (4-Methoxyphenyl) amino] propionamide monohydrochloride (75 mg) was obtained as white crystals. Example 44

3— [N- (1,3—benzodioxol-1 41-yl) amino] 1-N— (2,6-diisopropyrufenyl) propionamide 530mg Dissolve in 10 ml of N, N-dimethylformamide, add 400 mg of anhydrous carbon dioxide, 430 mg of sodium iodide and 270 mg of 4-ethylpentyl chloride at room temperature. Stir for 3 hours. 50 ml of ethyl acetate was added to the reaction solution, washed with a saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. To a colorless oil (175 mg) obtained by elution with a mixed solvent of ethyl acetate and n-hexane (1: 10-1: 5), add 35 mg of oxalic acid and crystallize from disopropyl ether. Thus, 3- [N- (1,3-benzodioxol-1 4-yl) -1N- (4-ethylbenzyl) amino] 1 N- (2,6-diisopropylpropylphenyl) propionamide 1 oxalate (40 mg) as white crystals. Example 45

 N — (2, 6 — diisopropylpropyl) 1-3 — [N — phenyl-N-(2-promoethyl) amino] propionamide 960 mg and 1-piperazinecarboxylic acid ethyl ester 550 mg acetonitride The mixture was heated to reflux in 20 ml of linole. After allowing to cool, the reaction solution was poured into 100 ml of 0.5 N NaOH aqueous solution, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and the crude product obtained by elution with a mixed solvent of chloroform and methanol (100: 1) was treated with oxalic acid (160 mg). , 4 1 [2- [N- [2 -— [N- (2,6-diisopropylphenylcarbamoyl] ethyl] -1-N-phenylamino] ethyl] — 1-pyrazinecarboxylic acid ethyl ester 1 シ ュ920 mg of the acid salt were obtained as white crystals.

N- (2,6-diisopropylphenyl) -1-3-phenylamino 500 mg of oral pionamide and 1.27 g of 1- (3-bromopropyl) -4-phenylpiperazine were dissolved in 10 ml of hexanemethylphosphoric acid triamide, and the mixture was stirred at 100 at 6.5 hours. After allowing the reaction solution to cool, 200 ml of ethyl acetate was added, and the mixture was washed successively with an aqueous solution of sodium hydrogencarbonate and brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. The crude product obtained by eluting with a mixed solvent of ethyl acetate and n-hexane (1: 1) was purified. N- (2,6-diisopropylpropenyl) — 3 -— [N-phenyl-2-N- [3- (4-phenyl-1-pyrazinyl) propyl] amino] 310 mg of pionamide were obtained as white crystals. Example 47

 N- (2,6-diisopropylpropenyl) 1-3- [N-phenyl-N- (2-promoethyl) amino] propionamide 500 mg, N- (2-fluorophenyl) pidazine monohydrochloride 520 mg, And 330 mg of carbon dioxide were heated under reflux in 20 ml of acetonitrile for 30 minutes. After allowing the reaction solution to cool, 50 ml of ethyl acetate was added, washed with INNaOH aqueous solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was applied to silica gel gel chromatography, and the crude product obtained by elution with a mixed solvent of ethyl acetate and n-hexane (1: 2) was obtained. The product is crystallized from n-hexane to give N- (2,6-diisopropylpropyl) -l- [N-phenyl-N- [2-[4- (2-fluorophenyl) -1-1] 451 mg of piperazinyl [ethyl] amino] propionamide were obtained as white crystals. Example 48

3- [N- (2-promoethyl) 1-N-phenylamino] 1-N- (2,6-diisopropylpropyl) Propionamide 400 mg N, N-di After dissolving in 10 ml of methylformamide, 160 mg of phthalimide and 265 mg of anhydrous carbon dioxide were added sequentially, and the mixture was stirred at 40 ° C for 3 hours. 50 ml of ethyl acetate was added to the reaction solution, washed with water, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. A yellow solvent (400 mg) obtained by elution with a mixed solvent of ethyl acetate and n-hexane (1: 10 → 1: 5) was mixed with a mixed solvent of acetate and n-hexane (1: 3). N- (2,6-diisopropylpropyl) -1- [N-phenyl-2- (N- (2-phthalimidethyl) amino] propionami (190 mg) as yellow crystals. Example 49

