JP2002212179A - New anilide derivative or salt thereof and medicine containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new anilide derivative or a salt thereof having excellent microsomal triglyceride transfer protein-(MTP) inhibiting actions, etc., and useful as a medicine for prophylaxis and therapy of hyperlipidemia and/or arteriosclerosis, etc. SOLUTION: The anilide derivative represented by general formula (1) [wherein, R1 is an alkoxy, an alkylthio or the like; R2 is an alkoxy, an alkylthio or the like or forms a bicyclic or a tricyclic condensed hydrocarbon or condensed heterocycle together with the neighboring ring by combining with R6; R3 is H or the like; R4 is an alkyl, a cycloalkyl or the like; A is N or CR6 (R6 is H or forms the condensed rings by combining with R2); B is N, CH or the like; W is an aryl or the like; D is O or the like; E ring is an aromatic hydrocarbon or the like; G is a group represented by formula (a) or the like; X is O, single bond or the like; Y is an alkylene, an aryl, a heteroaryl or the like; Z is single bond, an alkylene or the like; and R5 is H, an alkyl or the like] or the salt thereof and the medicine containing the compound as an active ingredient are provided.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel anilide derivative or a salt thereof having an excellent activity of inhibiting microsomal triglyceride transfer protein, and a medicament containing the substance as an active ingredient.

[0002]

2. Description of the Related Art Hyperlipidemia is one of the risk factors for arteriosclerotic diseases such as ischemic heart disease as well as diabetes, hypertension, smoking, etc., and its improvement is extremely important in the treatment of such diseases. It is an issue. Hyperlipidemia includes primary hyperlipidemia caused by enzymes involved in lipoprotein metabolism, genetic abnormalities such as protein or lipoprotein receptor, and hyperlipidemia caused by various diseases and drugs. Although there is secondary hyperlipidemia, hyperlipidemia caused by enhanced lipoprotein synthesis in the liver is particularly important as a pathological condition in the overnutrition situation as in today.

Heretofore, as a therapeutic agent for hyperlipidemia, an anticholesterolemia agent useful for prevention and treatment of arteriosclerosis and a triglyceride lowering agent useful for prevention and treatment of ischemic heart disease have been known. ing. However, the mechanism of the lipid-lowering action of the triglyceride lowering agent (fibrate) is complicated, and there is a drawback that the dosage is large.
In addition, in patients with hypertriglyceride and hypercholesterolemia (type IIb), a statin-based cholesterol synthesis inhibitor and a fibrate-based triglyceride lowering agent are often used in combination. It has been reported that severe side effects due to additive or synergistic enhancement may occur.

[0004] On the other hand, triglyceride absorbed in the small intestine forms a chylomicron complex with apoprotein B (apo B), phospholipid and cholesterol in a rough parcel of small intestinal epithelial cells, and the blood passes through lymphatic vessels. And is transferred to other tissues including adipose tissue. Microsomal triglyceride transfer protein (MTP) is purified as a soluble protein of the microsomal fraction in the liver and small intestine and has a molecular weight of about 1
50,000 proteins (Wetterau JR, Aggerbeck LP, Lapla
nd PM, McLean LR, Biochemistry 30, 4406-4412, 199
1) It has an activity to transfer neutral lipids, especially triglycerides to apo B, and is said to be deeply involved in the production of chylomicron and VLDL (Sharp D, Binderman L, Comb)
s KA, Kienzel B, Ricci B, Wager SK, Gill CM, Turck CW, B
ouma ME, RaderDJ, Aggerbeck LP, Gregg RE.Gordon DA, We
tterau JR, Nature 365, 65-69, 1993: Wetterau JR, Zil
versmit DB, J Biol Chem 259, 10863-10866, 1984).
In addition, it has been recently revealed that MTP is deficient in β-lipoproteinemia, a hereditary disease exhibiting hypolipidemia (Wetterau JR, Zilversmit DB, Biochem.
Biophys Acta 875, 610-617, 1986), lipoprotein secretion does not occur due to MTP deficiency, resulting in hypolipidemia,
Conversely, it is speculated that hyperlipidemia is caused by an increase in MTP activity. Therefore, it is considered that an inhibitor of MTP activity can be an excellent therapeutic agent for hyperlipidemia which suppresses the production of lipoproteins such as chylomicron and VLDL. It is also expected that suppression of intestinal MTP will suppress chylomicron production and suppress excessive triglyceride absorption, which is a cause of hyperlipidemia. Can be

[0005] As described above, the MTP inhibitor has a well-defined mechanism and can lower the serum triglyceride amount more strongly than the conventional triglyceride lowering agent. Further, it is predicted that the cholesterol is reduced simultaneously with the triglyceride. Is expected to have a wide range of clinical applications, including patients with type IIb hyperlipidemia in which both triglyceride and triglyceride are high. However, only a few reports have been reported so far (Japanese Patent Application Laid-Open Nos. -165
712, WO96 / 26205, WO96
/ 40640, WO97 / 43257, W
O98 / 27979, WO98 / 54135, SCIENCE, vol. 282, p751, 1998), and there are no clinically applied drugs yet.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to provide an MT
An object of the present invention is to provide a novel compound which has a P inhibitory effect and can be used as a medicament for preventing and treating hyperlipidemia.

[0007]

Under such circumstances, the present inventors have synthesized and studied various compounds. As a result, the specific anilide derivative and its salt have excellent MTP inhibitory activity, and The present invention has been found to inhibit lipoprotein secretion and is useful as a preventive / therapeutic agent for hyperlipidemia and / or arteriosclerosis, and completed the present invention. That is, the present invention provides the following general formula (1)

[0008]

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Wherein R ¹ is a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkoxy group which may have a substituent, An alkylthio group which may have a group, an amino group which may have a substituent, a saturated cyclic amino group which may have a substituent or a halogen atom, and R ² represents a hydrogen atom, a substituent An alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkoxy group which may have a substituent, an alkylthio group which may have a substituent, Represents an amino group which may be substituted, a saturated cyclic amino group which may have a substituent or a halogen atom, or 2 or 3 or 4 together with an adjacent ring together with R ⁶ when A is CR ^6. Tricyclic fused hydrocarbon or fused heterocyclic ring Form, R ³ represents a hydrogen atom, an alkyl group or a halogen atom, R ⁴ represents a cycloalkyl group which may have an optionally substituted alkyl group or a substituent, A is nitrogen Represents an atom or CR ⁶ (where R ⁶ is taken together with a hydrogen atom or R ² to form the above fused ring), B represents a nitrogen atom or CH, W is a hydrogen atom, a halogen atom, An aryl group which may have a group or a heteroaryl group which may have a substituent, D represents an oxygen atom or a sulfur atom, and E ring is an aromatic hydrocarbon, an aromatic hetero ring or G represents a saturated cyclic hydrocarbon, and G represents the following formulas (a) to (d)

[0010]

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(Where e represents an integer of 3 to 7, f represents an integer of 1 or 2, g represents an integer of 2 or 3, h
Represents an integer of 0 or 1, i represents an integer of 1 to 3, j
Represents an integer of 0 to 5; n represents an integer of 0 or 1;
Represents NH, an oxygen atom or a sulfur atom (however, when h is 0, i represents an integer of 2 or 3). X represents an oxygen atom, a sulfur atom or a single bond, and Y represents a single bond, an alkylene group, an alkenylene group, an amino group, an aryl group which may have a substituent or a substituent. Represents a heteroaryl group which may be a single bond, an alkylene group,
An alkenylene group, an aryl group which may have a substituent or a heteroaryl group which may have a substituent (however, Y and Z do not simultaneously represent a single bond, and one of them has a substituent; When an aryl group or a heteroaryl group which may have a substituent, the other represents a single bond, an alkylene group or an alkenylene group, and when Y is an amino group, Z represents An alkylene group, an alkenylene group, an aryl group which may have a substituent or a heteroaryl group which may have a substituent), and R ⁵ is
Represents a hydrogen atom, an alkyl group or an aralkyl group). ] The anilide derivative represented by these, or its salt is provided.

Further, the present invention provides a medicament comprising the anilide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a prophylactic / therapeutic agent for hyperlipidemia and / or arteriosclerosis containing the anilide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION The general formula (1) representing the compound of the present invention
Wherein the alkyl group in the optionally substituted alkyl group represented by R ¹ , R ² and R ⁴ has 1 carbon atom
To 12 straight-chain or branched alkyl groups,
Among them, a linear or branched alkyl group having 1 to 8 carbon atoms is preferable, and in particular, a methyl group, an ethyl group, an n-propyl group,
Isopropyl group, n-butyl group, isobutyl group, ter
A linear or branched alkyl group having 1 to 6 carbon atoms such as a t-butyl group, an n-pentyl group and an n-hexyl group is preferred.

The alkenyl group in the alkenyl group which may have a substituent represented by R ¹ and R ² includes a linear or branched alkenyl group having 4 to 12 carbon atoms. A linear alkenyl group of 1 to 8 is preferable, and in particular, an allyl group, a vinyl group, a 1-propenyl group,
-Butenyl group, 3-butenyl group, 2-pentenyl group, 3
A linear alkenyl group having 1 to 6 carbon atoms such as -pentenyl group, 4-pentenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group and 5-hexenyl group is preferred.

Examples of the optionally substituted alkoxy group represented by R ¹ and R ² include a linear or branched alkoxy group having 1 to 12 carbon atoms. 8 straight-chain or branched-chain alkoxy groups are preferred,
Particularly, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, te
A linear or branched alkoxy group having 1 to 6 carbon atoms such as an rt-butoxy group, an n-pentyloxy group and an n-hexyloxy group is preferred.

Examples of the alkylthio group which may have a substituent represented by R ¹ and R ² include a linear or branched alkylthio group having 1 to 12 carbon atoms. Preferred are straight-chain or branched-chain alkylthio groups of 8, especially methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, n-pentylthio, n- A linear or branched alkylthio group having 1 to 6 carbon atoms such as a hexylthio group is preferred.

The group which can be substituted on the alkyl group, alkenyl group, alkoxy group and thioalkoxy group includes
A halogen atom such as a C _3-6 cycloalkyl group, a chlorine atom, a fluorine atom, an amino group, an alkyl group (eg, methyl, ethyl, propyl, etc.) or an amino protecting group (eg, benzyl, 2-phenylethyl, tert-butoxycarbonyl, Benzyloxycarbonyl, benzhydryl or the like), an alkoxy group such as methoxy, ethoxy, propoxy, etc., formyl, acetyl, propionyl, butyryl, isobutyryl, an alkanoyl group such as valeryl, isovaleryl, pivaloyl, and a nitro group. , Hydroxy group, carboxy group, cyano group, benzoyl group,
Phenyl group, aryl group such as naphthyl group, pyridyl group,
Examples include a heteroaryl group such as a furyl group and a thienyl group.

Examples of the amino group which may have a substituent represented by R ¹ and R ² include an amino group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group and a tert- group. Alkyl groups such as butyl group, alkoxy groups such as methoxy group, ethoxy group, propoxy group and butoxy group; aralkyl groups such as benzyl group, 2-phenylethyl group, 3-phenylpropyl group and 4-phenylbutyl group; Examples include an amino-protecting group such as a butoxycarbonyl group, a benzyloxycarbonyl group, and a benzhydryl group, and an amino group substituted by 1 to 2 with a hydroxy group.

Examples of the saturated cyclic amino group in the optionally substituted saturated cyclic amino group represented by R ¹ and R ² include a 4- to 8-membered group such as an azetidinyl group, a pyrrolidinyl group, a piperidino group and a piperazinyl group. Examples of the group which can be substituted on the ring include the same as the above-mentioned substituents on the amino group which may have a substituent.

Examples of the halogen atom represented by R ¹ , R ² , R ³ and W include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, of which R ¹ , R ² and R ³ are a fluorine atom Alternatively, a chlorine atom is preferable, and W is preferably an iodine atom or a bromine atom.

As the alkyl group represented by R ³ and R ⁵ , those similar to those represented by R ¹ , R ² and R ⁴ can be mentioned.

The cycloalkyl group in the optionally substituted cycloalkyl group represented by R ⁴ includes:
Examples thereof include a cycloalkyl group having 3 to 8 carbon atoms, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group, which may be substituted with 1 to 3 substituents. As the substituent, an alkyl group such as a methyl group, an ethyl group, and a propyl group;
Examples include a halogen atom, a nitro group, a hydroxy group, a carboxy group, a cyano group, and an amino group.

The aralkyl group represented by R ⁵ includes aralkyl having an alkylene chain having 1 to 6 carbon atoms and having 6 to 14 carbon atoms, of which phenyl-C _1-6 alkyl is preferred, and benzyl is particularly preferred. And a 2-phenylethyl group.

Examples of the alkylene group represented by Y and Z include alkylene having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and the like.

The alkenylene group represented by Y and Z is preferably an alkenylene group having 3 to 6 carbon atoms, such as propenylene, butenylene, pentenylene, hexenylene and the like.

The aryl group which may have a substituent represented by W, Y and Z includes an aromatic hydrocarbon group having 6 to 14 carbon atoms, such as phenyl and naphthyl. These may be substituted with 1 to 5 substituents, such substituents as a C _1-6 alkyl group,
C _1-6 alkenyl group, formyl group, fluoromethyl group,
Halogenoalkyl groups such as difluoromethyl group and trifluoromethyl group, alkoxy groups such as methoxy group and ethoxy group, halogenoalkoxy groups such as fluoromethoxy group, difluoromethoxy group and trifluoromethoxy group, methylthio group, ethylthio group and propylthio group And an alkanoyl group such as an acetyl group and a propionyl group, and a halogen atom such as a fluorine atom, a chlorine atom and a bromine atom.

Examples of the optionally substituted heteroaryl group represented by W, Y and Z include a 5- to 14-membered monocyclic or bicyclic ring having 1 to 3 nitrogen, oxygen or sulfur atoms. Heteroaryl groups of the formula include, for example, pyridyl, furyl, thienyl, pyrrolyl, pyrimidinyl, imidazolyl, triazolyl, pyrazolyl, isothiazolyl, isoxazolyl, thiazolyl, oxazolyl, thiadiazolyl, tetrazolyl, pyridazinyl, pyrazinyl, benzofuryl, benzothienyl, benzothiazolyl, benzopyranyl. Quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, indolyl, isoindolyl, etc., wherein W is a 6-membered heteroaryl group such as pyridyl and 1,3
-A benzodioxole group or the like is preferable, and Y is preferably a 5- to 6-membered heteroaryl group such as a furyl, thienyl, or pyridyl group. These may be substituted with 1 to 5 substituents. Examples of such substituents include halogenoalkyl groups such as C _1-6 alkyl, fluoromethyl, difluoromethyl, and trifluoromethyl; Preferred are an alkoxy group such as a ethoxy group, a halogen atom such as a fluorine atom, a chlorine atom and a bromine atom, an amino group, a nitro group and the like.

As the aromatic hydrocarbon represented by the ring E,
Examples thereof include 6- to 14-membered aromatic hydrocarbons such as benzene and naphthalene, and a benzene ring is particularly preferable.

The aromatic heterocyclic ring represented by ring E includes furan, thiol, pyrrole, pyridine, pyrimidine, imidazole, triazole, pyrazole, isothiazole, isoxazole, thiazole, oxazole, thiadiazole, pyridazine, pyrazine, benzofuran. And 5- to 10-membered aromatic heterocycles such as benzothiol, benzopyran, quinoline, phthalazine, naphthyridine, quinoxaline and quinazoline, and in particular, a 5- to 6-membered monocyclic aromatic ring such as furan, thiol, pyrrole and pyridine. Group heterocycles are preferred.

Examples of the unsaturated cyclic hydrocarbon represented by the ring E include 4- to 12-membered unsaturated cyclic hydrocarbons such as cyclobutene, cyclopentene, cyclohexene and cycloheptene, and particularly 1-cyclopentene, 1-cyclohexene and the like. And a 5- to 6-membered unsaturated cyclic hydrocarbon are preferred.

Further, specific embodiments of the ring WXX are shown below.

[0033]

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When G is one of the formulas (a) to (d), for example, (a) may be azetidine, pyrrolidine, azetidin-3-ylmethyl, pyrrolidin-3-ylmethyl, piperidine, piperidine-3-piperidin. Ilmethyl,
Piperidin-4-ylmethyl, (b) piperazin-3-ylmethyl, morpholin-3-ylmethyl, thiomorpholin-3-ylmethyl, (c) 3-azabicyclo [3.1.0] hexane, 3-azabicyclo [3 .2.0] heptane, 3-azabicyclo [3.3.
0] octane, (d) as indoline, isoindoline, 1,2,3,4-tetrahydroquinoline, 1,2,2
3,4-tetrahydroisoquinoline and the like.

Further, specific embodiments of ZGN will be shown below.

[0036]

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In the case where R ² and R ⁶ together with an adjacent ring form a ring, the bicyclic or tricyclic fused hydrocarbon and the bicyclic or tricyclic fused heterocyclic ring are specifically described as It is as follows.

[0038]

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Further, in a preferred embodiment of the compound represented by the general formula (1) of the present invention, R ¹ is an alkoxy group or an alkylthio group, R ² is an alkoxy group or an alkylthio group, and R ³ is hydrogen. R ⁴ is an alkyl group, A is CH or a nitrogen atom, and B is CH
Or a nitrogen atom, W is a phenyl group, D is an oxygen atom, E ring is a benzene ring, pyridine ring, cyclohexenyl ring, G is the formula (a), X is a single bond, , Y is an alkylene group and Z is a single bond.