 3-[N— (2-Promoethyl) -N-phenylamino] — N— (2,6-Diisopropylpropyl) propionamide 330 mg dissolved in ethanol 10 mL, morpholin 160 mg, anhydrous One OO mg of potassium carbonate was added, and the mixture was stirred at 80 ° C for 2 hours. The solvent was distilled off under reduced pressure, and 50 ml of ethyl acetate was added to the residue, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was applied to silica gel column chromatography. A colorless oil (200 mg) obtained by elution with a mixed solvent of methanol and black form (1:40) was dissolved in ethyl acetate, and crystals precipitated by adding 41 mg of oxalic acid were added. The crystals were collected by filtration and dried to give N- (2,6-diisopropylpropyl) -1- [N- (2-morpholinoethyl) -1-N-phenylamino] propionamide 1 oxalate (200 mg) as white crystals. Get as

7 Example 50

N- (2,6-diisopropylpropyl) -1-3- [N-fuyuni N- (2-phthalimidoethyl) amino] 290 mg of propionamide It was dissolved in 10 ml of methanol, 10 ml of 40% methylamine methanol solution was added, and the mixture was refluxed for 3 hours. After concentrating the reaction mixture under reduced pressure, ethyl acetate was added to the residue and washed with water. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. The colorless amorphus (200 mg) obtained by elution with a mixed solvent of methanol and chloroform (1:10 to 1: 5) was dissolved in ethyl acetate, 50 mg of oxalic acid was added, and the resulting crystals were filtered. The residue is dried and dried to give 3- [N— (2—aminoethyl) -1-N-phenylamino] —N— (2,6—diisopropylpropylphenyl) propionamide 1 oxalate (210 mg) Was obtained as white crystals. Example 51

 Dissolve 410 mg of 3-[N-(4-Aminobutyl) 1 N-phenyl] 1 N-(2,6-diisopropylphenyl) propionamide in 10 ml of ethanol, add 120 mg of benzaldehyde under ice-cooling, and gradually add it. The mixture was stirred at room temperature for 1 hour. The reaction solution was ice-cooled again, 40 mg of sodium borohydride was added, the temperature was gradually returned to room temperature, and the mixture was stirred for 1 hour. To the reaction mixture was added 50 ml of ethyl acetate, washed with water and a saturated aqueous solution of sodium hydrogen carbonate in that order, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. A colorless oil (460 mg) obtained by elution with a mixed solvent of methanol and black form (1:20) is dissolved in ethyl acetate, and the crystals precipitated by adding oxalic acid (80 mg) are collected by filtration and dried. As a result, 450 mg of 3- [N- (4-benzylaminobutyl) -1-N-phenyl] —N— (2,6-diisopropylpropylphenyl) propionamide 1 oxalate was obtained as white crystals. . Example 52

N— (2,6-diisopropyl phenyl) 1 3— [N-phenyl N- (3-Bromopropyl) amino] 420 mg of propionamide and 640 mg of imidazole were refluxed twice in 10 ml of acetonitrile. After allowing the reaction solution to cool, 200 ml of ethyl acetate was added, washed with brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was applied to silica gel column chromatography, and the crude product obtained by elution with a mixed solvent of chromate-form and methanol (50: 1) was removed. N- (2,6-diisopropylphenyl) -1- [N- [3- (1H-imidazo-l-l-yl) -propyl] -N-phenyl [Mino] propionamide monooxalate (270 mg) was obtained as white crystals. Example 53

 N— (2,6-diisopropylpropyl) 1-3— [N-phenyl N- (2-promoethyl) amino] Propionamide 900mg and 2-phenylimidazole 910mg The mixture was refluxed for 30 minutes in 30 ml of tonitrile. After allowing the reaction solution to cool, 200 ml of ethyl acetate was added, and the mixture was washed successively with an aqueous solution of sodium hydrogen carbonate and brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. The crude product obtained by elution with a mixed solvent of ethyl acetate and n-hexane (1: 1) was treated with oxalic acid (35 mg). N- (2,6-diisopropylphenyl) 13- [N-phenyl N- [2- (2-phenyl-1H-imidazole-11-yl) ethyl [Amino] Propionamide monooxalate 230 mg was obtained as white crystals. Example 54

N- (2,6-diisopropylpropyl) -1-3- [N-phenyl-N- (3-bromopropyl) amino] propionamide 330 mg, 4- (1-imidazolyl) phenol, and Carbonated room 300mg N, The mixture was stirred in 10 ml of N-dimethylformamide at room temperature for 30 minutes. 200 ml of ethyl acetate was poured into the reaction solution, washed with brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was applied to silica gel column chromatography, and eluted with a mixed solvent (50: 1) of chloroform and methanol. , 6-diisopropipirnil) 1-3-[N-Fernyl N-[3-[4-(1H-imidazo 1-1 1 yl) fu Xoxy] propyl] amino] Propionamide 130 mg were obtained as white crystals. Example 55