The salt of the compound (1) of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt.
(A) salts with mineral acids such as hydrochloric acid and sulfuric acid, (b) salts with organic carboxylic acids such as formic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid and maleic acid, (c) methanesulfonic acid, Acid addition salts such as salts with sulfonic acids such as benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, and naphthalenesulfonic acid; (i ') salts with alkali metals such as sodium and potassium;
(B) Salts with alkaline earth metals such as calcium and magnesium, (c) ammonium salts, (d) trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N -Methylmorpholine, diethylamine, cyclohexylamine, procaine, dibenzylamine, N-
Benzyl-β-phenethylamine, 1-ephenamine,
Base addition salts such as salts with nitrogen-containing organic bases such as N, N'-dibenzylethylenediamine can be mentioned.

The compound (1) of the present invention or a salt thereof also includes a solvate represented by a hydrate.

Further, the compound (1) of the present invention, depending on the type and combination of the substituents, may have a geometrical isomer such as a cis-form or a trans-form, an optical isomer such as a d-form or an 1-form, or a rotational isomer. Although various isomers may exist, the present invention includes all such isomers.

The compound (1) of the present invention or a salt thereof is
For example, it is manufactured by any of the following manufacturing examples 1 and 2.

[Production Example 1]

[0045]

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Wherein P represents an amino-protecting group and G ′ =
N represents a formula (a) to (d) represented by G, L represents a leaving group such as a halogen atom, a methanesulfonyl group or a p-toluenesulfonyl group, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
A, B, W, X, Y, Z and E rings are the same as defined above]

That is, a compound (A) is used as a raw material, a compound (B) is obtained by introducing an amino protecting group into the compound, a compound (C) is obtained by N-alkylation, and a compound is obtained by removing the amino protecting group. (D) or compound (A) as a raw material, acylation and reduction followed by reduction to compound (D), and reaction with compound (E) or compound (F) to form compound (G). And further reacted with compound (H) to produce compound (I) of the present invention.

The amino protecting group represented by P includes te
hydrogenation of rt-butoxycarbonyl group, benzyloxycarbonyl group, diphenylmethoxycarbonyl group, anthrylmethoxycarbonyl group or the like or aralkyl group such as benzyl group, p-methoxybenzyl group, phenethyl group, benzhydryl group, triphenylmethyl group or the like; Alternatively, a group which can be eliminated by hydrolysis is preferable.

The amino group protection reaction is carried out, for example, by adding benzyloxycarbonyl chloride or the like to compound (A) using an inorganic base such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate or cesium carbonate or pyridine, picoline, N , N-dimethylaniline, N-methylmorpholine, dimethylamine, triethylamine, 1,
8-diazabicyclo [5.4.0] undecene (DB
In the presence or absence of an organic base such as U), aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran, diethyl ether and dioxane, ketones such as acetone and methyl ethyl ketone or acetonitrile, N, N- 0 ° C to 100 ° C, preferably 50 ° C to 1 ° C in an aprotic polar solvent such as dimethylformamide.
The reaction can be performed at 00 ° C. for 30 minutes to 10 hours, preferably for 1 hour to 10 hours.

The alkylation of the compound (B) is carried out, for example, by reacting the compound (B) with an alkyl halide such as alkyl bromide or alkyl iodide or an alcohol activated with a sulfonyl group such as methanesulfonyl or p-toluenesulfonyl. Sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, cesium carbonate, sodium methoxide,
Of inorganic bases such as sodium ethoxide or organic bases such as pyridine, picoline, N, N-dimethylaniline, N-methylmorpholine, dimethylamine, triethylamine, 1,8-diazabicyclo [5.4.0] undecene (DBU) In the presence or absence of aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran and dioxane, or aprotic polar solvents such as acetonitrile and N, N-dimethylformamide at 0 ° C to 1 ° C.
00 ° C., preferably at 0 ° C. to room temperature, for 30 minutes to 10 hours,
Preferably, the reaction can be carried out for 30 minutes to 1 hour.

The elimination of the amino protecting group of the compound (C) is carried out by a generally known deprotection reaction, and is usually carried out by catalytic reduction, for example, in the presence of palladium-carbon, palladium hydroxide-carbon, etc., as a hydrogen source. Using hydrogen or ammonium formate, in an alcohol such as methanol or ethanol or a solvent such as acetic acid, room temperature to 100 ° C, preferably 70 ° C to 120 ° C.
C., for 30 minutes to 10 hours, preferably 1 hour to 5 hours, or a hydrolysis reaction with a mineral acid such as hydrochloric acid or sulfuric acid or an organic acid such as trifluoroacetic acid.

The acylation reaction of the compound (A) and the subsequent reduction reaction are carried out by a generally known method. For example, the acylation reaction is carried out by activating the compound (A) with an activated compound such as a corresponding acid halide. Acids and metal hydrides such as lithium hydride, sodium hydride, calcium hydride, etc .; inorganic salts such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, etc .; sodium methoxide, sodium Bases such as sodium alkoxides such as ethoxide, potassium-tert-butoxide and the like; pyridine;
Dimethylaminopyridine, picoline, N, N-dimethylaniline, N-methylmorpholine, dimethylamine, triethylamine, diisopropylethylamine, 1,8
-Diazabicyclo [5.4.0] undecene (DBU)
In the presence or absence of an organic base such as, methylene chloride, chloroform, carbon tetrachloride, halogenated hydrocarbons such as chlorobenzene, benzene, aromatic hydrocarbons such as toluene, tetrahydrofuran, diethyl ether, ethers such as dioxane Ketones such as acetone, methyl ethyl ketone, aprotic polar solvents such as acetonitrile, N, N-dimethylformamide or solvents such as ethyl acetate at -50C to 200C, preferably 0C to 100C.
For 10 minutes to 72 hours, preferably 1 hour to 12 hours, and the reduction reaction is carried out by a generally known reaction, and usually, the product of the acylation reaction is lithium aluminum hydride. Methylene chloride in the presence of a reducing agent such as sodium borohydride, borane,
In solvents such as halogenated hydrocarbons such as chloroform, carbon tetrachloride and chlorobenzene, aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran, diethyl ether and dioxane, and alcohols such as methanol, ethanol and propanol. -20 ° C to 150
C., preferably 0 ° C. to 100 ° C., for 1 hour to 50 hours, preferably 1 hour to 12 hours.

The compound (j) wherein X is a single bond among the amino compounds (H) can be synthesized by the following method.

[0054]

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[In the formula, Z ¹ represents a halogen atom or a trifluoromethanesulfonyl group, R ⁷ represents a carboxy protecting group, M represents a hydrogen atom, a copper atom, a lithium atom, a metal halide or a group -B (OR ⁹ ) ₂ (where R ⁹ represents a hydrogen atom or a lower alkyl group), and R ⁵ , W, G ′ =
The N and E rings are the same as defined above.

The compound (e) and the compound (f) are subjected to a cross-coupling reaction to give a compound (g), which is then deprotected to a carboxylic acid form (h) and reacted with the cyclic amine (i) to give a compound (g). (J) is manufactured.

The cross-coupling reaction is preferably carried out using a transition metal catalyst. Specifically, when M of the compound (f) in the above reaction formula is copper, lithium, or a metal halide, benzene, In an inert solvent such as toluene, diethyl ether, tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide,
It is preferably carried out in the presence of a nickel complex, a platinum complex, preferably a palladium complex. Also, Z ¹ is -B (OR ⁹ )
_In the case of ₂ , a nickel complex, a platinum complex, a suitable solvent such as benzene, toluene, diethyl ether, tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide, methanol, ethanol, propanol, dimethoxyethane, and water; Preferably in the presence of a palladium complex, triethylamine, non-nucleophilic tertiary amines such as diisopropylethylamine, potassium carbonate, sodium carbonate, sodium carbonate, cesium carbonate,
The reaction is preferably performed under basic conditions by adding an inorganic base such as thallium carbonate, potassium hydroxide, sodium hydroxide, and thallium hydroxide, or an alkoxide of these alkali metals. When an inorganic base that is insoluble in an organic solvent is used, it must be used as an aqueous solution, and is preferably used in the presence of a phase transfer catalyst such as tetra-n-butylammonium bromide or crown ether.

In the above reaction formula, examples of the halogen atom represented by Z ¹ include a chlorine atom, a bromine atom and an iodine atom, and preferably a bromine atom and an iodine atom.

In the above reaction formula, examples of the metal halide represented by M include a —ZnCl group and a —MgCl
Group, -CuCl group, -BCl ₂ group, -ZnBr group, -M
gBr group, -CuBr group, -BBr ₂ group, and-
B The (OR ⁹⁾ _2, for example, -B (OH) ₂ group, -B (OC
H _{3) 2 group, -B [OCH (CH 3)} 2] 2 groups, and the like.

As the palladium catalyst used in the above reaction formula, tetrakis (triphenylphosphine)
Examples include palladium, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) palladium, and a divalent palladium phosphine complex.

In this reaction, the reaction can be carried out by activating the catalyst in the reaction mixture. For example, tris (dibenzylideneacetone) palladium is added to a reaction mixture to which triphenylphosphine has been added, and an activated triphenylphosphine palladium complex formed is used.
Activation of the catalyst is carried out by using a divalent palladium salt such as palladium chloride, palladium bromide, palladium acetate and a triarylphosphine, generally a dialkyl zinc,
The reaction is carried out by reacting triphenylphosphine in the presence of a reducing agent such as alkyl zinc halide, dialkyl magnesium, alkyl magnesium halide, trialkyl aluminum, dialkyl aluminum halide, sodium borohydride, hydrazine, arylboronic acid, preferably diethyl zinc. You can also.

The deprotection reaction of the compound (g) is carried out by a usual hydrolysis or the like, for example, a basic compound such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate; hydrochloric acid, sulfuric acid, hydrobromic acid Water in the presence of an organic acid such as p-toluenesulfonic acid or the like;
The reaction is carried out in an alcohol such as methanol, ethanol, propanol and the like; an ether such as tetrahydrofuran and dioxane; a ketone such as acetone and methyl ethyl ketone; a solvent such as acetic acid or a mixed solvent thereof. This reaction is carried out usually at room temperature to 180 ° C, preferably at room temperature to 140 ° C, and the reaction time is usually 1 hour to 2 hours.
4 hours.

The reaction between compound (h) and compound (i) can be carried out in the same manner as described above.

The compound (o) in which X is an oxygen atom or a sulfur atom among the amino compounds (H) can be synthesized by the following method.

[0065]

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Wherein R ⁸ represents a cyano group or an alkoxycarbonyl group, X ′ represents an oxygen atom or a sulfur atom, and R ⁵ , W, G ′ = N, Z ¹ and the ring E are the same as those described above. Show)

The compound (k) and the compound (l) are subjected to a coupling reaction to give a compound (m), which is then hydrolyzed to a carboxylic acid compound (n), which is reacted with a cyclic amine (i) to give a compound (m). (O) can be obtained.

The coupling reaction is carried out in the presence or absence of a copper catalyst in the presence or absence of benzene, toluene, diethyl ether, tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide, N-methylpyrrolidone, methanol, ethanol, propanol, dimethoxy. In a suitable solvent such as ethane, ethyl acetate, dichloromethane, tetrahydrofuran, ether, dioxane,
Under basic conditions by addition of an inorganic base such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, etc., under basic conditions, 0 ° C to 200 ° C, preferably 100 ° C.
C. to 180.degree. C. for a reaction time of 30 minutes to 10 hours, preferably 5 hours to 10 hours.

Examples of the copper catalyst used in the above reaction include copper powder, cuprous halides such as cuprous bromide and cuprous iodide, and the like.
Cupric oxide or the like is used.

The hydrolysis reaction of the compound (m) is carried out by a generally known reaction. For example, when R ⁸ is an alkoxycarbonyl group, an inorganic base such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, etc. In the presence of water; alcohols such as methanol, ethanol and propanol; ethers such as tetrahydrofuran, diethyl ether and dioxane; ketones such as acetone and methyl ethyl ketone;
C. for 1 hour to 24 hours. In the case where R ⁸ is a cyano group, a solvent such as ethanol, ethylene glycol, or water in the presence of a mineral acid such as hydrochloric acid or sulfuric acid, or a base such as potassium hydroxide, sodium hydroxide, or barium hydroxide may be used. The reaction can be performed at 200 ° C., preferably at room temperature to 60 ° C., for 1 hour to 24 hours.

The reaction between compound (n) and compound (i) can be carried out in the same manner as in the above method.

[Production Example 2]

[0073]

Embedded image

[Wherein Hal represents a halogen atom;
^{1, R 2, R 3,} R 4, R 5, A, B, L, W, X, Y,
Z, E ring, G ′ = N and P are the same as described above]

That is, using the compound (G) as a raw material, the compound (J) is reacted with the compound (J) to obtain a compound (L), or the compound (K) is reacted with the compound (K) to obtain a compound (M). Compound (N) of the present invention is produced by reacting compound (O) with compound (N) by protecting or reducing compound (M).

The reduction reaction of the compound (M) is carried out by a generally known reaction, and is usually carried out by catalytic reduction, for example, using hydrogen or ammonium formate as a hydrogen source in the presence of palladium-carbon, palladium hydroxide-carbon or the like. ,methanol,
Room temperature to 100 ° C., preferably 7
Reaction at 0 ° C. to 120 ° C. for 30 minutes to 10 hours, preferably 1 hour to 5 hours, or reaction of a metal such as iron or tin in an alcohol solvent such as methanol or ethanol in the presence of an acid such as hydrochloric acid. Can be performed.

The reaction of compound (G) with compound (J) or compound (K), the deprotection reaction of compound (L), and the reaction of compound (N) with compound (O) were all used in Production Example 1. It can be performed in the same manner as the method.

The compound of the present invention thus obtained can be isolated and purified according to a conventional method. Depending on the conditions of isolation and purification, the compound can be obtained in the form of a salt, a free carboxylic acid or a free amine, which can be mutually converted if desired to produce a desired compound of the present invention.

The obtained compound (1) of the present invention or a salt thereof has an excellent MTP inhibitory activity and an inhibitory activity on secretion of apoB lipoprotein, and is useful as an agent for preventing or treating hyperlipidemia and arteriosclerosis. Useful as a medicine.

When the compound (1) of the present invention or a salt thereof is used as a medicament, the composition is combined with a pharmaceutically acceptable carrier for parenteral administration such as injection, rectal administration, or oral administration in solid or liquid form. Can be prescribed as

Forms of the compositions according to the present invention for injection include pharmaceutically acceptable sterile water, non-aqueous solutions, suspensions or emulsions. Examples of suitable non-aqueous carriers, diluents, solvents or vehicles include propylene glycol,
Vegetable oils such as polyethylene glycol and olive oil; and injectable organic esters such as ethyl oleate. Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. These compositions, for example, by filtration through a bacteria retaining filter,
Alternatively, sterilization can be achieved by incorporating a sterilizing agent in the form of a sterile solid composition, which can be dissolved in sterile water or some other sterile injectable medium immediately before use. Solid preparations for oral administration include capsules, tablets, pills, powders, granules and the like. In preparing this solid preparation, the compound of the present invention is generally mixed with at least one inert diluent, for example, sucrose, lactose, starch and the like. The formulation may also include additional substances other than inert diluents in normal formulation such as lubricants such as magnesium stearate. In the case of capsules, tablets and pills, a buffer may also be included.
Tablets and pills can additionally be provided with an enteric coating.

Liquid preparations for oral administration include inert diluents commonly used by those skilled in the art, such as pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing water. Is mentioned. In addition to such inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying, suspending, sweetening, flavoring, and flavoring agents. In the case of a preparation for rectal administration, it is preferable to contain excipients such as cocoa butter and a suppository wax in addition to the compound of the present invention.

The dose of the compound (1) of the present invention or a salt thereof depends on the nature of the compound to be administered, the administration route, the desired treatment period and other factors, but it is generally about 0.1 to 100 mg per day. / Kg, especially about 0.5-50 mg /
kg is preferred. If desired, the daily dose can be divided and administered in 2 to 4 times.

[0084]

Next, the present invention will be described in detail with reference to examples.

Reference Example 1 5-Amino-4,6-diethoxypyrimidine (1) 4,6-Diethoxy-5-nitropyrimidine (8 g) was dissolved in ethanol (100 ml), and 10% palladium on carbon (120 mg) was added. In addition, the mixture was stirred overnight at room temperature under a hydrogen stream. After removing the catalyst by filtration, the filtrate was distilled off. The obtained residue was dissolved in chloroform and washed with a 10% aqueous sodium carbonate solution. The organic layer was dried over anhydrous magnesium sulfate and evaporated to give 7.2 g of the title compound. Property: colorless prism crystal Melting point: 62-63 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.41 (6H, t, J = 7 Hz), 2.02 (2H, brs), 4.43
(4H, q, J = 7Hz), 7.94 (1H, s)

Reference Example 2 Benzyl (4,6-diethoxypyrimidin-5-yl) carbamate (2) The compound (1) (1.8 g) obtained in Reference Example 1 was treated with 8% sodium hydroxide (10 ml) and , 1,4-dioxane (20 ml) and benzyl chloroformate (4.0).
g) was added dropwise, and the mixture was stirred at 50 ° C. for 3 hours. Then, chloroform was added to the reaction solution, followed by washing with water. After the organic layer was dried over anhydrous magnesium sulfate, the residue obtained by evaporation was dispersed in diisopropyl ether, collected by filtration and dried to give the title compound.
5 g were obtained. Properties: colorless needles Melting point: 110-111 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.36 (6H, t, J = 7 Hz), 4.44 (4H, q, J = 7 Hz),
5.19 (2H, s), 5.86 (1H, brs), 7.31-7.38 (5H, m), 8.29 (1H, s)