 3- [N- (2-Isopropoxhetyl) -N-phenylamino] Propionic acid (500 mg) was dissolved in chloroform (10 ml), and oxalyl chloride (550 mg) was added under ice-cooling. The mixture was stirred at the same temperature for 1 hour. The solvent was distilled off under reduced pressure, the residue was dissolved in 10 ml of chloroform, and 2 ml of a 400 mg solution of diisopropylamine in chloroform and 230 mg of triethylamine were added sequentially under ice cooling. The reaction solution was gradually returned to room temperature and stirred for 2 hours. The reaction solution was washed successively with water and a saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of ethyl acetate and n-hexane (1: 5) to obtain 560 mg of a white solid. By crystallization from a mixed solvent of acetone and n-hexane (1: 3), N- (2,6-diisopropylphenyl) 13- [N- (2-isopropoxhetyl) — [N-phenylamino] propionamide (430 mg) was obtained as white crystals. Example 56

N- (2,6-diisopropyl phenyl) 1 3- [N-phenyl N- (2-promoethyl) amino] propionamide lOOOOmg, 4,5-diphenylimigusol-2-thiol 580mg , And carbon dioxide 690 mg of the amide was heated and refluxed for 2.5 hours in a mixed solvent of 30 ml of acetone and 20 ml of methanol. After cooling, the solvent was distilled off under reduced pressure, and the residue was applied to silica gel gel chromatography. The crude product obtained by elution with a black form was crystallized from geethylether to give N— (2,6-diisopropylphenyl) -1-3-N- [2 — [(4, 5-diphen 2-1 H-imidazo-1-2-thio] ethyl]-N-phenylamino] propionamide (630 mg) was obtained as white crystals. The structural formulas of the compounds of Examples 1 to 24 obtained above are shown in Tables 5 and 6, and the structural formulas and melting points of the compounds of Examples 25 to 56 are shown in Tables 7 and 8.

Five

6

S9 £ Z0 / L6d £ / lDd 99 zo / 86 OAV Table 8

Examples 74, 81, 82, 84, 86, 88, 90-92, 104, 115-117, 120-123, 125, 129, 131, 133-141, 144, 145, 147 in the same manner as in Example 1. I got

 In the same manner as in Example 8, Examples 148 to 159 and 184 to 186 were obtained. In the same manner as in Example 9, Examples 163 and 168 were obtained.

 In the same manner as in Example 13, Examples 94-103, 105-113, and 194-196 were obtained.

 In the same manner as in Example 25, Examples 58-65, 68-72, 75-80, 83, 85, 114, 127, 128, 130, 164, 165, 175, 176, 179 were obtained.

 Example 67 was obtained in the same manner as Example 26, Example 66 was obtained in the same manner as Example 27, and Examples 118, 119, 124, 142, 143 and 192 were obtained in the same manner as Example 28.

 Examples 89 and 200 were obtained in the same manner as in Example 29, Example 73 was obtained in the same manner as in Example 30, and Example 180 was obtained in the same manner as in Example 31.

 In the same manner as in Example 33, Examples 87, 93, 126, 146, 190, and 191 were obtained.

 Example 197 was obtained in the same manner as in Example 38.

 Example 57 was obtained in the same manner as Example 43, Example 132 was obtained in the same manner as Example 44, Example 160 was obtained in the same manner as Example 45, and Examples 161 and 162 were obtained in the same manner as Example 47. Was. In the same manner as in Example 49, Examples 166, 167 and 183 were obtained.

 Examples 181 and 182 were obtained in the same manner as in Example 51, Example 169 was obtained in the same manner as in Example 52, and Examples 170 to 174 were obtained in the same manner as in Example 53.

Examples 177 and 178 were obtained in the same manner as in Example 54, and Examples 187 to 189 were obtained in the same manner as in Example 56. Example 193

N- (2,6-Diisopropylpropyl) 13- [N- (3,5-xylyl) amino] 600 mg of propionamide is dissolved in 10 ml of N, N-dimethylformamide, and anhydrous potassium carbonate is dissolved. 470 mg, sodium iodide 250 mg and piperonyl chloride mouth 350 mg were sequentially added at room temperature. After heating at 80 ° C for 2 hours, allow to cool to room temperature, add 50 ml of ethyl ethyl carbonate, wash with 50 ml of saturated aqueous sodium hydrogen carbonate solution and 50 ml of saturated saline, and wash the organic layer with anhydrous magnesium sulfate. Dried. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of ethyl acetate and _n- hexane (1: 5) to obtain a colorless foam. Was. This was crystallized from diisopropyl ether to give 390 mg of N- (2,6-diisopropylphenyl) -13- [N-pyronyl-N- (3,5-xylyl) amino] propionamide. White crystals were obtained.