Reference Example 3 5-butylamino-4,6-diethoxypyrimidine (3) Compound (2) (254 mg) obtained in Reference Example 2
To an N-dimethylformamide solution (1 ml) was added 60% oily sodium hydride (42 mg) at room temperature, followed by 1 ml.
-Bromobutane (104 µl) was added, and the mixture was stirred at room temperature for 1 hour. Water (10 ml) was added to the reaction mixture, and the mixture was extracted with ether (10 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Residue in ethanol (4
ml), ammonium formate (202 mg) and an aqueous suspension of palladium black (3 ml) were added, and the mixture was heated under reflux for 26 hours. After removing the catalyst by filtration, the filtrate was distilled off. The resulting residue was extracted with ethyl acetate, dried over magnesium sulfate,
It was concentrated under reduced pressure. 190 mg of the title compound were obtained. Properties: colorless oil ¹ H-NMR (CDCl ₃ ) δ: 0.91 (3H, t, J = 7 Hz), 1.33-1.47 (4H, m),
1.39 (6H, t, J = 7Hz), 3.25 (2H, t, J = 7Hz), 4.42 (4H, q, J = 7H
z), 7.96 (1H, s)

Example 1 N-butyl-N- (4,6-diethoxypyrimidine-5
-Yl) -5- [4- (4'-trifluoromethylbiphenyl-2-carboxamide) piperidino] pentanamide (4) The compound (3) (180 mg) obtained in Reference Example 3 and
Triethylamine (250 μl) was added to methylene chloride (2 m
To the mixture added to 1), 5-bromovaleryl chloride (120 μl) was added at room temperature, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of potassium dihydrogen phosphate. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. Hexane was added to the obtained solid residue, and the solid was collected by filtration to obtain 327 mg of N-butyl-N- (4,6-diethoxypyrimidin-5-yl) -5-bromopentanamide. The resulting N-butyl-N-
To a solution of (4,6-diethoxypyrimidin-5-yl) -5-bromopentanamide (202 mg) in acetonitrile (5 ml) was added N- (piperidin-4-yl)-.
4′-Trifluoromethylbiphenyl-2-carboxamide (175 mg), potassium carbonate (83 mg), and potassium iodide (83 mg) were added, and the mixture was heated under reflux for 22 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with methylene chloride. The extract was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 40/1) to obtain 130 mg of the title compound. Properties: colorless amorphous ¹ H-NMR (CDCl ₃ ) δ: 0.84 (3H, t, J = 7 Hz), 1.24-1.38 (9H, m),
1.32 (6H, t, J = 7Hz), 1.49 (2H, t, J = 7Hz), 1.62-1.64 (2H, m),
1.91 (2H, t, J = 7Hz), 3.51 (2H, s), 1.99-2.14 (2H, m), 2.20 (2H
H, t, J = 7Hz), 2.57 (1H, brs), 3.49 (2H, t, J = 7Hz), 3.89 (1H, b
rs), 4.39-4.44 (4H, m), 5.19 (1H, brs), 7.32-7.34 (1H, m),
7.42-7.52 (4H, m) 7.60-7.65 (3H, m), 8.31 (1H, s)

Reference Example 4 5-ethylamino-4,6-diethoxypyrimidine (5) Compound (2) (254 mg) obtained in Reference Example 2
To an N-dimethylformamide solution (1 ml) was added 60% oily sodium hydride (42 mg) at room temperature, followed by 1 ml.
-Bromoethane (72 µl) was added, and the mixture was stirred at room temperature for 1 hour. Water (10 ml) was added to the reaction mixture, and the mixture was extracted with ether (10 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Residue in ethanol (4
ml), ammonium formate (202 mg) and an aqueous suspension of palladium black (3 ml) were added, and the mixture was heated under reflux for 14 hours. After removing the catalyst by filtration, the filtrate was distilled off. The resulting residue was extracted with ethyl acetate, dried over magnesium sulfate,
It was concentrated under reduced pressure. 157 mg of the title compound was obtained. Properties: colorless oil ¹ H-NMR (CDCl ₃ ) δ: 1.13 (3H, t, J = 7 Hz), 1.40 (6H, t, J = 7 Hz),
3.29 (2H, q, J = 7Hz), 4.41 (4H, q, J = 7Hz), 7.97 (1H, s)

Example 2 N-ethyl-N- (4,6-diethoxypyrimidine-5
-Yl) -5- [4- (4'-trifluoromethylbiphenyl-2-carboxamido) piperidino] pentanamide (6) Compound (5) (74 mg) obtained in Reference Example 4 and triethylamine (117 µl) were obtained. Methylene chloride (1m
To the mixture added to 1), 5-bromovaleryl chloride (57 μl) was added at room temperature, and the reaction mixture was added at room temperature for 6 hours.
Stirred for 0 minutes. The reaction mixture was washed with a saturated aqueous solution of potassium dihydrogen phosphate. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. Acetonitrile (3 ml), N- (piperidin-4-yl) -4′- were added to the obtained residue.
Trifluoromethylbiphenyl-2-carboxamide (115 mg), potassium carbonate (58 mg), and potassium iodide (58 mg) were added, and the mixture was heated under reflux for 24 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with methylene chloride. The extract was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: chloroform / methanol = 40/1) to obtain 88 mg of the title compound. Properties: colorless amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.01 (3H, t, J = 7 Hz), 1.21 (2H, brs), 1.33
(6H, t, J = 7Hz), 1.38 (2H, brs), 1.48-1.52 (2H, m), 1.64-1.6
6 (2H, m), 1.93 (2H, t, J = 7Hz), 2.06 (2H, brs), 2.24 (2H, br
s), 2.61 (2H, brs), 3.57 (2H, q, J = 7Hz), 3.81 (1H, brs), 4.40
-4.47 (4H, m), 5.21 (1H, brs), 7.35 (1H, d, J = 8Hz), 7.44-7.5
3 (4H, m), 7.62-7.66 (3H, m), 8.33 (1H, s)

Example 3 N-ethyl-N- (4,6-diethoxypyrimidine-5
-Yl) -4- [4- (4'-trifluoromethylbiphenyl-2-carboxamido) piperidino] butanamide (7) Compound (5) (53 mg) and triethylamine (70 μl) obtained in Reference Example 4 were converted to chlorides. Methylene (4 ml)
Was added to 4-bromobutyryl chloride (35).
μl) was added at room temperature and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water (4ml). The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. Acetonitrile (4 ml), N- (piperidin-4-yl) -4′-trifluoromethylbiphenyl-2-carboxamide (87 mg), potassium carbonate (4
1 mg) and potassium iodide (42 mg).
The mixture was heated under reflux for 3 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The extract was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: chloroform / methanol = 40/1) to obtain 64 mg of the title compound. Properties: colorless amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.01 (3H, t, J = 7 Hz), 1.33 (6H, t, J = 7 Hz),
1.60-1.69 (4H, m), 1.90-1.99 (6H, m), 2.17 (2H, t, J = 7Hz),
2.55 (2H, brs), 3.57 (2H, q, J = 7Hz), 3.76 (1H, brs), 4.37-4.
46 (4H, m), 5.12 (1H, brs), 7.35 (1H, d, J = 8Hz), 7.43-7.53 (4
H, m), 7.62-7.66 (3H, m), 8.32 (1H, s)

Example 4 N-ethyl-N- (4,6-diethoxypyrimidine-5
-Yl) -3- [4- (4'-trifluoromethylbiphenyl-2-carboxamido) piperidino] propanamide (8) Compound (5) (53 mg) and triethylamine (70 µl) obtained in Reference Example 4 were obtained. Methylene chloride (4ml)
To the mixture added to was added 3-bromopropionyl chloride (30 μl) at room temperature and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water (4ml). The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. Acetonitrile (4 ml), N- (piperidin-4-yl) -4′-trifluoromethylbiphenyl-2-carboxamide (87 mg), potassium carbonate (41 mg), and potassium iodide (42 mg) were added to the obtained residue. In addition, the mixture was heated under reflux for 23 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The extract was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 40/1) to obtain 10 mg of the title compound. Properties: colorless amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, t, J = 7 Hz), 1.34 (6H, t, J = 7 Hz),
1.60-2.62 (12H, m), 3.57 (2H, q, J = 7Hz), 3.78 (1H, brs), 4.4
1-4.48 (4H, m), 5.13 (1H, brs), 7.35 (1H, d, J = 7Hz), 7.45-7.
55 (4H, m), 7.63-7.66 (3H, m), 8.34 (1H, s)

Example 5 N-isopropyl-N- (4,6-diethoxypyrimidin-5-yl) -4- [4- (4'-trifluoromethylbiphenyl-2-carboxamide) piperidino] butanamide (9) N, of compound (2) (254 mg) obtained in Reference Example 2
To a N-dimethylformamide solution (1 ml) was added 60% oily sodium hydride (42 mg) at room temperature, followed by 2 ml.
-Bromopropane (91 µl) was added, and the mixture was stirred at room temperature for 1.5 hours, and then heated at 70 ° C for 1 hour. Water (10 ml) was added to the reaction mixture, and the mixture was extracted with ether (10 ml). The extract was dried over anhydrous magnesium sulfate, and under reduced pressure,
Concentrated. The residue was dissolved in ethanol (4 ml), ammonium formate (202 mg) and an aqueous suspension of palladium black (3 ml) were added, and the mixture was heated under reflux for 14 hours. After removing the catalyst by filtration, the filtrate was distilled off. The obtained residue was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 165 mg of colorless oily 5-isopropylamino-4,6-diethoxypyrimidine. 81 mg of which was mixed with methylene chloride (1 m) together with triethylamine (122 μl).
l). To the mixture was added 4-bromobutyryl chloride (51 μl) at room temperature and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with a saturated aqueous solution of potassium dihydrogen phosphate. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. Acetonitrile (4 ml), N- (piperidin-4-yl) -4′- were added to the obtained residue.
Trifluoromethylbiphenyl-2-carboxamide (119 mg), potassium carbonate (60 mg), and potassium iodide (60 mg) were added, and the mixture was heated under reflux for 27 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The extract was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 40/1) to obtain 65 mg of the title compound. Properties: colorless amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.06, 1.07 (each 3H, each s), 1.14-1.0
9 (2H, m), 1.34 (6H, t, J = 7Hz), 1.62-1.70 (4H, m), 1.84 (2H, m
t, J = 7Hz), 2.00 (2H, t, J = 11Hz), 2.18 (2H, t, J = 7Hz), 2.54 (2H
H, brs), 3.78 (1H, brs), 4.46-4.37 (4H, m), 4.68-4.70 (1H,
m), 5.17 (1H, brs), 7.36 (1H, d, J = 7Hz), 7.44-7.54 (4H, m),
7.63-7.67 (3H, m), 8.34 (1H, s)

Example 6 N- [1- (2- (3-ethyl-3- (4,6-diethoxypyrimidin-5-yl) ureido) ethyl) piperidin-4-yl] -4'-trifluoro Methylbiphenyl-2-carboxamide (10) The compound (5) (53 mg) obtained in Reference Example 4 was dissolved in acetonitrile (4 ml), 2-chloroethyl isocyanate (43 µl) was added, and the mixture was stirred overnight at room temperature. 2-Chloroethyl isocyanate (86 μl) was added to the reaction solution, heated at 70 ° C. for 1 hour, and heated under reflux for 3 hours. The solvent was distilled off, and the obtained residue was added with acetonitrile (5 m
1), N- (piperidin-4-yl) -4′-trifluoromethylbiphenyl-2-carboxamide (87 m
g), potassium carbonate (41 mg) and potassium iodide (42 mg) were added, and the mixture was heated under reflux for 19 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The extract was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: chloroform / methanol = 20/1).
And 15 mg of the title compound was obtained. Properties: colorless amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, t, J = 7 Hz), 1.33 (6H, t, J = 7 Hz),
1.53-1.55 (2H, m), 2.00-2.04 (4H, m), 2.29 (2H, t, J = 5Hz),
2.38 (2H, brs), 3.19 (2H, d, J = 5Hz), 3.55 (2H, q, J = 7Hz), 3.8
1-3.84 (1H, m), 4.35-4.45 (4H, m), 4.67 (1H, brs), 5.12 (1H, m
brs), 7.37 (1H, d, J = 8Hz), 7.45-7.56 (4H, m), 7.63-7.69 (3
H, m), 8.28 (1H, s)

Reference Example 5 5-propylamino-4,6-diethoxypyrimidine (11) The compound (1) (3.66 g) obtained in Reference Example 1 and
Triethylamine (3.34 ml) was added to methylene chloride (2
0 ml), propionyl chloride (1.91 ml) was added dropwise under ice-cooling, and the reaction mixture was stirred at room temperature for 45 minutes. The reaction mixture was washed with water, the organic phase was dried over magnesium sulfate and concentrated under reduced pressure. Ether was added to the obtained solid residue, and the solid was collected by filtration to obtain 4.82 g of N- (4,6-diethoxypyrimidin-5-yl) propanamide as a colorless powder. 2.3 of them
9 g was dissolved in tetrahydrofuran (40 ml), sodium borohydride (0.61 g) was added, and then trifluoroborane-ether complex (2.7 ml) was added dropwise at room temperature over 15 minutes. Stirred at room temperature for 2 days. Sodium borohydride (0.31 g) was added to the reaction mixture, and a trifluoroborane-ether complex (1.4 ml) was added.
Was added dropwise and stirred at room temperature for 1 day. Water (10
0 ml) was added slowly and stirred for 1 hour. The reaction mixture was extracted three times with ethyl acetate (150 ml) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/4) to give 0.92 g of the title compound. Properties: pale yellow oil ¹ H-NMR (CDCl ₃ ) δ: 0.94 (3H, t, J = 7 Hz), 1.42 (6H, t, J = 7 Hz),
1.47-1.54 (2H, m), 3.24 (2H, t, J = 7Hz), 4.44 (4H, q, J = 7Hz),
7.98 (1H, s)

Example 7 N-propyl-N- (4,6-diethoxypyrimidine-
5-yl) -5- [4- (4′-trifluoromethylbiphenyl-2-carboxamido) piperidino] pentanamide (12) Compound (11) (56 mg) obtained in Reference Example 5, and
Triethylamine (70 μl) was added to methylene chloride (5 m
To the mixture added to 1), 5-bromovaleryl chloride (40 μl) was added at room temperature, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with water. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. Acetonitrile (5 ml), N- (piperidin-4-yl) -4′-trifluoromethylbiphenyl- were added to the obtained residue.
2-carboxamide (87 mg), potassium carbonate (41
mg) and potassium iodide (42 mg).
Heated to reflux for an hour. The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The extract was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 30/1) to give the title compound (6).
5 mg were obtained. Properties: colorless amorphous ¹ H-NMR (CDCl ₃ ) δ: 0.87 (3H, t, J = 7 Hz), 1.10-1.12 (2H, m),
1.34 (6H, t, J = 7Hz), 1.40-1.53 (6H, m), 1.63-1.65 (2H, m),
1.92-2.01 (4H, m), 2.18 (2H, t, J = 7Hz), 2.54 (2H, brs), 3.48
(2H, t, J = 7Hz), 3.79 (1H, brs), 4.41-4.46 (4H, m), 5.14 (1H,
d, J = 8Hz), 7.36 (1H, d, J = 8Hz), 7.44-7.55 (4H, m), 7.64-7.6
7 (3H, m), 8.33 (1H, s)

Example 8 N-propyl-N- (4,6-diethoxypyrimidine-
5-yl) -5- [4- (4'-trifluoromethylbiphenyl-2-carboxamido) piperidino] pentanamide 1/2 fumarate (13) Compound (12) (96 mg) obtained in Example 7 And fumaric acid (8 mg) were dissolved in methanol (5 ml), and the solvent was distilled off under reduced pressure. Add ether to solidify,
The precipitated solid was collected by filtration to give the title compound (64 mg). Properties: pale yellow powder Melting point: 110-112 ° C ¹ H-NMR (CDCl ₃ ) δ: 0.85 (3H, t, J = 7 Hz), 1.32 (6H, t, J = 7 Hz),
1.36-1.43 (2H, m), 1.53 (4H, s), 1.71 (5H, s), 1.95 (2H, t, J =
6Hz), 2.42 (2H, brs), 2.67 (2H, brs), 3.16 (1H, brs), 3.45 (2
H, t, J = 7Hz), 3.91 (1H, brs), 4.39-4.46 (4H, m), 6.06 (1H, br
s), 6.56 (1H, s), 7.32 (1H, d, J = 7Hz), 7.40-7.51 (4H, m), 7.5
6-7.63 (3H, m), 8.31 (1H, s)

Example 9 N-propyl-N- (4,6-diethoxypyrimidine-
5-yl) -6- [4- (4′-trifluoromethylbiphenyl-2-carboxamido) piperidino] nicotinamide (14) Compound (11) (113 mg) obtained in Reference Example 5 and triethylamine (84 μl) To methylene chloride (5
6) was added to the mixture added at room temperature, and the reaction mixture was stirred at room temperature for 2 hours and 20 minutes. The reaction mixture was washed with water.
The mixture was concentrated under reduced pressure to obtain 153 mg of N-propyl-N- (4,6-diethoxypyrimidin-5-yl) -6-chloronicotinamide. 73 mg thereof was added to a mixture of N- (piperidin-4-yl) -4′-trifluoromethylbiphenyl-2-carboxamide (70 mg), N, N-diisopropylethylamine (70 μl), and dimethylsulfoxide (1 ml), 18 at 140 ° C
Heated for hours. Water was added and washed with ethyl acetate. The aqueous phase is neutralized with sodium hydrogen carbonate and extracted with chloroform.
The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate / hexane = 1 /
Purification in 1) gave 31 mg of the title compound. Properties: light brown oil _{^{1 H-NMR (CDCl 3)}} δ: 0.90 (3H, t, J = 7Hz), 0.99-1.05 (2H, m),
1.32 (6H, t, J = 7Hz), 1.53 (2H, q, J = 8Hz), 1.67-1.70 (4H, m),
2.91 (2H, t, J = 11Hz), 3.58 (2H, t, J = 8Hz), 3.93-3.95 (2H, t
m), 4.29-4.41 (4H, m), 5.15 (1H, d, J = 8Hz), 6.34 (1H, d, J = 9H
z), 7.35 (1H, d, J = 7Hz), 7.41-7.53 (4H, m), 7.63-7.66 (3H,
m), 8.04 (1H, d, J = 2Hz), 8.19 (1H, s)