 Melting point: 131-132 ° C

Elemental analysis value (C _Q1 H ₃₈ N ₂ 0 ₃ )

 C (%) H (%) N (%)

 Theory 76.51 7.87 5.76

 Experimental value 76.48 7.95 5.60 Example 198

(1,3-benzodioxo-1-yl 5-yl) 1N— (4,6-dimethyl-2-pyridyl) sulfonamide In 500 ml of a solution of 500 mg of tetrahydrofuran in a solution of triphenylphosphine at room temperature. 520 mg were added. To this solution are added N- (2,6-diisopropylphenyl) -13-hydroxypropionamide (410 mg) and getyl azodicarboxylate (290 mg) at room temperature, and the mixture is stirred overnight at the same temperature. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography. Colorless amorphus obtained by elution with chloroform [N- (1,3-Benzodioxol-5-yl) sulfonyl] 1 N-(4,6-dimethyl) by crystallization from a mixed solvent of hexane and n-hexane (1: 4) Chill-2-pyridyl) amino] -N- (2,6-diisopropylphenyl) propionamide 420 mg was obtained as white crystals.

 Melting point: 160-161 ° C

Elemental analysis _{(C 29 H 35 N 3 O} c S)

 C (%) H (%) N (%) S (%) Theoretical 64.78 6.56 7.82 5.96 Experimental 64.85 6.46 7.84 5.97 Examples 203, 205, 206, 207, 208, 209, 210 in the same manner as in Example 198. , 212, 213, 214 were obtained. Example 199

 N- (2,6-diisopropylphenyl) -13- [N- (3,5-xylyl) amino] propionamide (600 mg) was dissolved in 20 ml of porcine, and 200 mg of pyridine was added to this solution. (1,3-benzodioxol 5-yl) Sulfonyl chloride (450 mg) was sequentially added, and the mixture was stirred at room temperature for 9 hours. The solvent was distilled off under reduced pressure, 50 ml of toluene was added, and the solvent was distilled off again under reduced pressure. 100 ml of ethyl acetate was added to the residue, washed with 100 ml of water, the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. The pale-yellow solid obtained by eluting with a black hole form was crystallized from a mixed solvent of acetate and n-hexane (1: 1) to give 3- [N-[(1,3– Benzodoxo-l-5-yl) sulfonyl] -N- (3,5-xylyl) amino] -N- (2,6-diisopropylpropyl) propionamide 480 mg was obtained as white crystals.

Melting point: 236—238 Elemental analysis _{(C 3 () H 36 N} 2 0 5 S)

C (%) H (%) N (%) S (%) Theoretical value 67.14 6.76 5.22 5.97 Experimental value 67.00 6.69 5.10 5.92 In the same manner as in Example 199, Examples 201, 202, 204, 211, and 215 were obtained. . Table 9 and Table 18 show the structural formulas and melting points of the compounds of Examples 57 to 215 obtained above.

6 Halla

S8 £ Z0 / L6dT / IDd ZL Table 10

 urn

SS £ Z0IL6dT / lDd PL Table 12

Table 13

Table 14

 SI Halla

 S8 £ Z0 / L6d £ fL3d

0/86 OAV Table 16

Table 17

Table 18

However, if the melting point cannot be measured or has not been measured, other physical properties are shown below.

 Example 65 Mass spectrometry value (m / z): FAB 521

 Example 89 Mass spectrometry value (m / z): FAB431

Example 148 infrared absorption spectrum max (KBr) cm- ¹

3448, 2974, 2878, 2596, 2452, 1644, 1617, 1542, 1470, 1440, 1386, 1275, 1239, 1185, 765, 699

 Example 165 Quality analysis (mZz): EI 525

Example 169 Infrared absorption spectrum max (KBr) cm— ¹ :

3274, 2974, 2878, 1662, 1599, 1506, 1467, 1365, 1278, 1257, 1230, 1191, 1110, 1080, 810, 750, 666 Example 176 Mass spectrometry (mZz): FAB 445

Example 177 Infrared absorption spectrum max (KBr) cm- ¹

3448, 3166, 2974, 2878, 1665, 1602, 1545, 1515, 1473, 1254, 1185, 1059, 837

Example 186 nuclear magnetic resonance spectrum (DMSO- d _6, TMS internal standard)

 δ: 0.8—1.3 (15H, m), 2.61 (2H, m)

 2.96 (4H, m), 3.4-3.8 (6Η, m),

6.7-7.5 (14H, m), 9.24 (1H.m). In addition to the compounds of the above Examples, other compounds of the present invention are shown in Table 19 below. These compounds can be synthesized using the synthetic routes and methods described in the above Preparations and Examples, and modifications thereof known to those of ordinary skill in the art. It is not needed. 19

Claims

The scope of the claims

1. A propionanilide derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

(However, the symbols in the formula have the following meanings.