Reference Example 6 5-Cyclopropylmethylamino-4,6-diethoxypyrimidine (15) Compound (2) (635 mg) obtained in Reference Example 2 was treated with N,
60% oily sodium hydride (104 mg) was added to the N-dimethylformamide solution (2 ml) at room temperature, followed by bromomethylcyclopropane (0.23 ml).
Stirred at room temperature for 4 hours. Water (20 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol (7 ml), ammonium formate (505 mg) and an aqueous suspension of palladium black (7 ml) were added, and the mixture was heated under reflux for 16 hours. After removing the catalyst by filtration, the filtrate was distilled off. The obtained residue was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate /
Hexane = 1/10) to give 217m of the title compound.
g was obtained. Properties: colorless oil ¹ H-NMR (CDCl ₃ ) δ: 0.16-0.18 (1H, m), 0.45-0.48 (1H, m), 0.
90-0.97 (2H, m), 1.41 (6H, t, J = 7Hz), 1.61-1.69 (1H, m), 3.0
8 (2H, t, J = 5Hz), 4.41-4.45 (4H, m), 7.98 (1H, s)

Example 10 N-cyclopropylmethyl-N- (4,6-diethoxypyrimidin-5-yl) -5- [4- (4'-trifluoromethylbiphenyl-2-carboxamide) piperidino] pentanamide (16) 1/2 fumarate To a mixture of compound (15) (210 mg) obtained in Reference Example 6 and triethylamine (0.24 ml) in methylene chloride (5 ml), 5-bromovaleryl chloride ( 0.14 ml) was added at room temperature and the reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was washed with water. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure.
Acetonitrile (10 ml), N-
(Piperidin-4-yl) -4′-trifluoromethylbiphenyl-2-carboxamide (307 mg), potassium carbonate (146 mg), and potassium iodide (147
mg), and the mixture was heated under reflux for 19 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The extract was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 10/1). Fumaric acid (21 mg) was added, and methanol (2 m
1) After dissolving in a mixed solvent of -ethyl acetate (2 ml),
The solvent was distilled off under reduced pressure. Ether was added to solidify, and the precipitated solid was collected by filtration to obtain 90 mg of the title compound. Properties: colorless amorphous ¹ H-NMR (CDCl ₃ ) δ: 0.30-0.32 (2H, m), 1.19-1.22 (2H, m), 1.
34 (6H, t, J = 7Hz), 1.55-1.71 (7H, m), 2.37-2.59 (9H, m), 3.0
6 (1H, brs), 3.42 (2H, t, J = 7Hz), 3.92 (1H, brs), 4.44 (4H, q,
J = 7Hz), 5.82 (1H, brs), 6.59 (1H, s), 7.34-7.66 (8H, m), 8.3
4 (1H, s)

Example 11 N-propyl-N- (4,6-diethoxypyrimidine-
5-yl) -3-nitro-4- [4- (4'-trifluoromethylbiphenyl-2-carboxamido) piperidino] benzamide (17) 4-fluoro-3-nitrobenzoic acid (111 mg) and N, N- Dimethylformamide (1 μl) was added to methylene chloride (5 ml), and oxalyl chloride (61 μl) was added.
Was added at room temperature. After stirring the reaction mixture for 2 hours, the solvent was distilled off and the residue was dissolved in methylene chloride (5 ml). 4 obtained
A solution of -fluoro-3-nitrobenzoyl chloride in methylene chloride was prepared using the compound (11) (11) obtained in Reference Example 5.
3 mg) and triethylamine (104 μl) in methylene chloride (5 ml) at room temperature, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with water, 10
Washed with a 20% aqueous sodium bicarbonate solution. The solvent was concentrated under reduced pressure, hexane was added to the obtained residue, and the solid was collected by filtration.
N-propyl-N- (4,6-diethoxypyrimidine-
133 mg of 5-yl) -4-fluoro-3-nitrobenzamide were obtained. 120 mg thereof was added to a mixture of N- (piperidin-4-yl) -4′-trifluoromethylbiphenyl-2-carboxamide (107 mg), N, N-diisopropylethylamine (67 μl), and dimethylsulfoxide (1 ml), Heated at 140 ° C. for 2 hours. The reaction mixture was poured into water (10 ml), and the precipitated solid was collected by filtration. The resulting solid was washed with ethyl acetate (20
ml), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ether was added to the residue, and the solid was collected by filtration to obtain 153 mg of the title compound. Properties: yellow powder Melting point: 155-156 ° C (decomposition) ¹ H-NMR (CDCl ₃ ) δ: 0.92 (3H, t, J = 7 Hz), 1.26 (2H, d, J = 8 Hz),
1.35 (6H, t, J = 7Hz), 1.57 (2H, s), 1.71 (2H, s), 2.78 (2H, t, J
= 11Hz), 2.97 (2H, s), 3.59 (2H, t, J = 7Hz), 3.90 (1H, brs), 4.
36-4.40 (4H, m), 5.17 (1H, d, J = 9Hz), 6.78 (1H, d, J = 9Hz), 7.
35-7.68 (9H, m), 7.82 (1H, s), 8.19 (1H, s)

Example 12 N-propyl-N- (4,6-diethoxypyrimidine-
5-yl) -3-amino-4- [4- (4′-trifluoromethylbiphenyl-2-carboxamide) piperidino] benzamide (18) Compound (17) obtained in Example 11 (140 mg)
Then, 10% palladium carbon (30 mg) and ethanol (15 ml) were added thereto, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The insoluble material was filtered off, the solvent was distilled off, isopropyl ether was added to the residue, and the solid was collected by filtration to give the title compound as 131
mg. Properties: orange powder Melting point: 194-198 ° C. (decomposition) ¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, t, J = 7 Hz), 1.15 (2H, d, J = 6 Hz),
1.35 (6H, t, J = 7Hz), 1.64-1.77 (4H, m), 2.55 (2H, brs), 2.72
-2.78 (2H, m), 3.64 (2H, brs), 3.90 (1H, brs), 4.34-4.39 (4
H, m), 5.18 (1H, brs), 6.68 (1H, d, J = 9Hz), 7.40-7.70 (10H,
m), 8.18 (1H, s)

Example 13 N-propyl-N- (4,6-diethoxypyrimidine-
5-yl) -3-bromo-4- [4- (4'-trifluoromethylbiphenyl-2-carboxamide) piperidino] benzamide (19) amyl nitrite (10 μl), copper (II) bromide (13 m
g) and acetonitrile (1 ml) were added with a suspension of compound (18) (35 mg) obtained in Example 12 in acetonitrile (4 ml), and the mixture was heated under reflux under a nitrogen atmosphere for 2 hours. The solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane = 1/1). 11 mg of the title compound were obtained. Properties: pale yellow oil ¹ H-NMR (CDCl ₃ ) δ: 0.92 (3H, t, J = 7 Hz), 1.26 (2H, brs), 1.36
(6H, t, J = 7Hz), 1.52-1.64 (2H, m), 1.76 (2H, d, J = 10Hz), 2.6
1 (2H, t, J = 11Hz), 3.00 (2H, m), 3.60 (2H, t, J = 8Hz), 3.92 (1
H, brs), 4.37 (4H, q, J = 7Hz), 5.16 (1H, d, J = 8Hz), 6.67 (1H,
d, J = 8Hz), 7.13 (1H, d, J = 6Hz), 7.37 (1H, d, J = 7Hz), 7.45-7.
69 (8H, m), 8.18 (1H, s)

Example 14 N-propyl-N- (4,6-diethoxypyrimidine-
5-yl) -4- [4- (4'-trifluoromethylbiphenyl-2-carboxamido) piperidino] benzamide (20) 2 of the compound (18) (80 mg) obtained in Example 12
Sodium nitrite (9 mg) was added to a 0% hydrochloric acid (1 ml) suspension under ice-cooling, followed by stirring for 5 minutes. A suspension of copper (I) oxide (67 mg) in ethanol (2 ml) was added to the reaction mixture, and the mixture was stirred under ice cooling for 10 minutes and at room temperature for 1 hour. Water (20 ml) was added, and the mixture was extracted with ethyl acetate. The insoluble material was separated by filtration, and the solvent was distilled off. The residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate / hexane = 1)
/ 1). 4 mg of the title compound were obtained. Properties: colorless amorphous ¹ H-NMR (CDCl ₃ ) δ: 0.92 (3H, t, J = 8 Hz), 1.35 (8H, t, J = 7 Hz),
1.52-1.76 (4H, m), 2.62 (2H, t, J = 11Hz), 3.02-3.04 (2H, m),
3.60 (2H, t, J = 8Hz), 3.90-3.92 (1H, m), 4.37 (4H, q, J = 7Hz),
5.22 (1H, d, J = 8Hz), 6.67 (1H, d, J = 8Hz), 7.08 (1H, dd, J = 6H
(z, 2Hz), 7.35-7.69 (10H, m), 8.18 (1H, s)