 A ring group: selected from a nitrogen atom, an oxygen atom or a sulfur atom, which may be condensed with cyclopentane, dioxole or dioxane and may be substituted, or may be substituted 5- or 6-membered heterocyclic group having 1 to 3 hetero atoms

1¾ ¹ and 1¾: Same or different and lower alkyl group

 R °: hydrogen atom or lower alkyl group

 B: a bond, a lower alkylene group which may be substituted, a lower alkenylene group or a lower alkynylene group, or a group represented by the formula S (0) n—

 n: 0, 1 or 2

R ⁴ may be condensed with an alkyl group, an aralkyl group, a carboxyl group, a lower alkoxycarbonyl group, a cycloalkyl group, an optionally substituted pyridyl group, cyclopentane, thiadiazole, dioxol or dioxane; An aryl group which may be substituted, or a group represented by the formula: OR ⁵ , —SR ⁶ or

R hydrogen atom or aryl group which may be substituted R ⁶ : imidazolyl group which may be condensed with a benzene ring and may be substituted

R ⁷ and R ^{8 are the} same or different and are a hydrogen atom, a lower alkyl group, an optionally substituted aryl group, an aralkyl group, or

R ⁷ and R ⁸ become bodies

 (1) A 5- or 6-membered nitrogen-containing saturated or unsaturated heterocyclic group which may contain one hetero atom selected from nitrogen, oxygen or sulfur as another hetero atom. The nitrogen-containing saturated or unsaturated heterocyclic group may be substituted and may be fused with a substituted or unsubstituted benzene ring.

 Or

 (2) Cyclic imid which may be condensed with a benzene ring

2. Ring A is an aryl group or a pyridyl group which may be substituted, B is a lower alkylene group or a group represented by the formula —S (0) n—. R ⁴ is an alkyl group, Or an aryl group or a group represented by the formula which may be condensed with dioxol.

3. The compound according to claim 1, wherein

3.3— [N — [(1,3-benzodioxol-5-yl) sulfonyl] —N— (4,6-dimethyl-2-pyridyl) amino] N— (2 , 6-diisopropylphenyl) propionamide or a pharmaceutically acceptable salt thereof.

4. N- (2,6-Diisopropylpyrudinyl) -1-3- [N-pironyl-N- (3,5-xylyl) amino] propionamide or a pharmaceutically acceptable salt thereof.

5. 3— [N-[(1,3-benzodioxol-5-yl) sulfonyl] —N— (3,5-xylyl) amino] N— (2,6-diisop Mouth pirfenil) Propionamide or a pharmaceutically acceptable salt thereof.

6. N— (2,6-diisopropylpropyl) -1-3- [N- (4-ethylbenzyl) -1-N— (3,5-xylyl) amino] propionamide or a pharmaceutically acceptable salt thereof Salt.

7. N- (2,6-diisopropylpropylphenyl) -3- [N-hexyl-N- (3,5-xylyl) amino] propionamide or a pharmaceutically acceptable salt thereof .

8. N- (2,6-diisopropylpropenyl) -1-3- [N-phenyl-N- [2- (4-phenyl-2-piperazinyl) ethyl] amino] propionamide or pharmaceutically acceptable Salt.

9. N- (2,6-diisopropylpropyl) -3- (N-hexyl-1-N-phenylamino) propionamide or a pharmaceutically acceptable salt thereof

¾ ΧπΛ.

10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition according to claim 10, which is an ACAT inhibitor.

12. The pharmaceutical composition according to claim 10, which is a macrophage ACAT inhibitor.

13. The pharmaceutical composition according to claim 10, which is a foaming inhibitor for macrophages.

 14. The pharmaceutical composition according to claim 10, which is a blood cholesterol lowering agent.

 15. The pharmaceutical composition according to claim 10, which is an activator for a cholesterol reverse transfer system.

 16. The pharmaceutical composition according to claim 10, which is an agent for preventing or treating arteriosclerosis or various diseases caused by arteriosclerosis.