Example 15 N-propyl-N- (4,6-diethoxypyrimidine-
5-yl) -3- [4- (4'-trifluoromethylbiphenyl-2-carboxamido) piperidino] methylbenzamide (21) m-toluic acid (82 mg) and N, N-dimethylformamide (1 μl) were treated with methylene chloride. (2 ml)
Oxalyl chloride (61 μl) was added at room temperature. After stirring the reaction mixture for 3 hours, the solvent was distilled off and the residue was dissolved in methylene chloride (5 ml). The methylene chloride solution of the obtained m-toluoyl chloride was mixed with the compound (11) (113 mg) obtained in Reference Example 5 and triethylamine (10
(4 μl) in a mixture of methylene chloride (4 ml) at room temperature and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with water, 10% aqueous sodium hydrogen carbonate.
The solvent was concentrated under reduced pressure, and N-propyl-N-
171 mg of (4,6-diethoxypyrimidin-5-yl) -3-methylbenzamide was obtained. 160m of which
g, N-bromosuccinimide (83 mg) and 2,
2′-Azobis (isobutyronitrile) (1 mg) was added to carbon tetrachloride (5 ml), and the mixture was heated under reflux for 5 hours. The reaction mixture was washed with a 10% aqueous sodium hydrogen carbonate solution. The solvent was distilled off, and N- (piperidin-4-yl)-was added to the residue.
4'-trifluoromethylbiphenyl-2-carboxamide (164 mg), anhydrous potassium carbonate (78 mg),
And acetonitrile (10 ml) were added, and the mixture was heated under reflux for 1.5 hours. The solvent was distilled off, water (10 ml) was added, and the residue was extracted with ethyl acetate (10 ml). Evaporate the solvent,
The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane = 2/1). 61 mg of the title compound were obtained. Properties: colorless amorphous ¹ H-NMR (CDCl ₃ ) δ: 0.93 (3H, t, J = 7 Hz), 1.05 (2H, d, J = 10H)
z), 1.34 (6H, t, J = 7Hz), 1.53-1.62 (4H, m), 1.88 (2H, t, J = 10
Hz), 2.35 (2H, s), 3.22 (2H, s), 3.63 (2H, t, J = 8 Hz), 3.75 (1
H, brs), 4.11-4.37 (4H, m), 5.12 (1H, d, J = 8Hz), 7.08-7.68
(12H, m), 8.09 (1H, s)

Example 16 N-propyl-N- (4,6-diethoxypyrimidine-
5-yl) -3- [4- (4′-trifluoromethylbiphenyl-2-carboxamido) piperidino] methylbenzamide (22) p-Toluic acid (569 mg) and N, N-dimethylformamide (10 μl) were treated with methylene chloride. (15 ml) and oxalyl chloride (0.43 ml) at room temperature. After stirring the reaction mixture for one and a half hours, the solvent was distilled off and the residue was dissolved in methylene chloride (5 ml). The obtained m-chloride solution of p-toluoyl chloride was added to a mixture of compound (11) (784 mg) obtained in Reference Example 5 and methylene chloride (15 ml) of triethylamine (0.70 ml) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with water, 10% aqueous sodium hydrogen carbonate. The solvent was concentrated under reduced pressure, and the resulting orange oily N
-Propyl-N- (4,6-diethoxypyrimidine-5
-Yl) -4-methylbenzamide to 1.28 g of N-
Bromosuccinimide (712 mg), 2,2'-azobis (isobutyronitrile) (10 mg) and carbon tetrachloride (20 ml) were added, and the mixture was heated under reflux for 8 hours. The reaction mixture was washed with a 10% aqueous sodium hydrogen carbonate solution. The solvent was distilled off, and N- (piperidin-4-yl) -4′- was added to the residue.
Trifluoromethylbiphenyl-2-carboxamide (1.39 g), anhydrous potassium carbonate (0.66 g), and acetonitrile (20 ml) were added, and the mixture was heated under reflux for 2 hours. The solvent was distilled off, water (20 ml) was added, and the residue was extracted with ethyl acetate (20 ml). The solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10/1). 597 mg of the title compound were obtained. Properties: pale yellow amorphous ¹ H-NMR (CDCl ₃ ) δ: 0.92 (3H, t, J = 8 Hz), 1.05 (2H, d, J = 10H)
z), 1.32 (6H, t, J = 7Hz), 1.53-1.62 (4H, m), 1.96 (2H, t, J = 10
Hz), 2.40 (2H, brs), 3.28 (2H, s), 3.63 (2H, t, J = 8Hz), 3.76
(1H, brs), 4.25-4.38 (4H, m), 5.08 (1H, d, J = 8Hz), 7.02 (2H,
d, J = 8Hz), 7.21 (2H, d, J = 8Hz), 7.34-7.66 (8H, m), 8.13 (1H,
s)

Test Example 1 Test for ApoB Lipoprotein Secretion Inhibition of Cultured Cells HepG2 cells derived from human liver cancer, which had been precultured for 48 hours in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum, were cultured in a medium containing the test compound. After the treatment for 16 hours, the apoB lipoprotein secreted into the culture supernatant was quantified. For quantification, a sandwich ELISA method was used in which apoB lipoprotein in the culture supernatant bound to an ELISA plate on which an anti-human apoB protein mouse monoclonal antibody was immobilized was detected using a peroxidase-labeled anti-human apoB protein mouse monoclonal antibody. The secretion inhibition rate was calculated using the solvent control as a control. Table 1 shows the results.

[0108]

[Table 1]

[0109]

The compound (1) of the present invention or a salt thereof has an excellent MTP inhibitory action and an inhibitory action on apoB lipoprotein secretion, strongly lowers the amount of triglyceride in serum and simultaneously lowers cholesterol, As a medicament for the prevention and treatment of blood and / or arteriosclerosis, a wide range of clinical indications including patients with type IIb hyperlipidemia can be expected.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Kenichi Inokuma 1624 Yukinaga Pharmaceutical Co., Ltd., Koda-cho, Takada-gun, Hiroshima Pref. F term (reference) 4C063 AA01 BB09 CC29 DD10 EE01 4C086 AA01 AA02 AA03 BC42 GA07 GA12 MA01 MA04 NA14 ZA45 ZC33

Claims (3)

[Claims] 1. The following general formula (1): [In the formula, R ¹ represents a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkoxy group which may have a substituent, An alkylthio group which may be substituted, an amino group which may have a substituent, a saturated cyclic amino group which may have a substituent or a halogen atom, and R ² has a hydrogen atom or a substituent An alkyl group which may be substituted, an alkenyl group which may have a substituent, an alkoxy group which may have a substituent, an alkylthio group which may have a substituent, Represents an amino group, a saturated cyclic amino group which may have a substituent or a halogen atom, or a bicyclic or tricyclic ring together with an adjacent ring together with R ⁶ when A is CR ^6. condensation hydrocarbon or condensed heterocyclic form of, R ³ is A hydrogen atom, an alkyl group or a halogen atom, R ⁴ represents an alkyl group which may have a substituent or a cycloalkyl group which may have a substituent, and A represents a nitrogen atom or CR ⁶ (Where R ⁶ forms a condensed ring together with a hydrogen atom or R ² ), B represents a nitrogen atom or CH, and W represents a hydrogen atom, a halogen atom, An aryl group or a heteroaryl group which may have a substituent;
Represents an oxygen atom or a sulfur atom, ring E represents an aromatic hydrocarbon, aromatic heterocyclic ring or unsaturated cyclic hydrocarbon, and G represents the following formulas (a) to (d). (Here, e represents an integer of 3 to 7, f represents an integer of 1 or 2, g represents an integer of 2 or 3, h represents an integer of 0 or 1, and i represents an integer of 1 to 3. J represents an integer of 0 to 5; n represents an integer of 0 or 1; J represents NH, an oxygen atom or a sulfur atom (however, when h is 0, i is an integer of 2 or 3) X is an oxygen atom, a sulfur atom or a single bond, and Y is an amino group, a single bond or an alkylene group, an alkenylene group, an aryl group or a substituent which may have a substituent. Represents a heteroaryl group which may have a single bond or an alkylene group, an alkenylene group, an aryl group which may have a substituent or a heteroaryl group which may have a substituent. (However, Y and Z do not simultaneously represent a single bond, and one of them may have a substituent. To indicate Lumpur group or an optionally substituted heteroaryl group, the other is a single bond,
An alkylene group or an alkenylene group, and when Y is an amino group, Z represents an alkylene group, an alkenylene group, an aryl group which may have a substituent, or a heteroaryl group which may have a substituent. And R ⁵ represent a hydrogen atom, an alkyl group or an aralkyl group). ] The anilide derivative represented by these, or its salt. 2. A medicament comprising the anilide derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 3. Hyperlipidemia containing the anilide derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient and / or
Or a prophylactic / therapeutic agent for arteriosclerosis.